While hepatitis B might not always be front and center in the minds of busy primary care physicians, they can play a proactive role in identifying more undiagnosed patients and ensuring that they get potentially life-saving monitoring for years to come.
In the United States, an estimated 847,000 people are living with chronic hepatitis B (HBV) infection, although roughly two-thirds of them don't realize it, according to clinical guidance for vaccination and screening published Dec. 5, 2017, by Annals of Internal Medicine. Not only does that lack of knowledge boost the likelihood of transmission, but it also undercuts monitoring for liver damage, including cancer, said Brian McMahon, MD, MACP, a coauthor.
“Liver cancer is the only cancer in the U.S. for which the death rate has increased over the last couple of decades,” said Dr. McMahon, who is the medical and research director of the Liver Disease and Hepatitis Program for the Alaska Native Tribal Health Consortium in Anchorage. “It's because of the lack of awareness about the fact that you need to diagnose chronic hepatitis and then treat those people appropriately if they need treatment, and then monitor them for the development of liver cancer.”
Along with the recent guidance published in Annals, there have been several other recent reports and other guidance on both HBV prevention and treatment, including from the federal Advisory Committee on Immunization Practices (ACIP), the World Health Organization, and the American Association for the Study of Liver Diseases (AASLD). All have reprised a common theme: Clearly vulnerable individuals are too often missed. One recent study, published on Dec. 26, 2017, by Annals, found that 44.2% of HIV patients were candidates for HBV vaccination. But after a year in HIV care, only one out of every 10 had been protected.
While liver cancer makes up only 2.4% of all new malignancies, according to National Cancer Institute data, its mortality trends are among the worst in recent years. From 2003 to 2012, cancer deaths in the U.S. have continued to decline by an average of 1.5% annually, according to an analysis published in 2016 in the journal Cancer. But fatalities from liver cancer are up by an average of 2.8% annually in men and 2.2% in women.
Hepatitis B and C remain significant risk factors, along with others such as obesity and heavy alcohol consumption. But earlier diagnosis, paired with close monitoring, can make a life-saving difference. Overall, just 18% of liver cancer patients survive at least five years, but that rate increases to 31% if the disease is diagnosed while still confined to the liver, according to National Cancer Institute data.
In the U.S., many residents are already protected through vaccination, particularly if they were born after 1991, when universal childhood vaccination was recommended by ACIP.
But immigrants moving to the United States from other regions of the world where HBV is more common, such as Asia, can go either undetected or unmonitored for viral-related complications until it's too late, said Norah Terrault, MD, MPH, a professor of medicine in the division of gastroenterology and hepatology at the University of California, San Francisco. “It's not rare for us to get referred a patient who is newly diagnosed and they are presenting with liver cancer,” she said.
In the recent Annals guidance, a table details the countries and regions of the world where HBV prevalence is 2% or higher, a list that includes all of Africa and Asia as well as nearly all of Eastern Europe and the Middle East, along with selected countries elsewhere. Individuals from these regions should be screened for HBV, wrote the authors of the clinical guidance, which was developed by ACP in conjunction with the CDC.
A partial list of other groups clinicians should screen includes men who have sex with men, people who are infected with HIV or those who inject drugs, those with hepatitis C virus (HCV) infection, and pregnant women, and any babies born to mothers already infected. Plus, doctors should check for the virus in patients who are about to start chemotherapy or treatment with other immunosuppressive drugs, said Jordan Feld, MD, MPH, who chairs the hepatitis B special interest group at AASLD.
Patients may not realize that they are infected or may have forgotten because the HBV hasn't been active for years, said Dr. Feld, a hepatologist at the Toronto Centre for Liver Disease. “That's where they [doctors] can honestly save lives,” he said, by screening prior to treatment. Otherwise, he said, the risk is that the patient gets an immunosuppressive drug “and boom, the hepatitis B comes roaring back.”
The ACP/CDC guidance also includes a lengthy list of individuals who should be vaccinated if they haven't been already. Along with routinely vaccinating pregnant women, the authors recommend protecting various at-risk groups, including those with HIV infection, adults with chronic liver disease or end-stage kidney disease, health care workers vulnerable to blood exposure, individuals living with those who are already infected, and any adult traveling to a region with high rates of HBV.
“Hepatitis B is one of the most easily transmitted viruses, as far as a virus that can cause a chronic infection goes,” Dr. McMahon said. Plus, he said, “The virus does survive on environmental surfaces for indefinite periods of time.”
For that reason, health care workers can be vulnerable even if they aren't engaging in any other risky behaviors, Dr. McMahon said. And given that the virus is contracted more easily than HIV, anyone who is “very sexually active” should be vaccinated, although he quickly added, “We don't know what the magic number of lifetime partners is” to fall into that category.
Speaking personally, and not in his role as an author of the ACP/CDC guidance, Dr. McMahon pointed out that since so many groups already fall under the at-risk categories, and since HBV can be asymptomatic, “why not go all of the way, and vaccinate everyone,” he said. But he's not surprised that some studies, such as the recent Annals analysis involving adults with HIV, indicate that many still miss out. Until HBV immunization becomes routine for adults, such as it is for tetanus, doctors won't make it a regular practice and may not even keep the vaccine on hand, he said.
Working up to treatment
If hepatitis B is suspected, a battery of blood tests is available to determine the presence and the activity of the virus, said Tarek Hassanein, MD, FACP, who directs the Southern California GI & Liver Centers. When giving presentations to primary care doctors, Dr. Hassanein typically talks about “the rule of three” as a good first step approach.
Typically, Dr. Hassanein starts by ordering a panel of three tests: hepatitis B core antibody to see if the patient has been exposed, hepatitis B surface antigen to look for chronic infection, and hepatitis B surface antibody to determine immunity to the virus. If all tests come back negative, the patient has never been exposed, and the vaccine can be administered, Dr. Hassanein said.
In addition, further workup is not needed for patients who test positive for the hepatitis B surface antibody, because they're already immune to HBV, Dr. Hassanein said. However, if the patient is surface antigen-positive, further tests will be needed to characterize the type, he said. These include hepatitis B e-antigen, e-antibody, and a viral DNA test. “These three tests can tell me exactly the type of chronic infection,” Dr. Hassanein said.
Meanwhile, blood testing for liver enzymes can indicate if there is liver inflammation or other damage, Dr. Hassanein said, while Dr. McMahon noted that a low platelet count can suggest the possibility of cirrhosis and portal hypertension. AASLD, in its 2016 chronic hepatitis B treatment guidelines and 2018 treatment guidance, also recommends screening for HIV, HCV, and the hepatitis delta virus (HDV) as part of the workup.
Given that hepatitis B is a dynamic disease, with the diagnosis often occurring long after the time of infection, Dr. Feld suggests that physicians repeat bloodwork over the course of at least several months to get a sense of how the HBV is progressing.
“If you look at the liver tests or the hepatitis B tests at one point in time, you may get a false sense of security or a false sense of concern,” Dr. Feld said. For instance, if the liver enzymes are initially normal, test again in six months to see if that's changed, he said. If they're initially abnormal, test again, but sooner than six months.
Dr. Hassanein's “rule of three” guidepost also applies to treatment. Three drugs, he said, are currently the preferred first-line medications: the oral drugs entecavir and tenofovir (two forms), as well as an injection drug, interferon-alfa.
“Most patients say, ‘No injections, give me the pills,’” Dr. Hassanein said. Typically after several months of taking the pills, the patient's virus level is negative and liver tests are normal, although the treatment should continue indefinitely, he said.
One advantage of the newer version of tenofovir, approved by federal officials in 2016 and dubbed TAF for tenofovir alafenamide, is that it doesn't appear to pose any elevated risk for the kidneys or the bones, Dr. Terrault said. While those side effects are relatively rare, primary care doctors don't have to check for them with TAF, as they do with the older version of tenofovir, called tenofovir disoproxil fumarate, or TDF, she said. Price may also become a consideration, however, Dr. McMahon said, noting that TDF will likely become generic by the end of 2018 and its cost is anticipated to be much lower.
If a patient does test positive for hepatitis B surface antigen, it's useful to get a baseline liver ultrasound for monitoring moving forward, Dr. Feld said. The 2009 AASLD practice guidelines recommend regular imaging to check for liver cancer every six to 12 months for specific categories of patients, including anyone with cirrhosis or a family history of liver cancer, starting after age 40 years for Asian men and after age 50 years for Asian women and beginning even earlier, after age 20 years, for those of African descent. But most practitioners have extended the start of screening for patients who don't fit into any one of the above categories to after age 40 years for men and after age 50 years for women, according to Dr. Feld.
Risk of liver cancer persists even if blood tests show very inactive disease and the patient's liver enzymes are normal, Dr. Feld said. One challenge with the years of imaging, he said, is “surveillance fatigue” if the ultrasounds continue to be normal, lulling both the patient and doctor into a false sense of security. Since cancer risk increases with age, he said, “It's important not to let that surveillance fatigue happen.”
Primary care doctors should keep in mind that ultrasounds can vary in quality, either because the medical center where they're performed doesn't treat a lot of liver disease or the patient is difficult to image for some reason, such as obesity, Dr. Feld said. One option is to order an alpha-fetoprotein (AFP) test as well, he said, while keeping in mind that levels of the blood tumor marker could be elevated for reasons other than liver cancer or might not rise at all if the malignancy is quite small.
As they treat and monitor their hepatitis B patients, likely for years, physicians must be ready for unanticipated curveballs. For instance, if a physician cures a patient's hepatitis C, a relatively inactive hepatitis B virus might unexpectedly “wake up,” Dr. Hassanein said. Without the suppressive effect of hepatitis C on HBV, the virus has a free environment in which to replicate, he said.
Doctors should also continue to counsel HBV patients about other risk factors they can reduce, such as avoiding alcohol, achieving a healthy body weight, and keeping diabetes under control, Dr. Terrault said. “We want to minimize any other second hits to the liver,” she said.
Meanwhile, pharmaceutical companies are racing to develop better treatments, with potentially new types of antivirals and immune-based therapies in the pipeline, Dr. Feld said. “Hopefully over the next three to five years, there will be progress, and we may have treatments that are more likely to be finite and curative as opposed to long-term suppressive.”