Hepatitis C is a Hot Topic and a Nobel Winner

2020 has been a remarkable year for Medical Microbiology not just because of COVID-19 pandemic but also for milestones in HIV and hepatitis C disease. Hepatitis C discovery is the Nobel winner for 2020, which underscores its importance for the USMLE. Dr. Harvey Alter was a young man on Dr. Baruch Samuel Blumberg's team when they discovered hepatitis B in 1965. Their landmark paper announcing their discovery of HBsAg (what was then known as 'the Australian Antigen') on Feb 15, 1965, is a classic! [Refer to JAMA. 252 (2): 252-7]. Dr. Blumberg received the Nobel for their work on HBV in 1975. 

But then in the mid-1970s, Dr. Alter discovered a new hepatitis virus in the serum of transfusion patients which was neither hepatitis A nor B. He demonstrated that most post-transfusion hepatitis cases were not due to hepatitis A and hepatitis B but a new form of hepatitis, which was initially called 'non-A, non-B hepatitis.' This work eventually led to the isolation of that virus in 1988; it was named hepatitis C. It is often called 'transfusion-related hepatitis.'

Fast-forward 3 decades later and now Hepatitis C is very curable with some groundbreaking therapy, and Dr. Alter is due to receive the global acclaim he has always deserved. Congratulations to him!

Hepatitis C has been such a hot topic for USMLE purposes, and no prep course prepares USMLE candidates with lectures on the critical elemental concepts in this subject area.  Recent advances in Pharmacology is one critical area to become conversant with. Some drugs have such unique properties or attributes or impact that one cannot help but predict their immediate relevance for the USMLE. In fact, you would be a fool not to prepare for something like this.  

Check out one of our USMLE questions on these concepts. This is one of the questions written by our panel of experts that our students must be able to answer confidently during the USMLE Insider Prep Course for USMLE Step 1. Test yourself with this and let us see how you do. We will discuss the answer and offer explanations later. 

1. A 65-year-old man with a history of blood transfusion from several years ago has just been diagnosed hepatitis C disease. He also has several comorbidities and has been taking    many medications. His physician prescribes elbasvir/grazoprevir to combat hepatitis C. Concurrent administration of which of the following medications will be a contraindication

A. Atenolol
B. Cyclobenzaprine
C. Cyclosporine
D. Hydrochlorothiazide
E. Sildenafil
F. Warfarin

Explanation:
The answer is C. Grazoprevir is an OATP1B1/3 substrate, CYP3A4 substrate, and P-glycoprotein (P-gp) substrate, while elbasvir is a CYP3A4 and P-gp substrate. 

Solute carrier organic anion transporter family member 1B3 (SLCO1B3), also known as organic anion-transporting polypeptide 1B3 (OATP1B3), is a transmembrane domain influx transporter that is normally expressed in the liver and functions to uptake large, non-polar drugs and hormones from the portal vein.  

Drugs that inhibit these proteins, such as cyclosporine, rifampicin, and a number of HIV drugs (atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cobicistat), can cause a significant increase in grazoprevir blood plasma levels. These drugs may increase the risk of ALT elevations owing to a significant increase in grazoprevir plasma concentrations.  

Because both grazoprevir and elbasvir are degraded by the liver enzyme CYP3A4, coadministration with drugs that induce this enzyme, such as efavirenz, carbamazepine or St. John's wort, may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of elbasvir/grazoprevir and loss of virologic response. Coadministration with such drugs is contraindicated.

Combination with CYP3A4 inhibitors may increase plasma levels.

(Choices A, B, and D) None of these agents has any interactions with elbasvir/grazoprevir.
(Choices E and F) Both sildenafil and warfarin are substrates of CYP3A4 and would not interfere in the action of elbasvir/grazoprevir.