Treatment as Prevention: Characterization of Partner Infections in the HIV Prevention Trials Network 052 Trial

Abstract

HIV Prevention Trials Network 052 demonstrated that antiretroviral therapy (ART) prevents HIV transmission in serodiscordant couples. HIV from index-partner pairs was analyzed to determine the genetic linkage status of partner infections. Forty-six infections were classified as linked, indicating that the index was the likely source of the partner's infection. Lack of viral suppression and higher index viral load were associated with linked infection. Eight linked infections were diagnosed after the index started ART: 4 near the time of ART initiation and 4 after ART failure. Linked infections were not observed when the index participant was stably suppressed on ART.

Figure 1. Analysis of partner infections in HPTN 052

(A) The chart shows an overview of the linkage status of partner infections in HPTN 052. Data are presented separately for couples where the partner was diagnosed with HIV infection before the index participant started antiretroviral therapy (ART) in the trial (N=46) or after the index participant started ART in the trial (N=32). Infections were classified as linked if the index participant was the likely source of the partner’s infection, and unlinked if the partner was most likely infected from another source. (B) Seventy-eight partner infections were identified in the HPTN 052 trial. The dates (month/year) of milestones in the HPTN 052 trial are shown on the X-axis. A vertical dashed line indicates the date that the interim report was released, showing the benefit of early initiation of ART. Horizontal arrows show the number of person-years of follow-up for partners who were HIV-uninfected at study enrollment. Partner infections are represented by diamonds. Data are presented separately for linked and unlinked partner infections. Open diamonds indicate infections in the delayed ART arm of the study that were diagnosed before the index participant started ART. Shaded diamonds indicate infections in the delayed ART arm of the study that were diagnosed after the index participant started ART. Black diamonds indicate infections in the Early ART arm of the study, all of which were diagnosed after the index participant started ART. Eight linked partner infections were diagnosed after the index started ART (Key cases, arrows). ^aIn six cases, linkage status could not be determined because HIV RNA in the index and/or partner sample(s) could not be amplified (failed cases). In three cases, HIV RNA could not be amplified because the index was virally suppressed at all study visits (including the enrollment visit). In two of those cases, the index participant was on ART at study enrollment, but did not disclose this to study staff; in the third case, ARV drugs were not detected in study specimens, indicating that the index participant was most likely an elite controller. In the fourth case, the partner was diagnosed with HIV infection and started ART outside of the study and was virally suppressed at subsequent study visits. It is not clear why amplification was unsuccessful in the other two cases. In those cases, attempts to amplify HIV RNA using a nested PCR method and alternate amplification primers were not successful. ^b3 early ART arm; 5 delayed ART arm.

Figure 2. Analysis of the timing of linked partner infections that were diagnosed when the index participant was virally suppressed

The figure shows data for three partner infections where the partner was diagnosed shortly after the index participant started antiretroviral therapy (ART), when the index was virally suppressed. The vertical line at Day 0 indicates the day of that the index participant started ART. Days before the start of ART are indicated with negative numbers; days after the start of ART are shown with positive numbers. Index and partner viral load (VL) values are indicated. The date of the partner’s first positive HIV test is indicated (WB+: Western blot positive). The solid horizontal lines indicate the estimated transmission date with 95% confidence intervals (CI) obtained using BEAST. Dotted lines indicate the estimated transmission date with 95% CI obtained using the Poisson Fitter. Dashed lines indicate the time between the earliest possible transmission date (7 days before the partner’s last test where HIV RNA was undetectable) and the end of the likely transmission period, determined by the Fiebig stage of the partner at the first HIV positive visit. (A) In Case A, the partner was diagnosed with HIV infection on Day +35. HIV RNA was undetectable (<40 copies/mL) on Day −35, indicating that the earliest possible transmission date was Day −42 (based on a 7-day eclipse period). The Western blot was positive on Day +35 (Fiebig stage V), indicating that the transmission event occurred before Day +12. BEAST analysis estimated that the transmission event occurred on Day −5. Poisson fitter analysis estimated that the transmission event occurred on Day +1. (B) In Case B, the partner was diagnosed with HIV infection on Day +84. HIV RNA was undetectable on Day −1, indicating that the earliest possible transmission date was Day −8. The Western blot was positive on Day +84 (Fiebig stage VI), indicating that the transmission event occurred before Day +29. BEAST analysis estimated that the transmission event occurred on Day 0. Poisson fitter analysis was not performed in this case because of the complexity of the partner’s viral population. (C) In Case C, the partner was diagnosed with HIV infection on Day +59. HIV RNA was undetectable on Day 0, indicating that the earliest possible transmission date was Day −7. The Western blot was positive on Day +59 (Fiebig stage V), indicating that the transmission event occurred before Day +36. BEAST analysis estimated that the transmission event occurred on Day +5. Poisson fitter analysis estimated that the transmission event occurred on Day +17.