key: cord-0857414-jdxvumx6 authors: Becquet, Valentine; Nouaman, Marcellin; Plazy, Mélanie; Agoua, Aline; Zébago, Clémence; Dao, Hervé; Montoyo, Alice; Jary, Aude; Coffie, Patrick A.; Eholié, Serge; Larmarange, Joseph title: A community-based healthcare package combining testing and prevention tools, including pre-exposure prophylaxis (PrEP), immediate HIV treatment, management of hepatitis B virus, and sexual and reproductive health (SRH), targeting female sex workers (FSWs) in Côte d’Ivoire: the ANRS 12381 PRINCESSE project date: 2021-12-04 journal: BMC Public Health DOI: 10.1186/s12889-021-12235-0 sha: 53d878d3c5948defa51b9b255bb1d9f62393e37c doc_id: 857414 cord_uid: jdxvumx6 BACKGROUND: Pre-exposure prophylaxis (PrEP) is recommended by the WHO for HIV prevention among female sex workers (FSWs). A study conducted in 2016–2017 in Côte d’Ivoire showed that if PrEP is acceptable, FSWs also have many uncovered sexual health needs. Based on this evidence, the ANRS 12381 PRINCESSE project was developed in collaboration with a community-based organization. The main objective is to develop, document, and analyze a comprehensive sexual and reproductive healthcare package among FSWs in Côte d’Ivoire. METHODS: PRINCESSE is an open, single-arm interventional cohort of 500 FSWs in San Pedro (Côte d’Ivoire) and its surroundings. Recruitment started on November 26th, 2019 and is ongoing; the cohort is planned to last at least 30 months. The healthcare package (including HIV, hepatitis B, and sexually transmitted infection management, pregnancy screening, and contraception) is available both at mobile clinics organized for a quarterly follow-up (10 intervention sites, each site being visited every two weeks) and at a fixed clinic. Four waves of data collection were implemented: (i) clinical and safety data; (ii) socio-behavioral questionnaires; (iii) biological data; and (iv) in-depth interviews with female participants. Four additional waves of data collection are scheduled outside the cohort itself: (i) the medical and activity records of Aprosam for the PRINCESSE participants; (ii) the medical records of HIV+ FSW patients not participating in the PRINCESSE cohort, and routinely examined by Aprosam; (iii) in-depth interviews with key informants in the FSW community; and (iv) in-depth interviews with PRINCESSE follow-up actors. DISCUSSION: The PRINCESSE project is one of the first interventions offering HIV oral PrEP as part of a more global sexual healthcare package targeting both HIV- and HIV+ women. Second, STIs and viral hepatitis B care were offered to all participants, regardless of their willingness to use PrEP. Another innovation is the implementation of mobile clinics for chronic/quarterly care. In terms of research, PRINCESSE is a comprehensive, interdisciplinary project combining clinical, biological, epidemiological, and social specific objectives and outcomes to document the operational challenges of a multidisease program in real-life conditions. TRIAL REGISTRATION: The PRINCESSE project was registered on the Clinicaltrial.gov website (NCT03985085) on June 13, 2019. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-021-12235-0. Most countries in West Africa have mixed HIV epidemics: a limited HIV prevalence in the general population and some key populations that are overwhelmingly affected, particularly female sex workers (FSWs) and men who have sex with men (MSM) [1] . In 2019, 19% of new HIV infections in West and Central Africa occurred among FSWs and 27% among clients of FSWs and other sexual partners of key populations [1] . In Côte d'Ivoire, HIV prevalence among FSWs was estimated to be 11.4% in Abidjan in 2014 [2] , and HIV incidence was 3.2% in San Pedro and 1.5% in Abidjan in 2016-2017 [3] vs. 0.5% in the general population in 2019 [4] . FSWs are exposed to HIV, as they do not systematically use condoms with their male partners-primarily because of coercion, the primacy of men's sexual pleasure, or to obtain protection from their partner against the threat of violence [5] [6] [7] or with their clients in order to earn more, or because of violence from some clients [5, [8] [9] [10] [11] [12] . However, this population often lacks access to adequate services to prevent HIV acquisition and access to HIV care when HIV-positive [13] . In this global context, a new tool for HIV prevention was developed in the last decade: oral pre-exposure prophylaxis (PrEP), which consists of antiretroviral drugs taken by HIV-negative people to prevent HIV acquisition. When taken properly, oral PrEP has been shown to be very effective in preventing HIV acquisition, with a relative reduction of 75 to 86% [14] [15] [16] . Since 2015, oral PrEP has been recommended by the WHO for populations "at substantial risk" of being infected by HIV [17] , such as FSWs. However, the effective implementation of PrEP raises questions, particularly among women, and needs more operational research [17] . First, clinical trials conducted in South and East Africa have shown low adherence among women, resulting in little or no effect of PrEP on HIV acquisition [18, 19] . Likewise, implementation trials conducted in Africa among FSWs have revealed relatively low retention, even when a priori acceptability of PrEP was high [20] [21] [22] . Second, PrEP does not protect against sexually transmitted infections (STIs) or unwanted pregnancies; sexual and reproductive health (SRH) needs beyond HIV must therefore be addressed [23] . More specifically, in Côte d'Ivoire, oral PrEP is not yet implemented at scale, and the National AIDS Programme has been asking for operational research before scaling up. In 2016-2017, we conducted the ANRS 12361 PrEP-CI, a cross-sectional and mixed-methods study, to explore sexual healthcare needs that should be considered within a PrEP program targeting FSWs in Côte d'Ivoire, in order to better describe the experiences of FSWs who are reached via peer educators, and to test the pertinence and a priori feasibility of such programs [5] . Implemented at prostitution sites in two Ivorian cities (Abidjan and San Pedro) in collaboration with two Ivorian community-based organizations (Espace Confiance and Aprosam), the PREP-CI study included (i) a quantitative survey among 1000 FSWs who had never been tested or previously tested HIV-negative, including a socio-behavioral questionnaire, HIV testing, and, for those who tested HIV-positive, collecting a dried blood spot for a recent infection assay to estimate HIV incidence; and (ii) a qualitative survey based on individual interviews and focus-group discussions among 66 FSWs. A final workshop was organized with six community non-governmental organizations (NGOs) and the National AIDS Programme to discuss the main results and to elaborate on an operational research project. Thus, the ANRS 12381 PRINCESSE project was developed based on evidence generated by this PrEP-CI study. The community clinics dedicated to FSWs are mainly frequented by HIV+ FSWs, despite the existence of services for all FSWs. However, their health needs go beyond HIV prevention and care. The non-systematic use of condoms exposes FSWs to STIs and unwanted pregnancies, which increase morbidity and mortality [24] . According to two studies conducted in Côte d'Ivoire in 2014, 70% of FSWs who have ever been pregnant have had at least one abortion [2, 25] , the majority of them clandestinely, as abortion is illegal in Côte d'Ivoire (except for saving the mother's life or in the case of rape since 2019). In the PrEP-CI study, 50% of the surveyed FSWs said they had had at least one abortion in their lifetime, and 65% reported having contracted an STI in the past 12 months. Qualitative interviews revealed the frequent use of cloth or cotton pieces for menstrual hygiene, a source of bacterial infection [26, 27] . Further, contraceptive prevalence is low, despite a high risk of unintended pregnancy. In the PrEP-CI study, 42% of FSWs declared having had an unwanted pregnancy, but 61% were not using contraception other than condoms, thus confirming trends already observed in Abidjan in 2014 [2, 25] . The interviews revealed that FSWs did not use modern contraception for fear of becoming infertile. Hence, there is a need to enhance their sexual health outcomes and to reduce undesirable events such as STIs and unwanted pregnancies. The a priori acceptability of PrEP appeared to be very high (more than 95% of FSWs declared interest in such tools in the PrEP-CI survey). Beyond the availability of PrEP, the entire follow-up of HIV-negative FSWs needs to be (re) designed. Indeed, as efficacy trials have shown, oral PrEP requires quarterly monitoring of users/participants, including renal monitoring and the systematic screening of STIs, since syndromic screening is not sufficient [28] . However, the current priorities of public policies in Côte d'Ivoire and international donors are the identification of new HIV-positive cases and their referral for HIV treatment. It is necessary to develop tools and a new organization of care that allows for the chronic follow-up of HIV-negative FSWs for the proper use of, and adherence to, PrEP. In the context of a high prevalence of hepatitis B, antiretroviral drugs (ARVs) to prevent HIV cannot be made available without making the same ARVs available to treat hepatitis B The prevalence of hepatitis B virus (HBV) is high in Côte d'Ivoire; different studies showed an HBV prevalence situated between 9.4% [29] and 11.1% [30] in the 2010s. A prevalence of hepatitis B surface antigen (HbsAg) of 6.2% was also estimated in a cross-sectional study conducted among FSWs in Abidjan in 2014-2015 [31] . In addition, few FSWs are vaccinated (only 5.2% in the PrEP-CI survey according to FSW self-reports). However, there is currently no free hepatitis B treatment program in Côte d'Ivoire, except for HIV/HBV coinfected patients. Tenofovir-based antiretroviral treatments used for HIV PrEP can also treat hepatitis B. It would be unethical to provide a drug freely for prevention when the same drug is not available for treatment. The implementation of HIV PrEP is an opportunity to articulate HIV prevention and HBV prevention/care. On the one hand, FSWs face many situations of stigmatization and judgmental attitudes from their neighborhood, their entourage, and from health professionals, which complicate their access to care [32] [33] [34] . This is probably amplified for HIV+ FSWs, knowing that people living with HIV also face many stigmatizing situations [35] [36] [37] . On the other hand, SRH requires the concern all FSWs, whether or not they are infected with HIV. For these reasons, also supported by NGO field workers' feedback, it seems essential not to dissociate the followup of HIV-infected and HIV-negative FSWs. It may also help to improve HIV care among FSWs. The NGOs Aprosam and Espace Confiance both carry out outreach activities with peer educators who go to prostitution sites to conduct HIV prevention and rapid testing. Occasionally, they also use mobile clinics to offer an additional syndromic screening of STIs. However, access to fixed community clinics that follow up on these outreach activities remains limited; Espace Confiance estimates that only half of the FSWs who are newly diagnosed with HIV at prostitution sites access a community clinic for HIV care. The interviews conducted in the PrEP-CI study showed that few FSWs were seeking care after unprotected sexual intercourse. The majority were not aware of the availability of prevention tools such as HIV post-exposition prophylaxis or the morningafter pill, despite the information provided by peer educators. They tended to self-medicate rather than visit a healthcare provider. FSWs revealed a reluctance to go to community health centers, mainly because they wished to remain anonymous (for fear of stigmatization by the neighborhood) and because opening hours did not fit their work schedules. In 2011, a KAP (knowledge, attitudes, practices) survey conducted among FSWs in 18 cities in Côte d'Ivoire showed that 81% had heard about a community clinic, but only 60% had ever accessed a community clinic at least once [38] . This could be relevant for implementing mobile clinics that operate directly at prostitution sites, not only for punctual activities, but also for long-term follow-up. According to PrEP-CI data, FSWs migrate seasonally (especially during the coffee and cocoa season in San Pedro, between September and December) or more occasionally (when sex work is done in a different city from their home city). Therefore, their work periods are variable, from some days in a week or month to several months a year. Based on prior evidence, the ANRS 12381 PRINCESSE project aims to implement and evaluate, in Côte d'Ivoire, a community-based comprehensive sexual and reproductive healthcare package, including HIV PrEP, STIs, and HBV management, targeting FSWs. The PRINCESSE study is taking place in San Pedro and its surroundings, Côte d'Ivoire, which is a region with farming businesses (coffee and cocoa in urban zones, and palm oil and hevea in rural areas), thus leading to a high degree of labor migration among men. The harbor of San Pedro is one of the most important harbors in West Africa and the world's largest in terms of cocoa bean exports. The PRINCESSE study was developed in collaboration with the Aprosam community-based organization, which delivers HIV prevention and testing services directly at prostitution sites (outreach activities) and provides HIV and SRH care services to FSWs through a community clinic in San Pedro. In the PrEP-CI study, HIV incidence was estimated at 3.2% in 2016-2017 among FSWs reached by Aprosam in this region [3] . The ANRS 12381 PRINCESSE project is a single-arm interventional cohort of FSWs aiming to develop, document, and analyze a community-based healthcare package that combines testing and prevention tools, including PrEP, immediate HIV treatment, the management of HBV, and SRH. The recruitment of the PRINCESSE cohort (baseline participants) started on November 26th, 2019 and is ongoing, partly due to the pandemic of COVID-19; the cohort is planned to last at least 30 months. Recruitment of participants is made possible by the Aprosam organization's networks of peer educators and their access to the population. In total, the PRINCESSE cohort aims to include 500 FSWs at prostitution sites. A pragmatic approach was taken to determine the sample size of the study, considering the absorption capacity of the mobile clinic. The mobile clinic is organized to return to the same site every two weeks. Operating five days a week, ten different sites are covered. In order to ensure sufficient consultation time for each FSW, our target was a maximum of ten consultations per trip. Since PRINCESSE follow-up consists of a quarterly visit on average, with the same site being visited five to six times per quarter, the target number of FSWs followed up periodically for a mobile clinic is 5 (visits on each site per quarter) × 10 sites × 10 consultations/visit = 500 FSWs per mobile clinic. Considering an HIV prevalence of around 20% [2] , it was anticipated to recruit 100 (500 × 20%) HIV-positive FSWs and 400 (500 × 80%) HIV-negative FSWs. Most outcomes listed in Table 3 (see below) are proportions. A minimum sample of n = 402 is required to estimate the 95% confidence interval of an expected proportion of 50% with a precision of ±5. For an expected proportion of 10% (or 90%), with a precision of ±3, a minimum sample of n = 414 is required. To have 80% power to detect with an alpha risk of 5% an evolution of ±10 points (e.g. from 50 to 60%) between two time points, a minimum sample of n = 408 is required. The inclusion criteria are: • Being a woman over 18 years of age • Self-reporting as being a sex worker • Wishing to enroll in a regular clinical follow-up • Agreeing to participate in the study and signing the informed consent form • Not already participating in another biomedical or behavioral study on HIV, viral hepatitis, or STIs • Regardless of HIV status (infected or not) • Whether or not the participant has already taken antiretrovirals • Whether or not the participant is already followed by Aprosam The PRINCESSE intervention is delivered using a mobile clinic at 10 prostitution sites: 5 urban sites in the city of San Pedro and 5 rural sites around San Pedro (Fig. 1) . Care services are also available at the fixed community clinic of Aprosam in San Pedro. Each prostitution site is visited every two weeks, and the operating hours vary according to each site. After inclusion, participants are invited to be followed up with every 3 months, either in the mobile or fixed clinic, at their preference. FSWs can also access the clinics anytime they need to, in addition to planned quarterly visits. The mobile clinic team comprises a medical doctor, a laboratory technician, a community counselor, a driver, two FSW peer-educators, and an independent interviewer. The PRINCESSE healthcare package is summarized in Table 1 and detailed below. All participants are screened for HIV during the inclusion visit using rapid tests according to the national testing algorithm: Determine ® (sensitivity: 100%; specificity: 98.9%), Stat-pak ® (sensitivity: 99.5%; specificity: 100%), and Biolane ® in the case of a discrepancy. In the case of a new HIV diagnosis, a blood sample is collected for confirmation in a laboratory. All participants are also screened for antigen HBs (AgHBs) using the rapid test Determine ® (sensitivity: 93.6%; specificity: 100%) or VIKIA ® (sensitivity: 96.5%: specificity: 99.9%). In case of a negative result for AgHBs, a blood sample is collected for anti-HBs and anti-HBc antibody testing in a laboratory. In case of a positive result for AgHBs, blood samples are collected for measuring HBV viral load, antigen HBe, platelets, ALT, and AST in a laboratory. The fibrosis level (F0-F1-F2 or F3-F4) is estimated using the FIB-4 indicator [39] . HIV treatment guidelines [40] , HIV PrEP guidelines [41] , and Hepatitis B guidelines [39] have been combined to produce the HIV/HBV care algorithm for the PRIN-CESSE participants ( Table 2 and Fig. S1 ). Participants who are HIV-and AgHBs-negative are offered the chance to initiate TDF/FTC (tenofovir and emtricitabine) for daily oral PrEP. For those interested, a blood sample is collected to measure creatinine clearance using the equation of Cockcroft & Gault. PrEP will only be prescribed if renal function is normal (creatinine clearance ≥60 mL/min); there is no contraindication to TDF and FTC; there are no clinical manifestations suggestive HIV-infected participants are followed according to Ivorian national treatment guidelines [40] . Antiretroviral treatment is proposed as soon as possible, regardless of CD4 count. In the case of HIV-HBV coinfection, antiretroviral treatment is adapted. Patients not immunized against HBV (HBs and HBc antibodies, testing negative for both) are offered the chance to get vaccinated (4 times a double dose, at M0, M1, M2, and M6). For patients infected by HBV for whom treatment is recommended (a high level of HBV DNA or transaminases or fibrosis ≥F2), a blood sample is collected to measure creatinine clearance using the equation of Cockcroft & Gault. If creatinine clearance is ≥60 mL/ min, TDF/FTC (1 pill/day) is prescribed. TDF/FTC is one of the regimens recommended by the WHO ([39], Table 6 .1.a). For patients with creatinine clearance below 60 mL/min, only tenofovir (TDF) is prescribed at a reduced dosage, as recommended by the WHO ([39], Table 9 .1): 50-59 mL/min: one 300 mg tablet every 24 h; 30-49 mL/min: one 300 mg tablet every 48 h; 10-29 mL/ min: one 300 mg tablet every 72-96 h; and < 10 mL/min: one 300 mg tablet every 7 days. These patients are advised that there is no demonstrated prophylactic effect against HIV, with non-daily TDF, and will be encouraged to maintain the use of other HIV prevention tools. For patients infected by HBV for whom treatment is not yet recommended (a low level of HBV DNA or ALT or fibrosis