Current progress in the treatment of chronic hepatitis C

Abstract

Over the last decade, the standard of care for the treatment of chronic hepatitis C has been the combination of pegylated-interferon-alfa (PEG-IFN) and ribavirin (RBV) which results in sustained virological response (SVR) rates of 75%-85% in patients with genotypes 2 or 3 but only of 40%-50% in patients with genotype 1. Currently, there are rapid and continuous developments of numerous new agents against hepatitis C virus (HCV), which are the focus of this review. Boceprevir and telaprevir, two first-generation NS3/4A HCV protease inhibitors, have been recently licensed in several countries around the world to be used in combination with PEG-IFN and RBV for the treatment of genotype 1 patients. Boceprevir or telaprevir based triple regimens, compared with the PEG-IFN/RBV combination, improve the SVR rates by 25%-31% in treatment-naïve genotype 1 patients, by 40%-64% in prior relapsers, by 33%-45% in prior partial responders and by 24%-28% in prior null responders. At the same time, the application of response-guided treatment algorithms according to the on-treatment virological response results in shortening of the total therapy duration to only 24 wk in 45%-55% of treatment-naïve patients. There are, however, several challenges with the use of the new triple combinations in genotype 1 patients, such as the need for immediate results of HCV RNA testing using sensitive quantitative assays, new and more frequent adverse events (anemia and dysgeusia for boceprevir; pruritus, rash and anemia for telaprevir), new drug interactions and increasing difficulties in compliance. Moreover, the SVR rates are still poor in very difficult to treat subgroups of genotype 1 patients, such as null responders with cirrhosis, while there is no benefit for patients who cannot tolerate PEG-IFN/RBV or who are infected with non-1 HCV genotype. Many newer anti-HCV agents of different classes and numerous combinations are currently under evaluation with encouraging results. Preliminary data suggest that the treatment of chronic HCV patients with well tolerated combinations of oral agents without PEG-IFN is feasible and may lead to a universal HCV cure over the next 5-10 years.

Key Words: Chronic hepatitis C; Pegylated interferon; Ribavirin; Protease inhibitors; Nucleos(t)ide analogue inhibitors; Non-nucleos(t)ide analogue inhibitors; Hepatitis C virus polymerase; NS5A inhibitors; Cyclophilin inhibitors

INTRODUCTION

Chronic hepatitis C virus (HCV) infection affects approximately 170 million people worldwide[1]. Chronic hepatitis C may lead to the development of cirrhosis, liver decompensation and hepatocellular carcinoma and is a major indication for liver transplantation, particularly in Western countries[2]. HCV is classified into 6 major genotypes. Some genotypes have a restricted geographical distribution (genotypes 4-6), while others (genotypes 1-3) are more broadly disseminated. Genotype 1 (subtypes 1a and 1b) is the most prevalent genotype in the world. Genotype 2 is found in clusters in the Mediterranean region, genotype 3 is most prevalent among intravenous drug users and genotype 4 is found mostly in Egypt, while genotypes 5 and 6 are less frequent[3,4]. The HCV genotypes strongly affect the likelihood of the response to treatment.

During the last decade, the standard of care (SOC) for chronic HCV patients consisted of pegylated interferon-alfa (PEG-IFN)-2a or -2b combined with ribavirin (RBV). The treatment duration has been based on the on-treatment virological responses, mainly estimated at 4 wk [rapid virological response (RVR)] and 12 wk of therapy (early virological response)[3,5]. Recently, polymorphisms of the interleukin 28b (IL28B, interferon lambda 3) gene were strongly associated with the rates of sustained virological response (SVR) to PEG-IFN/RBV therapy and therefore their determination may be useful to identify a patient’s likelihood of response to treatment, but the predictive value is low[5]. In patients with HCV genotypes 2 or 3, the combination of PEG-IFN/RBV is usually given for 24 wk, achieving rates of SVR, i.e., absence of HCV RNA at 6 mo or more after cessation of therapy, of about 75%-85%. In patients with HCV genotypes 1 and 4, the combination of PEG-IFN and RBV is usually given for 48 wk, resulting in SVR rates of 40%-50% for genotype 1 and 55%-65% for genotype 4 patients[5,6]. The SVR rates are substantially lower in previous non-responders to PEG-IFN and RBV, in whom the proportion of genotype 1 patients is higher due to the lower initial SVR rates. It has been reasonable, therefore, that new treatments with improved efficacy were mostly needed for patients with genotype 1. In addition and regardless of HCV genotype, there are chronic HCV patients who cannot be treated with PEG-IFN and RBV for several reasons. First and of most clinical relevance, PEG-IFN therapy is contraindicated in patients with decompensated liver disease. Second, patients may not tolerate and/or may have other contraindication(s) to PEG-IFN or RBV. Thus, there has definitely been a need for new antiviral drugs with better efficacy, improved tolerance and good safety profiles for chronic HCV patients.

The current review focuses on the recent rapid and continuous developments in the management of chronic HCV infection, which have been based on a better understanding of the structure of the HCV genome and the key viral enzymes.

HCV GENOME ORGANIZATION AND NEW ANTIVIRALS

HCV has a positive-sense, single-stranded RNA genome of some 9.6 kilobases that encodes a polyprotein of about 3000 amino acids[7,8]. The open reading frame for the polyprotein is flanked by 5’ and 3’ untranslated regions, which contain elements that regulate translation and replication. The polyprotein is generated by the host cell translation machinery and cleaved co- and post-translationally by viral and host proteases to yield the mature viral proteins. The N-terminal segment of the polyprotein encodes the structural components of the virus (Core, E1, E2 and p7). Core protein forms the capsid shell into which the virus genome is packaged, while the glycoproteins are considered to locate to the lipid envelope surrounding the capsid. P7 is required for the virus assembly[9,10].

The C-terminal component of the polyprotein contains non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B). NS2 and NS3 are viral proteases required for the processing of the HCV polyprotein[11]. NS3 is a multifunctional enzyme, which provides a serine protease and helicase/nucleotide triphosphatase activity and forms a stable eterodimeric complex with its cofactor NS4A, which is essential for protein folding. The NS3/NS4A complex cleaves the junction between NS3/4A, NS4A/NS4B, NS4B/NS5A and NS5A/NS5B. NS3 has also a helicase activity and is necessary for HCV replication supporting the unwinding of HCV[12]. NS4B is the presumed central organizer of the HCV replicase complex and a main inducer of intracellular membrane rearrangements[13]. NS5A is a RNA-binding phosphoprotein required for RNA replication and assembly of infectious virus particles[14]. NS5B RNA-dependent RNA-polymerase is required for viral replication.

The nonstructural proteins mentioned above have been the major targets for the evolving directly acting antivirals (DAAs) or specifically targeted antiviral therapy for hepatitis C. In particular, DAAs under development mainly include NS3/4A protease inhibitors, NS5B polymerase inhibitors and NS5A inhibitors. In addition, inhibitors of cyclophilin, which is a host protein with an important role in the HCV lifecycle, are also under development (Table 1).

Table 1 New agents against hepatitis C virus currently evaluated in phase II or III trials.

Drug	Company
NS3/4A protease inhibitors
First generation, linear
Boceprevir (Approved)	MERCK
Telaprevir (Approved)	JANSSEN
Narlaprevir	MERCK
First generation, macrocyclic
BI201335	BOEHRINGER Ingelheim
TMC435	TIBOTEC/JANSSEN
Danoprevir	ROCHE
Vaniprevir	MERCK
Asunaprevir	BRISTOL-MYERS SQUIBB
ABT-450	ABBOTT
GS-9451	GILEAD
GS-9256	GILEAD
ACH-1625	ACHILLION
Second generation, macrocyclic
MK-5172	MERCK
Nucleos(t)ide analogue inhibitors of HCV polymerase
PSI/GS-7977	PHARMASSET/GILEAD
Mericitabine	ROCHE
IDX-184	IDENIX
Non-nucleoside analogue inhibitors of HCV polymerase
Tegobuvir	GILEAD
Filibuvir	PFIZER
ANA-598/Setrobuvir	ANADYS/ROCHE
BI207127	BOEHRINGER Ingelheim
ABT-333	ABBOTT
ABT-072	ABBOTT
VX-222	VERTEX
NS5A inhibitors
Daclatasvir	BRISTOL-MYERS SQUIBB
GS-5885	GILEAD
GSK2336805	GSK
Cyclophilin inhibitors
Alisporivir1	NOVARTIS
SCY-635	Scynexis

¹On hold by the United States Food and Drug Administration because of toxicity (pancreatitis cases with one death). HCV: Hepatitis C virus.

NS3/4A PROTEASE INHIBITORS

Two first-generation, linear NS3/4A protease inhibitors, boceprevir and telaprevir, have recently been approved in several countries around the world for clinical use in patients with genotype 1, while many new NS3/4 protease inhibitors are currently under evaluation in clinical trials (Table 1). Boceprevir and telaprevir have high antiviral potency only against genotypes 1 and 2[15], but a low barrier to resistance. In particular, resistant HCV strains develop within a few days of monotherapy with one of these two agents[16,17], while most mutations confer cross-resistance to both drugs (V36A/M, T54S/A, V55A, R155K/T/Q, A156S, A156T/V)[18]. HCV subtype 1a develops resistance more frequently and more rapidly than subtype 1b[19], as just one (instead of two in subtype 1b) nucleotide change (R155K) is enough for an amino acid replacement and emergence of a resistant strain. Because of the low barrier to resistance, boceprevir and telaprevir should always be used in triple combinations together with PEG-IFN/RBV. Since viral resistance may develop even in triple combinations with PEG-IFN/RBV, strict stopping rules are recommended to be applied with the use of boceprevir- or telaprevir-based regimens. Newer, first-generation NS3/4A inhibitors under development are mainly macrocyclic (danoprevir, vaniprevir, asunaprevir, etc.), and are expected to have better pharmacokinetics and tolerability compared with boceprevir and telaprevir. Second-generation NS3/4A inhibitors (MK-5172) are expected to have pan-genotype antiviral activity and improved resistance profiles.

Efficacy data from phase III clinical trials with boceprevir- or telaprevir-based regimens in treatment-naïve patients with genotype 1

SPRINT-2 was a randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of boceprevir-based regimens compared with the previous SOC, as well as the efficacy of boceprevir-based response-guided therapy (RGT) compared with a fixed 48-wk boceprevir regimen[20]. In total, 1097 (938 nonblack and 159 black) treatment-naïve genotype 1 patients were randomly assigned to one of three treatment arms (1:1:1). They all received PEG-IFN-2b and RBV for the first 4 wk (lead-in period) followed by (1) placebo plus PEG-IFN-2b/RBV for 44 wk (control arm); (2) boceprevir plus PEG-IFN-2b/RBV for 24 wk with or without an additional 20-wk course of placebo plus PEG-IFN-2b/RBV (boceprevir RGT arm); or (3) boceprevir plus PEG-IFN-2b/RBV for a standard period of 44 wk (boceprevir fixed arm). PEG-IFN-2b was administered subcutaneously at a dose of 1.5 μg/kg per week, RBV orally at a total daily dose of 600-1400 mg according to body weight and boceprevir orally with food at a dose of 800 mg every 7-9 h. In the boceprevir RGT arm, treatment was stopped at 28 wk in patients who achieved an extended RVR (eRVR) defined as undetectable HCV RNA between 8 and 24 wk, or continued until week 48 in patients who did not achieved such an eRVR.

The SVR rate was significantly lower in the control arm (38%) compared with both boceprevir arms (RGT: 63%, fixed: 66%; P < 0.001) (Table 2). In all arms, black patients achieved lower SVR rates compared with nonblack patients (control arm: 23% vs 40%, boceprevir RGT arm: 42% vs 67%, boceprevir fixed arm: 53% vs 69%). In the RGT arm, a total of 44% of patients were eligible to receive only 28 wk of treatment having an excellent SVR rate of 96% (97% for nonblacks and 87% for blacks). The relapse rates were 22% in the control arm and 9% in the two boceprevir arms. In conclusion, boceprevir-based regimens, compared with the PEG-IFN/RBV combination, offer a 25%-28% benefit in the likelihood of SVR in treatment-naïve genotype 1 patients, while a RGT-based duration of boceprevir-based therapy has excellent results in patients with an eRVR and is not overall inferior than a fixed 48-wk boceprevir-based regimen.

Table 2 Sustained virological response rates in phase III clinical trials with hepatitis C virus protease inhibitor-based regimens in treatment-naïve and treatment-experienced patients.

Name of trial		SVR
Naïve patients - Treatment group
SPRINT-2
BOC/RGT		63%
BOC44/PR48		66%
PR48		38%
ADVANCE
T12PR		75%
T8PR		69%
PR		44%
ILLUMINATE
T12PR24 (eRVR+)		92%
T12PR48 (eRVR+)		87%
T12PR48 (eRVR-)		64%
< 20 wk		23%
Treatment-experienced patients - Treatment group
RESPOND-2
Prior relapsers	PR48	29%
	BOC/RGT	69%
	BOC44/PR48	75%
Prior partial responders	PR48	7%
	BOC/RGT	40%
	BOC44/PR48	52%
REALIZE
Prior relapsers	PR48	24%
	LIT12PR48	88%
	T12PR48	83%
Prior partial responders	PR48	15%
	LIT12PR48	54%
	T12PR48	59%
Prior null responders	PR48	5%
	LIT12PR48	33%
	T12PR48	29%

BOC: Boceprevir; RGT: Response-guided therapy; P: Pegylated interferon-alfa; R: Ribavirin; T: Telaprevir; eRVR: Extended rapid virological response; LI: Lead-in; SVR: Sustained virological response.

ADVANCE was a randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of telaprevir-based regimens compared with previous SOC as well as the optimal duration of telaprevir triple combination[21]. In total, 1088 treatment-naïve genotype 1 patients were randomized to one of three treatment arms (1:1:1): (1) telaprevir plus PEG-IFN-2a/RBV for the first 12 wk followed by 12 or 36 wk of PEG-IFN-2a/RBV (T12PR arm); (2) telaprevir plus PEG-IFN-2a/RBV for the first 8 wk and placebo plus PEG-IFN-2a/RBV for another 4 wk followed by 12 or 36 wk of PEG-IFN-2a/RBV (T8PR arm); or (3) PEG-IFN-2a/RBV for 48 wk together with placebo for the first 12 wk (PR arm). PEG-IFN-2a was administered subcutaneously at a standard weekly dose of 180 μg, RBV orally at a total daily dose of 1000-1200 mg according to body weight and telaprevir orally with food at a dose of 750 mg every 8 h. In both telaprevir arms, treatment was stopped at 24 wk in patients who achieved an eRVR defined as undetectable HCV RNA at weeks 4 and 12, and continued up to 48 wk in patients who did not achieve such an eRVR.

Significantly more patients in the telaprevir arms achieved an SVR compared with controls (75% and 69% vs 44%, P < 0.001), while patients of the T12PR arm showed a trend for a higher SVR rate compared with patients of the T8PR arm, but this did not reach statistical significance (T12PR: 75% vs T8PR: 69%, P = 0.088). The rates of eRVR were 57% and 58% in the T12PR and T8PR arms, respectively, compared with 8% in the control arm. Among those patients with an eRVR who received only 24 wk of therapy, an SVR was achieved in 89% and 83% of cases in the T12PR and T8PR arms, respectively. Among patients who did not achieve an eRVR and continued therapy up to 48 wk, the SVR rates were 54% and 50% in the T12PR and T8PR arms, respectively (Table 2). The relapse rate was 9% in both telaprevir arms compared with 28% in the control arm.

Based on these data, we can conclude that telaprevir-based regimens, compared with the PEG-IFN/RBV combination, offer a 25%-31% benefit in the likelihood of SVR in treatment-naïve genotype 1 patients despite more than 50% of patients in the telaprevir arms receiving only 24 wk instead of 48 wk of therapy. Because of the numerically higher response rates in the T12PR than in the T8PR arm, the 12-wk telaprevir triple combination regimens were considered to be optimal for the treatment of genotype 1 patients.

ILLUMINATE was another phase III trial which included 440 treatment-naïve genotype 1 patients to assess whether 24 wk of a telaprevir-based regimen was sufficient for patients with an eRVR[22]. All patients received telaprevir plus PEG-IFN-2a/RBV in the same doses used in the ADVANCE trial for the first 12 wk followed by PEG-IFN-2a/RBV for 12 or 36 wk[3]. In particular, patients with an eRVR (undetectable HCV RNA at weeks 4 and 12) were randomized at week 20 to continue PEG-IFN-2a and RBV until 24 or 48 wk, while all patients without an eRVR were maintained on PEG-IFN-2a/RBV until 48 wk. Among the 60% of patients who achieved an eRVR and continued treatment after 20 wk, SVR rates were comparable between those treated for a total duration of 24 or 48 wk (92% vs 88%, respectively) (Table 2). In the 22% of patients who did not achieve an eRVR but continued treatment after 20 wk, the SVR rate was 64%, while treatment was discontinued prematurely before the randomization at week 20 in 18% of cases. The conclusion of the ILLUMINATE trial was that 24 wk of a telaprevir-based regimen is enough for the treatment-naïve genotype 1 patients who achieve an eRVR.

Efficacy data from phase III clinical trials with boceprevir- or telaprevir-based regimens in treatment-experienced patients with genotype 1

RESPOND-2 was a randomized, placebo-controlled trial designed to evaluate the efficacy and safety of boceprevir-based regimens compared with previous SOC for the retreatment of treatment-experienced genotype 1 patients. In total, 403 patients (259 relapsers: HCV RNA undetectable at the end but detectable at 6 mo after the end of previous therapy; 144 partial responders: HCV RNA decline > 2 log₁₀ IU/mL at 12 wk but detectable during previous therapy) were randomly assigned to one of three treatment arms (1:2:2) similar to those used in the SPRINT-2 trial (control, boceprevir RGT and boceprevir fixed 48-wk arm)[23]. The only difference was in the RGT arm, which included the initial 4-wk lead-in phase with only PEG-IFN-2b and RBV followed by boceprevir plus PEG-IFN-2b/RBV for 32 wk (week 4 to 36) with or without the addition of 12 wk of PEG-IFN-2b/RBV in patients with or without detectable HCV RNA at 8 wk of therapy.

SVR rates were higher in the two boceprevir arms (RGT: 59%; fixed: 66%) than in the control arm (21%, P < 0.001) (Table 2). SVR rates were also higher in the boceprevir arms in both relapsers (RGT: 69%, fixed: 75%, control: 29%) and partial responders (RGT: 40%, fixed: 52%, control: 7%), Among patients with undetectable HCV RNA at week 8, SVR was 86% after 36 wk of therapy in the boceprevir RGT arm and 88% after 48 wk of therapy in the boceprevir fixed arm. The overall SVR rates were found to be lower in the boceprevir RGT than the fixed arm in patients with advanced fibrosis (metavir F3-F4) (44% vs 68%) or mostly in patients with cirrhosis (35% vs 77%), but similar between these two arms in patients with milder fibrosis. The negative effect of cirrhosis on SVR was observed in both prior relapsers and prior partial responders. The probability of an SVR was also significantly higher in patients with than without a > 1 log₁₀ IU/mL HCV RNA drop at the end of the 4-wk lead-in phase (76% vs 33%). These data showed that boceprevir-based regimens compared with the PEG-IFN/RBV combination can improve the SVR rates by 40%-46% in previous relapsers and by 33%-45% in previous partial responders with genotype 1. Moreover, it was shown that a boceprevir-based RGT might be applied in treatment-experienced non-cirrhotic patients who achieve early (at 8 wk) HCV RNA undetectability. It should be noted, however, that the probability of an SVR is not very high in patients without a > 1 log₁₀ IU/mL HCV RNA drop at the end of the 4-wk lead-in phase of a boceprevir-based regimen.

Since null responders (< 2 log₁₀ IU/mL decline in HCV RNA at 12 wk) were not included in the RESPOND-2 trial, a fixed 48-wk boceprevir-based regimen (4-wk lead-in with PEG-IFN-2b/RBV followed by 44 wk of triple combination with boceprevir plus PEG-IFN-2b/RBV) was subsequently evaluated in a rollover, single arm, prospective study[24]. Preliminary results reported an SVR rate of 38% in 42 previous null responders.

REALIZE was a randomized, placebo-controlled trial designed to evaluate the efficacy and safety of telaprevir-based regimens compared with the previous SOC in treatment-experienced genotype 1 patients as well as to determine whether a 4-wk lead-in therapy with only PEG-IFN/RBV can affect the probability of SVR in telaprevir-based regimens[1]. In total, 663 patients (354 relapsers, 124 partial responders, 184 null responders) were randomly assigned to one of three arms (1:2:2): (1) telaprevir plus PEG-IFN-2a/RBV for the first 12 wk followed by PEG-IFN-2a/RBV for another 36 wk (T12PR48 arm); (2) 4-wk lead-in phase with PEG-IFN-2a/RBV and then telaprevir plus PEG-IFN-2a/RBV for 12 wk followed by PEG-IFN-2a/RBV for another 32 wk (lead-in T12PR48 arm); or (3) PEG-IFN-2a/RBV for 48 wk (control PR48 arm).

SVR rates were similar in the two telaprevir arms (64% and 66%) and significantly higher compared with the control arm (17%, P < 0.001). In particular, SVR rates were higher in the telaprevir arms in prior relapsers (83% and 88% vs 24%, P < 0.001), prior partial responders (59% and 54% vs 15%, P < 0.001) and prior null responders (29% and 33% vs 5%, P < 0.001) (Table 2). The presence of cirrhosis was found to negatively affect the SVR rates in the telaprevir arms in prior partial responders (mild-moderate fibrosis: 72%, bridging fibrosis: 56%, cirrhosis: 34%) and mostly in prior null responders (mild-moderate fibrosis: 41%, bridging fibrosis: 39% cirrhosis: 14%), but not in prior relapsers (mild-moderate fibrosis: 86%, bridging fibrosis: 85% cirrhosis: 84%). Among the patients of the lead-in telaprevir arm, the probability of an SVR was significantly higher in patients with than without a > 1 log₁₀ IU/mL HCV RNA drop at the end of the 4-wk lead-in phase (82% vs 33%), but this effect was more clinically relevant in prior null responders (54% vs 15%) than in prior partial responders (59% vs 56%) or in prior relapsers (94% vs 62%). Thus, according to these data, telaprevir-based regimens compared with PEG-IFN/RBV improve the SVR rates by 59%-64% in prior relapsers, by 39%-45% in prior partial responders and by 24%-28% in prior null responders, while a 4-wk lead-in phase with only PEG-IFN/RBV does not offer any advantage to telaprevir-based regimens.

Safety issues with boceprevir- or telaprevir-based regimens

The most common and clinically important adverse event in the boceprevir trials was anemia, which developed in approximately 50% of patients treated with boseprevir-based regimens, compared with 30% of patients treated with only PEG-IFN/RBV[20,23]. Erythropoietin was administered by the investigators in 41%-46% of boceprevir-treated patients and in 21%-24% of the controls, while discontinuation due to anemia was necessary in 2% of patients in the boceprevir arms and in 1% of patients in the control arms. It should be noted that the SVR rates in the boceprevir arms were similar in patients with or without anemia, with or without erythropoietin use and with or without RBV dose reduction. Dysgeusia was another clinically important adverse event that was reported more frequently in the boceprevir than in the control arms (37%-43% vs 18%)[20,23].

The most clinically important adverse events in the telaprevir trials were pruritus, rash and anemia. In particular, pruritus was reported by 45%-50% of telaprevir-treated patients compared with 36% of controls, and rash developed in 35%-56% and 19%-37% of cases, respectively[21,22,25]. The rash during telaprevir therapy was typically eczematous and mild-to-moderate in > 90% of patients, while it was severe (involving > 50% of the body surface area) in 6%, leading to discontinuation of telaprevir in 5%-7% of patients (1% of controls) and of all drugs in 0.5%-1.4% of patients treated with telaprevir-based regimens (0% in controls)[21,22,25]. The mean time for the occurrence of rash was 22 d and the majority of rashes occurred during the first 4 wk of therapy. Anemia also developed more commonly in telaprevir-treated patients than in controls (37%-39% vs 19%)[21,22,25]. Anemia was managed with RBV dose reduction, which did not affect the SVR rate[21,22,25].

Another problem that may arise with the use of the protease inhibitors is the interactions with concomitant medications. Both boceprevir and telaprevir use hepatic drug metabolizing enzymes such as cytochrome P450 2C (CYP2C), CYP3A4, or CYP1A[15]. Therefore, caution is definitely required for the use of these agents in patients taking other dugs metabolized by the same pathways, such as statins, calcineurin inhibitors, antiretroviral agents, methadone, etc.[15]. Updated information on the possible drug-drug interactions with boceprevir and telaprevir can be found at the Food and Drug Administration (FDA) website (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm) or other relevant sites (e.g., http://www.hep-druginteractions.org).

Use of boceprevir or telaprevir in current clinical practice

Both boceprevir and telaprevir have now been approved for the treatment of genotype 1 patients in several countries around the world. However, the approved treatment algorithms differ between the two drugs and according to the type of patients (Figures 1 and 2). In addition, there are some differences between the treatment algorithms of boceprevir-based regimens recommended by the United States and European regulatory authorities (Figure 1).

Figure 1 Treatment algorithms of boceprevir-based regimens for genotype 1 chronic hepatitis C virus patients recommended by the European Medicines Agency. All patients should start with a 4-wk lead-in phase with only pegylated interferon-alfa and ribavirin (PR). After 4 wk, boceprevir (BOC) is added. In treatment-naïve patients without cirrhosis who achieve an extended rapid virological response [eRVR: undetectable hepatitis C virus (HCV) RNA (< 10 IU/mL) at 8 and 24 wk], the triple therapy should last 24 wk and treatment end at 28 wk. In non-cirrhotic treatment-naïve patients who do not achieve such an eRVR and in all previous relapsers or partial responders without cirrhosis, the triple therapy should last 32 wk (until 36 wk of therapy) and should be followed by an additional 12 wk of PR. The United States Food and Drug Administration (FDA) recommendations suggest that prior relapsers or partial responders without cirrhosis who achieve an eRVR under BOC triple therapy can stop therapy at 36 wk without an additional 12-wk course of PR that is suggested by the European Medicines Agency. Finally, in all cirrhotics (treatment-naïve and experienced) and null responders, the triple therapy should last 44 wk (up to 48 wk of treatment). All patients should be tested for HCV RNA levels at 12 and 24 wk of total therapy and treatment should be discontinued for inefficacy if HCV RNA levels are > 100 IU/mL at 12 wk or HCV RNA is still detectable at 24 wk of therapy.

Figure 2 Treatment algorithms of telaprevir-based regimens for genotype 1 chronic hepatitis C virus patients recommended by both the European Medicines Agency and the Food and Drug Administration. All patients should start directly with the triple combination of telaprevir (TPV) plus pegylated interferon-alfa and ribavirin (PR). The triple combination should always last 12 wk. In treatment-naïve or previous relapser patients without cirrhosis who achieve an extended rapid virological response (eRVR) [undetectable hepatitis C virus (HCV) RNA (< 10 IU/mL) at 4 and 12 wk], triple therapy is followed by 12 wk of PR. In contrast, in non-cirrhotic treatment-naïve or relapser patients without an eRVR as well as in all cirrhotics or previous partial and null responders, triple therapy is followed by 36 wk of PR. Treatment should be discontinued for inefficacy if HCV RNA levels are > 1000 IU/mL at 4 or 12 wk or if HCV RNA is detectable at 24 or 36 wk of therapy.

All patients who receive boceprevir should start with a 4-wk lead-in phase with only PEG-IFN/RBV. PEG-IFN-2b or PEG-IFN-2a may be used, while RBV should be administered at a weight-based dosage. After 4 wk, boceprevir is added, given with food at a dose of 800 mg (4 capsules of 200 mg each) every 8 h. In treatment-naïve patients without cirrhosis who achieve an eRVR [undetectable HCV RNA by a sensitive polymerase chain reaction (PCR) assay (HCV RNA < 10 IU/mL) at 8 and 24 wk], the triple therapy should last 24 wk and treatment finish at 28 wk. In non-cirrhotic treatment-naïve patients who do not achieve an eRVR and in all previous relapsers or partial responders without cirrhosis, triple therapy should last 32 wk (until 36 wk of therapy) and should be followed by an additional 12 wk of PEG-IFN/RBV. Finally, in all cirrhotics (treatment-naïve and experienced) and null responders, triple therapy should last 44 wk (up to 48 wk of treatment). All patients should be tested for HCV RNA levels at 12 and 24 wk of total therapy and treatment should be discontinued for inefficacy if HCV RNA levels are > 100 IU/mL at 12 wk or HCV RNA is still detectable at 24 wk of therapy.

All patients who receive telaprevir should start directly with the triple combination of telaprevir plus PEG-IFN/RBV. Theoretically, PEG-IFN-2a or PEG-IFN2b may be used, although PEG-IFN-2a has been used in all telaprevir trials. RBV is administered at a weight-based dosage, while telaprevir should be administered orally with a fatty meal at a dose of 750 mg (2 capsules of 375 mg each) every 8 h. The triple combination should always last 12 wk. In treatment-naïve or previous relapser patients without cirrhosis who achieve an eRVR [undetectable HCV RNA by a sensitive PCR assay (HCV RNA < 10 IU/mL) at 4 and 12 wk], triple therapy is followed by 12 wk of PEG-IFN and RBV. In contrast, in non-cirrhotic treatment-naïve or relapser patients without an eRVR as well as in all cirrhotics or previous partial and null responders, triple therapy is followed by 36 wk of PEG-IFN/RBV. Treatment should be discontinued for inefficacy if HCV RNA levels are > 1000 IU/mL at 4 or 12 wk or if HCV RNA is detectable at 24 or 36 wk of therapy.

OTHER DIRECT-ACTING ANTIVIRALS

NS5B polymerase inhibitors

There are 2 categories of NS5B polymerase inhibitors: nucleos(t)ide inhibitors (NIs) and non-nucleoside inhibitors (NNIs) (Table 1). NIs mimic the naturally occurring nucleotides and thus are incorporated into the nascent RNA chain causing chain termination[26]. NIs are considered to have a high genetic barrier to resistance, although single amino acid substitutions are able to confer drug resistance in vitro. Nevertheless, because the active site of NS5 is highly conserved and amino acid substitutions in any position of the active site can result in loss of function, such resistant variants fit poorly, requiring weeks or months to grow to detectable levels in the presence of the drug. NIs have antiviral activity against all HCV genotypes (pan-genotype activity) as the active site of NS5B is well conserved across genotypes[27]. GS-7977 seems to be a promising representative of the NIs, as it appears to be rather safe and effective, achieving very high SVR rates (100%) in genotype 2 and 3 patients even when the drug is given for 12 wk only in combination with RBV[28].

NNIs bind to a distant site of the HCV polymerase and cause a conformational change rendering the enzyme ineffective. In particular, NNIs bind to one of 4 allosteric sites at the surface of HCV polymerase (“thumb” domain I, “thumb” domain II, “palm” domain I, “palm” domain II). NNIs have a more limited spectrum of activity being specifically against genotype 1. Because NNIs bind more distantly from the active site, resistant variants can fit in the presence of the drug, and therefore NNIs have a low barrier to resistance.

NS5A inhibitors

NS5A protein is a regulator of replication. NS5A inhibitors have high antiviral activity against different genotypes, but they have a low genetic barrier to resistance. Daclatasvir, a representative of this group (Table 1), is under evaluation in several combinations with promising results [29].

Cyclophilin A inhibitors

Cyclophilins are host proteins involved in protein folding. They play an important role in the HCV life cycle as a regulator of replication. The cyclophilin inhibitor, alisporivir (DEB-025) (Table 1), is a cyclosporine analogue without immunosuppressive properties that has shown pan-genotype antiviral activity and has been used either alone or in combination with PEG-IFN/RBV with promising results[30-32]. Phase III trials with alisporivir were ongoing, but very recently the development of this drug was put on hold by the FDA due to safety concerns (a few cases of pancreatitis, one of which was fatal). SCY-635 (Scynexis) is another cyclophilin inhibitor under development.

NEW COMBINATIONS

Numerous trials of many combinations of the above drugs from different classes are currently ongoing. Much effort and interest has been given to the development of PEG-IFN-free regimens. Protease inhibitors have been combined with NNIs (telaprevir plus VX-222[33], BI201335 plus BI207127[34,35], GS-9256 plus tegobuvir[36]), NIs (danoprevir plus mericitabine)[37] or NS5A inhibitors as double or triple combinations including RBV[28]. Double combinations of a NI with RBV (GS-7977 and RBV) or with NS5 inhibitors are also being evaluated. Promising examples of PEG-IFN-free trials include the combination of the NI GS-7977 with RBV which has been shown to achieve an SVR in 10 out of 10 genotype 2 or 3 treatment-naïve chronic HCV patients treated for 12 wk[28,38] or the combination of the NS5A inhibitor daclatasvir and the NS3 protease inhibitor asunaprevir, which has shown interesting results in difficult to treat, genotype 1, prior null responders treated for 24 wk. The latter combination showed that an SVR can be achieved in 36% of 11 genotype 1 (mostly 1a) prior null responders from the United States[29] and in ≥ 90% of 21 genotype 1b prior null responders coming from Japan[39]. Similarly, encouraging preliminary results have been reported by a 12-wk course of the NS3 protease inhibitor ABT-450 given with ritonavir boosting the combination of NNI ABT-072 and RBV, which achieved an SVR in > 90% of treatment-naïve genotype 1, IL28B rs12979860 genotype CC, non-cirrhotic chronic HCV patients[40]. Thus, it is clear that an SVR can be achieved with interferon-free regimens even in difficult to treat chronic HCV patients.

CONCLUSION

The recently approved boceprevir and telaprevir used in combination with PEG-IFN/RBV substantially improves the SVR rates in both treatment-naïve and treatment-experienced genotype 1 patients, while the treatment duration can be reduced to only 24 wk in a large proportion of mainly treatment-naïve patients. There are, however, several challenges with the use of the new triple combinations. There is a need for immediate results of HCV RNA testing using sensitive quantitative assays, there are new and more frequent adverse events and drug-drug interactions, and there will be increasing difficulties in compliance. In addition, the SVR rates are still poor in very difficult to treat subgroups of genotype 1 patients, such as null responders with cirrhosis, while there is no benefit in patients who cannot tolerate PEG-IFN/RBV and in patients infected with a non-1 HCV genotype. Many new drugs and combinations are currently under evaluation with encouraging results. Although it is yet early, preliminary data suggest that the treatment of chronic HCV patients with well tolerated combinations of oral agents without PEG-IFN is feasible and may lead to a universal HCV cure over the next 5-10 years.