Incidence of sexually transmitted infections before and after preexposure prophylaxis for HIV

Background and rationale

Preexposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate and emtricitabine (TDF-FTC or Truvada) has been demonstrated to be highly effective at preventing HIV infection in high-risk MSM in three landmark studies [1–3]. In the United States, the Food and Drug Agency approved the use of PrEP in July 2012 [4] and PrEP is now reimbursed through the Medicaid program and the majority of private insurers. PrEP is offered through a patchwork of schemes in the United States, and has been pioneered in a number of clinics in the San Francisco Bay Area [5,6]. PrEP was approved by Health Canada in February 2016 as part of a comprehensive HIV Prevention strategy [7,8]. In Quebec, TDF-FTC has been covered as a general benefit of the provincial healthcare coverage since 2007, without restriction to use as PrEP [9].

Concerns have been raised that PrEP use may be accompanied by the phenomena of risk compensation or behavioural disinhibition, whereby PrEP users’ perception of decreased risk of HIV acquisition may lead them to engage in overall riskier sexual practices and increase their chances of acquiring sexually transmitted infections (STIs) [10]. Modifiable behaviours which may impact transmission of STIs include: condom use, number of partners, concurrency or gaps between partners, partner characteristics, and healthcare-seeking behaviours [11]. Additionally, MSM may alter HIV risk mitigation practices while on PrEP by decreasing seroadaptive practices such as seeking a partner of similar perceived serostatus (e.g. serosorting), or the use of strategic positioning whenever engaging in anal sex with a partner of known HIV positive status (seropositioning) [12]. Among PrEP users, high rates of STIs have been reported [13–15], as well as high rates of condomless sex [14], and increasing rates of STIs over time [6]. However, data from the US National HIV Behavioural Surveillance surveys have documented secular trends of decreasing rates of condom use prior to PrEP, with the percentage of men with no condomless anal sex partners decreasing from 61% in 2001, to 54% in 2011 and 40% in 2014 [16].

To our knowledge, no published articles have ascertained increases in the rates of STIs in PrEP users measuring incidence rates of STIs prior to and following the initiation of PrEP. Observation of high or increasing rates of STIs in MSM already on PrEP does not establish PrEP as a cause of increased STIs nor the presumed mechanism of risk compensation whenever there is no baseline level with which to compare. Rather than risk compensation, an alternative hypothesis to explain high rates of STIs observed in some PrEP users is that PrEP does not lead to increases in risky sex, but rather that PrEP brings into care a population of MSM who are already at high risk for HIV and STIs. This alternative hypothesis is suggested by the fact that both the PROUD and IPERGAY studies recruited MSM with a substantially higher HIV incidence during study follow-up than expected. Whereas the expected HIV incidence was estimated to be 2.5–3.0 cases per 100 person-years at risk, the observed seroconversion rate per 100 person-years was 9.0 and 6.6 in the deferred PrEP group of the PROUD study and the placebo group of IPERGAY, respectively [2,3].

If PrEP use increases rates of STIs, this suggests a need to reinforce counselling and STI diagnosis and treatment efforts. This would also suggest that PrEP provides an important public health benefit beyond the immediate prevention of HIV infection because it brings into care high-risk MSM who might not otherwise be seeking care for STIs. Even if PrEP is not associated with an increase in STIs, the benefits of bringing presumably higher risk men into care will have public health benefits in terms of HIV prevention. The public health implications of PrEP are, therefore, significant, but different, depending on which scenario is the case. As a result, we conducted a study to ascertain STI diagnoses in a cohort of MSM prior to and after receiving PrEP as well as in a cohort of postexposure prophylaxis (PEP) patients.

Objectives

In this retrospective cohort study, our key objective was to determine whether prescription of PrEP led to an increase in STIs. We compared the incidence of Chlamydia trachomatis, Neisseria gonorrhoeae and new infections with syphilis or hepatitis C virus (HCV) 12 months prior to and 12 months following the prescription of PrEP in a cohort of MSM. We also compared incidence of STIs over 12 months to a control group of MSM prescribed PEP. Additionally, the incidence of HIV seroconversion was measured in both cohort groups.

Setting

The study was conducted at Montreal's Clinique médicale l’Actuel, the leading sexual health provider for Canada's second largest city, which has a metropolitan population slightly over 4 million. The clinic is located at the heart of the city's gay ‘Village’ and was founded in 1984 specifically to offer sexual health services to MSM. Self-identified gay men continue to constitute the core clientele of the clinic. L’Actuel follows a large number of MSM who consult regularly for sexual health and adhere to recommendations for at least annual STI and HIV screening. The clinic began offering PrEP to high-risk MSM in 2011, in response both to promising results that had already begun to emerge and to requests from patients. Messages about PrEP availability were disseminated through gay media and word-of-mouth and the l’Actuel website [17]. Our study covers the period from 2010 to 2015. All patients signed an informed consent form authorizing use of anonymized clinical data in epidemiological studies. Ethical approval was obtained from Veritas Institutional Review Board.

Participants

From a cohort of PrEP patients, we selected MSM who had at least 12 months of follow-up prior to and following PrEP prescription. Data was collected from a baseline PrEP questionnaire including behavioural, clinical, and risk assessments. Individuals were prescribed PrEP if they were at least 18 years old and considered at high risk based on reporting at least one seropositive sexual partner with a detectable viral load, or engaging in condomless anal sex with multiple partners whose HIV status was unknown. PrEP was offered as a once-daily or an intermittent (’on-demand’) regimen. After inclusion, baseline visit and questionnaire, visits were scheduled every 3 months, and involved repeat behavioural, risk, adherence and side-effect assessment via questionnaire. Screening was performed at the patients’ discretion in the year prior to PrEP and scheduled at 3-month intervals during the year on PrEP.

The PEP group included MSM who were prescribed a 28-day course of PEP and had at least one visit for HIV and STI screening within the year after prescription of PEP. Patients were prescribed PEP based on physicians’ evaluation of a high-risk exposure within 72 h of consultation; that is, either condomless sex or condom failure with a known seropositive individual believed to have a detectable viral load or via a contact with substantial risk of HIV transmission, such as an anonymous contact at sauna, backroom, or a ‘hook-up’ through a mobile app.

Variables

Demographic data was obtained from questionnaires filled out by participants in both PrEP and PEP groups. For all patients, screening visits consisted of a standard set of tests: oral and anal swabs and urine samples were collected to test for Chlamydia trachomatis/Neisseria gonorrhoeae and blood was drawn to test for HIV, syphilis and hepatitis C virus (HCV). HIV rapid tests were performed in clinic (INSTI HIV-1/HIV-2 Antibody Test), and all biological specimens obtained from patients were sent to a nearby hospital laboratory for analysis. The Cobas 4800 real-time polymerase chain reaction (PCR) Assay or the BD ProbeTech PCR Assay was used for C. trachomatis/N. gonorrhoeae was performed on anal and oral swabs and urine samples. The Cobas 4800 assay has been validated for the detection of extra-genital C. trachomatis/N. gonorrhoeae[18]. For syphilis, all patients were screened with the standard cascade tests: IgG enzyme-linked immunosorbent assays antibody tests, followed by Rapid Plasma Reagin (RPR) tests and treponemal assays (TP-PA). We defined active Syphilis infections based on either a first-ever positive IgG antibody test, with a documented prior negative IgG test on record and a positive confirmatory TP-PA; or a four-fold increase in RPR titres among individuals with a history of syphilis infection. HCV antibody testing was performed using the Monolisa anti-HCV-Plus assay. HIV antigen–antibody tests were performed for all patients regardless of HIV rapid test results. If either the HIV rapid test or antigen–antibody test was returned positive, a confirmatory western blot was performed.

Laboratory results were transmitted as PDF files to physicians and scanned into the electronic medical record. Laboratory results were also transferred electronically into a database used for research purposes containing only patient identification numbers. STI diagnoses were ascertained for each patient using the research database. Chart review of electronic medical records for each patient allowed us to validate cases reported in the database. The accuracy of electronically ascertained results in the research database was verified by manually comparing database results with those in the patient's chart for over 50% of PrEP patients irrespective of STI results. Once the reliability of the electronically received results was established, only positive STI results in the research database were verified by manually confirming if the result was the same in the patient's chart and that each diagnosis represented an incident case of N. gonorrhoeae or C. trachomatis and a new infection for syphilis. STI cases diagnosed at the PrEP baseline consultation were counted as cases occurring in the year prior to PrEP. Finally, we collected data on the number of STI screening visits for each participant in the 12 months prior to PrEP and following PrEP or for the 12 months following the PEP episode.

Statistical analysis

Baseline sociodemographic and behavioural variables were compared between groups using Mann–Whitney U-tests and chi-square tests. For all patients, we measured the number of anal, oral pharyngeal and/or urethral C. trachomatis or N. gonorrhoeae diagnoses, infectious syphilis diagnoses and HCV diagnoses in the year following enrolment (start of PrEP or PEP prescription). For PrEP patients, all cases of STIs in the year prior to PrEP were also counted. We calculated the frequency of STIs per 100 person-years for C. trachomatis, N. gonorrhoeae, syphilis, HCV and overall rates of infection (all sites combined) by dividing the number of infections per stratum by the stratum-specific person-time at risk. The incidence-rate-ratio (relative risk) and 95% confidence intervals (CIs) for STIs in the 12 months following PrEP initiation as compared with the 12 months prior to PrEP was examined in a Poisson regression model [19]. In order to account for potential systematic error because of detection bias, we ran adjusted multivariate Poisson models controlling for the number of screening visits during the pre-PrEP and post-PrEP periods.

We also compared 12-month STI incidence following the date of PrEP prescription versus PEP prescription. For these analyses, we used univariate Poisson regression models and multivariate models adjusted for measured confounders including age, education and frequency of STI screening visits. All analyses were performed using Stata 14.0 (Stata Corp., College Station, Texas, USA).

Conclusion

This study evaluated the impact of PrEP on STI in a cohort of MSM before and after initiation of PrEP. In this real-world population, PrEP appears to have been effective based on the fact that no HIV infections occurred among patients who were adherent to PrEP and seronegative at baseline. The increase in STIs was more notable for infections that are usually asymptomatic than for those with florid symptoms, as could be expected since symptoms would drive behavioural changes to reduce transmission (i.e. abstinence or condom use during symptoms). This study suggests that in our population of MSM in a large North American city, PrEP may lead to increased risk of STIs, and that STI prevention, diagnosis and treatment should continue to be offered at quarterly intervals.

Conflicts of interest

V.K.N. has received speaker's fees from Gilead. H.T. has received grants through her institution from ViiV, Merck and Gilead. R.T. has received grants and personal fees from Gilead, Merck, ViiV and AbbVie.