Supply of nirmatrelvir/ritonavir and molnupiravir for patients with COVID-19 in the first eight months since listing on the Australian Pharmaceutical Benefits Scheme: A retrospective observational study.

OBJECTIVES: To compare the supply of molnupiravir and nirmatrelvir/ritonavir in relation to patient characteristics and other co-prescribed medicines and to estimate the number of patients without contraindications to nirmatrelvir/ritonavir who were treated with molnupiravir. STUDY DESIGN, SETTING: Retrospective observational study of patients identified in the Pharmaceutical Benefits Scheme (PBS) 10 % sample dataset who were supplied with either molnupiravir or nirmatrelvir/ritonavir between May and December 2022. We supplemented the PBS dataset with aggregated counts from published literature to determine prevalence of clinical contraindications to nirmatrelvir/ritonavir. MAIN OUTCOME MEASURES: We used multivariable Poisson regression to estimate risk ratios (RR) of receiving nirmatrelvir/ritonavir over molnupiravir. RESULTS: We identified 54,550 patients who received either nirmatrelvir/ritonavir (26.8 %) or molnupiravir (73.2 %). Their average age was 71.6 (SD = 13.4) years and 57.1 % were female. Patients were less likely to receive nirmatrelvir/ritonavir with increasing age (RR = 0.50; 95 % CI: 0.48-0.53; for ages 85 + compared to < 65 years) or who had received medicines contraindicated for use with nirmatrelvir/ritonavir (RR = 0.66; 95 % CI: 0.64-0.68). During the study period, we estimated that between 28.4 % and 45.4 % of patients aged ≥ 65 years had received molnupiravir in the absence of pharmacological and clinical contraindications to nirmatrelvir/ritonavir. CONCLUSION: Many prescriptions were written for molnupiravir where there were no contraindications to nirmatrelvir/ritonavir. The benefits that followed from prompt government action in approving and obtaining nirmatrelvir/ritonavir were therefore likely to be less than they could potentially have been. Governments should consider investing in quality improvement systems to ensure the best outcomes in terms of efficacy and safety.

Comorbidities and the use of comedications among patients with chronic hepatitis C in Korea: A nationwide cross-sectional study.

BACKGROUND/AIMS: Chronic hepatitis C (CHC) is the second leading cause of liver-related mortality and is more prevalent in the elderly population in Korea. Decisions to initiate treatment and selection of proper antiviral agents may be challenging among elderly patients due to relevant comorbidities, comedications, and drug-drug interaction (DDI). It may be helpful to understand the current demographic status and comorbidities of CHC patients in the country. METHODS: Patients aged ≥ 18 years and diagnosed with CHC (KCD-7 code B18.2) were extracted from the Korean Health Insurance Review & Assessment Service database in 2018. Data on comorbidities and comedications were assessed and potential DDIs were analyzed. RESULTS: A total of 50,476 patients with CHC, with a mean age of 60.3 years and 46.7% male patients were identified. The proportion of patients with cirrhosis, hepatocellular carcinoma, and liver transplantation was 6.0%, 4.1%, and 0.3%, respectively and 37.2% of patients were more than 65 years of age. The three most common comorbidities were diseases of the digestive system (83.7%), respiratory system (58.2%), and musculoskeletal system and connective tissue (57.6%). The three most common comedications were analgesics (91.6%), gastrointestinal agents (85%), and antibacterials (80.3%). Lipid-lowering agents and anticonvulsants were prescribed in 28.5% and 14.8% of patients. Rate of potential DDI for contraindication was 2.2%, 13.1%, and 15.6% with sofosbuvir/velpatasvir, ledipasvir/sofosbuvir, and glecaprevir/pibrentasvir. CONCLUSION: With the increasing age of patients with CHC, comorbidity, comedication, and potential DDI should be considered when choosing antivirals in Korea. Sofosbuvir-based regimens showed favorable DDI profiles among Korean patients.

Clinical and Therapeutic Approach to Hospitalized COVID-19 Patients: A Pediatric Cohort in Portugal.

INTRODUCTION: Coronavirus disease 2019, or COVID-19, in children is usually a mild disease, but severe illness has been reported. Currently, the therapy benefits of antiviral experimental drugs are still uncertain. The main aim of this study is to describe the experience of a level III hospital regarding therapeutic management of hospitalized children with COVID-19 and to characterize clinical features and evolution. MATERIAL AND METHODS: This is a descriptive study of patients with COVID-19 in a level III pediatric hospital in Portugal between March and June 2020. Experimental drugs were administered according to the best scientific evidence at the time as 'off-label use'. RESULTS: Among 200 children with SARS-CoV-2 infection, 37 were admitted due to COVID-19. Median age was one year (23 days - 18 years), 43% had comorbidities and 20/37 (54%) received antiviral therapy. Hydroxychloroquine was administered in 13 patients, in monotherapy or combined with lopinavir/ritonavir or azithromycin. Lopinavir/ritonavir was administered in eight patients and three children were treated with remdesivir. The patients who were treated had pneumonia (14), multisystem inflammatory syndrome in children (2), sepsis (2), myocarditis (1), acute respiratory distress syndrome (1), and mild illness with comorbidities (3). Other therapies included methylprednisolone and immunoglobulin (3), enoxaparin (2), antibiotics (16), oxygen (7), corticosteroids, and other inhaled therapy (16). DISCUSSION: Several treatment approaches have been proposed for severe COVID-19, even though none of them had been proven effective or approved for small children. Currently, remdesivir is approved for children aged above 12 years-old. Although 54% of our patients were treated with antivirals, it is important to understand that the favorable clinical evolution could be related with the natural course of the disease. CONCLUSION: A significant proportion of our population presented severe and critical disease, was hospitalized and received treatment according to the most recent data, although most patients had mild disease. COVID-19 treatment in children is a clinical challenge and clinical trials are urgently needed.

Introdução: A infeção SARS-CoV-2 em idade pediátrica cursa maioritariamente com doença ligeira. No entanto, pode ocorrer doença grave, ainda que com menor frequência. Atualmente, os benefícios das terapêuticas antivirais experimentais ainda são incertos. O objetivo deste estudo consiste em descrever a experiência de um hospital terciário no tratamento de crianças internadas por COVID-19 e caracterizar a clínica e evolução. Material e Métodos: Estudo descritivo em doentes até aos 18 anos de idade, internados com COVID-19 num hospital pediátrico de nível III em Portugal, de março a junho de 2020. Os fármacos antivirais foram administrados em regime de off-label. Resultados: Identificaram-se 200 casos de infeção SARS-CoV-2, dos quais 37 foram internados com COVID-19. A idade mediana foi de um ano (23 dias - 18 anos), 43% apresentavam comorbilidades e 20/37 (54%) receberam terapêutica antiviral. A hidroxicloroquina foi administrada em 13 doentes em monoterapia ou associada a lopinavir/ritonavir ou azitromicina. O lopinavir/ritonavir foi utilizado em oito doentes e três doentes receberam remdesivir. O tratamento antiviral foi aplicado a doentes com pneumonia (14), sépsis (2), síndrome inflamatório multisistémico pediátrico (2), síndrome dificuldade respiratória aguda (1), miocardite (1) e crianças com doença ligeira e comorbilidades (3). Realizaram-se também outras terapêuticas que incluíram metilprednisolona e imunoglobulina (3), enoxaparina (2), antibióticos (16), oxigenoterapia (7) e broncodilatadores e corticoides inalados (16). Discussão: Diversas abordagens terapêuticas têm sido sugeridas para casos graves de COVID-19, embora nenhuma seja até à data considerada eficaz, ou esteja aprovada em crianças pequenas. Atualmente, o remdesivir está aprovado para idades superiores a 12 anos. Apesar de 54% dos nossos doentes terem sido tratados com antivirais, é importante compreender que a evolução favorável poderá ter estado associada à evolução natural da doença. Conclusão: Uma percentagem significativa da população apresentou doença grave a crítica, com necessidade de internamento e tratamento, este último definido com base nas recomendações da comunidade científica à data, embora a maioria apresentasse doença ligeira. O tratamento da COVID-19 em idade pediátrica é um desafio, sendo urgente realizar ensaios clínicos relativos a esta matéria.

Experience of a Portuguese Center: Effectiveness of Direct-Acting Antiviral Therapy for Hepatitis C.

INTRODUCTION: In late 2014, Portugal implemented a national program for the treatment of patients with chronic hepatitis C with directacting antiviral agents. This program has made Portugal one of the first European countries to implement a structured measure of treatment to eliminate this serious public health problem. The aim of this study was to assess the effectiveness of direct-acting antiviral therapy in the treatment of patients with chronic hepatitis C virus infection. MATERIAL AND METHODS: A retrospective observational study was conducted at Centro Hospitalar de Lisboa Ocidental on the national online platform from December 2014 until February 2017 and included patients with hepatitis C virus infection who underwent treatment. The primary endpoint was sustained virologic response at least 12 weeks post treatment. Data was analyzed with the SPSS 17.0 program. RESULTS: During the study period, 820 patients completed therapy and achieved sufficient follow-up time to assess sustained virologic response with an overall response rate of 97.2% (n = 797) and a response rate of 98.0%, 99.5%, 90.9%, 95.1% and 94.2% for genotypes 1a, 1b, 2, 3 and 4, respectively. Data suggested that advanced fibrosis (F3/F4), human immunodeficiency virus co-infection and treatment failure with interferon and ribavirin were not negatively related with sustained virologic response in our population. Most patients (80.1%) completed treatment with ledipasvir/sofosbuvir ± ribavirin. The most common adverse events were fatigue and insomnia followed by headache and weight loss. DISCUSSION: Patients predominantly had genotype 1 infection which correlates with HCV distribution in Europe, but we found a major proportion in genotype 4 which can be explained by immigration from African countries. Our patients' ages ranging from 22 to 90 years, reflected a new approach with no upper age limit. Direct-acting antivirals regimens resulted in remarkably high SVR rates compared to interferon-based regimens, which were consistent with clinical trials data. CONCLUSION: Our data showed that direct-acting antiviral-based regimens are safe and have a high success rate in the treatment of patients with hepatitis C virus infection in a real-world setting.

Introdução: No final de 2014 foi implementado em Portugal um programa nacional para o tratamento de doentes com infecção crónica por vírus da hepatite C com recurso a antivíricos de acção directa. Este programa fez com que Portugal fosse um dos primeiros países europeus a implementar uma medida estruturante para a eliminação da hepatite C. Este estudo tem como objectivo a avaliação da efectividade dos antivíricos de acção directa no tratamento da hepatite C crónica. Material e Métodos: Estudo retrospectivo observacional dos doentes seguidos no Centro Hospitalar de Lisboa Ocidental, entre dezembro de 2014 e fevereiro de 2017. O objectivo primário do estudo é avaliar a resposta virológica sustentada a partir das 12 semanas pós tratamento. Analisámos os dados com o programa SPSS 17.0. Resultados: Durante o período do estudo 820 doentes completaram o tratamento e o tempo necessário para avaliação da resposta virológica sustentada. A resposta virológica sustentada global foi de 97.2% (n = 797), com taxas de resposta de 97,2%, 98,5%, 90,9%, 95,1% e 94,2% para os genótipos 1a, 1b, 2, 3 e 4, respectivamente. Os dados sugerem não haver relação entre a fibrose avançada (F3 / F4), a coinfecção pelo vírus da imunodeficiência humana e a falência do tratamento com interferão e ribavirina e uma menor resposta ao tratamento. A maioria dos doentes (80,1%) concluiu o tratamento com ledipasvir/sofosbuvir ± ribavirina. Os eventos adversos mais frequentes foram a fadiga e a insónia, seguida de dor de cabeça e perda de peso. Discussão: A população em estudo apresentou maior prevalência de infecção pelo genótipo 1, à semelhança dos restantes países Europeus, contudo a prevalência do genótipo 4 foi superior, reflectindo a imigração africana. A faixa etária (22 - 90 anos) dos doentes tratados reflecte uma nova abordagem sem limite superior de idade. A taxa de RVS obtida, muito superior à obtida com regimes baseados em interferão, foi consistente com os dados dos ensaios clínicos. Conclusão: Os dados encontrados demonstram que os regimes baseados em antivirais de acção directa, em contexto de vida real, são seguros e eficazes no tratamento de doentes com infecção por vírus da hepatite C.

Aumento dos lípides durante tratamento para VHC: ação do vírus ou da medicação? / Increase of lipids during hcv treatment: virus action or medication?

ABSTRACT BACKGROUND: The interaction between serum lipids and C virus infection is well known, as are serum lipid levels in the Peg-IFN / RBV-based treatment. However, with direct action antivirals (DAAs) this behavior is still unclear. OBJECTIVE: To compare serum lipids levels between patients treated with Peg-IFN/RBV and DAAs and to evaluate lipids in sustained virological response (SVR) with DAAs. METHODS: Retro prospective study comparing the behavior of total cholesterol (TC), low-density lipoprotein (LDL) and triglycerides (TG) serum levels during treatment with DAAs (G-DAAs) and a control historic group Peg-IFN/RBV (G-PR). Coorte, prospective study, to study the behavior of lipids in the SVR with DAAs. Data were collected at the beginning of treatment (baseline: t-base) and at week 12 of treatment (t-12) for G-DAAs and at week 24 (t-24) for G-PR, groups. In the cohort evaluation, the samples at t-base and at week 12 after the end of treatment (t-SVR). Delta lipids: difference between lipids in t-12 / t-24 minus t-base for comparison between G-PR and G-AADs groups and t-SVR minus t-base for lipid analysis in SVR. Analysis with Kruskal Wallis and Wilcoxon tests to compare the delta lipids of the groups. The P value was 0.05. RESULTS: In the assessment between G-PR and G-DAAs groups, we included 63 and 121 patients, respectively. The groups did not differ one from the other (BMI, sex, genotype, fibrosis, total cholesterol, LDL, and TG) except by age (50.38±10.44 vs 56±9.69, P=0.0006). We observed a decrease in levels of TC and LDL and an increase in TG, in G-PR, and in G-DAAs the opposite (Δ TC -13.9±34.5 vs 4.12±34.3 P=0.0005, Δ LDL -7.16±32 vs 10.13±29.92, P=0.003, Δ TG 4.51±53.7 vs -8.24±49.93, P=0.0025). In the coorte analysis, we included 102 patients, 70% men and 56% F4, 95 of them reached SVR. We observed an increase of TC and LDL and a decrease of TG in both groups (SVR and non SVR), with no statistical difference (Δ TC P=0.68; Δ LDL P=0.69; Δ TG P=0.43). We did not find significant difference in delta evaluation by genotype 1 and 3 (Δ TC +29.7±40.2 vs +13.4±30.3, P=0.06; Δ LDL +21.4±28.6 vs +16.6±31.3, P=0.41; Δ TG -3.6±60.6 vs -0.7±40, P=0.91). CONCLUSION: Serum lipids level differed during treatment with Peg-IFN and DAAs. Treatment with DAAs was associated with an increase of TC and LDL and a decrease of TG, independently of SVR.

RESUMO CONTEXTO: A interação entre lípides séricos e infecção pelo vírus C já é bem conhecida, assim como o comportamento dos níveis séricos daqueles durante o tratamento com Peg-IFN/RBV. No entanto, com antivirais de ação direta (AADs) este comportamento ainda não está claro. OBJETIVO: Comparar os níveis séricos de lípides entre pacientes tratados com Peg-IFN/RBV e AADs e avaliar os lípides na resposta virológica sustentada (RVS) com AADs. MÉTODOS: Estudo retro prospectivo comparando o comportamento dos níveis séricos de colesterol total (CT), lipoproteínas de baixa densidade (LDL) e triglicérides (TG) durante o tratamento com AADs (G-AADs) e um grupo histórico de controle Peg-IFN/RBV (G-PR). Coorte, estudo prospectivo, para estudar o comportamento dos lípides na RVS com AADs. Os dados foram coletados no início do tratamento (baseline: t-base) e na décima segunda semana de tratamento (t-12) para G-AADs e na vigésima quarta semana de tratamento (t-24) para G-PR para a análise comparativa entre os dois grupos. Na avaliação de coorte, as amostras foram coletadas no t-base e na décima segunda semana após o término do tratamento (t-RVS). Delta lípides: diferença entre lípides em t-12/t-24 menos t-base para comparação entre os grupos G-PR e G-AADs e t-RVS menos t-base para análise de lípides na RVS. A análise estatística descritiva, os testes não paramétricos de Kruskal Wallis e Wilcoxon foram utilizados para comparar o delta lípides dos grupos. O valor de P considerado foi de 0,05. RESULTADOS: Na avaliação entre os grupos G-PR e G-AADs, incluímos 63 e 121 pacientes, respectivamente. Os grupos não diferiram um do outro (IMC, sexo, genótipo, fibrose, colesterol total, LDL e TG), exceto por idade (50,38±10,44 vs 56±9,69, P=0,0006). Observamos uma diminuição nos níveis de CT e LDL e um aumento de TG no G-PR, no G-AADs ocorreu o oposto (Δ CT -13,9±34,5 vs 4,12±34,3 P=0,0005, Δ LDL -7,16±32 vs 10,13±29,92, P=0,003, Δ TG 4,51±53,7 vs -8,24±49,93, P=0,0025). Na análise de coorte, foram incluídos 102 pacientes, 70% homens e 56% F4. Noventa e cinco deles atingiram a RVS. Observamos um aumento de CT e LDL e uma diminuição de TG em ambos os grupos (RVS e não RVS), sem diferença estatística (Δ CT P=0,68; Δ LDL P=0,69; Δ TG P=0,43). Não encontramos diferença significativa na avaliação dos deltas pelos genótipos 1 e 3 (Δ CT +29,7±40,2 vs +13,4±30,3, P=0,06; Δ LDL + 21,4±28,6 vs +16,6±31,3, P=0,41; Δ TG -3,6±60,6 vs -0,7±40, P=0,91). CONCLUSÃO: O nível de lípides séricos diferiu durante o tratamento com Peg-IFN/RBV e AADs. O tratamento com AADs foi associado a um aumento de CT e LDL e uma diminuição de TG, independentemente da RVS.

Fulminant cytomegalovirus myocarditis in an immunocompetent host: resolution with oral valganciclovir.

We report a case of fulminant myocarditis after a primary cytomegalovirus infection, in a previously healthy 72-year-old woman. The infection underwent clinical and immunologic resolution consequent to treatment with oral valganciclovir. In an immunocompetent host, the primary cytomegalovirus infection is usually asymptomatic or manifests itself as a heterophile-negative mononucleosis-like syndrome. Cytomegalovirus myocarditis is uncommon in immunocompetent patients. After presenting our case, we review the literature on cytomegalovirus myocarditis in immunocompetent individuals.