Epidemiology, methods of diagnosis, and clinical management of patients with arginase 1 deficiency (ARG1-D): A systematic review.

BACKGROUND: Arginase 1 Deficiency (ARG1-D) is a rare, progressive, metabolic disorder that is characterized by devastating manifestations driven by elevated plasma arginine levels. It typically presents in early childhood with spasticity (predominately affecting the lower limbs), mobility impairment, seizures, developmental delay, and intellectual disability. This systematic review aims to identify and describe the published evidence outlining the epidemiology, diagnosis methods, measures of disease progression, clinical management, and outcomes for ARG1-D patients. METHODS: A comprehensive literature search across multiple databases such as MEDLINE, Embase, and a review of clinical studies in ClinicalTrials.gov (with results reported) was carried out per PRISMA guidelines on 20 April 2020 with no date restriction. Pre-defined eligibility criteria were used to identify studies with data specific to patients with ARG1-D. Two independent reviewers screened records and extracted data from included studies. Quality was assessed using the modified Newcastle-Ottawa Scale for non-comparative studies. RESULTS: Overall, 55 records reporting 40 completed studies and 3 ongoing studies were included. Ten studies reported the prevalence of ARG1-D in the general population, with a median of 1 in 1,000,000. Frequently reported diagnostic methods included genetic testing, plasma arginine levels, and red blood cell arginase activity. However, routine newborn screening is not universally available, and lack of disease awareness may prevent early diagnosis or lead to misdiagnosis, as the disease has overlapping symptomology with other diseases, such as cerebral palsy. Common manifestations reported at time of diagnosis and assessed for disease progression included spasticity (predominately affecting the lower limbs), mobility impairment, developmental delay, intellectual disability, and seizures. Severe dietary protein restriction, essential amino acid supplementation, and nitrogen scavenger administration were the most commonly reported treatments among patients with ARG1-D. Only a few studies reported meaningful clinical outcomes of these interventions on intellectual disability, motor function and adaptive behavior assessment, hospitalization, or death. The overall quality of included studies was assessed as good according to the Newcastle-Ottawa Scale. CONCLUSIONS: Although ARG1-D is a rare disease, published evidence demonstrates a high burden of disease for patients. The current standard of care is ineffective at preventing disease progression. There remains a clear need for new treatment options as well as improved access to diagnostics and disease awareness to detect and initiate treatment before the onset of clinical manifestations to potentially enable more normal development, improve symptomatology, or prevent disease progression.

Stakeholder point of view on prescription drug affordability - a systematic literature review and content analysis.

OBJECTIVES: The objectives of this research were to: 1) understand perspectives on affordability of pharmaceutical drugs from the point of view of stakeholders as reported in published peer-reviewed journals and conferences; 2) evaluate if (and how) perspectives on affordability overlapped across stakeholders. METHODS: The systematic literature review followed Cochrane and PRISMA guidelines. Content analysis with iterative and systematic coding of text was conducted, to identify themes. RESULTS: A total of 7,372 unique citations were eligible, and 126 articles included for final synthesis. For patients, 6 core themes emerged: financial barriers, adherence, access, patient-provider communication, financial distress, and factors that impact affordability. For payers, 5 core themes: financing schemes, cost-effectiveness, budget impact, private vs. public preferences, and ethics. For providers, 3 themes: patient-provider communication, physician prescribing behavior, and finding alternatives to support patient access. For policymakers, 2 themes: measuring affordability and the role of government. Limited articles representing the manufacturer perspective were identified. Perspectives of decision makers (payers, policymakers) did not overlap with those affected by affordability (patients, providers). CONCLUSIONS: This research highlights the multi-dimensionality of drug "affordability." Multiple factors beyond cost influence patient affordability implying interventions can help alleviate affordability issues for some patients. The lack of overlap highlights potential hazards that decisions related to out-of-pocket spending, insurance coverage, reimbursement, and rationing occur without explicitly considering patient and provider perspectives.

Cost-effectiveness of Direct Antiviral Agents for Hepatitis C Virus Infection and a Combined Intervention of Syringe Access and Medication-assisted Therapy for Opioid Use Disorders in an Injection Drug Use Population.

BACKGROUND: There are too many plausible permutations and scale-up scenarios of combination hepatitis C virus (HCV) interventions for exhaustive testing in experimental trials. Therefore, we used a computer simulation to project the health and economic impacts of alternative combination intervention scenarios for people who inject drugs (PWID), focusing on direct antiviral agents (DAA) and medication-assisted treatment combined with syringe access programs (MAT+). METHODS: We performed an allocative efficiency study, using a mathematical model to simulate the progression of HCV in PWID and its related consequences. We combined 2 previously validated simulations to estimate the cost-effectiveness of intervention strategies that included a range of coverage levels. Analyses were performed from a health-sector and societal perspective, with a 15-year time horizon and a discount rate of 3%. RESULTS: From a health-sector perspective (excluding criminal justice system-related costs), 4 potential strategies fell on the cost-efficiency frontier. At 20% coverage, DAAs had an incremental cost-effectiveness ratio (ICER) of $27 251/quality-adjusted life-year (QALY). Combinations of DAA at 20% with MAT+ at 20%, 40%, and 80% coverage had ICERs of $165 985/QALY, $325 860/QALY, and $399 189/QALY, respectively. When analyzed from a societal perspective (including criminal justice system-related costs), DAA at 20% with MAT+ at 80% was the most effective intervention and was cost saving. While DAA at 20% with MAT+ at 80% was more expensive (eg, less cost saving) than MAT+ at 80% alone without DAA, it offered a favorable value compared to MAT+ at 80% alone ($23 932/QALY). CONCLUSIONS: When considering health-sector costs alone, DAA alone was the most cost-effective intervention. However, with criminal justice system-related costs, DAA and MAT+ implemented together became the most cost-effective intervention.

Setting ambitious targets for surveillance and treatment rates among patients with hepatitis C related cirrhosis impacts the cost-effectiveness of hepatocellular cancer surveillance and substantially increases life expectancy: A modeling study.

BACKGROUND: Hepatocelluar cancer (HCC) is the leading cause of death among people with hepatitis C virus (HCV)-related cirrhosis. Our aim was to determine the optimal surveillance frequency for patients with HCV-related compensated cirrhosis. METHODS: We developed a decision analytic Markov model and validated it against data from the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) study group and published epidemiologic studies. Four strategies of different surveillance intervals were compared: no surveillance and ultrasound surveillance every 12, 6, and 3 months. We estimated lifetime survival, life expectancy, quality adjusted life years (QALY), total costs associated with each strategy, and incremental cost effectiveness ratios. We applied a willingness to pay threshold of $100,000. Analysis was conducted for two scenarios: a scenario reflecting current HCV and HCC surveillance compliance rates and treatment use and an aspirational scenario. RESULTS: In the current scenario the preferred strategy was 3-month surveillance with an incremental cost-effectiveness ratio (ICER) of $7,159/QALY. In the aspirational scenario, 6-month surveillance was preferred with an ICER of $82,807/QALY because treating more people with HCV led to a lower incidence of HCC. Sensitivity analyses suggested that surveillance every 12 months would suffice in the particular circumstance when patients are very likely to return regularly for testing and when appropriate HCV and HCC treatment is readily available. Compared with the current scenario, the aspirational scenario resulted in a 1.87 year gain in life expectancy for the cohort because of large reductions in decompensated cirrhosis and HCC incidence. CONCLUSIONS: HCC surveillance has good value for money for patients with HCV-related compensated cirrhosis. Investments to improve adherence to surveillance should be made when rates are suboptimal. Surveillance every 12 months will suffice when patients are very likely to return regularly for testing and when appropriate HCV and HCC treatment is readily available.

Budget Impact Analysis of Eliglustat for the Treatment of Gaucher Disease Type 1 in the United States.

BACKGROUND: Gaucher disease type 1 (GD1) is a rare, genetic, lysosomal storage disease with no cure. Current treatment options include intravenous (IV) enzyme replacement therapy ([ERT]; imiglucerase, velaglucerase alfa, or taliglucerase alfa) or oral substrate reduction therapy ([SRT]; eliglustat or miglustat). The cost to U.S. payers of an IV-administered drug can vary depending on the site of care (i.e., home, outpatient clinic, or hospital setting). Treatment with oral eliglustat may present an opportunity for cost savings. OBJECTIVE: To evaluate the budget impact from a U.S. payer perspective associated with transitioning patients receiving ERTs to the oral SRT eliglustat for the treatment of adults with GD1. METHODS: A budget impact model estimated the change in pharmaceutical and administration costs resulting from increasing the market share of eliglustat from 12% (current) to 44% (new). The market share for eliglustat was drawn equally from existing shares of imiglucerase (40%) and velaglucerase alfa (40%) and assumed to be static over the analysis period. ERT costs were adjusted to account for site of care-based markup and the proportion of patients receiving infusions in each site of care (home, infusion center, or hospital outpatient). Annual ERT costs were calculated assuming a biweekly dose of 47.4 U per kg, a 72-kg patient weight, and 24 infusions per year. The effect of key variables was tested in the sensitivity analyses. All costs are expressed in 2017 U.S. dollars. RESULTS: In a new plan with 5 million members and 25 GD1 treated patients, increased use of eliglustat resulted in an annual savings of $1,526,710 and a total savings of $4,580,130 (13.6%) over 3 years. The corresponding annual per member per month savings was $0.025. This is further illustrated in the sensitivity and scenario analyses where the use of eliglustat was cost saving in all cases. Shifting more patients receiving ERT in the hospital outpatient setting to eliglustat resulted in increased savings. CONCLUSIONS: Based on these analyses, increased use of eliglustat resulted in meaningful cost savings to a payer's overall budget. Cost savings are highest among patients switching from ERT administered in a hospital outpatient setting. The results suggest that cost savings are also likely achievable from initiating patients on oral eliglustat instead of infusion-based therapy from the outset of treatment. DISCLOSURES: This study was sponsored by Sanofi Genzyme. Evidera received funding from Sanofi Genzyme to conduct this study and prepare the manuscript. The sponsor collaborated on the study design, analysis, interpretation of results, and writing of the manuscript. Nalysnyk is an employee of and shareholder in Sanofi Genzyme. Ward, Cele, and Uyei are employees of Evidera, which provides consulting and other research services to biopharmaceutical companies. Sugarman was also an Evidera employee when the study was being conducted and the manuscript written. This study was presented as a poster at the Academy of Managed Care Pharmacy Nexus 2016, October 3-6, 2016; National City, MD, and at the International Society for Pharmacoeconomics and Outcomes Research, 22nd Annual International Meeting; May 20-24, 2017; Boston, MA.

Using value of information methods to determine the optimal sample size for effectiveness trials of alcohol interventions for HIV-infected patients in East Africa.

BACKGROUND: Unhealthy alcohol consumption exacerbates the HIV epidemic in East Africa. Potential benefits of new trials that test the effectiveness of alcohol interventions could not be evaluated by traditional sampling methods. Given the competition for health care resources in East Africa, this study aims to determine the optimal sample size given the opportunity cost of potentially re-allocating trial funds towards cost-effective alcohol treatments. METHODS: We used value of information methods to determine the optimal sample size by maximizing the expected net benefit of sampling for a hypothetical 2-arm intervention vs. control randomized trial, across ranges of policymaker's willingness-to-pay for the health benefit of an intervention. Probability distributions describing the relative likelihood of alternative trial results were imputed based on prior studies. In the base case, policymaker's willingness-to-pay was based on a simultaneously resource-constrained priority (routine HIV virological testing). Sensitivity analysis was performed for various willingness-to-pay thresholds and intervention durations. RESULTS: A new effectiveness trial accounting for the benefit of more precise decision-making on alcohol intervention implementation would benefit East Africa $67,000 with the optimal sample size of 100 persons per arm under the base case willingness-to-pay threshold and intervention duration of 20 years. At both a conservative willingness-to-pay of 1 x GDP/capita and a high willingness-to-pay of 3 x GDP/capita for an additional health gain added by an alcohol intervention, a new trial was not recommended due to limited decision uncertainty. When intervention duration was 10 or 5 years, there was no return on investment across suggested willingness-to-pay thresholds. CONCLUSIONS: Value of information methods could be used as an alternative approach to assist the efficient design of alcohol trials. If reducing unhealthy alcohol use is a long-term goal for HIV programs in East Africa, additional new trials with optimal sample sizes ranging from 100 to 250 persons per arm could save the opportunity cost of implementing less cost-effective alcohol strategies in HIV prevention. Otherwise, conducting a new trial is not recommended.

Effects of naloxone distribution alone or in combination with addiction treatment with or without pre-exposure prophylaxis for HIV prevention in people who inject drugs: a cost-effectiveness modelling study.

BACKGROUND: In the USA, an epidemic of opioid overdose deaths is occurring, many of which are from heroin. Combining naloxone distribution with linkage to addiction treatment or pre-exposure prophylaxis (PrEP) for HIV prevention through syringe service programmes has the potential to save lives and be cost-effective. We estimated the outcomes and cost-effectiveness of five alternative strategies: no additional intervention, naloxone distribution, naloxone distribution plus linkage to addiction treatment, naloxone distribution plus PrEP, and naloxone distribution plus linkage to addiction treatment and PrEP. METHODS: We developed a decision analytical Markov model to simulate opioid overdose, HIV incidence, overdose-related deaths, and HIV-related deaths in people who inject drugs in Connecticut, USA. Model input parameters were derived from published sources. We compared each strategy with no intervention, as well as simultaneously considering all strategies. Sensitivity analysis was done for all variables. Linkage to addiction treatment was referral to an opioid treatment programme for methadone. Endpoints were survival, life expectancy, quality-adjusted life-years (QALYs), number and percentage of overdose deaths averted, number of HIV-related deaths averted, total costs (in 2015 US$) associated with each strategy, and incremental cost per QALY gained. FINDINGS: In the base-case analysis, compared with no additional intervention, the naloxone distribution strategy yielded an incremental cost-effectiveness ratio (ICER) of $323 per QALY, and naloxone distribution plus linkage to addiction treatment was cost saving compared with no additional intervention (greater effectiveness and less expensive). The most efficient strategies (ie, those conferring the greatest health benefit for a particular budget) were naloxone distribution combined with linkage to addiction treatment (cost saving), and naloxone distribution combined with PrEP and linkage to addiction treatment (ICER $95 337 per QALY) at a willingness-to-pay threshold of $100 000. In probabilistic sensitivity analysis, the combination of naloxone distribution, PrEP, and linkage to addiction treatment was the optimal strategy in 37% of iterations and the combination of naloxone distribution and linkage to addiction treatment was the optimal strategy in 34% of iterations. INTERPRETATION: Naloxone distribution through syringe service programmes is cost-effective compared with syringe distribution alone, but when combined with linkage to addiction treatment is cost saving compared with no additional services. A strategy that combines naloxone distribution, PrEP, and linkage to addiction treatment results in greater health benefits in people who inject drugs and is also cost-effective. FUNDING: State of Connecticut Department of Public Health and the National Institute of Mental Health.

Integrated delivery of HIV and tuberculosis services in sub-Saharan Africa: a systematic review.

Tuberculosis is a major cause of morbidity and mortality in people with HIV and about a quarter of HIV-related deaths are attributed to tuberculosis. In this Review we identify and synthesise published evidence for the effectiveness and cost-effectiveness of eight integrated strategies recommended by WHO that represent coordinated delivery of HIV and tuberculosis services. Evidence supports concurrent screening for tuberculosis and HIV, and provision of either co-trimoxazole during routine tuberculosis care or isoniazid during routine HIV care and at voluntary counselling and testing centres. Although integration of antiretroviral therapy into tuberculosis care has shown promise for improving health outcomes for patients, evidence is insufficient to make conclusive claims. Evidence is also insufficient on the accessibility of condoms at tuberculosis facilities, the benefits of risk reduction counselling in patients with tuberculosis, and the effectiveness of tuberculosis infection control in HIV health-care settings. The vertical response to the tuberculosis and HIV epidemics is ineffective and inefficient. Implications for policy makers and funders include further investments in implementing integrated tuberculosis and HIV programmes with known effectiveness, preferably in a way that strengthens health systems; evaluative research that identifies barriers to integration; and research on integrated strategies for which effectiveness, efficiency, and affordability are not well established.