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Based on pure numbers, the current pipeline for HIV drug development appears reasonably robust, with at least a dozen agents in phase II or III testing. However, few of these are likely to change treatment paradigms. Most will, at best, offer incremental benefits in terms of tolerance and convenience. The most notable drugs in the pipeline right now are bevirimat, because it represents a new drug class, and elvitegravir, GSK-572, and rilpivirine, because they have the potential to be incorporated into one-pill, once-daily regimens.
Bevirimat is a maturation inhibitor that effectively hampers the processing of the gag capsid/p2 precursor protein. However, some 40% of patients will be resistant to it because of naturally occurring polymorphisms in HIV's gag gene (JW AIDS Clin Care Nov 10 2008). Furthermore, recent studies show that prior PI treatment can result in accumulation of bevirimat resistance mutations (AIDS 2009; [e-pub ahead of print]). Consequently, baseline resistance testing will be mandatory for any patient considering bevirimat use.
Elvitegravir, a once-daily integrase inhibitor, is moving forward in phase III trials and could be approved in early 2010. Because it requires pharmacokinetic boosting, elvitegravir is being studied in combination with the new ritonavir derivative GS-9350, which has no antiviral efficacy and lacks most of ritonavir's side effects (JW AIDS Clin Care Mar 9 2009). These two compounds, along with tenofovir/FTC, are part of a new once-daily, 4-in-1 “quad pill” that is currently being studied as initial therapy.
A second-generation integrase inhibitor, GSK-572, demonstrated extremely promising anti-HIV activity in a relatively small, 10-day monotherapy study (JW AIDS Clin Care Aug 31 2009). The 50-mg dose produced an average viral-load reduction of >2 log copies/mL, and 7 of 10 patients in this dose group achieved viral loads below 50 copies/mL. No serious adverse events were reported, and no patients withdrew from the trial because of side effects. In vitro, GSK-572 was active against several raltegravir-resistant isolates. If successful in phase III studies, GSK-572 is expected to be coformulated with abacavir/3TC as another once-daily, triple-drug combination pill.
The NNRTI rilpivirine is also being evaluated in phase III studies (ECHO and THRIVE). If found to be as efficacious as efavirenz, it too will be incorporated into a fixed-dose combination, with tenofovir/FTC.