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Does Patient Gender Affect Human Immunodeficiency Virus Levels?
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Monica Gandhi,1 Peter Bacchetti,1 Paolo Miotti,2 Thomas C. Quinn,3,4 Fulvia Veronese,2 and Ruth M. Greenblatt1
1Department 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
Clinical Infectious Diseases 2002;35:313-322
Received 4 December 2001; revised 20 February 2002; electronically published 2 July 2002.
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 cross-sectional 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.
Commentary by Jules Levin: study trends suggest that viral load among women appear to be significantly lower than for men following serocenversion but after about 5 years the difference between men and women disappears; t appears that viral load in women increases more quickly.
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 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 found that male sex appeared to confer a survival benefit in AIDS, later studies, which controlled for access to care, antiretroviral use, and disease stage, found similar rates of progression and survival for both sexes. Several studies have reported that men and women differ in access to HIV care, with women being less likely to receive prophylaxis for opportunistic infections or to start appropriate antiretroviral therapy (ART) (even in a single-clinic setting). Given the clear survival benefit with current HIV therapeutics, differential use of antiretrovirals for purely societal reasons may lead to survival disadvantages for women.
In terms of the biological rationale for differential, sex-based HIV therapeutics, current recommendations for initiating ART 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, direct timing of ART, and assess of therapeutic efficacy. Subsequent studies have examined differences in the prognostic marker of viral load among men and women. Even after adjustment for CD4 cell count or time since seroconversion, some reports indicate that viral loads are lower in women than in men, whereas other reports show no significant differences by sex or a differential that wanes with advancement in HIV disease. Infected women appear to progress to AIDS and death at rates similar to those for men, despite initially having lower viral loads, leading some authors to suggest that initiating ART should include consideration of the patient's sex. 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 >350 cells/mm3" [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.
We searched the MEDLINE database for studies from 19952000 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 19901994, 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 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 and 4 longitudinal studies met inclusion criteria.
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, lower viral loads in women could be a result of later seroconversion dates. 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 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.
RESULTS
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). (editorial comment by Jules Levin: the article did not say how long these women had HIV. It has been observed that viral load is lower for several years after seroconversion, perhaps up to 5, but then becomes equal to that for men. Trends reported below suggest that for many female seroconverters viral load appears significantly lower compared to men but oftentimes the difference equalizes after about 5 years.
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.
One study followed a prospective cohort of HIV-infected Air Force members and compared viral load measurements at 3 time points over 4 years. At study entry (median CD4 cell count, 700 cells/L), median HIV RNA levels were 0.52 log10 (3.3 times) lower in women than in men (P = .04); at the second time point (median CD4 cell count, 500 cells/L), levels were 0.69 log10 (4.9 times) lower in women (P = .03); at the third time point (median CD4 cell count, 400 cells/L), levels were 0.2 log10 (1.5 times) lower in women (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 = .065). This 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 = .012), an estimate unadjusted for CD4 cell count, age, transmission mode, or ART use.
Finally, Sterling et al. performed 2 analyses using 2 different subsets of men and women from the AIDS Linked to the Intravenous Experience (ALIVE) cohort, a longitudinal study of injection drug users with or without HIV infection. 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, 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 = .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., 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 = .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.
One study 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, initiating treatment at an appropriate point in the infection trajectory is critical.
The authors conclude that 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.
Sterling study report on recent seroconverters from Durban
www.natap.org/2000/oct/summer2000_newsletter/when_to_begin_101800.htm
In the Sterling study reported above, he says:
"...study was performed among HIV-1 seroconverters within a cohort of injection drug users ... from the AIDS Linked to the Intravenous Experience (ALIVE) study group. the increase in VL over time among female patients was significantly greater than the increase among male patients (0.24 log VL/year for women vs. 0.003 log VL/year for men; P = .002). Thus, despite a significantly lower median VL after seroconversion in women, median viral loads were equivalent in both women and men within 5 years after seroconversion. The rate of increase in VL over time was also greater in female than in male controls (0.087 log VL/year for women vs. -0.057 log VL/year for men; P = .04); VL trajectories of female and male controls tended to converge within 7 years after seroconversion.
The mechanism underlying the sex difference in plasma virus load is unknown, but there are several possible hypotheses. Hormonal differences could be responsible. Estrogen down-regulates expression of tumor necrosis factor, which in turn directly affects HIV-1 expression. The more pronounced cell-mediated and humoral immune response in women, which is possibly hormone related, could affect the cytotoxic T cell response, which appears to control HIV-1 replication and to slow disease progression. A second hypothesis relates to the rapid rate of CD4 cell turnover in HIV-1 infection. Sex differences in factors responsible for CD4 cell turnover (e.g., target cell infection, viral replication, and rate of CD4 cell killing) could result in less release of HIV-1 into plasma in women, resulting in lower VL but similar CD4 cell counts and similar time to AIDS. A third possible explanation could be that women are more likely to become HIV-infected through heterosexual exposure rather than via injection drug use and thus possibly receive a smaller inoculum of HIV-1. Women and men were equally likely to report recent injection drug use at the study visit prior to seroconversion, however, and it is unknown whether the inoculum via heterosexual transmission is smaller than that via injection drug use."
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