Pharmacodynamic Activity of Dapivirine and Maraviroc Single Entity and Combination Topical Gels for HIV-1 Prevention.

PURPOSE: Dapivirine (DPV), a non-nucleoside reverse transcriptase inhibitor, and maraviroc (MVC), a CCR5 antagonist, were formulated into aqueous gels designed to prevent mucosal HIV transmission. METHODS: 0.05% DPV, 0.1% MVC, 0.05% DPV/0.1% MVC and placebo gels were evaluated for pH, viscosity, osmolality, and in vitro release. In vitro assays and mucosal tissues were used to evaluate anti-HIV activity. Viability (Lactobacilli only) and epithelial integrity in cell lines and mucosal tissues defined safety. RESULTS: The gels were acidic and viscous. DPV gel had an osmolality of 893 mOsm/kg while the other gels had an osmolality of <100 mOsm/kg. MVC release was similar from the single and combination gels (~5 µg/cm(2)/min(1/2)), while DPV release was 10-fold less from the single as compared to the combination gel (0.4331 µg/cm(2)/min(1/2)). Titrations of the gels showed 10-fold more drug was needed to protect ectocervical than colonic tissue. The combination gel showed ~10- and 100-fold improved activity as compared to DPV and MVC gel, respectively. All gels were safe. CONCLUSIONS: The DPV/MVC gel showed a benefit blocking HIV infection of mucosal tissue compared to the single entity gels. Combination products with drugs affecting unique steps in the viral replication cycle would be advantageous for HIV prevention.

Adjusting for time-dependent sensitivity in an illness-death model, with application to mother-to-child transmission of HIV.

In mother-to-child transmission of HIV, identifying infected infants relies on a diagnostic test with imperfect sensitivity that is administered at scheduled visits. Under this scenario, a participant's true state may be unknown at the start and end times of the study, and the detection of transitions into illness may be delayed or missed altogether. This could lead to biased estimates of the risk of transmission and covariate associations. When a test has imperfect sensitivity, but perfect specificity, the additional uncertainty can be captured as a random variable measuring delay in detection. The cumulative distribution then defines a time-dependent sensitivity function that increases over time. We present a maximum likelihood based illness-death model that accounts for imperfect sensitivity by including the delay as an exponential distribution. We specify transition rates as penalized B-splines to allow for nonhomogeneity of risk and discuss the model under Markov and semi-Markov assumptions. We apply this method to our motivating data set, a study of 1499 mother and infant pairs at three sites in Africa.

A collaborative initiative to improve the care of elderly Medicare patients with hypertension.

Qualidigm, the Connecticut Quality Improvement Organization (QIO), collaborated with 17 primary care physicians (PCPs) in private practice to improve the care of elderly patients with hypertension. Patients were identified from Medicare billing data and care was assessed from medical records. Improvement interventions included feedback of baseline performance data and provision of a variety of practice enhancing materials. Care was assessed for 590 patients in 1997 (16-47 patients/PCP) and 547 patients in 1999 (7-51 patients/PCP). Patient characteristics were similar in both periods. Use of recommended therapies and blood pressure control, ie, percent < 140/90 mm Hg, was low and did not improve significantly between the 2 periods (aggregate 39% in 1997 versus 42% in 1999; P = .24). Care of elderly patients with hypertension was not improved with a multifaceted QIO intervention. Additional study is required to determine incentives, barriers, and facilitating factors for quality improvement in the private practice primary care setting.