Background: The risk of sexual HIV transmission in serodiscordant couples when the HIV-positive partner has full virologic suppression on combination antiretroviral therapy (cART) is debated. This study aims to systematically review observational studies and randomized controlled trials (RCTs), evaluating rates of sexual HIV transmission between heterosexual serodiscordant couples when the HIV-positive partner has full suppression on cART. Methods and Findings: We searched major bibliographic databases to November 2012 for relevant observational studies and RCTs without language restrictions. Conference proceedings, key journals and bibliographies were also searched. Studies reporting HIV transmission rates, cART histories and viral loads of the HIV-positive partners were included. Two reviewers extracted methodologic characteristics and outcomes. Of 20,252 citations, 3 studies met all eligibility criteria with confirmed full virologic suppression in the HIV-positive partner. We included 3 additional studies (2 cohort studies, 1 RCT) that did not confirm viral suppression in the HIV-positive partner at transmission in a secondary meta-analysis. Methodologic quality was reasonable. The rate of transmission in the 3 studies confirming virologic suppression was 0 per 100 person-years (95% CI = 0–0.05), with low heterogeneity (I = 0%). When we included the 3 studies that did not confirm virologic suppression, the rate of transmission was 0.14 per 100 person-years (95%CI = 0.04–0.31) (I = 0%). In a sensitivity analysis including all 6 studies, the rate of transmission was 0 per 100 person-years (95%CI = 0–0.01) after omitting all transmissions with known detectable or unconfirmed viral loads, as full suppression in these cases was unlikely. Limitations included lack of data on same-sex couples, type of sexual intercourse (vaginal vs. anal), direction of HIV transmission, exact viral load at the time of transmission, sexually transmitted infections (STI) rates, and extent of condom use. Conclusions: Our findings suggest minimal risk of sexual HIV transmission for heterosexual serodiscordant couples when the HIV-positive partner has full viral suppression on cART with caveats regarding information on sexual intercourse type, STIs, and condom use. These findings have implications when counseling heterosexual serodiscordant couples on sexual and reproductive health. More research is needed to explore HIV transmission risk between same-sex couples. Citation: Loutfy MR, Wu W, Letchumanan M, Bondy L, Antoniou T, et al. (2013) Systematic Review of HIV Transmission between Heterosexual Serodiscordant Couples where the HIV-Positive Partner Is Fully Suppressed on Antiretroviral Therapy. PLoS ONE 8(2): e55747. doi:10.1371/journal.pone.0055747 Editor: Sarah Pett, University of New South Wales, Australia Received June 19, 2012; Accepted December 31, 2012; Published February 13, 2013 Copyright: 2013 Loutfy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grant # KRS-102081 (www.cihr-irsc.gc.ca.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Dr. MRL is a PLOS ONE Editorial Board member and this does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: mona.loutfy@wchospital.ca Introduction The risk of horizontal HIV transmission between serodiscordant couples when the HIV-positive partner has full viral suppression with combination antiretroviral therapy (cART) remains unclear [1–3]. This issue is of particular importance to longstanding monogamous discordant couples and to discordant couples considering conception through vaginal heterosexual intercourse [4–6]. In the midst of uncertainty regarding the risk of sexual HIV transmission in these contexts, the Swiss National AIDS Commission issued a statement in January 2008 specifying that HIVinfected individuals could be considered non-infectious if they met three conditions: adherence to cART under the care of an HIV PLOS ONE | www.plosone.org 1 February 2013 | Volume 8 | Issue 2 | e55747 physician, virologic suppression below the level of detection for at least six months, and absence of concomitant sexually transmitted infections (STIs) [7]. The ‘‘Swiss statement’’ was highly contentious, particularly in light of evidence demonstrating viral particles in the genital secretions of 5–48% of patients with undetectable plasma viremia [8–10]. Since the release of the Swiss Statement [7], 4 systematic reviews have been published quantifying the risk of sexual HIV transmission in serodiscordant couples [11–14]. Powers et al (2008) [11] and Boily et al (2009) [12] synthesized evidence on the rates of HIV transmission between HIV-positive individuals and uninfected partners per coital act, with a particular focus on contributing co-factors such as genital ulcer disease, circumcision, and stage of illness. However, neither review accounted for the impacts of antiretroviral use or the viral load of index cases on the risk of transmission. These limitations were somewhat addressed by Attia et al, who conducted a systematic review examining the role of cART use and viral load on HIV transmission between heterosexual discordant couples [13]. However, of the 5 studies included in their review, 3 were conference abstracts and the 2 studies with viral load data were not recent (from 2005 and 2008). The most recent systematic review, available in the Cochrane library examining the impact of cART on sexual transmission of HIV in serodiscordant couples, did not consider the influence of undetectable HIV plasma viral load on the risk of HIV transmission between discordant partners [14]. In addition, these reviews were published prior to the availability of data from the multicenter, randomized controlled trial (RCT), HIV Prevention Trials Network (HPTN) Study 052 [15]. In this trial of 1,763 serodiscordant couples, early initiation of cART was associated with a 96% reduction in the number of linked HIV-1 transmissions relative to delayed cART (i.e. waiting to initiate cART when a clinical event occurred or CD4+ cell count reduced ,250 cells/ mL) [15]. In summary, existing systematic reviews neither address all factors that could modulate the risk of horizontal HIV transmission between heterosexual serodiscordant couples when the HIVpositive partner has full viral suppression on cART including HIV RNA levels, genital ulcer disease, male circumcision status, and hormonal contraceptive use, nor do they include the most up-todate evidence surrounding this topic [11,15]. Consequently, we undertook a systematic review and meta-analysis of quantitative observational studies and RCTs to quantify the risk of horizontal transmission between serodiscordant couples when the HIVpositive partner has full viral suppression on cART. We hypothesize that the risk of horizontal transmission between serodiscordant heterosexual couples when the HIV-positive partner has full viral suppression on cART will be extremely low. Methods Protocol and Registration This project was not prospectively registered. A protocol was developed during the planning process (Grant# KRS 102081). Literature Search Strategy This systematic review adheres to guidelines outlined in The Cochrane Group Handbook for Systematic Reviews of Interventions [16]. As well, the PRISMA flow diagram and checklist and MOOSE checklist were used [17,18]. In consultation with a librarian, a strategy (available in online appendix) was developed for searching MEDLINE (1950– November 2012), EMBASE (1980– November 2012), CINAHL (1980– November 2012), and Web of Science (2004– November 2012) for all relevant observational studies and RCTs regardless of country or language.
