Background Hepatitis B virus (HBV) is the most common cause of chronic liver disease worldwide. HBV is a DNA virus that is transmitted primarily through blood exposure and sexual contact, and from mothers to their children. Because HIV and HBV share transmission routes, up to 90% of HIV-infected patients have evidence of previous or current HBV infection. Most people who become infected with HBV are able to clear the virus without treatment, and they subsequently become immune to HBV. A small proportion of individuals infected with HBV (approximately 10% in the general population) develop chronic HBV infection. Over time, chronic HBV can cause hepatic fibrosis and eventually cirrhosis, end-stage liver disease (ESLD), and hepatocellular carcinoma (HCC). HIV infection appears to increase the risk of developing chronic HBV infection after HBV exposure. Patients coinfected with HBV and HIV also tend to have faster progression of liver disease, with associated morbidity and mortality. To identify patients with HBV coinfection, and to identify and vaccinate susceptible individuals, all HIV-infected persons should be tested for HBV. Table 1 outlines routine baseline HBV serologic screening tests for HIV-infected individuals:
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| Hepatitis B surface antigen (HBsAg) | Active HBV | Usually indicates absence of HBV infection; may be falsely negative in some patients with active HBV | | Hepatitis B surface antibody (HBsAb) | Immune to HBV (through past exposure or vaccination) | Not immune; if active HBV disease is not present, consider vaccination | | Hepatitis B core antibody (HBcAb), IgG | Past exposure to HBV; does not indicate whether patient has active infection or has cleared infection (check HBsAg and HBsAb) | Probably has not been infected with HBV |
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A positive result for hepatitis B surface antigen (HBsAg) that persists longer than 6 months indicates chronic infection. In some cases of active HBV infection, a positive result for hepatitis B core antibody (HBcAb) may be the only detectable marker, because HBsAg may be negative. Ongoing viral replication and infectiousness is indicated by the presence of HBV DNA or a positive result for hepatitis B envelope antigen (HBeAg). S: SubjectiveSymptoms of acute HBV infection may include fatigue, nausea, vomiting, arthralgias, fever, right upper quadrant pain, jaundice, dark urine, and clay-colored stools. Some patients may have no symptoms. Patients with chronic HBV are often asymptomatic until ESLD has developed. Progressive HBV can lead to decompensated liver disease, portal hypertension, cirrhosis, esophageal varices, coagulopathy, thrombocytopenia, hepatic encephalopathy, and HCC, or some combination of these conditions. Patients may experience fatigue, right upper quadrant pain, or complications of ESLD such as jaundice, increased abdominal girth, easy bruising, gastrointestinal bleeding, and altered mentation. O: ObjectivePerform a thorough physical examination, with special attention to the eyes and mouth (icterus, gum bleeding), skin (jaundice, palmar erythema, petechiae, ecchymoses), abdomen (caput medusa, distention, ascites, hepatomegaly, splenomegaly), heart and lungs (signs of congestive heart failure), extremities (edema), and the neurologic system. A: AssessmentA partial differential diagnosis includes: - Medication-induced hepatotoxicity
- Alcohol- or drug-related liver injury
- Fungal, bacterial, or other viral infection
P: PlanDiagnostic Evaluation - Assess the severity of liver disease at the time of diagnosis and at least every 6 months with alanine aminotransferase (ALT), albumin, bilirubin, prothrombin time, platelet count, and complete blood count.
- Consider checking the HBV DNA (viral load). DNA levels are usually high in persons with active HBV (in the absence of treatment) and can be used to confirm active disease (in those not taking effective treatment) and monitor the response to treatment (in patients taking HBV treatment). Note, however, that HBV DNA levels apparently do not predict the progression of liver disease.
- Check for HBeAg; this test indicates active infection and infectiousness, as does the HBV viral load.
- Persons with chronic HBV are at elevated risk for HCC. Consider screening for HCC every 6-12 months with the serum alpha-fetoprotein (AFP) level or imaging of the liver (ultrasound, computed tomography, or magnetic resonance imaging). Screening is especially important if the patient is in a high-risk group (eg, patients aged >45 years, those with cirrhosis, or those with a family history of HCC).
- Liver biopsy is the only definitive test to assess the grade (inflammation) and stage (degree of fibrosis) of liver disease. Many experts recommend liver biopsy to guide decisions about therapy, whereas others start therapy based on ALT and HBV DNA, without liver biopsy.
Treatment The optimal treatment strategies for patients with HIV and HBV coinfection have not been defined, and individual patient characteristics should be used to guide therapy. The patient's need for HIV treatment (antiretroviral therapy [ART]) should be considered carefully because it will influence the selection of HBV therapy. When ART is indicated, agents that have activity against both HIV and HBV (eg, lamivudine, emtricitabine, tenofovir) can be considered for inclusion in the ART regimen. Patients who need HBV treatment but are not candidates for HIV treatment can be given agents that do not have activity against HIV at standard doses (eg, interferon, adefovir, entecavir). For some therapies, data on efficacy and safety are limited, the proper duration of treatment is not yet clear, and the role of combination therapy has not been defined. Studies of treatment in HIV/HBV-coinfected populations are ongoing. Consider consulting with an HBV treatment expert to
determine the best approach to HBV treatment for a particular patient. Some experts treat all patients with proven chronic HBV, whereas others consider treatment for patients with both of the following: - Positive HBeAg or HBV DNA >10,000 copies/mL
- ALT >2 times the upper limit of normal, or inflammation or fibrosis on liver biopsy
Table 2 describes the possible treatments for HBV. Treatment considerations - Adefovir, interferon, and entecavir are preferred for HIV/HBV coinfected patients who do not require ART.
- For HIV/HBV-coinfected patients who require ART, consider agents with both anti-HIV and anti-HBV activity.
- When lamivudine is used as a single agent, HBV resistance develops in many patients by 1-2 years. Although combination therapy has not been well studied, specialists recommend using 2 nucleoside/nucleotide combinations that have activity against HBV (lamivudine + tenofovir, or emtricitabine + tenofovir [Truvada]) as part of the antiretroviral regimen, to treat HBV and to prevent HBV resistance.
- For patients infected with hepatitis C virus (HCV) as well as HBV and HIV, evaluate the need for HIV therapy first. If ART is not required, consider treating HCV first, because interferon therapy is active against both HCV and HBV. If interferon-based therapy for HCV has failed, consider treating chronic HBV with an oral agent.
- Patients taking therapy should be monitored regularly for changes in ALT. If possible, HBeAg (if initially positive) and HBV DNA should also be monitored.
- Some patients treated with ART may experience worsening of HBV symptoms and laboratory markers in the weeks after ART initiation, because of immune reconstitution. Hepatic decompensation due to immune reconstitution must be distinguished from other causes, such as medication toxicity, or other infection. Liver function tests should be monitored closely in patients starting ART.
- Some antiretroviral medications are hepatotoxic and should be avoided or used cautiously. These include nevirapine, tipranavir, and high-dose ritonavir.
- Numerous other medications (eg, fluconazole and issoniazid) are known to be hepatotoxic and can pose problems for people with impaired liver function.
- For patients with treatment failure, consult an HBV specialist.
- Caution: Discontinuation of HBV medications in patients with HIV/HBV coinfection may cause a flare of liver disease. If this occurs, consider reinstating HBV therapy as soon as possible. Be very cautious when discontinuing HBV-active medications from an HIV ART regimen. In this scenario, consider continuing or substituting the HBV-active medications to avoid rebound liver inflammation and decompensation. For example, if it is decided to discontinue HIV treatment for an HIV/HBV-coinfected patient taking lamivudine + tenofovir + lopinavir/ritonavir, consider starting adefovir or entecavir to maintain activity against HBV.
Other care issues Acute hepatitis A virus (HAV) or HCV in persons with chronic HBV infection can cause decompensated liver disease. All patients with HBV infection should be tested for immunity to HAV and HCV. Patients who are not immune to HAV should be vaccinated and patients who are not immune to HCV should be counseled about how to avoid the acquisition of HCV. All HBV-infected individuals should be taught how to reduce the risk of HBV transmission to others. As appropriate, patients should be counseled to adopt "safer sex" approaches, avoid blood exposures (eg, from sharing razors or tattoo equipment), and practice safe drug injection techniques. Persons with HBV infection should be counseled to avoid exposure to hepatotoxins, including alcohol and hepatotoxic medications (eg, acetaminophen in large doses, fluconazole, and isoniazid). |
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| Interferon-alfa 2a or 2b | 5 million units (MU) daily or 10 MU 3 times weekly for 4-6 months* | - Interferon is contraindicated in patients with decompensated cirrhosis.
- Expect the CD4 count to drop by 100-150 cells/µL or more during treatment with interferon or pegylated interferon. (The CD4 percentage usually remains stable.)
| | Pegylated interferon-alfa 2a (Pegasys) | 180 micrograms per week for 4-6 months* | | Lamivudine (Epivir, 3TC)# | 150 mg twice daily or 300 mg daily (dosage as part of ART regimen) for 1 year or more* | - Use only as part of an effective HIV ART regimen.
- High rate of HBV resistance occurs after 1-2 years of treatment. Lamivudine-resistant HBV is also resistant to emtricitabine.
- Most specialists recommend combination with a second agent (eg, tenofovir or emtricitabine).
| | Tenofovir (Viread)# | 300 mg daily: treatment duration unknown* | - Use only as part of an effective HIV ART regimen.
- Active against lamivudine-resistant strains of HBV.
- Most specialists recommend combination with a second agent (eg, lamivudine or emtricitabine).
| | Emtricitabine (Emtriva)# | 200 mg daily: treatment duration unknown* | - Use only as part of an effective HIV ART regimen.
- Emtricitabine-resistant HBV also is resistant to lamivudine.
- Most specialists recommend combination with a second agent (eg, tenofovir or lamivudine).
| | Adefovir (Hepsera) | 10 mg daily: treatment duration unknown* | - Active against lamivudine-resistant strains of HBV.
| | Entecavir (Baraclude) | 0.5-1.0 mg daily: treatment duration unknown* | - Active against lamivudine-resistant strains of HBV.
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Patient Education- Most patients with HBV will remain asymptomatic for several years. However, ongoing injury to the liver occurs during this time, and can culminate in liver failure. Patients can slow the damage by avoiding alcohol and any medications (including over-the-counter drugs and recreational drugs) that may damage the liver. Instruct patients to call their pharmacist or health care provider if they have questions about a specific medication or supplement.
- As with HIV, patients must avoid passing HBV to others. Instruct patients not to share toothbrushes, dental appliances, razors, sex toys, tattoo equipment, injection equipment, or personal care items that may have blood on them. Emphasize the importance of safer sex to protect themselves and their partner(s).
- Tell patients to discuss HBV with their sex partner(s), and suggest that partner(s) get tested for HBV.
- Certain antiretroviral drugs are more likely to cause problems with the liver because of HBV. Advise patients that if they start an ART regimen, their liver function tests should be watched carefully to determine whether the body is able to process the medicines.
- Patients who have not been vaccinated against HAV, will need to receive 2 vaccinations 6 months apart. HAV can cause severe illness, liver damage, or even death, in people with HBV.
- Patients who have not been tested for HCV should be tested for this virus.
- HCV can worsen liver function greatly if it is acquired in addition to HBV. Patients with HCV should use safe sex practices (latex barriers) to avoid exposure. Patients who use injection drugs should not share needles or injection equipment.
- If children were born after women were infected with HBV, consider having them tested. Even though their risk is low, they should be screened for HBV.
- HBV treatments may cause adverse effects. Most of these are treatable with medications. Patients should contact their health care provider know right away if they experience adverse effects or new symptoms.
References- Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association/Infectious Diseases Society of America. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents. MMWR Recomm Rep. 2004 Dec 17; 53(RR15);1-112. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=14. Accessed May 19, 2006.
- Keeffe E. Clinical Care Options Management Series: Diagnosis, Treatment, and Chronic Care Options for Hepatitis B. Accessed February 7, 2006.
- 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 Feb 18;19(3):221-40.
- Thio CL. Management of chronic hepatitis B in the HIV-infected patient. AIDS Read. 2004 Mar;14(3):122-9, 133, 136-7.
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