Kim, Maria H. MD*; Cox, Carrie MD*; Dave, Anjalee MD*; Draper, Heather R. MS*; Kabue, Mark DrPH†; Schutze, Gordon E. MD, FAAP*; Ahmed, Saeed MD*; Kazembe, Peter N. MBBS†; Kline, Mark W. MD, FAAP*; Manary, Mark MD‡,§
*Baylor College of Medicine International Pediatrics AIDS Initiative at Texas Children's Hospital, Houston, TX
†Baylor College of Medicine-Abbott Fund Children's Clinical Centre of Excellence, Lilongwe, Malawi
‡Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
§College of Medicine, University of Malawi, Blantyre, Malawi.
Correspondence to: Maria H. Kim, MD, Assistant Professor of Pediatrics, Baylor College of Medicine, 1102 Bates, Houston, TX 77030 (e-mail: email@example.com).
Presented at the 17th Conference on Retrovirology and Opportunistic Infections, February 16–19, 2010, San Francisco, CA.
The authors have no funding or conflicts of interest to disclose.
Received August 8, 2011
Accepted November 3, 2011
HIV infection in children in sub-Saharan Africa is often accompanied by moderate or severe acute malnutrition.1 The combination of HIV infection and acute malnutrition is associated with longer recovery times,2,3 lower rates of recovery,4 and increased mortality.5 In areas where HIV is endemic and food insecurity is the predominant cause of childhood malnutrition, clinical practice is often to administer therapy for malnutrition first, and if the child fails to respond to therapeutic or supplementary feeding, to investigate the child for wasting secondary to HIV infection.5,6 Antiretroviral therapy (ART) may not typically be started unless the malnourished child has failed to recover in a feeding program. Unfortunately, this practice is associated with very high-case fatality rates.5–8
Early ART has been demonstrated to improve survival and nutritional status in HIV-infected children.9–12 However, severe wasting has been associated with death in children after ART initiation.13–15 Data to help elucidate optimal timing of ART initiation16–18 in HIV-infected malnourished children remains scarce.
This retrospective observational study looks at a cohort of HIV-infected malnourished children, some whom started ART concurrent with nutritional therapy, and compares the effect of prompt ART on nutritional and clinical recovery.
All HIV-infected children aged 6–60 months seen at the Baylor College of Medicine–Abbott Fund–Children's Clinical Center of Excellence in Lilongwe, Malawi, with uncomplicated acute malnutrition and good appetite treated as outpatients between February 2007 and February 2008 were included. Acute malnutrition was defined as weight-for-height <80% (National Center for Health Statistics reference median) or mid-upper arm circumference (MUAC) <12 cm or bilateral pitting edema. Good appetite was defined as consumption of 30 g of ready-to-use therapeutic food (RUTF) when offered RUTF on admission. Children unable to consume RUTF, or with the following complications were excluded: (1) severe edema, (2) weight-for-height <60%, (3) weight <3 kg, (4) axillary temperature ≥39°C or <35°C, (5) tachypnea or respiratory distress, (6) poor hydration, (7) hemoglobin <70 g/L, (8) lethargy or seizures, (9) severe diarrhea or vomiting, and (10) anorexia. In accordance with Malawi Ministry of Health guidelines,15 children with any of these complications were referred for inpatient care. Children receiving ART more than 21 days before admission to the feeding program were excluded from the study. HIV infection was confirmed by polymerase chain reaction diagnosis for those <18 months old and by enzyme-linked immunosorbent assay for children >18 months old. The Center of Excellence offers free care in the largest urban area in Malawi and serves as the main referral center for complicated pediatric HIV cases throughout the country.
Ethics approval was given by the National Health Sciences Research Committee of Malawi and Baylor College of Medicine institutional review board.
This was a retrospective observational study. The purpose was to determine whether prompt use of ART affected clinical outcomes. Receiving ART promptly was defined as having initiated ART within 21 days from initiation of RUTF. This period was chosen based on an estimate of the amount of time it takes in the outpatient clinical setting to diagnose the need for ART, identify responsible caregivers, and ensure that the caregivers are trained on proper ART administration. The primary outcome was nutritional recovery; secondary outcomes include rates of weight gain and death. Data were collected by review and tabulation of the electronic medical record and the child's written medical record.
The medical records captured weight, height, MUAC, appetite, and symptoms since last visit including diarrhea, cough, fever, ART status, CD4 count, and CD4 percentage. Proper use of RUTF and indications to return to clinic were reviewed with patient caregivers. Children with severe malnutrition were seen weekly for repeat anthropometric evaluation, clinical review, and refill of RUTF, although children with moderate malnutrition were seen fortnightly. Quantity of RUTF given was 200 kcal/kg/day. Children were considered to have reached nutritional recovery if they attained 85% weight-for-height, MUAC >12 cm, with resolution of edema. A child was discharged if he/she met the above criterion for 2 consecutive visits.
HIV care was integrated with malnutrition treatment and included recognition and treatment of opportunistic infections. All children received cotrimoxazole prophylaxis. CD4 counts were collected every 6 months. ART for children was available in Malawi during the entire study period and the standard first-line regimen was stavudine-lamivudine-nevirapine. Eligibility for ART initiation included World Health Organization (WHO) stage III or IV disease or severe level of immunosuppression according to CD4 percentage (CD4% <25% if <12 months old, <20% if 12–35 months old and <15% if 36–60 months old). Readiness for ART treatment was assessed before initiation. Universal treatment of infants <12 months old was not standard of care at this time.
The paper medical record data was crosschecked with the electronic medical record for accuracy. Anthropometric indices were calculated using WHO Child Growth Standards. Children were categorized as having received prompt ART or not. Comparisons were made for continuous parameters using Student t test and for dichotomous parameters using Fisher exact test or χ2 test. Mann–Whitney U was used to compare median time to recovery.
The association between recovery and prompt ART was assessed by binary logistic regression modeling (SPSS 17.0 for Windows). This allowed for the control of differences between groups in severity of malnutrition and HIV disease. Covariates included in the model were those tested with univariate logistic regression modeling and found to have a P value <0.25, which were age, weight-for-height z-score, presence of edema, presence of severe thrush, and WHO disease stage. A P <0.05 was considered to be a significant predictor for any 1 covariate.
Of the 175 children admitted to outpatient feeding therapy, 35 were on ART >21 days before admission and therefore, were excluded from the analyses. One hundred forty children were included in the analyses (Table 1). At admission, 111 children (79%) met eligibility for ART, but only 55 (39%) initiated ART within 21 days of initiation of feeding. A higher proportion of children receiving prompt ART recovered (86% vs. 60%, P < 0.01) (Table 2). None of the children in the prompt ART group developed edema during the course of therapy.
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.
1. Black RE, Allen LH, Bhutta ZA, et al.. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet. 2008;371:243–260.
2. Bahwere P, Piwoz E, Marthias JC, et al.. Uptake of HIV testing and outcomes with community-based therapeutic care (CTC) programme to treat severe acute malnutrition in Malawi: a descriptive study. BMC Infect Dis. 2008;8:106.
3. Sandige H, Ndekha MJ, Briend A, et al.. Home-based treatment of malnourished malawian children with locally produced or imported ready-to-use food. J Pediatr Gastroenterol Nutr. 2004;392:141–146.
4. Ndekha MJ, Manary MJ, Ashorn P, et al.. Home-based therapy with ready-to-use therapeutic food is of benefit to malnourished, HIV-infected Malawian children. Acta Paediatr. 2005;942:222–225.
5. Fergusson P, Tomkins A. HIV prevalence and mortality among children undergoing treatment for severe acute malnutrition in Sub-Saharan Africa: a systematic review and meta-analysis. Trans R Soc Trop Med Hyg. 2009;103:541–548.
6. Sadler K, Kerac M, Collins S, et al.. Improving the management of severe acute malnutrition in an area of high HIV prevalence. J Trop Pediatr. 2008;54:6.
7. Bachou H, Tylleskär T, Downing R, et al.. Severe malnutrition with and without HIV-1 infection in hospitalized children in Kampala Uganda, differences in clinical features, haematological findings and CD4+ Cell counts. Nutr J. 2006;5:27.
8. Chinkhumba J, Tomkins A, Banda T, et al.. The impact of HIV on mortality during inpatient rehabilitation of severely malnourished children in Malawi. Trans R Soc Trop Med Hyg. 2008;102:639–644.
9. Sutcliffe CG, van Dijk JH, Munsanje B, et al.. Weight and height z-scores improve after initiating ART among HIV-infected children in rural Zambia: a cohort study. BMC Infect Dis. 2011;11:54.
10. Violari A, Cotton MF, Bigg DM, et al.. Early antiretroviral therapy and mortality among HIV infected infants. N Engl J Med. 2008;359:2233–2244.
11. Weigel R, Phiri S, Chiputula F, et al.. Growth response to antiretroviral treatment in HIV-infected children: a cohort study from Lilongwe, Malawi. Trop Med Int Health. 2010;15:934–944.
12. McGrath C, Chung M, Richardson B, et al.. Younger age at HAART initiation is associated with more rapid growth reconstitution. AIDS. 2011;25:345–35.
13. Wang ME, Castillo ME, Montano SM, et al.. Immune reconstitution inflammatory syndrome in human immunodeficiency virus-infected children in Peru. Pediatr Infect Dis J. 2009;28:900–903.
14. Taye B, Shiferaw S, Enquselassie F. The impact of malnutrition in survival of HIV infected children after initiation of antietroviral therapy. Ethiop Med J. 2010;48:1.
15. Callens S, Shabani N, Lusiama J, et al.. Mortality and associated factors after initiation of pediatric antiretroviral treatment in the democratic republic of the Congo. Pediatr Infect Dis J. 2009;28:1.
16. World Health Organization. Children and AIDS: Third Stocktaking Report (2008). Geneva, Switzerland: World Health Organization; 2008:32–45.
17. Heikens GT, Bunn J, Amadi B, et al.. Case management of HIV-infected severely malnourished children: challenges in the area of highest prevalence. Lancet. 2008;371:1305–1307.
18. Prendergast A, Bwakura-Dangarembizi MF, Cook AD, et al.. Hospitalization for severe malnutrition among HIV-infected children starting antiretroviral therapy. AIDS. 2011;25:951–956.
19. Sauvageot D, Schaefer M, OlsonD, et al.. Antiretroviral therapy outcomes in resource-limited settings for HIV-infected children<5years of age. Pediatrics. 2010;125:E1039–E1047.
20. Fergusson P, Tomkins A, Kerac M. Improving survival of children with severe acute malnutrition in HIV-prevalent settings. Int Health. 2009;1:10–16.
21. Kerac M, Bunn J. Excess Mortality Risk associated with HIV Infection in a Large Malawi Nutrition Rehabilitation Unit. Presented at: Malawi Nutritional Conference; November 24, 2007; Blantyre, Malawi.
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