15 / 2020
In a cooperation project of the German Research Society (Deutsche Forschungsgemeinschaft, DFG) between the Hospital of the Goethe University at Frankfurt/Main and the Paul-Ehrlich-Institut, researchers have identified four adjacent point mutations (four-point mutation) in the genome of the hepatitis-B virus, which, in the cohort studies, were associated with a very good prognosis for the clinical course of a chronic hepatitis B infection. This four point mutation could serve as biomarker for classifying the disease and as an aid for further therapeutic action in patients with a hepatitis-B infection. The results are reported in JCI Insight in its online version of 15 October 2020.
A chronic hepatitis B virus (HBV) infection affects around 257 million people world-wide and is one of the major causes of severe liver diseases and liver cancer. The individual risk of progressive liver disease or the development of liver cancer is variable and depends both on the characteristics of the virus and factors in the infected the person. Currently available antiviral treatment strategies are cost-intensive, long-term treatments that may involve considerable adverse effects. For that reason, it is important to have prognostic markers to identify the target group that will benefit from the treatment to a particularly high degree.
Patients who do not meet the required treatment criteria need to receive follow-up medical treatment, as they continue to have an increased risk of progressive disease and the development of liver cancer. It is therefore desirable to have prognostic biomarkers which provide information on the further clinical development. Established biomarkers include the viral load (amount of virus DNA in the blood) or the determination of the amount of surface antigen of the virus in the blood. In the meantime, however, other biomarker candidates have been detected, some of them partly refer to one or multiple (neighbouring) point mutations in the virus genome. However, so far, they have not become part of clinical every-day practice. They include gene polymorphisms and mutations such as the double mutation A1762T/G1764A (BCP double point mutation), the most frequent mutation in the basal core promoter (BCP), which, in some studies, were associated with course of the disease and response to treatment.
In cooperation with researchers in Italy, researchers in the team of Dr Kai-Henrik Peiffer, Senior Doctor at the Medical Hospital 1 of the University Hospital at Frankfurt, Professor Stefan Zeuzem, Decan at the Medical Department of the Goethe University at Frankfurt, and Professor Eberhard Hildt, head of Division Virology of the Paul-Ehrlich-Institut, have teamed up to identify biomarkers for the clinical forecast of a chronic hepatitis B infection. For this purpose, certain regions of the hepatitis B virus genome were sequenced in serum samples of 560 inactive HBV carriers in Europe. Although inactive HBV carriers carry the virus, they do not show any signs of a liver inflammation or relevant liver damage. In blood samples of these patients, the research team for the first time identified an obviously wide-spread and prognostically relevant four-point mutation (GCAC1809-1812TTCT) – four-point mutation of adjacent nucleic bases – in a certain virus genome area (Kozak sequence). This mutation was found in 42 percent of all samples and was closely associated with both the BCP double point mutation and – which is good news for the affected persons – with low levels of HBV DNA in the blood. In-vitro studies confirm this favourable connection. In addition, this four-point mutation was not found in any of the 125 patients with HBV associated liver cirrhosis (advanced liver restructuring).
The conclusion which the research team drew from this analysis and others was that there is a close association between four-point mutations and an inactive carrier status (non-active hepatitis B infection). For the BCP double mutation, however, a strong correlation was identified with the occurrence of liver cirrhosis, however, only if a four-point mutation was missing. The four-point mutation thus frequently exists in inactive HBV carriers and seems to compensate for the BCP double point mutation, which is associated with prognostics for a worse outcome.
"Our data suggest that the four-point mutation we have described may be a reliable biomarker for the prognosis of a favourable clinical course of a hepatitis B infection,"
stated Dr Kai-Henrik Peiffer, explaining the significance of the results.
Updated: 28.10.2020
