- Email: [email protected]
Vaccination Against Cervical Cancer
Review Article
VACCINATION AGAINST CERVICAL CANCER Urvashi Prasad Jha* and Swasti** *Senior Consultant Gynaecologist, Laparoscopic and Gynae-Onco Surgeon, Academic Co-ordinator, ** Clinical Assistant, Jha’s Gynae Endoscopy and Cancer Unit, Department of Obstetrics & Gynaecology, Indraprastha Apollo Hospitals, Saria Vihar, New Delhi 110 076, India. Correspondence to: Dr. Urvashi Prasad Jha, E-24, Defence Colony, Ring Road, New Delhi 110 024. e-mail: [email protected], [email protected] According to estimates from the World Health Organization, worldwide annual incidence of human papilloma virus (HPV) infection and low-and high-grade dysplasia is 300 million, 30 million, and 10 million cases, respectively. The World Health Organization estimates that 30 million cases of genital warts occur every year. Upto 90-100% of cervical cancers are associated with HPV infection. In India every year 1,32,082 women are diagnosed with cervical cancer and 74,118 die from the disease. Annual incidence and deaths of cervical cancer cases in India accounts for approx 27% of worldwide incidence and deaths. HPV types 16 and 18 account for 76.7% of cervical cancer in India. HPV infection with oncogenic types, notably types 16 and 18, is associated with both low-grade and highgrade cervical lesions. HPV infection with these types can lead to cervical cancer. Non-oncogenic HPV types, notably types 6 and 11, are associated with low-grade cervical lesions and anogenital warts. Effective interventions against cervical cancer include screening and now vaccination. There are two vaccines available globally-quadrivalent vaccine and bivalent vaccine. Bivalent vaccine protects against HPV type 16 & 18 related cervical cancers while Quadrivalent vaccine protects not only against HPV type 16 & 18 related cervical cancers but also against HPV Type 6 and 11 related genital warts, vaginal intraepithelial neoplasia (VAIN) and vulvar intraepithelial neoplasia (VIN). The quadrivalent vaccine will now be available in India by Oct 2008 for use: a boon to all girls and women! Keywords: Cervical Cancer, Human Papiloma Virus.
HPV INFECTION ACCORDING to estimates from the World Health Organization, worldwide annual incidence of HPV infection and low- and high-grade dysplasia is 300 million, 30 million, and 10 million cases, respectively [1]. The World Health Organization estimates that 30 million cases of genital warts occur every year [2]. The largest numbers of cervical HPV infection cases have no detectable cytologic abnormalities, and many of these are self-limited. However, an important subset will subsequently become associated with disease [1]. HPV infection with oncogenic types, notably types 16 and 18, is associated with both low-grade and high-grade cervical lesions. HPV infection with these types can lead to cervical cancer [3]. Nononcogenic HPV types, notably types 6 and 11, are Apollo Medicine, Vol. 5, No. 3, September 2008
218
associated with low-grade cervical lesions and with anogenital warts [3-5]. In a study by Gissmann and colleagues (N=63), HPV 6 and 11 DNA were detected in >90% of anogenital warts [5]. Link between HPV and Cervical Cancer Over the past 20 years, several lines of evidence converged to identify HPV as perhaps the only cause of cervical cancer. The finding of HPV genomes in cervical carcinomas was a key discovery in the late 1970s. HPV was cloned, and its family defined as large and closely related. The mechanisms of HPV transformation were elucidated, and it was demonstrated that HPV is a true “tumor virus,” carrying genes encoding multiple proteins that interfere with cell cycle control, leading to transformation and uncontrolled cell growth [6]. The link between cervical cancer and HPV was validated by evidence found in epidemiological case-
Review Article
control studies. The data from a large, case-control study of 500 women with cervical intraepithelial neoplasia (CIN) and 500 controls by Schiffman and colleagues showed that the majority (76%) of all CIN grades were attributable to HPV infection [7]. Muñoz and colleagues conducted a study of 1918 cases of histologically confirmed invasive cervical cancer and 1923 controls that indicated there was a strong association between 15 types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) and invasive cervical cancer [8]. Currently, there are over 100 known types of HPV, [9] of which ~30-40 affect the anogenital area and 15-20 are classified as oncogenic [4,8,9]. Pooled analysis across clinical and epidemiological studies has shown that HPV was found in 90%-100% of cervical cancer specimens [10]. HPV TYPES RELATED TO CERVICAL CANCER Papillomaviruses such as HPV are nonenveloped, double-stranded DNA viruses [11]. More than 100 HPV types have been detected [9], with >80 types sequenced and classified [4]. Approximately 30-40 types of HPV are anogenital, of which ~15-20 types are oncogenic [4,9]. In an international meta-analysis, HPV types 16 and 18 were found to be oncogenic and accounted for more than 70% of all cervical cancers-the next 5 most prevalent types (31,33, 45,52,58) account for an additional 17% of cases [8]. Other oncogenic HPV types include 35, 39, 51, and 56. 2 HPV types 6 and 11 are nononcogenic and are associated with external anogenital warts [4]. Natural History of Cervical Cancer Squamous intraepithelial lesions (SILs) are subdivided into low-grade squamous intraepithelial lesions (LSIL) and high-grade intraepithelial lesions (HSIL), based on cytology results. LSIL often is the marker of CIN 1, and HSIL of CIN 2&3 [12]. Incident HPV infection is the new detection of HPV infection in women who were previously HPV-negative. Although common in sexually active persons, more than 90% of infections are spontaneously cleared by the immune system within approximately 1 year without treatment [13]. Persistent HPV infection is the detection of the same HPV type in follow-up visits 6-12 months apart in women who were naive for that particular HPV type at baseline [13]. The schematic diagram shows the progression from oncogenic HPV infection to cervical cancer. The known steps from HPV infection to cervical cancer include oncogenic HPV infection of the cervix; development of undetected cellular changes, LSIL or HSIL; development of HSIL; and progression to cervical cancer. The sequential steps of progression include: LSIL and undetected cellular
changes to HSIL to cervical cancer. However, some LSIL may progress directly to cervical cancer, and some initial HPV infection may progress directly to HSIL. The literature suggests that between one-third and two-thirds of women with HSIL will progress to cervical cancer if left untreated [14]. Approximately 60% of CIN 1 lesions (or low-grade dysplasia), the most common clinical manifestation of cervical HPV infections, regress without treatment, and about 10% can progress to CIN 2 and CIN 3 [13,15]. CIN 2 (moderate-grade dysplasia) also can regress; however, women with CIN 2 are still at risk for developing invasive cervical cancer. In a meta-analysis of studies on the natural history of CIN, it was estimated that 22% of CIN 2 lesions that were not treated will progress [13,15]. CIN 3 lesions (high-grade precancerous lesions and carcinoma in situ) are more likely to progress to cancer, with regression being less common [13]. The mean age of invasive cervical cancer is approximately 50 years. The mean age of women with HSIL is approximately 28 years of age [14]. Burden of cervical cancer in India The population of women in the world is increasing continuously. WHO estimates says India has a population of 365.71 millions women ages 15 years and older who are at risk of developing cervical cancer and every year 1,32,082 women are diagnosed with cervical cancer and 74,118 die from the disease. Cervical cancer ranks the first most frequent cancer in women in India, and the first most frequent cancer. Annual incidence and deaths of cervical cancer cases in India accounts for approx 27% of worldwide incidence and deaths. HPV types 16 and 18 account for 76.7% of cervical cancer in India [16]. Anecdotally, we are beginning to see younger and younger girls even in their teens with CIN and cervical cancer. Screening Cervical cancer can be prevented by screening women systematically through organized population based programmes. Screening aims to detect the disease at the precancer stage when it is amenable to simple treatment and cure. In many of the developed countries the annual incidence and mortality from this cancer have gone down by 50-70% because of the introduction of population based screening. There are various limitations in undertaking organized population based cervical cancer screening programmes in India. The resources and infrastructure varies widely in different parts of the country and within states. Pap smear based cervical screening has reduced cervical cancer
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Review Article
Fig.1 Depiction of progression of HPV infection to cervical precancerous lesions or cervical neoplasia
incidence and mortality in different parts of the world. If facilities and resources are available such options can be undertaken. However, for the large population of India the infrastructure and resources do not permit Pap smear based screening programmes except in a few settings [17]. In India, conventional Pap smear is one of the most common screening methods used in India. There are various limitations of conventional Pap testing such as the fact that results are not available immediately, systems needed to ensure timely communication of test results and follow-up of women, transport required for specimen to laboratory and for the results to the clinics, it requires laboratory quality assurance and last but not the least has only a moderate sensitivity. The Vaccines Two vaccines have been licensed globally; a quadrivalent vaccine from Merck and the other a bivalent vaccine from GSK. Both are manufactured by recombinant DNA technology that produces non-infectious virus like particles (VLP) comprising of the HPV L1 protein, the major capsid protein of HPV. Clinical trials with both vaccines have used efficacy against cervical intraepithelial neoplasia (CIN) 2/3 and adenocarcinoma in situ (AIS) caused by HPV strains contained in the concerned vaccine as primary end points, and both vaccines have also looked at cross protection against HPV strains not contained in the concerned vaccine. It must be understood that both vaccines do not protect against the serotype with which infection has already occurred before vaccination. Apollo Medicine, Vol. 5, No. 3, September 2008
Quadrivalent vaccine has shown 100% efficacy at a median follow up of 1.9 years against types 16,18 related CIN-2/3 and adenocarcinoma-in-situ (AIS) in per protocol analysis (women who received all three doses of the vaccine and who remained uninfected with vaccine HPV type at onset and for 1 month after completion of the vaccine schedule). Additionally 99-100% efficacy was seen against vaccine type (HPV Type 6,11,16&18 ) related genital warts, vaginal intraepithelial neoplasia (VaIN) and vulvar intraepithelial neoplasia (VIN). Local adverse effects with HPV vaccination against cervical cancer reported were pain at the injection site in 83% of vaccinees (mainly mildmoderate intensity) and, swelling and erythema in 25%. Systemic adverse effects such as fever reported in 4% of vaccines. No serious vaccine related adverse events have been reported so far [19]. Bivalent vaccine has shown 90% efficacy against type 16/18 related CIN2/3 and AIS at 15 month follow up in modified intention to treat analysis (included women who were at baseline negative for HPV DNA of vaccine type virus and who received at least 1 dose of the vaccine.) Local side effects reported were pain (mild and moderate intensity) in 90% and swelling and erythema in 40%. Systemic side effects such as fever were seen in 12%. No serious vaccine related adverse effects were observed [19]. Efficacy End Points The primary objective of vaccination is to reduce cervical cancer. Ethical and time considerations make it necessary to use a surrogate end point in clinical trials of vaccine efficacy. As per US FDA, the only surrogate clinical
220
Review Article papillomavirus infection. Report of a technical meeting, 1618 February 1999. Geneva, Switzerland: World Health Organization; 1999:1-22.
condition is biopsy-confirmed CIN 2 or 3 or AIS. These lesions are the obligate precursor to invasive cervical cancer and are always treated [13,20]. A demonstration that HPV vaccination prevents the development of CIN 2 or 3 or AIS lesions caused by vaccine HPV types would constitute a demonstration that HPV vaccination prevents cervical cancer caused by vaccine HPV types.20 Therefore, CIN 2 or 3 or AIS are strong surrogate markers for cervical cancer and have been used as primary endpoints for various trials rather than antibody titres.
2. World Health Organization. Sexually transmitted infections increasing-250 million new infections annually. WHO Office of Information. WHO Features. 1990; 152:1-6. 3. Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003;16:1-17. 4. Wiley DJ, Douglas J, Beutner K, et al. External genital warts: diagnosis, treatment, and prevention. Clin Infect Dis. 2002; 35(suppl 2):S210-S224.
Need for Booster As with any other vaccine, a study over next few years will determine the need of booster. Vaccines inducing immune memory induce long term protection. Quadrivalent vaccine resulted in potent anti-HPV 6,11,16 and 18 anamnestic responses after administration of immune challenge dose of quadrivalent vaccine at 5 yrs to individuals who were previously immunized with quadrivalent HPV vaccine [21].
5. Gissmann 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 USA. 1983; 80: 560-563. 6. Jansen KU, Shaw AR. Human papillomavirus vaccines and prevention of cervical cancer. Annu Rev Med. 2004;55:319-331. 7. Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst. 1993; 85: 958-964.
RECOMMENDATION Only quadrivalent vaccine is approved by US FDA so Advisory Committee on Immunization Practices (ACIP) recommendations are available only for quadrivalent vaccine for use among females 9-26 years of age [22]. Indian Academy of Pediatrics (IAP) has recommended the use of the cervical cancer vaccine in young girls 10-12 years of age. It should be remembered that girls should be vaccinated before exposure to HPV and hence before they become sexually active. CONCLUSIONS HPV infection is the most common cause of cervical cancer. HPV type 16 & 18 are mainly attributed to invasive cervical cancers (approx. 76.7% in India). Annual number of deaths from cervical cancer in India accounts for 27% of deaths worldwide. Effective interventions against cervical cancer include screening and now vaccination. There are two vaccine available globally – quadrivalent vaccine and bivalent vaccine. Bivalent vaccine protects against HPV type 16&18 related cervical cancers while quadrivalent vaccine protects not only against HPV type 16&18 related cervical cancers but also against HPV Type 6 and 11 related genital warts, vaginal intraepithelial neoplasia (VAIN) and vulvar intraepithelial neoplasia (VIN). The quadrivalent vaccine will now be available in India by October 2008 for use: a boon to all girls and women! REFERENCES 1. World Health Organization. The current status of development of prophylactic vaccines against human
8. Muñoz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348: 518-527. 9. Schiffman M, Castle PE. Human papillomavirus: Epidemiology and public health. Arch Pathol Lab Med. 2003;127: 930-934. 10. Bosch FX, de Sanjosé S. Human papillomavirus and cervical cancer—Burden and assessment of causality. J Natl Cancer Inst Monogr. 2003;31: 3-13. 11. Howley PM, Lowy DR. Papillomaviruses and their replication. In: Knipe DM, Howley PM, eds. Fields Virology. 4th ed. Philadelphia, Pa: Lippincott-Raven; 2001: 21972229. 12. Solomon D, Davey D, Kurman R, et al. for the Forum Group Members and the Bethesda 2001 Workshop. The 2001 Bethesda System: Terminology for reporting results of cervical cytology. JAMA. 2002;287:2114-2119. 13. Pagliusi SR, Aguado MT. Efficacy and other milestones for human papillomavirus vaccine introduction. Vaccine. 2004;23: 569-578. 14. Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin Virol. 2006;32S:S16-S24. 15. Ostor AG. Natural history of cervical intraepithelial neoplasia: A critical review. Int J Gynecol Pathol. 1993;12:186-192. 16. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. (Accessed on 18th March 2008. Available at www. who. int/
221
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Review Article hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer).
vaccines (FDA briefing document #1). Vaccines and Related Biological Products Advisory Committee Meeting, November 28-29, 2001. Available at: http://www.fda.gov/ ohrms/dockets/ac/01/briefing/3085b1.htm. Accessed January 18, 2006.
17. Guidelines for Cervical Cancer Screening Programme, Government of India-World Health Organization Collaborative Programme (2004-2005). 18. Comprehensive cervical cancer control; A guide to essential practice - 2006. 19. Indian Academy of Pediatrics Committee Immunization. Consensus Recommendations Immunization, 2008. Indian Pediatrics 2008; 635-648.
on on 45:
20. Pratt D, Goldenthal K, Geber A. Discussion of possible endpoints for licensure of human papillomavirus (HPV)
Apollo Medicine, Vol. 5, No. 3, September 2008
21. Olsson S E, Villa L L, Costa R L R, et al. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/ 18 L1 virus-like particle (VLP) vaccine. Vaccine 2007; 25: 4931-4939. 22. Centers for Disease Control and Prevention. Quadrivalent Human Papillomavirus Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2007; 56(RR-2): 1-24.
222
VACCINATION AGAINST CERVICAL CANCER Urvashi Prasad Jha* and Swasti** *Senior Consultant Gynaecologist, Laparoscopic and Gynae-Onco Surgeon, Academic Co-ordinator, ** Clinical Assistant, Jha’s Gynae Endoscopy and Cancer Unit, Department of Obstetrics & Gynaecology, Indraprastha Apollo Hospitals, Saria Vihar, New Delhi 110 076, India. Correspondence to: Dr. Urvashi Prasad Jha, E-24, Defence Colony, Ring Road, New Delhi 110 024. e-mail: [email protected], [email protected] According to estimates from the World Health Organization, worldwide annual incidence of human papilloma virus (HPV) infection and low-and high-grade dysplasia is 300 million, 30 million, and 10 million cases, respectively. The World Health Organization estimates that 30 million cases of genital warts occur every year. Upto 90-100% of cervical cancers are associated with HPV infection. In India every year 1,32,082 women are diagnosed with cervical cancer and 74,118 die from the disease. Annual incidence and deaths of cervical cancer cases in India accounts for approx 27% of worldwide incidence and deaths. HPV types 16 and 18 account for 76.7% of cervical cancer in India. HPV infection with oncogenic types, notably types 16 and 18, is associated with both low-grade and highgrade cervical lesions. HPV infection with these types can lead to cervical cancer. Non-oncogenic HPV types, notably types 6 and 11, are associated with low-grade cervical lesions and anogenital warts. Effective interventions against cervical cancer include screening and now vaccination. There are two vaccines available globally-quadrivalent vaccine and bivalent vaccine. Bivalent vaccine protects against HPV type 16 & 18 related cervical cancers while Quadrivalent vaccine protects not only against HPV type 16 & 18 related cervical cancers but also against HPV Type 6 and 11 related genital warts, vaginal intraepithelial neoplasia (VAIN) and vulvar intraepithelial neoplasia (VIN). The quadrivalent vaccine will now be available in India by Oct 2008 for use: a boon to all girls and women! Keywords: Cervical Cancer, Human Papiloma Virus.
HPV INFECTION ACCORDING to estimates from the World Health Organization, worldwide annual incidence of HPV infection and low- and high-grade dysplasia is 300 million, 30 million, and 10 million cases, respectively [1]. The World Health Organization estimates that 30 million cases of genital warts occur every year [2]. The largest numbers of cervical HPV infection cases have no detectable cytologic abnormalities, and many of these are self-limited. However, an important subset will subsequently become associated with disease [1]. HPV infection with oncogenic types, notably types 16 and 18, is associated with both low-grade and high-grade cervical lesions. HPV infection with these types can lead to cervical cancer [3]. Nononcogenic HPV types, notably types 6 and 11, are Apollo Medicine, Vol. 5, No. 3, September 2008
218
associated with low-grade cervical lesions and with anogenital warts [3-5]. In a study by Gissmann and colleagues (N=63), HPV 6 and 11 DNA were detected in >90% of anogenital warts [5]. Link between HPV and Cervical Cancer Over the past 20 years, several lines of evidence converged to identify HPV as perhaps the only cause of cervical cancer. The finding of HPV genomes in cervical carcinomas was a key discovery in the late 1970s. HPV was cloned, and its family defined as large and closely related. The mechanisms of HPV transformation were elucidated, and it was demonstrated that HPV is a true “tumor virus,” carrying genes encoding multiple proteins that interfere with cell cycle control, leading to transformation and uncontrolled cell growth [6]. The link between cervical cancer and HPV was validated by evidence found in epidemiological case-
Review Article
control studies. The data from a large, case-control study of 500 women with cervical intraepithelial neoplasia (CIN) and 500 controls by Schiffman and colleagues showed that the majority (76%) of all CIN grades were attributable to HPV infection [7]. Muñoz and colleagues conducted a study of 1918 cases of histologically confirmed invasive cervical cancer and 1923 controls that indicated there was a strong association between 15 types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) and invasive cervical cancer [8]. Currently, there are over 100 known types of HPV, [9] of which ~30-40 affect the anogenital area and 15-20 are classified as oncogenic [4,8,9]. Pooled analysis across clinical and epidemiological studies has shown that HPV was found in 90%-100% of cervical cancer specimens [10]. HPV TYPES RELATED TO CERVICAL CANCER Papillomaviruses such as HPV are nonenveloped, double-stranded DNA viruses [11]. More than 100 HPV types have been detected [9], with >80 types sequenced and classified [4]. Approximately 30-40 types of HPV are anogenital, of which ~15-20 types are oncogenic [4,9]. In an international meta-analysis, HPV types 16 and 18 were found to be oncogenic and accounted for more than 70% of all cervical cancers-the next 5 most prevalent types (31,33, 45,52,58) account for an additional 17% of cases [8]. Other oncogenic HPV types include 35, 39, 51, and 56. 2 HPV types 6 and 11 are nononcogenic and are associated with external anogenital warts [4]. Natural History of Cervical Cancer Squamous intraepithelial lesions (SILs) are subdivided into low-grade squamous intraepithelial lesions (LSIL) and high-grade intraepithelial lesions (HSIL), based on cytology results. LSIL often is the marker of CIN 1, and HSIL of CIN 2&3 [12]. Incident HPV infection is the new detection of HPV infection in women who were previously HPV-negative. Although common in sexually active persons, more than 90% of infections are spontaneously cleared by the immune system within approximately 1 year without treatment [13]. Persistent HPV infection is the detection of the same HPV type in follow-up visits 6-12 months apart in women who were naive for that particular HPV type at baseline [13]. The schematic diagram shows the progression from oncogenic HPV infection to cervical cancer. The known steps from HPV infection to cervical cancer include oncogenic HPV infection of the cervix; development of undetected cellular changes, LSIL or HSIL; development of HSIL; and progression to cervical cancer. The sequential steps of progression include: LSIL and undetected cellular
changes to HSIL to cervical cancer. However, some LSIL may progress directly to cervical cancer, and some initial HPV infection may progress directly to HSIL. The literature suggests that between one-third and two-thirds of women with HSIL will progress to cervical cancer if left untreated [14]. Approximately 60% of CIN 1 lesions (or low-grade dysplasia), the most common clinical manifestation of cervical HPV infections, regress without treatment, and about 10% can progress to CIN 2 and CIN 3 [13,15]. CIN 2 (moderate-grade dysplasia) also can regress; however, women with CIN 2 are still at risk for developing invasive cervical cancer. In a meta-analysis of studies on the natural history of CIN, it was estimated that 22% of CIN 2 lesions that were not treated will progress [13,15]. CIN 3 lesions (high-grade precancerous lesions and carcinoma in situ) are more likely to progress to cancer, with regression being less common [13]. The mean age of invasive cervical cancer is approximately 50 years. The mean age of women with HSIL is approximately 28 years of age [14]. Burden of cervical cancer in India The population of women in the world is increasing continuously. WHO estimates says India has a population of 365.71 millions women ages 15 years and older who are at risk of developing cervical cancer and every year 1,32,082 women are diagnosed with cervical cancer and 74,118 die from the disease. Cervical cancer ranks the first most frequent cancer in women in India, and the first most frequent cancer. Annual incidence and deaths of cervical cancer cases in India accounts for approx 27% of worldwide incidence and deaths. HPV types 16 and 18 account for 76.7% of cervical cancer in India [16]. Anecdotally, we are beginning to see younger and younger girls even in their teens with CIN and cervical cancer. Screening Cervical cancer can be prevented by screening women systematically through organized population based programmes. Screening aims to detect the disease at the precancer stage when it is amenable to simple treatment and cure. In many of the developed countries the annual incidence and mortality from this cancer have gone down by 50-70% because of the introduction of population based screening. There are various limitations in undertaking organized population based cervical cancer screening programmes in India. The resources and infrastructure varies widely in different parts of the country and within states. Pap smear based cervical screening has reduced cervical cancer
219
Apollo Medicine, Vol. 5, No. 3, September 2008
Review Article
Fig.1 Depiction of progression of HPV infection to cervical precancerous lesions or cervical neoplasia
incidence and mortality in different parts of the world. If facilities and resources are available such options can be undertaken. However, for the large population of India the infrastructure and resources do not permit Pap smear based screening programmes except in a few settings [17]. In India, conventional Pap smear is one of the most common screening methods used in India. There are various limitations of conventional Pap testing such as the fact that results are not available immediately, systems needed to ensure timely communication of test results and follow-up of women, transport required for specimen to laboratory and for the results to the clinics, it requires laboratory quality assurance and last but not the least has only a moderate sensitivity. The Vaccines Two vaccines have been licensed globally; a quadrivalent vaccine from Merck and the other a bivalent vaccine from GSK. Both are manufactured by recombinant DNA technology that produces non-infectious virus like particles (VLP) comprising of the HPV L1 protein, the major capsid protein of HPV. Clinical trials with both vaccines have used efficacy against cervical intraepithelial neoplasia (CIN) 2/3 and adenocarcinoma in situ (AIS) caused by HPV strains contained in the concerned vaccine as primary end points, and both vaccines have also looked at cross protection against HPV strains not contained in the concerned vaccine. It must be understood that both vaccines do not protect against the serotype with which infection has already occurred before vaccination. Apollo Medicine, Vol. 5, No. 3, September 2008
Quadrivalent vaccine has shown 100% efficacy at a median follow up of 1.9 years against types 16,18 related CIN-2/3 and adenocarcinoma-in-situ (AIS) in per protocol analysis (women who received all three doses of the vaccine and who remained uninfected with vaccine HPV type at onset and for 1 month after completion of the vaccine schedule). Additionally 99-100% efficacy was seen against vaccine type (HPV Type 6,11,16&18 ) related genital warts, vaginal intraepithelial neoplasia (VaIN) and vulvar intraepithelial neoplasia (VIN). Local adverse effects with HPV vaccination against cervical cancer reported were pain at the injection site in 83% of vaccinees (mainly mildmoderate intensity) and, swelling and erythema in 25%. Systemic adverse effects such as fever reported in 4% of vaccines. No serious vaccine related adverse events have been reported so far [19]. Bivalent vaccine has shown 90% efficacy against type 16/18 related CIN2/3 and AIS at 15 month follow up in modified intention to treat analysis (included women who were at baseline negative for HPV DNA of vaccine type virus and who received at least 1 dose of the vaccine.) Local side effects reported were pain (mild and moderate intensity) in 90% and swelling and erythema in 40%. Systemic side effects such as fever were seen in 12%. No serious vaccine related adverse effects were observed [19]. Efficacy End Points The primary objective of vaccination is to reduce cervical cancer. Ethical and time considerations make it necessary to use a surrogate end point in clinical trials of vaccine efficacy. As per US FDA, the only surrogate clinical
220
Review Article papillomavirus infection. Report of a technical meeting, 1618 February 1999. Geneva, Switzerland: World Health Organization; 1999:1-22.
condition is biopsy-confirmed CIN 2 or 3 or AIS. These lesions are the obligate precursor to invasive cervical cancer and are always treated [13,20]. A demonstration that HPV vaccination prevents the development of CIN 2 or 3 or AIS lesions caused by vaccine HPV types would constitute a demonstration that HPV vaccination prevents cervical cancer caused by vaccine HPV types.20 Therefore, CIN 2 or 3 or AIS are strong surrogate markers for cervical cancer and have been used as primary endpoints for various trials rather than antibody titres.
2. World Health Organization. Sexually transmitted infections increasing-250 million new infections annually. WHO Office of Information. WHO Features. 1990; 152:1-6. 3. Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003;16:1-17. 4. Wiley DJ, Douglas J, Beutner K, et al. External genital warts: diagnosis, treatment, and prevention. Clin Infect Dis. 2002; 35(suppl 2):S210-S224.
Need for Booster As with any other vaccine, a study over next few years will determine the need of booster. Vaccines inducing immune memory induce long term protection. Quadrivalent vaccine resulted in potent anti-HPV 6,11,16 and 18 anamnestic responses after administration of immune challenge dose of quadrivalent vaccine at 5 yrs to individuals who were previously immunized with quadrivalent HPV vaccine [21].
5. Gissmann 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 USA. 1983; 80: 560-563. 6. Jansen KU, Shaw AR. Human papillomavirus vaccines and prevention of cervical cancer. Annu Rev Med. 2004;55:319-331. 7. Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst. 1993; 85: 958-964.
RECOMMENDATION Only quadrivalent vaccine is approved by US FDA so Advisory Committee on Immunization Practices (ACIP) recommendations are available only for quadrivalent vaccine for use among females 9-26 years of age [22]. Indian Academy of Pediatrics (IAP) has recommended the use of the cervical cancer vaccine in young girls 10-12 years of age. It should be remembered that girls should be vaccinated before exposure to HPV and hence before they become sexually active. CONCLUSIONS HPV infection is the most common cause of cervical cancer. HPV type 16 & 18 are mainly attributed to invasive cervical cancers (approx. 76.7% in India). Annual number of deaths from cervical cancer in India accounts for 27% of deaths worldwide. Effective interventions against cervical cancer include screening and now vaccination. There are two vaccine available globally – quadrivalent vaccine and bivalent vaccine. Bivalent vaccine protects against HPV type 16&18 related cervical cancers while quadrivalent vaccine protects not only against HPV type 16&18 related cervical cancers but also against HPV Type 6 and 11 related genital warts, vaginal intraepithelial neoplasia (VAIN) and vulvar intraepithelial neoplasia (VIN). The quadrivalent vaccine will now be available in India by October 2008 for use: a boon to all girls and women! REFERENCES 1. World Health Organization. The current status of development of prophylactic vaccines against human
8. Muñoz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348: 518-527. 9. Schiffman M, Castle PE. Human papillomavirus: Epidemiology and public health. Arch Pathol Lab Med. 2003;127: 930-934. 10. Bosch FX, de Sanjosé S. Human papillomavirus and cervical cancer—Burden and assessment of causality. J Natl Cancer Inst Monogr. 2003;31: 3-13. 11. Howley PM, Lowy DR. Papillomaviruses and their replication. In: Knipe DM, Howley PM, eds. Fields Virology. 4th ed. Philadelphia, Pa: Lippincott-Raven; 2001: 21972229. 12. Solomon D, Davey D, Kurman R, et al. for the Forum Group Members and the Bethesda 2001 Workshop. The 2001 Bethesda System: Terminology for reporting results of cervical cytology. JAMA. 2002;287:2114-2119. 13. Pagliusi SR, Aguado MT. Efficacy and other milestones for human papillomavirus vaccine introduction. Vaccine. 2004;23: 569-578. 14. Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin Virol. 2006;32S:S16-S24. 15. Ostor AG. Natural history of cervical intraepithelial neoplasia: A critical review. Int J Gynecol Pathol. 1993;12:186-192. 16. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. (Accessed on 18th March 2008. Available at www. who. int/
221
Apollo Medicine, Vol. 5, No. 3, September 2008
Review Article hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer).
vaccines (FDA briefing document #1). Vaccines and Related Biological Products Advisory Committee Meeting, November 28-29, 2001. Available at: http://www.fda.gov/ ohrms/dockets/ac/01/briefing/3085b1.htm. Accessed January 18, 2006.
17. Guidelines for Cervical Cancer Screening Programme, Government of India-World Health Organization Collaborative Programme (2004-2005). 18. Comprehensive cervical cancer control; A guide to essential practice - 2006. 19. Indian Academy of Pediatrics Committee Immunization. Consensus Recommendations Immunization, 2008. Indian Pediatrics 2008; 635-648.
on on 45:
20. Pratt D, Goldenthal K, Geber A. Discussion of possible endpoints for licensure of human papillomavirus (HPV)
Apollo Medicine, Vol. 5, No. 3, September 2008
21. Olsson S E, Villa L L, Costa R L R, et al. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/ 18 L1 virus-like particle (VLP) vaccine. Vaccine 2007; 25: 4931-4939. 22. Centers for Disease Control and Prevention. Quadrivalent Human Papillomavirus Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2007; 56(RR-2): 1-24.
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