"AIDS Treatment News" online * New Issue #302 (searchable/indexed)

George M. Carter gmc0 at ix.netcom.com
Sun Oct 11 10:14:35 EST 1998


johnburgin at worldnet.att.net wrote:

>>In any event, speaking of dementia, it was your idiotic statement that
>>people now were taking LESS than the former commonly prescribed dose.

>I gave you a study, I can give you others, ergo, it wasn't idiotic.

No.  It was just dead cold wrong.  AZT was approved in 1987.  By the
early 90's, it became apparent that the lower dose (600 mg/d or
thereabouts) worked as well with less side effects.

*****
Zidovudine treatment of AIDS and ARC in Denmark 1987. Scand J Infect
Dis 1989;21(4):367-73 
Teglbjaerg LL, Mathiesen LR, Soeberg B, Nielsen L, Thorsen B, Buhl M,
Pedersen C, Bonnevie O, Nielsen C, Vestergaard BF, et al
Department of Infectious Diseases, Hvidovre Hospital, Copenhagen,
Denmark. 

In 1987, a total of 138 Danish patients (94 AIDS and 44 ARC) received
treatment with zidovudine, a total observation period of 572 treatment
months. 15 AIDS and 1 ARC patient died after a median of 70 days
(range 2-295). In the ARC group 4 patients developed AIDS (3
Pneumocystis carinii pneumonia, 1 Kaposi's sarcoma). Among the AIDS
patients 38 new opportunistic infections were reported. 24 of these
opportunistic infections occurred within 6 weeks after treatment
initiation. 79 patients were observed for more than 3 months, 25 of
these had their daily dose zidovudine reduced, usually from 1,200 mg
to 600 mg, 9 others were temporarily off drug. HIV antigen was
analyzed in serum samples from 93 patients. Of these, 28 (52%) of 54
initially HIV antigen-positive became antigen-negative, 7 (18%) of 39
initially HIV antigen-negative became antigen-positive within the
first 8 weeks of zidovudine treatment. In 57 patients the total count
of CD4+ cells were evaluated. A significant increase in the number of
CD4+ cells was observed during treatment. In nearly all patients an
increase in MCV and a decrease in neutrophil count was observed. 44 of
the patients received a total of 307 blood transfusions on 94
occasions and 19 (14%) patients required multiple transfusions. The
mortality among the AIDS patients was significantly lower compared to
historical controls. In our experience zidovudine treatment is
reasonably well tolerated and the side effects are manageable. 
******

Ann Intern Med 1988 Feb;108(2):175-80 
Human immunodeficiency virus (HIV) antigenemia (p24) in the acquired
immunodeficiency syndrome (AIDS) and the effect of treatment with
zidovudine (AZT).
Jackson GG, Paul DA, Falk LA, Rubenis M, Despotes JC, Mack D, Knigge
M, Emeson EE
Department of Medicine, University of Illinois College of Medicine,
Chicago. 

Infection with human immunodeficiency virus (HIV) may cause viral
antigenemia, detected primarily as p24 viral core protein. Among 16
patients with the acquired immunodeficiency syndrome (AIDS) or
AIDS-related complex studied serially, 12 had or developed antigenemia
ranging from 16 to 3006 pg/mL in plasma. The level could be
categorized as high (greater than 100 pg/mL) or low (15 to 65 pg/mL).
Three patients with anti-p24 antibody had no antigenemia. Zidovudine
(AZT), 200 or 250 mg every 4 hours, reduced antigenemia by about 90%;
other regimens were less effective. Leukocyte cultures were positive
for HIV from patients with antigenemia, and in one third of samples in
the absence of antigenemia. High levels of antigenemia correlated with
symptoms, CD4 cell count, and prognosis. Drug toxicity requiring a
lower dose was followed by increased antigenemia, recurrent symptoms,
and decreased CD4 cells, suggesting lymphocyte toxicity. Monitoring
antigenemia can be useful in evaluating patients with HIV infection
and in evaluating the effect of antiviral chemotherapy. 

*******
Intern Med 1992 Jul;31(7):871-6 
A randomized trial of reduced doses of azidothymidine in Japanese
patients with human immunodeficiency virus type 1 infection.
Kimura S, Oka S, Toyoshima T, Hirabayashi Y, Kikuchi Y, Mitamura K,
Shimada K
Department of Infectious Diseases and Applied Immunology, University
of Tokyo, Japan. 

Adverse reactions to the standard dose (1,200 mg/day-1,500 mg/day) of
azidothymidine (AZT) are serious. An in vitro pharmacokinetic study
of intracellular AZT-5'-triphosphate suggested the feasibility of a
clinical trial with reduced doses of AZT. A randomized trial with
reduced doses of AZT (group A; 400 mg/day, n = 15, group B; 800
mg/day, n = 13), was conducted enrolling 28 patients with human
immunodeficiency virus infection. The effective rate of AZT on CD4+
lymphocyte counts was similar for both groups, but the duration of the
effect of AZT was significantly longer in group A (p less than 0.05).
In group B, adverse reactions were more frequently observed (p less
than 0.01), and AZT was withdrawn or the dose was reduced more
frequently (p less than 0.05). These results suggest that AZT at a
dose of 400 mg/day is less toxic, and is more beneficial for long-term
treatment. 

>You simply proved my point, that is, that higher amounts were given in
>the past.  Do you want to keep going with this or put it to rest?

I'll keep going.  

You stated that people were taking 1200 mg or some high dose until the
protease inhibitors came along, then the dose dropped.  To support the
notion that people SUDDENLY started taking a lot less.  This is just
dead cold wrong.  

		George M. Carter

See also:  Ann Intern Med 1992 Jun 15;116(12 Pt 1):961-6 
Quality-of-life evaluation in a clinical trial of zidovudine therapy
in patients with mildly symptomatic HIV infection. The AIDS Clinical
Trials Group.  Gelber RD, Lenderking WR, Cotton DJ, Cole BF, Fischl
MA, Goldhirsch A, Testa MA

Also:
Ann Intern Med 1992 Sep 15;117(6):487-501 
Zidovudine: five years later.
McLeod GX, Hammer SM
New England Deaconess Hospital, Boston, Massachusetts. 

Zidovudine, a nucleoside analog, was the first agent proved to be
effective in the management of human immunodeficiency virus type 1
(HIV-1) infection. After demonstration of zidovudine's in-vitro
activity against HIV-1 in 1985, the drug was rapidly evaluated in
phase I and phase II clinical trials and was found to be effective in
decreasing both mortality and the incidence of opportunistic
infections in patients with the acquired immunodeficiency syndrome
(AIDS) and advanced AIDS-related complex; the drug was also found to
have a substantial but tolerable toxicity profile. Since the licensure
of zidovudine in 1987, an intensive clinical research effort has
established the drug's efficacy in the prevention of disease
progression in asymptomatic and mildly symptomatic HIV-infected
persons and has established the success of lower-dose therapy in
patients at all stages of disease. The current recommendation is to
use zidovudine at a dose of 500 to 600 mg/d in both symptomatic and
asymptomatic persons with CD4 counts of less than 500/mm3. The major
toxicities of anemia and neutropenia are less frequent at the lower
doses presently used and can be managed by dose reduction or by use of
hematopoietic growth factors. The inexorable disease progression seen
despite zidovudine therapy and the isolation of clinical strains of
HIV-1 resistant to zidovudine in vitro highlight the limitations of
prolonged monotherapy with this agent. Although alternative
dideoxynucleoside agents (for example, didanosine [dideoxyinosine and
zalcitabine dideoxycytidine]) are available for the management of
HIV-infected persons, zidovudine remains the cornerstone of
antiretroviral therapy. Current research efforts are directed at
elucidating the clinical relevance of zidovudine resistance and
studying regimens in which zidovudine is used in combination with
other agents. This latter approach holds great promise for improving
efficacy, limiting toxicity, and perhaps preventing the emergence of
viral resistance. For the forseeable future, zidovudine will continue
to play a role in the development and in our understanding of
antiretroviral therapy. 






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