The first pan-genotypic regimen for the treatment of genotypes 1–6 HCV was the combination of sofosbuvir plus velpatasvir.[34,35] Sofosbuvir (NS5B inhibitor) plus velpatasvir (NS5A inhibitor) is a coformulated, once-daily, single-pill regimen. The recommended treatment duration is 12 weeks for all patients. Rates of SVR ≥ 95% were reported in clinical trials. Patients with Gt 3 HCV who have cirrhosis and/or in whom peginterferon (pegIFN) plus ribavirin has previously failed have been observed to have slightly lower rates of SVR (89%–93%). For this group, consider adding ribavirin to the treatment regimen (Tables 3 and 4). Patients with decompensated liver disease should also be treated with sofosbuvir plus velpatasvir plus ribavirin (see Treatment of decompensated liver disease).
The most common adverse events in clinical trials were headache, fatigue, nausea and nasopharyngitis; rates were not significantly different compared with placebo.[34,35] 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/1.73m2, sofosbuvir is not recommended in this setting (see People with severe renal impairment). The combination of sofosbuvir plus velpatasvir is safe and well tolerated even in people with decompensated cirrhosis (see Treatment of decompensated liver disease).
The combination of glecaprevir (NS3/4A protease inhibitor) plus pibrentasvir (NS5A inhibitor) is the second pan-genotypic regimen to be approved for treating genotypes 1–6 HCV. Three tablets are taken orally, once daily, with food. Treatment duration varies according to the presence of cirrhosis and IFN-based treatment history (Tables 3 and 4). In treatment-naive individuals, the duration of therapy is 8 weeks for those with no cirrhosis, and 12 weeks for those with cirrhosis. SVR rates > 95% have been observed for all genotypes of HCV.
Glecaprevir plus pibrentasvir is also approved for people who did not respond to prior therapy with regimens containing IFN, pegIFN, ribavirin and/or sofosbuvir, as well as those previously treated with an NS5A inhibitor without prior treatment with an NS3/4A protease inhibitor (Table 4). Glecaprevir plus pibrentasvir should not be used for people in whom treatment that included both an NS3/4A protease inhibitor and an NS5A inhibitor has previously failed. The recommended treatment duration varies from 8 to 16 weeks according to prior treatment history, HCV genotype and the presence of cirrhosis (Table 4). A detailed discussion of the recommended management of non-responders to HCV therapy is presented in Salvage therapy.
Glecaprevir plus pibrentasvir was well tolerated in clinical studies. Headache, fatigue and nausea were the most common reported adverse effects but were uncommon and typically mild. Elevations in total bilirubin level of at least two times the upper limit of normal (ULN) were observed in 1% of participants, related to glecaprevir-mediated inhibition of bilirubin transporters and metabolism. Bilirubin elevations were asymptomatic, typically occurred early during treatment and were transient. Bilirubin elevations were predominantly indirect and not associated with alanine aminotransferase (ALT) elevations. Note that coadministration of glecaprevir plus pibrentasvir with ethinyloestradiol-containing products may increase the risk of ALT elevations and is contraindicated. Alternative contraceptive agents (eg, progestin-only contraception) or methods (eg, non-hormonal contraceptive method) are recommended for women in whom treatment with glecaprevir plus pibrentasvir is planned.
Exposure to glecaprevir is increased in the setting of hepatic impairment, and caution is recommended because of the possibility of drug-induced liver injury. No dose adjustment is required for patients with mild hepatic impairment (Child–Pugh class A). However, glecaprevir plus pibrentasvir is not recommended for patients with moderate hepatic impairment (Child–Pugh class B) and is contraindicated for patients with severe hepatic impairment (Child–Pugh class C).
The major route of elimination of both glecaprevir and pibrentasvir is biliary–faecal, and < 1% of the dose is excreted in the urine. No dose adjustment is required for patients with any degree of renal impairment, including patients on dialysis. Glecaprevir plus pibrentasvir is therefore a first-line treatment for people with renal impairment (Treatment of HCV in people with renal impairment).
This triple-therapy regimen is the third pan-genotypic regimen for the treatment of HCV. The regimen includes three classes of antiviral agent: an NS5B nucleotide inhibitor (sofosbuvir), NS5A inhibitor (velpatasvir) and NS3 protease inhibitor (voxilaprevir). All three drugs are coformulated into a once-daily, single-pill regimen. The regimen was specifically developed as a salvage regimen for people who did not respond to previous treatment with a first-line DAA regimen (see Non-responders to interferon-free therapy). It has been approved by the TGA but not yet listed on the PBS. It is expected that this regimen will be listed on the PBS in 2019 for the treatment of people who did not respond to treatment with a first-line DAA. It will not be approved for people who are treatment-naive.
In clinical trials, SVR rates > 95% were observed. SVR rates were high regardless of prior treatment experience (prior NS5A inhibitor, prior regimen that did not involve an NS5A inhibitor), the presence of cirrhosis or HCV genotype. The recommended treatment duration is 12 weeks for all patients (Table 4). This treatment regimen is discussed in further detail in 'Non-responders to interferon-free therapy'.