From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Re: Letter to SF Sentinel
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 5922
Organization: unspecified
Date: Tue, 18 Aug 92 13:23:35 PDT

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Published by Community AIDS Treatment Information Exchange 
Suite 324 -- 517 College Street, Toronto, Ontario  M6G 1A8 
(416) 944-1916 

Permission granted for Noncommercial reproduction on condition 
that direct quotations are cited.  Sean Hosein.  The production 
of this publication is made possible by a grant from the Trillium 
Foundation (Ontario). 

TREATMENT UPDATE #29 - December 1991

I. ANTI-HIV AGENTS 

      A. AZT and ddC 

      Over the long term, the beneficial effects of AZT are known 
to wear off, and patients experience declines in CD4+ cell counts 
and more opportunistic infections.  The reasons for the eventual 
failure of AZT to delay disease progression are uncertain, but 
they may be related to the development of drug-resistant virus, 
to the increasing toxicity of the drug over time, or to other, as 
yet unknown, factors. 

      One potential alternative to the use of AZT alone 
(monotherapy) is a combination which, in the short-term, appears 
beneficial is AZT with ddC; in some laboratory experiments with 
viruses and cells, the combination appears to have greater anti- 
HIV effect then either drug abuse.  Preliminary results of 
studies in the USA were presented in TreatmentUpdate 24 and 
detailed results are now available. 

      Fifty-six subjects were enrolled into a study whose aim was 
to test various dose combinations of AZT and ddC.  All subjects 
had fewer than 201 CD4+ cells, were never supposed to have used 
anti-retroviral agents, had AIDS or advanced ARC (defined as oral 
yeast infections, unintentional weight loss of at least 10% of 
body weight, persistent diarrhea, and fever).  All subjects 
received aerosolized pentamidine for the prevention of PCP.  The 
various combinations used in the trial were meant to be taken 
orally, every 8 hours:  group 1 -- AZT 100 mg and ddC 0.01 mg/kg 
of body weight, group 2 -- AZT 200 mg and ddC 0.005 mg/kg., group 
3 -- AZT 50 mg. and ddC 0.005 mg./kg., group 4 -- AZT 100 mg. and 
ddC 0.01, group 5 -- 200 mg. and ddC 0.01 mg/kg., and group 6 -- 
50 mg. of AZT without ddC.  Doses were reduced as required. 

      At least half the subjects remained in the study for up to 
40 weeks; a total of 18 subjects were removed from the trial for 
various reasons, including the appearance of opportunistic 
infections and/or cancer within the initial 8 weeks of the study 
(9 subjects), self-withdrawal (4 subjects), not taking the study 
drugs as directed (4 subjects), and death (1 subject).  Two 
subjects developed and pain in the lower extremities, likely due 
to ddC toxicity, and were removed from the study.  Another 4 
subjects developed mild peripheral neuropathy, but the study 
investigators decided that this was not caused by ddC.  Ten 
subjects experienced various anemias at some point.  The use of 
ddC did not appear to increase the bone marrow suppressive effect 
of AZT. 

      The average CD4+ count increased in all groups during the 
first 4 weeks.  The increase was not statistically significant in 
the 6 groups.  CD4+ cell decline rates in groups 2 and 5 were 
slower than in group 6.  According to the investigators, several 
of the combinations produced "persistent increases in CD4+ 
lymphocyte counts above pre-treatment values for at least 10 
months in many patients receiving the high-dose regimens. 
Although these results must be interpreted with caution because 
of the small study sample and the possible effects of differences 
in dropout rates among the regimens, the response rates of CD4+ 
lymphocytes seen in our patients differ sufficiently from those 
reported in previous studies to merit comment." 

      The investigators suggest several reasons for the improved 
immune response to the drug combinations.  First, it is possible 
that the use of AZT and ddC together had an additive effect, 
resulting in sustained HIV suppression, greater than would occur 
with AZT alone.  Second, the combination may have delayed the 
appearance of drug resistant virus.  The doctors plan to use 
regimen 5 (AZT 600 mg/day with ddC 0.03 mg/kg/day) for future 
studies Doctors disagree on the best way to deal with AZT- 
resistant strains of HIV; some favour combinations, others think 
that monotherapy with another agent may be best.  Although 
regimen 5 appears promising, whether the increases in CD4+ cell 
counts result in significantly increased survival compared to 
survival with AZT monotherapy remains to be demonstrated in 
controlled clinical trials. 

REFERENCES: 

1.  Meng T-C, Fischl MA, Boota AM et al.  Combination therapy 
with Zidovudine and dideoxycytidine in patients with advanced 
Human Immno- deficiency Virus infection:  a phase I/II study. 
Annals of Internal Medicine 1992:  116(1):  13-20. 

***** 

B. AZT and nutritional complications 

      While the adverse effects of AZT on bone marrow are well 
known, the drug may also alter the balance of nutrients in the 
body -- use of AZT has been associated with reduced levels of the 
element selenium and vitamin B2.  Studying the effect of AZT -- 
or other anti-retrovirals -- on nutrients in the body is 
important because deficiencies of many vitamins and minerals can 
have an unfavorable impact on the immune system. 

      As part of a larger, one-year study of 130 subjects on the 
role of nutrition on disease progression in people with HIV 
infection, researchers at the Universities of Miami and Alabama 
also investigated the effect of AZT on the nutritional status of 
a smaller group of subjects.  All 37 subjects were male and apart 
from persistently swollen lymph glands had no symptoms.  Of the 
37, 15, whose CD4+ count was approximately 350 cells, were given 
AZT in doses of between 500 to 1200 mg/day.  These 15 subjects 
were compared to a control group of 22 subjects with a similar 
CD4+ cell count who were not given AZT. At the start of the study 
(baseline), no significant differences in nutrient levels between 
the groups were noted.  Both groups had similar dietary histories 
at baseline. 

      The researchers found that a large number of subjects on 
AZT had decreased blood levels of zinc despite "adequate" zinc in 
their diets.  The exact cause of this deficiency is uncertain, 
but may be due to several factors.  Changes in metabolism when 
recovering from infections, and increasing loss and replacement 
of cells may increase zinc requirements.  Interestingly, the 
enzymes used to convert AZT into its active or anti-viral form 
require zinc.  Thus, use of AZT may place additional demand on 
the available zinc in the body.  Among the AZT-treated subjects 
who had "adequate" blood levels of zinc, immune functions 
necessary to respond to invading organisms seemed better than 
those in subjects using AZT who did not have "adequate" blood 
levels of zinc.  Although there were also decreases in the blood 
levels of copper, these did not appear to hamper immune 
functions.  The interplay between copper and zinc in the body is 
complex and is discussed in further detail later in this issue of 
TreatmentUpdate.  So far, there have not been large, randomized 
trials conducted to investigate the effect of zinc 
supplementation on disease progression in AZT users. 

REFERENCES: 

1.  Baum MK, Javier JJ, Mantero-Atienzs et al.  Zidovudine 
associated adverse reactions in a longitudinal study of 
asymptomatic HIV-1 infected homosexual males .  Journal of 
Acquired Immune Deficiency Syndromes 1991;4(12):  1218-1226. 

Newsgroups: sci.med.aids