|Tamiflu (Oseltamivir) is currently the antiviral of choice for the treatment of human H5N1 infections. It is also stockpiled by many countries in preparation for a possible pandemic from the virus, whether for treatment, containment, protection of essential personnel, or prophylaxis in contacts. Hence, any emergence of a tamiflu-resistant strain is a development that, rightly, evokes significant concern and requires the closest scrutiny and investigation.
Events of the past few days have caused me to be concerned not just about the virus or whether it is tamiflu-resistant, but about whether WHO as an institution, its officers, and main-stream media are doing their jobs properly with regards to the responsible dissemination of credible information based on sound scientific methods and analysis.
First of all, a little background science. To demonstrate that a particular virus has a particular mutation, scientists have to determine the genetic sequence of the virus. This however, does not tell us whether the virus is resistant to a drug. To determine that, one needs to do either a NA enzyme inhibition assay, or animal experiments, as described here http://www.newfluwik...
Having said that, if previous studies have consistently shown, in a particular virus genome, a consistent and statistically significant correlation between a mutation and a specific drug resistance, then one need not do sensitivity assays in each patient, and assume the sample was resistant if the mutation is present. In addition, demonstration of resistance in the laboratory does not necessarily imply that the virus is drug resistant in actual clinical infections. You also need examination of clinical information to determine that.
Let's look at the current case in point, starting with the official WHO update released on January 18th. It states,
Viruses with a genetic mutation, linked in laboratory testing to moderately reduced susceptibility to oseltamivir, have been discovered in two persons previously reported with H5N1 infections in Egypt
At first sight, most people would assume that "linked in laboratory testing to moderately reduced susceptibility to oseltamivir" implies laboratory testing has indeed been done on these two specific samples, and these have shown moderately reduced susceptibility. Indeed, the WHO press release goes on to say that
Confirmatory testing and genetic sequencing was done at NAMRU-3 and at two WHO Collaborating Centres located in Atlanta, USA and London, UK. and
Current laboratory testing suggests that the level of reduced susceptibility is moderate.
However, note that in none of these statements was it made explicit that such tamiflu sensitivity tests had indeed been done on samples from the Egyptian patients. Why is that important?
Let's examine the 'evidence' for tamiflu-resistance in the particular mutation discovered in these 2 patients - N294S.
This mutation was described in a Vietnamese girl in 2005, (details here http://www.newfluwik...) who made a full recovery after the initial low (prophylactic) dose was increased to the dose recommended currently for seasonal flu.
However, the clinical significance of this mutation is uncertain, given that
- the girl's symptoms never got worse than 'fever and severe cough', they showed clinical response to the normal dose of tamiflu, and she made an uneventful recovery
- the change in susceptibility of N294S clones (measured by IC50) was very small, indeed close to marginal (7.1 - 12.5 nM) compared to normal range (0.1 - 10nM)
- there were additional clones of virus with the H274Y mutation, which showed a far higher degree of resistance (IC50 range 763 - 1088 nM), which could have accounted for (assuming it was significant) the initial failure to respond to the prophylactic dose
So, that's one case. (ie n=1)
In addition, the WHO also said
This mutation has previously been identified in Viet Nam in one case in 2005. Moreover, these mutations are not associated with any known change in the transmissibility of the virus between humans.
What it did NOT say, however, was that transmission studies based on this particular mutation has or has not ever been done. I have done a series of searches, and the only NA inhibitor resistance transmission studies were based on several other mutations and in different NA subtypes, H274Y in N1 (transmissible), E119V and R292K in N2 (not transmissible).
The WHO statement is technically accurate in that N294S is not associated with any known change in transmissibility, but we don't know whether such lack of association is because no one ever did any research on it!
Adding to the confusion, let's look at some MSM headlines. If you have stayed with this diary so far, you will now be able to observe the difference in nuance and meaning.
New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug
Bird flu mutations in Egypt suggest antiviral resistance
Moderately Tamiflu-resistant bird flu in Egypt--WHO
(Here's a test: Which of these 3 headlines would you say describes the situation most accurately?)
And the words of some experts:
"What we've confirmed is that H5N1 viruses isolated from two patients in recent cases in Egypt both showed this so-called 294S change," Keiji Fukuda, coordinator for the WHO's global influenza programme, told Reuters. "But based on what we see from laboratory tests, we expect any reduction in sensitivity or increase in resistance is going to be on the moderate side,"
"What the resistance tests look for are markers associated with antiviral resistance," though finding the markers did not necessarily mean Tamiflu would not work, said Dr. Angus Nicoll, flu director at the European Centre for Disease Prevention and Control.
The development "is not a big surprise, but it certainly is disheartening," said Dr. Anne Moscona, an expert on flu treatment at Weill Cornell Medical College.
"Based on the information we have, we can't yet rule out human-to-human transmission," said Dr. Fred Hayden, a WHO bird flu and anti-virals expert. "We need to better understand the dynamics of this outbreak."
But the grand prize should go to the WHO spokesman himself
"Given the information we have, we don't see any broad public health implications," said Dick Thompson, a spokesman for the organization.
despite the fact that:
Mr. Thompson was unsure which Egyptian cluster of flu infections the patients were part of.
So What do we know?
- 2 people died
- they were both given tamiflu
- they found the N294S mutation in samples from both, 2 days after starting tamiflu
- there was a third confirmed case in the cluster who also died
What do we not know? Here are some but by no means all the questions that remain unanswered about this business.
- did they do any tamiflu sensitivity assays on the samples?
- has there been other reports of N294S apart from the single case in Vietnam?
- if yes, did the clinical picture and/or laboratory assays suggest tamiflu resistance?
- is this h2h?
- have they taken any samples from birds in the area?
- did any of these and other avian sequences show N294S?
- did they sequence the virus from the third patient?
- If yes, did that sequence contain the N294S OR NOT?
As in the case of transmission studies above, despite the report from NY Times, (probably a la Thompson?) that "The resistant strain did not spread to anyone else, including a third family member who also had avian flu." we cannot assume this is accurate until the WHO confirms whether a sequence analysis has been done and what it shows.
- could this be sampling/laboratory/specimen labelling error?
- did either one or both patients take any medication prior to hospitalization?
- if yes, is someone tracing the medication history to find out whether they might have taken tamiflu prior to hospitalization?
Need I say more about the importance of good science and clear accurate communications? Including what we DON'T know?
Can the WHO start treating the citizens of the world as grown-ups please?