Assessment of the Potential Adverse Events Related to Ribavirin-Interferon Combination for Novel Coronavirus Therapy.

PURPOSE: We aimed to analyze and evaluate the safety signals of ribavirin-interferon combination through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS), so as to provide reference for the rationale use of these agents in the management of relevant toxicities emerging in patients with novel coronavirus pneumonia (COVID-19). METHODS: Reports to the FAERS from 1 January 2004 to 8 March 2020 were analyzed. The proportion of report ratio (PRR), reporting odds ratio (ROR), and Bayesian confidence interval progressive neural network (BCPNN) method were used to detect the safety signals. RESULTS: A total of 55 safety signals were detected from the top 250 adverse event reactions in 2200 reports, but 19 signals were not included in the drug labels. All the detected adverse event reactions were associated with 13 System Organ Classes (SOC), such as gastrointestinal, blood and lymph, hepatobiliary, endocrine, and various nervous systems. The most frequent adverse events were analyzed, and the results showed that females were more likely to suffer from anemia, vomiting, neutropenia, diarrhea, and insomnia. CONCLUSION: The ADE (adverse drug event) signal detection based on FAERS is helpful to clarify the potential adverse events related to ribavirin-interferon combination for novel coronavirus therapy; clinicians should pay attention to the adverse reactions of gastrointestinal and blood systems, closely monitor the fluctuations of the platelet count, and carry out necessary mental health interventions to avoid serious adverse events.

Risk of De Novo Hepatocellular Carcinoma Following Use of Direct Acting Antiviral Medications for Treatment of Chronic Hepatitis C.

Direct-acting antivirals (DAA) are now the mainstay of treatment for patients with chronic hepatitis C virus (HCV); however, there is some controversy over whether use of DAAs for HCV, as compared with IFN-based regimens, leads to an increased risk for hepatocellular carcinoma (HCC) development. We investigated the association between use of DAAs and subsequent development of HCC in longitudinal data from patients with HCV from diverse backgrounds (various ages, ethnicities, and geographic regions) across the United States. The design was a retrospective study performed using medical and pharmacy claims from OptumLabs. HCV treatment exposure was categorized as DAA-only, DAA + IFN, any-DAA, or IFN-only. To account for confounding by indication, inverse probability of treatment weighting was performed. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). We identified 5,781 patients with HCV with no history of HCC at baseline. Compared with IFN-only regimen, no significant increase in HCC risk was found for use of DAA-only (HR, 1.53; 95% CI, 0.73-3.23), DAA + IFN (HR, 1.02; 95% CI, 0.51-2.06), or any-DAA (HR, 1.04; 95% CI, 0.65-1.65). When stratified by sustained virological response (SVR), we noted a higher HCC risk for DAA-only among patients who achieved SVR post-treatment (HR, 7.53; 95% CI, 1.48-38.34), but the CIs were wide, which might be due to the small sample size of the subgroups. Among those who did not achieve SVR, no association was found for use of DAA-only (HR, 0.59; 95% CI, 0.19-1.91). These findings do not provide compelling evidence for the conception that use of DAAs for HCV is associated with increased risk of HCC development.

Lower HCV treatment uptake in women who have received opioid agonist therapy before and during the DAA era: The ANRS FANTASIO project.

BACKGROUND: In the era of direct-acting antivirals (DAA) for the treatment of hepatitis C virus (HCV) infection, HCV treatment uptake remains insufficiently documented in key populations such as people with opioid dependence. Access to opioid agonist therapy (OAT) is facilitated in France through delivery in primary care, and individuals with opioid dependence can be identified as those receiving OAT. Women with opioid dependence are especially vulnerable because of associated sex-related stigma, discrimination, and marginalization, all of which negatively interfere with access to HCV prevention and care. This study, based on data collected between 2012 and 2016 in France, aimed to assess whether (i) chronically HCV-infected women with opioid dependence had lower rates of HCV treatment uptake than their male counterparts during the same period (i.e., study period), and (ii) the advent of DAA resulted in increased treatment uptake rates in these women. METHODS: Individuals with opioid dependence were identified as those receiving OAT at least once during the study period. Analyses were based on exhaustive anonymous care delivery data from the French national healthcare reimbursement database. We used multinomial logistic regression to estimate sex-based disparities in HCV treatment uptake (DAA or pegylated-interferon (Peg-IFN)-based treatment versus no treatment) while accounting for potential confounders. RESULTS: The study sample comprised 27,127 individuals, including 5640 (20.8%) women. Median [interquartile range] age was 45 [40-49] years. Between 2012 and 2016, 70.9 (women: 77.2; men: 69.3), 17.3 (14.2; 18.2) and 11.7% (8.6%; 12.5%) of the study sample received, respectively, no HCV treatment, DAA and Peg-IFN-based treatment only. After multiple adjustment for potential confounders, women were 41% (adjusted odds-ratio (AOR) [95% confidence interval (CI]): 0.59[0.53-0.65]) and 28% (0.72[0.66-0.78]) less likely than men to have had Peg-IFN-based and DAA treatment, respectively. CONCLUSION: Despite increased HCV treatment uptake in women with opioid dependence in the DAA era, rates remain lower than for men. In the coming years, access to DAA treatment will continue to increase in France thanks to a forthcoming simplified model of HCV care which includes primary care as an entry point. Nevertheless, a greater understanding of sex-specific barriers to HCV care and the implementation of appropriate sex-specific measures remain a priority.

Cloridrato de propranolol (solução oral 3, 75 mg/mL) para pacientes com hemangioma infantil / Propranolol hydrochloride (oral solution 3. 75 mg/mL) for patients with childhood hemangioma

INTRODUÇÃO: Os hemangiomas infantis (HI) são os tumores vasculares benignos mais comuns na infância, presentes em cerca de 4%-5% da população. A grande maioria dos HI não apresenta complicações nem necessita de intervenção terapêutica, mas alguns deles podem estar associados a alterações estéticas relevantes e morbidade manifesta. São caracterizados por uma fase de rápida proliferação de vasos sanguíneos no primeiro ano de vida, seguida por uma fase de involução, na qual ocorre uma regressão gradual do tecido vascular, que é substituído por tecido fibroso, e uma fase na qual não há mais modificação na lesão, chamada involuída. Para pacientes com HI complicados, que necessitam tratamento, a conduta medicamentosa é a escolha para a maioria dos pacientes. As principais opções terapêuticas são o propranolol, os glicocorticoides e a alfainterferona. Contudo, antes da escolha terapêutica, é fundamental a avaliação do risco/benefício de cada uma das opções. TECNOLOGIA: Cloridrato de Propranolol (Promangiol®). PERGUNTA: O uso do Cloridrato de Propranolol (Promangiol®) 3,75 mg/mL de solução oral é mais eficaz, seguro ou custo-efetivo em pacientes com hemangioma infantil proliferativo quando comparado as alternativas já disponíveis atualmente no SUS? EVIDÊNCIAS CIENTÍFICAS: Os estudos demostram eficácia e segurança do Cloridrato de Propranolol em comparação ao placebo, mas nenhum estudo que avaliasse comparativamente as duas formas farmacêuticas de Cloridrato de Propranolol (comprimido e solução oral), ou outros comparadores foi encontrado. Portanto não podemos inferir sobre a superioridade, inferioridade ou igualdade entre Promangiol® e as alternativas já disponíveis no SUS. Também não encontramos nenhum estudo que avaliou adesão ao tratamento ou qualidade de vida entre os comparadores. AVALIAÇÃO ECONÔMICA: O demandante apresentou uma análise de custo-utilidade, os dados de eficácia e efetividade resultaram em um total de anos de vida ajustados à qualidade de 15,45 anos para o Cloridrato de Propranolol (Promangiol®) e de 10,80 para o placebo (resultado considerando desconto). O resultado incremental foi de 4,65 anos de vida ganhos ajustados à qualidade para o Promangiol® (propranolol) quando comparado com a opção de tratamento placebo. A relação entre esses dois resultados é a taxa de custo-utilidade incremental. Esse foi de R$ 776,34/QALY ganho para o Promangiol® (propranolol) comparado com placebo. O modelo possui grandes limitações nos dados de utilidades e no levantamento dos custos, limitando a interpretação dos resultados. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário estimado da incorporação do Cloridrato de Propranolol (Promangiol®) solução oral 3,75 mg/ml no SUS, dados os parâmetros considerados, é de R$166.086.958,58 em cinco anos. O valor anual do impacto variou entre R$ 12.987.986,92 (2019) e R$50.674.403,28 (2023). O modelo possui grandes limitações na análise, o que inviabiliza a interpretação dos resultados. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foi encontrada uma tecnologia nova no horizonte para tratamento do hemangioma infantil: o nadolol suspensão oral. O estudo clínico NCT02505971, de fase 3, que está em andamento, compara nadalol com propranolol suspensão oral. A previsão de término do estudo é dezembro de 2018. CONSIDERAÇÕES: Embora o Cloridrato de Propranolol tem sido usado off-label durante vários anos para o tratamento de hemangioma infantil, ainda devemos ser cautelosos quanto à sua segurança. O perfil de segurança do tratamento em longo prazo em pacientes pediátricos ainda não foi estabelecido. Além disso, apesar das evidências clínicas demonstradas nos estudos apresentados, uma redução de preço seria necessária para justificar o financiamento da tecnologia. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros presentes em sua 71º reunião ordinária, no dia 04 de outubro de 2018, deliberaram que o tema fosse submetido à consulta pública com recomendação preliminar desfavorável à incorporação do Cloridrato de Propranolol (Promangiol®) 3,75 mg/mL de solução oral para tratamento de pacientes com hemangioma infantil proliferativo. CONSULTA PÚBLICA: Foram recebidas 5 contribuições técnico-científicas e 35 contribuições de experiência e opinião durante o período de consulta pública, entre 16 de outubro a 05 de novembro de 2018. Dentre as contribuições, a maioria foram contrárias à recomendação da CONITEC. Nenhuma evidência científica adicional foi encontrada nas contribuições. Os principais argumentos abordados foram a segurança de dosagem, formulação especifica para pacientes pediátricos e eficácia comprovada da tecnologia. O plenário da CONITEC entendeu que não houve argumentação suficiente para alterar a recomendação inicial. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da CONITEC presentes na 73ª reunião ordinária, nos dias 05 e 06 de dezembro de 2018, deliberaram, por unanimidade, a não recomendação de incorporação ao SUS do medicamento Cloridrato de Propranolol (Promangiol®) solução oral. Foi assinado em 06 de dezembro o registro de deliberação nº 412/2018 pela não incorporação do Cloridrato de Propranolol (Promangiol®) solução oral ao SUS. DECISÃO: Não incorporar o cloridrato de propranolol (solução oral 3,75 mg/ml) para pacientes com hemangioma infantil, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 89, publicada no Diário Oficial da União (DOU) nº 249, seção 1, página 434, em 28 de dezembro de 2018.

Preferences for antiviral therapy of chronic hepatitis C: a discrete choice experiment.

BACKGROUND: The German Institute for Quality and Efficiency in Health Care (IQWiG) uses patient-relevant outcomes to inform decision-makers. OBJECTIVE: IQWiG conducted a pilot study to examine whether discrete choice experiments (DCEs) can be applied in health economic evaluations in Germany to identify, weight, and prioritize multiple patient-relevant outcomes, using the example of antiviral therapy for chronic hepatitis C (HCV). A further objective was to contribute to a more structured approach towards eliciting and comparing preferences across key stakeholders. METHODS: In autumn 2010, a DCE questionnaire was sent to patients with chronic HCV to estimate preferences across seven outcomes ("attributes"), including treatment efficacy [sustained viral response (SVR) at 6 months], adverse effects (flu-like symptoms, gastrointestinal symptoms, psychiatric symptoms, and skin symptoms/alopecia), and measures of treatment burden (duration of therapy, frequency of injections). A linear model and an effects coded full model were applied to assess the relative importance of the attributes. RESULTS: In total N = 326 patients were included. A clear preference for SVR was shown; frequency of injections and duration of therapy shared the second rank, while psychiatric symptoms ranked third. The duration of flu-like symptoms was the least important attribute. CONCLUSION: Our findings indicate that it is possible to perform a DCE at the national level in a health technology assessment agency. The weighting of multiple outcomes allows an indication-specific and evidence-based measure to be used in health economic evaluations. In decision-making in health care, the approach generally allows for consideration of patient-relevant trade-offs regarding the benefits and harms of medical interventions.

Vulvodynia: Assessment and Treatment.

INTRODUCTION: Vulvodynia constitutes a highly prevalent form of sexual pain in women, and current information regarding its assessment and treatment is needed. AIM: To update the scientific evidence published in 2010, from the Third International Consultation on Sexual Medicine, pertaining to the assessment and treatment of women's sexual pain. METHODS: An expert committee, as part of the Fourth International Consultation on Sexual Medicine, was comprised of researchers and clinicians from biological and social science disciplines for the review of the scientific evidence on the assessment and treatment of women's genital pain. MAIN OUTCOME MEASURES: A review of assessment and treatment strategies involved in vulvodynia. RESULTS: We recommend the following treatments for the management of vulvodynia: psychological interventions, pelvic floor physical therapy, and vestibulectomy (for provoked vestibulodynia). We also support the use of multidisciplinary treatment approaches for the management of vulvodynia; however, more studies are needed to determine which components are most important. We recommend waiting for more empirical evidence before recommending alternative treatment options, anti-inflammatory agents, hormonal agents, and anticonvulsant medications. Although we do not recommend lidocaine, topical corticosteroids, or antidepressant medication for the management of vulvodynia, we suggest that capsaicin, botulinum toxin, and interferon be considered second-line avenues and that their recommendation be revisited once further research is conducted. CONCLUSION: A comprehensive assessment is needed to understand the pain experience of women presenting with vulvodynia. In addition, treatment typically progresses from less invasive to more invasive, and several treatment options are worth pursuing.

Real-world medical costs of antiviral therapy among patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND AND AIMS: Very potent direct acting antivirals for the treatment of chronic hepatitis C virus infection were recently introduced into daily clinical practice. Currently, treatment uptake is hampered by their high costs, eliciting prioritization of treatment. We aimed to evaluate the direct medical costs during interferon (IFN)-based antiviral treatment and the costs per sustained virological response (SVR) among patients with advanced hepatic fibrosis. METHODS: This retrospective cohort study included all consecutive patients with chronic hepatitis C virus infection and biopsy-proven bridging fibrosis or cirrhosis (Ishak 4-6) treated with IFN-based regimens in five hepatology units of tertiary care centers in Europe and Canada. Direct medical costs, expressed in 2013 Euros, during therapy were assessed. The components of care were quantified by three distinct categories: treatment, safety/ monitoring, and complications. Cost per SVR was calculated by dividing the mean cost by the SVR rate. RESULTS: In total, 672 interferon-based treatments administered to 455 patients were included. Total medical costs per patient were averaged to €14 559 (95% confidence interval [CI], €13 323-€15 836). The mean cost per SVR was €38 514 (95% CI, €35 244-€41 892). The costs per SVR were €26 105 (95% CI, €23 068-€29 296) for patients with a normal platelet count and €50 907 (95% CI, €44 151-€59 612) for patients with thrombocytopenia, with the costs per SVR of €74 961 (95% CI, €55 463-€103 541) among those patients with a platelet count below 100 * 109 /L. CONCLUSIONS: Because of the lower SVR rates, the cost per SVR of IFN-based treatment increased when patients with more advanced liver disease were treated. Additional costs of IFN-free therapy could be limited among these patients.

Hepatitis C virus treatment as prevention in people who inject drugs: testing the evidence.

PURPOSE OF REVIEW: The majority of hepatitis C virus (HCV) infections in the United Kingdom and many developing countries were acquired through injecting. New clinical guidance suggests that HCV treatment should be offered to people with a transmission risk - such as people who inject drugs (PWID) - irrespective of severity of liver disease. We consider the strength of the evidence base and potential problems in evaluating HCV treatment as prevention among PWID. RECENT FINDINGS: There is good theoretical evidence from dynamic models that HCV treatment for PWID could reduce HCV chronic prevalence and incidence among PWID. Economic evaluations from high-income settings have suggested HCV treatment for PWID is cost-effective, and that in many settings HCV treatment of PWID could be more cost-effective than treating those at an equivalent stage with no ongoing transmission risk. Epidemiological studies of older interferon treatments have suggested that PWID can achieve similar treatment outcomes to other patient groups treated for chronic HCV. Impact and cost-effectiveness of HCV treatment is driven by the potential 'prevention benefit' of treating PWID. Model projections suggest that more future infections, end stage liver disease, and HCV-related deaths will be averted than lost through reinfection of PWID treated successfully for HCV. However, there is to date no empirical evidence from trials or observational studies that test the model projections and 'prevention benefit' hypothesis. In part this is because of uncertainty in the evidence base but also there is unlikely to have been a change in HCV prevalence due to HCV treatment because PWID HCV treatment rates historically in most sites have been low, and any scale-up and switch to the new direct acting antiviral has not yet occurred. There are a number of key uncertainties in the data available on PWID that need to be improved and addressed to evaluate treatment as prevention. These include estimates of the prevalence of PWID, measurements of HCV chronic prevalence and incidence among PWID, and how to interpret reinfection rates as potential outcome measures. SUMMARY: Eliminating HCV through scaling up treatment is a theoretical possibility. But empirical data are required to demonstrate that HCV treatment can reduce HCV transmission, which will require an improved evidence base and analytic framework for measuring PWID and HCV prevalence.

[Cost-effectiveness and safety of telaprevir and boceprevir for chronic hepatitis C in real-world clinical practice]. / Coste-efectividad y seguridad de telaprevir y boceprevir para el tratamiento de la hepatitis C crónica en la práctica clínica.

INTRODUCTION: Triple therapy with telaprevir or boceprevir has proven to be effective in the treatment of chronic hepatitis C with response rates of up to 88%. However, the treatment may be associated with important adverse effects and a high economic impact. OBJECTIVE: To assess the cost-effectiveness and safety of triple therapy with telaprevir or boceprevir for the treatment of chronic hepatitis C. METHODS: Retrospective observational study. We included all patients who had started treatment with protease inhibitors before July 31(st), 2013. We evaluated sustained virological response, the cost per patient achieving sustained virological response, and the cost of the supportive treatment for adverse events associated with triple therapy. RESULTS: Fifty-nine patients were included; 35 had been treated with telaprevir (59.3%) and 24 with boceprevir (40.7%). Sustained virological response was achieved by 38 (64.4%) patients: 24 (68.6%) patients in the telaprevir treatment arm and 14 (58.3%) patients in the boceprevir treatment arm. The cost per patient with sustained virological response was 43,555 € (95% CI 35,389-51,722 €). There were no statistically significant differences between the overall costs of therapy with telaprevir, 43,494 € (95% CI 34,795 €-55,092 €) versus boceprevir, 42,005 € (95% CI 32,122-64,243€). The mean cost of supportive care per patient was 1,500 €, while the maximum cost was 11,374 €. Due to adverse events, 8 (13.6%) patients required hospital admission, 22 (37.3%) patients attended the accident and emergency department, and 26 (44.1%) patients needed additional medical consultations. CONCLUSIONS: The treatment of triple therapy with telaprevir or boceprevir resulted in high cost per patient with sustained virological response. Due to adverse events, a high number of patients required supportive care, whose costs should be added to those of triple therapy.

[Financial burden of hepatitis C infection and its treatment]. / A hepatitis C-vírus-fertozés és kezelésének költségvonzata.

The worldwide prevalence of hepatitis C infection is 2-3%. In addition to its individual consequences, it generates huge financial impact on national level. In particular, lack of recognition or late diagnosis of the disease is associated with high rate of liver cirrhosis related complications (hepatic encephalopathy, ascites, variceal bleeding, hepatocellular carcinoma) and/or demands liver transplantation. Loss of quality assisted life years and/or those spent in employment, reduced work productivity, as well as costs of antiviral therapy also contribute to the financial burden. The costs of new interferon-free therapies may exceed the prices of previous pegylated interferon based therapies with or without protease inhibitors; however, shorter treatment durations and extremely low rates of severe side-effects with much less related expenses can reduce total costs of these treatments. In addition to the moral obligations, published cost-effectiveness analyses conclude that early diagnosis and treatment of this primarily iatrogenic infection through organized screening programs and wide access to effective therapies may lead to long term financial benefit.

Cost-effectiveness of telaprevir in patients with genotype 1 hepatitis C in Australia.

BACKGROUND: Protease inhibitors such as telaprevir (Incivo) are reimbursed in Australia for the treatment of patients with genotype 1 hepatitis C virus (HCV) infection in combination with pegylated interferon and ribavirin (PR). OBJECTIVES: To assess the cost-effectiveness of telaprevir plus PR compared with PR alone in 1) previously untreated patients and 2) patients who had received treatment with PR earlier. METHODS: Sustained virological response rates and average treatment durations of telaprevir and PR (given with or without telaprevir) were taken from the telaprevir ADVANCE and REALIZE clinical trials but were modified to take account of differences in prescribing rules between the trials and Australian clinical practice. The probability of transitioning between Markov disease states was based on data from the Australian Kirby Institute where possible and supplemented using data from the published literature. Utility values obtained from the EuroQol five-dimensional questionnaire data collected in the ADVANCE and REALIZE trials were used to represent the utility during HCV treatment. Utility values for Markov health states were taken from the published literature. Unit costs (2014 AU $) were taken from Australian sources. RESULTS: In treatment-naive patients, the discounted cost per life-years gained was AU $37,706 and the discounted cost per quality-adjusted life-year was AU $19,283. In treatment-experienced patients, the discounted cost per life-year gained was AU $23,855 and the discounted cost per quality-adjusted life-year was AU $14,948. CONCLUSION: Telaprevir plus PR in the Australian setting is cost-effective when compared with PR alone in patients infected with genotype 1 HCV.

Efectividad y seguridad de sorafenib en pacientes con cáncer renal de células claras, metastásico, sin respuesta a inhibidores de tirosin-quinasa o citoquinas (interleuquina o interferón), riesgo bajo-intermedio / Effectiveness and safety of sorafenib in patients with clear-cell, metastatic renal cancer without response to tyrosine kinase inhibitors or cytokines (interleukin or interferon), low-intermediate risk

Introducción: en el mundo, en relación con la frecuencia de todos de cánceres de cualquier localización, el cáncer renal se encuentra dentro de los diez más frecuentes en hombres y el catorceavo en mujeres (1). Existen varias opciones terapéuticas de segunda línea en aquellos pacientes con cáncer renal avanzado o metastásico, sin respuesta a inhibidores de tirosina-quinasa o citoquinas, que pueden incluir medicamentos como: Inhibidores de mTOR (Temsirolimus, everolimus), inhibidores de tirosinquinasa (Sunitinib, sorafenib, pazopanib, axitinib), y otros inhibidores de la angiogénesis como bevacizumab. Dadas las opciones planteadas se hace necesario conocer la efectividad y la seguridad de estas intervenciones. Objetivo: examinar los beneficios y riesgos del uso de sorafenib como uno de los criterios para informar la toma de decisiones relacionada con la posible inclusión de tecnologías en el Plan Obligatorio de Salud, en el marco de su actualización ordinaria para el año 2015. Metodología: la evaluación fue realizada de acuerdo con un protocolo definido a priori por el grupo desarrollador. Se realizó una búsqueda sistemática en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, LILACS y Google, sin restricciones de idioma, fecha de publicación y tipo de estudio. Las búsquedas electrónicas fueron hechas en noviembre de 2014 y se complementaron mediante búsqueda manual en bola de nieve y consulta con expertos temáticos. La tamización de referencias se realizó por dos revisores de forma independiente y los desacuerdos fueron resueltos por consenso. La selección de estudios fue realizada mediante la revisión en texto completo de las referencias preseleccionadas, verificando los criterios de elegibilidad predefinidos. Las características y hallazgos de los estudios fueron extraídos a partir de las publicaciones originales. Resultados: Efectividad existe mejoría significativa para el desenlace de supervivencia libre de progresión a favor de sorafenib comparado con placebo, con un HR 0,44 (IC 95 % 0,35-0,55; I2 11%) mediante comparación indirecta; se reportó mejoría significativa para el desenlace de supervivencia libre de progresión a favor de sunitinib comparado con sorafenib, con un HR 1,63 (IC 95% 1,09- 2,45); mejoría significativa para el desenlace de supervivencia libre de progresión a favor de axitinib comparado con sorafenib, con un HR 0,67 (IC 95% 0,54- 0,81). Seguridad: mediante comparación indirecta, reportó que el axitinib disminuye del 45% del abandono de terapia secundaria a eventos adversos cuando se compara con sorafenib (IC 95% 0,24-0,84). No se encontraron diferencias estadísticamente significativas para los desenlaces de: abandono de terapia y diarrea. Para el desenlace de fatiga se presenta un incremento del riesgo con axitinib comparado con sorafenib, RR 2,30 (IC 95% 1,34-4,10). Sorafenib incrementa el riesgo de reacción cutánea mano-pie comparado con axitinib, RR 0,31 (IC 95% 0,17-0,52), así como, incremento del riesgo de rash, RR 0,10 (IC 95% 0,02-0,41) en la misma comparación. El axitinib incrementa el riesgo de estomatitis RR 8,1 (IC 95% 1,1->100). Conclusiones: efectividad: Sorafenib presenta mejoría significativa en la supervivencia libre de progresión cuando se compara con placebo. Al comparar de manera indirecta sorafenib con otros agentes como axitinib y sunitinib, se reportó mejoría de la supervivencia libre de progresión significativa clínicamente a favor de axitinib y sunitinib. No se reportaron desenlaces de efectividad clínicamente significativos con otros agentes como: pazopanib, everolimus, temsirolimus. En esta revisión no se identificó evidencia que cumpliera con los criterios de inclusión y que comparara sorafenib con bevacizumab, ni evidencia que reporte los desenlaces de supervivencia global y calidad de vida. Seguridad: En relación con la seguridad del tratamiento de segunda línea con sorafenib se evidencia de manera general un aumento del riesgo de presentar eventos adversos grado III/IV. Al evaluar el desenlace de abandono de terapia secundaria a eventos adversos se evidencia que sorafenib aumentó el riesgo, comparado con axitinib. Para el desenlace de reacción cutánea mano-pie el uso de sorafenib presenta aumento del riesgo comparado con placebo, pazopanib, axitinib y everolimus. Sorafenib reporta aumento de riesgo de presentar rash comparado con axitinib, así como, de diarrea cuando se compara con placebo. En esta revisión no se identificó evidencia que cumpliera con los criterios de elegibilidad y que comparara sorafenib con bevacizumab.(AU)

[Topical chemotherapy for conjunctival tumours - the medical and legal bearings of the case]. / Lokale Chemotherapie von Tumoren der Bindehaut - interdisziplinär medizinische und administrative Aspekte.

The treatment management of malignant tumours is characterised and limited by specific features of the topographical structure of the eye. The anatomic characteristics of the conjunctival sac, the movable tissue structures and the need to take care of corneal transparency and conjunctival stability are the main concerns of the experts. Clinical studies have revealed adjuvant chemotherapy to have a positive effect as a therapeutic treatment for neoplasia of the conjunctiva and cornea. Although mitomycin and interferon are widely used, there are no phase III studies on local adjuvant chemotherapy (interferon, mitomycin, 5-fluorouracil) that evaluate the proof of effectiveness, potential adverse effects or interactions with other drugs. For this reason, the currently available studies fail to comply with the jurisdiction of the German Federal Social Court. Hence, the Medical Service of the Health Insurance Funds (MDK) regionally does not accept the medical preconditions for reimbursement of the costs in adjuvant local chemotherapy. A doctor's unquestioned acceptance of such an MDK decision could have legal consequences. An off-label use is acceptable by law if there is no alternative treatment available with a higher evidence level that conforms to the medical standard. It is therefore recommendable for the Joint Federal Committee commissions the experts in ophthalmology and oncology on off-label use, to review the scientific evidence regarding adjuvant therapy of malignant tumours of the ocular surface. Only in this way can regional disparities in patient care, and intrusions on the doctor-patient relationship, be avoided.

Should we await IFN-free regimens to treat HCV genotype 1 treatment-naive patients? A cost-effectiveness analysis (ANRS 95141).

BACKGROUND & AIMS: In treatment-naive patients mono-infected with genotype 1 chronic HCV, treatments with telaprevir/boceprevir (TVR/BOC)-based triple therapy are standard-of-care. However, more efficacious direct-acting antivirals (IFN-based new DAAs) are available and interferon-free (IFN-free) regimens are imminent (2015). METHODS: A mathematical model estimated quality-adjusted life years, cost and incremental cost-effectiveness ratios of (i) IFN-based new DAAs vs. TVR/BOC-based triple therapy; and (ii) IFN-based new DAAs initiation strategies, given that IFN-free regimens are imminent. The sustained virological response in F3-4/F0-2 was 71/89% with IFN-based new DAAs, 85/95% with IFN-free regimens, vs. 64/80% with TVR/BOC-based triple therapy. Serious adverse events leading to discontinuation were taken as: 0-0.6% with IFN-based new DAAs, 0% with IFN-free regimens, vs. 1-10% with TVR/BOC-based triple therapy. Costs were €60,000 for 12weeks of IFN-based new DAAs and two times higher for IFN-free regimens. RESULTS: Treatment with IFN-based new DAAs when fibrosis stage ⩾F2 is cost-effective compared to TVR/BOC-based triple therapy (€37,900/QALY gained), but not at F0-1 (€103,500/QALY gained). Awaiting the IFN-free regimens is more effective, except in F4 patients, but not cost-effective compared to IFN-based new DAAs. If we decrease the cost of IFN-free regimens close to that of IFN-based new DAAs, then awaiting the IFN-free regimen becomes cost-effective. CONCLUSIONS: Treatment with IFN-based new DAAs at stage ⩾F2 is both effective and cost-effective compared to TVR/BOC triple therapy. Awaiting IFN-free regimens and then treating regardless of fibrosis is more efficacious, except in F4 patients; however, the cost-effectiveness of this strategy is highly dependent on its cost.

The cost-effectiveness of improved hepatitis C virus therapies in HIV/hepatitis C virus coinfected patients.

OBJECTIVES: To evaluate the effectiveness and cost-effectiveness of strategies to treat hepatitis C virus (HCV) in HIV/HCV coinfected patients in the United States. PARTICIPANTS: Simulated cohort of HIV/HCV genotype 1 coinfected, noncirrhotic, HCV treatment-naive individuals enrolled in US HIV guideline-concordant care. DESIGN/INTERVENTIONS: Monte Carlo simulation comparing five strategies: no treatment; dual therapy with pegylated-interferon (PEG) and ribavirin (RBV); 'PEG/RBV trial' in which all patients initiate dual therapy and switch to triple therapy upon failure; 'IL28B triage' in which patients initiate either dual therapy or triple therapy based on their IL28B allele type; and PEG/RBV and telaprevir (TPV) triple therapy. Sensitivity analyses varied efficacies and costs and included a scenario with interferon (IFN)-free therapy. MAIN MEASURES: Sustained virologic response (SVR), life expectancy, discounted quality-adjusted life expectancy (QALE), lifetime medical costs, and incremental cost-effectiveness ratios (ICERs) in $/quality-adjusted life years (QALY) gained. RESULTS: 'PEG/RBV trial,' 'IL28B triage,' and 'triple therapy' each provided 72% SVR and extended QALE compared with 'dual therapy' by 1.12, 1.14, and 1.15 QALY, respectively. The ICER of 'PEG/RBV trial' compared with 'dual therapy' was $37 500/QALY. 'IL28B triage' and 'triple therapy' provided little benefit compared with 'PEG/RBV trial,' and both had ICERs exceeding $300 000/QALY. In sensitivity analyses, IFN-free treatment attaining 90% SVR had an ICER less than $100 000/QALY compared with 'PEG/RBV trial' when its cost was $109 000 or less (125% of the cost of PEG/RBV/TVR). CONCLUSION: HCV protease inhibitors are most efficiently used in HIV/HCV coinfection after a trial of PEG/RBV, sparing protease inhibitors for those who attain rapid virologic response and SVR. The cost-effectiveness of IFN-free regimens for HIV/HCV coinfection will depend on the cost of these therapies.

Comparative effectiveness of fingolimod versus interferons or glatiramer acetate for relapse rates in multiple sclerosis: a retrospective US claims database analysis.

OBJECTIVE: Disease-modifying therapies, such as fingolimod, interferon (IFN) and glatiramer acetate (GA), have differing effects on relapse rates in patients with multiple sclerosis (MS), but little is known about the real-world differences in relapse rates with these treatments. This retrospective study assessed relapse rates in patients with active MS initiating fingolimod, IFN or GA therapy in a real-world setting. METHODS: Using administrative claims data from the US PharMetrics Plus database, we identified previously treated and untreated patients with MS who initiated fingolimod, IFN or GA treatment between 1 October 2010 and 31 March 2011 and had experienced a relapse in the previous year. A claims-based algorithm was used to identify relapses over the persistence period in patients with 540 days of post-index continuous enrolment. A logistic regression model assessed the probability of having at least one relapse and a generalized linear model estimated differences in annualized relapse rates (ARRs). RESULTS: The study enrolled 525 patients (fingolimod, n = 128; combined IFN/GA cohort, n = 397) of the 31,041 initially identified. Similar findings for fingolimod and IFN/GA were observed for the unadjusted proportion of patients experiencing relapses (31.3% vs. 34.0%, respectively; p = 0.5653) and ARRs (0.50 vs. 0.55, respectively) while persistent to treatment. After adjusting for baseline differences, fingolimod was associated with a 52% reduction in the probability of having a relapse (odds ratio, 0.48; 95% confidence interval [CI], 0.28-0.84; p = 0.0097) and a 50% reduction in ARR (rate ratio, 0.50; 95% CI, 0.34-0.75; p = 0.0006) compared with IFN/GA. LIMITATIONS: Identification of relapses is based on the claims in the database rather than on a clinical assessment. CONCLUSIONS: In a real-world setting, fingolimod was shown to be associated with significantly lower relapse rates than IFN/GA in patients with MS who had a history of relapses.

Cost effectiveness of hepatitis C-related interventions targeting substance users and other high-risk groups: a systematic review.

BACKGROUND AND OBJECTIVE: In developed countries, injection drug users have the highest prevalence and incidence of hepatitis C virus (HCV) infection. Clinicians and policy makers have several options for reducing morbidity and mortality related to HCV infection, including preventing new infections, screening high-risk populations, and optimizing uptake and delivery of antiviral therapy. Cost-effectiveness analyses provide an estimate of the value for money associated with adopting healthcare interventions. Our objective was to determine the cost effectiveness of hepatitis C interventions (prevention, screening, treatment) targeting substance users and other groups with a high proportion of substance users. METHODS: We conducted a systematic search of MEDLINE, EMBASE, CINAHL, HealthSTAR and EconLit, and the grey literature. Studies were critically appraised using the Drummond and Jefferson, Neumann et al. and Philips et al. checklists. We developed and applied a quality appraisal instrument specific to cost-effectiveness analyses of HCV interventions. In addition, we summarized cost-effectiveness estimates using a single currency and year ($US, year 2009 values). RESULTS: Twenty-one economic evaluations were included, which addressed prevention (three), screening (ten) and treatment (eight). The quality of the analyses varied greatly. A significant proportion did not incorporate important aspects of HCV natural history, disease costs and antiviral therapy. Incremental cost-effectiveness ratios (ICERs) ranged from dominant (less costly and more effective) to $US603,352 per QALY. However, many ICERs were less than $US100,000 per QALY. Screening and treatment interventions involving pegylated interferon and ribavirin were generally cost effective at the $US100,000 per QALY threshold, with the exception of some subgroups, such as immune compromised patients with genotype 1 infections. CONCLUSIONS: No clear consensus emerged from the studies demonstrating that prevention, screening or treatment provides better value for money as each approach can be economically attractive in certain subgroups. More high-quality economic evaluations of preventing, identifying and treating HCV infection in substance users are needed.

Interferon-free hepatitis C therapy: how close are we?

Two oral direct-acting antivirals (DAA) are now available for the treatment of chronic hepatitis C infection and several generations of DAA are in development. Expectations are that, at some time in the near future, hepatitis C will be 'curable' with an all-oral DAA regimen. This article reviews the current problems associated with interferon-based hepatitis C treatments that are combined with DAAs, including adverse events and complications of therapy, contraindications, drug-drug interactions and cost. The article further discusses difficulties with new drug development and provides an opinion on the research issues still to be dealt with and the requirements for the successful implementation of such a strategy. These include lack of efficacy in certain populations, unexpected side effects, antiviral resistance, late relapse, lack of cooperation between drug developers and cost.

Effect of discounting on estimation of benefits determined by hepatitis C treatment.

The combination of either boceprevir or telaprevir with ribavirin and interferon (triple therapy) has been shown to be more effective than ribavirin+interferon (dual therapy) for the treatment of genotype 1 hepatitis C. Since the benefit of these treatments takes place after years, simulation models are needed to predict long-term outcomes. In simulation models, the choice of different values of yearly discount rates (e.g., 6%, 3.5%, 2%, 1.5% or 0%) influences the results, but no studies have specifically addressed this issue. We examined this point by determining the long-term benefits under different conditions on the basis of standard modelling and using quality-adjusted life years (QALYs) to quantify the benefits. In our base case scenario, we compared the long-term benefit between patients given a treatment with a 40% sustained virologic response (SVR) (dual therapy) and patients given a treatment with a 70% SVR (triple therapy), and we then examined how these specific yearly discount rates influenced the incremental benefit. The gain between a 70% SVR and a 40% SVR decreased from 0.45 QALYs with a 0% discount rate to 0.22 QALYs with a 6% discount rate (ratio between the two values = 2.04). Testing the other discounting assumptions confirmed that the discount rate has a marked impact on the magnitude of the model-estimated incremental benefit. In conclusion, the results of our analysis can be helpful to better interpret cost-effectiveness studies evaluating new treatment for hepatitis C.