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

What Food and Micronutrients Should

Be Provided for HIV-infected Patients

Wafaie FawziDepartments of Nutrition and Epidemiology

Harvard School of Public Health

Interaction of HIV and Nutrition

impairs

HIVHIV NutritionNutrition

exacerbates

Reduction in production in a household with an AIDS death, Zimbabwe

Source: Stover & Bollinger, 1999

•

•

•

•

•

Crops Reduction in output

Maize

Cotton

Vegetables

Groundnuts

Cattle owned

49%

37%

29%

47%

61%

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

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

Micronutrients and Pregnancy Outcomes among HIV-positive

women•Iron and Folic Acid•Vitamin A•Vitamins B-complex, C and E•Zinc•Selenium

MATERNAL VITAMIN A LEVELS AND MOTHER-TO-CHILD TRANSMISSION OF HIV-1

Semba, Lancet 1994;343:1593

Ve

rtic

al t

ran

sm

iss

ion

of

HIV

-1 %

Serum Vitamin A (µmol/L)

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

DA

ILY

@ DELIV

ER

Y

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

EFFECT OF MULTIVITAMIN EFFECT OF MULTIVITAMIN SUPPLEMENTATION ON FETAL DEATHSSUPPLEMENTATION ON FETAL DEATHS

OutcomeMultivitamins

n (%)

No Multivitamin

sn (%)

RR (95%CI) P

Miscarriage

12 (2.3) 18 (3.5)0.66 (0.32-

1.36)0.26

Stillbirth 18 (3.5) 31 (6.1)0.58 (0.33-

10.2)0.05

Fetal death 30 (5.9) 49 (9.6)0.61 (0.39-

0.94)0.02

Fawzi, Lancet 1998;351:1477

EFFECT OF VITAMIN A SUPPLEMENTATION EFFECT OF VITAMIN A SUPPLEMENTATION ON FETAL DEATHSON FETAL DEATHS

OutcomeVitamin A

n (%)No Vitamin A

n (%)RR (95%CI) P

Miscarriage

13 (2.5) 17 (3.4)0.73 (0.36-

1.50)0.39

Stillbirth 25 (4.8) 24 (4.8)1.00 (0.58-

1.73)1.00

Fetal death 38 (7.3) 41 (8.2)0.89 (0.58-

1.36)0.59

Fawzi, Lancet 1998;351:1477

EFFECT OF MULTIVITAMIN EFFECT OF MULTIVITAMIN SUPPLEMENTATION ON PREGNANCY SUPPLEMENTATION ON PREGNANCY

OUTCOMESOUTCOMES

OutcomeMultivitamin

sn (%)

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

SGA 39 (10.0) 66 (17.6) 0.57 (0.39-0.82) 0.002

Fawzi, Lancet 1998;351:1477

EFFECT OF VITAMIN A SUPPLEMENTATION EFFECT OF VITAMIN A SUPPLEMENTATION ON PREGNANCY OUTCOMESON PREGNANCY OUTCOMES

OutcomeVitamin 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

SGA 48 (12.4) 57 (15.0) 0.83 (0.58-1.18) 0.29

Fawzi, Lancet 1998;351:1477

EFFECT OF VITAMIN A SUPPLEMENTATION EFFECT OF VITAMIN A SUPPLEMENTATION ON HIV INFECTION OF OFFSPRINGON HIV INFECTION OF OFFSPRING

Fawzi, AIDS 2002;16:1935

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.

MULTIVITAMINS DECREASED THE RISK OF MULTIVITAMINS DECREASED THE RISK OF INFECTION THROUGH BREASTFEEDING IN INFECTION THROUGH BREASTFEEDING IN

POPULATION SUBGROUPSPOPULATION SUBGROUPS

↓ L

YM

PH

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↑

LYM

PH

HB ≥

85 g

/LH

B <

85 g

/L

ESR <

81 m

m/h

ESR ≥

81 m

m/h

BW

≥ 2

500 g

BW

< 2

500 g

RELATIVE RISK

P=0.03 P=0.06 P=0.06P=0.04

Fawzi, AIDS 2002;16:1935

MULTIVITAMINS DECREASED THE RISK OFMULTIVITAMINS DECREASED THE RISK OFDEATH BY 24 MONTHS IN POPULATION DEATH BY 24 MONTHS IN POPULATION

SUBGROUPSSUBGROUPS

Fawzi, AIDS 2002;16:1935

↓ L

YM

PH

↑ LY

MPH

VIT

E ≥

9.6

μm

ol/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

μm

ol/L

P=0.05 P=0.008

MULTIVITAMINS DECREASED THE RISK OFMULTIVITAMINS DECREASED THE RISK OFHIV INFECTION OR DEATH BY 24 MONTHS HIV INFECTION OR DEATH BY 24 MONTHS

IN POPULATION SUBGROUPSIN POPULATION SUBGROUPS

Fawzi, AIDS 2002;16:1935

↓ L

YM

PH

↑ LY

MPH

RELATIVE RISK

P=0.06 P=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 m

m/h

ESR ≥

81 m

m/h

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 GroupDifference = 151 cells/L (95% CI, 64-237 cells/ L ; P=.0006

CID 2003:36;1053-62

Effect of Maternal Vitamin Effect of Maternal Vitamin Supplements Supplements

on Child Anemiaon 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

Effect of Maternal Vitamin Effect of Maternal Vitamin Supplements Supplements

on Child Growthon 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 scoresby 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.

Effect of Maternal Vitamin Effect of Maternal Vitamin Supplements Supplements

on Child Developmenton 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.

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

Micronutrients and HIV Disease Progression

•Vitamin A•Vitamins B-complex, C and E

•Zinc•Selenium•Iron

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

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)

Effect of Three Vitamin Regimens on Viral Load Compared to the

Placebo GroupViral Load (log 10)

Difference P_________________________________________________________________________________________________

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

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

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

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

Effect of Multivitamins on HIV Disease Progression

Stage 4 or AIDS-Related Death

No. of Events

Relative Risk (95% CI)*

P

Whole Period

Multivitamins B, C and E 67 0.71 (0.51, 0.98) 0.04

Multivitamins and Vitamin A 70 0.80 (0.58, 1.10) 0.17

Vitamin A alone 79 0.88 (0.64 1.19) 0.40

Placebo Group 83 1.0

Fawzi et al., NEJM 2004

Kaplan-Meier Curves of Progression to WHO Stage 4 or Death, by Regimen

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72

Months after randomization

Fra

ctio

n a

live

wit

h st

age

< 4

Multivitamins B, C, and EMultivitamins and Vitamin AVitamin A alonePlacebo

No. at risk Multivitamins B, C, and E 271 195 157 119 Multivitamins and Vitamin A

267 181 143 102

Vitamin A alone 272 190 147 104 Placebo 267 173 145 101

Fawzi et al., NEJM, 2004

Multivitamins and HIV-Related Complications Multivitamins and HIV-Related Complications

Fawzi et al., NEJM, 2004

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

0 2 4 6 8 10 12 14 16 18 20 22 24

TIME (mo)

P (

MU

AC

≥ 2

2 cm

)

PLACEBO

VITAMIN A

MULTIVITAMINS

MVITS + VIT A

Effects of Multivitamins on Hemoglobin Concentrations (g/dL)

PeriodPlacebo(N=219)Mean (SD)

MVits(N = 228)Difference

PMVits + A(N = 226)Difference

PVit A Alone(N=233)Difference

P

Whole Period

10.84 (1.31)

0.20 (0.00,0.40)

0.05 0.21 (0.02, 0.40)

0.03 0.04 (-0.16,0.23)

0.70

Up to 70 Days Postpartum

10.16 (1.87)

0.59 (0.22, 0.97)

0.002

0.53 (0.15, 0.91)

0.006 0.32 (-0.06,0.70)

0.10

First 2 Years

10.64 (1.49)

0.37 (0.13, 0.62)

0.003

0.36 (0.12, 0.60)

0.003 0.17 (-0.08,0.42

0.18

First 4 Years

10.88 (1.42)

0.27 (0.06, 0.48)

0.01 0.27 (0.07, 0.48)

0.009 0.09 (-0.12,0.30)

0.42

Fawzi et al., 2006

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

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

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

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

–AnthropometryBMI, Weight, Height/Length

–Dietary AssessmentDietary Recall, Food Frequency

Questionnaires

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

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

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))

Recommendations – Management of Malnutrition

• Definitions/Entry criteria for Severe Malnutrition

– Children: Weight for height Z-score < -2

– Adults: BMI < 17 kg/m2

– Pregnant women: First trimester: BMI < 20

Second trimester BMI < 21Third trimester : BMI <

22

Future Directions : Implementation

and Public Health EvaluationMicronutrient 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

Future Directions : Implementation

and Public Health EvaluationMacronutrients/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 ?