HBV-HIV Coinfection

Introduction

Medical Care Criteria Committee, August 2013

Hepatitis B virus (HBV) is a double-stranded DNA, enveloped virus that replicates in hepatocytes. Its primary routes of transmission are vertical (mother-to-child), blood exposure, and sexual exposure. It is significantly more transmissible than HIV via blood-borne exposure, and some fluids that do not normally transmit HIV, such as saliva and sweat, contain infectious HBV but at much lower levels than blood. In many cases, a patient’s route of infection is not identified.

Approximately 1 to 1.25 million people are HBV carriers in the United States [ACIP 1991], and four to five thousand deaths due to HBV-related cirrhosis or hepatocellular carcinoma (HCC) occur annually in the United States. HBV infection resolves spontaneously in 90% to 95% of immunocompetent adults who are infected [Mahoney 1999]; however, 5% to 10% develop chronic HBV infection that is characterized by persistence of circulating hepatitis B surface antigen (HBsAg) in the blood. Individuals with chronic hepatitis B are at risk for progression to cirrhosis or HCC, as well as for transmitting HBV to others.

The similar routes of transmission for HIV and HBV place patients with either infection at greater risk for HIV/HBV co-infection. The rate of HBV infection in patients with HIV varies widely depending on the population. The highest rates of HIV/HBV co-infection (5% to 10% in the United States) are generally in men who have sex with men (MSM) and injection drug users (IDUs) [Kellerman et al. 2003; Lincoln et al. 2003]. In the HIV Outpatient Study (HOPS), the annual prevalence of HIV/HBV co-infection ranged from 7.8% to 8.4%, with MSM comprising the majority of those patients (63% to 72%) [Spradling et al. 2010]. A retrospective study of patients with HIV in New York City found that 4.6% of patients in one hospital center were co-infected with HBV; of those patients, 45.4% and 40.8% were MSM and heterosexual IDUs, respectively [Kim et al. 2012]. Women with HIV in the United States have co-infection rates of 3% to 4% [Tien et al. 2004]. Patients with HIV in the EuroSIDA cohort had a co-infection rate of 9% [Konopnicki et al. 2005].

Patients with HIV have lower rates than patients without HIV of hepatitis B envelope antibody (anti-HBe) and hepatitis B surface antibody (anti-HBs) seroconversion, resulting in higher rates of chronic HBV. Individuals with HIV also have increased rates of HBV replication and accelerated disease progression, with increased incidence of liver fibrosis, cirrhosis, end-stage liver disease, HCC, and liver-related deaths compared with HBV mono-infected patients [Colin et al. 199; Yanagimoto et al. 2012; Ioannou et al. 2013]. In the Multicenter AIDS Cohort Study (MACS) cohort, patients with HIV/HBV co-infection had a risk of liver-related mortality that was 13 times higher than patients with HIV only [Thio et al. 2002]. A study of the US Military HIV Natural History Study (NHS) cohort found higher rates of AIDS-related events and death among patients with HIV/HBV co-infection compared with those with HIV mono-infection (p <.001) [Chun et al. 2012].

Assessment for HBV infection is part of the baseline evaluation of all patients with HIV (see the NYSDOH AI guideline Primary Care Approach), and treatment of HBV in these patients requires consideration of both infections (see the Treatment and Management section of this guideline).

References

ACIP. Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep 1991;40(RR-13);1-19. [PubMed]

Chun HM, Roediger MP, Hullsiek KH, et al. Hepatitis B virus coinfection negatively impacts HIV outcomes in HIV seroconverters. J Infect Dis 2012;205:185-193. [PubMed]

Colin JF, Cazals-Hatem D, Loriot MA, et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology 1999;29:1306-1310. [PubMed]

Ioannou GN, Bryson CL, Weiss NS, et al. The prevalence of cirrhosis and hepatocellular carcinoma in patients with human immunodeficiency infection. Hepatology 2013;57:249-257. [PubMed]

Kellerman SE, Hanson DL, McNaghten AD, et al. Prevalence of chronic hepatitis B and incidence of acute hepatitis B infection in HIV-infected subjects. J Infect Dis 2003:188;571-577. [PubMed]

Kim JH, Psevdos G Jr, Sharp V. Five-year review of HIV-hepatitis B virus (HBV) co-infected patients in a New York City AIDS center. J Korean Med Sci 2012;27:830-833. [PubMed]

Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: Prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS 2005:19:593-601. [PubMed]

Lincoln D, Petoumenos K, Dore GJ. Australian HIV Observational Database. HIV/HBV and HIV/HCV coinfection, and outcomes following highly active antiretroviral therapy. HIV Med 2003;4:241-249. [PubMed]

Mahoney FJ. Update on diagnosis, management, and prevention of hepatitis B virus infection. Clin Microbiol Rev 1999;12:351-366. [PubMed]

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;17:879-886. [PubMed]

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;360:1921-1926. [PubMed]

Tien PC, Kovacs A, Bacchetti P, et al. Association between syphilis, antibodies to herpes simplex virus type 2, and recreational drug use and hepatitis B virus infection in the Women’s Interagency HIV Study. Clin Infect Dis 2004;39:1363-1370. [PubMed]

Yanagimoto S, Yotsuyanagi H, Kikuchi Y, et al. Chronic hepatitis B in patients coinfected with human immunodeficiency virus in Japan: A retrospective multicenter analysis. J Infect Chemother 2012;18:883-890. [PubMed]

Clinical Syndromes

Medical Care Criteria Committee, August 2013

Acute HBV Infection

The incubation period for HBV is 30 to 180 days (mean = 90 days), and acute infections may vary from asymptomatic or mild to severe jaundice and, rarely, fulminant hepatic failure. Fever, right upper-quadrant abdominal pain, headache, and malaise are common, as are elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Up to 20% of patients may develop arthralgias or arthritis. Symptoms resolve in 4 to 6 weeks, and 90% to 95% of patients who do not have HIV develop anti-HBs and are considered HBV-immune [Mahoney et al. 1999]. However, the rate of anti-HBs development in patients with HIV is lower than in individuals without HIV [Puoti 2006].

During acute infection, hepatitis B core antibody (anti-HBc) IgM (IgM anti-HBc) appears within 4 weeks of HBsAg and is sometimes used as a marker for acute infection, although it may reappear during reactivation of chronic infection. The emergence of anti-HBs levels signals resolving infection (see Figure 1).

Chronic HBV Infection

Patients with HIV/HBV co-infection are those who have HIV and chronic HBV. Chronic HBV infection can be subdivided into hepatitis B envelope antigen (HBeAg)-positive and HBeAg-negative HBV. Chronic hepatic inflammation, sometimes with elevated serum ALT levels, may progress to hepatic fibrosis and cirrhosis. In contrast to HCC in hepatitis C virus (HCV), HCC can develop in HBV infection without prior cirrhosis. Chronic HBV infection is often asymptomatic, although some patients experience periodic jaundice. In patients without HIV, HBsAg will clear in 2% of chronic carriers per year. HBeAg may often clear despite persistent HBsAg and is frequently associated with resolution of inflammation and hepatic recovery. This corresponds with continued expression of HBsAg from HBV DNA integrated into the hepatocyte genome with little viral replication.

Chronic HBV infection has been categorized into high and low replication: 

• High replication: Presence of HBeAg, high levels of HBsAg and HBV DNA (defined as >2000 IU/mL), and elevated serum ALT levels
• Low replication: Absence of HBeAg, low levels of HBsAg and HBV DNA (defined as ≤2000 IU/mL), and low or normal serum ALT levels

This distinction is further complicated by variants of HBeAg-negative HBV infection, including the “precore” and “core promoter” mutants, which result in a state of high viral replication. These mutations are present in up to 10% of HBeAg-negative patients. Identification of these cases is important because despite the absence of HBeAg, liver disease progression is similar to that in patients who are positive for HBeAg (see the Evaluation of Chronic HBV section of this guideline). Figure 2 shows the serologic responses to chronic HBV infection.

Reactivation

Reactivation is defined as reappearance of active necroinflammatory disease of the liver in a person known to have the inactive HBsAg carrier state or resolved HBV (as defined in Table 1: Serologic and Virologic Responses to HBV) [Lok and McMahon 2001]. This is rare and is usually associated with severe immunosuppression but may be more common in patients with HIV, including those who experience immune reconstitution after initiation of antiretroviral therapy (ART) [Proia et al. 2000]. Reactivation may result in severe hepatitis and should be considered as a potential cause of hepatitis in patients who have had previously resolved HBV infection. During reactivation, serum ALT levels will be elevated, and patients who were previously HBeAg- and/or HBsAg-negative may become both HBeAg-positive and HBsAg-positive. This requires confirmation by one of the following serologic tests: HBeAg, anti-HBe, or HBV DNA levels.

Hepatitis Delta Virus

Hepatitis delta virus (HDV) is a defective virus that requires active HBV infection for its replication and is associated with more severe liver disease, hepatic flares, and more rapid progression of liver disease when present in patients with HBV. Some clinicians assess for HDV with a serum total HDV IgM and IgG test in patients who are positive for HBsAg, particularly if the patient is from an HDV-endemic area. According to the Centers for Disease Control and Prevention (CDC), such areas include southern Italy, parts of Russia and Romania, and isolated regions in the Amazon River Basin [CDC]. IDUs, particularly those with HIV infection, also have disproportionately high rates of HDV [Kucirka et al. 2010]. For additional information, see the Treatment and Management section of this guideline.

HIV/HBV/HCV Tri-Infection

HCV in the presence of HBV is of particular concern for clinicians treating patients with HIV. Studies have indicated that patients with chronic HBV/HCV co-infection have a significantly higher degree of liver fibrosis [Sagnelli et al. 2004; Sagnelli et al. 2005; Albertu et al. 2005], as well as hepatocellular apoptosis, bile duct damage, and ductular proliferation [Sagnelli et al. 2005].

These findings suggest more severe forms of HCV-related cirrhosis attributable to the presence of HBV [Sagnelli et al. 2005]. Furthermore, HBV/HCV co-infection may be associated with rapid progression to HCC [Kubo et al. 1999].

References

Alberti A, Clumeck N, Collins S, et al. Short statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. J Hepatol 2005;42:615-624. [PubMed]

Centers for Disease Control and Prevention: National Center for HIV/AIDS, STD, and TB Prevention. Geographic Distribution of HDV Infection. Available at: www.cdc.gov/hepatitis/index.htm

Kubo S, Nishiguchi S, Hirohashi K, et al. Clinical significance of prior hepatitis B virus infection in patients with hepatitis C virus-related hepatocellular carcinoma. Cancer 1999;86:793-798. [PubMed]

Kucirka LM, Farzadegan H, Feld JJ, et al. Prevalence, correlates, and viral dynamics of hepatitis delta among injection drug users. J Infect Dis 2010;202:845-852. [PubMed]

Lok AS, McMahon BJ; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology 2001;34:1225-1241. [PubMed]

Mahoney FJ. Update on diagnosis, management, and prevention of hepatitis B virus infection. Clin Microbiol Rev 1999;12:351-366. [PubMed]

Proia LA, Ngui SL, Kaur S, et al. Reactivation of hepatitis B in patients with human immunodeficiency virus infection treated with combination antiretroviral therapy. Am J Med 2000;108:249-251. [PubMed]

Puoti M, Torti C, Bruno R, et al. Natural history of chronic hepatitis B in co-infected patients. J Hepatol 2006;44(1 Suppl):S65-S70. [PubMed]

Sagnelli E, Pasquale G, Coppola N, et al. Influence of chronic coinfection with hepatitis B and C virus on liver histology. Infection 2004;32:144-148. [PubMed]

Sagnelli E, Pasquale G, Coppola N, et al. Liver histology in patients with HBsAg negative anti-HBc and anti-HCV positive chronic hepatitis. J Med Virol 2005;75:222-226. [PubMed]

Baseline Evaluation and Screening

Medical Care Criteria Committee, August 2013

Baseline Hepatic Evaluation

Liver function, including serum AST and ALT levels, should be assessed at baseline in all patients with HIV. If serum AST or ALT levels are elevated, the clinician should assess for causes of hepatic inflammation. Although the patient’s platelet count may decrease as a result of many factors, low platelet count could be an indication of cirrhosis. Low albumin, high cholesterol, and elevated prothrombin time international normalized ratio (PT/INR) may indicate cirrhosis or end-stage liver disease, although they remain insensitive for liver dysfunction.

Hepatitis Screening

Screening for HBV should include obtaining anti-HBs, HBsAg, and anti-HBc. Patients with anti-HBs levels of ≥10 IU/L are considered to be immune to HBV. Patients who are positive for anti-HBc but are negative for anti-HBs and HBsAg may have: (1) resolved HBV infection with <10 IU/L anti-HBs; (2) acute HBV infection; (3) occult HBV infection and thus will be positive for HBV DNA; (4) a false-positive result; or (5) reactivation of previously resolved HBV infection.

Table 1 shows the serologic and virologic responses to HBV, and Table 2 shows interpretation of HBV serologies.

Prevention

Medical Care Criteria Committee, August 2013

Primary HBV Vaccination

The New York State Department of Health and CDC recommend the HBV vaccination series for all patients with HIV who are susceptible to HBV infection (see Figure 3).

Patients should be counseled to prevent HBV infection through avoidance of high-risk sexual behaviors and needle-sharing. Because of the lower response rate to HBV vaccination among patients with HIV, quantitative anti-HBs levels should be obtained 1 to 2 months after administration of the last dose of the vaccine series. Nonresponders, defined as those with anti-HBs <10 IU/L, should be re-vaccinated (see HBV Re-Vaccination in Nonresponders with HIV).

Lower CD4 counts at the time of vaccination [Tedaldi et al. 2004], as well as lower nadir CD4 counts [Tedaldi et al. 2004; Kim et al. 2008], have been associated with decreased response to HBV vaccination in patients with HIV. Studies have also shown that HIV suppression to <400 copies/mL is a significant predictor of a protective response to HBV vaccination [Kim et al. 2008; Overton et al. 2005].

All New York State Medicaid-sponsored programs reimburse HBV vaccination when administered according to CDC recommendations, including those for patients with HIV. According to New York State regulations, all children in pre-kindergarten through grade 12 are required to receive the HBV vaccine to attend school.

HBV Vaccination Strategies for Patients with HIV

A number of studies have provided strong evidence of an improved response in patients with HIV when a double-dose vaccination series is administered in three doses [Fonseca et al. 2005; de Vries-Sluijs et al. 2008; Psevdos et al. 2010; Cardell et al. 2008; Bunupuradah et al. 2013]. A double-dose vaccination series administered in four doses has also been investigated [Launay et al. 2011; Potsch et al. 2010]. In a prospective, randomized controlled trial, 145 patients were given the standard 20-µg vaccine in three injections (0, 4, and 24 weeks), and 148 were given the double, 40-µg dose in four injections (0, 4, 8, and 24 weeks). The response rates were 65% in the standard dose arm of the study versus 82% in the double-dose, four-injection arm of the study (p = 0.002). No additional adverse events were noted [Launay et al. 2011]. On the basis of these findings, consideration of an alternative three- or four-injection double-dose vaccination series for primary HBV vaccination in patients with HIV is reasonable (BII).

Accelerated dosing schedules have also been investigated. A randomized trial 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 non-inferior response rate for patients with CD4 counts >500 cells/mm³; this schedule may increase patient adherence to the full vaccination 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 patients with CD4 counts <200 cells/mm³, the results were inconclusive for that patient 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 the initiation of the series.

Below is dosing information on the two HBV vaccination formulations that are available in the United States.

Engerix-B: 

• Single dose: 20 µg (as a 1-mL dose containing 20 µg/mL vaccine) in three or four IM injections
• Double dose: 40 µg (as two 1-mL doses of 20 µg/mL vaccine) in three or four IM injections
• For patients with end-stage renal disease or other immunocompromising conditions: 40 µg/mL (as two 1-mL doses of 20 µg/mL vaccine) given in three IM injections
• Dosing schedule for all: Three injections: at 0, 4, and 24 weeks. Four injections: at 0, 4, 8, and 24 weeks.

RECOMBIVAX:

• Single dose: 10 µg (as a 1-mL dose containing 10 µg/mL vaccine) in three or four IM injections. Three injections: at 0, 4, and 24 weeks. Four injections: at 0, 4, 8, and 24 weeks.
• Double dose: 20 µg (as two 1-mL doses containing 10 µg/mL vaccine) in three or four IM injections. Three injections: at 0, 4, and 24 weeks. Four injections: at 0, 4, 8, and 24 weeks.
  • Double dosing with RECOMBIVAX has not been as well studied as double dosing with Engerix-B. However, RECOMBIVAX may be the only formulation available at some institutions.
• For patients with end-stage renal disease or other immunocompromising conditions: 40 µg (as 1 mL of higher-strength vaccine: 40 µg/mL formulation) in four IM injections

HBV Re-Vaccination in Non-Responders

Nonresponders to the primary HBV vaccination series (anti-HBs <10 IU/L) should be re-vaccinated. Compared with standard re-vaccination, double-dose HBV re-vaccination has been shown to induce an increased response among some patients with HIV [de Vries-Sluijs et al. 2008; Psevdos et al. 2010; Cardell et al. 2008; Bunupuradah et al. 2013]. Patients who do not respond to the initial HBV vaccination series should be re-vaccinated with a double dose, and based on available evidence, a four-dose schedule should be considered (BII) [Launay et al. 2011; Potsch et al. 2010].

Re-vaccination can be deferred for patients initiating ART until CD4 count is ≥200 cells/mm³ because 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]. If anti-HBs is not induced by primary vaccination and re-vaccination, then HBV DNA testing may be performed to determine whether the patient is a primary nonresponder or has chronic HBV infection (see Table 1: Serologic and Virologic Responses to HBV, Table 2: Interpretation of the HBV Panel, and Figure 3, above). Primary nonresponders are individuals who are HBsAg-negative but are unable to develop immunity (i.e., anti-HBs ≥10 IU/L) after receiving HBV vaccinations that are administered according to standard protocols. Primary nonresponders are considered susceptible to HBV infection [ACIP/HICPAC 1997]. These patients should be retested if they present with signs and/or symptoms of HBV infection.

HAV Vaccination

Hepatitis A virus (HAV) and HBV vaccines should be administered regardless of CD4 counts to patients who are all of the following: HAV IgG-, anti-HBs-, and HBsAg-negative. A combined hepatitis A and B vaccine (TWINRIX) is available and can be used in persons susceptible to both HAV and HBV. However, the combination vaccine is not recommended for double-dose or four-injection vaccination in patients with HIV.

Patients who do not require HBV vaccination may benefit from deferral of HAV vaccination until CD4 counts reach ≥200 cells/mm³ [Kemper et al. 2003]. Such deferral is not advisable in pregnant women or in patients who are not likely to achieve CD4 counts ≥200 cells/mm³.

HBV Post-Exposure Prophylaxis

HBV is more infectious than HIV, and the risk of HBV transmission increases significantly in the presence of HBeAg. The mean risk following an occupational percutaneous exposure to HIV is approximately 0.3% [Bell 1997]. By comparison, the risk of HBV transmission is 1% to 6% when HBeAg is absent in the source patient, and the risk increases to 22% to 31% when HBeAg is present [U.S. Public Health Service 2001]. Although the highest concentrations of HBV are in blood, lower concentrations of HBV are present in other body fluids, including wound exudates, semen, vaginal secretions, and saliva [CDC 2010].

Patients with HIV who have a known exposure to HBV should be assessed for post-exposure prophylaxis (PEP), and the exposed person’s vaccination status should be considered. However, decision-making should not be delayed while testing for anti-HBs. Instead, determination of antibody response of previously vaccinated exposed persons should be based on information available at presentation. For patients receiving PEP, both hepatitis B immune globulin (HBIG) and the first dose of the HBV vaccine series should be ideally administered within 24 hours of exposure; HBIG should not be given later than 14 days post-exposure. HBV antibodies should be obtained 1 to 2 months after completion of the last dose of the vaccine; however, anti-HBs levels may be falsely elevated if the exposed person received HBIG within the past 3 to 4 months.

References

ACIP/HICPAC. Immunization of health-care workers: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR Recomm Rep 1997;46(RR-18):1-42. [PubMed]

Bell DM. Occupational risk of human immunodeficiency virus infection in healthcare workers: An overview. Am J Med 1997;102:9-15. [PubMed]

Bunupuradah T, Ananworanich J, Puthanakit T. Double-dose hepatitis B revaccination in nonresponsive HIV-infected adolescents. J Int Assoc Provid AIDS Care 2013;12:157-158. [PubMed]

Cardell K, Akerlind B, Sällberg M, et al. Excellent response rate to a double dose of combined hepatitis A and B vaccine in previous nonresponders to hepatitis B vaccine. J Infect Dis 2008;198:299-304. [PubMed]

CDC. Sexually Transmitted Diseases Treatment Guidelines. 2010. http://cdc.gov/std/treatment [accessed 2018 Apr 4]

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;197:292-294. [PubMed]

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;203:984-991. [PubMed]

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;23:2902–2908. [PubMed]

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;191:1435-1441. [PubMed]

Kemper CA, Haubrich R, Frank I, et al. Safety and immunogenicity of hepatitis A vaccine in human immunodeficiency virus-infected patients: A double-blind, randomized, placebo-controlled trial. J Infect Dis 2003;187:1327-1331. [PubMed]

Kim HN, Harrington RD, Van Rompaey SE, et al. Independent clinical predictors of impaired response to hepatitis B vaccination in HIV-infected persons. Int J STD AIDS 2008;19:600-604. [PubMed]

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;305:1432-1440. [PubMed]

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;41:1045-1048. [PubMed]

Potsch DV, Oliveira ML, Ginuíno C, et al. High rates of serological response to a modified hepatitis B vaccination schedule in HIV-infected adults subjects. Vaccine 2010;28:1447-1450. [PubMed]

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;24:403-407. [PubMed]

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

U.S. Public Health Service. Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis. MMWR Recomm Rep 2001;50(RR-11):1-52. [PubMed]

Evaluation of Chronic HBV

Medical Care Criteria Committee, August 2013

History, Physical Examination, and Initial Laboratory Testing

Clinicians should obtain an HBV-related history for patients with HIV who are positive for HBsAg, including assessment for risk factors and previous and current signs and symptoms of advanced liver disease. Risk of hepatocellular carcinoma (HCC) should be assessed according to standard guidelines (see the Monitoring > Risk for Hepatocellular Carcinoma section of this guideline). Serial serum ALT measurements should be obtained because of the possibility of significant fluctuation. Fluctuations in serum ALT levels do not directly correlate with liver disease; however, persistent serum ALT elevation increases the likelihood of significant liver disease with rapid disease progression.

All patients with chronic HBV infection should be tested for HBeAg and anti-HBe. Patients who are positive for HBeAg usually have higher HBV DNA levels and more rapid progression of liver disease. One of the goals of treatment for patients who are positive for HBeAg is seroconversion to anti-HBe, which is associated with normalized serum ALT levels, decreased levels of HBV DNA, and, in some cases, reversal of fibrosis [Hui et al. 2007] and halted progression of cirrhosis [Hsu et al. 2002]. However, some patients who seroconvert from HBeAg to anti-HBe may still have liver disease that progresses to cirrhosis or HCC [Hsu et al. 2002].

HBV DNA levels should be obtained at baseline in patients with chronic HBV. If the baseline HBV DNA level is ≤2000 IU/mL in anti-HBe-positive patients with elevated serum ALT levels, then HBV DNA levels should be measured serially because wide fluctuation of serum ALT levels in these patients makes it an unreliable indicator. The laboratory that measures HBV DNA should participate in external quality control and use an assay with high sensitivity and a wide range (e.g., 80/mL to 10¹⁰/mL).

HBV has multiple genotypes (i.e., A through G). The prevalence of each genotype varies geographically, but all have been found in the United States [Chu et al. 2003]. Recent evidence suggests that HBV genotypes may influence progression of liver disease, rates of seroconversion of HBeAg, and risk of HCC [Lin and Kao 2011]. Therefore, some experts recommend obtaining an HBV genotype because it may help guide decisions on frequency of monitoring for disease progression and response to antivirals [Wong et al. 2010; Tujios and Lee 2012].

Assessment for Inflammation and Fibrosis

As part of the initial evaluation of patients with HIV/HBV co-infection, liver biopsy is considered the gold standard to assess fibrosis and inflammation and to stage chronic disease. Ultrasound of the liver can sometimes detect cirrhosis and steatosis, and triple-phase computed tomography (CT) can be used during the initial assessment to detect HCC. However, because patients with HIV are at higher risk for fibrosis, liver biopsy may be prudent for patients with HIV/HBV co-infection with normal serum ALT or low HBV DNA levels who are considering deferral of anti-HBV therapy or who also have HCV.

Liver stiffness measurements and calculations of a fibrosis score from noninvasive tests, such as serum ALT level and platelet count, as well as the biomarker test known as FibroSure [Kim et al. 2012], can be used; however, these have not yet been validated in patients with HIV/HBV co-infection. Another noninvasive method for calculating liver stiffness is the elastography technique known as FibroScan, which has demonstrated promising results [Fraquelli and Branchi 2011] and has been approved by the Food and Drug Administration for use in the United States.

References

Chu CJ, Keeffe EB, Han SH, et al. Hepatitis B virus genotypes in the United States: Results of a nationwide study. Gastroenterology 2003;125:444-451. [PubMed]

Fraquelli M, Branchi F. The role of transient elastography in patients with hepatitis B viral disease. Dig Liver Dis 2011;43(Suppl 1):S25-S31. [PubMed]

Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 2002;35:1522-1527. [PubMed]

Hui CK, Leung N, Shek TW, et al. Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B Chinese patients. Hepatology 2007;46:690-698. [PubMed]

Hunt CM, McGill JM, Allen MI, et al. Clinical relevance of hepatitis B virus mutations. Hepatology 2000;31:1037-1044. [PubMed]

Kim BK, Kim SU, Kim HS, et al. Prospective validation of FibroTest in comparison with liver stiffness for predicting liver fibrosis in Asian subjects with chronic hepatitis B. PLoS One 2012;7:e35825. [PubMed]

Lin CL, Kao JH. The clinical implications of hepatitis B virus genotype: Recent advances. J Gastroenterol Hepatol 2011;26(Suppl 1):123-130. [PubMed]

Tujios SR, Lee WM. New advances in chronic hepatitis B. Curr Opin Gastroenterol 2012;28:193-197. [PubMed]

Wong VW, Sung JJ. Diagnosis and personalized management of hepatitis B including significance of genotypes. Curr Opin Infect Dis 2012;25:570-577. [PubMed]

Counseling

Medical Care Criteria Committee, August 2013

Alcohol consumption: Heavy alcohol consumption accelerates liver fibrosis and decreases response to anti-HBV treatment [Frieden et al. 1999]. Psychological, social, and medical support to decrease alcohol intake is strongly recommended. 

HBV transmission: HBV is significantly more transmissible through exposure to blood and body fluid than HIV and requires more frequent assessment for behaviors that increase risk for HIV/HBV transmission. Barrier protection, including latex or polyurethane condoms and dental dams, should be recommended to decrease the risk of sexual transmission.

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. New York State’s two syringe access initiatives are the Expanded Syringe Access Demonstration Program and the Syringe Exchange Program. Injection drug users should also receive information about safe disposal and storage of needles/syringes, as well as safer techniques for injection.

Reference

Frieden TR, Ozick L, McCord C, et al. Chronic liver disease in central Harlem: The role of alcohol and viral hepatitis. Hepatology 1999;29:883-888. [PubMed]

Treatment and Management

Medical Care Criteria Committee, August 2013

Few studies address anti-HBV therapy recommendations in the setting of HIV. The recommendations provided in this section are based on this Committee’s expert opinion.

Acute HBV Infection

Most cases of acute HBV infection resolve spontaneously without specific therapy, and there is no evidence that treatment in the acute phase improves the likelihood that the patient will seroconvert to anti-HBs [Kumar et al. 2007]. However, some patients with acute HBV infection may develop acute hepatic failure, or fulminant liver disease. Lamivudine treatment has been shown to increase patient survival in this setting [Tillmann et al. 2006]; therefore, therapy with lamivudine is indicated for fulminant hepatic failure despite the risk of developing lamivudine-resistant HIV. Because of the high concomitant rate of renal failure in fulminant hepatitis, neither adefovir nor tenofovir should be prescribed. Initiation of ART should be deferred until resolution of the acute hepatic insult, including stabilization of liver function and associated complications, such as encephalopathy and coagulopathy. For patients with fulminant liver disease who are already receiving ART, the regimen should be adjusted to include lamivudine. Tenofovir should be withdrawn if the patient is already receiving it until the hepatic insult has resolved.

Chronic HBV Infection

No large controlled trials have been conducted to define efficacy of combination therapies in patients with HIV/HBV co-infection. These guidelines are therefore extrapolated from the treatment of patients with HBV mono-infection, limited data from patients with HIV/HBV co-infection, and best practices for HIV treatment [Alberti et al. 2005; Soriano et al. 2006; Nunez and Soriano 2005; Keeffe et al. 2004; Benhamou 2006].

Initiation of treatment that is active against both HIV and HBV is indicated for patients with HIV/HBV co-infection patients [AIDSinfo 2011]. When initiating ART and anti-HBV therapy simultaneously, a standard ART regimen that includes two drugs that are also active against HBV should be used (see Table 3, below). HBV resistance may result if only one dually active anti-HIV/HBV drug is included in the regimen.

Once treatment is initiated, the interruption of therapy for either infection should be avoided whenever possible. Treatment interruption of anti-HIV/HBV agents can cause transaminase flares.

The addition of anti-HBV agents to a fully suppressive existing ART regimen should be weighed against restructuring the ART regimen to include medications that are active against both HIV and HBV. Tenofovir plus either lamivudine or emtricitabine provides a backbone active against both HIV and HBV when combined with one other agent that is active against HIV. If first-line therapy with tenofovir and lamivudine/emtricitabine cannot be used safely, or the HBV strain is resistant to any of these agents, then clinicians should consult with a provider experienced in the treatment of HIV and HBV to consider alternative anti-HBV therapies (see Table 3, below). When assessment for HBV resistance is not possible, obtaining HBV DNA levels after 3 months can indicate treatment efficacy in these cases. Maintenance of HBV suppression should be monitored every 3 to 6 months (see Monitoring).

The anti-HBV activity of lamivudine, emtricitabine, and tenofovir warrants the continuation of their use even when HIV resistance indicates that they should be discontinued as part of the ART regimen. In addition, these agents should be continued after anti-HBV therapy response has been achieved, even when the ART regimen needs to be changed.

HDV Infection

Existing data indicate that pegylated interferon (PegIFN) 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 receiving PegIFN [Wedemeyer et al. 2011]. No data are available regarding the efficacy of PegIFN therapy in patients with HIV/HBV/HDV tri-infection. Because of the dependence of HDV on HBV, HBsAg seroconversion should be the primary goal for patients with HIV/HBV/HDV tri-infection. Prompt initiation of anti-HBV and anti-HIV therapy should be strongly encouraged.

References

AIDSinfo. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. 2011. http://aidsinfo.nih.gov/guidelines [accessed 2018 Apr 4]

Alberti A, Clumeck N, Collins S, et al. Short statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. J Hepatol 2005;42:615-624. [PubMed]

Benhamou Y. Treatment algorithm for chronic hepatitis B in HIV-infected patients. J Hepatol 2006;44(1 Suppl);S90-S94. [PubMed]

Benhamou Y, Bochet M, Thibault V, et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: An open-label pilot study. Lancet 2001:358:718-723. [PubMed]

Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology 1999;30:1302-1306. [PubMed]

Borroto-Esoda K, Waters JM, Bae AS, et al. Baseline genotype as a predictor of virological failure to emtricitabine or stavudine in combination with didanosine and efavirenz. AIDS Res Hum Retroviruses 2007;23:988-995. [PubMed]

Bryant ML, Bridges EG, Placidi L, et al. Antiviral L-nucleosides specific for hepatitis B virus infection. Antimicrob Agents Chemother 2001;45:229-235. [PubMed]

Di Martino V, Thevenot T, Colin JF, et al. Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B. Gastroenterology 2002;123:1812-1822. [PubMed]

FDA. HEPSERA (adefovir dipivoxil) prescribing information. 2012. www.accessdata.fda.gov/drugsatfda_docs/label/2012/021449s020lbl.pdf

EASL. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-185. [PubMed]

Hadler SC, Judson FN, O’Malley PM, et al. Outcome of hepatitis B virus infection in homosexual men and its relation to prior human immunodeficiency virus infection. J Infect Dis 1991;163:454-459. [PubMed]

Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol 2004;2:87-106. [PubMed]

Kim JW, Park SH, Louie SG. Telbivudine: A novel nucleoside analog for chronic hepatitis B. Ann Pharmacother 2006;40:472-478. [PubMed]

Kumar M, Satapathy S, Monga R, et al. A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology 2007;45:97-101. [PubMed]

Lai CL, Leung N, Teo EK, et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 2005;129:528-536. [PubMed]

McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavir – Effects on HIV-1 replication and resistance. N Engl J Med 2007;356:2614-2621. [PubMed]

Nuñez M, Soriano V. Management of patients co-infected with hepatitis B virus and HIV. Lancet Infect Dis 2005;5:374-382. [PubMed]

Pessoa W, Gazzard B, Huang A, et al. Entecavir in HIV/HBV co-infected patients: Safety and efficacy in a phase II Study (ETV-038). Abstract 123. CROI; 2005 Feb 22-25; Boston, MA. 

Sheldon JA, Corral A, Rodés B, et al. Risk of selecting K65R in antiretroviral-naïve HIV-infected individuals with chronic hepatitis B treated with adefovir. AIDS 2005:19:2036-2038. [PubMed]

Soriano V, Barreiro P, Nuñez M. Management of chronic hepatitis B and C in HIV-coinfected patients. J Antimicrob Chemother 2006;57:815-818. [PubMed]

Soriano V, Puoti M, Bonacini M, et al. Care of patients with chronic hepatitis B and HIV co-infection: Recommendations from an HIV-HBV International Panel. AIDS 2005;19;221-240. [PubMed]

Tillmann HL, Hadem J, Leifeld L, et al. Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience. J Viral Hepat 2006;13:256-263. [PubMed]

Wedemeyer H, Yurdaydìn C, Dalekos GN , et al. HIDIT Study Group. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 2011;364:322-331. [PubMed]

Monitoring

Medical Care Criteria Committee, August 2013

An initial decrease in HBV DNA of ≥1 log within 3 months for nucleoside or nucleotide analog regimens is considered a response to anti-HBV therapy. Although the appropriate interval for monitoring HBV DNA and seroconversion to anti-HBe has not been established, monitoring every 3 to 6 months is a reasonable approach because of the risk of future virologic resistance and a subsequent hepatic flare. Transaminase flares are also possible after initiation of ART [EASL 2012; Bessesen et al. 1999]. If HBV DNA increases by >1 log in adherent patients, then resistance should be suspected.

Detailed monitoring considerations are provided in Table 4.

Patients with Cirrhosis

To reduce the risk of morbidity associated with IRIS, monthly monitoring of serum transaminases for the first 3 months after initiation of ART is particularly important for patients with HBV who have cirrhosis. Patients with HBV with known cirrhosis should be referred for endoscopy every 1 to 2 years to monitor for esophageal varices.

Risk for Hepatocellular Carcinoma

Risk assessment: Hepatocellular carcinoma (HCC) is a major cause of death in patients with chronic HBV infection, and all patients with HIV should be assessed for the risk of HCC. However, determining an individual’s risk can be challenging. According to guidelines from the American Association for the Study of Liver Diseases (AASLD) [Bruix and Sherman 2010] and the European Association for the Study of the Liver (EASL) [EASL-EORTC 2012], the patient populations listed below are at high risk for HCC.

Patients at high risk for hepatocellular carcinoma, per AASLD [Bruix and Sherman 2010] and EASL guidelines [EASL-EORTC 2012]:

• Asian men over 40 years and Asian women over 50 years of age [Bruix and Sherman 2010]
• Black patients over 20 years of age [Bruix and Sherman 2010]
• Patients over 40 years of age with persistent or intermittent serum ALT elevation and/or HBV DNA level >2000 IU/mL [Bruix and Sherman 2010; EASL-EORTC 2012]
• Patients with cirrhosis [Bruix and Sherman 2010; EASL-EORTC 2012] including those awaiting transplantation [EASL-EORTC 2012]
• Patients with a family history of HCC [Bruix and Sherman 2010; EASL-EORTC 2012]
• Patients with chronic HCV infection and advanced liver fibrosis [EASL-EORTC 2012]

Nomograms have been published to assist in determining whether an individual patient should undergo surveillance for HCC [Yang et al. 2010]. These nomograms can be used to predict an individual’s risk for HCC based on known risk factors, including age, sex, alcohol intake, family history of HCC, elevated serum ALT level, presence of HBeAg, HBV DNA level, and HBV genotype.

Surveillance: When a clinician determines that a patient is at risk for HCC, surveillance for HCC should be performed. Because treatment has improved dramatically for HCC when it is detected early, the AASLD considers surveillance for HCC to be cost-effective in patients with HBV with an expected risk for HCC of greater than 0.2% per year (see above) [Bruix and Sherman 2010].

In patients who do not have HIV, treatment with lamivudine, which is active against HBV, has been shown to lower the risk of HCC [Liaw et al. 2004]. In patients with HIV, treatment with lamivudine, entecavir, tenofovir, or tenofovir/emtricitabine fixed-dose tablets would be presumed to also decrease the risk for HCC, but the extent of the decrease is unknown. The AASLD recommends that patients with advanced liver disease who were candidates for HCC surveillance before initiation of lamivudine be offered continued surveillance, even after therapy-induced seroconversion or therapy-induced remission of inflammatory activity [Bruix and Sherman 2010].

The sensitivity of ultrasound for early detection of HCC is operator-specific. Specialized training for those performing ultrasound is recommended. If ultrasound by a trained sonographer is not available, then α-fetoprotein (AFP) in combination with ultrasound or AFP alone may be considered. However, AFP should be considered only if ultrasound by a trained sonographer is not available. AASLD and EASL guidelines no longer recommend AFP for HCC surveillance due to lack of sensitivity [Bruix and Sherman 2010; EASL-EORTC 2012].

Evidence for multidetector CT scan or magnetic resonance imaging (MRI) as part of ongoing surveillance to determine the presence of HCC is lacking, and these tests may lead to false-positive results. CT may be considered when cirrhosis is identified during the patient’s initial evaluation or in patients with obesity, intestinal gas, and chest wall deformity that may prevent an adequate ultrasound assessment. However, the radiation risk of repeated CT scan and high cost of MRI are factors to consider in long-term use.

References

Bessesen M, Ives D, Condreay L, et al. Chronic active hepatitis B exacerbations in human immunodeficiency virus-infected patients following development of resistance to or withdrawal of lamivudine. Clin Infect Dis 1999:28:1032-1035. [PubMed]

Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: An update. American Association for the Study of Liver Diseases: Alexandria, VA; 2010. Available at: www.aasld.org/practiceguidelines/Documents/HCCUpdate2010.pdf

European Association for the Study of the Liver (EASL). EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-185. [PubMed]

European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer (EASL-EORTC). EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2012;56:908-943. [PubMed]

Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-1531. [PubMed]

Tujios SR, Lee WM. New advances in chronic hepatitis B. Curr Opin Gastroenterol 2012;28:193-197. [PubMed]

Wong VW, Sung JJ. Diagnosis and personalized management of hepatitis B including significance of genotypes. Curr Opin Infect Dis 2012;25:570-577. [PubMed]

Yang H-I, Sherman M, Su J, et al. Nomograms for risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J Clin Oncol 2010;28:2437-2444. Available at: http://jco.ascopubs.org/content/28/14/2437.full.pdf

All Recommendations

Medical Care Criteria Committee, August 2013