Pharmacology of HIV Cure: Site of Action

Abstract

Despite significant advances in HIV treatment over the past 30 years, critical barriers to an HIV cure persist. The HIV reservoir, defined at both the cellular and anatomical level, constitutes the main barrier to cure. While the mechanisms underlying the reservoir are not yet well understood, one theory to explain persistence at the anatomical level is that subtherapeutic exposure to antiretroviral therapy (ART) within certain tissue compartments permits ongoing replication. Characterizing ART pharmacology throughout the body is important in the context of these potential pharmacologic sanctuaries and for maximizing the probability of success with forthcoming cure strategies that rely on latency reversal and require ART to prevent reseeding the reservoir. In this review, we provide a comprehensive overview of ART and latency reversal agent distribution at the site of action for HIV cure (i.e., anatomical sites commonly associated with HIV persistence, such as lymphoid organs and the central nervous system). We also discuss methodologic approaches that provide insight into HIV cure pharmacology, including experimental design and advances within the computational, pharmaceutical, and analytical chemistry fields. The information discussed in this review will assist in streamlining the development of investigational cure strategies by providing a roadmap to ensure therapeutic exposure within the site of action for HIV cure.

Controversies in the Design of Strategies for the Cure of HIV Infection

“…They determined that in lymph nodes with diameters less than 0.1 mm (which translates to an absence of inflammation) there is no persistent viral replication despite low drug levels, although the chances of replication increase as the node size increases. Protease inhibitors [ 117 , 118 ] are the therapeutic group that diffuses the worst in this tissue, and regimens based on these drugs are the ones that could be most associated with the establishment of drug sanctuaries [ 116 ]. Tenofovir disoproxil difumarate, emtricitabine, atazanavir, darunavir and efavirenz also have poor activity in lymphoid tissue [ 112 , 118 ], as well as integrase inhibitors [ 118 , 119 , 120 , 121 ].…”

“…Protease inhibitors [ 117 , 118 ] are the therapeutic group that diffuses the worst in this tissue, and regimens based on these drugs are the ones that could be most associated with the establishment of drug sanctuaries [ 116 ]. Tenofovir disoproxil difumarate, emtricitabine, atazanavir, darunavir and efavirenz also have poor activity in lymphoid tissue [ 112 , 118 ], as well as integrase inhibitors [ 118 , 119 , 120 , 121 ]. However, there is recent evidence supporting the better diffusion of tenofovir alafenamide at the lymph node level, which would be an theoretical advantage when using these drugs [ 122 ] ( Table 1 ).…”

HIV Pharmacology Data Repository (PDR): Setting the New Information Sharing Standard for Pharmacokinetic Studies

“…3233 Additionally, strategies to cure HIV are complicated in part by pharmacological challenges (eg, limited drug distribution at effector sites such as in tissues, inadequate therapeutic efficacy, and unfavorable drug toxicity). 3435…”

Pharmacogenetics of efavirenz exposure in cervicovaginal fluid during pregnancy and postpartum

“…The understanding of antiretroviral pharmacokinetics in the female genital tract (FGT) is of growing interest in the HIV prevention field because of its importance in designing more effective therapeutic options to reduce serodiscordant and mother-to-child HIV transmission [1]. Although a number of clinical studies that focus on quantifying antiretroviral drugs in the FGT have been reported in the literature [2][3][4][5][6].…”