Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort.

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin.This study was sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Support for third-party writing assistance for this manuscript, furnished by Blair Jarvis MSc, ELS, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. Results: SVR24 rates were 46.1 % (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1,2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. Conclusions: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginter-feron alfa-2a/ribavirin

Factors that may affect treatment outcome of triple Helicobacter pylori eradication therapy with omeprazole, amoxicillin, and clarithromycin

Factors affecting Helicobacter pylori eradication rate With omeprazole (OME), clarithromycin (CL), and amoxicillin (AMO) have not been extensively studied. We have investigated the effect of age, sex, smoking, ulcer disease, compliance with therapy, H. pylori colonization density, degree and activity of antral gastritis, the coexistence of corpus gastritis, and the presence of lymphoid follicles on H. pylori eradication rate. We studied 80 consecutive H. pylori-positive patients, with duodenal ulcer (N = 35) or nonulcer dyspepsia (N = 45) treated with OME 20 mg, CL 500 mg, and AMO 1 g, each given twice daily for 10 days. H. pylori was eradicated in 71/80 (88.8%, 95% CI 82-96%) patients. The regimen failed to eradicate the only strain (1.8%, 95% CI 0-5.2%) that was clarithromycin resistant. Multivariate discriminant analysis showed that two histological variables (Wilks lambda = 0.74, chi(2) = 23.41, df = 2, P &lt; 0.001), absence of lymphoid follicles in routine gastric biopsies (F = 13.63, P &lt; 0.001) and coexistence of antral and body gastritis (F = 13.68, P &lt; 0.001), significantly increased H. pylori eradication rate. No other factor examined predicted H. pylori eradication with this regimen. Our data suggest that body gastritis is a positive and presence of lymphoid follicles in routine gastric biopsies is a negative predictive factor of treatment outcome with the omeprazole, clarithromycin, and amoxicillin regime

Riboflavin's time-dependent degradation rate induced by ultraviolet A irradiation.

To evaluate the time-dependent degradation rate of riboflavin after ultraviolet A (UVA) irradiation. Two solutions of commercially available riboflavin solution (0.1%) were used; one served as control, while the second was irradiated using UVA light at 370 nm wavelength. Four samples of riboflavin solution were retrieved prior to irradiance and at 1, 5, 15, 30, and 60 minutes after irradiation (group A); at the same time points samples of riboflavin were retrieved from the control solution in order to assess environmental time-induced degradation of riboflavin (group B). All samples were immediately analyzed using liquid chromatograph mass spectrometry to detect riboflavin and its 2 subproducts, lumiflavin (LF) and lumichrome (LC). Mean percentage of riboflavin degradation was 0.0, 5.3, 9.1, 15.3, 20.6, and 33.3 at 0, 1, 5, 15, 30, and 60 minutes after UVA irradiation, respectively (group A). The time-dependent riboflavin degradation was statistically significant (p&lt;0.05), while for group B there was no change in riboflavin concentration at all time intervals. In group A, mean LC concentration demonstrated a gradual concentration increase, reaching 2.386±1.526 ppm after 60 minutes of UVA exposure. The time-dependent degradation of riboflavin solution is significant, reaching 20.6% after 30 minutes of UVA exposure. It seems that only a small fraction of the overall riboflavin molecules break down since more than 65% remain intact even after 1 hour of UVA irradiation. Control riboflavin solution seems to be stable, as no degradation is evident even after 60 minutes

Effectiveness of two quadruple, tetracycline- or clarithromycin-containing, second-line, Helicobacter pylori eradication therapies

Background: There are no guidelines on second-line therapies for Helicobacter pylori eradication failures of omeprazole-clarithromycin-amoxicillin triple therapy. Aim: To compare the efficacy of two second-line therapies for persistent H. pylori infection. Methods: Over a 6-year period, patients with persistent H. pylori infection following omeprazole-clarithromycin-amoxicillin eradication therapy were randomized to receive omeprazole, 20 mg twice daily, bismuth, 120 mg four times daily, metronidazole, 500 mg twice daily, and either tetracycline, 500 mg four times daily, or clarithromycin, 500 mg twice daily, given for 7 days. Before therapy, patients underwent endoscopy with biopsies for histology, culture and antibiotic susceptibility tests. H. pylori infection was confirmed by histology. Results: Of the 95 randomized patients, 88 (93%,) completed the study. Age, sex, smoking, ulcer/non-ulcer dyspepsia ratio and antibiotic resistance were not significantly different between the treatment groups. On intention-to-treat analysis, eradication was achieved in 41 of the 49 patients (84%: 95% confidence interval, 70.4-92.79%) and 27 of the 46 patients (59%; 95%, confidence interval, 43.3-73.0%) of the tetracycline and clarithromycin-containing groups, respectively (P = 0.007). On multivariate regression analysis, the sensitivity of H. pylori to metronidazole had a likelihood ratio of 5.2 (P = 0.022), followed by the type of quadruple therapy (likelihood ratio, 4.4; P = 0.036). Conclusions: Tetracycline-containing quadruple rescue therapy is highly effective in treating H. pylori eradication failures of the omeprazole-amoxicillin-clarithromycin regimen

Lamivudine monotherapy in HBeAg-negative chronic hepatitis B: prediction of response-breakthrough and long-term clinical outcome

Background Factors that predict response and breakthrough phenomenon to lamivudine monotherapy in patients with HBeAg-negative chronic hepatitis B have not been well defined. Aim To determine pre-treatment and on treatment variables that predict initial response and breakthrough in patients with HBeAg-negative chronic hepatitis B receiving long-term lamivudine. Methods Seventy-nine patients, with chronic HBeAg-negative hepatitis B, who received lamivudine for a median of 31 months were included in the study. Results Initial virologic and biochemical response was observed in 73 (92%) and 70 (89%) patients, respectively, while 34 (47%) and 15 (21%) patients developed virological and biochemical breakthrough, respectively. High levels of necroinflammation in liver biopsy were associated with a higher probability of initial virological and biochemical response. Patients with pre-treatment serum hepatitis B virus DNA concentrations of more than 10(6) copies/mL were three times more likely to develop virologic breakthrough. Two patients died, one with baseline cirrhosis because of liver failure during biochemical breakthrough while the second death was liver and treatment unrelated. Conclusions In HBeAg-negative chronic hepatitis B, initial response to lamivudine therapy is associated with necroinflammation, while baseline serum hepatitis B virus DNA exceeding 10(6) copies/mL is a strong predictor for breakthrough because of drug-resistant mutations. Severe complications are uncommon and are associated with biochemical breakthrough and pre-existing cirrhosis