The Food and Drug Administration has approved the use of a single pill containing two different antiviral drugs for theÂ treatment for hepatitis C. It is the first combination pill approved for the disease, and also the first treatment that does not contain interferon or ribavirin.
The new hepatitis C drug, called Harvoni, is a mixture ofÂ the antiviral drugs ledipasvir and sofosbuvir. Ledipasvir (pictured) is an inhibitor of the hepatitis C virus protein NS5A, which has multiple roles in the viral replication cycle that include RNA synthesis and virus particle assembly.Â The mechanism of NS5A inhibition by ledipasvir is not known. Sofosbuvir is a previously licensed inhibitor that targets the viral RNA-dependent RNA polymerase. It is an analog of the nucleoside uridine, one of the four building blocks of RNA. Sofosbuvir is utilized by the viral RNA polymerase, leading to inhibition of viral RNA synthesis.
The use of single antiviral drugs (monotherapy) to treat RNA virus infections is always problematic because resistance usually arises rapidly. Dual-therapy pills like Harvoni are better, but the best are triple-therapy pills. Triple therapy formulationsÂ such as AtriplaÂ have been used successfully to treat infections with HIV-1, and presumably there willÂ be mixtures of three antiviral drugs for treating hepatitis C.
Let’sÂ use HIV-1 to illustrate the value of treating infections with multiple antiviral drugs. The HIV-1 viral genome, like that of HCV, is slightlyÂ less than 10,000 bases long. Assume that one mutation in the viral genome is needed for drug resistance. If the RNA polymerase mutation rate is 1 out of every 10,000 basesÂ synthesized, thenÂ each base in the viral genome is substituted in a collection of 10,000 viruses. An HIV-1 infected person can make as many as 10,000,000,000 virus particles each day, soÂ 1010/104 = one million viruses will be produced each day with resistance to one drug.
If we use two antiviral drugs, developing resistance to both occurs in everyÂ 104 xÂ 104 = 108 viruses. In this caseÂ 1010/108Â = 100Â viruses will be produced each day with resistance to twoÂ drugs.
If we use threeÂ antiviral drugs, developing resistance occurs in everyÂ 104Â xÂ 104Â xÂ 104= 1012Â viruses, which is more than what is produced each day.
This is why triple antiviral therapy has been so successful for the treatment of AIDS.
And yes, I’m sure someone has tested Sofosbuvir for inhibition of Ebola virus replication.