From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Re: Letter to SF Sentinel
Archive-Number: 5912
Organization: unspecifiedNote: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Date: Sun, 16 Aug 92 20:07:27 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 #23  - May 1991                  ISSN 11817186 
  I. ANTI-HIV AGENTS 

 A. Harvard team finds anti-virals immunosuppressive 

      Treatment of viral infections has always been difficult. 
Since viruses insert themselves into cells of the body, drugs 
intended to damage viruses, unless highly selective, will likely 
damage cells as well.  Indeed, traditional antiviral therapy has 
not always been effective and has, at times, been toxic. 
However, the efficacy and relatively low toxicity of the drug 
acyclovir (Zovirax) in treating herpes infections has been 
encouraging and has shown that effective treatment of certain 
viral infections is possible. 

      The link between AIDS and HIV has spurred research into 
anti-HIV agents.  The first licensed drug, AZT (Zidovudine, 
Retrovir), appears to have increasing limitations.  Although AZT 
usually provides short-term benefit to patients with symptoms of 
HIV infection, a recent trial (ACTG 019) with over a thousand 
subjects has shown that it delays disease progression in only 4% 
of symptom-free subjects (for more details on ACTG 019, please 
see TreatmentUpdate 14 and 17).  Indeed, 92% of subjects on AZT 
did not benefit from the drug.  Another 4% of subjects in the 
trial experienced disease progression despite getting AZT. 
Doctors find that patients given AZT eventually experience 
disease progression for a variety of reasons, perhaps including 
increasing bone marrow toxicity over time and viral resistance to 
the drug.  Some researchers have said that there appears to be an 
association between long-term use of AZT (3 years or more) and 
the development of a form of cancer known as non-Hodgkins 
lymphoma.  (The relationship among HIV, AZT, and lymphoma is the 
subject of a future article in TreatmentUpdate).  Now researchers 
at Harvard University and elsewhere have published results of 
their experiments with anti-viral drugs and have found several of 
them to have suppressive effects on cells of the immune system. 

      The researchers used various concentrations of AZT, ddI 
(Videx), ganciclovir (DHPG), ribavirin, and acyclovir in cell 
systems and assays.  Results showed that acyclovir had little 
adverse effect on cells of the immune system, even at high doses. 
The same was true for ddI.  By contrast, AZT, ganciclovir, and 
ribavirin had a variety of suppressive effects.  AZT, even at 
concentrations below which it had significant anti-HIV activity, 
diminished the activity of T-lymphocytes, impaired the growth 
cycles of cells, and reduced the protein content of activated 
cells.  This last effect is particularly serious, as the 
production of interferons and interleukins is dependent on 
protein synthesis.  Ribavirin and ganciclovir also had similar 
suppressive effects;  indeed, the literature accompanying 
ganciclovir makes it clear that the drug must be handled with 
care because of its potential for toxicity.  However, its value 
in preventing the blindness of CMV retinitis in patients with 
AIDS is thought to outweigh its short-term toxicity. 

     Ribavirin at high doses has been associated with decreases 
in the CD4+ cell count.  As well, a recent clinical trial found 
that the largest sustained increase in CD4+ cells occurred in 
subjects receiving 300 mg/day AZT compared with subjects 
receiving 600 mg/day or 1500 mg/day.  According to the Harvard 
authors,"These findings suggest that AZT may adversely affect 
immune functions...."  They also said, "In AIDS, where viral 
replication occurs in immune response cells, it is possible that 
the toxicity resulting from such an antiviral may be enhanced. 
Since patients with HIV disease have cellular immune deficiencies 
at the outset of treatment, any agent that further depresses the 
immune response may, particularly over the long term, provide 
little value to the patient." 

      Meanwhile, researchers in Italy have conducted a long-term 
study of the effect of AZT on the immune function of a small 
cohort of subjects.  Fifteen subjects (9 ARC, 6 AIDS) taking 750 
to 1000 mg/day AZT were followed for a minimum of 6 months, and 
researchers found that while AZT did not appear to affect some 
immune functions adversely, it did consistently depress the 
production of interferon-alpha.  It might be argued that 
subjects in this trial were experiencing declining immune 
function anyway and that this is what was really detected by the 
researchers, but in fact, the subjects could be divided into 2 
groups:  those who experienced disease progression and those who 
did not.  In both groups, the production of interferon-alpha was 
continuously depressed.  In the non-progressors, interferon-gamma 
production appeared unaffected by 6 months of AZT use.  By 
contrast, among the progressors, the interferon-gamma levels 
continued to decline.  While there were no statistically 
significant increases in the level of CD4+ cells (pre-treatment 
compared with post-treatment), some other measures of immune 
function indicated temporary improvement with AZT use. The 
researchers concluded that AZT does appear to affect the 
production of interferon-alpha, and they are conducting further 
research on this property of the drug. 

 REFERENCES: 

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

 2.  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. 

 3.  Biglino A, Pugliese A, Forno B.  Effects of long-term 
Zidovudine treatment on cell-mediated immune response and 
lymphokine production.  Journal of Acquired Immune Deficiency 
Syndromes 1991;4(3):261-266.