V. Loustaud-Ratti

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) – NCT01514890

BACKGROUND & AIMS In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.

Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS)

BACKGROUND Patients with cirrhosis resulting from chronic hepatitis C virus (HCV) infection are at risk of life-threatening complications, but consistently achieve lower sustained virological response (SVR) than patients without cirrhosis, especially if treatment has previously failed. We assessed the efficacy and safety of the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir, with and without ribavirin. METHODS In this multicentre, double-blind trial, between Oct 21, 2013, and Oct 30, 2014, we enrolled patients with HCV genotype 1 and compensated cirrhosis who had not achieved SVR after successive treatments with pegylated interferon and protease-inhibitor regimens at 20 sites in France. With a computer-generated randomisation sequence, patients were assigned in a 1:1 ratio to receive placebo matched in appearance to study drugs for 12 weeks followed by once daily combination fixed-dose tablets of 90 mg ledipasvir and 400 mg sofosbuvir plus weight-based ribavirin for 12 weeks, or ledipasvir-sofosbuvir plus placebo once daily for 24 weeks. The primary endpoint was SVR 12 weeks after the end of treatment (SVR12), for which 95% CIs were calculated with the Clopper-Pearson method. This study is registered with ClinicalTrials.gov, number NCT01965535. FINDINGS Of 172 patients screened, 155 entered randomisation, 77 were assigned to receive ledipasvir-sofosbuvir plus ribavirin and 78 ledipasvir-sofosbuvir. 114 (74%) were men, 151 (97%), were white, 98 (63%) had HCV genotype 1a, and 145 (94%) had non-CC IL28B alleles. SVR12 rates were 96% (95% CI 89-99) for patients in the ledipasvir-sofosbuvir plus ribavirin group and 97% (91-100) in the ledipasvir-sofosbuvir group. One patient discontinued treatment because of adverse events while receiving only placebo. The most frequent adverse events were asthenia and headache, pruritus, and fatigue. INTERPRETATION Ledipasvir-sofosbuvir plus ribavirin for 12 weeks and ledipasvir-sofosbuvir for 24 weeks provided similarly high SVR12 rates in previous non-responders with HCV genotype 1 and compensated cirrhosis. The shorter regimen, when given with ribavirin, might, therefore, be useful to treat treatment-experienced patients with cirrhosis if longer-term treatment is not possible. FUNDING Gilead Sciences.

Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection

BACKGROUND & AIMS The combination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of hepatitis C virus (HCV) genotype 1 infection. However, these drugs are not well tolerated because of their side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined the safety and efficacy of an interferon-free, ribavirin-free regimen of direct-acting antivirals, comprising daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection. METHODS We analyzed data from 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were assigned randomly to groups given daclatasvir (60 mg, once daily), asunaprevir (200 mg, twice daily), and BMS-791325 (75 or 150 mg, twice daily) for 12 or 24 weeks. The primary end point was an HCV-RNA level less than 25 IU/mL at 12 weeks after treatment (sustained virologic response at 12 weeks [SVR12]). RESULTS In 64 patients, HCV-RNA levels were less than 25 IU/mL by week 4 of treatment (including 48 of 49 patients with HCV genotype 1a infection and 45 of 46 patients with the non-CC interleukin 28B genotype). Sixty-one patients (92%) achieved SVR12, based on a modified intention-to-treat analysis. Virologic responses were similar between 12 and 24 weeks of treatment. During the study, 2 patients experienced viral breakthrough and 1 patient relapsed. There were no grade 3-4 increases in levels of alanine or aspartate aminotransferases or bilirubin; there were no deaths or discontinuations resulting from serious adverse events or adverse events related to the treatment regimen. The most common adverse events were headache, asthenia, and gastrointestinal symptoms. CONCLUSIONS In a phase 2a study, the all-oral, interferon-free, and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection. Further studies of this regimen are warranted. ClinicalTrials.gov, number NCT01455090.

Changing of hepatitis C virus genotype patterns in France at the beginning of the third millenium: The GEMHEP GenoCII Study.

Summary.  This cross‐sectional study aimed to investigate, during a short period between 2000 and 2001, in a large population of patients with chronic hepatitis C, the epidemiological characteristics of hepatitis C virus (HCV) genotypes in France. Data from 26 referral centres, corresponding to 1769 patients with chronic hepatitis C were collected consecutively during a 6‐month period. HCV genotyping in the 5′‐non‐coding region (NCR) was performed in each center using the line probe assay (LiPA, in 63% of cases), sequencing (25%) or primer‐specific polymerase chain reaction (PCR) (12%). HCV genotypes 1a, 1b, 2, 3, 4, 5, non‐subtyped 1 and mixed infection were found in 18, 27, 9, 21, 9, 3, 11 and 1% of our population, respectively. HCV genotype distribution was associated with gender, age, source and duration of infection, alanine aminotransferase (ALT) levels, cirrhosis, alcohol consumption, hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection. In multivariate analysis, only the source of infection was the independent factor significantly associated with genotype (P = 0.0001). In conclusion, this study shows a changing pattern of HCV genotypes in France, with i.v. drug abuse as the major risk factor, an increase of genotype 4, and to a lesser extent 1a and 5, and a decrease of genotypes 1b and 2. The modification of the HCV genotype pattern in France in the next 10 years may require new therapeutic strategies, and further survey studies.

Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C

The impact of ribavirin exposure on sustained virological response (SVR) in patients with chronic hepatitis C is unknown. Preliminary studies showed marked inter‐individual variability of ribavirin concentrations despite dose adjustment for body weight (BW) and suggested there was a correlation between single time point concentrations and SVR. None of them evaluated the global exposure to ribavirin. This study was conducted to determine whether early ribavirin global exposure is related with SVR. An exploratory pharmacokinetic‐pharmacodynamic (PK‐PD) study was conducted in genotype 1 hepatitis C patients treated with peginterferon alfa‐2a and ribavirin (dose‐adjusted for BW) for 12 weeks, to which amantadine was added for the following 36 weeks. Full and abbreviated ribavirin area under the concentration time curves (AUC0–12h, AUC0–4h) were derived from plasma concentration profiles at day 0 (D0), week 12 (W12), W12 + 1 day, and W24. Virological follow‐up was performed at D0 (0, 12, and 24 hours), W2, W4, W6, and monthly until W72 (TaqMan polymerase chain reaction, cut‐off 15 international units/mL). Twenty‐eight patients were enrolled in the study and 24 completed it. Patients with a SVR had a significantly higher D0 AUC0–12h (3695 [1571–6916] versus 2937 [1266–4913] μg/hour/L, P = 0.03) and D0 AUC0–4h (2010 [615–3175] versus 1340 [622–2246] μg/hour/L, P = 0.03). Patients with D0 AUCs above the cut‐off values defined by receiver operating characteristic curves (3014 μg/hour/L and 1755 μg/hour/L for AUC0–12h and AUC0–4h, respectively) had a significantly better chance of achieving an SVR than patients with AUCs under the thresholds (odds ratio = 16.0, 95% confidence interval 1.54–166.6, P = 0.02 and odds ratio = 8.9, 95% confidence interval, 1.4–56.6; P = 0.02). Conclusion: Ribavirin exposure at D0 is significantly related to SVR. To our knowledge, this is the first study to give an early pharmacokinetic predictor of SVR. We propose a minimum AUC0–4h threshold of 1755 μg/hour/L at D0 as a target for ribavirin dose adjustment. (HEPATOLOGY 2008;47:1453–1461.)

Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study

BACKGROUND Data about the response of hepatitis C virus (HCV) genotype 5 to approved and experimental treatment regimens are scarce. We assessed the efficacy and safety of combination therapy with the NS5A inhibitor ledipasvir and the NS5B polymerase inhibitor sofosbuvir in patients with HCV genotype 5. METHODS We did this open-label, multicentre, single-arm, phase 2 trial at five hospitals in France. Eligible patients were at least 18 years old and had chronic infection with HCV genotype 5, with plasma HCV RNA of at least 10,000 IU/mL. We used BLAST analyses of NS5B partial sequences to establish the genotype and subtype at screening. Patients were given a fixed-dose combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir orally once per day for 12 weeks. The primary endpoint was the proportion of patients with a sustained viral response, defined as HCV RNA concentration less than 15 IU/mL at 12 weeks after the end of treatment (SVR12). We analysed efficacy and safety in all patients who received at least one dose of ledipasvir-sofosbuvir. This trial is registered with EudraCT, number 2013-003978-27, and with ClinicalTrials.gov, number NCT02081079. FINDINGS From March 7 to June 10, 2014, we recruited 41 patients, including 21 who were treatment naive and 20 who were treatment experienced. All patients were of white ethnic origins. All 41 patients who started treatment completed the full 12 weeks of treatment and had undetectable HCV RNA at their final treatment visit. In the overall study population, 39 (95%, 95% CI 83-99) of 41 patients achieved SVR12. SVR12 was achieved by 20 (95%, 76-100) of the 21 patients who were treatment naive and 19 (95%, 75-100) of the 20 patients who were treatment experienced. Eight (89%) of nine patients with cirrhosis achieved SVR12, whereas 31 (97%) of the 32 patients without cirrhosis achieved SVR12. The two patients who did not reach SVR12 both had IL28B TT genotype and had viral relapse within 4 weeks of the end of treatment. The most common adverse events were asthenia (16 [39%] patients), headache (11 [27%] patients), and fatigue (four [10%] patients). One patient had a serious adverse event, worsening depression, which we judged to be unrelated to study treatment. INTERPRETATION The oral regimen of ledipasvir-sofosbuvir is an effective and well-tolerated treatment for patients with HCV genotype 5 infection who are treatment naive or treatment experienced. FUNDING Gilead Sciences.

Ledipasvir Plus Sofosbuvir for 12 Weeks in Patients With Hepatitis C Genotype 4 Infection

Genotype 4 hepatitis C virus (HCV) was considered difficult to treat in the era of pegylated interferon‐alpha (Peg‐IFN‐α) and ribavirin regimens. We evaluated the efficacy and safety of therapy with the nonstructural (NS) 5A inhibitor, ledipasvir, combined with the NS5B polymerase inhibitor, sofosbuvir, in patients with HCV genotype 4. In this phase 2, open‐label study, 44 patients (22 treatment naïve and 22 treatment experienced) received a fixed‐dose combination tablet of 90 mg of ledipasvir and 400 mg of sofosbuvir orally once‐daily for 12 weeks. The primary endpoint was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after stopping therapy (SVR12). Among study participants, HCV genotype 4 subtypes were well represented (4a, n = 25; 4d, n = 10; other subtypes, n = 9). Ten patients (23%) had compensated cirrhosis. Of the 22 treatment‐experienced patients, 21 (95%) had a non‐CC IL‐28B genotype. All 44 patients completed the full 12 weeks of dosing. The SVR12 rate was 93% (41 of 44; 95% confidence interval, 81‐99). SVR12 rates were similar between treatment‐naïve (95%; 21 of 22) and treatment‐experienced (91%; 20 of 22) patients. All 3 patients who did not achieve SVR12 had virological relapse within 4 weeks of the end of treatment; all 3 had baseline HCV RNA ≥800,000 IU/mL, a non‐CC IL‐28B genotype, and pretreatment NS5A resistance‐associated variants. None of the patients who relapsed had cirrhosis. The most common adverse events were asthenia, headache, and fatigue. No patients experienced a serious adverse event. Conclusion: The all‐oral regimen of ledipasvir and sofosbuvir is an effective and safe treatment for a wide range of HCV 4 subtypes in both treatment‐naïve and ‐experienced patients, including those with compensated cirrhosis. (EudraCT number: 2013‐003978‐27; Clinicaltrials.gov NCT02081079) (Hepatology 2016;64:1049‐1056)

Articular manifestations in primary Sjögren’s syndrome: clinical significance and prognosis of 188 patients

OBJECTIVES Articular manifestations (AMs) occurred in approximately 30-60% of patients with primary SS (pSS). We conducted the current study to describe clinical presentation, specific treatment and to report clinical outcome of pSS patients with AM in a large bicentric French cohort. METHODS Clinical, biological and immunological features of 419 consecutive patients with pSS were recorded in order to describe the clinical and immunological course of pSS AM and to point out the impact of those rheumatological features on pSS evolution. RESULTS A total of 188 patients with pSS (172 women, 16 men) exhibited AM. They preceded sicca symptoms in 32, were simultaneous to pSS diagnosis in 98 and followed diagnosis in 59 patients. Clinical presentation was polyarticular and concerned mostly peripheral joints (synovitis, n = 66). Symptoms responded readily to symptomatic treatment in 45 cases (24%). DMARDs or immunosuppressive treatments were introduced in 133 patients: HCQ (n = 111), corticosteroid (n = 53), MTX (n = 12), SSZ (n = 6), AZA (n = 3), LEF (n = 1), etanercept (n = 1) and allochrysine (n = 1). Only one case of RA was diagnosed during the evolution. Statistical analysis identified clinical and biological factors associated with AM (P < or = 0.05): RP, muscular manifestations, renal involvement, peripheral neuropathy, cutaneous vasculitis, and positivity of RF, anti-SSB antibodies and cryoglobulinaemia. Patients with AM at diagnosis were characterized by a multisystemic involvement at the end of the follow-up period (P < 0.001). CONCLUSION Although AMs are frequent and usually mild in pSS, these manifestations are associated with a pluri-systemic involvement of pSS.

Heterozygous Mutations in BMP6 Pro-peptide Lead to Inappropriate Hepcidin Synthesis and Moderate Iron Overload in Humans

BACKGROUND & AIMS Hereditary hemochromatosis is a heterogeneous group of genetic disorders characterized by parenchymal iron overload. It is caused by defective expression of liver hepcidin, the main regulator of iron homeostasis. Iron stimulates the gene encoding hepcidin (HAMP) via the bone morphogenetic protein (BMP)6 signaling to SMAD. Although several genetic factors have been found to cause late-onset hemochromatosis, many patients have unexplained signs of iron overload. We investigated BMP6 function in these individuals. METHODS We sequenced the BMP6 gene in 70 consecutive patients with a moderate increase in serum ferritin and liver iron levels who did not carry genetic variants associated with hemochromatosis. We searched for BMP6 mutations in relatives of 5 probands and in 200 healthy individuals (controls), as well as in 2 other independent cohorts of hyperferritinemia patients. We measured serum levels of hepcidin by liquid chromatography-tandem mass spectrometry and analyzed BMP6 in liver biopsy specimens from patients by immunohistochemistry. The functions of mutant and normal BMP6 were assessed in transfected cells using immunofluorescence, real-time quantitative polymerase chain reaction, and immunoblot analyses. RESULTS We identified 3 heterozygous missense mutations in BMP6 (p.Pro95Ser, p.Leu96Pro, and p.Gln113Glu) in 6 unrelated patients with unexplained iron overload (9% of our cohort). These mutations were detected in less than 1% of controls. p.Leu96Pro also was found in 2 patients from the additional cohorts. Family studies indicated dominant transmission. Serum levels of hepcidin were inappropriately low in patients. A low level of BMP6, compared with controls, was found in a biopsy specimen from 1 patient. In cell lines, the mutated residues in the BMP6 propeptide resulted in defective secretion of BMP6; reduced signaling via SMAD1, SMAD5, and SMAD8; and loss of hepcidin production. CONCLUSIONS We identified 3 heterozygous missense mutations in BMP6 in patients with unexplained iron overload. These mutations lead to loss of signaling to SMAD proteins and reduced hepcidin production. These mutations might increase susceptibility to mild-to-moderate late-onset iron overload.

Daclatasvir plus simeprevir with or without ribavirin for the treatment of chronic hepatitis C virus genotype 1 infection

BACKGROUND & AIMS We evaluated the combination of daclatasvir (pan-genotypic NS5A inhibitor) and simeprevir (NS3/4A protease inhibitor), with or without ribavirin, in hepatitis C virus genotype 1-infected patients. METHODS This phase II, open-label study enrolled treatment-naive patients or prior null responders with genotype 1b (n=147) or 1a (n=21) infection. Genotype 1b-infected patients were randomized 1:1 to receive daclatasvir 30mg plus simeprevir 150mg once daily with or without ribavirin; those who completed the initial 12-week treatment were re-randomized 1:1 to stop treatment or continue treatment through to week 24. Genotype 1a-infected patients received daclatasvir plus simeprevir with ribavirin for 24weeks. The primary endpoint was the proportion of patients with sustained virologic response at posttreatment week 12 (SVR12). RESULTS For genotype 1b, 84.9% (45/53) and 74.5% (38/51) of treatment-naive patients and 69.6% (16/23) and 95.0% (19/20) of prior null responders to peginterferon and ribavirin achieved SVR12 with daclatasvir plus simeprevir alone and with ribavirin, respectively. Treatment duration did not have a well-defined impact on response. For genotype 1a, daclatasvir plus simeprevir with ribavirin provided a 66.7% (8/12) response rate in treatment-naive patients and was not effective in prior null responders. Data suggest that baseline resistance polymorphisms influenced SVR12 rates. Daclatasvir plus simeprevir was well tolerated with or without ribavirin with low incidences of serious adverse events and adverse events leading to discontinuation. CONCLUSIONS Daclatasvir plus simeprevir, with or without ribavirin, was effective with a 12- or 24-week duration in genotype 1b-infected patients and was well tolerated. ClinicalTrials.gov identifier: NCT01628692.