Author: Rena Fox, MD
Hepatitis B virus (HBV) is the most common cause of chronic liver disease worldwide. Chronic HBV can cause necroinflammation and over time can cause hepatic fibrosis and eventually cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). It is estimated that 350 million people have chronic HBV infection, with approximately 1.25 million of them in the United States. HBV is a DNA virus that is spread through exposure to infected blood and body fluids. It typically is transmitted by parenteral, sexual, and vertical exposures, but may be transmitted through person-to-person contacts among household members, especially because HBV can survive outside the body for long periods of time. Because HIV and HBV share transmission routes, up to 90% of HIV-Infected patients have evidence of HBV exposure. In the United States, chronic HBV infection has been identified in 6-15% of HIV-infected persons.
The epidemiology of HBV infection varies by geographic region. In Southeast Asia and sub-Saharan Africa, HBV is highly prevalent and almost all infections occur perinatally or during early childhood. In the United States and Western Europe, most infections occur through sexual exposure or high-risk injection drug use behavior.
To identify patients with HBV coinfection, and to identify and vaccinate susceptible individuals, all HIV-infected persons should be tested for HBV (see chapters Initial and Interim Laboratory and Other Tests and Immunizations for HIV-Infected Adults and Adolescents). In addition, all patients with chronic HBV infection should be tested for HIV and all patients with evidence of prior resolved HBV infection should be strongly considered for HIV testing.
It is universally recommended that HBV vaccination should be given to all HIV-infected persons who test negative for all HBV seromarkers (see "Interpreting HBV test results," below, and chapter Immunizations for HIV-Infected Adults and Adolescents). If possible, it is recommended that the vaccine series be given when CD4 counts are >200 cells/µL, as doing so is associated with higher rates of vaccine response. For patients with CD4 counts of <200 cells/µL, it is recommended that they first receive antiretroviral therapy (ART) and then be vaccinated when the CD4 count rises to >200 cells/µL. HBV vaccination also is recommended for persons who test negative for HBV seromarkers but are at high risk (e.g., men who have sex with men [MSM], persons who are infected with hepatitis C virus [HCV], and persons who are in close contact with someone who has HBV infection).
The natural history of HBV infection is complex. The likelihood of developing chronic HBV after exposure varies with age, mode of infection, and immunocompromised status. Among newborns born to HBV-infected mothers, 90% develop chronic hepatitis B, whereas 30% of exposed infants and young children and <5% of exposed adults develop chronic infection. Most adults who become infected with HBV are able to clear the virus without treatment, and they subsequently become immune to HBV. Progressive HBV can lead to cirrhosis and then to decompensated liver disease including ascites, portal hypertension, esophageal varices, coagulopathy, thrombocytopenia, and hepatic encephalopathy. HCC can develop in patients with or without cirrhosis; in fact, 30-50% of HCC cases attributable to HBV occur in the absence of cirrhosis.
Factors associated with increased rates of cirrhosis include the following:
Factors associated with increased rates of HCC include the following:
Among individuals who are not taking ART, HIV infection significantly modifies the natural history of HBV infection. HIV infection appears to increase the risk of developing chronic HBV infection after acute HBV, and it is associated with a higher level of HBV DNA replication and lower rates of spontaneous HBeAg seroconversion. In patients with chronic HBV, HIV coinfection is associated with faster progression of liver disease and cirrhosis and increased rates of liver-related deaths. Although HIV coinfection itself is not known to increase the risk of HCC development, it does increase the risk of cirrhosis, which in turn increases the risk of HCC.
Treatment of HIV infection with effective ART has increased the life expectancy of HIV-infected patients in recent years, and paradoxically has given HIV/HBV-coinfected patients a longer lifespan during which cirrhosis may develop. Partly for this reason, the relative proportion of deaths attributable to liver disease among HIV-infected patients is rising. On the other hand, ART can positively impact the natural history of HBV infection. Effective ART can improve patients' immune responses against HBV. ART also may be used to treat HBV in coinfected patients. Several of the nucleoside analogues (NRTIs) used against HIV also are active against HBV, and these should be included in an ART regimen to treat both HIV and HBV for coinfected persons (see "Antiviral Treatment of Chronic HBV Infection," below). Withdrawal of NRTIs with anti-HBV activity can precipitate a reactivation of HBV. ART that contains anti-HBV NRTIs also may prevent acute infections in patients who are receiving them.
Persons with acute HBV infection may have symptoms including fatigue, nausea, vomiting, arthralgias, fever, right upper quadrant pain, jaundice, dark urine, and clay-colored stools. Some patients may have no symptoms at all.
Persons with chronic HBV, even with early cirrhosis, may be asymptomatic or may experience only fatigue or mild right upper quadrant tenderness. Patients with decompensated cirrhosis may experience increased abdominal girth, easy bruising, telangiectasis, pruritus, gastrointestinal bleeding, or altered mentation. Patients with early or small HCC may have no additional symptoms or may develop significant abdominal pain, weight loss, nausea, or bone pain.
Ask patients with known HBV infection about symptoms that suggest complications of HBV such as cirrhosis, decompensation, risk factors for worsening liver disease, and hepatotoxins. Questions should address the symptoms listed above, and the following:
Measure vital signs.
Perform a physical examination to include evaluation of the following:
As discussed above, all HIV-infected persons should be screened for HBV surface antigen (HBsAg), HBs antibody (HBsAb), and HBV core antibody (total) (HBcAb-total) and be vaccinated if not immune (see chapter Immunizations for HIV-Infected Adults and Adolescents).
Nonimmune persons with elevated transaminases or signs or symptoms of acute or chronic liver disease should be retested for HBV and HCV infection.
Routine baseline HBV serologic screening tests for HIV-infected individuals are outlined in Table 1.
Markers of chronic hepatitis B can manifest in a number of patterns (see Table 1).
|Acute Hepatitis B||Recovery from Acute Hepatitis B||Chronic HBeAg+ Disease||Chronic HBeAg- Disease||Occult Hepatitis B||Successful Vaccination||Isolated HBcAb|
|HBsAg||X (may clear)||X||X|
|Anti-HBc IgM||X (may be the only marker during window period)|
|Anti-HBe||X (in some cases)||X||X (in some cases)|
|DNA* (PCR if required)||X||X||X||X||(in rare cases may be +)|
Because of the complexity of HBV diagnosis and test interpretation, it is important to test for HBsAg, HBcAb, and HBsAb. If the result for either HBsAg or HBcAb is positive, then test for HBV DNA. The presence of HBsAg for >6 months indicates chronic HBV infection, but detectable HBV DNA is required for the diagnosis. HBV DNA should be tested before initiation of ART, if possible, as NRTIs with anti-HBV activity may suppress HBV viremia and interfere with diagnosis. Some persons with HIV infection can have chronic HBV infection with high HBV DNA levels and hepatic inflammation while testing negative for HBsAg and positive only for HBcAb. This sometimes is termed "occult hepatitis B infection." Patients with chronic HBV may test either positive or negative for HBeAg. Patients with inactive chronic HBV are positive for HBsAg but have persistently normal alanine aminotransferase (ALT) levels, low-level or no detectable HBV DNA, and negative HBeAg results. Ongoing viral replication and infectiousness is indicated by the presence of HBV DNA or a positive result for HBeAg.
Markers of immunity or previous exposure to HBV also can manifest in a number of patterns (see Table 1). Successful vaccination to HBV (in someone who has never been infected) will result in positive HBsAb but negative HBcAb results. Prior exposure to HBV may result in positive HBcAb and HBsAb findings, indicating the development of immunity. However, prior exposure may present as positive HBcAb only, with negative results for HBsAb, HBsAg, and HBV DNA. This pattern shows that the patient was previously infected with hepatitis B but did not develop chronic infection, and lost the HBsAb. This sometimes is termed "isolated core Ab," and it is seen more commonly in patients coinfected with HIV or HCV. It is not known whether patients who display this pattern would have sufficient immunity to ward off another HBV infection if they were reexposed. Some experts recommend vaccinating such patients so that they do mount an HBsAb response whereas others do not believe that vaccination for these patients is necessary.
In acute HBV infection, HBV DNA will be detectable before HBsAg, if highly sensitive nucleic acid testing is used. Otherwise, HBsAg (which takes an average of 30 days to develop) is the only marker detected during the first 3-5 weeks after infection. HBcAb develops at approximately 6 weeks after infection and both immunoglobulin M (IgM) and immunoglobulin G (IgG) will be evident. The IgM will decline within 6 months but the IgG will persist for life. Among individuals who recover from acute HBV infection, HBeAg typically seroconverts to HBeAb at approximately 3 months whereas, for those who develop chronic HBV infection, HBeAg typically persists for years.
When approaching the diagnosis of a patient with acute hepatitis B infection, the following steps should be taken:
Obtain history and perform physical examination.
Determine the time and route of infection if possible. Take a complete history, including HIV disease course and treatment, and other medical history. Perform physical examination, focusing on evidence of acute liver dysfunction.
Assess HBV replication serially.
As soon as acute infection is suspected, check HBsAg, HBV DNA, HBeAg, HBeAb, ALT, HBcAb-IgM, and HBsAb. Recheck each every 4 weeks to track the serologic course of infection.
Assess liver function serially.
When ALT is abnormal and rising, additional tests of liver function should be serially evaluated until it is clear that ALT is trending back down. Tests should include albumin, total bilirubin, prothrombin time, and platelet count.
Determine whether HBV infection resolves or persists as chronic HBV infection.
If the HBsAg is still present at 6 months after acute infection, the HBV infection has persisted and patient has chronic hepatitis B infection.
When approaching the diagnosis of a patient with chronic HBV infection, the following steps should be taken:
For patients who are not on treatment for HBV, regular monitoring of HBV replication and liver function should be performed.
For patients with the following seromarkers, recommendations are as indicated:
HBV DNA, HBeAg, and ALT testing should be performed every 3 months for the first year to determine whether the virus is truly inactive. If it remains inactive (with, negative HBeAg, normal ALT, and low-level DNA), monitoring can continue every 6-12 months; some specialists recommend more frequent monitoring.
Biopsy should be considered, and treatment should be considered. If treatment is not started, monitoring should occur every 3 months.
Follow-up should be performed every 3-6 months if treatment is not started.
Monitoring should be performed every 3 months and, if ALT is persistently elevated, a biopsy should be considered to guide the decision regarding initiation of HBV treatment.
Monitoring should be performed every 3-6 months to check for changes in ALT. If ALT rises significantly, treatment should be considered.
Treatment should be considered. If not treated, monitoring should be performed every 3-6 months.
The goals and markers of HBV treatment for HIV/HBV-coinfected patients are the same as for HBV-monoinfected patients.
The goals of treatment are as follows:
Treatment endpoints for the HBV/HIV-coinfected population are not well defined but efficacy is determined by the following measures:
The optimal duration of treatment is not clearly known; it generally is considered to be long-term, with the primary risks being the development of drug resistance and a subsequent reactivation of HBV.
The timing of treatment and choice of treatment for HBV/HIV-coinfected patients are important. Determine the patient's need for anti-HIV treatment (see chapters Risk of HIV Progression/Indications for ART and Antiretroviral Therapy).
|Dual activity against HBV and HIV||Yes||Yes||Yes||No (at the low HBV treatment dosage)||Yes||Uncertain||No|
|Recommended for use in HIV/HBV coinfection||With tenofovir, as part of fully suppressive ART||With tenofovir, as part of fully suppressive ART||With lamivudine or emtricitabine, as part of fully suppressive ART||If HIV is not being treated, or in combination with a lamivudine- or emtricitabine-containing ART regimen, if tenofovir is not used||With fully suppressive ART||With fully suppressive ART||If HIV is not being treated|
|Loss of HBV DNA||40-44%||76%||21%||67%||60%||25%|
|Class||Nucleoside analogue||Nucleoside analogue||Nucleoside analogue||Nucleotide analogue||Nucleoside analogue||Nucleotide analogue||Interferon|
Persons with chronic HBV are at increased risk of developing HCC. Note that HCC may occur even in the absence of cirrhosis. HCC screening should be performed every 6-12 months using ultrasound (computed tomography [CT] is an alternative); alpha-fetoprotein should be monitored if ultrasound reliability is low.
HBV-infected patients who should be screened for HCC include the following:
Persons with HCV infection should be counseled to avoid exposure to hepatotoxins, including alcohol and hepatotoxic medications (e.g., acetaminophen in large doses, fluconazole, isoniazid). Heavy alcohol use is a risk factor for increasing rate of fibrosis. It is not clear what degree of alcohol consumption is safe, so many experts recommend complete abstinence from alcohol.
All patients with HBV infection should receive individualized counseling on ways to reduce the risk of HBV transmission (including by sexual or needle-sharing behavior, perinatal routes, or household exposure), as appropriate.
Household members and sexual contacts should be vaccinated against HBV.
Women who are pregnant or considering pregnancy should consult with a specialist in both HBV and HIV to discuss ways of decreasing the infection risk for the fetus; this may include treatment for HBV and HIV. Infants born to coinfected women should receive HBV immune globulin and start the HBV vaccine series within 12 hours after birth (with subsequent vaccine doses per usual protocol).