Dolutegravir Plus Two Nucleoside Reverse Transcriptase Inhibitors versus Efavirenz Plus Two Nucleoside Reverse Transcriptase Inhibitors As Initial Antiretroviral Therapy for People with HIV: A Systematic Review
George W Rutherford, Hacsi Horvath, George W Rutherford, Hacsi Horvath
Abstract
Background: Dolutegravir (DTG) is a once-daily unboosted second-generation integrase-inhibitor that along with two nucleoside reverse transcriptase inhibitors is one of several regimens recommended by the United States, United Kingdom and European Union for first-line antiretroviral treatment of people with HIV infection. Our objective was to review the evidence for the efficacy and safety of DTG-based first-line regimens compared to efavirenz (EFV)-based regimens.
Methods: We conducted a systematic review. We comprehensively searched a range of databases as well as conference abstracts and a trials registry. We used Cochrane methods in screening and data collection and assessed each study's risk of bias with the Cochrane tool. We meta-analyzed data using a fixed-effects model. We used GRADE to assess evidence quality.
Results: From 492 search results, we identified two randomized controlled trials, reported in five peer-reviewed articles and one conference abstract. One trial tested two DTG-based regimens (DTG + abacavir (ABC) + lamivudine (3TC) or DTG + tenofovir + emtricitabine) against an EFV-based regimen (EFV+ ABC+3TC). The other trial tested DTG+ABC+3TC against EFV+ABC+3TC. In meta-analysis, DTG-containing regimens were superior to EFV-containing regimens at 48 weeks and at 96 weeks (RR = 1.10, 95% CI 1.04-1.16; and RR = 1.12, 95% CI 1.04-1.21, respectively). In one trial, the DTG-containing regimen was superior at 144 weeks (RR = 1.13, 95% CI 1.02-1.24). DTG-containing regimens were superior in reducing treatment discontinuation compared to those containing EFV at 96 weeks and at 144 weeks (RR = 0.27, 95% CI 0.15-0.50; and RR = 0.28, 95% CI 0.16-0.48, respectively). Risk of serious adverse events was similar in each regimen at 96 weeks (RR = 1.15, 95% CI 0.80-1.63) and 144 weeks (RR = 0.93, 95% CI 0.68-1.29). Risk of bias was moderate overall, as was GRADE evidence quality.
Conclusions: DTG-based regimens should be considered in future World Health Organization guidelines for initial HIV treatment.
Conflict of interest statement
The authors have declared that no competing interests exist.
Figures
References
- Kandel CE, Walmsley SL. Dolutegravir—a review of the pharmacology, efficacy, and safety in the treatment of HIV. Drug Des Devel Ther. 2015;9:3547–55. 10.2147/DDDT.S84850
- Taha H, Das A, Das S. Clinical effectiveness of dolutegravir in the treatment of HIV/AIDS. Infect Drug Resist. 2015;8:339–52. 10.2147/IDR.S68396
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. United States Department of Health and Human Services. Available: .
- European AIDS Clinical Society. Guidelines 8.0. October 2015. Available: .
- British HIV Association (BHIVA). BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015. Available: .
- Llibre JM, Pulido F, Garcia F, Garcia Deltoro M, Blanco JL, Delgado R. Genetic barrier to resistance for dolutegravir. AIDS Rev. 2015;17(1):56–64.
- Wainberg MA, Han YS. Will drug resistance against dolutegravir in initial therapy ever occur? Front Pharmacol. 2015;6:90 10.3389/fphar.2015.00090
- Curtis L, Nichols G, Stainsby C, Lim J, Aylott A, Wynne B, et al. Dolutegravir: clinical and laboratory safety in integrase inhibitor-naive patients. HIV Clin Trials. 2014;15(5):199–208. 10.1310/hct1505-199
- Stellbrink HJ, Reynes J, Lazzarin A, Voronin E, Pulido F, Felizarta F, et al. Dolutegravir in antiretroviral-naive adults with HIV-1: 96-week results from a randomized dose-ranging study. AIDS. 2013;27(11):1771–8. 10.1097/QAD.0b013e3283612419
- Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381(9868):735–43. 10.1016/S0140-6736(12)61853-4
- Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutierrez F, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807–18. 10.1056/NEJMoa1215541
- Clotet B, Feinberg J, van Lunzen J, Khuong-Josses MA, Antinori A, Dumitru I, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014;383(9936):2222–31. 10.1016/S0140-6736(14)60084-2
- Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382(9893):700–8. 10.1016/S0140-6736(13)61221-0
- World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach—Second edition Geneva: WHO, June 2016. Available: .
- Ford N, Shubber Z, Pozniak A, Vitoria M, Doherty M, Kirby C, et al. Comparative Safety and Neuropsychiatric Adverse Events Associated With Efavirenz Use in First-Line Antiretroviral Therapy: A Systematic Review and Meta-Analysis of Randomized Trials. J Acquir Immune Defic Syndr. 2015;69(4):422–9. 10.1097/QAI.0000000000000606
- Shubber Z, Calmy A, Andrieux-Meyer I, Vitoria M, Renaud-Thery F, Shaffer N, et al. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AIDS. 2013;27(9):1403–12. 10.1097/QAD.0b013e32835f1db0
- Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available: .
- Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097 10.1371/journal.pmed.1000097
- Guyatt GH, Oxman AD, Schunemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011;64(4):380–2. 10.1016/j.jclinepi.2010.09.011
- van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12(2):111–8. 10.1016/S1473-3099(11)70290-0
- Walmsley S, Berenguer J, Khuong-Josses M-A, et al. Dolutegravir Regimen Statistically Superior to Efavirenz/Tenofovir/Emtricitabine: 96-Week Results From the SINGLE Study (ING114467) [Abstract number 543]. 21st Conference on Retroviruses and Opportunistic Infection, Boston, Massachusetts, 3–6 March 2014.
- Raffi F, Rachlis A, Brinson C, Arasteh K, Gorgolas M, Brennan C, et al. Dolutegravir efficacy at 48 weeks in key subgroups of treatment-naive HIV-infected individuals in three randomized trials. AIDS. 2015;29(2):167–74. 10.1097/QAD.0000000000000519
- Walmsley S, Baumgarten A, Berenguer J, Felizarta F, Florence E, Khuong-Josses MA, et al. Brief Report: Dolutegravir Plus Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 and Week 144 Results From the SINGLE Randomized Clinical Trial. J Acquir Immune Defic Syndr. 2015;70(5):515–9. 10.1097/QAI.0000000000000790
- World Health Organization. WHO Handbook for Guideline Development 2nd edition Geneva: World Health Organization, 2014. Available: .
- Sinclair D, Isba R, Kredo T, Zani B, Smith H, Garner P. World Health Organization guideline development: an evaluation. PloS One. 2013;8(5):e63715 10.1371/journal.pone.0063715
Source: PubMed