Combination antiviral therapy for hepatitis C

Ledipasvir and SofosbuvirThe Food and Drug Administration has approved the use of a single pill containing two different antiviral drugs for the 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 of 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. 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 formulations such as Atripla have been used successfully to treat infections with HIV-1, and presumably there will be mixtures of three antiviral drugs for treating hepatitis C.

Let’s use HIV-1 to illustrate the value of treating infections with multiple antiviral drugs. The HIV-1 viral genome, like that of HCV, is slightly 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 bases synthesized, then 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, so 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 every 104 x 104 = 108 viruses. In this case 1010/108 = 100 viruses will be produced each day with resistance to two drugs.

If we use three antiviral drugs, developing resistance occurs in every 104 x 104 x 104= 1012 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.

Behind the scenes: TWiV 202 at the University of Nebraska

We recorded This Week in Virology #202 at the University of Nebraska in Lincoln, Nebraska on 5 October 2012, as part of the 12th Annual Symposium in Virology. Terence Dermody, Shou-Wei Ding, Grant McFadden and I spoke about our research, and then we recorded TWiV with University of Nebraska virologists James Van Etten, T. Jack Morris, and Charles Wood.

I was impressed by the fine virology being done at the Nebraska Center for Virology, as well as the collegiality of the virology community in Nebraska, Iowa, South Dakota, and Kansas – Symposium attendees were from all of those states! I met many young virologists at the poster session and I was touched by how many of them wanted to say hello and thank us for doing TWiV.

Many thanks to all the virologists who came to the Symposium and stayed to watch TWiV. Special thanks to Charles Wood, the Director of the Nebraska Center for Virology, who participated in TWiV #202 along with T. Jack Morris and James Van Etten.

Here are some behind the scenes photographs of this short but very informative visit.

TWiV 202: Huskers go viral

In episode #202 of the science show This Week in Virology, Vincent travels to the University of Nebraska to meet with members of the Nebraska Center for Virology and discuss their work on algal viruses, plant viruses, HIV and Kaposi’s sarcoma herpesvirus.

You can find TWiV #202 at www.microbe.tv/twiv.