1. Objectives
To evaluate the effectiveness of oral macronutrient interventions for the reduction of morbidity and mortality in adults and children with HIV infection
2. How studies were identified
The following databases were searched up to August 2011:
- CENTRAL (The Cochrane Library 2011, Issue 3)
- MEDLINE
- EMBASE
- LILACS
- National Library of Medicine GATEWAY
- ClinicalTrials.gov
Reference lists were searched and the authors directly contacted researchers and policymakers
3. Criteria for including studies in the review
3.1 Study type
Randomized controlled trials
3.2 Study participants
Adults and children with HIV infection. Studies including participants with TB/HIV co-infection were included if participants were stratified according to HIV status
(Studies enrolling HIV-infected pregnant women were excluded)
3.3 Interventions
Supplementation or replacement of the usual diet with 1 g/day or more of an oral macronutrient for at least four weeks, compared to usual diet, no macronutrient supplementation, dietary counselling or non-nutritive placebo
3.4 Primary outcomes
Mortality
- All-cause mortality
- Mortality related to HIV infection and other HIV-related conditions
Morbidity
- Frequency, types and duration of episodes of opportunistic infections
- Incidence of AIDS as defined by each study
- Hospital admissions
- Other illnesses related to HIV infection
Secondary outcomes included: disease progression according to WHO or CDC staging system; indices of viral load; markers of immune response (CD4+ T-lymphocyte count and CD4+ percent of total lymphocytes); nutritional status (body weight, body composition, lean body mass, body mass index (BMI), weight-for-height and linear growth in children); energy expenditure; biochemical markers; dietary intake and appetite; functional outcomes (child development, quality of life, level of physical activity)
4. Main results
4.1 Included studies
Fourteen randomized controlled trials, enrolling 1725 adults and 271 children, were included in this review
- Three trials were involved children and in six trials at least half or all of the participants received antiretroviral therapy (ART)
- In half of the included studies the majority or all of the participants were CDC category C (AIDS) or WHO Stage III/IV
- Diverse participant populations were included, such as those with normal weight, with stable weight loss, and those with malnutrition. One trial included participants with TB/HIV co-infection, while the remaining trials enrolled participants free of secondary infections
- Interventions included micronutrient-fortified liquid formulas or supplementary foods, and specific macronutrient supplements, such as amino acids, whey protein and spirulina. Follow-up periods ranged from six weeks to 12 months
4.2 Study settings
- Brazil, Burkina Faso, Central African Republic, Germany, India, Kenya, South Africa, Spain, Switzerland (2 trials) and the United States of America (4 trials)
- In three of the four African studies none of the participants received ART
- Trials were generally conducted in an out-patient setting
4.3 Study settings
How the data were analysed
Where it was clinically meaningful to combine studies, meta-analyses were performed using random effects models to calculate risk ratios (RR) for dichotomous data, and weighted mean differences (WMD) for continuous data, with 95% confidence intervals. Trials of adults and children were considered separately. In adults, the following comparisons were made: i) macronutrient formulas fortified with micronutrients plus nutrition counselling versus nutrition counselling alone in participants with and without weight loss (5 trials); ii) supplementary food fortified with micronutrients plus nutrition counselling versus nutritional counselling alone in malnourished participants (2 trials); and iii) specific macronutrient supplements versus placebo, no supplement or usual diet (4 trials). The following comparisons were made in trials involving children: i) macronutrient supplements fortified with micronutrients given to provide protein and/or energy by replacing or supplementing usual diet versus no supplement or standard care (1 trial); ii) Specific macronutrient supplements versus placebo, no supplement or usual diet (2 trials).
As none of the included trials presented data in a format that allowed for extraction according to pre-specified subgroups (by disease progression, ART status, and age), subgroup analyses were not performed.
Results
Mortality
All-cause mortality in adults
In an Indian study comparing a cereal-lentil mixture (930 kcal/day) plus micronutrient supplementation and nutrition counselling to nutrition counselling alone in adults with TB/HIV co-infection, there was no significant difference in the risk of death at six months (RR 2.14, 95% CI [0.10 to 47.38]; 1 trial/22 participants). Spirulina supplementation of 10 g/day compared to placebo green clay in a study of ART-naïve adults in the Central African Republic did not reduce the risk of death at six months (p=0.8; 1 trial/160 individuals).
All-cause mortality in children
In a trial of HIV-infected South African infants who had prolonged diarrhoea, a casein-maltodextrin-based formula (150 kcal/kg/day, 4.0 to 5.5 g protein/kg/day, 15% of calories as protein) continued after the diarrhoea had resolved did not reduce the risk of death at eight weeks follow-up (odds ratio (OR) 1.42, 95% CI [0.59 to 3.40], p=0.43; 1 trial/169 infants) or at 26 weeks follow-up (OR 1.48, 95% CI [0.74 to 2.98], p=0.27; 1 trial/169 infants) in comparison to standard nutritional care.
Morbidity
Morbidity in adults
A one-year, three-armed trial in the United States of America compared 1-2 cans per day of standard oral formula (Ensure Plus®: 355 cal/can, 15% protein, 53% carbohydrates, 32% fat) plus nutrition counselling versus 1-2 cans per day of immune-enhancing oral formula (Advera®: 303 cal/can, 19% protein, 65% carbohydrates, 16% fat) plus nutrition counselling versus nutrition counselling alone. The authors of this trial reported no significant differences between the groups for clinical symptoms. In the spirulina trial, the authors reported a higher mean Karnofsky score in the treatment group at three months (p=0.0045), and at six months a lower number of pneumonia cases (p=0.01; 1 trial/160 participants). In a Kenyan study, those individuals not yet receiving ART and randomized to a supplementary food blend of maize, soya, vegetable oil, sugar, whey protein concentrate and micronutrient pre-mix (1320 kcal/day, 48 g/day protein) plus nutritional counselling in comparison to nutritional counselling alone had statistically significantly fewer days of poor health for the first two months of treatment (data presented graphically). A significant difference was also observed for those receiving ART, but for the second month of treatment only.
Morbidity in children
In the trial involving HIV-infected infants with prolonged diarrhoea, based on the cumulative frequency of clinical signs, the pattern of morbidity between enhanced and standard nutritional care groups did not differ throughout the follow-up period of 26 weeks. Whey protein concentrate was compared to placebo and maltodextrin in a small (n=18), 16 week study of vertically infected children on ART in Brazil. Compared to the combined placebo and maltodextrin groups, the authors reported that whey protein concentrate reduced the incidence of co-infection to a borderline statistically significant level (22% versus 78% co-infection, p=0.0567).
Adverse effects
In the three-armed formula trial, no difference in tolerance was found between groups receiving standard oral formula or immune-enhancing formula. In a separate trial, medium-chain triglyceride formula (Lipisorb® Liquid Nutrition: 17% protein, 48% carbohydrates, 35% fat) plus nutrition counselling was compared to nutrition counselling alone for six weeks in 99 HIV-infected men in the United States of America. One man receiving the formula reported nausea and epigastric pain, and another did not like the taste. Supplementary monohydrated L-ornithine alpha-ketoglutarate (OKG) was compared to an isonitrogenous placebo containing 9 g of milk proteins in 46 HIV-infected adults in Switzerland. The OKG group reported a statistically significant increased risk of gastrointestinal adverse events (RR 1.59, 95% CI [1.06 to 2.39], p=0.02; 1 trial/46 participants).
Additional outcomes
CD4 cell count and viral load in adults
Nine studies in adults reported on CD4 cell counts, of which two provided data for meta-analysis, where no statistically significant difference was observed between the treatment groups. One study reported a significant effect of a food blend plus nutritional counselling in comparison to nutritional counselling alone on the CD4 cell count at three months of those participants who were not yet on ART (+7.4 cells/mm³ versus -32.59 cells/mm³, p=0.01). Viral load was assessed in three studies in adults, and was reported to decrease significantly in one study in the United States of America among those provided with an amino acid blend (14 g glutamine, 14 g arginine, 3 g β-hydroxy-β-methylbutyrate, citric acid) compared to those given a maltodextrin placebo (MD -3.71 log10 copies/mL, 95% CI [-12.16 to -4.74], p=0.007; 1 trial/66 participants).
CD4 cell count and viral load in children
In the trial of infants with prolonged diarrhoea, no significant differences were found in CD4 cell count or viral load between those receiving enhanced versus standard nutritional care. Whey protein concentrate supplementation had no effect on CD4 cell count after 16 weeks (1 trial/18 participants).
Nutritional intake and status in adults
Macronutrient formula interventions designed to increase energy and protein intake in the treatment group were all conducted in high-income countries, and achieved a statistically significant increase in energy intake (MD 394 kcal/day, 95% CI [225 to 562], p<0.00001; 3 trials/131 participants) and protein intake (MD 23.25 g/day, 95% CI [12.68 to 34.01], p<0.00001; 2 studies/81 participants) in pooled analyses. Despite this, there was no parallel increase in body weight in pooled analyses compared with nutrition counselling alone (MD in body weight -0.17 kg, 95% CI [-1.10 to 0.75], p=0.72; 4 trials/233 participants), and only one study (Ensure® versus nutrition counselling alone for 12 weeks) reported a statistically significant increase in weight in the intervention group (2.75% increase, p<0.05; 1 trial/70 participants), although this was primarily due to increased fat mass. A supplementary food mixture plus nutritional counselling in comparison to nutritional counselling alone resulted in a statistically significant difference in body weight gain among participants not receiving ART, MD 1.22 kg (95% [0.31 to 2.12], p=0.008) at three months and MD 2.06 kg (95% [0.82 to 3.30], p=0.0012) at six months (1 trial/157 and 211 individuals, respectively). This finding was also reflected in a statistically significant MD in body weight at three (MD 2.82 kg (95% CI [1.02 to 4.62], p=0.002) and six months (MD 3.67 kg, 95% CI [1.50 to 5.84], p=0.0009). Pooled analysis demonstrated no statistically significant difference in percent body fat between treatment and control groups in trials of macronutrient formulas (MD -1.14%, 95% CI [-2.58 to 0.29], p=0.12; 4 trials/233 individuals), or in fat-free mass (MD -0.37 kg, 95% CI [-2.77 to 2.03], p=0.78; 3 trials/218 participants). An amino acid supplement increased weight (MD 2.63 kg, 95% CI [0.72 to 4.54], p=0.007) and fat-free mass (MD 3.25 kg, 95% CI [1.25 to 5.25], p=0.001) in comparison to a maltodextrin control over eight weeks (1 trial/43 participants). OKG supplementation was reported to result in statistically significant increases in body weight, BMI and triceps skinfold thickness at 12 weeks in comparison to a milk protein control (all p<0.05).
Nutritional intake and status in children
Children receiving enhanced nutritional support following prolonged diarrhoea in comparison to standard nutritional support achieved a higher weight-for-age standard deviation score (WFA-SDS) from eight to 26 weeks follow-up (all p<0.05), with a WFA-SDS of -1.01 in comparison to -1.68 at six months.
Biochemical indices
Both adults receiving ART and those who were not receiving ART achieved a greater increase in haemoglobin following treatment with a supplementary food blend at three and six months follow-up (all p≤0.05). Treatment with spirulina in adults increased serum protein concentrations in comparison to placebo at three and six months (both p≤0.01). No significant effects were noted for biochemical indices in children.
Quality of life
In the initial period of treatment with a supplementary food blend, adults not receiving ART reported improved self-perceived health, but this difference was not sustained. In a trial conducted in the United States of America of L-glutamine and antioxidants versus a placebo of glycine, there was no difference between groups in self-rated mood after 12 weeks.
5. Additional author observations*
The diversity of study settings and participant groups represented in this review is important because HIV-infected individuals in high-income and resource-constrained countries differ in terms of their personal income level, adequacy of nutritional intake, and access to healthcare and ART. Of the 14 identified trials, only two examined the effect of the same intervention. Thus, meta-analysis was limited and only performed for trials of macronutrient formulas fortified with micronutrients plus nutrition counselling versus nutritional counselling alone, all of which were conducted in high-income settings. The generalisabilty of this evidence is therefore restricted, and the quality of the evidence was rated moderate to very low. In addition, all of the macronutrient formula interventions included micronutrients which may be a possible confounder, as the effects observed may be due to either the increased energy and protein intake or to the additional micronutrients.
While there is limited evidence from randomized trials conducted in predominantly high-income countries that macronutrient supplementation increases energy and protein intake in HIV-infected adults on ART, the effects of supplementation on mortality, morbidity, body weight, and immunological and biological indices requires further investigation. Future research participants should be diverse in regard to stage of disease, use of ART, and immune and nutritional status, and future interventions should be aimed at determining the optimal composition of fortified macronutrient supplements, including a cost-benefit evaluation.
