The concluding part of our investigation into a global healthcare scandal. Is the way we test for HIV more harmful than the disease itself?
By Neville Hodgkinson – The Business , 16/17 May 2004
FROM the start HIV tests had severe limitations. But these were disregarded, and their widespread use rapidly led to the idea that hundreds of thousands of Americans and millions of Africans are infected. Now a group of scientists based in Perth, western Australia, has claimed that no HIV test kit is capable of showing a person to be infected. Legal challenges are being mounted in the United States and France by people diagnosed as HIV-positive and told they would die from Aids. They remain healthy.
As long ago as 1986, Dr Thomas Zuck, a scientist with the US Food and Drug Administration (FDA) warned that the first test kits, using a technology called Elisa, were intended to screen blood donations – not to screen people at risk from Aids. He admitted that use had spread beyond the original intention but told a World Health Organisation meeting that it was “simply not practical” to stop it.
Other experts admit there were early problems with HIV tests, but say these were soon overcome. Not true, according to evidence cited in the 1994 edition of Aids Testing, a 400-page textbook edited by two US Centres for Disease Control experts. In a review of the various test methods used, they emphasise the need not to tell people they are HIV-positive or take medical decisions about them based on Elisa alone. “Testing by the sensitive EIA [Elisa] is done to identify those persons who need additional, more specific supplemental testing,” they say. “Counselling and medical decisions are made based on the results of the supplemental assay, not on those of the screening test alone.”
Dr Jay Epstein, another FDA scientist, says in another chapter that western blot, a method used to check first results, remains by far the most widely used “confirmatory” procedure; but with this “the greatest concern has been the high prevalence of non-specific banding patterns, resulting in indeterminate test results”. Unfortunately, he says, this phenomenon is intrinsic to the technology.
The FDA has relaxed its criteria for a positive result on the western blot to get over the embarrassing fact that with the first kit licensed for confirmatory testing, which required a positive result on three different bands, fewer than half of AIDS patients tested HIV-positive. Other authors comment that production of the western blot strips is not a precise process. There had been extensive debate over how the tests should be interpreted. “Differences in protein concentrations, identities and positions are observed between manufacturers and even between lots from the same manufacturer.”
Depending on the choice of proteins used as antigens, the tests give widely differing results in different patient groups. Elisa tests using genetically engineered or synthetic proteins bring the same problems.
If you cannot be told you are HIV-infected on the basis of the Elisa and there are such big problems with the western blot (in the UK, it is considered so unreliable as to be useful only as a research tool), which test does confirm you are infected?
In the early AIDS years, scientists often equated and described as “virus isolation” the detection in cultured cells of reverse transcriptase, an enzyme that enables a retrovirus to become integrated with the DNA of its host cell. It is now known that this enzyme has a much wider role in cell function and does not specify the presence of any retroviruses, let alone a specific one.
Similarly, detection of a protein of a particular molecular weight, believed but never proved to belong to HIV, also turned out to be of little diagnostic value. Both techniques “may be insensitive and/or non-specific”, according to guidance issued by UK Public Health Laboratory experts.
Today, a technique called the polymerase chain reaction (PCR), used to detect genetic sequences attributed to HIV by amplifying them millions of times over, is employed extensively in monitoring so-called “HIV disease”. Like the antibody tests, the method probably has value in indicating certain types of immune system activation or disturbance; but the segments of genetic material detected have not been shown to belong to a specific virus, HIV or any other.
Dramatically different results are obtained depending on the genetic “primers” chosen to start the reaction off, the probes used to analyse the results, the concentration of the various reagents used and the temperature and time over which the reaction is run. Such factors explain why results quoted in papers cited by US government scientists as having “confirmed the validity of the antibody tests” are not reproducible in other laboratories.
A meta-analysis by researchers from several institutions in the USA of relevant PCR studies published between 1988 and 1994 concluded: “The false-positive and false-negative rates of PCR that we determined are too high to warrant a broader role for PCR in either routine screening or in the confirmation of diagnosis of HIV infection. This conclusion is true even for the results reported from more recent, high-quality studies that used commercially available, standardized PCR assays …We did not find evidence that the performance of PCR improved over time.”
So, contrary to the impression most have lived with for years, the HIV test has never been proved to specify the presence of HIV. “The general belief that almost all individuals, healthy or otherwise, who are HIV-antibody-positive are infected with a lethal retrovirus, has not been scientifically substantiated,” the Perth group says.
THERE is a strong association between testing HIV-positive and the risk of developing AIDS. Evidence to this effect was and is the main reason why scientists believe HIV is the cause of AIDS. But the link is a consequence of the way the test kits were constructed, calibrated and clinically tested.
As described above, it never proved possible to validate HIV tests by culturing, purifying and analysing particles of the purported virus from patients who test positive, then demonstrating that these particles are not present in patients who test negative. This was despite heroic efforts to make the virus reveal itself in patients with AIDS or at risk of AIDS, in which their immune cells were stimulated in laboratory cultures with a variety of agents, sometimes over many weeks.
After the cells had been activated in this way, HIV pioneers selected some of the 30 or so proteins found in the filtered material that gathered at the density characteristic for retroviruses, and attributed some of these to various parts of the virus. But they never presented evidence that these so-called “HIV antigens” were constituents of a retrovirus particle of any kind, let alone a unique new retrovirus.
So, how did they define the proteins as being from HIV?
Amazingly, on the basis of selecting proteins most reactive with antibodies in blood samples from AIDS patients and those at risk of AIDS. This means that HIV antigens are being defined as such on the basis that they react with antibodies in AIDS patients, and AIDS patients are then diagnosed as being infected with HIV on the basis that they have antibodies reactive with those same antigens. The reasoning is entirely circular – which is probably why Zuck was so emphatic that none of the “HIV tests” was suitable for confirming HIV infection.
It gets worse. When Elisa test kits were developed, the priority was to protect blood supplies. For this, two limits were established. As a measure of the sensitivity of the kits in detecting unsafe blood, it was postulated that 100% of blood samples from patients with AIDS would be reactive and therefore test positive. So, if the actual proportion of samples from AIDS patients that prove reactive in clinical trials is 98%, that defines the sensitivity of that kit.
Second, as a measure of how specific the kits are in detecting unsafe blood – that is, in not causing healthy blood to test positive – it was postulated that 0% of healthy blood donors would be repeatedly reactive. Thus, if 2% of samples from healthy blood donors were found reactive during clinical trials, the specificity would be defined as 98%.
On the basis of such trials, the World Health Organisation and other agencies say that current HIV antibody tests have sensitivity and specificity in excess of 98% and are therefore extremely reliable. In reality, these measures tell us nothing about whether or not a person is infected with HIV.
The tests discriminate between healthy blood on the one hand and the blood of patients with AIDS or AIDS-like conditions on the other. That is why they are useful as a screen for the safety of blood supplies. Since AIDS patients suffer a range of active infections and other blood abnormalities, some of which will be transmissible through blood, the tests definitely help to safeguard blood quality.
Gay men leading “fast-track” sex lives, drug addicts, blood product recipients and others whose immune systems are exposed to multiple challenges and who are at risk of AIDS are much more likely to have raised levels of the antibodies looked for by the tests than healthy Americans – because the antigens in the tests were chosen on the basis that they were reactive with antibodies in AIDS patients. But this association does not prove the presence or otherwise of a lethal new virus.
In the absence of a specific test for HIV, the tests had to be calibrated so as to try to find a balance between detecting suspect blood samples and not causing healthy blood to be discarded. The safety of supplies was given priority, so the cut-off value for defining blood as reactive was set appropriately low. This ensures that the tests detect most samples of blood from people with AIDS.
But a low cut-off value also means that in screening surveys covering large numbers of people, many healthy individuals test positive. In early surveys covering 8m blood donors in the USA, it was found that of samples testing positive with a single Elisa, 96% were not reactive with the western blot test.
When the tests are used for the purpose for which they were originally designed – as a screen for blood safety – these flaws are not too big a price to pay. Repeated testing reduces the number of suspect samples and therefore the waste of healthy blood. But the flaws are deadly when it comes to screening for or diagnosing HIV/AIDS.
In wealthy countries that can afford repeated testing using a variety of approaches, and where the risks in a patient’s life are also taken into account in interpreting test results, the numbers of people falsely given to understand that they are infected with a lethal virus will be much lower than in poor countries where only a single positive result can be a sentence of death.
In the UK, for example, currently fewer than 200 deaths a year are designated HIV/AIDS, out of a nation of 60m people. Estimates for the total number of people infected with HIVstood at around 30,000 throughout the 1990s, though there has been a recent increase mostly accounted for by HIV-positivity among new immigrants from impoverished and war-torn countries.
Even so, in the light of the evidence and reasoning described above, to tell even one person that they are HIV-infected on the grounds that they have antibodies that react with the proteins in these unvalidated tests is an unwarranted assault. Manufacturers may be aware of this and some include cautious statements in their packet inserts, such as: “At present there is no recognized standard for establishing the presence or absence of antibodies to HIV in human blood.”
In countries where a single test is commonly all that can be afforded, screening surveys have given rise to the idea that millions are HIV-infected. The tests have caused countless individuals to be falsely diagnosed and nations to be deceived into believing that HIV/AIDS is set to decimate their population.
Dr Etienne de Harven, former professor of pathology, University of Toronto, who worked on retroviruses for many years at the Sloan Kettering Institute, New York, told a recent conference on AIDS at the European Parliament in Brussels: “There is a major problem with isolation and purification of HIV. The major problem being that, in spite of innumerable claims to the contrary, this retrovirus has never been isolated or purified in a scientifically acceptable manner that would satisfy the classic requirements of virology.”
He added that over the past 20 years, the medical literature “has been inundated with innumerable papers attempting to dodge the lack of electron microscope evidence for the presence of retroviral particles in samples directly collected from AIDS patients.”
Ann James, a Houston, Texas lawyer, writes in AIDS Testing: “No other disease, except perhaps leprosy from the beginning of the millennium to the 1800s, has brought so much societal pressure on its victims and caused such cataclysmic social consequences over such a long period.”
Remarkably, this cataclysm may have been caused not so much by AIDS itself as by the concept of an epidemic of HIV disease, a concept that arose because in the atmosphere of emergency surrounding the idea that a deadly virus was spreading surreptitiously among sexually-active people, public health experts considered it “simply not practical” to stop the HIV test from being used for a purpose for which it was unsuited.
As Eleni Papadopulos-Eleopulos, who heads the Perth group of scientists, puts it: “In our view the greatest single obstacle to understanding and solving AIDS is HIV.”