From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Re: CMV Article in Sentinel
Archive-Number: 5913
Organization: unspecifiedNote: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Date: Sun, 16 Aug 92 20:21:46 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 #26 - September 1991
I. ANTI-HIV AGENTS 

      A.  AZT:  Danish Study Suggests Supplementary Antibodies 

     Previous randomized, controlled studies suggest that AZT 
provides benefit to subjects with ARC and AIDS, although the 
optimal dose has not been determined.  However, the effectiveness 
of AZT is known to wane eventually, perhaps owing to the 
development of viral resistance, to the increasing toxicity of 
the drug over time, or to other, as yet unknown factors. 
Scientists at the University of Arhus, Denmark, have been 
conducting immunologic studies on cells from people with HIV as 
well as from those uninfected by the virus.  They have found that 
AZT can impair certain immune functions of T-cells. 

     Cooperation between T and B-cells is necessary for 
successful control of infections.  AZT, in the Danish studies, 
appears to suppress the ability of T-cells to alert B-cells to 
invading organisms which, over the long term, could result in a 
reduced ability to fight off infections in patients who are given 
AZT.  Considering this, the Danish researchers think that 
supplementary treatment with antibodies should be given "serious 
consideration" for people who use AZT.  Results of a clinical 
trial of such a combination are reported below. 


     1.  Tauris P, Moller B, Munck P & Black FT. Effects of 3'- 
azido 3'-oxythymidine (AZT) on short-term cultured human 
peripheral blood lymphocytes.  European Journal of Clinical 
Investigation 19 9;19:167-171. 

     2.  Noelle RJ & Snow EC. T helper cell-dependent B cell 
activation.  Federation of American Societies for Experimental 
Biology Journal 1991;5(13):2770-2776. 

***** 

      B.  AZT and Antibodies -- A Randomized Trial 

     The immune deficiency which results from HIV infection is 
said to be the cause of the body's inability to control many 
infections.  Several immune boosters -- Imreg 1, interleukin 2, 
Isoprinsine, and thymic hormones -- affect T-cells, and require a 
minimum level of immune competence in order to function properly. 
In advanced HIV infection, accompanied by a damaged thymus gland 
and severe immune suppression, the effectiveness of T-cell-based 
therapies may be reduced. 

     Another approach is to give patients supplementary 
antibodies (immunoglobulins), which can protect them from 
infection.  Small studies in Germany have produced results (see 
Treatment Update 20) which suggest that antibody infusions, as 
compared to placebo, can reduce the incident of life- threatening 
infections in people with ARC.  Experiments with HIV- infected 
children also show a beneficial effect. 

     Researchers in Italy enrolled 30 HIV-infected subjects (18 
males, 12 females) for a trial of AZT with or without intravenous 
immunoglobulins (IVIG).  Fifteen subjects had AIDS, 9 had ARC, 
and 6 were symptom-free.  Equal numbers of subjects were randomly 
assigned to two groups; in group A, subjects were given AZT 500 
mg/day, and in group B, subjects were also given 500 mg/day AZT, 
as well as IVIG 400 mg/kg of body weight for 3 consecutive days 
and then IVIG 600 mg/kg of body weight every 4 weeks.  There were 
no significant differences between groups before the study.  The 
trial period was 12 months. 

     Side effects -- nausea and stomach pains -- were reported by 
approximately equal numbers of subjects in both groups, and so 
were attributed to AZT.  However, nearly twice as many 
opportunistic infections occurred in group A as in group B. The 
probability of developing an opportunistic infection was greater 
in group A then in group B; a statistically significant result. 
Twelve of 15 subjects in group B experienced rises in their 
platelet levels, compared with only 3 of 15 in group A, also 
statistically significant.  The Italian researchers concluded 
that a regimen of AZT with IVIG appears to provide greater 
protection against disease and preservation of platelet counts 
than does AZT alone.  No additional toxicity was seen in IVIG 
users.  Although the trial lasted for only one year, and involved 
only a small number of subjects, the study's authors say that "it 
should be emphasized that usually a reduced incidence of 
opportunistic infections in these patients is considered 
predictive of longer survival rate and better quality of life." 
They also point out that the expense of therapy with IVIG "could 
be compensated by reduced time of hospitalization and use of 
antimicrobial chemotherapeutic agents."  Several brands of 
immunoglobulins are licensed in Canada, including the brand used 
in the Italian trial, Sandoglobulin, made by Sandoz. 


     1.  De Simone C, Tzantzoglou S, Santini G et all.  Clinical 
and immunological effects of combination therapy with intravenous 
immunoglobulins and AZT in HIV-infected patients. 
Immunopharmacology and Immunotoxicology 1991;13(3):447-45 

***** 

      C.  AZT:  Second Study Confirms "Cellular Resistance" 

     Scientists around the world have been investigating the 
behavior of AZT once it gets inside cells.  This type of research 
is critical for formulating recommendations about the spacing of 
doses as well as for examining issues of toxicity.  After a dose 
of AZT is absorbed into the blood stream, it slowly accumulates 
inside cells where it is altered, through a series of reactions, 
into its activated form, called the triphosphate.  Only in its 
activated state can AZT exert its anti-viral effect against the 
essential viral enzyme RT (reverse transcriptase).  Since AZT 
interrupts viral replication, it must be inside a cell to do so, 
and so it is the concentration of drug inside the cell 
(intracellular) that really matters. 

     A team of researchers at the University of Cincinnati has 
been studying white blood cells taken from a small group of 
subjects with HIV infection who were treated with AZT.  The group 
consisted of 12 adult subjects (11 of whom were 500 mg/day AZT 
and 1 who was on 1200 mg/day) and one 10-month- old infant, on 
240 mg/day.  The researchers found that there appeared to be no 
relationship between blood levels of AZT and the concentration of 
activated AZT inside cells.  The original dosing regimen (every 4 
hours) was based on maintaining high blood levels of the drug, 
but since AZT really works intracellularly, the original 
recommendations have come under criticism.  The available data 
suggests that doses can be taken less frequently. 

     In other experiments, the researchers found that the ability 
of subjects to activate AZT varied by as much as 25% over 12 
weeks.  It appears that there are factors which, in the short- 
term, may affect the activation of AZT, but the researchers do 
not know what accounts for this.  There was a trend, however, 
over the long-term, which suggested that cells had a decreasing 
ability to activate the drug.  In this study, the ability to 
activate AZT remained more or less the same for "up to 3 months". 
After that, the level of activated AZT began to decline. 

     According to the Cincinnati data, measuring the gradual 
decrease in intracellular concentrations of AZT and calculating a 
dosing regimen is difficult.  The data do suggest that taking the 
drug every 4 hours is unnecessary, but the American researchers 
were unable to calculate a precise schedule.  Perhaps an answer 
can emerge from Sweden, where laboratory experiments on activated 
AZT have been underway at the Karolinska Institute in Stockholm. 
According to these experiments, AZT may need to be taken only 
every 6 to hours.  The Cincinnati study raises questions about 
the duration of AZT therapy, confirming findings by researchers 
at the University of Southern California School of Medicine, who 
have also found that the ability of cells to activate AZT erodes 
after 3 months of continuous use of the drug (see Treatment 
Update 24).  Some alternatives to constant dosing with the drug 
include alternating regimens of different agents.  The Swedish 
study raises questions and attempt to answer them by conducting 
clinical studies. 


     1.  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. 

     2.  Tornevik Y, Jacobsson B, Britton S & Eriksson S. 
Intracellular metabolism of 3'-Aziodothymidine in isolated human 
peripheral blood mononuclear cells.  AIDS Research and Human 
Retroviruses 1991;7(9):751-75 

***** 

      D.  AZT and Suppression of Interferon-alpha:  A Shifting 
Risk/Benefit Ratio? 

     AZT (Azidothymidine, Retrovir, Zidovudine) is the current 
drug of choice for treating HIV infection.  Results from 
randomized, double-blind, placebo-controlled trials of AZT versus 
placebo in people with AIDS and ARC suggest that in the short- 
term, survival is increased, and there is a decreased risk of 
developing opportunistic infections.  However, results from a 
controlled trial in symptom-free subjects using the drug for just 
over 1 year have been more controversial.  Preliminary results 
from a long-term, placebo-controlled study in the USA (VA 29 ) on 
subjects given AZT, compared to those given placebo, showed that 
over 2 years the drug did not appear to provide enhanced 
survival.  (Subjects in this trial had between 200-500 CD4+ cells 
at entry and no prior opportunistic infections).  For a critical 
review of AZT and related issues please see Treatment Update 17, 
20, and 23. 

     Why patients using AZT eventually experience disease 
progression is not understood, but may be related to the 
development of drug-resistant strains of the virus, to the 
increasing toxicity over time of AZT, or to other as yet unknown 
factors.  The toxic effects of AZT on bone marrow are well- 
documented, as are the less life-threatening reactions, such as 
nausea and headache.  However, AZT may have other, more subtle 
effects.  Scientists at the University of Arhus (Denmark) and at 
Harvard University have demonstrated the immune-suppressive 
properties of the drug in laboratory experiences.  Researchers at 
the University of Turin have confirmed some of that work in 
experiments on HIV-infected humans given AZT.  In particular, AZT 
appears to suppress production of interferon-alpha (IFN-a) by 
white blood cells.  This is not as alarming as it might first 
seem:  suppression of IFN-a, at least in the short-term, may 
provide benefit to people with HIV infection. 

     People with HIV infection are known to produce an abnormal 
form of IFN-a, called acid-labile as it is destroyed by acid. 
High levels of this interferon may herald the onset of 
opportunistic infections and/or cancers. 

     Researchers at Toronto's Hospital for Sick Children suggest 
that this abnormal IFN-a may hasten disease progression by 
accelerating the loss of CD4+ cells, increasing HIV replication 
and playing a role in the wasting syndrome.  Unfortunately, it 
seems likely that AZT appears to suppress both normal IFN-a as 
well as the acid-labile form.  As IFN-a plays a crucial role in 
the defense against opportunistic infections and cancer, the 
long-term consequences of this kind of interferon suppression are 
uncertain.  Before these immunologic studies were conducted at 
Harvard and elsewhere, anecdotal reports from doctors in New York 
City suggested that patients using AZT often had reduced levels 
of acid-labile IFN-a, a finding their doctors were previously at 
a loss to explain. 

     Now workers at NIAID (National Institutes of Allergy and 
Infectious Diseases, Bethesda, Maryland) as well as Beth Israel 
Hospital (New York) have documented the effect of AZT on levels 
of acid-labile interferon.  In a subgroup of subjects in a 
placebo-controlled trial, 19 people with AIDS or advanced ARC 
were followed for disease progression.  The researchers noted 
that the subjects producing acid-labile interferon at the start 
of the study had a tendency to have more severe symptoms, lower 
CD4+ counts, and high levels of viral replication.  Over time, 
the levels of acid-labile interferon fell in those subjects on 
AZT but not in those on placebo.  The long-term effect of AZT 
therapy in this group of subjects was not stated.  The 
researchers noted that elevated levels of interferon are also 
found in other diseases in which autoimmunity plays a role, such 
as arthritis and systemic lupus erythematosus.  Since subjects 
with reduced levels of acid-labile interferon appeared to have 
improved chances of survival, the researchers suggested that 
acid-labile interferon be considered as a potential surrogate 
marker, much like CD4+ counts. 


     1.  Heagy W, Crumpacker C, Lopez PA et al.  Inhibition of 
Immune functions by antiviral drugs.  Journal of Clinical 
Investigation 1991; 7:1916-1924. 

     2.  Biglino A, Pugliese A, Forno B et al.  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. 

     3.  Lau AS, Der SD, Read SE, and Williams BRG. Regulation of 
Tumor necrosis factor receptor expression by acid-labile 
interferon-alpha from AIDS sera.  AIDS Research and Human 
Retroviruses 1991;7(6):545-552. 

     4.  Buimovici-Klein E, Lange M, Klein RJ et al.  Long-term 
follow-up of serum-interferon and its acid-stability in a group 
of homosexual men.  AIDS Research (now called AIDS Research & 
Human Retrovirus) 19 6;2(2):99-10 

     5.  Baron S, Tyring Sk, Fleischmann WR et al.  The 
interferons:  Mechanisms of action and clinical applications. 
Journal of the American Medical Association 1991;266(10):1375-13 
3. 

     6.  Mildvan D, Machado SG, Wilets I, and Grossberg SE. 
Endogenous interferon as an index of therapeutic response in 
AIDS.  Annual meeting of the International Society for Interferon 
Research, Nice, France.  1991.  Abstract 132. 

***** 

      E.  AZT:  Mutations Prevented with Interferon-Beta 

     DNA is a molecule found inside the nucleus or "control 
center" of a cell.  DNA, the genetic material, contains 
instructions for making essential components for the cell.  Since 
most cells in the body must be eventually replaced, the DNA from 
the old cell must be duplicated and placed in the new cell.  If 
errors are make copying the DNA, mutations can happen, although 
cells have error correction systems and can usually repair 
damaged DNA. However, if mutations in the genetic material are 
left unchecked, they can result in a dysfunctional cell, which in 
some cases can cause tumors.  Indeed, at a recent workshop 
convened by the National Institutes of Health (USA) on the role 
of mutations in cancer, data was represented on the relation 
between abnormalities in the DNA and the development of non- 
Hodgkin's lymphoma. 

     Burroughs Wellcome has admitted that AZT in high 
concentrations causes mutations in some tests (mouse tk+/- 
lymphoma assay).  Researchers with the EPA (Environmental 
Protection Agency, USA) and Monsanto and Upjohn have recently 
reviewed the effectiveness of this assay and concluded that the 
test is sensitive when used under appropriate conditions.  The 
test is used in determining the cancer-causing potential of 
substances.  In studies with human cells, Burroughs Wellcome has 
found that AZT in high concentrations has caused abnormalities of 
the genetic material. 

     The drug has the potential to do the same in human users, a 
conclusion supported by recently published research in the 
journal Antiviral Research.  Scientists studied 11 subject with 
AIDS, 7 of whom were being given AZT (1200 mg/day) as their only 
therapy, for between 4 weeks to 11 months.  (If a drug has the 
potential to cause genetic damage, it will generally do so within 
that time).  The other 4 subjects were not receiving AZT.  No 
subjects were smokers, none had cancer, none had had cancer 
previously, none had undergone chemotherapy or radiation therapy 
-- all factors which can cause mutations.  The average CD4+ count 
was 172 cells at the start of the study. 

     The researchers found that the number of abnormal cells 
increased 16 fold in AZT users, compared with non-AZT users, in 
as little as 4 weeks of use.  This result was statistically 
significant, that is, not likely due to chance.  This work 
confirms the results of studies conducted by Harvard University 
researchers, who found abnormalities in the growth cycles of 
cells in laboratory experiments with even low concentrations of 
AZT.  It would not be hard to infer the same possibility in human 
given AZT. 

     According to the Texas researchers:  "These data suggest 
that [AZT] has the ability to induce genetic damage at 
therapeutic levels of dosing which could produce a potential 
increase in carcinogenic risk associated with its prolonged 
intake." 

     In related experiments, the Texas researchers found that 
giving the genetically abnormal cells high concentrations of 
interferon-beta (IFN-b) reduced the incidence of mutation by as 
much as 99%.  Even low doses resulted in a significant reduction 
( 1%) in abnormal cells.  Exactly how IFN can provide beneficial 
effects to AZT-damaged cells has not been fully established. 
However, researchers at Chiba University in Japan may have an 
answer.  In experiments with cells and radiation, they found that 
IFN-a prevents the appearance of mutations.  Their explanation is 
that IFN-a activates error correction systems which repair 
damaged DNA. Based on the results of their experiments with AZT, 
the Texas researchers concluded that IFN-b may have a role to 
play as a protective agent for people using AZT.  In controlled 
trials, IFN-b has been safely administrated in doses as high as 
90 million international units per day (5 days/week).  Results 
from a clinical trial in people with advanced HIV suggests it 
offers protection from opportunistic infections.  The drug 
activates the immune system and has anti-CMA and herpes virus 
properties.  In North America, IFN-b is made by Berlex 
Laboratories, Alameda, California (415) 769-5242. 

     Burroughs Wellcome has found that some rats given long-term 
"therapy" with AZT can develop cancer.  Given the results of the 
lymphoma assay and other work carried out with AZT, this is not 
entirely surprising.  Recently, scientists at Duke University 
(Durham, North Carolina) have found that, in laboratory 
experiments, the drug may suppress the activity of certain 
lymphocytes specializing in cancer control.  In light of recent 
reports of non-Hodgkin's lymphoma in long-term (3 or more years) 
AZT-users, the Texas researchers said, "Although the benefits of 
the drug outweigh the potential risk of increased carcinogenicity 
in untreated HIV infection, the potential hazard of the drug will 
have to be taken into consideration, particularly in HIV patients 
who are asymptomatic with normal [bone marrow/blood] and 
immunological parameters with less than the previously acceptable 
standard clinical indication for treatment."  Perhaps now that 
most patients are using doses of AZT which are less than 600 
mg/day, the development of mutations will not be as high as 
reported in the Texas research. 


     1.  Isom H, Kitchingman G, Roy-Burman P et al.  Workshop 
report from the Division of Research Grants, National Institute 
of Health:  The role of chromosome rearrangements, deletions, and 
point mutations in cancer -- A pathology B study section 
workshop.  Cancer Research 1991;51:5440-5444. 

     2.  Li AP, Aaron CS, Auletta AE et al.  An evaluation of the 
roles of mammalian cell mutation assays in the testing of 
chemical genotoxicity.  Regulatory Toxicology and Pharmacology 
1991;14:24-40. 

     3.  Shfik HM, Nokta MA & Pollard RB. Recombinant human 
interferon beta ser protects against Zidovudine-induced genetic 
damage in AIDS patients.  Antiviral Research 1991;16(2):205-212. 

     4.  Heagy W, Crumpacker C, Lopez PA et al.  Inhibition of 
Immune functions by antiviral drugs.  Journal of Clinical 
Investigation 1991; 7:1916-1924. 

     5.  Suzuki N & Suzuki H. Suppression of UV mutagenicity by 
human interferon.  Mutation Research 19 ;202:179-1 3. 

     6.  Stine KC, Tyler DS, Stanley SD et al.  The effect of AZT 
on in vitro lymphokine-activated killer (LAK) activity in Human 
Immunodeficiency Virus Type-1 (HIV-1) infected individuals. 
Cellular Immunology 1991;136:165- 172. 

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

     8.  (name lost) E et al.  Beta-interferon therapy in 
patients with poor- prognosis Kaposi sarcoma related to the 
Acquired Immunodeficiency Syndrome (AIDS):  A phase II trial with 
preliminary evidence of antiviral activity and low incidence of 
opportunistic infections.  Annals of Internal Medicine 
1990;112():5 2-5 9. 

      F.  AZT and Food 

     One factor which may affect the amount of AZT absorbed from 
the stomach is the presence of food.  A meal affects blood flow, 
the acidity in the stomach, and movement through the intestine. 
To investigate the influence of food on the absorption of AZT, 
doctors in Berlin enrolled 13 subjects (10 males, 3 females) with 
AIDS.  None of the subjects had any intestinal, liver, or kidney 
disease.  Experiments were performed while subjects took AZT (250 
mg) on an empty stomach with water or in the middle of a meal. 

     The doctors found that blood levels of AZT were higher for 
the first 2 hours in those subjects who took AZT on an empty 
stomach than in subjects who took the drug with meals 
(statistically significant).  Eventually blood concentrations 
fell to the same level in both groups.  The time taken to reach a 
high concentration in the blood was shorter in those subjects who 
took the drug on an empty stomach than in those who took AZT with 
food.  These findings are not really surprising and confirm the 
findings of American doctors who carried out research on similar 
issues several years ago (reported in Treatment Update #4).  As 
the German study was only done for a short time the long-term 
implications are unclear.  According to the German researchers, 
taking AZT 1 hour before a meal allows for high blood 
concentrations of the drug, while taking AZT during meals results 
in a range of blood levels.  These researchers speculate that 
"reduced efficacy and toxicity" may be the result of taking AZT 
with food. 


     1.  Lotterer E, Ruhnke M, Trautmann M et al.  Decreased and 
variable systemic availability of Zidovudine in patients with 
AIDS if administered with a meal.  European Journal of 
Pharmacology 1991;40(3):305-30 

***** 

      G.  AZT:  Bacterial Resistance Reported 

     In experiments with animals, AZT has been shown to have 
antibiotic properties, and it is thought to have the same effect 
in humans, so much so that the drug's antibiotic qualities may 
come to be recognized in the same way its antiviral effects are. 
(See Treatment Update 22).  Strains of bacteria resistant to AZT 
have now been isolated from patients using the drug.  Researchers 
at the University of Edinburgh, have found these drug-resistant 
bacteria from urine and eye samples taken from patients with AIDS 
who have used the drug.  Resistance to AZT did not mean that 
bacteria were resistent to other antibiotics, with the exception 
of 2 strains of E. coli also resistant to trimethoprim (an 
ingredient found in Bactrim/Septra).  But this is unlikely a 
result of patients' using Bactrim/Septra in addition to AZT. 
Unfortunately, the length of time that patients were on AZT 
therapy was not given. 


     1.  Lewin CS, Watt B, and Naden M. Zidovudine resistance in 
clinically significant bacterial isolates from AIDS patients. 
Journal of Antimicrobial Chemotherapy 1991;(November):77 -7 0.