Braz J Med Biol Res. 2013 Jun;46(6):533-8. doi: 10.1590/1414-431X20132519.

Human papillomavirus infection among sexual partners attending a Sexually Transmitted Disease Clinic in Rio de Janeiro, Brazil.

Afonso LA, Rocha WM, Carestiato FN, Dobao EA, Pesca LF, Passos MR, Cavalcanti SM.

Universidade Federal Fluminense, Laboratório de Diagnóstico Virológico, Departamento de Microbiologia e Parasitologia, Instituto Biomédico, Niterói, RJ, Brasil.



Cervical cancer is a major source of illness and death among women worldwide and genital infection with oncogenic human papillomavirus (HPV) its principal cause. There is evidence of the influence of the male factor in the development of cervical neoplasia. Nevertheless, the pathogenic processes of HPV in men are still poorly understood. It has been observed that different HPV types can be found among couples. The objective of the present study was to investigate HPV infections in female patients (n = 60 females/group) as well as in their sexual partners and to identify the concordance of HPV genotypes among them. By using the polymerase chain reaction, we detected a 95% prevalence of HPV DNA in women with cervical intraepithelial neoplasia (CIN) compared to 18.3% in women with normal cervical epithelium, with a statistically significant difference (P < 0.001). The HPV DNA prevalence was 50% in male partners of women with CIN and 16.6% in partners of healthy women. In the control group (healthy women), only 9 couples were simultaneously infected with HPV, and only 22.2% of them had the same virus type, showing a weak agreement rate (kappa index = 0.2). Finally, we observed that HPV DNA was present in both partners in 30 couples if the women had CIN, and among them, 53.3% shared the same HPV type, showing moderate agreement, with a kappa index of 0.5. This finding supports the idea of circulation and recirculation of HPV among couples, perpetuating HPV in the sexually active population, rather than true recurrences of latent infections.

PMID: 23739745



Human Papillomavirus Infection: natural history, pathogenesis and biomarkers

Silvia Maria Baeta Cavalcanti

Human papillomavirus (HPV) infection causes one of the most prevalent sexually transmitted diseases (STDs) worldwide. The pathological and epidemiological features of HPV infection have been studied extensively in women due to the prevalence of this disease and its well-established link to cervical cancer (CC).

Our research group, after studying HPV for more than 24 years, have established several branches of research regarding HPV natural history, pathogenesis, epidemiological aspects and the study of risk factors associated with HPV and contributing to cancer development.

Regarding women infection, persistence and progression to cervical cancer, our studies focused on molecular epidemiology and biomarkers for cancer prognosis. These research line is based on the fact that high-risk human papillomavirus (hr-HPV) infection is necessary but not sufficient for cervical cancer development. Recently, P16INK4A gene silencing through hypermethylation have been proposed as an important cofactor in cervical carcinogenesis due to its tumor suppressor function. We aimed to investigate P16INK4A methylation status in normal and neoplastic epithelia and evaluate an association with HPV infection and genotype. HPV detection and genotyping were performed with 141 cervical samples from patients attending at Hospital Moncorvo Filho, Rio de Janeiro, through PCR and P16INK4A methylation by nested-methylation specific PCR (MSP). HPV frequency was 62.4% (88/141). The most common HPV were HPV16 (37%), HPV18 (16.3%), HPV33/45 (15.2%). An upward trend was observed concerning P16INK4A methylation and lesion degree: normal epithelia (10.7%), low grade lesions (20%), high grade (57.1%) and carcinoma (93.1%) (p<0.0001). A multivariate analysis was performed to evaluate an association between methylation, age, tobacco exposure, HPV infection and genotyping. A correlation was found concerning methylation with HPV infection (p<0.0001), hr-HPV (p=0.01), HSIL (p<0.0007) and malignant lesions (p<0.0001). Since viral infection and epigenetic alterations are related to cervical carcinoma, we suggest that P16INK4A methylation profile may be thoroughly investigated as a biomarker to identify patients at risk for cancer. (published in CARESTIATO, Fernanda Nahoum et al. AN UPWARD TREND IN DNA P16INK4A METHYLATION PATTERN AND HIGH RISK HPV INFECTION ACCORDING TO THE SEVERITY OF THE CERVICAL LESION. Rev. Inst. Med. trop. S. Paulo. 2013, vol.55, n.5, pp. 329-334. ISSN 0036-4665.

HPV infection is also an important concern in men due to the risk of transmission to women and the disease burden. As widely known, anogenital HPV in men may cause anogenital warts (AGWs), which, although benign, may constitute a psychosocial stigma leading to depression and compromised quality of life. The AGW recurrence rate is ~50%, generating multiple visits to health services, requiring different treatments, imposing a high social cost. It has also recently been associated with several cancers that affect men, including anal, oral, and some penile cancers. The incidence of HPV-related anal cancers is increasing in the general population, and is growing even faster among men who have sex with men (MSM) with human immunodeficiency virus (HIV) infection. Recently reported data suggest that HPV infection may increase the risk of HIV infection in men. One of our research focuses was to evaluate these infections and their consequent pathologies. The oncogenic potential of some HR-HPV types in the male anogenital tract was observed, with a high prevalence of oncogenic genotypes in high grade lesions, contrasting with the predominance of low risk types in benign pathologies. Passive anal sex was related to the prevalence of HR-HPV (HPV 16). HR-HPV and perianal lesions were significantly more frequent in HIV+ than in HIV– patients in our sample. We also found that high-grade lesions were more frequent and diagnosed at a significantly younger age in HIV+ than in HIV– patients. HPV infection clearly manifests earlier and is more severe in HIV+ patients than in the general population. An interesting result observed by us was the low variability in detected HPV genotypes (predominantly HPVs 6 and 11 and only one HPV53), despite the inclusion of HIV+ patients.

The detection of biomarkers for prognostic evaluation of HPV lesion progression to malignancy was also performed. The tumor suppressor protein p16INK4a has been studied and we observed a significant association between p16INK4a positivity and HPV 16 presence, indicating that p16INK4a may serve as a complementary biomarker for HR-HPV.

We think it is important to emphasize that anogenital HPV infection and related pathologies in men are associated with intangible economic losses and issues extending far beyond HPV transmission to women. For these reasons, we believe that experience and appropriate clinical examination remain the best tools for early diagnosis of malignant disease. We noted that patients, physicians in HIV clinics, and specialists attending MSM rarely conducted anogenital (self-)inspection or digital anal (self-)examination. However, we believe that a crucial difference between this early diagnosis and that of CC is the index of clinical suspicion, i.e., understanding the importance of screening. The need for cervical cytological screening in women is widely recognized in the medical community and the public, but the risk of anal carcinoma has not received such recognition. We observed that few men, especially HIV+ MSM, knew that they were at risk of developing anal carcinoma. Our experience indicates that the education of men (like women) in self-examination and risk factors, and the awareness of healthcare staff regarding the need for prevention, are effective and low-cost measures to prevent HPV lesion progression to invasive anal SCC. Furthermore, HPV infection is not frequently included in differential diagnoses, reflecting the need for clarification and clinical education.

In order to study the association of HPV and biomarkers in penile cancer,  a potentially mutilating disease, we extended our studies to evaluate its etiology and natural history.  Although its occurrence is relatively rare worldwide, penile cancer rates can be high in developing countries. A few studies have been conducted on the involvement of human papillomavirus (HPV) in penile carcinoma, which have found HPV present in 30-70% of penile malignant lesions, with a higher prevalence of HPV 16 and 18. It has been assumed that cofactors, such as Epstein-Barr virus (EBV) infections, may play a role in the progression of penile neoplasia. Hence, we studied HPV and EBV prevalence in 135 penile malignant lesions from Brazilian men through the use of MY09/11 polymerase chain reaction (PCR), type-specific PCR and restriction fragment length polymorphism analysis. HPV prevalence among the men tested was 60.7%. Of the men who tested positive, 27 presented with HPV 16 (29.7%), five with HPV 18 (5.5%), 21 with HPV 45 (23.1%) and nine with HPV 6 (9.9%). Regarding EBV positivity, 46.7% of the samples contained EBV DNA with EBV-1 as the most prevalent type (74.6%). More than 23% of the men were co-infected with both HPV and EBV, while 35% presented exclusively with HPV DNA and 20% presented only with EBV DNA. Penile carcinoma etiology has not been fully elucidated and the role of HPV and EBV infections individually or synergistically is still controversial. Hence, more studies are needed to determine their possible role in carcinogenesis. (published in  Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 107(1): 18-23,  2012. Prevalence of human papillomavirus and Epstein-Barr virus DNA in penile cancer cases from Brazil. Afonso LA et al.).

The most recent publication of our group had the goal to trace the spectrum of HPV types in Rio de Janeiro state, and HPV prevalence according to cytological status. A cross-sectional study population included 891 infected women whose cervical smears have been taken from 2003 to 2010. The overall HPV prevalence was 32.8% (292/891). The frequency of HPV infection to each cytological category was: normal (19%), ASCUS (35.7%), LSIL (80.4%), HSIL (78.3%), and CA (96.6%). Thirty-four different HPV genotypes have been identified. When we considered only the HPV positive samples, HPV 16 was found in 27.7%, HPV 6 in 10.3%, HPV 18 in 7.2%, and HPV  31 in 6.2% of the persons. The types 26, 35, 39, 51, s82  (high risk), 40, 42, 44, 54, 70, LX100 (low risk), and 32, 62, 69, 83, and 84 (undetermined), were found in frequency so low that we speculate if they have clinical importance. These types, except HPV 39, were not associated with severe neoplasias.

Finally, a research that we are beginning to conducted is related with self inoculation and presence of HPV among different body sites, trying to verify if its presence in oral tract may reflect its genital infection (cervical, penile and anal sites). Preliminary results showed that HPV DNA was detected in 64.5% of the samples from which 33.8% were positive for HPV on healthy oral mucosal. In 55.13% of cases, both sites were infected. Our study reached a prevalence concordance of genital types in 13 (23.6 %) cases. In such cases, 8 (84.6%) were HPV11 followed by 2 (15.4 %) of HPV 6 , 2 (15.4%) cases of mixed infection with HPV 6 and HPV 11 and 1 (7.6%) with HPV 45. Oral infection, separated by male and female, showed statistical significance in the chi-squared test (p = 0.0038), with markedly higher prevalence of oral infection on men. Our results indicate that oral infection does not predispose genital infection, but further studies are required to clarify the natural history of HPV infections, mainly in relation to oral infection.

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