Clinical Development of Microbicides for the Prevention of HIV Infection

Abstract

The HIV/AIDS pandemic continues its spread at a rate of over 15,000 new infections every day. Sexual transmission of HIV-1 is the dominant mode of this pandemic spread. For the first time since the disease emerged in the early 1980s, about half the 42 million people now living with HIV/AIDS worldwide are women. Worldwide, more than 90 percent of all adolescent and adult HIV infections have resulted from heterosexual intercourse. The "feminization" of the pandemic largely driven by the social, economic, and biological factors warrants urgent attention particularly for the adolescent female population. In the absence of an effective prophylactic anti-HIV therapy or vaccine, current efforts are aimed at developing intravaginal/intrarectal topical formulations of anti-HIV agents or microbicides to curb the mucosal and perinatal HIV transmission. Microbicides would provide protection by directly inactivating HIV or preventing HIV from attaching, entering or replicating in susceptible target cells as well as dissemination from target cells present in semen or the host cells that line the vaginal/rectal wall. Thus, ideally, anti-HIV microbicides should be capable of attacking HIV from different angles. In addition, a contraceptive microbicide could help prevent unintended pregnancies worldwide. To be a microbicide, these agents must be safe, effective following vaginal or rectal administration, and should cause minimal or no genital symptoms following long-term repeated usage. A safe and efficacious anti-HIV microbicide is not yet available despite the fact that more than 60 candidate agents have been identified to have in vitro activity against HIV, 18 of which have advanced to clinical testing. Targeting HIV entry has been a favored approach because it is the first step in the process of infection and several readily available anionic polymeric products seem to variably interfere with these processes are the primary candidates for potential microbicides. Formulations of some anionic polymeric antiviral agents have been tested at various doses and various durations for safety, tolerability, and acceptability in Phase I/II clinical trials (vaginal, rectal, or penile studies) in HIV-uninfected and/or HIV-infected populations. Current multicenter Phase I/II safety and Phase II/III efficacy studies that are being conducted or planned in different geographical locations by various special interest groups are designed for rapid clinical development of candidate products. The currently marketed detergent-type spermicide, nonoxynol-9 (N-9), has failed in Phase III clinical trials, due to the drug-induced formation of localized genital lesions that might in fact actually promote virus transmission. Alternative "first-generation" microbicides that have undergone Phase I/II safety and tolerability studies in HIV-uninfected and/or HIV-infected volunteers include polymeric viral fusion inhibitors (dextrin sulfate/Emmelle, carrageenans [PC-213, PC-503, PC-515/Carraguard], cellulose sulfate/Ushercell, polystyrene sulfonate, naphthale...

The paradoxical effects of using antiretroviral-based microbicides to control HIV epidemics

“…They are currently considered to be one of the most promising biomedical interventions for preventing heterosexual transmission. Because the majority of the ϳ3 million HIV infections that occur each year are in women (4,5), effective female-initiated prevention methods are urgently needed. Second-generation microbicides, containing antiretrovirals (ARVs), are now being tested for efficacy in phase III clinical trials [supporting information (SI) Table S1].…”

“…This will be closely followed by a microbicide containing dapivirine, which belongs to the nonnucleoside reverse transcriptase inhibitor (NNRTI) class of ARVs (6); trial results will be available in 2010. Three other ARV-based microbicides, containing NNRTIs, are in earlier-phase trials (3,5,(7)(8)(9)(10). ARV-based microbicides are anticipated to be highly effective; however, there is concern that, if used by HIV-positive women, class-specific drug resistance may emerge.…”

Ligand-induced and nonfusogenic dissolution of a viral membrane

“…Our data demonstrated that PAs can be effective if applied directly to the site of virus replication, in this case the respiratory system for viral pneumonia. Recent advances in the design and modification of PAs have reduced toxicity, and several anionic polymers are now in clinical trials as topical and therapeutic antiviral agents against HIV infection (47,48).…”

Pharmacokinetic study to compare the absorption and tolerability of two doses of levonorgestrel following single vaginal administration of levonorgestrel in Carraguard® gel: a new formulation for “dual protection” contraception

“…However, initial clinical studies evaluating OTC spermicides as potential microbicides had mixed results [21][22][23][24] and were eventually abandoned with the disappointing results from the COL-1492 study, showing that the OTC spermicide nonoxynol-9 (N-9) could be toxic to the vaginal tissue thereby increasing the risk of HIV infection [25]. There are other candidate microbicides currently in clinical trials that might demonstrate dual protection [26][27][28][29][30]. However, none of the products are proven contraceptives.…”