Published: Nov 14, 2014
BOSTON -- Evidence is mounting that new direct-acting agents against hepatitis C (HCV) can cure the disease when it recurs after liver transplant.
In a small open-label phase II trial, an investigational combination of HCV drugs led to sustained virologic response in 97% of patients, researchers reported here at the American Association for the Study of Liver Diseases annual meeting and online in the New England Journal of Medicine.
The report comes just days after investigators reported here that another drug combination had similar results in a three-center case series, although not all patients had complete data.
HCV is the leading indication for liver transplant in the U.S., but the virus always re-infects the new liver, often leading quickly to cirrhosis and even graft loss.
The investigational drugs are the so-called 3D combination :
- the NS5A inhibitor ombitasvir,
-the ritonavir-boosted protease inhibitor ABT-45,
-and the non-nucleoside NS5B polymerase inhibitor dasabuvir.
The drugs are given with ribavirin, a nonspecific antiviral.
Investigators led by Paul Kwo, MD, of the Indiana University School of Medicine in Indianapolis enrolled 34 liver transplant recipients with recurrent genotype 1 HCV but either no or mild fibrosis.
Nearly three-quarters of the patients (71%) had previously been treated with pegylated interferon and ribavirin, and 76% had the unfavorable non-CC IL28B genotype, which predicts an increased risk of failing interferon-based therapy. The median time since transplant was 3.3 years, and 85% of patients were on tacrolimus-based immunosuppression.
They were given the 3D combination for 24 weeks, with the dose of ribavirin and any subsequent dose modifications in response to anemia left up to the treating physician.
The primary endpoint of the single-arm study, dubbed CORAL-1, was sustained virologic response 12 weeks after the end of treatment (SVR12), defined as a plasma HCV RNA level of less than 25 IU per milliliter.
Of the 34 patients, 33 reached SVR12 and remained without evidence of HCV infection at 24 weeks post-treatment, Kwo and colleagues found.
All patients had HCV RNA below 25 IU per milliliter by week four of therapy and remained below that level at the end of treatment. But one patient relapsed 3 days after treatment ended, with resistance-associated variants in all three of the regimen's viral targets that emerged during treatment.
Adverse events were common -- mostly fatigue, headache, and cough -- but most were mild or moderate, the researchers reported. There were no cases of rejection and no deaths.
One patient stopped the study drugs after 18 weeks, because of rash, memory impairment, and anxiety that researchers thought might be related to the medications. The patient reached SVR12 despite the premature stop, they reported.
As well, 19 patients had their ribavirin dose modified, nine of them owing to declining hemoglobin levels, a known side effect of the drug.
This all-oral, interferon-free regimen eradicated HCV in patients "who are at high risk for severe illness and death and for whom treatment options are currently limited," the researchers concluded.
The report came after other researchers told the meeting that the combination of sofosbuvir (Sovaldi) and simeprevir (Olysio) also yielded high SVR12 rates in transplant patients -- more than 90% -- but with a shorter treatment duration of just 12 weeks.
The data were immature; both drugs were only recently approved (and the combination was off-label during the study period) and so many patients either remain in treatment or have not reached the 12-week time point after the end of therapy.
One key issue is that the drugs are expensive, commented Susan Orloff, MD, of the Oregon Health and Science University in Portland, who was not involved in either study.
"The major issue with all of the direct-acting agents is they are very expensive and insurance companies are not covering these for our patients," she told MedPage Today. "Physicians have to appeal, appeal again, and appeal a third time ... It's a huge process."
Indeed, she said, the use of the combination earlier in the disease course might prevent the need for transplant, saving $200,000 or so for the procedure itself and also about $10,000 a year for immune suppression.
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