AIDS-defining illnesses, especially TB, more frequent at high CD4 counts in Africa and Asia

Rates of death and illness remained 'substantial' even at higher CD4 cell counts among people receiving antiretroviral therapy in lower-income settings, and much greater efforts to get people onto treatment earlier will be needed to reduce this burden in people living with HIV, according to findings of an international review of treatment outcomes in seven countries published in the Journal of Acquired Immune Deficiency Syndromes.

The analysis pooled data from 13 cohorts in five sub-Saharan and two Asian countries, comprising close to 4000 adults who received ART between 1998 and 2008.

It found that, although patterns of mortality according to current CD4 cell count were similar to those seen in Europe and North America, people living with HIV in lower-income settings remain at higher risk of developing AIDS-defining illnesses at all CD4 counts when compared to their counterparts in European cohort studies.

Almost half of all the AIDS-defining events in these cohorts were cases of pulmonary or disseminated tuberculosis (TB), which may occur at CD4 cell counts above 200. TB is less likely to develop in people with higher CD4 cell counts, and for this reason there has been strong advocacy for earlier antiretroviral treatment in order to limit cases of TB in settings where TB transmission is endemic and where a high proportion of people are likely to be latently infected with TB.

Established in 2009, the objective of the ANRS 12222 collaboration is to describe CD4-specific rates of death and disease among people with HIV in resource-poor settings.

The authors pooled available data from cohorts of HIV-infected adults on ART in five sub-Saharan African (Benin, Burkina Faso, Cameroon, Ivory Coast and Senegal) and two Asian (Cambodia and Laos) countries to estimate CD4-specific rates of death and AIDS-related disease.

CD4 cell count is the most important predictor of HIV-related death and disease. Incidence rates of death and disease by CD4 cell count for people on ART in resource-poor settings have mostly been estimated in the low CD4 cell count range based on pre-ART CD4 values.

Information on rates of death or illness according to on-treatment CD4 counts is limited, and more complete information could demonstrate the extent of the burden of illness and death that is not being prevented as a result of current recommendations for treatment.

In this analysis, cohort eligibility was based on initial study procedures including: repeated CD4 cell count measurements; a follow-up period on ART; and an active strategy to retain patients. Within the eligible cohorts inclusion of patients comprised: being 18 years of age or above at enrolment; having at least one CD4 count measurement available; and followed-up at least one day on ART.

CD4 cell count strata considered were: under 50, 51-100, 101-200, 201-350, 351-500, 501-650 and over 650 cells/mm³.

CD4-specific incidence rates of death, of AIDS, or a combined criterion of death or AIDS and of loss to follow-up per 100 person-years were estimated by dividing the number of first events [since starting ART] happening within a specific CD4 stratum divided by the time spent within the stratum. 

Of the 3917 adults (2318 in Africa and 1599 in Asia) with a cumulated follow-up of 10,154 person-years, two-thirds were female, the median age was 34 years and median CD4 cell count before ART was 148 cells/mm³.

One third was in the 201 to 350 cells/mm³ stratum and close to a half in the over 350 cells/mm³ stratum. Median follow-up was 2.3 years and the median number of CD4 counts for each person was six.

Death rates in the under 50, 51-100, 101-200, 201-350, 351-500, 501-650 and above 650 cells/mm³stratum were 20.6, 11.8, 6.7, 3.3, 1.8, 0.9 and 0.3 per 100 person-years, respectively. The corresponding AIDS-defining disease rate by CD4 count was 50.5, 32.9, 11.5, 4.8, 2.8, 2.2 and 2.2 per 100 person-years, respectively.

The most frequent AIDS-defining events included: pulmonary tuberculosis, disseminated tuberculosis, recurrent bacterial pneumonia, cryptococcosis, CMV infection, toxoplasmosis, oesophageal candidiasis, Kaposi’s sarcoma, wasting syndrome, non-tuberculosis mycobacteriosis and systemic mycosis.

Loss to follow-up decreased with increasing CD4 counts (4.9, 6.1, 3.5, 3.1, 2.9, 1.7 and 1.2 per 100 person-years, respectively) with no significant difference between the first and following years.

Death rates among males have been reported as consistently higher than among females. Three-quarters of patients included in the studies from resource-rich settings were male, while in their analysis two-thirds were female, note the authors.

The main limitation was the relatively small sample size especially among those with counts under 100 cells/mm³. This also prevented analysis of the major determinants of death and disease for example, gender, age and time on ART beyond the first year. The authors suggest data in larger and longer-term cohorts would be useful.

The authors propose three recommendations drawn, directly and indirectly, from their findings.

1. Despite the economic crisis and its impact on HIV/AIDS funding national AIDS programmes must not be swayed from implementing the World Health Organization (WHO) 2010 recommendations of raising the threshold of starting ART in asymptomatic patients from 200 cells/mm³ to 350 cells/mm³. In the near future – as in resource-rich settings – starting ART above 350 cells/mm³ should be envisaged.

2. Additional means necessary to improve diagnosis and treatment of opportunistic infections in patients on ART include laboratory equipment, training, mentoring and supervision of healthcare workers, accessibility to preventive and curative drugs and education of patients.

3. Scheduling of clinical visits must take into account not only the time on ART but also the current CD4 cell count, a finding that further supports the need for immunological monitoring in patients on treatment.

They conclude: “Death and AIDS rates remained substantial after starting ART even in people with high CD4 cell counts. Ensuring earlier ART initiation and optimising case finding and treatment for AIDS-defining diseases should be seen as priorities.”

The ANRS 12222 Morbidity/Mortality Study Group.Mortality, AIDS-morbidity an loss to follow-up by current CD4 cell count among HIV-1 infected adults receiving antiretroviral therapy in Africa and Asia: data from the ANRS collaboration. Advance online edition J Acquir Immun Defic Syndr, doi: 10.1097/QAI.0b013e3182821821, 2013.