Can Epidemiology Determine Whether Drugs or HIV Cause AIDS?

Peter H. Duesberg
Professor Dr. Peter H. Duesberg, Department of Molecular and Cell Biology, 229 Stanley Hall, University of California, Berkeley, CA 94720, USA.

Original Publication
AIDS-Forschung (AIFO)
12, pp. 627-635
December 1993

Summary

Two recent longitudinal surveys of homosexual men, one from San Francisco, the other from Vancouver, have reinvestigated the question whether AIDS is caused by HIV or drugs. During 8-year observation periods the San Francisco survey observed that 215 out of 445 HIVpositive drug users developed AIDS and the Vancouver survey that 136 out of 365 HIV antibody-positive drug users developed AIDS. On the basis of these correlations both surveys have concluded that HIV causes AIDS, and have rejected my hypothesis that recreational drugs and anti-HIV drugs, like AZT, cause AIDS. However, these conclusions are worthless because the authors failed to recognize that: i) even a perfect correlation with HIV (Koch's first postulate) does not prove causation without functional tests; ii) positive antibody tests do not prove HIV infection due to false-positives, e.g. 17% in the Vancouver group; iii) they lacked the only absolute epidemiological argument against the drug-AIDS hypothesis, drug-free AIDS cases; iv) drug toxicity is dosage dependent, i.e. "the dose is the poison." Since short-term drug users were not distinguished from long-term users, no drug dose-AIDS response relationships emerged; v) AZT, prescribed as an anti-HIV drug to HIV-positives, is immunotoxic and lymphomagenic. Contrary to the authors' conclusion, data of both surveys confirm the drug-AIDS hypothesis with consistent drug AIDS correlations, drug-AIDS dose-response relationships, and even drug-specific diseases. A definitive test to distinguish between HIV and drugs as causes of AIDS would: i) define all AIDS diseases clinically, independent of HIV; ii) test clinically defined AIDS cases (a) for HIV, not antibodies against HIV, and (b) for their lifetime dosage of recreational drugs and AZT; iii) conduct functional tests with drugs or HIV, if no drug-free or HIV-free AIDS cases can be found.

Introduction

Two longitudinal surveys, one of 812 homosexual men and 215 heterosexual controls from San Francisco (2), the other of 715 homosexual men from Vancouver (3), have recently reinvestigated the question whether recreational and aphrodisiac drugs or HIV cause AIDS. Both surveys took aim at my hypothesis that recreational drugs and AZT cause AIDS (4, 5). But the Vancouver team also credited me erroneously with the hypothesis that "chronic promiscuous male homosexual activity" causes AIDS (3). After an 8-year observation period the San Francisco survey had observed 215 AIDS cases out of 445 HIV-positive drug users (Table 1). The Vancouver survey had observed 136 AIDS cases out of 365 HIV-positive drug users after an observation period of 8.6 years (Table 1).

Table 1: Drug use, AIDS and health among HIV positives reported by the San Francisco and Vancouver surveys (2, 3).

*Drug use among HIV-positives is documented below.

Thus both surveys report perfect correlations between drug use and AIDS (see below), but claim to have refuted my hypothesis that injected and orally consumed recreational drugs and AZT cause AIDS (4, 5).

The epidemiologists from San Francisco state that "substance abuse as a main cause of AIDS has ... no basis in fact," and the epidemiologists from Vancouver state that "the hypothesis that AIDS in homosexual men is caused ... by drugs ... is rejected by these data," and that "HIV has an integral role in the pathogenesis of AIDS" but it "does not rule out a role for cofactors ..." (3). The Vancouver survey even warns that my drug hypothesis is "a hindrance to public health initiatives" (3), and the San Francisco survey advises "The energies of Duesberg and his followers could better be applied to unraveling the enigmatic mechanism of the HIV pathogenesis of AIDS."

Although my name was cited 13 times by the authors of the San Francisco survey in their 2-page Nature Commentary, the editor of Nature denied me the right of reply because I had asked "unanswerable rhetorical questions" (78). Two HIV researchers have seconded this decision and have even submitted procedures how I "should be stopped" (79).

Here I will demonstrate that inherent limitations of the epidemiological method, biases due to the HIV-based AIDS definition and the failures of both surveys to recognize the dosage dependence of drug toxicity and of drug-specific AIDS diseases invalidate their conclusions. Indeed, data of both teams confirm the drug hypothesis with consistent correlations, drug-AIDS dose-response relationships and drug-specific AIDS diseases.

1. Limits of the Epidemiological Method

i) Epidemiology not sufficient to prove that a microbe causes disease. Because a microbe can be pathogenic when it is active and abundant, and is harmless when it is inactive and rare, documenting the presence of a microbe is not sufficient to prove causation. The necessary tests to prove causation have been defined by Robert Koch and since termed Koch's postulates. According to these postulates i) the agent must be present in every case of the disease in amounts sufficient to cause disease; ii) it must be isolated in pure form; and iii) it must cause the disease if inoculated into a suitable host.

Because of its descriptive nature, epidemiological search for an infectious pathogen is restricted to correlations and thus only relevant for an appraisal of Koch's first postulate. Epidemiology can at best confirm Koch's first postulate and hence never prove that an infectious agent causes a disease.

ii) Epidemiology sufficient to prove that drugs cause disease, if dosage is determined. Clearly if drugs were to cause AIDS, the risk of a short-term user would be much lower than that of a long-term user. The toxicity of drugs depends on the dose that is consumed over a lifetime because "the dose is the poison." One year of smoking or drinking does not cause lung cancer or liver cirrhosis, but 10 to 20 years may do so (6). Thus, a drug dose-response relationship must be established to distinguish a toxic drug from other non-toxic agents. For this purpose groups controlled for the dosage of drug use must be compared to otherwise matched non-drug users. Final proof of causation is obtained by causing toxin-specific disease in animals. Thus, demonstrating unquantified drug use by AIDS patients is not sufficient to prove causation.

iii) Epidemiology can exclude possible causes of a disease. Epidemiology can exclude both an infectious and a noninfectious agent as a cause, if the disease occurs in its absence. Thus, drug-free AIDS cases must be identified to exclude drugs, or HIV-free AIDS cases to exclude HIV as causes of AIDS.

iv) Disease must be definable independent of a putative cause. In studies designed to find the cause of a disease, the disease must be clinically definable, independent of its putative cause. If A and B are investigated as possible causes, it must be possible to define the disease independent of A and B. The disease cannot be defined as A-disease, because such a definition would exclude all A-negative cases, and would bias the investigation in favour of a 100% correlation with A. Thus, AIDS cases must be first diagnosed clinically and only then analysed for the presence of drugs or HIV in order to study the roles of drugs and HIV in AIDS.

2. Correlation between HIV and AIDS Does Not Prove Causation

The surveys from San Francisco and Vancouver have stated that HIV causes AIDS because all of their AIDS cases were HIV antibody-positive (Table 1). However, this conclusion is flawed for three reasons.

i) Even a perfect correlation with HIV does not prove causation without functional evidence. It confirms only the first but not the third of Koch's postulates. Indeed, other microbes have been proposed as causes of AIDS on the basis of high or perfect correlations, as for example human T-cell leukemia virus I (7) and cytomegalovirus (8-12). Thus, it was arbitrary to single out HIV as the cause of AIDS, because other microbes also correlate with AIDS.

Since both surveys report perfect correlations not only between AIDS and HIV but also between AIDS and drugs (see below), the choice of HIV as the causative correlate was even more arbitrary than if it had been the only known AIDS correlate. This is because the epidemiological method cannot by itself distinguish between three consistent alternatives: HIV alone, drugs and HIV, and drugs alone.

ii) A positive HIV antibody test is not a rational prognosis for a viral disease, because antibodies are the classical indicator for a virus that has been rejected by the immune system. In response to antibodies, which of necessity include cellular immunity, the virus is either eliminated or restricted to latency-the reason why HIV is exceedingly difficult to isolate from antibody-positive carriers with and without AIDS (13-16). Thus, a positive antibody test is in general a counter-indication for future viral pathogenicity.

Moreover, a positive antibody test is not a reliable indicator for the presence of a virus (17, 18). According to a recent review entitled "HIV Testing: State of the Art," "depending on the population tested, 20 to 70% of ... two successive ELISAs are confirmed by Western blot [two variant antibody tests]," i.e. 30 to 80% are false positives (19). But even in groups with a high probability of infection, such as the San Francisco and Vancouver groups, significant numbers of false positive Western blots have been recorded (18). For example, Schechter et al. reported in 1991, that 33 out of 158 (17%) of Western blot-confirmed, antibody-positives in their Vancouver cohort were HIV-free, based on HIV DNA testing with the polymerase chain reaction (20). Two of these 33 had AIDS, the remainder had various degrees of immunodeficiency and lymphadenopathy, but not sufficient for a diagnosis for AIDS. The report also cites further studies documenting that 14 to 17% of antibody-positive homosexuals are HIV-provirus free.

Since a 100% correlation with antibody-positivity does not mean 100 % infection, it is probable that the AIDS cases from the San Francisco survey, and certain that the cases from the Vancouver survey included HIV-free AIDS.

iii) At least 4621 HIV-free AIDS cases have been documented in the literature, indicating that HIV is not necessary to cause AIDS (18).

Thus the conclusion of both surveys that HIV causes AIDS, because all AIDS cases appeared antibody-positive, is not valid.

3. Failure to Identify Drug-Free AIDS, the Absolute Argument against the Drug-AIDS Hypothesis

The most critical argument against the drug-AIDS hypothesis would be a group of drug-free AIDS patients. However neither the Vancouver nor the San Francisco survey provided drug-free AIDS cases.

All 136 AIDS patients from Vancouver belonged to a group of 365 HIV-positive drug users (Table 1). This is documented as follows: Among the 365 HIV-positive men surveyed, 88% reported consumption of nitrites and 80% the use of other "illicit" recreational drugs including cocaine, heroin, amphetamines, methylene amphetamines, lysergic acid, and diethylamide (3). Thus, assuming no specific linkages between the use of these different drugs, 98% have used at least one drug, because only 2% (12% x 20%) reported no use of recreational drugs. And 70% (88 x 80) have used at least two drugs. Even this high drug use may be an underestimate because illicit drug use is known to be underreported and because the Vancouver survey did not ever verify self-reported drug use by any tests. Indeed, a recent article by the Vancouver team reports that 100% of 87 AIDS patients had used nitrites (21). I followed their suggestion to "reread" their article for a statement that this group "includes some whose use was zero" (22), but I failed to find that statement. In addition the Vancouver survey failed to consider AZT use by HIV-positives (see below), but acknowledged it upon request (22) and in previous publications (20). Thus, the Vancouver survey lacks the most critical epidemiological argument to refute the drug-AIDS hypothesis-a group of verified non-drug users who developed AIDS.

In response to this critique (23), the Vancouver team has recently claimed that 19, or 5%, of the 365 HIV-positive men surveyed "... reported no recreational drug use ..." and that " ... their CD4 counts fell a mean of 138/microliter per year ..." (22). However there was no verification that these men were indeed recreational drug-free and no mention whether they were on AZT. Moreover, no claim was made that these presumably drug-free men ever developed AIDS.

Despite a claim to the contrary, the San Francisco survey also lacked drug-free AIDS. The survey reported that 100% of their 215 AIDS cases had used nitrites in its table 2 (2). Additional undetermined percentages of these cases had also used other illicit recreational drugs, such as cocaine and amphetamines (2). Moreover, since the introduction of AZT in 1987, 132 (84%) of the 157 AIDS cases observed by the San Francisco survey were on AZT (Ascher et al., personal communication, 9 April 1993). AZT is generally prescribed before AIDS, once T-cell counts drop below 500 per microliter (24). Thus, it is safe to conclude that all 215 AIDS patients from San Francisco were on multiple drugs including nitrites, one or more other recreational drugs and AZT (Table 1).

Yet the San Francisco survey claims a "group" of "seropositive no-drug" users who lost T-cells, although there are no data for such a group in their paper. This is documented as follows. According to the paper's table 1, all AIDS patients were HIV-positive homosexuals, and all HIV-positives were homosexuals (2). All heterosexuals were HIV-negative, except one who was a drug addict (Ascher, personal communication). According to Table 2, 100% of the homosexual men were either "heavy" or "light" nitrite users, namely 144 plus 668 out of 812 (text) (2). Thus, all AIDS patients and all HIV-positives in this study had used at least nitrites. In addition they had used cocaine, amphetamines, other recreational drugs and AZT. However, the corresponding figure purports, in color (!), to give data on "average adjusted" T-cell losses of three seropositive groups, with "no drug use," with "moderate drug use" and "heavy drug use," respectively. Three curves in that figure correspond to these three groups. Yet based on tables 1 and 2 the category "seropositive-no drug use" is an empty set representing nobody. Clearly the curve labeled "seropositive-no drug use" needs to be "adjusted" to reality.

In response to this critique (23), the San Francisco epidemiologists "acknowledge that it might have been clearer ... if we had labeled the latter group as 'none/light' in the table ..." (25).

Thus, neither the San Francisco nor the Vancouver survey provided the absolute epidemiological argument to exclude drugs as causes of AIDS, i.e. drug-free AIDS cases.

4. Failure to Quantitate Drug Dosage-the Key to Drug Toxicity

The San Francisco team relied for drug use information on statements "for the 24-month period before entry into the study" (2), and the Vancouver team on "ever versus never" statements. Thus the epidemiologists from San Francisco and Vancouver failed to quantitate drug consumption in three ways: i) They did not determine the cumulative lifetime drug dose of their subjects; ii) They did not verify self-reported drug use by any tests, although they acknowledged that illicit drug use is generally underreported (22); iii) They ignored AZT use altogether.

Indeed, the failure to quantitate drug consumption did not reflect a lack of suitable data, but a genuine disregard for drug toxicity. For example, the San Francisco survey stated "We examined the cohort at 6-month intervals for 96 months ..." But for correlations with AIDS over the 8-year study period "We compared heavy drug use for the 24-month period before entry into the study ..." (2). The Vancouver survey asked study subjects for drug use on an "ever versus never" basis, "once every six months" according to their 1993 study (3), and "on an annual basis" according to an earlier study (20). Clearly such efforts shed little light on the lifetime drug dosage of study subjects.

If one were to correlate lung cancer with information on smoking for only 24 months or on an "ever versus never" smoking statement the results would be as inconclusive as the results on drugs and AIDS described by the San Francisco and Vancouver teams. Drug use would indeed be as "casually [sic] associated with AIDS" as the San Francisco team writes in its paper (2). By not quantifying and by not verifying drug use, both teams missed the most relevant parameter of drug toxicity, the lifetime dosage.

Other epidemiological studies aimed at distinguishing between drugs and HIV as causes of AIDS in homosexuals from San Francisco (26) have likewise been invalidated by the failure to quantitate and verify drug consumption (27).

The casual disregard for drug toxicity by the San Francisco and Vancouver surveys is hard to reconcile with the solid documentation of drug toxicity in the literature. Toxicity has been documented empirically for all and mechanistically for many psychoactive drugs (4). For example, alkylnitrites are directly toxic as they are rapidly hydrolyzed in vivo to yield nitrite ions which react with all biological macromolecules (28). Toxicity for the immune system, the central nervous system, the hematological system and pulmonary organs has been observed after short exposure to nitrites in humans and animals (28-33). In addition, nitrites were among the first known mutagens and carcinogens, the reason they are considered health hazards in food (34, 35). The toxicity of the long-term use of cocaine, amphetamines and other illicit neurotropic, psychoactive drugs has been documented since 1909. It includes nearly all AIDS-defining diseases such as lymphopenia, lymphadenopathy, fever, weight loss, septicemia, increased susceptibility to infections, low T4 to T8 cell ratios and profound neurological disorders (4, 36-49). These drugs are neurotoxic directly and immunotoxic indirectly via malnutrition, insomnia and poor sanitation (4).

Unlike the toxicity of psychoactive drugs consumed by AIDS patients, the toxicity of the DNA chain terminator AZT is not a side effect, but a design. AZT was designed for chemotherapy over 30 years ago to kill all growing cells in cancer patients by terminating DNA synthesis (50). Since this is its only known function, its cytotoxic effects on the fast growing cells of the bone marrow (50-55), the source of T-cells, are equivalent to "AIDS by prescription" (4, 5).

Moreover, recreational drugs and AZT are used in sufficient quantities to explain fatal AIDS diseases. An approximate daily psychoactive dose of amyl nitrite is 1 ml (or 0.01 mol) (55, 56). This represents about 6 x 1021 molecules and corresponds to 6 x 107 molecules for every one of the 1014 cells of the human body, enough for abundant toxicity. The daily prescription of 500-1500 mg AZT also corresponds to 2-6 x 1021 molecules or 2-6 x 107 for every cell in the human body, more than enough to kill every cell that takes it up (4).

In response to this critique (23), the San Francisco and the Vancouver team now claim in letters to The Lancet that drugs do not cause AIDS because 39 (25) and 78 (22) HIV-free drug users did not develop AIDS. Again the self-reported drug use of these subjects was not quantitated and is likely to have been lower than in HIV-positives because HIV is a marker for drug use (see below). Another clear reason why they might not have developed AIDS diseases is that HIV-negatives are not prescribed the immunotoxic AZT (see above).

However, a negative representing a limited number of cases does not disprove any scientific hypothesis, including the drug-AIDS hypothesis. For example, subjects who have smoked for 20 years and not developed lung cancer do not disprove the smoke-cancer hypothesis, and subjects who have been drinking for 20 years and have no cirrhosis do not disprove the alcohol-cirrhosis hypothesis.

Likewise the absence of AIDS in 1 million healthy HIV-positive Americans and in 0.5 million healthy HIV-positive Europeans and in 8 million healthy HIV-positive Africans (57) does not disprove the HIV-AIDS hypothesis. The San Francisco survey even reported 230 healthy subjects, and the Vancouver survey reported 229 healthy subjects who were drug users and were HIV-positive but did not develop AIDS (Table 1). Indeed, the majority of the HIV-positive drug users remained healthy for 8 years (Table 1). Again these negatives neither disprove the drug nor the HIV-AIDS hypothesis.

5. Censoring HIV-Free AIDS with the HIV-Based AIDS Definition?

By adhering to the HIV-based AIDS definition AIDS researches bias against HIV-free AIDS. Indeed, American AIDS statistics from the Centers for Disease Control do not list the incidence of HIV-free AIDS cases (18).

Adherence to the HIV-based AIDS definition appears to be the reason why the survey from San Francisco did not distinguish between the 30 AIDS-defining diseases including dementia, diarrhea, lymphoma and pneumonia, except for Kaposi's sarcoma. In an effort to provide HIV-independent diagnoses of AIDS both surveys report T-cell depletion (3), as "a more objective and, indeed, the primary pathognomonic feature of AIDS" (2). However, both surveys fail to indicate how T-cell depletion relates to the incidence of AIDS in their cohorts, e.g. whether any of their AIDS cases was just diagnosed by a low T-cell count.

Furthermore both surveys fail to recognize that not all AIDS diseases are based on immunodeficiency (4). For example, in 1992, 39% of all American AIDS patients developed such non-immunodeficiency AIDS diseases as Kaposi's sarcoma (10%), wasting (20%), dementia (6%), and lymphoma (3%) (58). These diseases are not caused by and often not associated with immunodeficiency (4). This may be the reason why the San Francisco survey has listed AIDS and Kaposi's sarcoma as separate items in its table 2 (2).

The following examples suggest that the HIV-based AIDS definition (59, 60) has biased AIDS diagnoses from San Francisco and Vancouver against HIV-free AIDS. The Vancouver survey reports no AIDS in 350 HIV-negative homosexual men in 8.6 years ("no AIDS illnesses occurred in men who remained persistently negative for HIV-1 antibody") (3) and the San Francisco survey reports "0" cases of AIDS in 367 HIV-negative men in 8 years (2).

However, it is improbable that no AIDS-defining disease-e.g. diarrhea, pneumonia, candidiasis, herpes infection, dementia, >10% weight loss, fever for several weeks, toxoplasmosis, cryptococcosis, cryptosporidiosis, cytomegalovirus infection, mycobacterial infection and "other illnesses" (3)-would have occurred in 717 male drug users in over 8 years, since the very same diseases have been described in drug addicts since 1909 (see above). According to table 2 of the San Francisco survey, 100% of HIV-negative homosexual men had used nitrites and an unknown percentage had also used cocaine, amphetamines and other recreational drugs (2), and according to the Vancouver survey, 56% had used nitrites, and 58% had also used cocaine, amphetamines, heroin, lysergic acid, diethylamide and other illicit drugs (3). Thus, it appears that the reported absence of AIDS in these HIV-free groups reflects the bias of either not diagnosing or not reporting AIDS-defining diseases in HIV-negatives.

6. Drug Data from San Francisco and Vancouver Confirm the Drug-AIDS Hypothesis

Data from the San Francisco and Vancouver surveys confirm the drug hypothesis not only with perfect correlations but also with (i) quantitative and (ii) qualitative arguments for the drug hypothesis-despite the authors conclusions-on several grounds.

i) Dose response relationships (a-c). (a) The HIV-AIDS hypothesis and the authors of the surveys from San Francisco and Vancouver assume that AIDS follows HIV infection with an average lag of currently 10 years (20, 60). This lag is termed the latent period of HIV. According to this hypothesis healthy HIV carriers are those who have not accumulated sufficient HIV lag time to experience HIV-mediated AIDS.

However, since HIV is not active during this lag period and rarely even active during AIDS (4, 61-64), while the HIV carriers, as for example those from AIDS risk groups in San Francisco and Vancouver, are actively using recreational drugs and also AZT, this lag period in fact appears to be a quantitative measure for 10 years of drug use.

Indeed, studies that have measured toxicity of recreational drugs over time, have documented that about 10 years of nitrite use are necessary to cause Kaposi's sarcoma or pneumonia (29), even in persons without HIV (65). Likewise other recreational drugs cause in 10 years immunodeficiency diseases in persons with and without HIV (37, 47, 66-69). This toxicity threshold provides a rational explanation for the 10-year "enigmatic mechanism of the HIV pathogenesis of AIDS." (2).

(b) The claims that HIV-negatives from San Francisco and Vancouver did not develop AIDS diseases can also be illuminated in the light of the dosage argument. Drug use and HIV infection are linked via sexual activity. Recreational drugs are used by homosexuals at risk for AIDS as psychological and physiological aphrodisiacs. They generate euphoria and facilitate anal intercourse, particularly the nitrites which have been prescribed as vasodilators against angina since the 19th century (28, 29, 70). Since it takes about 1000 sexual contacts to pick up HIV (4), and since these contacts are frequently drug-promoted, HIV antibody-positives have consumed the drug the equivalent of 1000 contacts more than HIV-negatives.

Indeed, the Vancouver team acknowledges that "risk behaviors are known to correlate to HIV-1 infection ..." (3). And the San Francisco team reports that 72.9 % of the heavy drug users but only 50.9 % of the light users are HIV positive (see table 2, 2). Thus, HIV-positives are likely to have used more recreational drugs than HIV-negatives. It is for this reason that I have proposed HIV as a marker of AIDS risks, rather than the cause of AIDS: the more drug-mediated sexual contacts the more likely is infection by HIV (4). In addition, HIV-negatives were spared AIDS-diseases resulting from AZT, which is only prescribed to HIV-positives. Therefore in addition to biases due to the HIV-based AIDS definition (see above), a lower dosage of recreational drugs and the absence of AZT shed light on the observation that HIV-negatives were not reportedly developing AIDS diseases.

(c) The San Francisco survey confirms the quantitative aspect of the drug hypothesis even more directly with the observation that "heavy" drug users had 1.6 times as much AIDS and had 2 times as much Kaposi's sarcoma as "light" users (see table 2, 2). The authors correctly suggest that "this crude association is apparently the basis for Duesberg's hypothesis." The Vancouver team even acknowledged one HIV-positive death from drug overdose "excluding AIDS-related mortality" (3). Thus both teams provide drug-AIDS dose-response relationships-a definitive argument for the drug-AIDS hypothesis.

ii) Drug-specific diseases. The surveys from San Francisco and Vancouver also provide qualitative evidence in support of the drug-AIDS hypothesis. The San Francisco epidemiologists report that 43% (92/215) and the Vancouver epidemiologists that 25% (34/136) of their AIDS victims had Kaposi's sarcoma. This is 4.3 and 2.5 times higher than the U.S. national average of 10% (58). This result is compatible with national statistics indicating that Kaposi's sarcoma is about 20-times more common in male homosexuals than in all other risk groups (71).

The fact that Kaposi's sarcoma occurs almost exclusively in homosexuals but not in other risk groups is hard to reconcile with the claims of the San Francisco and Vancouver teams that HIV, contracted by "receptive anal intercourse," causes Kaposi's sarcoma (3, 72). Indeed, a controlled study has just excluded HIV, but not anal intercourse, as the cause of AIDS. The study showed that among two HIV-positive groups of homosexuals those who developed AIDS had practiced receptive anal intercourse more than twice as much as those who remained healthy (73). In view of such discrepancies with the virus hypothesis, its followers, including the Vancouver team (21), have postulated a second, as yet unknown sexually transmitted agent, to explain the restriction of Kaposi's sarcoma to homosexuals (71, 73, 74).

However Kaposi's sarcoma in homosexuals is totally consistent with the hypothesis that nitrites inhaled to facilitate anal intercourse cause pulmonary and epithelial Kaposi's sarcoma irrespective of the presence of HIV (4, 28). Indeed, 100 % of the AIDS patients from San Francisco and 100 % of the Kaposi cases from Vancouver (21) had inhaled nitrites.

Since HIV replicates via a DNA intermediate, DNA chain terminators, like AZT, are considered antiviral drugs and are prescribed as AIDS prophylaxis to healthy HIV-positives (53) and as therapy to HIV-positive AIDS patients (4). Since AZT kills all dividing human cells by DNA chain termination, it is particularly toxic to the rapidly proliferating bone marrow, the source of T-cells (4, 50-54). Thus, the widespread use of AZT by HIV-positives from the San Francisco and Vancouver groups (see above) explains the decline of T-cells in HIV-positives as AZT-specific disease.

Moreover, the widespread AZT use also sheds light on the 8% incidence of lymphoma among HIV-positive AIDS patients from Vancouver (3). This is high compared to the national average of 3% in the U.S. (58), but is normal for AZT recipients who have an annual lymphoma incidence of 9% (75).

7. Conclusions

The most urgent and growing problem facing the HIV-AIDS hypothesis is its total failure in terms of public health benefits. Despite enormous efforts over the last 10 years, costing the US taxpayer alone $4 billion, no vaccine has been developed, no AIDS patient has been cured, no prevention has slowed the spread of AIDS. These are the hallmarks of a flawed hypothesis.

Ten years of intensive research have failed to demonstrate that HIV causes AIDS or is even toxic to human cells (4, 76). Indeed HIV is mass-produced in indefinitely growing human T-cell lines at titers of up to 106 infectious units per ml (4, 77). Therefore the primary argument for the HIV-AIDS hypothesis is just HIV/AIDS correlations of the kind analysed here (59, 60, 74).

In the face of a 10-year history of scientific and public health failures, the scientific method calls for alternatives to the prevailing HIV-AIDS hypothesis such as the drug-AIDS hypothesis. This hypothesis is based on excellent correlations, e.g. according to the Centers for Disease Control, 30% of all American AIDS patients including nearly all heterosexuals with AIDS are intravenous drug users (58), and about 60% are male homosexuals who have used aphrodisiac drugs as has been demonstrated here and previously (4). Furthermore drug toxicity has been documented and dose-response relationships and drug-specific AIDS diseases have been described here and previously confirming the drug-AIDS hypothesis (4).

If both AIDS-correlates, drugs and HIV, were given unbiased consideration, the choice between drugs and HIV, or antibodies against HIV, would be easy. It would appear more rational to conclude that drug intake "has an integral role in CD4 depletion ... and AIDS" (3) than HIV or antiviral antibodies.

Therefore, I call for a reinvestigation of whether in the predominant AIDS risk groups in the U.S. and Europe, male homosexuals and intravenous drug users, HIV or drugs cause AIDS based on the following criteria:

i) AIDS must be determined clinically, independent of HIV. All AIDS-defining diseases must be identified in order to detect drug-specific diseases.

ii) HIV must be identified by virus tests, rather than antibody tests. A positive antibody test would be considered tentative until it is confirmed by HIV isolation.

iii) Drug use must be quantitated to determine dose-response relationships. Both recreational drug use and AZT use must be compounded.

iv) If no drug-free AIDS can be found to eliminate drugs, and no HIV-free AIDS to eliminate HIV, functional tests must be developed to identify the causative correlate. HIV toxicity could be tested in susceptible cells in culture, in animals and in accidentally infected humans who lack other risk factors. Drug toxicity could be tested in cells in culture, experimental animals or in HIV-free drug addicts. *

With Viewpoint, AIFO (AIDS-Forschung) has created a forum for scientific controversies. To date Viewpoint has covered diverse topics including measures to control AIDS-on which no consensus has been reached.

The drug-AIDS hypothesis (in contrast to the HIV-AIDS hypothesis) of Duesberg has been a source of several controversies over the last year. AIFO has contributed several articles of Duesberg to this controversy (AIFO 4, 115-126; 507-515; 517-521 [1989]; AIFO 6, 299-306 [1991]; AIFO 7, 619-641 [1992]).

Early in 1993 several articles appeared in the international press that appeared to refute Duesberg's theses (Ascher et al., Nature 362, 103; Schechter et al., Lancet 341, 658; Piatak et al., Science 259, 1749; Pantaleo et al., Nature 362, 355; Embretson, Nature 362, 359). Therefore AIFO has invited Duesberg to critically review and discuss his theses in view of these challenges.

-The editor of AIDS-Forschung

Acknowledgments

I thank Lars Chapsky, Bryan Ellison, Phil Johnson, Harry Rubin, Siggi Sachs, Jody Schwartz, Richard Strohman and Yue Wu for critical review and discussions. I am supported by The Council For Tobacco Research-USA, Inc. and by private donations from Bill Bowie (New York), Glenn Braswell (Los Angeles), Dr. Richard Fischer (Annandale, VA), Dr. Fabio Franchi (Trieste, Italy), Dr. Friedrich Luft (Berlin).

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