Treatment With Ledipasvir-Sofosbuvir for 12 or 24 Weeks in Kidney Transplant Recipients With Chronic Hepatitis C Virus Genotype 1 or 4 Infection: A Randomized Trial

Ann Intern Med. 2017 Jan 17;166(2):109-117 doi: 10.7326/M16-1205.
Abstract
BACKGROUND:

Use of interferon and ribavirin to treat chronic hepatitis C virus (HCV) infection in kidney transplant recipients is limited because of the risk for allograft rejection and poor tolerability.

OBJECTIVE:

To evaluate the safety and efficacy of the interferon- and ribavirin-free regimen ledipasvir-sofosbuvir in kidney transplant recipients with chronic genotype 1 or 4 HCV infection.

DESIGN:

Randomized, phase 2, open-label study. (ClinicalTrials.gov: NCT02251717).

SETTING:

5 sites in Europe.

PATIENTS:

Treatment-naive or -experienced kidney transplant recipients with chronic genotype 1 or 4 HCV infection, with or without compensated cirrhosis, and with an estimated glomerular filtration rate (eGFR) of 40 mL/min or greater were randomly assigned 1:1 to receive ledipasvir (90 mg) and sofosbuvir (400 mg) for 12 or 24 weeks.

MEASUREMENTS:

The primary end point was sustained virologic response at 12 weeks after therapy ended (SVR12).

RESULTS:

Among 114 patients, the median age was 53 years, 58% were male, 91% had genotype 1 infection, 69% were treatment naive, and 15% had compensated cirrhosis. The median eGFR was 56 mL/min (range, 35 to 135 mL/min). One hundred percent of patients (57 of 57) treated for 12 weeks (95% CI, 94% to 100%) and 100% of those (57 of 57) treated for 24 weeks (CI, 94% to 100%) achieved SVR12. Serious adverse events were reported in 13 patients (11%). Of these, 3 events-syncope, pulmonary embolism, and serum creatinine increase-in 3 patients were determined to be treatment related. One patient permanently discontinued treatment because of an adverse event (syncope). The most frequent adverse events overall were headache (n = 22 [19%]), asthenia (n = 16 [14%]), and fatigue (n = 11 [10%]).

LIMITATIONS:

The study was open label, no inferential statistics were planned, and only patients with genotype 1 or 4 infection were included. Few patients with HCV genotype 1a and cirrhosis were enrolled.

CONCLUSION:

Treatment with ledipasvir-sofosbuvir for 12 or 24 weeks was well-tolerated and seemed to have an acceptable safety profile among kidney transplant recipients with HCV genotype 1 or 4 infection, all of whom achieved SVR12.

PRIMARY FUNDING SOURCE:

Gilead Sciences.

CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion: This industry-sponsored study investigates the use of the combination of ledipasvir and sofosbuvir in stable renal transplant recipients with chronic hepatitis C. Patients were randomised to either 12 or 24 weeks of treatment, and both groups achieved sustained virological response at 12 weeks after the end of therapy of 100%. Treatment was well tolerated with only 3 serious adverse events reported to be due to the study medication. The SVR12 seen is impressive, and treatment appears much better tolerated in this population than standard treatment with interferon and ribavirin. The lack of a control arm on this standard therapy makes direct comparison impossible, however. The results do offer the possibility of opening up the HCV-positive donor pool to selected recipients, but this would warrant careful further investigation and consideration.
Expert Review
Reviewer: Dr Wilson Wong, King's College London, UK.
Conflicts of Interest: No
Clinical Impact Rating 1
Review: This study compares the use of combined Ledipasvir and Sofosbuvir treatment in kidney transplant recipients with chronic hepatitis C infection. They concluded that both 12 and 24 weeks of treatment were well tolerated and effective with significant reduction of viral load after treatment. This study has a number of significant limitations. It is unclear why the authors only included patients with genotype 1 and 4. Given that current guidelines already recommend treatment of 12 weeks, the rationale for performing this study is unclear, other than to see whether patients can tolerate 24 weeks of treatment. Whether 24 weeks of treatment would be more effective compared to 12 weeks would be a reason to perform such a study, but the way it was designed did not really allow the authors to examine this. In summary, the authors confirmed that current recommendations are well tolerated, but no conclusion can be drawn about its efficacy and whether longer duration of treatment is of benefit. Therefore, clinicians should continue to follow current guidelines.
Methodological quality
Jadad score 3
Allocation concealment NO
Data analysis AVAILABLE CASE ANALYSIS
Study Details
Aims: To compare the efficacy and safety of 12 and 24 weeks of ledipasvir–sofosbuvir without ribavirin in kidney transplant patients with chronic hepatitis C virus (HCV) genotype 1 or 4 infection.
Interventions: Participants were randomised to receive either 12 versus 24 weeks of treatment with a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg).
Participants: 114 recipients of a kidney transplant ≥6 months before the baseline study visit, aged ≥18 years who had chronic HCV genotype 1 or 4 infection, with plasma HCV RNA levels ≥15 IU/mL.
Outcomes: The primary outcomes measured were the percentage of patients with HCV RNA less than the lower limit of quantification (LLOQ) 12 weeks after stopping the study drug, and any adverse event leading to permanent discontinuation of the study drug.
Follow Up: 24 weeks
Metadata
Funding: Industry funding
Publication type: Multicenter Study, Randomized Controlled Trial, Randomised Controlled Trial
Trial registration: ClinicalTrials.gov - NCT02251717
Organ: Kidney
Language: English
Author email: massimo.colombo@unimi.it
MeSH terms: Adult; Aged; Antiviral Agents; Benzimidazoles; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Fluorenes; Genotype; Glomerular Filtration Rate; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Sofosbuvir