Re: Drug-resistant H7N9 strains to change treatment: researcher
Genetic Quantification Errors
The WHO comprehensive report contains
errors, including notations concerning
PB2 701N, a
very important mammalian adaptation. In two places (p6 and Table2), they exclude ChinaZhejiang2_64M_2013_04_03 though the sequence is clearly included in the
Hemagglutinin review (Table 1).
Page 6, Section
5. Characterization of the A(H7N9) viruses (emphases mine):
The PB2 proteins from some H7N9 viruses isolated from humans have mutations at positions 627 (Glu to Lys in the human isolates from Anhui, Hangzhou and Shanghai) or 701 (Asp to Asn in A/Zhejiang/DTID-ZJU01/2013) which impart enhanced replication at temperatures similar to that of the upper airway of mammalian hosts and possibly humans as well (Hatta et al. 2007, Massin et al. 2001).
Page 26
Table 2. Markers of mammalian adaptation in internal proteins of viruses of avian origin (emphasis mine):
Table 2, PB2
701Asn one human isolate
Neuraminidase Inhibition
This supplying of Tables 3a and 3b is not relevant to this thread because no H7N9 sequence with genotypic or phenotypic drug resistance is profiled in either table.
H3N2 drug resistance is managed
at depth for this H7N9 review from WHO with comparatives on 5 different H3N2 viruses with 2 types of genotypic drug resistance measured using 2 different protocols. They have thoroughly measured and thoroughly reported, but not on drug resistance risk / ratings for H7N9.
The experimental evaluation of a
100-fold genotypic and
multi-patient severity phenotypic H7N9 sequence was, in fact, produced in the paper that is the topic of this thread.
www.thelancet.com Published online May 28, 2013
http://dx.doi.org/10.1016/S0140-6736(13)61125-3
Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance
We have shown that A/Shanghai/1/2013 (H7N9) virus isolate contains a mixed population of Arg/Lys at position 292 of the NA gene, and by purifying virus plaques that carry NA Arg292 and Lys292, we have noted that this mutation increases resistance to oseltamivir by 100-fold and zanamivir by 30-fold in a fluorescence-based NA inhibition assay (unpublished data).
Qualitative Errors
Two points do come to mind, however, concerning potential
qualitative errors in the WHO Review:
Point A
Page 1, Section
Summary (emphasis mine):
Epidemiologic studies and laboratory analyses of virus isolates have provided a vast amount of information in a very short time.
This paper was published on May 31, 2013.
Does the "
vast amount of information" that is recognised by the authors on Page 1 in their tribute to transparency include the
9 human sequences with genotypic TamiFlu Resistance due to
NA 292K or the
single human sequence with genotypic mild TamiFlu Resistance due to
NA 152K?
10 Stealth H7N9 TamiFlu Resistant Sequences
Are the authors, WHO are self-reportedly working hand-in-hand with the bench scientists, aware of the early detection during treatment at
Day 2 for the
very first case of emergent H7N9 who expired on March 4, 2013, more than 7 weeks prior to this paper? Was the vast information flow limited at that time? Has consideration been given to the importance of resistance that
emerged at Day 4 for a case who expired after aggressive
oseltamivir / peramivir combination therapy with ECMO on April 29, 2013, more than 30 days prior to publication?
- If no author or reviewer is aware, then WHO is at the helm?
- If any notion of awareness does exist, then WHY are these resistant items absent from today's report?
- At prevailing market rates, what is the probability that genetic drug resistance produces official reporting aversion?
Point B
This section may be made moot if a supplemental pdf is available at some point detailing isolation method / experimental design variations between WHO Collaborating Centers in Atlanta, Tokyo and Melbourne. A search of the WHO Influenza H7N9 topic does not show a supplement, but does prominently
feature a claim that "limited information" exists for the disease.
emphasis mine:
As yet, there is limited information about the scope of the disease the virus causes and about the source of exposure.
The following evaluation cross-references data from Table 3a (Page 27) and Table 3b (Page 28) of today's "vast information" paper.
IC50 (nanoMolar) neuraminidase-inhibitor antiviral drugs
Protocol Legend
- F=fluorescent
- C=chemiluminescence
11.9 fold variance for same virus, different protocol, different lab.
Oseltamivir only
- H3N2 A/Fukui/45/2004 . . F. . 37.00 . . Atlanta
- H3N2 A/Fukui/45/2004 . . C. . 03.10 . . Tokyo
2.4 fold | 4.0 fold | 3.2 fold | 3.02 fold variance for same virus, same protocol, different lab.
Oseltamivir | Peramivir | Zanamivir | Laninamivir
- H7N9 A/Anhui/1/2013 . . F. . 0.17 | 0.06 | 0.33 | 0.46 . . Atlanta
- H7N9 A/Anhui/1/2013 . . F. . 0.41 | 0.24 | 1.06 | 1.39 . . Melbourne
Atlanta is higher on H3N2 and lower on H7N9? Are we to be concerned when drug efficiency scores are reported as highly variable with no clear annotations or explanations?
Additional Reading on Emergent H7N9 Genetics
We acknowledge the authors, originating and submitting laboratories of the sequences from GenBank & from GISAID’s EpiFlu™ Database on which this research is based. An additional list is detailed in the linked PDF entitled "GISAID_Citations_H5N1_2011" at Is H7N9 Spreading from Human to Human in China? Post#164
GISAID Citations
- GeneWurx Cross Serotype Homology Analysis, Open-Access, Full-Text version
- Human Emergent H7N9 from Zhejiang Province
- Environment Emergent H7N9 from Zhejiang
- Fatal H5N1 Homology to Emergent H7N9 from Shanghai in March
- Fatal H5N1 Karo Cluster Homology to Emergent H7N9 from First Fujian Case
- Receptor Binding Site Novelty from First Taiwan H7N9 Case
- China - H7N9 Human Isolates on Deposit at GISAID, Comprehensive Genetics Discussion
