Baseline characteristics of female and male study participants are shown in . Women constituted 124 (5.4%) of 2277 HIV seroconverters. No significant sex differences existed in the proportion of subjects identified as acutely or recently infected. The majority of men (77%) were white, whereas the majority of women (55%) were nonwhite. Women were younger and more likely to report intravenous drug use (IDU) and heterosexual contact as risk factors compared to men. The majority of subjects were recruited from North America, particularly the western United States. Almost half (45%) of nonwhite women, however, were recruited from the southern United States (also referred to herein as the South), and 79% of women recruited from the South were nonwhite. There were no sex differences in mean follow-up time.
Baseline Demographic and Clinical Characteristics
Baseline viral load was lower in women than in men (). A linear model was used to evaluate other factors that affect viral load. Viral load was higher by .07 log10 copies/mL (95% confidence interval [CI], .02–.12) per decade of life (P = .008), and higher in white, non-Hispanic individuals compared with all other races (.53 log10 copies/mL; 95% CI, .20–.86; P = .002). After adjusting for age and race, women had a lower viral load than men (mean difference .40 log10 copies/mL; 95% CI: .19–.60; P= .001) ().
Figure 1. Linear model of baseline human immunodeficiency virus (HIV) RNA concentration (A) and CD4+ T cell count (B) as a function of age, race, and sex. Viral load was lower (P < .001) and CD4+ T cell count was higher (P = .005) in women than in men. (more ...)
Women had higher baseline CD4+ T lymphocyte counts than men (). A linear model that included age and race was used to further evaluate baseline CD4+ T cell counts (). White, non-Hispanic individuals had higher CD4+ T cell counts (106 cells/μL; 95% CI, 32–180) than all other groups (P = .005), but no statistically significant differences were seen with increasing age (slope, −.32; 95% CI, −1.5 to .86; P = .6). After adjusting for age and race, women had more CD4+ T cells than men (mean difference, 66 cells/μL; 95% CI: 19–112; P = .006).
Frequently reported symptoms of acute retroviral syndrome included fever (78%), fatigue (72%), myalgia (57%), headache (50%), and pharyngitis (46%). Fewer women (62%) reported fatigue compared with men (73%, P = .02), but no sex differences were evident for other symptoms associated with primary infection. Higher viral load (difference, 1 log10 copy/mL) was predictive of 2 or more symptoms (odds ratio [OR], 1.46; 95% CI, 1.27–1.68; P < .001). Compared with individuals with a history of IDU, those without a history of IDU were more likely to present with 2 or more symptoms (OR, 3.62; 95% CI, 2.11–6.03; P < .001). Women were less likely than men to report 2 or more of the 6 most common symptoms (OR, .40; 95% CI, .24–.66; P < .001), but there were no differences in symptoms between nonwhites and whites (OR, .94; 95% CI, .63–1.38; P = .73). After controlling for baseline viral load, race, and IDU, women were still less likely to report 2 or more symptoms compared with men (OR, .48; 95% CI, .28–.84; P = .008).
ART was started by 79 (63.7%) women and 1475 (68.5%; P
= .28) men at some time during the study period. Many of the centers that participated in the AIEDRP database were conducting studies of ART in early HIV infection. Reasons for starting ART were not recorded in the database. Among subjects for whom clinical data were available near the time of treatment initiation (samples were collected an average of 9 days before treatment initiation), mean CD4+
T cells counts were similar in women (514 cells/μL; Standard Error [SE], 32; n
= 64) and men (476 cells/μL; SE, 6; n
= 1296; P
= .19), but mean viral load was lower in women (4.7 log10
copies/mL; SE, .11; n
= 70) than in men (5.0 log10
copies/mL; SE, .02; n
= 1370; P
= .002). Using the Kaplan-Meier method, we found that women were less likely to initiate ART at any time point (median, 271 d; 95% CI, 79–484) than men (median, 69 d; 95% CI, 57–89), although this difference was not statistically significant (P
= .09). Acutely infected subjects initiated ART earlier (median, 16 d) than recently infected subjects (median, 191 d; P
< .001). To adjust for this and other factors that influence time to ART initiation, a Cox proportional hazards model was used. This model stratified subjects by acute and recent infection and baseline CD4+
T cell count of <500 cells/μL and adjusted for baseline age, IDU, and time-varying: viral load, CD4+
T cell count, and CD4+
T cell count of ≤200 cells/μL before July 2004 or CD4+
T cell count of ≤350 cells/μL after July 2004 to account for changes in guidelines [16
] for initiation of ART. Compared with white men, white women were more likely to initiate ART, and nonwhite men and women were less likely to start ART at any time point ( and ). Compared with subjects from the South, subjects from other regions were more likely to initiate treatment (Hazard Ratio [HR], 1.26, 95% CI, 1.0–1.57; P
= .047). In a model evaluating race as an interactive effect with region, racial differences in time to initiation of ART persisted in other regions, but not in the South ().
Figure 2. Extended Cox proportional hazards model of time to initiation of antiretroviral therapy (ART) in acute (A) and recent (B) human immunodeficiency virus (HIV) infection. All race sex pairwise comparisons are statistically significant (P < .04) except (more ...)
Proportional Hazards Models for Time to Antiretroviral Therapy Initiation by Race and Sex and by Race Within Region
Similar percentages of women (77%) and men (81%) achieved a viral load of <400 copies/mL (P > .5) after 6 months of ART. After adjusting for CD4+ T cell count and viral load at the beginning of treatment, age, race, and IDU, no sex differences were detected in the probability of viral load of <400 copies/mL (OR, .90; 95% CI, .48–1.68; P = .73). A trend toward lower CD4+ T cell gains was seen during the first 6 months of ART in women (mean increase, 124 cells/μL; n = 33; 95% CI, 11–237) compared with men (mean increase, 206 cells/μL; n = 847; 95% CI, 190–222; P = .06). After adjustment for CD4+ T cell count and viral load at treatment initiation, race, and acute/recent infection status, no sex differences in CD4+ T cell reconstitution were detected (difference, 7 cells/μL; standard deviation, 31; P = .83).
Longitudinal viral load and CD4+ T cell counts were analyzed using a time-varying mixed effects model adjusting for age and race in individuals remaining off therapy for up to 3 years. Lower viral loads in women compared with men persisted through week 24 (viral load, .20 log10 copies/mL; 95% CI, .03–.36; P = .02), but by week 104, untreated women had higher viral loads compared with men (viral load, .24 log10 copies/mL; 95% CI, .07–.41; P < .01). Sex differences in CD4+ T cell counts persisted through week 24 with women having higher CD4+ T cell counts than men at that time (difference, 80 cells/μL; 95% CI, 43–117; P < .001). At subsequent time points, however, CD4+ T cell counts in treatment-naïve women and men were no longer significantly different.
Mortality in the cohort was low and did not differ between the sexes; 16 (.7%) deaths occurred in men, of which 2 (.1%) were attributed to HIV infection, and 1 (.8%) death that was not HIV-related occurred in a woman (P = .92). Similar proportions of women and men had at least one CD4+ T cell count of <200 cells/μL (P = .06; rate at 8 years, 16.5% and 25.3%, respectively). However, when evaluated by sex-race categories, a higher proportion of nonwhite women (40%; 95% CI, 25%–59%) had at least one CD4+ T cell count of <200 cells/μL compared with nonwhite men (20%; 95% CI, 14%–30%), white men (15%; 95% CI, 12%–20%), and white women (4.7%; 95% CI, 1.6%–14%; P < .001).
In an unadjusted time-to-event analysis, the occurrence of at least one non-AIDS HIV-related illness was higher in women (46%) compared with men (21%; P < .001) (), and this difference persisted when female-specific events were removed from the analysis (39%; P < .001). Women reported persistent generalized lymphadenopathy, diarrhea (otherwise undiagnosed), and peripheral neuropathy more often than men. Frequency of total AIDS-defining illnesses did not differ between the sexes, but women had higher rates of recurrent bacterial pneumonia and Candida esophagitis. Women had 2.17 times more combined HIV-related and AIDS-defining diseases per person than did men after adjusting for follow-up time (P < .001), and this difference remained after removing female-specific events and controlling for IDU (1.68 times more events per woman; P < .001). In an analysis of morbidity by sex and race, nonwhite women experienced more HIV-related and AIDS-defining illnesses than all other groups (). At 8 years’ follow-up, HIV-related events occurred in 64% (95% CI, 45%–83%) of nonwhite women and 21% (95% CI, 18%–24%) of other groups combined, and AIDS-defining events occurred in 22% (95% CI, 8%–50%) and 6% (95% CI, 4%–9%), respectively. IDU was associated with higher combined HIV- and AIDS-related diseases (36%; 95% CI, 23%–54%) compared to no IDU (25%; 95% CI, 21%–29%; P = .001). To further assess reasons for elevated morbidity in nonwhite women, relationships among sex and race and time to HIV- and AIDS-related illnesses were analyzed in a proportional hazards model censoring at time of ART initiation and stratified by IDU. Hazard ratios were reduced by 10%–20% compared to a sensitivity analysis that did not utilize stratification or censoring, but substantial unexplained morbidity in nonwhite women remained ().
Kaplan-Meier Failure Percentages for HIV-Related and AIDS-Defining Illnesses by Sex at 75th Percentile (8 Years) of Overall Follow-up
Figure 3. Kaplan-Meier curves for time to human immunodeficiency virus (HIV)–related (A) and AIDS-defining events (B) by sex and race, and time to HIV-related and AIDS-defining events by region (C). Nonwhite women were more likely to experience > (more ...)
Proportional Hazards Models for Time to HIV-Related and AIDS-Defining Illnesses by Race and Sex
Region of recruitment combined with race was strongly associated with HIV-related morbidity (). Approximately 8 years after diagnosis of acute or recent HIV infection, nonwhites from the South experienced the highest rate of at least 1 HIV- or AIDS-related event, (78%; 95% CI, 64%–89%) compared with whites from the South (37%; 95% CI, 26%–49%; P < .001), whites from other regions (24%; 95% CI, 19%–28%; P < .001), and nonwhites from other regions (17%; 95% CI, 12%–25%; P < .001). Whites from the South also experienced higher rates of events than did whites (P < .001) and nonwhites (P < .001) from other combined regions. Among whites, women had more morbidity than did men in the South (36% vs 22%; P = .006) and in other regions (21% vs 14%; P < .001). Similar to whites, nonwhite women had higher rates of events than men by region, (South, 81% vs 63%, p=1.0; other regions, 16% vs 12%, p=.19), but these differences did not reach statistical significance.