“Anti-HIV antibodies”, ARVs and informed consent
Note: This letter was rejected by the Medical Journal of Australia on 12th August
2003.
The response was “Many thanks for your recent contribution to the Journal. Your
manuscript was discussed at the Editorial Committee Meeting and unfortunately the
outcome was that we would not proceed with peer review or publication. As you are
probably aware, the competition for space in the journal is now particularly fierce and
we have to, by necessity, reject many deserving articles. We are sorry to disappoint
you and hope you are successful in securing publication elsewhere. With kind
regards, Dr. Ann T Gregory, Deputy Editor”
Paper at www.mja.com.au/public/issues/178_11_020603/osu10738_fm.html
================================================================
In a recent study1 published in the Journal prisoners were offered antiretroviral drugs
on the basis that a positive antibody test is proof for transmission of an AIDS causing
retrovirus HIV. Although this represents the majority view, the evidence in its favour
is not without problems.2-5 Antibodies are polyspecific and are apt to yield
confounding cross-reactivities.6, 7 These are particularly likely in AIDS patients for
several reasons including their typical hypergammaglobulinaemia and the fact that
90% of AIDS diagnoses involve fungal or mycobacterial agents8 which induce
antibodies reactive with the antigens employed in the antibody test kits.9-12
Proof that the antigens in the test kits react exclusively with antibodies directed
against a retrovirus HIV can be obtained only by comparing the reactions with HIV
itself. That is, HIV isolation is the only scientifically valid gold standard for
determining the specificity of a test claimed to diagnose HIV infection. Yet to date
there are no such data, a caveat repeatedly included in the packet insert of one test
manufacturer: “At present, there is no recognized standard for establishing the
presence or absence of antibodies to HIV-1 and HIV-2 in human blood”.13 Instead of
using the correct gold standard HIV experts and biotechnology companies determine
specificity for HIV using AIDS as a gold standard. Not only is this not the professed
outcome of the test,14 if AIDS is used as a gold standard then by definition, all
seropositive, AIDS-free individuals including gay men, drugs users, haemophiliacs,
Africans and those not in a defined risk group, healthy or otherwise, must be false
positives. Given the majority of seropositive individuals fall into these categories, no
such individuals can be infected with HIV, the positive predictive value of the tests is
insignificant and “the global burden of HIV” unsubstantiated.
Failure to use an HIV isolation gold standard has also resulted in the bizarre situation
where globally there are at least ten different sets of criteria for defining a positive,
“confirmatory”, HIV Western blot (WB) (Figure 1). The consequences are, for
example, an individual “confirmed” infected in New York City on the CDC criteria
would not be “confirmed” infected in Sydney, Australia. Or an Australian WB positive
with p41, p32, p24 and p18 bands would not be “confirmed” infected in Africa. Or an
African WB positive with a p41 and p120 band would not be positive in Australia,
parts of the USA or Europe. Or, as reported in the study by Kashala,11 up to 83% of
African leprosy patients and 64% of their contacts have a positive WB pattern not
considered positive by the World Health Organisation but considered positive by the
most “stringent” criteria of the Australian National Serology Reference Laboratory.
This confusion is confirmed in laboratory manuals, one of which advises, “Specific
guidelines for interpretation may differ depending on the local policies, GENELABS
recommends following the accepted policy to be in accordance with local
regulations”. It then adds further to the confusion by appending yet another set of
criteria for a positive Western blot.15 It seems remarkable that “local policies” and
“local regulations”, rather than the biological properties of a virus, determine WB
band patterns regarded as specific proof of infection and that such extensive
variation is regarded consistent with “extraordinarily accurate” antibody tests.16
Within the risk groups a positive antibody test, whatever its genesis, correlates with
the presence or development of the clinical AID syndrome. This relationship is not
under contention. What the minority view disputes is the claim that data based on an
AIDS gold standard prove the tests specific for a retroviral infection. In no way does
this view preclude the tests possessing a high degree of clinical relevance.
Physicians are familiar with several non-specific laboratory tests of diagnostic and
prognostic utility. For example, an elevated erythrocyte sedimentation rate (ESR) is
caused by "the dielectric effect of proteins in the surrounding plasma", especially
"fibrinogen, immunoglobulins, and other acute-phase reaction proteins", and their
increased levels in some disease states.17 Values exceeding 100 mm/hr have a 90%
positive predictive value for serious underlying pathology including infection, collagen
vascular disease or metastatic tumours.18 Thus, like a positive antibody test, an
elevated ESR also predicts a number of unrelated diseases including AIDS indicator
diseases19 and encompasses an increased probability of dying within the next
several years.
These matters have significant implications now that the November 1992 Australian
High Court ruling on Rogers-v-Whittaker obliges physicians to provide patients with
“all the relevant information to choose between undergoing and not undergoing the
treatment”.20 The same principle is echoed in the AMA Code of Ethics, “Make sure
that all research participants or their agents are fully informed”,21 and in the Helsinki
Declaration, “In any medical study, every patient – including those of a control group,
if any –should be assured of the best proven diagnostic and therapeutic method”.22
Prisoners are no exception to the need for informed consent with treatments based
on the interpretation of a laboratory test. In fact they present an extra ethical
dimension because they are held in captivity and, rightly or wrongly, may feel
coerced into accepting treatments which are potentially toxic. Neither is the issue of
providing full, relevant information a legal obligation only for prisoners. There may be
other individuals reluctant to question their physicians’ good intentions or who feel
unable to deal with a doctor who lacks awareness of other scientific opinion. This
places patients at risk of passively accepting treatments they might otherwise defer
or reject. Physicians and researchers offering treatments should acquaint their
patients with the scientific basis of the tests they use including scientific opinion at
variance with their own.
REFERENCES
1.
O'Sullivan BG, Levy MH, Dolan KA, Post JJ, Barton SG, Dwyer DE, et al. Hepatitis C
transmission and HIV post-exposure prophylaxis after needle- and syringe-sharing in Australian prisons.
Med J Aust 2003;178:546-9.
2.
Papadopulos-Eleopulos E, Turner VF, Papadimitriou JM. Is a positive Western blot proof of
HIV infection? Bio/Technology 1993;11:696-707.
3.
Papadopulos-Eleopulos E, Turner VF, Papadimitriou JM, Causer D. HIV antibodies: Further
questions and a plea for clarification. Curr Med Res Opinion 1997;13:627-634.
4.
Papadopulos-Eleopulos E, Turner VF, Papadimitriou JM, Causer D, Page B. HIV antibody tests
and viral load - more unanswered questions and a further plea for clarification. Curr Med Res Opinion
1998;14:185-186.
5.
Papadopulos-Eleopulos E, Turner VF, Papadimitriou JM, Alfonso H, Page BA, Causer D. A
critical analysis of the evidence for the existence of HIV. Online BMJ 2003.
http://bmj.com/cgi/eletters/326/7387/495#31507
6.
Nossal GJV. Antibodies and Immunity. Harmondsworth, UK: Penguin Books Ltd; 1971.
7.
Ternynck T, Avrameas S. Murine natural monoclonal antibodies: a study of their
polyspecificities and their affinities. Immunol Rev 1986;94:99-112.
8.
Hu DJ, Fleming PL, Castro KG, Jones JL, Bush TJ, Hanson D, et al. How important is
race/ethnicity as an indicator of risk for specific AIDS-defining conditions? J Acquir Immune Defic Syndr
Hum Retrovirol 1995;10:374-380.
9.
Muller WEG, Bachmann M, Weiler BE, Schroder HC, Uhlenbruck GU, Shinoda T, et al.
Antibodies against defined carbohydrate structures of Candida albicans protect H9 cells against
infection with human immunodeficiency virus-1 in vitro. J Acquir Immun Defic Syndr 1991;4:694-703.
10.
Matthews R, Smith D, Midgley J, Burnie J, Clark I, Connolly M, et al. Candida and AIDS:
Evidence for protective antibody. Lancet 1988;ii:263-266.
11.
Kashala O, Marlink R, Ilunga M, Diese M, Gormus B, Xu K, et al. Infection with human
immunodeficiency virus type 1 (HIV-1) and human T cell lymphotropic viruses among leprosy patients
and contacts: correlation between HIV-1 cross-reactivity and antibodies to lipoarabinomannan. J Infect
Dis 1994;169:296-304.
12.
Tessema TA, Bjune G, Hamasur B, Svenson S, Syre H, Bjorvatn B. Circulating antibodies to
lipoarabinomannan in relation to sputum microscopy, clinical features and urinary antilipoarabinomannan detection in pulmonary tuberculosis. Scand J Infect Dis 2002;34(2):97-103.
13.
Packet Insert Axsym system (HIV-1/HIV-2). Abbott LaboratoriesDiagnostics Division. 100
Abbott Park Rd. Abbott Park. Illinois: United States of America. 1988, 1998.
14.
Griner PF, Mayewski RJ, Mushlin AI. Selection and interpretation of diagnostic tests and
procedures. Ann Int Med 1981;94:559-563.
15.
Genelabs Diagnostics Pty Ltd HIV BLOT 2.2 Instruction Manual. Singapore; 1999.
16.
National Institute of Allergy and Infectious Diseases. Focus on the HIV-AIDS Connection.
2001. www.niaid.nih.gov/newsroom/focuson/hiv00/default.htm
17.
Wintrobe WM, Richard Lee G, Boggs DR, Bithell TC, Foerster J, Athens JW, et al. Clinical
Hematology. 8th ed. Philadelphia: Lea & Febiger; 1981.
18.
Brigden M. The erythrocyte sedimentation rate. Still a helpful test when used judiciously.
Postgrad Med 1998;103:257-62, 272-4.
19.
Papadopulos-Eleopulos E, Turner VF, Papadimitriou JM, Alfonso H, Page BAP, Causer D, et
al. High rates of HIV seropositivity in Africa-alternative explanation. Int J STD AIDS 2003;14:426-427.
20.
Rogers v. Whitaker (1992) 175 CLR 479 F.C. 92/045. The High Court of Australia; 1992.
www.austlii.edu.au/cgibin/disp.pl/au/cases/cth/high%5fct/175clr479.html?query=%22roger%22+and+%22whitaker%22
21.
Australian Medical Association Code of Ethics 2003. www.ama.com.au/web.nsf/doc/WEEN5M4VJV
22.
World Medical Association. The Declaration of Helsinki; 2000.
www.wma.net/e/ethicsunit/pdf/chapter_4_decl_of_helsinki.pdf
Global criteria defining a positive HIV Western blot
AFR AUS FDA RCX CDC CDC CON GER UK FRA MAC
1
2
ENV
p160
p120
p41
ANY
2
ANY ANY
1
1
p160/
ANY p120
AND
1
p41
p160/
p120
OR
p41
p160/
p120 ANY
OR
1
p41
ANY ALL
1
3
p32
GAG
p55
p39
p24
p18
ANY
1
p32
AND AND
AND OR
p32
p24
ANY
1
p24
p24
ANY 1 GAG OR POL
p53
ANY 3 GAG OR POL
POL
p68
p32
ANY
1
AND OR
p24
ANY
1
3 WEAK BANDS OR ANY STRONG BAND
HIV
WESTERN
BLOT STRIP*
AFR=Africa1 AUS=Australia2 FDA=US Food and Drug Administration3 RCX=US Red
Cross3 CDC=US Centers for Disease Control3 CON=US Consortium for Retrovirus
Serology Standardization3 GER=Germany
UK=United Kingdom FRA=France
MACS= US Multicenter AIDS Cohort Study 1987-1992.
* Bands not in
electrophoretic order
NOTES:
I.
“The Association of Public Health Laboratories now recommends that patients who have minimal positive
results on the WB, eg p24 and gp160 only, or gp41 and gp160 only, be told that these patterns have been
seen in persons who are not infected with HIV and that follow-up testing is required to determine actual
infective status”.4
II.
In February 1993 the US Food and Drug Administration relaxed their criteria in order to “reduce the number
of HIV-1 seroindeterminate Western blot interpretations”, that is, to increase the number of HIV positive
individuals.5
1.
2.
3.
4.
5.
WHO. (1990). Acquired Immunodeficiency Syndrome (AIDS). Proposed criteria for interpreting results from
Western blot assays for HIV-1, HIV-2 and HTLV-I/HTLV-II. Weekly Epidemiological Record 65:281-298.
Healy DS, Maskill WJ, Howard TS, et al. (1992). HIV-1 Western blot: development and assessment of
testing to resolve indeterminate reactivity. AIDS 6:629-633.
Lundberg GD. (1988). Serological Diagnosis of Human Immunodeficiency Virus Infection by Western blot
Testing. Journal of the American Medical Association 260:674-679. (Data presented in this paper reveal
that when the FDA criteria are used to interpret the HIV Western blot less than 50% of US AIDS patients
are HIV positive whereas 10% of persons not at risk of AIDS are also positive).
Mylonakis E, Paliou M, Greenbough TC, Flaningan TP, Letvin NL, Rich JD. Report of a false-positive HIV
test result and the potential use of additional tests in establishing HIV serostatus. Archives of Internal
Medicine 2000;160:2386-8.
Keinman S, Busch MP, Hall L, et al. (1998). False-positive HIV-1 test results in a low -risk screening setting
of voluntary blood donation. Journal of the American Medical Association 280:1080-1083.