PONE-D-19-25671

The impact of short term Antiretroviral Therapy (ART) interruptions on longer term maternal health outcomes – a randomized clinical trial

PLOS ONE

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Reviewer #1: This pre-planned analysis from PROMISE trial evaluated the impact of short term antretroviral therapy, followed by periods of treatment interruption on long- term maternal health outcomes.

Specifically this analysis focused on two pre-specified comparisons of the effect of maternal combination ART used only during the ante-partum period and the effect of maternal combination ART given only during the breastfeeding period followed by treatment interruption unless the women met standard -of –care treatment criteria.

The primary outcome was progression to AIDS or death. Secondary efficacy outcomes included time to WHOII/III clinical events. The secondary safety outcome included selected Grade 2 laboratory abnormalities and all Grade 3 or higher laboratory values and signs and symptoms.

The results showed that the rate of progression to AIDS and/or death was similar and low across all the comparison arms.

So Authors underline that this result provides reassurance that there were limited consequences for short term ART, followed by treatment interruptions, among pregnant and breastfeeding post -partum asymptomatic HIV infected women living in resource limited settings.

The study procedures are correct, sample size adequate, study outcomes clear, statistical analysis done well and the whole contribution is relevant.

I would like to ask Authors just a few questions:

Can they better clarify what they mean with treatment interruption (duration, start and stop criteria)?

Can they comment on the apparent contrast with the 2015 WHO recommendation to use lifelong ART initiated at the time of diagnosis?

Bearing in mind that people with undetectable viral load are significantly less likely to transmit virus and collectively individuals with lower viral load lead to communities with lower viral load so with less risk of HIV transmission, can Authors comment on that?

In order to ameliorate adherence even in resource limited settings, would Authors suggest to test simpler and better tollerated regimens instead of shorter periods of treatment?

Reviewer #2: Authors presented a sub-study of a trial conducted from 2011 to 2014 in Africa and India.

I found this study of limited interest in its field. The first reason is that the study has been conducted from 2011 to 2014 and I feel that these data are too much old to be applied today in clinical settings. International guidelines recommendations are constantly evolving; therefore, we have now robust evidence that immediate ART start is important to have a good clinical outcome.

The observation that in 1-4 years we will not have an excess in mortality is related to the fact that people included in this trial were almost immunocompetent. However, this explanation is not sufficient to understand these results. Moreover, the message that ART could be delayed I feel is quite dangerous for scientific community.

The comparison with START trial is not appropriate in this point of view. Nonetheless, the strong recommendations to have universal access to ART is related not only to the mortality risk but also to reach the goal in reducing chronic inflammation and immune activation.

I found the study almost forced in the conclusions.

Abstract: in the abstract are unclear the treatment options and the outcomes. Authors stated “The first analysis compared ART use limited to the antepartum period (AP-only) relative to women randomized to Zidovudine”. This is not an objective of a RCT.

The objectives and Methods are unclear and in particular is not clear as the RCT PROMISE is involved in this study. Actually, in the result section, Authors seem to compare two cohort and not two arms of a RCT.

Moreover, the paper is difficult to understand: study procedures are confusing and nor clear. Discussion is too long

Reviewer #3: This is a model of a well-written clinical trials paper from a statistical standpoint, following the CONSORT document to the letter. I have 2 minor questions:

1. In the original sample size section on page 10, it would be helpful to know what was observed, as well as what was assumed.

2. The lower than expected rates of disease progression are problematic. Was it considered to analyze the data using

techniques for small event rates (e.g., exact analyses) given that we have the computational resources now to do rare events simulation and exact nonparametric inference. Even more interesting would be a randomization test using censored logrank scores and re-randomization of 100,000 randomization sequences (see Rosenberger and Lachin, 2016, Randomization in Clinical Trials, Wiley).

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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The impact of short term Antiretroviral Therapy (ART) interruptions on longer term maternal health outcomes – a randomized clinical trial

PONE-D-19-25671R1

Dear Dr. Atuhaire,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Giuseppe Vittorio De Socio, MD, PhD

Academic Editor

PLOS ONE

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