Impact of AV2 Antiviral Drug on the Treatment of HPV-associated Lesions of the Uterine Cervix

1. Introduction Cervical cancer (CC) is a major public health problem in Low-income countries (LICs), particularly in the Democratic Republic of the Congo (DRC), where the estimated number of cases is 3839 per year. (WHO, 2010). Persistent infection with Human Papillomavirus (HPV) is recognized as the necessary cause for the development of CC. Thus, CC is a disease that is easily preventable primarily by vaccination against HPV and secondarily through screening and treatment of precancerous lesions of the cervix. In LICs, the high incidence of CC is due to both high rates of infection with HPV, a failure to initiate and sustain effective screening programs based on cytology and the non-availability of vaccination against HPV. These situations highlight the need to implement simple and inexpensive screening and treatment methods suitable for LICs. These methods include screening by visual inspection of the cervix after application of acetic acid (VIA) and treatment with a topical antiviral drug (AV2). 2. Aims This study aims to: * Evaluate the clinical efficacy of AV2 as a treatment for HPV-associated lesions of the uterine cervix; * Identify HPV genotypes found in Kinshasa; * Determine the cost-effectiveness of an algorithm combining screening by VIA and AV2 and that combining VIA and cryotherapy treatment; 3. Methods After basic training of local health workers on VIA, on collection of cervical samples for HPV testing (quantitative Polymerase Chain reaction, qPCR) and liquid-based cytology (LBC) and on application of AV2, a screening and treatment program will be offered to women aged 25 and older who will give their informed consent. All women with lesions on VIA will be randomized into one of two groups to receive either treatment by AV2 or placebo. All women with lesions on VIA will be monitored and reviewed after two months and after six months for repeat tests (VIA and LBC for lesions, qPCR for viral load, conversion and reinfection rates).

Sex

Female

Minimum age

25 Years

Inclusion Criteria:

* Sexually-active women
* Women with intact uterine cervix
* Voluntary written informed consent to participate in the study

Exclusion Criteria:

* Virgin women
* Pregnant or breast-feeding women, and women in the post-partum period
* Subject is already diagnosed with cervical cancer
* Medical history of any severe diseases like hepatitis, renal or liver dysfunction, cardiovascular, gastrointestinal, malignant tumor, or psychiatric disorders etc., which might influence the assessments or conduct of the trial by the discretion of the investigator
* Intake or application of antivirals or other prohibited concomitant medication within 30 days prior to application of AV2®, or patients who plan to take such drugs during the trial
* Known or suspected allergic or adverse response to the investigational product AV2 or its components (olive oil or d-limonene)
* Inability to follow the study protocol

• BACKGROUNDFerlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010 Dec 15;127(12):2893-917. doi: 10.1002/ijc.25516. PMID 21351269
• BACKGROUNDGissmann L, Wolnik L, Ikenberg H, Koldovsky U, Schnurch HG, zur Hausen H. Human papillomavirus types 6 and 11 DNA sequences in genital and laryngeal papillomas and in some cervical cancers. Proc Natl Acad Sci U S A. 1983 Jan;80(2):560-3. doi: 10.1073/pnas.80.2.560. PMID 6300854
• BACKGROUNDSankaranarayanan R, Chatterji R, Shastri SS, Wesley RS, Basu P, Mahe C, Muwonge R, Seigneurin D, Somanathan T, Roy C, Kelkar R, Chinoy R, Dinshaw K, Mandal R, Amin G, Goswami S, Pal S, Patil S, Dhakad N, Frappart L, Fontaniere B. Accuracy of human papillomavirus testing in primary screening of cervical neoplasia: results from a multicenter study in India. Int J Cancer. 2004 Nov 1;112(2):341-7. doi: 10.1002/ijc.20396. PMID 15352050
• BACKGROUNDSarian LO, Derchain SF, Naud P, Roteli-Martins C, Longatto-Filho A, Tatti S, Branca M, Erzen M, Serpa-Hammes L, Matos J, Gontijo R, Braganca JF, Lima TP, Maeda MY, Lorincz A, Dores GB, Costa S, Syrjanen S, Syrjanen K. Evaluation of visual inspection with acetic acid (VIA), Lugol's iodine (VILI), cervical cytology and HPV testing as cervical screening tools in Latin America. This report refers to partial results from the LAMS (Latin AMerican Screening) study. J Med Screen. 2005;12(3):142-9. doi: 10.1258/0969141054855328. PMID 16156945
• BACKGROUNDWorld Health Organization. HPV Summary Report 2010
• DERIVEDBaleka Mutombo A, Tozin R, Kanyiki H, Van Geertruyden JP, Jacquemyn Y. Impact of antiviral AV2 in the topical treatment of HPV-associated lesions of the cervix: Results of a phase III randomized placebo-controlled trial. Contemp Clin Trials Commun. 2019 May 16;15:100377. doi: 10.1016/j.conctc.2019.100377. eCollection 2019 Sep. PMID 31193477
• Mutombo AB, Tozin R, Simoens C, Lisbeth R, Bogers J, Van Geertruyden JP, Jacquemyn Y. Efficacy of antiviral drug AV2 in the treatment of human papillomavirus-associated precancerous lesions of the uterine cervix: A randomized placebo-controlled clinical trial in Kinshasa, DR Congo. (KINVAV study). Contemp Clin Trials Commun. 2017 Sep 28;8:135-139. doi: 10.1016/j.conctc.2017.09.008. eCollection 2017 Dec.