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Human Vaccines & Immunotherapeutics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/khvi20
Human papillomavirus vaccine: A boon or curse a
b
b
b
b
Sumit Chawla , Inderjeet Singh , Rambilas Jain , Bharti Mehta , Sneh Kumari & Soumya Swaroop Sahoo a
b
Department of Community Medicine; MMMC; Solan, Himachal Pradesh, India
b
Department of Community Medicine; PGIMS; Rohtak, Haryana, India Published online: 10 Feb 2015.
Click for updates To cite this article: Sumit Chawla, Inderjeet Singh, Rambilas Jain, Bharti Mehta, Sneh Kumari & Soumya Swaroop Sahoo (2014) Human papillomavirus vaccine: A boon or curse, Human Vaccines & Immunotherapeutics, 10:12, 3509-3512, DOI: 10.4161/21645515.2014.980689 To link to this article: http://dx.doi.org/10.4161/21645515.2014.980689
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
COMMENTARY Human Vaccines & Immunotherapeutics 10:12, 3509--3512; December 2014; © 2014 Taylor & Francis Group, LLC
Human papilloma virus vaccine: A boon or curse Sumit Chawla1,*, Inderjeet Singh2, Rambilas Jain2, Bharti Mehta2, Sneh Kumari2, and Soumya Swaroop Sahoo2 1
Department of Community Medicine; MMMC; Solan, Himachal Pradesh, India; 2Department of Community Medicine; PGIMS; Rohtak, Haryana, India
Downloaded by [University of Manitoba Libraries] at 05:49 26 August 2015
C
Keywords: cancer, vaccination, vaccine
HPV,
*Correspondence to: Sumit [email protected]
screening,
Chawla;
Email:
Submitted: 08/29/2014 Accepted: 09/15/2014 http://dx.doi.org/10.4161/21645515.2014.980689 www.landesbioscience.com
ervical cancer is the second most common cancer among women worldwide, with about 493,000 new cases diagnosed annually. Of 274,000 deaths due to cervical cancer each year, more than 80% occur in developing countries, and this proportion is expected to increase to 90% by 2020. Up to 70% of sexually active women will become infected with human papilloma virus (HPV) during their lifetime. Even though screening reduces the risk of cervical cancer, it does not prevent HPV infection or development of precancerous lesions which need careful follow-up and often need excision. It was observed in a study, pre-adolescent vaccination alone reduced cancer incidence by 44% and was more effective than screening alone. A combined approach of pre-adolescent vaccination and screening of adult women was more effective than either alone. The high probability of acquiring HPV infection once, one has become sexually active raises the question of whether the vaccine will be effective if given to girls who have already been infected with HPV type 16 or 18. In April 2010, The Indian parliament’s Standing Committee on Health, began probing the use of HPV vaccines in 2 states after the reported deaths of 7 girls, and concluded that “safety and rights of children were highly compromised and violated.” Though the question of immunization of older girls and women deserves attention, from a public health perspective, the first priority in resource-poor settings would be to vaccinate young adolescent girls.
Introduction More than any other cancer, cervical cancer reflects striking global health inequity. Of 274,000 deaths due to cervical Human Vaccines & Immunotherapeutics
cancer each year, more than 80% occur in developing countries, and this proportion is expected to increase to 90% by 2020.1 It is the second most common cancer among women worldwide, with about 493,000 new cases diagnosed annually. Affecting relatively young women, it is the largest single cause of years of life lost to cancer in the developing world. The deaths of women who are in their most productive years have a devastating effect on the well-being of their families. Up to 70% of sexually active women will become infected with human papilloma virus (HPV) during their lifetime.2 HPVs are nonenveloped, doublestranded DNA viruses in the family Papillomaviridae. Isolates of HPV are classified as “types,” and numbers are assigned in order of their discovery.3 Types are designated on the basis of the nucleotide sequence of specific regions of the genome. All HPVs have an 8 kb circular genome enclosed in a capsid shell composed of the major and minor capsid proteins L1 and L2, respectively. Although the majority of infections cause no symptoms and are selflimited, persistent genital HPV infection can cause cervical cancer in women and other types of anogenital cancers and genital warts in both men and women. Infections with low-risk types (e.g., types 6 and 11) can cause benign or lowgrade cervical cell changes, genital warts, and recurrent respiratory papillomatosis. High risk HPV types act as carcinogens in the development of cervical cancer and other anogenital cancers.4,5 High-risk types, including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 73, and 82, can cause low-grade cervical cell abnormalities, high-grade cervical cell abnormalities that are precursors to cancer, and anogenital cancers.6 3509
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Need for Vaccine Even though screening reduces the risk of cervical cancer, it does not prevent HPV infection or development of precancerous lesions,7 which need careful followup and often need excision.8 Moreover, HPV infections that manifest as genital warts arise in 1–2% of young adults,9 for which treatment is expensive and painful, and recurrences are common.10 More than 35 types of HPV infect the genital tract.3 Of these, types 16 and 18 cause about 70% of cervical cancer and highgrade cervical intraepithelial neoplasia (CIN); HPV 6 and 11 cause 90% of anogenital warts.10 A prophylactic vaccine that targets these types should thus substantially reduce the burden of HPVassociated clinical diseases. HPV infections are not treated; treatment is directed at the HPV-associated lesions. Condom use might reduce the risk for HPV and HPV-associated diseases (e.g., genital warts and cervical cancer). A study among newly sexually active college women demonstrated a 70% reduction in HPV infection when their partners used condoms consistently and correctly.11 Abstaining from sexual activity (i.e., refraining from any genital contact with another persons) is the
surest way to prevent genital HPV infection. For those who choose to be sexually active, a monogamous relationship with an uninfected partner is the strategy most likely to prevent future genital HPV infections. The majority of cervical cancer cases and deaths can be prevented through detection of pre-cancerous changes in the cervix by cytology using the Pap test. Pap test screening includes a conventional Pap or a liquid-based cytology.12 New options for cervical cancer prevention motivate important questions in low-income countries. Traditional cytology screening, conducted at frequent intervals and requiring multiple clinic visits for women with abnormal cytology (e.g., screening, diagnostic testing, and treatment), has been difficult to implement in India.13 Screening with HPV DNA testing and/or visual inspection with acetic acid (VIA) have been demonstrated to be acceptable and promising alternatives when embedded in a screening protocol that requires fewer visits14,15 and utilises cryotherapy conducted by nurses to treat the majority of early cancer precursors. These strategies, less dependent on existing health system infrastructure and associated with greater rates of follow-up, are also expected to be cost-effective.16
Figure 1. Effectiveness of preadolescent vaccination v/s screening.
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Human Vaccines & Immunotherapeutics
Health and Economic Impact of HPV 16 and 18 Vaccination Most recently, 2 new vaccines have been shown to be highly effective in preventing infection with HPV 16 and 18 in women without prior exposure to these types (FDA, 2006). Contemplating an HPV vaccination program adds complexity to decision making about India’s national approach to cervical cancer control. The country will want to consider the burden of cervical cancer, the comparative effectiveness – and potential synergies – of vaccination and screening, the financial costs required to initiate and sustain programs, their cost-effectiveness, and the programmatic capacity and infrastructure necessary to effectively deliver a 3-dose pre-adolescent vaccine. To provide insight to decision makers and stakeholders invested in reducing mortality from cervical cancer in India, the potential avertable burden of disease and cost-effectiveness associated with various vaccination and screening strategies should be assessed. In a study by Diaz M et al.17 preadolescent vaccination alone reduced cancer incidence by 44% (range, 28–57%) and was more effective than screening alone (Fig. 1, upper panel). A combined approach of pre-adolescent vaccination and screening of adult women was more effective than either alone (Fig. 1, lower panel). One vaccine (Gardasil) is a quadrivalent HPV-16/18 cervical cancer candidate vaccine that contains Virus Like Particle’s (VLPs) from 2 oncogenic HPV types, HPV-16 and HPV-18, and also contains VLPs from HPV types 6 and 11, which are not involved in cervical cancer pathogenesis but are linked to benign genital warts. The second vaccine (Cervarix) is a bivalent HPV-16/18 cervical cancer candidate vaccine that contains VLPs only from the 2 oncogenic HPVtypes, HPV-16 and HPV-18. Virus like particle–based vaccines have been shown to provide near complete type-specific protection against infection with HPV types included in the vaccine in the initial years following vaccination.18-20
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Given that HPV infection depends on the viral genome being present in the epithelial basal cells that give rise to the cells in the higher layers of the epithelium and that the L1 protein is only expressed in these higher cell layers, it is not clear whether the vaccine induced immune response directed against L1 would have curative potential among infected individuals.21 Most HPV infections, regardless of type, clear spontaneously, typically within 6 months to 2 y22 Risk of progression to in situ disease and invasive cancer is highest among the small subset of women with persistent infections beyond this period.23 Understanding whether vaccination provides any therapeutic benefit to infected women is of importance in countries where HPV DNA testing has been incorporated into cervical cancer screening programs.24,25 Women in such programs who test positive for HPV might want to avail themselves of the vaccine instead of waiting several months to determine whether their infections clear or opting for treatments based on excision or ablation of the cervical transformation zone where cancers arise. Because current management protocols often involve retesting HPV positive women within months of an initial HPV-positive result before treatment decisions are made, understanding the impact of vaccination on viral clearance in the first 6 to 12 months following an initial HPV-positive result would be informative. If effective at clearing established infections, it is reasonable to expect that vaccination would work within this time frame, given the near complete rate of seroconversion and high levels of immune response observed after 1 or 2 doses of vaccine. From a population (or public health) perspective, however, it is unclear whether, among women infected with HPV, the residual benefit of preventing infection with HPV types contained in the vaccine to which the women have not yet been exposed would be sufficient to warrant vaccination. However, since HPVs are very common viruses to which women are typically exposed in the initial months or years following sexual debut,23 vaccination of women after they have
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been exposed and infected (ie, after their peak period of exposure) is likely to be of less benefit than vaccination of women prior to initial exposure. Examination of the level of benefit provided by HPV vaccination of women who are past their peak period of exposure is currently under evaluation in several ongoing clinical efficacy trials. It is also not clear whether vaccination would benefit women with prevalent infection by increasing their immunologic resistance against reappearance (via reactivation or reinfection) with the same viral type in the future. Because HPV-infected women who clear their infection have demonstrated immune-competence to handle an established HPV infection, these women might be expected to be capable of handling subsequent infections without the need for vaccination. In particular, it is possible to hypothesize that T-cell responses developed following an initial HPV infection that successfully clears would be capable of adequately eradicating subsequent viral infections. This remains an open issue for future investigation.
HPV Vaccine –A Boon or Bane In a study by Hildesheim A et al. in women positive for HPV DNA, HPV-16/ 18 vaccination does not accelerate clearance of the virus and should not be used for purposes of treating prevalent infections. The high probability of acquiring HPV infection once, one has become sexually active raises the question of whether the vaccine will be effective if given to girls who have already been infected with HPV type 16 or 18. Though the question of immunization of older girls and women deserves attention, from a public health perspective, the first priority in resource-poor settings would be to vaccinate young adolescent girls. Fortunately, for older women in developing countries there are new options for cervical-cancer screening that are likely to provide cost-effective strategies for reducing the risk of cancer.26 Rights violation found in HPV vaccine studies in India – PATH & ICMR did demonstration project on the
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safety of the HPV vaccine in the states of Andhra Pradesh & Gujrat which was suspended by the Indian Govt. in response to demands from advocacy group. In April 2010, The Indian parliament’s Standing Committee on Health, began probing the use of HPV vaccines in 2 states after the reported deaths of 7 girls, and concluded that “safety and rights of children were highly compromised and violated.” In view of the reports finding of violation of human rights and clinical trial rules, the committee has recommended legal action against non-profit organization Program for Appropriate Technology in Health (PATH), which initiated the HPV project with the Indian Council of Medical Research (ICMR) in 2007, a year before marketing approval for HPV vaccines was given in India. The trial’s (by PATH & ICMR) purpose was to prepare ground for inclusion of the HPV vaccine in the Universal Immunization Program (UIP). The advocacy groups that pressured the Indian Government to halt and re-evaluate the HPV vaccine activities drew their information from many sources. They made fact-finding visits to study sites, combined with information from a USbased anti-HPV vaccination group, and additionally researched various public documents.27 As far as these groups were concerned, their arguments were evidencebased. Some of the points made by the advocacy groups and a member of parliament are generally reasonable: calling for increased funds for health, maximising investment in priority health issues, ensuring the safety of health interventions, communicating clearly and honestly any risks, and conducting ethical processes in research. Beyond these broader demands, there was a mix of facts, misinformation, principles, anger at injustices, and anger at perceived interference by multinational companies, funders, and international nongovernmental organisations in local concerns, and a final pointing to the government for its ultimate responsibility to protect people’s health and wellbeing. Consideration that the HPV-vaccine activities were in the interest of women’s
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health could have been more loudly articulated, but that argument would need a different type of evidence and argument than that used by the advocacy groups. Reluctance by public health authorities to respond to issues of public distrust for fear that they will exacerbate the problem is dangerous.28 Experience is increasingly showing that public distrust does not go away if unaddressed and can lead to program disruptions and even disease outbreaks. We need to find new ways to engage the public, early on, in health research and in the design and delivery of health programmes. That approach includes taking the time to listen to societal concerns, public emotions, and politics that can derail programmes or research. We might not always understand them, but we cannot ignore them.
Conclusion The resources, infrastructure, and technological expertise required, together with the need for repeated screening at frequent intervals, have made conventional cytology-based screening prohibitively difficult in most poor countries. With the availability of an effective, safe vaccine, there is real hope for reducing the global burden of cervical cancer. Although achieving broad coverage of young adolescents, negotiating tiered pricing, and securing financing will be challenging, it is sobering to realize that with every 5-year delay in bringing vaccination to developing countries, 1.5 million to 2 million more women will die. Vaccination has the potential to save many lives. Let us hope that a committed global effort makes fulfillment of the promise of the new vaccine possible.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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Refrences 1. Parkin DM, Bray F. Chapter 2: the burden of HPVrelated cancers. Vaccine 2006; 24: Suppl 3:S11–S25; http://dx.doi.org/10.1016/j.vaccine.2006.05.111 2. Bosch FX, de Sanjose S. Chapter 1: Human papillomavirus and cervical cancer-burden and assessment of causality. J Natl Cancer Inst Monogr 2003; 31:3-13; PMID:12807939; http://dx.doi.org/10.1093/ oxfordjournals.jncimonographs.a003479 3. de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur HH. Classification of papillomaviruses. Virology 2004; 324:17-27; PMID:15183049; http://dx.doi.org/ 10.1016/j.virol.2004.03.033 4. National Institutes of Health Consensus Development Panel. Cervical cancer. NIH Consensus Statement.1996; 14:1-38; PMID:9407932 5. World Health Organization. IARC monograph on the evaluation of carcinogenic risks to humans: human papillomaviruses. 1995. Lyons, France, IARC; 2000. 6. Munoz N, Bosch FX, de Sanjose S Herrero R, Castellsague X, Shah KV Snijders PJ, Meijer CJ. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348:518-27; PMID:12571259; http://dx.doi.org/ 10.1056/NEJMoa021641 7. Peto J, Gilham C, Fletcher O, Matthews FE. The cervical cancer epidemic that screening has prevented in the UK. Lancet 2004; 364:249-56; PMID:15262102; http://dx.doi.org/10.1016/S0140-6736(04)16674-9 8. Sadler L, Saftlas A, Wang W, Exeter M, Whittaker J, McCowan L. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA 2004; 291:2100-06; PMID:15126438; http://dx.doi.org/ 10.1001/jama.291.17.2100 9. Persson G, Andersson K, Krantz I. Symptomatic genital papillomavirus infection in a community: incidence and clinical picture. Acta Obstet Gynecol Scand 1996; 75:287-90; PMID:8607345; http://dx.doi.org/ 10.3109/00016349609047103 10. von Krogh G. Management of anogenital warts (condylomata acuminata). Eur J Dermatol 2001; 11:598-604; PMID:11701422 11. Winer RL, Hughes JP, Feng Q, O’Reilly S, Nancy B, Kiviat NB Holmes KK, Koutsky LA. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med 2006; 354:2645-54; PMID:16790697; http://dx.doi.org/10.1056/ NEJMoa053284 12. Ferenczy A, Franco E. Cervical-cancer screening beyond the year 2000. Lancet Oncol 2001; 2:27-32; PMID:11905615; http://dx.doi.org/10.1016/S14702045(00)00192-3 13. Sankaranarayanan R, Budukh A, Rajkumar R. Effective screening programs for cervical cancer in low- and middle- income developing countries. Bull World Health Organ, Suppl 2001; 79:954-62. 14. Bhatla N, Mukhopadhyay A, Kriplani A, Pandey RM, Gravitt PE, Shah KV. Evaluation of adjunctive tests for cervical cancer screening in low resource settings. Indian Journal of Cancer 2007; 44:51-5; PMID:17938481; http://dx.doi.org/10.4103/0019-509X.35811 15. Ramachandran S, Bhatla N, Virmani A, Bell L, Payne E, Dong L, et al. A fast affordable sensitive test for Hpv in developing countries: performance trial results from India. 24th International Papillomavirus Conference and Clinical Workshop, November 3 – 9, 2007, Beijing, China, PS6-59. 16. Goldie SJ, Gaffikin L, Goldhaber-Fiebert JD, GordilloTobar A, Levin C, Mahe C, Wright TC. Alliance for
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cervical cancer prevention cost working group costeffectiveness of cervical cancer screening in five developing countries. N Engl J Med 2005; 353:2158-68; PMID:16291985; http://dx.doi.org/10.1056/ NEJMsa044278 Diaz M, Kim JJ, Albero G, Sanjose S, Clifford G, Bosch FX. Health and economic impact of HPV 16 and 18 vaccination and cervical cancer screening in India. Brit J Cancer 2008; 99:230-8; PMID:18612311; http://dx.doi.org/10.1038/sj.bjc.6604462 Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, Wheeler CM, Koutsky LA, Malm C, Lehtinen M, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 viruslike particle vaccine in young women: a randomized double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005; 6:271-8; PMID:15863374; http://dx.doi.org/10.1016/S14702045(05)70101-7 Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Martins CM, Jenkins D, Schuind A, Costa Clemens SA, Dubin G. Sustained efficacy up to 4.5 years of a bivalent L1 viruslike particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006; 367:1247-55; PMID:16631880; http://dx.doi. org/10.1016/S0140-6736(06)68439-0 Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol 2006; 107:18-27; PMID: 16394035; http://dx.doi.org/10.1097/01.AOG. 0000192397.41191.fb Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. J Clin Invest. 2006; 116:1167-73; PMID:16670757; http://dx.doi.org/10.1172/JCI28607 Schiffman M, Herrero R, Desalle R, Hildesheim A, Wacholder S, Rodriguez AC, Bratti MC, Sherman ME, Morales J, Guillen D, et al. The carcinogenicity of human papillomavirus types reflects viral evolution. Virology 2005; 337:76-84; PMID:15914222; http:// dx.doi.org/10.1016/j.virol.2005.04.002 Schiffman MH, Hildesheim A. Cervical cancer. In: Schottenfeld D, Fraumeni JFF Jr, eds. Cancer Epidemiology and Prevention. Oxford, England: Oxford University Press; 2006:1044-1067. Wright TC Jr, Schiffman M, Solomon D, Cox JT, Garcia F, Goldie S, Hatch K, Noller KL, Roach N, Runowicz C, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004; 103:3049; PMID:14754700; http://dx.doi.org/10.1097/01. AOG.0000109426.82624.f8 Saslow D, Runowicz CD, Solomon D, Moscicki AB, Smith RA, Eyre HJ Cohen C. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 2002; 52:342-62; PMID: 12469763; http://dx.doi.org/10.3322/canjclin.52.6.342 Sankaranarayanan R, Gaffikin L, Jacob M, Sellors J, Robles S. A critical assessment of screening methods for cervical neoplasia. Int J Gynaecol Obstet 2005; 89: Suppl 2:S4- S12; PMID:15823266; http://dx.doi.org/ 10.1016/j.ijgo.2005.01.009 Ramanathan M, Varghese J. The HPV vaccine demonstration projects: weshould wait, watch and learn. Indian J Med Ethics 2010; 7:43-5; PMID:20166301 Cooper LZ, Larson HJ, Katz SL. Protecting public trust in immunization. Pediatrics 2008; 122:149-53; PMID:18595998; http://dx.doi.org/10.1542/ peds.2008-0987
Volume 10 Issue 12
Human Vaccines & Immunotherapeutics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/khvi20
Human papillomavirus vaccine: A boon or curse a
b
b
b
b
Sumit Chawla , Inderjeet Singh , Rambilas Jain , Bharti Mehta , Sneh Kumari & Soumya Swaroop Sahoo a
b
Department of Community Medicine; MMMC; Solan, Himachal Pradesh, India
b
Department of Community Medicine; PGIMS; Rohtak, Haryana, India Published online: 10 Feb 2015.
Click for updates To cite this article: Sumit Chawla, Inderjeet Singh, Rambilas Jain, Bharti Mehta, Sneh Kumari & Soumya Swaroop Sahoo (2014) Human papillomavirus vaccine: A boon or curse, Human Vaccines & Immunotherapeutics, 10:12, 3509-3512, DOI: 10.4161/21645515.2014.980689 To link to this article: http://dx.doi.org/10.4161/21645515.2014.980689
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
COMMENTARY Human Vaccines & Immunotherapeutics 10:12, 3509--3512; December 2014; © 2014 Taylor & Francis Group, LLC
Human papilloma virus vaccine: A boon or curse Sumit Chawla1,*, Inderjeet Singh2, Rambilas Jain2, Bharti Mehta2, Sneh Kumari2, and Soumya Swaroop Sahoo2 1
Department of Community Medicine; MMMC; Solan, Himachal Pradesh, India; 2Department of Community Medicine; PGIMS; Rohtak, Haryana, India
Downloaded by [University of Manitoba Libraries] at 05:49 26 August 2015
C
Keywords: cancer, vaccination, vaccine
HPV,
*Correspondence to: Sumit [email protected]
screening,
Chawla;
Email:
Submitted: 08/29/2014 Accepted: 09/15/2014 http://dx.doi.org/10.4161/21645515.2014.980689 www.landesbioscience.com
ervical cancer is the second most common cancer among women worldwide, with about 493,000 new cases diagnosed annually. Of 274,000 deaths due to cervical cancer each year, more than 80% occur in developing countries, and this proportion is expected to increase to 90% by 2020. Up to 70% of sexually active women will become infected with human papilloma virus (HPV) during their lifetime. Even though screening reduces the risk of cervical cancer, it does not prevent HPV infection or development of precancerous lesions which need careful follow-up and often need excision. It was observed in a study, pre-adolescent vaccination alone reduced cancer incidence by 44% and was more effective than screening alone. A combined approach of pre-adolescent vaccination and screening of adult women was more effective than either alone. The high probability of acquiring HPV infection once, one has become sexually active raises the question of whether the vaccine will be effective if given to girls who have already been infected with HPV type 16 or 18. In April 2010, The Indian parliament’s Standing Committee on Health, began probing the use of HPV vaccines in 2 states after the reported deaths of 7 girls, and concluded that “safety and rights of children were highly compromised and violated.” Though the question of immunization of older girls and women deserves attention, from a public health perspective, the first priority in resource-poor settings would be to vaccinate young adolescent girls.
Introduction More than any other cancer, cervical cancer reflects striking global health inequity. Of 274,000 deaths due to cervical Human Vaccines & Immunotherapeutics
cancer each year, more than 80% occur in developing countries, and this proportion is expected to increase to 90% by 2020.1 It is the second most common cancer among women worldwide, with about 493,000 new cases diagnosed annually. Affecting relatively young women, it is the largest single cause of years of life lost to cancer in the developing world. The deaths of women who are in their most productive years have a devastating effect on the well-being of their families. Up to 70% of sexually active women will become infected with human papilloma virus (HPV) during their lifetime.2 HPVs are nonenveloped, doublestranded DNA viruses in the family Papillomaviridae. Isolates of HPV are classified as “types,” and numbers are assigned in order of their discovery.3 Types are designated on the basis of the nucleotide sequence of specific regions of the genome. All HPVs have an 8 kb circular genome enclosed in a capsid shell composed of the major and minor capsid proteins L1 and L2, respectively. Although the majority of infections cause no symptoms and are selflimited, persistent genital HPV infection can cause cervical cancer in women and other types of anogenital cancers and genital warts in both men and women. Infections with low-risk types (e.g., types 6 and 11) can cause benign or lowgrade cervical cell changes, genital warts, and recurrent respiratory papillomatosis. High risk HPV types act as carcinogens in the development of cervical cancer and other anogenital cancers.4,5 High-risk types, including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 73, and 82, can cause low-grade cervical cell abnormalities, high-grade cervical cell abnormalities that are precursors to cancer, and anogenital cancers.6 3509
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Need for Vaccine Even though screening reduces the risk of cervical cancer, it does not prevent HPV infection or development of precancerous lesions,7 which need careful followup and often need excision.8 Moreover, HPV infections that manifest as genital warts arise in 1–2% of young adults,9 for which treatment is expensive and painful, and recurrences are common.10 More than 35 types of HPV infect the genital tract.3 Of these, types 16 and 18 cause about 70% of cervical cancer and highgrade cervical intraepithelial neoplasia (CIN); HPV 6 and 11 cause 90% of anogenital warts.10 A prophylactic vaccine that targets these types should thus substantially reduce the burden of HPVassociated clinical diseases. HPV infections are not treated; treatment is directed at the HPV-associated lesions. Condom use might reduce the risk for HPV and HPV-associated diseases (e.g., genital warts and cervical cancer). A study among newly sexually active college women demonstrated a 70% reduction in HPV infection when their partners used condoms consistently and correctly.11 Abstaining from sexual activity (i.e., refraining from any genital contact with another persons) is the
surest way to prevent genital HPV infection. For those who choose to be sexually active, a monogamous relationship with an uninfected partner is the strategy most likely to prevent future genital HPV infections. The majority of cervical cancer cases and deaths can be prevented through detection of pre-cancerous changes in the cervix by cytology using the Pap test. Pap test screening includes a conventional Pap or a liquid-based cytology.12 New options for cervical cancer prevention motivate important questions in low-income countries. Traditional cytology screening, conducted at frequent intervals and requiring multiple clinic visits for women with abnormal cytology (e.g., screening, diagnostic testing, and treatment), has been difficult to implement in India.13 Screening with HPV DNA testing and/or visual inspection with acetic acid (VIA) have been demonstrated to be acceptable and promising alternatives when embedded in a screening protocol that requires fewer visits14,15 and utilises cryotherapy conducted by nurses to treat the majority of early cancer precursors. These strategies, less dependent on existing health system infrastructure and associated with greater rates of follow-up, are also expected to be cost-effective.16
Figure 1. Effectiveness of preadolescent vaccination v/s screening.
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Health and Economic Impact of HPV 16 and 18 Vaccination Most recently, 2 new vaccines have been shown to be highly effective in preventing infection with HPV 16 and 18 in women without prior exposure to these types (FDA, 2006). Contemplating an HPV vaccination program adds complexity to decision making about India’s national approach to cervical cancer control. The country will want to consider the burden of cervical cancer, the comparative effectiveness – and potential synergies – of vaccination and screening, the financial costs required to initiate and sustain programs, their cost-effectiveness, and the programmatic capacity and infrastructure necessary to effectively deliver a 3-dose pre-adolescent vaccine. To provide insight to decision makers and stakeholders invested in reducing mortality from cervical cancer in India, the potential avertable burden of disease and cost-effectiveness associated with various vaccination and screening strategies should be assessed. In a study by Diaz M et al.17 preadolescent vaccination alone reduced cancer incidence by 44% (range, 28–57%) and was more effective than screening alone (Fig. 1, upper panel). A combined approach of pre-adolescent vaccination and screening of adult women was more effective than either alone (Fig. 1, lower panel). One vaccine (Gardasil) is a quadrivalent HPV-16/18 cervical cancer candidate vaccine that contains Virus Like Particle’s (VLPs) from 2 oncogenic HPV types, HPV-16 and HPV-18, and also contains VLPs from HPV types 6 and 11, which are not involved in cervical cancer pathogenesis but are linked to benign genital warts. The second vaccine (Cervarix) is a bivalent HPV-16/18 cervical cancer candidate vaccine that contains VLPs only from the 2 oncogenic HPVtypes, HPV-16 and HPV-18. Virus like particle–based vaccines have been shown to provide near complete type-specific protection against infection with HPV types included in the vaccine in the initial years following vaccination.18-20
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Given that HPV infection depends on the viral genome being present in the epithelial basal cells that give rise to the cells in the higher layers of the epithelium and that the L1 protein is only expressed in these higher cell layers, it is not clear whether the vaccine induced immune response directed against L1 would have curative potential among infected individuals.21 Most HPV infections, regardless of type, clear spontaneously, typically within 6 months to 2 y22 Risk of progression to in situ disease and invasive cancer is highest among the small subset of women with persistent infections beyond this period.23 Understanding whether vaccination provides any therapeutic benefit to infected women is of importance in countries where HPV DNA testing has been incorporated into cervical cancer screening programs.24,25 Women in such programs who test positive for HPV might want to avail themselves of the vaccine instead of waiting several months to determine whether their infections clear or opting for treatments based on excision or ablation of the cervical transformation zone where cancers arise. Because current management protocols often involve retesting HPV positive women within months of an initial HPV-positive result before treatment decisions are made, understanding the impact of vaccination on viral clearance in the first 6 to 12 months following an initial HPV-positive result would be informative. If effective at clearing established infections, it is reasonable to expect that vaccination would work within this time frame, given the near complete rate of seroconversion and high levels of immune response observed after 1 or 2 doses of vaccine. From a population (or public health) perspective, however, it is unclear whether, among women infected with HPV, the residual benefit of preventing infection with HPV types contained in the vaccine to which the women have not yet been exposed would be sufficient to warrant vaccination. However, since HPVs are very common viruses to which women are typically exposed in the initial months or years following sexual debut,23 vaccination of women after they have
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been exposed and infected (ie, after their peak period of exposure) is likely to be of less benefit than vaccination of women prior to initial exposure. Examination of the level of benefit provided by HPV vaccination of women who are past their peak period of exposure is currently under evaluation in several ongoing clinical efficacy trials. It is also not clear whether vaccination would benefit women with prevalent infection by increasing their immunologic resistance against reappearance (via reactivation or reinfection) with the same viral type in the future. Because HPV-infected women who clear their infection have demonstrated immune-competence to handle an established HPV infection, these women might be expected to be capable of handling subsequent infections without the need for vaccination. In particular, it is possible to hypothesize that T-cell responses developed following an initial HPV infection that successfully clears would be capable of adequately eradicating subsequent viral infections. This remains an open issue for future investigation.
HPV Vaccine –A Boon or Bane In a study by Hildesheim A et al. in women positive for HPV DNA, HPV-16/ 18 vaccination does not accelerate clearance of the virus and should not be used for purposes of treating prevalent infections. The high probability of acquiring HPV infection once, one has become sexually active raises the question of whether the vaccine will be effective if given to girls who have already been infected with HPV type 16 or 18. Though the question of immunization of older girls and women deserves attention, from a public health perspective, the first priority in resource-poor settings would be to vaccinate young adolescent girls. Fortunately, for older women in developing countries there are new options for cervical-cancer screening that are likely to provide cost-effective strategies for reducing the risk of cancer.26 Rights violation found in HPV vaccine studies in India – PATH & ICMR did demonstration project on the
Human Vaccines & Immunotherapeutics
safety of the HPV vaccine in the states of Andhra Pradesh & Gujrat which was suspended by the Indian Govt. in response to demands from advocacy group. In April 2010, The Indian parliament’s Standing Committee on Health, began probing the use of HPV vaccines in 2 states after the reported deaths of 7 girls, and concluded that “safety and rights of children were highly compromised and violated.” In view of the reports finding of violation of human rights and clinical trial rules, the committee has recommended legal action against non-profit organization Program for Appropriate Technology in Health (PATH), which initiated the HPV project with the Indian Council of Medical Research (ICMR) in 2007, a year before marketing approval for HPV vaccines was given in India. The trial’s (by PATH & ICMR) purpose was to prepare ground for inclusion of the HPV vaccine in the Universal Immunization Program (UIP). The advocacy groups that pressured the Indian Government to halt and re-evaluate the HPV vaccine activities drew their information from many sources. They made fact-finding visits to study sites, combined with information from a USbased anti-HPV vaccination group, and additionally researched various public documents.27 As far as these groups were concerned, their arguments were evidencebased. Some of the points made by the advocacy groups and a member of parliament are generally reasonable: calling for increased funds for health, maximising investment in priority health issues, ensuring the safety of health interventions, communicating clearly and honestly any risks, and conducting ethical processes in research. Beyond these broader demands, there was a mix of facts, misinformation, principles, anger at injustices, and anger at perceived interference by multinational companies, funders, and international nongovernmental organisations in local concerns, and a final pointing to the government for its ultimate responsibility to protect people’s health and wellbeing. Consideration that the HPV-vaccine activities were in the interest of women’s
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health could have been more loudly articulated, but that argument would need a different type of evidence and argument than that used by the advocacy groups. Reluctance by public health authorities to respond to issues of public distrust for fear that they will exacerbate the problem is dangerous.28 Experience is increasingly showing that public distrust does not go away if unaddressed and can lead to program disruptions and even disease outbreaks. We need to find new ways to engage the public, early on, in health research and in the design and delivery of health programmes. That approach includes taking the time to listen to societal concerns, public emotions, and politics that can derail programmes or research. We might not always understand them, but we cannot ignore them.
Conclusion The resources, infrastructure, and technological expertise required, together with the need for repeated screening at frequent intervals, have made conventional cytology-based screening prohibitively difficult in most poor countries. With the availability of an effective, safe vaccine, there is real hope for reducing the global burden of cervical cancer. Although achieving broad coverage of young adolescents, negotiating tiered pricing, and securing financing will be challenging, it is sobering to realize that with every 5-year delay in bringing vaccination to developing countries, 1.5 million to 2 million more women will die. Vaccination has the potential to save many lives. Let us hope that a committed global effort makes fulfillment of the promise of the new vaccine possible.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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