1. What Food and Micronutrients Should Be Provided for HIV-infected Patients Wafaie Fawzi Departments of Nutrition and Epidemiology Harvard School of Public Health

4. Interaction of HIV and Nutrition impairs HIVNutrition exacerbates

5. Reduction in production in a household with an AIDS death, Zimbabwe Source: Stover & Bollinger, 1999 CropsReduction in output Maize Cotton Vegetables Groundnuts Cattle owned 49% 37% 29% 47% 61%

6. Why Food and Micronutrients? –Immune-stimulation - Lower viral load – Slower disease progression –Strengthen epithelial integrity - Lower transmission –Reduce inflammation - Role in wasting –Maternal supplementation may lead to a more robust immune and GI system in the newborn - additional defense Mehta S and Fawzi W. Vitam Horm 2007;75:355-83

7. Overview – Are Micronutrient Supplements Beneficial in HIV Infection ? Perinatal and Child Outcomes -Mother-to-Child Transmission -Child Morbidity and Mortality Adult Outcomes: - Immunological and Virological Progression - Clinical Disease Progression and Mortality

8. Micronutrients and Pregnancy Outcomes among HIV-positive women Iron and Folic Acid Vitamin A Vitamins B-complex, C and E Zinc Selenium

9. MATERNAL VITAMIN A LEVELS AND MOTHER-TO- CHILD TRANSMISSION OF HIV-1 Semba, Lancet 1994;343:1593 Vertical transmission of HIV-1 % Serum Vitamin A (µmol/L)

10. REGIMEN 1. VITAMIN A ALONE (n=270) 2. MULTIVITAMINS EXCLUDING VIT A (n=269) 3. MULTIVITAMINS INCLUDING VIT A (n=266) 4. PLACEBO (n=264) PREFORMED VIT A : 5000 IU β-CAROTENE : 30 mg B1 : 20 mg B2 : 20 mg B6 : 25 mg NIACIN : 100 mg B12 : 50 µg C : 500 mg E : 30 mg FOLATE: 0.8 mg 1. & 3. VITAMIN A 200,000 IU 2. & 4. PLACEBO DAILY @ DELIVERY

11. All women received the following during pregnancy: Daily ferrous sulphate (400 mg equivalent to 120 mg ferrous iron) Daily folate (5 mg) Weekly chloroquine phosphate (500 mg ≈ 300 mg base) Standard prenatal care services including: Regular visits, clinical assessment, laboratory investigation, and appropriate treatment Continued psychosocial assessment, counseling and support PATIENT CARE

12. EFFECT OF MULTIVITAMIN SUPPLEMENTATION ON FETAL DEATHS Outcome Multivitamins n (%) No Multivitamins n (%) RR (95%CI)P Miscarriage12 (2.3)18 (3.5)0.66 (0.32-1.36)0.26 Stillbirth18 (3.5)31 (6.1)0.58 (0.33-10.2)0.05 Fetal death30 (5.9)49 (9.6)0.61 (0.39-0.94)0.02 Fawzi, Lancet 1998;351:1477

13. EFFECT OF VITAMIN A SUPPLEMENTATION ON FETAL DEATHS Outcome Vitamin A n (%) No Vitamin A n (%) RR (95%CI)P Miscarriage13 (2.5)17 (3.4)0.73 (0.36-1.50)0.39 Stillbirth25 (4.8)24 (4.8)1.00 (0.58-1.73)1.00 Fetal death38 (7.3)41 (8.2)0.89 (0.58-1.36)0.59 Fawzi, Lancet 1998;351:1477

14. EFFECT OF MULTIVITAMIN SUPPLEMENTATION ON PREGNANCY OUTCOMES Outcome Multivitamins n (%) No Multivitamins n (%) RR (95%CI)P LBW (<2500g)36 (8.8)62 (15.8)0.56 (0.38-0.82)0.003 LBW (<2000g)7 (1.7)16 (4.1)0.42 (0.18-1.01)0.05 Preterm (<37wk)96 (21.1)106 (24.5)0.86 (0.68-1.10)0.23 Preterm (<34wk)28 (6.2)44 (10.2)0.61 (0.38-0.96)0.03 SGA39 (10.0)66 (17.6)0.57 (0.39-0.82)0.002 Fawzi, Lancet 1998;351:1477

15. EFFECT OF VITAMIN A SUPPLEMENTATION ON PREGNANCY OUTCOMES Outcome Vitamin A n (%) No Vitamin A n (%) RR (95%CI)P LBW (<2500g)47 (11.6)51 (13.0)0.89 (0.61-1.29)0.54 LBW (<2000g)11 (2.7)12 (3.1)0.89 (0.40-1.98)0.77 Preterm (<37wk)105 (23.4)97 (22.1)1.06 (0.83-1.35)0.66 Preterm (<34wk)38 (8.5)34 (7.7)1.09 (0.70-1.70)0.70 SGA48 (12.4)57 (15.0)0.83 (0.58-1.18)0.29 Fawzi, Lancet 1998;351:1477

17. EFFECT OF VITAMIN A SUPPLEMENTATION ON HIV INFECTION OF OFFSPRING Fawzi, AIDS 2002;16:1935

18. Vitamin A Trial among HIV-infected Women Zimbabwe Examined efficacy of a single large dose of vitamin A given to women in the early postpartum period (400,000 IU) and/or to neonates (50,000 IU). Supplementing mothers or infants resulted in increased risk of HIV-infection or death, although providing the supplement to both mother and infant was apparently not different from placebo. Among the majority of infants, namely those who were PCR negative at 6 weeks, all three vitamin A regimens were significantly associated with an ~2- fold higher mortality. Humphrey et al.

20. MULTIVITAMINS DECREASED THE RISK OF INFECTION THROUGH BREASTFEEDING IN POPULATION SUBGROUPS ↓ LYMPH 0.99 0.37 1.01 0.48 1.03 0.51 1.07 0.27 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 ↑ LYMPH HB ≥85 g/LHB <85 g/L ESR <81 mm/hESR ≥81 mm/h BW ≥ 2500 g BW < 2500 g RELATIVE RISK P=0.03 P=0.06 P=0.04 Fawzi, AIDS 2002;16:1935

21. MULTIVITAMINS DECREASED THE RISK OF DEATH BY 24 MONTHS IN POPULATION SUBGROUPS Fawzi, AIDS 2002;16:1935 ↓ LYMPH ↑ LYMPH VIT E ≥9.6 μmol/L RELATIVE RISK 0.96 0.30 1.31 0.31 0.0 0.5 1.0 1.5 2.0 2.5 3.0 VIT E <9.6 μmol/L P=0.05P=0.008

22. MULTIVITAMINS DECREASED THE RISK OF HIV INFECTION OR DEATH BY 24 MONTHS IN POPULATION SUBGROUPS Fawzi, AIDS 2002;16:1935 ↓ LYMPH ↑ LYMPH RELATIVE RISK P=0.06P=0.01 0.96 0.50 0.98 0.36 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 ESR <81 mm/hESR ≥81 mm/h

23. CD4 cell counts among children of HIV Infected Mothers Who Were Not Known to be HIV Infected at 6 weeks of age, According to Maternal Multivitamin Group Difference = 151 cells/  L (95% CI, 64-237 cells/  L ; P=.0006 CID 2003:36;1053-62

24. Effect of Maternal Vitamin Supplements on Child Anemia Compared with placebo, multivitamins including B-complex, C and E, reduced risk of: –Anemia (HB <8.5) by 27% (95% CI: 5- 43) –Severe hypochromic microcytosis by 49% (95% CI: 16-69) –Macrocytosis by 63% (95% CI: 21-72) Vitamin A alone had no effect on all outcomes Fawzi et al, 2006

25. Effect of Maternal Vitamin Supplements on Child Growth Multivitamins (B-complex, C,E): –Increased attained weight by 459 g (95% CI: 35-882); P=0.03 –Increased weight-for age z scores by 0.42 (95% CI: 0.07-0.77); P=0.02 –Increased weight-for-length z scores by 0.38 (95% CI: 0.07-0.68); P=0.01 Vitamin A alone had no effect on child growth Villamor et al., AJCN, 2005.

26. Effect of Maternal Vitamin Supplements on Child Development Multivitamins (B-complex, C and E): - Increased Psychomotor Development Index score by 2.6 (95% CI: 0.1-5.1) –Reduced the risk for developmental delay on the motor scale by 60% (95% CI: 30-80) –Had no effect on mental development Vitamin A alone had no effect on mental or motor development McGrath et al., Pediatrics, 2006.

28. Overview – Are Micronutrient Supplements Beneficial in HIV Infection ? Perinatal and Child Outcomes -Mother-to-Child Transmission -Child Morbidity and Mortality Adult Outcomes: - Immunological and Virological Progression - Clinical Disease Progression and Mortality

29. Micronutrients and HIV Disease Progression Vitamin A Vitamins B-complex, C and E Zinc Selenium Iron

30. B Vitamins in Multiples of RDA and HIV-1 Mortality (Tang et al. 1996) Vitamin B1 (>=5 x RDA) RR=0.61, 95% CI: 0.38-0.98 Vitamin B2 (>=5 x RDA) RR=0.60, 95% CI: 0.37-0.97 Vitamin B6 (>=2 x RDA) RR=0.60, 95% CI: 0.39-0.93

31. Supplemental B Vitamins and Progression to AIDS and Death in South African HIV-infected Patients (Kanter et al. 1999) Observational study Black patients in Jo-Burg 1985-1997 Median time to progression=32.0 weeks for those without vitamins versus 72.7 for those who took vitamins (P=0.0044) Median survival for patients without vitamins=144.8 weeks and 264.4 weeks for those who took B vitamins (P=0.0014)

32. Effect of Three Vitamin Regimens on Viral Load Compared to the Placebo Group Viral Load (log 10) Difference P _________________________________________________________________________________________________

33. Vitamin E and C Supplementation and Viral Load in HIV-infected persons (Allard et al. 1998) Randomized placebo-controlled, double blinded trial. N=49 Duration=3 mo 800 IU daily of alpha-tocopherol and 1000 mg daily of vitamin C Or daily placebo

34. Vitamin E and C Supplementation and Viral Load in HIV-infected persons (Allard et al. 1998) Significant increase in plasma vitamins E and C levels Significant reduction in lipid peroxidation markers Trend towards reduction in viral load: -Mean -0.45 log (SD=0.39) versus +0.50 log (SD=0.40) P=0.10

35. Randomized Trial of Multiple Micronutrients and Mortality among Thai HIV-positive patients (Jiamton et al, 2003) Randomized placebo-controlled N=481, duration=48 weeks Overall death: RR=0.53, P=0.10 Among those with CD4 <200: RR=0.37, P=0.05 Among those with CD4 <100: RR=0.26, P=0.03

36. Trial of Vitamins, Tanzania Factorial design of Vitamin A, and Multivitamins B-complex, C, and E Women enrolled during pregnancy Followed up for median of 6 years Monthly assessments of clinical signs Regular assessment of CD4+ count, HB concentration, and viral load High compliance Fawzi et al., NEJM, 2004

37. Effect of Multivitamins on HIV Disease Progression Stage 4 or AIDS-Related Death Fawzi et al., NEJM 2004

38. Kaplan-Meier Curves of Progression to WHO Stage 4 or Death, by Regimen Fawzi et al., NEJM, 2004

39. Multivitamins and HIV-Related Complications Fawzi et al., NEJM, 2004

40. Effect of Multivitamins on Postpartum Wasting RR MVITS vs. PLACEBO = 0.66 (0.47, 0.94) Villamor et al., AJCN, 2005. 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00 024681012141618202224 TIME (mo) P (MUAC ≥ 22 cm) PLACEBO VITAMIN A MULTIVITAMINS MVITS + VIT A

41. Effects of Multivitamins on Hemoglobin Concentrations (g/dL) Period Placebo (N=219) Mean (SD) MVits (N = 228) Difference P MVits + A (N = 226) Difference P Vit A Alone (N=233) Difference P Whole Period 10.84 (1.31)0.20 (0.00,0.40)0.050.21 (0.02, 0.40)0.030.04 (-0.16,0.23)0.70 Up to 70 Days Postpartum 10.16 (1.87)0.59 (0.22, 0.97)0.0020.53 (0.15, 0.91)0.0060.32 (-0.06,0.70)0.10 First 2 Years10.64 (1.49)0.37 (0.13, 0.62)0.0030.36 (0.12, 0.60)0.0030.17 (-0.08,0.420.18 First 4 Years10.88 (1.42)0.27 (0.06, 0.48)0.010.27 (0.07, 0.48)0.0090.09 (-0.12,0.30)0.42 Fawzi et al., 2006

43. Wasting and Growth Failure Wasting or involuntary weight loss is a hallmark of HIV disease Decreased dietary intake is a major contributor –Poor Appetite –Malabsorption Increased energy expenditure Co-morbidities

44. Nutrition-based Interventions Zambia –Provision of monthly household food ration (comprising of micronutrient-fortified corn- soya blend from World Food Programme) to food insecure patients starting ART significantly increased CD4 counts at 12 months among the recipients compared to the non-recipients –The food supplements also led to a significant increase in adherence to ART by approximately 40% among the recipients as compared to the non-recipients. Both these results remained significant after adjusting for sex, WHO stage, and BMI at entry –However, there was no significant difference in weight gain in the two groups Megazzini K, et al. Abstract MOAB0401 XVI International AIDS Conference 2006

46. Overview – Are Micronutrient Supplements Beneficial in HIV Infection ? Perinatal and Child Outcomes -Mother-to-Child Transmission -Child Morbidity and Mortality Adult Outcomes: - Immunological and Virological Progression - Clinical Disease Progression and Mortality

47. Recommendations: Public Health Practice Nutritional Assessment –A comprehensive nutritional assessment at baseline and during follow-up will help target nutrition support for malnourished patients; such nutrition support is likely to help maximize the benefits of antiretroviral treatment particularly on HIV disease progression –Anthropometry BMI, Weight, Height/Length –Dietary Assessment Dietary Recall, Food Frequency Questionnaires

48. Recommendations - Micronutrients For HIV-infected pregnant women - a MV (B, C, E) is likely to help - this intervention has already been applied in various settings MV is possibly beneficial for HIV-infected persons in pre-ART stages to slow disease progression May enhance compliance, preserve ART for later stages, avert A/Es and decrease resistance associated with ART, result in improving QOL as well as Rx related cost

49. Recommendations - Micronutrients Vitamin A supplementation of HIV- infected pregnant women is to be avoided Periodic vitamin A supplementation of children after six months of age No conclusive evidence for other minerals or elements Concerns about universal iron supplementation in pregnant women

50. Recommendations - Macronutrients Increase total energy intake –Asymptomatic - ~10% –Symptomatic - ~20-30% –Children - 50-100% Energy and nutrient-dense foods needed to fulfill this need –Ready to use supplementary and therapeutic foods (RUSF, RUTF) Plumpy Nut (an energy-dense, fortified peanut butter/milk powder-based paste) –Fortified foods Fortified, blended flours (e.g. corn-soya blend (CSB))

51. Recommendations – Management of Malnutrition Definitions/Entry criteria for Severe Malnutrition –Children: Weight for height Z-score < -2 –Adults: BMI < 17 kg/m 2 –Pregnant women: First trimester: BMI < 20 Second trimesterBMI < 21 Third trimester: BMI < 22

52. Future Directions : Implementation and Public Health Evaluation Micronutrient Supplementation: –Effectiveness of Single vs. Multiple RDA –Direct multivitamin supplementation of children –MV supplementation and HAART –Micronutrients and HIV/TB co-infection –Safety and efficacy of minerals: Fe, Se

53. Future Directions : Implementation and Public Health Evaluation Macronutrients/Food: –Are food supplements necessary ? Do you they affect drug adherence ? Do they have clinical benefits ? –Is food insecurity an issue that affects all individuals, regardless of HIV status ? –Who should receive food supplements ? What entry criteria ? What Exit criteria ?