Kai Li Liaw

A Prospective Study of Human Papillomavirus (HPV) Type 16 DNA Detection by Polymerase Chain Reaction and Its Association with Acquisition and Persistence of Other HPV Types

Human papillomavirus (HPV)-16 causes about half the cases of cervical cancer worldwide and is the focus of HPV vaccine development efforts. Systematic data are lacking as to whether the prevention of HPV-16 could affect the equilibrium of infection with other HPV types and thus alter the predicted impact of vaccination on the occurrence of cervical neoplasia. Therefore, the associations of HPV-16 detection with subsequent acquisition of other HPV types and with the persistence of concomitantly detected HPV types were examined prospectively among 1124 initially cytologically normal women. Preexisting HPV-16 was generally associated with an increased risk for subsequent acquisition of other types. HPV-16 did not affect the persistence of concomitant infections, regardless of type. These findings suggest that the prevention or removal of HPV-16 is not likely to promote the risk of infection with other types, a theoretical concern with current vaccination efforts.

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 ≥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. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1611–22)

The Burden of Genital Warts: A Study of Nearly 70,000 Women from the General Female Population in the 4 Nordic Countries

OBJECTIVE To assess the burden and correlates of genital warts in women. METHODS We conducted a population-based cross-sectional study in 69,147 women (18-45 years of age) randomly chosen from the general population in Denmark, Iceland, Norway, and Sweden. Information on clinically diagnosed genital warts and lifestyle habits was collected using a questionnaire. RESULTS Overall, 10.6% reported ever having had clinically diagnosed genital warts. In addition, 1.3% reported having experienced genital warts within the past 12 months. The cumulative incidence for different birth cohorts, estimated on the basis of age at first diagnosis of genital warts, increased with each subsequent younger birth cohort (P<.01). The lifetime number of sex partners was strongly correlated with a history of genital warts (odds ratio for > or =15 partners vs. 1 partner, 9.45 [95% confidence interval, 7.89-11.30]). The likelihood of reporting genital warts also increased with a history of sexually transmitted disease, use of hormonal contraceptives, use of condoms, smoking, and higher education. CONCLUSIONS The data suggest that 1 in 10 women in the Nordic countries experience genital warts before the age of 45 years, with an increasing occurrence in younger birth cohorts. These data are important for developing and evaluating strategies (e.g., human papillomavirus [HPV] vaccination) to control and prevent HPV infection and disease in the population.

Prevalence of and Risk Factors for Human Papillomavirus (HPV) Infection Among HIV-Seronegative Men Who Have Sex With Men

BACKGROUND We examined the baseline prevalence of penile, scrotal, perineal/perianal, and intra-anal human papillomavirus (HPV) infection in human immunodeficiency virus (HIV)-seronegative men who have sex with men (MSM). METHODS Data were analyzed from 602 MSM aged 16-27 years with ≤ 5 lifetime sexual partners. Serum samples were tested for antibodies to HPV6/11/16/18. Swab samples were collected separately from several anogenital areas for detection of HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59 DNA. RESULTS The prevalence of any tested HPV type was 18.5% at the penis, 17.1% at the scrotum, 33.0% at the perineal/perianal region, 42.4% in the anal canal, and 48.0% at any site. Overall, 415 MSM (69.7%) were negative to HPV 6, 11, 16, and 18 at enrollment by both serology and DNA detection. Men residing in Europe and Latin America had significantly increased risk of HPV infection at external genital sites and the anal canal compared to men from Australia. Tobacco use and greater number of lifetime sexual partners was associated with higher HPV infection prevalence. CONCLUSIONS The prevalence of HPV infection is high among young sexually active MSM, with the anal canal being the most common site of infection. Lifetime number of sexual partners was the most important modifiable risk factor for anogenital HPV infection.

Persistence of Type-Specific Human Papillomavirus Infection and Increased Long-term Risk of Cervical Cancer

BACKGROUND Human papillomavirus (HPV) persistence is the pivotal event in cervical carcinogenesis. We followed a large-scale community-based cohort for 16 years to investigate the role of genotype-specific HPV persistence in predicting cervical cancer including invasive and in situ carcinoma. METHODS At the baseline examination in 1991-1992, 11,923 participants (aged 30-65 years) consented to HPV testing and cytology; 6923 participants were reexamined in 1993-1995. For HPV testing, we used a polymerase chain reaction-based assay that detected 39 HPV types. Women who developed cervical cancer were identified from cancer and death registries. Cumulative risks for developing cervical cancer among infected and persistently infected women were calculated by the Kaplan-Meier method. RESULTS Of 10,123 women who were initially cytologically normal, 68 developed cervical cancer. The 16-year cumulative risks of subsequent cervical cancer for women with HPV16, HPV58 (without HPV16), or other carcinogenic HPV types (without HPV16 or HPV58) were 13.5%, 10.3%, and 4.0%, respectively, compared with 0.26% for HPV-negative women. Women with type-specific persistence of any carcinogenic HPV had greatly increased risk compared with women who were HPV-negative at both visits (hazard ratio = 75.4, 95% confidence interval = 31.8 to 178.9). The cumulative cervical cancer risks following persistent carcinogenic HPV infections increased with age: The risks were 5.5%, 14.4%, and 18.1% for women aged 30-44 years, 45-54 years, and 55 years and older, respectively. However, newly acquired infections were associated with a low risk of cervical cancer regardless of age. CONCLUSIONS HPV negativity was associated with a very low long-term risk of cervical cancer. Persistent detection of HPV among cytologically normal women greatly increased risk. Thus, it is useful to perform repeated HPV testing following an initial positive test.

External Genital Human Papillomavirus Prevalence and Associated Factors Among Heterosexual Men on 5 Continents

BACKGROUND We examined the baseline prevalence of penile, scrotal, and perineal/perianal human papillomavirus (HPV) in heterosexual men (HM). We also evaluated baseline characteristics of HM to assess factors associated with prevalent HPV detection. METHODS We tested serum samples from 3463 HM aged 16-24 years with 1-5 lifetime female sexual partners for antibodies to HPV 6, 11, 16, and 18. We collected baseline swab specimens for the detection of DNA of HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 from 3 areas: penile, scrotal, and perineal/perianal. Risk factors for prevalent HPV DNA detection were evaluated. RESULTS The prevalence of any tested HPV type was 18.7% at the penis, 13.1% at the scrotum, 7.9% at the perineal/perianal region, and 21.0% at any site. Having >3 lifetime female sexual partners had the greatest impact on HPV prevalence: odds ratio (OR) 3.2 (95% confidence interval (CI) 2.1-4.9) for HPV 6, 11, 16, and 18; and OR 4.5 (95% CI 3.3-6.1) for all HPV types tested. HPV DNA detection was highest in Africa. Neither condom usage nor circumcision was associated with HPV DNA prevalence. CONCLUSION Genital-HPV DNA detection is common in young, sexually active HM. We found HPV to be most prevalent in African men and least prevalent in men from the Asia-Pacific region. Increased numbers of sexual partners was an important risk factor for HPV DNA prevalence.

Longitudinal Evaluation of Interobserver and Intraobserver Agreement of Cervical Intraepithelial Neoplasia Diagnosis Among an Experienced Panel of Gynecologic Pathologists

Histologic diagnoses of cervical intraepithelial neoplasia grades 2 and 3 (CIN 2/3) are the key end points in clinical trials that evaluate the efficacy of a prophylactic quadrivalent human papillomavirus vaccine against cervical cancer. Adjudication of end points uses a panel of 4 pathologists. Quality control slides (n=185) from a nonclinical trial study with preestablished gold standard CIN diagnoses were used to characterize the panels agreement on CIN diagnoses and monitor performance longitudinally. At 3-month intervals over 2 years, 1 of 6 different batches of quality control slides (n=30-31) was included with clinical trial slides for independent review by each of the 4 panelists. Unweighted kappas (κ) were estimated within each panelist pair by dichotomizing the diagnoses as CIN+ versus non-CIN+ (including normal, unsatisfactory, and atypical immature metaplasia) or CIN 2/3+ versus non-CIN 2/3+ (including normal, unsatisfactory, atypical immature metaplasia, and CIN 1). Quadratic weighted κ was calculated within each panelist pair using 4 diagnostic categories: normal, CIN 1, CIN 2, and CIN 3 or worse. Substantial interobserver agreement was observed (weighted κ=0.765 to 0.865). Agreement with weighted κ=0.779 to 0.887 was observed between the individual panelists and the gold standard, which is almost perfect agreement by Landis-defined categories. Intraobserver agreement was very high (weighted κ=0.756 to 0.883). Some fluctuation in intraobserver and interobserver agreement was observed over the study period but there was no decreasing time trend. These data indicate that the interpretation of histologic end points used in the quadrivalent vaccine clinical trial program is highly valid and reliable.

Young age at first intercourse and risk-taking behaviours—a study of nearly 65 000 women in four Nordic countries

BACKGROUND Risk-taking behaviours such as early initiation of smoking, alcohol drinking and sexual activity often cluster within individuals and could be characteristics of adolescents who in general are risk takers. In the present study, using a large population-based sample of 64 659 women aged 18-45 years in four Nordic countries, we investigate whether young age at first sexual intercourse is associated with subsequent risk-taking behaviours. METHODS We examined the association between young age at first sexual intercourse (age ≤14 years) and subsequent risk-taking behaviours by using multivariate logistic regression by which odds ratios (ORs) and the corresponding 95% confidence intervals (95% CIs) were estimated. RESULTS The OR of reporting more than 10 lifetime sexual partners was almost four times higher among women who reported a young age at first intercourse (OR = 3.79; 95% CI: 3.60-4.00) in comparison with women >14 years at first intercourse. Furthermore, women who were young at first intercourse were more likely to report two or more recent partners (OR = 1.67; 95% CI: 1.54-1.82) and to have a history of STIs (OR = 2.03; 95% CI: 1.93-2.13). In addition, young age at first intercourse was associated with current smoking (OR = 2.31; 95% CI: 2.20-2.43) and binge drinking (OR = 1.36; 95% CI: 1.28-1.44). All ORs were adjusted for age, years of education and country of residence. CONCLUSION Young age at first intercourse is associated with subsequent risk-taking behaviours. Our study emphasizes the importance of targeting prevention efforts towards the complexity of risk-taking behaviours.

Early smoking initiation sexual behavior and reproductive health - a large population-based study of Nordic women.

OBJECTIVE To investigate associations between early smoking initiation, risk-taking behavior and reproductive health. METHOD A random sample of 69,486 women aged 18-45 from Denmark, Iceland, Norway and Sweden was surveyed in 2004-2005. We compared behavior and health among women who initiated smoking early (before age 15), later (at 15 or later) and never smokers. RESULTS Adult women who initiated smoking early reported more lifetime and recent sexual partners and less condom use than women who initiated smoking later, and they had lower debut ages for coitus, pregnancy and alcohol consumption. Experiences of teenage pregnancy, abortion/miscarriage and having had at least one sexually transmitted infection (gonorrhea, herpes simplex, trichomonas vaginalis, chlamydia, genital warts) were more frequent among early than among later smoking initiators. Never smoking women reported fewer partners, later debut ages, and more condom use and were less likely to have experienced teenage pregnancy, abortion/miscarriage and having had at least one sexually transmitted infection than either group of smokers. CONCLUSION Early smoking initiators were more likely to engage in risk-taking behavior and experience adverse reproductive events than were smokers who initiated later. Age at smoking initiation may be an indicator of future reproductive health. Early smoking initiators represent targets for reproductive health information.

Genital chlamydia, genital herpes, Trichomonas vaginalis and gonorrhea prevalence, and risk factors among nearly 70,000 randomly selected women in 4 Nordic countries.

Background: The aim of this study was to assess the prevalence of women reporting ever having genital chlamydia, genital herpes, Trichomonas vaginalis, and gonorrhea, and to identify factors associated with each of these sexually transmitted infections (STIs). Methods: The study was based on a large cross-sectional survey conducted in 2004–2005 among randomly sampled women (18–45 years) from the computerized population registries in Denmark, Iceland, Norway, and Sweden. A total of 69,567 women were included in the study. Results: The overall prevalence in Denmark, Iceland, Norway, and Sweden was 1.5% for reporting ever having had Trichomonas vaginalis, 1.9% for gonorrhea, 4.8% for genital herpes, and 17.0% for genital chlamydia. The prevalence of each of these STIs varied with birth cohort and country. In addition, they were strongly associated with lifetime number of partners and having a previous diagnosis of another sexually transmitted infection. Moreover, a diagnosis of genital chlamydia or gonorrhea was associated with early age at first intercourse and smoking initiation. Finally, reporting genital chlamydia was associated with early age at drinking initiation, and ever use of hormonal contraceptives and condoms. Conclusion: Genital chlamydia occurs frequently among women in the Nordic countries. Risk-taking behavior, particularly sexual behavior, is strongly associated with STIs, which suggest that further information is needed about STIs and their consequences, targeting high-risk groups. There is also a need for continued monitoring of STIs in order to follow the prevalence and to gain further knowledge about risk factors.