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Patrick Marcellin,
Stuart K Roberts,
K Rajender Reddy,
Stephen A Harrison,
Donald M Jensen,
Stephanos Hadziyannis,
Moises Diago, Martin Weltman,
Diethelm Messinger,
Fernando Tatsch,
Mario Rizzetto
[show abstract]
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ABSTRACT: Objective: This analysis examines the safety profile of standard- versus high-dose peginterferon alfa-2a. Methods: Data were pooled from five trials including HCV genotype 1- or 4-infected naive and treatment-experienced patients (n = 2,940). Patients were randomized to receive peginterferon alfa-2a at 180 μg/week (standard-dose; n = 1,672) or 360 μg/week (high-dose; n = 1,268) plus ribavirin 1,000/1,200 mg/day for 12 weeks; after 12 weeks, all received standard dose. This safety analysis was restricted to the first 12 weeks. Results: In standard and high-dose groups, similar frequencies of serious adverse events (SAEs, 3.2 and 4.2%, respectively) and treatment discontinuations for safety reasons (2.8 and 2.9%) were reported. More patients reported weight decrease as an adverse event (AE) in the 360 μg/week group (7.7 vs. 3.3%). Significant (p < 0.05) independent predictors for discontinuation due to safety were older age, male gender, lower albumin and low neutrophil count, but not the starting dose of peginterferon alfa-2a. Although more laboratory abnormalities were reported in patients receiving high-dose peginterferon alfa-2a, this was not reflected in AEs or discontinuations, suggesting these are adequately managed by dose modification. Conclusions: High-dose peginterferon alfa-2a for 12 weeks does not significantly increase the incidence of SAEs or discontinuations for safety reasons, beyond that of a standard dose regimen.
Expert Opinion on Drug Safety 09/2012; 11(6):901-9. · 3.02 Impact Factor
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ABSTRACT: To determine hepatitis C (HCV) treatment effectiveness and predictors of response in the "real-world" Australian clinic setting.
Patients with chronic HCV, who were HCV-treatment-naive at enrolment, and were then treated with standard therapy (pegylated interferon-α plus ribavirin), were recruited prospectively through a national network of 24 HCV clinics between April 2008 and December 2009. Patients were interviewed and a medical record review was conducted at enrolment and at routine follow-up clinic visits.
Proportion of patients achieving a sustained virological response (SVR), predictors of SVR, and impact of treatment on biochemical markers of liver disease (alanine aminotransferase levels and aspartate aminotransferase-to-platelet ratio index scores).
The SVR by intention to treat was 60% (327/550). Infection with HCV genotype 2 or 3 (compared with genotype 1) was an independent predictor of SVR (odds ratio [OR], 2.45; 95% CI, 1.70-3.52), while HIV coinfection (OR, 0.28; 95% CI, 0.10-0.82), cirrhosis (OR, 0.38; 95% CI, 0.18-0.81), and increased body mass index for ≥ 30 kg/m(2) v ≤ 25 kg/m(2) (OR, 0.58; 95% CI, 0.35-0.96) were independently associated with lower SVR. There was a significant improvement in biochemical markers of liver disease following SVR (P< 0.001).
Our findings are similar to those seen in clinical trials, despite the inclusion of patients with a broad range of comorbid conditions such as injecting drug and alcohol use and psychiatric illness. They suggest that, with appropriate patient and infrastructure support, expansion of treatment services to the broader HCV-infected community is warranted.
The Medical journal of Australia 06/2012; 196(10):633-7. · 2.81 Impact Factor
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Darrell H G Crawford,
Gregory J Dore,
William Sievert,
Wendy S C Cheng, Martin Weltman,
Geoffrey McCaughan,
William Rawlinson,
Philippa S Marks,
Motoko Yoshihara,
Bishoy Rizkalla,
Stuart K Roberts
[show abstract]
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ABSTRACT: On-treatment HCV viral load during early therapy with pegylated interferon (PEG-IFN) and ribavirin is highly predictive of sustained virological response (SVR). We sought to provide further refinement of this prediction through an extensive evaluation of the effect of HCV viral loads at weeks 4, 8 and 12 on SVR, including analysis by liver disease stage grouping.
A total of 309 patients with genotype 1 chronic HCV and recent liver biopsy enrolled in the CHARIOT study received 180 μg of PEG-IFN-α2a weekly with 1,000/1,200 mg of ribavirin daily. The probability of an SVR was estimated using baseline METAVIR fibrosis stage and HCV viral loads at weeks 4, 8 and 12.
HCV RNA was undetectable in 27.5%, 50.3% and 62.6% of patients at weeks 4, 8 and 12, respectively. SVR was 80.0%, 76.8% and 72.4% among patients with undetectable HCV RNA at weeks 4, 8 and 12, respectively. SVR decreased in a progressive fashion with increasing HCV viral loads at each early time point, but was similar for patients with HCV viral load <15 IU/ml, 15-100 IU/ml and 100-1,000 IU/ml. The effect of fibrosis stage on SVR was modest for patients with HCV viral load <1,000 IU/ml at week 4, but more marked for those with week 4 HCV viral load >1,000 IU/ml, and all HCV viral load categories at weeks 8 and 12.
A combination of baseline fibrosis stage and on-treatment HCV viral load at early time points provides improved estimates for treatment response in patients with chronic HCV genotype 1.
Antiviral therapy 04/2012; 17(5):849-54. · 3.16 Impact Factor
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ABSTRACT: Introduction: There is clinical impetus to accurately monitor cannabis withdrawal symptoms. In doing this the impact of other drug and mental health comorbidities should be considered. Aims: To report patient demographics, psychiatric and substance use comorbidities and symptoms of cannabis withdrawal in the first 5 days of hospital admission for detoxification. Design: Daily self-reported symptom severity ratings were analysed as functions of gender, secondary drug use and recent mental health history. Setting: Specialised inpatient hospital unit for withdrawal management (detoxification) at a University of Sydney teaching hospital, Sydney, Australia. Participants: Total 193 consecutive patients admitted for routine inpatient cannabis withdrawal management over a 9-month period. Measurements: Patients screened via daily self-reported subjective ratings of cannabis withdrawal. Findings: Average cannabis used per day was 2.6 g. Most patients smoked tobacco daily (91%) and half of the sample (53%) reported other drug use. Alcohol was the main secondary drug used (29%). Half of the patients (51%) reported recent contact or interventions for mental health concerns. We were able to delineate principal withdrawal features to include “anxiety” (physical tension, hypermentation, palpitations and excessive worry), dysphoria (+ anergia, anhedonia, lethargy and somnolence) and irritability/agitation. Additional features identified included mood swings and cravings for cannabis. These features all significantly declined over a 5-day admission. Recent mental health concerns, but not gender or secondary drug use, correspond to greater global symptom severity over the course of admission. Conclusions: This study underscores a need to be alert to the impacts of comorbidities that are common in this treatment-seeking population, especially secondary drug use and the potential for mental health issues which add dimensions of complexity.
09/2011; 16(5):392-405.
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Vijayaprakash Suppiah,
Silvana Gaudieri,
Nicola J Armstrong,
Kate S O'Connor,
Thomas Berg, Martin Weltman,
Maria Lorena Abate,
Ulrich Spengler,
Margaret Bassendine,
Gregory J Dore, [......],
Tobias Müller,
Emma Hammond,
David Dunn,
Francesco Negro,
Pierre-Yves Bochud,
Simon Mallal,
Golo Ahlenstiel,
Graeme J Stewart,
Jacob George,
David R Booth
[show abstract]
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ABSTRACT: To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%-50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control.
We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 "G" was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10(-8), 1.67-2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10(-14), 2.67-5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05-2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10(-6), 2.03-7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B.
Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B.
PLoS Medicine 09/2011; 8(9):e1001092. · 16.27 Impact Factor
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Katherine R Smith,
Vijayaprakash Suppiah,
Kate O'Connor,
Thomas Berg, Martin Weltman,
Maria Lorena Abate,
Ulrich Spengler,
Margaret Bassendine,
Gail Matthews,
William L Irving,
Elizabeth Powell,
Stephen Riordan,
Golo Ahlenstiel,
Graeme J Stewart,
Melanie Bahlo,
Jacob George,
David R Booth
[show abstract]
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ABSTRACT: The hepatitis C virus (HCV) infects nearly 3% of the World's population, causing severe liver disease in many. Standard of care therapy is currently pegylated interferon alpha and ribavirin (PegIFN/R), which is effective in less than half of those infected with the most common viral genotype. Two IL28B single nucleotide polymorphisms (SNPs), rs8099917 and rs12979860, predict response to (PegIFN/R) therapy in treatment of HCV infection. These SNPs were identified in genome wide analyses using Illumina genotyping chips. In people of European ancestry, there are 6 common (more than 1%) haplotypes for IL28B, one tagged by the rs8099917 minor allele, four tagged by rs12979860.
We used massively parallel sequencing of the IL28B and IL28A gene regions generated by polymerase chain reaction (PCR) from pooled DNA samples from 100 responders and 99 non-responders to therapy, to identify common variants. Variants that had high odds ratios and were validated were then genotyped in a cohort of 905 responders and non-responders. Their predictive power was assessed, alone and in combination with HLA-C.
Only SNPs in the IL28B linkage disequilibrium block predicted drug response. Eighteen SNPs were identified with evidence for association with drug response, and with a high degree of confidence in the sequence call. We found that two SNPs, rs4803221 (homozygote minor allele positive predictive value (PPV) of 77%) and rs7248668 (PPV 78%), predicted failure to respond better than the current best, rs8099917 (PPV 73%) and rs12979860 (PPV 68%) in this cross-sectional cohort. The best SNPs tagged a single common haplotype, haplotype 2. Genotypes predicted lack of response better than alleles. However, combination of IL28B haplotype 2 carrier status with the HLA-C C2C2 genotype, which has previously been reported to improve prediction in combination with IL28B, provides the highest PPV (80%). The haplotypes present alternative putative transcription factor binding and methylation sites.
Massively parallel sequencing allowed identification and comparison of the best common SNPs for identifying treatment failure in therapy for HCV. SNPs tagging a single haplotype have the highest PPV, especially in combination with HLA-C. The functional basis for the association may be due to altered regulation of the gene. These approaches have utility in improving diagnostic testing and identifying causal haplotypes or SNPs.
Genome Medicine 08/2011; 3(8):57.
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William Sievert,
Gregory J Dore,
Geoffrey W McCaughan,
Motoko Yoshihara,
Darrell H Crawford,
Wendy Cheng, Martin Weltman,
William Rawlinson,
Bishoy Rizkalla,
Jean K Depamphilis,
Stuart K Roberts
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ABSTRACT: Anemia may increase the likelihood of achieving a sustained virological response (SVR) during pegylated interferon and ribavirin treatment of hepatitis C virus (HCV) infection. To determine whether hemoglobin decline is associated with SVR, we retrospectively evaluated the CHARIOT study of 871 treatment-naïve HCV genotype 1 patients. Anemia (serum hemoglobin <100 g/L) occurred in 137 (16%) patients, of whom only 14 (10%) received erythropoietin. Hemoglobin decline >30g/L from baseline occurred in 76% of patients overall, including 526 patients who did not become anemic. Virological responses were higher in anemic patients compared with those who did not develop anemia (end of treatment, 80% versus 65%, P = 0.003; SVR, 61% versus 50%, P = 0.02); these differences remained significant when patients receiving erythropoietin were excluded from analysis. SVR was also higher in patients with hemoglobin decline >30 g/L compared with patients without a similar decline. In multiple logistic regression analyses with treatment group and baseline characteristics, the odds ratio for SVR was 1.97 (95% confidence interval, 1.08-3.62) for anemia and 2.17 (95% confidence interval, 1.31-3.62) for hemoglobin decline >30 g/L. Patients who first developed a hemoglobin decline >30 g/L during weeks 5-12 and 13-48 were more likely to achieve SVR than those who first developed such changes in weeks 0-4 or who never experienced them. CONCLUSION: Patients with HCV genotype 1 infection who develop anemia or experience a hemoglobin decline >30 g/L during weeks 5-48 of therapy achieve higher virological responses to pegylated interferon and ribavirin therapy that are unrelated to erythropoietin use.
Hepatology 04/2011; 53(4):1109-17. · 11.66 Impact Factor
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Cristina Baleriola,
William D Rawlinson,
Gregory J Dore,
Sandra Chaverot,
Sacha Stelzer-Braid,
Motoko Yoshihara,
Darrell Crawford,
William Sievert,
Geoffrey McCaughan, Martin Weltman,
Wendy Cheng,
Bishoy Rizkalla,
Dwight Dubois,
James Thommes,
Stuart Roberts
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ABSTRACT: We examined the detection of low-level viraemia at week 24 as a predictor of sustained virological response (SVR) and viral relapse/breakthrough, and the agreement between the Roche Cobas TaqMan™ HCV RNA assay (TaqMan) and Roche Cobas(®) Amplicor HCV qualitative assay (Amplicor; both Roche Molecular Diagnostics, Pleasanton, CA, USA) for detection of low-level viraemia.
A total of 871 treatment-naive HCV genotype 1 patients participating in an induction-dose pegylated interferon therapy study had virological responses assessed using TaqMan. A total of 151 patients with HCV RNA levels ≤500 IU/ml had samples tested in parallel using the Amplicor and TaqMan assays.
SVR was significantly lower and relapse/breakthrough significantly higher in patients with low-level residual viraemia at week 24 compared with those who had undetectable viraemia: SVR was 72%, 29% and 14% (P<0.0001) and relapse/breakthrough 28%, 71% and 86% (P<0.0001) in patients with viraemia that was undetectable, detectable <15 IU/ml and detectable 15-<50 IU/ml, respectively, at week 24. The negative predictive value (NPV) for a week-24 virological response for SVR was 86%, 90% and 90% using TaqMan cutoffs of undetectable, <15 IU/ml and <50 IU/ml, respectively. The percentage agreement between Amplicor and TaqMan was similarly high for TaqMan cutoffs of 50 IU/ml and 15 IU/ml, but lower for undetectable viraemia (83%, 83% and 70%, respectively).
These data emphasize the importance of achieving undetectable HCV RNA during pegylated interferon therapy to maximize SVR; however, the current 24-week stopping rule of undetectable HCV RNA appears too stringent when using sensitive PCR assays given the observed lower NPV for SVR using the TaqMan undetectable cutoff. Our data also suggest that a TaqMan <15 IU/ml result is comparable to an Amplicor-negative result (that is, below the assay cutoff value) when monitoring viral response.
Antiviral therapy 01/2011; 16(2):173-80. · 3.16 Impact Factor
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ABSTRACT: To evaluate the efficacy, safety and adherence to hepatitis C (HCV) therapy in patients attending tertiary hepatitis clinics who are receiving opioid replacement therapy.
A non-randomized, open-label study. Participants were treated with pegylated interferon alpha-2a and weight-based ribavirin for 24 weeks (genotype non-1, n = 31) or 48 weeks (genotype 1, n = 22).
Four tertiary hospital hepatitis clinics in Australia.
Fifty-three patients with chronic HCV who were receiving opioid replacement therapy.
Patients were monitored for virological response, adverse events and adherence. They were also screened for psychiatric illness prior to and throughout the study utilizing two validated instruments: the Mini International Neuropsychiatric Interview (MINI) and Beck Depression Interview (BDI)-II.
The overall sustained virological response (SVR) rate was 57% (71% genotype non-1 versus 36% genotype 1), and was similar in active injectors (63%) and non-injectors (53%). The psychological profile of patients based on validated instruments did not change on therapy. The pattern and frequency of adverse effects were comparable to non-opioid replacement patients. Eighty-five per cent of patients were adherent to therapy by 80/80/80 criteria and only two patients who had an end-of-treatment response relapsed, one of whom was not an active injector.
Patients on opioid replacement therapy, even if they continue to inject actively, can achieve comparable sustained virological response rates to other populations with pegylated interferon alpha-2a and ribavirin therapy, suffer no excess rates of adverse effects or psychological complications and have good adherence to therapy.
Addiction 12/2010; 106(5):977-84. · 4.31 Impact Factor
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Wendy S C Cheng,
Stuart K Roberts,
Geoffrey McCaughan,
William Sievert, Martin Weltman,
Darrell Crawford,
William Rawlinson,
Philippa S Marks,
James Thommes,
Bishoy Rizkalla,
Motoko Yoshihara,
Gregory J Dore
[show abstract]
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ABSTRACT: The impact of fibrosis stage on chronic hepatitis C virus (HCV) treatment response was explored in CHARIOT, a study of high dose peginterferon alfa-2a (PEG-IFNalpha-2a) induction therapy in treatment naïve genotype 1 infection.
Eight hundred and ninety-six patients were randomised 1:1 to 360 microg (n=448) or 180 microg (n=448) PEG-IFNalpha-2a weekly with RBV 1000-1200 mg/day for 12 weeks followed by 36 weeks of 180 microg PEG-IFNalpha-2a weekly plus RBV 1000-1200 mg/day. Virological responses were assessed at week 4, 8, 12, 24, 48 (end of therapy), and 24 weeks following therapy (sustained virological response, SVR). As previously reported, there was no significant difference in SVR in the induction (53%) and standard (50%) arms, therefore the pooled study population was used for analysis of SVR and relapse.
A marked step-wise decline in SVR was evident by fibrosis stage: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001). Early virological responses were lower among F3/4 patients, including rapid virological response (RVR) (21% vs. 34% for F3/4 and F0-2, respectively) (p=0.0072), and the RVR positive predictive value was also lower (63% vs. 80%). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001). Cumulative PEG-IFNalpha-2a and ribavirin doses were similar among patients with F3/4 and F0-2 within treatment arms through week 4, 8, 12, and week 24.
Low virological response in hepatitis C genotype 1 patients with advanced fibrosis is not explained by inadequate cumulative PEG-IFN and ribavirin doses.
Journal of Hepatology 10/2010; 53(4):616-23. · 9.26 Impact Factor
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Kerry-Lee Milner,
David van der Poorten,
Michael Trenell,
Arthur B Jenkins,
Aimin Xu,
George Smythe,
Gregory J Dore,
Amany Zekry, Martin Weltman,
Vincent Fragomeli,
Jacob George,
Donald J Chisholm
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ABSTRACT: Chronic hepatitis C (CHC) is associated with insulin resistance (IR), liver steatosis (genotype 3), and increased diabetes risk. The site and mechanisms of IR are unclear.
We compared cross-sectionally 29 nonobese, normoglycemic males with CHC (genotypes 1 and 3) to 15 adiposity and age-matched controls using a 2-step hyperinsulinemic-euglycemic clamp with [6,6-(2)H(2)] glucose to assess insulin sensitivity in liver and peripheral tissues and (1)H-magnetic resonance spectroscopy to evaluate liver and intramyocellular lipid. Insulin secretion was assessed after intravenous glucose.
Insulin secretion was not impaired in CHC. Peripheral insulin sensitivity was 35% higher in controls vs CHC (P < .001) during high-dose (264.3 +/- 25 [standard error] mU/L) insulin (P < .001); this was negatively associated with viral load (R(2) = .12; P = .05) and subcutaneous fat (R(2) = .41; P < .001). IR was similar in both genotypes despite 3-fold increased hepatic fat in genotype 3 (P < .001). Hepatic glucose production (P = .25) and nonesterified free fatty acid (P = .84) suppression with insulin were not different between CHC and controls inferring no adipocyte IR, and suggesting IR is mainly in muscle. In CHC, intramyocellular lipid was nonsignificantly increased but levels of glucagon (73.8 +/- 3.6 vs 52.8 +/- 3.1 ng/mL; P < .001), soluble tumor necrosis factor receptor 2 (3.1 +/- 0.1 vs 2.3 +/- 0.1 ng/mL; P < .001), and Lipocalin-2 (36.4 +/- 2.9 vs 19.6 +/- 1.6 ng/mL; P < .001) were elevated.
CHC represents a unique infective/inflammatory model of IR, which is predominantly in muscle, correlates with subcutaneous, not visceral, adiposity, and is independent of liver fat.
Gastroenterology 12/2009; 138(3):932-41.e1-3. · 11.68 Impact Factor
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Vijayaprakash Suppiah,
Max Moldovan,
Golo Ahlenstiel,
Thomas Berg, Martin Weltman,
Maria Lorena Abate,
Margaret Bassendine,
Ulrich Spengler,
Gregory J Dore,
Elizabeth Powell,
Stephen Riordan,
David Sheridan,
Antonina Smedile,
Vincenzo Fragomeli,
Tobias Müller,
Melanie Bahlo,
Graeme J Stewart,
David R Booth,
Jacob George
[show abstract]
[hide abstract]
ABSTRACT: Hepatitis C virus (HCV) infects 3% of the world's population. Treatment of chronic HCV consists of a combination of PEGylated interferon-alpha (PEG-IFN-alpha) and ribavirin (RBV). To identify genetic variants associated with HCV treatment response, we conducted a genome-wide association study of sustained virological response (SVR) to PEG-IFN-alpha/RBV combination therapy in 293 Australian individuals with genotype 1 chronic hepatitis C, with validation in an independent replication cohort consisting of 555 individuals. We report an association to SVR within the gene region encoding interleukin 28B (IL28B, also called IFNlambda3; rs8099917 combined P = 9.25 x 10(-9), OR = 1.98, 95% CI = 1.57-2.52). IL28B contributes to viral resistance and is known to be upregulated by interferons and by RNA virus infection. These data suggest that host genetics may be useful for the prediction of drug response, and they also support the investigation of the role of IL28B in the treatment of HCV and in other diseases treated with IFN-alpha.
Nature Genetics 09/2009; 41(10):1100-4. · 35.53 Impact Factor
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ABSTRACT: To explore the effect of acamprosate and naltrexone on craving and alcohol consumption in the treatment of alcohol dependence.
A randomized, double-blind, single-dummy, placebo-controlled trial.
Three treatment centres in Sydney, Australia.
A total of 169 alcohol-dependent subjects were given naltrexone (50 mg/day), acamprosate (1998 mg/day) or placebo for 12 weeks, in conjunction with manualized medication compliance therapy.
During the course of the trial, participants kept a daily diary which included the number of standard drinks they consumed and their peak craving for alcohol that day rated on a 0-10 scale.
Subjective ratings of daily craving and daily drinking for the first 6 weeks of treatment.
Mixed/hierarchical linear models were employed on an intention-to-treat basis. Analyses revealed that craving was a significant predictor of daily drinking and baseline levels of depression were the best predictor of daily craving. There was no significant improvement in model fit when treatment group was added both in models of daily craving and daily drinking. Daily alcohol consumption was best predicted by a model incorporating baseline dependence and depression scores, and daily craving, entered as a time-varying covariate. However, there was a significant craving x time x treatment interaction (t = -3.365, df = 4413.712, P < 0.001), suggesting that at higher levels of craving drinking was reduced at a significantly greater rate with naltrexone compared to acamprosate.
Naltrexone had a greater effect on drinking when craving was high. These results support the role of naltrexone in reducing craving when that craving is highly salient. The role of acamprosate in reducing craving was not supported by these findings.
Addiction 06/2008; 103(6):953-9. · 4.31 Impact Factor
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Karina Razali,
Hla Hla Thein,
Jane Bell,
Mark Cooper-Stanbury,
Kate Dolan,
Greg Dore,
Jacob George,
John Kaldor,
Maria Karvelas,
Jiong Li, [......],
Sharyn McGregor,
Margaret Hellard,
Fiona Poeder,
Julianne Quaine,
Kim Stewart,
Helen Tyrrell, Martin Weltman,
Owen Westcott,
Alex Wodak,
Matthew Law
[show abstract]
[hide abstract]
ABSTRACT: Hepatitis C virus (HCV) infection in Australia is predominantly transmitted through injecting drug use. A reduction in the heroin supply in Australia in late 2000 and early 2001 may have impacted the number of injecting drug users (IDUs) and consequently the number of new hepatitis C infections in Australia. This paper updates estimates of HCV incidence and prevalence between 1960 and 2005.
Simple mathematical models were used to estimate HCV incidence among IDUs, migrants to Australia from high HCV-prevalence countries, and other HCV exposure groups. Recent trends in numbers of IDUs were based on indicators of injecting drug use. A natural history of HCV model was applied to estimate the prevalence of HCV in the population.
The modelled best estimate of past HCV incidence showed a consistent increasing rate of HCV infections to a peak of 14,000 new seroconversions in 1999, followed by a decline in 2001-2002 coincident with the decline in heroin availability. HCV incidence was estimated to be 9700 (lower and upper limits of 6600 and 13,200) in 2005. Of these, 88.7% were estimated to be through injecting drug use, 7.2% among migrants and 4.1% through other transmission routes. An estimated 264,000 (lower and upper limits of 206,000 and 318,000) people were HCV antibody positive in 2005.
Mathematical models suggest that HCV incidence in Australia decreased from a peak of 14,000 new infections in 1999 to 9700 new infections in 2005, largely attributable to a reduction in injecting drug use. The numbers of people living with HCV in Australia is, however, estimated to continue to increase.
Drug and Alcohol Dependence 01/2008; 91(2-3):228-35. · 3.38 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: To compare the efficacy of acamprosate and naltrexone in the treatment of alcohol dependence.
A double-blind, placebo-controlled trial.
Three treatment centres in Australia.
A total of 169 alcohol dependent subjects were given naltrexone (50 mg/day), acamprosate (1998 mg/day) or placebo for 12 weeks.
All subjects were offered manualized compliance therapy, a brief intervention that targets problems that may affect treatment compliance such as ambivalence and misperceptions about medication.
Time to the first drink, time to first relapse, drinks per drinking day and cumulative abstinence.
In intention-to-treat analyses, there were no differences between groups on outcome measures of drinking, craving or biochemical markers. Similarly, analyses of the 94 subjects that completed the study in full and demonstrated 80% compliance, revealed no significant treatment effects. Differential treatment effects were identified after stratification according to scores on the Alcohol Dependence Scale (ADS) and Depression Anxiety and Stress Scale (DASS). A significant beneficial treatment effect on time to first relapse was revealed for subjects with 'no depression' allocated to naltrexone (n = 56; P < 0.01). In addition, a significant beneficial treatment effect was revealed in subjects with 'low dependence' allocated to naltrexone (n = 34; P < 0.05).
The results of this study support the efficacy of naltrexone in the relapse prevention of alcoholism amongst those with low levels of clinical depression and alcohol dependence severity. No effect of acamprosate was found in our sample.
Addiction 10/2006; 101(10):1451-62. · 4.31 Impact Factor
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Shirley A Coverdale,
Mahbub H Khan,
Karen Byth,
Rita Lin, Martin Weltman,
Jacob George,
Dev Samarasinghe,
Christopher Liddle,
James G Kench,
Evelyn Crewe,
Geoffrey C Farrell
[show abstract]
[hide abstract]
ABSTRACT: Fibrotic severity, biochemical indices of poor liver function, and sporadic transmission are independent predictors of liver complications among people with chronic hepatitis C. After accounting for these factors, we tested whether interferon treatment or the treatment response reduces the rate of liver cancer, liver-related death or transplantation, and other liver complications during extended follow-up.
Liver clinic cohort of 455 patients with histologically proven chronic hepatitis C was followed prospectively for median 9 yr (IQ 6, 11 yr); 384 received interferon, 343 completed a treatment course. Liver complications were assessed in relation to treatment and treatment response in univariate and multivariate models, and survival to onset of liver-related complications was determined.
The annual incidence of total liver complications was 1.5% in treated and 2.9% in untreated patients and appeared quasilinear throughout 9-yr follow-up. Interferon treatment did not influence the rate of liver complications. However, the rate of complications increased exponentially with transition of the treatment response from sustained viral response (SVR), through response-relapse to nonresponse (or no treatment). By univariate analysis, response to interferon treatment was a significant predictor of complications. After adjustment for fibrosis score, serum albumin concentration and mode of transmission in a multivariate model, treatment response just failed to reach significance (p= 0.058) as a predictor of outcome.
Response to antiviral therapy, and particularly SVR, appears to reduce liver complications in chronic hepatitis C. However, in the absence of an antiviral treatment response, a course of interferon does not reduce risks of liver cancer or liver failure.
The American Journal of Gastroenterology 05/2004; 99(4):636-44. · 7.28 Impact Factor
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Shivakumar Chitturi,
Shehan Abeygunasekera,
Geoffrey C. Farrell,
Jane Holmes-Walker,
Jason M. Hui,
Caroline Fung,
Rooshdiya Karim,
Rita Lin,
Dev Samarasinghe,
Christopher Liddle, Martin Weltman,
Ph.D. Jacob George M.B.B.S
[show abstract]
[hide abstract]
ABSTRACT: Nonalcoholic steatohepatitis (NASH) is often linked with disorders that are clearly associated with insulin resistance (IR): obesity, type 2 diabetes mellitus, and hypertriglyceridemia. We tested the hypotheses that (1) IR is an essential requirement for the development of NASH and (2) a high association between IR and liver disease is relatively specific for NASH. We measured body mass index (BMI), waist/hip ratio, and fasting serum lipid, insulin, C-peptide, and glucose levels in 66 patients with NASH (21 with advanced fibrosis and 45 with mild fibrosis). IR was determined by the homeostasis model assessment (HOMA). We also determined the strength of the association of NASH with insulin resistance syndrome (IRS) as defined by World Health Organization criteria. To assess whether the finding of IR was relatively specific to NASH rather than simply to obesity or liver disease, we compared the results of a subset of 36 patients with less-severe NASH with 36 age- and sex-matched patients with chronic hepatitis C virus (HCV) of comparable fibrotic severity. IR was confirmed in 65 patients (98%) with NASH, and 55 (87%) fulfilled minimum criteria for IRS. IR was found in lean as well as in overweight and obese patients. The IR values and the prevalence of IRS (75% vs. 8.3%) were significantly higher in those with NASH than in comparable cases of HCV. Hyperinsulinemia was attributable to increased insulin secretion rather than decreased hepatic extraction. In conclusion, most patients with NASH have IRS, and there is a near-universal association between NASH and IR irrespective of obesity. IR is present in mild as well as advanced cases of NASH but is unusual in chronic HCV of similar fibrotic severity.
Hepatology 12/2003; 35(2):373 - 379. · 11.66 Impact Factor
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ABSTRACT: There is conflicting evidence regarding inheritance of hemochromatosis gene (HFE) mutations and influence of hepatic iron deposition as cofactors for development of fibrosis in patients with nonalcoholic steatohepatitis (NASH). We studied hepatic iron content (Perls' stain grade), frequency of HFE mutations, and serum iron indices in 93 patients with NASH from a multiethnic background; 59 (63%) were of Anglo-Celtic origin. Data on C282Y mutations were available for all 93 patients and on H63D for 69 patients. Respective controls were 206 (for C282Y, 141 [69%] of whom were Anglo-Celtic) and 180 (for H63D) blood donors. Hyperferritinemia was present in 38 patients (40%) with NASH, but transferrin saturation was increased (>55%) in only 5 (5%). Liver biopsy specimens showed advanced fibrosis in 31 (33%) (cirrhosis in 20%). Altogether, 9 biopsy specimens (10%) showed increased iron: 7 (8%) with grade 2 and 2 (2%) with grade 3 iron staining. Only 1 biopsy specimen with increased iron showed advanced fibrosis. The frequency of C282Y heterozygosity was increased in Anglo-Celtic patients with NASH compared with ethnic blood donor controls (22% vs. 9.2%; P =.035); there were no C282Y homozygotes in the NASH cohort. Although there was a trend toward higher serum ferritin levels among C282Y heterozygotes with NASH, there were no differences in histologic grades of steatosis, inflammation, or fibrosis between individuals with and without C282Y. The frequencies of compound C282Y/H63D heterozygotes (n = 1) or H63D heterozygotes (n = 10) were not increased in NASH. Multivariate analysis identified female sex, diabetes mellitus, and more severe liver inflammation but not HFE mutations, serum ferritin, iron saturation, or hepatic iron staining as independent predictors of hepatic fibrosis. In conclusion, hepatic iron is not a factor linked to hepatic fibrogenesis in patients with NASH. HFE mutations do not confer an additional risk of hepatic fibrosis in this disorder.
Hepatology 07/2002; 36(1):142-9. · 11.66 Impact Factor
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Shivakumar Chitturi,
Shehan Abeygunasekera,
Geoffrey C Farrell,
Jane Holmes-Walker,
Jason M Hui,
Caroline Fung,
Rooshdiya Karim,
Rita Lin,
Dev Samarasinghe,
Christopher Liddle, Martin Weltman,
Jacob George
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ABSTRACT: Nonalcoholic steatohepatitis (NASH) is often linked with disorders that are clearly associated with insulin resistance (IR): obesity, type 2 diabetes mellitus, and hypertriglyceridemia. We tested the hypotheses that (1) IR is an essential requirement for the development of NASH and (2) a high association between IR and liver disease is relatively specific for NASH. We measured body mass index (BMI), waist/hip ratio, and fasting serum lipid, insulin, C-peptide, and glucose levels in 66 patients with NASH (21 with advanced fibrosis and 45 with mild fibrosis). IR was determined by the homeostasis model assessment (HOMA). We also determined the strength of the association of NASH with insulin resistance syndrome (IRS) as defined by World Health Organization criteria. To assess whether the finding of IR was relatively specific to NASH rather than simply to obesity or liver disease, we compared the results of a subset of 36 patients with less-severe NASH with 36 age- and sex-matched patients with chronic hepatitis C virus (HCV) of comparable fibrotic severity. IR was confirmed in 65 patients (98%) with NASH, and 55 (87%) fulfilled minimum criteria for IRS. IR was found in lean as well as in overweight and obese patients. The IR values and the prevalence of IRS (75% vs. 8.3%) were significantly higher in those with NASH than in comparable cases of HCV. Hyperinsulinemia was attributable to increased insulin secretion rather than decreased hepatic extraction. In conclusion, most patients with NASH have IRS, and there is a near-universal association between NASH and IR irrespective of obesity. IR is present in mild as well as advanced cases of NASH but is unusual in chronic HCV of similar fibrotic severity.
Hepatology 03/2002; 35(2):373-9. · 11.66 Impact Factor
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Journal of Gastroenterology 01/1993; 28:32-36. · 4.16 Impact Factor
