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Sofosbuvir and Ledipasvir -- Just Six Weeks of Therapy

March/April 2014

As mentioned earlier in this issue of TreatmentUpdate, the duration of HCV therapy is shrinking, from 48 weeks a few years ago to 24 weeks and most recently 12 weeks. These shorter periods of therapy are made possible by the use of increasingly powerful anti-HCV drugs called DAAs (direct acting antivirals).

In a trial called Synergy, researchers at the U.S. National Institutes of Health (NIH) tested different combinations of anti-HCV drugs; with the exception of sofosbuvir, all were experimental agents. The drugs used were as follows:

  • sofosbuvir (a nucleotide inhibitor of the HCV protein NS5B) -- 400 mg once daily
  • ledipasvir (an NS5A inhibitor) -- 90 mg once daily
  • GS-9669 (a non-nuke that inhibits NS5B) -- 500 mg once daily
  • GS-9451 (a protease inhibitor that inhibits NS3/4) -- 80 mg once daily

Here is a list of the regimens used in the study along with the duration of therapy:

  • sofosbuvir + ledipasvir -- 12 weeks of treatment
  • GS-9669 + sofosbuvir + ledipasvir -- six weeks of treatment
  • GS-9451 + sofosbuvir + ledipasvir -- six weeks of treatment

None of the participants had previously been exposed to HCV treatment prior to the current study.

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Participants' average profile at the time they entered the study was as follows:

  • 75% men, 25% women
  • age: 56 years
  • 80-90% of participants were black
  • 55-85% had HCV genotype (GT) 1a
  • 65-75% of participants had an HCV viral load greater than 800,000 copies
  • 75-95% had genes that suggested an unfavourable response to interferon treatment
  • 25-40% had severe or extensive liver injury

Researchers noted that this patient population is reflective of what many doctors consider difficult to treat HCV in the U.S.


Results

The response to therapy was stunning given that many participants had factors that would impair their recovery from therapy had they been treated with interferon, and neither interferon nor ribavirin were used in this study. SVR12 (an undetectable viral load 12 weeks after a course of therapy has ended) is a very strong predictor of SVR24 and highly suggestive of recovery from HCV. SVR12 was observed in the following proportions of participants:

  • sofosbuvir + ledipasvir -- 100% (20 out of 20 participants)
  • sofosbuvir + ledipasvir + GS-9699 -- 95% (19 out of 20 participants; with one case of relapse)
  • sofosbuvir + ledipasvir + GS-9451 -- 100% (20 out of 20 participants)

The combination that drove HCV viral load down the fastest was the following:

  • sofosbuvir + ledipasvir + GS-9451

By the 14th day of therapy, at least 90% of participants had their HCV viral loads suppressed.


Results -- Side Effects

According to the researchers, the regimens were well tolerated. No one died during the study.

Common side effects reported were as follows:

  • headache: 25%
  • fatigue: between 10% and 20%
  • diarrhea: between 5% and 25%

Two serious adverse events were reported as follows:

  • pain -- this occurred in a participant who was recovering from a liver biopsy
  • vertigo (dizziness) -- this occurred in someone with a history of dizziness

Therefore, it seems unlikely that the study drugs caused these problems.

There were isolated abnormal blood test results from some participants, including the following:

  • less-than-normal levels of phosphate -- two participants; this was not linked to any symptoms
  • less-than-normal levels of red blood cells -- one participant; this person had a history of anemia
  • abnormalities in blood sugar -- one participant who had diabetes prior to entering the study
  • elevated levels of the waste product creatinine -- two participants who had tests suggestive of kidney injury prior to starting study medicines; this problem also occurred in a third participant who took 1,600 mg/day of ibuprofen (Advil, Motrin)

All abnormal test results returned to their pre-study level.


Bear in Mind

  1. This is the first study to suggest that a short course of therapy (six weeks) using potent anti-HCV drugs may cure patients. This result arises because of the power of the DAAs used in this study. Further monitoring is needed to confirm these results.
  2. The NIH researchers are planning to do additional studies, enrolling participants with severe liver injury (graded as F3 or F4) to find out if triple therapy with DAAs can also cure them in a relatively short period.
  3. The NIH team plans to study an even shorter course of treatment using all four drugs mentioned in this report.


Reference

Kohli A, Sims Z, Marti M, et al. Combination oral hepatitis C antiviral therapy for 6 or 12 weeks: Results of the Synergy trial. In: Programs and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections, 3-6 March 2014, Boston, U.S. Abstract 27 LB.




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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