A phase 1/2 trial to evaluate the pharmacokinetics, safety, and efficacy of NI-03 in patients with chronic pancreatitis: study protocol for a randomized controlled trial on the assessment of camostat treatment in chronic pancreatitis (TACTIC).

BACKGROUND: Chronic pancreatitis (CP) is a progressive, fibro-inflammatory disease characterized by enzymatic autoactivation and subsequent fibrotic replacement of acinar cells. A significant proportion of patients develop pain, which may be due to many causes, including perineural inflammation, altered central processing of pain signals, parenchymal structural changes, and ductal obstruction. Currently there are no approved medical treatment options for CP-associated pain. NI-03 (camostat mesilate) is an orally administered serine protease inhibitor that reduces pancreatic enzyme activity and has been widely used for the treatment of CP-associated pain in Japan. The current study will assess the safety and efficacy of NI-03 for reduction of CP-associated pain in the USA. METHODS: The current study consists of two phases. First, a phase I study will be performed to establish the pharmacokinetics and safety profile over a 1-week period following a single dose (100, 200, or 300 mg). Subsequently, a phase II study will be performed consisting of a double-blind, randomized, controlled trial (RCT). This RCT will evaluate the efficacy of each of the three doses of NI-03 given three times daily compared to placebo over 28 days. A 7-day, single-blind, run-in period will precede the double-blind phase to assess baseline pain characteristics. The primary efficacy outcome is the average of worst daily pain scores (numeric rating scale of 0-10) over the terminal 7 days of the study period compared to baseline. Secondary efficacy outcomes include change in opioid dose and quality of life measures, and time to first rescue intravenous analgesic. Adverse events will be recorded. DISCUSSION: NI-03 has been used successfully and safely in Japan to treat CP-associated pain. The aim of the current study is to assess the safety and efficacy of NI-03 using a rigorous RCT in a population in the USA. This study may fill an important clinical gap to provide an effective medical treatment option for CP-associated pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02693093 . Registered through the National Institutes of Health on 26 February 2016.

Status of use of protease inhibitors for the prevention and treatment of pancreatitis after endoscopic retrograde cholangiopancreatography: An epidemiologic analysis of the evidence-practice gap using a health insurance claims database.

Existing evidence suggests that protease inhibitors (PIs) used to prevent or treat pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) are ineffective, and their use is not recommended by clinical practice guidelines. However, in Japan, PIs are administered with the aim to prevent or treat post-ERCP pancreatitis. This study aimed to clarify the gap between guideline recommendations and contents of practice. We used the health insurance claims database of Japan Medical Data Center. Among patients who had undergone ERCP, those with acute pancreatitis or post-ERCP pancreatitis recorded in claims as disease names were defined as post-ERCP pancreatitis patients. The study period was divided into three terms according to the date of publication of clinical practice guidelines for acute pancreatitis. Among 2,945 patients who had undergone ERCP, 2,847 were eligible for analysis. Of these, 1,375 (48.3%) patients had claims with pancreatitis recorded as the disease name; PIs were prescribed to 1,238 (90.0%). Rates of prescription of PIs were 72.3% in 2005-07, 70.9% in 2008-09, and 83.6% in 2010-15, showing a significant increase (p < 0.001). In conclusion, PIs are administered in clinical practice in Japan for the purpose of preventing or treating pancreatitis, with an increasing trend in prescription in recent years.

Hepatitis C in Brazil: lessons learned with boceprevir and telaprevir.

In 2012, the first-generation protease inhibitors telaprevir (TVR) and boceprevir (BOC) were introduced in the Brazilian health system for treatment of chronic hepatitis C, after their approval by the National Committee for Health Technology Incorporation (CONITEC). However, these medicines were discontinued in 2015. The short period of use in therapy and their high cost require a discussion about the consequences for patients and for the health system of the early incorporation of new therapies. The article presents a qualitative analysis of the incorporation process of both medications in Brazil and the results of a multicenter study that included patients treated with BOC or TVR between January 2011 and December 2015 in five Brazilian cities. The study included 855 patients (BOC: n=247) and (TVR: n=608). The document analysis showed that CONITEC's decision to incorporate BOC and TVR was based on results of phase III clinical trials that compared sustained virologic response (SVR) rates of patients treated with BOC and TVR with rates of those that received placebo. However, these studies included a low percentage of cirrhotic patients. The SVR rates observed in this multicenter study were worse than clinical trials pointed out (BOC: 45.6%; TVR: 51.8%), but similar to those achieved with previously adopted therapies. The discontinuation rate due to adverse events was (BOC: 15.4%; TVR: 12.7%). Based on these unsatisfactory results, the study brings a discussion that goes beyond the therapy outcomes, exploring the incorporation of these high-cost medicines and the related decision-making process, contributing to future decisions in medicine policies and in the treatment of chronic hepatitis C.

Cost Effectiveness of Daclatasvir Plus Asunaprevir Therapy for Chinese Patients with Chronic Hepatitis C Virus Genotype 1b.

BACKGROUND AND OBJECTIVES: Daclatasvir plus asunaprevir has shown superior efficacy and safety for treating hepatitis C virus genotype 1b infection in comparison with pegylated interferon and ribavirin. The objective of this analysis is to investigate the cost effectiveness of daclatasvir plus asunaprevir compared with interferon-α-based therapies from the perspective of the Chinese healthcare system. METHODS: A Markov model was established to measure economic and health outcomes of daclatasvir plus asunaprevir compared with general interferon-α plus ribavirin and pegylated interferon plus ribavirin for hepatitis C virus genotype 1b infection. We also considered the two following scenarios: 24 weeks of daclatasvir plus asunaprevir used as a second-line treatment for ineligible/intolerant and non-responding patients with HCV during 48 weeks of first-line interferon-α plus ribavirin (interferon-α plus ribavirin and daclatasvir plus asunaprevir) or pegylated interferon plus ribavirin (pegylated interferon plus ribavirin and daclatasvir plus asunaprevir) treatment. Clinical costs and utility inputs were derived from the published literature. The incremental cost-effectiveness ratio was shown as costs in US dollars per quality-adjusted life-years gained. Uncertainty was examined by one-way and probabilistic sensitivity analyses. RESULTS: Compared with interferon-α plus ribavirin, pegylated interferon and ribavirin, interferon-α plus ribavirin plus daclatasvir plus asunaprevir, and pegylated interferon plus ribavirin plus daclatasvir plus asunaprevir strategies, daclatasvir plus asunaprevir gained an additional 0.62, 0.32, 0.20, and 0.15 quality-adjusted life-year with increasing costs of US$11,950, US$671, US$8366, and -$3783, respectively. The incremental cost-effectiveness ratios of pegylated interferon and ribavirin, daclatasvir plus asunaprevir, interferon-α plus ribavirin and daclatasvir plus asunaprevir, and pegylated interferon plus ribavirin and daclatasvir plus asunaprevir against the baseline interferon-α plus ribavirin strategy were US$37,930, US$19,233, US$8495, and US$33,031 per quality-adjusted life-year gained. Daclatasvir plus asunaprevir and interferon-α plus ribavirin plus daclatasvir plus asunaprevir were presented as the cost-effective alternatives, and pegylated interferon plus ribavirin and pegylated interferon plus ribavirin and daclatasvir plus asunaprevir strategies dominated. The model outputs were sensitive to a patient's age, discount rate, and the risk ratio between pegylated interferon plus ribavirin and interferon-α plus ribavirin. CONCLUSIONS: Daclatasvir plus asunaprevir in the Chinese setting is likely to be cost effective for treating hepatitis C virus genotype 1b infection.

Cost-effectiveness of PCSK9 inhibition in addition to standard lipid-lowering therapy in patients at high risk for vascular disease.

BACKGROUND: As proprotein convertase subtilisin-kexin type 9 (PCSK9) monoclonal antibodies are entering the market, we assessed the cost-effectiveness of PCSK9 inhibition added to standard lipid-lowering therapy in patient groups at high risk for major adverse cardiovascular events (MACE). METHODS: A lifetime Markov Model was designed to estimate healthcare costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) for PCSK9 inhibition added to standard therapy in patients with Familial Hypercholesterolemia (FH), patients with vascular disease at high MACE recurrence risk, and patients with vascular disease with diabetes mellitus. The balance between costs and health outcomes was established for a broad range of potential relative risk reductions and drug costs. RESULTS: The expected QALY gain per patient and ICER in the main scenario were 1.4 QALYs for €78,485/QALY gained in patients with FH, 0.22 QALYs for €176,735/QALY gained in those with vascular disease and a predicted risk of MACE ≥30% in 10years, and 0.22 QALYs for €295,543/QALY gained in those with vascular disease and diabetes. Results were sensitive to assumptions on PCSK9 inhibitor treatment efficacy, and vascular event risks. CONCLUSION: The costs and effects of PCSK9 inhibition added to standard lipid-lowering treatment in patient groups at high risk for MACE can be estimated and adapted to a specific clinical setting. PCSK9 inhibition could be cost-effective in patients with FH. In patients with vascular disease PCSK9 inhibition is less cost-effective, however, a price development may change clinical practice. This model may aid treatment and reimbursement decisions regarding PCSK9 inhibitors.

Seguridad y eficacia de telaprevir en pacientes con hepatitis crónica por virus hepatitis C que han recibido terapia dual con peginterferón alfa y ribavirina / Safety and efficacy of telaprevir in patients with chronic hepatitis C virus who have received dual therapy with peginterferon alfa and ribavirin

INTRODUCCIÓN: Antecedentes: El presente informe expone la evaluación del Telaprevir en pacientes con diagnóstico de Hepatitis Crónica por virus e Hepatitis C que han fallado o no han tenido respuesta adecuada con la terapia dual de Peginterferón alfa y Ribavirina, con el objetivo de lograr respuesta viral sostenida. Aspectos Generales: La Hepatitits C crónica es un problema a nivel mundial, que puede causar enfermedad aguda y crónica. El proceso agudo es autolimitado, rara vez causa falla hepática y usualmente suele progresar a enfermedad crónica, el cual tiene un curso que suele culminar en cirrosis hepática o carcinoma hepatocelular y teniendo finalmente la necesidad de trasplante hepático. El virus de la Hepatitis C se divide en 6 genotipos, los genotipos 1 y 4 son los más comunes, pero los genotipos 2 y 3 responden mejor al tratamiento antirretroviral que los serotipos 1 y 4. Tecnología Sanitaria de Interés: Telaprevir: Telaprevir es un inhibidor de proteasa, una enzima esencial para la replicación del VHC, el cual bloquea la acción de la enzima NS3-4a proteasa del virus de hepatitis C, esencial para su ciclo de vida. METODOLOGÍA: Estrategia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de Telaprevir en pacientes con diagnóstico de Hepatitis Crónica por virus de Hepatite C en pacientes con tratamiento previo dual con peginterferón alfa 2ao 2b asociado a ribavirina. Se realizó un búsqueda primaria de inforamación generada por Guías de Práctica Clínica (GPC) a través de los metabuscadores: Translating Research into Practice (TRIPDATABASE) y National Library of Medicine (Pubmed-Medline). Posteriormente, se realizó una búsqueda dentro de los grupos internacionales que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) tales como la Cochrane Library, The National Institute for Health and Care Excellence (NICE), The National Guideline of Clearinghouse, The Canadian Agency for Drugs and Technologies in Health (CADTH), The Scottish Medicines Consortium (SMC). RESULTADOS: Por cada uno de los desenlaces se presenta la evidencia disponible en Guías de Práctica Clínica Revisiones Sistemáticas y Ensayos clínicos. CONCLUSIONES: De acuerdo a la revisión de la información científica existente, se concluye que el fármaco Telaprevir administrado en dosis de 750mg, 03 veces al día (cada 8 horas) por 12 semanas asociado a peginterferón alfa y ribavirina, en pacientes con hepatitis crónica por virus de hepatitis C que han fallado o no han tenido respuesta adecuada con la terapia dual. Los estudios muestran que los pacientes que usaron Telaprevenir lograron una tasa de respuesta viral sostenida (RVS) mayor respecto a los pacientes que usaron terapia dual. Asimismo, se mostró que en los grupos que recibieron telaprevir el desarrollo de eventos adversos y abandono de tratamiento fue mayor. El tratamiento con terapia triple está indicado prioritariamente en pacientes con fibrosis significativa METAVIR F3-F4.En pacientes con fibrosis METAVIR F2 es importante considerar el tratamiento temprano. El tratamiento antiviral de pacientes con cirrosis hepática solo está indicadp en pacientes con enfermedad hepática compensada (estadio CHILD-PUGH A). El Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI, aprueba temporalmente el uso de telaprevir como tratamiento de base en la terapia triple junto a peginterferón alfa y ribavirina en aquel paciente que ha recibido terapia dual con peginterferón alfa 2a o 2b asociado a ribavirina y que no ha tenido respuesta adecuada, llámese respuesta nula, respuesta pacial o con recaída. Existe al momento nuevas alternativas que están ingreando al mercado peruano con aparente mejor perfil de eficacia y seguridadd, se considera que el efecto de telaprevir se evaluará con los datos obtenidos de los pacientes que hayan recibido teleprevir por un lapso de un año a fin de determinar el impacto de su uso en los desenlaces clínicos de interés de este dictamen. Esta información será tomada en cuenta la re-evaluación de este medicamento para efectos de un nuevo dictamen al terminar la vigencia del presente Dictamen Preliminar.

Hepatitis C, disease and its management: a cost-effectiveness analysis of the new generation oral protease inhibitors.

BACKGROUND: Hepatitis C, caused by a single-stranded RNA virus, has become a global health problem. Infecting millions of individuals in the United States alone, chronic HCV infection can lead to devastating medical problems including cirrhosis and hepatocellular carcinoma. These problems create millions of dollars in health-care costs for treatment and management. This study determines the cost-effectiveness of hepatitis C treatment with the new generation of oral protease inhibitors. METHODS: A Markov model was constructed to simulate the progression of genotype-1 chronic hepatitis C disease in a cohort of 50-year-old patients. A decision tree, along with the Markov model, was then used to determine duration of disease, treatment success, progression of disease and mortality. At the end of each stage in the model, the cost and quality-adjusted life years (QALY) were summed for each individual. These were then used to calculate the overall cost-effectiveness ratio (CER) using QALY as the unit of effectiveness. Four treatment options were modelled: sofosbuvir with pegylated interferon-α and ribavirin (SOF/PEG-IFN+RBV), sofosbuvir with ribavirin (SOF/RBV), simeprevir with pegylated interferon-α and ribavirin (SMV/PEG-IFN+RBV) and simeprevir with sofosbuvir (SMV/SOF). RESULTS: SOF/PEG-IFN+RBV yielded a CER ratio of $6,796.22/QALY, SMV/PEG-IFN+RBV of $7,642.60/QALY and SMV/SOF of $8,959.11/QALY. SOF/RBV had a higher CER of $16,295.30/QALY. It is important to note however that SMV/SOF had the highest QALY at 19.08. CONCLUSIONS: After consideration of quality of life, treatment regimens and treatment side effects, the SMV/SOF regimen yields acceptable cost-effectiveness ratios with high QALY.

Veruprevir, ritonavir, ombitasvir e dasabuvir para o tratamento de hepatite C crônica causada por infecção pelo genótipo 1 do HCV / Veruprevir, ritonavir, ombitasvir and dasabuvir for the treatment of chronic hepatitis C caused by HCV genotype 1 infection

Contexto: A hepatite C é uma doença sistêmica crônica caracterizada por processo inflamatório hepático crônico que se inicia alguns meses depois da infecção e, ao longo de décadas leva a dano celular contínuo, comprometimento do funcionamento hepático e a quadros clínicos de fibrose, cirrose e carcinoma hepatocelular. Além disso, a doença se caracteriza por manifestações sistêmicas extra-hepáticas de natureza predominantemente linfoproliferativa, como a crioglobulinemia. O Ministério da Saúde elaborou e disponibilizou, em julho de 2015, Protocolo Clínico e Diretrizes Terapêuticas (PCDT) para o tratamento da doença e o SUS faz a oferta de toda a linha de cuidado prevista no referido protocolo, que inclui além do diagnóstico, o tratamento por meio de medicamentos com associações entre antivirais de ação direta para todos os genótipos do vírus da hepatite C. Atualmente experimentou-se uma rápida evolução no tratamento da hepatite C, observando-se grande quantidade de estudos clínicos, pedidos de patentes e de registros em Agências reguladoras de medicamentos em todo o mundo, de forma que o monitoramento do horizonte tecnológico épeça fundamental na avaliação de medicamentos para a incorporação em sistemas de saúde como o SUS. O medicamento em análise nesse relatório, uma associação entre três antivirais de ação direta, é indicada para o tratamento de hepatite C causada por infecção pelo genótipo 1 em indivíduos não tratados previamente ou em falhos de tratamento prévio com peguinterferon e ribavirina. Evidências científicas: Não foram identificados estudos de comparação direta entre o medicamento que é alvo da proposta de incorporação e os medicamentos que estão incorporados ao SUS. Dessa forma, com o objetivo de avaliar a eficácia dos tratamentos para hepatite C baseados em associações entre antivirais de ação direta disponíveis no Brasil e outros países do mundo, foram avaliados 52 estudos entre intervencionais e observacionais. Avaliaram-se estudos que incluíam pacientes com fibrose avançada e cirrose, além de outras populações como os coinfectados com HIV, doentes renais crônicos, pós-transplantados e indivíduos com doença hepática avançada. Com relação à eficácia dos medicamentos, as taxas de resposta identificadas para indivíduos não tratados previamente e falhos de resposta prévia a interferon foram muito semelhantes (90 a 100%) para os medicamentos avaliados, entretanto, alguns dos medicamentos demonstraram ação mais pronunciada no subtipo 1b, associada à necessidade da adição de ribavirina e aumento do tempo de tratamento para melhorar as taxas de resposta no subtipo 1a. Alguns dos tratamentos avaliados mantêm altas taxas de resposta em indivíduos com cirrose. A combinação entre veruprevir, ritonavir, ombitasvir e dasabuvir não foi estudada em indivíduos falhos de tratamento prévio com inibidores de protease ou com sofosbuvir ou mesmo naqueles com doença hepática avançada (cirrose descompensada). Em indivíduos pós-transplantados, essa combinação foi estudada em pacientes com grau de fibrose menor que F2 em comparação com outros tratamentos que tiveram a eficácia avaliada em populações com maior dano hepático. . Em indivíduos com HIV, não se incluíram nos estudos clínicos com veruprevir, ritonavir, ombitasvir e dasabuvir aqueles que faziam uso de efavirenz, antiviral de primeira linha de uso no Brasil. Já os estudos com essa associação em pacientes com doença renal crônica incluíram poucos pacientes limitando a conclusões sobre a eficácia desse tratamento nessa população. Além disso, a associação entre veruprevir, ritonavir, ombitasvir e dasabuvir não é pangenotípica e é atualmente indicada para o genótipo 1 apenas, possui baixa barreira à resistência e o tratamento envolve maior número de comprimidos e posologia mais desfavorável, com duas administrações diárias, o que implicaria em aumento da complexidade do tratamento para o paciente e provável repercussão na adesão, em um momento em que a tendência para o tratamento dessa doença é eliminar os chamados coquetéis de medicamentos e simplificar o diagnóstico por meio da utilização de tratamentos pangenotípicos. Decisão: A decisão de não incorporação foi publicada no DOU nº 222, de 20 de novembro de 2015 por meio da Portaria N° 66 de 19 de novembro de 2015.

Esquemas con ombitasvir, paritaprevir y ritonavir en pacientes con hepatitis C / Ombitasvir, Paritaprevir and Ritonavir Regimens in Hepatitis C Patients

INTRODUCCIÓN: La infección crónica por el virus de la hepatitis C (VHC) es una de las principales causas de cirrosis y carcinoma hepatocelular. El VHC es un virus ARN que posee seis genotipos (1 a 6) siendo el genotipo 1 el más frecuente en Argentina. El objetivo principal de la terapia es curar la infección, lo cual se denomina respuesta virológica sostenida (RVS) y se refleja a través de la medición indetectable de ARN del VHC en sangre después de finalizada la terapia. El tratamiento con interferón pegilado asociado a ribavirina (RBV) fue durante muchos años el principal esquema de tratamiento. Actualmente aparecieron nuevos esquemas más eficaces y seguros e inclusive capaces de ser administrados en sujetos con cirrosis descompensada como sofosbuvir+simeprevir, sofosbuvir+ledipasvir, sofosbuvir+daclatasvir, daclatasvir+asunaprevir, ombitasvir, paritaprevir y ritonavir (OPR)+dasabuvir (DSV) entre otros. Se postula el uso de esquemas con OPR para el tratamiento de la hepatitis C crónica debido a que se podrían obtener mayores tasas de RVS, con menos efectos adversos y menor duración de tratamiento. TECNOLOGÍA: Ombistavir y Paritaprevir son inhibidores de la proteasa NS3/4a y NS5A del VHC que se administran combinados a un inhibidor del metabolismo de paritaprevir (ritonavir) en un comprimido. Usualmente se combina este esquema con DSV que es un inhibidor de la protesasa NS5B del VHC. OBJETIVO: Evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de esquemas con ombistavir, paritaprevir y ritonavir en pacientes con hepatitis C. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas (incluyendo Medline, Cochrane y CRD), en buscadores genéricos de Internet, agencias de evaluación de tecnologías sanitarias y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS) y económicas, guías de práctica clínica (GPC) y políticas de cobertura (PC) de otros sistemas de salud cuando estaban disponibles. RESULTADOS: Para pacientes no cirróticos sin tratamiento previo se seleccionaron cinco ECAs y con tratamiento previo tres ECAs; para pacientes cirróticos sin tratamiento previo se inluyó un ECA y con tratamiento previo otro ECA. Además se identificaron cinco GPC, tres ETS y cinco PC. CONCLUSIONES: La evidencia es abundante y de buena calidad. Los esquemas con ombitasvir, paritaprevir y ritonavir con o sin dasabuvir han demostrado lograr altas tasas de respuesta viral sostenida en diferentes grupos de pacientes, incluyendo pacientes cirróticos, con genotipos de VHC 1 y 4, comparables con la eficacia observada para otros esquemas con nuevas drogas. Aunque se encuentra contemplado por distintas guías de práctica clínica y evaluaciones de tecnologías sanitarias identificadas, su alto costo podría limitar la disponibilidad del tratamiento.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection is one of the main causes of cirrhosis and hepatocellular carcinoma. HCV is an RNA virus with six genotypes (1 to 6); genotype 1 being the most frequent in Argentina. The main objective of this therapy is to cure infection, which is called sustained virologic response (SVR) and it is reflected by measuring undetectable HCV RNA in blood once therapy is finished. Treatment with pegylated interferon combined with ribavirin (RBV) has been the main management scheme for many years. New, more efficacious and safer regimens such as sofosbuvir+simeprevir, sofosbuvir+ledipasvir, sofosbuvir+daclatasvir, daclatasvir+asunaprevir, ombitasvir, paritaprevir and ritonavir (OPR)+dasabuvir (DSV) among others have currently appeared; they can be administered even to subjects with decompensated cirrhosis. OPR regimens have been proposed for the treatment of chronic hepatitis C because better SVR rates could be obtained, with less adverse effect and shorter treatment duration. TECHNOLOGY: Ombistavir and Paritaprevir are HCV NS3/4a and NS5A protease inhibitors, administered in combination with a paritaprevir metabolism inhibitor (ritonavir) in a single tablet. In general, this regimen is combined with DSV, which is a HCV NS5B protease inhibitor. PURPOSE: To assess the available evidence on the efficacy, safety and coverage policy related aspect on the use of ombistavir, paritaprevir and ritonaviren regimens for the management of patients with hepatitis C. METHODS: A bibliographic search was carried out on the main databases (such as MEDLINE, Cochrane and CRD), in general Internet engines, in health technology assessment agencies and health sponsors. Priority was given to the inclusion of systematic reviews (SRs); controlled, randomized clinical trials (RCTs); health technology assessment (HTA) documents and economic evaluations; clinical practice guidelines (GCPs) and coverage policies (CPs) of other health systems, when available. RESULTS: For non-cirrhotic treatment-naive patients, five RCTs were selected and for those with prior treatment, three RCTs; for cirrhotic treatment-naive patients one RCT was included and for those with prior treatment another RCT was included. Furthermore, five CPGs, three HTA documents and five CPs were selected. CONCLUSIONS: There is abundant and good quality evidence. Ombitasvir, paritaprevir and ritonavir regimens with or without dasabuvir have proved to achieve high sustained virologic response rates in the different patient groups, including cirrhotic patients with genotype 1 and 4 HCV, comparable with the efficacy observed with other regimens with new drugs. Although they are no considered in the different Clinical Practice Guidelines and Health Technology Assessment documents identified, their high cost could limit treatment availability.

Ethical assessment of hepatitis C virus treatment: The lesson from first generation protease inhibitors.

Since chronic hepatitis C has mostly become curable, issues concerning choice and allocation of treatment are of major concern. We assessed the foremost ethical issues in hepatitis C virus therapy with 1st generation protease inhibitors using the personalist ethical framework within the health technology assessment methodology. Our aim was to identify values at stake/in conflict and to support both the physicians' choices in hepatitis C therapy and social (macro-) allocation decision-making. The ethical assessment indicates that: (1) safety/effectiveness profile of treatment is guaranteed if its use is restricted to the patients subgroups who may benefit from it; (2) patients should be carefully informed, particularly on treatment deferral, and widespread information on these therapies should be implemented; (3) since treatment was proven to be cost-effective, its use is acceptable respecting resource macro-allocation. Concerning individual (micro-) location criteria: (a) criteria for eligibility to treatment should be clearly identified and updated periodically; (b) information on criteria for eligibility/deferral to treatment for specific patients' subgroups should be made widely known. Interferon-based regimens will disappear from use within the next year, with the introduction of highly effective/tolerable combination regimens of direct-acting antivirals, thus profoundly changing social choices. Nonetheless, our model could support future ethical assessment since the evaluation pertaining ethical domains remains generally applicable.

Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.

Cost-effectiveness analysis of triple therapy with protease inhibitors in treatment-naive hepatitis C patients.

BACKGROUND: Chronic hepatitis C is the leading cause of chronic liver disease, representing a significant burden in terms of morbidity, mortality and costs. A new scenario of therapy for hepatitis C virus (HCV) genotype 1 infection is being established with the approval of two effective HCV protease inhibitors (PIs) in combination with the standard of care (SOC), peginterferon and ribavirin. OBJECTIVE: Our objective was to estimate the cost effectiveness of combination therapy with new PIs (boceprevir and telaprevir) plus peginterferon and ribavirin versus SOC in treatment-naive patients with HCV genotype 1 according to data obtained from clinical trials (CTs). METHODS: A Markov model simulating chronic HCV progression was used to estimate disease treatment costs and effects over patients' lifetimes, in the Spanish national public healthcare system. The target population was treatment-naive patients with chronic HCV genotype 1, demographic characteristics for whom were obtained from the published pivotal CTs SPRINT and ADVANCE. Three options were analysed for each PI based on results from the two CTs: universal triple therapy, interleukin (IL)-28B-guided therapy and dual therapy with peginterferon and ribavirin. A univariate sensitivity analysis was performed to evaluate the uncertainty of certain parameters: age at start of treatment, transition probabilities, drug costs, CT efficacy results and a higher hazard ratio for all-cause mortality for patients with chronic HCV. Probabilistic sensitivity analyses were also carried out. RESULTS: Incremental cost-effectiveness ratios (ICERs) of €2012 per quality-adjusted life-year (QALY) gained were used as outcome measures. According to the base-case analysis, using dual therapy as the comparator, the alternative IL28B-guided therapy presents a more favorable ICER (€18,079/QALY for boceprevir and €25,914/QALY for telaprevir) than the universal triple therapy option (€27,594/QALY for boceprevir and €33,751/QALY for telaprevir), with an ICER clearly below the efficiency threshold for medical interventions in the Spanish setting. Sensitivity analysis showed that age at the beginning of treatment was an important factor that influenced the ICER. A potential reduction in PI costs would also clearly improve the ICER, and transition probabilities influenced the results, but to a lesser extent. Probabilistic sensitivity analyses showed that 95 % of the simulations presented an ICER below €40,000/QALY. Post hoc estimations of sustained virological responses of the IL28B-guided therapeutic option represented a limitation of the study. CONCLUSION: The therapeutic options analysed for the base-case cohort can be considered cost-effective interventions for the Spanish healthcare framework. Sensitivity analysis estimated an acceptability threshold of the IL28B-guided strategy of patients younger than 60 years.

Protease inhibitors for hepatitis C: economic implications.

Chronic hepatitis C virus (HCV) infection, a blood-borne virus, is the leading cause of chronic liver disease and liver transplantation worldwide. Chronic HCV infection is usually asymptomatic in the early stages of the disease, making an estimation of the total population affected difficult to elicit. The gold standard treatment option to date has been a combination of pegylated interferon and ribavirin. Recent developments have led to the introduction of two protease inhibitors for use in chronic HCV-boceprevir and telaprevir. Phase III studies have shown both agents have the potential to significantly increase the probability of attaining a sustained virologic response (the primary outcome of interest in chronic HCV) in genotype 1 infections. However, the added cost of these agents also presents the need for decision makers to determine their place on drug formularies. The protease inhibitors are to be administered as triple therapy with the existing gold standard. However, significant variation exists as to the proposed duration of triple therapy, use of lead-in pegylated interferon and ribavirin and subsequent pegylated interferon therapy after finishing the course of triple therapy. Treatment algorithms also exist for the use of stopping rules in the case of early non-responders.The aim of this review is to highlight the current understanding of the economic impact protease inhibitors may have on health care systems and considerations required in the treatment of HCV. Economic and health-related quality of life issues are addressed from multiple viewpoints. The major aspects of the economic evaluations, to date, that included triple therapy as an alternative in the treatment of chronic HCV are brought to light. Future economic evaluations in alternative settings would be useful. The review also emphasizes the challenges for future research. This includes the potential for new therapies to no longer require inclusion of pegylated interferon and/or ribavirin, as well as the use of protease inhibitors in non-genotype 1 patients or those with significant co-morbidities such as HIV/AIDS.

The efficiency of continuous regional intra-arterial infusion in the treatment of infected pancreatic necrosis.

OBJECTIVE: Our aim was to investigate the efficiency of continuous regional intra-arterial infusion (CRAI) with antisecretory agents and antibiotics in the treatment of infected pancreatic necrosis. MATERIALS AND METHODS: CRAI was used as a new clinical technique to treat acute pancreatitis patients during a 4-year period at the First Affiliated Hospital, Wenzhou Medical College, China. In this retrospective study, thirty-four patients with proven infected pancreatic necrosis were included. Twelve patients were treated with CRAI, and were matched according to age, sex, APACHE II scores, Ranson scores and remote organ dysfunction, with 22 patients with IPN treated surgically. The clinical outcome following surgery and CRAI were compared. RESULTS: No difference was found between the two groups when comparing age, gender, APACHE II scores, Ranson scores and remote organ dysfunction (p > 0.05). The patients treated with CRAI had a lower incidence of complications (33.3% vs 72.7%), duration of hospitalization (27.1 ± 4.7 days vs 43.0 ± 12.0 days) and cost of hospitalization (4.09 ± 1.64 thousand RMB vs 8.77 ± 3.74 thousand RMB) as compared to patients treated with surgery (p < 0.05). The survival rate was significantly higher in the CRAI group as compared to the surgical group (91.7% vs 63.6%; p < 0.01). However, the two groups had similar rates of concomitant operative treatment and incidence of remote organ dysfunction (p > 0.05). CONCLUSIONS: CRAI or CRAI in combination with abscess drainage seemingly improve the clinical outcome in patients with infected pancreatic necrosis. Further confirmative prospective randomized multicenter studies are warranted prior to broad introduction of the CRAI concept.

Triple therapy with first generation HCV protease inhibitors: lead-in or no lead-in phase?

The standard therapeutic approach currently recommended for patients infected with genotype 1 hepatitis C virus (HCV) is the triple therapy combining pegylated interferon (PEG-IFN), ribavirin (RBV)and NS3/NS4 protease inhibitors, boceprevir or telaprevir [1]. Protease inhibitors (PIs) are direct acting antiviral drugs (DAA) which, when added to PEG-IFN and RBV, are able to achieve a significant gain in terms of sustained virological response (SVR), both in naïve and treatment-experienced patients [2­5]. The use of these new molecules, despite its in contestable benefits, reveals on the other hand new challenges: the emergence of variants with reduced sensitivity to PIs, the development of new or higher rate of side effects, drug to drug interactions, and significant increase in the overall cost of antiviral therapy. Among the two DAAs commonly used in combination with PEG-IFN and RBV (PEG-IFN/RBV) for the treatment of genotype 1 HCV patients, boceprevir has been licensed with a lead-in phase, while telaprevir has been licensed without. EMA approved regimens of both drugs are reported in Figs. 1 and 2. The lead-in phase represents an initial period of 4 weeks of dual therapy with PEG-IFN/RBV, in standard doses, followed by triple therapy. The concept of lead-in phase was initiated by the Schering­Plough company in order to improve efficacy of boceprevir-based triple therapy. Indeed, by lowering HCV RNA level, a short course of PEG-IFN/RBV may theoretically reduce the risk of viral breakthrough or resistance. However, there is still much controversy regarding the utility of the lead-in phase, some authors advocating its role in improving, and/or predicting triple therapy effectiveness, while others view it as a useless complication of the therapeutic regimen, its chief disadvantage being the inconvenience to the patient.

Optimizing HIV treatment.

PURPOSE OF REVIEW: There are at least seven million people eligible for antiretroviral treatment but not receiving it. An additional 19 million people will need to start treatment in the future, as their HIV disease progresses. Funding for Universal Access to HIV treatment has been restricted by the Global Financial Crisis. RECENT FINDINGS: There are three large randomized trials ongoing, designed to establish the efficacy of lower than approved doses of antiretrovirals. If successful, the results of these trials could lower costs of antiretrovirals and improve the safety profiles. Clinical trials evaluating efavirenz, atazanavir, ritonavir and stavudine are discussed. The costs of these and other antiretrovirals are presented. SUMMARY: The results of these trials could significantly lower the costs of Universal Access. Assuming 15 million people on antiretroviral treatment, the reduction in unit costs of tenofovir (TDF)/3TC/efavirenz from dose optimization of efavirenz to 400 mg once daily would save US$16 per person, leading to an overall saving of US$192 million per year. The switch from zidovudine (ZDV)/3TC/atazanavir (ATV)/r 300/100 once daily to dolutegravir along with ATV/r 200/50 once daily would save US$267 per person, leading to an overall saving of US$801 million. The combined saving in costs from first- and second-line treatment would therefore be US$993 million per year.

Cost-effective screening for acute hepatitis C virus infection in HIV-infected men who have sex with men.

BACKGROUND: We used a Monte Carlo computer simulation to estimate the effectiveness and cost-effectiveness of screening for acute hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected men who have sex with men. METHODS: One-time screening for prevalent HCV infection was performed at the time of enrollment in care, followed by either symptom-based screening, screening with liver function tests (LFTs), HCV antibody (Ab) screening, or HCV RNA screening in various combinations and intervals. We considered both treatment with pegylated interferon and ribavirin (PEG/RBV) alone and with an HCV protease inhibitor. Outcome measures were life expectancy, quality-adjusted life expectancy, direct medical costs, and cost-effectiveness, assuming a societal willingness to pay $100000 per quality-adjusted life-year (QALY) gained. RESULTS: All strategies increased life expectancy (from 0.49 to 0.94 life-months), quality-adjusted life expectancy (from 0.47 to 1.00 quality-adjusted life-months), and costs (from $1900 to $7600), compared with symptom-based screening. The incremental cost-effectiveness ratio of screening with 6-month LFTs and a 12-month HCV Ab test, compared with symptom-based screening, was $43 700/QALY (for PEG/RBV alone) and $57 800/QALY (for PEG/RBV plus HCV protease inhibitor). The incremental cost-effectiveness ratio of screening with 3-month LFTs, compared with 6-month LFTs plus a 12-month HCV Ab test, was $129 700/QALY (for PEG/RBV alone) and $229 900/QALY (for PEG/RBV plus HCV protease inhibitor). With HCV protease inhibitor-based therapy, screening with 6-month LFTs and a 12-month HCV Ab test was the optimal strategy when the HCV infection incidence was ≤1.25 cases/100 person-years. The 3-month LFT strategy was optimal when the incidence was >1.25 cases/100 person-years. CONCLUSIONS: Screening for acute HCV infection in HIV-infected MSM prolongs life expectancy and is cost-effective. Depending on incidence, regular screening with LFTs, with or without an HCV Ab test, is the optimal strategy.

Inibidores de protease (boceprevir e telaprevir) para o tratamento da hepatite crônica C / Protease inhibitors (boceprevir and telaprevir) for the treatment of chronic hepatitis C

ASPECTOS EPIDEMIOLÓGICOS E SOCIAIS: A infecção pelo vírus da hepatite C (HCV) é uma das causas mais frequentes de doença crônica do fígado. O HCV é responsável por 70% das hepatites crônicas, 40% dos casos de cirrose e 60% dos hepatocarcinomas. Além disso, a hepatite C é a primeira causa de transplante hepático no mundo. A progressão da infecção pelo HCV até a fase de cirrose hepática ocorre usualmente de maneira assintomática em média entre 20 e 30 anos de evolução da doença. Sem tratamento, aproximadamente 20% dos doentes com hepatite crônica C desenvolvem cirrose e destes, 20 a 30% progridem para o carcinoma hepatocelular ou para a insuficiência hepática com indicação de transplante. No Brasil, aproximadamente 70.000 casos de hepatite crônica C foram confirmados entre os anos de 1999 e 2010. A taxa média de detecção foi de 4,5 casos por 100 mil habitantes no ano de 2010, sendo as maiores taxas identificadas nas regiões Sul (7,2) e Sudeste (6,8). A maioria dos casos ocorreu nas faixas etárias superiores a 35 anos de idade (80.7%). De acordo com o último inquérito nacional, a prevalência de exposição ao HCV em populações de 10 a 69 anos variou de 0,7 a 2,1% no nosso país. Na última década, a hepatite C foi a principal causa de morte no Brasil entre as hepatites virais. Entre os anos de 2000 e 2010, aproximadamente 14.900 mortes foram atribuídas à infecção pelo HCV5. Esse número quase se duplica quando se considera o HCV também como condição que contribuiu para a morte, perfazendo um total de 27.231 mortes no mesmo período de dez anos. GENÓTIPOS DO VÍRUS DA HEPATITE C E RESPOSTA TERAPÊUTICA: O HCV é classificado em seis genótipos principais (designados 1 a 6) e diversos subtipos com base na heterogeneidade da seqüência genômica. Os genótipos 1, 2 e 3 têm uma distribuição mundial; entre eles, os subtipos 1a e 1b são os mais comuns, representando 60% das infecções no mundo. No Brasil, Campioto e col estudaram a distribuição dos genótipos em diferentes cidades e mostraram que aproximadamente 65% dos portadores crônicos do HCV eram do genótipo 1; 30% do genótipo 3; e menos de 5% apresentavam os genótipos 2, 4 e 5. O genótipo do HCV constitui um dos mais importantes preditores de resposta ao tratamento antiviral e de duração da terapia. De maneira geral, 40 a 50% dos pacientes com genótipo 1 apresentam uma resposta virológica sustentada ao tratamento com interferon peguilado alfa combinado com ribavirina. Por outro lado, os pacientes com genótipos 2 e 3 respondem numa porcentagem de aproximadamente 80%, frente a este esquema de tratamento. TRATAMENTO DOS INDIVÍDUOS INFECTADOS COM O GENÓTIPO 1 DA HEPATITE CRÔNICA C: O objetivo primário do tratamento é prevenir as complicações da infecção pelo HCV, o que é principalmente obtido pela erradicação do vírus no sangue. Assim, a resposta ao tratamento é freqüentemente caracterizada por resultados de testes de detecção do RNA do HCV (HCV-RNA) no soro. O principal marcador de evolução de doença na hepatite C crônica é representado pelo estadiamento de fibrose hepática, dado pela biópsia. O escore de fibrose METAVIR é considerado o mais amplamente validado para este fim, na literatura. Pacientes com METAVIR F0 = tem fígado normal, F1 = alargamento por fibrose restrito ao espaço porta (fibrose discreta), F2 = fibrose em espaço porta e com septos incompletos no parênquima hepático (fibrose clinicamente significante), F3 = fibrose com septos completos e esboço de nódulos (fibrose avançada) e F4 = formação de nódulos completos, com distorção significativa da morfologia do parênquima hepático, caracterizando cirrose. Esta forma de estadiamento é fundamental para se estimar o prognóstico da doença para complicações clínicas e óbito, além de ser o principal critério para a indicação de tratamento farmacológico. Em razão da lenta progressão da doença, o sucesso do tratamento é normalmente indicado por desfecho substituto denominado resposta virológica sustentada (RVS), definida por níveis não detectáveis de HCV-RNA 6 meses após o término do tratamento. A RVS é validada como marcador da resolução definitiva da infecção, uma vez que inúmeros estudos confirmam a forte correlação entre esse marcador e a intensa redução de desfechos clínicos a longo prazo. Dessa forma, quando a ocorrência de desfechos clínicos são monitorados ao longo de anos após o tratamento, observa-se que pessoas que atingiram RVS apresentam uma redução importante na mortalidade, progressão de doença e desenvolvimento de carcinoma hepatocelular, equiparando-se a população não infectada pelo HCV do mesmo sexo e faixa etária. O esquema atualmente recomendado no Brasil para tratamento e retratamento de pacientes infectados cronicamente pelo genótipo 1 do HCV é a associação de interferon peguilado e ribavirina (PR), por 48 a 72 semanas. INIBIDORES DE PROTEASE PARA TRATAMENTO DE HEPATITE CRÔNICA C: Nos últimos anos, ensaios clínicos utilizando agentes antivirais de ação direta contra o HCV, têm mostrado que os inibidores de protease (IP) são uma estratégia eficaz para o tratamento do genótipo 1. Boceprevir (BOC) e Telaprevir (TVR) são os primeiros IP para tratamento do HCV e foram recentemente registrados na ANVISA, permitindo sua introdução no arsenal terapêutico nacional. Essas duas medicações apresentam moléculas diferentes e atuam inibindo a enzima protease serina NS3 do HCV, agindo diretamente sobre o vírus da Hepatite C através do bloqueio da sua replicação. Ambos são utilizados em associação com PR, constituindo assim uma terapia tripla. CARACTERÍSTICAS DO BOCEPREVIR: A eficácia de BOC no tratamento da hepatite crônica C (genótipo 1) foi avaliada em aproximadamente 1.700 indivíduos adultos não tratados previamente (SPRINT-2) ou que apresentaram falha ao tratamento anterior com PR (RESPOND-2. Em todos os ensaios clínicos de fase III publicados e apresentados até a presente data, a adição de BOC ao esquema contendo PR aumentou significativamente as taxas de RVS quando comparada ao tratamento padrão. CARACTERÍSTICAS DO TELAPREVIR: A eficácia do TVR no tratamento da hepatite crônica C (genótipo 1) foi avaliada em aproximadamente 2.290 indivíduos adultos não tratados previamente ou que apresentaram falha ao tratamento anterior com PR. Em todos esses estudos de fase III, a adição de TVR ao esquema contendo PR aumentou significativamente as taxas de RVS quando comparadas as obtidas com o tratamento padrão. POLÍTICA DE INCORPORAÇÃO: A incorporação dos inibidores da protease para tratamento da hepatite C crônica, portadores do HCV genótipo 1, no Sistema Único de Saúde não ocorrerá apenas com sua inclusão nas diretrizes terapêuticas do Ministério da Saúde. Além das recomendações baseadas no uso racional de medicamentos, outras estratégias compõem a política de introdução dos novos medicamentos. Entre elas, devem ser destacadas: a) autorização centralizada que permite controlar as prescrições nos Comitês Estaduais; b) estabelecimento de fluxos para disponibilização dos medicamentos e c) definição do perfil dos serviços públicos que possuem experiência no tratamento da hepatite C, garantindo abordagem técnica adequada, também fazem parte desta política. Desde 2006, o DDSTAIDSHV vem estabelecendo a política para uso de antirretrovirais de terceira linha recentemente incorporados no país, que inclui a autorização para seu uso por câmaras técnicas estaduais para análise das indicações de antirretrovirais. A recente integração da resposta programática em AIDS e Hepatites e a rede de serviços ainda restrita para tratamento das Hepatites Virais levaram à inclusão dos serviços de AIDS no atendimento a portadores de hepatites. DIRETRIZES DE USO: Tratando-se de uma intervenção de recente desenvolvimento, com pouco tempo de experiência, necessidade de restrição de serviços para garantia de seu adequado manejo, elevado custo e estimativa de razão de custo-efetividade favorável para pacientes com fibrose mais avançada, a estratégia de incorporação dos IP deve estabelecer como prioridade pacientes com maior risco de progressão de doença e morte, definido pelo grau de fibrose F3 ou F4 ou evidências endoscópicas ou ecográficas de cirrose hepática. Pacientes com classificação de fibrose ≤ F2 que possuam indicação de tratamento devem receber o tratamento convencional, de acordo com o PCDT para hepatite C e coinfecções, atualizado em Julho de 2011. Portanto, a indicação de inibidores da protease proposta no Brasil inclui os pacientes com grau de fibrose 3 e 4, considerando dois grupos de pacientes: a) pacientes sem tratamento prévio (virgens de tratamento); b) retratamento daqueles que não responderam previamente ao tratamento convencional (PR) ­ recidivantes, não respondedores parciais e nulos de resposta. DECISÃO: PORTARIA SCTIE-MS N.º 20, de 25 de julho de 2012 - Torna pública a decisão de incorporar os inibidores de protease telaprevir e boceprevir para tratamento da hepatite crônica C no Sistema Único de Saúde (SUS).