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April 26, 2005
HCV and Cirrhosis
Treatment of HCV in Cirrhotic Patients
By Marina Nunez, MD, PhD
Hepatitis C virus (HCV) infection is considered difficult to treat in patients with cirrhosis. In addition to diminished response to current anti-HCV therapies, these subjects with cirrhosis have a higher risk to develop decompensation of their liver disease and other complications.
Two studies presented at the 40th EASL meeting evaluated the efficacy and safety of treatment of patients with HCV-related liver cirrhosis with interferon (IFN)-based therapies [1,2].
In the Canadian study, these cirrhotic patients in early stage of disease were compared with non-cirrhotics [1]. There were no differences between both groups of patients in adverse events, nor in the proportion of patients undergoing dose modifications.
A trend to have lower responses among cirrhotic subjects compared to non-cirrhotics was observed for all genotypes, being more marked the differences in HCV-1-infected individuals. The authors suggest HCV-infected compensated cirrhotic patients can be successfully treated, and that higher responses may be achieved with optimal doses of RBV (1,000-1,200 mg/day).
In the study from the US, with more advanced liver disease, a higher number of subjects required discontinuation of the HCV treatment, and 3% experienced decompensation of liver disease [2].
Anemia requiring erythropoietin (EPO), neutropenia requiring G-CSF, and infections occurred in 50%, 16%, and 9% of subjects, respectively. Of notice, 15.6% of the patients were removed from the transplant list due to clinical improvement.
Therefore, treatment of HCV infection in subjects with advanced liver disease may be successful in a subset of well selected patients, especially in those carrying HCV genotypes other than 1. However, more complications arise among these subjects, and although treatment seems to be safe, their follow-up during therapy is very challenging.
04/25/05
References
1. S Lee and others. Peginterferon alfa-2a (40 kD) (PEGASYS®) plus ribavirin (COPEGUS®) in cirrhotic patients with chronic hepatitis C: results of a Canadian multicenter open-label expanded access programme. Abstract 576. 40th EASL. April 13-17, 2005. Paris, France.
2. J K Lim and others. Safety and efficacy of antiviral therapy in patients with decompensated cirrhosis associated with chronic hepatitis C infection. Abstract 579. 40th EASL. April 13-17, 2005. Paris, France.
To see this entire article go here: http://tinyurl.com/7p5vo
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April 25, 2005
How HCV Escapes Your Immune System
The following is from HIVandHepatitis.com. They publish some of the best technical articles on Hepatitis c available on the internet.
Replicative Homeostasis: A New Hypothesis to Explain How Viruses Such as HIV, HCV and HBV Persist and Escape Immune Controls
This article offers a new hypothesis concerning the persistence of certain viruses such as HIV, HCV and HBV and how they escape control by the immune system. In 40 days it has become the most downloaded article ever published by Virology Journal, an "Open Access" journal published by BioMed Central. This means that anyone can read, without charge, the articles appearing in it as soon as they are published.
The article explains why RNA viruses like Hepatitis C, HIV, West Nile / Yellow Fever / SARS / Ebola, etc persist, and demonstrates a mechanism of genotype/species maintenance, and of generating escape mutants in response to immune and other pressures. It explains why interferon may fail in some cases of hepatitis C and also explains the mechanism of antibody mediated disease enhancement. It also implies novel treatments for West Nile / HCV (and HIV, HBV, etc) might be possible, and describes what form they might take.
Hepatitis C (HCV), hepatitis B (HBV), the human immunodeficiency viruses (HIV), and other viruses that replicate via RNA intermediaries, cause an enormous burden of disease and premature death worldwide.
These viruses circulate within infected hosts as vast populations of closely related, but genetically diverse, molecules known as "quasispecies". The mechanism(s) by which this extreme genetic and antigenic diversity is stably maintained are unclear, but are fundamental to understanding viral persistence and pathobiology. The persistence of HCV, an RNA virus, is especially problematic and HCV stability, maintained despite rapid genomic mutation, is highly paradoxical.
This paper presents the hypothesis, and evidence, that viruses capable of persistent infection autoregulate replication and the likely mechanism mediating autoregulation--Replicative Homeostasis--is described.
Replicative homeostasis causes formation of stable, but highly reactive, equilibria that drive quasispecies expansion and generates escape mutation. Replicative homeostasis explains both viral kinetics and the enigma of RNA quasispecies stability and provides a rational, mechanistic basis for all observed viral behaviours and host responses.
More importantly, this paradigm has specific therapeutic implication and defines, precisely, new approaches to antiviral therapy. Replicative homeostasis may also modulate cellular gene expression.
Note: This article uses highly technical language that many readers will find difficult to follow at times. Although the language is challenging for non scientists, it is worth the effort to read through the entire article, which offers compelling insights into the possible mechanisms of how HIV, HCV and HBV, among other viruses, persist.
You can access the article here: http://tinyurl.com/8nl26
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April 22, 2005
Newly Identified Protein Inhibits HCV
This is another case where researchers are using what already works (to a limited degree) and trying to find a way to improve their success rate. Interferon lambda is a newly discovered (or isolated) interferon that seems to have some success against HCV in a petri dish.
The encouraging fact is that much research is being done in a variety of approaches to controlling and curing Hepatitis c.
Newly Identified Protein May Inhibit Hepatitis Virus
A newly identified family of proteins may inhibit replication of the Hepatitis B (HBV) and C (HCV) viruses say researchers from California. Their findings appear in the March 2005 issue of the Journal of Virology.
Hepatitis B (HBV) and C (HCV) are viruses that infect the liver, and in some cases can cause liver failure requiring a transplant for survival. The protein interferon, produced by animal cells when they are invaded by viruses, is released into the bloodstream or intercellular fluid to induce healthy cells to manufacture an enzyme that counters the infection. One class of interferons (alpha) is used to treat chronic infection with HBV and HCV. There is a vaccine available to prevent the spread of HBV but not HCV.
In the study, a new class of interferons, interferon lambda, was tested for its ability to inhibit HBV and HCV replication. Results showed 90% inhibition of HBV after twenty-four hours and 90-99% inhibition in HCV five days posttreatment.
“We have demonstrated here that replication of HBV and HCV is sensitive to the antiviral activities of interferon lambda,” say the researchers. “These results suggest the possibility that interferon lambda may be therapeutically useful in the treatment of chronic HBV or HCV infection.”
(M.D. Robek, B.S. Boyd, F.V. Chisari. 2005. Lambda interferon inhibits hepatitis B and C virus replication. Journal of Virology, 79. 6: 3851-3854.)
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April 20, 2005
Hepatitis C and Diabetes (Type 2)
This article was a real surprise with regard to diabetes and Hepatitis C.
In the conclusions I found this mention quite fascinating: "Approximately 40% of patients with HCV infection will display symptoms of some extrahepatic manifestation during the illness (1). Most extraliver manifestations of chronic HCV infection are immunological..."
This mention that most patients who have symptoms experience immunolgical manifestations was an eye opener. I have long heard that the aches, pains, brain fog, fatigue, etc. that many patients experience are due to the immune system going a bit haywire with the virus circulating in the system. This surely seems to acknowledge that theory.
However, the article does go on to say that the virus also directly affects other organs and tissues in the body besides the liver. This accounts for many of the more serious symptoms people experience that have nothing to do with the liver being infected.
The more I learn about this disease, the more I realized there is to learn.
Hepatitis C Virus Infection and Human Pancreatic [Beta]-Cell Dysfunction
Abbreviations: HCV, hepatitis C virus.
Many patients with chronic hepatitis C virus (HCV) develop type 2 diabetes (1). This prevalence is much higher than that observed in the general population and in patients with other chronic liver diseases such as hepatitis B virus, alcoholic liver disease, and primary biliary cirrhosis. Furthermore, it has been shown that post- transplantation type 2 diabetes appears to be higher among patients with HCV (2). However, the pathogenetic basis for the association between HCV infection and diabetes has not been understood. A direct involvement of the virus in the development of insulin resistance has been proposed, and β-cell dysfunction in HCV-positive patients has been observed in some cases (1). Because HCV can infect many tissues other than the liver (3), we hypothesized that the virus might directly damage insulin-secreting cells. This article suggests that HCV may be present in human pancreatic β-cells and demonstrates that islet cells from HCV-positive patients have morphological and functional defects.
RESEARCH DESIGN AND METHODS- The pancreases of 5 HCV-positive (age 68 9 years, 3 men and 2 women, BMI 25.8 1.6 kg/m^sup 2^) and 10 HCV-negative (age 67 9 years, 6 men and 4 women, BMI 26.8 2.0 kg/m^sup 2^) donors were harvested and studied with the approval of our local ethics committee. Histological studies were performed by immunohistochemistry (using the monoclonal mouse anti-HCV E2 protein, clone IGH222 [Innogenetics, Gent, Belgium]) and electron microscopy, as described elsewhere (4,5). Isolated islets were prepared by enzymatic digestion and density gradient purification, and islet functional and survival studies were accomplished as previously described (5,6).
RESULTS- Histology results are summarized in Fig. 1. No sign of islet cell staining was found in HCV-negative pancreases by immunohistochemistry (Fig. 1A); however, focal or diffuse HCV- positive islet cells were observed in HCV-positive pancreatic glands (Fig. 1B). Positive staining was found in 39 12% of 140 examined islets, and the percentage of stained cells was 54 13% per islet. The appearance of a control β-cell at electron microscopy is given in Fig. 1C, showing the characteristic insulin granules and normally preserved mitochondria. In β-cells from HCV-positive pancreases, the presence of virus-like particles was observed, mainly close to the membranes of Golgi apparatus, which, in turn, appeared hyperplastic and dilated (Fig. 1D). The mitochondria appeared round-shaped with dispersed matrix and fragmented cristae (Fig. 1D). Additional β-cell changes were observed at the level of rough endoplasmic reticulum, which showed long and dilated tubular membranes, with numerous electrondense ribosomes bound to the latter (not shown). These morphological changes were accompanied by reduced in vitro glucose-stimulated insulin release (Table 1); however, apoptosis was similar in control as in infected islet cells (Table 1).
CONCLUSIONS- Approximately 40% of patients with HCV infection will display symptoms of some extrahepatic manifestation during the illness (1). Most extraliver manifestations of chronic HCV infection are immunological; however, the virus may have a direct cytopathic action, because it can infect many tissues other than the liver (3). In the present article we have suggested the presence of HCV infection in pancreatic β-cells of human subjects, and we have provided evidence that this was associated with morphological cell changes and altered islet cell function. The immunohistochemical method we have used to show the presence of infection in islet cells has been previously validated (4), and the electron microscopy morphological alterations of the β-cell are similar to those reported in other cell types during HCV infection (7). The insulin secretion functional defects of islets from HCV-positive donors might contribute to the development of diabetes in predisposed subjects. On the other hand, the absence of increased apoptosis is in line with the observation that reducing viral load is associated with improvement of diabetes in HCV-positive patients (8). In conclusion, the present article proposes that HCV can infect human pancreatic β-cells and that this is accompanied by β-cell dysfunction. A direct cytopathic effect of HCV at the islet cell level is therefore suggested to explain, at least in part, the association between HCV infection and diabetes, especially in predisposed subjects (1).
Table 1-Insulin secretion and apoptosis data of HCV-negative and HCV-positive pancreatic islets
Figure 1-A and B show the results obtained by an immunoperoxidase technique for anti-HCV-E2 in pancreatic islets (original magnification 400). in A, the endocrine cells from a control pancreas are completely devoid of the viral antigen. In B, the endocrine cells from an HCV-positive pancreas show a brown, finely granular staining, indicating the presence of the HCV proteins. C and D show the results obtained by electron microscopy (original magnification 46,000). In C, a control β-cell is shown, with the characteristic insulin granules (G) and normal mitochondria (M). In D, a β-cell from an HCV-positive pancreas is represented, showing virus-like particles (VL) close to dilated, hyperplastic Golgi apparatus (GA) and round-shaped mitochondria with dispersed matrix and fragmented cristae.
A table elsewhere in this issue shows conventional and Systme International (SI) units and conversion factors for many substances.
2005 by the American Diabetes Association.
References
1. Lecube A, Hernandez C, Genesca J, Esteban JI, Jardi R, Simo R: High prevalence of glucose abnormalities in patients with hepatitis C virus infection: a multivariate analysis considering the liver injury. Diabetes Care 27:1171-1175, 2004
2. Bruchfeld A, Wilczek H, Elinder CG: Hepatitis C infection, time in renal-replacement therapy, and outcome after kidney transplantation. Transplantation 78:745-750, 2004
3. Mayo MJ: Extrahepatic manifestations of hepatitis C infection. Am J Med Sci 325: 135-148, 2003
4. Verslype C, Nevens F, Sinelli N, Clarysse C, Pirenne J, Depla E, Maertens G, van Pelt J, Desmet V, Fevery J, Roskams T: Hepatic immunohistochemical staining with a monoclonal antibody against HCV- E2 to evaluate antiviral therapy and reinfection of liver grafts in hepatitis C viral infection. J Hepatol 38:208-214, 2003
5. Marchetti P, Del Guerra S, Marselli L, Lupi R, Masini M, Pollera M, Bugliani M, Boggi U, Vistoli F, Mosca F, Del Prato S: Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab 89:5535-5541, 2004
6. Marchetti P, Lupi R, Federici M, Marselli L, Masini M, Boggi U, Del Guerra S, Patan G, Piro S, Anello M, Bergamini E, Purrello F, Lauro R, Mosca F, Sesti G, Del Prato S: Insulin secretory function is impaired in isolated human islets carrying the Gly(972)[arrow right]Arg IRS-1 polymorphism. Diabetes 51:1419-1424, 2002
7. Falcon V, Acost-Rivero N, Chinea G, Gavilondo J, de la Rosa MC, Menendez I, Duenas Carrera S, Vina A, Garcia W, Gra B, Noa M, Reytor E, Barcelo MT, Alvarez F, Morale-Grillo J: Ultrastructural evidences of HCV infection in hepatocytes of chronically HCV- infected patients. Biochem Biophys Res Commun 305:1085-1090, 2003
8. Bahtiyar G, Shin JJ, Aytaman A, Sowers JR, McFarlane SI: Association of diabetes and hepatitis C infection: epidemiologic evidence and pathophysiologic insights. Curr Diab Rep 4:194-198, 2004
MATILDE MASINI, MD1
DANIELA CAMPANI, MD2
UGO BOGGI, MD3
MICHELE MENICAGLI, MD2
NICOLA FUNEL, MD1
MARIA POLLERA, MD1
ROBERTO LUPI, PHD1
SILVIA DEL GUERRA, PHD1
MARCO BUGLIANI, PHD1
SCILLA TORRI, PHD1
STEFANO DEL PRATO, MD1
FRANCO MOSCA, MD3
FRANCO FILIPPONI, MD4
PIERO MARCHETTI, MD, PHD1
From the 1 Metabolic Unit, Department of Endocrinology and Metabolism, University of Pisa and Pisa University Hospital, Pisa, Italy; the 2 Section of Transplantation Pathology, Division of Surgical, Molecular and Ultrastructural Pathology, Department of Oncology, University of Pisa and Pisa University Hospital, Pisa, Italy; the 3 Referral Center for the Treatment of Pancreas Diseases, Department of Oncology, University of Pisa and Pisa University Hospital, Pisa, Italy; and the 4 Liver Transplant Unit, University of Pisa and Pisa University Hospital, Pisa, Italy.
Address correspondence and reprint requests to Piero Marchetti, MD, Department of Endocrinology and Metabolism, Metabolic Unit, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa, Italy. E-mail: marchant@immr.med.unipi.it.
Received for publication 30 November 2004 and accepted in revised form 29 December 2004.
Copyright American Diabetes Association Apr 2005
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April 18, 2005
Early Treatment of HCV Questioned
You are not necessarily going to see information like this printed in the US press. It seems the party line is to not alienate the pharmaceutical industry.
Even when there are suspicions regarding certain drugs or studies there is generally nothing publicly noted until there is undeniable proof (see Bextra, Celebrex and Vioxx).
This article is also the first place I've seen the prognosis differential between infected women and men mentioned.
For doctors to recommend current therapy for anyone who shows up in their office with Hepatitis C seems short sighted, at best, and irresponsible, at least.
Bear this in mind when considering therapy for yourself or a loved one.
Report Questions Early Treatment of Hepatitis C
Monday April 18, 2005 (1525 PST)
ISLAMABAD: People with hepatitis C whose livers remain healthy may be better off not undergoing drug treatment, which can produce severe side effects such as nausea and depression and does not always work, researchers said.
The recommended 48-week course of treatment for the blood-borne virus -- injections of interferon and oral ingestion of ribavarin -- is effective in, at most, 60 percent of patients. It also has potentially severe side effects such as nausea, fatigue, depression and, in some cases, suicidal impulses.
The treatment, which costs in excess of $20,000, has been shown to lengthen the lives of hepatitis C sufferers with existing liver damage, a condition which can lead to deadly cirrhosis or cancer.
But a majority of hepatitis C patients do not develop liver damage before dying of other causes, so the drug treatment may not be cost-effective or helpful for them, the report from the Harvard School of Public Health's Center for Risk Analysis said.
In the United States, 2.7 million people have chronic cases of hepatitis C and there are about 25,000 new cases each year, most infected through needle sharing or from receiving blood from an infected donor. But four out of five have no signs or symptoms and many of them are unaware they have it.
The disease's progression varies considerably and milder cases, especially among women, may never progress to cirrhosis. The report's analysis of U.S. health data showed that the probability of infected men developing cirrhosis over a 30-year period was between 13 percent and 46 percent, and among women the probability was between 1 percent and 29 percent.
"There has been a huge effort over the last few years to identify people infected with (hepatitis C), but this wider group of patients will likely include those who are least likely to develop advanced liver disease," Sue Goldie, author of the report published in this week's issue of the Journal of the American Medical Association said in a statement.
"For patients at low risk of progressing, the overall health gain from treatment may be minimal given the potential for toxic side effects," she said.
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April 17, 2005
Viramidine Causes Less Anemia
Yet another variation on a theme. This one causese much less anemia than Ribavirin but is not more effective.
Viramidine Demonstrates Anti-HCV Genotype 1 Activity That Compares Favorably to Ribavirin, But without Complications of Severe Anemia
Dose-limiting anemia can be a prominent adverse event of therapy with pegylated interferon and ribavirin. This dose-ranging study examined whether viramidine, a liver-targeting prodrug of ribavirin, may be a safer alternative when used in combination with pegylated interferon alfa-2a/ PEG-IFN (Pegasys).
Of 180 HCV therapy-naive patients enrolled in the study, 171 patients received full-dose viramidine (400 mg: n = 47; 600 mg: n = 43; 800 mg: n = 44) versus ribavirin 1000-1200 mg/d (n = 37) in combination with PEG-IFN 180 µg/wk SC.
Patients were predominantly male (64%), Caucasian (76%), and genotype 1 (72%), with a median HCV RNA of 6.5 log10 copies/mL. Analyses assessed the incidence of anemia (hemoglobin <10 g/dL) and HCV RNA levels (Bayer TMA assay; sensitivity to 5 IU/mL) among patients without dose reduction due to anemia to evaluate the intrinsic activity of viramidine versus ribavirin without the confounder of dose modification.
Results
Among patients with no dose modification due to anemia at end of treatment (EOT), no significant differences were noted between viramidine (400, 600, and 800 mg BID) versus ribavirin in the proportion of patients with undetectable HCV RNA levels (55%, 63%, 55%, and 62%, respectively).
Rates of anemia at EOT for the viramidine 400, 600, and 800 mg groups were 0%, 2%, and 11%, respectively, versus 27% for the ribavirin arm.
Based on evaluable patients at EOT experiencing a decline in hemoglobin of at least 25%, the rate in the ribavirin group (48%) was higher versus the rate in the viramidine groups (400 mg: 14%; 600 mg: 18%; 800 mg: 15%).
Other types of adverse events were similar between treatment arms.
Conclusions
In conclusion, the authors note that at EOT in this Phase 2 study, “Viramidine demonstrated antiviral activity comparable to that of ribavirin when used in combination with pegylated interferon alfa-2a among patients with no dose modification due to anemia.”
“Patients in the viramidine arms also showed a significantly lower incidence of anemia.”
“Data lock for the Phase 2 study will occur by December 1, 2004, and sustained virologic response rates and safety outcomes will be presented at the 2005 EASL meeting.”
California Pacific Medical Center, San Francisco CA, USA, University of Florida, Gainesville FL, USA, University of New Mexico, Albuquerque NM, USA, University of North Carolina, Chapel Hill NC, USA, Hospital of the University of Pennsylvania, Philadelphia PA, USA, Valeant Pharmaceuticals International, Costa Mesa CA, USA.
04/15/05
Reference
R G Gish and others. VIROLOGIC RESPONSE AND SAFETY OUTCOMES IN THERAPY-NAIVE PATIENTS TREATED FOR CHRONIC HEPATITIS C WITH VIRAMIDINE IN COMBINATION WITH PEGYLATED INTERFERON ALFA-2A. Abstract 91. 40th EASL. April 13-17, 2005. Paris, France.
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April 15, 2005
Another Interferon
Here is another form of interferon being tested. It seems to have less severe side effects than current therapy.
Be sure to note the part that states genotype 1 patients have a 50% chance of clearing the virus with current therapies. Generally, the pharma companies would like you to believe the success rate is higher than that. Some still wonder if it is really even that high (if you account for drop-out rates due to severe side effects).
It is good to know, however, that nearly every drug company is scrambling for a treatement of Hepatitis c because of the huge number of people infected worldwide.
Stay tuned...
Human Genome Sciences Reports Positive Results of Phase 2 Clinical Trial of Albuferon(TM) in Treatment-Naive Patients With Chronic Hepatitis C
Thursday April 14, 10:45 am ET
- Mean Reduction in HCV Viral Load of 3.2 log at Day 28 Observed in the Combined 900 mcg and 1200 mcg Dose Cohorts -
ROCKVILLE, Md., April 14 /PRNewswire-FirstCall/ -- Human Genome Sciences, Inc. (Nasdaq: HGSI - News) today announced the results of a Phase 2 clinical trial of Albuferon(TM) (albumin-interferon alpha) in patients with chronic hepatitis C who are naive to interferon-alpha treatments. The results demonstrate that Albuferon is well tolerated, has a prolonged half-life and shows robust antiviral activity, with durable dose-dependent reductions in hepatitis C viral load.
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(Logo: http://www.newscom.com/cgi-bin/prnh/20010612/HGSLOGO )
The data were presented today in Paris at the 40th Annual Meeting of the European Association for the Study of the Liver (EASL) in an oral presentation entitled, "A Phase 2 Study to Assess Antiviral Response, Safety, and Pharmacokinetics of Albuferon in IFNalpha-Naive Subjects with Genotype 1 Chronic Hepatitis C."(1) The Phase 2 trial, which was conducted in Canada, was a randomized, open-label, multi-center, parallel-design, dose-ranging study to evaluate the safety, tolerability, pharmacology and optimal dosing of Albuferon.(2-3) A total of 56 patients were enrolled in the trial and randomized to 5 dose groups (200 mcg, 450 mcg, 670 mcg, 900 mcg and 1200 mcg).(4) Patients were given 2 doses of Albuferon monotherapy administered subcutaneously 14 days apart and were followed for safety and antiviral evaluations for a total of 6 weeks. The pharmacodynamic activity of Albuferon was evaluated based on hepatitis C (HCV) RNA viral load reductions over a 42- day period of exposure. One of the study objectives was to identify a range of active doses that Human Genome Sciences plans to evaluate in a larger 48- week study of Albuferon in combination with ribavirin in patients with HCV genotype 1 who are naive to interferon treatments.
The primary efficacy endpoint of the Phase 2 study was the rate of virologic response at Day 28, defined as at least a 2-log reduction in HCV viral load compared with baseline, or undetectable HCV viral load. The data presented show that Albuferon exhibited robust antiviral activity in genotype 1 HCV. A mean reduction in HCV viral load of 3.2 log at Day 28 was observed in the combined 900 mcg and 1200 mcg dose cohorts, with 69% of patients (18/26) in these cohorts showing a >2-log reduction in HCV viral load at Day 28. Undetectable viral load was observed at Day 42 (28 days after the second injection) in 23% of patients (6/26) in the combined 900 mcg and 1200 mcg dose cohorts. Robust dose-dependent viral kinetics were observed, with the majority of patients in the 900 mcg and 1200 mcg cohorts exhibiting a second- phase decline in viral load of >0.3 log per week, which has previously been shown to be predictive of sustained virologic response (SVR) in treatment with the pegylated interferons.(5) Reductions in viral load of equal to or greater than 2 log are reported in approximately 42% of genotype 1 HCV patients treated with pegylated interferon alpha products in combination with ribavirin.(6)
Consistent with clinical results to date(7-8), the results presented at EASL demonstrate that Albuferon remained in the blood substantially longer than is reported for recombinant interferon alpha and pegylated interferon alpha. Albuferon was detectable for up to 4 weeks following the second subcutaneous injection. The C-max (peak drug level) increases in a linear manner over the dose range evaluated (200-1200 mcg). Albuferon exhibited a median half-life of 148 hours, supporting dosing at intervals of 2-4 weeks. This compares to a reported mean (range) elimination half-life of 80 hours (50-140 hours) for Pegasys and 40 hours (22-60 hours) for PEG-Intron.(9-10)
The Phase 2 clinical trial results demonstrate that Albuferon was well tolerated with adverse events that were transient and mostly mild to moderate in severity. One serious adverse event was reported (acute colitis) and has subsequently resolved. There were no discontinuations due to reductions in hematologic cell counts. No subjects developed newly emergent antibodies to alpha interferon. One subject developed low-titer antibodies to human serum albumin. There was no apparent correlation between the emergence of antibodies and adverse events, antiviral response or pharmacokinetics.
Vincent Bain, M.D., Director of the Liver Unit and Professor of Gastroenterology, University of Alberta, said, "While therapies currently available for the treatment of chronic hepatitis C are effective, approximately half of genotype 1 patients fail to achieve sustained virologic response following treatment with regimens that include pegylated interferons. In addition, these therapies are frequently associated with side effects that require dose adjustments and may even require discontinuation of treatment. Most patients currently receive pegylated interferon once weekly, with daily doses of ribavirin. A significant need exists for more convenient treatment options with fewer side effects. The clinical results presented at the EASL meeting today show that Albuferon is well tolerated and exhibits a robust antiviral activity, with a pharmacokinetic profile that supports dosing at intervals of two to four weeks. These data are strongly supportive of further evaluation of Albuferon in combination with ribavirin in a larger study over a longer period of time in treatment-naive patients."
David C. Stump, M.D., Executive Vice President, Drug Development, said, "The results of the current Phase 2 trial will inform our identification of an optimal range of doses to evaluate in a larger 48-week combination study of Albuferon with ribavirin that we plan to conduct in treatment-naïve patients. These data, along with the preliminary results emerging from our ongoing Phase 2 combination study in treatment-experienced patients(3, 11), afford confidence in the ability to administer Albuferon actively and safely in combination with ribavirin to treatment-naive patients. We look forward to continuing our development of Albuferon as a potential treatment for chronic hepatitis C."
Hepatitis C is an inflammation of the liver caused by the hepatitis C virus. It is the most common chronic blood-borne infection in the developed world, and afflicts approximately four million people in the United States. The hepatitis C virus is transmitted primarily through significant or repeated exposures to infected blood. Intravenous drug use and sexual contact with infected persons account for the majority of new hepatitis C infections. When detectable levels of the hepatitis C virus in the blood persist for at least six months, a person is diagnosed as having chronic hepatitis C. The current standard of care for treating chronic hepatitis C is combination therapy consisting of pegylated interferon and ribavirin, an antiviral drug.(6, 9-10, 12-17)
Albuferon is a novel, long-acting form of interferon alpha. Recombinant interferon alpha is approved for the treatment of hepatitis C, hepatitis B and a broad range of cancers. Human Genome Sciences modified interferon alpha to improve its pharmacological properties by using the company's proprietary albumin fusion technology.
For more information about Albuferon, see http://www.hgsi.com/products/albuferon.html. Health professionals interested in more information about trials involving Human Genome Sciences products are encouraged to inquire via the Contact Us section of the Human Genome Sciences web site, http://www.hgsi.com/products/request.html, or by calling (301) 610-5790, extension 3550.
Human Genome Sciences is a company with the mission to treat and cure disease by bringing new gene-based protein and antibody drugs to patients.
HGS, Human Genome Sciences and Albuferon are trademarks of Human Genome Sciences, Inc.
This announcement contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. The forward-looking statements are based on Human Genome Sciences' current intent, belief and expectations. These statements are not guarantees of future performance and are subject to certain risks and uncertainties that are difficult to predict. Actual results may differ materially from these forward-looking statements because of the Company's unproven business model, its dependence on new technologies, the uncertainty and timing of clinical trials, the Company's ability to develop and commercialize products, its dependence on collaborators for services and revenue, its substantial indebtedness and lease obligations, its changing requirements and costs associated with planned facilities, intense competition, the uncertainty of patent and intellectual property protection, the Company's dependence on key management and key suppliers, the uncertainty of regulation of products, the impact of future alliances or transactions and other risks described in the Company's filings with the Securities and Exchange Commission. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of today's date. Human Genome Sciences undertakes no obligation to update or revise the information contained in this announcement whether as a result of new information, future events or circumstances or otherwise.
Footnotes:
1. Bain V, et al. A Phase 2 study to assess antiviral response, safety,
and pharmacokinetics of Albuferon in IFN.-naïve subjects with genotype
1 chronic hepatitis C. 40th Annual Meeting of the European
Association for the Study of the Liver (EASL), Paris. April 14, 2005.
Oral presentation. (Abstract #18.)
2. (HGSI Press Release) Human Genome Sciences Initiates Phase 2 Clinical
Trial of Albuferon for the Treatment of Chronic Hepatitis C. May 26,
2004.
3. (HGSI Press Release) Human Genome Sciences Completes Enrollment in a
Phase 2 Clinical Trial of Albuferon in Treatment-Naïve Patients with
Chronic Hepatitis C. February 16, 2005.
4. It is important to note that the method of measurement for dose
determination in the Phase 2 study of Albuferon in treatment-naïve
patients is different from the method of measurement in the Phase 1/2
study of Albuferon. Accordingly, the 200 mcg dose in the current
study is equivalent to a 150 mcg dose in the Phase 1/2 study, the 450
mcg dose is equivalent to 340 mcg in the prior study, and the 1200 mcg
dose is equivalent to 900 mcg.
5. Neumann AU et al. The second phase HCV decline slope is the best
predictor of sustained viral response during treatment of chronic HCV
genotype 1 patients with peg-interferon-a-2b and ribavirin. 53rd
Annual Meeting of the American Association for the Study of Liver
Diseases, Boston. November 1-5, 2002. Abstract #778. Hepatology
2002: Vol 36 No 4, Pt 2 of 2.
6. Di Bisceglie AM, Rustgi VK, Thuluvath P, et al. Pharmacokinetics and
pharmacodynamics of pegylated interferon alfa-2a or alfa-2b with
ribavirin in treatment naïve patients with genotype 1 chronic
hepatitis C. Hepatology 2004;40,4;734a, abstract LB18.
7. Balan V, et al. Albuferon -- A novel therapeutic agent for hepatitis
C: results of a Phase 1/2 study in treatment-experienced subjects
with chronic hepatitis C. 55th Annual Meeting of the American
Association for the Study of Liver Diseases, Boston. November 2,
2004. Oral presentation (Abstract #265).
8. (HGSI Press Release) Human Genome Sciences Reports Positive Results of
Phase 1/2 Clinical Trial of Albuferon in Chronic Hepatitis C.
November 2, 2004.
9. PEGASYS® Physicians Desk Reference. (Last updated December 2003).
10. PEG-INTRON® Physicians Desk Reference. (Last updated September
2003).
11. (HGSI Press Release) Human Genome Sciences Initiates Phase 2 Clinical
Trial of Albuferon in Combination with Ribavirin in Treatment-
Experienced Hepatitis C Patients. November 30, 2004.
12. Strader DB, Wright T, Thomas DL, and Seeff, LB. AASLD practice
guideline: diagnosis, management, and treatment of hepatitis C.
Hepatology 2004 April; 39 (4): 1147-1171.
13. Hadziyannis SJ, Sette H, Morgan TR, et al. Peginterferon-.2a and
ribavirin combination therapy in chronic hepatitis C. Ann Intern Med
2004; 140:346-355.
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2a and ribavirin in patients with chronic hepatitis C who have failed
prior treatment. Gastroenterology 2004; 126:1015-1023.
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April 06, 2005
Retinal Toxicity and Combination Therapy
This article from HIVandHepatitis.com makes a strong statement regarding the possible negative effects of interferon combination therapy on the eyes of patients.
Although warned of in package and label warnings this report brings the very real possiblity of serious damage home in a powerful way.
Retinal Toxicity During Pegylated Alfa Interferon Therapy for Chronic Hepatitis C
By Ronald Baker, PhD
There have been documented and anecdotal reports of ocular side effects during therapy with pegylated interferon and ribavirin. The aim of the current study was to evaluate the effect of therapy with pegylated interferon and ribavirin on the eyes of patients with chronic hepatitis C.
In this small study, 10 patients receiving peginterferon alfa-2a (Pegasys) and ribavirin and 10 healthy volunteers underwent full ophthalmic investigations and multifocal electroretinogram testing at baseline, and at regular intervals during treatment and post-treatment. The multifocal electroretinogram maps retinal function. Responses were compared with sequential recordings from healthy volunteers.
Results
All patients had normal clinical ophthalmic investigations at baseline. During therapy a single patient experienced central visual disturbance lasting 24 h with no prolonged ill effect.
No other patient was aware of any change in vision.
Fundal abnormalities [relating to the retinal area] appeared in five patients during treatment.
The multifocal electroretinogram showed reductions in retinal function in five patients.
Nine of 10 patients exhibited abnormalities on at least one multifocal electroretinogram or fundoscopic investigation.
The authors conclude, "Subclinical retinal toxicity during anti-viral therapy with pegylated alpha-interferon and ribavirin was frequent in this study and it suggests that patients should be warned of this risk and monitored during therapy."
Department of Clinical Physics and Bioengineering, Gartnavel General Hospital, Glasgow, UK.
See also Is Screening for Peginterferon-related Retinopathy in Hepatitis C Justified? and
Treatment with Pegylated Interferon May Cause Eye Complications in Patients with Chronic Hepatitis C
Commentary
Serious ocular disorders do not appear to occur frequently among patients using standard interferon or the peginterferons plus ribavirin. However, such problems can occur. If vision problems develop, patients should immediately call their physician and set up an appointment to see an ophthalmologist for a complete eye examination.
The product information on the pegylated interferons contains a warning about potential ophthalmologic disorders. The following text is excerpted from the WARNINGS section of the Pegasys Product Information (9). There is a similar WARNING on potential ocular disorders associated with peginterferon alfa-2b in the Peg-Intron/Rebetol product information:
“Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, and papilledema are induced or aggregated by treatment with PEGASYS or other alpha interferons.
“All patients should receive an eye examination at baseline. Patients with preexisting opthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic opthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination.
“Pegasys treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.” [emphasis added]
Selected Excerpts from the Literature on Retinal Toxicity Related to Therapy with Standard Interferon and/or Pegylated Interferon:
“The incidence of serious ocular pathology associated with anti-HCV therapy may be very high and is probably associated with peg-IFN alpha-2b. Increased monitoring of patients treated with peg-IFN alpha-2b for retinal and visual changes is warranted.” C Farel et al (3).
“Although ocular toxicity is uncommon, it should be emphasized that it can occur any time after the start of interferon therapy, and physicians now treating chronic hepatitis C patients with pegylated interferon must be aware of this potentially serious adverse event.” RA Willson (8).
The multifocal electroretinogram can detect retinal dysfunction in chloroquine retinopathy even when the full-field electroretinogram is normal and retinal alterations are subtle. Kellner et al (5).
“This case report underlines the necessity of an EOG on patients with INF-alpha therapy. Until now, the pathogenesis of this retinal toxicity has been poorly understood. These results show that the retinal pigmented epithelium is probably implicated at an early stage in this retinal toxicity.” M Crochet et al (2)
“Subclinical retinal toxicity during anti-viral therapy with pegylated alpha-interferon and ribavirin was frequent in this study and it suggests that patients should be warned of this risk and monitored during therapy.” Chisolm et al (1)
‘Subclinical neurovisual impairment is a frequent, largely unrecognized complication of low-dose IFN therapy, and patients with chronic hepatitis B and older age appear to be most susceptible. This apparently innocuous complication is long lasting, possibly irreversible in some patients, with yet undetermined consequences on visual function.” Manesis et al (6)
“8/19 patients, while on treatment, developed an asymptomatic retinopathy. Among these 3/8 were relapsers and 5/9 were non-responders to interferon monotherapy. All retinal changes faded, often while the patients continued the therapy. There was no significant association in occurrence of retinopathy with haematological and/or biochemical changes.” Jain et al (4)
“Although ocular toxicity is uncommon, it should be emphasized that it can occur any time after the start of interferon therapy, and physicians now treating chronic hepatitis C patients with pegylated interferon must be aware of this potentially serious adverse event.” Willson (8)
04/06/05
Citations
(1) J A Chisholm and others. Retinal toxicity during pegylated alpha-interferon therapy for chronic hepatitis C: a multifocal electroretinogram investigation. Alimentary Pharmacology & Therapeutics. 21(6): 23-32. March 15, 2005.
(2) M Crochet and others. Retinopathy caused by interferon alpha associated with ribavirin therapy and the importance of the electro-oculogram: a case report. Journal of French Ophthalmolology 27(3):257-262. March 2004.
(3) C Farel and others. Serious ophthalmic pathology compromising vision in HCV/HIV co-infected patients treated with peginterferon alpha-2b and ribavirin. AIDS 18(13):1805-9. September 3, 2004.
(4). K Jain and others. Retinopathy in chronic hepatitis C patients during interferon treatment with ribavirin. British Journal of Ophthalmology 85(10):1171-3. October 2001.
(5). U Kellner, Kraus H, Foerster MH.. Multifocal ERG in chloroquine retinopathy: regional variance of retinal dysfunction. Graefe's Archive for Clinical and Experimental Ophthalmology 238(1): 94-97. January 2000.
(6). E K Manesis and others. Neurovisual impairment: a frequent complication of alpha-interferon treatment in chronic viral hepatitis. Hepatology 27(5):1421-7. May 1998.
(7). A Tsolakos and N Zalatimo. Hepatitis C: a review of diagnosis, management, and ocular complications from treatment. Optometry 74(8): 517-23. August 2003.
(8). R A Willson. Visual side effects of pegylated interferon during therapy for chronic hepatitis C infection. Journal of Clinical Gastroenterology 38(8): 717-722. September 2004.
(9). Hoffman-La Roche. WARNINGS: Ophthalmologic Disorders. Pegasys Product Information. Page 10. January 2004.
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April 05, 2005
Coffee Reduces Chances of Liver Cancer
I drink a lot more green tea than coffee. This report makes me want to drink at least one cup of coffe per day even if just for therapeutic reasons.
Very convincing results to this study make this report very credible.
Coffee Consumption Reduces the Risk of Liver Cancer
Coffee Beans
Over the past 20 years, a body of data has accumulated that suggests a clear benefit for liver function and liver disease from drinking coffee. Several studies have demonstrated that drinking coffee lowers gamma-glutamyltransferase (GGT) activity, especially among heavy alcohol drinkers. In a Japanese study of 2494 men, the mean GGT was about 30% lower among those who drank 4 or more cups of coffee daily compared to non drinkers.
Although GGT is a relevant indicator of the risk for cirrhosis, serum alanine aminotransferase (ALT) activity is a more specific marker of liver injury, and a few population-based surveys from Italy and Japan have found a similar inverse relation between coffee drinking and ALT levels.
Results of a study by Gelatti et al published in the current issue of the Journal of Hepatology (April 2005) provide more evidence of an inverse relation between drinking coffee and hepatocellular carcinoma (HCC) [liver cancer].
The aim of this study was to investigate the role of coffee in HCC, taking the main risk factors into account. Researchers conducted the study in northern Italy, where they enrolled 250 hepatocellular (HCC) patients and 500 controls who had been hospitalized for any reason other than neoplasms and liver and alcohol-related diseases.
A standardized questionnaire provided information to the investigators concerning the patients' lifetime history of coffee.
Results
Coffee consumption by the study group in the decade prior to the questionnaire/interview was associated with a decreasing risk of HCC with a clear dose-effect relation.
With respect to non coffee drinking participants, the odds ratios (ORs) were: 0.8, for 1-2 cups/day, 0.4 for 3-4 cups/day and 0.3 for 5 or more cups/day.
The ORs for HCC decreased for drinking >2, compared to 0-2 cups/day of coffee, for an alcohol intake >80g/day, for presence of hepatitis B virus infection or hepatitis C virus infection.
The authors conclude, "Coffee drinking was inversely associated with hepatocellular carcinoma regardless of its etiology."
Discussion
Compared with non coffee drinkers, the relative risks (RRs) were 0.8 for drinkers of 1-2 cups per day, 0.4 for those of 3-4 cups, and 0.3 for drinkers of five or more cups per day. The inverse relation between coffee and primary liver cancer is stronger than in previous studies, indicating that the relation is probably real, and not due to chance.
The combined, pooled RR from three published studies of coffee and hepatocellular carcinoma for drinkers of three or more cups of coffee per day as compared to non coffee drinkers is approximately 0.6.
More important, the study by Gelatti et al. provides original information on the independent effect of coffee from the major recognized risk factors for primary liver cancer. The inverse relation with coffee, in fact, was of similar magnitude in subjects negative or positive for HBV or HCV serum markers, as well as in non- or moderate drinkers and in heavy drinkers.
Coffee appears to have a real, but moderate effect in reducing the risk of hepatocellular carcinoma. Various components of coffee have been related to such a favorable effect, including caffeine, coffee oils kahweol or cafestol, and antioxidant substances from coffee beans, but no definite evidence is available for any of these components.
Despite these uncertainties, HCC should be added to other digestive tract cancers on which a favorable role of coffee drinking has been suggested, including oral and pharyngeal, oesophageal and colorectal cancers.
04/04/05
References
U Gelatti and others (for the Brescia HCC Study Group). Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study. Journal of Hepatology 42(4): 528-534. April 2005.
C La Vecchia. Coffee, liver enzymes, cirrhosis and liver cancer (Editorial). Journal of Hepatology 42(4): 444-446. April 2005.
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