Alpha Diallo

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.

High Cure Rate With 24 Weeks of Daclatasvir-Based Quadruple Therapy in Treatment-Experienced, Null-Responder Patients With HIV/Hepatitis C Virus Genotype 1/4 Coinfection: The ANRS HC30 QUADRIH Study

BACKGROUND Few direct anti-hepatitis C virus (HCV) agents have been studied in difficult-to-treat null responder and cirrhotic human immunodeficiency virus (HIV)-coinfected patients. Daclatasvir and asunaprevir combined with pegylated interferon/ribavirin (peg-IFN/RBV) have shown promising results in HCV-monoinfected patients. METHODS An open-label, single-arm, phase 2 study was conducted in HIV/HCV genotype 1/4-coinfected patients who were null responders to prior peg-IFN/RBV standard therapy and on a raltegravir-based regimen with HIV RNA <400 copies/mL. They received a 4-week lead-in phase with peg-IFN/RBV, followed by 24 weeks of asunaprevir (100 mg twice daily), daclatasvir (60 mg once daily), and peg-IFN/RBV. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12) using intent-to-treat analysis. RESULTS Seventy-five patients were included, of whom 27 (36%) had cirrhosis. The median baseline CD4 count was 748 (interquartile range, 481-930) cells/µL. The global SVR12 rate was 96.0% (95% confidence interval [CI], 88.8%-99.2%; n = 72/75), 92.6% (95% CI, 75.7%-99.1%; n = 25/27) in cirrhotic patients, 94.6% (95% CI, 81.8%-99.3%; n = 35/37) in genotype 1 patients, and 97.4% (95% CI, 86.2%-99.9%; n = 37/38) in genotype 4 patients. Six patients (8%) stopped HCV therapy prematurely: 2 due to HCV breakthrough, 4 to adverse events (1 lung cancer, 3 infections). One patient with cirrhosis (with baseline platelet count <150 000 platelets/µL and albuminemia <35 g/L) died from multiorgan failure. Overall, 36 serious adverse events occurred in 21 (28%) patients. No HIV breakthrough was observed. CONCLUSIONS In HIV/HCV genotype 1/4-coinfected null responders, a 24-week regimen combining daclatasvir, asunaprevir, and peg-IFN/RBV was associated with a very high cure rate. The safety profile was acceptable, even though cirrhotic patients with low albuminemia and platelets should be monitored closely. This combination is a new option in this difficult-to-treat population. CLINICAL TRIALS REGISTRATION NCT01725542.

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).

Low-dose ritonavir-boosted darunavir in virologically suppressed HIV-1-infected adults: an open-label trial (ANRS 165 Darulight)

Objectives To assess whether low-dose ritonavir-boosted darunavir (darunavir/r) in combination with two NRTIs could maintain virological suppression in patients on a standard regimen of darunavir/r + two NRTIs. Design A multicentre, Phase II, non-comparative, single-arm, open-label study. Setting Tertiary care hospitals in France. Subjects One hundred HIV-1-infected adults with no darunavir or NRTI resistance-associated mutations (RAMs) and a plasma HIV RNA level ≤50 copies/mL for ≥12 months on once-daily darunavir/r (800/100 mg) + two NRTIs for ≥6 months were switched to darunavir/r 400/100 mg with the same NRTIs. Primary outcome measure Proportion of patients with treatment success: plasma HIV RNA level ≤50  copies/mL up to 48 weeks without any change in the study regimen, in a modified ITT (mITT) analysis. Results At baseline, most patients were male (78%), with a median age of 43 years, median duration of HIV RNA ≤50 copies/mL of 35 months and median CD4 T cell count of 633 cells/mm3. Seventy-six percent received tenofovir/emtricitabine and 24% abacavir/lamivudine. Five patients were excluded from the mITT analysis. The rate of treatment success through to week 48 was 91.6% (87/95; 95% CI 84.1%-96.3%). No RAM was detected in three amplifiable genotypes. A total of 212 adverse events (AEs) occurred in 64 patients (64%); 9 AEs were serious, none leading to treatment discontinuation. Conclusions In HIV-infected patients well suppressed with darunavir/r (800/100 mg) and two NRTIs, a reduction of the darunavir dose to 400 mg/day maintained virological efficacy and was safe over 48 weeks.

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.

Signal detection on a patient cohort: A disproportionality analysis of the ANRS CO22 HEPATHER cohort to identify associations between direct acting antivirals and adverse events in patients with hepatitis C virus chronic infection

Our aim was to explore a signal detection method for early identification of potential adverse drug reactions (ADRs) in a patient cohort.

Pharmacokinetic modelling of darunavir/ritonavir dose reduction (800/100 to 400/100 mg once daily) in a darunavir/ritonavir-containing regimen in virologically suppressed HIV-infected patients: ANRS 165 DARULIGHT sub-study

Background In the ANRS 165 DARULIGHT study (NCT02384967) carried out in HIV-infected patients, the use of a darunavir/ritonavir-containing regimen with a switch to a reduced dose of darunavir maintained virological efficacy (≤50 copies/mL) for 48 weeks with a good safety profile. Objectives To assess the total and unbound blood plasma pharmacokinetics of darunavir and associated antiretrovirals, and their penetration into semen before and after dose reduction. Patients and methods Patients receiving a darunavir/ritonavir (800/100 mg q24h)-containing regimen for >6 months with plasma HIV-RNA ≤50 copies/mL for >12 months were switched to 400/100 mg darunavir/ritonavir q24h at week 0. A 24 h intensive pharmacokinetic blood sampling and a trough seminal sampling were performed before (week 0) and after (week 12) dose reduction. Individual pharmacokinetic parameter estimates were obtained using non-linear mixed-effect modelling for darunavir/ritonavir in blood plasma and used to test for bioequivalence, whereas darunavir/ritonavir in seminal plasma and NRTIs were analysed using a non-compartmental approach. Results and conclusions Fifteen patients completed the intensive pharmacokinetic analysis. There was no significant decrease in total and unbound darunavir blood plasma exposure despite a 50% decrease in darunavir daily dose from 800 to 400 mg (AUC0-24 = 65 563 versus 52 518 ng·h/mL; P = 0.25). A decrease in apparent oral clearance (CL/F) of both darunavir and ritonavir at week 12 suggests a modification of the initial darunavir/ritonavir daily dose balance (800/100 to 400/100 mg), in favour of a reduced inducer effect of darunavir on cytochrome P450 and efflux transporters compared with the standard dose.