Salvage therapy - HCV Guidelines

Non-responders to interferon-free therapy

Non-response to DAA treatment can be defined simply by detectable serum HCV RNA after treatment. Non-response to a first-line DAA regimen can be due to true virological failure (virological break-through during DAA therapy, or virological relapse after treatment in a patient who achieved complete virological suppression during treatment), non-virological failure due to non-adherence, or HCV reinfection. True virological failure is attributable to the emergence of HCV variants that have selected RASs. It is more common in people with cirrhosis, especially advanced cirrhosis, as well as in those with Gt 3 HCV infection.

For people who do not respond to IFN-free DAA therapy, details of the first treatment course should be documented. A careful history should be taken to identify treatment adherence, as well as other factors that may have had limited adherence (social factors, adverse events or possible drug–drug interactions that may have led to inadvertent underdosing). Risk factors for reinfection should be explored. Clinicians should carefully assess for the presence of cirrhosis, which may not have been diagnosed before the first treatment course. People with cirrhosis should be referred to a specialist centre with experience in treating HCV infection (including salvage therapy) and advanced liver disease. Differentiating true virological failure from relapse caused by non-adherence, or from reinfection, may be difficult. True virological failure can be defined by HCV resistance testing; this is useful but, in practice, is not widely available, is not reimbursed and is unlikely to change management. HCV genotyping should be repeated, as a genotype switch indicates reinfection. However, the absence of a genotype switch does not exclude HCV reinfection.

In the setting of a confident diagnosis of HCV reinfection, we recommend treatment as for people who are treatment-naive. Otherwise, we recommend treatment for virological failure as described below.

Sofosbuvir plus velpatasvir plus voxilaprevir was specifically developed as a pan-genotypic salvage regimen for people who did not respond to previous treatment with a first-line DAA regimen. This is the preferred salvage regimen. It is not approved for people who are treatment-naive. 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 recommended treatment duration is 12 weeks for all patients (Table 2 and Table 3). In clinical trials, SVR rates > 95% were observed.[55] 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 presence of RASs at baseline (NS3/NS5A/NS5B, frequency > 15%) was not associated with lower SVR rates. [55]

The most common adverse events in clinical trials were headache, fatigue and diarrhoea. Diarrhoea was more common (18%–20%) than with sofosbuvir plus velpatasvir or placebo. Most occurrences of diarrhoea were mild in severity; the incidence of grade 2 diarrhoea was low (1% to 3%). As noted, sofosbuvir and its main metabolite GS-331007 are renally excreted, but no dose adjustment for sofosbuvir-containing regimens is required for patients with renal impairment, including those with ESRD requiring dialysis (see People with severe renal impairment). Voxilaprevir is a protease inhibitor, and exposure is increased in the setting of hepatic impairment. No dose adjustment is required for patients with mild hepatic impairment (Child–Pugh class A), but treatment with voxilaprevir is not recommended for patients with moderate or severe hepatic impairment (Child–Pugh class B or C).

People who do not respond to treatment with sofosbuvir plus velpatasvir plus voxilaprevir should be referred to a specialist centre with experience in treating HCV infection (including salvage therapy).

This regimen is approved for people who are treatment-naive (see Glecaprevir plus pibrentasvir), as well as for those who did not respond to prior IFN-free DAA therapy. Glecaprevir plus pibrentasvir is PBS-listed for i) people previously treated with an NS5A inhibitor without prior treatment with a protease inhibitor; or ii) people previously treated with a protease inhibitor without prior treatment with an NS5A inhibitor, as well as people treated with sofosbuvir plus ribavirin (Table 3). Glecaprevir plus pibrentasvir should not be used for people in whom treatment that included both a 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 3).

Although this regimen is a first-line pan-genotypic treatment option for people who are treatment-naive, the data supporting efficacy in people in whom DAA therapy has failed are limited. [62.63] MAGELLAN-1 was a randomised, multipart, open-label study of 141 patients with Gt 1 or 4 HCV who failed prior treatment with a regimen containing NS5A and/or protease inhibitors: Part 1 (n = 50) was a randomised dose-finding study, [62] and Part 2 (n = 91) was a randomised study of patients with or without cirrhosis that compared 12 weeks versus 16 weeks of treatment. [63]The SVR in protease inhibitor-experienced (NS5A inhibitor-naive) patients with or without cirrhosis who received 12 weeks of treatment was 100% (14/14). The SVR in patients who had treatment experience with NS5A inhibitors (alone or with a protease inhibitor) was 94% (17/18) in those exposed to an NS5A inhibitor only, and 81% (13/16) in those who had previously failed treatment that included both a protease inhibitor and an NS5A inhibitor.63 Glecaprevir plus pibrentasvir has not been evaluated as salvage therapy for people with Gt 2 or 3 HCV infection in whom treatment with sofosbuvir plus ribavirin has failed, but it is approved on the basis that these people have not been exposed to an NS5A inhibitor or protease inhibitor.

Salvage therapy for people with decompensated liver disease is complicated. The DAA regimens that are PBS-listed for the treatment of people in whom prior DAA therapy has failed both include protease inhibitors, which are not recommended or are contraindicated for people with Child–Pugh B or C cirrhosis. These people should therefore be considered for expedited liver transplantation (see treatment of decompensated liver disease).

For those who are not transplant candidates, treatment options are limited. PBS restrictions do not prohibit patients receiving retreatment with the same regimen, and treatment with sofosbuvir plus velpatasvir plus ribavirin for 24 weeks or longer should be considered (Section 8). These patients should be referred to a specialist experienced in the management of HCV and cirrhosis.

There are few people in whom previous treatment with pegIFN plus ribavirin, with or without a protease inhibitor, has failed and who have not yet been retreated with a DAA regimen. Several DAA regimens are approved for use in this situation (Table 3).

Response rates are similar to those observed in treatment-naive individuals. The combination of sofosbuvir plus velpatasvir plus voxilaprevir is not approved for people who have not yet received treatment with an IFN-free DAA regimen.