The clinical impact of hepatitis virus infection in HIV-positive patients has progressively grown since the introduction of highly active antiretroviral therapy (HAART), given the dramatic increase in survival experienced by these patients. On the other hand, HIV acts as a cofactor and accelerates the progression of liver disease due to hepatitis viruses.
Thus, according to a US study, HIV infection increases up to 12.7-fold the risk of liver-related mortality in HBV/HIV-coinfected patients, especially in those with low CD4 counts. Similar findings have been reported for hepatitis C virus (HCV)/HIV-coinfected patients.
Not surprisingly, chronic viral hepatitis in recent years has become one of the most frequent causes of hospital admissions and mortality among HIV-infected patients. In this way, chronic HBV and HCV actually behave as opportunistic infections in the context of HIV infection.
The goals of treatment of chronic HBV may be categorized in several steps, from less to more ambitious. First, treatment should pursue suppression of HBV replication, as reflected by the achievement of significant reductions in and/or clearance of serum HBV DNA. Second, therapy may shift HBV infection from active (hepatitis B e antigen [HBeAg]-positive) to nonreplicative forms of chronic HBV infection, reflected by anti-HBe seroconversion. Third, ideally, any anti-HBV therapy should pursue disappearance of the chronic HBV carrier status (HBsAg positive), reflected by anti-HBsAg seroconversion.
A back-and-forth interference between HIV and HBV takes place when both infections coexist. As a result, the treatment of chronic HBV poses specific problems in the context of HIV infection. On the one hand, anti-HBV drugs show poorer performance, with lower response rates and faster selection of HBV-resistant strains. On the other hand, drugs active against both HBV and HIV (e.g., lamivudine [3TC]), if not used appropriately, can induce the selection of resistance mutations in the HIV genome. Therefore, the management of both infections should be carefully coordinated.
In summary, data on the effect of interferon [IFN]-alfa against HBV/HIV-coinfected patients are scarce. Although they suggest that the response to IFN is superior to the response to no treatment, the response seems to be lower than in HIV-negative patients. The available data are insufficient to determine the optimal candidates for IFN-alfa treatment among HIV/HBV-coinfected patients. However, subjects with CD4 counts >350 cells/mm3 and transaminase levels elevated to at least twice the upper limit of normal might get the greatest benefit from IFN-alfa therapy.
Lamivudine is a nucleoside reverse transcriptase inhibitor (NsRTI) with both anti-HIV and anti-HBV activity. Although the inhibitory dosage for HBV is lower (100 mg/day) than that needed for HIV (300 mg/day) the higher dose should be given when treating HBV/HIV-coinfected patients, and 3TC should always be combined with two other antiretroviral agents. Otherwise, 3TC monotherapy rapidly selects HIV resistance mutations.
The emergence of 3TC resistance mutations has been associated with elevations in transaminase levels in a minority of patients and, occasionally, with fatal liver failure. Although resistance mutations may reduce HBV fitness and result in lower plasma HBV DNA levels, the histological and clinical benefit of continuing 3TC treatment for subjects infected with drug-resistant HBV is unclear. However, in the absence of other anti-HBV drugs, it might be advisable to continue treatment with 3TC despite the presence of resistance mutations, because hepatitis flares after discontinuation of 3TC have been described.
Adefovir is a nucleotide reverse transcriptase inhibitor (NtRTI) recently licensed for the treatment of chronic HBV at a dosage of 10 mg/day. It is able to suppress HBV replication and normalize alanine aminotransferase levels in up to 70 percent of patients with HBeAg-negative chronic hepatitis. It also induces HBeAg seroconversion in 23 percent of patients with HBeAg-positive chronic hepatitis B. It is active against 3TC-resistant HBV mutants. Adefovir does not have significant antiretroviral effect at this dosage and could be given to HIV-infected patients who are not taking HAART. There is a theoretical risk of inducing HIV resistance, which deserves careful evaluation.
Lamivudine has lost favor in the treatment of HBV infection in HIV-coinfected patients since the approval of tenofovir (TDF) for the treatment of HIV infection. Like adefovir, TDF is an NtRTI with both anti-HIV and anti-HBV activity. It has been proven to be a very potent inhibitor of HBV replication in vitro, even in the presence of 3TC resistance mutations. In recent studies of TDF, HBV DNA levels decreased by 4 log10 on average, despite the fact that the majority of patients carried 3TC resistance-associated mutations. No breakthroughs in HBV replication derived from the emergence of resistance mutations to tenofovir have been seen thus far.
New Drugs for HBV
The new compounds being tested for the treatment of HBV infection may be grouped in two categories. (Table 1) The first includes drugs active against both HBV and HIV. Another group includes medications with activity against HBV alone. These latest drugs might be indicated preferentially for persons who have not yet met criteria for beginning HIV therapy.
|Table 1: New Anti-HBV Nucleoside Analogues in Development|
|Drug Activity, Drug||Phase of Development||Active Against YMDD Mutants|
|Only Anti-HBV Activity|
Emtricitabine (FTC), a new NsRTI, has been recently approved for the treatment of HIV infection. It is well tolerated and has potent anti-HBV activity. It should not be used after 3TC failure, because both drugs show cross-resistance. Moreover, FTC resistance mutations in HBV were selected in 19 percent of patients after two years of FTC treatment.
Entecavir, another NsRTI with anti-HBV activity, has been shown to be a potent inhibitor of HBV replication. Patients treated with entecavir at doses of 0.5 mg and 1 mg (as a single daily dose) had mean decreases in plasma HBV DNA levels of 2.8 and 2.5 logs, respectively, at four weeks, 3.8 and 4.4 logs at 24 weeks, and 4.5 and 5.1 logs at 48 weeks of treatment. No significant adverse events occurred, and 26 percent of subjects achieved undetectable HBV DNA levels at 48 weeks with both doses. The results were superior when transaminase levels were elevated at baseline. Entecavir has also been proven to be effective in patients previously treated with IFN-alfa and against 3TC-resistant HBV strains.
Within the NsRTI family, telbivudine and clevudine are compounds in earlier stages of development as anti-HBV drugs. Of interest, preliminary data suggest that the inhibition of HBV replication is superior over monotherapy with either drug when 3TC and telbivudine are given in combination. The development of other NsRTIs with anti-HBV activity, such as L-Fd4C (2,3-Dideoxy-2,3-didehydro-L-fluorocyti-dine) and DAPD (amdoxovir), is in earlier phases, and data are scarce.
Famciclovir, the prodrug of penciclovir, inhibits HBV replication, but it is less potent than 3TC and shows cross-resistance. These facts, along with its thrice-daily dosing, have decreased the amount of interest in this drug as an anti-HBV agent. The results of studies of the efficacy of thymosin (thymic-derived peptides) are conflicting.
Finally, a new class of drugs, called heteroaryldihydropyrimidines (HAPs), is currently in preliminary stages of research as anti-HBV agents. They seem to act as inhibitors of the HBV nucleocapsid.
Treatment for HBV/HIV-Coinfection
All HIV-infected persons with active HBV replication (positive for HBsAg and detectable HBV DNA) and elevated transaminase levels should be considered candidates for HBV treatment, even if criteria for HAART are not met yet.
However, the optimal time for initiating anti-HBV therapy in coinfected patients has neither been established nor is it clear which drug(s) should be used. An integrated approach against both HIV and HBV is needed. On the basis of the advice of different panels of experts, if HBV infection is the only viral infection to be treated, IFN-alfa (preferably any of the pegylated forms) could be a valid option. However, given the low response to standard IFN-alfa and the lack of data on the effectiveness of pegylated IFN-alfa in HBV/HIV-coinfected subjects, it is desirable to treat these patients within clinical trials and in healthcare centers with experience.
Adefovir monotherapy (at dosages of 10 mg/day) may be considered a reasonable alternative option for treating HBV infection in HIV-positive patients who do not meet the criteria for HAART. However, the potential risk for selection of resistance mutations in HIV with long-term use should be of concern, although this option is being supported by recent European guidelines for the treatment of HBV.
The use of 3TC, FTC, or TDF in monotherapy should be avoided in HIV/HBV-coinfected patients, because these drugs favor the selection of HIV resistance mutations.
In patients who meet criteria for the treatment of HIV infection, a HAART regimen containing 3TC, FTC, and/or TDF should be administered. Of note, TDF seems to show a higher activity against HBV than do FTC or 3TC and has a great genetic barrier for resistance. However, the experience with TDF is scarce.
For patients who have already received 3TC as part of HAART and who have detectable HBV viremia, resistance of HBV to the drug should be suspected. Emtricitabine is not useful for treatment of HBV infection in these patients. However, adding or replacing it with TDF is a reasonable approach. If HIV is already suppressed, adefovir might also be considered.
As for the role of combination therapy in HBV treatment, data are scarce. In a recent study among non-carriers of HIV that compared adefovir with adefovir/3TC, combination treatment was not found to be superior to adefovir alone in the first 12 months of treatment.
Editor's Note: This article is a summary review of Nunez M et al. Treatment of Chronic Hepatitis B in the Human Immunodeficiency Virus-Infected Patient: Present and Future. Clin Infect Dis 2003;37:1678-1685. Reprinted with permission from HIV and Hepatitis.com (www.HIVandHepatitis.com).