AASLD 2006 - Clinical Advances in Hepatitis C

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http://www.medscape.com/viewarticle/548122

The Liver Meeting: 57th Annual Meeting of the American Association for the

Study of Liver Diseases | AASLD 2006: Viral Hepatitis

AASLD 2006 - Clinical Advances in Hepatitis B and Hepatitis C CME

Disclosures

Tram T. Tran, MD

Hepatitis C

Pegylated Interferon

The mainstay of treatment for patients with hepatitis C has been combination

therapy with pegylated interferon and ribavirin, which overall yields

sustained response rates in approximately 50% of patients treated. Few

options are available for those patients who do not respond to therapy, are

unable to tolerate the side effects of the interferon or ribavirin, or who

relapse after discontinuation of the medications.

More information has been accumulated in the past several years on early

predictors of nonresponse to therapy, whereby the lack of at least a 2-log

drop in the baseline viral load at week 12 was able to identify those

patients who had little chance of responding to therapy (early viral

response [EVR] rule). Clinicians, using this EVR rule, were able to

discontinue therapy in patients earlier, sparing them significant side

effects and associated costs. More recently, a positive 4-week hepatitis C

virus (HCV) RNA level has been shown to be predictive of higher rates of

relapse post therapy, and the use of this so-called rapid viral response

(RVR) is now gaining clinical applicability.

Shiffman and colleagues[14] reported results from the ACCELERATE trial

involving 1463 patients infected with HCV genotype 2 or 3 who were treated

with pegylated interferon alfa-2a plus ribavirin for either 16* or 24 weeks.

Currently, the standard of care is treatment for 24 weeks for patients with

HCV genotype 2 or 3. Results showed that, overall, patients who received 24

weeks of therapy had a 90% sustained virologic response (SVR) rate compared

with 82% of patients treated for 16 weeks. RVR and EVR rule were both highly

predictive of achieving SVR. Thus, RVR (HCV RNA undetectable at week 4 by

polymerase chain reaction [PCR]) and EVR are both highly predictive of

response to therapy in patients infected with HCV genotypes 2/3. Decreasing

duration of therapy to 16 weeks may be reasonable in patients who achieve an

RVR and have significant difficulty or side effects with treatment.

Pearlman and colleagues[15] examined the effect of longer duration of

therapy using pegylated interferon alfa-2b plus weight-based ribavirin

dosing in patients infected with HCV genotype 1 who, despite meeting the

criteria for EVR (> 2-log drop in baseline HCV RNA by PCR), were still HCV

RNA PCR detectable until week 24 of therapy. This group of " slower viral

responders " was then treated for either the usual 48 weeks or was extended

to 72 weeks* of therapy. Results showed a 39% SVR in the 72-week arm

compared with 18% SVR in the 48-week arm; treatment extension did not seem

to result in an increase in dose reductions or discontinuations. Thus,

treatment of hepatitis C has now evolved to a more individualized regimen,

using weight-based dosing of ribavirin and an adjusted duration of therapy,

depending on how rapidly patients respond to therapy. Longer duration of

therapy may improve sustained response rates in patients with slower viral

suppression.

Agents on the Horizon

Although great advances have been made with interferon and ribavirin-based

therapy, the most exciting new development on the horizon for hepatitis C is

the use of therapies that specifically target steps in the cycle of

hepatitis C replication as opposed to general immunomodulators or

antivirals. VX-950* is an oral HCV protease inhibitor that has been shown to

dramatically reduce HCV viral loads to undetectable levels within 2-4 weeks

in phase 2 trials.[16] However, some viral variants emerged with this

therapy. During this year's AASLD meeting, Kieffer and colleagues[17]

reported a detailed analysis of these variants; data were presented on 16

patients treated with VX-950 750 mg 3 times daily (n = 8) vs VX-950 750 mg 3

times daily plus pegylated interferon (n = 8) for 14 days. HCV RNA was

isolated after the treatment period for variants in the NS3 protease domain.

Six of 8 patients treated with VX-950 monotherapy had detectable mutations

by the end of the 14 days, whereas 4 of 8 of patients receiving combination

pegylated interferon plus VX-950 also had detectable virus (resistant or

wild-type) at day 8. After the 14 days of therapy, 15 of 16 patients were

treated with the standard pegylated interferon plus ribavirin and all

responded with complete viral suppression by week 24. This suggests that

although there may be some viral resistance due to mutations with the use of

the protease inhibitor, viral suppression occurs successfully with the

addition of pegylated interferon and ribavirin.

In a late-breaking abstract presented by and colleagues,[18] another

target-specific HCV therapy, R1626*, a nucleoside analog oral polymerase

inhibitor, was administered in a phase 1b trial involving 47 treatment-naive

patients infected with HCV genotype 1. Patients were given R1626 at doses of

500, 1500, 3000, and 4500 mg twice daily vs placebo for 14 days. The authors

found that a dose-dependent viral suppression occurred, with 5 of 9 patients

in the 4500-mg treatment arm having undetectable HCV RNA at day 15. Anemia

occurred in some patients; headache and gastrointestinal side effects were

noted at the highest dose.

New therapies targeting specific sites in the HCV replication cycle, such as

these protease or polymerase inhibitors, show early promise, although viral

resistance and side effects need further study in larger, phase 2 trials.

Consensus Interferon

One of the most difficult clinical issues in liver transplantation is the

recurrence of hepatitis C after transplantation. Recurrence is nearly

universal, and studies have shown a more aggressive course of HCV

progression after transplant, with up to 20% of patients developing

cirrhosis by 5 years.[19] Treating the cirrhotic patient before liver

transplant may reduce the likelihood of recurrence; however, treatment is

limited by constitutional side effects, anemia, thrombocytopenia, and

neutropenia in this patient population.

Bacon and colleagues[20] presented their results from the DIRECT (Daily-dose

consensus Interferon and Ribavirin Efficacy of Combined Therapy) trial using

consensus interferon* plus ribavirin in patients who previously failed to

respond to pegylated interferon + ribavirin therapy. Of note, 29% of

patients in this study were cirrhotic by liver biopsy and more than 50% had

bridging fibrosis. Patients received consensus interferon at a dose of 9

micrograms (mcg)/day or 15 mcg/day in combination with ribavirin vs no

treatment. Preliminary analysis at the end of treatment revealed a 29%

end-of-treatment response in patients with greater than 80% compliance with

the 15-mcg/day consensus interferon + ribavirin regimen. The lower dose of

consensus interferon demonstrated lower response rates (15%), and patients

with cirrhosis had very low response rates (< 8%). The most common side

effects were neutropenia and fatigue, with an overall 10% to 17%

discontinuation rate.

Consensus interferon has demonstrated some moderate success in the very

difficult-to-treat group of patients who have nonresponse to combination

pegylated interferon plus ribavirin. Early treatment of HCV infection offers

more benefit, as the more advanced the histologic disease, the lower the

chance of success with any therapy thus far.

Conclusion

Exciting new advances were presented in viral hepatitis at this year's AASLD

meeting. Our therapeutic armamentarium for hepatitis B now includes several

oral antiviral therapies, as well as immunomodulatory agents. The major

issues of viral resistance and predictors of response and resistance are now

under active study.

Hepatitis C is entering a new era of drug development with specifically

targeted therapies, although these strategies remain very early in clinical

development. Again, issues of safety and viral resistance will come to the

forefront in this arena. Individualized therapy with the current standard of

care, pegylated interferon plus ribavirin, is key to optimizing patient

outcomes.

*The US Food and Drug Administration has not approved this medication for

this use.

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