Greg Galler

Cyclosporine in severe ulcerative colitis refractory to steroid therapy.

BACKGROUND There has been no new effective drug therapy for patients with severe ulcerative colitis since corticosteroids were introduced almost 40 years ago. In an uncontrolled study, 80 percent of 32 patients with active ulcerative colitis refractory to corticosteroid therapy had a response to cyclosporine therapy. METHODS We conducted a randomized, double-blind, controlled trial in which cyclosporine (4 mg per kilogram of body weight per day) or placebo was administered by continuous intravenous infusion to 20 patients with severe ulcerative colitis whose condition had not improved after at least 7 days of intravenous corticosteroid therapy. A response to therapy was defined as an improvement in a numerical symptom score (0 indicated no symptoms, and 21 severe symptoms) leading to discharge from the hospital and treatment with oral medications. Failure to respond to therapy resulted in colectomy, but some patients in the placebo group who had no response and no urgent need for surgery were subsequently treated with cyclosporine. RESULTS Nine of 11 patients (82 percent) treated with cyclosporine had a response within a mean of seven days, as compared with 0 of 9 patients who received placebo (P < 0.001). The mean clinical-activity score fell from 13 to 6 in the cyclosporine group, as compared with a decrease from 14 to 13 in the placebo group. All five patients in the placebo group who later received cyclosporine therapy had a response. CONCLUSIONS Intravenous cyclosporine therapy is rapidly effective for patients with severe corticosteroid-resistant ulcerative colitis.

Peginterferon Alfa-2b or Alfa-2a with Ribavirin for Treatment of Hepatitis C Infection

BACKGROUND Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. METHODS At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 microg per kilogram of body weight per week or a low dose of 1.0 microg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 microg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen. RESULTS Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P=0.20 for standard-dose vs. low-dose peginterferon alfa-2b; P=0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], -2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and -1.1% (95% CI, -5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for low-dose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. CONCLUSIONS In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon-ribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials.gov number, NCT00081770.)

Interleukin-28B Polymorphism Improves Viral Kinetics and Is the Strongest Pretreatment Predictor of Sustained Virologic Response in Genotype 1 Hepatitis C Virus

BACKGROUND & AIMS We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphisms clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR. METHODS HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116). RESULTS In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1-6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001). CONCLUSIONS In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome.

Impact of weight-based ribavirin with peginterferon alfa-2b in african americans with hepatitis C virus genotype 1

WIN‐R (Weight‐based dosing of pegINterferon alfa‐2b and Ribavirin) was a multicenter, randomized, open‐label, investigator‐initiated trial involving 236 community and academic sites in the United States, comparing response to pegylated interferon (PEG‐IFN) alfa‐2b plus a flat or weight‐based dose of ribavirin (RBV) in treatment‐naive patients with chronic hepatitis C and compensated liver disease. Patients were randomized to receive PEG‐IFN alfa‐2b at 1.5 μg/kg/week plus flat‐dose (800 mg/day) or weight‐based‐dose RBV (800 mg/day for weight <65 kg, 1000 mg/day for 65‐85 kg, 1200 mg/day for >85‐105 kg, or 1400 mg/day for >105‐<125 kg). Sustained virologic response (SVR; undetectable [<125 IU/mL] hepatitis C virus [HCV] RNA at end of follow‐up) in patients ≥65 kg was the primary end point. Low SVR rates have been reported among African American individuals, in whom there is a preponderance of HCV genotype 1. This subanalysis of WIN‐R was conducted to evaluate the efficacy of weight‐based dosing among African American individuals with genotype 1 infection enrolled in the trial. Of 362 African American patients in the primary efficacy analysis, 188 received RBV flat dosing and 174 received weight‐based dosing. SVR rates were higher (21% versus 10%; P = 0.0006) and relapse rates were lower (22% versus 30%) in the weight‐based‐dose group than in the flat‐dose group. Safety and rates of drug discontinuation were similar between the 2 groups. Conclusion: Weight‐based dosing of RBV is more effective than flat dosing in combination with PEG‐IFN alfa‐2b in African American individuals with HCV genotype 1. Even with weight‐based dosing, response rates in African American individuals are lower than reported in other ethnic groups. (HEPATOLOGY 2007.)

Racial Differences in Hepatitis C Treatment Eligibility

Black Americans are disproportionally infected with hepatitis C virus (HCV) and are less likely than whites to respond to treatment with peginterferon (PEG‐IFN) plus ribavirin (RBV). The impact of race on HCV treatment eligibility is unknown. We therefore performed a retrospective analysis of a phase 3B multicenter clinical trial conducted at 118 United States community and academic medical centers to evaluate the rates of and reasons for HCV treatment ineligibility according to self‐reported race. In all, 4,469 patients were screened, of whom 1,038 (23.2%) were treatment ineligible. Although blacks represented 19% of treated patients, they were more likely not to be treated due to ineligibility and/or failure to complete required evaluations (40.2%) than were nonblack patients (28.5%; P < 0.001). After the exclusion of persons not treated due to undetectable HCV RNA or nongenotype 1 infection, blacks were 65% less likely than nonblacks to be eligible for treatment (28.1% > 17.0%; relative risk, 1.65; 95% confidence interval, 1.46‐1.87; P < 0.001). Blacks were more likely to be ineligible due to neutropenia (14% versus 3%, P < 0.001), anemia (7% versus 4%, P = 0.02), elevated glucose (8% versus 3%, P < 0.001), and elevated creatinine (5% versus 1%, P < 0.001). Conclusion: Largely due to a higher prevalence of neutropenia and uncontrolled medical conditions, blacks were significantly less likely to be eligible for HCV treatment. Increased access to treatment may be facilitated by less conservative neutrophil requirements and more effective care for chronic diseases, namely, diabetes and renal insufficiency. (HEPATOLOGY 2011;)

Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients

BACKGROUND & AIMS Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia. METHODS 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ≥80×10(9)/L and an absolute neutrophil count (ANC) ≥1500/mm(3). Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294). RESULTS 6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p=10(-10)). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p=10(-12), p=10(-7)) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=-0.28, p=10(-17)) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia. CONCLUSIONS Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.

Motility Abnormalities in Irritable Bowel Syndrome

Background/Aims: The intestinal pathophysiology in irritable bowel syndrome (IBS) is largely unknown. The lactulose breath test has been used to identify small bowel bacterial overgrowth in these patients. Methods: We studied intestinal transit in patients with IBS using of the SmartPill® (SP) wireless pH/pressure recording capsule and performed lactulose breath tests to look for physiologic abnormalities. Results: A total of 35/46 (76%) of the IBS patients had prolonged gastric emptying times. Constipation-predominant disease was associated with prolonged gut transit times. The mean hours ± SD for colonic transit time in the constipation group was 71.7 ± 61.1 (n = 13) compared with 22.5 ± 14.9 (n = 14) for diarrhea-predominant and 26.4 ± 21.5 (n = 20) for mixed clinical subtype (p = 0.0010). No correlation between small bowel transit time and abnormal breath hydrogen or methane excretion in the 46 combined patients with IBS was seen. Conclusions: Delayed gastric emptying was identified in IBS and in some patients may contribute to at least a component of their symptoms. Constipation-predominant IBS is associated with prolonged gut transit times. Otherwise, transit abnormalities do not appear to be important in IBS. Intestinal transit did not correlate with breath test results.

Splenic arteriovenous fistula. A rare lesion causing bleeding esophageal varices, ascites, and diarrhea.

SummaryWe report the case of a 39-year-old woman with portal hypertension caused by a splenic arteriovenous fistula that was diagnosed by Doppler ultrasound and splenic arteriography. She presented with esophageal variceal hemorrhage and was initially treated with sclerotherapy. Ascites and secretory diarrhea then developed. At laparotomy portal pressure was 60 cm H2O but fell to 26 cm H2O after the fistula was resected with a splenectomy. All symptoms disappeared shortly thereafter, and the patient has remained well for the past two years.

478 INFECTIONS DURING PEGINTERFERON (PEGIFN)/RIBAVIRIN (RBV) THERAPY ARE ASSOCIATED WITH THE MAGNITUDE OF DECLINE IN THE LYMPHOCYTE COUNT: RESULTS OF THE IDEAL STUDY

Primary endpoint was SVR 24 weeks post-therapy (Roche TaqMan LLD = 9.3 IU/mL). Relapse was the proportion of patients with undetectable HCV-RNA at end of treatment and detectable posttreatment. Results: In treatment-naive patients, anemia and EPO use occurred in: BOC 49.4% (363/734) and 43.3% (318/734), respectively; PR control, 29.7% (108/363) and 24.0% (87/363), respectively. In both placebo and BOC groups, SVR was more frequent in patients who developed anemia compared to those who did not (P < 0.001, Table). In previous-treatment-failure patients, anemia and EPO use occurred in: BOC 48.6% (157/323) and 43.3% (140/323), respectively; PR control, 25% (20/80) and 21.2% (17/80), respectively. In the BOC group, SVR was more frequent in patients who developed anemia compared to those who did not (P< 0.001, Table). In both patient groups, EPO was prescribed in 78.5% of anemic patients treated with BOC (408/520) and 68.0% (87/128) of those in the PR control group. Conclusions: Higher SVR rates were observed among previously untreated and previous-treatment-failure patients who developed anemia during BOC or control PR therapy. Since ~80% of anemic patients took EPO, additional research is needed to understand the relationship of SVR, R dose reduction, and EPO use.

304 METABOLIC SYNDROME (MS) IS A NEGATIVE PREDICTOR OF TREATMENT OUTCOME IN PATIENTS WITH CHRONIC HEPATITIS C: RESULTS FROM THE IDEAL STUDY

Background and Aims: Chronic hepatitis C (CHC) patients with failure to antiviral therapy are a challenge. Reports of retreatment have included nonresponders and relapsers mostly previously treated with conventional IFN and ribavirin (RBV). We evaluated the efficacy and factors related to sustained virological response (SVR) in CHC patients who have relapsed after a prior treatment with PEG-IFN plus RBV. Methods: Out of 1,228 CHC patients treated with PEG-IFN/RBV, 165 (13%) had a relapse. Among these, 62 patients were retreated between April 2003 and June 2008 with PEG-IFN-a-2a or -2b and RBV at a dose of 800 to 1200mg/day. Clinical, biological, virological and histological data were collected. Type of PEG-IFN, initial doses and modifications of therapy were analyzed. The efficacy was evaluated with a qualitative HCVRNA assay ( 15.2mg/kg/day), a better SVR rate was observed when compared to lower dose/weight (70% vs 35%, p = 0.04). All patients without complete EVR (undetectable HCVRNA at W12) did not achieve SVR (Negative Predictive Value, NPV=100%). In the logistic regression, independent predictors of response were: age (p = 0.018), genotype (p =0.048) and initial ribavirin dose/weight (p = 0.022). Conclusion: Retreatment with PEG-IFN plus ribavirin is effective in genotype 2 or 3 relapsers after a first course of PEG-IFN plus RBV, especially in young patients. High RBV dose per weight seems to be an important factor for the retreatment response. Furthermore, the presence of detectable HCVRNA at W12 should be considered a stopping rule in the retreatment of relapsers.