Micronutrients HIVAIDS A review of knowledge, gaps, and recommendations

1
Micronutrients HIV/AIDSA review of knowledge,
gaps, and recommendations

• Ellen G. Piwoz, ScD
• Africas Health in 2010
• Presentation at AED for ACCESS
• September 12, 2006

2
Overview of the Presentation

• Background
• Overview of micronutrient studies in adults and
  children
• Vitamin A
• Iron/anemia
• Zinc
• Multiple MN supplements
• Current recommendations

3
This is a complex field scientifically as well
as politically
South African political cartoon, April 2005
4
The Vicious Cycle of Malnutrition and HIV is well
recognized
Insufficient dietary intake Malabsorption,
diarrhea Altered metabolism and nutrient storage
Increased HIV replication Hastened disease
progression Increased morbidity
Nutritional deficiencies
Increased oxidative stress Immune suppression
Source Semba and Tang, 1999
5
HIV affects nutrition through multiple mechanisms

• Increased energy requirements
• 10 increase during asymptomatic infection
• 20-30 increase during secondary infections
• 50-100 increase for children (WHO, 2003)
• Reductions in dietary intake
• Due to appetite loss, depression, oral sores
• Food insecurity/loss of livelihoods
• Nutrient malabsorption and loss
• HIV-infection of GI cells
• Diarrhea-related losses
• Metabolic changes
• Cytokine-related changes affect appetite
• Impaired transport, storage, utilization of some
  nutrients (e.g. protein)
• Increased utilization of antioxidant vitamins and
  enzymes, resulting in oxidative stress may
  increase viral replication

Photo M McCrary
6
Several micronutrients affect the immune system
and increase resistance to infections Friis H,
WHO, 2005
7
Overview of studies on micronutrients and
HIVVitamin AIronZincMultiple MN supplements
8

Studies on micronutrients and HIV have measured a
range of outcomes

• Perinatal and Child Outcomes
• Mother-to-child transmission (MTCT)
• Other birth outcomes (BW, SGA, prematurity)
• Child morbidity, growth, and mortality
• Child immunologic status
• Adult Outcomes
• - Immunological and virological progression
• - Clinical disease progression and mortality

9
Methodological considerations (see Friis H, WHO,
2005 for a complete discussion of issues)

• Lack of adequate biomarkers of MN status,
  especially in presence of acute phase response
• Underlying nutritional status, diet intake
  infrequently measured yet may affect
  relationships
• Sometimes causes conflicting results
• Makes it difficult to compare across studies
• Potential confounding (SES/poverty) HIV-related
  reporting bias for dietary intakes when measured
  

10
Vitamin A
11
Early observational studies showed an inverse
dose-response relationship between maternal serum
retinol and HIV viral load (Kenya) and MTCT of
HIV-1 (Malawi)
KENYA
MALAWI
Serum retinol mmol/L
Semba, Lancet 19943431593
Nduati, J Infect Dis 19951721461
12
Adapted from Table by Friis, 2005
13
Summary of findings from VAS/MTCT trials

• Tanzania (Fawzi et al, 2000 2002 Baylin et al,
  2005)
• Improved infant serum retinol, reduced VAD
• No effect on birth outcomes
• No effect on PNT, mortality
• Total MTCT significantly higher by 24 months
  (34.2 v 25.4p0.009)
• Zimbabwe (Humphrey et al, 2006)
• If IP infected infants, VAS reduced mortality (by
  28 p 0.01)
• No effect on PNT
• 2-fold increased risk of death in infants alive,
  PCR negative at 6 w

• South Africa (Coutsoudis et al, 1999
  Kennedy-Oji et al, 2002)
• Lower risk of pre-term deliveries
• No overall effect on MTCT
• Improved maternal PP weight retention
• Malawi (Kumwenda et al, 2002)
• Higher BW weight length at 6 w,
• Lower PNT 6 w-24 mo (2.8 vs. 7.7 p0.04)
• Lower anemia at 6 w

14
The impact of Vitamin A supplementation on other
outcomes

• Positive impact of VAS on morbidity and growth of
  hospitalized children (HIV/HIV-) Tanzania
  Villamor et al. Pediatrics 2002
• Positive impact of VAS on morbidity of HIV
  children South Africa Coutsoudis et al, 1995
• No effect of VAS on vaginal shedding of HIV,
  plasma HIV levels, immune status in women Kenya
  Baeten et al, 2002
• Suggestive effect of maternal VAS on risk of
  maternal HIV acquisition Zimbabwe (next slide)

15
Low serum retinol low HB are risk factors for
maternal acquisition of HIV after delivery
(n9562)Humphrey et al, AIDS, 2006
Models adjusted for marital statussexual
activity occupation Incidence of new
infections 3.4 per year (95 CI 3.0-3.8) VAS
tended to be protective against incidence in
women with low Se Retinol Adj. HR 0.29 (95 CI
0.03 - 2.60 P0.26)
16
Iron/Anemia
17
There are multiple causes of Anemia in HIV

• Anemia of chronic disease (ACD)
• ? Hb, ? Reticulocytes, ? Serum Fe, ? Transferrin,
  ? Fe saturation, normal or ? serum ferritin,
  low serum EPO, normal or ? Fe stores in bone
  marrow
• Nutrient deficiencies (Fe, folate, B12)
• Hookworm, malaria
• Malignancies
• Opportunistic infections of bone marrow
• ART use (ZDV), other OI drugs suppress RBC
  production

18
Anemia is more common in HIV-positive pregnant
women
Sources Mali (Diallo et al, 2003) CI (Ramon et
al, 1999) BF (Meda et al, 1999)
and is associated with higher maternal
mortality, LBW, pre-maturity, MTCT (next slides)
19
Anemia is also an independent predictor of
mortality in HIV adults, including among
post-natal women
Taha et al Bull WHO, 2006 - Malawi predictors
of death by 24 months post-delivery
20
Severe anemia is an independent risk factor for
intra-partum (IP) and postnatal (PN) transmission
(6 w-24 m) of HIV - Zimbabwe Humphrey et al,
JID, 2006 Piwoz et al, AIDS, in press
Both models adjusted for maternal B/L plasma
viral load, CD4 cell count IP model
gestational age, duration of membrane rupture,
infant birth weight PN model maternal age, MUAC,
early feeding pattern, death during F/U Neither
VAS nor infant sex were significant predictors of
IP, PN transmission
21
What is known about iron supplementation in HIV?

• A few studies suggest that supplemental iron
  given to HIV may cause increased iron stores in
  bone marrow and other tissues, oxidative stress,
  faster HIV disease progression, and subsequent
  increased mortality (Friis et al., 2003 Boelart
  et al., 1996).
• Associated with haptoglobin 2-2, a specific type
  of this heme-binding protein (Friis et al., 2003
  Gordeuk et al., 2001 Delanghe et al., 1998).

22
Low-dose iron (60 mg twice weekly) does not
increase HIV-1 viral load in adults in Kenya
(Olsen et al, JAIDS, 2004)
P0.31 for test of difference in decline of VL
between groups no effect of Fe supplementation
after controlling for baseline VL, hookworm
infection
23
Zinc
24
There have been concerns about the safety of zinc
supplementation for HIV adults and children

• Early observational studies showed increased
  mortality (shorter survival) in HIV adults with
  higher zinc intakes
• Additional concerns that Zn supplementation may
  induce HIV replication
• HIV-Tat protein and HIV nucleocapsid protein
  NCp7, which play a role in viral replication, are
  strongly zinc dependent

25
The good news daily Zn supplementation is safe
and beneficial in HIV children 6-60 mo Bobat et
al, Lancet, 2005

• 96 HIV infants randomized to daily Zn sulfate
  (10 mg/d) vs. placebo in Durban, SA
• Block randomization stratified by age (6-23 m,
  24-41, 42-60 mo)
• Hypothesis Zn will increase plasma viral log
  (VL) by 0.5 log
• HIV RNA, CD4, CD4 , measured at baseline, 3
  wks, 3 mo, 6 mo post-intervention (NO EFFECT)
• Morbidity, growth, survival measured
  (BENEFIT-morbidity) - next slide
• Authors conclusion Zinc supplementation is
  safe and beneficial and 10 mg/day should be part
  of the nutritional package for HIV children

26
Zn supplementation was associated with reduced
incidence of watery diarrhea during routine and
sick child visits Bobat et al, 2005
Chi-square test comparing proportion of all
visits with diagnosis
27
However, daily Zn supplementation did not improve
immune status or birth outcomes in HIV pregnant
women in Tanzania Fawzi et al, AJCN, 2005

• 400 HIV women randomized to daily Zn (30 mg Zn
  sulfate) or placebo from 12-27 wks gestation to 6
  wks post partum (fizzy tablet)
• All received MV supplement (BCE), ferrous sulfate
  (400 mg120 mg ferrous Fe), folate (5 mg) daily,
  prophylactic chloroquine, sd NVP
• No effect of Zn on pregnancy duration (p0.99),
  BW (p0.96), BL (p0.87), change in CD4 (p0.97),
  CD4CD8 (p0.23)
• Zn associated with non-significant increase in
  fetal, peri-natal neonatal mortality MTCT -
  next 2 slides
• Zn associated with lower PP HB recovery (p0.03),
  change in RBC count (plt0.01), packed cell volume
  (p0.01), also associated with increased risk of
  wasting in HIV women (Villamor et al, 2006)

28
Non-significant adverse effect of maternal Zinc
supplements on fetal and early postpartum infant
survival
  1 Includes stillbirths and abortions
Slide provided by W Fawzi From Fawzi et al, 2004
29
Maternal Zinc supplements (25 mg/d) given in
addition to vitamins BCE from 12-27 wks gestation
through 6 wks post-delivery are associated with
non-significant increases in MTCT in HIV
Tanzanian mothers -2
Villamor et al, EJCN, 2006
30
Multiple Micronutrient Supplements
31
Which combination/dose of micronutrients is the
most effective and safe?
Beta carotene
Vit D
Vit A
Vit E
Iron
Zinc
Folacin
Vit C
Pantothenic Acid
Copper
Selenium
Vit B12
Vit K
Folic Acid
Iodine
Cystine
Magnesium
Vit B1
Vit B6
Vit B2
Niacin
Manganese
Chromium
A Tomkins slide
32
Micronutrient formulation in Thai study (yellow)
Beta carotene
Vit D
Vit A
Vit E
Iron
Zinc
Folacin
Vit C
Pantothenic Acid
Copper
Selenium
Vit B12
Vit K
Folic Acid
Iodine
Cystine
Magnesium
Vit B1
Vit B6
Vit B2
Niacin
Manganese
Chromium
A Tomkins slide
33
Daily micronutrient supplementation reduced
mortality in HIV Thai adults, particularly those
with low CD4 cell counts Jiamton et al, AIDS,
2003
(P0.10)
(P0.05)
(P0.03)
There was no effect on HIV viral load, genital
shedding
34
Micronutrient Formulation in Tanzania Trial
Beta carotene
Vit D
Vit A
Vit E
Iron
Zinc
Folacin
Vit C
Pantothenic Acid
Copper
Selenium
Vit B12
Vit K
Folic Acid
Iodine
Cystine
Magnesium
Vit B1
Vit B6
Vit B2
Niacin
Manganese
Chromium
35
Tanzanian mothers receiving daily high dose MV
(B, C, E) were less likely to experience
HIV-related disease progression or death during
follow upMV (n271) vs. placebo (n268)
Mean diff in viral load -0.18 log or est. 30
increase in survival time
Fawzi et al, NEJM, 2004
36
.and to they were less likely to experience
HIV-related morbidity during follow upMV (n271)
vs. placebo (n268)
Other protective effects gingival erythema,
angular chelitis, nausea and vomiting, difficulty
swallowing, painful mouth, fatigue, rash
Fawzi et al, NEJM, 2004
37
Daily MV supplementation (B,C,E) increased weight
gain during pregnancy in HIV Tanzanian women
Villamor et al, AJCN, 2002
238 g/wk
185 g/wk
38
and improved birth outcomes in their infants
Fawzi et al, 1998
Fetal Death
Low Birthweight (lt2500g)
Preterm Birth (lt37 weeks)
Severe Preterm Birth (lt34 weeks)
Small for Gestational Age
0 0.5 1.0 1.5 2.0
Relative Risk
Slide from W Fawzi
39
.and prevented MTCT by most vulnerable mothers
Fawzi et al, AIDS, 2002
40
The children of HIV mothers receiving MV
supplements also benefited

• Improved immune status if not HIV at 6 wks Fawzi
  et al, CID 2003
• Difference 151 cells/?L (95 CI, 64-237 cells/
  ?L P.0006

• Children exposed to BCE via BM weighed more on
  average by 24 mo than children on placebo (459 g
  p0.03)
• The effect was greatest (1332 g) amongst infants
  who were HIV (plt0.001 for interaction) Villamor
  et al, AJCN, 2005

41
Micronutrients used in Kenya HIV shedding of the
reproductive tract study - adverse effect
Beta carotene
Vit D
Vit A
Vit E
Iron
Zinc
Folacin
Vit C
Pantothenic Acid
Copper
Selenium
Vit B12
Vit K
Folic Acid
Iodine
Cystine
Magnesium
Vit B1
Vit B6
Vit B2
Niacin
Manganese
Chromium
42
Micronutrients (TZ vitamins Se) increased
vaginal tract shedding of HIV-1 in Kenya
(McClelland et al, JAIDS, 2004)

• 400 non-pregnant HIV women randomized to
  receive
• MN (20 mg B1, 20 mg B2, 25 mg B6, 100 mg niacin,
  50mg B12,,500 mg Vitamin C, 30 mg Vit. E, 0.8 mg
  folic acid, 200 mg selenium
• or placebo
• Follow up 6 wks later

• Findings
• MN women were 2.5 times more likely to have
  vaginal HIV-shedding (p0.001), and higher
  vaginal RNA levels (p0.004)
• MNS increased likelihood of HIV shedding in women
  who had no detectable HIV at baseline increase
  infectivity
• Interaction w/ baseline Se status if not
  deficient, then adverse impact, but no effect of
  MN supplements if Se deficient (lt 85mg/L)
• No other interactions

43
Micronutrients used in Zimbabwe trial
Beta carotene
Vit D
Vit A
Vit E
Iron
Zinc
Folacin
Vit C
Pantothenic Acid
Copper
Selenium
Vit B12
Vit K
Folic Acid
Iodine
Cystine
Magnesium
Vit B1
Vit B6
Vit B2
Niacin
Manganese
Chromium
44
MN supplements associated with increased BW in
infants born to HIV mothers in Zimbabwe(Friis
et al, AJCN 2004)
45
ARV use and micronutrients
46
MN may still play a role in the era of HAART
(Tang et al, AIDS, 2005)

• Metabolic syndrome may be associated with
  oxidative stress
• lipodystrophy, insulin resistance/glucose
  intolerance
• Some ARV drugs may induce oxidative stress,
  increasing demand for anti-oxidant nutrients
• These conditions increase the risk of CVD
  possible role for MN (anti-oxidants) for patients
  on ART

47
Two small studies suggest that MN supplements can
reduce oxidative stress

• Daily Vitamin E (800 IU) and C (1000 mg)
  supplements for 3 months reduced indicators of OS
  compared with placebo
• 75 of patients on HAART
• Daily MN Vitamin A (5000 IU), Vitamin E (100
  IU), Vitamin C (50 mg) for 6 months reduced OS
  compared to placebo
• Only 30 subjects, all on HAART

48
MN supplementation increased CD4 count in
patients on HAART Kaiser et al, JAIDS, August,
2006
These nutrients others were contained in the
supplement
Beta carotene
Vit D
Vit A
Vit E
Iron
Zinc
Folacin
Vit C
Pantothenic Acid
Copper
Selenium
Vit B12
Vit K
Folic Acid
Iodine
Cystine
Magnesium
Vit B1
Vit B6
Vit B2
Niacin
Manganese
Chromium
49
MN supplementation increased CD4 count in
patients on HAART with neuropathy symptoms (DSP)
Kaiser et al, JAIDS, August, 2006

• 18 patients in MN, 22 in placebo group (small
  sample)
• 24 increase in CD4 count in MN group (p0.01)
• 64.7 cells in 12 wks (plt0.03)
• NS reduction on HIV VL
• Authors note the robust immune recovery
  occurred in a short period of time (12 wks)
  compared to other studies
• Mechanisms unknown but additional anti-oxidants
  sulphur may have slowed CD4 apoptosis (cell
  death)
• No effect on neuropathy symptoms observed ? due
  to short duration of supplementation

Authors conclude MN supplements should be used
as adjuvant therapy with HAART
50
Daily selenium supplementation (200 mg/day)
reduced hospitalization rates in HIV adults
(Burbano et al, HIV Clin Trials, 2002)
Poisson regression model for effects of Se
supplementation on hospitalization rates in HIV
adults drug users in USA
Model also adjusted for CD4 at baseline, and use
of HAART (50), mono- and dual ARV therapy
51
Daily selenium supplementation (200 mg/day)
improved CD4 cell response in HIV Nigerian
adults on HAART (d4T/3TC/NVP) (Odonukwe et al.
IAS, MoAb0403, 2006)

• Randomized trial (n170 per group)
• HIV viral load, CD4 counts, hematological and
  biochemical indices measured at baseline every
  three months.
• At each visit, adherence and nutritional
  counseling were given.
• Patients were followed for 72 weeks.
• Median time for undetectable viral load was
  similar in the two groups (p 0.2),
• Patients in HAART selenium group had
• Improved CD4 recovery from B/l to 72 wks (120
  cells/mm3 versus 50 cells/mm3)
• Reduced OI incidence hospitalizations
• Increased WT gain (p0.004)
• Increased Hb response (30g/l versus 10g/l).
• Selenium might be a useful complement to HAART
  in the management of people with HIV with severe
  immune-suppression

52
Daily Zn supplementation (50 mg/day) had no
effect on immune response of HIV TB patients on
ART (Green et al, Int Lung Journal, 2005)

• Double blind randomized trial (n32 in Zn, n34
  in placebo)
• 50 mg/day for 28 days
• HIV viral load, CD4 counts, immune response to TB
  challenge, hematological and biochemical indices
  measured at baseline and day 28
• There was no significant change in immune
  response to human PPD stimulation in the Zn or
  placebo groups (P 0.31 between groups),
  absolute CD4/CD8 cell levels, other lymphocyte
  subsets, or viral load.
• Baseline zinc levels were normal in 62/66 (93.9)
  patients.
• Authors conclude No evidence for recommending
  daily oral zinc in HIV-positive patients without
  zinc deficiency.

53
Conclusions and Recommendations
54
So, in conclusion, micronutrient supplementation
studies have shown a wide range of benefits

• Reduced morbidity and hospitalizations in adults
  ( B, C, E - Fawzi et al, 2004 Se - Burbano et
  al, 2003)
• Increased survival in adults (Fawzi et al, 2004
  Jiamton et al, 2003)
• Improved immune recovery in adults on HAART
  (Kaiser et al, 2006 Odunukwe, 2006)
• Increased weight gain in HIV pregnant women
  (Villamor et al, 2002)
• Reduced morbidity and improved growth in HIV
  children (Vitamin A Coutsoudis et al, 1995 BCE
  Villamor et al, 2002 2005 Zinc Bobat et al,
  2005)
• Improved birth outcomes and infant immune status
  (Fawzi et al, 1998 2003 Friis et al, 2004)
• Reduced MTCT in nutritionally and immunologically
  vulnerable (Fawzi et al, 2002)

55
But a systematic Cochran review on MN
supplementation states

• There is no conclusive evidence at present to
  show that MN supplementation effectively reduces
  morbidity and mortality among HIV-infected
  adults. It is reasonable to support the current
  WHO recommendations to promote and support
  adequate dietary intake of MN at RDA levels
  wherever possible. There is evidence of benefit
  of VA supplementation in children. The long-term
  clinical benefits, adverse effects, and optimal
  formulation of MN supplements require further
  investigation. (Irlam et al, The Cochrane
  Collaboration, 2005)

56
Micronutrient requirements for PLWHA are not known

• gt 1 RDA may be needed to correct nutritional
  deficiencies
• But there is concern that high doses of some
  nutrients may cause adverse outcomes.
• Current MN requirements are similar for PLWHA
  until more data available (WHO 2003)
• Adequate intake is best met through an adequate
  diet. However, in settings where these intakes
  and status cannot be achieved, multiple
  micronutrient supplements may be needed in
  pregnancy and lactation. Pending additional
  information, micronutrient intakes at the RDA
  level are recommended for HIV-infected women
  during pregnancy and lactation.

57
Supplementation recommendations same as for
uninfected populations

• Vitamin A supplementation
• Clear evidence of benefit for HIV children
• No evidence of benefit for HIV mothers, with
  possible exception of those who are severely
  deficient, and harm not ruled out
• Zinc supplementation
• Evidence of benefit for HIV children
• No evidence of benefit for HIV adults (possible
  harm if not deficient same re Se)
• Iron supplementation
• Limited data
• Same recommendations as for HIV-negative pregnant
  women and treatment of anemia