Triple-drug HCV therapy comes with high risk of serious adverse events for people with cirrhosis

Currently available triple therapies for hepatitis C carry a high risk of serious side-effects for people in the most urgent need of treatment, and these patients have only a moderate chance of being cured, according to the findings of studies of telaprevir and boceprevir treatment in people with cirrhosis at liver centres in France and Austria reported last week at the 48th International Liver Congress (EASL 2013) in Amsterdam.

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

The hepatitis C protease inhibitors telaprevir (Incivo) and boceprevir (Victrelis) were made available through an early access programme in France prior to licensing in 2011, for people who could not obtain access to the drugs in phase III 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 for people with cirrhosis who had failed to respond to interferon-based therapy.

Previous results from the cohort were presented at the International Liver Congress in 2012 and at the American Liver Meeting in 2012. (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 people with cirrhosis required careful monitoring.

The findings presented at the 2013 International Liver Congress provide an update on the outcomes of 221 people who have been followed for at least 60 weeks after starting treatment.

The study population comprised people with compensated cirrhosis, all of whom had HCV genotype-1.

Participants received triple-drug HCV therapy incorporating one of the approved protease inhibitors boceprevir(Victrelis) or telaprevir (Incivo).

Telaprevir-based therapy was provided according to the following protocol:

• Phase 1 (12 weeks): telaprevir with pegylated interferon-2a and ribavirin.
• Phase 2 (36 weeks): pegylated interferon and ribavirin.

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

All patients had been treated previously. Approximately 40% in each group had achieved a prior partial response to treatment, and around 45% had experienced virologic relapse. Five per cent in the boceprevir group and ten per cent in the telaprevir group were prior null responders.

Interim analysis of outcomes in 221 patients who reached 60 weeks of follow-up showed that 41% of individuals treated with boceprevir and 40% of those receiving telaprevir had a sustained virological response (SVR) twelve weeks after completing therapy. SVR rates differed according to the outcome of earlier HCV therapy. They were highest for patients who had 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 genotype 1b infection (51% boceprevir; 46% telaprevir) than in genotype 1a infection (boceprevir 31%; telaprevir 34%). Multivariate analysis showed that patients with genotype 1b were almost twice as likely to achieve SVR 12 (odds ratio 1.92).

Serious adverse events were observed in 54% of patients treated with telaprevir and 51% of individuals receiving boceprevir. Discontinuation rates due to adverse events were somewhat higher in people taking telaprevir (boceprevir, 11%; telaprevir, 21%). Five per cent of people taking telaprevir developed grade 3 (serious) rash and two 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 2.4% mortality rate among the telaprevir-treated patients and 1.6% of individuals receiving boceprevir also died. Causes of death were not reported.mostly related to infections: In the telaprevir group, there were seven deaths. Three patients died of sepsis (blood poisoning) and another one of pneumonia (lung inflammation). Three further patients died because of variceal bleeding, or encephalopathy, or pulmonary neoplasia . In the boceprevir group there were three deaths, one due to pneumonia, another to sepsis and one to aneurysmal bleeding.

The incidence of serious grade 3 or 4 infections was 7% for telaprevir and 4.2% for boceprevir.

Liver decompensation was diagnosed in 5.1% of telaprevir-treated patients and 4.7% of individuals treated with boceprevir.

Erythropoietin (EPO) or blood transfusions were frequently required because of anemia. 168 telaprevir patients required EPO (56.9%) and 53 received blood transfusions (18%). Among those receiving boceprevir, 119 patients (62.6%) received EPO and 26 (13.7%) received blood transfusions.

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 people with cirrhosis treated with first-generation protease inhibitors

Further data on the use of telaprevir and boceprevir in people with liver cirrhosis 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 F3 (n = 37) or F4 fibrosis (n = 94). Sixty-six people with F3 or F4 fibrosis received boceprevir and 65 received telaprevir

Of the 131 people with F3 or F4 fibrosis, 37 achieved a sustained virologic response. The SVR rate among people with F4 fibrosis was 28%, compared to 47% in F3 patients and 65% in patients with F0-F2 fibrosis. Twenty-four cases of post-treatment virologic relapse occurred in this group.

Thirty study participants are still on treatment or have not completed 12 weeks of post-treatment follow-up. Twenty-seven people discontinued due to adverse events, of whom six nevertheless achieved a sustained virologic response.

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

A platelet count below 90,000 g/l was associated with a greater incidence of serious infections (24 vs 14%, p < 0.05). There was also a higher frequency of infections among people with serum albumin below 35 g/dl (60 vs 12%, p < 0.001). Pulmonary hypertension (a baseline hepatovenous pressure gradient [HVPG] above 10mmHg) was also predictive of severe infections.

There were also six cases of severe rash, one heart attack and one case of psychosis. Therapy was discontinued by 21% of people with F3 or F4 fibrosis due to a serious adverse event.

The investigators conclude that triple-drug therapy incorporating the currently licensed protease inhibitors for people with advanced liver disease 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.”