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: 5923
Organization: unspecified
Date: Tue, 18 Aug 92 13:26:24 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 #30  - February 1992

I. ANTI-HIV AGENTS 

A. AZT:  2-year study on early versus later use 

      Doctors in the USA have released detailed results from a 
placebo- controlled study of early versus later use of AZT.  The 
trial (VA 298) enrolled subjects with CD4+ counts between 200 to 
500 cells.  All subjects had symptoms of HIV infection including 
"thrush, oral hairy leukoplakia, shingles, unintentional weight 
loss, persistent diarrhea, fever, night sweats, fatigue or 
lymphadenopathy."  Subjects who had had an opportunistic 
infection and/or cancer, along with certain abnormal bone 
marrow/blood values, were excluded. 

      Subjects were randomly assigned to AZT (1500 mg/day) for 
the length of the trial ("early therapy") or to placebo until 
their CD4+ count fell to 199 cells or fewer or until they 
suffered an opportunistic infection ("late therapy").  In total, 
170 subjects were assigned to early AZT and 168 to placebo then 
AZT. 

      Forty-three subjects died during the study, 23 in the early 
AZT group and 20 in the late AZT group.  This difference was not 
statistically significant.  In the early AZT group, 28 subjects 
progressed to AIDS, while 48 subjects progressed to AIDS in the 
late AZT group (statistically significant).  Of the 28 patients 
in the early-therapy group who progressed to AIDS, 13 (46%) 
subsequently died, as compared with 20 (42%) of the 48 patients 
in the late AZT group who progressed to AIDS.  Analysis by 
several variables could not account for this difference in 
survival, which was not statistically significant anyway. 

      Early use of AZT, compared with later use, clearly delayed 
the decline in CD4+ counts.  Side effects of AZT were apparent -- 
including anemia, nausea, and diarrhea.  These results were 
statistically significant when compared to those from subjects on 
placebo.  Compared to subjects in the early AZT group, more 
subjects in the late AZT group developed skin rashes.  Compared 
to those receiving late AZT, more subjects receiving early AZT 
required transfusions and dose reductions. 

      Subjects assigned to early use of AZT were monitored for an 
average of 27 months, and those assigned to the late AZT group 
for an average of 28 months.  According to the study doctors, 
"After more than 2 years of follow up we found no difference in 
survival between the two treatment groups."  The doctors also 
report, "Early [AZT] therapy slowed the progression to AIDS but 
did not improve overall survival in our trial."  Approximately 
half the subjects in the study survived an average of 18 months 
before an opportunistic infection/cancer occurred.  This survival 
figure is similar to one seen in another large study of AZT 
users.  Although thc dose of AZT used in this study is higher 
than currently recommended by the FDA, "most published randomized 
studies have had one arm with a dosage similar [to this one]". 
Those other studies produced results which suggest that high 
doses are as effective as low doses but that low doses are less 
toxic.  The doctors involved with VA 298 say, "If this is true, 
our results should be applicable to low-dose therapy if they are 
not confounded by excess toxicity."  As the toxicity due to AZT 
was less than reported in another placebo-controlled trial, and 
dose reductions resulted in only a small number of subjects' 
leaving this study, the investigators involved with VA 298 say, 
"It therefore seems unlikely that adverse effects related to 
dosage could compromise the conclusions of our study." 

      In a previous 1-year, randomized, placebo-controlled study 
(known as ACTG 019) in subjects with fewer than 500 CD4+ cells, 
who were symptom-free, AZT was found to delay progression to AIDS 
in approximately 4% of subjects; 92% did not benefit from the 
drug, and another 4% worsened despite receiving AZT. 

      Preliminary results from a trial in the European Community 
and Australia suggest that AZT, in doses of 1000 mg/day, appears 
to delay progression to AIDS in subjects who are symptom-free and 
who have between 400 to 500 CD4+ cells.  That AZT can delay the 
appearance of symptoms in some subjects is not surprising, as 
this has been confirmed by several studies, including VA 298. 
Unfortunately trial ACTG 019, as well as the Burroughs Wellcome 
study H56-020, do not provide data on long-term survival.  The 
reasons for the eventual failure of AZT are uncertain, but may be 
related to the development of resistant virus, to the increasing 
toxicity of the drug over time, or to other, as yet unknown 
factors.  According to the authors of VA 298, "Because of the 
uncertainty about long-term effects of [AZT] and because no 
survival benefit has been observed, we also believe that one may 
consider delaying the initiation of [AZT] therapy in patients 
whose condition is stable and whose CD4+ counts are between [200 
and 500 cells]." 

REFERENCES 

1.  Hamilton JD, Hartigan PM, Simberkoff MS et al.  A controlled 
trial of early versus late treatment with Zidovudine in 
symptomatic human immunodeficiency virus infection:  Results of 
the Veterans Affairs Cooperative study.  New England Journal of 
Medicine 1992;326(7):  437-443. 

2.  Volberding PA, Lagakos SW, Kochma et al.  Zidovudine in 
asymptomatic Human Immunodeficiency Virus infection:  a 
controlled trial in persons with fewer than 500 CD4 positive 
cells per cubic millimetre.  New England Journal of Medicine 
1990;322:  1000-1002. 

3.  Peto TEA.  A critical analysis of recent data on Zidovudine 
therapy: use in asymptomatic HIV infection and early HIV disease, 
dosing and resistance issues.  AIDS 1990;4(supplement 1):  s187- 
s191. 

4.  Heagy W, Crumpacker C, Lopez PA et al.  Inhibition of Immune 
functions by antiviral drugs.  Journal of Clinical Investigation 
1991;87: 1916-1924. 

5.  Statement from the International Coordinating Committee. 
Wellcome study H56-020:  Zidovudine in "low-risk", HIV-positive 
asymptomatic individuals (CD4+ greater than 400/mm3).  31 
January, 1992. 

6.  Press release.  New data support earlier use of Retrovir. 
Burroughs Wellcome.  3 February, 1992. 

***** 

B. AZT failure:  resistance theory questioned 

      AZT (Azidothymidine, Retrovir, Zidovudine) has been shown 
to delay the appearance of opportunistic infections in HIV- 
infected subjects with between 200 to 500 CD4+ cells.  Compared 
to placebo, AZT reduces disease progression "by nearly 50%".  Yet 
this apparent benefit has no effect on survival.  The reasons for 
AZT's loss of efficacy are uncertain and may be due to complex 
interplay among several factors. 

      One factor which could play a role is the development of 
strains of HIV which are resistant to AZT.  This has certainly 
happened in other diseases, and is a likely possibility with 
anti-HIV agents.  It has not been conclusively proven, however, 
that AZT resistance is the cause of worsening symptoms in treated 
patients.  According to a recent editorial in the New England 
Journal of Medicine, "There is at present little information on 
the association between antiviral resistance and the clinical 
course of HIV infection." 

      In England, scientists with the Wellcome Foundation, who 
have been studying the development of drug-resistant virus have 
examined the long-term effect of AZT on HIV replication, and 
their recent discoveries raise questions about why AZT eventually 
loses its ability to delay both the decline in CD4+counts as well 
as disease progression itself.  In England, researchers 
considered experts in the field of viral resistance -- Brendan 
Larder, Graham Darby --  along with others in Amsterdam, have 
developed sophisticated techniques to identify viral genes 
responsible for bringing about resistance to AZT.  The drug works 
by inhibiting the formation of the enzyme RT (reverse 
transcriptase) without which new viruses cannot be produced. 
Over time, HIV, in users of AZT, has been found to develop ways 
of by-passing the inhibitory effects of AZT; these mutant viruses 
are either partially or wholly resistant to AZT. 

      The group of eighteen subjects studied for the joint 
Anglo/Dutch study on resistance were initially symptom-free or 
had persistently swollen lymph glands; their CD4~ counts did not 
exceed 500 cells.  After the first month of the study, most 
subjects were given 500 mg of AZT every 12 hours and then were 
followed for just over 2 years.  During this time, 6 of them 
developed AIDS.  The researchers found that partial resistance 
developed as early as 12 weeks into the study but that this 
eventually disappeared.  Resistance was not necessarily 
associated with disease progression.  For instance, among 
subjects who progressed to AIDS, the virus isolated was just as 
sensitive to AZT as virus from other subjects who remained 
symptom-free.  Although it is possible that these viruses may 
have been partially resistant to AZT, the research team says that 
"progression to AIDS from the asymptomatic stage of HIV disease 
to AIDS can occur in AZT treated individuals without the 
emergence of highly resistant isolates."  That this statement 
could be made by experts in viral resistance is significant in 
that it suggests that the reason(s) for disease progression in 
AZT-treated patients may be something other than drug-resistant 
virus.  The researchers do say that "it seems likely that 
additional factors [other than drug resistant virus] are involved 
[in disease progression in AZT treated subjects]." 

      This raises questions that lie at the heart of discussions 
about directions for therapy for HIV/AIDS.  What could be the 
reasons for disease progression?  One potential answer is 
"cellular resistance" to AZT, which has been identified so far by 
two research groups in the USA. Cellular resistance occurs when 
enzyme systems inside cells become worn down and can no longer 
process AZT into its activated (or antiviral state) at high 
levels.  This seems to occur after 3 months of continuous AZT 
use, when the level of activated AZT begins to decline.  Cellular 
resistance may also account for the eventual failure of 
ganciclovir therapy (DHPG) against CMV infection. 

      A second possible reason for AZT failure without the 
development of viral resistance is that the drug affects 
cofactors which may accelerate the decline of the immune system. 
According to doctors in France, there is some evidence that AZT 
protects patients from certain bacterial infections and perhaps 
other potential co-factors as well.  It may be that over time the 
antibacterial effect of the drug is lost. 

      Finally, although the immune-suppressive properties of AZT 
(reviewed in TreatmentUpdate 23 and 26) may provide benefit in 
the short term, it is possible that over time the toxic effects 
of the drug outweigh its beneficial effects, as has been 
suggested by American scientists at the National Institutes of 
Health.  Potential strategies to deal with AZT failure are 
discussed in TreatmentUpdate 20. 

REFERENCES 

1.  Boucher CAB, O'Sullivan E, Mulder JW et al.  Ordered 
appearance of Zidovudine resistant mutations during treatment of 
18 Human Immunodeficiency Virus positive subjects.  Journal of 
Infectious Diseases 1992;165:  105-110. 

2.  Corey L and Fleming TR.  Treatment of HIV infection -- 
progress in perspective.  Editorial.  New England Journal of 
Medicine 1992;326(7):  484-486. 

3.  Yarchoan, R, Mitsuya H and Broder S.  Immunologic issues in 
anti-retroviral therapy.  Immunology Today 1990;11(9):  327333. 

4.  Hill MD, Miles S, Gromperts E, et al.  Decreased activation 
of Zidovudine (AZT) in peripheral blood lymphocytes from patients 
with AIDS chronically treated with AZT.  VII International 
Conference AIDS, 1991, Florence, oral presentation THB 36. 

5.  Stretcher BN, Pesce AJ, Murray JA et al.  Concentrations of 
phosphorylated Zidovudine (ZDV) in patient leukocytes do not 
correlate with ZDV dose or plasma concentrations.  Therapeutic 
Drug Monitoring 1991;13(4): 325-331. 

6.  Salmon D, Detruchis P, Leport C et al.  Efficacy of 
Zidovudine in preventing relapses of Salmonella bacteremia in 
AIDS.  Journal of Infectious Diseases 1991;163:  415-416. 

7.  Shafik HM, Nokta MA & Pollard RB.  Recombinant human 
interferon beta ser protects against Zidovudine-induced genetic 
damage in AIDS patients.  Antiviral Research 1991;16(2):  205212. 

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