LinkedIn



Hepatitis B Virus 

Updated August 2013

What’s New and Key Recommendations — August 2013 Update
HBV Vaccination in HIV-Infected Patients (see Section IV)

    • Administer the HBV vaccination series to HIV-infected patients who are susceptible to HBV infection (see Figure 3)

 

    • Alternative vaccination strategies may be considered for primary HBV vaccination, such as a three- or four-injection double-dose vaccination series or an accelerated HBV vaccination schedule of 0, 1, and 3 weeks. Do not administer the accelerated HBV vaccination schedule to patients with CD4 counts <500 cells/mm3.

 

    • Test for anti-HBs 1 to 2 months after administration of the last dose of the vaccination series

 

  • Re-vaccinate with a double-dose vaccination series when HIV-infected patients do not respond to the primary HBV vaccination series (hepatitis B surface antibody <10 IU/L)

Treatment of HBV Infection in the Setting of HIV (see Section VII)

    • Strongly encourage HIV-infected patients with chronic HBV infection to initiate treatment for both viruses

 

    • Initiate treatment with an ART regimen that contains two agents that are also active against the patient’s HBV strain, including tenofovir plus either lamivudine or emtricitabine

 

    • Consult with a provider experienced in the treatment of hepatitis and HIV to determine an alternative anti-HBV regimen if first-line anti-HBV treatment with tenofovir plus lamivudine or emtricitabine cannot be prescribed because of HBV resistance to any of these agents or the presence of renal insufficiency or fulminant hepatic disease

 

  • Avoid discontinuation of either HBV or HIV treatment whenever possible and monitor serum ALT levels closely if discontinuation of anti-HBV therapy is unavoidable

Monitoring HIV-Infected Patients with Chronic HBV Infection (see Section VIII)

    • Monitor HIV/HBV co-infected patients according to the considerations listed in Table 4

 

    • Assess for the risk of hepatocellular carcinoma (HCC) in HIV-infected patients with chronic HBV infection according to standard guidelines (see Table 5)

 

 

I. INTRODUCTION

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,1 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 infected2; 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 HIV-infected patients 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).3,4 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%).5 A retrospective study of HIV-infected patients 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.6 HIV-infected women in the United States have co-infection rates of 3% to 4%.7 HIV-infected patients in the EuroSIDA cohort had a co-infection rate of 9%.8

HIV-infected patients have lower rates than non-HIV-infected patients of hepatitis B envelope antibody (anti-HBe) and hepatitis B surface antibody (anti-HBs) seroconversion, resulting in higher rates of chronic HBV. HIV-infected individuals 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.9-11 In the Multicenter AIDS Cohort Study (MACS) cohort, HIV/HBV co-infected patients had a risk of liver-related mortality that was 13 times higher than HIV mono-infected patients.12 A study of the US Military HIV Natural History Study (NHS) cohort found higher rates of AIDS-related events and death among HIV/HBV co-infected patients compared with those with HIV mono-infection (p <.001).13

Assessment for HBV infection is part of the baseline evaluation of all HIV-infected patients (see Primary Care Approach to the HIV-Infected Patient), and treatment of HBV in HIV-infected patients requires consideration of both infections (see Section VII. Treatment and Management of HBV Infection in the Setting of HIV).

back to top

II. CLINICAL SYNDROMES

A. 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 non-HIV-infected patients develop anti-HBs and are considered HBV-immune.2 However, the rate of anti-HBs development in HIV-infected patients is lower than in non-HIV-infected individuals.14

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).

Figure 1
Figure 1: Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course
Figure 1. Reprinted from Centers for Disease Control and Prevention. Available at: www.cdc.gov/hepatitis/index.htm

back to top

B. Chronic HBV Infection

HIV/HBV co-infected patients are those who have HIV infection 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 non-HIV-infected patients, 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 Section V. Evaluation of Patients with Chronic HBV). Figure 2 shows the serologic responses to chronic HBV infection.

Figure 2
Figure 2: Progression to Chronic Hepatitis B Virus Infection Typical Serologic Course
Figure 2. Reprinted from Centers for Disease Control and Prevention. Available at: www.cdc.gov/hepatitis/index.htm

back to top

C. 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).15 This is rare and is usually associated with severe immunosuppression but may be more common in HIV-infected patients, including those who experience immune reconstitution after initiation of antiretroviral therapy (ART).16 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.

back to top

D. 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 HBV-infected patients. 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.17 IDUs, particularly those with HIV infection, also have disproportionately high rates of HDV.18 For additional information, see Section VII. C. Treatment for HDV Infection.

back to top

E. HIV/HBV/HCV Tri-Infection

HCV in the presence of HBV is of particular concern for clinicians treating HIV-infected patients. Studies have indicated that patients with chronic HBV/HCV co-infection have a significantly higher degree of liver fibrosis,19-21 as well as hepatocellular apoptosis, bile duct damage, and ductular proliferation.20

These findings suggest more severe forms of HCV-related cirrhosis attributable to the presence of HBV.20 Furthermore, HBV/HCV co-infection may be associated with rapid progression to HCC.22

back to top

III. BASELINE HEPATIC EVALUATION AND SCREENING FOR HBV INFECTION

A. Baseline Hepatic Evaluation

RECOMMENDATION:
As part of the baseline assessment of HIV-infected patients, clinicians should evaluate liver function, including serum AST and ALT levels. (AI)

Liver function, including serum AST and ALT levels, should be assessed at baseline in all HIV-infected patients. 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.

back to top

B. Hepatitis Screening

RECOMMENDATIONS:
As part of the baseline assessment, clinicians should ask HIV-infected patients about their HBV vaccination history and should obtain all of the following serologic tests (AI):

  • HBV serologies: HBsAg, anti-HBs, and anti-HBc (IgG or total)
  • HAV: IgG
  • HCV: IgG

Clinicians should obtain an HBV DNA test for patients with negative anti-HBs, negative HBsAg, and positive anti-HBc to determine whether the patient has occult HBV infection (see Figure 3). (AI)

Clinicians must report all suspected or confirmed hepatitis B infections, and specify acute or chronic, to the local health department of the area where the patient resides according to NYS requirements (also see reportable communicable diseases).

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.

Table 1: Serologic and Virologic Responses to HBV
Stage of Infection HBsAg Anti-HBs Anti-HBc IgG Anti-HBc IgM HBeAg Anti-HBe HBV Viral Load
Incubation

+

+ or −

Low

Acute hepatitis B

+

+

+

+

High

HBsAg-negative acute hepatitis B

+

+

+ or −

High

Inactive HBsAg carrier

+

+++

+ or −

+

Low

Precore mutant

+

+ or −

+ or −

+

High

Occult infectiona

+

+ or −

High or low

Chronic hepatitis B

+

+++

+ or −

+ or −

High or low

Resolved HBV infectionb

++

++

+ or −

+

Undetectable

HBV vaccination

++

Undetectable

a Studies have found occult HBV infection in approximately 10% of anti-HBc-positive and HBsAg- and anti-HBs-negative HIV-infected patients.23,24 Occult infection may be associated with greater immunosuppression (<200 cells/mm3) and higher HIV DNA levels.25
b Formerly known as convalescent.

 

Table 2: Interpretation of the HBV Panel
Tests Results Interpretation
HBsAg Negative

Susceptible to infection

Anti-HBc* Negative
Anti-HBs Negative
HBsAg Negative

Immune

Anti-HBc Negative or positive
Anti-HBs Positive
HBsAg Positive

Acutely infected

Anti-HBc Positive
IgM anti-HBc Positive
Anti-HBs Negative
HBsAg Positive

Chronically infected

Anti-HBc Positive
IgM anti-HBc Negative
Anti-HBs Negative
HBsAg Negative Five possible interpretations:

  1. Recovering from acute HBV infection
  2. Distantly immune: test not sensitive enough to detect very low level of anti-HBs in serum
    (<10 IU/L)
  3. Susceptible with a false-positive anti-HBc
  4. A carrier with an undetectable level of HBsAg, although HBV DNA may be detectable in this setting
  5. Reactivation of previously resolved HBV infection
Anti-HBc Positive
Anti-HBs Negative
Adapted from Centers for Disease Control and Prevention. The Pink Book: Course Textbook. 12th Edition. Atlanta, GA: Centers for Disease Control and Prevention. 2012. Available at: www.cdc.gov/vaccines/pubs/pinkbook/hepb.html
* Note: in the context of chronic infection, IgG is the applicable anti-HBc marker. References to anti-HBc in these guidelines and elsewhere in the literature indicate IgG anti-HBc, not IgM anti-HBc, unless otherwise specified.

back to top

IV. PREVENTION OF HBV INFECTION: VACCINATION AND POST-EXPOSURE PROPHYLAXIS

A. Primary HBV Vaccination

RECOMMENDATION:
Clinicians should:

  • Administer the HBV vaccination series to HIV-infected patients who are negative for anti-HBs and are not chronically infected with HBV (see Figure 3) (AI)
  • Test for anti-HBs 1 to 2 months after administration of the last dose of the vaccination series (AI)

The New York State Department of Health and CDC recommend the HBV vaccination series for all HIV-infected patients 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 HIV-infected patients, 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 Section IV. B. HBV Re-Vaccination in HIV-Infected Nonresponders).

Lower CD4 counts at the time of vaccination,26 as well as lower nadir CD4 counts,26,27 have been associated with decreased response to HBV vaccination in HIV-infected patients. Studies have also shown that HIV suppression to <400 copies/mL is a significant predictor of a protective response to HBV vaccination.27,28

All New York State Medicaid-sponsored programs reimburse HBV vaccination when administered according to CDC recommendations, including those for HIV-infected patients. 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 HIV-Infected Patients

RECOMMENDATIONS:
If an accelerated HBV vaccination schedule of 0, 1, and 3 weeks is used for an HIV-infected patient, a fourth-dose booster should be administered at least 6 months after the initiation of the series. (AIII)

Clinicians should not administer the accelerated HBV vaccination schedule of 0, 1, and 3 weeks to patients with CD4 counts <500 cells/mm3. (AIII)

A number of studies have provided strong evidence of an improved response in HIV-infected patients when a double-dose vaccination series is administered in three doses.29-33 A double-dose vaccination series administered in four doses has also been investigated.34,35 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.34 On the basis of these findings, consideration of an alternative three- or four-injection double-dose vaccination series for primary HBV vaccination in HIV-infected patients 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.36 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/mm3.36 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.

Figure 3. Algorithm for HBV Pre-Vaccination Screening and Vaccination in HIV-Infected Patients
Figure 3: Algorithm for HBV Pre-Vaccination Screening and Vaccination in HIV-Infected Patients
a Based on available evidence, a four-dose schedule should also be considered.34,35 Re-vaccination can be deferred in patients initiating ART until CD4 count is ≥200 cells/mm3; re-vaccination should not be delayed in pregnant patients or those who are unlikely to experience immune reconstitution of ≥200 cells/mm3.
b A patient who is negative for all serologies and who does not respond to re-vaccination may be a primary nonresponder or have chronic infection. HBV DNA testing may be used to detect the presence of chronic HBV infection.

 

Key Points:

  • Two HBV vaccination formulations are available in the United States (see Table 3). The efficacy of these vaccines has been reported to be equivalent when used in non-HIV-infected patients; however, equivalent effectiveness between the two formulations has not been clearly established among HIV-infected patients.
  • Because no data are available regarding double-dose or four-injection vaccination with the combined HAV and HBV vaccine (TWINRIX) in the presence of HIV, the combined vaccine is not recommended for double-dose or four-injection vaccination.
  • Both Engerix B and RECOMBIVAX have received Food and Drug Administration approval for higher-strength regimens that are recommended in patients with end-stage renal disease (RECOMBIVAX: 1 mL of higher-strength 40 µg/mL formulation given in three IM injections at 0, 4, and 24 weeks; Engerix B: 2 mL of 20 µg/mL vaccine in four IM injections at 0, 4, 8, and 24 weeks). These higher-strength regimens may also be considered for patients with other immunocompromising conditions.

 

Table 3 provides dosing information on the two HBV vaccination formulations that are available in the United States.

Table 3: HBV Vaccine Formulations for Both Single and Double Dosing in HIV-Infected Adults (≥19 Years)
Formulation Dosing
Engerix B
  • Single dose: 20 µg (as a 1-mL dose containing 20 µg/mL vaccine) in three or four IM injectionsa
  • Double dose: 40 µg (as two 1-mL doses of 20 µg/mL vaccine) in three or four IM injectionsa
  • 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 injectionsa
RECOMBIVAX
  • Single dose: 10 µg (as a 1-mL dose containing 10 µg/mL vaccine) in three or four IM injectionsa
  • Double doseb: 20 µg (as two 1-mL doses containing 10 µg/mL vaccine) in three or four IM injectionsa
  • 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
a Three injections: at 0, 4, and 24 weeks. Four injections: at 0, 4, 8, and 24 weeks.
b 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.

back to top

B. HBV Re-Vaccination in HIV-Infected Nonresponders

RECOMMENDATIONS:
HIV-infected patients who do not respond to the primary HBV vaccination series (anti-HBs <10 IU/L) should be re-vaccinated with a double-dose vaccination series (see Figure 3). (AII)

If a patient’s CD4 count is <200 cells/mm3 or the patient has symptomatic HIV disease:

  • Re-vaccination may be deferred until several months after initiation of ART in an attempt to maximize the antibody response to the vaccine (BI)
  • Re-vaccination should not be deferred in pregnant patients or patients who are unlikely to achieve an increased CD4 count (AIII)

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 HIV-infected patients.30-33 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).34,35

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.37 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 Tables 1 and 2 and Figure 3). 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.38 These patients should be retested if they present with signs and/or symptoms of HBV infection.

Key Points:

  • Patient education regarding HBV vaccination is important to ensure awareness of the continued risk of acquiring HBV until adequate surface antibody response is documented.
  • Although one study of HIV-infected nonresponders demonstrated a re-vaccination response rate of up to 50% using a double dose of a 10-µg vaccine (HBvaxPro), this formulation is currently unavailable in the United States30; therefore, a double dose of the 20-µg vaccine is recommended (see Table 3 for additional information).

back to top

C. HAV Vaccination

RECOMMENDATION:
Clinicians should administer the HAV vaccine to HIV-infected patients who are negative for HAV IgG to prevent concurrent HAV infection (see Hepatitis A Virus). (AI)

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 HIV-infected patients.

Patients who do not require HBV vaccination may benefit from deferral of HAV vaccination until CD4 counts reach ≥200 cells/mm3 (see Hepatitis A Virus).39 Such deferral is not advisable in pregnant women or in patients who are not likely to achieve CD4 counts ≥200 cells/mm3.

back to top

D. HBV Post-Exposure Prophylaxis

RECOMMENDATION:
The HBV vaccination series plus hepatitis B immune globulin (HBIG) should be initiated in HIV-infected patients who sustain a blood or body fluid exposure and who are non-immune to HBV or who have unknown HBV immunity status at the time of presentation. (AI) Both HBIG and the first dose of the HBV vaccination series should ideally be administered within 24 hours of exposure (AII); HBIG should not be given later than 14 days post-exposure.

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%.40 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.41 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.42

HIV-infected patients with 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.

back to top

V. EVALUATION OF PATIENTS WITH CHRONIC HBV

RECOMMENDATIONS:
Clinicians should evaluate the extent of liver disease in patients with chronic HBV infection by:

  • Obtaining an HBV-related history, including assessment for risk factors and previous signs and symptoms of advanced liver disease (AI)
  • Performing a physical examination for current signs and symptoms of advanced liver disease (AI)
  • Measuring serial serum ALT levels, PT/INR, albumin, and platelet counts (AI)
  • Assessing for inflammation, fibrosis, HBV replication, and risk of HCC
  • Obtaining HBeAg, anti-HBe, and HBV DNA quantitative assay (nucleic acid amplification) (AI)
  • Obtaining HDV nucleic acid amplification or serologic assay if available (AIII)

If the baseline HBV DNA level is ≤2000 IU/mL in anti-HBe-positive patients with elevated serum ALT levels, then clinicians should perform serial HBV DNA measurements at least annually. (AIII)

back to top

A. HBV-Related History, Physical Examination, and Initial Laboratory Testing

Clinicians should obtain an HBV-related history for HIV-infected patients 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 Section VIII. B. Patients at Risk for Hepatocellular Carcinoma). 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 fibrosis43 and halted progression of cirrhosis.44 However, some patients who seroconvert from HBeAg to anti-HBe may still have liver disease that progresses to cirrhosis or HCC.44

Key Point:
Although seroconversion from HBeAg to anti-HBe is often associated with clinical improvement, greater HBV DNA replication and more rapid disease progression may occur in patients carrying mutations in either the precore or the basic core promoter region of the HBV genome.45

 

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.46 Recent evidence suggests that HBV genotypes may influence progression of liver disease, rates of seroconversion of HBeAg, and risk of HCC.47 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.48,49

back to top

B. Assessment for Inflammation and Fibrosis

As part of the initial evaluation of HIV/HBV co-infected patients, 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 HIV-infected patients are at higher risk for fibrosis, liver biopsy may be prudent for HIV/HBV co-infected patients with normal serum ALT or low HBV DNA levels who are considering deferral of anti-HBV therapy or who are also infected with HCV (see Hepatitis C Virus).

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,50 can be used; however, these have not yet been validated in HIV/HBV co-infected patients. Another noninvasive method for calculating liver stiffness is the elastography technique known as FibroScan, which has demonstrated promising results51 and has been approved by the Food and Drug Administration for use in the United States.

back to top

VI. COUNSELING FOR HIV/HBV CO-INFECTED PATIENTS

A. Alcohol Consumption

RECOMMENDATIONS:
Clinicians should educate HIV/HBV co-infected patients regarding the effects of alcohol on the course of HBV infection and should counsel patients with underlying liver disease to abstain from alcohol. (AI)

Clinicians should perform alcohol use screening for HIV/HBV co-infected patients as part of the baseline and annual substance use assessment (see the Substance Use Screening Quick Reference Guide and Clinical Management of Alcohol Use and Abuse in HIV-Infected Patients). (AI)

For HIV/HBV co-infected patients who screen positive for alcohol use, clinicians should:

  • Administer a more detailed screening tool such as the full AUDIT or CAGE (see Common Screening Tools for Identifying Substance and Alcohol Problems) (AIII)
  • Screen at-risk alcohol users every 3 months to determine whether intensified support, such as referral to an addiction provider, is required to reduce alcohol intake (AIII)
  • Strongly encourage patients with alcohol abuse or dependence to enroll in a rehabilitation program (AI)

Heavy alcohol consumption accelerates liver fibrosis and decreases response to anti-HBV treatment.52 Psychological, social, and medical support to decrease alcohol intake is strongly recommended. For information regarding alcohol use screening and management, see the Substance Use Screening Quick Reference Guide and Clinical Management of Alcohol Use and Abuse in HIV-Infected Patients.

back to top

B. HBV Transmission

RECOMMENDATIONS:
Clinicians should assess HBV transmission risk behaviors among patients who are positive for HBsAg and should:

  • Encourage all sexually active HIV/HBV co-infected patients to use effective barrier protection consistently and correctly, including latex or polyurethane condoms and dental dams, to reduce the risk of transmission of HIV and HBV (AI)
  • Advise household contacts of HBV carriers to be vaccinated for HBV and to avoid sharing objects that may be contaminated with blood, such as razors or toothbrushes, until their immunity has been confirmed (AI)

Clinicians should provide the following for all active injection drug users: (AI)

  • Referral for substance use treatment
  • Prescription of clean syringes and needles
  • Referral to needle-exchange programs
  • Education about safer-use practices (see Working with the Active User)

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 Syringe Exchange Programs. Injection drug users should also receive information about safe disposal and storage of needles/syringes, as well as safer techniques for injection (refer to Working with the Active User).

back to top

VII. TREATMENT AND MANAGEMENT OF HBV INFECTION IN THE SETTING OF HIV

RECOMMENDATIONS:
Clinicians should strongly encourage HIV-infected patients with chronic HBV infection to initiate treatment for both viruses. (AII)

HIV/HBV co-infected patients should be educated about the importance of adherence to anti-HBV therapy once treatment is initiated and about risk of transaminase flares and hepatic damage resulting from treatment interruption that is not carefully monitored. (AI)

Clinicians should consider immune reconstitution inflammatory syndrome (IRIS) in HIV/HBV co-infected patients who experience acute elevations of transaminases after initiation of ART and/or anti-HBV therapy (see Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV-Infected Patients). (AIII)

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.

Key Point:
Options for effective anti-HBV therapy are significantly increased when patients are treated concomitantly with ART.

back to top

A. Treatment for Acute HBV Infection

RECOMMENDATIONS:
Clinicians should consult with a provider experienced in the treatment of hepatitis and HIV when HIV-infected patients with acute HBV infection present with fulminant liver disease.

For HIV-infected patients with acute HBV infection who present with fulminant liver disease and are receiving ART for HIV: (AI)

  • The current anti-HIV therapy regimen should be adjusted to include lamivudine; tenofovir should be withdrawn if the patient is already receiving it until the hepatic insult has resolved
  • Neither tenofovir nor adefovir should be prescribed until the hepatic insult has resolved

For HIV-infected patients with acute HBV infection who present with fulminant liver disease and are not receiving ART for HIV: (AI)

  • Initiation of ART for HIV is not recommended during fulminant hepatic liver disease until the acute hepatic insult has resolved
  • Treatment with lamivudine alone is indicated for fulminant liver disease, despite the risk of developing lamivudine-resistant HIV; neither adefovir nor tenofovir should be prescribed until the hepatic insult has resolved

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.53 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 setting54; 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.

back to top

B. Treatment for Chronic HBV Infection

RECOMMENDATIONS:
Clinicians treating HIV/HBV co-infected patients should:

  • Initiate treatment with an ART regimen that contains two agents that are also active against the patient’s HBV strain, including tenofovir plus either lamivudine or emtricitabine (AII)
  • Consult with a provider experienced in the treatment of hepatitis and HIV to establish a schedule for monitoring (see Table 4) (AIII) and to discuss treatment decisions, including the following:
    • Changes to a patient’s existing ART regimen (AIII)
    • Determination of an alternative anti-HBV regimen if first-line anti-HBV treatment with tenofovir plus lamivudine or emtricitabine cannot be prescribed because of HBV resistance to any of these agents or the presence of renal insufficiency or fulminant hepatic disease (AIII)
    • Treatment and monitoring for patients with cirrhosis (AII)
  • Avoid discontinuation of either HBV or HIV treatment whenever possible and monitor serum ALT levels closely if discontinuation of anti-HBV therapy is unavoidable (AII)
  • Obtain serum ALT level before initiation of ART or when changing the ART regimen (AII)

When ART regimens require a change for HIV considerations, the agents active against HBV should be continued whenever possible to avoid the risk of reactivation of HBV. (AII)

No large controlled trials have been conducted to define efficacy of combination therapies in HIV/HBV co-infected patients. These guidelines are therefore extrapolated from the treatment of HBV mono-infected patients, limited data from HIV/HBV co-infected patients, and best practices for HIV treatment.21,55-58

Initiation of treatment that is active against both HIV and HBV is indicated for HIV/HBV co-infected patients.59 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 Appendix A). 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.

Key Point:
The primary goal of anti-HBV therapy for HIV/HBV co-infected patients is HBsAg clearance with anti-HBs seroconversion. However, because the rate of anti-HBs seroconversion is low among HIV-infected patients60and treatment should be considered lifelong once it is initiated, the following secondary goals are reasonable:

  • HBeAg to anti-HBe seroconversion
  • Suppression of HBV replication
  • Reduction of liver inflammation
  • Prevention or delay of progression of fibrosis, cirrhosis, and HCC

 

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 (see Antiretroviral Therapy). 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 Appendix A). 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 Section VIII. Monitoring Patients with Chronic HBV Infection).

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.

Key Point:
Agents with dual activity against both HBV and HIV can simplify treatment regimens because these agents can be used as part of a regimen to treat both viruses.

back to top

C. Treatment for HDV Infection

RECOMMENDATION:
Clinicians should strongly encourage HIV/HBV/HDV tri-infected patients to initiate anti-HBV and anti-HIV therapy. (AIII)

Existing data indicate that pegylated interferon (PegIFN) is the only effective anti-HDV treatment.61 However, fewer than 30% of non-HIV-infected patients with HDV infection achieve sustained HDV suppression when receiving PegIFN.62 No data are available regarding the efficacy of PegIFN therapy in HIV/HBV/HDV tri-infected patients. Because of the dependence of HDV on HBV, HBsAg seroconversion should be the primary goal for HIV/HBV/HDV tri-infected patients. Prompt initiation of anti-HBV and anti-HIV therapy should be strongly encouraged.

back to top

VIII. MONITORING PATIENTS WITH CHRONIC HBV INFECTION

RECOMMENDATIONS:
After initiation of anti-HBV therapy, clinicians should obtain HBV DNA level and should assess for HBeAg and HBsAg seroconversion every 3 to 6 months. (AI)

Clinicians should obtain serum transaminase levels for HIV/HBV co-infected patients:

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.61,63 If HBV DNA increases by >1 log in adherent patients, then resistance should be suspected.

Key Point:

  • Clinically relevant responses to anti-HBV therapy are a sustained seroconversion from HBsAg to anti-HBs, from HBeAg to anti-HBe, or normalization of ALT and sustained HBV DNA ≤2000 IU/mL.
  • Lamivudine, emtricitabine, and tenofovir generally should not be stopped as part of a patient’s ART regimen when anti-HBV therapy is discontinued.

 

Detailed monitoring considerations are provided in Table 4.

Table 4: Routine Laboratory Assessment and Therapeutic Monitoring of HIV/HBV Co-Infected Patientsa
Diagnostic Screen Frequency
Laboratory Testing
    HBeAg and anti-HBe
Baseline and every 3-6 months for patients receiving treatment who are HBeAg(+) and anti-HBe(−)
    Serum ALT levels
Before initiation of ART or when changing the ART regimen, monthly for the first 3 months after initiation of ART, and then serial measurements at least every 6 months thereafter or more frequently if stopping anti-HBV therapyb
    HBV DNA
  • Serial measurements at least annually if low (≤2000 IU/mL) in anti-HBe(+) patients with elevated serum ALT levels
  • Every 3-6 months to monitor therapy
    PT/INR, serum AST levels, platelets
Baseline and 6 months
    HBV genotype
Consider at baselinec
Liver Biopsyd Consider at baseline for the following:

  • Patients who are considering deferring anti-HBV therapy or
  • Patients who are HIV/HBV/HCV tri-infected
Imaging Studies
    Ultrasound or triple-phase CT
Consider at baseline to assess for inflammation and fibrosis in patients not receiving biopsy
    Ultrasound
In patients at risk for HCC,d ultrasound every 6-12 months by a sonographer with specialized training for detecting HCCe
a These routine assessment and monitoring procedures are performed in conjunction with those recommended for all HIV-infected adults (see Primary Care Approach to the HIV-Infected Patient).
b Lamivudine, emtricitabine, and tenofovir generally should not be stopped.
c Some experts recommend obtaining an HBV genotype because it may help guide decisions on frequency of monitoring for disease progression and response to antivirals.48,49
d If HCC is suspected, refer to a hepatologist or oncologist. Monitoring considerations are different for patients with HCC. For additional information about assessing for risk for HCC, see Section VIII. B. Patients at Risk for Hepatocellular Carcinoma.
e If ultrasound by a trained sonographer is not available, α-fetoprotein (AFP) in combination with ultrasound or AFP alone can be considered. However, AFP should be considered only if ultrasound by a trained sonographer is not available. For additional information, see Section VIII. B. Patients at Risk for Hepatocellular Carcinoma.

back to top

A. Patients with Cirrhosis

RECOMMENDATIONS:
Patients with hepatitis who develop symptomatic cirrhosis should be managed by a clinician experienced in the management of cirrhosis in HIV/HBV co-infected patients, preferably a hepatologist. (AII)

Clinicians should refer HIV/HBV co-infected patients with known cirrhosis for endoscopy at least once every 2 years to monitor for esophageal varices. (AIII)

Key Point:
HIV/HBV co-infected patients with cirrhosis are at increased risk for a life-threatening hepatitic flare due to IRIS after initiation of ART, particularly when their baseline CD4 count is <200 cells/mm3.

 

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 HBV-infected patients with cirrhosis. HBV-infected patients with known cirrhosis should be referred for endoscopy every 1 to 2 years to monitor for esophageal varices.

back to top

B. Patients at Risk for Hepatocellular Carcinoma

1. Risk Assessment for Hepatocellular Carcinoma

RECOMMENDATION:
Clinicians should assess for the risk of hepatocellular carcinoma in HIV-infected patients with chronic HBV according to standard guidelines (see Table 5).

Hepatocellular carcinoma (HCC) is a major cause of death in patients with chronic HBV infection, and all HIV-infected patients 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)64 and the European Association for the Study of the Liver (EASL),65 the patient populations listed in Table 5 are at high risk for HCC.

Table 5: Patients at High Risk for Hepatocellular Carcinoma*
  • Asian men over 40 years and Asian women over 50 years of age64
  • Black patients over 20 years of age64
  • Patients over 40 years of age with persistent or intermittent serum ALT elevation and/or HBV DNA level >2000 IU/mL64,65
  • Patients with cirrhosis64,65 including those awaiting transplantation65
  • Patients with a family history of HCC64,65
  • Patients with chronic HCV infection and advanced liver fibrosis65
* These patients are considered at risk according to AASLD64 and EASL guidelines.65

 

Nomograms have been published to assist in determining whether an individual patient should undergo surveillance for HCC (available at: http://jco.ascopubs.org/content/28/14/2437.full.pdf).66 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.

back to top

2. Surveillance for Patients at Risk for Hepatocellular Carcinoma

RECOMMENDATIONS:
Clinicians should perform surveillance for HCC among patients at high risk every 6-12 months according to standard guidelines64 (see Table 5 to determine risk).

Serum α-fetoprotein screening is no longer recommended as part of surveillance for HCC among patients at high risk. (AI)

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 HBV-infected patients with an expected risk for HCC of greater than 0.2% per year (see Table 5).64

Key Point:
Surveillance for patients at high risk for HCC involves standardized screening and monitoring protocols, as established by standard guidelines, such as the AASLD practice guidelines on the management of HCC.64

 

In non-HIV-infected patients, treatment with lamivudine, which is active against HBV, has been shown to lower the risk of HCC.67 In HIV-infected patients, 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.64

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.64,65

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.

back to top

REFERENCES

1. Centers for Disease Control and Prevention. 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. Available at: www.cdc.gov/MMWR/preview/mmwrhtml/00033405.htm

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

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

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

16. 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]

17. 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

18. 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]

19. 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]

20. 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]

21. 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]

22. 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]

23. Shire NJ, Rouster SD, Rajicic N, et al. Occult hepatitis B in HIV-infected patients. J Acquir Immune Defic Syndr 2004;36:869-875. [PubMed]

24. Lo Re V 3rd, Frank I, Gross R, et al. Prevalence, risk factors, and outcomes for occult hepatitis B virus infection among HIV-infected patients. J Acquir Immune Defic Syndr 2007;44:315-320. [PubMed]

25. Tsui JI, French AL, Seaberg EC, et al. Prevalence and long-term effects of occult hepatitis B virus infection in HIV-infected women. Clin Infect Dis 2007;45:736-740. [PubMed]

26. 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]

27. 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]

28. 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]

29. 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]

30. 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]

31. 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]

32. 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]

33. 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]

34. 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]

35. 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]

36. 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]

37. 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]

38. Advisory Committee on Immunization Practices (ACIP) and the Hospital Infection Control Practices Advisory Committee (HICPAC). Immunization of health-care workers. MMWR Recomm Rep 1997;46(RR-18):1-42. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/00050577.htm

39. 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]

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

41. Centers for Disease Control and Prevention. 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. Available at: www.cdc.gov/mmwr/pdf/rr/rr5011.pdf

42. Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2010. Available at: http://cdc.gov/std/treatment

43. 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]

44. 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]

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

46. 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]

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

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

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

50. 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]

51. 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]

52. 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]

53. 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]

54. 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]

55. 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]

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

57. 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]

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

59. 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. Available at: http://aidsinfo.nih.gov/guidelines

60. 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]

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

62. 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]

63. 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]

64. 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

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

66. 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

67. 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]

back to top

FURTHER READING

Mandel GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Philadelphia, PA: Churchill Livingstone; 2000.

Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP) part II: Immunization of adults. MMWR Recomm Rep 2006;55(RR-16):1-33. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5516a1.htm

back to top

APPENDIX A: CURRENTLY AVAILABLE ANTI-HBV MEDICATIONS

Appendix A: Currently Available Anti-HBV Medications
Tenofovir disoproxil fumarate Nucleotide reverse transcriptase inhibitor that inhibits both HIV and HBV (wild-type and lamivudine-resistant). It has been effective at decreasing the viral load levels of both HIV and HBV when used in combination with lamivudine. In a small trial of HIV/HBV co-infected patients, many of whom had been receiving lamivudine, addition of tenofovir decreased HBV DNA level 4 logs vs. 3.2 logs with adefovir.1 Tenofovir-resistant mutations have been described, but the rate of developing mutations is not defined.
Lamivudine Nucleoside analog that is active against HIV and inhibits HBV replication in most HIV/HBV co-infected patients, resulting in low seroconversion rates (10%). It should always be used at its 300-mg once daily or 150-mg twice-daily dose in HIV-infected patients. It should not be used as monotherapy for HBV in HIV-infected patients because HIV resistance will develop rapidly. Likewise, HBV resistance to lamivudine will develop in up to 30% of HIV-infected patients per year if used as the only active agent against HBV in a regimen.2 Serum ALT levels frequently increase 1 to 2 months after lamivudine is started, and this should not prompt discontinuation of the drug. Serum ALT levels may also increase during seroconversion from HBeAg- to anti-HBe-positive.
Emtricitabine Nucleoside analog, similar to lamivudine, that is active against both HIV and HBV. HBV resistance also develops rapidly (12% in 1 year) if used as monotherapy, and lamivudine-resistant isolates are also cross-resistant to emtricitabine.3
Entecavir Nucleoside analog that is active against both HIV and HBV. It is approved in the United States for use against HBV. In a small study, 84% of HIV/HBV co-infected patients failing lamivudine therapy achieved significant decrease in HBV DNA levels (vs. 0% of placebo) with entecavir.4 However, it can select for lamivudine/emtricitabine-resistant HIV; therefore, it is not recommended for treatment of HBV in HIV-infected patients not receiving ART.5 It is active against both wild-type and lamivudine-resistant HBV but more so against wild type.
Adefovir dipivoxil* Nucleoside analog reverse transcriptase inhibitor active against HBV, including lamivudine-resistant strains. At the 10-mg daily dose, it does not appear to affect HIV replication, and, in one study, there was a negligible rate of selection for K65R mutant HIV, although the true rate is yet to be determined.6 In a small trial of HIV/HBV co-infected patients, many of whom had lamivudine-resistant HBV, addition of adefovir decreased the HBV DNA level 3.2 log (vs. 4 log for tenofovir).7 However, the manufacturer warns against its use as monotherapy in HIV/HBV co-infected patients.8
Telbivudine Telbivudine has not been studied in HIV/HBV co-infected patients. It is a nucleoside analog that, in contrast to other nucleoside analogs, has no antiviral activity against any known human viruses other than HBV.1 Patients achieve normalization of transaminase levels at a higher rate with telbivudine than with lamivudine (86% vs. 63%).9 Telbivudine and lamivudine share cross-resistance,10,11 and combination of telbivudine and lamivudine is not more effective than telbivudine alone.9 The rate of anti-HBe seroconversion appears to be higher with telbivudine than with lamivudine (31% vs. 22%) but lower when telbivudine and lamivudine are combined (17%).9 Rates of telbivudine resistance are high; therefore, it is not recommended as monotherapy.
Interferon-alfa
  • Interferon (IFN)-alfa 2a or 2b or PegIFN-alfa 2a are used as therapy for HBV mono-infected patients. PegIFN-alfa 2a has been shown to be superior to the short-acting IFN. Some small studies suggest a lower response rate in HIV/HBV co-infected patients (approximately 10%), but it may be useful if an agent that is not active against HIV is desired. It has a higher success rate in HBeAg(+) patients and those with elevated serum ALT levels (>200 IU/L) and with CD4 counts ≥200 cells/mm3.12Advantages include the following:
    • A finite treatment duration—6 months for HBeAg(+) and 12 months for HBeAg(−)
    • Higher likelihood of HBeAg seroconversion
    • No activity against HIV to promote HIV resistance
  • IFNs have numerous side effects and toxicities that should be managed by a clinician experienced with its use. IFN-alfa cannot be used in patients with decompensated cirrhosis.
* A dose of >10 mg daily increases the likelihood of HIV resistance when used as HBV monotherapy. However, monotherapy with any agent other than IFN-alfa, regardless of dose, is not recommended.

APPENDIX A REFERENCES

1. 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]

2. 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]

3. 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]

4. 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). 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005, Boston, MA. Abstract 123.

5. 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]

6. 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]

7. 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]

8. HEPSERA (adefovir dipivoxil) prescribing information. Foster City, CA: Gilead Sciences, Inc.; 2012. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2012/021449s020lbl.pdf

9. 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]

10. 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]

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

12. 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]

back to top