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Sirius: Ledipasvir and Sofosbuvir in Cases of Severe Liver Injury

April 2015

A fixed-dose combination of ledipasvir + sofosbuvir (sold as Harvoni) has been licensed in Canada, the European Union and the U.S. for the treatment of HCV genotype 1. This single-tablet regimen contains:

  • ledipasvir -- 90 mg
  • sofosbuvir -- 400 mg

Harvoni is meant to be taken once daily, with or without food.


Sirius

In a trial called Sirius, researchers enrolled participants with the following clinical features:

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  • HCV genotype 1 infection
  • severe liver injury (cirrhosis)
  • previously unsuccessful treatment with interferon and ribavirin with or without the first generation of direct-acting antivirals (DAAs) boceprevir or telaprevir

Participants were randomly assigned to one of the following interventions:

  • ledipasvir + sofosbuvir + placebo for 24 weeks -- 77 people
  • placebo for 12 weeks, followed by ledipasvir + sofosbuvir + ribavirin for 12 weeks -- 77 people

As is standard in HCV clinical trials in the current era, the dose of ribavirin is based on a person's weight. People who weigh less than 75 kg took 1,000 mg/day and people who weighed 75 kg or more took 1,200 mg/day.

Doctors assessed the health of participants' livers in one of the following ways:

  • removal of a small piece of the liver for analysis (biopsy)
  • specialized ultrasound scans called Fibroscan
  • a cluster of blood tests called FibroTest

The average profile of participants was as follows:

  • 75% men and 25% women
  • age -- 57 years
  • HCV strain -- most common HCV genotype was 1a, found in 63% of participants
  • HCV viral load -- 6.5 log
  • very low levels of platelets in the blood -- 18%
  • enlarged blood vessels in the throat and abdomen -- 20%


Results -- SVR12

The proportion of participants who achieved an SVR12 was distributed as follows:

  • ledipasvir + sofosbuvir + placebo for 24 weeks -- 97% had an SVR12
  • ledipasvir + sofosbuvir + ribavirin for 12 weeks -- 96% had an SVR12


Other Results

Overall, regardless of whether or not ribavirin was used, researchers found significant improvements among participants who achieved an SVR12 when they reviewed the following laboratory tests of blood samples:

  • the amount of protein (albumin)
  • the levels of the liver enzyme ALT
  • the amount of the waste product bilirubin


Results -- Complications and Side Effects

Relatively high rates of potential side effects were reported by participants who received the following:

  • placebo -- 82%
  • ledipasvir + sofosbuvir -- 87%
  • ledipasvir + sofosbuvir + ribavirin -- 96%

Note that participants tend to report many possible side effects and complications in clinical trials. Collectively, drug side effects and complications are called "adverse events." These need to be investigated by researchers to determine if they were indeed drug side effects or due instead to the disease process caused by HCV (or in some cases HIV) or something else.

In Sirius, after investigation researchers attributed "serious" side effects as follows:

  • placebo -- zero
  • ledipasvir + sofosbuvir -- one person
  • ledipasvir + sofosbuvir + ribavirin -- zero

Less serious side effects were distributed as follows:

  • placebo -- 23%
  • ledipasvir + sofosbuvir -- 31%
  • ledipasvir + sofosbuvir + ribavirin -- 19%

Cases of anemia were uncommon and only occurred in one person taking placebo and in three people taking ledipasvir + sofosbuvir + ribavirin.

Two people left the study prematurely in the following regimens:

  • placebo -- one person had worsening liver injury
  • ledipasvir + sofosbuvir + ribavirin -- one person had arthritis caused by a bacterial infection

The following complications and/or side effects were of mild-to-moderate intensity:

General weakness

  • placebo -- 31%
  • ledipasvir + sofosbuvir -- 58%
  • ledipasvir + sofosbuvir + ribavirin -- 45%

Headache

  • placebo -- 21%
  • ledipasvir + sofosbuvir -- 27%
  • ledipasvir + sofosbuvir + ribavirin -- 40%

Itchy skin

  • placebo -- 18%
  • ledipasvir + sofosbuvir -- 58%
  • ledipasvir + sofosbuvir + ribavirin -- 45%

Dry skin

  • placebo -- 8%
  • ledipasvir + sofosbuvir -- 16%
  • ledipasvir + sofosbuvir + ribavirin -- 5%

Difficulty falling asleep

  • placebo -- 12%
  • ledipasvir + sofosbuvir -- 22%
  • ledipasvir + sofosbuvir + ribavirin -- 17%

Nausea

  • placebo -- 10%
  • ledipasvir + sofosbuvir -- 18%
  • ledipasvir + sofosbuvir + ribavirin -- 10%

Fatigue

  • placebo -- 4%
  • ledipasvir + sofosbuvir -- 9%
  • ledipasvir + sofosbuvir + ribavirin -- 19%

Bone and/or joint pain

  • placebo -- 6%
  • ledipasvir + sofosbuvir -- 8%
  • ledipasvir + sofosbuvir + ribavirin -- 15%

Bronchitis

  • placebo -- 1%
  • ledipasvir + sofosbuvir -- 5%
  • ledipasvir + sofosbuvir + ribavirin -- 17%


Key Points

In participants whose prior interferon-based regimens failed and who had cirrhosis, 24 weeks of ledipasvir + sofosbuvir + placebo or 12 weeks of ledipasvir + sofosbuvir + ribavirin resulted in about 97% of participants achieving an SVR12.

Only two side effects -- headache and fatigue -- were significantly more common among ledipasvir + sofosbuvir users than among placebo users.

Most side effects were of mild-to-moderate intensity.


Reference

Bourlière M, Bronowicki J, de Ledinghen V, et al. Ledipasvir/sofosbuvir fixed-dose combination is safe and efficacious in cirrhotic patients who have previously failed protease-inhibitor-based triple therapy. In: Program and abstracts of The Liver Meeting, 7-11 November 2014. Abstract LB-6.




This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication TreatmentUpdate. Visit CATIE's Web site to find out more about their activities, publications and services.

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