Review 2: "Clinical Outcomes After the Introduction of Dolutegravir for Second-line Antiretroviral Therapy in South Africa: A Retrospective Cohort Study"

Thanyawee Puthanakit; Torsak Bunupuradah

doi:doi:10.1162/2e3983f5.1f00fa58

Clinical outcomes after the introduction of dolutegravir for second-line antiretroviral therapy in South Africa: a retrospective cohort study

by Kwabena Asare, Yukteshwar Sookrajh, Johan van der Molen, Thokozani Khubone, Lara Lewis, Richard J Lessells, Kogieleum Naidoo, Phelelani Sosibo, Rosemary van Heerden, Nigel Garrett, and Jienchi Dorward

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Published on Jul 08, 2023
www.medrxiv.org

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ABSTRACT Background Dolutegravir is now recommended for second-line anti-retroviral therapy (ART) in low- and middle-income countries. We compared outcomes with dolutegravir (DTG) versus the previous lopinavir/ritonavir (LPV/r) regimen in South Africa.Methods We used routinely collected, de-identified data from 59 South African clinics. We included people living with HIV aged ≥ 15 years with virologic failure (two consecutive viral loads ≥1000 copies/mL) on first-line tenofovir disoproxil fumarate (TDF)-based ART and switched to second-line ART. We used modified Poisson regression models to compare outcomes of 12-month retention-in-care and viral suppression (<50 copies/ml) after switching to second-line regimens of zidovudine (AZT), emtricitabine/lamivudine (XTC), DTG and TDF/XTC/DTG and AZT/XTC/LPV/r.Findings Of 1214 participants, 729 (60.0%) were female, median age was 36 years (interquartile range 30 to 42), 689 (56.8%) were switched to AZT/XTC/LPV/r, 217 (17.9%) to AZT/XTC/DTG and 308 (25.4%) to TDF/XTC/DTG. Retention-in-care was higher with AZT/XTC/DTG (85.7%, adjusted risk ratio (aRR) 1.14, 95% confidence interval (CI) 1.03 to 1.27; 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%). Retention-in-care with TDF/XTC/DTG was not statistically significantly different from AZT/XTC/DTG (aRR 0.89, 95%CI 0.78 to 1.01; aRD - 9.85%, 95%CI -20.33 to 0.63). Of 799 participants who were 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%).Interpretation DTG-based second-line regimens were associated with similar or better retention-in-care and better viral suppression than the LPV/r-based regimen. TDF/XTC/DTG had similar viral suppression compared to AZT/XTC/DTG.Funding Bill & Melinda Gates Foundation, Africa Oxford Initiative.

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:

The study supports WHO recommendation of dolutegravir use replacing LPV/r for second-line regimen in resource-limited settings where the HIV drug resistance testing was not routinely performed. Use of recycling TDF in second-line regimen provided implementation benefit of using fixed dose combination of TDF/XTC/DTG single tablet regimen in second-line regimen.

The authors reported real world treatment outcome; 12-month retention in care and virological suppression rate of DTG-based second-line regimens from KwaZulu-Natal province, South Africa. The retrospective data of 1214 adult living with HIV (median age of 36 years old) who failed first line NNRTI-based regimen and initiated second-line regimen during December 2019 to November 2020. The median time on first line regimen was 2.9 years

The result showed retention in care was higher with AZT/XTC/DTG (85.7%) compared with AZT/XTC/LPV/r (75.2%), and similar with TDF/XTC/DTG (76.9%). The HIV viral suppression rate < 50 copies/ml threshold were AZT/XTC/DTG (59.3%) compared with AZT/XTC/LPV/r (46.7%), and similar with TDF/XTC/DTG (60.7%). The adjusted relative risk (aRR) was 1.25 (95% CI 1.06 to 1.47) for AZT/XTC/DTG regimen and 1.30 (95%CI 1.14 to 1.48). The HIV viral suppression rate < 1000 copies/ml threshold were AZT/XTC/DTG (86.0%) compared with AZT/XTC/LPV/r (69.4%), and similar with TDF/XTC/DTG (78.1%).

The study conclusion was in line with finding from clinical trials, DAWNING study (showed superiority of DTG vs LPV/r-based second line regimen) and NADIA study (showed non inferiority of recycling TDF versus AZT in second-line regimen when use in combination with DTG).

The study support WHO recommendation of dolutegravir use replacing LPV/r for second-line regimen in resource-limited settings. The real world data showed lower retention rate and virological suppression rate than clinical trial settings. The public health intervention such as enhanced adherence counselling and improved retention are warranted.

Review 2: "Clinical Outcomes After the Introduction of Dolutegravir for Second-line Antiretroviral Therapy in South Africa: A Retrospective Cohort Study"

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