February 12, 2003
In addition to its activity against HIV, tenofovir (TDF, Viread) has also been demonstrated to inhibit the replication of hepatitis B Virus (HBV). The antiviral effect of TDF, combined with 3TC (lamivudine, Epivir) on HBV, was examined in subjects with HIV and HBV co-infection enrolled in a large HIV treatment trial comparing TDF and d4T (stavudine, Zerit).
As reported yesterday, the Gilead 903 Study is a 600-person trial comparing TDF + 3TC + efavirenz (EFV, Sustiva) versus d4T + 3TC + EFV in HIV-infected patients naive to HIV therapy. Of the subjects enrolled in the study, 11 happened to have detectable hepatitis B surface antigen (HbsAg), an HBV viral load above 106 copies/mL and available blood samples at entry and week 48 of the study.
Five of the HIV/HBV dual-infected subjects had been randomized to TDF + 3TC + EFV and the remaining six to d4T + 3TC + EFV. Importantly, neither d4T nor EFV are known to have activity against HBV while 3TC, of course, does. Therefore, in effect, this substudy could be considered a preliminary comparison of the anti-HBV activity of TDF plus 3TC versus 3TC alone when these agents are used in conjunction with other antiretrovirals in HIV-positive patients.
The mean HBV DNA viral load at study entry was 8.30 log10 copies/mL in the TDF/3TC-receiving subjects compared to 8.86 log10 copies/mL in the other study arm. Four of the TDF/3TC subjects were hepatitis E antigen (HbeAg) positive as were all of those taking 3TC without TDF. Mean serum ALT levels was elevated in both groups (97 U/L in the TDF/3TC arm and 78 U/L in the 3TC alone arm).
At week 48 of the study, there was an average 2.85 log10 copies/mL drop from baseline in HBV viral load in the 3TC arm compared to a 4.70 log10 copies/mL decline in the TDF/3TC subjects. Four of the TDF-receiving subjects had a HBV viral load below 1,000 copies/ml, while only one in the 3TC arm had a level below this threshold. Liver test results improved in both groups. ALT levels dropped by a mean 55 U/L in the TDF-receiving patients and 22 U/L in the other group.
Development of the YMDD 3TC resistance mutation was not detected in the TDF arm (only one subject had the 1,000 or more copies/mL of HBV DNA required to perform resistance testing) but was found in four of the five subjects receiving 3TC without TDF with sufficient HBV viral load.
Overall, these data, despite involving only a few co-infected subjects, suggest that TDF can provide an antiviral effect against HBV in HIV-infected persons. The small number of co-infected subjects studied limits the ability to compare combined therapy with TDF and 3TC versus 3TC alone. Prospective studies certainly are needed (and are planned) to understand fully the effect of TDF as an HBV treatment.
Many clinicians -- aware of the demonstrated anti-HBV activity of TDF -- have reached for this agent when devising antiretroviral regimens for co-infected patients with active HBV. Use of TDF alone or with 3TC to treat HBV in co-infected patients, who by virtue of their CD4 cell count and/or HIV viral load have no indication for HIV therapy, should be cautiously considered in order to avoid development of HIV resistance to these agents.
Such early application of TDF and/or 3TC for non-HIV indications may limit the utility of these agents as antiretrovirals when and if they are needed. Adefovir (Hepsera), a compound related to TDF and approved for the treatment of active HBV, may be a better choice as the risk of cross resistance between this drug and approved antiretrovirals is very low.
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