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.

Alexander Pasternak ,Mwa Caan,Mm Mangas Ruiz,Fr Janssen,Af Girigorie,Margreet Bakker,Dp Benschop,D Fuchs,M Wezel,J Berkel,Ba Schmand,Jelmer Vroom,Bc Elsenga,M Totté,M De Graaff-Teulen,Hg Ruhé,Cblm Majoie,W Zikkenheiner,Dj Sharp,Ben Berkhout,Peter Reiss,Am Harskamp-Holwerda,Davide De Francesco,Marijn De Bruin,Ja Ter Stege,Fwnm Wit,Ra Van Zoest,Alan Winston,T Van Der Kuyl,Thilo Sindlinger ,Katherine W Kooij ,Michiel Heidenrijk ,Giovanni Guaraldi ,S Zaheri ,Neeltje A Kootstra ,Ken Legg ,Marjolein Martens ,Michelle Klein Twennaar ,M.m.j Hillebregt ,Claude Libert ,Ferdinand W N M Wit ,Solange Moll ,Henrik Zetterberg ,Nicki Doyle ,Alexander Bürkle ,Paolo Garagnani ,Esmay Frankin ,David M Burger ,Otto Erlwein ,Miriam Capri ,Ieke Visser ,María Moreno‐Villanueva ,Kees Weijer ,Gert J Geurtsen ,Leighton Mcdonald ,Amy Keller ,Sergey Y Kovalev ,Claudio Franceschi ,Judith Schouten ,Irma Maurer ,Y Ruijs ,Andries Kalsbeek ,Andrew Lovell ,Thijs Booiman ,Jan M Prins ,Jonathan Underwood ,Magnus Gisslén ,Robert Leech ,J F Cole ,Matthew A Stott ,Peter Portegies ,Joris Pothof ,Jan H.j Hoeijmakers ,Mariella Chiricolo ,P.h.l.t Bisschop ,Cherry I Kingsley ,Marc Van Der Valk ,Tanja Su ,Fabio Dall’olio ,Julien Villaudy ,Caroline Sabin ,Chiara Pirazzini ,Stefano Salvioli ,Sylviane Dewaele

doi:10.7554/elife.68174

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

Highlights

In individuals who are able to adhere to combination antiretroviral therapy (ART), therapy suppresses HIV replication, restores immune function, and prevents the development of AIDS [1]
COmorBidity in Relation to AIDS (COBRA) is a cohort of HIV-infected individuals aged 45 or older with sustained HIV suppression on ART recruited from two large European HIV treatment centers in Amsterdam and London
Of 132 COBRA participants with available PBMC samples, were treated with ART that consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either one nucleoside reverse transcriptase inhibitor (NNRTI) (n=58) or one ritonavir-boosted protease inhibitor (PI) (n=42) and were included in the analysis

Summary

Introduction

In individuals who are able to adhere to combination antiretroviral therapy (ART), therapy suppresses HIV replication, restores immune function, and prevents the development of AIDS [1]. Persistence of viral reservoirs forms the major obstacle to an HIV cure [3] Viral reservoir markers, such as low-level HIV RNA in plasma (residual viremia) and cell-associated (CA) HIV DNA and RNA, can be measured in most treated individuals with plasma HIV RNA suppressed to below the limit of quantification of commercial assays [4,5,6,7,8]. No decrease in residual HIV viremia could be demonstrated in these and other intensification trials [23,24,25] It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress HIV replication. We report the results of two crosssectional 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

Results

Conclusion