Hepatitis C has been in the news a lot recently. On one hand, the advances in research have some touting the disease on the verge of being "cured." On the other hand, the "Because We Can, That's Why" $1000 per pill regimens are coming under scrutiny from congress.

Many of us try to avoid Hepatitis C (HCV) because so much of the therapeutics are new and "foreign" to us. Also, the HCV treatment guidelines have changed at least twice in the time it's taken you to read this far. But HCV isn't going away. And you know it's going to be on the NAPLEX. So let's dig in, and see if we can't make some sense of this ever-evolving disease.

HCV Treatment History

Up until 2011, the only options you had for Hepatitis C (HCV) treatment were ribavirin (a nucleoside analogue) and interferon/pegylated interferon (which works just like the interferon in your body--through cytokines, or signaling proteins). Great. So what's the problem?

Do you want to have a baby? Well, sorry. Ribavirin is pregnancy category X, and contraception is required for both males and females...for 6 months after you've finished treatment. Ok fine. So no babies. That's not so bad. But it doesn't end there. Ribavirin also tends to make people incredibly tired and anemic. Not to be outdone, interferon makes you feel like you have the flu. And depressed. And suicidal.

Also treatment durations are 48 weeks. Can you imagine feeling like you have the flu for 48 weeks? So pretty much, if you had HCV, you hope you’re part of the group that spontaneously clears the virus. Or you figure “Hey, liver cirrhosis and cancer can’t be that bad, right?”

Then in 2011, a new hope arrived. Vertex and Merck brought to the market what at the time was considered a breakthrough in HCV therapy. Boceprevir and telaprevir, NS3/4A protease inhibitors, added targeted therapy to the management of HCV. This is similar to how cancer treatment has progressed from "kill all of the cells" to "just kill the cells with the screwed up chromosome." Though boceprevir and telaprevir brought modest improvements in treatment outcomes, there were still challenges to overcome. Namely, adherence to the stupidly high pill burden and the dietary requirements.

I mean, try convincing your patient to take a bunch of pills (5700 in total for a 48 week course of treatment) with a fatty diet (not as fun as it sounds). Really, if you want some fun reading, look up what the dietary requirements were for taking boceprevir and telaprevir. Hint: it's a lot of fat.

Throw in the 'fire-rrhea' someone might experience with telaprevir, and you might really start wondering if it was worth it at all. Again, treatment was 48 weeks (today's regiments are a fraction of that). Yet, these agents were basically all we had.

So, what the heck is an NS3/4A (protease) inhibitor?

Some of you HIV buffs might recognize that second part: protease inhibitor. If you do, congratulations! It's about the same idea. Viruses are like that one friend who you let crash at your house, but they don't bring anything with them. No toothbrush, no change of clothes. They end up using all your stuff and destroying the place on the way out (while somehow making copies of themselves).

This analogy stopped working.

Anyway, since viruses don't traditionally carry the proteins they need to replicate, they rely on the host cell to do it for them. By hijacking the transcription/translation system the virus creates the proteins needed for the capsule and other fun stuff to make a bunch of copies.

If you remember your biochem, you'll remember that the protease takes that super-long chain of amino acids and cleaves it into the individual proteins. For a visual analogy, check out how candy canes are made. Seriously. Especially where they cut the candy canes. That's what protease does.

So essentially, when you block this process, you get a bunch of jumbled up nonsense that the virus can't use. Which means no more copies. Or in candy cane world, no more christmas (hello Grinch?).

There was still a lot of unexplored avenues in the treatment of HCV at this point, but that all changed around the time this song became popular.

When Gilead came to the market with sofosbuvir in late 2013, it was hailed as the cure for HCV. Sofosbuvir is a NS5B RNA-dependent polymerase inhibitor with virologic response rates reported at over 90%. This dwarfs the older numbers that barely eclipsed 60%. Yet, the cost and accessibility issues led to a congressional inquiry and complaints from patient advocate groups.

Then you throw in that other Gilead drug: a NS5A (zinc-binding, proline-rich hydrophilic phosphoprotein) inhibitor named ledipasvir with sofosbuvir in a combination that you'll likely have heard a lot about: Harvoni. Single tablet regimen, SVR rates in the 90s, and virtually no side effects. Sounds like a pipe dream, no?

NS5A and NS5B??

Now, we have new terms and classes to stare at. NS5B (an RNA-dependent polymerase) inhibitor, and NS5A (a zinc-binding proline-rich hydrophilic phosphoprotein) inhibitor. The first part might be familiar again for all the HIV antiretroviral folks. But essentially NS5A and NS5B form a complex that replicate the RNA of the virus. NS5A seems to be the binding and activating portion, while NS5B does the heavy lifting.

Essentially, think of NS5A as the guy bringing the cotton into the warehouse, while the NS5B is the lady spinning the cotton into the thread. However, you'll probably see NS5A labeled as quite a few things, and part of that is simply because the research is still playing catch up. If you search HCV Genome on Google, you'll actually find NS5A labeled as "interferon resistance protein" or even '?'. Seriously.

Anyways, these proteins are essential for viral replication. So it goes without saying that wrecking this process basically puts a stop to the whole virus factory in your liver cells.

Midpoint Review

So now, as a quick midpoint summary. When you see NS3/4A, think protease. If you see NS5A, think polymerase activator or initiator. And for NS5B think polymerase. In terms of the order of operations, the polymerase (NS5A and NS5B) copies the full genome. Then the protease (NS3/4A) cleaves it up into individual proteins. These individual proteins are what make the virus do what viruses do. Make copies and wreck shit in the host cell. This will hopefully somewhat clear up the confusion with these drugs and how they work.

Alrighty then. Moving on.

As of May 2019, we have the following drugs in each class:

NS3/4A

Boceprevir & Telaprevir, the trailblazers (RIP)
Simeprevir
Paritaprevir
Grazoprevir
Glecaprevir
Voxilaprevir

NS5A

Ledipasvir
Ombitasvir
Daclatasvir
Elbasvir
Pibrentasvir
Velpatasvir

NS5B

Sofosbuvir
Dasabuvir

Overall, we've seen quite a bit of change as drugs were developed and released in the last few years. Interferon is no longer used (no more flu-like symptoms or depression!). But ribavirin may still be used based on the patient's presentation, prior treatment or disease progression.

Doesn’t anyone ever think about the unborn babies?

As with HIV treatment, newer agents are now complete regimens or single tablet regimens. This is fantastic from an adherence point of view. On top of that, some of the regimens are as short as 12 weeks. 25% of the 48 weeks we started with.

So far, as of May 2019, we have the following combination pills:

Harvoni (ledipasvir / sofosbuvir): NS5A and NS5B (activator + polymerase inhibition)
Viekira Pak (ombitasvir / paritaprevir / dasabuvir / ritonavir): NS3/4A, NS5A and NS5B + booster (block all the things)
Technivie (ombitasvir / paritaprevir / ritonavir): Viekira Pak minus dasabuvir (NS5A)
Zepatier (elbasvir / grazoprevir): NS5A and NS3/4A (activator + protease inhibitor)
Mavyret (glecaprevir / pibrentasvir): NS3/4A and NS5A
Epclusa (sofosbuvir / velpatasvir): NS5B and NS5A
Vosevi (sofosbuvir / velpatasvir / voxilaprevir): NS5B and NS5A and NS3/4A

As a quick note: Harvoni, Zepatier, Epclusa, and Vosevi are single-tablet regimens, while the others are not. Viekira Pak has four tablets (with BID dosing), and Technivie has two tablets (but at least it's QD dosing). Mavyret is three tablets once daily to be taken with food. Keep all of that in mind with regards to pill burden and patient compliance.

HCV Treatment

One thing that we won't do here is comment on first-line treatment or initial therapy. If you've read this far, the current recommendations have probably changed another 2 or 3 times.

One of the best resources you'll find for the most up-to-date HCV treatment is the actual treatment guideline, jointly maintained by AASLD and IDSA. Check it regularly. If it hasn't sunk in, they update often and things change all the time. Especially when new therapies hit the market.

We can, however, provide a few general principles to follow:

If you don't get a baseline viral load, Max will be sad. Don't make Max sad.

Always get a baseline viral load. People do spontaneously clear the disease from time to time. In between the viral load at diagnosis and when the decision is made to start treatment, the patient may have cleared the virus. Newer agents have definitely improved side effect profiles (no more anemia, no more sad babies, no more psych issues, no more feeling crummy). But starting someone on a $1000/day treatment when they don't need it probably isn't the best idea.
Get a genotype. It's kind of important when you are trying to decide the choice of therapy. And if a patient comes back with virus after completing therapy, you can't rule out a reinfection without testing again. Please, check it again.
Follow your patients. This goes without saying, but treatment success depends on adherence. And with the cost of medication and potential for resistance, don't test your faith in humanity and allow someone to royally screw this up. Case management is important (s/o to all the case managers out there!).

tl;dr

We may potentially be looking at HCV going the way of polio, bubonic plague, and other diseases that are essentially non-factors in modern medicine. Unless you live in a place where medicine still consists of blood-letting and witch doctors. If that's the case, I'm simply amazed you’re able to read this. It's an exciting time to be involved in the treatment of HCV. Hopefully now you have a basic understanding of the drugs. That will go a long way on the NAPLEX or when an HCV patient shows up in your pharmacy.

Hepatitis C Treatment 101