Ledipasvir-Sofosbuvir: Interferon-/ Ribavirin-Free Regimen for Chronic Hepatitis C Virus Infection
Michael A. Smith, PharmD1, Juliana Chan, PharmD2,3, and Rima A. Mohammad, PharmD4,5
Annals of Pharmacotherapy 1–8
© The Author(s) 2014 Reprints and permissions:
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Abstract
Objectives: To review the pharmacology, efficacy, and safety of ledipasvir-sofosbuvir for the treatment of chronic hepatitis C virus (HCV). Data Sources: A literature search through clinicaltrials.gov, EMBASE, and PubMed was conducted (January 1966 to October 2014) using the terms ledipasvir, sofosbuvir, GS-5885, and GS-7977. References from retrieved articles and abstracts presented at recent meetings were reviewed for any additional material. The prescribing information was also reviewed. Study Selection/Data Extraction: Phase 1, 2, and 3 human and animal studies describing the pharmacology, pharmacokinetics, efficacy, and safety of ledipasvir and sofosbuvir for HCV were identified. Data Synthesis: Ledipasvir- sofosbuvir, a fixed-dose combination (FDC) tablet inhibiting nonstructural (NS) 5A and 5B proteins, without peginterferon and ribavirin is indicated for adult patients with genotype 1 HCV infection who are treatment naïve or experienced, with or without cirrhosis. Pivotal trials (n = 1952) have demonstrated that once-daily administration of ledipasvir-sofosbuvir for 12 or 24 weeks is effective at achieving sustained virological response (SVR) rates (94%-99%) in treatment-naïve patients (12 weeks), treatment-experienced patients without cirrhosis (12 weeks), and treatment-experienced patients with cirrhosis (24 weeks). Treatment-naïve patients without cirrhosis and baseline viral levels of less than 6 million IU/mL may be considered for 8 weeks of treatment. The most common adverse drug events (ADEs) associated with ledipasvir-sofosbuvir include headache, fatigue, insomnia, nausea, and diarrhea. Conclusions: Ledipasvir-sofosbuvir is the first interferon- and ribavirin-free FDC agent that has SVR rates much greater than 94%, with minimal ADEs, for the treatment of chronic HCV genotype 1 in naïve and treatment-experienced patients.
Keywords
ledipasvir, sofosbuvir, hepatitis C virus
Introduction
Hepatitis C virus (HCV) affects more than 3 million people in the United States.1 Recently, the Centers for Disease Control and Prevention has expanded screening recommen- dations to include adults born between 1945 and 1965.1 Historically, treatment of HCV relied on peginterferon and ribavirin. With the addition of the first-generation direct-
HCV. This review aims to summarize the pharmacology and pharmacokinetics of ledipasvir (sofosbuvir was discussed previously in a recent review article)2 and the efficacy and safety of ledipasvir-sofosbuvir FDC. HCV therapy continues to evolve rapidly; thus, for current treatment recommenda- tions, a Web site, hcvguidelines.org, has been created to incorporate the newly approved HCV agents.3
acting antivirals (DAAs) in 2011, the backbone of peginter-
feron and ribavirin still persisted. Despite the approval of sofosbuvir and simeprevir in 2013, ribavirin with or without peginterferon still remains vital in achieving a high sustained virological response (SVR). Ledipasvir-sofosbuvir, a fixed- dose combination (FDC) tablet, is the first drug to be approved by the Food and Drug Administration (FDA) that does not include peginterferon or ribavirin. Given the shorter durations of treatment, improved SVR rates, and well- tolerated regimen of the FDC, it is anticipated that ledipasvir- sofosbuvir will have a significant impact on the treatment of
1University of the Sciences, Philadelphia, PA, USA
2University of Illinois at Chicago, IL, USA
3University of Illinois Hospital and Health Sciences Center, Chicago, IL, USA
4University of Michigan College of Pharmacy, Ann Arbor, MI, USA
5University of Michigan Health Systems, Ann Arbor, MI, USA
Corresponding Author:
Michael A. Smith, Department of Pharmacy Practice and Pharmacy Administration, Philadelphia College of Pharmacy, University of the Sciences, 600 S 43rd Street, Philadelphia, PA 19104-4495, USA. Email: [email protected]
2 Annals of Pharmacotherapy
Data Selection
Phase 1, 2, and 3 studies were identified through clinicaltri- als.gov, EMBASE, and PubMed (January 1966 to October 2014). Key search terms were ledipasvir, sofosbuvir, GS-5885, and GS-7977. The literature in English for each drug and the FDC were included. References included the prescribing information, and any articles or meeting abstracts were also reviewed for any additional publications.
Pharmacology
HCV is an RNA-based virus that requires nonstructural (NS) proteins in viral replication and virion assembly.4 Two NS proteins, 5A and 5B (NS5A and NS5B), are important to the mechanism of ledipasvir-sofosbuvir. NS5A lacks enzy- matic activity, but is vital in HCV replication.5,6 NS5B is an RNA-dependent polymerase that plays a key role in RNA synthesis.4 Once NS5A is inhibited in the HCV replicon cells, NS5A redistributes from the endoplasmic reticulum to lipid droplets, further disrupting the formation of new replication complexes. This results in a clinically signifi- cant decrease and eradication in HCV RNA levels and improved SVR rates.7
Ledipasvir, which inhibits NS5A, has a 50% effective
dysfunction had significantly increased drug exposure when sofosbuvir was administered; thus, the FDC is not recom- mended in patients with a CrCl <30 mL/min or end-stage renal disease requiring hemodialysis. Patients with hepatic impairment (Child-Pugh C) had no pharmacokinetic changes with ledipasvir. Although sofosbuvir drug concentrations were increased in Child-Pugh class B and C, there were no changes in patients with compensated cirrhosis.2,10
Clinical Trials
Treatment Definitions
For several decades, SVR24, 24 weeks after the completion of HCV therapy, was considered the primary end point of efficacy. If HCV RNA levels were undetectable at 24 weeks, then the patient was considered to have had a “virological cure.”13 More recently, data suggest that SVR12, 12 weeks after the completion of therapy, is just as durable as SVR24.14,15 These data have also been validated in patients treated with the ledipasvir-sofosbuvir FDC.16 Additionally, noteworthy definitions included in these trials are treatment naïve and treatment experienced. A treatment-naïve patient is defined as a patient who has not been previously treated for HCV. Treatment experienced is a broad term that
concentration (EC
) of 31 pM in genotype 1a replicons and
includes patients who did not achieve an SVR or failed
50 8,9
4 pM against genotype 1b replicons.
Sofosbuvir is a pro-
HCV treatment. Treatment-experienced patients may be
drug, which converts to an active metabolite (GS-461203) that inhibits NS5B. GS-461203 is dephosphorylated to an inactive metabolite, GS-331007. The pharmacology of sofosbuvir has previously been reported.2 Viral resistance is discussed separately.
Pharmacokinetics and Pharmacodynamics
Peak concentrations of ledipasvir and sofosbuvir are reached in approximately 4 hours and 1 hour, respectively. Ledipasvir is highly protein bound (99%) and primarily excreted in the feces, with an elimination half-life of 47 hours. Sofosbuvir is moderately protein bound (~65%) and is primarily excreted in the urine, and the half-life of GS-331007 is approximately 27 hours.6,10 Compared with fasting conditions, the area under the plasma concentration- time curve (AUC) of sofosbuvir is increased by approxi- mately 2-fold with moderate- to high-fat meals; however, exposure of GS-331007 and ledipasvir were not changed with meals. Therefore, ledipasvir-sofosbuvir may be given with or without food.10 Ledipasvir’s AUC is not affected by age, race, or the presence of cirrhosis.11
No pharmacokinetic changes were observed in patients with severe renal impairment (creatinine clearance [CrCl] < 30 mL/min) when a single dose of ledipasvir was adminis- tered.12 However, patients with varying degrees of renal
categorized as relapsers (a patient achieves an SVR, but the HCV RNA levels becomes detectable 12 or 24 weeks off of treatment), partial responders (at least a 2 log reduction in viral level from baseline, but remains detectable through the treatment duration), and null responders (no viral reduction at any time point during treatment). In studies, the treat- ment-experienced group could include patients who failed HCV treatment with peginterferon and ribavirin and/or with DAA-based therapy, especially with telaprevir- and boceprevir-based regimens.
The LONESTAR study, an open-label, randomized, phase II trial of ledipasvir-sofosbuvir FDC in adult patients with genotype 1 HCV showed that this combination achieved SVR12 rates of at least 95% across all treatment groups, which led to the phase III ION trials.17 The approval of ledipasvir-sofosbuvir FDC was based on 3 studies in treatment-naïve (ION-1 and ION-3) and treatment-experi- enced patients (ION-2).18-20 These trials evaluated genotype 1 HCV infections in patients with or without cirrhosis and are summarized in Table 1.
ION-1 was a phase III, open-label, multicenter, random- ized trial of treatment-naïve patients with HCV genotype 1 infection. Adult patients were randomized to 12 or 24 weeks of ledipasvir-sofosbuvir FDC once daily with or without weight-based ribavirin (n = 865). Patients were stratified by genotype (1a vs 1b) and the presence or absence of cirrho- sis. The trial design allowed for approximately 20% of
Smith et al 3
Table 1. Efficacy Studies of Ledipasvir-Sofosbuvir.
Study Patient
Study Design Population Genotype Cirrhosis (%)
Treatment SVR12 (%) Serious ADEs (%)
ION-118 R, OL, MC, Treatment naïve 67% 1a; 32% 1b 16 12 Weeks LDV/SOF (n = 214) 99 <1
phase III LDV/SOF/RBV 12 weeks (n = 217) 97 3
LDV/SOF 24 weeks (n = 217) 98 8
LDV/SOF/RBV 24 weeks (n = 217) 99 3
ION-220 R, OL, MC, Treatment 79% 1a; 21% 1b 20 LDV/SOF 12 weeks (n = 109) 94 0
phase III experienceda LDV/SOF/RBV 12 weeks (n = 111) 96 0
LDV/SOF 24 weeks (n = 109) 99 6
LDV/SOF/RBV 24 weeks (n = 111) 99 3
ION-319 R, OL, MC, Treatment naive 80% 1a; 20% 1b 0 LDV/SOF 8 weeks (n = 215) 94 2
phase III LDV/SOF/RBV 8 weeks (n = 216) 93 <1
LDV/SOF 12 weeks (n = 216) 95 2
Abbreviations: LDV, ledipasvir; MC, multicenter; OL, open-label; R, randomized; RBV, ribavirin; SOF, sofosbuvir.
a53% Of patients failed protease inhibitors.
patients to have cirrhosis but excluded patients with decom- pensated liver disease. Patients enrolled had normal renal function and baseline laboratory values. Exclusion criteria included solid-organ transplantation, malignancy, coinfec- tion with chronic hepatitis B or HIV, and recent drug or alcohol abuse. The FDC was 90 mg of ledipasvir and 400 mg of sofosbuvir. Ribavirin was weight based (1000 mg/d for weights <75 kg and 1200 mg/d for weights 75 kg). The primary end point was SVR12. The majority of patients were white (85%), with genotype 1a (67%), and without cirrhosis (84%). SVR12 rates were 98% to 99% in the ledi- pasvir-sofosbuvir treatment arm and 97% to 99% in patients receiving ribavirin. One patient had a virological break- through because of medication nonadherence, whereas 2 relapsed in the ledipasvir-sofosbuvir arm because they had resistant variants at baseline. Resistant variants were pres- ent among 16% of patients at baseline, of whom 96% achieved an SVR. Among patients with cirrhosis, SVR12 rates were 94% to 100%. All groups tolerated the medica- tion well. In the 24-week treatment arms, 4 patients in the ledipasvir-sofosbuvir group and 6 patients in the ledipasvir- sofosbuvir plus ribavirin group discontinued therapy because of adverse drug events (ADEs). Nearly all patients (79%-92%) experienced at least 1 ADE during treatment. A total of 33 patients (18 patients in the FDC group and 7 in the FDC plus ribavirin group) reported serious ADEs, of whom 25 (75%) were in the 24-week treatment arm. Serious ADEs included cellulitis, chest pain, noncardiac chest pain, pneumonia, hand fracture, and gastroenteritis.18
ION-3 was similar in design to ION-1, with the excep- tion of treatment duration. Treatment-naïve adult patients without cirrhosis (n = 647) were randomized to ledipasvir- sofosbuvir FDC for 8 or 12 weeks or ledipasvir-sofosbuvir FDC plus ribavirin for 8 weeks. Patients were stratified by genotype (1a vs 1b). Inclusion and exclusion criteria were similar to those previously reported with the primary end
point of SVR12. The majority of patients were white (78%) with genotype 1a (80%). The SVR12 rate for the ledipasvir- sofosbuvir 8-week group was 94%, compared with 95% in the 12-week group and 93% in the 8-week FDC plus ribavi- rin group. It was found that 8 weeks of treatment with ledi- pasvir-sofosbuvir was noninferior to the other treatment groups. Virological breakthrough during treatment was not observed; however, 23 patients had virological relapse (11 in the 8-week ledipasvir-sofosbuvir group, 3 in the 12-week group, and 9 in the 8-week ribavirin group). Three patients discontinued therapy because of ADEs (1 in the FDC plus ribavirin group and 2 in the 12-week FDC group). The majority experienced at least 1 ADE (67%-69% and 76% in the FDC and FDC plus ribavirin arm, respectively). ADEs reported were similar to those in the ION-1 trial.19
The ION-1 and ION-3 trials support the use of ledipas- vir-sofosbuvir FDC without ribavirin in treatment-naïve patients with or without cirrhosis.18,19 SVR rates were 96% to 99% in patients treated for 12 weeks and 94% in noncir- rhotic patients treated for 8 weeks.18,19 SVR rates among patients with viral levels less than 6 million IU/mL were 97% and 96% in the 8- and 12-week FDC treatment arms, respectively.10,19 Given the similar efficacy rates, consider- ation may be given to an 8-week regimen in treatment-naïve patients who do not have cirrhosis. Although the percentage of patients with cirrhosis was small in ION-1, SVR12 rates remained high. Ledipasvir-sofosbuvir FDC was well toler- ated in these trials.18,19
ION-2 was similar in design to ION-1, with the excep- tion of the patient population, which included treatment- experienced patients to interferon and ribavirin with or without a protease inhibitor who relapsed, had a break- through, or were null or partial responders (n = 440). Patients were stratified by genotype (1a vs 1b), the presence of cirrhosis, and previous response to therapy (relapse, breakthrough, or null response). Patients who discontinued
4 Annals of Pharmacotherapy
therapy because of an ADE were excluded. The inclusion and exclusion criteria as well as the primary end point (SVR12) mirrored the ION-1 trial. The majority of patients were white (81%) with genotype 1a (79%) and without cir- rhosis (80%). SVR12 rates were similar among all groups: 94% to 99% of ledipasvir-sofosbuvir–treated patients and 96% to 99% with the addition of ribavirin. A total of 11 patients (2%) in the 12-week treatment arms had a virologi- cal relapse, 55% of whom had a resistant variant at baseline. At the time of relapse, all 11 patients had a resistant variant present. One patient in the 24-week group had virological breakthrough because of medication nonadherence and one withdrew consent and, thus, did not achieve SVR. Among those with cirrhosis (n = 88), SVR12 rates were 86% and 100% in the 12- and 24-week groups of ledipasvir-sofosbu- vir and 82% and 100% in the ribavirin groups, respectively. The majority (67%-90%) in all treatment arms experienced at least 1 mild to moderate ADE. No patient discontinued treatment early or developed a serious ADE in the 12-week treatment arms; 6% in the 24-week ledipasvir-sofosbuvir treatment arm reported a serious ADE. Serious ADEs included acute cholecystitis, convulsions, hepatic encepha- lopathy, noncardiac chest pain, upper-gastrointestinal hem- orrhage, vaginal prolapse, unstable angina, wound infection, intervertebral disk protrusion, and spondylolisthesis.20
This trial supports the use of ledipasvir-sofosbuvir FDC without ribavirin for genotype 1 HCV infection in treat- ment-experienced patients without cirrhosis for 12 weeks and with cirrhosis for 24 weeks.20 This patient population included those who had previously failed a protease inhibi- tor. Among them, 94% achieved SVR12 with 12 weeks of treatment; however, it should be noted that SVR12 rates were lower in those with cirrhosis who were treated for 12 weeks (86%) versus 24 weeks (100%). Although the num- ber of patients was small, these data support the use of extended duration in treatment-experienced patients with cirrhosis.20 A post hoc analysis of the ION trials determined that the degree of fibrosis did not affect SVR12 rates.21 In an analysis that included more than 500 patients with geno- type 1 in the phase II and III trials, preliminary data suggest SVR12 rates of approximately 95%.22
Strengths of the ION trials included the use of a random- ized, multicenter design. The primary outcome, SVR12, is consistent with other studies evaluating new therapies to treat HCV. These trials have shown that ledipasvir-sofosbu- vir without ribavirin is effective in achieving SVR in treat- ment-naïve and experienced patients with and without cirrhosis. There were no notable SVR differences among subgroups, including African Americans, Latinos, over- weight patients (body mass index 30 kg/m2), and those with IL28B genotype, or with respect to age.18-20
However, several limitations should be noted. First, all studies were funded by the sponsor and, thus, had signifi- cant sponsor involvement, although this is standard practice
in the HCV arena. Second, the durability of the primary end point, SVR12, should be discussed. Only 1 trial, ION-2 reported SVR24, which has historically been the major end point. SVR24 was reached by 100% who achieved SVR12 in ION-2, but SVR24 was not reported in the other ION tri- als.18-20 The studies were open label and excluded patients with renal dysfunction (CrCl < 60 mL/min), decompensated disease, and coinfected patients (chronic hepatitis B or HIV) and included a small sample of cirrhotic patients.18-20 Additionally, the vast majority had genotype 1a; however, in the United States most are genotype 1, and 1a was previ- ously difficult to treat compared with 1b.18-20 Results from a Japanese study support the use of the FDC for genotype 1 treatment-naïve or -experienced patients.23 The utility of ledipasvir-sofosbuvir is being investigated in patients who have been transplanted24-26; those who have HIV,27,28 advanced liver disease,24,26,29,30 and other genotypes29,31-33; children and adolescents34; and those who failed previous sofosbuvir therapy.29,35
Preliminary data for several special populations are avail- able. Approximately 80% of patients with genotype 2 or 3 achieved SVR after 12 weeks of treatment (n = 10 noncir- rhotic patients).32 Initial results were reported in genotype 4 patients, with 75% achieving SVR12.33 In HCV/HIV coin- fected patients, 100% of antiretroviral-naïve and 97% of anti- retroviral-experienced patients achieved SVR12 with 12 weeks of the FDC.28 The FDC plus ribavirin therapy is being evaluated in those who failed a sofosbuvir-based regimen, with preliminary results suggesting that 12 weeks of treatment is effective, achieving SVR4 in 95% to 100% of patients.36 SVR4 rates were high in patients with decompensated liver disease (Child Pugh class B and C) with genotype 1 and 4 HCV, although final results are pending.30 A small study (n = 5) of patients with nosocomial infection and cardiac comor- bidities reported that all 5 genotype 1b patients achieved SVR.37 Baseline characteristics (genotype 1a, cirrhosis, race, obesity, IL28B, high viral load, and uncontrolled diabetes) typically associated with poor response did not influence SVR rates in a post hoc analysis of the ION trials.38
Drug Interactions
In vitro ledipasvir metabolism has shown no significant cytochrome P450 activity but rather slow oxidation, whereas sofosbuvir is extensively metabolized by the liver via hydrolysis. Drug interactions may occur via P-glycoprotein (P-gp); both ledipasvir and sofosbuvir are substrates of P-gp and breast cancer resistant protein (BCRP); however, the predominant metabolite of sofosbu- vir (GS-331007) is not a substrate of P-gp or BCRP. Inducers of P-gp may decrease concentrations of ledipasvir- sofosbuvir, and concomitant administration is not recom- mended. Increases in pH may also decrease solubility and concentration of ledipasvir; thus, medications that increase
Smith et al 5
gastric pH may interact with ledipasvir. Several recommen- dations are made in the prescribing information with regard to drug interactions, including: separating antacid adminis- tration from ledipasvir-sofosbuvir by 4 hours, monitoring digoxin concentrations with coadministration, and avoiding St John’s wort and concomitant administration with simeprevir. Additionally, monitoring may be required for anticonvulsants, antimycobacterials, antiretrovirals, and rosuvastatin.10
Clinically significant changes in ledipasvir and sofosbu- vir were not seen with the use of antiretrovirals (raltegravir, atazanavir/ritonavir, darunavir/ritonavir, efavirenz, rilpiv- irine, emtrictiabine, lamivudine, or abacavir). However, exposures to tenofovir may increase its concentrations; therefore, caution should be exercised when administered with the FDC, although no dosage adjustments were recom- mended.39 No clinically significant interaction exists among ledipasvir-sofosbuvir and tacrolimus or cyclosporine.10,39 A study in healthy women given oral contraceptives and sofosbuvir or ledipasvir showed no clinically significant interaction.40 Additionally, the FDC may be administered concomitantly with the histamine receptor antagonists or separated by at least 12 hours (doses should not exceed famotidine 40 mg twice daily or equivalent).10 Proton pump inhibitors (doses not exceeding omeprazole 20 mg daily or equivalent) should not be administered prior to the FDC but may be given with or up to 2 hours after the FDC.39 Drug- drug interactions are summarized in Table 2.
Safety
Patients treated with ledipasvir-sofosbuvir may experience headaches, fatigue, insomnia, nausea, and diarrhea.10,18-20 The rates of ADEs varied by length of therapy: 67%, 67% to 79%, and 81% to 82% in the 8-, 12-, and 24-week treat- ment groups, respectively.18-20 Rates of serious ADEs were 0% to 8% in trials (total of 34 patients of 1952 treated). Rates of serious ADEs were similar in treatment-naïve and treatment-experienced patients; however, those treated for
24 weeks had higher rates (6%-8% vs 0%-2%). Discontinuation resulting from ADEs was 0% to 2% in tri- als (total of 6 patients of 1952 treated). The most common ADE rates were either less than or similar to those treated with ledipasvir-sofosbuvir when compared with the combi- nation with ribavirin.18-20
Viral Drug Resistance
Sofosbuvir has a high barrier to resistance and has been pre- viously described in the Journal.2 Viral resistance was stud- ied in patients with genotype 1a and 1b who received 3 days of 1, 3, 10, 30, and 90 mg of ledipasvir monotherapy.7 Viral load reductions were significant across all dosing regimens. Baseline amino acid substitutions at positions 28, 30, 31, or
98 in the NS5A sequence in genotype 1a patients had small reductions in viral load, although mutants were not detected at the 30- and 90-mg doses. Presence of NS5A mutations Q30E (genotype 1a) and Y93H (genotype 1a and 1b) confer high-level resistance to ledipasvir.8 Other mutations (K26E and S38F in genotype 1a and L31l in genotype 1b) have been described in non–sofosbuvir-containing ledipasvir regimens and are associated with reduced ledipasvir sus- ceptibility.41 Sofosbuvir is active against ledipasvir- resistant mutants, whereas ledipasvir remains active against sofosbuvir-resistant mutants.10
Patients were tested for baseline viral resistance in the ION trials. Baseline NS5A-resistant variants were detected in 11% to 18% of patients; however, SVR rates in these patients were 89% to 96%.18-20 It should be noted that at baseline in the ION-1 trial, 71% of patients harbored resis- tant variants to NS3/4A, and 98% achieved SVR.18 Additionally, there were no S282T variants, which is asso- ciated with sofosbuvir resistance. Of patients who failed treatment in the trials, 46% (n = 17) had baseline NS5A resistant variants.18-20 Baseline resistant variants do not appear to affect SVR rates in patients with genotype 1 infec- tion.42 Current guidelines recommend against baseline viral resistance testing, and the data on ledipasvir do not support its use.3
Dosage and Administration
Ledipasvir-sofosbuvir FDC is supplied as 1 bottle contain- ing 28 film-coated orange tablets with GSI and 7985 embossed on opposite sides. The tablet consists of 90 mg of ledipasvir and 400 mg of sofosbuvir. The recommended dosage is 1 tablet by mouth once daily with or without food. The recommended duration of therapy is 12 weeks for treat- ment-naïve patients with or without cirrhosis, 12 weeks for treatment-experienced patients without cirrhosis, and 24 weeks in treatment-experienced patients with cirrhosis. Treatment-experienced patients include those previously treated with a protease inhibitor.10 A shorter duration of 8 weeks may be considered in certain treatment-naïve patients without cirrhosis who have low baseline HCV RNA levels (<6 million IU/mL).
Cost
Ledipasvir-sofosbuvir pricing is comparable to those of other available DAAs, at approximately $1125 per tablet.43 Although other DAAs cost less, ledipasvir-sofosbuvir may be used for shorter courses of therapy (8 weeks) in certain populations, which may counterbalance the slightly more expensive treat- ments. Pharmaceutical companies are becoming strategic about broadening access to DAAs with the use of voluntary licenses and tiered-pricing strategies for middle- to low-income countries.44 The pharmacoeconomics of ledipasvir-sofosbuvir
6 Annals of Pharmacotherapy
Table 2. Drug-Drug Interaction Profile of Ledipasvir-Sofosbuvir.
Concomitant Medication Interaction Recommendation Antacids10 Ledipasvir concentrations Administration should be separated by 4
hours
Digoxin10 Digoxin concentrations Monitor digoxin levels
St John’s wort10 Ledipasvir, sofosbuvir, and GS-331007 concentrations
Simeprevir10 Simeprevir and ledipasvir concentrations
Anticonvulsants10 Ledipasvir, sofosbuvir, and GS-331007 concentrations
Antimycobacterials10 Ledipasvir, sofosbuvir, and GS-331007 concentrations
Use is not recommended Use is not recommended
Use is not recommended for carbamazepine, phenytoin, phenobarbital, and oxcarbazepine
Use is not recommended with rifampin, rifabutin, or rifapentine
Tenofovir 10,39 Tenofovir concentrations Caution with concomitant use; no dosage
recommendations available
Raltegravir10,39 No significant interaction NA
Atazanavir/ritonavir10,39 No significant interaction NA
Darunavir/ritonavir10,39 No significant interaction NA
Tipranivir/ritonavir10,39 Ledipasvir, sofosbuvir, and GS-331007
concentrations
Use is not recommended
Efavirenz10,39 No significant interaction NA
Rilpivirine10,39 No significant interaction NA
Emtricitabine10,39 No significant interaction NA
Lamivudine10,39 No significant interaction NA
Abacavir10,39 No significant interaction NA
Rosuvastatin10 Rosuvastatin concentrations Use is not recommended
Tacrolimus10,39 No significant interaction NA
Cyclosporine10,39 No significant interaction NA
Oral contraceptives10,40 No significant interaction NA
Histamine receptor antagonists10
Ledipasvir concentrations Administration should be concomitant or separated by at least 12 hours; doses should not exceed famotidine 40 mg twice daily or equivalent
Proton pump inhibitors10,39 Ledipasvir concentrations Administration should be concomitant or up
to 2 hours after the FDC; doses should not exceed omeprazole 20 mg or equivalent
Abbreviation: FDC, fixed-dose combination.
have yet to be studied, although analytical models have shown that future hepatic complications may be reduced when treat- ing with the FDC. Markov models have shown that treatment of genotype 1 patients with the FDC reduces complications, improves quality of life, and leads to better health outcomes.45,46 Another Markov model describes the benefit of treating patients earlier in their disease progression rather than waiting for patients to develop advanced disease (stage 3 or 4), which involves a great risk of developing hepatocellular carcinoma and ultimately requiring a liver transplant.47
Summary
Ledipasvir-sofosbuvir FDC has been shown to be effective for the treatment of genotype 1 chronic HCV in treatment-naïve and treatment-experienced patients with and without cirrhosis. This is the first FDA-approved medication for chronic HCV
that is peginterferon and ribavirin free. Ledipasvir-sofosbuvir has high SVR rates, minimal ADEs, and simple administration compared with historical regimens.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
References
1. Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61(RR-4):1-32.
Smith et al 7
2. Rose L, Bias TE, Mathias CB, Trooskin SB, Fong JJ. Sofosbuvir: a nucleotide NS5B inhibitor for the treat- ment of chronic hepatitis C infection. Ann Pharmacother. 2014;48:1019-1029. doi:10.1177/1060028014534194.
3. Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. http://www. hcvguidelines.org/. Accessed November 29, 2014.
4. Lohmann V. Hepatitis C virus RNA replication. Curr Top Microbiol Immunol. 2013;369:167-198. doi:10.1007/978-3- 642-27340-7_7.
5. Belema M, Lopez OD, Bender JA, et al. Discovery and development of hepatitis C virus NS5A replication complex inhibitors. J Med Chem. 2014;57:1643-1672. doi:10.1021/ jm401793m.
6. Link JO, Taylor JG, Xu L, et al. Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection. J Med Chem. 2014;57:2033-2046. doi:10.1021/jm401499g.
7. Wong KA, Worth A, Martin R, et al. Characterization of hepatitis C virus resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-5885. Antimicrob Agents Chemother. 2013;57:6333-6340. doi:10.1128/aac. 02193-12.
8. Lawitz EJ, Gruener D, Hill JM, et al. A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C. J Hepatol. 2012;57:24-31. doi:10.1016/j.jhep.2011.12.029.
9. Link JO, Bannister R, Beilke L, et al. Nonclinical profile and phase I results in healthy volunteers of the novel and potent HCV NS5A inhibitor GS-5885. Poster presented at: 61st Annual Meeting of the American Association for the Study of Liver Diseases 2010; October 29 to November 2, 2010; Boston, MA.
10. Harvoni [prescribing information]. Foster City, CA: Gilead Sciences, Inc; 2014.
11. Kirby B, Li H, Kearney B, Mathias A. Population pharma- cokinetic analysis of ledipasvir (GS-5885) in healthy and hepatitis C virus-infected subjects. Abstract presented at: 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; May 19-21, 2014; Washington, DC.
12. Mogalian E, Mathias A, Yang C, et al. The pharmacokinet- ics of ledipasvir, an HCV specific NS5A inhibitor, in HCV- uninfected subjects with severe renal impairment [abstract]. Hepatology (Baltimore, Md). 2014;60:1145A-1146A.
13. Department of Health and Human Services. Management of hepatitis C: 2002 National Institutes of Health Consensus Conference Statement. http://consensus.nih.gov/2002/2002- hepatitisc2002116html.htm. Accessed November 29, 2014.
14. Chen J, Florian J, Carter W, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology. 2013;144:1450-5. e2. doi:10.1053/j.gastro.2013.02.039.
15. Guidance for industry chronic hepatitis C virus infection: devel- oping direct-acting antiviral drugs for treatment. http://www. fda.gov/downloads/drugs/guidancecomplianceregulatory information/guidances/ucm225333.pdf. Accessed November 29, 2014.
16. Bernstein DE, Mangia A, Brau N, et al. Concordance between SVR4, SVR12 and SVR24 in genotype 1 HCV-infected patients
who received all oral fixed-dose combination ledipasvir/sofos- buvir with or without ribavirin in phase 3 clinical trials [abstract]. Hepatology (Baltimore, Md). 2014;60:1142A-1143A.
17. Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledi- pasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with geno- type 1 hepatitis C virus infection (LONESTAR): an open- label, randomised, phase 2 trial. Lancet. 2014;383:515-523. doi:10.1016/s0140-6736(13)62121-2.
18. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbu- vir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:1889-1898. doi:10.1056/NEJMoa1402454.
19. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cir- rhosis. N Engl J Med. 2014;370:1879-1888. doi:10.1056/ NEJMoa1402355.
20. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofos- buvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370:1483-1493. doi:10.1056/NEJMoa131 6366.
21. Gordon SC, Fried MW, Kwo P, et al. No differences in efficacy of fixed-dose combination ledipasvir/sofosbuvir in patients according to fibrosis stage development deter- mined by liver biopsy or laboratory biomarker in phase
3 clinical trials [abstract]. Hepatology (Baltimore, Md). 2014;60:1149A-1150A.
22. Bourliere M, Sulkowski M, Omata M, et al. An integrated safety and efficacy analysis of >500 patients with compen- sated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin [abstract]. Hepatology (Baltimore, Md). 2014;60:239A.
23. Mizokami M, Takehara T, Yokosuka O, et al. 100% SVR4 in Japanese patients with chronic genotype 1 hepatitis C virus infection receiving ledipasvir/sofosbuvir fixed dose combina- tion for 12 weeks: results from a multicenter phase 3 study [abstract]. Hepatology (Baltimore, Md). 2014;60:1130A.
24. Gilead Sciences. Ledipasvir/sofosbuvir fixed-dose com- bination plus ribavirin in subjects with chronic HCV with advanced liver disease or post-liver transplant. http://clinical- trial.gov/ct2/show/NCT02010255?term=ledipasvir&rank=
13. Accessed November 29, 2014.
25. Gilead Sciences. Safety and efficacy of ledipasvir/sofos- buvir (LDV/SOF) fixed dose combination (FDC) for 12 or 24 weeks in kidney transplant recipients with chronic HCV infection. http://clinicaltrial.gov/ct2/show/NCT02251717? term=ledipasvir&rank=9. Accessed November 29, 2014.
26. O’Leary JG, Burton JR, Helmke SM, et al. Early improve- ment in HepQuant (HQ)-SHUNT function test during treat- ment with ledipasvir/sofosbuvir in liver transplant recipients with allograft fibrosis or cirrhosis and patients with decom- pensated cirrhosis who have not undergone transplantation [abstract]. Hepatology (Baltimore, Md). 2014;60:1134A.
27. Osinusi A, Townsend K, Nelson A, et al. O14 Use of sofosbuvir/ ledipasvir fixed dose combination for treatment of HCV geno- type-1 in patients coinfected with HIV [abstract]. J Hepatol. 2014;60(1):S7. doi:10.1016/S0168-8278(14)60016-7.
28. Townsend K, Osinusi A, Nelson A, et al. High efficacy of sofosbuvir/ledipasvir for the treatment of HCV genotype 1 in patients coinfected with HIV on or off antiretroviral
8 Annals of Pharmacotherapy
therapy: results from the NIAID ERADICATE trial [abstract].
Hepatology (Baltimore, Md). 2014;60:240A.
29. Gane EJ, Hyland RH, An D, et al. O6 Sofosbuvir/ledi- pasvir fixed dose combination is safe and effective in difficult-to-treat populations including genotype-3 patients, decompensated genotype-1 patients, and geno- type-1 patients with prior sofosbuvir treatment experience [abstract]. J Hepatol. 2014;60(1):S3-S4. doi:10.1016/S0168- 8278(14)60008-8.
30. Flamm SJ, Everson GT, Charlton M, et al. Ledipasvir/sofos- buvir with ribavirin for the treatment of HCV in patients with decompensated cirrhosis: preliminary results of a prospective, multicenter study [abstract]. Hepatology (Baltimore, Md). 2014;60:320A-321A.
31. Gilead Sciences. Efficacy and safety of ledipasvir/sofosbuvir fixed-dose combination in treatment-naïve and treatment- experienced subjects with chronic genotype 4 or 5 HCV infection. http://clinicaltrial.gov/ct2/show/NCT02081079?- term=ledipasvir&rank=16. Accessed November 29, 2014.
32. Gane EJ, Stedman CA, Hyland RH, et al. Once daily sofosbu- vir/ledipasivr fixed dose combination with or without ribavi- rin: the ELECTRON trial [abstract]. Hepatology (Baltimore, Md). 2013;58:243A.
33. Kapoor R, Kohli A, Sidharthan S, et al. All oral treatment for genotype 4 chronic hepatitis C infection with sofosbuvir and ledipasvir: interim results from the NIAID SYNERGY trial [abstract]. Hepatology (Baltimore, Md). 2014;60:321A.
34. Gilead Sciences. Safety and efficacy of ledipasvir/sofos- buvir fixed dose combination in adolescents and children with chronic HCV-infection. http://clinicaltrial.gov/ct2/ show/NCT-02249182?term=ledipasvir&rank=6. Accessed November 29, 2014.
35. Osinusi A, Marti M, Townsend K, et al. O11 Retreatment of relapsers to sofosbuvir/ribavirin with sofosbuvir/ledi- pasvir: complete and rapid virologic suppression by week 4 [abstract]. J Hepatol. 2014;60:S5-S6. doi:10.1016/S0168- 8278(14)60013-1.
36. Wyles DL, Pockros PJ, Yang C, et al. Retreatment of patients who failed prior sofobuvir-based regimens with all oral fixed-dose combination ledipasvir/sofosbuvir plus ribavirin for 12 weeks [abstract]. Hepatology (Baltimore, Md). 2014;60:317A-318A.
37. Chung RT, Lauer GM, Stamm LM, et al. Ledipasvir/sofos- buvir is safe and effective in nosocomially infected patients with advanced age and significant cardiac co-morbidities [abstract]. Hepatology (Baltimore, Md). 2014;60:1158A.
38. Jacobson IM, Kwo P, Kowdley KV, et al. Virologic response rates to all oral fixed-dose combination ledipasvir/sofosbuvir regimens are similar in patients with and without traditional
negative predictive factors in phase 3 clinical trials [abstract].
Hepatology (Baltimore, Md). 2014;60:1141A-1142A.
39. German P, Pang P, Fang L, Chung D, Mathias A. Drug-drug interaction profile of the fixed-dose combination tablet ledi- pasvir/sofosbuvir [abstract]. Hepatology (Baltimore, Md). 2014;60:1162A.
40. German P, Moorehead L, Pang P, Vimal M, Mathias A. Lack of a clinically important pharmacokinetic interaction between sofosbuvir or ledipasvir and hormonal oral contraceptives norgestimate/ethinyl estradiol in HCV-uninfected female sub- jects. J Clin Pharmacol. 2014;54:1290-1298. doi:10.1002/ jcph.346.
41. Kitrinos KM, Wyles DL, Dvory-Sobol H, et al. Evaluation of the resistance profile of ledipasvir (LDV), a nonstructural protein 5A (NS5A) inhibitor, in genotype (GT) 1 chronically infected HCV subjects treated with LDV-containing regimens without sofosbuvir (SOF) [abstract]. Hepatology (Baltimore, Md). 2014;60:1143A-1144A.
42. Sarrazin C, Dvory-Sobol H, Svarovskaia E, et al. Baseline and post-baseline resistance analyses of phase 2/3 studies of ledipasvir/sofosbuvir plus/minus RBV [abstract]. Hepatology (Baltimore, Md). 2014;60:1128A.
43. Pollack A. Harvoni, a hepatitis C drug from Gilead, wins FDA approval. http://mobile.nytimes.com/2014/10/11/business/ harvoni-a-hepatitis-c-drug-from-gilead-wins-fda-approval. html?_r=2&referrer=. Accessed November 29, 2014.
44. Londeix P. New treatments for hepatitis C virus: strategies for achieving universal access. http://www.hepcoalition.org/ IMG/pdf/daas_strategies_for_achieving_universal_access_ en.pdf. Accessed November 29, 2014.
45. Gordon SC, Ahmed A, Saab S, Younossi Z. Evaluation of the long-term health outcomes of ledipasvir/sofosbuvir (LDV/SOF) and sofosbuvir-based regimens for patients with chronic hepatitis C (CHC) and liver cirrhosis across genotypes 1 to 4 (GT 1-4): results form a decision-analytic markov model [abstract]. Hepatology (Baltimore, Md). 2014;60:1040A-1041A.
46. Younossi Z, Saab S, Ahmed A, Gordon SC. A decision- analytic markov model to evaluate the health outcomes of ledipasvir/sofosbuvir (LDV/SOF) for patients with chronic hepatitis C (HCV) genotype 1 (GT1) infection [abstract]. Hepatology (Baltimore, Md). 2014;60:1043A.
47. Ahmed A, Gordon SC, Saab S, Younossi Z. Evaluation of the health outcomes for ledipasvir/sofosbuvir in early vs. delayed treatment according to fibrosis stage of patients with chronic hepatitis C virus (HCV) genotype 1 infection: results from a decision-analytic Markov model [abstract]. Hepatology (Baltimore, Md). 2014;60:1041A.GS5885