KEYUR PATEL - Academia.edu (original) (raw)
Papers by KEYUR PATEL
Case Reports in Clinical Pathology, 2014
Fulminant hepatitis is a rare complication of herpes simplex virus (HSV-1 and HSV-2). Another rar... more Fulminant hepatitis is a rare complication of herpes simplex virus (HSV-1 and HSV-2). Another rare cause of fulminant hepatitis in pregnant women is acute fatty liver of pregnancy (AFLP). Here we present a female with fulminant hepatitis after a cesarean section whose infant clinically decompensated in the early neonatal period. Mother and child were diagnosed with fulminant hepatic failure from HSV, and the mother was found to have coexistent fatty liver of pregnancy on biopsy. Thus, two rare causes of fulminant hepatitis were co-morbid in the same patient. Rapid diagnosis enabled successful treatment, and both mother and infant recovered well.
Hepatology, 2015
Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral... more Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral replication. Chronic HCV infection is associated with altered metabolism, including dyslipidemia and insulin resistance (IR), which contributes to disease progression and influences response to therapy. To further understand the impact of HCV infection on host metabolism, we examined changes in serum lipid profiles and intrahepatic expression of lipid-related genes during interferon (IFN)-free treatment of chronic HCV, genotype 1 infection with sofosbuvir and ribavirin (RBV), and explored associations with treatment outcome. Serum lipids (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TGs]) and hemoglobin A1C (HbA1C) were measured during treatment, while gene expression of lipid-related genes was assessed using paired pre- and end-of-treatment (EOT) liver biopsies from 8 patients (n = 7 sustained virologic response [SVR]; n = 1 relapse) and unpaired EOT liver biopsies from 25 patients (n = 17 SVR; n = 8 relapse). Serum LDL concentration and particle size increased early in therapy, whereas TG concentration and very-low-density lipoprotein particle size decreased concomitantly, irrespective of treatment outcome. Whereas LDL increased in patients regardless of treatment outcome, average LDL concentration was lower at baseline and post-treatment in patients who relapsed. Analysis of paired liver biopsies revealed altered expression of genes associated with lipid transport, assembly, and signaling. In unpaired EOT liver biopsies, intrahepatic expression of fatty acid metabolism and lipid transport genes was lower in patients who experienced treatment relapse. Conclusion: Clearance of HCV using an IFN-free antiviral regimen results in rapid changes in peripheral and intrahepatic metabolic pathways, implicating a direct effect of HCV replication on lipid homeostasis. (Hepatology 2014).
The New England journal of medicine, Jan 16, 2013
Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment wit... more Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection. We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin (207 patients) or matching placebo (71) for 12 weeks. In a second trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks (103 patients) or 16 weeks (98). The primary end point was a sustained virologic response at 12 weeks after therapy. Among patients for whom treatment with peginterferon was not an option, the rate of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, -23 percentage points; 95% CI, -35 to -11;…
Current Gastroenterology Reports, 2009
Advanced liver disease and interferon-based treatment are both associated with varying degrees of... more Advanced liver disease and interferon-based treatment are both associated with varying degrees of cytopenia in patients with chronic hepatitis C. Growth factors to increase hemoglobin and neutrophils are commonly used in clinical practice, despite the absence of data to indicate benefits in terms of sustained viral response. Thrombocytopenia is observed frequently, is multi-factorial in etiology, and may result in significant limitations on interventional and therapeutic options. A small-molecule thrombopoietin mimetic, eltrombo-pag, has demonstrated a dose-response associated increase in platelet count in a phase 2 study, allowing initiation and completion of a 12-week course of peginterferon plus ribavirin in 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, or 75 mg of eltrombopag daily, respectively, compared with 6% in the placebo arm. Phase 3 studies are currently evaluating whether initiating and maintaining antiviral therapy with eltrombopag will lead to an increase in sustained virologic response in chronic hepatitis C infection.
Clinics in Liver Disease, 2005
McDonald/Evidence-Based Gastroenterology and Hepatology, 2010
Current Hepatitis Reports, 2008
Current Gastroenterology Reports, 2004
Chronic hepatitis C infection is associated with significant morbidity and mortality in addition ... more Chronic hepatitis C infection is associated with significant morbidity and mortality in addition to substantial social and health-related costs. Since the identification of the virus and determination of the HCV genome over a decade ago, considerable progress has been made in the treatment of chronic hepatitis C infection. However, the current standard combination of interferon-based therapies and ribavirin is effective in only 50% of patients. In addition, this combination is expensive, requires lengthy periods of administration, and is associated with significant side effects. Furthermore, no effective preventive measure, such as vaccination, is currently available. A number of newer therapies, including protease and helicase inhibitors, ribozymes, antisense therapies, and therapeutic vaccines, are in preclinical and clinical development and may significantly enhance existing therapeutic options for the future.
Current Hepatitis Reports, 2006
Current Hepatitis Reports, 2004
Current Gastroenterology Reports, 2010
Progressive hepatic fibrosis is the final common pathway for most chronic liver injuries, leading... more Progressive hepatic fibrosis is the final common pathway for most chronic liver injuries, leading to cirrhosis with risk of liver failure and hepatocellular carcinoma. It is now recognized that fibrosis is a dynamic process, and may be reversible prior to the establishment of advanced architectural changes to the liver. The most effective antifibrotic strategy is to cure the underlying disease process before advanced fibrosis has developed. Unfortunately, this is often not possible, and specific antifibrotic therapies are needed. Advances in the understanding of the pathogenesis of liver fibrosis have identified several potential novel therapeutic targets, but unfortunately clinical development has been disappointing. One major limitation has been the often prolonged natural history of fibrosis compared to experimental models, and difficulties in accurate noninvasive fibrosis assessment, thus making clinical trial design difficult. In this review, we highlight the most promising current antifibrotic strategies.
Clinics in Liver Disease, 2009
The current standard of care for the treatment of hepatitis C virus infection, pegylated interfer... more The current standard of care for the treatment of hepatitis C virus infection, pegylated interferon-alpha and ribavirin, is costly, associated with significant side effects, and effective in only 50% of patients. There is therefore a need for the development of novel antiviral therapies. One such approach involves the application of gene silencing technologies, including antisense oligonucleotides, ribozymes, RNA interference, and aptamers. However, despite great scientific advances over the past decade, and promising in vitro data, several significant challenges continue to limit the translation of this technology to the clinical setting. This review provides a concise update of the current literature.
Current Gastroenterology Reports, 2004
Chronic hepatitis C infection is associated with significant morbidity and mortality in addition ... more Chronic hepatitis C infection is associated with significant morbidity and mortality in addition to substantial social and health-related costs. Since the identification of the virus and determination of the HCV genome over a decade ago, considerable progress has been made in the treatment of chronic hepatitis C infection. However, the current standard combination of interferon-based therapies and ribavirin is effective in only 50% of patients. In addition, this combination is expensive, requires lengthy periods of administration, and is associated with significant side effects. Furthermore, no effective preventive measure, such as vaccination, is currently available. A number of newer therapies, including protease and helicase inhibitors, ribozymes, antisense therapies, and therapeutic vaccines, are in preclinical and clinical development and may significantly enhance existing therapeutic options for the future.
Clinics in Liver Disease, 2005
Clinics in Liver Disease, 2004
Hepatic steatosis is a common histologic feature observed in patients with chronic hepatitis C (C... more Hepatic steatosis is a common histologic feature observed in patients with chronic hepatitis C (CHC) . Even when well-defined causes of liver steatosis such as obesity, alcohol, type 2 diabetes, and hyperlipidemia are excluded, a significant number (30% to 40%) of hepatitis C virus (HCV) patients still have intrahepatic fat accumulation . The exact mechanisms of how HCV causes steatosis are not well understood; however, the published literature has elucidated some aspects of this relationship, suggesting a complex interplay between host and viral factors. HCV patients with steatosis are more likely to have a high body mass index (BMI), hyperlipidemia, and type II diabetes . Additionally, viral factors, particularly HCV genotype, have been implicated as critical determinants of the level of steatosis. More recently, steatosis has been shown to negatively impact response to antiviral therapy , increase the rate of fibrosis progression , and influence the development of hepatocellular carcinoma .
Journal of Hepatology, 2005
Hepatitis Prevention and Treatment, 2004
Since the identification of the hepatitis C virus (HCV) in the 1980s [1] and determination of the... more Since the identification of the hepatitis C virus (HCV) in the 1980s [1] and determination of the HCV genome in 1991 [2], there has been considerable progress in the management of chronic hepatitis C (CHC) in terms of achieving viral eradication and improving histology. Interferons (IFNs) were among the first agents used in the mid 1980s for the treatment of
Liver Transplantation, 2006
Improved understanding of hepatitis C virus (HCV) dynamics during and after liver transplantation... more Improved understanding of hepatitis C virus (HCV) dynamics during and after liver transplantation can be useful in optimizing antiviral therapy in transplant recipients. We analyzed serum HCV ribonucleic acid (RNA) levels during and after cadaveric liver transplantation in 6 HCV patients. After removal of the liver and before the new liver started producing virions, HCV RNA levels dropped with an average half-life (t1/2) of 0.8 hours. Viral loads then continued to drop up to 23 hours postimplantation (t1/2 = 3.4 hours), and began to rise (doubling-time = 2.0 days) as soon as 15 hours after the anhepatic phase. In 3 patients the viral load reached a plateau before rising, suggesting that a nonhepatic source supplied virions and balanced their intrinsic clearance. However, from the decline in viral load over the first 24 hours of the postanhepatic phase, we estimate that nonhepatic sources can at most correspond to 4% of total viral production, 96% of which occurs in the liver, even after we corrected for fluid exchanges during surgery. As the new liver was reinfected, production increased and viral load rose to a new steady state. Using nonlinear regression, we were able to fit the patients' HCV RNA data to a viral dynamic model and estimate the de novo infection rate (mean 1.5 × 10−6 mL/virion/day), as well as the average percentage of hepatocytes infected at the posttransplantation steady state (19%). In conclusion, we have quantified liver reinfection dynamics in the absence of posttransplantation antiviral therapy. Our findings support the notion that early antiviral therapy may delay or prevent reinfection. Liver Transpl 12:207–216, 2006. © 2006 AASLD.
Case Reports in Clinical Pathology, 2014
Fulminant hepatitis is a rare complication of herpes simplex virus (HSV-1 and HSV-2). Another rar... more Fulminant hepatitis is a rare complication of herpes simplex virus (HSV-1 and HSV-2). Another rare cause of fulminant hepatitis in pregnant women is acute fatty liver of pregnancy (AFLP). Here we present a female with fulminant hepatitis after a cesarean section whose infant clinically decompensated in the early neonatal period. Mother and child were diagnosed with fulminant hepatic failure from HSV, and the mother was found to have coexistent fatty liver of pregnancy on biopsy. Thus, two rare causes of fulminant hepatitis were co-morbid in the same patient. Rapid diagnosis enabled successful treatment, and both mother and infant recovered well.
Case Reports in Clinical Pathology, 2014
Fulminant hepatitis is a rare complication of herpes simplex virus (HSV-1 and HSV-2). Another rar... more Fulminant hepatitis is a rare complication of herpes simplex virus (HSV-1 and HSV-2). Another rare cause of fulminant hepatitis in pregnant women is acute fatty liver of pregnancy (AFLP). Here we present a female with fulminant hepatitis after a cesarean section whose infant clinically decompensated in the early neonatal period. Mother and child were diagnosed with fulminant hepatic failure from HSV, and the mother was found to have coexistent fatty liver of pregnancy on biopsy. Thus, two rare causes of fulminant hepatitis were co-morbid in the same patient. Rapid diagnosis enabled successful treatment, and both mother and infant recovered well.
Hepatology, 2015
Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral... more Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral replication. Chronic HCV infection is associated with altered metabolism, including dyslipidemia and insulin resistance (IR), which contributes to disease progression and influences response to therapy. To further understand the impact of HCV infection on host metabolism, we examined changes in serum lipid profiles and intrahepatic expression of lipid-related genes during interferon (IFN)-free treatment of chronic HCV, genotype 1 infection with sofosbuvir and ribavirin (RBV), and explored associations with treatment outcome. Serum lipids (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TGs]) and hemoglobin A1C (HbA1C) were measured during treatment, while gene expression of lipid-related genes was assessed using paired pre- and end-of-treatment (EOT) liver biopsies from 8 patients (n = 7 sustained virologic response [SVR]; n = 1 relapse) and unpaired EOT liver biopsies from 25 patients (n = 17 SVR; n = 8 relapse). Serum LDL concentration and particle size increased early in therapy, whereas TG concentration and very-low-density lipoprotein particle size decreased concomitantly, irrespective of treatment outcome. Whereas LDL increased in patients regardless of treatment outcome, average LDL concentration was lower at baseline and post-treatment in patients who relapsed. Analysis of paired liver biopsies revealed altered expression of genes associated with lipid transport, assembly, and signaling. In unpaired EOT liver biopsies, intrahepatic expression of fatty acid metabolism and lipid transport genes was lower in patients who experienced treatment relapse. Conclusion: Clearance of HCV using an IFN-free antiviral regimen results in rapid changes in peripheral and intrahepatic metabolic pathways, implicating a direct effect of HCV replication on lipid homeostasis. (Hepatology 2014).
The New England journal of medicine, Jan 16, 2013
Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment wit... more Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection. We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin (207 patients) or matching placebo (71) for 12 weeks. In a second trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks (103 patients) or 16 weeks (98). The primary end point was a sustained virologic response at 12 weeks after therapy. Among patients for whom treatment with peginterferon was not an option, the rate of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, -23 percentage points; 95% CI, -35 to -11;…
Current Gastroenterology Reports, 2009
Advanced liver disease and interferon-based treatment are both associated with varying degrees of... more Advanced liver disease and interferon-based treatment are both associated with varying degrees of cytopenia in patients with chronic hepatitis C. Growth factors to increase hemoglobin and neutrophils are commonly used in clinical practice, despite the absence of data to indicate benefits in terms of sustained viral response. Thrombocytopenia is observed frequently, is multi-factorial in etiology, and may result in significant limitations on interventional and therapeutic options. A small-molecule thrombopoietin mimetic, eltrombo-pag, has demonstrated a dose-response associated increase in platelet count in a phase 2 study, allowing initiation and completion of a 12-week course of peginterferon plus ribavirin in 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, or 75 mg of eltrombopag daily, respectively, compared with 6% in the placebo arm. Phase 3 studies are currently evaluating whether initiating and maintaining antiviral therapy with eltrombopag will lead to an increase in sustained virologic response in chronic hepatitis C infection.
Clinics in Liver Disease, 2005
McDonald/Evidence-Based Gastroenterology and Hepatology, 2010
Current Hepatitis Reports, 2008
Current Gastroenterology Reports, 2004
Chronic hepatitis C infection is associated with significant morbidity and mortality in addition ... more Chronic hepatitis C infection is associated with significant morbidity and mortality in addition to substantial social and health-related costs. Since the identification of the virus and determination of the HCV genome over a decade ago, considerable progress has been made in the treatment of chronic hepatitis C infection. However, the current standard combination of interferon-based therapies and ribavirin is effective in only 50% of patients. In addition, this combination is expensive, requires lengthy periods of administration, and is associated with significant side effects. Furthermore, no effective preventive measure, such as vaccination, is currently available. A number of newer therapies, including protease and helicase inhibitors, ribozymes, antisense therapies, and therapeutic vaccines, are in preclinical and clinical development and may significantly enhance existing therapeutic options for the future.
Current Hepatitis Reports, 2006
Current Hepatitis Reports, 2004
Current Gastroenterology Reports, 2010
Progressive hepatic fibrosis is the final common pathway for most chronic liver injuries, leading... more Progressive hepatic fibrosis is the final common pathway for most chronic liver injuries, leading to cirrhosis with risk of liver failure and hepatocellular carcinoma. It is now recognized that fibrosis is a dynamic process, and may be reversible prior to the establishment of advanced architectural changes to the liver. The most effective antifibrotic strategy is to cure the underlying disease process before advanced fibrosis has developed. Unfortunately, this is often not possible, and specific antifibrotic therapies are needed. Advances in the understanding of the pathogenesis of liver fibrosis have identified several potential novel therapeutic targets, but unfortunately clinical development has been disappointing. One major limitation has been the often prolonged natural history of fibrosis compared to experimental models, and difficulties in accurate noninvasive fibrosis assessment, thus making clinical trial design difficult. In this review, we highlight the most promising current antifibrotic strategies.
Clinics in Liver Disease, 2009
The current standard of care for the treatment of hepatitis C virus infection, pegylated interfer... more The current standard of care for the treatment of hepatitis C virus infection, pegylated interferon-alpha and ribavirin, is costly, associated with significant side effects, and effective in only 50% of patients. There is therefore a need for the development of novel antiviral therapies. One such approach involves the application of gene silencing technologies, including antisense oligonucleotides, ribozymes, RNA interference, and aptamers. However, despite great scientific advances over the past decade, and promising in vitro data, several significant challenges continue to limit the translation of this technology to the clinical setting. This review provides a concise update of the current literature.
Current Gastroenterology Reports, 2004
Chronic hepatitis C infection is associated with significant morbidity and mortality in addition ... more Chronic hepatitis C infection is associated with significant morbidity and mortality in addition to substantial social and health-related costs. Since the identification of the virus and determination of the HCV genome over a decade ago, considerable progress has been made in the treatment of chronic hepatitis C infection. However, the current standard combination of interferon-based therapies and ribavirin is effective in only 50% of patients. In addition, this combination is expensive, requires lengthy periods of administration, and is associated with significant side effects. Furthermore, no effective preventive measure, such as vaccination, is currently available. A number of newer therapies, including protease and helicase inhibitors, ribozymes, antisense therapies, and therapeutic vaccines, are in preclinical and clinical development and may significantly enhance existing therapeutic options for the future.
Clinics in Liver Disease, 2005
Clinics in Liver Disease, 2004
Hepatic steatosis is a common histologic feature observed in patients with chronic hepatitis C (C... more Hepatic steatosis is a common histologic feature observed in patients with chronic hepatitis C (CHC) . Even when well-defined causes of liver steatosis such as obesity, alcohol, type 2 diabetes, and hyperlipidemia are excluded, a significant number (30% to 40%) of hepatitis C virus (HCV) patients still have intrahepatic fat accumulation . The exact mechanisms of how HCV causes steatosis are not well understood; however, the published literature has elucidated some aspects of this relationship, suggesting a complex interplay between host and viral factors. HCV patients with steatosis are more likely to have a high body mass index (BMI), hyperlipidemia, and type II diabetes . Additionally, viral factors, particularly HCV genotype, have been implicated as critical determinants of the level of steatosis. More recently, steatosis has been shown to negatively impact response to antiviral therapy , increase the rate of fibrosis progression , and influence the development of hepatocellular carcinoma .
Journal of Hepatology, 2005
Hepatitis Prevention and Treatment, 2004
Since the identification of the hepatitis C virus (HCV) in the 1980s [1] and determination of the... more Since the identification of the hepatitis C virus (HCV) in the 1980s [1] and determination of the HCV genome in 1991 [2], there has been considerable progress in the management of chronic hepatitis C (CHC) in terms of achieving viral eradication and improving histology. Interferons (IFNs) were among the first agents used in the mid 1980s for the treatment of
Liver Transplantation, 2006
Improved understanding of hepatitis C virus (HCV) dynamics during and after liver transplantation... more Improved understanding of hepatitis C virus (HCV) dynamics during and after liver transplantation can be useful in optimizing antiviral therapy in transplant recipients. We analyzed serum HCV ribonucleic acid (RNA) levels during and after cadaveric liver transplantation in 6 HCV patients. After removal of the liver and before the new liver started producing virions, HCV RNA levels dropped with an average half-life (t1/2) of 0.8 hours. Viral loads then continued to drop up to 23 hours postimplantation (t1/2 = 3.4 hours), and began to rise (doubling-time = 2.0 days) as soon as 15 hours after the anhepatic phase. In 3 patients the viral load reached a plateau before rising, suggesting that a nonhepatic source supplied virions and balanced their intrinsic clearance. However, from the decline in viral load over the first 24 hours of the postanhepatic phase, we estimate that nonhepatic sources can at most correspond to 4% of total viral production, 96% of which occurs in the liver, even after we corrected for fluid exchanges during surgery. As the new liver was reinfected, production increased and viral load rose to a new steady state. Using nonlinear regression, we were able to fit the patients' HCV RNA data to a viral dynamic model and estimate the de novo infection rate (mean 1.5 × 10−6 mL/virion/day), as well as the average percentage of hepatocytes infected at the posttransplantation steady state (19%). In conclusion, we have quantified liver reinfection dynamics in the absence of posttransplantation antiviral therapy. Our findings support the notion that early antiviral therapy may delay or prevent reinfection. Liver Transpl 12:207–216, 2006. © 2006 AASLD.
Case Reports in Clinical Pathology, 2014
Fulminant hepatitis is a rare complication of herpes simplex virus (HSV-1 and HSV-2). Another rar... more Fulminant hepatitis is a rare complication of herpes simplex virus (HSV-1 and HSV-2). Another rare cause of fulminant hepatitis in pregnant women is acute fatty liver of pregnancy (AFLP). Here we present a female with fulminant hepatitis after a cesarean section whose infant clinically decompensated in the early neonatal period. Mother and child were diagnosed with fulminant hepatic failure from HSV, and the mother was found to have coexistent fatty liver of pregnancy on biopsy. Thus, two rare causes of fulminant hepatitis were co-morbid in the same patient. Rapid diagnosis enabled successful treatment, and both mother and infant recovered well.