Associations of modern initial antiretroviral therapy regimens with all-cause mortality in people living with HIV in resource-limited settings: a retrospective multicenter cohort study in China

Despite the proven virological advantages, there remains some controversy regarding whether first-line integrase strand transfer inhibitors (INSTIs)-based antiretroviral therapy (ART) contributes to reducing mortality of people living with HIV (PLHIV) in clinical practice. Here we report a retrospective study comparing all-cause mortality among PLHIV in China who were on different initial ART regimens (nevirapine, efavirenz, dolutegravir, lopinavir, and others [including darunavir, raltegravie, elvitegravir and rilpivirine]) between 2017 and 2019. A total of 41,018 individuals were included across China, representing 21.3% of newly reported HIV/AIDS cases collectively in the country during this period. Only the differences in all-cause mortality of PLHIV between the efavirenz group and the nevirapine group, the dolutegravir group and the nevirapine group, and the lopinavir group and the nevirapine group, were observed in China. After stratifying the cause of mortality, we found that the differences in mortality between initial ART regimens were mainly observed in AIDS-related mortality.

Table 1: What are the units for "Time to ART initiation"?Time to ART (%) is presumably also time to ART initiation.99.5% of people on EVG are receiving an "other" backbone.What backbone is this?Supplementary table 2 needs to be reformatted so the column indicating what the variables are is on the same page as the columns for CD4 improvement and mortality.I would move this table to the main paper.
"The proportion of PLHIV deaths and the mortality rate (per 1000 person-years) from 2017 to 2019 were shown in Figure 1B."The mortality rate is not shown in figure 1B.You should the proportion of PLHIV deaths by initial ART regimen.
In the sentence starting "In the multivariate Poisson regression model" you should define the comparator groups for the IRRs.
"We found no significant differences between patients who initiated most of the ART regimens."You need to clarify you mean differences in mortality.You found a difference for NVP.Why do you think there was this difference?Your table 1 shows that people on NVP were much older than on other regimens.This is not mentioned in the article.Why are people starting ART on NVP so much older than for other regimens?People who acquired HIV through injecting drug use were grouped into the "other" acquisition route category.However, they often have much worse prognosis.How many people included in the study acquired HIV through IDU?
In the discussion you raise these important points: "One possible reason for these findings is that long-term INSTI-based prescriptions are expensive in China.""However, the landscape of fully reimbursed ART in China before 2021 included two NNRTIs (EFV and NVP), and a single PI (LPV); along with several NRTIs.All INSTIs and most PIs were not available free of charge before 2021" "Therefore, INSTIs, including DTG, were mainly used for PLHIV who are more severely ill at the time of initiating ART and usually with CD4<200 cells/μL."(reference needed) I think it would be helpful to include this information into the introduction to help the reader better understand the context.
Was there any missing data?If so, how was this dealt with?

Response to the reviewers:
Reviewer #1 (Remarks to the Author): The manuscript by Wu et al. "Associations of modern initial antiretroviral therapy 2 regimens with all-cause mortality in people living with 3 HIV in resource-limited settings: a retrospective 4 multicenter cohort study in China" reported a large, multi-region retrospective study comparing all-cause mortality among PLHIV in China who were on different initial ART regimens between 2017 and 2019.The paper was well written and raised interesting issues, with some concerns needed to be addressed.

Authors' reply:
Thank you for this positive feedback.
1. Should provide a summarized conclusion in the "Abstract".

Authors' reply:
According to the reviewer's suggestion, we have added a summarized conclusion, and revised other parts to meet the word limit requirements of the Abstract section (page 4; line 77-90):

"Despite the proven virological advantages, there remains some controversy regarding whether first-line integrase strand transfer inhibitors (INSTIs)-based antiretroviral therapy (ART) contributes to reducing mortality of people living with HIV (PLHIV) in clinical practice. Here we report a retrospective study comparing all-cause mortality among PLHIV in China who were on different initial ART regimens (nevirapine, efavirenz, dolutegravir, lopinavir, and others [including darunavir, raltegravie, elvitegravir and rilpivirine]) between 2017 and 2019. A total of 41,018 individuals were included across
China, representing 21.3% of newly reported HIV/AIDS cases collectively in the country during this period.Only the differences in all-cause mortality of PLHIV between the efavirenz group and the nevirapine group, the dolutegravir group and the nevirapine group, and the lopinavir group and the nevirapine group, were observed in China.After stratifying the cause of mortality, we found that the differences in mortality between initial ART regimens were mainly observed in AIDS-related mortality." 2. Given that all INSTIs and most PIs were not available free of charge before 2021 in China, patients' social economic status or its proxy could be a critical confounding variable to be adjusted for when comparing the impact of NVP-based regimen versus LPV, DTG and other drugs-based regimens on CD4 improvement and mortality.This should be discussed.

Authors' reply:
We fully agree with the reviewer that the socioeconomic status could potentially affect our results and should be discussed.Due to the sensitivity of HIV data, in line with similar studies [1,2], obtaining and adjusting data on socioeconomic indicators such as income, employment status, and location of residence is challenging.However, we adjusted for a range of demographic factors (particularly region) in our multivariable models using current available data, which we believe helps to mitigate the potential impact of socioeconomic status.
We have updated our Discussion section to acknowledge the limitations regarding the potential impact of unmeasured factors (particularly socioeconomic status) on our results, and emphasized that if more data become available in the future, subsequent studies would further enhance our understanding of the topic (page 12; line 308-316): "For example, given that all INSTIs and most PIs were not available free of charge before 2021 in China, patients' socioeconomic status could potentially affect our results.Due to the sensitivity of HIV data, obtaining and adjusting data on socioeconomic indicators such as income, employment status, and location of residence is challenging, which is consistent with similar studies 19,53 .If more data become available in the future, subsequent studies would further enhance our understanding of the topic.However, we adjusted for a range of demographic factors (particularly region) in our multivariable models using current available data, which we believe helps to mitigate the potential impact of socioeconomic status."We thank the reviewer for bringing up this important issue.We have revised the Discussion section of our manuscript to acknowledge that alternative factors beyond those mentioned may contribute to this phenomenon and warranted further investigation (page 10; line 242-245): "However, we acknowledge that alternative factors beyond those mentioned may contribute to the differences in ART switch rates.Additional research is needed to further explore and elucidate the underlying reasons for these discrepancies." 4. The study period is relatively short for investigating the associations of modern initial firstline ART regimens with all-cause mortality (the main study objective) in PLWH in China, as AIDS-related deaths have been dramatically decreasing due to the overall effectiveness of treatall policy (no matter what the initiated first line regimen is) and aging-related noncommunicable chronic disease have been increasing taking over as the leading causes of death.This should be discussed as a limitation of the study.

Authors' reply:
We fully agree that the shorter study period may limit the ability to fully capture the impact of ART regimens on mortality.However, to avoid population-level interventions that could have affected the results of our study, we had to limit the study duration to three years (2017-2019).
Specifically, the implementation of the treat-all policy in China in 2016 adjusted the treatment eligibility for PLHIV [3], and the COVID-19 pandemic in 2020 had significant impacts on the HIV care continuum [4,5].We have included a discussion of this limitation in the revised manuscript and emphasized the need for long-term studies after the lifting of zero-COVID policy in December 2022 in China (page 13; line 322-327): "Finally, our study period may be relatively short to fully capture the outcomes among PLHIV.However, given the implementation of the treat-all policy in China in 2016, and the significant impact of COVID-19 on the HIV care continuum in 2020 52,54 , we had to limit the study duration to these three years.Additional long-term research is needed to further elucidate this topic after the lifting of zero-COVID policy in December 2022 in China." We also acknowledge the increasing prevalence of non-communicable chronic diseases among PLHIV, and have included an analysis of cause-specific mortality as suggested by the reviewer:  We appreciate the insightful suggestions from the reviewer and find that this updated result provides innovative insights into the effectiveness of different ART regimens in real-world practice.
5. The major outcome of the study was all-cause mortality.However, given the differential efficacy and side effects of different ARVs, it is worthy investigating the associations of ART regimens with cause-specific mortality.
Authors' reply: Thank you for your constructive feedback on our manuscript.We have conducted additional analyses on cause-specific mortality (AIDS-related mortality and non-AIDS-related mortality), and have included these results in the revised manuscript.After stratifying mortality, we found that the differences in mortality between initial ART regimens were mainly observed in AIDSrelated mortality.We find that this suggestion is highly valuable and has helped to improve the innovation and interpretability of our study results.

Reviewer #2 (Remarks to the Author):
This paper comparing outcomes for PLHIV starting on different ART regimens in China is robust.
Authors' reply: Thank you for this positive feedback.
I realise that English is unlikely to be the first-language of the authors, so I would advise the journal staff to do some English-language editing.However, the meaning of the author's sentences are still clear.
I would advise the authors to check through the paper for sentences that are unreferenced.For The authors state: "All patients were followed-up until study end (December 31, 2019)."This is not correct as you later on say that some individuals were censored before this.
You also later say "A total of 41,018 individuals were included in the analyses from January 2017 to September 2019."I believe you mean to say individuals that started ART between January 2017 and September 2019.
Authors' reply: Thank you for your comment.We have revised our manuscript accordingly to ensure clarity (page 14; line 346-347) (page 6; line 144-145): "The follow-up records were collected until study end (December 31, 2019)." "A total of 41,018 individuals who started ART between January 2017 and September 2019 were included in the analyses." "To explore the possibility of reverse causality, we stratified the follow-up time into a shortterm stratum of ≤2 years and a long-term stratum of >2 years."This is confusing.How could subsequent mortality cause someone to have been on a particular regimen beforehand?Do you mean that you are examining preferential prescribing?This analysis is not well explained and doesn't seem necessary.It also seems under-powered.I would remove it.
Authors' reply: Thank you for your constructive feedback on our manuscript.To clarify, our aim was to explore the possibility that a frailty bias could have led to preferential prescribing of certain regimens to patients who were at higher risk of death in the short term.After careful consideration and further examination of our data, we have come to the conclusion that this analysis was not necessary for our study and have removed this analysis from our manuscript.

3 .
The reason per se, raised by the authors to explain a higher rate of ART switch among patients who initiated NVP, DTG, or regimens based on other regimens compared to those who initiated EFV or LPV based is controversial.(Line 211-216, page 9) Authors' reply:

Figure 2 (
Figure 2 (part).Kaplan-Meier estimates of the cumulative incidence of ART switch, LTFU, CD4 improvement, all-cause mortality, AIDS-related mortality, and non-AIDS related mortality

"
Nonnucleoside reverse-transcriptase (NNRTI)-and PI-based ART regimens were used the most commonly in LMICs.""These regions collectively represent 20.8% of newly reported HIV/AIDS cases in China in 2019."Authors' reply: Thank you for your comment.We have carefully reviewed our manuscript and added appropriate references to the examples you mentioned (page 6; line 127-129) (page 14; line 352-354), as well as other similar sentences (page 5; line 102-104).

Table 3 (
part).Poisson regression model for the incidence of all-cause mortality, AIDS-related mortality, and non-AIDS-related mortality among people living with HIV on ART for each ART, antiretroviral therapy.NVP, nevirapine.EFV, efavirenz.DTG, dolutegravir.LPV, lopinavir.Others= darunavir, raltegravie, elvitegravir and rilpivirine.aIRR, adjusted incidence rate ratio.Poisson regression model with a time offset and robust variances was adjusted for main variables, including baseline age, sex, route of HIV acquisition, region, time to ART initiation, year of ART initiation, CD4+ T-cell counts, and NRTI backbone.NRTI, nucleotide reverse transcriptase inhibitor.