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
- Amsterdam UMC, University of Amsterdam, Netherlands
- Radboud University Medical Center, Netherlands
- University College London, United Kingdom
- Imperial College London, United Kingdom
- Amsterdam UMC, University of Amsterdam, New Caledonia
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 (padj=0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj=0.048 and padj=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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Alexander O Pasternak
Neeltje A Kootstra
Funding
ZonMw (09120011910035)
- Ben Berkhout
FP7 Health (305522)
- Peter Reiss
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Julie M Overbaugh, Fred Hutchinson Cancer Research Center, United States
Ethics
Human subjects: The COBRA study was approved by the institutional review board of the Academic Medical Center (Medisch Ethische Toetsingscommissie, reference number NL 30802.018.09) and a UK Research Ethics Committee (REC) (reference number 13/LO/0584 Stanmore, London). All participants provided written informed consent. The AIMS study was approved by the institutional review board of the Academic Medical Center (protocol number NTR176). The trial is registered at https://www.isrctn.com (ISRCTN97730834). All participants provided written informed consent.
Version history
- Received: March 7, 2021
- Preprint posted: March 26, 2021 (view preprint)
- Accepted: August 7, 2021
- Accepted Manuscript published: August 13, 2021 (version 1)
- Version of Record published: September 23, 2021 (version 2)
Copyright
© 2021, Pasternak et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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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
eLife 10:e68174.
https://doi.org/10.7554/eLife.68174
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