Two-months-off, four-months-on antiretroviral regimen increases the risk of resistance, compared with continuous therapy: a randomized trial involving West African adults.
BACKGROUND
A randomized trial was launched in Côte d'Ivoire in 2002 to compare continuous antiretroviral treatment (hereafter, "C-ART") to an ART regimen of 2 months off and 4 months on therapy (hereafter, "2/4-ART"). We report the final analysis.


METHODS
A total of 435 adults who were receiving successful ART ((median CD4 cell count prior to ART, 272 cells/mm(3); 88% were receiving a zidovudine-lamivudine-efavirenz regimen) were randomized to receive C-ART or 2/4-ART. The main primary end point was the percentage of patients with <350 CD4 cells/mm(3) at 24 months. The sample size ensured 80% power to demonstrate noninferiority (noninferiority bound, -15%), assuming that 30% of the patients in the C-ART arm would have <350 CD4 cells/mm(3). Other end points were mortality, morbidity, cost of care, genotypic resistance, adherence, and toxicity.


RESULTS
The percentage of patients with <350 CD4 cells/mm(3) at 24 months was 5.6% (6 of 107) in the C-ART arm and 14.6% (46 of 315) in the 2/4-ART arm (lower bound of the 95% CI for the difference, -14%). Cost was 18% higher in the C-ART arm, and resistance to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) was 20% higher in the 2/4-ART arm. Other end points were nonconclusive.


CONCLUSIONS
Although 2/4-ART met the predetermined criteria for noninferiority, the percentage of patients with <350 CD4 cells/mm(3) in the C-ART arm was lower than anticipated, which makes the clinical significance of this noninferiority uncertain. In addition, 2/4-ART led to an unacceptable additional risk of selecting for drug-resistant virus. This new argument against episodic ART strategies is also a caveat against any unplanned ART interruptions in Africa, where most patients receive NNRTIs.
Danel
Christine
C
INSERM, Unité 897, Centre de Recherche Epidémiologie et Biostatistique, Bordeaux, France.
Moh
Raoul
R
Chaix
Marie-Laure
ML
Gabillard
Delphine
D
Gnokoro
Joachim
J
Diby
Charles-Joseph
CJ
Toni
Thomas
T
Dohoun
Lambert
L
Rouzioux
Christine
C
Bissagnene
Emmanuel
E
Salamon
Roger
R
Anglaret
Xavier
X
D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D007560:Cote d'Ivoire / Q000453:epidemiology; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000502:physiology; D005260:Female; D006678:HIV / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007182:Income; D008297:Male; D009154:Mutation; D011897:Random Allocation; D016896:Treatment Outcome; D019562:Viral Load; D014765:Viral Vaccines / Q000627:therapeutic use
D044966:Anti-Retroviral Agents; D014765:Viral Vaccines