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BackgroundRisks and benefits of protease inhibitor (PI) (telaprevir or boceprevir) triple therapy in hepatitis C virus (HCV)-infected patients with mildly decompensated cirrhosis, including those wait-listed for liver transplantation (LT), are incompletely known.AimTo assess virological responses and safety of PI triple therapy in patients with mildly decompensated Child-Pugh (CP) CP ≥6 vs. compensated (CP = 5) cirrhosis.MethodsMulticentre cohort of 160 adults with cirrhosis treated with peginterferon/ribavirin (peg-IFN/RBV) plus telaprevir (69%) or boceprevir (31%), comparing outcomes between those with CP = 5 and CP ≥6.ResultsPatients, 47% with CP ≥6 cirrhosis (CP range 6-10), received PI triple therapy for a targeted duration of 48 weeks. The cohort was median age 59 years, 32% female, 59% genotype 1a, 35% previous null/partial responders. Sustained virological response at 12 weeks (SVR12) was achieved by 35% of patients with CP ≥6 vs. 54% of those with CP = 5 (P = 0.02). CP = 5, achievement of rapid virological response and genotype 1b/other, independently predicted SVR12. Compared to those with CP = 5, patients with CP ≥6 had more peg-IFN dose reductions, eltrombopag use, transfusions and hospitalisations to manage adverse events (all P < 0.05). Overall, 67 (42%) discontinued treatment early. Nine wait-listed patients were treated for a median of 97 days (IQR 60-160) prior to liver transplantation and five achieved post-LT SVR.ConclusionsIn the presence of mild decompensation (Child-Pugh ≥6), SVR12 rates with protease inhibitor triple therapy are significantly reduced and adverse events increased. Thus, treatment with protease inhibitor triple therapy, if judged as necessary, should be undertaken with close monitoring and awareness of the significant risks.

OBJECTIVES: Despite eligibility for subsidized insurance, low-income Latino children are at high risk of being medically uninsured. The authors sought to understand and improve access to medical insurance for Latino children living in a California community of predominantly low-income immigrant families. METHODS: During the summer of 1999, trained women from the community conducted interviews in Spanish with 252 randomly selected mothers of 464 children younger than age 19. Mothers provided information about family demographics, children's medical insurance, health care access, and experiences obtaining and maintaining children's insurance. RESULTS: Most children (83.3%) were eligible for subsidized medical insurance (48.4% Medi-Cal eligible; 35.0% Healthy Families eligible). Twenty-eight percent of eligible children were not enrolled. Non-enrolled eligible children were older (median age 7) than enrolled children (median age 4) and more likely to be born outside the U.S. (22.2%) than enrolled children (4.8%). Among children ages 3-18, those not enrolled were less likely to have visited a doctor in the past 12 months (58% compared to 78.7%) and less likely to have a usual source of care (96.3% compared to 99.5%). Mothers of non-enrolled children were more likely than mothers of enrolled children to have less than seven years of education (47.8% compared to 36.4%). Families with non-enrolled children were more likely to report out-of-pocket medical expenses (84.1% compared to 53%). Families with non-enrolled children were more likely to report barriers to the enrollment process, such as problems providing required documents (39.7% compared to 15.1%), problems understanding Spanish forms (19.4% compared to 8.9%), and confusing paperwork (39.7% compared to 24.7%). Most mothers (75.9%) reported that community organizations provided very useful help with children's insurance enrollment. Almost half (48.6%) preferred to receive enrollment assistance from community organizations. Only 43.3% of mothers had heard of the Healthy Families program. CONCLUSIONS: To reach the majority of uninsured Latino children, community-based outreach and insurance application assistance are crucial. Most important, the process of applying for and maintaining coverage in Medi-Cal or Healthy Families must be simplified. [ABSTRACT FROM AUTHOR]

Context: A Papanicolaou (Pap) test result of atypical squamous cells of undetermined significance (ASCUS) presents a clinical challenge. Only 5% to 10% of women with ASCUS harbor serious cervical disease, but more than one third of the high-grade squamous intraepithelial lesions (HSILs) in screening populations are identified from ASCUS Pap test results.Objective: To determine whether human papillomavirus (HPV) DNA testing of residual material from liquid-based Pap tests and referral of cases found to be HPV-positive directly to colposcopy could provide sensitive detection of underlying HSILs in women with ASCUS Pap results, compared with repeat Pap testing.Design and Setting: Natural history of women with ASCUS Pap smear results, all of whom had liquid-based cytology, HPV testing, and subsequent repeat Pap tests and colposcopy with histologic evaluation, conducted at 12 gynecology clinics in a large managed care organization between October 1995 and June 1996.Participants: From a cohort of 46009 women who had routine cervical examinations, 995 women with Pap test results of ASCUS who consented to participate were identified.Main Outcome Measures: Cervical histology, HPV test results, and repeat Pap smear results, and sensitivity of HPV testing to identify patients found to have HSIL+ histology.Results: Of 995 participants with ASCUS Pap test results, 973 had both a definitive histologic diagnosis and HPV result. Sixty-five (6.7%) had histologic HSIL or cancer. For women with histologic HSIL+, the HPV test was positive in 89.2% (95% confidence interval [CI], 78.4%-95.2%), and the specificity was 64.1 % (95% CI, 60.9%-67.2%). The repeat Pap smear result was abnormal in 76.2% (95% CI, 63.5%-85.7%). Triage based on HPV testing only or on repeat Pap testing only would refer similar proportions (approximately 39%) to colposcopy. The sensitivity of HPV DNA testing for HSIL was equivalent to, if not greater than, that of the repeat Pap test. We further estimated that an HPV-based algorithm including the immediate colposcopy of HPV-positive women, and then repeat Pap testing of all others, would provide an overall sensitivity of 96.9% (95% CI, 88.3%-99.5%).Conclusions: For women with ASCUS Pap tests, HPV DNA testing of residual specimens collected for routine cervical cytology can help identify those who have underlying HSIL. By testing the specimen collected at initial screening, the majority of high-risk cases can be identified and referred for colposcopy based on a single screening. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic studies have shown that the association of genital human papillomavirus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. There are more than 20 different cancer-associated HPV types, but little is known about their geographic variation.Purpose: Our aim was to determine whether the association between HPV infection and cervical cancer is consistent worldwide and to investigate geographic variation in the distribution of HPV types.Methods: More than 1000 specimens from sequential patients with invasive cervical cancer were collected and stored frozen at 32 hospitals in 22 countries. Slides from all patients were submitted for central histologic review to confirm the diagnosis and to assess histologic characteristics. We used polymerase chain reaction-based assays capable of detecting more than 25 different HPV types. A generalized linear Poisson model was fitted to the data on viral type and geographic region to assess geographic heterogeneity.Results: HPV DNA was detected in 93% of the tumors, with no significant variation in HPV positivity among countries. HPV 16 was present in 50% of the specimens, HPV 18 in 14%, HPV 45 in 8%, and HPV 31 in 5%. HPV 16 was the predominant type in all countries except Indonesia, where HPV 18 was more common. There was significant geographic variation in the prevalence of some less common virus types. A clustering of HPV 45 was apparent in western Africa, while HPV 39 and HPV 59 were almost entirely confined to Central and South America. In squamous cell tumors, HPV 16 predominated (51% of such specimens), but HPV 18 predominated in adenocarcinomas (56% of such tumors) and adenosquamous tumors (39% of such tumors).Conclusions: Our results confirm the role of genital HPVs, which are transmitted sexually, as the central etiologic factor in cervical cancer worldwide. They also suggest that most genital HPVs are associated with cancer, at least occasionally.Implication: The demonstration that more than 20 different genital HPV types are associated with cervical cancer has important implications for cervical cancer-prevention strategies that include the development of vaccines targeted to genital HPVs. [ABSTRACT FROM AUTHOR]

The epidemiologic determinants of seroreactivity to human papillomavirus (HPV) type 16 L1/L2 virus-like particles (VLPs) were assessed separately in HPV-16 DNA-positive and -negative women participating in a nested case-control study of incident cervical neoplasia. Seventy-four women with cervical HPV-16 DNA and 656 cytologically normal HPV-16 DNA-negative subjects were interviewed and tested at two time points for viral DNA and once (at the later time) for VLP seroreactivity. Among subjects who were currently HPV-16 DNA-negative, seroreactivity odds ratios increased from 2.9 for 2-5 male sex partners (vs. 0 or 1) to 5.4 for 6-9 partners and 14.0 for > or = 10. Thus, prior cervical infection may be a major determinant of seroreactivity in HPV-16 DNA-negative women. This trend was not observed in HPV-16 DNA-positive subjects. Seroreactivity was independently associated with oral contraceptive use, particularly in HPV-16 DNA-negative subjects with use for > or = 10 years. Consequently, a possible role for virus-steroid hormone interactions in seroconversion is suggested. [ABSTRACT FROM AUTHOR]

An ELISA to detect serum IgG antibody response to human papillomavirus (HPV) type 16 virus-like particles (VLPs) was evaluated in a case-control study of cervical neoplasia, nested within a prospective cohort study. Subjects included 688 controls with continued normal cytology and 152 cases with confirmed incident squamous intraepithelial lesions who were tested for DNA for a broad spectrum of HPV types at cohort and follow-up of controls, 16.6% were seropositive compared with 30.8% and 52.4% of cases with low- and high-grade lesions, respectively. Of HPV-16 DNA-negative subjects, 16.5% were seropositive. Seropositivity increased from 22.2% in subjects who were HPV-16 DNA-positive by polymerase chain reaction once only (enrollment or follow-up) to 83.3% in those who were HPV-16 DNA-positive at both time points. These data imply that serum antibody to HPV-16 VLPs is a relatively sensitive indicator of persisting cervical HPV-16 infection. [ABSTRACT FROM AUTHOR]

BACKGROUND: Given limited research, we investigated patient reports of processes of care related to screening follow-up, timing of result notification, communication issues, and adherence following an abnormal mammogram or Pap test. METHODS: Women age 50 and over with an abnormal screening mammogram and women age 18 and above with an abnormal Pap test result completed surveys. The mammogram and Pap survey instruments had similar items except pertaining to measures specific to mammography or Pap tests. Bivariate associations between processes of care variables (test results, result receipt, recommendation adherence, receipt of confusing/conflicting information) and global satisfaction were explored using chi-square contingency table analysis. Multivariable logistic regression modeling was conducted. RESULTS: One thousand one hundred thirty-four women (79.1%) completed the mammogram survey and 1087 women (69.7%) completed the Pap survey. The majority of women received test results quickly. High compliance was reported with recommendations for short-term follow-up. Conflicting/confusing information was reported by a minority of women, but was significantly and positively related to reporting that 'care could be better'. Patient's lack of understanding about equivocal findings was evident. CONCLUSIONS: This study confirms that patients need clear messages about recommendations, especially when findings are equivocal and where multiple providers are involved in the process of making clinical decisions. Copyright 2004 The Institute for Cancer Prevention and Elsevier Inc. [ABSTRACT FROM AUTHOR]

Purpose Play is a critical aspect of children's development, and researchers have long argued that symbolic deficits in play may be diagnostic of developmental disabilities. This study examined whether deficits in play emerge as a function of developmental disabilities and whether our perceptions of play are colored by differences in language and behavioral presentations. Method Ninety-three children participated in this study (typically developing [TD]; n = 23, developmental language disorders [DLD]; n = 24, attention-deficit/hyperactivity disorder [ADHD]; n = 26, and autism spectrum disorder [ASD]; n = 20). Children were videotaped engaging in free-play. Children's symbolic play (imagination, organization, elaboration, and comfort) was scored under conditions of both audible language and no audible language to assess diagnostic group differences in play and whether audible language impacted raters' perception of play. Results Significant differences in play were evident across diagnostic groups. The presence of language did not alter play ratings for the TD group, but differences were found among the other diagnostic groups. When language was audible, children with DLD and ASD (but not ADHD) were scored poorly on play compared to their TD peers. When language was not audible, children with DLD were perceived to play better than when language was audible. Conversely, children with ADHD showed organizational deficits when language was not available to support their play. Finally, children with ASD demonstrated poor play performance regardless of whether language was audible or not. Conclusions Language affects our understanding of play skills in some young children. Parents, researchers, and clinicians must be careful not to underestimate or overestimate play based on language presentation. Differential skills in language have the potential to unduly influence our perceptions of play for children with developmental disabilities.

The contribution of the host immune system to the efficacy of new anti-hepatitis C virus (HCV) drugs is unclear. We undertook a longitudinal prospective study of 33 individuals with chronic HCV treated with combination pegylated IFN-α, ribavirin, and telaprevir/boceprevir. We characterized innate and adaptive immune cells to determine whether kinetics of the host response could predict sustained virologic response (SVR). We show that characteristics of the host immune system present before treatment were correlated with successful therapy. Augmentation of adaptive immune responses during therapy was more impressive among those achieving SVR. Most importantly, active memory T cell proliferation before therapy predicted SVR and was associated with the magnitude of the HCV-specific responses at week 12 after treatment start. After therapy initiation, the most important correlate of success was minimal monocyte activation, as predicted by previous in vitro work. In addition, subjects achieving SVR had increasing expression of the transcription factor T-bet, a driver of Th1 differentiation and cytotoxic effector cell maturation. These results show that host immune features present before treatment initiation predict SVR and eventual development of a higher frequency of functional virus-specific cells in blood. Such host characteristics may also be required for successful vaccine-mediated protection., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Screening for oral leukoplakia, an oral cavity cancer (OCC) precursor, could lead to earlier detection of OCC. However, the progression rate from leukoplakia to OCC and the benefits of leukoplakia screening for improving OCC outcomes are currently unclear. We conducted a case-cohort study of U.S. adults ages ≥65 years in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linkage. We identified leukoplakia diagnoses through Medicare claims, and OCC diagnoses through SEER cancer registries. Weighted Cox regression was used to estimate leukoplakia associations with OCC incidence, and the absolute OCC risk following leukoplakia diagnosis was calculated. Among OCC cases, we compared OCC stage and OCC survival between cases with a prior leukoplakia diagnosis versus those without prior leukoplakia. Among 470,266 individuals in the SEER-Medicare subcohort, 1,526 (0.3%) had a leukoplakia diagnosis. Among people with leukoplakia, the cumulative OCC incidence was 0.7% at 3 months and 2.5% at 5 years. OCC risk was most increased <3 months after leukoplakia diagnosis (HR, 115), likely representing the diagnosis of prevalent cancers. Nonetheless, risk remained substantially increased in subsequent follow-up [HR ≥ 3 months, 24; 95% confidence interval (CI), 22-27; HR ≥ 12 months, 22, 95% CI, 20-25]. Among OCC cases (N = 8,927), those with prior leukoplakia were less likely to be diagnosed at regional/distant stage (OR, 0.36; 95% CI, 0.30-0.43), and had lower mortality (HR, 0.74; 95% CI, 0.65-0.84) when compared with OCC cases without a prior leukoplakia. Individuals with leukoplakia have substantially elevated risk of OCC. Lower stage and better survival after OCC diagnosis suggest that leukoplakia identification can lead to earlier OCC detection and reduced mortality., (©2015 American Association for Cancer Research.)

Objective: High-risk HPV (hrHPV) and cytology co-testing is utilized for primary cervical cancer screening and for enhanced follow-up of women who are hrHPV-positive, cytology negative. However, data are lacking on the utility of this method to detect pre-cancer or cancer in community-based clinical practice. This study describes cytology and hrHPV results preceding high-grade cervical intraepithelial neoplasia, adenocarcinoma in situ, or cervical cancer (i.e., CIN2+) in an integrated health system employing routine co-testing among women aged 30 years and older., Methods: We conducted a cross-sectional analysis of adult female members of Kaiser Permanente Northern California (KPNC) with incident CIN2+ between July 2008 and June 2009. The primary outcome was the proportions of cytologic diagnoses and hrHPV co-test results preceding a diagnosis of CIN2+. Cervical cytology and hrHPV testing results were abstracted from electronic medical records., Results: Of 1283 CIN2+ cases among adult women, 880 (68.5%) were among women aged 30 years and older and 145/880 (16.5%, 95% CI 14.1-19.1) had only normal cytology during the 12 months prior to diagnosis. Furthermore, 133/880 (15.1%, 95% 12.9-17.7) were preceded by only normal cytology and persistent hrHPV infection (at least 2 positive hrHPV tests) during the 6-36 months preceding CIN2+ diagnosis., Conclusions: Incident CIN2+ is frequently preceded by normal cytology and persistent hrHPV infection among women aged 30 years and older; screening strategies that employ HPV testing and cytology may improve the detection of CIN2+ compared with cytology alone.

Background: In 2011, the FDA approved telaprevir (TVR) and boceprevir (BOC) for use with pegylated interferon and ribavirin to treat hepatitis C virus (HCV) genotype 1. We aimed to evaluate the real-world application, tolerability, and effectiveness of TVR- and BOC-based HCV treatment in a large integrated care setting., Methods: We utilized Northern California Kaiser Permanente Medical Care Program (KPNC) electronic databases and medical records to study the experience of all KPNC patients who initiated TVR or BOC from June 2011 to March 2012., Results: Compared with the pool of 5,194 treatment-eligible patients, the 352 treatment initiators were more likely to be cirrhotic (24 vs. 10%, p < 0.001) and treatment-experienced (44 vs. 22%, p < 0.001). Among the treatment initiators, 211 received TVR and 141 BOC. Overall, 31% discontinued treatment prematurely; 16% of patients stopped treatment early because of side effects. One patient with cirrhosis died of sepsis during treatment. Premature discontinuation was highest among TVR-treated cirrhotic patients (58%). Sustained virologic response (SVR) was achieved in 55% overall and was similar comparing the TVR (56%)- and BOC (53%)-treated groups. The only independent predictors of treatment failure were cirrhosis at baseline [odds ratio (OR) for SVR 0.44, p = 0.004] and prior partial or null response (OR for SVR 0.57, p = 0.02)., Conclusions: In the initial application of TVR and BOC, patients with cirrhosis and prior treatment failure were prioritized for treatment. In this real-world experience, most patients successfully completed a full treatment course. However, side effect-related premature discontinuations were common, and SVR rates were lower than reported in clinical trials.

Background: Few population-based studies have described characteristics and management of patients with chronic hepatitis B (CHB) in the USA., Methods: We retrospectively studied adults with CHB in the Northern California Kaiser Permanente Medical Care Program (KPNC) from July 2009 to December 2010 (n = 12,016). Laboratory tests, treatment patterns, and hepatocellular carcinoma (HCC) surveillance were ascertained during a "recent" 18-month study window (July 2009-December 2010), or as "ever" based on records dating to 1995., Results: The mean age was 49 years; 51 % were men, 83 % Asian, and 87 % KPNC members >5 years. Overall, 51 % had ≥ 1 liver-related visit, 14 % with gastroenterology or infectious disease specialists, and 37 % with primary care providers (PCP) only. Less than 40 % of patients had both hepatitis B virus (HBV) DNA and ALT testing conducted recently, while 56 % of eligible patients had received HCC surveillance. Recent laboratory testing and HCC surveillance were more frequent in patients seen by a specialist versus PCP only (90 vs. 47 % and 92 vs. 73 %, respectively, p values <0.001). During the study period, 1,649 (14 %) received HBV treatment, while 5 % of untreated patients had evidence of treatment eligibility. Among 599 patients newly initiated on HBV therapy, 76 % had guideline-based indications for treatment., Conclusions: Most patients initiated on HBV treatment met eligibility, and very few patients with evidence of needing treatment were left untreated. However, monitoring of ALT and HBV DNA levels, as well as HCC surveillance, were not frequent, underestimating the proportion of patients that warranted HBV therapy. Viral monitoring and cancer surveillance are therefore important targets for improving the scope of CHB care in the community setting.

Objectives: We compared chronic liver disease (CLD) mortality from 1999 to 2009 between American Indians and Alaska Natives (AI/ANs) and Whites in the United States after improving CLD case ascertainment and AI/AN race classification., Methods: We defined CLD deaths and causes by comprehensive death certificate-based diagnostic codes. To improve race classification, we linked US mortality data to Indian Health Service enrollment records, and we restricted analyses to Contract Health Service Delivery Areas and to non-Hispanic populations. We calculated CLD death rates (per 100,000) in 6 geographic regions. We then described trends using linear modeling., Results: CLD mortality increased from 1999 to 2009 in AI/AN persons and Whites. Overall, the CLD death rate ratio (RR) of AI/AN individuals to Whites was 3.7 and varied by region. The RR was higher in women (4.7), those aged 25 to 44 years (7.4), persons residing in the Northern Plains (6.4), and persons dying of cirrhosis (4.0) versus hepatocellular carcinoma (2.5), particularly those aged 25 to 44 years (7.7)., Conclusions: AI/AN persons had greater CLD mortality, particularly from premature cirrhosis, than Whites, with variable mortality by region. Comprehensive prevention and care strategies are urgently needed to stem the CLD epidemic among AI/AN individuals.

Background: Interferon α (IFN-α) and ribavirin can induce a sustained virologic response (SVR) in some but not all hepatitis C virus (HCV)-infected patients. The mechanism of effective treatment is unclear. One possibility is that IFN-α differentially improves the functional capacity of classic myeloid dendritic cells (mDCs) by altering expression of surface molecules or cytokines. Others have proposed that antigen-presenting cell activation could be paradoxically detrimental during HCV infection because of the production by monocytes of substances inhibitory or toxic to plasmacytoid dendritic cells., Methods: We examined responses to in vitro IFN-α treatment of peripheral blood leukocyte samples from a retrospective treatment cohort of nearly 200 HCV-seropositive patients who had undergone antiviral therapy with ribavirin and pegylated IFN. We analyzed the variable responses of antigen-presenting cell subsets to drug., Results: We found that patients achieving SVR were no more likely to have robust mDC activation in response to IFN-α than those who did not achieve SVR. Rather, patients achieving SVR were distinguished by restrained monocyte activation in the presence of IFN-α, a factor that was second in importance only to IL28B genotype in its association with SVR., Conclusions: These results suggest that interindividual variability in the response of monocytes to IFN-α is an important determinant of treatment success with IFN-α-based regimens.

Background: Studies suggest that chronic hepatitis C patients who achieve sustained virologic response (SVR) have lower risks of liver-related morbidity and mortality. Given the substantial costs and complexity of hepatitis C virus (HCV) antiviral treatment, post-treatment benefits are important to understand.  , Objective: To determine whether health care costs and utilization for up to 5 years after treatment differed between patients who achieved SVR and those who did not. , Methods: Kaiser Permanente Medical Care Program patients receiving HCV treatment with pegylated interferon and ribavirin (Peg-IFN/RBV) from 2002 to 2007 were retrospectively analyzed, excluding those with human immunodeficiency virus (HIV) or chronic hepatitis B. Health care utilization and costs for up to 5 years after treatment completion were derived from electronic records. We compared mean annual cost and overall post-treatment costs (standardized to year-2007 dollars), and yearly utilization counts between the SVR and non-SVR groups, adjusting for pretreatment costs, age, sex, baseline cirrhosis, and race using gamma and Poisson regression models. , Results: The 1,924 patients eligible for inclusion were a mean age of 50 years; 63% male; 58% white, non-Hispanic; 62% with genotype 1; and 48% who had achieved SVR. The mean duration of post-treatment time was 3 years, and patients without SVR incurred significantly higher health care costs than patients with SVR. For each post-treatment year, total adjusted costs were significantly higher in the non-SVR group than in the SVR group, with rate ratios (RRs) and 95% CIs ranging from 1.26 (95% CI, 1.13-1.40) to 1.64 (95% CI, 1.38-1.96), driven mostly by hospital and outpatient pharmacy costs. When all post-treatment years were considered collectively, the non-SVR group had significantly higher costs overall (RR=1.41; 95% CI, 1.17-1.69) and in each category of costs. The adjusted difference in yearly total mean costs was $2,648 (95% CI, 737-4,560). In post-treatment years 2-5, adjusted liver-specific laboratory test rates were 1.8 to 2.3 times higher in the non-SVR group than in the SVR group (each year, P less than 0.001). During post-treatment years 1-5, adjusted yearly liver-related hospitalization rates were up to 2.45 times higher (95% CI, 1.56-3.85), and medicine/GI clinic visit rates were up to 1.39 times higher (95% CI, 1.23-1.54) in the non-SVR group compared with the SVR group. , Conclusion: Health care utilization and costs after HCV antiviral therapy with Peg-IFN/RBV, particularly for liver-related tests, outpatient drugs, and hospitalizations, were significantly lower for patients who achieved SVR than for those without SVR. Our observations are consistent with the potentially lower risk of severe liver disease among patients with SVR.

Background: Hepatitis C virus (HCV) antiviral therapy entails a long treatment course, as well as significant side effects that can lead to medication non-adherence and premature termination of treatment. Few large studies have comprehensively examined patient perspectives on the treatment experience, particularly the social and personal effects., Objective: We sought to understand how a diverse group of patients' lives were affected during HCV treatment, and to obtain suggestions about how to better support patients during treatment., Methods: On average, 13 months after therapy we interviewed by telephone a consecutive sample of 200 patients treated for hepatitis C with ribavirin and pegylated interferon in a comprehensive, integrated health plan in the years 2008-2010. Mixed (quantitative and qualitative) survey methods were used., Results: The response rate was 68.9 %. Mean age at treatment was 51 years; 63.0 % were men; and Black, Hispanic, Asian, and White non-Hispanic racial/ethnic groups were similarly represented. Patients whose treatment was managed by nurses or clinical pharmacists (vs. physicians) were more likely to report their providers as being part of their support system (83.5 % vs. 58.9 %; p < 0.001). Most patients reported flu-like symptoms (93.5 %) and psychiatric problems (84.5 %), and 42.5 % reported side effects lasted up to 6 months after treatment. Black patients reported discontinuing treatment prematurely due to side effects more often than non-Blacks (29.4 % vs. 12.1 %; p < 0.001). Physical side effects (69.5 % of patients), psychiatric issues (43.5 %), and employment (27.4 %) were ranked among the three most difficult challenges. Patients desired help in anticipating and arranging work modifications during treatment. Most patients rated peer support, nutritional guidance, and weekly provider contact by telephone as potentially helpful resources for future patients undergoing HCV treatment., Conclusions: Patient perspectives can help formulate and refine HCV treatment support programs. Effective support programs for diverse populations are crucial as the complexities and costs of HCV treatment increase. The call for greater support from peers, providers, and employers demands new systems such as patient-centered care teams.

Hepatitis C virus (HCV) genotypes influence response to therapy, and recently approved direct-acting antivirals are genotype-specific. Genotype distribution information can help to guide antiviral development and elucidate infection patterns. HCV genotype distributions were studied in a diverse cross-section of patients in the Northern California Kaiser Permanente health plan. Associations between genotype and race/ethnicity, age, and sex were assessed with multivariate logistic regression models. The 10,256 patients studied were median age 56 years, 62% male, 55% White non-Hispanic. Overall, 70% were genotype 1, 16% genotype 2, 12% genotype 3, 1% genotype 4, <1% genotype 5, and 1% genotype 6. Blacks (OR 4.5 [3.8-5.5]) and Asians (OR 1.2 [1.0-1.4]) were more likely to have genotype 1 than 2/3 versus non-Hispanic Whites. Women less likely had genotype 1 versus 2/3 than did men (OR 0.86 [0.78-0.94]). Versus non-Hispanic Whites, Asians (OR 0.38 [0.31-0.46]) and Blacks (OR 0.73 [0.63-0.84]) were less likely genotype1a than 1b; Hispanics (OR 1.3 [1.1-1.5]) and Native Americans (OR 1.9 [1.2-2.8]) more likely had genotype 1a than 1b. Patients age ≥65 years less likely had genotype 1a than 1b versus those age 45-64 (OR 0.34 [0.29-0.41]). The predominance of genotype 1 among all groups studied reinforces the need for new therapies targeting this genotype. Racial/ethnic variations in HCV genotype and subtype distribution must be considered in formulating new agents and novel strategies to successfully treat the diversity of hepatitis C patients., (Copyright © 2012 Wiley Periodicals, Inc.)

Assessment of liver fibrosis is important in determining prognosis and evaluating interventions. Due to limitations of accuracy and patient hazard of liver biopsy, non-invasive methods have been sought to provide information on liver fibrosis, including the European liver fibrosis (ELF) test, shown to have good diagnostic accuracy for the detection of moderate and severe fibrosis. Access to independent cohorts of patients has provided an opportunity to explore if this test could be simplified. This paper reports the simplification of the ELF test and its ability to identity severity of liver fibrosis in external validation studies in patients with chronic hepatitis C (CHC). Paired biopsy and serum samples from 347 naïve patients with CHC in three independent cohorts were analysed. Diagnostic performance characteristics were derived (AUROC, sensitivity and specificity, predictive values), and clinical utility modelling performed to determine the proportion of biopsies that could have been avoided if ELF test was used in this patient group. It was possible to simplify the original ELF test without loss of performance and the new algorithm is reported. The simplified ELF test was able to predict severe fibrosis [pooled AUROC of 0.85 (95% CI 0.81-0.89)] and using clinical utility modelling to predict severe fibrosis (Ishak stages 4-6; METAVIR stages 3 and 4) 81% of biopsies could have been avoided (65% correctly). Issues of spectrum effect in diagnostic test evaluations are discussed. In chronic hepatitis C a simplified ELF test can detect severe liver fibrosis with good accuracy.

Objectives: Chronic liver disease (CLD) is an important cause of morbidity and mortality, but the epidemiology is not well described. We conducted prospective population-based surveillance to estimate newly diagnosed CLD incidence, characterize etiology distribution, and determine disease stage., Methods: We identified cases of CLD newly diagnosed during 1999-2001 among adult county residents seen in any gastroenterology practice in New Haven County, Connecticut; Multnomah County, Oregon; and Northern California Kaiser Permanente Medical Care Program (KPMCP, Oakland, California [total population 1.48 million]). We defined CLD as abnormal liver tests of at least 6 months' duration or pathologic, clinical, or radiologic evidence of CLD. Consenting patients were interviewed, a blood specimen obtained, and the medical record reviewed., Results: We identified 2,353 patients with newly diagnosed CLD (63.9 cases/100,000 population), including 1,225 hepatitis C patients (33.2 cases/100,000). Men aged 45-54 yr had the highest hepatitis C incidence rate (111.3/100,000). Among 1,040 enrolled patients, the median age was 48 yr (range 19-86 yr). Hepatitis C, either alone (442 [42%]) or in combination with alcohol-related liver disease (ALD) (228 [22%]), accounted for two-thirds of the cases. Other etiologies included nonalcoholic fatty liver disease (NAFLD, 95 [9%]), ALD (82 [8%]), and hepatitis B (36 [3%]). Other identified etiologies each accounted for <3% of the cases. A total of 184 patients (18%) presented with cirrhosis, including 44% of patients with ALD., Conclusions: Extrapolating from this population-based surveillance network to the adult U.S. population, approximately 150,000 patients with CLD were diagnosed in gastroenterology practices each year during 1999-2001. Most patients had hepatitis C; heavy alcohol consumption among these patients was common. Almost 20% of patients, an estimated 30,000 per year, had cirrhosis at presentation. These results provide population-level baseline data to evaluate trends in identification of patients with CLD in gastroenterology practices.

Unlabelled: Standard death certificate-based methods for ascertaining deaths due to chronic liver disease (CLD), such as the U.S. vital statistics approach, rely on a limited set of diagnostic codes to define CLD. These codes do not include viral hepatitis or consider hepatocellular carcinoma (HCC) deaths, and thus, underestimate the true burden of CLD mortality. Deaths associated with CLD may be further misunderstood because of the inherent limitations of death record information. Using a comprehensive list of CLD-related codes to search death records, we investigated the CLD mortality rate and associated etiologies (derived from medical records) in a large managed care health plan. From the 16,970 deaths among health plan members in 2000, we confirmed 355 (2.1%) as CLD related, including 75 with HCC. The age-adjusted CLD mortality rate using the comprehensive codes was 11.9 per 100,000 compared with 6.3 per 100,000 using only conventional codes. Based on medical records, the underlying CLD was attributed to alcoholic liver disease (ALD) in 44% of deaths, HCV infection with ALD in 16%, HCV without ALD in 18%, and chronic HBV infection in 7%. Only 64% of HCV-associated, 48% of HBV-associated, and 64% of ALD-associated deaths ascertained by medical record had that specific etiology mentioned on the death certificate., Conclusion: CLD mortality burden was almost doubled by using a comprehensive list of mortality codes and considering HCC deaths as CLD related. Furthermore, the contributions of viral hepatitis and ALD to CLD mortality may be underestimated if based solely on death records.

Background: Little is known about the potential adverse hepatic effects of HMG-CoA reductase inhibitors ('statins') in patients with existing liver disease; therefore, we examined the risk of liver toxicity with lovastatin exposure in these patients., Methods: A retrospective cohort study was performed using data from a large integrated health plan in Northern California, USA. Patients with laboratory or clinical evidence of liver disease were identified and their exposure to lovastatin was determined. The primary outcome was a pattern of liver-test abnormalities associated with a poor prognosis among patients with drug-induced liver disease, based on Hy's Rule. Secondary outcomes included liver injury (defined as moderate or severe, depending on the degree of ALT level elevations) or the development of either clinical cirrhosis or liver failure. Incidence rate ratios (IRRs) were calculated and multivariate analyses conducted using extended Cox models., Results: A total of 93 106 patients met the entry criteria. Lovastatin exposure was associated with a lower incidence of all endpoints, including the primary outcome (IRR = 0.28, 95% CI 0.12, 0.55), moderate liver injury (IRR = 0.56, 95% CI 0.47, 0.65), severe liver injury (IRR = 0.50, 95% CI 0.29, 0.81) and the occurrence of either cirrhosis or liver failure (IRR = 0.29, 95% CI 0.21, 0.38); adjustment for age and sex resulted in some attenuation of this reduction in incidence. The observed effects were generally consistent across a range of baseline liver-disease diagnoses and greater cumulative lovastatin exposure was associated with fewer outcome events for some endpoints., Conclusions: In this retrospective analysis, exposure to lovastatin was not associated with an increased risk of adverse hepatic outcomes. These results do not support concern regarding lovastatin-related hepatotoxicity in patients with existing liver disease.

The purpose of this study was to develop an algorithm for identifying patients with chronic hepatitis B virus (HBV) using automated data sources from two US health systems and evaluate the algorithm's performance by quantifying the incidence of hepatocellular carcinoma (HCC) among chronic HBV patients. To allow comparisons with estimates from automated databases that may not contain all data elements used in this algorithm, we created three definitions of chronic HBV infection and used these definitions to create three overlapping cohorts. We compared the incidence of HCC in each cohort with the incidence of HCC in a matched general population comparison cohort with no evidence of HBV. Patients who met the most stringent criteria for chronic HBV infection (based on the standard definition of 6 months of infection using repeat laboratory tests and record review) were 146 times more likely to develop HCC than matched comparison patients (adjusted hazard ratio = 146.5, 95% CI: 74.0-289.8). Those not meeting the stringent criteria, but who met the criterion of at least one positive hepatitis B surface antigen test were 30 times more likely to develop HCC than comparison patients (adjusted hazard ratio = 29.8, 95% CI: 16.5-53.6). Finally, patients who met the criterion based on at least one HBV diagnosis were 38 times more likely to develop HCC than matched comparison patients (adjusted hazard ratio = 37.8, 95% CI: 25.9-55.1). The magnitude of the relative increase in HCC risk seen using different criteria used to define HBV infection indicate that these automated data algorithms can identify patients with chronic HBV infection.

Unlabelled: Although hepatitis C virus (HCV) infection has been shown to be associated with development of non-Hodgkin's lymphoma (NHL), few studies have investigated the association between chronic HBV infection and NHL. The purpose of this study was to compare the incidence of NHL between patients with and without chronic hepatitis B virus (HBV) infection. Using automated laboratory result and clinical data from two United States health systems, we identified individuals with chronic HBV infection from January 1, 1995 through December 31, 2001. Using each health system's population-based tumor registry, we identified all cases of NHL diagnosed through December 31, 2002. We excluded any individual with a history of NHL or human immunodeficiency virus (HIV). We fit Cox proportional hazards models to calculate hazard ratios comparing the incidence of NHL between chronic HBV-infected patients (N = 3,888) and patients without HBV (N = 205,203) drawn from the source populations. We identified 8 NHL cases in the chronic HBV infection cohort and 111 cases in the comparison cohort. Patients with chronic HBV infection were 2.8 times more likely to develop NHL than matched comparison patients (adjusted hazard ratio = 2.80, 95% confidence interval = 1.16-6.75), after controlling for age, race, sex, income, Charlson comorbidity index, study site, and HCV infection., Conclusion: chronic HBV-infected patients were nearly 3 times more likely to develop NHL than comparison patients.

Objective: To determine the incidence of abnormal laboratory test results among isotretinoin users., Design: Retrospective cohort., Setting: Comprehensive managed care health plan in Northern California., Participants: The study population comprised 13 772 patients aged 13 to 50 years with acne, undergoing oral isotretinoin therapy between March 1995 and September 2002., Main Outcome Measures: Laboratory values for serum triglyceride, total cholesterol, and liver transaminase levels; white blood cell count, hemoglobin level, and platelet count; and frequency of abnormal laboratory results by severity grade as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0., Results: Substantial increases in the cumulative incidence of abnormalities were seen in serum lipid and transaminase levels, but not in hematologic parameters, during isotretinoin treatment compared with the baseline period. The cumulative incidence of new abnormalities in patients with normal values at baseline was 44% for triglyceride level, 31% for total cholesterol level, and 11% for transaminase level. Moderate to severe abnormalities in lipid and transaminase levels were generally transient and reversible. New abnormalities in hematological test results were uncommon., Conclusions: The incidence of abnormally high serum lipid levels during isotretinoin treatment may be greater than previously estimated. Elevations in transaminase level are generally mild. Normal baseline values of serum lipid and transaminase levels do not preclude the development of new abnormalities during isotretinoin treatment. Routine monitoring of white blood cell count, hemoglobin level, and platelet count during isotretinoin therapy may be of little utility without clinical suspicion of an abnormality. The clinical significance of laboratory abnormalities during isotretinoin therapy remains to be determined.

Background: Invasive cervical cancer is highly preventable, yet it continues to occur, even among women who have access to cancer screening and treatment services. To reduce cervical cancer among such women, reasons for its occurrence must be better understood. We examined factors associated with the diagnosis of cervical cancer among women enrolled in health plans., Methods: We identified all cases of invasive cervical cancer (n = 833) diagnosed from January 1, 1995, through December 31, 2000, among women who were long-term members of seven prepaid comprehensive health plans and reviewed each woman's medical records for the 3 years prior to her cancer diagnosis. Women were classified into one of three categories based on Pap test histories 4-36 months before diagnosis: failure to screen with a Pap test, failure in detection by a Pap test, or failure in follow-up of an abnormal test result., Results: The majority of cases (n = 464; 56%) were in women who had no Pap tests during the period 4-36 months prior to diagnosis. Of the remaining cases, 263 (32%) were attributed to Pap test detection failure and 106 (13%) to follow-up failure. Being older (odds ratio [OR] = 6.48, 95% confidence interval [CI] = 3.89 to 10.79) or living in an area of higher poverty (OR = 1.72, 95% CI = 1.11 to 2.67) or having a lower education level (OR= 1.52; 95% CI = 1.07 to 2.16) was associated with the likelihood of being assigned to the failure to screen category versus either of the other two categories. A total of 375 (81%) of the 464 patients who had not had Pap screening had had at least one outpatient visit 4-36 months prior to cancer diagnosis. The cancer diagnostic process was triggered by a routine screening examination in 44% of patients, whereas 53% of the patients presented with symptoms consistent with cervical cancer; the remaining 3% were identified fortuitously during the course of receiving noncervical care., Conclusions: To reduce the incidence of invasive cervical cancer among women with access to screening and treatment, Pap screening adherence should be increased. In addition, strategies to improve the accuracy of Pap screening could afford earlier detection of cervical cancer.

We performed a cross-sectional study of newly diagnosed cases of nonalcoholic fatty liver disease (NAFLD) identified between December 1998 and December 2000 in the Chronic Liver Disease Surveillance Study. We compared the demographic and clinical features of NAFLD in a racially diverse representative U.S. population (Alameda County, CA). Diagnostic criteria for probable NAFLD were persistent unexplained elevation of serum aminotransferase levels, radiology (ultrasound or computed tomography scan) consistent with fatty liver, and/or two or more of the following: (i) body mass index of 28 kg/m(2) or more, (ii) type 2 diabetes, or (iii) hyperlipidemia, in the absence of significant alcohol use. Definite NAFLD cases required histological confirmation. Of the 742 persons with newly diagnosed chronic liver disease, 159 (21.4%) had definite or probable NAFLD. The majority were nonwhite: Hispanics (28%), Asians (18%), African Americans (3%), and other race(s) (6%). African Americans with NAFLD were significantly older than other racial or ethnic groups (P < .001), and in Asians, NAFLD was 3.5 times more common in males than in females (P = .016). Clinical correlates of NAFLD (obesity, hyperlipidemia, diabetes) were similar among racial and ethnic groups, except that body mass index was lower in Asians compared with other groups (P < .001). Compared with the base population (Kaiser Permanente members), Hispanics with NAFLD were overrepresented (28% vs. 10%) and whites were underrepresented (45% vs. 59%). In conclusion, these racial and gender variations may reflect differences in genetic susceptibility to visceral adiposity, including hepatic involvement, and may have implications for the evaluation of persons with the metabolic syndrome. Clinicians need to be aware of the variable presentations of NAFLD in different racial and ethnic groups.

Background: Mammography screening increases the detection of early-stage breast cancers. Therefore, implementing screening should reduce the percentage of women who are diagnosed with late-stage disease. However, despite high national mammography screening rates, late-stage breast cancers still occur, possibly because of failures in screening implementation., Methods: Using data from seven health care plans that included 1.5 million women aged 50 years or older, we conducted retrospective reviews of chart and automated data for 3 years before 1995-1999 diagnoses of late-stage (metastatic and/or tumor size > or =3 cm; case subjects, n = 1347) and early-stage breast cancers (control subjects, n = 1347). We categorized the earliest screening mammogram during the period 13-36 months before diagnosis as none (absence of screening), negative (absence of detection), or positive (potential breakdown in follow-up). We compared the proportion of case and control subjects in each category of screening implementation and estimated the likelihood (odds ratio [OR] with 95% confidence intervals [CIs]) of late-stage breast cancer. We also evaluated demographic characteristics associated with absence of screening in women with late-stage disease. All statistical tests were two-sided., Results: Absence of screening, absence of detection, and potential breakdown in follow-up were distributed differently among case (52.1%, 39.5%, and 8.4%, respectively) and control subjects (34.4%, 56.9%, and 8.8%, respectively) (P = .03). Among all women, the odds of having late-stage cancer were higher among women with an absence of screening (OR = 2.17, 95% CI = 1.84 to 2.56; P<.001). Among case patients, women were more likely to be in the absence-of-screening group if they were aged 75 years or older (OR = 2.77, 95% CI = 2.10 to 3.65), unmarried (OR = 1.78, 95% CI = 1.41 to 2.24), or without a family history of breast cancer (OR = 1.84, 95% CI = 1.45 to 2.34). A higher proportion of women from census blocks with less education (58.5% versus 49.4%; P = .003) or lower median annual income (54.4% versus 42.9%; P = .004) were in the absence-of-screening category compared with the proportion for the other two categories combined., Conclusions: To reduce late-stage breast cancer occurrence, reaching unscreened women, including elderly, unmarried, low-income, and less educated women, should be made a top priority for screening implementation.

We compared the performance of a prototype version of the Hybrid Capture 3 (HC3) human papillomavirus (HPV) DNA assay to the current generation Hybrid Capture 2 (HC2) assay, both of which target 13 oncogenic HPV types, for the detection of cervical intraepithelial neoplasia grade 3 and cancer (CIN3+) with cervicovaginal lavage specimens collected at enrollment into a 10-year cohort study at Kaiser Permanente (Portland, Oreg.). HC3 results for a risk-stratified sample (n = 4,364) were compared to HC2 results for the entire cohort (n = 20,810) with receiver operating characteristics curves, and the optimal cut points for both tests (relative light units [RLU]/positive control [PC]) for the detection of CIN3+ were determined. Specimens were also tested for HPV16 and HPV18 with separate HC3 type-specific probes. The optimal cut point for detecting CIN3+ was 1.0 RLU/PC for HC2, as previously shown, and was 0.6 RLU/PC for HC3. At the optimal cut points, HC3 and HC2 had similar screening performance characteristics for CIN3+ diagnosed at the enrollment visit. In analyses that included cases CIN3+ at enrollment and those diagnosed during early follow-up, HC3 had nonsignificantly higher sensitivity and equal specificity for the detection of CIN3+ compared to HC2; this increase in sensitivity was primarily the result of increased detection of CIN3+ in women who were 30 years of age or older and were cytologically negative (P = 0.006). We also compared the performance of the hybrid capture tests to MY09/11 L1 consensus primer PCR results (n = 1,247). HC3 was less likely than HC2 to test positive for specimens that tested positive by PCR for any untargeted types (P < 0.001). HC3 was less likely than HC2 to test positive for untargeted PCR-detected single infections with HPV53 (P = 0.001) and HPV66 (P = 0.01). There was good agreement between test positivity by PCR and by single type-specific HC3 probes for HPV16 (kappa = 0.76; 95% confidence interval [CI] = 0.71 to 0.82) and for HPV18 (kappa = 0.73; 95% CI = 0.68 to 0.79). In conclusion, we suggest that HC3 (>/=0.6 RLU/PC) may be slightly more sensitive than and equally specific test as HC2 (>/=1.0 RLU/PC) for the detection of CIN3+ over the duration of typical screening intervals.

This commentary presents a conceptual framework, Quality in the Continuum of Cancer Care (QCCC), for quality improvement studies and research. Data sources include review of relevant literature (cancer care, quality improvement, organizational behavior, health services evaluation, and research). The Detecting Early Tumors Enables Cancer Therapy (DETECT) project is used to apply the QCCC model to evaluate the quality of secondary prevention. Cancer care includes risk assessment, primary prevention, screening, detection, diagnosis, treatment, recurrence surveillance, and end-of-life care. The QCCC model represents a systematic approach for assessing factors that influence types of cancer care and the transitions between them, the factors at several levels (community, plan and practice setting) that potentially impact access and quality, and the strategies groups and organizations can consider to reduce potential failures. Focusing on the steps and transitions in care where failures can occur can facilitate more organized systems and medical practices that improve care, establish meaningful measures of quality that promote improved outcomes, and enhance interdisciplinary research.

Background: Healthcare utilization (HCU) following a sexually transmitted disease (STD) diagnosis is poorly characterized., Goal: The goal was to quantify HCU for new/recurrent STDs and other relevant Ob-Gyn and mental health problems in the 18 months subsequent to an STD diagnosis., Study Design: We compared HCU between a group of females aged 18 to 45 years who were Kaiser Permanente Medical Program members with a diagnosed STD (n = 1,205) and a medical center- and age group-matched sample of women seen for a non-STD diagnosis in the same time period (n = 4820), with controlling where appropriate for age, medical center, and chronic disease status., Results: An STD diagnosis was associated with significantly greater likelihood of subsequent visits for STDs (relative risk [RR] = 3.8), pelvic inflammatory disease/endometritis (RR = 2.9), candidiasis (RR = 2.0), vaginitis (RR = 2.4), cervical dysplasia (RR = 1.7), menstrual disorders/abnormal bleeding (RR = 1.3), high risk/complicated/ectopic pregnancy (RR = 1.5), and behavioral/mental health problems (RR = 1.3) than for women seen for a non-STD diagnosis., Conclusion: Detrimental sequelae of STDs are reflected in substantially elevated near-term HCU following an STD diagnosis.

Background: Sexual behaviors have been linked to seropositivity for human papillomavirus (HPV) but not with the magnitude of the seroreactivity., Goals: The objective of this analysis was to examine the association of sexual behavior, cervical HPV 16 DNA positivity at enrollment (past) and at diagnosis (current), and other potential determinants with the likelihood and magnitude of HPV 16 seropositivity at diagnosis., Study Design: With use of stored specimens from an incidence case-control study at Kaiser Permanente (Portland, OR), women were tested for seroreactivity to HPV 16 by enzyme-linked immunosorbent assay with virus-like particles at diagnosis and were tested for past and concurrent cervical HPV 16 DNA positivity with MY09/MY11 L1 consensus primer PCR. Questionnaire data were used to ascertain past sexual behavior., Results: Increased lifetime number of sex partners (P(Trend) < 0.001), past HPV 16 DNA positivity (odds ratio = 6.9; 95% confidence interval = 1.5-31), and a current cytologic diagnosis (P(Trend) < 0.03) were independently associated with HPV 16 seropositivity. Among the seropositive, only lifetime number of sex partners (P(Trend) < 0.001) and past HPV 16 DNA positivity (P = 0.003) were independently associated with mean signal strength (optical density) in an age-adjusted analysis. Women negative for past and concurrent HPV 16 DNA had a significant trend of increasing optical densities associated with greater numbers of lifetime partners (P(Trend) < 0.001). Conversely, the mean signal strength for those women who were ever HPV 16 DNA-positive during the study did not depend on lifetime numbers of sex partners (P(Trend) = 0.36)., Conclusions: HPV 16 seropositivity is a surrogate for past HPV 16 infection. Circulating levels of antibodies to HPV 16 may reflect recent HPV 16 infection or the frequency of past HPV 16 infection.

Background: Human papillomavirus (HPV) DNA testing may be useful in clarifying equivocal cervical cytologic interpretations. One application might be to standardize the meaning of equivocal interpretations from laboratories in various regions. Because international differences may be particularly marked, international comparisons of emerging data will require clear translations of "equivocal" and similar terms., Methods: To perform a three-country comparison, the authors selected a morphologically diverse set of 188 conventional Papanicolaou tests initially classified as "squamous atypia" from a study of more than 20,000 women in Portland, Oregon (1989-1990). Previously, five U.S. expert cytopathologists independently interpreted the slides with screening cytotechnologists' marks in place. For this comparison, one British and two Scandinavian reviewers involved in HPV research reviewed the slides after original marks had been removed. The authors compared all eight reviewers' classifications of negative, equivocal, or abnormal in a series of pairwise comparisons using the kappa statistic. They then compared cytologic interpretations with HPV DNA testing., Results: Oncogenic HPV DNA detection was significantly associated with increasingly abnormal interpretations for each reader. The British reader tended to rate tests as more abnormal than the American pathologists did, whereas the Scandinavians tended to rate tests as more normal. Reference to the HPV DNA standard clarified the tendency of readers to render systematically more or less severe interpretations. For example, the Scandinavian cytologists discounted subtle (often HPV-associated) changes in favor of cytologic certainty, making HPV triage of equivocal tests less applicable there., Conclusions: International research on cytopathology, particularly on the possible uses of HPV DNA testing, will require calibration of local cytologic definitions.

Five panelists independently reviewed 135 consecutive conventional cervical smears (CPs) originally classified as atypical glandular cells of undetermined significance (AGUS). A thin-layer slide (TP), prepared from the residual material, also was reviewed in each case. All patients underwent colposcopy that yielded at least 1 histologic specimen. Three or more of 5 reviewers retained the AGUS interpretation for 29% of CPs and 12% of the corresponding TPs. Interobserver variability infrequency of use of AGUS was marked, and interobserver agreement was poor. Agreement was improved for cases cytologically interpreted as a high-grade lesion, especially in TPs. Four of 5 reviewers retained the AGUS classification in CPs for all 7 biopsy-proven neoplastic glandular lesions. Of 95 CP interpretations made by 5 reviewers in the 19 histologically diagnosed high-grade lesions, 8 were "negative/reactive" and 6 were AGUS "favor reactive." AGUS is a poorly reproducible cytologic interpretation. Although most neoplastic glandular lesions may be distinguished by cytopathologists experienced in this area from mimics originally considered AGUS, attempts to increase the diagnostic specificity of AGUS may diminish sensitivity for an underlying high-grade precursor. Interobserver agreement was better for TPs than for the corresponding CPs. However, the split-sample TP slides may not have been fully comparable to the CPs.

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.

Serum IgG antibodies to human papillomavirus (HPV) types 16, 18, 31, and 45 virus-like particles were measured in a nested case-control study of cervical squamous intraepithelial lesions. HPV-16 seroreactivity was strongly associated with HPV-16 DNA detection (odds ratio, 9.0; 95% confidence interval, 4.4-19.4), and similar type specificity was observed for HPV-31 and -45. In contrast, seroreactivity to any type was associated with elevated seroreactivity to all others. Among cases and controls, HPV-16 showed the highest seroprevalence, with 23.8% of 80 cases and 10.5% of 258 controls seroreactive to HPV-16 alone, and another 27.5% and 5.4%, respectively, seroreactive to HPV-16 plus other types. Overall, 24 (30.0%) cases and 17 (6.6%) controls were seroreactive to multiple types. These data suggest that seroreactivity to a given type reflects mainly type-specific HPV infection as measured by DNA detection and may also signal past exposure to other types that are now only serologically detected.

A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)-based test which was used. The formerly HPV-negative cases from this study have therefore been reanalyzed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV-negative and a sample of 48 of the 866 cases which were HPV-positive in the original study. Moreover, 55 of the 66 formerly HPV-negative biopsies were also reanalyzed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR-negative and -positive. Type-specific E7 PCR for 14 high-risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV-negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA-positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV-negative on all PCR tests, as against 13 of the 21 that were inadequate ( p< 0.001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99.7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV-negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening., (Copyright 1999 John Wiley & Sons, Ltd.)

We intensively reviewed 137 smears initially classified as atypical glandular cells of undetermined significance (AGUS) to refine cytological criteria for evaluating these cases, evaluate histological outcomes, and assess the value of human papillomavirus (HPV) DNA testing in management. Consenting, nonpregnant study participants were identified from a cohort of 46,009 women receiving routine Pap smear screening in a managed care setting. Colposcopy was performed on all women, and at least one histological sample was obtained from each. Review diagnoses were assigned to smears and biopsy specimens by two separate panels of pathologists. DNA testing for cancer-associated HPV types was performed on rinses of cytological samplers after a smear and thin-layer slide had been made. On review, 47 (34%) smears were reclassified as negative, 44 (32%) as AGUS, 30 (22%) as atypical squamous cells of undetermined significance (ASCUS), and 16 (12%) as squamous intraepithelial lesions (SIL). The 19 smears interpreted as high-grade intraepithelial lesions on review included 13 high-grade SIL (HSIL), two HSIL with AGUS, favor neoplastic (endocervical adenocarcinoma in situ [AIS]), and four AGUS, favor neoplastic (AIS). Review histological diagnoses were negative in 105 (77%), squamous or glandular atypia in four (3%), low-grade SIL (LSIL) in nine (7%), HSIL in 12 (9%), AIS in five (4%, including two with concurrent HSIL), and endometrial carcinoma in one (1%). HPV testing identified 11 (92%) of 12 women with histologically confirmed HSIL and all five with AIS (100%). A high-grade intraepithelial lesion or carcinoma is detected in approximately 14% of women with community-based diagnoses of AGUS who are referred for immediate evaluation. Use of refined cytological criteria and HPV DNA testing may permit improved management of women with AGUS.

Background: Human papillomavirus (HPV) infection has been strongly associated with cervical carcinoma and its cytologic precursors, squamous intraepithelial lesions (SIL). We investigated the risk of SIL prospectively following polymerase chain reaction (PCR)-based DNA testing for a wide range of genital HPV types in a cohort of initially cytologically normal women, to clarify the role of HPV in the etiology of SIL., Methods: Starting in April 1989, 17,654 women who were receiving routine cytologic screening at Kaiser Permanente (Portland, OR) were followed for the development of incident SIL. During follow-up, 380 incident case patients and 1037 matched control subjects were eligible for this nested case-control study. Cervical lavages collected at enrollment and, later, at the time of case diagnosis (or the corresponding time for selection of control subjects) were tested for HPV DNA using a PCR-based method. The data were analyzed as contingency tables with two-sided P values or, for multivariable analyses, using odds ratios (ORs) with 95% confidence intervals (CIs)., Results: In comparison with initially HPV-negative women, women who tested positive for HPV DNA at enrollment were 3.8 times (95% CI = 2.6-5.5) more likely to have low-grade SIL subsequently diagnosed for the first time during follow-up and 12.7 times more likely (95% CI = 6.2-25.9) to develop high-grade SIL. At the time of diagnosis, the cross-sectional association of HPV DNA and SIL was extremely strong (OR = 44.4 and 95% CI = 24.2-81.5 for low-grade SIL and OR = 67.1 and 95% CI = 19.3-233.7 for high-grade SIL). HPV16 was the virus type most predictive of SIL, even low-grade SIL., Conclusions: These findings are consistent with the hypothesis that HPV infection is the primary cause of cervical neoplasia. Furthermore, they support HPV vaccine research to prevent cervical cancer and efforts to develop HPV DNA diagnostic tests.