Saturday, June 30, 2012

HCV Weekend Reading-The Management of Hepatitis C:Triple Therapy

Weekend Reading

Taken by Budapest-born photograher Andre Kertesz

Hello folks,
It sure is one hot Saturday here in Michigan, topping out at around 98 degrees. I just came in from the heat to cool off and enjoy a lovely evening with my family.

Sending out cool thoughts to everyone on this July 4th holiday.

Most weekends this blog offers information on HCV by sharing resource links, videos, or interesting articles in our "weekend reading" series. This weekend I am obsessed with the continuing medical education offered at "The Cleveland Clinic"  In the newly released CME readers have a chance to brush up on protease inhibitors telaprevir and boceprevir. Test your knowledge by answering questions on common side effects, treatment duration, stopping rules and drug-drug interactions. To begin click here or simply read through the questions and answers provided below.   

Here we go, grab a glass of iced coffee, sit back and take part in this CME on the management of hepatitis C.

The Cleveland Clinic Foundation Center for Continuing Education
Release Date: June 27, 2012 

Disease Management Clinical Decisions

The Management of Chronic Hepatitis C Virus (HCV) has been Transformed by Protease Inhibitor (PI) Therapy

A 48-year-old female who was diagnosed with chronic hepatitis C virus (HCV) infection in 1999 presents to you for HCV therapy after she heard about the “new medications” for hepatitis C. Her risk factors for acquiring HCV infection include remote history of intranasal cocaine use in the early 1980’s and having two tattoos. She was treated for HCV in 2002 with pegylated interferon a2a + weight-based ribavirin and her viral load was undetectable at the end of treatment. However, she had a relapse after she stopped therapy. She is interested in learning more about the recently FDA-approved protease inhibitors for HCV and the way they work.

1. All the following statements are true EXCEPT:

a.The HCV NS3/4A protease has an important role in viral replication by cleaving the HCV polyprotein.
b.Protease inhibitors are the first direct-acting antivirals to target HCV.
c.Both telaprevir and boceprevir are only approved for patients with HCV genotype 1 infection.
d.Both medications can be used as monotherapy for chronic hepatitis C infection but the efficacy is higher when combined with interferon.

HCV is a single-stranded RNA virus and its genome encodes a single polyprotein that is cleaved by proteases during and after translation to form structural and nonstructural proteins. Both telaprevir and boceprevir are direct-acting antiviral agents that target the HCV NS3/4A protease. They are only approved for treatment of chronic HCV genotype 1 infection. 2-5 Protease inhibitors are prone to viral resistance and should only be used in combination with pegylated interferon and ribavirin as part of a triple therapy regimen.

Her baseline data includes the following: ALT 71, AST 54, HCV genotype 1a, HCV RNA level 2,857,000 IU/ mL. Liver ultrasounds shows normal liver morphology with no evidence of cirrhosis or portal hypertension. She has never had a liver biopsy. The patient is upset when she finds out that she still has to take both pegylated interferon and ribavirin in addition to a protease inhibitor to re-treat HCV. She experienced flu-like symptoms with the interferon injections during her last course of treatment and did not “feel good” on treatment. She asks for your opinion.

2. Which of the following statements is CORRECT?

a.As many HCV-infected patients will not develop cirrhosis, a liver biopsy to assess for the stage of fibrosis can guide her decision.
b.Her baseline viral load is very high and she is at increased risk of cirrhosis and hepatocellular carcinoma if she declines treatment.
c.Her AST and ALT are elevated indicating significant inflammation in her liver and she should be treated as soon as possible.
d.She has a normal liver ultrasound and you advise against starting therapy at this time.

a. Correct.
The presence of clinically significant fibrosis (Metavir stage ≥2 or F 2-4) is a clear indication for initiating HCV therapy if no other contraindications exist. If she has no or minimal fibrosis, the patient may elect to hold off on treatment or wait for future therapies (such as polymerase inhibitors). HCV viral load dose not correlate with the development of cirrhosis and hepatocellular carcinoma. The decision to start HCV therapy should not be based on the AST or ALT levels which tend to fluctuate over time. A normal liver ultrasound cannot exclude the presence of significant liver fibrosis.

The patient undergoes a percutaneous liver biopsy that shows grade 2 inflammation and stage 2 fibrosis (F2). You discuss the findings with the patient and you recommend starting protease inhibitor-based therapy. After discussing response rates, treatment protocols, and side effect profiles of both telaprevir and boceprevir, the decision is made to start the patient on combination therapy with telaprevir, pegylated interferon, and ribavirin.

3. You inform the patient that her chances of achieving a cure of chronic hepatitis C infection with telaprevir-based triple therapy are:

a.100% sustained virologic response (SVR) rate if she is compliant with the treatment regimen
b.Around 85% SVR rate if she is compliant with the treatment regimen
c.You cannot predict her likelihood of response at this point, you have to wait for her viral load at week 4 on triple therapy
d.There is no “cure” from chronic hepatitis C, you can only suppress the virus.

b. Correct.
Once a sustained virologic response or SVR is achieved (defined as the absence of detectable HCV RNA in the serum 24 weeks after completion of therapy), lifetime cure of HCV infection is expected. SVR rates for patients with chronic hepatitis C genotype 1 infection who are treatment naïve with telaprevir-based triple therapy is around 70% as oppose to 40% with the old standard of care (pegylated interferon and ribavirin).

3 In treatment experienced patients (previously treated with pegylated interferon and ribavirin) the response rates are as follows:

1.prior relapsers (patients with undetectable HCV RNA at the end of a previous course of therapy with pegylated interferon and ribavirin with HCV RNA positivity thereafter) around 85%.
2. prior partial-responders (patients who had a reduction of 2 log10 or more in HCV RNA after 12 weeks but with detectable HCV RNA during the therapy period) around 60%.
3. prior null-responders (patients who had a reduction of less than 2 log10 in HCV RNA after 12 weeks) around 30%. This patient is considered a prior relapser and her chances of achieving an SVR are around 80%.

The patient informs you that she is taking atorvastatin for hypercholesterolemia and amlodipine for hypertension. She also takes acetaminophen occasionally for tension headaches.

4. Which of the following statements is CORRECT regarding drug-drug interaction with protease inhibitors?

a.Telaprevir should not affect the metabolism of her current medications.
b.Telaprevir is a strong inducer of cytochrome P450 (CYP) 2E1 and she should avoid taking acetaminophen while on triple therapy.
c.Telaprevir inhibits CYP 3A4 and should not be used in combination with drugs highly dependent on CYP 3A4 for clearance.
d.Boceprevir does not inhibit CYP 3A4 and you recommend changing to boceprevir-based triple therapy to avoid any interactions.

c. Correct.
Both telaprevir and boceprevir can inhibit CYP 3A4 and are contraindicated in combination with drugs highly dependent of CYP 3A4 for clearance and with drugs for which elevated plasma concentrations are associated with serious adverse events, such as atorvastatin and amlodipine. Patients can take acetaminophen while on protease inhibitor therapy to manage treatment-related side effects such as flu-like symptoms from interferon.

5. The patients asks you if she will qualify for a shorter duration of treatment for chronic HCV. Which of the following statements is CORRECT?

a.She will not be a candidate for shorter duration because she is a prior relapse.
b.She is a candidate for response guided therapy. If she has undetectable HCV RNA at weeks 4 and 12, she will be treated for 24 weeks only.
c.She is not a candidate for shorter duration because of the stage of fibrosis (F2).
d.There is no such thing as “shorter duration”. All patients are treated with triple therapy for 12 weeks and continue on pegylated interferon + ribavirin for an additional 36 weeks.

b. Correct.
Treatment naïve patients or prior relapsers who achieve extended early rapid virologic response (eRVR)- defined as undetectable HCV RNA at weeks 4 and 12 of therapy- can be treated for a total of 24 weeks with similar SVR rates to those treated for 48 weeks. This is termed response guided therapy (RGT). The American Association for the Study of Liver Disease (AASLD) recommends that those with cirrhosis (fibrosis stage 4) should be treated for 48 weeks regardless of their response at weeks 4 and 12. 6 This patient has stage 2 fibrosis and she may be a candidate for RGT. Some patients treated with boceprevir may also qualify for shorter duration of therapy based on their clinical characteristics and HCV RNA levels during treatment.

The patient is worried about side effects related to telaprevir. You inform the patient that in clinical trials for both boceprevir and telaprevir, the most common adverse events were related to pegylated interferon.

6. All the following statements regarding telaprevir-related side effects are true EXCEPT:

a.Telaprevir-based triple therapy is associated with more severe anemia than treatment with only pegylated interferon-ribavirin.
b.Nearly 50% of patients who receive telaprevir-based triple therapy will develop a skin rash.
c.Gastrointestinal side effects including nausea and diarrhea, are more common with telaprevir-based triple therapy.
d.In clinical trials, around 30% of patients had to discontinue all HCV drugs due to adverse events.

d. Correct.
In telaprevir clinical trials, the hemoglobin level decreased by an additional 1 g/dL in the telaprevir treatment groups compared with the groups treated with pegylated interferon-ribavirin. Skin rash was a common adverse event in patients receiving telaprevir occurring in 50% of patients. Severe rash occurred in 3% to 6%. Gastrointestinal side effects were more common in the telaprevir-based triple therapy arms of clinical trials compared to pegylated interferon-ribavirin alone arms. Around 10% of patients had to discontinue all HCV medications due to adverse events.

The patient starts combination therapy with telaprevir, pegylated interferon, and ribavirin. After 4 weeks of triple therapy, ALT is 41 and HCV RNA is 7,000 IU/ mL.

7. Which of the following would you advise?

a.Continue telaprevir, pegylated interferon and ribavirin and check HCV RNA at 12 weeks of therapy
b.Stop telaprevir and continue pegylated interferon and ribavirin for an additional 44 weeks
c.Stop telaprevir, pegylated interferon and ribavirin, no additional treatment at this time
d.Switch to boceprevir because the patient failed telaprevir-based therapy

c. Correct.
Triple therapy regimen with telaprevir has stopping rules for virologic futility as follows:
1. Patients who have HCV RNA > 1,000 IU/mL at weeks 4 or 12 should discontinue all medications as the likelihood of their achieving SVR is very low.
2. Patients with detectable HCV RNA level after 24 weeks of therapy should discontinue therapy. Switching to boceprevir is not indicated when a patient fails telaprevir-based triple therapy.

Triple therapy regimen with boceprevir also has stopping rules as follows:
1. Patients who have HCV RNA > 100 IU/mL at week 12 should discontinue all medications.
2. Patients with detectable HCV RNA level after 24 weeks of therapy should discontinue therapy.

1.The protease inhibitors telaprevir and boceprevir are direct-acting antivirals that were approved in 2011 to treat patients with chronic HCV infection genotype 1.
2.The addition of an oral protease inhibitor to pegylated interferon and ribavirin increased the sustained virologic response from 40% to 70%.
3.Protease inhibitors are prone to resistance and cannot be used as monotherapy.
4.The main adverse events associated with telaprevir in clinical trials were skin rash, anemia, pruritus, and diarrhea. Boceprevir was associated with anemia and dysgeusia.

If you enjoyed this CME you may also find this one interesting

Audio and Slides:
Understanding Resistance in Chronic HCV Infection: Lessons Learned From HIV and HBV
A CME discussion on how viruses become resistant to antiviral medications hosted by Dr. Jeffrey Burack with Dr. Steven Flamm, and Dr. Nancy Reau. Telaprevir and boceprevir are included in the topic, and the importance of  ribavirin as a backbone in future therapies.


And to stress what Nancy said earlier, the reason we haven't discussed resistance in HCV therapy to date is that the medications we have been using for the last 15 or so years do not act directly on the virus, and that is why resistance does not occur with their use. By contrast, there are many medications in the pipeline that we are going to talk about later, as well as the 2 that were just approved, that are targeted directly against one of the viral enzymes. And it's also important to know that the virus has many enzymes that help it replicate. The 2 recently approved antivirals act against just one of those enzymes, a protease.

I highly suggest listening to the audio and follow along by viewing the slides provided.

Click here for previous "Weekend Reading" articles.

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