Commentary: non-HIV hypotheses must be studied more carefully

BMJ 1996;312:210-211 (27 January)

Papers

Commentary: non-HIV hypotheses must be studied more carefully

Peter Duesberg, professor ^a

^a Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3206, USA

Patients with haemophilia treated with commercial factor VIIIand zidovudine are at risk of developing AIDS defining immunodeficiencydiseases like pneumonia, candidiasis, and toxoplasmosis butnot Kaposi's sarcoma or dementia. Their risk of these diseasesis proportional to their lifetime dosages of factor VIII andcytotoxic DNA chain terminators like zidovudine.*RF 1, 1a*

Haemophilia specific AIDS diseases have been explained in termsof two hypotheses. A non-infectious hypothesis holds that thelong term administration of immunosuppressive foreign proteinscontaminating commercial factor VIII and zidovudine causes AIDS.An infectious hypothesis holds that HIV causes AIDS.¹

Still no evidence for infection

Based on inadequate tests, Sabin et al reject the foreign protein-zidovudinehypothesis.² However, their data and those of others actuallysupport the hypothesis.

Sabin et al claim that HIV causes AIDS because all of theirhaemophilic patients had antibodies against the virus. But HIVcannot be enough for AIDS because six of their 17 HIV positivepatients (table 2) remained healthy for 10 years. Likewise 12000out of 15000 HIV positive American haemophilic patients haveremained AIDS free since 1985.¹ ³

Sabin et al observe that AIDS diseases occur, if at all, onlyfive to 10 years after the appearance of antibodies to HIV.However, "viral" AIDS should occur within weeks after infectionbecause viruses replicate exponentially. A single infected cellproduces over 100 HIV virions within 48 hours,⁴ generating 10¹⁴viruses within two weeks after infection--enough to infect everycell in the human body. Moreover, viral AIDS should be neutralised--notcaused--by the antiviral immunity that is detectable in haemophilia.

By contrast, long time periods are required to accumulate pathogenicdoses of foreign proteins via transfusions.¹ Because HIV isa rare contaminant of factor VIII, it seems to be just a surrogatemarker for high dosages of foreign proteins. Sabin et al confirmthis: "Most patients with severe haemophilia--and thereforethe highest users of clotting factor concentrate--were seropositiveto HIV. . . ."² Thus their results support the foreign proteinhypothesis.

An appropriate test of the foreign protein hypothesis wouldcompare HIV positive patients with HIV negative patients matchedfor the lifetime dosage of factor VIII. By contrast, Sabin etal matched patients for current usage. Plainly, a 60 year oldand a 14 year old would not be an appropriate match (table 1).²

The HIV hypothesis predicts the same pattern of AIDS diseasesin haemophilia as in other AIDS patients, but Kaposi's sarcomaand dementia were not observed in the haemophilic patients studiedby Sabin et al (table 2). However, the foreign proteinzidovudinehypothesis predicts the restriction to immunodeficiency diseasesobserved by Sabin et al exactly.

The HIV hypothesis predicts sexual transmission of AIDS. However,in the United States the wives of 15000 HIV positive haemophilicmen have only the normal background prevalence of AIDS definingdiseases.¹ ⁵

Strong temporal evidence

HIV is now said to cause AIDS 10 years after infection, andinfections by transfusions were stopped in 1985. Hence AIDSin patients with haemophilia should have peaked long before1995. Instead, cases declined until 1986¹ and then sharply increasedfrom 1987 both in the United States and in Britain when zidovudineand other drugs were introduced as treatment for and prophylaxisagainst HIV infection and AIDS.⁶ ⁷

Zidovudine kills all growing cells, particularly fast growingblood cells, and therefore must cause immunodeficiency. Eventhe manufacturer acknowledges, "It is often difficult to distinguishadverse events possibly associated with zidovudine administrationfrom underlying signs of HIV disease."⁸ An epidemiological studycited by Sabin et al directly confirms that zidovudine treatedHIV positive haemophilic patients have a 4.5-fold higher annualAIDS rate and a 2.4-fold higher annual death rate than untreatedcontrols.⁹ This explains why the morbidity of American⁶ andBritish⁷ patients with haemophilia has sharply increased since1987, when most HIV positive haemophilic patients began zidovudine.*RF1, 1a* Sabin et al confirm the zidovudine hypothesis, as "allnine HIV positive patients with AIDS received zidovudine" inaddition to the "toxic" pentamidine,¹⁰ co-trimoxazole, and fluconazole.²

The foreign protein hypothesis predicts that AIDS in patientswith haemophilia can be prevented if not cured by using factorVIII that is free of foreign protein. Sabin et al endorse this:"These concentrates seem to preserve the immune system. . .." Indeed, not only were the immune systems of HIV positivehaemophilic patients treated with pure factor VIII and no zidovudine"preserved" but their T cells increased by up to a quarter overthree years--despite the presence of the hypothetical T cellkiller HIV.¹¹ ¹²

Conclusion

The foreign protein-zidovudine hypothesis provides biochemicallyplausible candidates for pathogenicity--that is, large amountsof foreign proteins transfused over decades and DNA chain terminatorsprescribed indefinitely such as zidovudine. With a daily doseof 500 mg zidovudine a person receives 2x10²⁰ molecules, or2x10⁶ for every human cell, every day for the rest of his life.By contrast, after 11 years of research the HIV hypothesis hasyet to identify a single molecule that could be pathogenic.¹³In view of this and the complete failure of the HIV hypothesisto produce public health benefits, non-HIV hypotheses must bestudied more carefully.