Fox MP, Sanne IM, Conradie F, Zeinecker J, Orrell C, Ive P, Rassool M, Dehlinger M, van der Host C, McIntyre J, Wood R. Initiating patients on antiretroviral therapy at CD4 cell counts above 200 cells/µl is associated with improved treatment outcomes in South Africa. AIDS. 2010; 24:2041-50.
In November 2009, the World Health Organization (WHO) recommended that HIV-infected patients initiate antiretroviral therapy (ART) at CD4+ counts ≤350 cells/µL as opposed to ≤200 CD4+ cells/µL.(1) WHO recommendations were more conservative than guidelines used in high-income countries, where ART is often initiated at even higher CD4+ levels. The decision when to start ART balances medical benefit, toxicity, more rapid emergence of resistance, infectiousness and cost.(2, 3)
To examine the association between starting ART at the new higher CD4+ treatment threshold and treatment outcomes.
This study uses data collected as part of the Comprehensive International Program of Research on AIDS - South Africa (CIPRA-SA) randomized trial of physician-monitored versus nurse-monitored ART in South Africa.(4) The study population was HIV-infected ART-naïve patients ≥16 years of age with ≤350 CD4+ cells/µL or a prior AIDS-defining illness attending one of two urban clinical sites in South Africa.
Initial therapy was zidovudine (AZT) plus lamivudine (3TC) plus with nevirapine (NVP) or efavirenz (EFV); a small number of women of childbearing potential received protease inhibitors instead of NVP or EFV. Participants were analyzed as a cohort with the exposure variable being CD4+ count at time of ART initiation (≤200 vs. 201-350 CD4+ cells/µL) and outcome treatment failure.
Eight hundred twelve patients enrolled in the study; the median age was 32 years, and 70% were women. Patients were followed for a median of 27.5 months. Of the 812 participants, 518 (64%) had CD4+ counts ≤200 cells/µL and 294 (36%) >200 cells/µL. Participants with ≤200 CD4+ cells/µL were sicker; they had higher viral loads and were more likely to have WHO stage IV or CDC stage C disease. Twenty-one (2.6%) participants died, 83 (10.2%) failed treatment and 50 (6.2%) developed tuberculosis (TB); the risk of death was 5.39 higher (95% CI: 1.26-22.0), the risk of virologic failure 1.79 times higher (95% CI: 1.10-2.90) and the risk of TB was 2.59 times higher (95% CI: 1.27-5.24) in those with ≤200 CD4+ cells/µL compared to those with higher CD4+ counts. Those with higher CD4+ counts, however, were marginally more likely to be lost to follow up (14.3% vs. 10%, RR=0.70, 95% CI: 0.48-1.03).
This cohort analysis of CIPRA-SA data demonstrate improved mortality and virologic outcomes in patients who started ART at >200 CD4+ cells/µL compared to those who started at CD4+ counts of ≤200 cells/µL. These findings are consistent with data from the CIPRA-HT001 trial from Haiti, which found a 5.4-fold (95% CI: 1.3-23.0) increased risk of mortality or virologic failure.(5)
This is a cohort study, rather than a randomized controlled trial, so the likelihood of uncontrolled confounding is increased. As a cohort study, this analysis is of high quality with low lost-to-follow-up rates.
This analysis adds further weight to the WHO treatment guidelines, which have already recommended beginning HIV-infected patients on ART with ≤350 CD4+ cells/µL.
- WHO. Antiretroviral therapy for HIV infection in adults and adolescents. Recommendation for a public health approach. 2010 revision. Geneva: World Health Organization, 2010.
- Sabin CA, Phillips AN. Should HIV therapy be started at a CD4 cell count above 350 cells/microl in a symptomatic HIV-1-infected patients? Curr Opin Infect Dis. 2009; 22:191-97.
- Walensky RP, Wolf LL, Wood R, Fofana MO, Freedberg KA, Martinson NA, et al. When to start antiretroviral therapy in resource-limited settings. Ann Intern Med. 2009; 151:157-66.
- Sanne I, Orrell C, Fox MP, Conradie F, Ive P, Zeinecker J, et al., for the CIPRA-SA Study Team. Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial. Lancet. 2010; 376:33-40.
- Severe P, Juste MA, Ambroise A, Eliacin L, Marchand C, Apollon S, Edwards A, Bang H, Nicotera J, Godfrey C, Gulick RM, Johnson WD Jr, Pape JW, Fitzgerald DW. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med. 2010; 363:257-65. HIV Programming