Review of randomized controlled trials of nutritional supplementation in people living with HIV

Figures & data

Table 1 Randomized clinical trials of nutritional supplementation before initiation of ART

Authors (year)	Population	Formula	Outcomes
Sudfeld et al (2014)^Citation82	420 HIV+ pregnant women enrolled at 12–27-week gestation in Tanzania.	200 μg elemental Se (selenomethionine) All women received multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 0.8 mg folic acid, 500 mg vit C, 30 mg vit E and standard doses of antenatal folic acid and 120 mg ferrous iron.	Se supplementation increased the relative risk of HIV-1 RNA >50 copies/mL detection in breast milk (36% vs 27.5%) among primiparous but not multiparous women who were not receiving ART.
Baum et al (2013)^Citation79	878 HIV+ adults in Botswana.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 0.8 mg folic acid, 500 mg vit C, and 30 mg vit E, in one arm, or multivitamins combined with 200 μg of elemental Se (selenomethionine) in the second arm, or 200 μg of Se alone in the third arm, or placebo in the fourth	24-Month supplementation with a single supplement containing multivitamins and selenium was safe and reduced the risk of immune decline and morbidity when started in the early stages of HIV disease.
Mda et al (2013)^Citation99	201 children 4–24 months in South Africa.	300 μg retinol, 0.6 mg thiamin, 0.6 mg riboflavin, 8 mg niacin, 0.6 mg pyridoxine, 1 μg cobalamin, 70 μg folic acid, 25 mg ascorbic acid, 5 μg 1,25-dihydrocholecalciferol, 7 mg D,L-tocopherol, 700 μg copper, 8 mg iron, 30 μg selenium, and 8 mg zinc.	Micronutrient supplementation significantly reduced episodes of diarrhea and respiratory symptoms, and improved malnutrition.
Arsenault et al (2010)^Citation84	674 HIV+ anti retroviral-naïve Tanzanian women.	1) vitamin A (1,500 μg RE of retinol) plus 30 mg β-carotene; 2) multivitamins (20 mg thiamin, 20 mg riboflavin, 25 mg vitamin B6, 100 mg niacin, 50 μg vitamin B12, 500 mg vitamin C [purified L-ascorbic acid], 30 mg vitamin E [RRR-α-tocopherol acetate], and 0.8 mg folic acid); 3) multivitamins with vitamin A plus β-carotene; or 4) placebo. All newborns received: vit A at 100,000 IU at 6 months and 200,000 IU at the age of 1 year and every 6 months thereafter.	Supplementation of HIV-infected women with vitamins increased the risk of subclinical mastitis.
Villamor et al (2010)^Citation85	594 Tanzanian HIV+ women.	1) vitamin A with β-carotene (VA/BC): 5,000 IU preformed vitamin A plus 30 mg β-carotene); 2) multivitamins (20 mg thiamine, 20 mg riboflavin, 25 mg vit B6, 100 mg niacin, 50 μg vit B12, 0.8 mg folic acid, 500 mg vit C, and 30 mg vit E; 3) multivitamins plus VA/BC; or 4) placebo.	Vitamin A with β-carotene supplementation in lactating women increases the HIV load in breast milk.
Kawai et al (2010)^Citation57	1,129 HIV-infected pregnant women in Tanzania.	Multivitamin supplements: (B complex: thiamin, riboflavin, niacin, B6, B12, and vitamins C and E) at a single dose of the RI compared to 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 0.8 mg folic acid, 500 mg vit C, and 30 mg vit E. All women received standard doses of antenatal folic acid and 120 mg ferrous iron. All newborns received: vit A at 100,000 IU at 6 months and 200,000 IU at the age of 1 year and every 6 months thereafter.	Supplementation of multivitamins at the recommended intake (Rl) levels is as effective as multiple doses of the Rl in decreasing risk of adverse pregnancy outcomes among HIV+ women.
Kupka et al (2009)^Citation58	9 15 HIV+ pregnant Tanzanian women.	Supplement: selenomethionine, 200 μg daily, compared to placebo. All women received: antenatal ferrous iron (60 mg/d), and 20 mg riboflavin, 110 mg niacin, 25 mg vit B6, 50 μg vit B12, 0.8 mg folic acid, 500 mg vit C, and 30 mg vit E.	Supplementation with Se during pregnancy and postpartum reduced diarrheal morbidity risk by 40% with no significant risk for anemia. No effect on morbidity end points.
Webb et al (2009)^Citation83	626 HIV+ pregnant women in Tanzania.	Women were randomized into one of four formulas: 1. Vit A and β-carotene (VA + BCJ: 5,000 IU (1,500 μg retinol equivalents) of preformed vit A plus 30 mg of β-carotene). 2. Multivitamins: 20 mg of thiamine, 20 mg of riboflavin, 25 mg of vit B6, 100 mg of niacin, 50 μg of vitamin B12, 0.8 mg of folic acid, 500 mg of vit C, and 30 mg of vit E. 3. Multivitamins plus vit A. 4. Placebo. The two groups of women who receiving vit A also received a single dose of 200,000 IU of vit A at delivery. All women received standard doses of antenatal folic acid and 120 mg ferrous iron. All newborns received: vit A at 100,000 IU at 6 months and 200,000 IU at the age of 1 year and every 6 months thereafter.	Sustained supplementation of HIV-infected breastfeeding mothers with this multivitamin formula is an effective intervention to improve vitamin E concentrations in breast milk. Although supplementation with vitamin A and β-carotene increased concentrations of breast milk retinol, it was not recommended in HIV+ mothers due to the elevated risk of vertical transmission.
Kupka et al (2008)^Citation59	913 HIV-Infected pregnant women In Tanzania and their children.	Supplement: selenomethionine, 200 μg daily, compared to placebo. All women received: antenatal ferrous iron (60 mg/d), and 20 mg riboflavin, 110 mg niacin, 25 mg vit B6, 50 μg vit B12, 0.8 mg folic acid, 500 mg vit C, and 30 mg vit E. All newborns received: vit A at 100,000 IU at 6 months and 200,000 IU at the age of 1 year and every 6 months thereafter.	Maternal supplementation with selenium during pregnancy and postpartum reduced risk of child mortality after 6 weeks of delivery.
Villamor et al (2008)^Citation60	471 HIV-positive and 416 HIVnegative adults with pulmonary TB in Tanzania.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 0.8 mg folic acid, 500 mg vit C, 30 mg vit E, and 200 pig of Se, compared to placebo.	Multivitamin supplementation with selenium increased CD3+ and CD4+ cell counts and decreased the incidence of extrapulmonary TB and genital ulcers in HIV-negative patients. Reduced the incidence of peripheral neuropathy by 57%, irrespective of HIV status.
Villamor et al (2007)^Citation61	829 HIV+ pregnant and lactating women in Tanzania, and their infants up to 24 months of age.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 0.8 mg folic acid, 500 mg vit C, and 30 mg vit E, compared to placebo. Vitamin A: 30 mgβ-carotene + 5,000 IU preformed vitamin A, compared to placebo. Combined multivitamins with vit A compared to placebo. The two groups of women receiving vit A also received a single dose of 200,000 IU of vit A at delivery. All women received standard doses of antenatal folic acid and 120 mg ferrous iron. All newborns received: vit A at 100,000 IU at 6 months and 200,000 IU at the age of 1 year and every 6 months thereafter.	Children born to the supplemented women in the three arms (including vitamin A) significantly decreased the burden of malaria. Also children supplemented with vitamin A after 6 months of delivery and up to 24 months of age had reduced risk of malaria.
Fawzi et al (2007)^Citation62	1,078 HIV+ pregnant women in Tanzania.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 0.8 mg folic acid, 500 mg vit C, 30 mg vit E, compared to placebo. Vitamin A: 30 mg β-carotene + 5,000 IU preformed vitamin A, compared to placebo. Combined multivitamins with vit A compared to placebo. The two groups of women receiving vit A also received a single dose of 200,000 IU of vit A at delivery. All women received standard doses of antenatal folic acid and 120 mg ferrous iron. All newborns received: vit A at 100,000 IU at 6 months and 200,000 IU at the age of 1 year and every 6 months thereafter.	Multivitamin supplementation provided during pregnancy and in the postpartum period resulted in significant improvements in hematologic status among HIV-infected women and their children.
Smith Fawzi et al (2007)^Citation63	1,078 HIV+ pregnant women.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 0.8 mg folic acid, 500 mg vit C, 30 mg vit E, compared to placebo. Vitamin A: 30 mg β-carotene + 5,000 IU preformed vitamin A, compared to placebo. Combined multivitamins with vit A compared to placebo. The two groups of women receiving vit A also received a single dose of 200,000 IU of vit A at delivery. All women received standard doses of antenatal folic acid and 120 mg ferrous iron.	Multivitamin supplementation reduced the risk of elevated depressive symptoms comparable to major depressive disorder and improvement in quality of life.
Villamor et al (2006)^Citation75	400 HIV-infected pregnant women in Tanzania.	Supplement: 25 mg of zinc or placebo. All women received daily: 20 mg thiamin, 20 mg riboflavin, 25 mg vit B6, 100 mg niacin, 50 μg vit B12, 500 mg vit C, 30 mg vit E, ferrous sulfate 60 mg, and 800 μg folate.	No effect on pregnancy outcomes, or maternal disease progression. Reduction in maternal midarm circumference. Potential for promoting anemia. Recommended not supplementing in HIV+ pregnant women.
Cárcamo et al (2006)^Citation76	159 HIV-infected adults with >7 days of diarrhea recruited at hospitals in Peru.	Supplement: 100 mg of elemental Zn compared to placebo.	Zn supplementation at this level had no significant effect on the duration or remission of diarrhea in HIV+ adults.
McGrath et al (2006)^Citation64	1,078 HIV+ pregnant women in Tanzania, and subset of 327 children born to these mothers.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 0.8 mg folic acid, 500 mg vit C, and 30 mg vit E compared to placebo. Vitamin A: 30 mg β-carotene + 5,000 IU preformed vitamin A (alone or with multivitamins compared to placebo). Combined multivitamins with vit A compared to placebo. The two groups of women who received vit A also received a single dose of 200,000 IU of vit A at delivery. All women received standard doses of antenatal folic acid and 120 mg ferrous iron. All newborns received: vit A at 100,000 IU at 6 months and 200,000 IU at the age of 1 year and every 6 months thereafter.	Maternal supplementation with multivitamins was protective against the risk for developmental delay on the motor scale in children from HIV+ mothers.
Range et al (2006)^Citation66	213 patients with TB + HIV, 286 patients with TB and HIVnegative.	Multivitamin and mineral supplement: 5,000 IU vitamin A, 20 mg thiamin, 20 mg riboflavin, 25 mg vit B6, 40 mg niacin, 50 μg vit B12, 0.8 mg folic acid, 200 mg vitamin C, 60 mg vitamin E, 200 IU vitamin D3, 200 μg Se, 5 mg copper, and 45 mg Zn, compared to placebo.	Supplementation with multivitamins and minerals, including Zn, Cu, and Se during treatment of pulmonary TB reduced mortality in those coinfected with HIV and TB.
Bobat et al (2005)^Citation100	96 HIV+ children were randomized by age-group to receive Zn sulfate or placebo.	Supplement: 10 mg of elemental Zn as sulfate or placebo.	Children randomly assigned to Zn supplementation were less likely to get diarrhea than those on placebo (P=0.001). Supplementation did not have an adverse effect on viral load.
Villamor et al (2005)^Citation65	1,078 HIV+ pregnant women in Tanzania.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 0.8 mg folic acid, 500 mg vit C, 30 mg vit E compared to placebo. Vitamin A: 30 mg β-carotene + 5,000 IU preformed vitamin A (alone or with multivitamins compared to placebo). Combined multivitamins plus vit A compared to placebo. All women received standard doses of antenatal folic acid and 120 mg ferrous iron.	Supplementation with multivitamins protected against wasting in HIV+ pregnant women.
Merchant et al (2005)^Citation69	1,078 HIV+ pregnant women in Tanzania.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 500 mg vit C, 30 mg vit E, and 0.8 mg folic acid (compared to placebo). Vitamin A: 30 mg β-carotene + 5,000 IU preformed vitamin A (alone or with multivitamins compared to placebo). All women received standard doses of antenatal folic acid and 120 mg ferrous iron.	Women in the multivitamin supplementation groups reduced the risk for developing hypertension by 38% during pregnancy compared to those who were not on the multivitamins group.
Baylin et al (2005)^Citation70	716 HIV+ mother-infant pairs in Tanzania.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 500 mg vit C, 30 mg vit E, and 0.8 mg folic acid (compared to placebo). Vitamin A: 30 mg β-carotene + 5,000 IU preformed vitamin A (alone or with multivitamins compared to placebo). The two groups of women receiving vitamin A also received a single dose of 200,000 IU of vitamin A at delivery. All newborns received standard 200,000 IU or 100,000 IU if < 1 year of age of vitamin A. All women received standard doses of antenatal folic acid and 120 mg ferrous iron. All newborns received: vit A at 100,000 IU at 6 months and 200,000 IU at the age of 1 year and every 6 months thereafter.	Infants from supplemented mothers, including the vitamin A arms, compared to placebo, effectively improved the vitamin status of their children during the first 6 months of age, including retinol status.
Villamor et al (2005)^Citation71	886 HIV+ mother and their infants in Tanzania.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 500 mg vit C, 30 mg vit E, and 0.8 mg folic acid (compared to placebo). Vitamin A: 30 mg β-carotene + 5,000 IU preformed vitamin A (alone or with multivitamins compared to placebo). The two groups of women receiving vitamin A also received a single dose of 200,000 IU of vitamin A at delivery. All newborns received standard 200,000 IU or 100,000 UI if < 1 year of age of vitamin A. All women received standard doses of antenatal folic acid and 120 mg ferrous iron. All newborns received: vit A at 100,000 IU at 6 months and 200,000 IU at the age of 1 year and every 6 months thereafter.	Supplementation of HIV-infected women with multivitamins during pregnancy and lactation is an effective intervention for improving ponderal growth in their children.
Fawzi et al (2004)^Citation25	1,078 pregnant HIV+ women.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 500 mg vit C, 30 mg vit E, and 0.8 mg folic acid (compared to placebo). Vitamin A: 30 mg β-carotene + 5,000 IU preformed vitamin A (alone or with multivitamins compared to placebo). The two groups of women receiving vitamin A also received a single dose of 200,000 IU of vitamin A at delivery. All women received standard doses of antenatal folic acid and iron.	Supplementation with multivitamins delayed progression to WHO stage 4 (P=0.02), progression to stage 3 or higher (P=0.003). Multivitamins also resulted in significantly higher CD4+ and CD8+ cell counts and significantly lower viral loads.
McClelland et al (2004)^Citation68	400 HIV+ women in Kenya.	Multivitamin and selenium supplement: 20 mg thiamin, 20 mg riboflavin, 25 mg vit B6, 100 mg niacin, 50 μg vit B12, 500 mg vitamin C, 30 mg vitamin E, 0.8 mg folic acid, and 200 μg of Se, compared to placebo.	Supplementation resulted in higher CD4 and CD8 cell counts in the supplemented group, but increased participants’ genital shedding.
Fawzi et al (2003)^Citation72	1,078 pregnant HIV+ women.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 500 mg vit C, 30 mg vit E, and 0.8 mg folic acid (compared to placebo). Vitamin A: 30 mg β-carotene + 5,000 IU preformed vitamin A (alone or with multivitamins compared to placebo). The two groups of women receiving vitamin A also received a single dose of 200,000 IU of vitamin A at delivery. All women received standard antenatal folic acid and iron. All newborns received: vit A at 100,000 IU at 6 months and 200,000 IU at the age of 1 year and every 6 months thereafter.	Supplementation with multivitamins prenatally and during breastfeeding seems to be protective of adverse pregnancy and child outcomes.
Jiamton et al (2003)^Citation24	481 HIV-infected men and women in Thailand with CD4 cell counts In the range of 50–550 cells/mm^Citation3.	Multivitamin and Mineral supplement: Vitamins: 3,000 μg vitamin A, 6 mg p-carotene, 20 μg or 800 IU vitamin D3, 80 mg vitamin E, 180 μg vitamin K, 400 mg vitamin C, 24 mg thiamin, 15 mg riboflavin, 40 mg vitamin B6, 30 μg vitamin Bp, 100 μg folacin, and 40 mg panthothenic acid. Minerals: 10 mg Fe, 200 mg mg, 8 mg Mn, 30 mg Zn, 300 μg iodine, 3 mg Cu, 400 μg Se, 150 μg Cr, and 66 mg cysteine compared to placebo.	Multiple micronutrient supplementation improved the survival of HIV-infected individuals with CD4 cell counts <200 cells/mm^3.
Fawzi et al (2002)^Citation81	1,078 pregnant HIV+ women.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 500 mg vit C, 30 mg vit E, and 0.8 mg folic acid (compared to placebo). Vitamin A: 30 mg β-carotene + 5,000 IU preformed vitamin A (alone or with multivitamins compared to placebo). The two groups of women receiving vitamin A also received a single dose of 200,000 IU of vitamin A at delivery. All newborns received standard 200,000 IU or 100,000 IU if < 1 year of age of vitamin A. All women received standard doses of antenatal folic acid and 120 mg ferrous iron. All newborns received vitamin A at 100,000 IU at 6 months and 200,000 IU at the age of 1 year and every 6 months thereafter.	Vitamin A supplementation increased mother-to-child transmission (RR =1.38, P=0.009) and had no effect on mortality after 24 months of supplementation. Multivitamin supplementation, however, reduced transmission risk in mothers with low CD4 cell count, low hemoglobin, and low-birth-weight newborns. Multivitamins also reduced mortality and increased survival in HIV-negative children born to malnourished HIV+ mothers with advanced disease.
Villamor et al (2002)^Citation80	1,075 pregnant women.	Multivitamin supplement: 20 mg thiamin, 20 mg riboflavin, 100 mg niacin, 25 mg vit B6, 50 μg vit B12, 500 mg vit C, 30 mg vit E, and 0.8 mg folic acid (compared to placebo). Vitamin A: 30 mg β-carotene + 5,000 IU preformed vitamin A (alone or with multivitamins compared to placebo). The two groups of women receiving vitamin A also received a single dose of 200,000 IU of vitamin A at delivery. All newborns received standard 200,000 IU or 100,000 IU if < 1 year of age of vitamin A. All women received standard doses of antenatal folic acid and 120 mg ferrous iron. All newborns received: vit A at 100,000 IU at 6 months and 200,000 IU at the age of 1 year and every 6 months thereafter.	In pregnancy, supplementation with multivitamins, including multivitamins plus vitamin A, compared to placebo, and improved the rate of weight gain by 27% during the third trimester of pregnancy.
Kumwenda et al (2002)^Citation98	697 HIV+ pregnant women in Malawi.	The experimental group received 3 mg of retinol equivalent daily from the time of enrolment into the study to delivery. All women received standard 30 mg of elemental iron and 400 μg folate orally.	Vitamin A-supplemented pregnant women delivered higher birth-weight infants, and had fewer anemic infants at 6 weeks postpartum compared to placebo. Vitamin A supplementation did not affect mother-to-child perinatal HIV transmission.

Abbreviations: ART, antiretroviral treatment; HIV+, HIV positive; HAAT, highly active antiretroviral therapy; vit, vitamin; TB, tuberculosis; IU, international units; WHO, World Health Organization.

Table 2 Randomized clinical trials of supplementation among people living with HIV, who were receiving ART

Author (year)	Population	Design	Formula	Outcomes
Asdamongkol et al (2013)^Citation102	31 HIV+ patients with immunological discordance (controlled viral load, CD4 cell count <200 cells/μL).	RCT of supplementation for 6 months. Zn plasma levels were obtained at baseline.	Daily supplementation – 15 mg of chelated Zn compared to placebo.	The CD4+ cell count significantly increased (P=0.042) after zinc supplementation in patients with low plasma zinc levels at baseline (N=12).
Longenecker et al (2012)^Citation89	45 HIV+ adults in Cleveland (OH, USA) on ART and vit D deficiency.	Double-blinded RCT of supplementation for 12 weeks.	Vitamin D3 4,000 IU daily or placebo.	Improved vitamin D status and cholesterol but worsened insulin resistance without change in endothelial function.
Isanaka et al (2012)^Citation87	3,418 HIV+ initiating ART.	Double-blinded RCT of supplementation for 24 months.	Multivitamin supplements: low dose: 1.2 mg of thiamin, 1.2 mg of riboflavin, 15 mg of niacin, 1.3 mg of vit B6, 2.4 μg of vit B12, 500 mg vit C, and 15 mg of vit E at a single dose of the Rl compared to high dose: 20 mg of thiamin, 20 mg of riboflavin, 100 mg of niacin, 25 mg of B6, 50 μg of Bp, 0.8 mg folic acid, 500 mg vit C, and 30 mg vit E.	Receiving high-dose supplementation, compared to low dose, increased the relative risk of higher ALT levels by 44%, with no differential effect on disease progression. The study was stopped early.
Kakalia et al (2011)^Citation90	54 HIV+ children, 3–18 years old.	Nonblinded RCT of supplementation for 6 months.	One group received no supplementation, the second group received 5,600 IU/wk of vitamin D the third group received 11,200 IU/wk of vitamin D.	Vitamin D supplementation in doses of 11,200 IU/wk or higher does not impact CD4 count.
Baum et al (2010)^Citation39	231 HIV+ adults in Miami, FL, USA. 62.3% were on ART.	Double-blinded RCT of supplementation for 18 months.	Supplement: Zn gluconate (12 mg for females and 15 mg for males) compared to placebo.	Prevented immune failure (CD4 cell count <200 cells/mm^3) and decreased diarrhea over time.
Arpadi et al (2009)^Citation88	56 HIV+ children and adolescents aged 6–16 years with serum 25-OHD ≥ 12 ng/mL, on ART.	RCT of supplementation for 12 months.	Supplement: vitamin D (100,000 IU/every 2 months) and calcium 1 g/d (N=29) or placebo daily (N=27).	Supplementation was safe, did not affect viral control or disease progression, and resulted in significant increases in serum vitamin D concentrations.
Hurwitz et al (2007)^Citation67	262 HIV+ adults in Miami. Mixed ART, 26.5% with no ART at baseline.	RCT of supplementation for 9 months.	Supplement: selenium yeast providing 200 μg elemental selenium daily, compared to placebo.	Daily Se supplementation suppressed the increase of viral burden and provided indirect improvement in CD4 cell count.
Austin et al (2006)^Citation86	331 HIV+ patients In advanced disease (CD4 cell count ranged from 28 cells/mm^Citation3 to 114 cells/mm^Citation3) in Canada, and who were on combination protease inhibitor-based ART for at least 3 months.	Double-blinded RCT, multicenter (22 clinics). Supplementation for 13 months.	All participants received: β-carotene 30,000 IU (18 mg), 1,500 IU vit A, 56 IU vit D, 63 mg vit C, 56 IU vit E,9.38 mg thiamin, 4.68 mg riboflavin, 2.25 mg riboflavin−50-phosphate sodium, 3.75 mg niacin, 9.38 mg niacinamide, 18.75 mg D-calcium pantothenate, 9.38 mg vit B6, 3 mg vit B6 (pyridoxine-50-phosphate), 0.08 mg folacin, 0.06 mg biotin, 9.38 mg choline bltartrate, 37.5 mg mg, 7.5 mg Zn, 1.5 mg Fe, 0.38 mg Cu, 1.5 mg mg, 9.38 mg K, 0.018 mg Cr, 0.018 mg Se, 0.00938 mg Mb, 0.00938 mgV, and 0.00938 mg 1. Nonnutritional antioxidants: 150 mg N-acetyl-L-cysteine and 37.5 mg reduced glutathione. The treatment group also received: the formula above plus 72 mg of β-carotene/d.	β-Carotene supplementation, in addition to the multivitamm/mmeral/nonnutrient antioxidant formula, reduced mortality by more than three times (3.15 [1.10, 8.98], P=0.03) in those with advanced HIV disease after adjusting for baseline CD4 cell count and serum carotene.
Kaiser et al (2006)^Citation23	40 HIV+ patients.	Double-blinded RCT, comparing a formula to placebo. Supplementation for 12 weeks.	Nonnutritional antioxidants: 1,200 mg N-acetyl cysteine, 100 mg acetyl-L-carnitine, and 400 mg α-lipoic acid. Vitamins: vit A 8,000 IU, β-carotene 20,000 IU, vit C 1,800 mg, 60 mg thiamin, 60 mg riboflavin, 60 mg pantothenic acid, 60 mg niacinamide, 60 mg inositol, 50 μg biotin, 260 mg vit B6, 2.5 μg vit B12, 400 IU vit D, 800 IU vit E, 300 mg bioflavonoids, 800 μg folate, and 60 mg choline. Minerals: 800 mg Ca, 18 mg Fe, 30 mg Zn, 400 mg mg, 200 μg Se, 150 μg 1, 100 μg Cr, 10 mg Mn, 2.0 mg Cu, 300 μg Mb, 2.0 mg vit B, 99 mg K, and 150 mg betaine HCL.	Nutritional supplementation in HIV+ patients on stable ART significantly increased CD4 cell counts after 12 weeks and experienced some reduction of neuropathy.

Abbreviations: ART, antiretroviral treatment; HIV+, HIV positive; RCT, randomized clinical trial; vit, vitamin; 25-OHD, 25-hydroxyvitamin D; Rl, Recommended Intake; wk, week; Se, selenium supplementation; IU, international units; ALT, alanine aminotransferase.

Table 3 Randomized clinical trials of probiotic supplementation

Authors (year)	Population	Design	Formula	Outcomes
In PLWH (pre-ART)
Hummelen et al (2011)^Citation103	112 ART-naïve HIV patients in Tanzania	Randomized, doubleblind, controlled trial of micronutrient and yogurt for 4 weeks	Micronutrient fortified yogurt with/without additional probiotic. Amount pert 125 g of yogurt: Lactobacillus rhamnosus GR-1 at 10^Citation9 CFU/mL; vit A at 1,500 IU; vit E at 5.7 IU; niacinamide at 3.8 mg; thiamin at 0.3 mg; vit B12 at 0.6 μg; vit B6 at 0.3 mg; vit C at 21 mg; iron at 3.3 mg; selenium at 13.8 μg; zinc at 2.4 mg; DHA (omega-3) at 13 mg, and EPA (omega-3) at 19 mg	Micronutrient fortified yogurt was well tolerated by PLWH but not associated with a further increase in CD4 count after 4 weeks of supplement
Hummelen et al (2010)^Citation104	65 HIV+ women with aberrant microbiota in Tanzania (Nugent score 4–10)	Randomized, double-blind, placebo-controlled trial for 6 months	L. rhamnosus GR-I and Lactobacillus reuteri RC-14 supplementation compared to placebo	Supplementation of probiotic L. rhamnosus GR-1 and L. reuteri RC-14 did not enhance the cure of bacterial vaginitis but significantly increased beneficial pH (OR =3.8, P=0.02)
In HIV population (post-ART)
Van Niekerk et al (2014)^Citation105	74 HIV-exposed and 110 nonexposed premature (<34-week gestation) infants with a birth weight of ≥500 g and ≤ 1,250 g in Cape Town, South Africa	Randomized, double-blind, placebo-controlled trial supplemented for 28 days	Study group: breast milk plus a daily probiotic supplement of L. rhamnosus GG (0.35×10^9 colony-forming units [CFU]) and Bifidobacterium infantis (0.35×10^9 CFU); control group: breast milk plus a placebo consisting of medium-chain triacylglycerol (MCT) oil	Probiotics did not affect growth outcomes or incidence of feeding intolerance in HIVexposure infants, but they had significantly higher Z-scores for length and head circumference than the unexposed newborns at the end of the study
Villar-García et al (2015)^Citation106	44 PLWH with controlled viral load <20 copies/mL	Double-blind, randomized, placebo-controlled trial	Oral supplementation with probiotics (Saccharomyces boulardii) or placebo for 12 weeks	S. boulardii treatment decreased microbial translocation (LBP) and inflammation (IL-6) in HIV-1-infected patients with long-term virologic suppression

Abbreviations: PLWH, people living with HIV; ART, antiretroviral treatment; vit, vitamin; HIV+, HIV positive; OR, odds ratio; LBP, lipopolysaccharide-binding protein; IL-6, interleukin 6; EPA, eicosapentaenoic omega-3 fatty acid; DHA, decosahexaenoic omega-3 fatty acid.

Figure 1 Consort flow diagram.

Abbreviations: RCT, randomized clinical trial; PLWH, people living with HIV; ART, antiretroviral treatment.

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