The introduction of antiretroviral therapy (ART) to treat HIV infection has led to a significant reduction in the transmission of HIV to sexual partners.1 However, as the rates of HIV infection decrease, the rates of bacterial sexually transmitted infections (STIs), such as syphilis, continue to increase in urban centers internationally, including Canada.2–5 The burden is substantially higher among HIV-positive men who have sex with men (MSM).6–9
Among HIV-positive people not on ART, syphilis coinfection may increase HIV infectiousness by increasing HIV viral load (VL) replication.10–13 Yet less is known about the effect syphilis has on VL while on ART and whether it may mitigate its effectiveness. To accurately measure whether an effect exists, success of ART treatment should be considered because the effect of syphilis on VL would appear stronger in people with poorly controlled VLs. A meta-analysis on the topic identified that most of the past studies did not make this consideration and emphasized the need for more research.14
Additionally, the risk of STIs is higher among people using illicit drugs.9,15,16 Illicit drug use is associated with the risk of elevated HIV VLs, whether through poor ART adherence or other biological drug–drug interactions.17,18 Consequently, drug use fits the definition of a potential confounder in the relationship between syphilis and elevated HIV VL. However, past studies of this relation have not adjusted for drug use.14 Thus, our aim was to measure the unbiased effect of acute syphilis on virologic failure (VF) among HIV-positive MSM and to determine if drug use plays a role in this relationship.
To overcome previous study limitations, we explored the association among those who have achieved plasma VL suppression while on ART. We tested 2 hypotheses. First, that syphilis coinfection has an effect on VF among those who have achieved virologic suppression. Second, drug use is a confounder in this relationship. To our knowledge, this is the first study to assess the effect of drug use on the relationship between VF and syphilis coinfection among a large cohort of fully suppressed HIV-positive MSM on ART.
We analyzed data from the Ontario HIV Treatment Network Cohort Study (OCS), which follows people living with HIV and receiving care at 10 HIV clinics in Ontario. The study design has been described elsewhere.19 Briefly, participants must be aged 16 years and older and provide written informed consent. Clinical data were collected through chart review or from electronic medical records. Beginning in 2008, participants underwent annual interviews using structured questionnaires. We analyzed data from 2008 to 2015, at which time 6891 participants had ever enrolled. Analyses were restricted to male subjects who were on ART (249 excluded), had successful linkage to the Public Health Ontario Laboratories (PHOL) data (480 excluded), reported gay or bisexual orientation or reported sex with men as an HIV risk factor at baseline (2433 excluded), had 2+ VL records and were virologically suppressed at baseline based on the definition of having 2+ consecutive VL of <50 copies per milliliter within a 6-month period (998 excluded), and had ≥1 interview (99 excluded). The study received ethical approval from the University of Toronto (protocol reference 23,954) and from the participating OCS sites.
VL and Syphilis Testing
Syphilis serology and HIV VL results were obtained via linkage with PHOL. From 2006 to 2017, the syphilis testing algorithm included screening with a treponemal test, the Abbott chemiluminescent immunoassay, followed by confirmatory testing with the rapid plasma reagin and Treponema pallidum particle agglutination assay; the fluorescent treponemal antibody absorption test was performed if confirmatory results were inconclusive.20 HIV VL blood plasma specimens were tested by real-time polymerase chain reaction using the Abbott HIV1VL Assay.21 PHOL is the sole provider of VL and syphilis confirmatory testing in Ontario.
VF was defined as a single VL of ≥1000 copies per milliliter or 2 consecutive VLs of ≥200 copies per milliliter in ≥1 month apart.
Covariates of Interest
Similar to previous analyses,8 we defined acute syphilis as having a 4-fold increase in rapid plasma reagin titre. Men were considered exposed to syphilis 6 months before and 120 days after the positive syphilis test date. This definition was based on previous analyses,8 and the incubation period and recommendations on treatment follow-up found in the Canadian Guidelines on Sexually Transmitted Infection.12 As done previously,7,9 we included all participants, even those not regularly tested. Thus, we underestimated acute syphilis because infections among those untested were unascertainable.
We modeled acute syphilis as a time-varying covariate on VF using Poisson regression. Our model allowed for repeat exposures and VF events using generalized estimating equations with an exchangeable correlation structure. Men were removed from the analysis after a VF but were considered eligible for another VF event if (1) they remained on ART and (2) recovered by achieving VL suppression again. An offset for the total number of person-years at risk for VF was used to model the total number of events. Men were right censored at their last VL test date if still eligible for a VF event or the date of their last VF if not meeting the eligibility criteria to re-enter the analysis.
Drug use was our hypothesized confounder of interest (see Figure, Supplemental Digital Content, http://links.lww.com/QAI/B276). Self-reported drug use was operationalized as a time-varying categorical variable (no drug use/injection drug use/noninjection drug use) and included use of cocaine, methamphetamine, anabolic steroids, amphetamines, crack/freebase, club drugs, tranquilizers, heroin, poppers, and/or other opiates in the past 6 months. (Cannabis use was not included because these data were unavailable.) We also considered the sociodemographic variables such as age, education, race, income, and region as potential confounders based on the literature and previous analyses.6,22–24 Age, education, and income were time varying.
We assessed for confounding using an iterative process of removing and reintroducing the confounder in question. A covariate was removed from the final model if both criteria were met upon removal (1) the effect estimate of syphilis did not change by 10% and (2) model precision improved.25 We assessed for multicollinearity using the variance inflation factor. If the variance inflation factor was ≥10, there was evidence of multicollinearity.25 For missing data, we used the last observation carried forward method. Given greater variability in drug use, observations were carried over for a maximum of 2 years. We conducted all analyses using SAS version 9.3 (SAS Institute, Inc., Cary, NC). P values were 2 sided, and statistical significance was determined using a P value of <0.05.
The final sample size was 2632. At their first observed viral suppression during the study period, participants were on average 46.8 years of age (Table 1). Among all participants, 86% had ≥1 syphilis test, 14% had ≥1 positive syphilis test for acute syphilis, and 28% reported drug use at ≥1 of the annual interviews. Participants were followed for a median of 6.5 years for a sum of 14,559 person-years.
There were 525 VFs with an incidence of 3.5 per 100 person-years [95% confidence interval (CI): 3.4 to 4.2], and 431 men had ≥1 VF event. The median number of failures was 1 (interquartile range, 1–1). The median number of days between a positive syphilis test and related test showing VF was 24 days. The crude rate ratio for the association between acute syphilis and VF was 1.5 (95% CI: 0.9 to 2.4) (Table 2). Age, income, education, region, and drug use were considered confounders and were retained in the model. There was no evidence of multicollinearity. The rate ratio for acute syphilis in the final model after adjustment for drug use was 1.2 (95% CI: 0.7 to 1.9). When not adjusted for drug use but still adjusted for all other confounders, a change in estimate of 25% was seen in the rate ratio for syphilis; it was 1.6 (95% CI: 1.0 to 2.4), which suggested drug use explained a large part, but not all, of the relationship between acute syphilis and VF.
The incidence of VF was 3.5 per 100 person-years (95% CI: 3.4 to 4.2) among HIV-positive MSM in an Ontario clinical cohort from 2008 to 2015. Among those with a VF, 4% also had acute syphilis around that time. We did not find a statistically significant association between acute syphilis and risk of VF among virologically suppressed MSM on ART, with or without adjustment for drug use.
Strengths of this analysis include use of a large sample of HIV-positive MSM participating in a longitudinal cohort with close to 15,000 person-years of follow-up time and record linkage with the provincial laboratory. In previous OCS analyses, we have seen that the majority of syphilis tests are ordered by HIV clinics.6,9
There are limitations to our analyses. Because laboratory-based acute syphilis was used as a proxy for syphilis diagnosis, there is possibility for misclassification because not all men were tested, and among those with positive tests indicative of acute syphilis, exact dates of acquisition, clinical diagnoses, and staging were unknown. Nevertheless, 86% of participants were tested for syphilis at least once during the observation period. We attempted to mitigate potential misclassification caused by unknown acquisition dates by considering time before and after diagnosis as “exposed.” Furthermore, results may not be generalizable to all MSM living with HIV because the sample is selected from patients attending HIV care clinics, and OCS participation is voluntary. OCS participants are generally representative of cumulative HIV diagnoses in Ontario in terms of HIV exposure category, age at diagnosis, region, and sex, yet underrepresent those recently diagnosed.26
Studies on the effect of syphilis on VL among those on ART have been few with varied findings. In a similarly large cohort of HIV-infected men on ART in France, syphilis was significantly associated with an increase in VL22; however, the study had a more conservative outcome (increase in VL of ≥0.5 logs or >500 copies/mL). Conversely, and similar to our findings, a meta-analysis exploring the effect of STIs on VL among HIV-positive persons taking ART found no cumulative statistically significant effect.14 Nevertheless, STIs were not assessed independently, heterogeneity was high, there were few studies, and the majority had small sample sizes. Among the studies looking exclusively at MSM, the latest year of observation was 2006; and none of the studies focusing on syphilis and/or MSM adjusted for drug use. Our study provides a more recent, comprehensive picture using a robust design and a far larger sample. With the introduction of new combination HIV medicines27 and the move to less frequent HIV care visits,28 these findings depict a picture of a more present-day landscape. A unique aspect of our study is that we account for ART management by limiting to those achieving virologic suppression. Moreover, ours is the first to explicitly explore the relationship between drug use, syphilis, and VF.
It was hypothesized that if acute syphilis significantly affected risk of VF, the relationship may be confounded by drug use. Although there was no statistically significant association between syphilis and VF whether or not controlling for drug use, there was evidence of positive confounding. The other confounders were negative confounders, and without adjustment for drug use, the magnitude of the effect estimate indicated an association might exist. Specifically, when drug use was removed from the model, there was a 25% increase in the relative effect of syphilis on VF (rate ratio of 1.6 vs. 1.2). Thus, as hypothesized, drug use plays an important role as a confounder in this relationship.
Our findings demonstrate that in fully suppressed HIV-positive MSM on ART, acute syphilis may not lead to an increased risk of HIV treatment failure or VF events. Consequently, among men with acute syphilis, ART may still reduce HIV transmission risk to sexual partners. Additionally, our findings indicate that drug use is an important confounder in this relationship and future studies exploring the association between syphilis and VF in similar populations should include it in their analyses to avoid reporting of potentially spurious associations.
The authors gratefully acknowledge all of the people living with HIV who volunteer to participate in the OHTN Cohort Study. The authors also acknowledge the work and support of OCS Governance Committee and Scientific Steering Committee members: Joanne Lindsay (Co-Chair), Adrian Betts (Co-Chair), Les Bowman, Tracey Conway, Mark McCallum, John McTavish, Colleen Price, Rosie Thein, Claire Kendall, Breklyn Bertozzi, Sergio Rueda (Chair), Ann Burchell, Beth Rachlis, Barry Adam, David Brennan, Curtis Cooper, Trevor Hart, Mona Loutfy, and Kelly O'Brien. The OHTN Cohort Study also acknowledges the work of past Governance Committee and Scientific Steering Committee members.
The authors thank all interviewers, data collectors, research associates, coordinators, nurses, and physicians who provide support for data collection, and Public Health Ontario Laboratories for supporting record linkage with the HIV viral load, and syphilis test databases. The authors also thank OCS staff for data management, IT support, and study coordination: Madison Kopansky-Giles, Robert Hudder, Lucia Light, Veronika Moravan, Nahid Qureshi, Tsegaye Bekele and Adam McGee.
APPENDIX 1. OHTN Cohort Study Team
The OHTN Cohort Study Team consists of Drs. Abigail Kroch (Principal Investigator), OHTN and University of Toronto; Beth Rachlis, OHTN, Dignitas International and University of Toronto; Ann Burchell, St. Michael's Hospital and University of Toronto; Gordon Arbess, St. Michael's Hospital; Jeffrey Cohen, Windsor Regional Hospital; Curtis Cooper, Ottawa General Hospital; Don Kilby, University of Ottawa Health Services; Fred Crouzat and Mona Loutfy, Maple Leaf Medical Clinic; Nisha Andany and Nicole Mittmann, Sunnybrook Health Sciences Centre; Irving Salit, Toronto General Hospital; Michael Silverman, St. Joseph's Health Care; and Roger Sandre, Sudbury Regional Hospital.
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