Original article Ledipasvir and sofosbuvir for HCV infection in patients coinfected with HBV

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1 Antiviral Therapy 2016; 21: (doi: /IMP3066) Original article Ledipasvir and sofosbuvir for HCV infection in patients coinfected with HBV Edward J Gane 1,2 *, Robert H Hyland 3, Di An 3, Evguenia S Svarovskaia 3, Diana Brainard 3, John G McHutchison 3 1 Auckland Clinical Studies, Auckland, New Zealand 2 New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand 3 Gilead Sciences, Inc., Foster City, CA, United States *Corresponding author edgane@adhb.govt.nz Background: Currently there are no all-oral treatment regimens for HCV in patients coinfected with HBV. In this pilot study, we evaluated whether ledipasvir and sofosbuvir therapy can suppress HCV infection in patients coinfected with HBV. Methods: Patients with HBV and genotype-1 HCV received 90 mg ledipasvir and 400 mg sofosbuvir daily for 12 weeks. The efficacy end point was sustained virological response (HCV RNA <15 IU/ml) 12 weeks after the end of treatment. Results: Of the eight patients enrolled, six (75%) were male, five (63%) were Polynesian, seven (88%) had the CC IL28B genotype and two (25%) had cirrhosis. All eight patients (100%; 95% CI 63%, 100%) reached the primary end point of HCV RNA <15 IU/ml 12 weeks after treatment. In seven of eight patients (88%), serum HBV DNA levels increased during treatment, but none of the increases were greater than 20,000 IU/ml, and none were associated with clinical HBV flares or required treatment. The most common adverse events were viral infection (63%), fatigue (25%) and upper respiratory tract infection (25%). No patients had serious adverse events and none discontinued treatment for any reason. Conclusions: In this small sample, 12 weeks of ledipasvir/ sofosbuvir was a safe and effective treatment for genotype-1 HCV infection in patients coinfected with HBV. Larger studies with longer follow-up are warranted. Introduction Countries with endemic HBV infection have the highest rates of coinfection with HCV [1]. In these regions, HBV is generally acquired in early childhood through vertical or early horizontal infection, and HCV superinfection [2,3] can occur in adulthood through either iatrogenic transmission or injecting drug use. Superinfection can lead to a state known as viral interference, where one of the viruses is directly suppressed by interferon pathways [4]. In patients with HBV and HCV coinfection, HCV usually becomes dominant [5] especially when HCV superinfection occurs in adulthood many years after childhood-acquired HBV infection. At the time the current study was undertaken, the HCV treatment guidelines from the European Association for the Study of the Liver (EASL) recommended that HBV coinfected patients with dominant HCV infection be treated with pegylated interferon-a and ribavirin or pegylated interferon-a and ribavirin plus a protease inhibitor, which was previously the standard of care for HCV monoinfected patients [6]. The current EASL guidelines recommend treating coinfected patients with the same regimens as monoinfected patients [7]. During and after treatment for HCV, coinfected patients should be monitored for increases in HBV replication, indicating HBV reactivation [6,8,9]. Because treatment has always included interferon, which may suppress HBV reactivation, it is unknown whether eradicating HCV with an interferon-free regimen increases the likelihood of HBV reactivation. For patients with genotype-1 HCV monoinfection, treatment with the HCV NS5A inhibitor ledipasvir and the NS5B polymerase inhibitor sofosbuvir results in high rates of sustained virological response (SVR) [10 13]. In this pilot cohort study, we examined whether ledipasvir and sofosbuvir treatment can provide sustained suppression of chronic HCV infection in patients coinfected with HBV. We also evaluated the activity of chronic hepatitis B during and after treatment International Medical Press (print) (online) 605

2 EJ Gane et al. Methods Patients Eligible patients were at least 18 years old and had chronic infection with HBV and genotype-1 HCV. At least 6 months from the beginning of study treatment, patients had to be hepatitis B surface antigen (HBsAg) positive, and must not have received HBV treatment within the last 6 months. Plasma HCV RNA had to be >100 IU/ml. Patients could have compensated cirrhosis, as determined by biopsy, Fibroscan >12.5 kpa, or FibroTest >0.75 and AST:platelet ratio index >2. All patients had to have liver imaging in the 6 months prior to starting treatment to rule out hepatocellular carcinoma. Patients with any of the following conditions or characteristics were excluded from participation: treatment for HBV infection within 6 months of starting study treatment; body mass index <18 kg/m 2 ; decompensated liver disease; ECG with clinically significant abnormalities; chronic use of systemic immunosuppressive or immunomodulatory agents; HIV infection; creatinine clearance <60 ml/min as calculated by the Cockcroft Gault equation; albumin <3 g/dl; haemoglobin <11 g/dl for females and <12 g/dl for males; platelets <50,000/mm 3 ; total bilirubin >1.5 upper limit of normal (ULN), except for patients with Gilbert s syndrome; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >10 ULN, haemoglobin A 1c >8.5%. All patients provided written informed consent before undertaking any study-related procedures. Study design This open-label pilot study was administered at a single hospital. All patients self-administered on an out-patient basis ledipasvir/sofosbuvir in a fixed-dose combination tablet (90 mg ledipasvir, 400 mg sofosbuvir) once daily for 12 weeks. Patients were referred to the study by their treating physician. This analysis consists of one cohort of a larger Phase II, multicentre study to assess the efficacy and safety of sofosbuvir-containing regimens for the treatment of chronic HCV infection in various groups (ClinicalTrials.gov identifier: NCT ). The study protocol was approved by each institution s review board prior to study initiation. The study was conducted in accordance with the Declaration of Helsinki or the International Conference on Harmonisation guidelines. Efficacy assessments Blood samples for determining HCV RNA levels were drawn at the study hospital. Screening; on day 1 of treatment; at weeks 1, 2, 4, 6, 8, 10 and 12; and at follow-up weeks 2, 4, 8, 12, 16, 20 and 24. Serum HCV RNA was measured by using the Roche COBAS AmpliPrep/COBAS TaqMan HCV Test, v2.0 (Roche Molecular Systems, Inc., Branchburg, NJ, USA), which has a lower limit of quantification (LLOQ) of 15 IU/ml. Viral resistance monitoring Plasma samples for viral sequencing were collected on day 1 of treatment; at weeks 1, 2, 4, 6, 8, 10 and 12; and at follow-up weeks 2, 4, 8, 12, 16, 20 and 24. The HCV NS5A and NS5B coding regions were amplified by DDL Diagnostic Laboratory (Rijswijk, the Netherlands) using standard reverse transcription polymerase chain reaction (RT-PCR) technology at baseline for all patients. The PCR products from baseline samples were deep sequenced with an assay cut off of 1% by DDL or WuXi AppTec (Shanghai, China). Safety assessments Clinical laboratory and vital signs data were collected throughout treatment and follow-up. Blood samples were also collected throughout treatment and followup to monitor HBV DNA levels, hepatitis B e antigen (HBeAg) status, hepatitis B e antibody (HBeAb) status, quantitative HBsAg and hepatitis B surface antibody (HBsAb) status. Serum HBV DNA was measured using the COBAS AmpliPrep/COBAS TaqMan HBV Test v2.0 assay (Roche Molecular Systems, Inc.), with a cutoff of 29 IU/ml. Adverse events and concomitant medication were recorded throughout treatment and through week 4 of follow-up. Physical exams and ECG recordings were done on the first day of treatment and during the week 12 study visit. Treatment-emergent clinical and laboratory adverse events were summarized using the Medical Dictionary for Regulatory Activities (MedDRA ), version End points and statistical analyses The primary efficacy end point was SVR12, defined as HCV RNA <LLOQ (15 IU/ml) 12 weeks after stopping study drug. A 95% CI for the proportion of patients with SVR12 was calculated based on the Clopper-Pearson method. Statistical analyses were conducted using SAS version 9.2. Efficacy and safety were assessed in all patients who were enrolled and received at least one dose of the study drug. Results Study population From June through September 2014, eight patients were enrolled and treated at a single site in New Zealand. Of the eight patients enrolled, six (75%) were male, five (63%) were Polynesian, seven (88%) had the CC IL28B genotype and two (25%) had cirrhosis (Table 1). All patients were HBeAg-negative. All patients completed study treatment and 12 weeks of follow-up International Medical Press

3 LDV/SOF for HCV patients coinfected with HBV Table 1. Patient baseline characteristics Ledipasvir + sofosbuvir 12 weeks (n=8) Mean age, years (sd) 53 (6.9) Male, n (%) 6 (75) Race White, n (%) 2 (25) Asian, n (%) 1 (13) Polynesian (New Zealand Maori), n (%) 5 (63) BMI <30 kg/m 2, n (%) 6 (75) Genotype 1a, n (%) 6 (75) 1b, n (%) 2 (25) Mean HCV RNA, log 10 IU/ml (sd) 6.5 (0.5) IL-28B CC, n (%) 7 (88) CT, n (%) 1 (13) TT, n (%) 0 Cirrhosis Present, n (%) 2 (25) Median ALT, U/l (range) 64 (33 363) Median glomerular filtration rate a, ml/min (range) ( ) HBV genotype B, n (%) 1 (13) C, n (%) 1 (13) D, n (%) 3 (38) Unknown, n (%) 3 (38) a Estimated using Cockcroft Gault equation. ALT, alanine aminotransferase; BMI, body mass index. Antiviral response All eight patients had HCV RNA <LLOQ at the end of treatment, and all eight (100%; 95% CI 63.1%, 100.0%) achieved the primary end point of SVR12. Six patients (75%) had undetectable HCV RNA by week 2 of treatment, one patient (13%) did by week 4 and one patient (13%) did by week 8. Viral sequencing One patient (13%) had a pretreatment NS5A resistanceassociated variant, A92T. No patients had pretreatment NS5B resistance-associated variants. Because all eight patients reached SVR12, no post-treatment resistance analyses were done. Safety assessments The most common adverse events were viral infection (63%) and fatigue (25%) and upper respiratory tract infection (25%; Table 2). No serious adverse events were reported. Only one patient had an adverse event (fatigue) that was considered related to the study drug. No patients had clinically significant anaemia, defined as haemoglobin <10 g/dl. No clinically meaningful changes in white blood cells, neutrophils, lymphocytes, haemoglobin, reticulocytes or platelets were observed. No patients had ALT levels >5.0 ULN, AST levels >5.0 ULN, bilirubin increases >2.5 ULN or lipase increases >3.0 ULN. During the study period, all patients remained HBeAg-negative. Four patients had HBV DNA <LLOQ at baseline (Figure 1). In one patient, HBV DNA remained <LLOQ throughout treatment and follow-up, whilst in the other three patients, HBV DNA increased during treatment (median 1,585 IU/ml; range 1,238 4,250) but subsequently fell during post-treatment follow-up (median 215 IU/ml; range ). The remaining four patients had detectable HBV DNA at baseline (median 163 IU/ml; range 92 1,028), which increased during treatment (median 5,936 IU/ml; range ,290), but subsequently fell during post-treatment follow-up (median 384 IU/ml; range <LLOQ 6,544). Serum HBV DNA levels rose 2 log 10 IU/ml from baseline in three patients, but none were associated with ALT or AST elevations during or after treatment. HBsAg decreased during treatment in seven patients. For six of them, this effect reversed during follow-up. During treatment, the mean (sd) change from baseline for HBsAg ranged from (0.354) to (0.159) log 10 IU/ml. During the study and up to 48 weeks follow-up, no patient met criteria for starting antiviral therapy for HBV. Discussion In this pilot study of eight patients coinfected with HBV and HCV genotype-1, all eight (100%) had sustained suppression of HCV after undergoing 12 weeks of treatment with ledipasvir and sofosbuvir. Ledipasvir and sofosbuvir therapy was generally well tolerated. Although most patients (88%) had increases in HBV DNA during treatment, there were no liver events associated with the increases, and no patients had clinical HBV flares or required treatment for HBV infection. This may reflect a loss of host immune control of HBV. However, we did not conduct the necessary immunological studies to prove this. The increases in HBV DNA are consistent with a prior report of reappearance of HBV DNA during and after treatment in 47 of 76 (62%) HBV HCVcoinfected patients treated with pegylated interferona plus ribavirin [9]. Among these patients, reappearance of HBV DNA was most often transient (45%) or intermittent (26%). As in our study, none of the patients had hepatitis flares or met criteria for starting antiviral therapy for HBV. The eradication of the dominant HCV coinfection did not affect the host immune control of HBV, indicating that this was probably longstanding and not directly related to viral interference. Antiviral Therapy

4 EJ Gane et al. Table 2. Treatment-emergent adverse events Patients with any adverse event, n (%) 6 (75) Patients with a serious adverse event, n 0 Adverse event leading to discontinuation, n 0 Deaths, n 0 Adverse events Viral infection, n (%) 5 (63) Fatigue, n (%) 2 (25) Upper respiratory tract infection, n (%) 2 (25) Chest pain, n (%) 1 (13) Depression, n (%) 1 (13) Rhinorrhoea, n (%) 1 (13) Sneezing, n (%) 1 (13) Ledipasvir + sofosbuvir 12 weeks (n=8) The main limitation of this study is the small sample size. Additionally, the formal follow-up period was 24 weeks, which may not have been sufficient to capture late hepatitis B reactivations after HCV suppression [8]. In conclusion, in this pilot study of patients with HBV and HCV genotype-1 coinfection, ledipasvir and sofosbuvir therapy resulted in high SVR rates, was well tolerated, and was not associated with HBV-related safety events, including reactivation. Larger studies with longer follow-up are warranted. Acknowledgements Writing assistance was provided by Jennifer King of August Editorial, Durham, NC, USA. Figure 1. Mean and individual HBV DNA profiles at baseline, during and after ledipasvir/sofosbuvir treatment 5.0 Individual HBV DNA Mean HBV DNA 4.0 HBV DNA, log 10 IU/ml BL EOT Treatment week Post-treatment week Two patients are missing HBV DNA values at post-treatment week 20, and one patient is missing HBV DNA values at post-treatment weeks 2 and 24. BL, baseline; EOT, end of treatment International Medical Press

5 LDV/SOF for HCV patients coinfected with HBV All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. Disclosure statement EJG has served as a consultant for Gilead Sciences, AbbVie, Achillion Pharmaceuticals, Merck, Janssen Pharmaceuticals and Novira Therapeutics and has given sponsored lectures for Gilead Sciences, AbbVie, Novartis and Merck. The following authors are employees of Gilead Sciences and hold stock interest in the company: RHH, DA, ESS, DB and JGM. References 1. Liu C-J, Chen P-J. Updates on the treatment and outcomes of dual chronic hepatitis C and B virus infection. World J Gastroenterol 2014; 20: Liaw Y-F, Chen Y-C, Sheen I-S, Chien R-N, Yeh C-T, Chu C-M. Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology 2004; 126: Chu C-J, Lee S-D. Hepatitis B virus/hepatitis C virus coinfection: epidemiology, clinical features, viral interactions and treatment. J Gastroenterol Hepatol 2008; 23: Dianzani F. Viral interference and interferon. Ric Clin Lab 1975; 5: Konstantinou D, Deutsch M. The spectrum of HBV/HCV coinfection: epidemiology, clinical characteristics, viral interactions and management. Ann Gastroenterol 2015; 28: European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014; 60: European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C J Hepatol 2015; 63: Potthoff A, Berg T, Wedemeyer H, HEP-NET B/C Coinfection Study Group. Late hepatitis B virus relapse in patients co-infected with hepatitis B virus and hepatitis C virus after antiviral treatment with pegylated interferon-a2b and ribavirin. Scand J Gastroenterol 2009; 44: Yu M-L, Lee C-M, Chen C-L, et al. Sustained hepatitis C virus clearance and increased hepatitis B surface antigen seroclearance in patients with dual chronic hepatitis C and B during posttreatment follow-up. Hepatology 2013; 57: Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370: Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370: Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370: Mizokami M, Yokosuka O, Takehara T, et al. Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, Phase 3 trial. Lancet Infect Dis 2015; 15: Accepted 5 April 2016; published online 1 July 2016 Antiviral Therapy