Ombitasvir/paritaprevir/ritonavir plus ribavirin for 24 weeks in patients with HCV GT4 and compensated cirrhosis (AGATE‐I Part II)

Abstract Background and Aims AGATE‐I Part I previously reported high sustained virologic response rates in hepatitis C genotype 4 patients with cirrhosis, with 12 and 16 weeks' treatment with a combination of two direct‐acting antivirals, ombitasvir and paritaprevir (codosed with ritonavir), plus ribavirin. Part II, reported here, extended the trial to include a 24‐week treatment arm to fully assess treatment duration in patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis. Methods Enrollment took place between June and November of 2015. Treatment‐naive and interferon‐experienced patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis were enrolled into Arm C; patients previously treated with a sofosbuvir‐based regimen were enrolled into Arm D. All patients received a 24‐week treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. The primary outcome was the proportion of patients with a sustained virologic response (hepatitis C virus RNA < 25 IU/mL) at posttreatment week 12 in the intention‐to‐treat population. The safety population included all patients who received at least one dose of study drug. Results In total, 64 patients were enrolled into AGATE‐I Part II. Sustained virologic response at posttreatment week 12 was achieved in 57 of 61 patients (93.4%; 97.5% confidence interval, 92.6‐97.7) in Arm C and 3 of 3 patients (100%) in Arm D. Two patients were missing SVR12 data, and two prematurely discontinued treatment. The most common adverse events for Arm C were fatigue (16 [26%]) and asthenia (15 [25%]). Results were comparable with those reported in Part I. Conclusions AGATE‐I Part II indicates that extending treatment beyond 12 weeks in genotype 4–infected patients with compensated cirrhosis does not offer additional benefit.


| INTRODUCTION
Infection with hepatitis C virus (HCV) is associated with substantial morbidity and mortality, and affects more than 185 million people worldwide. 1,2 HCV genotype 4 accounts for more than 8% of total HCV cases (more than 90% of HCV infections in Egypt alone), 1 and its prevalence is characterized by wide regional variations, with the highest prevalence reported for the Middle East and sub-Saharan Africa. 1 An increase in distribution of HCV genotype 4 infections has been noted globally, because of effects of migration, with several European studies reporting 9% to 14% of HCV infections 1,3 attributable to genotype 4. HCV genotype 4 demonstrates substantial genetic variability, with 17 confirmed subtypes. 4,5 In Egypt, genotype 4a is the predominant subtype reported, 6,7 whereas Saudi Arabia and parts of Europe have high rates of subtypes 4,5 4a, 4c, and 4d.
Treatment guidelines from the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Disease (AASLD) now include recommendations for several all-oral direct-acting antiviral (DAA) regimens for patients with HCV genotype 4 infection, 8,9 including once-daily ombitasvir (an NS5A inhibitor), coformulated with paritaprevir (an NS3/4A protease inhibitor identified by AbbVie and Enanta) and the pharmaco-enhancer ritonavir, plus twice-daily ribavirin. The safety and efficacy of the all-oral direct-acting antiviral (DAA) regimen ombitasvir/paritaprevir/ritonavir plus ribavirin was first established in the phase 2b PEARL-I study, in which this combination given for 12 weeks achieved sustained virologic response 12 weeks after the end of treatment (SVR12) in all 91 treatment-naive (n = 42) and treatment-experienced (n = 49) patients with HCV genotype 4 infection without cirrhosis. 10,11 Although there are recommended regimens for patients with HCV genotype 4 infection with compensated cirrhosis, these patients are often underrepresented in clinical trials. [12][13][14][15][16][17] More extensive efficacy and safety data are needed in this patient population, particularly to address the unresolved issue of appropriate treatment duration in these patients. The phase 3 AGATE-I trial was the first large, prospective clinical trial to study the efficacy and safety of an investigational agent in HCV genotype 4 patients with compensated cirrhosis across a set of three treatment durations. 18 Part I of the trial, previously published, 18 randomized 120 patients to 12 or 16 weeks of treatment with ombitasvir/paritaprevir/ritonavir plus ribavirin, and demonstrated SVR12 rates of 97% and 100% (the latter previously reported as 98% because one patient was initially lost to follow-up but has since returned to clinic and achieved SVR), respectively. 18 Here, we report the results of Part II, which expanded the scope of the AGATE-I trial to include a 24-week treatment group in order to identify the optimal treatment duration for HCV genotype 4 patients with compensated cirrhosis. Additionally, a study arm for patients with treatment history of virologic failure with sofosbuvir/pegylated interferon plus ribavirin or sofosbuvir plus ribavirin was included to explore efficacy and safety of ombitasvir/paritaprevir/ritonavir plus ribavirin in these patients with limited treatment options.  18 Enrollment into Part II (Arms C and D) began after randomization in Part I was completed (full eligibility criteria can be found in the appendix p2).

| Study design and patients
Patients in Arm C were either treatment naive or previously treated with interferon plus ribavirin or pegylated interferon plus ribavirin. Prior treatment responses included null responders, partial responders, and relapsers (full definitions of prior treatment experience are given in the appendix p5). A minimum of 10 null responders were to be enrolled to ensure adequate representation of historically harder-to-treat patients.
Patients to be enrolled into Arm D were previously treated with sofosbuvir and pegylated interferon plus ribavirin or sofosbuvir plus ribavirin and were classified as either prior breakthrough/nonresponders or prior relapsers (full definitions are given in the appendix p5). All prior therapy must have been completed no fewer than 2 months prior to the screening visit. Complete inclusion and exclusion criteria are available in the appendix (p2).
The study was designed accordingly to Good Clinical Practice guidelines, the 1975 Declaration of Helsinki, and applicable regulations, with institutional review board approval for all study sites. A list of the International Ethics Committees can be found in the supporting information. All patients provided written informed consent prior to enrollment.

| Procedures
All patients received two tablets of coformulated oral ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg), taken with food once daily, plus a total daily oral dose of 1000 mg ribavirin if the patient's bodyweight was less than 75 kg, or 1200 mg if bodyweight was 75 kg or more, taken in two doses daily for 24 weeks. All patients who received at least one dose of study drugs were monitored for 48 weeks after last dose of treatment. Full details on ribavirin dose modification protocols, RNA quantification, genotyping, and phylogenetic analysis are available in the appendix (pp6-7).

| Outcomes
The primary efficacy end point for Part II was the proportion of patients who achieved SVR12 (HCV RNA less than lower limit of quantification at posttreatment week 12) in Arm C.
The secondary outcomes for Part II were to assess the proportion of patients with either on-treatment virologic failure or posttreatment relapse and to compare the proportion of patients achieving SVR12 between Arms B and C. The number and percentage of patients with treatment-emergent adverse events (any event that begins or worsens in severity after initiation of study drug through 30 days poststudy drug dosing) were tabulated by severity and by relationship to study drug. Laboratory variables were assessed throughout the study. Further information on definitions of relapse and virologic failure and additional outcomes and monitoring is available in the appendix (p8).

| Statistical analysis
The study was designed to test the hypothesis that percentages of treatment-naive and interferon-experienced HCV genotype 4infected patients with compensated cirrhosis treated with ombitasvir/paritaprevir/ritonavir coadministered with ribavirin for 12, 16, and 24 weeks achieving SVR12 were superior to the historical rate of 67% (appendix p9). Full details of all statistical analyses carried out are available in the appendix (p9).

| RESULTS
In Part II of the AGATE-I study, 64 patients were enrolled between June 10, 2015, and November 19, 2015: 61 patients to Arm C and 3 patients to Arm D. All patients were assigned to receive 24 weeks of treatment. All patients received at least one dose of study drug.
Arm C included 30 (49%) treatment-experienced patients, of whom 13 (21%) were null responders, 7 (11%) were partial responders, and 10 (16%) were relapsers to prior treatment. All three patients in Arm D had virologic relapse after prior treatment with sofosbuvir plus ribavirin with or without pegylated interferon. Full patient demographics and baseline disease characteristics are summarized in Table 1. SVR12 was achieved in 57 of 61 patients (93.4%; 97.5% confidence interval [CI], 82.6-97.7) in Arm C and all three patients in Arm D (100%; Figure 1). In Arm C, patients not achieving SVR12 were two patients with missing SVR12 data and two patients with premature discontinuation of treatment: one patient due to an adverse event of acute liver toxicity and one due to unknown HCV RNA (log 10 IU/mL), mean ± SD 6.1 ± 0.5 5.2 ± 1 HCV ≥ 800,000 IU/mL, n (%) 41 (68%) … Interferon or ribavirin treatment experience, n (%) reasons. Superiority to historical rates achieved with pegylated interferon plus ribavirin was shown in Arm C because the lower bound of the 97.5% CI for SVR12 was higher than the predefined threshold (67%).
Comparison of SVR12 by HCV genotype 4 subtypes revealed that the percentages of patients achieving SVR12 for all subtypes were consistent with those of the overall intention-to-treat population, with no clinically meaningful differences between subgroups ( Figure 2).
A sensitivity analysis excluding patients who did not achieve SVR12 for reasons other than virologic failure (eg, early discontinuation or missing SVR12 data) showed SVR12 was achieved in 57 of 57 patients (100%; 95% CI, 93.7-100) in Arm C and in all three patients in Arm D (100%; Figure 1).
Comparison of SVR12 rates from the 24-week treatment Arm C with Arm B using the stratum-adjusted Mantel-Haenszel method showed that no significant difference was observed in SVR12 between patients receiving treatment for either 12 (Arm A) versus 16 weeks (Arm B), or 16 versus 24 weeks (Arm C; Figure S1, appendix p11). for patients in Arm C are presented in Table 2. Grade 2 hemoglobin reductions (<10 g/dL) occurred in 7 (11%) of 61 patients, and no patient experienced a grade 3 or 4 reduction in hemoglobin (<8 g/dL; Table 2). In total, three patients experienced a grade 3 (>5 × ULN) elevation in ALT levels ( Table 2). One patient had an isolated incident of ALT elevations at posttreatment week 1 (223 U/L). Two patients had prolonged elevations: The first patient (also described above) experienced acute liver toxicity with ALT elevations 166 to 219 U/L from day 15 to day 17, and the second patient experienced ALT elevations 248 to 383 U/L from weeks 2 to 6, which resulted in the patient discontinuing the study drug. ALT elevations were resolved by end of treatment in the second patient and were not associated with FIGURE 2 Efficacy of ombitasvir, paritaprevir, and ritonavir plus ribavirin in patients with hepatitis C virus genotype 4 infection and compensated cirrhosis by subtype. * One patient was lost to follow-up and one prematurely discontinued study drug; † patient prematurely discontinued study drug; ‡ one patient was lost to follow-up Fourteen (93%) of 15 patients who had ribavirin dose reduction achieved SVR12. The one patient who did not achieve SVR12 was the patient that prematurely discontinued the study in treatment week 3 because of acute liver toxicity.

| DISCUSSION
The efficacy and safety of all-oral interferon-free combination regimens  Figure S1, appendix p11). Part II also included a study arm for patients with treatment history of prior virologic failure with sofosbuvir with pegylated interferon plus ribavirin or sofosbuvir plus ribavirin to assess  HCV genotype 4 has previously been considered difficult to treat because of variable efficacy between GT4 subtypes, with multiple studies reporting higher SVR rates in HCV GT4a-infected patients than in HCV GT4d-infected patients. 5,19,20  The treatment-emergent adverse events observed in Part II were generally mild and manageable, with only two patients discontinuing treatment in the 24-week treatment arm because of a treatmentrelated adverse event. One patient experienced prolonged elevations of ALT levels, and the other experienced grade 4 acute liver toxicity.
In the latter case, concomitant increases in ALT and total bilirubin levels to grade 3 were reported; however, levels returned to normal after study drug was discontinued. Transient bilirubin levels were in part attributed to increases in indirect bilirubin, which is consistent with the inhibition or organic anion-transporting protein 1B1 and 1B3 by paritaprevir and can also be attributed to ribavirin use. 24 Twenty-three percent of patients in Part II modified ribavirin dosage, with the most common cause for this being hemoglobin decrease, with no effect on overall SVR rates.

FUNDING
AbbVie funded the study (nct02265237); contributed to study design; and participated in the collection, analysis, and interpretation of data, and preparation and approval of this report. All authors had access to all relevant study data, reviewed and approved the final report, and take full responsibility for the accuracy of the data and statistical analysis. The corresponding author contributed to the study design, had full access to all relevant study data, and had final responsibility for the decision to submit for publication.