High Frequency of Tregs After Curing Hepatitis C Could Enhance Liver Cancer Risk

Accelerated production of regulatory T cells common with chronic hepatitis C infection did not return to normal levels in a group of patients who had been successfully treated with direct-acting antiviral (DAA) drugs, a recent study found.

Researchers from the University of Bonn in Germany, who have studied CD4+ regulatory T cells for years, found that the cells, often called Tregs, can reduce antiviral immune responses in people who are chronically infected with hepatitis C. The virus is a blood-borne illness that if left untreated can seriously damage the liver over time.

“We found that in chronic hepatitis C virus (HCV) infection, Tregs gradually expand during the course of infection and reduce antiviral immune responses, promote liver fibrosis and thus may enhance the risk for liver cancer,” lead author, Bettina Langhans, of the Department of Internal Medicine at the university, said in an email to MD Magazine.

Modern direct-acting antivirals (DAAs) “have revolutionized” hepatitis C therapy, providing successful outcomes to numerous patients, Langhans noted. Whether Tregs are normalized after the virus is cured is important because these cells may potently modify multiple immune functions—and thus, determine the further course of liver disease even after the virus has cleared the body.

Langhans and colleagues set out to investigate the expansion of Tregs in a study that compared DAA treatment to conventional interferon-based treatment.

The study involved 26 patients who had genotype 1 hepatitis C and were treated with the DAA drug sofosbuvir or a combination sofosbuvir-and interferon regimen. Within the first four weeks of treatment, all patients had a rapid decrease in serum hepatitis C-RNA levels and ultimately achieved a sustained virological response (SVR), an indication that the virus is no longer detected in the blood.

Researchers examined Foxp3⁺CD25⁺CD4⁺ T cells in patients at baseline, at the end of treatment, and at 12 and 24 weeks after SVR was achieved, as well as a year after treatment. Similar to previous studies, the frequency of Treg cells was significantly higher in patients with hepatitis C than in healthy control patients.

A serial long-term analysis showed that Treg cells decreased slightly after hepatitis C treatment but did not reach normal levels. On average, the frequencies of Treg cells among the two treatment groups remained at 36% to 44% higher than the healthy control group.

The results showed that DAAs “do not normalize the increased and activation status of Tregs even long-term after hepatitis C elimination,” Langhans noted in her email. “Thus, Tregs may persistently modulate functions of the immune system even after “cure” of hepatitis C and might contribute to rapid tumor recurrence and expansion reported to occur short-term after apparently successful DAA therapy in some patients with prior HCC [Hepatocellular carcinoma].”

Tregs could also be helpful in another way. High frequencies may be a biomarker to predict which patients will develop certain complications from DAA therapy.

The novel findings from this recent research are in line with other reports which also showed long-term persistence of Tregs after patients received interferon-based, DAA-free treatment.

“However, it is still unknown whether modern DAAs have higher risk for inhibited immune response than the older therapy,” Langhans added.

The study abstract titled, “Increased peripheral cd4+ regulatory t cells persist after successful direct-acting antiviral treatment of chronic hepatitis C,” appeared in December in the Journal of Hepatology.

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