Patients' experience of accessing hepatitis C treatment through the Myanmar national hepatitis C treatment program: a qualitative evaluation.

BACKGROUND: Globally, 56.8 million people are living with hepatitis C and over three-quarters of those reside in low and middle-income countries (LMICs). Barriers and enablers to hepatitis C care among people who inject drugs in high-income countries are well documented. However, there is scant literature describing the patient experience in LMICs. Understanding the barriers and enablers to care from the patient perspective is important to inform service refinements to improve accessibility and acceptability of hepatitis C care. METHODS: We conducted a qualitative evaluation of the patient experience of accessing the national hepatitis C program at eight hospital sites in Myanmar. Semi-structured interviews were conducted with four to five participants per site. Interview data were analysed thematically, with deductive codes from Levesque et al.'s (2013) Framework on patient-centred access to healthcare. RESULTS: Across the eight sites, 38 participants who had completed treatment were interviewed. Barriers to accessing care were mostly related to attending for care and included travel time and costs, multiple appointments, and wait times. Some participants described how they did not receive adequate information on hepatitis C, particularly its transmission routes, and on the level of cirrhosis of their liver and what they were required to do after treatment (i.e. reduce alcohol consumption, liver cirrhosis monitoring). Many participants commented that they had few or no opportunities to ask questions. Provision of treatment at no cost was essential to accessibility, and gratitude for free treatment led to high acceptability of care, even when accessing care was inconvenient. CONCLUSIONS: These findings highlight the importance of streamlining and decentralising health services, adequate human resourcing and training, and affordable treatment in maximising the accessibility and acceptability of hepatitis C care in LMICs. Findings from this work will inform future service delivery refinements for national program and other decentralised programs to improve accessibility and acceptability of hepatitis C care in Myanmar.

Feasibility of decentralised, task-shifted hepatitis C testing and treatment services in urban Myanmar: implications for scale-up.

OBJECTIVES: To assess the feasibility considerations for a decentralised, one-stop-shop model of care implemented in Yangon, Myanmar. SETTING: Two primary care level clinics in urban Yangon, Myanmar. DESIGN: This is a feasibility study of a highly effective care model. Using Intervention Complexity Framework by Gericke et al, we collated and analysed programmatic data and evaluation data to outline key project implementation requirements and experiences. PARTICIPANTS: Programmatic data were collected from clinical records, GeneXpert device test and maintenance reports, national guidelines, product and device instructions and site monitoring visit reports. Healthcare providers involved in delivering care model contributed interview data. RESULTS: The main feasibility considerations are appropriate storage for test kits and treatments (in response to temperature and humidity requirements), installation of a continuous stable electricity supply for the GeneXpert device, air-conditioning for the laboratory room hosting GeneXpert, access to a laboratory for pretreatment assessments and clear referral pathways for specialist consultation when required. Lessons from our project implementation experiences included the extensive time requirements for patient education, the importance of regular error monitoring and stock storage reviews and that flexible appointment scheduling and robust reminder system likely contributed to high retention in care. CONCLUSIONS: Detailed documentation and dissemination of feasibility requirements and implementation considerations is vital to assist others to successfully implement a similar model of care elsewhere. We provide 10 recommendations for successful implementation. TRIAL REGISTRATION NUMBER: The trial was registered at ClinicalTrials.gov NCT03939013 on May 6, 2019. This manuscript presents post-results data on feasibility.

Retreatment of Chronic Hepatitis C Infection: Real-World Regimens and Outcomes From National Treatment Programs in Three Low- and Middle-Income Countries.

Access to recommended second-line treatments is limited for patients who fail initial hepatitis C virus (HCV) therapy in low- and middle-income countries. Alternative regimens and associated outcomes are not well understood. Through a pooled analysis of national program data in Egypt, Georgia, and Myanmar, we observed SVR rates >90% for alternative retreatment regimens.

Hepatitis C elimination in Myanmar: Modelling the impact, cost, cost-effectiveness and economic benefits.

BACKGROUND: Myanmar has set national hepatitis C (HCV) targets to achieve 50% of people diagnosed and 50% treated by 2030. The WHO has additional targets of reducing incidence by 80% and mortality by 65% by 2030. We aimed to estimate the impact, cost, cost-effectiveness and net economic benefit of achieving these targets. METHODS: Mathematical models of HCV transmission, disease progression and the care cascade were calibrated to 15 administrative regions of Myanmar. Cost data were collected from a community testing and treatment program in Yangon. Three scenarios were projected for 2020-2030: (1) baseline (current levels of testing/treatment); and testing/treatment scaled up sufficiently to reach (2) the national strategy targets; and (3) the WHO targets. FINDINGS: Without treatment scale-up, 333,000 new HCV infections and 97,000 HCV-related deaths were estimated to occur in Myanmar 2020-2030, with HCV costing a total $100 million in direct costs (testing, treatment, disease management) and $10.4 billion in lost productivity. In the model, treating 55,000 people each year was sufficient to reach the national strategy targets and prevented a cumulative 40,000 new infections (12%) and 25,000 HCV-related deaths (25%) 2020-2030. This was estimated to cost a total $189 million in direct costs ($243 per DALY averted compared to no treatment scale-up), but only $9.8 billion in lost productivity, making it cost-saving from a societal perspective by 2024 with an estimated net economic benefit of $553 million by 2030. Reaching the WHO targets required further treatment scale-up and additional direct costs but resulted in greater longer-term benefits. INTERPRETATION: Current levels of HCV testing and treatment in Myanmar are insufficient to reach the national strategy targets. Scaling up HCV testing and treatment in Myanmar to reach the national strategy targets is estimated to generate significant health and economic benefits. FUNDING: Gilead Sciences.

Outcomes of the CT2 study: A 'one-stop-shop' for community-based hepatitis C testing and treatment in Yangon, Myanmar.

BACKGROUND: With the advent of low-cost generic direct-acting antivirals (DAA), hepatitis C (HCV) elimination is now achievable even in low-/middle-income settings. We assessed the feasibility and effectiveness of a simplified clinical pathway using point-of-care diagnostic testing and non-specialist-led care in a decentralized, community-based setting. METHODS: This feasibility study was conducted at two sites in Yangon, Myanmar: one for people who inject drugs (PWID), and the other for people with liver disease. Participants underwent on-site rapid anti-HCV testing and HCV RNA testing using GeneXpert(R) . General practitioners determined whether participants started DAA therapy immediately or required specialist evaluation. Primary outcome measures were progression through the HCV care cascade, including uptake of RNA testing and treatment, and treatment outcomes. FINDINGS: All 633 participants underwent anti-HCV testing; 606 (96%) were anti-HCV positive and had HCV RNA testing. Of 606 tested, 535 (88%) were RNA positive and had pre-treatment assessments; 30 (6%) completed specialist evaluation. Of 535 RNA positive participants, 489 (91%) were eligible to initiate DAAs, 477 (98%) completed DAA therapy and 421 achieved SVR12 (92%; 421/456). Outcomes were similar by site: PWID site: 91% [146/161], and liver disease site: 93% [275/295]). Compensated cirrhotic patients were treated in the community; they achieved an SVR12 of 83% (19/23). Median time from RNA test to DAA initiation was 3 days (IQR 2-5). CONCLUSIONS: Delivering a simplified, non-specialist-led HCV treatment pathway in a decentralized community setting was feasible in Yangon, Myanmar; retention in care and treatment success rates were very high. This care model could be integral in scaling up HCV services in Myanmar and other low- and middle-income settings.

Knowledge, practice pattern and attitude toward asthma management amongst physicians from Nepal, Malaysia, Lebanon, Myanmar and Morocco.

OBJECTIVE: This survey aimed to understand the physicians' practice pattern and challenges faced while treating their patients with asthma in five countries-Malaysia, Nepal, Myanmar, Morocco and Lebanon. METHODS: Questionnaire-based data was gathered from internal medicine doctors (209), general practitioners (206), chest physicians (152) and pediatricians (58) from 232 locations from across the five countries. RESULTS: Of the 816 physicians, 374 physicians encountered at least 5 asthma patients daily. Approximately, 38% physicians always used spirometry for diagnosis and only 12% physicians always recommended Peak flow meter (PFM) for home-monitoring. Salmeterol/fluticasone (71%) followed by formoterol/budesonide (38%) were the most preferred ICS/long-acting beta2-agonists (LABA); Salbutamol (78%) was the most preferred reliever medication. 60% physicians said >40% of their patients were apprehensive to use inhalers. 72% physicians preferred a pressurized metered-dose inhaler (pMDI) to a dry powder inhaler (DPI) with only a third of them using a spacer with the pMDI. 71% physicians believed that using similar device for controller and reliever can be beneficial to patients. Skipping medicines in absence of symptoms (64%), incorrect inhaler technique (48%) and high cost of medication (49%) were considered as major reasons for non-adherence by most physicians. Incorrect inhaler technique (66%) and nonadherence (59%) were considered the most common causes of poor asthma control. CONCLUSIONS: There are opportunities to improve the use of diagnostic and monitoring tools for asthma. Non-adherence, incorrect inhaler technique and cost remain a challenge to achieve good asthma control. Asthma education, including correct demonstration of inhaler, can potentially help to improve inhaler adherence.

Decentralized, Community-Based Hepatitis C Point-of-Care Testing and Direct-Acting Antiviral Treatment for People Who Inject Drugs and the General Population in Myanmar: Protocol for a Feasibility Study.

BACKGROUND: The advent of direct-acting antivirals (DAAs) and point-of-care (POC) testing platforms for hepatitis C allow for the decentralization of care to primary care settings. In many countries, access to DAAs is generally limited to tertiary hospitals, with limited published research documenting decentralized models of care in low-and middle-income settings. OBJECTIVE: This study aims to assess the feasibility, acceptability, effectiveness, and cost-effectiveness of decentralized community-based POC testing and DAA therapy for hepatitis C among people who inject drugs and the general population in Yangon, Myanmar. METHODS: Rapid diagnostic tests for anti-hepatitis C antibodies were carried out on-site and, if reactive, were followed by POC GeneXpert hepatitis C RNA polymerase chain reaction tests. External laboratory blood tests to exclude other major health issues were undertaken. Results were given to participants at their next appointment, with the participants commencing DAA therapy that day if a specialist review was not required. Standard clinical data were collected, and the participants completed behavioral questionnaires. The primary outcome measures are the proportion of participants receiving GeneXpert hepatitis C RNA test, the proportion of participants commencing DAA therapy, the proportion of participants completing DAA therapy, and the proportion of participants achieving sustained virological response 12 weeks after completing DAA therapy. RESULTS: Recruitment was completed on September 30, 2019. Monitoring visits and treatment outcome visits are scheduled to continue until June 2020. CONCLUSIONS: This feasibility study in Myanmar contributes to the evidence gap for community-based hepatitis C care in low- and middle-income settings. Evidence from this study will inform the scale-up of hepatitis C treatment programs in Myanmar and globally.

An expert review on the use of tenofovir alafenamide for the treatment of chronic hepatitis B virus infection in Asia.

Asia has intermediate-to-high prevalence and high morbidity of hepatitis B virus (HBV) infection. The use of guideline-recommended nucleos(t)ide analogs with high barrier to resistance, such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF), is one of the key interventions for curbing HBV infection and associated morbidity in Asia. However, there are some challenges to the use of ETV and TDF; while ETV is associated with high resistance in lamivudine (LAM)-exposed (especially LAM-refractory) patients; bone and renal safety issues are a major concern with TDF. Hence, a panel of twenty-eight expert hepatologists from Asia convened, reviewed the literature, and developed the current expert opinion-based review article for the use of TAF in the resource-constrained settings in Asia. This article provides a comprehensive review of two large, phase 3, double-blind, randomized controlled trials of TAF versus TDF in HBeAg-negative (study 0108) and HBeAg-positive (study 0110) chronic HBV patients (> 70% Asians). These studies revealed as follows: (1) non-inferiority for the proportion of patients who had HBV DNA < 29 IU/mL; (2) significantly high rate of normalization of alanine aminotransferase levels; (3) no incidence of resistance; and (4) significantly better bone and renal safety, with TAF vs. TDF up to 144 weeks. Considering the benefits of TAF, the expert panel proposed recommendations for optimizing the use of TAF in Asia, along with guidance on specific patient groups at risk of renal or bone disease suitable for TAF therapy. The guidance provided in this article may help clinicians optimize the use of TAF in Asia.

Asian consensus recommendations on optimizing the diagnosis and initiation of treatment of hepatitis B virus infection in resource-limited settings.

Asia has an intermediate-to-high prevalence of and high morbidity and mortality from hepatitis B virus (HBV) infection. Optimization of diagnosis and initiation of treatment is one of the crucial strategies for lowering disease burden in this region. Therefore, a panel of 24 experts from 10 Asian countries convened, and reviewed the literature, to develop consensus guidance on diagnosis and initiation of treatment of HBV infection in resource-limited Asian settings. The panel proposed 11 recommendations related to diagnosis, pre-treatment assessment, and indications of therapy of HBV infection, and management of HBV-infected patients with co-infections. In resource-limited Asian settings, testing for hepatitis B surface antigen may be considered as the primary test for diagnosis of HBV infection. Pre-treatment assessments should include tests for complete blood count, liver and renal function, hepatitis B e-antigen (HBeAg), anti-HBe, HBV DNA, co-infection markers and assessment of severity of liver disease. Noninvasive tests such as AST-to-platelet ratio index, fibrosis score 4 or transient elastography may be used as alternatives to liver biopsy for assessing disease severity. Considering the high burden of HBV infection in Asia, the panel adopted an aggressive approach, and recommended initiation of antiviral therapy in all HBV-infected, compensated or decompensated cirrhotic individuals with detectable HBV DNA levels, regardless of HBeAg status or alanine transaminase levels. The panel also developed a simple algorithm for guiding the initiation of treatment in noncirrhotic, HBV-infected individuals. The recommendations proposed herein, may help guide clinicians, to optimize the diagnosis and improvise the treatment rates for HBV infection in Asia.

Inadequate knowledge about snakebite envenoming symptoms and application of harmful first aid methods in the community in high snakebite incidence areas of Myanmar.

INTRODUCTION: Every year millions of people in developing countries suffer from snakebite, causing a large number of deaths and long term complications. Prevention and appropriate first aid could reduce the incidence and improve the health outcomes for those who suffer bites. However, many communities where snakebite is a major issue suffer from a lack of information about prevention and first aid measures that a family or community member could take to prevent severe envenoming, complications and poor outcomes. Myanmar suffers from a high burden of snakebites with a large number of deaths. As part of a health services and community development program, a community survey was conducted to identify communities' knowledge about snakebite and their sequelae, and knowledge and practice about first aid and health services use. METHOD: 4,276 rural residents of Kyaukse and Madaya townships in the Mandalay region were recruited by cluster sampling, involving random selection of 144 villages and random sampling of 30 households from each village. One adult member of each household was interviewed using a structured questionnaire. RESULTS: The incidence of snakebite was 116/100,000 people. Respondents reported 15 different types of snakes in the area, with Russell's Viper, Cobra and Green snakes as the most common. 88% of the people informed that working in the fields and forests was when most of the bites occur. A majority knew about snakebite prevention methods such as wearing long boots. However, only a few people knew about the specific symptoms caused by snakebites. Only 39% knew about the correct methods of first aid. More than 60% mentioned tourniquet as a first aid method, though this may cause significant complications such as ischaemia of the limb. 88% said that they would take a snakebite victim to a government hospital, and 58% mentioned availability of antivenom as the reason for doing this. At the same time, the majority mentioned that traditional methods existed for first aid and treatment and 25% mentioned at least one harmful traditional method as an effective measure that they might use. CONCLUSION: The community is aware of snakebites as a major public health issue and know how to prevent them. However, the high incidence of snakebites point to lack of application of preventive methods. The community recognise the need for treatment with antivenom. However, inadequate knowledge about appropriate first aid methods, and a reliance on using tourniquets require a targeted education program. Existing knowledge in communities, albeit insufficient, provides a good starting point for mass media educational campaigns.

Home return following invasive mechanical ventilation for the oldest-old patients in medical intensive care units from two US hospitals.

BACKGROUND: The aging of the US population has been associated with an increase in intensive care unit (ICU) utilization and correspondingly, invasive mechanical ventilation (IMV) among the oldest-old (age ≥80 years). While previous studies have examined ICU and IMV outcomes in the elderly, very few have focused on patient-centered outcomes, specifically home return, in the oldest-old. We investigated the rate of immediate home return following IMV in the medical ICU in previously home-dwelling oldest-old patients relative to that of a comparison group of 50-70-year olds. METHODS: Data were extracted retrospectively from patient records at Elmhurst Hospital Center in Elmhurst, NY, USA, encompassing the period from January 2009 to May 2014 and Jacobi Medical Center in the Bronx, NY, USA, from January 2010 to March 2014. Medical ICU admissions within those date ranges were screened for possible inclusion into one of two study groups based on age: ≥80 years old and 50-70 years old. The primary end point was hospital discharge: home return versus no home return (death or nonhome discharge). Cox proportional hazards' regression models were used to estimate crude and multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for failure to return home. RESULTS: A total of 375 patients were included in the analysis: 279 (74%) patients aged 50-70 years and 96 (26%) patients aged ≥80 years. Compared to 50-70-year olds, being ≥80 years old was associated with a nearly two-fold greater risk of no home return: adjusted HR: 1.96; 95% CI 1.43-2.67. The oldest-old was at significantly increased risk of both being discharged to a skilled nursing facility or subacute rehabilitation (adjusted HR: 2.19; 95% CI 1.33-3.59) as well as of dying in the hospital (adjusted HR: 1.81; 95% CI 1.21-2.71). CONCLUSION: Previously home-dwelling oldest-old are at significantly increased risk of failing to return home immediately following medical ICU admission with IMV as compared to patients aged 50-70 years. These results can help medical ICU staff establish appropriate expectations when addressing the families of their oldest patients. Further studies are needed to evaluate the potential for delayed home return among the oldest old and to assess the ability of frailty indices to predict home return within this ICU population.

Snakebite incidence in two townships in Mandalay Division, Myanmar.

INTRODUCTION: The global incidence of snakebite is estimated at more than 2.5 million cases annually, with greater than 100,000 deaths. Historically, Myanmar has one of the highest incidences of venomous snakebites. In order to improve the health outcomes of snakebite patients in Myanmar, access to accurate snakebite incidence data is crucial. The last population-based study in Myanmar was conducted more than a decade ago. In 2014, the Ministry of Health and Sports data from health facilities indicated an incidence of about 29.5 bites/ 100,000 population/year (a total of 15,079 bites). Since data from health facilities lack information about those who do not seek health care from government health services, a new population-based survey was conducted in 2 rural areas of Mandalay region. The survey data were compared to those obtained from healthcare services. METHOD: 4,276 rural respondents in Kyaukse and Madaya townships in Mandalay Division were recruited using cluster sampling that involved random selection of 150 villages and random sampling of 30 households from each village. One adult member of each household was interviewed using a structured questionnaire. RESULTS: One respondent from each of 4,276 households represented 19,877 residents from 144 villages. 24 people in these households had suffered snakebite during the last one year giving an annual incidence of 116/100,000. During the last ten years, 252 people suffered snakebites. 44.1% of the victims were women. 14% of the villages reported 4 or more bites during the last ten years, whereas 27% villages reported no snakebites. 92.4% of the victims recovered fully, 5.4% died, and 2% suffered long term health issues. One victim was reported to have died from causes unrelated to the snakebite. While there was no statistically significant difference between outcomes for children and adults, 4 of 38 of those under 18 years of age died compared to 7 of 133 adults between 19 to 40 years of age. CONCLUSION: This incidence reported by the community members points to substantially more snakebites than the number of snakebite patients attending health facilities. This higher incidence points to the need for a nation-wide population-based survey, community education about gaining access to care where antivenom is available, and to the potential need for a larger supply of antivenom and expansion of medical care in rural areas.

Confirmation of elevated arsenic levels in groundwater of Myanmar.

Millions of villagers across South and Southeast Asia are exposed to toxic levels of arsenic (As) by drinking well water. In order to confirm the field-kit results that Myanmar is also affected, a total of 55 wells were tested in the field in January 2013 and sampled for laboratory analysis across seven villages spanning a range of As contamination in the lower Ayeyarwady basin. Elevated concentrations of As (50-630 µg/L) were measured in wells up to 60 m deep and associated with high levels of Fe (up to 21 mg/L) and low concentrations of SO4 (<0.05 mg/L). Concentrations of As <10 µg/L were measured in some shallow (<30 m) grey sands and in both shallow and deep orange sands. These results indicate that the main mechanism of As release to groundwater in Myanmar is the reductive dissolution of Fe oxyhydroxides, as in the neighboring Bengal, Mekong, and Red River basins. Concentrations of As in groundwater of Myanmar are therefore unlikely to change rapidly over time and switching to existing low-As wells is a viable way of reducing exposure in the short term. However, only 17 of the 55 well owners interviewed correctly recalled the status of their well despite extensive testing in the region. A renewed effort is thus needed to test existing wells and new wells that continue to be installed and to communicate the health risks of exposure to As for infants, children, and adults.

Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase.

The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (-)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (-)-4a are described.

Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase.

A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation.

Distribution of common genetic subgroups in childhood acute lymphoblastic leukemia in four developing countries.

An international project was conducted to identify the common acute lymphoblastic leukemia (ALL)-specific fusion genes (ETV6-RUNX1,MLL-AF4,TCF3-PBX1, and BCR-ABL1) in developing countries to provide additional prognostic information at diagnosis. A total of 181 children with newly diagnosed ALL were tested by reverse transcriptase-polymerase chain reaction at laboratories in India, Pakistan, Myanmar, and Sudan, following a common protocol. To our knowledge, this report is novel in its report from these countries, except India. Across the four countries, the ETV6-RUNX1 (TEL-AML1) fusion gene was present in only 5% of cases. All the positive samples were from children aged 1 to 10 years, in whom the prevalence of this fusion gene, which is associated with good prognosis, was 7.4% (9 out of 121 samples), a much lower rate than reported from Western populations. In the 18 ALL cases tested in Sudan, a notable excess of MLL-AF4 (17%) and BCR-ABL1 (22%) fusion genes was found. This study highlights the need for wider international surveys of the molecular epidemiology of ALL.

Discovery of 2-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-5-(5-fluoropyrimidin-2-yl)benzamide as a potent and CNS penetrable P2X7 receptor antagonist.

Focused SAR studies were carried out around 5-heteroaryl and 1-amide portions of the 2-chlorobenzamide scaffold, resulting in the discovery of a potent, metabolically stable and centrally penetrable antagonist against P2X(7) receptor.

Identification of SD-0006, a potent diaryl pyrazole inhibitor of p38 MAP kinase.

Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38alpha kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006.