Development of antiviral agents that target the hepatitis C virus (HCV) has improved the success and tolerability of treatment, especially for patients with HCV genotype 1 infection. The new treatment options mean that clinicians are better able to prevent complications from chronic HCV infection. The field of direct-acting antiviral therapies for HCV infection continues to advance at a rapid pace, and many more potential treatment regimens are being investigated. This article presents a summary of the current treatments available for patients infected with HCV genotype 1 and looks ahead to those that may play a role in the future.
Key points
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Direct-acting antivirals (DAAs) have become standard treatment of HCV genotype 1 infection.
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For many treatment regimens, the duration is just 12 weeks.
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Ribavirin may provide additional efficacy for patients with cirrhosis or HCV subtype 1a infection.
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The continued rapid development of DAAs suggests that new regimens will become available for shorter duration of therapy.
Introduction
There has been a rapid evolution in treatments of hepatitis C virus (HCV) genotype 1 infection. From 1993 until 2011, treatment regimens for HCV included interferon-based therapy. Interferon in combination with ribavirin had not only low success rates but also high discontinuation rates because it was associated with hematologic adverse events (AEs), fatigue, fever, rash, and depression.
A better understanding of the life cycle of HCV and of viral protein structure has helped in the design of drugs that act against specific viral targets, in contrast to interferon and ribavirin, which do not specifically target the virus. Drugs that act directly on the HCV are called DAAs. There are 3 major classes of DAAs ( Table 1 ): NS3/4A protease inhibitors, NS5B polymerase inhibitors (both nucleoside/nucleotide and nonnucleoside), and NS5A inhibitors.
| NS3/4A Protease Inhibitors | NS5B Polymerase Inhibitors | NS5A Inhibitors |
|---|---|---|
| These agents stop HCV replication by inhibiting the HCV NS3/4A serine protease, which is responsible for the cleavage of polyprotein | Two types: nucleoside/nucleotide analogue inhibitors and nonnucleoside inhibitors. Inhibit the polymerase at a site different from the catalytic site | Thought to inhibit viral replication, assembly, and release, although the exact function of NS5A protein is unknown |
| Telaprevir Boceprevir Simeprevir Paritaprevir Grazoprevir Asunaprevir | Sofosbuvir (nucleotide) Dasabuvir (nonnucleoside) | Ledipasvir Ombitasvir Daclatasvir Elbasvir |
Genotype 1 is the most common HCV genotype in the world and has been difficult to treat with interferon-based regimens. Therefore, treating genotype 1 HCV infection has been a priority for clinical development of DAAs. The recent regulatory approval of interferon-free, HCV treatment regimens including DAAs has increased sustained virologic response (SVR) rates from approximately 40% with interferon-based therapies to more than 90%.
The first-generation DAAs, the NS3/4A protease inhibitors telaprevir and boceprevir, had low genetic barriers to resistance, thrice-daily dosing, and significant adverse effects, including anemia. Simeprevir is a next-generation NS3/4A protease inhibitor with greatly improved safety and once-daily dosing. Sofosbuvir became the first nucleotide analogue NS5B polymerase inhibitor to be approved by the US Food and Drug Administration (FDA) and is highly effective in treating all HCV genotypes, including genotype 1. In contrast, dasabuvir is a nonnucleoside NS5B inhibitor that is active against genotype 1 and is approved in combination with the protease inhibitor paritaprevir, which is pharmacologically boosted by ritonavir, and the NS5A inhibitor, ombitasvir. Ledipasvir is also an inhibitor of NS5A that is currently approved in combination with sofosbuvir for treating patients with HCV genotype 1 infection. Other NS5A inhibitors, such as daclatasvir, are active against genotype 1 as well as other HCV genotypes, including genotype 3. Daclatasvir has been approved in some regions of the world in combination with sofosbuvir for multiple genotypes, including genotype 3, and in combination with asunaprevir for HCV genotype 1b infection. The treatment of HCV/human immunodeficiency virus coinfection, HCV infection post–liver transplant, and HCV-infected patients with renal impairments is not covered in this review.
Introduction
There has been a rapid evolution in treatments of hepatitis C virus (HCV) genotype 1 infection. From 1993 until 2011, treatment regimens for HCV included interferon-based therapy. Interferon in combination with ribavirin had not only low success rates but also high discontinuation rates because it was associated with hematologic adverse events (AEs), fatigue, fever, rash, and depression.
A better understanding of the life cycle of HCV and of viral protein structure has helped in the design of drugs that act against specific viral targets, in contrast to interferon and ribavirin, which do not specifically target the virus. Drugs that act directly on the HCV are called DAAs. There are 3 major classes of DAAs ( Table 1 ): NS3/4A protease inhibitors, NS5B polymerase inhibitors (both nucleoside/nucleotide and nonnucleoside), and NS5A inhibitors.
| NS3/4A Protease Inhibitors | NS5B Polymerase Inhibitors | NS5A Inhibitors |
|---|---|---|
| These agents stop HCV replication by inhibiting the HCV NS3/4A serine protease, which is responsible for the cleavage of polyprotein | Two types: nucleoside/nucleotide analogue inhibitors and nonnucleoside inhibitors. Inhibit the polymerase at a site different from the catalytic site | Thought to inhibit viral replication, assembly, and release, although the exact function of NS5A protein is unknown |
| Telaprevir Boceprevir Simeprevir Paritaprevir Grazoprevir Asunaprevir | Sofosbuvir (nucleotide) Dasabuvir (nonnucleoside) | Ledipasvir Ombitasvir Daclatasvir Elbasvir |
Genotype 1 is the most common HCV genotype in the world and has been difficult to treat with interferon-based regimens. Therefore, treating genotype 1 HCV infection has been a priority for clinical development of DAAs. The recent regulatory approval of interferon-free, HCV treatment regimens including DAAs has increased sustained virologic response (SVR) rates from approximately 40% with interferon-based therapies to more than 90%.
The first-generation DAAs, the NS3/4A protease inhibitors telaprevir and boceprevir, had low genetic barriers to resistance, thrice-daily dosing, and significant adverse effects, including anemia. Simeprevir is a next-generation NS3/4A protease inhibitor with greatly improved safety and once-daily dosing. Sofosbuvir became the first nucleotide analogue NS5B polymerase inhibitor to be approved by the US Food and Drug Administration (FDA) and is highly effective in treating all HCV genotypes, including genotype 1. In contrast, dasabuvir is a nonnucleoside NS5B inhibitor that is active against genotype 1 and is approved in combination with the protease inhibitor paritaprevir, which is pharmacologically boosted by ritonavir, and the NS5A inhibitor, ombitasvir. Ledipasvir is also an inhibitor of NS5A that is currently approved in combination with sofosbuvir for treating patients with HCV genotype 1 infection. Other NS5A inhibitors, such as daclatasvir, are active against genotype 1 as well as other HCV genotypes, including genotype 3. Daclatasvir has been approved in some regions of the world in combination with sofosbuvir for multiple genotypes, including genotype 3, and in combination with asunaprevir for HCV genotype 1b infection. The treatment of HCV/human immunodeficiency virus coinfection, HCV infection post–liver transplant, and HCV-infected patients with renal impairments is not covered in this review.
Goal of therapy
The aim of treating HCV infection is to cure the chronic viral infection, thereby preventing complications of HCV-related liver disease, including cirrhosis, hepatocellular carcinoma (HCC), and the need for a liver transplant. Cure from HCV infection can be measured by SVR, which is defined as the absence of HCV RNA by polymerase chain reaction after cessation of antiviral therapy. Classically, SVR was measured 24 weeks after stopping therapy, but the FDA has accepted the absence of HCV RNA 12 weeks after therapy as the definition of SVR for the approval of HCV treatment regimens.
Patient evaluation overview
Routine laboratory evaluation and assessment of the degree of fibrosis, mostly by noninvasive measures, are extremely important to prioritize patients for treatment and to determine the appropriate treatment regimen and duration. According to the HCV guidance from the American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA), patients with advanced fibrosis, cirrhosis, or with extrahepatic complications of HCV have priority for treatment compared with patients with mild or no liver fibrosis. However, treatment is also justified for patients with mild fibrosis and should be prioritized for those at risk of transmitting the infection, regardless of fibrosis stage. Treatment is not recommended for patients with limited life expectancy (less than 1 year).
The choice of treatment drug and duration of therapy depends largely on 3 factors: the subtype of HCV genotype 1 (a or b) (patients with subtype 1a infection tend to experience treatment failure at higher rates than those with 1b), whether the patient has had previous treatment failure with interferon/ribavirin alone or in combination with a DAA, and whether cirrhosis is present or absent. Guidance for monitoring patients with HCV genotype 1 infection is shown in Fig. 1 . Before the selection of an HCV treatment regimen, it is also essential that potential drug-drug interactions be evaluated.
Treatment options
The current HCV treatment guidelines from a joint collaboration of the AASLD, IDSA, and International Antiviral Society USA (IAS-USA) and from the European Association for the Study of the Liver include later-generation DAAs in their recommendations for treatment of genotype 1 infection. Summarized versions of these guidelines can be seen in Tables 2–4 . Updated and detailed versions of the guidelines should be accessed on their respective Web pages ( http://www.HCVguidelines.org ) ( http://www.easl.eu ).
| Regimen | Weeks |
|---|---|
| Ledipasvir/sofosbuvir | 12 a |
| OMV/PTV/RTV + DSV ± RBV | 12 b |
| Simeprevir + sofosbuvir ± RBV | 12 c |
| Sofosbuvir + daclatasvir | 12 c |
a Shorter course can be considered in patients with pretreatment HCV RNA less than 6 million IU/mL. For patients with cirrhosis, RBV should be added or treatment should be extended to 24 wk.
b Subtype 1b with cirrhosis should receive dose plus RBV. Subtype 1a should receive dose plus RBV. Subtype 1a with cirrhosis should receive RBV for 24 wk.
c For patients with cirrhosis, add RBV or extend treatment to 24 wk.
| Genotype | Without Cirrhosis | Compensated Cirrhosis | ||
|---|---|---|---|---|
| Regimen | Weeks | Regimen | Weeks | |
| 1a or ab | Ledipasvir/sofosbuvir | 12 a | Ledipasvir/sofosbuvir | 12 |
| 1a | OMV/PTV/RTV + DSV + RBV | 12 | OMV/PTV/RTV + DSV + RBV | 24 |
| 1b | OMV/PTV/RTV + DSV | 12 | OMV/PTV/RTV + DSV + RBV | 12 |
| 1a | Simeprevir + sofosbuvir ± RBV | 12 | Simeprevir + sofosbuvir ± RBV | 24 |
| 1b | Simeprevir + sofosbuvir | 12 | Simeprevir + sofosbuvir | 24 |
a An 8-wk course can be considered in patients with pretreatment HCV RNA less than 6 million IU/mL.
| Population | Without Cirrhosis | Compensated Cirrhosis | ||
|---|---|---|---|---|
| Regimen | Weeks | Regimen | Weeks | |
| Prior PEG-IFN/RBV | ||||
| GT 1a or b | Ledipasvir/sofosbuvir | 12 | Ledipasvir/sofosbuvir | 24 |
| GT 1a or b | — | — | Ledipasvir/sofosbuvir + RBV | 12 |
| GT 1a | OMV/PTV/RTV + DSV + RBV | 12 | OMV/PTV/RTV + DSV + RBV | 24 |
| GT 1b | OMV/PTV/RTV + DSV | 12 | OMV/PTV/RTV + DSV + RBV | 12 |
| GT 1a or b | Simeprevir + sofosbuvir ± RBV | 12 | Simeprevir + sofosbuvir ± RBV | 24 |
| Prior SOF | ||||
| GT 1a or b | Defer therapy | — | Ledipasvir/sofosbuvir ± RBV | 24 |
| Prior PI | ||||
| GT 1a or b | Ledipasvir/sofosbuvir | 12 | Ledipasvir/sofosbuvir | 24 |
| Ledipasvir/sofosbuvir + RBV | 12 | |||
These recommendations are based on several clinical trials that have consistently shown strong evidence for the efficacy of DAAs in increasing SVR for patients with HCV genotype 1 infection ( Table 5 ). The combination of sofosbuvir and ribavirin is not recommended in patients infected with genotype 1 because of lower efficacy and longer treatment duration. In addition, given the substantial toxicity and high discontinuation rates with interferon-containing regimens, they are not recommended for the treatment of HCV genotype 1 and are not discussed in this review.
| Treatment Regimen | Clinical Evidence | |||
|---|---|---|---|---|
| Sofosbuvir plus simeprevir with or without RBV for 12 wk | Phase 2 COSMOS trial. In both treatment-naive and treatment-experienced patients. In the prior null responder group, SVR12 was 96% with RBV and 93% without RBV | Phase 2 COSMOS trial. Included patients with different grades of fibrosis. The SVR12 rate ranged from 79% to 100% | — | — |
| Ledipasvir/sofosbuvir in combination (FDA approved October 2014) | ELECTRON study in treatment-naive patients with SVR12 rates were 100% for 12 wk, 100% for 8 wk, and 68% for 6 wk | Phase 3 ION-1 trial. SVR12 was 98% with ribavirin and 97% without ribavirin | Phase 3 ION-3 trial. Excluded patients with cirrhosis and investigated shortening therapy from 12 wk to 8 wk. SVR12 was 93%–95% | Phase 2 SIRIUS study. Patients with compensated cirrhosis who failed to achieve an SVR after PEG-IFN, RBV, and either telaprevir or boceprevir. SVR12 rates of 96% and 97% |
| Paritaprevir/ritonavir/ombitasvir plus dasabuvir with RBV (FDA approved for treating HCV genotype 1a infection in treatment-naive patients) | Phase 3 SAPPHIRE-I trial. SVR12 rate 95%. Higher overall virologic failure for genotype 1a than genotype 1b | Phase 3 PEARL-IV trial. SVR12 was 90% in the RBV-free arm vs 97% in the RBV-containing arm. Confirmed the need for RBV for patients with HCV genotype 1a | Phase 3 TURQOUISE-II trial. Overall, SVR12 rates were 89% in the 12-wk arm and 95% in the 24-wk arm | — |
| Daclatasvir and sofosbuvir | Phase 2b trial. With 24 wk of therapy, the SVR rates were 100% in treatment-naive patients and 100% and 95% without and with ribavirin, respectively, in patients who did not respond to PEG-IFN, ribavirin, and either telaprevir or boceprevir | — | — | — |
There are 3 treatment regimens approved by the FDA for treating HCV genotype 1. For the purpose of this review, patients are classified as being treatment naive or treatment experienced, having the absence or presence of cirrhosis, and having failed previous therapy with a DAA.
Treatment-Naive Patients
Ledipasvir plus sofosbuvir
Ledipasvir plus sofosbuvir with and without ribavirin was approved by the FDA for treating HCV genotype 1 infection on October 10, 2014. The approval was based on data from the 2 phase 3 ION trials (ION-1 and ION-3). The recommended treatment of treatment-naive patients with HCV genotype 1 infection without cirrhosis is the fixed-dose combination of ledipasvir (NS5A inhibitor) and sofosbuvir (nucleotide analogue NS5B inhibitor) for 12 weeks without ribavirin. According to the US prescribing information, patients with viral load less than 6 million IU/mL can be considered for 8 weeks’ therapy. However, the HCV guidance panel favored 12 weeks of therapy as the standard approach for this patient population.
The ION-1 investigators enrolled 865 treatment-naive patients with HCV genotype 1 infection, including 20% who had cirrhosis. Among 4 treatment cohorts, they compared 12 and 24 weeks of therapy with ledipasvir/sofosbuvir with and without ribavirin. SVR12 rates were extremely high: 97% to 99% across all arms. The conclusion from ION 1 was that 12 weeks of therapy was as effective as 24 weeks and that adding ribavirin to ledipasvir/sofosbuvir therapy was not necessary, even for patients with cirrhosis.
In ION-3, investigators enrolled 647 treatment-naive, HCV genotype 1–infected patients without cirrhosis and examined the effect of shortening ledipasvir/sofosbuvir with or without ribavirin therapy to 8 weeks. This was a noninferiority study that showed similar SVR rates between the regimens, with an SVR12 of 94% with 8 weeks of ledipasvir/sofosbuvir, 93% with 8 weeks of ledipasvir/sofosbuvir with ribavirin, and 95% with 12 weeks of ledipasvir/sofosbuvir. However, more patients treated for 8 weeks experienced virologic relapse after stopping therapy (4.6%) compared with those treated for 12 weeks (2%). Post hoc analyses suggested that patients with baseline HCV RNA level less than 6 million IU/mL who received 8 weeks of therapy had a similar relapse rate, 2%, as those who received 12 weeks of therapy. Once again, ribavirin provided no benefit with respect to increasing the SVR rate or decreasing the relapse rate. No sofosbuvir resistance was observed. Most patients (15 of 23 tested) who did not reach SVR because of relapse posttreatment had NS5A resistance-associated variants at the time of relapse.
The results from the ION trials confirmed the safety and tolerability of the ledipasvir/sofosbuvir regimen with and without ribavirin. Fewer than 1% of patients either receiving ribavirin or not discontinued treatment because of an AE. Treatment-related AEs were much less common in the arms without versus with ribavirin (45% vs 71%). Without ribavirin, headache and fatigue were the most common adverse effects.
Paritaprevir/ritonavir/ombitasvir and dasabuvir
Paritaprevir/ritonavir/ombitasvir and dasabuvir, with or without ribavirin, were approved by the FDA for the treatment of HCV genotype 1 infection on December 19, 2014. The approval was based on data from several phase 3 clinical trials. Paritaprevir is an NS3/4A serine protease inhibitor that is coformulated with ritonavir, an antiretroviral drug that is also a potent inhibitor of CYP3A/4. The addition of low-dose ritonavir allows for high intracellular concentrations of paritaprevir and facilitates once-daily dosing. Paritaprevir/ritonavir is further coformulated with ombitasvir, a NS5A inhibitor. These drugs are also combined with dasabuvir, a nonnucleoside NS5B polymerase inhibitor.
SAPPHIRE-I investigators compared 12 weeks of the paritaprevir/ritonavir/ombitasvir and dasabuvir combination plus ribavirin to matching placebo in 631 treatment-naive patients without cirrhosis. The SVR rates were 95% in patients with HCV genotype 1a infection and 98% in patients with HCV 1b infection. Virologic failure was rare, with only 1 individual experiencing virologic breakthrough during therapy, and 7 patients (<2%) had virologic relapse after the 12-week treatment was discontinued. In the single patient who had breakthrough, resistance-associated variants were observed in the NS3, NS5A, and NS5B domains. In the patients with relapse, all but 1 patient had HCV genotype 1a infection with the presence of NS3 or NS5A resistance-associated variants. The single patient with HCV genotype 1b infection who experienced relapse had resistance-associated variants against the NS3, NS5A, and NS5B domains.
Because this trial was placebo controlled, the combination of DAAs with or without ribavirin could be compared with a no-treatment group. In the active treatment groups, fatigue and headache were the most common AEs; however, their incidence was not different compared with the placebo groups. Other common AEs included pruritus, asthenia, nausea, and insomnia, and these were more commonly observed in the treatment arms. Anemia occurred exclusively in patients taking the active drug regimen and was attributable to ribavirin-induced hemolytic anemia. No patients discontinued treatment because of anemia, which was managed with dose reduction of ribavirin.
The PEARL III and IV studies examined the paritaprevir/ritonavir/ombitasvir and dasabuvir combination with and without ribavirin in treatment-naive patients with HCV genotype 1b (n = 419) (PEARL III) or 1a (n = 305) (PEARL-IV) infection. Patients with cirrhosis were excluded from both studies. The SVR12 rates in HCV genotype 1b participants did not differ between the cohorts, with 99.5% and 99% achieving SVR12 with and without ribavirin, respectively. However, with HCV genotype 1a, the SVR12 rate was 97% with ribavirin and 90% without ribavirin. In the HCV genotype 1a cohort, the rate of virologic failure was higher in the ribavirin-free arm (8% vs 2%). The conclusion from the trial is that ribavirin added benefit for patients infected with HCV genotype 1a but not for those with genotype 1b.
Sofosbuvir plus simeprevir
Simeprevir, an NS3/4A protease inhibitor, was approved by the FDA on November 22, 2013, for the treatment of HCV genotype 1 in combination with peginterferon-alfa and ribavirin. On November 5, 2014, the FDA approved the combination of sofosbuvir/simeprevir as all-oral therapy for HCV genotype 1 infection based on data from the COSMOS trial. COSMOS was a phase 2, open-label trial, in which 167 patients with chronic HCV genotype 1 infection received sofosbuvir plus simeprevir, with or without ribavirin, for either 12 or 24 weeks. Patients were randomly assigned in a 2:1:2:1 ratio to receive simeprevir and sofosbuvir daily for 24 weeks with or without ribavirin or for 12 weeks with or without ribavirin, in 2 cohorts: previous nonresponders with metavir scores F0-F2 (cohort 1) and previous nonresponders and treatment-naive patients with metavir scores F3-F4 (cohort 2). SVR12 was achieved in 92% (154 of 167) of all patients in the study and in 90% (72 of 80) of patients in cohort 1 and 94% (82 of 87) of patients in cohort 2. The most common AEs were fatigue (31%), headache (20%), and nausea (16%). Extending therapy to 24 weeks did not seem to improve SVR rates, except in patients with prior relapse and advanced fibrosis. However, compared with 12 weeks, this longer duration of therapy was associated with lower rates of virologic relapse among patients with cirrhosis who completed therapy, leading to the recommendation that patients with cirrhosis receive 24 weeks of therapy with this combination.
The OPTIMIST-1 study evaluated the efficacy, safety, and quality-of-life outcomes for 8 or 12 weeks of simeprevir plus sofosbuvir without ribavirin in treatment-naive and treatment-experienced patients without cirrhosis. The SVR12 rate was 97% in the 12-week group compared with 83% in the 6-week treatment group. The presence of the NS3/4A protease Q80K mutation, which is a simeprevir resistance-associated variant, did not seem to affect treatment efficacy in these noncirrhotic patients who received 12 weeks of treatment. The 8-week arm resulted in high SVR12 rates only in select patient subgroups: those with genotype 1b (92%), with lower baseline HCV RNA (96%), and with IL28B CC genotype (93%).
When simeprevir is combined with peginterferon-alfa and ribavirin, patients with HCV genotype 1a infection and the NS3/4A protease Q80K polymorphism at baseline have higher virologic failure rates than patients with genotype 1b infection or genotype 1a infection without this baseline mutation. Therefore, it was recommended that testing for baseline Q80K be done for all HCV genotype 1a–infected patients before the use of simeprevir with peginterferon-alfa and ribavirin. In contrast, the presence of the Q80K polymorphism does not preclude treatment with simeprevir and sofosbuvir, because of previously mentioned data from the OPTIMIST-1 study and analyses from the COSMOS study, in which the SVR rate was high (88%; 51 of 58) among HCV genotype 1a–infected patients with the NS3/4A Q80K polymorphism. Overall, based on the OPTIMIST-1 study, noncirrhotic, HCV genotype 1–infected patients with or without the Q80K polymorphism should receive 12 weeks of treatment with simeprevir plus sofosbuvir.
Treatment-Experienced Patients
Ledipasvir plus sofosbuvir
In the ION-2 trial, 440 treatment-experienced, HCV genotype 1–infected patients who had failed peginterferon/ribavirin with or without telaprevir or boceprevir were randomized to receive 12 or 24 weeks of treatment with ledipasvir/sofosbuvir with or without ribavirin. The SVR12 rates for 12 weeks of ledipasvir/sofosbuvir were 94% without ribavirin and 96% with ribavirin; for 24 weeks of ledipasvir/sofosbuvir, the SVR12 rates were 99% both with and without ribavirin. Approximately 20% of patients in this trial had cirrhosis (data reviewed in the cirrhosis section). Overall, the recommendation was that noncirrhotic patients who had failed prior treatment (including those nonresponsive to telaprevir or boceprevir) should be treated with ledipasvir/sofosbuvir for 12 weeks without ribavirin.
Paritaprevir/ritonavir/ombitasvir and dasabuvir
The PEARL II study evaluated paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for 12 weeks in 179 peginterferon/ribavirin treatment-experienced HCV genotype 1b–infected patients without cirrhosis. Patients who had failed to respond to telaprevir or boceprevir were excluded because cross-resistance with the protease inhibitor, paritaprevir, was anticipated. The SVR rates were 97% with ribavirin and 100% without ribavirin. As expected, reductions in hemoglobin level were more frequently observed in the arms containing ribavirin. This study confirmed that for the combination of paritaprevir/ritonavir/ombitasvir and dasabuvir, ribavirin does not seem to affect clinical efficacy in HCV genotype 1b–infected patients without cirrhosis.
SAPPHIRE-II, a phase 3 randomized controlled trial, examined the efficacy and safety of paritaprevir/ritonavir/ombitasvir and dasabuvir with ribavirin for 12 weeks in 394 HCV genotype 1–infected patients without cirrhosis who had previously failed treatment with peginterferon/ribavirin. Among all patients, 96% achieved SVR12, with similar results observed for HCV genotype 1a (96%) and 1b (97%). The SVR12 rates were similar regardless of prior treatment: 95% for prior relapse, 100% for partial response, and 95% for null response. Thus, among noncirrhotic patients, the type of prior response to peginterferon/ribavirin did not affect the likelihood of SVR with this treatment regimen.
Sofosbuvir plus simeprevir
Data from the COSMOS and OPTIMIST-1 trials indicate the sofosbuvir/simeprevir combination is effective in patients who previously failed peginterferon/ribavirin therapy. Patients who failed to respond to telaprevir or boceprevir have been excluded from studies of this regimen because of the likelihood for cross-resistance between these first-generation protease inhibitors and simeprevir. Of the 80 patients in COSMOS with a null response to peginterferon-alfa and ribavirin treatment who had fibrosis (Metavir stage ≤F2), 79% to 96% achieved SVR in the ribavirin-containing arms and 93% achieved SVR in both ribavirin-free arms. In OPTIMIST-1 study, which enrolled noncirrhotic patients, rates of SVR12 for treatment-experienced patients were 95% for 12 weeks of therapy and 77% for 8 weeks of therapy. The data suggest that for patients who failed previous therapy, sofosbuvir/simeprevir is effective but only for a period of 12 weeks.
Patients with Established Cirrhosis
Curing HCV infection in patients with cirrhosis has been shown to confer considerable clinical benefit, including stopping the progression of liver disease, reducing the risk of dying, reducing the risk of HCC, decreasing the need for liver transplant, and improving patient-reported quality of life.
TURQUOISE-II is phase 3, multicenter, open-label, randomized controlled trial that enrolled treatment-naive and treatment-experienced patients with chronic HCV genotype 1 infection and Child-Turcotte-Pugh class A cirrhosis (n = 380). The investigators evaluated the efficacy of ombitasvir-paritaprevir-ritonavir and dasabuvir plus ribavirin for 12 weeks or 24 weeks. SVR12 rates were 92% for 12 weeks’ treatment and 96% for 24 weeks’ treatment. For patients with HCV genotype 1a infection, SVR12 rates were 89% for 12 weeks’ treatment and 94% for 24 weeks’ treatment. For patients with HCV genotype 1b infection, SVR12 rates were 99% for 12 weeks’ treatment and 100% for 24 weeks’ treatment. Subgroup analysis suggested treatment-experienced patients with HCV genotype 1a infection benefit from extending the treatment duration to 24 weeks. On further post hoc analysis, the observation was made that all HCV genotype 1–infected patients with posttreatment virologic relapse were in the 12-week treatment groups, leading to the recommendation that treatment-naive and treatment-experienced patients with cirrhosis and genotype 1a infection receive 24 weeks of the regimen plus ribavirin. In contrast, 12 weeks of treatment in patients with genotype 1b infection and cirrhosis is sufficient. Because all patients in TURQUOISE-II received ribavirin, the role of ribavirin in these patients with genotype 1b infection is being investigated in a randomized controlled trial. At this time, the recommendation is that ribavirin be included for the treatment of all cirrhotic patients when using this regimen.
In pooled analysis of 513 patients with compensated cirrhosis from phase 2 and 3 clinical trials, in which 70% were treatment experienced, treatment with ledipasvir/sofosbuvir resulted in an SVR12 rate of 96%. The lowest rate of SVR12 occurred in treatment-experienced patients who received 12 weeks of therapy without ribavirin; further analysis of the data suggested that adding ribavirin and extending the treatment duration from 12 weeks to 24 weeks improved likelihood of reaching SVR. The presence of portal hypertension and severity of liver disease were important predictors for reduced SVR. Based on this analysis, HCV guidance recommended that treatment-naive patients with cirrhosis be treated with 12 weeks of ledipasvir/sofosbuvir alone and that treatment-experienced patients with cirrhosis be treated with 24 weeks of ledipasvir/sofosbuvir alone or with 12 weeks of ledipasvir/sofosbuvir plus ribavirin.
In the SOLAR-1 trial, investigators examined the efficacy and safety of ledipasvir/sofosbuvir with ribavirin for 12 or 24 weeks in 108 patients with decompensated cirrhosis. Most patients had a baseline model for end-stage liver disease (MELD) score between 10 and 20. SVR12 rates were 87% for 12 weeks of treatment and 89% for 24 weeks of treatment. There were no differences in SVR rates between patients with Child-Turcotte-Pugh B or C cirrhosis. Antiviral therapy was associated with improved MELD scores in most patients (60%–79%). Tolerance was good, and only 3 patients discontinued therapy as a result of AEs.
The SIRUS trail is a phase 2, double-blind trial that compared the efficacy of a 12-week course of ledipasvir-sofosbuvir plus ribavirin versus a 24-week course of ledipasvir-sofosbuvir in treatment-experienced patients with HCV genotype 1 infection and compensated cirrhosis who failed prior treatment with an NS3/4A protease inhibitor. This study suggests that in genotype 1 treatment-experienced patients with cirrhosis, a 12-week course of ledipasvir-sofosbuvir plus ribavirin provides SVR12 rates similar to those of a 24-week course of ledipasvir-sofosbuvir. The 12-week regimen has the advantage of being more cost-effective.
Data from the ALLY-1 phase 3 study suggest that in HCV genotype 1–infected patients with cirrhosis, 12 weeks of sofosbuvir/daclatasvir plus ribavirin has a good safety profile and results in an SVR12 rate of 83%. In the study, the likelihood of SVR12 diminished as severity of cirrhosis increased: more than 90% of patients with Child-Turcotte-Pugh class A and B cirrhosis reached SVR12, whereas only 56% of patients with Child-Turcotte-Pugh class C cirrhosis did. Daclatasvir is currently available in Europe, parts of Asia and Latin America and was recently approved in the US by FDA in July 24, 2015.
The OPTIMIST-2 investigators studied the safety and efficacy of sofosbuvir/simeprevir for 12 weeks in treatment-naive or treatment-experienced patients with chronic HCV genotype 1 infection and cirrhosis. The SVR12 rate was 88%. Further analysis indicated that SVR12 rates were higher in patients who were treatment naive, had genotype 1b infection, or had a higher baseline platelet count. In contrast to the OPTIMIST-1 study, which evaluated this regimen in noncirrhotic patients, patients with genotype 1a infection who had the Q80K polymorphism were less likely to achieve SVR (74%) compared with those with genotype 1b infection (84%) or genotype 1a infection/no Q80K polymorphism (92%). Based on this finding, cirrhotic patients with HCV genotype 1a infection with the Q80K polymorphism should not be treated with simeprevir plus sofosbuvir because other available regimens are expected to yield higher rates of SVR.
Real-life data from the TARGET registry in the United States suggest that sofosbuvir/simeprevir is well tolerated in patients with cirrhosis but that SVR rates are lower in patients with decompensated cirrhosis (83%) than in patients with compensated cirrhosis (93%). In a multivariate analysis, thrombocytopenia, hypoalbuminemia, prior hepatic decompensation, and treatment failure following telaprevir or boceprevir therapy were independent predictors of lower likelihood of SVR.
Although there is firm consensus on the benefit of treatment of patients with compensated cirrhosis (Child-Turcotte-Pugh A) with low MELD score, the risk and benefit of antiviral treatment in patients with more advanced cirrhosis (Child-Turcotte-Pugh B and C) is less clear. Further, many of these patients with advanced disease are on liver transplant waiting lists. In the context of liver transplant, achieving SVR with advanced clinical disease may be disadvantageous if clinical improvements are not enough to avoid liver transplant. The concern is that if a patient has modest improvement in MELD score with SVR, it might delay organ allocation for transplant because the current system is based on MELD score rather than on clinical signs and symptoms, such as ascites and encephalopathy. Further research is needed to define the role of antiviral therapy in patients with Child-Turcotte-Pugh B and C disease before transplant. Nonetheless, there is consensus around one patient population that is expected to benefit greatly from treatment before liver transplant, patients with HCC, because these patients are often well compensated and DAAs can result in a high cure rate. Because of the diagnosis of HCC, these patients can receive a transplant in many regions regardless of their native MELD score. However, in all patient groups, including those with HCC, viral cure before liver transplant may limit the available pool of organs because patients with HCV cure should not receive livers from an anti-HCV-positive donor. In regions with a high prevalence of anti-HCV-positive donors, this may lead to prolonged wait time. Thus, although DAA therapy is safe and highly effective, it is transformative in the context of advanced liver disease, and more studies are needed to determine the best approach for using DAAs for HCV before liver transplant.
In summary, available data suggest that the likelihood of reaching SVR with DAA therapy is lower for patients with decompensated cirrhosis than for those with compensated cirrhosis, and this is particularly true for treatment-experienced patients. Approaches to improving SVR rates in patients with decompensated cirrhosis include extending the duration of therapy, adding ribavirin, and possibly adding another DAA. Based on several studies, the presence of severe thrombocytopenia and hypoalbuminemia may be important predictors of patients for whom the benefits of HCV cure may be limited.
Patients Who Failed Previous Therapy Including a Direct-Acting Antiviral
Sofosbuvir and daclatasvir in combination for 24 weeks has been investigated in 41 HCV genotype 1–infected treatment-naive patients who were nonresponsive to prior treatment, including the first-generation protease inhibitors telaprevir or boceprevir. Among these patients, 98% had an SVR12. Patients who failed telaprevir and boceprevir were also included in the ION-2 and SIRIUS studies of ledipasvir/sofosbuvir with or without ribavirin. Unexpectedly, prior protease inhibitor failure did not adversely affect the likelihood of HCV cure with retreatment with sofosbuvir plus ledipasvir, an inhibitor of NS5A.
Similarly, an open-label trial studied the efficacy and safety of ledipasvir and sofosbuvir plus ribavirin for 12 weeks in 51 patients with HCV genotype 1 infection who failed previous sofosbuvir-based regimens. Of the 51 patients enrolled, 25 had previously received sofosbuvir plus peginterferon-alfa and ribavirin, 20 had received sofosbuvir and ribavirin, 5 had received sofosbuvir placebo plus peginterferon-alfa and ribavirin, and 1 (2%) had received monotherapy with GS-0938, an NS5B polymerase inhibitor. SVR12 was achieved by 50 of the 51 patients (98%) treated. This study established the proof of principle that sofosbuvir can be used to re-treat patients who failed a prior sofosbuvir-based regimen; this is likely due to this agent’s high barrier to the emergence of HCV variants with resistance during and after treatment. In vitro, sofosbuvir-resistant HCV variants that harbor the S282T mutation in the NS5B region are markedly less fit than wild-type variants, which may explain the successful reuse of this drug.
In contrast, patients who fail to respond to regimens that include NS5A inhibitors, including ledipasvir/sofosbuvir and paritaprevir/ritonavir/ombitasvir + dasabuvir, are likely to have HCV variants that are resistant to NS5A inhibitors that are selected during treatment and can persist for years. In one study, of 41 HCV genotype 1–infected patients who previously failed ledipasvir/sofosbuvir therapy, 71% achieved SVR12 after retreatment with ledipasvir and sofosbuvir for 24 weeks. SVR12 rates were lower in patients with versus without baseline NS5A resistance-associated variants. Four patients with NS5A resistance-associated variants developed evidence of sofosbuvir resistance, suggesting that they had been re-treated with functional sofosbuvir monotherapy. This result suggests that, unlike sofosbuvir, NS5A inhibitors should not be reused in patients who harbor a resistant variant after prior treatment with these agents.
The question of whether any HCV protease inhibitor–based therapy is effective in persons who failed prior treatment with drugs in the same class was investigated in the C-SALVAGE study, which evaluated combination therapy with the NS3/4A protease inhibitor grazoprevir, the NS5A inhibitor elbasvir, and ribavirin in 79 patients with genotype 1 HCV infection and previous failure with boceprevir, simeprevir, or telaprevir plus peginterferon-alfa and ribavirin therapy. The SVR12 rate was 96%, with similar efficacy regardless of previous virologic failure or presence of baseline resistance-associated variants to boceprevir, simeprevir, or telaprevir. Of the 3 patients who did not reach SVR12, all experienced relapse posttreatment and had resistance-associated variants to NS3 or NS5A or both at baseline. Grazoprevir and elbasvir are being investigated in phase 3 clinical trials and are not yet approved for market.
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