Download Does Patient Sex Affect Human Immunodeficiency Virus Levels?

REVIEW ARTICLE
HIV/AIDS
Does Patient Sex Affect Human
Immunodeficiency Virus Levels?
Monica Gandhi,1 Peter Bacchetti,1 Paolo Miotti,2 Thomas C. Quinn,3,4 Fulvia Veronese,2 and Ruth M. Greenblatt1
1
Department of Medicine, Infectious Diseases Division, University of California, San Francisco; and 2Office of AIDS Research and 3National
Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, and 4Johns Hopkins University, Baltimore, Maryland
We undertook a critical epidemiological review of the available evidence concerning whether women have
lower levels of human immunodeficiency virus (HIV) RNA than do men at similar stages of HIV infection.
The 13 studies included in this analysis reported viral load measurements in HIV-infected men and women
at a single point in time (cross-sectional studies) or over time (longitudinal studies). Seven of the 9 crosssectional studies demonstrated that women had 0.13–0.35 log10 (∼2-fold) lower levels of HIV RNA than do
men, despite controlling for CD4+ cell count. Four longitudinal studies revealed that women had 0.33–0.78
log10 (2- to 6-fold) lower levels of HIV RNA than do men, even when controlling for time since seroconversion.
Adjustment for possible confounders of the relationship between sex and viral load, including age, race, mode
of virus transmission, and antiretroviral therapy use, did not change this outcome. This finding is significant,
because viral loads are frequently used to guide the initiation and modification of antiretroviral therapy.
Recent UNAIDS statistics report that women constitute
47% of adults living with HIV/AIDS worldwide. In the
United States, the number of prevalent AIDS cases
among women is steadily increasing; the Centers for
Disease Control and Prevention [1] now estimate that
23% of the reported AIDS diagnoses occur in women.
Women also represent the fastest-growing group with
incident HIV infection, with the highest rates being
among black and Hispanic women.
Recently, a volume of research has been undertaken
to define survival, disease progression, access to care,
and prognostic markers for HIV-infected women. Although early reports [2, 3] found that male sex appeared to confer a survival benefit in AIDS, later studies,
which controlled for access to care, antiretroviral use,
Received 4 December 2001; revised 20 February 2002; electronically published
2 July 2002.
Reprints or correspondence: Dr. Monica Gandhi, Dept. of Medicine, Infectious
Diseases Division, University of California, San Francisco, Box 1352, San Francisco,
CA 94143 ([email protected]).
Clinical Infectious Diseases 2002; 35:313–22
2002 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2002/3503-0015$15.00
and disease stage, found similar rates of progression
and survival for both sexes [4–7]. Several studies have
reported that men and women differ in access to HIV
care [8], with women being less likely to receive prophylaxis for opportunistic infections [9] or to start appropriate antiretroviral therapy (ART) [9, 10] (even in
a single-clinic setting [11]). Given the clear survival
benefit with current HIV therapeutics [12, 13], differential use of antiretrovirals for purely societal reasons
may lead to survival disadvantages for women.
In terms of the biological rationale for differential, sexbased HIV therapeutics, current recommendations for
initiating ART [14] stem from studies largely of male
cohorts. In men, 2 key markers—the absolute count or
relative percentage of CD4 lymphocytes and the number
of plasma HIV RNA copies (viral load)—are used to
prognosticate disease progression and mortality [15–19],
direct timing of ART, and assess of therapeutic efficacy
[15–17, 20–23]. Subsequent studies have examined differences in the prognostic marker of viral load among
men and women [23–35]. Even after adjustment for CD4
cell count or time since seroconversion, some reports
indicate that viral loads are lower in women than in
HIV/AIDS • CID 2002:35 (1 August) • 313
Table 1.
Characteristics of studies investigating relationship between patients’ sexes and viral loads.
Study design,
year [reference]
Name of cohort
Sample size,
no. of patients
No. (%) of men/
no. (%) of women
Median or range of
CD4⫹ cell count, cells/mL
Cross-sectional
1996 [29]
—
40
20 (50)/20 (50)
Men, 212; women, 210
1996 [23]
ACTG 175
391
320 (82)/71 (18)
Men, 343; women, 346
1998 [24]
ALIVE
Baseline, 527
421 (80)/106 (20)
518 (men and women)
Follow-up, 285
196 (69)/89 (31)
390 men and 417 women
1999 [30]
Johns Hopkins Clinic
1773
1197 (68)/576 (32)
1999 [25]
Swiss cohort study
1337
690 (52)/647 (48)
1999 [27]
ICONA
2011
1299 (65)/712 (35)
Men, 415; women, 469
2000 [28]
ICONA
415
245 (59)/170 (41)
Men, 487; women, 511
2000 [26]
WIHS and MACS
2859
1603 (56)/1256 (44)
!200 to 1500 (3 strata)
2000 [35]
VATS
494
392 (79)/102 (21)
Men, 16; women, 12.5
Tri-Service HIV-1 Natural
History Program
42
14 (33)/28 (67)
1999 [31]
ISS
149
98 (66)/51 (34)
Men, 485; women, 485
1999 [32]a
ALIVE
71
51 (72)/20 (28)
Men, 723; women, 803
2001[34]
ALIVE
202
156 (77)/46 (23)
Men, 659; women, 672
!100 to 1750 (6 strata)
IDUs, 307 men and 327 women
Heterosexual exposure, 313 men and 360 women
Longitudinal
1997 [33]
700, 500, 400 (3 time points)
NOTE. ACTG, AIDS Clinical Trials Group; ALIVE, AIDS Link to Intravenous Experiences; bDNA, branched DNA; CPT, citrate cell preparation tubes; IDU,
intravenous drug user; ISS, Istituto Superiore di Sanità [37]; MACS, Multicenter AIDS Cohort Study; NASBA, nucleic acid sequence–based amplification; RT,
reverse transcriptase; VATS, Viral Activation Transfusion Study; WIHS, Women’s Interagency HIV Study.
a
Longitudinal study in nested case-control study.
men [23–28], whereas other reports show no significant differences by sex [29, 30] or a differential that wanes with advancement in HIV disease [32, 35]. Infected women appear to progress
to AIDS and death at rates similar to those for men [4], despite
initially having lower viral loads, leading some authors to suggest
that initiating ART should include consideration of the patient’s
sex [24, 26, 28, 32]. Indeed, current treatment guidelines acknowledge the possibility of sex-based differences in viral load,
concluding that “clinicians may wish to consider lower plasma
HIV RNA thresholds for initiating therapy for women with CD4⫹
T cell counts 1350 cells/mm3” [14, p.75].
A putative finding that women progress to AIDS at rates
similar to those for men but from lower viral load set points
has implications for HIV management and mechanisms of viral
pathogenesis in women. We report the results of a critical review
of the evidence regarding the effects of sex on viral load, with
an exploration of the significance and biological plausibility.
314 • CID 2002:35 (1 August) • HIV/AIDS
METHODS
We searched the MEDLINE database for studies from
1995–2000 that examined the relationship between a patient’s
sex and viral load, using permutations of the keywords “HIV,”
“viral load,” “HIV RNA,” “women,” “gender,” and “sex”; the
search was restricted to articles in the English language that
involved human subjects. A total of 502 articles were identified.
The MEDLINE search was repeated for articles from
1990–1994, from which we identified 39 additional articles.
Searches on AIDSLINE and Dissertation Abstracts Online
yielded no additional papers. Relevant reviews and articles were
examined for references to other studies.
Inclusion criteria restricted the articles to those in which
viral loads were compared among men and women. Studies
were either cross-sectional in design or longitudinal (defined
as multiple viral load comparisons between groups of men and
Table 1.
(Continued.)
Viral load measurement
Plasma type
Mean difference in log10 RNA for
women vs. men (95% CI)
HIV quantification assay
P
Fresh samples
Chiron bDNA 1.0 assay
⫺0.32 (⫺1.00 to 0.36)
Frozen heparinized plasma
Roche Amplicor
⫺0.35 (⫺0.54 to ⫺0.16)
!.001
Frozen heparinized plasma
Microculture, Chiron bDNA 2.0,
Roche Amplicor
Baseline, ⫺0.29 (⫺0.51 to ⫺0.07)
!.01
Follow-up, ⫺0.31 (⫺0.62 to 0.00)
!.05
.36
Fresh samples
Roche Amplicor
No difference seen in any CD4⫹ cell strata
Fresh samples
Roche Amplicor
IDUs, ⫺0.23 (⫺0.40 to ⫺0.06)
.009
Heterosexual exposure, ⫺0.04 (⫺0.10 to 0.02)
.21
Fresh samples
Roche for 42%, NASBA for 20%, and
Chiron 1.0 for 38%
⫺0.13 (⫺0.21 to ⫺0.05)
!.001
Fresh samples
Roche for 219 samples (57.6%) and
Chiron 1.0 for 161 (42.4%)
⫺0.23 (⫺0.40 to ⫺0.05)
.01
Frozen heparinized plasma for MACS
and CPT for WIHS
Chiron 1.0 bDNA for MACS and
NASBA for WIHS
!200 CD4⫹ cells, 0.05 (⫺0.12 to 0.52)
Fresh samples
Roche Amplicor
0.13 (⫺0.11 to 0.37)
.28
Frozen heparinized plasma
RT-PCR assay
⫺0.5 (⫺0.52 to ⫺1.02) and ⫺0.7 over
first 2 years
.03
200–350 CD4⫹ cells, ⫺0.17 (⫺0.31 to ⫺0.02)
350–500 CD4⫹ cells, ⫺0.30 (⫺0.43 to ⫺0.17)
1500 CD4⫹ cells, ⫺0.27 (⫺0.37 to ⫺0.16)
—
!.05
!.005
!.005
Frozen heparinized plasma
Roche Amplicor
⫺0.33 (⫺0.68 to 0.02)
Frozen heparinized plasma
Roche Amplicor
At seroconversion, ⫺0.78 (⫺1.21 to ⫺0.35)
!.001
Frozen heparinized and EDTAtreated plasma
Roche Amplicor
At seroconversion, ⫺0.5 (⫺0.79 to ⫺0.21)
!.001
women over time). All of the studies that we reviewed were
required to report viral load differences between men and
women with some attempt to control for stage of HIV infection.
Nine cross-sectional [23–30, 35] and 4 longitudinal [31–34]
studies met inclusion criteria. The following information was
abstracted from each article: study design and year, sample size,
CD4⫹ cell counts (ranges or median values), storage and assay
conditions for HIV RNA measurements, covariates analyzed,
and estimates of the difference (with 95% CIs) in log10 viral
load measurements between the groups of men and women
being compared. The 95% confidence intervals (95% CIs) were
calculated from reported P values, when necessary. For studies
that reported only median values and Mann-Whitney P values,
the difference in mean log10 viral load was assumed to equal
the difference in median log10 viral load, and it was assumed
that a t test comparing the means would produce the same P
value. These assumptions would hold if log10 viral loads were
normally distributed [36].
.065
RESULTS
The 13 studies provided data on 6702 men and 3894 women
with HIV infection. Table 1 summarizes the relevant features
and findings of these reports. Figure 1 shows the key mean
log10 viral load differences with 95% CIs.
Multiple factors influence the viral load, including genetic
traits [38, 39], age [37, 40], race [26], CD4 cell count [41],
immunologic activation [42, 43], antiretroviral use, concurrent
illnesses and recent immunizations [44–46], active injection
drug use [47–49], HIV subtype [50–52], and presence of syncytium-inducing virus [53, 54]. Some of these factors are associated with the patient’s sex and function as confounding
variables in the relationship between sex and viral load. Table
2 shows confounding variables adjusted for in each study. None
of the studies provided data on recent vaccinations or HIV
subtype. Variability in HIV quantification methods (listed in
Table 1) may also bias study outcomes; differences in specimen
HIV/AIDS • CID 2002:35 (1 August) • 315
Figure 1. Estimated differences in mean log10 HIV RNA levels between women and men, with 95% CIs. Studies are shown in ascending order of
median CD4 cell count, with multiple strata indicated in parentheses for [26] (I–IV) and [30] (I–VI). Two different groups of subjects are shown for
[25]: subjects with heterosexual transmission (H) and injection drug users (IDU). *Assumes differences in mean log10 HIV RNA levels would equal
reported difference in median log10 HIV RNA levels, and t test P value would equal reported Mann-Whitney P value.
type, storage anticoagulant, freezing duration [55], and interassay variability (table 3) [56–58] can all contribute to variation
in viral loads.
Cross-sectional studies. The stage of HIV infection is a
major confounding variable in the comparison of viral loads
between men and women. Because the majority of HIV-infected
women have acquired HIV more recently than the majority of
HIV-infected men on a population basis [59–61], lower viral
loads in women could be a result of later seroconversion dates
[62, 63]. The 9 cross-sectional studies were limited to the assessment of viral load measurements at a single point in time
from seroprevalent cohorts, with little available information
regarding the duration between seroconversion and observation. Although one study [28] was able to adjust for years since
seroconversion (albeit within 24 months), the remainder used
CD4 cell count as the sole marker for stage of HIV infection
in the 2 groups.
One study controlled for CD4 cell count in the design phase
by individually matching men and women according to CD4
levels [29]. Six studies controlled for CD4 cell count in the
316 • CID 2002:35 (1 August) • HIV/AIDS
analytic phase (of which 2 stratified patients according to the
range of CD4 cell count [26, 30] and 4 adjusted for CD4 levels
in multivariate regression models [24, 27, 28, 35]). The final 2
studies [23, 25] compared baseline CD4 cell counts among men
and women and indicated that no such control was necessary.
Although one [23] of these 2 latter studies verified that there
was a relatively precise correspondence between baseline CD4
concentrations in the 2 groups (mean value SE: men,
343 6 cells/mL; women, 346 14 cells/mL), the women in
the second report [25] had higher CD4 cell counts than did
the men (20 cells/mL higher among injection drug using women
and 47 cells/mL higher among the heterosexually infected
women). Of note, all but one of the cross-sectional investigations [35] studied patients in a relatively early stage of HIV
infection, with median CD4⫹ cell counts ranging from 1200
to 1750 cells/mL (Table 1).
Seven of the 9 studies showed lower HIV RNA levels in
women than in men, with mean differences ranging from 0.13
to 0.35 log10 copies (1.35- to 2.2-fold). Six of these differences
had P values of !.05. One study [35] found that viral loads in
Table 2.
Covariates controlled for in studies investigating the relationship between sex and viral loads.
Age
CD4⫹
cell count
Antiretroviral
therapy
Time since
seroconversion
Mode of
transmission
Active
symptoms
Active
IDU
Race
1996 [29]
⫹
⫹
⫺
⫺
⫺
⫺
⫺
⫺
1996 [23]
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
Study design, year
[reference]
Cross-sectional
a
1998 [24]
⫺
⫹
⫺
⫹
⫹
⫹
⫹
1999 [30]
⫺
⫺
⫹
⫺
⫹
⫺
⫺
⫹
1999 [25]
⫺
⫹
⫺
⫹
⫺
⫺
⫺
1999 [27]
⫹
⫹
⫹
⫺
⫹
⫺
⫺
⫹
2000 [28]
⫹
⫹
⫹
⫹
⫹
⫺
⫺
⫹
2000 [26]
⫺
⫹
⫺
⫺
⫹
⫺
⫹
⫹
2000 [35]
⫹
⫹
⫺
⫺
⫹
⫺
⫺
⫹
1997 [33]
⫹
⫹
⫺
c
⫺
⫺
⫺
⫹
1999 [31]
⫺
⫹
⫺
⫹
⫺
⫺
⫺
⫺
1999 [32]
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫹
2001 [34]
⫹
⫹
⫹
⫹
⫹
⫺
⫺
⫹
b
Longitudinal
NOTE.
a
b
c
IDU, injection drug use; ⫹, covariate was controlled for; ⫺, covariate was not controlled for.
Adjusted only for use of zidovudine, although other antiretrovirals were becoming available.
Adjusted only for combination therapy, not monotherapy.
See text for details.
women were higher by a mean of 0.13 log10 copies, but the
95% CI included the possibility that the mean viral load was
0.11 log10 copies lower in women; this study included patients
in a significantly more advanced stage of illness than the others
(median CD4 cell count, 14 cells/mL). The final study [30]
controlled for differences in CD4 cell counts among men and
women by dividing them into 6 CD4 cell count strata (1750,
500–750, 350–500, 200–350, 100–200, and !100 cells/mL); univariate analysis revealed that the mean viral load differences in
the groups were minimal (range, 0.11–0.05 log10 copies), although the 95% CIs indicated the possibility that women had
mean log10 viral loads that were 0.3 lower than those for men
in all CD4⫹ cell count strata 1200 cells/mL (figure 1). However,
this univariate analysis failed to control for antiretroviral use,
despite the fact that 18% of patients were receiving ART. Multivariate regression analysis that adjusted for combination ART
resulted in “no significant interactions between sex and HIV
type 1 (HIV-1) load for any of the CD4 ranges” [30, p. 464];
this analysis controlled for differences in CD4 cell counts by
dividing the subjects into broader strata (1750, 500–750,
200–499, !200 cells/mL) than those used in the univariate
analysis.
CD4 cell counts serve as imperfect gauges of HIV disease
progression, and they differ according to sex. CD4 levels are
reported to be 75–100 cells/mm3 higher among HIV-uninfected
women than they are among HIV-uninfected men [64]; sexbased differences in CD4 counts have also been reported among
HIV-infected adults up to 5 years after seroconversion [65, 66].
Because HIV-infected women develop and die of AIDS at higher
CD4 cell counts than do men [37, 67], these higher CD4 levels
do not appear to have great functional significance. The use of
CD4 cell counts to adjust for disease progression would bias
results toward higher viral loads in women, who would have
more-advanced HIV infection than would men at the same
CD4 concentrations. Some of the studies even adjusted analyses
for sex differences in CD4 cell counts, and these adjustments
did not eliminate—and, in some cases [26], even increased—sex-based differences in HIV RNA levels. Therefore,
either this expected sampling bias is not significant, or the
association between female sex and lower viral load is strong
enough to outweigh the potential bias. In fact, one of the crossTable 3. SDs and lower limits of detection for standard HIV
RNA quantification assays used in studies investigating the relationship between sex and viral load.
HIV RNA quantification
assay (manufacturer)
SD, log10
NASBA Nuclisens (Organon)
0.15–0.23
Lower limit
of detection,
copies/mL
4000
Amplicor monitor (Roche)
0.20–0.24
400
National Genetics Institute
0.13
100
bDNA assay 1.0 (Chiron)
0.05–0.08
10,000
bDNA assay 2.0 (Chiron)
0.06–0.17
500
HIV/AIDS • CID 2002:35 (1 August) • 317
sectional studies [28] did measure time since seroconversion
and still found significantly lower viral loads for women.
With a single exception [29], the cross-sectional studies analyzed participants in prospective cohorts, for which specimen
sampling is usually performed over long time intervals. Thus,
some of these analyses [23, 24, 26] used thawed plasma specimens that were frozen and stored for months to years before
viral loads were determined. However, in all studies but one
[26], freezing conditions, anticoagulants, and RNA quantification procedures were similar between sex groups. Any variability in viral load measurements between sexes should thus
be randomly distributed and not bias the sex–viral load association. One study [26] compared viral loads in men and
women by use of 2 separate cohorts with disparate plasma
storage conditions and RNA quantitation assays. The authors
attempted adjustment for these disparities by use of a translation formula to standardize the 2 cohorts’ HIV RNA assay
results to a third method. Although different quantitation techniques could result in an apparent difference in median viral
load between sexes, the use of serum samples that were stored
longer before analysis in the men’s cohort (Multicenter AIDS
Cohort Study) would have favored artifactually lower HIV RNA
values for the men, contrary to observation.
Longitudinal studies. Because CD4 cell count serves as a
limited surrogate for disease stage, longitudinal studies allow
comparisons between sex groups while controlling for duration
of infection. Four of the studies [31–34] were longitudinal in
design (i.e., serial viral load measurements were compared over
time between sexes). These studies involved cohorts of patients
at high risk of acquiring HIV infection, among whom observation began prior to seroconversion. The date of HIV infection
for each subject could be determined within a time period
between the last visit at which the subject was HIV seronegative
and the first at which the subject was HIV seropositive. All 4
studies used consistent specimen processing techniques and
HIV quantification assays.
One study followed a prospective cohort of HIV-infected Air
Force members and compared viral load measurements at 3
time points over ∼4 years [33]. At study entry (median CD4
cell count, 700 cells/mL), median HIV RNA levels were 0.52
log10 (3.3 times) lower in women than in men (P p .04); at
the second time point (median CD4 cell count, 500 cells/mL),
levels were 0.69 log10 (4.9 times) lower in women (P p .03);
at the third time point (median CD4 cell count, 400 cells/mL),
levels were 0.2 log10 (1.5 times) lower in women (P p .11).
None of the subjects were taking therapy for HIV infection at
study entry. Time from seroconversion to study entry was, on
average, 3 months shorter for the women than for the men.
The second study found women to have mean viral loads
that were 0.33 log10 (2.13-fold) lower than those for men
temporally proximate to seroconversion (P p .065 ) [31]. This
318 • CID 2002:35 (1 August) • HIV/AIDS
comparison was adjusted for CD4 cell count, age, time since
seroconversion, and injection drug use, but not for receipt of
ART (although 60% of participants received treatment at
some point during study follow-up). An analysis of viral loads
a median of 3.5 years after seroconversion (and up to 11.3
years after seroconversion) revealed that women had 0.52 log10
(3.3-fold) lower viral loads than did men (P p .012), an estimate unadjusted for CD4 cell count, age, transmission
mode, or ART use.
Finally, Sterling et al. [32, 34] performed 2 analyses using 2
different subsets of men and women from the AIDS Linked to
the Intravenous Experience (ALIVE) cohort [32, 34], a longitudinal study of injection drug users with or without HIV
infection [68]. Because ∼95% of participants of both sexes were
African American, race was not a confounding variable in the
2 studies. Date of seroconversion was known to within !12
months for all participants. In the first report [32], a multiple
regression analysis that adjusted for time since seroconversion
and CD4 cell count revealed that the mean viral load for women
was 0.78 log10 (6.0-fold) lower than for men (P ! .001). This
difference in mean value decreased by 0.16 log10 for each year
following seroconversion (P p .002 ), with the viral load trajectories of men and women crossing 5.8 years after infection.
Therefore, the rate of viral load increase over time in the 6
years after seroconversion was greater for women than for men,
as women began with lower HIV RNA levels.
In the second report by Sterling et al. [34], none of the
participants reported receipt of ART at the study visit after
seroconversion. After adjustment for age, CD4 cell count at
seroconversion, and time between estimated seroconversion
date and the first viral load measurement, the initial median
viral load was 0.5 log10 (3.16 times) lower for women than it
was for men (P p .001). Multivariate proportional hazards
models stratified by sex and controlling for initial CD4 cell
count and age showed no significant difference between men
and women in the risk of progression to AIDS in ∼5 years of
follow-up, despite women starting with lower HIV RNA loads.
Thus, although the relative viral load has a similar predictive
value for progression to AIDS for men and women, the same
absolute viral load seems to confer disparate risks for AIDS
between the sexes.
Differences in access to health care between men and women
could result in healthier outcomes and lower viral loads in one
population over another. However, most of the 13 studies enrolled participants from longitudinal cohorts (Table 1), which
provide some routine health care. Even if health care access
differed according to sex, the expected bias would result in
lower viral loads in men, secondary to more-frequent ART use
among men than women at similar stages of infection [11].
Although most of the studies did not show lower viral loads
in men, this access bias may have played a role in the 3 cross-
sectional studies [29, 30, 35] that showed no sex differential.
Finally, although several studies [29, 32, 33] in this review and
others [69] evaluated relatively small samples of men and
women, an association between female sex and lower viral load
at higher CD4 cell count was still observed.
DISCUSSION
The majority of the studies in this review demonstrate that
women have lower numbers of circulating HIV RNA copies
than do men, particularly before marked CD4 cell depletion.
Of the 3 studies that found no sex-based difference in the levels
of viremia, one was a study of participants in an advanced stage
of HIV infection [35]; one showed a trend toward lower viral
loads in women, despite wide confidence intervals [29] (figure
1); and one included the possibility of women having lower
viral loads than men at higher CD4⫹ cell counts [30]. Because
HIV-infected women tend to progress to AIDS and death in a
time course similar to that for men [4, 7], women apparently
progress to these end points with initially lower viral loads. This
finding could have implications for the timing of ART initiation
[24, 26, 28, 32]. One study [34] calculated that only 37% of
their female participants (compared with 74% of male participants) would have qualified for ART at the visit following
seroconversion (P ! .001), despite having similar risks of disease
progression. Because women may achieve virological suppression with antiretroviral therapy more quickly than men, and
because women may sustain more-durable responses [70], initiating treatment at an appropriate point in the infection trajectory is critical.
A recent Institute of Medicine report called Exploring the
Biological Contributions to Human Health: Does Sex Matter? [71]
emphasizes the impact of sex differences on disease from the
cellular to the societal level. Because manifestations of HIV
infection stem from the interplay between viral and host factors,
sex differences in immune modulation will likely play instrumental roles in determining the course of disease. Many examples of differential responses to infections in males and females exist, as do models of the effects of sex steroids on the
immune system, providing a basis for understanding sex-based
differences in HIV infection.
For example, women are more likely than men to achieve
undetectable serum levels of hepatitis C and G RNA, perhaps
because of differences in virus clearance [72–74]. Serological
responses to hepatitis B [75, 76], hepatitis A [77], and measles
[78] vaccinations are more vigorous in women than they are
in men. Human T-lymphotropic virus type 1–infected women
are more likely than men to retain cell-mediated immune responses to Mycobacterium tuberculosis [79]. Sex steroids can
demonstrably influence susceptibility to a range of pathogens:
the susceptibility of lower genital tract tissues to Chlamydia
trachomatis [80, 81] and simian immunodeficiency virus [82]
infection is enhanced after progesterone administration, and
the increased susceptibility of pregnant women to coccidioidomycosis [83, 84] is thought to result from hormone-related
impairment in cell-mediated immunity.
Because estrogen and progesterone levels fluctuate in ovulating females, effects on immune function may vary during
the ovulatory cycle [85, 86]. In terms of HIV replication, viral
loads in women do in fact vary with the ovulatory cycle, with
HIV RNA levels decreasing a median of 0.16 log10 from the
early follicular to the midluteal phase [87]. Possible hormonal
mechanisms include the estrogen-mediated down-regulation of
TNF-a [88], an inflammatory mediator that directly affects
HIV-1 expression [89]. Furthermore, human lymphocytes express a glucocorticoid receptor with a distinct progesteronebinding domain, with progesterone exerting a dose-dependent
inhibitory effect on C-chemokine receptor 5 (CCR5) expression
on activated T cells [90]. CCR5 density is significantly lower
on the CD4 cells of women than of men [91], and studies
involving male-to-female transsexuals have shown that there is
a decrease in CCR5 expression with administration of female
hormones [92]. A strong correlation between HIV load and
CD4⫹ lymphocyte CCR5 density was recently reported [38].
Therefore, lower CCR5 density on the CD4 cells of women
could explain the lower viral loads. However, why women proceed to the clinical end points of AIDS and death as quickly
as men, despite having lower levels of viremia, remains
unexplained.
HIV-infected female infants (age, !18 months) have recently
been reported to have lower viral loads (mean difference, 0.4
log10; 95% CI, 0.2–0.7) than male infants, despite comparable
courses of disease [93]; a longitudinal analysis [94] showed that
girls had HIV RNA levels that were up to 0.5 log10 lower than
levels in boys aged 4–15 years. Because sex steroid levels vary
by sex in infants [95] and children [96], lower viral loads in
girls may involve some of the same hormonal mechanisms
implicated in adults.
This review demonstrates that there is a consistent association between female sex and lower HIV RNA level. Given that
women and men progress to AIDS and death at similar rates,
the rate of increase in viral load over time is presumably greater
for women. The possibility of initiating ART at lower viral loads
in women, especially during the early stages of infection, merits
further study. Studies on viral dynamics and lymphocyte turnover in women during all phases of the ovulatory cycle and
periods of hormonal flux (e.g., menopause) should be undertaken. Studies of HIV infection, course, treatment indication,
and prognosis should include sufficient numbers of women, so
that sexual dimorphisms in disease expression can be identified
and investigated. Given the potential implications of this review’s findings on the management of HIV infection in women,
HIV/AIDS • CID 2002:35 (1 August) • 319
the Institute of Medicine’s [71] conclusion that the patient’s
“sex really does matter” should inform research design on HIV
pathogenesis and clinical care.
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