Inmaculada Fernández

Peginterferon Plus Ribavirin and Sustained Virological Response in HCV-Related Cirrhosis: Outcomes and Factors Predicting Response

OBJECTIVES Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response. METHODS Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1-81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353-7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752-5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418-6.927); baseline viral load <6 × 10(5) (OR=2.597; 95% CI: 1.583-4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26-3.39). No patient with a HCV-RNA decline <1 log(10) at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32-5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81-5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546-4). Improved outcome was more evident in responders with less advanced disease at baseline. CONCLUSIONS SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.OBJECTIVES:Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response.METHODS:Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes.RESULTS:Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1–81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353–7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752–5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418–6.927); baseline viral load <6 × 105 (OR=2.597; 95% CI: 1.583–4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26–3.39). No patient with a HCV-RNA decline <1 log10 at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32–5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81–5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546–4). Improved outcome was more evident in responders with less advanced disease at baseline.CONCLUSIONS:SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.

Decreased bone mineral density after therapy with alpha interferon in combination with ribavirin for chronic hepatitis C

BACKGROUND/AIMS Several thousand patients with chronic hepatitis C have been treated with interferon plus ribavirin. After observing a male patient who developed severe bone loss during this treatment, we studied skeletal status and bone mineral metabolism in patients on therapy with interferon plus ribavirin. METHODS Bone mineral density and biochemical bone markers were studied in 32 male patients (31-58 years old) treated for 12 months with either interferon alone (group 1; n=13) or interferon plus ribavirin (group 2; n= 19). RESULTS Bone mineral density was significantly lower in group 2 (0.877-0.07 g/cm2) than in group 1 (1.108+/-0.08 g/cm2, p<0.001). Likewise, T- and Z-score values were also decreased in group 2 (T: -1.95+/-0.6. Z: -1.76+/-0.51) compared with group 1 (T: 0.19+/-0.6; p<0.001. Z: 0.26+/-0.6; p<0.001). Serum and urine biochemical bone markers were normal in both groups. However, urinary calcium excretion was decreased in patients on combined therapy. CONCLUSION Treatment of chronic hepatitis C with interferon plus ribavirin may induce bone loss. This secondary effect should be investigated during the follow-up of these patients, since they may require therapies aimed at prevention or amelioration of these defects.

Substance P stimulates translocation of protein kinase C in brain microvessels

The action of substance P on protein kinase C in cerebral microvessels, isolated from bovine, was investigated. We found that in untreated microvessels 85% of the total activity was localized to the cytosolic fraction. Substance P caused a shift of activity to the membrane fraction, accompanied by a loss of activity in the cytosolic fraction. This effect resulted in dose-dependence and it was evident after 5 min treatment. These data suggest that substance P may be involved in the regulation of processes underlying protein phosphorylation in the blood-brain barrier.

Safety and on-treatment efficacy of telaprevir: the early access programme for patients with advanced hepatitis C

Background and aim Severe adverse events (AEs) compromise the outcome of direct antiviral agent-based treatment in patients with advanced liver fibrosis due to HCV infection. HEP3002 is an ongoing multinational programme to evaluate safety and efficacy of telaprevir (TVR) plus pegylated-interferon-α (PEG-IFNα) and ribavirin (RBV) in patients with advanced liver fibrosis caused by HCV genotype 1 (HCV-1). Methods 1782 patients with HCV-1 and bridging fibrosis or compensated cirrhosis were prospectively recruited from 16 countries worldwide, and treated with 12 weeks of TVR plus PEG-IFN/RBV, followed by 12 or 36 weeks of PEG-IFN and RBV (PR) alone dependent on virological response to treatment and previous response type. Results 1587 patients completed 12 weeks of triple therapy and 4 weeks of PR tail (53% cirrhosis, 22% HCV-1a). By week 12, HCV RNA was undetectable in 85% of naives, 88% of relapsers, 80% of partial responders and 72% of null responders. Overall, 931 patients (59%) developed grade 1–4 anaemia (grade 3/4 in 31%), 630 (40%) dose reduced RBV, 332 (21%) received erythropoietin and 157 (10%) were transfused. Age and female gender were the strongest predictors of anaemia. 64 patients (4%) developed a grade 3/4 rash. Discontinuation of TVR due to AEs was necessary in 193 patients (12%). Seven patients died (0.4%, six had cirrhosis). Conclusions In compensated patients with advanced fibrosis due to HCV-1, triple therapy with TVR led to satisfactory rates of safety, tolerability and on-treatment virological response with adequate managements of AEs.

Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C

BACKGROUND & AIMS The development of direct-acting antiviral agents (DAAs) is a major step forward in the treatment of hepatitis C (HCV). The aims of the study were to evaluate the efficacy and tolerability of DAAs in kidney transplant (KT) recipients. METHODS Hepa-C is a Spanish registry of patients treated with DAAs in which clinical, virological and analytical data were prospectively included. We report on the data from 103 KT recipients who received DAAs. RESULTS The most commonly used DAAs combinations were sofosbuvir/ledipasvir (n=59, 57%) and sofosbuvir+daclatasvir (n=18, 17%). Ribavirin was used in 41% of patients. Sustained viral response after 12weeks (SVR12) rate was 98%. Grade 2 or 3 anemia appeared in 14 (33%) of patients receiving ribavirin and in 9 (15%) without (p=0.03). There were three episodes of acute humoral graft rejection. No patient discontinued therapy due to adverse events. Importantly, 57 (55%) patients required immunosuppression dose adjustment. Overall, there were no statistically significant differences in the mean level of serum creatinine, eGFR and proteinuria before and after treatment. Nonetheless, seventeen (16%) patients experienced renal dysfunction (increase in serum creatinine >25%) during antiviral therapy, of whom 65% were cirrhotic in comparison with only 29% cirrhotic patients who did not develop significant renal dysfunction (p=0.004). CONCLUSIONS Antiviral therapy with DAAs was highly efficacious and safe in KT recipients. Nevertheless, a non-negligible number of patients, most of them cirrhotic, developed mild allograft dysfunction and a significant proportion of patients required immunosuppression dose adjustment, warranting a close follow-up during therapy. LAY SUMMARY Infection by hepatitis C virus is often found in kidney transplant patients and its presence increases mortality and graft failure. We investigated the efficacy and safety of the new direct-acting hepatitis C antivirals in this population, in which previous information is scarce. Our data shows that, as occurs in the non-transplant setting, new anti-HCV antivirals are highly efficacious kidney transplant patients. Overall, this therapy is also quite safe, although worsening of renal function is observed in 16% of patients warranting a close follow-up observation of graft function during antiviral therapy.

Sustained virological response with telaprevir in 1078 patients with advanced hepatitis C: The international telaprevir access program

BACKGROUND & AIMS There is little information regarding the extent to which difficult to cure patients with advanced liver fibrosis, due to hepatitis C virus genotype-1 (HCV-1) can successfully and safely be treated with triple therapy with telaprevir (TVR), pegylated interferon alpha (P) and ribavirin (R). In the TVR early access program HEP3002 we aimed to explore treatment safety and efficacy, and identify predictors of sustained virological response at week 24 (SVR24). METHODS 1078 patients with bridging fibrosis (n=552) or cirrhosis (n=526) diagnosed by either liver biopsy or non-invasive markers, with compensated bone marrow (neutrophils >1500/mm(3), Hb >12/13 g/dl) and liver function (Albumin >3.3g/dl, Platelets >90,000/ml) received TVR PR for 12 weeks, followed by a PR tail according to label. RESULTS Overall, 614 (57%) achieved SVR24 by intention-to-treat analysis. The SVR24 rate was 68% in 221 treatment naïve patients (62.8% F4), 72% in 356 prior relapsers (64.4% F4), 55% in 139 partial responders (53.2% F4), and 34% in 294 null responders (28.6% F4). The SVR24 rate to response-guided therapy (24 weeks treatment duration if undetectable viremia at weeks 4 and 12) was 84% in 222 naïve/relapser F3 patients. Independent predictors of response were: (A) F3 (odds ratio (OR)=1.51, 95% CI 1.31-2.00, p=0.005), (B) subtype 1b (OR=1.63, 95% CI 1.18-2.24, p=0.0029), (C) alpha-fetoprotein <10 ng/ml (OR=2.50, 95% CI 1.87-3.36, p<0.0001) and (D) any prior response other than null (OR=3.29, 95% CI 2.40-4.52, p<0.0001). SVR24 rose for patients who had more of these predictive factors: 6/32 (19%) for none, 38/139 (27%) for 1, 129/260 (50%) for 2, 202/329 (61%) for 3, and 194/235 (83%) for 4 factors. Grade 2-4 treatment-related adverse events (AE) were experienced by 719 (67%) patients; 169 (16%) discontinued therapy for AE and 7 (0.6%) died during the PR tail. CONCLUSIONS Naïve and experienced patients with advanced fibrosis or cirrhosis due to HCV-1 who have compensated bone marrow and liver function, can effectively and safely be treated by TVR triple therapy. Baseline predictors of outcome have been identified to optimize pre-treatment counselling.

Role of protein kinase C and mitochondrial permeability transition pore in the neuroprotective effect of ceramide in ischemia-induced cell death

In this study, we investigated the role of protein kinase C (PKC) and mitochondrial permeability transition pore (mPTP) on the effect of ceramide in an in vitro model of ischemia in SH‐SY5Y neuroblastoma cells. In ischemic cell viability studies, a dual effect of ceramide was observed, depending on ceramide concentration. PKC isoforms are involved in the protective effect of low concentrations of ceramide. During ischemia, ceramide treatment leads to an increase in the formation of reactive oxygen species (ROS), which induces a controlled opening of mPTP. This fact prevents mitochondrial Ca2+ overload, which is clearly protective.

Involvement of mitochondria on neuroprotective effect of sphingosine-1-phosphate in cell death in an in vitro model of brain ischemia.

Sphingosine-1-phosphate (S1P) has been demonstrated to be an important regulator of cell death and survival. Although it has been suggested that the sphingolipid may act as a neuroprotector in the cell apoptosis induced by traumatic brain injury, the mechanisms involved in this action are unknown. In this study, the relationship between S1P and neuroprotective effect was studied in an in vitro model of ischemia, maintaining SH-SY5Y human neuroblastoma cells under oxygen-glucose deprivation (OGD). When cells were treated with 1 microM S1P simultaneously with OGD and recovery, cell viability increases in a dose-response manner. S1P treatment reduces significantly both necrosis and apoptosis cell death. On the other hand, the treatment with specific PKC epsilon (V1-2), prevents S1P protective effect of OGD/recovery-induced necrosis. Moreover, S1P treatment provokes the translocation of PKC epsilon to the mitochondria. From these results, it is reasonable to assume that S1P protection from necrosis is mediated by PKC epsilon. We also studied the action of S1P on mitochondrial inner membrane potential and mitochondrial Ca(2+) levels during ischemia. In this regard, we must point out that S1P treatment reduces the OGD-induced membrane depolarization and also reduces the increase of Ca(2+) in mitochondria during OGD. Results also indicate that mitochondria from OGD treated cells have significantly less ability to resist swelling on Ca(2+) loading than those obtained in presence of oxygen and glucose. Nevertheless, when S1P was added, this resistance increases considerably. These findings suggest that S1P may have a potential role as a neuroprotective agent in brain injury.

PAF-induced activation of polyphosphoinositide-hydrolyzing phospholipase C in cerebral cortex

The action of platelet-activating factor (PAF) on phosphoinositide hydrolysis was studied in rat brain slices. PAF produced a significant increase of 32P incorporation into phosphoinositides and phosphatidic acid (PA), in a dose- and time-dependent manner. Concomitantly, an increase of inositol phosphates and diacylglycerol (DAG) production was observed. Both inositol bisphosphate (IP2) and inositol trisphosphate (IP3) were detected as early as 5 s and they returned immediately to basal levels; concomitantly, formation of inositol monophosphate (IP) was detected. These findings demonstrated that PAF causes a rapid hydrolysis of polyphosphoinositides in cerebral cortex by a phospholipase C-dependent mechanism followed by subsequent resynthesis.

Lipoprotein changes in patients with chronic hepatitis C treated with interferon-α

Objective:The aim of this study was to evaluate the effects of interferon-α therapy on the lipid profile of patients with chronic hepatitis C.Methods:In 36 consecutive patients with chronic hepatitis C, fasting lipoproteins were evaluated prospectively at baseline, 1, 3 and 6 months during interferon-α therapy and 3 months after the end of treatment.Results:During interferon-α therapy, there was a progressive increase in total and very low density lipoprotein (VLDL)-triglycerides, VLDL-cholesterol and a sustained raise in apolipoprotein (apo) B. In parallel, there was a reduction in high density lipoprotein (HDL)-cholesterol and apo A1 levels. In contrast, total and low density lipoprotein (LDL)-cholesterol and lipoprotein (a) levels remained essentially unchanged during interferon-α therapy. Three patients developed chylomicronemia, two of them with severe hypertriglyceridemia, although none of them presented with pancreatitis. Chylomicronemia and severe hypertriglyceridemia were more common in patients with basal triglycerides above 200 mg/dl. Nineteen patients responded to interferon-α therapy, but their lipid profile did nor differ from that of nonresponders. Three months after the end of interferon-α therapy lipid changes subsided, although VLDL and HDL-cholesterol and apo B did not reach basal levels.Conclusion:In patients with chronic hepatitis C, interferon-α therapy is associated with an increase of total and VLDL-triglycerides, VLDL-cholesterol and apo B, and a decline of HDL-cholesterol and apo A1. The development of chylomicronemia and severe hypertriglyceridemia in some cases makes mandatory a close monitoring of triglycerides during interferon-α therapy, particularly among patients with increased triglycerides at baseline.