Antiviral duo found effective for hepatitis E despite virus mutations

Hepatitis C medications help to clear hepatitis E virus from 2 chronic patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A combination of the antiviral medications ribavirin and sofosbuvir efficiently cleared the hepatitis E virus (HEV) from two chronically infected patients despite the emergence of mutated virus strains in their bodies over time, a study shows.

Lab studies indicated that while these mutations did make the virus more resistant to antiviral treatments, a high enough dose of the combination therapy, which was originally developed for hepatitis C, is likely able to overcome those defense mechanisms.

“In both cases, the combination therapy was more effective than treatment with just one active ingredient,” André Gömer, one of the study’s co-first authors at the Ruhr University Bochum, in Germany, said in a university press release. “The viral [molecules] in the blood and stool initially dropped almost to the detection limit.”

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Study results ‘inform the next generation of antiviral treatments’

“Our results provide novel insights into evolutionary dynamics of HEV during treatment and thus inform the next generation of antiviral treatments,” researchers wrote.

The findings were published as a short communication, titled “Dynamic evolution of the sofosbuvir-associated variant A1343V in HEV-infected patients under concomitant sofosbuvir-ribavirin treatment,” in JHEP Reports.

As with other forms of hepatitis, hepatitis E is characterized by inflammation of the liver. It is mainly transmitted through contaminated food or drinking water.

Hepatitis E, which is caused by an infection with the HEV, often does not lead to any notable symptoms, and when it does, symptoms are typically mild and resolve over time. While antiviral medications do not specifically target this type of hepatitis, they’re usually not required to treat most people.

However, people who are pregnant or immunocompromised, or have other pre-existing liver problems may be more susceptible to chronic or serious complications that necessitate treatment.

In the absence of specific therapies for hepatitis E, researchers have focused on repurposing existing antiviral drugs. These include sofosbuvir (sold as Sovaldi) and ribavirin (sold as Virazole, with generics available) that are used to treat hepatitis C.

Even though drugs such as ribavirin, interferon and sofosbuvir have shown potential, the rapid emergence of resistant variants poses a considerable challenge.

Hepatitis-causing viruses can mutate to escape effects of antiviral therapies

However, as hepatitis-causing viruses can mutate by making small changes in their genetic code to escape the effects of antiviral therapies, the emergence of treatment-resistant variants can limit treatment success.

Indeed, recent analyses indicate an HEV mutation called A1343V is associated with viral relapse in patients treated with sofosbuvir, the researchers noted.

“Even though drugs such as ribavirin, interferon and sofosbuvir have shown potential, the rapid emergence of resistant variants poses a considerable challenge,” said Benjamin Massoumy, MD, a study author and professor at Hannover Medical School, in Germany.

In the study, scientists described the effects of such mutations in two patients with chronic HEV infections who were being treated with a combination of ribavirin and sofosbuvir.

Both patients were organ transplant recipients on chronic immunosuppressive therapies, which the researchers deemed the likely cause of their chronic HEV infections. They had been previously treated with ribavirin alone but the virus had not successfully been cleared.

The presence of HEV was monitored by measuring levels of its genetic material, called RNA, in the blood and stool. RNA levels of HEV in the blood and stools of both patients dropped significantly after they started the combination treatment. The levels eventually rose in the stool of both patients, but remained generally low.

For one patient, the infection did resolve completely over time. The other patient eventually had a complete absence of HEV RNA in the blood and stool after another course of ribavirin.

“Combination therapy with sofosbuvir should be considered in cases of severe courses of chronic hepatitis E after failed ribavirin monotherapy,” said Katja Dinkelborg, MD, the study’s other co-first author at Hannover Medical School.

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Stool samples analyzed to identify HEV mutations

The scientists then conducted genetic analyses on the patients’ stool samples to identify HEV mutations that might have influenced treatment efficacy over time. Multiple HEV variants were detected, and those containing the A1343V and G1634R mutations in particular were found to accumulate during treatment.

To learn more, the team then assessed the effects of ribavirin/sofosbuvir on these different versions of the HEV in laboratory studies. They found the combination treatment effectively controlled the growth, or replication, of HEV, but did so less efficiently against variants carrying the A1343V mutation, alone or in combination with G1634R.

These differences became less pronounced when the concentrations of the medications were increased. At the highest concentrations of the medications, viral replication was found to be low, regardless of the viral strain.

Overall, the findings indicate that while the A1343V and G1634R variants may contribute to viral persistence, high enough doses of the combination therapy are likely able to overcome this resistance.

Given that only a few studies have investigated the issue, “future studies should systematically investigate the effects of concurrent treatment and drug doses, while monitoring HEV diversity,” the scientists wrote.