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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 multiple-micronutrient 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 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 HIV-infected individuals younger than 18 years of age in low-income 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.

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

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).

Figure 1.

Search results for systematic review.

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 randomized-controlled studies^30,31 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.^{11

–14,16,17,23,33,34} Two of the included publications studied the same Zimbabwean cohort.^16,33 Four publications studied the same Tanzanian cohort^12
–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 risk [RR] = 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] = 0.47; 95% CI: 0.23-0.96) and a suggestion of decreased chronic diarrhea, though these findings were nonsignificant (OR = 0.48; 95% CI: 0.19-1.18).²³

Table 1.

Study Characteristics.

Source	Country	Patients	Control Group	Intervention Group	Age Group	Study Design	Intervention	Method of Group Assignment	Quality^a
Micronutrients
Bobat, et al¹⁰	South Africa	96 HIV-infected children	50 HIV-infected children	46 HIV-infected children	6-60 months	Double-blind, placebo controlled	Zinc (10 mg of elemental zinc) daily for 6 months	Block-randomized in 3 age strata (6-23, 24-41, and 42-60 months)	Strong
Coutsoudis, et al¹¹	South Africa	118 offspring of HIV-infected women	58 (13 were HIV infected)	60 (15 were HIV infected)	0-18 months	Randomized placebo controlled	Vitamin A of 50 000 IU at 1 and 3 months, 100 000 IU at 6 and 9 months, and 200 000IU at 12 and 15 months	Randomly allocated from a table of random numbers	Moderate
Fawzi, et al¹²; Fawzi, et al¹³; Villamor, et al¹⁴	Tanzania	648 children admitted to hospital for pneumonia	285 children (23 were HIV infected)	289 children (24 were HIV infected)	6-60 months	Randomized controlled	Vitamin A (200 000 IU for children over 1 year old and 100 000 IU for infants) to be given while hospitalized (2 doses) at 4 months and 8 months	Randomly assigned in blocks of 20	Strong
Humphrey, et al¹⁵; Miller, et al¹⁶	Zimbabwe	4495 mother (HIV positive)-infant pairs	2876 children with PCR negative at baseline and 6 weeks	381 HIV infected at baseline; 504 initially negative but HIV infected at 6 weeks	0-24 months	Randomized placebo controlled	Vitamin A (2000 00 IU for mothers, 50 000 IU for infants) was given as 1-time dose to both, either mother or infant, or neither	Randomized as described in Hussey G abstract (23)	Strong Moderate
Hussey, et al¹⁷	South Africa	75 children	n/a	n/a	Mean age 17 months	Randomized controlled	Vitamin A (200 000 IU for 2 days)	n/a	n/a
Luabeya, et al¹⁸; Chhagan, et al¹⁹	South Africa	373 children, (187 uninfected, 154 HIV uninfected, HIV exposed, 32 HIV infected)	n/a	n/a	6-24 months	Double-blind, randomized controlled	Multiple-micronutrient supplementations included one of the following: vitamin A, vitamin A + zinc, or a multivitamin	By HIV status	Strong Strong
Mda, et al²⁰	South Africa	118 HIV-infected children admitted with diarrhea or pneumonia	52 children	54 children	4-24 months	Double-blind, randomized controlled	Multivitamin (at allowances based on needs of a 1 year old) given once daily until discharge	Simple randomizations schedule	Strong
Ndeezi, et al²¹; Ndeezi, et al²²	Uganda	847 HIV-infected children, stratified into ARV medications receiving (85 of 847) and non-ARV medications (762 of 847)	421 HIV-infected children	426 HIV-infected children	1-5 years old	Double-blind, randomized controlled	14-multiple-micronutrient supplement versus “standard of care” 6-multivitamin supplement	Computer randomization at a ratio of 1:1 in permuted blocks of 4-20 to each one of the study supplements	Strong Strong
Semba, et al²³	Uganda	181 HIV-infected children enrolled through a hospital (49 died prior to completion of study)	94 HIV-infected children	87 HIV-infected children	Enrolled 6-15 months, intervention from 15-36 months	Double-blind, randomized, placebo controlled	Vitamin A or 60 mg retinol equivalent every 3 months from 15-36 months	n/a	Moderate
Srinivasan, et al²⁴	Uganda	352 children hospitalized for severe pneumonia	176 children (7 were HIV infected)	176 children (28 were HIV infected)	6-59 months	Double-blind, randomized, placebo controlled	Zinc (20 mg for children 1 year and older, 10 mg for those younger than 12 months) daily for 7 days	Enrolled in serial order and randomized	Strong
Macronutrients
Choto, et al²⁶	Zimbabwe	840 children (460 had HIV-related disease)	n/a	n/a	12-36 months	Prospective cohort study	Nutrition Mix-1A: 6 grams given once daily for 10 months	n/a	Weak
Fergusson, et al²⁵	Malawi	454 children with severe acute malnutrition (79 children were HIV infected)	n/a	n/a	6-60 months	Prospective cohort study	F75/F100	n/a	Strong
Kundu, et al²⁷	India	180 HIV-infected children in outpatient clinic	100 HIV-infected children	80 HIV-infected children	2-12 years	Clinic-based observational study	Food rations providing ½ caloric and ½ proteins recommended for daily allowance for child’s age given monthly	Computer generated random number table helped pick cohort	Strong
Moreno, et al²⁸	Brazil	18 vertically HIV-infected children	n/a	n/a	1-6 years	Prospective double-blind clinical trial	Whey protein given 1-2 times daily started as 20% daily protein needs and increased to 50%	n/a	Strong
Ndekha, et al²⁹	Malawi	93 HIV-infected children, severely malnourished children discharged from hospital. Not on ARV medications	45 children received maize/soy flour	20 children received RUTF, 28 received RUTF supplement	12-60 months	Three arm prospective cohort study	Maize/soy flour with micronutrient supplementation versus RUTF versus RUTF supplement	Prospectively, systematically allocated to groups based on their week of discharge from hospital	Moderate
Rollins, et al³⁰	South Africa	169 HIV-infected children	83 HIV-infected children	86 HIV-infected children	6-36 months	Randomized nonblinded study	Formula with increased caloric and protein density versus standard formula and diet. All received micronutrients	Computer generated block randomization	Weak
Simpore, et al³¹	Burkina Faso	170 children	80 children (40 were HIV infected)	90 children (44 were HIV infected)	12-60 months	Randomized controlled	Spirulina supplementation to traditional meals (millet, vegetable fruit) for 8 weeks	Progressive number given to each participant and a casual number generator program was used	Weak
Sunguya, et al³²	Tanzania	219 HIV infected, ART treated	n/a	n/a	Younger than 5 years of age	Cross-sectional study	Ready to use therapeutic food—Plumpynut 200 kcal/kg/d for 6-10 weeks	n/a	Moderate

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.

Table 2.

Study Outcomes by Intervention Type.

Source	Intervention Type	Outcome
Coutsoudis, et al¹¹	Vitamin A	For HIV-infected patients, morbidity associated with diarrhea was significantly reduced in supplemented groups
Fawzi, et al¹²; Fawzi, et al¹³; Villamor, et al¹⁴	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
Humphrey, et al¹⁵; Miller, et al¹⁶	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
Hussey, et al¹⁷	Vitamin A	Increased TCD4 counts 4 weeks after supplementation
Semba, et al²³	Vitamin A	Mortality rates were lower when supplemented (relative risk of 0.54); decreased prevalence of cough and chronic diarrhea
Bobat, et al¹⁰	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
Srinivasan, et al²⁴	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
Mda, et al²⁰	Multivitamin	No change in anthropometric indices and micronutrient concentrations; shorter duration of hospitalizations in those with intervention
Luabeya, et al¹⁸; Chhagan, et al¹⁹	Multiple-micronutrient supplementation	No significant difference in overall diarrhea among treatment arms; HIV-infected children 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
Ndeezi, et al²¹; Ndeezi, et al²²	Multiple-micronutrient supplementation	No significant change in mortality, growth, or TCD4 counts with intervention No significant difference in incidence or prevalence of diarrhea with intervention
Choto, et al²⁶	Nutrition Mix-1A	Significant weight gain over the 10-month study period (3-6 kg); subjective decrease in episodes of illness reported by mothers
Fergusson, et al²⁵	F75/F100	All children achieved nutritional recovery (>85% weight-for-height and no edema)
Rollins, et al³⁰	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
Kundu, et al²⁷	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
Moreno, et al²⁸	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
Simpore, et al³¹	Spirulina	Weight gain of 15 g/d in HIV-infected patients when taken daily; decreased level of anemia
Ndekha, et al²⁹	Ready-to-use therapeutic foods	Half of the children achieved complete anthropometric recovery with any home-based therapy; therapy with RUTF reached this goal more frequently and quickly when compared to RUFT supplement or maize/soy flour
Sunguya, et al³²	Ready-to-use therapeutic foods	Less likely to have underweight and wasting compared to controls; when treated for at least 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.

The Tanzania Vitamin A Study (n = 648 with 58 HIV-infected 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 A intervention was dependent on age (100 000 IU of vitamin A if <1 year in age or 200 000 IU of vitamin A if 1-5 years in age). One study found that HIV-infected children receiving vitamin A had reductions in all-cause mortality by 63% (RR = 0.37; 95% CI: 0.17-0.84) and in AIDS-related deaths by 68% (RR = 0.32: 95% CI: 0.1-0.99).¹² Another publication by the same author highlighted a nonsignificant reduction in cough and tachypnea (RR = 0.54; 95% CI: 0.24-1.20) and a nonsignificant increase in acute diarrhea (RR = 1.55; 95% CI: 0.75-3.17).¹³ An RCT conducted in Tanzania found that 4 months after the first vitamin A dose, HIV-infected children had gained, on average, 2.8 cm (95% CI: 1.0-4.6) height compared to children who received placebo.¹⁴

A study performed in South Africa enrolled HIV-exposed children, 28 of whom were HIV infected.¹¹ In this small subgroup of HIV-infected children, vitamin A supplementation (50 000 IU at 1 and 3 months, 10 000 IU at 6 and 9 months) suggested a reduction in both acute diarrhea (OR = 0.51; 95% CI: 0.27-0.99) and chronic diarrhea (OR = 0.44; 95% CI: 0.17-1.18). A nonsignificant reduction in thrush (OR = 0.66; 95% CI: 0.25-1.73) and lower respiratory tract infection (OR = 0.60; 95% CI: 0.29-1.24) was also noted.¹¹

Two studies reported results from the Zimbabwe Vitamin A for Mothers and Babies Project (ZVITAMBO).^16,33 The project examined vitamin A supplementation in the following 4 different treatment groups: both mother and infant, mother only, infant only, or neither in a 2 × 2 factorial design. One of these studies found that in infants who were HIV polymerase chain reaction (PCR) negative at baseline and PCR positive at 6 weeks, vitamin A supplementation (of 50 000 IU) reduced mortality by 28% (P = .01),³³ while the other study found that supplementation had no effect on anemia or hemoglobin.¹⁶

A small trial (n = 75) that provided vitamin A (200 000IU) for 2 days to 75 South African children of mean age 17 months was associated with increased CD4 counts 4 weeks later, but more detailed outcomes were not available.¹⁷

Zinc

There were limited studies examining zinc supplementation in HIV-infected children. An RCT that was conducted to determine the safety and efficacy of zinc supplementation (10 mg elemental zinc as sulfate) in HIV-infected children in South Africa (n = 96, aged 6-60 months)¹⁰ showed that after 6 months of supplementation, children gained a median of 7% of their body weight when compared to only a 2% gain in children given placebo (P = .02). Children receiving zinc were also less likely than placebo to get diarrhea (7.4% versus 14.5%), but zinc did not affect the CD4 counts, HIV-1 viral loads, or hemoglobin levels.¹⁰

Another RCT in Uganda looked at zinc adjunct therapy in cases of severe childhood pneumonia.²⁴ Of the 352 children in the study, 55 were found to be HIV positive (28 in the zinc group and 27 in the placebo group).²⁴ In addition to standard antibiotics, participants were also given once-daily placebo or zinc dosing for 7 days (10 mg of zinc gluconate for children less than 12 months or 20 mg of zinc gluconate for those older than 12 months). In this small sample, mortality in the HIV-infected patients receiving placebo was 7 of 27 (25.9%) versus 0 of 28 (0%) among those receiving zinc (RR = 0.1; 95% CI: 0.0-1.0).²⁴

Multivitamin supplement

Several articles examined multivitamin supplementation^21,22; however, only 1 placebo-controlled study was found examining pediatric HIV-infected patients.²⁰ The study looked at children aged 4 to 24 months (n = 118) who were hospitalized for diarrhea or pneumonia²⁰ and either given multimicronutrient supplements or placebo during their entire inpatient stay. The multivitamins contained various vitamins and minerals at amounts based on recommended dietary allowances for a 1-year-old child. The duration of hospitalization for diarrhea was 1.6 days shorter in children who were receiving supplements than in those receiving placebos (P < .05). For pneumonia, the hospitalization duration was 1.9 days shorter for children receiving supplements (P < .05).²⁰

Multiple-micronutrient supplementations

Two publications described findings from a South African RCT of children aged 6 to 24 months, which divided children into the following 3 micronutrient treatment arms: daily vitamin A, daily vitamin A with zinc, and daily multiple micronutrients that included both vitamin A and zinc.^18,19 Thirty-two HIV-infected children were divided among the 3 treatment arms. One publication describing the results of this trial examined the effects of supplementation on diarrheal disease, finding that HIV-infected children had a higher incidence of diarrhea than that of uninfected children.¹⁹ Moreover, when the HIV-infected children received zinc or multiple-micronutrient supplementation, they had higher incidence of persistent and severe diarrhea than those supplemented with vitamin A alone (P = .02 for persistent diarrhea and P = .01 for severe diarrhea).¹⁹ A subsequent publication from this RCT found no significant difference in diarrhea episodes (P = .260) or reported pneumonia (P = .755) in HIV-infected children receiving any of the 3 interventions.¹⁸ Two articles compared a standard multivitamin to another multivitamin with an increased dose of micronutrients in the same sample of Ugandan children aged 1 to 5 years (n = 373)^21,22 and found no significant difference in overall mortality at 12 months between the intervention arm (5.9%) and comparative arm (6.7%), and no significant difference in mean weight for height at 12 months or CD4 counts.²¹ The incidence of diarrhea was similar between those receiving the standard multivitamin and the intervention group, with some decrease in diarrhea reported by those on ART compared to those who are not.²²

Macronutrient Supplementation

Ready-to-use therapeutic foods

Among articles examining the use of ready-to-use therapeutic foods (RUTFs) in HIV-infected children,^26,29,32,35 4 met criteria for inclusion in this study. Prior to coining the term RUTFs, a study in Zimbabwe looked at the use of Nutrition mix-1 in children (n = 840). Of those participants, 460 had HIV-related disease.²⁶ This dietary supplement, which was a powdered milk protein-based dietary supplement with multiple vitamins and minerals added, was given to children 12 to 36 months of age for a period of 10 months. The average weight gain for children with HIV-related disease was found to be 51.2%, which was higher than that of noninfected children (26.0%).²⁶

One RCT looked at an enhanced nutritional supplement compared to the standard supplement for HIV-infected children, aged 6 to 36 months, with prolonged diarrhea.³⁰ The standard supplement was milk formula and a porridge/maize/pureed vegetable/oil diet. The enhanced nutritional supplement contained more protein and caloric density than the standard supplement (at least 150 kcal/kg/d versus 100-115 kcal/kg/d). All children also received a daily multivitamin twice according to the US Department of Agriculture -recommended daily requirement for 2 weeks as well as additional doses of folate, zinc, and vitamin A. Between enrollment and 8 weeks, children receiving the enhanced nutritional supplement achieved significantly more weight gain (P < .001) than children on the standard diet.³⁰ After 8 weeks, the median weight velocity normalized and was similar between the 2 groups. Median CD4 counts and 26-week mortality rates were also similar between the groups.³⁰

In 2010, a cross-sectional study in Tanzania looked at the impact of the RUTF Plumpynut on weight, wasting, and stunting in HIV-infected children on ART.³² Children (n = 140) younger than 5 years were given Plumpynut at the recommended dosage of 200 kcal/kg/d until they reached their target weight. Children treated with ART and RUTF were less likely than children on ART without RUTF to be underweight (adjusted OR [AOR] 0.19, 95% CI: 0.04-0.78, P = .021) or to have wasting (AOR = 0.24, 95% CI: 0.07-0.81, P = .021).³² The risk of stunting was not significantly different (AOR = 0.80; 95% CI: 0.41-1.57, P = .511).³²

Whey protein

A small, prospective, double-blinded RCT evaluated the outcomes of whey protein concentrate supplements for HIV-infected children (n = 18).²⁸ During the study, 22% of children in the intervention group and 78% in the control group presented with coinfections, such as otitis media, pneumonia, and tonsillitis (Fisher exact test P = .0567).²⁸ There was a significant decrease in TCD8 counts in the group that received supplementation (P = .046), contributing to the intervention group having a nonsignificant increase in CD4/CD8 counts (from 0.8 to 1.04; P = .12) from the start to end of the study.²⁸

F75/F100

F75 and F100 “starter” formulas are typically used in the acute management of pediatric malnutrition.³⁶ In Malawi, a prospective cohort study examined nutritional recovery using F75 and F100 formulas.²⁵ Among 454 children with severe acute malnutrition, 79 (17.4%) were HIV infected; 35.4% (28 of 79) of the HIV-infected children died during hospitalization, compared with 10.4% (39 of 375) of children not infected with HIV (P = .001).²⁵ Regardless of the HIV status, all children who survived achieved nutritional recovery with F75 or F100 formula, which was considered >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 = .03).²⁵ Although HIV-infected children had longer hospitalizations (28.8 days versus 24.3 days; P = .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 = 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 = .004; control: P = .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 = 80).²⁷ The food incentive was associated with significant improvement in clinic adherence (P = .027), increased mean number of clinic visits (6.65 ± 1.43 versus 8.01 ± 1.52, P = .000), and increased mean CD4 counts (P = .028).²⁷ Provision of incentive correlated well with the number of visits (Pearson r = .345) which in turn had a strong correlation with weight gain (r = .548) and a negative correlation with episodes of AIDS-defining illnesses (r = −.412) and hospitalization (r = −.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 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.

Footnotes

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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A Systematic Review of Nutritional Supplementation in HIV-Infected Children in Resource-Limited Settings

Abstract

Background:

Methods:

Results:

Conclusion:

Keywords

Introduction

Methods

Results

Micronutrient Supplementation

Vitamin A

Zinc

Multivitamin supplement

Multiple-micronutrient supplementations

Macronutrient Supplementation

Ready-to-use therapeutic foods

Whey protein

F75/F100

Spirulina

Supplementary food rations

Discussion

Footnotes

Authors’ Note

Declaration of Conflicting Interests

Funding

References