The WHO recently reported that the mean age of starting ART in HIV-infected African children is 5-9 years 9
. As testing programs expand throughout Africa, increasing numbers of HIV-infected children in this age range will be identified 4
. It is critical that the risk of and factors contributing to disease progression for this growing population be understood.
In this study of 192 HIV-infected children with a median age of 6.4 years, we found that 19% progressed with clinical events or immunologic decline within 2 years. CD4%, HIV RNA level, and age less than 3 years were independently predictive of HIV-disease progression. These findings are similar to those from studies of children in the USA and Europe, which have shown CD4% and HIV RNA level to be important predictors of short term disease progression 10, 11
and mortality 11, 12
. There have been only a few studies examining predictors of HIV-disease progression in children living in resource-limited settings, and they have primarily focused on infants13, 14
or children under 3 years of age 15
. The largest study of older HIV-infected children, a recently published meta-analysis of 9 African and 1 Brazilian cohorts, found that CD4 count and weight-for age were the strongest predictors of mortality; however this study did not have adequate data to evaluate HIV RNA level, and adjustments were made for variable usage of trimethoprim-sulfmethoxazole, a strong factor in mortality16
. Notably, most of these studies included children with advanced disease and low CD4 counts that would be eligible for ART based on current guidelines. In our study of children not eligible for ART, HIV RNA level and a decrease in CD4%, were important predictors of short term disease progression in HIV-infected African children.
We also found that CD4 and CD8 cell activation levels were significant univariate predictors of HIV disease progression. Several prospective studies of adults in the USA and Europe showed that levels of CD817-19
cell activation predicted disease progression, with similar results for children 21, 22
. We previously showed that HIV-infected Ugandan children in our cohort had higher levels of T-cell activation compared to HIV-uninfected Ugandan controls23
, and that reduction of T-cell activation seemed important to CD4 recovery with ART 8
, as has been shown for adults24
in the USA and Europe. The present study builds on these findings, showing elevated levels of CD4 and CD8 activation to be significant univariate predictors of disease progression specifically among HIV-infected children with CD4 counts and percentages above the threshold for ART initiation. After adjustment for CD4 percent and HIV viral load, the hazard ratio for measures of immune activation changed little (data not shown), suggesting an independent effect, but lost statistical significance due to the number of predictors in the model and the small number of observed progression events. It will be important to elucidate the impact of immune activation on HIV-disease in African children because data suggest that Africans have higher levels of T-cell activation compared to European controls, presumably related to non-HIV infectious burden 26, 27
Among the HIV-infected children who progressed during the follow up period, 43% did so by experiencing a new WHO stage 3 or 4 clinical event, or death. These events occurred in our cohort which benefited from a level of monitoring beyond what is possible in most limited resource settings. Improved preventive care such as pneumococcal vaccination or isoniazid preventive therapy would likely decrease some HIV-related morbidity. It is also plausible that ART initiation in African children at higher CD4 levels could additionally reduce this HIV-related morbidity, but this strategy requires further evaluation.
The optimal timing for the initiation of ART in HIV-infected children continues to be a topic of much debate and ongoing study. With few data from resource-limited settings, the 2006 WHO treatment guidelines for children were based on progression data primarily from HIV-infected children in the USA and Europe 11, 28, 29
. But recent studies have shown that children in resource-limited settings suffer higher mortality at any given CD4 value compared to children in resource rich countries16
. In 2008, the WHO modified guidelines for ART initiation in children 36-95 months of age, raising the CD4% cutoff to 20% 2
; on re-examination of our data, this change would have led to earlier initiation of ART in a few children, but not among those that experienced clinical events. In 2009, the WHO similarly raised the CD4 count thresholds for treatment of adolescents30
. For infants less than 12 months of age, the WHO now recommends universal ART regardless of immune status,2
because of studies in South Africa that demonstrated early initiation of ART significantly decreases mortality this age group,31
Our findings here, that children older than 12 months continue to suffer significant morbidity while ineligible for ART, underscore the need for controlled clinical studies investigating the potential benefits of ART initiation at higher CD4 thresholds in this age group.
Limitations of our study include its small size, which reduced the power to evaluate all baseline variables. Children enrolled in this study constituted a healthy survivor cohort, comprised of children that escaped the very high infant mortality associated with HIV infection. The exclusion of children with low weight (<5 kg) and residence greater than 20 kilometer from our clinic and the loss of 7 children to follow up may have led to underestimates of disease progression. Our analysis was also limited by the fact that children with high HIV RNA levels had generally low CD4 percentages; such colinearity in variables makes it difficult to establish truly independent effects in multivariate models.
In summary, in this cohort of HIV-infected Ugandan children over 1 year of age, nearly one fifth experienced disease progression within 2 years of enrollment, with half experiencing WHO stage III clinical disease. CD4 % was the strongest laboratory predictor of HIV disease progression and death, followed by HIV RNA levels. The high rate of HIV related clinical disease in this cohort prior to meeting ART initiation criteria underscores the importance of close monitoring and research on optimal timing of ART in children.