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A Systematic Review of Nutritional Supplementation in HIV-Infected Children in Resource-Limited Settings Megan S. McHenry, Avika Dixit and Rachel C. Vreeman Journal of the International Association of Providers of AIDS Care (JIAPAC) published online 18 June 2014 DOI: 10.1177/2325957414539044 The online version of this article can be found at: http://jia.sagepub.com/content/early/2014/06/18/2325957414539044
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Article
A Systematic Review of Nutritional Supplementation in HIV-Infected Children in Resource-Limited Settings
Journal of the International Association of Providers of AIDS Care 1-11 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/2325957414539044 jiapac.sagepub.com
Megan S. McHenry, MD1, Avika Dixit, MBBS, MPH1, and Rachel C. Vreeman, MD, MS1,2
Abstract Background: In resource-limited settings, malnutrition is the major cause of death in young children, but the precise benefits of nutritional supplementation for HIV-infected children are not well understood. Methods: Two researchers reviewed studies conducted in low- or middle-income countries that involved macro- and micronutrient supplementation in HIV-infected individuals 18 years. Results: Fifteen studies focused on micronutrients, including vitamin A, zinc, multivitamins, and multiplemicronutrient supplementation. The 8 macronutrient studies focused on ready-to-use foods (4 studies), spirulina, whey protein, general food rations, and F75 and F100 starter formulas. Vitamin A was associated with improved mortality rates, ranging from 28% to 63%. Multiple-micronutrient supplementations were not associated with improvement of measured health outcomes. Ready-to-use foods were associated with improvement in certain anthropometrics. Conclusion: Periodic vitamin A supplementation is associated with reduced mortality. Macronutrient supplementation is linked to improved anthropometrics. More research is needed to determine how nutritional supplementation benefits this particularly vulnerable population. Keywords nutritional supplementation, HIV, AIDS, children, clinical outcomes, nutrition
Introduction Individuals living with HIV are frequently affected by malnutrition for multiple reasons. Developing countries have a high prevalence of HIV, and the average diet in those communities frequently does not meet the recommended daily requirements of nutrients.1 Moreover, in severe HIV disease, patients may have increased losses of nutrients because of malabsorption.1-3 HIV-infected individuals may also have secondary infections, appetite suppression, and increased energy expenditures, all of which contribute to poor nutritional status.1-4 Nutritional status is an important predictor of immunological status for HIV-infected children, with morbidity compounded by the presence of poor nutritional status.5 Despite the general understanding that malnutrition and HIV are closely linked, the impact of nutritional supplementation for HIV-infected children has not been clear. Although several reviews have examined specific micronutrient supplementation for HIV-infected children,6,7 most studies focused on serum vitamin levels as a primary outcome. Generalizable research regarding macronutrients is also limited. The objective of this review is to compare general health outcomes among HIV-infected children and youth receiving nutritional supplementation to those not receiving supplementation. This review focuses specifically on developing and least
developed countries, as this is a population at greatest risk of nutritional deficiencies.
Methods We searched several bibliographic databases, including MEDLINE, EMBASE, The Cochrane Collaboration, Google scholar, as well as bibliographies of pertinent articles (all as of April 1, 2013). Our search strategies included using MeSH terms related to HIV, the pediatric population, and nutritional supplementation. Two authors (MSM and AD) reviewed the titles of all returned articles to select abstracts warranting review. From these abstracts, full articles were chosen for review to determine which studies looked at nutritional supplementation in HIV-infected children. The 2 authors then 1
Department of Pediatrics, Children’s Health Services Research, Indiana University School of Medicine, Indianapolis, IN, USA 2 USAID-Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya Corresponding Author: Rachel C. Vreeman, MD, MS, Children’s Health Services Research, 410 W. 10th St, HITS #1000, Indianapolis, IN 46202, USA. Email: [email protected]
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Journal of the International Association of Providers of AIDS Care Quality of the evidence was assessed using guidelines from Effective Public Health Practice Project.9 We aggregated data from publications reporting outcomes measured over the same time period in the same population. If the outcomes were the same in previously mentioned publications, they were excluded. Interventions and outcomes were too heterogeneous to allow for quantitative meta-analysis, but results were synthesized qualitatively by intervention type.
Results
Figure 1. Search results for systematic review.
independently reviewed the selected full articles and independently decided whether articles met predetermined inclusion criteria. Disagreements were discussed among all authors (MSM, AD, and RCV) to come to consensus. Randomized-controlled trials (RCTs) and observational studies, including case–control and cohort, involving HIVinfected individuals younger than 18 years of age in lowincome or middle-income countries as classified by the World Bank,8 were included. In addition, studies needed to measure outcomes, such as anthropometrics, frequency of HIV comorbid infections/conditions, HIV-related disease staging, or mortality rates. Included studies examined nutritional supplementation interventions in the form of food, protein or caloric supplements, ready-to-use therapeutic foods, or micronutrients. In this analysis, ‘‘food’’ refers to items that were traditionally part of a population’s diet but were supplemented in an additional amount for the intervention. Studies focusing on breast-feeding or HIV transmission, maternal supplementation, and case studies with less than 10 study participants were excluded.
The systematic literature search identified 5269 articles, with 2020 articles from the MEDLINE search and 3249 from EMBASE. Of these articles, 172 full-text articles were reviewed. Two additional publications were identified through the review of the bibliographies. Twenty-three of the articles reviewed met all predetermined inclusion criteria and were included in this study (Figure 1). Fifteen publications focused on micronutrient supplementation, describing 10 separate populations. All 15 micronutrient studies were RCTs.10-24 Of the populations, 3 had some antiretroviral therapy (ART) availability.10,18,19,21,22 In 1 population, ART was made available in country mid-way through the study, and HIV-infected patients were referred for treatment at that time.18,19 In another population, HIV-infected patients were stratified into 2 groups based on their ART status.21,22 A third group was given 1 dose of nevirapine (NVP) at birth.10 The other publications either did not have patients on ART or they did not describe ART use in their methods sections. Eight publications examined macronutrient supplementation in separate populations.25-32 In all, 2 were randomizedcontrolled studies30,31 and 6 were cohort studies.25-29,32 Three of the studies described some ART availability in their populations.25,27,32 One study enrolled children who were naive to antiretroviral medications and those children eligible for ART based on clinical conditions were started on medications.27 In another study, ART was made available in country during the study period so HIV-infected children were referred for treatment.25 In the third study, all children were on ART.32
Micronutrient Supplementation Vitamin A. Twelve studies looked at vitamin A supplementation in pediatric HIV-infected population. Two of the studies used vitamin A in 1 of 3 treatment arms, which is described later.18,19 Eight studies met the inclusion criteria of this review.1114,16,17,23,33,34 Two of the included publications studied the same Zimbabwean cohort.16,33 Four publications studied the same Tanzanian cohort12-14,34; however, 1 study examined predictors of anemia and did not specifically focus on micronutrient supplementation as an outcome so it was not included for review.34 An RCT in Uganda randomized HIV-infected children to receive vitamin A supplementation (200 000 IU, then 60 mg retinal equivalent) every 3 months from age 15 months to 36 months compared to placebo.23 Those receiving vitamin A had a 46% reduction in all-cause mortality (adjusted relative
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Tanzania
Zimbabwe
South Africa
South Africa
South Africa
Fawzi, et al12; Fawzi, et al13; Villamor, et al14
Humphrey, et al15; Miller, et al16
Hussey, et al17
Luabeya, et al18; Chhagan, et al19
Mda, et al20
South Africa
South Africa
Micronutrients Bobat, et al10
Coutsoudis, et al11
Country
Source
Table 1. Study Characteristics.
285 children (23 were HIV infected)
58 (13 were HIV infected)
50 HIV-infected children
Control Group
289 children (24 were HIV infected)
60 (15 were HIV infected)
46 HIVinfected children
Intervention Group
Study Design
6-60 months Randomized controlled
0-18 months Randomized placebo controlled
Method of Group Assignment Qualitya
Block-randomized Strong in 3 age strata (6-23, 24-41, and 42-60 months) Moderate Vitamin A of 50 000 IU Randomly allocated from a at 1 and 3 months, table of random 100 000 IU at 6 and 9 numbers months, and 200 000IU at 12 and 15 months Strong Vitamin A (200 000 IU Randomly assigned in for children over 1 blocks of 20 year old and 100 000 IU for infants) to be given while hospitalized (2 doses) at 4 months and 8 months Strong Vitamin A (2000 00 IU Randomized as Moderate described in for mothers, 50 000 Hussey G IU for infants) was abstract (23) given as 1-time dose to both, either mother or infant, or neither
Intervention
6-60 months Double-blind, Zinc (10 mg of elemental zinc) daily placebo for 6 months controlled
Age Group
(continued)
0-24 months Randomized 2876 children with 381 HIV placebo infected PCR negative at controlled at baseline; baseline and 6 504 initially weeks negative but HIV infected at 6 weeks 75 children n/a n/a Mean age 17 Randomized Vitamin A (200 000 IU n/a n/a months controlled for 2 days) Strong n/a n/a 6-24 months Double-blind, Multiple-micronutrient By HIV status 373 children, (187 Strong supplementations randouninfected, 154 included one of the mized HIV uninfected, following: vitamin A, controlled HIV exposed, 32 vitamin A þ zinc, or a HIV infected) multivitamin Strong Simple 52 children 54 children 4-24 months Double-blind, Multivitamin (at 118 HIV-infected randomizations allowances based on randochildren admitted schedule needs of a 1 year old) mized with diarrhea or given once daily until controlled pneumonia discharge 4495 mother (HIV positive)-infant pairs
648 children admitted to hospital for pneumonia
118 offspring of HIV-infected women
96 HIV-infected children
Patients
4
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Zimbabwe
India
Brazil
Kundu, et al27
Moreno, et al28
Fergusson, et al25 Malawi
Macronutrients Choto, et al26
176 children (7 were HIV infected)
Srinivasan, et al24 Uganda
18 vertically HIVinfected children
n/a
n/a 840 children (460 had HIV-related disease) n/a 454 children with severe acute malnutrition (79 children were HIV infected) 100 HIV-infected 180 HIV-infected children children in outpatient clinic
352 children hospitalized for severe pneumonia
94 HIV-infected 181 HIV-infected children children enrolled through a hospital (49 died prior to completion of study)
Uganda
Semba, et al23
Control Group
421 HIV-infected 847 HIV-infected children children, stratified into ARV medications receiving (85 of 847) and non-ARV medications (762 of 847)
Patients
Uganda
Country
Ndeezi, et al21; Ndeezi, et al22
Source
Table 1. (continued)
n/a
80 HIVinfected children
n/a
n/a
176 children (28 were HIV infected)
87 HIVinfected children
426 HIVinfected children
Intervention Group
Study Design Intervention
Method of Group Assignment Qualitya
1-6 years
2-12 years
Nutrition Mix-1A: 6 grams given once daily for 10 months F75/F100
n/a
n/a
Clinic-based Food rations providing Computer generated ½ caloric and ½ observarandom proteins tional study number table recommended for helped pick daily allowance for cohort child’s age given monthly n/a Whey protein given 1-2 Prospective times daily started as double20% daily protein blind clinineeds and increased cal trial to 50%
Prospective cohort study 6-60 months Prospective cohort study
12-36 months
(continued)
Strong
Strong
Strong
Weak
Strong Computer 1-5 years old Double-blind, 14-multipleStrong randomization micronutrient suprandoat a ratio of 1:1 plement versus mized in permuted ‘‘standard of care’’ 6controlled blocks of 4-20 multivitamin to each one of supplement the study supplements n/a Moderate Enrolled 6- Double-blind, Vitamin A or 60 mg retinol equivalent rando15 every 3 months from mized, plamonths, 15-36 months cebo intervencontrolled tion from 15-36 months 6-59 months Double-blind, Zinc (20 mg for children Enrolled in serial Strong order and 1 year and older, 10 randorandomized mg for those younger mized, plathan 12 months) daily cebo for 7 days controlled
Age Group
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Burkina Faso
Tanzania
Simpore, et al31
Sunguya, et al32
Control Group
219 HIV infected, ART treated
170 children
n/a
80 children (40 were HIV infected)
45 children 93 HIV-infected received maize/ children, severely soy flour malnourished children discharged from hospital. Not on ARV medications 169 HIV-infected 83 HIV-infected children children
Patients
Age Group
n/a
90 children (44 were HIV infected)
86 HIVinfected children
Intervention
Maize/soy Three arm flour with prospective micronutrient cohort supplementation study versus RUTF versus RUTF supplement
Study Design
Prospectively, systematically allocated to groups based on their week of discharge from hospital
Moderate
Method of Group Assignment Qualitya
Weak 6-36 months Randomized Formula with increased Computer generated block caloric and protein nonblinded randomization density versus study standard formula and diet. All received micronutrients Weak Progressive 12-60 Randomized Spirulina number given to months controlled supplementation to each participant traditional meals and a casual (millet, vegetable number fruit) for 8 weeks generator program was used n/a Moderate Ready to use CrossYounger therapeutic food— sectional than 5 Plumpynut 200 kcal/ study years of kg/d for 6-10 weeks age
12-60 20 children months received RUTF, 28 received RUTF supplement
Intervention Group
Abbreviations: PCR, polymerase chain reaction; n/a, not applicable; RUTF, ready-to-use therapeutic food; ARV, antiretroviral. a Per Effective Public Health Practice Project Criteria.
South Africa
Malawi
Country
Rollins, et al30
Ndekha, et al29
Source
Table 1. (continued)
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Table 2. Study Outcomes by Intervention Type. Source
Intervention Type
Coutsoudis, et al11
Vitamin A
Fawzi, et al12; Fawzi, et al13; Villamor, et al14 Humphrey, et al15; Miller, et al16
Hussey, et al17 Semba, et al23 Bobat, et al10 Srinivasan, et al24 Mda, et al20 Luabeya, et al18; Chhagan, et al19 Ndeezi, et al21; Ndeezi, et al22 Choto, et al26 Fergusson, et al25 Rollins, et al30 Kundu, et al27
Moreno, et al28
Simpore, et al31 Ndekha, et al29 Sunguya, et al32
Outcome
For HIV-infected patients, morbidity associated with diarrhea was significantly reduced in supplemented groups Vitamin A Reduction in all-cause mortality by 63%in HIV-infected patients and AIDS-related deaths by 68% Nonsignificant reduction in cough and tachypnea and a nonsignificant increase in acute diarrhea Significant increase in height, in particular in children between 6 and 18 months of age Vitamin A For infants who were HIV PCR negative at baseline and positive at 6 weeks, supplementation reduced mortality; maternal supplementation not associated with significant effects; HIV negative infants given vitamin A had 2-fold higher mortality HIV-infected children were noted to have increased risk of anemia; however, intervention had no effect on anemia or hemoglobin Vitamin A Increased TCD4 counts 4 weeks after supplementation Vitamin A Mortality rates were lower when supplemented (relative risk of 0.54); decreased prevalence of cough and chronic diarrhea Zinc No significant change in HIV-1 viral load, TCD4 counts, or median hemoglobin concentration; those given supplements were less likely to get watery diarrhea; increased weight gain in children receiving zinc Zinc Mortality rate was decreased in HIV-infected patients receiving zinc compared with those receiving placebo; no other significant effect on respiratory rate, temperature, or oxygen saturation was found Multivitamin No change in anthropometric indices and micronutrient concentrations; shorter duration of hospitalizations in those with intervention Multiple-micronutrient No significant difference in overall diarrhea among treatment arms; HIV-infected children supplementation receiving zinc or multivitamin had higher incidence of persistent and severe diarrhea than vitamin A supplemented children No differences between treatment arms in the prevalence of diarrhea or pneumonia Multiple-micronutrient No significant change in mortality, growth, or TCD4 counts with intervention supplementation No significant difference in incidence or prevalence of diarrhea with intervention Nutrition Mix-1A Significant weight gain over the 10-month study period (3-6 kg); subjective decrease in episodes of illness reported by mothers F75/F100 All children achieved nutritional recovery (>85% weight-for-height and no edema) Enhanced formula Significant weight gain was noted in the first 8 weeks with the enhanced formula (P < .0001) with similar weight gain compared to standard formula thereafter; no significant difference in TCD4 counts Food supplementation Significant improvement in clinic adherence along with increased mean clinic visit and mean TCD4 count with incentive; this also correlated well with number of visits, which in turn had strong correlation with weight gain, episodes of AIDS-defining illnesses, and hospitalizations Whey protein No significant change in hemoglobin, leukocytes, platelets, MCV; significant decreased in the TCD8 count in those receiving supplementation that contributed to a nonsignificant increase in TCD4/TCD8 counts; lower occurrence of associated coinfections was also observed Spirulina Weight gain of 15 g/d in HIV-infected patients when taken daily; decreased level of anemia Ready-to-use therapeutic Half of the children achieved complete anthropometric recovery with any home-based foods therapy; therapy with RUTF reached this goal more frequently and quickly when compared to RUFT supplement or maize/soy flour Ready-to-use therapeutic Less likely to have underweight and wasting compared to controls; when treated for at least foods 4 months, were less likely to be underweight, wasted, and stunted
Abbreviations: PCR, polymerase chain reaction; RUTF, ready-to-use therapeutic food; MCV, mean corpuscular volume.
risk [RR] ¼ 0.54; 95% confidence interval [CI]: 0.30-0.98) after a follow-up period of 17.8 months.23 Vitamin A also improved morbidities, with decreased persistent cough (odds ratio [OR] ¼ 0.47; 95% CI: 0.23-0.96) and a suggestion of decreased chronic diarrhea, though these findings were nonsignificant (OR ¼ 0.48; 95% CI: 0.19-1.18).23
The Tanzania Vitamin A Study (n ¼ 648 with 58 HIVinfected patients) was the focus of 3 included publications between 1999 and 2002.12-14 HIV-infected children aged 6 to 60 months were given either placebo or vitamin A supplementation at baseline during hospitalization as well as at 4 and 8 months after hospital discharge. Dosing of the vitamin
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McHenry et al
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A intervention was dependent on age (100 000 IU of vitamin A if 85% weight for height
and no edema. The HIV-infected children gained more weight than children not infected with HIV (1.45 kg versus 1.21 kg; P ¼ .03).25 Although HIV-infected children had longer hospitalizations (28.8 days versus 24.3 days; P ¼ .03), their rate of weight gain was slightly higher (8.9 g/kg/d versus 8.0 g/kg/d).25 Spirulina. Spirulina was used as an intervention in a study performed in Burkina Faso (n ¼ 170).31 Children aged 12 to 60 months were divided into the following 4 groups: HIV-infected children with and without spirulina supplementation and children not infected with HIV with and without spirulina supplementation. All children were also given traditional meals with millet, fruits, and vegetables. When comparing pre- and poststudy weight-for-height z scores (WHZ), all children had significant improvement (intervention: P ¼ .004; control: P ¼ .000). HIV-infected children receiving spirulina had greater improvement in WHZ than those who did not (22% versus 10.4%).31 Supplementary food rations. One clinic-based observational study looked at whether a food supplementation intervention impacted clinic visit adherence among HIV-infected children aged 2 to 12 years (n ¼ 80).27 The food incentive was associated with significant improvement in clinic adherence (P ¼ .027), increased mean number of clinic visits (6.65 + 1.43 versus 8.01 + 1.52, P ¼ .000), and increased mean CD4 counts (P ¼ .028).27 Provision of incentive correlated well with the number of visits (Pearson r ¼ .345) which in turn had a strong correlation with weight gain (r ¼ .548) and a negative correlation with episodes of AIDS-defining illnesses (r ¼ .412) and hospitalization (r ¼ .279).27
Discussion This systematic review evaluated the impact of nutritional supplementation on clinical outcomes for HIV-infected children in resource-limited settings, revealing a limited body of evidence supporting the use of particular types of supplementation. For micronutrients, although there is no conclusive evidence that vitamin A supplementation reduces diarrhea, anemia, or pneumonia, there is some evidence that periodic vitamin A supplementation for HIV-infected children younger than 5 years of age reduces all-cause and HIV-related mortality.12,23,33 Multivitamins were associated with fewer hospitalizations for diarrhea in HIV-infected children20 but supplements combining multiple micronutrients did not improve diarrhea, pneumonia, mortality, growth, or CD4 counts.18,19,21,22 Macronutrient supplementation was closely linked to improved anthropometrics for HIV-infected children. In the compiled evidence, RUTF increased average weight gain in HIV-infected children, especially when given with ART.26,32 F75 and F100 formulas improved mortality rates among malnourished HIV-infected children.25 Whey protein was associated with a decrease in the reporting of HIV coinfections as well as significant decrease in TCD8 counts.28 Accumulating evidence suggests that a newer supplement, spirulina, can also
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improve anthropometrics such as WHZ for HIV-infected children.31 Food itself is the macronutrient that makes a clear difference for both clinic-related and clinical outcomes; in one study, giving food at clinic visits improved clinic adherence, as well as mean CD4 counts and weight gain, and decreased AIDS-defining illnesses and hospitalizations.27 Along with the findings that periodic vitamin A and macronutrient supplementation may be beneficial for HIV-infected children, it is important to highlight the mixed evidence for certain micronutrients, which may not be effective or may even cause harm. Although one study suggested that zinc supplementation improved weight gain for HIV-infected children, and limited evidence also supported a decrease in mortality,10,24 in another study, children receiving zinc or multivitamins had a higher incidence of persistent and severe diarrhea than those children given vitamin A supplementation.18 The potential for zinc to have limited effectiveness or even to cause harm for HIV-infected children is significantly different than the benefits cited for malnourished, populations not infected with HIV.37 Part of the utility of this critical review of the evidence is the reminder that receiving more nutrients is not always better for this population. Less than 40% of the populations compiled in this systematic review (7 of 18) were analyzed for the impact of nutritional supplementation on immunologic or virologic markers of HIV disease such as CD4 counts or viral loads.10,15,17,21,27,28,30 The majority focused on clinical outcomes, such as coinfections and rates of mortality. This is in contrast to other studies examining the impact of nutritional supplementation on CD4 counts, viral loads, or both that were not conducted in a developing or least developed country and thus not included in this systematic review.38-40 The emphasis of the included studies on clinical outcomes is consistent with the focus and monitoring capacity of resource-limited settings. Although it would be beneficial to examine the impact of nutritional supplementation on viral load and CD4 counts, this type of laboratory testing may not be available or affordable in all settings. Moreover, in these settings with such high under-5 mortality rates, death and coinfections are likely more valuable measures than changes in CD4 counts or viral load. However, benefits of nutritional supplementation on these intermediary markers for disease progression may therefore be missed. There are several limitations related to this review that merit consideration. Although malnutrition is a huge issue for under-5 mortality, there are a limited number of randomized control trials examining nutritional supplementation for the HIV-infected population. Large, rigorous trials are still needed though we compiled the best evidence available. Another limitation is that our search strategy focused on published literature. Through bibliography searches, we did identify a relevant conference abstract; unpublished trials and conference presentations were not actively sought out, which could have led to publication biases. On the other hand, we wanted to compile the most rigorous evidence available for this population, even if it limited our search results. Another limitation is that we did not evaluate all non-English translations, which may
have prevented us from reviewing some literature from developing or least developed countries, but very few such articles were identified. This article reviews various types of nutritional supplementation in developing and least developed countries because adequate nutrition plays a significant role in the health of those who are HIV infected and individuals living in these countries who are at most risk of baseline malnutrition.41 The findings of our critical review are aligned with the World Health Organization (WHO) guidelines in regard to periodic vitamin A supplementation for HIV-infected children older than 6 months of age in developing and least developed countries.42 Our review also did not find substantial evidence to support the use of multivitamins or zinc, which is a finding that should be highlighted, so that resources are used only in an evidenced-based manner. Use of RUTF, food rations, and F75/F100 were found to help HIV-infected children meet WHZ and weight goals and use of these therapies in malnourished HIV-infected individuals is also supported by the WHO guidelines.42 Although the inference that increasing calories and protein will increase weight is not revolutionary, it is an important adjunct to ART in improving the health and well-being of this special population. Future research on nutritional supplementation for children with HIV should focus not only on which types of supplementation might improve children’s outcomes, but particularly on the optimal timing of nutritional supplementation with ART. None of these studies evaluated whether outcomes would be maximized if nutritional supplementation occurred before, at the time of, or after the initiation of ART. Moreover, evaluation of the feasibility and cost-effectiveness of implementation of supplementation is needed for programs operating with limited resources and caring for large populations. Nutritional supplementation may maximize the benefits of ART for HIV-infected children, and targeted research will help to improve outcomes for this vulnerable population. Authors’ Note The abstract for this article was presented as a poster at the International AIDS Society meeting on July 1, 2013, in Kuala Lumpur, Malaysia.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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3. Bentler M, Stanish M. Nutrition support of the pediatric patient with AIDS. J Am Dietetic Assoc. 1987;87(4):488-491. 4. Henderson RA, Saavedra JM. Nutritional considerations and management of the child with human immunodeficiency virus infection. Nutrition. 1995;11(2):121-128. 5. Ross AC. Vitamin A and retinoic acid in T cell-related immunity. Am J Clin Nutr. 2012;96(5):10. 6. Adetifa I, Okomo U. Iron supplementation for reducing morbidity and mortality in children with HIV. Cochrane Database Syst Rev. 2009;(1):CD006736. 7. Irlam JH, Visser MM, Rollins NN, Siegfried N. Micronutrient supplementation in children and adults with HIV infection. Cochrane Database Syst Rev. 2010;(12):CD003650. 8. Countries and Economies. Working for a World Free of Poverty April 12, 2013; http://data.worldbank.org/country, 2013. 9. Armijo Olivo S, Stiles CR, Hagen NA, Biondo PD, Cummings GG. Assessment of study quality for systematic reviews: a comparison of the cochrane collaboration risk of bias tool and the effective public health practice project quality assessment tool: methodological research. J Eval Clin Pract. 2012;18(1):12-18. 10. Bobat R, Coovadia H, Stephen C, et al. Safety and efficacy of zinc supplementation for children with HIV-1 infection in South Africa: a randomised double-blind placebo-controlled trial. Lancet. 2005;366(9500):1862-1867. 11. Coutsoudis A, Bobat RA, Coovadia HM, Kuhn L, Tsai WY, Stein ZA. The effects of vitamin A supplementation on the morbidity of children born to HIV-infected women. Am J Public Health. 1995; 85(8 pt 1):1076-1081. 12. Fawzi WW, Mbise RL, Hertzmark E, et al. A randomized trial of vitamin A supplements in relation to mortality among human immunodeficiency virus-infected and uninfected children in Tanzania. Pediatr Infect Dis J. 1999;18(2):127-133. 13. Fawzi WW, Mbise R, Spiegelman D, Fataki M, Hertzmark E, Ndossi G. Vitamin A supplements and diarrheal and respiratory tract infections among children in Dar es Salaam, Tanzania. J Pediatr. 2000;137(5):660-667. 14. Villamor E, Mbise R, Spiegelman D, et al. Vitamin A supplements ameliorate the adverse effect of HIV-1, malaria, and diarrheal infections on child growth. Pediatrics. 2002;109(1):E6. 15. Humphrey JH, Iliff PJ, Marinda ET, et al. Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality. J Infect Dis. 2006;193(6):860-871. 16. Miller MF, Stoltzfus RJ, Iliff PJ, et al. Effect of maternal and neonatal vitamin A supplementation and other postnatal factors on anemia in Zimbabwean infants: a prospective, randomized study. Am J Clin Nutr. 2006;84(1):212-222. 17. Hussey G HJ, Potgieter S, Kessow G, et al. Vitamin A status and supplemetation and its effect on immunity in children with AIDS, p. 81. Report of XVII International Vitamin A consultative Group (IVACG) Meeting (Guatemala City, Guatemala). Washington, DC: International Life Sciences Institute. 1996. 18. Luabeya KK, Mpontshane N, Mackay M, et al. Zinc or multiple micronutrient supplementation to reduce diarrhea and respiratory disease in South African children: a randomized controlled trial. PLoS One. 2007;2(6):e541.
19. Chhagan MK, Van den Broeck J, Luabeya KKA, Mpontshane N, Tucker KL, Bennish ML. Effect of micronutrient supplementation on diarrhoeal disease among stunted children in rural South Africa. Eur J Clin Nutr. 2009;63(7):850-857. 20. Mda S, van Raaij JMA, de Villiers FPR, MacIntyre UE, Kok FJ. Short-term micronutrient supplementation reduces the duration of pneumonia and diarrheal episodes in HIV-infected children. J Nutr. 2010;140(5):969-974. 21. Ndeezi G, Tylleskar T, Ndugwa CM, Tumwine JK. Effect of multiple micronutrient supplementation on survival of HIV-infected children in Uganda: a randomized, controlled trial. J Int AIDS Soc. 2010;13:18. 22. Ndeezi G, Tylleskar T, Ndugwa CM, Tumwine JK. Multiple micronutrient supplementation does not reduce diarrhoea morbidity in Ugandan HIV-infected children: a randomised controlled trial. Paediatr Int Child Health. 2012;32(1):14-21. 23. Semba RD, Ndugwa C, Perry RT, et al. Effect of periodic vitamin A supplementation on mortality and morbidity of human immunodeficiency virus-infected children in Uganda: a controlled clinical trial. Nutrition. 2005;21(1):25-31. 24. Srinivasan MG, Ndeezi G, Mboijana CK, et al. Zinc adjunct therapy reduces case fatality in severe childhood pneumonia: a randomized double blind placebo-controlled trial. BMC Med. 2012;10: 14. 25. Fergusson P, Chinkhumba J, Grijalva-Eternod C, Banda T, Mkangama C, Tomkins A. Nutritional recovery in HIVinfected and HIV-uninfected children with severe acute malnutrition. Arch Dis Child. 2009;94(7):512-516. 26. Choto RG. Clinical evaluation of Nutrition Mix-1.A. Dietary supplement in sick and undernourished children. Cent Afr J Med. 1994;40(2):29-32. 27. Kundu CK, Samanta M, Sarkar M, Bhattacharyya S, Chatterjee S. Food supplementation as an incentive to improve pre-antiretroviral therapy clinic adherence in HIV-positive children–experience from eastern India. J Trop Pediatr. 2012;58(1):31-37. 28. Moreno YF, Sgarbieri VC, da Silva MN, Toro AADC, Vilela MMd. Features of whey protein concentrate supplementation in children with rapidly progressive HIV infection. J Trop Pediatr. 2006;52(1):34-38. 29. Ndekha MJ, Manary MJ, Ashorn P, Briend A. Home-based therapy with ready-to-use therapeutic food is of benefit to malnourished, HIV-infected Malawian children. Acta Paediatr. 2005; 94(2):222-225. 30. Rollins NC, Van Den Broeck J, Kindra G, Pent M, Kasambira T, Bennish ML. The effect of nutritional support on weight gain of HIV-infected children with prolonged diarrhoea. Acta Paediatr. 2007;96(1):62-68. 31. Simpore J, Zongo F, Kabore F, et al. Nutrition rehabilitation of HIV-infected and HIV-negative undernourished children utilizing spirulina. Ann Nutr Metab. 2005;49(6):373-380. 32. Sunguya BF, Poudel KC, Mlunde LB, et al. Ready to Use Therapeutic foods (RUTF) improves undernutrition among ART-treated, HIV-positive children in Dar es Salaam, Tanzania. Nutr J. 2012; 11:60. 33. Humphrey JH, Iliff PJ, Marinda ET, et al. Effects of a single large dose of vitamin A, given during the postpartum period to
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HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality. [Erratum appears in J Infect Dis. 2008 May 15;197(10):1485]. J Infect Dis. 2006;193(6):860-871. Villamor E, Mbise R, Spiegelman D, Ndossi G, Fawzi WW. Vitamin A supplementation and other predictors of anemia among children from Dar Es Salaam, Tanzania. Am J Trop Med Hygiene. 2000;62(5):590-597. Sandige H, Ndekha MJ, Briend A, Ashorn P, Manary MJ. Homebased treatment of malnourished Malawian children with locally produced or imported ready-to-use food. J Pediatr Gastroenterol Nutr. 2004;39(2):141-146. Nutrition MaC. Management of Malnutrition in Children Under Five Years. 11 April 2013; http://motherchildnutrition. org/malnutrition-management/info/feeding-formulas-f75-f100.html. Accessed April 13, 2013. Temple VJ, Masta A. Zinc in human health. P N G Med J. 2004; 47(3-4):146-158. Arpadi SM, McMahon D, Abrams EJ, et al. Effect of bimonthly supplementation with oral cholecalciferol on serum 25-hydroxyvitamin
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D concentrations in HIV-infected children and adolescents. Pediatrics. 2009;123(1):e121-e126. Reich EN, Church JA. Oral zinc supplementation in the treatment of HIV-infected children. Pediatr AIDS HIV Infect. 1994;5(6): 357-360. Hanekom WA, Yogev R, Heald LM, Edwards KM, Hussey GD, Chadwick EG. Effect of vitamin A therapy on serologic responses and viral load changes after influenza vaccination in children infected with the human immunodeficiency virus. J Pediatr. 2000;136(4):550-552. Nalwoga A, Maher D, Todd J, Karabarinde A, Biraro S, Grosskurth H. Nutritional status of children living in a community with high HIV prevalence in rural Uganda: a crosssectional population-based survey. Trop Med Int Health. 2010;15(4):414-422. WHO Guidelines Approved by the Guidelines Review Committee. Guidelines for an intergrated approach to nutritional care of HIV-infeced children (6 months-14 yrs). Geneva: World Health Organization; 2009:92.
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A Systematic Review of Nutritional Supplementation in HIV-Infected Children in Resource-Limited Settings Megan S. McHenry, Avika Dixit and Rachel C. Vreeman Journal of the International Association of Providers of AIDS Care (JIAPAC) published online 18 June 2014 DOI: 10.1177/2325957414539044 The online version of this article can be found at: http://jia.sagepub.com/content/early/2014/06/18/2325957414539044
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Article
A Systematic Review of Nutritional Supplementation in HIV-Infected Children in Resource-Limited Settings
Journal of the International Association of Providers of AIDS Care 1-11 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/2325957414539044 jiapac.sagepub.com
Megan S. McHenry, MD1, Avika Dixit, MBBS, MPH1, and Rachel C. Vreeman, MD, MS1,2
Abstract Background: In resource-limited settings, malnutrition is the major cause of death in young children, but the precise benefits of nutritional supplementation for HIV-infected children are not well understood. Methods: Two researchers reviewed studies conducted in low- or middle-income countries that involved macro- and micronutrient supplementation in HIV-infected individuals 18 years. Results: Fifteen studies focused on micronutrients, including vitamin A, zinc, multivitamins, and multiplemicronutrient supplementation. The 8 macronutrient studies focused on ready-to-use foods (4 studies), spirulina, whey protein, general food rations, and F75 and F100 starter formulas. Vitamin A was associated with improved mortality rates, ranging from 28% to 63%. Multiple-micronutrient supplementations were not associated with improvement of measured health outcomes. Ready-to-use foods were associated with improvement in certain anthropometrics. Conclusion: Periodic vitamin A supplementation is associated with reduced mortality. Macronutrient supplementation is linked to improved anthropometrics. More research is needed to determine how nutritional supplementation benefits this particularly vulnerable population. Keywords nutritional supplementation, HIV, AIDS, children, clinical outcomes, nutrition
Introduction Individuals living with HIV are frequently affected by malnutrition for multiple reasons. Developing countries have a high prevalence of HIV, and the average diet in those communities frequently does not meet the recommended daily requirements of nutrients.1 Moreover, in severe HIV disease, patients may have increased losses of nutrients because of malabsorption.1-3 HIV-infected individuals may also have secondary infections, appetite suppression, and increased energy expenditures, all of which contribute to poor nutritional status.1-4 Nutritional status is an important predictor of immunological status for HIV-infected children, with morbidity compounded by the presence of poor nutritional status.5 Despite the general understanding that malnutrition and HIV are closely linked, the impact of nutritional supplementation for HIV-infected children has not been clear. Although several reviews have examined specific micronutrient supplementation for HIV-infected children,6,7 most studies focused on serum vitamin levels as a primary outcome. Generalizable research regarding macronutrients is also limited. The objective of this review is to compare general health outcomes among HIV-infected children and youth receiving nutritional supplementation to those not receiving supplementation. This review focuses specifically on developing and least
developed countries, as this is a population at greatest risk of nutritional deficiencies.
Methods We searched several bibliographic databases, including MEDLINE, EMBASE, The Cochrane Collaboration, Google scholar, as well as bibliographies of pertinent articles (all as of April 1, 2013). Our search strategies included using MeSH terms related to HIV, the pediatric population, and nutritional supplementation. Two authors (MSM and AD) reviewed the titles of all returned articles to select abstracts warranting review. From these abstracts, full articles were chosen for review to determine which studies looked at nutritional supplementation in HIV-infected children. The 2 authors then 1
Department of Pediatrics, Children’s Health Services Research, Indiana University School of Medicine, Indianapolis, IN, USA 2 USAID-Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya Corresponding Author: Rachel C. Vreeman, MD, MS, Children’s Health Services Research, 410 W. 10th St, HITS #1000, Indianapolis, IN 46202, USA. Email: [email protected]
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Journal of the International Association of Providers of AIDS Care Quality of the evidence was assessed using guidelines from Effective Public Health Practice Project.9 We aggregated data from publications reporting outcomes measured over the same time period in the same population. If the outcomes were the same in previously mentioned publications, they were excluded. Interventions and outcomes were too heterogeneous to allow for quantitative meta-analysis, but results were synthesized qualitatively by intervention type.
Results
Figure 1. Search results for systematic review.
independently reviewed the selected full articles and independently decided whether articles met predetermined inclusion criteria. Disagreements were discussed among all authors (MSM, AD, and RCV) to come to consensus. Randomized-controlled trials (RCTs) and observational studies, including case–control and cohort, involving HIVinfected individuals younger than 18 years of age in lowincome or middle-income countries as classified by the World Bank,8 were included. In addition, studies needed to measure outcomes, such as anthropometrics, frequency of HIV comorbid infections/conditions, HIV-related disease staging, or mortality rates. Included studies examined nutritional supplementation interventions in the form of food, protein or caloric supplements, ready-to-use therapeutic foods, or micronutrients. In this analysis, ‘‘food’’ refers to items that were traditionally part of a population’s diet but were supplemented in an additional amount for the intervention. Studies focusing on breast-feeding or HIV transmission, maternal supplementation, and case studies with less than 10 study participants were excluded.
The systematic literature search identified 5269 articles, with 2020 articles from the MEDLINE search and 3249 from EMBASE. Of these articles, 172 full-text articles were reviewed. Two additional publications were identified through the review of the bibliographies. Twenty-three of the articles reviewed met all predetermined inclusion criteria and were included in this study (Figure 1). Fifteen publications focused on micronutrient supplementation, describing 10 separate populations. All 15 micronutrient studies were RCTs.10-24 Of the populations, 3 had some antiretroviral therapy (ART) availability.10,18,19,21,22 In 1 population, ART was made available in country mid-way through the study, and HIV-infected patients were referred for treatment at that time.18,19 In another population, HIV-infected patients were stratified into 2 groups based on their ART status.21,22 A third group was given 1 dose of nevirapine (NVP) at birth.10 The other publications either did not have patients on ART or they did not describe ART use in their methods sections. Eight publications examined macronutrient supplementation in separate populations.25-32 In all, 2 were randomizedcontrolled studies30,31 and 6 were cohort studies.25-29,32 Three of the studies described some ART availability in their populations.25,27,32 One study enrolled children who were naive to antiretroviral medications and those children eligible for ART based on clinical conditions were started on medications.27 In another study, ART was made available in country during the study period so HIV-infected children were referred for treatment.25 In the third study, all children were on ART.32
Micronutrient Supplementation Vitamin A. Twelve studies looked at vitamin A supplementation in pediatric HIV-infected population. Two of the studies used vitamin A in 1 of 3 treatment arms, which is described later.18,19 Eight studies met the inclusion criteria of this review.1114,16,17,23,33,34 Two of the included publications studied the same Zimbabwean cohort.16,33 Four publications studied the same Tanzanian cohort12-14,34; however, 1 study examined predictors of anemia and did not specifically focus on micronutrient supplementation as an outcome so it was not included for review.34 An RCT in Uganda randomized HIV-infected children to receive vitamin A supplementation (200 000 IU, then 60 mg retinal equivalent) every 3 months from age 15 months to 36 months compared to placebo.23 Those receiving vitamin A had a 46% reduction in all-cause mortality (adjusted relative
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Tanzania
Zimbabwe
South Africa
South Africa
South Africa
Fawzi, et al12; Fawzi, et al13; Villamor, et al14
Humphrey, et al15; Miller, et al16
Hussey, et al17
Luabeya, et al18; Chhagan, et al19
Mda, et al20
South Africa
South Africa
Micronutrients Bobat, et al10
Coutsoudis, et al11
Country
Source
Table 1. Study Characteristics.
285 children (23 were HIV infected)
58 (13 were HIV infected)
50 HIV-infected children
Control Group
289 children (24 were HIV infected)
60 (15 were HIV infected)
46 HIVinfected children
Intervention Group
Study Design
6-60 months Randomized controlled
0-18 months Randomized placebo controlled
Method of Group Assignment Qualitya
Block-randomized Strong in 3 age strata (6-23, 24-41, and 42-60 months) Moderate Vitamin A of 50 000 IU Randomly allocated from a at 1 and 3 months, table of random 100 000 IU at 6 and 9 numbers months, and 200 000IU at 12 and 15 months Strong Vitamin A (200 000 IU Randomly assigned in for children over 1 blocks of 20 year old and 100 000 IU for infants) to be given while hospitalized (2 doses) at 4 months and 8 months Strong Vitamin A (2000 00 IU Randomized as Moderate described in for mothers, 50 000 Hussey G IU for infants) was abstract (23) given as 1-time dose to both, either mother or infant, or neither
Intervention
6-60 months Double-blind, Zinc (10 mg of elemental zinc) daily placebo for 6 months controlled
Age Group
(continued)
0-24 months Randomized 2876 children with 381 HIV placebo infected PCR negative at controlled at baseline; baseline and 6 504 initially weeks negative but HIV infected at 6 weeks 75 children n/a n/a Mean age 17 Randomized Vitamin A (200 000 IU n/a n/a months controlled for 2 days) Strong n/a n/a 6-24 months Double-blind, Multiple-micronutrient By HIV status 373 children, (187 Strong supplementations randouninfected, 154 included one of the mized HIV uninfected, following: vitamin A, controlled HIV exposed, 32 vitamin A þ zinc, or a HIV infected) multivitamin Strong Simple 52 children 54 children 4-24 months Double-blind, Multivitamin (at 118 HIV-infected randomizations allowances based on randochildren admitted schedule needs of a 1 year old) mized with diarrhea or given once daily until controlled pneumonia discharge 4495 mother (HIV positive)-infant pairs
648 children admitted to hospital for pneumonia
118 offspring of HIV-infected women
96 HIV-infected children
Patients
4
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Zimbabwe
India
Brazil
Kundu, et al27
Moreno, et al28
Fergusson, et al25 Malawi
Macronutrients Choto, et al26
176 children (7 were HIV infected)
Srinivasan, et al24 Uganda
18 vertically HIVinfected children
n/a
n/a 840 children (460 had HIV-related disease) n/a 454 children with severe acute malnutrition (79 children were HIV infected) 100 HIV-infected 180 HIV-infected children children in outpatient clinic
352 children hospitalized for severe pneumonia
94 HIV-infected 181 HIV-infected children children enrolled through a hospital (49 died prior to completion of study)
Uganda
Semba, et al23
Control Group
421 HIV-infected 847 HIV-infected children children, stratified into ARV medications receiving (85 of 847) and non-ARV medications (762 of 847)
Patients
Uganda
Country
Ndeezi, et al21; Ndeezi, et al22
Source
Table 1. (continued)
n/a
80 HIVinfected children
n/a
n/a
176 children (28 were HIV infected)
87 HIVinfected children
426 HIVinfected children
Intervention Group
Study Design Intervention
Method of Group Assignment Qualitya
1-6 years
2-12 years
Nutrition Mix-1A: 6 grams given once daily for 10 months F75/F100
n/a
n/a
Clinic-based Food rations providing Computer generated ½ caloric and ½ observarandom proteins tional study number table recommended for helped pick daily allowance for cohort child’s age given monthly n/a Whey protein given 1-2 Prospective times daily started as double20% daily protein blind clinineeds and increased cal trial to 50%
Prospective cohort study 6-60 months Prospective cohort study
12-36 months
(continued)
Strong
Strong
Strong
Weak
Strong Computer 1-5 years old Double-blind, 14-multipleStrong randomization micronutrient suprandoat a ratio of 1:1 plement versus mized in permuted ‘‘standard of care’’ 6controlled blocks of 4-20 multivitamin to each one of supplement the study supplements n/a Moderate Enrolled 6- Double-blind, Vitamin A or 60 mg retinol equivalent rando15 every 3 months from mized, plamonths, 15-36 months cebo intervencontrolled tion from 15-36 months 6-59 months Double-blind, Zinc (20 mg for children Enrolled in serial Strong order and 1 year and older, 10 randorandomized mg for those younger mized, plathan 12 months) daily cebo for 7 days controlled
Age Group
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Burkina Faso
Tanzania
Simpore, et al31
Sunguya, et al32
Control Group
219 HIV infected, ART treated
170 children
n/a
80 children (40 were HIV infected)
45 children 93 HIV-infected received maize/ children, severely soy flour malnourished children discharged from hospital. Not on ARV medications 169 HIV-infected 83 HIV-infected children children
Patients
Age Group
n/a
90 children (44 were HIV infected)
86 HIVinfected children
Intervention
Maize/soy Three arm flour with prospective micronutrient cohort supplementation study versus RUTF versus RUTF supplement
Study Design
Prospectively, systematically allocated to groups based on their week of discharge from hospital
Moderate
Method of Group Assignment Qualitya
Weak 6-36 months Randomized Formula with increased Computer generated block caloric and protein nonblinded randomization density versus study standard formula and diet. All received micronutrients Weak Progressive 12-60 Randomized Spirulina number given to months controlled supplementation to each participant traditional meals and a casual (millet, vegetable number fruit) for 8 weeks generator program was used n/a Moderate Ready to use CrossYounger therapeutic food— sectional than 5 Plumpynut 200 kcal/ study years of kg/d for 6-10 weeks age
12-60 20 children months received RUTF, 28 received RUTF supplement
Intervention Group
Abbreviations: PCR, polymerase chain reaction; n/a, not applicable; RUTF, ready-to-use therapeutic food; ARV, antiretroviral. a Per Effective Public Health Practice Project Criteria.
South Africa
Malawi
Country
Rollins, et al30
Ndekha, et al29
Source
Table 1. (continued)
6
Journal of the International Association of Providers of AIDS Care
Table 2. Study Outcomes by Intervention Type. Source
Intervention Type
Coutsoudis, et al11
Vitamin A
Fawzi, et al12; Fawzi, et al13; Villamor, et al14 Humphrey, et al15; Miller, et al16
Hussey, et al17 Semba, et al23 Bobat, et al10 Srinivasan, et al24 Mda, et al20 Luabeya, et al18; Chhagan, et al19 Ndeezi, et al21; Ndeezi, et al22 Choto, et al26 Fergusson, et al25 Rollins, et al30 Kundu, et al27
Moreno, et al28
Simpore, et al31 Ndekha, et al29 Sunguya, et al32
Outcome
For HIV-infected patients, morbidity associated with diarrhea was significantly reduced in supplemented groups Vitamin A Reduction in all-cause mortality by 63%in HIV-infected patients and AIDS-related deaths by 68% Nonsignificant reduction in cough and tachypnea and a nonsignificant increase in acute diarrhea Significant increase in height, in particular in children between 6 and 18 months of age Vitamin A For infants who were HIV PCR negative at baseline and positive at 6 weeks, supplementation reduced mortality; maternal supplementation not associated with significant effects; HIV negative infants given vitamin A had 2-fold higher mortality HIV-infected children were noted to have increased risk of anemia; however, intervention had no effect on anemia or hemoglobin Vitamin A Increased TCD4 counts 4 weeks after supplementation Vitamin A Mortality rates were lower when supplemented (relative risk of 0.54); decreased prevalence of cough and chronic diarrhea Zinc No significant change in HIV-1 viral load, TCD4 counts, or median hemoglobin concentration; those given supplements were less likely to get watery diarrhea; increased weight gain in children receiving zinc Zinc Mortality rate was decreased in HIV-infected patients receiving zinc compared with those receiving placebo; no other significant effect on respiratory rate, temperature, or oxygen saturation was found Multivitamin No change in anthropometric indices and micronutrient concentrations; shorter duration of hospitalizations in those with intervention Multiple-micronutrient No significant difference in overall diarrhea among treatment arms; HIV-infected children supplementation receiving zinc or multivitamin had higher incidence of persistent and severe diarrhea than vitamin A supplemented children No differences between treatment arms in the prevalence of diarrhea or pneumonia Multiple-micronutrient No significant change in mortality, growth, or TCD4 counts with intervention supplementation No significant difference in incidence or prevalence of diarrhea with intervention Nutrition Mix-1A Significant weight gain over the 10-month study period (3-6 kg); subjective decrease in episodes of illness reported by mothers F75/F100 All children achieved nutritional recovery (>85% weight-for-height and no edema) Enhanced formula Significant weight gain was noted in the first 8 weeks with the enhanced formula (P < .0001) with similar weight gain compared to standard formula thereafter; no significant difference in TCD4 counts Food supplementation Significant improvement in clinic adherence along with increased mean clinic visit and mean TCD4 count with incentive; this also correlated well with number of visits, which in turn had strong correlation with weight gain, episodes of AIDS-defining illnesses, and hospitalizations Whey protein No significant change in hemoglobin, leukocytes, platelets, MCV; significant decreased in the TCD8 count in those receiving supplementation that contributed to a nonsignificant increase in TCD4/TCD8 counts; lower occurrence of associated coinfections was also observed Spirulina Weight gain of 15 g/d in HIV-infected patients when taken daily; decreased level of anemia Ready-to-use therapeutic Half of the children achieved complete anthropometric recovery with any home-based foods therapy; therapy with RUTF reached this goal more frequently and quickly when compared to RUFT supplement or maize/soy flour Ready-to-use therapeutic Less likely to have underweight and wasting compared to controls; when treated for at least foods 4 months, were less likely to be underweight, wasted, and stunted
Abbreviations: PCR, polymerase chain reaction; RUTF, ready-to-use therapeutic food; MCV, mean corpuscular volume.
risk [RR] ¼ 0.54; 95% confidence interval [CI]: 0.30-0.98) after a follow-up period of 17.8 months.23 Vitamin A also improved morbidities, with decreased persistent cough (odds ratio [OR] ¼ 0.47; 95% CI: 0.23-0.96) and a suggestion of decreased chronic diarrhea, though these findings were nonsignificant (OR ¼ 0.48; 95% CI: 0.19-1.18).23
The Tanzania Vitamin A Study (n ¼ 648 with 58 HIVinfected patients) was the focus of 3 included publications between 1999 and 2002.12-14 HIV-infected children aged 6 to 60 months were given either placebo or vitamin A supplementation at baseline during hospitalization as well as at 4 and 8 months after hospital discharge. Dosing of the vitamin
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A intervention was dependent on age (100 000 IU of vitamin A if 85% weight for height
and no edema. The HIV-infected children gained more weight than children not infected with HIV (1.45 kg versus 1.21 kg; P ¼ .03).25 Although HIV-infected children had longer hospitalizations (28.8 days versus 24.3 days; P ¼ .03), their rate of weight gain was slightly higher (8.9 g/kg/d versus 8.0 g/kg/d).25 Spirulina. Spirulina was used as an intervention in a study performed in Burkina Faso (n ¼ 170).31 Children aged 12 to 60 months were divided into the following 4 groups: HIV-infected children with and without spirulina supplementation and children not infected with HIV with and without spirulina supplementation. All children were also given traditional meals with millet, fruits, and vegetables. When comparing pre- and poststudy weight-for-height z scores (WHZ), all children had significant improvement (intervention: P ¼ .004; control: P ¼ .000). HIV-infected children receiving spirulina had greater improvement in WHZ than those who did not (22% versus 10.4%).31 Supplementary food rations. One clinic-based observational study looked at whether a food supplementation intervention impacted clinic visit adherence among HIV-infected children aged 2 to 12 years (n ¼ 80).27 The food incentive was associated with significant improvement in clinic adherence (P ¼ .027), increased mean number of clinic visits (6.65 + 1.43 versus 8.01 + 1.52, P ¼ .000), and increased mean CD4 counts (P ¼ .028).27 Provision of incentive correlated well with the number of visits (Pearson r ¼ .345) which in turn had a strong correlation with weight gain (r ¼ .548) and a negative correlation with episodes of AIDS-defining illnesses (r ¼ .412) and hospitalization (r ¼ .279).27
Discussion This systematic review evaluated the impact of nutritional supplementation on clinical outcomes for HIV-infected children in resource-limited settings, revealing a limited body of evidence supporting the use of particular types of supplementation. For micronutrients, although there is no conclusive evidence that vitamin A supplementation reduces diarrhea, anemia, or pneumonia, there is some evidence that periodic vitamin A supplementation for HIV-infected children younger than 5 years of age reduces all-cause and HIV-related mortality.12,23,33 Multivitamins were associated with fewer hospitalizations for diarrhea in HIV-infected children20 but supplements combining multiple micronutrients did not improve diarrhea, pneumonia, mortality, growth, or CD4 counts.18,19,21,22 Macronutrient supplementation was closely linked to improved anthropometrics for HIV-infected children. In the compiled evidence, RUTF increased average weight gain in HIV-infected children, especially when given with ART.26,32 F75 and F100 formulas improved mortality rates among malnourished HIV-infected children.25 Whey protein was associated with a decrease in the reporting of HIV coinfections as well as significant decrease in TCD8 counts.28 Accumulating evidence suggests that a newer supplement, spirulina, can also
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improve anthropometrics such as WHZ for HIV-infected children.31 Food itself is the macronutrient that makes a clear difference for both clinic-related and clinical outcomes; in one study, giving food at clinic visits improved clinic adherence, as well as mean CD4 counts and weight gain, and decreased AIDS-defining illnesses and hospitalizations.27 Along with the findings that periodic vitamin A and macronutrient supplementation may be beneficial for HIV-infected children, it is important to highlight the mixed evidence for certain micronutrients, which may not be effective or may even cause harm. Although one study suggested that zinc supplementation improved weight gain for HIV-infected children, and limited evidence also supported a decrease in mortality,10,24 in another study, children receiving zinc or multivitamins had a higher incidence of persistent and severe diarrhea than those children given vitamin A supplementation.18 The potential for zinc to have limited effectiveness or even to cause harm for HIV-infected children is significantly different than the benefits cited for malnourished, populations not infected with HIV.37 Part of the utility of this critical review of the evidence is the reminder that receiving more nutrients is not always better for this population. Less than 40% of the populations compiled in this systematic review (7 of 18) were analyzed for the impact of nutritional supplementation on immunologic or virologic markers of HIV disease such as CD4 counts or viral loads.10,15,17,21,27,28,30 The majority focused on clinical outcomes, such as coinfections and rates of mortality. This is in contrast to other studies examining the impact of nutritional supplementation on CD4 counts, viral loads, or both that were not conducted in a developing or least developed country and thus not included in this systematic review.38-40 The emphasis of the included studies on clinical outcomes is consistent with the focus and monitoring capacity of resource-limited settings. Although it would be beneficial to examine the impact of nutritional supplementation on viral load and CD4 counts, this type of laboratory testing may not be available or affordable in all settings. Moreover, in these settings with such high under-5 mortality rates, death and coinfections are likely more valuable measures than changes in CD4 counts or viral load. However, benefits of nutritional supplementation on these intermediary markers for disease progression may therefore be missed. There are several limitations related to this review that merit consideration. Although malnutrition is a huge issue for under-5 mortality, there are a limited number of randomized control trials examining nutritional supplementation for the HIV-infected population. Large, rigorous trials are still needed though we compiled the best evidence available. Another limitation is that our search strategy focused on published literature. Through bibliography searches, we did identify a relevant conference abstract; unpublished trials and conference presentations were not actively sought out, which could have led to publication biases. On the other hand, we wanted to compile the most rigorous evidence available for this population, even if it limited our search results. Another limitation is that we did not evaluate all non-English translations, which may
have prevented us from reviewing some literature from developing or least developed countries, but very few such articles were identified. This article reviews various types of nutritional supplementation in developing and least developed countries because adequate nutrition plays a significant role in the health of those who are HIV infected and individuals living in these countries who are at most risk of baseline malnutrition.41 The findings of our critical review are aligned with the World Health Organization (WHO) guidelines in regard to periodic vitamin A supplementation for HIV-infected children older than 6 months of age in developing and least developed countries.42 Our review also did not find substantial evidence to support the use of multivitamins or zinc, which is a finding that should be highlighted, so that resources are used only in an evidenced-based manner. Use of RUTF, food rations, and F75/F100 were found to help HIV-infected children meet WHZ and weight goals and use of these therapies in malnourished HIV-infected individuals is also supported by the WHO guidelines.42 Although the inference that increasing calories and protein will increase weight is not revolutionary, it is an important adjunct to ART in improving the health and well-being of this special population. Future research on nutritional supplementation for children with HIV should focus not only on which types of supplementation might improve children’s outcomes, but particularly on the optimal timing of nutritional supplementation with ART. None of these studies evaluated whether outcomes would be maximized if nutritional supplementation occurred before, at the time of, or after the initiation of ART. Moreover, evaluation of the feasibility and cost-effectiveness of implementation of supplementation is needed for programs operating with limited resources and caring for large populations. Nutritional supplementation may maximize the benefits of ART for HIV-infected children, and targeted research will help to improve outcomes for this vulnerable population. Authors’ Note The abstract for this article was presented as a poster at the International AIDS Society meeting on July 1, 2013, in Kuala Lumpur, Malaysia.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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