Triple combination cures HCV patients that don’t respond to established dual treatment.

Hepatitis viruses cause inflammation of the liver. The most common types are hepatitis A, B and C. While hepatitis A virus only causes acute, short-term infections, hepatitis B and C viruses can cause both acute and chronic infections leading to long-term liver problems. There are vaccines to treat hepatitis A and B, but not for hepatitis C. Chronic HCV infections can lead to cirrhosis (scarring of the liver) or liver cancer. According to the Centers for Disease Control and Prevention (CDC), approximately 2.7-3.9 million people in the United States have chronic hepatitis C. In addition, approximately 75%–85% of people who become infected with Hepatitis C virus develop chronic infections. In 2014, just over 30,000 cases of acute HCV infections were reported in the US alone.

Some patients with chronic hepatitis C infections are not successfully treated with current therapies, including the most advanced dual combination therapies. For these patients, if they have no urgent indications, the recommendation is typically to hold off on further treatment until new therapies are developed.

Researchers at the University of Colorado may have a solution - a new triple combination therapy - for these patients, who David L Wyles, Chief of Infectious Diseases Denver Health, Medical Center, University of Colorado and the lead author of the study, considers to be “one of the most difficult-to-treat populations studied thus far with new direct-acting antiviral (DAA)regimens.”

Wyles and his colleagues conducted two international Phase II clinical trials with two separate groups of patients with HCV infections who previously failed treatment with an oral DAA combination that included an NS5A inhibitor. The patient groups included those with genotype 1 (GT1) and those with GT1, 2 or 3. The latter group not only failed to respond to an initial DAA combination, but also had characteristics suggesting failure to other treatments was likely, such as the presence of resistance associated substitution (RAS) viral mutations. Patients with GT1 and GT3 tend to respond more poorly to DAA therapies and also to have cirrhosis and prior interferon failure.

 According to the researchers in their paper published in July in the journal Hepatology: "Effective treatment options for people who have failed the current generation of all-oral DAA regimens will require a combination of drugs of sufficient potency to overcome multiple negative predictors, while simultaneously presenting a high barrier to resistance to overcome baseline RASs (potentially multi-class) and prevent emergence of new RASs.”

The results of the Phase II trials suggest that a new once-daily triple-drug regimen under evaluation as a fixed-dose oral combination for HCV may be the therapy that HCV patients have been waiting for. The oral triple combination includes n NS3/4A protease inhibitor (grazoprevir 100 mg); a "next generation" pan-genotypic NS5A inhibitor (ruzasvir 60mg); and an NS5B polymerase nucleotide inhibitor (uprifosbuvir 450mg).

In the C-SURGE trial with patients with GT1 infections that were unresponsive to a commercially available DAA treatment, some received the triple combination drug with additional ribavirin (RBV, 800-1400mg/day) for 16 weeks and others received just the triple combination drug for 24 weeks. Several additional patients with GT1, GT2 or GT3 that were resistant to an experimental short course of DAA also received the triple regimen and RBV for 16 weeks. The patients in this trial, according to Wyles, are the most difficult to re-treat and more representative of the small percentage of patients who fail currently available HCV treatments.

In a separate C-CREST trial, none of the patients had cirrhosis, which according to Wyles complicates re-treatment and decreases response. The scientists found that the treatment was well tolerated. As expected, more adverse events occurred in patients taking RBV. Notably, the adverse event profiles were generally similar in cirrhotic and noncirrhotic patients. Only one patient in each trial dropped out. All patients who completed the study achieved the primary efficacy goal of sustained virologic response (SVR), or the successful elimination of the hepatitis C virus, whether they received RBV or not and across of three genotypes. 

Noted Wyles: "The lack of virologic failures is impressive, particularly in the very difficult to treat C-SURGE study population. However, further studies are needed to determine if shorter durations and the omission of RBV from the treatment regimen maintain this high cure rate."