New Developments in the Management of Hepatitis B Virus/HIV Coinfection
Raymond T. Chung, MD
Since the introduction of potent antiretroviral therapy, HIV has been successfully converted from a uniformly fatal illness to a manageable chronic infection. Correspondingly, during the past 6 years the opportunistic infections that complicate profound immunosuppression have been replaced with newer forms of morbidity and even mortality. Chief among these has been the development of progressive liver disease due to hepatitis C virus (HCV) and hepatitis B virus (HBV). Because of their shared routes of transmission, HCV and HBV are frequently found in the HIV-infected host. While HCV coinfection has deservedly gained considerable attention as a major cause of mortality in the post-HAART era, complications of HBV-related liver disease are being increasingly recognized, especially as drug-resistant forms of HBV have become nearly universal in antiretroviral-experienced HIV-infected patients. This article will review the pathogenesis of HBV-related liver disease, diagnosis and screening strategies, current and forthcoming antiviral medications, and practical issues regarding the clinical management of HBV/HIV-coinfected patients.
HBV: Genomic Organization and Viral Lifecycle
HBV, like HIV, is both a blood-borne pathogen and a sexually transmitted disease. A member of the hepadnavirus family, HBV is a partially double-stranded DNA virus with a complex lifecycle. Following entry into the hepatocyte, the viral DNA genome moves to the nucleus, where the partial double-strand becomes fully double-stranded and assumes a highly stable conformation in the nucleus. This DNA becomes the template for transcription of the 4 major gene products of the virus: S, core, pol, and X proteins. The HBV pol product is a dual-function DNA polymerase that carries out not only DNA-dependent DNA replication but also RNA-dependent DNA replication (reverse transcriptase) activity in synthesizing first-strand cDNA off the pregenomic RNA template. The S protein forms the outer envelope and can be detected as HBsAg. The core protein is produced from a fusion precore-core protein, which is proteolytically processed to yield the mature core as well as HBeAg, a surrogate marker of active HBV replication. The X protein's function is not fully defined but it appears to act as an activator of a variety of host growth-related genes.
Liver disease, in the form of a chronic inflammatory hepatitis, is mostly confined to persons who harbor replicative disease, usually marked by the active secretion of HBeAg and the detection of large copy numbers of HBV DNA (typically > 100,000 copies/mL) by PCR or a comparable amplification assay. Occasionally, a mutant form known as the precore mutant -- so named because a mutation leads to the premature truncation of the HBeAg in the precore portion of the core gene -- will produce a comparable clinical picture, but without detectable HBeAg. In this situation, detection of large copy numbers of HBV DNA will permit distinction from persons who are simple HBsAg carriers.
Chronic replicative HBV causes liver disease because of a vigorous response directed at virus-infected hepatocytes by the cytolytic T lymphocyte. While immunosuppression secondary to solid organ transplantation, receipt of chemotherapy or corticosteroids, or infection with HIV may diminish the strength of the cellular immune response and therefore modulate liver injury in the short term, HBV replication (and appearance of its markers) is enhanced under these conditions. Indeed, over the long term, it appears that the equilibrium between viral replication and host immune response is sufficiently perturbed to adversely affect the natural history of chronic HBV.
Thus, conditions that favor return of a functional immune response, while they may transiently worsen the course of HBV-related liver disease by recognizing target cells harboring significantly elevated levels of viral antigen, would with time be expected to restore a more favorable equilibrium. Indeed, there are reports of the development of immune reconstitution-related flares of HBV following initiation of HAART. While these flares are uncommon in light of the inclusion of lamivudine in most HAART regimens, a flare should be suspected when serum liver enzymes rise, sometimes dramatically, within the first 12 weeks of initiation of HAART in an HBsAg-positive person. The recommendation that all HIV-infected persons be assessed for HBV status before antiretroviral therapy is initiated should permit selection of appropriate regimens to minimize the occurrence of flares.
Diagnosis and Screening
The hallmark of chronic HBV infection is detection of circulating HBsAg. This is typically accompanied by IgG anti-HBcore reactivity. However, it is being increasingly recognized that reactivity to anti-HBcore alone reflects latent HBV infection. Thus, in assessment of baseline HBV status, HBsAg, anti-HBs, and anti-HBcore should all be obtained. Persons who test HBsAg-positive should then have HbeAg, anti-HBe, and HBV DNA status established to determine the replicative state of the infection and the possible need for antiviral therapy for HBV. A positive test result for anti-HBcore but negative results for HBsAg and anti-HBs should prompt an HBV DNA amplification test to exclude a possible false-positive anti-HBcore test.
Management of Hepatitis B Virus/HIV Coinfection
from Medscape HIV/AIDS eJournal[TM]
Scope of the Problem in HIV Coinfection
A study presented at the 9th Conference on Retroviruses and Opportunistic Infections in February 2002 helped to define the magnitude of the chronic HBV problem among the HIV-infected population in the United States. A large cohort of 5293 gay men was followed prospectively and mortality was assessed based on HBV serologic status. A total of 65% of the cohort was HIV-infected and 6% were HBsAg-positive. The mortality rate attributable to liver disease was significantly higher among HBsAg-positive persons compared with those who were HBsAg-negative (RR 12.7; 95% CI, 7.2-21.6). When liver-attributable mortality was examined in those who were HIV-infected, coinfection with HBV significantly increased the risk (14.2/1000 person-years, P < .001) compared with those with HIV alone (1.7/1000 person-years) or HBV alone (0.8/1000 person-years). The relationship between HBV coinfection and liver mortality was strengthened in the period after 1996 and among persons with lower CD4+ cell counts.
These data suggest that HBV, like HCV, has acted as an opportunist in the post-HAART era. They also reinforce the concept that advanced states of immunosuppression are deleterious to the host-virus equilibrium. Finally, in view of high coinfection rates, they underscore the need to determine baseline HBV infection status in all persons with HIV.
Treatment Options in HIV/HBV Coinfection
There are currently 2 licensed treatments for the management of chronic replicative HBV monoinfection: lamivudine and interferon alfa-2b.
Lamivudine has activity not only against the HIV reverse transcriptase but also against the HBV DNA polymerase. In monotherapy trials, treatment with lamivudine (100 mg daily) for 1 year produced HBV DNA clearance or significant reductions in nearly all patients, and HBeAg seroconversion in 17% of patients. Follow-up studies have suggested that these seroconversion rates increase with longer treatment. Nonetheless, the low rate of seroconversion (a relatively durable end point) has led most practitioners to adopt a chronic suppressive treatment approach, especially in those persons with histologically advanced disease, marked by higher inflammatory and fibrotic indices.
Because lamivudine gained nearly universal use as part of initial antiretroviral regimens, an unwitting consequence of these regimens was the initial control of unappreciated HBV infection. Over time, however, continued therapy has led to the selection of lamivudine-resistant isolates of HBV. These isolates harbor amino acid substitutions in the HBV DNA polymerase active site motif YMDD, and have therefore been called YMDD mutants. Studies from HIV/HBV-infected persons receiving lamivudine as part of a stable antiretroviral regimen have revealed the nearly inevitable selection of YMDD mutants (90% at 4 years). However, 2 important clinical characteristics of these variants, compared with wild-type HBV infection, should be noted. First, upon removal of lamivudine, return of wild-type HBV is universal. Second, the flare associated with emergence of YMDD mutants is generally attenuated compared with the original wild-type HBV disease. These data suggest that YMDD mutants are less replication-competent compared with wild-type HBV. However, the emergence of mutant HBV may worsen already advanced liver disease. Thus, the recent development of newer nucleoside and nucleotide analogues with activity against both wild-type and mutant forms of HBV will assist greatly in the management of persons who are lamivudine-experienced.
In a person on longstanding lamivudine with apparent virologic control, a new rise in HBV DNA and aminotransferase levels should provoke the suspicion of the emergence of a YMDD mutant. However, because abrupt withdrawal of lamivudine can be associated with a severe hepatic flare, lamivudine should not be discontinued. Rather, consideration should be given to the merits of adding a nucleotide analogue (see below).
Interferon alfa-2b (IFN)
This agent, approved either as a daily dose of 5 MU administered subcutaneously (SQ) daily or 10 MU SQ thrice weekly for 16 weeks, produces comparable rates of clinical response to lamivudine. Clinical trials suggest that it actually produces higher HBeAg seroconversion and even HBsAg clearance rates. However, IFN does not appear to work well in persons with perinatally acquired disease or among Asian patients. In addition, IFN has an inordinate number of potential adverse effects, including neuropsychiatric alterations, flu like symptoms, and bone marrow suppression. As a result, IFN has been infrequently used in the treatment of chronic replicative HBV. The difficulty with adverse effects has therefore limited its extension to the HBV/HIV-coinfected patient population.
Longer-acting, polyethylene glycol-modified (pegylated) forms of interferon (PEG-IFN) have been developed, which permit once-weekly dosing because of delayed clearance. These have been associated with superior antiviral efficacy in chronic HCV infection when compared with unmodified IFN. This advance suggests a possible role for PEG-IFN in trials of chronic HBV, including HBV/HIV coinfection. A trial of PEG-IFN in HBV-HIV infected persons will be conducted shortly through the US AIDS Clinical Trials Group (ACTG).
Summary: Treatment Strategies for HBV/HIV-Coinfected Patients
Recent Developments in the Therapy of HBV
Nucleotide Reverse Transcriptase Inhibitors
Adefovir dipivoxil (not FDA-approved) and tenofovir disoproxil fumarate (FDA-approved for HIV) have activity against both the HIV reverse transcriptase but also against the HBV DNA polymerase. In addition, however, both have activity against YMDD mutant forms of HBV both in vitro and in animal models. A number of recent studies suggest that these agents work effectively against HBV in coinfected subjects.
French investigators have reported interim data from a planned 96-week study of adefovir dipivoxil 10 mg daily -- a lower dose than the 30 mg used in clinical trials of adefovir dipivoxil for HIV -- added to existing antiretroviral therapy, including lamivudine. They enrolled 35 patients, all of whom had well-controlled HIV, detectable HBV DNA, and documented lamivudine-resistant (YMDD mutant) HBV. The mean decrease in HBV DNA was -3.4 log10 copies/mL at week 24, -4.07 log10 copies/mL at week 48, and -4.80 log10 copies/mL at week 72. A total of 9 patients achieved undetectable HBV DNA (< 1000 copies/mL) at week 72, and 9% of the HBeAg-positive patients seroconverted. Serum ALT also fell. In the 14 patients with paired liver biopsies at baseline and 1 year, median inflammatory scores and fibrosis scores dropped, the former significantly. Control of HIV remained unchanged. Adefovir dipivoxil was well tolerated. Use of adefovir dipivoxil at these doses does not appear to be associated with the acquisition of resistance mutations in the HIV reverse transcriptase.
Tenofovir disoproxil fumarate (tenofovir DF) is another nucleotide analogue with demonstrated excellent activity against wild-type and nucleoside-resistant HBV. Data have been presented on its efficacy in HBV/HIV-coinfected patients enrolled in a global study of tenofovir DF for HIV infection, in which 550 patients were randomized to receive either tenofovir DF (300 mg/day) or placebo for 24 weeks, added to a pre-existing antiretroviral regimen. Thereafter, all subjects received tenofovir DF from weeks 24-48. Among the overall study population, 94% had HIV NRTI resistance mutations at baseline. A total of 12 HBV-coinfected subjects (10 in the treatment arm, 2 on placebo) were monitored for the full 48 weeks, with HBV DNA > 6 log10 copies/mL. All were lamivudine-experienced, and 7 had YMDD mutations at baseline. At 24 weeks, the mean decrease in HBV DNA was -4.44 log10 copies/mL among those treated with tenofovir DF, compared with an increase of 1.23 log10 copies/mL in the placebo group (P = .04). The mean decrease in HBV DNA at 48 weeks was -3.94 log10 copies/mL. HBeAg seroconversion occurred in 1 patient. The drug was well tolerated, and reductions in plasma HIV-1 RNA levels in coinfected patients were similar to those in patients infected with HIV alone. No new HBV mutations were seen during follow-up.
Interim, week-16 data have also been presented from a French study in which 11 HBV/HIV-coinfected patients receiving lamivudine added tenofovir DF (300 mg daily) to their regimens. All had YMDD mutant HBV, and 10 were HBeAg-positive. The median decrease in HBV DNA was -3.67 log10 copies/mL at week 16. The drug was well tolerated. One patient with elevated serum creatinine (2.6 mg/dL) at baseline had to have tenofovir DF stopped at week 12 because of an increase to 4.3 mg/dL, which was not considered treatment-related.
In August 2002, the antiviral advisory committee of the Food and Drug Administration recommended that adefovir dipivoxil be approved for the treatment of HBV monoinfection. Both adefovir dipivoxil and tenofovir DF are also undergoing clinical trials in HIV/HBV coinfection in the US ACTG.
Newer Nucleoside Analogues
Emtricitabine. Emtricitabine is an NRTI with dual activity against HIV and HBV. In one study, 98 coinfected patients were randomized to receive emtricitabine (25 mg, 100 mg, or 200 mg/day). At 1 year, 37%, 42%, and 61% of the 3 dose groups, respectively, had undetectable HBV DNA, and 32%, 38%, and 50% lost HBeAg. The incidence of HBV mutants at 1 year was 12% in the 2 lower-dose groups and 6% in the higher-dose group. Three patients discontinued emtricitabine due to adverse reactions, 1 in each dose group.
L-dT. L-dT is an L-nucleoside analogue with potent activity against wild-type HBV in early clinical testing, producing up to 3.6 log10 reductions in HBV DNA at 4 weeks. Unlike the other nucleoside and nucleotide analogues, it does not possess anti-HIV activity. L-dT is currently undergoing clinical testing in HIV/HBV-coinfected persons in the ACTG.
At least 4 other nucleoside analogues are in early phases of clinical testing in HBV monoinfection (Table 1).
New Developments in the Management of Hepatitis B Virus/HIV Coinfection
[Medscape HIV/AIDS eJournal 8(5), 2002. © 2002 Medscape]
Table 1. Summary: Selected Antiviral Agents for the Treatment of Hepatitis B