Potential impact of a nonavalent HPV vaccine on the occurrence of HPV-related diseases in France.

BACKGROUND: Human Papillomavirus (HPV) infection is known to be associated with a number of conditions including cervical, vaginal, vulvar, penile, anal neoplasias and cancers, oropharynx cancers and genitals warts (GW). Two prophylactic vaccines are currently available: a bivalent vaccine designed to prevent HPV type 16 and 18 infection and a quadrivalent vaccine targeting HPV 6, 11, 16, and 18. In France, HPV vaccination is recommended in 11-14 year-old girls with a catch-up for girls aged 15-19. The objective of this study was to assess the potential impact of an HPV 6/11/16/18/31/33/45/52/58 nonavalent vaccine on anogenital and oropharyngeal HPV-related diseases in France. METHODS: HPV genotype distributions from 6 multicentric retrospective studies (EDiTH I to VI) were analyzed including 516 cases of invasive cervical cancers (ICC), 493 high-grade cervical neoplasias (CIN2/3), 397 low-grade squamous intraepithelial lesions (LSIL), 423 GW, 366 anal cancer and 314 oropharyngeal carcinomas. Low and high estimates of HPV vaccine impact were calculated as follows: low estimate: prevalence of HPV 6/11/16/18/31/33/45/52/58 genotypes alone or in association but excluding presence of another HPV type; high estimate: prevalence of HPV 6/11/16/18/31/33/45/52/58 genotypes alone or in association, possibly in presence of another HPV type. RESULTS: Estimates of potential impact varied from 85% (low estimate) to 92% (high estimate) for ICC, 77% to 90% for CIN2/3, 26% to 56% for LSIL, 69% to 90% for GW, 81% to 93% for anal cancer, and 41% to 44% for oropharyngeal carcinomas. Compared to the quadrivalent vaccine, the proportion of additional cases potentially prevented by the nonavalent vaccine was 9.9%-15.3% for ICC, 24.7%-33.3% for CIN2/3, 12.3%-22.7% for LSIL, 2.1%-5.4% for GW, 8.5%-10.4% for anal cancer, and 0.0%-1.6% for oropharyngeal carcinoma. CONCLUSIONS: The nonavalent HPV vaccine showed significant increased potential impact compared to the HPV 6/11/16/18 quadrivalent vaccine for ICC, CIN2/3 and LSIL. Considering a 100% vaccine efficacy and high vaccine coverage, about 90% of ICC, CIN2/3, GW or anal cancer cases could be prevented by a nonavalent HPV vaccine in France.

Prevention of sexually transmitted infections among girls and young women in relation to their HPV vaccination status.

BACKGROUND: Having been vaccinated against the human papilloma virus (HPV) may affect other behaviours related to sexual health. This study assessed knowledge and behaviour relevant to the prevention of sexually transmitted infections (STIs) among girls/women aged 14-23 years in relation to their HPV vaccination status. METHODS: From November 2008 to February 2009, 328 girls/women from the Rhône-Alpes region were recruited by general practitioners and completed a self-administered questionnaire. RESULTS: In all, 316 of the 328 respondents provided information on their HPV vaccination status: 135 (42.7%) had been vaccinated (51.2% of girls aged 14-16 years, 44% of women aged 17-20 years and 18.9% of 21-23-year-olds). Knowledge about HPV and the Pap smear was poor overall but greater in those who had been vaccinated: vaccinated 14-16-year-olds were significantly more likely to know the aim of the Pap smear than those not vaccinated (72.7% vs. 41.3%, P < 0.001), and vaccinated 21-23-year-olds were more likely to know about the need to continue Pap smear screening, despite vaccination (60.0% vs. 25.6%, P = 0.06). Irrespective of vaccination status, >80% cited condoms as a means of STI prevention and >85% of those who were sexually active used them. No difference was observed between vaccinated and non-vaccinated groups regarding requests for HIV serology, history of abortions or emergency hormonal contraception. CONCLUSION: Knowledge about cervical cancer prevention was better among those who had been vaccinated against HPV than among those who had not. Knowledge and behaviour relevant to STI prevention seemed appropriate whatever the respondents' vaccination status.

French women's knowledge of and attitudes towards cervical cancer prevention and the acceptability of HPV vaccination among those with 14 - 18 year old daughters: a quantitative-qualitative study.

BACKGROUND: In France, it is recommended that girls and women aged 14-23 are vaccinated against the human papillomavirus (HPV). However, French women's knowledge of and attitude towards the vaccine has been little studied. METHODS: Thirty-nine general practitioners, representative of those working in the large Rhône-Alpes region, offered a self-administered questionnaire on cervical cancer (CC) prevention to all 18-65 year-old women who came for consultation during June and July 2008. In addition, semi-structured interviews were undertaken with a sample of those who had daughters aged 14-18. RESULTS: Of the 1,478 women who completed the questionnaire, only 16.9% mentioned HPV as the cause of CC, even though 76.2% knew of the vaccine. 210 women had daughters aged 14-18, and 32 were interviewed. Compared with the wider group, more of these women were aware of the HPV vaccine (91.4%). 44.8% knew the target population and 17.1% the recommended ages for vaccination. 54.3% favoured HPV vaccination; 37.2% were undecided and only 0.9% were opposed. The main barrier to acceptance was the recency of the vaccine's introduction and concern about possible side effects (54.9%); 14.1% preferred to rely on their GP's decision. Factors associated with acceptance of the HPV vaccine were having previously vaccinated a child against pneumococcus (OR=3.28 [1.32-8.11]) and knowing the target population for HPV vaccination (OR=2.12 [1.15-3.90]). Knowing the recommended frequency of Papanicolaou smear testing (Pap test) screening was associated with lower acceptance (OR=0.32 [0.13-0.82]). CONCLUSIONS: Few mothers are opposed to HPV vaccination. Factors associated with acceptability were knowledge about the vaccine, acceptance of other vaccines and, unexpectedly, lack of knowledge about the recommended frequency of Pap testing. On multivariate analysis, compliance with recommendations for Pap test screening and socioeconomic factors had no effect on views about HPV vaccination. Given that concern about possible side effects is the major barrier to wider acceptance of the HPV vaccine in France, GPs have a key role in providing information.

Human papillomavirus genotype distribution in anal cancer in France: the EDiTH V study.

Anal cancer is a rare cancer but its incidence is increasing. Human papillomavirus (HPV) infection seems to be associated with the occurrence of most cases. The genotype-specific prevalence of HPV in anal cancer was estimated to assess the potential benefit of HPV vaccination in France. Anal cancer histological specimens were retrospectively recruited in 2008 from 16 French centres and centrally tested for HPV genotyping using the INNO-LiPA assay allowing the detection of 28 genotypes. Results were analyzed according to age, gender, HIV status when available and histological diagnosis. A total of 366 anal cancer cases were analyzed among which 62% were females. Mean age at diagnosis was 54.8 years in males and 66.4 years in females (p < 0.001). HPV was found in 96.7% of cases, 72% being infected by a single HPV type. Presence of at least one high-risk genotype was observed in 91% of cases (96% in females and 83% in males; p < 0.001). HPV16 was by far the most prevalent genotype (75%), followed by HPV18, HPV52, HPV33, and HPV51 (4-6%). HPV16/18 alone or in association were found in 78% of all cases. HIV-positive cases had a higher proportion of multiple HPV infection than HIV-negative cases and a slightly different HPV type distribution with an under-representation of HPV16 and an over-representation of other types. Our results indicate that anal cancer rarely occurs in the absence of HPV and emphasize the predominant role of HPV16. The potential benefit of HPV vaccine on the occurrence of anal cancer should be further evaluated.

Human papillomavirus genotype distribution in external acuminata condylomata: a Large French National Study (EDiTH IV).

BACKGROUND: External acuminata condylomata (EAC) are among the most common sexually transmitted diseases. Although it is understood that low-risk human papillomavirus (HPV) genotypes 6 and 11 are associated with EAC, there have only been a few, small, published studies reporting the genotype-specific prevalence of HPV. The objective of our study was to assess the prevalence of HPV genotypes for a large number of cases involving both men and women and to evaluate the potential benefit of a quadrivalent (genotypes 6, 11, 16, and 18) HPV vaccine in France. METHODS: A total of 256 women and 260 men who presented with EAC to French gynecologists, dermatologists, and proctologists were prospectively recruited during the period January through April 2007. Specimens were collected with a cytobrush, and the HPV genotype was determined using the INNO-LiPA assay (Innogenetics), which detects 24 HPV genotypes. RESULTS: Four hundred twenty-three beta-globin-positive samples could be analyzed. The median age of patients was 30 years (range, 18-72 years). The overall prevalence of HPV DNA in patients with EAC was 99% (33% of patients were coinfected with another pathogen). Low-risk genotypes predominated, with a prevalence of 89%. The most prevalent genotypes were 6 (69%) and 11 (16%), followed by 16 (9%), 51 (8%), 52 (7%), 66 (6%) 53 (5%), 31 (3%), and 18 (3%). The cumulative prevalence of genotypes 6 and 11 was 83%, and the cumulative prevalence of genotypes 6, 11, 16, and 18 was 88%. CONCLUSIONS: This study is, to our knowledge, the first large, multicenter survey to provide solid data on HPV genotype distribution among patients with EAC. Our results provide strong evidence that, in France, the most prevalent HPV genotypes in persons with EAC are 6 and 11. Because of its 99% efficacy for the prevention of EAC and a vaccine coverage of 100%, the quadrivalent HPV vaccine could prevent 62%-87% of EAC cases in France.

Human papillomavirus (HPV) genotype distribution in invasive cervical cancers in France: EDITH study.

Invasive cervical cancer (ICC) remains a significant cause of morbidity and mortality in France. Since human papillomavirus (HPV) is the necessary cause of ICC, the aim of this study was to assess the type-specific prevalence of HPV in ICC in France in order to locally evaluate the potential benefit of an HPV 16/18 L1 virus-like particles (VLP) vaccination. A total of 516 histological specimens collected in 15 centers were analyzed. Among them, 86% had a diagnosis of squamous cell carcinoma (SCC) whereas 14% were adenocarcinomas (ADC). HPV genotyping was performed using the INNO-LiPA assay allowing the specific detection of 24 HPV genotypes both high risk (HR) and low risk (LR). The overall HPV prevalence in ICC was 97%. The most prevalent genotypes were HPV 16 (73%) and HPV 18 (19%) followed by HPV 31 (7%), 33, 68, 45, 52 and 58 (4.1-2.3%). HPV 16 and/or 18 were associated with 82% of ICC, 10% being HPV 16 and 18 coinfections. While HPV 16 was the most prevalent type in both SCC (74%) and ADC (64%), HPV 18 was by far more prevalent in ADC (37%) compared to SCC (16%; p < 0.001). Multiple infections with at least two different HR HPV genotypes were observed in 22% of ICC. Given the high HPV 16/18 prevalence and taking into account possible production of crossneutralizing antibodies against other HPV types, HPV 16/18 L1 VLP vaccination would be expected to significantly reduce the burden of ICC in France.

Human papillomavirus genotype distribution in high grade cervical lesions (CIN 2/3) in France: EDITH study.

High grade cervical intraepithelial neoplasia (CIN 2/3) have a high potential to progress to invasive cervical cancer (ICC). Pap testing including follow-up and treatment of CIN 2/3 is currently the best prevention of ICC, but is associated with morbidity, namely obstetrical adverse effects and psychological distress. Human papillomavirus (HPV) is universally accepted as the necessary cause of ICC. The objective of the present study was to describe the type-specific prevalence of HPV in CIN 2/3 in France and hereby to locally estimate the potential benefit of an HPV 16/18 L1 virus-like particles (VLP) vaccine. A total of 493 formalin-fixed and paraffin-embedded CIN 2/3 specimens were analyzed. Medical records were examined for patient related data. HPV were genotyped with the INNO-LiPA assay allowing the detection of 24 HPV genotypes. The overall prevalence of LiPA detectable HPV was 98%. The most prevalent genotype was HPV 16 (62%) followed by HPV 31 (15%), 33 (12%), 52 (9%), 51 (8%), 58 (7%), 35 and 18 (4%). Multiple infection with at least two different high-risk (HR) HPV genotypes was observed in 26% of all specimens including 2.6% with HPV 16 and 18 multiple infections. The present study indicates that HPV 16 is by far the most common HPV type associated with CIN 2/3 in France. With an HPV 16 and 18 prevalence of 64%, HPV 16/18 L1 VLP vaccines would be expected to significantly reduce the burden associated with the management and treatment of CIN 2/3 in France.

Human papillomavirus genotype distribution in low-grade squamous intraepithelial lesions in France and comparison with CIN2/3 and invasive cervical cancer: the EDiTH III study.

OBJECTIVES: In the present study (EDiTH III study), the genotype-specific prevalence of HPV in low-grade squamous intraepithelial lesions (LSIL) was estimated to predict the potential benefit of HPV vaccination in France. This prevalence was compared to that previously reported in France in high-grade cervical intraepithelial neoplasia (CIN2/3, EDiTH II study) and squamous cell carcinoma (SCC, EDiTH I study) to identify the genotypes preferentially associated with a progression to malignancy. METHODS: 397 smears with LSIL diagnosis (Preservcyt) were retrospectively collected in different centres in France and genotyped using the INNO-LiPA assay allowing the detection of 24 HPV genotypes. RESULTS: HPV was found in 98% of cases. The most prevalent genotypes in LSIL in France were HPV 66 (25%), HPV 16 (21%), HPV 53 (18%), 51 (17%) and 52 (14%). HPV 16 and/or 18 were present in 28% and HPV 6, 11, 16 and/or 18 in 33% of LSIL. The highest SCC/LSIL prevalence ratios were shown for HPV 16, 33 and 18. CONCLUSIONS: With a 95% vaccine efficacy on CIN1 and theoretical vaccine coverage of 100%, HPV vaccination might prevent 27% (with a 16, 18 bivalent vaccine) and up to 32% (with a 6, 11, 16, 18 quadrivalent vaccine) of LSIL cases in France. In this study, LSIL related to HPV 16, 18 or 33 are at highest risk of progression to malignancy and thus could require a stringent surveillance. Conversely, anxiety and over-treatment could be avoided in women with low risk of progression.

Potential impact of the human papillomavirus vaccine on the incidence proportion of genital warts in French women (EFFICAE study): a multicentric prospective observational study.

UNLABELLED: Background The objective was to evaluate the effect of a HPV vaccination program on the incidence proportion of a proxy, genital warts (GW), in women in France. METHODS: The number of primary GW cases was prospectively recorded over two 4-month periods before (T0: Dec 2008 to March 2009) and after (T1: Dec 2011 to March 2012) a HPV vaccination program. A total of 160 gynaecologists participated in T0 and 189 in T1. Primary genital herpes (HSV) infection was used as a control. RESULTS: During T0, 39190 15- to 26 year-old women were seen, of whom 176 were diagnosed with GW (incidence proportion: 0.45%) and 155 with primary HSV infection (incidence proportion: 0.39%). During T1, 45628 females were seen [229 with GW (incidence proportion: 0.50%) and 202 with HSV (incidence proportion: 0.44%)]. In the 15-20 years age category, the incidence proportion of primary GW decreased from 0.41% to 0.30% (P=0.128) between T0 and T1, and the proportion of women newly diagnosed with primary genital herpes diseases slightly increased from 0.34% to 0.38% (P=0.620). In the 15-18 years age group, this decrease became significant (0.34% to 0.18%; P=0.048). CONCLUSIONS: A trend for a non-significant decreased incidence proportion of GW was observed in young women below 20 years who are more frequently vaccinated. This may be the result of HPV vaccination and suggests that a substantial increase in vaccine coverage could lead to a more pronounced decreased incidence proportion of GW in the future.

Disparities of perceptions and practices related to cervical cancer prevention and the acceptability of HPV vaccination according to educational level in a French cross-sectional survey of 18-65 years old women.

INTRODUCTION: We aimed to study the relationships between educational level, women's knowledge about cervical cancer (CC), and acceptance of HPV vaccination for their daughters. METHODS: We analysed data from a quantitative (self-administrated questionnaire) and qualitative (semi-structured interviews) cross-sectional study performed in 2008 among 1,229 French 18-65-year-old women recruited by general practitioners. Women were categorized into three educational level groups: low (LEL: 43.9%), medium (MEL: 33.4%) and high (HEL: 22.6%). RESULTS: Knowledge about CC and its prevention was lower among LEL women. In the 180 mothers of 14-18-year-old daughters (99 LEL, 54 MEL, 45 HEL), acceptance of HPV vaccine was higher in LEL (60.4%) and MEL (68.6%) than in HEL mothers (46.8%). Among LEL mothers, those who were favourable to HPV vaccination were more likely to be young (OR = 8.44 [2.10-34.00]), to be vaccinated against hepatitis B (OR = 4.59 [1.14-18.52]), to have vaccinated their children against pneumococcus (OR = 3.52 [0.99-12.48]) and to present a history of abnormal Pap smear (OR = 6.71 [0.70-64.01]). CONCLUSION: Although LEL women had poorer knowledge about CC and its prevention, they were more likely to accept HPV vaccination than HEL mothers.

State of the art: Could nursing mothers be vaccinated with attenuated live virus vaccine?

Recently two cases of vaccine-associated neurologic disease have been reported in breastfed infants whose mothers had received live attenuated yellow fever vaccine. These two cases have focused attention on the transmission of attenuated yellow fever vaccine virus from mother to infant via breastfeeding, and more generally of all other live attenuated viruses used to immunize nursing mothers. This article provides an overview of the rare literature on possible virus excretion in breast milk after vaccination of nursing mothers with live attenuated virus vaccine and on cases of infection via breastfeeding in infants whose mothers had been vaccinated postpartum. Before implementing postpartum vaccination in a nursing mother, the vaccinator needs to weigh up the risk of transmission to and adverse effects in the baby from live vaccine virus against the beneficial effects of the vaccine for the mother, taking into account her need for vaccination.

Human papillomavirus genotype distribution in tonsil cancers.

BACKGROUND: The incidence of tonsil cancers has increased in several countries. French data on HPV prevalence in tonsil cancers are scarce. The objective of this study was thus to assess the overall and type specific HPV prevalence in tonsil histological samples. METHODS: This French retrospective multicenter study involved 12 centres located throughout the country. Were included 185 histological samples collected from year 2000 to 2009 with a validated diagnosis of tonsil invasive carcinomas. HPV prevalence was studied according to gender, age and histological type of cancer. RESULTS: Overall HPV prevalence was 57% in tonsil cancers. Mean age of diagnosis was comparable in HPV positive tonsils cases (60 ± 11.2) and HPV negative tonsil cases (59 ± 9.6). HPV prevalence was significantly higher in female than in male cases (28/35 versus 78/150 in tonsil cases, respectively, P = 0.003). About 53% of tonsil cases were infected by a single HPV type. Only eight (4%) samples were infected by more than one HPV type. Among HPV positive samples, HPV 16 was found in 89% of tonsil cases. All other HPV types had prevalence below 5%. CONCLUSIONS: Our results indicate that HPV is common in tonsil carcinomas and emphasize the predominant role of HPV 16.

Human papillomavirus genotype distribution in oropharynx and oral cavity cancer in France--The EDiTH VI study.

BACKGROUND: The incidence of oropharyngeal cancers has gradually increased over the last decades. Recent studies suggest an association between human papillomavirus (HPV) infection and several head and neck cancers, especially oropharyngeal and oral cavity invasive carcinomas. OBJECTIVES: The objective was to assess the overall and type specific HPV prevalence in oropharyngeal and oral cavity carcinomas in France. STUDY DESIGN: Paraffin-embedded tumour specimens were retrospectively collected in 12 French centres and centrally tested for HPV detection and genotyping (INNO-LiPA assay). RESULTS: A total of 523 cases (77% males) were collected, among which 60% were oropharyngeal and 40% oral cavity carcinomas. The most frequent anatomical sites were tonsil (58.9%) and base of tongue (13.7%) for the oropharynx and floor of mouth (41.1%) and oral tongue (38.3%) for the oral cavity. Overall HPV prevalence was 46.5% in oropharyngeal carcinomas and 10.5% in oral cavity carcinomas and was higher in female than in male cases (63.5% vs 42.2% in oropharynx and 17.2% vs 8.0% in oral cavity). About 95% of HPV-positive cases were infected by a single HPV type. HPV 16 was the most prevalent type and was found in 89.7% and 95.5% of HPV-positive oropharyngeal and oral cavity carcinoma cases, respectively. All other HPV types had prevalence below 5%. CONCLUSIONS: Our results indicate that HPV is common among oropharyngeal and oral cavity carcinoma cases in France and emphasize the predominance of HPV 16. The potential benefit of HPV vaccination on the occurrence of head and neck carcinomas should be further evaluated.

[What should be known for the introduction of an HPV vaccine?]. / Quelles données épidémiologiques sont nécessaires pour la mise en place de la vaccination contre le papillomavirus humain?

CONTEXT: Genital human papillomavirus (HPV) infection is one of the most common sexually transmitted infections worldwide. Two HPV vaccines are now available in many countries: (i) the first vaccine is quadrivalent and indicated in the prevention of CIN 2/3, cervical cancers, VIN 2/3, VaIN 2/3 and genital warts associated with the HPV types 6, 11, 16 and 18, (ii) the second vaccine is bivalent and indicated in the prevention of CIN 2+ and cervical cancers associated with the HPV types 16 and 18. OBJECTIVES: To critically review all epidemiological aspects of the HPV infection and its relation with preneoplasic lesions of the cervix and cervical cancer to assist the relevant public health authorities to make plans for the introduction of HPV vaccines that have been recently commercialized. METHODS: Only articles published in English in peer reviewed journals have been selected in Date base PubMed (National Library of Medicine - National Institutes of Health) with Keywords HPV, risk factor, cervical cancer, CIN2/3, incidence, prevalence, transmission, prevention, genital cancer, HPV vaccines, screening. A critical review of most papers published during the last 10 years was made. The topics covered included: diseases caused by HPV, prevalence, incidence and transmission of HPV, risk factors for the acquisition of HPV, natural history of HPV infection, risk factors determining the progression from HPV to cancer, protective factors blocking the progression from infection to cancer (screening) and primary prevention of HPV by vaccines and other methods. The information was interpreted and summarized. RESULTS: It was concluded that HPV infection is one of the most common sexually transmitted infections, that it is the necessary cause of cervical cancer and the cause of other genital cancers and cancers of the upper aerodigestive tract. Fortunately most infections regress, but those infections that persist are the ones leading to cancer. Primary prevention by the introduction of prophylactic vaccines is the ideal means of preventing cervical cancer and other cancers associated to HPV. CONCLUSION: This review is to my knowledge, the most comprehensive and up-to date review to be published in French on HPV epidemiology and related diseases. It will be of great value to educate medical and paramedical personnel on HPV infection and associated diseases and it will be of great help to public health authorities and decision makers when they have to evaluate the convenience of introducing HPV vaccination in a given population.

Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir.

Mutations within the hepatitis B virus (HBV) polymerase gene conferring drug-resistance are selected during prolonged lamivudine (3TC) or adefovir dipivoxil (ADV) treatment. Because there is no other approved drug against HBV, treatments with 3TC or ADV are used either sequentially or in addition, depending on treatment response or failure. Considering the use of de novo or add-on 3TC+ADV bitherapy, we investigated the possibility of the emergence of an HBV strain harboring polymerase mutations conferring resistance to both 3TC (rtL180M+M204V) and ADV (rtN236T). We constructed the L180M+M204V+N236T mutant and determined its replication capacity and its susceptibility to different nucleos(t)ide analogs in transiently transfected hepatoma cell lines. The triple mutant replicates its genome in vitro, but less efficiently than either the wild-type (wt) HBV or L180M+M204V and N236T mutants. Phenotypic assays indicated that the L180M+M204V+N236T mutant is resistant to pyrimidine analogs (3TC, -FTC, beta-L-FD4C, L-FMAU). Compared with wt HBV, this mutant displays a 6-fold decreased susceptibility to ADV and entecavir and a 4-fold decreased susceptibility to tenofovir. Interferon alfa inhibited equally the replication of wt and L180M+M204V+N236T HBV. In conclusion, the combination of rtL180M+M204V and rtN236T mutations impairs HBV replication and confers resistance to both 3TC and ADV in vitro. These results suggest that the emergence of the triple mutant may be delayed and associated with viral resistance in patients treated with 3TC+ADV. However, other nucleos(t)ide analogs in development showed an antiviral activity against this multiresistant strain in vitro. This provides a rationale for the clinical evaluation of de novo combination therapies.