June 6, 2013

Hepatitis C: The Pace of Progress

Medscape Gastroenterology

Digestive Disease Week (DDW) 2013

William F. Balistreri, MD

Jun 06, 2013

Progress in Treating Hepatitis C Infection

Hello. I am Dr. Bill Balistreri, Professor at Cincinnati Children's Hospital. I am here at Digestive Disease Week (DDW) in Orlando, reporting for Medscape.

A major focus of the research and the state-of-the-art summaries presented here at DDW has been the pace of progress in developing new treatment strategies for hepatitis C. Speakers highlighted the fact that the agents and approaches for treatment of hepatitis C virus (HCV) infection are in constant change and may, in fact, be in for an upgrade.

The standard of care for several years consisted of a combination of pegylated interferon and ribavirin. With advanced understanding of the biology of HCV came the identification of specific proteins involved in its replication and the understanding that these proteins can be targeted by protease and polymerase inhibitors.

Last year, the US Food and Drug Administration approved 2 NS3 protease inhibitors -- telaprevir and boceprevir -- for the treatment of HCV genotype 1 in combination with standard therapy. Clinical trials of the 2 agents showed significantly improved sustained virologic response (SVR) rates in treatment-naive patients. Therefore, the American Association for the Study of Liver Diseases guidelines were altered to recommend triple therapy consisting of a protease inhibitor (either telaprevir or boceprevir) plus peginterferon and ribavirin.

Side Effects Still Bothersome

In studies reported here, several investigators[1-4] have found high response rates with either triple-therapy regimen in treatment-naive patients or in previously treated patients who had relapsed. Triple therapy was generally well tolerated. However, troublesome side effects, including rashes, occurred in many patients. Although there was no difference in discontinuation rates between telaprevir and boceprevir, more patients withdrew because of side effects or intolerance than because of nonresponse to the drug.

These studies also underscored the point that patients must be closely followed to reinforce appropriate adherence to the complex algorithmic triple-therapy approach. Protease inhibitors have greatly enhanced SVR rates. However, these inhibitors are active only against the dominant viral genotype type (type 1) found in North America and Europe. Furthermore, 30%-35% of patients with genotype 1 infection will not have sustained viral repression, and there is the potential for resistance. Protease inhibitor-based triple therapy is also limited by the complex dosing regimens, which require intensive monitoring and side-effect management.

Next-in-Line Antivirals: Simeprevir and Sofosbuvir

The good news is that the guidelines may once again be revised. Preliminary results reported here have documented superior efficacy and tolerability of novel therapeutic strategies based on several new antivirals.

The first is simeprevir, a potent, once-daily oral investigational NS3/4A protease inhibitor that was shown to be effective in treatment of genotype 1 infection both in treatment-naive patients and nonresponders when coadministered with standard therapy (peginterferon and ribavirin).[5,6]

The second agent is sofosbuvir, a nucleotide analog that inhibits NS5B-directed HCV replication, which was also shown to be highly effective. This drug in combination with standard therapy was associated with SVR rates of 90% at 12 weeks post-treatment compared with 58% in placebo-treated patients.[7]

Most reported adverse effects were associated with peginterferon and ribavirin and not with new agents. Thus, these drugs represent an advance in management capable of inducing high sustained response rates with a shorter duration of therapy, better tolerability, and no resistance development, but they still require the addition of interferon to the regimen.

Interferon-Free Treatment: Still Searching

There is a high degree of optimism, however. Important observations presented this week may usher in the next generation of interferon-free treatment of HCV infection. Investigators have documented that several treatment protocols, which did not include interferon, were indeed capable of inducing high SVR rates in patients with chronic HCV.

In one study,[8] 3 direct-acting antiviral agents were administered in combination with ribavirin. These were ABT-450 (a potent NS3 protease inhibitor), ABT-330 (a nonnucleoside NS5B polymerase inhibitor), and ABT-267 (an NS5A inhibitor). The treatment regimen achieved high SVR rates in noncirrhotic treatment-naive patients and previous nonresponders, and the drugs were well tolerated. This preliminary study indicated that 12 weeks of therapy with this combination of 3 direct-acting antivirals and ribavirin may be effective for the treatment of HCV genotype 1 infection.

Other potential combinations of direct-acting antivirals were also discussed. In recently published studies,[9] sofosbuvir combined with ribavirin alone was shown to be effective for hepatitis C genotype 2 and 3 and possibly genotype 1. This regimen offers a low incidence of side effects, a relatively short duration of treatment, and was effective against all genotypes. These advantages may lower the threshold for HCV treatment for both patients and physicians.

A Glimpse of Future Treatments

Speakers here also gave us a glimpse of the future. Second-generation protease inhibitors and small-molecule drugs to inhibit other viral enzymes are being evaluated in clinical studies. Drug cocktails that target multiple HCV enzymes simultaneously may ultimately become the standard of treatment. This has certainly been an effective strategy for the management of infection with HIV.

It was also suggested that future strategies will include unique approaches to the treatment of viral hepatitis. One interesting approach is to use RNA interference. Speakers highlighted a recently reported breakthrough -- the use of a microRNA designed to interfere with HCV replication at the intracellular level.[10] An antisense oligonucleotide microRNA binds highly conserved sites in HCV. The liver-expressed microRNA normally serves to protect HCV. By binding to messenger proteins in liver cells, this agent prevents HCV replication and survival and effectively reduces the viral load.

The antisense nucleotide induced a dose-dependent drop in HCV RNA levels, and the biologic effects lasted for weeks, suggesting that agents of this type can be administered infrequently, possibly at monthly intervals. This study offers proof of concept that a new class of RNA interference drugs is possible. Larger studies will determine the safety and effectiveness of this approach.

Barriers to Care Continue

Presentations here allow us to envision a multifaceted treatment scenario, which uses an antisense oligonucleotide perhaps in combination with other therapeutic agents: small interfering RNAs directed against conserved sequences in the viral protease replication complex or polymerase genes. The bottom line is that these exciting advances in antiviral therapy will lead to significant improvements in response rates and reduced adverse effects.

However, only a minority of HCV-infected patients may benefit because of multiple barriers which have been identified and which impede delivery of HCV therapy.

The study presented here reported perceived barriers to care.[11,12] Most surveyed physicians viewed patient-level barriers as highly significant. These include fear of the side effects and concerns about treatment duration and cost. Another barrier is inadequate case finding, an obstacle that could be overcome by widespread screening.

A report from the Centers for Disease Control and Prevention,[13] released last week, contained updated testing guidelines. The report states that many persons who test positive for hepatitis C do not receive the necessary follow-up to determine whether they require medical care. Therefore, enhanced efforts to improve awareness, education, and specialist availability are needed.

The high prevalence of HCV infection worldwide also should stimulate expanded efforts in primary prevention, including vaccine development, as well as aggressive approaches to secondary and tertiary prevention. These efforts will reduce the burden of chronic liver disease and improve survival.

Thank you for listening. This is Bill Balistreri for Medscape.


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