Multi-drug Resistance in Two Immunocompromised Patients

[mixin]

There have been two cases written about recently and I'm seeing some strange interpretations of these studies appearing all over the net. In this thread, I'd like to sort out the fact from fiction.

First is the case of the 14 year old girl :tiphat: tetano
http://www.flutrackers.com/forum/showthread.php?t=152835

This was a very sick girl who was in respiratory failure when she was first brought into the hospital. We've seen healthy people die from this flu; so I'm not sure what her survival odds were...even if she had not developed a drug resistance. The evidence of resistance to the 2 other antivirals was of much lower degrees.

Therefore, I'm not sure it's accurate to say Relenza resistance/ I222R (I223R) mutation is related to or caused her death. It would be helpful to have more information on her case before we make that kind of a call.

(Slightly summarized)
A 2009 H1N1 flu virus that contributed to the death of a 14-year-old girl was resistant to three neuraminidase inhibitors... The girl, who had systemic lupus erythematosus and other illnesses, was hospitalized with respiratory failure in October 2009. She was first treated with oseltamivir (Tamiflu) for several weeks and later with intravenous zanamivir (Relenza), but she died of complications in late December. Testing of samples taken in November showed that the virus was highly resistant to oseltamivir. It also showed evidence of resistance to peramivir and zanamivir, though to much lower degrees. Sequencing of the virus showed its neuraminidase protein contained two mutations: H275Y, which is known to confer resistance to oseltamivir but not zanamivir, and I223R. In one previous case, the I223R mutation alone was associated with slight resistance to oseltamivir and peramivir, the report says. Compared with strains featuring either mutation alone, the "dual mutant I223R/H275Y" showed greater resistance.
http://www.cidrap.umn.edu//cidrap/co...0h1n1scan.html

 

[mixin]

Re: Multi-drug Resistance in Two Immunocompromised Patients

Our other case is that of a 5 year old boy who was also very sick for a long time. I have included the graph from the study that shows he was responding to treatment (even though the virus was shown to be multi-resistant) prior to his death.

So, once again, I don't believe it's accurate to attribute Relenza resistance or I222R (I223R) to his death.



Emergence of a Multidrug-Resistant Pandemic Influenza A (H1N1) Virus

We report the emergence of a pandemic influenza virus in a patient treated with neuraminidase inhibitors, with a novel resistance pattern that conferred resistance to oseltamivir, zanamivir, and peramivir.

On November 11, 2009, a 5-year-old boy with high-risk acute lymphoblastic leukemia (undergoing preparation for hematologic stem-cell transplantation) was admitted to the hospital because of influenza-like symptoms.

Treatment with broad-spectrum antibiotics and oseltamivir (45 mg twice daily [pediatric dose]) was initiated and continued during conditioning for transplantation. Consequently, influenza virus was not detected in two consecutive respiratory specimens, and allogeneic transplantation was performed on November 23.

On December 2, however, an increased influenza viral load was detected, and since the H275Y mutation was present in a specimen from November 23,3 intravenous zanamivir therapy (20 mg per kilogram of body weight twice daily) was started on December 3 under an emergency investigational-new-drug protocol. The viral load decreased (to the lower limit of assay detection), and the patient recovered clinically; he was discharged home on December 23.

On January 11, 2010, he was readmitted with signs of a lower respiratory tract infection, and intravenous zanamivir therapy was reinitiated. In addition to influenza virus, cytomegalovirus DNA was detected in the blood (for which ganciclovir was administered), and rhinovirus was detected in respiratory specimens. Unfortunately, the patient's clinical situation worsened. The acute respiratory distress syndrome developed, and he ultimately died.

Sequencing of the neuraminidase gene of a virus isolated on February 9 revealed a novel isoleucine-to-arginine amino acid substitution at residue 223 (I223R). This residue has been linked to oseltamivir resistance for another influenza subtype (H3N2).

Subsequent in vitro phenotypic testing of the virus showed that the 50% inhibitory concentration for the drugs taken by this patient (oseltamivir and zanamivir) was increased by a factor of 45 and 10, respectively. Moreover, when we tested the sensitivity to peramivir, we observed an increase in the 50% inhibitory concentration by a factor of seven.

The absence of an adequate immune response and possibly suboptimal drug levels may have contributed to the emergence of the I223R mutant. Further research is warranted to determine the clinical and epidemiologic consequences of mutants with reduced sensitivity to neuraminidase inhibitors, since they leave physicians with limited treatment options.

Erhard van der Vries, M.Sc., Foekje F. Stelma, M.D., Ph.D., Charles A.B. Boucher, M.D., Ph.D.

http://www.nejm.org/doi/full/10.1056/NEJMc1003749

 

[mixin]

Re: Multi-drug Resistance in Two Immunocompromised Patients

The only isolate available for this case is from a later sampling, showing I223R; but not H275Y (oseltamivir resistance). At some point, it had apparently become sensitive to oseltamivir again.

It's always been my understanding that once a virus gains a mutation, it won't revert to its original status.

I asked gs how the virus could be sensitive, then resistant, then sensitive once again and below is his reply. I hadn't even considered that there could still be a small amount of the original virus lingering undetected, and then starting replication again.

some of the old viruses are still be present.
If they don't enter cells, Tami won't kill them
the old viruses may have an advantage in a Tamiflu-free environment