Zinc and Malaria

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Zinc and Malaria

• Davidson H. Hamer, M.D.
• Division of Geographic Medicine and Infectious
  Diseases
• Tufts-New England Medical Center,
• Tufts University Friedman School of Nutrition
  Science and Policy, and
• Center for International Health
• Boston U. School of Public Health

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Beneficial Effects of Zinc

• Zinc supplementation beneficial for growth,
  especially stunted or underweight children
• Zinc supplementation has been found to be
  effective for the prevention of
• Acute and persistent diarrhea
• Acute respiratory infections

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Zinc and Malaria Background

• Murine models have shown that zinc deficiency can
  exacerbate
• Malaria parasitemia
• Mortality
• Lipid peroxidation during infection
• Arif et al. Indian J Malariol 1987 Shankar FASEB
  J 1995
• Papua New Guinea and Malawi
• Associations between zinc status, anemia, and
  malaria suggest that zinc status is inversely
  correlated with P. falciparum malaria
• Gibson et al. Am J Clin Nutr 1991 Gibson et al.
  AJCN 1998

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Zinc and Prevention of Malaria
Placebo-Controlled Trials (1)

• The Gambia
• N 110 children aged 6 to 28 months
• Twice weekly supplementation with 70 mg zinc
  reduced Pf malaria-attributable health center
  attendance by 30 (p.09) (impact greatest after
  the first month p0.054)
• Bates et al. Brit J Nutr 199369243-55.
• Papua New Guinea
• N 274 children aged 6 to 60 months
• Zinc gluconate (10 mg/d given 6 days/week) for a
  total of 46 weeks
• Primary outcome number of slide-confirmed
  Pf-attributable clinic-based febrile episodes
• Shankar AS et al. Am J Trop Med Hyg,
  200062663-9.

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Summary of Effects of Zinc on Malaria Morbidity
in Papua New Guinea

• 38 (95 CI 3 to 60, p0.034) reduction in
  Pf-attributable health center attendance
• 69 (95 CI 27 to 86, p0.009) reduction in Pf
  attacks with parasitemia gt100,000/?L
• No effect on P. vivax episodes
• No consistent effects on parasite density,
  hemoglobin, spleen rates, or prevalence, and no
  evidence of age specificity
• Shankar AS et al. Am J Trop Med Hyg,
  200062663-9.

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Zinc and Prevention of Malaria Placebo-Controlled
Trials (2)

• Burkina Faso
• N 709 children between 6 to 31 months of age
• Zinc sulfate (12.5 mg/day given 6 days/week)
  supplemented during the rainy season (about 6
  months)
• Primary outcome clinical episodes of Pf malaria
  defined as axillary temperature ?37.5ºC and
  ?5,000 parasites/?L
• Muller O et al. Brit Med J 20013221-6.

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Burkina Faso Study Results

• No difference in P. falciparum incidence, even
  when different parasitemia cutoff points were
  used
• No difference in duration or severity of malaria
  episodes
• Fewer children died in the Zn than in the P group
• (5/341 vs. 12/344 p 0.1)
• Serum zinc was significantly higher in the zinc
  group after 3 months of supplementation
• 15.3 ?mol/L (Zn) vs. 12.4 ?mol/L (P)

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Why Are There Conflicting Results?

• Population studied in Burkina Faso had lower
  levels of subclinical zinc deficiency
• Mean baseline plasma zinc concentration 77.0
  ?g/dL and was even higher after 3 months of
  supplementation (in contrast to deficiency cutoff
  point of 60 ?g/dL)
• Duration of supplementation may have been too
  short in Burkina Faso (6 mo vs. 48 weeks in PNG)
• Possible benefit seen in Burkina Faso in terms of
  malariometric indices (Pf prevalence and density
  of parasitemia)

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Zinc Against Plasmodium (ZAP) Study
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ZAP StudyMethods

• Multicenter, randomized, double-blind,
  placebo-controlled clinical trial of children
  aged 6-59 months with
• Axillary temperature ?37.5C
• Blood smear with ? 2000/mm3 asexual forms of P.
  falciparum
• Children were treated with standard antimalarial
  therapy plus zinc sulfate or placebo for 3 days
• 20 mg/d of zinc for infants lt12 mo
• 40 mg/d for children 12-60 mo

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ResultsPrimary Outcomes

• Zinc and placebo groups were similar at baseline
• Zinc sulfate was well tolerated
• Time to resolution of fever similar in the two
  groups
• Zinc 24.2 and placebo 24.0 hours (p 0.37)
• Proportion of children with reduction of
  parasitemia by ?75 was similar in the two groups
• Zinc 73.4 and placebo 77.6 (p 0.11)
• No differences between treatment groups after
  controlling for baseline plasma zinc, nutritional
  status, and parasitemia

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ResultsSecondary Outcomes

• No differences between the zinc and placebo
  groups in terms of
• Proportion of children aparasitemic at 72 hours,
  days 7, 14, and 28
• Hemoglobin levels at days 7, 14, and 28
• Plasma zinc levels increased more in the zinc
  supplemented group than in the control group

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Baseline Plasma Zinc Levels By Baseline
Parasitemia Quartile
200
150
Plasma Zinc (?g/dL)
100
50
0
1
2
3
4
Parasitemia Quartile
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Discussion

• Potential explanations for the lack of efficacy
  of zinc in the ZAP study include
• Study population was not zinc deficient
• Unlikely given low plasma zinc levels and high
  phytate diets common in these countries
• Longer duration of supplementation may be needed
  to result in improvements in immune function
• Too small a dose of zinc was used
• However, higher doses may be harmful
• High levels of chloroquine treatment failures

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Future Studies of Zinc and Malaria

• Determine whether there is a beneficial effect of
  zinc for the prevention of morbidity due to
  falciparum malaria
• Evaluation of combinations of zinc with vitamin A
  or iron versus use of a multiple micronutrient
  supplement
• To evaluate whether the beneficial effects of
  vitamin A and zinc are additive or synergistic
• To determine whether the use of zinc helps to
  limit the increase in malaria parasitemia seen
  during iron replacement
• To evaluate the impact on anemia and growth in
  children in malaria-endemic regions