THE FAUCI FILES, Vol 3( 24): HIV Cocktail Failure NOT Based on Viral "Resistance"

fred fredshaw at primenet.com
Wed Jan 26 15:15:57 EST 2000


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.   

;) end ---
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