Clinical Trials

MainTitle

Tenofovir/Emtricitabine With Doxycycline for Combination HIV and Syphilis Pre-exposure Prophylaxis in HIV-negative MSM (DuDHS)

This study is ongoing, but not recruiting participants.
Sponsor
British Columbia Centre for Disease Control


Information provided by (Responsible Party)
Jonathan Troy Grennan, British Columbia Centre for Disease Control

ClinicalTrials.gov Identifier
NCT02844634

First received: July 22, 2016
Last updated: July 11, 2019
Last Verified: July 2019
History of Changes
Purpose

Purpose

Men who have sex with men remain at high risk for HIV infection. Targeting prevention interventions to MSM at highest risk of seroconversion is an important goal of combination prevention interventions. Antecedent diagnosis of another sexually transmitted infection (STI), particularly syphilis, may serve as an entry point for biomedical prevention as these individuals are at highest risk for incident HIV. The use of the antiretroviral combination of tenofovir/emtricitabine has been shown to be associated with an overall 44% reduction in HIV acquisition in high-risk MSM when taken daily as PrEP. In those individuals with detectable drug levels, the benefit was as high as 90% risk reduction. In real-world evaluations of PrEP, high-risk sexual behaviour may continue as evidenced by high rates of intercurrent sexually transmitted infections. As such, biomedical interventions that may offer additional reduction in acquisition of common sexually transmitted infections should also be evaluated.

Recently a small pilot study has demonstrated potential benefit from a similar strategy for syphilis prevention. In this study 30 MSM were randomized to receive either 100mg doxycycline once daily or contingency management strategies linked to remaining free of sexually transmitted diseases at progressive study visits. Overall, those receiving doxycycline were significantly less likely to be diagnosed with any STI during followup than those in the comparator arm.

The investigators therefore propose to undertake a pilot study to evaluate the feasibility of using both tenofovir/emtricitabine and doxycycline (immediate or deferred use) for pre-exposure prophylaxis amongst HIV-negative MSM with recent history of syphilis infection in Vancouver, Canada.

Condition Intervention Phase
HIV
Syphilis

Drug : Doxycycline 100mg PO daily x 12 months
Drug : Tenofovir/emtricitabine 200/300mg PO daily
Drug : Doxycycline 100mg PO daily x 6 months
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Use of Tenofovir/Emtricitabine With Immediate or Deferred Doxycycline 100mg PO Daily for Combination HIV and Syphilis Pre-exposure Prophylaxis in HIV-negative Men Who Have Sex With Men: a Pilot Study of Dual Daily HIV and Syphilis PrEP. (The DuDHS Trial).

Further study details as provided by Jonathan Troy Grennan, British Columbia Centre for Disease Control:

Primary Outcome Measures

  • The proportion of participants who are eligible and consent to participate amongst those approached. [ Time Frame: 12 months ]
    To evaluate the feasibility of recruitment for a larger study
  • Proportion of participants reporting > 95% adherence to both HIV and syphilis PrEP therapies [ Time Frame: 12 months ]
    To assess adherence of dual HIV and syphilis PrEP therapies
  • The proportion of individuals with detectable doxycycline at each study time point. [ Time Frame: 12 months ]
    To assess adherence of syphilis PrEP therapy
  • The proportion of individuals reporting grade 3 or 4 adverse events in the immediate vs. deferred arms. [ Time Frame: 12 months ]
    To assess the tolerability of dual HIV and syphilis PrEP therapies
  • The proportion of individuals with evidence of tetracycyline class resistance in common flora [ Time Frame: 6 and 12 months ]
    To evaluate antimicrobial resistance over time
Secondary Outcome Measures:
  • To evaluate changes in sexual activity reported by study participants over the study period. [ Time Frame: 12 months ]
    Evaluation of sexual activity over time
  • To evaluate incidence of recurrent syphilis re-infection stratified by use immediate versus deferred doxycycline PrEP. [ Time Frame: 12 months ]
    Evaluation of syphilis incidence rates between the two study arms
  • To describe incidence of gonorrhea or chlamydia infection over the study period. [ Time Frame: 12 months ]
    Assessment of the frequency of other STIs over time
Other Outcome Measures:
  • To assess the incidence of HIV in study participants [ Time Frame: 12 months ]
    Exploratory outcome to access incidence rates for HIV infection
  • To assess the incidence of doxycycline resistance in those with documented T. pallidum infection. [ Time Frame: 12 months ]
    Exploratory outcome to assess incidence rates for doxycycline resistance
  • To assess the changes in the composition of the rectal microbiome [ Time Frame: 6 and 12 months ]
    Exploratory outcome to determine percentage changes in the bacterial genius of the rectal microbiome

Enrollment: 52
Study Start Date: May 15, 2018
Estimated Study Completion Date: June 30, 2020
Estimated Primary Completion Date: May 28, 2020 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Immediate doxycycline 100mg PO daily
Individuals will receive tenofovir/emtricitabine one tablet daily in an open-label fashion. Subjects are randomized to immediate (12 months duration) doxycycline 100mg PO daily.
Drug: Doxycycline 100mg PO daily x 12 months

Immediate use of daily doxycycline (12 months duration, to start immediately)

Drug: Tenofovir/emtricitabine 200/300mg PO daily

Daily use of tenofovir/emtricitabine

Active Comparator: Deferred doxycycline 100mg PO daily
Individuals will receive daily tenofovir/emtricitabine one tablet daily and will begin doxycycline 100mg PO daily after 6 months for a total duration of 6 months
Drug: Tenofovir/emtricitabine 200/300mg PO daily

Daily use of tenofovir/emtricitabine

Drug: Doxycycline 100mg PO daily x 6 months

Deferred use of doxycycline (6 months duration, to start 6 months post-randomization)

Detailed Description:

  1. Rationale: ~#o3~1 Men who have sex with men with antecedent diagnosis of another sexually transmitted infection, particularly syphilis, are at high risk for HIV infection.

Men who have sex with men (MSM) continue to experience high rates of HIV incident infections in Canada and a disproportionately high burden of disease relative to the general population. In 2011, approximately 48% of new diagnoses occurred in MSM across Canada, a figure that has been relatively stable for the last decade. Within British Columbia (BC), although HIV new diagnosis rates overall have been declining over the last decade (dropping from a rate of 10.6 cases/100,000 in 2004 to 5.9 cases/100,000 in 2013), MSM made up an increasing majority of new diagnoses (59%) within BC in 2013. Within Vancouver Coastal Health Authority (VCH), approximately 70% of all new HIV diagnoses annually from 2012-15 were amongst MSM.
Targeting prevention interventions to MSM at highest risk is important when determining potential publicly funded biomedical interventions, particularly the use of HIV pre-exposure prophylaxis (PrEP). Antecedent diagnosis of another sexually transmitted infection (STI) may serve as an entry point for biomedical prevention as these individuals are at highest risk for incident HIV. In an evaluation of HIV incidence following diagnosis of syphilis infection in New York City, the annual HIV incidence was
  • 6% (95% Confidence Interval [CI]: 3.27% - 3.97%), with overall HIV incidence amongst MSM of 5.56% (1). In those males with syphilis and a subsequent additional STI the HIV incidence was even greater at 7.89% (95% CI: 6.62% - 9.24%). A similar analysis of clients attending STI clinics in BC has revealed that antecedent STI is predictive of an elevated risk for subsequent HIV seroconversion with clients who ever had a diagnosis of syphilis having an HIV incidence of 3.6% person-years (95%CI: 2.5-4.9), gonorrhea (2.0%; 95%CI: 1.6-2.5), rectal gonorrhea (4.5% person-years; 95%CI: 3.4-5.8), while individuals with rectal gonorrhea and syphilis had an incidence rate of 12.6 % person-years (95%CI:
  • 4-21.8).

  • Evaluating the use of PrEP in MSM with antecedent STI is an important component to inform HIV prevention programs in BC and nationally. The STI clinics operated by the BC Centre for Disease Control are well-positioned for this evaluation as about 15 and 25% of all HIV diagnoses in BC and VCH, respectively are diagnosed at these clinics.
    1. 2. STI prevention strategies may also benefit from biomedical prevention interventions

    Novel biomedical strategies have been shown to be effective in preventing acquisition of STI such as HIV, and are now considered to be standard of care for at-risk MSM in the United States. The use of the antiretroviral combination of tenofovir/emtricitabine has been shown to be associated with an overall 44% reduction in HIV acquisition in high-risk MSM when taken daily as PrEP. In those individuals with detectable drug levels, the benefit was as high as 90% risk reduction. In real-world evaluations of PrEP, high-risk sexual behaviour may continue as evidenced by high rates of intercurrent STI (50% of PrEP users after 12 months in a study of 657 PrEP initiators in San Francisco). As such, biomedical interventions that may offer additional reduction in acquisition of common sexually transmitted infections should be evaluated.
    Recently a small pilot study has demonstrated potential benefit from a similar strategy for syphilis prevention (2). In this study 30 MSM were randomized to receive either 100mg doxycycline once daily or contingency management strategies linked to remaining free of sexually transmitted diseases at progressive study visits. Doxycycline 100mg daily was chosen based on prior studies indicating that doses as low as once weekly doxycycyline could serve as prophylaxis for leptospirosis, another spirochete infection.
    Overall, those receiving doxycycline were significantly less likely to be diagnosed with any STI during follow-up than those in the comparator arm (odds ratio [OR] 0.27; 95% CI
  • 09 - 0.83). Specific protection against syphilis infection was not seen during the on-treatment phase (OR 0.27; 95% CI 0.04 - 1.73), possibly reflecting the small sample size. During the study period, no change in sexual behaviours between arms was noted, supporting the potential role of doxycycline prophylaxis. A larger pilot evaluation of this strategy, in combination with HIV PrEP, would be a novel syndemic approach to addressing both the HIV and syphilis burden amongst the highest risk MSM.

  • The investigators therefore propose to undertake a randomized trial of immediate vs. deferred doxycycline in conjunction with daily tenofovir/emtricitabine to determine the feasibility of combined HIV and syphilis pre-exposure prophylaxis amongst HIV-negative MSM with recent history of syphilis infection in Vancouver, Canada.
  • Objectives:

  • We propose to undertake a pilot trial of immediate vs. deferred doxycycline in conjunction with daily tenofovir/emtricitabine to determine the feasibility of combined HIV and syphilis pre-exposure prophylaxis amongst HIV-negative MSM with recent history of syphilis infection in Vancouver, Canada. We will meet this aim through the following objectives:
  • To assess feasibility of using dual daily HIV and syphilis PrEP, as defined by:

  • a. Evaluation of feasibility of recruitment for a larger study i. Proportion of participants approached for study who are eligible and agree to participate.
    b. Adherence to 6 or 12 months of tenofovir/emtricitabine and doxycycline i. Determine proportion of individuals with >95% adherence to dual therapy over 6 and 12 months ii. Proportion of individuals with detectable doxycycline plasma level at each study visit.
    Additional measures of feasibility will include the assessment of:
    c. Tolerability of dual PrEP i. Comparison of grade 3 or 4 adverse events in those receiving immediate vs. deferred PrEP
  • To evaluate antimicrobial resistance over time.

  • a. Change in proportion of participants with evidence of tetracycline class resistance in common flora, namely Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae from baseline to 6 and 12 months.

    SECONDARY OBJECTIVES
      will include:
    1. To evaluate changes in sexual activity reported by study participants over the study period.
    2. To compare syphilis incidence between those in the immediate vs. deferred doxycycline arms.
    3. To describe frequency of other STI's diagnosed in study participants over the study period.

    Exploratory objectives will include:
  • To evaluate doxycycline resistance in individuals with documented T.pallidum infection.
  • To evaluate HIV incidence and syphilis re-infection rates over a 12 month period.
  • Characterize changes in the rectal microbiome from baseline to 6 and 12 months after initiation of doxycycline

    Eligibility

    Eligibility

    Ages Eligible for Study: 19 Years and older  
    Sexes Eligible for Study: Male  
    Accepts Healthy Volunteers: No  

    Criteria

    Inclusion Criteria:

      1. Age ≥ 19 years of age.
      2. Self-reported MSM status.
      3. Self-report condomless anal sex with a man within the last 6 months.
      4. HIV negative based on HIV nucleic acid amplification testing (NAT).
      5. Prior diagnosis of syphilis within preceding 36 months (defined on the basis of a new positive serum rapid plasma reagin (RPR) test, or ≥2-dilution rise in titre if previous syphilis, or positive darkfield microscopy result or T. pallidum direct fluorescent antibody test or PCR from a primary lesion).
      6. Able to provide informed consent.


    Exclusion Criteria:
      1. HIV-positive individuals.
      2. Recent (within last 30 days) use of HIV post-exposure prophylaxis (PEP).
      3. Impaired renal function defined as glomerular filtration rate < 60 mL/min.
      4. Chronic active Hepatitis B infection.
      5. History of myasthenia gravis.
      6. History of tetracycline/doxycycline allergy.

    contacts and locations

    Contacts and Locations

    Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

    Please refer to this study by its ClinicalTrials.gov identifier: NCT02844634

    Locations

    Canada
    BC Centre for Disease Control
    Vancouver, British Columbia, Canada, V5Z4R4

    Sponsors and Collaborators

    British Columbia Centre for Disease Control

    Investigators

    Principal Investigator: Troy Grennan, MD BC Centre for Disease Control
    More Information

    More Information


    Responsible Party: Jonathan Troy Grennan, Physician Lead HIV/STI Program, British Columbia Centre for Disease Control  
    ClinicalTrials.gov Identifier: NCT02844634   History of Changes  
    Other Study ID Numbers: BritishCCDC  
    Study First Received: July 22, 2016  
    Last Updated: July 11, 2019  
    Individual Participant Data    
    Plan to Share IPD: No  

    Studies a U.S. FDA-regulated Drug Product: No  
    Studies a U.S. FDA-regulated Device Product: No  

    Keywords provided by Jonathan Troy Grennan, British Columbia Centre for Disease Control:

    pre-exposure prophylaxis
    men who have sex with men
    HIV prevention
    sexually transmitted infection
    syphilis

    Additional relevant MeSH terms:
    Syphilis
    Tenofovir
    Emtricitabine
    Doxycycline

    ClinicalTrials.gov processed this data on October 15, 2019
    This information is provided by ClinicalTrials.gov.