Latin American Federation for Colposcopy and Pathology of the LGT

State of the Art HPV Vaccination

Elsa Díaz López Principal of GESFEM SC México Disclosures

• I have recived honoraries from MSD like speaker • I have recived Honoraries from Sigfried Labs • No financial relationships or conflict of interest to disclose Statistics of cervical cancer

Is the fourth most common cancer in women with an incidence estimated of 528,000 new cases (85% of them diagnosed in developing countries).

Is the second largest cause of mortality due to cancer in women in the developing world.1 Like Latin America.

Every year are diagnosed 63.068 women with cervical neoplasia, registering 29.222 deaths by this sickness 2.

If current trends continue, the number of deaths in the Americas will grow by 45% in 2030. Mortality rates are 3 times higher in Latin America and the Caribbean than in North America, demonstrating huge inequalities in health. 1Ferlay et al., 2015 SITUACIÓN DE LOS PROGRAMAS PARA LA PREVENCIÓN Y EL CONTROL DEL CÁNCER CERVICOUTERINO OPS 2’00 Maribel Almonte, PhD, Lazcano et al.Nuevos paradigmas y desafíos en la prevención y control del cáncer de cuello uterino en América Latina. Salud pública de méxico / vol. 52, no. 6, noviembre-diciembre de 2010 What happen in Latino América?

Most of the developing countries recognized the huge burden of disease and the need for positive actions in reducing the incidence of new cases of cervical cancer and its mortality.

All countries have a National Program for prevention and control of cervical cancer.

Primary and secondary prevention : -Difficulty in reaching the coverage -Timely diagnosis and tratments -Underreporting

SITUACIÓN DE LOS PROGRAMAS PARA LA PREVENCIÓN Y EL CONTROL DEL CÁNCER CERVICOUTERINO OPS 2’00 Vaccination coveraje recent Although it is recommended that each issue be addressed in a fully informed decision-making process, some factors may outweigh and override others, depending on the speciﬁc circumstances. In addition, each country must decide what locally-gathered evidence they require in order to make a decision, and for what types of evidence they can rely on country or regional estimates (e.g., disease burden, cost-effectiveness) prepared by other groups, instead of conducting their own studies.

As a result of this assessment of the issues, the decision might be to intr oduce the vaccine or not to introduce it at this time. Policy-makers may have to make further decisions about the scope of vaccination, target ages and schedule, and the specific vaccine product, since these have policy and financial implications. Countries that choose not to introduce a vaccine may decide to revisit the issue at a later date as Cervical Cancer in mor Latine evidence of the diseaseAmerica burden or impact and cost-effectiveness of the vaccine becomes available, or as conditions change, such as the supply and price of the vaccine, financial resources, and the ability of the immunization pr ogramme and health system to handle the vaccine.

Most of these countries the cytology is used FIG. 1. Key issues to consider when deciding on the introduction of a vaccine as a technique for screening from 35 years THE DISEASE THE VACCINES ago, has not been achieved a significant reduction

The demographic differences, policy, SHOULD THE VACCINE management of preventive programs, social BE INTRODUCED NOW? inequality, technological resources, financing, monitoring and follow-up of actions, vaccination strategies and management of STRENGTH OF THE IMMUNIZATION information to the population, make it a PROGRAMME AND HEALTH SYSTEM challenge modify the incidence and mortality of cervical cancer in this region.

SITUACIÓN DE LOS PROGRAMAS PARA LA PREVENCIÓN Y EL CONTROL DEL CÁNCER CERVICOUTERINO OPS 2’00 Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008, Cancer Incidence and 2.1 | Deciding on the introduction of a vaccine 13 Mortality Worldwide: IARC Cancer Base No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http:// globocan.iarc.fr Vaccines again HPV current status

Safety Controversies profiles

HPV vaccines prevent infection Efficacy with certain Future species of HPV associated with the development of cervical cancer or genital warts. Three HPV vaccines are available on the market

Bivalent HPV vaccine produced by GlaxoSmithKline contains the VLP form antigen of HPV types 16 and 18.

qHPV vaccine contains HPV types 6, 11, 16, and 18 L1 proteins for its antigen.

9-valent HPV (nHPV) vaccine produced by Merck contains HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58

R. Angioli et al. /Ten years of HPV vaccines: State of art and controversies Critical Reviews in Oncology/Hematology 102 (2016) 65–72 HPV Vaccination Programs

HPV vaccination programs have been implemented in many countries between 2006 and 2009, two different human papillomavirus virus (HPV) vaccines were licensed.1 Both vaccines were shown to prevent up to 90–100% of infection of HPV and precancerous lesions in women not infected with HPV 16–18 at the time of vaccination. In 2014 a nonavalent vaccine was licensed to protect against the five most common oncogenic HPV types that account for the 90% of invasive cervical cancer in the world.2

1Herrero et al., 2015 2. Joura et al., 2014; Tjalma et al., 2013. HPV Role In The Etiology Of Other Neoplasias

The persistent high-risk HPV infection is necessary but not sufficient in the pathogenesis of cervical cancer (Walboomers et al., 1999) and it is well known that HPV has a major role in the etiology of squamous cell carcinoma of the anus, vulva, vagina, penis, mouth and oropharynx.1

EDL EDL EDL 1. Bosch et al., 2002; Parkin and Bray, 2006). HPV associated to other sickness

Clinical Therapeutics/Volume 36, Number 1, 2014 Fotografía Elsa Díaz López HPV vaccine results

Quadrivalent vaccine showed a 100% efficacy in preventing vulvar and vaginal lesions associated with vaccine HPV types, furthermore in men it was able to reduce 90% penile, perianal and perineal diseases and 100% of penile intraepithelial lesions associated with HPV types.

Palefsky et al., 2011 : US Assessment of HPV Types in Cancers: Implications for Current and 9-Valent HPV Vaccines

• HPV DNA was detected in 90.6% of cervical • 91.1% of anal • 75.0% of vaginal • 70.1% of oropharyngeal • 68.8% of vulvar • 63.3% of penile • 32.0% of oral cavity • and 20.9% of laryngeal cancers • 98.8% of cervical cancer in situ (CCIS).

Saraiya M US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines.JNCI J Natl Cancer Inst (2015) 107 (6): djv086. 7 HPV PREVENTIVE STRATEGIES - 224 -

7.2 HPV vaccination 7.2.1VaccinationHPV vaccine licensureCoverageand introduction Figure 119: Status of HPV vaccination programs worldwide

Data accessed at 15 nov. 2015. For Afghanistan, Angola, Albania, Andorra, Armenia, Antigua & Barbuda, Azerbaijan, Burundi, Benin, Burkina Faso, Bangladesh, Bulgaria, Bahrain, Bahamas, Bosnia & Herzegovina, Belarus, Belize, Bolivia, Barbados, Brunei, Botswana, Central African Republic, ChileData, China, accessedCôte d’Ivoireat 15, nov.Cameroon, 2015 Congo, DR, Congo, Colombia, Comoros, Cape Verde, Costa Rica, Cuba, Czech Republic, Djibouti, Dominica, Dominican Republic, Algeria, Ecuador, Egypt, Eritrea, Western Sahara, Ethiopia, Micronesia, FS, Gabon, Georgia, Ghana, Guinea, Gambia, Guinea-Bissau, Equat orial Guinea, Grenada, Guatemala, Guyana, Honduras, Croatia, Haiti, Indonesia, India, Iran, Iraq, Israel, Jamaica, Jordan, Japan, Kazakhstan, Kenya, Kyrgyzstan, Cambodia, St Kitts & Nevis, Korea, Republic of, Kuwait, Laos, Lebanon, Liberia, Libya, St Lucia, Liechtenstein, Sri Lanka, Lesotho, Morocco, Monaco, Republic of Moldova, Madagascar, Maldives, Mali, Myanmar, Montenegro, Mongolia, Mozambique, Mauritania, Mauritius, Malawi, Namibia, Niger, Nigeria, Nicaragua, Niue, Nepal, Nauru, Oman, Pakistan, Philippines, Papua New Guinea, Korea, DPR, Paraguay, Palestine, Qatar, Saudi Arabia, Sudan, Senegal, Solomon Islands, Sierra Leone, El Salvador, Somalia, Serbia, South Sudan, Sao Tome & Principe, Suriname, Swaziland, Seychelles, Syria, Chad, Togo, Thailand, Tajikistan, Turkmenistan, Timor-Leste, Tonga, Trinidad & Tobago, Tunisia, Turkey, Tuvalu, Tanzania, Uganda, Ukraine, Uruguay, Uzbekistan, St Vincent & The Grenadines, Venezuela, Viet Nam, Vanuatu, Samoa, Less developed regions, More developed regions, Least developed countri es, Eastern Europe, Northern Europe, Europe PREHDICT, Southern Europe, Western Europe, Europe, Sub-Saharan Africa, Eastern Africa, Middle Africa, Northern Africa, Southern Africa, Western Africa, Africa, GAVI Countries, Caribbean, Central America, Latin America & Caribbean, Northern America, South America, Americas, Australia & New Zealand, Melanesia, Polynesia, Oceania, Central Asia, Eastern Asia, Southern Asia, South-Eastern Asia, Western Asia, Asia, World, Yemen, South Africa, Zambia, Zimbabwe the source is: Cervical Cancer Action, June2013 [accessed on July 15th 2013], available at Theinformation represented here has been collected through interviews with individuals and organizations involved with the countries represented and has not been veriﬁed with individual Ministries of Health. Any versights or inaccuracies are unintentional. Brazil the source is: WHO vaccine-preventable diseases: monitoring system. 2013 global summary. Available at: Last updated 20-Octl-2013 (data as of 16-Oct-2013); next overall update June 2014. Cyprus, Estonia, Finland, Hungary, Iceland, Lithuania, Poland, Slovakia the source is: European Centre for Disease Prevention and Control. Introduction of HPV vaccines in EU countries an update. Stockholm: ECDC; 2012. Available at Iceland the source is: Health Ministry of Iceland (august 2012). HPV vaccination. Available at:

Russian Federation the source is: Kesic V, Poljak M, Rogovskaya S. Cervical cancer burden and prevention activities in Europe. Cancer Epidemiol Biomarkers Prev. 2012 Sep;21(9):1423-33

ICO HPV Information Centre Vaccination program in LA Start of vaccination program Short time (months) Reduction of Infection of HPV in tenager girls . Long term (decades) Incidence of genital warts • Incidence reduction cervical cancer

Medium term (x= 5 years) • Incidence reduction of cervical 1.Brotherton JM et al. Expert Rev. Anti Infect Ther. 2011;9(8):627-639 lesions (pre-malignants) and HPV 2. Franceschi et al. Int J Cancer 2009 infections in screened populations Vaccine Safety

 The most common AE seen with HPV 16/18 vaccine were: pain, fatigue, redness, swelling, fever, GI symptoms (diarrhea, nausea, vomiting), headache, myalgia and arthralgia (Harper et al., 2004; Bhatla et al., 2010; Kim et al., 2010; Medina et al., 2010; Ngan et al., 2010; Kim et al., 2011; Kang et al., 2008; Munoz et al., 2009; Lazcano-Ponce et al., 2009).

 Four studies reported serious AE but they were considered not related to the vaccination (Bhatla et al., 2010; Medina et al., 2010; Kim et al., 2011; Munoz et al., 2009).

 With the HPV 6/11/16/18 vaccine, fewer AE were reported probably because only four papers were included in our review. AE were general symptoms, pain, swelling and general symptoms did not appear to be vaccine related.  In the NCT00543543 trial comparing the nHPV vaccine and the qHPV, adverse events were more common in the nHPV group than the qHPV group (90.7% vs 84.9%). Pain in the injection site represented the most common adverse event. (55.8% vs 54.9%).

 SAEs were reported being 3.3% and 2.6% in the nHPV group and in the qHPV group respectively (Joura et al., 2015). R. Angioli et al. /Ten years of HPV vaccines: State of art and controversies Critical Reviews in Oncology/Hematology 102 (2016) 65–72 Vaccine Safety

 A meta-analysis; six clinical trials showed that adverse events and deaths were similar between the vaccine and control groups 1.  Analysis showed no significant increase in miscarriages in vaccinated women when compared to controls2 20102.  Vaccination during pregnancy is still not recommended.  No significant risk of Guillain-Barrèsyndrome , stroke, allergic reaction and anaphylaxis was reported 3  The Global Advisory Committee on Vaccine Safety, established by the WHO to provide independent e scientifically rigorous data, stated that vaccine are safe 4 1 Rambout et al., 2007 2. (Wacholder et al. 3. (Gee et al., 2011) 4. (Centers for Disease, 2013). Vaccines….Ten Years Of Experience

The available vaccines are safe and also efficacious (90–100%), but their real efficacy would be confirmed after a total period of 20 years follow up.1,2 We have multple evidencies in open population about the efficacious in short y medium time with HPV infections, warts, pre cancerous lesions. Actually vaccine long-term efficacy and safety is not known and the superiority of vaccine in preventing cervical cancer compared to HPV screening is not proven. 1. R. Angioli et al. /Ten years of HPV vaccines: State of art and controversies Critical Reviews in Oncology/Hematology 102 (2016) 65–72 2. JNCI jnci.oxfordjournals.org. Vol 104; Issue 22 November 21, 2012 . Vaccines….Ten Years Of Experience: Eschemes

Alternative dose schedules of HPV vaccines are comparable to the standard three-dose series over 6 months. Several clinical trials have shown that a 2-dose vaccine schedule delivered at 0 and 6 months among young adolescents is equivalent to a 3-dose schedule delivered at 0, 1/2 and 6 months among 16–26-year- old females with respect to immunogenicity. Long-term duration of immunogenicity following a two- versus three-dose vaccine schedule has not been assessed beyond 3 years post-dose two. Stanley, Sudenga & Giuliano. Alternative dosage schedules with HPV virus-like particle vaccines Expert Rev. Vaccines 13(8), 2014. HPV Vaccine Information Source; Behaviors Among Physicians

HPV vaccine information-seeking behaviors among US physicians: Government, media, or colleagues? Shalanda A. Bynuma et al. Vaccine 29 (2011) 5090–5093 Role Of Obstetrician-gynecologists And Other Healthcare Providers Is To Provide Patients And Their Parents With Information On The Benefits And Safety Of The HPV Vaccine

Advisory Committee on Immunization Practices (ACIP).

The American Academy of Pediatrics (AAP), The American Academy of Family Physicians (AAFP), y The American College of Obstetrics and Gynecology (ACOG).

Vaccination in Adults : AAFP, ACOG, and the American College of Physicians (ACP), ACIP and CDC.

Human Papillomavirus Vaccination Recommendations of the Advisory Committee on Immunization Practices (ACIP) Centers of diseases control Morbidity andMortality Weekly Report Recommendations and Reports / Vol. 63 / No. 5 August 29, 2014 Obstacles for vaccinating against HPV

a) Economics b) Lack of support from insurance services c) Irregular health prevention d) Abscence or poor internal comunication in health services e) The parents have negative information about vaccines from social networks. f) Diminiched perception of acquisition of HPV g) Abscence of infomation about benefits to boys and man.

1Recommended Adult Immunization Schedule United States Department of Health of Human Services. Center for Disease Control and Prevention 2016. www.cdc.gov/vaccines/pubs/pinkbook/index.html 2 Updated ACOG Recommendations for Human Papillomavirus Vaccine. Au, Tara Haelle Medscape july 2015 Recomendations The CDC and ACOG recommend that girls and boys routinely receive HPV vaccination. The Advisory Committee on Immunization Practices has subsequently recommended use of the 9-valent HPV vaccine. The US Food and Drug Administration licensed this vaccine in Dec. 2014 for for two genders since11 to 12 years old. Pregnant women should not be vaccinated. Breastfeeding women may be vaccinated for HPV.

Medscape Education Clinical BriefsUpdated ACOG Recommendations for Human Papillomavirus Vaccine CME/CE . Tara Haelle CME Laurie Barclay, MD Faculty and Disclosures Julio 2015 2) Update:HPV prevention. Ob Gyn Obstetrics Gynecology and Woman Health. February 2016. Obstacles against VPH vaccination

Only 33% of US girls in the recommended age group (13 - 17 years) have received all 3 vaccine doses, and only 50% have received at least 1 vaccine dose.

The CDC estimates that if HPV vaccination coverage increases to 80%, an additional 53,000 cases of cervical cancer could be prevented younger than 12 years, and for every year that coverage does not increase, an additional 4400 women will go on to have cervical cancer.

“Crucial" that obstetrician-gynecologists and other members of the healthcare team inform their young patients and their parents regarding the benefits and safety of HPV vaccination. ACOG

With massive vaccination programs, we will probably face with an increase in HPV types different from the types of the vaccines, for this reason the HPV screening still has a major role in cancer prevention and should be improved in low-income countries.

Next vaccine generations should be not only more effective, with a bigger coverage but also cheap. The screening in vaccinated groups could be every five years New vaccines should have a therapeutic effect.

R. Angioli et al. /Ten years of HPV vaccines: State of art and controversies Critical Reviews in Oncology/Hematology 102 (2016) 65–72 Outreach of vaccination

The 9-valent vaccine also targeting HPV 31/33/45/52/58 may A vaccine targeting HPV prevent an additional 4.2% 16/18 potentially prevents to 18.3% of cancers: 3944 the majority of invasive cases annually. cervical (66.2%), anal (79.4%), oropharyngeal (60.2%), and vaginal (55.1%) cancers, as well as many penile (47.9%), vulvar (48.6%) cancers: 24 858 cases annually. Outstanding issues

¨Until we reach the national goal of 80% of men and women fully vaccinated against HPV, the prevention of multiple cancers with a relatively simple intervention will remain a dream.¨

Providers are the key to implementing the national vaccine recommendations, ensuring this dream becomes a reality

How many cases of cancer can be prevented by HPV vaccination?

Giuliano et al. The Beginning of the End: Vaccine Prevention of HPV-Driven Cancers JNCI J Natl Cancer Inst (2015) 107(6): djv128 • GESFEM S.C • Grupo Especializado en Salud Femenina • www.gesfem.com.mx • [email protected]