THE FAUCI FILES, Vol 3( 24): HIV Cocktail Failure NOT Based on
Viral "Resistance"
January 24, 2000
Since 1996, I have offered the scientific findings from the
peer-reviewed biomedical literature that clearly illustrated the
absurdity of the HAART cocktail treatment theory that was based
on a bizarre patient-blaming notion of treatment failure. Martin
Delaney, Pharmaceutical PsychoFascist Director of Project Inform
(San Francisco) encapsulated the blame-patient-for-failure model
of cocktail mistreatment so beautifully:
"You have one chance to get it right or else..."
It worked like this: being gullible in believing that less viral
particles in the blood meant better disease outcome, the stern
doctor prescribes the cocktail of "antiretroviral" drugs, telling
patient not to miss a single dose at the exact time prescribed.
Patient dutifully gulps down the chemo-swill exactly as doctor
ordered. Months of this sadomasochistic medical ritual elapse
during which the patient reports "doing well" while the lab tests
show higher CD4s and "undetectable viral loads" (patient claims to
"do well" on the false assumption that only dead patients don't
use "antiretrovirals").
This S&M charade goes on for months, until one day the doctor has
bad news: the viral load has rebounded, indicating the disease is
accelerating (another ridiculous superstition). In the doctor's
pea-sized "mind" the patient is not being compliant, after all,
how could the virus "mutate" around these wonderful, life-saving
"antiretrovirals" that kept that virus under control until now?
The doctor sees the patient's compliance as the only open
variable, thus blame is assigned to the patient and the doctor
will focus his limited and valuable time on working with those
patients who choose to live, rather than those "treatment hobos"
who don't care about their health.
Here's a small sample of the bad news for the pharmaceutical
PsychoFascists:
"Multiple investigators have reported ongoing viral
replication during therapy without demonstrable resistance."
Oops! Looks like everybody has blown their "One chance to get
it right or else..." WITHOUT any drug viral "resistance"!
So naturally, in Y2K, our PsychoFascist Cocktail Evangelists --
who aren't about to accept the terrorism of science lying down
-- are busy crafting their next hoax in "drugs into bodies" therapy:
The Cocktail "Holiday" !!!
So you see, in 1996 it was: Don't miss a dose or die.
in 2000 it becomes Don't miss a drug holiday or die.
All of these horrors, of course, have been -- and continue to be -
- promulgated and orchestrated under the tutelage of NIH/NIAID
Dictator-Direktor, Dr. Anthony "Mussolini" Fauci, who remains
prominent among these...
Crooked Murdering Bastards!
W. Fred Shaw
Note: the following reported findings are by Aaron Diamond
Research Center's Dr. Martin Markowitz, but first, let's take
a quick look at Dr. Markowitz' financial disclosure (conflicts of
interest) to see exactly what might be wrong with AIDS research
today:
Financial Disclosure: Dr Markowitz has received grants,
funding, and honoraria from EIGHT drug companies:
Abbott
Agouron
Bristol-Myers Squibb
Glaxo Wellcome
Hoffmann-La Roche
Merck
Pharmacia-Upjohn
Triangle Pharmaceuticals
Dr. Markowitz has served as a consultant for:
Agouron
Glaxo Wellcome
Pharmacia-Upjohn
Triangle Pharmaceuticals.
Care to guess what the Big Problem might be with the search for
the cure for AIDS?
------------
Most interestingly, this information comes from Dr. Martin
Markowitz of Aaron Diamond Research Center (ADRC) and Rockefeller
University, who has been "involved" with the pharmaceutical
companies producing HIV antiviral therapies. Markowitz is
eminently qualified to evaluate the two articles in the 1/12/00
JAMA concerning virological failure of HAART.
In his excellent 1/12/00 JAMA Editorial, Dr. Markowitz states: "These
studies indicate that virologic failure is indeed multifactorial and not
solely the result of multidrug resistance."
"Multiple investigators have reported ongoing viral replication
during therapy without demonstrable resistance."
"Potential mechanisms of cellular resistance recently have been
identified and include interactions between inducible cellular
gene products such as p-glycoprotein (MDR-1) and multiple
drug-resistance proteins with substrates known to include
protease inhibitors and nucleoside reverse transcriptase
inhibitors, respectively."
"Taken together, these studies demonstrate that virologic
failure is complex and not exclusively mediated by viral
resistance."
"Nonadherence is clearly a critical factor but cannot be
assumed to be the origin of treatment failure in the
presence of rebound with wild-type virus."
------------------------------------------------------------------
Lack of adherence (non-adherence) with various drug regimens is
considered an explanation for treatment failure (JAMA 2000 Jan
12;283:205-211).
In the ACTG 175 clinical trial, Hammer et al. (1996) reported
treatment success:
"Treatment with zidovudine plus didanosine, zidovudine plus
zalcitabine, or didanosine alone slows the progression of HIV
disease and is superior to treatment with zidovudine alone.
Antiretroviral therapy can improve survival in patients with
200 to 500 CD4 cells per cubic millimeter"
(AIDS Clinical Trials Group Study 175 Study Team.
N Engl J Med 1996 Oct 10;335:1081-90).
Yet, in a strange twist of fate, study participants in ACTG 175 were not
adherent to their antiretroviral medications.
Kastrissios et al. (1998) state:
"Among the four treatment arms, adherence to all three active study
medications deviated substantially from ideal, with a trend towards
lower adherence in the combination therapy arms compared with those
assigned to receive monotherapy," and
"Drug-taking behavior for all three active study medications
differed from that prescribed. One result of this erratic adherence
was that study participants sustained little antiretroviral effect
during more than 25% of the monitoring period"
(AIDS 1998 Dec 3;12:2295-2303).
Kastrissios et al. (1998) state:
"Of 722 plasma samples analyzed, approximately 75% contained
detectable concentrations of the assigned drugs and 5-14.5%
contained no detectable drugs. Approximately 7 and 13% of sample
from participants assigned to monotherapy arms contained non-
prescribed dideoxynucleosides, and 14 and 19% assigned to
combination therapies contained only one drug"
(AIDS 1998 Dec 3;12:2305-2311).
================================
JAMA, January 12, 2000, Volume 283, Pages 250-251.
Resistance, Fitness, Adherence, and Potency
Mapping the Paths to Virologic Failure
Martin Markowitz, MD
Aaron Diamond AIDS Research Center, Rockefeller University, 455
First Ave, 7th Floor, New York, NY 10016 (e-mail:
mmarkowitz at adarc.org). Financial Disclosure: Dr Markowitz has
received grants, funding, and honoraria from Abbott, Agouron,
Bristol-Myers Squibb, Glaxo Wellcome, Hoffmann-La Roche, Merck,
Pharmacia-Upjohn, and Triangle Pharmaceuticals, and has served as
a consultant for Agouron, Glaxo Wellcome, Pharmacia-Upjohn, and
Triangle Pharmaceuticals.
http://jama.ama-assn.org/issues/v283n2/full/jed90103.html
A near-uniformly fatal clinical syndrome, acquired
immunodeficiency syndrome (AIDS), has been transformed during the
past 5 years into a treatable infectious disease. The availability
of potent antiretroviral agents coincided with the ability to
measure levels of circulating virus in vivo. When used in tandem,
an understanding of human immunodeficiency virus (HIV) replication
dynamics in vivo was made possible, forming the scientific basis
for the use of combination antiretroviral therapy. (1) However, the
treatment of HIV infection remains far from perfect, and new
issues arise with regularity. Critical to achieving optimal
therapeutic outcomes is an understanding of treatment failure.
Early clinical trials of protease inhibitor monotherapy suggested
that the pathway to treatment failure was exclusively via drug
resistance. (2, 3) Viral rebound was thought to reflect failure of
all components of a regimen. Furthermore, it was assumed that the
absence of resistance-conferring genotypic changes reflected
patient nonadherence. In this issue of THE JOURNAL, articles by
Descamps and colleagues (4) and Havlir and colleagues (5) question these
assumptions in the context of 2 large clinical trials, Trilege (6)
and AIDS Clinical Trials Group 343. (7) The inferior outcomes
observed in patients randomly assigned to receive less intensive
maintenance therapy have been recently published. (6, 7) In the
articles in this issue, the authors seek to understand the
findings. In the Trilege Study, a 3-month induction phase with
zidovudine, lamivudine, and indinavir was followed by
randomization to either zidovudine and lamivudine, zidovudine and
indinavir, or continued triple-drug therapy if the level of HIV
RNA in plasma was less than 500 copies/mL. The primary end point
was virologic failure, defined by 2 consecutive plasma
measurements above 500 copies/mL on 2 consecutive visits, 6 weeks
apart. Fifty-eight (20.8%) of the 279 randomly assigned patients
met this end point, 29 receiving zidovudine and lamivudine, 21
receiving zidovudine and indinavir, and 8 receiving triple
therapy. Fifty-eight study patients with durable virologic
suppression were carefully selected by investigators as case-
controls. The results of genotypic studies revealed the presence
of the lamivudine resistance-conferring M184V substitution in
reverse transcriptase in nearly all patients treated with
lamivudine. However, primary-resistance mutations associated with
reduced susceptibility to indinavir did not emerge during
combination therapy with zidovudine and indinavir or triple
therapy. Similarly, zidovudine-associated resistance-conferring
mutations were rare and when present were confined to changes at
codons 41 and 70 of reverse transcriptase.
Adherence as measured by pill counts revealed a statistically
significant difference in median adherence rates between cases and
controls for patients prescribed either zidovudine or indinavir
during maintenance therapy. Furthermore, patients randomly
assigned to receive zidovudine with indinavir only demonstrated
statistically significant differences in adherence rates compared
with controls. Plasma indinavir levels were found to be lower than
expected in 2 groups, those failing triple therapy and those
failing zidovudine and indinavir maintenance in association with a
greater loss in antiviral efficacy. Indinavir levels tended to be
in the expected range in those patients in the zidovudine and
indinavir group in whom virologic failure was associated with a
modest loss of antiviral activity. Of note, plasma indinavir
levels were clearly higher in controls compared with cases in both
the triple therapy and zidovudine and indinavir groups. In the
AIDS Clinical Trials Group 343 study, after a 6-month induction
with the same triple combination regimen as used in Trilege,
patients with plasma HIV RNA levels below 200 copies/mL were
randomly assigned to receive zidovudine and lamivudine, indinavir
monotherapy, or continued triple therapy. Patients were followed
up monthly and the study end point, virologic failure, was defined
as a subsequent plasma HIV RNA level of 200 copies/mL or greater.
Plasma indinavir levels and resistance testing by both genotypic
assay and a novel recombinant phenotypic assay were performed
retrospectively in 9 of 23 patients in the indinavir monotherapy
group who reached the study end point, as well as in 17 of 75
patients who experienced virologic failure during the induction
phase, and 10 controls with sustained suppression throughout the
course of study. In those failing indinavir monotherapy, plasma
HIV RNA levels of 103 to 105 copies/mL were found at the time of
viral rebound. In all 9 patients, resistance testing showed no
reduced susceptibility to indinavir or resistance-conferring
genotypic changes. Among patients receiving triple therapy, the
M184V codon substitution in reverse transcriptase was observed in
14 of 17 patients. In 1 patient, a primary-resistance mutation in
the HIV protease (M41L) was associated with rebound. Otherwise,
resistance testing using both assays was consistent with retained
indinavir susceptibility.
Plasma indinavir levels were available for 2 patients who received
indinavir monotherapy, and 7 who received triple therapy during
both suppression and virologic rebound whereas the remainder had
drug levels available only during the period of suppression. No
differences in weighted mean indinavir concentrations were
observed among the 3 groups. However, the proportion of patients
with at least 1 extremely low indinavir level was significantly
higher in the group failing triple therapy.
These studies indicate that virologic failure is indeed
multifactorial and not solely the result of multidrug resistance.
Undoubtedly, adherence to a treatment regimen is essential. The
time and degree of failure observed in the Trilege study were
associated with the degree of adherence. Less toxic, simpler, and
more patient-friendly regimens are urgently needed, but as these
studies point out, not at the expense of the regimen potency.
Reductions in the potency of antiretroviral regimens during the
maintenance phase allowed for the higher incidence of virologic
rebound. In patients receiving zidovudine and indinavir and
indinavir monotherapy, rebound occurred in the absence of readily
demonstrable virus-mediated resistance to the antiviral agents
being used. One explanation is that the rebounding virus
population is a mixture of indinavir-susceptible and indinavir-
resistant quasi species and the more fit population, wild-type,
predominates. However, an additional consideration is drug
potency.
Bonhoeffer and colleagues (8) and Perno and colleagues (9) have
suggested that drugs may exhibit differential efficacy in
different cellular populations. Reduction of potency of 1 of the
maintenance regimens may have allowed ongoing wild-type virus
replication in populations of infected cells in which indinavir,
or perhaps indinavir and zidovudine, do not exert a strong
selective pressure for the emergence of resistant virus. Multiple
investigators have reported ongoing viral replication during
therapy without demonstrable resistance. (10-12) Potential mechanisms
of cellular resistance recently have been identified and include
interactions between inducible cellular gene products such as p-
glycoprotein (MDR-1)13 and multiple drug-resistance proteins (14)
with substrates known to include protease inhibitors and
nucleoside reverse transcriptase inhibitors, respectively.
Taken together, these studies demonstrate that virologic failure
is complex and not exclusively mediated by viral resistance.
Furthermore, these studies point out the relevance of resistance
testing in the setting of virologic rebound. Nonadherence is
clearly a critical factor but cannot be assumed to be the origin
of treatment failure in the presence of rebound with wild-type
virus. Understanding issues surrounding drug potency and cellular
resistance seem critical at this juncture. Perhaps with better
understanding of these issues, the elusive universal response to
HIV therapy may be achieved.
REFERENCES
1. Perelson AS, Essunger P, Ho DD. Dynamics of HIV-1 and CD4+
lymphocytes in vivo. AIDS. 1997;suppl A:17-24.
2. Condra JH, Schleif WA, Blahy OM, et al. In vivo emergence of
HIV-1 variants resistant to multiple protease inhibitors. Nature.
1995;374:569-571.
3. Molla A, Korneyeva M, Gao Q, et al. Ordered accumulation of
mutations in HIV protease confers resistance to ritonavir. Nat
Med. 1996;2:760-766.
4. Descamps D, Flandre P, Calvez V, et al. Mechanisms of virologic
failure in previously untreated HIV-infected patients from a trial
of induction-maintenance therapy. JAMA. 2000;283:205-211.
5. Havlir DV, Hellmann NS, Petropoulos CJ, et al. Drug
susceptibility in HIV infection after viral rebound in patients
receiving indinavir-containing regimens. JAMA. 2000;283:229-234.
6. Pialoux G, Raffi F, Brun-Vezinet F, et al. A randomized trial
of three maintenance regimens given after three months of
induction therapy with zidovudine, lamivudine, and indinavir in
previously untreated HIV-1-infected patients. N Engl J Med.
1998;339:1269-1276.
7. Havlir DV, Marschner IC, Hirsch MS, et al. Maintenance
antiretroviral therapies in HIV-infected subjects with
undetectable plasma HIV RNA after triple-drug therapy. N Engl J
Med. 1998;339:1261-1268.
8. Bonhoeffer S, Coffin JM, Nowak MA. Human immunodeficiency virus
drug therapy and virus load. J Virol. 1997;71:3275-3278.
9. Perno CF, Newcomb FM, Davis DA, et al. Relative potency of
protease inhibitors in monocytes/macrophages acutely and
chronically infected with human immunodeficiency virus. J Infect
Dis. 1998;178:413-422.
10. Lewin SR, Vesanen M, Kostrikis L, et al. Use of real-time PCR
and molecular beacons to detect virus replication in human
immunodeficiency virus type 1-infected individuals on prolonged
effective antiretroviral therapy. J Virol. 1999;73:6099-6103.
11. Zhang L, Ramratnam B, Tenner-Racz K, et al. Quantifying
residual HIV-1 replication in patients receiving combination
antiretroviral therapy. N Engl J Med. 1999;340:1605-1613.
12. Furtado MR, Callaway DS, Phair JP, et al. Persistence of HIV-1
transcription in peripheral-blood mononuclear cells in patients
receiving potent antiretroviral therapy. N Engl J Med.
1999;340:1614-1622.
13. Lee CG, Gottesman MM, Cardarelli CO, et al. HIV-1 protease
inhibitors are substrates for the MDR1 multidrug transporter.
Biochemistry. 1998;37:3594-3601.
14. Schuetz JD, Connelly MC, Sun D, et al. MRP4: a previously
unidentified factor in resistance to nucleoside-based antiviral
drugs. Nat Med. 1999;5:1048-1051.
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