Review 1: "Clinical Outcomes After the Introduction of Dolutegravir for Second-line Antiretroviral Therapy in South Africa: A Retrospective Cohort Study"

RR:C19 Evidence Scale rating by reviewer:

• Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

This manuscript by Asare et al describes the clinical outcomes of adults with HIV following switched to second-line antiretroviral regimens due to virologic failure, and comparing outcomes by the regimens received, including zidovudine (AZT), emtricitabine/lamivudine (XTC), dolutegravir (DTG) and TDF/XTC/DTG and lopinavir/ritonavir + AZT/XTC.

This manuscript has many strengths. The introduction makes a concise case for the study to reporting data about these regimens and outcomes from real world clinical settings, adding to what has been learned from clinical trials such as DAWNING and NADIA. The methods match their study objective and very clearly described. For this retrospective analysis, they utilized electronic medical record data from 59 facilities in the KwaZulu-Natal province of South Africa. They provide participant eligibility criteria, and a straightforward analysis plan for the primary and secondary outcomes. Their results clearly describe how they arrived at their analytic population. Their key findings were that retention in care was slightly higher among those receiving AZT/XTC/DTG (85.7%, adjusted risk ratio (aRR) 1.14, 95% confidence interval (CI) 1.03 to1.27; adjusted risk difference (aRD) 10.89%, 95%CI 2.01 to 19.78) but not different with TDF/XTC/DTG (76.9%, aRR 1.01, 95%CI 0.94 to 1.10; aRD 1.04%, 95%CI -5.03 to 7.12) compared to AZT/XTC/LPV/r (75.2%) . And that among participants retained-in-care with a 12-month viral load, viral suppression was higher with AZT/XTC/DTG (59.3%, aRR 1.25, 95%CI 1.06 to 1.47; aRD 11.57%, 95%CI 2.37 to 20.76) and TDF/XTC/DTG (60.7%, aRR 1.30, 95%CI 1.14 to 1.48; aRD 14.16%, 95%CI 7.14 to 21.18) than with the AZT/XTC/LPV/r regimen (46.7%). The discussion section situates their findings in what is known from other studies. The limitations and conclusions were accurate and well-explained. The authors effectively followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting data from observational studies.

I have given this manuscript a strong rating due to the rigor of their methods and clarity of this report, even if the impact of their findings is limited. With dolutegravir now recommended as first line treatment, the population to which their results apply will diminish over the coming years. That said, they do provide strong real-word data in support current guidelines and the common practice of using dolutegravir-based regimens as second line treatment. I was glad to see the authors highlight that one of the most concerning findings was not the differences among the regimens, but how poor the outcomes were overall with only 34.6% of people changing to second line achieving programmatic retention-in-care and viral suppression milestones at 12 months.

For the second-line treatment for people with HIV failing efavirenz or nevirapine based antiretroviral based treatment, dolutegravir-based regimens lead to comparable or better retention and virologic suppression outcomes compared to lopinavir/ritonavirbased regimens. However, overall outcomes remain poor underscoring the need for better treatment options.

REFERENCE: von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008 Apr;61(4):344-9. doi: 10.1016/j.jclinepi.2007.11.008. PMID: 18313558.