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CROI Resistance Report 7: New Drugs—Reyataz; TMC-114; Reverset
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Written for NATAP by Andrew Zolopa, MD
Stanford University
Drug Resistance, New Drugs and New Pathways: Reyataz & the 50L mutation
Given the prevalence of drug resistance and the problem of cross resistance, we continue to require new drugs with unique resistance profiles and new classes of antiretrovirals to treat many HIV infected patients in care today. The 50L mutation associated with ATV is unique to this PI and appears in vitro to not cause resistance to the other PI's. In fact, phenotypes with the 50L tend to be hypersusceptable to the other PI's in clinical isolates. Colonno and the group from BMS, reported on the resistance profile of patients failing ATV regimens from various BMS trials. [abstract 656] The investigators report that 50L is more commonly seen in PI-naïve patients who fail ATV as their first PI. In the 034 trial of PI-naive patients treated with unboosted ATV, 83% (5/6) who failed with PI resistance had the 50L mutation. In contrast, in PI-experienced patients treated with an ATV-containing regimen, the 50L mutation was seen less frequently. In the various trials of treatment-experienced patients, the 50L was observed in 0% to 35% of patients failing with new PI-resistance. In PI-experienced patients with preexisting PI resistance, the determinates for the development of 50L versus non-50L resistance pathway remain unclear -- nor is it clear what the PI sequencing implications are after failure with 50L versus a non-50L pathway.
TMC-114, new protease inhibitor for PI-resistant HIV
Investigators from Tibotec reported additional in vitro data TMC 114, a PI which demonstrates impressive in vitro activity against many PI-resistant isolates. [abstract 620] Using the Virco repository of clinical isolates, the investigators evaluated the phenotype fold change (FC) profile of TMC 114 in over 2200 samples that had at least some degree of resistance to at least one of the approved PI's (defined as IC50> 4 FC to at least one PI). The results remain encouraging from previous reports of similar data. The IC50's for TMC114 remained <4 FC for even the most highly resistant isolates. In isolates with phenotypic resistance to 6 out of 7 PI's the TMC114 FC remained <4 in nearly 80% and for isolates resistant to all 7 other PI's, TMC114 FC was less than 4 in over half the cases.
Once again TMC114 showed impressive short term virologic response in patients on failing PI regimens who had their PI switch to one of 3 different doses of TMC114, boosted with RTV (300mg/100mg BID, 600mg/100mg BID or 900mg/100mg q day) compared to a control group who remained on their failing PI. [abstract 533]. In this randomized phase 2a controlled study, 38 patients were enrolled and viral load response was monitored over 14 days. At day 14, viral load declines averaged 1.2 to 1.5 logs in the 3 TMC114 groups with maximal declines of up to 2.5 log seen. Interestingly, baseline susceptibility to TMC114 was not predictive of response. We look forward to the further development of this drug, particularly in patients with PI-resistance.
Reverset: new nuke in early study for nuke resistant HIV
Reverset (RVT-202) is a novel cytidine nRTI analog (D-D4FC) with in vitro activity against HIV-1 strains that are resistant to AZT, 3TC, TDF and others. However, the multi-nucleoside resistance patterns (69insert and Q151M complex) appear in vitro to cause resistance to RVT-202. In vitro there is no mitochondrial toxicity noted and the compound has a long intracellular half life. Rob Murphy reported a phase I, monotherapy study in antiviral naïve subjects. [abstract 137]. In this dose ranging study, 30 subjects were randomized equally to one of three doses of RVT (50mg, 100mg or 200mg) versus placebo. Subjects were dosed for 10 days with 4 weeks of follow up. Viral loads declined in all treatment groups, with average declines of 1.2 to 1.7 logs by day 10. No statistically significant differences were seen between the study arms, although a trend favored the highest dose after day 10. The plasma half live was measured at 5.2 hours and no nRTI-associated resistance emerged during the course of the study. More patients receiving the RVT had "cold symptoms" compared to the placebo group but there were no other safety concerns. We anticipate clinical trials in patients with various patterns of nRTI-associated resistance.
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