Health-related quality of life and tolerability in treatment-experienced HIV-1-infected patients on tipranavir versus comparator regimens.

BACKGROUND: Antiretroviral therapy including tipranavir boosted with ritonavir (TPV/r) has shown superior viral suppression and immunological response compared with comparator ritonavir-boosted protease inhibitor (CPI/r) regimens in treatment-experienced HIV-1-infected patients. This study assesses the influence of adverse events (AEs) on health-related quality of life (HRQOL) and change in HRQOL in patients treated with TPV/r versus CPI/r regimens. METHODS: Changes in HRQOL over 48 weeks were assessed using Medical Outcomes Study HIV Health Survey (MOS-HIV) data combined from two randomized, open-label, Phase III studies (RESIST-1 and RESIST-2). Generalized estimating equations (GEE) were used to compare physical health and mental health summary scores and 10 subscale scores, and to compare scores of patients with and without AEs. To compare AE incidences in the two treatment groups, AEs were exposure-adjusted. RESULTS: There were 984 patients in the HRQOL analysis. AE occurrence and severity resulted in significantly lower MOS-HIV scores across both treatment arms (P<0.05). Overall incidence of AEs was higher in the CPI/r versus TPV/r group (562.8 versus 514.4 per 100 patient-exposure years); treatment-related AEs were more frequent in the TPV/r group (75.0 versus 56.6 per 100 patient-exposure years). HRQOL was maintained in patients on TPV/r over 48 weeks of treatment across all summary and subscale scores. Compared with CPI/r, TPV/r was associated with a significant but small (SD<0.2) improvement in pain scores (+4.8 points; P<0.05). CONCLUSIONS: HRQOL was maintained across both summary and all subscale scores from baseline to 48 weeks in the TPV/r and CPI/r treatment arms, despite the incidence of treatment-related AEs.

Cost-effectiveness of tipranavir in treatment-experienced HIV patients in the United States.

OBJECTIVE: To compare the estimated long-term outcomes, costs, and cost-effectiveness of tipranavir boosted with ritonavir (TPV/r) versus investigator-selected ritonavir-boosted comparator protease inhibitor (CPI/r) using the observed 48-week data from the RESIST trials in a previously published Markov model. METHOD: A previously developed 3-stage Markov model was modified to reflect US practice patterns for treatment-experienced HIV patients using 2007 costs and combined phase III tipranavir trial data (RESIST-1 and -2). The 12 model health states were defined by CD4 cell count and viral load that have previously been identified as predictors of HIV/AIDS progression. Resource use and quality of life weights were linked to each health state. Disease progression beyond the 48-week trial period was based on HAART treatment-experienced patients from data collected by the University of South Carolina. Costs were estimated from the payer perspective. RESULTS: TPV/r patients remained longer in health states defined by higher CD4 cell count and lower viral load compared to CPI/r patients. This reduced the rate of AIDS-defining events by 12.35% over 5 years and resulted in 0.64 quality-adjusted life-years (QALYs) gained (discounted at 3%) over the model time horizon (remaining lifetime). The incremental cost-effectiveness ratio (ICER) of TPV/r versus CPI/r was $56,517/QALY (discounted at 3%). Excluding patients also treated with enfuvirtide reduced the ICER to $46,147/QALY. CONCLUSION: TPVI/r is cost-effective in the United States compared to CPI/r in treatment-experienced HIV-1-infected patients.

Cost-effectiveness of tipranavir versus comparator protease inhibitor regimens in HIV infected patients previously exposed to antiretroviral therapy in the Netherlands.

BACKGROUND: This study compares the costs and effects of a regimen with ritonavir-boosted tipranavir (TPV/r) to a physician-selected genotypically-defined standard-of-care comparator protease inhibitor regimen boosted with ritonavir (CPI/r) in HIV infected patients that were previously exposed to antiretroviral therapy in the Netherlands. METHODS: We compared the projected lifetime costs and effects of two theoretical groups of 1000 patients, one receiving a standard of care regimen with TPV/r as a component and the other receiving a standard of care regimen with CPI/r. A 3-stage Markov model was formulated to represent three different consecutive HAART regimens. The model uses 12 health states based on viral load and CD4+ count to simulate disease progression. The transition probabilities for the Markov model were derived from a United States cohort of treatment experienced HIV patients. Furthermore, the study design was based on 48-week data from the RESIST-2 clinical trial and local Dutch costing data. Cost and health effects were discounted at 4% and 1.5% respectively according to the Dutch guideline. The analysis was conducted from the Dutch healthcare perspective using 2006 unit cost prices. RESULTS: Our model projects an accumulated discounted cost to the Dutch healthcare system per patient receiving the TPV/r regimen of euro167,200 compared to euro145,400 for the CPI/r regimen. This results in an incremental cost of euro21,800 per patient. The accumulated discounted effect is 7.43 life years or 6.31 quality adjusted life years (QALYs) per patient receiving TPV/r, compared to 6.91 life years or 5.80 QALYs per patient receiving CPI/r. This translates into an incremental effect of TPV/r over CPI/r of 0.52 life years gained (LYG) or 0.51 QALYs gained. The corresponding incremental cost effectiveness ratios (iCERs) are euro41,600 per LYG and euro42,500 per QALY. CONCLUSION: We estimated the iCER for TPV/r compared to CPI/r at approximately euro40,000 in treatment experienced HIV-1 infected patients in the Netherlands. This ratio may well be in range of what is acceptable and warrants reimbursement for new drug treatments in the Netherlands, in particular in therapeutic areas as end-stage oncology and HIV and other last-resort health-care interventions.

A cross-country review of data collected on non-small cell lung cancer (NSCLC) patients in cancer registries, databases, retrospective and non-randomized prospective studies.

INTRODUCTION: An increased number of pharmacotherapies exist to treat advanced NSCLC. This necessitates a review of the available information on routine-care treatment patterns, the outcome of treatment, and resource utilization for patients diagnosed and treated with advanced NSCLC that could inform evidence-based treatment decisions and aid decisions on the most cost-effective treatment alternatives. METHODS: PubMed and the Health Economic Evaluations Database were searched for retrospective or non-randomized prospective studies between January 2000 and May 2012 that included information on treatment patterns, treatment outcomes including health-related quality-of-life (HRQoL), and resource utilization. In addition, registries and databases were identified from retrieved publications and internet searches. Data collected in registries and databases was summarized for eight European countries (Belgium, France, Germany, Italy, Sweden, Turkey, the Netherlands, the UK), Australia, and Canada. RESULTS: The literature search resulted in 410 studies, whereof 87 studies met the study inclusion criteria. In total, 49 were retrospective chart reviews or database analyses, 30 non-randomized prospective studies, and eight HRQoL studies. Two studies compared treatment patterns and/or treatment outcomes across countries. Altogether, 181 cancer registries in the countries studied were identified. Clinical cancer-specific patient registries were identified in Australia and Germany. Databases or linkage systems that enable retrieval of complete information of patient disease history were found in Australia, Canada, the Netherlands, Sweden, and the UK. Cancer registries and databases were found to collect information on NSCLC patient demographics, NSCLC or lung cancer diagnosis, disease stage, performance status, treatment, treatment outcomes, and resource use. Differences existed between country registries and databases in whether information was collected on each of these data points. CONCLUSION: The literature review revealed few published NSCLC studies on treatment, treatment outcomes, and resource use in routine clinical practice and on HRQoL. Registries and databases were found to collect some of this information, however not systematically.

Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUX-Lung 1).

BACKGROUND: Patient-reported symptom and health-related quality of life (HRQoL) benefit of afatinib, a novel, irreversible, ErbB Family Blocker, was investigated in a double-blind, randomized, phase IIb/III trial (LUX-Lung 1). METHODS: Five hundred and eighty-five patients with lung adenocarcinoma (stage IIIb/IV), who had progressed after chemotherapy (1-2 lines) and at least 12 weeks of erlotinib or gefitinib, were randomized (2:1) to receive either afatinib plus best supportive care (BSC) or placebo plus BSC. Symptom and HRQoL benefit were measured using the lung cancer-specific European Organisation for Research and Treatment of Cancer (QLQ-C30/LC13) and EuroQol (EQ-5D) questionnaires. Non-small-cell lung cancer-related symptoms (cough, dyspnea, and pain) were prespecified using three preplanned analyses (percentage of patients improved/worsened/stable, change in scores over time, and time to deterioration of scores). RESULTS: Compared with patients on placebo, a significantly higher proportion of afatinib-treated patients showed an improvement in cough (p < 0.0001), dyspnea (p = 0.006), and pain (p < 0.0001). Afatinib also significantly improved the mean scores over time for cough (p < 0.0001), dyspnea (p = 0.0161), and pain (p = 0.0056); significantly delayed the time to deterioration for cough (p < 0.001); and showed a trend in delaying dyspnea (p = 0.170) and pain (p = 0.287). Consistent with the adverse-event profile of afatinib, a significantly (p < 0.05) higher proportion of afatinib-treated patients showed worsening of diarrhea, sore mouth, dysphagia, and appetite scores. However, compared with placebo, afatinib significantly (p < 0.05) improved QoL assessed with the EQ-5D questionnaire and global health status/QoL, physical functioning, and fatigue, which were assessed with the European Organisation for Research and Treatment of Cancer questionnaires. CONCLUSION: In the LUX-Lung 1 trial, the addition of afatinib to BSC significantly improved non-small-cell lung cancer-related symptoms (cough, dyspnea, and pain), fatigue, physical functioning, and HRQoL and significantly delayed time to deterioration of cough.

Health-related quality of life and utility in patients with advanced non-small-cell lung cancer: a prospective cross-sectional patient survey in a real-world setting.

BACKGROUND: Non-small-cell lung cancer (NSCLC) has a significant impact on patients' health-related quality of life (HRQOL). This study aimed to measure health state utility values representing the individual's preferences for specific health-related outcomes in advanced NSCLC patients and to assess predictive parameters. METHODS: We conducted a prospective quality-of-life survey on advanced NSCLC patients in 25 hospitals in Europe, Canada, Australia, and Turkey. HRQOL was assessed using the EuroQol (EQ-5D) questionnaire and EQ-5D utility and EQ-visual analog (EQ-VAS) scores were estimated. RESULTS: Three hundred nineteen patients were recruited of which 263 had evaluable data. Mean utility for progression-free (PF) patients on first-, second-, and third-/fourth-line treatment was 0.71 (SD = 0.24), 0.74 (SD = 0.18), and 0.62 (SD = 0.29), respectively. Mean utility for patients with progressive disease (PD) while on first-, second- and third-/fourth-line treatment was 0.67 (SD = 0.2), 0.59 (SD = 0.34), and 0.46 (SD = 0.38), respectively. Overall, patients with PD had lower mean utility scores than PF patients (0.58 versus 0.70). The results of the EQ-VAS showed that the score decreased with later treatment lines. Patients with PD had a 10-point decrease in VAS scores compared with PF patients (53.7 versus 66.6). The regression analysis revealed that stage IV disease, higher lines of treatment, and health state were significant predictors of utility at the 10% level. CONCLUSION: The results presented indicate a substantial impact of lung cancer on patients' HRQOL, with stage IV disease, line of treatment, and PD, resulting in considerable deterioration of utility. The values obtained here will inform evaluations of cost-utility for NSCLC therapies.

Patients' preferences for treatment outcomes for advanced non-small cell lung cancer: a conjoint analysis.

BACKGROUND: Treatment decisions for advanced non-small cell lung cancer (NSCLC) are complex and require trade-offs between the benefits and risks experienced by patients. We evaluated the benefits that patients judged sufficient to compensate for the risks associated with therapy for NSCLC. METHODS: Participants with a self-reported diagnosis of NSCLC (n=100) were sampled from an online panel in the United Kingdom. Eligible and consenting participants then completed a self-administered online survey about their disease and their treatment preferences were assessed. This involved respondents choosing among systematically paired profiles that spanned eight attributes: progression-free survival [PFS], symptom severity, rash, diarrhoea, fatigue, nausea and vomiting, fever and infection, and mode of treatment administration (infusion and oral). A choice model was estimated using mixed-logit regression. Estimates of importance for each attribute level and attribute were then calculated and acceptable tradeoffs among attributes were explored. RESULTS: A total of 89 respondents (73% male) completed all choice tasks appropriately. Increases in PFS together with improvements in symptom severity were judged most important and increased with PFS benefit - 4 months: 5.7; 95% CI: 3.5-7.9; 5 months: 7.1; 95% CI: 4.4-9.9; and 7 months: 10.0; 95% CI: 6.1-13.9. However, improvements in PFS were viewed as most beneficial when disease symptoms were mild and as detrimental when patients had severe symptoms. Fatigue (5.0; 95% CI: 2.7-7.3) was judged to be the most important risk, followed by diarrhoea (2.8; 95% CI: 0.7-4.9), nausea and vomiting (2.1; 95% CI: 0.1-4.1), fever and infection (2.1; 95% CI: 0.2-4.1), and rash (2.0; 95% CI: 0.2-3.9). Oral administration was preferred to infusion (1.8; 95% CI: 0.0-3.6). Patients with mild and moderate symptoms traded PFS for less risks or more convenience if the severe symptoms were not experienced. CONCLUSION: This study demonstrates the value of conjoint analysis in the study of patient preferences for cancer treatments. In this small sample of patients with NSCLC from the UK, we demonstrate that the value of improvements in PFS is conditional upon the severity of disease symptoms; and that risks are valued differently.

Treatment patterns, use of resources, and costs of advanced non-small-cell lung cancer patients in Spain: results from a Delphi panel.

INTRODUCTION: Approximately 80-85% of lung cancer patients are diagnosed with non-small-cell lung cancer (NSCLC), of which 50% of patients present with advanced or metastatic disease. The objective of this study was to describe treatment patterns, use of resources and costs associated with treating advanced or metastatic NSCLC patients in Spain. METHODS: A two-round Delphi consensus panel of clinical experts was carried out to describe local clinical patterns based on treatment algorithms from SEOM and ASCO treatment guidelines. The panel consisted of 19 oncologists and 1 hospital pharmacist, who were asked during the first round to define therapeutic pathways for NSCLC by the patients' performance status, age and histology; to quantify the use of resources associated with the preparation and administration of anticancer pharmacotherapy; management of adverse events associated with anticancer pharmacotherapy; and best supportive care (BSC). The second round was used to try to reduce the variability of responses in some questions and to further describe differences between intravenous and oral therapy. 2009 unit costs were applied to the use of resources described by the clinical experts. The perspective of the study was from the Spanish National Healthcare System. RESULTS: Performance status guided therapy decision and led to differences in costs. Patients with a performance status of 0-2 were expected to receive anticancer pharmacotherapy while patients with a performance status of 3-4 received BSC including analgesics and corticosteroids. Anticancer pharmacotherapies containing cisplatin or carboplatin were used preferably in first-line treatment, while the usual second- and third-line treatments were docetaxel, erlotinib or pemetrexed monotherapy. The importance of the cost of anticancer pharmacotherapy as a proportion of total healthcare costs was higher for combination therapies containing bevacizumab or pemetrexed. The anticancer pharmacotherapies associated with adverse events like febrile neutropenia or infection increased the total treatment cost. Administration costs were more relevant in regimens containing cisplatin and were low for orally administered therapies. The total cost per patient with advanced or metastatic NSCLC from starting anticancer therapy until death was estimated to be between €11,301 and €32,754 depending on the number of treatment lines received. CONCLUSIONS: In the treatment of advanced or metastatic NSCLC, healthcare costs are impacted by line of treatment, patient performance status, type of administration of therapy and adverse event management.

Treatment of lung cancer patients and concomitant use of drugs interacting with cytochrome P450 isoenzymes.

OBJECTIVE: The majority of anticancer medicines used in the therapy of lung cancer patients are metabolized by cytochrome P450 (CYP450) enzymes, but little is known about the frequency of prescribed concomitant medicines interacting via the same enzyme system. This study analyzed the use of medications that could cause drug-drug interactions (inhibition or induction) in lung cancer patients before and during anticancer treatment. RESEARCH DESIGN AND METHODS: In this retrospective cross sectional study, all lung cancer patients (ICD-9 codes 162.2-162.9, 231.2) aged ≥18 years who received any anticancer medicines between 1/1/2004 and 6/30/2008 were identified in the US Thomson Reuters MarketScan(®) Claims Database. Patients had to have data for at least 12 months prior to (pre-period) and during their treatment, had no other cancer or use of other anticancer treatment in the pre-period. Patients with renal disease, renal failure, or liver failure were excluded. Drugs known to induce or inhibit P450 enzymes and used before and during lung cancer treatment were categorized with respect to their potency (strong, moderate, low). RESULTS: Out of 144,959 lung cancer patients, 6647 (4.6%) patients met the study entry criteria. Mean age was 67 years, 53% were men, and mean Charlson combordity index was 3.5. 99% of patients received at least one drug known as a substrate, inhibitor or inducer of P450 (98% inhibitors, 93% inducers, 98% substrates) during the patient's anticancer treatment episode. Mean co-treatment duration with any CYP450 agent was 99 days (76% of the episode length); ≥2 different CYP450 agents were prescribed during 98% of episodes, and ≥10 different CYP450 agents were prescribed during 44% of episodes. Use of CYP450 agents was similar in the pre-treatment period: at least one CYP450 agent was prescribed during 99% of episodes (99% inhibitors, 79% inducers, 98% substrates). CONCLUSIONS: Drugs which may cause drug-drug interactions while affecting the CYP 450 enzymes are frequently prescribed both before and during anticancer treatment of lung cancer patients.

Handling missing quality of life data in HIV clinical trials: what is practical?

AIMS: Missing health-related quality of life (HRQOL) data in clinical trials can impact conclusions but the effect has not been thoroughly studied in HIV clinical trials. Despite repeated recommendations to avoid complete case (CC) analysis and last observation carried forward (LOCF), these approaches are commonly used to handle missing data. The goal of this investigation is to describe the use of different analytic methods under assumptions of missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR) using HIV as an empirical example. METHODS: Medical Outcomes Study HIV (MOS-HIV) Health Survey data were combined from two large open-label multinational HIV clinical trials comparing treatments A and B over 48 weeks. Inclusion in the HRQOL analysis required completion of the MOS-HIV at baseline and at least one follow-up visit (weeks 8, 16, 24, 40, 48). Primary outcomes for the analysis were change from week 0 to 48 in mental health summary (MHS), physical health summary (PHS), pain and health distress scores analyzed using CC, LOCF, generalized estimating equations (GEE), direct likelihood and sensitivity analyses using joint mixed-effects model, and Markov chain Monte Carlo (MCMC) multiple imputation. Time and treatment were included in all models. Baseline and longitudinal variables (adverse event and reason for discontinuation) were only used in the imputation model. RESULTS: A total of 511 patients randomized to treatment A and 473 to treatment B completed the MOS-HIV at baseline and at least one follow-up visit. At week 48, 71% of patients on treatment A and 31% on treatment B completed the MOS-HIV survey. Examining changes within each treatment group, CC and MCMC generally produced the largest or most positive changes. The joint model was most conservative; direct likelihood and GEE produced intermediate results; LOCF showed no consistent trend. There was greater spread for within-group changes than between-group differences (within MHS scores for treatment A: -0.1 to 1.6, treatment B: 0.4 to 2.0; between groups: -0.7 to 0.4; within PHS scores for treatment A: -1.5 to 0.4, treatment B: -1.7 to -0.2; between groups: 0.1 to 1.1). The size of within-group changes and between-group differences was of similar magnitude for the pain and health distress scores. In all cases, the range of estimates was small <0.2 SD (less than 2 points for the summary scores and 5 points for the subscale scores). CONCLUSIONS: Use of the recommended likelihood-based models that do not require assumptions of MCAR was very feasible. Sensitivity analyses using auxiliary information can help to investigate the potential effect that missing data have on results but require planning to ensure that relevant data are prospectively collected.

The hospital cost of vertebral fractures in the EU: estimates using national datasets.

The purpose of this study was to estimate the hospital cost of vertebral fractures in the EU using national datasets to explore some of the methodologic limitations associated with such an approach. Hospital costs for vertebral fractures across the EU were compared with the hospital costs associated with hip fractures. Additionally, these costs were placed into the health care context by making comparisons with national health care expenditure. All EU Ministries of Health were contacted to identify national datasets to estimate the average length of stay, cost per diem and the number of patients discharged with vertebral fractures. Where national information was not available expert opinion and data from the relevant literature were used instead. Countries show a marked difference in the length of stay between men and women, with differences ranging from 0.32 days in Austria to 20.2 days in Spain. The average hospitalization rate was found to be 8% across the EU, with higher rates found for men than for women. Interestingly a positive correlation between health expenditure per capita and hospitalization rates was found. The total cost of vertebral fractures in the EU was estimated at euro 377 million per year. Across the EU the hospital cost of a vertebral fracture was on average 63% that of a hip fracture. National datasets allow us to estimate the cost of vertebral fractures in the EU but show limitations. In the absence of large scale prospective studies, national datasets need to be further refined to ensure more accurate estimations of the cost of vertebral fractures in the EU.