Budget impact analysis of two treatment approaches for hepatitis C in Malaysia through the use of voluntary and compulsory licensing options.

Introduction: A scaled-up treatment cascade with direct-acting antiviral (DAA) therapy is necessary to achieve global WHO targets for hepatitis C virus (HCV) elimination in Malaysia. Recently, limited access to sofosbuvir/daclatasvir (SOF/DAC) is available through compulsory licensing, with access to sofosbuvir/velpatasvir (SOF/VEL) expected through voluntary licensing due to recent agreements. SOF/VEL has superior clinical outcomes but has higher drug acquisition costs compared to SOF/DAC. A stratified treatment cascade might be the most cost-efficient approach for Malaysia whereby all HCV patients are treated with SOF/DAC except for patients with cirrhosis who are treated with SOF/VEL. Methods: This study aimed to conduct a 5-year budget impact analysis of the proposed stratified treatment cascade for HCV treatment in Malaysia. A disease progression model that was developed based on model-predicted HCV epidemiology data was used for the analysis, where all HCV patients in scenario A were treated with SOF/DAC for all disease stages while in scenario B, SOF/DAC was used only for non-cirrhotic patients and SOF/VEL was used for the cirrhotic patients. Healthcare costs associated with DAA therapy and disease stage monitoring were included to estimate the downstream cost implications. Results: The stratified treatment cascade with 109 in Scenario B was found to be cost-saving compared to Scenario A. The cumulative savings for the stratified treatment cascade was USD 1.4 million over 5 years. Discussion: A stratified treatment cascade with SOF/VEL was expected to be cost-saving and can result in a budget impact reduction in overall healthcare expenditure in Malaysia.

Cognitive assessment in patients with Hepatitis C submitted to treatment with Sofosbuvir and Simeprevir or Daclatasvir.

BACKGROUND: Hepatitis C can be defined as an infectious disease that develops an inflammatory activity, which may cause an impairment in the central nervous system, may cause cognitive impairments and symptoms of depression. OBJECTIVE: The objective of this study was to verify the cognitive performance of patients with chronic hepatitis C before and after treatment with simeprevir, sofosbuvir, and daclatasvir. METHODS: A prospective study was carried out in three stages: before, right after treatment, and six months after. Fifty-eight patients under clinical follow-up were evaluated at the Emílio Ribas Infectology Institute, in São Paulo, Brazil. The following instruments were used: sociodemographic questionnaire, Lawton's Scale, Beck's Depression Inventory, and a battery of neuropsychological tests that evaluated: intellectual function, memory, attention, executive function, and motor and processing speed). For statistical analysis, the analyses described (mean, frequency, and standard deviation), chi-square, and ANOVA were used. RESULTS: Most of the participants were male (n=30, 51.7%), with a mean of 58.23±8.79 years, mean schooling of 9.75±4.43 years. Comparing the results of neuropsychological evaluations (before, just after completion of drugs, and six months), a significant improvement was observed in relation to the acquisition of new knowledge (p=0.03), late visual memory (p=0.01), and tendency towards alternate attention (p=0.07). CONCLUSION: The treatment of the hepatitis C virus improved cognitive performance, especially in relation to memory.

Decentralized care with generic direct-acting antivirals in the management of chronic hepatitis C in a public health care setting.

BACKGROUND & AIMS: The prevalence of anti-hepatitis C virus antibody in Punjab, India is 3.6%, with 728,000 people estimated to have viremic chronic hepatitis C (CHC). The Mukh-Mantri Punjab Hepatitis C Relief Fund, launched on 18th June 2016, provides no-cost generic direct-acting antivirals (DAAs) with sofosbuvir + ledipasvir ±â€¯ribavirin or sofosbuvir + daclatasvir ±â€¯ribavirin with the goal of eliminating CHC from Punjab. We assessed the safety and efficacy of decentralized treatment of CHC in a public health care setting. METHODS: Primary care providers from 3 university and 22 district hospitals were trained to provide algorithm-based DAA treatment and supervised by telehealth clinics conducted fortnightly. The diagnosis of cirrhosis was based on clinical and radiological evidence, including aspartate aminotransferase-to-platelet ratio index (APRI ≥2.0) and FIB-4 score (>3.25), or on liver stiffness measurement ≥12.5 kPa on Fibroscan®. RESULTS: We enrolled 48,088 individuals with CHC (63.8% male; mean age 42.1 years; 80.5% rural; 14.8% compensated cirrhosis; 69.9% genotype [GT] 3) between 18th June 2016 to 31st July 2018. While 36,250 (75.4%) patients completed treatment, 5,497 (11.4%) had treatment interruptions and 6,341 (13.2%) patients are currently ongoing treatment. Sustained virological response at 12 weeks after treatment completion (SVR12) was achieved in 91.6% of patients per protocol, 67.6% in intention-to-treat (ITT) analysis, where all interruptions were treated as failures, and 91.2% in a modified ITT analysis where all patients with successful SVR12 in the interruptions arm were included as cured. SVR12 rates in patients with and without cirrhosis and GT3 versus non-GT3 were comparable. The SVR12 rate was 84.4% in patients who had treatment interruptions. CONCLUSION: Decentralized care of patients with CHC using generic all-oral DAA regimens is safe and effective regardless of genotype or presence of cirrhosis. ClinicalTrials.gov number: NCT01110447. LAY SUMMARY: We assessed the safety and efficacy of public health care using no-cost all-oral generic direct-acting antiviral drugs against hepatitis C in the state of Punjab, India. The goal is elimination of chronic hepatitis C (CHC) by 2030 and involves primary care providers at 25 sites in the state. We enrolled 48,088 individuals (63.8% male; mean age 42.1 years; 80.5% rural; 14.8% compensated cirrhotic; 69.9% genotype 3) between 18th June 2016 to 31st July 2018. Cure was achieved in 91.6% of patients, demonstrating that decentralized care of CHC with generic all-oral regimens is safe and effective.

Cost-effectiveness of generic pan-genotypic sofosbuvir/velpatasvir versus genotype-dependent direct-acting antivirals for hepatitis C treatment.

BACKGROUND AND AIM: Treatment of hepatitis C virus (HCV) infection with low-cost generic direct-acting antivirals (DAAs) available in India and other developing countries needs determination of HCV genotype ("genotype-dependent" regimens). Generic velpatasvir, a DAA that obviates the need for genotype determination ("pan-genotypic" regimen), recently became available but is costlier. The aim of this study was to evaluate the cost-effectiveness of genotype-dependent versus pan-genotypic DAA treatments in India. METHODS: A previously validated microsimulation model, adapted to Indian population, was used to compare the costs and long-term outcomes of three scenarios: no treatment, treatment with genotype-dependent regimens, and treatment with pan-genotypic regimen. Input parameters were derived from literature. Using a payer's perspective and lifetime time horizon, quality-adjusted life-years (QALYs), total costs, and incremental cost-effectiveness ratio were calculated. Both deterministic and probabilistic sensitivity analyses were also conducted. RESULTS: At the current price ($US223 for 4 weeks), pan-genotypic regimen was cost-saving compared with no treatment. Compared with genotype-dependent regimens, it increased QALYs by 0.92 and increased costs by $US107 but was deemed cost-effective with an incremental cost-effectiveness ratio of $US242 per QALY gained. Probabilistic sensitivity analysis also supported the cost-effectiveness of pan-genotypic regimen. At the reduced price of $US188 for 4 weeks, the pan-genotypic regimen will become cost-neutral to genotype-dependent regimens (current price: $US100 for 4 weeks). CONCLUSIONS: At current prices, velpatasvir-based pan-genotypic regimen is cost-effective for HCV treatment in India where generic drugs are available. A reduction in the prices of pan-genotypic regimen has the potential to make its use cost-saving while simplifying treatment in community-level programs aimed at HCV elimination.

Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.

BACKGROUND: In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. AIM: To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. METHODS: In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9 months, 3-9 months and 4.5 months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles. RESULTS: The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73 m2 /month, P = 0.03) independently of the pre-treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child-Pugh B and C vs lower stages, P = 0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). CONCLUSION: The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients.

[Current drug treatment of hepatitis C : Useful therapy algorithms taking into consideration economical aspects]. / Aktuelle Arzneimitteltherapie der Hepatitis C : Sinnvolle Therapiealgorithmen unter Berücksichtigung ökonomischer Aspekte.

Treatment of chronic hepatitis C (HCV) has changed dramatically since the approval of the direct-acting antivirals (DAA). Depending on the HCV genotype and the stage of liver disease, sustained HCV clearance can be achieved in more than 95% of patients with a treatment duration of 8-12 weeks in most of the cases. The selection and combination of the drugs depends on previous antivirals therapies, the stage of liver fibrosis, HCV genotype and subtype, viral load at baseline, and renal function. Nowadays, potent antiviral therapy with minimal side effects can be offered to almost every patient. In the real-world setting, a high quality of HCV therapy considering economic aspects has been documented in the German Hepatitis C Registry. A reduction of clinical complications of chronic liver disease by clearance of HCV has already been documented.

Benefit-risk assessment for sofosbuvir/velpatasvir/voxilaprevir based on patient population and hepatitis C virus genotype: U. S. Food and Drug Administration's evaluation.

On July 18, 2017, the U.S. Food and Drug Administration (FDA) approved sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) (Vosevi) fixed-dose combination (FDC), an interferon-free, complete regimen for adult patients with chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have: • genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing a nonstructural protein 5A (NS5A) inhibitor; and • genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor. Approval was based on an acceptable safety profile and high sustained virological response rates 12 weeks after the end of treatment (SVR12) in two phase 3 clinical trials in subjects previously treated with a direct-acting antiviral (DAA) regimen. In POLARIS-1, 96% of SOF/VEL/VOX-treated subjects achieved SVR12. In POLARIS-4, 98% of SOF/VEL/VOX-treated subjects achieved SVR12. A key and challenging question in evaluating the data was determining the contribution of VOX to SOF/VEL and how this differed depending on the genotype and patient population. In this article, we provide our perspective on the issues considered in making these determinations, especially regarding the POLARIS-4 data in subjects who have previously been treated with a chronic HCV regimen containing sofosbuvir without an NS5A inhibitor. Conclusion: We seek to provide context as to why a broad indication was given for NS5A inhibitor-experienced patients (HCV genotypes 1-6) while the indication for NS5A inhibitor- naïve patients was limited to HCV genotypes 1a and 3 only. (Hepatology 2018;67:482-491).

Curing Chronic Hepatitis C: A Cost Comparison of the Combination Simeprevir Plus Sofosbuvir vs. Protease-Inhibitor-Based Triple Therapy

ABSTRACT Introduction. Interferon-free, multi-direct acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection is highly effective and well tolerated, but costly. To gain perspective on the evolving economics of HCV therapy, we compared the cost per cure of a multi-DAA regimen with the prior standard of triple therapy. Material and methods. Patients infected with HCV genotype 1 who were treated through the University of Colorado Hepatology Clinic between May 2011 and December 2014 comprised the study population. The multi-DAA regimen of simeprevir plus sofosbuvir (SMV/SOF) was compared to the triple therapy regimen consisting of peginterferon and ribavirin, with either boceprevir or telaprevir (TT). Sustained-virologic response (SVR) rates, total costs per treatment and adverse events were recorded. Total cost per SVR were compared for the two treatments, controlling for patient demographics and clinical characteristics. Results. One hundred eighty-three patients received SMV/SOF (n = 70) or TT (n = 113). Patients receiving SMV/SOF were older, more treatment experienced, and had a higher stage of fibrosis. SVRs were 86% and 59%, average total costs per patient were $152,775 and $95,943, and average total costs per SVR were $178,237 vs. $161,813.49 for SMV/SOF and TT groups, respectively. Medication costs accounted for 98% of SMV/SOF and 85% of TT treatment costs. Conclusion. The high cure rate of multi-DAA treatment of HCV is offset by the high costs of the DAAs, such that the cost per cure from TT to multi-DAA therapy has been relatively constant. In order to cure more patients, either additional financial resources will need to be allocated to the treatment of HCV or drug costs will need to be reduced.

The Role of e-Health in Optimizing Task-Shifting in the Delivery of Antiviral Therapy for Chronic Hepatitis C.

PURPOSE: Recently, we reported the successful application of task-shifting to improve the management of patients with chronic hepatitis C virus (HCV) infection receiving treatment with direct-acting antiviral (DAA) agents in underserved areas of California. We assessed the impact of e-health on task-shifting in our treatment model. METHODS: In a retrospective analysis, we reviewed the impact of e-health on optimizing the delivery of DAA-based regimen to HCV-infected patients in outreach clinics in medically underserved areas of California. A nonphysician healthcare provider worked in close conjunction with a hepatologist to monitor the patients during the course of antiviral therapy. We exclusively used our institution-based, secured e-health portal as the means of communication with the local staff and patients in outreach clinics. RESULTS: From January 2015 to June 2016, we treated over 100 HCV-infected patients with DAA-based regimens using the task-shifting model. During the study period, we did not experience any delay in the care of our patients undergoing treatment with DAA agents. Communication with the patient and staff using e-health was prompt, secured, and documented in electronic medical records. Due to the optimization of task-shifting by e-health and safety/tolerability of DAA, 95% patients did not need a follow-up clinic visit during the treatment. Return clinic visits during the treatment were unrelated to DAA use or associated with ribavirin-related anemia. In addition, we noted improvement in access and capacity of our outreach clinic. CONCLUSIONS: We report a positive impact of e-health in optimizing task-shifting for DAA in HCV-infected patients in underserved outreach clinics. More importantly, a secondary improvement in access and capacity of our clinic was noted.

Curing Chronic Hepatitis C: A Cost Comparison of the Combination Simeprevir Plus Sofosbuvir vs. Protease-Inhibitor-Based Triple Therapy.

INTRODUCTION: Interferon-free, multi-direct acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection is highly effective and well tolerated, but costly. To gain perspective on the evolving economics of HCV therapy, we compared the cost per cure of a multi-DAA regimen with the prior standard of triple therapy. MATERIAL AND METHODS: Patients infected with HCV genotype 1 who were treated through the University of Colorado Hepatology Clinic between May 2011 and December 2014 comprised the study population. The multi-DAA regimen of simeprevir plus sofosbuvir (SMV/SOF) was compared to the triple therapy regimen consisting of peginterferon and ribavirin, with either boceprevir or telaprevir (TT). Sustained-virologic response (SVR) rates, total costs per treatment and adverse events were recorded. Total cost per SVR were compared for the two treatments, controlling for patient demographics and clinical characteristics. RESULTS: One hundred eighty-three patients received SMV/SOF (n = 70) or TT (n = 113). Patients receiving SMV/SOF were older, more treatment experienced, and had a higher stage of fibrosis. SVRs were 86% and 59%, average total costs per patient were $152,775 and $95,943, and average total costs per SVR were $178,237 vs. $161,813.49 for SMV/SOF and TT groups, respectively. Medication costs accounted for 98% of SMV/SOF and 85% of TT treatment costs. CONCLUSION: The high cure rate of multi-DAA treatment of HCV is offset by the high costs of the DAAs, such that the cost per cure from TT to multi-DAA therapy has been relatively constant. In order to cure more patients, either additional financial resources will need to be allocated to the treatment of HCV or drug costs will need to be reduced.

Assessment of the clinical cardiac drug-drug interaction associated with the combination of hepatitis C virus nucleotide inhibitors and amiodarone in guinea pigs and rhesus monkeys.

In 2015, European and U.S. health agencies issued warning letters in response to 9 reported clinical cases of severe bradycardia/bradyarrhythmia in hepatitis C virus (HCV)-infected patients treated with sofosbuvir (SOF) in combination with other direct acting antivirals (DAAs) and the antiarrhythmic drug, amiodarone (AMIO). We utilized preclinical in vivo models to better understand this cardiac effect, the potential pharmacological mechanism(s), and to identify a clinically translatable model to assess the drug-drug interaction (DDI) cardiac risk of current and future HCV inhibitors. An anesthetized guinea pig model was used to elicit a SOF+AMIO-dependent bradycardia. Detailed cardiac electrophysiological studies in this species revealed SOF+AMIO-dependent selective nodal dysfunction, with initial, larger effects on the sinoatrial node. Further studies in conscious, rhesus monkeys revealed an emergent bradycardia and bradyarrhythmia in 3 of 4 monkeys administered SOF+AMIO, effects not observed with either agent alone. Morever, bradycardia and bradyarrhythmia were not observed in rhesus monkeys when intravenous infusion of MK-3682 was completed after AMIO pretreatment. CONCLUSIONS: These are the first preclinical in vivo experiments reported to replicate the severe clinical SOF+AMIO cardiac DDI and provide potential in vivo mechanism of action. As such, these data provide a preclinical risk assessment paradigm, including a clinically relevant nonhuman primate model, with which to better understand cardiovascular DDI risk for this therapeutic class. Furthermore, these studies suggest that not all HCV DAAs and, in particular, not all HCV nonstructural protein 5B inhibitors may exhibit this cardiac DDI with amiodarone. Given the selective in vivo cardiac electrophysiological effect, these data enable targeted cellular/molecular mechanistic studies to more precisely identify cell types, receptors, and/or ion channels responsible for the clinical DDI. (Hepatology 2016;64:1430-1441).

Adoption of new agents and changes in treatment patterns for hepatitis C: 2010-2014.

OBJECTIVES: A number of new hepatitis C virus (HCV) medications have become available in the United States, but little is known about how these treatments have been adopted into practice and their financial burden on patients. The aim of this study was to examine whether the introduction of new HCV medications was associated with changes in treatment rates and out-of-pocket (OOP) costs. STUDY DESIGN: Retrospective analysis of administrative claims data from Optum Labs Data Warehouse. METHODS: We performed a retrospective analysis using a large, US commercial insurance database to identify 56,116 adults with chronic HCV between January 1, 2010, and December 31, 2014. Logistic regression was performed to calculate patients' predicted probability of being treated before and after the new medications became available. RESULTS: A total of 5436 (9.7%) of patients with HCV received treatment during an average of 1.8 years of follow-up. In the last quarter of 2014, 0.1% of patients with HCV received interferon/ribavirin as the primary treatment; no one received boceprevir or telaprevir, 1.1% received sofosbuvir combined with simeprevir, 1.4% received sofosbuvir or simeprevir alone, and 2.0% received ledipasvir/sofosbuvir. The introduction of new medications was significantly associated with an increased treatment rate, from 5.4% to 6.8% (P < .001). The increase was high among elderly patients and patients with liver transplant, liver cancer, and liver disease or cirrhosis. The median OOP costs of patients receiving new regimens were relatively low ($112-$340), but great variations existed. CONCLUSIONS: At the end of 2014, patients were almost exclusively using new therapies, which was associated with increased treatment rate, especially among patients who may need urgent treatment but are intolerant or ineligible for interferon-based regimens.

Use of sofosbuvir-based direct-acting antiviral therapy for hepatitis C viral infection in patients with severe renal insufficiency.

Sofosbuvir-based direct-acting antiviral therapy revolutionized the treatment of hepatitis C virus (HCV) infection. However, sofosbuvir use is not approved for patients with severe renal insufficiency (estimated glomerular filtration (eGFR) rate below 30 ml/min) or end-stage renal disease (ESRD) based on concerns raised during premarket animal testing over hepatobiliary and cardiovascular toxicity in this population. We report the first published data on use of sofosbuvir-based regimens in patients with severe renal insufficiency and ESRD, focusing on clinical efficacy and safety. Six patients were treated with full dose sofosbuvir; three received sofosbuvir and simeprevir, two received sofosbuvir and ribavirin, and one received sofosbuvir, ribavirin, and interferon. Three of the patients had cirrhosis. On-treatment viral suppression was 100% and sustained virological response (SVR) rate at 12 weeks was 67%. One patient had to discontinue antiviral therapy early due to side effects. No hepatobiliary or cardiovascular toxicity was reported.

Therapy for hepatitis C genotype 3: moving forward.

Until recently, the standard of care for hepatitis C virus genotype 3 infection was response-guided therapy with pegylated interferon plus ribavirin for 16 to 48 or 72 weeks. The introduction of sofosbuvir plus ribavirin has revolutionized hepatitis C virus therapy. Nowadays, the recommend treatment regimen is a combination of sofosbuvir and a weight-based ribavirin dose for 24 weeks. For easy to treat patients (e.g. naïve or previously treated patients without cirrhosis), this combination achieves high sustained virologic response rates and is well tolerated. However, in treatment-experienced patients with cirrhosis, sustained virologic response is lower due to unknown reasons. The combination of two direct-acting antiviral agents, sofosbuvir and daclatasvir, for 12 weeks is also associated with low sustained virologic response rates in this special population, for whom new drugs and different strategies are now under evaluation. Currently, the high cost of all these drugs limits access to treatment in many countries.