Ann N. Burchell

Epidemiology and Natural History of Human Papillomavirus Infections and Type-Specific Implications in Cervical Neoplasia

Worldwide human papillomavirus (HPV) prevalence in women with normal cytology at any given point in time is approximately 10% indicating that HPV is one of the most common sexually transmitted infections. HPV-16 is consistently the most common type and HPV-18 the second with some minor regional differences. Furthermore, across the spectrum of cervical lesions, HPV-16 is consistently the most common HPV type contributing to 50-55% of invasive cervical cancer cases strongly suggesting that this viral type has a biological advantage for transmission, persistency and transformation. The same phenomenon is observed albeit at a lower level for HPV-18 and HPV-45. Sexual behavioral patterns across age groups and populations are central to the description of the HPV circulation and of the risk of infection. The concept of group sexual behavior (in addition to individual sexual behavior) is important in exploring HPV transmission and has implications for defining and monitoring HPV and cancer prevention strategies. In natural history studies, the pattern of HPV DNA prevalence by age groups is similar to the patterns of HPV incidence. Rates of exposure in young women are high and often include multiple types. There is a spontaneous and rapid decrease of the HPV DNA detection rates in the middle-age groups followed by a second rise in the post-menopausal years. This article reviews: 1) the evidence in relation to the burden of HPV infections in the world and the contributions of each HPV type to the spectrum of cervical cellular changes spanning from normal cytology to invasive cervical cancer; 2) the critical role of the patterns of sexual behavior in the populations; and 3) selected aspects of the technical and methodological complexity of natural history studies of HPV and cervical neoplasia.

Epidemiology of human papillomavirus infection in men, cancers other than cervical and benign conditions.

Human papillomavirus (HPV) infection is commonly found in the genital tract of men and women with or without any clinical lesion. The association of HPV DNA with several different ano-genital cancers other than cervical has been reported for the vulva, vagina, anus and penis. HPV DNA has also been identified in head and neck cancers in the oral cavity, the oropharynx and the larynx in both sexes. In men, 80-85% of anal cancers and close to 50% of penile cancers are associated with HPV infection. In women, HPV DNA is prevalent in 36-40% vulvar cancer cases and close to 90% of vaginal cancers. There is limited data available on the natural history and HPV-related diseases in the genital tract in men, although studies are ongoing. Efficacy of HPV vaccines in the prevention of HPV infection and disease among men also remains unknown. Among HPV DNA positive ano-genital cancer cases, HPV-16 is the most frequently found followed distantly by HPV-18. In benign HPV-related diseases such as genital warts or recurrent respiratory papillomatosis HPV-6 and 11, the two most frequent non-oncogenic types, are the predominant types detected. Oncogenic types are rarely detected. In this article we summarize and review studies describing the natural history of HPV infections among men and its impact on HPV related disease in women. We summarize the evidence linking HPV in the epidemiology and etiology of cancers of the vulva, vagina, anus and oropharynx and present recent estimates of the burden of and HPV type distribution in genital warts and in cases of HPV infection of the airways.

Epidemiology of Mucosal Human Papillomavirus Infection and Associated Diseases

This article describes the epidemiology of mucosal human papillomavirs (HPV) in adults and children, its mode of transmission and its associated diseases. Over 40 genotypes of HPV infect the epithelial lining of the anogenital tract and other mucosal areas of the body. HPV is the most common sexually transmitted infection globally, with high prevalences found in both females and males. The predominant route of transmission is via sexual contact, although mother-to-child transmission is also possible. HPV infection may exist asymptomatically or may induce the formation of benign or malignant tumours in the genital, oral or conjunctival mucosa. Although most infections clear spontaneously, those that persist result in substantial morbidity and invoke high costs associated with the treatment of clinically relevant lesions. Some 13–18 mucosal HPV types are considered to have high oncogenic potential. HPV is recognized unequivocally as the main causal factor for cervical cancer, and is further responsible for a substantial proportion of many other anogenital neoplasms and head and neck cancers. Infections with HPV types that have low oncogenic risk, such as HPV-6 and 11, are associated with benign lesions of the anogenital areas known as condylomata acuminata (genital warts), oral papillomas, conjunctival papillomas, as well as low-grade squamous intra-epithelial lesions of the cervix. Perinatally acquired HPV can also cause recurrent respiratory papillomatosis in infants and young children. The implementation of HPV vaccination therefore has the potential to prevent a substantial proportion of HPV-related disease in the future.

Increases in HIV incidence among men who have sex with men undergoing repeat diagnostic HIV testing in Ontario, Canada.

ObjectiveTo estimate HIV incidence density for different exposure categories among people undergoing repeat testing in Ontario, Canada. MethodsPersons using voluntary, diagnostic HIV testing at least twice were identified by computerized and manual record linkage. In the 1992–2000 period, 980 seroconverters and 340 994 repeat negative testers contributed 936 145 person years (PY) of observation. Incidence density (ID) was calculated according to Kitayaporn et al.. Poisson regression was used to evaluate differences in incidence. ResultsAmong men who have sex with men (MSM), ID declined between 1992–1996, from 1.23 per 100 PY in 1992 to 0.79 per 100 PY in 1996 [relative risk (RR), 0.86 per year; 95% confidence interval (CI), 0.77–0.96]. Subsequently, ID increased to 1.39 per 100 PY in 1999 (RR, 1.18 per year; 95% CI, 1.05–1.34). In 2000, ID was 1.16 per 100 PY but this decrease was not statistically significantly different from 1999. MSM in their twenties had the highest ID in 1992–1996, but in 1996–2000 MSM in their thirties had the highest risk of infection. Among injecting drug users (IDU), ID decreased from 0.64 per 100 PY in 1992 to 0.14 per 100 PY in 2000 (RR, 0.87 per year; 95% CI, 0.80–0.94). Among heterosexuals, annual incidence remained constant at about 0.03 per 100 PY in 1992–2000. ConclusionsIncreases in ID were identified among MSM from 1996 to 1999. These findings are consistent with other research. Continued vigilance and improved surveillance are needed to better understand and control the epidemic.

Human papillomavirus infections among couples in new sexual relationships.

Background: No studies have examined human papillomavirus (HPV) infections among couples early in their sexual relationships when transmission is most likely. Our objective was to describe the distribution of HPV infections among recently formed couples, using the partnership as the unit of analysis. Methods: Women aged 18–24 years attending a university or junior college in Montreal enrolled in a longitudinal study with their new male partners. Self-collected vaginal swabs and clinician-collected swabs from the penis and scrotum were tested for 36 HPV genotypes. Participants self-reported sexual behavior in computerized questionnaires. We analyzed patterns of genital HPV infection in 263 couples using data obtained at enrollment. Results: Couples had engaged in vaginal sex for a median of 3.9 months. HPV was detected in 64% (169/263) of couples. In 41% (109/263), both partners harbored the same HPV type—nearly 4 times more than expected if HPV status of partners were uncorrelated. There were 583 type-specific HPV infections among 169 couples for whom at least one partner was infected. Of these, 42% were of the same type for both partners (95% confidence interval = 36%–47%). This rose from 25% among those engaging in vaginal sex for less than 2 months to 68% among those at 5 to 6 months. Conclusions: Although HPV is common, detection of the same type in persons initiating a sex relationship would be rare given type-specific prevalence rates. The high degree of concordance we found suggests a high probability of transmission.

Genital Transmission of Human Papillomavirus in Recently Formed Heterosexual Couples

We estimated human papillomavirus (HPV) transmission rates among persons with documented sexual exposure to an infected partner. Recently formed couples enrolled in the HITCH Study (HPV Infection and Transmission among Couples through Heterosexual activity) in Montreal, Canada, and provided genital specimens for DNA testing of 36 HPV genotypes. At enrollment, 179 couples were discordant for ≥1 HPV types; transmission was observed at follow-up in 73 partnerships. There was little difference between the male-to-female (3.5 per 100 person-months, 95% confidence interval [CI], 2.7-4.5) and female-to-male (4.0 per 100 person-months, 95% CI, 3.0-5.5) transmission rates. Rates did not vary with the lifetime number of partners reported by the initially uninfected partner, providing no evidence of reduced susceptibility for those with extensive sexual histories. Transmission was also relatively homogeneous across HPV genotypes and alpha species and oncogenic risk categories. The findings contribute to a small but growing evidence base regarding the natural history of HPV transmission.

Prevalence of HIV and hepatitis C virus infections among inmates of Ontario remand facilities

Background: Each year more than 56 000 adult and young offenders are admitted to Ontarios remand facilities (jails, detention centres and youth centres). The prevalence of HIV infection in Ontario remand facilities was last measured over a decade ago, and no research on the prevalence of hepatitis C virus (HCV) infection has been conducted in such facilities. We sought to determine the prevalence of HIV infection, HCV infection and HIV–HCV coinfection among inmates in Ontarios remand facilities. Methods: A voluntary and anonymous cross-sectional prevalence study of HIV and HCV infections was conducted among people admitted to 13 selected remand facilities across Ontario between Feb. 1, 2003, and June 20, 2004. Data collection included a saliva specimen for HIV and HCV antibody screening and an interviewer-administered survey. Prevalence rates and 95% confidence intervals were calculated and examined according to demographic characteristics, region of incarceration and self-reported history of injection drug use. Results: In total, 1877 participants provided both a saliva specimen and survey information. Among the adult participants, the prevalence of HIV infection was 2.1% among men and 1.8% among women. Adult offenders most likely to have HIV infection were older offenders (≥ 30 years) and injection drug users. The prevalence of HCV infection was 15.9% among men, 30.2% among women and 54.7% among injection drug users. Adult offenders most likely to have HCV infection were women, older offenders (≥ 30 years) and injection drug users. The prevalence of HCV–HIV coinfection was 1.2% among men and 1.5% among women. It was highest among older inmates and injection drug users. Among the young offenders, none was HIV positive and 1 (0.4%) was HCV positive. On the basis of the study results, we estimated that 1079 HIV-positive adults and 9208 HCV-positive adults were admitted to remand facilities in Ontario from Apr. 1, 2003, to Mar. 31, 2004. Interpretation: Adult offenders entering Ontario remand facilities have a considerably higher prevalence of HIV and HCV infections than the general population.

End-Stage Renal Disease Among HIV-Infected Adults in North America

BACKGROUND Human immunodeficiency virus (HIV)-infected adults, particularly those of black race, are at high-risk for end-stage renal disease (ESRD), but contributing factors are evolving. We hypothesized that improvements in HIV treatment have led to declines in risk of ESRD, particularly among HIV-infected blacks. METHODS Using data from the North American AIDS Cohort Collaboration for Research and Design from January 2000 to December 2009, we validated 286 incident ESRD cases using abstracted medical evidence of dialysis (lasting >6 months) or renal transplant. A total of 38 354 HIV-infected adults aged 18-80 years contributed 159 825 person-years (PYs). Age- and sex-standardized incidence ratios (SIRs) were estimated by race. Poisson regression was used to identify predictors of ESRD. RESULTS HIV-infected ESRD cases were more likely to be of black race, have diabetes mellitus or hypertension, inject drugs, and/or have a prior AIDS-defining illness. The overall SIR was 3.2 (95% confidence interval [CI], 2.8-3.6) but was significantly higher among black patients (4.5 [95% CI, 3.9-5.2]). ESRD incidence declined from 532 to 303 per 100 000 PYs and 138 to 34 per 100 000 PYs over the time period for blacks and nonblacks, respectively, coincident with notable increases in both the prevalence of viral suppression and the prevalence of ESRD risk factors including diabetes mellitus, hypertension, and hepatitis C virus coinfection. CONCLUSIONS The risk of ESRD remains high among HIV-infected individuals in care but is declining with improvements in virologic suppression. HIV-infected black persons continue to comprise the majority of cases, as a result of higher viral loads, comorbidities, and genetic susceptibility.

Impact of age on retention in care and viral suppression

Background:Retention in care is important for all HIV-infected persons and is strongly associated with initiation of antiretroviral therapy and viral suppression. However, it is unclear how retention in care and age interact to affect viral suppression. We evaluated whether the association between retention and viral suppression differed by age at entry into care. Methods:Cross-sectional analysis (2006–2010) involving 17,044 HIV-infected adults in 14 clinical cohorts across the United States and Canada. Patients contributed 1 year of data during their first full-calendar year of clinical observation. Poisson regression examined associations between retention measures [US National HIV/AIDS Strategy (NHAS), US Department of Health and Human Services (DHHS), 6-month gap, and 3-month visit constancy] and viral suppression (HIV RNA ⩽200 copies/mL) by age group: 18–29 years, 30–39 years, 40–49 years, 50–59 years, and 60 years or older. Results:Overall, 89% of patients were retained in care using the NHAS measure, 74% with the DHHS indicator, 85% did not have a 6-month gap, and 62% had visits in 3–4 quarters of the year; 54% achieved viral suppression. For each retention measure, the association with viral suppression was significant for only the younger age groups (18–29 and 30–39 years): 18–29 years [adjusted prevalence ratio (APR) = 1.33, 95% confidence interval (CI): 1.03 to 1.70]; 30–39 years (APR = 1.23, 95% CI: 1.01 to 1.49); 40–49 years (APR = 1.06, 95% CI: 0.90 to 1.22); 50–59 (APR = 0.92, 95% CI: 0.75 to 1.13); ≥60 years (APR = 0.99, 95% CI: 0.63 to 1.56) using the NHAS measure as a representative example. Conclusions:These results have important implications for improving viral control among younger adults, emphasizing the crucial role retention in care plays in supporting viral suppression in this population.

Characterization of an emerging heterosexual HIV epidemic in Russia.

Background: The Russian Federation is currently experiencing one of the fastest growing HIV epidemics worldwide. The objective was to identify sexual risk factors for recent heterosexually-acquired HIV infections. Methods: A case-control study of recent HIV infection was conducted in the regions of Altaiskiy Krai, Krasnoyarskiy Krai, Saratov Oblast, and Tverskaya Oblast. Data from 166 participants who did not report recent injection drug use were analyzed (19 male cases, 22 male controls, 67 female cases, 58 female controls). Independent risk factors for HIV infection are reported as adjusted odds ratios (AOR) with 95% confidence intervals (CI). Results: Risk factors were unprotected sex with an HIV-positive/status unknown regular partner (among women only: AOR 5.4, 95% CI 2.1–13); a regular sexual partner who was an injection drug user (AOR 3.6, 95% CI 1.5–8.5); 5 or more sexual partners (among men only: AOR 2.7, 95% CI 0.66–11); unprotected sex with a partner who had a diagnosed sexually transmitted infection (STI) or signs/symptoms of an STI (AOR 6.4, 95% CI 1.1–38); and undiagnosed signs/symptoms of an STI (AOR 3.4, 95% CI 1.5–7.6). Conclusions: These data provide evidence of bridging between the injecting and noninjecting populations. Concomitant STI seem to have a major role in fueling the Russian HIV epidemic.