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1.  Evaluation of clinical performance of a novel urine-based HPV detection assay among women attending a colposcopy clinic 
Background
Human papillomavirus (HPV) testing in urine offers a convenient approach for cervical cancer screening but has previously suffered from limited clinical sensitivity.
Objectives
We evaluated clinical performance of the prototype Trovagene HPV test, a novel polymerase chain reaction assay that targets the E1 region of the HPV genome and detects and amplifies short fragments of cell-free HPV DNA in urine.
Study design
We conducted a pilot study among seventy two women referred to colposcopy following abnormal screening. Participants provided a urine sample prior to clinician-collected cervical sampling and colposcopically-directed punch biopsy. Trovagene HPV test results on urine samples were compared with cervical and urine testing by Linear Array HPV Genotyping Test (LA-HPV) for detection of histologically-confirmed cervical precancerous lesions.
Results
There was high concordance between urine samples tested by the Trovagene HPV test and corresponding cervical (87.5%) and urine (81.9%) samples tested by LA-HPV. The Trovagene HPV test had high sensitivity (92.3% for detecting CIN2/3, and 100% for CIN3), comparable to LA-HPV testing on cervical samples (96.0% and 100%, respectively), and higher than LA-HPV testing on urine samples (80.8% and 90.0%, respectively). In this referral population, the specificity of the Trovagene urine HPV test was non-significantly lower (29% f CIN2/3 and 25% for CIN3) than corresponding estimates of LA-HPV testing on cervical (36% and 28%, respectively) and urine (42% and 38%, respectively) samples.
Conclusions
This pilot study suggests that the Trovagene HPV test has high sensitivity for urine-based detection of cervical precancer and merits evaluation in larger studies.
doi:10.1016/j.jcv.2014.04.016
PMCID: PMC4146457  PMID: 24881489
human papillomavirus; cervical cancer; urine; screening
2.  Comparison of Human Papillomavirus Detections in Urine, Vulvar, and Cervical Samples from Women Attending a Colposcopy Clinic 
Journal of Clinical Microbiology  2014;52(1):187-192.
While urine-based sampling for human papillomavirus (HPV) is being explored as a simple and noninvasive approach for cervical cancer screening, data comparing HPV genotyping in urine and those in cellular sampling of the cervix and vulva, and their correlation with rigorously confirmed cervical disease status, are sparse. We performed HPV genotyping on voided-urine and clinician-collected vulvar and cervical samples from 72 women undergoing colposcopy. Although urine-based HPV carcinogenic HPV detection was lower (58.3%) than cervical (73.6%) and vulvar (72.1%) detection (P = 0.05 and 0.07, respectively), the agreement of urine HPV with cervical and vulvar HPV was moderate (kappa = 0.55) and substantial (kappa = 0.62), respectively. Urine-based carcinogenic HPV detection had a clinical sensitivity of 80.8% (95% confidence interval [CI] = 60.7 to 93.5) and a specificity of 53.3% (95% CI = 37.9 to 68.3) for diagnosing cervical intraepithelial neoplasia grades 2/3 (CIN2/3) on histology; 90.0% of CIN3 was positive for urine HPV. The corresponding sensitivity and specificity values for vulvar sampling were 92% (95% CI = 74 to 99) and 40.5% (95% CI = 25.6 to 56.7), and those for cervical sampling were 96.2% (95% CI = 80.4 to 99.9) and 40% (95% CI = 25.7 to 55.7), respectively. HPV16 was the most common carcinogenic genotype detectable in 25% of urine, 33.8% of vulvar, and 31.9% of cervical samples overall, with prevalence increasing with cervical disease grade, regardless of the sampling method. Stronger cervical HPV PCR signal strengths were associated with increased frequency of urine HPV detection. In summary, the relatively lower detection rates but comparable clinical performance of urine-based HPV sampling underscore the need for larger studies to evaluate urine-based sampling for cervical cancer screening, epidemiologic studies, and postvaccination HPV disease surveillance.
doi:10.1128/JCM.01623-13
PMCID: PMC3911475  PMID: 24197879
4.  The Risk of Hepatocellular Carcinoma Among Individuals With Acquired Immunodeficiency Syndrome in the United States 
Cancer  2012;118(24):6226-6233.
BACKGROUND
Hepatocellular carcinoma (HCC) is a concern among individuals with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS).
METHODS
The authors analyzed population-based registry linkage data from the US HIV/AIDS Cancer Match Study (1980–2009) to examine the risk and trends of HCC among individuals with AIDS. Standardized incidence ratios (SIRs) were used to measure HCC risk relative to the general population, and Poisson regression was used to calculate incidence rate ratios (RR) comparing incidence among individuals with AIDS. People with AIDS were categorized according to their HIV risk group into high and low hepatitis C virus (HCV) prevalence groups based on their HIV transmission risk category.
RESULTS
Among 615,150 individuals with AIDS, HCC risk was elevated almost 4 times compared with the risk in the general population (N = 366; SIR, 3.8; 95% confidence interval, 3.5–4.3). Although HCC incidence increased steadily across calendar periods (Ptrend < .0001; adjusted for sex and age), the excess risk in individuals with AIDS compared with the general population remained somewhat constant (SIRs range, 3.5–3.9) between the monotherapy/dual therapy era (1990–1995) and the recent highly active antiretroviral therapy era (2001–2009). In a multivariate model adjusting for sex, race/ethnicity, and attained calendar period, HCC incidence increased with advancing age (Ptrend < .0001) and was associated with HIV risk groups with a known higher prevalence of HCV (adjusted RR, 2.2; 95% confidence interval, 1.8–2.8).
CONCLUSIONS
HCC incidence in individuals with AIDS has increased over time despite improved HIV treatment regimens, likely reflecting prolonged survival with chronic liver disease. The high incidence in older adults suggests that this cancer will increase in importance with aging of the HIV-infected population.
doi:10.1002/cncr.27694
PMCID: PMC3965349  PMID: 22736272
hepatocellular carcinoma; human immunodeficiency virus; acquired immunodeficiency syndrome; epidemiology; hepatitis C virus
5.  Human Papillomavirus Genotype Attribution and Estimation of Preventable Fraction of Anal Intraepithelial Neoplasia Cases Among HIV-Infected Men Who Have Sex With Men 
The Journal of Infectious Diseases  2012;207(3):392-401.
Background. The prevention of human papillomavirus (HPV)–induced anal cancer in high-risk populations such as human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) remains an urgent priority, given rising incidence rates despite widespread antiretroviral therapy use.
Methods. HPV genotypes and anal disease prevalence, by cytology and histopathologic findings, were evaluated among 363 HIV-infected MSM. We modeled fractions of high-grade anal intraepithelial neoplasia (HGAIN) attributable to individual carcinogenic HPV genotypes and estimated the range of the proportion of HGAIN cases potentially preventable by prophylactic HPV vaccines.
Results. HPV16 was the most common genotype overall (26.4% of cases) and among HGAIN cases (55%). Prevalence of multiple (≥2) carcinogenic HPV genotypes increased from 30.9% in cases of AIN grade <1 to 76.3% in cases of AIN grade 3 (Ptrend < .001). The fractions of HGAIN cases attributable to carcinogenic HPV16/18 targeted by currently licensed bivalent and quadrivalent HPV vaccines ranged from 12% to 61.5%, and the fractions attributable to carcinogenic HPV16/18/31/33/45/52/58 targeted by an investigational nonavalent HPV vaccine ranged from 39% to 89.4%.
Conclusions. Our analytical framework allows estimation of HGAIN cases attributable to individual HPV genotypes in the context of multiple concurrent HPV infections, which are very common among HIV-infected MSM. Our results suggest that licensed and investigational HPV prophylactic vaccines have the potential to prevent a substantial proportion of HGAIN cases in this population.
doi:10.1093/infdis/jis694
PMCID: PMC3537447  PMID: 23162133
Anal cancer; human papillomavirus; human immunodeficiency virus; anal intraepithelial neoplasia; men who have sex with men; genotypes; attribution
6.  Nonsteroidal Anti-inflammatory Drug Use, Chronic Liver Disease, and Hepatocellular Carcinoma 
Background
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated.
Methods
We analyzed prospective data on 300504 men and women aged 50 to 71 years in the National Institutes of Health–AARP Diet and Health Study cohort and linked self-reported aspirin and nonaspirin NSAID use with registry-confirmed diagnoses of HCC (n=250) and death due to CLD (n=428, excluding HCC). We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided.
Results
Aspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of nonaspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI= 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use nonaspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users.
Conclusions
Aspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.
doi:10.1093/jnci/djs452
PMCID: PMC3514167  PMID: 23197492
8.  Utilization of Cervical Cancer Screening Services and Trends in Screening Positivity Rates in a ‘Screen-And-Treat’ Program Integrated with HIV/AIDS Care in Zambia 
PLoS ONE  2013;8(9):e74607.
Background
In the absence of stand-alone infrastructures for delivering cervical cancer screening services, efforts are underway in sub-Saharan Africa to dovetail screening with ongoing vertical health initiatives like HIV/AIDS care programs. Yet, evidence demonstrating the utilization of cervical cancer prevention services in such integrated programs by women of the general population is lacking.
Methods
We analyzed program operations data from the Cervical Cancer Prevention Program in Zambia (CCPPZ), the largest public sector programs of its kind in sub-Saharan Africa. We evaluated patterns of utilization of screening services by HIV serostatus, examined contemporaneous trends in screening outcomes, and used multivariable modeling to identify factors associated with screening test positivity.
Results
Between January 2006 and April 2011, CCPPZ services were utilized by 56,247 women who underwent cervical cancer screening with visual inspection with acetic acid (VIA), aided by digital cervicography. The proportion of women accessing these services who were HIV-seropositive declined from 54% to 23% between 2006–2010, which coincided with increasing proportions of HIV-seronegative women (from 22% to 38%) and women whose HIV serostatus was unknown (from 24% to 39%) (all p-for trend<0.001). The rates of VIA screening positivity declined from 47% to 17% during the same period (p-for trend <0.001), and this decline was consistent across all HIV serostatus categories. After adjusting for demographic and sexual/reproductive factors, HIV-seropositive women were more than twice as likely (Odds ratio 2.62, 95% CI 2.49, 2.76) to screen VIA-positive than HIV-seronegative women.
Conclusions
This is the first ‘real world’ demonstration in a public sector implementation program in a sub-Saharan African setting that with successful program scale-up efforts, nurse-led cervical cancer screening programs targeting women with HIV can expand and serve all women, regardless of HIV serostatus. Screening program performance can improve with adequate emphasis on training, quality control, and telemedicine-support for nurse-providers in clinical decision making.
doi:10.1371/journal.pone.0074607
PMCID: PMC3776830  PMID: 24058599
9.  Comparison of visual inspection with acetic acid and cervical cytology to detect high-grade cervical neoplasia among HIV-infected women in India 
Human immunodeficiency virus (HIV)-infected women in India and other developing country settings are living longer on antiretroviral therapy, yet their risk for human papillomavirus (HPV)-induced cervical cancer remains unabated because of lack of cost-effective and accurate secondary prevention methods. Visual inspection after application of dilute acetic acid on the cervix (VIA) has not been adequately studied against the current standard: conventional cervical cytology (Pap smears) among HIV-infected women. We evaluated 303 nonpregnant HIV-infected women in Pune, India, by simultaneous and independent screening with VIA and cervical cytology with disease ascertainment by colposcopy and histopathology. At the cervical intraepithelial neoplasia (CIN2+) disease threshold, the sensitivity, specificity and positive and negative predictive value estimates of VIA were 80, 82.6, 47.6 and 95.4% respectively, compared to 60.5, 59.6, 22.4 and 88.7% for the atypical squamous cells of undetermined significance or severe (ASCUS+) cutoff on cytology, 60.5, 64.6, 24.8 and 89.4% for the low-grade squamous intraepithelial cells or severe (LSIL+) cutoff on cytology and 20.9, 96.0, 50.0 and 86.3% for high-grade squamous intraepithelial lesion or severe (HSIL+) cutoff on cytology. A similar pattern of results was found for women with the presence of carcinogenic HPV-positive CIN2+ disease, as well as for women with CD4+ cell counts <200 and <350 µL−1. Overall, VIA performed better than cytology in this study with biologically rigorous endpoints and without verification bias, suggesting that VIA is a practical and useful alternative or adjunctive screening test for HIV-infected women. Implementing VIA-based screening within HIV/acquired immunodeficiency syndrome care programs may provide an easy and practical means of complementing the highly anticipated low-cost HPV-based rapid screening tests in the near future, thereby contributing to improve program effectiveness of screening.
doi:10.1002/ijc.25971
PMCID: PMC3516675  PMID: 21387289
cervical cancer; visual inspection; cytology; screening; HIV/AIDS; India
10.  Clinical Performance of Digital Cervicography and Cytology for Cervical Cancer Screening in HIV-infected Women in Lusaka, Zambia 
While there is a growing literature on the clinical performance of VIA in HIV-infected women, to our knowledge none have studied VIA enhanced by digital cervicography. We estimated clinical performance of cervicography and cytology to detect cervical intraepithelial neoplasia grade 2 or worse. Sensitivity and specificity of cervicography were 84% (95% confidence interval [CI]: 72%–91%) and 58% (95%CI: 52%–64%). At the high-grade squamous intraepithelial lesion or worse cutoff for cytology, sensitivity and specificity were 61% (95%CI: 48%–72%) and 58% (95%CI: 52%–64%). In our study, cervicography appears to be as good as cytology in HIV-infected women.
doi:10.1097/QAI.0000000000000270
PMCID: PMC4162769  PMID: 24977474
Cervical cancer; cytology; digital cervicography; HIV/AIDS; screening
11.  Statin use and risk of hepatocellular carcinoma in a U.S. population 
Cancer epidemiology  2014;38(5):523-527.
Purpose
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are medications widely prescribed to reduce cholesterol levels. Observational studies in high-risk populations, mostly in Asia, have suggested that statins are associated with a reduced risk of hepatocellular carcinoma (HCC). The current study sought to evaluate the association of statin use and HCC in a U.S.-based, low-risk, general population.
Methods
A nested case-control study was conducted among members of the Health Alliance Plan HMO of the Henry Ford Health System enrolled between 1999 and 2010. Electronic pharmacy records of statin use were compared among tumor registry-confirmed cases of HCC (n=94) and controls (n=468) matched on age, sex, diagnosis date, and length of HMO enrollment.
Results
In multivariate analyses, ever-use of statins was significantly inversely associated with development of HCC (Odds Ratio (OR):0.32, 95%CI: 0.15–0.67). No clear dose-response relationship was evident as statin use for ≤2 years (OR=0.32, 95%CI=0.13–0.83) and >2 years (OR=0.31, 95CI%=0.12–9.81) resulted in very similar ORs.
Conclusions
The use of statins among populations in low-risk HCC areas may be associated with decreased risk of HCC.
doi:10.1016/j.canep.2014.06.009
PMCID: PMC4188715  PMID: 25113938
statins; liver cancer; epidemiology
12.  The burden of cervical pre-cancer and cancer in HIV positive women in Zambia: a modeling study 
BMC Cancer  2015;15:541.
Background
HIV infection is associated with a higher incidence of precancerous cervical lesions and their progression to invasive cervical cancer (ICC). Zambia is a global epicenter of HIV and ICC, yet the overall burden of cervical pre-cancer [cervical intraepithelial neoplasia 3 (CIN3)] and ICC among its HIV positive adult female population is unknown. The objective of this study was to determine the burden of cervical disease among HIV positive women in Zambia by estimating the number with CIN3 and ICC.
Methods
We conducted a cross-sectional study among 309 HIV positive women attending screening in Lusaka (Zambia’s most populated province) to measure the cervical disease burden by visual inspection with acetic acid enhanced by digital cervicography (DC), cytology, and histology. We then used estimates of the prevalence of CIN3 and ICC from the cross-sectional study and Spectrum model-based estimates for HIV infection among Zambian women to estimate the burden of CIN3 and ICC among HIV positive women nationally.
Results
Over half (52 %) of the study participants screened positive by DC, while 45 % had cytologic evidence of high grade squamous intraepithelial lesions (SIL) or worse. Histopathologic evaluation revealed that 20 % of women had evidence of CIN2 or worse, 11 % had CIN3 or worse, and 2 % had ICC. Using the Spectrum model, we therefore estimate that 34,051 HIV positive women in Zambia have CIN3 and 7,297 have ICC.
Conclusions
The DC, cytology, and histology results revealed a large cervical disease burden in this previously unscreened HIV positive population. This very large burden indicates that continued scale-up of cervical cancer screening and treatment is urgently needed.
doi:10.1186/s12885-015-1558-5
PMCID: PMC4512016  PMID: 26205980
Cervical cancer; Cervical intraepithelial neoplasia; HIV; Zambia
13.  Population-Level Scale-Up of Cervical Cancer Prevention Services in a Low-Resource Setting: Development, Implementation, and Evaluation of the Cervical Cancer Prevention Program in Zambia 
PLoS ONE  2015;10(4):e0122169.
Background
Very few efforts have been undertaken to scale-up low-cost approaches to cervical cancer prevention in low-resource countries.
Methods
In a public sector cervical cancer prevention program in Zambia, nurses provided visual-inspection with acetic acid (VIA) and cryotherapy in clinics co-housed with HIV/AIDS programs, and referred women with complex lesions for histopathologic evaluation. Low-cost technological adaptations were deployed for improving VIA detection, facilitating expert physician opinion, and ensuring quality assurance. Key process and outcome indicators were derived by analyzing electronic medical records to evaluate program expansion efforts.
Findings
Between 2006-2013, screening services were expanded from 2 to 12 clinics in Lusaka, the most-populous province in Zambia, through which 102,942 women were screened. The majority (71.7%) were in the target age-range of 25–49 years; 28% were HIV-positive. Out of 101,867 with evaluable data, 20,419 (20%) were VIA positive, of whom 11,508 (56.4%) were treated with cryotherapy, and 8,911 (43.6%) were referred for histopathologic evaluation. Most women (87%, 86,301 of 98,961 evaluable) received same-day services (including 5% undergoing same-visit cryotherapy and 82% screening VIA-negative). The proportion of women with cervical intraepithelial neoplasia grade 2 and worse (CIN2+) among those referred for histopathologic evaluation was 44.1% (1,735/3,938 with histopathology results). Detection rates for CIN2+ and invasive cervical cancer were 17 and 7 per 1,000 women screened, respectively. Women with HIV were more likely to screen positive, to be referred for histopathologic evaluation, and to have cervical precancer and cancer than HIV-negative women.
Interpretation
We creatively disrupted the 'no screening' status quo prevailing in Zambia and addressed the heavy burden of cervical disease among previously unscreened women by establishing and scaling-up public-sector screening and treatment services at a population level. Key determinants for successful expansion included leveraging HIV/AIDS program investments, and context-specific information technology applications for quality assurance and filling human resource gaps.
doi:10.1371/journal.pone.0122169
PMCID: PMC4401717  PMID: 25885821
14.  Analytic and Clinical Performance of cobas HPV Testing in Anal Specimens from HIV-Positive Men Who Have Sex with Men 
Journal of Clinical Microbiology  2014;52(8):2892-2897.
Anal human papillomavirus (HPV) infections are common, and the incidence of anal cancer is high in HIV-infected men who have sex with men (MSM). To evaluate the performance of HPV assays in anal samples, we compared the cobas HPV test (cobas) to the Roche Linear Array HPV genotyping assay (LA) and cytology in HIV-infected MSM. Cytology and cobas and LA HPV testing were conducted for 342 subjects. We calculated agreement between the HPV assays and the clinical performance of HPV testing and HPV genotyping alone and in combination with anal cytology. We observed high agreement between cobas and LA, with cobas more likely than LA to show positive results for HPV16, HPV18, and other carcinogenic types. Specimens testing positive in cobas but not in LA were more likely to be positive for other markers of HPV-related disease compared to those testing negative in both assays, suggesting that at least some of these were true positives for HPV. cobas and LA showed high sensitivities but low specificities for the detection of anal intraepithelial neoplasia grade 2/3 (AIN2/3) in this population (100% sensitivity and 26% specificity for cobas versus 98.4% sensitivity and 28.9% specificity for LA). A combination of anal cytology and HPV genotyping provided the highest accuracy for detecting anal precancer. A higher HPV load was associated with a higher risk of AIN2/3 with HPV16 (Ptrend < 0.001), HPV18 (Ptrend = 0.07), and other carcinogenic types (Ptrend < 0.001). We demonstrate that cobas can be used for HPV detection in anal cytology specimens. Additional tests are necessary to identify men at the highest risk of anal cancer among those infected with high-risk HPV.
doi:10.1128/JCM.03517-13
PMCID: PMC4136172  PMID: 24899025
15.  The diversity of human papillomavirus infection among human immunodeficiency virus-infected women in Yunnan, China 
Virology Journal  2014;11:202.
Background
Yunnan has one of the oldest and the most severe human immunodeficiency virus (HIV) epidemics in China. We conducted an observational study to evaluate the human papillomavirus (HPV) genotype distribution in relation to cervical neoplastic disease risk among HIV-infected women in Yunnan.
Methods
We screened 301 HIV-infected non-pregnant women in Mangshi prefecture in Yunnan province. All consenting participants underwent simultaneous and independent assessment by cervical cytology, colposcopy-histopathology, and HPV genotyping. Unadjusted and multivariable-adjusted multinomial logistic regression analysis was conducted to evaluate factors associated with single or multiple carcinogenic HPV genotypes.
Results
HPV genotypes were present in 43.5% (131/301) overall, and carcinogenic HPV genotypes were present in 37.5% (113/301) women. Among women with carcinogenic HPV genotypes, 80 (70.8% of 113) had a single carcinogenic HPV type, while 33 (29.2%) women had multiple (2 or more) carcinogenic HPV types. Overall, the most common carcinogenic HPV types were HPV52 (7.3%), HPV58 (6.6%), HPV18 (6.3%), HPV16 (6.0%), and HPV33 (5.3%). In women with cervical precancerous lesions (i.e., high-grade squamous intraepithelial lesions [HSIL] on cytology or cervical intraepithelial neoplasia grade 2 or worse [CIN2+] detected on colposcopy-histology), the most commonly detected genotypes were HPV16 (28.6%), HPV52 (25.0%), HPV58 (17.9%), HPV18 (10.7%) and HPV31 (10.7%). Increasing age was an independent risk factor associated with presence of single carcinogenic HPV types (adjusted odds ratio: 1.04, 95%CI: 1.01-1.07, p = 0.012) but not with the presence of multiple carcinogenic types in the multivariable-adjusted models.
Conclusions
As HIV-infected women continue to live longer on antiretroviral therapy in China, it will be increasingly important to screen for, and prevent, HPV-associated cervical cancer in this population, especially given the wide diversity and multiplicity of HPV genotypes.
doi:10.1186/s12985-014-0202-3
PMCID: PMC4279793  PMID: 25481842
HPV; Genotypes; HIV; Cervix; China
16.  Risk Factors for Anal HPV Infection and Anal Precancer in HIV-Infected Men Who Have Sex With Men 
The Journal of Infectious Diseases  2013;208(11):1768-1775.
Background. Carcinogenic human papillomaviruses (HPVs) cause a large proportion of anal cancers. Human immunodeficiency virus (HIV)–infected men who have sex with men (MSM) are at increased risk of HPV infection and anal cancer compared with HIV-negative men. We evaluated risk factors for HPV infection and anal precancer in a population of HIV-infected MSM.
Methods. Our study included 305 MSM at an HIV/AIDS clinic in the Kaiser Permanente Northern California Health Maintenance Organization. Logistic regression was used to estimate associations of risk factors comparing men without anal HPV infection; men with anal HPV infection, but no precancer; and men with anal precancer.
Results. Low CD4 count (<350 cells/mm3) and previous chlamydia infection were associated with an increased risk of carcinogenic HPV infection (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.28–10.40 and OR, 4.24; 95% CI, 1.16–15.51, respectively). History of smoking (OR, 2.71 95% CI, 1.43–5.14), duration, recency, and dose of smoking increased the risk of anal precancer among carcinogenic HPV-positive men but had no association with HPV infection.
Conclusions. We found distinct risk factors for anal HPV infection and anal precancer. Risk factors for HPV infection and anal precancer are similar to established risk factors for cervical cancer progression.
doi:10.1093/infdis/jit374
PMCID: PMC3814839  PMID: 23908478
anal cancer; human papillomavirus (HPV); human immunodeficiency virus (HIV); men who have sex with men (MSM); anal intraepithelial neoplasia (AIN)
17.  Implementation of cervical cancer prevention services for HIV-infected women in Zambia: measuring program effectiveness 
HIV therapy  2010;4(6):703-722.
Background
Cervical cancer kills more women in low-income nations than any other malignancy. A variety of research and demonstration efforts have proven the efficacy and effectiveness of low-cost cervical cancer prevention methods but none in routine program implementation settings of the developing world, particularly in HIV-infected women.
Methods
In our public sector cervical cancer prevention program in Zambia, nurses conduct screening using visual inspection with acetic acid aided by digital cervicography. Women with visible lesions are offered same-visit cryotherapy or referred for histologic evaluation and clinical management. We analyzed clinical outcomes and modeled program effectiveness among HIV-infected women by estimating the total number of cervical cancer deaths prevented through screening and treatment.
Results
Between 2006 and 2008, 6572 HIV-infected women were screened, 53.6% (3523) had visible lesions, 58.5% (2062) were eligible for cryotherapy and 41.5% (1461) were referred for histologic evaluation. A total of 75% (1095 out of 1462) of patients who were referred for evaluation complied. Pathology results from 65% (715 out of 1095) of women revealed benign abnormalities in 21% (151), cervical intraepithelial neoplasia (CIN) I in 30% (214), CIN 2/3 in 33% (235) and invasive cervical cancer in 16.1% (115, of which 69% were early stage). Using a conditional probability model, we estimated that our program prevented 142 cervical cancer deaths (high/low range: 238–96) among the 6572 HIV-infected women screened, or one cervical cancer death prevented per 46 (corresponding range: 28–68) HIV-infected women screened.
Conclusion
Our prevention efforts using setting-appropriate human resources and technology have reduced morbidity and mortality from cervical cancer among HIV-infected women in Zambia. Financial support for implementing cervical cancer prevention programs integrated within HIV/AIDS care programs is warranted. Our prevention model can serve as the implementation platform for future low-cost HPV-based screening methods, and our results may provide the basis for comparison of programmatic effectiveness of future prevention efforts.
doi:10.2217/hiv.10.52
PMCID: PMC4237284  PMID: 25419240
cervical cancer; HIV/AIDS; program effectiveness; screening; Zambia
18.  Human papillomavirus genotyping, human papillomavirus mRNA expression, and p16/Ki-67 cytology to detect anal cancer precursors in HIV-infected MSM 
AIDS (London, England)  2012;26(17):2185-2192.
Objective
Anal cancer incidence is high in HIV-infected MSM. Screening for anal intraepithelial lesions and cancers is performed at specialized clinics and relies on high-resolution anoscopy (HRA) and anal cytology. Both approaches have limited reproducibility and sensitivity for detecting anal cancer precursors. We evaluated biomarkers for human papillomavirus (HPV)-related disease in a population of HIV-infected MSM.
Methods
A cross-sectional screening study with passive follow-up included 363 MSM followed at a HIV/AIDS clinic. All men had anal cytology samples taken and were evaluated using HRA and anal biopsies. Using a composite endpoint of biopsy results and cytology, we compared the performance of HPV16/18 genotyping, HPVE6/E7 mRNA expression, and p16/Ki-67 cytology to detect high-grade anal intraepithelial neoplasias (AINs).
Results
For all biomarkers analyzed, there was a significant trend of increasing percentage of men testing positive with increasing severity of disease (P< 0.001). HPV DNA testing had the highest sensitivity for anal intraepithelial neoplasia grade 2 and anal intraepithelial neoplasia grade 3 (AIN3), followed by p16/Ki-67, HPVE6/E7 mRNA testing, and HPV16/18 genotyping. The highest Youden's index was observed for HPVE6/E7 mRNA testing, followed by HPV16/18 genotyping, p16/Ki-67 cytology, and HPV DNA testing. Increasing the threshold for positivity of p16/Ki-67 to five or more positive cells led to significantly higher specificity, but unchanged sensitivity for detecting AIN3.
Conclusion
Molecular features of anal disease categories are similar to those of corresponding cervical lesions. Biomarkers evaluated for cervical cancer screening may be used for primary anal cancer screening or to decide who should require immediate treatment vs. expectant management.
doi:10.1097/QAD.0b013e328359f255
PMCID: PMC4144865  PMID: 23018436
anal cancer screening; HIV; human papillomavirus; human papillomavirus mRNA; MSM; p16
21.  Fertility Drugs and the Risk of Breast and Gynecologic Cancers 
Seminars in reproductive medicine  2012;30(2):131-145.
The evaluation of cancer risk among patients treated for infertility is complex, given the need to consider indications for use, treatment details, and the effects of other factors (including parity status) that independently affect cancer risk. Many studies have had methodologic limitations. Recent studies that have overcome some of these limitations have not confirmed a link between drug use and invasive ovarian cancers, although there is still a lingering question as to whether borderline tumors might be increased. It is unclear whether this merely reflects increased surveillance. Investigations regarding breast cancer risk have produced inconsistent results. In contrast, an increasing number of studies suggest that fertility drugs may have a special predisposition for the development of uterine cancers, of interest given that these tumors are recognized as particularly hormonally responsive. Additional studies are needed to clarify the effects on cancer risk of fertility drugs, especially those used in conjunction with in vitro fertilization. Because many women who have received such treatments are still relatively young, further monitoring should be pursued in large well-designed studies that enable assessment of effects within a variety of subgroups defined by both patient and disease characteristics.
doi:10.1055/s-0032-1307421
PMCID: PMC4106369  PMID: 22549713
infertility; ovulation-inducing drugs; cancer; risk
22.  Improving diagnostic capability for HPV disease internationally within the NIH-NIAID-Division of AIDS Clinical Trial Networks 
Objectives
To evaluate an external quality assurance (EQA) program for the laboratory diagnosis of human papillomavirus (HPV) disease that was established to improve international research capability within the Division of AIDS at the National Institute of Allergy and Infectious Disease–supported Adult AIDS Clinical Trials Group network.
Methods
A three-component EQA scheme was devised comprising assessments of diagnostic accuracy of cytotechnologists and pathologists using available EQA packages, review of quality and accuracy of clinical slides from local sites by an outside expert, and HPV DNA detection using the commercially available HPV test kit.
Results
Seven laboratories and 17 pathologists in Africa, India, and South America participated. EQA scores were suboptimal for standard packages in three of seven laboratories. There was good agreement between the local laboratory and the central reader 70% of the time (90% confidence interval, 42%-98%). Performance on the College of American Pathologists’ HPV DNA testing panel was successful in all laboratories tested.
Conclusions
The prequalifying EQA round identified correctable issues that will improve the laboratory diagnosis of HPV related cervical disease at the international sites and will provide a mechanism for ongoing education and continuous quality improvement.
doi:10.1309/AJCPIBIS19QIYHJY
PMCID: PMC4017200  PMID: 24225757
External Quality Assurance; EQA; HPV; cervical pathology; cervical cytology; histopathology; HPV DNA testing
23.  eC3—A Modern Telecommunications Matrix for Cervical Cancer Prevention in Zambia 
Journal of lower genital tract disease  2010;14(3):10.1097/LGT.0b013e3181cd6d5e.
Objectives
Low physician density, undercapacitated laboratory infrastructures, and limited resources are major limitations to the development and implementation of widely accessible cervical cancer prevention programs in sub-Saharan Africa.
Materials and Methods
We developed a system operated by nonphysician health providers that used widely available and affordable communication technology to create locally adaptable and sustainable public sector cervical cancer prevention program in Zambia, one of the world’s poorest countries.
Results
Nurses were trained to perform visual inspection with acetic acid aided by digital cervicography using predefined criteria. Electronic digital images (cervigrams) were reviewed with patients, and distance consultation was sought as necessary. Same-visit cryotherapy or referral for further evaluation by a gynecologist was offered. The Zambian system of “electronic cervical cancer control” bypasses many of the historic barriers to the delivery of preventive health care to women in low-resource environments while facilitating monitoring, evaluation, and continued education of primary health care providers, patient education, and medical records documentation.
Conclusions
The electronic cervical cancer control system uses appropriate technology to bridge the gap between screening and diagnosis, thereby facilitating the conduct of “screen-and-treat” programs. The inherent flexibility of the system lends itself to the integration with future infrastructures using rapid molecular human papillomavirus–based screening approaches and wireless telemedicine communications.
doi:10.1097/LGT.0b013e3181cd6d5e
PMCID: PMC3809081  PMID: 20592550
cervical cancer; visual inspection; telemedicine; developing countries; Zambia
24.  Human papillomavirus and cervical cancer: biomarkers for improved prevention efforts 
Future microbiology  2011;6(9):10.2217/fmb.11.87.
While organized screening programs in industrialized countries have significantly reduced cervical cancer incidence, cytology-based screening has several limitations. Equivocal or mildly abnormal Pap tests require costly retesting or diagnostic work-up by colposcopy and biopsy. In low-resource countries, it has been difficult to establish and sustain cytology-based programs. Advances in understanding human papillomavirus biology and the natural history of human papillomavirus-related precancers and cancers have led to the discovery of a range of novel biomarkers in the past decade. In this article, we will discuss the potential role of new biomarkers for primary screening, triage and diagnosis in high-resource countries and their promise for prevention efforts in resource constrained settings.
doi:10.2217/fmb.11.87
PMCID: PMC3809085  PMID: 21958146
accuracy; biomarkers; cervical cancer; HPV; prevention; risk prediction; screening
25.  HPV Prevalence and Cervical Intraepithelial Neoplasia among HIV-infected Women in Yunnan Province, China: A Pilot Study 
Objectives
To determine the prevalence of HPV and cervical neoplasia among HIV-infected women in southwestern China.
Methods
Cervical cytology, HPV detection by Hybrid Capture-2™ assay, and diagnostic colposcopy were followed by cervical biopsy if indicated. Logistic regression analysis was used to analyze associations between HPV co-infection and cervical intraepithelial neoplasia (CIN), and HIV-related clinical and laboratory parameters.
Results
Colposcopic-histopathologically proven CIN2+ lesions were present in 7/83 (8.4%) HIV-infected women. Nearly half (41/83, 43%) were co-infected with carcinogenic HPV genotypes. HPV co-infection was higher in women with colposcopic-histopathologically proven CIN2+ lesions than women with
Conclusions
HIV/AIDS care and treatment programs should integrate effective cervical cancer prevention services to mitigate the risk of invasive cervical cancer among HIV-infected women in China.
PMCID: PMC3809115  PMID: 22502720
China; HIV/AIDS; HPV; cervical cancer; screening; prevention

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