Indonesia never fails to shock and astound when it comes to H5N1. After allowing the virus to become endemic in poultry and infect people on a significant scale the government is withholding human samples from the WHO. This means WHO scientists and collaborating laboratories around the world are essentially unaware of virus mutations within Indonesia. These gaps in knowledge have clear dangerous consequences for assessing virulence, infectivity, efficacy of anti-viral drugs like Tamiflu and design of well matched vaccines.
Indonesia resumed sending samples in late May 2007 following a string of promises but only sent three samples. Government ministers made clear on several occasions that delivery of the other 20 plus samples from 2007 cases would depend on satisfying demands for sample sharing and vaccine supply that WHO is in no position to guarantee.
Indonesia has clearly chosen the wrong time to hold back samples. June 2007 saw a clutch of worrying trends and reports indicating changes in virulence and sensitivity to key anti-viral drugs which need prompt clarification. Trouble is those in a position to help (WHO affiliated scientists and labs around the world) are in no position to do so
In early June ’Bayu Krisnamurthi’, chief executive for Indonesia’s National Committee for Avian Influenza and Control and Pandemic Influenza Preparedness, said the Indonesian H5N1 virus had changed (mutated), from previously when human infections required high-density and high-density exposure. “There are now suspicions that this (infection) has become easier”, he said, adding that fatality rate had increased to 86.4 per cent by May 2007 up from 74.5 per cent in 2006.
Wayan Teguh Wibawan, a microbiologist from Indonesia’s avian flu commission went further telling Reuters that suspicions are based on preliminary results of genetic tests at laboratories in Indonesia. The amino acid structure of poultry H5N1 samples is increasingly similar to that seen in human H5N1 samples, he said. He went on to claim that similarity in amino acid structure makes it easier for the virus to attach to receptors on epithelial cells that line the throat and lungs. The virus would have to attach readily to human cell receptors to pass easily from birds to humans, he said. He told Reuters of “gradual changes” in the virus samples he receives each month, but gave no further details.
These claims from Indonesia were largely dismissed by scientists and officials with WHO, who gave the whole idea ‘short shrift’. WHO spokesman Gregory Hartl told Reuters WHO had not seen any evidence that the virus has become more transmissible to humans. The WHO has received very few isolates from Indonesia recently”, he told CIDRAP News. WHO has received just three samples gathered from two patients this year with samples from over twenty 2007 cases outstanding. “Without virus characterisation, we cannot say whether the virus has changed or not”, said Hartl.
Lo Wing-Iok, an infectious diseases expert in Hong Kong, told Reuters that suspicion of mutations made it crucial for Indonesia to share its samples with the rest of the world. “These (suspected mutations) must be confirmed and the world must be forewarned if there has been such an important change. If there is a change, it would not only mean that the virus can jump more easily from bird to man, but from human to human too.”
“I think it would be important to know the entire (genetic) sequence of these Indonesian viruses before we can make any assessments about changes in virulence or host transmissibility changes”, said Dr Michael Perdue of the WHO’s global influenza programme and quoted by CTVglobemedia. “We would certainly look forward to having the full sequence and antigenic analysis of these viruses as soon as possible”, he said.
However, he went on to take issue with assertions by Krisnamurthi that recent human cases in Indonesia have become infected from less intensive exposure to the virus than had previously been the case. He questioned which cases Krisnamurthi was referring to or how the exposure was measured.
It is not even clear how exposure could be measured in many of Indonesia’s cases claimed Perdue, because a large number of the 101 human infections recorded in Indonesia have occurred in people for whom no link to infected poultry was ever established. Ministry of Health officials in Jakarta have told the WHO that in at least thirty per cent of cases no firm proof of how the people had come into contact with the virus could be established.
As regards changes in amino acid structure claimed by the microbiologist Wayan Teguh Wibawan, Perdue said it is important to find out whether Indonesian scientists are basing conclusions on a study of the complete genetic ‘blueprints’ of the viruses isolated from humans or just a portion of the haemagglutinin gene. Haemagglutinin is the surface protein that plays a key role in ability of influenza viruses to infect different hosts such as birds, humans or other mammals like felines and canines.
That H5N1 can infect some people but clearly not the majority was initially ascribed to the haemagglutinin protein being better suited for attachment to particular receptors and especially those found in birds. It followed that simple mutations at the receptor binding site on the virus was all that would be required to convert this bird virus into a human virus.
But recent research findings from a number of laboratories and explained by Hong Kong influenza expert Dr Malik Peiris at a recent conference in Canada casts doubt on this previous simplistic view. “It still remains an open question over what it will take to allow this virus to go human-to-human”, says Peiris.
Michael Perdue agrees, saying almost all influenza experts concur that a single change in a particular region is unlikely to be sufficient to trigger a major change in virus behaviour.
Reasons behind Indonesian observations on exposure and death rates are almost certainly simpler. Indonesia appears to have given up on surveillance, identification and documentation of H5N1 outbreaks in poultry, as seen by inability to link one third of recent human cases to poultry. Indonesian reports on other cases simply contain some vague reference to sick or dying fowls in the affected area. The last outbreak in poultry logged by the Indonesian government with OIE (World Organisation for Animal Health) was for August 2006.
With the disease becoming progressively more entrenched and endemic in the Indonesian environment clearly more people will be exposed to the disease more often and for longer periods of time. As far as death rate is concerned Indonesian officials admit that most people, especially in rural areas, do not understand that this particular poultry disease has human dimensions. Since symptoms of H5N1 are not dissimilar to many other respiratory diseases including ‘ordinary’ human flu then people are clearly not coming forward in time if at all.
Indonesian Health Minister Siti Fadilah Supari recently compared the unfavourable 80+% death rate from H5N1 in Indonesia with the much lower death rate (around 50%) recorded in Egypt. But the two may not be comparable because a majority of recent cases and survivors in Egypt have been very young children (under six years of age) with ‘fledgling’ immune systems.
WHO suggests the high survival rate in Turkey during early 2006 was due to the very young age of almost all patients. Death is invariably not a direct result of H5N1 infection but due to over-reaction of strong immune systems in young fit adults within the 16 to 35/40 age range. This belief was enforced when Indonesia’s latest (101st) human case identified on 22 June responding within days to treatment at the Arifin Achmad Hospital in Pakanburu on Sumatra. The patient from the town of Rumbai in Riau province was a 3 year old girl.
More trouble for Indonesia appeared when Jennifer McKimm-Breschkin, research scientist at Australia's CSIRO (Commonwealth Scientific and Industrial Research Organization) presented findings on H5N1 susceptibility to oseltamvir (Tamiflu). She told a major international influenza conference of tests which showed that H5N1 viruses from Indonesia were 20 to 30 times less susceptible to oseltamvir compared to H5N1 viruses circulating in Cambodia several years ago.
Reduced sensitivity in the Indonesian viruses is an unwelcome development, said McKimm-Breschkin, given that oseltamivir does not have a great track record against the family group (clade 1) to which the Cambodian H5N1 viruses belong. Tests were only conducted on samples from poultry but clearly need to be repeated on the latest human samples from Indonesia, but only Indonesia’s commercial partners in the pharmaceutical industry apparently have access to these genetic sequences.
They say trouble always comes in threes. Indonesian Health Minister Supari claimed the human H5N1 vaccine based on Indonesian genetic sequences and manufactured under special preferential agreement by pharmaceutical manufacturer ‘Baxter International’ could be available this July.
This was clearly good news but she went on to say that Indonesia will use the vaccine immediately. This is completely contrary to advice from the WHO that advises stockpiling and use when only absolutely necessary. There was a predictable and understandable ‘stony’ silence at the WHO.
Indonesia continues to play a dangerous game with H5N1 HPAI, withholding samples and essentially doing its own thing, while the WHO and others can do very little to assist even when it is asked to do so.