HCV CARE

Treatment of Chronic HCV Infection with Direct-Acting Antivirals

Purpose of This Guideline

Hepatitis C Virus Infection Guideline Committee, July 2017

This guideline on treatment of chronic hepatitis C virus (HCV) infection was developed by the New York State (NYS) Department of Health (DOH) AIDS Institute (AI) to guide primary care providers and other practitioners in New York State in treating patients with chronic HCV infection. The guideline aims to achieve the following goals:

  • Increase the number of NYS residents with chronic HCV infection treated with the new direct-acting antiviral (DAA) therapies that cure chronic HCV infection.
  • Increase compliance with the 2014 NYS public health law that requires HCV antibody screening be offered to every individual born between 1945 and 1965 who receives healthcare services from a physician, physician assistant, or nurse practitioner in a primary care or inpatient hospital setting.
  • Reduce the growing burden of morbidity and mortality associated with chronic HCV infection.
  • Integrate current evidence-based clinical recommendations into the HCV-related implementation strategies of the Ending the Epidemic (ETE) initiative, which seeks to end the AIDS epidemic in NYS by the end of 2020.   

The NYSDOH AI is publishing these guidelines at a critical time: 1) new treatments are available that can cure chronic HCV infection; 2) the burden of HCV disease is increasing in NYS [1]; and 3) primary care providers and other clinical care practitioners in NYS are playing an essential role in screening for and diagnosing chronic HCV infection and in providing state-of-the-art therapy for their patients.

New Standard of Care for Treatment of Chronic HCV Infection

The availability of safe and effective regimens of oral DAAs has revolutionized HCV care. New DAA agents and new combinations of agents continue to be tested and approved, and these efficacious combinations have replaced earlier treatments as the standard of care for curing chronic HCV infection. The DAA regimens make cure possible for many patients, but these patients must first be identified, engaged in care, offered appropriate screening for status of their HCV infection/disease, and have access to treatment.

The goal of HCV therapy is a sustained virologic response (SVR), which is defined as the absence of detectable HCV RNA at least 12 weeks after completion of therapy. An SVR is the equivalent of cure. DAA regimens have been associated with an SVR rate of more than 90% and have excellent tolerability in both treatment-naive and treatment-experienced patients with and without cirrhosis [2-8].

References
  1. Centers for Disease Control and Prevention, National Center for Health Statistics. Multiple Cause of Death 1999-2015 on CDC WONDER Online Database, released December, 2016. [accessed March 21, 2017]. http://wonder.cdc.gov/mcd-icd10.html
  2. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370(20):1889-98. [PMID: 24725239]
  3. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370(16):1483-93. [PMID: 24725238]
  4. Poordad F, Schiff ER, Vierling JM, et al. Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology 2016;63(5):1493-505. [PMID: 26754432]
  5. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014;370(21):1973-82. [PMID: 24725237]
  6. Kwo P, Gitlin N, Nahass R, et al. Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study. Hepatology 2016;64(2):370-80. [PMID: 26799692]
  7. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med 2015;163(1):1-13. [PMID: 25909356]
  8. Falade-Nwulia O S-CC, Nelson DR, Fried MW, Segal JB, Sulkowski, MS. Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review. Ann Intern Med 2017;166. [PMID: 28319996]

Purpose of This Guideline: Burden of HCV Disease

Hepatitis C Virus Infection Guideline Committee, July 2017

First isolated in 1989, hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States [1,2], and research suggests that more than 50% of persons with HCV infection are unaware of their infection status [3]. Injection drug use is associated with the highest risk of contracting HCV [4,5]. Other key routes of HCV transmission include receipt of infected blood or organs (before 1992) or blood products (before 1987), mother-to-child transmission (also known as vertical transmission), sexual transmission, and needle sticks/exposure in healthcare settings [6]. According to National Health and Nutrition Examination Study (NHANES) data, among patients participating from 2001 to 2008, the prevalence of HCV infection in persons aged >20 years was 1.3% in the United States. After adjusting for populations not sampled in the NHANES surveys, such as the incarcerated and homeless, the researchers estimated that 3.5 million people were living with chronic HCV infection in the U.S. [7,8]. Approximately 75% of reported cases were among persons born between 1945 and 1965 [2,3,7].

The Centers for Disease Control and Prevention (CDC) reported 162,863 cases of chronic HCV infection (past or present) nationwide in 2015 [17]. The number of reported cases in New York State (excluding New York City) and New York City for 2014 are provided in Box 1.

Box 1. Chronic HCV Infection Cases Reported in New York State and New York City

New York State*  [10]

  • 109,593 cases reported from 2001 to 2015
  • 2015 cases: 8,489 reported
    • 38% of cases reported from the 1945 to 1965 birth cohort, with 67% male and 33% female
    • 2,302 (27.1%) aged <30 years, with 53% male and 46% female

*excluding New York City

New York City [11]

  • 152,030 cases reported from 2001 to 2015
  • 2015 cases: 7,328 reported, a decrease of 4.7% from 2014
    • 49.7% from the 1945 to 1965 birth cohort, with 62.5% male and 37.5% female
    • 886 (12.1%) aged <30 years, with 58% male and 42% female

Ensuring access to effective DAA treatment for all individuals with chronic HCV and curing chronic HCV infection in as many as 90% of patients will prevent substantial morbidity and mortality. Approximately 25% to 30% of persons with untreated chronic HCV infection will advance to cirrhosis within 20 to 30 years, with progression occurring more quickly in men, in patients who use alcohol, in those who acquire HCV infection after age 40, and in patients with HIV/HCV coinfection [12,13]. Of those with cirrhosis, >25% will develop end-stage liver disease or hepatocellular carcinoma (HCC), resulting in death if a liver transplant is not received [14].

Chronic HCV infection drives the development of HCC by inducing fibrosis and cirrhosis [15]. From 1999 through 2013, deaths from primary liver cancer in the U.S. increased at the highest rate of all cancer sites, and liver cancer incidence rates increased sharply, second only to thyroid cancer [16]. Men had more than twice the incidence rate of liver cancer than women, and rates increased with age for both sexes. Population modeling performed in 2011 posited that if new antiviral regimens consistently resulted in an 80% response rate, and if 50% of all HCV patients were treated, then, within 10 years, there would be a 15% reduction in cases of cirrhosis, a 30% reduction in cases of HCC, and 34% fewer deaths from liver disease, indicating the substantial effects that treatment would have in reducing liver disease morbidity [17].

In New York State (including New York City), the mortality rate associated with HCV increased from 4.0 per 100,000 population in 2001 to 5.5 per 100,000 population in 2015 [18]. The HCV-related mortality rate in New York State surpassed the HIV-related mortality rate in 2012, indicating the severity of disease burden and the urgency for wider treatment availability.

References:
  1. Chen S, Morgan, TR. The natural history of hepatitis C virus (HCV) infection. Int J Med Sci 2006;3(2):47-52. [PMID: 16614742]
  2. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006;144(10):705-14. [PMID: 16702586]
  3. Denniston MM, Klevens RM, McQuillan GM, et al. Awareness of infection, knowledge of hepatitis C, and medical follow-up among individuals testing positive for hepatitis C: National Health and Nutrition Examination Survey 2001-2008. Hepatology 2012;55(6):1652-61. [PMID: 22213025]
  4. Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol 2007;13(17):2436-41. [PMID: 17552026]
  5. Alter MJ. Hepatitis C virus infection in the United States. J Hepatol 1999;31 Suppl 1:88-91. [PMID: 10622567]
  6. CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep 1998;47(Rr-19):1-39. [PMID: 9790221]
  7. CDC. Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR Morb Mortal Wkly Rep 2013;62(18):362-5. [PMID: 23657112]
  8. Edlin BR, Eckhardt BJ, Shu MA, et al. Toward a more accurate estimate of the prevalence of hepatitis C in the United States. Hepatology 2015;62(5):1353-63. [PMID: 26171595]
  9. CDC. Summary of Notifiable Infectious Diseases and Conditions — United States, 2014. MMWR Morb Mortal Wkly Rep 2016;October 14, 2016 / 63(54):1-152. [PMID: 27736829]
  10. New York State Department of Health (NYSDOH) Communicable Disease Electronic Surveillance System. 2016 Aug 4.
  11. New York City (NYC) Department of Health and Mental Hygiene (DOHMH). Annual Report: Hepatitis B and C in New York City 2015 [accessed 2017 Apr 26]. http://www1.nyc.gov/assets/doh/downloads/pdf/cd/hepatitis-b-and-c-annual-report.pdf
  12. Klevens M HX, Yeo A editor The Burden of Liver Disease Among Persons With Hepatitis C in the United States (Abstract 145). Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, Washington.
  13. Younossi ZM, Otgonsuren M, Henry L, et al. Inpatient resource utilization, disease severity, mortality and insurance coverage for patients hospitalized for hepatitis C virus in the United States. J Viral Hepat 2015;22(2):137-45. [PMID: 24813350]
  14. Klevens RM, Hu DJ, Jiles R, et al. Evolving epidemiology of hepatitis C virus in the United States. Clin Infect Dis 2012;55 Suppl 1:S3-9. [PMID: 22715211]
  15. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012;142(6):1264-73.e1. [PMID: 22537432]
  16. Ryerson AB, Eheman CR, Altekruse SF, et al. Annual report to the nation on the status of cancer, 1975-2012, featuring the increasing incidence of liver cancer. Cancer 2016;122(9):1312-37. [PMID: 26959385]
  17. Rosen HR. Clinical practice. Chronic hepatitis C infection. N Engl J Med 2011;364(25):2429-38. [PMID: 21696309]
  18. Centers for Disease Control and Prevention NCfHS. Multiple Cause of Death 1999-2015 on CDC WONDER Online Database, released December, 2016. [accessed March 21, 2017]. http://wonder.cdc.gov/mcd-icd10.html

Purpose of This Guideline: Role of NYS Primary Care Providers in Treatment of HCV

Hepatitis C Virus Infection Guideline Committee, July 2017

Primary care providers in New York State (NYS) are assuming a major role in the screening, diagnosis, treatment, and monitoring of patients with chronic HCV infection. The NYS Department of Health (DOH) has developed specific criteria, listed below, to define experienced HCV care providers who are qualified to prescribe HCV antiviral therapy. Clinical experience and appropriate continuing education are both important to ensure that HCV medications are prescribed safely and correctly and that all patients receive the highest quality of care.

NEW YORK STATE QUALIFICATIONS FOR PRESCRIBING HCV ANTIVIRAL THERAPY

Providers must meet all 3 criteria.

1. Clinical experience:

  • Management AND treatment of at least 10 patients with HCV infection within the past 12 months OR 
  • Management and treatment of 10 patients with HCV infection in partnership (defined as consultation, preceptorship, or via telemedicine) with an experienced HCV provider who meets the above criteria.

2. Continuing Medical Education: At least 10 HCV-related CME credits in the last 12 months.

3. Licensure: A current, valid MD, DO, PA, or NP New York State license.

This guideline covers screening, diagnosis, pretreatment assessment, treatment, and post-treatment monitoring for primary care providers treating patients with chronic HCV infection. In terms of HCV treatment, the guideline includes recommendations for initial HCV treatment in patients with and without cirrhosis and for retreatment in patients with and without cirrhosis who have failed previous non-DAA regimens.

As stated in these recommendations, care providers new to HCV treatment should consult an experienced HCV care provider who meets the three criteria listed above when treating patients with chronic HCV infection and any of the following conditions:

  • Compensated cirrhosis
  • Concurrent hepatobiliary conditions
  • Extrahepatic manifestations of HCV, including renal, dermatologic, and rheumatologic manifestations
  • Significant renal impairment (creatinine clearance <30 mL/min)
  • Active hepatitis B (HBV) infection, defined as HBV surface antigen–positive and detectable HBV DNA
  • Ongoing HCV infection after DAA treatment failure

Care providers should refer patients with chronic HCV infection and decompensated liver disease and patients who are pre- or post-transplant to a liver disease specialist. Depending on their level of experience and expertise, care providers may also want to refer patients who have coexisting conditions (including HIV) that require treatment with complex drug regimens to a care provider with experience in the management of complex patients with HCV infection.

Purpose of This Guideline: Development of This Guideline

Hepatitis C Virus Infection Guideline Committee, July 2017

This guideline was developed by the New York State (NYS) Department of Health (DOH) AIDS Institute (AI) Clinical Guidelines Program, which is a collaborative effort between the NYSDOH AI Office of the Medical Director and the Johns Hopkins University School of Medicine, Division of Infectious Diseases.

Established in 1986, the goal of the Clinical Guidelines Program is to develop and disseminate evidence-based, state-of-the-art clinical practice guidelines to improve the quality of care provided to people with HIV, HCV, and STIs and to improve drug user health and LGBT health throughout the State of New York. NYSDOH AI guidelines are developed by committees of clinical experts through a consensus-driven process.

The NYSDOH AI Hepatitis C Virus Infection Guideline Committee was charged with developing evidence-based clinical recommendations for primary care providers in NYS who treat patients with chronic HCV infection. The resulting recommendations are based on an extensive review of the medical literature and reflect consensus among this panel of HCV experts. Each recommendation is rated for strength and for quality of the evidence (see Recommendation Rating Scheme, below). If recommendations are based on expert opinion, the rationale for the opinion is included. See About this Guideline for a full description of the development process, including evidence collection and recommendation development.

Recommendation Rating Scheme: 

  • Strength of recommendation: A (Strong), B (Moderate), C (Optional)
  • Quality of evidence: I (One or more randomized trials with clinical outcomes and/or validated laboratory endpoints), II (One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes), III (Expert opinion)

Screening for HCV Infection

Hepatitis C Virus Infection Guideline Committee, July 2017

More than 50% of people with chronic hepatitis C virus (HCV) infection may not be aware of their infection [1]. Because approximately 75% of cases are among persons born between 1945 and 1965 [1-3], age-cohort screening of asymptomatic adults with no recognized risk factors is thought to increase identification and treatment for these patients. In addition to required HCV screening in the specific birth cohort, healthcare providers should screen patients with other risk factors for HCV infection (see the section on Risk-Based Screening in this guideline).

As part of HCV screening and diagnosis, a series of serologic and virologic tests are used, including laboratory-based antibody tests, point-of-care rapid HCV antibody tests for initial screening, and laboratory-based HCV RNA tests for HCV diagnosis.

KEY POINT: REPORTING
  • New York State (NYS) Public Health law mandates that clinicians report all suspected or confirmed cases of HCV infection, specifying acute or chronic, to the local health department of the area where the patient resides. See New York State Department of Health (NYSDOH): Communicable Disease Reporting 
 References
  1. Denniston MM, Klevens RM, McQuillan GM, et al. Awareness of infection, knowledge of hepatitis C, and medical follow-up among individuals testing positive for hepatitis C: National Health and Nutrition Examination Survey 2001-2008. Hepatology 2012;55(6):1652-61. [PMID: 22213025]
  2. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006;144(10):705-14. [PMID: 16702586]
  3. CDC. Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR Morb Mortal Wkly Rep 2013;62(18):362-5. [PMID: 23657112]

Screening for HCV Infection: Cohort-Based

Hepatitis C Virus Infection Guideline Committee, July 2017

NEW YORK STATE REQUIREMENT
  • New York State (NYS) Public Health Law mandates that primary care clinicians offer hepatitis C virus (HCV) screening to individuals born from 1945 to 1965 in a culturally and linguistically appropriate manner.

In NYS, physicians, physician assistants, and nurse practitioners delivering primary care must provide HCV screening, regardless of setting and without regard to certification. Care providers working in hospitals (inpatient units and outpatient clinics) and other healthcare settings where primary care services are being delivered are also required to offer HCV screening. Emergency departments are not required by law to offer HCV screening, but in NYS, they are encouraged to do so.

If the initial screening is reactive, clinicians must offer follow-up healthcare, including HCV diagnostic testing, or referral to an experienced HCV care provider. By requiring HCV antibody screening for this age cohort in traditional medical settings and supporting screening efforts in community-based locations, NYS is actively seeking to identify people with chronic HCV infection and link them to treatment before irreversible liver damage occurs.

In response to the law, hospitals, clinics, health centers, and other primary care medical facilities have established HCV screening programs. However, people with HCV infection may face significant barriers to accessing care in clinical settings, including lack of health insurance, physical disability, ongoing substance use, mental health disorders, and housing instability. Locating HCV screening sites in a variety of community-based organizations, such as syringe exchange programs, sexually transmitted disease (STI) clinics, and local health departments, is integral to the effort to provide HCV screening, treatment, and education in diverse settings.

Birth cohort screening is particularly important because patients may not be aware of or remember exposures or may not disclose prior behavioral risks for HCV infection (see the Risk-Based Screening section of this guideline). Patient education is needed to ensure that patients know about risk factors for transmitting or acquiring HCV infection. While birth cohort screening is important, screening for HCV beyond the required birth cohort is needed in areas where HCV prevalence is high.

KEY POINTS
  • Cohort and risk-based screening are both crucial to identifying adults with HCV infection.
  • In geographical areas with high HCV prevalence, screening should be performed in all people who may have been exposed to HCV through any means of transmission.

Screening for HCV Infection: Risk-Based

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATIONS
  • Clinicians should perform hepatitis C virus (HCV) screening at least once for patients of any age who are not known to have HCV infection and currently have, or have a history that includes, any of the following risk factors:
    • Injection drug use (AI)
    • Intranasal drug use (AII)
    • Sex partner(s) with HCV infection (AII)
    • Incarceration (AII)
    • Long-term hemodialysis (AI)
    • Receipt of blood transfusion or organs before 1992, or of clotting factor concentrates from human plasma before 1987 (AI)
    • A mother with a reactive HCV antibody test result (AI)
    • Tattoo, piercing, or acupuncture obtained in a nonsterile setting (AII)
    • HIV infection (AII)
    • Unexplained liver disease or abnormal transaminase levels (AI)
  • Clinicians should offer HCV screening at least annually to individuals who are not known to have HCV infection and:
    • Use injection drugs (AII)
    • Use intranasal drugs (AII)
    • Receive current long-term hemodialysis (AII)
  • Clinicians should offer HCV screening at least annually to men who have sex with men (MSM) and to others who are not known to have HCV infection and:
    • Engage in receptive anal sex and other behaviors that may tear mucous membranes (AII)
    • Have multiple sex partners (AII)
    • Engage in sex while using recreational mind-altering substances, particularly methamphetamine (AII)
    • Have been diagnosed with another sexually transmitted infection (STI) within the previous 12 months (AII)
  • Clinicians should perform HCV screening for individuals who are not known to have HCV infection and have a possible exposure in a healthcare setting, including those who:
    • Have a break in the skin caused by a sharp object that is contaminated with blood, visibly bloody fluid, or other potentially infectious material or that has been in the source patient’s blood vessel (AII)
    • Have been bitten by an individual with visible bleeding in the mouth that causes bleeding in the exposed worker (AII)
    • Have been splashed on a mucosal surface with blood, visibly bloody fluid, or other potentially infectious material (AIII)
    • Have non-intact skin (e.g., dermatitis, chapped skin, abrasion, or open wound) that has been exposed to blood, visibly bloody fluid, or other potentially infectious material (AIII)

In the United States, an estimated 60% of chronic HCV infections result from use of shared needles, syringes, or other drug-use paraphernalia [1]. Overall, sexual transmission accounts for approximately 5% of HCV infections, although transmission rates differ in select groups, as discussed below. Vertical transmission (transmission from mother to child) accounts for 5% to 6% of infection; receipt of contaminated organs or blood component transfusions before HCV testing of the blood supply began in 1992 accounts for approximately 5% of HCV infections [1]. The average incidence of anti-HCV seroconversion after unintentional needle sticks or sharps exposures from a source with confirmed HCV infection is estimated at 1.8% [1], and HCV infection has also resulted from unsterile skin piercing activities, such as tattoos in prisons (1%) [2]. There are a few case reports that might suggest transmission during trauma, including biting [3] and fist fighting [4], when there is potential for blood-to-blood transmission, but there are insufficient data to limit patients with HCV from participating in sports such as boxing or wrestling at this time.

Injection drug use: Sharing of injection drug use (IDU) equipment is an efficient method of transmitting HCV. In the U.S., a reduction in new HCV infections between 1992 and 2009 was attributed to expansions of syringe-access programs, safer injection practices among people who inject drugs (PWID), and increased enrollment in drug treatment programs [5]. However, HCV prevalence among PWID entering substance use treatment in New York City (n= 1,535) was 67% (95% confidence interval: 66% to 70%) during the 2006 to 2013 period and was not significantly different from that observed from 2000 to 2001 [6].

The demographics of IDU now include many young people living in suburban and rural regions [5]. Adolescents and young adults may advance to IDU after first becoming addicted to prescription oral opioids [7]. Reports from several states (including New York State), underscore the importance of awareness of HCV risk among adolescent and young adult patients and of offering HCV screening to this population [8-13].

KEY POINT: HCV SCREENING IN ADOLESCENTS AND YOUNG ADULTS
  • Epidemics of HCV infection that parallel opioid-use epidemics have been observed among young male and female injection drug users, primarily in suburban and rural areas [8-13].
  • HCV screening should be offered to at-risk adolescents and young adults.
  • In 2015, 2,309 (27.2%) of HCV cases reported in New York State (excluding New York City) were in people <30 years of age [14]. Among those <30 for whom risk information is available, 91% reported a history of IDU.

Intranasal drug use: In a systematic review of 28 studies on the prevalence of HCV in noninjecting drug users who smoked, sniffed, or snorted such drugs as heroin, powder or crack cocaine, or methamphetamine, investigators found HCV prevalence rates ranging from 2.3% to 35.3% [15,16]. Among noninjecting drug users, sharing of oral and nasal drug use equipment is associated with an increased risk of HCV infection [17-19]. In addition, blood and HCV RNA have been confirmed in the nasal secretions and drug-sniffing paraphernalia of HCV-infected intranasal drug users [20].

Sexual transmission: Because many with HCV infection have a history of drug use, estimation of sexual transmission is a challenge (as reviewed in [21]). Sexual transmission of HCV among monogamous heterosexual couples is infrequent. The estimated maximum prevalence of HCV infection among sex partners of individuals with chronic HCV infection was only 1.2%, and the maximum incidence of HCV transmission through sex contact was 0.07% per year or approximately 1 per 190,000 sexual contacts [22]. Sexual transmission risk increases in the setting of multiple partners, STIs, HIV, and exposure to blood [21]. Several reports have demonstrated isolated outbreaks of sexual HCV transmission among MSM with HIV infection who engage in receptive anal intercourse [12,23-25]. In a report from New York City on sexual transmission among HIV-infected MSM with no previous history of injection drug use, new HCV infections were highly correlated with receptive anal intercourse, engaging in sex while using methamphetamine, or participating in group sex [12].

History of incarceration: Incarcerated populations are a significant but declining portion of the HCV epidemic in the United States [26-28]. A study from 2009 to 2013 at two maximum-security prisons in New York State estimated an HCV prevalence of 10.1%; injection drug use, being the partner of a PWID, and HIV diagnosis were most strongly associated with HCV infection [28]. In New York City, the rate of newly reported chronic HCV infection in 2015 was 86.3 per 100,000. In the incarcerated population of the city, the rate was 964.3 per 100,000 for the same year [29].

Exposure to blood in a healthcare setting: The average incidence of anti-HCV seroconversion after unintentional needle sticks or sharps exposures from a source with HCV infection is 1.8% [1]. Healthcare-related transmission of HCV is documented infrequently in the United States [30,31]. In 2014, among reported acute HCV cases that included information on exposure type, 1% was considered to be occupationally acquired [32].

Hemodialysis: The estimated 8% prevalence of anti-HCV antibodies among chronic hemodialysis patients is significantly higher than the estimated 1.6% prevalence in the general U.S. population [1]. Nationally, 36 cases of acute HCV infection in 19 different hemodialysis clinics in 8 states were reported between 2014 and 2015, with epidemiologic and viral sequencing confirming transmission between patients [33]. The Centers for Disease Control and Prevention (CDC) recommend HCV antibody screening upon admission for chronic hemodialysis patients, followed by screening every 6 months thereafter [33,34]. The National Kidney Foundation stratifies by prevalence and recommends antibody screening upon admission to facilities with a low HCV prevalence and consideration of HCV RNA testing upon admission to facilities with high HCV prevalence [35].

Receipt of blood transfusion or organ transplant before 1992 or clotting factor concentrates from human plasma before 1987: Donor screening for HCV infection and inactivation procedures for pooled plasma and plasma derivative products have virtually eliminated the risk of HCV transmission through blood products in the U.S. [1,36].

Vertical transmission: A 2011 meta-analysis estimated that the risk of vertical HCV infection to children of HCV antibody-reactive and HCV RNA detectable women was 5.8% for children of HIV-uninfected women and 10.8% for children of women with HIV infection [37]. From 2011 to 2014, the national rate of HCV infection among women of childbearing age (15-44 years old) increased by 22% (from 139 to 169 per 100,000), and the national rate of infants born to women diagnosed with HCV infection increased by 68% (from 0.19% to 0.32%) [38]. Factors associated with an increased risk of perinatal transmission include HIV coinfection and higher maternal HCV viral loads [37,39]. Neither delivery by cesarean-section nor refraining from breastfeeding has been demonstrated to reduce vertical transmission [39].

Tattoos, piercings, or acupuncture obtained in nonsterile settings: Tattoos or piercings obtained in nonsterile settings, and especially those obtained during incarceration, have been associated with HCV infection, even after controlling for injection drug use and transfusion before 1992 [40,41]. Low levels of HCV RNA have been detected on acupuncture needles from individuals known to have HCV infection [42], although acupuncture has not been established as a confirmed route of transmission.

HIV infection: HCV infection is common among persons with HIV infection because the routes of acquisition are similar. For decades, injection drug use has been recognized as the main risk factor for HIV/HCV coinfection, but an increasing number of sexually transmitted HCV infections have been documented in MSM with HIV [43-45]. In a recent study among MSM with HIV in Europe, Australia, and Canada, HCV incidence significantly increased from 1990 to 2014 [24]. In this population, sexual acts that may tear mucous membranes, sex while using methamphetamines, and having other STIs have been associated with HCV infection [43,44].

Unexplained liver disease or abnormal transaminase levels: In primary care patients with an alanine transaminase (ALT) level 50 to 100 IU/L, HCV prevalence is 10-fold higher than in the general population, whereas hepatitis B (HBV) prevalence was not increased [46].

References
  1. CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep 1998;47(Rr-19):1-39. [PMID: 9790221]
  2. Alter MJ. Hepatitis C virus infection in the United States. J Hepatol 1999;31 Suppl 1:88-91. [PMID: 10622567]
  3. Dusheiko GM, Smith M, Scheuer PJ. Hepatitis C virus transmitted by human bite. Lancet 1990;336(8713):503-4. [PMID: 1975005]
  4. Bourliere M, Halfon P, Quentin Y, et al. Covert transmission of hepatitis C virus during bloody fisticuffs. Gastroenterology 2000;119(2):507-11. [PMID: 10930386]
  5. Klevens RM, Hu DJ, Jiles R, et al. Evolving epidemiology of hepatitis C virus in the United States. Clin Infect Dis 2012;55 Suppl 1:S3-9. [PMID: 22715211]
  6. Jordan AE, Des Jarlais DC, Arasteh K, et al. Incidence and prevalence of hepatitis c virus infection among persons who inject drugs in New York City: 2006-2013. Drug Alcohol Depend 2015;152:194-200. [PMID: 25891230]
  7. Mateu-Gelabert P, Guarino H, Jessell L, et al. Injection and sexual HIV/HCV risk behaviors associated with nonmedical use of prescription opioids among young adults in New York City. J Subst Abuse Treat 2015;48(1):13-20. [PMID: 25124258]
  8. CDC. Use of enhanced surveillance for hepatitis C virus infection to detect a cluster among young injection-drug users–new York, November 2004-April 2007. MMWR Morb Mortal Wkly Rep 2008;57(19):517-21. [PMID: 18480744]
  9. Zibbell JE, Iqbal K, Patel RC, et al. Increases in hepatitis C virus infection related to injection drug use among persons aged </=30 years – Kentucky, Tennessee, Virginia, and West Virginia, 2006-2012. MMWR Morb Mortal Wkly Rep 2015;64(17):453-8. [PMID: 25950251]
  10. CDC. Hepatitis C virus infection among adolescents and young adults:Massachusetts, 2002-2009. MMWR Morb Mortal Wkly Rep 2011;60(17):537-41. [PMID: 21544042]
  11. CDC. Notes from the field : hepatitis C virus infections among young adults–rural Wisconsin, 2010. MMWR Morb Mortal Wkly Rep 2012;61(19):358. [PMID: 22592276]
  12. CDC. Sexual transmission of hepatitis C virus among HIV-infected men who have sex with men–New York City, 2005-2010. MMWR Morb Mortal Wkly Rep 2011;60(28):945-50. [PMID: 21775948]
  13. Pollini RA, Banta-Green CJ, Cuevas-Mota J, et al. Problematic use of prescription-type opioids prior to heroin use among young heroin injectors. Subst Abuse Rehabil 2011;2(1):173-80. [PMID: 23293547]
  14. New York State Department of Health (NYSDOH) Communicable Disease Electronic Surveillance System. August 4, 2016.
  15. Stern RK, Hagan H, Lelutiu-Weinberger C, et al. The HCV Synthesis Project: scope, methodology, and preliminary results. BMC Med Res Methodol 2008;8:62. [PMID: 18789163]
  16. Scheinmann R, Hagan H, Lelutiu-Weinberger C, et al. Non-injection drug use and Hepatitis C Virus: a systematic review. Drug Alcohol Depend 2007;89(1):1-12. [PMID: 17174481]
  17. Macias J, Palacios RB, Claro E, et al. High prevalence of hepatitis C virus infection among noninjecting drug users: association with sharing the inhalation implements of crack. Liver Int 2008;28(6):781-6. [PMID: 18312289]
  18. Koblin BA, Factor SH, Wu Y, et al. Hepatitis C virus infection among noninjecting drug users in New York City. J Med Virol 2003;70(3):387-90. [PMID: 12767001]
  19. Neaigus A, Gyarmathy VA, Zhao M, et al. Sexual and other noninjection risks for HBV and HCV seroconversions among noninjecting heroin users. J Infect Dis 2007;195(7):1052-61. [PMID: 17330797]
  20. Aaron S, McMahon JM, Milano D, et al. Intranasal transmission of hepatitis C virus: virological and clinical evidence. Clin Infect Dis 2008;47(7):931-4. [PMID: 18764772]
  21. Tohme RA, Holmberg SD. Is sexual contact a major mode of hepatitis C virus transmission? Hepatology 2010;52(4):1497-505. [PMID: 20635398]
  22. Terrault NA, Dodge JL, Murphy EL, et al. Sexual transmission of hepatitis C virus among monogamous heterosexual couples: the HCV partners study. Hepatology 2013;57(3):881-9. [PMID: 23175457]
  23. Urbanus AT, van de Laar TJ, Stolte IG, et al. Hepatitis C virus infections among HIV-infected men who have sex with men: an expanding epidemic. Aids 2009;23(12):F1-7. [PMID: 19542864]
  24. van de Laar T, Pybus O, Bruisten S, et al. Evidence of a large, international network of HCV transmission in HIV-positive men who have sex with men. Gastroenterology 2009;136(5):1609-17. [PMID: 19422083]
  25. Wandeler G, Gsponer T, Bregenzer A, et al. Hepatitis C virus infections in the Swiss HIV Cohort Study: a rapidly evolving epidemic. Clin Infect Dis 2012;55(10):1408-16. [PMID: 22893583]
  26. Varan AK, Mercer DW, Stein MS, et al. Hepatitis C seroprevalence among prison inmates since 2001: still high but declining. Public Health Rep 2014;129(2):187-95. [PMID: 24587554]
  27. Larney S, Kopinski H, Beckwith CG, et al. Incidence and prevalence of hepatitis C in prisons and other closed settings: results of a systematic review and meta-analysis. Hepatology 2013;58(4):1215-24. [PMID: 23504650]
  28. Alvarez KJ, Befus M, Herzig CT, et al. Prevalence and correlates of hepatitis C virus infection among inmates at two New York State correctional facilities. J Infect Public Health 2014;7(6):517-21. [PMID: 25182508]
  29. New York City (NYC) Department of Health and Mental Hygiene (DOHMH). Annual Report: Hepatitis B and C in New York City 2015 [accessed 2017 Apr 26]. http://www1.nyc.gov/assets/doh/downloads/pdf/cd/hepatitis-b-and-c-annual-report.pdf
  30. Henderson DK. Managing occupational risks for hepatitis C transmission in the health care setting. Clin Microbiol Rev 2003;16(3):546-68. [PMID: 12857782]
  31. Tomkins SE, Elford J, Nichols T, et al. Occupational transmission of hepatitis C in healthcare workers and factors associated with seroconversion: UK surveillance data. J Viral Hepat 2012;19(3):199-204. [PMID: 22329374]
  32. Centers for Disease Control and Prevention (CDC). Viral Hepatitis Surveillance Data. [accessed 2017 Apr 26]. http://www.cdc.gov/Hepatitis/Statistics/index.htm
  33. CDC. CDC urging dialysis providers and facilities to assess and improve infection control practices to stop hepatitis C virus transmission in patients undergoing hemodialysis. Am J Transplant 2016;16(5):1633-4. [PMID: 27111815]
  34. Centers for Disease Control and Prevention (CDC). Dialysis safety: Guidelines and Recommendations. 2016 [accessed March 7, 2017]. http://www.cdc.gov/dialysis/guidelines/
  35. Kidney Disease: Improving Global Outcomes (KDIGO). Clinical practice guidelines for the prevention d, evaluation, and treatment of hepatitis in chronic kidney diseases. Kidney Disease: Improving Global Outcomes (KDIGO). Clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis in chronic kidney diseases. 2008 [accessed 2017 Apr 26]. http://www.kdigo.org/clinical_practice_guidelines/pdf/KDIGO%20Hepatitis%20C%20Guideline.pdf
  36. Watson HG, Ludlam CA, Rebus S, et al. Use of several second generation serological assays to determine the true prevalence of hepatitis C virus infection in haemophiliacs treated with non-virus inactivated factor VIII and IX concentrates. Br J Haematol 1992;80(4):514-8. [PMID: 1581236]
  37. Arshad M, El-Kamary SS, Jhaveri R. Hepatitis C virus infection during pregnancy and the newborn period–are they opportunities for treatment? J Viral Hepat 2011;18(4):229-36. [PMID: 21392169]
  38. Koneru A NN, Hariri S, et al. Increased Hepatitis C Virus (HCV) Detection in Women of Childbearing Age and Potential Risk for Vertical Transmission — United States and Kentucky, 2011–2014. MMWR Morb Mortal Wkly Rep 2016;65:705–10. [PMID: 27641002]
  39. Benova L, Mohamoud YA, Calvert C, et al. Vertical transmission of hepatitis C virus: systematic review and meta-analysis. Clin Infect Dis 2014;59(6):765-73. [PMID: 24928290]
  40. Carney K, Dhalla S, Aytaman A, et al. Association of tattooing and hepatitis C virus infection: a multicenter case-control study. Hepatology 2013;57(6):2117-23. [PMID: 23315899]
  41. Tohme RA, Holmberg SD. Transmission of hepatitis C virus infection through tattooing and piercing: a critical review. Clin Infect Dis 2012;54(8):1167-78. [PMID: 22291098]
  42. Lemos MA, Jr., Silva JB, Braga AC, et al. Acupuncture needles can carry hepatitis C virus. Infect Control Hosp Epidemiol 2014;35(10):1319-21. [PMID: 25203197]
  43. Hagan H, Jordan AE, Neurer J, et al. Incidence of sexually transmitted hepatitis C virus infection in HIV-positive men who have sex with men. Aids 2015;29(17):2335-45. [PMID: 26258525]
  44. Fierer DS, Factor SH. Defining the scope of sexually transmitted hepatitis C virus epidemic among HIV-infected men who have sex with men in New York City. Sex Transm Dis 2015;42(7):400-1. [PMID: 26222756]
  45. Breskin A, Drobnik A, Pathela P, et al. Factors associated with hepatitis C infection among HIV-infected men who have sex with men with no reported injection drug use in New York City, 2000-2010. Sex Transm Dis 2015;42(7):382-6. [PMID: 26222751]
  46. Helsper C, van Essen G, Frijling BD, et al. Follow-up of mild alanine aminotransferase elevation identifies hidden hepatitis C in primary care. Br J Gen Pract 2012;62(596):e212-6. [PMID: 22429439]

Diagnosis of HCV Infection

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATIONS
  • Clinicians should perform hepatitis C virus (HCV) screening using either a laboratory-based HCV antibody test or point-of-care rapid antibody test. (AI)
  • If the HCV antibody test result is reactive, clinicians should obtain confirmatory HCV RNA testing from a laboratory that uses a nucleic acid test (NAT) approved by the U.S. Food and Drug Administration (FDA). (AI)
  • If HCV RNA is detected after a reactive antibody result, the patient has confirmed HCV infection and clinicians should evaluate for treatment of chronic or acute HCV infection. (AII)
  • If the HCV antibody test result is nonreactive:
    • Clinicians should perform subsequent HCV screening based on individual patient risk factors (AIII)
    • And if acute HCV infection is suspected, clinicians should perform a diagnostic HCV RNA test using an FDA-approved NAT (AI)
  • In patients with a history of a reactive HCV antibody test, clinicians should use an HCV RNA test (not an HCV antibody test) for subsequent screening. (AI)
NEW YORK STATE (NYS) PUBLIC HEALTH LAW
  • Beginning in January 2014, NYS public health law requires that HCV antibody screening be offered to every individual born between 1945 and 1965 who receives healthcare services from a physician, physician assistant, or nurse practitioner in a primary care or inpatient hospital setting [1].
  • HCV screening is required unless the healthcare practitioner believes that: 1) the individual is being treated for a life-threatening emergency, 2) the individual has previously been offered or has received an HCV screening test, or 3) the individual lacks capacity to consent to a HCV screening test.

HCV Antibody Testing

HCV antibody testing is the first step in identifying whether a person has been exposed to the virus [2] (See Centers for Disease Control and Prevention [CDC]: Recommended Testing Sequence for Identifying Current HCV Infection).

HCV antibody testing with a third-generation enzyme immunoassay (EIA) is most frequently performed in the laboratory; this test has a sensitivity of approximately 99% even when used in low-prevalence populations [3-6].  

Reflex testing is an automatic HCV RNA test of the same specimen that is performed after a reactive HCV antibody test. This testing provides confirmation or exclusion of active infection with a single laboratory test order, eliminating the need for the patient to return for follow-up testing and expediting linkage to care for those who are HCV-infected (see Table 1: Interpretation of HCV Test Results, below). Knowledge of the laboratory’s HCV reflex testing procedures is necessary, including the availability of reflex testing and, if available, whether is it performed automatically or must be requested. If reflex testing is not available, confirmatory HCV RNA testing should be performed soon as possible after a reactive HCV antibody test result is received.

Rapid, point-of-care HCV antibody screening tests are also available; they can be performed with a finger stick blood sample and produce results within 20 to 40 minutes. Sensitivities and specificities are equivalent to traditional EIA testing [7,8]. The NYSDOH HCV Rapid Testing Program and others are using this simple and convenient testing method outside of traditional healthcare settings in drug treatment centers, syringe-exchange programs, and other community-based locations. The short testing process means the test can be performed and the result given while the patient is still present, and, if the patient is HCV antibody-positive, the follow-up appointment for confirmatory HCV RNA testing can be made.

If the HCV antibody test is nonreactive, the immunocompetent patient does not have chronic HCV infection; ongoing individual risk factors will determine the need for future screening and the need for ongoing education about risk-reduction strategies. However, a false-negative (false-nonreactive) antibody test result may occur in patients who may have been exposed to the virus within the previous 6 months and may be experiencing acute HCV infection (see the Acute HCV Infection section of this guideline) [9]. HCV RNA is usually detectable within days to 2 weeks after an exposure [10,11], whereas it may take 2 to 6 months for HCV antibodies to be detectable (“window period”). False-nonreactive antibody test results may also occur in patients who are immunocompromised due to advanced HIV infection, use of immunosuppressive therapy, long-term hemodialysis, or other conditions [12,13]. In these patients, confirmatory HCV RNA testing should be performed.

If the HCV antibody test is reactive, confirmatory HCV RNA testing should be performed [14,15]. It is important to inform patients that the reactive antibody result does not confirm active HCV infection.

HCV RNA Testing

Molecular diagnostic tests specifically detect HCV RNA through the use of an NAT. A number of FDA-approved HCV RNA tests are available, and these tests can identify the presence of virus as early as 2 weeks post-exposure, rather than the 8 to 24 weeks needed for HCV antibodies to develop [16] (see American Association for the Study of Liver Disease (AASLD): FDA-approved, Commercially Available Anti-HCV Screening Assays). Ultrasensitive HCV quantitative RNA assays can detect as few as 5 copies/mm3.

If HCV RNA is not detected after a reactive antibody test, then 1) the patient had previous exposure to HCV but has cleared the virus and does not have active HCV infection, or 2) the result of the HCV antibody test was falsely-reactive. In these patients, ongoing HCV screening should occur based on individual risk factors. Because the presence of HCV antibodies can be lifelong, detection of current HCV infection in antibody-reactive patients requires HCV RNA testing. Repeat HCV antibody testing is not useful in patients with previously reactive antibody tests.

If HCV RNA is detected after a reactive antibody result, the patient has confirmed HCV infection and should be evaluated for treatment of chronic or acute HCV infection (see the Pretreatment Assessment section of this guideline). It is important to advise all patients with HCV viremia that they may be infectious and should take precautions to avoid transmitting HCV to others.

KEY POINTS: HCV ANTIBODIES
  • The presence of HCV antibodies alone may not indicate active HCV infection.
  • In patients with a history of a reactive HCV antibody test, subsequent screening requires an HCV RNA test, not an HCV antibody test, to detect infection.
  • HCV antibodies do not prevent future HCV infections; prevention measures are needed for those with ongoing risk factors.
Table 1. Interpretation of HCV Test Results*
Anti-HCV Antibody HCV RNA Interpretation Response
Positive Detected Acute or chronic HCV infection Evaluate for treatment
Positive Not detected
  • Resolution of HCV by spontaneous or treatment-related clearance, or
  • HCV infection during period of intermittent viremia, or
  • False positive antibody screening result
  • HCV RNA testing based on risk factors
  • Repeat HCV RNA testing if acute exposure is known or suspected
Negative Detected
  • Early acute HCV infection, or
  • Chronic HCV infection in setting of immunosuppressed state
  • Evaluate for treatment if person has risk factors
  • Repeat testing if person has no risk factors or exposure and false positive is suspected
Negative Unknown Presumed absence of HCV infection if the HCV RNA testing was not performed or the status is unknown HCV antibody test based on risk factors
*Adapted from CDC [2].
References
  1. New York State Department of Health AI, unpublished data.
  2. Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR Morb Mortal Wkly Rep 2013;62(18):362-5. [PMID: 23657112]
  3. Lee SR, Wood CL, Lane MJ, et al. Increased detection of hepatitis C virus infection in commercial plasma donors by a third-generation screening assay. Transfusion 1995;35(10):845-9. [PMID: 7570915]
  4. Abdel-Hamid M, El-Daly M, El-Kafrawy S, et al. Comparison of second- and third-generation enzyme immunoassays for detecting antibodies to hepatitis C virus. J Clin Microbiol 2002;40(5):1656-9. [PMID: 11980937]
  5. Gretch DR. Use and interpretation of HCV diagnostic tests in the clinical setting. Clin Liver Dis 1997;1(3):543-57, vi. [PMID: 15560057]
  6. Colin C, Lanoir D, Touzet S, et al. Sensitivity and specificity of third-generation hepatitis C virus antibody detection assays: an analysis of the literature. J Viral Hepat 2001;8(2):87-95. [PMID: 11264728]
  7. Lee SR YG, Guillon GB, Kurtz LA, Fischl M, Friel T, et al. Evaluation of a rapid, point-of-care test device for the diagnosis of hepatitis C infection. J Clin Virol 2010;48(1):15-7. [PMID: 20362493]
  8. Lee SR, Yearwood GD, Guillon GB, et al. Evaluation of a rapid, point-of-care test device for the diagnosis of hepatitis C infection. J Clin Virol 2010;48(1):15-7. [PMID: 20362493]
  9. Nastouli E, Thomson EC, Karayiannis P, et al. Diagnosing acute hepatitis C in HIV-infected patients: nucleic acid testing compared with antibody and antigen-antibody detecting methods. J Clin Virol 2009;44(1):78-80. [PMID: 18986830]
  10. Maheshwari A, Thuluvath PJ. Management of acute hepatitis C. Clin Liver Dis 2010;14(1):169-76; x. [PMID: 20123448]
  11. Wang TY, Kuo HT, Chen LC, et al. Use of polymerase chain reaction for early detection and management of hepatitis C virus infection after needlestick injury. Ann Clin Lab Sci 2002;32(2):137-41. [PMID: 12017194]
  12. Larouche A, Gaetan G, El-Bilali N, et al. Seronegative hepatitis C virus infection in a child infected via mother-to-child transmission. J Clin Microbiol 2012;50(7):2515-9. [PMID: 22535990]
  13. Thomson EC, Nastouli E, Main J, et al. Delayed anti-HCV antibody response in HIV-positive men acutely infected with HCV. Aids 2009;23(1):89-93. [PMID: 19050390]
  14. Freiman JM, Tran TM, Schumacher SG, et al. Hepatitis C Core Antigen Testing for Diagnosis of Hepatitis C Virus Infection: A Systematic Review and Meta-analysis. Ann Intern Med 2016;165(5):345-55. [PMID: 27322622]
  15. Moorman AC, Drobenuic J, Kamili S. Prevalence of false-positive hepatitis C antibody results, National Health and Nutrition Examination Study (NHANES) 2007-2012. J Clin Virol 2017;89:1-4. [PMID: 28171829]
  16. Kamili S, Drobeniuc J, Araujo AC, et al. Laboratory diagnostics for hepatitis C virus infection. Clin Infect Dis 2012;55 Suppl 1:S43-8. [PMID: 22715213]

Diagnosis of HCV Infection: Acute HCV Infection

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATIONS
  • Clinicians should suspect acute hepatitis C virus (HCV) infection if a patient who had a nonreactive antibody test documented within the previous 6 months has a new reactive antibody test or has detectable HCV RNA in the absence of a reactive antibody test. (AIII)
  • Clinicians should not prescribe pre- or post-exposure prophylaxis to prevent HCV infection. (AI)
  • If chronic HCV infection is established, clinicians should evaluate patients for treatment. (AI)
  • Clinicians should screen all patients with possible acute HCV infection for HIV, hepatitis A virus (HAV), and hepatitis B virus (HBV) infections, given the similar risk factors for acquisition. (AII)
KEY POINTS
  • Clinicians and their patients should determine the timing of HCV treatment with respect to the likelihood of spontaneous clearance and patient or care provider concerns regarding risk of transmission.
  • Patient education should include the following information:
    • If patients have acute HCV infection, they may be infectious and should take precautions to avoid transmitting HCV to others.
    • HCV infection may clear spontaneously (i.e., without treatment).
    • Treatment options are available if HCV infection is established.

The acute phase is considered the first 6 months of HCV infection. Approximately 65% to 75% of patients with acute HCV infection are asymptomatic [1]. When symptoms are present, they last a few weeks to months after exposure and may range from a clinical hepatitis with jaundice, choluria (tea-colored urine), steatorrhea and abdominal pain, to only vague, nonspecific symptoms, such as fatigue, anorexia, low-grade fever, myalgias, arthralgia, mood disturbances, and nausea or vomiting [1-3]. As a result, in the absence of a clearly defined risk factor for transmission, the acute phase is rarely diagnosed. During acute infection, serum aminotransferase levels also vary and may be normal or up to 20 times the upper limit of normal [4].

An estimated 20% to 45% of patients with HCV infection will clear the virus spontaneously, generally within 12 to 16 weeks [5]. Approximately 11% of those who remain viremic 6 months after infection will eventually experience spontaneous clearance [6]. Predictors of spontaneous clearance include female sex, age <40 years, IL28B CC genotype (highest incidence in East and South Asians and Europeans, lowest in African Americans), symptomatic infection (jaundice), and a competent immune system (no immunosuppressive therapy or uncontrolled HIV) [7]. Because both aminotransferases and HCV viral load may fluctuate during the acute phase, durable spontaneous clearance, if it occurs, is not expected until 24 weeks after inoculation or exposure. Following spontaneous clearance, patients will remain antibody reactive.

Known exposure: After a known exposure, which generally occurs in an occupational setting, baseline testing with both HCV RNA and antibody tests is reasonable to distinguish between acute or chronic infection.

Given the excellent response rates with current DAA therapy, at this time, there is no clear advantage to treatment of HCV in the acute phase [8]. It is reasonable to wait a minimum of 24 weeks to repeat HCV RNA and antibody tests to assess for spontaneous clearance or confirm infection. In some circumstances, clinicians and their patients may decide to initiate therapy sooner; however, if patients have an increased risk of transmitting HCV, are HIV-infected men who have sex with men (MSM), and/or use injection drugs, a minimum of 12 to 16 weeks is needed to assess for spontaneous clearance before initiation of therapy. Other factors influencing decisions to initiate early treatment may be current access to healthcare, concerns for delay due to family planning, and known cirrhosis or preexisting liver disease. The recommended DAA regimens used in these situations are the same as those indicated for chronic HCV therapy.

It is important to educate patients with potential acute HCV infection about the possibility of spontaneous clearance, the need to avoid or minimize hepatotoxic drugs (including alcohol), and the need to take precautions to prevent HCV transmission to others (see patient education information at NYSDOH AI HCV Educational Materials).

References
  1. Marcellin P. Hepatitis C: the clinical spectrum of the disease. J Hepatol 1999;31 Suppl 1:9-16. [PMID: 10622554]
  2. Gerlach JT, Diepolder HM, Zachoval R, et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 2003;125(1):80-8. [PMID: 12851873]
  3. Loomba R, Rivera MM, McBurney R, et al. The natural history of acute hepatitis C: clinical presentation, laboratory findings and treatment outcomes. Aliment Pharmacol Ther 2011;33(5):559-65. [PMID: 21198704]
  4. Maheshwari A, Ray S, Thuluvath PJ. Acute hepatitis C. Lancet 2008;372(9635):321-32. [PMID: 18657711]
  5. Kamal SM. Acute hepatitis C: a systematic review. Am J Gastroenterol 2008;103(5):1283-97; quiz 98. [PMID: 18477352]
  6. Seeff LB. Natural history of hepatitis C. Hepatology 1997;26(3 Suppl 1):21s-28s. [PMID: 9305659]
  7. Grebely J, Page K, Sacks-Davis R, et al. The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection. Hepatology 2014;59(1):109-20. [PMID: 23908124]
  8. Naggie S, Holland DP, Sulkowski MS, et al. Hepatitis C Virus Postexposure Prophylaxis in the Healthcare Worker: Why Direct-Acting Antivirals Don’t Change a Thing. Clin Infect Dis 2017;64(1):92-99. [PMID: 27682067]

Pretreatment Assessment

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATIONS
  • Clinicians should assess all patients with a confirmed diagnosis of chronic hepatitis C virus (HCV) infection for treatment. (AI)
  • Clinicians new to treating chronic HCV infection should consult with an experienced HCV care provider when treating chronic HCV infection in patients with any of the following conditions (AIII):
    • Compensated cirrhosis
    • Concurrent hepatobiliary conditions
    • Extrahepatic manifestations of HCV, including renal, dermatologic, and rheumatologic manifestations
    • Significant renal impairment (creatinine clearance <30 mL/min)
    • Active hepatitis B virus (HBV) infection, defined as HBV surface antigen positive and detectable HBV DNA
    • Ongoing HCV infection after failure of treatment with direct acting antivirals (DAAs)
  • Clinicians should refer patients with chronic HCV infection and decompensated liver disease and patients who are pre- or post-transplant to a liver disease specialist (AIII)

With few exceptions, all patients with confirmed HCV infection are candidates for treatment [1-3]. Treatment of HCV reduces all-cause mortality, regardless of disease stage [1]. The only patients who are not candidates for treatment with DAAs are those with a life expectancy of less than 12 months or for whom treatment would not improve symptoms or prognosis [4]. Depending on their level of experience and expertise, clinicians may choose to refer complex patients to a care provider with experience in the management of complex patients with HCV infection.

References
  1. Simmons B, Saleem J, Heath K, et al. Long-term treatment outcomes of patients infected with hepatitis C virus: a systematic review and meta-analysis of the survival benefit of achieving a sustained virological response. Clin Infect Dis 2015;61(5):730-40. [PMID: 25987643]
  2. Smith-Palmer J, Cerri K, Valentine W. Achieving sustained virologic response in hepatitis C: a systematic review of the clinical, economic and quality of life benefits. BMC Infect Dis 2015;15:19. [PMID: 25596623]
  3. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. Jama 2012;308(24):2584-93. [PMID: 23268517]
  4. American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA). HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. August 24, 2016 [accessed 2017 Apr 26]. http://www.hcvguidelines.org

Pretreatment Assessment: Medical History and Physical Exam

Hepatitis C Virus Infection Guideline Committee, July 2017

The patient’s medical history and physical examination are essential components of pretreatment assessment. Table 2, below, lists elements of the patient history and physical examination that apply specifically to pretreatment assessment of patients with chronic hepatitis C virus (HCV) infection.

Screening of mental health status and for alcohol/substance use and treating or referring patients with disorders is an essential component of patient care. The approach to patients with mental health or substance use disorders is the same for patients with HCV as for other patients. Mental health conditions that have been stabilized and substance use disorders that are being treated are not contraindications to HCV treatment.

Table 2. Key Elements of a Pre-HCV Treatment Patient History and Physical Examination
Elements of Patient History Rationale
Previous treatment for HCV infection Previous regimen and treatment outcome will guide choice and duration of therapy
History of hepatic decompensation Warrants referral to an experienced HCV care provider
History of renal disease Findings may influence choice of regimen
Medication history and current medications, including over-the counter and herbal products

Carefully consider drug-drug interactions with direct-acting antiviral (DAA) regimens

Pregnancy status and plans
  • HCV treatment is deferred during pregnancy
  • Birth control use is essential during HCV treatment and for 6 months after treatment if patients are receiving ribavirin (RBV)
HIV infection
  • If HIV infection is confirmed, offer patient antiretroviral therapy (ART) 
  • If the patient is being treated with antiretroviral medications, assess potential drug-drug interactions
  • Presence of HIV infection may influence fibrosis assessment modality, choice of treatment, duration, and monitoring
History of infection/ vaccination status
  • Hepatitis A virus (HAV): Obtain HAV antibody (immunoglobulin [IgG] or total)
  • Hepatitis B virus (HBV): Obtain hepatitis B surface antigen (HBsAg), antibody to HB surface antigen (anti-HBs), and anti-hepatitis B core antibody (anti-HBc) (total)
  • Administer pneumococcal polysaccharide vaccination (PPSV23) as follows:
    • All patients with cirrhosis, which is associated with increased susceptibility to bacterial infections [1]
    • Patients aged 19 to 64 years
    • As a 1-time revaccination 5 years after the first dose of PPSV23
    • Patients aged 65 or older who received 1 or 2 doses of PPSV23 before age 65 years for any indication, if at least 5 years have passed since their previous dose
  • Annual influenza: See U.S. Food and Drug Administration (FDA): Influenza Virus Vaccine Safety & Availability
Elements of a Pretreatment
Physical Examination
Clinical Details
Presence or absence of ankle edema, abdominal veins, jaundice, palmar erythema, gynecomastia, spider telangiectasia, ascites, encephalopathy, and asterixis Presence may suggest cirrhosis or decompensated cirrhosis and may require additional evaluation and management or treatment
Presence or absence of physical signs related to extrahepatic manifestations of HCV, such as porphyria cutanea tarda, vasculitis, or lichen planus  

Presence may increase urgency of HCV treatment and may require additional evaluation and treatment needs

Liver size by palpation or auscultation for hepatomegaly or splenomegaly, as well as tenderness or hepatic bruits Size and tenderness may suggest severity of liver disease and may require additional evaluation
Cardiac status Findings may influence choice of RBV-containing regimen, RBV dosing, or complete blood count (CBC) monitoring frequency
References
  1. Jalan R, Fernandez J, Wiest R, et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol 2014;60(6):1310-24. [PMID: 24530646]

Pretreatment Assessment: Mental Health, Substance Use, and Barriers to Adherence

Hepatitis C Virus Infection Guideline Committee, July 2017

Mental Health

If stabilized, mental health disorders are not contraindications to treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs). Strategies to overcome mental health-related barriers to successful HCV treatment include counseling and education and referral to psychiatry and behavioral health services. Patients with mental health disorders may need increased attention to management of adverse effects and coordination of care during HCV treatment. An integrated care model, in which mental health providers provide HCV treatment and risk reduction counseling, has been effective for treating HCV [1]. Few data are currently available regarding the effect of an existing psychiatric diagnosis on patient adherence to any oral HCV treatment regimens.

With interferon-free regimens, depression is no longer a common side effect of HCV treatment. However, antidepressant and antipsychotic drug-drug interactions have been reported with DAAs, so monitoring is necessary. Similarly, it is important to be aware of patient use of nonprescription medication: St John’s wort, an herbal self-remedy for depression, may decrease the effectiveness of DAA therapy [2-5].

Alcohol and Other Substance Use

A history, or active use, of alcohol, tobacco, marijuana, and other substances, is not a contraindication to HCV treatment unless the drug or alcohol use is believed to interfere with adherence to medications or appointments. Studies have demonstrated that active substance users who are receiving addiction treatment can be effectively treated for chronic HCV infection [6-13].

Once a patient’s alcohol consumption habits have been assessed, counseling may help the patient to reduce or eliminate alcohol use [14]. It is important for patients with HCV infection who use alcohol to be made aware of the effects of alcohol on the course of HCV disease. Alcohol use has been associated with increased rates of liver disease progression and hepatocellular carcinoma (HCC) in persons with chronic HCV infection. In one such study, the risk of end-stage liver disease was higher in patients who reported ingesting more than 260 g (approximately 9 ounces) of alcohol per week [15].  Moderate alcohol intake is also associated with an increased risk of fibrosis progression [16], and light-to-moderate alcohol intake is associated with an increased risk of HCC in patients with compensated cirrhosis [15]. There is no consensus on a safe level of alcohol ingestion for persons with chronic HCV infection, and no evidence is currently available regarding the effects of alcohol use on response to DAA treatment. Abstinence has been associated with improvement in chemical markers and decreased HCV RNA levels among previously heavy drinkers with HCV infection [17,18].

Barriers to Adherence

Though HCV treatment regimens are relatively short in duration, assessing a patient’s readiness for treatment and ability to adhere to medications and medical appointments before initiating DAA therapy is essential. The purpose of the adherence assessment is to optimize support, not to deny access to treatment. After the pretreatment assessment and before treatment initiation, a plan can be developed with the patient to address potential barriers and/or to put support resources in place. Support groups and peer programs can promote increased patient engagement.

KEY POINTS
  • The purpose of the adherence assessment is to optimize support, not to deny access to treatment.
  • Though HCV treatment regimens are relatively short in duration, assessing a patient’s readiness for treatment and ability to adhere to a medication regimen and medical care appointments before initiating DAA therapy is essential. 
  • After the pretreatment assessment and before treatment initiation, a plan can be developed with the patient to address potential barriers and/or to put support resources in place
References
  1. Groessl EJ, Sklar M, Cheung RC, et al. Increasing antiviral treatment through integrated hepatitis C care: a randomized multicenter trial. Contemp Clin Trials 2013;35(2):97-107. [PMID: 23669414]
  2. FDA. Sovaldi (sofosbuvir) Tablets. 2015 [accessed March 7, 2017]. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm441356.htm
  3. FDA. Olysio (simeprevir), 150 mg capsules. 2015 [accessed March 7, 2017]. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm417602.htm
  4. FDA. Harvoni (ledipasvir/sofosbuvir) Fixed-dose Combination Tablet. 2015 [accessed March 7, 2017]. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm441357.htm
  5. FDA. (Daclatasvir) tablets, for oral use. 2015 [accessed March 7, 2017]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206843Orig1s000lbl.pdf
  6. Jerkeman A, Norkrans G, Lidman C, et al. Treatment for chronic hepatitis C in a cohort of opiate substitution therapy recipients in three Swedish cities – completion rates and efficacy. Eur J Gastroenterol Hepatol 2014;26(5):523-31. [PMID: 24637496]
  7. Alavi M, Grebely J, Micallef M, et al. Assessment and treatment of hepatitis C virus infection among people who inject drugs in the opioid substitution setting: ETHOS study. Clin Infect Dis 2013;57 Suppl 2:S62-9. [PMID: 23884068]
  8. Bojovic K, Simonovic J, Katanic N, et al. The comparison of chronic hepatitis C treatment outcome between intravenous drug users and non-intravenous drug users. Biomed Pharmacother 2013;67(6):517-20. [PMID: 23639229]
  9. Newman AI, Beckstead S, Beking D, et al. Treatment of chronic hepatitis C infection among current and former injection drug users within a multidisciplinary treatment model at a community health centre. Can J Gastroenterol 2013;27(4):217-23. [PMID: 23616960]
  10. Brunner N, Senn O, Rosemann T, et al. Hepatitis C treatment for multimorbid patients with substance use disorder in a primary care-based integrated treatment centre: a retrospective analysis. Eur J Gastroenterol Hepatol 2013;25(11):1300-7. [PMID: 23571610]
  11. Seidenberg A, Rosemann T, Senn O. Patients receiving opioid maintenance treatment in primary care: successful chronic hepatitis C care in a real world setting. BMC Infect Dis 2013;13:9. [PMID: 23298178]
  12. Dore GJ, Altice F, Litwin AH, et al. C-EDGE CO-STAR: Efficacy of grazoprevir and elbasvir in persons who inject drugs (PWID) receiving opioid agonist therapy. Abstract 40. 66th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2015; 2015 Nov 13-17; San Francisco, CA. http://onlinelibrary.wiley.com/doi/10.1002/hep.28172/full
  13. Dore GJ, Altice F, Litwin AH, et al. Elbasvir-Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Randomized Trial. Ann Intern Med 2016;165(9):625-34. [PMID: 27537841]
  14. EASL. EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol 2015;63(1):199-236. [PMID: 25911336]
  15. Vandenbulcke H, Moreno C, Colle I, et al. Alcohol intake increases the risk of HCC in hepatitis C virus-related compensated cirrhosis: A prospective study. J Hepatol 2016;65:543–51. [PMID: 27180899]
  16. Westin J, Lagging LM, Spak F, et al. Moderate alcohol intake increases fibrosis progression in untreated patients with hepatitis C virus infection. J Viral Hepat 2002;9(3):235-41. [PMID: 12010513]
  17. Cromie SL, Jenkins PJ, Bowden DS, et al. Chronic hepatitis C: effect of alcohol on hepatitic activity and viral titre. J Hepatol 1996;25(6):821-6. [PMID: 9007708]
  18. Lieber CS. Alcohol and hepatitis C. Alcohol Res Health 2001;25(4):245-54. [PMID: 11910701]

Pretreatment Assessment: HCV Genotype

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATION
  • Clinicians should obtain hepatitis C virus (HCV) genotype/subtype testing for all patients before starting treatment with direct-acting antivirals (DAAs). (AI)

HCV genotype influences the choice of DAA regimen and treatment duration in patients with chronic HCV infection; therefore, HCV genotype/subtype testing is needed for all patients being considered for HCV therapy [1]. There are 6 common HCV genotypes and over 100 subtypes [2]. Approximately 70% of chronic HCV infections in the United States are genotype 1, the majority of which are subtype 1a [3].

References
  1. American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA). HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. August 24, 2016 [accessed 2017 Apr 26]. http://www.hcvguidelines.org
  2. Chevaliez S, Pawlotsky JM. Hepatitis C virus: virology, diagnosis and management of antiviral therapy. World J Gastroenterol 2007;13(17):2461-6. [PMID: 17552030]
  3. CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep 1998;47(Rr-19):1-39. [PMID: 9790221]

Pretreatment Assessment: Fibrosis Assessment

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATIONS
  • Clinicians should assess the degree of fibrosis in patients with chronic hepatitis C virus (HCV) infection to aid in determining the following (AI):
    • Need for pretreatment screening for varices and hepatocellular carcinoma (HCC).
    • Duration of antiviral treatment.
    • Need to include ribavirin (RBV) in the treatment regimen.
    • Need for post-treatment follow-up. 
  • Clinicians should assess patients with chronic HCV infection for decompensated liver disease. (AI)
  • Clinicians should refer patients with decompensated cirrhosis to a liver disease specialist. (AIII)

Fibrosis stage predicts HCV treatment response [1]. An assessment of the degree of fibrosis should be performed regardless of alanine aminotransferase (ALT) patterns because significant fibrosis may be present in patients with repeatedly normal ALT [2]. In one study, approximately 50% of HCV-infected persons born between 1945 and 1965 had severe fibrosis or cirrhosis as measured by fibrosis (FIB)-4 scoring [3]. It is particularly important to identify patients with bridging fibrosis or cirrhosis; these findings may influence treatment selection and duration and may dictate post-treatment follow-up, such as the need for ongoing assessment for esophageal varices, hepatic function, and surveillance monitoring for HCC [4-6]. Patients with lower severity of fibrosis have a higher likelihood of response to therapy and improved post-treatment prognosis [2]. Patients known to have cirrhosis do not require repeat determination of degree of fibrosis before treatment.

Fibrosis stage can be assessed using noninvasive modalities such as transient elastography, aspartate aminotransferase-to-platelet ratio index (APRI), FIB-4, and assays of direct markers of liver fibrosis (see Table 3, Methods for Staging Fibrosis, below). Noninvasive modalities are well suited for rapid pretreatment assessment of chronic HCV infection in the primary care setting. Indirect serum markers use mathematical algorithms with different variables to predict fibrosis and are easily accessible in the primary care setting. Tests such as the APRI and FIB-4 index (age, AST, ALT, platelet count) appear efficacious in patients with little or no fibrosis and in those with cirrhosis. However, these tests have limited ability to discriminate between intermediate stages of fibrosis [7-9]. Several studies have found FIB-4 to predict fibrosis more accurately than APRI [10,11].

Liver biopsies are not routinely required. They are useful for patients with highly discordant results on noninvasive testing and in patients suspected of having a second etiology for liver disease in addition to HCV infection. Liver biopsy is an important instrument for diagnosing concurrent disease, such as metabolic nonalcoholic steatohepatitis (NASH), hemochromatosis (HHC), autoimmune primary biliary cholangitis (PBC), and autoimmune hepatitis (AIH). Although liver biopsy is safe and has a very low risk of complications (1/4,000 to 10,000), invasive procedures may be difficult to obtain in a timely fashion or may be unacceptably costly for uninsured patients [12].

An APRI calculator, FIB-4 index calculator, and other online clinical tools are available at Hepatitis C Online. Assays of direct markers of liver fibrosis measure various combinations of liver matrix components in combination with standard biochemical markers. These assays (FibroSure, FibroTest, FibroMeter, FIBROSpect II, and HepaScore) appear efficacious in patients with little or no fibrosis and in those with cirrhosis, but, like FIB-4 and APRI, they have limited ability to discriminate between intermediate stages of fibrosis [7-9]. These tests will provide an indication of disease progression over time and can be helpful in counseling patients who are considering treatment [13].

Vibration-controlled transient elastography (VCTE) measures shear wave velocity (expressed in kilopascals) and assesses a larger volume of liver parenchyma than liver biopsy. VCTE is most efficacious in F0-1 and F4 fibrosis but may be difficult to interpret in patients with F2 and F3 disease [7,9,14,15]. Although VCTE is FDA-approved, it is not widely available. Other technologies, such as acoustic radiation force imaging, portal venous transit time, and MRI elastography, show promise for possible future use; these procedures are not recommended at this time because of their lack of sensitivity and specificity in early fibrosis, high cost, and limited availability [2,16].

Table 3. Methods for Staging Fibrosis
Method Procedure Advantages Disadvantages
Indirect serum markers APRI, FIB-4* Noninvasive; inexpensive Limited ability to differentiate intermediate stages of fibrosis
Direct markers FibroSure, FibroTest, FibroMeter, FIBROSpect II, and HepaScore Noninvasive; easily accessible Limited ability to differentiate intermediate stages of fibrosis
VCTE Shear wave velocity Noninvasive; assesses large volume of liver parenchyma May be difficult to interpret in F2 and F3 liver disease; limited availability
Liver biopsy Pathologic examination Diagnostic standard; diagnoses concurrent liver disease Invasive procedure; costly; sampling error
*See Hepatitis C online for the following: APRI Calculator and FIB-4 Calculator
References
  1. Ogawa E, Furusyo N, Shimizu M, et al. Non-invasive fibrosis assessment predicts sustained virological response to telaprevir with pegylated interferon and ribavirin for chronic hepatitis C. Antivir Ther 2015;20(2):185-92. [PMID: 24941012]
  2. EASL. EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol 2015;63(1):199-236. [PMID: 25911336]
  3. Klevens M HX, Yeo A editor The Burden of Liver Disease Among Persons With Hepatitis C in the United States (Abstract 145). Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, Washington.
  4. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011;53(3):1020-2. [PMID: 21374666]
  5. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46(3):922-38. [PMID: 17879356]
  6. American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA). HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. August 24, 2016 [accessed 2017 Apr 26]. http://www.hcvguidelines.org
  7. Castera L, Winnock M, Pambrun E, et al. Comparison of transient elastography (FibroScan), FibroTest, APRI and two algorithms combining these non-invasive tests for liver fibrosis staging in HIV/HCV coinfected patients: ANRS CO13 HEPAVIH and FIBROSTIC collaboration. HIV Med 2014;15(1):30-9. [PMID: 24007567]
  8. Patel K, Shackel NA. Current status of fibrosis markers. Curr Opin Gastroenterol 2014;30(3):253-9. [PMID: 24671009]
  9. Schiavon Lde L, Narciso-Schiavon JL, de Carvalho-Filho RJ. Non-invasive diagnosis of liver fibrosis in chronic hepatitis C. World J Gastroenterol 2014;20(11):2854-66. [PMID: 24659877]
  10. Amorim TG, Staub GJ, Lazzarotto C, et al. Validation and comparison of simple noninvasive models for the prediction of liver fibrosis in chronic hepatitis C. Ann Hepatol 2012;11(6):855-61. [PMID: 23109448]
  11. Shaikh S, Memon MS, Ghani H, et al. Validation of three non-invasive markers in assessing the severity of liver fibrosis in chronic hepatitis C. J Coll Physicians Surg Pak 2009;19(8):478-82. [PMID: 19651008]
  12. Seeff LB, Everson GT, Morgan TR, et al. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol 2010;8(10):877-83. [PMID: 20362695]
  13. Poynard T, Vergniol J, Ngo Y, et al. Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest) and transient elastography (FibroScan(R)). J Hepatol 2014;60(4):706-14. [PMID: 24291240]
  14. Verveer C, Zondervan PE, ten Kate FJ, et al. Evaluation of transient elastography for fibrosis assessment compared with large biopsies in chronic hepatitis B and C. Liver Int 2012;32(4):622-8. [PMID: 22098684]
  15. Tapper EB, Castera L, Afdhal NH. FibroScan (vibration-controlled transient elastography): where does it stand in the United States practice. Clin Gastroenterol Hepatol 2015;13(1):27-36. [PMID: 24909907]
  16. Bohte AE, de Niet A, Jansen L, et al. Non-invasive evaluation of liver fibrosis: a comparison of ultrasound-based transient elastography and MR elastography in patients with viral hepatitis B and C. Eur Radiol 2014;24(3):638-48. [PMID: 24158528]

Pretreatment Assessment: Cirrhosis Evaluation

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATIONS
  • Clinicians should refer all patients with hepatitis C virus (HCV)-related cirrhosis for an upper endoscopy to screen for the presence of esophageal varices. (AIII)
  • Clinicians should screen for hepatocellular carcinoma (HCC) with ultrasound, computerized axial tomography (CT), or magnetic resonance imaging (MRI) every 6 months in patients with HCV-related bridging fibrosis or cirrhosis. (AIII)

HCV treatment and the achievement of a sustained viral response (SVR) in patients with advanced liver disease dramatically decrease hepatic decompensation events, HCC, and liver-related mortality [1]. To classify the severity of cirrhosis, the Model for End-Stage Liver Disease score (MELD calculator) or the Child-Turcotte-Pugh (CTP) score (Table 4, below) may be used.

Table 4. Calculating the Child-Turcotte-Pugh (CTP) Score for Severity of Cirrhosis
  1 point* 2 points* 3 points*
Encephalopathy None Stage 1 to 2
(or precipitant-induced)
Stage 3 to 4
(or chronic)
Ascites None

Mild/moderate 
(diuretic-responsive)

Severe 
(diuretic-refractory)

Bilirubin (mg/dL) <2.0 2.0 to 3.0 >3.0
Albumin (g/dL) >3.5 2.8 to 3.5 <2.8

Prothrombin time 
(sec prolonged) or INR

<4.0 4.0 to 6.0 >6.0
<1.7 1.7 to 2.3 >2.3

*CTP score is obtained by adding the score for each parameter. CTP class:
A = 5 to 6 points (compensated, least severe liver disease)
B = 7 to 9 points (decompensated, moderately severe liver disease)
C = 10 to 15 points (decompensated, most severe liver disease)

Adapted from: U.S. Department of Veterans Affairs: Viral Hepatitis for Health Care Providers. Child-Turcotte-Pugh (CTP) Calculator.

Assessment for decompensation in patients with cirrhosis can be accomplished through medical history-taking and initial laboratory testing (see Table 5, Evaluation and Follow-Up Screening for Patients with Cirrhosis, below). Decompensation is defined as a MELD score of >15 or the presence of ascites, hepatic encephalopathy, portal hypertensive bleeding, HCC, intractable pruritus, hepatopulmonary syndrome, coagulopathy, or portopulmonary hypertension [2]. Because of the clinical complexity of the condition, patients with a history or presence of decompensated cirrhosis should be referred to a liver disease specialist.

All patients with cirrhosis should undergo an upper endoscopy to screen for the presence of esophageal varices. Patients with HCV-related bridging fibrosis or cirrhosis are at increased risk of developing primary HCC and should undergo surveillance with an ultrasound every 6 months [3,4]. Alpha-fetoprotein (AFP) determination lacks adequate sensitivity and specificity for effective use in surveillance and diagnosis of HCC. Elevated AFP levels may be seen in HCV infection in the absence of HCC [5,6].

For additional risk stratification and diagnosis information, see American Association of the Study of Liver Diseases (AASLD): Practice Guidance on Portal Hypertensive Bleeding in Cirrhosis [7]

Table 5. Evaluation and Follow-up Screening for Patients with Cirrhosis
Type of Evaluation Rationale

Assess for decompensation; refer to a liver disease specialist if history of decompensation or Child’s class B or C

  • Decompensation is defined as the presence (or history) of 1 of the following:
  • MELD score of >15
  • Ascites
  • Hepatic encephalopathy
  • Portal hypertensive bleeding
  • HCC
  • Intractable pruritus
  • Hepatopulmonary syndrome
  • Portopulmonary hypertension
Abdominal ultrasound to screen for HCC
Upper endoscopy Screen for varices
References
  1. American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA). HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. August 24, 2016 [accessed 2017 Apr 26]. http://www.hcvguidelines.org
  2. Fox AN BRJ. Is the patient a candidate for liver transplantation? Clin Liver Dis 2012 16(May 2012):(2):435-48 [PMID: 22541708]
  3. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011;53(3):1020-2. [PMID: 21374666]
  4. Shoreibah MG, Bloomer JR, McGuire BM, et al. Surveillance for hepatocellular carcinoma: evidence, guidelines and utilization. Am J Med Sci 2014;347(5):415-9. [PMID: 24759379]
  5. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340(10):745-50. [PMID: 10072408]
  6. EASL. EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol 2015;63(1):199-236. [PMID: 25911336]
  7. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology 2017;65(1):310-35. [PMID: 27786365]

Pretreatment Assessment: Baseline Laboratory Testing

Hepatitis C Virus Infection Guideline Committee, July 2017

Baseline laboratory testing essential to pre-HCV treatment is listed in Table 6, below.

Table 6. Baseline Laboratory Testing for Pre-Hepatitis C Virus (HCV) Treatment Assessment
Test Clinical Note
HCV RNA quantification HCV RNA test confirms active HCV infection
Genotype/subtype Genotype and subtype guide choice of regimen
Complete blood count (CBC)
  • Low platelets (<140,000 platelets/µL) suggest cirrhosis and portal hypertension [1,2]
  • Anemia may necessitate choice of a regimen that does not contain ribavirin (RBV)
Serum electrolytes with creatinine
  • Marked electrolyte abnormalities may suggest decompensated cirrhosis (e.g., hyponatremia)
  • Renal function will influence choice of regimen
Hepatic function panel
  • Elevated direct bilirubin suggests decompensated cirrhosis
  • Markedly elevated transaminases may suggest comorbidities
International normalized ratio (INR) Elevated INR suggests decompensated cirrhosis
Pregnancy test for all women of childbearing potential If pregnant, suggest treatment deferral
Hepatitis A virus (HAV) antibodies Obtain HAV antibody (IgG or total) and administer the full HAV vaccine series in patients not immune to HAV
Hepatitis B virus (HBV) antibodies Obtain HBsAg, anti-HBs, and anti-HBc (total) and recommend administration of the HBV vaccine series (0, 1, and 6 months) for HBV-susceptible patients (negative for all serologies)

  • In patients with positive HBsAg, perform HBV DNA testing to assess for active HBV infection
  • If HBV DNA is detectable, care providers new to HCV treatment should consult an experienced HCV care provider on treatment for HBV and HCV
HIV test if status is unknown

If HIV infection is confirmed, offer patient antiretroviral therapy

Urinalysis Protein may suggest extrahepatic manifestation of HCV
Fibrosis serum markers If not previously evaluated by biopsy or FibroScan
References
  1. Ebell MH. Probability of cirrhosis in patients with hepatitis C. Am Fam Physician 2003;68(9):1831-3. [PMID: 14620604]
  2. Kaul VV, Munoz SJ. Coagulopathy of liver disease. Curr Treat Options Gastroenterol 2000;3(6):433-38. [PMID: 11096602]

Pretreatment Assessment: Cardiac, Renal, HAV/HBV, Pregnancy, and Metabolic Status

Hepatitis C Virus Infection Guideline Committee, July 2017

Cardiovascular Status

RECOMMENDATION
  • For individuals with chronic hepatitis C virus (HCV) infection who are aged >50 years, clinicians should perform cardiovascular risk assessment before initiation of treatment with ribavirin (RBV). (AII)

Cardiovascular disease and congestive heart failure may be worsened by possible anemia associated with the use of RBV-containing regimens. Individuals taking RBV-containing regimens may be at risk of anemia and subsequent high-output failure, as well as decreased oxygen-carrying capacity and subsequent ischemia [1]. In patients being considered for RBV-containing regimens, it is important to assess for underlying cardiac disease and, if unstable cardiac disease is present, stabilize these patients before initiation of RBV.

Drug-drug interactions between direct-acting antiviral (DAA) medications and cardiovascular medications have been reported and may require adjustments or changes before initiation of therapy (see the Drug-Drug Interactions section of this guideline).

Renal Status

RECOMMENDATIONS
  • Clinicians should assess creatinine clearance in all patients with HCV infection. (AI)
  • Clinicians new to HCV treatment should consult an experienced HCV care provider on HCV treatment in patients with severe renal impairment (creatinine clearance <30 mL/min). (AIII)

A patient’s renal status will influence the choice of DAA regimen. Evaluation for renal disease includes assessing HCV-related causes of kidney disease such as membranoproliferative glomerulonephritis and membranous glomerulonephritis, even if patients have other comorbidities also associated with kidney disease, such as diabetes and hypertension.

HAV and/or HBV Immunity Status

RECOMMENDATIONS
  • Clinicians should obtain HAV antibody (IgG or total) and administer the full HAV vaccine series in patients who are not immune to HAV. (AIII)
  • Clinicians should obtain HBV surface antigen (HBsAg), anti-hepatitis H surface (HBs), and anti-hepatitis B core antigen (HBc), total, and recommend administration of the anti-hepatitis B virus (HBV) vaccine series (0, 1, and 6 months) for HBV-susceptible patients (negative for all serologies). (AIII)
    • In patients with positive HBsAg, clinicians should perform HBV DNA testing to assess for active HBV infection (AI)
    • If HBV DNA is detectable, clinicians new to HCV treatment should consult an experienced HCV care provider on treatment for HBV and HCV (AI)

Completion of HAV and HBV vaccination is not a pretreatment mandate and is appropriate during or after treatment for chronic HCV infection. Coinfection with HCV and either HAV or HBV may result in additional liver inflammation and pathology, and vaccination against HAV and HBV is important for patients with HCV infection to prevent acute decompensation and the sequelae of chronic superinfection by HBV [2]. Approximately 40% to 50% of patients with HCV have no documented immunity against HAV or HBV [3].

If a patient is susceptible to both HAV and HBV infection, the combined vaccination series should be initiated. The laboratory assessment and vaccination (as appropriate) for HAV and HBV should be performed as soon as possible, but completion of the vaccination series is not necessary before initiation of HCV treatment. For more information, see: Hepatitis C Online.

Vaccination of patients with a reactive anti-HBc and nonreactive HBsAg and anti-HBs (i.e., isolated anti-HBc) is controversial because results are subject to several interpretations. In patients from regions in which HBV infection is highly endemic or in patients with risk factors for acquiring HBV, a reactive anti-HBc result may represent acute or chronic active HBV or serologic clearance of anti-HBs after a prior infection. In patients who have no risk factors or who are from regions in which HBV infection rates are low, a reactive anti-HBc result may represent a false positive result. In patients with isolated anti-HBc, HBV DNA testing to assess for active HBV infection is recommended, with subsequent vaccination if results are negative.

HBV reactivation and HBV-related hepatic flares, sometimes fulminant, have been reported both during and after DAA therapy in patients who were not receiving concurrent HBV treatment [4-10]. Studies have demonstrated that HCV has a suppressive effect on HBV replication, and previous interferon-based treatments were active against both viruses [11-14]. However, unlike interferon, DAAs are not active against HBV, and when HCV is eradicated, HBV may be able to replicate. For more information about the risk of HBV reactivation, see: U.S. Food and Drug Administration (FDA) Drug Safety Warning.

KEY POINT
  • For patients with active HBV infection, treatment of both HBV and HCV should be provided in consultation with a clinician experienced in the management of both infections (HCV and HBV).

Pregnancy Status and Contraception

RECOMMENDATIONS
  • Clinicians should perform a pregnancy test in all women of childbearing potential before initiation of HCV treatment and defer HCV treatment in pregnant women. (AII)
  • Before initiating ribavirin (RBV), clinicians should (AII):
    • Confirm a negative pregnancy test
    • Advise patients to use 2 methods of birth control to avoid pregnancy during therapy and for 6 months after completion of therapy
    • Counsel female and male patients on effective contraceptive use
  • Contraindication: Clinicians should not use RBV in treatment of the following patients:
    • Female or male patients planning conception within 6 months of the last dose of RBV. (AII)
    • Male patients who have pregnant partners. (AII)
  • Contraindication: Clinicians should not use ombitasvir/paritaprevir/ritonavir/dasabuvir (PrOD) in treatment of women taking ethinyl estradiol-containing contraceptives. (AII)

The data on use of DAA therapy in pregnancy is limited, and treatment of pregnant women is currently not recommended. For women who are considering pregnancy, it is important to discuss the risks and benefits of deferring treatment until after pregnancy.

For all women and men planning conception within 6 months of treatment, use of RBV is contraindicated due to the teratogenic effects of the drug [15]. Before prescribing an RBV-containing regimen for a woman of childbearing potential, a negative pregnancy test is required immediately before initiation of therapy and 2 forms of contraception or abstinence are advised during therapy and for 6 months after. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in female patients and in female partners of male patients who are taking RBV.

The ombitasvir/paritaprevir/ritonavir/dasabuvir regimen is contraindicated in women taking ethinyl estradiol-containing medication/contraceptives [16]. Among patients taking ombitasvir/paritaprevir/ritonavir plus dasabuvir, the incidence of clinically relevant alanine transaminase (ALT) elevations was 25% (4/16) among women taking a concomitant ethinyl estradiol-containing medication compared with 3% among women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy (2/59). This result suggests that the need for use of alternative methods of contraception (progestin-only contraception or non-hormonal methods) during treatment with this regimen [16].

KEY POINTS
  • RBV is contraindicated in female and male patients planning conception within 6 months of treatment [15]
  • To use an RBV-containing regimen in women of childbearing potential or in the male sex partners of these women, extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy:
    • A negative pregnancy test is required immediately before initiation of therapy; and
    • Two forms of contraception or abstinence are advised during, and for 6 months after, therapy 

Metabolic Status

Obesity does not affect treatment of HCV with DAAs. Among individuals with HCV infection, both obesity and hepatic steatosis have been associated with progression of fibrosis and increased risk of advanced liver disease [17-20].

Chronic HCV infection appears to be associated with an increased risk of development of type 2 diabetes mellitus (DM2) in predisposed individuals [21-23]. Insulin resistance (IR) and diabetes are associated with increased liver fibrosis [24-26] cirrhosis [27], and hepatocellular carcinoma [28-31] in patients with HCV infection. Successful treatment of chronic HCV infection may be associated with improved IR, reduced incidence of DM2, and potentially decreased DM2-associated renovascular complications [32-34]. No serious drug-drug interactions have been reported with DAA agents and insulin-sensitizing or diabetic medications.

References
  1. Kaul VV, Munoz SJ. Coagulopathy of liver disease. Curr Treat Options Gastroenterol 2000;3(6):433-38. [PMID: 11096602]
  2. Lau DT, Hewlett AT. Screening for hepatitis A and B antibodies in patients with chronic liver disease. Am J Med 2005;118 Suppl 10A:28s-33s. [PMID: 16271538]
  3. Henkle E, Lu M, Rupp LB, et al. Hepatitis A and B immunity and vaccination in chronic hepatitis B and C patients in a large United States cohort. Clin Infect Dis 2015;60(4):514-22. [PMID: 25371489]
  4. Hayashi K IM, Ishizu Y1, Kuzuya T, Honda T, Nishimura D, Goto H1, Hirooka Y. A case of acute hepatitis B in a chronic hepatitis C patient after daclatasvir and asunaprevir combination therapy: hepatitis B virus reactivation or acute self-limited hepatitis? Clin J Gastroenterol 2016;Aug;9(4):252-6. [PMID: 27329484]
  5. Takayama H ST, Ikeda F, Fujiki S. Reactivation of hepatitis B virus during interferon-free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus co-infection. Hepatol Res 2016 Mar 46(5):489-91. [PMID: 26297529]
  6. Ende AR KN, Yeh MM, Harper J, Landis CS. Fulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report. J Med Case Rep 2015 Jul 28:164. [PMID: 26215390]
  7. Collins JM RK, Terry C, Cartwright EJ, Pillai A, Anania FA, Farley MM. Hepatitis B Virus Reactivation During Successful Treatment of Hepatitis C Virus With Sofosbuvir and Simeprevir. Clin Infect Dis 2015 Oct 15;61(8):1304-6. [PMID: 26082511]
  8. De Monte A CJ, Anty R, Cua E, Naqvi A, Mondain V, Cottalorda J, Ollier L, Giordanengo V. Direct-acting antiviral treatment in adults infected with hepatitis C virus: Reactivation of hepatitis B virus coinfection as a further challenge. J Clin Virol 2016;May;78:27-30. [PMID: 26967675]
  9. Sulkowski MS CW, Kao JH3, Yang JC, Gao 4, Brainard DM, Han KH5, Gane E. No Evidence of Reactivation of Hepatitis B Virus Among Patients Treated With Ledipasvir-Sofosbuvir for Hepatitis C Virus Infection. Clin Infect Dis 2016 Nov 1;63(9):1202-04. [PMID: 27486112]
  10. Wang C JD, Chen J, Shao Q, Li B, Liu J, Wu V, Wong A, Wang Y, Zhang X, Lu L, Wong C, Tsang S, Zhang Z, Sun J, Hou J, Chen G, Lau G. Hepatitis due to Reactivation of Hepatitis B Virus in Endemic Areas Among Patients With Hepatitis C Treated With Direct-acting Antiviral Agents. Clin Gastroenterol Hepatol 2017 Jan;15(1):132-36. [PMID: 27392759]
  11. Chen S KC, Chen CM, Shih CM, Hsu MJ, Chao CH, Wang SH, You LR, Lee YH. Mechanisms for inhibition of hepatitis B virus gene expression and replication by hepatitis C virus core protein. J Biol Chem 2003;Jan 3;278(1):591-607. [PMID: 12401801]
  12. Chu CM YC, Liaw YF. Low-level viremia and intracellular expression of hepatitis B surface antigen (HBsAg) in HBsAg carriers with concurrent hepatitis C virus infection. J Clin Microbiol 1998 Jul;36((7):):2084-6. [PMID: 9650968]
  13. Liu Z HJ. Hepatitis B virus (HBV) and hepatitis C virus (HCV) dual infection. Int J Med Sci 2006;3(2):57-62. [PMID: 16614744]
  14. Shih CM LS, Miyamura T, Chen SY, Lee YH. Suppression of hepatitis B virus expression and replication by hepatitis C virus core protein in HuH-7 cells. J Virol 1993 Oct;67(10):5823-32. [PMID: 8396658]
  15. FDA. Copegus (ribavirin) tablets. 2015 [accessed March 7, 2017]. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm218877.htm
  16. FDA. (Dasabuvir, ombitasvir, paritaprevir, and ritonavir tablets), Copackaged for Oral Use. 2016 [accessed March 7, 2017]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208624s001s003lbl.pdf
  17. Charlton MR, Pockros PJ, Harrison SA. Impact of obesity on treatment of chronic hepatitis C. Hepatology 2006;43(6):1177-86. [PMID: 16729327]
  18. Bressler BL, Guindi M, Tomlinson G, et al. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 2003;38(3):639-44. [PMID: 12939590]
  19. Dyal HK, Aguilar M, Bhuket T, et al. Concurrent obesity, diabetes, and steatosis increase risk of advanced fibrosis among HCV patients: a systematic review. Dig Dis Sci 2015;60(9):2813-24. [PMID: 26138651]
  20. Goossens N, Negro F. The impact of obesity and metabolic syndrome on chronic hepatitis C. Clin Liver Dis 2014;18(1):147-56. [PMID: 24274870]
  21. Mehta SH, Brancati FL, Sulkowski MS, et al. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000;133(8):592-9. [PMID: 11033586]
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  24. Patel K, Thompson AJ, Chuang WL, et al. Insulin resistance is independently associated with significant hepatic fibrosis in Asian chronic hepatitis C genotype 2 or 3 patients. J Gastroenterol Hepatol 2011;26(7):1182-8. [PMID: 21410752]
  25. Moucari R, Asselah T, Cazals-Hatem D, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology 2008;134(2):416-23. [PMID: 18164296]
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  27. Gordon SC, Lamerato LE, Rupp LB, et al. Prevalence of cirrhosis in hepatitis C patients in the Chronic Hepatitis Cohort Study (CHeCS): a retrospective and prospective observational study. Am J Gastroenterol 2015;110(8):1169-77; quiz 78. [PMID: 26215529]
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  34. Thompson AJ, Patel K, Chuang WL, et al. Viral clearance is associated with improved insulin resistance in genotype 1 chronic hepatitis C but not genotype 2/3. Gut 2012;61(1):128-34. [PMID: 21873466]

Treatment Options

Hepatitis C Virus Infection Guideline Committee, July 2017

The treatment of chronic hepatitis C virus (HCV) infection has evolved significantly in recent years following advances in the understanding of the HCV genome and HCV proteins [1]. As a result, new, highly effective therapies are available for patients who are treatment-naive and -experienced, who do and do not have cirrhosis, and who have any HCV genotype (see Box 2, below). Before the availability of these new therapies, many patients and practitioners had been reluctant to initiate therapy for chronic HCV infection due to suboptimal sustained virologic response (SVR) rates and significant rates of adverse events. These concerns are no longer applicable with direct-acting antivirals (DAAs).

DAAs are molecules that work at different stages of the HCV lifecycle, targeting and inhibiting specific nonstructural proteins of HCV to disrupt viral replication and infection [1]. The four classes of DAAs are defined by their mechanism of action and therapeutic target.

Box 2. Direct-Acting Antiviral (DAA) Drugs for Treatment of HCV
  • Protease inhibitors [-previrs]:  grazoprevir, paritaprevir, simeprevir, telaprevir*, boceprevir*
  • NS5a inhibitors [-asvirs]: daclatasvir, elbasvir, ledipasvir, ombitasvir, velpatasvir
  • NS5B nucleoside polymerase inhibitors [-buvirs]: sofosbuvir
  • NS5V non-nucleoside polymerase inhibitors [-buvirs]: dasabuvir

*No longer available in the United States

Goals of Treatment and DAA Regimen Choice

The goal of treatment in patients with chronic HCV infection is to attain a virologic cure, as evidenced by an SVR, in order to reduce all-cause mortality and liver-related complications, including end-stage liver disease, hepatocellular carcinoma (HCC), and the morbidity and mortality associated with the extrahepatic manifestation of chronic HCV infection. With the significant advances in treatment, all patients with chronic HCV infection, regardless of fibrosis stage, are considered candidates for antiviral therapy [2-4].

This section of the guideline includes recommendations for treating patients with chronic HCV infection, with consideration of individual characteristics, such as viral genotype, presence of cirrhosis, and previous treatment history. There are several options for treatment in each category, and no single regimen in any given category is prioritized or recommended over another. Regimens are listed alphabetically. The choice of treatment is based on specific individual patient factors, such as concomitant medical conditions, potential drug-drug interactions, and cost/coverage.

KEY POINTS
  • Clinicians can increase their patients’ ability to understand treatment-related information and to participate in decision-making if they communicate with language that is clear, easily understood, jargon-free, and culturally sensitive.
  • Patient preferences are central to all treatment decisions.
References
  1. Pockros PJ. Direct-acting antivirals for the treatment of hepatitis C virus infection. UpToDate. [accessed June 30, 2017]. https://www.uptodate.com/contents/direct-acting-antivirals-for-the-treatment-of-hepatitis-c-virus-infection
  2. Simmons B, Saleem J, Heath K, et al. Long-term treatment outcomes of patients infected with hepatitis C virus: a systematic review and meta-analysis of the survival benefit of achieving a sustained virological response. Clin Infect Dis 2015;61(5):730-40. [PMID: 25987643]
  3. Smith-Palmer J, Cerri K, Valentine W. Achieving sustained virologic response in hepatitis C: a systematic review of the clinical, economic and quality of life benefits. BMC Infect Dis2015;15:19. [PMID: 25596623]
  4. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. Jama 2012;308(24):2584-93. [PMID: 23268517]

Treatment Options: Considerations

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATIONS
  • Clinicians should assess creatinine clearance before initiating antiviral therapy. (AI)
  • Clinicians new to hepatitis C virus (HCV) treatment should consult an experienced HCV care provider when treating patients who:
    • Have severe renal impairment (creatinine clearance <30 mL/min). (AIII)
    • Have failed prior treatment with direct-acting antivirals (DAAs). (AIII)
  • Clinicians should prescribe ribavirin (RBV) with caution for patients with a creatinine clearance <50 mL/min. (AI)
    • If prescribed, a reduced dose of 200 mg per day is required.
    • Non-RBV-containing regimens can be prescribed without dose adjustments for patients with a creatinine clearance ≥30 mL/min.
  • Contraindication: Clinicians should not use RBV in treatment of the following patients:
    • Female or male patients planning conception within 6 months of the last dose of RBV. (AII)
    • Male patients who have pregnant partners. (AII)
  • Contraindication: Clinicians should not use ombitasvir/paritaprevir/ritonavir/dasabuvir (PrOD) in treatment of women who are taking ethinyl estradiol-containing contraceptives. (AII)

Selection of a treatment regimen for patients with chronic HCV infection is based on viral genotype, the presence of cirrhosis, treatment history (treatment-naive vs -experienced), the potential for drug-drug interactions, and other specific considerations, noted previously, such as the presence of cardiac disease, renal function, and choice of contraception.

The most suitable regimen for any individual patient depends on the patient’s preference and the clinician’s assessment of comorbidities, such as chronic kidney disease, potential drug-drug interactions with the patient’s current prescription and over-the-counter medications (see the Drug-Drug Interactions section of this guideline); medication tolerability and adverse event profile; and duration of treatment. Sex, age, viral load levels, substance use disorders, mental health disorders, pill burden, and HIV coinfection are not considerations in selecting HCV treatment regimens.

KEY POINT
  • Cardiac disease and other comorbidities may affect a patient’s ability to tolerate RBV-induced anemia and should be considered before initiating an RBV-containing regimen.

Renal Impairment

For patients with a creatinine clearance <50 mL/min, RBV should be used with caution; if used, a reduced dose of 200 mg per day is recommended [1]. Limited evidence is available to support the use of daclatasvir, fixed-dose combination ledipasvir/sofosbuvir, simeprevir, and sofosbuvir in treating patients with HCV infection and severe renal impairment (creatinine clearance <30 mL/min). Fixed-dose combination paritaprevir/ritonavir/ombitasvir without ribavirin does not require dose adjustment in severe renal impairment, but data on treatment of patients receiving hemodialysis are limited. The combination elbasvir/grazoprevir requires no dose adjustment for renal impairment even when used in patients receiving hemodialysis [2,3].

Resistance Testing

At present, testing for resistance-associated variants (RAV) is not universally recommended. RAVs are also referred to as resistance analysis populations (RAP) and resistance-associated substitutions (RAS). However, this committee recommends that clinicians test for the presence of NS5A RAVs before starting therapy with elbasvir/grazoprevir in all patients with HCV genotype 1a infection (see the Recommended DAA Regimens section of this guideline) [4]. The presence of one or more HCV NS5A RAVs at position M28, Q30, L31 or Y93 was associated with a reduced efficacy of elbasvir/grazoprevir given for 12 weeks, regardless of prior treatment history or the presence or absence of cirrhosis [5]. Sixteen weeks of elbasvir/grazoprevir plus weight-based RBV was associated with an SVR rate of 100% in genotype 1a patients with NS5A RAVs [5]. RAV testing is also performed in persons in whom DAA regimens containing an NS5A or NS5B inhibitor have failed and are being considered for retreatment.

Pregnancy and Contraception

For all women and men planning conception within 6 months of treatment, use of RBV is contraindicated due to the teratogenic effects of the drug [1]. Before prescribing an RBV-containing regimen for a woman of childbearing potential, a negative pregnancy test is required immediately before initiation of therapy and 2 forms of contraception or abstinence are advised during therapy and for 6 months after. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in female patients and in female partners of male patients who are taking RBV.

The ombitasvir/paritaprevir/ritonavir/dasabuvir regimen is contraindicated in women taking ethinyl estradiol-containing medication/contraceptives [6]. Among patients taking ombitasvir/paritaprevir/ritonavir plus dasabuvir, the incidence of clinically relevant alanine aminotransferase (ALT) elevations was 25% (4/16) among women taking a concomitant ethinyl estradiol-containing medication compared with 3% among women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy (2/59). This result suggests that alternative methods of contraception (progestin-only contraception or non-hormonal methods) are needed during treatment with this regimen [6].

DAA Treatment Failure

There are limited data on the retreatment of persons in whom DAA regimens have failed, and retreatment recommendations have not yet been formulated for these individuals.

References
  1. FDA. Copegus (ribavirin) tablets. 2015 [accessed March 7, 2017]. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm218877.htm
  2. Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet 2015;386(10003):1537-45. [PMID: 26456905]
  3. American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA). HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. August 24, 2016 [accessed 2017 Apr 26]. http://www.hcvguidelines.org
  4. Zeuzem S, Mizokami M, Pianko S, et al. NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome. J Hepatol 2017;66(5):910-18. [PMID: 28108232]
  5. FDA. (Elbasvir and grazoprevir) tablets, for oral use. [accessed March 7, 2017]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208261Orig1s000lbl.pdf
  6. FDA. (Dasabuvir, ombitasvir, paritaprevir, and ritonavir tablets), Copackaged for Oral Use. 2016 [accessed March 7, 2017]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208624s001s003lbl.pdf

Recommended DAA Regimens

Hepatitis C Virus Infection Guideline Committee, July 2017

All regimens listed in this guideline were available as of July 1, 2017

These recommendations on treatment of chronic HCV were developed by the New York State (NYS) Department of Health (DOH) Hepatitis C Virus Infection Guideline Committee to guide primary care providers and other clinicians in NYS in treating patients with chronic HCV infection.

KEY POINTS: CHOOSING AN ANTI-HCV TREATMENT REGIMEN
  • Treatment regimen recommendations are organized according to HCV genotype and subtype, the presence or absence of compensated cirrhosis, and HCV treatment history.
  • The recommended regimens within each list are in alphabetical order, not in order of preference.
  • No single regimen is recommended over another within each list of options; data on direct comparisons of treatment regimens have not been published.
  • The choice of regimen should be based on individual pretreatment assessment findings, the general considerations detailed above, and insurance coverage.
  • The regimens recommended for retreatment are for patients who have been treated previously with pegylated interferon (PEG-IFN) plus ribavirin (RBV).

Recommended oral direct-acting antiviral drugs and drug regimens are listed in Table 7, below. All regimens listed in drug regimen tables for all HCV genotypes refer to oral medications.

Table 7. Recommended Oral Direct-Acting Antiviral Drugs and Drug Regimens
Drug/Combination Tradename
Daclatasvir Daklinza
Elbasvir/grazoprevir* Zepatier
Ledipasvir/sofosbuvir* Harvoni
Ombitasvir/paritaprevir/ritonavir/dasabuvir* (PROD) Viekira XR
Simeprevir Olysio
Sofosbuvir Sovaldi
Sofosbuvir/velpatasvir* Epclusa
*These drugs are co-formulated (indicated by the “/”)

 

Recommended DAA Regimens: Genotype 1a

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATIONS
  • Based on the results of the pretreatment assessment, clinicians should choose from among the treatment regimens for patients with hepatitis C virus (HCV) genotype 1a listed in tables 8 through 11, below.
  • Clinicians should test for the presence of NS5A resistance-associated variants (RAVs) before starting therapy with elbasvir/grazoprevir in all patients with HCV genotype 1a infection. (AIII)
  • If a regimen with weight-based ribavirin (RBV) is chosen, clinicians should dose as follows: (AI)
    • <75 kg: RBV 400 mg once daily + 600 mg once daily (total daily dose: 1000 mg)
    • ≥75 kg: RBV 600 mg twice daily (total daily dose: 1200 mg)

The regimens listed in tables 8 through 11, below, are recommended for patients with HCV genotype 1a. All drugs in the recommended regimens below are oral medications. Multiple factors influence the choice of regimen, including, but not limited to, the patient’s treatment status (naive or previous HCV treatment failure), the presence of cirrhosis, preferences, and all previously noted considerations.

Drug names: Use of a “/” between two drug names indicates a co-formulated tablet. Use of the word “plus” indicates two separate drugs.

Rating of regimens: All regimen choices listed below are rated AI (strong recommendation, with high quality evidence from at least 1 randomized trial with clinical outcomes and/or validated laboratory endpoints). 

Table 8.  Genotype 1a • Treatment-naive • No cirrhosis

Choose 1 of the following regimens: (AI)

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily [1]

12 weeks

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [2]

12 weeks

Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/dasabuvir 600 mg once daily plus weight-based ribavirin twice daily [3,4]

12 weeks

Sofosbuvir 400 mg plus simeprevir 150 mg once daily [5]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [6]

12 weeks

Without baseline NS5A polymorphisms: Elbasvir 50 mg/grazoprevir 100 mg once daily [7-9]

12 weeks

With baseline NS5A polymorphisms: Elbasvir 50 mg/grazoprevir 100 mg once daily plus weight-based ribavirin twice daily [10,11]

16 weeks

 

Table 9. Genotype 1a • Treatment-naive • Compensated cirrhosis

Choose 1 of the following regimens (AI):

Duration

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [2,12]

12 weeks

Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/dasabuvir 600 mg once daily plus weight-based ribavirin twice daily [13]

24 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [6]

12 weeks

Without baseline NS5A polymorphisms: Elbasvir 50 mg/grazoprevir 100 mg once daily [7,8]

12 weeks

With baseline NS5A polymorphisms: Elbasvir 50 mg/grazoprevir 100 mg once daily plus weight-based ribavirin twice daily [10,11]

16 weeks

Sofosbuvir 400 mg plus simeprevir 150 mg once daily, with or without weight-based ribavirin twice daily [5,14]

24 weeks

 

Table 10. Genotype 1a • Prior failure with PEG-IFN plus RBV* • No cirrhosis 

Choose 1 of the following regimens for retreatment (AI):

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily [1]

12 weeks

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [16]

12 weeks

Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/dasabuvir 600 mg once daily plus weight-based ribavirin twice daily [17]

12 weeks

Sofosbuvir 400 mg plus simeprevir 150 mg once daily [14,18]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [6]

12 weeks

Without baseline NS5A polymorphisms: Elbasvir 50 mg/grazoprevir 100 mg once daily [15]

12 weeks

With baseline NS5A polymorphisms: Elbasvir 50 mg/grazoprevir 100 mg once daily plus weight-based ribavirin twice daily [19]

16 weeks

*Pegylated interferon plus ribavirin.

 

Table 11. Genotype 1a • Prior failure with PEG-IFN plus RBV* • Compensated cirrhosis

Choose 1 of the following regimens for retreatment (AI):

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily [20]

12 weeks

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [21,22]

24 weeks

Ledipasvir 90 mg/sofosbuvir 400 mg once daily plus weight-based ribavirin twice daily [21,22]

12 weeks

Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/dasabuvir 600 mg once daily plus weight-based ribavirin twice daily [11]

24 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [6]

12 weeks

Without baseline NS5A polymorphisms: Elbasvir 50 mg/grazoprevir 100 mg once daily [8]

12 weeks

With baseline NS5A polymorphisms: Elbasvir 50 mg/grazoprevir 100 mg once daily plus weight-based ribavirin twice daily [12,13]

16 weeks

Sofosbuvir 400 mg plus simeprevir 150 mg once daily, with or without weight-based ribavirin twice daily [14,23]

24 weeks

*Pegylated interferon plus ribavirin.

References
  1. Sulkowski MS, Jacobson IM, Nelson DR. Daclatasvir plus sofosbuvir for HCV infection. N Engl J Med 2014;370(16):1560-1. [PMID: 24738674]
  2. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014;370(20):1879-88. [PMID: 24720702]
  3. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014;370(21):1983-92. [PMID: 24795200]
  4. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014;370(17):1594-603. [PMID: 24720703]
  5. Childs-Kean LM, Hand, E. O. Simeprevir and sofosbuvir for treatment of chronic hepatitis C infection. Clin Ther 2015;37(2):243-67. [PMID: 25601269]
  6. Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015;373(27):2599-607. [PMID: 26571066]
  7. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med 2015;163(1):1-13. [PMID: 25909356]
  8. Lawitz E, Gane E, Pearlman B, et al. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet 2015b;385(9973):1075-86. [PMID: 25467591]
  9. Sulkowski M, Hezode C, Gerstoft J, et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. Lancet 2015;385(9973):1087-97. [PMID: 25467560]
  10. Reddy KR, Bourliere M, Sulkowski M, et al. Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: An integrated safety and efficacy analysis. Hepatology 2015;62(1):79-86. [PMID: 25846144]
  11. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014;370(21):1973-82. [PMID: 24725237]
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  14. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014b;384(9956):1756-65. [PMID: 25078309]
  15. Forns X, Gordon SC, Zuckerman E, et al. Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent. J Hepatol 2015;63(3):564-72. [PMID: 25895428]
  16. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370(16):1483-93. [PMID: 24725238]
  17. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014;370(17):1604-14. [PMID: 24720679]
  18. Kwo P, Gitlin N, Nahass R, et al. Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study. Hepatology 2016;64(2):370-80. [PMID: 26799692]
  19. Buti M, Gordon SC, Zuckerman E, et al. Grazoprevir, Elbasvir, and Ribavirin for Chronic Hepatitis C Virus Genotype 1 Infection After Failure of Pegylated Interferon and Ribavirin With an Earlier-Generation Protease Inhibitor: Final 24-Week Results From C-SALVAGE. Clin Infect Dis 2016;62(1):32-6. [PMID: 26371152]
  20. Poordad F, Schiff ER, Vierling JM, et al. Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology 2016;63(5):1493-505. [PMID: 26754432]
  21. Bourliere M, Bronowicki JP, de Ledinghen V, et al. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis 2015;15(4):397-404. [PMID: 25773757]
  22. Bourliere M SM, Omata M et al. An integrated safety and efficacy analysis of >500 patients with compensated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin. [Abstract 82.] 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) November 7-11, 2014; Boston, MA.
  23. Lawitz E, Matusow G, DeJesus E, et al. Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: A phase 3 study (OPTIMIST-2). Hepatology 2016;64(2):360-9. [PMID: 26704148]

Recommended DAA Regimens: Genotype 1b

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATIONS
  • Based on the results of the pretreatment assessment, clinicians should choose from among the treatment regimens for patients with hepatitis C virus (HCV) genotype 1b listed in tables 12 through 15, below.
  • If a regimen with weight-based ribavirin (RBV) is chosen, clinicians should dose as follows: (AI)
    • <75 kg: RBV 400 mg once daily + 600 mg once daily (total daily dose: 1000 mg)
    • ≥75 kg: RBV 600 mg twice daily (total daily dose: 1200 mg)

The regimens listed in tables 12 through 15, are recommended for patients with HCV genotype 1b. All drugs in the recommended regimens below are oral medications. Multiple factors influence the choice of regimen, including, but not limited to, the patient’s treatment status (naive or previous HCV treatment failure), the presence of cirrhosis, preferences, and all previously noted considerations.

Drug names: Use of a “/” between two drug names indicates a co-formulated tablet. Use of the word “plus” indicates two separate drugs.

Rating of regimens: All regimen choices listed below are rated AI (strong recommendation, with high quality evidence from at least 1 randomized trial with clinical outcomes and/or validated laboratory endpoints). 

Table 12. Genotype 1b • Treatment-naive • No cirrhosis

Choose 1 of the following regimens (AI):

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily [1]  

12 weeks

Elbasvir 50 mg/grazoprevir 100 mg once daily [2-4]

12 weeks

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [5]

12 weeks

Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/dasabuvir 600 mg once daily [6,7]

12 weeks

Sofosbuvir 400 mg plus simeprevir 150 mg once daily [8,9]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [10]

12 weeks

Table 13. Genotype 1b • Treatment-naive • Compensated cirrhosis

Choose 1 of the following regimens (AI):

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily, with or without weight-based ribavirin twice daily [11]

24 weeks

Elbasvir 50 mg/grazoprevir 100 mg once daily [2,3]

12 weeks

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [12-14]

12 weeks

Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/dasabuvir 600 mg once daily [6]

12 weeks

Sofosbuvir 400 mg plus simeprevir 150 mg once daily, with or without weight-based ribavirin twice daily [8,9,15,16]

24 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [10]

12 weeks

Table 14. Genotype 1b • Prior failure with PEG-IFN plus RBV • No cirrhosis

Choose 1 of the following regimens for retreatment (AI):

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily [4]

12 weeks

Elbasvir 50 mg/grazoprevir 100 mg once daily [3]

12 weeks

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [13,17]

12 weeks

Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/dasabuvir 600 mg once daily [18]

12 weeks

Sofosbuvir 400 mg plus simeprevir 150 mg once daily [9,16]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [10]

12 weeks

Table 15. Genotype 1b • Prior failure with PEG-IFN plus RBV* • Compensated cirrhosis

Choose 1 of the following regimens for retreatment (AI):

Duration

Elbasvir 50 mg/grazoprevir 100 mg once daily [3]

12 weeks

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [19,20]

24 weeks

Ledipasvir 90 mg/sofosbuvir 400 mg once daily plus weight-based ribavirin twice daily [19,20]

12 weeks

Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/dasabuvir 600 mg once daily [21]

12 weeks

Sofosbuvir 400 mg plus simeprevir 150 mg once daily, with or without weight-based ribavirin twice daily [15,16]

24 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [10]

12 weeks

*Pegylated interferon plus ribavirin.

References
  1. Sulkowski MS, Jacobson IM, Nelson DR. Daclatasvir plus sofosbuvir for HCV infection. N Engl J Med 2014;370(16):1560-1. [PMID: 24738674]
  2. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med 2015;163(1):1-13. [PMID: 25909356]
  3. Lawitz E, Gane E, Pearlman B, et al. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet 2015b;385(9973):1075-86. [PMID: 25467591]
  4. Sulkowski M, Hezode C, Gerstoft J, et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. Lancet 2015;385(9973):1087-97. [PMID: 25467560]
  5. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014;370(20):1879-88. [PMID: 24720702]
  6. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014;370(17):1594-603. [PMID: 24720703]
  7. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014;370(21):1983-92. [PMID: 24795200]
  8. Childs-Kean LM, Hand, E. O. Simeprevir and sofosbuvir for treatment of chronic hepatitis C infection. Clin Ther 2015;37(2):243-67. [PMID: 25601269]
  9. Kwo P, Gitlin N, Nahass R, et al. Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study. Hepatology 2016;64(2):370-80. [PMID: 26799692]
  10. Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015;373(27):2599-607. [PMID: 26571066]
  11. Poordad F, Schiff ER, Vierling JM, et al. Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology 2016;63(5):1493-505. [PMID: 26754432]
  12. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370(20):1889-98. [PMID: 24725239]
  13. Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet 2014a;383(9916):515-23. [PMID: 24209977]
  14. Reddy KR, Bourliere M, Sulkowski M, et al. Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: An integrated safety and efficacy analysis. Hepatology 2015;62(1):79-86. [PMID: 25846144]
  15. Lawitz E, Matusow G, DeJesus E, et al. Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: A phase 3 study (OPTIMIST-2). Hepatology 2016;64(2):360-9. [PMID: 26704148]
  16. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014b;384(9956):1756-65. [PMID: 25078309]
  17. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370(16):1483-93. [PMID: 24725238]
  18. Andreone P, Colombo MG, Enejosa JV, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. Gastroenterology 2014;147(2):359-65.e1. [PMID: 24818763]
  19. Bourliere M, Bronowicki JP, de Ledinghen V, et al. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis 2015;15(4):397-404. [PMID: 25773757]
  20. Bourliere M SM, Omata M et al. An integrated safety and efficacy analysis of >500 patients with compensated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin. [Abstract 82.] 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2014 Nov 7-11; Boston, MA.
  21. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014;370(21):1973-82. [PMID: 24725237]

Recommended DAA Regimens: Genotype 2

Hepatitis C Virus Infection Guideline Committee, July 2017

Recommendation
  • Based on the results of the pretreatment assessment, clinicians should choose from among the treatment regimens for patients with hepatitis C virus (HCV) genotype 2 listed in tables 16 through 18, below.

The regimens listed tables 16 through 18, below, are recommended for patients with HCV genotype 2. All drugs in the recommended regimens below are oral medications. Factors that determine choice of regimen include the patient’s treatment status (naive or previous HCV treatment failure), the presence of cirrhosis, preferences, and all previously noted considerations.

Drug names: Use of a “/” between two drug names indicates a co-formulated tablet. Use of the word “plus” indicates two separate drugs.

Note: The daclatasvir plus sofosbuvir regimen is not approved by the U.S. Food and Drug Administration for treatment of patients with genotype 2 HCV infection as of March 31, 2017; however, published evidence [1] supports use of this combination, and it is commonly prescribed.

Table 16. Genotype 2 • Treatment-naive • No cirrhosis

Choose 1 of the following regimens (AI):

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily [1]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [2]

12 weeks

 

Table 17. Genotype 2 • Treatment-naive • Compensated cirrhosis

Choose 1 of the following regimens (AI):

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily [1]

16 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [2]

12 weeks

 

Table 18. Genotype 2 • Prior failure with PEG-IFN plus RBV* • No cirrhosis • Compensated cirrhosis

Choose 1 of the following regimens for retreatment (AI):

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily [1]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [2]

12 weeks

*Pegylated interferon plus ribavirin.

 References

  1. Wyles DL, Ruane PJ, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015;373(8):714-25. [PMID: 26196502]
  2. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med 2015;373(27):2608-17. [PMID: 26575258]

Recommended DAA Regimens: Genotype 3

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATIONS
  • Based on the results of the pretreatment assessment, clinicians should choose from among the treatment regimens for patients with hepatitis C virus (HCV) genotype 3 listed in tables 19 through 22, below.
  • If a regimen with weight-based ribavirin (RBV) is chosen, clinicians should dose as follows: (A1)
    • <75 kg: RBV 400 mg once daily + 600 mg once daily (total daily dose: 1000 mg)
    • ≥75 kg: RBV 600 mg twice daily (total daily dose: 1200 mg)

The regimens listed in tables 19 through 22, below, are recommended for patients with HCV genotype 3. All drugs in the recommended regimens below are oral medications. Factors that determine choice of regimen include the patient’s treatment status (naive or previous HCV treatment failure), the presence of cirrhosis, preferences, and all previously noted considerations.

Drug names: Use of a “/” between two drug names indicates a co-formulated tablet. Use of the word “plus” indicates two separate drugs.

Sustained virologic response (SVR) rate: SVR rates are listed from studies of patients with HCV genotype 3 (reference numbers are cited in each table). These data have been included only for genotype 3 because, to date, achievement of an SVR in these patients, especially those with cirrhosis, has proven to be more difficult than it is in patients with other HCV genotypes.

Table 19.  Genotype 3 • Treatment-naive • No cirrhosis

Choose 1 of the following regimens (AI):

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily (SVR 97%) [1]

12 weeks

Sofosbuvir 400/velpatasvir 100 mg once daily (SVR 98%) [2]

12 weeks

 

Table 20. Genotype 3 • Treatment-naive • Compensated cirrhosis

Choose 1 of the following regimens (AI):

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily (SVR 86%) [1]

24 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily (SVR 93%) [2]

12 weeks

 

Table 21. Genotype 3 • Prior failure with Peg-IFN plus RBV* • No cirrhosis

Choose 1 of the following regimens for retreatment (AI):

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily (SVR 92%) [1]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily (SVR 91%) [2]

12 weeks

*Pegylated interferon plus ribavirin.

 

Table 22. Genotype 3 • Prior failure with PEG-IFN plus RBV* • Compensated cirrhosis

Choose 1 of the following regimens for retreatment (AI):

Duration

Daclatasvir 60 mg plus sofosbuvir 400 mg once daily plus weight-based ribavirin twice daily (SVR 92%)[3,4]

24 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily (SVR 89%) [1]

12 weeks

*Pegylated interferon plus ribavirin.

References
  1. Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 2015;61(4):1127-35. [PMID: 25614962]
  2. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med 2015;373(27):2608-17. [PMID: 26575258]
  3. Leroy V, Angus P, Bronowicki JP, et al. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+). Hepatology 2016;63(5):1430-41. [PMID: 26822022]
  4. Welzel TM PJ, Herzer K,  Ferenci P, et al. Daclatasvir plus sofosbuvir, with or without ribavirin, achieved high sustained virological response rates in patients with HCV infection and advanced liver disease in a real-world cohort. Gut 2012; 65(11):1861–70. [PMID: 27605539]

Recommended DAA Regimens: Genotype 4

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATIONS
  • Based on the results of the pretreatment assessment, clinicians should choose from among the treatment regimens for patients with hepatitis C virus (HCV) genotype 4 listed in tables 23 and 24, below.
  • If a regimen with weight-based ribavirin (RBV) is chosen, clinicians should dose as follows: (AI)
    • <75 kg: RBV 400 mg once daily + 600 mg once daily (total daily dose: 1000 mg)
    • ≥75 kg: RBV 600 mg twice daily (total daily dose: 1200 mg)

The regimens listed in tables 23 and 24, below, are recommended for patients with HCV genotype 4. All drugs in the recommended regimens below are oral medications. Factors that determine choice of regimen include the patient’s treatment status (naive or previous HCV treatment failure), preferences, and all limitations noted in Considerations in Treatment of HCV Infection, above.

Drug names: Use of a “/” between two drug names indicates a co-formulated tablet. Use of the word “plus” indicates two separate drugs.

Table 23. Genotype 4 • Treatment-naive • No cirrhosis • Compensated cirrhosis

Choose 1 of the following regimens (AI):

Duration

Elbasvir 50 mg/grazoprevir 100 mg once daily [1]

12 weeks

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [2,3]

12 weeks

Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg once daily plus weight-based ribavirin twice daily [4]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [5]

12 weeks

 

Table 24. Genotype 4 • Prior failure with Peg-IFN plus RBV* • No cirrhosis • Compensated cirrhosis

Choose 1 of the following regimens for retreatment (AI):

Duration

Elbasvir 50 mg/grazoprevir 100 mg once daily plus weight-based ribavirin twice daily* [1,6]

16 weeks

Ledipasvir 90 mg/sofosbuvir 400 mg once daily  [2]

12 weeks

Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg once daily plus weight-based ribavirin twice daily [4]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [5]

12 weeks

*Pegylated interferon plus ribavirin.

References

  1. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med 2015;163(1):1-13. [PMID: 25909356]
  2. Kohli A, Kapoor R, Sims Z, et al. Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study. Lancet Infect Dis 2015;15(9):1049-54. [PMID: 26187031]
  3. Abergel A, Asselah T, Metivier S, et al. Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study. Lancet Infect Dis 2016;16(4):459-64. [PMID: 26803446]
  4. Hezode C, Asselah T, Reddy KR, et al. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet 2015;385(9986):2502-9. [PMID: 25837829]
  5. Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015;373(27):2599-607. [PMID: 26571066]
  6. FDA. (Elbasvir and grazoprevir) tablets, for oral use. [accessed March 7, 2017]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208261Orig1s000lbl.pdf

Recommended DAA Regimens: Genotype 5

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATION
  • Based on the results of the pretreatment assessment, clinicians should choose from among the treatment regimens for patients with hepatitis C virus (HCV) genotype 5 listed in tables 25 and 26, below.

The regimens listed in tables 25 and 26, below, are recommended for patients with HCV genotype 5. All drugs in the recommended regimens below are oral medications. Factors that determine the choice of regimen include the patient’s treatment status (naive or previous HCV treatment failure) and preferences.

Drug names: Use of a “/” between two drug names indicates a co-formulated tablet. Use of the word “plus” indicates two separate drugs.

All drugs in the recommended regimens below are oral medications.

Table 25. Genotype 5 • Treatment-naive  • No cirrhosis • Compensated cirrhosis

Choose 1 of the following regimens (AI):

Duration

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [1]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [2]

12 weeks

 

Table 26. Genotype 5 • Prior failure with PEG-IFN plus RBV* • No cirrhosis • Compensated cirrhosis

Choose 1 of the following regimens for retreatment (AI):

Duration

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [1]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [2]

12 weeks

*Pegylated interferon plus ribavirin.

References
  1. Abergel A, Asselah T, Metivier S, et al. Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study. Lancet Infect Dis 2016;16(4):459-64. [PMID: 26803446]
  2. Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015;373(27):2599-607. [PMID: 26571066]

Recommended DAA Regimens: Genotype 6

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATION
  • Based on the results of the pretreatment assessment, clinicians should choose from among the treatment regimens for patients with hepatitis C virus (HCV) genotype 6 listed in tables 27 and 28, below.

The regimens listed in tables 27 and 28, below, are recommended for patients with HCV genotype 6. All drugs in the recommended regimens below are oral medications. Factors that determine the choice of regimen include the patient’s treatment status (naive or previous HCV treatment failure) and preferences.

Drug names: Use of a “/” between two drug names indicates a co-formulated tablet. Use of the word “plus” indicates two separate drugs.

All drugs in the recommended regimens below are oral medications.

Table 27. Genotype 6 • Treatment-naive  • No cirrhosis/Compensated cirrhosis

Choose 1 of the following regimens (AI):

Duration

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [1]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [2]

12 weeks

 

Table 28. Genotype 6 • Prior failure with PEG-IFN plus RBV* • No cirrhosis/Compensated cirrhosis

Choose 1 of the following regimens for retreatment (AI):

Duration

Ledipasvir 90 mg/sofosbuvir 400 mg once daily [1]

12 weeks

Sofosbuvir 400 mg/velpatasvir 100 mg once daily [2]

12 weeks

*Pegylated interferon plus ribavirin.

 

References
  1. Gane EJ, Hyland RH, An D, et al. Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection. Gastroenterology 2015;149(6):1454-61.e1. [PMID: 26261007]
  2. Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015;373(27):2599-607. [PMID: 26571066]

Monitoring During DAA Treatment

Hepatitis C Virus Infection Guideline Committee, July 2017

RECOMMENDATIONS
  • While patients are taking ribavirin (RBV), clinicians should perform hemoglobin testing at weeks 2 and 4 of treatment and every 4 weeks thereafter until therapy is complete. (AI)
  • In patients taking regimens that contain a direct-acting antiviral (DAA) protease inhibitor (ombitasvir/paritaprevir/ ritonavir and dasabuvir; elbasvir/grazoprevir; and regimens with simeprevir), clinicians should monitor alanine aminotransferase (ALT) 4 weeks after initiating treatment and continue to obtain serum aminotransferase as needed according to the drug’s prescribing information. (AIII)
  • In patients who are hepatitis B virus surface antigen (HBsAg) positive and have no detectable HBV DNA, clinicians should monitor for HBV reactivation by performing aspartate aminotransferase (AST), ALT, and HBV DNA tests every 4 weeks during HCV treatment. (AIII)
  • Clinicians new to HCV treatment should consult an experienced HCV care provider for further evaluation of patients who develop detectable HBV DNA. (AIII)
  • If a woman becomes pregnant during therapy with a regimen containing RBV, clinicians should stop the RBV. (AI)
  • If a woman becomes pregnant during therapy with any DAA regimen, clinicians should discuss with her the benefits and risks of using DAAs during pregnancy. (AIII)

The adverse events associated with DAA treatment are listed in Table 29, below, and most are manageable. Patients who are taking RBV and experience insomnia may need to adjust the timing of the dose to earlier in the afternoon to avoid any sleep disruption.

Transient transaminase and bilirubin elevations may occur during the normal course of DAA therapy, but severe laboratory value elevations and rare hepatic decompensation have been reported with protease inhibitors during the treatment of patients with cirrhosis [1-3]. Therefore, if at 4 weeks after treatment is initiated, the ALT level is elevated above baseline, testing should be repeated and levels monitored according to the drug’s prescribing information [1-3].

HBV reactivation and HBV-related hepatic flares have occurred both during and after DAA therapy in patients who were not receiving HBV treatment [4-10]. The U.S. Food and Drug Administration (FDA) has issued a drug safety warning regarding these risks.

Table 29. Adverse Events Associated with Direct-Acting Antiviral Agents

Drug or combination
(brand name)

Most Common Adverse Reactions (proportion observed)

Elbasvir/grazoprevir
(Zepatier)

  • Fatigue, headache, nausea, insomnia, and diarrhea (≥5%)
  • With ribavirin: anemia and headache (≥5%)

Daclatasvir
(Daklinza)

  • With sofosbuvir: headache and fatigue (≥10%)
  • With sofosbuvir and ribavirin: headache, anemia, fatigue, and nausea (≥10%)

Ledipasvir/sofosbuvir
(Harvoni)

  • Asthenia, headache, and fatigue (≥10%)

Ombitasvir/paritaprevir/ritonavir/dasabuvir
(Viekira XR)

  • Nausea, pruritus, and insomnia (≥5%)
  • With ribavirin: fatigue, nausea, pruritus or other skin reactions, insomnia, and asthenia (>10%)

Ribavirin
(Copegus)

  •  Fatigue/asthenia, pyrexia, myalgia, and headache  in adults receiving combination therapy (>40%)

Simeprevir
(Olysio)

  • With sofosbuvir: fatigue, headache, and nausea (≥20%)

Sofosbuvir
(Sovaldi)

  • With ribavirin: fatigue and headache (≥20%)

Sofosbuvir/velpatasvir
(Epclusa)

  • With velpatasvir/sofosbuvir: headache and fatigue (≥10%, all grades)
  • With velpatasvir/sofosbuvir and ribavirin in patients decompensated cirrhosis: fatigue, anemia, nausea, headache, insomnia, and diarrhea (≥10%, all grades)

Sources: [1-3,11-15]

References

  1. FDA. (Dasabuvir, ombitasvir, paritaprevir, and ritonavir tablets), Copackaged for Oral Use. 2016 [accessed March 7, 2017]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208624s001s003lbl.pdf
  2. FDA. (Elbasvir and grazoprevir) tablets, for oral use. [accessed March 7, 2017]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208261Orig1s000lbl.pdf
  3. FDA. Olysio (simeprevir), 150 mg capsules. 2015 [accessed March 7, 2017]. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm417602.htm
  4. Hayashi K, Ishigami M, Ishizu Y, et al. A case of acute hepatitis B in a chronic hepatitis C patient after daclatasvir and asunaprevir combination therapy: hepatitis B virus reactivation or acute self-limited hepatitis? Clin J Gastroenterol 2016;Aug;9(4):252-6. [PMID: 27329484]
  5. Takayama H, Sato T, Ikeda F, et al. Reactivation of hepatitis B virus during interferon-free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus co-infection. Hepatol Res 2016 Mar 46(5):489-91. [PMID: 26297529]
  6. Ende AR, Kim NH, Yeh MM, et al. Fulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report. J Med Case Rep 2015 Jul 28:164. [PMID: 26215390]
  7. Collins JM, Raphael KL, Terry C, et al. Hepatitis B Virus Reactivation During Successful Treatment of Hepatitis C Virus With Sofosbuvir and Simeprevir. Clin Infect Dis 2015 Oct 15;61(8):1304-6. [PMID: 26082511]
  8. De Monte A, Courjon J, Anty R, et al. Direct-acting antiviral treatment in adults infected with hepatitis C virus: Reactivation of hepatitis B virus coinfection as a further challenge. J Clin Virol 2016;May;78:27-30. [PMID: 26967675]
  9. Sulkowski MS, Chuang WL, Kao JH, et al. No Evidence of Reactivation of Hepatitis B Virus Among Patients Treated With Ledipasvir-Sofosbuvir for Hepatitis C Virus Infection. Clin Infect Dis 2016 Nov 1;63(9):1202-04. [PMID: 27486112]
  10. Wang C, Ji D, Chen J, et al. Hepatitis due to Reactivation of Hepatitis B Virus in Endemic Areas Among Patients With Hepatitis C Treated With Direct-acting Antiviral Agents. Clin Gastroenterol Hepatol 2017 Jan;15(1):132-36. [PMID: 27392759]
  11. FDA. (Daclatasvir) tablets, for oral use. 2015 [accessed March 7, 2017]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206843Orig1s000lbl.pdf
  12. FDA. Harvoni (ledipasvir/sofosbuvir) Fixed-dose Combination Tablet. 2015 [accessed March 7, 2017]. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm441357.htm
  13. FDA. (Sofosbuvir and velpatasvir) tablets, for oral use 2016 [accessed March 7, 2017]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208341s000lbl.pdf
  14. FDA. Sovaldi (sofosbuvir) Tablets. 2015 [accessed March 7, 2017]. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm441356.htm
  15. FDA. Copegus (ribavirin) tablets. 2015 [accessed March 7, 2017]. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm218877.htm

Drug-Drug Interactions

Hepatitis C Virus Infection Guideline Committee, July 2017

The charts contained in this section are meant to provide guidance on significant interactions between DAAs and common primary care medications. While these guidelines can be helpful, they are not a substitute for sound clinical judgement and practice.

In some cases, the medications listed below are contraindicated in the U.S. Food and Drug Administration (FDA) labeling for the medication, or the label may state elsewhere that co-administration is not recommended. For some, the recommendation may be to “Avoid Co-administration,” but in some clinical situations it may be necessary to use the medications concurrently. When this is the case, clinicians are encouraged to consult additional references or an experienced HCV care provider for additional guidance.

KEY POINT
  • Though significant interactions associated with the use of direct-acting antivirals (DAAs) and drugs used commonly in the treatment of substance use disorders are unlikely, care providers should always monitor for excess sedation when making alterations to a patient’s drug therapy while he/she is taking methadone, buprenorphine, naltrexone, and naloxone.

The links below open pages with tables for each of the following drugs:

Drug-Drug Interactions: Daclatasvir

Hepatitis C Virus Infection Guideline Committee, July 2017

Table 35. Daclatasvir Drug-Drug Interactions
Avoid co-administration; see clinical comments
Class (medications) Clinical comments
Antiarrhythmics (amiodarone)
  • Serious symptomatic bradycardia may occur if used concomitantly with sofosbuvir and daclatasvir
  • Concurrent use not recommended
Anticonvulsants (carbamazepine, phenytoin) Significant decrease in daclatasvir level
Antimycobacterial (rifampin) Significant decrease in daclatasvir level
Herbal product (St. John’s wort) Significant decrease in daclatasvir level
Co-administration possible; see clinical comments
Class (medications) Clinical comments

Strong inhibitors of cytochrome 3A metabolic system (CYP3A):

  • Antibiotics (clarithromycin, telithromycin)
  • Antifungals (itraconazole, ketoconazole, posaconazole, voriconazole)
  • Antidepressant (nefazodone)
  • Strong CYP3A inhibitors are expected to increase daclatasvir levels
  • Decrease daclatasvir dose to 30 mg once daily

Moderate inducers of CYP3A:

  • Antibiotic (nafcillin)
  • Antimycobacterial (rifapentine)
  • Corticosteroid (dexamethasone)
  • Endothelin antagonist (bosentan)
  • Wakefulness-promoting agent (modafinil)
  • Moderate CYP3A inducers are expected to decrease daclatasvir levels
  • Increase daclatasvir dose to 90 mg once daily
Anticoagulant (dabigatran)
  • Potential for increased dabigatran level in patients with renal impairment
  • See dabigatran label for further information
Antiarrhythmics (digoxin)
  • If already taking daclatasvir and initiating digoxin:
    • Use lowest digoxin dose possible
    • Monitor level
    • Titrate as needed
  • If already taking digoxin and initiating daclatasvir:
    • Measure serum digoxin level prior to starting daclatasvir
    • Reduce digoxin dose by 15% to 30%
    • Monitor level
    • Titrate as needed

HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin)

  • Increased HMG-CoA reductase inhibitor drug levels
  • Monitor for adverse events such as myopathy
Narcotic analgesics (buprenorphine, buprenorphine/naloxone)
  • Increased narcotic analgesic drug levels expected
  • No dose adjustment required
  • Clinical monitoring recommended
Source: FDA. Highlights of Prescribing Information: Daklinza (daclatasvir) tablets, for oral use. Accessed July 3, 2017.

Drug-Drug Interactions: Elbasvir/Grazoprevir

Hepatitis C Virus Infection Guideline Committee, July 2017

Table 34. Elbasvir/Grazoprevir Drug-Drug Interactions
Avoid co-administration; see clinical comments
Class (medications) Clinical comments
Anticonvulsants (carbamazepine, phenytoin) Significant decrease in elbasvir/grazoprevir levels
Antimycobacterial (rifampin) Significant decrease in elbasvir/grazoprevir levels
Herbal product (St. John’s wort) Significant decrease in elbasvir/grazoprevir levels
IV medications (efavirenz, atazanavir, darunavir, lopinavir, saquinavir, tipranavir)
  • Efavirenz: Significant decrease in elbasvir/grazoprevir levels
  • Atazanavir, darunavir, lopinavir, saquinavir, tipranavir: Significant increase in grazoprevir level
    • May lead to ALT elevation
Immunosuppressant (cyclosporine)

Significant increase in grazoprevir level; may lead to ALT elevation

Co-administration possible; see clinical comments
Class (medications) Clinical comments
Antibiotic (nafcillin) Decreased concentrations of elbasvir/grazoprevir levels
Antifungal (ketoconazole)
  • Significant increase in elbasvir/grazoprevir levels
  • Increased risk of hepatotoxicity
Endothelin antagonist (bosentan) Significant decrease in elbasvir/grazoprevir levels
HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, lovastatin, rosuvastatin, simvastatin)
  • Increase in statin drug levels expected
  • Atorvastatin: Max daily dose 20 mg
  • Fluvastatin, lovastatin, or simvastatin: Use lowest doses possible; titrate with close monitoring
  • Rosuvastatin: Max daily dose 10 mg 
Immunosuppressant (tacrolimus)
  • Significant increase in tacrolimus level expected
  • Frequent monitoring required for tacrolimus level, changes in renal function, and tacrolimus-associated adverse events
Wakefulness-promoting agent (modafinil) Significant decrease in elbasvir/grazoprevir levels
Source: FDA. Highlights of Prescribing Information: Zepatier (elbasvir and grazoprevir) tablets, for oral use.  Accessed July 3, 2017.

Drug-Drug Interactions: Ledipasvir/Sofosbuvir

Hepatitis C Virus Infection Guideline Committee, July 2017

Table 31. Ledipasvir/Sofosbuvir Drug-Drug Interactions
Avoid co-administration; see clinical comments
Class (medications) Clinical comments
Antiarrhythmic (amiodarone)
  • Significant bradycardia, especially in patients who are taking beta-blockers, have underlying cardiac abnormalities, or have advanced liver disease
  • If concurrent use is required, cardiac monitoring is recommended
  • See package insert for additional information
Herbal product (St. John’s wort) Significant decrease in ledipasvir/sofosbuvir level
Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin) Significant decrease in ledipasvir/sofosbuvir level
Antimycobacterials (rifampin, rifabutin, rifapentine) Significant decrease in ledipasvir/sofosbuvir level
HMG-CoA reductase inhibitor (rosuvastatin) Significant increase in rosuvastatin level
NS3/4A HCV protease inhibitor (simeprevir) Significant increases in ledipasvir and simeprevir level
Co-administration possible; see clinical comments
 Class (medications) Clinical comments
Antacids
  • Ledipasvir solubility decreases as pH increases
  • Separate administration of aluminum- and magnesium-containing antacids and ledipasvir/sofosbuvir by 4 hours
Antiarrhythmic (digoxin)
  • Increase in digoxin level expected
  • Monitor digoxin level
H2-receptor antagonists 
  • Administer simultaneously with, or 12 hours apart from, ledipasvir/ sofosbuvir
  • Do not exceed doses comparable to famotidine 40 mg twice daily 
Proton-pump inhibitors  If co-administration is required, doses comparable to omeprazole 20 mg or lower can be administered simultaneously with ledipasvir/sofosbuvir under fasting conditions
Source: FDA. Highlights of prescribing information: Harvoni (ledipasvir and sofosbuvir) tablets, for oral use. Accessed July 2, 2017.

Drug-Drug Interactions: Ombitasvir/Paritaprevir/ Ritonavir/Dasabuvir

Hepatitis C Virus Infection Guideline Committee, July 2017

Table 30. Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir (PrOD) Drug-Drug Interactions
Avoid co-administration; see clinical comments 
Class (medications) Clinical Comments
Alpha 1-antagonist (alfuzosin)
  • Significant increase in alfuzosin level
  • Potential for severe hypotension
Antianginal (ranolazine) Significant increase in ranolazine level
Antiarrhythmics (amiodarone, dronedarone, dofetilide, disopyramide, flecainide, lidocaine, mexiletine, propafenone, quinidine)
  • Increased antiarrhythmic drug levels, potential for cardiac arrhythmias
  • Therapeutic concentration monitoring of antiarrhythmic drug level recommended if available
Anticonvulsants (carbamazepine, oxcarbazepine, phenytoin, phenobarbital)  Significant decrease in PrOD levels 
Antigout (colchicine)
  • Significant increase in colchicine level
  • Potential for renal impairment and pancytopenia 
 Antihyperlipidemic (gemfibrozil)  Significant (10-fold) increase in dasabuvir level leading to increased risk of QT prolongation 
Antimycobacterial (rifampin)
  • Significant decrease in PrOD levels
  • Potential for HCV treatment failure 
Antipsychotics, 1st generation, typical (pimozide, lurasidone)

Significant increase in antipsychotic levels

Ergot derivatives (ergotamine, dihydroergot-amine, ergonovine, methylergonovine) Significant increase in ergot derivative level leading to acute ergot toxicity
Ethinyl estradiol-containing products (oral contraceptives)
  • Significant increase in PrOD level
  • Alanine transaminase (ALT) elevations associated with concurrent use of ethinyl estradiol
Herbal product (St. John’s wort) Significant decrease in PrOD levels
HIV medication (efavirenz)
  • Co-administration of efavirenz-based regimens with paritaprevir, ritonavir plus dasabuvir poorly tolerated
  • Results in liver enzyme elevation
HMG-CoA reductase inhibitors (atorvastatin, lovastatin, simvastatin)
  • Significant increase in atorvastatin, lovastatin and simvastatin levels
  • Potential for rhabdomyolysis
Immunosuppressants (everolimus, sirolimus, tacrolimus) Increased potential for immunosuppressant-associated adverse events
Phosphodiesterase-5 inhibitors (sildenafil, when used in pulmonary arterial hypertension) Increased potential for sildenafil adverse events, such as priapism, visual disturbances, and hypotension
Sedative/hypnotics (oral midazolam, triazolam) Significant increases in oral midazolam or triazolam level
Co-administration possible; see clinical comment
Class (medications) Clinical Comments
Angiotensin receptor blockers (ARBs) (candesartan, olmesartan, telmisartan)
  • Increased ARB drug levels
  • Consider ARB dose reduction
  • Monitor closely for hypotension
Antifungal (oral ketoconazole, voriconazole)
  • Oral ketoconazole: Increase in ketoconazole level; dose should not exceed 200 mg in a 24-hour period
  • Voriconazole: Significant decrease in voriconazole level
Antipsychotic, 2nd generation, atypical (quetiapine)
  • Significant increase in quetiapine level
  • Consider alternative HCV therapy or reduce quetiapine dose to 1/6 of current dose
  • Monitor for adverse events, including increased blood pressure
Beta adrenoceptor agonist (long-acting salmeterol)
  • Significant increase in salmeterol level
  • Monitor for QT prolongation, palpitations, and sinus tachycardia
Calcium channel blockers (CCBs) (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil) 
  • Increased CCB drug levels
  • Consider CCB drug dose reduction
  • Monitor closely for hypotension and bradycardia
Corticosteroids (inhaled or nasal fluticasone)  With nasal or inhaled use, significant increase in fluticasone level, which can lead to Cushing’s Syndrome 
Diuretic (furosemide) 
  • Possible increase in furosemide level
  • Monitor closely based upon response
HMG-CoA reductase inhibitors (atorvastatin, pravastatin, rosuvastatin)
  • Increased HMG-CoA reductase inhibitor drug levels
  • Atorvastatin: Do not exceed 20 mg in a 24-hour period
  • Pravastatin: Do not exceed 40 mg in a 24-hour period
  • Rosuvastatin: Do not exceed 10 mg in a 24-hour period
Immunosuppressants (cyclosporine, tacrolimus) 
  • Increase in cyclosporine and tacrolimus levels
  • Interactions are complex; consult PrOD package insert for additional dosing guidance
Muscle relaxants (carisoprodol, cyclobenzaprine)
  • Decrease in muscle relaxant drug levels
  • Consider increasing dose of muscle relaxant if clinically indicated
Narcotic analgesics (buprenorphine/naloxone, acetaminophen/hydrocodone)
  • Buprenorphine/naloxone: Monitor for sedation
  • Acetaminophen/hydrocodone: Reduce hydrocodone dose by 50%
    • Monitor for respiratory depression and sedation
Phosphodiesterase-5 inhibitors, when used for erectile dysfunction (sildenafil, tadalafil, vardenafil)
  • Increase in phosphodiesterase-5 inhibitor drug level
  • Sildenafil: Do not exceed 25 mg in a 48-hour period
  • Tadalafil: Do not exceed 10 mg in a 72-hour period
  • Vardenafil: Do not exceed 2.5 mg in a 72-hour period
Proton-pump inhibitor (omeprazole) 
  • Decrease in omeprazole level
  • Consider increase in omeprazole dose for patients not well controlled
  • Do not exceed omeprazole 40 mg daily equivalent 
Sedative/hypnotics (alprazolam,  diazepam)
  • Alprazolam: Increase in drug level
    • Monitor for excess sedation
    • Consider decrease in alprazolam dose
  • Diazepam: Decrease in drug level
    • Consider increase in diazepam dose if clinically indicated
Source: FDA. Highlights of Prescribing Information: Viekira XR (dasabuvir, ombitasvir, paritaprevir, and ritonavir) extended-release tablets, for oral use. Accessed July 3, 2017.

Drug-Drug Interactions: Simepravir

Hepatitis C Virus Infection Guideline Committee, July 2017

Table 32. Simeprevir Drug-Drug Interactions
Avoid co-administration; see clinical comments
Class (medications) Clinical comments
Antiarrhythmics (amiodarone, disopyramide, flecainide, mexiletine, propafenone, quinidine)
  • Amiodarone: Significant bradycardia, especially in patients who are taking beta-blockers, have underlying cardiac abnormalities, or have advanced liver disease
    • If concurrent use is required, cardiac monitoring is recommended
    • Consult package insert for additional information
  • Disopyramide, flecainide, mexiletine, propafenone, quinidine: Increase in antiarrhythmic drug levels
    • Therapeutic concentration monitoring of antiarrhythmic drug levels recommended if possible
Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin) Significant decrease in simeprevir level leading to reduced simeprevir efficacy
Antibiotics (clarithromycin, erythromycin, telithromycin) Significant increase in simeprevir or antibiotic level due to CYP3A4 and P-glycoprotein inhibition
Antifungals (oral or IV: fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole) Significant increase in simeprevir level due to CYP3A4 inhibition from antifungals
Antimycobacterials (rifampin, rifabutin, rifapentine) Significant decrease in simeprevir level leading to reduced simeprevir efficacy
GI motility agent (cisapride; limited availability in the U.S.)
  • Significant increase in cisapride level
  • Potential for cardiac arrhythmias
Herbal products (milk thistle, St. John’s wort)
  • Milk thistle: Significant increase in simeprevir level
  • St. John’s wort: Significant decrease in simeprevir level
Immunosuppressant (cyclosporine) Significant increase in simeprevir and cyclosporine levels, leading to adverse effects of both medications
Co-administration possible; see clinical comments
Class (medications) Clinical comments
Antiarrhythmics  (digoxin)
  • Increase in digoxin level expected
  • Monitor digoxin level
Calcium channel blockers (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil)
  • Potential increase in CCB drug levels
  • Monitor for bradycardia and hypotension
Corticosteroid (dexamethasone) Significant decrease in simeprevir level leading to reduced simeprevir efficacy
HMG-CoA reductase inhibitors (lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin)
  • Lovastatin, pitavastatin, pravastatin, simvastatin: Use lowest dose possible; titrate carefully
  • Rosuvastatin: Increase in rosuvastatin level
    • Initiate with 5 mg daily; do not exceed 10 mg daily
Phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil)
  • Increase in phosphodiesterase-5 inhibitor levels
  • Use lowest dose possible
Sedative/hypnotics (oral midazolam, triazolam)
  • Use lowest doses possible
  • Titrate carefully
Source: FDA. Highlights of Prescribing Information: Olysio (simeprevir) capsules, for oral use. Accessed July 3, 2017.

Drug-Drug Interactions: Sofosbuvir

Hepatitis C Virus Infection Guideline Committee, July 2017

Table 33. Sofosbuvir Drug-Drug Interactions
Avoid co-administration; see clinical comments
Class (medications) Clinical comments
Antiarrhythmic (amiodarone)
  • Significant bradycardia, especially in patients who are taking beta-blockers, have underlying cardiac abnormalities, or have advanced liver disease.
  • If concurrent use is required, cardiac monitoring is recommended
  • See package insert for additional information
Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin) Significant decrease in sofosbuvir level expected leading to reduced sofosbuvir efficacy
Antimycobacterials (rifampin, rifabutin, rifapentine) Significant decrease in sofosbuvir level expected leading to reduced sofosbuvir efficacy
Herbal product (St. John’s wort) Significant decrease in sofosbuvir level expected leading to reduced sofosbuvir efficacy
Source: FDA. Highlights of Prescribing Information: Sovaldi (sofosbuvir) tablets, for oral use. Accessed July 3, 2017.

Drug-Drug Interactions: Sofosbuvir and Velpatasvir

Hepatitis C Virus Infection Guideline Committee, July 2017

Table 36. Sofosbuvir and Velpatasvir Drug-Drug Interactions

Avoid co-administration; see clinical comments
Class (medications) Clinical comments
Antiarrhythmic (amiodarone)
  • Significant bradycardia, especially in patients who are taking beta-blockers, have underlying cardiac abnormalities, or have advanced liver disease
  • If concurrent use is required, cardiac monitoring is recommended
  • See package insert for additional information
Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin) Significant decrease in sofosbuvir level expected, leading to reduced sofosbuvir and/or velpatasvir drug levels
Antimycobacterials (rifampin, rifabutin, rifapentine) Potential significant decrease in sofosbuvir and/or velpatasvir drug levels
Herbal product (St. John’s wort) May significantly decrease sofosbuvir and/or velpatasvir drug levels
Co-administration possible; see clinical comments
Class (medications) Clinical comments
Antacids (aluminum and magnesium hydroxide)
  • May decrease concentration of velpatasvir
  • Separate administration of antacid and velpatasvir/sofosbuvir by 4 hours
Antiarrhythmic (digoxin)
  • Increase in digoxin level expected
  • Monitor digoxin level
Anticancer (topotecan) Significant increase in topotecan expected
H2-receptor antagonist (famotidine)
  • Velpatasvir solubility decreases as pH increases
  • May decrease concentration of velpatasvir
  • H2-receptor antagonists may be administered simultaneously with, or 12 hours apart from velpatasvir/sofosbuvir, at a dose that does not exceed doses comparable to famotidine 40 mg twice daily
HMG-CoA reductase inhibitor (rosuvastatin)
  • May significantly increase the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis
  • Rosuvastatin may be administered at a dose not greater than 10 mg daily
Proton-pump inhibitor (omeprazole)
  • May decrease concentration of velpatasvir
  • Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower can be administered simultaneously with velpatasvir/sofosbuvir under fasting conditions
Source: FDA. Highlights of Prescribing Information: Epclusa (sofosbuvir and velpatasvir) tablets, for oral use. Accessed July 3, 2017.

Post-Treatment Care

Hepatitis C Virus Infection Guideline Committee, July 2017

After treatment for chronic hepatitis C virus (HCV) infection, follow-up care is based on individual patient factors, including response to recent treatment, previous treatment history, degree of hepatic fibrosis, comorbidities, and cofactors for other sources of liver injury, such as alcohol use or fatty liver disease.

Evaluating the Response to HCV Treatment

RECOMMENDATIONS
  • Clinicians should perform HCV RNA testing 12 weeks after treatment is complete to verify that a sustained virologic response (SVR) has been achieved. (AI)
  • If SVR is achieved, as established by undetectable HCV RNA at 12 weeks after treatment, clinicians should:
    • Inform their patients that the HCV infection has been cured (AII)
    • Explain the risk of HCV reinfection and that HCV antibodies are not protective against reinfection. (AI)
  • To assess for reinfection in patients with ongoing risk factors, clinicians should perform follow-up screening with HCV RNA testing (not HCV antibody testing) at least annually, even with a history of an SVR. (AI)
  • If HCV RNA is detectable at 12 weeks after treatment, clinicians should:
    • Inform patients that treatment has failed (AI)
    • If clinician is new to HCV treatment, consult with an experienced HCV care provider for retreatment evaluation (AIII)

All treated individuals should have HCV RNA testing performed 12 weeks after treatment. If there is no detectable HCV RNA at 12 weeks, HCV infection has been cured. In the absence of recurrent risk factors, subsequent HCV testing is not required. However, with late relapse reported in rare (<0.5%) cases, some clinicians may choose to retest at 24 and/or 48 weeks after end of treatment [1].

Successful treatment of chronic HCV infection results in no detectable HCV RNA, but antibodies to HCV are typically retained for life. It is important for treated individuals to understand that they will continue to have antibodies but not active HCV infection. It is also important for patients to understand that, although antibodies to HCV will continue to be present after treatment, HCV antibodies do not offer protection from HCV reinfection. All individuals with no detectable HCV RNA are considered susceptible to reinfection if re-exposed to HCV. While the overall rate of reinfection is low, it is elevated among populations at higher risk [2]. A meta-analysis of 59 studies reporting on recurrence after a sustained viral response (SVR) in 9,049 patients found that the summary 5-year risk of HCV reinfection among high-risk populations was 10.67% [3]. High risk was defined as having one or more risk factors for reinfection (current or former persons who inject drugs [PWID], imprisonment, and men who have sex with men [MSM]). Among low-risk populations, defined as those with no known risk factors, the summary 5-year recurrence risk of was 0.95% [3]. For discussion of risk factors, see the Screening and Diagnosis sections of this guideline.

Post-Treatment Monitoring

RECOMMENDATIONS
  • For patients taking ribavirin (RBV)-containing HCV treatment regimens, clinicians should:
    • Advise female and male patients to take extreme care to avoid pregnancy for 6 months after completion of therapy (AII)
    • Counsel female and male patients on effective contraceptive use (AII)
  • If a woman becomes pregnant within 6 months of completing an RBV-containing HCV treatment, clinicians should discuss with her the risks of using DAAs and RBV during pregnancy (AIII)

It is important to monitor for the resolution of patients’ HCV treatment-related adverse events. RBV-containing regimens are teratogenic; patients receiving RBV-containing regimens and their partners should be counseled to avoid pregnancy during treatment and up to 6 months post-treatment. Two forms of effective birth control should be used [4].

See Monitoring During DAA Treatment > Table 29: Adverse Events Associated with DAAs, for a list of adverse events associated with DAA regimens. During treatment with RBV, patients may experience hemolytic anemia, nausea, cough, shortness of breath, rash, dry skin, pruritus, lactic acidosis, or pancreatitis [4]. Patients should be monitored through the follow-up period for resolution of any symptoms.

Hepatitis B virus (HBV) reactivation: HBV-related hepatic flares have been reported during and after DAA therapy in patients who were not receiving concurrent HBV treatment [5-11]. The U.S. Food and Drug Administration (FDA) has issued a drug safety warning regarding these risks. Although data are insufficient to make a definitive recommendation regarding monitoring in the setting of isolated anti-HBc [12], it is important to consider HBV reactivation as part of the differential diagnosis for patients with HBV infection who experience unexplained increases in liver enzymes either during or after completion of DAA treatment.

Patients with Persistent Liver Disease

RECOMMENDATIONS
  • Clinicians should evaluate patients with persistent abnormal transaminase levels after SVR for other causes of liver disease and consult with a liver disease specialist. (AIII)
  • In patients with underlying bridging fibrosis or cirrhosis, clinicians should screen for hepatocellular carcinoma (HCC) every 6 months. (AI)

While cessation of the progression of fibrosis and histological improvement are among the benefits of treating chronic HCV infection [13,14], patients should still be monitored for potential risk of post-treatment decompensation [1].

Individuals in whom HCV infection is cured remain at risk of liver disease progression if their baseline fibrosis is sufficiently advanced or if they have comorbidities, such as metabolic syndrome, alcohol use, or uncontrolled coinfection with HIV or HBV, or are at risk of liver injury from drugs or dietary supplements [15].

Although there is wide individual variation in the time needed for fibrosis progression to occur in chronic HCV infection, it is important to maintain an elevated level of suspicion for progression of fibrosis and the complications associated with hepatic decompensation, particularly in individuals with long-term chronic HCV infection or comorbidities that would predispose them to faster progression. Transient elastography is not available in all clinical settings, but once it is more widely available, it will aid in monitoring fibrosis progression after HCV treatment.

For patients with bridging fibrosis or cirrhosis, an ultrasound should be performed every 6 months, regardless of SVR, to screen for HCC [1]. The risk of HCC for patients with stage 3 or higher fibrosis is 1.5% to 5% per year, but it is not known whether the histologic improvement after successful treatment mitigates this risk [16].

References
  1. Jacobson IM LJ, Fried MW. American Gastroenterological Association Institute Clinical Practice Update—Expert Review: Care of Patients Who Have Achieved a Sustained Virologic Response After Antiviral Therapy for Chronic Hepatitis C Infection. Gastroenterology 2017;152(6):1578-1587. [PMID: 28344022]
  2. Martinello M, Grebely J, Petoumenos K, et al. HCV reinfection incidence among individuals treated for recent infection. J Viral Hepat 2017;24(5):359-70. [PMID: 28027424]
  3. Simmons B, Saleem J, Hill A, et al. Risk of Late Relapse or Reinfection With Hepatitis C Virus After Achieving a Sustained Virological Response: A Systematic Review and Meta-analysis. Clin Infect Dis 2016;62(6):683-94. [PMID: 26787172]
  4. FDA. Copegus (ribavirin) tablets. 2015 [accessed March 7, 2017]. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm218877.htm
  5. Hayashi K IM, Ishizu Y1, Kuzuya T, Honda T, Nishimura D, Goto H1, Hirooka Y. A case of acute hepatitis B in a chronic hepatitis C patient after daclatasvir and asunaprevir combination therapy: hepatitis B virus reactivation or acute self-limited hepatitis? Clin J Gastroenterol 2016;Aug;9(4):252-6. [PMID: 27329484]
  6. Takayama H ST, Ikeda F, Fujiki S. Reactivation of hepatitis B virus during interferon-free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus co-infection. Hepatol Res 2016 Mar 46(5):489-91. [PMID: 26297529]
  7. Ende AR KN, Yeh MM, Harper J, Landis CS. Fulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report. J Med Case Rep 2015 Jul 28:164. [PMID: 26215390]
  8. Collins JM RK, Terry C, Cartwright EJ, Pillai A, Anania FA, Farley MM. Hepatitis B Virus Reactivation During Successful Treatment of Hepatitis C Virus With Sofosbuvir and Simeprevir. Clin Infect Dis 2015 Oct 15;61(8):1304-6. [PMID: 26082511]
  9. De Monte A CJ, Anty R, Cua E, Naqvi A, Mondain V, Cottalorda J, Ollier L, Giordanengo V. Direct-acting antiviral treatment in adults infected with hepatitis C virus: Reactivation of hepatitis B virus coinfection as a further challenge. J Clin Virol 2016;May;78:27-30. [PMID: 26967675]
  10. Sulkowski MS CW, Kao JH3, Yang JC, Gao 4, Brainard DM, Han KH5, Gane E. No Evidence of Reactivation of Hepatitis B Virus Among Patients Treated With Ledipasvir-Sofosbuvir for Hepatitis C Virus Infection. Clin Infect Dis 2016 Nov 1;63(9):1202-04. [PMID: 27486112]
  11. Wang C JD, Chen J, Shao Q, Li B, Liu J, Wu V, Wong A, Wang Y, Zhang X, Lu L, Wong C, Tsang S, Zhang Z, Sun J, Hou J, Chen G, Lau G. Hepatitis due to Reactivation of Hepatitis B Virus in Endemic Areas Among Patients With Hepatitis C Treated With Direct-acting Antiviral Agents. Clin Gastroenterol Hepatol 2017 Jan;15(1):132-36. [PMID: 27392759]
  12. American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA). HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. August 24, 2016 [accessed 2017 Apr 26]. http://www.hcvguidelines.org
  13. George SL, Bacon BR, Brunt EM, et al. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology 2009;49(3):729-38. [PMID: 19072828]
  14. Toccaceli F, Laghi V, Capurso L, et al. Long-term liver histology improvement in patients with chronic hepatitis C and sustained response to interferon. J Viral Hepat 2003;10(2):126-33. [PMID: 12614469]
  15. Vandenbulcke H, Moreno C, Colle I, et al. Alcohol intake increases the risk of HCC in hepatitis C virus-related compensated cirrhosis: A prospective study. J Hepatol 2016;65(3):543–51. [PMID: 27180899]
  16. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011;53(3):1020-2. [PMID: 21374666]

All Recommendations

Hepatitis C Virus Infection Guideline Committee, July 2017

ALL RECOMMENDATIONS
Cohort-Based Screening
  • New York State (NYS) Public Health Law mandates that primary care clinicians offer hepatitis C virus (HCV) screening to individuals born from 1945 to 1965 in a culturally and linguistically appropriate manner.
  • See New York State Department of Health (NYSDOH): Hepatitis C Testing Law
Risk-Based Screening
  • Clinicians should perform HCV screening at least once for patients of any age who are not known to have HCV infection and currently have, or have a history that includes, any of the following risk factors:
    • Injection drug use (AI)
    • Intranasal drug use (AII)
    • Sex partner(s) with HCV infection (AII)
    • Incarceration (AII)
    • Long-term hemodialysis (AI)
    • Receipt of blood transfusion or organs before 1992, or of clotting factor concentrates from human plasma before 1987 (AI)
    • A mother with a reactive HCV antibody test result (AI)
    • Tattoo, piercing, or acupuncture obtained in a nonsterile setting (AII)
    • HIV infection (AII)
    • Unexplained liver disease or abnormal transaminase levels (AI)
  • Clinicians should offer HCV screening at least annually to individuals who are not known to have HCV infection and:
    • Use injection drugs (AII)
    • Use intranasal drugs (AII)
    • Receive current long-term hemodialysis (AII)
  • Clinicians should offer HCV screening at least annually to men who have sex with men (MSM) and to others who are not known to have HCV infection and:
    • Engage in receptive anal sex and other behaviors that may tear mucous membranes (AII)
    • Have multiple sex partners (AII)
    • Engage in sex while using recreational mind-altering substances, particularly methamphetamine (AII)
    • Have been diagnosed with another sexually transmitted infection (STI) within the previous 12 months (AII)
  • Clinicians should perform HCV screening for individuals who are not known to have HCV infection and have a possible exposure in a healthcare setting, including those who:
    • Have a break in the skin caused by a sharp object that is contaminated with blood, visibly bloody fluid, or other potentially infectious material or that has been in the source patient’s blood vessel (AII)
    • Have been bitten by an individual with visible bleeding in the mouth that causes bleeding in the exposed worker (AII)
    • Have been splashed on a mucosal surface with blood, visibly bloody fluid, or other potentially infectious material (AIII)
    • Have non-intact skin (e.g., dermatitis, chapped skin, abrasion, or open wound) that has been exposed to blood, visibly bloody fluid, or other potentially infectious material (AIII)
Diagnosis 
  • Clinicians should perform HCV screening using either a laboratory-based HCV antibody test or point-of-care rapid antibody test. (AI)
  • If the HCV antibody test result is reactive, clinicians should obtain confirmatory HCV RNA testing from a laboratory that uses a nucleic acid test (NAT) approved by the U.S. Food and Drug Administration (FDA). (AI)
  • If HCV RNA is detected after a reactive antibody result, the patient has confirmed HCV infection and clinicians should evaluate for treatment of chronic or acute HCV infection. (AII)
  • If the HCV antibody test result is nonreactive:
    • Clinicians should perform subsequent HCV screening based on individual patient risk factors (AIII)
    • And if acute HCV infection is suspected, clinicians should perform a diagnostic HCV RNA test using an FDA-approved NAT (AI)
  • In patients with a history of a reactive HCV antibody test, clinicians should use an HCV RNA test (not an HCV antibody test) for subsequent screening. (AI)
Acute HCV Infection
  • Clinicians should suspect acute HCV infection if a patient who had a nonreactive antibody test documented within the previous 6 months has a new reactive antibody test or has detectable HCV RNA in the absence of a reactive antibody test. (AIII)
  • Clinicians should not prescribe pre- or post-exposure prophylaxis to prevent HCV infection. (AI)
  • If chronic HCV infection is established, clinicians should evaluate patients for treatment. (AI)
  • Clinicians should screen all patients with possible acute HCV infection for HIV, hepatitis A virus (HAV), and hepatitis B virus (HBV) infections, given the similar risk factors for acquisition. (AII)
Pretreatment Assessment
  •  Clinicians should assess all patients with a confirmed diagnosis of chronic HCV infection for treatment. (AI)
  • Clinicians new to treating chronic HCV infection should consult with an experienced HCV care provider when treating chronic HCV infection in patients with any of the following conditions (AIII):
    • Compensated cirrhosis
    • Concurrent hepatobiliary conditions
    • Extrahepatic manifestations of HCV, including renal, dermatologic, and rheumatologic manifestations
    • Significant renal impairment (creatinine clearance <30 mL/min)
    • Active HBV infection, defined as hepatitis B (HBV) surface antigen positive and detectable HBV DNA
    • Ongoing HCV infection after failure of treatment with direct-acting antivirals (DAAs)
  • Clinicians should refer patients with chronic HCV infection and decompensated liver disease and patients who are pre- or post-transplant to a liver disease specialist (AIII)
Medical History and Physical Exam
HCV Genotype
  • Clinicians should obtain HCV genotype/subtype testing for all patients before starting HCV treatment. (AI)
 Fibrosis Assessment
  • Clinicians should assess the degree of fibrosis in patients with chronic HCV infection to aid in determining the following (AI):
    • Need for pretreatment screening for varices and HCC.
    • Duration of antiviral treatment
    • Need for ribavirin (RBV).
    • Need for post-treatment follow-up. 
  • Clinicians should assess patients with chronic HCV infection for decompensated liver disease. (AI)
  • Clinicians should refer patients with decompensated cirrhosis to a liver disease specialist. (AIII)
Cirrhosis Evaluation
  • Clinicians should refer all patients with HCV-related cirrhosis for an upper endoscopy to screen for the presence of esophageal varices. (AIII)
  • Clinicians should screen for hepatocellular carcinoma with ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) every 6 months in patients with HCV-related bridging fibrosis or cirrhosis. (AIII)
Baseline Laboratory Testing
Cardiac, Renal, HAV/HBV, Pregnancy, and Metabolic Status Considerations
  • Cardiovascular status: For individuals with chronic HCV infection who are aged >50 years, clinicians should perform cardiovascular risk assessment before initiation of treatment with RBV. (AII)
  • Renal Status: Clinicians should assess creatinine clearance in all patients with HCV infection. (AI)
    • Clinicians new to HCV treatment should consult an experienced HCV care provider on HCV treatment in patients with severe renal impairment (creatinine clearance <30 mL/min). (AIII)
  • HAV and/or HBV Immunity Status: Clinicians should obtain HAV antibody (IgG or total) and administer the full HAV vaccine series in patients who are not immune to HAV. (AIII)
  • Clinicians should obtain hepatitis B virus surface antigen (HBsAg), anti-hepatitis H surface (HBs), and anti-hepatitis B core antigen (HBc), total, and recommend administration of the anti-hepatitis B virus (HBV) vaccine series (0, 1, and 6 months) for HBV-susceptible patients (negative for all serologies). (AIII)
    • In patients with positive HBsAg, clinicians should perform HBV DNA testing to assess for active HBV infection (AI)
    • If HBV DNA is detectable, clinicians new to HCV treatment should consult an experienced HCV care provider on treatment for HBV and HCV (AI)
  • Pregnancy Status and Contraception: Clinicians should perform a pregnancy test in all women of childbearing potential before initiation of HCV treatment and defer HCV treatment in pregnant women. (AII)
    • Before initiating RBV, clinicians should (AII):
      • Confirm a negative pregnancy test
      • Advise patients to use 2 methods of birth control to avoid pregnancy during therapy and for 6 months after completion of therapy
      • Counsel female and male patients on effective contraceptive use
    • Contraindication: Clinicians should not use RBV in treatment of the following patients:
      • Female or male patients planning conception within 6 months of the last dose of RBV. (AII)
      • Male patients who have pregnant partners. (AII)
    • Contraindication: Clinicians should not use ombitasvir/paritaprevir/ritonavir/dasabuvir (PrOD) in treatment of women taking ethinyl estradiol-containing contraceptives. (AII)
 Treatment Options: Considerations
  • Clinicians should assess creatinine clearance before initiating antiviral therapy. (AI)
  • Clinicians new to HCV care should consult an experienced HCV care provider when treating patients who:
    • Have severe renal impairment (creatinine clearance <30 mL/min) (AIII)
    • Have failed prior DAA treatment (AIII)
  • Clinicians should prescribe RBV with caution for patients with a creatinine clearance <50 mL/min. (AI)
    • If prescribed, a reduced dose of 200 mg per day is required.
    • Non-RBV-containing regimens can be prescribed without dose adjustments for patients with a creatinine clearance ≥30 mL/min.
  • Contraindication: Clinicians should not use RBV in treatment of the following patients:
    • Female or male patients planning conception within 6 months of the last dose of RBV. (AII)
    • Male patients who have pregnant partners. (AII)
  • Contraindication: Clinicians should not use ombitasvir/paritaprevir/ritonavir/dasabuvir (PrOD) in treatment of women who are taking ethinyl estradiol-containing contraceptives. (AII)
Recommended DAA Regimens
  • Based on the results of the pretreatment assessment, clinicians should choose from among the treatment regimens for patients with HCV genotypes 1 through 6 listed in tables 8 through 28.
  • Clinicians should test for the presence of NS5A resistance-associated variants (RAVs) before starting therapy with elbasvir/grazoprevir in all patients with HCV genotype 1a infection. (AIII)
  • If a regimen with weight-based RBV is chosen, clinicians should dose as follows: (AI)
    • <75 kg: RBV 400 mg once daily + 600 mg once daily (total daily dose: 1000 mg)
    • ≥75 kg: RBV 600 mg twice daily (total daily dose: 1200 mg)
Monitoring During DAA Treatment
  • While patients are taking RBV, clinicians should perform hemoglobin testing at weeks 2 and 4 of treatment and every 4 weeks thereafter until therapy is complete. (AI)
  • In patients taking regimens that contain a DAA protease inhibitor (ombitasvir/paritaprevir/ritonavir and dasabuvir; elbasvir/grazoprevir; and regimens with simeprevir), clinicians should monitor alanine aminotransferase (ALT) 4 weeks after initiating treatment and continue to obtain serum aminotransferase as needed according to the drug’s prescribing information. (AIII)
  • In patients who are HBsAg positive and have no detectable HBV DNA, clinicians should monitor for HBV reactivation by performing aspartate aminotransferase (AST), ALT, and HBV DNA tests every 4 weeks during HCV treatment. (AIII)
  • Clinicians new to HCV treatment should consult an experienced HCV care provider for further evaluation of patients who develop detectable HBV DNA. (AIII)
  • If a woman becomes pregnant during therapy with a regimen containing RBV, clinicians should stop the RBV. (AI)
  • If a woman becomes pregnant during therapy with any DAA regimen, clinicians should discuss with her the benefits and risks of using DAAs during pregnancy. (AIII)
Post-Treatment Care
  • Clinicians should perform HCV RNA testing 12 weeks after treatment is complete to verify that a sustained virologic response (SVR) has been achieved. (AI)
  • If SVR is achieved, as established by undetectable HCV RNA at 12 weeks after treatment, clinicians should:
    • Inform their patients that the HCV infection has been cured (AII)
    • Explain the risk of HCV reinfection and that HCV antibodies are not protective against reinfection. (AI)
  • To assess for reinfection in patients with ongoing risk factors, clinicians should perform follow-up screening with HCV RNA testing (not HCV antibody testing) at least annually, even with a history of an SVR. (AI)
  • If HCV RNA is detectable at 12 weeks after treatment, clinicians should:
    • Inform patients that treatment has failed (AI)
    • If clinician is new to HCV treatment, consult with an experienced HCV care provider for retreatment evaluation (AIII)
  • For patients taking RBV-containing HCV treatment regimens, clinicians should:
    • Advise male and female patients to take extreme care to avoid pregnancy for 6 months after completion of therapy (AII)
    • Counsel female and male patients on effective contraceptive use (AII)
  • If a woman becomes pregnant within 6 months of completing and RBV-containing HCV treatment, clinicians should discuss with her the risks of using DAAs and RBV during pregnancy (AIII)
  • Clinicians should evaluate patients with persistent abnormal transaminase levels after SVR for other causes of liver disease and consult with a liver disease specialist. (AIII)
  • In patients with underlying bridging fibrosis or cirrhosis, clinicians should screen for hepatocellular carcinoma every 6 months. (AI)

About this Guideline

July 2017

NYSDOH AIDS Institute Hepatitis C Virus Infection Guideline Committee 

The New York State Department of Health (NYSDOH) AIDS Institute (AI) protects and promotes the health of New York State’s diverse population through disease surveillance and the provision of quality services for prevention, health care, and psychosocial support for those affected by HIV/AIDS, sexually transmitted diseases, viral hepatitis and related health concerns. In addition, the NYSDOH AI promotes the health of LGBT populations, substance users, and the sexual health of all New Yorkers. In response to the availability of effective new treatments for HCV, the AIDS Institute convened the Hepatitis C Virus Infection Guideline Committee in 2014 to develop a New York State guideline for the clinical care of HCV infection.

Committee Makeup

The members of the HCV committee (see Figure A1: HCV Committee Leaders, Members, and External Reviewers) were appointed by the NYSDOH AI to ensure representation of clinical practice in all major regions of the state, relevant medical disciplines and sub-specialties, key NYS agencies, community stakeholders, and patient advocates. Individuals confirmed as Committee members are required to disclose any potential conflicts of interest; disclosures are reviewed and approved by the NYSDOH AIDS Institute Office of the Medical Director (see Funding and Financial Disclosure of Potential Conflicts of Interest).

Committee Role

Committee members actively participate in guideline development, including evidence review, drafting of recommendations and text, manuscript review, consensus approval of all recommendations, and rating of recommendations.

Committee Leadership

The HCV Planning Group of committee leaders refined the manuscript, facilitated consensus approval of all recommendations, addressed feedback from external peer and consumer reviewers, and elicited input from other key AI guideline committees, including the Medical Care Criteria Committee (Adult HIV guidelines) and the Perinatal Transmission Prevention Committee.

Johns Hopkins University (JHU) Editorial Role

The JHU editorial team coordinated, guided, and documented all Committee activities, and edited the guideline material for clarity, flow, and style.

HCV Planning Group (Members of the full committee and reviewers are listed below)

  • Joshua S. Aron, MD, Co-Chair
  • Christine A. Kerr, MD, Co-Chair
  • David Bernstein, MD, FACG, AGAF, FACP, Contributing Committee Member
  • Colleen Flanigan, RN, MS, AIDS Institute Hepatitis Bureau Director
  • Charles J. Gonzalez, MD, AIDS Institute Deputy Medical Director
  • Christopher J. Hoffmann, MD, MPH, JHU Principal Investigator

JHU Editorial Team

  • Mary Beth Hansen, MA, JHU Project Director
  • Christina Norwood, MS, ELS, Senior Medical Editor
  • Jen Ham, MPH, JHU Medical Editor; Lead Editor
  • Hanna Gribble, MA, JHU Medical Editor
  • Celine Daly, MD, JHU, Contributing Editor
  • Jesse Ciekot, Program Coordinator
Figure A1. Hepatitis C Virus Infection Guideline Committee: Leadership, Contributing Members, Liaisons, and Guideline Reviewers 

Committee Leadership

  • Co-Chair: Joshua S. Aron, MD, Elmhurst Hospital Center, Elmhurst, NY
  • Co-Chair: Christine A. Kerr, MD, Hudson River Healthcare, Beacon, NY
  • Medical Director: Bruce D. Agins, MD, MPH, New York State Department of Health AIDS Institute, New York, NY
  • Deputy Director: Lyn C. Stevens, MS, NP, ACRN, New York State Department of Health AIDS Institute, Albany, NY
  • Principal Investigator: Christopher J. Hoffmann, MD, Johns Hopkins University School of Medicine, Baltimore, MD

Contributing Members

  • Mary Angerame, MS, APN-BC, Jordan Health, Rochester, NY
  • Ayse Aytaman, MD, AGAF, FACG, Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY
  • David Bernstein, MD, FAASLD, FACG, AGAF, FACP, Hofstra-Northwell School of Medicine Manhasset, NY
  • Lorna M. Dove, MD, MPH, New York-Presbyterian Hospital, New York, NY*
  • John J. Faragon, PharmD, BCPS, AAHIVP, Albany Medical Center, Albany, NY
  • Douglas G. Fish, MD, New York State Department of Health, Albany, NY
  • Alain H. Litwin, MD, MPH, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY
  • Kristen Marks, MD, Weill Cornell Medical College, New York, NY
  • Anthony D. Martinez, MD, University at Buffalo, Buffalo, NY
  • Brianna Norton, DO, MPH, Montefiore Medical Group, Bronx, NY
  • Russell Perry, MD, FAAFP, Bronx Lebanon Hospital, Bronx, NY
  • Ponni V. Perumalswami, MD, Icahn School of Medicine at Mount Sinai, New York, NY
  • Jeffrey J. Weiss, PhD, MS, Mount Sinai School of Medicine, New York, NY

Agency, Consumer, and Program Liaisons

  • Consumer Liaisons: Ivan Flores*, The Wellness Center at Port Morris, Bronx, NY; Cheryl Santoro, Hudson River Health Care, Peekskill, NY
  • Medical Society of the State of New York: William M. Valenti, MD, FIDSA, Trillium Health, Rochester, NY
  • New York City Department of Health and Mental Hygiene: Fabienne Laraque*, MD, MPH, Long Island City, NY
  • NYC Health + Hospitals: Vinh Pham, MD, PhD, Bellevue Hospital Center, New York, NY
  • New York State Department of Corrections and Community Supervision (NYS DOCCS): Paula R. Bozer, MD, Wende Correctional Facility, Alden, NY; and Carl J. Koenigsmann, MD, Albany, NY
  • New York State Office of Alcoholism and Substance Abuse Services Liaison: Michele Falkowski*, RN, BSN, CARN, Orangeburg, NY
  • Treatment Action Group (TAG): Annette Gaudino, New York, NY; Tracy Swan*, New York, NY

AIDS Institute Staff

  • Director, Bureau of Hepatitis Health Care: Colleen Flanigan, RN, MS, Albany, NY 
  • Associate Medical Director for Science and Policy: Charles J. Gonzalez, MD, New York, NY
  • Medical Director, Clinical Education Initiative: Cheryl A. Smith, MD, New York, NY
  • Guidelines Program Coordinator: Laura Duggan Russell, MPH, Albany, NY
  • Guidelines Program Coordinator (former): Tracy Hatton, MPH, New York, NY

AIDS Institute HIV Clinical Guidelines Program Committee Reviewers

  • Medical Care Criteria Committee:Samuel T. Merrick, MD (Chair), New York-Presbyterian Hospital, New York, NY; Joseph P. McGowan, MD, FACP, FIDSA (Vice-Chair), Northwell Health, Manhasset, NY; Judith A. Aberg, MD, FIDSA, FACP (Chair Emeritus), Icahn School of Medicine at Mount Sinai, New York, NY
  • Committee for the Prevention of Mother to Child Transmission of HIV:Rodney L. Wright, MD, MS (Co-Chair), Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY

External Peer Reviewers

  • Douglas T. Dieterich, MD, Icahn School of Medicine at Mount Sinai, New York, NY
  • Ira M. Jacobson, MD, Mount Sinai Beth Israel, New York, NY
  • Oluwaseun Falade-Nwulia, MBBS, MPH, Johns Hopkins University School of Medicine, Baltimore, MD
  • Karla Thorton, MD, University of New Mexico School of Medicine, Albuquerque, NM
  • Susan Lee, PharmD, BCPS, CDE, Hofstra-Northwell School of Medicine Manhasset, NY

*These individuals participated in the early development of the HCV guideline but were no longer in their positions, or were not able to serve as liaisons, at the conclusion of the project.

About this Guideline: Funding and Disclosure of Potential Conflicts of Interest

July 2017

Funding

The Treatment of Chronic Hepatitis C Virus (HCV) with Direct-Acting Antivirals (DAAs) guideline was developed using New York State funds awarded as a grant to the Johns Hopkins University School of Medicine, Division of Infectious Diseases, from the New York State Department of Health AIDS Institute.

Conflicts of Interest

All active committee members, invited consultants and coauthors, peer reviewers, and program staff are required to disclose financial relationships with commercial entities, including gifts that may be actual conflicts of interest or may be perceived as conflicts. These individuals must disclose financial relationships annually, for themselves, their partners/spouses, and their organization/institution. On their annual disclosures, committee members are asked to report for the previous 12 months and the upcoming 12 months.

No conflicts were reported by the Committee Chair and Co-Chair, the majority of Committee members, and all NYSDOH AI and JHU program staff. Figure A2, below, lists the conflicts reported by eight Committee members.

Management of Potential Conflicts of Interest

All reported financial relationships with commercial entities are reviewed by the NYSDOH AI guidelines program to assess the potential for undue influence on guideline recommendations made by the Committee. For the Committee members reporting conflicts, it was determined that: 1) in this guideline, no individual drug or device is recommended over another; and 2) individual committee members reported concurrent conflicts with competing pharmaceutical companies.

Any potential for undue influence is also mitigated by the consensus process.  All guideline recommendations received consensus approval of the full HCV Committee. The Committee Chairs and the NYSDOH AI Medical Director, none of whom reported conflicts of interest, performed the final review and approve the guideline.

All external reviewers, including peer reviewers and representatives from other NYSDOH AI Clinical Guidelines committees, were also required to submit conflict of interest/financial disclosure information, which were similarly screened. Three reviewers reported conflicts, which are listed in Figure A2.

Figure A2. Reported Conflicts of Interest/Financial Disclosure Results
Committee/Guideline Role Relationships disclosed for the previous and upcoming 12 months
Committee and Planning Group Member
  • Consultant to: AbbVie, Bristol-Myers Squibb, Gilead, Merck,
  • Research support from: Merck, AbbVie, Bristol-Myers Squibb, Gilead
  • Speakers’ bureau for: BMS, Gilead, Merck, AbbVie
Committee Member
  • Consultant to: Bristol-Myers Squibb, Gilead, and ViiV
  • Speaker: AbbVie, Janssen, Merck
Committee Member Consultant to:  Gilead Sciences,  Merck Pharmaceuticals,  AbbVie
Committee Member
  • Consultant to: Gilead,  Bayer, Intercept: Consulting       
  • Research support from: AbbVie, Salix, Gilead, AbbVie
  • Speakers’ bureau for: Merck, Bayer, Intercept, Gilead, AbbVie, Salix
Committee Member
  • Advisory Board for: Gilead (Primary Care Advisory Board HCV)
  • Speakers’ bureau for:  AbbVie
Committee Member
  • Consultant to: Roche Diagnostics
  • Research support from: Gilead
Committee Member
  • Consultant to: AbbVie
  • Research support from: Gilead
Committee Member Research support from: BMS, Gilead, and Merck
NYSDOH AI Medical Care Criteria Committee Reviewer
  • Consultant to: Merck
  • Research support from: ViiV, Gilead
External Peer Reviewer Consultant to: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck
External Peer Reviewer
  • Consultant to: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck: Achillion, Intercept, Trek
  • Research support from: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck
  • Speakers bureau for: AbbVie, Bristol-Myers Squibb, Gilead, Janssen

About this Guideline: Evidence Collection and Review

July 2017

The NYSDOH AI guideline development process is based on a systematic search and analysis of the published evidence. Figure A1, below, illustrates the evidence review and selection process.

Figure A1. Evidence Collection and Review Processes
Step 1 HCV Committee defines the goal of the guideline: To provide evidence-based clinical recommendations for primary care management of chronic hepatitis C infection, including screening, diagnosis, pretreatment assessment, treatment options, and post-treatment monitoring
Step 2 With individual authors, JHU editorial staff conducts a systematic literature search in PubMed using MESH terms. All searches limited to studies that 1) were published in the 5 years prior to the date of the literature search (see Table A3); 2) involved only human subjects; and 3) were published in English
Step 3 Authors review studies identified in searches; specific exclusion criteria include: 1) Studies involving interferon (IFN) treatment for chronic HCV infection; 2) Studies of HCV-associated comorbidities except those influencing HCV treatment decisions
Step 4 Authors and editorial staff conduct additional searches using PubMed and online databases to identify:

  • Studies published prior to the 5-year search limit
  • Studies published during the guideline development process
  • Recent conference abstracts, such as the annual conferences of the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL). Committee authors also consulted the HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C Infectious Diseases Society of America, a website produced by the AASLD and IDSA, which features current guidelines for treating HCV.
  • New York State epidemiologic data
Step 5  Development of guideline recommendations

  • Authors review evidence and draft recommendations
  • Planning Group members review, refine, and approve draft recommendations
  • Full committee reviews and reaches consensus on recommendations
  • Rating subcommittee reviews the cited evidence and assigns a two-part rating to each recommendation to indicate the strength of the recommendation and the quality of the supporting evidence; consensus is reached on ratings. 
Step 6   Ongoing Update Process

  • JHU editorial staff continue to collect evidence related to original searches and monitor for new drug approval
  • Planning Group reviews new evidence at least 3 times per year, more often if newly published studies, new drug approval, or drug-related warning indicates need for an immediate change to the published guideline.
  • Committee reviews and approves changes to the guideline 
  • Committee initiates a full review of guideline 4 years after the original publication date
  • NYSDOH AI publishes an update 5 years after the previous publication date

About this Guideline: Recommendation Development and Rating Process

July 2017

The clinical recommendations presented in this guideline were developed by consensus based on a synthesis of the current evidence collected through the systematic search described above. If no data were available, the recommendations are based on expert opinion, and this status is indicated in the rating and in the text.

The Planning Group met via monthly teleconferences over 18 months to finalize the guideline and reach consensus on recommendations and rationale. Once consensus among the Planning Group members was reached, the guideline was reviewed by the full HCV Committee, including consumer liaisons, and consensus was reached on all recommendations. These deliberations were conducted by teleconference; committee members were invited to submit comments in writing as well. Full committee review discussions were recorded, and recordings were reviewed carefully to ensure that all decisions and changes were captured and integrated into the manuscript.

Members of the Planning Group then individually reviewed the evidence for each recommendation and assigned a two-part rating (see Table A3). The individual ratings were compiled into a report distributed to all raters, and conference call discussions were held to deliberate ratings for which consensus was needed. Once all raters agreed on the interpretation of evidence and ratings for all recommendations, the guideline was sent to the NYSDOH AI for review and approval.

Figure A3. AIDS Institute HIV Clinical Guidelines Program Recommendations Rating Scheme
Strength of Recommendation Quality of Supporting Evidence
A = Strong 1 = At least 1 randomized trial with clinical outcomes and/or validated laboratory endpoints
B = Moderate 2 = One or more well-designed, nonrandomized trial or observational cohort study with long-term clinical outcomes
C = Optional 3 = Expert opinion

About this Guideline: External Review

July 2017

Five external peer reviewers recognized for their experience and expertise in the treatment of chronic HCV infection were identified by program leaders (see Figure A1: HCV Committee Leadership, Members, and External Reviewers). These individuals submitted a financial disclosure statement for the purpose of identifying potential conflicts of interest before participating as peer reviewers.  Disclosure information is included in Figure A2: Conflicts of Interest/Financial Disclosure Results.

Peer reviewers were asked to review the guideline for accuracy, balance, clarity, and practicality of the recommendations for primary care providers. The Planning Group addressed peer review feedback; any conflicting opinions were resolved by the Committee chairs.

Members of NYSDOH AI Medical Care Criteria Committee (Adult HIV Guidelines Committee) and the Perinatal Transmission Prevention Committee also provided reviews.

About this Guideline: Guideline Updates

July 2017

Members of the HCV Committee will monitor developments in the field of HCV treatment in an ongoing structured manner to maintain guideline currency. Once the guidelines are published on the program website: www.hivguidelines.org, any updates will be made to the HTML document as needed as treatment of chronic HCV with DAAs is a rapidly evolving field.

Notification of newly published studies will be automated, and the Planning Group will review new data at least every 4 months. Newly published data that provide support for existing recommendations will be cited in the text, and the studies will be added to the reference list(s).

If newly published data prompt a revision to recommendations or rationale, the Planning Group will propose appropriate edits and determine whether the changes warrant full committee review and approval. If full committee review is required, a conference call will be convened for that purpose.

If a new medication or formulation is approved, the Planning Group will be convened via conference call to examine the data, consider inclusion in the guideline, and determine the need for full committee review and approval.

The full guideline will be reviewed and updated on the 4th anniversary of publication to prepare for publication of an updated guideline on or before the 5th anniversary of publication.