- Email: [email protected]
HPV vaccine: A breakthrough in prevention of cervical cancer
Apollo Medicine 2012 June Volume 9, Number 2; pp. 87e90
Original Article
HPV vaccine: A breakthrough in prevention of cervical cancer R. Sharma*
ABSTRACT Background: Cervical cancer is one of the commonest cancers in women. As it affects young women it has grave personal, social and economic consequences. It is unfortunate that despite cancer cervix being a preventable disease, we have failed to reduce the number of deaths related to it. Recent developments in the understanding of the disease process and its link to the oncogenic strains of Human Papilloma Virus (HPV) has opened new avenues in the way of prevention of cervical cancer. Method: The information was collected through literature search using the key words HPV, cancer cervix and prevention. Result: It is now well established that almost all cervival cancers are caused by oncogenic Human Papilloma Viruses (HPV), with types 16 and 18 being responsible for almost 70%. This fact has led to the development of a vaccine with great potential of preventing the disease by preventing the causative infection in the target population. Conclusion: A prophylactic vaccine to prevent HPV-related precancerous lesions and cancers would save lives, reduce the need for costly medical procedures and provide both women and communities throughout the world, with substantial benefits. The reduction in the incidence of cervical cancer and mortality is expected to be greatest in low and middle-income countries where there is no or only limited screening for cervical cancer. Copyright © 2012, Indraprastha Medical Corporation Ltd. All rights reserved. Keywords: Cervical cancer, HPV, Prevention
INTRODUCTION Cervical cancer is one of the commonest cancers in women worldwide, second only to breast cancer.1 As it affects young women it has grave personal, social and economic consequences. In India it is still the commonest cancer in women accounting for about 130,000 new cases and 80,000 deaths annually.2 Unfortunately, prevention of cervical cancer is not yet among the top ten National health priorities in India and a comprehensive National Health Strategy for cervical cancer prevention is still lacking. As a result, despite cancer cervix being a preventable disease, we fail to reduce the number of deaths related to it. The long pre-cancerous stage of cancer cervix provides a great opportunity to treat a cervical lesion before it turns malignant. The resourceful countries that managed to run an organized screening programme using Pap smear as
a screening test, achieved about 70% reduction in the disease related mortality.3 Screening by Pap smear cytology has certain limitations, especially in resource-poor countries. In addition to having low sensitivity, the laboratory based infrastructure and skilled health care professionals for taking, making, transporting and interpreting smears, are hard to find even in urban health care facilities in India. Communicating the results to women, and providing confirmatory diagnostic tests in the form of colposcopy and directed biopsy, and treatment of precancer (CIN) are other limitations in low resourceful countries.4 Some recent developments over the last few years have the potential to change the way we address the problem of cervical cancer prevention. One such significant development is the availability of two very effective vaccines against human papilloma virus (HPV).
Senior Consultant, Department of Obstetrics and Gynaecology, Indraprastha Apollo Hospitals, Mathura Road, Sarita Vihar, New Delhi 110076, India. * Tel.: þ91 11 26925858, 26925801, email: [email protected] Received: 1.5.2012; Accepted: 2.5.2012; Available online: 9.5.2012 Copyright Ó 2012, Indraprastha Medical Corporation Ltd. All rights reserved. doi:10.1016/j.apme.2012.05.005
88
Apollo Medicine 2012 June; Vol. 9, No. 2
Sharma
HPV AND CANCER CERVIX
HOW HPV INDUCES CANCER
Nearly all cervical cancers (99.7%) are preceded by persistent infection with one or more of the oncogenic types of HPV.5 establishing that HPV infection is the cause of cervical precancer and cancer. This association provides a tremendous opportunity for cervical cancer prevention through vaccination against oncogenic HPV viruses especially in medium and low resourceful countries.
All types of HPV have an affinity to epithelial cells of skin and mucous membranes, and infect the keratinocytes in the basal layers of a stratified squamous epithelium. The virus replicates and assembles exclusively in the nucleus. In humans, cell division is regulated largely by two proteins e Rb and p53. These proteins are responsible for the cell’s death if it becomes diseased or its DNA is damaged. Two genes in HPV, E6 and E7, produce proteins that can attach themselves to Rb and p53 and block their effect on regulating cell division.8 When this happens, the infected cells reproduce without any control and tumours are created from unregulated proliferation. However, a large amount of evidence suggests the existence of p53-independent functions of E6 that are also necessary and important for transformation. While the virus serves only as the initiating event, over time some of the wildly growing cells develop permanent changes in their genetic structure that cannot be repaired. Once this happens, some may eventually turn into cancer cells.
THE HPV VIRUS HPVs are double stranded, circular, non-enveloped DNA viruses of Papovaviridae family. As it is non-enveloped, it is more resistant to the environment and prescription medication. Out of more than 100 known HPV genotypes only a few are associated with carcinogenesis. Of these, at least 13 may cause cervical cancer or are associated with other anogenital and oropharyngeal cancers. HPV types 16 and 18 cause about 70% of all cases of invasive cervical cancer worldwide, with type 16 having the greatest oncogenic potential.6 The distribution of HPV types varies among geographical regions, but the dominant oncogenic type in all regions is HPV-16.
THE HPV INFECTION Human papilloma virus (HPV) is the most prevalent sexually transmitted infection in the world, occurring in up to 75% of sexually active women at some stage in their life.7 However, few are aware of the infection. HPVs are highly transmissible via close skin-to-skin contact, predominantly, not exclusively through penetrative intercourse. Most HPV infections are acquired in young age, are short lived and are due to non-oncogenic strains. When an active infection becomes dormant it is not possible to predict whether or when the virus will become active again. Currently there is no treatment for HPV infection, therefore once infected, a person may remain infected for life. Persistent genital infection with oncogenic strains can lead to the development of anogenital precancers and cancers over 10e20 years. Occasionally, early lesions can become malignant within a year or two. The infections are restricted to the intraepithelial layer of the mucosa and do not induce a vigorous immune response. Only half of all infected women develop detectable serum antibodies that do not necessarily provide protection against subsequent infection by the same HPV type. The median time from infection to seroconversion is approximately 8e12 months, although immunological response varies by individual and HPV type.
THE HPV VACCINE The facts that HPV infection with oncogenic strains is necessary for the development of cervical cancer and that more than 70 per cent of the cervical cancers are attributed to types 16/18 led to the development of the HPV vaccines directed to HPV-16/18. Both the vaccines have been found to be very effective in preventing persistent infection with HPV-16/18 and consequent high grade CIN attributed to these two subtypes. This is likely to be translated into high protection against cervical cancer in the vaccinated population. One mathematical model suggested that a vaccine with 98 per cent efficacy against 16 and 18 could reduce cervical cancer incidence by 51 per cent, if all adolescent girls were vaccinated before sexual debut.9 The two vaccines GardasilÒ-quadrivalent (Merck), and CervarixÔ-bivalent (GlaxoSmithKline) that got FDA approval are against the two most prevalent oncogenic strains of HPV in cancer cervix i.e.16 and 18 responsible for about 70% of cancer cervix worldwide,9 leaving other less common ones responsible for the remaining 30% of cervical cancers. Vaccinating girls and women before their sexual debut or those who are naïve to these two strains has potential to reduce the disease burden by 70%. Using recombinant technology the vaccines are prepared from purified L1 structural proteins that form HPV typespecific virus-like particles (VLPs). Neither vaccine contains live biological products or viral DNA, so they are non-infectious. HPV vaccines are designed for prophylactic use only, they do not clear existing HPV infection or
HPV vaccine: A breakthrough in prevention of cervical cancer
treat HPV-related disease. The mechanisms by which these vaccines induce protection have not been fully understood but seem to involve both cellular immunity and neutralizing immunoglobulin G antibodies.
WHO SHOULD BE VACCINATED? The HPV vaccine is most effective before a woman is infected with an HPV, which is why the vaccine has been recommended for girls as young as nine. It’s also approved for women up to the age of 26, and tests are under way to see if it’s effective for women above that age. Most countries that have licenced these vaccines, recommend their use in girls aged 10e14 years. Some national programmes also recommend routine or temporary catch-up vaccination of older adolescent females and young women.
SCHEDULE The quadrivalent vaccine is given at baseline and again after 2 months and 6 months. A minimum interval of 4 weeks between the first and second dose, and a minimum interval of 12 weeks between the second and third dose, are recommended by the manufacturer if flexibility in the schedule is necessary. The bivalent vaccine is given at baseline and again after 1 month and 6 months. If flexibility in the schedule is necessary, the manufacturer recommends that the second dose be administered between 1 and 2.5 months after the first dose. Currently, the manufacturers do not recommend a booster dose following completion of the primary series.
POST VACCINATION IMMUNOGENICITY AND CLINICAL EFFICACY With both vaccines, practically all adolescent and young women who were initially naive to vaccine related HPV types developed an antibody response to these antigens after 3 doses. Serum antibody titres from adolescents aged 10e15 years were higher than titres in sera from older females (aged 15e25 years). The protective effect of the vaccine has been maintained throughout its observation period, currently extending to 6.4 years for bivalent vaccine and 5 years for quadrivalent vaccine.6 The vaccine appears to have partial efficacy against infections caused by HPV types 31 and 45, which are genetically related to types 16 and 18.6
SAFETY In June 2007, WHO’s Global Advisory Committee on Vaccine Safety10 concluded that both vaccines had good
Original Article
89
safety profile. Mild and transient local reactions at the site of injection (erythema, pain or swelling) may occur in 10e20% but no systemic or serious adverse reactions were assessed to be causally associated with the HPV immunization. Selecting target ages for HPV vaccination that usually precede the onset of sexual activity reduces the likelihood of inadvertently vaccinating pregnant or lactating females.
CONTRAINDICATIONS AND PRECAUTIONS HPV vaccines should not be given to people who have experienced severe allergic reactions after a previous vaccine dose or to a component of the vaccine. Several countries recommend that HPV vaccination should be delayed for individuals who have severe acute illness. Findings support an increased occurrence of post vaccination syncope among adolescent girls. Observation for 15 min after the injection is administered, is recommended. HPV vaccines are not recommended for use in pregnant females. The quadrivalent vaccine may be administered to lactating females because available data do not indicate any safety concerns.
WHO POSITION ON HPV VACCINES WHO recognizes the importance of cervical cancer and other HPV-related diseases as global public health problems and recommends that routine HPV vaccination should be included in national immunization programmes.
SUMMARY HPV vaccination programmes for young adolescent females (10e13 years) have a potential to substantially reduce the incidence of cervical cancers if coverage is high (>70%) and vaccine induced protection lasts for 10 years. Considerable reduction in incidence may also be expected for the less frequent cancers of the vagina, vulva, anus, and head and neck associated with HPV-16 and HPV-18. The reduction in the incidence of cervical cancer and mortality is expected to be greatest in low and middle-income countries where there is no or only limited screening for cervical cancer. Since HPV vaccines are prophylactic, the largest impact of vaccination is expected to result from high coverage of young adolescent girls before first intercourse rather than from vaccinating older girls, because a smaller proportion of older girls would be naive to vaccine related types before vaccination. HPV vaccination is a primary prevention tool and does not eliminate the need for screening later in life, since
90
Apollo Medicine 2012 June; Vol. 9, No. 2
HPV types other than 16 and 18 cause up to 30% of all cases of cervical cancer. Educating women on high risk behaviour for acquiring HPV infection and spreading awareness about the diagnosis and treatment of cervical precancer have a great role to play in prevention of cancer cervix. Messages should emphasize that HPV vaccines do not cure cancer; they prevent some, but not all, HPV-related cancers; they are most effective when given before the onset of sexual activity; they require 3 doses; they are not recommended for pregnant females; and they will not prevent HIV infection or other sexually transmitted infections. Thus a prophylactic vaccine to prevent HPV-related precancerous lesions and cancers would save lives, reduce the need for costly medical procedures and provide both women and communities throughout the world, with substantial benefits.
Sharma
2. 3. 4.
5.
6. 7. 8.
REFERENCES 1. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide, IARC
9. 10.
Cancer Base no.5, version 2.0. Lyon: IARC Press, http://www. ncbi.nlm.nih.gov/pmc/articles/PMC1472295/; 2004:1. National Cancer Registry Project (NCRP) Biennial Report 2001. New Delhi: Indian Council of Medical Research; 2001. Kitchener H, Castle PE, Cox JT. Achievements and limitations of cervical cytology screening. Vaccine. 2006;24S3:63e70. Sankaranarayanan R, Thara S, Sharma A, et al. Multicentre study group on cervical cancer early detection in India. Accuracy of conventional cytology: results from a multicentre screening study in India. J Med Screen. 2004;11:77e84. Judson FN. Interactions between human papillomavirus and human immunodeficiency virus infections. Scientific Pub. 1992;119:199e207. http://www.paterson.man.ac.uk/Research/groups.aspx?id¼11 &page_id¼117. Groopman J. Contagion. The New Yorker. 1999;(13 September): 44e49. Massimi P, Banks L. Repression of p53 transcriptional activity by the HPV E7 proteins. Virology. 1997;227(1):255e259. Basu P, Chowdhury D. Indian J Med Res. September 2009; 130:241e246. Weekly epidemiological record. 10 February 2012, 87th year No. 6, 2012, 87, 53e60 http://www.who.int/wer/2012/wer8706.pdf.
Original Article
HPV vaccine: A breakthrough in prevention of cervical cancer R. Sharma*
ABSTRACT Background: Cervical cancer is one of the commonest cancers in women. As it affects young women it has grave personal, social and economic consequences. It is unfortunate that despite cancer cervix being a preventable disease, we have failed to reduce the number of deaths related to it. Recent developments in the understanding of the disease process and its link to the oncogenic strains of Human Papilloma Virus (HPV) has opened new avenues in the way of prevention of cervical cancer. Method: The information was collected through literature search using the key words HPV, cancer cervix and prevention. Result: It is now well established that almost all cervival cancers are caused by oncogenic Human Papilloma Viruses (HPV), with types 16 and 18 being responsible for almost 70%. This fact has led to the development of a vaccine with great potential of preventing the disease by preventing the causative infection in the target population. Conclusion: A prophylactic vaccine to prevent HPV-related precancerous lesions and cancers would save lives, reduce the need for costly medical procedures and provide both women and communities throughout the world, with substantial benefits. The reduction in the incidence of cervical cancer and mortality is expected to be greatest in low and middle-income countries where there is no or only limited screening for cervical cancer. Copyright © 2012, Indraprastha Medical Corporation Ltd. All rights reserved. Keywords: Cervical cancer, HPV, Prevention
INTRODUCTION Cervical cancer is one of the commonest cancers in women worldwide, second only to breast cancer.1 As it affects young women it has grave personal, social and economic consequences. In India it is still the commonest cancer in women accounting for about 130,000 new cases and 80,000 deaths annually.2 Unfortunately, prevention of cervical cancer is not yet among the top ten National health priorities in India and a comprehensive National Health Strategy for cervical cancer prevention is still lacking. As a result, despite cancer cervix being a preventable disease, we fail to reduce the number of deaths related to it. The long pre-cancerous stage of cancer cervix provides a great opportunity to treat a cervical lesion before it turns malignant. The resourceful countries that managed to run an organized screening programme using Pap smear as
a screening test, achieved about 70% reduction in the disease related mortality.3 Screening by Pap smear cytology has certain limitations, especially in resource-poor countries. In addition to having low sensitivity, the laboratory based infrastructure and skilled health care professionals for taking, making, transporting and interpreting smears, are hard to find even in urban health care facilities in India. Communicating the results to women, and providing confirmatory diagnostic tests in the form of colposcopy and directed biopsy, and treatment of precancer (CIN) are other limitations in low resourceful countries.4 Some recent developments over the last few years have the potential to change the way we address the problem of cervical cancer prevention. One such significant development is the availability of two very effective vaccines against human papilloma virus (HPV).
Senior Consultant, Department of Obstetrics and Gynaecology, Indraprastha Apollo Hospitals, Mathura Road, Sarita Vihar, New Delhi 110076, India. * Tel.: þ91 11 26925858, 26925801, email: [email protected] Received: 1.5.2012; Accepted: 2.5.2012; Available online: 9.5.2012 Copyright Ó 2012, Indraprastha Medical Corporation Ltd. All rights reserved. doi:10.1016/j.apme.2012.05.005
88
Apollo Medicine 2012 June; Vol. 9, No. 2
Sharma
HPV AND CANCER CERVIX
HOW HPV INDUCES CANCER
Nearly all cervical cancers (99.7%) are preceded by persistent infection with one or more of the oncogenic types of HPV.5 establishing that HPV infection is the cause of cervical precancer and cancer. This association provides a tremendous opportunity for cervical cancer prevention through vaccination against oncogenic HPV viruses especially in medium and low resourceful countries.
All types of HPV have an affinity to epithelial cells of skin and mucous membranes, and infect the keratinocytes in the basal layers of a stratified squamous epithelium. The virus replicates and assembles exclusively in the nucleus. In humans, cell division is regulated largely by two proteins e Rb and p53. These proteins are responsible for the cell’s death if it becomes diseased or its DNA is damaged. Two genes in HPV, E6 and E7, produce proteins that can attach themselves to Rb and p53 and block their effect on regulating cell division.8 When this happens, the infected cells reproduce without any control and tumours are created from unregulated proliferation. However, a large amount of evidence suggests the existence of p53-independent functions of E6 that are also necessary and important for transformation. While the virus serves only as the initiating event, over time some of the wildly growing cells develop permanent changes in their genetic structure that cannot be repaired. Once this happens, some may eventually turn into cancer cells.
THE HPV VIRUS HPVs are double stranded, circular, non-enveloped DNA viruses of Papovaviridae family. As it is non-enveloped, it is more resistant to the environment and prescription medication. Out of more than 100 known HPV genotypes only a few are associated with carcinogenesis. Of these, at least 13 may cause cervical cancer or are associated with other anogenital and oropharyngeal cancers. HPV types 16 and 18 cause about 70% of all cases of invasive cervical cancer worldwide, with type 16 having the greatest oncogenic potential.6 The distribution of HPV types varies among geographical regions, but the dominant oncogenic type in all regions is HPV-16.
THE HPV INFECTION Human papilloma virus (HPV) is the most prevalent sexually transmitted infection in the world, occurring in up to 75% of sexually active women at some stage in their life.7 However, few are aware of the infection. HPVs are highly transmissible via close skin-to-skin contact, predominantly, not exclusively through penetrative intercourse. Most HPV infections are acquired in young age, are short lived and are due to non-oncogenic strains. When an active infection becomes dormant it is not possible to predict whether or when the virus will become active again. Currently there is no treatment for HPV infection, therefore once infected, a person may remain infected for life. Persistent genital infection with oncogenic strains can lead to the development of anogenital precancers and cancers over 10e20 years. Occasionally, early lesions can become malignant within a year or two. The infections are restricted to the intraepithelial layer of the mucosa and do not induce a vigorous immune response. Only half of all infected women develop detectable serum antibodies that do not necessarily provide protection against subsequent infection by the same HPV type. The median time from infection to seroconversion is approximately 8e12 months, although immunological response varies by individual and HPV type.
THE HPV VACCINE The facts that HPV infection with oncogenic strains is necessary for the development of cervical cancer and that more than 70 per cent of the cervical cancers are attributed to types 16/18 led to the development of the HPV vaccines directed to HPV-16/18. Both the vaccines have been found to be very effective in preventing persistent infection with HPV-16/18 and consequent high grade CIN attributed to these two subtypes. This is likely to be translated into high protection against cervical cancer in the vaccinated population. One mathematical model suggested that a vaccine with 98 per cent efficacy against 16 and 18 could reduce cervical cancer incidence by 51 per cent, if all adolescent girls were vaccinated before sexual debut.9 The two vaccines GardasilÒ-quadrivalent (Merck), and CervarixÔ-bivalent (GlaxoSmithKline) that got FDA approval are against the two most prevalent oncogenic strains of HPV in cancer cervix i.e.16 and 18 responsible for about 70% of cancer cervix worldwide,9 leaving other less common ones responsible for the remaining 30% of cervical cancers. Vaccinating girls and women before their sexual debut or those who are naïve to these two strains has potential to reduce the disease burden by 70%. Using recombinant technology the vaccines are prepared from purified L1 structural proteins that form HPV typespecific virus-like particles (VLPs). Neither vaccine contains live biological products or viral DNA, so they are non-infectious. HPV vaccines are designed for prophylactic use only, they do not clear existing HPV infection or
HPV vaccine: A breakthrough in prevention of cervical cancer
treat HPV-related disease. The mechanisms by which these vaccines induce protection have not been fully understood but seem to involve both cellular immunity and neutralizing immunoglobulin G antibodies.
WHO SHOULD BE VACCINATED? The HPV vaccine is most effective before a woman is infected with an HPV, which is why the vaccine has been recommended for girls as young as nine. It’s also approved for women up to the age of 26, and tests are under way to see if it’s effective for women above that age. Most countries that have licenced these vaccines, recommend their use in girls aged 10e14 years. Some national programmes also recommend routine or temporary catch-up vaccination of older adolescent females and young women.
SCHEDULE The quadrivalent vaccine is given at baseline and again after 2 months and 6 months. A minimum interval of 4 weeks between the first and second dose, and a minimum interval of 12 weeks between the second and third dose, are recommended by the manufacturer if flexibility in the schedule is necessary. The bivalent vaccine is given at baseline and again after 1 month and 6 months. If flexibility in the schedule is necessary, the manufacturer recommends that the second dose be administered between 1 and 2.5 months after the first dose. Currently, the manufacturers do not recommend a booster dose following completion of the primary series.
POST VACCINATION IMMUNOGENICITY AND CLINICAL EFFICACY With both vaccines, practically all adolescent and young women who were initially naive to vaccine related HPV types developed an antibody response to these antigens after 3 doses. Serum antibody titres from adolescents aged 10e15 years were higher than titres in sera from older females (aged 15e25 years). The protective effect of the vaccine has been maintained throughout its observation period, currently extending to 6.4 years for bivalent vaccine and 5 years for quadrivalent vaccine.6 The vaccine appears to have partial efficacy against infections caused by HPV types 31 and 45, which are genetically related to types 16 and 18.6
SAFETY In June 2007, WHO’s Global Advisory Committee on Vaccine Safety10 concluded that both vaccines had good
Original Article
89
safety profile. Mild and transient local reactions at the site of injection (erythema, pain or swelling) may occur in 10e20% but no systemic or serious adverse reactions were assessed to be causally associated with the HPV immunization. Selecting target ages for HPV vaccination that usually precede the onset of sexual activity reduces the likelihood of inadvertently vaccinating pregnant or lactating females.
CONTRAINDICATIONS AND PRECAUTIONS HPV vaccines should not be given to people who have experienced severe allergic reactions after a previous vaccine dose or to a component of the vaccine. Several countries recommend that HPV vaccination should be delayed for individuals who have severe acute illness. Findings support an increased occurrence of post vaccination syncope among adolescent girls. Observation for 15 min after the injection is administered, is recommended. HPV vaccines are not recommended for use in pregnant females. The quadrivalent vaccine may be administered to lactating females because available data do not indicate any safety concerns.
WHO POSITION ON HPV VACCINES WHO recognizes the importance of cervical cancer and other HPV-related diseases as global public health problems and recommends that routine HPV vaccination should be included in national immunization programmes.
SUMMARY HPV vaccination programmes for young adolescent females (10e13 years) have a potential to substantially reduce the incidence of cervical cancers if coverage is high (>70%) and vaccine induced protection lasts for 10 years. Considerable reduction in incidence may also be expected for the less frequent cancers of the vagina, vulva, anus, and head and neck associated with HPV-16 and HPV-18. The reduction in the incidence of cervical cancer and mortality is expected to be greatest in low and middle-income countries where there is no or only limited screening for cervical cancer. Since HPV vaccines are prophylactic, the largest impact of vaccination is expected to result from high coverage of young adolescent girls before first intercourse rather than from vaccinating older girls, because a smaller proportion of older girls would be naive to vaccine related types before vaccination. HPV vaccination is a primary prevention tool and does not eliminate the need for screening later in life, since
90
Apollo Medicine 2012 June; Vol. 9, No. 2
HPV types other than 16 and 18 cause up to 30% of all cases of cervical cancer. Educating women on high risk behaviour for acquiring HPV infection and spreading awareness about the diagnosis and treatment of cervical precancer have a great role to play in prevention of cancer cervix. Messages should emphasize that HPV vaccines do not cure cancer; they prevent some, but not all, HPV-related cancers; they are most effective when given before the onset of sexual activity; they require 3 doses; they are not recommended for pregnant females; and they will not prevent HIV infection or other sexually transmitted infections. Thus a prophylactic vaccine to prevent HPV-related precancerous lesions and cancers would save lives, reduce the need for costly medical procedures and provide both women and communities throughout the world, with substantial benefits.
Sharma
2. 3. 4.
5.
6. 7. 8.
REFERENCES 1. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide, IARC
9. 10.
Cancer Base no.5, version 2.0. Lyon: IARC Press, http://www. ncbi.nlm.nih.gov/pmc/articles/PMC1472295/; 2004:1. National Cancer Registry Project (NCRP) Biennial Report 2001. New Delhi: Indian Council of Medical Research; 2001. Kitchener H, Castle PE, Cox JT. Achievements and limitations of cervical cytology screening. Vaccine. 2006;24S3:63e70. Sankaranarayanan R, Thara S, Sharma A, et al. Multicentre study group on cervical cancer early detection in India. Accuracy of conventional cytology: results from a multicentre screening study in India. J Med Screen. 2004;11:77e84. Judson FN. Interactions between human papillomavirus and human immunodeficiency virus infections. Scientific Pub. 1992;119:199e207. http://www.paterson.man.ac.uk/Research/groups.aspx?id¼11 &page_id¼117. Groopman J. Contagion. The New Yorker. 1999;(13 September): 44e49. Massimi P, Banks L. Repression of p53 transcriptional activity by the HPV E7 proteins. Virology. 1997;227(1):255e259. Basu P, Chowdhury D. Indian J Med Res. September 2009; 130:241e246. Weekly epidemiological record. 10 February 2012, 87th year No. 6, 2012, 87, 53e60 http://www.who.int/wer/2012/wer8706.pdf.