Table 3. Characteristics of the randomized controlled trials for efavirenz compared to different regimens used to treat antiretroviral–naive HIV-infected adult patients.
| Study author, year of publication, study type, sites | Population | Study duration | Interventions* |
|---|---|---|---|
| background regimen (2 NRTIs/2 NRTIs+1 PI) + efavirenz vs background regimen + NNRTI | |||
| [15] Cohen 2011, THRIVE, RCT, double-blind, double-dummy, 98 centers in 21 countries (United States and Puerto Rico, Canada, Australia, Europe, South Africa, Asia, Latin America) | ART-naive, age ≥18 years, pVL >5 000 copies/ml | 96 weeks | A: 2 NRTI + EFV, N = 340; B: 2 NRTI + RPV, N = 340; (2 NRTI included: TDF + FTC or AZT + 3TC or ABC + 3TC) |
| [16] Gaytán 2004, RCT, open-label, 1 center in Mexico | ART-naive, age ≥18 years, pVL >55 000 copies/ml | 48 weeks | A: AZT + 3TC + EFV, N = 30; B: AZT + 3TC + NVP, N = 28 |
| [17] Gazzard 2011, [18] Nelson 2011, SENSE, RCT, double-blind, centers in Europe, Russia and Israel | ART-naive, pVL>5 000 copies/ml | 48 weeks | A: 2 NRTI + EFV, N = 78; B: 2 NRTI + ETV, N = 79; (2 NRTI included: TDF + FTC or AZT + 3TC or ABC + 3TC) |
| [19] Molina 2011, ECHO, RCT, double-blind, double-dummy, 112 centers in 21 countries (United States, Canada, Australia, South Africa, Europe, Asia, Latin America) | ART-naive, age ≥18 years, pVL>5 000 copies/ml | 96 weeks | A: TDF + FTC + EFV, N = 348; B: TDF + FTC + RPV, N = 346 |
| [20] Núñez 2002, SENC, RCT, open-label, 1 center in Spain | ART-naive, age > 18 years, pVL: 500–100 000 copies/ml | 48 weeks | A: ddI + d4T + EFV, N = 31; B: ddI + d4T + NVP, N = 36 |
| [21] Pozniak 2010, TMC278-C204, RCT, open-label, 54 centers in 14 countries (Asia, South Africa, Uganda, Europe, United States, Russia, Puerto Rico, Latin America) | ART-naive, age ≥18 years (≤2 weeks treatment with NRTI and/or PI was allowed), pVL >5 000 copies/ml | 96 weeks | A: 2 NRTI + EFV, N = 89; B: 2 NRTI + RPV, N = 279 (25 mg N = 93, 75 mg N = 95, 150 mg N = 91); (2 NRTI included: TDF + FTC or AZT + 3TC) |
| [22] van den Berg-Wolf 2008, NNRTI substudy of FIRST trial [23], RCT, open-label, 17 clinical trials units at 80 sites in the United States | ART-naive (less than 4 weeks of prior NRTI use or 1 week of 3TC use was allowed), age ≥13 years | median—5 years | patients randomized to NNRTI+NRTIs strategy (N = 110) or PI+NNRTI+NRTIs strategy (118) and then randomized to: A: EFV, N = 111; B: NVP, N = 117 (NRTIs included: ABC + 3TC or ddI + d4T or AZT + 3TC or d4T + 3TC; PI included: NFV, INV, /r |
| [24] van Leth 2004, 2NN, RCT, open-label, centers in North and South America, Australia, Europe, South Africa and Thailand | ART-naive, age ≥16 years, pVL >5 000 copies/ml | 48 weeks | A: d4T+ 3TC+ EFV, N = 400; B: d4T + 3TC + NVP (400 mg once daily), N = 220; C: d4T + 3TC + NVP (200 mg twice daily), N = 387 |
| [25] Vernazza 2013, A5271015, RCT, double-blind, centers in Argentina, Australia, Canada, Italy, Mexico, Poland, South Africa, Switzerland and the United Kingdom | ART-naive (less than 14 days of prior ART was allowed), age ≥18 years, pVL ≥1 000 copies/ml | 96 weeks | A: TDF + FTC + EFV, N = 63; B: TDF + FTC + LRV (500 mg), N = 66; C: TDF + FTC + LRV (750 mg), N = 66 |
| [26] Wester 2010, TSHEPO, RCT, open-label, one center in Botswana | ART-naive, age ≥ 18 years, pVL >55 000 copies/ml | 3 years | A: 2 NRTI + EFV, N = 325; B: 2 NRTI + NVP, N = 325; (2 NRTI included: AZT + 3TC or AZT + ddI or d4T + 3TC) |
| background regimen (2 NRTIs) + efavirenz vs background regimen + InSTI | |||
| [28] Cohen 2011, GS-236-014, RCT, double-blinded, double-dummy, mulit-center (centers not described) | ART-naive, age ≥18 years, pVL ≥5 000 copies/ml | 48 weeks | A: FTC + TDF + EFV, N = 23; B: FTC + TDF + EVG + COBI, N = 48 |
| [29] Lennox 2009, [30] Lennox 2010, STARTMRK, RCT, double-blind, 67 study centers in Australia, Brazil, Canada, Chile, Colombia, France, Germany, India, Italy, Mexico, Peru, Spain, Thailand, and United States | ART-naive, age ≥18 years, pVL >5 000 copies/ml | 96 weeks | A:TDF + FTC + EFV, N = 284; B: TDF + FTC + RAL, N = 282 |
| [31] Markowitz 2007, [32] Markowitz 2009, Protocol 004 part II, RCT, double-blinded, 29 centers in United States, Canada, Latin America, Thailand, and Australia | ART-naive (less than 7 days of ART was permitted), 30 patients received 10 days of RAL in monotherapy as a first part of the study**), age ≥18 years, pVL ≥5 000 copies/ml | 96 weeks | A: TDF + 3TC + EFV, N = 39; B: TDF + 3TC + RAL (100 mg bid N = 41, 200 mg bid N = 40, 400 mg bid N = 41, 600 mg bid N = 40) |
| [33] Sax 2012, [34] Zolopa 2013, GS-US-236-0102, RCT, double-blinded, centers in North America | ART-naive, age ≥18 years, pVL ≥5 000 copies/ml | 96 weeks | A: FTC + TDF + EFV, N = 354; B: FTC + TDF + EVG + COBI, N = 353 |
| [35] van Lunzen 2012, [36] Stellbrink 2013, SPRING-1, RCT, open-label (only dose but not drug allocation was masked), 34 sites in France, Germany, Italy, Russia, Spain, and the United States | ART-naive (up to 10 days of ART was permitted), age ≥18 years, pVL>1 000 copies/ml | 96 weeks | A: 2 NRTI + EFV, N = 50; B: 2 NRTI + DTG (10 mg N = 53, 25 mg N = 51, 50 mg N = 51); (2 NRTI included: TDF + FTC or ABC + 3TC) |
| [37] Walmsley 2013, SINGLE, RCT, double-blind, centers in North America, Europe, and Australia | ART-naive, age ≥18 years, pVL ≥1 000 copies/ml | 48 weeks | A: TDF + FTC + EFV, N = 419; B: ABC + 3TC + DTG, N = 414 |
| background regimen (2 or 3 NRTIs) + efavirenz vs background regimen + bPI | |||
| [38] Albini 2012, RCT, open-label, 4 centers in Italy | ART-naive, age ≥18 years | 48 weeks | A: TDF + FTC + EFV, N = 43; B: TDF + FTC + ATV/r, N = 48 |
| [39] Bartlett 2006, CLASS, RCT, open-label, centers in United States | ART-naive (less than 2 weeks of prior ART), pVL ≥5 000 copies/ml | 96 weeks | A: ABC + 3TC + EFV, N = 97; B: ABC + 3TC + APV/r, N = 96 |
| [40] Cameron 2008, M03-613, RCT, open-label, centers in Canada, United States and Spain | ART-naive, pVL >1 000 copies/ml | 96 weeks | A: AZT + 3TC + EFV, N = 51; B: AZT + 3TC + LPV/r, N = 104 |
| [41] Daar 2011, A5202, RCT, open-label (only NRTI treatment was blinded), 59 centers in the United States and Puerto Rico | ART-naive (up to 7 days of ART was allowed), age ≥16 years | median—138 weeks | A: 2 NRTI + EFV, N = 929; B: 2 NRTI + ATV/r, N = 928; 2 NRTI included: ABC + 3TC or TDF + FTC*** |
| [42] Echeverría 2010, LAKE, RCT, open-label, 19 centers in Spain and Italy | ART-naive, age ≥18 years | 48 weeks | A: ABC + 3TC + EFV, N = 63; B: ABC + 3TC + LPV/r, N = 63 |
| [43] Honda 2011, RCT, open-label, 1 center in Japan | ART-naive, CD4+ T lymphocyte 100–300 cell/mm3, men only | 96 weeks | A: 3TC + ABC + EFV, N = 36; B: 3TC + ABC + ATV/r, N = 35 |
| [44] Josephson 2010, [45] Edén 2010, [46] Andersson 2013, NORTHIV, RCT, open-label, centers in Sweden and Norway | ART-naive, age ≥16 years | 144 weeks | A: 2 NRTI + EFV, N = 78 [46]; B: 2 NRTI + ATV/r, N = 82 [46]; C: 2 NRTI + LPV/r, N = 83 [46]; 2 NRTI included: ABC + 3TC or TDF + FTC OR AZT + 3TC or others |
| [47] Kumar 2013, SUPPORT, RCT, open-label, centers in United States | ART-naive (≤14 days of treatment with any ART), pVL >5 000 copies/ml | 96 weeks | A: ABC + 3TC + EFV, N = 50; B: ABC + 3TC + FPV/r, N = 51 |
| [47] Mallolas 2008, TRIZEFAL, RCT, open-label, 18 centers in Spain | ART-naive, pVL >10 000 copies/ml | 72 weeks | A: ABC + 3TC + AZT + EFV, N = 109 (N = 104 were analyzed); B: ABC + 3TC + AZT + LPV/r, N = 111 (N = 105 were analyzed) |
| [49] Miró 2010, ADVANZ, RCT, open-label, 6 centers in Spain | ART-naive, age ≥18 years, CD4+ T lymphocyte <100 cells/μl | 36 months | A: AZT + 3TC + EFV, N = 35; B: AZT + 3TC + IDV/r, N = 35 |
| [50] Puls 2010, ALTAIR, RCT, open-label, 36 centers in Australia, Thailand, Argentina, France, Singapore and United Kingdom | ART-naive, age >18 years, pVL >2 000 copies/ml | 48 weeks | A: TDF + FTC + EFV, N = 115; B: TDF + FTC + ATV/r, N = 107 |
| [51] Ratsela 2010, PHISIDA II, RCT, open-label, 6 centers in the Republic of South Africa | ART-naive (less than 7 days of ART was allowed), age ≥14 years, CD4+ T lymphocyte <200 cell counts | median 24.7 months | A: 2 NRTI + EFV, N = 888; B: 2 NRTI + LPV/r, N = 883; 2 NRTI included: AZT + ddI or d4T + 3TC |
| [52] Riddler 2008, A5142, RCT, open-label, centers in United States, centre in Dublin and Durban | ART-naive, age ≥13 years, pVL ≥2 000 copies/ml | 96 weeks | A: 2 NRTI + EFV, N = 250; B: 2 NRTI + LPV/r, N = 253; (2 NRTI included: 3TC and: AZT or d4T or TDF) |
| [53] Sierra-Madero 2010, RCT, open-label, 10 centers in Mexico | ART-naive, age ≥18 years, pVL ≥1 000 copies/ml | 48 weeks | A: AZT + 3TC + EFV, N = 95; B: AZT + 3TC + LPV/r, N = 94 |
| [54] Torti 2005,[55] Torti 2008, substudy of SISTHER, RCT, open-label, 1 center in Italy | ART-naive, pVL ≥1 000 copies/ml | 52 weeks | A: TDF + 3TC + EFV, N = 37 [55], N = 10 [54]; B: AZT + 3TC + LPV/r, N = 27[55], N = 9 [54]; C: TDF + ddI + EFV#, N = 11 [54] |
| background regimen (2 NRTIs) + efavirenz vs background regimen + CCR5 | |||
| [56] Copper 2010, [57] Sierra-Madero 2010, MERIT, RCT, double-blinded, double-dummy, centers in North and South America, Europe, South Africa, and Australia | ART-naive, age ≥16 years, pVL ≥2 000 copies/ml | 96 weeks## | A: AZT + 3TC + EFV, N = 361; B: AZT + 3TC + MVC, N-360 |
| [58] Currier 2008, ASCENT, RCT, partially double-blinded, 33 centers in United States, 4 in Canada and 24 in European Union | ART-naive, age ≥13 years, pVL ≥10 000 copies/ml, | 96 weeks### | A: 3TC + AZT + EFV, N = 29; B: 3TC + AZT + APL (600 mg N = 58, 800 mg N = 58) |
| [59] Landovitz 2008, RCT, double-blinded (centers not described) | ART-naive (less than 2 weeks of ART was allowed, patients in VCV arm received VCV for 14 days in monotherapy), age ≥18 years, pVL ≥5 000 copies/ml | 48 weeks | A: AZT + 3TC + EFV, N = 24; B: AZT + 3TC + VCV, N = 68 (all doses combined) |
3TC—lamivudine, ABC—abacavir, APL—aplaviroc, APV—amprenavir, ART—antiretroviral therapy, ATV—atazanavir, AZT—zidovudine, bid—twice a day, bPI—ritonavir-boosted protease inhibitor, CCR5—CC chemokine receptor type 5, COBI—cobicistat, d4T - stavudine, ddC—zalcitabine, ddI—didanosine, DTG—dolutegravir, EFV—efavirenz, ETV—etravirine, EVG—elvitegravir, FPV—fosamprenavir, FTC—emtricitabine, IDV—indinavir, MVC—maraviroc, LPV—lopinavir, LRV—lersivirine, NFV—nelfinavir, NNRTI—non-nucleoside reverse transcriptase inhibitor, NRTI—nucleoside reverse transcriptase inhibitor, NVP—nevirapine, PI—protease inhibitor, r—ritonavir, RAL—raltegravir, RCT—randomized controlled trial, RPV—rilpivirine, SQV—saquinavir, TDF—tenofovir, pVL—plasma HIV RNA, VCV—vicriviroc.
* interventions included in meta-analysis only.
**raltegravir monotherapy did not influenced the efficacy results, so both groups (pretreated and not pretreated with raltegravir were combined).
***results for groups assigned EFV + different NRTIs and separately ATV/r + different NRTIs were combined.
#enrolment in the TDF + ddI + EFV arm was stopped as soon as the high rate of virological failure was recognized.
##once-daily MVC arm was discontinued prematurely and not analyzed.
###stopped prematurely due to unexpected hepatotoxicity.