Treatment of Naive Patients with Chronic Hepatitis C Genotypes 2 and 3 with Pegylated Interferon Alpha and Ribavirin in a Real World Setting: Relevance for the New Era of DAA

Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10-20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN +/- sofosbuvir/RBV in well-selected naive G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources

Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial

Background Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy. Methods In the original RCT, patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 μg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE. Results A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004). Conclusions Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints

Flow chart of patients recruited in the HCV genotype 2/3 registry.

<p>Flow chart of patients recruited in the HCV genotype 2/3 registry.</p

Baseline characteristics of patients with RVR and non-RVR.

<p>*Continuous values are indicated in median.</p>+<p>Not all parameters are available for each patient. Only available parameter were considered for calculations.</p>++<p>Country of Origin.</p><p>**Interferon.</p>∼<p>Ribavirin.</p>#<p>body weight.</p><p>Baseline characteristics of patients with RVR and non-RVR.</p

SVR rates in all patients with genotypes 2 and 3 (ITT and PP analysis).

<p>SVR rates in all patients with genotypes 2 and 3 (ITT and PP analysis).</p

Baseline characteristics of patients with HCV Genotype 3 who started treatment with PegIFN/RBV.

<p>*Continuous values are indicated in median.</p>#<p>Chi-Square or t-test results.</p><p>CoO = Country of Origin.</p><p>Baseline characteristics of patients with HCV Genotype 3 who started treatment with PegIFN/RBV.</p

SVR rates in patients with RVR treated for 16 or 24 weeks in the overall cohort and in HCV genotype 3 patients.

<p>A: All patients had low viral, no signs of cirrhosis, RVR and were recommended for 16 weeks of treatment. B: All patients had low viral, no signs of cirrhosis, RVR and were recommended for 16 weeks of treatment.</p

Therapy regimens and treatment durations in different groups of patients.

<p>A: Patients are divided in three different groups according to week 4 response and duration of therapy. B: The first group consists of the so called easy to treat patients with low viral load, no cirrhosis and RVR. In the second group are patients with RVR but high viral load irrespective of stage of liver fibrosis and the last group contains all patients with non-RVR.</p