Combined Prevention of Sexually Transmitted Infections (STIs) in Men Who Have Sex With Men and Using Oral Tenofovir Disoproxil Fumarate/ Emtricitabine (TDF/FTC) for HIV Pre-Exposure Prophylaxis (PrEP)

Study Overview
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Brief Summary
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The study ANRS 174 Doxyvac is a clinical trial that will use Combined Prevention of Sexually Transmitted Infections (STIs) in Men Who Have Sex with Men and using oral TDF/FTC for HIV Pre-Exposure Prophylaxis (PrEP) and vaccination with Bexsero.

Detailed Description
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This is a randomized study with a factorial design for the 2 biomedical interventions (interventions 1 and 2). Subjects will be randomized and assigned to two different interventions: Intervention 1: PEP with doxycycline or no PEP. Subjects will be randomized 2/1 to receive doxycycline PEP or no PEP Intervention 2: Meningococcal B vaccine (Bexsero®) or no vaccine Subjects will be randomized 1/1 to received 2 doses of Bexsero® vaccine (at the first visit and two months later) or no vaccine Participants will be randomized in one of the following arms: Arm 1: doxycycline and Bexsero® vaccine (240 participants) Arm 2: doxycycline and no Bexsero® vaccine (240 participants) Arm 3: no doxycycline and Bexsero® vaccine (120 participants) Arm 4: no doxycycline and no Bexsero® vaccine (120 participants) Randomization will be stratified by whether or not the participant enters in the ancillary study intestinal microbiota.

Official Title
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Combined Prevention of Sexually Transmitted Infections (STIs) in Men Who Have Sex With Men and Using Oral Tenofovir Disoproxil Fumarate/ Emtricitabine (TDF/FTC) for HIV Pre-Exposure Prophylaxis (PrEP)

Conditions
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Unsafe Sex, Risk-Taking

Intervention / Treatment
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* Drug: Experimental: doxycycline
* Biological: Bexsero® vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Mens who have sex with mens (MSM) enrolled in the ANRS PREVENIR study. At least 6-month experience with PrEP (within the ANRS PREVENIR study or before starting the ANRS PREVENIR study). No clinical manifestation of primary HIV infection and no symptom of bacterial STI (chlamydia, gonorrhea, M. genitalium or syphilis). History of documented bacterial STI with at least one episode in the last 12 months. Participants who agree to sign the information and consent form specific to this study. Valid health insurance (State medical aid (AME) is not health insurance). Exclusion Criteria: Syphilis diagnosed prior to inclusion without serologic evidence of cure (cure is defined as decreased by at least 4-fold of the non-treponemal antibody titer [Venereal Disease Research Laboratory (VDRL), Rapid Plasma Reagin (RPR)] relative to the titer at initiation of treatment of syphilis). HIV infection. Previous vaccination with Bexsero® or any other meningococcal B vaccine. Vaccination during the 4 weeks (28 days) preceding the first vaccination of the study. Previous vaccination with an experimental vaccine in the previous 5 years. Systemic treatment with retinoids : isotretinoin (Acnetrait®, Procuta®, Curacné®, Contracné®, …). Treatment with enzyme-inducing anticonvulsants (carbamazepine, phenobarbital, phenytoin, ….). Participant who has received immunoglobulins, a transfusion of blood or blood derivatives in the last 3 months. Known or suspected congenital or acquired immunodeficiency; immunosuppressive treatment in the last 6 months, such as cancer chemotherapy or radiotherapy; long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks in the last 3 months) Known allergy to antibiotics of the tetracycline family. Known allergy to any component of the Bexsero® vaccine. Known allergy to any component of the doxycycline pill. Known allergy to latex (contained in the vaccine cap). Thrombocytopenia or any other known coagulation disorder, which would be a contraindication to an intramuscular injection of Bexsero® vaccine. Documented oesophageal lesion Acute respiratory infection or severe acute febrile illness or systemic reaction that may present a significant risk if vaccinated in the month prior to inclusion. Any condition (clinical) that, in the investigator's opinion, would contraindicate intramuscular vaccination and blood sampling. Oral Anticoagulant treatment. Continuous treatment with doxycycline at inclusion. Vitamin A treatment in case of intake of 10 000 international unit or more. Participation in another research including an exclusion period still in progress at the time of inclusion. Under guardianship or curator, or deprived of liberty by a judicial or administrative decision.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Arm 1 : doxycycline and Bexsero vaccine Arm 2 : doxycycline and no vaccine Arm 3 : No doxycycline and Bexsero vaccine Arm 3 : No doxycycline and No Bexsero vaccine
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: doxycycline and Bexsero® vaccine<br>-doxycycline will be taken by participants as PEP (prophylaxy post exposition) and participants will received Meningococcal B vaccine (Bexsero®) at D0 and M2 | Drug: Experimental: doxycycline<br>* 2 tablets of doxycycline 100 mg (monohydrate form) will be taken orally after each risk sexual intercourse, ideally within 24 hours after sex and no more than 72 hours. PEP should not be taken more than 3 times over a 7 days' period. If a participant has risk sexual intercourse for several consecutive days, PEP should be taken at least 48 hours apart and no more than 3 times 2 tablets over 7 days. A maximum of 3 intakes of 2 tablets will be allowed over a period of 7 days.<br>Biological: Bexsero® vaccine<br>* 1st injection of Bexsero® vaccine at inclusion visit, 2nd injection at week 8.<br>|
| Experimental: doxycycline<br>-doxycycline will be taken by participants as PEP (prophylaxy post exposition) | Drug: Experimental: doxycycline<br>* 2 tablets of doxycycline 100 mg (monohydrate form) will be taken orally after each risk sexual intercourse, ideally within 24 hours after sex and no more than 72 hours. PEP should not be taken more than 3 times over a 7 days' period. If a participant has risk sexual intercourse for several consecutive days, PEP should be taken at least 48 hours apart and no more than 3 times 2 tablets over 7 days. A maximum of 3 intakes of 2 tablets will be allowed over a period of 7 days.<br>|
| Experimental: Bexsero® vaccine<br>-Meningococcal B vaccine (Bexsero®) at D0 and M2 | Biological: Bexsero® vaccine<br>* 1st injection of Bexsero® vaccine at inclusion visit, 2nd injection at week 8.<br>|
| No Intervention: No treatment<br>-no doxycycline and no Bexsero® vaccine | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For intervention 1 (with or without doxycycline PEP) : 1st occurence of chlamydia or syphilis after the enrolment visit (Day 0) | Intervention 1 (with or without doxycycline PEP) is the first episode of chlamydia or syphilis after the enrolment visit (Day 0) (chlamydia and syphilis diagnosed at the enrolment visit will not be included in the primary endpoint). Chlamydia détection will be performed by polymerase chain reaction.Syphilis détection will be performed by antigen. | Month 24 | 
| For intervention 2 with or without Bexsero® vaccine : 1st occurence of gonorrhea reported one month after the second vaccine injection | Intervention 2 (with or without Bexsero® vaccine) is the first episode of gonorrhea reported one month after the second vaccine injection, so starting at the month 3 visit (gonorrhea episodes diagnosed at the enrolment visit and before the month 3 visit will not be included in the primary endpoint). In these analyses, subject follow-up will be right-censored at the time of the first STI. Gonorrhea détection will be performed by polymerase chain reaction. | Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| - Occurrence of a first episode of each of the bacterial STIs as well as cumulative incidence of each bacterial STIs | - Occurrence of a first episode of each of the bacterial STIs as well as cumulative incidence of each bacterial STIs (syphilis, chlamydia; gonorrhoea and Mycoplasma genitalium) during the trial. In that case, the entire follow-up will be considered. Chlamydia détection will be performed by polymerase chain reaction. Syphilis détection will be performed by antigen. Mycoplasma genitalium be performed by polymerase chain reaction. Gonorrhea détection will be performed by polymerase chain reaction. | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Occurrence of a new episode of anal or urinary gonorrhoea. | - Occurrence of a new episode of anal or urinary gonorrhoea. Gonorrhea détection will be performed by polymerase chain reaction. | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Occurrence of a first symptomatic episode of chlamydia infection or gonorrhea | - Occurrence of a first symptomatic episode of chlamydia infection or gonorrhea at urinary or anal sites. Chlamydia détection will be performed by polymerase chain reaction. Gonorrhea détection will be performed by polymerase chain reaction. | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Proportion of patient with Methicillin-Resistant Staphylococcus Aureus and/or doxycycline resistant Staphylococcus aureus from throat. Fecal carriage of Extended-Spectrum Beta-Lactamase-producing Enterobacteriaceae Composition of intestinal microbiota | detection from throat swab of carriage of MRSA (methicillin-resistant Staphylococcus aureus) and/or doxycycline resistant Staphylococcus aureus, fecal carriage of ESBL (extended-spectrum beta-lactamase) -producing Enterobacteriaceae, and composition of the intestinal microbiota), all détected by polymerase chain reaction assay | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Incidence of clinical and biological adverse events | Proportion of patients experiencing a clinical or biological adverse events (ANRS scale) | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Proportion of patients taking doxycycline | Adherence will be evaluated by doxycycline pills taken by patients | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Concentration of doxycycline in hair | Adherence will be evaluated by détection of doxycyclin in hair | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Proportion of patients with Antibiotic susceptibilities of all strains of NG (Neisseria gonorrhoeae), CT (chlamydiae trachomatis), MG (mycoplasma genitalium) | identification of Antibiotic susceptibilities of all strains of NG (Neisseria gonorrhoeae), CT (chlamydiae trachomatis), MG (mycoplasma genitalium) to doxycycline, macrolides, fluoroquinolones and third generation cephalosporin will be performed by PCR (polymerase chain reaction assay) | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Rate of cured STIs after treatment with or without PEP. | declaration of illnesses from infection to healing | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Incidence of resistance to antibiotics of Neisseria gonorrhoeae with or without doxycycline. | Proportion of participants with resistance to antibiotics of Neisseria gonorrhoeae will be evaluated by polymerase chain reaction to detect mutations | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Incidence of Serum bactericidal activity against meningococcal and gonococcal antigens over time in participants of Bexsero®'s arm. | Proportion of participants with Serum bactericidal activity against meningococcal and gonococcal antigens | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Incidence of clinical and biological adverse events following Bexsero® vaccine. | Proportion of participants experiencing a clinical and biological adverse events following Bexsero® vaccine (ANRS scale) | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Prevalence and incidence of meningococcal carriage in pharyngeal, anal and urine swabs. | detection of meningococcal carriage in pharyngeal, anal and urine swabs will be performed | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Impact of PEP or Bexsero® vaccine on sexual behaviour | rates of condom use for receptive anal intercourse, number of sexual partners and number of sex acts over time | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 
| - Incidence of HIV infection with both prophylaxis strategies. | HIV infection will be tested by serology and western blot assay | Month 2, Month 3, Month 6, Month 12, Month 18, Month 21, Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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STI infection, PREVENTION