Faster Elimination of HPV Infection and Cervical Cancer Using Concomitant HPV Vaccination and HPV Screening: A Demonstration Project in Rwanda

Summary

Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women, with an estimated 604,000 new cases and 342,000 deaths worldwide in 2020. Rwanda is among countries with a high burden cervical cancer, with an annual incidence of 28.2/100,000 women (1,229 new cases in 2020) and a mortality rate of 20.1/100,000 (829 deaths in 2018) according to WHO (IARC 2020). Cervical cancer is almost completely preventable because of the highly effective primary (HPV vaccine) and secondary (HPV screening) prevention measures. However, these measures have not been equitably implemented across and within LMICs countries. Given the current situation, where the screening coverage is still low due to financial and operational challenges, it will take many years to achieve the elimination targets as included in the global elimination strategy. We are proposing to implement an innovative strategy to accelerate the elimination of cervical cancer in Rwanda consisting of concomitant HPV vaccination and HPV screening for young women aged 23-29 years old. HPV screening and vaccination are complementary preventive options often implemented as separate public health programs. This project proposal aims to address this disconnect by combining both strategies with the ultimate purpose of accelerating the reduction of cervical cancer incidence and mortality in Rwanda and making the programs both cost-effective and sustainable. Primary objective The study aims to evaluate whether organized, concomitant HPV vaccination and HPV screening offered to girls and women aged 23-29 years will result in more rapid elimination of HPV infections in the target districts in Rwanda. The study design is a before-after study design of the intervention, where the projected incidences and prevalence at the 2-year follow-up visit are modeled using the data from the baseline visit, with evaluation using Observed/expected numbers. Secondary objectives The study will evaluate whether concomitant vaccination and cervical screening result in an improved efficiency and/or safety of the cervical cancer screening program. These objectives will be examined among women who participated in the combined screening and vaccination study. i) Protection of Gardasil 9 against HPV infection and against CIN2+ by Gardasil 9 HPV vaccine types in 23 to 29-year-old women from the study districts. This analysis will be performed every 2 years, and the first analysis will determine the effectiveness of one-dose vaccination (incident infections of HPV vaccine types at 2 years), whereas all subsequent analysis will determine the effect of 2-dose vaccinations. The study will be powered to detect a decline in invasive cervical cancer among the study participants, using the cervical cancer incidence in the surrounding districts of Rwanda as the reference. ii) Efficiency will also be measured by the yield of histopathologically confirmed high-grade cervical cancer precursors or cancer (cervical intraepithelial neoplasia grade 2, 3, or cervical cancer) in relation to the consumption of resources and convenience for the women, using the yield at the baseline visit (10% of women tested) as the comparator. The hypothesis is that 2 years after vaccination, there will be only a few incident infections (only some old, persistent infections) resulting in high PPV and high yield of CIN2+ at modest consumption of resources. End of the study One screening interval (2 years) after the last visit of the last subject, defined as the day the last study subject receives her second vaccination. The study will be implemented in 4 districts of Rwanda covering 100,000 women aged 23 to 29 years old. We will use Gardasil 9, the HPV the second generation HPV Vaccine manufactured by Merck.

Timeline

Start

2024-09-01

Primary completion

2025-03-30

Completion

2026-03-30

Publications

• Results Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.
• Results Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol. 2002 Apr;55(4):244-65. doi: 10.1136/jcp.55.4.244.
• Results Guan P, Howell-Jones R, Li N, Bruni L, de Sanjose S, Franceschi S, Clifford GM. Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J Cancer. 2012 Nov 15;131(10):2349-59. doi: 10.1002/ijc.27485. Epub 2012 Mar 20.
• Results Denny L, Adewole I, Anorlu R, Dreyer G, Moodley M, Smith T, Snyman L, Wiredu E, Molijn A, Quint W, Ramakrishnan G, Schmidt J. Human papillomavirus prevalence and type distribution in invasive cervical cancer in sub-Saharan Africa. Int J Cancer. 2014 Mar 15;134(6):1389-98. doi: 10.1002/ijc.28425. Epub 2013 Nov 14.
• Results Carrillo-Garcia A, Ponce-de-Leon-Rosales S, Cantu-de-Leon D, Fragoso-Ontiveros V, Martinez-Ramirez I, Orozco-Colin A, Mohar A, Lizano M. Impact of human papillomavirus coinfections on the risk of high-grade squamous intraepithelial lesion and cervical cancer. Gynecol Oncol. 2014 Sep;134(3):534-9. doi: 10.1016/j.ygyno.2014.06.018. Epub 2014 Jun 27.
• Results Cheng L, Wang Y, Du J. Human Papillomavirus Vaccines: An Updated Review. Vaccines (Basel). 2020 Jul 16;8(3):391. doi: 10.3390/vaccines8030391.
• Results Ronco G, Dillner J, Elfstrom KM, Tunesi S, Snijders PJ, Arbyn M, Kitchener H, Segnan N, Gilham C, Giorgi-Rossi P, Berkhof J, Peto J, Meijer CJ; International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014 Feb 8;383(9916):524-32. doi: 10.1016/S0140-6736(13)62218-7. Epub 2013 Nov 3.
• Results Knaul FM, Farmer PE, Krakauer EL, De Lima L, Bhadelia A, Jiang Kwete X, Arreola-Ornelas H, Gomez-Dantes O, Rodriguez NM, Alleyne GAO, Connor SR, Hunter DJ, Lohman D, Radbruch L, Del Rocio Saenz Madrigal M, Atun R, Foley KM, Frenk J, Jamison DT, Rajagopal MR; Lancet Commission on Palliative Care and Pain Relief Study Group. Alleviating the access abyss in palliative care and pain relief-an imperative of universal health coverage: the Lancet Commission report. Lancet. 2018 Apr 7;391(10128):1391-1454. doi: 10.1016/S0140-6736(17)32513-8. Epub 2017 Oct 12. No abstract available.
• Results Binagwaho A, Wagner CM, Gatera M, Karema C, Nutt CT, Ngabo F. Achieving high coverage in Rwanda's national human papillomavirus vaccination programme. Bull World Health Organ. 2012 Aug 1;90(8):623-8. doi: 10.2471/BLT.11.097253. Epub 2012 May 23.
• Results Gatera M, Bhatt S, Ngabo F, Utamuliza M, Sibomana H, Karema C, Mugeni C, Nutt CT, Nsanzimana S, Wagner CM, Binagwaho A. Successive introduction of four new vaccines in Rwanda: High coverage and rapid scale up of Rwanda's expanded immunization program from 2009 to 2013. Vaccine. 2016 Jun 17;34(29):3420-6. doi: 10.1016/j.vaccine.2015.11.076. Epub 2015 Dec 17.
• Results Schiller JT, Castellsague X, Garland SM. A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine. 2012 Nov 20;30 Suppl 5(0 5):F123-38. doi: 10.1016/j.vaccine.2012.04.108.
• Results Bogaards JA, Coupe VM, Meijer CJ, Berkhof J. The clinical benefit and cost-effectiveness of human papillomavirus vaccination for adult women in the Netherlands. Vaccine. 2011 Nov 8;29(48):8929-36. doi: 10.1016/j.vaccine.2011.09.055. Epub 2011 Sep 22.
• Results Lei J, Ploner A, Elfstrom KM, Wang J, Roth A, Fang F, Sundstrom K, Dillner J, Sparen P. HPV Vaccination and the Risk of Invasive Cervical Cancer. N Engl J Med. 2020 Oct 1;383(14):1340-1348. doi: 10.1056/NEJMoa1917338.
• Results Karimi-Zarchi M, Allahqoli L, Nehmati A, Kashi AM, Taghipour-Zahir S, Alkatout I. Can the prophylactic quadrivalent HPV vaccine be used as a therapeutic agent in women with CIN? A randomized trial. BMC Public Health. 2020 Feb 27;20(1):274. doi: 10.1186/s12889-020-8371-z.
• Results Castellsague X, Munoz N, Pitisuttithum P, Ferris D, Monsonego J, Ault K, Luna J, Myers E, Mallary S, Bautista OM, Bryan J, Vuocolo S, Haupt RM, Saah A. End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24-45 years of age. Br J Cancer. 2011 Jun 28;105(1):28-37. doi: 10.1038/bjc.2011.185. Epub 2011 May 31.
• Results Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano-Ponce E, Salmeron J, Del Rosario-Raymundo MR, Verheijen RH, Quek SC, da Silva DP, Kitchener H, Fong KL, Bouchard C, Money DM, Ilancheran A, Cruickshank ME, Levin MJ, Chatterjee A, Stapleton JT, Martens M, Quint W, David MP, Meric D, Hardt K, Descamps D, Geeraerts B, Struyf F, Dubin G; VIVIANE Study Group. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet. 2014 Dec 20;384(9961):2213-27. doi: 10.1016/S0140-6736(14)60920-X. Epub 2014 Sep 1.
• Results Ibrahim Khalil A, Zhang L, Muwonge R, Sauvaget C, Basu P. Efficacy and safety of therapeutic HPV vaccines to treat CIN 2/CIN 3 lesions: a systematic review and meta-analysis of phase II/III clinical trials. BMJ Open. 2023 Oct 24;13(10):e069616. doi: 10.1136/bmjopen-2022-069616.
• Results Sayinzoga F, Umulisa MC, Sibomana H, Tenet V, Baussano I, Clifford GM. Human papillomavirus vaccine coverage in Rwanda: A population-level analysis by birth cohort. Vaccine. 2020 May 19;38(24):4001-4005. doi: 10.1016/j.vaccine.2020.04.021. Epub 2020 Apr 24.
• Results Lehtinen M, Baussano I, Paavonen J, Vanska S, Dillner J. Eradication of human papillomavirus and elimination of HPV-related diseases - scientific basis for global public health policies. Expert Rev Vaccines. 2019 Feb;18(2):153-160. doi: 10.1080/14760584.2019.1568876. Epub 2019 Feb 7.

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