Hepatitis: Desmond P

Nguyen T, Locarnini S, Desmond P. · No affiliation provided · J Gastroenterol Hepatol. · Pubmed #18853991 No free full text.

This publication has no abstract.

Richmond J, Dunning P, Desmond P. · Gastroenterology Department, St. Vincent's Hospital, Melbourne, Victoria. · Aust Nurs J. · Pubmed #19149457 No free full text.

Abstract: Hepatitis C has reached epidemic proportions in Australia. Because of its association with injecting drug use, which is a main transmission mode, hepatitis C is a highly stigmatising health condition. In fact, the stigma attached to hepatitis C means hepatitis C is not just a medical diagnosis, but also a social diagnosis. The limited available research indicates hepatitis C-related discrimination is most likely to occur in health care settings. A strategic and evidenced-based approach is required to combat the social impact of hepatitis C.

Mohamed R, Desmond P, Suh DJ, Amarapurkar D, Gane E, Guangbi Y, Hou JL, Jafri W, Lai CL, Lee CH, Lee SD, Lim SG, Guan R, Phiet PH, Piratvisuth T, Sollano J, Wu JC. · Department of Medicine, University Malaya, Kuala Lumpur, Malaysia. · J Gastroenterol Hepatol. · Pubmed #15304110 No free full text.

Abstract: The Asia-Pacific Expert Committee on Hepatitis B Management recently reviewed the impact of hepatitis B in the region and assessed the differences and similarities observed in the practical management of the disease in individual Asia-Pacific countries. Hepatitis B is a major health concern in the Asia-Pacific region, and of all chronically infected carriers worldwide, approximately 75% are found in Asia. The disease poses a considerable burden on healthcare systems, and is likely to remain a cause of substantial morbidity and mortality for several decades. Disease prevention activities, including screening and vaccination programs, have been implemented successfully in some Asia-Pacific countries and similar measures are being established in other parts of the region. The management of hepatitis B in the Asia-Pacific varies throughout the region, with each country confronting different issues related to treatment options, disease monitoring and duration of therapy. The influence of cost, availability of diagnostic equipment, and patient awareness and compliance are of additional concern. Although guidelines such as those developed by the Asian Pacific Association for the Study of the Liver have been created to address problems encountered in the management of hepatitis B, many physicians in the region still find it difficult to make satisfactory management decisions because of the treatment choices available. This article examines the different approaches to hepatitis B management in a number of Asia-Pacific countries, and highlights the difficulties that can arise when adhering to treatment guidelines and disease prevention solutions that have proved to be successful in the region.

Ryan M, Desmond P. · St Vincent's Hospital, Melbourne, Victoria. · Aust Fam Physician. · Pubmed #11432014 No free full text.

Abstract: BACKGROUND: Adverse reaction to prescription medications, over the counter medications and complementary medicines, are an important cause of liver toxicity. OBJECTIVE: To highlight the importance of drug induced liver toxicity in patients presenting with abnormal liver function tests. DISCUSSION: In patients who present with symptoms of liver dysfunction such as anorexia, itch or Jaundice and in whom liver function tests are abnormal, the possibility of an adverse reaction to medications should be considered. A detailed history of all medications taken in the past few months, including complementary medicines, should be obtained. After exclusion of other causes of liver disease such a viral hepatitis or gallstones, the cessation of the offending medication and the normalisation of liver tests is usually sufficient to establish a diagnosis. Occasionally, referral to a specialist and liver biopsy may be required.

Pockros PJ, Carithers R, Desmond P, Dhumeaux D, Fried MW, Marcellin P, Shiffman ML, Minuk G, Reddy KR, Reindollar RW, Lin A, Brunda MJ, Anonymous00313. · Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, California 92037, USA. · Am J Gastroenterol. · Pubmed #15233669 No free full text.

Abstract: OBJECTIVES: This study compared the efficacy and safety of peginterferon alpha-2a 135 microg/wk, peginterferon alpha-2a 180 microg/wk and interferon alpha-2a in patients with chronic hepatitis C. METHODS: A total of 639 patients received peginterferon alpha-2a 135 microg or 180 microg once weekly, or interferon alpha-2a 3 MIU thrice weekly for 48 wk. RESULTS: Sustained virological responses were significantly higher with peginterferon alpha-2a than with interferon alpha-2a 3 MIU (28% in the 135 microg and 180 microg peginterferon alpha-2a groups vs 11% with interferon alpha-2a, p = 0.001). The proportion of patients with clinically significant histological improvement was lower in the peginterferon alpha-2a 135 microg (48%) than the 180 microg group (58%, p = 0.035 vs peginterferon alpha-2a 135 microg), but similar to that in the interferon alpha-2a group (45%, p = 0.820 vs peginterferon alpha-2a 135 microg and p = 0.017 vs peginterferon alpha-2a 180 microg, respectively). The overall safety profiles were similar for the three treatments. In patients with chronic hepatitis C, peginterferon alpha-2a 135 microg/wk and 180 microg/wk produced similar sustained virological response rates, both of which were significantly higher than that achieved with interferon alpha-2a thrice weekly. A significantly higher proportion of patients treated with the 180 microg dose of peginterferon alpha-2a had clinically significant histological improvement.

de Man RA, Marcellin P, Habal F, Desmond P, Wright T, Rose T, Jurewicz R, Young C. · University Hospital Rotterdam, Rotterdam, The Netherlands. · Hepatology. · Pubmed #10915751 No free full text.

Abstract: We conducted a randomized, placebo-controlled clinical study evaluating famciclovir (500 mg 3 times daily and 1.5 g once daily) for 1 year (6 months post-treatment follow-up) in patients with chronic hepatitis B e antigen (HBeAg)-positive hepatitis B virus (HBV) infection. The study was conducted in 80 centers in North America, Europe, and Australia/New Zealand. A total of 417 patients with histologically documented chronic hepatitis B (histologic activity index [HAI] 9.5-11.0) received famciclovir (500 mg 3 times daily or 1.5 g once daily) or placebo. Famciclovir 500 mg 3 times daily significantly reduced HBV DNA and median HAI scores versus placebo. By week 8, median HBV DNA decreased from 1,645 to 283 MEq/mL (famciclovir 500 mg 3 times daily) and from 1,147 to 304 MEq/mL (famciclovir 1.5 g once daily), while increasing for placebo (1,617 to 1,685 MEq/mL). Median change in HBV DNA at the end of therapy was -76% (famciclovir 500 mg 3 times daily; P <.01) and -60% (famciclovir 1.5 g once daily; P =.25) versus -37% for placebo. Median change in HAI was -1.5 points (famciclovir 500 mg 3 times daily; P =.02) and -1.0 point (famciclovir 1.5 g once daily; P =.35) and zero for placebo. Fifty percent of patients receiving famciclovir 500 mg 3 times daily (P =.07) and 43% receiving 1.5 g once daily (P =.41) experienced >/=2 points improvement in HAI versus 37% for placebo. Nine percent of patients treated with famciclovir 500 mg 3 times daily underwent anti-HBeAg seroconversion with undetectable HBV DNA at end of follow-up versus 3% in the placebo group (P =.05). Famciclovir was well tolerated; the incidence of post-treatment alanine transaminase (ALT) elevations was comparable with placebo. In conclusion, famciclovir 500 mg 3 times daily gave modest suppression of viral replication, but translated into significant histologic improvement in median HAI score at 1 year.

Chang JJ, Sirivichayakul S, Avihingsanon A, Thompson AJ, Revill P, Iser D, Slavin J, Buranapraditkun S, Marks P, Matthews G, Cooper DA, Kent SJ, Cameron PU, Sasadeusz J, Desmond P, Locarnini S, Dore GJ, Ruxrungtham K, Lewin SR. · Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia. · J Virol. · Pubmed #19458009 No free full text.

Abstract: Hepatitis B virus (HBV)-specific T cells play a key role both in the control of HBV replication and in the pathogenesis of liver disease. Human immunodeficiency virus type 1 (HIV-1) coinfection and the presence or absence of HBV e (precore) antigen (HBeAg) significantly alter the natural history of chronic HBV infection. We examined the HBV-specific T-cell responses in treatment-naïve HBeAg-positive and HBeAg-negative HIV-1-HBV-coinfected (n = 24) and HBV-monoinfected (n = 39) Asian patients. Peripheral blood was stimulated with an overlapping peptide library for the whole HBV genome, and tumor necrosis factor alpha and gamma interferon cytokine expression in CD8+ T cells was measured by intracellular cytokine staining and flow cytometry. There was no difference in the overall magnitude of the HBV-specific T-cell responses, but the quality of the response was significantly impaired in HIV-1-HBV-coinfected patients compared with monoinfected patients. In coinfected patients, HBV-specific T cells rarely produced more than one cytokine and responded to fewer HBV proteins than in monoinfected patients. Overall, the frequency and quality of the HBV-specific T-cell responses increased with a higher CD4+ T-cell count (P = 0.018 and 0.032, respectively). There was no relationship between circulating HBV-specific T cells and liver damage as measured by activity and fibrosis scores, and the HBV-specific T-cell responses were not significantly different in patients with either HBeAg-positive or HBeAg-negative disease. The quality of the HBV-specific T-cell response is impaired in the setting of HIV-1-HBV coinfection and is related to the CD4+ T-cell count.

Preiss S, Thompson A, Chen X, Rodgers S, Markovska V, Desmond P, Visvanathan K, Li K, Locarnini S, Revill P. · Research and Molecular Development, Victorian Infectious Disease Reference Laboratories (VIDRL), Melbourne, Australia. · J Viral Hepat. · Pubmed #18673429 No free full text.

Abstract: Hepatitis B virus (HBV) infection is a major cause of liver-related morbidity and mortality. Toll-like receptors (TLRs) have recently been recognized to play an important role in the pathogenesis of chronic hepatitis B (CH-B). Furthermore, manipulation of TLR signalling pathways shows potential as an antiviral therapeutic strategy. Whether hepatocytes themselves possess intact TLR signalling pathways remains controversial. It is critical that cell culture models be developed to allow investigation of the interaction between HBV and the TLR signalling pathways. We have screened three hepatocyte cell lines for the integrity of pro-inflammatory responses and antiviral cytokines following stimulation with interleukin-1 (IL-1) and different TLR ligands. We observed that Huh-7, HepG2 and PH5CH8 cells selectively responded to IL-1 and TLR2 ligands, leading to the activation of NF-kappaB. In addition, the PH5CH8 cell lines were able to induce type 1 interferon (IFN) via both TLR3 and RIG-I following stimulation with poly I:C, HepG2 cells mounted an IFN response via RIG-I only, whereas Huh-7 cells were unresponsive. We conclude that the hepatocyte cell lines investigated display a repertoire of TLR signalling, albeit limited, suggesting that hepatocytes may themselves play an active role in innate immune responses to viruses such as HBV. Furthermore, particular hepatoma cell lines are suitable for investigating the interaction between HBV and hepatocyte-expressed pattern recognition receptors.

Preiss S, Littlejohn M, Angus P, Thompson A, Desmond P, Lewin SR, Sasadeusz J, Matthews G, Dore GJ, Shaw T, Sozzi V, Yuen L, Lau G, Ayres A, Thio C, Avihingsanon A, Ruxrungtham K, Locarnini S, Revill PA. · Victorian Infectious Diseases Reference Laboratories, Research and Molecular Development, North Melbourne, Victoria, Australia. · Hepatology. · Pubmed #18571815 links to  free full text

Abstract: Defective hepatitis B virus DNA (dDNA) is reverse-transcribed from spliced hepatitis B virus (HBV) pregenomic messenger RNA (pgRNA) and has been identified in patients with chronic HBV (CH-B). The major 2.2-kb spliced pgRNA encodes a novel HBV gene product, the hepatitis B splice protein (HBSP) via a deletion and frame shift within the polymerase. Although spliced RNA and HBSP expression have been associated with increased HBV DNA levels and liver fibrosis, the role of dDNA in HBV-associated disease is largely undefined. Our aims were to (1) compare the relative proportions of dDNA (% dDNA) in a range of HBV-infected serum samples, including patients with human immunodeficiency virus (HIV)/HBV coinfection and HBV-monoinfected persons with differing severities of liver disease, and (2) determine the effect of mutations associated with drug resistance on defective DNA production. Defective DNA was detected in 90% of persons with CH-B. There was no significant difference in the relative abundance of dDNA between the monoinfected and HIV/HBV-coinfected groups. We also found no association between the % dDNA and alanine aminotransferase, hepatitis B e antigen status, HBV DNA levels, fibrosis levels, compensated or decompensated liver cirrhosis, genotype, or drug treatment. However, the % dDNA was significantly lower in individuals infected with lamivudine-resistant (LMV-R) HBV compared with wild-type HBV (P < 0.0001), indicating that antiviral drug resistance alters the balance between defective and genomic length DNA in circulation. Experiments in vitro using HBV encoding LMV-R mutations confirmed these results. CONCLUSION: Our results identified no association between dDNA and parameters associated with disease status and suggested that the relative abundance of dDNA is largely dependent on the integrity of the HBV polymerase and is unrelated to the severity of liver disease.

Chang JJ, Thompson AJ, Visvanathan K, Kent SJ, Cameron PU, Wightman F, Desmond P, Locarnini SA, Lewin SR. · Department of Microbiology and Immunology, University of Melbourne, Australia. · Hepatology. · Pubmed #17924445 No free full text.

Abstract: Hepatitis B virus (HBV)-specific T cells play a key role in clearance of the virus and in the pathogenesis of liver disease. Peripheral blood (n = 25) and liver biopsies (n = 19) were collected from individuals with chronic untreated HBV infection. Whole blood, cultured peripheral blood mononuclear cells (PBMCs), and cultured liver-infiltrating lymphocytes (LILs) were each stimulated with an overlapping peptide library to the whole HBV genome. The expression of T helper 1 (Th1) cytokines [interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin 2 (IL-2)] and interleukin 10 (IL-10) was analyzed by intracellular cytokine staining and flow cytometry. In ex vivo whole blood, more lymphocytes produced Th1 cytokines than IL-10. When comparing cultured LILs with cultured PBMCs, we found a significantly higher magnitude of CD8(+) T cells from the liver producing IL-10 (P = 0.044), primarily in hepatitis B e antigen positive (HBeAg(+)) individuals. A positive correlation resulted between the magnitude of HBV-specific TNF-alpha(+) CD4(+) T cells in the liver and the degree of liver inflammation and fibrosis (P = 0.002 and P = 0.006, respectively). Conclusion: The differences in cytokine production from HBV-specific T cells in blood and liver may explain the capacity for HBV to persist in the absence of significant hepatic destruction and highlights the balance between cytokine-mediated viral control and liver damage.

Visvanathan K, Skinner NA, Thompson AJ, Riordan SM, Sozzi V, Edwards R, Rodgers S, Kurtovic J, Chang J, Lewin S, Desmond P, Locarnini S. · Murdoch Children's Research Institute, Melbourne, Australia. · Hepatology. · Pubmed #17187404 No free full text.

Abstract: Toll-like receptors (TLRs) play a key role in the innate immune response. The aim of this study was to examine the expression of TLR2 and TLR4 in chronic hepatitis B (CHB). The TLR2 and TLR4 expression on hepatocytes and Kupffer cells from fresh liver biopsies was measured from 21 patients with untreated hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB. Parallel studies were also undertaken on monocytes from their peripheral blood. Expression of TLR2 on hepatocytes, Kupffer cells, and peripheral monocytes was significantly reduced in patients with HBeAg-positive CHB in comparison with HBeAg-negative CHB and controls, whereas it was significantly increased in HBeAg-negative CHB compared with controls. The level of TLR4 expression did not differ significantly between the groups. These results were confirmed in vitro using hepatic cell lines transduced with recombinant HBV baculovirus expressing wild-type HBV (HBeAg-positive), precore stop codon (G1896A) mutant HBV (HBeAg-negative). The functional relevance of these findings was established by the demonstration of significantly reduced cytokine production (TNF-alpha) and phospho-p38 kinase expression in the presence of the HBeAg. In the absence of HBeAg, HBV replication was associated with up-regulation of the TLR2 pathway leading to increased TNF-alpha production. CONCLUSION: This study demonstrates a potentially important interaction between HBeAg, HBV, and the innate immune response.

Chen RY, Edwards R, Shaw T, Colledge D, Delaney WE, Isom H, Bowden S, Desmond P, Locarnini SA. · Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia. · Hepatology. · Pubmed #12500185 No free full text.

Abstract: Hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) is frequently caused by a mutation (G1896A) in the hepatitis B virus (HBV) precore (PC) reading frame that creates a stop codon, causing premature termination of the PC protein. During lamivudine treatment, drug resistance develops at a similar rate in HBeAg positive and HBeAg negative CHB. Lamivudine-resistant HBV mutants have been shown to replicate inefficiently in vitro in the absence of PC mutations, but it is unknown whether the presence of PC mutations affects replication efficiency or antiviral sensitivity. This study utilized the recombinant HBV baculovirus system to address these issues. HBV baculoviruses encoding the G1896A PC stop codon mutation were generated in wild-type (WT) and lamivudine-resistant (rtM204I and rtL180M + rtM204V) backgrounds, resulting in a panel of 6 related recombinant baculoviruses. In vitro assays were performed to compare the sensitivities of the PC mutant viruses with lamivudine and adefovir and to compare relative replication yields. The PC mutation did not significantly affect sensitivities to either adefovir or lamivudine. WT HBV and PC mutant HBV showed similar replication yields, whereas the replication yields of the lamivudine-resistant mutants were greatly reduced in HBeAg positive HBVs, confirming previous observations. However, the presence of the PC mutation was found to compensate for the replication deficiency in each of the lamivudine-resistant mutants, increasing the replication yields of each virus. In conclusion, the PC stop codon mutation appears to increase the replication efficacy of lamivudine-resistant virus but does not affect in vitro drug sensitivity.

Crowley S, Tognarini D, Desmond P, Lees M, Saal G. · GlaxoSmithKline Research and Development, London, United Kingdom. · J Gastroenterol Hepatol. · Pubmed #11966945 No free full text.

Abstract: BACKGROUND: Chronic hepatitis B (CHB) is associated with a significant burden of illness and treatment involves substantial health-care costs. This study estimates clinical outcomes and cost-effectiveness of lamivudine compared with other treatment scenarios for CHB, from an Australian health-care provider perspective. METHODS: A two-step modeling approach depicted clinical progression of hepatitis B in hypothetical patient cohorts using three different treatment scenarios: scenario A, lamivudine and alpha-interferon (IFN-alpha) available; scenario B, IFN-alpha available only; and scenario C, no treatment available. Assumptions were based on clinical trials, published studies, a hepatologist's questionnaire and an expert panel follow up. One-year clinical outcomes and costs were estimated using a decision tree, while lifetime costs and outcomes were estimated using available clinical trial data for lamivudine (up to 4 years therapy duration) and a Markov model. RESULTS: The analysis considered only patients with pretreatment elevated alanine aminotransferase levels > or = 2 x upper limit of normal. In the short term, the introduction of lamivudine is expected to result in almost 3.5 times more CHB patients receiving therapy (lamivudine or IFN-alpha) compared to IFN-alpha only (67% compared to 20%, respectively). Hence, scenario A subsequently doubled the seroconversion rate. The incremental cost-effectiveness ratio was $3341 Australian per additional seroconversion. Also, non-seroconverted lamivudine patients are less likely to progress to cirrhosis than those receiving IFN-alpha/no treatment. One-year progression to cirrhosis was estimated at 5.1% with scenario A, compared to 12.2% and 12.7%, scenarios B and C, respectively. From the long-term analysis, lamivudine is expected to increase life expectancy by years and reduce the lifetime risk of compensated cirrhosis, decompensated cirrhosis and hepatocellular carcinoma by 6%, 12% and 12%, respectively. Additionally, the introduction of lamivudine decreases lifetime costs by $548, thus making it a cost-saving and life-extending strategy. In both short- and long-term models, worst case scenarios in sensitivity analyses still associate lamivudine with a favorable cost-effectiveness ratio. CONCLUSION: Introduction of lamivudine is expected to improve health outcomes in CHB patients, resulting in overall savings in health-care costs. In this model, compared with IFN-alpha only and no treatment, lamivudine allowed more CHB patients to be treated, increased the seroconversion rate, delayed disease progression and prolonged life expectancy.

Pianko S, Patella S, Ostapowicz G, Desmond P, Sievert W. · Monash University, Department of Medicine and Gastroenterology Unit, Monash Medical Centre, Melbourne, Australia. · J Viral Hepat. · Pubmed #11703571 No free full text.

Abstract: Epidemiological studies have established that heavy alcohol consumption in persons with chronic hepatitis C virus (HCV) infection is associated with advanced liver disease, including cirrhosis. The aims of this study were to evaluate the relationship between alcohol consumption and hepatocyte apoptosis in HCV-infected patients and to determine the role of Fas in HCV-mediated apoptosis. Liver tissue from 44 HCV-infected patients with variable alcohol consumption, and 10 normal control subjects who did not consume alcohol was examined for hepatocyte apoptosis, proliferation and Fas expression. Alcohol consumption was assessed using the 'Lifetime Drinking History' alcohol questionnaire. HCV RNA, alanine aminotransferase (ALT) and ferritin were also assessed in addition to demographic data. Hepatocyte apoptosis was significantly greater in HCV-infected patients compared to controls. Expression of Fas (CD95) was found in HCV patients but not in controls. The degree of Fas expression correlated with hepatocyte apoptosis as detected by terminal UTP nick end labelling (TUNEL). Active ethanol consumption led to a significant increase in hepatocyte apoptosis. Fas expression correlated with fibrosis in HCV-infected patients who were not actively drinking ethanol. In summary, HCV leads to increased apoptotic cell death in hepatocytes. Programmed cell death can be further up-regulated by active ethanol consumption. The correlation between Fas expression and TUNEL supports the hypothesis that the Fas-Fas ligand interaction is the major mechanism for HCV-induced hepatocyte apoptosis.

Desmond P. · Department of Gastroenterology, St Vincent's Hospital, Melbourne, Victoria, Australia. · J Gastroenterol Hepatol. · Pubmed #10921394 No free full text.

Abstract: The prevalence of hepatitis C varies greatly between countries of the Asia-Pacific region. The incidence of new cases is also markedly different between countries, particularly related to the prevalence of injecting drug use. Overall, the currently available treatments for hepatitis C are unlikely to have a major impact in the control of the infection from a population perspective while success rates are relatively low (20-45% sustained antiviral response) and treatment costs are high. There are some specific situations, such as reducing the incidence of mother-to-baby transmission or sexual transmission, where antiviral treatment can be used as a strategy to prevent further infection. The major aims of prevention of hepatitis C infection should lie with public health measures to prevent new infections, particularly amongst injecting drug users, and ultimately the development of an effective vaccine..