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  9th Conference on Retroviruses and Opportunistic Infections
Seattle, Washington, February, 2002
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Hepatitis B Report : More Acute HBV Infection in HIV-Patients; 3TC Protective; 14% Vaccinated
Written by Jules Levin
  Researchers from the CDC (Kellerman, abstract 671-M) reported on the incidence of acute HBV infection, HBV vaccination, and the effect of being on 3TC on contracting acute HBV-infection. They analyzed data from 13,000 patients followed in the Adult/Adolescent Spectrum of Disease Project, a longitudinal medical record review project containing information collected at 6-month intervals from the records of people in care for HIV in 11 cities in this study. They followed people from July 1998 through December 2000 and reported 113 cases of acute HBV infection, and found the incidence rate to be much higher than in the adult US population (7.3 cases/1000 person-years vs 1.5 cases/1000 person/years).
Acute HBV-infection was found more often in women, and in persons with a history of IVDU or alcohol abuse. Only 14% of the patients received an HBV vaccine with more than 1 vaccine dose. But incidence of acute HBV was lower in vaccinated individuals. Patients on ART including 3TC compared to patients not receiving ART had a lower incidence rate of acute HBV-infection. Despite being in care for HIV and the known protective benefit from the HBV vaccine, the 14% rate of vaccination is scary. It suggests that perhaps doctors are not offering vaccination and/or patients do not followup for the set of multiple vaccinations required over a period of time. The authors cautioned that the risk factors associated with higher incidence (women, alcohol abuse, IVDU) could be due to these individuals being more likely to be tested since their doctors know of their behavior. However, the higher rates could be due to the fact that IVDU and alcohol abuse are common among HIV-infected individuals, and this behavior and related lifestyle may increase the likelihood of exposure to HBV. The authors also suggested that being a woman came up as a risk factor because they may be more likely to be tested for obstetrics or gynecological care. But, HIV-infected women may also be more likely to be exposed to HBV due to lifestyle and behavior. The authors also cautioned that perhaps some patients received an HBV vaccine in other clinics.
It appears clear that HIV-infected individuals may be more likely to be exposed to other pathogens including HBV, and therefore will be exposed to many comorbidities. We need programs to insure that HIV infected patients receive the HBV vaccine. And we need studies to confirm that 3TC does in fact have a protective effect in preventing acute HBV infection. The authors cautioned that this study may not necessarily reflect the entire US population.
Tenofovir for HBV
At Retrovirus David Cooper reported on an exploratory look at the safety and antiviral activity of Tenofovir in 12 HBV/HIV coinfected patients in study 907, which is a 48 week study of Tenofovir in HIV.
Up to 10% of HIV-infected patients are HbsAg-positive and this can be associated with a risk for HBV-related cirrhosis and decreased survival compared to non coinfected patients. The incidence of 3TC resistant HBV appears to increase with duration of 3TC treatment reaching 50% after 2 years and 67% after 4 years. Cooper said that 3TC resistance has been associated with progressive liver disease. Tenofovir is taken as 1 300mg tablet once daily and was approved for treating HIV in October 2001 in the US and February 2002 in Europe. In vitro, Cooper reported, TNF appeared equally active against wild-type and 3TC-resistant virus. Study 907 randomized 550 patients who were on stable ART for 8 weeks or greater at a 2:1 ratio (368:182) to TNF or TNF placebo. But after week 24 patients randomized to TNF placebo received TNF. 12 coinfected patients were randomized received TNF and 2 coinfected patients were randomized to TNF placebo.
11 of Mean HBV DNA (viral load) was 8.74 log in the TNF group and 8.05 in the TNF placebo group. Mean HIV RNA was 3.40 log in the TNF group and 3.43 in the TNF placebo group. Mean CD4s were 500 in the TNF group and 600 in the TNF placebo group. All patients had a mean 3.4-3.8 years of prior 3TC use, and 50%-58% had 3TC resistance (1 in the TNF placebo group and 7 in the TNF group). Mean ALT was 56-71. In the TNF group 10 patients had ALT >ULN, and 1 in the TNF placebo group.
After 24 weeks the 12 coinfected patients achieved a mean reduction in HBV DNA of -4.81 log compared to the 2 placebo patients whose HBV DNA increased 1.23 log (p=0.04). In patients with 3TC wild-type virus (n=4) baseline viral load was 9.65 log and was reduced by -5.39 log at week 24. In 3TC resistance patients (n=7) baseline HBV DNA was 8.50 log and was reduced by -4.58 log at week 24. However, Cooper said that since all the patients were exposed to 3TC perhaps some of the patients had 3TC resistance that may have reverted to wild-type.
ALT remained mostly unchanged at week 24 but 2 patients normalized (<43 IU/L) ALT. HbeAg seroconversion was observed in 1 TNF patient. The mean HIV RNA reduction was no worse in the HIV/HBV coinfected than in the HIV monoinfected patients (-0.61 log for HIV monoinfected vs -0.75 in the coinfected; this difference is not significant).
There did not appear to be any safety concerns. There were 3 serious adverse events in the TNF group (fever, schizophrenic reaction, pneumonia) but none were considered related to TNF. 1 patient discontinued TNF due to grade 3 ALT/AST elevations at week 20 considered possibly related to TNF. Elevated LFTs resolved 12 weeks after stopping drug and the reaction was not associated with hepatic decompensation.
Cooper said there were no new HBV mutations. Cooper mentioned there are two studies of TNF in HBV/HIV coinfected patients: GS-99-903 is a study in HIV where ART-naive patients will receive either d4T/3TC/EFV or TNF/3TC/EFV, so this offers a comparison of TNF/3TC to 3TC alone in coinfected patients. ACTG study 5127 is looking an adefovir 10 mg vs TNF 300 mg in HBV/HIV coinfected patients with 3TC resistant virus. Estimated to start 2002, 2nd QTR.
In poster 675-M, M Bochet and Gilead reported interim 24-week results on 12 HBV/HIV coinfected patients who received 300 mg TNF as part of a single center substudy of the French TNF Compassionate Use Program. These patients were already taking 3TC as part of their current HIV regimen and this study was non-comparative and open-label. TNF was added to their current regimen. The median duration of 3TC was 56 months; the median time from emergence of HBV resistance to starting TNF was 30 months. Mean HIV RNA was 2.8 log and CD4 count was 440. 11/12 patients were HbeAg positive. Mean serum HBV DNA was 7.42 log. Mean ALT was 102 IU/L.
After 24 weeks, mean HBV DNA was reduced by -3.87 log (n=8). Mean ALT did not change (n=8). Bochet reported TNF was discontinued in one patient with baseline renal function impairment (serum creatinine 2.65 mg/dL at baseline; renal dysfunction at baseline secondary to familial polycystic kidney disease; serum creatinine increased by 1.70 mg/dL at week 12. No other alterations of renal function tests or adverse events were reported in the short-term study. There were no significant changes reported in HIV RNA and CD4 count. Bochet concluded by saying longer study is required to assess safety, tolerability, histology, TNF resistance, and HbeAg seroconversion rates.
Adefovir for Hepatitis B in 3TC Resistant Patients
Yves Benhamou and Gilead Sciences reported on an open-label study of adefovir (ADV) 10mg per day in 35 HBV/HIV coinfected patients with 3TC resistance. Benhamou reminded listeners previous studies showing adefovir efficacy after 1 year of therapy against wild-type chronic HBV-infected patients (Marcellin, AASLD, Nov 2001), pre-core mutant chronic HBV-infected patients (EASL, April 2002), and 3TC resistant HBV in HIV coinfected patients (Benhamou, Lancet, 2001;358: 718-723). Benhamou reported interim results of 88 weeks of dosing of adefovir 10 mg once daily.
Patients were HBV/HIV coinfected. They had HIV RNA viral load <2.60 log; adequate renal function. They had serum HBV DNA despite ongoing 3TC resistance and had HBV mutations (m550V or m5501). ADV was added to existing ART including 3TC. All patients continued 3TC but changes in ART regimen were permitted during the study. Mutation gene sequencing was performed.
The median time of prior 3TC use was 42 months. Mean HBV DNA was 8.64 log. Mean HIV viral load and CD4 were 2.88 log and 423. 33/35 patients were HbeAg positive. Liver histology (METAVIR, n=23): mean activity 1.52, mean fibrosis 2.04, cirrhosis 5/23.
There was a biphasic HBV DNA reduction, about 1.5 log by week 2. Subsequent HBV DNA reduction was slower with a -5.13 log reduction at week 92 (n=13). At week 88 n=22. Mean ALT increased from about 100 to 145 by week 24, but then started to progressively decline and by week 64 reached about 55. And ALT remained significantly lower compared to baseline value.
4/33 patients were HbeAg negative by week 88; 2/33 had HbeAg seroconversion; 7/35 became HBV DNA negative (<2.6 log).
15 patients were evaluable with paired biopsies after 1 year of treatment. There was a significant reduction in mean METAVIR score of necroinflamatory activity (8 patients improved by 2 points, 7 had no change, and none worsened). Fibrosis score did not on average improve. There was no change in HIV CD4 count or viral load.
RESISTANCE. Benhamou reported there was no HBV DNA rebound was seen through week 92; mutation sequencing revealed no resistance mutations in HBV through week 48; there was no HIV RT mutations at codons 65 and 70 at baseline, w12, w24, and w48 in all 11 tested patients.
SAFETY. One 64 year old man developed HCC (hepatic cellular carcinoma) at week 72 and ADV was discontinued. Benhamou said this was not related to ADV. One patient discontinued ADV due to insomnia which was perhaps related to ADV. One patient developed diabetes which required insulin therapy. He had a family history, ADV was discontinued, and he was also treated with d4T and ddC.
After 48 weeks of ADV there were no serum phosphate abnormalities and 2 serum creatinine lab abnormalities (44 umol/L [0.5 mg/dL]), both were considered unrelated to ADV. One patient had 1.4 mg/dL (grade 1) (126 umol/L) with onset at week 28. ADV was maintained and acyclovir was discontinued. The abnormality resolved in 1 week and there was no recurrence. A second patient had 2.0 mg/dL (180 umol/L) with onset at week 32. ADV was interrupted and indinavir discontinued. Lab abnormality resolved in 4 weeks and ADV was reintroduced at week 36. There has been no recurrence out to week 88.
Researchers from Triangle Pharmaceuticals reported on FTC in 98 HBV monoinfected patients at Retrovirus Conference (abstract 674-M). FTC is a NRTI with activity against HIV and HBV in humans. Resistance to FTC is associated with the 3TC resistance mutation M184V. It has been reported that this mutation may appear to develop more slowly with FTC than with 3TC. In a phase 3 double blinded rabdomized trial of FTC vs 3TC in HIV, genotypic analysis of viral failures showed a lower incidence of the M184V mutation for patients receiving FTC vs 3TC (21% vs 48%, p=0.036). Further studies are needed to confirm this initial finding.
FTCB 102 is a 48-week double-blind, randomized comparison of FTC as 25, 100, and 200 mg once daily dosing (n=32 or 33 per dose week). At week 48 patients were switched to open-label FTC 200 mg once daily. 67%-76% of the patients were men. 79%-88% were Asian. 64%-69% were FTC naive. Average age was 36 (20-64).
Median HBV DNA was about 7.5-7.75 log for the 3 dose groups at baseline. Viral load was measured by Digene Hybrid Capture !! with a limit of detection (LOD) of 4700 copies/ml. After week 48, both the 100 and 200 mg dose groups had about a 4 log reduction in HBV DNA, while the 25 mg dose group reduction was not quite as good, about a 3.5 log reduction. The maximum used dose of 200 mg showed the steepest initial decline in HBV DNA and the lowest declines throughout the 48 week period. The 100 mg dose group had the same 4 log reduction at week 48 but the declines were less steep throughout the 48 week study period. And the 25 mg dose displayed less decline throughout the study period although it approached similar overall reduction by week 48. After week 48 all patients received the 200 mg dose and had about a 4 log reduction. The 100 mg group appeared to rebound a bit at week 96.
After 1 year of FTC therapy, HBV DNA was < LOD in 12/32 (38%) in the 25 mg dose group, 14/33 (42%) in the 100 mg dose group, and 20/33 (61%) in the 200 mg dose group. After 2 years of followup, 14/32 (44%) were < LOD in the 25 mg group, 13/33 (39%) in the 100 mg group, and 14/33 (42%) in the 200 mg dose group.
8/22 (36%) in the 25 mg group experienced HbeAg loss after 1 year, 11/29 (38%) in the 100 mg group, and 13/26 (50%) in the 200 mg group; after 2 years, the rate appeared to increase a little: 9/22 (41%) in 25 mg group, 16/29 (55%) in the 100 mg group, and 14/26 (54%) in the 200 mg group, (LOCF analysis used).
Seroconversion to anti-Hbe-- 5/22 (23%) in the 25mg group, 7/29 (24%) in the 100mg group, 6/26 (23%) in the 200 mg group after 1 year; after 2 years, 7/22 (32%) in the 25 mg group, 8/29 (28%) in the 100 mg group, and 7/26 (27%) in the 200 mg group.
Median ALT decreased in all dose groups: from 80 to 30 in the 200 mg group; from 65 to 40 in the 100 mg group; and from 50 to 30 in the 25 mg group.
Genotypic resistance testing was performed on all patients with detectable virus at 1 year. The overall incidence of resistance with mutations were 16% (5/32) in the 25 mg arm, 12% (4/33) in the 100 mg arm, and 6% (2/33) in the 200 mg arm. After 2 years, resistance was 25% (8/320 in the 25 mg arm, 10/33 (30%) in the 100mg arm, and 18% (6/33) in the 200 mg arm. Patients with less or no resistance appeared to maintain better viral suppression. Patients with no or less resistance appeared to be more likely to normalize ALT.
Patients who achieved HBV DNA < LOD (4700 copies/ml) had the better percentages of HbeAg loss compared to patients with >LOD with or without mutations (75% vs 10% & 10%, respectively; and these patients also achieved better seroconversion rates: 40% vs 0% and 10%, respectively.