Treatment of muscle-invasive urothelial cancer with nivolumab (CheckMate 274 study): a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a paper published in a medical journal that describes the results of a study called CheckMate 274. This study looked at a new treatment for muscle-invasive urothelial cancer, a type of cancer found in the urinary tract that has spread from the inner lining of the urinary tract or bladder and into the surrounding muscle wall where it can then spread to other parts of the body. The standard treatment for muscle-invasive urothelial cancer is surgery to remove affected parts of the urinary tract. However, cancer returns in more than half of people after this surgery. Adjuvant therapy is given to people after surgery with muscle-invasive urothelial cancer with a goal to reduce the risk of the cancer coming back; however, at the time this study started, there was no standard adjuvant treatment. WHAT HAPPENED IN THE STUDY?: In the CheckMate 274 study, researchers compared nivolumab with a placebo as an adjuvant treatment for people with muscle-invasive urothelial cancer. The aim of the study was to understand how well nivolumab worked to reduce the chance of the cancer returning after surgery. The study also looked at what side effects (unwanted or unexpected results or conditions that are possibly related to the use of a medication) people had with treatment. WHAT DO THE RESULTS MEAN?: The results showed that people who received nivolumab versus placebo: Survived longer before the cancer was detected again, including people who had programmed death ligand-1 (shortened to PD-L1) on their cancer cells. Survived longer before a secondary cancer outside of the urinary tract was detected. Experienced no differences in health-related quality of life (the impact of the treatment on a person's mental and physical health). Had similar side effects to the people who received nivolumab in other studies. Clinical Trial Registration: NCT02632409 (ClinicalTrials.gov).

Adjuvant nivolumab versus placebo following radical surgery for high-risk muscle-invasive urothelial carcinoma: a subgroup analysis of Japanese patients enrolled in the phase 3 CheckMate 274 trial.

BACKGROUND: The phase 3 CheckMate 274 trial demonstrated superiority of adjuvant nivolumab over placebo after radical surgery in patients with high-risk muscle-invasive urothelial carcinoma. However, the efficacy and safety of adjuvant nivolumab in Japanese patients with muscle-invasive urothelial carcinoma have not been clarified. METHODS: Patients with muscle-invasive urothelial carcinoma were randomized to adjuvant nivolumab 240 mg or placebo (every 2 weeks via intravenous infusion) up to 120 days after radical surgery in CheckMate 274. RESULTS: Of 49 patients in the Japanese subgroup, 27 and 22 patients were randomized to nivolumab and placebo, respectively. Eleven and 8 patients, respectively, had tumor PD-L1 expression level of 1% or more. The median disease-free survival times in the nivolumab and placebo groups were 29.67 months (95% confidence interval 7.79-not reached) and 9.72 months (95% confidence interval 4.73-not reached), respectively (hazard ratio 0.77, 95% confidence interval 0.35-1.69). The corresponding values in patients with tumor PD-L1 expression level of 1% or more were 29.67 months (95% confidence interval 2.63-not reached) and 25.95 months (95% confidence interval 5.59-not reached) (hazard ratio 1.10, 95% confidence interval 0.31-3.92), respectively. Treatment-related adverse events of Grade 3-4 occurred in 25.9 and 13.6% of patients in the nivolumab and placebo groups, respectively. The most common treatment-related adverse events in the nivolumab group were lipase increased, amylase increased and diarrhea. The changes in quality of life scores from baseline over time were similar in both groups. CONCLUSIONS: The efficacy and safety results in the Japanese subgroup were consistent with the overall population of CheckMate 274.

Treatment and disease management patterns for bacillus Calmette-Guérin unresponsive nonmuscle invasive bladder cancer in North America, Europe and Asia: A real-world data analysis.

Background: This study examined real-world treatment and management of bacillus Calmette-Guérin (BCG)-unresponsive patients across 3 continents, including patients unable or unwilling to undergo cystectomy. Materials and methods: Physicians actively involved in managing patients with nonmuscle invasive bladder cancer completed online case report forms for their 5 consecutive patients from the broad BCG-unresponsive population and a further 5 consecutive BCG-unresponsive patients who did not undergo cystectomy (in Japan, physicians provided a total of 5 patients across both cohorts). Results: Most patients had received 1 (37%) or 2 (24%) maintenance courses of BCG. Five or more maintenance BCG courses were received by patients in Japan (59%) and China (31%), while in Germany 76% of patients received only 1 course. Most patients became BCG-unresponsive during their first (44%) or second (22%) treatment course; in Germany, 77% became BCG-unresponsive during their first treatment course. Most countries did not provide another course of BCG after a patient first became unresponsive, whereas unresponsive patients in Japan and China were most likely to be retreated with BCG. "Untreated - on watch and wait" was the main treatment/management approach received post-BCG treatment for 42% or more of patients in most countries except China (39%) and the United States (36%). "Following treatment guidelines" was consistently the top reason for post-BCG treatment selection across all treatment options. Conclusions: This study confirmed the global unmet need for patients with nonmuscle invasive bladder cancer, and found that many patients experienced periods of no treatment after not responding to BCG therapy.

Health-related Quality of Life with Adjuvant Nivolumab After Radical Resection for High-risk Muscle-invasive Urothelial Carcinoma: Results from the Phase 3 CheckMate 274 Trial.

BACKGROUND: The programmed death-1 (PD-1) inhibitor nivolumab prolongs disease-free survival in patients with muscle-invasive urothelial carcinoma (MIUC). OBJECTIVE: To evaluate the effects of nivolumab on health-related quality of life (HRQoL) after radical resection in patients with MIUC. DESIGN, SETTING, AND PARTICIPANTS: We used data from 709 patients in CheckMate 274 (NCT02632409; 282 with programmed death ligand 1 [PD-L1] expression ≥1%), an ongoing randomized, double-blind, placebo-controlled phase 3 trial of adjuvant nivolumab. INTERVENTION: Intravenous injection of nivolumab (240 mg) or placebo every 2 wk for ≤1 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EQ-5D-3L. Linear mixed-effect models for repeated measures were used to compare nivolumab and placebo on changes in HRQoL. Time to confirmed deterioration (TTCD) of HRQoL was analyzed by Cox proportional hazards regression. RESULTS AND LIMITATIONS: In the full HRQoL evaluable population, no clinically meaningful deterioration of HRQoL was observed in either treatment arm. Moreover, nivolumab was noninferior to placebo on changes from baseline for all main outcomes. The median TTCD for fatigue was 41.0 wk for nivolumab and 44.3 wk for placebo (hazard ratio [HR]: 1.11, 95% confidence interval [CI], 0.89-1.39). For the visual analog scale, the median TTCD was not reached for nivolumab and it was 57.6 wk for placebo (HR: 0.78, 95% CI, 0.61-1.00). The median TTCD for the other main outcomes was not reached in either treatment arm. The findings were similar for patients with PD-L1 expression ≥1%. CONCLUSIONS: These results demonstrate that nivolumab did not compromise the HRQoL of patients with MIUC in CheckMate 274. PATIENT SUMMARY: Nivolumab is being researched as a new treatment for patients with bladder cancer (urothelial carcinoma). We found that nivolumab maintained quality of life while increasing the time until cancer returns in patients whose bladder cancer had spread or grown and who had unsuccessfully tried platinum-containing chemotherapy.

Multi-country clinical practice patterns, including use of biomarkers, among physicians' treatment of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC).

BACKGROUND: Intravesical bacillus Calmette-Guérin (BCG) fails in a considerable proportion of non-muscle invasive bladder cancer (NMIBC) patients despite treatment per recommended protocol. This real-world study aimed to understand the current patterns of treatment and disease management for the broad BCG-unresponsive NMIBC patient population, alongside collecting sufficient data on patients who do not undergo cystectomy. METHODS: This was a multicenter, retrospective survey of physicians treating BCG-unresponsive NMIBC patients. Data were collected in eight countries - France, Germany, Spain, Italy, United Kingdom, United States, China, and Japan - between January and May 2019. The study consisted of a short online physician survey and a retrospective chart review of eligible BCG-unresponsive NMIBC patients. Physicians abstracted chart data for the last 10 (five patients in Japan) eligible BCG-unresponsive NMIBC patients meeting the inclusion criteria, and the data were analysed for all countries combined using descriptive statistics. Country-specific analyses were also carried out, as appropriate. RESULTS: Overall, 508 physicians participated in the study. Almost one-quarter (22.9%) of physicians' current NMIBC patient caseload was BCG-unresponsive, whereby BCG therapy was no longer considered an option. Half of physicians (49.4%) did not regularly use biomarker tests in their practice, with particularly few physicians undertaking biomarker testing in Spain and Japan. Biomarker testing varied considerably, with the proportions of physicians selecting 'none' ranging from 11.4% in China to 70.3% in Japan. Physicians reported transurethral resection of the bladder tumor (TURBT) and BCG as the most common current treatments received by their patients. Chemotherapy and anti-PD-L1 treatment options were considered impactful new therapies by 94.7% and 90.0% of physicians surveyed in this study, respectively. CONCLUSIONS: The most common treatments received by patients in this study were TURBT and BCG. Emerging new treatments are driven by exploring biomarkers, but in real-world clinical practice only half of physicians or fewer regularly tested their NMIBC patients for biomarkers; PD-1/PD-L1 was the most common biomarker test used. Most physicians reported that, in addition to chemotherapy, anti-PD-L1 was an impactful new therapy.

Real-world treatment patterns and clinical outcomes among patients with advanced urothelial carcinoma in the United States.

INTRODUCTION: This large-scale, US-based study characterized real-world treatment patterns and clinical outcomes in patients with advanced or metastatic urothelial carcinoma (aUC). METHODS: This retrospective cohort analysis included patients with stage IV or node-positive aUC between January 1, 2011, and August 31, 2020, from an electronic health record-derived, de-identified database (Flatiron Health). Baseline characteristics and treatment patterns were assessed by first-line (1L) systemic treatment received and cisplatin eligibility status. Overall survival (OS) and progression-free survival (PFS) were evaluated. RESULTS: Of 8,183 patients included, 5,855 (71.6%) received systemic 1L therapy and 2,328 (28.4%) did not. Median (range) follow-up from aUC diagnosis was 9.7 (0.2-116.6) months. Of patients who received 1L systemic therapy, 30.1% were cisplatin-eligible, 39.2% were cisplatin-ineligible, 10.5% did not receive cisplatin despite qualifying ECOG PS and renal function, and cisplatin eligibility was unknown in 20.2%. Of those treated, 74.8% received 1L chemotherapy and 23.0% received 1L immuno-oncology-based monotherapy. Median OS (95% CI) was 14.5 (14.0-15.2) months in patients who received 1L systemic therapy and 6.8 (6.2-7.3) months in those who did not. Of those treated, cisplatin-ineligible patients had worse OS and PFS outcomes vs. other subgroups. Among cisplatin-ineligible patients, 1L immuno-oncology monotherapy (n = 865) was associated with worse OS and PFS outcomes than 1L chemotherapy (n = 1,369). CONCLUSIONS: More than 25% of aUC patients did not receive 1L systemic therapy; of patients who were treated, most received chemotherapy, with less than 25% receiving immuno-oncology-based monotherapy. Overall, these results highlight the substantial unmet need in this population, specifically among cisplatin-ineligible patients.

Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma.

BACKGROUND: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group. CONCLUSIONS: In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).

Effectiveness of in-service training plus the collaborative improvement strategy on the quality of routine malaria surveillance data: results of a pilot study in Kayunga District, Uganda.

BACKGROUND: Surveillance data are essential for malaria control, but quality is often poor. The aim of the study was to evaluate the effectiveness of the novel combination of training plus an innovative quality improvement method-collaborative improvement (CI)-on the quality of malaria surveillance data in Uganda. METHODS: The intervention (training plus CI, or TCI), including brief in-service training and CI, was delivered in 5 health facilities (HFs) in Kayunga District from November 2015 to August 2016. HF teams monitored data quality, conducted plan-do-study-act cycles to test changes, attended periodic learning sessions, and received CI coaching. An independent evaluation was conducted to assess data completeness, accuracy, and timeliness. Using an interrupted time series design without a separate control group, data were abstracted from 156,707 outpatient department (OPD) records, laboratory registers, and aggregated monthly reports (MR) for 4 time periods: baseline-12 months, TCI scale-up-5 months; CI implementation-9 months; post-intervention-4 months. Monthly OPD register completeness was measured as the proportion of patient records with a malaria diagnosis with: (1) all data fields completed, and (2) all clinically-relevant fields completed. Accuracy was the relative difference between: (1) number of monthly malaria patients reported in OPD register versus MR, and (2) proportion of positive malaria tests reported in the laboratory register versus MR. Data were analysed with segmented linear regression modelling. RESULTS: Data completeness increased substantially following TCI. Compared to baseline, all-field completeness increased by 60.1%-points (95% confidence interval [CI]: 46.9-73.2%) at mid-point, and clinically-relevant completeness increased by 61.6%-points (95% CI: 56.6-66.7%). A relative - 57.4%-point (95% confidence interval: - 105.5, - 9.3%) change, indicating an improvement in accuracy of malaria test positivity reporting, but no effect on data accuracy for monthly malaria patients, were observed. Cost per additional malaria patient, for whom complete clinically-relevant data were recorded in the OPD register, was $3.53 (95% confidence interval: $3.03, $4.15). CONCLUSIONS: TCI improved malaria surveillance completeness considerably, with limited impact on accuracy. Although these results are promising, the intervention's effectiveness should be evaluated in more HFs, with longer follow-up, ideally in a randomized trial, before recommending CI for wide-scale use.

Detecting tuberculosis in pregnant and postpartum women in Eswatini.

BACKGROUND: Tuberculosis diagnosis in pregnancy is complex because tuberculosis symptoms are often masked by physiological symptoms of pregnancy. Untreated tuberculosis in pregnant and postpartum women may lead to maternal morbidity and low birth weight. Tuberculosis in HIV-positive pregnant women increases the risk of maternal and infant mortality. OBJECTIVE: This study aimed to determine tuberculosis prevalence stratified by HIV status and identify screening algorithms that maximise detection of active tuberculosis among pregnant and postpartum women in Eswatini. METHODS: Women were enrolled at antenatal and postnatal clinics in Eswatini for tuberculosis screening and diagnostic investigations from 01 April to 30 November 2015 in a cross-sectional study. Sputum samples were collected from all participants for tuberculosis diagnostic tests (smear microscopy, GeneXpert, MGIT culture). Blood and urine samples were collected from HIV-positive women for cluster-of-differentiation-4 cell count, interferon gamma release assay and tuberculosis lateral flow urine lipoarabinomannan tests. RESULTS: We enrolled 990 women; 52% were pregnant and 47% were HIV-positive. The prevalence of tuberculosis among HIV-positive pregnant women was 5% (95% confidence interval [CI]: 2-7) and among postpartum women it was 1% (95%CI: -1-3). Tuberculosis prevalence was 2% (95%CI: 0-3) in HIV-negative pregnant women and 1% (95%CI: -1-2) in HIV-negative postpartum women. The national tuberculosis symptom screening tool failed to identify women who tested tuberculosis-culture positive. CONCLUSION: Routine tuberculosis symptom screening alone is insufficient to rule out tuberculosis in pregnant and postpartum women. Only sputum culture maximised the detection of tuberculosis, indicating a need to balance access and cost in developing countries.

The cost-effectiveness of three methods of disseminating information to improve medical male circumcision in Uganda.

BACKGROUND: Uganda is working to increase voluntary medical male circumcision (VMMC) to prevent HIV infection. To support VMMC quality improvement, this study compared three methods of disseminating information to facilities on how to improve VMMC quality: M-providing a written manual; MH-providing the manual plus a handover meeting in which clinicians shared advice on implementing key changes and participated in group discussion; and MHC-manual, handover meeting, and three site visits to the facility in which a coach provided individualized guidance and mentoring on improvement. We determined the different effects these had on compliance with indicators of quality of care. METHODS: This controlled pre-post intervention study randomized health facility groups to receive M, MH, or MHC. Observations of VMMCs performance determined compliance with quality indicators. Intervention costs per patient receiving VMMC were used in a decision-tree cost-effectiveness model to calculate the incremental cost per additional patient treated to compliance with indicators of informed consent, history taking, anesthesia administration, and post-operative instructions. RESULTS: The most intensive method (MHC) cost $28.83 per patient and produced the biggest gains in history taking (35% improvement), anesthesia administration (20% improvement), and post-operative instructions (37% improvement). The least intensive method (M; $1.13 per patient) was most efficient because it produced small gains for a very low cost. The handover meeting (MH) was the most expensive among the three interventions but did not have a corresponding positive effect on quality. CONCLUSION: Health workers in facilities that received the VMMC improvement manual and participated in the handover meeting and coaching visits showed more improvement in VMMC quality indicators than those in the other two intervention groups. Providing the manual alone cost the least but was also the least effective in achieving improvements. The MHC intervention is recommended for broader implementation to improve VMMC quality in Uganda.

Cost-Effectiveness of a Family Planning Voucher Program in Rural Pakistan.

INTRODUCTION: This study reports on the effectiveness and efficiency from the program funder's perspective of the Suraj Social Franchise (SSF) voucher program in which private health-care providers in remote rural areas were identified, trained, upgraded, and certified to deliver family planning services to underserved women of reproductive age in 29 districts of Sindh and 3 districts of Punjab province, Pakistan between October 2013 and June 2016. METHOD: A decision tree compared the cost of implementing SSF to the program funder and its effects of providing additional couple years of protection (CYPs) to targeted women, compared to business-as-usual. Costs included vouchers given to women to receive a free contraceptive method of their choice from the SSF provider. The vouchers were then reimbursed to the SSF provider by the program. RESULTS: A total of 168,206 married women of reproductive age (MWRA) received SSF vouchers between October 2013 and June 2016, costing $3,278,000 ($19.50/recipient). The average effectiveness of the program per voucher recipient was an additional 1.66 CYPs, giving an incremental cost-effectiveness of the program of $4.28 per CYP compared to not having the program (95% CI: $3.62-5.31). CONCLUSION: The result compares favorably to other interventions with similar objectives and appears affordable for the Pakistan national health-care system. It is therefore recommended to help address the unmet need for contraception among MWRA in these areas of Pakistan and is worthy of trial implementation in the country more widely.

Pilot study of quality of care training and knowledge in Sub-Saharan African medical schools.

OBJECTIVES: To identify the level of knowledge and competencies related to quality of care during medical education in sub-Saharan African medical schools. METHODS: A cross-sectional study design was utilized to examine the capacity of medical schools in sub-Saharan African (SSA) countries to teach about the concepts of quality of care and the inclusion of these concepts in their curriculum. A purposeful convenience sampling technique was used to select participants from 25 medical schools in 5 sub-Saharan African countries. Respondents included medical school deans or senior academic personnel.  A survey was developed using the Institute of Medicine's definition of quality of care as the guiding framework.  Sample means and summary statistics were used to present the results of the survey responses. RESULTS: While 45% of the schools surveyed are teaching on at least one of the six domains of the Institute of Medicine's definition of quality of care, there are some schools who report not teaching about quality at all, or that they "do not know". Despite these low numbers, when asked about topics related to quality of care, many schools are teaching applied management related topics and almost all schools teach about equity and patient-centered care. CONCLUSIONS: The results have important impacts both for incorporating quality of care into medical education and for practitioners.  The tool developed for this study can be used in future qualitative and quantitative studies to further understanding of how to improve the teaching and learning about quality of care in medical schools. Keywords: quality of care, medical schools, sub-Saharan Africa, medical errors, healthcare improvement.

Screening in Maternity to Ascertain Tuberculosis Status (SMATS) study.

BACKGROUND: Diagnosis of tuberculosis is difficult among pregnant women because the signs and symptoms of the disease, such as fatigue, shortness of breath, sweating, cough, and mild fever are similar to some manifestations of pregnancy. It is particularly challenging among HIV-infected women as symptoms are often masked or atypical. Currently, WHO recommends a standard four-symptom screening tool for pregnant and lactating women. There is evidence from South Africa that this screening tool (which, despite complex symptomology in this population, recommends identification of patients with weight loss, fever, current cough and night sweats), may be missing true active TB cases. However there exist several laboratory and clinical procedures that have the potential to improve the sensitivity and specificity of this screening tool. METHODS: This study will evaluate the sensitivity and specificity of the current TB screening tool for pregnant and lactating women, both HIV positive and negative. We will also assess several different enhanced screening algorithm using LAM, IGRA, TST and chest radiography and clinical/laboratory procedures and tests. The study will use a cross-sectional analytical study design involving pregnant and lactating women up to six months post-delivery attending antenatal or postnatal care, respectively in one of three selected public health units in Swaziland. Participants will be consecutively enrolled and will be in one of four groups of interest: HIV infected pregnant women, non-HIV infected pregnant women, HIV infected lactating women and non-HIV infected lactating women. DISCUSSION: We expect in conducting all procedures on all participants regardless of result of the symptom screening we may experience a high refusal rate. However, this risk will be mitigated by the long data collection period of five or more months.

Assessment of a quality improvement intervention to strengthen pharmaceutical human resources and improve availability and use of HIV medicines in Uganda.

Inadequate medication dispensing and management by healthcare providers can contribute to poor outcomes among HIV-positive patients. Gaps in medication availability, often associated with pharmacy workforce shortages, are an important barrier to retention in HIV care in Uganda. An intervention to address pharmacy staffing constraints through strengthening pharmaceutical management, dispensing practices, and general competencies of facility clinical and pharmacy staff was implemented in 14 facilities in three districts in eastern Uganda. Teams of staff were organised in each facility and supported to apply quality improvement (QI) methods to address deficits in availability and rational use of HIV drugs. To evaluate the intervention, baseline and end line data were collected 24 months apart. Dispensing practices, clinical wellness and adherence to antiretrovirals improved by 45%, 28% and 20% from baseline to end line, respectively. All clients at end line received the medications prescribed, and medications were correctly, completely and legibly labelled more often. Clients better understood when, how much and for how long they were supposed to take their prescribed medicines at end line. Pharmaceutical management practices also improved from baseline in most categories by statistically significant margins. Facilities significantly improved on correctly recording stock information about antiretroviral drugs (53%vs100%, P<0.0001). Coinciding with existing staff taking on pharmaceutical roles, facilities improved management of unwanted and expired drugs, notably by optimising use of existing health workers and making pharmaceutical management processes more efficient. Implementation of this improvement intervention in the 14 facilities appeared to have a positive impact on client outcomes, pharmacy department management and providers' self-reported knowledge of QI methods. These results were achieved at a cost of about US$5.50 per client receiving HIV services at participating facilities.

Evaluation of an Intervention to Improve Essential Obstetric and Newborn Care Access and Quality in Cotopaxi, Ecuador.

BACKGROUND: Despite improvements in health-care utilization, disadvantages persist among rural, less educated, and indigenous populations in Ecuador. The United States Agency for International Development-funded Cotopaxi Project created a provincial-level network of health services, including community agents to improve access, quality, and coordination of essential obstetric and newborn care. We evaluated changes in participating facilities compared to non-participating controls. METHODS: The 21 poorest parishes (third-level administrative unit) in Cotopaxi were targeted from 2010 to 2013 for a collaborative health system performance improvement. The intervention included service reorganization, integration of traditional birth attendants (TBAs) with formal supervision, community outreach and education, and health worker technical training. Baseline (n = 462) and end-line (n = 412) household surveys assessed access, quality and use of care, and women's knowledge and practices. TBAs' knowledge and skills were assessed from simulations. Chart audits were used to assess facility obstetric and newborn care quality. Provincial government data were used for change in neonatal mortality between intervention and non-intervention parishes using weighted linear regression. RESULTS: The percentage of women receiving a postnatal visit within first 2 days of delivery increased from 53 to 81 in the intervention group and from 70 to 90 in the comparison group (p ≤ 0.001). Postpartum/counseling on newborn care increased 18% in the intervention compared with 5% in the comparison group (p ≤ 0.001). The project increased community and facility care quality and improved mothers' health knowledge. Intervention parishes experienced a nearly continual decline in newborn mortality between 2009 and 2012 compared with an increase in control parishes (p ≤ 0.001). CONCLUSION: The project established a comprehensive coordinated provincial-level network of health services and strengthened links between community, primary, and hospital health care. This improved access to, quality, use, and provision of essential obstetric and neonatal care and survival. Ecuador's Ministry of Health is scaling up the model nationally.

Effectiveness and Efficiency of Improving HIV Service Provision for Key Populations in Nicaragua.

OBJECTIVE: HIV in Nicaragua is concentrated among key populations (KPs) - men who have sex with men, female sex workers, and female transgender - in whom prevalence is 600-4,000 times higher than the general population. The United States Agency for International Development PrevenSida project is aimed at increasing healthy behavior among KPs and people with HIV and improving testing, counseling, and continuity of prevention and treatment by building capacity and improving performance of non-governmental organizations (NGOs) providing services to KPs. We evaluated the cost-effectiveness of PrevenSida's activities. METHODS: This retrospective observational evaluation used individuals in KPs covered by NGOs receiving assistance from PrevenSida from 2012 to 2014. Cost-effectiveness analysis compared PrevenSida's intervention with business-as-usual. Model inputs were generated from epidemiological modeling and PrevenSida's records. RESULTS: By 2014, 24 NGOs received grants and technical assistance from PrevenSida with 72,955 people in KPs served at $11.32/person ($9.39-$16.55/person, depending on region). The estimated incremental cost-effectiveness ratio was $50,700/HIV case averted or $2,600/Disability-adjusted Life Year (DALY) averted (95% CI: $1,000-$99,000 and $50-$5,100, respectively). CONCLUSION: PrevenSida distributed about $600,000 in grants and used $230,000 to support 24 NGOs in 2014. Cost-effectiveness from the program perspective compared to no program was slightly over half of GDP per capita per DALY averted, considered highly cost-effective by WHO criteria. Cost and efficiency varied by region, reflecting the number of people in KPs receiving services. Cost-sharing by NGOs improved cost-effectiveness from the program perspective and likely promotes sustainability. Focused interventions for KP service provision organizations can be acceptably efficient in this setting.

Why Economic Analysis of Health System Improvement Interventions Matters.

There is little evidence to direct health systems toward providing efficient interventions to address medical errors, defined as an unintended act of omission or commission or one not executed as intended that may or may not cause harm to the patient but does not achieve its intended outcome. We believe that lack of guidance on what is the most efficient way to reduce medical errors and improve the quality of health-care limits the scale-up of health system improvement interventions. Challenges to economic evaluation of these interventions include defining and implementing improvement interventions in different settings with high fidelity, capturing all of the positive and negative effects of the intervention, using process measures of effectiveness rather than health outcomes, and determining the full cost of the intervention and all economic consequences of its effects. However, health system improvement interventions should be treated similarly to individual medical interventions and undergo rigorous economic evaluation to provide actionable evidence to guide policy-makers in decisions of resource allocation for improvement activities among other competing demands for health-care resources.

Cost-effectiveness of implementing the chronic care model for HIV care in Uganda.

OBJECTIVE: The chronic care model (CCM) is an integrated, population-based approach for treating those with chronic diseases that involves patient self-management, delivery system design and decision support for clinicians to ensure evidence-based care. We sought to determine effectiveness and cost-effectiveness of implementing the CCM for HIV care in Uganda. DESIGN: This controlled, pre/post-intervention study used difference-in-differences analysis to evaluate effectiveness of the CCM to improve patient adherence to antiretroviral therapy (ART) and CD4 counts. SETTING: One district hospital and two smaller facilities each in one intervention and one control district in Uganda. PARTICIPANTS: About 46 randomly sampled patients receiving HIV services at three control sites and 56 patients from three intervention sites. INTERVENTION: Two group training sessions and monthly coaching visits from improvement experts over 1 year, implementing the CCM. MAIN OUTCOME MEASURE(S): Patient adherence to ART prescriptions (pill counts) and CD4 counts were measured at baseline and en dline. RESULTS: The odds of increased CD4 in the intervention group was 3.2 times higher than controls (P = 0.022). Clinician-reported ART adherence was 60% (P = 0.001) higher in the intervention group. The intervention cost $11 740 and served 7016 patients ($1.67 per patient). Incremental cost-effectiveness ratios of the intervention compared to business-as-usual was $6.90 per additional patient with improved CD4 and $3.40 per additional ART patient with stable or improved adherence. CONCLUSION: For modest expenditure, it is possible to improve indicators of HIV care quality using the CCM. We recommended implementing the CCM in Uganda; it may be applicable in similar settings in other countries.