What Food and
Micronutrients Should Be
Provided for
HIV-infected Patients
Wafaie Fawzi
Departments of Nutrition and
Epidemiology
Harvard School of Public Health
Interaction of HIV and Nutrition
impairs
HIV
exacerbates
Nutrition
Reduction in production in a household
with an AIDS death, Zimbabwe
Crops
• Maize
• Cotton
• Vegetables
• Groundnuts
• Cattle owned
Reduction in output
61%
47%
49%
37%
29%
Source: Stover & Bollinger, 1999
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
Mehta S and Fawzi W. Vitam Horm 2007;75:355-83
newborn - additional defense
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
Vertical transmission of HIV-1 %
MATERNAL VITAMIN A LEVELS AND MOTHER-TOCHILD TRANSMISSION OF HIV-1
Serum Vitamin A (µmol/L)
Semba, Lancet 1994;343:1593
DAILY
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
• B12
: 50 µg
• B2
: 20 mg
• C
: 500 mg
• B6
: 25 mg
• E
: 30 mg
• NIACIN : 100 mg
• FOLATE: 0.8 mg
@
2. & 4. PLACEBO
DELIVERY
1. & 3. VITAMIN A 200,000 IU
PATIENT CARE
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
•
EFFECT OF MULTIVITAMIN SUPPLEMENTATION ON
FETAL DEATHS
Multivitamins
n (%)
No
Multivitamins
n (%)
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
Outcome
Fawzi, Lancet 1998;351:1477
EFFECT OF VITAMIN A SUPPLEMENTATION ON
FETAL DEATHS
Vitamin 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
Outcome
Fawzi, Lancet 1998;351:1477
EFFECT OF MULTIVITAMIN SUPPLEMENTATION ON
PREGNANCY OUTCOMES
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
SGA
39 (10.0)
66 (17.6)
0.57 (0.39-0.82)
0.002
Outcome
Fawzi, Lancet 1998;351:1477
EFFECT OF VITAMIN A SUPPLEMENTATION ON
PREGNANCY OUTCOMES
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
SGA
48 (12.4)
57 (15.0)
0.83 (0.58-1.18)
0.29
Outcome
Fawzi, Lancet 1998;351:1477
EFFECT OF VITAMIN A SUPPLEMENTATION ON 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 ~2fold higher mortality.
Humphrey et al.
MULTIVITAMINS DECREASED THE RISK OF
INFECTION THROUGH BREASTFEEDING IN
POPULATION SUBGROUPS
RELATIVE RISK
1.8
1.6
P=0.06
P=0.03
P=0.06
P=0.04
1.4
1.2
1.0
0.99
1.07
1.03
1.01
0.8
0.6
0.48
0.4
0.51
0.37
0.27
0.2
0.0
Fawzi, AIDS 2002;16:1935
MULTIVITAMINS DECREASED THE RISK OF
DEATH BY 24 MONTHS IN POPULATION SUBGROUPS
RELATIVE RISK
3.0
P=0.05
P=0.008
2.5
2.0
1.5
1.31
1.0
0.96
0.5
0.30
0.0
Fawzi, AIDS 2002;16:1935
0.31
MULTIVITAMINS DECREASED THE RISK OF
HIV INFECTION OR DEATH BY 24 MONTHS
IN POPULATION SUBGROUPS
RELATIVE RISK
1.6
P=0.06
P=0.01
1.4
1.2
1.0
0.98
0.96
0.8
0.6
0.50
0.4
0.2
0.0
Fawzi, AIDS 2002;16:1935
0.36
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
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: 543)
– 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 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.
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.
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)
Difference
P
Effect of Three Vitamin Regimens
on Viral
Mean (SD)
Placebo Group
4.67 (0.86)
Period
Load Whole
Compared
toin the
Placebo
Group
-0.18 (-0.32, -0.03)
Viral Load (log
10)
0.02
Multivitamins and Vitamin A
-0.07 (-0.21, 0.09)
0.40
Vitamin A alone
Difference
-0.03
(-0.17, 0.11)
P
0.68
Multivitamins B, C and E
_________________________________________________________________________________________________
First Two Years
Mean (SD) in Placebo Group 4.59 (0.86)
Multivitamins B, C and E
-0.18(-0.34, -0.03)
0.02
Multivitamins and Vitamin A
-0.11 (-0.27, 0.05)
0.17
Vitamin A alone
-0.07 (-0.23, 0.08)
0.35
First Four Years
Mean (SD) in Placebo Group 4.65(0.86)
Multivitamins B, C and E
-0.18 (-0.33, -0.04)
0.01
Multivitamins and Vitamin A
-0.09 (-0.24, 0.06)
0.24
Vitamin A alone
-0.04 (-0.18, 0.10)
0.57
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
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
Whole Period
Fawzi et al., NEJM 2004
Kaplan-Meier Curves of Progression to WHO Stage 4 or Death, by
Regimen
Fraction alive with stage < 4
1.0
0.9
0.8
Multivitamins B, C, and E
Multivitamins and Vitamin A
Vitamin A alone
Placebo
0.7
0.6
0
12
24
36
48
60
72
Months after randomization
No. at risk
Multivitamins B, C, and E
Multivitamins and Vitamin A
Vitamin A alone
Placebo
271
267
272
267
195
181
190
173
157
143
147
145
119
102
104
101
Fawzi et al., NEJM, 2004
Multivitamins and HIV-Related Complications
Fawzi et al., NEJM, 2004
Effect of Multivitamins on Postpartum Wasting
1.00
0.95
P (MUAC ≥ 22 cm)
0.90
0.85
0.80
MULTIVITAMINS
0.75
MVITS + VIT A
0.70
VITAMIN A
PLACEBO
0.65
0.60
RR MVITS vs. PLACEBO = 0.66 (0.47, 0.94)
0.55
0.50
0
2
4
6
8
10
12
14
TIME (mo)
16
18
20
22
24
Villamor et al., AJCN, 2005.
Effects of Multivitamins on
Hemoglobin Concentrations (g/dL)
Placebo
(N=219)
Mean (SD)
MVits
(N = 228)
Difference
10.84 (1.31)
0.20 (0.00,0.40)
0.05
0.21 (0.02, 0.40)
Up to 70
Days
Postpartum
10.16 (1.87)
0.59 (0.22, 0.97)
0.002
First 2 Years
10.64 (1.49)
0.37 (0.13, 0.62)
First 4 Years
10.88 (1.42)
0.27 (0.06, 0.48)
Period
Whole
Period
Vit A Alone
(N=233)
Difference
P
0.03
0.04 (-0.16,0.23)
0.70
0.53 (0.15, 0.91)
0.006
0.32 (-0.06,0.70)
0.10
0.003
0.36 (0.12, 0.60)
0.003
0.17 (-0.08,0.42
0.18
0.01
0.27 (0.07, 0.48)
0.009
0.09 (-0.12,0.30)
0.42
P
MVits + A
(N = 226)
Difference
P
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 cornsoya 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 inMegazzini
adherence
to ART by
K, et al. Abstract MOAB0401 XVI International AIDS Conference 2006
approximately 40% among the recipients as
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
–Anthropometry
BMI, Weight, Height/Length
–Dietary Assessment
Dietary 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 HIVinfected 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)
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 < 21
Third trimester : BMI < 22
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
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 ?