Real-world Safety and Effectiveness of 24-week Sofosbuvir and Ribavirin Treatment in Patients Infected with Rare Chronic Hepatitis C Virus Genotypes 3, 4, 5, or 6 in Japan

Abstract

Objectives

Real-world evidence on the safety and effectiveness of direct-acting antivirals in patients infected with chronic hepatitis C virus (HCV) genotypes (GTs) 3, 4, 5, or 6 in Japan is limited. This prospective observational study assesses the real-world safety profile and treatment effectiveness among patients prescribed sofosbuvir with ribavirin (SOF+RBV) for HCV GT3-6 infection in Japan.

Methods

Adults receiving 24-week SOF+RBV treatment for HCV GT3-6 infection were prospectively enrolled and observed through 24 weeks post-treatment for treatment-emergent adverse events (AEs) considered related to SOF and/or RBV by treating physicians and for a sustained virologic response at 12 and 24 weeks post-treatment (SVR12, SVR24). Incidence rates of related AEs and serious AEs (SAEs) were calculated. Proportions of patients experiencing related AEs/SAEs and those achieving SVR12 and SVR24 were assessed overall and by baseline characteristics, including treatment experience and cirrhosis status.

Results

Among the 50 patients included in the safety analysis, 92% had GT3 infection. The incidence rates of related AEs and SAEs were low overall (1.52 and 0.25 per 100 person-weeks, respectively), with 6.0% and 14.0% patients experiencing AEs related to SOF or RBV, respectively. There were no marked differences in the occurrence of related AEs/SAEs by patient baseline characteristics. SVR12 and SVR24 were achieved in 83.7% (41/49) and 82.2% (37/45) of patients, respectively. Lower effectiveness was observed among treatment-experienced patients and patients with cirrhosis at baseline.

Conclusion

This study demonstrated that SOF+RBV treatment for HCV GT3-6 infection was safe, effective, and an important treatment option for this difficult-to-treat patient population in Japan.

Introduction

Chronic hepatitis C virus (HCV) infection remains a global issue, with an estimated prevalence of 64 to 103 million people, although the burden of HCV and the distribution of HCV genotypes (GTs) vary by country (1,2). The different HCV GTs (labeled 1 through 6) are genetically distinct groups of the virus that have evolved over time, each having unique clinical characteristics and different treatment options. Amongst the estimated 1.5 to 2.0 million people infected with HCV in Japan, the predominant HCV GTs are 1b and 2, which are endemic to the country. Genotypes 3, 4, 5 and 6 (GT3-6) comprise the remaining ≤1% of the HCV-infected population, of which GT3 is the most prevalent, with individuals mainly having contracted HCV via contaminated blood products that were used for blood transfusions from the 1970s to 1990s (1,3-6). Consequently, the prevalence of HCV GT3-6 infection (6-8) as well as coinfection with human immunodeficiency virus (HIV) (9,10) is higher among hemophiliacs in Japan, who required blood transfusions during that time, than among others, with one survey reporting that more than 15% of HCV/HIV coinfected patients had GT3 infection (11).

Patients with HCV GT3 infection are more difficult to treat than those with other GTs, showing a faster onset of fibrosis, higher prevalence of steatosis (grade 3), and higher incidence of hepatocellular carcinoma (HCC) (12-15). Compared to GT1 and GT2, the treatment response to direct-acting antivirals (DAAs) is generally lower among GT3 patients (16-18). Less is known about the natural history of GT4-6 infection, although the presence of cirrhosis and HCV treatment history may influence the response to DAA treatment (1). Given that therapeutic options for HCV GT3-6 infection are limited in Japan, there remains a significant unmet medical need in this patient population, particularly among those who are most challenging to treat, including patients with cirrhosis or those who have previously failed to achieve a sustained virologic response (SVR) after HCV therapy.

DAA options for HCV GT3-6 infection have only been available in Japan since 2017, and treatment indications vary by treatment experience and presence of compensated or decompensated cirrhosis (19). The combination of sofosbuvir (SOF; 400 mg), an NS5B nucleotide polymerase inhibitor, with ribavirin (RBV; dosage based on patient body weight) was originally approved in 2015 for the treatment of HCV GT2 in Japan. Given the substantial unmet medical need of this challenging condition in Japan, the indication was expanded to include GT3-6 in 2017 based on favorable safety and efficacy results from clinical trials of SOF+RBV for HCV GT3 infection conducted outside of Japan (20,21). In clinical trials, serious adverse events (SAEs) occurred in less than 5% of patients, and the most commonly reported adverse events (AEs) were headache (30-40% of patients), fatigue (22-38%), and nausea (21%); decreased hemoglobin levels (＜10 g/dL) associated with RBV use were observed among 6% of GT3 patients in one clinical trial (17,22,23). In Japan, SOF+RBV is contraindicated for patients with severe renal impairment [estimated glomerular filtration rate (eGFR) ＜30 mL/min/1.73 m²] and for patients with end-stage renal disease requiring dialysis, irrespective of GT, due to a lack of data in this population and increased levels of SOF and its metabolite in pharmacokinetic studies. However, SOF+RBV can be safely administered in patients with mild to moderate renal impairment (24). The efficacy and effectiveness of SOF+RBV for GT3 infection ranged from 60% to 90% of patients achieving SVR at 12 weeks post-treatment (SVR12) in clinical trials and observational studies conducted outside of Japan (17,22,23,25-27). The response to treatment varied by treatment history and cirrhosis status at treatment start, with patients with a treatment history who were cirrhotic at baseline experiencing SVR12 rates between 42% to 58% (17,23,26).

Although no clinical trials had yet been conducted to assess the safety and efficacy of this indication among a Japanese cohort, SOF+RBV for HCV GT3-6 treatment had already been approved in nearly 70 countries at the time the indication was expanded in Japan. The significant need for treatment alternatives was recognized by patient associations and academic societies, such as the Japanese Society for AIDS Research, the Japan Society of Hepatology, and the Japanese Society on Thrombosis and Hemostasis, who requested that the Pharmaceuticals and Medical Devices Agency (PMDA) expand the indication of SOF+RBV to include GT3-6 infection under these unique circumstances (21). Thus, upon expansion of the SOF+RBV indication in Japan in 2017, the PMDA required the conduct of a real-world observational study to investigate the safety and effectiveness among patients with HCV GT3-6 infection in Japan.

We herein report a prospective observational study conducted to fulfill this requirement from the PMDA. The safety and effectiveness of 24 weeks of SOF+RBV treatment among patients with HCV GT3-6 infection, a rare and difficult-to-treat patient population, were assessed under real-world conditions in Japan. The occurrence of AEs considered causally related to SOF and/or RBV treatment by treating physicians and the SVR12 and SVR24 rates were explored in the overall patient population and by baseline characteristics, including patient treatment history, presence of cirrhosis, and degree of renal impairment.

Materials and Methods

Study design and patients

In this multicenter, observational study, HCV-infected patients with neither GT1 nor GT2 infection were prospectively enrolled from clinical sites throughout Japan between September 2017 and June 2019. Adults with or without compensated cirrhosis and prescribed 24 weeks of SOF+RBV treatment (following the guidance in the Japanese prescribing information) were eligible for enrollment. Aside from the exclusion of patients with GT1 or GT2 infection, there were no other exclusion criteria for study enrollment in order to allow for a full assessment of real-world SOF+RBV utilization in clinical practice. The observational periods of both the safety and effectiveness analyses were from the start of treatment through 24 weeks after the end or early discontinuation of treatment (approximately 48 weeks total).

The study was conducted in accordance with PMDA regulation, following the principles of the International Conference on Harmonization Pharmacovigilance Planning E2E guidelines, Good Post-marketing Study Practice, and Good Pharmacovigilance Practices.

Clinical and laboratory assessments

Data were collected prospectively using standardized electronic case report forms (eCRFs) to extract data from patient medical records at enrollment and subsequent clinical care visits through the observational period. Collected information included demographics, the medical history, baseline medical conditions, the HCV treatment history, treatment-emergent AEs related to SOF and/or RBV, and HCV RNA levels for the assessment of the SVR. Laboratory measures at baseline (within six weeks of starting treatment) and end-of-treatment (within six weeks of ending treatment) were also collected for the following: alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum albumin, hemoglobin, serum creatinine, and the eGFR, which was calculated using the chronic kidney disease epidemiology collaboration method (28).

Safety profile and effectiveness

Enrolled patients who had a clinic visit after SOF+RBV treatment start were assessed for safety. Treatment-emergent AEs were identified and determined to be related to SOF and/or RBV (related AEs) by the treating physicians during routine clinical practice. The AEs were reported using the standardized eCRFs, which included detailed descriptions of AEs, assessments of seriousness, and evaluations of causal relationship to SOF and/or RBV. Seriousness, defined as an outcome of death, hospitalization, disability, congenital anomaly, a medically important event, or life-threatening condition, was determined by the treating physician and study sponsor to identify SAEs, with the more conservative determination used for discrepant evaluations. The determination of whether an AE was causally related to SOF and/or RBV was based on the treating physician's evaluation. The occurrences of AEs and SAEs were examined by preferred term (PT), tabulated from the Japanese translation of the Medical Dictionary for Regulatory Activities (MedDRA, version 23.0J), to further characterize the safety profile and assess identified and potential safety risks, which included hepatitis B virus reactivation, hypertension, cerebrovascular disease, anemia, and any AEs among patients with severe renal impairment or requiring dialysis.

Patients who had HCV RNA laboratory results after treatment completion or early discontinuation of treatment were further evaluated for effectiveness. SVR was defined as HCV RNA levels below the lower limit of quantification at approximately 12 and 24 weeks post-treatment (SVR12 and SVR24, respectively). As the frequency of clinical visits varies among patients in the real-world setting, SVR12 and SVR24 were assessed using the HCV RNA level closest to 12 or 24 weeks after the end of treatment, between 6 and 20 weeks and after 21 weeks post-treatment, respectively.

Statistical analyses

All analyses were performed using the SAS software program, version 9.4 (SAS Institute, Cary, USA). Baseline demographic and clinical characteristics were expressed using counts and percentages for categorical data and distributions for continuous data. Mean values of laboratory measures at baseline and end-of-treatment were also calculated among patients with results at both time points. To further assess laboratory value changes within patients over time, mean differences were also calculated, and paired Student's t-tests were performed. The incidences of AEs and SAEs attributed to either SOF or RBV utilization were summarized as a rate overall (number of first events per 100 person-weeks at risk) and as cumulative frequencies (number of patients with at least one AE or SAE divided by the total number of patients). Multiple reports of the same AE occurring on the same date for a given patient were counted as a single event. SVR12 and SVR24 were assessed separately using proportions (number of patients who achieved SVR12 or SVR24 divided by the number of patients with available SVR12 or SVR24 achievement results).

The exact method assuming a binomial distribution was used to calculate 95% confidence intervals (CIs) around mean values, proportions, and rates (assuming a Poisson distribution). Chi-square tests were used to examine potential differences by baseline demographic and clinical characteristics, including the HCV treatment history, cirrhosis status, and degree of renal impairment, for both the frequency of AEs considered related to treatment and proportion of patients achieving SVR. Fisher's exact tests were used if the expected frequency was less than five. A significance level of 5% was used for all statistical comparisons.

Results

Enrollment and baseline characteristics

A total of 50 patients were enrolled from 40 clinical sites across Japan. Baseline demographic and clinical characteristics are presented in Table 1. Most were men (68.0%) and of Japanese descent (58.0%), and the mean [±standard deviation (SD)] age at the start of treatment was 56 (±13) years old. Nearly all patients had HCV GT3 infection (92.0%), while the remaining had GT6 (n=2), GT4 (n=1), and an unknown GT that was neither 1 nor 2 (n=1). There were 20 (40.0%) HCV treatment-experienced patients, of whom 85.0% had previously received pegylated-interferon (or interferon) with or without RBV, and 90.0% experienced either relapse/breakthrough (65.0%) or non-response (25.0%) as a result of their most recent HCV treatment. Cirrhosis was present among 11 (22.0%) patients (10 compensated, 1 unknown stage). One patient was coinfected with HBV, and one patient had HCC at baseline.

Table 1.

Baseline Demographic and Clinical Characteristics.

	Total patients (n=50)
Sex (n, %)
Female	16	(32.0)
Male	34	(68.0)
Age at treatment start (years)
Minimum, maximum	34.0, 81.0
Mean (Standard deviation)	56 (13)
Median (Q1, Q3)	56 (46, 67)
<65 (n, %)	34	(68.0)
≥ 65 (n, %)	16	(32.0)
Race/ethnicity (n, %)
Asian, Japanese	29	(58.0)
Asian, Non-Japanese	17	(34.0)
White	4	(8.0)
Body mass index (kg/m2) (n, %)
<18.5	2	(4.0)
18.5 to <25.0	25	(50.0)
≥25.0	14	(28.0)
Unknown	9	(18.0)
HCV genotype (n, %)
3	46	(92.0)
4	1	(2.0)
5	0	(0.0)
6	2	(4.0)
Unknown (neither GT1 nor GT2)	1	(2.00)
Prior HCV treatment history (n, %)
Treatment-naïve	30	(60.0)
Treatment-experienced	20	(40.0)
Prior HCV treatment
Peg-IFN (or IFN)	2	(10.0)
Peg-IFN (or IFN)+RBV	15	(75.0)
Other (unspecified)	3	(15.0)
Outcome of most recent prior HCV treatment
Non-response	5	(25.0)
Relapse/breakthrough	13	(65.0)
Unknown	2	(10.0)
Clinical conditions present at baseline (yes; n, %)
Cirrhosis	11	(22.0)
Compensated	10	(90.9)
Unknown	1	(9.1)
HBV infection	1	(2.0)
HCC	1	(2.0)
Chronic liver disease of non-HCV etiology (except HBV and HCC)	0	(0.0)
Bleeding disorder (including hemophilia)	5	(10.0)
HIV infection	5	(10.0)
Chronic cardiovascular disease	1	(2.0)
Hypercholesterolemia	1	(2.0)
Other†	0	(0.0)
Hypertension	15	(30.0)
Cerebrovascular disease	0	(0.0)
Diabetes mellitus	9	(18.0)
Allergies	2	(4.0)
eGFR (CKD-EPI, mL/min/1.73 m2) (n, %)
≥90 (Normal)	30	(60.0)
60 to <90 (Mild to normal reduction)	12	(24.0)
30 to <60 (Mild/moderate to severe reduction)	0	(0.0)
15 to <30 (Severe reduction)	0	(0.0)
<15	0	(0.0)
Unknown	8	(16.0)

Q1: 25th percentile, Q3: 75th percentile, Peg-IFN: pegylated-interferon, eGFR: estimated glomerular filtration rate, CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration

^†Includes coronary artery disease, congestive heart failure, cardiac arrhythmia, bradycardia, and other chronic cardiovascular disease.

Regarding the non-hepatic clinical conditions at baseline, hypertension was the most prevalent (30.0%), followed by diabetes mellitus (18.0%), bleeding disorder (including hemophilia, 10.0%), and HIV coinfection (10.0%). Renal function, categorized by eGFR at baseline, was normal (≥90 mL/min/1.73 m²) in 60.0% of patients, between mildly reduced and normal (60 to ＜90 mL/min/1.73 m²) in 24.0%, and unknown among the rest.

Assessments of laboratory measures

Mean laboratory values from baseline to end-of-treatment for the ALT, AST, serum albumin, hemoglobin, serum creatinine, and eGFR among patients with measurements at both time points are presented in Figure. Among the 41 patients with ALT measures, the mean ALT level was 86.3 IU/L (95% CI: 60.1-112.6) at baseline and 22.7 IU/L (95% CI: 19.8-25.6) at the end-of-treatment, with an average decrease of 63.6 IU/L (95% CI: 38.0-89.2; p value ＜0.0001). Similarly, among the 41 patients with AST measurements, the mean AST level was lower on average at the end-of-treatment [26.7 IU/L (95% CI: 23.4-29.9)] when compared to baseline [81.5 IU/L (95% CI: 55.9-107.1)], with an average decrease of 54.8 IU/L (95% CI 29.3-80.5; p value ＜0.0001). The mean serum albumin levels were 4.1 g/dL (95% CI 3.9-4.2) at baseline and 4.2 g/dL (95% CI: 4.0-4.3) at end-of-treatment, with an average increase of 0.12 g/dL (95% CI: 0.03-0.21; n=39; p value=0.01). The mean hemoglobin levels were 14.0 g/dL (95% CI: 13.4-14.6) at baseline and 12.7 g/dL (95% CI: 12.1-13.3) at the end-of-treatment, with an average decrease of 1.3 g/dL (95% CI: 0.8-1.9; n=40; p value ＜0.0001). There were no statistically significant changes observed over time for mean serum creatinine or mean eGFR values (n=41 each).

Figure.

Means and 95% confidence intervals at baseline and end-of-treatment of laboratory measures: alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum albumin (ALB), hemoglobin, serum creatinine (Cr), and the estimated glomerular filtration rate (eGFR).

Safety

A total of 47 patients (94.0%) completed the full 24-week treatment of SOF+RBV as indicated on the local prescribing information. Among the 3 patients who did not, 2 discontinued treatment early due to pregnancy in 1 (at approximately 18 weeks of treatment) and an unspecified reason in the other (at approximately 12 weeks of treatment). The remaining patient had treatment interruption 2 weeks after starting due to an AE (folliculitis, considered unrelated to SOF or RBV by the treating physician). This patient resumed SOF+RBV treatment after recovering from the AE and received approximately 22 weeks total of treatment.

Among the 50 patients evaluated for safety, AEs considered related to treatment by the treating physician were reported in 13 patients (26.0%), resulting in an incidence rate of 1.52 (95% CI: 0.90-2.40) per 100 person-weeks (18 first events). Three patients (6.0%) had AEs that were considered causally related to SOF, and 12 (24.0%) had AEs considered related to RBV, including 1 patient who experienced AEs that were considered related to both SOF and RBV (blood uric acid increase, chronic gastritis, and gastroesophageal reflux disease). Anemia was the most reported related AE, which occurred in 7 (14.0%) patients and was considered related to RBV in all instances (Table 2). All other related AEs occurred in no more than 1 patient each. There were no marked differences in the occurrence of related AEs by patient baseline demographic and clinical characteristics, including age (≥65 years old), presence of cirrhosis, and renal impairment categorized by eGFR (Supplementary Material).

Table 2.

Occurrence of AEs and SAEs Considered Related to SOF+RBV Treatment by MedDRA PTs.

Adverse events	Related to SOF and/or RBV	Number of patients (%)
Any AE related to SOF and/or RBV	-	13 (26.0%)
Any SAE related to SOF and/or RBV	-	3 (6.0%)
MedDRA PT
Anemia	RBV	7 (14.0)
Bilirubin conjugated increased	SOF	1 (2.0)
Blood bilirubin unconjugated increased†	SOF	1 (2.0)
Blood uric acid increased	SOF and RBV	1 (2.0)
Chronic gastritis	SOF and RBV	1 (2.0)
Gastric ulcer†	RBV	1 (2.0)
Gastroesophageal reflux disease	SOF and RBV	1 (2.0)
Hemoglobin decreased	RBV	1 (2.0)
Headache	SOF	1 (2.0)
Hydronephrosis†	RBV	1 (2.0)
Hyperuricemia	RBV	1 (2.0)
Stomatitis	RBV	1 (2.0)

AE: adverse event, SOF: sofosbuvir, RBV: ribavirin, SAE: serious adverse event, MedDRA: Medical Dictionary for Regulatory Activities, version 23.0J, PT: preferred term

^†SAE.

Multiple AEs of the same PT that were reported with the same onset date for one patient were counted only once.

A total of 3 SAEs related to SOF and/or RBV were reported in 3 patients (6.0%), resulting in an incidence rate of 0.25 (95% CI: 0.05-0.74) per 100 person-weeks. The 3 SAEs were blood bilirubin unconjugated increased (related to SOF), gastric ulcer (related to RBV), and hydronephrosis (related to RBV), which occurred in one patient each. In the patients who experienced the blood bilirubin unconjugated increased and hydronephrosis events, SOF+RBV treatment was continued without modification to the dosage, and the patients were recovering or had recovered by approximately 1 month after treatment completion. In the patient who experienced the gastric ulcer event, RBV was discontinued 6 days before the end of the 24-week treatment, while SOF was continued until the end of treatment; the patient recovered approximately 17 weeks post-treatment.

Regarding the safety risks of interest under investigation (hepatitis B virus reactivation, hypertension, cerebrovascular disease, anemia, and any AEs among patients with severe renal impairment or requiring dialysis), anemia-related AEs were the only events observed in the study, all of which were related to RBV use. These occurred in 8 patients (16.0%), including anemia in 7 patients and hemoglobin decrease in 1 patient, and all patients had recovered or were recovering by study completion.

Effectiveness

Of the 50 enrolled patients, one did not have HCV RNA post-treatment results, leaving 49 patients for the effectiveness analysis. Among those, SVR12 was achieved in 41 patients overall (83.7%, 95% CI: 70.3-92.7%). Seven of the eight patients in total who failed to achieve SVR12 had undetectable HCV RNA levels at least once during the observational period but had detectable levels at the time of the SVR12 assessment. The remaining patient had undetectable HCV RNA levels during treatment and one day post-treatment but did not have subsequent HCV RNA results and was therefore conservatively assessed as failing to achieve SVR12. There were 45 patients in total with HCV RNA results available for the SVR24 assessment, and among them, SVR24 was achieved in 37 overall (82.2%, 95% CI: 68.0-92.0%). Among those assessed for SVR24, there were no additional patients who failed to achieve SVR after the SVR12 assessment period.

Of the 49 patients in the effectiveness analysis, 45 had GT3 infection. SVR12 was achieved in 37 patients with GT3 infection (82.2%, 95% CI: 67.9-92.0%). There were 42 patients with GT3 infection who had HCV RNA results available for the SVR24 assessment, and of those, 34 achieved SVR24 (81.0%, 95% CI: 65.9-91.4%).

The proportion of patients who achieved SVR12 stratified by baseline patient demographic and clinical characteristics is presented in Table 3. Statistically significant differences in SVR12 were observed among patients with an HCV antiviral treatment history based on whether cirrhosis was present at baseline (p value=0.03). Among these 20 treatment-experienced patients, the proportion who achieved SVR12 was lower among cirrhotic patients [50.0% (2/4 patients)] than non-cirrhotic patients [100.0% (16/16)], although the denominator for patients with cirrhosis was small. Similarly, among all 49 patients in the effectiveness analysis, the SVR12 was lower [63.6% (7/11)] in patients who were cirrhotic at baseline than in non-cirrhotic patients [89.5% (34/38)], although the difference was not statistically significant (p value=0.06). No other patient characteristic comparisons showed statistically significant differences between subgroups, and findings were consistent for SVR24 (results not shown).

Table 3.

SVR12 by Select Baseline Demographic and Clinical Characteristics.

	Number of patients	SVR12 achieved		p value
		n	% (95% CI)
Total	49	41	83.7 (70.3-92.7)	-
Sex				0.41
Female	15	14	93.3 (68.0-99.8)
Male	34	27	79.4 (62.1-91.3)
Age at treatment start (years)				1.00
<65	33	28	84.8 (68.1-94.9)
≥65	16	13	81.2 (54.4-96.0)
Race/ethnicity				0.32
Asian, Japanese	28	22	78.6 (59.1-91.7)
Asian, non-Japanese	17	16	94.1 (71.3-99.9)
White	4	3	75.0 (19.4-99.4)
HCV genotype				1.0
3	45	37	82.2 (67.9-92.0)
4	1	1	100.0 (2.5-100.0)
5	0	0	-
6	2	2	100.0 (15.8-100.0)
Unknown (neither GT1 nor GT2)	1	1	100.0 (2.5-100.0)
eGFR (CKD-EPI, mL/min/1.73 m2)				1.00
≥90 (Normal)	29	24	82.8 (64.2-94.1)
60 to <90 (Mild to normal reduction)	12	10	83.3 (51.6-97.9)
30 to <60 (Mild/moderate to severe reduction)	0	0	-
15 to <30 (Severe reduction)	0	0	-
<15 (Kidney failure)	0	0	-
Any hepatic clinical condition				0.32
Yes	13	9	69.2 (38.6-90.9)
No	36	32	88.9 (73.9-96.9)
Cirrhosis				0.06
Yes	11	7	63.6 (30.8-89.1)
No	38	34	89.5 (75.2-97.1)
Prior HCV treatment history				0.44
Treatment-naïve	20	18	90.0 (68.3-98.8)
Treatment-experienced	29	23	79.3 (60.3-92.0)
Treatment experience and cirrhosis status at baseline
Treatment-naïve, non-cirrhotic	22	18	81.8 (59.7-94.8)	0.61
Treatment-naïve, cirrhotic	7	5	71.4 (29.0-96.3)
Treatment-experienced, non-cirrhotic	16	16	100.0 (79.4-100.0)	0.03
Treatment-experienced, cirrhotic	4	2	50.0 (6.8-93.2)

SVR12: sustained virologic response 12-weeks post-treatment, CI: confidence interval, GT: genotype, eGFR: estimated glomerular filtration rate, CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration

Chi-square tests were used to examine potential differences by baseline and clinical characteristics. Fisher's exact tests were used when the expected frequencies were less than 5.

Discussion

In this prospective observational study of SOF+RBV treatment in HCV patients with mostly GT3 infection, detailed safety and effectiveness results through 24 weeks post-treatment are presented. To date, this is the largest real-world study of this rare patient population in Japan. Occurrences of related AEs and SAEs were very low, and the proportions of patients who achieved SVR12 and SVR24 were both greater than 82%, which is comparable to clinical and observational studies of 24-week treatment of SOF+RBV for HCV GT3 infection conducted outside of Japan.

Safety data for this study were prospectively collected and rigorously assessed for causal relationships with SOF and/or RBV by treating physicians, and there were no additional safety concerns nor any new adverse drug reactions considered causally related to SOF in this real-world study. These results are consistent with other findings on SOF-containing regimens for the treatment of HCV GT3 infection, where SOF-containing regimens were well-tolerated by patients across clinical and post-marketing studies (18,29,30). The mean levels of ALT and AST indicate a clinically significant decrease on average from treatment start to end in the overall study population. The differences observed in the overall mean levels of serum albumin from baseline to end-of-treatment may not be considered clinically relevant given that the mean levels were within a generally recognized normal range (3.5 to 4.5 g/dL) (31). However, among this patient population, the statistically significant increase over time may indicate an improved liver function, as lower serum albumin values are associated with more severe liver disease (32). Taken together, the changes observed for these liver function tests provide some evidence of hepatocyte injury resolution and liver function normalization over time among patients while on treatment.

Use of SOF+RBV in patients with severe renal impairment or in subjects with end-stage renal disease is contraindicated in Japan, due to elevated levels of SOF and its metabolite, GS-331007, and a lack of data in this population (33). The current study provides evidence that real-world use of SOF among patients with severe renal impairment or renal insufficiency requiring dialysis is not observed in Japan, in line with the prescribing information, as all patients had eGFR values of ≥60 mL/min/1.73 m² at baseline. Furthermore, patients in this study who had mild to normal renal impairment at baseline did not experience new or worsening renal events upon SOF+RBV use, so treatment was determined to be safe and effective. Overall, the serum creatinine and eGFR results at baseline and end-of-treatment on average remained stable over time, further indicating there was no negative impact on renal function during treatment.

The primary toxicity that may arise from RBV use is hemolytic anemia, which is expected to occur within one to two weeks of treatment initiation; thus, hemoglobin levels and signs of anemia are recommended to be monitored with RBV use (34). Safety findings from this study align with the known safety profile of RBV, demonstrating an overall decrease in mean hemoglobin levels from baseline to end-of-treatment among patients with available laboratory measurements as well as anemia-related AEs in 8 patients that were causally attributed to RBV. In 4 of those patients, SOF+RBV treatment was continued without dosing or administration changes, while the RBV dosage was reduced in the other 4 for the remainder of treatment. All patients who experienced anemia-related AEs had fully recovered or were recovering by study end. In summary, the safety of SOF+RBV treatment in patients with GT3-6 in this study is consistent with that observed in previous Japanese studies for the treatment of GT2 hepatitis C, including a representative, nationwide observational study (35) and a study in elderly patients (36).

In relation to the effectiveness, the proportion of patients who achieved SVR12 in this study (over 82% overall and among those with GT3 infection only) aligns with SVR12 rates observed in previous clinical trials and observational studies among HCV-infected patients with GT3 that took place outside of Japan. In clinical trials, SVR12 rates ranged from 80% to 90% (17,23,27,37), while SVR12 rates were lower in observational studies (60% to 87%) (25,26,38). When the present results were stratified by baseline patient characteristics, the highest rates of effectiveness were observed in non-cirrhotic patients and treatment-naïve patients, which is in line with data observed in clinical trials and the real-world setting involving patients with GT3 infection (17,22,26). However, SVR12 rates were lower in this study among cirrhotic patients and treatment-experienced patients, with the lowest rates being observed among cirrhotic patients who were also treatment-experienced (50.0%, 2/4 patients), although there were very few such patients in this subgroup. These results reflect the findings in other studies among patients prescribed 24 weeks of SOF+RBV for HCV GT3 infection, in which treatment-experienced patients with cirrhosis at baseline had the lowest SVR12 rates, ranging from 62% (17) to 76% (37) in clinical trials and as low as 42% in an observational study of 197 patients (26).

The Japanese Society of Hepatology guidelines recommend glecaprevir/pibrentasvir (GLE/PIB) for 12 weeks as the preferred treatment for patients with GT3-6 (19), given that it is RBV-free and has a shorter dosing period than SOF+RBV treatment. The SVR rates of SOF+RBV in this study are similar to those observed with GLE/PIB in a clinical trial conducted in Japan, where 10 of 12 (83%) patients with GT3 achieved SVR12 (39). However, SOF-based regimens licensed in Japan do not contain protease inhibitors and have fewer drug-drug interactions than GLE/PIB; therefore, SOF+RBV may be a preferred treatment option in patients with advanced fibrosis, people living with HIV, and patients taking multiple drugs.

The observational period for this study was through 24 weeks post-treatment, and among those who had HCV RNA results during the SVR24 assessment window, no additional patients experienced virological failure after the SVR12 assessment. It is well established that SVR12 is highly concordant with SVR24 in clinical trials assessing SOF-containing regimens for HCV and serves as an appropriate efficacy endpoint in that setting (40). We thus established that longer-term durability at SVR24 was achieved in the real-world setting of SOF+RBV usage for GT3-6 patients in clinical practice, including the 7 patients who were cirrhotic at baseline and achieved SVR12.

Several limitations associated with the present study warrant mention. The single treatment group design precluded direct comparisons to other treatments. However, enrollment of a sufficiently large sample size would not have been feasible given the very low prevalence of the HCV genotypes under investigation in Japan. Although the generalizability of the findings may be limited, the study does provide some descriptive information concerning this rarely investigated patient population, which may inform treatment practices. Furthermore, the study results largely reflect HCV-infected patients with GT3 infection, as there were few patients with GT4-6 infection. Study enrollment did not aim to oversample specific GTs, and the GT makeup of the patient population within the study likely closely reflects that of the clinical sites included in the study, as it established that a small number of patients with GT4-6 infection exist in Japan (41).

In conclusion, this prospective observational study demonstrated that patients who received 24 weeks of SOF+RBV for the treatment of HCV GT3-6 infection according to the local prescribing information in Japan experienced a favorable safety profile and high rates of effectiveness for this difficult-to-treat patient population. There were no additional safety concerns identified, and the occurrence of AEs considered related to SOF+RBV by the treating physicians was low overall and among subgroups analyzed, including treatment-experienced patients, those who were cirrhotic, and those who had mild renal impairment or normal renal function at baseline. Both observed SVR12 and SVR24 rates were consistent with those found in clinical trials and other observational studies within similar populations, and there were no additional patients who failed to achieve SVR after the initial 12-week assessment. The results from this real-world study in Japan thus demonstrate that SOF+RBV for this indication is highly safe and effective and remains an important treatment option for patients with HCV GT3-6 infection.

Author's disclosure of potential Conflicts of Interest (COI).

Eiji Mita: Honoraria, Gilead Sciences. Lauren J. Liu: Employment, Gilead Sciences; Stock ownership, Gilead Sciences. Danielle Shing: Employment, Gilead Sciences; Stock ownership, Gilead Sciences. Lindsey Force: Employment, Gilead Sciences; Stock ownership, Gilead Sciences. Kouji Aoki: Employment, Gilead Sciences; Stock ownership, Gilead Sciences. Daisuke Nakamoto: Employment, Gilead Sciences; Stock ownership, Gilead Sciences. Akinobu Ishizaki: Employment, Gilead Sciences; Stock ownership, Gilead Sciences. Hiroki Konishi: Employment, Gilead Sciences; Stock ownership, Gilead Sciences. Hajime Mizutani: Employment, Gilead Sciences; Stock ownership, Gilead Sciences. Leslie J. Ng: Employment, Gilead Sciences; Stock ownership, Gilead Sciences.

Financial Support

This study was funded in full by Gilead Sciences, Tokyo, Japan.