Clinical efficacy of antiretroviral combination therapy based on protease inhibitors or non-nucleoside analogue reverse transcriptase inhibi
http://www.100md.com
《英国医生杂志》
1 Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing, Faculté de Médecine de Lille, BP 619, F 59208 Tourcoing, France, 2 Department of Social Medicine, University of Bristol, 3 Department of Social and Preventive Medicine, University of Bern, Switzerland, 4 INSERM U593, Bordeaux, France
Correspondence to: Y Yazdanpanah yyazdan@yahoo.com
Abstract
The introduction in industrialised countries of highly active antiretroviral therapy—a combination of three drugs including either a protease inhibitor or a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI) and two nucleoside analogue reverse transcriptase inhibitors (NRTIs)—led to a dramatic decline in morbidity and mortality among patients infected with HIV-1.1-3 Many different combinations of highly active antiretroviral therapy regimens are available, some of which differ in toxicity, adverse events, their ability to suppress viral replication, the development of viral resistance, and patient adherence.4-7
Randomised clinical trials are accepted as the most powerful tool for assessing the effectiveness of medical interventions, yet no trials have compared the clinical effectiveness of protease inhibitor based and NNRTI based combination therapies. Thus it is unclear whether there are relevant differences between the regimens in prevention of clinical progression to AIDS or death. In trials comparing highly active antiretroviral therapy regimens the low rate of disease progression made it impractical to use clinical events as primary end points. A meta-analysis of 16 randomised trials showed that treatments resulting in similar changes in HIV-1 RNA or CD4 cell counts were associated with widely varying clinical outcomes.8 Trials exclusively reporting surrogate endpoint data therefore have to be interpreted with caution.9
In the absence of trials comparing two treatments, indirect comparisons have been advocated.10 We performed indirect comparisons between triple regimens based on protease inhibitors and NNRTIs by using clinical and surrogate endpoint data from randomised controlled trials comparing triple regimens with dual regimens.
Methods
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 Two unpublished trials were identified from conference proceedings (fig 1). The 14 trials totalled 6785 patients (table 1).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.
Fig 1 Identification of relevant trials
Table 1 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
Clinical progression occurred in 445 of 3392 patients (13.1%) receiving triple therapy and 651 of 3393 (19.2%) patients receiving dual therapy (fig 2): 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 (2 = 0.073, test of heterogeneity P = 0.090).
Fig 2 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).
Figure 3 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 (fig 3). 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).
Fig 3 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; table 2). 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).
Table 2 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
Discussion
Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 1998;352: 1725-30.
Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;338: 853-60.
Egger M, Hirschel B, Francioli P, Sudre P, Wirz M, Flepp M, et al. Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. Swiss HIV cohort study. BMJ 1997;315: 1194-9.
Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, et al. 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 1999;341: 1865-73.
Walmsley S, Bernstein B, King M, Arribas J, Beall G, Ruane P, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002;346: 2039-46.
Fellay J, Boubaker K, Ledergerber B, Bernasconi E, Furrer H, Battegay M, et al. Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV cohort study. Lancet 2001;358: 1322-7.
Trotta MP, Ammassari A, Cozzi-Lepri A, Zaccarelli M, Castelli F, Narciso P, et al. Adherence to highly active antiretroviral therapy is better in patients receiving non-nucleoside reverse transcriptase inhibitor-containing regimens than in those receiving protease inhibitor-containing regimens. AIDS 2003;17: 1099-102.
Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: a meta-analysis. HIV Surrogate Marker Collaborative Group. AIDS Res Hum Retroviruses 2000;16: 1123-33.
Bucher HC, Guyatt GH, Cook DJ, Holbrook A, McAlister FA. Users' guides to the medical literature: XIX. Applying clinical trial results. A. How to use an article measuring the effect of an intervention on surrogate end points. Evidence-Based Medicine Working Group. JAMA 1999;282: 771-8.
Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003;326: 472.
Lefebvre C, Clarke M. Identifying randomised trials. In: Egger M, Smith G, Altman D, eds. Systematic reviews in health care: meta-analysis in context, 2nd ed. London: BMJ Books, 2001: 69-86.
Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med 2002;137: 381-433.
Yeni PG, Hammer SM, Carpenter CC, Cooper DA, Fischl MA, Gatell JM, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA 2002;288: 222-35.
Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. JAMA 1993;269: 460.
Jüni P, Altman D, Egger M. Assessing the quality of controlled clinical trials. BMJ 2001;323: 42-6.
Deeks J, Altman D, Bradburn M. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Smith G, Altman D, eds. Systematic reviews in health care: meta-analysis in context, 2nd ed. London: BMJ Books, 2001: 285-312.
Thompson S, Sharp S. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med 1999;18: 2693-708.
Egger M, Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: 629-34.
Sterne J, Egger M, Smith G. Investigating and dealing with publication and other biases in meta-analysis. BMJ 2001;323: 101-5.
Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997;337: 734-9.
Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997;337: 725-33.
Cameron DW, Heath-Chiozzi M, Danner S, Cohen C, Kravcik S, Maurath C, et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet 1998;351: 543-9.
D'Aquila RT, Hughes MD, Johnson VA, Fischl MA, Sommadossi JP, Liou SH, et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Ann Intern Med 1996;124: 1019-30.
Collier AC, Coombs RW, Schoenfeld DA, Bassett RL, Timpone J, Baruch A, et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N Engl J Med 1996;334: 1011-7.
Henry K, Erice A, Tierney C, Balfour HH Jr, Fischl MA, Kmack A, et al. A randomized, controlled, double-blind study comparing the survival benefit of four different reverse transcriptase inhibitor therapies (three-drug, two-drug, and alternating drug) for the treatment of advanced AIDS. AIDS Clinical Trial Group 193A Study Team. J Acquir Immune Defic Syndr Hum Retrovirol 1998;19: 339-49.
Montaner JS, Reiss P, Cooper D, Vella S, Harris M, Conway B, et al. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study. JAMA 1998;279: 930-7.
Hirsch M, Steigbigel R, Staszewski S, Mellors J, Scerpella E, Hirschel B, et al. A randomized, controlled trial of indinavir, zidovudine, and lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior antiretroviral therapy. J Infect Dis 1999;180: 659-65.
Garcia F, Romeu J, Grau I, Sambeat MA, Dalmau D, Knobel H, et al. A randomized study comparing triple versus double antiretroviral therapy or no treatment in HIV-1-infected patients in very early stage disease: the Spanish Earth-1 study. AIDS 1999;13: 2377-88.
Floridia M, Bucciardini R, Ricciardulli D, Fragola V, Pirillo MF, Weimer LE, et al. A randomized, double-blind trial on the use of a triple combination including nevirapine, a nonnucleoside reverse transcriptase HIV inhibitor, in antiretroviral-naive patients with advanced disease. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20: 11-9.
Friedland GH, Pollard R, Griffith B, Hughes M, Morse G, Bassett R, et al. Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease with CD4 counts of 100 to 500 cells/mm3 (ACTG 261). ACTG 261 Team. J Acquir Immune Defic Syndr 1999;21: 281-92.
Stellbrink HJ, Hawkins DA, Clumeck N, Cooper DA, Myers R, Delfraissy JF, et al. Randomised, multicenter phase III study of saquinavir plus zidovudine plus zalcitabine in previously untreated or minimally pretreated HIV-infected patients. Clin Drug Invest 2000;20: 295-307.
Green S, Para MF, Daly PW, et al. Interim analysis of plasma viral burden reductions and CD4 increases in HIV-1-infected patients with rescriptor, retrovir, and epivir. 12th World AIDS conference, Geneva, 1998.
Moyle G, de Cian W, Hawkins D, Wood R, Horban A, White D. Final 54-week analysis of a placebo-controlled trial (13 C) of delavirdine plus two nucleoside analogs (NA) versus two NA in drug-naive and experienced individuals. 39th interscience conference on antimicrobial agents chemotherapy, San Francisco, CA, 26-9 Sept 1999.
Cozzi-Lepri A, Phillips AN, d'Arminio Monforte A, Piersantelli N, Orani A, Petrosillo N, et al. Virologic and immunologic response to regimens containing nevirapine or efavirenz in combination with 2 nucleoside analogues in the Italian Cohort Naive Antiretrovirals (I.Co.N.A.) study. J Infect Dis 2002;185: 1062-9.
Matthews GV, Sabin CA, Mandalia S, Lampe F, Phillips AN, Nelson MR, et al. Virological suppression at 6 months is related to choice of initial regimen in antiretroviral-naive patients: a cohort study. AIDS 2002;16: 53-61.
Phillips AN, Pradier C, Lazzarin A, Clotet B, Goebel FD, Hermans P, et al. Viral load outcome of non-nucleoside reverse transcriptase inhibitor regimens for 2203 mainly antiretroviral-experienced patients. AIDS 2001;15: 2385-95.
Van Leth F, Hassink E, Phanuphak P, Miller S, Gazzard B, Cahn P, et al. Results of the 2NN study: a randomized comparative trial of first-line antiretroviral therapy with regimens containing either nevirapine alone, efavirenz alone or both drugs combined, together with stavudine and lamivudine. 10th conference on retroviruses and opportunistic infections, Boston, MA, 10-14 Feb 2003.
Richman DD, Havlir D, Corbeil J, Looney D, Ignacio C, Spector SA, et al. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 1994;68: 1660-6.
Albrecht MA, Bosch RJ, Hammer SM, Liou SH, Kessler H, Para MF, et al. Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. N Engl J Med 2001;345: 398-407.
Podzamczer D, Ferrer E, Consiglio E, Gatell JM, Perez P, Perez JL, et al. A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study). Antivir Ther 2002;7: 81-90.
Van Leeuwen R, Katlama C, Murphy RL, Squires K, Gatell J, Horban A, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003;17: 987-999.
Weidle PJ, Malamba S, Mwebaze R, Sozi C, Rukundo G, Downing R, et al. Assessment of a pilot antiretroviral drug therapy programme in Uganda: patients' response, survival, and drug resistance. Lancet 2002;360: 34-40.(Yazdan Yazdanpanah, senio)
Correspondence to: Y Yazdanpanah yyazdan@yahoo.com
Abstract
The introduction in industrialised countries of highly active antiretroviral therapy—a combination of three drugs including either a protease inhibitor or a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI) and two nucleoside analogue reverse transcriptase inhibitors (NRTIs)—led to a dramatic decline in morbidity and mortality among patients infected with HIV-1.1-3 Many different combinations of highly active antiretroviral therapy regimens are available, some of which differ in toxicity, adverse events, their ability to suppress viral replication, the development of viral resistance, and patient adherence.4-7
Randomised clinical trials are accepted as the most powerful tool for assessing the effectiveness of medical interventions, yet no trials have compared the clinical effectiveness of protease inhibitor based and NNRTI based combination therapies. Thus it is unclear whether there are relevant differences between the regimens in prevention of clinical progression to AIDS or death. In trials comparing highly active antiretroviral therapy regimens the low rate of disease progression made it impractical to use clinical events as primary end points. A meta-analysis of 16 randomised trials showed that treatments resulting in similar changes in HIV-1 RNA or CD4 cell counts were associated with widely varying clinical outcomes.8 Trials exclusively reporting surrogate endpoint data therefore have to be interpreted with caution.9
In the absence of trials comparing two treatments, indirect comparisons have been advocated.10 We performed indirect comparisons between triple regimens based on protease inhibitors and NNRTIs by using clinical and surrogate endpoint data from randomised controlled trials comparing triple regimens with dual regimens.
Methods
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 (fig 1). The 14 trials totalled 6785 patients (table 1).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.
Fig 1 Identification of relevant trials
Table 1 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
Clinical progression occurred in 445 of 3392 patients (13.1%) receiving triple therapy and 651 of 3393 (19.2%) patients receiving dual therapy (fig 2): 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 (2 = 0.073, test of heterogeneity P = 0.090).
Fig 2 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).
Figure 3 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 (fig 3). 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).
Fig 3 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; table 2). 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).
Table 2 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
Discussion
Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 1998;352: 1725-30.
Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;338: 853-60.
Egger M, Hirschel B, Francioli P, Sudre P, Wirz M, Flepp M, et al. Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. Swiss HIV cohort study. BMJ 1997;315: 1194-9.
Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, et al. 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 1999;341: 1865-73.
Walmsley S, Bernstein B, King M, Arribas J, Beall G, Ruane P, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002;346: 2039-46.
Fellay J, Boubaker K, Ledergerber B, Bernasconi E, Furrer H, Battegay M, et al. Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV cohort study. Lancet 2001;358: 1322-7.
Trotta MP, Ammassari A, Cozzi-Lepri A, Zaccarelli M, Castelli F, Narciso P, et al. Adherence to highly active antiretroviral therapy is better in patients receiving non-nucleoside reverse transcriptase inhibitor-containing regimens than in those receiving protease inhibitor-containing regimens. AIDS 2003;17: 1099-102.
Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: a meta-analysis. HIV Surrogate Marker Collaborative Group. AIDS Res Hum Retroviruses 2000;16: 1123-33.
Bucher HC, Guyatt GH, Cook DJ, Holbrook A, McAlister FA. Users' guides to the medical literature: XIX. Applying clinical trial results. A. How to use an article measuring the effect of an intervention on surrogate end points. Evidence-Based Medicine Working Group. JAMA 1999;282: 771-8.
Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003;326: 472.
Lefebvre C, Clarke M. Identifying randomised trials. In: Egger M, Smith G, Altman D, eds. Systematic reviews in health care: meta-analysis in context, 2nd ed. London: BMJ Books, 2001: 69-86.
Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med 2002;137: 381-433.
Yeni PG, Hammer SM, Carpenter CC, Cooper DA, Fischl MA, Gatell JM, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA 2002;288: 222-35.
Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. JAMA 1993;269: 460.
Jüni P, Altman D, Egger M. Assessing the quality of controlled clinical trials. BMJ 2001;323: 42-6.
Deeks J, Altman D, Bradburn M. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Smith G, Altman D, eds. Systematic reviews in health care: meta-analysis in context, 2nd ed. London: BMJ Books, 2001: 285-312.
Thompson S, Sharp S. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med 1999;18: 2693-708.
Egger M, Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: 629-34.
Sterne J, Egger M, Smith G. Investigating and dealing with publication and other biases in meta-analysis. BMJ 2001;323: 101-5.
Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997;337: 734-9.
Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997;337: 725-33.
Cameron DW, Heath-Chiozzi M, Danner S, Cohen C, Kravcik S, Maurath C, et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet 1998;351: 543-9.
D'Aquila RT, Hughes MD, Johnson VA, Fischl MA, Sommadossi JP, Liou SH, et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Ann Intern Med 1996;124: 1019-30.
Collier AC, Coombs RW, Schoenfeld DA, Bassett RL, Timpone J, Baruch A, et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N Engl J Med 1996;334: 1011-7.
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