HCV CARE

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

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]

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]

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]

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]

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]

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]

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 B 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.

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