Study Participants

Figure 1. Figure 1. Enrollment and Outcomes. This trial profile describes recruitment of couples from the general population, randomization, HIV-1–uninfected partner's enrollment, seroconversion at baseline, retention, and loss-to-follow-up for assessment of the primary end point of linked HIV-1 transmission. Enrolled partners were followed on a quarterly-visit schedule, although attendance at semiannual visits is shown.

A total of 10,838 persons were screened in order to enroll 1763 HIV-1–serodiscordant couples; 886 couples were randomly assigned to the early-therapy group and 877 to the delayed-therapy group) (Figure 1, and the Supplementary Appendix). Twelve additional HIV-1–uninfected partners were enrolled as the result of a new relationship.

Table 1. Table 1. Baseline Characteristics of the Participants.

The majority of couples (97%) were heterosexual, and 94% were married; 50% of HIV-1–infected participants were men. The majority of participants (61%) were between 26 and 40 years of age. At enrollment, 1291 of HIV-1–infected participants (73%) and 1281 of HIV-1–uninfected partners (72%) reported having had at least one sexual encounter during the previous week. During the same period, 5% and 6%, respectively, reported having unprotected sex. The median CD4 counts for the HIV-1–infected partners were 442 cells per cubic millimeter in the early-therapy group and 428 cells per cubic millimeter in the delayed-therapy group. The median log 10 plasma viral load was 4.4 in each study group. Participants in the two study groups were similar in educational status, self-reported sexual behavior, and rate of condom use (Table 1).

At enrollment, less than 5% of participants had a sexually transmitted infection, and rates and types of infection were similar in the two study groups (see the Supplementary Appendix). A total of 84 of 449 HIV-uninfected male partners (19%) in the early-therapy group and 64 of 460 (14%) in the delayed-therapy group had been circumcised (P=0.05). New sexually transmitted infections were detected with similar frequency among participants in the early-therapy group and the delayed-therapy group during the study, with 36 and 34 syphilis infections, 6 and 8 gonorrhea infections, 10 and 11 chlamydia infections, and 22 and 19 trichomonas infections, respectively. Among HIV-1–infected participants, a mean of 96% of those in the early-therapy group and 95% of those in the delayed-therapy group reported 100% condom use during the study.

On April 28, 2011, the data and safety monitoring board recommended that the results of the study be released on the basis of data collection through February 21, 2011. At that time, 90% of couples remained enrolled in the study, with a median follow-up of 1.7 years; the total number of person-years of follow-up was 1585 in the early-therapy group and 1567 in the delayed-therapy group. The expected effect of early versus delayed antiretroviral therapy on log 10 plasma viral load and CD4 counts in the HIV-1–infected participants was observed shortly after enrollment. By 3 months after randomization, 89% of the participants in the early-therapy group had a plasma viral load of less than 400 copies per milliliter, as compared with 9% in the delayed-therapy group. CD4 counts in the early-therapy group rose after the initiation of antiretroviral therapy, from a median of 442 cells per cubic millimeter at enrollment to 603 cells per cubic millimeter by 12 months, and the counts continued to rise throughout the follow-up period (see the Supplementary Appendix). A modest decline in CD4 counts was observed in the delayed-therapy group, from a median of 428 cells per cubic millimeter at enrollment to 399 cells per cubic millimeter by 12 months. A total of 21% of HIV-1–infected participants in the delayed-therapy group began taking antiretroviral therapy after a median of 42 months. Among all participants, 72% received a combination of zidovudine, lamivudine, and efavirenz (see the Supplementary Appendix). Adherence to the study regimen of at least 95% (as measured by pill count) was observed in 79% of participants in the early-therapy group and in 74% of those in the delayed-therapy group. Details with respect to regimens of antiretroviral therapy and pill counts are provided in the Supplementary Appendix.

Virologic failure was observed in 45 of 886 participants (5%) in the early-therapy group and in 5 of 184 participants in the delayed-therapy group who initiated antiretroviral therapy (3%) (P=0.23). Of all treated participants, 66% initiated a second-line regimen.

Primary Prevention Outcome

Table 2. Table 2. Incidence of Partner-Linked and Any HIV-1 Transmission and Clinical and Composite Events.

Figure 2. Figure 2. Kaplan–Meier Estimates for Partner-Linked and Any HIV-1 Transmission and for Clinical and Composite Monitoring Events. Shown are Kaplan–Meier estimates for the cumulative probabilities of linked HIV-1 transmission between partners (Panel A), any HIV transmission (Panel B), clinical events (Panel C), and composite monitoring events (Panel D) among participants in the early-therapy and delayed-therapy groups.

A total of 39 HIV-1 transmission events were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7), with 4 events in the early-therapy group (incidence rate, 0.3 per 100 person-years; 95% CI, 0.1 to 0.6) and 35 events in the delayed-therapy group (incidence rate, 2.2 per 100 person-years; 95% CI, 1.6 to 3.1), for a hazard ratio in the early-therapy group of 0.11 (95% CI, 0.04 to 0.32; P<0.001) (Table 2 and Figure 2; also see the Supplementary Appendix for details regarding the incidence of transmission). Through viral genetic analysis, 28 transmissions were linked to the HIV-1–infected participant (incidence rate, 0.9 per 100 person-years; 95% CI, 0.6 to 1.3), with 1 transmission in the early-therapy group (incidence rate, 0.1 per 100 person-years; 95% CI, 0.0 to 0.4) and 27 transmissions in the delayed-therapy group (incidence rate, 1.7 per 100 person-years; 95% CI, 1.1 to 2.5), for a hazard ratio in the early-therapy group of 0.04 (95% CI, 0.01 to 0.27; P<0.001). The remaining 11 transmissions (3 in the early-therapy group and 8 in the delayed-therapy group) included 7 transmissions that were unlinked (3 in the early-therapy group and 4 in the delayed-therapy group), 3 transmissions that could not be classified on the basis of available data, and 1 transmission that has not yet been evaluated. The latter 4 transmissions were all in the delayed-therapy group.

The rate of transmission events in the delayed-therapy group was relatively constant across the first 3 years of study follow-up for both linked and any transmissions. Of the 28 HIV-1–infected participants who had linked transmission to a partner, 17 (61%) had a CD4 count of more than 350 cells per cubic millimeter at the study visit before the detection of linked HIV-1 transmission. The single linked transmission in the early-therapy group was identified 3 months after the HIV-1–infected participant initiated treatment; all linked transmissions in the delayed-therapy group occurred while the HIV-1–infected participant was not receiving antiretroviral therapy. The Kaplan–Meier curves for both linked and any transmissions show immediate and sustained reduction in the risk of HIV-1 transmission after the initiation of antiretroviral therapy (Figure 2).

Table 3. Table 3. Hazard Ratios for Prognostic Factors for Partner-Linked and Any HIV-1 Transmission and for Clinical and Composite Events.

Of the 28 linked transmissions, 23 (82%) occurred at African sites. HIV-1–infected women were the source of infection in 18 of 27 (67%) linked transmissions in the delayed-therapy group, and a man was the source of the single transmission in the early-therapy group. Women were the HIV-1–infected participant in 58% of African couples. A high viral load in blood plasma of infected participants at baseline increased the risk of HIV-1 transmission (Table 3). The median plasma viral load in 27 participants at the visit most proximal to the detection of HIV-1 transmission was 4.9 log 10 (range, 2.6 to 5.8). Conversely, self-reported 100% condom use at baseline was associated with a reduced risk of HIV-1 transmission. In the stratified multivariate analysis according to site, the adjusted hazard ratio for linked transmission in the early-therapy group was 0.04 (95% CI, 0.01 to 0.28; P<0.001) (Table 3).

Primary Treatment Outcome

A total of 105 treatment end points, as measured by the first serious HIV-1–related clinical event or death, were observed in HIV-1–infected participants: 40 in the early-therapy group and 65 in the delayed-therapy group (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01 (Table 2, and the Supplementary Appendix). Of such clinical events, 44% occurred in Asia and 45% in Africa. The baseline plasma viral load was an important predictor of clinical events, as assessed on multivariate analysis (Table 3). In the stratified multivariate model, the adjusted hazard ratio for clinical events in the early-therapy group was 0.59 (95% CI, 0.40 to 0.89). The difference in the rate of clinical events appeared to be driven mainly by the incidence of extrapulmonary tuberculosis, which developed in 3 participants in the early-therapy group and 17 in the delayed-therapy group (P=0.002); of these cases, 55% were observed in India. Pulmonary tuberculosis was observed in 13 participants in the early-therapy group and 15 in the delayed-therapy group; isoniazid prophylaxis was administered to only 4% of participants in each study group. There were 23 deaths during the course of the study, 10 in the early-therapy group and 13 in the delayed-therapy group (hazard ratio, 0.77; 95% CI, 0.34 to 1.76; P=0.27) (for details regarding causes of death, see the Supplementary Appendix).

Composite Monitoring Events

Among 102 composite monitoring events, there were 39 transmission events in which the sexual partner acquired HIV-1. Among HIV-1–infected participants, 21 died and 42 had WHO stage 4 clinical events. Of these monitoring events, 58 (57%) occurred in Africa, 31 (30%) in Asia, and 13 (13%) in the Americas. Overall, 23 monitoring events were observed in the early-therapy group and 79 in the delayed-therapy group (hazard ratio, 0.28; 95% CI, 0.18 to 0.45; P<0.001) (Table 2). According to the monitoring guidelines that were based on the Lan–DeMets implementation of O'Brien–Fleming boundaries, the computed z statistic was 4.43, which exceeded the prespecified cutoff of 3.93 and thus ruled out the hypothesis that early therapy would provide at most a 20% reduction in the risk of the composite monitoring end point.

Adverse Events

After the exclusion of primary clinical end points (death, WHO stage 4 events, pulmonary tuberculosis, and severe bacterial infections), 246 HIV-1–infected participants had one or more severe or life-threatening adverse events (grade 3 or 4): 127 of 886 (14%) were in the early-therapy group and 119 of 877 (14%) were in the delayed-therapy group (P=0.64). The most frequently reported adverse events included infections, psychiatric and nervous system disorders, metabolism and nutrition disorders, and gastrointestinal disorders (for details, see the Supplementary Appendix). Grade 3 or 4 laboratory abnormalities during study follow-up occurred in 242 participants (27%) in the early-therapy group and 161 participants (18%) in the delayed-therapy group (P<0.001). The most frequent laboratory abnormalities included neutropenia, abnormal phosphate level, and total bilirubin elevations (with bilirubin elevations observed primarily in participants taking atazanavir as part of their drug regimen) (see the Supplementary Appendix).