Dolutegravir for second-line antiretroviral therapy: the beat goes on
Authors: Nosipho Shangase, Tendesayi Kufa
Journal: The Lancet Global Health (2023)

Dolutegravir (DTG) has been recommended by the WHO for use in second-line antiretroviral therapy (ART) regimens since 2019.1WHOUpdate of recommendations on first- and second-line antiretroviral regimens. World Health Organization, Geneva2019Google Scholar The recommendation followed the findings of the multicountry, multicentre DAWNING trial, which showed superior viral suppression and fewer adverse events with DTG compared with a boosted lopinavir (LPV)-based regimen in people living with HIV who had had virological failure on a regimen based on efavirenz (EFV) or nevirapine (NVP) and had been switched to second-line therapy.2Aboud M Kaplan R Lombaard J et al.Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial.Lancet Infect Dis. 2019; 19: 253-264Summary Full Text Full Text PDF PubMed Scopus (106) Google Scholar Subsequent trials of DTG for second-line therapy showed that DTG-based regimens were either superior or non-inferior to protease inhibitors-based regimens, with or without testing for resistance when switching to a regimen containing or not a recycled nucleoside reverse transcriptase inhibitors (NRTI) backbone.3Papot E Jacoby S Arlinda D et al.Adaption of an ongoing clinical trial to quickly respond to gaps in changing international recommendations: the experience of D(2)EFT.HIV Res Clin Pract. 2022; 23: 37-46Google Scholar, 4Paton NI Musaazi J Kityo C et al.Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial.Lancet HIV. 2022; 9: e381-ee93Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 5Keene CM Cassidy T Zhao Y et al.Recycling tenofovir in second-line antiretroviral treatment with dolutegravir: outcomes and viral load trajectories to 72 weeks.J Acquir Immune Defic Syndr. 2023; 92: 422-429Crossref Scopus (1) Google Scholar, 6Mulenga LB, Fwoloshi S, Mweemba A, et al. Dolutegravir with recycled nRTIs is non-inferior to PI-based ART: VISEND trial. Conference on Retroviruses and Opportunistic Infections; Feb 12–16, 2022 (abstr 135).Google Scholar Since the non-inferiority or superiority of DTG had been analysed in clinical trial settings, Kwabena Asare and colleagues7Asare K Sookrajh Y van der Molen J et al.Clinical outcomes with second-line dolutegravir in people with virological failure on first-line non-nucleoside reverse transcriptase inhibitor-based regimens in South Africa: a retrospective cohort study.Lancet Glob Health. 2023; (published online Dec 21.)https://doi.org/10.1016/S2214-109X(23)00516-8Google Scholar decided to investigate the effectiveness of DTG-based second-line therapy in 59 routine health-care clinics in eThekwini Metropolitan Municipality, KwaZulu-Natal, South Africa. Their study, published in The Lancet Global Health, describes retention in care and viral suppression at 12 months after switching to one of two DTG-based second-line regimens (tenofovir disoproxil fumarate [TDF]/emtricitabine or lamivudine [XTC]/DTG or zidovudine [AZT]/XTC/DTG) compared with an LPV-based regimen (AZT/XTC/ritonavir-boosted LPV [LPV/r]) in people living with HIV who had virological failure on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimen.7Asare K Sookrajh Y van der Molen J et al.Clinical outcomes with second-line dolutegravir in people with virological failure on first-line non-nucleoside reverse transcriptase inhibitor-based regimens in South Africa: a retrospective cohort study.Lancet Glob Health. 2023; (published online Dec 21.)https://doi.org/10.1016/S2214-109X(23)00516-8Google Scholar This retrospective cohort study based on record review included people living with HIV aged 15 years or older switching to second-line ART from Dec 1, 2019, to Nov 30, 2020, who were followed up for over 12 months, to measure retention in care and viral suppression (<50 copies per mL) among those retained in care at 12 months.7Asare K Sookrajh Y van der Molen J et al.Clinical outcomes with second-line dolutegravir in people with virological failure on first-line non-nucleoside reverse transcriptase inhibitor-based regimens in South Africa: a retrospective cohort study.Lancet Glob Health. 2023; (published online Dec 21.)https://doi.org/10.1016/S2214-109X(23)00516-8Google Scholar Of 1214 people living with HIV included in the analysis, 689 (57%) were switched to AZT/XTC/LPV/r, 217 (18%) were switched to AZT/XTC/DTG, and 308 (25%) were switched to TDF/XTC/DTG. Retention in care at 12 months was higher for the AZT/XTC/DTG group (86%) than for the AZT/XTC/LPV/r group (75%; adjusted risk ratio [aRR] 1·14, 95% CI 1·03–1·27, p=0·012), and it did not differ between the TDF/XTC/DTG group (77%) and the AZT/XTC/LPV/r group (75%; aRR=1·01, 0·94–1·10, p=0·73).7Asare K Sookrajh Y van der Molen J et al.Clinical outcomes with second-line dolutegravir in people with virological failure on first-line non-nucleoside reverse transcriptase inhibitor-based regimens in South Africa: a retrospective cohort study.Lancet Glob Health. 2023; (published online Dec 21.)https://doi.org/10.1016/S2214-109X(23)00516-8Google Scholar Viral suppression was higher in patients on DTG-based regimens (61% of those receiving TDF/XTC/DTG, 59% of those receiving AZT/XTC/DTG) than in those on AZT/XTC/LPV/r (47%; aRRs of 1·25, 1·06–1·47, p=0·0093, and 1·30, 1·14–1·48, p<0·0001, respectively). Outcomes were also poorer in people with higher viral load at baseline, possibly indicating continuing or ongoing poor adherence. While the study confirms what clinical trials had already shown, it also highlights key gaps in DTG use for second-line therapy in resource-limited settings. First, the findings showed an early and high rate of substitution or changes to the prescribed second-line regimens, which could have been due to adverse events. Better documentation and monitoring of drug-related adverse events is needed as they affect individual adherence and programme performance.8Onoya D Nattey C Budgell E et al.Predicting the need for third-line antiretroviral therapy by identifying patients at high risk for failing second-line antiretroviral therapy in South Africa.AIDS Patient Care and STDs. 2017; 31: 205-212Crossref PubMed Scopus (0) Google Scholar Second, the findings showed suboptimal retention in care and viral suppression on second-line ART in this cohort (relative to global targets of 95%). The viral suppression was less than 76·4% at 24 months observed in a similar cohort from France.9Landman R Marcelin AG Bennani M et al.COPEDOL: a two-year observational study in pretreated HIV-1-infected patients switching to a dolutegravir-based regimen.Infect Dis Now. 2022; 52: 93-100Crossref Scopus (0) Google Scholar Additional ongoing psychosocial and adherence support is needed for these outcomes to improve, otherwise people living with HIV who fail on first-line therapy may fail again on second-line therapy, as the conditions that predisposed to failure will likely remain. How to support and maximise treatment adherence remains a challenge in many resource-poor settings. Finally, the study highlights the need for better monitoring of HIV-1 drug resistance among those with viraemia on DTG-based regimen, especially with recycled NRTI backbones.10Loosli T Hossmann S Ingle SM et al.HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis.Lancet HIV. 2023; 10: e733-e741Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Depending on the level of resistance to the NRTI backbone and associated loss of viral fitness during replication, being on a recycled DTG-based regimen could be akin to taking monotherapy or dual therapy, which are both associated with increased risk of resistance. Although DTG resistance is uncommon among those on second-line therapy and with viraemia on DTG, it does occur. Affordable technologies for detecting HIV drug resistance are needed to distinguish between people living with HIV with HIV drug-resistance and those living with HIV who have suboptimal adherence. Despite these gaps, countries need to continue scaling up DTG rollout for both first-line and second-line therapy and improve viral suppression for epidemic control. We declare no competing interests. Clinical outcomes with second-line dolutegravir in people with virological failure on first-line non-nucleoside reverse transcriptase inhibitor-based regimens in South Africa: a retrospective cohort studyThese findings from routine care support further implementation of WHO's recommendation to use DTG instead of LPV/r in people living with HIV who experience virological failure while receiving first-line NNRTI-based ART. Full-Text PDF Open Access