Genotypes of the human papillomavirus: relevance to Indian field trials of the vaccine.HPV HPV human papillomavirus.
human papilloma virus
Human papilloma virus (HPV) vaccines are likely to become available for use in India shortly. The availability and validation of the vaccines to prevent oncogenic HPV oncogenic HPV A human papillomavirus–HPV genotype, especially types 16, 18, but also types 31, 33, and 51, which is pathogenically linked to intraepithelial neoplasia–eg, uterine cervix, termed CIN. See CIN, HPV. infection associated lesions from progressing to cancer has clearly offered a cost effective long-term strategy to reduce the cervical cancer Cervical Cancer Definition
Cervical cancer is a disease in which the cells of the cervix become abnormal and start to grow uncontrollably, forming tumors. burden, particularly for developing countries where effective screening programmes are not available. The enthusiasm for these new vaccines duly justified, are we in reality targeting the actual delinquent by prompting these vaccines in India? The answer would be no as we may not be essentially implementing a rational fool-proof vaccine program which will aid in preventing HPV-related diseases, for the simple reason that there is a lack of understanding about the underlying HPV types responsible for cervical cancer in India. Field trials involving large populations form a major part of continued analysis in understanding any disease and India is still short of such a trial as far as cervical cancer is concerned. Conducting such studies, might also act as prevention programs that will save lives and improve public health in a substantive manner.
Key words Cervical cancer--HPV--HPV 16--HPV vaccine
Vaccines are an effective public health measure. Papillomavirus research and introduction of vaccines to prevent one of the major cancers in women-cervical cancer, is an excellent example of translational research, wherein the collective knowledge of molecular biology molecular biology, scientific study of the molecular basis of life processes, including cellular respiration, excretion, and reproduction. The term molecular biology was coined in 1938 by Warren Weaver, then director of the natural sciences program at the Rockefeller , virology virology, study of viruses and their role in disease. Many viruses, such as animal RNA viruses and viruses that infect bacteria, or bacteriophages, have become useful laboratory tools in genetic studies and in work on the cellular metabolic control of gene expression , immunology and biotechnology from bench has been brought into the clinic. The WHO has stated that they will work in consultation with expert advisors to develop guidelines to assist countries in integrating HPV (human papillomavirus human papillomavirus (HPV), any of a family of more than 60 viruses that cause various growths, including plantar warts and genital warts, a sexually transmitted disease. Detectable warts can be or removed, usually by chemicals, freezing, or laser, but often recur. ) vaccination into their immunization immunization: see immunity; vaccination. , cancer control, reproductive health and adolescent health programmest. The impact of this new vaccine will be realized only if and when it is effectively delivered to the populations that need it most. Considerations for policy makers include the disease burden, health infrastructure, capacity for initiating and sustaining an immunization program for adolescents, affordability, cultural acceptability, political will and of course public support. But, we should also take into account that while the current vaccines confer type-specific immunity against two most commonly prevalent "high-risk" (HR) or oncogenic oncogenic /on·co·gen·ic/ (-jen´ik) giving rise to tumors or causing tumor formation; said especially of tumor-inducing viruses.
on·co·gen·ic or on·cog·e·nous
adj. types, at least 15 types of HR HPV have been associated with progression to invasive cervical cancer (ICC ICC
See: International Chamber of Commerce ). Do we have sufficient data on the HPV type distribution in India? Will the implementation of the current vaccine programme be adopted to the Indian conditions? This review will discuss cervical cancer with respect to HPV infection, with special emphasis on the prevalence and distribution of the major HPV types in Indian population for introducing in India the currently available HPV vaccine.
Cancer of the cervix uteri, is the second most common cancer among women worldwide, with an estimated 493,000 new cases and 274,000 deaths in 2002. The disease represents a major health inequity; approximately 83 per cent of the cases occur in developing countries; for the reason that cervical cancer affects relatively young women, it is an important cause of lost years of life in the developing world (2).
The majority of cases of cervical cancer are squamous cell carcinomas (SCCs); adenocarcinomas are less common (3,4). However, in various countries, over the past two to three decades, for reasons not yet known, the trend is shifting towards more in the cervical adenocarcinoma adenocarcinoma: see neoplasm. cases (3,4). The rates of incidence and mortality of cervical cancer, has declined in the last 40 years in many western countries, primarily due to screening. In developing countries, the incidence and mortality rates have been relatively stable or have shown modest declines. The absence of overall decline--as observed in resource-rich populations-probably reflects the lack of screening programmes, or where programmes have been introduced, their low population coverage and poor cytology cytology (sītŏl`əjē), in biology, the study of the structure of all normal and abnormal components of cells and the changes, movements, and transformations of such components. (5).
Cervical cancer detection: role of screening
Existing patterns of incidence worldwide, reflects the underlying risk and prevention of its manifestation as invasive cancer by effective screening. The goal of cervical cytologic cytological, cytologic
pertaining to cytology.
examination of material for purposes of cytology. Carried out on cerebrospinal fluid, joint fluid, aspirates of body cavities and cystic lesions. screening programs is the detection of cervical cancer and precursor lesions. The Pap (Papanicolau) cytological cytological, cytologic
pertaining to cytology.
examination of material for purposes of cytology. Carried out on cerebrospinal fluid, joint fluid, aspirates of body cavities and cystic lesions. test relies on the microscopic examination of exfoliated cervical cells. But, the sensitivity and specificity of cytological screening vary widely (6). Improved, liquid-based cytology, visual inspection with 3-5 per cent acetic acid, magnified visual inspection with acetic acid and visual inspection with Lugol's iodine have been evaluated as alternative tests. More recently, since infection with oncogenic HPV has been identified as the underlying cause of cervical cancer, there is interest in the use of HPV testing by hybridisation procedures or polymerase chain reactions, as a primary screening test for cervical cancer (7).
Cervical cancer: role of human papillomavirus
Genital HPV infections, commonly sexually transmitted, have strongly and definitely been linked as the primary cause of cervical cancer in women. A landmark study has shown that HPV DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. can be found in 99.7 per cent of cervical cancer specimens (7). HPV fulfils the criteria for a carcinogenic carcinogenic
having a capacity for carcinogenesis. agent defined by the International Agency for Research on Cancer The International Agency for Research on Cancer (IARC, or CIRC in its French acronym) is an intergovernmental agency forming part of the World Health Organisation of the United Nations.
Its main offices are in Lyon, France. (IARC) (7) and in a few instances can also cause cancer of the anal canal, vulvae, penis and oropharynx oropharynx /oro·phar·ynx/ (-far´inks) the part of the pharynx between the soft palate and the upper edge of the epiglottis.
n. . Recognition of the association between cervical cancer and a subset of HR genital papillomavirus infections, first postulated by Zur Hausen and colleagues, was confirmed through painstaking research over 25 years by epidemiologists (8).
Studies have reported that HPV infection occurs shortly after the onset of sexual debut. When a woman is infected with oncogenic HPV types, a spectrum of cellular and molecular events can result. It begins by primary infection of the proliferating basal cells of the squamous epithelium. Most of the HPV infections are benign, but, women with persistent oncogenic infections have the greatest risk of developing cervical precancer and cancer (9). The longer the HPV infection persists, the less likely a patient can clear her infection (10). It is unclear why HPV infections resolve in certain individuals while it results in more severe lesions in others, but individual susceptibility and other enabling factors may play a role. When the infections resolve whether it is by complete viral clearance or by maintenance of a latent state in the basal-cell epithelium, in which the virus replicates at extremely low levels without full viral expression, is also unclear.
CIN CIN cervical intraepithelial neoplasia.
Cervical intraepithelial neoplasia (CIN)
A term used to categorize degrees of dysplasia arising in the epithelium, or outer layer, of the cervix. 1 (cervical intra epithelial neoplasia neoplasia /neo·pla·sia/ (-pla´zhah) the formation of a neoplasm.
cervical intraepithelial neoplasia ), most likely the initial infective and potential progressive state, develops from the infected normal cervical epithelium in the vulnerable transformation zone. SCCs are the most commonly occurring form of cervical cancer and develop from CIN 1 (11). The progression from HPV infection to HPV persistence to the development of high-grade CIN (cervical intraepithelial neoplasia cervical in·tra·ep·i·the·li·al neoplasia
Dysplastic changes beginning at the squamocolumnar junction in the uterine cervix that may be precursor to squamous cell carcinoma. ) and ultimately cervical cancer appears to take, on average, up to 15 yr, although cases of rapid-onset cancers do occur (12,13). Further, the time of invasion reflects the time needed for additional genetic events to occur such as integration of HPV into host genome (14), inactivation inactivation /in·ac·ti·va·tion/ (in-ak?ti-va´shun) the destruction of biological activity, as of a virus, by the action of heat or other agent. of host tumour suppressor genes and ultimately the realization of effects of proteins produced by oncogenic HPV which allow the accumulation of irreparable and irreversible mutations in the host genome. "Precancer" is the intraepithelial precursor to invasive cancer. Progression through each step involves a number of known and unknown external and internal co-factors including host immune responses.
Papillomaviruses: human papillomavirus
The papillomaviruses were initially known as members of the Papovaviridae family but considering the genetic diversity now they have been reclassified as independent Papillomavirus family. Papillomaviruses are small, non-enveloped, viruses that contain a double stranded, circular DNA genome. They are ubiquitous infectious agents characterized by strict species specificity--thus HPVs infect only humans. They are also tissue tropic with a preference for infection of either cutaneous cutaneous /cu·ta·ne·ous/ (ku-ta´ne-us) pertaining to the skin.
Of, relating to, or affecting the skin.
Pertaining to the skin. or internal squamous mucosal surfaces. Papillomaviruses are classified by genotype and approximately 130 HPV types have been identified by sequencing. More than 40 of these types infect the epithelial and mucosal lining of the anogenital a·no·gen·i·tal
Relating to the anus and the genitals.
relating to the region of the anus and the genitalia, especially the external genitalia. tract and other areas following sexual transmission, and about 15 of them are highly carcinogenic (15-17). The HPV genome can be divided into three domains: a non coding URR URR Urea Reduction Ratio (urinary dialysis laboratory data)
URR Ultimately Recoverable Resources (oil reserves)
URR Union Railroad Company
URR Unconstrained Requirements Report
URR Unscheduled Removal Rate (upstream regulatory region), an early region with ORFs (open reading frames) E6, E7, El, E2, E4 and E5, and a late region encoding two genes-L1, the major capsid capsid /cap·sid/ (kap´sid) the shell of protein that protects the nucleic acid of a virus; it is composed of structural units, or capsomers.
n. protein, and L2, the minor capsid protein. E6 and E7 play a significant role in HPV mediated carcinogenesis car·ci·no·gen·e·sis
The production of cancer.
production of cancer.
viruses and some parasites are capable of initiating neoplasia. (14). L1 and L2 are capsid proteins produced for assembly of complete virions. L1 self-assembles to form VLPs (virus-like particles), which can also incorporate L2 if co-expressed. However, L2 protein does not form a VLP VLP Virus-like particles, see there when expressed on its own.
Based on the individual viruses' predilection for either cutaneous or mucosal surfaces, HPVs are classified into cutaneous and mucosal types. Cutaneous types of HPV are epidermitrophic and target the skin of the hands and feet. Mucosal types infect the lining of the mouth, throat, respiratory tract or anogenital epithelium. Within the groups of skin or mucosal viruses, depending on their oncogenic potential, they can be separated into HR or LR (low-risk) types (17,18).
Human papillomavirus types and types in histology of cervical cancer: a worldwide perspective
In women, the prevalence of genital HPV ranges from 7 to 37 per cent depending on the country and age of the study group (19), and it is a necessary cause for the development of cervical and other anogenital malignancies. Infection with HPV, considering all possible types, achieves a lifetime cumulative incidence of up to 70 per cent, whereas cervical cancer is a relatively rare disease, with a lifetime incidence range of 1.1 to 3.0 per cent across the world (20,21). By far, the most common histological type of cervical cancer is squamous cell carcinoma squamous cell carcinoma
A carcinoma that arises from squamous epithelium and is the most common form of skin cancer. Also called cancroid, epidermoid carcinoma. constituting approximately 80 per cent of cervical cancers (22). Adenocarcinoma is the second most common histologic type and, as noted above, shows a rising incidence, even in developed countries (23-29). More than 99 per cent of cervical cancers, including both squamous and adenocarcinoma histologies have identifiable HPV sequences (7,26).
The HPV are classified into types based on their DNA sequence. By definition, the nucleotide sequences of the E6, E7 and L1 ORFs of a new HPV type should be no more than 90 per cent homologous to the corresponding sequences of known HPV types. HPVs have further been classified into subtypes, when they have 90 to 98 per cent sequence similarity to the corresponding type and variants when they show no more than 98 per cent sequence homology to the prototype (18). Table I shows HPV type and disease association other than that in cervical cancer.
Although over 99 per cent of cervical cancers possess HPV DNA, the simple detection of HPV DNA is a poor predictor for the risk of cancerous transformation (7,29). However, there is a better correlation between certain HR HPV types and cervical cancer (30). As a result, genital HPV types have been subdivided into LR types, which typically produce benign genital warts, and HR types, which are more frequently associated with invasive cervical cancer and other malignancies (31). A large epidemiologic study has identified 15 HR HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), 3 probable high-risk HPV types (26, 53, and 66), and 12 LR HPV types (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108) (30). It is interesting to note that most of HR types are phylogenetically phy·lo·ge·net·ic
1. Of or relating to phylogeny or phylogenetics.
2. Relating to or based on evolutionary development or history: a phylogenetic classification of species. related to either HPV 16 (31, 33, 35, 52 and 58) or HPV 18 (39, 45, 59, 68) (32).
IARC sponsored study named the HPV types involved in cervical cancer (Table II). This study compared the epidemiological classification (based on their study) with the phylogenetic phy·lo·ge·net·ic
1. Of or relating to phylogeny or phylogenetics.
2. Relating to or based on evolutionary development or history. grouping. A discrepancy was observed only in two types: HPV type 70, which was classified as a HR type phylogenetically but as a LR type by their epidemiologic study; and type 73, which was classified as a LR type phylogenetically but a HR type epidemiologically (30).
Preliminary data from 9 countries (India not included) indicate the prevalence of the four most common HPV types among 1545 cases with single infections were: HPV 16-59 per cent, OR-(Odd's ratio) 182 , HPV-18-12 per cent, OR-231, HPV-45 -4.8 per cent OR- 148, HPV-31-3.7 per cent OR-71.5 (52). Other less common types showing equally high odd's ratio were- HPV-33, -35, -51, -52, -58, -5933.
In a meta-analysis of epidemiological studies on HPV type distribution in women with and without cervical neoplastic neoplastic /neo·plas·tic/ (ne?o-plas´tik)
1. pertaining to a neoplasm.
2. pertaining to neoplasia.
pertaining to neoplasia or a neoplasm. diseases (34), HPV-16/18 were estimated to account for 70 per cent of all cervical cancers worldwide, although the estimated HPV16/18 fraction was slightly higher in more developed (72-77%) than in less developed (65-72%) regions. About 41-67 per cent of high-grade squamous intraepithelial lesion Squamous intraepithelial lesion (SIL)
A term used to categorize the severity of abnormal changes arising in the squamous, or outermost, layer of the cervix. (HSIL HSIL High-grade squamous intraepithelial lesion, see there ), 16-32 per cent of low-grade squamous intraepithelial lesion (LSIL LSIL Low-grade squamous intraepithelial lesion, see there ) and 6-27 per cent of atypical squamous cells of undetermined significance (ASCUS as·cus
n. pl. as·ci
A membranous, often club-shaped structure in which typically eight spores are formed through sexual reproduction of ascomycetes.
pl. asci; the spore case of Ascomycetes. ) were also estimated to be HPV- 16/18-positive, thus highlighting the increasing relative frequency of HPV-16/18 with increasing lesion severity.
A comprehensive meta-analysis (16) comprised of 10,058 cervical cancer cases. India was one of the countries included in the region 'Asia'--for the study along with Mainland China, Indonesia, Japan, Korea, Malaysia, Philippines, Taiwan and Thailand. Asia (31%) and Europe (33%) had the majority of the cases in the study. The HPV prevalence among the cases did not vary significantly with regions, but HPV DNA was less likely detected in ADC (1) See A/D converter.
(2) (Apple Display Connector) A peripheral connector from Apple that combines digital video display, USB and power in one cable. (collective term representing both adeno carcinoma and adenosquamous carcinoma) -76.5 per cent than in SCC-87.3 per cent (16).
This study was recently updated to include more than 14,500 cases from studies published up to January 2006 (34,35). The most common HPV types identified were -HPV-16,-18, -33, -45, -31, -58, -52, -35, -59, -56, -51, -39, -6, -68, -73, -66 and -70 in order of decreasing prevalence. Table III shows the most recent metaanalysis on the prevalence of HR HPV type in invasive cancer and high-grade cervical lesions.
HPV type prevalence-worldwide: general picture
HPV -16 and -18 accounted for 70 per cent of all cervical cancer cases worldwide, and eight most common types (HPV-16, -18, -33, -45, -31, -58, -52, and -35) accounted for 90 per cent of the cases. The same eight types were most frequent in each of the world regions--Africa, Asia, and Europe, North America and south and Central America, with HPV-56 being the eighth most common type instead of HPV-52 in Europe. In Asia, HPV-58 prevalence was particularly high, and HPV 52 was also more frequently identified. HPV-16 prevalence varies from 52 per cent in Asia to 58 per cent in Europe, and HPV-18 prevalence varies from 13 per cent in South/Central America to 22 per cent in North America.
HPV type prevalence and histology -worldwide: general picture
After HPV 16, HPV-18 is the type most clearly shown by epidemiologic data to be a human carcinogen carcinogen: see cancer.
Agent that can cause cancer. Exposure to one or more carcinogens, including certain chemicals, radiation, and certain viruses, can initiate cancer under conditions not completely understood. . The evidence is limited to cervix, in which HPV-18 appears to be strongly linked to a substantial minority of squamous cancers and approximately half of the adenocarcinomas. The meta-analysis also showed that HPV type-distribution varies significantly between SCC SCC - strongly connected component and ADC. HPV-16 being identified more often in SCC than in ADC. The same was found for HPV 16 phylogenetically related types 31, 33, 52 and 58, but not 35. Conversely, HPV-18 was more prevalent in ADC than in SCC. The HPV 18 phylogenetically related type 45 was also more prevalent in ADC than in SCC.
To sum up, HPV-type distribution is broadly consistent across cervical cancer in world regions, particularly with respect to HPV-16 (HPV-16 prevalence is estimated to be the highest among European cases although the differences are not very relevant when compared to the rest of the world) and -18. Nevertheless, some inter- and intra regional variations in the relative importance of the next most common types namely HPV-31, -33, -45, -52, -58 and -35 have been reported (16).
The most consistently observed geographical variation concerns the prevalence of HPV-16 relative to non-HPV-16 types in cytologically normal women. In a study (36), by the IARC on the distribution of HPV types in cytologically normal women, 15 613 sexually active women aged between 15 and 74 yr, all with valid HPV test results and normal cytological findings, were included. The study included 1799 subjects from India, in the 'Asia' group. The Fig. shows the percentage of HPV infections by different types of HPV in Asian region.
Overall HPV prevalence was lowest in Spain and highest in Nigeria with intermediate prevalence in South America and Asia. The most common HPV type, in either single or multiple infections, was HPV16, followed by HPV42, HPV58, HPV31, HPV 18, HPV56, HPV81, HPV35, HPV33, and HPV45. HPV16 was twice as frequent as any other high-risk type in all regions except sub-Saharan Africa, where HPV35 was equally common. The next most common HR-HPV types were HPV33 and HPV56 in Asia, HPV58 in South America, and HPV31 in Europe. With respect to other HR HPVs (3.7%) and LR HPVs (4.2%), HPV 16 showed only a prevalence of 1.7 per cent in women in Asia. HPV-positive women in Asia had proportions of HPV16 infection in between those for Europe and sub-Saharan Africa, but heterogeneity was significant across areas in Asia. HPV-positive women in Europe were significantly less likely to be infected with HR types of HPV other than HPV16 than were women in sub-Saharan Africa. HPV-positive women from Asia and from South America had intermediate risks of such infection (36).
Risk of HPV18 infection among HPV-positive women was similar for all regions, although some heterogeneity for HPV18 was evident within the regions of South America and Europe. Heterogeneity was significant between regions for HPV31, HPV33, and HPV35 (which was particularly prevalent in sub-Saharan Africa compared with other regions), HPV45, and HPV58. Heterogeneity was also evident within South America for HPV35 and within Asia for HPV58. The pooled data analyses provide evidence for regional variation in distribution of HPV type for women without cytological abnormalities (36).
Pretet et al in his two recent reports (37,38) on studies conducted in France-for the EDITH EDITH Exit Drills In The Home (Fire Prevention)
EDITH European Development on Indexing Techniques for Databases with Multidimensional Hierarchies group (Etude e·tude
1. A piece composed for the development of a specific point of technique.
2. A composition featuring a point of technique but performed because of its artistic merit. la Distribution des types d' HPV en France), HPV 31 as the most prevalent HPV type after HPV 16 in high grade lesions while in invasive cancers it was the most common HPV type only after HPV 16 and HPV 18. Likewise, another study (39) reported the prevalence of HPV genotypes -16 and -31 as most commonly distributed in cervical specimens from French women with or without abnormalities. Similarly, Antonishyn et al 40 reported HPV-31 as a major type contributing significantly to the proportion of women with CIN in Saskatchewan, Canada.
The relative type prevalence seems to fluctuate and HPV-31 was the most common HPV infection in women that were referred for colposcopy Colposcopy Definition
Colposcopy is a procedure that allows a physician to take a closer look at a woman's cervix and vagina using a special instrument called a colposcope. It is used to check for precancerous or abnormal areas. . This observation is not typical, as most studies have found HPV-18 as the second most prevalent HR HPV type in clinical populations (30,41,42). However, a high prevalence of HPV31 types has been observed in some population (42-44), and studies on European populations have also shown HPV-31 as the second most common HPV type in low-grade cervical lesions (45). HPV-58 or -52 is the second' most common type in Asia (46,47).
Human papillomavirus types, histology: state of affairs in India
Despite the high incidences of cervical cancer reported from India, large-scale population based studies on the HPV prevalence and genotype distribution are very few.
The HPV type distribution in a rural community was studied (48) in women attending the regional cancer centre in Hyderabad. Among the HPV positive cancers, (n=41) the overall type distribution of the major HR HPV types was as follows: HPV 16 (66.7%), HPV 18 (19.4%), HPV 33 (5.6%), HPV 35 (5.6%), HPV 45 (5.6%), HPV 52 (2.8%), HPV 58 (2.8%), HPV 59 (2.8%) and HPV 73 (2.8%). In the women participating in the community screening programme, belonging to the Medchal community, the most frequently detected HPV types are HPV 52 and 16.
This differs slightly from that of the study in a rural area in Dindugal, Tamil Nadu district, where the major types were HPV 16 and 56, followed by HPV 31, 33, and HPV 18 (49). The same group conducted a hospital-based case-control study in Chennai, Southern India (49). In a total of 205 invasive cervical cancer cases, and 213 frequency age-matched control women, 23 different HPV types were found. HPV 16 was the most common type in either case or controls, followed by HPV 18, HPV 33, HPV 35 and 45. This was consistent with the type distribution shown in cervical carcinoma worldwide (16,30). Similarly another study from Mumbai reported HPV prevalence statistics which broadly matched the existing literature, HPV 16 and HPV 18 accounted for the bulk of the HPV infections followed by HPV 33, -31, and -45. They also reported considerably large number of HPV 16/18 coinfections from the non-malignant group (50).
Clare et al reported an overall prevalence of HPV in two communities near Trivandrum, in Southern India. The overall prevalence of HR-HPV in this south Indian population was 3.9 per cent. HPV 16 was the most common type, accounting for 47 per cent of the HR infections, either alone or with another type. The next most common type was HPV33, accounting for 10 per cent (51).
A cross-sectional biopsy study from 100 patients from South India and 30 patients from East India showed 60 per cent HPV 16 infection, 14 per cent HPV 18 infection as the most frequent HPV types. This constitutes only 70 per cent of the total cases. 16 other types were identified- HPV-26, -31, -33, 35, -42, -45, -51, -52, -53, -56, -58, -61, -62, -64, -81 and -82 (52).
A study from North India reported that in HPV positive samples, exfoliated cervical swabs collected from unscreened married women aged 16-24 yr, type 16 was seen in 36.2 per cent and type 51 and 59, 13 per cent each. A single HPV type was found in 58 per cent cases and mixed infection was seen in 42 per cent (53). But yet another hospital-based study in New Delhi, North India, found that, in 106 ICC cases found that HPV 16 type was the commonest type, seen in 73.6 per cent of the cases, followed by HPV 18 (14.2%) and HPV 45 (11.3%) (54).
Distribution of HPV types: Implication in the effectiveness of the currently available vaccine
HPV 16 appear to be believed the most prevalent type of HPV in cervical cancer, worldwide and in India, although with minor regional differences. The prevalence of HPV-16 over other types may be related to the complex geographical and biological interplay between virus and host immunogenetic factors. Regardless of the underlying mechanism, trying to identify which types account for geographical variation in the non-HPV-16 fraction of cervical lesions, is difficult because of their lower frequency and the variability in sensitivity of different assays to detect them; it is even more difficult in case of India, since the information available is so less and meagre mea·ger also mea·gre
1. Deficient in quantity, fullness, or extent; scanty.
2. Deficient in richness, fertility, or vigor; feeble: the meager soil of an eroded plain.
3. considering the vast, widespread geography of the sub-continent.
Human papillomavirus infection: host immune interventions
The viral replication and assembly occur in a cell already destined for death by natural causes, far from the sites of immune surveillance. So, there is no cytolysis Cytolysis
An important immune function involving the dissolution of certain cells. There are a number of different cytolytic cells within the immune system that are capable of lysing a broad range of cells. as a consequence of HPV replication, assembly or release and inflammation or "danger signal" to alert the immune system to the virus's presence. Despite HPV's ability to impede host defences, a successful immune response to genital HPV infections is established in most cases. This seems to be characterised by strong, local, cell-mediated immunity that is associated with lesion regression and the generation of serum neutralising antibody (17). Such antibody is generated in most, but not all, infected individuals and is directed against conformational epitope epitope: see immunity. (s) on the L1 protein displayed on the outer surface of the intact virus particle. Serum neutralizing antibody levels following natural HPV infections, even at peak titres, are low (55-58). This probably reflects the exclusively intraepithelial infectious cycle (the absence of a viremia viremia /vi·re·mia/ (vi-re´me-ah) the presence of viruses in the blood.
The presence of viruses in the bloodstream. ), as well as the production of virus particles in the superficial epithelial cells, distant from APCs (antigen presenting cells) and patrolling macrophages. Despite these low antibody levels, seropositive seropositive /se·ro·pos·i·tive/ (-poz´i-tiv) showing positive results on serological examination; showing a high level of antibody.
adj. animals are protected against further viral challenge (59) and this protection can be transferred from resistant to native animals by passive transfer of serum (60). A vaccine that will generate neutralizing antibody to the major capsid protein L1 of genital HPVs would be protective against infection, L1 protein must be in the tertiary or native form and assembled as a multimer for neutralizing antibody to be generated these observations formed the basis for vaccine development against HPV (61).
HPV vaccine: prophylactic vaccines
Vaccines against HPV may be prophylactic or therapeutic. Prophylactic vaccines must be given to individuals prior to virus exposure and to be effective, must be able to stimulate a high neutralising antibody response, preferably at the mucosal surface. A therapeutic vaccine however, would be utilised once infection has occurred to induce specific T-cell-mediated response, leading to regression of an existing lesion.
While most anti-viral vaccines are based upon virions to induce anti-virion antibodies, it is difficult to produce sufficient quantities of HPV virions in cultured cells to induce a host response. It was discovered that by inducing expression of the major HPV capsid protein-L1 in cultured eukaryotic eukaryotic /eu·kary·ot·ic/ (u?kar-e-ot´ik) pertaining to a eukaryon or to a eukaryote.
pertaining to eukaryosis.
see cell. cells, with or without the presence of the minor capsid protein-L2, it is possible to produce what are known as HPV virus-like particles, or VLPs. These VLPs are morphologically identical to the native HPV virions, though they lack the viral DNA core. Thus, they can be injected into a host, to induce an antibody response, without any oncogenic risks (62). The L1 protein is highly conserved antigenically and bears epitopes that are broadly cross-reactive or even group specific among all the papillomaviruses of man and animals, but they are exposed only on disrupted virions or on capsid monomers. By contrast, intact virions and virus-like particles expose mainly a type-specific conformational epitope and there are few or no cross-reactions between the intact viruses (63).
Clinical trials of multivalent L1 VLP vaccines show safety, immunogenicity immunogenicity /im·mu·no·ge·nic·i·ty/ (-je-nis´it-e) the property enabling a substance to provoke an immune response, or the degree to which a substance possesses this property. and high efficacy (64-66). The mechanisms by which VLPs elicit protection are not completely understood. At present there are two vaccines: A bivalent bivalent /bi·va·lent/ (bi-va´lent)
2. the structure formed by a pair of homologous chromosomes by synapsis along their length during the zygotene and pachytene stages of the first meiotic prophase. that includes antigens of HPV 16 and 18 and a quadrivalent quad·ri·va·lent
1. Having four valences.
2. Having a valence of four; tetravalent.
having a valence of four. that includes HPV 16, 18, 6 and 11 (58,66,67). Types 16 and 18 cause 70 per cent of cervical cancers and 6 and 11 cause about 90 per cent of genital warts.
Cervarix[TM], developed by GlaxoSmithKline Biologicals, Rixensart, Belgium, is a bivalent HPV16/18 L1 VLP vaccine. The L 1 protein of each HPV type is expressed by a recombinant baculovirus baculovirus
group of rod-shaped, double-stranded, DNA viruses which infect and kill a large number of different invertebrate species especially insects, including Lepidoptera, Hymenoptera, Diptera, Neuroplera, Trichoptera, Coleoptera and Homoptera, and also prawns; used as vector, and the VLPs are generated separately and then combined (68). Cervarix[TM] consists of purified L1 VLPs of HPV types 16/18 at 20/20 [micro]g/dose, respectively, formulated on an ASO ASO arteriosclerosis obliterans.
ASO 1 Administrative services organization, see there 2 Allele-specific–oligonucleotide hybridization 3 Anti-streptolysin O, see there 4 adjuvant adjuvant /ad·ju·vant/ (aj?dbobr-vant) (a-joo´vant)
1. assisting or aiding.
2. a substance that aids another, such as an auxiliary remedy.
3. consisting of aluminum hydroxide 500 [micro]g and 3-deacylated monophosphoryl lipid A 50 [micro]g. It is administered as a 0.5 mL intramuscular injection in a three dose immunization protocol at 0, 1 and 6 months.
Clinical trial data indicate that vaccine protection is maintained over a period of 4.5 years with the Cervarix[TM] bivalent vaccine (67). A multicenter, randomized follow-up trial (n=776) demonstrated that 98 per cent seropositivity Seropositivity is the presence of a certain antibody in a blood sample. A patient with seropositivity for a particular antigen or agent is termed seropositive. was maintained for HPV-16/18 antibodies at 4.5 years. The bivalent vaccine was 96.9 per cent effective against incident HPV-16/18 infection and 100 per cent effective against 12-month persistent infection. A combined analysis of the initial and follow-up studies showed 100 per cent vaccine efficacy against CIN lesions associated with HPV-16/1867.
Gardasil[R], a quadrivalent HPV-16/18/6/11 L1 VLP vaccine, has been developed by Merck & Co. Inc. (69) For each HPV VLP, the L1 protein is expressed via a recombinant Saccharomyces Saccharomyces: see yeast. pombe vector and the vaccine is comprised of purified L1 VLPs of HPV types 6/11/16/18 at 20/40/40/20 [micro]g/dose, respectively, formulated on a proprietary alum adjuvant (68). Gardasil[R] is available as a 0.5 mL intramuscular injection administered in a three-dose immunization protocol at 0, 2 and 6 months.
Data from a phase II randomized, multicenter study (n=552) that followed women aged 16 to 23 yr for up to 5 yr demonstrated that vaccination of adolescents and young adults with Gardasil[R] at 0, 2 and 6 months resulted in 100 per cent vaccination coverage and effectively prevented persistent infection and disease caused by HPV types 6/11/16/18 (70). Pooled data from four studies in 20,583 women aged 16 to 26 yr, who were followed., for a mean of 3 yr, indicate that the quadrivalent vaccine has the potential to substantially reduce the incidence of HPV-16 and -18-related cervical precancers and cancers (71) In the per-protocol analysis, women who were negative for HPV- 16 or -18 (n=17,129) demonstrated 99 per cent vaccine efficacy for the primary endpoint of the combined incidence of HPV-16 and-18-related CIN 2/3, adenocarcinoma in situ, or cervical cancer. In the intention-to-treat analysis, which included women who were infected with HPV-16 and/or-18 at day 1, vaccine efficacy for the primary endpoint was 44 per cent (71).
The implementation of HPV vaccination is predicted to have wide ranging impact with regard to a reduction in the use of healthcare resources. Cost-effective vaccination strategy is thought to reduce pap screening (72), work load at the sexually transmitted diseases clinics (73). The Markov model predicted that, over the lifetime of a cohort of 12-yr old females, a 100 per cent vaccination coverage and 95 per cent vaccination efficacy against HPV-16 and -18 infections result in a 76 per cent reduction in cervical cancer deaths and a 66 per cent reduction in high-grade cervical lesions (74).
Thus, the available vaccines are effective and safe, and can protect against HPV infections responsible for about 70 per cent of cervical cancer. They need to be given before infection occurs, and are, for countries where cervical cancer screening programs are already in place, an adjunct to, rather than a replacement for these existing screening programs. Their general introduction will perhaps reduce considerable amount of surgical intervention to treat precancerous lesions and should substantially reduce the economic and social burden of cervical cancer in the developing and the developed world.
Introducing the prophylactic HPV vaccine in India: what are the issues for implementation?
Vaccines can be optimally effective and successful only if their coverage, i.e., the number of people vaccinated against a disease in a given population, continuously remains at a sufficiently high level. The community benefits of vaccination are thus directly related to the percentage of the population that has been immunised and this percentage varies according to the vaccine in question. Can India achieve this goal with the implementation and widespread introduction of the current vaccines- Cervarix and Gardasil? A vital issue requiring careful consideration is the cost of the vaccine(s), social, cultural and economical factors and geographical variation in the HPV type-distribution.
The current vaccines available--both bivalent and quadrivalent--offer protection against only two of the HR HPVs most commonly seen-HPV-16 and HPV-18. Although there is some evidence of cross reactivity among certain HPV types, it accounts for less than 1 per cent of the antibody reactivity, indicating that protection to infection is type-specific (75).
Economics of vaccination in India
Even as the developed world countries are making mandatory, the vaccination programmes for their adolescent girls and contemplating on the age and group to be vaccinated, Indian scientific community and policy makers should think whether these new expensive vaccines will really help India? Mass immunization with these vaccines at this critical juncture might greatly reduce the cervical cancer incidence. Theoretically, a 100 per cent efficient vaccine with 100 per cent coverage on populations will reduce the cervical cancer burden by 70 per cent. But the spectrum of HPV types targeted in current vaccine trials is based largely on the prevalence of HPV types in cancers from the developed world, especially the European population. Heterogeneity in HPV type distribution should be taken into account when predicting the effect of vaccines on the incidence of infection or in developing screening tests for virus. HPV types other than HPV-16 and -18 still account for 25 to 30 per cent of cervical cancer cases, and this percentage maybe higher in certain populations. The efficacy of the current vaccine formulations being type-specific, it may not be possible at all to achieve the true purpose of vaccination programs in India. The most annoying barrier in discerning the effectiveness if the existing vaccine is implemented in India, is lack of knowledge, lack of data, about the HPV types affecting the Indian women. Despite high encumbrance A burden, obstruction, or impediment on property that lessens its value or makes it less marketable. An encumbrance (also spelled incumbrance) is any right or interest that exists in someone other than the owner of an estate and that restricts or impairs the transfer of the estate or from cervical cancer, there are few large population studies on cervical cancer cases, unscreened populations or cytologically normal women, from India, describing either HPV prevalence or type distribution. HPV being a sexually transmitted disease sexually transmitted disease (STD) or venereal disease, term for infections acquired mainly through sexual contact. Five diseases were traditionally known as venereal diseases: gonorrhea, syphilis, and the less common granuloma inguinale, , the obvious cultural and social diversity existing in various parts of India, will have an immense impact on HPV prevalence in the entire country. Hence, it is important that each jurisdiction will need the knowledge of the baseline HPV causing disease in their community, region, to implement vaccine programs and uncover their efficiency. These components make it all the more apparent to describe and find out by multi representative population studies, the HPV genotypes in cancer case and community samples. Baseline studies will be compromised if HPV is only categorized as either HR or low risk without discriminating as to which actual HPV types are present. So, the study should be well monitored, sufficiently quality assured and unbiased. These data can then be generalized for application in national cancer prevention strategies or in devising the optimum strategy for vaccination in India. Based on the huge database regarding the incidence and frequency of the dominant HPV types in the west, Merck has already performed clinical trials in Western nations with an octavalent HPV VLP vaccine, including benign L1 VLP types 6 and 11, and six oncogenic HPV types (16, 18, 31, 45, 52, and 58) (76). However, data have not yet been released and it is unclear how this program will advance. An L2-based vaccine is in early phase clinical trials at the University of Alabama at Birmingham, as preclinical studies have demonstrated that L2-based vaccines can be used to generate broad spectrum cross neutralizing antibodies and could reduce the number of VLP types required for protection (77,78).
Knowledge on different HPV types may have clinical utility as well, like in the risk assessment in cervical cancer. The data on prevalent HPV types in a population will also help in determining the extent of cross immunity among the different HPV types once the vaccination takes place. Further, since HR HPV contributes to a significant fraction of head and neck, anal, penile penile /pe·nile/ (pe´nil) of or pertaining to the penis.
Of or relating to the penis.
of or pertaining to the penis. , vulvar vulvar
pertaining to or emanating from the vulva.
failure of the orifice to open may occur with imperforate anus as a congenital defect. and vaginal cancers, such a broad study will also be helpful in determining whether the benefits of HPV preventive vaccine extend beyond cervical cancer.
Most cancer epidemiology studies involve people living in North America and Europe which represent only a fraction of the global population. Taking into account, the fact that, approximately 14 per cent of women in the world live in rural India (79), the new study from regions where data is lacking and a collaborative reanalyses of all existing data will have substantial potential to be of worldwide significance in cervical cancer prevention including development of efficient second generation vaccines. Such an epidemiology research need sustained support in a developing country like India with outreaching educational programmes, better infrastructure like development of common accessible cancer registries with the ability to follow up on the study subjects. Also, a central analysis centre which ensures uniformity in the experiments and analyses performed, and, most importantly the fostering of fair and effective collaborations between clinicians, researchers and technicians are needed.
The other minor issues affecting the outcome of the multivalent vaccines in question maybe the presence of HPV L1 variants, differences in immune response haplotypes and multiple HPV co infections and redistribution of the HR HPV types, post vaccine implementation.
(i) The presence of HPV L1 variants
Recent research has focused on the nucleic acid sequence variation within HPV 16 long control region, E6 and L1 regions. HPV variants differ in biological and chemical properties and pathogenicity (80). Based on sequence variation of the L1, L2, and LCR See least cost routing. regions of HPV-16, five naturally occurring phylogenetic clusters have been defined for HPV-16: European (E), Asian (As), Asian-American (AA), African-1 (Aft), and African-2 (Af2). Intratypic sequence variation has also been found in the E2, E4, E5, E6, and E7 genes of HPV-16. Since the LCR contains several E2 binding sites in addition to binding sites for several transcription factors, nucleotide sequence variation in the LCR, E2, E6, and E7 genes may be of functional significance. The oncogenicity oncogenicity The capacity to induce tumors of specific HPV variants appears to vary geographically and also with the ethnic origin of the population studied. One study suggested that because of increased transcriptional activity and changes in the progesterone progesterone (prōjĕs`tərōn'), female sex hormone that induces secretory changes in the lining of the uterus essential for successful implantation of a fertilized egg. response elements, Asian-American variants might have enhanced oncogenic activity compared to European isolates (81). The L1 variants with a 2 per cent sequence divergence have been observed in the L1 neutralising epitopes, which suggests selection to escape neutralization neutralization, chemical reaction, according to the Arrhenius theory of acids and bases, in which a water solution of acid is mixed with a water solution of base to form a salt and water; this reaction is complete only if the resulting solution has neither acidic nor (82,83). The geographical distribution of HPV variants and its relevance in HPV testing for vaccine development are still uncertain. But given the HPV sequences are very stable over time, and with evidence of cross-neutralization with variants of the same genotype (84,85), immune escape is unlikely to be a significant issue.
(ii) Differences in immune response haplotypes
A statistically significant association of the non-european variant with the presence of HLA HLA human leukocyte antigens.
human leukocyte antigen
HLA (human leuckocyte antigen) class II alleles was reported (86). Other studies (87-89) have reported the association of HLA class II alleles with cervical HPV disease although these associations appear to be relatively weak. These studies however, suggest that host genetics may need to be investigated in concert with HPV typing to fully understand geographic variation in type-specific HPV prevalence.
(iii) Multiple HPV co infections and redistribution of the HR HPV types, post vaccine implementation
The presence of multiple HPV coinfections has been reported (90-92). The majority of multiple coinfections contain two HPV genotypes, but samples of three, four or five genotypes have also been reported (90,92)
In a multiple coinfection, especially, when two or more HPV types belong to the HR types, it is not clear as to the persistence of which HR type leads to the progression of lesions. It is still ambiguous whether they coexist with synergy or competition (9,93-96) But, the major disadvantage of the multiple coinfection along with the introduction of type-restricted protection (like the current vaccines) against HPV seems to be the possibility of genotype replacement as HPV vaccination is implemented.
When the multiple HPV types are present in the same system, each of them coexists with the other in a delicate balance of individual 'ecological niches'. Alternatively, infection by a single type of HPV might be also because one of them has been able to completely competitively exclude other types (97,98). When type-specific vaccination against the most common cancer causing types becomes effective, a large 'potential niche' created, opens for the nontargeted types and allows them to proliferate (99). Using a mathematical model, Lipsitch found that in a system with two or more serotypes, elimination of one of those serotypes by a monovalent vaccine may cause an increase in the other serotypes that is actually greater than the reduction of the targeted serotype serotype /se·ro·type/ (ser´o-tip) the type of a microorganism determined by its constituent antigens; a taxonomic subdivision based thereon.
v. . While Lipsitch's studies are based upon bacterial systems, replacement is a potential problem for viral systems as well (97,98). Nevertheless, studies (67,100,101) indicate that in the short term, there is no expansion of other HPV types implying that HPV infections are independent of each other which does not suggest a probable genotype replacement. In the unlikely event that this does occur over time, additional VLP types, or perhaps an L2 cross-protective antigen, could be included in the vaccine.
Research on HPV has progressed rapidly and we have reached a point where prevention of cervical cancer by vaccination against HPV infection will be possible in the foreseeable future. Evidence suggests that risk for progression to invasion is closely related to the infecting human papillomavirus type. Studies indicate a geographical variation in the HPV types' distribution in the population and in patients with cervical cancer. The implications of such variability on HPV vaccination is unknown and not clear. The outcome would even be more confusing in India, where, understanding about presence and prevalence of variable HPV types in the diverse Indian population is very scanty. Broad, extensive and far-reaching studies involving large population samples from diverse and distinct locales covering the Indian peninsula are needed.
Received February 16, 2009
(1.) Available from: http://www.who.int/vaccine_research/ documents/816%20%20HPV%20meeting.pdf
(2.) Ferlay J, Bray F, Pisani P, Parkin DM. Mortality and prevalence worldwide GLOBOCAN 2002 cancer incidence. IARC Cancer Base. No. 5 version 2.0. Lyon: IARC Press; 2004.
(3.) Sherman ME, Wang SS, Carreon J, Devesa SS. Mortality trends for cervical squamous and adenocarcinoma in the United States. Relation to incidence and survival. Cancer 2005; 103 : 1258-64.
(4.) Bray F, Carstensen B, Moiler H, Zappa M, Zakelji MP, Lawrence G, et al. Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiol Biomarkers Prev 2005; 14 : 2191-9.
(5.) International Agency for Research on Cancer. Handbooks of cancer prevention, vol 9. Cervix cancer screening. Lyon: IARC Press; 2004.
(6.) Nanda K, McCrory DC, Myers ER, Bastian LA, Hasselblad V, Hickey JD, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med 2000; 132 : 810-9.
(7.) Walboomers JM, Jacobs V, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189 : 12-9.
(8.) Wright Jr TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical cancer screening. N Engl J Med 2003; 348 : 489-90.
(9.) Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Normal history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998; 338 : 423-8.
(10.) Snijders PJ, Steenbergen RD, Heiderman DA, Meijer CJ. HPV-mediated cervical carcinogenesis: concepts and clinical implications. J Pathol 2006; 208 : 152-64.
(11.) Hildesheim A, Hadjimichael O, Schwartz PE, Wheeler CM, Barnes W, Lowell DM, et al. Risk factors for rapid onset cervical cancer. Am J Obstet Gynecol 1999; 180 : 571-7.
(12.) Schwartz PE, Hadjimichael O, Lowell DM, Merino Merino
Breed of medium-sized sheep originating in Spain that has become prominent worldwide. It has a white face, white legs, and crimped fine-wool fleece. Known as early as the 12th century, it may have been a Moorish importation. MJ, Janerich D. Rapidly progressive cervical cancer: the Connecticut experience. Am J Obstet Gynecol 1996; 175 : 1105-19.
(13.) Einstein MH, Cruz Y, El-Awady MK, Popescu NC, DiPaolo JA, Ranst M, et al. Utilization of the human genome sequence localizes human papillomavirus type 16 DNA integrated into the TNFAIP TNFAIP Tumor Necrosis Factor Alpha-Induced Protein 2 gene in a fatal cervical cancer from a 39-year old woman. Clin Cancer Res 2002; 8 : 549-54.
(14.) Stanley MA, Pett MR, Coleman N. HPV: from infection to cancer. Biochem Soc Trans 2007; 35 : 1456-60.
(15.) Schiffman M, Castle PE. Human papillomavirus: epidemiology and public health. Arch Pathol Lab Med 2003; 127 : 930-4.
(16.) Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer 2003; 88 : 63-73.
(17.) Margaret S. Immune responses to human papillomavirus. Vaccine 2006; 24 : 16-22.
(18.) Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev 2003; 16 : 1-17.
(19.) Bosch F, Sanjose S, Castellsague X, Moreno V, Munoz N. Epidemiology of human papillomavirus infections and associations with cervical cancer: new opportunities for prevention. In: Campo M, editor. Papillomavirus research: From natural history to vaccines and beyond. Norfolk, England: Caister Academic Press; 2006. p. 19-40.
(20.) Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med 1997; 102 : 3-8.
(21.) Parkin D, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55 : 74-108.
(22.) Smith HO, Tiffany MF, Qualls CR, Key CR. The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States-a 24-year population-based study. Gynecol Onco1 2000; 78 : 97-105.
(23.) Castellsague X, Diaz M, de Sanjose S, Munoz N, Herrero R, Franceschi S, et al. Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. J Natl Cancer Inst 2006; 98 : 303-15.
(24.) Wang SS, Sherman ME, Hildesheim A, Lacey JV, Devesa S. Cervical adenocarcinoma and squamous cell carcinoma incidence trends among white women and black women in the United States for 1976-2000. Cancer 2004; 100 : 1035-44.
(25.) Kyndi M, Frederiksen K, Kruger-Kjaer S. Cervical cancer incidence in Denmark over six decades (1943-2002). Acta Obstet Gyncol Scand 2006; 85 : 106-11.
(26.) Clavel C, Masure M, Bory JP, Putaub I, Mangeonjean C, Lorenzato M, et al. Hybrid Capture II-based human-papillomavirus detection, a sensitive test to detect in routine high-grade cervical lesions: a preliminary study on 1518 women. Br J Cancer 1999; 80 : 1306-11.
(27.) Bonnez W, Reichman RC. Papillomaviruses. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett's principles and practice of infectious diseases, 5th ed. Philadelphia, Pa: Churchill Livingston; 2000. p. 1630-40.
(28.) Bosch F, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, et al. International Biological Study on Cervical Cancer (IBSCC IBSCC International Board Sailing Club of Charlotte (North Carolina) ) Study Group. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst 1995; 87 : 796-802.
(29.) Clavel C, Masure M, Bory J, Putaud I, Mangeonjean C, Lorenzato M, et al. Human papillomavirus testing in primary screening for the detection of high-grade cervical lesions: a study of 7932 women. Br J Cancer 2001; 84 : 1616-23.
(30.) Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348: 518-27.
(31.) Severson J, Evans T, Lee P., Chan T, Arany I, Tyring S. Human papillomavirus infections: epidemiology, pathogenesis, and therapy. J Cutan Med Surg 2001; 5 : 43-60.
(32.) Chan Y, Delius H, Halpern AL, Bernard HU. Analysis of genomic sequences of 95 papillomavirus types: uniting typing, phylogeny and taxonomy. J Virol 1995; 69 : 3074-83.
(33.) Munoz N, Bosch FX, Chichareon S, Eluf-Neto J, Ngelangel C, Caceres E, et al. A multinational case-control study on the risk of cervical cancer linked to 25 HPV types: which are the high-risk types? In: Castellsague X, Bosch FX, de Snjose S, Moreno V, Ribes J, editors. 18th International papillomavirus conference- program and abstracts book. Barcelona: Thau SL, 2000: 125. Available from: http:/www.hpv2000.com.
(34.) Gary Clifford, Silvia Franceschi, Mireia Diaz, Nubia Munoz, Luisa Lina Villa. HPV type-distribution in women with and without cervical neoplastic diseases. Vaccine 2006; 24 : S3/26-S3/34.
(35.) Smith JS, Lindsay L, Hoots hoots
Variant of hoot2. B, Keys J, Franceschi S, Winer R, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a metaanalysis update. Int J Cancer 2007; 121 : 621-32.
(36.) Clifford GM, Gallus S, Herrero R, Munoz N, Snijders PJF PJF Policía Judicial Federal (Spanish: Federal Judicial Police, Mexico)
PJF Pre-Joycean Fellowship (used by writer, Steve Brust)
PJF Professor John Frink (Simpsons cartoon) , Vaccarella S, et al and the IARC HPV Prevalence Surveys Study Group. Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet 2005; 366 : 991-8.
(37.) Pretet JL, Jacquard AC, Carcopino X, Monnier-Benoit S, Averous G, Soubeyrand B, et al. EDITH study group. Human papillomavirus genotype distribution in high grade cervical lesions (CIN 2/3) in France: EDITH study. Int J Cancer 2008; 122 : 424-7.
(38.) Pretet JL, Jacquard AC, Carcopino X, Charlot JF, Bouhour D, Kantelip B, EDITH study group. Human papillomavirus (HPV) genotype distribution in invasive cervical cancers in France: EDITH study. Int J Cancer 2008; 122 : 428-32.
(39.) Pannier-Stockman C, Segard C, Bennamar S, Gondry J, Boulanger JC, Sevestre H, et al. Prevalence of HPV genotypes determined by PCR PCR polymerase chain reaction.
polymerase chain reaction
Polymerase chain reaction (PCR) a DNA sequencing in cervical specimens from French women with or without abnormalities. J Clin Virol 2008; 42 : 353-60.
(40.) Antonishyn NA, Horsman GB, Kelln RA, Saggar J, Severini A. The impact of the distribution of human papillomavirus types and associated high-risk lesions in a colposcopy population for monitoring vaccine efficacy. Arch Pathol Lab Med 2008; 132 : 54-60.
(41.) Weller SC, Stanbery LR. Estimating the population prevalence of HPV. JAMA 2007; 297 : 876-8.
(42.) Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, et al. Prevalence of HPV infection among females in the United States. JAMA 2007; 297 : 813-9.
(43.) Beerens E, Van Renterghem L, Praet M, Sturtewagen Y, Weyers S, Temmerman M, et al. Human papillomavirus DNA detection in women with primary abnormal cytology of the cervix: prevalence and distribution of HPV genotypes. Cytopathology 2005; 16 : 199-205.
(44.) Rassu M, Bertolini G, Mengoli C, Peron A, Benedetti P, Palu G. HpV genotype prevalence in cervical specimens with abnormal cytology : a report from North-East Italy. Scand J Infect Dis 2005; 37 : 476-81.
(45.) Clifford GM, Rana RK, Franceschi S, Smith JS, Gough G, Pimenta JM. Human papillomavirus genotype distribution in low-grade cervical lesions: comparison by geographic region and with cervical cancer. Cancer Epidemiol Biomarkers Prev 2005; 14 : 1157-64.
(46.) Camara GN, Cerqueira DM, Oliveira AP, Silva EO, Carvalho LG, Martins CR. Prevalence of human papillomavirus types in women with pre-neoplastic and neoplastic cervical lesions in the Federal District of Brazil. Mem Inst Oswaldo Cruz 2003; 98 : 879-83.
(47.) Lin H, Ma YY, Moh JS, Ou YC, Shen Shen, in the Bible, place, perhaps close to Bethel, near which Samuel set up the stone Ebenezer. SY, Chang Chien CC. High prevalence of genital human papillomavirus type 52 and 58 infection in women attending gynaecologic practitioners in South Yaiwan. Gynecol Oncol 2006:101 : 40-5.
(48.) Sowjanya PA, Jain M, Poli UR, Padma S, Das M, Shah KV, et al. Prevalence and distribution of high-risk human papilloma virus human papilloma virus
n. Abbr. HPV
A DNA virus of the genus Papillomavirus, certain types of which cause cutaneous and genital warts in humans, including condyloma acuminatum. (HPV) types in invasive squamous cell carcinoma of the cervix and in normal women in Andhra Pradesh, India. BMC (BMC Software, Inc., Houston, TX, www.bmc.com) A leading supplier of software that supports and improves the availability, performance, and recovery of applications in complex computing environments. Infect Dis 2005; 5 : 116. Available from: http://www. biomedcentral, com/1471-2334/5/116.
(49.) Franceschi S, Rajkumar R, Snijders PJF, Arslan A, Mahe C, Plummer M. Papillomavirus infection in rural women in Southern India. Br J Cancer 2005; 92 : 601-6.
(50.) Travasso CM, Anand M, Samarth M, Deshpande A, Sinha CK. Human papillomavirus genotyping by multiplex pyrosequencing in cervical cancer patients from India. J Biosci 2008; 33 : 73-80.
(51.) Gilham C, Varghese C, Gibson I, Peto J. HPV infection in a population-based cohort study in Kerala, India. 23rd International Papillomavirus Conference & Clinical Workhop; September 1-7, 2006. Prague. Czech Republic.
(52.) Peedicayil A, Abraham P, Sathish N, John S, Shah K, Sridharan G, et al. Human papillomavirus genotypes in tissue with cervical neoplasia in India. Int J Gynecol Cancer 2006; 16 : 1591-5.
(53.) Datta P, Patro RK, Bhatla N, Singh N. Prevalence of human papillomavirus (HPV) infection in a cohort of young women in Delhi, India. Available from:fasebj.org/cgi/content/meeting abstract.
(54.) Bhatla N, Dar L, Rajkumar PA, Kriplani A, Gulati A, Verma K. Human papillomavirus type distribution in cervical cancer in Delhi, India. Int J Gynecol Pathol 2006; 25 : 398-402.
(55.) Kirubauer R, Hubbert NL, Wheeler CM, Becker TM, Lowy DR, Schiller JT. A virus-like particle enzyme-linked immunosorbent assay enzyme-linked immunosorbent assay
Enzyme-linked immunosorbent assay (ELISA)
A diagnostic blood test used to screen patients for AIDS or other viruses. detects serum antibodies in a majority of women infected with human papillomavirus type 16. J Natl Cancer Inst 1994; 86: 494-9.
(56.) Wikstrom A, van Doornum GJJ GJJ Gracie Jiu-Jitsu , Quint WGV WGV Westfälischer Genossenschaftsverband (German: federation of Westfalian cooperatives)
WGV Württembergische Gemeinde- Versicherung aG
WGV Windows Genuine Validation , Schiller JT, Dillner J. Identification of human papillomavirus seroconversions. J Gen Virol 1995; 76:529-39.
(57.) Carter JJ, Wipf GC, Hagensee ME, McKnight B, Habel LA, Lee SK, et al. Use of human papillomavirus type 6 capsids to detect antibodies in people with genital warts. J Infect Dis 1995; 172 : 11-8.
(58.) Villa LL, Costa RLR RLR Rahal Letterman Racing (motorsports racing team owned by David Letterman and Bobby Rahal)
RLR Red Light Running
RLR Reinforcement Learning Repository
RLR Receiving Loudness Rating , Petta CA, Andrade RP, Ault KA, Giuliano AR, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11 16 and 18) L1 virus-like particle vaccine in young women: a randomised Adj. 1. randomised - set up or distributed in a deliberately random way
irregular - contrary to rule or accepted order or general practice; "irregular hiring practices" double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005; 6 : 271-8.
(59.) Kreider JW, Bartlett GL. The Shope papilloma-carcinoma complex of rabbits: a model system of neoplastic progression and spontaneous regression. Adv Cancer Res 1981; 35 : 81-110.
(60.) Suzich JA, Ghim S J, Palmer-Hill F J, White WI, Tamura JK, Bell JA, et al. Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas. Proc Natl Acad Sci USA 1995; 92 : 11553-7.
(61.) Dillner J. The serological serological
pertaining to or emanating from serology.
one involving examination of blood serum usually for antibody. response to papillomaviruses. Semin Cancer Biol 1999; 9:423-30.
(62.) Kimbauer R. Papillomavirus-like particles for serology Serology
The division of biological science concerned with antigen-antibody reactions in serum. It properly encompasses any of these reactions, but is often used in a limited sense to denote laboratory diagnostic tests, especially for syphilis. and vaccine development. Intervirology 1996; 39 : 54-61.
(63.) Hilleman MR. Overview of vaccinology vac·ci·nol·o·gy
The science or methodology of vaccine development.
vaccinology A nascent field of expertise related to the creation and deployment of vaccines; the field 'borrows' from epidemiology, immunology, with special reference to papillomavirus vaccines. J Clin Virol 2000; 19 : 79-90.
(64.) Ault KA, Giuliano AR, Edwards RP, Tamms G, Kim LL, Smith JF, et al. A phase I study to evaluate a human papillomavirus (HPV) type 18 L1 VLP vaccine. Vaccine 2004; 22: 3004-7.
(65.) Fife KH, Wheeler CM, Koutsky LA, Barr E, Brown DR, Schiff MA, et al. Dose-ranging studies of the safety and immunogenicity of human papillomavirus Type 11 and Type 16 virus-like particle candidate vaccines in young healthy women. Vaccine 2004; 22 : 2943-52.
(66.) Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004; 364 : 1757-65.
(67.) Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Martins CM, et al. on behalf of the HPV Vaccine Study group. Sustained efficacy up to 4-5 years of a bivalent L1 virus-like particle vaccine against human Papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006; 367 : 1247-55.
(68.) Stanley M, Lowy DR, Frazer I. Chapter 12: prophylactic HPV vaccines: underlying mechanisms. Vaccine 2006; 24 (Suppl 3) : S106-13.
(69.) Gardasil[R]. Merck & Co., Inc, Whitehouse Station, NJ 08889, USA. Prescribing information; 2007.
(70.) Villa LL, Costa RLR, Petta CA, Andrade RP, Paavonen J, Iversen O-E, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer 2006; 95 : 1459-66.
(71.) Future II Study Group. Effect of prophylactic human papillomavirus L 1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet 2007; 369 : 1861-88.
(72.) Eltoum IA, Roberson J. Impact of HPV testing, HPV vaccine development, and changing screening frequency on national Pap test volume: projections from the National Health Interview Survey (NHIS NHIS National Health Interview Survey
NHIS New Hampshire International Speedway
NHIS National Health Insurance Scheme (Ghana)
NHIS National Health Insurance System ). Cancer 2007; 111 : 34-40.
(73.) Dempsey AF, Koutsky LA, Golden M. Potential impact of human papillomavirus vaccines on public STD (Subscriber Trunk Dialing) Long distance dialing outside of the U.S. that does not require operator intervention. STD prefix codes are required and billing is based on call units, which are a fixed amount of money in the currency of that country. clinic workloads and on opportunities to diagnose and treat other sexually transmitted diseases. Sex Transm Dis 2007; 34 : 1-5.
(74.) Kohli M, Ferko N, Martin A, Franco EL, Jenkins D, Gallivan S, et al. Estimating the long-term impact of a prophylactic human papillomavirus 16/18 vaccine on the burden of cervical cancer in the UK. Br J Cancer 2007; 96 : 143-50.
(75.) Combita AL, Touze A, Bousarghin L, Christenen ND, Coursaget P. Identification of two cross-neutralising linear epitopes within the L1 major capsid protein of human papillomaviruses. J Virol 2002; 76 : 6480-6.
(76.) Ferenczy A, Franco EL. Prophylactic human papillomavirus vaccines: potential for sea change. Expert Rev Vaccines 2007; 6 : 511-25.
(77.) Slupetzky K, Gambhira R, Culp TD, Shafti-Keramat S, Schellenbacher C, Christensen ND, et al. A papillomavirus-like particle (VLP) vaccine displaying HPV16 L2 epitopes induces cross-neutralizing antibodies to HPV11. Vaccine 2007; 25 : 2001-10.
(78.) Xu Y, Wang Q, Han Y, Song G, Xu X. Type-specific and cross-reactive antibodies induced by human papillomavirus 31 L1/ L2 virus-like particles. J Med Microbiol 2007; 56 : 907-13.
(79.) India census 2001. Available from: http://www.censusindia. net/, accessed on September 20, 2008.
(80.) Conrad-Stoppler MC, Ching KH, Stoppler K, Clancy R, Schlegle, Icenogle J. Natural variants of the human papillomavirus type 16 E6 protein differ in their abilities to alter keratinocyte keratinocyte /ke·rat·i·no·cyte/ (ker-at´in-o-sit) the epidermal cell that synthesizes keratin, known in its successive stages in the layers of the skin as basal cell, prickle cell, and granular cell. differentiation and to induce p53 degradation. J Virol 1996; 70 : 6987-93.
(81.) Veress G, Szarka K, Dong XP, Gergely L, Pfister H. Functional significance of sequence variation in the E2 gene and the long control region of human papillomavirus type 16. J Gen Virol 1999; 80:1035-53.
(82.) Roden RB, Armstrong A, Haderer P, Christensen ND, Hubbert NL, Lowy DR, et al. Characterization of a human papillomavirus type 16 variant-dependent neutralizing epitope. J Virol 1997; 71 : 6247-52.
(83.) White WI, Wilson SD, Palmer-Hill FJ, Woods RM, Ghim SJ, Hewitt LA, et al. Characterization of a major neutralizing epitope on human papillomavirus type 16 L1. J Virol 1999; 73 : 4882-9.
(84.) Roden RB, Greenstone green·stone
Any of various altered basic igneous rocks colored green by chlorite, hornblende, or epidote.
NZ a type of green jade used for Maori carvings and ornaments
HL, Kimbauer R, Booy FP, Jessie J, Lowy DR, et al. In vitro generation and type-specific neutralization of a human papillomavirus type 16 virion virion
Entire virus particle, consisting of an outer protein shell (called a capsid) and an inner core of nucleic acid (either RNA or DNA). The core gives the virus infectivity, and the capsid provides specificity (i.e., determines which organisms the virus can infect). pseudotype. J Virol 1996; 70 : 5875-83.
(85.) Pastrana DV, Vass WC, Lowy DR, Schiller JT. NHPV NHPV Norwegian Human Powered Vehicles 16 VLP vaccine induces human antibodies that neutralize divergent variants ofHPV16. Virology 2001; 279 : 361-9.
(86.) Hildesheim A, Schiffman M, Bromley C, Wacholder S, Herrero R, Rodriuez AC, et al. Human papillomavirus type 16 variants and risk of cervical cancer. J Natl Cancer Inst 2001; 93: 315-8.
(87.) Allen M, Kalantari MN, Pettersson YB, Hagmar BL, Johansson SB, Petterson U, et al. HLA DQ-DR haplotype haplotype /hap·lo·type/ (-tip) the group of alleles of linked genes, e.g., the HLA complex, contributed by either parent; the haploid genetic constitution contributed by either parent.
n. and susceptibility to cervical carcinoma: indications of increased risk for development of cervical carcinoma in individuals infected with HPV 18. Tissue Antigens 1996; 48 : 32-7.
(88.) Apple RJ, Becker TM, Wheeler CM, Erlich HA. Comparison of human leukocyte antigen human leukocyte antigen
n. Abbr. HLA
A gene product of the major histocompatibility complex; these antigens have been shown to have a strong influence on human allotransplantation, transfusions in refractory patients, and certain disease DR-DQ disease associations found with cervical dysplasia and invasive cervical carcinoma. J Natl Cancer Inst 1995; 87 : 427-36.
(89.) Bontkes HJ, Duin VM, deGruijl TD, Duggan-Keen DJ, Walboomers JM, Stukart MJ, et al. HPV 16 infection and progression of cervical intraepithelial neoplasia: analysis of HLA polymorphism and HPV 16 E6 sequences variants. Int J Cancer 1998; 78 : 166-71.
(90.) Jacobs MV, Snijders P J, van den Brule AJ, Helmerhorst TJ, Meijer CJ, Walboomers JM, et al. A general primer P5_/ GP6-mediated PCR enzyme immunoassay Immunoassay
An assay that quantifies antigen or antibody by immunochemical means. The antigen can be a relatively simple substance such as a drug, or a complex one such as a protein or a virus. method for rapid detection of 14 high-risk and 6 low-risk human papillomavirus genotypes in cervical scrapings. J Clin Microbiol 1997; 35 : 791-5.
(91.) Kleter B, Van Doom LJ, Schrauwen L, Molijn A, Sastrowijoto S, TerSchegget J, et al. Development and clinical evaluation of a highly sensitive PCR-reverse hybridization hybridization /hy·brid·iza·tion/ (hi?brid-i-za´shun)
1. crossbreeding; the act or process of producing hybrids.
2. molecular hybridization
3. line probe assay for detection and identification of anogenital human papillomavirus. J Clin Microbiol 1999; 37 : 2508-17.
(92.) Quint WG V, Scholte G, Van Doom LJ, Kleeter B, Smits PHM, Lindeman J. Comparative analysis of human papillomavirus infections in cervical scrapes and biopsy specimens by general SPF (1) (Stateful Packet Firewall) See stateful inspection.
(2) (Sender Policy Framework) An e-mail authentication system that verifies that the message came from an authorized mail server. 10 PCR and HPV genotyping. J Pathol 2001; 194 : 51-8.
(93.) Woodman CB, Collins S, Winter H, Bailey A, Ellis J, Prior P, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet 2001; 357: 1831-6.
(94.) Perrons C, Jelley R, Kleter B, Quint W, Brink N. Detection of persistent high risk human papillomavirus infections with hybrid capture II and SPF10/LiPA. J Clin Virol 2005; 32 : 278-85.
(95.) Rousseau MC, Franco EL, Villa LL, Sobrinho JP, Termini L, Prado JM, et al. A cumulative case-control study of risk factor profiles for oncogenic and nononcogenic cervical human papillomavirus infections. Cancer Epidemiol Biomarkers Prev 2000; 9 : 469-76.
(96.) Liaw KL, Hildesheim A, Burk RD, Gravitt P, Wacholder S, Manos MM, et al. Aprospective study of human papillomavirus (HPV) type 16 DNA detection by polymerase chain reaction and its association with acquisition and persistence of other HPV types. J Infect Dis 2001; 183 : 8-15.
(97.) Lipsitch M. Vaccintaion against colonizing bacteria with multiple sero types. Proc Natl Acad Sci USA 1997; 94 : 6571-6.
(98.) Lipsitch M. Bacterial vaccines and serotype replacement: lesions from Haemophilus influenzae and prospectus for Streptococus pneumoniae. Emerg Infect Dis 1999, 5 : 336-45.
(99.) Roden R, Wu TC. How will HPV vaccines affect cervical cancer? Nature Rev Cancer 2006; 6 : 753-63.
(100.) Koutsky LA. Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002; 347 : 1645-51.
(101.) Mao C, Koutsky LA, Ault KA, Wheeler CM, Brown DR, Wiley D J, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial A randomized controlled trial (RCT) is a scientific procedure most commonly used in testing medicines or medical procedures. RCTs are considered the most reliable form of scientific evidence because it eliminates all forms of spurious causality. . Gynecol Obstet 2006; 107 : 18-27.
Reprint requests: Dr M. Radhakrishna Pillai, Director, Laboratory of Translational Cancer Research, Rajiv Gandhi Centre for Biotechnology Rajiv Gandhi Centre for Biotechnology (RGCB) is located at Thiruvananthapuram (Trivandrum), the capital city of the state of Kerala in India. This is a premier research institute in India, exclusive devoted to Biotechnology. Thycaud PO, Poojappura, Thiruvananthapuram 695 014, India e-mail: firstname.lastname@example.org, email@example.com
Indhu Hariharan & M. Radhakrishna Pillai
Laboratory of Translational Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
Table I. HPV type and disease association other than that in cervical cancer Disease HPV type Plantar warts 1, 2, 4, 6, 3 Common warts 2, 1,7 4, 26, 27, 29, 41, 57, 65, 77, 1, 3, 4, 10, 28 Flat warts 3, 10, 26, 27, 28, 38, 41, 48, 60, 72, 73 Other cutaneous lesions (e.g., 6, 11, 16, 30, 33, 36, 37, 38, epidermoid cysts, laryngeal 41, 48, 60, 72, 73 carcinoma) Epidermodysplasia verruciformis 2, 3, 10, 5, 8, 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, 36, 37, 37, 47, 50 Recurrent respiratory 6, 11 papillomatosis Focal epithelial hyperplasia of 13, 32 heck Conjunctival papillomas/ 6, 11, 16 carcinomas Condyloma acuminata (genital 6, 11, 30, 42, 43, 45, 51, 54, warts) 55, 70 Data from Ref. 27, 28 Order indicates relative frequency; bold type indicates most frequent association Table adapted from Ref. 18 Table II. Phylogenetic and epidemiological classification of HPV types High risk Low risk Epidemiological classifcation of HPV types: 16, 18, 31, 33, 35, 39, 45, 51, 6, 11, 40, 42, 43, 44, 54, 61, 52, 56, 58, 59, 68, 82, 73, 26 *, 72, 81, CP6108, 70 53 *, 66 * Phylogenetic classification of HPV types: 16, 18, 31, 33, 35, 39, 45, 51, 6, 11, 40, 42, 43, 44, 54, 61, 52, 56, 58, 59, 68, 82, 70, 26 *, 72, 81, CP6108, 73 53 *, 66 * * indicates epidemiologic classification of these types as probable HR types is based on zero controls and one to three positive cases in a pooled data from 11 case-control studies from nine countries involving 1918 women with histologically confirmed SCC and 1928 control women. Table adapted from Ref. 30 Table III. Proportion of cervical cancer caused by the carcinogenic HPV types HPV type Proportion of cervical cancers caused (in %) HPV16 54.6 HPV18 15.8 HPV33 4.4 HPV45 3.7 HPV52 3.5 HPV35 3.4 HPV59 2.5 HPV31 1.8 HPV58 1.1 HPV56 0.8 HPV51 0.7 HPV39 0.7 HPV73 0.5 HPV68 0.5 HPV82 0.2 No type identified 5.2 Data adapted from Ref. 35
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||Review Article|
|Author:||Hariharan, Indhu; Pillai, M. Radhakrishna|
|Publication:||Indian Journal of Medical Research|
|Date:||Sep 1, 2009|
|Previous Article:||Cervical cancer screening & HPV vaccination: a comprehensive approach to cervical cancer control.|
|Next Article:||The clinical utility of HPV DNA testing in cervical cancer screening strategies.|