1. Medicine
  2. Microbiology and Infectious Disease
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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

  1. Alexander O Pasternak  Is a corresponding author
  2. Jelmer Vroom
  3. Neeltje A Kootstra
  4. Ferdinand WNM Wit
  5. Marijn de Bruin
  6. Davide De Francesco
  7. Margreet Bakker
  8. Caroline A Sabin
  9. Alan Winston
  10. Jan M Prins
  11. Peter Reiss
  12. Ben Berkhout
  13. on behalf of The Co-morBidity in Relation to Aids (COBRA) Collaboration
  1. Amsterdam UMC, University of Amsterdam, Netherlands
  2. Radboud University Medical Center, Netherlands
  3. University College London, United Kingdom
  4. Imperial College London, United Kingdom
  5. Amsterdam UMC, University of Amsterdam, New Caledonia
Research Article
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Cite this article as: eLife 2021;10:e68174 doi: 10.7554/eLife.68174

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

  1. Alexander O Pasternak

    Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
    For correspondence
    a.o.pasternak@amsterdamumc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4097-4251
  2. Jelmer Vroom

    Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Neeltje A Kootstra

    Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9429-7754
  4. Ferdinand WNM Wit

    Global Health, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Marijn de Bruin

    Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  6. Davide De Francesco

    Institute for Global Health, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Margreet Bakker

    Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Caroline A Sabin

    Institute for Global Health, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Alan Winston

    Medicine, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Jan M Prins

    Internal Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, New Caledonia
    Competing interests
    The authors declare that no competing interests exist.
  11. Peter Reiss

    Global Health, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  12. Ben Berkhout

    Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

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.

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.

Reviewing Editor

  1. Julie M Overbaugh, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: March 7, 2021
  2. Preprint posted: March 26, 2021 (view preprint)
  3. Accepted: August 7, 2021
  4. Accepted Manuscript published: August 13, 2021 (version 1)
  5. 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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