Updated August 2013
Hepatitis B virus (HBV) is a double-stranded DNA, enveloped virus that replicates in hepatocytes. Its primary routes of transmission are vertical
(mother-to-child), blood exposure, and sexual exposure. It is significantly more transmissible than HIV via blood-borne exposure, and some fluids that do not normally transmit HIV, such as saliva and sweat, contain infectious HBV but at much lower levels than blood. In many cases, a patient’s route of infection is not identified.
Approximately 1 to 1.25 million people are HBV carriers in the United States,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).
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).
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.
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.
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.
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
III. BASELINE HEPATIC EVALUATION AND SCREENING FOR HBV INFECTION
A. Baseline Hepatic Evaluation
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.
B. Hepatitis Screening
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 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.
IV. PREVENTION OF HBV INFECTION: VACCINATION AND POST-EXPOSURE PROPHYLAXIS
A. Primary HBV Vaccination
- 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
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.
- 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.
B. HBV Re-Vaccination in HIV-Infected Nonresponders
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.
- 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).
C. HAV Vaccination
Hepatitis A virus (HAV) and HBV vaccines should be administered regardless of CD4 counts to patients who are all of the following: HAV IgG-, anti-HBs-, and HBsAg-negative. A combined hepatitis A and B vaccine (TWINRIX) is available and can be used in persons susceptible to both HAV and HBV. However, the combination vaccine is not recommended for double-dose or four-injection vaccination in 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.
D. HBV Post-Exposure Prophylaxis
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.
V. EVALUATION OF PATIENTS WITH CHRONIC HBV
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)
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
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
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.
VI. COUNSELING FOR HIV/HBV CO-INFECTED PATIENTS
A. Alcohol Consumption
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.
B. HBV Transmission
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).
VII. TREATMENT AND MANAGEMENT OF HBV INFECTION IN THE SETTING OF HIV
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.
Options for effective anti-HBV therapy are significantly increased when patients are treated concomitantly with ART.
A. Treatment for Acute HBV Infection
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.
B. Treatment for Chronic HBV Infection
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.
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 patients60 and 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.
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.
C. Treatment for HDV Infection
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.
VIII. MONITORING PATIENTS WITH CHRONIC HBV INFECTION
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:
- Before initiation of ART or when changing the ART regimen (AII)
- Monthly for the first 3 months after initiation of ART to monitor for possible IRIS (see Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV-Infected Patients) (AIII) and
- At least every 6 months thereafter (AII)
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.
- 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.
A. Patients with Cirrhosis
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)
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.
B. Patients at Risk for Hepatocellular Carcinoma
1. Risk Assessment for Hepatocellular Carcinoma
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.
Nomograms have been published to assist in determining whether an individual patient should undergo surveillance for HCC (available at: http://jco.ascopubs.org/
2. Surveillance for Patients at Risk for Hepatocellular Carcinoma
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
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.
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APPENDIX A: CURRENTLY AVAILABLE ANTI-HBV MEDICATIONS