Pharmacokinetics and Pharmacodynamics in HIV Prevention; Current Status and Future Directions: A Summary of the DAIDS and BMGF Sponsored Think Tank on Pharmacokinetics (PK)/Pharmacodynamics (PD) in HIV Prevention

Abstract

Thirty years after its beginning, the HIV/AIDS epidemic is still raging around the world. According to UNAIDS, in 2011 alone 1.7M deaths were attributable to AIDS, and 2.5M people were newly infected by the virus. Despite the success in treating HIV-infected people with potent antiretroviral drugs, preventing HIV infection is the key to ending the epidemic. Recently, the efficacy of topical and systemic antiviral chemoprophylaxis (i.e., preexposure prophylaxis or "PrEP"), using the same drugs used for HIV treatment, has been demonstrated in a number of clinical trials. However, results from other trials have been inconsistent, especially those evaluating PrEP in women. These inconsistencies may result from our incomplete understanding of pharmacokinetics (PK)/pharmacodynamics (PD) at the mucosal sites of sexual transmission: the male and female gastrointestinal and reproductive tracts. The drug concentrations used in these trials were derived from those used for treatment; however, we still do not know the relationship between the therapeutic and the preventive dose. This article presents the first comprehensive review of the available data in the HIV pharmacology field from animal models to human studies, and outlines gaps, challenges, and future directions. Addressing these pharmacological gaps and challenges will be critical in selecting and advancing future PrEP candidates and strategies with the greatest impact on the HIV epidemic.

The evolution of three decades of antiretroviral therapy: challenges, triumphs and the promise of the future

“…One small study successfully reduced the dose of efavirenz in patients with the CYP2B6 516 G→T polymorphism using adjunctive TDM [64]. The CYP2B6 516 G→T polymorphism is particularly prevalent in Black African and African American populations (up to 20%), and PK studies have demonstrated higher exposure in these populations [65].…”

Precise engineering of dapivirine-loaded nanoparticles for the development of anti-HIV vaginal microbicides

“…6A for PCL-based NPs [11,14]. These differences may be explained by HIV transmission [65], namely in the case of dapivirine [66]. 665 Results for cell monolayer retention (Fig.…”

“…Most microbicide products developed and tested so 61 far in human clinical trials have relied in semi-solid dosage forms, 62 particularly gels. These are coitally-dependent systems (i.e., require 63 administration shortly before/after intercourse) that frequently 64 lead to poor user adherence and, thus, potentially reduced ability 65 to protect against transmission [3]. However, modified and sus- 66 tained drug delivery systems, such as vaginal rings, may be prefer- 67 able and are receiving a lot of the current attention as these can 68 provide coitally-independent options for protection [4].…”

Correlation between Plasma, Intracellular, and Cervical Tissue Levels of Raltegravir at Steady-State Dosing in Healthy Women

“…Genital fluid concentrations of raltegravir are higher than plasma concentrations, an attractive quality for a PrEP agent (8,9). However, no studies have examined intracellular tissue concentrations of raltegravir in the genital tract, where the level of the drug would be critical to ensuring efficacy (10). Raltegravir is a substrate for P glycoprotein transporter, which is expressed in cervical tissue (11) and is partially regulated by progesterone (12,13), and thus intracellular concentrations could vary throughout the menstrual cycle.…”