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Solar-1: Ledipasvir and Sofosbuvir in People With Symptoms of Severe Liver Injury

April 2015

As mentioned earlier in this issue of TreatmentUpdate, doctors and nurses can grade severe liver injury based on the presence and severity of symptoms.

Cases of cirrhosis with symptoms are called decompensated cirrhosis and can include the following symptoms:

  • enlarged veins in the stomach and throat that can sometimes burst, leading to internal bleeding
  • buildup of fluid in the abdomen and legs
  • difficulty thinking clearly and problems with concentration
  • difficulty falling asleep and staying asleep
  • unexpected mood changes
  • yellowing of the skin and whites of the eyes (jaundice)

Most studies of emerging and new oral therapies for HCV have enrolled participants with generally mild-to-moderate liver injury. However, corporations are increasingly testing these new therapies in HCV-infected people with severe liver injury. In some cases, the broad-spectrum antiviral drug ribavirin is included in regimens for people with severe liver injury.

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In a clinical trial called Solar-1, researchers enrolled 108 participants with severe liver injury who had symptoms of cirrhosis and randomly assigned them to receive one of the following regimens:

  • 12 weeks of ledipasvir + sofosbuvir + ribavirin -- 53 people
  • 24 weeks of ledipasvir + sofosbuvir + ribavirin -- 55 people

Ribavirin was introduced at a dose of 600 mg/day and gradually increased.

Participants did not have a history of the following:

  • liver cancer
  • liver transplantation

The average profile of participants at the start of the study was as follows:

  • 67% men and 33% women
  • age -- 60 years
  • HCV strain -- genotype 1a was found in 60% of participants and others had genotype 4
  • HCV viral load -- 5.9 log
  • about 10% of participants were obese
  • prior treatment -- more than 50% of participants had been previously treated
  • fluid buildup in the abdomen occurred in more than 60% of participants
  • brain-related problems (a consequence of severe liver injury) -- more than 60% of participants


Results -- By the Fourth Week of the Study

Researchers noted that dramatic improvements in liver health and overall health occurred in many participants within the first four weeks of receiving study medications. Furthermore, as early as the fourth week of the study, CTP (Child-Turcotte-Pugh) scores declined. Reductions in CTP scores were generally greater among participants graded as CTP-B whether they received 12- or 24-week regimens.

Among participants classed as CTP-C at the start of the study, improvements in symptoms and scores were seen, however, they were not as dramatic as in participants who were not as ill at the start of the study (for example, those who had a CTP-B grade).


Safety and Tolerability

Adverse events, a term that includes drug side effects and complications that can arise because of the disease process, occurred in nearly all participants.

The proportion of participants with severe or extremely serious adverse events was distributed as follows:

Participants with CTP-B

  • 12-week regimen -- 7%
  • 24-week regimen -- 28%

Participants with CTP-C

  • 12-week regimen -- 100%
  • 24-week regimen -- 100%

Deaths occurred during the study (bear in mind that this was a very ill population) and were distributed as follows:

Participants with CTP-B

  • 12-week regimen -- one death
  • 24-week regimen -- two deaths

Participants with CTP-C

  • 12-week regimen -- two deaths
  • 24-week regimen -- one death

Causes of death included the following:

  • overwhelming bacterial infections
  • collapse of many organ-systems combined with overwhelming bacterial infections
  • kidneys stopped working
  • heart attack


Results -- Effectiveness

Overall, rates of SVR12 were similar regardless of the duration of therapy.

Participants with CTP-B

  • 12-week regimen -- 87%
  • 24-week regimen -- 89%

Participants with CTP-C

  • 12-week regimen -- 86%
  • 24-week regimen -- 90%

Bear in mind that the number of participants within subgroups in this study was relatively small, so differences in SVR12 between regimens are not meaningful.


Key Points

  • The combination of ledipasvir + sofosbuvir + ribavirin in participants with HCV genotypes 1 or 4 resulted in relatively high rates of SVR12 in those with cirrhosis and poor life expectancy.
  • Longer duration of therapy (24 weeks vs. 12 weeks) did not improve SVR12 rates.
  • People with symptoms of severe liver injury are ill and severe complications during treatment should be expected in some patients who receive treatment.


Reference

Flamm SL, Everson GT, Charlton M, et al. Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with decompensated cirrhosis: Preliminary results of a prospective, multicenter study. In: Program and abstracts of The Liver Meeting, 7-11 November 2014. Abstract 239.




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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