Regimens for chronic infection Gt 1 HCV
There are four IFN-free DAA regimens that are available for PBS prescription for the treatment of Gt 1 HCV (Table 3):
- sofosbuvir + ledipasvir
- sofosbuvir + daclatasvir ± ribavirin
- paritaprevir (ritonavir-boosted) + ombitasvir + dasabuvir ± ribavirin
- elbasvir + grazoprevir ± ribavirin
These four well tolerated regimens have efficacy ≥ 95% across all patient groups, including people with cirrhosis and those who have not responded previously to pegIFN plus ribavirin therapy.
Sofosbuvir plus ledipasvir
Sofosbuvir plus ledipasvir is a coformulated, once-daily, single-pill regimen. The recommended treatment duration is 12 weeks, except for people with cirrhosis who have not responded to pegIFN therapy, who should receive treatment for 24 weeks (Table 3).24,25 Rates of SVR ≥ 95% are achieved in all patient groups, including those with cirrhosis and non-responders to first-generation protease inhibitor therapy (Table 3).24,25 Response rates are similar for Gt 1a and Gt 1b HCV. A shortened treatment duration of 8 weeks may be considered in treatment-naive people with no cirrhosis who have baseline HCV RNA levels < 6 × 106 IU/mL.31 Baseline HCV RNA levels ≥ 6 × 106 IU/mL are associated with higher relapse rates with 8 versus 12 weeks of treatment (10% v 1%).31 In people with cirrhosis who have not responded to pegIFN-based therapy, recent data suggest that outcomes are similar when comparing 24 weeks of treatment with sofosbuvir plus ledipasvir versus 12 weeks with sofosbuvir plus ledipasvir plus ribavirin.32 Note that the combination of sofosbuvir, ledipasvir and ribavirin is not currently available on the PBS. Combination sofosbuvir and ledipasvir is safe even with decompensated cirrhosis (see section under Special Populations: treatment of decompensated liver disease). Fatigue, headache and nausea are the most common adverse effects, but are uncommon and typically mild.24,25 Sofosbuvir, and its main metabolite GS-331007, are renally excreted. As safety data are lacking in people with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 , sofosbuvir is not recommended in this setting (see section under Special Populations: treatment of HCV in people with renal impairment).
Sofosbuvir plus daclatasvir, with or without ribavirin
Sofosbuvir plus daclatasvir therapy is available for PBS prescription as a first-line treatment for Gt 1 HCV. 33,34 SVR rates are ≥ 95%. The recommended treatment duration is 12 weeks for people with no cirrhosis who are treatment-naive, or in whom treatment with pegIFN and ribavirin has previously failed (Table 3). People with cirrhosis are harder to cure and should be treated with either sofosbuvir plus dacla- tasvir plus ribavirin for 12 weeks or sofosbuvir plus daclatasvir (no ribavirin) for 24 weeks. Sofosbuvir plus daclatasvir (no ribavirin) for 24 weeks is the recommended treatment for people with or without cirrhosis who have not responded to prior treatment with a protease inhibitor plus pegIFN and ribavirin (Table 3). Sofosbuvir plus daclatasvir is well tolerated, with low (≤ 1%) discontinuation rates due to adverse events. The most common treatment- related adverse effects are fatigue, headache and nausea; again, these are typically infrequent and mild. Addition of ribavirin increases the frequency of adverse reactions, as outlined in Section under Ribavirin-related adverse events.
Paritaprevir–ritonavir, ombitasvir and dasabuvir ± ribavirin
The regimen of paritaprevir (ritonavir-boosted), ombitasvir and dasabuvir (PrOD) in combination is used with ribavirin for HCV Gt 1a, or without ribavirin for HCV Gt 1b (Table 3). 35-39 Treatment is for 12 weeks, except for Gt 1a patients with cirrhosis and prior null response to pegIFN plus ribavirin; this group should receive treatment for 24 weeks. SVR rates ≥ 95% are observed in all groups treated according to the label. PrOD therapy is not recommended for prior non-responders to protease inhibitor therapy due to concern about reduced efficacy of paritaprevir. The regimen should be used with caution in people with compensated cirrhosis and is contraindicated in patients with decompensated cirrhosis and/or prior history of liver decompensa- tion. Caution is recommended because of the unlikely but real possibility of drug-induced liver injury associated with this regimen. No dosage adjustment of any components of this regimen is required in patients with renal impairment. Recent data suggest that PrOD with no ribavirin is very effective for the treatment of Gt 1a and Gt 1b HCV in people with severe renal impairment (eGFR < 30 mL/min/1.73 m2 , including those receiving haemodialysis or peri- toneal dialysis) (see section under Special Populations: treatment of HCV in people with renal impairment)40.
PrOD is well tolerated, with low (≤ 1%) discontinuation rates.35 The most commonly reported adverse effects are nausea, pruritus and insomnia; these are uncommon and mild in most people. Serum alanine aminotransferase (ALT) level rises of > 5 times the upper limit of normal (ULN) are observed in approximately 1% of patients and typically occur during the first 4 weeks of therapy. Rises in ALT level are more common in women taking ethinyl estradiol-containing medication, and this should be stopped before starting treatment. Alternative contraceptive agents (eg, progestin-only contraception) or methods (eg, non-hormonal contraceptive method) are recommended. ALT level elevations generally occur without bilirubin elevation and resolve with ongoing treatment. Around 2% of patients receiving this treatment (15% in those taking concomitant ribavirin) have developed transient hyperbilirubinaemia > 2 × ULN, due to paritaprevir-induced inhibition of biliary transporters. Bilirubin elevations typically occur early (peak, Weeks 1–2), are not associated with serum ALT elevations and generally resolve with ongoing therapy. Elevation of ALT above baseline and/or elevation of bilirubin > 2 × ULN during treatment should prompt close monitoring of liver function test results, and specialist opinion.
Elbasvir plus grazoprevir
The combination of elbasvir plus grazoprevir with or without ribavirin is the most recent regimen to become available under the PBS for the treatment of Gt 1 HCV. Elbasvir and grazoprevir have been coformulated into a once-daily, single-pill regimen. The recommended treatment regimen differs accord- ing to Gt 1 subtype (Table 3). All people with Gt 1b HCV infection should be treated with elbasvir plus grazoprevir for 12 weeks. For Gt 1a HCV, treatment regimen varies according to treatment history. 41,42 In people who are treatment-naive, as well as people who have previously relapsed after dual therapy with pegIFN and ribavirin or triple therapy with pegIFN and ribavirin plus boceprevir, simeprevir or telaprevir, the recommended treatment regimen is elbasvir plus grazoprevir for 12 weeks. In people who have previously experienced on-treatment fail- ure during dual therapy with pegIFN and ribavirin or triple therapy with pegIFN and ribavirin plus boceprevir, simeprevir or telaprevir (partial respond- ers and non-responders), the recommended regimen is elbasvir plus grazoprevir plus ribavirin for 16 weeks. 43 Overall SVR rates ≥ 95% were observed in Phase III studies using the recommended treatment regimens. 41-43
Elbasvir plus grazoprevir is effective for people in whom treatment with pegIFN and ribavirin plus boceprevir, simeprevir or telaprevir has previously failed — grazoprevir is a second-generation protease inhibitor with an increased barrier to resistance compared with first-generation protease inhibitors. 44 The efficacy of elbasvir plus grazoprevir ± ribavirin in an open-label study of treatment-experienced patients in whom pegIFN and ribavirin plus HCV protease inhibitor therapy had previously failed was 96%. The regimen should be used with caution in people with compensated cirrhosis and is contraindicated in patients with decompensated cirrhosis and/or a history of liver decompensation. Exposure to all protease inhibitors on the market is increased in the setting of hepatic impairment, and caution is recommended because of the possibility of drug-induced liver injury.
No dosage adjustment of elbasvir or grazoprevir is required in patients with renal impairment. In patients with severe renal impairment (eGFR < 30 mL/min/1.73 m 2 ) or with end-stage renal dis- ease, including patients receiving dialysis, elbasvir plus grazoprevir should be administered without ribavirin (see Section 12). 45 Elbasvir plus grazoprevir is well tolerated, and dis- continuation rates in the registration studies were less than 1%. Headache, nausea and fatigue were the most common adverse effects, but were typically mild and occurred at the same frequency as observed in people who were treated with placebo. Typical ribavirin-related adverse events were observed in those who received ribavirin. Elbasvir plus grazoprevir may be associated with biochemical abnormali- ties. Late rises in serum ALT level have been reported in people treated with grazoprevir. Less than 1% of people (13/1690) treated with elbasvir plus grazo- previr ± ribavirin in clinical trials were reported to experience an elevated ALT level > 5 × ULN, typi- cally at or after Week 8 of treatment. Most of these late elevations in ALT level were asymptomatic and resolved despite ongoing treatment. Cirrhosis was not a risk factor for rise in ALT level, but the frequency was higher in people with higher grazoprevir plasma concentrations, making careful evaluation for possible drug–drug interactions an important pre-treatment assessment. Liver function tests should be performed before therapy and at Week 8 of treatment. For people receiving 16 weeks of therapy, additional liver function tests should be performed at Week 12 of treatment (see under section On-treatment monitoring). Elbasvir plus grazoprevir should be discontinued if ALT levels remain persistently > 10 × ULN.
Elevations in serum bilirubin level were also observed in a small proportion of people treated with elbasvir plus grazoprevir. Elevations in bilirubin level > 2.5 × ULN were observed in 6% of patients receiving elbasvir plus grazoprevir with ribavirin, compared with < 1% in those receiving elbasvir plus grazoprevir alone. 46 These increases in bilirubin level were predominantly indirect. Elevations in bilirubin level were typically not associated with serum ALT level elevations.
Ribavirin-related adverse events
Adverse events associated with ribavirin therapy include anaemia, rash, cough, dyspnoea, insomnia and anxiety. Anaemia is common but typically mild–moderate — the mean reduction in haemoglobin level associated with PrOD plus ribavirin was 24 g/L. It is important that ribavirin is started at the full recommended starting dose according to eGFR. Dose reduction of ribavirin in the setting of symptomatic anaemia is appropriate according to the product information and will not reduce the likelihood of SVR.
Ribavirin is teratogenic and therefore both women and men should be counselled about the risks of pregnancy. Both women and men should be coun- selled that two forms of contraception are required while taking ribavirin and for 6 months after treat- ment. As noted, ethinyl estradiol-containing con- traceptives should not be used in combination with PrOD; alternative contraceptive agents or methods are recommended. Ribavirin is renally excreted and dose adjustment is required according to eGFR (see section under Special Populations: treatment of HCV in people with renal impairment).
Treatment of Gt 1 HCV with an NS3 protease inhibitor (simeprevir, telaprevir or boceprevir) combined with pegIFN plus ribavirin is no longer standardof-care, and these treatment regimens are actively discouraged because of the lower rates of efficacy, longer treatment duration and higher toxicity profile (see section on peginterferon-alfa-related adverse events under treatment for chronic HCV). Treatment with sofosbuvir plus pegIFN plus ribavirin for 12 weeks’ duration is also available for prescription under the PBS, but is not recommended as a first-line treatment. Although there are no head-to-head comparisons with IFN-free DAA treatments, the SVR rates observed in clinical trials evaluating sofosbuvir plus pegIFN plus ribavirin were lower than those observed in studies that evaluated the TGA-approved IFN-free treatments for Gt 1 HCV.47