Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels as compared with therapy based on protease inhibitors

Abstract

BACKGROUND: It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress HIV replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). METHODS: CA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n=100, n=124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically measured adherence to ART. RESULTS: In both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho=0.70 and rho=0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (p=0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (p=0.048 and p=0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals. CONCLUSIONS: All current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size.

Integrated analysis of viral blips, residual viremia, and associated factors in people with HIV: Results from a retrospective cohort study

“…30 Indeed, some studies into reservoir measures like cell-associated HIV RNA and DNA have shown a correlation between these measures and RV, suggesting that RV is at least partially indicative of the reservoir size. 28,31 In contrast to the association between Fiebig stage and RV, no statistically significant impact of Fiebig stage on blips was found in this study, but both blips and ART initiation in the acute phase of infection were relatively rare, precluding a rigorous assessment of their potential relationship.…”

“…Moreover, an inverse relationship between CD4 + nadir and HIV‐1 proviral DNA in circulating CD4 + T cells on ART has previously been suggested to either reflect the repopulation of the CD4 + compartment after ART initiation by the relatively highly frequent infected CD4 + T cells harboring HIV‐1 (proviral) DNA (resulting in a larger reservoir) or the incomplete suppression of HIV‐1 replication in PWH with low CD4 + nadirs 30 . Indeed, some studies into reservoir measures like cell‐associated HIV RNA and DNA have shown a correlation between these measures and RV, suggesting that RV is at least partially indicative of the reservoir size 28,31 . In contrast to the association between Fiebig stage and RV, no statistically significant impact of Fiebig stage on blips was found in this study, but both blips and ART initiation in the acute phase of infection were relatively rare, precluding a rigorous assessment of their potential relationship.…”

Qualitative plasma viral load determination as a tool for screening of viral reservoir size in PWH

“…Kumar et al [40] have found significantly lower levels of integrated DNA in resting CD4 + T cells from PWH on protease inhibitor-based regimens compared with NNRTI-based regimens. Moreover, it was recently shown by Pasternak et al [41] that NNRTI-based regimen is associated with lower reservoir size (measured as CA-RNA and CA-DNA) compared with protease inhibitor-based regimens. Additionally, a large study of Darcis et al [42] showed that the probability of having a detectable viral load below 20 copies/ml (target detected) decreases over time and that protease inhibitor-based ART regimens are associated with a significantly higher probability of detectable residual virus compared with NNRTI or INSTI-based ART regimens.…”

Persistent HIV-1 transcription during ART: time to reassess its significance?

“…Once integrated, the provirus persists for the lifetime of the cell, and division of an infected cell provides each progeny cell with a copy of the integrated provirus. The reservoir persists primarily through cellular longevity and proliferation [8–12], although replenishment by low-level residual virus replication, for example due to limited penetration of antiretroviral drugs into tissues, has been suggested to contribute as well [13–15].…”