We present the results of the trials conducted in adults followed by the results of the trials conducted in children. Where it was possible to combine the results of outcomes in a meta-analysis, we report on the meta-analysis of these outcomes. When meta-analysis was not possible, we provide reasons for this and report the results for each trial.
Macronutrient interventions, fortified with micronutrients, given to provide protein and/or energy by replacing or supplementing usual diet plus nutrition counselling versus nutrition counselling alone or standard care
MACRONUTRIENT FORMULAS FORTIFIED WITH MICRONUTRIENTS PLUS NUTRITION COUNSELLING VERSUS NUTRITION COUNSELLING ALONE IN PARTICIPANTS WITH AND WITHOUT WEIGHT LOSS
Five trials assessed the effects of macronutrient supplements given to provide protein and/or energy in conjunction with nutrition counselling compared to nutrition counselling alone in adequately nourished participant with or without weight loss (Berneis 2000; de Luis 2003; Keithley 2002; Rabeneck 1998; Schwenk 1999). All the interventions included micronutrients in varied percentages of the Recommended Daily Allowance (details from product web sites). This may be a possible confounder in the outcomes of these studies, as one cannot distinguish between the effect of the increased energy supply or that of the vitamins and minerals. Excluding the Keithley 2002 trial, all the participants entered the trials with a loss of body weight of more than 5% or a reduction in their BMI in the previous 6 months. As Keithley 2002 was a three-armed trial we report the comparisons between each of the two intervention groups and the control group.
Only Keithley 2002 reported on clinical symptoms but did not define the symptoms nor provide numerical data. The authors report that there were no significant differences between reported clinical symptoms among the two intervention groups and the nutritional counselling control group.
Meta-analysis of three trials (N = 131; Berneis 2000; de Luis 2003; Schwenk 1999) comparing balanced nutritional supplements (consisting of 50-60% carbohydrate, 15-30% protein and 20-30% fat aimed at improving energy intake by 600-960 kcal/day) with no nutritional supplements, showed significantly increased energy intake by 394kcal/day in the intervention arm (Mean Difference: 393.57kcal/day; 95%CI: 224.66, 562.47; p < 0.00001). See Analysis 1.1. The increase was statistically significant and could be as much as an increase of 562 kcal/day or as little as 225 kcal/day. There was little statistical heterogeneity between the trial results (Ҳ2 = 2.75; df = 2; p = 0.25) with the heterogeneity quantified by an I2 of 27%.
Although no p values were presented, Keithley 2002 reported no statistically significant differences in energy intake between the groups at any of the study visits. We calculated the mean difference, 95% CI and level of significance for energy intake at 12 months between each group. At 12 months there was no statistically significant difference in the mean energy intake between a) the Ensure Plus group (2236kcal/day, SD 1045) and the control group (1855 kcal/day, SD 991; mean difference: 381 kcal/day; 95%CI: -218.92,980.92; p=0.22); b) the Advera (Immune-enhancing formula) group (2461 kcal/day, SD 1019) and the control group (1855 kcal/day, SD 991; mean difference: 606 kcal/day; 95%CI: -17.30,1229.30; p=0.06); and c) the Ensure Plus group (2236kcal/day, SD 1045) and the Advera group (2461 kcal/day, SD 1019; mean difference:-225; 95%CI:-817.69, 367.69; p=0.46).
Rabeneck 1998 do not provide the numerical energy intake data but report that 56% of the group receiving the specialized MCT formula and 50% of the control group (nutritional counselling) achieved 80% or more of the energy target, defined as 960kcal/day greater than estimated total energy expenditure (p=0.56).
Meta-analysis of two trials (N = 81; Berneis 2000; de Luis 2003) showed supplementation with a liquid formula providing an additional 600-795 kcal/day and consisting of 14-17% protein, 55-60% carbohydrates and 26-32% fat, significantly increased daily protein intake compared with no supplements (Mean Difference: 23.25g/day; 95% CI: 12.68, 34.01; p < 0.00001). See Analysis 1.2. There was no statistical heterogeneity between results (Ҳ2 = 0.09; df = 1; p = 0.77) with the heterogeneity quantified by an I2 of 0%.
Keithley 2002; Rabeneck 1998 and Schwenk 1999 did not report protein intake.
One trial reported on BMI at baseline and at 6 and 12 months (Keithley 2002). Rabeneck 1998 did not provide data for BMI as an outcome despite recording the method of analysis used for it. In Keithley 2002 mean BMI at 12 months did not differ statistically significantly between the Ensure Plus group (Mean BMI: 24, SD 4 kg/m2) and the control group (Mean BMI: 27, SD 7 kg/m2; Mean Difference: -3, 95%CI: -6.5, 0.5; p=0.07); between the Advera group (Mean BMI: 26, SD 5 kg/m2) and the control group (Mean BMI: 27, SD 7 kg/m2; Mean Difference: -1, 95%CI: -4.8, 2.8; p=0.6) or between the Ensure Plus group (Mean BMI: 24, SD 4 kg/m2) and the Advera group (Mean BMI: 26, SD 5 kg/m2; Mean Difference: 2, 95%CI: 0.79, 4.79; p=0.17). Mean difference and p values were calculated in Review Manager.
A meta-analysis of 4 trials (N=233; Berneis 2000; de Luis 2003; Rabeneck 1998; Schwenk 1999) found no statistically significant difference in body weight between the supplemented group and those receiving nutrition counselling alone (Mean Difference: -0.17; 95% CI: -1.10, 0.75; p = 0.72). See Analysis 1.3. Statistical heterogeneity was quantified at 9% by the I2 and was not statistically significant (Ҳ2 = 3.30; df = 3; p = 0.35). For this outcome we combined both mean change from baseline to end-point data and actual mean body weight at the end-point of the study. Berneis 2000 reported that body weight did not change significantly from baseline in either group after 12 weeks and there was no significant difference between the groups at the study endpoint. After 6 weeks Rabeneck 1998 found no significant difference in body weight between the group receiving nutrition counselling and supplementation with a specialised MCT formula and those receiving nutrition counselling alone. Schwenk 1999 reported a similar increase in body weight in both groups after 8 weeks. de Luis 2003 was the only study to report a significant change in body weight in the supplemented group. Following 3 months of supplementation, de Luis 2003 reported a 2.75% (p<0.05) increase in body weight in the Ensure® group, with the weight gain mainly due to an increase in fat mass.
Keithley 2002 reported no statistically significant differences in body weight between the groups after 12 months, but did not present the p values. Using Review Manager we calculated the mean difference, 95%CI and p values between the groups at 12 months. At 12 months the mean body weight for the Ensure Plus group was 72kg (SD 17) while the mean body weight in the control group was 78kg (SD 23; mean difference: -6.0; 95%CI:-18.23, 6.23; p=0.32). The mean body weight for the Advera group (mean body weight=78kg, SD 13) and the control group (mean body weight=78kg, SD 23) were practically identical (Mean difference was 0, 95%CI: -11.74,11.74; p=1). Even though there was a 6 kg difference in mean body weight between the Ensure Plus group and the Advera group at 12 months this difference was not significant (Mean difference: 6; 95%CI: -2.57, 14.58; p=0.19).
A meta-analysis of four trials (N = 233; Berneis 2000; de Luis 2003; Rabeneck 1998; Schwenk 1999) showed no statistically significant difference in fat mass, measured as a percentage of total body weight, between the supplemented and non-supplemented groups (mean difference: -1.14%; 95% CI: -2.58, 0.29; p = 0.12). See Analysis 1.4. There was no statistical heterogeneity between results (Ҳ2 = 1.34; df = 3; p = 0.72) with the heterogeneity quantified by an I2 of 0%.
In Keithley 2002 body fat mass was presented in kg/m2. At 12 months the mean body fat mass in the Ensure Plus and in the Advera group was 9kgm2(SD 2), and in the control group it was 9kg/m2(SD 1). The authors report that there were no statistically significant differences between the groups but do not report the p values. Using Review Manager we calculated the following p values between the three groups at 12 months: mean fat mass in the Ensure Plus group versus the control group, p=1.0; mean fat mass in the Advera group compared to the control, p=1.0; mean fat value in the Ensure Plus group compared to the Advera group, p=1.0.
In a meta-analysis of three trials (N = 218; de Luis 2003; Rabeneck 1998; Schwenk 1999) there was no statistically significant difference in fat free mass between the supplemented and the non-supplemented groups (MD: -0.37; 95% CI: -2.77, 2.03; p = 0.78). See Analysis 1.5. Statistical heterogeneity between results was not significant (Ҳ2 = 4.77; df = 2; p = 0.09) but was high with the heterogeneity quantified by an I2 of 58%.
Fat free mass was not reported in Keithley 2002 or in Berneis 2000.
A meta-analysis of the two trials which reported on this outcome (N = 81; Berneis 2000; de Luis 2003) showed no statistically significant difference in CD4 cell count between the supplemented and the non-supplemented groups (Mean Difference: -114.48; 95%CI: -233.20, 4.23; p = 0.06). See Analysis 1.6. Heterogeneity was not significant (Ҳ2 = 0.13; df = 1; p = 0.72) with the heterogeneity quantified by an I2 of 0%.
Keithley 2002 reported no significant difference in mean CD4 cell counts between the three groups at any of the time points. At 12 months the mean CD4 cell count in the Ensure Plus group was 471 cells/mm3 (SD 175), compared to the mean CD4 cell count in the Advera group (459 cells/mm3, SD 198; mean difference: 12; 95%CI: -96.15, 120.15; p=0.82) and the mean CD4 cell count in the control group (437 cells/mm3, SD 182; mean difference: 34; 95%CI: -71.93, 139.93; p=0.5). There was also no significant difference in the mean CD4 cell count between the Advera and the control group (459 cells/mm3, SD 198 vs 437 cells/mm3, SD 182; mean difference: -22; 95%CI: -139.76, 95.76; p=0.72) at 12 months.
Rabeneck 1998 reports that there was no significant change observed in CD4 counts between the groups (no data provided).
Schwenk 1999 did not report on CD4 counts.
Only one of the five trials (de Luis 2003) reported on the change in viral load over the course of the trial. After 12 weeks no statistically significant difference was noted in HIV viral load (log10copies/ml) between the supplemented and non-supplemented groups (N=66 participants; Mean Difference: -3.71 log10copies/ml; 95% CI: -12.16, 4.74; p = 0.39) in this study.
Adverse effects were poorly reported and in general, were related to tolerance rather than adverse effects. Keithley 2002 reports that no significant differences were found in acceptance and tolerance of the formulas. Rabeneck 1998 noted that one participant discontinued the supplement due to nausea and epigastric pain and one discontinued as he did not like the taste of the supplement.
SUPPLEMENTARY FOOD FORTIFIED WITH MICRONUTRIENTS PLUS NUTRITION COUNSELLING VS NUTRITIONAL COUNSELLING ALONE IN MALNOURISHED PARTICIPANTS
A study conducted in Kenya evaluated the impact of supplementary food on nutritional and clinical status, treatment progress and quality of life of malnourished HIV-infected adults on ART and pre-ART (i.e. HIV-infected adults who did not qualify for ART according to the Kenyan National HIV treatment protocol. ART was only provided to HIV-infected adults who met the WHO Stage IV disease criteria, or who had a CD4 count <200 cells/µl FANTA-KEMRI study 2011). This trial pre-dated the recommendation to commence ART at CD4 counts less than 350 cells/µl. The food products were distributed monthly, for six months or until subjects reach the exit criterion of BMI = 23 kg/m2, whichever occurred first, and participants were followed up for a year. The food product was a blend of maize, soya, vegetable oil, sugar, whey protein concentrate, and micronutient pre-mix. The food was provided in 300 gram packets and provided 1320 kcal/day energy and 48 g/day protein. At the time of the study, the cost of the food product was approximately $1/kg, or $0.30/300g dose, or $0.23/1,000 kcal. All patients in the study received nutrition counselling according to national protocols and using counselling materials and job aids provided by NASCOP. The nutrition counseling was usually carried out by a trained nutritionist or dietician and focused on supporting the client in appropriate weight gain and management of diet-related symptoms and food-drug interactions.
The authors noted that at baseline pre-ART participants had higher weight and BMI compared to the ART participants. Throughout the trial pre-ART participants gained less weight each month than the ART participants.
Amongst participants receiving ART there was no significant difference in mean body weight at any of the time points between the supplement and no supplement group (See Analysis 2.1. However, in the first 3 months of the trial the supplement group appeared to gain weight more rapidly than the no supplement group, as they had a significantly greater change in body weight gain compared to the no supplement group at these time points. After this time point the change in body weight was not significantly different between the groups (See Analysis 2.2). Mean BMI and change in BMI in the supplement group was significantly higher in the first 3 months compared to the no supplement group (See Analysis 2.3). After 3 months there was no significant difference in weight gain, BMI or BMI gain between the supplement and no supplement groups in the participants receiving ART.
Amongst participants not receiving ART, at 3 months (p=0.0027) and 6 months (p=0.001), the supplement group had a significantly greater mean body weight than the no supplement group (See Analysis 2.1). In the first 4 months of the trial and at the 6 month and 9 month time point, the supplement group had a significantly greater body weight gain compared with the no supplement group (See Analysis 2.2). In the first 3 months of the trial and in month 6, 7 and 9, mean BMI in the supplement group was significantly greater than in the no supplement group (See Analysis 2.3). In the first 4 months of the trial and months 6, 7, 8 and 9 the supplement group exhibited a significantly greater gain in BMI than the no supplement group.
There was no significant difference in % lean body mass or changes in % lean body mass between the supplement and no supplement group at any time point for both the ART arm and the pre-ART arm (See Analysis 2.4).
There was no significant difference in mean CD4 cell count between the supplement and no supplement group at any time point for both the ART arm and the pre-ART arm. However, in the pre-ART arm, at 3 months, the mean CD4 cell count in the supplement group increased by 7.4±123.5 and the mean CD4 cell count in the no supplement group decreased by 32.59±103.5 (p=0.01, authors own data).
Supplemented ART participants had significantly higher increase in hemoglobin levels at month 3 compared to the no supplement group (change in hemoglobin: 1.23±2.3 in supplement group vs 0.69±2.4 in the no supplement group, p=0.05). Supplemented pre-ART participants had a significantly higher increase in hemoglobin levels at 3 (0.93±2.7 in the supplement group vs 0.01±2.3 in the no supplement group; p=0.01) and 6 months (0.78±3.1 in the supplement group vs -0.18±0.6 in the no supplement group; p=0.05) compared to the no supplement group.
The authors only present the 3 month values for changes in serum albumin. Based on this data there was no difference in changes in serum albumin at this time point between the supplement and no supplement groups for either arms of the study.
The authors report that most of the changes in quality of life occurred during the initial months of the study. The majority of the ART and pre-ART participants experienced improvements in perceived health or their perceived health remained good, in both supplement and no supplement groups. The authors report that pre-ART participants receiving supplementary food on average experienced significantly greater improvement and less of a decline in perceived health than those not receiving food. These differences did not persist over longer periods of follow-up. Among ART participants, the difference in changes in perceived health between those receiving food and those not receiving food was smaller and not statistically significant (data presented graphically).
In the report, quality of life was also measured by the number of days per month that subjects reported having had poor physical health during the first three months. The authors report that among pre-ART participants, those receiving food had fewer poor health days than those not receiving food, and the differences were significant during the first and second months, but not subsequently. Among ART participants, the difference was significant in the second month only (data presented graphically).
Attrition, defined as discontinuation of care and treatment at the health facility for any reason, including death, loss-to-follow-up, or relocation was high in all groups. Authors report that the highest rate of attrition occurred during the first month of the study: with an attrition rate of 26% in the ART arm and 24% in the pre-ART arm. By the third month of follow-up, 37% and 39% of participants in the food and no-food groups of the ART arm and 37% and 48% of the food and no-food groups in the pre-ART arm respectively had been lost from the study. The difference in attrition between the food and no-food groups in the pre-ART arm was significant (p=.039), and the difference between the groups in the ART arm was not significant (data reported by author).
In the ART arm, the mean durations that participants were retained in the study were 6.3 months and 5.9 months for the food and no-food groups respectively. In the pre-ART arm the mean durations that subjects were retained in the study were 5.9 and 5.4 months for the food and no-food groups respectively (author's results).
The above data is from an unpublished report prepared by the study coordinators (See FANTA-KEMRI study 2011). The report does not include data on all of the measured outcomes, such as adherence to ART, survival, number of severe clinical events (defined as the sum of hospitalizations and deaths) and number of non-severe clinical events (defined as the number of new opportunistic infections and new symptoms for which medication is required).
In a study conducted in India (Sudarsanam 2011) participants with pulmonary tuberculosis, with and without HIV co-infection, and a BMI <19 kg/m² were randomised to receive a cereal-lentil mixture, micronutrient supplement plus standard care versus standard care alone. The supplement consisted of three daily servings of a cereal and lentil mixture (providing 930 kcal and 31.5 g protein) and a once a day multivitamin tablet. Patients were given a months supply of supplement at a time. TB/HIV-coinfected individuals were treated for TB but did not receive ART, as per protocol in India at the time. Despite randomisation the supplemented group had poorer initial nutritional status as measured by most parameters.
There was no significant difference in risk of death at 6 months (22 TB/HIV participants: RR: 2.14, 95% CI: 0.10, 47.38), cure rate at 6 months (22 TB/HIV participants: RR: 1.38, 95% CI: 0.46, 4.14) and treatment failure before 6 months (22 TB/HIV participants: RR: 0.69, 95% CI: 0.12, 4.05) between the two groups. (Data and information retrieved from recently updated Cochrane review: Nutritional supplements for people being treated for active tuberculosis Sinclair 2011).
At the end of the trial there was no significant difference in mean CD4 cell count (See Analysis 5.2: 221±142 cell count.mm-3 in supplemented group vs 249±387 cell count.mm-3 in no supplement group, SMD: -0.10 95% CI: -0.95, 0.75) and median viral load (845819 HIV viral load.ml-1 in supplemented group vs 1435700 HIV viral load.ml-1 in no supplement group) between the two groups in the TB/HIV-coinfected individuals.
Although supplementation resulted in a significant increase in daily caloric (11.15±882.2 in supplement group vs -375.42±893.2 kcal in no supplement group, p=0.05), protein (4.6±29.2g in supplement group vs -9.85±25.9 g in no supplement group, p=0.019) and fat (2.86±18.9 g in supplement group vs -10.78±17.1 g in no supplement group, p=0.009) intakes, compared to the no supplement group, changes in lean body mass and fat mass in both groups were similar at the end of the trial (change in lean body mass: 2.37±4.97 kg in supplement groups vs 2.40±6.3 kg in no supplement group, p=0.479; change in fat mass: 1.72±4.8 kg in supplement groups vs 1.1±5.4 kg in no supplement group, p=0.573). Data for mean weight are only presented graphically. Authors reported no difference in mean weight changes between the two groups throughout the study. These results are for all the participants, both TB and TB/HIV participants. We have requested information for the TB/HIV participants alone but have not yet received it from the author.
Specific macronutrient supplements versus placebo, no supplements or usual diet
Four trials assessed specific supplements compared either with a placebo or traditional meals in adults (Clark 2000; Karsegard 2004; Shabert 1999; Yamani 2010). Two trials were conducted in participants with weight loss or low BMI (Clark 2000; Yamani 2010). Two trials were conducted in participants with normal or assumed normal weight (Karsegard 2004; Shabert 1999).
ARGININE, GLUTAMINE AND B-HYDROXY-B-METHYLBUTYRATE
Clark 2000 compared the effects of an amino acid mixture containing 14g arginine (free base), 14g glutamine, 3g ß-hydroxy-ß-methylbutyrate (HMB, calcium salt) and citric acid (ph 4.5) with maltodextrin control formulation in participants with unintentional weight loss of 5% or more in the past 3 months who were on ART. After 8 weeks the arginine group gained significantly greater body weight than the control group (MD: 2.63 95% CI: 0.72, 4.54). See Analysis 3.1. There was no significant difference in change in fat mass between the two groups (MD: -0.64 g; 95% CI: -2.69, 1.41; p = 0.54). See Analysis 3.2. The increase in fat-free mass was statistically significantly greater in the arginine group compared with controls (MD: 3.25kg; 95% CI: 1.25 to 5.25; p = 0.001). See Analysis 3.3. CD4 count in the arginine group was reported to increase but not statistically significantly so (p = 0.10). Viral load was reported to decrease statistically significantly (p = 0.007) in the arginine group but actual data for the study endpoint is not presented. Energy intake was not reported on in this study.
The trial by Yamani 2010 was conducted in ARV naive adults from the Central African Republic. A total of 160 patients were included in the trial. Patients in the spirulina group (N=79) received 10g spirulina per day and participants in the placebo group (N=81) received green clay. Each week all participants received food packages from the World Food Program consisting of 14g maize flour, 500g mixture of maize and soya bean, 2kg garden peas, 500g sugar, 150g iodized salt and 500ml oil.
During the 6 month follow-up, 16 patients died and 16 patients were lost to follow up. There was no significant difference in the distribution of lost cases or deaths between the two groups (Spirulina group: 6 deaths and 6 lost to follow-up vs placebo group: 10 deaths and 10 lost to follow-up (p=0.8).
The authors report a statistically significant gain in weight from baseline in each group after 6 months. There was no significant difference in weight gain between the two groups over this time period. Arm circumference also increased significantly in each group, without significant difference between both the groups.
At 3 months the authors reported a significant decrease in mean Karnofsky score in the placebo group versus the spirulina group (p=0.0045). Thereafter the mean Karnofsky score in the placebo group increased to a value similar to that of the spirulina group.
The authors reported a lower number of pneumonia cases in the spirulina group versus the placebo group at 6 months (p=0.01, number of pneumonia cases in each group not presented. Specific information has been requested from author).
After 6 months CD4 count increased in both groups. This increase was not significant and there was no difference in CD4 count between the two groups at the end of the trial. Hemoglobin values decreased in both groups between months 0 and 6, with no significant difference between spirulina and placebo groups.
In both groups serum protein concentration increased in the first 3 months and then decreased in the following 3 months. There was a significant increase in serum protein (g/L) in the spirulina group between months 0-3 (p value not shown) and months 0-6 (p=0.0001). At 3 months (p=0.01) and 6 months (p=0.00001) serum protein concentrations were significantly higher in the spirulina group compared to the placebo group. In both groups, serum creatinine levels decreased at month 3 and then increased again at month 6. At 3 months serum creatinine levels were significantly higher in the spirulina group compared to the placebo group (p=0.01).
MONOHYDRATED L-ORNITHINE ALPHA-KETOGLUTARATE
Karsegard 2004 compared glutarate supplementation with an isonitrogenous placebo containing 9g of milk proteins. Nutrition counselling was provided to all participants. No morbidity data were reported. At study endpoint there were no statistically significant differences between the groups in daily energy intake, body weight, fat mass, fat-free mass or in the CD4 cell counts or viral loads. See Analysis 4.1; Analysis 4.2; Analysis 4.3; Analysis 4.4; Analysis 4.5; Analysis 4.6; Analysis 4.7. The authors conducted ANOVA tests with last known reported values used for missing data and found that there were statistically significant increases in body weight (mean body weight at baseline: 61.2, SD 11.9 in placebo and 56.4 SD 11.2 in OKG group vs mean body weight at 12 weeks: 61.8 SD 11.5 in placebo and 56.8 SD 11.6 in OKG group), BMI (mean BMI at baseline: 20.6, SD 3.0 in placebo and 20.0, SD 2.4 in OKG group vs mean BMI at 12 weeks: 20.8, SD 2.9 in placebo and 20.2, SD 2.5 in OKG group), and triceps skinfold thickness (mean triceps skinfold thickness at baseline: 14.0, SD 5.4 in placebo and 13.4, SD 4.9 in OKG group vs mean triceps skinfold thickness at 12 weeks: 15.5, SD 5.6 in placebo and 15.0, SD 6.1 in OKG group) from baseline in both groups. They do not report specific p values but only p < 0.05 for these outcomes.
The authors report that appetite and food tolerance remained stable over time but that frequency of gastrointestinal events was significantly higher in the OKG group (authors' reported p value < 0.05). Of the 22 participants taking OKG, 19 reported at least one GI adverse event compared with 13 out of 24 in the placebo group with participants in the OKG group one and a half times more likely to experience GI adverse events (RR = 1.59, 95% CI: 1.06, 2.39; p = 0.02).
L-GLUTAMINE AND ANTIOXIDANTS
Shabert 1999 compared a supplement comprising L-glutamine and antioxidants (ascorbic acid, a-tocopherol, ß-carotene, selenium and N-acetyl cysteine) with a placebo supplement comprising 40g glycine. Nutrition counselling and multivitamin supplementation was provided to all participants.
Mean weight at study endpoint was not statistically significantly different between the groups (MD: -1.30kg; 95% CI: -10.18, 7.58; p = 0.77). See Analysis 5.1. Data were not provided to calculate the change in weight over time, but the authors report in the text that the mean change in weight from baseline to week 12 was 2.2kg in the glutamine group and 0.3kg in the placebo group (p =0.04). Similarly mean change in body cell mass (the total mass of all the cellular elements in the body which constitute all the metabolically active tissue of the body; includes muscle tissue, organ tissue, intracellular and extracellular water, and bone tissue) was reported as statistically significantly different between the groups with a greater increase in the glutamine group (mean gain = 1.8kg) than in the placebo (mean gain = 0.4kg). No standard deviations are provided; the authors report a p = 0.007. Mean fat mass was not different between groups at study endpoint (MD: -1.00kg; 95% CI: -32.40, 30.40; p = 0.95). See Analysis 5.2.
Mean CD4 count was not statistically significant between groups (MD: 66.00; 95% CI: -53.39, 185.39; p = 0.28). See Analysis 5.3. The authors conducted an assessment of mood questionnaire at baseline and week 12 using a 30-item profile of the Short Form 36 and report no statistically significant differences between the groups. The authors did not observe any adverse effects in either of the groups.
Macronutrient supplementation (fortified with micronutrients) versus no supplement or standard care
ENHANCED NUTRITIONAL SUPPORT VS STANDARD NUTRITIONAL SUPPORT IN CHILDREN WITH PROLONGED DIARRHOEA
The primary outcome of the study by Rollins 2007 was weight change from enrolment until 8 weeks among 169 HIV-infected children. The study reported that children receiving enhanced nutrition support had significantly more weight gain in the first 8 weeks than children receiving standard care (weight gain was expressed as the median change in age- and sex specific weight standard deviation scores (SDS): +1.02 (enhanced nutritional support group) vs +0.01 (standard nutritional support group), p < 0.0001).
Mean weight-for-age standard deviation score (WFA-SDS) at baseline of those who dropped out was not different between groups: (Standard nutritional support group dropouts: –3.24 vs; enhanced nutritional support group dropouts: –3.39; p > 0.05) standard nutritional support group completers: –3.00, vs enhanced nutritional support group completers: –3.19, p > 0.05). Therefore, the observed outcome among the completers appeared to be unaffected by dropout bias.
After 8 weeks, weight gain was similar between groups, with only a slight increase in weight-SDS over time in each group. Median change in weight-SDS from 8 to 14 weeks of follow-up: +0.21 (enhanced nutritional support group) vs. 0.00 (standard nutrition support group: 14 to 26 weeks of follow-up: +0.12 (enhanced nutritional support group) vs. +0.24 (standard nutritional support).
Children receiving enhanced nutritional support exhibited significantly higher median attained WFA-SDS after 8 weeks (-1.99 vs -3.06, p<0.05), 14 weeks (-1.69 vs -2.96, p,0.05) and 26 weeks (-1.32 vs -2.63, p,0.05) compared to the children receiving standard nutritional support. Children in the enhanced nutritional support group who were randomised to continue with the enhanced nutrition support until 6 months showed a further improvement in median attained WFA-SDS (−1.01 SDS) at 6 months compared to those who reverted back to standard home diet who maintained the same median value attained at 3 months (-1.68 SDS).
No significant differences in CD4 cell counts or viral load between groups or over time were reported. However, it should be noted that changes in viral load could only be assessed in a subset of 70 children. The pattern of morbidity throughout the study was also similar between groups based on the cumulative frequency of clinical signs recorded during the follow-up intervals of 0–8, 8–14 and 14–26 weeks.
Dropout rates at the end of the study were high in both groups (Standard nutritional support: 27/83 (33%); Enhanced nutritional support: 38/86 (44%); difference 11%, 95%CI: −3 to +26). Authors reported the primary reason for attrition in the study was death. There was no significant difference between the two groups for death at 8 weeks (Death at 8 weeks: 10/83 (12%) in standard nutritional support group vs 14/86 (16%) in enhanced nutritional support group; OR: 1.42 95% CI: 0.59, 3.40; p=0.43; See Analysis 6.1) or death at 26 weeks (Death at 26 weeks: 18/83 (22%) in standard nutritional support group vs 25/86 (29%) in enhanced nutritional support group; OR: 1.48 95% CI: 0.74, 2.98; p=0.27; See Analysis 6.2).
Specific macronutrient supplements versus placebo, no supplements or usual diet (two trials)
Two trials assessed supplementation with specific macronutrients compared either with a placebo or traditional meals in children. One trial was conducted in Brazilian children with rapidly progressive HIV infection (Moreno 2005). One trial, conducted in Africa investigated the effects of Spirulina in undernourished children (Simpore 2005).
WHEY PROTEIN CONCENTRATE
Moreno 2005 was conducted in Brazil in rapidly progressive HIV vertically infected children (N=18). Participants received whey protein concentrate, maltodextrin or placebo. In the final data analysis the results of the maltodextrin and the placebo groups were combined (will be referred to as the placebo group) and compared with those of the whey protein concentrate group. All children were on some form of ART.
Overall attrition was high at 27.7% (5/18), but similar in both groups (3 lost from whey protein concentrate group vs 2 lost from the placebo group). Authors reported that 22.2% (2/9) of the children in the whey protein concentrate group developed co-infections during the 16 week study compared to 77.7% (7/9) of the children in the placebo group (p=0.0567, author's data).
While a non-significant increase in median CD4 cell count was demonstrated in both groups, no significant difference in median CD4 cell count between the two groups was noted throughout the study. Median CD8 cell count decreased over time in the whey protein concentrate group, with a significant difference noted between the 8 weeks and the 16 week values (p=0.046). Since viral load was only measured in 6 children in the whey protein concentrate group, differences between treatment groups could not be assessed. There was no significant difference between the groups for levels of leukocytes, erythrocytes, hemoglobin and platelets.
The trial by Simpore 2005 was conducted in undernourished HIV-negative and HIV-positive children in Burkina Faso. Only the results of 84 HIV-positive children who participated in the trial will be reported in this review. The intervention group received 10g spirulina daily along with traditional meals of millet, vegetables and fruit whereas the comparison group received traditional meals only for 8 weeks.
There was a significant increase in weight-for-height z scores (WHZ) in both groups after 8 weeks. There was no difference in WHZ between the groups at the end of the study. See Analysis 7.1. There was also a significant increase in weight-for-age z-scores in both groups after 8 weeks but no differences between the groups were noted. See Analysis 7.2.
Authors reported that treatment compliance was excellent and none of the children dropped out or were lost to follow up.