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Featured researches published by Kosh Agarwal.


The New England Journal of Medicine | 2014

Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection

Nezam H. Afdhal; Stefan Zeuzem; Paul Y. Kwo; Mario Chojkier; Norman Gitlin; Massimo Puoti; Manuel Romero-Gómez; Jean Pierre Zarski; Kosh Agarwal; Peter Buggisch; Graham R. Foster; Norbert Bräu; Maria Buti; Ira M. Jacobson; G. Mani Subramanian; Xiao Ding; Hongmei Mo; Jenny C. Yang; Phillip S. Pang; William T. Symonds; John G. McHutchison; Andrew J. Muir; Alessandra Mangia; Patrick Marcellin

BACKGROUND In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection. METHODS We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir-sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir-sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea. CONCLUSIONS Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. (Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.).


The New England Journal of Medicine | 2014

ABT-450/r–Ombitasvir and Dasabuvir with Ribavirin for Hepatitis C with Cirrhosis

Fred Poordad; Christophe Hézode; Roger Trinh; Kris V. Kowdley; Stefan Zeuzem; Kosh Agarwal; Mitchell L. Shiffman; Heiner Wedemeyer; Thomas Berg; Eric M. Yoshida; Xavier Forns; Sandra S. Lovell; Barbara Da Silva-Tillmann; Christine Collins; Andrew Campbell; T. Podsadecki; Barry Bernstein

BACKGROUND Interferon-containing regimens for the treatment of hepatitis C virus (HCV) infection are associated with increased toxic effects in patients who also have cirrhosis. We evaluated the interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir (ABT-267), the nonnucleoside polymerase inhibitor dasabuvir (ABT-333), and ribavirin in an open-label phase 3 trial involving previously untreated and previously treated adults with HCV genotype 1 infection and compensated cirrhosis. METHODS We randomly assigned 380 patients with Child-Pugh class A cirrhosis to receive either 12 or 24 weeks of treatment with ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. The rate of sustained virologic response in each group was compared with the estimated rate with a telaprevir-based regimen (47%; 95% confidence interval [CI], 41 to 54). A noninferiority margin of 10.5 percentage points established 43% as the noninferiority threshold; the superiority threshold was 54%. RESULTS A total of 191 of 208 patients who received 12 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 91.8% (97.5% CI, 87.6 to 96.1). A total of 165 of 172 patients who received 24 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 95.9% (97.5% CI, 92.6 to 99.3). These rates were superior to the historical control rate. The three most common adverse events were fatigue (in 32.7% of patients in the 12-week group and 46.5% of patients in the 24-week group), headache (in 27.9% and 30.8%, respectively), and nausea (in 17.8% and 20.3%, respectively). The hemoglobin level was less than 10 g per deciliter in 7.2% and 11.0% of patients in the respective groups. Overall, 2.1% of patients discontinued treatment owing to adverse events. CONCLUSIONS In this phase 3 trial of an oral, interferon-free regimen evaluated exclusively in patients with HCV genotype 1 infection and cirrhosis, multitargeted therapy with the use of three new antiviral agents and ribavirin resulted in high rates of sustained virologic response. Drug discontinuations due to adverse events were infrequent. (Funded by AbbVie; TURQUOISE-II ClinicalTrials.gov number, NCT01704755.).


Lancet Infectious Diseases | 2016

Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial

Michael P. Manns; Didier Samuel; Edward Gane; David Mutimer; G. McCaughan; Maria Buti; Martín Prieto; Jose Luis Calleja; Markus Peck-Radosavljevic; Beat Müllhaupt; Kosh Agarwal; Peter W Angus; Eric M. Yoshida; M. Colombo; Mario Rizzetto; Hadas Dvory-Sobol; Jill Denning; Sarah Arterburn; Phillip S. Pang; Diana M. Brainard; John G. McHutchison; Jean-François Dufour; Hans Van Vlierberghe; Bart van Hoek; Xavier Forns

BACKGROUND Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease. METHODS We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600-1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255). FINDINGS Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70-96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81-100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66-96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60-91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84-98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93-100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91-100) of 30 CTP-A patients (12 weeks treatment); 27 (96%, 84-100) of 28 CTP-A patients (24 weeks treatment); 19 (95%, 78-100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86-100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3-98) of two CTP-C patients (12 weeks treatment); and four (80%, 34-99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55-100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56-92) of 18 patients (12 weeks treatment) and 16 (94%, 75-100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir-sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation. INTERPRETATION Ledipasvir-sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation. FUNDING Gilead Sciences.


Journal of Hepatology | 2016

Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis

Graham R. Foster; William L. Irving; Michelle C.M. Cheung; Alex J. Walker; Benjamin Hudson; Suman Verma; John McLauchlan; David Mutimer; Ashley Brown; W. Gelson; Douglas C. MacDonald; Kosh Agarwal

BACKGROUND & AIMS All oral direct acting antivirals (DAAs) effectively treat chronic hepatitis C virus (HCV) infection, but the benefits in advanced liver disease are unclear. We compared outcomes in treated and untreated patients with decompensated cirrhosis. METHODS Patients with HCV and decompensated cirrhosis or at risk of irreversible disease were treated in an expanded access programme (EAP) in 2014. Treatment, by clinician choice, was with sofosbuvir, ledipasvir or daclatasvir, with or without ribavirin. For functional outcome comparison, untreated patients with HCV and decompensated cirrhosis who were registered on a database 6months before treatment was available were retrospectively studied. Primary endpoint was sustained virological response 12weeks post antiviral treatment (treated cohort) and the secondary endpoint (both cohorts) was adverse outcomes (worsening in MELD score or serious adverse event) within 6months. RESULTS 467 patients received treatment (409 decompensated cirrhosis). Viral clearance was achieved in 381 patients (81.6%) - 209 from 231 (90.5%) with genotype 1 and 132 from 192 (68.8%) with genotype 3. MELD scores improved in treated patients (mean change -0.85) but worsened in untreated patients (mean+0.75) (p<0.0001). Patients with initial serum albumin <35g/L, aged >65 or with low (<135mmol/L) baseline serum sodium concentrations were least likely to benefit from therapy. CONCLUSIONS All oral DAAs effectively cured HCV in patients with advanced liver disease. Viral clearance was associated with improvement in liver function within 6months compared to untreated patients. The longer term impact of HCV treatment in patients with decompensated cirrhosis remains to be determined.


The Lancet | 2011

Increasing burden of liver disease in patients with HIV infection

Deepak Joshi; John O'Grady; Doug Dieterich; Brian Gazzard; Kosh Agarwal

Introduction of effective combined antiretroviral therapy has made HIV infection a chronic illness. Substantial reductions in the number of AIDS-related deaths have been accompanied by an increase in liver-related morbidity and mortality due to co-infection with chronic hepatitis B and C viruses. Increases in non-alcoholic fatty liver disease and drug-induced hepatotoxicity, together with development of hepatocellular carcinoma, also potentiate the burden of liver disease in individuals with HIV infection. We provide an overview of the key causes, disease mechanisms of pathogenesis, and recommendations for treatment options including the evolving role of liver transplantation.


Journal of Hepatology | 2000

CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis

Kosh Agarwal; David Jones; Ann K. Daly; Oliver F. W. James; Bijayesirar Vaidya; Simon Pearce; Margaret F. Bassendine

BACKGROUND/AIM Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease thought to develop through a complex interaction of genetic and environmental factors. It is characterised by T-cell-mediated non-suppurative destructive cholangitis. We have studied the polymorphic cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene, which encodes a molecule that is a vital negative regulator of T-cell activation, as a candidate susceptibility locus for PBC. This gene on chromosome 2q33 (designated IDDM12) is associated with susceptibility to both type 1 diabetes and autoimmune thyroid disease. METHODS The CTLA-4 exon 1 polymorphism (A/G encoding for threonine or alanine, respectively) was genotyped via polymerase chain reaction in 200 Caucasoid PBC patients and 200 non-related geographically matched Caucasoid controls. RESULTS There was significant overrepresentation of the G/A and G/G genotypes in PBC patients compared to controls (G/A 53% vs 40%; G/G 18.5% vs 10.5%, Odds Ratio (OR)=2.45 [95% CI 1.6-3.7], p=0.00006, chi2=19.4). Likewise, there was a significant difference in allele frequencies (G encoding alanine at codon 17, PBC 0.45 vs controls 0.305: OR=1.9 [1.4-2.5], p<0.0002). This association remained significant (p=0.00027) when patients with autoimmune thyroid disease were excluded from the analysis. CONCLUSIONS The CTLA-4 exon 1 polymorphism is the first non-major histocompatibility complex gene to be identified as a susceptibility locus for PBC. Our data support the hypothesis that clinically distinct autoimmune disease may be controlled by a common set of susceptibility genes.


Journal of Hepatology | 2016

Outcomes after successful direct acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis

Michelle C.M. Cheung; Alex J. Walker; Benjamin Hudson; Suman Verma; John McLauchlan; David Mutimer; Ashley Brown; W. Gelson; Douglas C. MacDonald; Kosh Agarwal; Graham R. Foster; William L. Irving

BACKGROUND & AIMS Direct-acting antivirals have become widely used for patients with chronic hepatitis C virus infection with decompensated cirrhosis. Virological responses are excellent and early improvements in liver function, at least in a proportion of patients, have been observed but the longer term impact of viral clearance on end-stage liver disease complications is unclear. METHODS Prospective study of patients with decompensated cirrhosis who received 12weeks of all-oral direct-acting antivirals through the English Expanded Access Programme. Endpoints were deaths, liver transplantation, hepatocellular carcinoma, serious decompensation events, sepsis or hospitalisations, and MELD scores between start of therapy to 15months post-treatment start. An untreated cohort of patients was retrospectively studied over 6months for comparison. RESULTS Amongst 317/406 patients who achieved sustained virological response at 24weeks post-treatment, there were 9 deaths (3%), 17 new liver cancers (5%), 39 transplantations (12%) and 52 with serious decompensations (16%), over 15months. When compared to the first six months from treatment start and to untreated patients, there was a reduction in incidence of decompensations [30/406 (7%) in months 6-15 and 72/406 (18%) in months 0-6 for treated patients vs. 73/261 (28%) in untreated patients]. There was no significant difference in liver cancer incidence (10/406 (2.5%) in months 6-15 and 17/406 (4%) in months 0-6 for treated patients vs. 11/261 (4%) in untreated patients). CONCLUSIONS This study suggests that antiviral therapy in patients with decompensated cirrhosis led to prolonged improvement in liver function, with no evidence of paradoxical adverse impact nor increase in liver malignancy. LAY SUMMARY This is a report of a large group of patients in England who have hepatitis C virus (HCV) infection with advanced liver disease. They have been treated with new anti-HCV drugs, which cured the infection in the majority. This study looks at their outcomes a year following treatment, in terms of deaths, cancers and other complications of advanced liver disease. We conclude that in most patients anti-HCV treatment is beneficial even in advanced liver disease.


Hepatology | 2012

The protease inhibitor, GS‐9256, and non‐nucleoside polymerase inhibitor tegobuvir alone, with ribavirin, or pegylated interferon plus ribavirin in hepatitis C

Stefan Zeuzem; Peter Buggisch; Kosh Agarwal; Patrick Marcellin; Daniel Sereni; Hartwig Klinker; Christophe Moreno; Jean-Pierre Zarski; Yves Horsmans; Hongmei Mo; Sarah Arterburn; Steven J. Knox; David Oldach; John G. McHutchison; Michael P. Manns; Graham R. Foster

Tegobuvir (GS‐9190), a non‐nucleoside nonstructural protein (NS)5B polymerase inhibitor, and GS‐9256, an NS3 serine protease inhibitor, individually have activity against hepatitis C virus (HCV) genotype 1. The antiviral activity of tegobuvir and GS‐9256 as oral combination therapy, or together with ribavirin (RBV) or pegylated interferon (Peg‐IFN) alpha‐2a and RBV, was assessed in a phase II, randomized, open‐label trial. Treatment‐naïve patients with genotype 1 HCV were assigned 28 days of tegobuvir 40 mg twice‐daily (BID) and GS‐9256 75 mg BID (n = 16), tegobuvir and GS‐9256 plus RBV 1,000‐1,200 mg daily (n = 15), or tegobuvir and GS‐9256 plus Peg‐IFN alpha‐2a (180 μg once‐weekly)/RBV (n = 15). The primary efficacy endpoint was rapid virologic response (RVR), with HCV RNA <25 IU/mL at day 28. After 28 days, all patients received Peg‐IFN/RBV. All patients with viral rebound or nonresponse, defined as >0.5‐log10 increase in HCV RNA from nadir or <2‐log decrease at day 5, initiated Peg‐IFN/RBV immediately. Median maximal reductions in HCV RNA were −4.1 log10 IU/mL for tegobuvir/GS‐9256, −5.1 log10 IU/mL for tegobuvir/GS‐9256/RBV, and −5.7 log10 IU/mL for tegobuvir/9256/Peg‐IFN/RBV. RVR was observed in 7% (1 of 15) of patients receiving tegobuvir/GS‐9256, 38% (5 of 13) receiving tegobuvir/GS‐9256/RBV, and 100% (14 of 14) receiving tegobuvir/9256/PEG‐IFN/RBV. The addition of Peg‐IFN/RBV at day 28 or earlier resulted in HCV RNA <25 IU/mL at week 24 in 67% (10 of 15), 100% (13 of 13), and 94% (13 of 14) of patients in the three treatment groups. Transient elevations in serum bilirubin occurred in all treatment groups. Conclusion: In genotype 1 HCV, adding RBV or RBV with Peg‐IFN provides additive antiviral activity to combination therapy with tegobuvir and GS‐9256. (HEPATOLOGY 2012)


Alimentary Pharmacology & Therapeutics | 2012

UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients

A Fraser; Kosh Agarwal; A. Austin; Ashley Brown; Graham R. Foster; R. Fox; Peter C. Hayes; Clifford Leen; Peter R. Mills; David Mutimer; Sd Ryder; John F. Dillon

The nonstructural 3 serine protease inhibitors (PIs), boceprevir and telaprevir, represent the first in a new generation of directly acting antivirals against genotype 1 hepatitis C (HCV) infection. When used in combination with pegylated interferon and ribavirin, these drugs greatly improve sustained virological response rates in both treatment‐naïve patients and patients who have had previous virological failure on treatment. However, the addition of these new agents will increase the complexity of therapeutic regimens, the rates of side‐effects and costs.


Hiv Medicine | 2010

British HIV Association guidelines for the management of coinfection with HIV-1 and hepatitis B or C virus 2010

G Brook; J Main; Mark Nelson; Sanjay Bhagani; E Wilkins; Clifford Leen; Martin Fisher; Y Gilleece; Richard Gilson; Andrew Freedman; Ranjababu Kulasegaram; Kosh Agarwal; Caroline Sabin; C Deacon-Adams

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I. Carey

University of Cambridge

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M. Bruce

University of Cambridge

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Abid Suddle

University of Cambridge

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Graham R. Foster

Queen Mary University of London

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Nigel Heaton

University of Cambridge

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John O'Grady

University of Cambridge

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Deepak Joshi

University of Cambridge

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M. Horner

University of Cambridge

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Stefan Zeuzem

Goethe University Frankfurt

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