Christoph R. Werner

Telaprevir‐based triple therapy in liver transplant patients with hepatitis C virus: A 12‐week pilot study providing safety and efficacy data

After liver transplantation (LT), the management of recurrent hepatitis C virus (HCV) infections still remains a major challenge. In HCV genotype 1 patients not undergoing transplantation, the introduction of protease inhibitor (PI)–based regimens has increased the sustained virological response rate significantly. This pilot study investigated both the safety and efficacy of telaprevir (TVR)‐based triple therapy in HCV‐infected LT patients with a special emphasis on drug‐drug interactions between immunosuppressants and PIs. Safety and efficacy data were gathered for 12 weeks for 9 HCV‐infected LT patients who were treated with a combination of TVR, pegylated interferon, and ribavirin (RBV) in parallel with immunosuppressive drugs such as tacrolimus (TAC; n = 4), cyclosporine A (CSA; n = 4), and sirolimus (SIR; n = 1). Seven of the transplant patients completed the 12 weeks of triple therapy. At week 4, 4 of the patients were found to be HCV RNA–negative, and importantly, 8 were found to be negative at week 12. During the 12‐week course of triple therapy, short‐term measurements of immunosuppressant trough levels required individual dose reductions in all patients (CSA, 2.5‐fold; SIR, 7‐fold; and TAC, 22‐fold). Furthermore, two‐thirds of the patients exhibited hematological side effects requiring RBV dose reductions, the administration of erythropoietin, or even blood transfusions. In conclusion, this pilot study provides evidence showing that TVR‐based triple therapy is effective within the first 4 to 12 weeks in LT patients suffering from HCV genotype 1 recurrence, and it also provides evidence showing that drug‐drug interactions between TVR and immunosuppressants can be handled appropriately through the close monitoring of trough levels and adequate dosage adjustments. Liver Transpl, 2012.

Efficacy and Safety of Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake Inhibitors, and Placebo for Common Psychiatric Disorders Among Children and Adolescents: A Systematic Review and Meta-analysis

Importance Depressive disorders (DDs), anxiety disorders (ADs), obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD) are common mental disorders in children and adolescents. Objective To examine the relative efficacy and safety of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and placebo for the treatment of DD, AD, OCD, and PTSD in children and adolescents. Data Sources PubMed, EMBASE, PsycINFO, Web of Science, and Cochrane Database from inception through August 7, 2016. Study Selection Published and unpublished randomized clinical trials of SSRIs or SNRIs in youths with DD, AD, OCD, or PTSD were included. Trials using other antidepressants (eg, tricyclic antidepressants, monoamine oxidase inhibitors) were excluded. Data Extraction and Synthesis Effect sizes, calculated as standardized mean differences (Hedges g) and risk ratios (RRs) for adverse events, were assessed in a random-effects model. Main Outcomes and Measures Primary outcomes, as defined by authors on preintervention and postintervention data, mean change data, and adverse event data, were extracted independently by multiple observers following PRISMA guidelines. Results Thirty-six trials were eligible, including 6778 participants (3484 [51.4%] female; mean [SD] age, 12.9 [5.1] years); 17 studies for DD, 10 for AD, 8 for OCD, and 1 for PTSD. Analysis showed that SSRIs and SNRIs were significantly more beneficial compared with placebo, yielding a small effect size (g = 0.32; 95% CI, 0.25-0.40; P < .001). Anxiety disorder (g = 0.56; 95% CI, 0.40-0.72; P < .001) showed significantly larger between-group effect sizes than DD (g = 0.20; 95% CI, 0.13-0.27; P < .001). This difference was driven primarily by the placebo response: patients with DD exhibited significantly larger placebo responses (g = 1.57; 95% CI, 1.36-1.78; P < .001) compared with those with AD (g = 1.03; 95% CI, 0.84-1.21; P < .001). The SSRIs produced a relatively large effect size for ADs (g = 0.71; 95% CI, 0.45-0.97; P < .001). Compared with participants receiving placebo, patients receiving an antidepressant reported significantly more treatment-emergent adverse events (RR, 1.07; 95% CI, 1.01-1.12; P = .01 or RR, 1.49; 95% CI, 1.22-1.82; P < .001, depending on the reporting method), severe adverse events (RR, 1.76; 95% CI, 1.34-2.32; P < .001), and study discontinuation due to adverse events (RR, 1.79; 95% CI, 1.38-2.32; P < .001). Conclusions and Relevance Compared with placebo, SSRIs and SNRIs are more beneficial than placebo in children and adolescents; however, the benefit is small and disorder specific, yielding a larger drug-placebo difference for AD than for other conditions. Response to placebo is large, especially in DD. Severe adverse events are significantly more common with SSRIs and SNRIs than placebo.

Second-generation direct-acting-antiviral hepatitis C virus treatment: Efficacy, safety, and predictors of SVR12

AIM To gather data on the antiviral efficacy and safety of second generation direct acting antiviral (DAA) treatment with respect to sustained virological response (SVR) 12 wk after conclusion of treatment, and to determine predictors of SVR12 in this setting. METHODS Two hundred and sixty patients treated with SOF combination partners PR (n = 51), R (n = 10), SMV (n = 30), DCV (n = 81), LDV (n = 73), or 3D (n = 15). 144/260 were pre-treated, 89/260 had liver cirrhosis, 56/260 had portal hypertension with platelets < 100/nL, 25/260 had a MELD score ≥ 10 and 17/260 were post-liver transplantation patients. 194/260 had HCV GT1, 44/260 HCV GT3. RESULTS Two hundred and forty/256 (93.7%) patients achieved SVR12 (mITT); 4/260 were lost to follow-up. SVR12 rates for subgroups were: 92% for SOF/DCV, 93% for each SOF/SMV, SOF/PR, 94% for SOF/LDV, 100% for 3D, 94% for pretreated, 87% for liver cirrhosis, 82% for patients with platelets < 100/nL, 88% post-liver transplantation, 95% for GT1a, 93% for GT1b, 90% for GT3, 100% for GT2, 4, and 6. 12 patients suffered from relapse, 6 prematurely discontinued treatment, of which 4 died. Negative predictors of SVR12 were a platelet count < 100/nL, MELD score ≥ 10 (P < 0.0001), liver cirrhosis (P = 0.005) at baseline. In Interferon-free treatment GT3 had significantly lower SVR rates than GT1 (P = 0.016). Side effects were mild. CONCLUSION Excellent SVR12 rates and the favorable side-effect profile of DAA-combination therapy can be well translated into “real-world”. Patients with advanced liver disease, signs of portal hypertension, especially with platelets < 100/nL and patients with GT3 are in special need for further research efforts to overcome comparatively higher rates of virological failure.

Trust in the health care professional and health outcome: A meta-analysis

Objective To examine whether patients’ trust in the health care professional is associated with health outcomes. Study selection We searched 4 major electronic databases for studies that reported quantitative data on the association between trust in the health care professional and health outcome. We screened the full-texts of 400 publications and included 47 studies in our meta-analysis. Data extraction and data synthesis We conducted random effects meta-analyses and meta-regressions and calculated correlation coefficients with corresponding 95% confidence intervals. Two interdependent researchers assessed the quality of the included studies using the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Results Overall, we found a small to moderate correlation between trust and health outcomes (r = 0.24, 95% CI: 0.19–0.29). Subgroup analyses revealed a moderate correlation between trust and self-rated subjective health outcomes (r = 0.30, 0.24–0.35). Correlations between trust and objective (r = -0.02, -0.08–0.03) as well as observer-rated outcomes (r = 0.10, -0.16–0.36) were non-significant. Exploratory analyses showed a large correlation between trust and patient satisfaction and somewhat smaller correlations with health behaviours, quality of life and symptom severity. Heterogeneity was small to moderate across the analyses. Conclusions From a clinical perspective, patients reported more beneficial health behaviours, less symptoms and higher quality of life and to be more satisfied with treatment when they had higher trust in their health care professional. There was evidence for upward bias in the summarized results. Prospective studies are required to deepen our understanding of the complex interplay between trust and health outcomes.

Efficacy and safety of telaprevir (TVR) triple therapy in a ‘real‐life’ cohort of 102 patients with HCV genotype 1: interim analysis after 24 weeks of treatment

Since 2011, telaprevir (TVR)‐based triple therapy is the new treatment standard for hepatitis C genotype 1 virus infection. The aim of our retrospective interim analysis encompassing the first 24 weeks on TVR‐based triple therapy was to assess ‘real‐life’ antiviral efficacy and side effects in a large single‐centre cohort, both in comparison with the data obtained in large prospective clinical trials. In total, we treated 102 patients: 24 treatment‐naïve patients, 58 patients pretreated with PEG‐IFN/RBV (thereof: 28 with nonresponse, 25 with relapse, five unknown) and 20 patients who previously had received nonpegylated interferon. 74 of 102 patients were assigned with HCV genotype 1b; 34 of 102 patients were treated in the context of liver cirrhosis. 72 of 102 patients have reached treatment week 24 (mean treatment duration 31 weeks). In the ITT analysis, overall response rates were at: week 4: 66%; week 12: 85%; and week 24: 78%. So far, 24 patients discontinued treatment prematurely, of those, 10 patients were due to virological failure. Haematological side effects were frequent (40% anaemia), as were ‘flu‐like’ symptoms (94%), rash (65%) and pruritus (79%). According to our interim ITT analysis encompassing up to 24 weeks of TVR‐based triple therapy, our ‘real‐life’ antiviral effects are comparable to the results of large multicentric clinical trials. However, TVR‐based triple therapy exhibited a high frequency of side effects requiring multiple therapeutic interventions. Notably, in our ‘real‐life’ cohort, no lethal case was observed so far.

Feasibility of Telaprevir-Based Triple Therapy in Liver Transplant Patients with Hepatitis C Virus: SVR 24 Results

Management of recurrent Hepatitis C virus (HCV) infection following liver transplantation remains a major challenge. In non-transplanted HCV genotype 1 patients, the introduction of protease inhibitor-based regimens has significantly increased the rate of sustained virological response. In this follow-up study, on the first published cohort of post-liver transplant patients treated with telaprevir-based triple therapy, we investigated both efficacy and safety data in follow-up to 24 weeks (SVR 24) after end of treatment (EOT). SVR 24 efficacy and safety data from 9 liver transplant HCV patients being treated with telaprevir, pegylated interferon, and ribavirin, showed 5 of the transplanted patients accomplished the full duration of the 48 week triple therapy. Notable were the 4 patients found to be HCV RNA-negative at week 4, and 8 patients at week 12. Upon EOT, at week 48, 6 patients were HCV RNA-negative. Importantly, at follow-up (24 weeks after EOT), a favorable sustained virological response rate was observed in 5 of these patients with HCV RNA remaining negative, including in one patient who discontinued treatment prematurely. Due to side effects, 2 patients discontinued, 2 suffered from virological breakthrough after the telaprevir treatment phase, and 1 patient had a relapse after EOT. Two thirds of patients exhibited hematological side effects requiring ribavirin dose reductions, administration of erythropoetin, or even blood transfusions. This retrospective analysis provides evidence that - with respect to SVR 24 - liver transplant patients suffering from HCV genotype 1 recurrence may benefit from a telaprevir-based triple therapy as this new regimen showed acceptable antiviral efficacy in this small cohort of mostly pre-treated patients. Management of drug-drug interactions is challenging, but feasible. In part severe side effects are frequent during treatment and require therapeutic interventions.

First-generation protease inhibitor-triple therapy: SVR 24, safety, and predictors of response in a large single center cohort

Background/AimsAim of this retrospective study was to analyze the efficacy, safety, and predictors of treatment success for first-generation-PI triple therapies, including either boceprevir or telaprevir, in a mono-centric “real-life” setting with respect to SVR 24.Patients131 patients (102 patients telaprevir, 29 patients boceprevir) were treated. Of these, 33/131 patients were treatment naïve, 72/131 patients had been pretreated with PEG-IFN/RBV (PR) (thereof: 36 with non-response, 30 with relapse, 6 unknown), and 26/131 patients previously had received non-pegylated interferon. 96/131 patients were infected with HCV genotype 1b. 41/131 patients had liver cirrhosis.Results95/131 (73%) patients achieved SVR 24. SVR rates for subgroups were: 26/33 (79%) for treatment naïve, 25/30 (83%) for PR-relapse, 20/36 (56%) for PR-non-response, 21/26 (81%) for non-PR pretreated patients, (26/41) 63% for patients with liver cirrhosis, 23/35 (66%) genotype 1a, 72/96 (75%) genotype 1b. Predictors of SVR 24 were eRVR and a negative viral load at PI-treatment week 4 (p < 0.0001), negative predictors were quantifiable HCV viral load at PI-treatment week 4 (p < 0.0001), baseline platelet count < 100/nl (p < 0.0001), and previous PR-non-response (p = 0.006). 33/131 (25%) patients discontinued treatment prematurely, of those 14/131 (11%) patients due to virological failure. Side effects were frequent (anemia 59/131 [45%], severe infections 6/131 [5%]).ConclusionsAccording to our SVR 24 results, efficacy of PI-based triple therapy in our “real-life” cohort is comparable to the large multi-centric clinical trials. Pronounced side effects are frequent during therapy and often need complex therapeutic interventions. Since new DAA are available, it is open to discussion, if first-generation PI-triple therapy is no longer indicated at all.

[Unexpected complication following esophageal variceal hemorrhage - Case 2/2011].

HISTORY AND ADMISSION FINDINGS A 50-year-old patient with alcoholic liver cirrhosis was admitted due to hematemesis and melaena. DIAGNOSIS Endoscopy showed esophageal variceal hemorrhage. A dose of erythromycin was administered before endoscopy for optimal endoscopic view. TREATMENT AND COURSE After conservative treatment with hemopressin, ciprofloxacin, and substitution with blood and fresh frozen plasma, the patient had an episode of atrial fibrillation with rapid ventricular response. The episode was terminated by intravenous administration of amiodarone, with subsequent conversion to sinus rhythm. Later on, the patient suffered from torsades de pointes tachycardia. CONCLUSION Secondary torsades de pointes tachycardias have a low incidence, but often fatal outcome. Torsades de pointes tachycardias mostly are the result of administration of QT-active drugs, and other cofactors. Emergency treatment addresses the reestablishment, and stabilization of sinus rhythm. Preferably, drug-induced torsades de pointes tachycardias are prevented by permanent critical review of administered drugs with respect to indications, interactions, and adverse reactions.

Successful direct acting antiviral (DAA) treatment of HCV/HIV-coinfected patients before and after liver transplantation

OBJECTIVES The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively. METHODS When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7-21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)). RESULTS Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up. CONCLUSION DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.

Effekte, Bedingungen und Anwendung von Placebos

Placeboeffekte sind nicht nur eine Storgrose in wissenschaftlichen Wirksamkeitsuntersuchungen, sondern auch eine nicht zu vernachlassigende Wirkkomponente in Interventionen. Die Ubersichtsarbeit stellt exemplarisch dar, unter welchen Bedingungen Placeboeffekte auftreten und wie diese in der klinischen Praxis berucksichtigt und ggf. genutzt werden konnten.