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  • 2byteme@bellsouth.net
    Ortho-Clinical Diagnostics, Inc. Launches New Early Detection HCV Test First Direct Detection Test for Hepatitis C Virus Core Antigen Now Available Outside the
    Message 1 of 106 , Sep 1, 2000
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      Ortho-Clinical Diagnostics, Inc. Launches New Early Detection HCV Test

      First Direct Detection Test for Hepatitis C Virus Core Antigen Now
      Available

      Outside the United States

      RARITAN, N.J., Aug. 31 /PRNewswire/ -- A new in vitro diagnostic assay,

      ORTHO(R) Antibody to HCV Core Antigen ELISA Test System, is now
      commercially available in countries outside of the United States. This
      is
      the first test to be commercialized for the direct detection of HCV core

      antigen, a marker of early infection in Hepatitis C infected
      individuals.
      Availability of this assay will reduce the worldwide transmission of HCV

      infection through infected blood.

      HCV Ag Test System: Closing The Window For Hepatitis C Virus

      International field studies with the ORTHO HCV core antigen assay
      demonstrate a significant performance improvement versus current
      immunoassay techniques in closing the HCV infectious window by 40-50
      days.
      Performance data shared at the 1st Scientific Symposium on Technology
      for
      the Detection of Hepatitis C Virus Core Antigen held in Paris in March
      2000 established the HCV Ag test as a viable option for the
      identification
      of HCV infectious blood donor units throughout the world. "Implementing

      the HCV core antigen test to screen blood donations would significantly
      improve transfusion safety," said Anne-Marie Courouce, PhD, Head of the
      Unit of Virology at the National Institute of Blood Transfusion in
      Paris.
      Dr. Courouce presented data which showed the HCV Ag test detecting HCV
      infection approximately 49 days earlier than existing HCV antibody
      assays.

      ORTHO HCV core antigen assay is also the only direct detection test
      system
      available today which provides results in under 3 hours, is compatible
      with existing equipment and is suitable for large-scale screening of
      individual blood donors. "We have worked diligently to bring ORTHO
      Antibody to HCV Core Antigen ELISA Test System to market because of its
      potential to improve the safety of the world's blood supply," states
      Gerard Vaillant, Ortho-Clinical Diagnostics, Company Group Chairman
      Diagnostics Worldwide. "This assay has helped us continue the tradition

      of delivering breakthrough assays in the field of hepatitis."

      Worldwide Commercialization

      Commercialization of the ORTHO HCV core antigen assay will include
      product
      registration worldwide. "We are actively involved in registration
      processes in key geographies around the globe and will continue to
      participate in studies to further our development of diagnostic
      applications and the next generation Ortho HCV core antigen blood
      screening test," said Bill Skillman, Vice President, Transfusion
      Medicine,
      Ortho-Clinical Diagnostics. The Ortho HCV core antigen assay is
      currently
      registered for use in France and Hungary and available for sale in Spain

      and Belgium.

      The Investigational New Drug (IND) application for the United States
      filing was submitted to the U.S. Food and Drug Administration on August
      30, 2000.

      About Ortho-Clinical Diagnostics

      Ortho-Clinical Diagnostics, a Johnson & Johnson company, is a leading
      provider of high-value diagnostic solutions for the global health-care
      community. Committed to developing the most advanced tests for early
      detection or diagnosis of disease, the Company brings products to market

      that provide timely information and help to facilitate better medical
      decisions. Ortho-Clinical Diagnostics also provides blood screening and
      typing products that help to ensure the safety of the world's blood
      supply. In addition, through its patented dry slide and enhanced
      chemiluminescence technologies, the Company has transformed the way that

      clinical laboratories perform testing. Worldwide, health care
      professionals rely on Ortho-Clinical Diagnostics for innovative
      diagnostic
      solutions that promote effective diagnoses and enhance patient care.

      (Note: ORTHO is a registered trademark of Ortho-Clinical Diagnostics,
      Inc.)

      SOURCE Ortho-Clinical Diagnostics, Inc.
    • 2byteme@bellsouth.net
      Hepatology Focus Update on Hepatitis C Treatment Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA School of Medicine, Los Angeles,
      Message 106 of 106 , Feb 25, 2001
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        Hepatology Focus
        Update on Hepatitis C Treatment

        Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA
        School of
        Medicine, Los Angeles, California

        Sammy Saab, MD, Clinical Instructor, UCLA School of Medicine, Los
        Angeles, California, and
        Paul Martin, MD, Medical Director, Liver Transplantation, Cedars-Sinai
        Medical Center,
        Associate Professor of Medicine, UCLA School of Medicine, Los Angeles,
        California

        [Medscape Gastroenterology 3(1), 2001. © 2001 Medscape, Inc.]

        Background

        Although screening of blood products and other interventions such as
        clean-needle exchange
        programs have significantly reduced the incidence of acute hepatitis C
        in the United States and
        elsewhere, there remains a large reservoir of chronically infected
        individuals, many of whom are
        unaware of their infection. Current estimates suggest a seroprevalence
        of 1.8% among Americans,
        most of whom are viremic.[1] The clinical burden of chronic hepatitis C
        virus (HCV) infection is
        expected to increase over the next 2-3 decades as a large cohort of
        patients infected between the
        1960s and 1980s, primarily as a result of recreational drug use,
        develops progressive liver disease.
        Between 8000 and 10,000 deaths each year in the United States are
        believed to be caused by
        infection with HCV -- which is now the most frequent indication for
        liver transplantation.[2]

        Even before identification of HCV, interferon-alfa (IFN-alfa) had been
        evaluated as a potential
        therapy for what had been called chronic non-A, non-B hepatitis.[3]

        Further studies using normalization of serum alanine aminotransferase
        (ALT) levels and
        improvement in liver histology as endpoints demonstrated the efficacy of
        IFN-alfa as therapy for
        the causative agent of chronic non-A, non-B hepatitis (HCV).[4,5]
        Subsequent advances in
        molecular diagnosis have now increasingly allowed establishment of
        virologic criteria to evaluate
        efficacy of treatment in patients with chronic hepatitis C (see Table).

        Definition of Virologic Response in Patients Receiving Therapy for
        Chronic Hepatitis C

        End-of-treatment response (ETR) refers to absence of viremia (ie, serum
        HCV RNA below level
        of detection) at completion of therapy. Sustained response (SR)
        indicates persistent absence of
        serum HCV RNA 6 months or more after cessation of therapy. A study by
        Marcellin and
        coworkers[6] on the long-term clinical outcome in 80 patients with
        chronic HCV followed for a
        mean of 4 years following therapy highlighted the clinical implications
        of a virologic SR. Persistent
        absence of HCV RNA from serum was observed in 96% of patients with a
        lack of histologic
        progression on serial liver biopsy. In addition, ALT levels were
        persistently normal in over 90%.
        The most recent follow-up biopsy showed normal or near normal histologic
        findings in 62% of
        these patients. Thus, virologic SR was shown to be associated with both
        an absence of detectable
        serum HCV RNA and marked histologic improvement.

        Relapsers are defined as patients who have undetectable serum HCV RNA at
        completion of
        therapy but who subsequently redevelop viremia. Nonresponders (NRs) are
        patients who fail to
        clear HCV RNA from serum during therapy.

        A recent paper by Everson and associates[7] underscores the importance
        of HCV RNA testing in
        defining treatment response. In patients with marked fibrosis and
        cirrhosis, they found a major
        discrepancy between biochemical (ALT) and virologic (HCV RNA) responses
        to therapy. Two of
        7 (29%) patients with marked fibrosis and 2 of 6 (33%) patients with
        cirrhosis cleared HCV RNA
        without normalizing ALT. In contrast, only 3 patients (10%) without
        significant fibrosis had an
        HCV RNA response without normalization of ALT. Thus, clinical trials for
        chronic HCV are now
        typically reported using virologic response rates.

        What then are the current goals of antiviral therapy in patients with
        chronic hepatitis C? Immediate
        goals are eradication of viral replication and improvement in hepatic
        inflammation and fibrosis.
        Long-term potential goals include prevention of cirrhosis,
        hepatocellular carcinoma, and liver
        failure.

        Interferon Monotherapy

        IFN-alfa 2 was the first agent approved for the treatment of chronic
        HCV. Since the initial trials
        establishing its efficacy, data regarding treatment duration and dose
        have evolved. Currently, 2
        forms of IFN-alfa that differ by a single amino acid residue are
        approved for treatment of chronic
        HCV infection: IFN-alfa 2b (Schering-Plough, Kenilworth, New Jersey) and
        IFN-alfa 2a
        (Hoffmann-La Roche, Basel, Switzerland). The recommended dose is 3
        million units 3 times each
        week for up to 12 months.

        When used alone in monotherapy, the alfa interferons have similar
        efficacies, with SRs of only 10%
        to 20%, with the modestly higher response rates associated with more
        prolonged therapy.
        Higher-dose IFN-alfa (ie, > 9 million units per week) results in SRs
        between 8% and 20% in
        treatment-naive patients. High-dose IFN-alfa has also been studied in
        NRs and relapsers, but with
        mixed results. With prior NR, SRs achieved with higher doses are only
        between 0% and 4%. In
        relapsers, SRs range from 20% to 40%. However, side effects are more
        troublesome with higher
        doses.[8]

        Because of the low overall response rate to standard IFN-alfa, more
        recent studies have focused
        on newer regimens, including synthetic IFN (IFN alfacon-1),
        "combination" therapy (IFN-alfa 2b
        + ribavirin), and longer-acting IFNs (pegylated IFNs). A number of major
        pretherapy predictors
        of NR have been identified, notably HCV genotype 1, the presence of
        cirrhosis, and higher viral
        load.[9] In addition, patient's race appears to affect response to IFN,
        with African Americans
        having an overall low SR to therapy.[10]

        Combination Therapy

        A significant improvement in SR resulted from the addition of ribavirin
        to standard IFN-alfa.
        Ribavirin, a guanosine analogue, was initially evaluated as monotherapy
        for chronic HCV because
        of its antiviral activity against other RNA viruses.[11-13] Although as
        monotherapy it reduces ALT
        levels, it does not appear to have a direct antiviral effect and fails
        to lower serum HCV RNA
        levels. Moreover, results of most studies with ribavirin have found no
        improvement in hepatic
        histology, although a longer 2-year treatment regimen was shown to
        reduce necroinflammatory
        activity.[13]

        However, in combination with IFN-alfa 2b, ribavirin leads to a
        significant increase in SR in
        treatment-naive patients.[14] SRs of 31% with 24 weeks and 38% with 48
        weeks of combination
        therapy were achieved vs 6% with 24 weeks and 13% with 48 weeks of IFN
        monotherapy.[14] In
        relapsers, enhanced SR rates also occur on retreatment using combination
        therapy, from 30% to
        49%; in prior NRs, SR of 14% has been reported with 6 months of
        combination therapy.[15,16]

        Histologic improvement was more common among treatment-naive patients
        treated with
        combination therapy.[14] Similar improvement was found in a randomized
        controlled trial of
        treatment-relapse patients.[15]

        However, the improved SR rates observed with combination therapy are
        also associated with
        more expense and an increased frequency of adverse effects compared with
        IFN-alfa
        monotherapy.[14] Dose-related hemolytic anemia is a particular concern
        with ribavirin[11,13] as is
        teratogenicity, based on animal studies.[16] The mean drop in hemoglobin
        in patients treated with
        combination therapy is between 2 and 3 g/dL, although a fall of more
        than 4 g/dL has been
        observed in about 10% of patients. The anemia may be poorly tolerated in
        patients with ischemic
        heart disease in particular as treatment is extended to older
        patients.[17] Accumulation of ribavirin
        metabolites that are not cleared by dialysis occurs in end-stage renal
        disease.(18)

        Consensus Interferon

        Consensus IFN (CIFN; IFN alfacon-1, Amgen, Thousand Oaks, California) is
        a genetically
        engineered compound synthesized by combining the most common amino acid
        sequences from
        naturally occurring IFNs.[19,20] CIFN shares 88% homology with IFN-alfa
        and 30% with
        IFN-beta. Although it has greater cytokine induction, antiviral,
        antiproliferative, natural killer cell,
        and gene-induction activities than both IFN-alfa 2a and IFN-alfa 2b on
        an equal mass basis, initial
        studies with the recommended CIFN dose of 9 mcg in IFN-naive patients
        with chronic hepatitis C
        resulted in viral response rates similar to those achieved with standard
        IFN-alfa monotherapy.[19,20]

        More recently, higher-dosage CIFN regimens of 15 mcg thrice weekly were
        reported to result in
        virologic SRs of 13% in prior NRs and 58% in relapsers treated for 48
        weeks.[21]

        Pegylated Interferon

        Pharmacokinetic studies have provided a rationale for enhanced IFN
        dosing. The initial decline in
        serum HCV RNA levels seen after a single dose of IFN therapy is believed
        to reflect a direct
        antiviral effect, whereas the subsequent and more delayed decline in HCV
        RNA levels is due to
        destruction of infected hepatocytes.[22] An important limitation of the
        antiviral effect of standard
        IFN dosing is the rapid decline in circulating drug level with
        thrice-weekly administration. The short
        half-life of the drug and the rapid production of HCV virions diminish
        the efficacy of standard IFN
        therapy. In an effort to achieve more stable and efficacious IFN
        activity, pegylated formulations
        have been developed.

        The production of a pegylated IFN involves the addition of a nontoxic
        long-acting formulation of
        interferon using the drug delivery system of pegylation. Polyethylene
        glycol molecules are added to
        IFN-alfa 2a (Pegasys, Hoffmann-La Roche) and IFN-alfa 2b (PEG-Intron,
        Schering-Plough).
        Pegylation is already used in the delivery of other drugs. Its
        attachment to IFN-alfa permits
        once-weekly dosing.

        In a recent report, Zeuzem and colleagues[23] indicate that at week 72,
        the SR was 39% after 48
        weeks of therapy at a dose of 180 mcg with pegylated IFN alfa-2a
        compared with a 19% SR in
        control patients. Drug discontinuation in these treatment-naive patients
        and frequency of dose
        reduction were similar in the 2 treatment arms. Heathcote and
        colleagues[24] have also reported on
        the use of pegylated IFN alfa-2a in a controlled trial in cirrhotic
        patients. SR was 30% following 48
        weeks of therapy with 180 mcg, compared with 8% for patients treated
        with standard alfa IFN,
        again without a significant increase in side effects with the pegylated
        product.

        Trepo and colleagues[25] have also reported, in abstract form, initial
        studies with pegylated IFN-alfa
        2b. Virologic SR for the unmodified IFN-alfa 2b (3 million units, thrice
        weekly for 48 weeks) was
        12%, whereas the SR for the pegylated IFN-alfa 2b was 18%, 25%, and 23%
        with 0.5 mcg/kg,
        1.0 mcg/kg, and 1.5 mcg/kg, respectively, administered weekly in
        treatment-naive patients.

        As with standard IFN-alfa monotherapy, ribavirin may augment response
        rates when combined
        with the pegylated IFNs.[26,27] Recent trials will help evaluate further
        the role of ribavirin in
        augmenting the efficacy of pegylated IFN (see Figure).



        Figure. Initial antiviral therapy against hepatitis C virus.*
        * Abbreviations: IFN = interferon; CSN = consensus interferon;
        IFN/RIB =
        interferon + ribavirin; PEG = pegylated interferon; PEG/RIB =
        pegylated interferon +
        ribavirin.

        Future Trends

        There has been continued interest in developing non-IFN-based therapies
        for HCV despite the
        promise of the pegylated IFNs. A recent study examined the role of human
        interleukin-10 in
        treating prior NRs with chronic HCV.[28] Although, HCV RNA remained
        detectable in all patients
        at the end of treatment,[25] 5 (23%) of the 22 treated patients had
        persistent ALT normalization at
        the end of follow-up. Future studies should determine whether combining
        interleukin-10 with other
        antiviral agents will increase efficacy in this setting. Interleukin-12
        has also been evaluated as
        monotherapy, again without clear antiviral benefit.[29]

        There is also increasing enthusiasm for targeting HCV molecular
        products. For example, ribozyme
        gene therapy has the potential to accurately degrade HCV RNA.[30] Human
        studies are anticipated.

        Conclusion

        Treatment options for HCV infection continue to expand. Whereas SRs of
        10% were achieved
        with IFN monotherapy only several years ago, it may soon be possible to
        achieve SR rates greater
        than 50% with combination pegylated IFN and ribavirin. Molecular-based,
        specific therapeutic
        strategies are also likely to become a reality in the future, although
        therapy will remain
        interferon-based the next several years.

        Table. Response (HCV RNA/ALT*) to Antiviral Therapy

        Type of Response†
        During
        Treatment
        End of
        Treatment
        6 Months After
        Treatment
        Completed
        End-of-Treatment
        Negative
        Negative

        Sustained
        Negative
        Negative
        Negative
        Relapse
        Negative
        Negative
        Positive
        Nonresponder
        Positive
        Positive
        Positive


        * HCV RNA measured by polymerase chain reaction; ALT = alanine
        aminotransferase; HCV = hepatitis C virus.
        † Positive denotes HCV RNA present in the serum by polymerase chain
        reaction and
        abnormal alanine aminotransferase values. Negative denotes no serum
        HCV RNA by
        polymerase chain reaction and normal alanine aminotransferase
        values.

        References

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        hepatitis C virus
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