Jenny C. Yang

Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection

BACKGROUND In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection. METHODS We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir-sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir-sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea. CONCLUSIONS Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. (Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.).

Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection

BACKGROUND Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need. METHODS We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir-sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286.).

Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1

BACKGROUND Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need. METHODS We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events. CONCLUSIONS Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.).

Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: An integrated safety and efficacy analysis

Patients with hepatitis C virus (HCV) infection and cirrhosis are underrepresented in clinical trials of interferon‐free regimens of direct‐acting antiviral agents, making it difficult to optimize therapy. We performed a post‐hoc analysis of data from seven clinical trials to evaluate the efficacy and safety of the fixed‐dose combination of ledipasvir (LDV) and sofosbuvir (SOF), with and without ribavirin (RBV), in 513 treatment‐naïve and previously treated patients with genotype 1 HCV and compensated cirrhosis. All patients received LDV‐SOF for 12 or 24 weeks with or without RBV. We determined the rates of sustained virological response (SVR) 12 weeks after treatment (SVR12) overall and for subgroups. Of the 513 patients analyzed, 69% were previously treated and 47% had failed previous treatment with a protease‐inhibitor regimen. Overall, 493 patients (96%; 95% confidence interval [CI]: 94%‐98%) achieved SVR12, 98% of treatment‐naïve and 95% of previously treated patients. SVR12 rates did not vary greatly by treatment duration (95% of patients receiving 12 weeks and 98% of patients receiving 24 weeks of treatment), nor by addition of RBV (95% of patients receiving LDV‐SOF alone and 97% of those who received LDV‐SOF plus RBV), although previously treated patients receiving 12 weeks of LDV‐SOF without RBV had an SVR12 rate of 90%. One patient discontinued LDV‐SOF because of an adverse event (AE). The most common AEs were headache (23%), fatigue (16%‐19%), and asthenia (14%‐16%). One patient (<1%) of those receiving LDV‐SOF alone, and 4 (2%) of those receiving LDV‐SOF plus RBV had treatment‐related serious AEs. Conclusions: This analysis suggests that 12 weeks of LDV‐SOF is safe and effective for treatment‐naïve patients with HCV genotype 1 and compensated cirrhosis. The relatively lower SVR in treatment‐experienced patients treated with 12 weeks of LDV‐SOF raises the question of whether these patients would benefit from adding RBV or extending treatment duration to 24 weeks. (Hepatology 2015;62:79‐86)

Ledipasvir‐sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens

Patients who fail to achieve sustained virological response (SVR) after treatment with sofosbuvir (SOF) plus ribavirin (RBV) with or without pegylated interferon (Peg‐IFN) do not have established retreatment options. We conducted an open‐label trial to assess the efficacy and safety of ledipasvir (LDV)‐SOF plus RBV in patients with genotype 1 hepatitis C virus (HCV) who did not achieve SVR after treatment in phase II and III trials of SOF regimens. We enrolled 51 patients at 24 sites in the United States. All patients received the fixed‐dose combination tablet of LDV‐SOF once‐daily plus weight‐based RBV (1,000 or 1,200 mg/day) for 12 weeks. The efficacy endpoint was the proportion of patients with SVR 12 weeks after discontinuation of therapy (SVR12). Of the 51 patients enrolled, 25 (49%) had previously received SOF plus Peg‐IFN‐RBV, 20 (39%) had received SOF‐RBV, 5 (10%) had received SOF placebo plus Peg‐IFN‐RBV, and 1 (2%) received GS‐0938 monotherapy. Fourteen (27%) had compensated cirrhosis at baseline, and 47 (92%) had non‐CC interleukin‐28B genotypes. SVR12 was achieved by 50 of the 51 patients (98%) treated. Among the 45 patients who received SOF in earlier treatment, 44 (98%) achieved SVR12. The only patient who did not achieve SVR12 was a patient with genotype 3a HCV who had been incorrectly genotyped as 1a in the previous study. Given the high rates of SVR12, no differences among patient subgroups were discernible. Of 51 patients, 41 (80%) experienced at least one adverse event (AE), but most events were mild to moderate in severity. The most common AEs were fatigue, headache, and diarrhea. One patient discontinued treatment because of an unrelated AE (bipolar disorder). Conclusion: Twelve weeks of LDV‐SOF plus RBV was an effective and safe treatment for patients who have not achieved SVR with earlier regimens that included SOF. (Hepatology 2015;61:1793–1797)

Safety and Tolerability Of Ledipasvir/Sofosbuvir With and Without Ribavirin in Patients With Chronic Hepatitis C Virus Genotype 1 Infection: Analysis of Phase III ION Trials

In phase III studies, treatment with the once‐daily fixed‐dose combination tablet of ledipasvir/sofosbuvir (LDV/SOF) with and without ribavirin (RBV) resulted in high rates of sustained virological response (SVR) in patients chronically infected with genotype 1 hepatitis C virus, including those with compensated cirrhosis. We conducted an analysis of data from these trials to compare the safety and tolerability profile of LDV‐SOF with and without RBV. We analyzed treatment‐emergent adverse events (AEs) and laboratory abnormalities in patients who were randomized to 8, 12, and 24 weeks of LDV/SOF with or without RBV. In total, data from 1,952 patients (of whom 872 received LDV/SOF with RBV and 1,080 received LDV/SOF alone) were analyzed. Overall, 308 patients (16%) were African American, 224 (11%) had compensated cirrhosis, 501 (26%) had a body mass index ≥30 kg/m2, and 440 (23%) were treatment experienced. Treatment‐related AEs occurred in 71% and 45% of patients treated with and without RBV, respectively, including fatigue, insomnia, irritability, and rash/pruritus. Patients receiving RBV with LDV/SOF were more likely to require dose modification, interruptions of treatment resulting from AEs, or require the use of concomitant medications than those receiving LDV/SOF alone. Rates of treatment‐related serious AEs and discontinuations resulting from AEs were similarly low (<1%) in both groups. The rate of SVR in those receiving RBV and those not receiving RBV was the same (97%). Conclusion: LDV/SOF plus RBV was associated with a greater incidence of AEs as well as concomitant medication use than LDV/SOF alone. Use of RBV did not impact the efficacy of LDV/SOF regimens in the ION phase III studies. (Hepatology 2015;62:25‐30)

Safety and efficacy of ledipasvir-sofosbuvir in black patients with hepatitis C virus infection: A retrospective analysis of phase 3 data

Black patients chronically infected with genotype 1 hepatitis C virus (HCV) have historically had lower rates of response to interferon‐based treatment than patients of other races. In the phase 3 ION program, the single‐tablet regimen of the NS5A inhibitor ledipasvir and NS5B nucleotide polymerase inhibitor sofosbuvir was shown to be safe and highly effective in the general population. The aim of this study was to evaluate the safety and efficacy of ledipasvir/sofosbuvir in black patients using data from the three open‐label ION clinical trials, which evaluated the safety and efficacy of 8, 12, and 24 weeks of ledipasvir/sofosbuvir with or without ribavirin for the treatment of treatment‐naïve and treatment‐experienced patients with genotype 1 HCV, including those with compensated cirrhosis. The primary endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). For our analysis, rates of SVR12, treatment‐emergent adverse events, and graded laboratory abnormalities were analyzed in black versus non‐black patients. Of the 1949 patients evaluated, 308 (16%) were black. On average, black patients were older, had higher body mass index, were more likely to be IL28B non‐CC, and had a lower serum alanine aminotransferase at baseline than non‐black patients. Overall, 95% of black and 97% of non‐black patients achieved SVR12. The rate of relapse was 3% in black patients as compared with 2% in non‐black patients. The most common adverse events included fatigue, headache, nausea, and insomnia. The majority of adverse events occurred more frequently in the ribavirin‐containing arms of the studies. No differences were observed in overall safety by race. Conclusion: A once‐daily dosage of ledipasvir/sofosbuvir was similarly effective in black and non‐black patients with genotype 1 HCV infection. The addition of ribavirin did not appear to increase SVR12 but was associated with higher rates of adverse events. (Hepatology 2016;63:437–444)

GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study.

GS‐9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1–6 and improved coverage against commonly encountered NS3 resistance‐associated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS‐9857 were evaluated in patients with chronic HCV genotype 1–4 infection. Patients with genotype 1–4 infection received placebo or once‐daily GS‐9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS‐9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS‐9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS‐9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log10 IU/mL following administration of a 100‐mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS‐9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1–4 infection, GS‐9857 exhibited linear PK and was associated with a median half‐life of 29–42 h, supporting once‐daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS‐9857 support its further evaluation for treatment of patients with chronic HCV infection.

A phase 3b study of sofosbuvir plus ribavirin in treatment-naive and treatment-experienced Korean patients chronically infected with genotype 2 hepatitis C virus.

In Korea, patients with chronic hepatitis C virus (HCV) infection are typically treated with pegylated interferon‐alpha plus ribavirin, but interferons are contraindicated in many patients and are often poorly tolerated, particularly by the elderly and those with advanced liver disease. No interferon‐free treatment regimens are approved in Korea. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV nonstructural 5B RNA polymerase. It is approved in the USA, European Union and Japan for treating a number of HCV genotypes, including genotype 2. Genotype 2 has a seroprevalence of 38–46% in Korea. This single‐arm, phase 3b study (NCT02021643) examined the efficacy and safety of sofosbuvir plus ribavirin (12‐week duration) in chronic genotype 2 HCV‐infected treatment‐naive and treatment‐experienced Korean patients with and without cirrhosis. The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12) was 97% (125/129), with 96% (101/105) of treatment‐naive and 100% (24/24) of treatment‐experienced patients achieving SVR12. Two patients experienced virologic failure (n = 1, on‐treatment failure; n = 1, relapse). No patient discontinued study treatment due to an adverse event (AE). The most common treatment‐emergent AEs were headache (18%, 23/129) and pruritus (15%, 19/129). Few patients had grade 3 AEs (5%, 6/129) or grade 3 laboratory abnormalities (12%, 15/129). No grade 4 AE was reported. These data suggest that 12 weeks of treatment with the all‐oral, interferon‐free regimen of sofosbuvir plus ribavirin is effective and well tolerated in Korean patients with chronic genotype 2 HCV infection.

A phase 3b study of sofosbuvir plus ribavirin in Taiwanese patients with chronic genotype 2 hepatitis C virus infection

In Taiwan, patients with chronic hepatitis C virus (HCV) infection are currently treated with pegylated interferon‐alpha plus ribavirin, but interferon‐based regimens can be poorly tolerated, especially by those with advanced liver disease and the elderly. Sofosbuvir, an oral nucleotide analogue inhibitor of HCV NS5B polymerase, is approved in Europe, the USA and Japan for treating chronic HCV infection. This phase 3b study examined the efficacy and safety of sofosbuvir plus ribavirin in Taiwanese patients with chronic genotype 2 HCV infection ± compensated cirrhosis.