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New Direct-acting Antiviral Agents in the Treatment of Hepatitis C Genotype 1 Infection

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PHYSICIAN PERSPECTIVE - Viewpoint based on presentations from the 49th Annual Meeting of the European Association for the Study of the Liver (EASL)

London, UK / April 9-13, 2014

Guest Editor:

Jordan J. Feld, MD, MPH
Toronto Centre for Liver Disease
Toronto Western Hospital
Francis Family Liver Clinic
University Health Network
McLauglin-Rotman Centre for Global Health
Toronto, Canada 

Introduction 

Twenty-five years since the discovery of the hepatitis C virus (HCV), the start of a new era in the treatment of HCV infection was officially unveiled at this year’s EASL/ILC congress. With the development of new direct-acting antiviral agents (DAAs) and orally-administered interferon-free regimens of only 12 weeks’ duration, hepatitis C has become the first chronic viral infection that can be cured on a significant scale. Data were presented from large international Phase 3 trials of new dual- or triple-fixed dose combination anti-HCV regimens that showed sustained virologic response (SVR) (cure) rates of over 90% in patients with HCV genotype 1 infection, the predominant genotype in North America and Europe. This was also demonstrated in traditionally hard-to-treat patients, such as transplant recipients and those with cirrhosis. Few relapses were recorded and rates of treatment discontinuation were low, reflecting good safety and tolerability profiles.

 

“This week is making history, because hepatitis C is now curable in almost everyone,” declared congress Honorary President, Prof. Giorgina Mieli-Vergani (King’s College Hospital, London, UK), chair of the opening session. “We now have the tools to eliminate this virus; we have reached the end of the development road for hepatitis C,” asserted Prof. Graham R. Foster, Queen Mary University of London, UK. In Canada, like Western Europe, the goal should be to eliminate hepatitis C and optimistically, this is doable within a decade. More than 300,000 people in Canada are living with chronic hepatitis C, but less than half are aware of it. HCV infection, which can lead to liver cirrhosis, liver failure, and hepatocellular carcinoma, causes more lost years of life and illness than any other infectious disease in Canada.

Interferon-Free Combinations

The first-generation direct-acting antiviral agents (DAA), telaprevir and boceprevir, which became available in 2011, are administered with peginterferon and ribavirin. They are associated with sustained virologic response (SVR) rates of 67-75% among previously untreated patients (Jacobson IM et al. N Engl J Med 2011;364:2405-16; Poordad F et al. N Engl J Med 2011;364:1195-206) and 29-38% in patients with a prior null response to peginterferon and ribavirin treatment (Zeuzem S et al. N Engl J Med 2011;364:2417-28; Vierling JM et al. J Hepatol 2014;60:748-56). These first regimens were interferon-based and had significant additional side effects, resulting in treatment-limiting toxicity. Late in 2013, two new DAAs were approved in Canada and elsewhere—sofosbuvir, an NS5B nucleotide polymerase inhibitor and simeprevir, a protease inhibitor—but each is currently indicated in combination with peginterferon and ribavirin in patients with HCV genotype 1 infection.

At EASL, Phase 3 data were presented for two new orally-administered non-interferon DAA regimens that have been submitted for regulatory review worldwide. One, referred to here as “3D”, consists of co-formulated ABT-450, an NS3/4A protease inhibitor, co-dosed with ritonavir as a booster, ombitasvir (ABT-267), an NS5A inhibitor (150 mg/100 mg/25 mg daily), and dasabuvir (ABT-333), a non-nucleoside HCV NS5B inhibitor (250 mg twice daily) with ribavirin (1000-1200 mg daily). In total, this leads to 3 pills taken in the morning and taken at night along with ribavirin. The other regimen is a fixed-dose combination of an NS5A inhibitor, ledipasvir (90 mg), with sofosbuvir (400 mg), in a single pill taken once daily with/without ribavirin twice daily.

Treatment-Naïve Patients

The results of SAPPHIRE-I, a large Phase 3 international, randomized placebo-controlled trial with an all-oral, interferon-free regimen in previously untreated adults with HCV genotype 1 infection showed the 3D regimen to be a potent and efficacious therapy with very good tolerability. Among the 473/631 patients randomized to receive the 3D regimen, 96% achieved SVR12 (Abstract 060; Feld JJ et al. N Engl J Med 2014;370:1594-603). SVR12 rates were high regardless of HCV genotype subtype (1a vs. 1b) (Figure 1) and >90% in all subgroups including those previously associated with low response rates. There was no difference in response by gender, race, BMI, fibrosis stage, baseline HCV RNA level, and ribavirin dose modification.

 

Figure 1. 

The rate of virologic failure was very low with only one on treatment breakthrough (0.2%) and 7 relapses (1.5%) after completion of therapy. All of these patients developed at least one amino acid variant known to confer resistance to at least one, and likely all of the DAAs in the regimen. Patients will be followed to see whether these variants persist or return to baseline levels. All adverse events (AEs) were mild in the active treatment and placebo groups and overall ribavirin was well tolerated in the absence of interferon. Although the rate of reported AEs was higher in the active treatment group, 73% of the patients on placebo complained of ≥1 adverse event. This is important because it tells us that a lot of the AEs are probably not treatment-related.

Also presented here, a trial investigating ledipasvir-sofosbuvir in 865 treatment-naïve HCV genotype 1 patients, ION-1, concluded that there was no additional benefit gained from adding ribavirin or extending treatment from 12 to 24 weeks (Abstract O164; Afdhal N et al. N Engl J Med Published online April 12, 2014). Dr. Alessandra Mangia, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy, reported SVR rates of 99% and 97% with or without ribavirin after 12 weeks and 98% and 99%, respectively, after 24 weeks of treatment. There was no statistical difference between SVRs among prespecified subgroups. Sixteen patients did not achieve SVR; 3 had virologic failure (all relapses), but no clinical factors were identified as predictors for relapse. AEs and laboratory abnormalities were mainly associated with ribavirin, but treatment discontinuation rates were higher in the groups treated for 24 weeks, Dr. Mangia reported.

To investigate a shorter treatment duration, the ION-3 trial enrolled 647 noncirrhotic patients to ledipasvir-sofosbuvir for 8 or 12 weeks, with or without ribavirin (Abstract 066; Kowdley KV et al. N Engl J Med Published online April 11, 2014). Dr. Kris Kowdley, Virginia Mason Medical Center, University of Washington, Seattle, also reported no difference in efficacy between 8 and 12 weeks of treatment (SVR 93%/94% with/without ribavirin after 8 weeks vs 95% after 12 weeks without ribavirin). Relapse was more common with 8 than 12 weeks of treatment (5% vs 1%). “Whether a third antiviral agent may be appropriate or between 6 and 8 weeks of therapy would be possible remains to be explored,” Dr. Kowdley acknowledged. “Based on the results of the ELECTRON study, we know that 6 weeks of therapy is not optimal with this regimen,” he noted (Gane EJ et al. Gastroenterology 2014;146:736-43).

HCV Genotype 1b Patients

“Very clear-cut” data demonstrating the safety and efficacy of the 3D regimen in patients with HCV genotype 1b, the most prevalent HCV genotype worldwide, were presented by Prof. Peter Ferenci, Medical University of Vienna, Austria. In the double-blind, placebo-controlled PEARL-III study, 419 treatment-naïve patients were randomized to treatment with or without ribavirin (Abstract P1299). Following 12 weeks of treatment, 99% of each treatment group achieved SVR. “The take-home message is that in these noncirrhotic HCV genotype 1b patients there is no need to give ribavirin,” Prof. Ferenci said. High response rates were observed across all patients in the study, including patient populations with characteristics (male gender, black race, and the non-CC IL28B genotype) historically associated with having a decreased response to treatment. No patient discontinued study drug due to AEs and none of the patients receiving the regimen without ribavirin had virologic relapse or treatment breakthrough.

Treatment-Experienced Patients

Patients (n=440) who previously failed peginterferon-based therapy with or without a protease inhibitor were studied in the open-label ION-2 trial of treatment with ledipasvir-sofosbuvir with or without ribavirin given for 12 or 24 weeks (Abstract 0109; Afdhal N et al. N Engl J Med 2014;370:1483-93). SVR12 was similar in all groups (94-99%), suggesting that adding ribavirin and/or extending treatment duration did not significantly increase SVR rates, reported Dr. Nezam Afdhal, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston. In prior null responders with cirrhosis, there was a trend toward benefit of extending treatment to 24 weeks, but the numbers were limited. Notably, this trial included patients who had previously failed a regimen with a first-generation protease inhibitor (telaprevir/boceprevir). The response rates were similar whether patients were previously treated with peginterferon and ribavirin alone or with a protease inhibitor. There is no overlap in resistance profiles between sofosbuvir and protease inhibitors, allowing this to be used as salvage therapy.

SAPPHIRE-II, a large Phase 3 international randomized, placebo-controlled trial of an interferon-free regimen in patients who had previously failed peginterferon-based treatment, showed high SVR12 rates similar to those seen in SAPPHIRE-I, reported Prof. Stefan Zeuzem, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany. SAPPHIRE-II involved 394 patients: 79% prior relapsers, 22% prior partial responders, and 49% prior null responders (Abstract O1; Zeuzem S et al. N Engl J Med 2014;370:1604-14). SVR12 rates were 96% overall, similar for HCV genotypes 1a and 1b, and in patients with prior relapse, null or partial response – “astonishing results,” Prof. Zeuzem declared (Figure 2). No patients had virologic breakthrough over the 12 weeks of therapy. Seven relapses, the majority in patients with prior null response to peginterferon-ribavirin, occurred between weeks 2 and 8 after completing treatment. Pruritus, the most common AE, was significantly more frequent with active treatment. Rates of discontinuation due to AEs were low (1%) and among the serious adverse events (SAE) (2.0%), only 1 was considered possibly related to 3D treatment. “In our experience it is a perfectly tolerable therapy,” Prof. Zeuzem confirmed.

 

Figure 2.  

Difficult-to-Treat Populations

Dr. Ed Gane from New Zealand presented data from the ELECTRON 2 study, which evaluated the sofosbuvir/ledipasvir fixed-dose combination in small groups of difficult-to-cure patients. The first arm of the study included patients who had relapsed after a previous sofosbuvir-containing treament. All 19 patients achieved SVR with 12 weeks of the combination therapy with ribavirin. Although this was a small study, it clearly demonstrated that the barrier to resistance of sofosbuvir is extremely high, with failure only occurring due to relapse and with no emergence of clinically significant resistance. The ability to be able to retreat the small number of patients who do not respond is very important. The trial also included 20 patients wtih Child-Pugh class B cirrhosis who received treatment with the fixed-dose combination for 12 weeks. Although only 13 (65%) achieved SVR, this was an important demonstration of the safety and potential efficacy of this regimen in patients with very advanced liver disease. The patients experienced clinical improvement and will be followed to determine if treatment prevents or reduces the risk of long-term complications, particularly the need for liver transplantation.

In TURQUOISE-II, the first dedicated trial of an all-oral, interferon-free regimen in patients with compensated cirrhosis, the efficacy and safety of the 3D regimen was similar to noncirrhotic patients (Abstract 0163; Poordad F et al. N Engl J Med Published online April 12, 2014). The randomized, open-label study involved 380 treatment-naïve and treatment-experienced patients with cirrhosis, making it the largest trial ever performed in an entirely cirrhotic population of patients with HCV. The study included patients often considered ineligible for clinical trials, such as those with significant thrombocytopenia, hypoalbuminemia and even radiographic ascites. Following 12 or 24 weeks of 3D treatment plus ribavirin, 92% and 96% of patients, respectively, achieved SVR, “a stunning response rate,” declared Dr. Fred Poordad, Texas Liver Institute-University of Texas Health Science Center, San Antonio (Figure 3).

 

Figure 3.

The regimen was well tolerated in both treatment arms, with low rates of SAEs and treatment discontinuations. Breakthrough was only seen in 1 patient but 12 relapsed in the 12-week arm, bringing the total virologic failure rate to 6% compared to 2% in the 24-week arm, “perhaps indicating that some of these patients would benefit from extending therapy,” Dr. Poordad suggested. The only specific group who seemed to fare better with longer therapy were those patients with genotype 1a infection and a prior null response to peginterferon and ribavirin.

An ongoing Phase 2 study in liver transplant recipients with recurrent HCV genotype 1a or 1b is showing high response rates to treatment with the 3D plus ribavirin regimen given over 24 weeks, Dr. Paul Kwo, Indiana University School of Medicine, Indianapolis reported. Among 34 patients, all treatment-naïve post-transplant, 100% achieved rapid virologic response (RVR) and end-of-treatment response (EOTR) and 97% achieved SVR4 and 96% SVR12 (Abstract 0114). The regimen was well tolerated; AEs were generally mild, with only 1 patient discontinuing due to AEs. No deaths, graft losses, or episodes of acute or chronic rejection were recorded and calcineurin inhibitor (tacrolimus or cyclosporine) dosing was manageable over the period of the study. “With these data we may be able to remove liver transplant patients from the special populations, as we appear to have removed HIV in the era of DAAs, and we look forward to further follow-up,” Dr. Kwo declared.

Summary

It is rare that data from a single medical meeting have such remarkable impact. With well-tolerated treatments that can cure almost everyone, including those with advanced liver disease, for the first time there is a realistic prospect to actually eliminate hepatitis C from our country. New drugs are only the first step. To achieve the lofty goal of an HCV-free Canada, we will need to invest in our healthcare infrastructure to screen our populations to identify those who have the infection, train more healthcare professionals to treat the disease and improve access to all of those who are diagnosed. With these tools in place we will be able to deliver real-world results that are as good as the trial data. The timing of these advances is critical. Canada is at the cusp of a huge increase in the rate of liver failure and liver cancer, which will have huge economic and health impact if we do not act quickly. Fortunately, these remarkable new therapies give us the tools we need to start down the road to rid our country of the terrible burden of HCV. 

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