H1N1 viruses gain Tamiflu resistance without losing fitness

Mar 2, 2009 (CIDRAP News) – Studies published today confirm that influenza A/H1N1 viruses have become widely resistant to oseltamivir (Tamiflu), the leading flu drug, without losing their ability to make people sick—thereby underlining the need for new antiviral drugs.

The findings also underscore the possibility that H5N1 avian influenza could gain resistance to oseltamivir, calling into question the value of stockpiling the drug in preparation for a potential flu pandemic, according to two experts who comment on the latest findings in an accompanying editorial. The research reports and editorial were released online today by the Journal of the American Medical Association.

To the surprise of many, H1N1 resistance to oseltamivir rose sharply last year, reaching 12.3% in the United States and 16% worldwide. So far this season, it is far higher: more than 98% (321 of 325) of H1N1 isolates tested by the Centers for Disease Control and Prevention (CDC) were resistant to the drug.

None of the H1N1 isolates have shown resistance to zanamivir (Relenza), the other flu drug in the neuraminidase inhibitor class. H1N1 is one of three flu subtypes that circulate each season, along with A/H3N2 and influenza B.

Because of the spread of resistance, the CDC in December changed its recommendations on antiviral treatment for flu. For patients suspected of having influenza A, the CDC recommended using zanamivir or a combination of oseltamivir and rimantadine (an older flu drug in a different class) instead of oseltamivir alone.

In one of the new studies, a team from the CDC and several state health departments compared people infected with oseltamivir-resistant and oseltamivir-susceptible strains of H1N1 last season and found no differences in patient characteristics, symptoms, or severity of illness. They report that four patients infected with resistant strains died.

A second study describes an outbreak of resistant H1N1 infections in four patients in a Dutch hospital in February 2008. Three immunocompromised patients became ill after exposure to a patient who was sick with a resistant H1N1 strain, and genetic analysis showed that the viruses all matched, making it clear that the infection spread from person to person in the hospital.

Taken together, the two studies "dispel the notion that oseltamivir resistance compromises virulence," states the accompanying editorial by David M. Weinstock, MD, and Gianna Zuccotti, MD, of Harvard Medical School in Boston.

Resistance in 2007-08 US season
The CDC-state study reports that oseltamivir resistance was found in 142 of 1,155 (12.3%) H1N1 viruses tested last season. Resistant viruses were reported in 24 states. Of the 142 patients who had resistant viruses, 99 supplied information.

None of the 99 reported taking oseltamivir before being tested for flu, nor did they have close contact with others who had taken it. Four of the patients died, two of them in hospitals and the other two on the way to a hospital or in the emergency department.

After seven cases from one state were excluded, the authors compared 92 patients who had resistant H1N1 infections with 182 who had susceptible strains. They found no differences by age, sex, race, underlying medical conditions, or clinical symptoms.

The analysis did indicate that patients with susceptible viruses were more likely to be hospitalized, but this difference disappeared when the two patients with resistant viruses who died before they could be admitted to hospitals were classified as hospital admissions.

Before last season, oseltamivir resistance had been seen only in patients who were treated with the drug, the authors note, adding that it is unclear why oseltamivir-resistant H1N1 viruses emerged during the season and continue to circulate.

"Additional options for the treatment and prophylaxis are critically needed," the report concludes.

Hospital outbreak
In the other report, the Dutch researchers write that three hospital patients apparently acquired oseltamivir-resistant H1N1 infections from another patient who was found to have the virus while being treated for systemic lupus erythematosus.

The three were in the same ward as the presumed index patient at the same time, though they never shared a room. Two patients, a hematopoietic stem-cell transplant recipient and an 89-year-old man, died of the illness.

Genetic sequencing revealed that isolates from the four patients matched closely. All four had not only the H274Y mutation associated with resistance, but also a rare mutation known as T284A.

Five healthcare workers got sick with flu-like symptoms while the index patient was hospitalized, but none of them were tested for flu, the report says.

"This study confirmed that circulating H274Y-mutated A(H1N1) viruses can retain significant pathogenicity and lethality, as shown in these elderly or immunocompromised patients with lymphocytopenia, underlining the need for the introduction of new effective antiviral agents and therapeutic strategies," the authors conclude.

Findings shouldn't be surprising
"The widespread belief that oseltamivir would retain activity against epidemic influenza strains has crumbled, but this should come as no surprise," write Weinstock and Zuccotti, in the editorial accompanying the two reports. They say that surveillance over the past several years indicated that resistance was rising on a path that closely paralleled the rise of adamantane (amantadine and rimantadine) resistance 3 years earlier.

Further, recent laboratory studies have shown that the H274Y mutation that confers resistance in H1N1 viruses does not necessarily interfere with the virus's ability to replicate in animal models, the editorial says.

One corollary of the new studies, according Weinstock and Zuccotti, is that "oseltamivir resistance is likely to develop during the treatment of other N1-containing strains, including avian influenza A(H5N1). Thus, stockpiles to mitigate an influenza pandemic should not be limited oseltamivir."

Oseltamivir is the leading antiviral drug in national stockpiles for pandemic preparedness. The US stockpile is about 80% oseltamivir and 20% zanamivir, federal officials have said.

Vaccination remains key tool
Other experts said the findings show that vaccination remains the key tool for battling influenza. They share the concern about the risk of resistance in H5N1 viruses.

"These developments further support the use of influenza vaccine as the cornerstone for influenza prevention and control," said Kathleen M. Neuzil, MD, MPH, a member of the Pandemic Influenza Task Force of the Infectious Diseases Society of America and director of the Influenza Vaccine Project at PATH in Seattle.

Concerning the risk of resistance in H5N1, she said, "These recent findings represent a paradigm shift. We need to be prepared for the possibility that H5N1, or other influenza strains, could become resistant to oseltamivir and still be pathogenic and transmissible. This advocates for research and development into new antiviral and effective pandemic vaccines."

Dr. Keiji Fukuda, director of the World Health Organization's Global Influenza Programme, called H5N1 resistance "a theoretical possibility."

"So far, oseltamivir resistance has been rarely reported in H5N1 human isolates (three in Vietnam with H275Y mutation, two in Egypt with N294S mutation which confers mild reduction of oseltamivir susceptibility)," he commented by e-mail. "This is another situation where monitoring is essential." (The resistance mutation is sometimes called H275Y, depending on the naming system.)

Fukuda observed that all the resistant H1N1 viruses tested so far have been sensitive to zanamivir and the adamantanes. "Of course, empiric therapy is difficult when you do not know the specific influenza virus type and subtype—as one typically does not in clinical practice—because in some countries most of the circulating H3N2 viruses are resistant to adamantanes," he added. "But when national surveillance is good, empirically selected therapy is rational and possible."

Both experts allowed for a possibility that H1N1 will eventually become susceptible to oseltamivir.

"As these [resistant Brisbane-like] strains continue to evolve and be replaced by other strains, it's possible that the resistance will go down. This needs to be monitored," said Fukuda.

Neuzil commented, "No one knows, but it [resistance] could certainly disappear as rapidly as it developed, as without widespread use of oseltamivir, it appears unlikely that antiviral pressure will favor resistant viruses."

Dharan NJ, Gubarcva LV, Meyer JJ, et al. Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States. JAMA 2009;301(10) (early online publication) [Full text]

Gooskens J, Jonges M, Claas ECJ, et al. Morbidity and mortality associated with nosocomial transmission of oseltamivir-resistant influenza A(H1N1) virus. JAMA 2009;301(10) (early online publication) [Full text]

Weinstock DM, Zuccotti G. The evolution of influenza resistance and treatment. (Editorial) JAMA 2009;301(10) (early online publication) [Full text]

See also:

CDC's weekly flu surveillance report
http://www.cdc.gov/flu/weekly/

Dec 19, 2008, CIDRAP News story "With H1N1 resistance, CDC changes advice on flu drugs"

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