Among the children who died, 4 of 16 occurred in the prompt ART initiation group. Three of the 4 children had multiple underlying infections [pulmonary tuberculosis (TB) (n = 2), oral thrush (n = 2), diarrhea (n = 2), pneumonia (n = 1), BCG adenitis (n = 1)]. Of the 12 of 16 children who died who were not given prompt ART, all had underlying infections [pulmonary TB (n = 3), oral thrush (n = 7), diarrhea (n = 10), pneumonia (n = 4), BCG adenitis (n = 1), scalp abscess (n = 1), malaria (n = 1), suppurative otitis media (n = 1)]; 10 children had multiple infections.
Binary logistic regression modeling for nutritional recovery(r = 0.57, P < 0.001) found that older age [odds ratio (OR): 1.06, 95% confidence interval (CI): 1.00 to 1.12], greater weight-for-height z-score (OR: 2.02, 95% CI: 1.18 to 3.45), absence of edema (OR: 9.53, 95% CI: 2.11 to 43.0), absence of severe thrush (OR: 5.86, 95% CI: 1.29 to 26.5), and prompt ART (OR: 5.38, 95% CI: 1.98 to 14.5) were associated with recovery. Children with more advanced WHO disease stage were less likely to recover in the model.
Twenty-nine children did not meet eligibility for ART at initiation of therapeutic feeding. In this group, 19 (66%) recovered, 3 (10%) remained malnourished, 4 (14%) died, 3 (10%) were lost to follow-up (LTFU). Mean age of the group was 22 months.
Children were followed 6 months after nutritional therapy was complete (Table 2) and at that time 44 of 85 of those who did not receive prompt ART had started ART.
The major findings from this study are that malnourished HIV-infected children in urban Malawi who initiated ART within 21 days of therapeutic feeding were more likely to recover, and prompt ART was the most significant modifiable covariate associated with recovery.
The study is limited in that it is a retrospective comparison, and thus the conclusions are preliminary. Only 140 children were included in the analyses. These children represent a referral population to an urban specialty HIV clinic. This may have implications in terms of differences in clinical severity of HIV disease and socioeconomic status. Therefore, the study population is not representative of either all HIV+ children or all malnourished children in Malawi. In addition, there was lack of control for potential confounders that could contribute to achieving nutritional recovery such as access to health care, socioeconomic status, or mother's health.
There have been anecdotal observations in sub-Saharan Africa that kwashiorkor occurs in some children with marasmus after initiation of ART. Some have conjectured that this phenomenon may be an example of IRIS. In a recent study18 of 1207 children starting ART, half of those who were hospitalized for malnutrition developed edema. Median age of those developing edema was 4 years. In our study, in the prompt ART group, no children developed edema and very few required hospitalization. This difference might be attributed to the younger age of our study population or the fact that the study population was a select group without symptoms of serious clinical illness.
The population studied here had uncomplicated acute malnutrition. Therefore, any child with 1 or more findings of complicated illness listed in the methods was not included in this analysis. Despite this, 14% of the children died during nutritional therapy. Furthermore, even amongst the group of children who did not meet eligibility criterion for ART initiation and theoretically represent a healthier subgroup, nutritional recovery was poor. This emphasizes the critically ill nature of the malnourished HIV-infected child and highlights the need for comprehensive coordinated care for malnutrition, HIV, TB, and opportunistic infections. This is best provided during a single clinic visit at the same location.
In this study, prompt ART was defined as initiation within 21 days of nutritional therapy. Unfortunately, the process of initiation of ART in children in sub-Saharan Africa can be lengthy and cumbersome due to delays in HIV diagnosis; limited access to CD4 testing; need for evaluation and treatment of coinfections including TB; ART training for 2 willing caregivers; and financial challenges surrounding transport and lost days of work. Prompt initiation of ART was facilitated in this study by rapid HIV testing, availability of ART, and comprehensive care for HIV, TB, opportunistic infections, and nutritional rehabilitation.
As shown in several studies, HIV and malnutrition cannot be treated independently.5,8,9,18,19 Investing resources into and improving the coordination between nutritional rehabilitation and HIV diagnosis and treatment is critical to improving child survival and growth in this vulnerable population. Malnutrition is often encountered in HIV clinics, and these clinics should be prepared to offer nutritional therapy. In addition, malnutrition clinics should make efforts to ensure that prompt HIV diagnosis and referrals to care are made, utilizing strategies such as opt-out HIV testing.20
In this study, ART initiation was often postponed due to the practice of delaying ART initiation pending response to nutritional therapy to help discern HIV-related wasting from other causes of malnutrition. The findings in this study suggest that this practice may pose significant mortality risk to HIV-infected children and needs urgent re-evaluation.
Although not statistically significant, there was a trend toward lower mortality in the prompt ART arm, with the percentage of deaths twice as high in the deferred arm. This was despite the fact that those in the prompt ART arm had higher rates of severe immunosuppression. A study21 in Blantyre, Malawi, that followed malnourished children enrolled in a nutritional feeding program found that children LTFU by-in-large have died. If we speculate that half of the children LTFU in this study died, then prompt ART would be associated with a significant decrease in risk of death and increased recovery. Even if the LTFU are not considered deaths, the higher rate of LTFU in the deferred ART treatment arm suggests that ART may have contributed to the decreased LTFU in the prompt ART group and may act as an incentive for caregivers to remain in care.
This preliminary evidence suggests that prompt ART is associated with improved outcomes in HIV-infected Malawian children with uncomplicated malnutrition.
The authors would like to thank the participating families; Concern Worldwide who helped establish the outpatient nutritional therapeutic program at the Baylor Clinic; Staff at the Baylor Center of Excellence; and Malawi Ministry of Health.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; children; HIV; malnutrition