February 14, 2003
As described in an earlier report on the 96-week preliminary results from the Gilead 903 study, a comparison of tenofovir (TDF, Viread) + 3TC (lamivudine, Epivir) + efavirenz (EFV, Sustiva) versus d4T (stavudine, Zerit) + 3TC + efavirenz in treatment-naive subjects with HIV RNA levels >5,000 copies/mL was presented at the 10th Conference on Retroviruses and Opportunistic Infections.
This study demonstrated the continued equivalence of the two regimens in suppressing HIV replication and achieving impressive virologic control. However, the study regimens were distinguished by their toxicities. Significantly greater elevations in fasting LDL cholesterol and triglycerides were seen in the d4T arm while the TDF-receiving subjects had larger increases in HDL cholesterol. Peripheral neuropathy and investigator-described lipodystrophy also were disproportionately reported in the d4T-assigned subjects. Cross-sectional analysis of limb fat by DEXA scanning at week 96 also favored the TDF containing regimen.
Absent from the poster presentation, however, were details of the bone mineralization changes observed during the study. Early in the study, baseline DEXA results were reported demonstrating higher than expected rates of osteopenia in patients naive to any antiretroviral therapy (McGowan et al. 8th CROI, 2001, Abstract 628). Animal studies have revealed bone mineralization changes, prompting the FDA to request that DEXA scans be included in this study.
Bone mineralization results were made available after the conference in response to requests for these data from investigators and clinicians. Fortunately, major changes in median bone mineralization were not seen in either arm. However, there were some differences between the study groups. The median percent change in spine bone mineral density from entry to week 96 was -1.6 percent in the d4T arm compared to -2.3 percent in the TDF arm. For the hip, the median percent change was -2.0 percent among d4T assigned subjects and -3.4 percent in the TDF group. The differences between the study arms, while maybe statistically significant, are not clinically significant. There were no reports of fractures not related to significant trauma during the study.
Other presentations at this conference have illustrated that the relationship between antiretroviral therapies and changes in bone mineralization in HIV-infected persons has turned out to be more complex than anticipated early on. Longitudinal data from this trial may contribute to improving our understanding of risk for bone changes as well as any differences between the treatments being studied. That these data can now be evaluated along with the other toxicity and efficacy results of this important study is a tremendous benefit to patients considering their treatment options and the clinicians who advise them.
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