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Ledipasvir and Sofosbuvir With or Without Ribavirin in Compensated Cirrhosis

April 2015

Some people with severe liver injury (cirrhosis) caused by hepatitis C virus (HCV) have no symptoms, at least initially. Doctors describe this symptom-free stage of severe liver injury as "compensated cirrhosis."

Researchers collected data from several studies where ledipasvir + sofosbuvir were used, with or without ribavirin, and analysed the results. Pooling the data from several studies allows researchers to see broad trends that may not have been noticeable in smaller studies.

The pooled studies contained the following regimens and numbers of participants:

  • ledipasvir + sofosbuvir for 12 weeks -- 118 participants
  • ledipasvir + sofosbuvir + ribavirin for 12 weeks -- 204 participants
  • ledipasvir + sofosbuvir for 24 weeks -- 133 participants
  • ledipasvir + sofosbuvir + ribavirin for 24 weeks -- 58 participants

All 513 participants had HCV genotype 1 and symptoms of cirrhosis.

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Data were collected from the following studies:

  • Lonestar
  • Electron-1
  • Electron-2
  • a phase III study in Japan
  • ION-1
  • ION-2
  • Sirius

Participants from the pooled studies were distributed as follows:

  • no previous treatment -- 161 people
  • previous and unsuccessful treatment -- 352 people

Of the latter participants, 68% had been exposed to boceprevir or telaprevir as part of their prior treatment regimen.

The average profile of participants upon entering the study was as follows:

  • 67% men and 33% women
  • age -- 58 years
  • HCV strains -- 60% had genotype 1a and 40% had genotype 1b
  • HCV viral load -- 6.4 log

Nearly 50% of participants had their liver health assessed with a biopsy.


Results -- Overall

A total of 513 participants were treated with ledipasvir + sofosbuvir and in some cases the addition of ribavirin, as follows:

  • ledipasvir + sofosbuvir with or without ribavirin for 12 weeks (322 participants) -- 95% achieved an SVR12
  • ledipasvir + sofosbuvir with or without ribavirin for 24 weeks (191 participants) -- 98% achieved an SVR12


Results -- Overall and Subgroups

The proportions of participants who achieved an SVR12 were distributed as follows:

Overall

  • no previous treatment -- 98% had an SVR12
  • with previous treatment -- 95% had an SVR12

Results sorted by treatment history and duration:

No previous treatment

  • treated for 12 weeks -- 97% had an SVR12
  • treated for 24 weeks -- 99% had an SVR12

With previous treatment

  • treated for 12 weeks -- 94% had an SVR12
  • treated for 24 weeks -- 98% had an SVR12

Results sorted by composition of regimens:

No previous treatment

  • ledipasvir + sofosbuvir -- 96% had an SVR12
  • ledipasvir + sofosbuvir + ribavirin -- 99% had an SVR12

With previous treatment

  • ledipasvir + sofosbuvir -- 95% had an SVR12
  • ledipasvir + sofosbuvir + ribavirin -- 96% had an SVR12

Results sorted both by duration and composition of regimens:

No previous treatment

  • ledipasvir + sofosbuvir for 12 weeks -- 96% had an SVR12
  • ledipasvir + sofosbuvir + ribavirin for 12 weeks -- 98% had an SVR12
  • ledipasvir + sofosbuvir for 24 weeks -- 97% had an SVR12
  • ledipasvir + sofosbuvir + ribavirin for 24 weeks -- 100% had an SVR12

With previous treatment

  • ledipasvir + sofosbuvir for 12 weeks -- 90% had an SVR12
  • ledipasvir + sofosbuvir + ribavirin for 12 weeks -- 96% had an SVR12
  • ledipasvir + sofosbuvir for 24 weeks -- 98% had an SVR12
  • ledipasvir + sofosbuvir + ribavirin for 24 weeks -- 100% had an SVR12

Results sorted by genotype:

No previous treatment

  • genotype 1a -- 98% SVR12
  • genotype 1b -- 97% had SVR12

With previous treatment

  • genotype 1a -- 95% SVR12
  • genotype 1b -- 96% had SVR12

Results sorted by age:

No previous treatment

  • less than 65 years old -- 98% had SVR12
  • 65 years or greater -- 94% had SVR12

With previous treatment

  • less than 65 years old -- 95% had SVR12
  • 65 years or greater -- 98% had SVR12


Results -- Platelet Levels

Platelets are small red blood cells. They help blood to clot and fight infections. Normal platelet levels are at least 150 platelets/μL. Technically this is written as 150,000 platelets/microlitre. However, in everyday conversation, doctors and nurses shorten this to simply "150." In people with HCV infection, low platelet counts are suggestive of serious liver injury.

In the pooled data researchers segregated results based on treatment history and platelet counts. The distributions of SVR12 are as follows:

No treatment history

  • less than 75 platelets -- 90% had an SVR12
  • between 75 and 99 platelets -- 100% had SVR12
  • between 100 and 124 platelets -- 98% had an SVR12
  • platelet count of 125 or more -- 98% had an SVR12

With treatment history

  • less than 75 platelets -- 82% had an SVR12
  • between 75 and 99 platelets -- 98% had SVR12
  • between 100 and 124 platelets -- 93% had an SVR12
  • platelet count of 125 or more -- 98% had an SVR12


Improvements in Lab Tests

In general, small but statistically significant improvements in levels of the following occurred in the blood of participants who achieved an SVR12:

  • protein (albumin)
  • the liver enzyme ALT
  • the waste product bilirubin
  • platelets


Safety and Tolerability

The following proportions of participants had treatment-related side effects:

  • ledipasvir + sofosbuvir -- 47%
  • ledipasvir + sofosbuvir + ribavirin -- 75%

One person who received ledipasvir + sofosbuvir + ribavirin died.

One person who received ledipasvir + sofosbuvir prematurely left the study.

Overall, serious laboratory test abnormalities occurred in some participants and were distributed as follows:

  • ledipasvir + sofosbuvir -- 16%
  • ledipasvir + sofosbuvir + ribavirin -- 13%

Specific laboratory test abnormalities:

Less-than-normal levels of hemoglobin

  • ledipasvir + sofosbuvir -- less than 1%
  • ledipasvir + sofosbuvir + ribavirin -- 10%


Key Points

  • Overall, 96% of 513 study participants with symptoms of cirrhosis achieved SVR12.
  • Rates of SVR12 were relatively high among subgroups.
  • In participants who had previously been exposed to treatment, 12 weeks of ledipasvir + sofosbuvir resulted in 90% achieving an SVR12. Adding ribavirin to this regimen or doubling the duration of treatment to 24 weeks resulted in an SVR12 rate of at least 96%.
  • The use of ribavirin was associated with more side effects and affected hemoglobin levels.


Reference

Bourlière M, Sulkowski MS, Omata M, et al. An integrated safety and efficacy analysis of more than 500 patients with compensated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin. In: Program and abstracts of The Liver Meeting, 7-11 November 2014. Abstract 82.




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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