Prevention and Management of Hepatitis B Virus Infection in Adults With HIV

Prevention and Management of Hepatitis B Virus Infection in Adults With HIV

Purpose of This Guideline

Lead author: Alok Gupta, MBBS, University of Rochester Medical Center
Publication date: August 30, 2022
Writing group: Steven M. Fine, MD, PhD; Rona M. Vail, MD; Joseph P. McGowan, MD, FACP, FIDSA; Samuel T. Merrick, MD; Asa E. Radix, MD, MPH, PhD, FACP, AAHIVS; Charles J. Gonzalez, MD; Christopher J. Hoffmann, MD, MPH
Committee: Medical Care Criteria Committee

Purpose: This guideline on prevention and management of hepatitis B virus (HBV) infection in adults with HIV has been developed by the New York State Department of Health AIDS Institute (NYSDOH AI) to guide clinicians in New York State who provide medical care for adults (≥18 years old) with HIV who are at risk of acquiring HBV or have HBV coinfection.

The goals of this guideline are to:

  • Raise awareness among clinicians about the prevalence and associated risks of chronic HBV in patients with HIV.
  • Increase screening for and vaccination against HBV in adults with HIV.
  • Provide up-to-date, evidence-based recommendations on diagnosis, assessment, treatment, and monitoring of chronic HBV infection in patients with HIV, with emphasis on the essential components of antiretroviral therapy to treat coinfection.

HBV transmission: There are an estimated 1.25 to 2.49 million people with chronic HBV in the United States [Lim, et al. 2020] and thousands of deaths annually from HBV-related complications, including cirrhosis and hepatocellular carcinoma (HCC) [CDC 2020]. The primary routes of HBV transmission are perinatal transmission to the child, blood exposure, and sexual exposure. HBV DNA has been detected in various bodily secretions, including tears, urine, and saliva, but there is no firm evidence of HBV transmission via body fluids other than blood, semen, or vaginal secretions [Tripathi and Mousa 2022; Komatsu, et al. 2012].

Approximately 95% of individuals who acquire HBV in adulthood will mount an immune response, resulting in spontaneous recovery and production of protective HBV antibodies (anti‐HBs). However, some individuals will develop persistent HBV due to failure of the initial immune response to clear the virus, which results in chronic HBV infection [Bennett, et al. 2019]. Chronic HBV infection is defined as circulating hepatitis B surface antigen (HBsAg) in the blood for ≥6 months [Terrault, et al. 2018].

HIV/HBV coinfection: HIV and HBV share similar transmission routes and both infections are often diagnosed in the same patients. Individuals with HIV born in the United States generally acquire HBV through sexual contact and injection drug use. In contrast, people with HIV born in HBV-endemic regions most commonly acquire the infection at birth or in early childhood [Alter 2006].

In a large U.S. cohort study of individuals with HIV, from 1996 to 2007, 8.4% overall tested positive for HBsAg or detectable HBV DNA; prevalence was higher (10.3%) among men who have sex with men than among individuals who inject drugs (8.5%) and heterosexual individuals with risk factors (5.2%) [Spradling, et al. 2010].

HIV/HBV coinfection can significantly influence the natural history, progression, management, morbidity, and mortality associated with both infections. HBV viremia and the risk of chronic HBV are increased in people with HIV [Thio 2009]. In addition, HIV infection is associated with decreased clearance of HBV e antigen. Individuals with HIV who acquire protective anti‐HBs through HBV infection remain at risk of developing low antibody levels and subsequent reactivation of HBV (reverse seroconversion). Individuals with HIV/HBV coinfection also tend to have a decreased inflammatory response to chronic HBV, indicated by decreased serum alanine transaminase levels, an increased risk of progression to cirrhosis and HCC, and increased mortality compared with individuals with HBV monoinfection [Sun, et al. 2021; Pinato, et al. 2019; Singh, et al. 2017; Thio 2009].

Post-exposure prophylaxis: For recommendations on HBV post-exposure prophylaxis, see the NYSDOH AI post-exposure prophylaxis (PEP) guideline section on Management of Potential Exposure to Hepatitis B Virus.

References

Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol 2006;44(1 Suppl):S6-9. [PMID: 16352363

Bennett J, Dolin R, Blaser MJ. 2019. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 9th ed. Elsevier. https://www.elsevier.com/books/mandell-douglas-and-bennetts-principles-and-practice-of-infectious-diseases/bennett/978-0-323-48255-4

CDC. Viral hepatitis surveillance report 2018 — hepatitis B. 2020 Jul 27. https://www.cdc.gov/hepatitis/statistics/2018surveillance/HepB.htm#Figure2.8 [accessed 2022 Jul 15]

Komatsu H, Inui A, Sogo T, et al. Tears from children with chronic hepatitis B virus (HBV) infection are infectious vehicles of HBV transmission: experimental transmission of HBV by tears, using mice with chimeric human livers. J Infect Dis 2012;206(4):478-485. [PMID: 22508939

Lim JK, Nguyen MH, Kim WR, et al. Prevalence of chronic hepatitis B virus infection in the United States. Am J Gastroenterol 2020;115(9):1429-1438. [PMID: 32483003

Pinato DJ, Allara E, Chen TY, et al. Influence of HIV infection on the natural history of hepatocellular carcinoma: Results from a global multicohort study. J Clin Oncol 2019;37(4):296-304. [PMID: 30562130

Singh KP, Crane M, Audsley J, et al. HIV-hepatitis B virus coinfection: epidemiology, pathogenesis, and treatment. AIDS 2017;31(15):2035-2052. [PMID: 28692539

Spradling PR, Richardson JT, Buchacz K, et al. Prevalence of chronic hepatitis B virus infection among patients in the HIV Outpatient Study, 1996-2007. J Viral Hepat 2010;17(12):879-886. [PMID: 20158604

Sun J, Althoff KN, Jing Y, et al. Trends in hepatocellular carcinoma incidence and risk among persons with HIV in the US and Canada, 1996-2015. JAMA Netw Open 2021;4(2):e2037512. [PMID: 33595662

Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67(4):1560-1599. [PMID: 29405329

Thio CL. Hepatitis B and human immunodeficiency virus coinfection. Hepatology 2009;49(5 Suppl):S138-145. [PMID: 19399813

Tripathi N, Mousa OY. StatPearls: Hepatitis B. 2022 Jun 11. https://www.ncbi.nlm.nih.gov/books/NBK555945/ [accessed 2022 Jul 18]

HBV Screening and Diagnosis

Lead author: Alok Gupta, MBBS, with the Medical Care Criteria Committee; August 30, 2022

RECOMMENDATIONS
Screening Tests
  • Clinicians should determine the HBV vaccination and immune status of patients with HIV by performing laboratory testing for HBsAg, anti-HBs, and anti-HBc (total). (A*)
  • Clinicians should repeat laboratory screening annually in patients who are not immune to HBV, choose not to be vaccinated, and are at ongoing risk of acquiring HBV. (A3)
Diagnosis
  • In patients with positive baseline (screening) HBsAg test results, clinicians should perform HBeAg, anti-HBe, and HBV DNA testing to diagnose the phase of HBV infection. (B2†)
  • If a patient with HIV and unknown HBsAg status has signs or symptoms of acute hepatitis (i.e., elevated ALT), the clinician should perform HBsAg, anti-HBc IgM, HBeAg, anti-HBe (A*), and HBV DNA (A3) testing along with other diagnostic testing for acute hepatitis.
Acute HBV Infection
  • If acute HBV infection is confirmed and the patient is asymptomatic, the clinician should repeat ALT testing within 2 to 4 weeks to assess for symptoms of liver disease progression (B3) and repeat HBsAg, HBeAg, anti-HBe, and HBV DNA testing 6 months later to determine whether infection has cleared. (A3)
  • If a patient with HIV and acute HBV is not taking ART, the clinician should recommend ART initiation.  (A1)
Transmission Prevention
  • Clinicians should advise patients who have a positive HBsAg test result that they can transmit HBV (A*) and encourage sexually active patients to use effective barrier protection to reduce the risk of HBV transmission. (A2†)
  • Clinicians should inform patients with HBV that their household contacts should be vaccinated and counsel the patients to avoid sharing items such as razors or toothbrushes that could expose others to HBV-contaminated blood. (A2†)
  • For individuals who inject drugs, clinicians should offer or refer for substance use treatment, ensure access to clean needles and syringes, and provide harm reduction counseling. (A2†)

———
Abbreviations: ALT, alanine transaminase; anti-HBc, hepatitis B core antibody; anti-HBe, antibody to HBeAg; anti-HBs, hepatitis B surface antibody; ART, antiretroviral therapy; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgG, immunoglobulin G; IgM, immunoglobulin M.

NEW YORK STATE LAW: REPORTING HBV INFECTION

Screening Tests

Clinicians should screen all patients with HIV for HBV risk, vaccination history, and infection upon entry into medical care and perform baseline testing to determine HBV immune status. Initial laboratory testing includes serologic testing for HBsAg, anti-HBc total, and anti-HBs, with results interpreted as detailed in Table 1, below. Patients with anti-HBs levels of ≥10 IU/mL are considered immune to HBV [DHHS 2022]. If a patient with HIV decides against HBV vaccination and remains at risk, annual laboratory screening is recommended [Terrault, et al. 2018]. See the guideline section HBV Vaccination.

Table 1: Interpretation of HBV Screening Test Results
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HBsAg Anti-HBs Anti-HBc Interpretation
IgG IgM
Negative Negative Negative Negative Susceptible to HBV infection
Negative Positive Negative Negative Immune due to HBV vaccination
Negative Positive Positive Negative Immune due to natural HBV infection
Positive Negative Positive Positive Acute HBV infection
Positive Negative Positive Negative/
Positive
Chronic HBV infection
Negative Negative Positive Negative/
Positive

Isolated anti-HBc positivity. Possible interpretations:

  • Resolved HBV infection with waning anti-HBs titers
  • False-positive result
  • Occult HBV infection
  • Resolving acute HBV infection
Abbreviations: anti-HBc, hepatitis B core antibody; anti-HBs, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgG, immunoglobulin G; IgM, immunoglobulin M.

Diagnosis

For patients with positive HBsAg screening test results, follow-up laboratory testing should be performed to confirm HBV status (see Table 2, below). If a patient with HIV and unknown HBsAg status presents with signs or symptoms of acute hepatitis (i.e., elevated ALT), the clinician should perform HBsAg, anti-HBc IgM, HBeAg, anti-HBe, and HBV DNA testing to confirm a diagnosis.

Table 2: Serologic and Virologic Responses to HBV Infection
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Stage of Infection HBsAg Anti-HBs Anti-HBc IgG Anti-HBc IgM HBeAg Anti-HBe HBV DNA Level
Incubation + + or  − Low
Acute HBV infection + + + + High
HBs-negative acute HBV + + + or  − High
Inactive HBsAg carrier + +++ + or  − + Low
Precore mutant [a] + + or  − + or  − + High
Occult infection + + or  − High or low
Chronic HBV infection + +++ + or  − + or  − High or low

Abbreviations: anti-HBc, hepatitis B core antibody (IgG or IgM); anti-HBe, antibody to HBeAg; anti-HBs, hepatitis B surface antibody; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgG, immunoglobulin G; IgM, immunoglobulin M.

Note:

  1. For more information, see Medscape: Precore Mutant Chronic Hepatitis B — Approach to Management.

Acute HBV infection: Following exposure, HBV enters the bloodstream and circulates to the liver. The post-exposure time to the onset of abnormal liver enzymes averages 60 days (range, 40 to 90 days), and the onset of jaundice averages 90 days (range, 60 to 150 days). Acute HBV infection is asymptomatic in approximately 70% of patients, and <1% of patients develop fulminant hepatic failure. When symptoms manifest, they may include anorexia, malaise, nausea, vomiting, arthralgias, and right upper quadrant abdominal pain. Symptoms generally resolve within 4 weeks, with normalization of transaminase levels in 2 to 8 weeks.

Acute HBV infection is diagnosed through the detection of HBsAg and anti-HBc IgM. During the initial phase of infection, HBeAg and HBV DNA are also present (see Figure 1, below). Recovery is marked by the disappearance of HBV DNA and seroconversion of HBeAg to anti-HBe and of HBsAg to anti-HBs [Shiffman 2010].

Figure 1: Typical Serologic Course of Acute Hepatitis B Virus Infection With Recovery
Reprinted from Centers for Disease Control and Prevention Recommendations for Identification and Public Health Management of Persons with Chronic Hepatitis B Virus Infection

Download Figure 1 PDF

Abbreviations: anti-HBc, hepatitis B core antibody; anti-HBe, antibody to HBeAg; anti-HBs, hepatitis B surface antibody; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; IgM, immunoglobulin M.

 

The ideal management strategy for symptomatic acute HBV infection in patients with HIV is not clear. Treatment with entecavir (ETV), tenofovir alafenamide (TAF), or tenofovir disoproxil fumarate (TDF) outside of a fully active anti-HIV regimen could lead to HIV resistance, but initiation of a fully active ART regimen may worsen acute liver disease due to immune reconstitution inflammatory syndrome (IRIS); see the NYSDOH AI guideline Management of IRIS. For most patients with acute HBV, treatment is mainly supportive. Antiviral therapy is generally not indicated in patients with symptomatic acute HBV because most immunocompetent adults with acute HBV recover spontaneously.

However, antiviral treatment is indicated for patients with acute liver failure or a protracted, severe course of HBV, as indicated by a total bilirubin level >3 mg/dL (or direct bilirubin level >1.5 mg/dL), an international normalized ratio >1.5, encephalopathy, or ascites. ETV, TAF, and TDF are the preferred antiviral agents for these patients. Treatment should be continued until HBsAg clearance is confirmed or should be continued indefinitely in patients who undergo liver transplantation [Terrault, et al. 2018]. Patients with HIV who are already taking a fully active ART regimen that includes TAF or TDF should continue with the regimen.

If acute HBV infection is confirmed in an asymptomatic patient, the clinician should repeat ALT testing within 2 to 4 weeks to assess for symptoms of liver disease progression and repeat HBsAg, HBeAg, anti-HBe, and HBV DNA testing in 6 months to determine whether infection has cleared. Patients with symptomatic acute HBV require more frequent monitoring tailored to the patient’s condition.

Chronic HBV infection: HBV infection is a dynamic disease, and individuals can transition through the defined clinical phases with variable levels of serum ALT activity, HBV DNA, and HBV antigens. See the guideline sections Assessment Before HBV Treatment and HBV Treatment and Monitoring for recommendations on the management of chronic HBV infection in patients with HIV.

Reactivation: Chronic HBV can resolve in some patients, and tests will indicate a sustained loss of HBsAg, undetectable serum HBV DNA levels, and absence of clinical or histologic evidence of active viral infection. However, reactivation of HBV replication, characterized by the reappearance of HBeAg and HBsAg and a rise in serum HBV DNA, can occur. Reactivation is usually seen in patients taking immunosuppressive therapy for a concurrent medical condition; in rare instances, patients with prior resolved HBV infection who are anti-HBs-positive can have reactivation of HBV during subsequent immunosuppressive therapy. For a list of medications associated with increased risk for HBV reactivation, see Medscape > Hepatitis B Treatment & Management. Reactivation of HBV can also occur in individuals with HIV, including those who experience immune reconstitution after initiation of ART. HBV reactivation may result in severe hepatitis and should be considered a potential cause of hepatitis in patients with previously resolved HBV infection. During reactivation, serum ALT levels will be elevated, and patients who were HBeAg- or HBsAg-negative may become both HBeAg- and HBsAg-positive. HBV reactivation can vary from mild and asymptomatic to severe with possible fulminant hepatic failure.

Occult HBV infection is defined as detectable HBV DNA in HBsAg-negative patients. Most patients with occult HBV have very low or undetectable serum levels, but HBV DNA is often detected in the liver. Patients with occult infection are at risk of HBV reactivation if they receive potent immunosuppressive therapy or chemotherapy. Occult HBV infection has been associated with chronic liver disease and increased risk of hepatocellular carcinoma [Raimondo, et al. 2007].

Transmission Prevention

HBV is significantly more transmissible through exposure to blood and body fluid than HIV and requires more frequent assessment for behaviors that increase HIV/HBV transmission risk. Barrier protection, including latex or polyurethane condoms, should be recommended to decrease the risk of sexual transmission [Smith, et al. 2015; Weller and Davis 2002], and sexual partners should be vaccinated if possible. It is important to advise patients that household contacts should be vaccinated against HBV and that they should avoid sharing any objects that may be contaminated with blood, such as razors or toothbrushes.

All active injection drug users should be prescribed clean syringes and needles and offered referrals to substance use treatment, such as opioid substitution. Referral to needle-exchange programs should also be offered (see NYSDOH Drug Use Resources). Injection drug users should also receive information about safe disposal and storage of needles/syringes and safer injection techniques.

Figure 2: Algorithm for HBV Screening and Vaccination in Patients With HIV

Download Figure 2 PDF

Abbreviations: anti-HBc, hepatitis B core antibody; anti-HBs, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.

Notes:

  1. In patients with positive anti-HBc, negative anti-HBs, and negative HBsAg test results, vaccinate with 1 standard dose of HBV vaccine and check anti-HBs titer after 8 weeks. If titer is <100 mlU/mL, complete remaining doses in the vaccine series and recheck titer 8 weeks after the last vaccine.
  2. In patients with anti-HBs levels <10 mlU/mL (vaccine nonresponse), revaccination is recommended with the Heplisav-B vaccine series or a double dose of the vaccine series previously administered.
  3. A patient who is negative for all serologies and who does not respond to revaccination may have a primary nonresponse or chronic infection. HBV DNA testing may be used to detect the presence of chronic HBV infection.
References

DHHS. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. 2022 Nov 13. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/hepatitis-b-virus-infection?view=full [accessed 2021 Apr 16]

Raimondo G, Pollicino T, Cacciola I, et al. Occult hepatitis B virus infection. J Hepatol 2007;46(1):160-170. [PMID: 17112622

Shiffman ML. Management of acute hepatitis B. Clin Liver Dis 2010;14(1):75-91; viii-ix. [PMID: 20123442

Smith DK, Herbst JH, Zhang X, et al. Condom effectiveness for HIV prevention by consistency of use among men who have sex with men in the United States. J Acquir Immune Defic Syndr 2015;68(3):337-344. [PMID: 25469526

Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67(4):1560-1599. [PMID: 29405329

Weller S, Davis K. Condom effectiveness in reducing heterosexual HIV transmission. Cochrane Database Syst Rev 2002;(1):Cd003255. [PMID: 11869658

HBV Vaccination

Lead author: Alok Gupta, MBBS, with the Medical Care Criteria Committee; August 30, 2022

RECOMMENDATIONS
Primary Vaccination
  • Clinicians should offer HBV vaccination with the 3-dose Engerix-B or Recombivax HB vaccine series (A1) or the 2-dose Heplisav-B vaccine series (A2†) to patients with negative test results for HBsAg, anti-HBs, and anti-HBc.
  • Clinicians should not defer initial HBV vaccination in patients with a CD4 count <200 cells/mm3 who are at risk for HBV infection. (A2)
  • Clinicians should repeat anti-HBs testing 4 to 16 weeks, based on the patient’s visit schedule, after completion of the vaccination series to ensure immunity (anti-HBs ≥10 mIU/mL). (A3)
  • In a patient with negative HBsAg, negative anti-HBs, and positive anti-HBc test results (isolated anti-HBc positive), the clinician should offer a 1-time dose of HBV vaccine. (A2)
    • Repeat anti-HBs testing 8 weeks after vaccination, and if the anti-HBs titer is <100 mIU/mL, complete the HBV vaccine series and repeat anti-HBs testing 8 weeks after the last vaccine. (A2)
    • If vaccination is refused or if follow-up anti-HBs titer testing cannot be assured, perform HBV DNA testing to evaluate for occult HBV infection. (A2)
  • Clinicians should not defer initial vaccination or revaccination in pregnant patients with HIV who do not have immunity to HBV. (A3)
Revaccination
  • In previously vaccinated patients with anti-HBs levels <10 mIU/mL (vaccine nonresponse), clinicians should recommend revaccination with the Heplisav-B vaccine series or a double dose of the vaccine series previously administered. (A2)

———
Abbreviations: anti-HBc, hepatitis B core antibody; anti-HBs, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.

Vaccination effectively prevents HBV infection. Patients with HIV with negative anti-HBs, anti-HBc, and HBsAg test results have no evidence of immunity and should be offered vaccination against HBV [DHHS 2022]; see Figure 2: Algorithm for HBV Screening and Vaccination in Patients With HIV and Table 1: Interpretation of HBV Screening Test Results. Conversely, patients with positive anti-HBc and anti-HBs test results have resolved HBV infection and do not require vaccination.

Primary Vaccination Strategies

The single-antigen HBV vaccines currently approved by the U.S. Food and Drug Administration (FDA) for individuals ≥18 years old are Engerix-B, Recombivax HB, and Heplisav-B. Prehevbrio, a new 3-antigen recombinant HBV vaccine, was approved in 2021 by the FDA for use for individuals ≥18 years old [FDA 2021], but experience regarding its use in patients with HIV is lacking at this time.

The level of immune response to HBV vaccination in individuals with HIV can be lower than in adults who are HIV seronegative [Mast, et al. 2006; Rey, et al. 2000; Tayal and Sankar 1994; Loke, et al. 1990]. Many studies have shown that the presence of detectable HIV RNA [Overton, et al. 2005; Tedaldi, et al. 2004] and low CD4 cell counts [Veiga, et al. 2006; Fonseca, et al. 2005; Tedaldi, et al. 2004; Keet, et al. 1992] correlates with a poor immune response to vaccination. Ideally, based on the data, the HBV vaccine should be administered before a patient’s CD4 count declines to <350 cells/mm3 to improve immunogenicity; however, vaccination should not be deferred in patients who have CD4 counts <350 cells/mm3.

The initial vaccine series using conventional HBV vaccines (Engerix-B, Recombivax HB) is typically administered intramuscularly as 3 standard doses at 0, 4, and 24 weeks (see Table 3, below).  Whether patients with HIV should receive a standard or double dose of these vaccines is still being debated. This Committee and the U.S. Department of Health and Human Services Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV recommend administering the standard 3-dose regimen. If the patient does not respond, a higher dose can be administered when the patient is revaccinated [DHHS 2022].

Heplisav-B, a 2-dose (4 weeks apart) recombinant HBsAg vaccine with a novel adjuvant, is also available for individuals ≥18 years old [FDA 2020]. In 3 randomized controlled trials among individuals without HIV, administration of 2 doses of Heplisav-B was associated with a higher seroprotection rate than 3 doses of Engerix-B [FDA 2020].

A recent retrospective cohort study among individuals with HIV found seroprotection rates were increased with the Heplisav-B vaccine compared with other previously used HBV vaccines [Schnittman, et al. 2021]. In addition, a recent modeling study determined that use of Heplisav-B among individuals with HIV results in lower costs and increased benefits compared with Engerix-B [Rosenthal, et al. 2020]. A 2-dose series may increase adherence because it requires fewer follow-up visits and a shorter wait time between doses than the 3-dose vaccines. No data are available to support use of other recombinant vaccines for the second dose if Heplisav-B is used for the initial dose.

Combined HBV and hepatitis A virus (HAV) vaccine: Twinrix is a combination vaccine that includes recombinant HBV and HAV vaccines; it is approved by the FDA for use in individuals ≥18 years old in the United States. For individuals with HIV who are not immune to both HAV and HBV, Twinrix may be administered as an initial series and administered in 3 doses at 0, 4, and 24 weeks. No data are available to support the administration of this vaccine as a double-dose or 4-dose series, so these strategies are not recommended in patients with HIV.

Table 3: HBV Vaccine Dosing Schedule
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Vaccine Dosing Notes
Engerix-B

Single dose: 20 µg as one 1 mL dose containing 20 µg/mL vaccine administered as follows:

  • 3 IM injections at weeks 0, 4, and 24 OR
  • 4 IM injections at weeks 0, 4, 8, and 24

Double dose: 40 µg as two 1 mL doses of 20 µg/mL vaccine administered as follows:

  • 3 IM injections at weeks 0, 4, and 24 OR
  • 4 IM injections at weeks 0, 4, 8, and 24
Patients with ESRD or other immunocompromising conditions [a]: 40 µg/mL as two 1 mL doses of 20 µg/mL vaccine administered in 3 IM injections at weeks 0, 4, 8, and 24
Recombivax HB

Single dose: 10 µg as one 1 mL dose containing 10 µg/mL vaccine administered as follows:

  • 3 IM injections at weeks 0, 4, and 24 OR
  • 4 IM injections at weeks 0, 4, 8, and 24

Double dose [b]: 20 µg as two 1 mL doses containing 10 µg/mL vaccine administered as follows:

  • 3 IM injections at weeks 0, 4, and 24 OR
  • 4 IM injections at weeks 0, 4, 8, and 24
Patients with ESRD or other immunocompromising conditions [a]: 40 µg/mL as 1 mL of higher-strength vaccine administered in 4 IM injections at weeks 0, 4, and 24
Heplisav-B [c]

Single dose: 20 µg as one 0.5 mL dose containing 20 µg/mL vaccine administered as follows:

  • 2 IM injections at weeks 0 and 4
  • Patients with ESRD: Standard dosing [Awad, et al. 2021]
  • Pregnant patients: Insufficient data to recommend use
Twinrix [d]

Single dose: 1 mL administered as follows:

  • 3 IM injections at weeks 0, 4, and 24
For patients who are not immune to either HBV or HAV

Abbreviations: ESRD, end-stage renal disease; HAV, hepatitis A virus; HBV, hepatitis B virus; IM, intramuscular.

Notes:

  1. Higher-strength regimens of both Engerix-B and Recombivax HB are approved by the U.S. Food and Drug Administration for use in patients with ESRD; these higher-strength regimens may also be considered for patients with other immunocompromising conditions.
  2. Double dosing with Recombivax HB has not been as well studied as double dosing with Engerix-B. However, Recombivax HB may be the only formulation available at some institutions.
  3. Double dosing and an accelerated schedule with Heplisav-B have not been well studied.
  4. Double dosing and use of a 4-dose series with Twinrix have not been well studied in patients with HIV and are not recommended.

Double-dose and 4-dose strategies: Other vaccination approaches are to administer a double dose of vaccine on a standard 3-dose schedule or to add a fourth dose at 2 months to a 3-dose vaccine series. Several studies have shown improved immune response to double-dose vaccinations given in a 3-dose schedule [Psevdos, et al. 2010; de Vries-Sluijs, et al. 2008; Fonseca, et al. 2005]. A 2013 meta-analysis (5 studies, n=883) found that increasing the vaccine dosage may significantly improve immune responses in participants with HIV [Ni, et al. 2013]. A 2015 multicenter, open-label, randomized controlled trial (RCT) compared standard-dose (20 μg) with double-dose (40 μg) HBV revaccination in adults who did not respond to primary vaccination [Rey, et al. 2015]. In this study, double-dose revaccination was not associated with a higher response rate than revaccination with a standard single-dose regimen at week 4 after vaccination. However, the proportion who responded to the vaccine and the geometric mean titers at week 4 after vaccination were higher in the double-dose group than in the standard-dose group. Seroprotective responses at week 72 were greater in the double-dose group than in the standard-dose group. The safety profile was similar between the groups [Rey, et al. 2015].

An RCT conducted in 2013 compared the immunogenicity and safety of 4 standard doses and 4 double doses with 3 standard doses of HBV vaccination in adults with HIV [Chaiklang, et al. 2013]. Response rates were higher in the 4-dose group than in the standard 3-dose group, but the difference was not statistically significant. Local adverse effects were more common with increased frequency and dosage of vaccine, but systemic and serious adverse effects were extremely rare [Chaiklang, et al. 2013]. Based on these data, it is reasonable to consider an alternative primary HBV vaccination approach with a 3- or 4-injection double-dose vaccine series in patients with HIV.

Accelerated vaccination: An RCT using the standard-dose HBV vaccine compared an accelerated schedule (0, 1, and 3 weeks) with the standard schedule (0, 4, and 24 weeks) and demonstrated a noninferior response rate for participants with CD4 counts >500 cells/mm3; this schedule may increase patient adherence to the full vaccine series [de Vries-Sluijs, et al. 2011]. However, the accelerated schedule was inferior in patients with CD4 counts of 200 to 500 cells/mm3. Because of the low number of participants with CD4 counts <200 cells/mm3, the results were inconclusive for this population.

Based on these findings, the accelerated schedule may be considered for patients with CD4 counts ≥500 cells/mm3 but is not recommended for patients with CD4 counts <500 cells/mm3 [de Vries-Sluijs, et al. 2011]. If an accelerated HBV vaccination schedule is used, the patient should also receive a fourth-dose booster at least 6 months after initiation of the vaccine series.

Pregnancy: Clinicians should not defer initial vaccination or revaccination in pregnant patients with HIV who do not have immunity to HBV. There are no well-controlled studies designed to evaluate the recommended anti-HBV vaccines during pregnancy. However, available data do not suggest an increased risk of miscarriage or major congenital disabilities in individuals who received Engerix-B, Twinrix, Recombivax HB, or Heplisav-B vaccines during pregnancy compared with individuals in the general U.S. population who were not vaccinated during pregnancy [FDA 2020, 2018a, 2018b, 2018c].

Isolated anti-HBc positivity: Defined as having negative HBsAg, negative anti-HBs, and positive anti-HBc test results, isolated anti-HBc positivity has been reported in 0.4% to 1.7% of blood donors in low prevalence areas and 10% to 20% of the population in endemic countries [Lok, et al. 1988]. It has been estimated that 17% to 41% of patients with HIV have isolated anti-HBc positivity [Bhattacharya, et al. 2016; Witt, et al. 2013; Neau, et al. 2005]. As shown in Table 1: Interpretation of HBV Screening Test Results, there are 4 possible interpretations of this result: resolved HBV infection with waning anti-HBs titers, false-positive result, occult HBV infection, or resolving acute HBV infection [Mast, et al. 2006].

Most patients with HIV and isolated anti-HBc positivity are HBV DNA-negative, not immune to HBV [Gandhi, et al. 2005], and routinely checking HBV DNA is no longer recommended. Clinicians should offer patients with HIV and isolated anti-HBc a single standard dose of HBV vaccine [DHHS 2022]. Anti-HBs testing should be performed 8 weeks after the first dose. If the anti-HBs titer is <100 mIU/mL, the remaining vaccines in the series should be administered, and anti-HBs testing should be repeated 8 weeks after the vaccine series is complete [DHHS 2022; Piroth, et al. 2016]. In a prospective study of 54 patients with HIV and isolated anti-HBc, 46% responded to a single dose of vaccine. Of those who did not respond to a single dose, 89% developed immunity after a 3-dose series of double-dose vaccine [Piroth, et al. 2016]. For patients with an anti-HBs titer ≥100 mIU/mL, clinicians may opt to discontinue the vaccine series. There are few data to guide the optimal number of vaccine doses for these patients but no evidence of harm in completing the full vaccination series.

However, if patients with HIV and isolated anti-HBc refuse vaccination or if post-vaccination anti-HBs testing cannot be assured, then a reasonable approach is to perform HBV DNA testing [Chang, et al. 2018]. HBV DNA testing may also be performed in patients with isolated anti-HBc who do not respond to the full vaccine series. A positive HBV DNA test result in a patient with isolated anti-HBc test results indicates occult HBV infection (see the guideline section HBV Screening and Diagnosis > Diagnosis > Reactivation).

Follow-up Testing

Clinicians should repeat anti-HBs testing 4 to 16 weeks, based on the patient’s visit schedule, after vaccination to ensure immunity [Rubin, et al. 2014]. If the anti-HBs titer is ≥10 mIU/mL, the patient is considered immune to HBV. If the anti-HBs titer is <10 mIU/mL, the patient may have primary nonresponse to the vaccine and require revaccination, or the patient may have chronic HBV infection. HBV DNA testing may be used to detect chronic HBV.

KEY POINT
  • Patient education regarding HBV vaccination is important to ensure awareness of the continued risk of acquiring and subsequently transmitting HBV until adequate anti-HBs response is confirmed.

Revaccination

Individuals with HIV who do not respond (anti-HBs <10 mIU/mL) to the primary HBV vaccine series should be revaccinated with Heplisav-B or a double dose of the vaccine series previously administered. In a recent retrospective, cross-sectional study among individuals with HIV who failed to seroconvert after vaccination (HBsAg- and anti-HBs-negative) with Engerix-B or Recombivax HB, revaccination with Heplisav-B was highly effective in achieving seroprotection [Khaimova, et al. 2021]. If Heplisav-B is not administered as the initial HBV vaccination series, revaccination with the 2-dose series may be considered.

If the primary HBV vaccination was a 3-dose series, a 4-dose series may be considered. Compared with a single-dose vaccine series for revaccination, a double-dose HBV vaccine series for revaccination improved immune response in some individuals with HIV [Rey, et al. 2015; Chaiklang, et al. 2013; Launay, et al. 2011; de Vries-Sluijs, et al. 2008].

Revaccination can be deferred for patients initiating ART until the CD4 count is ≥200 cells/mm3; response rates to vaccination may be higher in patients with CD4 counts ≥200 cells/mm3 than those with lower CD4 cell counts [Gandhi, et al. 2005].

References

Awad AM, Ntoso A, Connaire JJ, et al. An open-label, single-arm study evaluating the immunogenicity and safety of the hepatitis B vaccine HepB-CpG (HEPLISAV-B®) in adults receiving hemodialysis. Vaccine 2021;39(25):3346-3352. [PMID: 34001345

Bhattacharya D, Tseng CH, Tate JP, et al. Isolated hepatitis B core antibody is associated with advanced hepatic fibrosis in HIV/HCV infection but not in HIV infection alone. J Acquir Immune Defic Syndr 2016;72(1):e14-17. [PMID: 26829660

Chaiklang K, Wipasa J, Chaiwarith R, et al. Comparison of immunogenicity and safety of four doses and four double doses vs. standard doses of hepatitis B vaccination in HIV-infected adults: a randomized, controlled trial. PLoS One 2013;8(11):e80409. [PMID: 24265819

Chang JJ, Mohtashemi N, Bhattacharya D. Significance and management of isolated hepatitis B core antibody (anti-HBc) in HIV and HCV: strategies in the DAA era. Curr HIV/AIDS Rep 2018;15(2):172-181. [PMID: 29572624

de Vries-Sluijs TE, Hansen BE, van Doornum GJ, et al. A randomized controlled study of accelerated versus standard hepatitis B vaccination in HIV-positive patients. J Infect Dis 2011;203(7):984-991. [PMID: 21266513

de Vries-Sluijs TE, Hansen BE, van Doornum GJ, et al. A prospective open study of the efficacy of high-dose recombinant hepatitis B rechallenge vaccination in HIV-infected patients. J Infect Dis 2008;197(2):292-294. [PMID: 18177248

DHHS. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. 2022 Nov 13. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/hepatitis-b-virus-infection?view=full [accessed 2021 Apr 16]

FDA. Engerix-B [hepatitis B vaccine (recombinant)] injectable suspension, for instramuscular use. 2018a Dec 21. https://www.fda.gov/media/119403/download [accessed 2022 Mar 2]

FDA. Recombivax HB hepatitis B vaccine (recombinant). 2018b Dec. https://www.fda.gov/media/74274/download [accessed 2022 Mar 2]

FDA. Twinrix [hepatitis A & hepatitis B (recombinant) vaccine] injectable suspension, for intramuscular use. 2018c Dec 18. https://www.fda.gov/media/119351/download [accessed 2022 Mar 2]

FDA. Heplisav-B [hepatitis B vaccine (recombinant), adjuvanted] solution for intramuscular injection. 2020 May. https://www.fda.gov/vaccines-blood-biologics/vaccines/heplisav-b [accessed 2022 Jul 18]

FDA. Prehevbrio [hepatitis B vaccine (recombinant)]. 2021 Dec 1. https://www.fda.gov/media/154561/download [accessed 2022 Mar 21]

Fonseca MO, Pang LW, de Paula Cavalheiro N, et al. Randomized trial of recombinant hepatitis B vaccine in HIV-infected adult patients comparing a standard dose to a double dose. Vaccine 2005;23(22):2902-2908. [PMID: 15780739

Gandhi RT, Wurcel A, Lee H, et al. Response to hepatitis B vaccine in HIV-1-positive subjects who test positive for isolated antibody to hepatitis B core antigen: implications for hepatitis B vaccine strategies. J Infect Dis 2005;191(9):1435-1441. [PMID: 15809901

Keet IP, van Doornum G, Safary A, et al. Insufficient response to hepatitis B vaccination in HIV-positive homosexual men. AIDS 1992;6(5):509-510. [PMID: 1535502

Khaimova R, Fischetti B, Cope R, et al. Serological response with Heplisav-B® in prior hepatitis B vaccine non-responders living with HIV. Vaccine 2021;39(44):6529-6534. [PMID: 34600748

Launay O, van der Vliet D, Rosenberg AR, et al. Safety and immunogenicity of 4 intramuscular double doses and 4 intradermal low doses vs standard hepatitis B vaccine regimen in adults with HIV-1: a randomized controlled trial. JAMA 2011;305(14):1432-1440. [PMID: 21486976

Lok AS, Lai CL, Wu PC. Prevalence of isolated antibody to hepatitis B core antigen in an area endemic for hepatitis B virus infection: implications in hepatitis B vaccination programs. Hepatology 1988;8(4):766-770. [PMID: 2968945

Loke RH, Murray-Lyon IM, Coleman JC, et al. Diminished response to recombinant hepatitis B vaccine in homosexual men with HIV antibody: an indicator of poor prognosis. J Med Virol 1990;31(2):109-111. [PMID: 2143776

Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep 2006;55(Rr-16):1-33; quiz CE31-34. [PMID: 17159833

Neau D, Winnock M, Jouvencel AC, et al. Occult hepatitis B virus infection in HIV-infected patients with isolated antibodies to hepatitis B core antigen: Aquitaine cohort, 2002-2003. Clin Infect Dis 2005;40(5):750-753. [PMID: 15714424

Ni JD, Xiong YZ, Wang XJ, et al. Does increased hepatitis B vaccination dose lead to a better immune response in HIV-infected patients than standard dose vaccination: a meta-analysis? Int J STD AIDS 2013;24(2):117-122. [PMID: 23467291

Overton ET, Sungkanuparph S, Powderly WG, et al. Undetectable plasma HIV RNA load predicts success after hepatitis B vaccination in HIV-infected persons. Clin Infect Dis 2005;41(7):1045-1048. [PMID: 16142673

Piroth L, Launay O, Michel ML, et al. Vaccination Against Hepatitis B Virus (HBV) in HIV-1-Infected Patients With Isolated Anti-HBV Core Antibody: The ANRS HB EP03 CISOVAC Prospective Study. J Infect Dis 2016;213(11):1735-1742. [PMID: 26768256

Psevdos G, Kim JH, Groce V, et al. Efficacy of double-dose hepatitis B rescue vaccination in HIV-infected patients. AIDS Patient Care STDS 2010;24(7):403-407. [PMID: 20586648

Rey D, Krantz V, Partisani M, et al. Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients. Effects on HIV-1 viral load. Vaccine 2000;18(13):1161-1165. [PMID: 10649616

Rey D, Piroth L, Wendling MJ, et al. Safety and immunogenicity of double-dose versus standard-dose hepatitis B revaccination in non-responding adults with HIV-1 (ANRS HB04 B-BOOST): a multicentre, open-label, randomised controlled trial. Lancet Infect Dis 2015;15(11):1283-1291. [PMID: 26257021

Rosenthal EM, Hall EW, Rosenberg ES, et al. Assessing the cost-utility of preferentially administering Heplisav-B vaccine to certain populations. Vaccine 2020;38(51):8206-8215. [PMID: 33160756

Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014;58(3):e44-100. [PMID: 24311479

Schnittman SR, Zepf R, Cocohoba J, et al. Brief report: Heplisav-B seroprotection in people with HIV: A single-center experience. J Acquir Immune Defic Syndr 2021;86(4):445-449. [PMID: 33196553

Tayal SC, Sankar KN. Impaired response to recombinant hepatitis B vaccine in asymptomatic HIV-infected individuals. AIDS 1994;8(4):558-559. [PMID: 7912087

Tedaldi EM, Baker RK, Moorman AC, et al. Hepatitis A and B vaccination practices for ambulatory patients infected with HIV. Clin Infect Dis 2004;38(10):1478-1484. [PMID: 15156488

Veiga AP, Casseb J, Duarte AJ. Humoral response to hepatitis B vaccination and its relationship with T CD45RA+ (naïve) and CD45RO+ (memory) subsets in HIV-1-infected subjects. Vaccine 2006;24(49-50):7124-7128. [PMID: 16884833

Witt MD, Lewis RJ, Rieg G, et al. Predictors of the isolated hepatitis B core antibody pattern in HIV-infected and -uninfected men in the multicenter AIDS cohort study. Clin Infect Dis 2013;56(4):606-612. [PMID: 23090927

Assessment Before HBV Treatment

Lead author: Alok Gupta, MBBS, with the Medical Care Criteria Committee; August 30, 2022

RECOMMENDATIONS
Liver Disease Assessment
  • Before initiating HBV treatment in patients with HIV, clinicians should obtain a complete physical examination and medical history, including the use of hepatoxic medications (A*); noninvasive fibrosis evaluation (A2†); baseline ultrasonography for HCC [a] (A2†); and the following laboratory testing: CBC, albumin, bilirubin, alkaline phosphatase, PT/INR, ALT, AST, and a basic metabolic panel. (A*)
  • Clinicians should refer patients with HIV/HBV coinfection and cirrhosis to a gastroenterologist or hepatologist to assess and manage complications of portal hypertension. (A3)
  • In patients with HIV/HBV coinfection and cirrhosis, clinicians should screen for HCC with ultrasound every 6 months. (A2†)
Alcohol Use Screening and Education
  • Clinicians should perform alcohol use screening in patients with HIV/HBV coinfection at baseline and at least annually and refer patients for treatment as needed. (A3)
  • Clinicians should educate patients about the detrimental effects of alcohol use on the course of HBV infection and counsel patients with underlying liver disease to abstain from or minimize alcohol use. (A*)
HAV, HCV, and HDV Status
  • Clinicians should perform anti-HAV IgG or total (IgM and IgG) serum testing and administer the full HAV vaccine series in patients who are not immune to HAV. (A3)
  • Clinicians should determine patients’ HCV status by medical history and serum testing and recommend treatment with DAA therapy if chronic HCV infection is diagnosed. (A1)
  • Clinicians should perform anti-HDV total (IgM and IgG) serum testing to screen for HDV in all patients with HIV/HBV coinfection. (B2)

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Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; CBC, complete blood count; DAA, direct-acting antiviral; HAV, hepatitis A virus; HBV, hepatitis B virus; HCC; hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; IgG, immunoglobulin G; IgM, immunoglobulin M; PT/INR, prothrombin time/international normalized ratio.

Note:

  1. Baseline ultrasound for HCC is performed in all patients with HIV/HBV coinfection. In patients with HIV/HCV coinfection, an ultrasound is performed only in patients with cirrhosis.

Liver Disease Assessment

Initial assessment of patients with chronic HBV should include a detailed history and physical examination to evaluate for any signs of advanced liver disease, including bruising, jaundice, dark urine, light stools, history of gastrointestinal bleeding, and pruritus. A prior treatment history, including medication history, should be obtained to determine whether the patient has previously taken hepatotoxic medications or lamivudine or emtricitabine, which have been associated with HBV resistance when taken as monotherapy. On examination, identify any stigmata of advanced liver disease, such as spider angiomas, splenomegaly, palmar erythema, and asterixis. The presence of ascites or encephalopathy indicates decompensated liver disease. Baseline laboratory tests include CBC, albumin, bilirubin, alkaline phosphatase, prothrombin time, ALT, and AST. Low albumin levels or elevated prothrombin time may suggest advanced liver disease with hepatic decompensation. Leukopenia and thrombocytopenia may indicate the presence of portal hypertension.

All individuals should be evaluated for liver fibrosis using noninvasive methods, such as transient elastography (FibroScan), serum testing for biomarkers (FibroSure), or AST to platelet ratio index (APRI) calculation. Liver biopsy is no longer preferred because of the risk of complications (e.g., bleeding, infection) and the possibility of a sampling error when only a small portion of the liver is evaluated. All patients with HIV/HBV coinfection should have a baseline ultrasound to screen for HCC [Terrault, et al. 2018], and those with cirrhosis should be referred to a hepatologist to screen for esophageal varices [Garcia-Tsao, et al. 2017; de Franchis 2015].

Results of the liver disease assessment determine the phase of chronic HBV infection. Liver biopsy results are included below as part of the description of each stage. However, liver biopsy is rarely indicated in patients with HIV/HBV. The procedure can be considered in patients who have persistently elevated ALT but persistently low HBV DNA to exclude other causes of liver disease.

  • Immune tolerance: Characterized by hepatitis B e antigen (HBeAg) positivity with elevated HBV DNA levels but normal or minimally elevated ALT levels. Liver biopsies are generally benign, without signs of necroinflammation or fibrosis [Tran 2011].
  • Immune active: Subdivided into HBeAg-positive and HBeAg-negative. In HBeAg-positive patients, HBV DNA levels are typically >20,000 IU/mL, and serum ALT levels are elevated. In HBeAg-negative patients, HBV DNA levels tend to be lower (2,000 to 20,000 IU/mL) with low to normal serum ALT levels. Liver biopsy often reveals chronic hepatitis with variable signs of necroinflammation or fibrosis [Terrault, et al. 2018].
  • Inactive chronic HBV: These patients are HBeAg-negative and antibody to HBeAg-positive. Serum HBV DNA is usually <2000 IU/mL or undetectable, and ALT levels are normal. Liver biopsy indicates an absence of significant necroinflammation and variable levels of fibrosis [Terrault, et al. 2018].

Alcohol Use Screening and Education

In 2020, there were an estimated 29,000 deaths from alcoholic liver disease and 51,000 deaths from chronic liver disease and cirrhosis in the general U.S. population [CDC 2022a, 2022b]. Chronic alcohol use in patients with HBV infection results in increased oxidative stress and liver inflammation, which can progress to cirrhosis and lead to the development of HCC [Donato, et al. 1997; Nakanuma and Ohta 1983]. These effects are even more pronounced in patients with HIV/HBV coinfection in whom increased levels of liver inflammation, liver fibrosis, drug-induced hepatotoxicity, liver cirrhosis, and death from liver disease and HCC have been observed [Marcellin, et al. 2008; Poynard, et al. 2003; Núñez, et al. 2001]. Patient education is essential to helping patients understand the effects of alcohol use on the course of HBV infection, as is counseling for patients with underlying liver disease so that patients can make informed decisions regarding alcohol use or abstinence. Studies have shown that individual counseling and peer group education and support can be effective in reducing alcohol use in patients with HIV [Knox, et al. 2013; Velasquez, et al. 2009].

HAV, HCV, and HDV Status

HAV: For information on HAV/HIV coinfection, see the NYSDOH AI guideline Prevention and Management of Hepatitis A Virus Infection in Adults With HIV > Management of HAV/HIV Coinfection.

HCV: HBV/HCV coinfection is associated with higher rates of cirrhosis, increased severity of liver disease, and increased risk of HCC than HBV or HCV monoinfection [Mavilia and Wu 2018]. This is of particular concern in patients with HIV/HBV coinfection; patients with HIV infection have more severe liver disease and higher rates of liver complications than patients without HIV [Bräu, et al. 2007; Thio, et al. 2002]. For information on screening, diagnosis, and treatment of HCV in patients with HIV, see the NYSDOH AI guideline Treatment of Chronic HCV with Direct-Acting Antivirals.

HDV: Formerly known as hepatitis delta virus, HDV is a defective satellite RNA virus that requires active HBV infection to replicate. HIV/HBV/HDV tri-infection is associated with more rapid liver disease progression and higher rates of decompensated cirrhosis, HCC, and mortality than HIV/HBV coinfection [Béguelin, et al. 2017; Fernández-Montero, et al. 2014; Castellares, et al. 2008; Sheng, et al. 2007]. HDV infection is uncommon in the United States; it is not a reportable disease, and the prevalence is unknown [Patel, et al. 2019]. The majority of cases occur among people who migrate or travel to the United States from countries with high HDV endemicity (i.e., Eastern Europe, Southern Europe, the Mediterranean region, the Middle East, West and Central Africa, East Asia, and the Amazon River Basin in South America) [CDC 2020].

Existing data indicate that pegylated interferon (PEG-IFN) is the only effective anti-HDV treatment [EASL 2012]. However, fewer than 30% of people without HIV who have HDV achieve sustained HDV suppression when treated with PEG-IFN [Wedemeyer et al. 2011]. No data are available regarding the efficacy of PEG-IFN therapy in patients with HIV/HBV/HDV tri-infection. Because HDV depends on HBV to replicate, HBsAg seroconversion should be the primary goal for patients with HIV/HBV/HDV tri-infection. In patients with tri-infection, prompt initiation of anti-HBV and anti-HIV therapy should be strongly encouraged.

Little guidance is available on optimal monitoring strategies for patients with HIV/HBV coinfection and positive serum anti-HDV total (IgM and IgG) test results. It is reasonable to perform baseline HDV RNA testing and consult with an experienced care provider about ongoing HDV RNA and DNA testing [Farci and Anna Niro 2018].

References

Béguelin C, Moradpour D, Sahli R, et al. Hepatitis delta-associated mortality in HIV/HBV-coinfected patients. J Hepatol 2017;66(2):297-303. [PMID: 27746337

Bräu N, Fox RK, Xiao P, et al. Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.-Canadian multicenter study. J Hepatol 2007;47(4):527-537. [PMID: 17692986

Castellares C, Barreiro P, Martín-Carbonero L, et al. Liver cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome. J Viral Hepat 2008;15(3):165-172. [PMID: 18233989

CDC. Viral hepatitis: hepatitis D. 2020 Jun 22. https://www.cdc.gov/hepatitis/hdv/index.htm [accessed 2022 Jul 18]

CDC. National Center for Health Statistics: Alcohol use. 2022a Jan 13. https://www.cdc.gov/nchs/fastats/alcohol.htm [accessed 2022 Jul 18]

CDC. National Center for Health Statistics: Chronic liver disease and chirrhosis. 2022b Jan 5. https://www.cdc.gov/nchs/fastats/liver-disease.htm [accessed 2022 Mar 21]

de Franchis R. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63(3):743-752. [PMID: 26047908

Donato F, Tagger A, Chiesa R, et al. Hepatitis B and C virus infection, alcohol drinking, and hepatocellular carcinoma: a case-control study in Italy. Brescia HCC Study. Hepatology 1997;26(3):579-584. [PMID: 9303486

Farci P, Anna Niro G. Current and future management of chronic hepatitis D. Gastroenterol Hepatol (N Y) 2018;14(6):342-351. [PMID: 30166948

Fernández-Montero JV, Vispo E, Barreiro P, et al. Hepatitis delta is a major determinant of liver decompensation events and death in HIV-infected patients. Clin Infect Dis 2014;58(11):1549-1553. [PMID: 24633686

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):310-335. [PMID: 27786365

Knox TA, Jerger L, Tang AM. 2013. Alcohol, HIV/AIDS, and liver disease. In: Watson RR, Preedy VR, Zibadi S, editors. Alcohol, nutrition, and health consequences. New York: Humana Press. https://link.springer.com/chapter/10.1007/978-1-62703-047-2_23

Marcellin P, Pequignot F, Delarocque-Astagneau E, et al. Mortality related to chronic hepatitis B and chronic hepatitis C in France: evidence for the role of HIV coinfection and alcohol consumption. J Hepatol 2008;48(2):200-207. [PMID: 18086507

Mavilia MG, Wu GY. HBV-HCV coinfection: Viral interactions, management, and viral reactivation. J Clin Transl Hepatol 2018;6(3):296-305. [PMID: 30271742

Nakanuma Y, Ohta G. Morphology of cirrhosis and occurrence of hepatocellular carcinoma in alcoholics with and without HBsAg and in non-alcoholic HBsAg-positive patients. A comparative autopsy study. Liver 1983;3(4):231-237. [PMID: 6323910

Núñez M, Lana R, Mendoza JL, et al. Risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2001;27(5):426-431. [PMID: 11511818

Patel EU, Thio CL, Boon D, et al. Prevalence of hepatitis B and hepatitis D virus infections in the United States, 2011-2016. Clin Infect Dis 2019;69(4):709-712. [PMID: 30605508

Poynard T, Mathurin P, Lai CL, et al. A comparison of fibrosis progression in chronic liver diseases. J Hepatol 2003;38(3):257-265. [PMID: 12586290

Sheng WH, Hung CC, Kao JH, et al. Impact of hepatitis D virus infection on the long-term outcomes of patients with hepatitis B virus and HIV coinfection in the era of highly active antiretroviral therapy: a matched cohort study. Clin Infect Dis 2007;44(7):988-995. [PMID: 17342655

Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67(4):1560-1599. [PMID: 29405329

Thio CL, Seaberg EC, Skolasky R, Jr., et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet 2002;360(9349):1921-1926. [PMID: 12493258

Tran TT. Immune tolerant hepatitis B: a clinical dilemma. Gastroenterol Hepatol (N Y) 2011;7(8):511-516. [PMID: 22298987

Velasquez MM, von Sternberg K, Johnson DH, et al. Reducing sexual risk behaviors and alcohol use among HIV-positive men who have sex with men: a randomized clinical trial. J Consult Clin Psychol 2009;77(4):657-667. [PMID: 19634959

HBV Treatment and Monitoring

Lead author: Alok Gupta, MBBS, with the Medical Care Criteria Committee; August 30, 2022

RECOMMENDATIONS
Treatment
  • Clinicians should recommend immediate ART initiation for any patient with HIV/HBV coinfection who is not taking ART. (A1)
  • Preferred: In patients with HIV and chronic HBV, clinicians should recommend an ART regimen that includes 2 agents active against HBV (see Table 4: Available Medications for Treatment of HBV Infection in Adults With HIV). Preferred regimens include a backbone of either TAF/FTC, TDF/FTC, or TDF/3TC. (A2)
  • Clinicians should not prescribe a 2-drug regimen of TAF/FTC, TDF/FTC, or TDF/3TC alone to treat patients with HIV/HBV coinfection; a fully suppressive ART regimen is required. (A1)
  • Nonadherence with or discontinuation of anti-HBV treatment may result in transaminase flares and hepatic damage. Clinicians should educate patients about the treatment adherence requirements (A*), and if treatment must be interrupted or discontinued, consult with a care provider experienced in HIV/HBV coinfection. (A3)
  • Alternative: If a patient cannot or chooses not to take TDF or TAF, the clinician should initiate treatment with ETV and a fully suppressive ART regimen for HIV. (A3)
Pregnant Patients
  • Clinicians should offer pregnant patients treatment with an ART regimen that includes 2 agents active against both HIV and HBV; 3TC, FTC, TAF, and TDF can be used safely during pregnancy at standard doses. (A2†)
Monitoring

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Abbreviations: 3TC, lamivudine; ALT, alanine transaminase; ART, antiretroviral therapy; ETV, entecavir; FTC, emtricitabine; HBV, hepatitis B virus; HDV, hepatitis D virus; IRIS, immune reconstitution inflammatory syndrome; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

Treatment

Goals: The goals of treatment for chronic HBV infection in adults with HIV are to reduce liver inflammation (as indicated by normalization of ALT), obtain seroconversion of hepatitis B e antigen (HBeAg) to antibody to HBeAg, and suppress HBV viral replication. These changes will help reduce the risk of hepatic decompensation, halt or reverse liver fibrosis, prevent the development of hepatocellular carcinoma (HCC), and decrease HBV-related mortality [Kim, et al. 2021; Terrault, et al. 2018; Soriano, et al. 2008].

As indicated in the NYSDOH AI guideline When to Initiate ART, With Protocol for Rapid Initiation, clinicians should recommend ART to all patients diagnosed with HIV infection. For patients with HIV/HBV coinfection, the regimen should include medications that suppress both HIV and HBV (see Table 4, below). Optimal treatment for both viruses should be taken simultaneously to prevent the development of HIV and HBV drug resistance. Optimal treatment of both infections may also help reduce the risk of IRIS, which is increased in patients with high levels of HBV viremia [Avihingsanon, et al. 2012; Crane, et al. 2009]. See the guideline section Monitoring.

Table 4: Available Medications for Treatment of HBV Infection in Adults With HIV
Download PDF
Medication Clinical Comment
Tenofovir disoproxil fumarate (TDF)
  • A prodrug of the NRTI tenofovir active against HIV and HBV, including 3TC-resistant HBV
  • A preferred agent for chronic HBV treatment because of its high virologic efficacy and low risk of HBV resistance [Terrault, et al. 2018]
  • Potential association with renal impairment and loss of bone density [McComsey, et al. 2011; Gupta 2008]
  • Initiate only in patients with CrCl ≥50 mL/min.
Tenofovir alafenamide (TAF)
  • A prodrug of the NRTI tenofovir active against HIV and HBV that achieves higher intracellular concentrations in peripheral blood mononuclear cells and hepatocytes than TDF [Agarwal, et al. 2018]
  • Improved biomarkers for renal and bone safety compared with TDF while maintaining high rates of HIV and HBV viral suppression [Lampertico, et al. 2020; Gallant, et al. 2016; Callebaut, et al. 2015]
  • In HIV/HBV coinfection, switching from a TDF- to a TAF-containing regimen demonstrated similarly high levels of HBV virologic control [Gallant, et al. 2016].
  • Initiate only in patients with CrCl ≥30 mL/min.
Lamivudine (3TC)
  • An HBV reverse transcriptase inhibitor and HIV NRTI active against HIV and HBV
  • Has a low genetic barrier to HIV and HBV resistance and should not be used as the sole anti-HBV drug in an ART regimen. Studies found the rate of HBV resistance reached 90% after 4 years of 3TC monotherapy [Benhamou, et al. 1999]. Avoid 3TC monotherapy.
Emtricitabine (FTC)
  • An NRTI similar to 3TC and active against HIV and HBV
  • 3TC-resistant isolates are also cross-resistant to FTC [Gallant 2006].
  • Do not use as the sole anti-HBV drug in an ART regimen.
Entecavir (ETV)
  • An NRTI active against HIV and HBV
  • May select for 3TC- and FTC-resistant HIV
  • ETV monotherapy for HBV is not recommended in patients with HIV unless combined with a fully active ART regimen to treat HIV.
Interferon (IFN)
  • IFN alfa-2a or -2b or PEG-IFN alfa-2a is used as HBV treatment in patients with HBV monoinfection.
  • Contraindicated in patients with decompensated liver disease (Child-Turcotte-Pugh class B or C)
  • PEG-IFN alfa-2a monotherapy for up to 48 weeks may be considered for HBV treatment in patients with HIV/HBV coinfection if concurrent ART active against HIV and HBV is not possible.
  • PEG-IFN alfa-2a is not associated with HBV drug resistance [DHHS 2022].
Abbreviations: ART, antiretroviral therapy; CrCl, creatinine clearance; HBV, hepatitis B virus; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; PEG-IFN, pegylated interferon.

Preferred regimen: Because FTC, 3TC, TDF, and TAF all have activity against HIV and HBV, an ART regimen for a patient with HIV/HBV coinfection should include a nucleoside/nucleotide reverse transcriptase inhibitor backbone of either TAF/FTC, TDF/FTC, or TDF/3TC as part of a fully suppressive regimen. TDF or TAF should not be used alone in the absence of a fully suppressive ART regimen because resistance mutations may develop [DHHS 2022, 2019]. For the use of TDF or TAF in patients with reduced renal function, see the NYSDOH AI guideline  Selecting an Initial ART Regimen > ARV Dose Adjustments for Hepatic or Renal Impairment.

Alternative regimen: If patients cannot or choose not to take TDF or TAF, the alternative recommended regimen is ETV in addition to a fully suppressive HIV ART regimen [DHHS 2022, 2019]. ETV should not be considered part of the HIV ART regimen. The ETV dose should be increased from 0.5 mg per day to 1.0 mg per day in patients with known or suspected 3TC-resistant HBV infection. However, ETV resistance may emerge rapidly in patients with 3TC-resistant HBV infection [Terrault, et al. 2018]. Therefore, ETV should be used with caution in patients with HIV/HBV coinfection who do not take TAF or TDF, and frequent monitoring (every 3 months) of HBV DNA levels should be performed to detect viral breakthrough (see the guideline section Monitoring).

The anti-HBV activity of 3TC, FTC, TDF, and TAF warrants their continued use whenever possible, even when HIV resistance indicates that they should be discontinued as part of the ART regimen. These agents should be continued after an anti-HBV therapy response has been achieved, even if the ART regimen has to be changed. Patients should be advised against discontinuing HIV or HBV treatment because the cessation of therapy has been associated with reactivation of HBV leading to exacerbations of hepatitis and hepatic failure [DHHS 2022]. Hepatitis flares can occur in patients with HBV monoinfection and those with HIV/HBV coinfection, but the risk of hepatic injury and fulminant hepatic failure is greater in patients with HIV/HBV coinfection [Moreno-Cubero, et al. 2018; Boyd, et al. 2017; Dore, et al. 2010].

Two-drug regimens for HIV: For patients with HIV/HBV coinfection, a 2-drug ART regimen should not be used as initial ART unless combined with an additional agent(s) with activity against HBV; see Table 5, below, for recommended additions. The same is true for patients with controlled HIV/HBV coinfection who switch to a 2-drug regimen for HIV ART—an agent with anti-HBV activity is required. Patients switching to a 2-drug regimen for HIV plus the additional agent(s) to treat HBV should be closely monitored for potential HBV flare (see the guideline section Monitoring).

Table 5: Recommended Additions to 2-Drug HIV ART Regimens for Patients With Chronic HBV
2-Drug HIV ART Regimen Addition for HBV Treatment
DTG/3TC TAF, TDF, or ETV
DTG/RPV TAF/FTC, TDF/FTC, or TDF/3TC
CAB/RPV TAF/FTC, TDF/FTC, or TDF/3TC
Abbreviations: 3TC, lamivudine; ART, antiretroviral therapy; CAB, cabotegravir; DTG, dolutegravir; ETV, entecavir; FTC, emtricitabine; HBV, hepatitis B virus; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

HBV treatment during pregnancy: Clinicians should offer pregnant patients with HIV/HBV coinfection ART that includes agents active against HIV and HBV. 3TC, FTC, TAF, and TDF can be safely used during pregnancy [DHHS 2022; Terrault, et al. 2018]. The preferred regimen is DTG plus TDF or TAF in combination with either FTC or 3TC. An alternative regimen is ritonavir-boosted darunavir (DRV/r) plus TDF or TAF with FTC or 3TC [DHHS 2022].

Monitoring

Recommended clinical evaluation and laboratory monitoring are described in Table 6, below. See also the NYSDOH AI guideline Laboratory Monitoring for Adverse Effects of ART.

Table 6: Recommended Monitoring After HBV Treatment Initiation in Adults With HIV
Laboratory Test Every 3 Months Every 6 Months Every 12 Months
HBV DNA Until HBV DNA is undetectable [a] After HBV DNA is undetectable  
HBeAg     Check for HBeAg-negative result [b]
Electrolyte panel   X  
Serum creatinine   X  
Urinalysis [c]     X
Liver function panel [c] Until HBV DNA is undetectable [a] After HBV DNA is undetectable  

Abbreviations: HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.

Notes:

  1. Undetectable is defined as <10 IU/mL.
  2. Patients who have been taking anti-HBV treatment for several years may not convert to HBeAg-negative [Singh, et al. 2017].
  3. See the NYSDOH AI guideline Laboratory Monitoring for Adverse Effects of ART > Frequency of Laboratory Monitoring During ART > Table 1: Minimum Laboratory Monitoring Frequency With Initiation of or Change in Antiretroviral Therapy for Patients <50 Years Old and Without Chronic Comorbidities.

Response to treatment: HBV viral load levels generally decline more slowly after treatment initiation than HIV viral load levels. Anti-HBV treatment responses are defined as follows [DHHS 2022]:

  • Primary nonresponse: HBV DNA <1 log10 decline at 12 weeks
  • Complete virologic response: Undetectable HBV DNA by polymerase chain reaction assay at 24 to 48 weeks
  • Partial virologic response: ≥1 log10 decline but still detectable HBV DNA at 24 weeks
  • Maintained virologic response: A response that continues while on therapy
  • Sustained virologic response: A virologic response that is still present 6 months after cessation of therapy

Renal toxicity: Renal toxicity with increased creatinine or renal tubular dysfunction has been associated with tenofovir use, and the association is stronger with TDF than TAF [Gupta, et al. 2019]. This renal toxicity may be reversible with dose adjustments of TDF or switching to TAF. Clinicians should evaluate electrolytes, serum creatinine levels, and urinalysis every 6 months [DHHS 2022].

Cirrhosis: Patients with HIV/HBV coinfection and cirrhosis should be referred to a gastroenterologist or hepatologist to assess and manage complications of portal hypertension such as gastroesophageal varices and ascites. Patients with HIV/HBV coinfection and cirrhosis should undergo esophagogastroduodenoscopy at the time of chronic HBV diagnosis and every 1 to 2 years thereafter [DHHS 2022; Terrault, et al. 2018].

Acute flare: If a patient being treated for chronic HBV develops signs or symptoms of acute hepatitis (nausea, vomiting, elevated ALT or bilirubin levels), clinicians should evaluate the patient, rule out HBV IRIS and HDV flare among other potential causes, and consult with an HIV-experienced hepatologist. Hepatic flares are usually mild and self-limited but can result in decompensation in individuals with preexisting cirrhosis [Anderson, et al. 2010; Crane, et al. 2009; Perrella, et al. 2006; Konopnicki, et al. 2005; Drake, et al. 2004].

In patients with HIV, initiation of or a change in ART introduces the potential for IRIS, which may manifest as a worsening of previously diagnosed disease or the appearance of a previously undiagnosed disease. In patients with HIV/HBV coinfection, IRIS can present as an acute flare of HBV disease; see the NYSDOH AI guideline Management of IRIS). It can often be difficult to distinguish HBV IRIS from other causes of an acute HBV flare, such as drug or alcohol hepatotoxicity or other viral infection (hepatitis A, C, D, or E virus, Epstein-Barr virus, herpes simplex virus, or cytomegalovirus). Reviewing medication history and testing for serum HBV DNA, HBeAg, HIV viral load, and CD4 cell count can help distinguish between these possibilities [DHHS 2022].

HBV IRIS is usually detected within the first 6 to 12 weeks after ART is initiated, based on a noticeable rise in ALT levels that coincides with rising CD4 cell counts (immune reconstitution) and signs and symptoms characteristic of acute hepatitis and with no other cause for the flare [DHHS 2022]. Risk factors for HBV IRIS include high HBV viral load, elevated ALT level, and low CD4 cell count at baseline [Singh, et al. 2017].

Ongoing Screening for Hepatocellular Carcinoma

Compared with HBV monoinfection, HIV/HBV coinfection is associated with an increased risk of developing HCC and increased mortality rates [Sun, et al. 2021; Pinato, et al. 2019; Singh, et al. 2017]. Patients with HIV/HBV coinfection and cirrhosis should be screened with ultrasound for HCC every 6 months [Terrault, et al. 2018].

There is no consensus on how frequently to screen for HCC in patients with HIV/HBV coinfection who do not have cirrhosis. In patients with HBV monoinfection, screening is recommended every 6 months for groups at increased risk for developing HCC, including Asian men >40 years old, Asian women >50 years old, Black men >40 years old, individuals with a first-degree family member who has a history of HCC, or individuals with HDV [Terrault, et al. 2018; Sarin, et al. 2016; Zhang, et al. 2004].

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Callebaut C, Stepan G, Tian Y, et al. In vitro virology profile of tenofovir alafenamide, a novel oral prodrug of tenofovir with improved antiviral activity compared to that of tenofovir disoproxil fumarate. Antimicrob Agents Chemother 2015;59(10):5909-5916. [PMID: 26149992

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All Recommendations

Lead author: Alok Gupta, MBBS, with the Medical Care Criteria Committee; August 30, 2022

ALL RECOMMENDATIONS: PREVENTION AND MANAGEMENT OF HEPATITIS B VIRUS INFECTION IN ADULTS WITH HIV
Screening Tests
  • Clinicians should determine the HBV vaccination and immune status of patients with HIV by performing laboratory testing for HBsAg, anti-HBs, and anti-HBc (total). (A*)
  • Clinicians should repeat laboratory screening annually in patients who are not immune to HBV, choose not to be vaccinated, and are at ongoing risk of acquiring HBV. (A3)
Diagnosis
  • In patients with positive baseline (screening) HBsAg test results, clinicians should perform HBeAg, anti-HBe, and HBV DNA testing to diagnose the phase of HBV infection. (B2†)
  • If a patient with HIV and unknown HBsAg status has signs or symptoms of acute hepatitis (i.e., elevated ALT), the clinician should perform HBsAg, anti-HBc IgM, HBeAg, anti-HBe (A*), and HBV DNA (A3) testing along with other diagnostic testing for acute hepatitis.
Acute HBV Infection
  • If acute HBV infection is confirmed and the patient is asymptomatic, the clinician should repeat ALT testing within 2 to 4 weeks to assess for symptoms of liver disease progression (B3) and repeat HBsAg, HBeAg, anti-HBe, and HBV DNA testing 6 months later to determine whether infection has cleared. (A3)
  • If a patient with HIV and acute HBV is not taking ART, the clinician should recommend ART initiation.  (A1)
Transmission Prevention
  • Clinicians should advise patients who have a positive HBsAg test result that they can transmit HBV (A*) and encourage sexually active patients to use effective barrier protection to reduce the risk of HBV transmission. (A2†)
  • Clinicians should inform patients with HBV that their household contacts should be vaccinated and counsel the patients to avoid sharing items such as razors or toothbrushes that could expose others to HBV-contaminated blood. (A2†)
  • For individuals who inject drugs, clinicians should offer or refer for substance use treatment, ensure access to clean needles and syringes, and provide harm reduction counseling. (A2†)
Primary Vaccination
  • Clinicians should offer HBV vaccination with the 3-dose Engerix-B or Recombivax HB vaccine series (A1) or the 2-dose Heplisav-B vaccine series (A2†) to patients with negative test results for HBsAg, anti-HBs, and anti-HBc.
  • Clinicians should not defer initial HBV vaccination in patients with a CD4 count <200 cells/mm3 who are at risk for HBV infection. (A2)
  • Clinicians should repeat anti-HBs testing 4 to 16 weeks, based on the patient’s visit schedule, after completion of the vaccination series to ensure immunity (anti-HBs ≥10 mIU/mL). (A3)
  • In a patient with negative HBsAg, negative anti-HBs, and positive anti-HBc test results (isolated anti-HBc positive), the clinician should offer a 1-time dose of HBV vaccine. (A2)
    • Repeat anti-HBs testing 8 weeks after vaccination, and if the anti-HBs titer is <100 mIU/mL, complete the HBV vaccine series and repeat anti-HBs testing 8 weeks after the last vaccine. (A2)
    • If vaccination is refused or if follow-up anti-HBs titer testing cannot be assured, perform HBV DNA testing to evaluate for occult HBV infection. (A2)
  • Clinicians should not defer initial vaccination or revaccination in pregnant patients with HIV who do not have immunity to HBV. (A3)
Revaccination
  • In previously vaccinated patients with anti-HBs levels <10 mIU/mL (vaccine nonresponse), clinicians should recommend revaccination with the Heplisav-B vaccine series or a double dose of the vaccine series previously administered. (A2)
Liver Disease Assessment
  • Before initiating HBV treatment in patients with HIV, clinicians should obtain a complete physical examination and medical history, including the use of hepatoxic medications (A*); noninvasive fibrosis evaluation (A2†); baseline ultrasonography for HCC [a] (A2†); and the following laboratory testing: CBC, albumin, bilirubin, alkaline phosphatase, PT/INR, ALT, AST, and a basic metabolic panel. (A*)
  • Clinicians should refer patients with HIV/HBV coinfection and cirrhosis to a gastroenterologist or hepatologist to assess and manage complications of portal hypertension. (A3)
  • In patients with HIV/HBV coinfection and cirrhosis, clinicians should screen for HCC with ultrasound every 6 months. (A2†)
Alcohol Use Screening and Education
  • Clinicians should perform alcohol use screening in patients with HIV/HBV coinfection at baseline and at least annually and refer patients for treatment as needed. (A3)
  • Clinicians should educate patients about the detrimental effects of alcohol use on the course of HBV infection and counsel patients with underlying liver disease to abstain from or minimize alcohol use. (A*)
HAV, HCV, and HDV Status
  • Clinicians should perform anti-HAV IgG or total (IgM and IgG) serum testing and administer the full HAV vaccine series in patients who are not immune to HAV. (A3)
  • Clinicians should determine patients’ HCV status by medical history and serum testing and recommend treatment with DAA therapy if chronic HCV infection is diagnosed. (A1)
  • Clinicians should perform anti-HDV total (IgM and IgG) serum testing to screen for HDV in all patients with HIV/HBV coinfection. (B2)
Treatment
  • Clinicians should recommend immediate ART initiation for any patient with HIV/HBV coinfection who is not taking ART. (A1)
  • Preferred: In patients with HIV and chronic HBV, clinicians should recommend an ART regimen that includes 2 agents active against HBV (see Table 4: Available Medications for Treatment of HBV Infection in Adults With HIV). Preferred regimens include a backbone of either TAF/FTC, TDF/FTC, or TDF/3TC. (A2)
  • Clinicians should not prescribe a 2-drug regimen of TAF/FTC, TDF/FTC, or TDF/3TC alone to treat patients with HIV/HBV coinfection; a fully suppressive ART regimen is required. (A1)
  • Nonadherence with or discontinuation of anti-HBV treatment may result in transaminase flares and hepatic damage. Clinicians should educate patients about the treatment adherence requirements (A*), and if treatment must be interrupted or discontinued, consult with a care provider experienced in HIV/HBV coinfection. (A3)
  • Alternative: If a patient cannot or chooses not to take TDF or TAF, the clinician should initiate treatment with ETV and a fully suppressive ART regimen for HIV. (A3)
Pregnant Patients
  • Clinicians should offer pregnant patients treatment with an ART regimen that includes 2 agents active against both HIV and HBV; 3TC, FTC, TAF, and TDF can be used safely during pregnancy at standard doses. (A2†)
Monitoring

———
Abbreviations: 3TC, lamivudine; ALT, alanine transaminase; anti-HBc, hepatitis B core antibody; anti-HBe, antibody to HBeAg; anti-HBs, hepatitis B surface antibody; ART, antiretroviral therapy; AST, aspartate transaminase; CBC, complete blood count; DAA, direct-acting antiviral; ETV, entecavir; FTC, emtricitabine; HAV, hepatitis A virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; IgG, immunoglobulin G; IgM, immunoglobulin M; IRIS, immune reconstitution inflammatory syndrome; PT/INR, prothrombin time/international normalized ratio; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

Note:

  1. Baseline ultrasound for HCC is performed in all patients with HIV/HBV coinfection. In patients with HIV/HCV coinfection, an ultrasound is performed only in patients with cirrhosis.

Guideline Information

Guideline Information
Intended users

New York State clinicians in outpatient settings who provide primary and HIV specialty care for adults who have or are at risk of acquiring hepatitis B virus infection

Lead author

Alok Gupta, MBBS, University of Rochester Medical Center

Publication date

August 30, 2022

Writing group

Steven M. Fine, MD, PhD; Rona M. Vail, MD; Joseph P. McGowan, MD, FACP, FIDSA; Samuel T. Merrick, MD; Asa E. Radix, MD, MPH, PhD, FACP, AAHIVS; Charles J. Gonzalez, MD; Christopher J. Hoffmann, MD, MPH

Committee

Medical Care Criteria Committee

Developer and funding

New York State Department of Health AIDS Institute (NYSDOH AI)

Development

See Guideline Development and Recommendation Ratings Scheme, below.

Peer Reviewers
  • Daniel Fierer, MD, Icahn School of Medicine at Mt. Sinai
  • Lisa Ganjhu, DO, FACG, AGAF, NYU Langone School of Medicine
  • Harmit S. Kalia, DO, Northwell Health
Updates

August 30, 2022

Alok Gupta, MBBS, with the MCCC: Comprehensive update of original 2013 guideline
Guideline Development: New York State Department of Health AIDS Institute Clinical Guidelines Program
Developer New York State Department of Health AIDS Institute (NYSDOH AI) Clinical Guidelines Program
Funding Source NYSDOH AI
Program Manager

Clinical Guidelines Program, Johns Hopkins University School of Medicine, Division of Infectious Diseases. See Program Leadership and Staff.

Mission To produce and disseminate evidence-based, state-of-the-art clinical practice guidelines that establish uniform standards of care for practitioners who provide prevention or treatment of HIV, viral hepatitis, other sexually transmitted infections, and substance use disorders for adults throughout New York State in the wide array of settings in which those services are delivered.
Expert Committees

The NYSDOH AI Medical Director invites and appoints committees of clinical and public health experts from throughout NYS to ensure that the guidelines are practical, immediately applicable, and meet the needs of care providers and stakeholders in all major regions of NYS, all relevant clinical practice settings, key NYS agencies, and community service organizations.

Committee Structure
  • Leadership: AI-appointed chair, vice chair(s), chair emeritus, clinical specialist(s), JHU Guidelines Program Director, AI Medical Director, AI Clinical Consultant, AVAC community advisor
  • Contributing members
  • Guideline writing groups: Lead author, coauthors if applicable, and all committee leaders
Conflicts of Interest Disclosure and Management
  • Annual disclosure of financial relationships with commercial entities for the 12 months prior and upcoming is required of all individuals who work with the guidelines program, and includes disclosure for partners or spouses and primary professional affiliation.
  • The NYSDOH AI assesses all reported financial relationships to determine the potential for undue influence on guideline recommendations and, when indicated, denies participation in the program or formulates a plan to manage potential conflicts.
  • Disclosures are listed for each committee member.
Evidence Collection and Review
  • Literature search and review strategy is defined by the guideline lead author based on the defined scope of a new guideline or update.
  • A comprehensive literature search and review is conducted for a new guideline or an extensive update using PubMed, other pertinent databases of peer-reviewed literature, and relevant conference abstracts to establish the evidence base for guideline recommendations.
  • A targeted search and review to identify recently published evidence is conducted for guidelines published within the previous 3 years.
  • Title, abstract, and article reviews are performed by the lead author. The JHU editorial team collates evidence and creates and maintains an evidence table for each guideline.
Recommendation Development
  • The lead author drafts recommendations to address the defined scope of the guideline based on available published data.
  • Writing group members review the draft recommendations and evidence and deliberate to revise, refine, and reach consensus on all recommendations.
  • When published data are not available, support for a recommendation may be based on the committee’s expert opinion.
  • The writing group assigns a 2-part rating to each recommendation to indicate the strength of the recommendation and quality of the supporting evidence. The group reviews the evidence, deliberates, and may revise recommendations when required to reach consensus. 
Review and Approval Process
  • Following writing group approval, draft guidelines are reviewed by all contributors, program liaisons, and a volunteer reviewer from the AI Community Advisory Committee.
  • Recommendations must be approved by two-thirds of the full committee. If necessary to achieve consensus, the full committee is invited to deliberate, review the evidence, and revise recommendations when required.
  • Final approval by the committee chair and the NYSDOH AI Medical Director is required for publication.
External Reviewers
  • External peer reviewers recognized for their experience and expertise review guidelines for accuracy, balance, clarity, and practicality and provide feedback.
  • Peer reviewers may include nationally known experts from outside of New York State.
Update Process
  • JHU editorial staff ensure that each guideline is reviewed and determined to be current upon the 3-year anniversary of publication; guidelines that provide clinical recommendations in rapidly changing areas of practice may be reviewed annually. Published literature is surveilled to identify new evidence that may prompt changes to existing recommendations or development of new recommendations.
  • If changes in the standard of care, newly published studies, new drug approval, new drug-related warning, or a public health emergency indicate the need for immediate change to published guidelines, committee leadership will make recommendations and immediate updates.
  • All contributing committee members review and approve substantive changes to, additions to, or deletions of recommendations; JHU editorial staff track, summarize, and publish ongoing guideline changes.
Recommendation Ratings Scheme
Strength Quality of Evidence
Rating Definition Rating Definition
A Strong 1 Based on published results of at least 1 randomized clinical trial with clinical outcomes or validated laboratory endpoints.
B Moderate * Based on either a self-evident conclusion; conclusive, published, in vitro data; or well-established practice that cannot be tested because ethics would preclude a clinical trial.
C Optional 2 Based on published results of at least 1 well-designed, nonrandomized clinical trial or observational cohort study with long-term clinical outcomes.
  2† Extrapolated from published results of well-designed studies (including nonrandomized clinical trials) conducted in populations other than those specifically addressed by a recommendation. The source(s) of the extrapolated evidence and the rationale for the extrapolation are provided in the guideline text. One example would be results of studies conducted predominantly in a subpopulation (e.g., one gender) that the committee determines to be generalizable to the population under consideration in the guideline.
3 Based on committee expert opinion, with rationale provided in the guideline text.