A cross-sectional study of symptoms and health-related quality of life in menopausal-aged women in China.

OBJECTIVE: To measure symptoms and health-related quality of life in a cross-sectional cohort of menopausal-aged women in China. METHOD: A cross-sectional survey was conducted in a general population cohort of 2,000 Chinese females over the age of 45 years. Patients completed the Chinese version of the EuroQol-5D five level (EQ5D5L) health-related quality of life instrument via Personal Digital Assistant. Raw scores were converted to utility tariffs using value sets for China. Statistical analysis included Pearson's chi-square test, z test for multiple comparisons with adjustment by the Bonferroni method, independent-sample t-test, ANOVA, and adjustment by the Tukey method for multiple comparison. Results were considered statistically significant when p < 0.05 and the study was reported according to the STROBE recommendations. RESULTS: In a cohort of 2000 women, 732 (37%) were premenopausal, 798 (40%) were perimenopausal and 470 (23%) were postmenopausal. Perimenopausal women reported significantly more symptoms (91%) compared to premenopausal (77%) and postmenopausal (81%) women. Health-related quality of life was significantly lower in symptomatic perimenopausal women compared to premenopausal (0.919, p < 0.05) and postmenopausal (0.877, p < 0.05) women. Within each group there was a statistically significant difference between the health-related quality of life of women with symptoms compared to without symptoms. CONCLUSION: The perimenopausal phase of menopause is associated with significantly more symptoms and significantly lower HRQoL compared to premenopausal and postmenopausal phases.

Why is this study needed?• It is important to understand the impact of menopausal symptoms on women's quality of life so that decisions can be made about what healthcare services to provide and what treatments to fund.• Currently there are only a few older studies investigating menopausal symptoms in the perimenopausal phase, which is characterised by hormone fluctuations and symptoms likely to impact quality of life, and lasts up to four years. What is the key problem this manuscript addresses?• This research measures symptoms and the impact on quality of life of menopausal women in China. What are your main results and what do they mean?• Women in the perimenopausal phase are disproportionately affected by symptoms compared to premenopausal and postmenopausal women.• Perimenopausal women have significantly lower HRQoL compared to premenopausal and postmenopausal women.• This information is critical to informing pharmacoeconomic decisions about healthcare provision and publicly funded treatments in China.

Determinants of health-related quality of life in people with Human Immunodeficiency Virus, failing first-line treatment in Africa.

BACKGROUND: Antiretroviral treatment improves health related quality of life (HRQoL) of people with human immunodeficiency virus (PWH). However, one third initiating first-line treatment experience virological failure and the determinants of HRQoL in this key population are unknown. Our study aims to identify determinants of among PWH failing antiretroviral treatment in sub-Saharan Africa. METHODS: We analysed data from a cohort of PWH having virological failure (> 1,000 copies/mL) on first-line ART in South Africa and Uganda. We measured HRQoL using the EuroQOL EQ-5D-3L and used a two-part regression model to obtain by-country analyses for South Africa and Uganda. The first part identifies risk factors that were associated with the likelihood of participants reporting perfect health (utility = 1) versus non-perfect health (utility < 1). The second part identifies risk factors that were associated with the EQ-5 L-3L utility scores for participants reporting non-perfect health. We performed sensitivity analyses to compare the results between the two-part model using tobit models and ordinary least squares regression. RESULTS: In both countries, males were more likely to report perfect health and participants with at least one comorbidity were less likely to report perfect health. In South Africa, participants with side effects and in Uganda those with opportunistic infections were also less likely to report perfect health. In Uganda, participants with 100% ART adherence were more likely to report perfect health. In South Africa, high HIV viral load, experiencing ART side effects, and the presence of opportunistic infections were each associated with lower HRQoL, whereas participants with 100% ART adherence reported higher HRQoL. In Uganda participants with lower CD4 count had lower HRQoL. CONCLUSION: Markers of advanced disease (opportunistic infection, high viral load, low CD4), side effects, comorbidities and lack of ART adherence negatively impacted HRQoL for PWH experiencing virological failure. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02787499.

Seemingly Unrelated Regression Analysis of the Cost and Health-Related Quality of Life Outcomes of the REVAMP Randomized Clinical Trial.

OBJECTIVE: This study aimed to evaluate the 9-month cost and health-related quality of life (HRQOL) outcomes of resistance versus viral load testing strategies to manage virological failure in low-middle income countries. METHODS: We analyzed secondary outcomes from the REVAMP clinical trial: a pragmatic, open label, parallel-arm randomized trial investigating resistance versus viral load testing for individuals failing first-line treatment in South Africa and Uganda. We collected resource data, valued according to local cost data and used the 3-level version of EQ-5D to measure HRQOL at baseline and 9 months. We applied seemingly unrelated regression equations to account for the correlation between cost and HRQOL. We conducted intention-to-treat analyses with multiple imputation using chained equations for missing data and performed sensitivity analyses using complete cases. RESULTS: For South Africa, resistance testing and opportunistic infections were associated with statistically significantly higher total costs, and virological suppression was associated with lower total cost. Higher baseline utility, higher cluster of differentiation 4 (CD4) count, and virological suppression were associated with better HRQOL. For Uganda, resistance testing and switching to second-line treatment were associated with higher total cost, and higher CD4 was associated with lower total cost. Higher baseline utility, higher CD4 count, and virological suppression were associated with better HRQOL. Sensitivity analyses of the complete-case analysis confirmed the overall results. CONCLUSION: Resistance testing showed no cost or HRQOL advantage in South Africa or Uganda over the 9-month REVAMP clinical trial.

Clinical and economic burden of benign and malignant skin lesions in renal transplant recipients.

BACKGROUND: Studies evaluating the economic burden of dermatological care in the transplant setting are currently not available in Australia. AIMS: To evaluate the clinical and economic burden of benign and malignant skin lesions in renal transplant recipients in Central Queensland. METHODS: A bottom-up approach was used to determine the clinical burden and direct costs from patient-level Medicare data obtained from Service Australia for skin lesions. RESULTS: Seventy-six percent of the renal transplant population in Central Queensland participated in this study. The median age was 57.0 years (standard deviation ± 13.6) and the majority (61.8%) of participants were men. The mean duration after transplant surgery was 99.9 months (interquartile range, 73.2-126.6 months). During a 2-year follow-up, 22 (40%) patients were diagnosed with benign skin lesions, 21 (38%) with nonmelanoma skin carcinoma (NMSC) and one (2%) with melanoma. There was a total of 231 visits to clinicians for diagnostic and therapeutic skin procedures and the direct costs to Medicare was $48 806 Australian Dollars (AUD) or $30 427 US Dollars (USD). Approximately 86% of the total direct costs was spent for nonNMSC and mean direct costs for NMSC was $763 AUD (or $476 USD). CONCLUSION: This Medicare data-based study provides further insight into the burgeoning clinical and economic burden of the care for benign and malignant skin lesions in the renal transplantation setting in Australia.

Evaluating the cost utility of racecadotril in addition to oral rehydration solution versus oral rehydration solution alone for children with acute watery diarrhea in four low middle-income countries: Egypt, Morocco, Philippines and Vietnam.

AIM: To evaluate the cost utility of adjunct racecadotril and oral rehydration solution (R + ORS) versus oral rehydration solution (ORS) alone for the treatment of diarrhoea in children under five years with acute watery diarrhoea in four low-middle income countries. METHOD: A cost utility model, previously developed and independently validated, has been adapted to Egypt, Morocco, Philippines and Vietnam. The model is a decision tree, cohort model programmed in Microsoft Excel. The model structure represents the country-specific clinical pathways. The target population is children under the age of five years presenting with symptoms of acute watery diarrhea to an outpatient clinic or general physician practice. A healthcare payer perspective has been analysed with the model parameterised with local data, where available. Most recent cost data has been used to inform the drug, outpatient and inpatient costs. Uncertainty has been explored with univariate deterministic sensitivity. RESULTS: According to the base case models, R + ORS is dominant (cost-saving, more effective) versus ORS alone in Egypt, Morocco, Philippines and Vietnam. The incremental cost-effectiveness ratios in each country fall in the southeast (cost-saving, more effective) quadrant and represent a cost savings of -304,152 EGP per QALY gain in Egypt; -6,561 MAD per QALY gain in Morocco; -428,612 PHP per QALY gain in Philippines and -113,985,734 VND per QALY gain in Vietnam. Univariate deterministic sensitivity analysis shows that the three most influential parameters across all country adaptations are the utility of children without diarrhea; the utility of inpatient children with diarrhea and the cost of one night of inpatient care. CONCLUSION: In keeping with similar findings in upper-middle and high-income countries, the cost utility of R + ORS versus ORS is favourable in low-middle income countries for the treatment of children under five with acute watery diarrhoea.

PLAIN LANGUAGE SUMMARYDecision-makers rely on cost utility models to inform decisions about whether to publicly fund treatments as part of Universal Health Care. In low-middle income countries, the capacity to prepare cost utility models may be limited and using existing validated models is a practical solution to assist decision making. This study uses a cost utility model developed and independently validated for the United Kingdom, and adapts it to Philippines, Egypt, Morocco and Vietnam. The model evaluates the clinical benefit and economic impact of using racecadotril in addition to rehydration solution to treat diarrhoea in children. The results show that racecadotril is cost-saving and improves the quality of life for children in Philippines, Egypt, Morocco and Vietnam.

Meta-analysis of health state utility values measured by EuroQol 5-dimensions (EQ5D) questionnaire in Chinese women with breast cancer.

BACKGROUND: To synthesise EQ5D health state utility values in Chinese women with breast cancer for parameterising a cost utility model. METHODS: Eligible studies had to report health state utility values measured by EQ-5D in Chinese women diagnosed with breast cancer. Risk of bias was assessed using the Newcastle Ottawa Scale (NOS). Data from single arm studies was pooled using meta-analysis of single proportions to provide overall point estimates and 95% confidence intervals for fixed and random effects models using the inverse variance and Der Simonian-Laird methods respectively. Heterogeneity was evaluated using the I2 statistic and sensitivity analysis and meta-regression were conducted. RESULTS: Five papers were included, when all studies were combined (n = 4,100) the mean utility (95% confidence interval) for random effects model was 0.83 (0.78, 0.89); for TNM 0-1 0.85 (0.75, 0.95); for TNM II 0.85 (0.78, 0.93); for TNM III 0.83 (0.77, 0.90) and for TNM IV 0.73 (0.63, 0.82).The utility of patients in State P (first year after primary breast cancer) 0.84 (0.80, 0.88); in State R (first year after recurrence) 0.73 (0.69, 0.76), in State S (second and following years after primary breast cancer or recurrence) 0.88 (0.83, 0.92); and in State M (metastatic disease) 0.78 (0.74, 0.82). Mean utility for duration since diagnosis 13 to 36 months was 0.88 (0.80, 0.96, I2 =95%); for 37 to 60 months 0.89 (0.82, 0.96, I2 =90%); for more than 60 months 0.86 (0.76, 0.96, I2 =90%). Mean utility for chemotherapy was 0.86 (0.79, 0.92, I2 =97%); for radiotherapy 0.83 (0.69, 0.96, I2 =97%); surgery 0.80 (0.69, 0.91, I2 =98%); concurrent chemo-radiation 0.70 (0.60, 0.81, I2 =86%) and endocrine therapy 0.90 (0.83, 0.97, I2 =91%). CONCLUSION: This study synthesises the evidence for health state utility values for Chinese women with breast cancer which is useful to inform cost utility models.

Who's slipping through the cracks? A comprehensive individual, clinical and health system characterization of people with virological failure on first-line HIV treatment in Uganda and South Africa.

OBJECTIVES: HIV virological failure remains a major threat to programme success in sub-Saharan Africa. While HIV drug resistance (HIVDR) and inadequate adherence are the main drivers of virological failure, the individual, clinical and health system characteristics that lead to poor outcomes are not well understood. The objective of this paper is to identify those characteristics among people failing first-line antiretroviral therapy (ART). METHODS: We enrolled a cohort of adults in HIV care experiencing virological failure on first-line ART at five sites and used standard statistical methods to characterize them with a focus on three domains: individual/demographic, clinical, and health system, and compared each by country of enrolment. RESULTS: Of 840 participants, 51% were women, the median duration on ART was 3.2 years [interquartile range (IQR) 1.1, 6.4 years] and the median CD4 cell count prior to failure was 281 cells/µL (IQR 121, 457 cells/µL). More than half of participants [53%; 95% confidence interval (CI) 49-56%] stated that they had > 90% adherence and 75% (95% CI 72-77%) took their ART on time all or most of the time. Conversely, the vast majority (90%; 95% CI 86-92%) with a completed genotypic drug resistance test had any HIV drug resistance. This population had high health system use, reporting a median of 3 (IQR 2.6) health care visits and a median of 1 (IQR 1.1) hospitalization in the preceding 6 months. CONCLUSIONS: Patients failing first-line ART in sub-Saharan Africa generally report high rates of adherence to ART, have extremely high rates of HIV drug resistance and utilize significant health care resources. Health systems interventions to promptly detect and manage treatment failure will be a prerequisite to establishing control of the HIV epidemic.

Resistance Testing for Management of HIV Virologic Failure in Sub-Saharan Africa : An Unblinded Randomized Controlled Trial.

BACKGROUND: Virologic failure in HIV predicts the development of drug resistance and mortality. Genotypic resistance testing (GRT), which is the standard of care after virologic failure in high-income settings, is rarely implemented in sub-Saharan Africa. OBJECTIVE: To estimate the effectiveness of GRT for improving virologic suppression rates among people with HIV in sub-Saharan Africa for whom first-line therapy fails. DESIGN: Pragmatic, unblinded, randomized controlled trial. (ClinicalTrials.gov: NCT02787499). SETTING: Ambulatory HIV clinics in the public sector in Uganda and South Africa. PATIENTS: Adults receiving first-line antiretroviral therapy with a recent HIV RNA viral load of 1000 copies/mL or higher. INTERVENTION: Participants were randomly assigned to receive standard of care (SOC), including adherence counseling sessions and repeated viral load testing, or immediate GRT. MEASUREMENTS: The primary outcome of interest was achievement of an HIV RNA viral load below 200 copies/mL 9 months after enrollment. RESULTS: The trial enrolled 840 persons, divided equally between countries. Approximately half (51%) were women. Most (72%) were receiving a regimen of tenofovir, emtricitabine, and efavirenz at enrollment. The rate of virologic suppression did not differ 9 months after enrollment between the GRT group (63% [263 of 417]) and SOC group (61% [256 of 423]; odds ratio [OR], 1.11 [95% CI, 0.83 to 1.49]; P = 0.46). Among participants with persistent failure (HIV RNA viral load ≥1000 copies/mL) at 9 months, the prevalence of drug resistance was higher in the SOC group (76% [78 of 103] vs. 59% [48 of 82]; OR, 2.30 [CI, 1.22 to 4.35]; P = 0.014). Other secondary outcomes, including 9-month survival and retention in care, were similar between groups. LIMITATION: Participants were receiving nonnucleoside reverse transcriptase inhibitor-based therapy at enrollment, limiting the generalizability of the findings. CONCLUSION: The addition of GRT to routine care after first-line virologic failure in Uganda and South Africa did not improve rates of resuppression. PRIMARY FUNDING SOURCE: The President's Emergency Plan for AIDS Relief and the National Institute of Allergy and Infectious Diseases.

Health Economic Decision Tree Models of Diagnostics for Dummies: A Pictorial Primer.

Health economics is a discipline of economics applied to health care. One method used in health economics is decision tree modelling, which extrapolates the cost and effectiveness of competing interventions over time. Such decision tree models are the basis of reimbursement decisions in countries using health technology assessment for decision making. In many instances, these competing interventions are diagnostic technologies. Despite a wealth of excellent resources describing the decision analysis of diagnostics, two critical errors persist: not including diagnostic test accuracy in the structure of decision trees and treating sequential diagnostics as independent. These errors have consequences for the accuracy of model results, and thereby impact on decision making. This paper sets out to overcome these errors using color to link fundamental epidemiological calculations to decision tree models in a visually and intuitively appealing pictorial format. The paper is a must-read for modelers developing decision trees in the area of diagnostics for the first time and decision makers reviewing diagnostic reimbursement models.

Cost utility, budget impact, and scenario analysis of racecadotril in addition to oral rehydration for acute diarrhea in children in Malaysia.

OBJECTIVE: To perform cost utility (CU) and budget impact (BI) analyses augmented by scenario analyses of critical model structure components to evaluate racecadotril as adjuvant to oral rehydration solution (ORS) for children under 5 years with acute diarrhea in Malaysia. METHODS: A CU model was adapted to evaluate racecadotril plus ORS vs ORS alone for acute diarrhea in children younger than 5 years from a Malaysian public payer's perspective. A bespoke BI analysis was undertaken in addition to detailed scenario analyses with respect to critical model structure components. RESULTS: According to the CU model, the intervention is less costly and more effective than comparator for the base case with a dominant incremental cost-effectiveness ratio of -RM 1,272,833/quality-adjusted life year (USD -312,726/quality-adjusted life year) in favor of the intervention. According to the BI analysis (assuming an increase of 5% market share per year for racecadotril+ORS for 5 years), the total cumulative incremental percentage reduction in health care expenditure for diarrhea in children is 0.136578%, resulting in a total potential cumulative cost savings of -RM 73,193,603 (USD -17,983,595) over a 5-year period. Results hold true across a range of plausible scenarios focused on critical model components. CONCLUSION: Adjuvant racecadotril vs ORS alone is potentially cost-effective from a Malaysian public payer perspective subject to the assumptions and limitations of the model. BI analysis shows that this translates into potential cost savings for the Malaysian public health care system. Results hold true at evidence-based base case values and over a range of alternate scenarios.

The cost utility and budget impact of adjuvant racecadotril for acute diarrhea in children in Thailand.

OBJECTIVE: To evaluate the cost utility and the budget impact of adjuvant racecadotril for the treatment of acute diarrhea in children in Thailand. METHODS: A cost utility model has been adapted to the context of Thailand to evaluate racecadotril plus oral rehydration solution (R+ORS) versus oral rehydration solution (ORS) alone for acute diarrhea in children <5 years old. The decision tree Excel model evaluates the costs and effects (quality-adjusted life years) over a 6-day time horizon from a public health care payer's perspective in Thailand. Deterministic sensitivity analysis and budget impact analysis have been undertaken. RESULTS: According to the cost utility model, the intervention (R+ORS) is less costly and more effective than the comparator (ORS) for the base case with a dominant incremental cost-effectiveness ratio of -2,481,390฿ for the intervention. According to the budget impact analysis (assuming an increase of 5% market share for R+ORS over 5 years), the year-on-year reduction for diarrhea as a percentage of the total health care expenditure is -0.0027%, resulting in potential net cost savings of -35,632,482฿ over 5 years. CONCLUSION: Subject to the assumptions and limitations of the models, adjuvant racecadotril versus ORS alone is potentially cost-effective for children in Thailand and uptake could translate into savings for the Thailand public health care system.

The REVAMP trial to evaluate HIV resistance testing in sub-Saharan Africa: a case study in clinical trial design in resource limited settings to optimize effectiveness and cost effectiveness estimates.

BACKGROUND: In sub-Saharan Africa, rates of sustained HIV virologic suppression remain below international goals. HIV resistance testing, while common in resource-rich settings, has not gained traction due to concerns about cost and sustainability. OBJECTIVE: We designed a randomized clinical trial to determine the feasibility, effectiveness, and cost-effectiveness of routine HIV resistance testing in sub-Saharan Africa. APPROACH: We describe challenges common to intervention studies in resource-limited settings, and strategies used to address them, including: (1) optimizing generalizability and cost-effectiveness estimates to promote transition from study results to policy; (2) minimizing bias due to patient attrition; and (3) addressing ethical issues related to enrollment of pregnant women. METHODS: The study randomizes people in Uganda and South Africa with virologic failure on first-line therapy to standard of care virologic monitoring or immediate resistance testing. To strengthen external validity, study procedures are conducted within publicly supported laboratory and clinical facilities using local staff. To optimize cost estimates, we collect primary data on quality of life and medical resource utilization. To minimize losses from observation, we collect locally relevant contact information, including Whatsapp account details, for field-based tracking of missing participants. Finally, pregnant women are followed with an adapted protocol which includes an increased visit frequency to minimize risk to them and their fetuses. CONCLUSIONS: REVAMP is a pragammatic randomized clinical trial designed to test the effectiveness and cost-effectiveness of HIV resistance testing versus standard of care in sub-Saharan Africa. We anticipate the results will directly inform HIV policy in sub-Saharan Africa to optimize care for HIV-infected patients.

Methods to construct a step-by-step beginner's guide to decision analytic cost-effectiveness modeling.

BACKGROUND: Although guidance on good research practice in health economic modeling is widely available, there is still a need for a simpler instructive resource which could guide a beginner modeler alongside modeling for the first time. AIM: To develop a beginner's guide to be used as a handheld guide contemporaneous to the model development process. METHODS: A systematic review of best practice guidelines was used to construct a framework of steps undertaken during the model development process. Focused methods review supplemented this framework. Consensus was obtained among a group of model developers to review and finalize the content of the preliminary beginner's guide. The final beginner's guide was used to develop cost-effectiveness models. RESULTS: Thirty-two best practice guidelines were data extracted, synthesized, and critically evaluated to identify steps for model development, which formed a framework for the beginner's guide. Within five phases of model development, eight broad submethods were identified and 19 methodological reviews were conducted to develop the content of the draft beginner's guide. Two rounds of consensus agreement were undertaken to reach agreement on the final beginner's guide. To assess fitness for purpose (ease of use and completeness), models were developed independently and by the researcher using the beginner's guide. CONCLUSION: A combination of systematic review, methods reviews, consensus agreement, and validation was used to construct a step-by-step beginner's guide for developing decision analytical cost-effectiveness models. The final beginner's guide is a step-by-step resource to accompany the model development process from understanding the problem to be modeled, model conceptualization, model implementation, and model checking through to reporting of the model results.

Evaluating the cost utility of racecadotril for the treatment of acute watery diarrhea in children: the RAWD model.

BACKGROUND: The safety and efficacy of racecadotril to treat acute watery diarrhea (AWD) in children is well established, however its cost effectiveness for infants and children in Europe has not yet been determined. OBJECTIVE: To evaluate the cost utility of racecadotril adjuvant with oral rehydration solution (ORS) compared to ORS alone for the treatment of AWD in children younger than 5 years old. The analysis is performed from a United Kingdom National Health Service (NHS) perspective. METHODS: A decision tree model has been developed in Microsoft(®) Excel. The model is populated with the best available evidence. Deterministic and probabilistic sensitivity analyses (PSA) have been performed. Health effects are measured as quality-adjusted life years (QALYs) and the model output is cost (2011 GBP) per QALY. The uncertainty in the primary outcome is explored by probabilistic analysis using 1000 iterations of a Monte Carlo simulation. RESULTS: Deterministic analysis results in a total incremental cost of -£379 in favor of racecadotril and a total incremental QALY gain in favor of racecadotril of +0.0008. The observed cost savings with racecadotril arise from the reduction in primary care reconsultation and secondary referral. The difference in QALYs is largely attributable to the timely resolution of symptoms in the racecadotril arm. Racecadotril remains dominant when base case parameters are varied. Monte Carlo simulation and PSA confirm that racecadotril is the dominant treatment strategy and is almost certainly cost effective, under the central assumptions of the model, at a commonly used willingness to pay proxy threshold range of £20,000-£30,000 per QALY. CONCLUSION: Racecadotril as adjuvant therapy is more effective and less costly compared to ORS alone, from a UK payer perspective, for the treatment of children with acute diarrhea.