Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

English version České info

Background:
Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.

Methods and Findings:
1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure.

An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI 0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04; p = 0.007).

Conclusion:
EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.

Trial Registration: www.ClinicalTrials.gov NCT00084136

Please see later in the article for the Editors' Summary.

Vyšlo v časopise: Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings. PLoS Med 9(8): e32767. doi:10.1371/journal.pmed.1001290
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pmed.1001290

Souhrn

Zdroje

1. World Health Organization (2010) Treatment 2.0: Is this the future of treatment? World Health Organization. Available: http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2010/20100713_outlook_treatment2_0_en.pdf. Accessed 8 August 2011

2. HirnschallG, SchwartlanderB (2011) Treatment 2.0: catalysing the next phase of scale-up. Lancet 378: 209–211.

3. World Health Organization (2010) Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. Geneva: World Health Organization

4. StaszewskiS, Morales-RamirezJ, TashimaKT, RachlisA, SkiestD, et al. (1999) Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 341: 1865–1873.

5. GulickRM, RibaudoHJ, ShikumaCM, LustgartenS, SquiresKE, et al. (2004) Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 350: 1850–1861.

6. GallantJE, DeJesusE, ArribasJR, PozniakAL, GazzardB, et al. (2006) Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 354: 251–260.

7. SquiresK, LazzarinA, GatellJM, PowderlyWG, PokrovskiyV, et al. (2004) Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr 36: 1011–1019.

8. MalanDR, KrantzE, DavidN, WirtzV, HammondJ, et al. (2008) Efficacy and safety of atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy regimens in antiretroviral-naive patients. J Acquir Immune Defic Syndr 47: 161–167.

9. SanneI, PilieroP, SquiresK, ThiryA, SchnittmanS (2003) Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr 32: 18–29.

10. BerenguerJ, GonzalezJ, RiberaE, DomingoP, SantosJ, et al. (2008) Didanosine, lamivudine, and efavirenz versus zidovudine, lamivudine, and efavirenz for the initial treatment of HIV type 1 infection: final analysis (48 weeks) of a prospective, randomized, noninferiority clinical trial, GESIDA 3903. Clin Infect Dis 47: 1083–1092.

11. MolinaJM, JournotV, Morand-JoubertL, YeniP, RozenbaumW, et al. (2005) Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz in HIV-1-infected adults with viral suppression receiving a protease inhibitor-based regimen: a randomized trial. J Infect Dis 191: 830–839.

12. MolinaJM, JournotV, FurcoA, PalmerP, DeCN, et al. (2007) Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial). Antivir Ther 12: 417–422.

13. Sanchez-CondeM, PalaciosR, SanzJ, Rodriguez-NovoaS, RivasP, et al. (2007) Efficacy and safety of a once daily regimen with efavirenz, lamivudine, and didanosine, with and without food, as initial therapy for HIV Infection: the ELADI study. AIDS Res Hum Retroviruses 23: 1237–1241.

14. SaagMS, CahnP, RaffiF, WolffM, PearceD, et al. (2004) Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial. JAMA 292: 180–189.

15. Division of AIDS (2004; 2010) Table for grading the severity of adult and pediatric adverse events Available: http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of_Adult_Pediatric_Adverse_Events.pdf. Accessed 12 January 2011.

16. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (2002) Guidance for industry: antiretroviral drugs using plasma HIV RNA measurements - clinical considerations for accelerated and traditional approval. Available: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070968.pdf. Accessed 13 October 2010.

17. XuX, TianL, WeiLJ (2003) Combining dependent tests for linkage or association across multiple phenotypic traits. Biostatistics 4: 223–229.

18. FletcherCV, JiangH, BrundageRC, AcostaEP, HaubrichR, et al. (2004) Sex-based differences in saquinavir pharmacology and virologic response in AIDS Clinical Trials Group Study 359. J Infect Dis 189: 1176–1184.

19. KingJR, KakudaTN, PaulS, TseMM, AcostaEP, et al. (2007) Pharmacokinetics of saquinavir with atazanavir or low-dose ritonavir administered once daily (ASPIRE I) or twice daily (ASPIRE II) in seronegative volunteers. J Clin Pharmacol 47: 201–208.

20. PaiMP, SchrieverCA, az-LinaresM, NovakRM, RodvoldKA (2004) Sex-related differences in the pharmacokinetics of once-daily saquinavir soft-gelatin capsules boosted with low-dose ritonavir in patients infected with human immunodeficiency virus type 1. Pharmacotherapy 24: 592–599.

21. RichmanDD, FischlMA, GriecoMH, GottliebMS, VolberdingPA, et al. (1987) The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 317: 192–197.

22. JacobsonMA, LiuRC, DaviesD, CohenPT (1997) Human immunodeficiency virus disease-related neutropenia and the risk of hospitalization for bacterial infection. Arch Intern Med 157: 1825–1831.

23. MooreRD, KerulyJC, ChaissonRE (1995) Neutropenia and bacterial infection in acquired immunodeficiency syndrome. Arch Intern Med 155: 1965–1970.

24. HermansP, SommereijnsB, VanCN, ClumeckN (1999) Neutropenia in patients with HIV infection: a case control study in a cohort of 1403 patients between 1982 and 1993. J Hematother Stem Cell Res 8 Suppl 1: S23–S32.

25. KuritzkesDR, ParentiD, WardDJ, RachlisA, WongRJ, et al. (1998) Filgrastim prevents severe neutropenia and reduces infective morbidity in patients with advanced HIV infection: results of a randomized, multicenter, controlled trial. AIDS 12: 65–73.

26. PozniakAL, GallantJE, DeJesusE, ArribasJR, GazzardB, et al. (2006) Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes–a 96-week analysis. J Acquir Immune Defic Syndr 43: 535–540.

27. Joint United Nations Programme on HIV/AIDS (UNAIDS) (2010) Global report: UNAIDS report on the global AIDS epidemic 2010. Available: http://www.unaids.org/globalreport/Global_report.htm. Accessed 14 September 2011.

28. d'ArminioMA, GonzalezL, HaberlA, SherrL, Ssanyu-SserumaW, et al. (2010) Better mind the gap: addressing the shortage of HIV-positive women in clinical trials. AIDS 24: 1091–1094.

29. MooreRD, FortgangI, KerulyJ, ChaissonRE (1996) Adverse events from drug therapy for human immunodeficiency virus disease. Am J Med 101: 34–40.

30. CurrierJS, SpinoC, GrimesJ, WofsyCB, KatzensteinDA, et al. (2000) Differences between women and men in adverse events and CD4+ responses to nucleoside analogue therapy for HIV infection. The AIDS Clinical Trials Group 175 Team. J Acquir Immune Defic Syndr 24: 316–324.

31. ClarkR (2005) Sex differences in antiretroviral therapy-associated intolerance and adverse events. Drug Saf 28: 1075–1083.

32. Nielsen-SainesK, KomarowL, Cu-UvinS, JourdainG, KlingmanK, et al. (2012) Assessment of safety and toxicity following maternal antiretroviral exposure in infants born To HIV-infected women enrolled in antiretroviral treatment protocols in diverse areas of the world. Eighteen month results of AIDS Clinical Trials Group (ACTG) Study 5190/Pediatric AIDS Clinical Trials Group (PACTG) 1054. Pediatrics 129: e1525–e1532.