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Effectiveness of antiretroviral treatment in a South African program: a cohort study
Global Health Sciences Literature Digest
Published May 6, 2008
Journal Article

Fairall LR, Bachmann MO, Louwagie GM, van Vuuren C, Chikobvu P, Steyn D, et al. Effectiveness of antiretroviral treatment in a South African program: a cohort study. Arch Intern Med 2008 Jan 14;168(1):86-93.


To study the effects of highly active antiretroviral treatment (HAART) on mortality, tuberculosis, CD4 cell counts, and body weight among HIV-infected patients who qualify for treatment in a public facility in South Africa.

Study Design

A cohort study with repeated measures was conducted from May 3, 2004 until December 31, 2005.


Twenty sites in a public sector antiretroviral treatment project in Free State, South Africa.


14,267 patients at least 16 years old with HIV infection were enrolled in the Comprehensive Care, Management and Treatment of HIV and AIDS Program and followed for up to 20 months after enrollment.


Patients received health care at 13 assessment clinics, four treatment sites, and three combined assessment and treatment sites that were located in all five districts of the Free State province. After being diagnosed with HIV infection at any Free State clinic, patients were referred to nurse-run assessment sites. Patients with World Health Organization (WHO) stage 4 AIDS or a CD4 cell count of 200 cells/µL or less were referred to a physician at a treatment site for possible initiation of HAART. For patients with active tuberculosis or other serious opportunistic infections, HAART was deferred until patients were clinically stable or until the intensive phase of tuberculosis treatment was completed. Cotrimoxazole prophylaxis was indicated if the CD4 cell count was 200 cells/µL or less or if WHO stage 3 or 4 disease was present. Patients receiving HAART were monitored monthly at clinic visits and quarterly by a hospital physician.

Primary Outcomes

The primary outcomes were death, newly diagnosed tuberculosis, and changes in CD4 cell count and weight.


Of the 14,267 patients enrolled, 3619 (25%) received HAART for up to 19 months, 68.3% stavudine, lamivudine and efavirenz, and 29.7% a regimen that substituted nevirapine for efavirenz. Of 4,570 patients followed up for at least 1 year, 53.2% died, and 87% of those dying had not received HAART. HAART was associated with lower mortality (hazard ratio, 0.14; 95% confidence interval [CI], 0.11-0.18) and with the presence of tuberculosis (hazard ratio, 0.61; 95% CI, 0.46-0.81) after adjusting for age, sex, weight, clinic, district, CD4 cell count, cotrimoxazole therapy, tuberculosis at baseline, and previous antiretroviral therapy. Cotrimoxazole therapy was associated with lower mortality (hazard ratio, 0.37; 95% CI, 0.32-0.42). Each month of HAART was associated with an increase in CD4 cell count of 15 cells/µL (95% CI, 14.7-15.5 cells/µL) and with an increase in body weight of 602 g (95% CI, 548-658 g).


The authors conclude that HAART provided through these South African government health services seems as effective as that provided in high-income countries. Delays starting HAART contributed to higher mortality rates.

Quality Rating

Based on the Newcastle-Ottawa quality rating for cohort studies, this study is of high quality. Some of its strengths include active follow-up of survival through data linkage with the national death register; use of the statistical method of marginal structural models, which corrects for bias due to time-varying covariates that both predict treatment and are an outcome measure for treatment, a classic example of which is CD4 cell count;(6,7,8) presenting results with and without the weighting method that is used in marginal structural models; estimation of the effect of HAART on body weight; estimation of the independent effect of cotrimoxazole therapy combined with HAART; inclusion of almost all patients enrolled in a province-wide government program; and successive CD4 cell count and weight measurements. The study was limited by the following: lack of viral loads and WHO staging for untreated patients; possible unreported deaths among the 15.9% of patients without national identifiers; possible underestimation of the incidence of tuberculosis; assumption that patients continued to receive HAART or cotrimoxazole therapy once started. The relatively short follow-up does not permit extrapolation to longer periods of treatment.

In Context

No studies have compared patients receiving HAART with similar patients not receiving HAART in developing countries, as has been done in cohort studies from Europe and the United States. However, several research studies and HAART programs have shown similar levels of health improvements attributed to HAART, as demonstrated in this study. For example, non-governmental organizations and research-supported HAART services in South Africa(1,2) and Haiti,(3) countrywide treatment in Malawi,(4) and routine treatment in Europe and the United States(5,6,7,8) all provide corroborating evidence of the effectiveness of HAART programs in developed and developing countries. HAART delivered outside the research or non-government organization setting, as in this report, is most similar to the report by Libamba et al in Malawi.(4)

Programmatic Implications

Many countries have already developed ART roll-out programs to reach patients who are in need of HAART. However, lack of health system infrastructure and resources has often led to uneven distribution of treatment in resource-limited settings. This study shows that HAART provided by South African public sector health services can be effective. The results of this study reflect patients who were selected as being most ready to provide or receive HAART; therefore, they cannot be extrapolated directly to larger-scale provision. However, the findings of high death rates among those untreated do suggest that there is an urgent need to increase coverage and commencement of HAART among those who qualify for treatment.


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  2. Bekker LG, Myer L, Orrell C, Lawn S, Wood R. Rapid scale-up of a community-based HIV treatment service: programme performance over 3 consecutive years in Guguletu, South Africa. S Afr Med J 2006;96(4):315-20.
  3. Severe P, Leger P, Charles M, et al. Antiretroviral therapy in a thousand patients with AIDS in Haiti. N Engl J Med 005;353(22):2325-34.
  4. Libamba E, Makombe S, Mhango E, de Ascurra Teck O, Limbambala E, Schouten EJ, et al. Supervision, monitoring and evaluation of nationwide scale-up of antiretroviral therapy in Malawi. Bull World Health Organ 2006;84(4):320-6.
  5. Sterne JA, Hernan MA, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet 2005;366(9483):378-84.
  6. Cole SR, Hernan MA, Robins JM, Anastos K, Chmiel J, Detels R, et al. Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models. Am J Epidemiol 2003;158(7):687-94.
  7. Cole SR, Hernan MA, Margolick JB, Cohen MH, Robins JM. Marginal structural models for estimating the effect of highly active antiretroviral therapy initiation on CD4 cell count. Am J Epidemiol 2005;162(5):471-78.
  8. Hernan MA, Brumback BA, Robins JM. Estimating the causal effect of zidovudine on CD4 count with a marginal structural model for repeated measures. Stat Med 2002;21(12):1689-1709.