Our study demonstrates the effectiveness of NNRTI-based first-line regimens used at Korle-Bu Teaching Hospital for HIV-infected children. For 83.3% of the study participants, the first-line ART regimen was effective. At 24 months of follow-up, about 71% of our participants had viral load <400 copies/ml. Both absolute CD4 cell counts and CD4 cell percentages demonstrated a sustained immunologic response through 24 months of follow-up for all participants. Our findings are consistent with reports of effectiveness of ART in HIV-infected children from other countries in sub-Saharan Africa
Furthermore, we found high tolerance of the first-line ART regimen in our population based on the low levels of toxicity, and fewer regimen switches. Our rates of regimen switching and toxicity are comparable to previous studies in the region and in other resource-limited settings
[4, 6]. There were no deaths among the children during the study period. Most importantly, our rates of effectiveness, toxicity, and mortality are comparable to that reported among HIV-infected children in resource-rich countries. Therefore, the unprecedented global effort at scaling up HAART in resource-limited countries is paying off.
The rate of virologic treatment failure after at least 24 weeks was 16.7% among our study participants on their first-line regimen. This is consistent with previously reported rates in pediatric HIV cohorts from the sub-region ranging from 13% to 44%
[24–26]. First, consistent with other reports, we found low sensitivity of clinical and immunologic monitoring for detecting virologic treatment failure resulting in HIV drug resistance
[27–30]. Interestingly, only two of the virologic failures would have been captured by the WHO criteria for either immunologic or clinical failure – the gold standard for detection of treatment failure
. Second, consistent with limited number of studies on early virologic failure in children in sub-Saharan African, the median time to virologic treatment failure in our cohort was 7.8 months (range, 5.5 to 27.6 months)
[24, 25, 30]. Adje-Toure et al found that 58% of a cohort of children in Abidjan with detectable viral load after three to five months on therapy harbored HIV DRMs
. Therefore, if decisions regarding treatment failure are based solely on clinical or immunologic criteria, most of these children could accumulate multiple DRMs before they are switched to a second-line regimen. Taken together, in the absence of routine virologic testing, HIV-infected children starting ART are at risk for undetectable virologic failure with concomitant development of multiple DRMs that will limit their options for effective second-line regimens.
At virologic failure, 67% of the children harbored viruses with ≥ 1 DRMs, and dual-class resistance was observed in 50% with M84V/K103N being the predominant resistance pathway. Most importantly, our study adds to the limited data on the contribution of early virologic failure to evolution of DRMs in HIV-infected children in sub-Saharan Africa
. Furthermore, we observed that the pattern and evolution of resistance mutations is consistent with the components of the first-line regimen as previously reported
[24, 25, 32]. This is valuable information for treatment programs in resource-limited countries in procurement of first- and second-line regimens. Our findings and that of others underscore the urgent need for implementation of viral load monitoring of HIV treatment programs in sub-Saharan Africa to prevent accumulation of DRMs
The arguments against routine use of laboratory monitoring in resource-limited settings are sustained by consideration of cost, technical expertise, and lack of infrastructure
. While efforts at developing low-cost technologies continue, the question to be answered is: can we adopt a less frequent and targeted testing schedule for CD4 and viral load monitoring? To answer this question, we explored whether readily obtainable data on patients’ characteristics could predict the trajectories of change in CD4 absolute count, CD4 percentage, and HIV viral load. Thus, these predictor variables could inform targeted monitoring strategies. Following ART initiation, we observed a statistically significant increase in CD4 absolute count and CD4 percentage over time. However, the trajectories with time were not linear; they leveled off over time. There was a great degree of variability among children, as expressed by 65% and 61% ICC for CD4 absolute counts and percentages, respectively, supporting the inclusion of the random effect in the model. There were differences in terms of predictors of CD4 absolute counts vs. CD percentages. The negative quadratic slope observed for children with more severe WHO clinical stages suggests a significant slowing in the increase in CD4 absolute counts for that group. This suggests that immune reconstitution may not be robust and complete in severely immuno-compromised HIV-infected children initiating ART. To our surprise, gender and caregiver status played important roles in CD4 absolute count trajectory. Having a biologic parent as a primary caregiver was positively associated with gains in CD4 absolute count. This can be attributed to the benefits of having a stable family with more consistent routines, as compared to losing a parent and having a child’s life disrupted. Female children had better CD4 trajectory. We previously reported that female gender was associated with faster CD4 recovery after initiation of ART
. Moreover, a recent Thai study reported that female children had a better immunologic and virologic response than males
. There are no reports on association between CD4 recovery or trajectory and gender in pediatrics from sub-Saharan Africa, with the exception of one study that found male gender to be associated with virologic failure
. The reasons for this gender effect are not well understood. Interestingly, in HIV-infected adults, gender differences in treatment outcome (i.e., immunologic and virologic) have received mixed reviews
[37, 38]. The trajectory of change in HIV viral load was a negative reflection of the CD4 longitudinal profile. Of note, female children started out having higher viral loads, but their rate of decrease over time was significantly greater than that of the male children. The role of gender in HIV treatment outcome is very intriguing and needs further investigation.
There are certain limitations to our study. First, this is a single center study and, therefore, one has to be cautious in generalization of our findings. Moreover, the limitations of this analysis include having a relatively small sample size for an observational longitudinal analysis. However, some of the limitations reflect realities in carrying out such a study in a resource-limited setting. At the same time, an important strength of our study is the setting of a real world pediatric HIV clinical care in a resource-limited country with all the perennial laboratory capacity challenges that could represent an overwhelming majority of pediatric HIV clinics in sub-Saharan Africa.