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Clinical efficacy of antiretroviral combination therapy based on protease inhibitors or non-nucleoside analogue reverse transcriptase inhibitors: indirect comparison of controlled trials

BMJ 2004; 328 doi: (Published 29 January 2004) Cite this as: BMJ 2004;328:249
  1. Yazdan Yazdanpanah, senior doctor of infectious disease (yyazdan{at},
  2. Daouda Sissoko, doctor of infectious disease1,
  3. Matthias Egger, professor of clinical epidemiology2,
  4. Yves Mouton, professor of infectious disease1,
  5. Marcel Zwahlen, senior epidemiologist3,
  6. Geneviève Chêne, professor of clinical epidemiology4
  1. 1Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing, Faculté de Médecine de Lille, BP 619, F 59208 Tourcoing, France
  2. 2Department of Social Medicine, University of Bristol
  3. 3Department of Social and Preventive Medicine, University of Bern, Switzerland
  4. 4INSERM U593, Bordeaux, France
  1. Correspondence to: Y Yazdanpanah
  • Accepted 6 January 2004


Objective To compare the clinical efficacy of triple antiretroviral regimens based on protease inhibitors and non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) in adults positive for antibodies to HIV-1.

Design Systematic review and meta-analysis using indirect comparisons of clinical trials comparing three drug regimens based on two nucleoside reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor or an NNRTI with two drug regimens (two NRTIs). Participants had no previous exposure to protease inhibitors or NNRTIs.

Data sources Medline, the Cochrane controlled trials register, Aidstrials, Aidsdrugs, conference proceedings, and trial registers.

Main outcome measure Progression to AIDS or death.

Results 14 trials, totalling 6785 patients, were identified. Most patients had been exposed to an NRTI and had advanced immunodeficiency at baseline; 1096 progressed to AIDS or died. Seven trials assessed protease inhibitors based triple regimens and seven assessed NNRTI based triple regimens (nevirapine or delavirdine). Triple therapy was more effective than dual therapy. The effect was pronounced for protease inhibitor based regimens (odds ratio 0.49, 95% confidence interval 0.41 to 0.58) but non-significant for NNRTI based regimens (0.90, 0.71 to 1.15). Indirect comparison of the two regimens gave an odds ratio of 0.54 (0.49 to 0.73) in favour of protease inhibitor based treatments. Increases in CD4 cell counts were smaller and suppression of viral replication less with NNRTI based regimens.

Conclusions Indirect evidence shows that protease inhibitor based triple regimens are superior to regimens based on the NNRTIs nevirapine and delavirdine in patients with advanced immunodeficiency who have been exposed to NRTIs. Large trials with clinical end points are required.


  • Contributors GC had the idea for the review and ME proposed the indirect comparisons. YY, DS, YM, and GC initiated the review and designed the original protocol. DS was responsible for data collection under the supervision of YY and GC. DS, YY, and MZ performed the statistical analyses under the supervision of ME. YY together with ME and GC wrote the first draft of the paper. All authors contributed to the final version. YY will act as guarantor for the paper.

  • Funding None.

  • Competing interests YY has received travel grants from various pharmaceutical companies including Aventis, Boehringer Ingelhem, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Pfizer, Roche, and Schering Plough. He has received honorariums for presentation at workshops and consultancy honorariums from Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, and Pfizer. ME has received travel grants, grants, or honorariums from Boehringer Ingelheim, Bristol-Myers-Squibb, and GlaxoSmithKline. YM has received travel grants, grants, or honorariums from Abbott, Aventis, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp and Dohme, Pfizer, Roche, and Schering. GC has received consultancy honorariums from Aventis, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and Roche.

  • Ethical approval None required.

  • Accepted 6 January 2004
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