Kevork M. Peltekian

Burden of disease and cost of chronic hepatitis C virus infection in Canada

BACKGROUND: Chronic infection with hepatitis C virus (HCV) is a major cause of cirrhosis, hepatocellular carcinoma and liver transplantation.

Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy

Background: The management of patients with chronic hepatitis C who have relapsed or failed to respond to interferon based therapies is an important issue facing hepatologists. Aims: We evaluated the efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in this population by conducting a multicentre open label study. Patients: Data from adults with detectable serum hepatitis C virus (HCV) RNA who had not responded or had relapsed after previous conventional interferon or conventional interferon/ribavirin combination therapy were analysed. Methods: Patients were retreated with peginterferon alfa-2a (40KD) 180 µg/week plus ribavirin 800 mg/day for 24 or 48 weeks at the investigators’ discretion. The study was conceived before the optimal dose of ribavirin (1000/1200 mg/day) for patients with genotype 1 was known. The primary endpoint was sustained virological response (SVR), defined as undetectable HCV RNA (<50 IU/ml) after 24 weeks of follow up. The analysis was conducted by intention to treat. Results: A total of 312 patients (212 non-responders, 100 relapsers) were included. Of these, 28 patients were treated for 24 weeks and 284 for 48 weeks. Baseline characteristics between non-responders and relapsers were similar although more non-responders had genotype 1 infection (87% v 69%). Overall SVR rates were 23% (48/212) for non-responders and 41% (41/100) for relapsers. When data were analysed by genotype, SVR rates were 24% (61/253) in genotype 1 and 47% (28/59) in genotype 2/3. Conclusions: These results in a large patient cohort demonstrate that it is possible to cure a proportion of previous non-responders and relapsers by retreating with peginterferon alfa-2a (40KD) plus ribavirin.

Serum creatinine in patients with advanced liver disease is of limited value for identification of moderate renal dysfunction: Are the equations for estimating renal function better?

BACKGROUNDnThe Cockcroft-Gault formula (CGF) is used to estimate the glomerular filtration rate (GFR) based on serum creatinine (Cr) levels, age and sex. A new formula developed by the Modification of Diet in Renal Disease (MDRD) Study Group, based on the patients Cr levels, age, sex, race and serum urea nitrogen and serum albumin levels, has shown to be more accurate. However, the best formula to identify patients with advanced liver disease (ALD) and moderate renal dysfunction (GFR 60 mL/min/1.73 m2 or less) is not known. The aim of the present study was to compare calculations of GFR, using published formulas (excluding those requiring urine collections) with standard radionuclide measurement of GFR in patients with ALD.nnnMETHODSnFifty-seven consecutive subjects (40% women) with a mean age of 50 years (range 16 to 67 years) underwent 99m-technetium-diethylenetriamine pentaacetic acid (99mTc-DTPA) (single injection) radionuclide measurement of GFR. To calculate GFR, three formulas were used: the reciprocal of Cr multiplied by 100 (100/Cr), the CGF and the MDRD formulas. Pearsons correlation coefficient (r) and Bland-Altman analyses of agreement were used to analyze the association between 99mTc-DTPA clearance and the three equations for GFR.nnnRESULTSnThe mean 99mTc-DTPA clearance was 83 mL/min/1.73 m2 (range 28 mL/min/1.73 m2 to 173 mL/min/1.73 m2). Mean calculated GFRs by 100/Cr, the CGF and the MDRD formula were 106 mL/min/1.73 m2, 98 mL/min/1.73 m2 and 86 mL/min/1.73 m2, respectively. Regression analysis showed good correlation between radionuclide GFR and calculated GFR with r(100/Cr)=0.74, r(CGF)=0.80, r(MDRD)=0.87, all at P > or = 0.0001. The MDRD formula provided the least bias. The Bland-Altman plot showed best agreement between GFR calculated by the MDRD formula and 99mTc-DTPA clearance, with only 3 mL/min/1.73 m2 overestimation. There was higher variability between radionuclide GFR and calculated GFR by the CGF and by 100/Cr. Although there was no difference in precision, GFR calculated by the MDRD formula had the best overall accuracy. The sensitivity and specificity for detection of moderate renal dysfunction by the MDRD formulas were 73% and 87%, respectively.nnnCONCLUSIONSnAmong the Cr-based GFR formulas, the MDRD formula showed a larger proportion of agreement with radionuclide GFR in patients with ALD. In clinical practice, the MDRD is the best formula for detection of moderate renal dysfunction among those with ALD.

Tacrolimus as intervention in the treatment of hyperlipidemia after liver transplant.

Background. To measure the effect on serum lipids and other risk factors for cardiovascular disease, we converted the primary immunosuppression of dyslipidemic stable liver transplant recipients from cyclosporine A to tacrolimus. Methods. Patients underwent a four-month dietary stabilization period (American Heart Association Step II diet) and serum lipid samples were collected for analysis at a central laboratory. After conversion, dietary counseling and lipid analyses were performed over a six-month postconversion observation period. Results. Enrollment was terminated prematurely due to low patient recruitment rates. Thirteen patients were enrolled and provided postconversion data showing surprisingly strong results. At six months postconversion, total cholesterol (C) was reduced by a mean of 0.61 mmol/L (P=0.017), high density lipoprotein cholesterol (HDL-C) remained unchanged; the mean total C:HDL-C ratio was reduced by 0.87 (P=0.001). Low density lipoprotein cholesterol (LDL-C) reductions were not statistically significant, but we observed a significant and persistent decrease in apolipoprotein B (−0.15 g/L six months postconversion, P=0.031). No changes in homocysteine or in vitamins B6 and B12 were discerned, but although red cell folate remained stable, serum folate increased after conversion. We observed no rejection episodes or any other clinically notable events following conversion. Conclusions. In this study, conversion from cyclosporine to tacrolimus provided a safe and well-tolerated alternative that reduced hyperlipidemia and other recognized cardiovascular risk factors.

Complementary and Alternative Medicine Use by Patients Chronically Infected with Hepatitis C Virus

Complementary and alternative medicine (CAM) is becoming increasingly popular in North America. The use of CAM is also popular in patients with chronic liver disease but is not well documented. The extent of use of CAM in chronic hepatitis C virus (HCV) infected patients was determined, and the demographic and clinical data between users and nonusers of CAM was compared. Seventy-six patients (30% female) with chronic HCV were interviewed. The mean age was 43+/-8 years. Current use of CAM for HCV was reported by 35 of 76 patients (46%). Eighteen of 76 patients within this group used herbal supplements (24%). The most commonly used herb was Silybum marianum (milk thistle), reported by 10 of 76 patients (13.2%). Commonly reported benefits of CAM use included reduction in fatigue, boost in the immune system and improved gastrointestinal function. No adverse effects of CAM use were reported. In the present study, four of 18 patients (22%) with chronic liver disease taking herbal therapies were on herbs that increased bleeding time. The use of CAM in chronic HCV patients is significant. Patients should be asked specifically about their use of CAM. CAM use may have implications affecting conventional treatment and management of HCV.

Sofosbuvir-Based Antiviral Therapy Is Highly Effective In Recurrent Hepatitis C in Liver Transplant Recipients: Canadian Multicenter "Real-Life" Experience.

Background This study evaluates the efficacy, safety, and tolerability of regimens containing sofosbuvir (SOF) in the treatment of hepatitis C virus (HCV) recurrence in all genotypes in patients outside of clinical trials in all Canadian transplant centers. Methods One hundred twenty liver transplantation recipients from across Canada with HCV recurrence were started on SOF-based regimens (SOF + simeprevir ± ribavirin (RBV), n = 53; SOF + pegylated interferon + RBV, n = 25; SOF + RBV, n = 36; and SOF + ledipasvir, n = 6) between January and November 2014. Mean age 58 ± 6.85 years, majority (83%) were genotype 1, male (81%), and treatment experienced (82%). Twenty-seven percent had fibrosing cholestatic hepatitis/early aggressive HCV in the graft, and 48% had F3/4 fibrosis. The primary outcomes included patient and graft survival, on- and end-of-treatment response and sustained virological response at 12 weeks after treatment end (SVR12), and adverse events. Results One hundred thirteen of 120 (94%) patients were HCV RNA undetectable at end of treatment, and SVR12 was achieved in 102/120 (85%) patients, with 7 relapses, 1 nonresponder, and 10 deaths (liver-related complications). Sixty-three percent had HCV RNA levels below the lower limit of quantification at week 4. Serum creatinine levels remained stable throughout the treatment. Severe anemia occurred in 13% of patients, primarily in RBV-based regimens. Conclusions Sofosbuvir-based antiviral therapy for HCV recurrence after liver transplantation was well tolerated, with an overall high SVR12 rate (85%) including patients with severe disease recurrence and F3-4 cirrhosis. The response rate was higher (91%) in mild HCV recurrence, suggesting earlier treatment might be beneficial.

Open Trial of Cyclosporine in Patients with Severe Active Crohn's Disease Refractory to Conventional Therapy

Fifteen patients with severe active Crohns disease, refractory to conventional ntherapy, were given a 16 week course of cyclosporine ar an initial oral daily ndose of 10 mg/kg, adjusted to maintain cyclosporine scrum trough levels between 100 nand 200 ng/ml. Five patients withdrew early because of side effects, poor absorption or nnoncompliance. T he remaining 10 patients all improved within four weeks as nmeasured by three different clinical indices: Crohns Disease Activity Index, Simple nIndex of Crohns Disease Activity and Mean Score of Therapeutic Goals (MSTG). nSeven patients maintained this initial improvement and prednisone was either nreduced or discontinued. Four of these seven patients relapsed with in four weeks of nstopping cyclosporine, and three remain in remission after 75 ± 2 weeks. Side effects nwere minor and easily reversible. When the various clinical and laboratory indices nwere compared, MSTG was found to be the most useful index for the assessment of ntherapy. Cyclosporine appears to be a safe and effective therapy in patients with severe nactive Crohns disease refractory to conventional therapy.

Retreatment with Pegylated Interferon Alpha-2a and Ribavirin in Patients with Chronic Hepatitis C Who Have Relapsed or Not Responded to a First Course of Pegylated Interferon-Based Therapy

BACKGROUNDnPegylated interferon (pegIFN) and ribavirin combination therapy remains the first-line treatment for chronic hepatitis C virus (HCV) infection. In contrast to the wealth of studies in treatment-naive patients, the effectiveness of retreatment in patients who have previously failed pegIFN-based therapy is largely unreported.nnnAIMnTo assess the effectiveness of the retreatment of patients who have previously failed an initial course of pegIFN-based therapy with pegIFNalpha-2a and ribavirin.nnnMETHODSnA post-hoc analysis of a multicentre open-label study was performed. Patients received pegIFNalpha-2a and ribavirin at a dose of 800 mg/day and later 1000 mg/day to 1200 mg/day for 24 to 48 weeks at the discretion of the investigator. Outcomes at week 12 (early virological response [EVR]) and week 24 (sustained virological response [SVR]) were analyzed.nnnRESULTSnEighty-seven patients who had relapsed after previous pegIFN-based therapy (n=28; 78% genotype 1) or were nonresponders (n=59; 71% genotype 1) were analyzed. Of the relapsers, 86% achieved an EVR and 68% achieved an SVR. In relapsers to pegIFN monotherapy (n=15) or pegIFN plus ribavirin (n=13), 60% and 77% achieved an SVR, respectively. Fibrosis and genotype did not affect the likelihood of SVR in relapsers although this may be the result of the relatively small number of patients. In previous nonresponders, an EVR was achieved in 53% but an SVR occurred in only 17%. In nonresponders to pegIFN monotherapy (n=9) and pegIFN plus ribavirin (n=50), 33% and 14% achieved an SVR, respectively. Genotype did not affect SVR in nonresponders. Only 10% with a METAVIR score of F3 or F4 on liver biopsy achieved an SVR.nnnCONCLUSIONSnRelapse after previous pegIFN-based therapy is associated with a strong probability of treatment success whereas retreatment of those with previous nonresponse does not.

Rescue Therapy Using a Rifabutin-Based Regimen is Effective for Cure of Helicobacter pylori Infection

OBJECTIVEnTo evaluate the efficacy of rescue therapy using rifabutin, amoxicillin and a proton pump inhibitor (PPI) in the eradication of Helicobacter pylori in patients who have failed at least one course of PPI-based triple therapy.nnnMETHODSnThe present study was a single-centre case series of 16 consecutive patients who had received at least one course of standard eradication therapy. Pretreatment evaluation included endoscopy with biopsies for histology and culture for H pylori infection. Treatment consisted of a one-week regimen containing a PPI twice daily, amoxicillin (A) 1 g twice daily and rifabutin (R) 300 mg once daily (PPI-AR). Post-treatment evaluation consisted of a repeat endoscopy with biopsy for histology and culture, or a validated urea breath test at least four weeks after treatment was completed. Pretreatment antibiotic susceptibility to metronidazole, clarithromycin and A was evaluated using a validated epsilometer test.nnnRESULTSnOf the 16 patients, four had previously received one course of triple therapy, 10 had received two courses and two had received more than two courses. The overall success rate of PPI-AR was 63% (10 of 16). Resistance to A was 0% (0 of 13), metronidazole 77% (10 of 13), clarithromycin 70% (seven of 10), and both metronidazole and clarithromycin 60% (six of 10). There was no correlation between resistance patterns and cure rate.nnnCONCLUSIONSnAn R-containing regimen such as PPI-AR is a viable option as rescue therapy for H pylori infection.

The 1F7 idiotype is selectively expressed on CD5+ B cells and elevated in chronic hepatitis C virus infection.

Antibodies against different chronic viruses, including hepatitis C virus (HCV), express a public cross‐reactive idiotype (Id) designated as 1F7. The prominence of this Id may reflect selective engagement of B1 B cells by chronic pathogens. We investigated this by comparing 1F7 Id expression on CD5+ and CD5− B cells, total IgG, total IgM and anti‐HCV core antibodies in different HCV exposure settings. By flow cytometry, we observed a selective increase in 1F7 Id+CD5+ B cells in chronic HCV infection. 1F7 Id levels in different immunoglobulin compartments were measured by enzyme‐linked immunosorbent assay. 1F7 Id expression was prominent in anti‐HCV core antibodies of ∼90% of 141 HCV‐exposed individuals tested. In the Canadian and Armenian study groups, participants who spontaneously cleared HCV infection had lower median 1F7 Id levels on total plasma IgG and anti‐HCV core antibodies. Armenian spontaneous clearers, who were younger and more recently infected than their Canadian counterparts, also had had lower median 1F7 Id levels on total plasma IgM. Engagement by HCV of B‐cell receptors within, or overlapping with the CD5+ B1 B‐cell repertoire is reflected in the production of 1F7 Id+ anti‐HCV antibodies and expansion of 1F7 Id+CD5+ B cells. Higher 1F7 Id expression levels are associated with chronic infection.