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WASHINGTON -- Hepatitis D may be the loneliest hepatitis virus around, but it's still here and needs attention, several speakers said here at the Digestive Disease Week meeting.
"Even though it's been forgotten, it has unfortunately not been lost," said Joseph Ahn, MD, MS, director of clinical hepatology at Oregon Health & Science University in Portland.
The hepatitis D virus (HDV) was first recognized for its pathogenicity in the 1970s, and in the 1980s it was estimated that about 5% of all hepatitis B patients worldwide were co-infected with hepatitis D -- about 15 million people, Ahn said. (HDV is considered an "incomplete" virus because it cannot replicate on its own, instead .)
However, over the next two decades, interest in the disease appeared to wane. "HDV became more of a forgotten virus; people felt like it was not a major problem," Ahn said. "The [news] headlines said things like, 'Is This a Vanishing Disease?' There was less interest and diminished attention."
But the disease has remained, with ongoing outbreaks in the Amazon region, Greenland, Russia, and Africa, he continued. Localized clusters of disease have been reported in Burkina Faso as well as Taiwan, Vietnam, Turkey, Iran, and Italy. In the U.S. of 1,191 chronic hepatitis B patients in California found that among 499 of those patients who had been tested for hepatitis D, 8% were co-infected with that virus.
Decreasing Prevalence or Less Detection?
Although the virus continues to surface, its prevalence appears to be decreasing, Ahn said, citing increased hepatitis B virus vaccination, the use of universal precautions for HIV and hepatitis, and a natural decrease in the pool of hepatitis D patients who survived previous epidemics as possible reasons for the decrease. However, he added, it could also be that the numbers could be down due to lower rates of testing and detection.
"Why might that be?" he asked. Part of it may be due to physicians having less experience with HDV; few lectures are devoted to it in medical school. In addition, testing may be hard to come by, and those diagnosed with it tend to be people on the margins of society, such as the homeless and the undocumented who don't have regular access to medical care. "So it may be that we're looking for it less and there is less testing," said Ahn. "I think it's a combination."
So why should doctors care about HDV? First of all, "you can't manage or help what you don't know about," he said. In addition, hepatitis B patients' prognosis is worse if they're coinfected with HDV, and there are new therapies being developed that might help.
The American Association for the Study of Liver Diseases recommends HDV screening in select patients, including:
- HIV positive patients
- Patients who inject drugs
- Men who have sex with men
- Patients at risk for sexually transmitted diseases
- Immigrants from areas with high endemic rates of HDV
In addition, patients with low hepatitis B DNA levels and those with high ALT levels may be considered for screening.
Good Treatments Scarce
Treatments for HDV have been hard to come by, according to Patrizia Farci, MD, of the hepatic pathogenesis section of the National Institute of Allergy and Infectious Diseases, in Bethesda, Md. That's in part because the hepatitis D virus doesn't possess any enzymatic-specific function that can be easily targeted by conventional antivirals, she said.
And, to add insult to injury, HDV causes the least common but most severe form of viral hepatitis, leading to cirrhosis in up to 80% of cases by 10 years -- meaning that most HDV patients who need treatment already have an established cirrhosis, she said.
Currently, the only treatment options for HDV are antiviral therapy and liver transplant, Farci continued. Nucleoside and nucleotide analogues such as famciclovir (Famvir), adefovir (Hepsera) and tenofovir (Viread) have been found to have little to no effect on their own in treating HDV. Conversely, various studies have shown efficacy for interferon alpha, with various studies conducted from 2006-2014 showing a loss of HDV RNA at 24 weeks' follow-up ranging from 17% to 47% of patients.
However, adding antivirals to interferon doesn't seem to help, she said. of interferon and ribavirin found a 25% response rate for interferon alone after 24 weeks' followup compared with 18% for combined therapy with interferon and ribavirin, while of interferon combined with adefovir showed a 31% response rate for interferon combined with placebo compared with a 24% response for the interferon-adefovir combination.
The preferred type of interferon therapy is pegylated interferon, and it should be offered to both interferon-naive patients as well as those who haven't responded to conventional interferon. Therapy should be offered for 1 year; in those with a viral response, therapy should be continued until hepatitis B surface antigen (HBsAg) is lost, said Farci. It is contraindicated, however, in patients with decompensated liver disease, for whom transplantation is the only therapeutic choice.
New Compounds Being Explored
Although interferons are effective in some patients, they still have unpleasant side effects, so additional treatments are needed, Farci continued. One therapeutic category researchers are looking at is "entry inhibitors," compounds that act by interfering with hepatis B surface antigen (HBsAg) at the level of viral entry.
In of the entry inhibitor Myrcludex B, two of seven patients receiving Myrcludex B and five of seven patients receiving a combination of Myrcludex B and interferon were serum HDV RNA negative at Week 24 of therapy, compared with one of seven patients receiving interferon alone, she said. However, the effect did not last, and HDV RNA eventually reappeared in all patients. Myrcludex B also had no effect on titers of HBsAg, which was the study's primary endpoint.
Investigators are also looking at lonafarnib, a prenylation inhibitor. This type of compound interferes with prenylation of the large hepatitis D antigen, which is a critical part of virus assembly, Farci explained. One study of lonafarnib found that it did reduce HDV RNA levels; however, it was associated with serious gastrointestinal symptoms, including weight loss and intermittent vomiting.
A third category of treatment is nucleic acid polymers, which appear to block the release of HBsAg particles from infected hepatocytes. In -- known as REP 2139 -- combined with pegylated interferon, 7 of 12 patients were HDV RNA-negative at 1 year post-treatment, "the best results reported so far in the treatment of chronic hepatitis D," she said. However, the study was small and none of the patients had cirrhosis.
The mechanisms of actions of all three new compounds "remain to be fully elucidated and, as a consequence, concerns about safety remain," she said. "Thus, despite recent progress, the search for the right drug continues."