Association between history of HBV vaccine response and anti-SARS-CoV-2 spike antibody response to the BioNTech/Pfizer's BNT162b2 mRNA SARS-CoV-2 vaccine among healthcare workers in Japan: A prospective observational study.

INTRODUCTION: Inadequate vaccine response is a common concern among healthcare workers at the frontlines of the COVID-19 pandemic. We aimed to investigate if healthcare workers with history of weak immune response to HBV vaccination are more likely to have weak responses against the BioNTech/Pfizer's BNT162b2 mRNA SARS-CoV-2 vaccine. METHODS: We prospectively tested 954 healthcare workers for the Anti-SARS-CoV-2 spike (S) protein antibody titers prior to the first and second BNT162b2 vaccination doses and after four weeks after the second dose using Roche's Elecsys® assay. We calculated the percentage of patients who seroconverted after the first and second doses. We estimated the relative risk of non-seroconversion after the first BNT162b2 vaccine (defined as anti-SARS-CoV-2-S titer <15 U/mL) among HBV vaccine non-responders (HBs-Ab titer <10 mIU/mL) and weak responders (≥10 and <100 mIU/mL) compared to normal responders (≥100 mIU/mL). RESULTS: Among 954 healthcare workers recruited between March 9 and March 24, 2021 at Osaka Medical and Pharmaceutical University, weak and normal HBV vaccine responders had comparable S-protein titers after the first BNT162b2 dose (51.4 [95% confidence interval 25.2-137.0] versus 59.7 [29.8-138.0] U/mL, respectively). HBV vaccine non-responders were more likely than normal responders to not seroconvert after a single dose (age and sex-adjusted relative risk 1.85 95% confidence interval [1.10-3.13]) although nearly all participants seroconverted after the second dose. After limiting the analysis to 382 patients with baseline comorbidity data, the comorbidity-adjusted relative risk of non-seroconversion among HBV vaccine non-responders to normal responders was 1.32 (95% confidence interval [0.59-2.98]). DISCUSSION: Long term follow-up studies are needed to understand if protective immunity against SARS-CoV-2 wanes faster among those with history of HBV vaccine non-response and when booster doses are warranted for these healthcare workers.

Cost and cost-effectiveness of a simplified treatment model with direct-acting antivirals for chronic hepatitis C in Cambodia.

BACKGROUND & AIMS: In 2016, Médecins Sans Frontières established the first general population Hepatitis C virus (HCV) screening and treatment site in Cambodia, offering free direct-acting antiviral (DAA) treatment. This study analysed the cost-effectiveness of this intervention. METHODS: Costs, quality adjusted life years (QALYs) and cost-effectiveness of the intervention were projected with a Markov model over a lifetime horizon, discounted at 3%/year. Patient-level resource-use and outcome data, treatment costs, costs of HCV-related healthcare and EQ-5D-5L health states were collected from an observational cohort study evaluating the effectiveness of DAA treatment under full and simplified models of care compared to no treatment; other model parameters were derived from literature. Incremental cost-effectiveness ratios (cost/QALY gained) were compared to an opportunity cost-based willingness-to-pay threshold for Cambodia ($248/QALY). RESULTS: The total cost of testing and treatment per patient for the full model of care was $925(IQR $668-1631), reducing to $376(IQR $344-422) for the simplified model of care. EQ-5D-5L values varied by fibrosis stage: decompensated cirrhosis had the lowest value, values increased during and following treatment. The simplified model of care was cost saving compared to no treatment, while the full model of care, although cost-effective compared to no treatment ($187/QALY), cost an additional $14 485/QALY compared to the simplified model, above the willingness-to-pay threshold for Cambodia. This result is robust to variation in parameters. CONCLUSIONS: The simplified model of care was cost saving compared to no treatment, emphasizing the importance of simplifying pathways of care for improving access to HCV treatment in low-resource settings.

High sustained viral response rate in patients with hepatitis C using generic sofosbuvir and daclatasvir in Phnom Penh, Cambodia.

Safe and efficacious pan-genotypic direct-acting antiviral (DAA) regimens, such as sofosbuvir and daclatasvir (SOF + DCV), facilitate simplified models of care for hepatitis C virus (HCV). However, in Cambodia access to HCV testing and treatment has typically been low. In response, Médecins Sans Frontières (MSF) implemented a HCV testing and treatment pilot project in Phnom Penh, Cambodia in 2016. This project provides the first real-world evidence of SOF + DCV effectiveness across a large patient cohort using a simplified care model in Cambodia. Patients treated with SOF + DCV from September 2016 to June 2019 were included in the analysis. Medical standard operational procedures (SOPs) were simplified significantly across the study period. Treatment effectiveness was assessed by sustained viral response at 12 weeks post-treatment (SVR12) according to a modified intention-to-treat methodology. Treatment safety was assessed by clinical outcome and occurrence of serious and nonserious adverse events (S/AE). Of 9158 patients, median age was 57 years and 39.6% were male. At baseline assessment, 27.2% of patients had compensated cirrhosis and 2.9% had decompensated cirrhosis. Genotype 6 was predominant (53.0%). Among patients analysed according to modified intention to treat (n = 8525), treatment effectiveness was high, with 97.2% of patients achieving SVR12. Occurrence of SAE was low (0.7%). Treatment effectiveness and safety was not affected by the iterative simplification to treatment modality. In conclusion, in this large treatment cohort in Phnom Penh, Cambodia, the SOF + DCV regimen showed high rates of treatment effectiveness and safety across patient sub-groups and during progressive simplification.

Use of intensity-modulated radiation therapy for nasopharyngeal cancer in Japan: analysis using a national database.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) yields better outcomes and fewer toxicities for radiation therapy (RT) of head and neck cancers (HNCs), including nasopharyngeal cancer (NPC). IMRT is the standard RT treatment and has been widely adopted in Western countries to treat HNCs. However, its uptake in clinical practice among NPC patients has never been studied. METHODS: We investigated the use of IMRT for NPC using data from a nationwide cancer registry to describe the use of IMRT among NPC patients in Japan. We analyzed the data of patients with HNC, including NPC, who underwent IMRT between 2012 and 2014, as recorded in the hospital-based cancer registries linked with insurance claims. We calculated the proportion of patients with NPC who underwent IMRT at each hospital. To evaluate the use of IMRT for NPC, the IMRT use for NPC was compared with the proportion of patients with prostate cancer who underwent IMRT. RESULTS: Among 508 patients with NPC who underwent RT at one of 87 hospitals, 348 (69%) underwent IMRT. This proportion gradually increased between 2012 and 2014 (62%, 64% and 77%). Meanwhile, 4790 patients with prostate cancer (90%) underwent IMRT. Although some hospitals where IMRT was performed treated many patients with NPC, the proportion of patients with NPC who were treated with IMRT was low. CONCLUSIONS: IMRT has not been widely adopted in Japan for treating NPC. Barriers for adopting its use should be identified to close the gap between the standard and actual medical practice in Japan.

Molecular epidemiology of hepatitis C virus in Cambodia during 2016-2017.

In Cambodia, little epidemiological data of hepatitis C virus (HCV) is available. All previous studies were limited to only small or specific populations. In the present study, we performed a characterization of HCV genetic diversity based on demography, clinical data, and phylogenetic analysis of HCV non-structural 5B (NS5B) sequences belonging to a large cohort of patients (n = 3,133) coming from majority part of Cambodia between September 2016 and December 2017. The phylogenetic analysis revealed that HCV genotype 1 and 6 were the most predominant and sharing equal proportions (46%). The remaining genotypes were genotype 2 (4.3%) and unclassified variants (3.6%). Among genotype 1, subtype 1b was the most prevalent subtype accounting for 94%. Within genotype 6, we observed a high degree of diversity and the most common viral subtypes were 6e (44%) and 6r (23%). This characteristic points to the longstanding history of HCV in Cambodia. Geographic specificity of viral genotype was not observed. Risks of HCV infection were mainly associated with experience of an invasive medical procedure (64.7%), having partner with HCV (19.5%), and blood transfusion (9.9%). In addition, all of these factors were comparable among different HCV genotypes. All these features define the specificity of HCV epidemiology in Cambodia.

Quality of primary care provided in community clinics in Japan.

BACKGROUND: Quality indicators (QIs) for primary care are used worldwide. To date, however, the use of QIs to assess the quality of primary care in Japan has not been reported besides diabetes care. Here, we used QIs to evaluate the quality of primary care services provided by local clinics in Japan. METHODS: Four primary care clinics participated in the retrospective medical chart review in 2015. To assess primary care quality, we used 18 process-oriented QIs from the Quality Indicators for Primary Care practice in Japan (QIPC-J) those we previously developed by using a modified Delphi appropriateness method, which comprises 39 QIs in five categories (Comprehensive care/Standardized care, Access, Communication, Coordination, and Understanding of patient's background). Adult subjects were selected from among patients who visited each clinic within the previous one year using medical claims data. We collected data by reviewing medical charts, and calculated the quality score for each QI and clinic. RESULTS: A cumulative total of 4330 medical charts were reviewed. The overall quality score was 31.5%. Adherence to QIs ranged from 3.2% to 85.6%. Some quality scores varied substantially between clinics but the overall quality of care among clinics varied less, from 29.2% to 34.0%. CONCLUSIONS: The quality of primary care services provided by local clinics in Japan varies by both QI and clinic. Strategies to improve the quality of care are warranted.

Demonstration of the diagnostic agreement of capillary and venous blood samples, using hepatitis-C virus SD Bioline© rapid test: A clinic-based study.

BACKGROUND: Simplifying hepatitis C virus (HCV) screening is a key step in achieving the elimination of HCV as a global public health threat by 2030. OBJECTIVES: The objective of this study was to demonstrate the agreement of capillary blood and venipuncture specimens when using SD Bioline© HCV, a low-cost rapid diagnostic test (RDT), prequalified by WHO in 2016 on venous blood samples. STUDY DESIGN: Recruitment was conducted prospectively among adult patients presenting for HCV testing at the Médecins Sans Frontières (MSF) clinic of Preah Kossamak Hospital (Phnom Penh, Cambodia) between October and November 2017. Capillary and venous blood samples were collected from consenting patients and tested with SD Bioline© HCV. Two independent, blinded readers, and in the case of disagreement, a third reader, interpreted the results of each blood sample. Concordance between results was compared using Cohen's Kappa interrater reliability statistic. Discrepant sample pairs were tested with an enzyme immunoassay, the reference standard, at the Institute Pasteur of Cambodia. RESULTS: Among 421 pairs of samples collected, reader disagreement occurred for 0.7% (n = 3) of the participants. Sixty-four percent of capillary and venous blood sample pairs tested positive for HCV, with a Kappa statistic of 0.985 between the two methods. Three participants with discrepant sample pair results tested positive with EIA. CONCLUSIONS: Capillary and venous blood samples were concordant when tested with HCV SD Bioline© in a clinical context. This simplified testing approach is essential to the scale-up of HCV screening and useful in resource-limited settings or among populations for whom venipuncture is problematic.

Field evaluation of GeneXpert® (Cepheid) HCV performance for RNA quantification in a genotype 1 and 6 predominant patient population in Cambodia.

GeneXpert® (Cepheid) is the only WHO prequalified platform for hepatitis C virus (HCV) nucleic acid amplification testing that is suitable for point-of-care use in resource-limited contexts. However, its application is constrained by the lack of evidence on genotype 6 (GT6) HCV. We evaluated its field performance among a patient population in Cambodia predominantly infected with GT6. Between August and September 2017, we tested plasma samples obtained from consenting patients at Médecins Sans Frontières' HCV clinic at Preah Kossamak Hospital for HCV viral load (VL) using GeneXpert® and compared its results to those obtained using COBAS® AmpliPrep/Cobas® TaqMan® HCV Quantitative Test, v2.0 (Roche) at the Institut Pasteur du Cambodge. Among 769 patients, 77% of the seropositive patients (n = 454/590) had detectable and quantifiable VL using Roche and 43% (n = 195/454) were GT6. The sensitivity and specificity of GeneXpert® against Roche were 100% (95% CI 99.2, 100.0) and 98.5% (95% CI 94.8, 99.8). The mean VL difference was -0.01 (95% CI -0.05, 0.02) log10  IU/mL for 454 samples quantifiable on Roche and -0.07 (95% CI -0.12, -0.02) log10  IU/mL for GT6 (n = 195). The limit of agreement (LOA) was -0.76 to 0.73 log10  IU/mL for all GTs and -0.76 to 0.62 log10 IU/mL for GT6. Twenty-nine GeneXpert® results were outside the LOA. Frequency of error and the median turnaround time (TAT) for GeneXpert® were 1% and 0 days (4 days using Roche). We demonstrated that the GeneXpert® HCV assay has good sensitivity, specificity, quantitative agreement, and TAT in a real-world, resource-limited clinical setting among GT6 HCV patients.

Development and Pilot Testing of Quality Indicators for Primary Care in Japan.

INTRODUCTION: To the best of our knowledge, no quality indicators (QIs) for primary care provided by local clinics have yet been developed in Japan. We aimed to develop valid and applicable QIs to evaluate primary care in Japan. METHODS: Two focus group interviews were held to identify conceptual categories. Existing indicators for these categories were identified, and initial sets of potential QIs were developed. Using a modified Delphi appropriateness method, a multidisciplinary expert panel then developed and selected the QIs. Feasibility and applicability of these QIs were then confirmed in pilot testing at six local clinics in Hokkaido, Japan. To determine patient acceptance of these quality improvement activities, the survey asked two questions, "Do you think it is preferable that the patients of this clinic be periodically surveyed?" and "Do you think it is preferable that this clinic periodically undergo an external quality review by an independent body?" RESULTS: Seven categories emerged from the focus group discussions as key components of primary care in Japan. Thirty-nine QIs under five categories (Comprehensive care/Standardized care, Access, Communication, Co-ordination, and Understanding of patient background) were finally selected and named the QIs for Primary Care Practice in Japan. In pilot testing at six primary care clinics in 2015, 65.4% of patients answered favorably to the idea that clinics should conduct regular patient surveys, and 71.8% answered favorably to the idea that clinics should undergo periodic external quality review by an independent body. CONCLUSIONS: We developed QIs to assess primary care services provided by clinics in Japan, for the first time. Although further refinement is required, establishment of these QIs is the first step in quality improvement for primary care practices in Japan.

Monitoring and evaluating the quality of cancer care in Japan using administrative claims data.

The importance of measuring the quality of cancer care has been well recognized in many developed countries, but has never been successfully implemented on a national level in Japan. We sought to establish a wide-scale quality monitoring and evaluation program for cancer by measuring 13 process-of-care quality indicators (QI) using a registry-linked claims database. We measured two QI on pre-treatment testing, nine on adherence to clinical guidelines on therapeutic treatments, and two on supportive care, for breast, prostate, colorectal, stomach, lung, liver and cervical cancer patients who were diagnosed in 2011 from 178 hospitals. We further assessed the reasons for non-adherence for patients who did not receive the indicated care in 26 hospitals. QI for pretreatment testing were high in most hospitals (above 80%), but scores on adjuvant radiation and chemoradiation therapies were low (20-37%), except for breast cancer (74%). QI for adjuvant chemotherapy and supportive care were more widely distributed across hospitals (45-68%). Further analysis in 26 hospitals showed that most of the patients who did not receive adjuvant chemotherapy had clinically valid reasons for not receiving the specified care (above 70%), but the majority of the patients did not have sufficient reasons for not receiving adjuvant radiotherapy (52-69%) and supportive care (above 80%). We present here the first wide-scale quality measurement initiative of cancer patients in Japan. Patients without clinically valid reasons for non-adherence should be examined further in future to improve care.

Patterns of prescribing radiotherapy and bevacizumab in nationwide practice - analysis of 101 designated cancer care hospitals in Japan.

Radiotherapy and bevacizumab are each effective in treating patients with advanced cancer, but their concurrent use may cause serious adverse events (SAEs). Whereas sequential administration can theoretically reduce the risk of SAEs while maintaining the anticancer effects, this hypothesis remains unconfirmed, leading to variations in practice. To elucidate current practices, the patterns of care received by patients in Japan with regard to these two therapies were assessed in a large database of a hospital-based cancer registry linked with insurance claims. This database contained information on 106 057 patients diagnosed with seven major cancers in 2011 and the care they received up to the end of 2012. In total, 335 patients from 101 hospitals in the database were treated with both radiotherapy and bevacizumab. Of these patients, 50.8% had lung cancer, and 51.3% had Stage IV cancer. Of the 335 patients, 75 (22.4%) received these therapies concurrently. In patients treated sequentially, the time from the last dose of bevacizumab to the start of radiotherapy was most frequently 4-5 weeks (12.4%), whereas the time from the end of radiotherapy to the start of bevacizumab was most frequently 1-2 weeks (10.6%). The cumulative proportions of patients in these two groups receiving sequential therapies within 3 weeks were 19.0% and 26.1%, respectively. Many practices appeared to avoid the concurrent use of bevacizumab and radiation, but some provided concurrent therapy. Additional data are required to determine whether the avoidance of concurrent use should become a standard of care.

A national profile of the impact of parental cancer on their children in Japan.

OBJECTIVE: Dependent children under the age of 18 are particularly vulnerable to the stress of parental death from cancer or of having a parent diagnosed and treated for the disease. More and more Japanese couples are postponing parenthood, which increases their chances of developing cancer while they still have a dependent child. However, the problem has not received enough attention from healthcare professionals and policy-makers because the extent and breadth of the problem has never been examined in the Japanese population. Therefore, we aimed to estimate the nationwide incidence of cancer patients who have children under the age of 18 years, as well as the incidence of children who have a parent diagnosed with cancer in Japan. STUDY DESIGN: We calculated the proportion of patients who have children stratified by age, gender and cancer type using electronic medical records of cancer patients (20-59 years old) admitted to the National Cancer Center Hospital (NCCH) for the first time between January 2009 and December 2013. We projected these estimates onto the Japanese population using 2010 population-based cancer registry data, and repeated the projection using 2011 hospital-based cancer registry data so that estimates of patients receiving care at Designated Cancer Care (DCC) hospitals could be obtained. RESULTS: We found that an estimated 56,143 cancer patients who have 87,017 dependent children are diagnosed with cancer every year in Japan. The proportion of children in Japan who had a parent newly diagnosed with cancer in 2010 was approximately 0.38%. We estimated that in 2011 there were on average about 82 cancer patients with minor children and 128 minor children who have at least one parent diagnosed with cancer in every DCC hospital in Japan. CONCLUSION: Parental cancer is common. We have identified that many adults diagnosed with cancer have the double burden of coping with the diagnosis and treatment as well as supporting their children through this experience. Additional data on socioeconomic characteristics and needs assessment of these patients are required to understand how best to help children and families cope with cancer.

Accuracy of using Diagnosis Procedure Combination administrative claims data for estimating the amount of opioid consumption among cancer patients in Japan.

OBJECTIVE: The state of opioid consumption among cancer patients has never been comprehensively investigated in Japan. The Diagnosis Procedure Combination claims data may be used to measure and monitor opioid consumption among cancer patients, but the accuracy of using the Diagnosis Procedure Combination data for this purpose has never been tested. METHODS: We aimed to ascertain the accuracy of using the Diagnosis Procedure Combination claims data for estimating total opioid analgesic consumption by cancer patients compared with electronic medical records at Aomori Prefectural Central Hospital. We calculated percent differences between estimates obtained from electronic medical records and Diagnosis Procedure Combination claims data by month and drug type (morphine, oxycodone, fentanyl, buprenorphine, codeine and tramadol) between 1 October 2012 and 30 September 2013, and further examined the causes of discrepancy by reviewing medical and administrative charts between April and July 2013. RESULTS: Percent differences varied by month for drug types with small prescription volumes, but less so for drugs with larger prescription volumes. Differences also tended to diminish when consumption was compared for a year instead of a month. Total percent difference between electronic medical records and Diagnosis Procedure Combination data during the study period was -0.1% (4721 mg per year per hospital), as electronic medical records as baseline. Half of the discrepancy was caused by errors in data entry. CONCLUSION: Our study showed that Diagnosis Procedure Combination claims data can be used to accurately estimate opioid consumption among a population of cancer patients, although the same conclusion cannot be made for individual estimates or when making estimates for a group of patients over a short period of time.

Are hospitals in Japan with larger patient volume treating younger and earlier-stage cancer patients? An analysis of hospital-based cancer registry data in Japan.

OBJECTIVE: Differences in hospital case-mix have not been adequately accounted for in hospital volume and patient outcome studies in Japan. We aimed to examine whether differences may exist by investigating the distribution of patients' stage and age across designated cancer treatment hospitals of varying patient volume across Japan. METHODS: We analyzed data of gastric, breast, colorectal, lung and liver cancer patients who were included in the national database of hospital-based cancer registries between 2008 and 2011. We investigated the association between hospital volume, cancer stage and patient age. Hospitals were classified into five groups according to patient volume. RESULTS: In total, 676 713 patients met the inclusion criteria. The proportion of patients with early-stage (tumor-node-metastasis Stage 0 or I) cancer was higher among high-volume hospitals for all cancer types except small cell lung cancer. The proportion of older patients (age >75 years) was smaller among high-volume hospitals for all cancer types. The difference in the proportion of patients with early-stage cancers between very low-volume and very high-volume hospitals was greatest for non-small cell lung cancer (26.5% for very low and 43.5% for very high). This difference for the proportion of older patients was also greatest for non-small cell lung cancer (48.9% for very low and 30.3% for very high). CONCLUSIONS: We showed that the proportions of early-stage cancer patients and younger patients are greater in higher-volume hospitals compared with lower-volume hospitals in Japan. Researchers conducting volume-outcome studies and policymakers analyzing hospital performance should be cautious when making interhospital comparisons.

Estimated life expectancy and risk of death from cancer by quartiles in the older Japanese population: 2010 vital statistics.

Data on life expectancies and risk of death from cancer are essential information to have when making informed decisions about cancer screening and treatment options, but has never been presented in a way that is readily available to use for physicians in Japan. We provided estimates of life expectancies and predicted risk of death from seven most common types of cancer (lung, gastric, liver, colon, prostate, breast, and cervical) by quartiles for the older Japanese population above 50 years old, using 2010 life tables and cancer mortality statistics data. We found that there was a large difference in life expectancy between older persons in the upper and lower quartiles. Risk of death from breast cancer was low. By using this data, physicians can more accurately obtain life expectancy estimates by assessing which quartile the patient is most likely to fall under, and help patients make better informed decisions.