Self-applied carrageenan-based gel to prevent human papillomavirus infection in sexually active young women: Final analysis of efficacy and safety of a randomised controlled trial

IntroductionThe Carrageenan-gel Against Transmission of Cervical Human papillomavirus trials interim analysis (June 2017, n=277) demonstrated a 36% protective effect of carrageenan against incident human papillomavirus (HPV) infections. We report the trials final results on efficacy and safety of a carrageenan-based gel in reducing HPV incidence and prevalence. MethodsA phase IIB randomised, placebo-controlled trial, recruited healthy young women aged [&ge;]18 primarily from health service clinics at two Canadian Universities in Montreal, Canada. Participants were randomised (1:1) to a carrageenan-based or placebo gel to be self-applied every other day for the first month and before/after intercourse. Primary outcomes were HPV type-specific incidence and clearance of prevalent infections. At each visit (months 0, 0.5, 1, 3, 6, 9, 12), participants provided questionnaire data and a self-collected vaginal sample (tested for 36 HPV types, Linear Array). Intention-to-treat analyses were conducted using Cox proportional hazards regression models. Incidence and clearance analyses were restricted to participants with [&ge;]2 visits. Trial registration:ISRCTN96104919. Findings461 participants (enrolled January 16th/2013-September 30th/2020) were randomised to carrageenan (n=227) or placebo (n=234) arm. Incidence, clearance, and safety analyses included 429, 240, and 461 participants, respectively. We found 51{middle dot}9% (108/208) of participants in carrageenan and 66{middle dot}5% (147/221) in placebo arm acquired [&ge;]1 HPV type (hazard ratio [HR] 0{middle dot}63 [95% CI: 0{middle dot}49-0{middle dot}81]). Among participants who tested HPV-positive at baseline, clearance (two consecutive HPV-negative visits following [&ge;]1 positive visit) was comparable between groups; 31{middle dot}8% (34/107) in carrageenan and 29{middle dot}3% (39/133) in placebo arm cleared their infections (HR 1{middle dot}16 [95% CI: 0{middle dot}73-1{middle dot}84]). Adverse events were reported by 34{middle dot}8% (79/227) and 39{middle dot}7% (93/234) of participants in carrageenan and placebo arm (p<0.27), respectively. InterpretationConsistent with the interim analysis, use of a carrageenan-based gel resulted in a 37% reduction in the risk of incident genital HPV infections in women. A carrageenan-based gel may complement HPV vaccination. FundingCanadian Institute of Health Research (grants MOP-106610 and FDN-143347 to ELF), CarraShield Labs Inc. (St Petersburg, FL) [provided gels in kind]. RESEARCH IN CONTEXT Evidence before this studyWe published in 2021 a narrative review summarizing carrageenans preventive effect on human papillomavirus (HPV) based on results from 19 experimental research articles that reported on carrageenans anti-HPV activity. Since publication and without applying language or date restriction, we identified four additional records based on a PubMed search using the keywords "carrageenan" and "human papillomavirus" or "HPV" up to January 9th, 2023. Altogether, these records consist of ten in vitro (including 4 ex vivo), five in vitro and in vivo, three in vivo, and five clinical studies (including one post-hoc phase III randomised controlled trial [RCT], one observational study, one interim analysis of a phase IIB RCT in women, and two records for the interim analyses of a phase IIB RCT in men). Studies assessed carrageenan alone or in combination with other anti-microbial agents. The results from pre-clinical studies were consistent with a protective effect of carrageenan against HPV. Overall, eight studies were conducted in humans. The samples collected were either 1) cervicovaginal lavage samples to assess anti-HPV activity in vitro (in three ex vivo studies, two being phase I RCTs), or 2) genital samples from women (post-hoc RCT [cervical], observational study [sample type not reported], and RCT phase II [vaginal]) or anal samples from men (one study of incidence and one of clearance). In the three ex vivo studies, intravaginal use of carrageenan-containing gels was associated with strong anti-HPV activity. In a post-hoc sub study of the trial, a lower HPV prevalence in the carrageenan compared to placebo arm was found at the trial end, but only among the most compliant users (adjusted odds ratio [aOR] 0{middle dot}62 [95% CI 0{middle dot}41-0{middle dot}94], n=348). There were, however, no baseline or intermediate measurements to assess HPV status. An observational study reported that a carrageenan-based gel may accelerate clearance of existing HPV infection (aOR 4{middle dot}9 [95% CI 1{middle dot}60-15{middle dot}1], n=75). The interim analysis of the CATCH study found a 36% protective effect of carrageenan against incident HPV infection(s) (HR 0{middle dot}64 [95% CI 0{middle dot}45-0{middle dot}89], n=277). Conversely, a clinical trial conducted in men who have sex with men did not demonstrate a protective effect of carrageenan on incidence (HR 1{middle dot}21 [95% CI 0{middle dot}86-1{middle dot}70]), or clearance (HR 0{middle dot}84 [95% CI 0{middle dot}31-2{middle dot}27]) of anal HPV infections, and reported more adverse events in the carrageenan (59{middle dot}8%) relative to the placebo (39{middle dot}8%) arm. Added value of this studyThe CATCH study is the first clinical trial designed to assess the efficacy of a carrageenan-based gel in reducing the risk of incident and prevalent HPV infections in women. Results were consistent when considering HPV subgenera and type-specific analyses. The addition of carrageenan to a lubricant gel does not appear to impact gel tolerability. Implications of all the available evidenceThe results of the CATCH trial indicate that carrageenan-based gels could complement HPV vaccination in protecting against HPV-related diseases. Our findings of the clinical efficacy of carrageenan may encourage future research in this area. It would be important to further examine adherence by looking at determinants of adherence, explore the possibility of the addition of carrageenan to condoms, assess the impact of a carrageenan-based gel on anal HPV infections in women, and continue research in the area of multi-purpose prevention technology for agents against HPV, HIV, and other sexually transmitted infections.