Sep 5, 2008 (CIDRAP News) – Amid concern about rising resistance to oseltamivir (Tamiflu) in influenza A/H1N1 viruses, a Dutch team this week reported the death of a leukemia patient who was infected with an H1N1 virus that was resistant to the antiviral drug.

In a letter in this week´s New England Journal of Medicine (NEJM), the Dutch authors said the case suggests that oseltamivir-resistant H1N1 viruses can cause disease, despite evidence from animal studies that the resistance mutation makes the viruses much less dangerous. The letter said the man´s virus was also resistant to amantadine, an older antiviral drug.

On Aug 20, the World Health Organization (WHO) reported that 31% of influenza A/H1N1 isolates from 16 countries that conducted recent tests carried the H274Y mutation, which confers resistance to oseltamivir. Resistance levels ranged from 100% (10 of 10 isolates) in Australia to 13% (4 of 32 isolates) in Chile.

Emergence of the oseltamivir-resistant H1N1 virus was first noted in Norway in January, and since then researchers have found the virus in 35 countries, including the United States and Canada.

The spread of the oseltamivir-resistant H1N1 virus has puzzled experts because it has not been clearly linked to treatment with the drug.

In the case report, authors from Erasmus University Medical Center in Rotterdam wrote that a 67-year-old man who was on chemotherapy in a 3-year battle with chronic lymphocytic leukemia was hospitalized with shortness of breath, a dry cough, and fever. On his second hospital day, he experienced acute respiratory failure, and his physicians placed him on a ventilator and started empirical antibiotic treatment.

Computed tomography (CT) revealed that the patient had patchy lung infiltrates, and tests on samples from his respiratory tract showed he had influenza A/H1N1.

On the sixth hospital day the man received oseltamivir, but by day 13 physicians discontinued the drug because sequence analysis of the virus revealed the H274Y mutation and there was no decrease in the viral load.

The authors reported that the mutation was found in samples obtained before the patient began oseltamivir therapy. The man´s family and the hospital record revealed that he had had no contact with patients who were taking oseltamivir.

On the 15th hospital day the man´s doctors prescribed amantadine, and after a few days his neutrophil count increased, a sign of bone marrow recovery, the group reported.

On day 20 doctors took the patient off the ventilator and instituted zanamivir treatment. However, 2 days later the man had respiratory failure again, and his medical team put him back on the ventilator and discontinued zanamivir therapy. (Like osteltamivir, zanamivir is a neuramnidase inhibitor, but no increase in zanamivir resistance has been reported recently.)

By day 26 physicians detected no influenza virus, but did note that sequence analysis showed an amantadine-resistance mutation in the viral M2 protein (L26F). They wrote that recovery of the immune system was probably responsible for clearing the virus, because the patient had received only three doses of zanamivir.

A repeat CT scan taken on day 28 showed that pulmonary infiltrates had progressed. Because of the man´s poor prognosis, the ventilator was removed on day 34, and he died 3 days later.

The authors cited animal studies indicating that oseltamivir resistance leaves H1N1 viruses "severely compromised." Despite these reports, they wrote, "the case we describe suggests that this oseltamivir-resistant virus can be pathogenic, at least in an immunocompromised patient."

In an editorial published by Eurosurveillance in January, authorities said resistant viruses with the H274Y mutation had been seen in previous flu seasons but were rare and did not spread easily. But the more recent H1N1 isolates with the mutation were "fitter" and were spreading in the community, they wrote.

Van der Vries E, Van den Berg B, Schutten M. Fatal oseltamivir-resistant influenza virus infection. N Engl J Med 2008 Sep 4;359(10):1074-76 [Full text]