RESUMO
INTRODUCTION: Functional cure, defined as sustained HBsAg seroclearance, is associated with favorable outcomes in chronic hepatitis B (CHB). While nucleos(t)ide analogues (NAs) are effective in suppressing HBV replication, NAs are unable to induce functional cure at high rates. A range of novel HBV antivirals, aiming to induce functional cure, are currently under development. AREAS COVERED: This article covered novel hepatitis B virus (HBV) antivirals that have entered phase II trials. Virus-directing agents covered include entry inhibitors, transcription inhibitors, RNA silencers, core protein allosteric modulators, noncompetitive polymerase inhibitors, and viral protein export inhibitors. Immunomodulators covered include innate immune stimulators, T-cell modulators, therapeutic vaccines, and monoclonal antibodies. Upcoming developmental directions would also be discussed. EXPERT OPINION: Among novel HBV antivirals, RNA silencers, viral protein export inhibitors (with pegylated interferon), and entry inhibitors (with pegylated interferon) appear to be effective in suppressing HBsAg and may even induce functional cure. The other virus-targeting agents have variable effects on HBV DNA, HBsAg, HBeAg, and HBcrAg. Immunomodulators have modest effects on HBsAg but may have important roles in combination therapy. Upcoming trials will answer important questions on ideal dosing, long-term drug effects, and efficacy of combination regimens.
Assuntos
Hepatite B Crônica , Hepatite B , Antivirais/farmacologia , Antivirais/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Hepatite B/tratamento farmacológico , Antígenos de Superfície da Hepatite B/farmacologia , Antígenos de Superfície da Hepatite B/uso terapêutico , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Humanos , Fatores Imunológicos/farmacologia , Interferons/farmacologia , Interferons/uso terapêutico , Polietilenoglicóis , RNA/farmacologia , RNA/uso terapêutico , Proteínas Virais/farmacologia , Proteínas Virais/uso terapêuticoRESUMO
BACKGROUND & AIMS: NVR 3-778 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator that can inhibit HBV replication. We performed a proof-of-concept study to examine the safety, pharmacokinetics, and antiviral activity of NVR 3-778 in patients with chronic HBV infection. METHODS: We performed a phase 1 study in 73 hepatitis B envelope antigen (HBeAg)-positive patients with chronic HBV infection without cirrhosis. In a 2-part study (part 1 in New Zealand and part 2 in Hong Kong, Singapore, Taiwan, Korea, and the United States), patients were randomly assigned to groups that were given oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1000 mg twice daily) or placebo for 4 weeks. Additional groups received combination treatment with pegylated interferon (pegIFN) and NVR 3-778 (600 mg twice daily) or pegIFN with placebo. RESULTS: Reductions in serum levels of HBV DNA and HBV RNA were observed in patients receiving ≥1200 mg/d NVR 3-778. The largest mean reduction in HBV DNA was observed in the group given NVR 3-778 plus pegIFN (1.97 log10 IU/mL), compared with the groups given NVR 3-778 or pegIFN alone (1.43 log10 IU/mL and 1.06 log10 IU/mL, respectively). The mean reduction in HBV RNA was also greatest in the group given NVR 3-778 plus pegIFN (2.09 log10 copies/mL), compared with the groups given NVR 3-778 or pegIFN alone (1.42 log10 copies/mL and 0.89 log10 copies/mL, respectively). There was no significant mean reduction in HBsAg during the 4-week treatment period. There were no discontinuations and no pattern of dose-related adverse effects with NVR 3-778. CONCLUSIONS: In a phase 1 study of HBeAg-positive patients with chronic HBV infection without cirrhosis, NVR 3-778 was well tolerated and demonstrated antiviral activity. The agent reduced serum levels of HBV DNA and HBV RNA, to the greatest extent in combination with pegIFN. The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778. Clinicaltrials.gov no. NCT02112799 (single-center) and NCT02401737 (multicenter).
Assuntos
Antivirais/farmacocinética , Benzamidas/farmacocinética , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Piperidinas/farmacocinética , Replicação Viral/efeitos dos fármacos , Administração Oral , Adulto , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Ásia , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , DNA Viral/sangue , DNA Viral/genética , Esquema de Medicação , Quimioterapia Combinada , Feminino , Antígenos E da Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/crescimento & desenvolvimento , Vírus da Hepatite B/imunologia , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/virologia , Humanos , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Polietilenoglicóis/administração & dosagem , RNA Viral/sangue , RNA Viral/genética , Proteínas Recombinantes/administração & dosagem , Resultado do Tratamento , Estados Unidos , Carga Viral , Adulto JovemRESUMO
In-stent restenosis (ISR) remains the most common complication of percutaneous coronary intervention. Due to shared risk factors, it is postulated that non-alcoholic fatty liver disease (NAFLD) patients have an increased risk of ISR. This study aimed to determine the association between NAFLD and ISR in patients after bare metal stenting. This study included a cohort of 210 consecutive patients (150 men and 60 women) undergoing follow-up angiography. The primary end-point was angiographic ISR. Multivariate logistic regression analysis was used to identify independent risk factors for ISR. The cumulative ISR rate during follow-up was analyzed by Kaplan-Meier method. Subgroup analyses were also done for different gender. The ISR rate was 29.5%. Patients with NAFLD had a significantly higher prevalence of ISR than patients without NAFLD (43.3 vs. 16.0%, P < 0.001). In logistic regression analysis, NAFLD was associated with increased ISR, independent of low-density lipoprotein cholesterol, body mass index (adjusted odds ratio: 2.688, 95% confidence intervals: 1.285-5.537, P < 0.001). Male NAFLD patients had a higher prevalence of ISR than patients without NAFLD (48.4 vs. 15.3%, P < 0.001), while the prevalence of ISR in female patients with and without NAFLD were comparable (7.7 vs. 17.0%, P = 0.404). Kaplan-Meier analysis showed a significant association between NAFLD and ISR in all patients (log-rank P = 0.008) and in male subgroup (log-rank P = 0.033), but not in female subgroup (log-rank P = 0.313). This preliminary study suggests that NAFLD could independently associate with a high prevalence of ISR, especially in male patients.
Assuntos
Angiografia Coronária/efeitos adversos , Reestenose Coronária/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Intervenção Coronária Percutânea/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , LDL-Colesterol/sangue , Angiografia Coronária/instrumentação , Reestenose Coronária/sangue , Reestenose Coronária/patologia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Intervenção Coronária Percutânea/instrumentação , Fatores de Risco , Fatores Sexuais , Aço Inoxidável , StentsRESUMO
BACKGROUND/AIMS: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. METHODS: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. RESULTS: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1-2, and no linvencorvir-related serious adverse events were reported. CONCLUSION: 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.
Assuntos
Antivirais , Hepatite B Crônica , Imidazóis , Pirazinas , Humanos , Antivirais/efeitos adversos , Capsídeo , DNA Viral , Antígenos E da Hepatite B , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Polietilenoglicóis , RNA , Padrão de Cuidado , Resultado do TratamentoRESUMO
Currently approved treatment of patients with chronic hepatitis B infection is insufficient to achieve functional cure. Numerous new compounds are identified, and among many, capsid assembly modulators (CAMs) and nucleic acid polymers (NAPs) are 2 classes of virus-directing agents in clinical development. CAMs interfere with viral pregenomic RNA encapsidation and are effective in viral load reduction but have limited effects on hepatitis B surface antigen (HBsAg). NAPs prevent HBsAg release from hepatocytes and induce intracellular degradation, leading to potent suppression of serum HBsAg when combined with nucleoside analogues and pegylated interferon demonstrated by initial data, but awaiting further confirmation studies.
Assuntos
Hepatite B Crônica , Hepatite B , Ácidos Nucleicos , Humanos , Hepatite B Crônica/tratamento farmacológico , Antígenos de Superfície da Hepatite B , Capsídeo/metabolismo , Vírus da Hepatite B , Antivirais/uso terapêutico , Antivirais/farmacologia , Hepatite B/tratamento farmacológico , Desenvolvimento de Medicamentos , Ácidos Nucleicos/uso terapêutico , Ácidos Nucleicos/metabolismo , Ácidos Nucleicos/farmacologia , Polímeros/uso terapêutico , Polímeros/metabolismo , Polímeros/farmacologia , DNA ViralRESUMO
Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naïve and virally suppressed individuals with chronic HBV infection. The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration. Participants with CHB infection ≥6 months and serum HBsAg ≥50 IU ml-1 were enrolled from seven centers across Hong Kong and the Republic of Korea and randomized (3:1 within each dose cohort) to receive bepirovirsen or placebo via subcutaneous injection twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Participants were then followed for 26 weeks. Twenty-four participants were treatment-naïve and seven were receiving stable NA therapy. Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-naïve participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%). Transient, self-resolving alanine aminotransferase flares (≥2× upper limit of normal) were observed in eight treatment-naïve participants and three participants on stable NA regimens in the bepirovirsen treatment arms. HBsAg reductions were observed and were significant versus placebo for treatment-naïve participants receiving bepirovirsen 300 mg (P = 0.001), but not for the bepirovirsen 150 mg group (P = 0.245) or participants receiving stable NA therapy (P = 0.762). Two participants in each of the 300 mg dose groups achieved HBsAg levels below the lower limit of quantitation by day 29 (n = 3) or day 36 (n = 1). Bepirovirsen had a favorable safety profile. These preliminary observations warrant further investigation of the safety and activity of bepirovirsen in a larger CHB patient population.
Assuntos
Antivirais/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Oligonucleotídeos Antissenso/administração & dosagem , Adolescente , Adulto , Antivirais/efeitos adversos , Quimioterapia Combinada , Feminino , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/sangue , Hepatite B Crônica/genética , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos Antissenso/efeitos adversos , Placebos , Polietilenoglicóis/química , República da Coreia/epidemiologia , Adulto JovemAssuntos
Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Pirofosfatases/genética , Adolescente , Adulto , Idoso , Feminino , Genótipo , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Interferons , Interleucinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes , Ribavirina/uso terapêutico , Adulto JovemRESUMO
More than 170 million people worldwide are chronically infected with the hepatitis C virus (HCV), which is responsible for more than 100000 cases of liver cancer per year, with similar numbers of digestive haemorrhage and ascites episodes. Major breakthroughs have been made in diagnosis and treatment, and advances in molecular biology mean that the replicative state of the virus can now be assessed. Genotype and serum viral load are useful predictors of response to treatment. The combination of pegylated interferon and ribavirin can eradicate the virus in more than 50% of patients. These antiviral treatments reduce liver fibrosis progression and can reverse cirrhosis. Unfortunately, even in developed countries, death due to hepatitis C is increasing because of inadequate detection and treatment.
Assuntos
Hepatite C , Adulto , Antivirais/farmacologia , Antivirais/uso terapêutico , Comorbidade , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Humanos , Interferon alfa-2 , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Interferons/farmacologia , Interferons/uso terapêutico , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , RNA Viral/análise , RNA Viral/genética , RNA Viral/imunologia , Proteínas Recombinantes , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Sorotipagem , Índice de Gravidade de DoençaRESUMO
BACKGROUND: To date, no study has evaluated pegylated interferon for the treatment of chronic infection with hepatitis C virus (HCV) genotype 6. We aimed to determine the efficacy of pegylated interferon plus ribavirin for treating infection with genotype 6 versus genotype 1. METHODS: Forty-two patients chronically infected with HCV (for genotype 1, n = 21; for genotype 6, n = 21) were treated with pegylated interferon alpha-2a (n = 20) or alpha-2b (n = 22) combined with oral ribavirin for 48 weeks. RESULTS: There was no difference between genotypes 1 and 6 in the rates of early virological response (76% vs. 81%; P > .05) and end-of-treatment response (71% vs. 81%; ). Patients infected with genotype 6 had a higher rate of sustained virological response (SVR) than did patients infected with genotype 1 (86% vs. 52%; P = .019). The overall adverse-effects profile was similar in both genotype groups. There was no significant difference in the rate of SVR between patients receiving pegylated interferon alpha-2a and those receiving alpha-2b. Multivariate analysis showed that genotype was the only significant factor associated with SVR (P = .039). CONCLUSIONS: Treatment with pegylated interferon and ribavirin for 48 weeks resulted in a significantly higher rate of SVR in patients infected with genotype 6 than in those infected with genotype 1. Further studies are required to determine whether lower dosages and 24 weeks of therapy may be sufficient for the treatment of genotype 6 infection.