Genital Immune Cell Activation and Tenofovir Gel Efficacy: A Case-Control Study

Abstract

Genital inflammation (GI) undermines topical HIV pre-exposure prophylaxis (PrEP) efficacy through unknown mechanisms. Here, associations between activated endocervical CD4+ T cell numbers and higher deoxyadenosine triphosphate (dATP) concentrations suggest that competition for intracellular metabolites within HIV target cells may reduce the efficacy of antiretroviral-based PrEP in women with GI.

A randomized clinical trial of on-demand oral pre-exposure prophylaxis does not modulate lymphoid/myeloid HIV target cell density in the foreskin

“…This was similarly the finding with CD1a + cells in the foreskin showing that epithelial dendritic cells [ 21 , 30 ] and/or epidermal Langerhans cells [ 23 ] were consistently present across the different trial arms but unchanged in numbers. In contrast to studies using topical PrEP whereby 1% tenofovir gel increased T-cell densities in rectal tissue [ 11 ] and CD4 + T-cell activation in endocervical tissue [ 13 ], we show in our study that oral PrEP dosing has no effect on local foreskin T-cell immunity. Previously, we showed that the CHAPS study resulted in modulation of gene expression in the foreskin resulting in a potentially unfavourable environment for HIV replication [ 18 ].…”

“…Tenofovir gel has been evaluated for vaginal and rectal PrEP [ 11 , 12 ], with the CAPRISA 004 study [ 12 ] showing up to 54% lower HIV incidence in women in the gel arm. However, women receiving 1% tenofovir gel had an accumulation of activated endocervical CD4 + T cells, which were associated with increased drug metabolite levels in the tissue [ 13 ]. Although these studies focused on topically applied PrEP, their findings raise the issue of host immune activation in response to drug, which may undermine the potential efficacy of PrEP.…”

Women for science and science for women: Gaps, challenges and opportunities towards optimizing pre-exposure prophylaxis for HIV-1 prevention

“…This suggests that when TFV concentrations are below ideal levels, factors that increase target cell presence on the mucosal surface, such as inflammation or damage, would overcome the TFV protective effects. This concept is supported by CAPRISA 004 clinical data describing ideal conditions for increased intracellular metabolite competition and reduced drug efficacy in the context of inflammation and immune cell activation ( 93 ).…”