Five-year outcome of children with idiopathic nephrotic syndrome: the NEPHROVIR population-based cohort study.

BACKGROUND: The optimal therapeutic regimen for children at onset of idiopathic nephrotic syndrome (INS) is still under debate. A better knowledge of the disease's course is necessary to design more appropriate and/or personalized treatment protocols. METHODS: We report the 5-year outcome of patients included from December 2007 to May 2010 in the prospective multicentric and multiethnic population-based NEPHROVIR study. Patients were treated at onset according to the French steroid protocol (3990 mg/m2, 18 weeks). Data were collected at 5 years or last follow-up. RESULTS: Out of the 188 children with nephrotic syndrome (121 boys, 67 girls; median age 4.1 years), 174 (93%) were steroid-sensitive. Six percent of steroid-sensitive patients required intravenous steroid pulses to get into remission. Relapse-free rate for steroid-sensitive patients was 21% (36/174) at last follow-up (median 72 months). A first relapse occurred in138 steroid sensitive patients (79%) with a median time of 8.3 months (IQ 3.4-11.3). Out of the 138 relapsers, 43 were frequent relapsers. Age at onset below 4 years was the only predictive factor of relapse, while gender, ethnicity, and delay to first remission were not. At 96 months of follow-up, 83% of frequent relapsers were still under steroids and/or immunosuppressive drugs. CONCLUSIONS: The treatment of the first flare deserves major improvements in order to reduce the prevalence of relapsers and the subsequent long-lasting exposure to steroids and immunosuppression.

Multicenter Experience using Ledipasvir/Sofosbuvir ± RBV to Treat HCV GT 1 Relapsers after Simeprevir and Sofosbuvir Treatment.

INTRODUCTION AND AIM: Approximately 10%-15% of patients with hepatitis C genotype 1 (HCV GT1) experience virological relapse after all-oral antiviral regimen using simeprevir (SMV) and sofosbuvir (SOF). The efficacy and safety of treating such relapsers using ledipasvir/sofosbuvir (LDV/SOF) with/without ribavirin (RBV) has been limited. OBJECTIVE: Report the virological response and safety of LDV/SOF with/without RBV for 12-24 weeks in treating HCV GT1 relapsers after SMV + SOF. MATERIAL AND METHODS: Patients treated with standardized clinical protocol utilizing LDV/SOF with/without RBV at three transplant centers were retrospectively reviewed. RESULTS: Forty-five patients (29% post-LT, 82% male, 13% non-white, 73% subtype 1a, 86% IL28B CT/TT, 78% F3-4) started LDV/SOF with/without RBV at a median of 22 weeks (range 7-55 weeks) after the last dose of SMV+SOF treatment. Thirty-seven patients received LDV/SOF for 24 weeks (24/37 patients with RBV) and eight patients received LDV/SOF for 12 weeks (5/8 patients with RBV). RBV dose was adjusted for renal function. Sixteen patients who were RBV-ineligible received LDV/SOF without RBV for 12 or 24 weeks. SVR 12 was achieved in 96% (43/45) of patients. Baseline viral load, RBV use, or GT1 subtype did not impact SVR 12. Minimal adverse events were reported in those without RBV; 45% of patients who received RBV developed significant anemia requiring RBV dose reduction and/or discontinuation. In LT recipients, minimal immunosuppression dose adjustments were required and no biopsy-proven acute rejection occurred. CONCLUSIONS: Treatment with LDV/SOF with/without RBV for 12-24 weeks was very well tolerated and resulted in high SVR 12 rates (96%) in HCV GT1 relapsers to SMV + SOF treatment.

Safety and efficacy of faldaprevir in combination with pegylated interferon α-2b and ribavirin in Japanese patients with genotype-1 chronic hepatitis C virus infection.

AIM: We evaluated the safety and efficacy of the hepatitis C virus (HCV) NS3/4A A protease inhibitor faldaprevir plus pegylated interferon α-2b and ribavirin (PegIFNα-2b/RBV) in Japanese patients with HCV genotype-1 infection. METHODS: Treatment-naïve patients were randomized (1:1) to faldaprevir 120 mg q.d. for 12 or 24 weeks (response-guided therapy [RGT], n = 44), or faldaprevir 240 mg q.d. for 12 weeks (n = 43), each combined with PegIFNα-2b/RBV for 24 or 48 weeks (RGT). Response-guided therapy was based on early treatment success (HCV RNA <25 IU/mL at week 4 and <25 IU/mL undetected at week 8). Treatment-experienced patients received 240 mg q.d. for 24 weeks, plus PegIFNα-2b/RBV RGT (24 or 48 weeks, prior relapsers, n = 29) or PegIFNα-2b/RBV (48 weeks, 5 prior partial responders/breakthroughs, 10 prior null responders). The primary objective was safety; sustained virologic response 12 weeks post-treatment (SVR12) was a secondary end-point. RESULTS: All except one patient experienced drug-related adverse events. Adverse events led to faldaprevir discontinuation in 1 (2%), 13 (20%), and 3 (6.8%) patients on faldaprevir 120 mg, faldaprevir 240 mg 12 weeks, and faldaprevir 240 mg 24 weeks, respectively. The SVR12 rates were: 86% with faldaprevir 120 mg and 74% with faldaprevir 240 mg among treatment-naïve patients; and 86%, 60%, and 40% among prior relapsers, partial responders/breakthroughs, and null responders, respectively. CONCLUSIONS: In treatment-naïve Japanese patients, faldaprevir 120 mg q.d. plus PegIFNα-2b/RBV was better tolerated than faldaprevir 240 mg q.d. plus PegIFNα-2b/RBV, with at least comparable efficacy. In treatment-experienced patients, most prior relapsers achieved SVR12 with 24 weeks of faldaprevir 240 mg q.d. plus PegIFNα-2b/RBV. Clinicaltrials.gov NCT01579474.

The impact of an educational program on HCV patient outcomes using boceprevir in community practices (OPTIMAL trial).

OBJECTIVES: Although effective, direct acting antiviral (DAA) therapies for genotype 1 (GT 1) hepatitis C virus (HCV) have been associated with compliance challenges. Additionally, treatment at predominantly community-based centers has been associated with low retention of patients on treatment and higher dropout rates. The OPTIMAL Phase IV interventional trial (ClinicalTrials.gov Identifier: NCT01405027) was designed to evaluate the impact of an education program for community investigator (CI) sites participating in a Chronic Liver Disease Foundation study treating chronic GT 1 HCV patients. METHODS: This physician educational program was administered by 22 Hepatology Centers of Educational Expertise (HCEE) academic sites to 33 CI sites asked to participate from December 2011 to July 2012. The HCEE mentors from DAA-experienced academic sites educated those at CI sites on therapeutic management, practice, and patient outcomes through a series of four standardized educational sequence visits regarding the use of first generation HCV protease inhibitors and the overall treatment of HCV. RESULTS: Treatment duration compliance rates for patients treated at CI sites versus those treated at HCEE academic sites were evaluable in 77 of 84 HCEE academic site patients, 102 of 113 patients treated at CI sites, and 179 of 197 overall patients. The treatment duration compliance rates for patients treated at HCEE academic sites, CI sites and overall were 85.4 ± 25.39%, 83.8 ± 27.37%, and 84.5 ± 26.48%, respectively, and did not differ statistically between the groups (p = 0.49). Almost half (47%) of the patients in the study achieved a sustained virological response for 24 weeks (SVR24) regardless of the type of site (p = 0.64). Safety profiles were similar at both HCEE and CI sites. CONCLUSIONS: These results demonstrated that education of CI sites unfamiliar with DAAs resulted in patient outcomes consistent with those observed at DAA-experienced academic sites.

Identification of naïve HVC-4 patients who may be treated with pegylated-interferon and ribavirin according to IL28B polymorphisms.

BACKGROUND: The current treatment of HCV-4 patients is dual therapy with PEG-IFN and ribavirin; however, new drugs against this genotype will be available within few months. Despite the evidenced good virological response in IFN-free regimens, the high cost of these new therapies will require patient selection. In our paper we propose the use of both rs8099917 and rs12979860 IL28-B polymorphisms, in order to identify potentially categories of SVR, null-responder and relapse and consequently to choose the dual therapy or novel approach. METHODS: One hundred and sixty-nine patients with chronic hepatitis C and genotype 4 treated with pegylated interferon and ribavirin for 48weeks were retrospectively studied. All patients were genotyped for rs8099917 and rs12979860 interleukin-28B polymorphisms. RESULTS: 80 patients with SVR (88.8%) had the TT/CC or TT/TC (rs8099917/rs12979860) (p<0.001) genotypes; the null-responders (n=13), 9 (69.2%) showed the GG/TT allelic distribution (p<0.001); relapsers showed a prevalent distribution of the TG/TC genotype (83.3%) (p<0.001). The 6 (100%) breakthrough patients showed TT/TC genotype, while the partial responders patients did not show any particular IL-28B genetic profile. Genetic profiles different from TT/CC showed 94.9% negative predictive value for SVR, with 92.6% of sensitivity and 65.2% of specificity. Insulin-resistance, diabetes and liver fibrosis were not relevant in our multivariate analysis. CONCLUSIONS: The combination of both rs8099917/rs12979860 polymorphisms is useful for early identification of SVR, null-responders and relapsers. This could be used to chose between standard dual therapy or novel approach with IFN-free regimens.

Management of chronic hepatitis C treatment failures: role of consensus interferon.

A significant proportion of patients with chronic hepatitis C virus (HCV) infection who undergo antiviral therapy have persistent or recurrent viremia and fail to achieve a sustained virologic response (SVR). Factors associated with treatment failure include HCV genotype 1 infection, high serum HCV RNA levels, and advanced fibrosis. Consensus interferon (CIFN) is a synthetic type I interferon derived from a consensus sequence of the most common amino acids found in naturally occurring alpha interferon subtypes. Several prospective clinical studies have demonstrated that CIFN may be a treatment option in patients who have failed prior interferon-based therapy, including those who have failed combination therapy with standard interferon or peginterferon plus ribavirin. Daily CIFN in combination with ribavirin may be an effective regimen in this setting; however, optimal dose and treatment duration of CIFN therapy have not been well established. Patients who achieve viral suppression during prior interferon-based therapy and those who do not have advanced fibrosis have a greater likelihood of achieving a SVR with CIFN retreatment. Individualized therapy targeting specific patient groups will be an important consideration in the successful management of prior treatment failures. Additional prospective studies are required in order to identify optimal treatment strategies for the use of CIFN in these patients.

Evaluation of the Indications of Renal Biopsy in Children with Primary Nephrotic Syndrome

PURPOSE: Percutaneous renal biopsy in children with primary nephrotic syndrome(NS) contributed to establish the renal pathology and clinicopathological correlation. The most common minimal change lesion(MCL) was steroid sensitive and could be predicted by clinical and laboratory findings. It was uniformly agreed that most nephrotic children who were predicted as MCL, should receive an 8 week course of prednisolone before considering renal biopsy. Early indications of renal biopsy has been those nephrotic children with the age below 1 year and above 8 years, hypertension, hematuria, low serum C3, renal insufficiency which are not compatible with MCL. Late indications has been frequent relapser(FR), steroid dependent(SDNS) and steroid resistant nephrotic syndrome(SRNS). The indications have been challenging recently and we tried to evaluate the commonly recommended indications. METHODS: Clinical, laboratory, pathologic findings and therapeutic responses were compared in 81 children with primary nephrotic syndrome who had renal biopses beteen 1984 and 1996. RESULTS: 1) Among 11 children with the age indication, MCLs were diagosed in 9(81.8%), mesangial proliferative glomerulonephritis(MsPGN) in 1(9.1%) and membranous nephropathy(MGN) in 1(9.1%). 2) Among 4 children with microscopic hematuria, MCLs were diagosed in 3(75.0%), MsPGN in 1(25.01%). In 13 children with hypertension, macrohematuria, azotemia and low serum C3, focal segmental glomerulosclerosis(FSGS), membrano-proliferative glomerulonephritis(MPGN) and IgA nephropathy(IgA) were frequently diagnosed instead of MCL. 3) All 5(100%) frequent relapsers were diagnosed as MCLS Among 30 children with the indication of SDNS, MCLs were diagosed in 28(93.3%), MsPGN in 2(6.7%) 4) Among 18 children with the indication of SRNS, MCLs were diagosed in 6(33.3%), MsPGN in 6(33.3%), FSGS in 6(33.3%) 5) The probability to diagnose MCL was 81.8%(9/11) in age indication, 75.0%(3/4) in microscopic hematuria, 100%(5/5) in FR and 93.3%(28/30) in SDNS. 6) The response rate to standard steroid treatment were 81.8%(9/11) in age indication 75.0%(3/4) in microscopic hematuria, 100%(5/5) in FR and 96.7%(29/30) in SDNS. CONCLUSIONS: Among the commmon indications of renal biopsy in children with primary nephrotic syndrome, age, microscopic hematuria, frequent relapser and steroid dependant should be reevauated to reduce the unnecessary renal biopsy.