Immunodeficiency in Hemophiliacs
Vol. 95, pp. 51-70. 1995. Abstract
With and Without HIV
has been interpreted in terms of two hypotheses: the foreign-protein-AIDS
hypothesis and the Human Immunodeficiency Virus (HIV)-AIDS hypothesis.
The foreign-protein-AIDS hypothesis holds that proteins contaminating
commercial clotting factor VIII cause immunosuppression. The foreign-protein
hypothesis, but not the HIV hypothesis, correctly predicts seven
characteristics of hemophilia-AIDS: 1) The increased life span of
American hemophiliacs in the two decades before 1987, although 75%
became infected by HIV-because factor VIII treatment, begun in the
1960s, extended their lives and simultaneously disseminated harmless
HIV. After 1987 the life span of hemophiliacs appears to have decreased
again, probably because of widespread treatment with the cytotoxic
anti-HIV drug AZT. 2) The distinctly low, 1.3-2%, annual AIDS risk
of hemophiliacs, compared to the higher 5-6% annual risk of intravenous
drug users and male homosexual aphrodisiac drug users-because transfusion
of foreign proteins is less immunosuppressive than recreational
drug use. 3) The age bias of hemophilia-AIDS, i.e. that the annual
AIDS risk increases 2-fold for each 10-year increase in age-because
immunosuppression is a function of the lifetime dose of foreign
proteins received from transfusions. 4) The restriction of hemophilia-AIDS
to immunodeficiency diseases-because foreign proteins cannot cause
non-immunodeficiency AIDS diseases, like Kaposi's sarcoma. 5) The
absence of AIDS diseases above their normal background in sexual
partners of hemophiliacs-because transfusion-mediated immunotoxicity
is not contagious. 6) The occurrence of immunodeficiency in HIV-free
hemophiliacs-because foreign proteins, not HIV, suppress their immune
system. 7) Stabilization, even regeneration, of immunity of HIV-positive
hemophiliacs by long-term treatment with pure factor VIII. This
shows that neither HIV nor factor VIII plus HIV are immunosuppressive
by themselves. Therefore, AIDS cannot be prevented by elimination
of HIV from the blood supply and cannot be rationally treated with
genotoxic antiviral drugs, like AZT. Instead, hemophilia-AIDS can
be prevented and has even been reverted by treatment with pure factor
Drug- and Hemophilia-AIDS Epidemics in America and Europe
About 30 previously
known diseases are now called AIDS if they occur in the presence
of antibody against human immunodeficiency virus (HIV) (Institute
of Medicine, 1988; Centers for Disease Control and Prevention, 1992).
These diseases are thought to be consequences of an acquired
immuno deficiency syndrome and hence are grouped
together as AIDS (Institute of Medicine, 1988). From its beginning
in 1981, AIDS has been restricted in America and Europe to specific
risk groups (Centers for Disease Control, 1986; World Health Organization,
1992b). Currently, over 96% of all American AIDS cases come from
AIDS risk groups, rather than from the general population (Centers
for Disease Control, 1993). These include over 60% male homosexuals
who have been long-term oral users of psychoactive and aphrodisiac
drugs, 33% mostly heterosexual, intravenous drug users and their
children, 2% transfusion recipients, and about 1% hemophiliacs (Duesberg,
1992a; Centers for Disease Control, 1993). Altogether, about 90%
of all American and European AIDS patients are males (World Health
Organization, 1992a; Centers for Disease Control, 1993).
group has specific AIDS diseases. For example, Kaposi's sarcoma
is almost exclusively seen in male homosexuals, tuberculosis is
common in intravenous drug users, and pneumonia and candidiasis
are virtually the only AIDS diseases seen in hemophiliacs (Duesberg,
In view of
these epidemiological and clinical criteria, American and European
AIDS has been interpreted alternatively as an infectious and a non-infectious
epidemic by the following hypotheses:
virus-AIDS hypothesis. This hypothesis postulates that all AIDS
is caused by the retrovirus HIV, and thus an infectious epidemic.
The inherent danger of a transmissable disease quickly promoted
the HIV hypothesis to the favorite of "responsible" health
care workers, scientists and journalists (Booth, 1988). For example,
a columnist of The New York Times wrote in July 1994 that
all non-HIV AIDS science is "cruelly irresponsible anti-science"
(Lewis, 1994). And the retrovirologist David Baltimore warned in
Nature "There is no question at all that HIV is the
cause of AIDS. Anyone who gets up publicly and says the opposite
is encouraging people to risk their lives." (Macilwain, 1994).
the U.S.' Centers for Disease Control (CDC) have favored the HIV-AIDS
hypothesis from the beginning (Centers for Disease Control, 1982;
Centers for Disease Control, 1986; Shilts, 1987; Booth, 1988; Oppenheimer,
1992), because-according to Red Cross official Paul Cumming in 1983-"the
CDC increasingly needs a major epidemic to justify its existence"
(Associated Press, 1994). Indeed, there has been no viral or microbial
epidemic in the U.S. and Europe since polio in the 1950s. All infectious
diseases combined now account for less than 1% of morbidity and
mortality in the Western World (Cairns, 1978). The control of infectious
diseases is the primary mission of the CDC.
drug-AIDS hypothesis. This hypothesis holds that AIDS in the
major risk groups is caused by group-specific, recreational drugs
and by anti-HIV therapy with cytocidal DNA chain terminators, like
AZT, and is thus not infectious (Lauritsen & Wilson, 1986; Haverkos
& Dougherty, 1988; Duesberg, 1991, 1992a; Oppenheimer, 1992).
The drug-AIDS hypothesis was favored by many scientists, including
some from the CDC, before the introduction of the HIV-AIDS hypothesis
in 1984 (Marmor et al., 1982; Mathur-Wagh et al.,
1984; Haverkos et al., 1985; Mathur-Wagh, Mildvan & Senie,
1985; Newell et al., 1985; Haverkos & Dougherty, 1988;
Duesberg, 1992a; Oppenheimer, 1992).
foreign-protein-hemophilia AIDS hypothesis. This hypothesis
holds that hemophilia-AIDS is caused by the long-term transfusion
of foreign proteins contaminating factor VIII and other clotting
factors and thus not infectious. This hypothesis also preceded the
virus hypothesis and has coexisted with it, despite the rising popularity
of the HIV hypothesis (see Section 3).
and non-infectious AIDS hypotheses indicate entirely different strategies
of AIDS prevention and therapy. Here we analyze the cause of hemophilia-AIDS
in the lights of the HIV-AIDS hypothesis and the foreign-protein-AIDS
hypothesis. The hemophiliacs provide the most accessible group to
test AIDS hypotheses of infectious versus non-infectious causation.
This is because the time of infection via transfusion can be estimated
more accurately than HIV infection from sexual contacts, and because
the role of treatment-related AIDS risks can be controlled and quantitated
much more readily than AIDS risks due to the consumption of illicit,
The HIV hypothesis
claims that AIDS began to appear in hemophiliacs in 1981 (Centers
for Disease Control, 1982) because (i) hemophiliacs were accidentally
infected via transfusions of factor VIII contaminated with HIV since
the 1960s, when widespread prophylactic factor VIII treatment began
(but no longer after 1984 when HIV was eliminated from the blood
supply) and because (ii) AIDS is currently assumed to follow HIV
infection on average only after 10 years (Centers for Disease Control,
1986; Institute of Medicine, 1988; Chorba et al., 1994).
Indeed, about 15,000 of the 20,000 American hemophiliacs, or 75
%, are HIV antibody-positive from transfusions of HIV-contaminated
clotting factors received before HIV was detectable (Tsoukas et
al., 1984; Institute of Medicine and National Academy of Sciences,
1986; Sullivan et al., 1986; McGrady, Jason & Evatt,
1987; Institute of Medicine, 1988; Koerper, 1989). Contamination
of factor VIII with HIV reflects the practice, developed in the
1960s and 1970s, of preparing factor VIII and other clotting
factors from blood pools collected from large numbers of donors
(Aronson, 1983; Koerper, 1989; Chorba et al., 1994).
The HIV hypothesis
claims that 2,214 American hemophiliacs developed AIDS-defining
diseases between 1982 and the end of 1992 because of HIV (Centers
for Disease Control, 1993). However, this corresponds only to a
1.3% annual AIDS risk, i.e. 201 cases per 15,000 HIV-positive hemophiliacs
per year. (Note that the non-age adjusted annual mortality of an
American with a life expectancy of 80 years is 1.2%). Further, the
HIV-AIDS hypothesis claims that the mortality of hemophiliacs has
increased over 2-fold in the 3-year period from 1987 to 1989 compared
to periods from 1968 to 1986, although infection with HIV via transfusions
had already been halted with the HIV-antibody test in 1984 (Chorba
et al., 1994).
HIV is thought
to cause immunodeficiency by killing T-cells, but paradoxically
only after the virus has been neutralized by antiviral immunity,
and only on average 10 years after infection (Institute of Medicine,
1988; Duesberg, 1992a; Weiss, 1993). However, HIV, like all other
retroviruses, does not kill T-cells or any other cells in vitro;
in fact, it is mass-produced for the HIV antibody test in immortal
T-cell lines (Duesberg, 1992a). Moreover, the basis for the 10-year
latent period of the virus, which has a generation time of only
24-48 h, is entirely unknown (Duesberg, 1992a; Weiss, 1993; Fields,
1994). It is particularly paradoxical that the loss of T-cells in
hemophiliacs over time does not correspond to viral activity and
abundance. No T-cells are lost prior to antiviral immunity, when
the virus is most active (Duesberg, 1993a; Piatak et al.,
1993). Instead, most T-cells are lost when the virus is least active
or latent in hemophiliacs (Phillips et al., 1994a) and other
risk groups (Duesberg, 1992a; 1993a, 1994; Piatak et al.,
1993; Sheppard, Ascher & Krowka, 1993), namely after it is neutralized
by antiviral immunity (a positive HIV-antibody test). Indeed, there
are healthy, HIV-antibody positive persons in which 33 to 43 times
more cells are infected by latent HIV than in AIDS patients (Simmonds
et al., 1990; Bagasra et al., 1992; Duesberg, 1994).
Even Gallo, who claims credit for the HIV-AIDS hypothesis (Gallo
et al., 1984), has recently acknowledged: "I think that
if HIV is not being expressed and not reforming virus and replicating,
the virus is a dud, and won't be causing the disease ... nobody
is saying that indirect control of the virus is not important ...."
There is also
no explanation for the profound paradoxes that AIDS occurs only
after HIV is neutralized and that antiviral immunity does not protect
against AIDS, although this immunity is so effective that free virus
is very rarely detectable in AIDS patients (Duesberg, 1990, 1992a,
1993a; Piatak et al., 1993). The high efficiency of this
antiviral immunity is the reason that leading AIDS researchers had
notorious difficulties in isolating HIV from AIDS patients (Weiss,
1991; Cohen, 1993).
All of the
above associations between HIV and AIDS support the hypothesis that
HIV is a passenger virus, instead of the cause of AIDS (Duesberg,
1994). A passenger virus differs from one that causes a disease
in three criteria:
1. The time
of infection by the passenger virus is unrelated to the initiation
of the disease. For example, the passenger may infect 10 years prior
to, or just immediately before, initiation of the disease-just as
HIV does in AIDS.
2. The passenger
virus may be active or passive during the disease, i.e. the disease
is not influenced by the activity of the passenger virus or the
number of virus-infected cells, as is the case for HIV in AIDS.
3. The disease
may occur in the absence of the passenger virus. In the case of
AIDS, over 4621 HIV-free AIDS cases have been clinically diagnosed
(Duesberg, 1993b; see also Section 4.6).
HIV meets each of the classical criteria of a passenger virus-exactly
since HIV is not active in most AIDS patients, and often more active
in healthy carriers than in AIDS patients (Duesberg, 1993a, 1994;
Piatak et al., 1993), and since AIDS patients with and without
HIV are clinically identical (Duesberg, 1993b), HIV is in fact only
a harmless passenger virus. It is harmless, because it does not
contribute secondary diseases to AIDS pathogenicity, as for example
pneumocystis pneumonia, candida or herpes virus do. These microbes
each cause typical AIDS-defining opportunistic infections. But HIV
does not appreciably affect the pathogenicity of AIDS as HIV-free
and HIV-positive AIDS cases are clinically indistinguishable (Duesberg,
1993b, 1994). Likewise, there is no clinical distinction between
AIDS cases in which HIV is active and those in which it is totally
latent and restricted to very few cells (Duesberg, 1993a; Piatak
et al., 1993).
enormous efforts in the last 10 years, there is no rational explanation
for viral pathogenesis, and the virus-AIDS hypothesis stands unproved
(Weiss & Jaffe, 1990; Duesberg, 1992a; Weiss, 1993; Fields,
1994). Above all, the hypothesis has failed to make any verifiable
predictions, the acid test of a scientific hypothesis. For example,
the predicted explosion of AIDS into the general population, or
among female prostitutes via sexual transmission of HIV, or among
health care workers treating AIDS patients via parenteral transmission
did not occur (Duesberg, 1992a, 1994).
As yet, the
hypothesis is supported only by circumstantial evidence, i.e. correlations
between the occurrence of AIDS and antibodies against HIV in AIDS
patients (Blattner, Gallo & Temin, 1988; Institute of Medicine,
1988; Weiss & Jaffe, Weiss, 1993). However, because AIDS is
defined by correlation between diseases and antibodies against HIV
(Institute of Medicine, 1988), the relevance of the correlation
argument for AIDS etiology has been challenged (Duesberg, 1992a,
1993b, 1994; Thomas Jr., Mullis & Johnson, 1994). States Mullis,
at a London Sunday Times Nobel Laureate lecture in 1994,
"Any postgraduate student who had written a convincing paper
demonstrating that HIV 'causes' AIDS would ... have published 'the
paper of the century'" (Dickson, 1994).
In view of
the circularity of the correlation argument, the apparent transmission
of AIDS to hemophiliacs via transfusion of HIV-infected blood or
factor VIII has been cited as the most direct support for the virus-AIDS
hypothesis (Blattner, Gallo & Temin, 1988; Institute of Medicine,
1988; Weiss & Jaffe, 1990; Weiss, 1993). However, the HIV-hemophilia-AIDS
hypothesis is weakened by the extremely long intervals between infection
and AIDS, averaging between 10 years (Institute of Medicine, 1988)
and 35 years (Duesberg, 1992a; Phillips et al., 1994b), compared
to the short generation time of HIV which is only 24 to 48 h (see
Section 4.2). During such long intervals other risk factors could
have caused AIDS diseases, particularly in hemophiliacs who depend
on regular transfusions of clotting factors for survival. The fact
that HIV is typically not more active, and often even less active,
in those who develop AIDS than in those who are healthy, further
weakens the HIV-hemophilia-AIDS hypothesis (see above).
introduction of the HIV-AIDS hypothesis, but after the introduction
of prophylactic long-term treatment of hemophilia with blood-derived
clotting factors had begun, numerous hematologists had noticed immunodeficiency
and corresponding opportunistic infections in hemophiliacs. Several
of these had advanced the foreign-protein-hemophilia-AIDS hypothesis,
which holds that the long-term transfusion of foreign proteins contaminating
commercial factor VIII, and possibly factor VIII itself, is the
cause of immunosuppression in hemophiliacs. Indeed, until recently
most commercial preparations of factor VIII contained from 99% to
99.9% foreign, non-factor VIII proteins (Brettler & Levine,
1989; Mannucci et al., 1992; Seremetis et al., 1993;
Gjerset et al., 1994). According to the foreign-protein hypothesis
immunodeficiency in hemophilia patients is proportional to the lifetime
dose of foreign proteins received (Menitove et all., 1983;
Madhok et al., 1986; Schulman, 1991).
HIV had been discovered, it was known empirically that "transfusion
of patients undergoing renal transplantation is associated with
improved graft survival and it has been suggested that transfusion
is immunosuppressive in an as yet unidentified way." (Jones
et al., 1983). The authors had cited this empirical knowledge
to explain immunosuppression in eight, and Pneumocystis pneumonia
in six British hemophiliacs (Jones et al., 1983). A multicenter
study investigating the immune systems of 1,551 hemophiliacs, treated
with factor VIII from 1975 to 1979, documented lymphocytopenia in
9.3% and thrombocytopenia in 5% (Eyster et al., 1985). Further,
the CDC reported AIDS-defining opportunistic infections in hemophiliacs
between 1968 and 1979, including 60% pneumonias and 20% tuberculosis
(Johnson et al., 1985). An American hematologist commented
on such opportunistic infections in hemophiliacs, including two
candidiasis and 66 pneumonia deaths that had occurred between 1968
and 1979, "... it seems possible that many of the unspecified
pneumonias in hemophiliacs in the past would be classified today
as AIDS" (Aronson, 1983).
In 1983, Gordon
from the National Institutes of Health noted that all hemophiliacs
with immunodeficiency identified by the CDC had received factor
VIII concentrate. While acknowledging the possibility of a "transmissible
agent," Gordon argued that "repeated administration of
factor VIII concentrate from many varied donors induces a mild disorder
of immune disregulation by purely immunological means, without the
intervention of infection." (Gordon, 1983). Froebel et al.
also argued against the hypothesis that immunodeficiency in
American hemophiliacs was due to a virus, and suggested that it
was due to treatments with factor VIII because "Scottish patients
with hemophilia, most of whom had received no American factor VIII
concentrate for over two years, were found to have immunological
abnormalities similar to those in their American counterparts ..."
(Froebel et al., 1983). Already in 1983 Menitove et al.
described a correlation between immunosuppression of hemophiliacs
and the amount of factor VIII received over a lifetime; the more
factor a hemophiliac had received the lower was his T4/T8-cell ratio.
Their data were found to be "consistent with the possibility
that commercially prepared lyophilized factor VIII concentrates
can induce an AIDS-like picture ..." (Menitove et al.,
1983). Also in 1983, Kessler et al. proposed that "Repeated
exposure to many blood products can be associated with development
of T4/T8 abnormalities" and "significantly reduced mean
T4/T8 ratios compared with age and sex-matched controls" (Kessler
et al., 1983).
introduction of the HIV-AIDS hypothesis in 1984, Carr et al.
studied immunodeficiency in HIV-positive and HIV-negative hemophiliacs
and proposed "that the abnormalities [low T4 to T8 cell ratios]
result from transfusion of foreign proteins" (Carr et al.,
1984). Likewise, Tsoukas et al. concluded "These data
suggest that another factor, or factors, instead of, or in addition
to, exposure to HTLV-III [old term for HIV] is required for the
development of immunedysfunction in hemophiliacs" (Tsoukas
et al., 1984).
In 1985 even
the retrovirologist Weiss reported "the abnormal T-lymphocyte
subsets are a result of the intravenous infusion of factor VIII
concentrates per se, not HTLV-III infection" (Ludlam et
al., 1985). Likewise, the hematologists Pollack et al. deduced
that, "Derangement of immune function in hemophiliacs results
from transfusion of foreign proteins or a ubiquitious virus rather
than contracting AIDS infectious agent" (Pollack et al.,
1985). The "AIDS infectious agent" was a reference to
HIV, because in 1985 HIV was extremely rare in blood concentrates
outside the U.S., but immunodeficiency was observed in Israeli,
Scottish, and American hemophiliacs (Pollack et al., 1985).
A French AIDS-hemophilia group also observed "... allogenic
or altered proteins present in factor VIII ... seem to play a role
of immunocompromising agents." They stated that "A correlation
between treatment intensity and immunologic disturbances was found
in patients infused with factor VIII preparations, irrespective
of their positive or negative LAV [HIV] antibody status" (AIDS-Hemohilia
French Study Group, 1985). Likewise, Hollan et al. reported
in 1985 "an immunodeficiency independent of HTLV-III infection"
in Hungarian hemophiliacs (Hollan et al., 1985).
In 1986, Madhok
et al. arrived at the conclusion that "clotting factor
concentrate impairs the cell mediated immune response to a new antigen
in the absence of infection with HIV" (Madhok et al.,
1986). Moreover, Jason et al. from the CDC observed that,
"Hemophiliacs with immune abnormalities may not necessarily
be infected with HTLV-III/LAV, since factor concentrate itself may
be immune suppressive even when produced from a population of donors
not at risk for AIDS" (Jason et al., 1986). Sullivan
et al. deduced from a comprehensive study of hemophiliacs
that "hemophiliacs receiving commercial factor VIII concentrate
experience several stepwise incremental insults to the immune system:
alloantigens in factor VIII concentrate [etc.] ..." (Sullivan
et al., 1986).
In 1987, Sharp
et al. commented that "Five out of 12 such patients
had a mild T4 lymphocytopenia, and this may have been related to
parenteral administration of large quantities of protein."
(Sharp et al., 1987). And Aledort observed that "chronic
recipients ... of factor VIII, factor IX and pooled products ...
demonstrated significant T-cell abnormalities regardless of the
presence of HIV antibody" (Aledort, 1988). Brettler and Levine
proposed in 1989 that "Factor concentrate itself, perhaps secondary
to the large amount of foreign-protein present, may cause alterations
in the immune systems of hemophiliac patients" (Brettler &
Levine, 1989). And even Stehr-Green et al. from the CDC conceded
that foreign proteins were at least a cofactor of HIV in immunosuppression:
"Repeated exposure to factor concentrate ... could also account
for more rapid progression of HIV infection with age." (Stehr-Green
et al., 1989).
et al. claimed in 1990 that clotting factor does not cause
immunodeficiency, they showed that immunodeficiency in hemophiliacs
increases with both the age and the cumulative dose of clotting
factor received during a lifetime (Becherer et al., 1990).
Likewise, Simmonds et al. observed in 1991 that even among
HIV-positive hemophiliacs "The rate of disease progression,
as assessed by the appearance or not of AIDS symptoms or signs within
five years of seroconversion, was related ... to the concentration
of total plasma IgM before exposure to infection ..." (Simmonds
et al., 1991). The hematologist Prince noted in a review
from 1992 that "When serum samples from these [immunodeficient
hemophilia] patients were tested for antibodies to HIV-1, it was
found that a sizable group of hemophilia patients, usually 25% to
40%, were seronegative for HIV-1," and "... all found
marked anergy, lack of response, in HIV-seronegative concentrate
recipients. Taken together, these findings were interpreted as evidence
that clotting factor concentrates suppressed the immunocompetence
of recipients ..." (Prince, 1992).
In 1991, Schulman
concluded that "immunosuppressive components in F VIII concentrates"
cause immunodeficiency not only in HIV-positive but also in HIV-negative
hemophiliacs (Schulman, 1991). Schulman had observed reversal of
immunodeficiency and thrombocytopenia in HIV-positive hemophiliacs
treated with purified factor VIII, and that immunity "was inversely
correlated with the annual amount of factor VIII infused" (Schulman,
At the same
time several groups have reported that T-cell counts are stabilized,
or even increased in HIV-positive hemophiliacs treated with factor
VIII free of foreign proteins (de Biasi et al., 1991; Hilgartner
et al., 1993; Seremetis et al., 1993; Goedert et
al., 1994) (see also Section 4.7). And in 1994, the editor of
aids News, published by the Hemophilia Council of California,
granted foreign proteins the role of a cofactor of HIV in hemophilia
AIDS with an editorial "Factor concentrate is a Co-factor"
to the foreign-protein hypothesis, antibodies against HIV and against
other microbes would merely be markers of the multiplicity of transfusions
received (Evatt et al., 1984; Pollack et al., 1985;
Brettler et al., 1986; Sullivan et al., 1986; Koerper,
1989). Since HIV has been a rare contaminant of blood products,
even before 1984, only those who have received many transfusions
would become infected. The more immunosuppressive transfusions a
person has received, the more likely that person is to become infected
by HIV and other microbes contaminating factor VIII (see Section
4.6). For example, only 30% of hemophiliacs who had received less
than 400 units factor VIII per kg per year were HIV-positive, but
80% of those who had received about 1000 units, and 93% of those
who had received over 2100 units per kg per year were HIV-positive
(Sullivan et al., 1986).
of the Foreign-protein- and HIV-AIDS Hypotheses
Here we compare
the HIV- and the foreign-protein-AIDS hypotheses in terms of how
well their predictions can be reconciled with hemophilia-AIDS:
of hemophiliacs with and without HIV.The virus-AIDS hypothesis
predicts that the mortality of HIV-positive hemophiliacs will be
higher than that of matched HIV-free counterparts. Considering the
high, 75%-rate of infection of American hemophiliacs by HIV since
1984, one would expect that the median age of all American hemophiliacs
would have significantly decreased and that their mortality increased.
The HIV-AIDS hypothesis predicts that in 1994, at least one 10-year-latent-period
after most American hemophiliacs were infected, over 50% of the
15,000 HIV-positive American hemophiliacs would have developed AIDS
or died from AIDS (Institute of Medicine, 1988; Duesberg, 1992a).
But despite the many claims that HIV causes AIDS in hemophiliacs
(Centers for Disease Control, 1986; Institute of Medicine, 1988;
Weiss & Jaffe, 1990; Chorba et al., 1994), there is not
a single controlled study showing that the morbidity or mortality
of HIV-positive hemophiliacs is higher than that of HIV-negative
controls matched for the lifetime consumption of factor VIII.
mortality of American hemophiliacs has decreased and their median
age has increased since 75% were infected by HIV. The median age
of American hemophiliacs has increased from 11 years in 1972, to
20 years in 1982, to 25 years in 1986, and to 27 years in 1987,
although 75% had become HIV antibody-positive prior to 1984 (Institue
of Medicine and National Academy of Sciences, 1986; Koerper, 1989;
Stehr-Green et al., 1989). Likewise, their median age at
death has increased from about 40 to 55 years in the period from
1968 to 1986 (Chorba et al., 1994).
the HIV-AIDS hypothesis, one could make a logical argument that
HIV, instead of decreasing the life span of hemophiliacs, has in
fact increased it. A more plausible argument suggests that the life
span of American hemophiliacs has increased as a consequence of
the widespread use of factor VIII that started in the late 1960s
(see above). As predicted by the foreign-protein hypothesis, the
price for the extended life span of hemophiliacs by treatment with
commercial factor VIII was immunosuppression due to the long-term
parenteral administration of large quantities of foreign protein
(see Section 4.2). Prior to factor VIII therapy, most hemophiliacs
died as adolescents from internal bleeding (Koerper, 1989).
a recent CDC study reports that the mortality of American hemophiliacs
suddenly increased 2.5-fold in the period from 1987 to 1989, after
it had remained almost constant in the period from 1968 to 1986
(Chorba et al., 1994). Since American hemophiliacs
became gradually infected via the introduction in the 1960s of pooled
factor VIII treatments until 1984, when HIV was eliminated from
the blood supply (see above), one would have expected first a gradual
increase in hemophilia mortality and then a rather steep decrease.
The increase in mortality would have followed the increase of infections
with a lag defined by the time that HIV is thought to require to
cause AIDS. The presumed lag between HIV and AIDS has been estimated
at 10 months by the CDC in 1984 (Auerbach et al., 1984) and
at 10 years by a committee of HIV researchers, including some from
the CDC, in 1988 (Institute of Medicine, 1988). Therefore the sudden
increase in hemophilia deaths in 1987 is not compatible with HIV-mediated
mortality. Hemophilia mortality should have gradually decreased
after 1984, when HIV was eliminated from the blood supply, depending
on the lag period assumed between infection and AIDS. Even if the
lag period from HIV to AIDS were 10 years, the mortality of hemophiliacs
should have significantly decreased by 1989, 5 years after new infections
had been stopped.
explanation for the chronological inconsistency between infection
of hemophiliacs with HIV since the 1960s and the sudden increase
in their mortality 20 years later is the introduction of the cytotoxic
DNA chain terminator AZT as an anti-HIV drug in 1987. AZT has been
recommended and prescribed to symptomatic HIV carriers since 1987
(Fischl et al., 1987; Richman et al., 1987) and to
healthy HIV carriers with lower than 500 T-cells since 1988 (Volberding
et al., 1990; Goldsmith et al., 1991; Phillips et
al., 1994b). Approximately 200,000 HIV antibody-positives with
and without AIDS diseases are currently prescribed AZT worldwide
(Duesberg, 1992a). According to a preliminary survey of hemophiliacs
from a national group, Concerned Hemophiliacs Acting for Peer Strength
(CHAPS), 35 out of 35 HIV-positive hemophiliacs asked had taken
AZT, and 20 out of 35 who had taken AZT at some time were currently
on AZT (personal communication, Brent Runyon, executive director
of CHAPS, Wilmington, N.C.).
The DNA chain
terminator AZT was developed 30 years ago to kill growing human
cells for cancer chemotherapy. Because of its intended toxicity,
chemotherapy is typically applied for very limited periods of time,
i.e. weeks or months, but AZT is now prescribed to healthy HIV-positives
indefinitely, despite its known toxicity (Nussbaum, 1990; Volberding
et al., 1990). Indeed, AZT has been shown to be toxic in
HIV-positives and proposed as a possible cause of AIDS diseases
since 1991 (Duesberg, 1991, 1992c, 1992a, 1992b). Recently, the
European "Concorde trial" (Seligmann et al., 1994)
and several other studies have shown that, contrary to earlier claims,
AZT does not prevent AIDS (Oddone et al., 1993; Tokars et
al., 1993; Lenderking et al., 1994; Lundgren et al.,
1994). The Concorde trial even showed that the mortality of healthy,
AZT-treated HIV-carriers was 25% higher than that of placebo-treated
controls (Seligmann et al., 1994). Likewise, an American
multicenter study showed that the death risk of hemophiliacs treated
with AZT was 2.4 times higher, and that their AIDS risk was even
4.5 times higher than that of untreated HIV-positive hemophiliacs
(Goedert et al., 1994). Thus, the widespread use of AZT in
HIV-positives could be the reason for the sudden increase in hemophilia
mortality since 1987.
hypothesis and the foreign-protein-AIDS hypothesis both predict
that hemophilia-AIDS would stay constant or increase as long as
unpurified factor VIII is used and AZT is prescribed to HIV-positive
hemophiliacs. By contrast, the HIV-AIDS hypothesis predicts that
hemophilia-AIDS should have decreased with time since 1984 when
HIV was eliminated from the blood supply. The HIV hypothesis further
predicts that AIDS should have decreased precipitously since 1989
when AZT was prescribed as AIDS prevention to inhibit HIV.
But the decrease
in hemophilia-AIDS predicted by the HIV-AIDS hypothesis was not
observed. Instead, the data confirm the AZT-/foreign-protein-AIDS
hypotheses: The CDC reports 300 hemophilia AIDS cases in 1988, 295
in 1989, 320 in 1990, 316 in 1991,316 in 1992 and, after broadening
the AIDS definition as of January 1993 (Centers for Disease Control
and Prevention, 1992), 1096 in 1993 (Centers for Disease Control,
1993; Centers for Disease Control and Prevention, 1994; and prior
HIV/AIDS Surveillance reports).
AIDS risk of HIV-positive hemophiliacs compared to other HIV-positive
AIDS risk groups.The HIV-AIDS hypothesis predicts that
the annual risk of HIV-positive hemophiliacs would be the same as
that of other HIV-infected risk groups. One could in fact argue
that it should be higher, because the health of hemophiliacs is
compromised compared to AIDS risk groups without congenital health
the foreign-protein-AIDS hypothesis makes no clear prediction about
the annual AIDS risk of hemophiliacs compared to drug-AIDS risk
groups, because the relative risks have not been studied and are
hard to quantitate.
By the end
of 1992, 2,214 American hemophiliacs with AIDS were reported to
the CDC (Centers for Disease Control, 1993; Chorba et al.,
1994). Since there are about 15,000 HIV-positive American hemophiliacs,
an average of only 1.3% (201 out of 15,000) have developed AIDS
annually between 1981 and 1992 (Tsoukas et al., 1984; Hardy
et al., 1985; Institute of Medicine and National Academy
of Sciences, 1986; Sullivan et al., 1986; Stehr-Green et
al., 1988; Goedert et al., 1989; Koerper, 1989; Morgan,
Curran & Berkelman, 1990; Gomperts, De Biasi & De Vreker,
1992). But after the inclusion of further diseases into the AIDS
syndrome (Institute of Medicine, 1988), and the introduction of
AZT as an anti-HIV drug, both in 1987, the annual AIDS risk of American
hemophiliacs appears to have stabilized at 2%, e.g. about 300 out
of 15,000 per year until 1993 when the AIDS definition was changed
again (Centers for Disease Control, 1993) (see Section 4.1).
statistics from Germany are compatible with American counterparts:
about 50% of the 6,000 German hemophiliacs are HIV-positive (Koerper,
1989). Only 37 or ~ 1% of these developed AIDS-defining diseases
during 1991 (Leonhard, 1992), and 186 or 1.5% annually during the
four years from 1988 to 1991 (Schwartlaender et al., 1992).
The 1.3% to
2% annual AIDS risk indicates that the average HIV-positive hemophiliac
would have to wait for 25 to 35 years to develop AIDS diseases from
HIV. Indeed latent periods of over 20 years have just been calculated
for HIV-positive hemophiliacs based on the loss of T-cells over
time (Phillips et al., 1994b).
the annual AIDS risk of the average, HIV-positive American is currently
6%, because there are now about 60,000 annual AIDS cases (Centers
for Disease Control, 1993) per 1 million HIV-positive Americans
(Curran et al., 1985; Centers for Disease Control, 1992b;
Duesberg, 1992a). This reflects the annual AIDS-risks of the major
risk groups, the male homosexuals and intravenous drug users who
make up about 93% of all American AIDS patients (Centers for Disease
Control, 1993). The annual AIDS risks of intravenous drug users
(Lemp et al., 1990) and male homosexuals appear to be the
same, as both were estimated at about 5-6% (Anderson & May,
1988; Lui et al., 1988; Lemp et al., 1990) (Table
In view of
the compromised health of hemophiliacs, it is surprising that the
annual AIDS risk of HIV-infected hemophiliacs is only 1.3% to 2%
and thus 3-5 times lower than that of the average HIV-infected,
non-hemophiliac American or European (Table 1). Commenting on the
relatively low annual AIDS risk of hemophiliacs compared to that
of homosexuals, the hematologists Sullivan et al. noted that
"The reasons for this difference remain unclear" (Sullivan
et al., 1986). Hardy et al. from the CDC also noted
the discrepancy in the latent periods of different risk groups.
"The magnitude of some of the differences in rates is so great
that even gross errors in denomination estimates can be overcome"
(Hardy et al. 1985). And Christine Lee, senior author of
the study that had estimated latent periods of over 20 years from
infection to hemophilia AIDS (Phillips et al., 1994b), commented
on the paradox "It may be that hemophiliacs have got that cofactor
[of foreign blood contaminants], homosexuals have got another cofactor,
drug users have got another cofactor, and they all have the same
effect, so that at the end of the day you get [approximately] the
same progression rate." (Jones, 1994).
3-5-fold difference between the annual AIDS risks of HIV-positive
hemophiliacs and the other major risk groups is not compatible with
the HIV hypothesis. However, it can be reconciled with the foreign-protein
and drug-AIDS hypothesis (Duesberg, 1992a, 1994), because different
causes, i.e. drugs and foreign proteins, generate AIDS diseases
at different rates.
age bias of hemophilia-AIDS.The HIV-AIDS hypothesis predicts
that the annual AIDS risks of HIV-positive hemophiliacs is independent
of their age, because virus replication is independent of the age
of the host. Predictions would have to be adjusted, however, by
the hypothetical lag period between infection and AIDS. If the average
latent period from HIV to AIDS is 10 months, as was postulated in
1984 (Auerbach et al., 1984), less than 10-month-old HIV-positive
hemophiliacs would have a lower probability of having AIDS. If the
average latent period from HIV to AIDS is 10 years (Institute of
Medicine, 1988; Lui et al., 1988; Lemp et al., 1990;
Weiss, 1993), HIV-positive hemophiliacs under 10 years of age would
have a lower probability of having AIDS. In other words, if the
time of infection is unknown, the annual AIDS risks of HIV-positive
hemophiliacs over 10 months or 10 years, respectively, would be
independent of the age of the HIV-positive hemophiliac.
the foreign-protein hypothesis predicts that the annual AIDS risk
of HIV-positive and negative hemophiliacs increases with age because
immunosuppression is the result of the lifetime dose of proteins
transfused (Pollack et al., 1985; Brettler et al.,
1986; Sullivan et al., 1986; Koerper, 1989) (see above).
The more years a hemophiliac has been treated with unpurified blood
products, the more likely he is to develop immunodeficiency. Thus,
the foreign-protein hypothesis predicts that the annual AIDS risk
of a hemophiliac would increase with age.
Annual AIDS risks of HIV-infected groups.
Risk Group AIDS in % References
1.3-2 see textMale homosexuals 5-6 Lui et al., 1988, Anderson & May,
1988, Lemp et al., 1990Intravenous drug users 5-6 Lui et al. 1988,
Anderson & May, 1988, Lemp et al., 1990
show that the median age of hemophiliacs with AIDS in the U.S. (Evatt
et al., 1984; Koerper, 1989; Stehr-Green et al., 1989)
and other countries (Darby et al., 1989; Biggar and the International
Registry of Seroconverters, 1990; Blattner, 1991) is about 5-15
years higher than the average age of hemophiliacs. In the U.S.,
the average age of hemophiliacs was 20-27 years from 1980 to 1986,
while that of hemophiliacs with AIDS was 32-35 years (Evatt et
al., 1984; Koerper, 1989; Stehr-Green et al., 1989).
the annual AIDS risk of HIV-positive hemophiliacs shows a strong
age bias. An international study estimated the annual AIDS risk
of children at 1% and that of adult hemophiliacs at 3% over a 5-year
period of HIV-infection (Biggar and the International Registry of
Seroconverters, 1990). In the U.S., Goedert et al. reported
that the annual AIDS risk of 1- to 17-year-old hemophiliacs was
1.5%, that of 18- and 34-year-old hemophiliacs was 3%, and that
of 64- year-old hemophiliacs was 5% (Goedert et al., 1989).
Goldsmith et al. reported that the annual T-cell loss of
hemophiliacs under 25 years was 9.5% and for hemophiliacs over 25
years 17.5% (Goldsmith et al., 1991).
al. reported that the annual AIDS risk of hemophiliacs 11 years
after HIV seroconversion was 31% under 25 years and 56% over 25
years (Lee et al., 1991). They estimated that the relative
risk of AIDS increased 5-fold over 25 years. The same group confirmed
in 1994 that the annual AIDS risk of HIV-positive hemophiliacs over
30 years is 2-times higher than in those under 15 years of age (Phillips
et al., 1994b). Stehr-Green et al. estimated that
"... the risk of AIDS increased two fold for each 10 year increase
in age after controlling for year of seroconversion." (Stehr-Green
et al., 1989). Likewise, Fletcher et al. reported
a 4-fold higher incidence of AIDS in hemophiliacs over 25 years
of age than in those aged 5 to 13 years (Fletcher et al., 1992).
Thus, the annual AIDS risk of hemophiliacs increases about 2-fold
for each 10-year increase in age.
the foreign-protein hypothesis, which holds that the cumulative
dose of transfusions received is the cause of AIDS-defining diseases
among hemophiliacs. According to the hematologist Koerper, "this
may reflect lifetime exposure to a greater number of units of concentrate,
..." and to Evatt et al., "This age bias may be
due to differences in duration of exposure to blood products ..."
(Evatt et al., 1984; Koerper, 1989). A recent study of HIV-free
hemophiliacs is directly compatible with the foreign-protein hypothesis.
The study showed that despite the absence of HIV "with increasing
age, numbers of CD4+CD45RA+ cells decreased and continued to do
so throughout life" (Fletcher et al., 1992).
AIDS caused by an autonomous infectious pathogen would be independent
of the age of the recipient because the replication cycle of viruses,
including HIV, is independent of the age of the host. Thus the foreign-protein-AIDS
hypothesis, rather than the HIV-AIDS hypothesis, correctly predicts
the age bias of hemophilia-AIDS.
AIDS diseases.The 30 AIDS diseases fall into two categories,
the microbial immunodeficiency diseases and the non-immunodeficiency
diseases, i.e. diseases that are neither caused by, nor consistently
associated with, immunodeficiency (Duesberg, 1992a, 1994). Based
on their annual incidence in America in 1992, 61% of the AIDS diseases
were microbial immunodeficiency diseases, including pneumocystis
pneumonia, candidiasis, tuberculosis, etc., and 39% were non-immunodeficiency
diseases, including Kaposi's sarcoma, lymphoma, dementia, and wasting
disease (Table 2) (Centers for Disease Control, 1993).
hypothesis predicts that the probability of all HIV-infected persons
to develop a given immunodeficiency or non-immunodeficiency AIDS
disease is the same and independent of the AIDS risk group. By contrast,
the hypothesis that AIDS is caused by drugs or by foreign proteins
predicts specific diseases for specific causes (Duesberg, 1992a).
99% of the hemophiliacs with AIDS have immunodeficiency diseases,
of which 70% are fungal and viral pneumonias (Evatt et al.,
1984; Koerper, 1989; Papadopulos-Eleopulos et al., 1994).
Only one study reports that 1% of hemophiliacs with AIDS had Kaposi's
sarcoma (Selik, Starcher & Curran, 1987). The small percentage
of Kaposi's sarcoma may be due to aphrodisiac nitrite inhalants
used by male homosexual hemophiliacs as sexual stimulants (Haverkos
& Dougherty, 1988; Duesberg, 1992a). There are no reports of
wasting disease or dementia in American hemophiliacs. An English
study also reported predominantly pneumonias and other immunodeficiency
diseases among hemophiliacs, and also three cases of wasting syndrome
(Lee et al., 1991). It appears that the AIDS diseases
of hemophiliacs are virtually all immunodeficiency diseases, whereas
39% of the AIDS diseases of intravenous drug users and male homosexuals
are non-immunodeficiency diseases (Table 2). Since AIDS diseases
in hemophiliacs and non-hemophiliacs are not the same, their causes
can also not be the same.
exclusive occurrence of immunodeficiency AIDS diseases among hemophiliacs
is correctly predicted by the foreign-protein-AIDS hypothesis, but
not by the HIV-AIDS hypothesis. The prediction of the HIV hypothesis,
that the distribution of immunodeficiency and non-immunodeficiency
diseases among hemophiliacs is the same as in the rest of the American
AIDS population, is not confirmed.
hemophilia-AIDS contagious?The virus-AIDS hypothesis
predicts that AIDS is contagious, because HIV is a parenterally
and sexually transmitted virus. It predicts that hemophilia-AIDS
is sexually transmissible. Indeed, AIDS researchers claim that the
wives of hemophiliacs develop AIDS from sexual transmission of HIV
(Booth, 1988; Lawrence et al., 1990; Weiss & Jaffe, 1990;
Centers for Disease Control, 1992a, 1993). Further, the HIV-AIDS
hypothesis predicts that wives of hemophiliacs will develop the
same AIDS diseases as other risk groups.
hypothesis predicts that AIDS is not contagious and that the wives
and sexual partners of hemophiliacs do not contract AIDS from their
To test the
hypothesis that immunodeficiency of hemophiliacs is sexually transmissible,
the T4 to T8-cell ratios of 41 spouses and female sexual partners
of immunodeficient hemophiliacs were analyzed (Kreiss et al.,
1984). Twenty-two of the females had relationships with hemophiliacs
with T-cell ratios below 1, and 19 with hemophiliacs with ratios
of 1 and greater. The mean duration of relationships was 10 years,
the mean number of sexual contacts was 111 during the previous year,
and only 12% had used condoms (Kreiss et al., 1984). Since
the T-cell ratios of all spouses were normal, averaging 1.68-exactly
like those of 57 normal controls-the authors concluded that "there
is no evidence to date for heterosexual or household-contact transmission
of T-cell subset abnormalities from hemophiliacs to their spouses
..." (Kreiss et al., 1984).
The CDC reports
that between 1985 and 1992, 131 wives of American hemophiliacs were
diagnosed with unnamed AIDS diseases (Centers for Disease Control,
1993). If one considers that there have been 15,000 HIV-positive
hemophiliacs in the U.S. since 1984 and that one-third are married,
then there are 5,000 wives of HlV-positive hemophiliacs. About 16
of these women have developed AIDS annually during the 8 years (131:
8) from 1985 to 1992. But these 16 annual AIDS cases would have
to be distinguished from the at least 80 wives of hemophiliacs that
are expected to die per year based on natural mortality. Considering
the human life span of about 80 years and that on average at least
1.6% of all those over 20 years of age die annually, about 80 out
of 5,000 wives over 20 would die naturally per year. Thus, until
controls show that among 5,000 HIV-positive wives of hemophiliacs
16 more than 80, i.e. 96, die annually, the claim that wives of
hemophiliacs die from sexual or other transmision of HIV is unfounded
it has been pointed out that all AIDS-defining diseases of the wives
of hemophiliacs are typically age-related opportunistic infections,
including 81% pneumonia (Lawrence et al., 1990). Kaposi's
sarcoma, dementia, lymphoma, and wasting syndrome are not observed
in wives of hemophiliacs (Lawrence et al., 1990).
foreign-protein, but not the HIV hypothesis, correctly predicts
the non-contagiousness of hemophilia-AlDS. It also predicts the
specific spectrum of AIDS diseases in wives of hemophiliacs. By
contrast, the virus-AIDS hypothesis predicts the same spectrum of
AIDS diseases among wives of hemophiliacs as among the major risk
groups (see Table 2). It appears that the virus-AIDS hypothesis
is claiming normal morbidity and mortality of the wives of hemophiliacs
in HIV-positive and -negative hemophiliacs.The HIV hypothesis
predicts that immunodeficiency is observed only in HIV-positive
hemophiliacs. By contrast, the foreign-protein hypothesis predicts
that immunodeficiency is a function of the lifetime dose of transfusions
received, and not dependent on HIV or antibodies against HIV. The
foreign-protein hypothesis also predicts that HIV-positive hemophiliacs
are more likely to be immunosuppressed than HIV-negatives because
HIV is a rare contaminant of blood transfusion and thus is a marker
for the number of transfusions received (see Section 3, and below)
(Tsoukas et al., 1984; Ludlam et al., 1985; Kreiss
et al., 1986; Sullivan et al., 1986; Koerper, 1989;
Fletcher et al., 1992).
studies, summarized in Table 3, have observed 1,186 immunodeficient
hemophiliacs, 416 of whom were HIV-free. Immunodeficiency in these
studies was either defined by a T4 to T8-cell ratio of about 1 or
less than 1, compared to a normal ratio of 2, or by other tests
such as immunological anergy. Since immunodeficiency was observed
in the absence of HIV, most of the studies listed in Table 3 have
concluded that immunodeficiency in hemophiliacs was caused by transfusion
of factor VIII and contaminating proteins. According to the first
of Koch's postulates (Merriam-Webster, 1965), the absence of a microbe,
i.e. HIV, from a disease excludes it as a possible cause of that
disease. Thus, transfusion of foreign protein, not the presence
of HIV, emerges as the common denominator of all hemophiliacs with
several of the controlled studies listed in Table 3, which compare
HIV-negative to HIV-positive hemophiliacs, have shown that immunodeficiency
is more often associated with HIV-positives than with negatives.
Although some studies did not report immunodeficiency in HIV-positives,
Table 3 lists 770 HIV-positives and 416 HIV-negatives per 1,186
immunodeficient hemophiliacs. In view of this, one could argue that
HIV is one of several possible causes of immunodeficiency.
of the investigators listed in Table 3 (Tsoukas et al., 1984;
Ludlam et al., 1985; Kreiss et al., 1986; Madhok et
al., 1986; Sullivan et al., 1986) and others who have
not performed controlled studies (Koerper, 1989) have proposed that
HIV is just a marker for the number of transfusions received (Section
3). As a rare contaminant of factor VIII, HIV has in fact been a
marker for the number of transfusions received before it was eliminated
from the blood supply in 1984, just like hepatitis virus infection
was a marker of the number of transfusions received until it was
eliminated from the blood supply earlier (Anonymous, 1984; Koerper,
1989). According to Kreiss et al., "seropositive hemophiliac
subjects, on average, had been exposed to twice as much concentrate
... as seronegative[s]" (Kreiss et al., 1986). Sullivan
et al. also reported that "Seropositivity to LAV/HTLV-III
(HIV) was 70% for the hemophiliac population and ... varied directly
with the amount of factor VIII received" (see Section 3) (Sullivan
et al., 1986). More recently, Schulman reported that "a
high annual consumption" of factor VIII concentrate "predisposed"
to HIV-seroconversion (Schulman, 1991), and Fletcher et al. described
a positive "relationship between the amount of concentrate
administered and anti-HIV prevalence rate ..." (Fletcher et
of studies investigating immunodeficiency in HIV-free hemophiliacs
faithfully reflects the popularity of the HIV hypothesis: the more
popular the HIV hypothesis became over time the fewer studies investigated
immunodeficiency in HIV-free hemophiliacs. Indeed, most of the controlled
studies investigating the role of HIV in immunodeficiency of HIV-positive
and matched HIV-negative hemophiliacs were conducted before the
virus hypothesis became totally dominant in 1988 (Institute of Medicine,
1988), namely between 1984 and 1988 (Table 3). The studies by Jin,
Cleveland and Kaufman, and Lang et al., both dated 1989,
and the studies by Becherer et al. and by Jason et al.,
both dated 1990, all described data collected before 1988 (Table
3). After 1988 the question whether HIV-free hemophiliacs developed
immunodeficiency became increasingly unpopular. As a result, only
a few studies have described immunodeficiency in HIV-free hemophiliacs.
Schulman reported "worrisome evidence of similar immunological
disturbances has been observed, albeit to a lesser degree, in anti-HIV-negative
hemophiliacs" and that immunodeficiency in hemophiliacs "correlates
more strongly with annual consumption of factor concentrates than
with HIV status" (Schulman, 1991). Fletcher et al. published
a median T4/T8-cell ratio of 1.4, with a low 10-percentile of 0.8,
in a group of 154 HIV-free hemophiliacs, and also showed a steady
decline of T-cell counts with treatment years (Fletcher et al.,
1992). Likewise, Hassett et al. reported that "patients
with hemophilia A without human immunodeficiency virus type 1 (HIV-1
) infection have lower CD4+ counts and CD4+/CD8+ ratios than controls"
(Hassett et al., 1993). The study observed an average T4/T8-cell
ratio of 1.47 in a group of 307 HIV-free hemophiliacs, differing
over 50 years in age, compared to an average of 1.85 in normal controls.
Unlike others Hassett et al. attributed the lowered CD4+
counts to a hemophilia-related disorder rather than to foreign proteins,
but like others they attributed increased CD8+ counts to treatment
with commercial factor VIII. However, Fletcher et al.'s and
Hassett et al.'s practice of averaging immunodeficiency
markers of large numbers of people, differing over 50 years in age,
obscures how far the immunity of the longest, and thus most treated
cases had declined compared to cases which have received minimal
authors of these studies did not report the life time dosage of
factor VIII treatments of HIV-free hemophiliacs, a correlation between
foreign-protein dosage and immunosuppression cannot be determined.
On the contrary, averaging immunodeficiency parameters of newcomers
and long-term treatment recipients obscures the relationship between
the lifetime dosage of factor VIII and immunosuppression.
the CDC reported 7 HIV-free hemophiliacs with AIDS (Smith et
al., 1993). This study was one of a package that proposed to
set apart HIV-free AIDS from HIV-positive AIDS with the new term
idiopathic CD4 lymphocytopenia. The goal of these
studies was to save the virus-AIDS hypothesis, despite the presence
of HIV-free AIDS (Duesberg, 1993b, 1994; Fauci, 1993). Nevertheless
all of the 7 HIV-free hemophiliacs met one or more criteria of the
CDC's clinical AIDS definition from 1993 (Centers for Disease Control
and Prevention, 1992), e.g. they all had less than 300 T-cells per
microliter (range from 88 to 296), and three also had AIDS defining
diseases such as herpes and thrombocytopenia (Smith et al.,
of immunodeficiency in HIV-free hemophiliacs demonstrates most directly
that long-term transfusion of foreign proteins contaminating factor
VIII is sufficient to cause immunodeficiency in hemophiliacs. To
prove the foreign-protein hypothesis it would be necessary to show
that treatment of HIV-positive hemophiliacs with pure factor VIII
does not cause immunodeficiency. It is shown below that this is
actually the case.
even regeneration of immunity of HIV-positive hemophiliacs by treatment
with pure factor VIII.Commercial preparations of factor VIII
contain between 99% and 99.9% non-factor VIII proteins (Eyster &
Nau, 1978; Brettler & Levine, 1989; Gjerset et al., 1994;
Mannucci et al., 1992; Seremetis et al., 1993). The
foreign-protein-hemophilia-AIDS hypothesis predicts that long-term
transfusion with commercial factor VIII would be immunosuppressive,
because of the presence of contaminating proteins. Further, it predicts
that pure factor VIII, containing 100- to 1,000-times less foreign
protein per functional unit, may not be immunosuppressive.
have recently tested whether the impurities of factor VIII or factor
VIII by itself are immunosuppressive in HIV-positive hemophiliacs.
De Biasi et al. showed that over a period of two years the
average T-cell counts of ten HIV-positive hemophiliacs treated with
non-purified, commercial factor VIII declined two-fold, while those
of matched HIV-positive controls treated with pure factor VIII remained
unchanged. Moreover, four out of six anergic HIV-positive patients
treated with purified factor VIII recovered immunological activity
(de Biasi et al., 1991). Goldsmith et al. also found
that the T-cell counts of 13 hemophiliacs treated with purified
factor VIII remained stable for 1.5 years (Goldsmith et al.,
1991). Seremetis et al. have confirmed and extended de Biasi
et al.'s conclusion by establishing that the T-cells of HIV-positive
hemophiliacs were not depleted after treatment with pure factor
VIII for three years (Seremetis et al., 1993). Indeed, the
T-cell counts of 14 out of 31 HIV-positive hemophiliacs increased
up to 25% over the three-year period of treatment with purified
factor VIII-despite infection by HIV. By contrast, in the group
treated with unpurified factor VIII, the percentage of those with
less than 200 T-cells per ml increased from 7% at the beginning
of the study to 47% at the end.
et al. reported individual increases of T-cell counts
of up to 50% in a group of 36 HIV-positive hemophiliacs treated
with purified factor VIII whose average T-cell count had declined
1% during 6 months (Hilgartner et al., 1993). Goedert et
al. have also reported that "T-cell counts fell less rapidly
with high purity products" (Goedert et al., 1994). Moreover,
Schulman observed that four HIV-positive hemophiliacs recovered
from thrombocytopenia upon treatment with pure factor VIII for 2-3
years, and others from CD8-related immunodeficiency upon treatment
for 6 months (Schulman, 1991).
the evidence that purified factor VIII is beneficial in maintaining
or even increasing T-cell counts, several studies testing purified
factor VIII are ambiguous about its effectiveness in preventing
or treating AIDS (Goldsmith et al., 1991; Hilgartner et
al., 1993; Gjerset et al., 1994; Goedert et al.,
1994; Phillips et al., 1994a). Some of these studies have
only tested partially purified, i.e. 2-10 units/mg, instead of highly
purified, i.e. 2000-3000 units/mg, factor VIII (Gjerset et al.,
1994). But each of the studies that are ambiguous about the benefits
have also treated their patients with toxic antiviral DNA chain
terminators like AZT. Indeed the study by de Biasi et al. was
the only one that has tested purified factor VIII in the absence
of AZT. The study by Seremetis et al. initially called for
no AZT, but later allowed it anyway. Thus in all but one study,
the potential benefits of highly purified factor VIII have been
obscured by the toxicity of AZT (see Section 5.4).
It is concluded
that treatment of HIV-positive hemophiliacs with pure factor VIII
provides lasting stabilization of immunity, and even allows regeneration
of lost immunity. It follows that foreign proteins, rather than
factor VIII or HIV, cause immunosuppression in HIV-positive hemophiliacs.
of proof have been applied to distinguish between the virus and
the foreign-protein hypothesis of hemophilia-AIDS: (i) correlation,
(ii) function (Koch's third postulate), (iii) predictions, (iv)
therapy and prevention. Each of these criteria proved the foreign-protein
hypothesis valid and the HIV hypothesis invalid.
between hemophilia-AIDS and the long-term administration of foreign
proteins or HIV.Although correlation is not sufficient, it is
necessary to prove causation in terms of Koch's postulates (Merriam-Webster,
1965). The first of Koch's postulates calls for the presence of
the suspected cause in all cases of the disease, i.e. a perfect
correlation; the second calls for the isolation of the cause; and
the third for causation of the disease with the isolated causative
with immunodeficiency described here have been subject to long-term
treatment with foreign proteins contaminating factor VIII. This
establishes a perfect correlation between foreign-protein transfusion
and hemophilia-AIDS, and fulfills Koch's first postulate.
a summary of 21 separate studies showed that 416 of 1,186 immunodeficient
hemophiliacs were HIV-free (Table 3). Since HIV does not correlate
well with hemophilia-AIDS, it fails Koch's first postulate and is
thus not even a plausible cause of AIDS.
hypothesis, but not HIV hypothesis, meets Koch's third postulate
as cause of immunodeficiency.The fact that all hemophiliacs
with immunodeficiency had been subject to long-term treatment with
foreign proteins, and that factor VIII treatment in the absence
of foreign proteins does not cause immune suppression, and may even
revert it, provides functional proof for the foreign-protein hypothesis.
Thus, the foreign-protein hypothesis meets Koch's third postulate
of immunity of HIV-positives by treatment with pure factor VIII
further indicates that HIV by itself or in combination with factor
VIII is not sufficient for hemophilia-AIDS. Therefore, HIV fails
Koch's third postulate as a cause of AIDS.
hypothesis correctly predicts hemophilia-AIDS and resolves paradoxa
of HIV hypothesis.The ability to make verifiable predictions
is the hallmark of a correct scientific hypothesis. Application
of the two competing hypotheses to hemophilia-AIDS proved that the
foreign-protein hypothesis, but not the HIV hypothesis, correctly
predicts seven characteristics of hemophilia-AIDS (see Sections
1. The increased
life span of American hemophiliacs, despite infection of 75% by
HIV, due to factor VIII treatment, that extended their lives and
disseminated harmless HIV;
2. the 3-5
times lower annual AIDS risk of hemophiliacs, compared to other
AIDS risk groups;
3. the age
bias of the annual AIDS risk of hemophiliacs, increasing 2-fold
for each 10-year increase in age;
4. the restriction
of hemophilia-AIDS to immunodeficiency-related AIDS diseases, setting
it apart from the spectrum of AIDS diseases in other risk groups;
5. the non-contagiousness
of hemophilia-AIDS, i.e. the absence of AIDS diseases above their
normal background in sexual partners of hemophiliacs;
6. the occurrence
of immunodeficiency in HIV-free, factor VIII-treated hemophiliacs;
7. the stabilization,
even regeneration, of immunity of HIV-positive hemophiliacs upon
long-term treatment with pure factor VIII.
that the foreign-protein hypothesis, but not the HIV hypothesis,
correctly predicts hemophilia-AIDS. In addition, the foreign-protein
hypothesis resolves all remaining paradoxa of the HIV hypothesis
(see Section 2):
1. The failure
of HIV neutralizing antibody to protect against AIDS-because HIV
is not the cause of AIDS.
2. The non-correlation
between the loss of T-cells and HIV activity-because foreign proteins
rather than HIV are immunotoxic.
3. The failure
of HIV to kill T-cells-because T-cell synthesis is suppressed by
immunotoxic foreign proteins.
4. The latent
periods of 10 to 35 years between HIV and hemophilia-AIDS-because
the lifetime dosage of foreign proteins, not HIV, causes AIDS.
and prevention of AIDS.The prevention or cure of a disease,
by eliminating or blocking the suspected cause, provides empirical
proof of causation.
based on HIV hypothesis: On the basis of the HIV hypothesis,
AIDS has been treated since 1987 with anti-HIV drugs, such as the
DNA chain terminators AZT, ddI, etc. (Duesberg, 1992a). The rationale
of the AZT treatment is to prevent HIV DNA synthesis at the high
cost of inhibiting cellular DNA synthesis, the original target of
AZT cancer chemotherapy (see above). However, not a single AIDS
patient has ever been cured with AZT. Since 1989, healthy HIV-positive
hemophiliacs have also been treated with DNA chain terminators in
efforts to prevent AIDS. But the alleged ability of AZT to prevent
AIDS has recently been discredited by several large clinical trials
(Oddone et al., 1993; Tokars et al., 1993; Goedert
et al., 1994; Lenderking et al., 1994; Lundgren et
al., 1994; Seligmann et al., 1994). Moreover, all studies
of AZT treatments have confirmed the unavoidable cytotoxicity of
DNA chain terminators (Duesberg, 1992; Oddone et al., 1993;
Tokars et al., 1993; Lenderking et al., 1994; Lundgren
et al., 1994; Seligmann et al., 1994). One study observed
a 25% increased mortality (Seligmann et al., 1994), and another
a 4.5-fold higher annual AIDS risk and a 2.4-fold higher annual
death risk in AZT-treated HIVpositive hemophiliacs compared to untreated
controls (Goedert et al., 1994).
of AZT therapy to cure or prevent AIDS indicates either that the
drug is not sufficient to inhibit HIV or that HIV is not the cause
of AIDS. The lower mortality and much lower incidence of AIDS defining
diseases among hemophiliacs not treated with AZT compared to those
treated indicates that AZT causes AIDS defining diseases and mortality.
Thus, there is currently no rational or empirical justification
for AZT treatment of HIV-positives with or without AIDS.
ability of AZT to cause AIDS defining and other diseases in hemophiliacs
is just one aspect of the many roles that drugs play in the origin
of AIDS (see footnote).1
based on foreign-protein hypothesis: In the light of the foreign-protein
hypothesis, hemophiliacs have been treated with factor VIII freed
of foreign proteins. This treatment has provided lasting stabilization
of immunity in HIV-positive hemophiliacs. Moreover, the long-term
treatment of immunodeficient, HIV-positive hemophiliacs with purified
factor VIII has even regenerated lost immunity. Immunological anergy
has disappeared and the T-cells in HIV-positive hemophiliacs have
increased up to 25% in the presence of pure factor VIII (see Section
4.7) (de Biasi et al., 1991; Seremetis et al., 1993).
Thus, therapeutic benefits including AIDS prevention and even recovery
of lost immunity by omission of foreign proteins from factor VIII
lend credence to the foreign-protein-AIDS hypothesis.
treatment hypotheses-and one treatment dilemma: The failure
to distinguish between two alternative hypothetical AIDS causes,
HIV and foreign proteins, has created a dilemma for contemporary
hemophilia treatment. For example, Goedert et al. acknowledge
that "CD4 count fell less rapidly with high purity products"
(Goedert et al., 1994). But since they are also treating
their patients with toxic AZT (see Section 4.1 ), they observe that
"F VIII related changes in CD4 concentration may have little
relevance to clinical disease" (Goedert et al., 1994).
Indeed the group had published a rare comparison between the annual
AIDS- and death risks of hemophiliacs treated and not treated with
AZT which indicated that the AIDS risk of AZT-treated hemophiliacs
is 4.5-times and the death risk 2.4-times higher than in untreated
In order to
reconcile the apparent benefits of purified factor VIII on T-cell
counts with the apparent toxicity of simultaneous AZT treatment,
they try to separate T-cell loss from AIDS diseases. However, despite
non-immunodeficiency AIDS diseases (see Table 2, Section 4.4), AIDS
is defined as a T-cell deficiency (Institute of Medicine and National
Academy of Sciences, 1986; Institute of Medicine, 1988) and dozens
of AIDS researchers have observed that "AIDS tends to develop
only after patients' CD4 lymphocyte counts have reached low levels
..." (Phillips et al., 1994b). Indeed, as of January
1993 the CDC defined less than 200 T-cells per ml as an AIDS disease
(Centers for Disease Control and Prevention, 1992), and sequential
T-cell counts of hemophiliacs are used as a basis to calculate their
long-term survival (Phillips et al., 1994b).
their exclusive faith in the HIV-AIDS hypothesis, readers of the
study by Seremetis et al. (Seremetis et al., 1993),
which had demonstrated that foreign proteins associated with factor
VIII suppress T-cell counts, have even proposed to "consider
the use of high-purity factor VIII concentrates in non-hemophiliac-HIV-positive
patients" as a treatment for other AIDS patients, i.e. intravenous
drug users and homosexuals. Since hemophiliacs treated with pure
factor VIII did either not develop immunodeficiency or even recovered
lost immunity, they assumed, in view of the HIV-hypothesis, that
pure factor VIII must inhibit HIV and thus would help all AIDS patients
(Schwarz et al., 1994).
to the treatment dilemma can only come from treatments that are
each based only on one hemophilia-AIDS hypothesis: To test the foreign-protein
hypothesis, two groups of hemophiliacs must be compared that are
matched for their life time dosage of factor VIII, for their percentage
of HIV-positives (for their percentage and dosage of prior AZT treatment,
if applicable), and for their age. All AIDS-defining diseases must
be diagnosed in each group clinically for the duration of the test.
No anti-HIV treatments must be performed. One group would be treated
with purified factor VIII, the other with commercial factor VIII
contaminated with foreign proteins.
To test the
HIV-AIDS hypothesis, two groups of hemophiliacs must be compared
that are matched for their life time dosage of factor VIII treatment
and their age. The two groups must differ only in the presence of
antibody against HIV. Both groups would be treated with the same
factor VIII preparation. Only the HIV-positive group would receive
AZT. All compensatory treatments of AZT recipients, e.g. blood transfusions
to treat for AZT-induced anemia, neutropenia or pancytopenia (Richman
et al., 1987; Volberding et al., 1990; Duesberg, 1992),
would have to be recorded. During the duration of the test, all
AIDS-defining diseases would each be recorded clinically in both
of each treatment strategy, purified factor VIII or AZT, would be
determined based on morbidity and mortality, including AZT morbidity
and mortality, and corrected for treatments compensating for AZT
toxicity. As yet, no controlled treatment studies based on a single
AIDS hypothesis have been performed.
the study by de Biasi et al. (de Biasi et al., 1992)
and with reservations that by Seremetis et al. (Seremetis
et al., 1993) come close to the stated criteria for a test
of the foreign-protein hypothesis (Section 4.7). Seremetis et
al. initially excluded, but later allowed AZT treatment. Both
studies showed that purified factor VIII improved immunodeficiency
(see ii). However, since all subjects in these studies were HIV-positive,
one could indeed argue that the improvement of those treated with
purified factor VIII was due to a cooperation between HIV and purified
treatment of immunodeficiency in hemophiliacs, or of hemophilia-AIDS,
could be only as far away as the duration of one carefully controlled
I thank Siggi
Sachs, Russell Schoch, and Jody Schwartz (Berkeley) for critical
reviews, and Robert Maver (Overland Park, MO), Scott Tenenbaum,
Robert Garry (Tulane University, New Orleans), Jon Cohen (Science,
Washington, DC) and Michael Verney-Elliot (MEDITEL, London)
for critical information. This investigation was supported in part
by the Council for Tobacco Research, USA, and private donations
from Tom Boulger (Redondo Beach, CA, USA), Glenn Braswell (Los Angeles,
CA, USA), Dr. Richard Fischer (Annandale, VA, USA), Dr. Fabio Franchi
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