Human papillomavirus genotype distribution in genital warts among women in Harare-Zimbabwe.

This study aimed to determine the prevalence of HPV genotypes in genital warts among women in Harare, Zimbabwe. Women aged 18-45 years attending gynaecology and genitourinary clinics with a clinical diagnosis of genital-warts were recruited. HPV-DNA was extracted from tissue biopsies. HPV-DNA testing and typing was done by Southern Dot Blot Hybridisation. A hundred samples from 100 women were analysed. Median age of participants was 30.3 years (range 18-45 years). Seventy-eight percent of participants were HIV infected. HPV prevalence was 98%. Low risk genotypes predominated at 86% prevalence. The most prevalent genotypes were 11 (47%), 6 (42%) and 16 (14%). This is the first study on HPV genotype distribution among women with genital warts in Zimbabwe. The high prevalence of HR-HPV 16 in clinically benign lesions shows that warts should have histological analysis to exclude pre-malignancy and malignancy.Impact statementWhat is already known on this subject? Genital warts (GWs), also known as condylomata acuminata (EAC), are a clinical manifestation of persistent infection with 'low risk' or non-oncogenic HPV genotypes. HPV 6 and 11 are examples of low risk genotypes, and both are associated with 90% of GWs. Data on HPV genotypes causing genital warts in the population under study are scarce.What do the results of this study add? A high prevalence (98%) of HPV DNA in genital warts, confirms that the biopsied lesions were HPV related. Over and above the high prevalence of low risk HPV 11 (47%) and HPV 6 (42%), the women had 14% prevalence of HPV 16, an oncogenic genotype, in genital warts. Seventy-eight percent of the participants were HIV infected. The HIV infected women had a 33.3% prevalence of HR-HPV as compared to the 15.8% prevalence in the HIV uninfected women.What are the implications of these findings for clinical practice and/or further research? The population under study will benefit more if an HPV vaccine that includes anti-HPV 6 and 11 is used. The high prevalence of the HR-HPV in apparently benign lesions shows that warts should have histological analysis to exclude vulvar cancer and vulvar intraepithelial neoplasia. All women presenting with genital warts should be offered an HIV test.

Carcinogenesis Associated with Human Papillomavirus Infection. Mechanisms and Potential for Immunotherapy.

Human papillomavirus (HPV) infection is responsible for approximately 5% of all cancers and is associated with 30% of all pathogen-related cancers. Cervical cancer is the third most common cancer in women worldwide; about 70% of cervical cancer cases are caused by the high-risk HPVs (HR HPVs) of genotypes 16 and 18. HPV infection occurs mainly through sexual contact; however, viral transmission via horizontal and vertical pathways is also possible. After HPV infection of basal keratinocytes or ecto-endocervical transition zone cells, viral DNA persists in the episomal form. In most cases, infected cells are eliminated by the immune system. Occasionally, elimination fails, and HPV infection becomes chronic. Replication of HPVs in dividing epithelial cells is accompanied by increased expression of the E6 and E7 oncoproteins. These oncoproteins are responsible for genomic instability, disruption of the cell cycle, cell proliferation, immortalization, and malignant transformation of HPV-infected cells. Besides, E6 and E7 oncoproteins induce immunosuppression, preventing the detection of HPV-infected and transformed cells by the immune system. HPV integration into the genome of the host cell leads to the upregulation of E6 and E7 expression and contributes to HPV-associated malignization. Prophylactic HPV vaccines can prevent over 80% of HPV-associated anogenital cancers. The vaccine elicits immune response that prevents initial infection with a given HPV type but does not eliminate persistent virus once infection has occurred and does not prevent development of the HPV-associated neoplasias, which necessitates the development of therapeutic vaccines to treat chronic HPV infections and HPV-associated malignancies.

Seroprevalence of HPV 6, 11, 16 and 18 and correlates of exposure in unvaccinated women aged 16-64 years in Puerto Rico.

BACKGROUND: To understand risk factors for HPV exposure in Puerto Rican women, we evaluated HPV 6, 11, 16, and 18 serology in women aged living in the San Juan metropolitan area. METHODS: As part of a cross-sectional study, a population-based sample of 524 HPV unvaccinated Hispanic women ages 16-64 years completed face-to-face and computer assisted interviews and provided blood and self-collected anal and cervical specimens. Serology used multiplex virus-like particle based-IgG ELISA and HPV DNA was detected with L1-consensus PCR. RESULTS: 32% and 47% were seropositive to HPV types included in the bivalent (16/18) and quadrivalent (6/11/16/18) vaccines, respectively. Type-specific seroprevalence was HPV6 - 29%, HPV11 - 18%, HPV16 - 23%, and HPV18 - 17%; seroprevalence was high in the youngest age-group (16-19: 26-37%). HPV seropositivity was associated with having ≥ 3 lifetime sexual partners (OR=2.5, 95% CI=1.7-3.9) and detection of anogenital HPV DNA (OR=1.8, 95% CI=1.2-2.6). CONCLUSIONS: The high cumulative exposure of HPV vaccine types 6/11/16/18 in this Hispanic population was influenced by factors related to HPV exposure through sexual behavior. High seroprevalence in the youngest age-group indicates early age of exposure to HPV in Puerto Rico, highlighting the need for HPV vaccination starting prior to age 16.

HPV vaccination of immunocompromised hosts.

It is well-established that immunocompromised people are at increased risk of HPV-related disease compared with those who are immunocompetent. Prophylactic HPV sub-unit vaccines are safe and immunogenic in immunocompromised people and it is strongly recommended that vaccination occur according to national guidelines. When delivered to immunocompromised populations, HPV vaccines should be given as a 3-dose regimen.

Factors Associated with HPV Vaccine Awareness in a Population-Based Sample of Hispanic Women in Puerto Rico.

OBJECTIVES: The objective of this study was to investigate the factors associated with HPV awareness among women aged 16 to 64 years, among underserved minority Hispanic women living in Puerto Rico. METHODS: A population-based, cross-sectional sample of 566 women, ages 16 to 64 years, living in the San Juan metropolitan area were surveyed regarding sexual behavior, HPV knowledge, and HPV vaccine uptake. Data was analyzed using descriptive statistics and multivariate logistic regression. RESULTS: Overall, 64.8 % of the women in the sample had heard about the HPV vaccine. Among those in the recommended catch-up vaccination age range (16-26 years, n = 86), 4.7 % had received at least one dose of the HPV vaccine. Of those aware of the availability of the HPV vaccine, most had learned about it through the media, whereas, only 39.6 % had learned about it from a physician. Multivariate logistic regression analysis showed that HPV awareness (OR 8.6; 95 % CI 5.0-14.8) and having had an abnormal Pap smear (OR 2.0; 95 % CI 1.2-3.4) were associated with HPV vaccine awareness (p < 0.05). CONCLUSION: HPV vaccine awareness among Hispanic women in the San Juan metropolitan area of Puerto Rico continues to be low. Strong recommendations from physicians and participation in HPV vaccine educational efforts are essential if the rate of HPV vaccination is to increase in the targeted population. Compared to the USA, and to their US Hispanic counterparts, a health disparity with regard to HPV vaccine awareness and coverage is evident in Puerto Rico; targeted action to deal with this disparity is urgently needed.

Human papillomavirus-related oropharyngeal cancer in the HIV-infected population.

Human papillomavirus (HPV) is a common sexually transmitted virus and an important etiologic factor in head and neck cancers. HIV-infected individuals are at increased risk of developing oropharyngeal cancers (OPC) compared with the general population. HPV-positive OPC are also increasingly a significant cause of morbidity and mortality for HIV-infected individuals in the era of effective combination antiretroviral therapy. The epidemiology and natural history of oral HPV infection have not been well established, but it appears that oral HPV infection is less common than anal infection, and more common among HIV-infected persons than the general population. Prevention of OPC is therefore increasingly important in HIV-infected individuals. Although not demonstrated in randomized controlled trials, HPV vaccination may prevent oral HPV infection as well. The focus of organized HPV cancer prevention programs should include prophylactic HPV vaccination to reduce the burden of high-risk HPV and low-risk HPV types who have not yet been exposed.

Prevalence, genotyping, and correlates of anogenital HPV infection in a population-based sample of women in Puerto Rico.

BACKGROUND: Oncogenic HPV infection is associated to anogenital cancer. We estimate the prevalence and correlates of anogenital HPV infection among a population-based sample of women aged 16-64 years living in the metropolitan area of Puerto Rico. METHODS: 564 women completed face-to-face and computer assisted interviews and self-collected anal and cervical specimens. HPV DNA testing used MY09/MY11 consensus HPV L1 primers and beta-globin as an internal control for sample amplification. Positive specimens were typed by dot-blot hybridization. RESULTS: Weighted prevalence of cervical, anal, and cervical/anal co-infection was 29.4%, 38.6%, and 17.1%, respectively. The commonest oncogenic HPV types detected in the cervix and anus were: 68 (8% vs. 7%) and 16 (5.5% vs. 5.1%), correspondingly. Having ≥3 lifetime sexual partners (OR: 2.3; 95% CI: 1.5-3.5) and last year anal intercourse (OR: 1.6; 95% CI: 1.1-2.5) increased the odds of anogenital HPV infection. Cervical infection was independently associated to anal infection (OR: 3.0; 95% CI: 2.0-4.6). CONCLUSIONS: Similar to others, our results confirm the burden of anogenital HPV infection in women and its relationship with sexual behavior. As vaccination increases, future studies should monitor changing trends in HPV infection in this population, and the relationship between anal and cervical HPV-related disease.

Immunogenicity and safety of the 9-valent HPV vaccine in men.

OBJECTIVES: This study was designed to evaluate the immunogenicity and tolerability of a prophylactic 9-valent HPV (types 6/11/16/18/31/33/45/52/58) VLP (9vHPV) vaccine in young men 16-26 years of age in comparison to young women 16-26 years of age (the population that was used to establish 9vHPV vaccine efficacy). Safety and immunogenicity data from this study will be used to bridge 9vHPV vaccine efficacy findings in 16-26 year old women to 16-26 year old men. METHODS: This study enrolled 1106 heterosexual men (HM) and 1101 women who had not yet received HPV vaccination. In addition, 313 men having sex with men (MSM) were enrolled and were evaluated separately for immunogenicity because previous results showed that antibody responses to quadrivalent HPV (types 6/11/16/18) VLP (qHPV) vaccine were lower in MSM than in HM. All subjects were administered a 3-dose regimen (Day 1, Month 2, Month 6) of 9vHPV vaccine. Serum samples were collected for anti-HPV assays. Safety information was collected for ∼ 12 months. RESULTS: The geometric mean titers (GMTs) for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 for HM were non-inferior to those of women at Month 7. For all vaccine HPV types, Month 7 GMTs were numerically lower in MSM than in HM. Over 99.5% of subjects were seropositive at Month 7 for each vaccine HPV type. Administration of 9vHPV vaccine to both 16-26 year old men and women was generally well tolerated. CONCLUSIONS: These results support bridging the efficacy findings with 9vHPV vaccine in young women 16-26 years of age to men 16-26 years of age.

Anal human papillomavirus infection in a street-based sample of drug using HIV-positive men.

HIV facilitates an increase in human papillomavirus (HPV)-associated conditions. HIV-positive men living in a substance use context in Los Angeles, USA, were recruited using respondent-driven sampling, completed a questionnaire and had biological samples including an anal HPV swab taken. A total of 316 evaluable men were enrolled in the study. The prevalence of any HPV, high-risk (HR) infection and multiple-type infection was highest for men who have sex with men (MSM) (93.9%, 64.6% and 29.7%, respectively). When any HPV and HR-HPV prevalence in all men was stratified by age, the youngest group had 100% and 68.2% prevalence, respectively, with similarly high rates maintained up to age 49 years. The individual's use of alcohol, marijuana, cocaine, methamphetamine or heroin was not significantly associated with anal HPV detection. In this marginalized population, high prevalence rates of anal HPV and HR-HPV occurring over a wide age range may increase the individual's risk for anal dysplasia and anal cancer.

Factors associated with prevalent abnormal anal cytology in a large cohort of HIV-infected adults in the United States.

BACKGROUND: The prevalence of and risk factors for abnormal anal cytology among men and women with human immunodeficiency virus (HIV) infection have not been extensively investigated. METHODS: The Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN study) is a prospective cohort study of HIV-infected patients in 4 US cities. Baseline questionnaires were administered and anal samples for cytology and human papillomavirus (HPV) detection and genotyping were collected. RESULTS: Among 471 men and 150 women (median age, 41 years), 78% of participants were receiving combination antiretroviral therapy, 41% had a CD4(+) cell count of ≥500 cells/µL, and 71% had an HIV RNA viral load of <400 copies/mL. The anal cytology results were as follows: 336 participants (54%) had negative results, 96 participants (15%) had atypical squamous cells, 149 participants (24%) had low-grade squamous intraepithelial lesions, and 40 participants (6%) had high-grade squamous intraepithelial lesions. In a multivariate analysis, abnormal anal cytology was associated with number of high-risk and low-risk HPV types (adjusted odds ratio [AOR] for both, 1.28; P < .001), nadir CD4(+) cell count of <50 cells/µL (AOR, 2.38; P = .001), baseline CD4(+) cell count of <500 cells/µL (AOR, 1.75; P = .004), and ever having receptive anal intercourse (AOR, 2.51; P < .001). CONCLUSION: HIV-infected persons with multiple anal HPV types or a nadir CD4(+) cell count of <50 cells/µL have an increased risk for abnormal anal cytology.

Esophageal verrucous carcinoma arising from hyperkeratotic plaques associated with human papilloma virus type 51.

Esophageal verrucous carcinoma is a rare variant of esophageal squamous cell carcinoma. We report a case of esophageal verrucous carcinoma associated with human papilloma virus (HPV) type 51. The patient had long-standing dysphagia and odynophagia, and white esophageal plaques showing hyperkeratosis on biopsy. At repeat endoscopy, the esophagus was covered with verrucous white plaques and areas of nodular mucosa with white fronds, with a distal 10-cm smooth mass protruding into the lumen. Biopsies demonstrated an atypical squamoproliferative lesion but no frank malignancy. HPV type 51 DNA was detected in endoscopic biopsy specimens by polymerase chain reaction. Because the size of the lesion favored an underlying verrucous carcinoma, our patient underwent minimally invasive esophagectomy with gastric pull-up and cervical anastomosis. The pathologic diagnosis was a well-differentiated esophageal verrucous carcinoma. One year after esophagectomy, the patient feels well and is free of disease. Although HPV DNA was not detected in the cancer tissue obtained at surgery, our case suggests an association between HPV type 51 and esophageal verrucous carcinoma. The clinical evolution in this case highlights the importance of endoscopic surveillance in patients with exuberant esophageal hyperkeratosis, and of definitive surgical resection when malignancy is suspected even if frank malignancy is not demonstrated on superficial biopsies.

Prevalence, distribution and correlates of endocervical human papillomavirus types in Brazilian women.

We determined the prevalence, distribution and correlates of human papillomavirus (HPV) types in 386 mixed-income, sexually active women in São Paulo, Brazil. Endocervical samples were tested for HPV DNA with L1 primers MY09 and MY11; negative and indeterminate samples were retested using GP 5+/6+ consensus primers. HPV was detected in 35% of all women; high-risk/probable high-risk types in 20%; low-risk types in 7%; and an indeterminate type in 10%. Twenty-five HPV types were found overall: 17 (probable) high-risk types and eight low-risk types. Approximately one-third (29%) of women with HPV infection were positive for type 16 or 18 and 36% were positive for types 6, 11, 16 or 18. The presence of (probable) high-risk HPV was associated with younger age, more lifetime sex partners and abnormal vaginal flora. Additional studies mapping the distribution of HPV types worldwide are necessary to prepare for vaccination programmes and direct future vaccine development.

S100A8 triggers oxidation-sensitive repulsion of neutrophils.

The inflammatory response to tissue injury is a multi-faceted process. During this process, neutrophils migrate in the extravascular spaces, directed to the site of injury by chemical gradients generated by chemotactic molecules. S100A8, a protein associated with a wide variety of inflammatory conditions, is heavily over-expressed in association with inflammation. We hypothesized that human S100A8 possesses neutrophil-repelling properties that result in an anti-inflammatory effect in vivo. The chemotactic activity of S100A8 on neutrophils was tested in Transwell chemotaxis assays. Analysis of the data indicates that S100A8 causes a repulsion of peripheral neutrophils, an activity that S100A8 loses upon its oxidation. Using a mutant of S100A8 resistant to oxidation and consistent with the in vitro findings, we demonstrated that S100A8 causes a strong anti-inflammatory effect in the rat air-pouch model of inflammation in vivo. These data highlight a naturally occurring novel anti-inflammatory pathway and provide potential molecular targets for the development of novel anti-inflammatory therapeutics. Abbrevations: ethylene diamine tetraacetic acid (EDTA); limulus amoebocyte lysate assay (LAL); pertussis toxin (PTX); forward scatter (FSC); Interleukin-8 (IL-8); formyl-Met-Leu-Phe (fMLP); monocyte chemotactic protein 1 (MCP1).

Biology of HPV in HIV infection.

HIV-positive men and women are at increased risk of anogenital and oral HPV infection. The risks for HPV-associated high-grade intra-epithelial neoplasia (IN) and cancer are also increased. The prevalence of oral, anal, and cervical HPV infection in HIV-positive individuals compared with HIV-negative individuals increases with progressively lower CD4+ levels, as does incident high-grade IN. In contrast to IN, development of cancer is not related to lower CD4+ level. With increasing grades of IN and cancer, the proportion of tissues with copy-number abnormalities (CNA) increases, with one of the most common genetic changes being amplification of chromosome 3q. The presence of CNA is associated with the integration of HPV DNA into the host genome, with loss of HPV E2 and/or E2 rearrangement. This suggests a link between CNA and increased HPV-induced chromosomal instability mediated through de-repressed E6 and E7 expression consequent to loss of functional E2 protein. In addition, epigenetic changes occur with increasing frequency in high-grade IN and cancer, such as hypermethylation leading to down-regulation of potential tumor suppressor genes. Analysis of these data together suggests that immune suppression plays a more prominent role in the earlier stages of HPV-associated disease, up to and including incident high-grade IN. Persistent high-grade IN and development of cancer may be more strongly related to the cumulative effect of HPV-associated genetic instability and the resulting host genetic changes. There are few data to suggest a direct role for HIV in the pathogenesis of HPV-associated neoplasia, but HIV-associated attenuation of HPV-specific immune responses may allow for persistence of high-grade IN and sufficient time for accumulation of genetic changes that are important in progression to cancer.

Effect of highly active antiretroviral therapy on the natural history of anal squamous intraepithelial lesions and anal human papillomavirus infection.

The effect of highly active antiretroviral therapy (HAART) on the natural history of anal squamous intraepithelial lesions (ASIL)-the likely anal cancer precursor-and anal human papillomavirus (HPV) infection is unknown. ASIL severity and level of anal HPV DNA were evaluated among HIV-positive men who have sex with men (MSM) for at least 6 months before initiation of HAART. The results were compared with those from a 6-month period after initiation of HAART. Anal swabs for cytology and HPV studies were obtained, followed by high-resolution anoscopy and biopsy. Among men whose most severe pre-HAART diagnosis was atypical squamous cells of undetermined significance or low-grade ASIL, 18% (confidence interval [CI], 6-31%, 7 of 38) progressed and 21% (CI, 8-34%, 8 of 38) regressed 6 months after starting HAART. Seventeen percent (CI, 0-38%, 2 of 12) of study subjects who began with a normal diagnosis developed ASIL. Only 4% (CI, 0-10%, 1 of 28) of study subjects with high-grade ASIL regressed to normal. There was no reduction in the proportion of study subjects who tested positive for HPV DNA or HPV DNA levels after HAART initiation. The ASIL and HPV data were similar to those of the pre-HAART comparison period. These results indicate that HAART has little effect on either ASIL or HPV in the first 6 months after HAART initiation.

Determinants of HIV-1 shedding in the genital tract of women.

BACKGROUND: Plasma HIV-1 RNA concentration has been the best predictor for risk of heterosexual and perinatal transmission. However, direct contact with HIV-1 present locally in the genital tract might be necessary for transmission. We aimed to assess the relation between HIV-1 shedding (RNA or culturable virus) in female genital secretions and other factors that might affect HIV-1 shedding. METHODS: This was a cross-sectional study within the Women's Interagency HIV Study (WIHS), a prospective longitudinal cohort study of HIV-infected women. We enrolled 311 HIV positive women from Jan 30, 1997 to July 1, 1998. We did clinical assessments, cultured HIV-1, and measured RNA in peripheral blood mononuclear cells (PBMC) and genital secretions. We compared the results with univariate and multivariate analyses. Presence of HIV-1 RNA or culturable virus in genital secretions was defined as HIV-1 shedding. FINDINGS: HIV-1 RNA was present in genital secretions of 57% (152/268) of women whereas infectious virus was detected only in 6% (17/271). Genital tract HIV-1 shedding was found in 80% (130/163) of women with detectable plasma RNA and 78% (116/148) of women with positive PBMC cultures. 33% (27/83) of women with less than 500 copies/mL plasma RNA and 39% (35/90) of those with negative PBMC cultures also had genital tract shedding. INTERPRETATION: Plasma RNA concentration, both qualitatively and quantitatively, was the most important factor in predicting genital HIV-1 shedding, even among women receiving potent antiretroviral therapy. However, HIV-1 shedding did occur in women with less than 500 copies/mL plasma HIV-1 RNA. This finding suggests that a separate reservoir of HIV-1 replication may exist in some women.

The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women.

OBJECTIVE: Cervical intraepithelial neoplasia (CIN), a common condition among HIV-infected women, has been linked to HIV load and immune status. Highly active antiretroviral therapy (HAART) improves immunologic and virologic status. This study was undertaken to determine the relationship between HAART use and CIN. DESIGN: Cohort study. The Women's Interagency HIV Study (WIHS) in five cities in the USA (Bronx/Manhattan, New York; Brooklyn, New York; Chicago, Illinois; Los Angeles, California; San Francisco Bay area, California; Washington, District of Columbia). METHODS: HIV-infected women were followed every 6 months with Papanicolaou smears and cervicovaginal lavage for human papillomavirus (HPV) DNA testing. To characterize exposures that changed over time and to capture the dynamic nature of cytologic changes, Papanicolaou smear findings from each participant's consecutive visits were defined as a pair. We determined the proportion of all pairs that exhibited either regression or progression, according to HAART exposure, HPV results and Papanicolaou smear status. As participants could contribute multiple pairs, inferences were based on robust methods to adjust for correlated observations. RESULTS: Women with persistent HPV infection were more likely to have progression of their lesions. After adjustment for CD4 cell count and Papanicolaou smear status, women on HAART were 40% (95% confidence interval, 4-81%) more likely to demonstrate regression and less likely (odds ratio, 0.68; 95% confidence interval, 0.52-0.88) to demonstrate progression CONCLUSIONS: HAART altered the course of HPV disease in HIV-infected women, reducing progression and increasing regression. As HPV disease is a common sex-specific manifestation of HIV disease this effect of HAART would be a major additional benefit from this modality of therapy.