Advertisement
Advertisement

Read Now: News and Research From IDWeek 2014

News

Abbvie's Potent HCV Drug Combination

March/April 2014

Abbvie (formerly Abbott Laboratories) is developing many drugs for the treatment of HCV. The corporation's first generation of drugs consists of the following agents:

  • ABT-450 interferes with the HCV proteins NS3/4A and it is taken once daily with a small dose (100 mg) of another drug called ritonavir (Norvir). The purpose of the small dose of ritonavir is to boost and maintain levels of ABT-450 in the blood. Ritonavir does not have activity against HCV and has only minimal activity against HIV at such a low dose.
  • ABT-267 (ombitasvir) interferes with the HCV protein NS5A and is taken once daily.
  • ABT-333 (dasabuvir) interferes with the HCV protein NS5B and is taken twice daily.

ABT-450, 267 and 333 are examples of DAAs (direct-acting antiviral agents).

Many clinical trials of these drugs have taken place. One of the latest studies whose results were released is called Pearl-III. This study was a phase III trial of the drugs mentioned above with or without the nuke ribavirin in participants who had not previously been treated and who did not have severe liver injury (cirrhosis). All participants had HCV genotype 1b.

Preliminary results from Pearl-III suggest that the combination of three DAAs being developed by Abbvie is extremely powerful, resulting in very high cure rates of about 99%. Furthermore, the combination appears to be as effective with or without ribavirin. Also, the combination of three DAAs appears to be safer than regimens containing ribavirin.

The Pearl-III study is important for other reasons. Historically, many of the problems associated with HCV treatment were blamed on exposure to interferon. However, the Pearl-III study was interferon-free and compared two regimens, one containing ribavirin and the other without ribavirin. The rate of side effects in Pearl-III was greater among ribavirin users.


Advertisement

Study Details

A total of 419 participants were randomized to receive one of the following regimens:

  • 3 DAAs + ribavirin: 210 participants
  • 3 DAAs + fake ribavirin (placebo): 209 participants

Although participants will only have been exposed to the study drugs for 12 weeks, researchers plan to monitor them for 60 weeks.

The doses of medicines were as follows:

  • ABT-450: 150 mg
  • ritonavir: 100 mg
  • ABT-267: 25 mg

All of the three drugs listed above were co-formulated (put into one pill) and taken once daily.

The dose of ABT-333 was 250 mg twice daily.

The dose of ribavirin was as follows:

  • for people who weighed less than 75 kg: 1,000 mg per day
  • for people who weighed 75 kg or more: 1,200 mg per day

The average profile of participants at the start of the study was as follows:

  • similar proportions of men and women
  • age: 49 years
  • most participants (70%) had minimal liver injury
  • 20% had a moderate amount of liver injury
  • 10% had extensive liver injury
  • HCV viral load: 2 million copies


Results

  • Among participants who received three DAAs + ribavirin: 99.5% (209 out of 210) had no detectable viral load at the 12th week of therapy (SVR12)
  • Among participants who received three DAAs + placebo, 99% (207 out of 209) had no detectable viral load at the 12th week of therapy (SVR12)

This difference between the two regimens suggests that a ribavirin-free regimen of three DAAs was statistically no worse than three DAAs + ribavirin (the technical term for this is "non-inferior").

Comparing both combinations to historical results based on the current standard of care -- telaprevir + interferon + ribavirin (assuming that this historical regimen resulted in a 75% cure rate) -- found that both regimens, three DAAs with and without ribavirin, were statistically superior.

Three participants in the current study did not develop SVR12 for the following reasons:

  • one participant taking three DAAs + ribavirin experienced treatment failure
  • two participants in the ribavirin-free arm stopped returning to the study clinic; one of them developed undetectable HCV at week 4 of the study

There was no impact of race, gender or genetics on the response to therapy.


Adverse Events

Researchers must note all adverse events that occur in a study to later analyse them and determine if they were caused by the medications used. Here are some adverse reactions reported:

Headache (generally of mild intensity):

  • 24% with both study regimens

Fatigue:

  • 22% with both study regimens

Differences in adverse events emerged as follows:

Itchy skin:

  • 3 DAAs + ribavirin: 12% of participants
  • 3 DAAs: 5%

Nausea

  • 3 DAAs + ribavirin: 11%
  • 3 DAAs: 4%

Weakness:

  • 3 DAAs + ribavirin: 11%
  • 3 DAAs: 5%

Difficulty falling asleep:

  • 3 DAAs + ribavirin: 9%
  • 3 DAAs: 3%

Cough:

  • 3 DAAs + ribavirin: 9%
  • 3 DAAs: 2%

Serious adverse events (SAE) occurred in four participants on each regimen. However, only one SAE -- a case of arthritis -- appeared to be linked to exposure to the three DAAs.

Differences in lab tests were distributed among the regimens' users as follows:

Anemia:

  • 3 DAAs + ribavirin: 7%
  • 3 DAAs: 1%

Hemoglobin (a protein that helps to transport oxygen to tissues) levels less than 10 grams per dL:

  • 3 DAAs + ribavirin: 9%
  • 3 DAAs: 0%

The dose of ribavirin had to be decreased in 19 out of 210 people (9%) because of anemia and other problems. However, all were still able to recover from HCV.

Bilirubin (a waste product; elevated levels of which can temporarily discolour the skin and whites of the eyes) levels more than three times the upper limit of normal:

  • 3 DAAs + ribavirin: 6%
  • 3 DAAs: 1%

ALT (alanine aminotransferase; a liver enzyme) levels greater than five times the upper limit of normal:

  • 3 DAAs + ribavirin: 1%
  • 3 DAAs: 0%

AST (aspartate aminotransferase; a liver enzyme) levels greater than five times the upper limit of normal:

  • 3 DAAs + ribavirin: 0%
  • 3 DAAs: 0%

The results from Pearl-III are compelling and show that a regimen of the three Abbvie DAAs is very powerful and generally safe. Furthermore, it appears that in some patients with only a small degree of liver injury, ribavirin is not necessary when used with the three DAAs in this study. Further studies of these drugs will be featured in a future issue of TreatmentUpdate.

Abbvie is developing its second-generation anti-HCV therapy whereby the company hopes to simplify a regimen to one pill, once daily, perhaps without ritonavir boosting. However, it will be several years before we will know if such a regimen can work in large numbers of participants.


Reference

Ferenci P, Nyberg A, Enayati P, et al. Pearl III: SVR ≥ 99% after 12 weeks of ABT-450/r/267 + ABT-333 ± ribavirin in treatment-naïve HCV genotype 1b infection. In: Program and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections, 3-6 March 2014, Boston, U.S. Abstract 29LB.




This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication TreatmentUpdate. Visit CATIE's Web site to find out more about their activities, publications and services.
 

No comments have been made.
 

Add Your Comment:
(Please note: Your name and comment will be public, and may even show up in
Internet search results. Be careful when providing personal information! Before
adding your comment, please read TheBody.com's Comment Policy.)

Your Name:


Your Location:

(ex: San Francisco, CA)

Your Comment:

Characters remaining:

Advertisement