(year) location Quality of study design (reporting, loss to follow- up) Quality of exposure measurement Quality of outcome measurement Quality of statistical analysis Overall external validity Overall grade Raguenaud et al. (2009) Fair - Large cohort of children on HAART. LTFU was low (1.8%) for children on HAART. For children who were not treated, LTFU was higher (22%) so there were likely more unreported deaths in the untreated group. Used an active tracing system for children on HAART who failed to attend a clinic appointment in order to reduce LTFU. Not applicable for KQ 2 although no data on adherence. Patients and caregivers received at least three HAART- preparation counseling sessions before starting treatment to maximize adherence.
Fair - Not all causes of death were reliably ascertained. Nevertheless, given that both HIV programs were situated within provincial referral hospitals and that medical doctors performed all consultations, the authors believe that the level of error in attributing cause of death was limited.
Not applicable for KQ 2. Fair – Generalizable to other rural populations with low socioeconomic status. Poor
Lumbiganon et al. (2011)
Fair – Does not report period- specific LTFU rates. Overall, 154 children (8.8%) were LTFU. Comparing the high 3-month mortality rate (10.2 per 100 child-years) to a 3-month LTFU rate would have allowed authors to hypothesize whether some patients who had died were misclassified as LTFU during this high risk time period. A comparatively lower 3-month LTFU rate would give confidence that children LTFU were correctly classified and had not actually died. Fair – KQ 2 does not necessarily require an exposure measurement although providing adherence data would have increased reliability that children were actually taking HAART when they died. No information about the specific HAART regimen for each death. Fair – Authors note that because data were both retrospectively and prospectively collected, specific causes of death and outcomes of children LTFU were not fully ascertainable. Authors also state that although there were at least 3 children with suspected IRIS, they were unable to assess the impact of immune reconstitution on mortality. Unclear what authors mean by death due to AIDS when other causes of death include opportunistic infections and pneumonia/sepsis. Retrospective data were not standardized across clinic sites. Outcomes may have been verified differently at different clinics or at different times within the same clinic.
Not applicable for KQ 2. The study reports causes of death within the first 90 days of HAART initiation and therefore met the inclusion criteria.
Fair – Participating study sites are mainly
university-based clinics and major referral centers so the extent to which these findings can be generalized to more primary- care-focused clinics and rural clinics is unclear.
Poor
Table 2b. Quality ratings (KQ 2).
Synthesis of Results
Key Question 1
For KQ 1, Bong et al found that WHO clinical stage 4 disease, severe wasting (defined as weight for height <70%), and severe immunodeficiency (defined as baseline CD4 count below
age threshold) were significantly associated with early mortality by 3 months after starting treatment. Lumbiganon et al observed that among the 43 children who died in the first 3 months of ART (37.3% of all deaths), 25 children (58.1%) were ages 5-12, 19 children (44.2%) had baseline CD4%<5%, 23 children (53.5%) had WHO clinical stage 4 disease, and the median weight-for-age z-score was -5.1. Although Lumbiganon et al does not calculate the period- specific risk of death in a multivariable model as in Bong et al, the results of the study are consistent with the findings in Bong et al. Overall, the high early mortality and identified risk factors in the children in both studies are similar to those found in adults and to those found in pediatric studies measuring predictors of overall mortality.3,8,23,28-34
Key Question 2
In Lumbiganon et al, the leading causes of mortality during the first three months of HAART were tuberculosis (7 children, 44%) and respiratory tract infections (4 children, 25%). There were three patients with suspected IRIS in Lumbiganon et al; however, the impact of immune reconstitution on mortality in these patients was unclear. Among the 43 children who died within three months of starting HAART in Raguenaud et al, the most common causes of death were pneumonia/sepsis (15 children, 35%), opportunistic infections (12 children, 28%), and AIDS (7 children, 16%).
Overall Grade of Evidence
Key Question 1
The overall grade of the evidence describing risk factors associated with early mortality is low. Conducting observational pediatric HIV studies in low-income countries without significant risk of bias is impossible. There are many challenges to developing pediatric
HAART programs outside well-equipped settings that make studying pediatric cohorts in these settings extremely difficult. It is also likely that genetic, dietary, and social differences among patient populations, as well as differences in general health care access, local medical practices, and concurrent medicines and illnesses, influence clinical outcomes in resource-poor settings.2 Nevertheless, the two studies are consistent in terms of which baseline characteristics predict early mortality in HAART-naive, HIV-infected children beginning treatment. The small sample size in Bong et al resulted in wide confidence intervals around the adjusted HR point estimates which detract from precision. One similar pediatric HIV cohort study excluded from the
systematic review reported 99 percent of deaths occurring during the first 90 days after HAART initiation with deceased children being younger, more malnourished, and presenting with lower CD4 counts.32 The consistency between these three studies and other studies of predictors of overall mortality after HAART initiation in children should give us confidence in the reliability of these findings. Overall, there is weak, but growing, evidence indicating that malnutrition, WHO clinical stage 4 disease severity, and low CD4 count are the most important predictors of early death in children initiating HAART and therefore should be used to identify those children most in need of increased medical attention.
Key Question 2
The overall grade of the evidence is insufficient to draw conclusions about the causes of early death in children initiating HAART. As HAART becomes much more widely available in resource-limited settings, IRIS has emerged as an important complication of HAART.49 Without improved cause-of-death reporting, the contribution of IRIS to early mortality in children
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