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News Review

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HEPATITIS JOURNAL REVIEW:
A Bi-Monthly Publication of the Hepatitis Support Project

February 12, 2006
Volume 3, Issue 3


Liz Highleyman

To download pdf version click here


In This Issue: Hepatitis C


Experimental Drug Development

Disappointing Results for Antisense Agent

Benefits – or not – of Amantadine

Consensus Interferon for Nonresponders

New HCV Assays


Experimental Drug Development
Two recent journal reviews have looked at development of new therapies for hepatitis C. In a February 2006 Hepatology supplement, Jean-Michel Pawlotsky reviewed recent progress in HCV treatment thanks to a better understanding of how the virus behaves and how interferon and ribavirin work, new assays that aid treatment decision-making, better management of adverse side effects, and greater knowledge of how to treat special populations such as injection drug users and HIV/HCV coinfected individuals. Novel therapies — including new interferons, alternatives to ribavirin, specific inhibitors of the HCV lifecycle, and immune modulators – should improve treatment even more in the years ahead.

In the February 2006 Journal of Hepatology, Pawlotsky, John McHutchison, and colleagues looked at future HCV antiviral drug development and how recent advances in understanding the virus may be translated into improved clinical practice. New laboratory cell culture methods have enabled a better understanding of viral replication and host-viral interactions, offering opportunities to develop novel therapeutic approaches that disrupt HCV early in its lifecycle. Among the most promising types of experimental drugs are HCV protease inhibitors, polymerase inhibitors, toll-like receptor agonists, and RNA gene therapies. The authors noted the importance of using multiple agents acting through different mechanisms to help prevent the development of drug resistance. The authors acknowledged, however, that despite progress in the laboratory, it remains a challenge to translate advances in understanding HCV into safe and effective drugs on pharmacy shelves.

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Disappointing Results for Antisense Agent
Several recently published studies illustrate that not every agent that initially appears promising in the laboratory is destined for clinical success. In the January 2006 Journal of Hepatology, McHutchison and colleagues reported on a study of ISIS-14803, an antisense oligonucleotide that binds to HCV’s internal ribosome entry site (IRES). In this Phase I, open-label trial, 28 participants received 0.5-3 mg/kg of ISIS-14803 three times weekly for four weeks by intravenous infusion or subcutaneous injection. In 89% of the patients, ISIS-14803 did not reduce HCV viral load. However, three patients did experience a transient virological response (HCV RNA reductions of 1.2-1.7 log copies). These three individuals plus two others experienced unexplained self-resolving ALT flare-ups while taking ISIS-14803. The researchers concluded that further studies are needed to evaluate this novel agent and its side effects.

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Benefits – or not – of Amantadine
In the February 2006 Journal of Hepatology, Peter Ferenci and colleagues reported on a randomized, placebo-controlled trial of pegylated interferon (Pegasys) plus ribavirin plus either amantadine or placebo in just over 200 treatment-naive patients with chronic genotype 1 hepatitis C. Researchers have hypothesized that amantadine may augment virological response to interferon, but research to date has produced mixed data. In this study, patients taking amantadine and those taking placebo had similar virological response at 24 weeks (64% vs 66%) and comparable sustained virological response (SVR) rates at week 72 (47% vs 52%). Adverse event profiles were also similar in the two groups. The authors concluded that amantadine “does not augment virological response rates” and “did not improve health-related quality of life” compared with placebo in genotype 1 patients.

In contrast, in another 200-person study by Marianne Maynard and colleagues, reported in the “Article in Press” section of the Journal of Hepatology website, previous interferon nonresponders who received amantadine in addition to pegylated interferon plus ribavirin for retreatment were more likely to achieve SVR than those who added placebo (24% vs 16%, respectively). Patients in the amantadine group also experienced better biochemical response. Given the conflicting results of these two studies, the jury is still out on the value of amantadine in the retreatment of hepatitis C.

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Consensus Interferon for Nonresponders
One critical area of drug development is new therapies for patients who do not respond to initial standard therapy. Also in the February Journal of Hepatology, Markus Cornberg and colleagues reported on a pilot study of consensus interferon in 77 previous nonresponders to treatment with interferon-alpha-based therapy (90% with genotype 1). Patients were randomly assigned to receive either an 8-week induction dose of 18 μg daily consensus interferon followed by 9 μg for 40 weeks, or else 9 μg daily for the entire 48-week treatment period; all patients also received 1000-1200 mg ribavirin. Overall, 82% of participants experienced early virological response, 65% had an end-of-treatment response, and 30% achieved SVR. The SVR rate was lower (22%) among nonresponders who had previously been treated with interferon plus ribavirin (as opposed to interferon monotherapy). Patients receiving the induction regimen had a larger first-phase decrease in HCV RNA, but were not more likely to achieve SVR, which the researchers attributed to a higher rate of dose modification in the higher-dose arm. Sustained responders and relapsers showed improved liver histology, but not those who failed to suppress the virus. The researchers concluded that, “Daily dosing of [consensus interferon] plus ribavirin may be a promising concept for selected nonresponder patients before considering therapies which are antiviral but not curative.”

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New HCV Assays
As Pawlotsky noted in his Hepatology review, new assays can contribute to improved management of hepatitis C, since advances in the measurement of HCV in the body can help assess the need for and benefits of treatment. In the January 2006 Journal of Hepatology, Martina Gerotto and colleagues reported that 26 of 208 hepatitis C patients (13%) who had repeated undetectable HCV viral load tests at the end of pegylated interferon/ribavirin treatment using common polymerase chain reaction (PCR) technology still showed evidence of residual detectable HCV RNA using a more sensitive transcription-mediated amplification (TMA) assay. Among the TMA-positive subjects, 96% were classified as relapsers using PCR tests, compared with just 14% who relapsed among the TMA-negative patients. These data suggest that patients who appear to be “relapsers” using the traditional PCR method actually may never have achieved complete virological suppression at all, as determined by the more sensitive TMA test.

Looking at another measure of HCV replication, Nobukazu Yuki and colleagues analyzed the presence of negative-strand and positive-strand HCV RNA (genetic material); negative-strand RNA is the most direct indicator of active viral replication. The researchers utilized rTth-based strand-specific real-time PCR technology to measure negative-strand and positive-strand HCV RNA in the livers of 48 patients with chronic hepatitis C. As reported in the February 2006 Journal of Hepatology, they found that the ratio of negative to positive strands varied by 2 logs, and was directly related to HCV replication as assessed by negative strands in the liver. However, the ratio was not related to positive strands in the liver or circulating plasma HCV RNA. Among 27 patients treated with interferon-based therapy, a reduction in the amount of negative-strand RNA in the liver was the only independent factor predicting SVR. The researchers concluded that “[n]egative-strand quantitation is uniform in the liver and bears distinct relevance to the disease.”

Finally, in the January 2006 Journal of Viral Hepatitis, M. Moreno and colleagues reported on the long-term evolution of serum and liver viral markers in 176 treated hepatitis C patients (132 with SVR and 44 nonresponders). Serum HCV core antigen (HCVcAg) was detected in 4% of both sustained responders and nonresponders. All participants who had measurable serum HCV RNA (i.e., nonresponders) also had detectable HCV RNA in their livers, but so did about 4% of sustained responders with no measurable HCV genetic material in their blood. The researchers found a good correlation between serum HCVcAg and HCV RNA levels. Looking at specific anti-HCV antibodies in 45 patients using a commercial line immunoblot assay, they found a decrease in the number who showed reactivity to bands E2 and NS4 when comparing sustained responders of five or more years to patients with a shorter duration of sustained response. Taken together, these studies help expand and refine the menu of testing options available to assist patients and health-care providers in managing hepatitis C.


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