virology blog

About viruses and viral disease

sofosbuvir

Combination antiviral therapy for hepatitis C

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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.

What price antiviral drugs?

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SofosbuvirThe Federal Drug Administration of the US approves new drugs solely on the basis of safety and effectiveness, with no value assessment. Pharmaceutical companies may set their drug prices based mainly on what the market will bear. Nevertheless, the announcement that Gilead Sciences would price their just-approved, anti-hepatitis C virus (HCV) drug sofosbuvir (Solvaldi) at $84,000 for 12 weeks of treatment was met with considerable complaints.

Solvaldi is a member of a class of antiviral drugs called nucleoside analogs. They act as chain terminators and inhibit viral RNA synthesis. When the viral RNA polymerase is copying the viral RNA, to enable the production of more virus particles, it normally uses the pool of ATP, UTP, GTP, and CTP to produce more RNA. When Solvaldi is incorporated into the growing RNA chain by the viral enzyme, no additional triphosphates can be added, because the drug contains a fluorine atom at the 2′-position of the ribose. Its presence inhibits addition of the next nucleoside by the polymerase to the 3′-OH. Viral RNA synthesis therefore stops, and production of virus particles is inhibited. For more information on chain terminators, see my virology lecture on antivirals.

Gilead believes that the price of the drug is fully justified: a spokesperson said “We’re just looking at what we think was a fair price for the value that we’re bringing into the health care system and to the patients.”

It could cost up to $300,000 to treat patients with chronic HCV infection using less effective and more difficult to tolerate regimens. The potential benefit of a cure for patients with liver disease is clear, as the virus is the main reason that nearly 17,000 Americans are waiting for a liver transplant. The need for a well-tolerated, effective regimen is equally critical for people infected with HIV and HCV, because having both infections accelerates liver damage.

Despite these arguments, the high price will be a significant barrier for many, especially those in limited and fixed-budget programs such as Medicare and Medicaid. A panel of experts in San Francisco estimated that switching HCV infected Californians to Sovaldi would raise annual drug expenditures in the state by at least $18 billion.

Gilead has agreed to help U.S. patients pay for Sovaldi if they cannot afford it, or help patients obtain drug coverage. The company also plans to charge substantially less for a course of treatment in India ($2000 for the 12 week course), Pakistan, Egypt ($990 for the 12 week course), and China, where most people infected with HCV live. These deals have prompted some to ask if the US is being forced to subsidize the cost of the drug worldwide. I personally do not object to helping other countries solve their HCV problem.

What is a fair price for a drug that can eliminate HCV infection? Gilead paid more than $11 billion in 2011 to acquire the company that developed Sovaldi, and it is reasonable for them to recoup that investment. Andrew Hill of the Department of Pharmacology and Therapeutics at Liverpool University estimates the manufacturing cost of a 12 week course of treatment with this drug to be $150 to $250 per person. The answer to our fair price question must lie somewhere between these extremes.

There are parallels between Sovaldi (and other new anti-HCV drugs in the pipeline) and the initially expensive antivirals that were introduced ~20 years ago to treat HIV. Anti-retrovirals revolutionized the treatment of a chronic, lethal infection that is major global health problem, and the anti-HCV drugs could have the same effect. But there are also important differences: based on the number of infected individuals, HCV is a much larger public health threat than HIV. Furthermore, the new HCV antivirals can eliminate the virus completely, whereas anti-HIV drugs only suppress virus replication, so they must be taken (and paid for) for life.

At some point in the future competition among pharmaceutical companies and manufacturers of generic drugs should make it possible to treat everyone infected with HCV with affordable, curative antivirals. If the cost and efficiency of diagnosis and drug delivery keeps pace, it might be possible to eradicate HCV. That accomplishment might well be priceless.