There was no significant difference in EBR or GZR exposure between the CP-B participants who received EBR 50 mg plus GZR 50 mg and the noncirrhotic participants who received EBR 50 mg plus GZR 100 mg (see Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/CTG/A5). GZR exposure was numerically slightly higher in participants with CP-B cirrhosis receiving the 50-mg dose compared with noncirrhotic participants receiving the 100-mg dose. EBR (50 mg) exposure was similar in both populations. Of the 2 participants who relapsed, one had low GZR and EBR plasma concentrations 4 hours after dosing and low GZR trough concentrations, whereas the other had low EBR trough concentrations.
Change in MELD and CP scores
At FW12, 12/29 (41.4%) CP-B participants experienced an improvement in MELD score (1-point improvement, n = 5; 2-point, n = 4; 3-point, n = 3), 11 (37.9%) had no change and 6 (20.7%) had a worsening in MELD score (1-point, n = 5; 6-point, n = 1). Improvements in MELD scores were primarily attributable to decreasing bilirubin levels. Similarly, at FW12, 20/29 (69.0%) CP-B participants had improvements in CP score compared with baseline (1-point improvement, n = 15; 2-point, n = 4; 3-point, n = 1), 7 participants had no change, and 2 participants had a 1-point worsening. The participant who died during follow-up had MELD scores of 11 at baseline and at end of treatment, and a baseline CP score of 7 (no CP score was available at the end of treatment for this participant). Further description of change in MELD and CP scores at FW24 is provided in the Supplementary Text and in Supplementary Figure 1 (see Supplementary Digital Content 1, http://links.lww.com/CTG/A5).
Overall, 34/40 (85.0%) participants reported 1 or more AEs during the treatment or follow-up (Table 3), of which 14/40 (35.0%) were recorded by the investigator as treatment related. No serious treatment-related AEs occurred. One participant experienced an overdose of study medication during treatment, which, per protocol, was classified as an ECI. No hepatic ECIs occurred during the study. One participant died during the follow-up period. This participant had a baseline CP score of 7 and presented at TW9 with fever, and was subsequently diagnosed with culture-positive (Streptococcus viridans) spontaneous bacterial peritonitis (a non–treatment-related serious AE that resolved with ceftriaxone) and endocarditis (based on transthoracic echocardiography). After completing 12 weeks of treatment, his condition worsened, with subsequent cerebral infarction, oliguric renal failure, and progressive hepatic failure at FW4. At screening, this participant's medical history included anemia, ascites, esophageal varices, portal vein thrombosis, and splenomegaly-associated thrombocytopenia. The episodes of spontaneous bacterial peritonitis were not associated with increases in ALT, AST, or total bilirubin, and the participant did not experience a late ALT/AST elevation event while receiving study medication. HCV RNA levels at FW4 were not obtained. This participant had MELD scores of 11 at baseline and at end-of-treatment. The death was assessed by the investigator as unrelated to treatment.
AEs occurring in >10% of participants in either group were fatigue (CP-B: 30.0%; noncirrhotic: 30.0%), arthralgia (16.7%; 20.0%), nausea (10.0%; 20.0%), and headache (10.0%; 50.0%; Table 3). No participants discontinued treatment because of an AE. One CP-B participant had a grade 1 ALT increase, and 2 participants had a grade 1 AST increase. There were no ALT or AST increases >2.5× baseline or >5× the upper limit of normal. Four participants had grade 3 bilirubin increases 2.6–5.0× the upper limit of normal that were mild and transient and resolved with ongoing therapy. There were no grade 4 bilirubin increases.
In this phase 2, open-label study, high rates of SVR12 (90%) were achieved in participants with HCV GT1 infection and CP-B decompensated cirrhosis receiving EBR 50 mg plus GZR 50 mg for 12 weeks. This regimen was well tolerated, with no evidence of hepatotoxicity. MELD scores and CP scores remained stable or were reduced in most participants, with only a minority showing a deterioration in liver health status or increased risk of mortality. Of the 30 participants with CP-B cirrhosis, 27 achieved SVR12 and 2 experienced relapse. Both participants who experienced relapse had RASs in both NS3 and NS5A regions at the time of failure.
The approved EBR/GZR fixed-dose combination contains a 100-mg dose of GZR, in contrast to the 50-mg dose administered to the CP-B participants in the present study. The lower dose of GZR was selected for this study based on the previous phase 1 studies showing elevated GZR plasma concentrations in non–HCV-infected individuals with hepatic impairment compared with those with normal hepatic function. In the phase 1 clinical trial, GZR concentrations were 1.7-fold, 5-fold, and 12-fold higher in people with mild, moderate, and severe hepatic impairment, respectively, compared with those with normal hepatic function (22). Furthermore, GZR steady-state area-under-the-curve values are projected to be 1.65-fold higher in HCV-infected individuals with compensated cirrhosis compared with HCV-infected noncirrhotic individuals (22). Given that a GZR dose of 100 mg is known to be well tolerated in HCV-infected individuals with CP-A cirrhosis and without cirrhosis, a starting GZR dose of 50 mg was considered appropriate for the participants with CP-B cirrhosis in this study. Data from the present study showed no statistically significant difference in GZR exposure in CP-B participants receiving GZR 50 mg compared with noncirrhotic participants receiving GZR 100 mg. In consideration of these data, exposure for dose assessments between the 2 groups would suggest that CP-B participants have higher drug exposures than noncirrhotic participants, which is consistent with the observations from previous studies (22). Elevated GZR concentrations in individuals with compensated cirrhosis may also contribute to the high efficacy seen in the EBR/GZR phase 2/3 clinical development program, with several studies reporting SVR rates of 94%–100% in participants with compensated cirrhosis receiving the clinically approved EBR 50 mg/GZR 100 mg FDC for 12 weeks (16–18,20). However, because of the elevated GZR concentrations seen in participants with moderate or severe (CP-B or -C) hepatic impairment, and the consequent increased risk of ALT elevations, the FDC of EBR 50 mg/GZR 100 mg is contraindicated in this population (22). Similarly, other regimens containing HCV protease inhibitors are also listed as not recommended or contraindicated in this population (25–28). An FDC tablet containing EBR plus the lower GZR 50-mg dose is not clinically available, and EBR and GZR are also not available clinically as separate entities.
SVR12 was achieved by 90% of CP-B participants in the current study, which is consistent with rates of 83%–100% reported from other recent open-label clinical trials of DAAs in participants with decompensated liver disease (5–7). In the phase 2 SOLAR-2 study, the combination of sofosbuvir 400 mg and ledipasvir 90 mg plus ribavirin 600–1,200 mg daily for 12 weeks produced SVR12 in 22/26 (84.6%) CP-B participants who had not undergone transplant (SVR was 87% in those with GT1 infection and 67% in those with GT4 infection) (6). A 24-week regimen slightly increased efficacy, with 24/25 (96.0%) participants achieving SVR12 (96% with GT1 and 100% with GT4 infection) (6). In the phase 3 ALLY-1 study, 30/32 (93.8%) CP-B participants achieved SVR12 after treatment with sofosbuvir 400 mg and daclatasvir 60 mg plus ribavirin 600–1,000 mg (7). In the phase 3 ASTRAL-4 study, 90 HCV-infected CP-B participants received 400 mg sofosbuvir plus 100 mg velpatasvir for 12 weeks, and 75 (83.3%) achieved SVR12 (88% of participants with GT1, 50% with GT3, and 100% with GT2 or GT4 infection) (5). The addition of ribavirin to this 12-week treatment regimen slightly improved efficacy (82/87 [94.3%] of participants achieved SVR12), but a longer treatment duration of 24 weeks had no noticeable effect (77/90 [85.6%] achieved SVR12) (5). Although the number of participants in these clinical studies is small, the efficacy of DAAs in treating HCV-infected people with decompensated liver disease is supported by real-world evidence encompassing several thousand individuals (8,9,12).
Based on the overall size of the trial population, as well as the small number of RASs in the 2 participants with virologic failure, limited conclusions can be drawn from this study regarding the impact of NS3 and NS5A RASs on SVR12. One participant who relapsed had baseline NS5A RASs, and both participants who relapsed had lower drug concentrations, which potentially may have contributed to the development of treatment-emergent RASs.
The safety profile of EBR plus GZR in CP-B participants in the current study is comparable to the safety profile in participants without cirrhosis and those with CP-A cirrhosis as assessed during the clinical development program (16–20). One participant experienced decompensation and death during follow-up with repeated episodes of spontaneous bacterial peritonitis, but had no increase in AST, ALT, or total bilirubin while receiving treatment. This decompensation event was considered unrelated to study medication. No treatment-related serious AEs or hepatic ECIs were reported during this study.
Individuals with decompensated liver cirrhosis frequently receive medications for comorbidities, and therefore, the potential for drug–drug interactions should be evaluated when considering treatment options for this population. EBR and GZR are substrates of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp) (22). Co-administration of EBR/GZR with moderate or strong inducers of CYP3A may therefore decrease EBR and GZR plasma concentrations, leading to reduced therapeutic effect, whereas co-administration of EBR/GZR with strong CYP3A inhibitors may increase EBR or GZR concentrations. Some studies have suggested that the magnitude of drug interactions that arise through reversible inhibition of CYP3A may be reduced or even eliminated in people with advanced cirrhosis because of decreased hepatic drug uptake and reduced hepatic enzyme expression (29). In the present study, concomitant use of strong CYP3A/P-gp inhibitors, such as clarithromycin and itraconazole, strong/moderate CYP3A/P-gp inducers, such as rifampin and carbamazepine, and organic anion transporting polypeptide inhibitors, such as cyclosporine, was not permitted.
In conclusion, the treatment regimen of EBR 50 mg plus GZR 50 mg administered for 12 weeks was highly effective and well tolerated in a traditionally hard-to-treat population with few currently approved treatment options. Although this regimen of EBR and reduced-dose GZR is not available for people with CP-B cirrhosis, the results of this trial complement phase 2/3 trial data and real-world experience with EBR/GZR.
CONFLICTS OF INTEREST
Guarantor of the article: Ira M. Jacobson, MD.
Specific author contributions: I.M.J. provided study concept and design, acquisition of data, initial drafting of the manuscript, and critical revision of the manuscript for important intellectual content. F.P., R.F.-M., G.T.E., and E.C.V. performed the acquisition of data. S.B. and P.H. provided analysis and interpretation of data and statistical analysis. L.C. performed analysis and interpretation of data. M.R. provided study concept and design. E.D.C. and H.P. provided study concept and design and initial drafting of the manuscript. All authors have approved the final draft submitted.
Financial support: Funding for this research was provided by Merck Sharp & Dohme Corp. (MSD), a subsidiary of Merck & Co., Inc., Kenilworth, NJ. Medical writing support was provided by Tim Ibbotson, PhD, of ApotheCom, Yardley, Pennsylvania. This assistance was funded by MSD.
Potential competing interests: I.M.J. is a consultant for AbbVie, Assembly Biosciences, Bristol-Myers Squibb, Gilead, Intercept, Janssen, Merck & Co., Inc., Novo Nordisk, Springbank, and Trek; has received research funding from Assembly Biosciences, Bristol-Myers Squibb, Enanta, Gilead, and Merck & Co., Inc.; and has conducted speaking and teaching activities for AbbVie, Gilead, Intercept, and Merck. F.P. is on the speakers' bureau for and has received grants from Merck, Gilead, and AbbVie. R.F.-M. has received research grants from Merck. E.C.V. is an advisor for Gilead. S.B. and L.C. are employed by Merck & Co., Inc., Kenilworth, NJ. P.H., M.R., and H.P. are employed by and own stock in Merck & Co., Inc., Kenilworth, NJ. E.D.C. was formerly employed by and owns stock in Merck & Co., Inc., Kenilworth, NJ, and is currently employed by and owns stock in Bristol-Myers Squibb. G.T.E. discloses no conflicts.
WHAT IS KNOWN
- ✓ EBR/GZR is approved for the treatment of HCV GT 1/4 infection.
- ✓ EBR/GZR is not approved for use in people with Child-Pugh B cirrhosis.
WHAT IS NEW HERE
- ✓ This study assessed EBR plus low-dose GZR in participants with Child-Pugh B cirrhosis.
- ✓ EBR 50 mg plus GZR 50 mg was effective and well tolerated in this study.
- ✓ Although EBR plus reduced-dose GZR is not available for people with CP-B cirrhosis, these results complement phase 2/3 trial data and real-world experience with EBR/GZR.
We extend our gratitude to the patients, their families, investigators, and site personnel who participated in this study. The primary investigators in the C-SALT study were Saleh Alqahtani, Michael R. Charlton, Raymond Chung, Gregory T. Everson, Roberto J. Firpi-Morell, Ira M. Jacobson, Paul Y. Kwo, Fred Poordad, Andrew H. Talal, and Elizabeth C. Verna.
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Supplemental Digital Content
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