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Treatment
forv HIV infection:
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Abstract
The mortality rate due to AIDS has gradually dropped in the past
9 years. This fact is mainly attributed to antiretroviral treatment.
We shall hence study the related evidence, which has been found
to be highly deficient. The main reasons lie in some less known
statistical repercussions and in the abnormal setting of drug
efficacy studies, which in the first place are designed to obtain
results on "surrogate markers" rather than on clinical
advantages. Other options could lead both to progress in treatment
and to a better understanding of this complex and articulated
syndrome.
Introduction
Starting from the assumption that every cognitive progress' foundation
is a critical awareness of previous knowledge with the recognition
of past errors, to this end we propose: 1) some methodological
considerations on antiretroviral treatment in the light of the
results gradually obtained; 2) a discussion on the treatment's
current goals (control of surrogate markers); and, 3) an evaluation
of practical alternative proposals.
What appears clear is that antiretroviral treatment has undergone
important modifications through the years and that a remarkable
reduction in AIDS-related mortality has been observed since 1996,
the year new drug classes were introduced. However the assumption
that such a reduction results only from this factor is very limiting.
This review plans on demonstrating it in three short chapters:
1) HISTORY OF ANTIRETROVIRAL TREATMENT
Evaluation of the mortality rate reduction Evaluation of the treatment's
risks and advantages
2) VALIDITY OF SURROGATE MARKERS
3) PROPOSALS FOR ALTERNATIVE TREATMENT
1. HISTORY OF ANTIRETROVIRAL
TREATMENT
Thousands of studies, which tested the efficacy of treatment in
HIV infections, have been published. However it is unusual that
those which are considered as methodologically appropriate are
rare and have invariably produced irrelevant or negative results
for antiretroviral drugs.
We should specify right away that a correct evaluation of a drug's
efficacy necessarily requires detailed preliminary studies followed
by methodologically appropriate clinical studies (randomized,
placebo controlled, double blind) to reduce any bias. We wish
to recall that a drug against AIDS (ditiocarb), which seemed to
be promising and which had positively passed various small well
structured studies, was withdrawn from circulation due to just
one negative study (1). This study was more extensive, had a greater
statistical relevance and was on the other hand interrupted at
an early stage . Such a measure is justified as long as the premises
are correct because 100 positive corroboration controls are not
worth a good falsification, as Karl Popper the philosopher of
science taught us. However in other similar situations the same
principle was not applied. We must also observe that currently:
1) to enable speedy approval of drugs we resort to fast track
approval, which drastically cuts short the preliminary phases
of experimentation and study to 24 weeks (2) (normally 5-10 years);
2) clinical trials with appropriate features are rare and they
do not show advantages for treated patients (S. Garattini (3));
and,
3) from 1993 these were curiously abolished for "ethical
reasons", in other words not to deprive some patients (those
meant for placebo treatment in the control group) of the benefits
of the antiretroviral drugs studied. But these benefits are only
presumed and not proved at all. We can explain this by merely
mentioning the results of some studies, which reveal the periods
studied and which can be considered as paradigmatic by the community
of researchers.
A. (1987-1990) Evidence of AZT inefficacy
for individuals suffering from AIDS.
The first antiretroviral drug (AZT) was approved following a study
- published in 1987 and closed prematurely 4 months after the
start, which proved that the mortality rate in patients suffering
from AIDS who had received a placebo treatment seemed to be far
higher than those treated with AZT (19 vs. 1) (4); however this
study was proved to be both fraudulent (5) and highly mistaken
in the evaluation of results (6). To confirm the lack of efficacy,
a follow up of the same group of patients performed by the same
researchers revealed a high mortality rate after a few months
(42.4% after 21 months) and a lower mortality rate for the group
that had taken ACT for a shorter period (35% in the same period)
(7,8).
B. Evidence of the inefficacy of AZT in AIDS prophylaxis
in asymptomatic individuals (1990-1995).
In the study that in 1990 inaugurated the use of AZT in asymptomatic
seropositive individuals (Volberding) (9), the best results declared
in terms of survival and quality of life were reviewed by the
same author: 4 years later: in 1994 he admitted that "when
life threatening side effects were also counted the placebo group
in practice had gained some advantage on both AZT groups in terms
of interval without symptoms of disease or toxicity" (10).
This statement should have been handed over to public opinion
much earlier.
| Box 1 |
| The apparently illogical consequence of these disappointing results was that almost the entire world of research grouped round the same previous setting without considering the data available. At that stage control groups treated with placebo were not used anymore in experiments and the new drugs (inserted in the "life saving" category) were and still are assessed through a comparative study with the previous ones in an endless logical chain, whose first weak link was to be precise the (in) efficacy of AZT. But there is another consequence that is less serious - real progress was obscured by the lack of methodology in the premises. |
Still another study, the last in sequential order,
had a placebo group: the Concorde Trial (which designed to calm
doubts and controversy instead gave rise to prolonged discussions).
A clear disadvantage was proved in the group of patients who had
been administered early treatment with AZT (25% additional deaths
though partly due to causes other than AIDS) (11). But this proof
did not involve an adjustment in the therapeutic trend, rather
the opposite.
C. (1995-2003) David Ho's revolutionary
discovery. The multidrug treatment.
The turning point was marked by an article authored by David Ho
and published in the New England Journal of Medicine (12) in 1995.
In this article the American researcher declared with conviction
that the time had come to forcefully strike HIV at an early stage
with many drugs, … because monotherapy was heading for failure
(an explicit authoritative admission).
Three "scientific pillars" supported his theory:
1) the sudden detection of large quantities of virus with the
new tests (quantitative PCR, which would indicate the Viral Load);
2) a new study in which AZT treatment administered in the early
stage of the infection seemed to produce a considerable advantage
compared to untreated patients (13);
3) the availability of other drug classes, in other words protease
inhibitors (three of these were approved by the FDA in less than
three months, which was no doubt a record time) (14).
Concerning the first point the use of the modified PCR method
to calculate the Viral Load was considered as invalid and a real
oxymoron (15) by a leading expert who was also the one to discover
it. He was the Nobel prize winner Kari Mullis. However, whether
the viral load found was high or low, the infected lymphocytes,
which were very few before 1995 remained very few (1:1000, 1:10.000)
in the following years though they were surrounded by millions
of "viral particles" (16). Concerning the second point,
the study mentioned by D. Ho (17) would prove a paradoxical result
from a virological perspective, in other words a clinical advantage
for patients and at the same time void of effects on the disease's
causal agent. In fact the duration and characteristics of the
initial mononucleosis syndrome at the moment of maximum viral
replication at the start of the immune response was the same both
in those who had taken AZT and in those who had taken the placebo.
The same occurred concerning the isolation of the surrogate P24
marker and the RNA particles revealed by PCR (with no significant
difference between the two groups).
The study however lasted for a few initial months compared to
the disease, whose average estimate incubation period was 10-14
years.
The third point, in other words the possibility of considerably
limiting the infection from spreading by treating it at an early
stage, was a mere theory, an assumption to be checked though it
was presented as a solution that seemed quite obvious.
This sufficed to once again speed up the huge convoy of HAART
(Highly Active Antiretroviral Therapy) prophylaxis and treatment
for all seropositive patients for an unlimited period of time.
This convoy was running the risk of coming to a standstill with
the sole use of AZT.
The initial success was so considerable that the expression "Lazarus
effect" (18) was coined to designate the fact that hospital
wards had been emptied because patients had recorded such an improvement
and did not require frequent hospitalization anymore.
In many centres more or less all patients were treated with HAART.
In three years - from 1994 to 1997 - the European percentage of
untreated patients dropped from 37% to 9%. The number of AIDS
cases dropped considerably and so did the incidence of opportunistic
diseases (i.e. CMV retinitis, Cryptosporidiosis, cerebral toxoplasmosis).
But in the years that followed problems of multiple toxicity related
to "lifelong therapy" appeared in all their clarity.
The initial enthusiasm was partly put back into perspective (it
was not "strike hard, strike early" anymore) and current
international protocols are far more restrictive in recommending
the start of treatment. This is an admission that the course so
enthusiastically indicated by D. Ho was not sustainable.
Evaluation of data related to the
current progressive reduction in mortality since 1996.
There is doubtless a considerable reduction in the mortality of
individuals suffering from AIDS after 1996, the year "cocktails"
(combinations of three drugs) were introduced, in other words
in the subgroup of seropositive individuals who had already contracted
an opportunistic disease. The explanation is however not easy
to grasp as the information is "unrefined" and comprises
many confusing variables and factors (i.e. it combines both treated
and untreated patients, those who cooperated with the physician's
specifications and those who did not, those who followed other
treatment and those who followed a prophylactic treatment).
Edges are very poorly defined in murky waters and everyone believes
they see the profile they wish to see. In other words the phenomenon's
explanation is hindered by the lack of a crucial comparison between
treated and untreated groups with a correct degree of randomization.
For example in two of the studies that are most frequently mentioned
to support this thesis (clear reduction in the mortality rate
compared to the past), the control group that was not administered
the placebo was either insufficient, inadequate or absent; besides
most individuals involved in the studies were initially asymptomatic
(let us recall that the mean incubation period for untreated AIDS
is 10-14 years, which corresponds to 5% - 3.6% of its yearly incidence).
In the study conducted by Palella (20) the authors found that
the mortality in asymptomatic seropositive individuals (with less
than 100 CD4) treated with antiretroviral drugs was 8.8/100 people
a year. The mortality rate proved to be less after the introduction
of protease inhibitors.
In the second follow up study conducted on 1,219 seropositive
individuals (87% were initially asymptomatic) treated with antiretroviral
drugs, the mortality rate dropped to 6.7% a year with a clear
reduction in the introduction of Protease Inhibitors (PI) after
the year 1996. But the very authors also made an embarrassing
confession: patients who had taken protease inhibitors had a double
risk of dying (though a multivariate analysis showed that their
use did not alter the outcome) (21). Clearly these results were
not as expected!
| Box 2 |
| The United States' definition of AIDS differs from the European one and both were introduced in 1993: the former also includes asymptomatic individuals with CD4 counts that are below 200/µL. This can explain the lesser mortality rate considering that over 60% of AIDS cases reported every year in the US belongs to this subgroup (I). In Europe and in Italy asymptomatic individuals are excluded from our definition of AIDS. In Italy however epidemiological data confirms a clear reduction in the death rate among seropositive individuals who were already infected by AIDS. |
 |
Fig.1
The plot shows how
in Italy the mortality rate of individuals suffering from
the syndrome after 1-2-3-4 years following the initial diagnosis
dropped from 1988 to 2004 (i.e. in 1988 the mortality rate
3 years after the diagnosis was 78% while in 2004 it dropped
to about 16%). |
This greater survival rate was entirely attributed to the use
of drug cocktails; however other factors too are involved as possible
causes of these changes in time:
a) A new selection of patient types compared to the past with
a considerable reduction in the quota of drug addicts who are
struck by a greater mortality rate (in Italy the quota of drug
addicts has dropped from 70 to 20% (22)). This was confirmed by
the EuroSIDA study, which noticed "a significant reduction
in the time of death in patients who were not treated" (23)
(this further proves how the comparison with what occurred in
the past can be misleading in this context).
b) A transitory beneficial effect of one or more components of
the cocktail (this point will be developed in the following chapter)
irrespective of the antiretroviral treatment (24).
c) HAART's protective antibiotic effect towards opportunistic
pathogens (25).
d) Improved specialist prophylactic, diagnostic and therapeutic
skills.
e) The exclusion of the death count resulting from antiretroviral
drugs in seropositive individuals free of AIDS (this plot only
counts individuals with AIDS).
| Box 3 |
| Two are the queries, whose clear answers would be useful: how many are the seropositive individuals who have not been infected by AIDS thanks to drugs and who have lived discretely well? How many instead are those who have long remained asymptomatic without HAART treatment and who instead have suffered from heavy side effects? We lack this crucial information to draft a final balance, hence we can only make some assumptions on the basis of indirect data with the limits this process involves. |
Since many patients have benefited from drugs, we wonder whether
it is possible to isolate the factors that are behind their improvement,
reducing at the same time the highly relevant pointless and harmful
factors.
The treatment's risk-benefit evaluation - HAART-related toxicity
Drugs must only be offered when there is a strong sign of their
advantages especially when the risk is very clear (D. Sackett,
the "father" of Evidence-Based Medicine) (26).
Regarding antiretroviral drugs it is clear that they were able
to solve clinical situations that would have been desperate once.
They have succeeded in stabilizing discrete conditions for a protracted
period of time in the type of patient who was once destined to
fall ill repeatedly. The reduction in opportunistic diseases was
drastic.
But a more objective perspective requires an objective performance
appraisal both in the short term and in the medium and long term
too. Hence we shall study:
A) declared toxicity,
B) HAART's effects on seronegative individuals,
C) the EuroSIDA study,
D) the American study on 4th degree adverse events, and,
E) long term non progressors.
A) Declared toxicity
Adverse events envisaged and listed in the information sheets
are many. They strike patients in a high percentage of cases appearing
either at an early stage or more often at a later stage. They
have a moderate (i.e. nausea) and high intensity with a risk for
life (i.e. lactic acidosis), besides they affect the gastrointestinal
system (i.e. diarrhoea), the haemopoietic system (i.e. anaemia),
the nervous system (i.e. neuritis) and the skin (severe allergies).
They can cause lipodistrophy and progressive liver failure.
B) HAART administered to "non
infected" individuals
Warnings concerning the drugs in question also specify that toxic
symptoms can be confused with those of HIV. To avoid this risk,
nothing is better then to check them on healthy uninfected individuals.
The occasion is provided by work accidents and the related post-exposure
statistics. In the Italian ones for example (27) it is clear that:
"63.2-66.5% of cases complained of side effects; treatment
was discontinued due to them in 28.7-32% cases after 7-8 days
(average)".
They were healthy individuals who had to be treated for a month!
No difference between the various protocols occurred in the proportions
of workers who discontinued treatment.
C) The EuroSIDA Study: "negligible"
HAART-related toxicity.
It would be very strange then to observe that these side effects,
which are so expected and frequent in healthy individuals, should
after all be negligible in seropositive individuals.
And yet this very fact ensured the success of an extensive multicentre
prospective study (EuroSIDA study) (28) involving 5 large groups
of seropositive individuals: a clear reduction in the mortality
rate and incidence of AIDS (up to one fifteenth compared to the
pre-HAART period) (29) was detected from 1995 to 2002. Results
seem to be reassuring also because "problems related to serious
adverse events […] did not alter the population's mortality
and morbidity". The difference between total mortality and
HIV-related mortality was in fact very small. It is curious to
observe that in another section the authors of the same study
say that, considering the 23% reduction in AIDS-related yearly
mortality rate, there is a "32% yearly increase in other
causes of death" (the term "other" mainly designates
HAART-related side effects). However: a) a considerable group
of patients had CD4 over 200 (many > 500) and were initially
asymptomatic, b) even those who had taken drugs for a few days
were considered as "treated" for the study's entire
duration, d) we do not know how many have taken them for the entire
observation period, how many have discontinued them and for how
long they have discontinued their use, e) there is no control
group, hence we cannot understand how a statistical method such
as the Intention to Treat Approach, which clearly envisages the
presence of a control group, has been implemented, f) calculations
do not include the negligible group of those who dropped out during
the followup phase (30).
We believe that it is a very complex analysis, which gives rise
to more questions and doubts than the ones it solves.
D) Grade 4 adverse events.
A clearer contribution towards understanding the various factors
involved is given by a study conducted on over 2.000 seropositive
patients (60% of whom were initially asymptomatic) treated with
HAART (31). Details were published in JAIDS in 2003. The incidence
of serious adverse reactions was double the opportunistic diseases
(675 vs. 332); in the same manner there were more deaths caused
by toxicity-related events than those resulting from opportunistic
diseases (153 vs. 117).
Mortality in case of an adverse event was high (22.7%). It is
important to note that 201 entirely asymptomatic patients with
CD4>200 suffered from serious toxicity and 84 of them died
due to drugs without having ever suffered from opportunistic diseases.
NB: lastly numbers reported in the study and in the tables are
inconsistent.
| Box 4 |
| There are further important considerations to make: a) deaths due to serious toxicity without AIDS cannot be strictly counted among deaths caused by AIDS. Hence the need to keep in mind that in mortality rate plots: a) there are dead who do not appear; b) it is easy for patients who died of toxicity to be counted among deaths caused by AIDS if they had previously suffered from an opportunistic disease (individuals with AIDS who have died due to iatrogenic causes); c) the study clearly revealed that the longer a patient had taken drugs the greater probability he had of suffering from serious toxicity (30.8% after 36 months) with a clear progression in time. |
 |
Fig.2
Probability of AIDS or adverse events in treatises (Reisler RB et al. JAIDS 2003;34:379-86) |
The probability of a serious adverse event resulting from HAART
is about double that of an opportunistic infection with a considerable
increase in time (according to the study the rate of mortality
would be similar in both cases).
Calculating the statistics of mortality caused by AIDS with data
provided by the study in question, the mortality rate is higher
due to treatment than to diseases in a period of 20.7 months (average)
(as per the table below).
 |
E) Long Term Non Progressors
Another observation that is worthy of note is that invariably
all LTNP (long term healthy seropositive individuals - Long term
non progressors) reported in literature in the period prior to
1995 (32) and more recently up to 2004 (33) had not taken antiretroviral
drugs.
Conclusions
Though it is likely an associated positive contribution to new
treatment, caution is a must due to the incident of ATZ treatment,
which was considered valid in the past but proved to be disadvantageous
in time (D. Sackett). At a time when all researchers seem to support
and carefully use "evidence-based medicine", evidence
is lacking in this case and remains unsought. At times the less
presentable aspects are also expertly "toned down",
as we observed in the EuroSida study.
2. SURROGATE MARKERS' VALIDITY
As reported in the previous paragraph, placebo controlled randomised
clinical studies have led to overall negative results and other
trials have not been started since 1992. Besides clinical end
points have been replaced by laboratory goals ("surrogate
markers"), which should have mirrored them faithfully. (Box
5) HIV infections' reference surrogate marker is
the viral load (VL), in other words the number of viral particles
that are found in the blood with the quantitative Polymerase Chain
Reaction method.
The same applies to therapeutic protocols, which also consider
the CD4/mm3 count.
Drugs are still approved by the American FDA (and subsequently
throughout the world) on the basis of their effect on the VL (34).
The "rest" of the evaluation is entrusted to post-marketing
(35)!
| Box 5 |
| The optimal
surrogate marker's features The surrogate marker must have the following features to be practically useful: a) a clear, logical, pathophysiological association with the disease, b) a well defined role in the natural history of the disease, c) it must be detected in most affected individuals, d) it must change with the clinical condition in a measurable manner (both in the disease's progression and regression), e) it must change consistently with the success or inefficacy of the therapeutic treatment. |
Viral Load and
Other Markers
Efficacy studies conducted on new drug combinations hence focus
on extremely clear viral suppression. The advert for a recently
introduced drug (enfuvirtide) launches the following message:
"Detectable is unacceptable" stressing on resetting
the viral load back to zero. In other words, despite its clear
inadequacy, the treatment's first target has been the same for
the past 10 years.
The viral load has often proved to be a poorly relevant index
both concerning the immune system's degree of competence and the
clinical evolution. In studies focused on it the divergence between
CD4 and the viral load, in other words the increase in CD4 despite
the lack of a reduction in the viral load, occurs in a relevant
number of cases (36 ). A group of researchers declared the following
on the topic: "These observations also give rise to doubts
concerning emphasis on HIV RNA levels as a surrogate marker in
clinical trials." (37)
| Box 6 |
| Reported
below are some of the many observations published in literature. In one of the studies mentioned (II), "T lymphocytes CD4(+) and CD8(+) (including the memory and progenitor subpopulations) had increased in a similar manner among patients with plasma viral loads that either persistently dropped or temporarily dropped or did not diminish at all." In another study (III) the expected results occurred only in 34% of cases (low viral load and increased CD4 levels) and in 9% of cases (high viral load and CD4 reduction). Paradoxically the viral load is not linked to the percentage of infected cells, hence according to recent publications the number of infected CD4 lymphocytes is limited to 1:1000, 1:10.000 (IV) and the reduction in the various lymphocyte populations (numbering CD8 lymphocytes) is necessarily attributed to processes other than direct viral cell killing (V). Recent publications confirm that direct cell killing in HIV cannot explain the reduction in lymphocytes and progenitor cells(VI). The progenitor cells that however have a reduced regenerative capacity are not infected. (VII) According to other studies high viraemia and low immunoactivation are associated with a poor cell apoptosis (VIII) and, on the contrary, chronic immunoactivation even when it is associated with viraemia control leads to clinical progression. (IX) |
We can conclude that the VL is not a very reliable
marker and that it is erratic because unforeseen and inconsistent
results greatly surpass 4-6% (a tolerable gap). If clinical and
immunological improvements can occur despite the VL, then it would
be logical that its use should be discontinued in the drug approval
process for "HIVrelated diseases" and that we should
refer to other more significant parameters.
Probably there are no excellent markers, hence it is imperative
to however maintain the reference to clinical endpoints such as
the state of well-being, the quality of life, the incidence of
diseases, side effects and mortality (38).The following seem to
be better markers than the VL:
a) The CD4 count in the blood (39), the increase or reduction
in the state of chronic immunoactivation (40) along with the excessive
production of certain cytokines (41), the Th1-Th2 shift (42),
cell health indicators and the redox status (43).
We must keep in mind that the very CD4 count is not perfectly
related to the immune system's efficiency, for example opportunistic
diseases can also strike individuals with CD4 >200 (cerebral
toxoplasmosis strikes 9% and PCP 14.5% of individuals with over
200 CD4, even with pre-AIDS antiretroviral treatment - Italian
data from 1999 to 31.12.04, AIDS Operational Centre), while some
individuals can remain asymptomatic for long with CD4 < 100.
The chronic immunoactivation condition is characterised in seropositive
individuals who face the risk of a deteriorating condition (44).
Chronic immunoactivation leads to clinical progression even when
it is associated with viraemia control (45). Stress oxidative
markers play a relevant role. Passi observed that oxidative stress
was gradually more evident on various parameters with the increased
evidence of immunodeficiency (46).
3. PROPOSALS FOR ALTERNATIVE TREATMENT
Immunomodulating Drugs
A. Fauci, director of the American NIAID (47), L. Montagnier (48)
and many other researchers have highlighted the usefulness of
controlling chronic immunoactivation and oxidative stress in HIV
infections by proposing targeted treatments: there are drugs that
could control immunoactivation (and indirectly the improvement
of immune conditions, the same HIV infection and clinical conditions).
These number:
a) Antioxidants: the use of antioxidants has been extensively
accepted though we must keep in mind that results have often been
disappointing.
This can be explained by the fact that only one antioxidant was
used or that inappropriate dosages of substances, which can become
prooxidant in the body were administered. Siro Passi's more convincing
theory states that an appropriate diet correction associated with
a pool of natural antioxidants measured to suit the deficiencies
found leads to real benefit concerning the inhibition of the disease's
progression. Small controlled studies have proved the integrated
diet's good efficacy in reestablishing normal levels of antioxidants
(49).
Other interesting and complex theories too lean towards the same
direction: those proposed by Eleni Eleopulos Papadopulos (50)
and Heinrich Kremer (51).
b) The same antiretroviral drugs seem to have the abovementioned
activities (52). Most likely this effect can be obtained with
lower dosages and different drug combinations compared to those
used according to current protocols designed to achieve control
of the VL (53). Anti-HIV drugs have an antiretroviral effect and
they also modulate immunoactivation, which is controlled or reduced
by them (54).
c) Some antinflammatory drugs influence the control of immunoactivation:
low dosage cortisone drugs (55), acetylsalicylic acid (56) and
salazopyrin (57).
Similar better targeted drugs with less side effects could be
found. (Box 7)
We propose better evaluating the clinical end-points and their
association with:
a) immunoactivation parameters;
b) redox conditions and other cell health indicators;
c) the lymphocyte and CD4 count;
d) reactivity to the cell immunity test (Multitest); and,
e) the cytokine dosage.
The use of antiretroviral drugs at minimum effective dosages can
be taken into consideration to control the parameters mentioned,
but not the VL, in a pattern that envisages discontinuing the
treatment when improvements are consolidated. Hence these drugs
need not be taken for life.
| Box 7 |
| Summarising,
treatment could be scheduled as follows: 1) Recognition and correction of unhealthy lifestyles (problems faced mainly by many dissident scientists numbering P Duesberg, E Eleopulos, J Lauritsen, S Passi, L De Marchi and H Kremer); 2) Implementation of a rich and adequate diet (S Passi); 3) Recognition (cell health indicators) and correction of metabolic deficiencies (S. Passi, H. Kremer); 4) Use of antiretroviral drugs only if there is a decided tendency for conditions and immunity to worsen (CD4 < 200 and important signs of immunoactivation and immunodepression, opportunistic diseases) for limited periods; 5) Concerning antiretroviral drugs, we theorize that less costly combinations (one or two drugs) could be investigated at doses that can control crucial metabolic aspects (i.e. the use in monotherapy of protease inhibitors, whose positive effects in vivo have already been reported (dosages that are 30 times less than those specified in the treatment can increase both peripheral blood cell survival (X) and clinical survival (XI); 6) Reintroduction of reliable study criteria of drugs, including randomised double blind clinical trials with placebo ("vanished" for over 12 years), removing the convenient loopholes of the fast track approval. |
Postscript
Both the logic and clinical application of antiretroviral treatment
applied to HIV infections was extensively criticised in the past
by "dissident" researchers (E Eleopulos P Duesberg),
but their argumentative statements were not followed by scientific
confutations. However we report them for detailed study purposes.
(58)
Fabio Franchi
Specialist in Hygiene, Preventive Medicine
and Infectious Diseases in Trieste, Italy.