Predictors of infant mortality

Polly Clayden, HIV I-Base

Two posters looked at predictors of mortality, one comparing children with adults, and another evaluated children in resource limited settings.

CASCADE/HPPMCS

David Dunn and coworkers from the MRC London and Entebbe and the Royal Free and UCL Medical School London performed a comparison of two large studies, analyses of the association of CD4 count with short-term risk of disease progression in untreated HIV-infected adolescents/adults aged 15 years or above (CASCADE) and perinatally infected children from birth to 14 years (HPPMCS).

The investigators used a common methodology to give a more complete picture of how disease progression rates varied by age, and to assess whether there is an age threshold in children, where the association of CD4 count with the rate of progression approximates to that of adults.

Follow-up for each patient was censored at date last known to be alive or the last clinical visit, or December 31, 1995, prior to widespread use of dual ART. AIDS and death incidence rates (expressed as per 100 person-years) were tabulated by most recent CD4 count and age, spanning from birth to >/=60 years.

This analysis included 6741 patients (3244 from HPPMCS and 3497 from CASCADE). The investigators observed 595/665 deaths and 949/945 AIDS/death endpoints from HPPMCS/CASCADE respectively. Young children (age <5 years) experienced much higher rates of disease progression than older children and adults. Among children >/=5 yrs, the effect of age (1.7% mortality decrease per year; 95%CI 6.5 to 9.9%) was not statistically significant.

In adults, mortality increased by an estimated 3.1% (95%CI 2.4 to 3.8%) per year. Mortality rates were comparable in children aged >/=5 years and adults aged ~ 20 years; at CD4 200 to 350 cells/mm3 it was 0.9 in children vs 0.7 and 1.1 in adults aged 15 to 24 and 25 to 34 years, respectively.

For children >/=5 years and adults at all ages, mortality increased sharply at CD4 <150 to 200 cells/mm3, with 71% deaths occurring at CD4 <50 cells/mm3. AIDS incidence in children >/=5 years and adults aged 25 to 34 years was very similar at CD4 200 to 350 cells/mm3 (both 6.1), but increased to 7.7 and 10.0 in adults 45 to 55 and >55 years, respectively. AIDS incidence was lower in children >/=5 years than adults 25 to 34 years when CD4 <100 cells/mm3 (eg, at CD4 50 to 100 cells/mm3, 19.6 vs 57.6, respectively), but higher at CD4 350 to 500 (4.4 vs 2.3) and at CD4 >500 (3.5 vs 1.1).

Recurrent bacterial infection was the most common AIDS diagnosis in children >/= 5 years.

The investigators wrote that their findings suggest that similar CD4 count criteria for starting antiretroviral therapy can be applied to adults and children >5 years. They noted that CD4 criteria, for younger children, is more problematic and it is still uncertain whether CD4 count or percentage is the more appropriate marker in this age group.

They suggest that the inclusion of older children in a when-to-start trial would increase its generalisability, if one were to be undertaken.

3Cs4kids

In resource limited settings, high background infection rates and malnutrition increase mortality in HIV infected children. But WHO and national paediatric treatment guidelines in resource limited settings have been largely informed by findings from studies conducted in industrialised countries.

3Cs4kids is a study conducted by Di Gibb from the MRC in London and coworkers from South Africa, Zambia, Cote dIvoire, Malawi, Uganda and Brazil to evaluate the short term predictive value of CD4%, CD4 count and total lymphocyte count (TLC) in untreated children on disease progression. Additionally, they evaluated haemaglobin and growth markers

In this study longitudinal data on children aged >12 months from 11 studies (10 African, 1 Brazilian) were combined. Prognostic values for laboratory markers (CD4 percentage, CD4 count, total lymphocyte count, hemoglobin), growth (weight-for-age and height-for-age) on mortality in the next 12 months were assessed using crude mortality rates. Multivariate Poisson regression analysis was conducted, adjusting for age, cotrimoxazole (CTX) use (assuming a 43% reduction in mortality) and study effects.

The investigators found that over 3,769 patient-years, 2,510 children aged >12 months contributed 357 deaths. 81% follow-up occurred after start of CTX. At first measurement, the median age of the children was 4.0 (IQR, 2.2 to 7.0) years, median CD4 was 15% and weight z-score 1.9. CD4 percentage and CD4 count were the strongest predictors of mortality, followed by weight for age and hemoglobin. After adjusting for these markers, total lymphocyte count and height-for-age had only modest effects.

Children with both weight-for-age z-score <3 and hemoglobin <8 had particularly high mortality (rate 55.2/100 patient-years compared to 6.9 for those with weight-for-age z-score 3 to 1 and hemoglobin 8 to <10, and 1.4 when weight-for-age z-score >/=1 and hemoglobin >/=10).

This interaction remained even for children with CD4 >15%: mortality risk was 17.3 vs 1.2/100 patient-years for weight-for-age z-score <3 and >3, respectively, and 13.2 vs 2.4/100 patient-years for hemoglobin <8 and >/=8 g/dL. Where weight-for-age z-score >3 and hemoglobin >8 g/dL (75% follow-up time), mortality rates increased from 1.3/100 patient-years with CD4 15 25%, to 6.6 and 12.6 at CD4 10 to 14% and <10%, respectively. In children >5 years, where CD4 count may be the preferred marker, corresponding rates increased from 1.1/100 patient-years when CD4 >400 cells/mm3, to 4.5, 4.5, and 17.2 when CD4 300 to 399, 200 to 299, and <200, cells/mm3 respectively. Although numbers are small, for both CD4 percentage and CD4 count, mortality was higher and thresholds less marked where weight-for-age z-score was <3 or haemoglobin <8 g/dL.

The investigators noted that the limitations of this analysis include: likely under ascertainment of deaths in several cohorts and variations between studies; lack of data on AIDS diagnosis, so confined to mortality risks; and limited follow up compared to HPPMCS.

In conclusion they wrote: CD4 percentage and count strongly predict mortality as in European/U.S. studies, whereas total lymphocyte count appears less predictive. However, for children with severe malnutrition or anemia, mortality was high, even at high CD4 percentage and count. Weight-for-age and hemoglobin need consideration in clinical management of children in resource-limited settings, as recommended by recent revisions to WHO ART treatment guidelines.

References:

All references are to the Programme and Abstracts of the 14th Conference on Retrovireuses and Opportunistic Infections, 25-28 February 2007, Los Angeles.

Dunn D, Woodburn P, Duong T, et al. A comparison of the association on current CD4 cell count with short-term risk of AIDS or death in HIV-infected children and adults. Abstract 700.
Gibb D, Duong T, 3Cs4kids Cohort Collaboration. Markers for predicting mortality in HIV-infected children in resource-limited settings. Abstract 701.