Strategic Treatment Reduction in Very Early Liver Disease With 4 Weeks Sofosbuvir Plus Glecepravir-pibrentasvir

The capacity to eliminate HCV through rapid direct acting antiviral (DAA) therapy scale-up would be enhanced by shortened duration therapy in key populations. The "next generation" DAA regimen of glecaprevir/pibrentasvir (300mg/120mg), an NS3/4a protease inhibitor and NS5A inhibitor, provides key features for potential simplified shortened duration therapy in people with early liver disease (F0-2), including pangenotypic activity, high efficacy, and favourable on-treatment HCV RNA kinetics. The addition of sofosbuvir (400 mg) may provide further feasibility for shortened duration therapy with a potent triple class DAA regimen.

Shortened duration therapy (4-6 weeks) has been evaluated in chronic HCV populations with several DAA regimens, with generally unfavourable outcomes (SVR<50%) for 4 week durations.8-11 In a study among a predominantly African American population of 4 week duration therapy of 3 or 4 DAAs, with sofosbuvir/ledipasvir/GS-9451 (protease inhibitor) and sofosbuvir/ledipasvir/GS-9451/GS-9669 (non-nucleoside polymerase inhibitor), SVR was only 40% (10/25) and 20% (5/25) in the 3 and 4 DAA regimen groups, respectively.10 In separate phase II studies that included evaluation of 6 weeks sofosbuvir (400mg)/velpatasvir (100mg)/voxilaprevir (100 mg) in treatment naïve patients without cirrhosis, SVR was 88% (29/33) among patients with genotype 2, 3, 4, or 6,12 93% (14/15) in patients with genotype 13,13 and and 71% (24/34) in patients with genotype 1.14 Non-published data (provided by Gilead Sciences) from the latter study demonstrates a higher SVR (88%, 14/16) in the sub-population of patients with F0-2. Thus, in patients with relatively early liver disease virological failure is uncommon with 6-week duration sofosbuvir/velpatasvir/voxilaprevir therapy.

These studies would suggest that a 6-week duration therapy, particularly with a potent 3 DAA triple class regimen, may be feasible for many patients with chronic HCV infection, but a 4-week duration would probably compromise treatment outcomes. However, in a small study (n=16) among younger people who inject drugs (PWID) with early liver disease (<50 years, F0-2) in Denmark, a 4-week regimen of sofosbuvir/ledipasvir plus ribavirin provided a per protocol (PP)(n=13) SVR of 92% (one relapse) with intention to treat (ITT) SVR of 75%. In the same study 16 PWID were treated with the same regimen plus pegylated interferon with PP and ITT SVR of 100% and 94%, respectively. Further evidence for the potential of ultra-short duration DAA therapy comes from a response-guided study in Hong Kong. Patients with HCV genotype 1b were treated with three different triple class DAA regimens, including sofosbuvir/ledipasvir + asunaprevir, sofosbuvir + daclatasvir + simeprevir, or sofosbuvir + daclatasvir + asunaprevir, and those with an ultra-rapid virological response (HCV RNA <500 IU/mL at day 2; 18/26) had treatment duration shortened to three weeks. The SVR rate was 100% (18/18) in the three-week treated population.

While efficacy has been suboptimal in most studies of short duration DAA therapy to date, the emergence of clinically significant resistance-associated substitutions (RAS) has not been seen, and retreatment with the same regimen for 12 weeks has been successful.8,9 The FOURward study examined the safety and efficacy of short-duration therapy (4 or 6 weeks) with sofosbuvir + daclatasvir/asunaprevir/beclabuvir in patients with HCV genotype 1 and without cirrhosis.9 Although efficacy was suboptimal (SVR12 43%), among those with virological relapse (n=16), 44% (n=7) had no emergent RAS detected at failure. Furthermore, in the nine patients with treatment-emergent NS5A RAS, the clinical significance was uncertain, as all emergent NS5A RAS conferred low-nanomolar resistance in vitro. Regardless of RAS emergence, retreatment of patients who experienced virological relapse with 12 weeks sofosbuvir + daclatasvir/asunaprevir/beclabuvir + ribavirin resulted in SVR of 100%. C-SWIFT evaluated the efficacy and safety of sofosbuvir + elbasvir/grazoprevir in patients with HCV genotype 1 and without cirrhosis for four and six weeks, with SVR12 rates of 32% (10/31) and 87% (26/30), respectively.8 All patients with virological relapse who received retreatment with 12 weeks of sofosbuvir + elbasvir/grazoprevir + ribavirin achieved SVR12, despite the majority having NS5A and/or NS3 RAS.

The combination of sofosbuvir (400 mg) + glecaprevir/pibrentasvir (300mg/120mg) has not been evaluated as a shortened duration triple class DAA regimen. It has been evaluated as a 12 and 16-week regimen in combination with ribavirin for treatment of prior glecaprevir-pibrentasvir virological failure (8 or 12-week duration prior therapy), with very high efficacy of 96% (22/23) and good tolerability (Wyles D. et al. ILC 2018). A non-ribavirin containing regimen would be expected to have further enhanced tolerability.