High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation.

BK virus (BKV) reactivation has been increasingly associated with the occurrence of late-onset hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT (allo-HSCT) resulting in morbidity and sometimes mortality. We investigated the incidence, risk factors and outcome of BKV-HC in 323 consecutive adult patients undergoing allo-HSCT over a 5-year period. BK viremia values for HC staging were evaluated, as well as the medico-economic impact of the complication. Forty-three patients developed BKV-HC. In univariate analysis, young age (P=0.028), unrelated donor (P=0.0178), stem cell source (P=0.0001), HLA mismatching (P=0.0022) and BU in conditioning regimen (P=0.01) were associated with a higher risk of developing BKV-HC. In multivariate analysis, patients receiving cord blood units (CBUs) (P=0.0005) and peripheral blood stem cells (P=0.011) represented high-risk subgroups for developing BKV-HC. BK viremia was directly correlated to HC severity (P=0.011) with a 3 to 6-log peak being likely associated with grades 3 or 4 HC. No correlation was found between BKV-HC and acute graft versus host disease or mortality rate. Patients with BKV-HC required a significantly longer duration of hospitalization (P<0.0001), more RBC (P=0.0003) and platelet transfusions (P<0.0001). Over the 5-year study period, the financial cost of the complication was evaluated at \[euro]2 376 076 ($3 088 899). Strategies to prevent the occurrence of late-onset BKV-HC after allo-HSCT are urgently needed, especially in CBU and peripheral blood stem cell recipients. BK viremia correlates with the severity of the disease. Prospective studies are required to test prophylactic approaches.

Cost-effectiveness of cidofovir treatment of polyomavirus nephropathy in kidney transplant recipients.

BACKGROUND: BK virus nephropathy (BKVAN) causes about 10% of late kidney graft loss. Cidofovir is widely used to treat BKVAN, but the magnitude of the health benefits and costs are largely unknown. We aimed to evaluate the incremental health benefits and costs of cidofovir and immunosuppression reduction compared with immunosuppression reduction alone in kidney transplant patients with BKVAN. METHODS: A probabilistic decision analytic model was developed to simulate a cohort of kidney transplant recipients aged 45 years and above with BKVAN who received cidofovir treatment compared with those who received standard care. The duration of the cycle was 1 year, and the model terminated when all recipients were deceased. RESULTS: Compared with immunosuppression reduction alone, in the base-case, the incremental health benefits of cidofovir were 0.0061 life-years saved (2.2 days), with savings of $20,756 over the lifetime of a transplant recipient. When varying the most influential variables (the probability of response to treatment and graft loss) between best and worst case scenarios, the incremental health outcomes ranged from -0.967 to 1.093 life-years saved, with incremental costs ranging from an extra $27,313 to saving $20,756. CONCLUSIONS: Compared with immunosuppression reduction alone, based on best available data, cidofovir treatment and immunosuppression reduction for BKVAN seem to be cost saving and improves health outcomes. However, because of weak clinical data, particularly around comparative effectiveness, there is still moderate uncertainty in the incremental cost effectiveness. Adequately powered trials are still needed to better define optimal treatment strategies for BKVAN before cidofovir can be recommended strongly as routine therapy.

Cost-efficient screening for BK virus in pediatric kidney transplantation: a single-center experience and review of the literature.

BKVNP is an increasingly recognized cause of graft dysfunction and loss in kidney transplant recipients. Protocols for BKV screening and for the diagnosis of BKVNP are still evolving. PCR-based BKV detection became available at our institution in 2007, when we began using it according to published guidelines. We subsequently reviewed our experience with urine and plasma BKV PCR testing in our pediatric kidney transplant recipient population. We found rates of viruria, viremia, and BKVNP that were similar to the published literature. We also conducted a cost analysis suggesting that urine PCR testing, as used by us, is not cost efficient in the detection of BKV. We conclude that plasma only-based PCR testing for BKV may be sufficient in most clinical settings.

Cost-effectiveness analysis of human papillomavirus vaccination in the Netherlands.

BACKGROUND: In the Netherlands, low cervical cancer incidence and mortality rates might limit the cost-effectiveness of vaccination against the human papillomavirus (HPV). We examined the effect on cervical cancer incidence and mortality of adding HPV vaccination to the current Dutch cervical cancer screening situation and calculated the cost-effectiveness. METHODS: Costs and effects were estimated under favorable assumptions (ie, that HPV vaccination provides lifelong protection against 70% of all cervical cancers, has no side effects, and is administered to all women regardless of their risk of cervical cancer) by using the microsimulation screening analysis (MISCAN) model. The impact of changes in the price of vaccination, number of booster vaccinations, vaccination attendance rate, vaccination efficacy, cervical cancer incidence level, and quality-of-life assumptions was investigated in sensitivity analyses. RESULTS: Using the current price of euro118 per vaccine dose and with discounting of costs and effects at an annual rate of 3%, adding HPV vaccination to the current Dutch screening situation had a cost-effectiveness ratio of euro53 500 per quality-adjusted life-year (QALY) gained. The threshold price per vaccine dose at which the cost-effectiveness of vaccination would correspond to an acceptability threshold of euro20 000 per QALY gained was euro40. With the addition of one or more (up to four) booster vaccinations during a lifetime, this threshold price decreased to euro33 for one booster (to euro16 for four boosters). With a doubling of the cervical cancer incidence level, the cost-effectiveness ratio was euro24 400 per QALY gained and the maximum price per dose at threshold of euro20 000 was euro97. All threshold prices were lower under less favorable effectiveness assumptions. CONCLUSIONS: In the Netherlands, HPV vaccination is not cost-effective even under favorable assumptions. To become cost-effective, the vaccine price would have to be decreased considerably, depending on the effectiveness of the vaccine.

Case studies in cost effectiveness of molecular diagnostics for infectious diseases: pulmonary tuberculosis, enteroviral meningitis, and BK virus nephropathy.

Pathogen genome amplification is used to detect and identify microorganisms, assess response to therapy, and detect mutations associated with drug resistance. Nucleic acid amplification tests have been shown to be superior to conventional culture-based testing methods in many circumstances. However, the enthusiasm for the technology in clinical laboratories may be decreased by the practical considerations of cost, complexity of the technology, and lack of US Food and Drug Administration-approved tests. The impact of nucleic acid amplification tests on the diagnosis and management of patients with tuberculosis, enteroviral meningitis, and BK virus transplant nephropathy will be examined, with an emphasis on the potential for health care cost savings.

Lifetime effects, costs, and cost effectiveness of testing for human papillomavirus to manage low grade cytological abnormalities: results of the NHS pilot studies.

OBJECTIVES: To predict the incremental lifetime effects, costs, and cost effectiveness of using human papillomavirus testing to triage women with borderline or mildly dyskaryotic cervical smear results for immediate colposcopy. DESIGN: Modelling study. SETTING: Three centres participating in NHS pilot studies, United Kingdom. Population Women aged 25-64 with borderline or mildly dyskaryotic cervical smear results. INTERVENTIONS: Screening using conventional cytology, liquid based cytology, and four strategies with different age cut-off points and follow up times that used combined liquid based cytology and human papillomavirus testing (adjunctive human papillomavirus testing). RESULTS: The model predicts that compared with using conventional cytology without testing for human papillomavirus, testing for the virus in conjunction with liquid based cytology for women with borderline or mildly dyskaryotic cervical smear results (aged 35 or more) would cost 3735 pounds sterling (5528 euros; 6474 dollars) per life year saved. Extending adjunctive human papillomavirus testing in combination with liquid based cytology to include women aged between 25 and 34 costs an additional 4233 pounds sterling per life year saved. Human papillomavirus testing is likely to reduce lifetime repeat smears by 52%-86% but increase lifetime colposcopies by 64%-138%. CONCLUSIONS: Testing for human papillomavirus to manage all women with borderline or mildly dyskaryotic cervical smear results is likely to be cost effective. The predicted increase in lifetime colposcopies, however, deserves careful consideration.

Projected clinical benefits and cost-effectiveness of a human papillomavirus 16/18 vaccine.

BACKGROUND: Human papillomavirus (HPV) vaccine may be commercially available in a few years. We explored the clinical benefits and cost-effectiveness of introducing an HPV16/18 vaccine in a population with an organized cervical cancer screening program. METHODS: A computer-based model of the natural history of HPV and cervical cancer was used to project cancer incidence and mortality, life expectancy (adjusted and unadjusted for quality of life), lifetime costs, and incremental cost-effectiveness ratios (i.e., the additional cost of a strategy divided by its additional clinical benefit compared with the next most expensive strategy) associated with different cancer prevention policies, including vaccination (initiated at age 12 years), cytologic screening (initiated at 18, 21, 25, 30, or 35 years), and combined vaccination and screening strategies. We assumed that vaccination was 90% effective in reducing the risk of persistent HPV16/18 infections and evaluated alternative assumptions about vaccine efficacy, waning immunity, and risk of replacement with non-16/18 HPV types. RESULTS: Our model showed that the most effective strategy with an incremental cost-effectiveness ratio of less than 60 dollars-000 per quality-adjusted life year is one combining vaccination at age 12 years with triennial conventional cytologic screening beginning at age 25 years, compared with the next best strategy of vaccination and cytologic screening every 5 years beginning at age 21 years. This triennial strategy would reduce the absolute lifetime risk of cervical cancer by 94% compared with no intervention. These results were sensitive to alternative assumptions about the underlying patterns of cervical cancer screening, duration of vaccine efficacy, and natural history of HPV infection in older women. CONCLUSIONS: Our model predicts that a vaccine that prevents persistent HPV16/18 infection will reduce the incidence of HPV16/18-associated cervical cancer, even in a setting of cytologic screening. A program of vaccination that permits a later age of screening initiation and a less frequent screening interval is likely to be a cost-effective use of health care resources.

Clinical and economic benefit of HPV-load testing in follow-up and management of women postcone biopsy for CIN2-3.

This study aimed to evaluate the clinical and economic implications of integrating human papilloma virus (HPV) load testing into the follow-up and management protocol of women postconisation for high-grade cervical intraepithelial neoplasia (CIN2-3). We evaluated 130 suitable women: 63 were screened biannually by Pap smears ('conventional approach') and 67 also had HPV-load testing ('HPV approach'). More stringent criteria for undergoing colposcopy or reconisation were observed by the former group compared to the latter. Both approaches were analysed for cost effectiveness. There were 33 out of 67 (49.2%) colposcopic referrals and 24 out of 67 (35.8%) reconisation/hysterectomies with the 'conventional approach' compared to 9 out of 63 (14.2%) and 7 out of 63 (11.1%) with the 'HPV approach'. Cervical intraepithelial neoplasia 2-3 residual disease was detected in 7 out of 67 (10.5%) and 7 out of 63 (11.1%) women. The 'conventional approach' had more negative colposcopic biopsies and more negative reconisation/hysterectomy histologies than the 'HPV approach'. The respective cost per detection of one case of residual disease was US$3573 and US$3485. The 'HPV approach' required fewer colposcopic and reconisation procedures to detect one case of residual CIN2-3. Its higher positive predictive value than that of cytology provided a significant decrease in false positive rates and a reduction of US$88 per detected case.

Chapter 15: Public health policy and cost-effectiveness analysis.

Recent scientific advances are providing an opportunity to revisit strategies for cervical cancer prevention. How to invest health resources wisely, such that public health benefits are maximized-and opportunity costs are minimized-is a critical question in the setting of enhanced cytologic screening methods, human papillomavirus DNA testing, and vaccine development. Developing sound clinical guidelines and public health policy will require careful consideration of the incremental benefits, harms, and costs associated with new interventions compared with existing interventions, at both an individual and a population level. In addition to an intervention's effectiveness, public health decision making requires the consideration of its feasibility, sustainability, and affordability. No clinical trial or single cohort study will be able to simultaneously consider all of these components. Cost-effectiveness analysis and disease-simulation modeling, capitalizing on data from multiple sources, can serve as a valuable tool to extend the time horizon of clinical trials, to evaluate more strategies than possible in a single clinical trial, and to assess the relative costs and benefits of alternative policies to reduce mortality from cervical cancer.

Age-restricted cervical screening: HPV testing at age 50 identifies a high risk group for cervical disease.

Changes to the present age policy of cervical screening are currently under consideration. We conducted a retrospective matched case-control study and cost analysis study to identify risk factors for the development of an abnormal smear after age 50 and to determine the impact of age-restricted cervical screening on the annual cost of the screening program. All women (229) from an 11-year birth cohort who developed an abnormal smear at age 50 or over were age-matched for two controls with negative smears. Routine screening smears taken between age 48 and 52 were tested for human papillomavirus (HPV) subtypes 16 and 18. Epidemiologic data were collected by postal questionnaire. Changes in costs under a policy of HPV testing and age-restricted screening were assessed. We found that HPV 16 status was the only independently significant risk factor for abnormal cytology after age 50 with an odds ratio of 10.26 (95% CI 1.25-84.11). A policy of early withdrawal from screening at age 50 on the basis of HPV testing would produce net cost savings. These findings suggest that HPV testing could be a valuable means of identifying the small proportion of women still at risk after 50, and of releasing health care resources.

Oncogenic human papillomavirus (HPV) infection and uterine cervical cancer: a screening strategy in the perspective of rural India.

The predominance of cervical cancer in India can mostly be attributed to the lack of early screening. The objective of the present study has been, therefore, to determine a cost-effective oncogenic human papillomavirus (HPV)-based cervical cancer screening plan for rural Indian women. The results showed that in normal women, highest prevalence of HPV 16/18 infection was in the age group < or =23 years and lowest in > or =44 years with an insignificant change in between. HPV 16/18 infection was significantly associated with cervical erosion at age < or =23 years, but not with cytology or visual inspection with acetic acid testing at any age. The low-grade cytological lesions, however, increased only with increase in age. Fourteen per cent of the cervical malignancy was also found to be present in the age group 24-33 years with an 87% HPV infection. Here we proposed a cost-effective screening scheme in which HPV testing must be performed in women (a) < or =23 years with cervical erosion and (b) 24-43 years, as an adjunct to Pap smears (both HPV and cytology were prevalent in this group). For women > or =44 years, HPV testing might not be useful, since abnormal cytology was more prominent over the viral infection. We infer that by not performing HPV test in the group < or =23 years, approximately 76% of the high-risk HPV-infected individuals potentially "at risk" for developing cervical cancer might be missed.

Cost of screening for cancerous and precancerous lesions of the cervix.

This paper is part of the cost-effectiveness study of cervical cancer screening conducted by the French Society of Clinical Cytology (SFCC). It describes the evaluation of costs of conventional smear tests, thin-layer smear tests (ThinPrep 2000 system), and viral typing by the HCS test. For 100,000 examinations per year, the average cost of a conventional smear test is 11.53 dollars in a private anatomo-pathology clinic. The cost of the thin-layer test for the same number of examinations and in the same type of clinic is 13.93 dollars. For 20,000 annual tests, the average cost of human papillomavirus (HPV) is 23.43 dollars in the public sector and 23.48 dollars in the private one. The higher price of the thin-layer method is only justifiable if this screening technique outperforms the conventional method. Furthermore, the high cost of the HPV test means that its integration into a population-based screening program must be carefully defined.

Costs and effectiveness of alternative strategies for cervical cancer screening in military beneficiaries.

OBJECTIVE: To estimate the potential effects, on costs and outcomes, of changes in sensitivity and specificity associated with new screening methods for cervical cancer in the military. METHODS: A Markov model of the natural history of cervical cancer was created to simulate a cohort of 100,000 military beneficiaries aged 18-85. Probability estimates for various outcomes and the accuracy of screening tests were obtained from the literature. Cost estimates were obtained from military sources where available; otherwise, civilian costs were used. The outcomes and costs of conventional cytology, liquid-based cytology, and liquid-based cytology with human papillomavirus (HPV) triage were compared at 1-, 2-, and 3-year screening frequencies. RESULTS: Marginal reductions in the incidence of cervical cancer from increasing screening sensitivity are greater than reductions in cancer mortality at every screening interval. Incremental improvements in both cancer incidence and mortality are higher at less frequent screening intervals. Increases in the ratio of low- to high-grade lesions result from increasing the sensitivity of the screening test or shortening the screening interval. Both liquid-based cytology and liquid-based cytology with HPV testing are cost effective (less than $50,000 per life-year saved) when performed at 3-year screening intervals. However, neither strategy is cost-effective when performed more frequently than every 3 years. CONCLUSION: Use of a more sensitive cervical cancer screening test increases costs. However, a more sensitive test performed less frequently may be more effective and less expensive than conventional cytology done annually. In the military setting, this has significant implications for both expense reduction and readiness enhancement.

Clinical and economic implications of adding HPV tests to the routine cytology follow-up and management of patients with histologically defined cervical intraepithelial neoplasia grade 1.

OBJECTIVE: The objective of this study was to evaluate the clinical and economic implications of adding human papillomavirus (HPV) testing to the follow-up and management protocol of women with a histological diagnosis of low-grade cervical intraepithelial neoplasia (CIN1). METHODS: The study cohort consisted of 314 women with histological diagnosis of CIN1 and who met the inclusion criteria. They were followed-up by pap smears and samples for HPV tests that were obtained and analyzed on the first visit after referral. HPV assessment was carried out later. Colposcopy and biopsies were performed when there were two consecutive abnormal pap results or positive HPV tests. Women with any degree of CIN underwent cone biopsies. RESULTS: The positive predictive value (PPV) of low-grade squamous intraepithelial lesion and high-grade squamous epithelial lesion to identify high-grade lesions (CIN2-3) were 48.9 and 95%, respectively. The PPV of low-risk HPV type for CIN1 and that of high-risk HPV type for CIN2-3 were both 97%. Of the 314 study participants, 68 (21.6%) patients were positive for HPV analysis, and 67 of these (98.5%) had either CIN1 or CIN2-3 on the cone biopsy, with an overall PPV of 95%. The cost effectiveness ratio was $1457 per additional case detected by the "HPV approach." CONCLUSIONS: Testing for the presence of high-risk HPV types is both clinically and economically more beneficial than cytology in the follow-up and management of patients with a diagnosis of CIN 1 because of its better sensitivity, specificity, and PPV reports.