The Immune-Based Therapies and Preventive Technologies Pipeline
risk by 33% with a p-value of 0.06 (the standard threshold for significance is 0.05). A CROI audience member noted that a comparison between the PRO2000 gel group and a combination of two control groups in the trial (one that received no gel and another that received a placebo gel) would push the result into significance. To his credit, Abdool Karim explicitly resisted this illegitimate statistical maneuver because combining the control groups was not part of the prespecified plan. Abdool Karim’s caution proved prescient when the results of a far larger phase III efficacy trial of PRO2000 gel (which enrolled close to 10,000 women) were announced at the end of 2009. HIV infection rates were essentially identical between placebo and active gel recipients (Chisembele 2010). While disappointing, the outcome has reinforced a shift in microbicide research toward antiretroviral-based products. Efficacy results from an important first test of this approach—a phase IIb study of a gel form of the reverse transcriptase inhibitor tenofovir (Viread)—are expected to be released at the International AIDS Conference in Vienna on July 21, 2010. The trial started in South Africa in 2007 and is sponsored by a collaboration involving the Centre for the AIDS Programme of Research in South Africa, Family Health International, the United States Agency for International Development, LIFElab, and CONRAD. A number of other antiretroviral microbicides are advancing in human trials. The reverse transcriptase inhibitor UC-781, originally developed by Uniroyal Chemical and Biosyn, is in a phase I trial sponsored by CONRAD (Schwartz 2008). UC-781 is also being explored for potential rectal use, with encouraging results from a phase I trial published recently (Ventuneac 2010). The International Partnership for Microbicides (IPM) is developing a nonnucleoside reverse transcriptase inhibitor, dapirivine gel (licensed from Tibotec and formerly known as TMC120), that is currently in phase I/II trials. The IPM has pioneered studies of novel delivery methods, and results indicate that dapirivine can be safely delivered via a matrix intravaginal ring (Nel 2009). The push toward long-acting delivery methods for microbicides reflects longstanding concerns about the usability and efficacy of topically applied candidates. Adherence to the use of coitally dependent products has been reported to be an issue in some trials (Skoler-Karpoff 2008), and even if adherence is optimal there is evidence that the physical act of sex may affect the genital-tract distribution of a topical microbicide and thereby reduce its ability to inhibit HIV infection (Keller 2010).
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