Ina U. Park

Evaluation and Management of Anal Intraepithelial Neoplasia in HIV-Negative and HIV-Positive Men Who Have Sex with Men

The incidence of human papillomavirus (HPV)–associated anal cancer in men who have sex with men (MSM) is striking and has not been mitigated by the use of highly active antiretroviral therapy. Detection and treatment of high-grade anal intraepithelial neoplasia (HGAIN) may reduce the incidence of anal cancer. Anal cytology is a useful tool to detect HGAIN; annual screening of HIV-positive MSM and biennial screening of HIV-negative MSM appears to be cost-effective. MSM with abnormal cytology should be referred for high-resolution anoscopy and biopsy. Individuals with HGAIN should receive treatment; treatment modalities for HGAIN demonstrate moderate efficacy and are usually well tolerated, but greater study is required to determine which treatment is optimal. Large prospective studies are needed to document the efficacy of screening and treatment of HGAIN on anal cancer incidence. The HPV vaccine holds promise for primary prevention of anal cancer in MSM, but significant implementation challenges remain.

Reduction in HPV 16/18-associated high grade cervical lesions following HPV vaccine introduction in the United States – 2008–2012☆

BACKGROUND Prevention of pre-invasive cervical lesions is an important benefit of HPV vaccines, but demonstrating impact on these lesions is impeded by changes in cervical cancer screening. Monitoring vaccine-types associated with lesions can help distinguish vaccine impact from screening effects. We examined trends in prevalence of HPV 16/18 types detected in cervical intraepithelial neoplasia 2, 3, and adenocarcinoma in situ (CIN2+) among women diagnosed with CIN2+ from 2008 to 2012 by vaccination status. We estimated vaccine effectiveness against HPV 16/18-attributable CIN2+ among women who received ≥1 dose by increasing time intervals between date of first vaccination and the screening test that led to detection of CIN2+ lesion. METHODS Data are from a population-based sentinel surveillance system to monitor HPV vaccine impact on type-specific CIN2+ among adult female residents of five catchment areas in California, Connecticut, New York, Oregon, and Tennessee. Vaccination and cervical cancer screening information was retrieved. Archived diagnostic specimens were obtained from reporting laboratories for HPV DNA typing. RESULTS From 2008 to 2012, prevalence of HPV 16/18 in CIN2+ lesions statistically significantly decreased from 53.6% to 28.4% among women who received at least one dose (Ptrend<.001) but not among unvaccinated women (57.1% vs 52.5%; Ptrend=.08) or women with unknown vaccination status (55.0% vs 50.5%; Ptrend=.71). Estimated vaccine effectiveness for prevention of HPV 16/18-attributable CIN2+ was 21% (95% CI: 1-37), 49% (95% CI: 28-64), and 72% (95% CI: 45-86) in women who initiated vaccination 25-36 months, 37-48 months, and >48 months prior to the screening test that led to CIN2+ diagnosis. CONCLUSIONS Population-based data from the United States indicate significant reductions in CIN2+ lesions attributable to types targeted by the vaccines and increasing HPV vaccine effectiveness with increasing interval between first vaccination and earliest detection of cervical disease.

Screening for Syphilis With the Treponemal Immunoassay: Analysis of Discordant Serology Results and Implications for Clinical Management

BACKGROUND Screening for syphilis with treponemal chemiluminescence immunoassays (CIA) identifies patients with discordant serology who are not identified with traditional screening methods (eg, CIA-positive, rapid plasma regain (RPR)-negative). We sought to describe the clinical characteristics and management of patients with discordant syphilis serology. METHODS From August 2007-October 2007, patients with CIA-positive, RPR-negative serology were tested with the Treponema pallidum particle agglutination assay (TP-PA) at Kaiser Permanente Northern California. Clinical and demographic characteristics, prior syphilis history and CIA index values were compared for CIA-positive, RPR-negative patients according to TP-PA status. RESULTS Of 21,623 assays, 439 (2%) were CIA-positive and 255/439 (58%) were RPR-negative; subsequently, 184 (72%) were TP-PA-positive and 71 (28%) were TP-PA--negative. TP-PA--positive patients were more likely to be male, HIV-positive, homosexual, previously treated for syphilis (57% versus 9%), with higher median CIA index values (9.8 versus 1.6) (all P < .0001). After repeat testing, 7/31 (23%) CIA-positive, RPR-negative, TP-PA--negative patients seroreverted to CIA-negative. CONCLUSIONS TP-PA results in conjunction with clinical/behavioral assessment helped guide the management of patients with CIA-positive, RPR-negative serology. TP-PA-positive patients were both highly likely to have prior syphilis and major epidemiologic risk factors for syphilis. CIA-positive, RPR-negative, TP-PA-negative serology may represent a false-positive CIA in low-prevalence populations.

Race and Ethnicity in Trials of Antihypertensive Therapy to Prevent Cardiovascular Outcomes: A Systematic Review

PURPOSE We wanted to systematically review (1) the participation of racial and ethnic minorities in clinical trials of antihypertensive drug therapy and (2) racial differences in the efficacy of these therapies for the prevention of cardiovascular outcomes. METHODS MEDLINE, EMBASE, LILACS, African Index Medicus, and the Cochrane Library were searched from their inception to December 2005 for randomized controlled trials testing the efficacy of antihypertensive drug therapy in preventing myocardial infarction, stroke, revascularization, or cardiovascular death. MEDLINE was also searched from 2005 through 2006. The 2 authors independently assessed studies for inclusion and quality. RESULTS Twenty-eight studies met inclusion criteria. Eight trials reported results by racial subgroup. Trials with black and Hispanic participants (ALLHAT, INVEST, VALUE) found similar primary outcomes, but ALLHAT found a greater magnitude of benefit for blacks on diuretic therapy compared with nonblacks. One trial (PROGRESS) compared Asians with non-Asians, reporting that angiotensin-converting enzyme inhibitors (vs placebo) were equally effective for preventing stroke in both groups. In the LIFE trial, post hoc analyses showed different outcomes for blacks and nonblacks, raising questions about the usefulness of angiotensin-receptor blockers as first-line antihypertensive agents in blacks. In 3 studies conducted exclusively in Asians (JMIC-B, FEVER, NICS-EH), calcium channel blockers were effective in preventing cardiovascular outcomes. No trials described cardiovascular outcomes in Native Americans. CONCLUSIONS Five trials made interethnic group comparisons; 4 had similar primary outcomes for ethnic minorities and whites. Increased minority participation in future studies is needed to determine optimal prevention therapies, especially in outcome-driven trials comparing multidrug antihypertensive treatment regimens.

Anal human papillomavirus infection and abnormal anal cytology in women with genital neoplasia.

OBJECTIVES Describe the type-specific prevalence of anal HPV infection in women with lower genital tract intraepithelial neoplasia and cancer. Describe the prevalence of abnormal anal cytology and identify risk factors for anal HPV infection and abnormal anal cytology in this population. METHODS We performed a cross-sectional study of women attending 2 university-based colposcopy clinics with high-grade lower genital tract intraepithelial neoplasia or cancer. Participants received anal HPV testing/typing, anal cytology and completed a questionnaire detailing medical history and sexual behavior. RESULTS Of the 102 women enrolled, 92 (90%) had adequate beta-globin for analysis of HPV DNA status, and 47/92 women (51%) had detectable anal HPV. Of the 15 HPV types identified, 9 (60%) were oncogenic types and 6 (40%) were non-oncogenic or undetermined risk types. Overall, 9 women (9%) had abnormal anal cytology, and 7 of those had corresponding anal intraepithelial neoplasia grade I (AIN I). Women with vulvar disease had the highest proportion of abnormal anal cytology (21%) compared to women with cervical disease alone (7%), but this difference was not statistically significant (p=0.10). Neither anal HPV infection nor abnormal cytology was significantly associated with anal sex practices, smoking or number of sexual partners. CONCLUSIONS Anal infection with high-risk HPV types is common in women with high-grade genital neoplasia, but was not associated with known risk factors for genital HPV infection. Other unidentified risk factors may play a role in the anal HPV infection in this population. Abnormal anal cytology was rare and larger studies are needed to identify risk factors associated with abnormal cytology and anal intraepithelial neoplasia in this population.

HPV and HPV-Associated Diseases

Human papillomavirus (HPV) is the most common sexually transmitted infection. HPV is associated with a significant burden of disease and cancer, including anogenital warts and recurrent respiratory papillomatosis, and anogenital and oropharyngeal cancers. Effective prevention is available, including primary prevention of cancers and anogenital warts through HPV vaccination, and secondary prevention of cervical cancer through screening and treatment of precancer. This article focuses on HPV infection and the clinical consequences of infection, with attention to cervical and anogenital squamous intraepithelial neoplasia and anogenital warts.

Human Papillomavirus and Genital Warts: A Review of the Evidence for the 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines.

To provide updates for the 2015 Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines on human papillomavirus (HPV) and anogenital warts (AGWs), a review of the literature was conducted in key topic areas: (1) epidemiology and burden of disease; (2) transmission and natural history; (3) diagnosis and management of AGWs; (4) occupational exposure of healthcare workers; (5) anal cancer screening among men who have sex with men (MSM); and (6) HPV vaccine recommendations. Most sexually active persons will have detectable HPV at least once in their lifetime; 14 million persons are infected annually, and 79 million persons have prevalent infection. HPV is transmitted frequently between partners; more frequent transmission has been reported from females to males than from males to females. A new formulation of imiquimod (3.75% cream) is recommended for AGW treatment. Appropriate infection control, including performing laser or electrocautery in ventilated rooms using standard precautions, is recommended to prevent possible transmission to healthcare workers who treat anogenital warts, oral warts, and anogenital intraepithelial neoplasias (eg, cervical intraepithelial neoplasia). Data are insufficient to recommend routine anal cancer screening with anal cytology in persons living with human immunodeficiency virus (HIV)/AIDS or HIV-negative MSM. An annual digital anorectal examination may be useful for early detection of anal cancer in these populations. HPV vaccine is recommended routinely for 11- or 12-year-olds, as well as for young men through age 21 years and young women through age 26 years who have not previously been vaccinated. HPV vaccine is also recommended for MSM, people living with HIV/AIDS, and immunocompromised persons through age 26 years.

Population-Based Trends in High-Grade Cervical Lesions in the Early Human Papillomavirus Vaccine Era in the United States

Cervical intraepithelial neoplasia grade 2, 3, and adenocarcinoma in situ (CIN2+) lesions can be monitored as early indicators of human papillomavirus (HPV) vaccine impact. Changes to screening utilization will affect observed reductions in CIN2+ rates and complicate the interpretation of vaccine impact.

A systematic review of randomized trials assessing human papillomavirus testing in cervical cancer screening

Our objective was to assess the sensitivity and specificity of human papillomavirus (HPV) testing for cervical cancer screening in randomized trials. We conducted a systematic literature search of the following databases: MEDLINE, CINAHL, EMBASE, and Cochrane. Eligible studies were randomized trials comparing HPV-based to cytology-based screening strategies, with disease status determined by colposcopy/biopsy for participants with positive results. Disease rates (cervical intraepithelial neoplasia [CIN]2 or greater and CIN3 or greater), sensitivity, and positive predictive value were abstracted or calculated from the articles. Six studies met inclusion criteria. Relative sensitivities for detecting CIN3 or greater of HPV testing-based strategies vs cytology ranged from 0.8 to 2.1. The main limitation of our study was that testing methodologies and screening/management protocols were highly variable across studies. Screening strategies in which a single initial HPV-positive test led to colposcopy were more sensitive than cytology but resulted in higher colposcopy rates. These results have implications for cotesting with HPV and cytology as recommended in the United States.

HPV Type Attribution in High-Grade Cervical Lesions: Assessing the Potential Benefits of Vaccines in a Population-Based Evaluation in the United States

Background: Two currently available vaccines targeting human papillomavirus (HPV) types 16 and 18 could prevent 70% of cervical cancers and 50% of high-grade cervical lesions. Next-generation vaccines against additional types, such as a candidate 9-valent vaccine against HPV6/11/16/18/31/33/45/52/58, could further reduce HPV-associated disease burden. Methods: HPV was typed in archived tissues from women ages 21 to 39 years residing in five catchment areas in the United States with cervical intraepithelial neoplasia 2/3 and adenocarcinoma in situ (CIN2+) using L1 consensus PCR and type-specific hybridization. Type attribution was estimated using weights to account for lesions with multiple types detected. Results: From 2008 to 2011, 5,498 of 6,306 (87.2%) specimens obtained from 8,469 women with CIN2+ had valid typing results; HPV DNA was detected in 97.3%. Overall, 50.1% of lesions were attributable to HPV16/18, ranging from 50.3% to 52.4% among those ages 21 to 34 years, and significantly declined in 35 to 39 year-olds (43.5%). HPV16/18 attribution was higher in non-Hispanic whites (56.4%) versus racial/ethnic minorities (range, 41.8%–45.9%; P < 0.001). HPV31/33/45/52/58 attribution was 25.0% overall and increased with age (P < 0.001). A higher proportion of CIN2+ was attributable to HPV31/33/45/52/58 in non-Hispanic black (29.9%), Hispanic (29.2%), and Asian (33.1%) women compared with non-Hispanic whites (22.8%; P < 0.001). Conclusions: Overall, 75% of lesions were attributable to 7 oncogenic HPV types: 50% to HPV16/18 and 25% to HPV31/33/45/52/58. HPV16/18 had the largest attributable fraction in CIN2+ across all subpopulations, although to a lesser extent in older women and racial/ethnic minorities. Impact: Vaccines targeting additional oncogenic HPV types could prevent more high-grade cervical lesions, especially among racial/ethnic minorities. Cancer Epidemiol Biomarkers Prev; 24(2); 393–9. ©2014 AACR.