Page One

Daily Interferon Alfacon-1 Treatment with Ribavirin Appears Promising For HCV Infection

PHILADELPHIA, Feb. 6 /PRNewswire/ -- An accelerated, daily regimen of interferon alfacon-1 (Infergen, Amgen) plus treatment with a widely used antiviral agent is a promising treatment option for patients infected with the hepatitis C virus (HCV), according to a recent randomized study.

Earlier research on interferon alfacon-1 had suggested that daily, or ``induction,'' regimens of 9 mcg or 15 mcg might be more effective against HCV infection and as safe as the conventional 9 mcg three times weekly. Other studies indicated that the addition of ribavirin, an antiviral drug, to interferon might keep HCV out of the bloodstream more effectively than interferon alone.

``So if we improve the initial response rates using induction interferon dosing, by adding ribavirin we would hope to hold that improvement to the end of treatment,'' said Paul J. Pockros, MD, who is head of the Division of Gastroenterology and Hepatology at the Scripps Clinic and Research Foundation, La Jolla, Calif.

In the study, 21 patients with HCV infection were randomly assigned to daily treatment with 9 mcg interferon alfacon-1 for 48 weeks. Nineteen others received the drug on the same schedule along with ribavirin at 1,000-1,200 mg/day, also for 48 weeks. Dr. Pockros reported the study's 24-week findings at the October 2000 scientific meeting of the American Association for the Study of Liver Diseases in Dallas.

The two treatments were about equal in their ability to eliminate the viral infection. Statistically similar proportions of patients (about 52% and 42%, respectively) had no detectable levels of the hepatitis C virus.

In addition, 58% of patients in the combined-therapy group, as compared with only 38% of those who received interferon alone, achieved a biochemical remission -- that is, they showed normal blood levels of alanine transaminase. Elevated levels of the enzyme are a sign of worsened liver disease.

Those similar viral responses were not a surprise, Dr. Pockros said, because both groups received the same amount of interferon alfacon-1. But the purpose of the other agent, ribavirin, is to suppress resurgence of the virus after its levels have been reduced. Thus, ``one would expect that by the end of therapy at 48 weeks, the patients getting the combination of Infergen and ribavirin would show a higher sustained response rate,'' he said.

Tests designed to reveal how the patients tolerated the treatments generally showed similar results for the two groups. However, reduced hemoglobin levels over the first 24 weeks were more often observed among patients on the Infergen-ribavirin combination. The reduced hemoglobin levels were a sign of hemolytic anemia, a recognized ribavirin side effect.

For further news on hepatitis C and its treatment, visit Med On Scene (www.medonscene.com) and Hep C Research (www.hepcresearch.com).

SOURCE: Patients Newswire

SOURCE: Titan Pharmaceuticals Inc.

First Albumin Fusion Protein Trial

ROCKVILLE, Md., March 23 /PRNewswire/ -- Human Genome Sciences, Inc. (Nasdaq: HGSI - news) today announced that it has begun a Phase I human clinical trial of Albuferon(TM) in patients infected with Hepatitis C.

David C. Stump, M.D., Senior Vice President, Drug Development, said, ``Hepatitis C is a significant public health problem in both developed and developing countries. A need exists for more effective and better tolerated treatments that will allow patients to avoid the long-term liver damage associated with this serious and insidious disease. We hope that Albuferon will become a useful therapy and meet an important need for these patients. We are excited to begin clinical trials with this novel product of a new class of drug.''

Albuferon is created by fusing the gene for a human protein, interferon alpha, to the gene of another human protein, albumin. Based on preclinical studies, Albuferon should provide patients with a longer acting therapeutic activity and may offer an improved side-effect profile when compared to the current first line therapy, recombinant human interferon alpha.

The Phase I clinical trial is a multi-center, open-label study to determine the safety and pharmacology of single and double escalating doses of Albuferon in approximately 40 patients infected with Hepatitis C. Hepatitis C, a virus-caused liver inflammation, is transmitted by body fluids and affects 170 million people worldwide, or 3% of the world's population. Of these, about 95% of infected individuals reside in developing countries. In the U.S., Hepatitis C affects 3.9 million individuals, or approximately 1.8% of the U.S. population. An additional 37,000 new patients are diagnosed annually. Of these, 85% develop chronic infection and the remainder recover spontaneously from their disease within two to twelve weeks. The death toll from Hepatitis C in the U.S. is approximately 8,000 to 10,000 individuals per year.

William A. Haseltine, Ph.D., Chairman and Chief Executive Officer, said, ``Initiation of a clinical trial of Albuferon is demonstration that the new technology acquired by the purchase of Principia last year is fruitful. The technology allows us to create and to manufacture new and hopefully substantially improved versions of approved biotherapeutic proteins. These compounds will be new products, not generic versions of existing drugs. We also plan to use this technology to improve the pharmaceutical characteristics of human proteins that we discover ourselves. The technology may also reduce the cost of manufacturing our own novel drugs as well.''

Individuals interested in Albuferon are encouraged to contact Human Genome Sciences at 301-610-5790, extension 3550 or via the Internet at http://www.hgsi.com .

Human Genome Sciences is a company with the mission to treat and cure disease by bringing new gene-based drugs to patients.

HGS, Human Genome Sciences and Albuferon are registered trademarks of Human Genome Sciences, Inc. For additional information on Human Genome Sciences, Inc., visit the company's web site at http://www.hgsi.com . Copies of HGS press releases are also available by fax 24 hours a day at no charge by calling 800-758-5804, ext. 121115.

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, dependence on new technologies, uncertainty as to clinical trial results, ability to develop and commercialize products, dependence on collaborators for services and revenue, substantial indebtedness, intense competition, uncertainty of patent and intellectual property protection, dependence on key management, uncertainty of regulation of products, dependence on key suppliers and other risks that may be 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.

Backgrounder:
Human Genome Sciences Begins Phase I Clinical Trial of Albuferon In Hepatitis C Patients

Human Genome Sciences, Inc. today announced that it has begun a Phase I human clinical trial of Albuferon(TM) in patients infected with Hepatitis C.

March 23, 2001

Hepatitis C is a chronic liver disease caused by the hepatitis C virus (HCV). HCV is the most common chronic bloodborne disease in the United States and is four times as common as HIV, the virus that causes AIDS. HCV is a serious, often asymptomatic disease that leads to significant long-term damage and, potentially, carcinoma of the liver, in infected individuals. The disease is considered a major public health problem in both developed and developing countries and is the leading reason for liver transplant in the US.

HCV is an RNA virus that was initially identified in 1989. Although significant advancements have been made in understanding the virus and developing drugs against it, the virus continues to prove a challenging one for scientists to study. Unlike some other viruses, HCV is difficult to grow in cell culture and also changes its genetic makeup as it replicates, leading to a number of mutations as the virus has evolved. These mutations have now been classified into at least 6 major genotypes (classified as 1 to 6) and their closely related subtypes (classified as 1a, 1b, etc.). This genetic fluidity of the virus has posed a significant challenge to scientists attempting to develop a vaccine against the virus.

The mechanism by which HCV causes disease is poorly understood, however, it is believed that the body's cytotoxic T cells, which play a key role in the body's defenses against infection, kill the liver cells infected with HCV, thereby leading to liver damage.

Patient Population

HCV affects 170 million people worldwide (3% of the population worldwide), with 95% of infected individuals residing in developing countries. In the US, HCV affects 3.9 million individuals, representing approximately 1.8% of the US population. An additional 37,000 new patients are diagnosed annually; 85% of these individuals develop chronic infection, while the remainder recover spontaneously from their disease within 2 to 12 weeks. The death toll from hepatitis C in the US is approximately 8,000 to 10,000 individuals per year.

HCV genotypes 1, 2, and 3a are found worldwide, while the remaining genotypes are found in isolated geographic regions. In the US, genotype 1 accounts for 70% to 80% of HCV cases, genotype 2 accounts for approximately 15% of cases, and genotype 3 accounts for 5%. Most patients are infected with a single genotype of the virus. There is evidence that response to therapy varies with genotype. The mix of genotypes varies in the different infected populations around the world.

The incidence of HCV in the developed world is declining thanks to the availability of reliable diagnostic tests enabling routine screening of the blood supply. Despite the falling incidence of HCV, the disease is expected to be a major health care burden in the next few decades. Officials with the Centers for Disease Control and Prevention predict that the death toll from hepatitis C will triple in the next 20 years, eclipsing that of AIDS.

HCV is a disease of the adult population. Approximately 65% of cases in the US occur in individuals ages 30 to 49, with new cases found predominantly in adults aged 20 to 45.

Transmission

Hepatitis C is transmitted primarily through significant or repeated exposures to blood. In the U.S, injectable drug use and sexual contact with infected persons are the two exposures that presently account for the majority of HCV cases. In developing countries, HCV transmission occurs predominantly via administration of non-sterile injections.

Prior to the early 1990's, exposure from the blood supply was a significant source of HCV infection, as was injectable drug use. As of 1992, however, reliable diagnostic tests became available to undertake routine screening of the blood supply, such that the risk of exposure to HCV from the blood supply is now estimated to be quite low (at 1 in 100,000 transfusion recipients). At the present time, approximately 60% of new HCV cases with an identifiable risk factor are the result of injectable drug use and 15-20% occur due to sexual contact with infected persons.

Risk factors currently used to determine whether to screen a patient for HCV include:

	History of injecting illegal drugs
	Receipt of a blood transfusion or organ transplant prior to 1992
	Receipt of a blood product for hemophilia or other clotting factor condition before 1987
	Persistent normal alanine aminotransferase (ALT) levels
	Long-term kidney dialysis
	Exposure to blood or needlesticks in the workplace (e.g., health care, emergency or public safety workers), or
	Being born to an HCV-infected mother.

Screening for HCV is recommended in the presence of one or more risk factors.

Diagnosis

Typically, patients are evaluated for the presence of HCV if they have one or more risk factors listed above or if elevated alanine aminotransferase levels are found in a routine blood test. Alanine aminotransferase is an enzyme that is released by liver cells when they die; chronic abnormally high levels are indicative of liver damage. When HCV is suspected, routine laboratory tests are followed with antibody tests to determine whether antibodies to the HCV virus are present in the blood and whether the RNA for the HCV virus itself is present. A liver biopsy is also performed to determine the extent to which the virus has damaged the liver. Genotyping of the virus is done to aid in planning therapy, since it is believed that different genotypes require different courses of treatment.

Symptoms

While HCV is a serious condition, it is a silent disease, with only 25% to 30% of patients reporting symptoms. When they occur, the symptoms of the disease tend to be vague, (e.g. fatigue, stomach pain, fever, loss of appetite, nausea, and joint pain) and common to a number of acute or chronic medical conditions, thus they are not particularly helpful in pointing physicians to a diagnosis of hepatitis. As the disease progresses, patients may develop jaundice, a yellow discoloration of the skin that indicates a decline in liver function.

Treatment

Chronically infected HCV patients are prescribed therapy if they have persistently elevated alanine aminotransferase levels indicative of liver damage, detectable RNA for the hepatitis C virus, and an abnormal liver biopsy.

The mainstay of treatment for HCV is interferon alfa therapy, typically given via injection under the skin in combination with capsules of ribavirin, an antiviral agent. A new pegylated, or long-acting version of interferon alfa was approved by the FDA in January 2001 in the U.S. This new therapy is likely to become incorporated into the standard of care for hepatitis C once it becomes available.

While combination therapy for the treatment of HCV has provided hope for the many patients afflicted with the disease, this complex regimen has a number of shortcomings.

First, the effectiveness of interferon therapy, even in combination with ribavirin, is far from optimal. In clinical studies, approximately 40% of previously untreated patients receiving this combination therapy had undetectable levels of the virus at 48 weeks in controlled studies, while approximately 46% of relapsed patients receiving this combination therapy had undetectable levels at 24 weeks. While interferon combination therapy provides an opportunity for cure in a significant number of patients, improvement in the effectiveness of HCV therapy clearly is needed.

Second, interferon therapy is associated with numerous side effects. Flu- like symptoms are common early in treatment and fatigue, hair loss, rash, and a severe form of anemia, which places a patient at increased risk of heart problems, can occur during treatment. Irritability, apathy, depression, and other mental changes also occur and prevent use of the therapy in some patients. Rarely, serious side effects such as autoimmune disease, depression with suicidal risk, seizures, acute kidney failure, eye diseases, scarring of lung tissue, hearing impairment, and serious infections, can occur. Over one- fourth of patients receiving interferon combination therapy in clinical trials required a change in their regimen due to side effects.

Lastly, interferon therapy is inconvenient, requiring a lengthy course of therapy (6 to 12 months) involving injections which patients must give to themselves under the skin 3 times weekly at home along with multiple ribavirin capsules taken twice daily.

While new agents are likely to offer some improvements in efficacy and convenience over the current regimens, further improvements in effectiveness, safety, and convenience of HCV therapy remain highly desirable.

Long-Term Consequences

While HCV may remain silent for many years, it has serious long-term consequences for afflicted individuals. Chronic liver disease, 40% of which is HCV-related, is currently the tenth leading cause of death in the US. Approximately 20% of patients afflicted with chronic hepatitis C develop cirrhosis, or scarring of the liver, typically after a period of approximately 20 to 30 years. Liver transplant is the only available treatment for patients who develop severe cirrhosis.

Other Resources

American Digestive Health Foundation http://www.adhf.org
American Liver Foundation http://www.liverfoundation.org
Centers for Disease Control and Prevention http://www.cdc.gov/hepatitis 

About Human Genome Sciences, Inc.

Human Genome Sciences is a company with the mission to treat and cure disease by bringing new gene-based drugs to patients.

HGS, Human Genome Sciences and Albuferon are registered trademarks of Human Genome Sciences, Inc. For additional information on Human Genome Sciences, Inc., visit the company's web site at http://www.hgsi.com . Copies of HGS press releases are also available by fax 24 hours a day at no charge by calling 800-758-5804, ext. 121115.

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, dependence on new technologies, uncertainty as to clinical trial results, ability to develop and commercialize products, dependence on collaborators for services and revenue, substantial indebtedness, intense competition, uncertainty of patent and intellectual property protection, dependence on key management, uncertainty of regulation of products, dependence on key suppliers and other risks that may be 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.

SOURCE: Human Genome Sciences, Inc.

Table 1  

PCR (Amplicor 2.0)           TMA (Versant)(TM)   

Classification        Positive      Negative     Positive      Negative   

Sustained Response        0            59             1           58   

End of Treatment   

Response-Relapse         0            47            24           23   

Non-Response             49             0            48            1   

Sarrazin, et al. Hepatology. October 2000. 

SOURCE American College of Gastroenterology
CO: American College of Gastroenterology
ST: District of Columbia
IN: MTC
SU:
 

Note: Ceplene(TM), MaxDerm(TM), Maxamine®, and the Maxim logo are trademarks of the company. 

Editor's Note: This release is also available on the Internet at: http://www.maxim.com. 

Contact: 

     Maxim Pharmaceuticals, San Diego
     Larry G. Stambaugh, 858/453-4040
          or
     Dale A. Sander, 858/453-4040
          or
     Burns McClellan
     Ethan Denkensohn, 212/213-0006
          or
     Kathy Jones, 212/213-0006 This release is also available on the Internet at: http://www.maxim.com 

Pegylated Interferon's, Improved Molecular Tools Brighten Potential Outcomes for Patients With Hepatitis

WASHINGTON, April 9 /PRNewswire/ -- Treatment and outcomes for patients with chronic hepatitis (HCV) continues to improve with the recent approval of pegylated interferon. An expert panel, convened by the American College of Gastroenterology (ACG) on Friday, April 6 met in Dallas, TX to discuss the most recent data in the field of hepatitis diagnosis and treatment.

With a huge expansion in scientific knowledge relating to diagnosis and treatment of hepatitis B and C, the ACG symposium brought together a scientific think tank of experts and thought leaders on hepatitis and liver disease. The American College of Gastroenterology is a physician organization of over 7500 gastrointestinal specialists, which has a strong focus toward clinical, patient treatment oriented issues. The prime objective of the symposium was to prepare treatment approaches and recommendations, reflecting the latest scientific advances that could be applied by individual gastroenterologists as they encounter patients with hepatitis in their day-to- day practice.

The panel of 16 experts presented the most recent data on a number of recent developments relating to hepatitis. Hepatitis C is a chronic, debilitating disease of the liver that affects approximately 4 million individuals in the United States. Until recently, the success rate in treating and alleviating the symptoms and systemic ill effects of hepatitis has been in the range of 40%.

The recent conference compiled critical treatment data spanning new developments: (a) on molecular tools to measure response to therapy for Hepatitis C (e.g. TMA diagnostic test recently available through Bayer Diagnostics); (b) on two new pegylated interferon's (Roche's Pegasys and Schering's PEG Intron; and ways to optimize treatment outcomes for patients treated for chronic hepatitis C (i.e. Procrit for ribavirin induced hemolytic anemia).

Because of the critical advances in these new diagnostic and therapeutic advances, which it is believed may increase success rates by at least 30%, the results of the meeting will be sent to all 7500 ACG member physicians in the form of a CD-ROM, with other follow-up educational materials in the works.

The ACG was formed in 1932 to advance the scientific study and medical treatment of disorders of the gastrointestinal tract. The College promotes the highest standards in medical education and is guided by its commitment to meeting the needs of clinical gastroenterology practitioners.

SOURCE American College of Gastroenterology
CO: American College of Gastroenterology
ST: District of Columbia
IN: MTC
SU:
04/09/2001 17:15 EDT http://www.prnewswire.com

SOURCE: Schering-Plough Research Institute

PEGASYS(R) (peginterferon Alfa-2a) Studied in Post-Liver Transplant Patients With Recurrent Hepatitis C Infection

Investigational Treatment Option for Most Difficult to Treat Patients CHICAGO, May 15 /PRNewswire/ -- Preliminary data presented in a plenary session at the American Society of Liver Transplantation (AST) is the first to study PEGASYS® (peginterferon Alfa-2a) in patients with recurrent hepatitis C infection after liver transplantation.

Some 4,900 people undergo liver transplantation in the US each year. The majority of these cases are caused by hepatitis C, a blood-borne virus that chronically infects an estimated 2.7 million Americans. Although many patients with HCV infection remain symptom-free for up to 20 years, others develop cirrhosis and advanced liver disease, which in some cases will eventually require a liver transplant. Of all patients who undergo liver transplants related to HCV infection, more than 95 percent are re-infected as early as four weeks after transplant surgery because hepatitis C can remain in the bloodstream and re-attack their new liver.

``Although only a very small percentage of people with hepatitis C will ever need a liver transplant, because so many liver transplantations are related to hepatitis C, it is a critical connection,'' said Chris Pappas, MD, Medical Director for Roche.

``This study is especially important because it examines the effect of PEGASYS on post-transplant HCV positive patients, who present a particularly difficult problem,'' said Caroline Riely, M.D., University of Tennessee, Memphis, who presented the study. ``It is important to study the effects of PEGASYS in this population, where it is often challenging to attain a response.''

The study investigates the efficacy and safety of PEGASYS in patients with recurrent HCV infection 6-to-60 months after liver transplantation. Of the 56 treatment-naive patients in the study, 78 percent (44 of 56) were infected with genotype-1 and 88 percent (49 of 56) had HCV viral loads greater than 1 x 106 IU/ml. Half (28 of 56) were given PEGASYS once-weekly injections (180 mcg.) and the other half did not receive treatment. After 24 weeks on PEGASYS, 44 percent of patients (7 of 16) exhibited an HCV RNA 2log drop. Additionally, 25 percent of patients on PEGASYS (4 of 16) had undetectable virus levels (defined as <50 IU/ml as assessed by Amplicor Monitor v2.0) at 24 weeks. This study will be completed in January 2002 with comprehensive study data available shortly thereafter.

The most common side effects associated with PEGASYS in this study were fatigue, nausea, diarrhea, fever, abdominal pain and headache. Of the subjects on PEGASYS, 95 percent experienced at least one side effect, while 81 percent of the subjects left untreated displayed similar reactions. None of the subjects discontinued treatment due to side effects.

More About Pegylation

Pegylation is the attachment of one or more chains of polyethelene glycol (also known as PEG) to another molecule. In PEGASYS, a 40 kilodalton branched, mobile PEG is covalently bound to the interferon alfa-2a molecule and provides a selectively protective barrier, without significantly reducing binding site receptivity. Pharmacokinetic behavior of a pegylated molecule depends on the size of the PEG and the structure of the link between the PEG moiety and the protein.

Researchers believe the PEG creates a barrier that shields the interferon alfa-2a molecule from being rapidly degraded by proteases in the body and maintains its ability to consistently suppress the hepatitis C virus over the one-week dosing period. Specifically, clinical trials have demonstrated that drug levels following a single dose of PEGASYS last more than one full week (168 hours).

Preliminary pre-clinical and human volunteer data suggest that the high molecular weight (40 kilodalton) branched PEG in PEGASYS helps provide sustained pegylated interferon alfa-2a exposure at clinically significant levels over the one-week dosing period. In contrast, according to earlier Roche studies using smaller PEGs developed by the company, interferons with smaller PEGs are degraded quickly, requiring more frequent dosing.

About Roche

Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. prescription drug unit of the Roche Group, a leading research-based health care enterprise that ranks among the world's leaders in pharmaceuticals, diagnostics and vitamins. Roche discovers, develops, manufactures and markets numerous important prescription drugs that enhance people's health, well-being and quality of life. Among the company's areas of therapeutic interest are: dermatology; genitourinary disease; infectious diseases, including influenza; inflammation, including arthritis and osteoporosis; metabolic diseases, including obesity and diabetes; neurology; oncology; transplantation; vascular diseases; and virology, including HIV/AIDS and hepatitis C. For more information on the Roche pharmaceuticals business in the United States, visit the company's website at: http://www.rocheusa.com

SOURCE: Hoffmann-La Roche Inc.

Conference Report: Hepatitis C Infection -- Optimizing Treatment, Patient Management, and Basic Aspects

36th Annual Meeting of the European Association for the Study of the Liver (EASL)
April 18-22, 2001
Prague, Czech Republic

Michael P. Manns, MD, Heiner Wedemeyer, MD, Department of Gastroenterology and Hepatology, Medical School of Hannover, Hannover, Germany

[Medscape Gastroenterology, 3(3) 2001. © 2001 Medscape, Inc.]

Introduction -- Therapy of Chronic Hepatitis C Infection

Treatment of chronic hepatitis C virus (HCV) infection has improved significantly since the introduction of combination interferon (IFN) alfa and ribavirin therapy in 1998. However, there are several groups of patients (eg, patients with the most prevalent HCV genotype 1, high viral load, or liver cirrhosis) who still have an unfavorable outcome to therapy, with sustained response rates of less than 30%. Additionally, patients who fail to respond to an earlier course of IFN monotherapy have shown disappointing response rates to a standard combination regimen. New treatment strategies must be evaluated for patients with unfavorable baseline characteristics. Options for improving sustained response rates include modified regimes such as IFN-alfa induction dosing or daily dosing, new therapeutic agents in combination with IFN-alfa, and the use of novel IFNs (eg, pegylated IFNs, consensus IFN). At the 36th annual meeting of the European Association for the Study of the Liver (EASL), held April 18-22, 2001, in Prague, Czech Republic, several studies were presented that investigated strategies for improving response rates in "difficult-to-treat" patients.

Treatment of Nonresponder Patients

Prolonged Treatment
Standard combination therapy with IFN-alfa (3 MU/3 times per week) and ribavirin (1000/1200 mg daily) is not recommended as the "standard of care" in patients who have failed to clear the virus after treatment with IFN-alfa alone ("nonresponder patients"). In 1998 we summarized 23 trials and demonstrated that standard combination therapy for 6-12 months' duration resulted in a sustained virologic response in only 7.4% of patients.[1] An Italian multicenter study presented during this year's EASL meeting addressed the question of whether longer treatment and higher doses of IFN might represent a strategy for increasing response rates in these nonresponder patients.[2] Patients (n=594) were randomized into 4 treatment arms and received either 3 or 5 MU IFN alfa-2b for 6 or 12 months in combination with ribavirin. With the most aggressive treatment regime, sustained responses were significantly higher only among those patients with HCV genotype 1, and not among patients with HCV genotypes 2 or 3. However, the overall sustained response was still low, at 23%, even in patients treated with 5 MU IFN-alfa 3 times per week in combination with ribavirin for 12 months.

Triple Therapy

Results of other studies from Italy have suggested that a combination of IFN alfa, ribavirin, and amantadine ("triple therapy") may represent a promising option for nonresponder patients. Sustained response rates of up to 60% have been reported in this setting.[3] However, a combination of IFN alfa and amantadine (without ribavirin) alone failed to show a beneficial effect for amantadine in naive[4] and nonresponder[5] patients. During these meeting proceedings, results of a German multicenter study were presented that evaluated the efficacy of triple vs IFN/ribavirin combination therapy in 134 nonresponder patients.[6] IFN alfa was given in an intensified regimen of 5 MU daily for the first 4 weeks followed by 5 MU 3 times per week for 20 weeks and then 3 MU for an additional 24 weeks. The sustained response rates were slightly higher in patients receiving amantadine (23.4%) compared with patients treated with the IFN alfa/ribavirin combination alone (17.1%), but this difference was not statistically significant.

Thus, the promising results from the first amantadine trials could not be confirmed, and therefore triple therapy (IFN + ribavirin + amantadine) cannot be recommended as a standard treatment option for nonresponder patients at this time.

Daily Induction Dosing

Early viral clearance is important for a sustained response to antiviral treatment in hepatitis C. Zeuzem and colleagues[7] have demonstrated that all patients with a sustained virologic response had an initial decline in serum HCV RNA levels of more than 3 logs within the first 4 weeks of treatment. Viral kinetic studies gave evidence for an increased antiviral effect of higher dosages of IFN alfa (induction-dosing) and daily vs thrice-weekly IFN treatment schedules.
Many groups have assessed the impact of IFN alfa dose and regimen (3 times weekly vs daily) on HCV kinetics.[8,9] In these studies, it was shown that there was a significant and more rapid reduction in HCV RNA levels among patients who were treated with daily dosing schedules. However, as recently as the American Association for the Study of Liver Diseases Annual Meeting held in Dallas, Texas, in October 2000, it has been shown that a high daily dose of IFN alfa has no significant effect on the long-term results in previously untreated patients if the treatment schedule is changed to a 3-times-weekly regimen later on during therapy.[10] Similar results for nonresponder patients were also presented during proceedings of this year's EASL meeting.[11]

Overall, more aggressive treatment regimens (ie, higher doses, longer treatment, daily dosing with additional combination partners) may be able to increase sustained response rates in nonresponder patients to some degree. However, side effects and the associated costs of these intensified therapies are often significant ,and more than two thirds of the patients will still not clear the virus. Thus, alternative treatment regimens must be developed for this group of patients.

Patients With Persistently Normal Aminotransferase (ALT) Levels
Natural History
Because most patients with persistently normal ALT levels (ie, 20%-30% of all patients infected with HCV) present with only mild, if any, liver disease, it has been a matter of debate whether these patients should receive antiviral treatment. In fact, some studies reported an increase in inflammatory activity by IFN alfa, and thus therapy may even be contraindicated in this group of patients.
However, some patients with normal liver enzymes can develop fibrosis or even cirrhosis. Christian Trépo from Lyon, France, presented data on 4728 patients collected from 6 European centers.[12] In 65% of those patients who had normal ALT levels in serial testings over a period of 6 months, liver fibrosis of stage F1 was present using the METAVIR scoring system. Important to note was that no complete cirrhosis was detectable in this group of patients. Long-term follow-up is needed before a final conclusion may be drawn.

Therapy
The French Study Group for Chronic Hepatitis C With Normal Aminotransferase Levels conducted a randomized study to evaluate the efficacy of IFN alfa-2a monotherapy in patients with persistently normal ALT levels.[13] Patients were randomized to treatment (n=31) or to no treatment (n=31). Important to note was that liver biopsies were performed not only prior to treatment, but also after 1 year of follow-up. As expected for IFN monotherapies, the virologic sustained response rate was low, at 15%. However, histologic disease activity improved in 19% of patients, remained unchanged in 71%, and increased in 10%. Fibrosis scores improved in 15%, did not change in 55%, and worsened in 30% of the treated individuals. Of interest, nearly identical histologic results were observed for patients who did not receive any therapy.

Thus, in conclusion, patients with persistently normal ALTs should not be treated with IFN alfa alone. In our opinion, only in rare cases will patients with normal liver enzymes require antiviral therapy, even if more potent treatment strategies are available. Currently, there is no evidence that these patients will ever develop liver failure if no additional risk factors are present. Therefore, risks, costs, and side effects must be weighed carefully before a decision to initiate treatment is made.

Pegylated Interferons

Polyethylene glycol (PEG) is a small molecule that can be polymerized into long chains and attached to proteins. Two pegylated IFNs are now undergoing clinical trials.* PegIFN alfa-2a is a modified form of IFN alfa-2a to which a branched 40-kd methoxy PEG moiety has been covalently attached.[14] PegIFN alfa-2b consists of IFN alfa-2b attached to a single 12-kd PEG molecule. Both PegIFN alfa-2a and PegIFN alfa-2b have a decreased systemic clearance rate and a prolonged plasma half-life (approximately 10-fold) compared with standard IFNs; this allows for once-weekly dosing with the pegylated formulations.[15] The 2 PegIFNs appear to have discrete characteristics -- their half-lives are slightly different and their metabolism and elimination rates also differ. PegIFN alfa-2a is predominantly metabolized in the liver, whereas PegIFN alfa-2b is eliminated predominantly by the kidney.[16] Due to these disparate properties, comparison of these 2 PegIFNs is difficult. Initial clinical trials demonstrated that monotherapy with PegIFN alfa-2a or PegIFN alfa-2b improved sustained response rates compared with standard IFNs.[17,18] Even in patients with liver cirrhosis, 30% of patients had a sustained virologic response when treated with 180 mcg PegIFN alfa-2a once weekly for 48 weeks.[19] Recently it was shown that sustained virologic response rates could be further enhanced to more than 50%, by combination of PegIFN with ribavirin.[20] More detailed analysis of data from this trial were presented in Prague, and indicated that dosing of not only PEG-IFN alfa-2b, but also ribavirin, should be adjusted according to patient body weight in order to achieve optimal response rates.[21] The new recommendation is to use 1.5 mcg/kg PegIFN alfa-2b and 800 mg ribavirin for patients who weigh less than 65 kg, 1000 mg ribavirin for patients who weigh 65-85 kg, and 1200 mg ribavirin for patients whose body weight exceeds 85 kg.

First data on the combination of PegIFN alfa-2a with ribavirin and amantadine have also been presented, indicating that this combination is safe and that its efficacy appears to be comparable to or slightly improved over that of standard IFN alfa-2b 3 times per week plus ribavirin combination therapy.[22]

* Editor's note: The United States FDA approved pegylated IFN alfa-2b monotherapy in January 2001.

Consensus Interferon (CIFN)
CIFN is a novel bioengineered "consensus" molecule, composed of the most frequently observed amino acid in each corresponding position in the natural alpha interferons. CIFN shares an 89%, 30%, and 60% homology with IFN alpha, IFN beta, and IFN omega, respectively. CIFN has a 10-fold increased affinity for the type-1 IFN receptor compared with IFN alpha-2a or IFN alpha-2b. When compared on an equal-mass basis, CIFN displays 5-10 times greater biological activity than other type-1 interferons.[23-25] CIFN has proven effective, especially in difficult-to-treat patients (eg, patients infected with HCV genotype 1.)[26]
Using a combination of CIFN and ribavirin, an Italian group achieved a sustained virologic response in 55% of patients who were infected with HCV genotype 1 and who had high viral load.[27] These promising results must be confirmed in larger trials, because only 20 patients were randomized into the combination treatment arm of this study.

Patient Management

Transmission of HCV to Newborns in HIV-Coinfected Mothers The frequency of HCV transmission from mother to child has been reported to be in the range of 0% to 30%, depending on the social status of the mother and also on the status of coinfection with HIV. At present, there are no data analyzing transmission rates of HCV in mothers coinfected with HIV who receive antiretroviral treatment. Investigators from Bergamo and Milano in Italy identified 26 HIV/HCV-coinfected pregnant women who were treated with a double or triple antiretroviral regimen.[28] No transmission of HCV to the child was observed in this group of patients vs 10 cases of HCV transmission to newborns that occurred in 390 anti-HIV-negative/HCV-positive mothers. Cesarean section was used in nearly all of these observed cases, which is consistent with findings from a recent report published in The Lancet demonstrating that the risk of HCV transmission can be reduced by this method of delivery.[29]

Hepatitis B Virus (HBV)/HCV Coinfection

Several studies have investigated the effect of HBV coinfection on the course of chronic hepatitis C. Although there is some agreement that hepatitis B surface antigen (HBsAg)-positive/anti-HCV-positive patients have a more severe liver disease, occult HBV infections (detection of HBV DNA by PCR in HBsAg-negative individuals) have also been reported as associated with a poor IFN response and a more severe clinical course.[30] Data from 3170 anti-HCV-positive German patients were presented during these meeting proceedings and confirmed these previous findings.[31] Liver fibrosis scores were higher in dually infected patients than in patients who had cleared HBV infection (the frequency of occult HBV infections is usually high among this patient group) or in patients without any apparent previous exposure to HBV. Interesting to note was that each virus seemed to interfere with the replication of the respective other virus. Although HCV RNA was detectable in 85% of anti-HCV-positive patients who were negative for anti-HBc, 82% of anti-HBc-positive/HBsAg-negative patients tested positive for HCV RNA. However, HCV RNA was detectable in only 44% of patients coinfected with HBV and HCV (ie, HBsAg-positive/anti-HCV-positive). The most important factor distinguishing HCV RNA-positive from HCV RNA-negative patients was the presence of antibodies to hepatitis D virus (HDV). This factor indicates that HDV is not only able to suppress replication of HBV but also of HCV.

Overall, serologically active -- as well as silent -- HBV coinfection significantly affects the clinical outcome of HCV infection. Treatment guidelines for this important patient population must be developed.

Interferon Therapy for Hepatitis C Infection and Disposal of Needles

Treatment with IFN alfa requires daily or thrice-weekly subcutaneous injections. Usually the patient is trained by nurses in hospitals or in outpatient clinics and self-administers these injections at home. An interesting survey conducted by a French group investigated the way in which contaminated needles are disposed of in at-home settings.[32] Only 32% of patients received special containers for disposal of used needles, whereas in nearly one fourth of cases, the syringes were disposed of in the regular trash without being recapped. In 6.5% of cases, needle-stick injuries were reported, and in one of those cases a family member was involved.

The results of this study demonstrate the importance of patient information and proper training in the technique of self-injection. It is strongly recommended that patients be provided with appropriate containers for disposal of HCV-contaminated needles.

Basic Aspects of HCV -- Implications for Future Therapies

Several studies on the basic aspects of viral hepatitis, with potential implications for the development of new antiviral or immunotherapies, have been conducted. Analyses of cellular immune responses are an important prerequisite to the development of any immunotherapy. Our group[33] demonstrated that HCV-specific CD8+ T cells are not deleted but instead are functionally impaired in patients with chronic hepatitis C infection. Thus, uncontrolled activation of these T cells could be potentially harmful and lead to more severe inflammatory activity.

Additionally, researchers from London showed that intrahepatic T-cell responses display a more Th2-type pattern in patients with higher inflammatory activities.[34] These findings may have significant implications for the development of alternative immunotherapies, for the poor antiviral response seen in HCV-related cirrhosis, and for understanding the immunopathogenesis of chronic liver disease.

Interactions between viral and host proteins have been proposed as a mechanism involved in interferon response as well as in the process of carcinogenesis. The results of one study showed that the HCV-NS3 protein induces the cellular MAP kinase pathway and, subsequently, the expression of transcription factors AP-1 and AFT-2, which are involved in the development of hepatocellular carcinoma (HCC).[35] Thus, understanding this interaction in more detail may provide insight into the prevention of liver tumors in HCV-related cirrhosis.

The cellular IFN-induced protein kinase R (PKR) has been shown to interact with HCV proteins NS5A and E2. Mutations within these 2 proteins are associated with increased response rates to IFN in patients with chronic hepatitis C. During the proceedings of the EASL meeting, data were presented that showed, for the first time, that the HCV core protein also binds to and activates PKR.[36] And, interesting to note, this effect was only observed to occur with an HCV core, encoded by an HCC tumor-derived sequence, but not with HCV core derived from nontumor sequences. Additional studies are currently ongoing to investigate in greater detail the implications underlying this interaction.

There are several possible clinical applications for anti-HCV antibodies. For example, these antibodies may be used after liver transplantation to prevent reinfection of the graft with HCV, a procedure similar to that currently used posttransplantation for HBV-induced liver failure. Nussbaum and colleagues[37] presented a small animal model to evaluate antibodies for their potency on preventing HCV infection and for decreasing viral load once an infection has been established. These study authors used the "trimera mouse model," a system that provides a mouse model for human HBV infection. It involves reconstitution of bone marrow deri