At enrollment, HIV-1–infected partners were primarily female (67%) and their median age was 32 years (interquartile range [IQR], 26–38 years); 34% of HIV-1–infected males were circumcised (). The median plasma HIV-1 RNA concentration at enrollment was 3.91 log10 copies/mL (IQR, 3.16–4.53 log10 copies/mL). HIV-1–uninfected partners were slightly older (median, 33 [IQR, 28–40]), 68% were HSV-2 seropositive, and 55% of men were circumcised. HIV-1–infected partners had genital herpes recurrences (genital ulcer disease [GUD]) on exam or self-reported symptoms in the prior interval) at 9.2% of quarterly follow-up visits and HIV-1–uninfected partners had GUD on exam or by self-report at 5.2% of quarterly follow-up visits.
Characteristics of the 3297 Couples
The median number of unprotected and protected acts over the preceding 30 days, as reported by the HIV-1–infected partners at enrollment, was 0 (IQR, 0–1) and 3 (IQR, 1–5), respectively. Over follow-up, the median rate of unprotected and protected acts per 30 days, as reported by the HIV-1–infected partners, was 0 (IQR, 0–0) and 3.3 (IQR, 1.8–5.9), respectively, and 93% of sex acts were reported as protected. The median total number of sex acts per 30 days declined steadily from 4.0 at enrollment to 2.5 by month 24.
Overall, 86 linked transmission events were observed during follow-up. shows the relationship between total number of reported acts within a testing interval and the HIV-1 test result at the end of that interval. There were 3 transmissions (3.5%) in which the HIV-1–infected partner reported 0 acts in the interval immediately prior to a linked infection (although in 1 of these cases, the report only covered a portion of the interval). In none of these cases did the HIV-1–uninfected partner report sex acts with anyone other than their study partner. These 3 transmissions cannot be included in estimates of infectivity as they lead to an infinite likelihood in the statistical analysis.
Total Number of Acts (With and Without a Condom) and Transmissions, by Gender of the HIV-1–Infected Partner, Within Testing Intervals
In a model that included only condom use and gender, the estimated risks of unprotected MTF and FTM transmission were 0.0019 (95% CI, .0010–.0037) and 0.0010 (95% CI, .00060–.0017), respectively (relative risk [RR] = 1.95; P = .003). However, after adjustment for plasma HIV-1 RNA and HSV-2 status and age of the uninfected partner (all of which differed significantly depending on the gender of the HIV-1–infected partner), the RR for MTF transmission was attenuated to 1.03 (P = .93), suggesting that the higher risk of MTF transmission was largely due to higher viral loads in men (over follow-up, mean viral load measurement in men = 4.1 log10 copies/mL; in women = 3.8 log10 copies/mL) and other sources of confounding.
Log10 plasma HIV-1 RNA was entered linearly into model (2). A more complex functional form using cubic splines did not significantly improve the fit (P = .2, comparing the linear model to the spline model). shows the relationship between infectivity and log10 plasma HIV-1 RNA in a model that includes plasma HIV-1 RNA and reported condom use only. Each log10 increase in plasma HIV-1 RNA increases the per-act risk of transmission by a factor of 2.89 so that the estimated per act risk of transmission without a condom at 3, 4, 5, and 6 logs is 0.00028, 0.00082, 0.0024, and 0.0068, respectively.
Figure 1. Per-act probability of transmission (infectivity) vs log10 plasma HIV-1 RNA (copies/mL) from a model that includes plasma human immunodeficiency virus type 1 RNA and condom use only. Solid line is without reported condom use and dashed line is with reported (more ...)
shows the RR, overall and by gender, for characteristics of the HIV-1–infected and HIV-1–uninfected partner in univariate analyses. In a multivariate model (), plasma HIV-1 RNA and condom use reported by the HIV-1–infected partner and age, HSV-2 serostatus, GUD by exam or self-report, T. vaginalis (at enrollment), cervicitis or vaginitis (during follow-up), and male circumcision status of the HIV-1–uninfected partner remained significant. Circumcision in male HIV-1–uninfected partners was associated with significantly lower infectivity (RR, 0.53 [95% CI, .29–.96]), and infectivity also declined as the age of the HIV-1–uninfected partner increased (RR, 0.82 per 5-year increase [95% CI, .71–.94]). We found similar results when the age of the HIV-1–infected partner was substituted for that of the uninfected partner in the model. Condom use reduced infectivity by 78% (RR, 0.22 [95% CI, .11–.42]). However, 56 linked transmissions occurred in intervals in which all acts were reported to be protected. The protective effects of reported condom use was similar regardless of whether the HIV-1–infected partner was male (RR, 0.14) or female (RR, 0.29) (P value for gender by condom interaction = 0.29). HSV-2 seropositivity (RR, 2.14; [95% CI, 1.18–3.88]), GUD by exam or self-report (RR, 2.65 [95% CI, 1.35–5.19]), T. vaginalis infection at enrollment (RR, 2.57 [95% CI, 1.42–4.65]) and a clinical diagnosis of vaginitis or cervicitis during follow-up (RR, 3.63 [95% CI, 1.47–8.92]) in the HIV-1–uninfected partner were independently associated with an elevated per-act risk of transmission. Characteristics of the HIV-1–infected partner (including recurrent genital herpes by exam or self-report, T. vaginalis positivity, antiretroviral agent use, and circumcision status), presence of other curable STI (C. trachomatis, T. pallidum) in either partner, urethritis in male partners, partnership duration, and time on study were not significant in the multivariate analysis (P > .20).
Relative Risks for Various Risk Factors in Univariate Analyses
Relative Risks in Per-Act Probability of HIV-1 Transmission
We also found evidence of additional unexplained heterogeneity in infectivity—the addition of a random effect for infectivity significantly improved the fit (P = .005; data not shown). This suggests that there are unmeasured viral, host, or behavioral factors that induce additional variation in infectivity among couples; inaccurate reporting of the number of acts and condom use may also contribute to unexplained heterogeneity.