A comprehensive natural history model of HPV infection and cervical cancer to estimate the clinical impact of a prophylactic HPV-16/18 vaccine

The object of our study is to project the impact of a prophylactic vaccine against persistent human papillomavirus (HPV)-16/18 infection on age-specific incidence of invasive cervical cancer. We developed a computer-based mathematical model of the natural history of cervical carcinogenesis to incorporate the underlying type-specific HPV distribution within precancerous lesions and invasive cancer. After defining plausible ranges for each parameter based on a comprehensive literature review, the model was calibrated to the best available population-based data. We projected the age-specific reduction in cervical cancer that would occur with a vaccine that reduced the probability of acquiring persistent infection with HPV 16/18, and explored the impact of alternative assumptions about vaccine efficacy and coverage, waning immunity and competing risks associated with non-16/18 HPV types in vaccinated women. The model predicted a peak age-specific cancer incidence of 90 per 100,000 in the 6th decade, a lifetime cancer risk of 3.7% and a reproducible representation of type-specific HPV within low and high-grade cervical precancerous lesions and cervical cancer. A vaccine that prevented 98% of persistent HPV 16/18 was associated with an approximate equivalent reduction in 16/18-associated cancer and a 51% reduction in total cervical cancer; the effect on total cancer was attenuated due to the competing risks associated with other oncogenic non-16/18 types. A vaccine that prevented 75% of persistent HPV 16/18 was associated with a 70% to 83% reduction in HPV-16/18 cancer cases. Similar effects were observed with high-grade squamous intraepithelial lesions (HSIL) although the impact of vaccination on the overall prevalence of HPV and low-grade squamous intraepithelial lesions (LSIL) was minimal. In conclusion, a prophylactic vaccine that prevents persistent HPV-16/18 infection can be expected to significantly reduce HPV-16/18-associated LSIL, HSIL and cervical cancer. The impact on overall prevalence of HPV or LSIL, however, may be minimal. Based on the relative importance of different parameters in the model, several priorities for future research were identified. These include a better understanding of the heterogeneity of vaccine response, the effect of type-specific vaccination on other HPV types and the degree to which vaccination effect persists over time.     

Characterization of HPV genotype profile in squamous cervical lesions in Portugal, a southern European population at high risk of cervical cancer.

A different prevalence of human papillomavirus (HPV) types has been reported in distinct populations. Although Portugal has a relatively high incidence of cervical cancer within the European Union, no studies have been reported in the Portuguese population. Recently, a clinical trial using a vaccine targeted against HPV-16 demonstrated a high efficacy in preventing HPV-16 cervical lesions. The aim of the present study was the characterization of HPV genotype profile in squamous intraepithelial lesions (SIL) and invasive cervical cancer (ICC) from 608 patients using polymerase chain reaction (PCR) methodology. We frequently detected HPV-6/11 and HPV-16 in low-grade SIL (HPV-6/11, 18.9%; HPV-16, 44.2%). In high-grade SIL, HPV-16 was demonstrated in 74.2% of those lesions and in 80.0% of the cases with ICC. HPV-18 was found in 3.1%, 0.8% and in 15.0% of low, high SIL and ICC, respectively. The overall prevalence of multiple infections with high-risk HPV was 7.2%. Other types of HPV were detected in 7.0% of all cases. Our results demonstrate a high prevalence of HPV-16 in SIL and ICC in Portuguese women. Therefore, a prophylactic HPV-16/18 vaccine may be effective in the prevention of cervical cancer in a significant number of women from this southern European population.     

Primäre Prävention des Zervixkarzinoms

The association between infection with human papilloma virus (HPV) and the incidence of cervical cancer is unique and well documented. The global disease burden of cervical cancer is estimated at 500,000 new cases and 270,000 deaths every year. Two prophylactic vaccines have been developed for the primary prevention of this cancer. They are directed against types HPV16 and 18 and HPV6 and 11. Clinical studies have demonstrated the safety, immunogenicity, and a 100% efficacy against HPV infection and dysplasia. Data from follow-up analyses of up to 4.5 years demonstrate cross protection by the Cervarix vaccine with related HPV types 45 and 31, increasing its efficacy. The primary target population for vaccination will be girls 9–14 years of age. Whether the vaccination of boys and older males will also be protective, has still to be shown.     

Vaccine-related HPV genotypes in women with and without cervical cancer in Mozambique: burden and potential for prevention

Knowledge about the burden of Human Papillomavirus (HPV) infections in Sub-Saharan Africa is very limited. We collected cervical samples from 262 women from the general population and 241 tumor samples from women with invasive cervical cancer in Mozambique and tested them for HPV genotyping by the SPF(10)-LiPA(25) PCR system. Among the 195 women without cervical abnormalities by cytology HPV prevalence was 75.9%. In this group of women, the most frequently identified HPV types among HPV-positive women were in descending order of frequency: HPV51 (23.6%), HPV35 (19.6%), HPV18 (14.2%), HPV31 (13.5%) and HPV52 (12.8%). In women with cervical cancer HPV DNA detection was 100%. The type-specific distribution of the most frequent types in descending order of frequency was: HPV16 (47.0%), HPV18 (31.3%), HPV51 (14.8%), HPV52 (14.3%), HPV45 (12.6%), HPV35 (10.4%), HPV33 (4.8%) and HPV31 (2.6%). HPVs 16/18 and HPVs 16/18/31/45 were detected in 71.7% and 80.9% of cervical cancer tissue, respectively. While HPVs 51 and 35 were the two most common types in cytologically normal women in Mozambique, HPVs 16 and 18 remained the two most frequently identified types in cervical cancer. The introduction of an efficacious HPV 16/18 vaccine could potentially prevent the occurrence of 72% of cervical cancer cases and up to 81% of the cases if full cross-protection against HPVs 31 and 45 is assumed.     

Prevalence of genotype‐specific human papillomavirus infection and cervical neoplasia in Taiwan: A community‐based survey of 10,602 women

Human papillomavirus (HPV) causes cervical neoplasia; but limited data are available from Asia. We conducted a large‐scale community‐based cohort study in Taiwan to estimate prevalence of genotype‐specific HPV infection and cervical neoplasia. Following written informed consent, cervical cells for cytology and HPV testing were collected from 11,923 participants (aged 30–65 years old, mean 46.3) in 1991–1992. Genotyping was performed using MY11/GP6+ PCR‐based HPV Blot (EasyChip) for 39 HPV types. The overall HPV prevalence was 16.2% for 10,602 eligible participants, and 13.8% for 10,190 cytologically normal participants. The most common carcinogenic types were HPV52 (2.5%), HPV16 (2.0%), HPV56 (1.8%), HPV18 (1.6%), HPV33 (1.2%), HPV58 (1.3%) and HPV39 (1.0%). Among the 56 prevalent invasive and in situ cases, HPV16 (48.2%) was most common, followed by HPV58 (25.0%), HPV52 (19.6%), HPV31 (8.9%), HPV33 (8.9%) and HPV18 (3.6%). HPV16 and HPV58 caused cytological HSIL+ at younger ages than HPV52. Approximately half of the cervical cancer cases and high‐grade precursors in Taiwan could be prevented by prophylactic vaccines against HPV16 and HPV18 infection. Up to 40% more could be prevented by targeting HPV58, HPV52, HPV33 and HPV31, arguing for the introduction of vaccines including more types.     

Efficacy of quadrivalent human papillomavirus (types 6, 11, 16 and 18) vaccine (GARDASIL) in Japanese women aged 18–26 years

A randomized double‐blind placebo‐controlled phase II trial was conducted to evaluate the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types most frequently associated with cervical cancer (types 16/18) and genital warts (types 6/11) in Japanese women aged 18–26 years. Participants were randomly assigned to either quadrivalent HPV (types 6/11/16/18) L1 virus‐like particle vaccine (GARDASIL) (n = 509) or placebo (n = 512). Participants underwent regular gynecological examinations, cervicovaginal sampling for HPV DNA, testing for serum neutralizing antibodies to HPV and Papanicolau testing. The primary end‐point was the combined incidence of persistent infection with HPV types 6, 11, 16 or 18 and cervical or external genital disease (i.e. cervical intraepithelial neoplasia, cervical cancer or external genital lesions related to HPV 6, 11, 16 or 18. Primary analyses were done per protocol. Combined incidence of persistent infection or disease with HPV 6, 11, 16 or 18 fell by 87.6% (95% confidence interval [CI], 59.2–97.6; P < 0.001), with HPV 6 or 11 by 73.1% (95% CI, ?1.1–97.3; P = 0.0756) and with HPV 16 or 18 by 94.5% (95% CI, 65.2–99.9; P < 0.001) in those assigned vaccine compared with those assigned placebo. The median duration of follow up after month 7 in subjects was 23 months. In addition, the vaccine was well tolerated in Japanese women aged 18–26 years. Quadrivalent HPV vaccine could significantly reduce the acquisition of infection and clinical disease caused by HPV types 6, 11, 16 and 18.     

Case-control study of human papillomaviruses and cervical cancer in Latin America

Human papillomavirus (HPV) types 16 and 18 have been implicated as risk factors for cervical dysplasia and neoplasia. However, most studies have been observational, uncontrolled and conducted in populations at low risk for invasive cancer. We report a pilot case-control study of incident invasive cervical cancer in Panama, Costa Rica and Bogota, Colombia. Between July and September 1985 we enrolled 46 consecutive newly diagnosed invasive cervical cancer cases and 51 age-matched control women. Subjects were interviewed and samples collected for HPV DNA assays. HPV infection was defined by a filter in situ DNA hybridization technique under non-stringent and stringent conditions against HPV-6/11, 16 and 18 DNA probes. More cases (91%) than controls (63%) had HPV DNA detected (non-stringent) and more cases than controls had HPV-16 or 18 DNA (67% vs. 43%, p = 0.02). Age at first intercourse was the most significant risk factor for HPV 16/18 infection in all subjects. Smoking was significantly associated with cervical cancer (52% of cases vs. 27% controls) but was not associated with HPV infection.     

Burden of Disease Associated with Cervical Cancer in Malaysia and Potential Costs and Consequences of HPV Vaccination

Background: An estimated 70% of cervical cancers worldwide are attributable to persistent infection withhuman papillomaviruses (HPV) 16 and 18. Vaccination against HPV 16/18 has been shown to dramatically reducethe incidence of associated precancerous and cancerous lesions. The aims of the present analyses were, firstly, toestimate the clinical and economic burden of disease attributable to HPV in Malaysia and secondly, to estimatelong-term outcomes associated with HPV vaccination using a prevalence-based modeling approach. Methods:In the first part of the analysis costs attributable to cervical cancer and precancerous lesions were estimated;epidemiologic data were sourced from the WHO GLOBOCAN database and Malaysian national data sources.In the second part, a prevalence-based model was used to estimate the potential annual number of cases ofcervical cancer and precancerous lesions that could be prevented and subsequent HPV-related treatment costsaverted with the bivalent (HPV 16/18) and the quadrivalent (HPV 16/18/6/11) vaccines, at the population level, atsteady state. A vaccine efficacy of 98% was assumed against HPV types included in both vaccines. Effectivenessagainst other oncogenic HPV types was based on the latest results from each vaccine’s respective clinical trials.Results: In Malaysia there are an estimated 4,696 prevalent cases of cervical cancer annually and 1,372 prevalentcases of precancerous lesions, which are associated with a total direct cost of RM 39.2 million with a furtherRM 12.4 million in indirect costs owing to lost productivity. At steady state, vaccination with the bivalent vaccinewas estimated to prevent 4,199 cervical cancer cases per year versus 3,804 cases for the quadrivalent vaccine.Vaccination with the quadrivalent vaccine was projected to prevent 1,721 cases of genital warts annually, whereasthe annual number of cases remained unchanged with the bivalent vaccine. Furthermore, vaccination with thebivalent vaccine was estimated to avert RM 45.4 million in annual HPV-related treatment costs (direct+indirect)compared with RM 42.9 million for the quadrivalent vaccine. Conclusion: This analysis showed that vaccinationagainst HPV 16/18 can reduce the clinical and economic burden of cervical cancer and precancerous lesions inMalaysia. The greatest potential economic benefit was observed using the bivalent vaccine in preference to thequadrivalent vaccine.     

Human papillomavirus infection and invasive cervical cancer in Paraguay

HPV types 16 and 18 have been categorized as human carcinogens based on their strong associations with cervical cancer in previous case-control studies. Recent IARC studies in the Philippines, Thailand and Morocco show strong associations between invasive cervical cancer and less common HPV types, including HPV 31, 33, 45, 51, 52 and 58. We present results of a further IARC case-control study conducted in Asunción, Paraguay, to examine the association between specific HPV types and invasive cervical cancer as well as risk factors other than HPV. One-hundred thirteen incident histologically confirmed invasive cervical cancer cases and 91 age-matched hospital controls were recruited. A standardized questionnaire was administered to investigate known and suspected risk factors for cervical cancer. For HPV status determination, cervical biopsy specimens from case subjects and exfoliated cervical cells from control subjects were obtained. HPV DNA was ascertained using a GP5+/6+ PCR-based assay capable of detecting more than 33 HPV types. Overall HPV prevalence was 97% in the cervical cancer cases and 20% in the control subjects. As a single infection, HPV 16 was the predominant type with a prevalence of 48% among case subjects and 5.5% among control subjects. Significant associations with the risk of cervical cancer were detected as follows: any HPV type (OR = 114; 95% CI: 36-361); HPV 16 (OR = 910); HPV 18 (infinite OR); HPV 31 (OR = 110); HPV 33 (OR = 261); HPV 45 (OR = 129); and HPV 58 (OR = 36). In the multivariate model, risk factors other than HPV significantly associated with cervical cancer risk were a higher number of lifetime sexual partners, lower educational status and never having had a Pap smear. Strong associations were found between invasive cervical cancer and specific HPV types 16, 18, 31, 33, 45 and 58.     

Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial

BACKGROUND: A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). METHODS: 277 young women (mean age 20.2 years [SD 1.7]) were randomly assigned to quadrivalent HPV (20 microg type 6, 40 microg type 11, 40 microg type 16, and 20 microg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20.0 years [1.7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. FINDINGS: Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71-97, p<0.0001) in those assigned vaccine compared with those assigned placebo. INTERPRETATION: A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.     

Influence of HPV type on prognosis in patients diagnosed with invasive cervical cancer

While much is known about the influence of HPV type on the progression of pre‐invasive cervical lesions, the impact of HPV type on cervical cancer prognosis is less evidenced. Thus, we assessed the impact of HPV type on the survival of women diagnosed with cervical cancer. A total of 370 cases of cervical cancer were assessed. Univariate analysis is presented using Kaplan–Meier survival curves and log‐rank statistics and multivariable Cox proportional hazard models were generated using age group, socio‐economic deprivation, FIGO stage, differentiation and HPV type. HPV grouping was considered in a number of ways with particular reference to the presence or absence of HPV 16 and/or 18. In the univariate analysis, FIGO, age at diagnosis and treatment were associated with poorer survival (p < 0.0001) as was absence of HPV 16 and/or 18 (p = 0.0460). The 25% mortality time in the non‐HPV 16/18 vs. HPV16/18 positive group was 615 days and 1,307 days respectively. An unadjusted Cox PH model based HPV16/18 vs. no HPV 16/18 resulted in a hazard ratio of 0.669 (0.450, 0.995). Adjusting for deprivation, FIGO and age group resulted in a hazard ratio of 0.609 (0.395, 0.941) p = 0.025. These data indicate that cancers associated with HPV 16 and/or 18 do not confer worse survival compared to cancers associated with other types, and may indicate improved survival. Consequently, although HPV vaccine is likely to reduce the incidence of cervical cancer it may not indirectly improve cervical cancer survival by reducing the burden of those cancers caused by HPV16/18.     

Understanding long‐term protection of human papillomavirus vaccination against cervical carcinoma: Cancer registry‐based follow‐up

Phase III clinical trials of human papilloma virus (HPV) vaccination have shown ≥95% efficacy against HPV16/18 associated cervical intraepithelial neoplasia (CIN) Grade 2/3. Long‐term surveillance is, however, needed to determine the overall vaccine efficacy (VE) against CIN3 and invasive cervical carcinoma (ICC). During population‐based recruitment between September 2002 and March 2003, 1,749 16? to 17‐year old Finns participated in a multi‐national randomized Phase III HPV6/11/16/18 vaccine (FUTURE II) trial for the determination of VE against HPV16/18 positive CIN2/3. The passive follow‐up started at the country‐wide, population‐based Finnish Cancer Registry (FCR) six months after the active follow‐up and voluntary cross‐vaccination in April 2007. A cluster randomized, population‐based reference cohort of 15,744 unvaccinated, originally 18–19 year old Finns was established in two phases in 2003 and 2005 after the FUTURE II recruitment. We linked these cohorts with the FCR in 2007–2011 (HPV vaccine and placebo cohorts) and 2006–2010 and 2008–2012 (unvaccinated reference cohorts 1 and 2) to compare their incidences of CIN3 and ICC. The four years passive follow‐up resulted in 3,464, 3,444 and 62,876 person years for the HPV6/11/16/18, original placebo and reference cohorts, after excluding cases discovered during the clinical follow‐up and individuals not at risk. The numbers of CIN3 and ICC cases identified were 0 and 0, 3 and 0, 59 and 3 for the HPV6/11/16/18, placebo and the unvaccinated reference cohorts. The corresponding CIN3 incidence rates were 0/100,000 (95% confidence interval 0.0–106.5), 87.1/100,000 (95% CI 17.9–254.5) and 93.8/100,000 (95% CI 71.4–121), respectively. Long‐term surveillance up to 8 years (and longer) post vaccination of the HPV6/11/16/18 vaccine and placebo cohorts, and the unvaccinated reference cohort (not exposed to interventions) for the most stringent efficacy end‐points by passive cancer registry‐based follow‐up is feasible.     

A systematic review of the prevalence and attribution of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in the United States

OBJECTIVES: To describe prevalence and estimated attribution of human papillomavirus (HPV) types in U.S. cervical, vaginal, and vulvar precancers and cancers. METHODS: U.S. studies reporting HPV typing for cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), and vaginal intraepithelial neoplasia (VaIN) and/or invasive cancers of those sites were gathered from the PubMed database (http://www.ncbi.nlm.nih.gov/sites/entrez/). Selected studies had PCR testing data for > or =10 cases for a disease endpoint. Analytic methods augmented prior reviews of cervical disease with an updated and expanded analysis (including vulvar and vaginal disease), new selection criteria for specimens, and adjustment for histologic type, where possible, among pooled cancer cases. In addition, for analyses of estimated attribution of HPV types, we incorporated accounting methods for lesions infected with multiple HPV types. RESULTS: Data from 22 U.S. studies meeting review eligibility criteria were tabulated. Following adjustment for the presence of multiple HPV types in a single specimen, the top two HPV types contributing to disease were CIN 1 (HPV 16/66; 15.3%), CIN 2/3 (HPV 16/31; 61.9%), cervical cancer (HPV 16/18; 79.2%), VIN 1 (HPV 6/11; 41.7%), VIN 3 (HPV 16/18; 84.0%), vulvar cancer (HPV 16/33; 55.5%), VaIN 3 (HPV 16/18; 65.1%), and vaginal cancer (HPV 16/18; 72.7%). CONCLUSIONS: The HPV type distribution and proportion of cases testing positive for any HPV type were observed to vary among U.S. cervical, vulvar, and vaginal neoplasias and by grade of disease. Adjustment for the presence of multitype HPV infections can have an important effect on the estimated attribution of HPV types to disease, particularly for types other than HPV 16.     

Prevalence of HPV types in cervical specimens from an integrated healthcare delivery system: baseline assessment to measure HPV vaccine impact

Purpose

Two human papillomavirus (HPV) vaccines are available to prevent cervical cancer. One early measure of HPV vaccine impact would be a reduction in vaccine-related HPV types (HPV 6, 11, 16, or 18, or HPV 16, 18) in cervical samples from young women. We aimed to assess feasibility of specimen collection and baseline HPV prevalence in an integrated healthcare delivery system.

Methods

Residual cervical specimens collected during routine cervical cancer screening (2006–2008) were retained consecutively from eligible females aged 11–29 years, stratified by age group. Specimens were evaluated for 37 HPV genotypes using the Roche Linear Array assay.

Results

Of 10,124 specimens submitted, 10,103 (99 %) were adequate for HPV testing. Prevalence of HPV 6, 11, 16, or 18 genotype was 11.4 % overall and was the highest in the youngest age group (18.1 % in the 11–19-year-olds, 12.5 % in the 20–24-year-olds, and 7.0 % in the 25–29-year-olds).

Conclusions

HPV types 6, 11, 16, or 18 prevalence could be measured over time to assess early HPV vaccine impact using residual specimens from an integrated healthcare delivery system, particularly if sampling focused on young women.     

Time trends of human papillomavirus types in invasive cervical cancer,from 1940 to 2007

Contribution over time of human papillomavirus (HPV) types in human cancers has been poorly documented. Such data is fundamental to measure current HPV vaccines impact in the years to come. We estimated the HPV type‐specific distribution in a large international series of invasive cervical cancer (ICC) over 70 years prior to vaccination. Paraffin embedded ICC cases diagnosed between 1940 and 2007 were retrieved from eleven countries in Central‐South America, Asia and Europe. Included countries reported to have low‐medium cervical cancer screening uptake. Information on age at and year of diagnosis was collected from medical records. After histological confirmation, HPV DNA detection was performed by SPF‐10/DEIA/LiPA25 (version1). Logistic regression models were used for estimating the adjusted relative contributions (RC) of HPV16 and of HPV18 over time. Among 4,771 HPV DNA positive ICC cases, HPV16 and HPV18 were the two most common HPVs in all the decades with no statistically significant variations of their adjusted‐RC from 1940–59 to 2000–07 (HPV16—from 61.5 to 62.1%, and HPV18—from 6.9 to 7.2%). As well, the RC of other HPV types did not varied over time. In the stratified analysis by histology, HPV16 adjusted‐RC significantly increased across decades in adenocarcinomas. Regarding age, cases associated to either HPV16, 18 or 45 were younger than those with other HPV types in all the evaluated decades. The observed stability on the HPV type distribution predicts a high and stable impact of HPV vaccination in reducing the cervical cancer burden in future vaccinated generations.     

Human papillomavirus 6 seropositivity is associated with risk of head and neck squamous cell carcinoma, independent of tobacco and alcohol use

Background: The risk of head and neck squamous cell carcinoma(HNSCC) associated with common human papillomavirus types hasnot been well defined. Methods: We conducted a case–control study of 1034 individuals(486 incident cases diagnosed with HNSCC and 548 population-basedcontrols matched to cases by age, gender, and town of residence)in Greater Boston, MA. Sera were tested for antibodies to humanpapillomavirus (HPV)6, HPV11, HPV16, and HPV18 L1. Results: HPV6 antibodies were associated with an increased riskof pharyngeal cancer [odds ratio (OR) = 1.6, 1.0–2.5],controlling for smoking, drinking, and HPV16 seropositivity.In HPV16-seronegative subjects, high HPV6 titer was associatedwith an increased risk of pharyngeal cancer (OR = 2.3, 1.1–4.8)and oral cancer (OR = 1.9, 1.0–3.6), suggesting that thecancer risk associated with HPV6 is independent of HPV16. Therewas no association between smoking and alcohol use and HPV6serostatus. Further, the risk of pharyngeal cancer associatedwith heavy smoking was different among HPV6-seronegative (OR3.1, 2.0–4.8) and HPV6-seropositive subjects (OR = 1.6,0.7–3.5), while heavy drinking also appears to conferdiffering risk among HPV6-negative (OR 2.3, 1.5–3.7) and-positive subjects (OR = 1.3, 0.6–2.9). Conclusions: There may be interactions between positive serologyand drinking and smoking, suggesting that the pathogenesis ofhuman papillomavirus in HNSCC involves complex interactionswith tobacco and alcohol exposure. Key words: epidemiology, head and neck squamous cell carcinoma, human papillomavirus, risk factors, serology Received for publication March 6, 2008. Revision received August 20, 2008. Accepted for publication August 26, 2008.     

No excess risk of cervical carcinoma among women seropositive for both HPV16 and HPV6/11

Human papillomavirus (HPV) types 16 and 18 are the major risk factors for cervical carcinoma, whereas HPV types 6 and 11 cause benign genital lesions. We wanted to study the joint effect of simultaneous infections with the oncogenic and non-oncogenic HPV types on risk of subsequent development of cervical carcinoma. A cohort of 530,000 women who had donated blood samples to Nordic serum banks between 1973 and 1994 was followed up by linkage to national cancer registries. We identified 182 prospective cases with invasive cervical carcinoma and selected 538 matched controls at random. HPV 6, 11, 16, 18 and 33 seropositivity was used as a marker for the different HPV infections, and seropositivity for Chlamydia trachomatis and cotinine were used as markers for risk-taking sexual behavior and smoking respectively. The adjusted odds ratio (OR) of cervical squamous-cell carcinoma (SCC) was 2.2 for HPV6/11 among HPV16 seronegatives and 5.5 for HPV16 among HPV6/11 seronegatives. Assuming multiplicative joint effect, the expected OR for seropositivity to both HPV6/11 and HPV16 would have been 12, but the observed OR was 1.0. The antagonistic interaction was statistically significant (p = 0.001) and present also under deterministic considerations of possible misclassification bias. Antagonistic interactions were also detected for combinations of HPV16 and HPV18 and of HPV16 and HPV33. The results are in line with the concept that HPV-specific immunity protects against SCC and support primary prevention of SCC by vaccination against the HPVs.     

Presence of human papilloma virus types 16 and 18 in genital warts and cervical neoplasias

Certain types of human papilloma viruses (HPV) are associated with human genital proliferative diseases, and among them HPV16 and HPV18 seem to play an important role in the occurrence of cervical cancer. We used restriction enzyme analysis and molecular hybridization, in order to investigate the type of viral infection and the physical state of viral DNA in gynecological benign, pre-malignant and malignant lesions. HPV6/11 specific sequences could only be detected as episomes and this in benign lesions classified as condylomata acuminata. On the other hand, HPV16 and HPV18 sequences were detected in non-malignant lesions such as flat condylomata (7 out of 14 cases), pre-malignant lesions including cervical intra-epithelial neoplasias (10 out of 20 cases), and most frequently in cervical invasive cancers (21 out of 27 cases). In a large number of virus-positive cases, HPV16 and HPV18 could only be discerned in forms consistent with the existence of episomes and/or randomly integrated head-to-tail oligomers. However, some invasive carcinomas and cervical intra-epithelial neoplasias contained, in addition, clonal outgrowths with detectable virus-cellular junction fragments of the integrated viral genomes. In the light of these data, monitoring the type of viral infection proves to be an important adjunct to histological analysis when assessing those patients affected by condyloma or cervical intra-epithelial neoplasia who are at risk for developing invasive carcinoma.     

Against which human papillomavirus types shall we vaccinate and screen? the international perspective

At least 15 types of HPV have been associated with cervical cancer, but current HPV vaccines confer only type-specific immunity. To determine geographic variations in the HPV type distribution in cervical cancer, we carried out a pooled analysis of data from an international survey of HPV types in cervical cancer and from a multicenter case-control study, both co-coordinated by the IARC. Study cases were 3,607 women with incident, histologically confirmed cervical cancer recruited in 25 countries. HPV DNA detection and typing in cervical cells or biopsies were centrally done using PCR assays. Estimates of the potential number of cases prevented by HPV type-specific vaccines and changes in the validity of different HPV screening cocktails were calculated. HPV DNA was detected in 96% of specimens, and 30 different types were detected. The 15 most common types were, in descending order of frequency, 16, 18, 45, 31, 33, 52, 58, 35, 59, 56, 39, 51, 73, 68 and 66. Higher than average proportions of type 16 were found in northern Africa, of type 18 in south Asia, of type 45 in sub-Saharan Africa and of type 31 in Central/South America. A vaccine including types 16 and 18 could potentially prevent 71% of cervical cancers worldwide, but its impact with regard to the percentage of cases potentially prevented would be higher in Asia and Europe/North America. In contrast, a vaccine containing the 7 most common HPV types would prevent about 87% of cervical cancers worldwide, with little regional variation. The impact of modifying the number of types in the screening cocktail tests would be small and probably irrelevant for screening programs.     

Different outcome of invasive cervical cancer associated with high‐risk versus intermediate‐risk HPV genotype

Human papillomavirus (HPV) DNA sequences are associated with the large majority of invasive cervical carcinoma but the role of specific genotype(s) in the outcome of the disease is still debated. To determine the viral epidemiology in the French population of patients and the prognostic value of HPV genotypes in cervical cancer, we performed a retrospective study in 515 patients treated in our Institution from 1985 to 2005. Ninety‐six percent of the cases were found associated with HPV DNA whereas 4% remained HPV negative. High‐risk HPV 16/18 genotypes were found in 70% of the cases. HPV 18 was more frequently associated with adenocarcinoma (40.6%) than HPV 16 (10.4%) and found in tumours developed in younger women (mean age, 45.8 years) than HPV 16 (48.3 years) or other HPV types (53.6 years). In multivariate analysis, node involvement (p < 0.0001), parametria invasion (p = 0.009), tumour size (p = 0.01) and HPV status (p = 0.02) were associated with disease‐free survival (median follow‐up 95 months). Disease outcome was better in tumours associated with intermediate risk HPV types (HPV 31, 33, 35, 39, 52, 53, 58, 59, 73) than in tumours with high oncogenic types (HPV 16, 18, 45) (p = 0.03). Node status and tumour size remained prognostic factor for overall survival. Our data show that HPV genotype is one of the biological factors associated with the outcome of cervical cancer. One third of invasive carcinoma were not associated with HPV 16/18, indicating that the screening for cervical neoplasia should be maintained after prophylactic vaccination against these HPV genotypes. © 2008 Wiley‐Liss, Inc.