Emilie Rossignol

Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence – The ANRS CUPILT study

BACKGROUND & AIMS HCV recurrence remains a major issue in the liver transplant field, as it has a negative impact on both graft and patient survival. The purpose of this study was to investigate the efficacy and safety of treating HCV recurrence with sofosbuvir (SOF) and daclatasvir (DCV) combination therapy. METHODS From October 2013 to March 2015, 559 liver recipients were enrolled in the prospective multicentre France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) Compassionate use of Protease Inhibitors in viral C Liver Transplantation cohort. We selected 137 patients with an HCV recurrence receiving SOF and DCV, whatever the genotype or fibrosis stage. The use of ribavirin and the duration of therapy were at the investigators discretion. The primary efficacy end point was a sustained virological response (SVR) 12weeks after the end of treatment. RESULTS The SVR rate 12weeks after completing treatment was 96% under the intention-to treat analysis and 99% when excluding non-virological failures. Only two patients experienced a virological failure. The serious adverse event (SAE) rate reached 17.5%. Four patients (3%) stopped their treatment prematurely because of SAEs. Anaemia was the most common AE, with significantly more cases in the ribavirin group (56% vs. 18%; p<0.0001). A slight but significant reduction in creatinine clearance was reported. No clinically relevant drug-drug interactions were noted, but 52% of patients required a change to the dosage of immunosuppressive drugs. CONCLUSIONS Treatment with SOF plus DCV was associated with a high SVR12 and low rates of serious adverse events among liver recipients with HCV recurrence. LAY SUMMARY The recurrence of hepatitis C used to be the first cause of graft failure in infected liver transplanted recipients. Our study demonstrates the great efficacy of one combination of new all-oral direct-acting antiviral, sofosbuvir and daclatasvir, to treat the recurrence of hepatitis C on the graft. Ninety-six per cent of recipients were cured. The safety profile of this combination seemed to be good, especially no relevant drug-drug interaction with immunosuppressive drugs.

Processed and unprocessed red meat consumption and hypertension in women

BACKGROUND High processed red meat consumption is associated with increased risk of cardiovascular disease. The high sodium content of processed red meat could increase blood pressure and explain the association with cardiovascular disease. OBJECTIVE We evaluated the relation between the consumption of unprocessed and processed red meat and incident hypertension. DESIGN In a prospective cohort of 44,616 disease-free French women who responded to a validated dietary questionnaire, we observed 10,256 incident cases of hypertension between 1993 and 2008. Cases were identified through self-reports of diagnosed or treated hypertension. Multivariate Cox regression models were adjusted for age, education, smoking, physical activity, body mass index, menopause, menopausal hormone therapy, and alcohol, bread, coffee, and fruit and vegetable consumption. RESULTS Women who consumed ≥5 servings of processed red meat/wk (50 g = 1 serving) had a 17% higher rate of hypertension than that of women who consumed <1 serving/wk (HR: 1.17; 95% CI: 1.09, 1.26; P-trend = 0.0002). No association was observed between unprocessed red meat consumption and hypertension. When women who consumed ≥5 servings of unprocessed red meat/wk (100 g = 1 serving) were compared with women who consumed <1 serving unprocessed red meat/wk, the multivariate HR was 0.99 (95% CI: 0.91, 1.08; P-trend = 0.63). CONCLUSIONS In this large prospective cohort of French women, we observed an association between the consumption of processed red meat and hypertension. We observed no association for unprocessed red meat consumption and hypertension.

Sofosbuvir-based treatment of hepatitis C with severe fibrosis (METAVIR F3/F4) after liver transplantation

Recurrence of hepatitis C virus (HCV) after liver transplantation (LT) can rapidly lead to liver graft cirrhosis and, therefore, graft failure and retransplantation or death. The aim of the present study was to assess efficacy and tolerance of sofosbuvir (SOF)–based regimens for the treatment of HCV recurrence in patients with severe fibrosis after LT. The Compassionate Use of Protease Inhibitors in Viral C Liver Transplantation (CULPIT) study is a prospective multicenter cohort including patients with HCV recurrence following LT treated with second generation direct antivirals. The present study focused on patients included between October 2013 and November 2014 and diagnosed with HCV recurrence and liver graft extensive fibrosis (METAVIR F3/F4). A SOF‐based regimen was administered to 125 patients fulfilling inclusion criteria. The median delay from LT was 95.9 ± 69.6 months. The characteristics of patients were as follows: mean age, 59.4 ± 9.0 years; 78.4% male; infected by HCV genotype 1: 78.2%, mean HCV RNA: 6.1 ± 1.0 log10 IU/mL. Eighty patients had failed previous post‐LT antiviral therapy (64.0%) including triple therapy with first generation protease inhibitors in 19 (15.2%) patients. The main combination regimen was SOF/daclatasvir (73.6%). Ribavirin was used in 60 patients. Sustained virological response 12 weeks after treatment was 92.8% (on an intention‐to‐treat basis); 7 patients with virological failure were observed. Serious adverse events occurred in 25.6% of the patients during antiviral treatment. During antiviral treatment and follow‐up, 3 patients were retransplanted and 4 patients died. In conclusion, SOF‐based antiviral treatment shows very promising results in patients with HCV recurrence and severe fibrosis after LT. Liver Transplantation 22 1367–1378 2016 AASLD.

Sofosbuvir-Based Regimens in HIV/HCV Coinfected Patients after Liver Transplantation: Results from the ANRS CO23 CUPILT Study

Background A recurrence of hepatitis C virus (HCV) after liver transplantation affects survival in human immunodeficiency virus (HIV)/HCV coinfected patients. This study assessed the efficacy and safety of sofosbuvir (SOF)-based regimens in HIV/HCV coinfected patients after liver transplantation. Methods Twenty-nine HIV/HCV coinfected transplanted patients receiving tacrolimus-, cyclosporine-, or everolimus-based immunosuppressive therapy were enrolled in the Compassionate Use of Protease Inhibitors in Viral C Liver Transplantation cohort. Their antiviral treatment combined SOF, daclatasvir with or without ribavirin (n = 10/n = 6), or SOF, ledipasvir with or without ribavirin (n = 2/n = 11). Results The median delay between liver transplantation and treatment initiation was 37.5 months (interquartile range [IQR], 14.4-99.2). The breakdown of HCV genotypes was G1, 22 patients (75.9%); G3, 3 patients (10.3%); and G4, 4 patients (13.8%). The treatment indications were HCV recurrence (≥ F1 n = 23) or fibrosing cholestatic hepatitis (n = 6). Before starting SOF, the HCV viral load and CD4 count were 6.7 log10 IU/mL (IQR, 5.9-7.2) and 342 cells/mm3 (IQR, 172-483), respectively. At week 4, the HCV viral load was less than 15 IU/mL in 12 (42.9%) patients. The overall sustained virological response 12 was 96.6%. No significant drug-drug interactions were observed. Conclusions SOF-based treatment regimens produced excellent results in HIV/HCV coinfected patients after liver transplantation, suggesting an important change in their prognosis.

12 Weeks of a Ribavirin‐Free Sofosbuvir and Nonstructural Protein 5A Inhibitor Regimen Is Enough to Treat Recurrence of Hepatitis C After Liver Transplantation

Sofosbuvir (SOF) combined with nonstructural protein 5A (NS5A) inhibitors has demonstrated its efficacy in treating a recurrence of hepatitis C virus (HCV) after liver transplantation (LT). However, the duration of treatment and need for ribavirin (RBV) remain unclear in this population. Our aim was to determine whether LT recipients could be treated with an SOF + NS5A inhibitor‐based regimen without RBV for 12 weeks post‐LT. Between October 2013 and December 2015, 699 LT recipients experiencing an HCV recurrence were enrolled in the multicenter ANRS CO23 CUPILT cohort. We selected patients receiving SOF and NS5A inhibitor ± RBV and followed for at least 12 weeks after treatment discontinuation. The primary efficacy endpoint was a sustained virological response 12 weeks after the end of treatment (SVR12). Among these 699 patients, 512 fulfilled the inclusion criteria. Their main characteristics were: 70.1% genotype 1, 18.2% genotype 3, 21.1% cirrhosis, and 34.4% previously treated patients. We identified four groups of patients according to their treatment and duration: SOF + NS5A without RBV for 12 (156 patients) or 24 (239 patients) weeks; SOF + NS5A + RBV for 12 (47 patients) or 24 (70 patients) weeks. SVR12 values reached 94.9%, 97.9%, 95.7%, and 92.9%, respectively (P = 0.14). Only 20 patients experienced a treatment failure. Under multivariate analysis, factors such as fibrosis stage, previous treatment, HCV genotype, and baseline HCV viral load did not influence SVR12 rates in the four groups (P = 0.21). Hematological adverse events (AEs) were more common in the RBV group: anemia (P < 0.0001) and blood transfusion (P = 0.0001). Conclusion: SOF + NS5A inhibitors without RBV for 12 weeks constituted reliable therapy for recurrent HCV post‐LT with an excellent SVR12 whatever the fibrosis stage, HCV genotype, and previous HCV treatment. (Hepatology 2018; 00:000‐000).

Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study

In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir‐based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable.

Direct-acting antiviral agent-based regimen for HCV recurrence after combined liver-kidney transplantation: Results from the ANRS CO23 CUPILT study

Hepatitis C virus (HCV) infection is associated with reduced patient survival following combined liver‐kidney transplantation (LKT). The aim of this study was to assess the efficacy and safety of second‐generation direct‐acting antivirals (DAAs) in this difficult‐to‐treat population. The ANRS CO23 “Compassionate use of Protease Inhibitors in Viral C Liver Transplantation” (CUPILT) study is a prospective cohort including transplant recipients with recurrent HCV infection treated with DAAs. The present work focused on recipients with recurrent infection following LKT. The study population included 23 patients. All patients received at least one NS5B inhibitor (sofosbuvir) in their antiviral regimen an average of 90 months after LKT. Ninety‐six percent of recipients achieved a sustained virological response (SVR) at week 12 (SVR12). In terms of tolerance, 39% of recipients presented with at least one serious adverse event. None of the patients experienced acute rejection during therapy and there were no deaths during follow‐up. The glomerular filtration rate (GFR) decreased significantly from baseline to the end of therapy. However, this study did not show that the decline in GFR persisted over time or that it was directly related to DAAs. The DAA‐based regimen is well tolerated with excellent results in terms of efficacy. It will become the gold standard for the treatment of recurrent HCV following LKT.