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Research Alert: Study Casts Doubt on "Shock and Kill" Cure Strategy

Daclatasvir and Asunaprevir -- A Potent Interferon-Free Regimen

July 2012

HCV-positive people whose HCV levels have not sufficiently responded to therapy are often referred to as "null responders" by researchers. Some of these people may show much better responses when retreated with triple therapy that includes boceprevir or telaprevir.

However, peginterferon is at best an unpleasant drug because of its side effects, including irritability, anxiety, difficulty falling asleep and staying asleep, fatigue and depression. Ribavirin can accentuate interferon-related side effects and cause anemia. Therefore, alternatives to these two drugs are needed.

Daclatasvir (BMS-790052) inhibits the HCV NS5A protein and in lab experiments may be effective against several genotypes of this virus.

Asunaprevir (BMS-650032) inhibits the HCV NS3 protein and has activity against genotypes 1 and 4.

Researchers in Japan conducted a phase II study in two populations, as follows:

  • 21 null responders -- people who have had less than a 2-log fall in HCV viral load after 12 or more weeks of peginterferon and ribavirin
  • 22 people who could not tolerate or in whom interferon and/or ribavirin was not recommended treatment

All participants received experimental therapy with the following:

  • daclatasvir 60 mg once daily + asunaprevir 200 mg twice daily, both drugs taken for 24 consecutive weeks

After this time, participants were monitored for 24 weeks.

The average profile of participants was as follows:

  • 35% men, 65% women
  • age -- 65 years
  • HCV viral load -- 5 million IU/ml


Results

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After four weeks of therapy, 70% of participants had a viral load less than 15 IU/ml.

At the end of 12 weeks of therapy, 88% had undetectable levels of HCV in their blood.

Overall, 24 weeks after experimental therapy ended, 77% of participants were cured of HCV. The distribution of cure rates was as follows:

  • 91% of null responders were cured
  • 64% of people who could not tolerate standard therapy were cured

Analysis of blood samples revealed that in almost all cases of virologic failure, the concentration of study drug was less than ideal. Moreover, most cases of virologic failure were associated with a mutation called Y93H, found in NS5A.


Side Effects

Serious adverse effects occurred in five patients, mainly high fever.

Three participants left the study prematurely due to elevated bilirubin and elevated liver enzymes.

Study drugs did not cause changes to heart rhythms.

No one died during the study.

Common side effects in 27% or more of participants were as follows:

  • headache
  • runny nose and/or sore throat
  • increased levels of the liver enzyme ALT

Some participants developed mild diarrhea while five others reported constipation.

In summary, the combination of asunaprevir and daclatasvir is very potent and likely better tolerated than regimens that include interferon. Further clinical trials are planned or underway with these two new promising anti-HCV agents.


Reference

Suzuki F, Ikeda K, Toyota J, et al. Dual oral therapy with the NS5A inhibitor Daclatasvir (BMS-790052) and NS3 protease inhibitor asunaprevir (BMS-650032) in HCV genotype 1b-infected null responders or ineligible/intolerant to peginterferon/ribavirin. In: Program and abstracts of the 47th annual meeting of the European Association for the Study of the Liver, 18-22 April 2012, Barcelona, Spain.




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.
 

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