Re: Re: Re: Re: The predictions based upon the 'HIV/AIDS' hypothesis have been fulfilled 4 February 2005
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Nicholas Bennett,
Infectious Disease Postdoc/Clinician
Department of Pediatrics, University Hospital, Syracuse, NY

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Re: Re: Re: Re: Re: The predictions based upon the 'HIV/AIDS' hypothesis have been fulfilled

I find it encouraging that Mr Spagnoli is taking the time to not only investigate some of the references provided, but also come up with a few of his own. This probably bodes well for his future PhD!

The first study looked at a specific subset of drug users - those suffering from an unusual complication called thrombocytopenia (lack of platlets, the blood cells involved in clotting). Since all of them were HIV+ it's hard to rule that out as a causative factor, and pre-selecting for a kind of auto-immune disease would also raise the percentage with hypergammaglobulinemia. The second reference is more interesting although just looking at the abstract it's hard to tell which of those with hypergammaglobulinemia did or did not test positive for HIV (only a subset were tested for HIV).

One study I looked at when I made the comments in the prior message was:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1671053

Jacobson et al J Infect Dis. 1991 Feb;163(2):240-6. "The evolution of lymphadenopathy and hypergammaglobulinemia are evidence for early and sustained polyclonal B lymphocyte activation during human immunodeficiency virus infection."

They mention that the hypergammaglobulinemia appeared post-seroconversion (which additionally shows that it wasn't present initially).

I didn't mean to imply that HGG was uncommon in HIV+ people, but I didn't want to commit to saying something more concrete like "many" or "most" (I've learnt the hard way that if you commit to anything on the web you'd better have dug out the reference in advance!). In fact it seems to be something you expect to see in the majority of cases - Field's virology uses the phrase "almost invariably". Hypergammaglobulinemia isn't AIDS defining because it occurs frequently in those who are HIV+ but without clinical immune suppression. I'm obviously biased, but HIV infection is the first cause of HGG that springs to my mind above and beyond any others.

Besides, if HGG is due to non-specific immune stimulation, it seems odd that the CD8 T cell responses are actually decreased in AIDS and pre-AIDS complex. In fact, antibody-responses are also functionally impaired, highlighting the fact that it's quality and not quantity of response that counts. It's interesting that a PubMed search for "hypergammaglobulinemia and IVDU" only brings up 3 citations, all of which involve HIV infection, whereas "hypergammaglobulinemia and HIV" brings up 245. "hypergammaglobulinemia and intravenous drug use" brings up 11 citations of which 9 include HIV, and the other two did not test for HIV (1 in fact pre-dated the first AIDS diagnosis). I think this highlights the relative rarity of the condition in drug users without HIV.

The malaria story is interesting, because it highlights an obvious confounding event that really should have been spotted earlier. The idea of immune complexes causing false positives has cropped up elsewhere, and also tested with negative results (in the paper under discussion for example). A clue is given in the text when they say "Possible explanations include coincidental distribution paralleling malaria..." Malaria causes anaemia, which is treated with blood transfusions in some areas. The association between HIV positive test results and malaria was that the patients WERE being infected with HIV, through their unscreened blood transfusions.

Greenberg et al JAMA. 1988 Jan 22-29;259(4):545-9. "The association between malaria, blood transfusions, and HIV seropositivity in a pediatric population in Kinshasa, Zaire."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3275815

As screening became more widespread this problem has decreased.

Shaffer et al AIDS. 1990 Dec;4(12):1231-6. "Trends and risk factors for HIV-1 seropositivity among outpatient children, Kinshasa, Zaire."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2088400

The exact studies you ask for regarding culture from African specimens probably haven't been done, at least not with regard to giving specificity and sensitivity measures from the tests. This is due to plain and simple operational limitations in terms of personel and equipment, and in addition aren't required for any other pathogen! In their absence the next best thing is to rule out various potential problems, and in most cases I simply don't see a reason to even suspect there to be a problem (e.g. malaria and TB). Such potential problems are usually highlighted by the anti-HIV dissidents by selective interpretation of the literature, rather than anyone actually finding a real problem. There are of course conditions associated with false positive HIV tests (ELISA-only nearly always) but many of the claims make no sense. Additionally, current rapid tests are much better than the initial ELISAs, partly because they've been optimised to avoid problems found from the earlier tests.

The papers by Jackson and Ho show the impressive sensitivity and specificity of the tests in two important risk groups - homosexuals and hemophiliacs. it isn't unreasonable to ask for extension studies in other risk groups, but equally it isn't unreasonable to extrapolate from one group to another. Unfortunately biology is nowhere near as tidy as fluid mechanics, but just because the specific data requested isn't written up doesn't mean the other related data doesn't apply. Since antibody results from certain tests correlate so well with culture and PCR, it seems entirely reasonable to test other tests against them. Running an HIV assay requires a lab coat, gloves, and basic science tools such as a Gilsen pippette and tips and a few reagents. It takes a few minutes to prepare a sample and run the assay, with most of the time (a few hours at most) taken up with waiting. Growing HIV requires around 2 weeks of labour involving at least twice weekly maintanence of cell lines and an assay at the end of it all roughly similar to (if not more complex than) the serological assay. HIV culture also requires specially trained workers and dedicated culture suites with modified airflow and filter facilities, along with protective clothing. Performing this kind of work on hundreds of samples would be a huge effort - the fact that it's been done at all is impressive.

The package inserts actually have to demonstrate superior reliability to anything sent through peer-review, since they have to pass FDA approval. Peer-reviewers do not come around to your lab to read your workbooks! Several validation papers are reported in the literature (e.g. Zaaijer et al Transfusion. 1998 Aug;38(8):776-81. "Validation of a new immunoblot assay (LiaTek HIV III) for confirmation of human immunodeficiency virus infection."). The problem associated with publishing in the literature is that, in many cases perhaps, the writers are being paid by the company manufacturing the test. Since peer review is less stringent that FDA approval it is perhaps inappropriate to published such results in that way. The results of clinical trials are also not often published in the literature in that way. There is a good argument that such evidence should be available, after of course being approved (or not!) by the FDA. One could argue that the fact that the validation studies are presented in the test package insert, and in many cases are available through the internet, satisfies this criteria.

Vast amounts of money have been spent on HIV research, arguably at the expensive of other areas of important healthcare, but most of this money seems to me to be involved in the blue-skies molecular research of unravelling the virus. There is no need to re-invent the wheel by performing proof of causation experiments over and over again, at least not by the arguments put forward by people such as the Perth Group.

Nick Bennett njb35@cantab.net

Competing interests: None declared