Geographical distribution and risk association of human papillomavirus genotype 52-variant lineages.

Human papillomavirus (HPV) genotype 52 is commonly found in Asian cases of cervical cancer but is rare elsewhere. Analysis of 611 isolates collected worldwide revealed a remarkable geographical distribution, with lineage B predominating in Asia (89.0% vs 0%-5.5%; P(corrected) < .001), whereas lineage A predominated in Africa, the Americas, and Europe. We propose that the name "Asian lineage" be used to denote lineage B, to signify this feature. Preliminary analysis suggested a higher disease risk for lineage B, although ethnogeographical confounders could not be excluded. Further studies are warranted to verify whether the reported high attribution of disease to HPV52 in Asia is due to the high prevalence of lineage B.

Geographical distribution and oncogenic risk association of human papillomavirus type 58 E6 and E7 sequence variations.

Human papillomavirus (HPV) 58 accounts for a notable proportion of cervical cancers in East Asia and parts of Latin America, but it is uncommon elsewhere. The reason for such ethnogeographical predilection is unknown. In our study, nucleotide sequences of E6 and E7 genes of 401 HPV58 isolates collected from 15 countries/cities across four continents were examined. Phylogenetic relationship, geographical distribution and risk association of nucleotide sequence variations were analyzed. We found that the E6 genes of HPV58 variants were more conserved than E7. Thus, E6 is a more appropriate target for type-specific detection, whereas E7 is more appropriate for strain differentiation. The frequency of sequence variation varied geographically. Africa had significantly more isolates with E6-367A (D86E) but significantly less isolates with E6-203G, -245G, -367C (prototype-like) than other regions (p ≤ 0.003). E7-632T, -760A (T20I, G63S) was more frequently found in Asia, and E7-793G (T74A) was more frequent in Africa (p < 0.001). Variants with T20I and G63S substitutions at E7 conferred a significantly higher risk for cervical intraepithelial neoplasia grade III and invasive cervical cancer compared to other HPV58 variants (odds ratio = 4.44, p = 0.007). In conclusion, T20I and/or G63S substitution(s) at E7 of HPV58 is/are associated with a higher risk for cervical neoplasia. These substitutions are more commonly found in Asia and the Americas, which may account for the higher disease attribution of HPV58 in these areas.

Laboratory and clinical aspects of human papillomavirus testing.

Human papillomavirus (HPV) infection is associated with a wide spectrum of disease that ranges from self-limited skin warts to life-threatening cancers. Since HPV plays a necessary etiological role in cervical cancer, it is logical to use HPV as a marker for early detection of cervical cancer and precancer. Recent advances in technology enable the development of high-throughput HPV assays of different formats, including DNA-based, mRNA-based, high-risk group-specific and type-specific methods. The ultimate goal of these assays is to improve the accuracy and cost-effectiveness of cervical screening programs. HPV testing has several potential advantages compared to cytology-based screening. However, since the cancer to transient infection ratio is always low in the general population, HPV test results are bound to have a low positive predictive value that may subject women to unnecessary follow-up investigations. The wide-spread administration of prophylactic HPV vaccine will substantially decrease the incidence of cancer and precancer. This poses a number of challenges to cytology-based screening, and the role of HPV testing is expected to increase. Finally, apart from technical and cost-effectiveness considerations, one should also keep in mind the psycho-social impact of using sexually-transmitted agents as a marker for cancer screening.

Identification of human papillomavirus type 58 lineages and the distribution worldwide.

BACKGROUND: Human papillomavirus type 58 (HPV-58) accounts for a much higher proportion of cervical cancers in East Asia than other types. A classification system of HPV-58, which is essential for molecular epidemiological study, is lacking. METHODS AND RESULTS: This study analyzed the sequences of 401 isolates collected from 15 countries and cities. The 268 unique concatenated E6-E7-E2-E5-L1-LCR sequences that comprised 57% of the whole HPV-58 genome showed 4 distinct clusters. L1 and LCR produced tree topologies that best resembled the concatenated sequences and thus are the most appropriate surrogate regions for lineage classification. Moreover, short fragments from L1 (nucleotides 6014-6539) and LCR (nucleotides 7257-7429 and 7540-52) were found to contain sequence signatures informative for lineage identification. Lineage A was the most prevalent lineage across all regions. Lineage C was more frequent in Africa than elsewhere, whereas lineage D was more prevalent in Africa than in Asia. Among lineage A variants, sublineage A2 dominated in Africa, the Americas, and Europe, but not in Asia. Sublineage A1, which represents the prototype that originated from a patient with cancer, was rare worldwide except in Asia. CONCLUSIONS: HPV-58 can be classified into 4 lineages that show some degree of ethnogeographic predilection in distribution. The evolutionary, epidemiological, and pathological characteristics of these lineages warrant further study.

An Innovative Approach to Designing Digital Health Solutions Addressing the Unmet Needs of Obese Patients in Europe.

According to the World Health Organization (WHO), the worldwide obesity rate has tripled since 1975. In Europe, more than half of the population is overweight and obese. Around 2.8 million people die each year worldwide as a result of conditions linked to being overweight or obese. This study aimed to analyze the policies, approaches, and solutions that address the social and health unmet needs of obese patients, at different levels, in order to simulate the definition of an integrated approach, and to provide and share examples of innovative solutions supporting health promotion, disease prevention, and integration of services to improve the collaboration between the different health and care stakeholders involved across the country and in the lives of obese patients. A collaborative approach involving various levels of government and regional experts from different European countries was applied to identify, explore, and evaluate different aspects of the topic, from the innovation perspective and focusing on a European and a regional vision. Currently, people prefer more foods rich in fats, sugars, and salt/sodium than fruits, vegetables, and fiber. This behavior leads to a significant negative impact on their health-related quality of life. Changes in healthcare systems, healthy policy, and approaches to patient care and better implementation of the different prevention strategies between all the stakeholders are needed, taking advantage of the digital transformation of health and care. Such changes can support obese patients in their fight against an unhealthy lifestyle and at the same time reduce healthcare costs.

Low rate of oral human papillomavirus (HPV) infection in women screened for cervical HPV infection in Southern Italy: A cross-sectional study of 140 immunocompetent subjects.

Even though the natural history of cervical and oral human papillomavirus (HPV) infection has been investigated intensely, the possibility that HPV may infect both sites in the same subject is not well documented. This study investigated the frequency of concurrent oral and cervical HPV infection in southern Italian women, in the light of some selected socio-behavioral variables. One hundred forty women (mean age: 36 years), with known cervical HPV status, were analyzed for oral HPV. Age, smoking/drinking habits, clinical and socio-behavioral history were assessed by personal interviews. Oral mucosal cells were collected by oral brushing and HPV DNA was sought by the use of nested PCR amplification followed by direct DNA sequencing and the commercial assay INNOLiPA HPV Genotyping (Innogenetics N.V., Ghent, Belgium). The data were analyzed by using the chi-square test and a logistic regression (logit) model (P < 0.05 statistically significant). Oral HPV infection was detected in 2/140 (1.4%) cases, being present in 2/76 (2.6%) women with cervical HPV infection and 0/64 uninfected women (P = 0.19). A lack of type-specific concordance in the two patients with concurrent infection was observed. In the sample of population examined, HPV cervical infection does not seem to predispose to oral transmission, even in the presence of oral-genital sexual habits, thus suggesting the independence of infection at the two mucosal sites.

Prevalence of cervical human papillomavirus infection and types among women immigrated to Sicily, Italy.

We determined the prevalence of human papillomavirus (HPV) cervical infection and HPV genotypes among 115 women immigrating to Sicily (Italy), with regard to abnormal cytology and socio-behavioral characteristics in a cross-sectional, observational study. Information was collected with the help of cultural mediators/translators. HPV-DNA was assayed by the INNOLiPA HPV assay and a nested PCR/sequencing method. Sixty (52.2%) women came from sub-Saharan Africa and 55 (47.8%) from Eastern Europe. HPV infection was found in 55 (47.8%) women. The most frequent types were the oncogenic types HPV-16 (7.8%), HPV-18 and 51 (6.0% each), HPV-52 (5.2%), 31, 53, and 68 (4.3% each). Twenty-seven (23.5%) women had cytological abnormalities associated with HPV infection (p=0.04). Being single (OR = 2.98; 95%CI: 1.30-6.84) and parity (OR = 0.29; 95%CI: 0.12-0.65) were consistent predictors of HPV infection. Only 21 (18.2%) women returned to collect the results of their Pap and HPV tests. The high prevalence of HPV infection and oncogenic types among immigrant women make them a priority group for cervical cancer screening. Linguistically and culturally appropriate prevention efforts are needed to sensitize immigrant women regarding HPV-related issues and to conduct vaccine strategies for cervical cancer prevention.

Prevalence of genital human papilloma virus infection and genotypes among young women in Sicily, South Italy.

Infection with oncogenic human papilloma virus (HPV) types is a necessary cause of cervical cancer. This study assessed the prevalence of HPV infection and genotypes among 1,006 randomly selected women, ages 18 to 24 years, living in Sicily (south Italy). The overall HPV rate was 24.1% (95% confidence interval, 21.5-26.9). The most frequent types were HPV-16 (4.5%), HPV-53 (2.7%), and HPV-84 (2.6%). The prevalence of vaccine types HPV-6, HPV-11, and HPV-18 was 1.4%, 0.1%, and 1.3%, respectively. Cytologic abnormalities were uncommon (3.1%) and associated with HPV detection (P < 0.0001). The only risk factor for HPV infection was the number of sexual partners (women with 2-3 partners versus women with 1 partner: odds ratio, 3.86; 95% confidence interval, 2.45-6.09). Genital HPV infection is relatively high in young Italian women. The high prevalence of viral types other than vaccine types should be taken into account to ensure accurate postvaccine surveillance and early detection of a possible genotype replacement.

HPV genotype prevalence in cytologically abnormal cervical samples from women living in south Italy.

Human papillomavirus (HPV) infection is the commonest sexually transmitted infection, and high-risk HPV types are associated with cervical carcinogenesis. This study investigated: the HPV type-specific prevalence in 970 women with an abnormal cytological diagnosis; and the association of HPV infection and cervical disease in a subset of 626 women with a histological diagnosis. HPV-DNA was researched by nested PCR/sequencing and the INNOLiPA HPV Genotyping assay. The data were analysed by the chi-square test (p

Potential impact of a nonavalent HPV vaccine on HPV related low-and high-grade cervical intraepithelial lesions: A referral hospital-based study in Sicily.

While bivalent and quadrivalent HPV vaccines have been used for about 10 years, a nonavalent vaccine against HPV types 6/11/16/18/31/33/45/52 and 58 has been recently approved by FDA and EMA and is now commercially available. The objective of our study was to evaluate the potential impact of the nonavalent vaccine on HPV infection and related low- and high-grade squamous intraepithelial lesions (LSIL, HSIL), compared to the impact of the quadrivalent vaccine, in a female population living in Sicily (Italy). Low estimates of HPV vaccine impact were calculated as prevalence of HPV 6/11/16/18/31/33/45/52 and 58 genotypes, alone or in association, but excluding presence of other HPV types; high estimates were calculated as prevalence of HPV 6/11/16/18/31/33/45/52 and 58 genotypes alone or in association, in the presence of other HPV types. The nonavalent HPV vaccine showed increased impact, compared to the quadrivalent vaccine. Estimates of potential impact varied from 30.9% (low estimate) to 53.3% (high estimate) for LSIL, and from 56.9% to 81,0% for HSIL. The proportion of additional cases potentially prevented by the nonavalent vaccine was 14.4%-23.8% for LSIL, and 19.0%-32.8% for HSIL. The benefit of the nonavalent vaccine compared to the quadrivalent vaccine was more than 80% for both low and high impact estimates for LSIL and more than 50% for both low and high impact estimates for HSIL. The present study confirms that the switch from a first generation HPV vaccines to a nonavalent vaccine would increase the prevention of cervical HSIL in up to 90% of cases.

Atypical squamous cells of undetermined significance-favour reactive compared to atypical squamous cells of undetermined significance-favour dysplasia: association with cervical intraepithelial lesions and human papillomavirus infection.

BACKGROUND AND OBJECTIVES: The current study compared the cervical cytological sub-category "atypical squamous cells of undetermined significance-favour reactive (AFR)", recently recommended to be eliminated by the Bethesda system, to the sub-category "atypical squamous cells of undetermined significance-favour dysplasia (ASC-US)", in terms of prevalence of coexistent squamous intraepithelial lesions of either low-grade (LSIL) or high-grade (HSIL) and rate of human papillomavirus (HPV) infection. STUDY DESIGN: One hundred women with AFR and 100 with ASC-US were consecutively included in the study. All patients underwent colposcopy, followed by biopsy when necessary, and were screened for HPV infection by the combined use of Hybrid Capture II (DIGENE) and PCR with MY09/11 primers, the latter followed by direct sequencing of the amplifications products for HPV genotyping. RESULTS: LSIL were detected in 5.6% of AFR and 18.5% of ASC-US (p=0.00812), HSIL only in 4.3% of ASC-US. HPV infection was diagnosed in 11.2% of AFR and 38.0% of ASC-US (p=0.00003); high-risk HPV types (namely, HPV-16, -18, -31, -66, -67 and -70) were found in 6.7% of AFR and 22.8% of ASC-US (p=0.00239). Evidence of HPV infection in absence of SIL was proven in 7.1% of AFR and in 22.5% of ASC-US (p=0.00622). CONCLUSION: The association of AFR with SIL and high-risk HPV infection is low but not inexistent. Thus, to avoid the risk of leaving some high-risk AFR patients untreated or without follow-up, it could be proposed to keep AFR as a cytological category and to triage it by HPV testing, similarly to what has been already recommended for ASC-US.

Use of fuzzy neural networks in modeling relationships of HPV infection with apoptotic and proliferation markers in potentially malignant oral lesions.

To evaluate in oral leukoplakia the relationship between HPV infection and markers of apoptosis (bcl-2, survivin) and proliferation (PCNA), also conditionally to age, gender, smoking and drinking habits of patients, by means of Fuzzy neural networks (FNN) system 21 cases of oral leukopakia, clinically and histologically diagnosed, were examined for HPV DNA presence, bcl-2, survivin and PCNA expression. HPV DNA was investigated in exfoliated oral mucosa cells by nested PCR (nPCR: MY09-MY11/GP5-GP6), and the HPV genotype determined by direct DNA sequencing. All markers were investigated by means of standardised immunohistochemistry procedure. Data were analysed by chi-square test, crude OR and the 95% CI; in blindness, FNN was applied. HPV DNA was found in 8/21 OL (38.1%); survivin, PCNA, and tobacco smoking were associated in univariate analysis (p = 0.04) with HPV DNA status. HPV-18 was the most frequently detected genotype (6/8), followed by HPV-16 (2/8). FNN revealed that survivin and PCNA, both being expressed in all of OL HPV+ve, were associated with HPV infection. In conclusion, the FNN allowed to hypothesise a model of specific variables associated to HPV infection in OL. The relevance of survivin and PCNA suggest that they may be involved in HPV-mediated deregulation of epithelial maturation and, conversely, that HPV may have a role in the expression level of these two markers. FNN system seems to be an effective tool in the analysis of correlates of OL and HPV infection.

Facilitators and barriers HPV unvaccinated girls after 5 years of program implementation.

Understanding perceptions and characteristics of human papillomavirus (HPV) vaccinated and non-vaccinated girls can inform communication activities and vaccine delivery strategies. The purpose of this study was to evaluate knowledge and factors associated with HPV unvaccinated girls after five years of vaccination program implementation in Sicily, an Italian region with low vaccination coverage (<50.0%). A cross-sectional study was conducted through a questionnaire designed to assess knowledge and vaccination status of girls of 1997, 1998, 1999, and 2000 birth cohorts. The sample consisted of 350 girls who attended three high schools. Multivariable logistic regression analysis was conducted to examine predictors of vaccine refusal. The survey sample of girls shows that the 43.1% were HPV unvaccinated. A significant increased risk of being unvaccinated originated from the belief that the vaccine was too new (AdjOR = 21.08, CI95% = 2.57-172.97) and that it may cause cervical cancer (AdjOR = 4.36, CI95% = 1.26-15.07), along with having friends as a source of information on the vaccine (AdjOR = 3.67, CI95% = 1.63-8.25). A significant inverse association was observed between being unvaccinated and having Pediatrician/General practitioner as a source of information on HPV vaccine (AdjOR = 0.40, CI95% = 0.24-0.68). Many girls lack the fundamental knowledge about the HPV vaccine. The key issue is the promotion and implementation of information programs to raise awareness of girls on the importance of the vaccine.

HPV DNA and survivin expression in epithelial oral carcinogenesis: a relationship?

HPV has been thought to be involved in the development of several oral diseases, such as premalignant mucosal lesions and oral carcinoma. Survivin is a recently characterized IAP protein, which is abundantly expressed in most solid and haematological malignancies, but undetectable in normal adult tissues. Aim of this study was to investigate survivin expression and HPV presence in oral premalignant lesions and oral carcinoma. 47 samples of oral tissue including 11 squamous cell carcinomas (OSCC), 16 oral leukoplakias (OL) and 20 normal oral mucosa specimens, after investigation of HPV presence by nested PCR (consensus MY/GP primers) and viral genotype identification by direct sequencing were investigated by immunohistochemistry to detect survivin expression. Survivin expression was evident in 4/7 (57.1%) HPV+ and 4/4 (100%) HPV- OSCC, 6/7 (85.7%) HPV+ and 5/9 (55.5%) HPV- OL and in 0/20 (0%) control samples. Data showed high levels of survivin expression in HPV-positive SCCs, even if mean values were lower than HPV-negative ones, which in particular showed survivin expression in 100% of cases. Conversely, survivin expression was greater in HPV+ precancerous lesions than in HPV- ones. Our findings suggest that survivin may be involved in HPV- mediated deregulation during maturation of squamous epithelium through modulation of the apoptotic processes and, conversely, HPV may have a direct or indirect effect on the regulation of the survivin expression level. In particular, the results of this study suggest distinguishing between cancerous and precancerous oral lesions with respect to survivin expression when HPV infection is present. The most unfavourable behaviour is likely to be for the HPV- OSCC.

HPV DNA in clinically different variants of oral leukoplakia and lichen planus.

OBJECTIVES: Our objectives were to determine the prevalence of human papillomavirus (HPV) infection in oral leukoplakia (OL) and oral lichen planus (OLP) in comparison with that in healthy oral mucosa, also conditionally to age, gender, smoking, and drinking habits of patients, so as to investigate any possible association of HPV infection with a specific clinical variant of OL or OLP. STUDY DESIGN: We did research on HPV DNA in 68 cases of OL (homogeneous form [H] in 45 cases and nonhomogeneous form [non-H] in 23 cases), and in 71 cases of OLP (nonatrophic/erosive form [non-AE] in 27 cases, atrophic/erosive form [AE] in 44 cases). HPV DNA was investigated in exfoliated oral mucosa cells by nested PCR (nPCR: MY09-MY11/GP5-GP6) and the HPV genotype determined by direct DNA sequencing. RESULTS: HPV DNA was found in 17.6% of OL, in 19.7% of OLP, and in 5.6% of controls, with a statistically significant higher risk of HPV infection in both lesion groups (for OL: P=.01; Odds Ratio [OR]=3.64; 95% CI: 1.21-10.80; for OLP: P=.005; OR=4.17; 95% CI: 1.41-12.18). Demographic variables analysis showed that the only significant association was between HPV status and current smoking in OL patients (OR'=3.40; 95% CI: 1.0-11.59). HPV DNA was found in 20% of H OL and 13% of non-H OL, without any association with the clinical variant (P=.73; OR=0.60; 95% CI: 0.14-2.48). HPV DNA was found in 18.5% of non-AE OLP and 20.4% of AE OLP, without any significant association with the clinical variant (P=.84; OR=1.13; 95% CI: 0.335-3.816). HPV-18 was the most frequently detected genotype (9/12 and 10/14 of HPV-positive OL and OLP, respectively), followed by HPV-16 (2/12 OL and 2/14 OLP), HPV-33 (1/12 OL), HPV-31 (1/14 OLP), and HPV-6 (1/14 OLP). CONCLUSIONS: An increased risk of HPV infection was found in OL and OLP; however, no specific clinical variant of OL or OLP was noted to be associated with HPV infection. It is not possible to predict the likelihood of HPV infection from the clinical features of OL and OLP.

Human papillomavirus infection in couples undergoing in vitro fertilization procedures: impact on reproductive outcomes.

A prospective study was performed to assess the relationship between human papillomavirus (HPV) infection in 199 infertile couples and outcome of assisted reproductive technologies (ARTs). A highly statistically significant correlation between pregnancy loss rate (proportion of pregnancies detected by ß-hCG that did not progress beyond 20 weeks) and positive HPV DNA testing in the male partner of infertile couples, compared with HPV negatives, was observed (66.7% vs. 15%).

Oral human papillomavirus infection in women with cervical HPV infection: new data from an Italian cohort and a metanalysis of the literature.

A key issue in oral HPV infection is whether it can be associated with a genital HPV infection, or whether it can be considered as an independent event. This analysis evaluated the frequency and type-concordance of oral HPV infection in women with cervical HPV infection by means of: (i) a cross-sectional study on a sample (n=98) of Italian women; and (ii) a literature-based metanalysis, including the experimental study the subject of this Paper and nine other published studies (n=1017), which also examined the influence of oral sampling procedure (oral brushing vs oral rinse) and HIV status on oral HPV detection. The prevalence of oral HPV infection in the Italian study was 14.3% (95% CI: 7.4-21.2); the prevalence of type-concordance was 21.4% (95% CI: 0.0-43.6) and it was only marginally significant (P=0.05). The prevalence of oral HPV infection in the metanalysis was estimated as 18.1% (95% CI: 10.3-25.9); the prevalence of type-concordance was 27.0% (95% CI: 12.3-41.7), and it was statistically significant (P=0.002). The metanalysis also showed that the oral sampling procedure was not a determinant of HPV detection; however, HIV status increased the likelihood of oral HPV infection (HIV-positive vs negative: 27.2%; 95% CI: 22.1-32.2 vs 15.5%; 95% CI: 6.9-24.2) and type-concordance (HIV-positive vs negative: 46.8%; 95% CI: 34.7-58.9 vs 15.6%; 95% CI: 0.8-30.4). Oral HPV infection and type-concordance in women with cervical HPV infection are more prevalent than could be expected by chance; this finding is consistent with the notion of a degree of dependence of the oral site on the cervical site. Furthermore, oral HPV prevalence and type-concordance are influenced by immunity.

Controversies surrounding human papilloma virus infection, head & neck vs oral cancer, implications for prophylaxis and treatment.

Head & Neck Cancer (HNC) represents the sixth most common malignancy worldwide and it is historically linked to well-known behavioural risk factors, i.e., tobacco smoking and/or the alcohol consumption. Recently, substantial evidence has been mounting that Human Papillomavirus (HPV) infection is playing an increasing important role in oral cancer. Because of the attention and clamor surrounding oral HPV infection and related cancers, as well as the use of HPV prophylactic vaccines, in this invited perspective the authors raise some questions and review some controversial issues on HPV infection and its role in HNC, with a particular focus on oral squamous cell carcinoma. The problematic definition and classification of HNC will be discussed, together with the characteristics of oral infection with oncogenic HPV types, the frequency of HPV DNA detection in HNC, the location of HPV-related tumours, the severity and prognosis of HPV-positive HNC, the diagnosis of oral HPV infection, common routes of oral infection and the likelihood of oro-genital HPV transmission, the prevention of HPV infection and novel therapeutic approaches.