Thursday, March 10, 2005

How oseltamivir (Tamiflu) works (and does it?)

If avian influenza transforms to a form easily passed from person to person it cannot be stopped. The question then becomes what to do at that point. At the moment there is no vaccine and it is likely that an effective vaccine will take many months to produce and many more to distribute. Social measures to reduce contact between people like cancellation of public gatherings, quarantine or isolation might have some effect and will certainly be tried. But the only other preventative is the use of antiviral medications. There are four currently effective against influenza A, but it appears that the two oldest, of the adamantine class, are ineffective against H5N1. That leaves two neuraminidase inhibitors, oseltamivir (Tamiflu)_and zanamivir (Relenza). The latter cannot be taken orally so it must either be given i.v. or via inhalation. Only the inhaled product is currently available.

This is a brief primer on influenza A virus and oseltamivir (many details have been omitted).

Influenza A/H5N1 and antiviral drugs

Viruses exist on the border between living and non-living. They don't grow and they don't metabolize. They just reproduce. And while they possess all the genetic information needed to reproduce, they have none of the machinery to do so. They are like a blueprint and a mailing envelope but no factory to make new copies of themselves, depending on their host's biological mechanisms to reproduce. Sometimes commandeering host machinery can be done peacefully. Sometimes it kills the host cell in the process.

The genetic information in influenza virus is encoded in RNA (we encode our genetic information in DNA, and use RNA as part of our protein manufacturing process). However the replication process in this virus is especially error prone, with an error rate roughly 100,000 times that of DNA replication. Thus every round of virus replication produces a number of variant copies, most of which will be changes disadvantageous to the chances for viral survival, but some few of which might confer a competitive advantage. They are the ones that come to predominate over time. As conditions change, new ones arise. Influenza A is a prime example of evolution in action. (NB: Not believing in evolution will not protect you against influenza.)

These individual copying errors are not the only way genetic variation can arise in this virus. The genetic material is segmented into eight sections, each of which codes for a particular protein important for viral survival and replication. If two different strains of virus, say one from a bird and another from a human, coinfect the same cell, they can "mix and match" segments and produce entirely new combinations. In addition, some suspect that occasionally pieces of segments from different strains can become swapped (a process called recombination), although this has been the subject of scientific debate. Whatever the mechanisms, this is a quickly mutating virus.

The consequence of mutation from our point of view is that it may affect how virulent the virus is (i.e., how likely it is to kill its host cell), what host species it can infect, how contagious it is and how much natural or previous immunity we have. Little is known about the genetic determinants of most of these important characteristics, but we know something about the question of immunity.

Most of the foreign viral proteins are invisible to our immune systems, but two of them are "seen" by it. Physically the virus has genetic material surrounded by a protein and fat-containing capsule which has two kinds of "spikes" sticking off its surface, called hemagglutinin and neuraminadase, abbreviated H and N. In bird species, which are the natural home or reservoir of all influenza viruses, there are 16 different H types (H1 - H16) and 9 N types (N1 - N9). Human infections have so far been limited mainly to the H1N1, H2N2 and H3N2 strains. We know of no previous (before 1997) infections with H5N1, which means the human species is immunologically naive to this strain, one of the main concerns of public health authorities.

The virus begins its life cycle by attaching to the cell surface of its host via its H protein spike. To do this it needs an attachment spot marked by a particular kind of molecule, its "receptor." This is an important place where genetic information determines what kind of host the virus can infect, because different influenza strains recognize different receptors. If the host doesn't have that receptor the virus can't attach. Other factors specific to the host cell are also required for attachment and subsequent events. Acquiring the genetic information that allows attachment to a new host is one instance where mutation or reassortment can produce strains of virus with entirely new properties.

Following attachment the virus fuses with the host cell membrane and enters the cell (we omit here some imortant detail related to other antivirals). After the virus replicates its genetic material inside the host cell and produces new viral proteins the components assemble themselves in many copies at the cell membrane, budding outward and incorporating some parts of the host cell's membrane in the enclosing capsid. However the resulting viral progeny are still stuck to the membrane via the receptors. The function of the N (neuraminidase) spike is to break that attachment and allow the virus to float off and find a new host cell within which to make still more copies of itself. Without the action of neuraminiadase the virus will remain stuck on the cell surface and not be able to reproduce further. That is where oseltamivir and zanamivir come in. By inhibiting neuraminidase they prevent the virus from leaving the cell surface.

It appears that the mutations in the N spike needed to make the virus resistant to oseltamivir also compromise the function of the neuraminidase enzyme so it is much less effective in releasing the virus. Thus, at the moment it seems viral resistance to oseltamivir does not develop easily or effectively. This could change as the cat and mouse game of virus and defenses continues. We don't know at this point.

Does it work?

Apparently, yes. Experience in animal models and human outbreaks shows that oseltamivir is quite effective if given prophylactically or within the first 48 hours of onset of illness, where it can shorten the duration and decrease the severity of illness. Because this is a short period, because illness onset may be hard to recognize and because viral replication and shedding peaks early, prophylaxis will be more effective than attempted rapid treatment in an epidemic situation. For this, of course, adequate supplies and a distribution system is required, neither of which we have. So while oseltamivir works, it is unlikely to help much if a pandemic comes within the next year or two, as many expect. Given the lead time we have had, this is inexcusable. But even if adquate supplies were available (and they are not), its use might slow but wouldn't stop a pandemic. However the added time could save many lives as the world hurries its preparations.

Those interested in more of the underlying clinical data might consult a recent paper by Ward et al. "Oseltamivir (Tamiflu(AR)) and its potential for use in the event of an influenza pandemic," Journal of Antimicrobial Chemotherapy (2005) 55, Suppl. S1l, i5 - i 21. This paper was written by scientists at Roche, the makers of Tamiflu. Given the rather sorry ethical history of big pharma, you should make up your own minds as to whether this affects its very positive assessment of their product. My reading suggests the information is accurate and reliable, but I would be interested in informed views to the contrary.