ABSTRACT
PURPOSE: 5-chloro-3-[phenylsulfonyl] indole-2-carboxamide (CSIC) is a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 which has been shown to have a more desirable resistance profile than other NNRTIs in development as HIV prevention strategies. This work involves generation of preformulation data for CSIC and systematic development of a cosolvent system to effectively solubilize this hydrophobic drug candidate. This system was then applied to produce a polymeric thin film solid dosage form for vaginal administration of CSIC for use in prevention of sexual acquisition of HIV. METHODS: Extensive preformulation, formulation development, and film characterization studies were conducted. An HPLC method was developed for CSIC quantification. Preformulation tests included solubility, crystal properties, stability, and drug-excipient compatibility. Cytotoxicity was evaluated using both human epithelial and mouse macrophage cell lines. Ternary phase diagram methodology was used to identify a cosolvent system for CSIC solubility enhancement. Following preformulation evaluation, a CSIC film formulation was developed and manufactured using solvent casting technique. The developed film product was assessed for physicochemical properties, anti-HIV bioactivity, and Lactobacillus biocompatibility during 12-month stability testing period. RESULTS: Preformulation studies showed CSIC to be very stable. Due to its hydrophobicity, a cosolvent system consisting of polyethylene glycol 400, propylene glycol, and glycerin (5:2:1, w/w/w) was developed, which provided a uniform dispersion of CSIC in the film formulation. The final film product met target specifications established for vaginal microbicide application. CONCLUSIONS: The hydrophobic drug candidate CSIC was successfully formulated with high loading capacity in a vaginal film by means of a cosolvent system. The developed cosolvent strategy is applicable for incorporation of other hydrophobic drug candidates in the film platform.
ABSTRACT
CONTEXT: Long-term adherence to antiretrovirals is critical for sustained virologic response to HIV therapy in blood. Although antiretroviral therapy (ART) reduces HIV seminal shedding, little is known about the relationship between adherence to ART and HIV suppression in semen. OBJECTIVE: To determine predictors of seminal HIV RNA suppression after 6 months of ART. DESIGN: Prospective observational cohort of 93 HIV-infected subjects before and after introduction of ART. Seminal HIV RNA was measured at baseline and 1, 2, 3, and 6 months after the introduction of therapy. Adherence to therapy was measured by self-report. SETTING: A large academic HIV reference center in Rio de Janeiro, Brazil. MAIN OUTCOME MEASURE: Detectable HIV RNA in semen. RESULTS: In a multivariate logistic model with undetectable seminal HIV RNA after 6 months of therapy as the outcome variable, adjusting for baseline seminal viral load, both being adherent to therapy (OR = 11.8, < 0.01) and using triple-drug ART (OR = 6.48, = 0.04) were independently associated with seminal HIV RNA suppression. CONCLUSIONS: Inability to adhere to therapy was strongly associated with persistent shedding of HIV RNA in semen. Measures to improve adherence are urgently needed to reduce the sexual spread of potentially drug-resistant HIV among subjects using antiretrovirals.
Subject(s)
Antiviral Agents/therapeutic use , HIV Infections/drug therapy , HIV/isolation & purification , RNA, Viral/isolation & purification , Semen/virology , Adult , Cohort Studies , HIV Infections/psychology , HIV Infections/virology , Humans , Male , Multivariate Analysis , Patient Compliance , Time FactorsABSTRACT
Determina a influência da NG associada a leucócitos polimorfonucleares - PMNsobre a replicação do HIV I. Para análise da replicação viral foram utilizadas células monocíticas pré-infectadas pelo HIV I. Para o ensaio bacteriano utilizou-se uma cepa de NG classificada como PorB3 serovar, pilli e opa positivas. A NG , isoladamente ou em associação ao PMN, aumentou significativamente a replicação in vitro do HIV I