Genotype-specific regimens for the treatment of people with HCV infection are still listed on the PBS. Elbasvir plus grazoprevir and sofosbuvir plus ledipasvir are genotype-specific treatment regimens, and HCV genotype should be determined before prescribing either of these regimens. Both regimens are well tolerated and have efficacy ≥ 95% in people with no cirrhosis, as well as in people with cirrhosis.
Several other genotype-specific regimens for the treatment of HCV infection are no longer marketed in Australia and have been removed from this consensus statement. These include sofosbuvir plus daclatasvir, with or without ribavirin; sofosbuvir plus ribavirin; and paritaprevir (ritonavir-boosted) plus ombitasvir plus dasabuvir (PrOD), with or without ribavirin.
The combination of elbasvir plus grazoprevir with or without ribavirin is available under the PBS for the treatment of Gt 1 and Gt 4 HCV. Elbasvir and grazoprevir have been coformulated into a once-daily, single-pill regimen. The recommended treatment regimen differs according to Gt 1 subtype. All people with Gt 1b HCV infection should be treated with elbasvir plus grazoprevir for 12 weeks. For Gt 1a and Gt 4 HCV, treatment regimen varies according to treatment history (Table 3).[45,46] 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 failure during dual therapy with pegIFN and ribavirin or triple therapy with pegIFN and ribavirin plus boceprevir, simeprevir or telaprevir (partial responders and non-responders), the recommended regimen is elbasvir plus grazoprevir plus ribavirin for 16 weeks (see People with Gt 1 HCV who did not respond to treatment with peginterferon-alfa plus ribavirin, with or without a protease inhibitor and Table 3).[47] Overall SVR rates ≥ 95% were observed in Phase III studies using the recommended treatment regimens.[45-47]
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 (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) or with end-stage renal disease, including patients receiving dialysis, elbasvir plus grazoprevir should be administered without ribavirin (see Treatment of HCV in people with renal impairment).[48]
Elbasvir plus grazoprevir is well tolerated, and discontinuation 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 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 abnormalities. 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 grazoprevir ribavirin in clinical trials were reported to experience an elevated ALT level > 5 × ULN, typically 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 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.[49] These increases in bilirubin level were predominantly indirect. Elevations in bilirubin level were typically not associated with serum ALT level elevations.
Note that ribavirin can cause adverse events, including anaemia, rash, cough, dyspnoea, insomnia and anxiety. Anaemia is more common in patients with decompensated liver disease, and it is recommended that ribavirin be started at a low dose of 600 mg daily for these patients. Ribavirin is renally excreted, and dose adjustment is required according to eGFR (see Special populations: treatment of HCV in people with renal impairment). Patients with renal impairment have increased risk of anaemia during ribavirin therapy. Monitoring of haemoglobin levels is recommended every 2–4 weeks during ribavirin therapy in people with decompensated liver disease.
As ribavirin is teratogenic, both women and men should be counselled about the risks of pregnancy and advised that two forms of contraception are recommended while taking ribavirin and for 6 months after treatment.
Sofosbuvir plus ledipasvir is a coformulated, once-daily, single-pill regimen for the treatment of Gt 1 HCV infection. 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).[33,34] Rates of SVR ≥ 95% are achieved in all patient groups, including those with cirrhosis and non-responders to first-generation protease inhibitor therapy.[33,34] Response rates are similar for Gt 1a and Gt 1b HCV. A shortened treatment duration of 8 weeks should be considered in treatment-naive people with no cirrhosis who have baseline HCV RNA levels < 6 × 106 IU/mL.[50] Baseline HCV RNA levels ≥ 6 × 106 IU/mL are associated with higher relapse rates with 8 versus 12 weeks of treatment (10% v 1%).[50] Combination sofosbuvir and ledipasvir is safe even with decompensated cirrhosis (see treatment of decompensated liver disease).
Fatigue, headache and nausea are the most common adverse effects, but are uncommon and typically mild.[33,34] As noted, sofosbuvir and its main metabolite GS-331007 are renally excreted. In view of emerging data supporting the safety of sofosbuvir in patients with severe renal impairment, the US FDA has recommended that no dosage adjustment of sofosbuvir-based regimens is required in patients with mild, moderate or severe CKD, including those on dialysis.[42] An update to the Australian product information is anticipated.