Tenofovir DF 907 study
Graeme Moyle, M.D. for The Body
The idea of intensification was previously, relatively successfully investigated in the abacavir development program and has the advantage of helping develop algorithms based on baseline resistance patterns to guide drug use in clinical practice.
Intensification has fallen in and out of fashion over the years. Part of the problem is that if it works it’s great and a smart choice has been made. The downside is it may not always work and risks squandering a potentially useful drug “foolishly.”
Those who use intensification apply rules for its implementation based around limiting unfavourable outcomes — don’t use a new drugs class, don’t use a drug to which resistance develops easily (e.g., NNRTIs, 3TC), choose patients with low viral load, check resistance beforehand to help guide the likelihood that the new agent will be active. Approaches include adding protease inhibitor booster drugs (e.g., RTV, DLV) for pharmacokinetic intensification, immune modulators (hydroxyurea with ddI, mycophenylate with ABC), or single agents from backbone classes (ABC, less commonly ddI).
Dr. Anton Pozniak presented new data on the use of tenofovir as an intensification agent. This was a double-blind, placebo-controlled study of 552 randomised patients with viral loads of 400-10,000 copies/ml who received either tenofovir 300mg od (n=368) or placebo. ART was required to be stable for >8 weeks and include a regimen with <4 co-medications (not counting ritonavir 100mg BID). Data were presented over 24 weeks follow-up. Baseline characteristics included viral load of 4,502 and 4,366 cps/ml and CD4 cell counts of 417 and 447/mm3 in the tenofovir and placebo arms respectively. Mean prior ART was for >5 years.
Only 6% of patients in each arm discontinued, 3% in each case related to adverse events. No differences in the rate or type of adverse events of all grades were observed between arms. Specifically, no substantial changes in creatinine (a measure for kidney function) were observed.
Viral load fell by a time-weighted average (called DAVG) of 0.61 log10 compared with 0.03 log10 in the placebo arm. This difference was statistically significant. Suppression of viral load to <400copies/ml (45% vs. 13%) and to <50copies/ml (22% vs. 1%) and time-weighted average change in CD4 (+12 vs. -10) also significantly favoured the tenofovir intervention.
Analysis of response by baseline mutations was also performed in a subset of 253 participants. In vitro, the presence of the 3TC/FTC/ABC selected mutation M184V appears to increase the activity of tenofovir. This appears also to be the case in patients, although the increase was modest. Those with no M184V at baseline had an average 0.42 log drop in viral load, whereas those with M184V (+/- other mutations) had a 0.63 log drop, and those with just the M184V in reverse transcriptase had a viral load decline of 0.81 log. On the other hand, thymidine-selected mutations (at codons 41, 67, 70, 210, 215 and 219) had a modest (non-significant) negative impact of tenofovir’s benefits, reducing it from 0.67 log without these mutations and 0.50 log with them. In this case, adding M184V did not increase tenofovir’s effects. The K65R mutation selected by tenofovir in vitro was present in 3% of patients at baseline and was noted to eliminate the benefits of tenofovir. Additionally, the K65R mutation arose in just five patients by week 24 and was associated with loss of viral effects. New mutations in reverse transcriptase for nucleoside analogues (15% vs. 22%), NNRTI (5% vs. 9%) and in protease (2% vs. 8%) all tended to be less common in the tenofovir relative to the placebo recipients.
A success rate of undetectability of 22% below 50 copies/ml may not be considered a great response to many physicians. That being said, assessment of a strategy depends on both risks and benefits. Tenofovir reduced viral load substantially without adverse events over 24 weeks and with a very infrequent development of new mutations, suggesting that the benefits come with few risks.
Pozniak AL et al. Tenofovir DF: A 24 week interim analysis from a phase III randomised, double blind, placebo controlled study in antiretroviral experienced patients. 8th ECCATH, Athens 2001. Abstract O17.