Pooled safety data: ledipasvir/sofosbuvir: HCV-1

Posted on May 17, 2015

Pooled analysis of safety data from the three multicenter, randomized, open-label ION Phase 3 clinical trials shows that the addition of ribavirin to ledipasvir/sofosbuvir HCV-1 treatment regimens increased toxicity without providing additional efficacy. Eliminating ribavirin from HCV therapy will likely increase patient adherence to treatment due to an improved quality of life resulting from fewer adverse events, less laboratory monitoring, the elimination of the risk of teratogenicity and a once daily single tablet regimen.

Ribavirin, with side effects including hemolytic anemia, fatigue, pruritus, and rash, continues to be included in a number of new interferon-free, direct-acting antiviral (DAA) agent regimens for hepatitis C infection. In an article recently published online ahead of print in the journal Hepatology, Dr. Saleh Alqahtani and colleagues compared the safety and tolerability profiles of patients with HCV genotype 1 (HCV-1) treated with a ribavirin-containing and a ribavirin sparing interferon-free DAA regimen (Algahtani SA, et al. Hepatology. 2015 May 11. doi: 10.1002/hep.27890. [Epub ahead of print]). Analyses were conducted on pooled safety data from the three multicenter, randomized, open-label ION Phase 3 clinical trials.

  • ION-1 ClinicalTrials.gov number NCT01701401, ION-2 ClinicalTrials.gov number NCT01768286, and ION-3 ClinicalTrials.gov number NCT01851330
    • A fixed dose combination tablet of ledipasvir/sofosbuvir 90mg/400mg was administered for 8, 12 or 24 weeks with and without weight-based ribavirin in patients with chronic HCV-1 infection and included patients with compensated cirrhosis
  • Primary objective of this safety analysis was to quantify adverse events and laboratory abnormalities associated with the use of ribavirin as part of an IFN-free, direct-acting antiviral-based regimen
    • Safety analysis was performed in the safety population (ie, all patients who received study drug)

In total, 1952 patients were enrolled and treated in the three ION phase 3 studies, of whom 1080 patients received ledipasvir/sofosbuvir alone and 872 patients received ribavirin with ledipasvir/sofosbuvir

  • 431 patients were treated for 8 weeks (ION-1)
  • 867 patients were treated for 12 weeks (ION-2 and ION-3)
  • 654 were treated for 24 weeks (ION-2 and ION-3)

Baseline clinical characteristics were generally well balanced among the treatment groups of all tree trials:

  • Mean age for all patients was 53 years (range, 18–80 years). Most patients were white (82%); 308 (16%) patients were African American.
  • Two hundred and twenty-four patients (11%) had compensated cirrhosis, 501 patients (26%) had a BMI ≥30 kg/m2, and 440 patients (23%) were treatment-experienced
  • Majority of the patients had HCV genotype 1a (74%) and a non-CC allele of IL28B genotype (75%)
  • Overall rate of sustained virologic response pooling all treatment groups was 97%. The rates of response in the individual treatment groups ranged from 93% to 99%, while among patients receiving 12 weeks of treatment, response rates ranged from 94% to 99%.

Both treatment regimens were generally well tolerated. The majority of the patients in each treatment group reported at least one adverse event

  • Incidence of adverse events was approximately 10% higher among patients receiving ledipasvir/sofosbuvir with ribavirin (85%) than among patients receiving ledipasvir/sofosbuvir alone (74%)
  • Most commonly reported adverse events were fatigue, headache, nausea, insomnia, and diarrhea
  • Treatment-related adverse events occurred in 617 (71%) patients treated with ledipasvir/sofosbuvir with ribavirin and in 484 (45%) patients treated with ledipasvir/sofosbuvir alone
  • Most adverse events in both treatment groups were mild or moderate in severity
  • Serious adverse events were reported by 34 patients (3%) who received ledipasvir/sofosbuvir with ribavirin and by 17 patients (2%) who received ledipasvir/sofosbuvir alone
    • Grade ≥3 adverse events were reported in 5% and 4% of patients in the ledipasvir/sofosbuvir with ribavirin group and ledipasvir/sofosbuvir alone group, respectively
  • For both groups, treatment-related serious adverse events (≤4%) and discontinuations due to adverse events (≤0.8%) were uncommon
  • Medical intervention due to treatment-related adverse events, and dose modification or interruption of study drug was more common in patients who received ledipasvir/sofosbuvir with ribavirin
  • Patients who received ribavirin were more likely to require the use of other medications during treatment than those who received ledipasvir/sofosbuvir alone (63% vs 53%, respectively) including topical corticosteroids (7% vs 3%), antihistamines (8% vs 5%), and sleeping aids (11% vs 6%)
  • No deaths were reported during the three clinical trials

The mean change in the hemoglobin level from baseline to end of treatment ranged from -0.2 to -0.4 g/dL in patients who received ledipasvir/sofosbuvir alone and from -1.9 to -2.3 g/dL in patients who received ledipasvir/sofosbuvir with ribavirin.

  • Anemia, defined as hemoglobin <10 g/dL, was experienced by 58 patients (7%) treated with ledipasvir/sofosbuvir with ribavirin , as compared with 1 patient (<1%) treated with ledipasvir/sofosbuvir alone (4 weeks after treatment end)
  • Treatment with ledipasvir/sofosbuvir with ribavirin was associated with an increase in total bilirubin, which is known to be associated with ribavirin-induced hemolysis, and a decrease in lymphocytes

This pooled safety analysis suggests that the addition of ribavirin to ledipasvir/sofosbuvir for HCV-1 therapy for patients without cirrhosis or with compensated cirrhosis was associated with increased adverse events and laboratory abnormalities without any improvement in the rates of sustained virologic response. The study authors conclude the following: “our findings suggest that the addition of ribavirin to ledipasvir/sofosbuvir treatment regimens increased toxicity without providing additional efficacy. A ribavirin-free regimen is an attractive option for many patients. Eliminating ribavirin from HCV therapy will likely increase patient adherence to treatment due to an improved quality of life resulting from fewer adverse events, less laboratory monitoring, the elimination of the risk of teratogenicity and a once daily single tablet regimen. Despite the increased rate of mild to moderate side effects with ribavirin, however, the possibility of shorter treatment duration and reduced treatment cost, may justify the continued use of ribavirin in specific populations.


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