Important note: Information in this article was accurate in October 2001. The state of the art may have changed since the publication date.
American Foundation for AIDS Research, October 2001
Gretchen Schmelz
Finally, the first anti-HIV drug of the year: On October 26, the FDA approved Gilead Sciences’ tenofovir disoproxil (Viread). The new agent is indicated for the treatment of HIV infection when taken in combination with other antiretroviral agents, even though the data came from studies of treatment-experienced individuals. Tenofovir inhibits reverse transcriptase in the same manner as ddI, but requires less intracellular processing. Gilead sought accelerated approval for the once-daily 300-mg tablet based on clinical trial results from four studies, including the pivotal 902 and 907 trials.
Both pivotal studies were randomized, double blind and predominantly male. Their primary measure of efficacy was the same (time-weighted change in viral load over 24 weeks). Because these were intensification studies, tenofovir or placebo was added to a stable antiretroviral regimen that volunteers had maintained for at least eight weeks. At enrollment, participants had comparable prior treatment experience – 4.9 years for study 907 and 4.0 years for 902.
The 552 volunteers in study 907 were required to have baseline viral loads between 400 and 10,000 copies/mL. Median baseline viral load was a mere 2,400 copies/mL, and the median CD4 count was a relatively healthy 427 cells/mm3[\sup]. At 24 weeks, the mean viral load was down 0.61 log (75%) in those who received 300-mg tenofovir and 0.03 log (7%) in those who received placebo. Compared to placebo, the tenofovir group exhibited a statistically significant improvement in the proportions of volunteers who suppressed viral loads to below 400 copies/mL (42% versus 12%) and 50 copies/mL (21% versus 1%).
Study 902, a phase 2 trial, was smaller (189 participants) and had several dosage arms. The volunteers received 75 mg, 150 mg, or 300 mg tenofovir or placebo for the first 24 weeks. Then the placebo group switched to 300-mg tenofovir, while those initially on 75 mg, 150 mg and 300 mg continued their regimens for another 24 weeks. (After the first 48 weeks of follow-up, everyone took open-label 300-mg tenofovir for 24 more weeks.)
The 902 study also had less restrictive viral load inclusion criteria, 400 to 100,000 copies/mL. Median baseline viral load was again low: 5,060 copies/mL. The median CD4 count was 374 cells/mm3. At 24 weeks, the reduction in viral load was 0.26 logs (45%) for the 75-mg arm, 0.34 logs (54%) for the 150-mg arm, and 0.58 logs (74%) 300-mg arm. These decreases in viral load were stable through 48 weeks. Those receiving placebo exhibited a 24-week viral load increase of 0.02 logs (5%).
Contrary to study 907, and perhaps due to the smaller study size, there were no statistically significant differences in the proportions of people who suppressed viral loads below 400 copies/mL or 50 copies/mL.
Adverse effects were comparable to placebo in both studies. Most common events were physical debilitation (19%), headache (14%), diarrhea (22%), nausea (20%), and pharyngitis (18%). Both kidney toxicity and reductions in bone mineral density occurred in animals involved in preclinical studies, but based on the animals’ weights, their tenofovir doses were much higher than the 300-mg dose administered in human trials. The FDA concluded that there were no significant human kidney toxicity or bone abnormalities associated with tenofovir. It did stress the importance of renal monitoring over the long term. Two years ago the FDA rejected adefovir, another Gilead drug with a structure similar to tenofovir, because of adefovir’s kidney toxicity. This side effect began to appear only after six months of taking adefovir.
Most recent approvals of anti-HIV drugs have been based to a large extent on studies persons without prior therapy. There were virtually no such data presented for tenofovir. The 741 participants in the 902 and 907 trials were treatment experienced, but they had comparatively modest viral loads and high CD4 counts. The trial results do not really demonstrate tenofovir’s advantage, whether as salvage therapy or as first-line.
The FDA’s Antiviral Drugs Advisory Committee informally voted nine to seven in favor of restricting the indication to treatment-experienced people. A European review committee recently recommended the use of tenofovir only for patients in “early virologic failure.” These are people who have begun to fail on other drugs but still have low viral lows.
The FDA decided on the broadest possible indication that included anyone with HIV infection. Because the FDA OKed tenofovir under its accelerated approval regulations, the company must conduct two confirmatory studies. Gilead already has an ongoing trial to test tenofovir as part of a first-line regimen. That 96-week trial, study 903, is in progress in Europe, South America and the U.S. It compares a combination of tenofovir, 3TC and efavirenz to d4T, 3TC and efavirenz. The study enrolled 601 people, and 48-week results should be released in the first half of next year. As a second confirmatory trial, Gilead has proposed an intensification study administering tenofovir to children already on treatment.
011010
AM011004
Copyright © 2001 by the American Foundation for AIDS Research (amfAR) and first displayed on amfAR's Treatment Directory web site (http://www.amfar.org/gl). They appear on AEGIS with amfAR's permission. Organizations wishing to reprint or redistribute these materials should request authorization from amfAR's Department of Treatment Information Services (212/806-1600).
AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2001. This material is designed to support, not replace, the relationship that exists between you and your doctor.
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1990, 2001. AEGiS & the Sisters of Saint Elizabeth of Hungary. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS and the Sisters of Saint. Elizabeth of Hungary, or the party credited as the provider of the content.
