Impact of antiviral AV2 in the topical treatment of HPV-associated lesions of the cervix: Results of a phase III randomized placebo-controlled trial.

BACKGROUND: Non-surgical topical therapies have been assessed in the treatment of precancerous lesions of the cervix. Their use can offer logistical and feasibility advantages in low-resource settings. Antiviral AV2® is a mixture of natural essential oils (eugenol, carvone, nerolidol, geraniol) in olive oil, and has a broad spectrum anti-viral activity. In a phase II randomized controlled trial (RCT), AV2® proved effective in reducing the size of cervical lesions associated with human papillomavirus (HPV). The purpose of the present study was to further evaluate the efficacy of AV2 over placebo in the topical treatment of HPV-associated cervical lesions. METHODS: Women aged 25 years and older were included in this phase 3 RCT. Cytology screening, HPV testing and visual inspection of the cervix with 5% acetic acid (VIA) were performed on all participants. VIA-positive women were randomized to one of two groups to receive treatment by either AV2® or placebo. The treatment consisted of 2 puffs of spray of the investigational drug directed to the cervix. Participants were subjected to repeat examinations two months and six months later for assessment of outcomes. The primary outcome was the change of lesions on VIA at 2 months after application of the investigational drug. Secondary outcomes were: HPV clearance and cytologic regression at 2 months and 6 months, and number of participants with AEs. RESULTS: A total 327 VIA positive women were randomized in two groups (168 in AV2 group and 159 in placebo group). Women in the 2 groups were similar with respect to baseline demographics and clinical characteristics. At 2 months, regression of lesions on VIA was observed in 127 (89.4%) out of 142 women in AV2 group compared to 120 (91.6%) out of 131 women in placebo group (P = 0.7). On cytology, regression of lesions occurred in 14 (56%) out of 25 women in the AV2 arm and in 13 (48.1) out of 27 women in the placebo arm (p = 0.7), and HPV clearance rates were 34.1% and 35% in AV2 group and placebo group respectively (p = 0.8). At 6 months cytologic regression was observed in 64.7% of women in AV2 group and 45.8% in placebo group (p = 0.2), while HPV clearance occurred in 11 (51.9%) out of 17 women in AV2 arm versus 11 (34.4%) in placebo arm (p = 0.3).Some local side effects (burning, itching, irritation) were similarly noted in the 2 groups (p-values = 0.169, 0.623 and 0.172 respectively) but they were mild and transitory. CONCLUSION: A topical application of AV2 onto the cervix can induce the regression of cervical precancerous lesions, but its efficacy does not significantly differ with that of placebo. The discrepancy between the expected and the recorded sample size as well as the huge number of lost to follow-up probably impeded the power of analyses, which could be one of the reasons for the lack of difference seen between AV2 and placebo. Further evaluation of the effects of AV2 with different diagnostic methods and treatment regimen and arms is warranted. CLINICAL TRIAL REGISTRATION: NCT02346227 registered on November 8, 2014.