Liver International
Article first published online: 23 DEC 2013
DOI: 10.1111/liv.12405
Abstract
The
treatment of hepatitis C virus (HCV) infection with pegylated
interferon (PEG-IFN) alfa and ribavirin (800 mg daily) (RBV) is the
standard of care (SOC) for hepatitis C virus genotype 3-infection
leading to a sustained virological response (SVR) in around 65% of
patients.
A better understanding of the HCV life-cycle has recently resulted in the development of several potential direct-acting antiviral drugs (DAAs) targeting viral proteins (NS3/4A protease, NS5B nucleos(t)idic and non-nucleos(t)idic polymerase, NS5A viral replication complex). First generation protease inhibitors in combination with PEG-IFN/RBV are not efficient in genotype 3-infected patients. The combination of PEG-IFN/RBV with Daclatasvir, a NS5A inhibitor for 12–24 weeks results in a SVR in around 75% while the triple combination of PEG-IFN/RBV with the oral nucleotidic polymerase inhibitor Sofosbuvir (GS-7977) for 12 weeks in naïve patients results in a SVR in more than 95%. The results of the first oral combination of Sofosbuvir and RBV for 12 weeks in genotype 3-infected patients have been rather disappointing with a slightly lower SVR than after 24 weeks of PEG-IFN: around 60%, and only 30% in patients with cirrhosis. Extending treatment from 12 to 16 weeks in treatment experienced patients doubled the SVR rate and an 80% SVR rate is expected by extending treatment to 24 weeks. The best oral combination of new DAAs is probably the combination of Sofosbuvir and a NS5A inhibitor (Daclatasvir, Ledipasvir…) for 24 weeks, which resulted in a 100% SVR rate in a limited series. The use of cyclophilin inhibitors, a host-targeted antiviral, in association with DAAs and/or RBV may also be of interest.
A better understanding of the HCV life-cycle has recently resulted in the development of several potential direct-acting antiviral drugs (DAAs) targeting viral proteins (NS3/4A protease, NS5B nucleos(t)idic and non-nucleos(t)idic polymerase, NS5A viral replication complex). First generation protease inhibitors in combination with PEG-IFN/RBV are not efficient in genotype 3-infected patients. The combination of PEG-IFN/RBV with Daclatasvir, a NS5A inhibitor for 12–24 weeks results in a SVR in around 75% while the triple combination of PEG-IFN/RBV with the oral nucleotidic polymerase inhibitor Sofosbuvir (GS-7977) for 12 weeks in naïve patients results in a SVR in more than 95%. The results of the first oral combination of Sofosbuvir and RBV for 12 weeks in genotype 3-infected patients have been rather disappointing with a slightly lower SVR than after 24 weeks of PEG-IFN: around 60%, and only 30% in patients with cirrhosis. Extending treatment from 12 to 16 weeks in treatment experienced patients doubled the SVR rate and an 80% SVR rate is expected by extending treatment to 24 weeks. The best oral combination of new DAAs is probably the combination of Sofosbuvir and a NS5A inhibitor (Daclatasvir, Ledipasvir…) for 24 weeks, which resulted in a 100% SVR rate in a limited series. The use of cyclophilin inhibitors, a host-targeted antiviral, in association with DAAs and/or RBV may also be of interest.
The oral combination of new DAAs (dual or triple combination of different antivirals) or of DAAs and host targets such as cyclophilin will probably become the SOC for genotype 3-infected treatment-naïve or -experienced patients.
Although the global distribution of hepatitis C virus (HCV) genotypes differs across geographical areas, genotype 3 is common worldwide, accounting for around 30% of infected patients in Northern Europe and Asia. Compared with other genotypes, genotype 3-infection, which is highly prevalent in South East Asia and in drug users, has been associated with an increased risk of the progression of fibrosis, steatosis and the development of hepatocellular carcinoma in patients with cirrhosis [1-4].
Treatment of chronic hepatitis C with pegylated interferon alfa (PEG-IFN) and ribavirin (RBV) for 24 weeks results in a sustained viral response (SVR), corresponding to a complete virological recovery, in around 70% of patients with HCV-genotype 3 compared with around 80% in those with genotype 2 and 45% in those with genotype 1 before the addition of protease inhibitors [5-10].
A better understanding of the HCV life-cycle and the characterization of viral enzymes that are potential antiviral targets [11] have led to the development of a number of potential new direct-acting antiviral drugs (DAAs) targeted against viral proteins [12].
Several new non-DAA agents, which may be associated with DAAs are also under development, e.g. new interferons, cyclophilin inhibitors and vaccine therapy [13, 14]. The different classes of DAA and non-DAA new agents are summarized in Figure 1.
Standard of care in 2013
The N-CORE trial in genotype 2- or 3 patients treated with PEG-IFN/RBV (RBV: 800–1200 mg/day) who did not achieve rapid viral response (RVR) (as defined by undetectable HCV RNA at week 4) (n = 235) but who had either undetectable HCV RNA or a >2 log10 decrease at week 12, randomized 188 patients either to stop at week 24 (n = 95) or to continue PEG-IFN until week 48 (n = 93) [19]. Per protocol analysis suggested a non-significant trend towards an improvement in SVR rates [63% vs. 52% with an odds ratio of 0.63 (CI 95%: 0.35–1.16)].
DAAs with pegylated interferon
NS3/NS4A protease inhibitors (PI)
Patients received 12 or 16 weeks of Daclatasvir (60 mg once daily) or 24 weeks of placebo, combined with standard PEG-IFN. Treatment was extended to 24 weeks (12 additional weeks of PEG-IFN) in Daclatasvir recipients who did not have an early virological response (EVR). The primary endpoint was the SVR 24 weeks after the end of treatment (SVR24) [24].
In patients with genotype 3, end-of-treatment responses were numerically higher in the Daclatasvir groups (89–96%) than with PEG-IFN and Ribavirin (78%). SVR24 rates were 69.2%, 66.7% and 59.3% in the Daclatasvir 12-week and 16-week groups and in the placebo arms respectively. Differences in SVR24 between genotypes 2 (83.3%, 82.6% and 62.5%, respectively) and 3 were largely because of the more frequent post-treatment relapse with the latter. SVR24 was less frequent in patients with genotype 3 and cirrhosis (45%) than in those without cirrhosis (74%) in the combined Daclatasvir arms and in the placebo arm (43% vs. 65% respectively).
Relapse rates were slightly higher in patients with cirrhosis, non-CC IL28B genotypes, high HCV RNA levels at baseline and high BMI while baseline Daclatasvir resistance-associated NS5A polymorphisms only partially contributed to relapse.
Thus, addition of Daclatasvir to PEG-IFN provided more rapid suppression of serum HCV RNA levels than PEG-IFN and Ribavirin, followed by similar or greater rates of SVR with shorter (12 or 16 weeks) durations of therapy, which is beneficial for both patients and healthcare providers.
Other NS5A inhibitors are under development and have been associated in oral combinations with interesting results (ABT-267 and GS-5885) (see below) while others are in rapid development (MK-8742, GSK-2336805, PPI-668).
NS5B polymerase inhibitors
All of these studies of second generation-DAAs in combination with PEG-IFN and Ribavirin usually result in higher antiviral potency with a better safety profile than those reported with the SOC. The limits to these studies are mainly the combination with IFN and the numerous PEG-IFN and Ribavirin-associated adverse events rather than the duration of the treatment. New combinations without IFN with greater antiviral potency and safety/tolerance are expected.
Interferon free oral DAA-combinations
In the POSITRON study, 278 genotype 2 and 3 naïve patients received 12 weeks of Sofosbuvir/GS-7977 (400 mg QD) and RBV (n = 207) or placebo (n = 71) (16% with cirrhosis, 51% genotype 2 and 49% genotype 3). SVR12 rates were 78% (compared with 0% in the placebo arm) in the overall population (93% in genotype 2 and 61% in genotype 3): 61% in patients without cirrhosis vs. 21% in genotype 3 patients with cirrhosis [30]. In the FISSION study, 499 genotype 2 and 3 naïve patients received a combination of Sofosbuvir/GS-7977 and RBV (1000–1200 mg/day) for 12 weeks (n = 256) or SOC PEG-IFN and Ribavirin for 24 weeks (n = 243) (20% with cirrhosis, 28% with genotype 2 and 72% with genotype 3). Although the SVR12 rates were similar with the new oral combination and with PEG-IFN (67%) they were different for genotype 2 (97% vs. 78%) and not different for genotype 3 (56% vs. 63%) or patients with cirrhosis (34% vs. 30%) [31].
Extending therapy from 12 to 16 weeks in the FUSION trial [32] in PEG-IFN-experienced genotypes 2- and 3- patients, resulted in: (i) an increase in the SVR12 from 50 to 73% (P < 0.001); (ii) doubling the SVR12 rate in genotype 3- patients (30% vs. 62%, P < 0.001) and (iii) a marked increase in the SVR12 from 19 to 61% in genotype 3 patients with cirrhosis by reducing the high rate of relapse.
These disappointing results in genotype 3 patients with cirrhosis (compared with the excellent results in genotype 2- patients whatever the stage of fibrosis) explains why treatment was extended from 12 to 24 weeks with the Sofosbuvir/RBV combination in genotype 3 patients from the European VALENCE study in February 2013. The SVR12 rate in genotype 3-infected patients was 94% and 92% in naïve non cirrhotic and cirrhotic patients, respectively and 87% and 60% in experienced non cirrhotic and cirrhotic patients, respectively (Zeuzem S et al. American Association for the Study of Liver Disease, Washington 2013).
Sofosbuvir and other inhibitors
Other DAA combinations
Several new non-DAA agents, which may be associated with DAAs are also under development, e.g. new interferons, cyclophilin inhibitors and vaccine therapy [13, 14]. The different classes of DAA and non-DAA new agents are summarized in Figure 1.
Standard of care in 2013
Twenty-four
weeks of PEG-IFN and RBV, the current SOC for the treatment of HCV
genotype 2- or 3-infection, results in a SVR in 70–80% of patients [5-10]. A meta-analysis of studies with PEG-IFN and RBV reported 74% and 68% SVR rates in genotypes 2- and 3-infection respectively [10].
The
recent European Association for the Study of the Liver (EASL) Clinical
Practice Guidelines recommended a dose of 15 mg/kg/day in genotype 1- or
4- patients and a fixed dose of 800 mg/day in genotype 2- or 3-
patients [9]: weight-based (800–1400 mg/day) compared with flat-dose (800 mg/day) RBV does not increase the SVR rate [15].
Baseline viral load is one of the determinants of outcome. SVR rates are consistently higher in patients with low baseline HCV RNA levels, usually defined as <800 000 IU/ml [5-7], even in genotype 3 patients. Host factors also affect the SVR, although less than genotype (except for the IL28B polymorphism) [16]. These include age, ethnicity (because of the distribution of the IL28B polymorphisms according to ethnic origin: African-Americans have a lower response rate than Caucasians), gender, weight, degree of liver fibrosis, ALT quotient [5-7] and immunosuppression.
Although this strategy was not shown to be effective in the ACCELERATE randomized controlled trial [17], a reduction in treatment duration to 12–16 weeks may be discussed in genotype 2- or 3- patients with a negative PCR at week 4 if the doses of RBV are weight-adjusted (around 15 mg/kg/day) and not fixed (800 mg/day) [18].
Thus, whether higher doses of RBV can reduce the duration of therapy (12–16 weeks instead of 24 weeks) or increase SVR in patients with negative baseline factors (high viral load, metabolic syndrome, extensive fibrosis or cirrhosis) is still under debate.
Finally, there is no evidence that extending the duration of therapy from 24 to 48 weeks significantly increases the SVR, even in patients with significant fibrosis [7].
Baseline viral load is one of the determinants of outcome. SVR rates are consistently higher in patients with low baseline HCV RNA levels, usually defined as <800 000 IU/ml [5-7], even in genotype 3 patients. Host factors also affect the SVR, although less than genotype (except for the IL28B polymorphism) [16]. These include age, ethnicity (because of the distribution of the IL28B polymorphisms according to ethnic origin: African-Americans have a lower response rate than Caucasians), gender, weight, degree of liver fibrosis, ALT quotient [5-7] and immunosuppression.
Although this strategy was not shown to be effective in the ACCELERATE randomized controlled trial [17], a reduction in treatment duration to 12–16 weeks may be discussed in genotype 2- or 3- patients with a negative PCR at week 4 if the doses of RBV are weight-adjusted (around 15 mg/kg/day) and not fixed (800 mg/day) [18].
Thus, whether higher doses of RBV can reduce the duration of therapy (12–16 weeks instead of 24 weeks) or increase SVR in patients with negative baseline factors (high viral load, metabolic syndrome, extensive fibrosis or cirrhosis) is still under debate.
Finally, there is no evidence that extending the duration of therapy from 24 to 48 weeks significantly increases the SVR, even in patients with significant fibrosis [7].
The N-CORE trial in genotype 2- or 3 patients treated with PEG-IFN/RBV (RBV: 800–1200 mg/day) who did not achieve rapid viral response (RVR) (as defined by undetectable HCV RNA at week 4) (n = 235) but who had either undetectable HCV RNA or a >2 log10 decrease at week 12, randomized 188 patients either to stop at week 24 (n = 95) or to continue PEG-IFN until week 48 (n = 93) [19]. Per protocol analysis suggested a non-significant trend towards an improvement in SVR rates [63% vs. 52% with an odds ratio of 0.63 (CI 95%: 0.35–1.16)].
DAAs with pegylated interferon
NS3/NS4A protease inhibitors (PI)
Most
first-generation NS3/NS4A protease inhibitors specifically target HCV
genotype 1 and are not very potent against genotype 3 [20].
Second-generation NS3/NS4A protease inhibitors have limited effect on
genotype 3 in association with PEG-IFN, although they are usually
considered to have a ‘pangenotypic’ antiviral activity. For example,
Simeprevir, which might be interesting because of its broader antiviral
spectrum (it inhibits viral replication of genotypes 1, 2, 4, 5 and 6 in vitro) has no antiviral potency against genotype 3 [21].
NS5A inhibitors
NS5A inhibitors
Daclatasvir
(DCV, BMS-790052), the first-in class NS5A inhibitor, is a potent and
highly selective NS5A replication complex inhibitor with broad genotypic
coverage (genotypes 1–5) and a pharmacokinetic profile that allows
once-daily dosing [22]. Daclatasvir in combination with PEG-IFN for 24 to 48 weeks resulted in a SVR rate of around 75% in genotype 1 patients [23].
A randomized, double-blind, phase 2b study assessed whether a combination of Daclatasvir and SOC improved treatment efficacy and shortened the duration of therapy in genotypes 2- and 3.
A randomized, double-blind, phase 2b study assessed whether a combination of Daclatasvir and SOC improved treatment efficacy and shortened the duration of therapy in genotypes 2- and 3.
Patients received 12 or 16 weeks of Daclatasvir (60 mg once daily) or 24 weeks of placebo, combined with standard PEG-IFN. Treatment was extended to 24 weeks (12 additional weeks of PEG-IFN) in Daclatasvir recipients who did not have an early virological response (EVR). The primary endpoint was the SVR 24 weeks after the end of treatment (SVR24) [24].
In patients with genotype 3, end-of-treatment responses were numerically higher in the Daclatasvir groups (89–96%) than with PEG-IFN and Ribavirin (78%). SVR24 rates were 69.2%, 66.7% and 59.3% in the Daclatasvir 12-week and 16-week groups and in the placebo arms respectively. Differences in SVR24 between genotypes 2 (83.3%, 82.6% and 62.5%, respectively) and 3 were largely because of the more frequent post-treatment relapse with the latter. SVR24 was less frequent in patients with genotype 3 and cirrhosis (45%) than in those without cirrhosis (74%) in the combined Daclatasvir arms and in the placebo arm (43% vs. 65% respectively).
Relapse rates were slightly higher in patients with cirrhosis, non-CC IL28B genotypes, high HCV RNA levels at baseline and high BMI while baseline Daclatasvir resistance-associated NS5A polymorphisms only partially contributed to relapse.
Thus, addition of Daclatasvir to PEG-IFN provided more rapid suppression of serum HCV RNA levels than PEG-IFN and Ribavirin, followed by similar or greater rates of SVR with shorter (12 or 16 weeks) durations of therapy, which is beneficial for both patients and healthcare providers.
Other NS5A inhibitors are under development and have been associated in oral combinations with interesting results (ABT-267 and GS-5885) (see below) while others are in rapid development (MK-8742, GSK-2336805, PPI-668).
NS5B polymerase inhibitors
Two
different classes of polymerase inhibitors are currently being
developed: nucleos(t)idic (Sofosbuvir/GS-7977 and Mericitabine) and
non-nucleosidic (ABT-333, VX-222, BI-207127, BMS-791325) inhibitors
which may or may not be combined interferon.
The combination of Mericitabine with PEG-IFN in genotype 1 patients resulted in a SVR of less than 60% [25]. On the other hand, the combination of Sofosbuvir (400 mg QD) and PEG-IFN and Ribavirin for 12 to 24 weeks in genotypes 1-, 4-, 5- and 6 resulted in a SVR12 rate of more than 90% with a fair safety profile. Similar results have been achieved in naïve genotype 2 and 3 patients. In the ELECTRON study a combination of Sofosbuvir (400 mg QD) and RBV for 12 weeks plus PEG-IFN for 4, 8 or 12 weeks in genotypes 2-, and 3 patients (n = 10 by arm) resulted in a 100% SVR12 rate [26]. In an open-label cohort of patients with genotypes 2- or 3- without cirrhosis who received Sofosbuvir (400 mg) and PEG-IFN and Ribavirin for 12 weeks, 23/25 (92%) achieved SVR12 (PROTON study) [27].
The combination of Mericitabine with PEG-IFN in genotype 1 patients resulted in a SVR of less than 60% [25]. On the other hand, the combination of Sofosbuvir (400 mg QD) and PEG-IFN and Ribavirin for 12 to 24 weeks in genotypes 1-, 4-, 5- and 6 resulted in a SVR12 rate of more than 90% with a fair safety profile. Similar results have been achieved in naïve genotype 2 and 3 patients. In the ELECTRON study a combination of Sofosbuvir (400 mg QD) and RBV for 12 weeks plus PEG-IFN for 4, 8 or 12 weeks in genotypes 2-, and 3 patients (n = 10 by arm) resulted in a 100% SVR12 rate [26]. In an open-label cohort of patients with genotypes 2- or 3- without cirrhosis who received Sofosbuvir (400 mg) and PEG-IFN and Ribavirin for 12 weeks, 23/25 (92%) achieved SVR12 (PROTON study) [27].
All of these studies of second generation-DAAs in combination with PEG-IFN and Ribavirin usually result in higher antiviral potency with a better safety profile than those reported with the SOC. The limits to these studies are mainly the combination with IFN and the numerous PEG-IFN and Ribavirin-associated adverse events rather than the duration of the treatment. New combinations without IFN with greater antiviral potency and safety/tolerance are expected.
Interferon free oral DAA-combinations
By
targeting various steps of viral replication a combination of several
DAA agents could induce viral suppression, prevent the emergence of
viral resistance and allow eradication of HCV in interferon-free
regimens. The most promising results of oral combinations have been
reported with the combinations of Daclatasvir and Asunaprevir in
genotype 1b-patients [28] or with Sofosbuvir in genotypes 1-, 2- and 3- patients [26, 27, 29-36].
Sofosbuvir and ribavirin
Sofosbuvir and ribavirin
The
ELECTRON study combining Sofosbuvir/GS-7977 and RBV for 12 weeks
(compared with Sofosbuvir/GS-7977 and PEG-IFN) resulted in a 100% SVR
rate in naïve genotype 2- and 3-patients without cirrhosis (10 patients
per arm) while 12-weeks of monotherapy wtih Sofosbuvir, reducing the
dose of RBV (800 mg) or decreasing treatment to 8 weeks reduced the SVR
rate (60%, 60% and 67% respectively) [26]. Finally, the 12-week Sofosbuvir/GS-7977 and RBV combination in 25 non-naïve patients resulted in a SVR rate of 68% [26].
The results of phase III studies in genotype 3- patients with cirrhosis were poor.
The results of phase III studies in genotype 3- patients with cirrhosis were poor.
In the POSITRON study, 278 genotype 2 and 3 naïve patients received 12 weeks of Sofosbuvir/GS-7977 (400 mg QD) and RBV (n = 207) or placebo (n = 71) (16% with cirrhosis, 51% genotype 2 and 49% genotype 3). SVR12 rates were 78% (compared with 0% in the placebo arm) in the overall population (93% in genotype 2 and 61% in genotype 3): 61% in patients without cirrhosis vs. 21% in genotype 3 patients with cirrhosis [30]. In the FISSION study, 499 genotype 2 and 3 naïve patients received a combination of Sofosbuvir/GS-7977 and RBV (1000–1200 mg/day) for 12 weeks (n = 256) or SOC PEG-IFN and Ribavirin for 24 weeks (n = 243) (20% with cirrhosis, 28% with genotype 2 and 72% with genotype 3). Although the SVR12 rates were similar with the new oral combination and with PEG-IFN (67%) they were different for genotype 2 (97% vs. 78%) and not different for genotype 3 (56% vs. 63%) or patients with cirrhosis (34% vs. 30%) [31].
Extending therapy from 12 to 16 weeks in the FUSION trial [32] in PEG-IFN-experienced genotypes 2- and 3- patients, resulted in: (i) an increase in the SVR12 from 50 to 73% (P < 0.001); (ii) doubling the SVR12 rate in genotype 3- patients (30% vs. 62%, P < 0.001) and (iii) a marked increase in the SVR12 from 19 to 61% in genotype 3 patients with cirrhosis by reducing the high rate of relapse.
These disappointing results in genotype 3 patients with cirrhosis (compared with the excellent results in genotype 2- patients whatever the stage of fibrosis) explains why treatment was extended from 12 to 24 weeks with the Sofosbuvir/RBV combination in genotype 3 patients from the European VALENCE study in February 2013. The SVR12 rate in genotype 3-infected patients was 94% and 92% in naïve non cirrhotic and cirrhotic patients, respectively and 87% and 60% in experienced non cirrhotic and cirrhotic patients, respectively (Zeuzem S et al. American Association for the Study of Liver Disease, Washington 2013).
Sofosbuvir and other inhibitors
Sofosbuvir plus Simeprevir (Cosmos Study) [33]
or Sofosbuvir plus Ledipasvir in experienced genotype 1 patients and
protease inhibitor-experienced patients, respectively, resulted in a
SVR12 rate of more than 95% in the Lonestar Study (34). Similar results
were reported in genotype 1 PEG-IFN experienced patients in whom the
SVR12 rate after 24 weeks of Daclatasvir plus Sofosbuvir with (n = 20) or without (n = 21) RBV was 95% and 100% respectively [35].
Daclatasvir was studied in combination with Sofosbuvir in the first study evaluating the combination of an NS5A inhibitor and a nucleotide NS5B inhibitor in an interferon-free regimen [36]. Treatment-naïve patients with HCV genotypes 1, 2 or 3 received Daclatasvir (60 mg QD) plus Sofosbuvir (400 mg QD), with or without a one week lead-in of Sofosbuvir and with or without RBV for 24 weeks [36]. In patients with HCV genotypes 2 or 3, 94–100% (15/16 and 14/14) of patients treated with the Daclatasvir plus Sofosbuvir combination, and 86% (12/14) of those receiving the Daclatasvir/Sofosbuvir/RBV combination had undetectable HCV RNA at Week 24 (end of treatment). 88–100% (14/16 and 14/14) of patients treated with the Daclatasvir plus Sofosbuvir combination, and 86% (12/14; two patients were lost to follow-up) of those receiving the Daclatasvir/Sofosbuvir/RBV combination achieved SVR4 and SVR12.
Thus, with an all-oral combination of Daclatasvir plus Sofosbuvir, SVR12 rates of >95% were achieved in HCV genotypes 2 and 3. The Sofosbuvir lead-in phase or the addition of RBV did not affect virological response, and the latter increased the frequency of anaemia (which was absent in the RBV-free arms).
Daclatasvir was studied in combination with Sofosbuvir in the first study evaluating the combination of an NS5A inhibitor and a nucleotide NS5B inhibitor in an interferon-free regimen [36]. Treatment-naïve patients with HCV genotypes 1, 2 or 3 received Daclatasvir (60 mg QD) plus Sofosbuvir (400 mg QD), with or without a one week lead-in of Sofosbuvir and with or without RBV for 24 weeks [36]. In patients with HCV genotypes 2 or 3, 94–100% (15/16 and 14/14) of patients treated with the Daclatasvir plus Sofosbuvir combination, and 86% (12/14) of those receiving the Daclatasvir/Sofosbuvir/RBV combination had undetectable HCV RNA at Week 24 (end of treatment). 88–100% (14/16 and 14/14) of patients treated with the Daclatasvir plus Sofosbuvir combination, and 86% (12/14; two patients were lost to follow-up) of those receiving the Daclatasvir/Sofosbuvir/RBV combination achieved SVR4 and SVR12.
Thus, with an all-oral combination of Daclatasvir plus Sofosbuvir, SVR12 rates of >95% were achieved in HCV genotypes 2 and 3. The Sofosbuvir lead-in phase or the addition of RBV did not affect virological response, and the latter increased the frequency of anaemia (which was absent in the RBV-free arms).
Other DAA combinations
Interesting
results have been reported in genotype 1- patients without cirrhosis
who received quadruple or quintuple combination ABT-450 boosted by
Ritonavir, the ABT-267 NS5A inhibitor, in association or not with the
NS5B non-nucleos(t)idic polymerase inhibitor ABT-333 and RBV for 8 to
12 weeks. The SVR12 rates were from 87 to 97% in naïve patients and 93%
in experienced non-responders, including 100% in subtype 1b patients [37].
Trials have begun with these combinations in genotypes 2- and 3-
patients. Similarly, a combination of Daclatasvir, Asunaprevir and a
non-nucleosidic polymerase inhibitor (BMS-791325) resulted in a SVR in
95 to 100% of naïve genotype 1 patients. Trials in genotypes 2 and 3 are
ongoing [38].
New non-DAA host-targeted antiviral agents
New non-DAA host-targeted antiviral agents
In
VITAL-1, a phase IIb study naïve genotype 2- and 3- patients received
the cyclophilin inhibitor Alisporivir (600 to 1000 mg/day) with or
without PEG-IFN or RBV (800 mg/day) for 24 weeks after a lead-in phase
of one week with Alisporivir 600 mg BID. The SVR12 was 81–83% in
Alisporivir-treated patients with or without RBV, 77% with
Alisporivir/PEG-IFN and 58% in the PEG-IFN/RBV arm [39].
The potential benefit of other host-targeted agents (lambda IFN which appeared to be better tolerated in the Emerge trial in genotype 2- and 3- patients or vaccine therapy, entry inhibitors, miRNAs) needs to be demonstrated.
Conclusion
The potential benefit of other host-targeted agents (lambda IFN which appeared to be better tolerated in the Emerge trial in genotype 2- and 3- patients or vaccine therapy, entry inhibitors, miRNAs) needs to be demonstrated.
Conclusion
In
conclusion, as treatment options have progressed and improved, HCV
genotype 3-infection has become the most difficult-to-treat genotype,
even if the SOC results in a SVR of 67%.
The Daclatasvir/PEG-IFN and Sofosbuvir/RBV combinations result in similar SVR rates with the differences in results in genotypes 2 and 3 explained by robust and similar on-treatment virological responses, but genotype-specific differences in post-treatment relapse.
The combination of Sofosbuvir/RBV for 24 weeks or Daclatasvir/PEG-IFN/RBV for 12 weeks will probably increase this rate to 75% and to >95% in the 12 week Sofosbuvir/PEG-IFN combination (at least in PEG-IFN-naïve patients; very recent results suggest a 85% SVR rate in genotype 3-infected patients with cirrhosis) (Fig. 2).
This impressive result is similar to that obtained with various DAA combinations with Sofosbuvir and NS5A inhibitors for 24 weeks (shorter durations are under evaluation) with a good tolerance.
Disclosure
Financial support:
Stanislas Pol has received consulting and lecturing fees from Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Vertex, Gilead, Roche, Schering-Plough/Merck, Novartis, Abbott, Sanofi and GlaxoSmithKline, and grants from Bristol-Myers Squibb, Gilead, Roche and Merck/Schering Plough. Anaïs Vallet-Pichard: oral presentations, national and international congress as auditor, subinvestigator in clinical trials for Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Vertex, Gilead, Roche, Schering-Plough/Merck, Novartis, Abbott and GlaxoSmithKline.
Marion Corouge has no conflict of interest to declare.
The Daclatasvir/PEG-IFN and Sofosbuvir/RBV combinations result in similar SVR rates with the differences in results in genotypes 2 and 3 explained by robust and similar on-treatment virological responses, but genotype-specific differences in post-treatment relapse.
The combination of Sofosbuvir/RBV for 24 weeks or Daclatasvir/PEG-IFN/RBV for 12 weeks will probably increase this rate to 75% and to >95% in the 12 week Sofosbuvir/PEG-IFN combination (at least in PEG-IFN-naïve patients; very recent results suggest a 85% SVR rate in genotype 3-infected patients with cirrhosis) (Fig. 2).
This impressive result is similar to that obtained with various DAA combinations with Sofosbuvir and NS5A inhibitors for 24 weeks (shorter durations are under evaluation) with a good tolerance.
Financial support:
Stanislas Pol has received consulting and lecturing fees from Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Vertex, Gilead, Roche, Schering-Plough/Merck, Novartis, Abbott, Sanofi and GlaxoSmithKline, and grants from Bristol-Myers Squibb, Gilead, Roche and Merck/Schering Plough. Anaïs Vallet-Pichard: oral presentations, national and international congress as auditor, subinvestigator in clinical trials for Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Vertex, Gilead, Roche, Schering-Plough/Merck, Novartis, Abbott and GlaxoSmithKline.
Marion Corouge has no conflict of interest to declare.
