The hepatitis C virus (HCV) protein NS5A plays an important role in the creation of new copies of HCV. As a result, pharmaceutical companies have developed (and continue to develop) drugs that disable this protein.
Currently approved drugs that target NS5A include the following:
Inhibitors of NS5A are generally considered to be the most powerful of anti-HCV drugs. Therefore, regimens that contain the above-listed drugs are powerful and rates of cure with such regimens in clinical trials are usually at least 95%. However, a small proportion of people may not be cured despite the use of powerful regimens. The reasons for this can vary and are discussed in TreatmentUpdate 215.
It is possible that in people whose regimens fail, HCV may change, or mutate, and develop the ability to resist inhibitors of NS5A. If that happens, new regimens containing more powerful NS5A inhibitors will be needed.
Velpatasvir is an anti-HCV drug that will be co-formulated (put in one pill) with another anti-HCV drug called sofosbuvir (Sovaldi). These two drugs in one pill will be sold as Epclusa. Velpatasvir is a powerful inhibitor of NS5A.
In a clinical trial where Epclusa was used along with the broad-spectrum antiviral drug ribavirin, the combination was able to cure 91% of participants who needed retreatment after their previous regimen had failed. Bear in mind that in this study 24 consecutive weeks of retreatment were necessary to effect such a high rate of cure.
The average profile of participants upon entering the study was as follows:
For 99% of participants, their previous experimental treatment was initially able to suppress HCV levels in the blood. However, once that course of treatment ceased, HCV levels resurged. Participants in this study either had been in previous phase I/II studies sponsored by Gilead Sciences that used very short durations of treatment or in studies where they may have received less-than-ideal doses of drug (as such studies were exploring different doses of medicines).
The dose of ribavirin used varied depending on a person's weight.
Overall, 91% (59 out of 65 participants) were cured.
Cure rates by genotype were as follows:
In cases of genotype 1 and 2 infections where mutations to NS5A were detected prior to retreatment, all participants were cured with sofosbuvir + velpatasvir + ribavirin. In cases of genotype 3 infection, 13 out of 16 people had mutations to NS5A detected at the start of the study. The cure rate in genotype 3 patients who were retreated was 77% (10 out of 13 people). Bear in mind that, in general, genotype 3 infection does not respond as well to DAAs as other genotypes do.
Common side effects were as follows:
Bear in mind that some of these side effects were likely due to exposure to ribavirin.
Researchers graded most of these side effects as mild to moderate. However, three people experienced severe side effects (details were not provided).
One participant left the study because of severe irritability.
No one died in the study.
Red blood cells help bring oxygen to tissues and remove the waste product carbon dioxide. Ribavirin can cause some red blood cells to prematurely die. As a result, people who use this drug can be at elevated risk for (temporarily) reduced levels of red blood cells -- anemia. They may also feel unexpectedly tired, have skin rash and can experience irritability and depression. Despite the effects of ribavirin, only four participants developed anemia in the study.
Overall, among people who were retreated with a combination of sofosbuvir + velpatasvir + ribavirin, cure rates were greater than 90%.
There was no impact of mutations associated with the HCV protein NS5A in people with HCV genotypes 1 or 2. However, such mutations in people with genotype 3 resulted in lower rates of cure.
A higher rate of effectiveness across all genotypes may be found with the following combination:
This combination has entered phase III clinical trials. Other combinations of potent anti-HCV drugs are also being tested and these may be candidates for some people who seek retreatment.
Gane EJ, Shiffman ML, Etzkorn K, et al. Sofosbuvir + velpatasvir in combination with ribavirin for 24 weeks is effective retreatment for patients who failed prior NS5A-containing DAA regimens: results of the retreatment study. The International Liver Congress, 13-17 April 2017, Barcelona, Spain. Abstract PS024.
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