Of 367 citations identified, we examined 54 articles in detail and found 12 trials that met our inclusion criteria. Two unpublished trials were identified from conference proceedings (). The 14 trials totalled 6785 patients ().20-33
Over 80% of participants were men, median age ranging from 31 to 41 years. Some trials exclusively enrolled patients with a history of AIDS and others enrolled patients free of AIDS, but most enrolled patients with advanced immunodeficiency. The median CD4 cell count at baseline ranged from 19 to 651 cells/μl, and the median HIV RNA ranged from 4.4 to 6.4 log10
copies/ml. Only three trials enrolled patients naive to NRTIs. Follow up ranged from 24 to 80 weeks. Of the 14 triple combinations, seven were based on a protease inhibitor and seven on an NNRTI. Seven trials used protease inhibitors: indinavir (three trials) and saquinavir and ritonavir (two each). Four trials used the NNRTI nevirapine and three the NNRTI delavirdine. The most common NRTI dual therapy regimen was zidovudine and didanosine (five trials) followed by zidovudine and lamivudine (four). Nine trials described adequate concealment of allocation and 12 used placebos to blind patients and caregivers.
Identification of relevant trials
Characteristics of 14 randomised controlled trials comparing protease inhibitor based triple therapy and non-nucleoside analogue reverse transcriptase inhibitor (NNRTI) based triple regimens with dual therapy
Clinical progression occurred in 445 of 3392 patients (13.1%) receiving triple therapy and 651 of 3393 (19.2%) patients receiving dual therapy (): combined odds ratio 0.65 (95% CI 0.52 to 0.81). Heterogeneity was evident between trials, with odds ratios ranging from 0.32 to 1.31 (τ2 = 0.073, test of heterogeneity P = 0.090).
Meta-analysis of randomised controlled trials comparing effect of triple antiretroviral regimens with dual regimens on progression to AIDS or death, stratified by type of triple regimen
In univariate meta-regression analysis, protease inhibitor based triple regimens showed larger treatment effects than those based on NNRTIs (P < 0.0001), triple regimens including didanosine showed smaller treatment effects than those that did not include didanosine (P < 0.0001), and trials that enrolled a larger proportion of patients with AIDS tended to show larger differences in treatment effects between triple and dual regimens (P = 0.067). These variables were responsible for the between trial heterogeneity. We found little evidence for an association with other variables entered in the model, including length of follow up (P = 0.76), year of publication of the trial (P = 0.22), publication in full or as abstract only (P = 0.34), median age of study populations at baseline (P = 0.98), whether patients were NRTI naive or not (P = 0.75), and CD4 cell count (P = 0.53) and viral load (P = 0.37) at baseline. Finally, there was little evidence that the censoring strategy (follow up censored at virological failure yes or no, P = 0.46) or the quality of trials influenced results (adequate concealment of allocation yes or no, P = 0.91; use of placebo yes or no, P = 0.63), and little evidence of funnel plot asymmetry (P = 0.27).
shows the results from direct comparisons of triple with dual regimens and from indirect comparisons between triple regimens. When triple regimens were compared with dual regimens the odds ratio for clinical progression was 0.49 (0.41 to 0.58) for a protease inhibitor regimen but 0.90 (0.71 to 1.15) for an NNRTI regimen. The crude odds ratio from the indirect comparison was 0.54 (0.40 to 0.73). This changed little when adjusting for whether or not the regimen included didanosine, for the proportion of study participants with AIDS, or for both variables, although adjustments resulted in odds ratios with wide confidence intervals, which included 1 (). When trials were excluded that examined saquinavir hard gel, which is no longer used, or the NNRTI delavirdine, which is not widely used, the protease inhibitor based triple regimens continued to show larger treatment effects than the NNRTI based regimens (0.54, 0.37 to 0.77).
Comparisons from meta-analysis of randomised controlled trials comparing the effects of triple antiretroviral regimens with dual regimens on risk of progression to AIDS or death
Differences in CD4 cell count and plasma HIV-1 RNA concentration
Eleven studies could be included in the analysis of CD4 cell counts. Compared with dual regimens, triple regimens led to a superior CD4 cell response (pooled difference in CD4 cell count, 40 cells/μl, 95% CI 19 to 60 cells/μl; ). When we stratified the analysis according to type of triple regimen, those based on protease inhibitors showed a greater improvement in CD4 cell count: 49 cells/μl compared with 18 cells/μl with NNRTI based regimens. An indirect comparison showed an additional increase of 25 CD4 cells/μl (-17 to 68) with protease inhibitor based regimens. Ten studies reported HIV-1 RNA concentrations at the end of follow up, and nine reported the proportion of patients with plasma HIV RNA concentrations ≤ 500 copies/ml. Again, triple therapy was superior to dual therapy, resulting in an estimated additional reduction of HIV-1 RNA concentrations of 0.56 log copies/ml (0.92 to 0.19 reduction in log copies/ml). The odds ratio for achieving a viral load below 500 copies/ml with triple compared with dual therapy was 9.6 (4.4 to 21.0). Protease inhibitor based triple regimens resulted in a more substantial reduction of HIV-1 RNA concentrations (-0.79 log copies/ml) than NNRTI based regimens (-0.20 log copies/ml), and a higher proportion of patients reached undetectable viral load with the protease inhibitor regimens (odds ratio 37.1) than with the NNRTI based regimens (4.1). The indirect comparison showed an additional reduction of HIV RNA concentration of -0.59 log copies/ml with protease inhibitor regimens (-1.32 to 0.15). The odds ratio for reaching an undetectable viral load was 6.0 (2.2 to 16.6).
Differences in CD4 cell counts and viral load at end of treatment with triple antiretroviral regimens or dual regimens, and probability of suppressing viral replication