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Hepatitis C & B Report from Retrovirus
Nancy Shulman, MD, Stanford University
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Selected hepatitis posters from Retrovirus
The biggest presentations of hepatitis in Boston this year were related to hepatitis G (HGV), otherwise known as GB virus C. This virus, which is prevalent in patients who are HIV+, does not appear to cause hepatitis or any other known illness, although it is related to hepatitis C in structure. A couple of years ago this virus was found to be associated with slower HIV progression in several large cohort studies in the pre-HAART era, although a couple of studies have not shown a survival benefit. This year's conference had more information about the impact of GB virus C on HIV progression including some possible mechanisms of the anti-HIV affect of GB virus C based on in vitro laboratory studies, and what happens to HIV disease when people spontaneously clear GB virus C from the bloodstream. For these exciting details, please see Dr. Dave Thomas' review (2/18/03) on this website:
http://www.natap.org/2003/Retro/day8.htm
Hepatitis B Serology and "Occult" Hepatitis infection in HIV+'s
People who have been infected by hepatitis B as shown by a positive hep B core antibody with or without a positive hep B surface antibody may have replication of HBV in the liver and even in the bloodstream without having detectable hepatitis B surface antigen in the bloodstream. This is termed "occult" hepatitis B. These patients can transmit HBV through organ donation (mainly by liver) and through blood transfusion to non-immune recipients. It is controversial whether occult hepatitis B worsens liver histology or increases the risk of cirrhosis/ hepatocellular carcinoma. This may in be a bigger problem in immunocompromised people such as HIV+ patients. A study by several ACTG investigators aimed to look at the prevalence of active hepatitis B (those with positive surface antigen) and those with occult infection (core antibody+, DNA+).
240 subjects randomly selected from two antiretroviral naive studies, ACTG 320 and 343 were selected for evaluation of hepatitis B serology and DNA. The representative population was 83% male, 50% white, with a median CD4 count of 137.
65% (156) had evidence of active or past infection with hepatitis B infection. Of the 156, 92 samples (38%) were thought to have cleared the virus (detectable antibodies to core and surface antigens, and no circulating hepatitis B surface antigen or HBV DNA). 6 (2.5%) were only positive for surface antibody consistent with prior hepatitis B vaccination. 7.1% (17) were positive for hepatitis B surface antigen and to core antibody consistent with acute or chronic infection. 10 of these had replicating HBV DNA. 38 (15.8%) subjects were positive for core antibody only and only 1 of those patients had replicating DNA in the blood. It appears that at least in this cohort that although hepatitis B exposure was high, "occult" hepatitis B was rare.
Another study from Paris attempted to look at the impact of prior exposure to HBV on liver histology (fibrosis rates and inflammation) of HIV/HCV coinfected patients. This was a subanalysis of the original study looking at the impact of HIV and CD4 count on fibrosis rates. All 145 selected for analysis were hepatitis B surface antigen negative. 78% had core antibodies, 22% did not. ALTs and necroinflammatory scores were similar in the two groups. In a multivariate analysis that controlled for alcohol consumption, CD4 count, and lamivudine therapy, being hepatitis B core antibody positive was associated with slower fibrosis rates (relative risk 0.31 with 95%CI 0.15-0.67). The author's conclusions were that past hepatitis B infection does not have a detrimental affect on histology in HIV/HCV infected patients and may be protective. The study did not check HBV DNA levels in the serum or stain for HBV in the liver, which would have been interesting to see if the small subgroup with "occult" hepatitis infection had worse disease. More studies of this nature are needed to validate the above results.
1. Abstract 820. Sherman, et al. Prevalence of occult hepatitis B infection in HIV-infected patients: analysis of a geographically distributed ACTG cohort.
2. Abstract 822. Benhamou, et al. The impact of prior hepatitis B virus infection on histologic lesions in HIV and hepatitis C virus co-infected patients.
Impact of HBV on HIV and mortality in an endemic area
HCV in most studies, has not had an impact on HIV progression or HIV-related mortality although HCV/HIV co-infected patients have more HAART-related toxicity and are at higher risk of liver disease progression and liver-related death, and may have a blunted CD4 reponse to HAART. Less is known about the impact of HBV on HIV due to lower rates of chronic HBV (particularly without HCV) in most western HIV+ cohorts. A study from Taiwan where HBV is endemic and rates of chronic HBV are high addressed some of these questions.
An observational cohort of 513 HIV infected patients were studied for the impact of chronic HBV infection on virologic, immunologic, and clinical outcomes between 1994 and 2002. Those with hepatitis C were excluded from the cohort analysis. 126 (25%) were chronically infected with HBV. The median observational period was 22 months for the cohort. Most of the cohort acquired HIV through sexual transmission. There were no differences in the HBV+ vs. HBV- in regards to age, sex, antiretroviral therapy, CD4 count at cohort entry (median 50 in each group). Baseline ALT and AST were higher in the HBV group (median 39 and 33 vs. 33 and 24). 33% of the HBV group developed a >5 fold increase in ALT/AST over normal during the observational period vs. 16% in the HBV- group. This was seen in both the pre and post-HAART period. 12 patients (9.5%) of the HBV+ group developed decompensated liver disease vs. 2 (0.5%) in the HBV- group. There were 9 vs. 0 liver-related deaths. There was no difference in virologic suppression rates and failure rates, and no difference in the numbers that achieved >100 CD4 count rise after HAART. OI rates were similar. Mortality rates were greater in the HBV+ patients overall and in the post-HAART era (adjusted odds ratio 2.03, 95%CI 1.26-3.26).
Conclusion: Like HCV, rates of liver disease, transaminitis, and liver related deaths are higher in the HBV/HIV coinfected groups. Although HIV disease and responses to HAART were not different in the groups, overall mortality was higher in the HBV+ group, particularly in the post-HAART era.
1. Abstract 823. Sheng, et al. Impact of chronic hepatitis B infection on outcomes of HIV infected patiens receiving HAART in an area hyperendemic for hepatitis B infection. An eight-year prospective observational study.
HBV treatment in HIV+ patients
Tenofovir is active against HBV and active against lamivudine-resistant HBV. A small French study where 10 patients on lamivudine, 9 with documented lamivudine resistant HBV had tenofovir added to their antiviral regimen. At 1 year, patients had a mean of 4.55 logs reduction in HBV viral load, including 3 patients with <200 copies/ml. ALT dropped a mean of 25. HBV genotyping revealed no new resistance mutations to tenofovir.
The Gilead 903 study offered an opportunity to look at HBV/HIV positive patients receiving tenofovir+lamivudine (3TC) vs 3TC alone inside an HIV regimen. HBV viral load reductions were better using tenofovir + lamivudine than lamivudine alone. This is reminiscent of the early combination HIV trials where we found out more is better. Gilead study 903 enrolled HIV-treatment-naive patients to receive stavudine (inactive against HBV) or tenofovir (active) with lamivudine (active) and efavirenz (inactive). There were 11 patients chronic hepatitis B, 5 in the tenofovir/lamivudine arm, and 6 in the lamivudine arm that had baseline and 48 week data and were included in the analysis. Baseline HBV DNA levels and ALT levels were similar in the two groups. The combination group with tenofovir/lamivudine had a mean change HBV DNA of -4.7 vs. -2.95 in the lamivudine group, including 4 and 1, respectively who achieved <1000 copies of HBV DNA/ml. Mean change in ALT was -55 for the combination group vs. -22 in the lamivudine group. In addition 4 patients in the lamivudine group vs. only one in the tenofovir/lamivudine group developed detectable lamivudine resistance. Just like in HIV, two active drugs are more potent than one and more potent therapy delays resistance development.
1. Abstract 824. Marcelin, et al. Long term tenofovir treatment of lamivudine-resistant chronic hepatitis B in HIV co-infected patients.
2. Abstract 825. Cooper, et al. Tenofovir disoproxil fumarate and lamivudine combination therapy compared to lamivudine alove for HBV in therapy-naive HIV/HBV co-infected patients: 48-week interim results.
Impact of immune reconstitution on histology in HCV-HIV coinfected patients
Co-infected patients often have elevation in their transaminases after initiating HAART. The role that immune reconstitution has in this is not clear. A small study from France attempted to look at the impact of immune reconstitution on liver histology. This study enrolled patients who were naive to HAART and had no HCV treatment within the last 12 months and who had no decompensated liver disease. Patients had serial ALTs, HIV and HCV RNAs pre and post HAART as well as paired liver biopsies at 0 and 12 months of HAART. Histologic progression was defined as 2 or more increase in the Knodell score and 1 or more increase in the Metavir score. Factors that might affect histologic progression were assessed in all including: sex, age, body mass index, CD4 count, AIDS diagnosis, HIV and HCV viral load, HCV genotype, alcohol consumption, type of HAART, immune reconstitution (defined as >100 increase in CD4 at 12 months or doubling of CD4 count), and transaminase elevation >5 fold above the upper limit of normal.
25 patients completed both biopsies and 5 had histologic progression. At month 12, 13 of the patients had immune reconstitution, 12 did not. 23% of the patients with immune reconstitution had histologic progression vs. 17% in those without immune reconstitution. The only variable assess that was associated with histologic progression was transaminase elevation. 4 of 5 patients with transaminase elevations >5 fold above the upper limit of normal had histologic progression vs. 1 of 20 without. This was a small study, but it had paired biopsies and ALT elevation was predictive of histologic progression.
1. Abstract 831. Zylerberg, et al. Progression of liver histologic status in HIV/HCV co-infected patients started on HAART. A prospective study.
HCV Treatment in HIV+
Final results of a large study done in the days prior to pegylated interferon were presented. A randomized controlled open-label study involving 68 sites compared interferon alpha-2b at 3 million units 3 times per week (TIW) vs. daily (q day), both in conjunction with ribavirin 800mg/day for 48 weeks in 180 HCV treatment naive co-infected patients. Active OI's and CD4 <100 were the HIV-related exclusion criteria. About 76% of the patients were male, mean age 44 yrs, 79% genotype 1, 85% were on ART, mean CD4 was 542, viral load about 3 logs. 162 were included in the ITT analysis.
At treatment week 12, 33% of the q day vs. 13% of the TIW arm were undetectable. 43% of the TIW and 20% of q day arm discontinued due to lack of response. The sustained virologic response ITT rates were very low at 9% and 4% respectively due to high drop out rates, mainly from virologic failure. There were no sustained responders in this group that were not undetectable at week 12 of treatment. The 12 week results are comparable to a preliminary 24 week report of ACTG 5071 which compared interferon alfa 2a TIW vs. pegylated interferon alfa 2a q week both with ribavirin 2. At 24-weeks 15% in the interferon TIW arm vs.44% in the pegylated arm had undetectable HCV RNA. The pegylated forms are superior to daily IFN which is superior to TIW IFN regimens. All of these response rates are substantially lower than has been observed with treatment in HCV-monoinfected patients.
1. Abstract 841. Sulkowski, et al. Final results of daily vs. 3-times weekly interferon alpha 2b plus ribavirin for the treatment of hepatitis C infection in HIV-infected persons: a multi-center, randomized open label study.
2. Abstract LB-15. Chung, et al. 9th CROI.
Predictive value of week 12 responses in HIV-HCV coinfected patients treated for HCV.
Very few patients who do not achieve at least a 2 log drop in HCV RNA from baseline to week 12 achieve a sustained virologic response to interferon-ribavirin based therapies in HCV-monoinfected patients. The above study found the same with their group. Another study from Spain evaluated 89 HIV+ patients who completed HCV treatment, 63 received pegylated interferon and 26 received standard interferon both in combination with ribavirin. Genotypes 2 and 3 were treated for 6 months, while genotype 1 was treated for 48 weeks. 52 patients (58%) achieved >2 log drop of HCV RNA at 12 weeks. 29 (32% overall, and 56% of the week 12 responders) achieved a sustained response in comparison to 0 who were week 12 non-responders. The odds are slim to none of achieving a sustained virologic response to HCV treatment in both co-infected and mono-infected HCV+ patients if there is not a 2+ log drop in HCV RNA at week 12 of treatment. The option of continuing to gain histologic benefit should still be discussed with each patient as we know that non-responders can have improvements in liver histology with treatment.
1. Abstract 842. Perez-Olmeda, et al. Predictive value of early virologic response (12 weeks) to pegylated interferon plus ribavirin in HIV-HCV co-infected patients.
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