Starting antiretroviral therapy early at higher CD4 cell counts improves short term treatment outcomes in resource-poor countries

HIV-positive adult Cote D’Ivoirians who started antiretroviral therapy before CD4 counts fell below 350 cells/mm³ experienced significantly improved treatment outcomes with fewer deaths when compared to those who started treatment later, according to the findings of a paper published in the November 30^th edition of AIDS.

International and national efforts across sub-Saharan Africa are on-going to provide universal antiretroviral therapy access to millions of HIV-positive patients. At present, the treatment guidelines recommend starting anti-HIV treatment when CD4 counts are less than 200 cells/mm³ in HIV-infected patients. However, some of these patients already have considerable immunosuppression and experience HIV disease progression or even death within a few months of starting antiretrovirals.

The incidence of deaths occurring during the early months following antiretroviral initiation is higher in African patients than that in patients from industrialized countries. With increasing access to antiretroviral therapy soon becoming a reality in Africa, it is important to institute interventions which prevent mortality in patients in resource-poor settings who start anti-HIV therapy when immunosuppression has advanced.

There is a paucity of information about risk factors which account for the increased incidence of mortality and morbidity within the first months following the initiation of anti-HIV treatment. A team of French and Cote D’Ivoirian researchers have addressed this issue in a cohort of HIV-infected adults in Cote D’Ivoire. The study was part of a bigger study of structured treatment interruption strategies in HIV-infected subjects in Abidjan.

This part of the study focused on the initiation of anti-HIV therapy in consenting patients 18n years old or older with no history of antiretroviral use, CD4 counts between 150 and 350 cells/mm³ or CD4 percentage between 12.5 and 20.0 %. All patients were given prophylaxis with cotrimoxazole.

All patients started continuous ART with either AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir) and efavirenz (Sustiva) or efavirenz or AZT, 3TC and indinavir/ritonavir. The patients were followed for eight months before being randomised for the second phase of the study. Patients in the treatment initiation phase therefore had CD4 cell counts which were higher than the recommended threshold for starting antiretroviral therapy.

The incidence of severe morbidity was monitored during the first months of treatment. Severe morbidity was defined as all World Health Organization (WHO) stage three or four four-defining morbidity events other than oral candidiasis. Virological success during the first months of anti-HIV treatment was defined as the first time when a viral load was undetectable. Immunological response was defined as the first time that there was a gain in CD4 cell counts of at least 50 cells/mm³ from baseline.

Trends for incidence of morbidity and death over time and the association of virological and immunological outcomes and other variables with severe morbidity and with death were analysed using statistical models.

Out of 840 adults enrolled in the trial, 48 were excluded from the analyses for various reasons. Out of the 792 patients who remained in the analyses, 71 % had a CD4 cell count of more than 200 cells/mm³ and 64 % were at WHO stage 1 or 2, indicating no or symptoms of HIV infection or very mild symptoms. This cohort started ART with a median CD4 cell count of 252 cells/mm³ and were followed for a median of eight months.

In patients with pre-ART CD4 cell count 350 cells/mm³, the incidence of mortality was 5.0, 1.7 and 0.0 /100 person-years, and incidence of severe morbidity was 13.3, 9.5 and 7.9/100 person-years, respectively.

The most frequent diseases were invasive bacterial diseases (32/65 episodes, 49%) and tuberculosis (TB, 5/65 episodes, 38%). The first episode of TB occurred when the median last CD4 count was 235 cells/mm³ and the median time since initiation of antiretroviral therapy was 3.7 months.

The overall incidence of mortality during the first, second, and third quarter following ART initiation was 3.1, 1.0, and 1.5/100 person-years, respectively. The overall incidence of severe morbidity during the same periods was 16.6, 10.2, and 6.6/100 person-years, respectively.

Patients who experienced severe illness had higher risks of mortality, virological failure and immunological failure. The baseline risk factors for mortality and/or severe morbidity were high viral load, advanced clinical stage, past history of TB, low body mass index (BMI), low haemoglobin and low CD4 cell count. During follow-up, low CD4 cell count and persistently detectable viral load were risk factors.

Treatment guidelines in industrialised countries are already being revised to recommend initiation of anti-HIV treatment when the CD4 cell count falls below 350 cells/mm³, and the findings from Cote d'Ivoire are likely to raise calls for earlier treatment in resource-limited settings.