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An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected individuals
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"....This study demonstrates that tenofovir is effective against HBV in HIV-1 infected individuals who have been previously exposed to 3TC and suggests that tenofovir may be used to overcome 3TC resistance"
Editorial note from Jules Levin: a recent publication of a study in 8 HBV/HIV coinfected patients conducted at Washington University School of Medicine found similar results. You can read details of that study at: www.natap.org/2002/Nov/112502_1.htm
We need larger studies of tenofovir in HBV/HIV coinfected patients to explore safety, resistance, and effectiveness. Gilead Sciences needs to initiate this research so this drug can be used properly.
At the European AIDS Conference in Glasgow (Nov 2002), a resistance analysis of Gilead study 903 raises some concerns. Patients in this study were treatment naive and received either a d4T or tenofovir based HAART regimen. 29 (9.7%) of the patients receiving the tenofovir HAART regimen, which also included efavirenz (Sustiva and 3TC), developed virologic failure. But, 24% of the 29 patients (7/29) developed tenofovir resistance and some phenotypic resistance to abacavir, ddI, and tenofovir was detected in some of these patients using the Virco phenotypic resistance test. Granted, by changing therapy these patients were able to re-suppress HIV viral load. But the viral failure was probably detected early thus perhaps making these patients more treatable. You can read a report of this study written by Graeme Moyle at:
www.natap.org/2002/6thIntlCongress/day7.htm
The point is that using tenofovir can lead to tenofovir and nuke resistance. This can reduce future HIV treatment options as tenofovir has clearly demonstrated itself to be a useful therapy for patients with nuke experience and also in salvage situations. I think itıs also important to bear in mind that using tenofovir to suppress HBV in a HAART regimen may result in tenofovir, or nuke resistance. In addition, a number of new drugs for HBV are in development such as entecavir, which is in phase III studies. Using tenofovir may reduce HBV treatment options in the future. If a patient can defer therapy for HBV, perhaps waiting until more treatment options are available may be beneficial. In HIV itıs clear combination therapy of 3 or more drugs is the standard of care. But, we will need studies to explore combination therapy for HBV. So if entecavir and other HBV drugs do in fact become available perhaps combination therapy of 2 or 3 drugs will be more effective in treating HBV.
Study Report. Tenofovir is a novel nucleotide analogue recommended for use in HIV-1 infected treatment-experienced patients. Recent data suggest an effect on Hepatitis B virus (HBV) replication. We therefore investigated the use of tenofovir in HIV-1 and HBV co-infected individuals.Twenty HIV-1/HBV co-infected patients with a median of 108 weeks lamivudine experience (range, 0-270 weeks) received tenofovir 245 mg daily in addition to or as part of their combination antiretroviral therapy at Chelsea & Westminster Hospital in London, UK. Their immunologic parameters and HIV-1 RNA and HBV DNA viral loads were followed over a period of 52 weeks. In addition, their HBV DNA polymerase was sequenced at baseline to measure the frequency of YMDD mutations that are associated with lamivudine resistance. A significant decrease in HBV DNA viral load (median 4 log reduction in HBV DNA in the first 24 weeks) and alanine aminotransferase levels was observed from 96 to 43 IU/ml. 46% normalized during this trial. There were no significant overall differences between the lamivudine-experienced (n = 15) and -naive (n = 5) individuals and tenofovir was well tolerated. Five patients (25%) underwent HBe antigen seroconversion during the study period. Out of the 15 lamivudine-experienced individuals, 10 had YMDD mutations and one had YIDD mutations in HBV DNA. These results indicate that 52 weeks of tenofovir in addition to antiretroviral therapy is active against HBV, and it appears to overcome lamivudine resistance. AIDS Jan 3, 2003; 17(1):F7-F10. M. Nelson; S. Portsmouth; J. Stebbing; M. Atkins; A. Barr; G. Matthews; D. Pillay a; M. Fisher b; M. Bower; B. Gazzard
These patients were treated as part of salvage protocols or because of increased HBV DNA despite prolonged use of 3TC. All 20 patients were homosexual males and their median age was 43 years (range, 22-52 years). Fifteen out of the 20 patients were 3TC experienced with a median exposure of 138 weeks (range, 8-270 weeks). The median HBV DNA viral load at baseline was 181,500 000 (interquartile range, 47,375,000-755 000 000) GEq/ml. The median in HBV DNA viral load decreased from 126,272,450 GEq/ml to 328,692
during the first 24 weeks. Serum albumin showed a small non-significant increase.
There was an increasing number of patients over time who reached undetectable. After 4 weeks, 5 of 20 patients achieved undetectable HBV-DNA. After 36 weeks 10 patients had undetectable, and after 52 weeks 13 patients had undetectable HBV-DNA. There was a trend towards an improved CD4 cell count and CD4 cell percentage. There were no significant changes in CD8 cell count and the median HIV-1 viral load remained below the limit of detection. Similarly, CD16/CD56 and CD19 counts remained unchanged.
At 24 weeks, two patients had seroconverted and by 52 weeks, five patients (25%) had seroconverted to HBe-antibody positivity. Three of these five individuals harboured 3TC resistant mutations. No patients experienced any drug-related toxicities or unwanted effects and one patient elected to stop therapy as he wished to discontinue antiretroviral treatment. Serum electrolytes and creatinine remained stable.
The rate of decrease in HBV DNA viral load demonstrated a more rapid initial decline in those individuals who harboured 3TC-resistant mutations compared with those who did not (P = 0.046; one-sided test of variance/central limit
theorem).
DISCUSSION by Authors. Anti-HBV efficacy is important in co-infected patients as HIV-1 induced immunosuppression leads to increased HBV replication. Historically, the development of anti-HIV-1 therapy led to early trials of monotherapy. This resulted in the accumulation of drug resistant mutations and subsequent treatment failure. Similarly, 3TC monotherapy for HBV infection leads to the rapid development of mutants that no longer respond to treatment. This in turn has implications for the clinical
outcome of chronic infection including cirrhosis and hepatocellular carcinoma. The use of tenofovir and 3TC as part of a highly active antiretroviral therapy regimen [in 3TC or nuke naive patients] may have superior potency and durability against both HIV-1 and HBV infection. Adefovir dipivoxil, at a dose of 10 mg daily is active against 3TC-resistant HBV in HIV-1/HBV co-infected individuals. At this dose, no activity against HIV-1 was observed although increased ALT and the development of diabetes
were seen. At an HIV-1 treatment dose of either 60 mg or 120 mg daily, nephrotoxicity has been observed in 33% and 42% of patients, respectively. Tenofovir at an HIV-1 treatment dose is active against HBV with no renal toxicity.
The loss of HBeAg in two patients in a relatively short time scale of 24 weeks and in five patients at 1 year is encouraging and should be studied in a larger cohort of patients including HIV-negative HBV-infected individuals. In
the largest study using adefovir, two patients out of 35 underwent HBe antigen seroconversion. However, the safety profile of tenofovir is comparable to that of placebo and we observed no adverse effects. Tenofovir increases the therapeutic options for HIV-1 and HBV co-infection.
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