Sofosbuvir + velpatasvir + voxilaprevir (Vosevi) for people with genotypes 1, 2 or 3 whose previous treatment failed
In a study called Polaris-4, researchers enrolled participants whose previous regimen(s) of direct-acting antivirals (DAAs) had failed to cure them. Researchers randomly assigned participants to receive one of the following regimens taken for 12 consecutive weeks:
- sof-vel-vox (sofosbuvir + velpatasvir + voxilaprevir) – 182 people
- sofosbuvir + velpatasvir (Epclusa) – 151 people
Participants had the following strains, or genotypes, of HCV: 1, 2, 3 or 4. Overall results were as follows:
- sof-vel-vox – 98% were cured
- sofosbuvir + velpatasvir – 90% were cured
Commonly reported adverse effects in this study included headache, fatigue, diarrhea and nausea.
Study details
Researchers recruited participants whose average profile upon entering the study was as follows:
- 77% men; 23% women
- age – 57 years
- common HCV genotypes – 1, 2 and 3
- 46% had extensive scarring of the liver
- HCV viral load – 2 million IU/mL
- most participants (73%) had been previously treated with an NS5B inhibitor. A majority of participants (60%) had been treated once prior to entering Polaris-4. The most common reason for previous treatment failure was relapse.
Participants received 12 consecutive weeks of either study regimen. Before, during and after the cessation of treatment, participants underwent extensive lab tests and other monitoring.
Results—Overall
Among participants who had been previously treated with DAAs (people who had used an NS5A inhibitor were excluded from this study), overall rates of cure were as follows:
- sof-vel-vox – 98% were cured
- sofosbuvir + velpatasvir – 90% were cured
As with the related clinical trial called Polaris-1, the vast majority of participants returned for additional blood testing 24 weeks after pill taking ceased and remained cured.
The most common reason for the failure of treatment to cure people was relapse. This was most common in people who had genotype 3a.
Results—Focus on cirrhosis
In past clinical trials of earlier DAAs with people with extensive scarring of the liver, treatment failure occurred in some patients. There were participants with cirrhosis in Polaris-4, however, none of them had the severe symptoms that can accompany cirrhosis. The distribution of cure rates in the present study were as follows:
No cirrhosis
- sof-vel-vox – 98%
- sofosbuvir + velpatasvir – 94%
Cirrhosis
- sof-vel-vox – 98%
- sofosbuvir + velpatasvir – 86%
Results—Pre-existing resistance
At the start of Polaris-4, nearly 50% of participants had strains of HCV that had mutated and, due to previous treatment failure, had become resistant to inhibitors of NS3 or NS5A. Researchers presented data on the response to current treatment distributed according to previous past treatment, as follows:
No pre-existing resistance
- sof-vel-vox – 100% cured
- sofosbuvir + velpatasvir – 90% cured
Having pre-existing resistance
- sof-vel-vox – 99% cured
- sofosbuvir + velpatasvir – 89% cured
Results—Safety issues
In general, the combinations of drugs used in Polaris-4 were well tolerated by participants.
The term adverse events is used by researchers to describe unfortunate events that can occur during a clinical trial. These events can include issues and symptoms that arise from exposure to treatment (side effects) and/or the underlying disease process or from factors that have nothing to do with the clinical trial, such as accidents, injuries and other trauma.
The overall distribution of adverse effects reported by participants was as follows:
- sof-vel-vox – 77%
- sofosbuvir + velpatasvir – 74%
Common adverse events reported by participants who used sof-vel-vox were as follows:
- headache – 27%
- fatigue – 24%
- diarrhea – 10%
Common adverse events reported by participants who used sofosbuvir + velpatasvir were as follows:
- headache – 28%
- fatigue – 28%
- diarrhea – 8%
According to the researchers, “the majority of cases of diarrhea were mild in severity.” There were no severe cases of diarrhea.
Lab test results
Most participants in Polaris-4 did not have severe abnormalities in their blood tests results, as follows:
- sof-vel-vox – 7% of participants
- sofosbuvir + velpatasvir – 7% of participants
The grading and distribution of abnormal or very abnormal blood tests only affected the following substances measured:
- creatine kinase (elevated levels of this enzyme are possibly suggestive of muscle injury)
- blood sugar (consistently elevated levels can indicate the develop of pre-diabetes or worsening of pre-existing diabetes)
- lipase (elevated levels of this enzyme are possibly suggestive of an inflamed pancreas gland)
Despite these abnormal lab test results, no participants developed symptoms of any of the issues associated with these tests.
Bear in mind
Overall, the results from Polaris-4 show that the combination of sof-vel-vox and, to a lesser extent, sofosbuvir + velpatasvir, is highly effective in curing people of chronic HCV whose prior regimen failed. Sof-vel-vox was effective in the vast majority of people who received this drug combination, which were people whose previous regimen had failed and who had HCV genotypes 1, 2 or 3.
There were several shortcomings to the study, as follows:
Only a small proportion of participants had been treated with the latest DAAs, such as Zepatier (a fixed-dose combination of elbasvir and grazoprevir) or Epclusa (a fixed-dose combination of sofosbuvir and velpatasvir). So, the effectiveness of sof-vel-vox against strains of HCV that are resistant to these drugs is not clear.
Certain populations were excluded from the study, including people co-infected with HIV or hepatitis B virus and people who had symptoms of cirrhosis. As such, it is not clear how effective this combination will be in these populations based on the data in Polaris-4.
—Sean R. Hosein
REFERENCE:
Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. New England Journal of Medicine. 2017; in press.