Upcoming Direct-Acting Antivirals for Prior Treatment Failure

( Alessio Aghemo ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Treatment of hepatitis C virus infection (HCV) with directly acting antivirals (DAAs) can achieve sustained virological response (SVR) rates of nearly 97-98% in real life cohorts. Treatment failure although rare can be challenging from a therapeutical point of view as most patients who will fail DAA treatment are characterized by advanced liver disease and thus are the most in need patients. Treatment failure can rarely be the direct consequence of suboptimal DAA treatment (incorrect genotyping, suboptimal schedules or poor adherence), however in most cases treatment failure to DAAs is the consequence of pre-existing Resistance Associated Substitutions (RASs) in the patient’s HCV quasispecies. High level RASs defined by an increase in the DAA EC 50 of more than 100 fold, impact on the activity of DAAs in the clinical setting and can significantly reduce SVR rates in the presence of other factors of non-response such as HCV genotype 1a or 3, presence of advanced fibrosis or high baseline viral load. Treatment failure is associated with selection of RASs to the DAA class that was given as first line treatment. While RASs selected after failure of a Protease inhibitor have been shown to revert to wild type within 1-2 years, and RASs to NS5B polymerase inhibitors very rarely occur, RASs to NS5A containing regimens have been shown to persist for at least 2 years following treatment failure. For this reason, most scientific guidelines suggest to perform RAS testing before starting re-treatment to guide treatment selection. This approach clashes with the fact that only 1 regimen is approved for the re-treatment of DAA failures, the combination of Sofobuvir/Velpatasvir/Voxilaprevir. This single tablet regimen has been evaluated in a large Phase III program, which studied 12 weeks of treatment in patients who failed a previous DAA regimen. Included were both patients who failed an NS5a containing regimen (Polaris 1) and those who failed a regimen which did not include an NS5A (Polaris 4). Overall the SVR rates were 96% and 97% respectively, with no significant safety signals. The main limit of this regimen is that Sofosbuvir is metabolized by the kidney, making it not recommended in patients with CKD stage 4-5, and Voxilaprevir is metabolized by the liver making it contraindicated and unsafe in patients with decompensated disease. In patients with decompensated liver diseases the current recommendation for the re-treatment of DAA failures is the combination of Sofosbuvir/Velapatasvir plus Ribavirin for 24 weeks.

Long-Term Follow-Up of Patients with Chronic HCV Infection and Compensated or Decompensated Cirrhosis Following Treatment with Sofosbuvir-Based Regimens

( Alessio Aghemo ),( Alessandra Mangia ),( Eric Lawitz ),( Ed Gane ),( Brian Conway ),( Peter J. Ruane ),( Armando Abergel ),( Sooji Lee ),( Brian McNabb ),( Anu Osinusi ),( Frances Chen ),( Hadas Dvo 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Early results from registries and cohort studies have demonstrated that patients with cirrhosis who achieve SVR with DAA experience improvements in liver-related morbidity, HCC risk, and mortality. However, follow-up time for these studies is generally short. This analysis from the Gilead Cirrhosis Registry evaluates long-term outcomes in patients with cirrhosis who achieved SVR following treatment with a sofosbuvir-(SOF) based regimen. Methods: Patients with cirrhosis who achieved SVR after receiving a SOF-based regimen were eligible for enrollment. Patients enrolled within 60 weeks of completing a treatment study or transfer from another SVR registry study, or within 2 years of achieving SVR following treatment in a clinical practice setting. Patients return for visits every 24 weeks for 5 years for laboratory, clinical, and radiographic assessments of durability of SVR and clinical progression of liver disease. In this abstract we report the HCC incidence, CTP scores, and SVR durability. Results: As of 5 OCT 2017, 1564 patients have been enrolled in the cirrhosis registry. Mean age (range) is 59 (26-86) years, 68% are male, and 84% of patients had pretreatment CTP scores A. Median (range) of registry follow-up time was 53 (<1-144) weeks. Overall, there were 55 observed events of HCC in 3922 person-years (PYs) of follow-up since the start of DAA treatment (34 cases in 3292 PYs of follow-up for CTP-A patients and 21 in 601 PYs of follow-up for CTP B+C patients). Overall, patients with pretreatment CTP-A cirrhosis maintained CTP-A status while patients with pretreatment CTP B or C cirrhosis showed improvement. Conclusions: In this ongoing registry of patients with cirrhosis who achieved SVR after treatment with a SOF-based regimen, HCC was uncommon and occurred more often in patients with decompensated cirrhosis. The majority of patients maintained or improved their CTP category relative to pretreatment through up to week 96.

Ledipasvir/Sofosbuvir for 12 or 24 Weeks Is Safe and Effective in Kidney-transplant Recipients with Genotype 1 or 4 HCV Infection

( Massimo Colombo ),( Alessio Aghemo ),( Lin Liu ),( Robert H. Hyland ),( Chohee Yun ),( Diana M. Brainard ),( John G. Mchutchison ),( Sunjin Hwang ),( Marc Bourliere ),( Markus Peck-radosavljevic ),( 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Methods: Kidney transplant recipients with chronic GT1 or GT4 HCV infection, treatment-naive and treatment-experienced, with or without compensated cirrhosis were randomized 1:1 at 5 sites in Europe to receive LDV/SOF (90 mg/400 mg) for 12 or 24 weeks. Randomization was stratified by HCV genotype, treatment history and presence or absence of cirrhosis. Cirrhosis was determined by liver biopsy (Metavir score = 4 or Ishak score ≥5), Fibroscan® >12.5 kPa, or Fibrotest® >0.75 and APRI >2. A pretreatment creatinine clearance <40 mL/min was an exclusionary criterion. The primary endpoint was SVR12. Results: 114 patients were randomized and treated; median age was 53, 58% were male, 94% were white, 72% carried the non-CC IL28B allele, 91% had GT 1 infection, 69% were treatment-naive, and 15% had compensated cirrhosis. The median eGFR was 56ml/min (range 35-135ml/min). All 92 patients with SVR4 data available achieved SVR4 including a patient discontinuing treatment at Week 4 due to an AE. SAEs were reported in 12 (11%) patients; 3 were assessed as treatment related: syncope, pulmonary embolism, and blood creatinine increased. The most frequent AEs were headache (19%), asthenia (13%), and fatigue (10%). Conclusions: Administration of LDV/SOF for 12 or 24 weeks in patients with chronic HCV genotype 1 or 4 patients who have undergone kidney transplant was safe and highly effective with an SVR4 rate of 100%. Treatment was well-tolerated. SVR12 data for all patients will be presented.

Upcoming direct acting antivirals for hepatitis C patients with a prior treatment failure

Tommaso Lorenzo Parigi,Maria Corina Plaz Torres,Alessio Aghemo 대한간학회 2019 Clinical and Molecular Hepatology(대한간학회지) Vol.25 No.4

Despite the high efficacy of direct acting antivirals (DAAs) not all patients successfully clear hepatitis C virus infection, in fact, approximately 1–3% fail to reach a sustained virological response 12 weeks after end of treatment. DAA failures are characterized by advanced liver disease, specific genotypes/subtypes and resistance associated substitutions to the DAA class they have been treated with. Current European Association for the Study of the Liver guidelines recommend three therapeutic options for such patients. The first is a 12 week course of sofosbuvir (SOF), velpatasvir (VEL) and voxilaprevir (VOX), which has shown to be effective in 90–99% of patients and was granted A1 level recommendation. The second option, reserved for patients who have predictors of failure consists in 12 weeks regimen with glecaprevir (GLE) and pibrentasvir (PIB), effective in 90–97%. Finally, although not supported by published data, for especially difficult to treat patients there should theoretically be a benefit in prolonged combinations of SOF+GLE/PIB or SOF/VEL/VOX±ribavirin. This review presents the latest evidence from both clinical trials and real-life on such therapeutic strategies.