Icides for prevention of HIV infectionmacaques.76,77 After careful pharmacokinetic and safety studies, TFV 1 gel was evaluated in Phase IIb studies in women for its efficacy to prevent sexual transmission of HIV 78 The Centre for the AIDS Program of Research in South . Africa (CAPRISA) 004 study for the first time indicated that PrEP with TFV was successful in prevention against HIV infection.79 The dosing regimen comprised using gel within 12 hours before coitus and a second dose as soon as possible after coitus but not exceeding 24 hours of the first dose. The success of this study has buoyed the microbicide field, providing the first proof of principle that vaginal microbicide gels can successfully function in a clinical trial setting to reduce the rate of HIV transmission. The TFV gel users were 39 less likely to become infected with HIV than other women, who received a placebo gel. TFV gel also reduced the rate of new genital herpes infections.80 The Microbicide Trials Network (MTN) conducted another Phase IIb safety and efficacy trial the Vaginal and Oral Interventions to Control the Epidemic (VOICE) study that tested two different HIV-prevention methods, oral PrEP (Viread and Truvada and a vaginal microbicide gel (1 TFV), with both pills and gel used daily regardless of sexual activity. Both the oral Viread and Truvada arms failed to show any effective decrease in HIV transmission. Further, HIV incidence was almost identical in women using TFV gel and the ones using placebo gel. As a result, both the TFV-gel and placebo-gel arms have now been stopped. The reasons for the differential efficacy of TFV 1 gel to prevent HIV transmission in the CAPRISA 004 and VOICE studies are not clear. One of the possible reasons may be the adherence towards usage of microbicides as advised.81 Prior to the announcement of VOICE results, another Phase III efficacytrial of TFV 1 gel was initiated in South Africa Follow-on African Consortium for Tenofovir Studies (FACTS) 001 using the same dosing regimen as in the CAPRISA 004 trial.Fmoc-Cys(Trt)-OH The study is likely to be completed in 2014 (Table 2). HIV-1-specific NNRTIs compared to NRTIs have the advantage of a very high therapeutic index and acting directly (without metabolization) against the virus replication. Two NNRTI-based microbicides, TMC120 (dapivirine) and UC781, are the most advanced in clinical trials as potential topical microbicides, and usually require at least two mutations before viral resistance occurs.82,83 These small molecules with low solubility in water or physiological fluids have the potential to form a long-lasting “depot” at sites susceptible to cervicovaginal HIV infection. This could allow application of the microbicide well before sexual intercourse.Metformin hydrochloride 84 However, the extremely poor water solubility of UC781 leads to a great challenge for its formulation development.PMID:35227773 A betacyclodextran-based drug-delivery system is being developed to enhance the aqueous solubility of UC781.85 Recently, an ongoing, multicenter, randomized, double-blind, Phase IIb clinical trial concluded that lersivirine (UK-453,061), a next generation NNRTI, is safe and displayed comparable efficacy to efavirenz in the treatment of na e HIV-1-infected patients.86 Among the integrase inhibitors, raltegravir was the first to be approved by the FDA, in 2007, to overcome the problem of multidrug resistance in AIDS patients. In August 2012, elvitegravir was also approved by the FDA as the second integrase inhibitor.87 S.
