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INTRODUCTION: Hepatitis delta virus (HDV) causes acute and chronic liver disease that requires the co-infection of the Hepatitis B virus and can lead to significant morbidity and mortality. Bulevirtide is a recently introduced entry inhibitor drug that acts on the sodium taurocholate cotransporting peptide, thereby preventing viral entry to target cells in chronic HDV infection. The mainstay of chronic HDV therapy prior to bulevirtide was interferon alpha, which has an undesirable side effect profile. AREAS COVERED: We review bulevirtide data from recent clinical trials in Europe and the United States. Challenges to development and implementation of bulevirtide are discussed. Additionally, we review ongoing trials of emerging drugs for HDV, such as pegylated interferon lambda and lonafarnib. EXPERT OPINION: Bulevirtide represents a major shift in treatment for chronic HDV, for which there is significant unmet need. Trials that compared bulevirtide in combination with interferon alpha vs interferon alpha monotherapy demonstrated significant increase in virologic response. Overall, treatment with different doses of bulevirtide were comparable. Bulevirtide was generally well tolerated, and no serious adverse events occurred. Understanding the true prevalence of HDV, as well as continued studies of emerging drugs will prove valuable to the larger goal of eradication of Hepatitis D.
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Hepatitis D , Humanos , Hepatitis D/tratamiento farmacológico , Lipopéptidos/farmacología , Lipopéptidos/uso terapéutico , Interferón-alfa/efectos adversos , Virus de la Hepatitis Delta/fisiología , Virus de la Hepatitis B , Antivirales/efectos adversosRESUMEN
Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of diseases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of the largest comprehensive and high-resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop the first supervised tissue deconvolution approach, a deep-learning-powered model, cfSort, for sensitive and accurate tissue deconvolution in cfDNA. On the benchmarking data, cfSort showed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical utilities of cfSort with two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated from cfSort reflected the clinical outcomes of the patients. In summary, the tissue methylation atlas and cfSort enhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring.
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Ácidos Nucleicos Libres de Células , Aprendizaje Profundo , Humanos , Ácidos Nucleicos Libres de Células/genética , Metilación de ADN , Biomarcadores , Regiones Promotoras Genéticas , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND AND AIMS: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. APPROACH AND RESULTS: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n = 106) and an independent validation cohort ( n = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). CONCLUSION: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.
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Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Biomarcadores de Tumor/análisis , Vesículas Extracelulares/química , Proteínas de la Membrana , Electrocardiografía , GlipicanosRESUMEN
Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our approach to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, allowing us to learn new features and expand to other cancer types as training cohorts grow.
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Ácidos Nucleicos Libres de Células , Neoplasias Gástricas , Ácidos Nucleicos Libres de Células/genética , Análisis Costo-Beneficio , Detección Precoz del Cáncer , Epigenoma , Humanos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genéticaRESUMEN
BACKGROUND & AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV. METHODS: HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24. RESULTS: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury. CONCLUSIONS: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile. CLINICAL TRIAL NUMBER: NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.
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Antivirales , Hepatitis B Crónica , Humanos , Antivirales/efectos adversos , ADN Viral , Guanina/análogos & derivados , Antígenos e de la Hepatitis B , Virus de la Hepatitis B , Hepatitis B Crónica/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , ARN , Resultado del Tratamiento , Quimioterapia Combinada/efectos adversos , Método Doble CiegoRESUMEN
BACKGROUND & AIMS: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs. METHODS: Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS: Of 73 patients enrolled, 47 were HBeAgâpositive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS: In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. CLINICAL TRIALS NUMBER: NCT03576066. LAY SUMMARY: Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.
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Hepatitis B Crónica , Antivirales/efectos adversos , ADN Viral , Antígenos de Superficie de la Hepatitis B , Antígenos e de la Hepatitis B , Virus de la Hepatitis B/genética , HumanosRESUMEN
Numerous studies in hepatocellular carcinoma (HCC) have proposed tissue-based gene signatures for individualized prognostic assessments. Here, we develop a novel circulating tumor cell (CTC)-based transcriptomic profiling assay to translate tissue-based messenger RNA (mRNA) signatures into a liquid biopsy setting for noninvasive HCC prognostication. The HCC-CTC mRNA scoring system combines the NanoVelcro CTC Assay for enriching HCC CTCs and the NanoString nCounter platform for quantifying the HCC-CTC Risk Score (RS) panel in enriched HCC CTCs. The prognostic role of the HCC-CTC RS was assessed in The Cancer Genome Atlas (TCGA) HCC cohort (n = 362) and validated in an independent clinical CTC cohort (n = 40). The HCC-CTC RS panel was developed through our integrated data analysis framework of 8 HCC tissue-based gene signatures and identified the top 10 prognostic genes (discoidin domain receptor tyrosine kinase 1 [DDR1], enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase [EHHADH], androgen receptor [AR], lumican [LUM], hydroxysteroid 17-beta dehydrogenase 6[HSD17B6], prostate transmembrane protein, androgen induced 1 [PMEPA1], tsukushi, small leucine rich proteoglycan [TSKU], N-terminal EF-hand calcium binding protein 2 [NECAB2], ladinin 1 [LAD1], solute carrier family 27 member 5 [SLC27A5]) highly expressed in HCC with low expressions in white blood cells. The panel accurately discriminated overall survival in TCGA HCC cohort (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.4-2.9). The combined use of the scoring system and HCC-CTC RS panel successfully distinguished artificial blood samples spiked with an aggressive HCC cell type, SNU-387, from those spiked with PLC/PRF/5 cells (P = 0.02). In the CTC validation cohort (n = 40), HCC-CTC RS remained an independent predictor of survival (HR, 5.7; 95% CI, 1.5-21.3; P = 0.009) after controlling for Model for End-Stage Liver Disease score, Barcelona Clinic Liver Cancer stage, and CTC enumeration count. Our study demonstrates a novel interdisciplinary approach to translate tissue-based gene signatures into a liquid biopsy setting. This noninvasive approach will allow real-time disease profiling and dynamic prognostication of HCC.
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Carcinoma Hepatocelular , Enfermedad Hepática en Estado Terminal , Neoplasias Hepáticas , Trasplante de Hígado , Células Neoplásicas Circulantes , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Células Neoplásicas Circulantes/metabolismo , Pronóstico , ARN Mensajero/genética , Índice de Severidad de la EnfermedadRESUMEN
Transcriptomic profiling of tumor tissues introduces a large database, which has led to improvements in the ability of cancer diagnosis, treatment, and prevention. However, performing tumor transcriptomic profiling in the clinical setting is very challenging since the procurement of tumor tissues is inherently limited by invasive sampling procedures. Here, we demonstrated the feasibility of purifying hepatocellular carcinoma (HCC) circulating tumor cells (CTCs) from clinical patient samples with improved molecular integrity using Click Chips in conjunction with a multimarker antibody cocktail. The purified CTCs were then subjected to mRNA profiling by NanoString nCounter platform, targeting 64 HCC-specific genes, which were generated from an integrated data analysis framework with 8 tissue-based prognostic gene signatures from 7 publicly available HCC transcriptomic studies. After bioinformatics analysis and comparison, the HCC CTC-derived gene signatures showed high concordance with HCC tissue-derived gene signatures from TCGA database, suggesting that HCC CTCs purified by Click Chips could enable the translation of HCC tissue molecular profiling into a noninvasive setting.
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Hepatitis B virus reactivation (HBVr) can occur spontaneously, but more often occurs when a patient is in an immunocompromised state or on immunosuppressive therapy. HBVr can lead to clinical hepatitis, acute liver failure, and even death. HBVr is preventable with screening of at-risk patients and initiation of prophylactic antiviral therapy for appropriate candidates. Screening for hepatitis B virus is recommended for all patients who plan to initiate immunosuppressive therapy. An individual's serological profile, underlying disease, and planned type of immunosuppression contribute to their risk of HBVr. This review serves to summarize the major society guidelines regarding screening, management of, and monitoring for HBVr in individuals on anticancer therapy and immunosuppressive therapy.
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Hepatitis B , Activación Viral , Antivirales/efectos adversos , Hepatitis B/diagnóstico , Hepatitis B/tratamiento farmacológico , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Humanos , Inmunosupresores/uso terapéuticoRESUMEN
We report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific extracellular vesicle (EV) purification system for early detection of HCC by performing digital scoring on the purified EVs. Earlier detection of HCC creates more opportunities for curative therapeutic interventions. EVs are present in circulation at relatively early stages of disease, providing potential opportunities for HCC early detection. We develop an HCC EV purification system (i.e., EV Click Chips) by synergistically integrating covalent chemistry-mediated EV capture/release, multimarker antibody cocktails, nanostructured substrates, and microfluidic chaotic mixers. We then explore the translational potential of EV Click Chips using 158 plasma samples of HCC patients and control cohorts. The purified HCC EVs are subjected to reverse-transcription droplet digital PCR for quantification of 10 HCC-specific mRNA markers and computation of digital scoring. The HCC EV-derived molecular signatures exhibit great potential for noninvasive early detection of HCC from at-risk cirrhotic patients with an area under receiver operator characteristic curve of 0.93 (95% CI, 0.86 to 1.00; sensitivity = 94.4%, specificity = 88.5%).
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Biomarcadores de Tumor/aislamiento & purificación , Carcinoma Hepatocelular/diagnóstico , Detección Precoz del Cáncer/métodos , Vesículas Extracelulares/genética , Neoplasias Hepáticas/diagnóstico , Anciano , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Estudios de Casos y Controles , Química Clic/instrumentación , Química Clic/métodos , Química Computacional , Simulación por Computador , Diagnóstico Diferencial , Dimetilpolisiloxanos/química , Progresión de la Enfermedad , Detección Precoz del Cáncer/instrumentación , Femenino , Células Hep G2 , Humanos , Dispositivos Laboratorio en un Chip , Biopsia Líquida/instrumentación , Biopsia Líquida/métodos , Cirrosis Hepática/sangre , Cirrosis Hepática/patología , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Técnicas Analíticas Microfluídicas/instrumentación , Técnicas Analíticas Microfluídicas/métodos , Persona de Mediana Edad , Nanoestructuras/química , Nanocables/química , Estadificación de Neoplasias , ARN Mensajero/genética , ARN Mensajero/aislamiento & purificación , Curva ROC , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/instrumentación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosRESUMEN
BACKGROUND: Limited data exist with regard to treatment outcomes in Asian Americans with chronic hepatitis C (CHC). We evaluated sofosbuvir (SOF)-based regimens in a national cohort of Asian Americans. METHODS: Eligible Asian Americans patients with CHC who had posttreatment follow-up of 24 weeks for SOF -based therapies from December 2013 to June 2017 were enrolled from 11 sites across the United States. The primary endpoint was sustained virologic response (SVR) rates at posttreatment weeks 12 and 24. Secondary endpoints were to evaluate safety by tolerability and adverse events (AEs). RESULTS: Among 231 patients screened, 186 were enrolled. At baseline, 31% (57/186) patients were cirrhotic, 34% (63/186) were treatment experienced. Most of the subjects (42%, 79/186) received ledispavir/SOF therapy. The overall SVR12 was 95%, ranging from 86% in genotype (GT) 1b on SOF+ribavirin to 100% in GT 1b patients on ledipasvir/SOF at subgroup analyses. SVR12 was significantly lower in cirrhotic than in noncirrhotic patients [88% (50/57) vs. 98% (126/129), P<0.01]. Stratified by GT, SVR12 were: 96% (43/45) in GT 1a; 93% (67/72) in GT 1b; 100% (23/23) in GT 2; 90% (19/21) in GT 3; 100% (1/1) in GT 4; 83% (5/6) in GT 5; and 100% (16/16) in GT 6. Cirrhotic patients with treatment failure were primarily GT 1, (GT 1a, n=2; GT 1b, n=4) with 1 GT 5 (n=1). Patients tolerated the treatment without serious AEs. Late relapse occurred in 1 patient after achieving SVR12. CONCLUSIONS: In Asian Americans with CHC, SOF-based regimens were well tolerated without serious AEs and could achieve high SVR12 regardless of hepatitis C viral infection GT.
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Antivirales/administración & dosificación , Asiático , Hepatitis C Crónica/tratamiento farmacológico , Sofosbuvir/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Bencimidazoles/administración & dosificación , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Fluorenos/administración & dosificación , Estudios de Seguimiento , Genotipo , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/virología , Humanos , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Ribavirina/administración & dosificación , Respuesta Virológica Sostenida , Resultado del Tratamiento , Uridina Monofosfato/administración & dosificación , Uridina Monofosfato/análogos & derivados , Adulto JovenRESUMEN
Background and Aims: Recurrent hepatitis C (HCV) disease in liver transplant (LT) recipients is associated with significant morbidity and mortality. With the availability of noninterferon-based therapy, eliminating HCV may be achievable in LT recipients. Methods: We studied all consecutive recipients who underwent LT at the University of California Los Angeles between January 2005 and June 2017. We collected data on date of transplant and last follow-up, as well as laboratory values. We also recorded type and timing of antiviral therapy relative to LT. Analyses were performed to assess the proportion of LT recipients who are viremic after transplant. Results: Six hundred thirty-four patients underwent LT with a diagnosis of HCV. There was a statistically significant trend for patients to be cured before (p < 0.001) and after liver transplantation (p < 0.001) for the study period of 2014 to 2016 relative to 2005 and 2013, respectively. Of the 634 recipients eligible for therapy, 8% and 74% were treated within 12 months of transplant for the study periods 2005 to 2013 and 2014 to 2016, respectively. There was a significant decrease between the two study periods in the proportion of patients undergoing re-LT 1 year after the original LT: 5.5% (n = 28/510) and 1.5% (n = 2/124) respectively for study periods 2005 to 2013 and 2014 to 2016 respectively (p = 0.011). Conclusions: The proportion of LT recipients who are viremic has decreased over time. Eliminating HCV in LT recipients is feasible after the introduction of direct-acting agents. Curing HCV should translate to improved clinical outcomes in LT recipients who were transplanted for HCV infection with longer follow-up. Preliminary results suggest the decreased need for transplant in the direct-acting agents era.
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OBJECTIVES: The impact of achieving a sustained viral response on extrahepatic manifestations after liver transplant is unclear. In this study, our aim was to evaluate whether sustained viral responses in hepatitis C-positive liver transplant recipients can lead to improved nonhepatic outcomes. MATERIALS AND METHODS: We studied 84 consecutive liver transplant recipients who achieved a sustained viral response with direct-acting antiviral agents at the University of California Los Angeles. We collected laboratory data before and after the sustained viral response was achieved. Paired t tests were performed. RESULTS: The mean age and standard deviation of our cohort was 62.4 ± 7.6 years. The mean time from achieving a sustained viral response to last follow-up in our cohort was 19.5 ± 10.8 months. In the entire cohort, there were no changes in mean fasting blood glucose (123 ± 42 vs 120 ± 35 mg/dL; P = .49). We observed a significant improvement in renal function in recipients with stage 1 and 2 chronic kidney disease (82 ± 15 vs 71.16 ± 16 mL/min/1.73 m2; P ⟨ .001) and in those treated within 3 months of liver transplant (75 ± 28 vs 61 ± 16 mL/min/1.73 m2; P = .035). Fasting blood glucose decreased in recipients with a diagnosis of impaired fasting blood glucose (109 ± 16 vs 103 ± 13 mg/dL; P = .001). CONCLUSIONS: The benefits on glucose metabolism and renal function after a sustained viral response in liver transplant recipients appear to be limited to those with early chronic kidney disease and those treated soon after transplant. The potential benefits from direct-acting antiviral agents on these parameters may be overshadowed by the effects of immunosuppressant therapy.
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Antivirales/uso terapéutico , Glucemia/efectos de los fármacos , Tasa de Filtración Glomerular/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Riñón/efectos de los fármacos , Trasplante de Hígado , Respuesta Virológica Sostenida , Anciano , Antivirales/efectos adversos , Biomarcadores/sangre , Glucemia/metabolismo , Femenino , Hepacivirus/patogenicidad , Hepatitis C/diagnóstico , Hepatitis C/virología , Humanos , Inmunosupresores/efectos adversos , Riñón/fisiopatología , Trasplante de Hígado/efectos adversos , Los Angeles , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Ascitis/diagnóstico por imagen , Ascitis/etiología , Taponamiento Cardíaco/diagnóstico por imagen , Ecocardiografía , Derrame Pericárdico/diagnóstico por imagen , Pericarditis Constrictiva/diagnóstico por imagen , Taponamiento Cardíaco/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Derrame Pericárdico/complicaciones , Pericarditis Constrictiva/complicacionesRESUMEN
Background and Aims: Recurrent infection of hepatitis C virus (HCV) in liver transplant (LT) recipients is universal and associated with significant morbidity and mortality. Methods: We retrospectively evaluated the safety and efficacy of ledipasvir/sofosbuvir with and without ribavirin in LT recipients with recurrent genotype 1 hepatitis C. Results: Eighty-five LT recipients were treated for recurrent HCV with ledipasvir/sofosbuvirwith and without ribavirin for 12 or 24 weeks. The mean (± standard deviation [SD]) time from LT to treatment initiation was 68 (±71) months. The mean (± SD) age of the cohort was 63 (±8.6) years old. Most recipients were male (70%). Baseline alanine transaminase, total bilirubin, and HCV ribonucleic acid (RNA) values (± SD) were 76.8 (±126) mg/dL, 0.8 (±1.3) U/L, and 8,010,421.9 (±12,420,985) IU/mL, respectively. Five of 43 recipients who were treated with ribavirin required drug cessation due to side effects, with 4 of those being anemia complications. No recipient discontinued the ledipasvir/sofosbuvir. Eighty-one percent of recipients had undetectable viral levels at 4 weeks after starting therapy, and all recipients had complete viral suppression at the end of therapy. The sustained viral response at 12 weeks after completion of therapy was 94%. Conclusion : Ledipasvir and sofosbuvir with and without ribavirin therapy is an effective and well-tolerated interferon-free treatment for recurrent HCV infection after LT. Anemia is not uncommon in LT recipients receiving ribavirin.
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Background and Aims: The lack of specificity has limited the role of serum alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) screening among patients with cirrhosis related to hepatitis C virus (HCV) infection. We sought to examine whether AFP may decrease after achieving a sustained virological response (SVR) in patients with HCV-related cirrhosis. Methods: We performed a retrospective study of patients with HCV-related cirrhosis who were cured with direct-acting antiviral (DAA) therapy at the University of California, Los Angeles. Laboratory values, including serum AFP, were measured before and after completing the DAA treatment. Results: Fifty-six patients met the inclusion criteria, with median (interquartile range [IQR]) age of 67 (58-69) years and with 51.8% being male. All patients received DAA therapy without interferon. AFP decreased from median (IQR) 7.2 (4.2-13.4) ng/mL before DAAs to 4.2 (2.7-6.3) ng/mL at the end of treatment and 4.2 (2.9-6.8) ng/mL at 12 weeks after treatment (p < 0.001). Model for end-stage liver disease (MELD), fibrosis-4 (FIB4), and aspartate transaminase (AST) to platelet ratio index (APRI) scores at baseline were not significantly associated with AFP reduction. On multivariate analysis, platelet count, AST and total bilirubin at baseline were significantly correlated to AFP reduction (p = 0.04, 0.009 and 0.04, respectively). The higher the baseline AFP, the greater the reduction in AFP. There was no statistically significant correlation between baseline AFP and MELD, FIB4 or APRI scores. Conclusion: There was a significant decrease in AFP in patients with cirrhosis who achieved a SVR with DAAs. Given a reduction in AFP after DAA treatment, AFP should be further studied as a screening modality for HCC in patients with cirrhosis.
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BACKGROUND: The use of direct acting agents has changed the management paradigm of hepatitis C (HCV) in liver transplant (LT) recipients. However, the appropriate antiviral regimen in LT recipients on hemodialysis (HD) remains unclear. METHODS: We retrospectively evaluated the safety and efficacy of sofosbuvir-based LT recipients on HD followed at the University of California Los Angeles. RESULTS: Twelve LT recipients on HD were treated for recurrent HCV with sofosbuvir-based therapy. Indications for antiviral therapy included fibrosing cholestatic hepatitis, symptomatic cryoglobulinemia, and recurrent HCV. The causes of renal failure included hepatorenal syndrome, acute tubular necrosis and cryoglobulinemia. Of those who were not on dialysis at the time of transplantation, the mean creatinine (±SD) was 1.7 (±0.8) mg/dL. The mean age (±SD) of the cohort was 62.2 (±6.0) years. Most recipients were male (67%) and infected with genotype 1 (83%). Baseline alanine aminotransferase, total bilirubin, hemoglobin and HCV RNA values (±SD) were 53.2 (±59.4) IU/L, 3.2 (±5.5) mg/dL, 10.5 (±1.8) g/dL, and 30,499,500 (±29,655,754) IU/mL. HCV RNA levels were undetectable in all recipients at the end of therapy. The trough mean (±SD) hemoglobin of patients on treatment and on HD was 8.4 (±2.3). The sustained viral response was 58% (7/12), and the overall patient survival was 42%. All the deaths occurred a mean (±SD) after 5.4 (±3.6) months after treatment was completed. CONCLUSIONS: All patients achieved viral suppression from therapy, and over half the recipients achieved a sustained virological response. A high mortality underscores the necessity of starting antiviral treatment sooner in LT recipients and the need for larger cohort studies.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Trasplante de Hígado , Complicaciones Posoperatorias/tratamiento farmacológico , Diálisis Renal , Sofosbuvir/uso terapéutico , Anciano , Femenino , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/virología , Diálisis Renal/métodos , Estudios Retrospectivos , Respuesta Virológica SostenidaRESUMEN
BACKGROUND & AIMS: GS-4774 is a heat-inactivated, yeast-based, T-cell vaccine designed to elicit hepatitis B virus (HBV)-specific T-cell responses. We evaluated the safety, tolerability and efficacy of GS-4774 in patients with chronic HBV infection. METHODS: In this phase II study, 178 patients with chronic HBV infection and no cirrhosis who were virally suppressed on an oral antiviral (OAV) for ⩾1year were randomized (1:2:2:2) to continue OAV alone or receive OAV plus GS-4774 2, 10, or 40 yeast units (YU) subcutaneously every 4weeks until week 20. OAV was continued for the remainder of the study. Efficacy was measured by decline in serum hepatitis B surface antigen (HBsAg) from baseline to week 24. RESULTS: Baseline characteristics were similar across groups (mean age, 45-50years; male, 62-74%; Asian, 68-80%; hepatitis B e antigen (HBeAg)-positive, 24-26%; mean HBsAg, 2.5-3.1log10IU/ml). There were no significant differences between groups in mean HBsAg declines from baseline to week 24 or 48. Five HBeAg-positive patients receiving GS-4774 experienced HBeAg loss vs. none in the control group. Three GS-4774 40 YU-treated patients had HBsAg declines ⩾0.5log10IU/ml, but no patient experienced loss of serum HBsAg. No virologic breakthrough occurred. Injection site reactions were the most frequent adverse event (AE), and there were no treatment discontinuations. CONCLUSIONS: GS-4774 was well tolerated, but did not provide significant reductions in serum HBsAg in virally suppressed patients with chronic hepatitis B. Efficacy of GS-4774 in treatment-naïve patients remains to be determined. LAY SUMMARY: GS-4774 is a therapeutic vaccine designed to improve the immune response against hepatitis B virus (HBV) in patients who already have chronic infection with HBV. In this study, GS-4774 was safe and well tolerated in patients with chronic HBV infection receiving oral antiviral therapy, but did not result in a clinical benefit. Combination approaches with other agents, and evaluation in other populations of patients with HBV are ongoing to determine if GS-4774 might have a therapeutic benefit. CLINICAL TRIAL REGISTRATION NUMBER: NCT01943799.