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EASL 2013: Triple-Drug HCV Therapy Comes with High Risk of Serious Adverse Events for Cirrhotics

Currently available triple therapies for hepatitis C using HCV protease inhibitors carry a high risk of serious side effects for patients in the most urgent need of treatment, and these individuals have only a moderate chance of being cured, according to findings from studies of telaprevir and boceprevir treatment in cirrhotic patients at liver centers in France and Austria reported last week at the 48th International Liver Congress in Amsterdam. In the Austrian study almost 1 in 10 cirrhotic patients were hospitalized with sepsis during triple therapy.

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Due to the high risk of progression from compensated to decompensated cirrhosis, people with hepatitis C and cirrhosis have a more urgent need for treatment. However, clinical trials of currently approved HCV protease inhibitors provided limited information about the effects of these drugs in people with cirrhosis.

The HCV protease inhibitors telaprevir (Incivek or Incivo) and boceprevir (Victrelis) were made available through an early access program in France prior to licensing in 2011, for people who could not obtain access to the drugs in Phase 3 clinical trials.

The Compassionate Use of Protease Inhibitors in Cirrhotics (CUPIC) cohort study was the first to collect data on the use of protease inhibitors in triple therapy with pegylated interferon and ribavirin for people with cirrhosis who had failed to respond to interferon-based therapy alone.

Previous results from the cohort were presented at the 2012 EASL International Liver Congress and at the 2012 AASLD Liver Meeting. (Read more about the background to this study by following the links.) The study showed a high rate of serious side effects. Investigators concluded that patients with cirrhosis required careful monitoring.

The findings presented at this year's International Liver Congress provide an update on the outcomes of 221 patients who have been followed for at least 60 weeks after starting treatment.

The study population comprised patients with compensated cirrhosis, all of who were infected with HCV genotype 1. Participants received triple-drug HCV therapy incorporating one of the approved protease inhibitors, boceprevir or telaprevir.

The regimen for the boceprevir-treated patients consisted of a 4-week lead-in phase of pegylated interferon and ribavirin, after which boceprevir was added. Treatment lasted for a further 44 weeks.

Telaprevir-based therapy was provided according to the following protocol: Phase 1 (12 weeks): telaprevir with pegylated interferon alfa-2a (Pegasys) and ribavirin; Phase 2 (36 weeks): pegylated interferon and ribavirin alone.

All patients had been treated previously. Approximately 40% in each group had achieved a prior partial response to treatment, and around 45% had experienced virological relapse. There were 5% in the boceprevir group and 10% in the telaprevir group who were prior null responders.

Interim analysis of outcomes in these 221 patients showed that 41% of individuals treated with boceprevir and 40% of those receiving telaprevir had a sustained virological response 12 weeks after completing therapy (SVR12).

SVR rates differed according to the outcome of earlier HCV therapy. They were highest for patients who had previously relapsed (boceprevir 51%; telaprevir 53%), followed by individuals with a partial response (boceprevir 40%; telaprevir 32%) and null responders (boceprevir 11%; telaprevir 29%). Multivariate analysis showed that prior relapsers were twice as likely to achieve SVR12 when compared to partial or null responders (odds ratio 2.03).

Cure rates were significantly better in HCV genotype 1b infection (boceprevir 51%; telaprevir 46%) than in genotype 1a infection (boceprevir 31%; telaprevir 34%). Again, multivariate analysis showed that patients with genotype 1b were almost twice as likely to achieve SVR12 (odds ratio 1.92).

Serious adverse events were observed in 51% of patients treated with boceprevir and 54% of individuals receiving telaprevir. Discontinuation rates due to adverse events were somewhat higher in patients treated with telaprevir (boceprevir 11%; telaprevir 21%). 5% of patients receiving telaprevir developed grade 3 (serious) rash and 2 patients suffered severe cutaneous adverse reaction (SCAR), a potentially life-threatening form of rash which produces systemic symptoms. Severe rash also occurred in 1% of boceprevir recipients.

There was a 1.6% mortality rate among the boceprevir-treated patients and 3% of individuals receiving telaprevir also died. Causes of death were not reported. The incidence of infections was 4.2% for boceprevir and 7% for telaprevir. Liver decompensation was diagnosed in 4.7% of boceprevir-treated patients and 5% of individuals treated with telaprevir. Anemia requiring blood transfusions or erythropoietin (EPO) were reported in 13.7% of boceprevir patients and 18% of those receiving telaprevir.

Outcomes were broadly similar to those observed among the sub-group of patients with advanced fibrosis or cirrhosis enrolled in the Phase 3 studies that led to the approval of these protease inhibitors. However, the rate of serious adverse events in this "real world" cohort was higher.

High Rate of Sepsis in Cirrhotic Patients

Further findings on the use of telaprevir and boceprevir in cirrhotic patients were reported from an Austrian cohort. Karoline Rutter of the Division of Gastroenterology and Hepatology at the Medical University of Vienna presented data on the safety and efficacy of triple therapy with boceprevir or telaprevir plus pegylated interferon and ribavirin in 191 patients. Of these patients, 131 had stage F3 (moderate; n=37) or F4 cirrhosis (cirrhosis; n=94). A total of 66 patients with F3-F4 fibrosis/cirrhosis received boceprevir and 65 received telaprevir.

Of the 131 patients, 37 achieved a sustained virological response (SVR). The SVR rate among patients with F4 cirrhosis was 28%, compared to 47% in F3 patients and 65% in patients with F0-F2 (absent to mild) fibrosis. There were 24 cases of post-treatment virological relapse among this group.

Another 30 patients are still on treatment or have not completed 12 weeks of post-treatment follow-up. 27 patients discontinued therapy due to adverse events, of whom 6 nevertheless achieved a sustained virological response.

Serious adverse events were observed in over one-fifth of patients (27%). These included 18 serious infections that required hospitalization, 7 of which were cases of sepsis. All cases of sepsis occurred in people with cirrhosis. Among those patients hospitalized for severe infections, 3 patients died of sepsis.

A platelet count below 90,000 g/L was associated with a significantly greater incidence of serious infections (24% vs 14%). There was also a higher frequency of infections among patients with serum albumin below 35 g/dL (60% vs 12%). Pulmonary hypertension (a baseline hepatovenous pressure gradient [HVPG] above 10 mmHg) was also predictive of severe infections.

There were also 6 cases of severe rash, 1 heart attack and 1 case of psychosis. Therapy was discontinued by 21% of patients with F3 or F4 fibrosis/cirrhosis due to a serious adverse event.

The investigators conclude that triple-drug therapy incorporating the currently licensed protease inhibitors for patients with advanced liver disease is "feasible" but is associated with poor outcomes, high rates of severe adverse events, and in some case, death due to sepsis. "These patients may benefit from antibiotic prophylaxis on triple therapy," Rutter suggested.

4/30/13

References

H Fontaine, C Hezode, C Dorival, et al. SVR12 rates and safety of triple therapy including telaprevir or boceprevir in 221 cirrhotic non responders treated in the French Early Access Program (ANRS CO20-CUPIC). 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam, April 24-28, 2013. Abstract 60.

K Rutter, A Ferlitsch, A Maieron, et al. Safety of triple therapy with telaprevir or boceprevir in hepatitis C patients with advanced liver disease – predictive factors for sepsis. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam, April 24-28, 2013. Abstract 65.