Comprehensive, up-to-date information on HIV/AIDS treatment, prevention, and policy from the University of California San Francisco

Coinfection with hepatitis B virus (HBV) and HIV is common, with 70-90% of HIV-infected individuals in the United States having evidence of past or active infection with HBV.(1, 2) Factors affecting the prevalence of chronic HBV include age at time of infection and mode of acquisition, which vary geographically. In the United States and Western Europe, HBV often is acquired in adolescence or adulthood via sexual contact or injection drug use. Although spontaneous clearance of HBV acquired in adulthood occurs in >90% of immunocompetent individuals, HIV-infected persons are half as likely as HIV-uninfected persons to spontaneously clear HBV. Therefore, chronic HBV infection occurs in 5-10% of HIV-infected individuals who are exposed to HBV, a rate 10 times higher than that for the general population.(3, 4) In the United States, HIV/HBV coinfection rates are highest among men who have sex with men (MSM) and injection drug users. In contrast, in Asia and sub-Saharan Africa, where vertical and early childhood exposure are the most common modes of transmission, respectively, and overall HBV prevalence is higher, the prevalence of HBV among HIV-infected individuals also is higher, at an estimated 20-30%.(5, 6)

HBV is a DNA virus that forms stable circular covalently closed (ccc) DNA that can persist in the liver indefinitely. Individuals with evidence of past infection (core antibody positivity) are at risk of HBV reactivation, particularly in the setting of severe immunocompromise, prolonged steroid use, or chemotherapy. There are 8 genotypes of HBV. Genotype G may be predictive of more severe fibrosis in HIV-coinfected patients,(7) and genotypes C and D may be more responsive to interferon.(8) However, in general, knowledge of the HBV genotype is not consistently associated with a response to nucleoside therapy and therefore is not particularly useful in clinical care of HIV/HBV coinfection, as nucleosides are the mainstays of HBV treatment.

The course of acute HBV may be modified in the presence of HIV infection, with a lower incidence of icteric illness and lower rates of spontaneous clearance of HBV.(9) Persons with HIV and chronic HBV coinfection have higher levels of HBV DNA and lower rates of clearance of the hepatitis B e antigen (HBeAg).(10, 11, 12, 13) Serum transaminase levels may be lower in HIV/HBV-coinfected patients than in HBV-monoinfected patients, but normal transaminase levels should not be interpreted to mean that there is no underlying hepatic fibrosis.

HIV increases the risk of cirrhosis and end-stage liver disease in HBV coinfection.(14) Liver-related disease has emerged as the leading cause of non-HIV-related mortality in parts of the world where effective antiretroviral therapy (ART) is widely available. In several cohort studies, the risk of liver-related mortality has been found to be 2-3 times higher in HIV/HBV-coinfected patients than in HIV-monoinfected patients (14% vs 6%).(15, 16) Lastly, HIV coinfection is associated with more frequent flares of hepatic transaminases, which can occur with immune reconstitution inflammatory syndrome (IRIS) owing to ART, interruption of HIV/HBV treatment, or the development of resistance to HIV/HBV treatment; they also can occur spontaneously.(17)

There are conflicting data with respect to the impact of HBV on the disease course of HIV infection. In the early ART era, some studies showed an increased rate of HIV progression to AIDS among individuals with markers of exposure to HBV,(18) whereas others did not show any change in the progression of HIV disease or survival.(12) More recent data have not found HBV coinfection to have a substantial impact on immunologic or HIV virologic responses to ART or on the development of AIDS-defining illness or HIV-related death.(19, 20)

Understanding the natural history of HBV and knowing how to interpret hepatitis B serologic studies are keys to evaluating the current stage of HBV infection and determining who may benefit from HBV treatment. The U.S. National Institutes of Health (NIH) has adopted consensus terminology to help clarify discussion of the natural history of HBV, as shown in Figure 1. Although transition through these stages can be a linear path over the course of time, it is important to recognize that individual patients may revert from inactive carrier status or, rarely, even from a state of resolved HBV infection to immune active status, particularly in the setting of immunocompromise, whether as a result of medications, chemotherapy, or advanced AIDS.(21, 22)

There are 3 main phases of chronic HBV disease (see Figure 1 and Figure 2),(23) as follows:

1. Immune tolerant phase: This phase is characterized by a high level of HBV replication with little or no evidence of active hepatic inflammation. Hepatic transaminases are normal and liver biopsy, if performed, would show little or no inflammation. Most children infected at birth or during early childhood will be immune tolerant and remain in the immune tolerant phase for years or even decades; however, most eventually will progress to immune active disease. Given the lack of immune response to HBV, treatment is not recommended during this period, but individuals should be monitored for transition to immune active disease as well as for hepatic fibrosis and hepatocellular carcinoma (HCC) as they age. HBV DNA is detectable, as are HBeAg and hepatitis B surface antigen (HBsAg). Because of the high level of HBV viremia, this is a highly infectious phase.

2. Immune active phase: This phase is characterized by elevated liver enzymes and liver inflammation on biopsy. Individuals infected in adolescence or adulthood, as is frequently seen in HIV/HBV coinfection in the United States, often begin the disease course in the immune active phase, and are never immune tolerant. This phase also is characterized by detectable HBV DNA, HBeAg and HBsAg, and risk of transmission to others.

3. Inactive carrier phase: During this phase, HBeAg is lost and HBV DNA declines, often to undetectable levels. Hepatitis B e antibody (HBeAb) seroconversion can occur, followed by hepatitis B surface antibody (HBsAb) seroconversion, indicating immune control of HBV infection. A small proportion of people will continue to have detectable low-level HBV DNA, which may be intermittent and is referred to as "occult" HBV infection (see below).

HBeAg-Negative Chronic Hepatitis: "e antigen negative" chronic hepatitis is a form of immune active hepatitis in which individuals have undergone loss of eAg and eAb seroconversion but still have HBV DNA present at fluctuating levels and evidence of active hepatitis with hepatic inflammation. eAg is not detectable because the HBV has undergone mutations in the precore or basal core promoter region, resulting in little to no eAg production. Despite the lower levels of HBV viremia, eAg-negative hepatitis can be difficult to treat, usually requiring indefinite treatment with nucleoside therapy, rarely transitions to inactive carrier phase, and is associated with a high risk of progression to fibrosis.(24) Both the eAg-negative and the inactive carrier phases are characterized by core antibody (cAb)-positive, eAb-positive, eAg-negative, and sAg-positive serologies. They are distinguished by detection of HBV DNA, measured at serial time points (every 3 months); evidence of detectable HBV DNA is suggestive of eAg-negative chronic hepatitis. In addition, eAg-negative disease is characterized by ongoing liver inflammation and, in most cases, elevated transaminases.

Resolved infection: HBV-infected individuals who have lost eAg and sAg and seroconverted to eAb and sAb positivity are referred to as having resolved their HBV infection. However, given the nature of the long-lived cccDNA that resides in hepatocytes during HBV infection, it may be more appropriate to think of these individuals as immunologically controlled because, in rare cases, HBV disease can reactivate in the setting of severe immunosuppression.

The interpretations of acute and chronic hepatitis serologies are summarized in Table 1.

Given the elevated rates of HBV among individuals who are infected with HIV and the shared routes of transmission between the two viruses, all HIV-infected individuals should be screened for HBV coinfection with HBsAg testing. Patients who do not have evidence of HBsAg should have HBcAb and HBsAb evaluated to assess for prior HBV infection as well as HBsAb, which provides evidence of immunologic control of prior infection or vaccination. Because HBV DNA can persist in the liver indefinitely, persons with cAb positivity are at risk of HBV reactivation even if they test positive for sAb, particularly if they become severely immunosuppressed (see Table 1 and Figure 2).

Isolated HBcAb: Some individuals will have isolated HBcAb positivity, in the absence of HBsAg or HBsAb. That indicates one of the following scenarios:

• "Occult" HBV viremia: HBV viremia may be detected in 4-88% of isolated cAb-positive patients.(25, 26, 27, 28) The clinical significance of occult viremia is unknown. However, as even low levels of HBV viremia may increase the risk of liver disease,(29) these individuals may be at higher risk of hepatic disease and many experts recommend managing these patients as chronically HBV infected.

• Waned HBsAb response: Loss of sAb can occur over time, particularly with immunosuppressed patients. In the absence of detectable HBV viremia, these individuals may respond to a single booster HBV vaccination. However, the rate of anamnestic response after 1 booster is low (7-16% in 2 studies of isolated cAb-positive patients),(30, 31) suggesting that it may be more efficient to complete a 3-vaccine series before checking sAb titer to determine response.

• False-positive HBcAb: Individuals who do not respond to a booster of HBV vaccination may have a false-positive HBcAb result or may have an impaired antibody response to prior infection. Vaccination with a full series is recommended.

Persons with detectable sAg should be evaluated for HBeAg, HBV DNA viral load, liver transaminases, prothrombin time/international normalized ratio (PT/INR), and platelets, and they should have baseline liver imaging to screen for cirrhosis and HCC (see below).

Patients with chronic HBV should be screened for hepatitis C virus (HCV) infection and should be vaccinated against hepatitis A virus (HAV) if they are not immune. HIV/HBV-coinfected patients should be counseled to avoid or limit intake of hepatotoxins, including alcohol and high dosages of acetaminophen.

Prevention of HBV Transmission

All HBsAg-positive patients should be counseled about reducing the risk of HBV transmission to close contacts. It is important to inform HIV/HBV-coinfected patients that HBV can be more infectious than HIV and can be transmitted to household contacts via dried blood, open cuts, and shared toothbrushes or razors. Sex partners, household members, children with close physical contact, and those who share injection drug equipment with the patient should be screened for HBV and vaccinated if they are not actively infected (see "Immunization," below). As with HIV prevention, condom use with sex and avoidance of shared needles and other equipment for injection drug use are recommended measures for reducing the risk of HBV transmission.

HBV Therapy

The goal of HBV treatment for persons with HIV coinfection is to suppress HBV viral replication and minimize ongoing hepatic damage. Loss of sAg and seroconversion to sAb indicating resolution of active HBV disease are uncommon in HIV/HBV coinfection; therefore, indefinite treatment of HBV for coinfected patients often is required.(32) Indications for treatment of HBV in HIV infection HBV therapy is recommended for all HIV/HBV-coinfected patients with abnormal alanine aminotransferase (ALT) values or HBV DNA levels of >2,000 IU/mL. Some guidelines cite >20,000 IU/mL as the threshold for treatment of eAg-positive patients (33); however, many experts recommend treatment of HBV for all HIV-coinfected patients in whom any HBV replication is present. If HBV viremia is low level (<2,000 IU/mL) and the ALT value is normal, a liver biopsy may be considered for patients who are not on HIV therapy, as those with no or limited fibrosis may not require HBV treatment. It is important to note that significant liver fibrosis may be present in persons with normal transaminases. If HBV treatment is deferred, transaminases and HBV DNA values should be monitored closely. Treatment of HBV in the setting of ART As most HIV treatment contains one or more HBV-active agents (eg, lamivudine [3TC], emtricitabine [FTC], tenofovir [TDF]), patients with an indication for HBV treatment should be started on fully active ART that contains HBV-active nucleoside/nucleotide analogues, regardless of the CD4 cell count, to ensure that HIV is not partially treated.(34) Similarly, any HIV/HBV-coinfected patient with an indication for ART should be started on HIV treatment that includes effective anti-HBV treatment. The combination of TDF with 3TC or FTC is recommended as a highly effective first-line treatment for HBV.(34) Individuals who cannot take TDF because of renal insufficiency or other intolerance may consider entecavir treatment (renally dosed if necessary) for HBV in lieu of TDF. Treatment with 3TC or FTC as the only HBV-active agent in ART (ie, HBV monotherapy) is not recommended owing to a high risk of developing HBV drug resistance over time.(35) Treatment of HBV in the absence of ART The current U.S. Department of Health and Human Services guidelines recommend fully active ART for HIV/HBV-coinfected patients who require HBV treatment, even if they do not have a current indication for HIV treatment.(36) However, in some circumstances, an individual may not tolerate HIV therapy or may wish to defer treatment for HIV. Treatment with HIV/HBV-active agents that are insufficient to fully suppress HIV should be avoided. Entecavir and telbivudine have been shown to have anti-HIV activity and to contribute to HIV drug resistance,(37, 38) as have traditional HIV-active agents used for HBV treatment (eg, 3TC, FTC, TDF). Whereas adefovir may be an option for treatment of HBV only, there is a concern that even low-dose adefovir used for HBV could have anti-HIV activity. Pegylated interferon (IFN) is an option in this scenario, but there are limited efficacy and safety data in HIV coinfection, and long-term treatment with IFN is not feasible because of toxicity and poor tolerability.

HBV Medications

Interferon IFN is most effective for HBV treatment in patients with low levels of viremia and elevated transaminases, and it therefore may be less useful in patients with HIV/HBV coinfection than in those with HBV alone. In coinfected patients, IFN has been associated with lower rates of HBV treatment success and increased toxicity.(39) It cannot be used for patients with decompensated cirrhosis and is not feasible as a long-term treatment, owing to adverse events and tolerability issues. There are no data for use of pegylated IFN in HIV/HBV coinfection. Lamivudine and emtricitabine These nucleoside analogues have similar activity against both HIV and HBV and they are commonly used components for HIV/HBV cotreatment. However, HIV-infected individuals should not receive 3TC or FTC monotherapy for HBV infection because resistance to those drugs develops in up to 90% of patients within 4 years of single-drug treatment.(35) Resistance to 3TC and FTC is characterized by the development of mutations at HBV rtM204 (also known as YMDD mutations). Once 3TC resistance has developed, HBV medications such as telbivudine will no longer have activity against HBV, and agents such as entecavir may be less efficacious and more prone to development of HBV resistance.(40) As with other agents that have activity against HIV, 3TC and FTC should be used only for patients on fully suppressive ART. Entecavir Entecavir is a guanosine analogue that appears to be more potent than either 3TC or adefovir. Entecavir resistance requires the development of several resistance mutations, including the rtM204 mutation that confers resistance to 3TC. In the presence of 3TC resistance, entecavir usually is active but may be more vulnerable to the development of further resistance (see above). Although entecavir initially was thought to have no anti-HIV activity, it has been demonstrated to select for the M184V mutation (37) and should not be used in the absence of combination ART with full suppression of HIV viremia. Telbivudine Telbivudine is a thymidine analogue that also selects for the HBV rtM204 mutation, which leads to 3TC cross-resistance, and should not be used after 3TC or FTC failure. Telbivudine also may have anti-HIV activity (38) and is not recommended for use without fully suppressive ART. Adefovir Adefovir initially was formulated as an anti-HIV agent but was not developed for that purpose, owing to an association with renal toxicity. At lower dosages, adefovir suppresses HBV replication but is less potent than telbivudine or tenofovir. Adefovir appears to be active against 3TC-resistant HBV.(41) The use of adefovir largely has been supplanted in favor of treatment with tenofovir, a related but more potent agent and one that is active against HIV. At the dosage used to treat HBV, adefovir does not appear to be active against HIV and has not been associated convincingly with the development of HIV resistance mutations such as K65R.(42) Adefovir is an option for HBV treatment in HIV-infected patients who decline or cannot take ART, but it should be used with caution. Tenofovir TDF is related to adefovir but it has more potent HBV activity and also can be used for HIV treatment. As with other agents that have activity against HIV, TDF should be used only for patients who are on fully suppressive ART. It usually is used in combination with 3TC or FTC as first-line therapy. HBV that is resistant to 3TC or adefovir can be treated effectively with TDF therapy.(43, 44)

HBV Resistance

HBV resistance can develop after long-term exposure to oral nucleoside and nucleotide analogues, particularly in the setting of 3TC or FTC monotherapy. However, TDF can be used effectively despite the presence of 3TC or adefovir resistance.(44) HBV genotyping is not recommended for HBV treatment-naive individuals, but may be considered for those who have failed to suppress HBV DNA on treatment, who have had significant 3TC monotherapy, or who have experienced a rebound in HBV DNA levels despite continued HBV treatment.

Monitoring on Therapy

The goal of therapy is suppression of HBV below the assay level of detection. For patients on treatment, HBV DNA should be monitored at 3-6 month intervals, along with transaminases and eAg. Virologic response is defined as a ≥2 log10 copies/mL decrease from baseline HBV DNA after 6 months of therapy. TDF-based HBV treatment will fully suppress HBV replication for the majority of patients, but that could take several years to accomplish. Development of TDF resistance despite ongoing viremia has not been documented; it is unclear whether there is a role for additional anti-HBV agents such as entecavir for patients in whom HBV replication has not been suppressed after a year or more of therapy. It is important to note that HBsAg and eAg may remain detectable for years despite HBV DNA suppression, and in some cases indefinitely. HBV treatment in HIV-infected individuals can be associated with hepatic decompensation and transaminase flares caused by immune responses to HBV infection; however, other causes of decompensation or increased transaminases must be considered, including drug toxicity, viral hepatitis coinfection, medication nonadherence, and development of viral resistance to current HBV treatment. Coinfected patients should be cautioned against interruption of HIV and HBV therapy, as treatment interruption can be associated with HBV viral rebound and hepatic decompensation. As a sustained loss of HBsAg is uncommon among HIV-coinfected patients, most of these individuals require indefinite HBV treatment with nucleosides or nucleotides, which are given as a component of HIV treatment, if possible.

HCC Screening

HBV infection is associated with development of HCC even in the absence of cirrhosis. The 2010 American Association for the Study of Liver Disease guidelines recommend screening for HCC every 6-12 months with alpha-fetoprotein (AFP) and with ultrasound in groups at risk of HCC, including patients with chronic HBV who are >40 years of age and those of African American ethnicity.(45) The guidelines also recommend ongoing HCC screening for patients with evidence of cirrhosis, regardless of age or other risk factors. The benefit of surveillance in patients with chronic HBV who are <40 years of age is not well established. However, given that liver disease progresses more rapidly in HIV/HBV-coinfected patients and that HCC may be more aggressive in HIV coinfection,(46) many experts recommend HCC surveillance for all HIV-infected patients with chronic sAg-positive HBV disease.

Immunization against HBV in HIV Infection

All HIV-infected patients who lack sAb and do not have sAg positivity or occult HBV should be vaccinated against HBV. Although transient HIV viremia has been reported after vaccination in some studies, it does not appear to be clinically relevant. Patients with HIV infection are less likely to develop protective sAb after HBV vaccination, with a response rate of 18-71%, compared with >90% for HIV-uninfected adults.(47, 48) Lower seroconversion rates are associated with lower CD4 cell counts, detectable HIV RNA, and HCV coinfection.(49, 50) HIV infection also is associated with lower mean HBV sAb titers and faster decline of sAb levels over time.(51) Administration of a higher dose of HBV vaccine ("double" or "renally" dosed at 40 mcg) has been associated with a trend toward increased effectiveness compared with the standard 20 mcg dose (47% vs 34%), an effect that was strongest in patients with CD4 counts of >350 cells/µL.(49) Those data have prompted some clinics to adopt 40 mcg dosing of HBV vaccine for all HIV-infected individuals, although data to support that practice are limited. Although low CD4 cell counts are associated with an impaired response to vaccination, HBV vaccination should not be deferred for patients with advanced HIV, as some individuals do develop protective antibody titers despite low CD4 cell counts. Postvaccination sAb levels should be checked 1-2 months after the vaccination series is completed to ensure titers of ≥10 IU/L.(52) Revaccination should be considered for patients who have not attained protective titers, and use of the higher dose (40 mcg) vaccine for repeat vaccination should be considered.(34) Several studies have reported that a second vaccination series, with 2 studies reporting a 40 mcg dosing for HBV vaccination, resulted in seroconversion rates of 50-76%.(53, 54, 55) Adjuvants such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and CpG 7909 (Vaximmune) have shown promise in boosting responses to the HBV vaccine, but are in use only for research purposes at the present time.(48, 56) For persons who develop sAb in response to vaccination, some experts recommend annual testing to ensure sAb titers remain adequate, extrapolating from recommendations for dialysis patients, in whom loss of protective antibody is associated with reduced protection against HBV.(34)

Markers of HBV exposure are present in a high proportion of HIV-infected individuals. HIV affects HBV viral replication and clearance, accelerates the development of liver disease, and contributes significantly to hepatic morbidity and mortality in HIV infection. HBV coinfection does not appear to influence the rate of HIV progression but may be a surrogate for factors associated with HIV seroconversion. Patients receiving HIV treatment should receive fully active HBV treatment as well, avoiding 3TC or FTC monotherapy. Conversely, it is preferred to give fully active ART in conjunction with HBV therapy, as there are limited options for effective HBV treatment that lack anti-HIV activity.