Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 10/06/14 For personal use only.
Perspective
Optimizing triple therapy and IFN/RBV-free regimens for hepatitis C virus infection Expert Rev. Gastroenterol. Hepatol. Early online, 1–10 (2014)
Kazuaki Chayama*1–3, Fukiko Mitsui1,3 and C Nelson Hayes1–3 1 Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan 2 Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima 734-8551, Japan 3 Liver Research Project Center, Hiroshima University, Hiroshima 734-8551, Japan *Author for correspondence: Tel.: +81 822 57 5190 Fax: +81 822 55 6220 [email protected]
Treatment of chronic hepatitis C virus infection has substantially improved following the advent of direct acting antiviral (DAA) agents. Although the first generation protease inhibitors telaprevir and boceprevir improved sustained viral response (SVR) rates, adverse events remain severe and immature termination of the therapy is frequent; however, intensive dose modification has improved completion and SVR rates. Interferon-free DAA combination therapies, such as asunaprevir and daclatasvir dual therapy are under development and promise higher SVR rates with fewer adverse events. Resistance monitoring and modification of DAA therapy based on pre-existing or de novo resistance variants should be considered. Future therapies are expected to have pan-genotypic activity with shorter duration and improved tolerability, even among cirrhotic and liver transplant patients. KEYWORDS: direct-acting antiviral agents • NS5A inhibitor • polymerase inhibitor • protease inhibitor • sustained viral response
Treatment of chronic hepatitis C virus infection
Originally investigated as an antiviral therapy for hepatitis B virus, recombinant interferon-a was shown to improve biochemical and histological findings in patients chronically infected with hepatitis C virus (HCV) [1,2]. Studies to optimize the effective dose and treatment duration improved the rate of sustained virological response (SVR), defined as undetectable HCV RNA 6 months after the end of treatment, from 6 to 16% in the mid-1990s [2]. The SVR rate more than doubled again to 34% in 1998 with the addition of ribavirin combination therapy. SVR rates again improved in 2000 with the introduction of pegylated interferon (peg-IFN), which increased the half-life of IFN and reduced the injection frequency to once per week [2]. Although long assumed to improve efficacy by prolonging expression of the JAK/STAT pathway, peg-IFN was recently shown to induce a larger number of IFN-stimulated genes, especially a subset of genes involved in the cellular immune response [3]. This combination therapy was the standard of care for a number of years and still forms the basis of therapy for
informahealthcare.com
10.1586/17474124.2015.960394
nongenotype 1 infections [4–6]. However, SVR rates were still far from satisfactory, especially for genotype 1-infected patients with high viral load for whom the SVR rate was only around 50%. Furthermore, the long-duration therapy was costly and accompanied by several serious adverse events such as psychiatric disorder and bone marrow suppression. Development of hepatocellular carcinoma (HCC) increases with progression of fibrosis and aging, as observed in Japan where the majority of infected patients are older than 60 years [7], and patients may still develop HCC even after achieving SVR [8]. Accordingly, the virus should be eradicated as early as possible. Alternative therapies are also needed for patients who do not respond to peg-IFN plus ribavirin therapy. Overview of direct-acting antivirals
Obstacles in the development of cell culture and small animal models limited success in drug development efforts, but recent advances have led to better insight into the HCV lifecycle and facilitated the development of directacting antivirals (DAAs). DAAs are small molecules designed to bind to HCV proteins with high affinity and strongly inhibit viral
2014 Informa UK Ltd
ISSN 1747-4124
1
Perspective
Chayama, Mitsui & Hayes
Structural proteins
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 10/06/14 For personal use only.
Core
Env1
Env2 p7
Non-structural proteins NS2
NS3
NS4A
NS4B
NS5A
NS5B
NS3/NS4A protease inhibitors:
NS5A NS5B inhibitors: inhibitors:
ABT-450/r Asunaprevir Boceprevir Danoprevir Faldaprevir MK-5172 Simeprevir Sovaprevir Telaprevir Vaniprevir
ACH-3102 Daclatasvir GS-5816 Ledipasvir MK-8742 Ombitasvir PPI-668 Samatasvir
NI Mericitabine Sofosbuvir NNI ABT-072 BMS-791325 Dasabuvir Deleobuvir Filibuvir GS-9669 Setrobuvir Tegobuvir VX-222
PIs are expected to have a higher barrier to resistance, improved activity against other genotypes, a more manageable once- or twice-daily dosing schedule and an improved safety profile [25]. Secondgeneration PIs attempt to extend activity to most or all HCV genotypes and are expected to be less vulnerable to resistance mutations affecting first-generation PIs. Polymerase inhibitors
DAAs that target other stages of the viral lifecycle are also in development. Polymerase inhibitors target the HCV NS5B RNA-dependent RNA polymerase (RdRp/NS5B), a low-fidelity polymerase Substitutions associated with resistance responsible for synthesizing negative V36M L31V S282T strand template RNA, which is then used T54A Y93H C316Y to produce multiple positive strand copies R155K M414T of the HCV genome for replication and R422K A156T D168V M423T translation [26]. Both nucleoside inhibitors (NIs) and non-nucleoside inhibitors Figure 1. Direct-acting antivirals and hepatitis C virus genome architecture. The (NNIs) are being developed. NIs such as hepatitis C virus RNA genome is initially translated as a polyprotein, which is then sofosbuvir act by triggering chain termicleaved first by host proteases and then by the viral encoded NS3/NS4A protease. nation when they are incorporated into Direct-acting antiviral agents have been developed against the NS3/NS4A protease, the elongating RNA sequence [27]. NS5A and the NS5B polymerase. NI: Nucleoside inhibitors; NNI: Non-nucleoside inhibitors. Although single amino substitutions can confer resistance to NIs, NI sites are highly conserved among all HCV genoreplication. DAAs that directly inhibit the NS3/4A serine protease, types and have relatively high fitness, making it difficult for the NS5A replication complex and the NS5B polymerase are cur- resistance variants to compete against wild-type strains [27]. As a rently under development (FIGURE 1). The first two DAAs approved result, NIs have the highest barrier to resistance among the curfor treatment of patients with chronic HCV were the protease rent DAA classes [25]. While NIs disrupt the active site, NNIs inhibitors (PI), telaprevir [9–13] and boceprevir [14,15]. Simeprevir, a suppress polymerase activity by binding to allosteric sites. Varisecond-generation PI [16–18], was also recently approved. ation among genotypes limits NNI activity to genotype 1 and results in a lower barrier to resistance, but NNIs may help to NS3/4A PI provide complementary protection with other DAAs by targetThe HCV RNA genome consists of a single open-reading ing different regions of the polymerase. frame encoding approximately 3000 amino acids polyprotein Sofosbuvir was the first polymerase inhibitor to be approved. containing three structural proteins and six nonstructural pro- In a Phase III open-label study, 90% of patients achieved SVR teins. Cellular proteases cleave the structural proteins, whereas after 12 weeks of treatment with peg-IFN, ribavirin and sofosthe NS3 cleaves the remaining polyprotein to release the non- buvir in treatment-naı¨ve patients with genotypes 1, 4, 5 or 6, structural proteins. PIs such as telaprevir and boceprevir inter- and patients with genotype 2 or 3 treated with sofosbuvir and fere with cleavage by mimicking and reversibly binding to the ribavirin responded equivalently to patients treated with pegcarboxy-terminal region of the HCV NS3/4 serine protease [19]. IFN and ribavirin [28]. NS3/4A is also used by the virus in immune evasion by degrading key immune signaling molecules. Therefore, target- NS5A inhibitors ing NS3/4A not only prevents cleavage of the polyprotein but While the core and envelope proteins are essential structural also helps to restore immune signaling [20–22]. The result is a components of viral particles, HCV replication requires formasubstantial improvement in the SVR rate, especially among tion of the replication complex, a membrane structure formed patients who showed a partial response relapse during prior by interaction of the NS3, NS4A, NS5A and NS5B nonstructherapy. However, PI monotherapy induces rapid selection for tural proteins with the endoplasmic reticulum assembly [29]. resistance variants [23,24] and must be administered as part of NS5A is required for viral assembly and inhibition of apoptotriple therapy along with peg-IFN and ribavirin. Second-wave sis, making it a promising drug target even though it has no doi: 10.1586/17474124.2015.960394
Expert Rev. Gastroenterol. Hepatol.
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 10/06/14 For personal use only.
Optimizing triple therapy & IFN/RBV-free regimens for HCV infection
known enzymatic activity, and several anti-HCV compounds have been found to act through it [30]. NS5A binds to RNA and directly interacts with the NS5B polymerase and the host protein cyclophilin A [31]. Even though the mechanism is unclear, NS5A inhibitors have high specificity and potency at picomolar concentrations across multiple genotypes and are among the most potent antiviral molecules known [32]. Nonetheless, naturally occurring resistance variants are likely to exist in patients prior to therapy, resulting in viral breakthrough and treatment stoppage [32]. Optimization of telaprevir triple therapy
While second-generation PI, polymerase inhibitors and NS5A inhibitors hold great promise, until these new therapies become available for clinical use, it is necessary to continue to optimize existing therapies. Telaprevir was one of the first DAAs approved for treatment of patients with chronic HCV, but it is restricted for use as part of a triple therapy with peg-IFN and ribavirin and is only approved for genotype 1. As a result of adding a new drug to an already difficult therapy, telaprevir triple therapy often causes severe adverse events, leading to discontinuation of the therapy. In the original clinical trials [9–13], the most frequent adverse events leading to discontinuation were skin problems such as pruritus and skin rash. In these trials, the majority of patients treated with telaprevir were Caucasians, and the discontinuation rate was relatively low [9–13]. In contrast, the rate of discontinuation was much higher in two studies conducted in Japan [33,34]. The dose of telaprevir (750 mg/day) in the two Japanese studies was the same as that used in the Western studies [9–13], but typical body weight is considerably lower in Japanese patients than in Caucasian patients, suggesting that reduction of telaprevir might lead to comparable outcomes with fewer side effects in Japanese patients. Because telaprevir and ribavirin are both known to cause anemia, an intensive ribavirin dose reduction scheme had been planned in these two trials as follows: the initial dose of ribavirin was reduced by 200 mg in patients with hemoglobin level less than 13 g/dl at baseline. The ribavirin dose was reduced by 200 mg per day in patients receiving 600 or 800 mg per day (by 400 mg per day in those receiving 1000 mg) when the hemoglobin level was less than 12 g/dl and was reduced by an additional 200 mg when the hemoglobin level decreased below 10 g/dl. The ribavirin dose was also reduced by 200 mg/day when hemoglobin level dropped by more than 1 g/dl within 1 week and the hemoglobin level was less than 13 g/dl. Telaprevir was withdrawn when hemoglobin level declined to less than 8.5 g/dl. Peg-IFN and ribavirin were discontinued when the hemoglobin level declined to less than 8.5 g/dl. Erythropoietin was not used in these trials. Despite the extensive dose reductions, in one of the studies, about 10% of treated patients discontinued the therapy due to anemia [33]. Grade 3 anemia (hemoglobin less than 8.0 g/dl) was significantly more frequent in patients undergoing telaprevir triple therapy (14/126) compared with peg-IFN plus ribavirin-treated patients (0/63) in another study (p < 0.0055). informahealthcare.com
Perspective
After telaprevir entered the postmarketing phase, more extensive ribavirin and telaprevir dose reductions were attempted in order to avoid the need to discontinue therapy. Telaprevir reduction guidelines were published by the Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis issued by the Ministry of Health, Labor and Welfare of Japan [35] and by the Japan Society of Hepatology. A postmarketing survey showed that SVR rates varied substantially among patients with different adherence and treatment periods (FIGURE 2). As shown in FIGURE 2A, SVR rates above 80% were obtained in patients who maintained ‡40% of the initial ribavirin dose, ‡60% of the telaprevir dose and ‡80% of the peg-IFN dose. Similarly, higher SVR rates were associated with longer duration with each drug (FIGURE 2B). These results suggest that continuous administration of all three drugs is important in achieving SVR even when ribavirin dose is reduced drastically early in therapy. However, DAA therapy should be discontinued in the event of viral breakthrough, which might otherwise complicate future DAA therapies and lead to crossresistance. We conducted a clinical trial to examine whether the dose of telaprevir could be reduced without compromising the SVR rate in order to reduce the side effects of telaprevir. To do this, we selected patients who had a high probability of achieving SVR, that is, relapsers under prior IFN therapy and treatmentnaı¨ve patients with the IL28B SNP rs8099917 TT genotype [36]. The results showed a significant reduction of side effects without compromising efficacy. Premature termination of the therapy by renal damage or anemia was significantly lower in patients treated with the reduced telaprevir dose regimen. We were therefore able to conclude that, at least among Asian patients with relatively lower body weight, relapsers and treatment-naı¨ve patients with rs8099917 genotype TT could be safely treated with a reduced dose (1500 mg/day) of telaprevir. We note, however, that careful monitoring of viral load is necessary in any DAA treatment to detect viral breakthrough. Boceprevir
Boceprevir, the other first-generation PI, was actually the first PI to be approved, but it was never approved for use in Japan and is used less frequently than telaprevir. In a comparative study of consecutive HCV patients undergoing triple therapy, rapid virological response and SVR rates were slightly but not significantly higher among patients treated with telaprevir compared to boceprevir, and the relapse rate was significantly higher in boceprevir-treated patients [37]. Fewer boceprevirtreated patients discontinued therapy due to adverse events, but incidence of anemia, neutropenia and dysgeusia were higher in boceprevir-treated patients. However, cutaneous adverse events and renal dysfunction were more common in telaprevir-treated patients. Another study focusing on patients with mildly decompensated cirrhosis found no significant differences in SVR, adverse events or early discontinuation between telaprevir and boceprevir, but the authors cautioned that the use of either PI in these patients should be considered carefully due to the doi: 10.1586/17474124.2015.960394
Perspective
Chayama, Mitsui & Hayes
modest SVR rate and high risk of adverse events in triple therapy [38].
Telaprevir
A
100 SVR (%)
80
Simeprevir
60 40
104
27
22
82
5
20
0 –> 10
80
PEG interferon
100
80
80 SVR (%)
60 40
60
50
32
47
16
20
60 40 20
0
183
17
19
17
2
First- & second-generation PI
B
0
80
–>
–
Perspective
Optimizing triple therapy and IFN/RBV-free regimens for hepatitis C virus infection Expert Rev. Gastroenterol. Hepatol. Early online, 1–10 (2014)
Kazuaki Chayama*1–3, Fukiko Mitsui1,3 and C Nelson Hayes1–3 1 Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan 2 Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima 734-8551, Japan 3 Liver Research Project Center, Hiroshima University, Hiroshima 734-8551, Japan *Author for correspondence: Tel.: +81 822 57 5190 Fax: +81 822 55 6220 [email protected]
Treatment of chronic hepatitis C virus infection has substantially improved following the advent of direct acting antiviral (DAA) agents. Although the first generation protease inhibitors telaprevir and boceprevir improved sustained viral response (SVR) rates, adverse events remain severe and immature termination of the therapy is frequent; however, intensive dose modification has improved completion and SVR rates. Interferon-free DAA combination therapies, such as asunaprevir and daclatasvir dual therapy are under development and promise higher SVR rates with fewer adverse events. Resistance monitoring and modification of DAA therapy based on pre-existing or de novo resistance variants should be considered. Future therapies are expected to have pan-genotypic activity with shorter duration and improved tolerability, even among cirrhotic and liver transplant patients. KEYWORDS: direct-acting antiviral agents • NS5A inhibitor • polymerase inhibitor • protease inhibitor • sustained viral response
Treatment of chronic hepatitis C virus infection
Originally investigated as an antiviral therapy for hepatitis B virus, recombinant interferon-a was shown to improve biochemical and histological findings in patients chronically infected with hepatitis C virus (HCV) [1,2]. Studies to optimize the effective dose and treatment duration improved the rate of sustained virological response (SVR), defined as undetectable HCV RNA 6 months after the end of treatment, from 6 to 16% in the mid-1990s [2]. The SVR rate more than doubled again to 34% in 1998 with the addition of ribavirin combination therapy. SVR rates again improved in 2000 with the introduction of pegylated interferon (peg-IFN), which increased the half-life of IFN and reduced the injection frequency to once per week [2]. Although long assumed to improve efficacy by prolonging expression of the JAK/STAT pathway, peg-IFN was recently shown to induce a larger number of IFN-stimulated genes, especially a subset of genes involved in the cellular immune response [3]. This combination therapy was the standard of care for a number of years and still forms the basis of therapy for
informahealthcare.com
10.1586/17474124.2015.960394
nongenotype 1 infections [4–6]. However, SVR rates were still far from satisfactory, especially for genotype 1-infected patients with high viral load for whom the SVR rate was only around 50%. Furthermore, the long-duration therapy was costly and accompanied by several serious adverse events such as psychiatric disorder and bone marrow suppression. Development of hepatocellular carcinoma (HCC) increases with progression of fibrosis and aging, as observed in Japan where the majority of infected patients are older than 60 years [7], and patients may still develop HCC even after achieving SVR [8]. Accordingly, the virus should be eradicated as early as possible. Alternative therapies are also needed for patients who do not respond to peg-IFN plus ribavirin therapy. Overview of direct-acting antivirals
Obstacles in the development of cell culture and small animal models limited success in drug development efforts, but recent advances have led to better insight into the HCV lifecycle and facilitated the development of directacting antivirals (DAAs). DAAs are small molecules designed to bind to HCV proteins with high affinity and strongly inhibit viral
2014 Informa UK Ltd
ISSN 1747-4124
1
Perspective
Chayama, Mitsui & Hayes
Structural proteins
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 10/06/14 For personal use only.
Core
Env1
Env2 p7
Non-structural proteins NS2
NS3
NS4A
NS4B
NS5A
NS5B
NS3/NS4A protease inhibitors:
NS5A NS5B inhibitors: inhibitors:
ABT-450/r Asunaprevir Boceprevir Danoprevir Faldaprevir MK-5172 Simeprevir Sovaprevir Telaprevir Vaniprevir
ACH-3102 Daclatasvir GS-5816 Ledipasvir MK-8742 Ombitasvir PPI-668 Samatasvir
NI Mericitabine Sofosbuvir NNI ABT-072 BMS-791325 Dasabuvir Deleobuvir Filibuvir GS-9669 Setrobuvir Tegobuvir VX-222
PIs are expected to have a higher barrier to resistance, improved activity against other genotypes, a more manageable once- or twice-daily dosing schedule and an improved safety profile [25]. Secondgeneration PIs attempt to extend activity to most or all HCV genotypes and are expected to be less vulnerable to resistance mutations affecting first-generation PIs. Polymerase inhibitors
DAAs that target other stages of the viral lifecycle are also in development. Polymerase inhibitors target the HCV NS5B RNA-dependent RNA polymerase (RdRp/NS5B), a low-fidelity polymerase Substitutions associated with resistance responsible for synthesizing negative V36M L31V S282T strand template RNA, which is then used T54A Y93H C316Y to produce multiple positive strand copies R155K M414T of the HCV genome for replication and R422K A156T D168V M423T translation [26]. Both nucleoside inhibitors (NIs) and non-nucleoside inhibitors Figure 1. Direct-acting antivirals and hepatitis C virus genome architecture. The (NNIs) are being developed. NIs such as hepatitis C virus RNA genome is initially translated as a polyprotein, which is then sofosbuvir act by triggering chain termicleaved first by host proteases and then by the viral encoded NS3/NS4A protease. nation when they are incorporated into Direct-acting antiviral agents have been developed against the NS3/NS4A protease, the elongating RNA sequence [27]. NS5A and the NS5B polymerase. NI: Nucleoside inhibitors; NNI: Non-nucleoside inhibitors. Although single amino substitutions can confer resistance to NIs, NI sites are highly conserved among all HCV genoreplication. DAAs that directly inhibit the NS3/4A serine protease, types and have relatively high fitness, making it difficult for the NS5A replication complex and the NS5B polymerase are cur- resistance variants to compete against wild-type strains [27]. As a rently under development (FIGURE 1). The first two DAAs approved result, NIs have the highest barrier to resistance among the curfor treatment of patients with chronic HCV were the protease rent DAA classes [25]. While NIs disrupt the active site, NNIs inhibitors (PI), telaprevir [9–13] and boceprevir [14,15]. Simeprevir, a suppress polymerase activity by binding to allosteric sites. Varisecond-generation PI [16–18], was also recently approved. ation among genotypes limits NNI activity to genotype 1 and results in a lower barrier to resistance, but NNIs may help to NS3/4A PI provide complementary protection with other DAAs by targetThe HCV RNA genome consists of a single open-reading ing different regions of the polymerase. frame encoding approximately 3000 amino acids polyprotein Sofosbuvir was the first polymerase inhibitor to be approved. containing three structural proteins and six nonstructural pro- In a Phase III open-label study, 90% of patients achieved SVR teins. Cellular proteases cleave the structural proteins, whereas after 12 weeks of treatment with peg-IFN, ribavirin and sofosthe NS3 cleaves the remaining polyprotein to release the non- buvir in treatment-naı¨ve patients with genotypes 1, 4, 5 or 6, structural proteins. PIs such as telaprevir and boceprevir inter- and patients with genotype 2 or 3 treated with sofosbuvir and fere with cleavage by mimicking and reversibly binding to the ribavirin responded equivalently to patients treated with pegcarboxy-terminal region of the HCV NS3/4 serine protease [19]. IFN and ribavirin [28]. NS3/4A is also used by the virus in immune evasion by degrading key immune signaling molecules. Therefore, target- NS5A inhibitors ing NS3/4A not only prevents cleavage of the polyprotein but While the core and envelope proteins are essential structural also helps to restore immune signaling [20–22]. The result is a components of viral particles, HCV replication requires formasubstantial improvement in the SVR rate, especially among tion of the replication complex, a membrane structure formed patients who showed a partial response relapse during prior by interaction of the NS3, NS4A, NS5A and NS5B nonstructherapy. However, PI monotherapy induces rapid selection for tural proteins with the endoplasmic reticulum assembly [29]. resistance variants [23,24] and must be administered as part of NS5A is required for viral assembly and inhibition of apoptotriple therapy along with peg-IFN and ribavirin. Second-wave sis, making it a promising drug target even though it has no doi: 10.1586/17474124.2015.960394
Expert Rev. Gastroenterol. Hepatol.
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 10/06/14 For personal use only.
Optimizing triple therapy & IFN/RBV-free regimens for HCV infection
known enzymatic activity, and several anti-HCV compounds have been found to act through it [30]. NS5A binds to RNA and directly interacts with the NS5B polymerase and the host protein cyclophilin A [31]. Even though the mechanism is unclear, NS5A inhibitors have high specificity and potency at picomolar concentrations across multiple genotypes and are among the most potent antiviral molecules known [32]. Nonetheless, naturally occurring resistance variants are likely to exist in patients prior to therapy, resulting in viral breakthrough and treatment stoppage [32]. Optimization of telaprevir triple therapy
While second-generation PI, polymerase inhibitors and NS5A inhibitors hold great promise, until these new therapies become available for clinical use, it is necessary to continue to optimize existing therapies. Telaprevir was one of the first DAAs approved for treatment of patients with chronic HCV, but it is restricted for use as part of a triple therapy with peg-IFN and ribavirin and is only approved for genotype 1. As a result of adding a new drug to an already difficult therapy, telaprevir triple therapy often causes severe adverse events, leading to discontinuation of the therapy. In the original clinical trials [9–13], the most frequent adverse events leading to discontinuation were skin problems such as pruritus and skin rash. In these trials, the majority of patients treated with telaprevir were Caucasians, and the discontinuation rate was relatively low [9–13]. In contrast, the rate of discontinuation was much higher in two studies conducted in Japan [33,34]. The dose of telaprevir (750 mg/day) in the two Japanese studies was the same as that used in the Western studies [9–13], but typical body weight is considerably lower in Japanese patients than in Caucasian patients, suggesting that reduction of telaprevir might lead to comparable outcomes with fewer side effects in Japanese patients. Because telaprevir and ribavirin are both known to cause anemia, an intensive ribavirin dose reduction scheme had been planned in these two trials as follows: the initial dose of ribavirin was reduced by 200 mg in patients with hemoglobin level less than 13 g/dl at baseline. The ribavirin dose was reduced by 200 mg per day in patients receiving 600 or 800 mg per day (by 400 mg per day in those receiving 1000 mg) when the hemoglobin level was less than 12 g/dl and was reduced by an additional 200 mg when the hemoglobin level decreased below 10 g/dl. The ribavirin dose was also reduced by 200 mg/day when hemoglobin level dropped by more than 1 g/dl within 1 week and the hemoglobin level was less than 13 g/dl. Telaprevir was withdrawn when hemoglobin level declined to less than 8.5 g/dl. Peg-IFN and ribavirin were discontinued when the hemoglobin level declined to less than 8.5 g/dl. Erythropoietin was not used in these trials. Despite the extensive dose reductions, in one of the studies, about 10% of treated patients discontinued the therapy due to anemia [33]. Grade 3 anemia (hemoglobin less than 8.0 g/dl) was significantly more frequent in patients undergoing telaprevir triple therapy (14/126) compared with peg-IFN plus ribavirin-treated patients (0/63) in another study (p < 0.0055). informahealthcare.com
Perspective
After telaprevir entered the postmarketing phase, more extensive ribavirin and telaprevir dose reductions were attempted in order to avoid the need to discontinue therapy. Telaprevir reduction guidelines were published by the Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis issued by the Ministry of Health, Labor and Welfare of Japan [35] and by the Japan Society of Hepatology. A postmarketing survey showed that SVR rates varied substantially among patients with different adherence and treatment periods (FIGURE 2). As shown in FIGURE 2A, SVR rates above 80% were obtained in patients who maintained ‡40% of the initial ribavirin dose, ‡60% of the telaprevir dose and ‡80% of the peg-IFN dose. Similarly, higher SVR rates were associated with longer duration with each drug (FIGURE 2B). These results suggest that continuous administration of all three drugs is important in achieving SVR even when ribavirin dose is reduced drastically early in therapy. However, DAA therapy should be discontinued in the event of viral breakthrough, which might otherwise complicate future DAA therapies and lead to crossresistance. We conducted a clinical trial to examine whether the dose of telaprevir could be reduced without compromising the SVR rate in order to reduce the side effects of telaprevir. To do this, we selected patients who had a high probability of achieving SVR, that is, relapsers under prior IFN therapy and treatmentnaı¨ve patients with the IL28B SNP rs8099917 TT genotype [36]. The results showed a significant reduction of side effects without compromising efficacy. Premature termination of the therapy by renal damage or anemia was significantly lower in patients treated with the reduced telaprevir dose regimen. We were therefore able to conclude that, at least among Asian patients with relatively lower body weight, relapsers and treatment-naı¨ve patients with rs8099917 genotype TT could be safely treated with a reduced dose (1500 mg/day) of telaprevir. We note, however, that careful monitoring of viral load is necessary in any DAA treatment to detect viral breakthrough. Boceprevir
Boceprevir, the other first-generation PI, was actually the first PI to be approved, but it was never approved for use in Japan and is used less frequently than telaprevir. In a comparative study of consecutive HCV patients undergoing triple therapy, rapid virological response and SVR rates were slightly but not significantly higher among patients treated with telaprevir compared to boceprevir, and the relapse rate was significantly higher in boceprevir-treated patients [37]. Fewer boceprevirtreated patients discontinued therapy due to adverse events, but incidence of anemia, neutropenia and dysgeusia were higher in boceprevir-treated patients. However, cutaneous adverse events and renal dysfunction were more common in telaprevir-treated patients. Another study focusing on patients with mildly decompensated cirrhosis found no significant differences in SVR, adverse events or early discontinuation between telaprevir and boceprevir, but the authors cautioned that the use of either PI in these patients should be considered carefully due to the doi: 10.1586/17474124.2015.960394
Perspective
Chayama, Mitsui & Hayes
modest SVR rate and high risk of adverse events in triple therapy [38].
Telaprevir
A
100 SVR (%)
80
Simeprevir
60 40
104
27
22
82
5
20
0 –> 10
80
PEG interferon
100
80
80 SVR (%)
60 40
60
50
32
47
16
20
60 40 20
0
183
17
19
17
2
First- & second-generation PI
B
0
80
–>
–
