Gene Variation Predicts Recovery in Decompensated Hep C

Damian McNamara

May 07, 2017

CHICAGO — For people with both hepatitis C infection and advanced cirrhosis, genetic variability could predict the likelihood of clinical recovery after a sustained virologic response to direct-acting antiviral therapy, a prospective cohort study reveals.

A virologic cure is achieved by 90% to 95% of people with hepatitis C cirrhosis who are treated with direct-acting antiviral therapy, said investigator Winston Dunn, MD, from the Kansas University Medical Center in Kansas City, during a press briefing held in advance of Digestive Disease Week (DDW) 2017.

"Unfortunately, about 5% of people with hepatitis C have the most serious form — decompensated cirrhosis — and some fail to clinically improve, or even worsen, after sustained virologic response," he reported.

"The entire point of our project was to find factors that will predict recovery and help clinicians stratify patients for transplant or closer observation," said lead investigator Anusha Vittal, MBBS, an internal medicine resident at Kansas University Medical Center. The goal was "to identify those who are not likely to improve, even after achieving sustained virologic response," she told Medscape Medical News.

The investigators, hypothesizing that there could be a genetic explanation for what physicians see in the clinical setting — that some patients fare better than others — assessed PNPLA3, a gene commonly associated with risk for steatosis in both alcoholic and nonalcoholic liver disease.

"PNPLA3 has been associated with progression in people with active disease," Dr Vittal explained. "We thought the factor affecting progression could also be affecting recovery after sustained virologic response."

The team used cheek swabs to collect DNA from 30 people with Child–Pugh class B or C cirrhosis due to hepatitis C infection who were treated with interferon-free direct-acting antiviral therapy and achieved a sustained virologic response.

Three patients had GG rs738409 base pairs, 11 had CG base pairs, and 16 had CC base pairs. Clinical factors and demographic characteristics were similar in these three groups, except mean body mass index was higher in the CC group than in the pooled GG and CG group (35 vs 29 kg/m²; P = .03).

The primary outcomes were changes in Child–Pugh and Model for End-Stage Liver Disease (MELD) scores after therapy. Patient response was assessed 12, 24, and 48 weeks after the achievement of sustained virologic response.

The investigators compared recovery by genetic polymorphism.

Table. Changes in Clinical Scores

Mean Score CC Genotype CG or GG Genotype
Baseline    
   Child–Pugh 8.6 7.6
   MELD 13 14
After sustained response    
   Better Child–Pugh, % 81 36
   Worse Child–Pugh, % 0 21
   Better MELD, % 50 29
   Worse MELD, % 0 29

 

On multivariable linear regression, after adjustment for confounders, Child–Pugh score was 1.7 points higher after treatment in people with a CG or GG genotype, and MELD score was 2.3 points higher.

"Patients with a higher MELD score tend to do worse," Dr Dunn explained. Therefore, genotype "should be a factor in determining which patients with decompensated cirrhosis should be considered for liver transplant."

 
This is a move toward precision medicine.
 

"This is a move toward precision medicine," he added, in which a healthcare plan is individualized for each patient. Currently, however, testing to determine DNA base pairs is only available in the laboratory setting.

"If we can figure out personalized medicine to the point of genetics indicating whether someone will respond or will not respond, that is the future of medicine. This is one small example of that, but that's the strength of this study," said Grace Elta, MD, from the University of Michigan in Ann Arbor, who is chair of the DDW.

However, this was "a small subset of patients with hepatitis C — those with end-stage liver disease who are ready to be transplanted — and even then it wasn't 100% accurate on who was going to respond and who wasn't," she told Medscape Medical News. "You're probably going to try to treat people anyway, even if they are negative, because of that lack of 100% accuracy."

"Is it really going to alter management right now? Maybe not, but it certainly opens the door to personalized medicine," she added. "It's a really cool development, but the practicality of it right now is limited."

Next, Drs Dunn and Vittal and their colleagues plan to investigate the association between these genetic findings and worse health outcomes, including the ways in which fatty liver disease and insulin resistance affect clinical recovery after treatment with direct-acting antivirals, they report.

The Frontiers Pilot and Collaborative Studies Funding Program provided financial support for this study. Dr Dunn, Dr Vittal, and Dr Elta have disclosed no relevant financial relationships.

Digestive Disease Week (DDW) 2017: Abstract Sa1535. Presented May 6, 2017.

Follow Medscape Gastroenterology on Twitter @MedscapeGastro and Damian McNamara @MedReporter

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