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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. 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