Safety and Efficacy of Telaprevir for Advanced HCV
Safety and Efficacy of Telaprevir for Advanced HCV
Background and aim Severe adverse events (AEs) compromise the outcome of direct antiviral agent-based treatment in patients with advanced liver fibrosis due to HCV infection. HEP3002 is an ongoing multinational programme to evaluate safety and efficacy of telaprevir (TVR) plus pegylated-interferon-α (PEG-IFNα) and ribavirin (RBV) in patients with advanced liver fibrosis caused by HCV genotype 1 (HCV-1).
Methods 1782 patients with HCV-1 and bridging fibrosis or compensated cirrhosis were prospectively recruited from 16 countries worldwide, and treated with 12 weeks of TVR plus PEG-IFN/RBV, followed by 12 or 36 weeks of PEG-IFN and RBV (PR) alone dependent on virological response to treatment and previous response type.
Results 1587 patients completed 12 weeks of triple therapy and 4 weeks of PR tail (53% cirrhosis, 22% HCV-1a). By week 12, HCV RNA was undetectable in 85% of naives, 88% of relapsers, 80% of partial responders and 72% of null responders. Overall, 931 patients (59%) developed grade 1–4 anaemia (grade 3/4 in 31%), 630 (40%) dose reduced RBV, 332 (21%) received erythropoietin and 157 (10%) were transfused. Age and female gender were the strongest predictors of anaemia. 64 patients (4%) developed a grade 3/4 rash. Discontinuation of TVR due to AEs was necessary in 193 patients (12%). Seven patients died (0.4%, six had cirrhosis).
Conclusions In compensated patients with advanced fibrosis due to HCV-1, triple therapy with TVR led to satisfactory rates of safety, tolerability and on-treatment virological response with adequate managements of AEs.
Chronic infection with HCV is a leading cause of liver-related morbidity and mortality worldwide, for which an effective antiviral treatment with pegylated-interferon (PEG-IFN) and ribavirin (PR) has been available since early 2000. The treatment outcome for difficult to cure patients, such as those chronically infected with HCV genotype 1 (HCV-1), has remarkably improved following the addition of the oral HCV protease inhibitors (PI) boceprevir (BOC) or telaprevir (TVR) to PR therapy. While eradication of HCV by PI+PR therapy is expected to greatly extend treatment success rates, resulting in a reduced risk of liver-related mortality, factors that may limit both the access as well as the response rates of patients to triple therapy have been identified. Perhaps the most relevant is the presence of advanced hepatic fibrosis, which affects tolerability and safety of triple therapy. The impact of this factor on treatment access and response rates is driven by an increased rate of myelosuppression-related adverse events (AEs) such as anaemia and infections in patients treated with triple therapy. In addition, suboptimal dosing due to poor treatment tolerability may impact the outcome of PI+PR therapy in patients with advanced fibrosis, leading to reduced rates of virus eradication and also to unaffordable cost to utility ratios. A French observational study with TVR- and BOC-based triple therapy in patients with cirrhosis revealed that 33%–46% of the patients had been ineligible for registration studies with one of these PIs due to their severe level of liver disease. Up to 11.7% of patients had to discontinue therapy until week 16 due to the onset of AEs including anaemia, neutropenia, rash, clinical decompensation and bacterial infections. In addition, more than half of the patients on TVR required treatment with bone marrow stimulating factors and 16.1% received blood transfusions to manage treatment-related anaemia. Another real-world study in Germany showed a high frequency of anaemia and SAEs in patients with cirrhosis who were treated with triple therapy, particularly in patients with low platelet counts. Therefore, the safety of triple therapy is now being perceived by hepatologists as a potential barrier to its use in patients with the most need, such as those with advanced fibrosis, who are more often vulnerable to myelosuppression-related complications.
To gain further insights into the safety and efficacy of TVR+PR treatment in patients with advanced liver fibrosis or cirrhosis due to HCV-1 infection, an open label expanded access programme (EAP) was launched in late 2011 involving 16 nations worldwide. Cumulatively, the programme enrolled more than 2000 treatment naive or experienced patients with bridging fibrosis or cirrhosis. We report here the analysis of the on-treatment virological response and safety in the first 1587 patients who reached week 16 of therapy.
Abstract and Introduction
Abstract
Background and aim Severe adverse events (AEs) compromise the outcome of direct antiviral agent-based treatment in patients with advanced liver fibrosis due to HCV infection. HEP3002 is an ongoing multinational programme to evaluate safety and efficacy of telaprevir (TVR) plus pegylated-interferon-α (PEG-IFNα) and ribavirin (RBV) in patients with advanced liver fibrosis caused by HCV genotype 1 (HCV-1).
Methods 1782 patients with HCV-1 and bridging fibrosis or compensated cirrhosis were prospectively recruited from 16 countries worldwide, and treated with 12 weeks of TVR plus PEG-IFN/RBV, followed by 12 or 36 weeks of PEG-IFN and RBV (PR) alone dependent on virological response to treatment and previous response type.
Results 1587 patients completed 12 weeks of triple therapy and 4 weeks of PR tail (53% cirrhosis, 22% HCV-1a). By week 12, HCV RNA was undetectable in 85% of naives, 88% of relapsers, 80% of partial responders and 72% of null responders. Overall, 931 patients (59%) developed grade 1–4 anaemia (grade 3/4 in 31%), 630 (40%) dose reduced RBV, 332 (21%) received erythropoietin and 157 (10%) were transfused. Age and female gender were the strongest predictors of anaemia. 64 patients (4%) developed a grade 3/4 rash. Discontinuation of TVR due to AEs was necessary in 193 patients (12%). Seven patients died (0.4%, six had cirrhosis).
Conclusions In compensated patients with advanced fibrosis due to HCV-1, triple therapy with TVR led to satisfactory rates of safety, tolerability and on-treatment virological response with adequate managements of AEs.
Introduction
Chronic infection with HCV is a leading cause of liver-related morbidity and mortality worldwide, for which an effective antiviral treatment with pegylated-interferon (PEG-IFN) and ribavirin (PR) has been available since early 2000. The treatment outcome for difficult to cure patients, such as those chronically infected with HCV genotype 1 (HCV-1), has remarkably improved following the addition of the oral HCV protease inhibitors (PI) boceprevir (BOC) or telaprevir (TVR) to PR therapy. While eradication of HCV by PI+PR therapy is expected to greatly extend treatment success rates, resulting in a reduced risk of liver-related mortality, factors that may limit both the access as well as the response rates of patients to triple therapy have been identified. Perhaps the most relevant is the presence of advanced hepatic fibrosis, which affects tolerability and safety of triple therapy. The impact of this factor on treatment access and response rates is driven by an increased rate of myelosuppression-related adverse events (AEs) such as anaemia and infections in patients treated with triple therapy. In addition, suboptimal dosing due to poor treatment tolerability may impact the outcome of PI+PR therapy in patients with advanced fibrosis, leading to reduced rates of virus eradication and also to unaffordable cost to utility ratios. A French observational study with TVR- and BOC-based triple therapy in patients with cirrhosis revealed that 33%–46% of the patients had been ineligible for registration studies with one of these PIs due to their severe level of liver disease. Up to 11.7% of patients had to discontinue therapy until week 16 due to the onset of AEs including anaemia, neutropenia, rash, clinical decompensation and bacterial infections. In addition, more than half of the patients on TVR required treatment with bone marrow stimulating factors and 16.1% received blood transfusions to manage treatment-related anaemia. Another real-world study in Germany showed a high frequency of anaemia and SAEs in patients with cirrhosis who were treated with triple therapy, particularly in patients with low platelet counts. Therefore, the safety of triple therapy is now being perceived by hepatologists as a potential barrier to its use in patients with the most need, such as those with advanced fibrosis, who are more often vulnerable to myelosuppression-related complications.
To gain further insights into the safety and efficacy of TVR+PR treatment in patients with advanced liver fibrosis or cirrhosis due to HCV-1 infection, an open label expanded access programme (EAP) was launched in late 2011 involving 16 nations worldwide. Cumulatively, the programme enrolled more than 2000 treatment naive or experienced patients with bridging fibrosis or cirrhosis. We report here the analysis of the on-treatment virological response and safety in the first 1587 patients who reached week 16 of therapy.
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