HAV outbreaks prompt robust public health response

Much attention has been paid to hepatitis B and C viruses, as is evident from public health programs and the drug development pipeline. But three other hepatitis viruses also cause disease in humans: hepatitis A, D and E.

HAV, especially, has been a cause of outbreaks in the United States, with cases increasing dramatically in recent years. As of June 21, 24 states had reported 20,512 cases of HAV in a multistate outbreak that was first identified in 2016, including 11,776 hospitalizations and 194 deaths, according to the CDC.

In a recent study published in MMWR, Monique A. Foster, MD, an epidemiologist in the CDC’s Division of Viral Hepatitis, and colleagues analyzed reports of HAV in the U.S. from 2013 to 2018. The results showed that HAV infections increased by nearly 300% in the U.S. between 2016 and 2018 compared with 2013 to 2015, driven by infections associated with people who report drug use or homelessness. The increases are expected to continue.

Source: CDC

“We are in the middle of another multistate HAV outbreak that exploded in 2018 and is mainly in homeless people and in people who use drugs,” Foster said during an interview.

After years of declines, the U.S. began to see a rise in HAV cases from 2012 to 2013 because of a large multistate outbreak associated with pomegranate arils imported from Turkey, according to the CDC. That was followed by a44% increase in cases from2015 to 2016 due to two outbreaks linked to imported foods.

“While transmission can be mitigated by good hand hygiene, the number one prevention strategy is vaccination,” Foster said. “The vaccine is more than 90% effective.”

Infectious Disease News spoke with experts about the ongoing outbreak of HAV, as well as the burden, prevention methods and treatment landscape of HAV and the two less common viruses: HDV and HEV.

‘Substantial mortality rate’

In the ongoing multistate HAV outbreak, common foods or drinks have not been identified as potential sources of infection. Instead, the virus is being spread from person to person, primarily among people who use injection and noninjection drugs, people experiencing homelessness and their close direct contacts, according to the CDC.

The rise in HAV cases has prompted an increase in vaccination efforts targeting adults in at-risk populations to help limit the size, duration and spread of person-to-person outbreaks. During a large outbreak in San Diego in which 40% of all cases occurred among the homeless, the city provided free vaccinations, installed hand-washing stations and used bleach to sanitize city streets.

“These outbreaks have surprised all of us in public health,” William Schaffner, MD, professor of preventive medicine at Vanderbilt University Medical Center, medical director for the National Foundation for Infectious Diseases, and an Infectious Disease News Editorial Board member, said in an interview. “A high proportion of affected individuals have been hospitalized and a substantial mortality rate is associated with these outbreaks, which is largely due to the fact that this is an underserved population with many underlying health issues.”

HAV is the most common cause of viral hepatitis worldwide, Foster and colleagues noted. Although the virus typically causes acute and self-limited symptoms, liver failure and mortality may occur in certain patients.

Since 1995, HAV has been a vaccine-preventable disease. National HAV guidelines recommend that children be vaccinated between their first and second birthday, and that other at-risk groups, including MSM, people who use drugs, patients with chronic liver disease and people experiencing homelessness — a recently added group — also receive the vaccine.

“HAV vaccination was implemented in 1995 in high-risk states for babies and young children born in high-risk states, and then in the early 2000s vaccination was expanded to every infant in the United States, thus, every infant should be vaccinated to prevent infection,” Chari Cohen, DrPH, MPH, senior vice president at the Hepatitis B Foundation and co-chair of the Hep B United coalition, said in an interview.

However, recent outbreaks have predominantly involved adults.

“In the past, outbreaks of hepatitis A virus infections occurred every 10 to 15 years and were associated with asymptomatic children. With the widespread adoption of universal childhood vaccination recommendations, asymptomatic children are no longer the main drivers of hepatitis A outbreaks,” Foster and colleagues wrote.

“Although the overall incidence rate of HAV infections has decreased within all age groups, a large population of susceptible, unvaccinated adults who were not infected by being exposed to the virus during childhood remain vulnerable to infection by contaminated foods ... and recently, on a much larger scale, through behaviors that increase risk for infection in certain vulnerable populations, such as drug use.”

Last year, the spike in cases among people experiencing homelessness prompted the CDC’s Advisory Committee on Immunization Practices (ACIP) to vote unanimously to recommend this population for routine vaccination. In addition to the outbreak in San Diego, states including Kentucky, Michigan, Tennessee and West Virginia have reported cases among the homeless, although outbreaks in these states are primarily driven by drug use, according to the CDC.

The ACIP Hepatitis Vaccines Work Group that made the recommendation said it would “allow homeless [people] to be vaccinated using the services and facilities that already provide established health care for the homeless population,” and that the recommendation makes it more likely that HAV vaccination will be considered by these providers.

Because people who are experiencing homelessness may be reluctant to seek and receive medical care, the recent outbreaks have strained the resources of public health departments, according to Schaffner.

“The recent outbreaks of hepatitis A across the country have thrust this infection into the limelight,” Schaffner said. “Public health officials have been trying to identify cases of illness in the homeless population and bring them to medical care as well as try to provide HAV vaccination to these populations. Of course, this has been difficult because it has required a lot of resources and personnel, vaccine purchase and the like, which has strained local health departments in their capacity to respond to these individuals.”

HAV vaccination requires either two doses of the monovalent vaccine or three doses of a combined HAV and HBV vaccine. Of note, nearly 90% of those vaccinated achieve protective antibody levels after one dose.

However, previous vaccination against HAV may not reliably protect against infection among some patients with HIV, according to a study by Schaffner and colleagues published in April in MMWR.

They reviewed confirmed HAV cases reported to the Tennessee Department of Health during an ongoing outbreak between Dec. 1, 2017, and Sept. 20, 2018. Among 249 confirmed HAV cases, 11 occurred in patients with HIV, including six men who had received a partial or complete vaccination series before acquiring acute HAV.

“These findings support the consideration by providers to administer [immune globulin] as post-exposure prophylaxis for all persons with HIV who experience high-risk exposure to a person with HAV infection, regardless of the exposed person’s prior vaccination history or immune status,” Schaffner and colleagues wrote.

Unlike HBV or HCV, HAV infection does not lead to chronic illness, thus, mortality associated with HAV has traditionally been rare — until now.

“The number of deaths observed so far in this most recent outbreak is much higher than normal. Health departments are hoping they can stop the outbreak, but the problem is that we are ‘running behind the train’ and it is hard to catch up and get in front of it,” Cohen said.

“Usually, we have very few people die from HAV. The virus does cause fulminant hepatitis in approximately 1% of people, but we do not normally see what we are seeing now, which is most likely because of the population affected. People who use drugs and homeless people may already have health issues, so the virus is impacting them differently. These populations may have liver damage from coinfection with another hepatitis type, which could be playing a role in the significant increase in morbidity and mortality.”

Experts with whom Infectious Disease News spoke expressed their appreciation for the continued hard work in response to HAV outbreaks at the state and local health department levels.

“All of these state health departments and local health departments that are working to respond to outbreaks are doing a phenomenal job at providing outreach in vaccination to the populations at risk,” Foster said. “Outbreak response for the ongoing HAV outbreak takes a tremendous amount of work and a lot of resources. These outbreaks tend to last for quite some time, and we all acknowledge all the hard work that is done to get these groups vaccinated and to stop transmission.”

A clearer picture of HDV

HDV — an incomplete virus that requires HBV to replicate — is transmitted through contact with infectious blood and can be acquired either as a coinfection with HBV or as superinfection in people with HBV infection, according to the CDC. It can be an acute, short-term or long-term chronic infection.

Although HDV has traditionally been uncommon in the U.S., officials have observed an increase in cases likely caused by the opioid crisis, according to Cohen.

“In terms of high-risk communities in the United States, HDV is possibly associated with drug use — the opioid crisis is definitely driving up infectious diseases — but there are not a lot of epidemiological studies conducted in the United States, so it is hard to definitively say,” Cohen said. “What is definitively known is that people coming from other areas of the world — China, Russia, the Middle East, Mongolia, Turkey, Romania, Georgia, Pakistan, some areas of the Amazon River basin, and some areas Africa — where hepatitis coinfection is common are more likely to have HDV. Anyone coming from these areas who has HBV also potentially has HDV and should be tested for it.”

In the U.S., 42% of adults with HBV are coinfected with HDV, recent study findings showed. This is a “significantly higher” prevalence than previously thought, suggesting that clinicians should consider routine HDV testing in patients with HBV, Eshan U. Patel, MPH, and colleagues from Johns Hopkins University wrote in Clinical Infectious Diseases.

Because HDV occurs only in those infected with HBV, the prevention strategies for these two infections are similar, said Eyasu H. Teshale, MD, medical officer in the CDC’s Division of Viral Hepatitis.

“Vaccination is the best way to prevent HBV, and while there is no vaccine for HDV, getting vaccinated for HBV will also protect from HDV,” Teshale told Infectious Disease News.

Recent research findings suggested that the global burden of HDV also is underestimated. To better understand it, researchers from the First Affiliated Hospital of Nanjing Medical University in China and Mercer University School of Medicine in Macon, Georgia, conducted a systematic review and meta-analysis of 182 international studies published between Jan. 1, 1977, and Dec. 31, 2016. The studies comprised a total of 40,127,988 individuals, representing approximately 0.54% of the global population.

Results showed that HDV prevalence was 0.98% (95% CI, 0.61-1.42) in the general population and 14.57% (95% CI, 12.93-16.27) among individuals positive for HBV surface antigen (HBsAg). Researchers found that the number of individuals infected with HDV and positive for HBsAg was twofold higher than previous estimates among those without high-risk behaviors. Moreover, the number was even higher among those who inject drugs or partake in risky sexual behavior.

“Our study showed that the global burden of HDV is not abated and has been underestimated,” the researchers wrote. “Moreover, the testing rates for HDV antibodies in the HBsAg-positive individuals are inappropriately low, which suggests a lack of awareness regarding the availability of a test for HDV in Europe.”

Additionally, no standard treatment exists for chronic HDV.

“The problem with HDV is there is only one approved treatment and it does not work that well — it is not a cure and only effectively suppresses HDV in about 30% of people who take it,” Cohen said. “Moreover, it is interferon, it has to be taken for a number of weeks or as long as 1 year, and it has serious side effects associated with it.”

However, trials are ongoing in the U.S. and around the world testing novel treatments for HDV. Lonafarnib (Eiger BioPharmaceuticals), a prenylation inhibitor designed to treat HDV, is currently under investigation in a phase 3 trial.

The D-LIVR Study is the first-ever, global registration trial in HDV and includes 300 patients and 100 controls, according to Eiger COO and executive medical officer David Apelian, MD, PhD. The primary endpoint is an HDV RNA decline of 2 log10 or higher and alanine aminotransferase normalization at the end of 48 weeks.

“Companies and nonprofit organizations are working to develop a better treatment and cure for HDV,” Cohen said. “We are hoping that within the next couple of years that we may actually see some promising new drugs and maybe even a cure for HDV.”

HEV rare, potentially under-recognized

Although HEV is rare in the U.S., it is common in other areas of the world, according to Teshale.

“Prevention of HEV relies primarily on good sanitation and the availability of clean drinking water,” Teshale said. “Travelers to developing countries can reduce their risk for infection by not drinking unpurified water. Also, boiling and chlorination of water will inactivate the virus. Avoiding raw pork and venison also can reduce the risk for transmission. In the majority of HEV cases, illness is mild, and symptoms usually improve with supportive treatment.”

Like HAV, HEV is a self-limiting virus. However, “HEV is zoonotic with poorly understood modes of transmission in the United States,” Teshale and colleague wrote recently in Cold Spring Harbor Perspectives in Medicine.

HEV does not usually result in chronic infection, but infection can progress to chronic hepatitis, mainly among solid organ transplant recipients, according to the CDC. The virus is transmitted from ingestion of fecal matter, and is usually associated with contaminated water in countries with poor sanitation. Populations at risk include those living in refugee camps or overcrowded temporary housing after natural disasters, according to the CDC.

There are four genotypes of HEV that cause human illness. Genotypes 1 and 2 are exclusively human and do not occur often in industrialized countries but are common in areas of Africa and Asia. Genotypes 3 and 4 affect swine and can be transmitted to humans.

“In Europe, there has been a fair amount of attention devoted to HEV, as it might be transmitted from swine to people particularly among farmers who raise the swine and have close contact with the animals. Butchers can also be infected directly because of their close contact with the infected meat,” Schaffner said. “Fortunately, HEV infections are usually mild, unless they occur in pregnant women, where they can be more severe.”

Writing in Open Forum Infectious Diseases, Narcisse Patrice Komas, PharmD, PhD, and colleagues from the Pasteur Institute in Bangui, Central African Republic, noted that HEV causes acute hepatitis in both immunocompromised and immunocompetent patients. The Central African Republic is one of the few countries in the world where HEV and HIV are both endemic, with HIV affecting 4.9% of adults aged 15 to 49 years.

In a study that included 200 people living with HIV, Komas and colleagues found that 7.5% (n = 15) were positive for the immunoglobulin that characterizes acute HEV infection. They observed an overall seroprevalence of anti-HEV antibodies of 68%, including 48% in women and 70.4% men, indicating that men are significantly more exposed to the virus, the researchers said.

“It might be possible to monitor biochemical, biological and hematological parameters in [people living with HIV] by ensuring good therapeutic management of HEV and to extend the study of risk factors by isolating HEV from the stools of [people living with HIV] and including samples from their environment,” the authors concluded.

In another study, Anton Andonov, MD, PhD, of the Public Health Agency of Canada’s National Microbiology Laboratory, and colleagues reported identifying a novel rat HEV strain as the cause of severe hepatitis in one patient in Canada and suggested that HEV may be an “under-recognized” cause of hepatitis infection.

Results showed the strain was genetically distinct from the first reported case of rat HEV transmission, which occurred in an immunocompromised transplant patient in Hong Kong. Andonov and colleagues suggested the strain “may represent a new genetic group.”

“The rat HEV infection in this study occurred in a previously healthy, immunocompetent patient, which suggests a more relevant clinical role of rat HEV for the general population,” Andonov previously told Infectious Disease News.

Whereas a recombinant HEV vaccine has been approved in China since 2012, there is no FDA-approved vaccine in the U.S. However, researchers recently began an NIH-sponsored phase 1 trial studying an HEV vaccine in healthy U.S. adults.

Of note, HEV typically resolves on its own without treatment.

“HEV is not often diagnosed in the United States and is not considered a major problem in this country,” Schaffner said. “However, there is some attention given to it in U.S. states with large animal industries that involve the raising of swine, but all in all it is not often identified as a major public health problem in this country.” – by Jennifer Southall

• References:
• Andonov A, et al. J Infect Dis. 2019;doi:10.1093/infdis/jiz025.
• Brennan J, et al. MMWR Morb Mortal Wkly Rep. 2019;doi:10.15585/mmwr.mm6814a3External.
• Chen HY, et al. Gut. 2018;doi:10.1136/gutnjl- 2018-316601.
• Foster MA, et al. MMWR Morb Mortal Wkly Rep. 2019;doi:10.15585/mmwr.mm6818a2.
• Hofmeister MG, et al. Cold Spring Harb Perspect Med. 2019;doi:10.1101/cshperspect.a033431.
• Patel EU, et al. Clin Infect Dis. 2018;doi:10.1093/cid/ciz001.
• Sibiro OAD, et al. Open Forum Infect Dis. 2018; doi.org/10.1093/ofid/ofy307.

• For more information:
• Chari Cohen, DrPH, MPH, can be reached at chari.cohen@hepb.org.
• Monique A. Foster, MD, can be reached at ydg9@cdc.gov.
• William Schaffner, MD, can be reached at william.schaffner@vumc.org.
• Eyasu H. Teshale, MD, can be reached at media@cdc.gov.

Disclosures: Cohen, Foster, Schaffner and Teshale report no relevant financial disclosures.