Modelling Health State Utilities as a Transformation of Time to Death in Patients with Non-Small Cell Lung Cancer.

BACKGROUND: When utilities are analyzed by time to death (TTD), this has historically been implemented by 'grouping' observations as discrete time periods to create health state utilities. We extended the approach to use continuous functions, avoiding assumptions around groupings. The resulting models were used to test the concept with data from different regions and different country tariffs. METHODS: Five-year follow-up in advanced non-small cell lung cancer (NSCLC) was used to fit six continuous TTD models using generalized estimating equations, which were compared with progression-based utilities and previously published TTD groupings. Sensitivity analyses were performed using only patients with a confirmed death, the last year of life only, and artificially censoring data at 24 months. The statistically best-fitting model was then applied to data subsets by region and different EQ-5D-3L country tariffs. RESULTS: Continuous (natural) [Formula: see text] and [Formula: see text] models outperformed other continuous models, grouped TTD, and progression-based models in statistical fit (mean absolute error and Quasi Information Criterion). This held through sensitivity and scenario analyses. The pattern of reduced utility as a patient approaches death was consistent across regions and EQ-5D tariffs using the preferred [Formula: see text] model. CONCLUSIONS: The use of continuous models provides a statistically better fit than TTD groupings, without the need for strong assumptions about the health states experienced by patients. Where a TTD approach is merited for use in modelling, continuous functions should be considered, with the scope for further improvements in statistical fit by both widening the number of candidate models tested and the therapeutic areas investigated.

Comparative Efficacy of Neoadjuvant Nivolumab Plus Chemotherapy versus Conventional Comparator Treatments in Resectable Non-Small-Cell Lung Cancer: A Systematic Literature Review and Network Meta-Analysis.

BACKGROUND: This study aimed to estimate the relative efficacy of neoadjuvant nivolumab in combination with chemotherapy (neoNIVO + CT) compared to relevant treatments amongst resectable non-metastatic non-small-cell lung cancer (rNSCLC) patients. METHODS: Treatment comparisons were based on a network meta-analysis (NMA) using randomized clinical trial data identified via systematic literature review (SLR). The outcomes of interest were event-free survival (EFS) and pathological complete response (pCR). NeoNIVO + CT was compared to neoadjuvant chemotherapy (neoCT), neoadjuvant chemoradiotherapy (neoCRT), adjuvant chemotherapy (adjCT), and surgery alone (S). Due to the potential for effect modification by stage, all-stage and stage-specific networks were considered. Fixed-effect (FE) and random-effects Bayesian NMA models were run (EFS = hazard ratios [HR]; pCR = odds ratios [OR]; 95% credible intervals [CrI]). RESULTS: Sixty-one RCTs were identified (base case = 9 RCTs [n = 1978 patients]). In the all-stages FE model, neoNIVO + CT had statistically significant EFS improvements relative to neoCT (HR = 0.68 [95% CrI: 0.49, 0.94]), S (0.59 [0.42, 0.82]), adjCT (0.66 [0.45, 0.96]), but not relative to neoCRT (HR = 0.77 [0.52, 1.16]). NeoNIVO + CT (5 RCTs) had statistically significant higher odds of pCR relative to neoCT (OR = 12.53 [5.60, 33.82]) and neoCRT (7.15 [2.31, 24.34]). Stage-specific model findings were consistent. CONCLUSIONS: This NMA signals improved EFS and/or pCR of neoNIVO + CT relative to comparators among patients with rNSCLC.

Cost-effectiveness analysis of nivolumab plus ipilimumab versus platinum-doublet chemotherapy for first-line treatment of stage IV or recurrent non-small cell lung cancer in the United States.

AIM: We evaluated the cost-effectiveness of nivolumab in combination with ipilimumab (NIVO + IPI) versus platinum-doublet chemotherapy (PDC) for the first-line treatment of stage IV or recurrent non-small cell lung cancer (NSCLC) from a third-party payer perspective in the United States (US). METHODS: A partitioned survival model was developed using efficacy, safety, and utility inputs derived from Part 1 of the phase 3 CheckMate 227 trial (NCT02477826) with 37.7-month minimum follow-up for overall survival (OS). OS and progression-free (PF) survival were extrapolated over a 20-year time-horizon using parametric spline-based models selected based on goodness of fit and validated with data from external sources. Duration of treatment Kaplan-Meier curves were used for treatment cost calculations. US-specific costs (2021 dollars) for drug acquisition, administration, and monitoring; disease management (PF and progressed disease health states); end-of-life care; adverse events; and subsequent treatments were derived from publicly available sources. Time-to-death utilities were applied in the base case, whereas treatment-specific progression-based utilities were tested in a scenario analysis. Main outcomes included incremental cost per life-year gained (LYG) and quality-adjusted life-year (QALY). Model uncertainty was assessed through deterministic and probabilistic sensitivity analyses. RESULTS: NIVO + IPI resulted in 1.53 additional life-years, 1.33 additional QALYs, and $142 088 in additional costs compared with PDC. The incremental cost per LYG was $92 651, whereas incremental cost per QALY gained was $106 553. The application of treatment-specific progression-based utilities yielded an incremental cost per QALY gained of $117 076. Probabilistic sensitivity analysis revealed a 98% probability that NIVO + IPI was cost-effective versus PDC at a willingness-to-pay threshold of $150 000 per QALY. CONCLUSIONS: NIVO + IPI was estimated to be cost-effective as a first-line treatment for stage IV or recurrent NSCLC in the US, with increased survival and higher cost compared with PDC.

Cost-effectiveness analysis of nivolumab plus ipilimumab plus two cycles of platinum-doublet chemotherapy versus platinum-doublet chemotherapy alone for first-line treatment of stage IV or recurrent non-small cell lung cancer in the United States.

AIM: This economic analysis evaluated the cost-effectiveness of nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of platinum-doublet chemotherapy (PDC) compared with four cycles of PDC as first-line treatment for patients with advanced NSCLC in the United States (US). METHODS: A partitioned survival model was constructed with three mutually exclusive health states: progression free, progressed disease, and death. The analysis was conducted from a US healthcare payer perspective, using a time horizon of 25 years. Costs and outcomes were discounted at 3% annually. Survival outcomes from CheckMate 9LA were extrapolated with longer follow-up data from CheckMate 227 Part 1 (NIVO + IPI) and validated against data from other relevant clinical trials and real-world registries. Health-related quality of life utility values were derived from EQ-5D-3L data collected in CheckMate 9LA. US-specific costs (2020 dollars) were used for disease management; drug acquisition, administration, and monitoring; end-of-life care; adverse events; and subsequent treatments. Model outcomes included life years (LYs) gained, quality-adjusted LYs (QALYs) gained, and incremental cost-effectiveness ratio (ICER) for NIVO + IPI + PDC versus PDC. Sensitivity and scenario analyses were conducted. RESULTS: NIVO + IPI + PDC was associated with higher projected health benefits than PDC, including gains in LYs (3.71 vs 1.89) and QALYs (2.86 vs 1.37), and higher costs ($317,581 vs $119,909). The ICER was $132,960/QALY gained. NIVO + IPI + PDC had a 78-100% probability of being cost-effective at a willingness-to-pay threshold of $150,000-$250,000/QALY. Sensitivity and scenario analyses indicated that the results were robust to changes in key parameters. LIMITATIONS: The inherent limitation in extrapolating clinical trial data was mitigated using data from the more mature CheckMate 227 Part 1 trial and validating the outcomes against data from other relevant trials and real-world registries. CONCLUSION: NIVO + IPI + PDC (two cycles) provides a new first-line treatment option for patients with advanced NSCLC that is cost-effective within a range considered acceptable in the US.

Cost-effectiveness of nivolumab in patients with NSCLC in the United States.

OBJECTIVES: To determine the lifetime cost-effectiveness of nivolumab vs docetaxel in advanced squamous and nonsquamous non-small cell lung cancer (NSCLC) following platinum-based chemotherapy from a US payer perspective. STUDY DESIGN: Trial- and cohort-based cost-effectiveness analyses. METHODS: The analyses used partitioned survival models with 3 mutually exclusive health states: progression free, progressed disease, and death. The mean starting age was 61 years. Clinical parameters were derived from the 2 registrational, randomized, phase 3 trials with a minimum follow-up of 5 years. Costs were derived from published literature. The primary outcomes were quality-adjusted life-years (QALYs), life-years gained (LYG), and incremental cost-effectiveness ratios (ICERs). Costs and outcomes were discounted at 3% per annum. Uncertainty was examined using univariate and probabilistic sensitivity analyses. RESULTS: In patients with squamous NSCLC, the use of nivolumab improved life-years (LYs) and QALYs by 1.23 and 0.99, respectively, compared with docetaxel. Costs were increased by $99,677, resulting in ICERs of $100,776 per QALY and $81,294 per LYG. In patients with nonsquamous NSCLC, nivolumab increased LYs and QALYs by 0.99 and 0.80, respectively. Costs were increased by $94,174, resulting in ICERs of $117,739 per QALY and $94,849 per LYG. ICERs were most sensitive to the discount rates applied to costs and outcomes. At a willingness-to-pay threshold of $150,000, nivolumab had probabilities of 91% and 99% of being cost-effective in patients with squamous and nonsquamous NSCLC, respectively. CONCLUSIONS: Nivolumab is likely to be cost-effective for the treatment of patients with advanced NSCLC following platinum-based chemotherapy in the United States.

Cost-effectiveness of nivolumab in squamous and non-squamous non-small cell lung cancer in Canada and Sweden: an update with 5-year data.

AIMS: Nivolumab has been approved for advanced squamous and non-squamous non-small cell lung cancer (NSCLC) following platinum-based chemotherapy in both Canada and Sweden. We aimed to determine the value-for-money of nivolumab versus docetaxel in a Canadian and Swedish setting based on 5-year data. METHODS: These cost effectiveness analyses used partitioned survival models with three mutually exclusive health states: progression-free, progressed disease, and death. All clinical parameters were derived from two registration phase 3 randomized trials, CheckMate 017 and CheckMate 057, with a minimum follow-up of 5 years. Treatment duration was based on time-on-treatment data from the clinical trials. Costs were derived from published sources. The primary outcomes of the analyses were quality-adjusted life-years (QALYs), life-years gained, and incremental cost-effectiveness ratios (ICERs). The model input parameters for each analysis were chosen in line with guidance from the respective HTA authorities. RESULTS: From a Canadian payer perspective, the ICERs were CAN$140,753 per QALY in the squamous population, and CAN$173,804 per QALY in the non-squamous population, assuming a 10-year time horizon and a 5% discount rate for both costs and outcomes. Sensitivity analyses demonstrated that changes to the discount rates for outcomes had the highest impact on the ICERs. In the Swedish analysis, the ICERs were SEK568,895 per QALY in the squamous population and SEK662,991 per QALY in the non-squamous population, assuming a 15-year time horizon, a 3% discount rate, and a 2-year maximum treatment duration for nivolumab. Sensitivity analyses demonstrated that the ICERs were most sensitive to changes in the discount rate for outcomes. CONCLUSION: These updated analyses, based on more mature trial data with a minimum follow-up of 5 years, generate more favorable ICERs versus the previously submitted HTA assessments that resulted in approval of nivolumab for patients with previously treated NSCLC in Canada and Sweden.

Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial.

BACKGROUND: New treatments are needed to shorten the time required to cure tuberculosis and to treat drug-resistant strains. The fluoroquinolone moxifloxacin is a promising new agent that might have additive activity to existing antituberculosis agents. We assessed the activity and safety of moxifloxacin in the initial stage of tuberculosis treatment. METHODS: We undertook a phase II, double-blind, randomised controlled trial of a regimen that included moxifloxacin in adults with sputum smear-positive tuberculosis at one hospital in Rio de Janeiro, Brazil. 170 participants received isoniazid, rifampicin, and pyrazinamide at standard doses and were assigned by permuted block randomisation to receive either moxifloxacin (400 mg) with an ethambutol placebo (n=85) or ethambutol (15-20 mg/kg) plus moxifloxacin placebo (n=85) 5 days per week for 8 weeks. The primary endpoint was the proportion of patients whose sputum culture had converted to negative by week 8. Analysis was by modified intention to treat (ITT); patients whose baseline cultures were negative, contaminated, or contained drug-resistant Mycobacterium tuberculosis were excluded from the analysis. Additionally, all missing 8-week results were deemed treatment failures. This study is registered with ClinicalTrials.gov, number NCT00082173. FINDINGS: 74 patients assigned to the moxifloxacin group and 72 in the ethambutol group were included in the modified ITT population. 125 patients had 8-week data (moxifloxacin n=64, ethambutol n=61); the main reason for absence of data was culture contamination. At 8 weeks, culture conversion to negative had occurred in 59 (80%) of 74 patients in the moxifloxacin group compared with 45 (63%) of 72 in the ethambutol group (difference 17.2%, 95% CI 2.8-31.7; p=0.03). There were 16 adverse events (eight in each group) in 12 patients. Only one event was judged related to study drug (grade 3 cutaneous reaction in the ethambutol group). INTERPRETATION: Moxifloxacin improved culture conversion in the initial phase of tuberculosis treatment. Trials to assess whether moxifloxacin can be used to shorten the duration of tuberculosis treatment are justified.

Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials.

BACKGROUND: UNICEF/WHO recommends that infants born to HIV-infected mothers who do not have access to acceptable, feasible, affordable, sustainable, and safe replacement feeding should be exclusively breastfed for at least 6 months. The aim of three trials in Ethiopia, India, and Uganda was to assess whether daily nevirapine given to breastfed infants through 6 weeks of age can decrease HIV transmission via breastfeeding. METHODS: HIV-infected women breastfeeding their infants were eligible for participation. Participants were randomly assigned to receive either single-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborns after birth) or 6 week extended-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborn babies after birth plus nevirapine 5 mg daily from days 8-42 for the infant). The randomisation sequences were generated by computer at a central data coordinating centre. The primary endpoint was HIV infection at 6 months of age in infants who were HIV PCR negative at birth. Analyses were by modified intention to treat, excluding infants with missing specimens and those with indeterminate or confirmed HIV infection at birth. These studies are registered with ClinicalTrials.gov, numbers NCT00074399, NCT00061321, and NCT00639938. FINDINGS: 2024 liveborn infants randomised in the study had at least one specimen tested before 6 months of age (1047 infants in the single-dose group and 977 infants in the extended-dose group). The modified intention-to-treat population included 986 infants in the single-dose group and 901 in the extended-dose group. At 6 months, 87 children in the single-dose group and 62 in the extended-dose group were infected with HIV (relative risk 0.80, 95% CI 0.58-1.10; p=0.16). At 6 weeks of age, 54 children in the single-dose group and 25 in the extended-dose group were HIV positive (0.54, 0.34-0.85; p=0.009). 393 infants in the single-dose group and 346 in the extended-dose group experienced grade 3 or 4 serious adverse events during the study (p=0.54). INTERPRETATION: Although a 6-week regimen of daily nevirapine might be associated with a reduction in the risk of HIV transmission at 6 weeks of age, the lack of a significant reduction in the primary endpoint-risk of HIV transmission at 6 months-suggests that a longer course of daily infant nevirapine to prevent HIV transmission via breast milk might be more effective where access to affordable and safe replacement feeding is not yet available and where the risks of replacement feeding are high. FUNDING: US National Institutes of Health; US National Institute of Allergy and Infectious Diseases; Fogarty International Center.

Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial.

BACKGROUND: Ecological and observational studies suggest that male circumcision reduces the risk of HIV acquisition in men. Our aim was to investigate the effect of male circumcision on HIV incidence in men. METHODS: 4996 uncircumcised, HIV-negative men aged 15-49 years who agreed to HIV testing and counselling were enrolled in this randomised trial in rural Rakai district, Uganda. Men were randomly assigned to receive immediate circumcision (n=2474) or circumcision delayed for 24 months (2522). HIV testing, physical examination, and interviews were repeated at 6, 12, and 24 month follow-up visits. The primary outcome was HIV incidence. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, with the number NCT00425984. FINDINGS: Baseline characteristics of the men in the intervention and control groups were much the same at enrollment. Retention rates were much the same in the two groups, with 90-92% of participants retained at all time points. In the modified intention-to-treat analysis, HIV incidence over 24 months was 0.66 cases per 100 person-years in the intervention group and 1.33 cases per 100 person-years in the control group (estimated efficacy of intervention 51%, 95% CI 16-72; p=0.006). The as-treated efficacy was 55% (95% CI 22-75; p=0.002); efficacy from the Kaplan-Meier time-to-HIV-detection as-treated analysis was 60% (30-77; p=0.003). HIV incidence was lower in the intervention group than it was in the control group in all sociodemographic, behavioural, and sexually transmitted disease symptom subgroups. Moderate or severe adverse events occurred in 84 (3.6%) circumcisions; all resolved with treatment. Behaviours were much the same in both groups during follow-up. INTERPRETATION: Male circumcision reduced HIV incidence in men without behavioural disinhibition. Circumcision can be recommended for HIV prevention in men.

Regression of significant tricuspid regurgitation after mitral balloon valvotomy for severe mitral stenosis.

BACKGROUND: Significant tricuspid regurgitation (TR) is occasionally associated with severe mitral stenosis and has an adverse impact on morbidity and mortality in patients undergoing mitral valve surgery. However, the effect of successful mitral balloon valvotomy (MBV) on significant TR is not fully elucidated. The aim of this study was to investigate TR after MBV in patients with severe mitral stenosis. METHODS: We analyzed the data of 53 patients with significant TR (grade > or =2, on a 1 to 3 scale) from the mitral balloon valvotomy database at our hospital. Patients were evaluated by Doppler echocardiography before valvotomy and at follow-up 1 to 13 years after MBV. Patients were divided into group A (27 patients), in whom TR regressed by > or =1 scale, and group B (26 patients), in whom TR did not regress. RESULTS: The Doppler-determined pulmonary artery systolic pressure was initially higher and decreased at follow-up more in group A (from 70.7 +/- 23.8 to 36.5 +/- 8.3 mm Hg; P < .0001) than in group B (from 48.7 +/- 17.8 to 41.6 +/- 13.1 mm Hg; P = NS). Compared with patients in group B, patients in group A were younger (25 +/-10 vs 35 +/- 11 years; P < .005), had higher prevalence of functional TR (85% vs 8%; P < .0001), and had lower incidence of atrial fibrillation (7% vs 38%; P < .005). Significant decrease in right ventricular end-diastolic dimension after MBV was noted in group A but not in group B. The mitral valve area at late follow-up was larger in group A than in group B (1.8 +/- 0.3 vs 1.6 +/- 0.3 cm2; P < .05). CONCLUSIONS: Regression of significant TR after successful MBV in patients with severe mitral stenosis was observed in patients who had severe pulmonary hypertension. This improvement in TR occurred even in the presence of organic tricuspid valve disease.

Frequency and predictive factors of malignancy in residual thyroid tissue and cervical lymph nodes after partial thyroidectomy for differentiated thyroid cancer.

BACKGROUND: The extent of surgery in differentiated thyroid cancer (DTC) has been a controversial issue. Total thyroidectomy potentially carries a higher operative risk, whereas partial thyroidectomy has the risk of leaving significant residual malignancy. The aim of this study was to assess the frequency and potential predictive factors of malignancy in the residual thyroid tissue and the cervical lymph nodes (CLN) in patients with DTC who had partial thyroid surgery and subsequently underwent completion thyroidectomy and/or modified neck dissection. Age, gender, pressure symptoms, duration of symptoms, size of the original tumor, tumor multifocality, perithyroidal tumor extension, soft tissue invasion, and serum thyroglobulin (Tg) level after first surgery were analyzed as potential predictive factors for the presence of malignancy in the thyroid remnant and the CLN. METHODS: We retrospectively reviewed the medical and pathologic data of 101 cases of DTC; 97 had papillary and 4 had follicular thyroid cancer. On the initial surgery, the median tumor size was 2.5 cm (range, 0.5 to 8.5 cm). Tumor multifocality occurred in 28 cases, perithyroidal tumor extension in 26 cases, and soft tissue invasion in 9 cases. Completion thyroidectomy was performed in 100 cases and modified neck dissection in 90 cases. RESULTS: On completion neck surgery, 39 patients had evidence of malignancy in the residual thyroid tissue and 36 patients in the CLN. In 23 (22.7%) cases, malignancy was present in both CLN and residual thyroid tissue. Only tumor multifocality and Tg level greater than 20 ng/mL after first surgery were predictive of the presence of malignancy in the thyroid remnant, whereas age older than 40 years, soft tissue invasion, perithyroidal tumor extension, and Tg level greater than 20 ng/mL were predictive of malignancy in CLN. CONCLUSIONS: Residual malignancy is common after partial thyroid surgery for DTC. Tumor multifocality and Tg level may be predictive of its presence in residual thyroid tissue. Age, perithyroidal tumor extension, soft tissue invasion, and Tg level are predictive of the presence of lymph node metastases.

Decreased axillary lymph node retrieval in patients after neoadjuvant chemotherapy.

BACKGROUND: The purpose of this study was to assess our clinical impression that fewer lymph nodes are retrieved after level I and II axillary dissection after neoadjuvant chemotherapy and whether there is a positive correlation between the total number of lymph nodes retrieved and the number of diseased lymph nodes. METHODS: Patients included those with stage IIB, IIIA, and IIIB breast cancer of whom 77 had neoadjuvant chemotherapy and 58 had initial surgery only. All had modified radical mastectomy with in continuity level I and II axillary dissection. RESULTS: Patients after neoadjuvant chemotherapy had 14.3 +/- 6.7 lymph nodes detected versus 16.9 +/- 8.8 (mean +/- SD; P <0.057) for those with initial surgery only. The number of positive nodes were 3.7 +/- 4.7 versus 6.6 +/- 8.7 (mean +/- SD; P <0.033) respectively and the number of negative nodes were 10.6 +/- 7.5 versus 10.4 +/- 8 (mean +/- SD; P <0.9). The correlation between the number of positive lymph nodes and the total number of lymph nodes was r = 0.58; P <0.001. CONCLUSIONS: It appears that fewer lymph nodes are retrieved after level I and II axillary dissection after neoadjuvant chemotherapy. The total number of lymph nodes retrieved increases directly with the number of positive lymph nodes in patients not treated with chemotherapy.

Prevalence and fate of severe pulmonary hypertension in 559 consecutive patients with severe rheumatic mitral stenosis undergoing mitral balloon valvotomy.

BACKGROUND AND AIM OF THE STUDY: The prevalence of severe pulmonary hypertension (PH) in patients with severe mitral stenosis (MS) remains unknown, and the long-term effect of mitral balloon valvotomy (MBV) in large numbers of these patients is not well characterized. METHODS: Details from the prospective MBV database at the authors' institution relating to 559 consecutive patients who had successful MBV were analyzed. Patients were allocated to three groups on the basis of their pulmonary artery systolic pressure (PASP) at cardiac catheterization immediately before MBV: group A (n = 345) had PASP <50 mmHg; group B (n = 183) had PASP 50-79 mmHg; and group C (n = 31) had PASP > or =80 mmHg. Patients were evaluated clinically and echocardiographically at six months after MBV, and annually thereafter for up to 13 years. RESULTS: No mortality was encountered after MBV. Immediately after MBV, the mean PASP was 38.5+/-6.8 mmHg in group A (mild PH), 59.0+/-7.7 mmHg in group B (moderately severe PH), and 97.8+/-17.0 mmHg in group C (severe PH). At follow up (ca. 4 years), Doppler-monitored PASP fell to normal, and was similar in groups A, B and C (29+/-8, 31+/-9, and 29+/-5 mmHg, respectively; p = NS). CONCLUSION: MBV was shown to be safe and effective in treating patients with MS and severe PH. The latter condition regressed to normal levels over 6-12 months after successful MBV.

A SAS macro for the analysis of cell survival curves.

This paper describes a SAS macro for the statistical analyses of cell survival data obtained after radiation treatment using the methods of R.E. Tarone et al. (Mutation Research 111 (1983) 79-96). These analyses are usually required on a routine basis by all biomedical research laboratories involved in cell survival assays generating dose-response curves aimed at characterizing radiosensitive mutant cell strains or individuals whose body cells exhibit enhanced sensitivity to radiation and other genotoxic agents. Statistical methods of linear regression are applied to data from repeated experiments with a cell line/strain and weighted estimates of a common slope and its variance are obtained. The methods are currently implemented in two APL programs. These programs are not easily accessible to most biomedical statisticians and researchers because APL is not a common software tool for statistical analysis. Implementation of these methods in SAS, a widely used commercial software for statistical analysis, is expected to help resolve this issue. We illustrate the application of the macro using an example data set obtained in our laboratory, and hope that other investigators may find it useful in analyzing their data.

Cost-Effectiveness of Infliximab for the Treatment of Acute Exacerbations of Ulcerative Colitis in the Netherlands.

INTRODUCTION: Infliximab is registered for the treatment of moderate-to-severe active ulcerative colitis (UC) adult patients who have had an inadequate response, or are intolerant, or have medical contraindications to therapy including corticosteroids and 5-aminosalicylates or thiopurines (6-mercaptopurine [6-MP] or azathioprine [AZA]). The authors estimate the costs and effects and evaluate the cost-effectiveness of infliximab at the licensed dose of 5 mg/kg versus cyclosporine or surgery for the treatment of adult Dutch patients hospitalized with acute exacerbations of UC, refractory to intravenous steroids. METHOD: An existing decision analytical model was updated to simulate disease progression of hospitalized UC patients in the Netherlands, refractory to intravenous corticosteroids, and to estimate the costs and benefits associated with infliximab compared to cyclosporine and surgery over a 1-year time horizon. Colectomy rates were derived from infliximab and cyclosporine randomized trials and synthesized using multiple treatment comparison methods. The utility estimates associated with health states of ulcerative colitis patients were obtained from the literature. Resource use and drug use frequencies as well as unit costs were obtained from Dutch sources. The primary effectiveness measure used in the analysis was quality-adjusted life years (QALYs). RESULTS: For a typical UC patient with body weight of 70 kg, the costs of treatment with infliximab, cyclosporine, and surgery over a 1-year treatment period were €17,062, €14,784, €13,979, respectively. The associated numbers of QALYs were 0.80, 0.70, and 0.58 for infliximab, cyclosporine, and surgery respectively. The incremental cost-effectiveness ratio for infliximab was €24,277 per QALY gained compared to cyclosporine, and €14,639 per QALY gained compared to surgery. CONCLUSIONS: Infliximab induction regimen appears to be a cost-effective treatment option in comparison to cyclosporine and surgery for hospitalized patients with acute exacerbations of UC, refractory to intravenous corticosteroids in the Netherlands.

Randomized controlled trial of trained patient-nominated treatment supporters providing partial directly observed antiretroviral therapy.

BACKGROUND: Directly observed therapy (DOT) for antiretroviral therapy (ART) may improve adherence, but there are limited data on its clinical effectiveness. METHODS: Adult patients initiating ART in a public clinic in Cape Town, South Africa, were randomized to treatment-supporter DOT-ART or self-administered ART. DOT-ART patients and supporters received baseline and follow-up training and monitoring. The primary endpoints were the proportions of patients with HIV viral load less than 400 copies/ml and change in CD4 cell counts at 12 and 24 months. RESULTS: Two hundred and seventy-four patients enrolled (137 in each arm) and baseline characteristics were similar for both arms. The study was stopped early for futility by an independent Data and Safety Monitoring Board. In an intention-to-treat analysis, the proportions of patients with viral load less than 400 copies/ml at 12 months were 72.8% in the DOT-ART arm and 68.4% in the Self-ART arm (P = 0.42). DOT-ART patients had greater median CD4 cell count (cells/microl) increases at 6 months [148 (IQR 84-222) vs. 111 (IQR 44-196) P = 0.02] but similar results at all other time-points. Survival was significantly better in the DOT-ART arm (9 deaths, 6.6%) than in the Self-ART arm (20 deaths, 14.6%; log-rank P = 0.02). In Cox regression analysis, mortality was independently associated with study arm [DOT vs. self-ART; HR 0.38, 95% confidence interval (CI) 0.17-0.86]. CONCLUSION: DOT-ART showed no effect on virologic outcomes but was associated with greater CD4 cell count increases at 6-month follow-up. Survival was significantly better for DOT-ART compared to Self-ART, but this was not explained by improved virologic or immunologic outcomes.

Cost-effectiveness analysis of raltegravir in treatment-experienced HIV type 1-infected patients in Spain.

Raltegravir, a novel HIV-1 integrase inhibitor, has superior efficacy with optimized background treatment (OBT) vs. placebo + OBT in treatment-experienced HIV-1 patients. This study assessed the long-term cost effectiveness of raltegravir from a Spanish National Healthcare System perspective. A cohort-state-transition model was used to estimate clinical and economic outcomes associated with raltegravir + OBT vs. OBT alone. Subjects were stratified into health states according to HIV RNA level, CD4 count, and opportunistic infection (OI) history, and could transition into different health states over time based on projected long-term efficacy. Each health state was associated with a distinct treatment cost and utility (QoL) score. Model inputs for mortality, resource utilization, unit costs, OI risk, and long-term durability of viral suppression were obtained from clinical trials, published studies, and database analyses. Model outcomes were reported as incremental cost-effectiveness ratios (ICERs) in 2007 Euros per quality-adjusted life-year (euro/QALY) gained. Costs and QALYs were discounted at 6% per year based on Spanish cost-effectiveness guidelines. Extensive sensitivity analyses were conducted. Five years of treatment with raltegravir + OBT resulted in an additional 4.5 years of undiscounted life expectancy vs. OBT alone. The ICER of raltegravir + OBT vs. OBT alone was euro22,908/QALY and euro31,431/QALY for 3- and 5-year use, respectively. Lower ICERs were observed with lower discount rates (3%) for costs and benefits, lower raltegravir price (20%), and shorter treatment duration (3 years). ICER was also sensitive to analytical time horizon and alternative sources of QoL scores. In treatment-experienced Spanish patients, raltegravir was projected to provide survival benefits and be cost effective.

A cluster-randomized trial of provider-initiated (opt-out) HIV counseling and testing of tuberculosis patients in South Africa.

OBJECTIVE: To determine whether implementation of provider-initiated human immunodeficiency virus (HIV) counseling would increase the proportion of tuberculosis (TB) patients who received HIV counseling and testing. DESIGN: Cluster-randomized trial with clinic as the unit of randomization. SETTING: Twenty, medium-sized primary care TB clinics in the Nelson Mandela Metropolitan Municipality, Port Elizabeth, Eastern Cape Province, South Africa. SUBJECTS: A total of 754 adults (18 years and older) newly registered as TB patients in the 20 study clinics. INTERVENTION: Implementation of provider-initiated HIV counseling and testing. MAIN OUTCOME MEASURES: Percentage of TB patients HIV counseled and tested. SECONDARY: Percentage of patients with HIV test positive, and percentage of those who received cotrimoxazole and who were referred for HIV care. RESULTS: : A total of 754 adults newly registered as TB patients were enrolled. In clinics randomly assigned to implement provider-initiated HIV counseling and testing, 20.7% (73/352) patients were counseled versus 7.7% (31/402) in the control clinics (P = 0.011), and 20.2% (n = 71) versus 6.5% (n = 26) underwent HIV testing (P = 0.009). Of those patients counseled, 97% in the intervention clinics accepted testing versus 79% in control clinics (P = 0.12). The proportion of patients identified as HIV infected in intervention clinics was 8.5% versus 2.5% in control clinics (P = 0.044). Fewer than 40% of patients with a positive HIV test were prescribed cotrimoxazole or referred for HIV care in either study arm. CONCLUSIONS: Provider-initiated HIV counseling significantly increased the proportion of adult TB patients who received HIV counseling and testing, but the magnitude of the effect was small. Additional interventions to optimize HIV testing for TB patients urgently need to be evaluated.