Doxycycline post-exposure prophylaxis for prevention of sexually transmitted infections among Kenyan women using HIV pre-exposure prophylaxis: study protocol for an open-label randomized trial.
ABSTRACT
Background: Women in Africa face a disproportionate risk of human immunodeficiency virus (HIV) acquisition, accounting for more than half of new infections in Africa and similarly face a disproportionate burden of sexually transmitted infections (STIs). Very high STI prevalence is being
observed globally, especially among people taking pre-exposure prophylaxis (PrEP) for HIV prevention. Doxycycline post-exposure prophylaxis (dPEP) has been proposed as an STI prevention strategy to reduce chlamydia, syphilis, and possibly gonorrhoea, and trials are ongoing among cisgender men who have sex with men (MSM) and transgender women who are taking PrEP in high-income settings. We designed and describe here the first open-label trial to determine the effectiveness of dPEP to reduce STI incidence among cisgender women
Methods: We are conducting an open-label 1:1 randomized trial of dPEP versus standard of care (STI screening and treatment and risk-reduction counselling without dPEP) among 446 Kenyan women aged ³18 and £30 years old women taking PrEP. Women are followed for 12 months, with quarterly STI testing, treatment, and adherence counselling. The primary trial outcome will be the combined incidence of Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum was compared between the randomized groups. We will also assess dPEP acceptability, tolerability, safety, impact on sexual behaviour, adherence, and occurrence of antimicrobial resistance (AMR) in N. gonorrhoeae and C. trachomatis
isolates. Finally, we will estimate the cost per incident STI case and complications averted accounting for nonadherence and benefits relative AMR or side effects.
Discussion: The results of this trial may have immediate implications for the global epidemic of STIs and sexual health. If effective, dPEP could put STI prevention into women’s hands. While dPEP may be able to prevent STIs, it carries important risks that could counter its benefits; global debate about the balance of these potential risks and benefits requires data to inform policy and implementation and our study aims
to fill this gap.
Trial registration: https://clinicaltrials.gov/ct2/show/NCT04050540
Background and rationale {6a}
More than two million persons become newly infected with human immunodeficiency virus (HIV) each year, the majority in sub-Saharan Africa.1 Cisgender woman in Africa face disproportionate HIV risk, accounting for more than half of new infections, and with incidence rates that are often double or more than their male age-mates. 2,3 At the same time, African women also face a disproportionate burden of sexually transmitted infections (STIs). Globally, the World Health Organization (WHO) estimates that 376 million new cases of four curable sexually transmitted infections – three bacterial pathogens (Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum [etiologic cause of syphilis]), plus the protozoan parasite Trichomonas vaginalis – are acquired worldwide each year. 4 The consequences of bacterial STIs on sexual and reproductive health can be profound and lasting, e.g., pelvic inflammatory Page 5/32 disease (PID), chronic pelvic pain, tubal infertility, pregnancy complications, fetal and neonatal death, and
increased susceptibility to HIV,5–11 and are overwhelmingly borne by women.
The past decade has witnessed monumental strides in the development of highly-effective HIV prevention interventions, including antiretroviral pre-exposure prophylaxis (PrEP).12–15 PrEP reduces incident HIV but was not expected to prevent bacterial STIs, including gonorrhoea, chlamydia, or syphilis. In high-income countries, like the US, the past decade has seen a resurgence in the incidence of bacterial STIs among men who have sex with men (MSM).16,17 HIV and STIs overlap in transmission pathways through sexual exposure; thus, it is not surprising that high STI rates are seen among persons who use or are eligible to use PrEP. PrEP scale-up for eligible women is expanding rapidly. In 2017, Kenya was one of the first countries in the world to launch a national PrEP program, making PrEP available to all populations at risk for HIV, with a major focus on young women. PrEP roll-out provides an opportunity to improve HIV rates, and target STI prevention interventions, in African women.
A recent open-label clinical trial among MSM in France (IPERGAY) found a 47% relative reduction in new bacterial STIs (specifically, either C. trachomatis, N. gonorrhoeae, or T. pallidum) among PrEP users who also took doxycycline following every sexual encounter.
18 This reduction was driven by reductions in incident C. trachomatis (70% reduction) and T. pallidum infections (73% reduction). The use of post-exposure doxycycline to prevent infections is already standard, recommended practice for other infectious diseases – for example, after tick exposure in areas of high Lyme disease prevalence or after flooding in leptospirosis endemic areas; doxycycline is also used as malaria pre-and post-exposure prophylaxis.19–21 The concept of STI prophylaxis has a long history.
18,22,23 Several studies on single dose or monthly antibiotics among female sex workers in Asia and Africa, demonstrated reduced disease burden with mixed efficacy.23–29
Conversely, multi-drug resistant N. gonorrhoeae is a growing international public health issue. 30–35 Notably, the IPERGAY results found no reduction in gonorrhea, which was expected given the high percentage (56%) of circulating strains of N. gonorrhoeae in Europe are already resistant to tetracyclines. 36,37 While dPEP may prevent STIs, it carries important risks, particularly if intermittent
doxycycline use induces tetracycline-resistant pathogens that could counter its benefits; global debate about the balance of these potential risks and benefits requires data to inform policy and implementation. 38 In Africa, antimicrobial resistance (AMR) data are sparse, but detection of plasmid-mediated tetracycline-resistant N. gonorrhoeae was highly prevalent (73-97%) .30,31,39,40 Rigorous studies are needed to quantify resistance in populations exposed to dPEP and whether dPEP use results in
additional resistance.
Due to the limited availability of etiologic STI testing in Africa, few studies have assessed STI risk among PrEP-using women in Africa. In those studies, STI rates are already comparable, with 27-53% C. trachomatis incidence per 100 person-years, to those seen among PrEP-using MSM in the US. 41–43 Prior to launching our pivotal trial, essentially all global conversation about dPEP for STI prevention has been directed towards MSM in high-income settings.
Objectives {7}
Our clinical trial aims to determine the effectiveness and benefit of dPEP to reduce STI incidence among Kenyan women taking PrEP for HIV prevention as well as assess associated risks of dPEP by exploring a) safety, b) acceptability, c) adherence, and d) resistance. We will also measure the cost of dPEP and estimate the cost per case averted, budget impact, and affordability.
Trial design {8}
The dPEP Kenya study is a 1:1 open-labelled, randomized trial to determine the effectiveness and benefit of dPEP to reduce STI (N. gonorrhoeae, C. trachomatis, and T. pallidum (syphilis)) incidence among women taking PrEP for HIV prevention.
Study setting {9}
All study procedures will be conducted at a research clinic in Kisumu, Kenya.
RCTP-cmr 