Why Do People Respond to HCV Treatment Differently?

In a presentation at Digestive Disease Week in Chicago on May 7, researchers presented findings that outlined factors that contribute to the effectiveness of hepatitis C (HCV) treatment.

Not much was known about how HCV interacts with the infected Host. That is, until researchers from the University of Oxford set out to map the genetic interaction between the virus and its host. This was the first “big-data study” of its kind. According to the study, this information is important since, “outcomes of HCV infection and treatment depend on viral and host genetic factors.” Research findings showed “an interaction between host IFNL4 genotypes and an amino acid residue in the HCV NS5A protein determines HCV viral load.” The authors concluded that these findings are important because they “highlight systemic differences in the innate human response and discuss how these might relate to previous associations with spontaneous clearance and clinical treatment.”

Now, the research presented at Digestive Disease Week found that, in HCV patients with advanced cirrhosis, identifying the genetic makeup of patients can help doctors predict the likelihood that these patients will improve with direct-acting antiviral (DAA) drugs. This early knowledge could minimize the need for liver transplants, a new study suggests.

Antiviral pills can cure most HCV patients in a shorter time with fewer side effects than previously available interferon-based treatments. But some people with decompensated cirrhosis, a serious type of liver damage often accompanied by confusion, swelling, and jaundice, fail to improve or deteriorate further even after taking DAA therapy, the researchers said.

“Our findings further the move toward precision medicine,” said Lead author of the study, Winston Dunn, MD, associate professor at the University of Kansas Medical Center. “We can potentially use a person’s genetic makeup to identify individuals who can benefit most from HCV treatment, even at a very late stage in the progression of their liver disease.”

Dr. Dunn and his team hypothesized that there could be a genetic explanation for the differing outcomes. They focused on the Rs738409 single nucleotide polymorphism, a variation in a single base pair of DNA in the PNPLA3 gene. The gene provides instructions for making a protein found in fat and liver cells and is the most important genetic risk factor for both alcoholic liver disease and nonalcoholic fatty liver disease, according to the researchers. There are three genotypes an individual can have in the gene: CC, CG, or GG.

The doctors followed 32 people with decompensated cirrhosis at the University of Kansas Medical Center. These patients had initially achieved sustained virologic response (SVR), or elimination of HCV, after DAA treatment. Twelve to 48 weeks after SVR, researchers tracked changes in 2 measures that assess the severity of chronic liver disease: the Model for End-Stage Liver Disease (MELD) and the Child-Pugh (CPT) scores.

Of the 16 patients with the CG or GG genotypes, 5 experienced worsened MELD or CPT scores. In comparison, only 1 with the CC genotype declined in either their CPT or MELD results.

The findings suggested that screening for the CG and GG genotypes could help identify individuals who are less likely to recover after achieving a cure of their HCV, noted Dr. Dunn.

“Until now, we have not had a method to distinguish between the individuals who would recover given equal severity in baseline disease,” Dr. Dunn said. He added that his team would examine the underlying mechanisms that may explain why the presence of these genotypes lead to worsened health outcomes.