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AASLD 2012: When Are HCV Direct-Acting Antivirals Needed, Who Should Be Prioritized?


When resources for hepatitis C treatment with new direct-acting antivirals are limited, findings from the U.S. suggest that previously untreated people with low HCV viral loads may stand a good chance of achieving sustained virological response without adding telaprevir or boceprevir to pegylated interferon and ribavirin, researchers reported at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) this month in Boston. A related study suggests that younger hepatitis C patients with advanced liver disease should be prioritized for treatment with the new drugs.

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Is a Third Drug Necessary for People with Low Viral Load?

Presenter Brian Pearlman from Atlanta Medical Center told the conference that people with hepatitis C genotype 1 and low HCV viral load represent about 20% of all genotype 1 infections. The current standard-of-care for people with genotype 1 is pegylated interferon plus ribavirin plus an oral HCV protease inhibitor, either boceprevir (Victrelis) or telaprevir (Incivek). An abbreviated 24-week course of treatment is recommended for those who achieve a rapid virological response at 4 weeks (RVR), which is observed in up to half of patients with low viral load.

However, no prospective trial has yet evaluated whether including a protease inhibitor results in superior virological outcomes in people with low viral loads. An abbreviated treatment course that does not include a direct-acting antiviral may prove to be better tolerated, but may be less effective in achieving sustained virological response, or a cure. It is also unclear if African-American patients can benefit from this same treatment abbreviation strategy, mainly due to their lower frequency of the IL28B CC host genotype that predicts interferon response.

This study recruited treatment-naive people with viral loads less than 600,000 IU/mL at 2 Atlanta clinics. Participants received 4 weeks of pegylated interferon alfa-2b (PegIntron; 1.5 mcg/kg/week) plus weight-based ribavirin (1000-1200 mg/day).

If they achieved rapid virological response at week 4, they were randomized 1:1 to receive either 24 additional weeks of pegylated interferon plus ribavirin plus boceprevir (800 mg 3 times daily) (28 weeks total therapy) or a further 20 weeks of pegylated interferon plus ribavirin alone (24 weeks total therapy).

Of the 198 patients reported who started treatment, 49% (n = 101) achieved HCV RNA undetectability at 4 weeks and were randomized to either add boceprevir (n = 49) or not (n = 52).

Patients were stratified by IL28B host genotype. The primary endpoint was sustained virological response, or undetectable HCV RNA, at 12 weeks post-treatment (SVR12).

There were no significant differences in baseline characteristics between the treatment groups. Participants were in their mid-50s and had a high BMI. Almost two-thirds were men, one-third had difficult-to-treat HCV genotype 1a, and two-thirds had the favorable IL28B CC host genotype. Approximately 20% had advanced liver disease (stage F3/F4 fibrosis/cirrhosis) and one-third were African-American.

Overall, SVR12 rates did not differ significantly between the triple therapy and pegylated interferon/ribavirin arms (90% vs 89%), and nor did relapse rates (4% vs 6%). When stratified by IL28B host genotype, SVR12 rates were similar by treatment allocation (96% in both CC groups; 77% in both non-CC groups). There was no significant difference in treatment outcomes for the African-American subset of the trial population (82% vs 84%).

People with hepatitis C genotype 1b achieved higher SVR rates than people with genotype 1a in both arms (triple therapy: 93% vs 84%; pegylated interferon/ribavirin: 93% vs 85%). Dose reductions (33% in both arms) and discontinuations were similar between arms.

This prospective, randomized trial shows that for genotype 1 patients with low viral load (below 600,000 IU/mL) who achieve a rapid response with pegylated interferon plus ribavirin, the addition of boceprevir does not result in a higher success rate, irrespective of IL28B genotype, viral subtype, or African-American ethnicity.

Since people with low viral load who achieve RVR at 4 weeks comprise approximately 10% of all genotype 1 infections, this treatment strategy of not adding a protease inhibitor could mean substantial cost savings. Pearlman said that the Atlanta group planned to evaluate the impact of raising the "low viral load" threshold to 800,000 to see if they can repeat these results in more people.

The present study is ongoing, and results will need to be duplicated in larger multicenter trials before this strategy can be considered for wider adoption.

Which Patients Should Be Prioritized for New Hepatitis C Treatments?

Younger patients with advanced liver disease caused by hepatitis C should be prioritized for treatment with newly licensed direct-acting antivirals to achieve the biggest reductions in ill health and hospitalization, according to a modeling exercise presented by University of Pittsburgh researchers.

According to Jagpreet Chhatwal, many patients who had deferred antiviral treatment for chronic hepatitis C with pegylated interferon plus ribavirin started to request treatment when boceprevir and telaprevir, the first oral direct-acting antiviral agents, were approved and marketed a little over a year ago.

This increase in the number of people willing to be treated resulted in waiting lists because of a limit on the number of people who could initiate treatment each week at a given clinic. Such waiting lists can be expected again in the future when next-generation direct-acting antivirals are approved.

Current guidelines recommend therapy for all hepatitis C patients with compensated advanced liver disease (stages F3 and F4), and the European Association for the Study of the Liver (EASL) says that therapy should be strongly considered for patients with moderate liver fibrosis (stage F2). The American Association for the Study of Liver Diseases says that it will address the question of which patients should be prioritized for treatment in a 2013 revision of its hepatitis C treatment guidelines.

Chhatwal’s study goal aimed to develop an algorithm for prioritizing patients for treatment on the basis of clinical need, using an assessment of quality-adjusted life-years (QALYs) gained for different categories of patient according to whether treatment was started immediately or deferred for 1 year.

The model projected the number of years of good health that could be expected per 1000 patients as a result of delaying or preventing decompensated cirrhosis, hepatocellular carcinoma, liver transplant, and liver-related death.

The model used efficacy data from the registration trials of boceprevir and telaprevir -- the SPRINT-2, RESPOND-2, ADVANCE, and REALIZE studies -- and estimated progression rates of hepatitis C disease from previously published studies, to simulate the effects of these 2 treatment strategies.

The researchers evaluated the impact of waiting for treatment according to fibrosis stage, previous treatment response, IL28B polymorphism, age, and sex. People who need treatment most urgently will be those with the most advanced Metavir score, which measures the degree of liver damage.

For a 50-year-old patient with cirrhosis, the projected gain in QALYs due to immediate access to treatment when compared to receiving treatment after 1 year was 0.54 (treatment-naive), 0.71 (previous relapser), 0.51 (previous partial responder), and 0.27 (previous null responder). The corresponding reductions in the incidence of decompensated cirrhosis, hepatocellular carcinoma, liver transplant, and liver-related death per 1000 patients were between 10-24, 12-31, 2-5, and 17-44 cases per thousand people, respectively.

The gain in QALYs due to immediate treatment of cirrhotic patients based on IL28B genotype were between 0.52 and 0.76, highest for people with the CC gene pattern who respond best to interferon-based treatment.

For people with a Metavir score of F4, indicating cirrhosis, the loss in QALYs due to waiting 1 year was 28 weeks. The gain in QALYs due to immediate treatment for patients with F0-F3 fibrosis was significantly lower (0.04-0.07 QALYs). The loss in QALYs would be very low for people with absent to moderate fibrosis: 4 weeks for people with an F3 score, and 3 weeks for those with scores of F0 to F2.

All other factors being equal, the gain in QALYs for younger patients was higher than that for older patients, Chhatwal said.

Among previously treated patients, prioritization of previous relapsers over previous partial responders and previous null responders would achieve greater gains in QALYs, owing to the higher likelihood of sustained virological response in these patients.

The researchers recommended prioritization order (from highest to lowest) based on patient characteristics is:

·      (1) Cirrhosis

o   (a) younger age

o   (b) prior relapser

o   (c) treatment-naive or previous partial responder

o   (d) IL28B CC host genotype

o   (e) others

·      (2) Metavir score F3

o   (a) younger age

o   (b) others

·      (3) Metavir score F0-F2.

The researchers said that their modeling exercise provides a needs-based patient prioritization score that they call "clinically intuitive," which will "maximize the value of [direct-acting antivirals] to society."



B Pearlman and C Ehlebenet. Hepatitis C virus (HCV) genotype 1 (G1) infection with low viral load (LVL) and rapid virologic response (RVR) to peginterferon and ribavirin (PEG/RBV) can be treated without a protease inhibitor (PI), irrespective of IL-28B status or patient ethnicity. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 151.

J Chhatwal, MA Dunn, MS Roberts, and KB Chopra. Prioritization of Hepatitis C Patients For Treatment with Direct Acting Antiviral Agents. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 152.