Epidemiologic natural history and clinical management of Human Papillomavirus (HPV) Disease: a critical and systematic review of the literature in the development of an HPV dynamic transmission model

<p>Abstract</p> <p>Background</p> <p>Natural history models of human papillomavirus (HPV) infection and disease have been used in a number of policy evaluations of technologies to prevent and screen for HPV disease (e.g., cervical cancer, anogenital warts), sometimes with wide variation in values for epidemiologic and clinical inputs. The objectives of this study are to: (1) Provide an updated critical and systematic review of the evidence base to support epidemiologic and clinical modeling of key HPV disease-related parameters in the context of an HPV multi-type disease transmission model which we have applied within a U.S. population context; (2) Identify areas where additional studies are particularly needed.</p> <p>Methods</p> <p>Consistent with our and other prior HPV natural history models, the literature review was confined to cervical disease and genital warts. Between October 2005 and January 2006, data were gathered from the published English language medical literature through a search of the PubMed database and references were examined from prior HPV natural history models and review papers. Study design and data quality from individual studies were compared and analyses meeting pre-defined criteria were selected.</p> <p>Results</p> <p>Published data meeting review eligibility criteria were most plentiful for natural history parameters relating to the progression and regression of cervical intraepithelial neoplasia (CIN) without HPV typing, and data concerning the natural history of HPV disease due to specific HPV types were often lacking. Epidemiologic evidence to support age-dependency in the risk of progression and regression of HPV disease was found to be weak, and an alternative hypothesis concerning the time-dependence of transition rates is explored. No data were found on the duration of immunity following HPV infection. In the area of clinical management, data were observed to be lacking on the proportion of clinically manifest anogenital warts that are treated and the proportion of cervical cancer cases that become symptomatic by stage.</p> <p>Conclusion</p> <p>Knowledge of the natural history of HPV disease has been considerably enhanced over the past two decades, through the publication of an increasing number of relevant studies. However, considerable opportunity remains for advancing our understanding of HPV natural history and the quality of associated models, particularly with respect to examining HPV age- and type-specific outcomes, and acquired immunity following infection.</p

Model for Assessing Human Papillomavirus Vaccination Strategies

A prophylactic quadrivalent vaccine can cost-effectively reduce the incidence of cervical cancer, cervical intraepithelial neoplasia, and genital warts

Progression and regression of incident cervical HPV 6, 11, 16 and 18 infections in young women

<p>Abstract</p> <p>Background</p> <p>We describe type-specific progression, regression and persistence of incident human papillomavirus (HPV)-6-11-16 and -18 infections, along with type distribution in cervical intra-epithelial neoplasia (CIN) lesions.</p> <p>Methods</p> <p>The study population consisted of 16–23 year-old women undergoing Pap testing and cervical swab polymerase chain reaction testing for HPV DNA at approximate 6 month intervals for up to 4 years in the placebo arm of a clinical trial of an HPV 16-vaccine. HPV types in incident infections were correlated with types in lesion biopsy specimens.</p> <p>Results</p> <p>56.7% of CIN-1 and nearly one-third of CIN-2/3 lesions following incident HPV-6-11-16 or -18 infections did not correlate with the incident infection HPV type. Cumulative 36-month progression rates to CIN-2/3 testing positive for the relevant HPV type were highest for HPV-16 infections (16.5%), followed by HPV-18 (8.2%). Overall, 26.0% of CIN-1, 50.0% of CIN-2 and 70.6% of CIN-3 biopsies tested positive for HPV-6-11-16-18 infections.</p> <p>Conclusion</p> <p>Women with a given HPV type may often be co-infected or subsequently infected with other types which may lead to subsequent cervical lesions. This issue has been addressed in this study reporting data for the natural history of HPV-6-11-16 and -18 infections and is a relevant consideration in designing future studies to evaluate the incidence/risk of CIN following other type-specific HPV infections.</p

Incidence, duration, and reappearance of type-specific cervical human papillomavirus infections in young women

Background: We describe the incidence and duration of cervical human papillomavirus (HPV) infection episodes along with the risk of infection reappearance following a period of nondetection. Methods:Women (1,788) ages 16 to 23 years underwent cytologic testing and PCR-based testing of cervical swab samples for HPV DNA (HPV-16/18/31/33/35/45/52/58/59) at ?6-month intervals for up to 4 years in the context of a phase 3 clinical trial (placebo arm). HPV type - specific incidence rates were estimated per 100 person-years. Duration of type-specific cervical infection episodes and risk of reappearance following a period of nondetection were estimated using Kaplan-Meier methods. Results: HPV-16 exhibited the highest (5.9), and HPV-35 and HPV-33 exhibited the lowest (1.0) incidence rates per 100 person-years. Mean cervical infection durations ranged from 13 months for HPV-59 to 20 months for HPV-16 and 58 (with ongoing infections censored at the time of treatment, if done). The risk of cervical infection reappearance within ?3 years following a period of nondetection ranged from 0% to 16% across HPV types, with a mean of 8%. Limited evidence was found for a role of false-positive HPV tests, missed infections that were above the threshold for detection, or new acquisition of infection in accounting for patterns of infection reappearance. Conclusions: Incidence of high-risk cervical infection was observed to vary considerably more across HPV types than infection duration. A nontrivial proportion of women exhibited infection reappearance following a period of nondetection, with a potential explanation for many such events observed within this analysis being a return to detectable levels of a previously acquired infection. Impact: The risk of HPV infection reappearance following a period of nondetection has not been previously reported for individual HPV types, and this study finds that a nontrivial proportion of infected women exhibit reappearances. Future studies could ascertain subject-level factors that potentially modify the risk of infection reappearance. ©2010 AACR

A Review of Health-Utility Data for Osteoarthritis: Implications for Clinical Trial-Based Evaluation

The objective of this review was to describe the performance of health-utility measures in valuing the quality-of-life (QOL) impact of changes in osteoarthritis (OA)-related chronic pain when administered within a clinical trial setting. Because the collection of utility data within a clinical trial is not always feasible in the development of health economic models, utility data from prior non-randomised studies conducted among patients with OA were also summarized. We conducted a literature review using the MEDLINE, EMBASE and PsycINFO databases. We selected studies employing validated direct and multi-attribute measures of health utility: the standard gamble, time trade-off, EuroQol index, Health Utilities Index, SF-6D, 15D and the Assessment of Quality of Life measure. We identified four randomized controlled trials and 17 observational studies. The results of prior clinical trials in which these health utility measures were used in evaluating OA are summarized and attributes of the utility measures such as the clinical importance and statistical significance of the results obtained are noted. Furthermore, the sensitivity of the utility measure to changes in co-administered non-utility based measures of health-related quality of life (e.g. visual analogue scale for pain, WOMAC(TM)) are also reported. Five findings emerged. First, the EQ-5D system was the most widely used metric to derive utilities. Second, for whatever utility measure was used, reported mean utilities for patient groups spanned a rather wide range of values across studies, potentially reflecting variation in illness severity, patient co-morbidities and/or patient treatment. Third, when studies reported more than one utility-based statistic, the utility valuations frequently differed by measure, suggesting that the choice of metric can potentially have an effect on QALY calculations. However, there was no consistent pattern as to which measure yielded the highest and lowest utility valuations. Fourth, changes in health-related QOL (HR-QOL) and utility measures displayed the expected relationships. When HR-QOL declined, the utility values also moved in this direction. The reverse was also true. In some instances, statistically significant changes in QOL measures were not mirrored by statistically significant changes in utility measures, suggesting that some studies may have been underpowered for the latter purpose. Finally, the body of clinical trial-based utility literature in OA was found to be relatively modest, with considerably more observational studies collecting utility data. Based on the limited number of trial-based health-utility evaluations in OA to date, there can potentially be divergent findings with respect to clinical and statistical significance of changes in utility measures and corresponding measures of health status. Analysts should carefully evaluate issues of statistical power and clinical sensitivity in utilizing these measures in clinical trials of OA interventions. DOI: 10.2165/0019053-200826110-00005Osteoarthritis, Quality-of-life-rating-scales, Utility-measurement

Acute/Subacute Herpes Zoster: Healthcare Resource Utilisation and Costs in a Group of US Health Plans

Background: Although there are estimated to be nearly 1 million cases of herpes zoster diagnosed in the US each year, the economic costs associated with herpes zoster in the US have not been well described. Objective: To describe the healthcare resource utilisation and costs associated with physician-diagnosed acute/subacute herpes zoster, from a payer perspective, using a large US healthcare claims database. Methods: Data for the period 2000-1 were obtained from the Medstat Marketscan healthcare claims database. The duration of acute/subacute herpes zoster was considered to include the 21 days preceding, and 90 days following, the initial herpes zoster diagnosis. Resource utilisation was examined for individuals with newly diagnosed acute/subacute herpes zoster (n_=_8741) and compared, through regression analyses, with that observed for control individuals from the same population (n_=_50_000). Similar analyses were conducted for costs; the costs included reflected healthcare payments from patients, insurers and other sources. Regression analyses controlled for demographics (age, gender), conditions that have been observed with greater frequency among patients with acute/subacute herpes zoster in prior studies (cancer, HIV infection, organ transplantation, other immunosuppressive conditions and therapies) and the number of billed services within each of seven categories of care that were potentially related to acute/subacute herpes zoster and that were utilised within the 30-180 days prior to the diagnosis for affected patients, and over an analogous period for controls. Results: The acute/subacute phase of herpes zoster was estimated to result in an average of 1.7 (standard error [SE] 0.02) additional physician and hospital outpatient visits, 0.05 (SE 0.003) additional emergency room visits, 0.03 (SE 0.003) additional inpatient hospital admissions, 2.1 (SE 0.03) additional prescriptions filled and $US431 (SE 17.60) in additional healthcare costs per patient. Among patients with acute/subacute herpes zoster, 21.1$US258 (SE 37.70) among patients aged =80 years. The numbers of additional outpatient visits, inpatient admissions, prescriptions filled for pain medications and coded complications were also substantially higher among older than younger patients with acute/subacute herpes zoster. Conclusions: The management of acute/subacute herpes zoster was found to result in substantial healthcare costs, with outpatient care and prescription drugs comprising the majority of the cost burden. To more fully understand the overall cost of herpes zoster disease to society, future studies should examine the healthcare costs associated with post-herpetic neuralgia and productivity losses due to herpes zoster and post-herpetic neuralgia.Cost-analysis, Cost-of-illness, Herpes-zoster, Resource-use

Assessing the Annual Economic Burden of Preventing and Treating Anogenital Human Papillomavirus-Related Disease in the US: Analytic Framework and Review of the Literature

The anogenital human papillomavirus (HPV) is estimated to be the most commonly occurring sexually transmitted infection in the US. Comprehensive estimates of the annual economic burden associated with the prevention and treatment of anogenital HPV-related disease in the US population are currently unavailable. The purpose of this paper is to (i) outline an analytic framework from which to estimate the annual economic burden of preventing and treating anogenital HPV-related disease in the US; (ii) review available US literature concerning the annual economic burden of HPV; and (iii) highlight gaps in current knowledge where further study is particularly warranted. Among eight US studies identified that describe the annual economic burden pertaining to one or more aspects of anogenital HPV-related disease, three met the review eligibility criteria (published between 1990 and 2004, examined multiple facets of annual anogenital HPV-related economic burden, and clearly articulated the data and methods used in the estimation process). All costs were adjusted to 2004 $US. Estimates of the annual direct medical costs associated with cervical cancer were comparable across studies (range$US300-400 million). In contrast, there was a wide range across studies for estimates of the annual direct medical costs associated with cervical intraepithelial neoplasia (range $US700 million-$US2.3 billion). Only one study reported direct medical costs for anogenital warts ($US200 million) and routine cervical cancer screening ($US2.3 billion). No studies examined direct medical costs attributable to HPV-related anal, penile, vaginal or vulvar cancers, or the work and productivity losses resulting from time spent receiving medical care, morbidity or mortality. Current economic burden estimates would suggest annual direct medical costs associated with the prevention and treatment of anogenital warts and cervical HPV-related disease of at least $US4 billion. This figure would likely rise to at least$US5 billion per year if direct medical costs associated with other disease entities caused by the sexual transmission of HPV were included, with further additions to the economic burden totalling in the billions of dollars if work and productivity losses were incorporated, a research priority for future studies.Cervical-cancer, Cervical-intraepithelial-neoplasia, Cost-of-illness, Papilloma, Warts

Trends in Malignant Melanoma Incidence and Mortality in Wisconsin, 1979-1997

OBJECTIVE: To explore trends in malignant melanoma incidence and mortality in Wisconsin from 1979 to 1997, by age, gender and time period. Comparisons are also made to US trends over this period. DATA: Incidence data for Wisconsin were provided by the Wisconsin Cancer Reporting System Bureau of Health Information, within the Wisconsin Department of Health and Family Services, while US data were extracted using SEER*Stat 3.0. Mortality data for both Wisconsin and the US were compiled using CDC WONDER. RESULTS: Wisconsin malignant melanoma incidence rates rose 25% from 1979 to 1998, compared to a US increase of 132%. For mortality rates, however, both Wisconsin (22%) and the US (15%) exhibited only modest increases. Between the mid-1980s and mid-1990s, the largest increases in both incidence and mortality (over 70%) occurred among males over age 65. In contrast, declines of 30% to 40% were found for males age 0-34. Patterns were less consistent among females. CONCLUSIONS: Since the mid-1980s, malignant melanoma incidence in Wisconsin appears to have increased sharply among males and females over age 65, with a corresponding rise in mortality among males in this age group. These trends should be a source of concern for clinicians and policy makers alike. Because current evidence on the effectiveness of early treatment is inconclusive, it is especially important to take preventive measures now--such as educational and community-based interventions--to reduce future incidence