Overcoming pharmacologic sanctuaries

Abstract

Purpose of review Current antiretroviral treatment regimens represent significant improvements in the management of HIV-1 infection; however, these regimens have not achieved a functional or sterilizing cure. One barrier to achieving a cure may be suboptimal antiretroviral concentrations in sanctuary sites throughout the body, including the central nervous system, gut-associated lymphoid tissue, lymph nodes, and tissue macrophages. This review will focus on the problems associated with achieving effective concentrations in these restricted sanctuary sites, and potential strategies to overcome these barriers. Recent findings Sufficient data exist to conclude that antiretroviral drug distribution is not uniform throughout the body. Low tissue/reservoir concentrations may be associated with viral replication. Multiple means to increase drug concentrations in sanctuary sites are being investigated, including modification of currently utilized drugs, blockade of transporters and enzymes that affect drug metabolism and pharmacokinetics, and local drug administration. Accumulating data suggest these methods increase antiretroviral concentrations in reservoirs of viral replication. No method has yet resulted in the complete clearance of HIV. Summary New strategies for increasing antiretroviral concentrations in predominant sites of viral replication may provide more effective means for elimination of viral sanctuaries. Additional research is necessary to optimize antiretroviral tissue distribution in order to inhibit virus replication fully, and avoid resistance and replenishment of viral reservoirs that may persist in the face of antiretroviral therapy.

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

“…Although several factors may contribute to the formation of the viral reservoir in the GALT, subtherapeutic concentrations of ARVs in the intestinal tissue and the potential for emergence of drug resistance may play a role in the observed local HIV replication. Indeed, previous studies have demonstrated that ARVs can have low and often subtherapeutic concentrations in lymphocytes isolated from the ileum and rectum-associated lymphoid tissue even in subjects receiving long-term ART who have undetectable plasma viral loads and that these low drug concentrations are associated with high viral counts detected in these tissues (10,11,43). Although tissue drug concentrations in the upper intestinal tract have not been investigated to date, formation of a viral reservoir is observed in GALT tissue isolated from the upper jejunum of HIV-infected subjects (6,31).…”

“…Some studies also suggest that poor drug penetration into these intestinal tissues may contribute to the lack of a local therapeutic response and the establishment of an HIV reservoir at this site (10,11). While drug transporters and metabolic enzymes are known to play a key role in drug disposition at the level of the intestinal epithelium and are suggested to contribute to the persistence of this viral reservoir, experimental evidence to support this rationale is currently lacking (9).…”

“…Antiretroviral drugs (ARVs) are reported to have highly variable penetration into the ileal and rectal tissues of HIV-infected subjects, and in some cases the tissue concentrations are significantly lower than therapeutic levels required for effective antiviral activity and much lower than the concentrations detected in plasma samples from the same individuals (9)(10)(11). Some studies also suggest that poor drug penetration into these intestinal tissues may contribute to the lack of a local therapeutic response and the establishment of an HIV reservoir at this site (10,11).…”

Infection par le virus de l’immunodéficience humaine

“…Il existe néanmoins une grande hétérogé-néité entre ces molécules en ce qui concerne leur séquestration par les protéines plasmatiques, leurs caractéristiques physico-chimiques et leur métabolisation intracellulaire [14,35]. Le développement de nouvelles molécules ayant de meilleures propriétés d'absorption intestinale, de distribution tissulaire et une demi-vie allongée comme le ténofovir alafenamide (TAF), commencent à répondre au problème de sous-exposition du compartiment digestif au TARV [36]. Une autre option destinée à juguler la réplication virale dans le GALT est l'intensification thérapeutique (Tableau I).…”

Can We Repurpose FDA-Approved Alefacept to Diminish the HIV Reservoir?

“…Apart from memory CD4 + T cells, HIV compartmentalization occurs both at the cellular level as well as different anatomical sites referred to as "viral sanctuaries" [60]. The CD4 + monocytemacrophage cell lineage including circulating monocytes, may contribute to the HIV reservoir.…”