Thursday, December 22, 2005

The magic bullet loses some of its magic

[NB: This post is perhaps more technical than some readers would find comfortable, but I wanted to register some ideas I didn't think were being adequately or at all covered elsewhere.]

A second New England Journal of Medicine (NEJM) paper from Vietnam detailing oseltamivir (Tamiflu) resistant H5N1 has just appeared and it is more ominous than the first, which described partial resistance in a patient that eventually recovered (see other posts here, here and here). The case reports today describe two more patients with fatal outcomes carrying a virus that was resistant to H5N1, as evidenced by continued viral load in the presence of recommended and timely treatment regimens and a mutation (H274Y) previously described as being related to Tamiflu resistance (in volunteers experimentally infected with H1N1; Gubareva et al. J Infect Dis. 2001 Feb 15;183(4):523-31.). It does not appear that any direct tests for Tamiflu resistance were done (such as NA inhibition or plaque assays in MDCK cells).

The paper is available for free download here (.pdf). Here are the points that struck me on first reading.

There are some important similarities between these cases and the volunteer infections with the (clinically safe) H1N1 reported earlier by Gubareva. In that experiment 54 infected volunteers were treated with Tamiflu doses of 20 mg, 100 mg and 200 mg/day. The viruses in two of these volunteers (4%) became resistant to Tamiflu on assay, and viral loads in both showed an initial decline followed by a rebound, similar to the cases described in today's NEJM article. Both were unique in carrying the H274Y mutation at the neuraminidase active site. Moreover, the two resistant cases were those on the highest dose of Tamiflu (200 mg/day), not the lowest as I would have guessed a priori. The current therapeutic recommendations for Tamiflu are 150 mg/day, so the resistant H1N1 viruses in the Gubareva study exceeded current dosing. In the earlier Vietnamese case of partial resistance, the young girl was initially treated with a prophylactic dose of 75 mg/day and when she became symptomatic this was increased to 150 mg/day and she recovered. These disparate findings leave us still in the dark regarding the influence of suboptimal dosing on the emergence of resistance.

Another point of interest was the co-existence of the H274Y mutant and wildtype H274 in the throat swabs, but a finding of only H274Y mutants in the MDCK cultured isolates. One of the issues that has hung in the background of Tamiflu resistance was whether resistant viruses are less fit genetically than wildtype. At least in terms of the ability to grow in tissue culture MDCK cells, the resistant virus was more fit, not less fit. However the relation of in vitro measures like growth in tissue culture and the replication of the virus in whole animals is still unclear. But given the clinical outcomes here, these cases do not give reason for optimism.

Tamilfu resistance is known to develop fairly quickly in Japanese children but rarely in adults treated for H3N2 infections. As this paper points out, this might be a reflection of some immunologic protection in adults and not children. This would mean that in contrast to the Japanese experience, Tamiflu resistance might just as easily develop in adults as children, since no one has any prior experience with the virus.

We note that the principal case described here was a 13 year old Vietnamese girl who develop symptoms a day after her mother died of H5N1. This would qualify as a family cluster, although no other historical information was given.

The bottom line, however, should be obvious (although it isn't a part of the news coverage so far). The best protection against the most serious effects of an epidemic infectious pandemic is not a magic bullet pharmaceutical like Tamiflu or biological like a vaccine, but a sturdy, effective and adequately supported social services and public health infrastructure. Tamiflu was never going to get us that far in mitigating the effects of a pandemic anyway because our ability to supply, dispense and provide the collateral medical support was never there. Nor could it be effectively used on a mass population basis. A vaccine, were one available, would be better, but there is an inevitable lag time between the emergence of a pandemic strain and the ability to produce and distribute the vaccine (the latter of which of course depends on a public health infrastructure). The lag is sufficiently long that a whole pandemic wave could wash over the globe before the first of a vaccine was administered. And the reliance on the private sector to provide lower profit biologicals has failed us time and again. It is time to try using public means to produce them. Finally, there is no guarantee a pandemic or epidemic organism will be H5N1 or even influenza. Tamiflu is an influenza/A specific pharmaceutical. It is worthless against any other infectious disease that might come along.

It is not just a matter of "putting all our eggs in the same basket." It is a matter of having neither eggs nor basket nor any way to distribute them. Dismantling our hospital, medical care and social services systems has left us defenseless. The likely evidence for the emergence of Tamiflu resistance is just another one of the obstacles we face, and in the Big Picture, probably one of minor importance.