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Randomized Controlled Trial
. 2010 Nov 15;202(10):1529-37.
doi: 10.1086/656718. Epub 2010 Oct 13.

A randomized factorial trial comparing 4 treatment regimens in treatment-naive HIV-infected persons with AIDS and/or a CD4 cell count <200 cells/μL in South Africa

Phidisa II Writing Team for Project Phidisa; Andrew Ratsela, Michael Polis, Sibongiseni Dhlomo, Sean Emery, Greg Grandits, Paul Khabo, Thandeka Khanyile, Stephanus Komati, James D Neaton, Lionel Chris David Naidoo, Daphne Magongoa, Duma Qolohle
Collaborators
Randomized Controlled Trial

A randomized factorial trial comparing 4 treatment regimens in treatment-naive HIV-infected persons with AIDS and/or a CD4 cell count <200 cells/μL in South Africa

Phidisa II Writing Team for Project Phidisa et al. J Infect Dis. .

Abstract

Background: Few randomized trials comparing antiretroviral therapy (ART) regimens have been conducted in resource-limited settings.

Methods: In the Republic of South Africa, antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals >14 years old with a CD4 cell count <200 cells/μL or a prior AIDS diagnosis were randomized to receive efavirenz (EFV) or lopinavir/ritonavir (LPV/r) with either zidovudine (ZDV) plus didanosine (ddI) or stavudine (d4T) plus lamivudine (3TC) in an open-label, 2-by-2 factorial study and followed up for the primary outcome of AIDS or death and prespecified secondary outcomes, including CD4 cell count and viral load changes, treatment discontinuation, and grade 4 events.

Results: In total, 1771 persons were randomized and followed up for a median of 24.7 months. AIDS or death occurred in (1) 163 participants assigned EFV and 157 assigned LPV/r (hazard ratio [HR], 1.04 [95% confidence interval {CI}, 0.84-1.30]) and in (2) 170 participants assigned ZDV+ddI and 150 assigned d4T+3TC (HR, 1.15 [95% CI, 0.93-1.44]). HIV RNA levels were lower (P < .001) and CD4 cell counts were greater (P < .01) over follow-up for d4T+3TC versus ZDV+ddI. Rates of potentially life-threatening adverse events and overall treatment discontinuation were similar for d4T+3TC and ZDV+ddI; however, more participants discontinued d4T because of toxicity (12.6%) than other treatments (<5%).

Conclusion: EFV and LPV/r are effective components of first-line ART. The poorer viral and immune responses with ZDV+ddI and the greater toxicity-associated discontinuation rate with d4T+3TC suggest that these treatments be used cautiously as initial therapy.

Trial registration: ClinicalTrials.gov identifier: NCT00342355.

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Conflict of interest statement

Sean Emery has received grant support, travel awards and honoriums from Abbott, Boehnringer-Ingleheim, Bristol Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, and Tibotec. All other authors do not have a commercial or other association that may pose a conflict of interest.

Figures

Figure 1
Figure 1
Randomization and follow-up of subjects on study Phidisa II study design.
Figure 2
Figure 2
Cumulative percent of subjects with HIV viral loads <400 copies/mL for EFV vs. LPV/r (2a) and for ZDV + ddI vs. d4T + 3TC (2b). CD4+ lymphocyte cell counts/mm3 for EFV vs. LPV/r (2c) and for ZDV + ddI vs. d4T + 3TC (2d) The numbers below the x-axis represent the numbers of subjects in each group at each time point. Figure 2a. Percent Viral Load < 400 Over Follow-up for Efavirenz vs. Lopinavir/Ritonavir Figure 2b. Percent Viral Load < 400 Over Follow-up for Zidovudine + Didanosine vs. Stavudine + Lamivudine Figure 2c. CD4 Count Over Follow-up for Efavirenz vs. Lopinavir/Ritonavir Figure 2d. CD4 Count Over Follow-up for Zidovudine + Didanosine vs. Stavudine + Lamivudine
Figure 2
Figure 2
Cumulative percent of subjects with HIV viral loads <400 copies/mL for EFV vs. LPV/r (2a) and for ZDV + ddI vs. d4T + 3TC (2b). CD4+ lymphocyte cell counts/mm3 for EFV vs. LPV/r (2c) and for ZDV + ddI vs. d4T + 3TC (2d) The numbers below the x-axis represent the numbers of subjects in each group at each time point. Figure 2a. Percent Viral Load < 400 Over Follow-up for Efavirenz vs. Lopinavir/Ritonavir Figure 2b. Percent Viral Load < 400 Over Follow-up for Zidovudine + Didanosine vs. Stavudine + Lamivudine Figure 2c. CD4 Count Over Follow-up for Efavirenz vs. Lopinavir/Ritonavir Figure 2d. CD4 Count Over Follow-up for Zidovudine + Didanosine vs. Stavudine + Lamivudine
Figure 2
Figure 2
Cumulative percent of subjects with HIV viral loads <400 copies/mL for EFV vs. LPV/r (2a) and for ZDV + ddI vs. d4T + 3TC (2b). CD4+ lymphocyte cell counts/mm3 for EFV vs. LPV/r (2c) and for ZDV + ddI vs. d4T + 3TC (2d) The numbers below the x-axis represent the numbers of subjects in each group at each time point. Figure 2a. Percent Viral Load < 400 Over Follow-up for Efavirenz vs. Lopinavir/Ritonavir Figure 2b. Percent Viral Load < 400 Over Follow-up for Zidovudine + Didanosine vs. Stavudine + Lamivudine Figure 2c. CD4 Count Over Follow-up for Efavirenz vs. Lopinavir/Ritonavir Figure 2d. CD4 Count Over Follow-up for Zidovudine + Didanosine vs. Stavudine + Lamivudine
Figure 2
Figure 2
Cumulative percent of subjects with HIV viral loads <400 copies/mL for EFV vs. LPV/r (2a) and for ZDV + ddI vs. d4T + 3TC (2b). CD4+ lymphocyte cell counts/mm3 for EFV vs. LPV/r (2c) and for ZDV + ddI vs. d4T + 3TC (2d) The numbers below the x-axis represent the numbers of subjects in each group at each time point. Figure 2a. Percent Viral Load < 400 Over Follow-up for Efavirenz vs. Lopinavir/Ritonavir Figure 2b. Percent Viral Load < 400 Over Follow-up for Zidovudine + Didanosine vs. Stavudine + Lamivudine Figure 2c. CD4 Count Over Follow-up for Efavirenz vs. Lopinavir/Ritonavir Figure 2d. CD4 Count Over Follow-up for Zidovudine + Didanosine vs. Stavudine + Lamivudine
Figure 3
Figure 3
Kaplan-Meier curves for death or progression of disease for EFV vs. LPV/r (3a), death for EFV vs. LPV/r (3b), death or progression of disease for ZDV + ddI vs. d4T + 3TC (3c), and death for ZDV + ddI vs. d4T + 3TC (3d). Figure 3a. KM Curve for Death or Progression of Disease for Efavirenz Versus Lopinavir/Ritonavir Figure 3b. KM Curve for Death for Efavirenz Versus Lopinavir/Ritonavir Figure 3c. KM Curve for Death or Progression of Disease for Zidovudine + Didanosine Versus Stavudine +Lamivudine Figure 3d. KM Curve for Death for Zidovudine + Didanosine Versus Stavudine +Lamivudine
Figure 3
Figure 3
Kaplan-Meier curves for death or progression of disease for EFV vs. LPV/r (3a), death for EFV vs. LPV/r (3b), death or progression of disease for ZDV + ddI vs. d4T + 3TC (3c), and death for ZDV + ddI vs. d4T + 3TC (3d). Figure 3a. KM Curve for Death or Progression of Disease for Efavirenz Versus Lopinavir/Ritonavir Figure 3b. KM Curve for Death for Efavirenz Versus Lopinavir/Ritonavir Figure 3c. KM Curve for Death or Progression of Disease for Zidovudine + Didanosine Versus Stavudine +Lamivudine Figure 3d. KM Curve for Death for Zidovudine + Didanosine Versus Stavudine +Lamivudine
Figure 3
Figure 3
Kaplan-Meier curves for death or progression of disease for EFV vs. LPV/r (3a), death for EFV vs. LPV/r (3b), death or progression of disease for ZDV + ddI vs. d4T + 3TC (3c), and death for ZDV + ddI vs. d4T + 3TC (3d). Figure 3a. KM Curve for Death or Progression of Disease for Efavirenz Versus Lopinavir/Ritonavir Figure 3b. KM Curve for Death for Efavirenz Versus Lopinavir/Ritonavir Figure 3c. KM Curve for Death or Progression of Disease for Zidovudine + Didanosine Versus Stavudine +Lamivudine Figure 3d. KM Curve for Death for Zidovudine + Didanosine Versus Stavudine +Lamivudine
Figure 3
Figure 3
Kaplan-Meier curves for death or progression of disease for EFV vs. LPV/r (3a), death for EFV vs. LPV/r (3b), death or progression of disease for ZDV + ddI vs. d4T + 3TC (3c), and death for ZDV + ddI vs. d4T + 3TC (3d). Figure 3a. KM Curve for Death or Progression of Disease for Efavirenz Versus Lopinavir/Ritonavir Figure 3b. KM Curve for Death for Efavirenz Versus Lopinavir/Ritonavir Figure 3c. KM Curve for Death or Progression of Disease for Zidovudine + Didanosine Versus Stavudine +Lamivudine Figure 3d. KM Curve for Death for Zidovudine + Didanosine Versus Stavudine +Lamivudine
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