1. 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.

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  2. 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.

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  3. 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.

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  4. 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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