Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2022 Oct 1.
Published in final edited form as: Expert Opin Pharmacother. 2021 Jul 1;22(14):1839–1846. doi: 10.1080/14656566.2021.1943359

An evaluation of ledipasvir + sofosbuvir for the treatment of chronic Hepatitis C infection

Pearson Balatow 1,#, Amber Sandlin 1,#, Theodore James Cory 1
PMCID: PMC8478781  NIHMSID: NIHMS1722296  PMID: 34157923

Abstract

Introduction:

Hepatitis C (HCV) is viral disease with a global impact. Over the last 10 years, the treatment of this disease has evolved. Treatment guidelines have evolved to adopt new medications for HCV. These drugs have shown efficacy over 90% throughout the class as well as a better safety profile than the previous recommended pharmacotherapy. Dual-therapy DAAs emerged with FDA approval of Ledipasvir/Sofosbuvir (LDV/SOF) in 2014.

Areas Covered:

LDV/SOF is a dual-therapy option for chronic HCV patients (>6 months of infection) in select genotypes. This article reviews the studies relevant to the pharmacokinetic/pharmacodynamic properties of these drugs as well as its trials leading to approval.

Expert opinion:

LDV/SOF is included in the AASLD/IDSA guidelines for the treatment of HCV genotypes 1a and 1b with or without cirrhosis and genotype 4 without cirrhosis with an evidence and recommendation rating of IA. Genotype 4 with cirrhosis and genotypes 5 and 6 carry a Class IIa level B recommendation. The combination is not FDA approved for genotypes 2 and 3. Single-pill regimens, like LDV/SOF, are important to maintain the quality of life of children and other special populations infected with HCV by shortening treatment regimens, avoiding complex pill regimens, and eliminating injection therapies.

Keywords: Direct Acting Antivirals, Hepatitis C, Ledipasvir, NS5A inhibitor, Sofosbuvir, NS5B inhibitor, Sustained virologic response after 12 weeks post-treatment (SVR12)

1.0. Introduction

The hepatitis C virus (HCV) emerged in the 1970’s as non-A, non-B hepatitis (NANBH), responsible for the majority of transfusion-associated hepatitis cases1, Once identified in 1989, the medical community began looking for a cure. Early treatments revolved around lengthy, invasive interferon-based regimens that boasted 50% response rates and extensive side effects1, 2. Due to the considerable side effect profile and low response rate, drug development for HCV shifted focus toward the inhibition of replication and the viral life cycle via direct-acting antivirals (DAAs). Protease inhibitors, including Telaprevir and Boceprevir, were among the first oral DAAs with clinical efficacy due to the inhibition of viral protein generation dependent on NS3 protease3. Sofosbuvir acts as a chain terminator to interfere with viral RNA production4, 5. The NS5A inhibitor, (LDV), for use in combination with Sofosbuvir to interrupt the replication and assembly of viral proteins4, 5. DAA combinations have revolutionized the treatment of chronic Hepatitis C by shortening therapy and decreasing side effects in most cases while achieving response rates greater than 95%1. The most recent innovations have also seen improved response rates among those with complicated cirrhosis or a history of treatment failure. As of 2015, 71.1 million people were chronically infected with HCV globally6. Thus, the World Health Organization developed an international action plan to eradicate viral hepatitis by 2030 with goals to reduce incidence by 80% and HCV-related mortality by 65%6, 7. Extensive advancements in medical treatment regimens have made HCV the first curable persistent viral infection utilizing 8 – 12 weeks of oral combination therapies. Extensive advancements in medical treatment regimens have made HCV the first curable persistent viral infection utilizing 8 – 12 weeks of oral combination therapies.

2.0. Overview of the Market

Direct-acting antivirals (DAAs) were initially introduced to the American pharmaceutical drug market in 2011 with the back-to-back approvals of telaprevir and boceprevir for the treatment of HCV genotype 1 infections when used in conjunction with pegylated interferon or RBV8-10. These treatments elicited an excellent SVR12 of 75% in treatment groups, but the regimens included three doses per day for 12 to 44 weeks. Second generation DAAs came to market between 2013 and 2016, including SOF, LDV, simeprevir (SIM), daclatasvir (DAC), dasabuvir (DAS) and others8-11.

Despite these remarkable improvements in treatment options available to people living with HCV, these regimens are still complex combinations requiring high levels of adherence, monitoring of possible drug interactions, and/or therapy changes due to resistance. Thus, there was still an unmet medical need among patients with resistant HCV, genotypes 2 – 6, or those that have failed previous treatment9, 12,13-15.

3.0. Introduction to the Compounds

SOF is a nucleotide analog which inhibits the action of the nonstructural protein 5B. The FDA approved drug is available alone or more commonly in combination with other anti-viral drugs like LDV 12. It was first approved in December 2013.

Ledipasvir, also known as GS-5885 or LDV, is an inhibitor of HCV phosphoprotein NS5A. It displays high activity against HCV genotype 1a and 1b and moderate activity against genotypes 4a, 4b, 5a, and 6a, but is only available in a coformulation with SOF 12.

3.1. Chemistry

3.1.1. Sofosbuvir

SOF is a 2’-deoxy-2’-a-fluoro-b-C-methyluridine-5’-monophosphate prodrug. It is a mixture of two isomers, PSI-7977 and GS-7977. Of the two stereoisomers, PSI-7977 possesses a higher level of efficacy against active hepatitis C16. The C-methyl and a-fluoro group located at the 2’ position are key structures on its sugar molecule that provide increased potency and decreased toxicity in relation to other polymerase inhibitors on the market17. The molecular formula of SOF is C22H29FN3O9P, and it has a molecular weight of 529.5 g/mol. The drug is moderately water soluble and generally stable in storage 12.

3.1.2. Ledipasvir

The molecular formula for LDV is C49H54F2N8O6 with a molecular weight of 889.00 g/mol 12. It is a dimeric molecule with a proline-valine-carbamate cap that allows it to directly bind and inhibit NS5A activity during viral replication18LDV is only slightly soluble (1.1mg/mL) in pH < 2.3 and is relatively insoluble (< 0.1mg/mL) at pH 3 – 7.512,19, 20.

3.2. Pharmacokinetics & Metabolism

3.2.1. Sofosbuvir

Absorption

The pharmacokinetic properties of sofosbuvir and its inactive metabolite GS-331007 were evaluated by a cohort study in groups with diagnosed hepatitis C. After oral administration of SOF, the drug is rapidly absorbed with a reported Cmax of 618ng/mL. When administered with a high fat meal the AUC may be increased 2-fold, with no significant effect on Cmax 12, 21.

Distribution

SOF is moderately protein bound (61-65%) and the protein binding is independent of drug concentration. The inactive metabolite has minimal protein binding12.

Metabolism

SOF is metabolized hepatically to its active form, GS-461203, after first pass metabolism. For activation to occur, human cathepsin A (CatA) or carboxylesterase 1 (HINT1) hydrolyzes the ester moiety, followed by phosphorylation. Sofosbuvir’s metabolism occurs through dephosphorylation to an inactive metabolite. The inactive metabolite accounts for greater than 90% systemic exposure12.

Elimination

After oral administration, approximately 80% of the drug is excreted in the urine. The major component in the urine is the inactive metabolite. GS-331007’s major elimination pathway is renal. The half-life of both sofosbuvir and GS-331007 is 0.5-27 hours12, 13.

3.2.2. Ledipasvir

Absorption

LDV reaches median peak concentration 4 – 4.5 hours after administration and absorption is not affected by food. LDV exhibits a maximum concentration (Cmax) of 323ng/mL and a steady-state AUC of 7290 ng x hr/mL in healthy individuals given 90mg orally once daily. In patients living with HCV, steady-state AUC and maximum concentration are shown to be 24% lower and 32% lower, respectively. LDV is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) leading to a potential 2-3 fold higher exposure when administered with P-gP or BCRP inhibitors. Pharmacokinetic analyses indicated a higher AUC and Cmax for female patients, but all subjects achieved high response rates with an SVR > 90%12.

Distribution

LDV displays greater than 99.8% protein binding leading to the high permeability and low solubility of the compound. LDV displays near-linear pharmacokinetics that is time-dependent12.

Metabolism

LDV is metabolized to various inactive metabolites through unidentified mechanisms. There are 3 metabolites of note: M19, M26, and M2712.

Elimination

LDV is primarily excreted unchanged in the feces with minor recovery of the oxidative metabolite, M19. Minimal amounts (<1%) of the administered dose may be recovered in the urine as various inactive metabolites, primarily recovered as M26 (0.63%). Therefore, LDV does not require dose adjustments for renal or hepatic impairment12.

3.3. Pharmacodynamics

3.3.1. Sofosbuvir

SOF inhibits HCV genotype 1b and S282T replicons with EC90 values of 0.42 and 0.78 μm. SOF possesses an excellent resistance profile across various HCV genotypes. Overall SOF demonstrated EC50 values of 0.0154 to 0.11 μm in genotypes 1a, 1b, 2a, 3a, 4a, 4d, and 1b replicons specifically encoding NS5B in genotypes 2b, 5a, and 6a12, 21, 22.

3.3.2. Ledipasvir

LDV, an NS5A inhibitor, only shows antiviral activity against HCV and is not known to cause any significant cytotoxicity in other cell lines. It is most potent against HCV genotypes 1a and 1b, but genotypes 2 through 6 are also susceptible. Genotype 1a displayed an EC50 of 0.031 nM compared to an EC50 of 0.004 nM in genotype 1b. The difference between genotypes 1a and 1b is likely due to NS5A amino acid substitutions (Y93H and Q30E) associated with HCV genotype 1a infections, rendering these strains less susceptible to LDV. As for genotypes 2 – 6 and relevant subtypes, the median EC50 ranges from 0.15 – 430 nM. Overall, genotype 6 has the highest median EC5012, 23.

4.0. Clinical Efficacy

4.1. Phase I Trials

4.1.2. Sofosbuvir

A double-blind, randomized, placebo-controlled study design was utilized for SOF dosing over a range of doses up to 800mg. Subjects were pre-screened for pre-existing conditions and assessed for 5 days inpatient after dose administration. A follow up assessment was held 7-10 days after the last dose. Vital signs, including blood pressure, heart rate, and respiratory rate, were measured pre-administration and during the experimental window. A 12-lead EKG was assessed prior to and in 12-hour increments throughout the testing period. In conclusion, SOF was determined to be generally well-tolerated, with no dose-limiting toxicities or maximum tolerated dose identified. There was no indication of increased adverse effects from the groups receiving between 25mg-800mg of drug. One outlier subject reported dizziness, but the side effect was considered moderate24. An additional double-blind, parallel-group, placebo-controlled, randomized study performed on SOF concluded that the PK profile was similar to the ascending dose trial mentioned. This study was conducted with treatment-naïve subjects that were Hepatitis C virus positive. This randomized study evaluated safety and tolerability in a similar manner to the above case with a comparable statistical analysis25.

4.1.3. Ledipasvir

A double-blind, randomized, placebo-controlled study was utilized for LDV, under the name of GS-5885, for hepatitis C infected patients. LDV was administered orally to different cohort groups that were monitored until assessment at a follow-up visit 14 days post-initiation. The monitoring consisted of adverse drug events, physical exams, clinically laboratory tests, vital signs, and 12-lead EKGs. Headaches were the most common adverse effect, and no serious adverse events were reported. There was no trend between different dosing and headache among the cohort groups. Two moderate rashes reported in the 1mg cohort, and headache and dysuria were reported in the 30mg cohort. There were no clinically significant abnormalities observed25.

4.2. Phase 2 Trials

Phase 2 trials of LDV/SOF with or without Ribavirin (RBV) have been conducted for HCV-infected patients with genotypes 1 - 6.

Genotype 1:

A randomized, double-blind, placebo-controlled study, called the SIRIUS trial (ClinicalTrixals.gov Identifier NCT01965535), compared the sustained virologic response 12 weeks after therapy completion (SVR12) of 155 subjects following LDV/SOF with or without ribavirin for 12 or 24 weeks or in Genotype 1 HCV-infected patients who presented with compensated cirrhosis and previously failed interferon or protease inhibitor-based regimens. 96% (74/77) of subjects achieved an SVR12 after completing 12 weeks of triple therapy, while 97% (75/77) of the 24-week dual-therapy group achieved an SVR12. Both groups displayed similarly high SVR12 rates without designation of a clear superior therapy 12, 26, 27.

In the LONESTAR study (ClinicalTrials.gov Identifier NCT01726517), 100 adult patients with genotype 1 HCV infection were given LDV/SOF with or without RBV for 8 – 12 weeks. Cohort A consisted of 60 treatment-naïve patients without cirrhosis and cohort B included 40 patients who experienced virological failure on protease inhibitor based therapy. Cohort A included 3 groups that were treated with LDV/SOF +/− RBV for 8 weeks (groups 1 and 2) or LDV/SOF only for 12 weeks. Cohort B included 2 groups treated with LDV/SOF +/− RBV for 12 weeks. The groups receiving ribavirin had an SVR12 rate of 100% compared to 95% in treatments without RBV. However, all treatment groups achieved high SVR12 rates regardless of cirrhosis or treatment history and are considered favorable treatment options 28.

Genotypes 4 and 5:

Study 1119 (ClinicalTrials.gov Identifier NCT02081079) conducted by Gilead Sciences focused on LDV/SOF 12-week therapy in patients with genotype 4 or 5 HCV infection. 44 subjects with genotype 4 HCV were in arm 1 and 41 subjects with genotype 5 HCV were included in arm 2. Approximately half of each group was treatment naïve and both arms included cirrhotic patients. The primary outcome of interest was the SVR12 which was 93% overall. SVR12 was similar regardless of prior therapy and cirrhotic status12.

Multiple genotypes with varying levels of hepatic impairment or cirrhosis:

The SOLAR-1 and SOLAR-2 trials determined the effect of LDV/SOF + RBV on SVR12 inpatients with genotype 1 or 4 HCV infection12.

SOLAR-1 (ClinicalTrials.gov Identifier NCT01938430) enrolled 337 subjects. Cohort A studied patients with cirrhosis or moderate-severe hepatic impairment without a previous liver transplant and cohort B focused on patients that had undergone liver transplantation and had varying levels of cirrhosis, hepatic impairment, or fibrosing cholestatic hepatitis. Both cohorts were treated with the LDV/SOF + RBV regimen for 12 - 24 weeks. Cohort A achieved SVR12 in 86 – 89% of patients. Cohort B exhibited 100% SVR12 achievement in those with fibrosing cholestatic hepatitis, 96 -98% with or without compensated cirrhosis, 85 – 88% in those with moderate hepatic impairment, and 60 – 75% in cases of severe hepatic impairment. LDV/SOF + RBV displayed high SVR12 achievement rates after 12 – 24 weeks of therapy in patients with advanced liver disease, even prior to or following liver transplantation29.

SOLAR-2 (ClinicalTrials.gov Identifier NCT02010255) evaluated treatment with LDV/SOF + RBV in 333 patients with genotype 1 or 4 HCV with advanced liver disease. Cohort A included patients with cirrhosis before transplant and Cohort B included patients with or without cirrhosis or fibrosing cholestatic hepatitis post-transplant. Subjects in both cohorts were divided based upon their Child-Turcotte-Pugh (CTP) score and given either 12 or 24 weeks of treatment. Both cohorts displayed high SVR12 achievement rates in varying stages of cirrhosis before and after liver transplantation. Results between the 12-week and 24-week treatment groups were deemed similar12, 26, 30-32.

4.3. Phase 3 Trials

Four phase 3 trials of LDV/SOF with or without Ribavirin have been conducted for HCV-infected patients with genotypes 1a, 1b, and 4. These trials are collectively known as the ION trials 1 – 4. At the time that the ION trials were conducted, HCV genotype 1 patients only had one 24-week interferon-free therapy option, SOF/RBV, and response rates were less than 70%. Furthermore, interferon and RBV-based regimens have significant side effects and exclusions of therapy. All of the ION trials aimed to identify treatment options for HCV patients that optimized safety, efficacy, and simplicity. ION trials 1, 2, 3, and 4 included 865, 440, 647 and 335 subjects, respectively, with HCV genotype 1a, 1b, and 4 infections26, 33-35.

ION 1 (ClinicalTrials.gov Identifier NCT01701401) examined the SVR12 of treatment-naïve patients after either 12 or 24 weeks of LDV/SOF therapy with or without ribavirin. The goal of ION 1 was to determine the safety and effectiveness of each regimen in a diverse pool of subjects with HCV genotype 1, including patients with cirrhosis. Subjects were randomized in a 1:1:1:1 ratio in the 4 treatment groups. Results showed that LDV/SOF administered once daily was highly successful in achieving SVR12 in previously untreated subjects with HCV genotype 1 infections with SVR12 rates between 97 and 99%. The most commonly reported adverse events were fatigue, headache, nausea, and insomnia12, 26, 36.

ION 2 (ClinicalTrials.gov Identifier NCT01768286) focused on HCV genotype 1 patients that are considered the hardest to cure after failing to achieve sustained virologic response after peginterferon treatment with or without a protease inhibitor. This study also included patients with compensated cirrhosis. Patients were randomized into four treatment groups that utilized LDV/SOF for 12 or 24 weeks with and without RBV. SVR12 was 94% or greater in all 4 treatment groups, regardless of treatment duration or addition of RBV. Among the 20% of patients that were cirrhotic, SVR12 rates were 82 – 86% with the 12-week regimen and comparable to non-cirrhotic patients in the 24-week groups for an average of 92% across all treatment groups. Adverse drug events and alanine aminotransferase (ALT) levels were also monitored in subjects of all treatment groups. 85 – 91% of subjects that presented with high ALT at baseline exhibited levels within normal limits by the second week of therapy and the most common adverse events across all groups were fatigue, headache, and nausea 12, 26, 33.

ION 3 (ClinicalTrials.gov Identifier NCT01851330) was similar to ION 1 in that it analyzed treatment-naïve patients without cirrhosis but utilized 8- or 12-week therapy durations. ION 3 was conducted to determine if the cure rate of a shortened 8-week regimen was comparable to the standard 12-week regimen because many patients living with HCV seek safe regimens that provide simplicity and efficacy. Patients were randomized into 3 treatment groups covering 8-week treatment with LDV/SOF with or without RBV and 12-week treatment with LDV/SOF alone. It determined that 8 weeks of LDV/SOF was not inferior to the 12-week therapeutic regimen or regimens including RBV due to a maximum 2% difference in SVR12 between groups. Additionally, both the lowest SVR12 and highest adverse event incidence were observed in the group receiving RBV 12, 26, 34, 35.

ION 4 (ClinicalTrials.gov Identifier NCT02073656) was a relatively unique trial because it studied subjects living with either genotype 1 or 4 HCV infections and HIV-1 coinfection while stable on antiretroviral therapy for HIV-1 for at least 8 weeks. Nearly half of the subjects were HCV treatment-experienced and 20% of patients had compensated cirrhosis. All patients received LDV/SOF once daily for 12 weeks and those who experienced relapse after therapy completion were eligible for a 24-week treatment regimen including LDV/SOF and RBV. Analysis of the SVR12 revealed a 96% achievement rate in individuals with genotype 1 and 100% in genotype 4. Results were similar among all subjects, including treatment-experienced patients and those with and without cirrhosis. Unlike the other ION trials, ION 4 also evaluated elevations in creatine kinase, and observed increases greater than or equal to ten-times the upper-limit of normal in 1% of patients treated for 12 weeks. However, the overall safety profile for LDV/SOF was comparable to individuals who are not co-infected with HIV-1 26, 37. The primary safety endpoints were discontinuation due to adverse events and HIV virologic rebound. Although headache, fatigue, and diarrhea were the most commonly reported adverse effects, no subject discontinued therapy due to adverse effects. Similarly, all subjects maintained HIV-1 viral suppression during treatment 26, 37.

5.0. Safety and Tolerability

5.1. Drug-Drug Interactions

Ledipasvir is an inhibitor of P-gp and breast cancer resistant protein (BCRP). Co-administration of substrates interacting with the related transporters may experience increased GI absorption. LDV/SOF are also substrates for P-gp and BCRP while Sofosbuvir’s inactive metabolite GS-331007 is not. P-g inducers result in reduced therapeutic drug concentrations of the HCV treatment and are not recommended. Concurrent Warfarin administration may pose a risk of INR fluctuations and frequent monitoring of INR is appropriate during and post-treatment. A list of a more diverse selection of clinically significant drug interactions associated with LDV/SOF is summarized (refer to table 1) 12, 38.

Table 1.

Potential drug-drug interactions with LDV/SOF

Antiarrhythmics LDV/SOF should not be co-administered with Amiodarone and Dronedarone. Co-administration with Digoxin may increase the antiarrhythmics concentration and should be monitored appropriate12, 38, 49.
Antibacterials LDV/SOF may have a potential interaction with Bedaquiline and potential weak interaction Isoniazid. Co-administration should be avoided with Rifabutin, Rifampicin, and Rifapentine due to decreased therapeutic efficacy from P-gP induction12.
Anticoagulant, Ant-platelet, and Fibrinolytics LDV/SOF possess a potential interaction with a handful of these drugs. Monitoring should be implemented appropriately for CYP 3A4 substrates.
Anticonvulsants Avoid P-gP inducing agents as they may reduce efficacy of the HCV treatment12, 50.
Antipsychotics/ Neuroepileptics Administration of concurrent Pimozide should be avoid due to weak CYP 3A4 inhibition per the EU and US drug label12, 51.
Gastrointestinal Agents Proton Pump Inhibitors, H2 Receptor Antagonists, and Antacids should not be administered pre- LDV/SOF dosing. A decrease in Ledipasvir exposure has been seen in some reports12, 52.
Hepatitis C Direct Acting Anti-Virals (DAAs) There is no data support co-administration of NS5A DAA’s. Avoid co-administration12, 53.
Herbals St. John’s wort is contraindicated due to P-gP induction12, 54.
HIV Protease Inhibitors Administration of Tipranavir should be avoided due to expected concentration reduction (P-gP induction) in LDV/SOF leading to sub-therapeutic effect. Potential for increased concentration of Tenofovir and related adverse drug reactions should be monitored12, 53, 55, 56.
Lipid Lowering Therapy Co-administration of Rosuvastatin is contraindicated due to increase in statin plasma concentration by inhibition of P-gP and BRCP by Ledipasvir12, 57.
Other Lumacaftor/Ivacaftor, a potent CYP3A4 inducer, is not recommended for co-administration because of decreased LDV/SOF therapeutic efficacy12, 58.
Open in a new tab

5.2. Side Effect profile

There is a black box warning of risk of HBV reactivation in patients coinfected with HCV and HBV. This has been reported in some cases resulting in fulminant hepatitis as well as failure and death. LDV/SOF therapy is associated with a risk of bradycardia and indicating symptoms such as fainting, dizziness, weakness, SOB, etc. This effect may be reinforced with concomitant Amiodarone use (refer to 5.1). Common side effects of the medication are tiredness, headache, and weakness12, 39.

5.3. Pregnancy

Currently, no large-scale trials have been conducted evaluating pregnancy and DAA treatment in pregnant patients. A small phase 1 open label study was conducted on pregnant women and their pharmacokinetic exposure to LDV/SOF compared to a non-pregnant female reference group. In conclusion, LDV/SOF was safe and effective without clinical difference in pregnant women compared to the reference group and is the only current DAA treatment with an FDA category B in the treatment of HCV infection 40.

5.4. Regulatory Affairs

LDV/SOF tablets (oral) and oral pellets were approved by the U.S. FDA in 2014. The combination therapy was approved by the European Medicines Agency November of 2014 12.

6.0. Conclusion

The therapeutic combination of LDV/SOF, a NS5B and NS5A protease inhibitor, is a well-tolerated and effective therapy for chronic HCV infection without cirrhosis. The combination is specifically indicated for HCV genotypes 1,4,5, or 6. LDV/SOF has a Black Box Warning for risk of HBV reactivation in patients coinfected with HCV and HBV. With concomitant infection, individuals may lose immune control and an increase the risk of enhance HBV replication41. The medication is generally well tolerated with a small side effect profile of tiredness, headaches, and weakness. According to the HCV treatment guidelines, LDV/SOF is first line treatment therapy for the indicated genotypes with a HCV cure rate above 90% in multiple clinical trials and use is also reinforced by the ability to treat children 3 years and older weighing 77lbs or greater42.

7.0. Expert Opinion

There are multiple HCV drugs currently on the market. Interferon therapy was the standard of care for years, but the development of new combination therapies has significantly decreased the role of interferon in HCV treatment. LDV/SOF was approved in 2014 followed by a rapid rise in combination HCV therapy approvals over a few years. The current market for combination HCV therapy is saturated with options. Elbasvir/grazoprevir was approved in 2016 for genotypes 1 and 4. Sofosbuvir/velpatasvir/voxilaprevir was approved in 2017 to treat any HCV genotype. This drug combination is also indicated for individuals who have had failure of treatment with sofosbuvir treatment alone. Glecaprevir/pibrentasvir was also approved in 2017 for the treatment of all HCV genotypes. It possesses the advantage of an 8-week treatment regimen.

LDV/SOF is included in the AASLD/IDSA HCV guidelines for the initial treatment of HCV genotypes 1a and 1b with or without cirrhosis and genotype 4 without cirrhosis with an evidence and recommendation rating of IA. Genotype 4 with cirrhosis and genotypes 5 and 6 carry a Class IIa level B recommendation. Sofosbuvir/Velpatasvir is more widely used in general treatment groups with simplified regimens available and more versatility in terms of susceptible genotypes43. LDV/SOF provided the first “one pill a day” regimen for 12 weeks for treatment of chronic HCV, which was a revolution in care in 201444. The US wholesale acquisition cost of LDV/SOF IS $94,500 for a complete 3-month regimen, averaging $31,500 per 28-day supply45. Although this cost seems daunting, discounts are available through the manufacturer and third-party discount websites boasting a 28-day supply for $5,50045. It is worth noting that even at full-price, LDV/SOF has proven to be a cost-effective treatment regimen for multiple genotypes of HCV when accounting for the relatively short treatment duration and consistent achievement of SVR12 rates over 90% in both treatment-naïve and treatment-experienced individuals with or without cirrhosis living with HCV34-37, 46, 47. Treatment success translates into a net gain in quality adjusted life years (QALYs) for patients and increased satisfaction, despite the cost47.

Single-pill regimens, like LDV/SOF, are important options to maintain the quality of life of children and other special populations infected with HCV by shortening treatment regimens, avoiding complex pill regimens, and eliminating injection therapies. For example, LDV/SOF carries the only level IA recommendation for genotypes 1, 4, 5, and 6 HCV patients with or without cirrhosis post kidney transplant. LDV/SOF is the only DAA-combination regimen approved for treatment-naïve or interferon-experienced children infected with HCV genotypes 1, 4, 5, and 6 between the ages of 3 and 6 years old with or without cirrhosis. Furthermore, it is the only guideline-recommended treatment for children 3 – 12 years of age with genotypes 1, 4, 5, and 6 who have previously failed another DAA treatment regimen 43, 46, 48.

Drug Summary Box.

Drug name ledipasvir + sofosbuvir
Phase Launched
Indication Infection, hepatitis-C virus
Pharmacology description HCV nonstructural protein 5A inhibitor
HCV nonstructural protein 5B inhibitor
Route of administration Oral
Chemical structure graphic file with name nihms-1722296-t0001.jpg
Pivotal trial(s) ION 1: Genotype 1 with or without cirrhosis
ION 2: Genotype 1 after failed peginterferon treatment
ION 3: Genotype 1 for either 8 or 12 weeks
ION 4: Genotypes 1 and 4 in people living with HIV/AIDS
Open in a new tab

Pharmaprojects - copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Informa-Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).

Acknowledgments

We wish to thank Dr. Wei Li for providing ChemDraw software, and Dr. Wei Li and Hanxuan Li for assistance with using the ChemDraw software.

Funding

The authors acknowledge financial support from the National Institute of Health Grant via the National Institute on Drug Abuse under grant no. DA042374.

Footnotes

Declaration of Interest:

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures:

One referee declares having participated in pediatric trials on ledipasvir and sofosbuvir funded by Gilead Sciences. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

References

  • 1.Houghton M Hepatitis C Virus: 30 Years after Its Discovery. Cold Spring Harb Perspect Med 2019December;9(12). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009August;361(6):580–93. [DOI] [PubMed] [Google Scholar]
  • 3.de Leuw P, Stephan C. Protease inhibitors for the treatment of hepatitis C virus infection. GMS Infect Dis 2017;5:Doc08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Subramanian GM, et al. Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology 2014March;146(3):736–43.e1. [DOI] [PubMed] [Google Scholar]
  • 5.Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, et al. Discovery of a β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem 2010October;53(19):7202–18. [DOI] [PubMed] [Google Scholar]
  • 6.Global health sector strategy on viral hepatitis 2016-2021. Towards ending viral hepatitis: World Health Organization; 2016. [Google Scholar]
  • 7.Lombardi A, Mondelli MU, (ESGVH) ESGfVH. Hepatitis C: Is eradication possible? Liver Int 2019March;39(3):416–26. [DOI] [PubMed] [Google Scholar]
  • 8.Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011June;364(25):2405–16. [DOI] [PubMed] [Google Scholar]
  • 9.Gohil K Huge growth seen in hepatitis C market. P T 2014July;39(7):517. [PMC free article] [PubMed] [Google Scholar]
  • 10.Pawlotsky JM. Hepatitis C Virus Resistance to Direct-Acting Antiviral Drugs in Interferon-Free Regimens. Gastroenterology 2016July;151(1):70–86. [DOI] [PubMed] [Google Scholar]
  • 11.World Health Organization. WHO; Hepatitis C; 2020.
  • 12.Gilead Sciences. Ledispasvis-Sofosbuvir (Harvoni) Package Insert. Foster City, CA: 2019:20–24. [Google Scholar]
  • 13.Gritsenko D, Hughes G. Ledipasvir/Sofosbuvir (harvoni): improving options for hepatitis C virus infection. P T 2015April;40(4):256–76. [PMC free article] [PubMed] [Google Scholar]
  • 14.Berenguer J, Alvarez-Pellicer J, Martin PM, Lopez-Aldeguer J, Von-Wichmann MA, Quereda C, et al. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology 2009August;50(2):407–13. [DOI] [PubMed] [Google Scholar]
  • 15.Sulkowski MS, Sherman KE, Dieterich DT, Bsharat M, Mahnke L, Rockstroh JK, et al. Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial. Ann Intern Med 2013July16;159(2):86–96. [DOI] [PubMed] [Google Scholar]
  • 16.Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, et al. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem 2010November5;285(45):34337–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Fung A, Jin Z, Dyatkina N, Wang G, Beigelman L, Deval J. Efficiency of incorporation and chain termination determines the inhibition potency of 2'-modified nucleotide analogs against hepatitis C virus polymerase. Antimicrob Agents Chemother 2014July;58(7):3636–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Roche V, Zito SW, Lemke T, Williams D. Foye's Principles of Medicinal Chemistry. 8 ed. Philadelphia, PA: Wolters Kluwer, 2020. [Google Scholar]
  • 19.Information NCfB. Ledipasvir. PubChem Compound Summary for CID 67505836 2021 2021. [Google Scholar]
  • 20.Smolders EJ, Jansen AME, Ter Horst PGJ, Rockstroh J, Back DJ, Burger DM. Viral Hepatitis C Therapy: Pharmacokinetic and Pharmacodynamic Considerations: A 2019 Update. Clin Pharmacokinet 2019October;58(10):1237–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Lawitz E, Rodriguez-Torres M, Denning JM, Albanis E, Cornpropst M, Berrey MM, et al. Pharmacokinetics, pharmacodynamics, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor, following multiple ascending doses in patients with chronic hepatitis C infection. Antimicrob Agents Chemother 2013March;57(3):1209–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Lam AM, Espiritu C, Bansal S, Micolochick Steuer HM, Niu C, Zennou V, et al. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother 2012June;56(6):3359–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.German P, Mathias A, Brainard D, Kearney BP. Clinical Pharmacokinetics and Pharmacodynamics of Ledipasvir/Sofosbuvir, a Fixed-Dose Combination Tablet for the Treatment of Hepatitis C. Clin Pharmacokinet 2016November;55(11):1337–51. [DOI] [PubMed] [Google Scholar]
  • 24.Denning J, Cornpropst M, Flach SD, Berrey MM, Symonds WT. Pharmacokinetics, safety, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor for hepatitis C virus, following single ascending doses in healthy subjects. Antimicrob Agents Chemother 2013March;57(3):1201–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Lawitz EJ, Gruener D, Hill JM, Marbury T, Moorehead L, Mathias A, 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 2012July;57(1):24–31. [DOI] [PubMed] [Google Scholar]
  • 26.Gilead Sciences. HARVONI ® (ledipasvir and sofosbuvir) package insert. 2014. [cited; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205834s000lbl.pdf [Google Scholar]
  • 27.Bourliere M, Bronowicki JP, de Ledinghen V, Hezode C, Zoulim F, Mathurin P, et al. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis 2015April;15(4):397–404. [DOI] [PubMed] [Google Scholar]
  • 28.Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet 2014February8;383(9916):515–23. [DOI] [PubMed] [Google Scholar]
  • 29.Charlton M, Everson GT, Flamm SL, Kumar P, Landis C, Brown RS Jr., et al. Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease. Gastroenterology 2015September;149(3):649–59. [DOI] [PubMed] [Google Scholar]
  • 30.Manns M, Samuel D, Gane EJ, Mutimer D, McCaughan G, Buti M, et al. Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial. Lancet Infect Dis 2016June;16(6):685–97. [DOI] [PubMed] [Google Scholar]
  • 31.Osinusi A, Townsend K, Kohli A, Nelson A, Seamon C, Meissner EG, et al. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection. JAMA 2015March24-31;313(12):1232–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Saleh-Langenberg J, de Vries S, Bak E, Kollen BJ, Flokstra-de Blok BMJ, Dubois AEJ. Incomplete and incorrect epinephrine auto-injector training to food-allergic patients by pharmacists in the Netherlands. Pediatr Allergy Immunol 2017May;28(3):238–44. [DOI] [PubMed] [Google Scholar]
  • **33. Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014April;370(16):1483–93. This was a phase 3 trial, also known as the ION 2 trial, that assessed LDV/SOF efficacy (SVR12) in treatment-experienced patients with genotype 1 HCV infection receiving 12 – 24 weeks of therapy.
  • **34. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014May;370(20):1879–88. This was the ION 3 trial conducted as a phase 3, open-label study evaluating differences in SVR12 achievement rates between 8-week and 12-week treatment groups of patients living with chronic HCV genotype 1 infection.
  • 35.Grebely J, Mauss S, Brown A, Bronowicki JP, Puoti M, Wyles D, et al. Efficacy and Safety of Ledipasvir/Sofosbuvir With and Without Ribavirin in Patients With Chronic HCV Genotype 1 Infection Receiving Opioid Substitution Therapy: Analysis of Phase 3 ION Trials. Clin Infect Dis 2016December1;63(11):1405–11. [DOI] [PubMed] [Google Scholar]
  • **36. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014May;370(20):1889–98. This was a phase 3 trial was better known as the ION 1 trial and it evaluated SVR12 rates in treatment-naïve patients with chronic HCV genotype 1 infections.
  • 37.Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, et al. Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med 2015August;373(8):705–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.German P, Mathias A, Brainard DM, Kearney BP. Drug-Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir. Clin Pharmacokinet 2018November;57(11):1369–83. [DOI] [PubMed] [Google Scholar]
  • 39.Caldeira D, Rodrigues FB, Duarte MM, Sterrantino C, Barra M, Goncalves N, et al. Cardiac Harms of Sofosbuvir: Systematic Review and Meta-Analysis. Drug Saf 2018January;41(1):77–86. [DOI] [PubMed] [Google Scholar]
  • 40.Chappell CA, Scarsi KK, Kirby BJ, Suri V, Gaggar A, Bogen DL, et al. Ledipasvir plus sofosbuvir in pregnant women with hepatitis C virus infection: a phase 1 pharmacokinetic study. Lancet Microbe 2020September;1(5):e200–e08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Aggeletopoulou I, Konstantakis C, Manolakopoulos S, Triantos C. Risk of hepatitis B reactivation in patients treated with direct-acting antivirals for hepatitis C. World J Gastroenterol 2017June28;23(24):4317–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Eisenman T FDA approves two hepatits C drugs for pediatric patients. In: FDA.gov, ed.: US-FDA; 2017. [Google Scholar]
  • *43. American Association for the Study of Liver Diseases Infectious Disease Society of America; HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. 2020. This reference provides access to the complete IDSA guidelines for the treatment and management of chronic hepatitis C infection.
  • 44.Terrault NA, Zeuzem S, Di Bisceglie AM, Lim JK, Pockros PJ, Frazier LM, et al. Effectiveness of Ledipasvir-Sofosbuvir Combination in Patients With Hepatitis C Virus Infection and Factors Associated With Sustained Virologic Response. Gastroenterology 2016December;151(6):1131–40 e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.University of Washington; Ledipasvir-Sofosbuvir. Hepatitis C online 2021. [Google Scholar]
  • *46. Schwarz KB, Rosenthal P, Murray KF, Honegger JR, Hardikar W, Hague R, et al. Ledipasvir-Sofosbuvir for 12 Weeks in Children 3 to <6 Years Old With Chronic Hepatitis C. Hepatology 2020February;71(2):422–30. This was a study evaluating efficacy, safety, and palatability of LDV/SOF when dosed based on weight in children between 3 and 6 years of age with or without cirrhosis.
  • 47.Najafzadeh M, Andersson K, Shrank WH, Krumme AA, Matlin OS, Brennan T, et al. Cost-effectiveness of novel regimens for the treatment of hepatitis C virus. Ann Intern Med 2015March17;162(6):407–19. [DOI] [PubMed] [Google Scholar]
  • *48. Murray KF, Balistreri WF, Bansal S, Whitworth S, Evans HM, Gonzalez-Peralta RP, et al. Safety and Efficacy of Ledipasvir-Sofosbuvir With or Without Ribavirin for Chronic Hepatitis C in Children Ages 6-11. Hepatology 2018December;68(6):2158–66. This trial evaluated LDV/SOF as a potential interferon-free treatment option for HCV patients under the age of 12 and yielded an overall SVR12 of 99% across treatment groups.
  • 49.Kuo MH, Tseng CW, Lee CH, Yang YC, Wu HJ, Lin HJ, et al. Identification and management of contraindicated drug-drug interactions through pharmaceutical care programs: Experience in direct-acting antivirals therapy. J Formos Med Assoc 2021January29. [DOI] [PubMed] [Google Scholar]
  • 50.Lutz JD, Kirby BJ, Wang L, Song Q, Ling J, Massetto B, et al. Cytochrome P450 3A Induction Predicts P-glycoprotein Induction; Part 1: Establishing Induction Relationships Using Ascending Dose Rifampin. Clin Pharmacol Ther 2018December;104(6):1182–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Morishita H, Okawa K, Ishii M, Mizoi K, Ito MA, Arakawa H, et al. Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein. PLoS One 2020;15(10):e0232438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Liu CJ, Tseng KC, Lo CC, Tseng IH, Cheng PN. Limited drug-drug interaction of elbasvir/grazoprevir for chronic hepatitis C. J Formos Med Assoc 2020May;119(5):933–40. [DOI] [PubMed] [Google Scholar]
  • 53.Ankrom W, Sanchez RI, Yee KL, Fan L, Mitra P, Wolford D, et al. Investigation of Pharmacokinetic Interactions between Doravirine and Elbasvir-Grazoprevir and Ledipasvir-Sofosbuvir. Antimicrob Agents Chemother 2019May;63(5). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Zhou S, Chan E, Pan SQ, Huang M, Lee EJ. Pharmacokinetic interactions of drugs with St John's wort. J Psychopharmacol 2004June;18(2):262–76. [DOI] [PubMed] [Google Scholar]
  • 55.Vourvahis M, Kashuba AD. Mechanisms of pharmacokinetic and pharmacodynamic drug interactions associated with ritonavir-enhanced tipranavir. Pharmacotherapy 2007June;27(6):888–909. [DOI] [PubMed] [Google Scholar]
  • 56.Solas C, Bregigeon S, Faucher-Zaegel O, Quaranta S, Obry-Roguet V, Tamalet C, et al. Ledipasvir and tenofovir drug interaction in human immunodeficiency virus-hepatitis C virus coinfected patients: Impact on tenofovir trough concentrations and renal safety. Br J Clin Pharmacol 2018February;84(2):404–09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Patel S, Andres J, Qureshi K. An Unexpected Interaction between Sofosbuvir/Ledipasvir and Atorvastatin and Colchicine Causing Rhabdomyolysis in a Patient with Impaired Renal Function. Case Rep Med 2016;2016:3191089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Schneider EK. Cytochrome P450 3A4 Induction: Lumacaftor versus Ivacaftor Potentially Resulting in Significantly Reduced Plasma Concentration of Ivacaftor. Drug Metab Lett 2018;12(1):71–74. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES