Predictors of mortality in untreated HIV-positive children

The Cross Continents Collaboration for Kids (3Cs4kids) performed a meta analysis of children aged 12 months and older from 10 studies (nine African, one Brazilian) to evaluate the predictive value of laboratory and growth markers on the short term mortality risk in untreated HIV-positive children.

All studies participating in 3Cs4kids are observational cohorts with the exception of the CHAP trial (a randomised trial of cotrimoxazole prophylaxis). Groups in the collaboration were asked to provide information on: date of birth, gender, date of enrolment or first clinic visit, date of starting any antiretroviral drugs, date of starting cotrimoxazole prophylaxis, date of death or last known to be alive, and available measurements for CD4%, CD4 cell count, total lymphocyte count (TLC), haemoglobin, weight and height. Children in the analysis were above 12 months of age.

The mortality risk within 12 months was estimated using Poisson regression models, adjusted for cotrimoxazole use and study effects.

Of 2510 children there were 357 deaths during 3769 child-years-at-risk, with 81% follow-up occurring after start of cotrimoxazole. Median follow up was 12.7 months (IQR, 6.4-24.6 months). At first measurement, median age was 4.0 years (IQR, 2.2-7.0 years), median CD4% was 15% and weight-for-age z-score -1.9. CD4% and CD4 cell count were the strongest predictors of mortality (for example the annual risk at 2 years of age increased from 5% to 10% as CD4% fell from 22% to 14%), followed by weight-for-age and haemoglobin.

In multivariate analysis weight for age and haemaglobin were strongly predictive after controlling for CD4% or CD4 count as well as each other (both p=0.001). The investigators wrote: For example, in a five year old child with CD4% of 20%, the 12 month risk of death increased by 3.6 times when weight for height decreased -1 to -3 and by 1.9 times when haemaglobin fell from 11 to 8g/dl.

Mortality remained high even at high CD4% or counts for young children with severe malnutrition and anaemia, particularly those 1-2 years old.

In adjusted analysis including weight for age, the hazard ratio for BMI-for-age was 0.87 (95% CI, 0,80 0.95, p=0.002) per unit increase in z-score, an approximate1.3-fold increase in risk when BMI decreases from 0 to -2 over a year.

The association between height-for-age and mortality went in the reverse direction with a hazard ratio of 1.21 per unit increase in z-score (95% CI, 1.06-1.38, p=0.004). The investigators suggested this reflects a greater degree of malnutrition among taller children of the same weight.

The investigators noted the strong effect of CD4% and CD4 count, argues once again for wider access to low cost laboratory monitoring, given that standard flow cytometry remains impractical and costly in many resource limited settings.

They concluded that when to start antiretroviral therapy in children in resource limited settings remains complex and that their findings indicate that growth markers and haemaglobin and the role of malnutrition warrant further research.

They wrote: For effective care of HIV-infected children in resource limited settings the prevention and treatment of malnutrition and anaemia need to be integrated within routine clinical management, while the optimal timing of starting ART in relation to these interventions requires clarification.

Cross Continents Collaboration for Kids (3Cs4kids) Analysis and Writing Committee. Markers for predicting mortality in untreated HIV-infected children in resource-limited settings: a meta-analysis. AIDS 22(1) 2 January 2008 p 97-105.