Tropical Medicine and International Health doi:10.1111/j.1365-3156.2011.02871.

volume 16 no 12 pp 1474–1482 december 2011

Systematic Review

Efficacy and safety of zinc supplementation for adults, children

and pregnant women with HIV infection: systematic review
Linan Zeng1,2 and Lingli Zhang1

1 Department of Pharmacy, West China Second University Hospital, Sichuan, China

2 School of Pharmacy, West China College, Si chuan University, Sichuan, China

Summary objectives To determine the efficacy and safety of zinc supplementary in children, adults and pregnant
women with HIV infection.
methods We conducted a comprehensive search in Medline, Embase, the Cochrane Library, CBM,
VIP and CNKI. Only randomized controlled trials conducted subsequent to the introduction of zinc
supplementation were included in this systematic review. Two reviewers assessed and extracted data
for analysis.
results Six trials with a total of 1009 participants were included. The findings in this review suggested
a benefit of zinc supplementation in reducing opportunistic infection for both adults and children with
HIV infection. In terms of increase in zinc level and CD4 counts, however, only adults with HIV
infection benefited. For other outcomes, such as viral load, mortality, mother-to-child transmission of
HIV and foetal outcomes, zinc supplementation conferred no benefit over placebo. No adverse event
related to zinc supplementation was found in all the included trials.
conclusion Based on the current evidence, zinc supplementation seems to be beneficial in adult patients
with HIV infection in some aspects. More research is needed in children and pregnant women. The
influence of zinc dose, duration and usage of antiretroviral medicine also requires further investigation.

keywords zinc supplementation, HIV infection, systematic review

changes essential for specific immunity (Coovadia &

Introduction
According to estimates by World Health Organization
(WHO) and the United Nations Joint Programme on
HIV ⁄ AIDS (UNAIDS), 33.4 million people were living
with HIV worldwide at the end of 2008, of whom,
2.1 million were children and 15.7 million were women
(WHO 2010). Sub-Saharan Africa is hardest hit; nearly
30 million adults and children there had HIV ⁄ AIDS in
2004 (WHO 2005). While antiretroviral drugs are
important for those with advanced HIV infection, nutri-
tion is of fundamental importance for all people with HIV
infection (Semba & Tang 1999; Baeten et al. 2002).
Adequate zinc status is critical for immune function
(Wellinghausen et al. 1997; Shankar & Prasad 1998).
Zinc acts as an antioxidant and may protect cells from
oxygen radicals produced during the non-specific immune
response (Coovadia & Bobat 2002). Zinc can bind to
thymulin (which enhances T cell maturation, interleukin-2
production and cytotoxicity) and produce conformational
Bobat 2002). Zinc deficiency in HIV-infected participants
was linked to declining CD4 cell counts (Baum et al.
2003; Fufa et al. 2009; Ndeezi et al. 2010) and reduced
survival (Miller & Strittmatter 1992). Thus, zinc supple-
mentation as a supporting therapeutic intervention seems
reasonable for patients with HIV ⁄ AIDS (Zazzo et al.
1989; Mocchegiani et al. 1995). However, in other
instances, zinc supplementation had no effect on immune
response, vaccination, CD4 ⁄ CD8 ratio or viral load
(Deloria-Knoll et al. 2006). Two nutritional studies
showed that increased intake of zinc in HIV-1-infected
patients led to an augmented risk of progression to AIDS
(Tang et al. 1993) and lower survival (Tang et al. 1996).
The San Francisco Men’s Health Study (Abrams et al.
1993) found no association between increased dietary
intakes of zinc (from food and supplements) and time to
progression to AIDS. It seems that current studies cannot
come to a consensus on the benefit of zinc supplementa-
tion. We therefore performed a systematic review to

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Tropical Medicine and International Health
L. Zeng & L. Zhang Zinc supplementation for people with HIV
evaluate the efficacy and safety of zinc supplement on
patients with HIV infection.
Methods
Only randomized controlled clinical trials with children,
adults or pregnant women who had confirmed HIV
infection were included in this systematic review. Zinc had
to be supplemented as an oral drug intervention; trials that
supplied zinc by dietary intake were excluded. Other basic
care supplied could include other trace elements (selenium,
magnesium, iron, iodine, copper, manganese, chromium,
cobalt and molybdenum), vitamins (A, D, E, C, B1, B2,
niacin, B6, B12, K, folate and beta-carotene). Outcome
measures were changes in zinc level; CD4 counts; viral
load; incidence of opportunistic infections (diarrhoea,
pneumonia, upper respiratory tract infection, ear infec-
tion); mortality; incidence of adverse events; mother-to-
child transmission (MTCT) of HIV; and foetal outcomes
(miscarriage, stillbirth, foetal death and neonatal death).
Search methods
Searches were performed in three English databases,
Cochrane Central Register of Controlled Trials (2010.09),
Ovid Medline (1947-2010.09) and Embase (1966-
2010.09), and three Chinese databases, Chinese Biomed-
ical Literature Database (CBM) (1978-2010.09), China
National Knowledge Infrastructure (CNKI) (1979-
2010.09) and VIP database for Chinese Technical Period-
icals (VIP) (1989-2010.09), using the following combina-
tion of search terms:
#1 HIV infections
#2 Human immunodeficiency virus
#3 Acquired immunodeficiency syndrome
#4 HIV
#5 #1 OR #2 OR #3 OR #4
#6 Zinc
#7 Trace elements
#8 Micronutrient
#9 #6 OR #7 OR #8
#10 #5 AND #9
We also checked the reference lists of relevant publica-
tions returned by the above searches.
Data collection and analysis
Study details (citation, country, founding and study design),
participant details (inclusion and exclusion criteria, diag-
nosis, age, sex, sample size and follow-up), interventions
details (dose, frequency and duration, whether multivita-
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volume 16 no 12 pp 1474–1482 december 2011
mins or antiretroviral therapy was given) and outcome
details (change in zinc level, change in CD4 counts, change in
viral load, opportunistic infection, mortality, adverse events,
MTCT and foetal outcomes) were extracted by reviewers.
For each outcome, the number of participants randomized
and the number of participants analysed were recorded for
each treatment group. For dichotomous data, the number
experiencing events was recorded. For continuous data,
arithmetic mean and standard deviation or medians and
ranges were recorded. Relative risks were calculated for
dichotomous data, and standardized mean differences for
continuous data or change in continuous data. Risk ratios
and standardized mean differences were presented with 95%
confidence intervals (CI). All P-values reported were two-
sided. Statistical significance in this study was defined as
P £ 0.05. All statistical analyses were conducted using
RevMan 5.0 (Nordic Cochrane Centre 2008). Heterogeneity
between trials was assessed using the chi-square test
(P < 0.1), which was quantified by the Higgins I2 statistic.
An I2 value of 50% or greater was an indication of
substantial heterogeneity. Subgroup analysis was conducted
in children, adults and pregnant women.
Quality assessment
The quality of evidence was assessed using GRADE
approach (GRADEpro 3.5.1) (Brozek et al. 2008), defining
the quality of evidence for each outcome as ‘the extent to
which one can be confident that an estimate of effect or
association is close to the quantity of specific interest’
(Higgins & Green 2008). There are four levels of quality:
high (further research is very unlikely to change our
confidence in the estimate of effect), moderate (further
research is likely to have an impact on our confidence in the
estimate of effect and may change the estimate), low (further
research is very likely to have an important impact on our
confidence in the estimate of effect and is likely to change the
estimate) and very low (we are very uncertain about the
estimate). Factors that may lower the quality of evidence are
limitation in design, inconsistency of results, indirectness of
evidence, imprecision and high probability of publication
bias. Factors that can raise the quality of evidence are as
follows: a large magnitude of effect, if all plausible
confounding would reduce a demonstrated effect; and a
dose-response gradient (Guyatt et al. 2008).
Results
Description of studies
Database searches yielded 1329 titles, 1324 of which were
excluded for not meeting inclusion criteria. Two more
references were identified through searching reference lists
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 Table 1 Characteristics of included studies

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Study design Participants Intervention

Age
(mean ± SD Dose and
No. of Founding Sample Follow-up Sex or median duration ART Multivitamin
Study ID Country centres source Type of trial ITT4 Duration Diagnosis size rate (male %) and range) of zinc use use

Baum et al. America 1 Y Randomized, Y 18 months Adults with 231 200 ⁄ 231 169 ⁄ 231 42.7 ± 7.0 Women: 144 ⁄ U
(2010) double-blind, HIV 12 mg ⁄ day 231
placebo- infection Men:15 mg ⁄
controlled day, for
trial 18 months
Carcamo Peru 1 Y Randomized, Y 2 weeks HIV-infected 159 108 ⁄ 159 110 ⁄ 159 Zinc: 30 100 mg U U
et al. double-blind, adults with (19–57) elemental
Tropical Medicine and International Health

(2006) placebo- persistent Placebo: 31 zinc ⁄ day,

controlled diarrhoea (19–64) for
trial 2 weeks
Green et al. Singapore 1 Y Randomized, N 28 days HIV-infected 66 65 ⁄ 66 61 ⁄ 66 Zinc: 50 mg 63 ⁄ U
(2005) double-blind, adults with 40 ± 7.8 element 64
placebo- a CD4 count Placebo: zinc ⁄ day,
controlled of <200 ⁄ mm3 40 ± 8.3 for 28 days
trial
L. Zeng & L. Zhang Zinc supplementation for people with HIV

Mocchegiani Italy 1 Y Randomized U 2 years* HIV-infected 57 U Stage III: Stage III: 45.5 mg 57 ⁄ U
et al. (1995) controlled adults at 19 ⁄ 35 26.5 ± 5 element 57
trial stage III or stage IV: stage IV: zinc ⁄ day,
stage IV 16 ⁄ 22 28 ± 4.3 for1 month
Bobat et al. South 1 Y Randomized, N 9 months HIV-infected 96 85 ⁄ 96 Zinc: 40.1 Zinc: 40.1 10 mg 96 ⁄ 91 ⁄ 96
(2005) Africa double-blind, children, aging (27.4–48.4) (27.4–48.4) element 96
placebo- between 6 and Placebo: Placebo: zinc ⁄ day,
controlled 60 months 36.6 36.6 for 6 months
trial (25–49.4) (25–49.4)
Fawzi et al. Tanzania 1 U Randomized, Y From 12–27 HIV-infected 400 397 ⁄ 400 Zinc: Zinc: 25 mg 400 ⁄ 400 ⁄ 400
(2005) and double-blind, gestational pregnant 26.7 ± 4.9 26.7 ± 4.9 element 400
Villamor placebo- age to women with Placebo: Placebo: zinc ⁄ day,
et al. controlled 6 weeks an estimated 27.0 ± 5.0 27.0 ± 5.0 from
(2006) trial post-partum gestational enrolment
age at until 6 weeks
randomization post-partum
of between 12
and 27 weeks

Y, Yes; N, No; U, Unclear; 4, Intention to treat.

*Body weight, plasma zinc, CD4 cells were detected 3 months after the beginning of zinc or placebo treatment; opportunistic infection were detected during the 2 years of
follow-up.

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Tropical Medicine and International Health
L. Zeng & L. Zhang Zinc supplementation for people with HIV
of relevant publications. Seven publications were retained
(Mocchegiani et al. 1995; Bobat et al. 2005; Fawzi et al.
2005; Green et al. 2005; Carcamo et al. 2006; Villamor
et al. 2006; Baum et al. 2010). Two reported the same trial
of zinc supplementation for pregnant women in Tanzania
(Fawzi et al. 2005; Villamor et al. 2006). Of the six trials
with a total of 1009 participants, four were in HIV-
infected adults (Mocchegiani et al. 1995; Green et al.
2005; Carcamo et al. 2006; Baum et al. 2010), one was in
HIV-infected children (Bobat et al. 2005) and one in
pregnant women with HIV infection (Fawzi et al. 2005;
Villamor et al. 2006). All participants in Carcamo et al.
(2006) had persistent diarrhoea lasting for more than
7 days. All of the studies were single-centred clinical trials,
three in developed countries and three in developing
countries (Table 1).
Effects of interventions
Four trials conducted in HIV-infected adults analysed the
change in zinc concentration (Mocchegiani et al. 1995;
Green et al. 2005; Carcamo et al. 2006; Baum et al.
2010). The zinc status at baseline was almost the same
among trials (Table 2). Only two studies that reported
the mean and SD could be combined (Mocchegiani et al.
1995; Green et al. 2005). However, heterogeneity be-
tween two trials was too great to perform a meta-
analysis (v2 = 10.22, I2 = 80%). Participants in these two
trials received moderate-dose, short-duration zinc sup-
plementation. In Green et al. (2005), the zinc level rose
in both zinc and placebo arm without statistical differ-
ence (P = 0.67); Mocchegiani et al. (1995) only observed
this in the intervention arm (Table 3). Participants
Table 2 Zinc status at baseline
Study ID
Baum et al. (2010) Serum zinc level: mean (SD)
Carcamo et al. (2006) N (%)
Green et al. (2005) Serum zinc: mean (SD)
Mocchegiani et al. (1995) Serum zinc: mean (SD) (ug ⁄ dl)
Bobat et al. (2005)
Fawzi et al. (2005) and
Villamor et al. (2006)
U: Unclear.
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volume 16 no 12 pp 1474–1482 december 2011
received low-dose, long-duration zinc supplementation
had significantly higher zinc levels than those in the
placebo group (b = 0.04; P = 0.047) (Baum et al. 2010).
In addition, participants who received high-dose, short-
duration zinc supplementation had a better outcome
(Carcamo et al. 2006). Studies conducted in children or
pregnant women did not report the change in zinc level
during trials.
CD4 counts rose in the zinc group for both adult and
children participants, but fell in the placebo or no
treatment group (Mocchegiani et al. 1995; Bobat et al.
2005). Zinc supplementation was effective in preventing
immunological failure in adults, which was defined as a
drop in CD4 counts to <200 cells ⁄ mm3 (Baum et al. 2010).
However, CD4 counts increased in HIV-infected mothers
at 6 weeks post-partum in both zinc and placebo groups,
without a statistically significant difference (P = 0.97)
(Fawzi et al. 2005) (Table 3).
There was no significant change in HIV viral load in
either zinc or placebo group in adult participants during
a 28-day intervention (Green et al. 2005). Likewise,
Log10 viral loads were similar between the zinc supple-
mentation and placebo groups during a 6-month
treatment in children (Bobat et al. 2005). Villamor et al.
(2006) selected 100 women for viral load analysis. The
baseline sample was collected at gestation week 22 on
average and the follow-up measurement at 6 weeks
post-partum. Log10 viral loads decreased from baseline
to the follow-up measurement in the zinc but not in
the placebo group. The risk of having a high viral load
(>100 000 copies ⁄ ml) at the post-partum visit was not
significantly lower in women who received zinc
(RR = 0.77, 95% CI: 0.42–1.40, P = 0.38) (Table 3).
Zinc status at baseline
All patient: 0.6 (0.1) mg ⁄ l
Zinc: 0.6 (0.1)
Placebo: 0.7 (0.2)
Zinc Placebo
Normal: 6 ⁄ 8 (75) 5 ⁄ 9 (55.6)
Marginal deficiency: 5 ⁄ 8 (62.5) 3 ⁄ 5 (60)
Overt deficiency: 19 ⁄ 34 (55.9) 23 ⁄ 40 (57.5)
Zinc: 14.1 (2.8) umol ⁄ l
Placebo: 13.3 (2.3)
Fourth Third
Zinc 78.0 (4.3) 76.8 (2.7)
Placebo 80.0 (3.1) 79.8 (3.5)
U
U
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L. Zeng & L. Zhang Zinc supplementation for people with HIV

Table 3 Outcomes, Zinc vs. Placebo (continuous data)

Zinc Placebo
Mean difference
Study or Subgroup Mean SD Total Mean SD Total IV, random, 95% CI

Change of zinc level, zinc vs. placebo

Adults
Green et al. (2005) 0.0043 0.0096 32 0.0038 0.0053 34 0.00 [)0.00, 0.00]
Mocchegiani et al. (1995) (stage 3) 0.0008 0.0004 18 )0.0012 0.0006 19 0.00 [0.00, 0.00]
Mocchegiani et al. (1995) (stage 4) 0.0006 0.0006 10 )0.0023 0.0006 11 0.00 [0.00, 0.00]
Change of CD4 counts, zinc vs. placebo
Adults
Mocchegiani et al. (1995) (stage 3) 49 20 17 )111 21 18 160.00 [146.42, 173.58]
Mocchegiani et al. (1995) (stage 4) 40 10 12 )30 10 10 70.00 [61.61, 78.39]
Children
Bobat et al. (2005) (3 months) 0 9.8 44 )1 8.3 41 1.00 [)2.85, 4.85]
Bobat et al. (2005) (6 months) 1 9.8 44 )1 8.7 41 2.00 [)1.93, 5.93]
Bobat et al. (2005) (9 months) 1 10.1 44 0 9.1 41 1.00 [)3.08, 5.08]
Pregnant women
Fawzi et al. (2005) 95 126 200 101 137 200 )6.00 [)31.80, 19.80]
Change of viral loads
Adults
Green et al. (2005) 2.912 41.832 31 )1.735 43.453 32 4647.00 [)16412.72, 25706.72]
Children
Bobat et al. (2005) (3 months) 0.1 0.66 44 0 0.73 41 0.10 [)0.20, 0.40]
Bobat et al. (2005) (6 months) 0.2 0.67 44 0 0.7 41 0.20 [)0.09, 0.49]
Bobat et al. (2005) (9 months) 0.2 0.64 44 0.1 0.79 41 0.10 [)0.21, 0.41]
Pregnant women
Villamor et al. (2006) )0.18 0.65 50 0.01 0.56 50 )0.19 [)0.43, 0.05]

Three studies reported opportunistic infections in HIV-
infected adults, of which only two could be combined in a
meta-analysis (Mocchegiani et al. 1995; Green et al.
2005). Zinc supplementation seemed to help reduce the
risk of infection in HIV-infected adults. An intent-to-treat
analysis in Baum et al. (2010) showed that zinc supple-
mentation significantly reduced the rate of diarrhoea over
time by more than half in adult patients (OR = 0.4, 95%
CI: 0.183–0.981, P = 0.019). Diarrhoea was significantly
associated with lower mean plasma levels of zinc
(0.59 ± 0.11 vs. 0.68 ± 0.21 mg ⁄ l). In children, the pro-
portion of scheduled and illness visits at which children
were diagnosed with watery diarrhoea (P = 0.001) or
pneumonia (P = 0.07) was smaller for the zinc group than
for the placebo group; the number of illness visits per
month was slightly lower in the zinc arm (0.11 illness
visits ⁄ month) than in the placebo arm (0.16 illness
visits ⁄ month, P = 0.05) (Bobat et al. 2005) (Table 4).
Mortality of adults and children in the zinc group was
slightly lower than that of placebo group, but without
statistical significance (RR = 0.79, 95% CI: 0.25–2.44,
P = 0.6; RR = 0.31, 95% CI: 0.07–1.42, P = 0.13,
respectively). However, three mothers in a zinc group
died after delivery while none died in the placebo group
for reasons that remain unclear (Fawzi et al. 2005)
(Table 4).
Zinc supplementation had no significant effect on
MTCT of HIV at birth (0–21 days) (RR = 1.37, 95% CI:
0.49–3.85, P = 0.55) or at 6 weeks post-partum
(RR = 1.40, 95% CI: 0.67–2.95, P = 0.37). This was
determined by testing whole blood samples from babies
using the Amplicor HIV-1 detection kit version 1.5
(Table 4).
Compared with placebo, zinc had no significant effect
on risk of death during the foetal (RR = 1.38, 95% CI:
0.70–2.75, P = 0.35) and early post-partum periods
(RR = 1.48, 95% CI: 0.57–3.79, P = 0.42) (Table 4).
No adverse events attributable to zinc supplementation
were observed in the included studies. However, indica-
tors of zinc toxicity, such as copper status, were not
monitored except in one trial, in which zinc supplemen-
tation did not induce copper deficiency (Carcamo et al.
2006).
Quality of included studies
There was low-quality evidence for a benefit from zinc
supplementation for change in zinc level, change in CD4

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L. Zeng & L. Zhang Zinc supplementation for people with HIV

Table 4 Outcomes, Zinc vs. Placebo (dichotomous data)

Zinc Placebo
Risk ratio M-H,
Study or Subgroup Events Total Events Total Weight (%) random, 95% CI

Opportunistic infection
Adults
Green et al. (2005) 4 32 3 34 18.4 1.42 [0.34, 5.84]
Mocchegiani et al. (1995) 9 29 13 28 81.6 0.67 [0.34, 1.31]
Subtotal (95% CI) 13 61 16 62 100.0 0.77 [0.42, 1.41]
Heterogeneity: s2 = 0.00; v2 = 0.90, df = 1 (P = 0.34); I2 = 0%
Test for overall effect: Z = 0.85 (P = 0.39)
Mortality
Adults
Baum et al. (2010) 11 115 8 116 35 1.39 [0.58, 3.32]
Carcamo et al. (2006) 0 81 0 78 Not estimable
Green et al. (2005) 0 32 0 34 Not estimable
Mocchegiani et al. (1995) 5 29 11 28 33.9 0.44 [0.17, 1.10]
Subtotal (95% CI) 16 257 19 256 69.0 0.79 [0.25, 2.44]
Heterogeneity: s2 = 0.45; v2 = 3.17, df = 1 (P = 0.08); I2 = 68%
Test for overall effect: Z = 0.41 (P = 0.68)
Children
Bobat et al. (2005) 2 46 7 50 22.2 0.31 [0.07, 1.42]
Test for overall effect: Z = 1.51 (P = 0.13)
Pregnant women
Fawzi et al. (2005) 3 200 0 200 8.8 7.00 [0.36, 134.64]
Test for overall effect: Z = 1.29 (P = 0.20)

Total (95% CI) 21 503 26 506 100.0 0.78 [0.29, 2.05]

Heterogeneity: s2 = 0.50; v2 = 6.74,df = 3 (P = 0.08); I2 = 56%
Test for overall effect: Z = 0.51 (P = 0.61)
Mother-to-child transmission of HIV
At birth (0–21 days)
Villamor et al. (2006) 8 141 6 145 100.0 1.37 [0.49, 3.85]
Test for overall effect: Z = 0.60 (P = 0.55)

By 6 weeks
Villamor et al. (2006) 15 141 11 145 100.0 1.40 [0.67, 2.95]
Test for overall effect: Z = 0.89 (P = 0.37)
Foetal outcomes
Miscarriage
Villamor et al. (2006) 5 198 3 199 100.0 1.68 [0.41, 6.91]
Test for overall effect: Z = 0.71 (P = 0.48)

Still birth
Villamor et al. (2006) 13 198 10 199 100.0 1.31 [0.59, 2.91]
Test for overall effect: Z = 0.65 (P = 0.51)
Foetal death
Villamor et al. (2006) 18 198 13 198 100.0 1.38 [0.70, 2.75]
Test for overall effect: Z = 0.93 (P = 0.35)
Neonatal death
Villamor et al. (2006) 10 180 7 186 100.0 1.48 [0.57, 3.79]
Test for overall effect: Z = 0.81 (P = 0.42)

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Table 5 Assessment of quality of evidence across studies by GRADE

Quality assessment

No of Other
studies Design Limitations Inconsistency Indirectness Imprecision considerations Quality Importance

Change of zinc level (follow-up mean 213 weeks; better indicated by higher values)
2 Randomized trials Serious* No serious inconsistency  No serious Seriousà None ¯¯OO Not important
indirectness Low
Tropical Medicine and International Health

Change of CD4 counts (better indicated by lower values)

3 Randomized trials Serious  No serious inconsistency No serious Serious§ None ¯¯OO Important
indirectness Low
Change of viral load (better indicated by lower values)
3 Randomized trials Serious* No serious inconsistency No serious No serious None ¯¯¯O Critical
indirectness imprecision Moderate
Opportunistic infection
4 Randomized trials Serious No serious inconsistency No serious Seriousà None ¯¯OO Critical
indirectness Low
L. Zeng & L. Zhang Zinc supplementation for people with HIV

Mortality
6 Randomized trials Serious* No serious inconsistency No serious No serious None ¯¯¯O Important
indirectness imprecision Moderate
Mother-to-child transmission of HIV
1 Randomized trials Serious– No serious inconsistency No serious No serious None ¯¯¯O Critical
indirectness imprecision Moderate
Foetal outcomes
1 Randomized trials Serious– No serious inconsistency No serious No serious None ¯¯¯O Important
indirectness imprecision Moderate

*The method of sequence generation and allocation concealment was not reported in Green et al. (2005) or Mocchegiani et al. (1995). And intent-to-treat analysis
was not performed in Green et al. (2005).
 The method of sequence generation and allocation concealment was not reported in Green et al. (2005). And intent-to-treat analysis was not performed in Green et al.
(2005) or Fawzi et al. (2005).
àGreen et al. (2005) and Mocchegiani et al. (1995) include few participants and few events and thus have wide confidence intervals.
§The confidence interval in Fawzi et al. (2005) is wide.
–Lack of allocation concealment in Fawzi et al. (2005) and Villamor et al. (2006).

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Tropical Medicine and International Health
L. Zeng & L. Zhang Zinc supplementation for people with HIV
counts and for opportunistic infection among HIV-infected
patients. The quality of evidence was downgraded for risk
of bias (lack of allocation concealment and lack of
intent-to-treat analysis) and imprecision (small number of
participants or events and thus wide confidence
intervals).There was moderate-quality evidence for effect
on viral load and mortality. The quality of evidence was
downgraded owing to the lack of allocation concealment
and intent-to-treat analysis. Despite low risk of bias from
the trial conducted in pregnant women with HIV infection,
the overall body of evidence for the effects of zinc
supplement was downgraded owing to the lack of
allocation concealment (Table 5).
Discussion
Potential bias in this review
This review is limited by the available literature on zinc
supplementation for treating HIV infection patients. Half
of the studies included in this review were conducted in
developed countries, and thus, results from such studies
might not well reflect the conditions in resource-con-
strained countries. Confounding factors were not well
balanced across trials. Only three of six trials reported the
HIV stage of participants, and the CD4 counts of partic-
ipants at baseline varied across trials. In adult studies, the
percentage of participants with CD 4 counts below
200 cells ⁄ mm3 in Carcamo’s study (2006) was much
higher than that of Baum et al. (2010). Difference in other
characteristics, such as multivitamin treatment, drug use
and sexual behaviour, may also have caused the hetero-
geneity in this review. Some intermediate outcomes may
not well indicate the efficacy of zinc, as they might be
influenced by other factors. Kupka and Fawzi (2002)
demonstrated that serum and plasma zinc levels can vary
widely as a result of circadian rhythm, meals and stress
(Kupka & Fawzi 2002). Zinc levels may also be depressed
by opportunistic infections (Graham et al. 1991; Fauci
et al. 1996). For those outcome measurements, we gave
limited level of importance in GRADE approach.
Implication for practice
In terms of rising zinc levels and CD4 counts and reducing
opportunistic infections, zinc supplementation is beneficial
for both adults and children with HIV infection, regardless
of dose and duration. In terms of reducing viral load,
preventing MTCT of HIV or foetal outcomes, zinc
supplementation made no difference. In terms of mortality,
its effect remains unclear as the numbers involved were too
small. Zinc supplementation caused no adverse events
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volume 16 no 12 pp 1474–1482 december 2011
regardless of dosage and duration of the intervention;
hence, it seems safe for patients with HIV infection.
Therefore, we conclude that zinc supplementation seems to
be beneficial in terms of change in zinc level, CD4 count
and prevention of opportunistic infection for patients with
HIV infection, but it is still uncertain that whether zinc has
any effect on viral load, mortality, MTCT of HIV and
foetal outcomes. However, as most of results were from
adult trials, the safety and efficacy of zinc supplementation
in children and pregnant women remain to be ascertained.
Implications for research
Most current studies mainly focused on the effect and
safety of micronutrient supplementation or dietary sup-
plementation in patients with HIV infection (Kelly et al.
1999; Jiamton et al. 2003; Irlam et al. 2005). Micronutri-
ents, however, often interact with each other (Wieringa
et al. 2003), and thus, the efficacy of a particular trace
element should be evaluated in single-interventional trials.
Studies evaluating zinc supplementation as single inter-
ventions may have been underpowered to assess efficacy
outcomes. There is a tremendous need for clinical research
on this issue by intervention trials and the influence of
treatment dose and duration on the efficacy. More trials
are needed in resource-limited countries where the burden
of disease is greatest, as the initial nutritional status and
other characteristics of participants may influence the
efficacy of zinc supplementation (Friis 2006); studies
should consider investigating its role in patients at partic-
ular HIV stages.
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