Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study

Roth, David; Nelson, David R.; Bruchfeld, Annette; Liapakis, AnnMarie; Silva, Marcelo; Monsour, Howard Paul; Martin, Paul; Pol, Stanislas; Londoño, María Carlota; Hassanein, Tarek; Zamor, Philippe J.; Zuckerman, Eli; Wan, Shaogui; Jackson, Beth; Nguyen, Bach Yen; Robertson, Michael; Barr, Eliav; Wahl, Janice; Greaves, Wayne

doi:10.1016/s0140-6736(15)00349-9

Cited by 637 publications

(617 citation statements)

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“…Renal insufficiency is common in recipients of liver transplantation and complicates the decision to treat. Although there are HCV regimens in evaluation27 and approved28 for use in patients with an eGFR <30 mL/minute/1.73 m 2 , SOF‐based regimens are often preferred in patients who have undergone liver transplantation due to high efficacy and less potential for drug–drug interactions 15. The study findings are also of particular interest in those with CTP class B or C cirrhosis as only SOF‐based treatment regimens are currently approved by the U.S. Food and Drug Administration in this population.…”

Section: Discussionmentioning

confidence: 99%

Sofosbuvir‐based regimens for the treatment of chronic hepatitis C in severe renal dysfunction

Cox-North

Hawkins

Rossiter

et al. 2017

Hepatology Communications

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Sofosbuvir (SOF) is a nonstructural 5B polymerase inhibitor with activity in all hepatitis C virus (HCV) genotypes and is the backbone of many anti‐HCV drug regimens. SOF is converted into inactive metabolites that undergo renal excretion. Patients with an estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.73 m2 may experience increased drug exposure and thus potential toxicities along with decreased efficacy due to dose reduction or drug discontinuation. This is a single‐center study evaluating safety and effectiveness of SOF‐based regimens in patients with severe renal dysfunction, defined as eGFR <30 mL/minute/1.73 m2, including those receiving concurrent hemodialysis. Data were collected from patients with HCV and severe renal dysfunction who started full‐dose (400 mg) SOF‐based antiviral therapy ± ribavirin between April 2014 and February 2016. Medical records were reviewed for demographics, medical history, laboratory, radiologic imaging, echocardiography, transplant status, and liver pathologic findings. Twenty‐nine patients were identified; 12 had cirrhosis and 4 of those had decompensated cirrhosis. Fourteen patients had undergone transplantation of liver and/or kidney and were on calcineurin inhibitors, with 42% requiring dose increases or decreases while on therapy. All patients attained viral suppression on treatment, and 97% had a sustained viral response at 12 weeks posttreatment. There were no early treatment discontinuations. One death occurred posttreatment from a non‐ST elevation myocardial infarction in a patient with a history of coronary artery disease and ischemic cardiomyopathy. Conclusion: SOF‐based regimens appear safe in a broad range of patients with severe renal dysfunction, including those with decompensated cirrhosis and liver transplant. To confirm these retrospective findings, prospective studies that include SOF and SOF metabolite measurements coupled with prospective serial monitoring of electrocardiograms and echocardiograms are needed. (Hepatology Communications 2017;1:248‐255)

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Section: Discussionmentioning

confidence: 99%

Sofosbuvir‐based regimens for the treatment of chronic hepatitis C in severe renal dysfunction

Cox-North

Hawkins

Rossiter

et al. 2017

Hepatology Communications

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“…This combination was studied in the C-SURFER Trial, the first prospective, randomized study of DAAs that focused exclusively on HCVinfected patients with CKD and HCV-infected patients with ESRD. 67 In this phase 3 trial, 224 patients with HCV genotype 1 infection and stage 4 or 5/5D CKD were randomly assigned to an immediate treatment group (n=111) or a deferred treatment group (n=113) that initially received placebo and then, was offered active therapy. Data from an intensive pharmacokinetic group (n=11) showed no requirement for dose adjustment in patients on hemodialysis.…”

Section: Grazoprevir and Elbasvirmentioning

confidence: 99%

“…Treatment with Zepatier resulted in SVR12s of 99%, with a low adverse event profile and no significant safety signals in this CKD population. 67,68 Velpatasvir Velpatasvir is a nonstructural protein 5A (NS5A) inhibitor with antiviral activity against genotypes 1-6. 69 Two studies have shown that velpatasvir combined with sofosbuvir provided high rates of SVR12 in patients with all genotypes, including the difficult to treat patients with genotype 3.…”

Section: Grazoprevir and Elbasvirmentioning

confidence: 99%

Hepatitis C Virus Infection in Chronic Kidney Disease

Ladino

Pedraza

Roth

2016

JASN

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Soon after the hepatitis C virus (HCV) was identified in 1989, it was recognized that the prevalence of infection in patients with ESRD far exceeded that in the general population. Infection with HCV predisposes to the hepatic complications of cirrhosis and hepatocellular carcinoma. However, important extrahepatic manifestations include immune complex glomerular disease, accelerated progression of CKD, increases in cardiovascular event risk, and lymphoproliferative disorders. Advances in understanding the molecular biology of HCV have ushered in a new era in the treatment of this infection. Second generation direct-acting antiviral agents have revolutionized therapy, with sustained virologic response rates (undetectable viral load 12 weeks after completing therapy) of .90% in most patients. Studies using direct-acting antivirals in patients with CKD and those on dialysis are showing excellent safety and efficacy as well. In this context, it is imperative that nephrologists become familiar with this literature, reviewed here, so that the important decisions, including which patients should be treated and the optimal timing to initiate therapy, are vetted in association with the compounding issues of CKD, ESRD, and kidney transplantation.

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“…The paritaprevir/ritonavir ombitasvir dasabuvir combination was also very efficient (100% response) but G1a subtype still needed ribavirin [55] . Finally, in the largest study so far, out of 226 G1 patients with severe renal insufficiency, 191 with chronic kidney disease stage 5 and 179 hemodialysed showed a 99% SVR when treated with grazoprevir elbasvir for 12 wk without ribavirin with an excellent tolerance [56] . These encouraging results will probably lead us to treat hemodialysed patients if no transplant perspective is envisaged, or before kidney transplantation, as HCV negatively impacts these patients' prognosis.…”

mentioning

confidence: 93%

Ribavirin: Past, present and future

Loustaud‐Ratti¹

2016

WJH

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Before the advent of direct acting antiviral agents (DAAs) ribavirin, associated to pegylated-interferon played a crucial role in the treatment of chronic hepatitis C, preventing relapses and breakthroughs. In the present era of new potent DAAs, a place is still devoted to the drug. Ribavirin associated with sofosbuvir alone is efficient in the treatment of most cases of G2 infected patients. All options currently available for the last difficult-to-treat cirrhotic G3 patients contain ribavirin. Reducing treatment duration to 12 wk in G1 or G4 cirrhotic compensated patients is feasible thanks to ribavirin. Retreating patients with acquired anti NS5A resistance-associated variants using ribavirin-based strategies could be useful. The addition of ribavirin with DAAs combinations however, leads to more frequent but mild adverse events especially in cirrhotic patients. Preliminary data with interferon-free second generation DAAs combinations without ribavirin suggest that future of the drug is jeopardized even in difficult-totreat patients: The optimization of ribavirin dosage according to an early monitoring of blood levels has been suggested to be relevant in double therapy with peginterferon or sofosbuvir but not with very potent combinations of more than two DAAs. Author contributions: Loustaud-Ratti V and Carrier P wrote the manuscript; Debette-Gratien M, Jacques J, Alain S, Marquet P, Sautereau D and Rousseau A read the manuscript and conducted a critical analysis. Conflict-of-interest statement:The authors have no conflict of interest concerning this work.Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/ INTRODUCTIONBefore the advent of direct acting antiviral agents (DAAs) ribavirin played a crucial role in the treatment of chronic hepatitis C associated to pegylated interferon [1] . This combination is still relevant in many parts of the world which do not have access to new therapies because of cost issues [2] . Although the role of ribavirin in the era of DAAs will probably decrease in the future with the arrival of second generation drugs, it remains essential in strategies decreasing treatment duration or in some difficult situations. The goal of this review is to briefly recall the recent past of ribavirin and consider its present and potential future. RIbavIRIN: meChaNIsms Of aCTIONSo far, multiple mechanisms of action of ribavirin have been described. The antiviral mechanism is probably the best documented, the erroneous incorporation of ribavirin triphosphate into replicating RNA strands inhibiting chain elongation [3] ...

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Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study

Abstract: Merck Sharp & Dohme Corp.

Cited by 637 publications

References 33 publications

Sofosbuvir‐based regimens for the treatment of chronic hepatitis C in severe renal dysfunction

Sofosbuvir‐based regimens for the treatment of chronic hepatitis C in severe renal dysfunction

Hepatitis C Virus Infection in Chronic Kidney Disease

Ribavirin: Past, present and future

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