There are six IFN-free DAA regimens that are available for PBS prescription for the treatment of Gt 1 HCV in people who are treatment-naive:
- sofosbuvir + velpatasvir
- glecaprevir + pibrentasvir
- elbasvir + grazoprevir
- sofosbuvir + ledipasvir
- sofosbuvir + daclatasvir ± ribavirin
- paritaprevir (ritonavir-boosted) + ombitasvir + dasabuvir ± ribavirin
These six well tolerated regimens have efficacy ≥ 95% across all patient groups.
As noted above, the combination of sofosbuvir plus velpatasvir is a safe and effective treatment for Gt 1 HCV (Sofosbuvir plus velpatasvir and Tables 3 and 4). The recommended treatment duration is 12 weeks for all patients. Cure rates > 95% were observed in clinical trials. Short treatment duration (8 weeks) was not evaluated in registration studies and cannot be recommended.
The combination of glecaprevir plus pibrentasvir is a safe and effective treatment for Gt 1 HCV (Glecaprevir plus pibrentasvir and Tables 3 and 4). The recommended treatment duration is 8 weeks for people with no cirrhosis and 12 weeks for people with cirrhosis. Cure rates > 95% were observed in clinical trials.
The combination of elbasvir plus grazoprevir with or without ribavirin is another regimen 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 according to Gt 1 subtype (Tables 3 and 4). 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.[38,39] 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 4).  Overall SVR rates ≥ 95% were observed in Phase III studies using the recommended treatment regimens.[38-40]
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 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).
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. These increases in bilirubin level were predominantly indirect. Elevations in bilirubin level were typically not associated with serum ALT level elevations.
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 (Tables 3 and 4).[27,28] Rates of SVR ≥ 95% are achieved in all patient groups, including those with cirrhosis and non-responders to first-generation protease inhibitor therapy (Tables 3 and 4).[27,28] 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.43 Baseline HCV RNA levels ≥ 6 × 106 IU/mL are associated with higher relapse rates with 8 versus 12 weeks of treatment (10% v 1%).43 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.[27,28] As noted, sofosbuvir and its main metabolite GS-331007 are renally excreted. Sofosbuvir is not recommended for people with an eGFR < 30 mL/min/1.73m2 (see People with severe renal impairment).
Sofosbuvir plus daclatasvir therapy is available for PBS prescription as a first-line treatment for Gt 1 HCV. , 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. People with cirrhosis are harder to cure and should be treated with either sofosbuvir plus daclatasvir plus ribavirin for 12 weeks, or sofosbuvir plus daclatasvir (no ribavirin) for 24 weeks. 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 Ribavirin-related adverse events.
Prescriptions for sofosbuvir plus daclatasvir have decreased since the introduction of sofosbuvir plus velpatasvir, which is a single-tablet regimen. There may be certain clinical situations in which sofosbuvir plus daclatasvir would be the preferred regimen, including for patients with severe symptomatic reflux oesophagitis requiring high-dose proton pump inhibitor therapy, or for patients with decompensated cirrhosis who are intolerant of ribavirin and in whom 24-week treatment duration is planned (see Special populations: treatment of decompensated liver disease).
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.[46-50] Ribavirin-containing regimens can no longer be recommended as first-line therapy for treatment-naive patients, and this regimen is no longer considered a preferred regimen.
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 history of liver decompensation. 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 peritoneal dialysis) (see Treatment of HCV in people with renal impairment). 
PrOD is well tolerated, with low (≤ 1%) discontinuation rates. The most commonly reported adverse effects are nausea, pruritus and insomnia; these are uncommon and mild in most people. Serum ALT level rises of > 5 × ULN are observed in about 1% of patients and typically occur during the first 4 weeks of therapy. Rises in ALT level are more common in women taking ethinyloestradiol-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. About 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.
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 counselled that two forms of contraception are recommended while taking ribavirin and for 6 months after treatment. As noted, ethinyloestradiol-containing contraceptives 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 Treatment of HCV in people with renal impairment).