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Gilead vs. FDA

Winter 1999/2000

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

The FDA reviewed four controlled trials to establish the activity of adefovir 120 mg; one bridging study to evaluate the relative efficacy and safety of 60 mg versus 120 mg; and analyses on adefovir's safety (including the reversibility of nephrotoxicity) and its activity in NRTI-resistant patients. While industry wants to present its data in the best possible light, the FDA's usual stance is that new drugs are guilty until proven innocent. When in doubt, they always take the most critical possible interpretation.

Supporting Study/Regimen Population and Baselines Gilead's
The FDA's Interpretation Comments from the Peanut Gallery
Study 408
Adefovir (ADV) plus HAART vs. HAART
Treatment Experienced
N = 442
HIV RNA = 30,000 copies/ml, CD4 = 350
A 0.39 log drop, (0.28 log drop DAVG24) A significant but small 0.28 log drop DAVG24. But no difference in the percent of patients with HIV RNA<400 copies/mL, and no difference in CD4 cell response. This study did demonstrate that adefovir 120 mg could be active. Unfortunately, it also demonstrated it was toxic.
Heavily Treatment Experienced N>500 Used only to show safety. Claimed the study was not "optimally designed to look for virologic efficacy." An increase in viral load on ADV of 0.9 log vs. no change on placebo, week 24. By allowing patients to change therapy at any time post-randomization, the study was so flawed that it couldn't show anything.
ACTG 359
6 arms: ADV or delavirdine (DLV) or the combination plus either ritonavir/saquinivir (SQV) or nelfinavir (NFV)/SQV
Treatment Experienced Didn't discuss, but disputed the FDA contention that there could be a negative drug interaction between ADV and DLV or SQV. DLV triple therapy better than ADV triple therapy, and the addition of ADV to DLV did not improve responses. The FDA then cited a sub-study that suggested ADV lowered blood levels of DLV and/or SQV. It should come as no surprise that DLV (an NNRTI) was more potent than ADV. It doesn't mean that ADV had no activity. The negative interaction with DLV provided the reason why adefovir added nothing to DLV triple therapy.
Study 411
5 arms; IDV plus either AZT/3TC, AZT/ADV, 3TC/ADV, d4T/ADV or AZT/3TC/ADV
Treatment Naive
N = 224
HIV RNA ~40,000 copies/ml
CD4 = 400
ADV containing 3 drug arms all equivalent to three drug control. The ADV containing 4 drug arm was not superior to the control arm. Lots of missing data. The FDA was being a little unfair because the study was not powered to show a difference between the 4 drug and 3 drug arms. The study did show that adefovir could be substituted for AZT or 3TC in a triple combination, albeit in naive, not experienced, patients.
Study 417
ADV (60 mg vs. 120 mg) plus either NFV + NRTI or SQV + NRTI
Treatment Experienced
N = 214
HIV RNA ~40,000 copies/ml
CD4 = 360
In the comparison between doses: 60 mg arm achieved 41% and 120 mg 31% below 400 copies/ml at week 20 (intent-to-treat analysis). In an as-treated analysis, the proportions were 48% and 45%, respectively. The difference in favor of the lower dose was powered by the high drop out rate on the high dose. The FDA also noted that the high-dose + SQV arm performed dramatically worse than the other arms, and if it were excluded, low dose ADV might be as much as 25% less active than high-dose ADV. Explanation: the possible ADV/SQV interaction. Bullseye! While ADV 120 mg was modestly active, arguably, Gilead could not prove beyond the shadow of a doubt that ADV 60 mg was equivalent.

Back to the GMHC Treatment Issues Winter 1999-2000 contents page.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
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