High early mortality after starting antiretroviral treatment in Africa

Patients starting antiretroviral therapy in sub-Saharan Africa have a high rate of mortality, according to a review article published in the October 1^st edition of AIDS. Many of the deaths occurred in the first three months of treatment, and there was also notable mortality in the interval between joining a treatment programme and actually starting therapy.

Although initial pessimism over large-scale antiretroviral treatment in sub-Saharan Africa has mostly proved to be unfounded (around 28% of people in need are now receiving treatment) early mortality rates are very high. An international team of investigators therefore reviewed the mortality rates, timing, risk factors, and causes of death among adult patients accessing antiretroviral programmes in sub-Saharan Africa.

Data from 18 published cohort studies were reviewed. The studies give information on 39,536 patients treated in nine countries, mostly through public antiretroviral therapy access schemes. The median baseline CD4 cell count in these studies ranged from 43 to 147 cells/mm³, and the duration of follow-up varied between three and 46 months. The vast majority of patients had never received antiretrovirals before, and most started treatment with two nucleoside analogues and one non-nucleoside reverse-transcriptase inhibitor.

The authors comment that high early mortality within antiretroviral programmes in sub-Saharan Africa “has emerged as a key challenge”. After twelve months, between 8% and 26% of patients who were not lost to follow up had died. The greatest burden of mortality occurred during the initial months of therapy. In most cohorts, mortality rates were high within the first year, and particularly the early months, despite good virological suppression, then fell substantially in the second year. However in some cohorts, mortality persisted in the second year, which might be explained by poorer responses to treatment.

These figures are worse than those from initial studies of mortality in similar programmes, note the authors. However mortality data are not always reliable, and in some cases mortality is likely to be underestimated as unascertained deaths may be misclassified as loss to follow-up. Cohorts in South Africa and Ivory Coast with good verification of outcomes found that, whereas most deaths occurred in the first months of treatment in patients with the lowest baseline CD4 cell counts, losses to follow-up were evenly distributed over time and were not associated with CD4 cell counts. However if a programme reports high loss to follow-up over initial months of treatment, this could point to high rates of unascertained deaths.

High mortality rates were also found during the period before starting treatment. In Cape Town, one study found that 67% of deaths during the first three months occurred in the period between enrolment and starting antiretroviral treatment (approximately 30 days). Another South African cohort reported 87% of deaths prior to starting therapy. The authors cite delays in patient referral, waiting lists for antiretroviral treatment, and time taken to prepare patients as likely contributing factors. “How to balance the need for thorough preparation of patients for life-long therapy with the high risk of death among individuals waiting to start therapy requires urgent research attention”, they advocate.

The key risk factors identified for early mortality were low CD4 cell counts and advanced disease (WHO stage 4). Compared with people with higher CD4 cell counts, individuals with a CD4 count of less than 50 cells/mm³ were two and a half times more likely to die (summary hazard ratio 2.5; 95% CI, 1.9–3.2). Compared with WHO stages 1-3, WHO stage 4 was also associated with more than a doubling in the hazard of death (summary hazard ratio 2.2; 95% CI, 1.5–3.2).

High early mortality, as much as four-fold higher, has also been reported from private programmes in which people must pay for treatment, possibly due to poorer adherence compared with public programmes. Although data are limited, leading causes of death appear to be tuberculosis, acute sepsis, cryptococcal meningitis, malignancy, and wasting syndrome. These reflect the causes of death prior to starting antiretroviral therapy, although immune reconstitution syndrome could also be a contributory cause. However, drug toxicity appears to be a relatively minor cause of early mortality.

The authors conclude that mortality rates are likely to depend not only on the care delivered by antiretroviral treatment programmes, but also on disease progression at programme enrolment and the quality of preceding health care. Strategies to reduce early mortality include promotion of early HIV diagnosis, strengthening of patient care before and during antiretroviral therapy, laboratory monitoring, timely initiation and provision of free therapy, support to encourage adherence, as well as optimal prevention, screening and management of opportunistic infections. TB is a particular issue and guidelines already suggest early initiation of TB treatment in people with CD4 cells below 100/mm³.

“Health system delays in antiretroviral treatment initiation must be minimised, especially in patients who present with advanced immunodeficiency,” urge the authors, adding that patients on treatment need monitoring and support to remain within treatment programmes. Further research required includes trials on management of reconstitution illness and studies to determine which type of health professional is best placed to facilitate good outcomes on treatment.