Hepatitis B Infection

Background

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 are susceptible to HBV infection (see "Interpreting HBV test results," below, and chapter Immunizations for HIV-Infected Adults and Adolescents). It is recommended that the vaccine series be given when CD4 counts are >200 cells/µL, if possible, as doing so is associated with higher rates of vaccine response, but vaccination should not be delayed for persons with lower CD4 counts.

The natural history of HBV infection is complex and dynamic, with phases of active replication and of inactive replication, and fluctuating alanine aminotransferase (ALT) levels. 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. Chronic 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:

  • Longer duration of infection
  • HBV genotype C
  • High levels of HBV DNA
  • Alcohol consumption
  • Smoking
  • Aflatoxin exposure
  • Coinfection with HIV
  • Coinfection with hepatitis D virus
  • Coinfection with HCV

Factors associated with increased rates of HCC include the following:

  • Male gender
  • Family history of HCC
  • Older age
  • Presence of HBV envelope antigen (HBeAg); history of reversion from anti-HBe to HBeAg
  • High levels of HBV DNA
  • Presence of cirrhosis
  • HBV genotype C
  • Core promoter mutation
  • Coinfection with HCV

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 cotreat 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. Current U.S. Department of Health and Human Services (HHS) guidelines recommend initiation of ART (and cotreatment of HBV) for all persons with HIV/HBV coinfection.

S: Subjective

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:

  • Fatigue
  • Weight loss
  • Impaired concentration
  • Chronic HCV
  • Alcohol intake
  • Substance use
  • Antiretroviral (ARV) medications that may cause hepatotoxicity (e.g., didanosine, protease inhibitors, nevirapine, maraviroc)
  • Medications with potential for hepatotoxicity or accumulation in persons with liver disease (e.g., acetaminophen, benzodiazepines, opiates)

O: Objective

Measure vital signs.

Perform a physical examination to include evaluation of the following:

  • Head, ears, eyes, nose, throat (HEENT): temporal wasting, icterus, gum bleeding
  • Heart and lungs: signs of congestive heart failure
  • Chest: gynecomastia
  • Abdomen: caput medusa, venous prominence, distention, signs of ascites, hepatomegaly, splenomegaly
  • Extremities: edema
  • Neurologic: alertness, mental status, asterixis
  • Skin: jaundice, palmar erythema, petechiae, ecchymoses, spider angiomata

P: Plan

HBV Testing

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.

Interpreting HBV test results

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).

Table 1. Interpreting HBV Laboratory Tests
 Acute Hepatitis BRecovery from Acute Hepatitis BChronic HBeAg+ DiseaseChronic HBeAg- DiseaseOccult Hepatitis BSuccessful VaccinationIsolated HBcAb

* Absence of detectable HBV DNA does not rule out chronic HBV infection in patients who are on ARVs with anti-HBV activity.

HBsAg X
(may clear)
 XX   
Anti-HBs X   X 
Anti-HBc IgM X
(may be the only marker during window period)
      
Anti-HBc XXXXX X
HBeAg X X X  
Anti-HBe  X
(in some cases)
 X  X
(in some cases)
DNA* (PCR if required) X XXX (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 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; current guidelines recommend the standard HBV vaccination series, followed by a check of HBsAb.

In acute HBV infection, HBV DNA will be detectable before HBsAg, if highly sensitive nucleic acid testing is used. Otherwise, HBsAg 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.

Diagnostic Evaluation of Acute HBV Infection

When approaching the diagnosis of a patient with acute hepatitis B infection, the following steps should be taken:

  1. 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.

  2. Assess HBV replication serially.

    As soon as acute infection is suspected, check HBsAg, HBV DNA, HBeAg, HBeAb, ALT, HBcAb-IgM, and HBsAb. HBsAg usually can be detected by 4 weeks (the range of detectability is 1-9 weeks). HBcAb-IgM is detectable at the onset of symptoms.

    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.

  3. 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 the patient has chronic hepatitis B infection.

Initial Diagnostic Evaluation of Chronic HBV Infection

When approaching the diagnosis of a patient with chronic HBV infection, the following steps should be taken:

  • Take a complete history, including family history of HBV or HCC, and HIV disease course and treatment. Perform physical examination.
  • Assess HBV replication to determine HBV DNA level, HBeAg and HBeAb serostatus, and ALT level. Note that HBV DNA levels may be difficult to interpret in patients who are on ARVs that have anti-HBV activity (HBV level may be low or undetectable because of these medications).
  • Assess liver disease - check complete blood cell count with platelet count, albumin, total bilirubin, transaminases (especially ALT), and prothrombin time.
  • Assess for possible overlying liver diseases (e.g., HCV, alcoholic liver disease, fatty liver disease).
  • Consider liver biopsy to assess histological degree of inflammation and fibrosis, especially if the result would affect the decision to use treatment.
  • Screen for HCC at baseline via ultrasound.
  • Test for hepatitis A antibodies (IgG) and vaccinate against hepatitis A if not immune.

Long-Term Monitoring of Chronic HBV Infection

It should be noted that current HHS guidelines strongly recommend treatment of both HIV and HBV in all coinfected persons. Nonetheless, some patients may wish to defer treatment or may not tolerate treatment. For those 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:

Negative HBeAg, low ALT, and low-level DNA (<2,000 IU/mL) (inactive HBV):

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.

Negative HBeAg, elevated ALT, and high HBV DNA (>20,000 IU/mL):

Biopsy should be considered, and treatment should be considered. If treatment is not started, monitoring should occur every 3 months.

Negative HBeAg, moderately elevated ALT, and moderately elevated DNA (2,000-20,000 IU/mL):

Follow-up should be performed every 3-6 months if treatment is not started.

Positive HBeAg, moderately elevated ALT:

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.

Positive HBeAg, high HBV DNA (>20,000 IU/mL) but low-level ALT:

Monitoring should be performed every 3-6 months to check for changes in ALT. If ALT rises significantly, treatment should be considered.

Cirrhosis:

Treatment should be considered. For patients who are not treated, monitoring should be performed every 3-6 months.

Antiviral Treatment of Chronic HBV Infection

HHS ARV guidelines and Centers for Disease Control and Prevention opportunistic infection guidelines recommend treatment of both HIV and HBV in all coinfected persons. 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:

  • To decrease progression of liver disease
  • To prevent development of cirrhosis
  • To prevent development of HCC

Treatment endpoints for the HBV/HIV-coinfected population are not well defined but efficacy is determined by the following measures:

  • HBeAg seroconversion to HBeAb (this is harder to achieve for coinfected patients than for HBV-monoinfected persons)
  • HBV DNA suppression
  • ALT normalization, which usually follows the changes in HBV DNA

The timing of treatment and choice of treatment for HBV/HIV-coinfected patients are important.

Treatment for HIV and HBV:

  • All HIV/HBV coinfected patients should be treated for both HIV and HBV infections, if possible.
  • If treatment for HIV is to be started, HBV should be treated concurrently with the HIV by using a potent ART regimen that includes two NRTIs that are active against both viruses (tenofovir + emtricitabine or tenofovir + lamivudine), if possible. If tenofovir is contraindicated, entecavir or another anti-HBV drug should be used (with emtricitabine or lamivudine) to construct a two-drug therapy for HBV, and the HIV ART regimen should be designed for complete HIV suppression (see Table 2). In this situation, liver biopsy to stage disease is not necessary because HBV treatment will be undertaken (incorporated into the HIV regimen). Note that treatment of HBV with a single NRTI is not recommended, because of the risk of HBV resistance; if tenofovir cannot be used, entecavir (plus combination ART) is the preferred alternative (see Table 2).
  • Most patients receiving ART who are treated for HBV will require HBV treatment indefinitely (lifelong).

Treatment for HBV alone:

  • If HBV treatment is indicated, HIV infection should be treated concurrently, if possible, as stated above. If treatment for HIV is deferred, the hepatitis B should be treated if the patient otherwise meets criteria for HBV treatment (see below).
  • Inactive chronic hepatitis B (HBV DNA is <2,000 IU/mL, HBeAg is negative, and ALT is not elevated): the HBV can be monitored and does not require treatment.
  • HBeAg positive, ALT is more than two times the upper limit of normal (ULN), and HBV DNA >20,000 IU/mL: consider HBV treatment.
  • HBeAg negative, ALT is more than two times the ULN and HBV DNA >2,000 IU/mL: consider HBV treatment.
  • HBeAg positive, HBV DNA >20,000 IU/mL, but ALT is less than two times the ULN: can use a biopsy to determine the need for HBV treatment.
  • HBeAg negative, DNA >2,000 IU/mL, but ALT is less than two times the ULN: can use a biopsy to determine the need for HBV treatment.
  • Any patient with cirrhosis (if not decompensated) and a detectable DNA level: should be considered for HBV treatment, regardless of HBeAg status and regardless of ALT level.
  • Patients with decompensated cirrhosis should not be treated for HBV but should be referred for transplant.
  • Some specialists recommend HBV treatment for all patients with detectable HBV DNA, particularly if ALT is elevated or inflammation or fibrosis is seen on liver biopsy.
  • If a decision is made to treat HBV but not HIV, HBV treatment should not include agents that are dually active, as that could lead to early HIV resistance. This limits choices to pegylated interferon alfa-2a (although it has not been studied in HIV/HBV-coinfected patients) or adefovir dipivoxil. Tenofovir, lamivudine, emtricitabine, entecavir, and telbivudine should not be used as monotherapy for HIV/HBV-coinfected patients, because HIV (and HBV) resistance may develop (see Table 2).
Table 2. Antiviral Therapies for Chronic HBV Infection
 LamivudineEmtricitabineTenofovirAdefovirEntecavirTelbivudinePegylated Interferon
Dual activity against HBV and HIVYesYesYesNo (at the low HBV treatment dosage), but theoretical concern remainsYesPossiblyNo
Recommended for use in HIV/HBV coinfectionWith tenofovir, as part of fully suppressive ARTWith tenofovir, as part of fully suppressive ARTWith lamivudine or emtricitabine, as part of fully suppressive ARTIf HIV is not being treated, or in combination with a lamivudine- or emtricitabine-containing ART regimen, if tenofovir is not usedWith fully suppressive ARTWith fully suppressive ARTIf HIV is not being treated
Loss of
HBV DNA
40-44% 76%21%67%60%25%
HBeAg seroconversion16-21% 21%12%21%22%27-32%
ClassNucleoside analogueNucleoside analogueNucleotide analogueNucleotide analogueNucleoside analogueNucleotide analogueInterferon

Additional points about treatment for HIV/HBV-coinfected patients:

  • When lamivudine is used as a single agent, HBV resistance develops in many patients by 1-2 years. Although combination therapy has not been well studied, specialists recommend using dual-NRTI combinations that have activity against HBV (lamivudine + tenofovir, or emtricitabine + tenofovir [Truvada]) as part of the ARV regimen, to treat HBV and to prevent HBV resistance.
  • Some patients treated with ART may experience worsening of HBV symptoms and laboratory markers in the weeks after ART initiation, because of immune reconstitution inflammatory reactions. Hepatic decompensation owing to immune reconstitution must be distinguished from other causes, such as medication toxicity, or other infection. Liver function tests should be monitored closely for patients starting ART.
  • Some ARV medications are hepatotoxic and should be avoided or used cautiously. These include nevirapine, tipranavir, and high-dose ritonavir. Numerous other medications (e.g., fluconazole, isoniazid) are hepatotoxic and can pose problems for patients with impaired liver function.
  • Discontinuation of HBV medications in patients with HIV/HBV coinfection may cause a flare of liver disease. Be very cautious when discontinuing HBV-active medications from an anti-HIV ART regimen. If the HBV DNA is suppressed, options include continuing the HBV-active ARVs, even if there is HIV resistance (modify the other parts of the ART regimen for maximal HIV suppression) or substituting other HBV-active medications to avoid rebound liver inflammation and decompensation. For example, if it is decided to discontinue a lamivudine/tenofovir-containing regimen in an HIV/HBV-coinfected patient on ART, consider starting interferon or possibly adefovir to maintain activity against HBV. If HBV therapy is discontinued and a flare occurs, consider reinstating HBV therapy as soon as possible.
  • Limited data exist on treatment of HBV in the setting of HIV and HCV. Consider consultation with an expert if optimal timing for treatment of the three infections is not clear.

Screening for HCC in patients with chronic HBV infection:

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:

  • Anyone with cirrhosis
  • Anyone over age 40 with elevated ALT or HBV DNA level of >2,000 copies/mL
  • Asian men aged >40
  • Asian women aged >50
  • Persons of African descent aged >20
  • Anyone with a family history of HCC

Interventions to slow progression and prevent complications

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.

  • No specific dietary measures are recommended.
  • Patients who are not already immune to hepatitis A should be vaccinated against hepatitis A.
  • Patients should be counseled on ways to avoid infection with hepatitis C.

Preventing transmission

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).

Patient Education

  • Advise patients that most people with HBV will remain asymptomatic for several years. However, ongoing injury to the liver occurs during this time and can culminate in liver failure. Patients can slow the progression of damage by avoiding alcohol and any medications (including over-the-counter drugs and recreational drugs) that may damage the liver. Patients should contact their pharmacist or health care provider if they have questions about a specific medication or supplement.
  • Advise patients that treatment for both HIV and HBV is recommended for anyone with HIV/HBV coinfection. ART can be used to treat both infections.
  • As with HIV, patients must avoid passing HBV to others. Instruct patients not to share toothbrushes, dental appliances, razors, sex toys, tattoo equipment, injection equipment, or personal care items that may have blood on them. Emphasize to patients the importance of safer sex to protect themselves and their partners.
  • Tell patients to discuss HBV with their sex partners, and suggest that partners be tested for HBV.
  • Nonimmune sex partners and individuals in close contact with persons with chronic hepatitis B (e.g., family and household members) should be vaccinated.
  • Pregnant women have a high risk of transmitting HIV or HBV to the fetus because each virus makes it easier to transmit the other. Women who are pregnant or considering pregnancy should talk with a specialist in HIV and HBV to discuss ways of decreasing the infection risk for the fetus.
  • Advise patients who are on treatment for HBV that abrupt discontinuation of HBV treatment can cause a flare of HBV; they should not stop treatment without medical supervision.
  • Certain ARV drugs are more likely than others to cause hepatotoxicity. Advise patients that their liver function should be monitored carefully if they start an ARV regimen, in order to determine whether the body is able to process the medicines.

References

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HRSA HAB Performance Measures

Abbreviations for Dosing Terminology

BID
twice daily
BIW
twice weekly
IM
intramuscular (injection), intramuscularly
IV
intravenous (injection), intravenously
PO
oral, orally
Q2H, Q4H, etc.
every 2 hours, every 4 hours, etc.
QAM
every morning
QD
once daily
QH
every hour
QHS
every night at bedtime
QID
four times daily
QOD
every other day
QPM
every evening
TID
three times daily
TIW
three times weekly