Tenofovir (Viread) is a relatively new anti-HIV drug that has been licensed in the United States and the countries of the European Union. In studies where tenofovir was used as part of combination therapy in heavily pre-treated HIV positive subjects, the drug helped lower viral loads and caused modest increases in CD4+ cell counts. Now tenofovir is being tested in people with HIV/AIDS (PHAs) who have had no prior exposure to anti-HIV drugs. The one-year results from this study, called GS-903, are very promising. One surprising finding from GS-903 is that tenofovir-containing combinations do not appear to cause significant increases in lipid — cholesterol and triglyceride — levels.

Study details

An international team enrolled 600 HIV positive subjects who had the following profile at the start of the study:

• none had previously used anti-HIV drugs
• 28% were female, 72% were male
• average viral load — 81,000 copies
• about 42% of subjects had high viral loads (more than 100,000 copies)
• average CD4+ cell count — 280 cells
• about 38% of subjects had low CD4+ counts (fewer than 200 cells)

Subjects were randomly assigned to receive one of the following two combinations:

• tenofovir, placebo (fake) d4T (stavudine, Zerit), efavirenz (Sustiva, Stocrin) and 3TC (lamivudine, Epivir)

• d4T, placebo (fake) tenofovir, efavirenz and 3TC

The study is supposed to continue for almost three years; at the Barcelona conference, researchers released data from the first year.

Results — Changes in viral load

Equal proportions of subjects — 80% — in each group achieved a viral load of fewer than 50 copies. Moreover, they were able to maintain this level of suppression for the first year of the study. Subjects who entered the study with high viral loads (more than 100,000 copies) were just as able to have it decrease to fewer than 50 copies as did subjects who started the study with low viral loads.

Results — Changes in CD4+ cells

The changes in CD4+ cells were also similar in both groups, with subjects gaining about 168 extra CD4+ cells over the course of the first year. Those subjects who entered the study with low CD4+ counts (fewer than 200 cells) had their counts increase just as much as subjects who entered the study with higher CD4+ cell counts.

Results — Changes to lipid levels

An unexpected development was the change in lipids — cholesterol and triglycerides — detected with blood tests. On average, subjects who received d4T had significantly greater increases in lipid levels than did subjects who received tenofovir. Moreover, triglyceride levels continued to rise over the course of the study in d4T users while in tenofovir users it initially increased then remained steady.

Until recently, increased lipid levels were commonly associated with the use of other anti-HIV drugs such as protease inhibitors and, to a lesser extent, non-nukes (non-nucleoside reverse transcriptase inhibitors). Now it seems that at least one member of another class of drugs commonly called nukes (nucleoside reverse transcriptase inhibitors) — d4T — may be associated with increased lipid levels as well.

Side effects

Since subjects in both groups were relatively healthy, it is not surprising that both combinations were generally well tolerated, with only about 1% of subjects leaving the study because of severe side effects. Nonetheless, physical side effects did occur, although they were reported in only a minority of subjects as follows:

Tenofovir group

• nerve damage to the hands and/or feet (peripheral neuropathy) – 2%
• lipodystrophy – 2%

d4T group

• nerve damage to the hands and/or feet (peripheral neuropathy) – 7%
• lipodystrophy – 4%

Laboratory testing of blood samples found that about 28% of tenofovir users and 31% of d4T users had very abnormal values. This is not necessarily dangerous; however, having highly abnormal blood tests for a prolonged period of time may eventually lead to complications. Major differences in lab values between the two study groups occurred in lipid levels.

Previous experiments on animals suggested that tenofovir, in high doses, caused kidney damage as well as thinning bones. In this study, about 1% of tenofovir users developed kidney dysfunction, compared with 2% of d4T users. In regard to bone fractures, one case occurred in the tenofovir group and four in the d4T group; all of these were apparently due to some kind of "trauma" not related to HIV. In general, the thickness of the bones of tenofovir users did not change during the course of the study.

All in all, these interim results suggest that tenofovir is generally safe and useful in initial therapy when used together with other anti-HIV drugs. We look forward to the long-term results of study GS-903.

REFERENCE

Staszewski S, Gallant J, Pozniak AL, et al. Efficacy and safety of tenofovir disoproxil fumarate (TDF) versus stavudine (d4T) when used in combination with lamivudine (3TC) and efavirenz in HIV-1-infected patients naïve to antiretroviral therapy: 48-week interim results of study GS-99-903. XIV International AIDS Conference, July 7-12, 2002, Barcelona. Abstract LbOr17