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

  1. Alexander O Pasternak
  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. The Co-morBidity in Relation to Aids (COBRA) Collaboration
  14. P Reiss
  15. FWNM Wit
  16. J Schouten
  17. KW Kooij
  18. RA van Zoest
  19. BC Elsenga
  20. FR Janssen
  21. M Heidenrijk
  22. W Zikkenheiner
  23. M van der Valk
  24. NA Kootstra
  25. T Booiman
  26. AM Harskamp-Holwerda
  27. I Maurer
  28. MM Mangas Ruiz
  29. AF Girigorie
  30. J Villaudy
  31. E Frankin
  32. AO Pasternak
  33. B Berkhout
  34. T van der Kuyl
  35. P Portegies
  36. BA Schmand
  37. GJ Geurtsen
  38. JA ter Stege
  39. M Klein Twennaar
  40. CBLM Majoie
  41. MWA Caan
  42. T Su
  43. K Weijer
  44. PHLT Bisschop
  45. A Kalsbeek
  46. M Wezel
  47. I Visser
  48. HG Ruhé
  49. C Franceschi
  50. P Garagnani
  51. C Pirazzini
  52. M Capri
  53. F Dall'Olio
  54. M Chiricolo
  55. S Salvioli
  56. J Hoeijmakers
  57. J Pothof
  58. M Prins
  59. M Martens
  60. S Moll
  61. J Berkel
  62. M Totté
  63. S Kovalev
  64. M Gisslén
  65. D Fuchs
  66. H Zetterberg
  67. A Winston
  68. J Underwood
  69. L McDonald
  70. M Stott
  71. K Legg
  72. A Lovell
  73. O Erlwein
  74. N Doyle
  75. C Kingsley
  76. DJ Sharp
  77. R Leech
  78. JH Cole
  79. S Zaheri
  80. MMJ Hillebregt
  81. YMC Ruijs
  82. DP Benschop
  83. D Burger
  84. M de Graaff-Teulen
  85. G Guaraldi
  86. A Bürkle
  87. T Sindlinger
  88. M Moreno-Villanueva
  89. A Keller
  90. C Sabin
  91. D de Francesco
  92. C Libert
  93. S Dewaele

  • Curated by eLife

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    Evaluation Summary:

    This study addresses how antiviral treatment regimens impact persistence of an HIV reservoir in individuals who are treated for a long period. The authors examine measures of viral reservoir to understand how different antiviral treatment regimens impact residual virus in HIV infection. They find that NNRTI-based treatments are associated with lower viral reservoirs and better viral suppression than PI-based regimens, suggesting they may have some advantage at reducing HIV levels long term.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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Abstract

It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress human immunodeficiency virus (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 an 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 adj = 0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (p adj = 0.048 and p adj = 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.

Funding:

This work was supported by ZonMw (09120011910035) and FP7 Health (305522).

Article activity feed

  1. Version published to 10.7554/elife.68174 on eLife
  2. Version published to 10.1101/2021.03.25.21254129v2 on medRxiv
  3. eLife

    Reviewer #3 (Public Review):

    The authors tested HIV-1 DNA and RNA levels in two large cohorts of ART-treated HIV-1 patient to evaluate possible differences in HIV-1 reservoir cell markers between NNRTI- and PI-based ART regimens, this question is relevant since millions of people living with HIV are currently receiving HIV treatment with these agents. Their major finding is that NNRTI-based treatment is associated with reduced cell-associated HIV-1 RNA and DNA levels; this finding is not entirely novel and well in line with a number of previous observations. The strengths of the study are the large clinical cohorts for which detailed clinical and demographical data are available. The analysis of HIV-1 DNA and RNA is informative, but the assays used do not distinguish between replication-competent and defective proviral species; this is appropriately identified as a limitation of this work. The authors do not address possible immunological consequences of higher HIV DNA levels in PI-treated patients - is this associated with higher levels of inflammatory markers? In addition, it is possible that higher levels of cell-associated HIV-1 RNA may stimulate cell-intrinsic innate (type I IFN-mediated) immunity in PI-treated patients - an aspect that the authors do not address. In the absence of such additional immunological data, it is difficult to assess the true significance and importance of the described observations.

  4. eLife

    Reviewer #2 (Public Review):

    This is a well-written study that will be of interest to many investigators working in the field of HIV persistence during ART. The strengths of the study include the analysis of samples from two relatively large cohorts of individuals (n= 100 and 124) and the use of multivariable models to adjust for numerous parameters. One weakness is the fact that the authors do not consider alternative models that may explain their results. The data is important but should not be overinterpreted, because it does not demonstrate that NNRTI have a better ability to suppress HIV replication. It shows that NNRTI usage is associated with lower levels of HIV persistence markers but does not provide a mechanistic explanation for that (and should not attempt to do so, at least not in the abstract). Overall, this is a well-conducted and important study, with new findings that have potential clinical implications.

  5. eLife

    Reviewer #1 (Public Review):

    The authors examine measures of viral reservoir to understand how different antiviral treatment regimens impact residual virus in HIV infection. They find that NNRTI-based treatments are associated with lower viral reservoirs than PI-based regimens, suggesting they may have some advantage at reducing HIV levels long term.

  6. eLife

    Evaluation Summary:

    This study addresses how antiviral treatment regimens impact persistence of an HIV reservoir in individuals who are treated for a long period. The authors examine measures of viral reservoir to understand how different antiviral treatment regimens impact residual virus in HIV infection. They find that NNRTI-based treatments are associated with lower viral reservoirs and better viral suppression than PI-based regimens, suggesting they may have some advantage at reducing HIV levels long term.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

  7. Version published to 10.1101/2021.03.25.21254129v1 on medRxiv