Sofosbuvir/ledipasvir safe and effective for genotype 1 HCV

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A single-tablet regimen containing the hepatitis C virus (HCV) nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir – the combination in Gilead Science's recently approved Harvoni pill – was well-tolerated and cured 97% of patients with HCV genotype 1 in the Phase 3 ION trials, researchers reported at the IDWeek 2014 meeting earlier this month in Philadelphia, United States.

The advent of direct-acting antiviral agents has revolutionised treatment for chronic hepatitis C, especially with the long-awaited arrival of all-oral regimens that dispense with interferon and its difficult side-effects.

Mark Sulkowski from Johns Hopkins University Medical School and colleagues presented pooled findings from a trio of pivotal Phase 3 studies that supported to the approval of the sofosbuvir/ledipasvir co-formulation. Results from these studies were previously presented in full at the EASL (European Association for the Study of the Liver) International Liver Congress this past April:

  • ION-1: (n = 865) previously untreated HCV genotype 1 (16% with cirrhosis) – 12 vs 24 weeks with or without ribavirin;
  • ION-2: (n = 440) prior non-responders HCV genotype 1 (20% with cirrhosis) – 12 vs 24 weeks with or without ribavirin;
  • ION-3: (n = 647) previously untreated HCV genotype 1 (without cirrhosis only) – 12 weeks without ribavirin, or 8 weeks with or without ribavirin.



Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).


Refers to the mouth, for example a medicine taken by mouth.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.


The return of signs and symptoms of a disease after a patient has been free of those signs and symptoms. 

Taken together, the ION trials included 1952 randomised and treated patients. A majority (60%) were men, most were white, 16% were black, and the median age was 53 years. Looking at factors associated with poorer response, 74% had harder-to-treat HCV subtype 1a (vs 1b), 23% were treatment-experienced (including 12% who had previously tried triple therapy with the first-generation HCV protease inhibitors boceprevir [Victrelis] or telaprevir [Incivek]), 12% had compensated liver cirrhosis, 26% had a body mass index >30, 75% had an unfavourable IL28B gene pattern, and most (82%) had high HCV viral load >800,000 IU/ml.

The primary endpoint in all the trials was sustained virological response, or continued undetectable HCV RNA viral load, at 12 weeks after completion of treatment (SVR12).


  • Overall, 97% of all patients achieved SVR12:

o   ION-1: 97% to 99%;

o   ION-2: 94% to 99%;

o   ION-3: 93% to 95%.

  • Among the 3% of participants who did not achieve SVR12:

o   1.8% relapsed after completing therapy;

o   0.1% experienced viral breakthrough while still on treatment;

o   1.3% were lost to follow-up or withdrew consent.

Overall, there was no significant difference in response rates between patients treated for 12 or 24 weeks.

In ION-3, relapse was more common in the 8-week arm compared with the 12-week arm (5 vs 1%), mostly occurring in people with high baseline HCV viral load. A cut-off of 6 million IU/ml was found to be the threshold for poorer response with 8 weeks of treatment in an ad hoc analysis.

People with cirrhosis had somewhat poorer response in the 12-week compared with 24-week treatment arms – confirming that people with cirrhosis should not be treated for only 8 weeks.

There was no significant difference in response rates between people who did or did not receive ribavirin.

Sofosbuvir/ledipasvir was generally safe and well-tolerated. Serious adverse events were uncommon (2% with and 3% without ribavirin), as were treatment discontinuations due to adverse events (1% with or without ribavirin). The most common side-effects were fatigue, headache, nausea, and insomnia. A majority of adverse events – including decreased haemoglobin – occurred more often among people who received ribavirin.

"All-oral, interferon-free therapy with ledipasvir/sofosbuvir for 8, 12, or 24 weeks resulted in high SVR in genotype 1 HCV," the researchers concluded. "Addition of ribavirin did not increase rate of SVR and resulted in more frequent adverse events and laboratory abnormalities."


Sulkowski M et al. Ledipasvir/sofosbuvir is safe and effective as a single-tablet-regimen for treatment of patients with genotype 1 chronic hepatitis C virus, including those with compensated cirrhosis. IDWeek 2014. Philadelphia, October 8-12, 2014. Abstract 1223.