1466 • JID 2004:189 (15 April) • Baeten et al.
M A J O R A R T I C L E
Vitamin A Supplementation and Genital Shedding
of Herpes Simplex Virus among HIV-1–Infected
Women: A Randomized Clinical Trial
Jared M. Baeten,1,aR. Scott McClelland,2Lawrence Corey,2,3,5Julie Overbaugh,6,7Ludo Lavreys,1
Barbra A. Richardson,4,7Anna Wald,1,2Kishorchandra Mandaliya,8Job J. Bwayo,9and Joan K. Kreiss1,2
and Divisions of
General Hospital, Mombasa, and
6Human Biology and
3Laboratory Medicine, and
7Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington;
9Department of Medical Microbiology, University of Nairobi, Kenya
4Biostatistics, University of Washington, and
5Program in Infectious Diseases
Cross-sectional analyses have associated vitamin A deficiency with genital shedding of herpes simplex virus
(HSV) among human immunodeficiency virus type 1 (HIV-1)–infected women. A randomized clinical trial of
vitamin A supplementation given daily for 6 weeks was conducted among 376 women in Mombasa, Kenya,
who were coinfected with HSV-2 and HIV-1. At follow-up, there was no significant difference in the detection
of genital HSV DNA between women receiving vitamin A supplementation and women receiving placebo(40%
vs. 44%, respectively; ) Among women shedding HSV, there was no significant difference in the mean
P p .5
HSV DNA quantity between the group that received vitamin A supplementation and the group that received
placebo (4.51 vs. 4.67 log10copies/swab;). HSV shedding was associated with significantly highervaginal
P p .6
and cervical HIV-1 shedding, even after controlling for the plasma HIV-1 load and the CD4 count. Vitamin
A supplementation is unlikely to decrease HSV shedding and infectivity.
Herpes simplex virus (HSV) type 2 is a common co-
infection among persons with HIV-1, and studies have
suggested significant synergy between the global epi-
demics of the 2 viruses . The presence of HSV-2
increases the risk of HIV-1 acquisition , and it has
been suggested that regional variation in the seroprev-
alence of HSV-2 may be one of the principal factors
that explains the spread of HIV-1 in Africa . HSV-
2 reactivation occurs withgreaterfrequencyamongHIV-
1–infected individuals than among individuals not in-
Received 30 August 2003; accepted 3 November 2003; electronically published
2 April 2004.
Financial support: National Institutes of Health (NIH; grants AI43844 and
AI39996). J.M.B. and R.S.M. were scholars in the International AIDS Research
and Training Program supported by the Fogarty International Center, NIH (grant
aPresent affiliation: Department of Medicine, Massachusetts General Hospital,
Reprints or correspondence: Dr. Jared M. Baeten, International AIDS Research
and Training Program, University of Washington, 325 Ninth Ave., Box 359909,
Seattle, WA 98104-2499 (email@example.com).
The Journal of Infectious Diseases
? 2004 by the Infectious Diseases Society of America. All rights reserved.
in genital tract secretions [4–6]. Thus, interventionsthat
decrease HSV-2 reactivation may reduce transmissionof
both HSV-2 and HIV-1.
We previously reported the results of a cross-sectional
study of genital shedding of HSV in HIV-1–infected
women . Among women who were not pregnant and
were not using hormonal contraception, lower serum
concentrations of vitamin A were strongly associated
with increased detection of HSV. Randomized trials per-
formed among vitamin A–deficient populations have
demonstrated that vitamin A supplementation can bean
infectious diseases . With these results in mind, we
conducted a randomized, double-blind, placebo-con-
trolled trial to assess the effect of vitamin A supplemen-
tation on shedding of HSV.
Participants and procedures.
through June 2000, a total of 400 HIV-1–seropositive
women who were attending outpatient clinics at Coast
Provincial General Hospital in Mombasa, Kenya, were
From September 1998
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Vitamin A and Shedding of HSV in Women • JID 2004:189 (15 April) • 1471
It seems likely that our previous study of vitamin A levels and
shedding of HSV, which found deficiency to be associated with
a 110-fold increase in detection of HSV among women who
were not pregnant or were not using hormonal contraception,
may have been similarly confounded .
One limitation of the present study is that a single follow-up
sample may be inadequate to reflect the day-to-day pattern of
shedding of HSV, because HSV is intermittently detectableinthe
genital tract . Detailed evaluations of shedding of HSV, in-
cluding daily sampling, may be more ideal for assessment of the
magnitude of effect that interventions may have on detection of
HSV. Nonetheless, our results provide no evidence that vitamin
A supplementation reduces HSV reactivation.
Two previous studies found a significant correlationbetween
the quantities of HSV DNA and HIV-1 RNA in genital tract
secretions of coinfected women, although this correlation was
found only in subgroup analyses that were restricted to women
who were shedding HSV [5, 6]. The results of the present study
demonstrate that the quantity of HIV-1 in the genital tract is
significantly higher among women who shed any amount of
HSV than among thosewho do notshedHSV,andtheyconfirm
a strong association between the quantities of HIV-1 and HSV
that are shed. These findings strengthen the argumentthatHSV
reactivation increasesHIV-1 infectivity.Fewwomeninthepres-
ent study had genital ulcer disease, and the associations of HSV
with shedding of HIV-1 were unchanged after women with
ulcers were excluded from the study, emphasizingthattheeffect
of HSV on HIV-1 infectivity may be largely a result of sub-
clinical HSV reactivation.
In summary, the present trial suggests that vitamin A sup-
plementation is unlikely to reduce shedding or infectivity of
HSV. The results emphasize the importance of randomized
clinical trials to verify or refute associations discoveredincross-
sectional studies. The present study confirms that shedding of
HSV is common among women coinfected with HSV-2 and
HIV-1 and that it may increase HIV-1 infectivity, even in the
absence of genital ulceration. Interventions to decrease HSV
reactivation, such as HSV suppressive therapy with acyclovir
, should be pursued as potential strategies to decreaseshed-
ding and transmission of HIV-1.
We acknowledge the dedication of the clinic, laboratory, and
administrative staff in Mombasa, Kenya, and Seattle, Washing-
ton. We especially thank Meei-Li Huang and Rhoda Morrow
for their assistance with testing of samples. We are grateful to
the administrationof Coast ProvincialGeneralHospital(Mom-
basa), for provision of clinic and laboratory space, and to the
women whose participation made this study possible.
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