From: Billi Goldberg <[email-masked]>

RESPONSE TO POST ON ANTIVIRALS
                         Billi Goldberg

In post <07-22-92 11:48:00 [email-masked] (Rolfe G. Petschek)> 
Rolfe writes:

>Wrong.  AZT, DDI and DDC established by good, clear, well-designed peer 
>reviewed studies to decrease the rate at which people with 
>significantly progressed disease die.  I believe that they are the only 
>such drugs with immediate impact on HIV, as opposed to opportunistic 
>infections.

Since physics requires an in-depth knowledge of math, statistics, etc., 
I couldn't think of an individual more suited to evaluate the results of 
ACTG016 and ACTG019: the clinical trials or studies that resulted in the 
widespread use of AZT for treatment of HIV infection.

It would be greatly appreciated if you would pull those studies and 
evaluate them from your physical science background, scientific 
objectivity and expertise.

ACTG016: "The Efficacy of Azidothymidine (AZT) in the Treatment of 
Patients with AIDS and AIDS-Related Complex, July 23, 1987, Number 4, 
The New England Journal of Medicine, pages 185-191 by Fischl et al.

ACTG019: "Zidovudine in Asymptomatic Human Immunodeficiency Virus 
Infection, April 5, 1990, Number 14, The New England Journal of 
Medicine, pages 941-949 by Volberding et al.

The following table is from Fischl's study: the first using AZT.

Counts in table refer to CD4 T cell counts.

                 AZT Group                     Placebo Group 
            Patients   Median    Mean     Patients   Median   Mean 
             Tested    Count     Count     Tested    Count    Count 

PATIENTS WITH AIDS 

Base line     85        54.0     65.6        75       49.0    77.0     
Week 4        69       133.0    151.6        68       38.5    68.8     
Week 8        72        96.0    123.4        60       43.1    64.4     
Week 12       67        68.0    105.7        56       32.7    55.8     
Week 16       44        49.0     81.0        36       29.0    60.2     
Week 20       25        49.0     64.7        14       32.0    47.3     
Week 24        8        18.5     36.6         5       20.0    34.0     

PATIENTS WITH AIDS-RELATED COMPLEX 

Base line     60       190.0    199.3        61      128.0   175.0     
Week 4        54       251.0    257.9        51      154.0   182.7     
Week 8        54       204.5    222.4        48      114.5   161.5     
Week 12       46       277.6    254.0        47       93.0   164.3     
Week 16       38       209.0    269.7        38      157.6   178.0    
Week 20       20       340.0    297.0        22      103.0   156.9   
Week 24       11       217.0    262.6         9      154.0   232.9     

The following info is contained on page 186 of this double-blind, 
placebo-controlled trial of the efficacy of AZT:

"The placebo was indistinguishable in appearance from AZT and was 
similar in taste.  Drug therapy was temporarily discontinued or the 
frequency of doses decreased to one capsule every eight hours or longer 
is severe adverse reactions were noted.  The study medication was 
withdrawn if unacceptable toxic effects or a neoplasm requiring therapy 
developed.  Subjects in whom an opportunistic infection developed were 
withdrawn from the study only if therapy with another experimental 
medication was required or if antimicrobial therapy might have resulted 
in serious additive toxic effects."

My training was as a civil engineer, and I spent many years working with 
statistical data concerning accidents on California's state highway.
I am not impressed with the statistical information derived from the 
above study.  Remember, it must be considered that the dosages were 
decreased in individuals that had side effects or adverse reactions. 
That action results in skewing of the data, and is certainly not kosher 
in a double-blinded placebo controlled study.  Also, when preparing 
results of studies and experiments for publication, you attempt to show 
the data in the best light possible.  

>I have never ceased to be amazed at the rate at which science is 
>supposed to progress.  Ever since I learned of AIDS I was convinced 
>that many, many people would die thereof before an effective vaccine, 
>to say nothing of a cure (or effective long term treatment) was found. 
>Had I known it was a retrovirus at the time I would have been yet more 
>convinced of this.  

I have never ceased to be amazed at what science says it can do as 
compared to what it has actually accomplished.  

>The scientific community is doing the very best it can to find drugs, 
>cures and vaccines for HIV.  Significant progress has been made.  The 
>fact that people continue to die of the disease in the meantime does 
>not imply that anyone is particularly hard-hearted -rather it reflects 
>the difficulty of finding a cure for this (or, indeed any) disease.  

Is it really doing the very best it can do or is it doing the very best 
it can depending on who pays for the research that leads to drugs and 
treatments that can make the most profit.  The majority of AIDS victims 
are Third World.  How many of the scientific community are developing 
cheap, efficient treatments for these individuals?  No, it does not 
imply that the scientists are *particularly* hard-hearted, just that 
they need money for research and to live.  The drug companies have the 
money so that is where the scientists go.  I can guarantee that drug 
companies are interested more in drugs that will realize profit than 
they are in being *humanitarians* and providing non-profit making drugs 
to indigent people.  

Do you really think that doctors and researchers are donating their time 
and efforts in running the multitude of AZT + everything studies?  I 
would surmise that Burroughs Wellcome is footing the bill and giving the 
doctors and researchers something extra for their time and effort along 
with *contributions* to proactive AIDS organizations that recommend BW 
drugs.

Now the focus of the research is shifting to the immune system and the 
cell mediated immune response.  Salk has stated that an antibody vaccine 
will not work as have many others.  There are now more and more 
discussions about T8 cells, dendritic cells, NK cells and focusing on 
treatments that will activate the immune system to fight off infections 
rather than just focusing on destruction of the HIV virus.

I figured out the immune system focus a few months after I became 
involved in AIDS.  Elswood, Epstein, Mills and others had a treatment 
years ago that focused on activating the immune system to fight 
microbial agents with DNCB.  

Why has it taken scientists 11 years to come to the same conclusion?  
Why do you think a contact sensitizing agent like DNCB works?  Why don't 
you check the literature about DNCB and activating the immune system?  
There were articles over 20 years ago that used the cell mediated immune 
system response and DNCB to control microbial agents and neoplasms.

Billi Goldberg

                    AZT AND THE IMMUNE SYSTEM
                          Billi Goldberg  

The following is from the CATIE Treatment Update #30 dated 2/92:

AZT FAILURE: RESISTANCE THEORY QUESTIONED

"One factor which could play 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.'"

>From a joint Anglo/Dutch study on resistance:

"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 seem 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 reason for 
disease progression?  One potential answer is "cellular resistance" to 
AZT, which has be 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 activated AZT begins to decline.  Cellular 
resistance may also account for the eventual failure of ganciclovir 
therapy (DPHG) against CMV infection."

"A second possible reason for AZT failure without the development of 
viral resistance is that the drug affects co-factors 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 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."

************************************************************************

Billi's Comments:

>From Haseltine's "Molecular biology of the human immunodeficiency virus 
type 1" (FASEB Journal, 5:7/91:2349-2360)

"Once integrated, viral DNA remains permanently associated with the host 
genetic material.  The viral information remains as part of the nuclear 
DNA as long as the cell is alive.  As the virus rarely kills the host 
cells, this feature of the life cycle ensures that, once infected, a 
person remains infected for life.  The consequence of this feature of 
the life cycle is that treatments for HIV-1 infection must be life-
long."

What difference then, does it make, if some of the new virions produced 
by the infected cell are resistant to AZT.  The provirus in the infected 
host cells will not change and will continue to produce virions in the 
same random way.  Even if the resistant strain(s) infect new or already 
infected cells, the resultant virions would not be the same as the 
provirus.  HIV is infamous for the point mutations (errors) when copying 
its integrated genes in the cellular genome to produce new viruses.

It appears that AZT can be both absorbed and adsorbed by various cells 
in the body especially circulating and resting lymphocytes in the 
peripheral blood and lymphoid organs.  If AZT works by terminating the 
formation of vDNA chains, wouldn't it have the same affect on the DNA 
chains formed upon activation and proliferation of lymphocytes (T4 and 
T8 cells) responding to antigens.  It would appear possible that AZT 
would also interfere with the intercellular formation of enzymes, 
cytokines and other biochemical actions that control cellular processes 
and immune responses.  

If resistance is not due to viral mutation, one could postulate that 
there is a certain AZT load required before the immune system becomes 
dysfunctional based on starting T4 counts greater than 200.  It appears 
that after about 6 months at a 1500 mg/day dose, CD4 cell count returns 
to baseline and viremia increases.  At a 300 mg/day dose, it takes 
approximately three years for return to baseline and increased viremia.  
This might suggest that the AZT saturation for immune dysfunction is 
based on some sort of an inverse ratio of dose to length of usage.

>From Langhoff et al.(Haseltine is PI) "Replication of human 
immunodeficiency virus type 1 in primary dendritic cell cultures" (Proc 
Natl Acad Sci 1991;88:7998-8002)

"The observation that purified dendritic cells support continued 
replication of HIV-1 replication without notable cytopathic effects 
suggests that these cells may play an important role in viral 
pathogenesis.  In the lymph nodes the dendritic cells are in close 
proximity to T cells, where infected dendritic cells may serve as a 
constant source of infection for CD4+ T cells.  It is reported that 
HIV-1 interferes with the normal antigen-presenting function of this cell
type.  However, recent studies indicate that HIV-1 infection does not affect
their ability to support long-term growth of T cells."

Dendritic cells, the primary antigen presenting cells in the immune 
system, do not use endoctyosis when preparing antigens for presentation.  
It is believed that the antigens are processed on the cell surface using 
ectoproteases (enzymes).  

If AZT interferes with the enzymic processes, the result could be an 
inability of antigen presenting cells such as dendritic cells to present
antigen and activate the immune system to destroy microbial antigens.  This
dysfunction could explain why AZT users are more affected by opportunistic
infections in the late chronic/crisis phase than are non-AZT users.  This
would also help to explain the elevated HIV viremia (determined by PCR) in
individuals that have progressed to the AIDS stage and used AZT.  The level of
viremia in AZT users at the AIDS stage is approximately four-fold higher than
individuals that have never used AZT and who are at a comparable state of
disease progression.

Recently, it has been variously reported from Steinman and others that 
dendritic cells isolated from AZT users were not infected and, even when 
infected, were able to initiate mixed lymphocyte reactions (MLR), in vitro,
resulting in proliferation of T cells when stimulated with various mitogens
including IL-2.  

But this points out, once again, the problems with using cultures to test the
complexities of the human immune system responses.  
Antigen presentation in the immune system consists of complex 
physiochemical (biochemical) interactions and processes resulting in 
production of ctyokines and other stimulatory factors for initiation of 
immune system responses.  The supposition that HIV and/or AZT would 
interfere with in vivo antigen presenting capability dependent on 
cellular enzymic production is quite logical and rational.  It cannot be
disproved with artifactual results from culture experimentation using 
artificial methods such as mitogenic stimulation.  Without antigen 
presentation, there can be no T cell proliferation in human immune 
systems.  These processes cannot be duplicated in vitro.

                       AZT AND IMMUNE SYSTEM EFFECTS 
                             Billi Goldberg

More thoughts about AZT and the immune system.

Givens:  According to Broder and Mitsuya, AZT has higher affinities for 
HIV reverse transcriptase than for cellular DNA polymerase.  Also 
nucleoside antiretroviral activity depends upon multiple factors 
including penetration into target cells, multistep anabolic 
phosphorylation, intracellular catabolism [breakdown], and relative 
affinities for reverse transcriptase and cellular DNA polymerases.
AZT terminates DNA chains because it lacks the 3'-OH group which is 
required for the DNA backbone.

Rather than questioning the findings of the first two main AZT studies: 
ACTG016 and ACTG019, I will accept them.  Also, I will accept that AZT 
has a greater affinity for viral reverse transcriptase than for cellular 
DNA polymerase when both activities are taking place at the same time.

For the first six months of treatment with AZT, CD4 T4 cells increase 
and opportunistic diseases decrease.  After using AZT for approximately 
6 months at 1500 mg/day or 36 months at 300 mg/day, CD4 T4 cell counts 
return to baseline and opportunistic infections increase.  It has been 
stated that AZT users get more opportunistic infections after the AZT 
usage periods stated previously.

One possible reason for the transient rise in T4 cells during usage 
could simply be an immune system response to the AZT in the body.  AZT 
is a non-self antigen that would be in the blood and tissues.  The body 
would activate both the humoral and cell mediated immune system to 
respond to the non-self antigen.  T4 helper cells and T8 cytotoxic 
cells would proliferate and effector cells would be activated since AZT 
would be presented by both self Class I and II MHC molecules.  This 
could explain the nausea, headaches, rashes, myalgia, neuropathy, 
anorexia, gastrointestinal distress, etc. in most AZT users.  These 
symptoms are quite common in over reactive immune responses due to 
excesses of interferons, interleukins, tumor necrosis factor, etc.

The primary opportunistic diseases leading to death due to uncontrolled 
microbial replication in ARC/AIDS are PCP, MAI/MAC, cytomegalovirus, 
toxoplasma encephalitis, cryptosporidiosis, and cryptococcosis. 

The immune system cells that proliferate when activated due to microbial
antigens are T lymphocytes (T4 and T8 cells), B cells/plasma cells, 
monocytes/macrophages, natural killer cells, and granulocytes 
(neutrophils, eosinophils, and basophils/mast cells).  

AZT is not specific for any cell type, therefore all the immune system cells
are able to absorb AZT.

Immune system lymphocytes susceptible to HIV-1 infection and 
proliferation are T4 cells and monocytes/macrophages.

If active transcription of HIV is taking place in the T4 cells, then AZT 
will have an affinity for the viral DNA being formed by reverse 
transcriptase.  If these cells are already infected, producing new 
viruses, or if HIV is dormant in the cells, there is no RT activity 
therefore AZT will be active against cellular DNA polymerase.

When the humoral and/or cell mediated immune system is activated, the 
immune system cells replicate (proliferate) to destroy the  microbial 
antigens.  If there is no reverse transcriptase activity in the immune 
system cells that are replicating, then AZT will terminate the cellular 
DNA chain being formed by the DNA polymerase.  This inhibition of 
replication is a gradual process and after six months to three years, 
the immune system cells are so dysfunctional, they can no longer respond 
to opportunistic infections.  This could explain why the AZT users have 
more opportunistic infections than non-AZT users after initial AZT usage of 6
months to three years.

All individuals, whether they use AZT or not, will have dysfunctional T4 
cells and antigen presenting cells (monoctyes/macrophages, 
Langerhans/dendritic cells and follicular dendritic cells) due to HIV-1 
infection.  Once a cell is infected with HIV-1, it will remain infected 
until the cell is destroyed or replaced.  T4 memory cells can exist for 
up to 20 years.

Along with this goes the possibility that even in immune system cells 
that are not activated or do not replicate, AZT could interfere with  
antigen presenting capabilities and cytokine production.

Why do AZT users have less opportunistic infections than non-AZT users during
the initial period of AZT use (six months to three years).  Most of the OIs
are in the mucosa-associated lymphoid tissues which are 
easily accessed by AZT as it circulates in the body.  Therefore, it can 
be assumed that the microbial cells would absorb the AZT.  As these 
microorganisms replicate, the new cellular DNA being formed by DNA 
polymerase would be subject to chain termination.  Remember, AZT is not 
specific for RT but only has a higher affinity for it, and there is no 
HIV-1 in the microbial cells. 

The primary OI microorganisms in AIDS would probably become resistant to 
AZT chain termination in time (6 months to 3 years) just like any other
antibiotic that is used once too often.  This resistance would probably be due
to inability of surviving microbial agents to  phosphorylize and/or catabolize
[breakdown] AZT.  The surviving microbial agents would replicate, thus
impairing the body once again.  This, along with HIV-1 caused immune system
dysfunction, could result in uncontrollable opportunistic infections and death.

All of the effects of AZT can be explained by utilzing present knowledge of
immunology, immune system reactions to both self and non-self antigens, and
the documented AZT DNA chain terminating capabilities.  AZT has never
fulfilled its promise as an HIV/AIDS prophylaxis and treatment.  The
information provided in this article might help to explain this failure.

                   PSORIASIS, UV, ZIDOVUDINE, AND AIDS
                         by Billi Goldberg

I found some very interesting info when researching UV effect on HIV+ 
individuals. Not only can UV initiate HIV replication, but it appears it 
can also cause KS to develop. Then when I looked for alternative 
treatments for psoriasis, I came across zidovudine (AZT). It appears 
that zidovudine is quite effective in clearing up psoriasis. Psoriasis 
is a common skin disease characterized by thickened patches of inflamed, 
red skin covered by silvery scales that may cause itching. The anti-
inflammatory aspect of the immune system appears to be shut down by 
zidovudine. Of course, zidovudine could also interfere with the 10 fold 
increase in production of skin cells by terminating the DNA replication 
of the skin cells.

It is significant that cyclosporine is also effective, along with 
topical steroids, in reducing psoriasis.

There are those that think that the so-called zidovudine benefits are 
due to immunosuppression rather that antiviral action. The ability of 
zidovudine to successfully treat psoriasis might lend support to the 
immunosuppression hypothesis.
**********************************************************************
The following excerpt is from "Papulosquamous disorders associated with 
human immunodeficiency virus infections" from Dermatologic Clinics 
1991;9(3):525.

"The initiation of zidovudine therapy has been reported to clear 
psoriasis, by both us and several others. Generally, high-dose therapy 
(200 mg every 4 hours) has been used, with symptomatic relief of itching 
occurring within the first week and partial or even complete clearing 
within 6 to 8 weeks after starting the therapy. Lower-dose schedules 
have not yet been reported, nor has zidovudine been studies in HIV-
negative patients with psoriasis. When the dose is stopped or reduced, 
the psoriasis recurs, as with other therapies, including most notably 
cyclosporine. Addition of topical steroids or anthralin, or both, is 
important in treating disease not responsive to zidovudine therapy."

"Immunosuppressive therapy with methotrexate has resulted in serious 
complications, including death. HIV testing prior to methotrexate's use 
in all psoriatic or Reiter's syndrome patients, who should not receive 
the medication is seropositive, is recommended. Phototherapy has been 
used in HIV patients with ARC or early infection, but more careful 
studies with serial T4 counts and p24 antigen are needed before it can 
be safely recommended. In vitro studies show that ultraviolet light 
activates HIV expression, and we have seen patients develop Kaposi's 
sarcoma while receiving ultraviolet irritation." (Duvic M, Johnson TM, 
Rapini RP, et al: Acquired immunodeficiency syndrome--associated 
psoriasis and Reiter's syndrome. Arch Dermatol 123:1622-1632, 1987.)
**********************************************************************
Bonnekoh B; Wevers A; Geisel J; Rasokat H; Mahrle G.
Antiproliferative potential of zidovudine in human keratinocyte 
cultures.
Journal of the American Academy of Dermatology, 1991 Sep, 25(3):483-90.

Abstract: 
Because the beneficial effects of zidovudine in human immunodeficiency 
virus infection-associated psoriasis have recently been observed, this 
study focused on the drug's action on the rapidly proliferating human 
HaCaT keratinocyte line as an in vitro model for epidermal 
hyperproliferation. Cultures in log growth phase were exposed to 
zidovudine for 2 days. Zidovudine slowed proliferation in a dose-
dependent fashion as evidenced by 50% inhibition concentrations of 33 
mumol/L (cell number), 30 mumol/L (protein content), 0.9 mumol/L 
(protein synthesis), and 0.7 mumol/L (DNA synthesis). Significant (p 
less than 0.01) reduction of cell viability to 94.6% and 87.2%, as well 
as morphologic manifestations of cytotoxicity, were first evident after 
2 days' exposure to maximal drug concentrations of 10 and 100 mumol/L, 
respectively. Control viability, assayed by trypan blue exclusion, was 
98.0%. Direct cytotoxic plasma membrane injury could be ruled out by the 
absence of any increase in cytoplasmic lactate dehydrogenase release 
into supernatants at least during the 1 day of maximal dosage exposure. 
The drug-induced inhibition of proliferation was reversible within 7 
days after a 2-day exposure to 100 mumol/L zidovudine. Two days of 
treatment with a 10 mumol/L dose did not alter the pattern and synthesis 
of keratins in vitro. Thus the known antipsoriatic efficacy of 
zidovudine might be explained, at least partly, by the drug's cytostatic 
potency.
**********************************************************************
Kaplan MH; Sadick NS; Wieder J; Farber BF; Neidt GW.
Antipsoriatic effects of zidovudine in human immunodeficiency
virus-associated psoriasis.
Journal of the American Academy of Dermatology, 1989 Jan, 20(1):76-82.

Abstract: 
Four patients with psoriasis complicating human immunodeficiency
virus (HIV) infection showed marked improvement in their psoriasis after 
being treated with oral zidovudine. The antipsoriatic effect persisted 
in two patients in spite of worsening helper T cell depletion. The 
antipsoriatic effect appeared to be dose-dependent and was associated 
with the development of erythrocyte macrocytosis, a known side effect of 
zidovudine. Zidovudine is useful for the therapy of HIV-associated 
psoriasis and should be tested for efficacy in non-HIV-associated 
psoriasis.
**********************************************************************
Rooney JF; Bryson Y; Mannix ML; Dillon M; Wohlenberg CR; Banks S; 
Wallington CJ; Notkins AL; Straus SE.
Prevention of ultraviolet-light-induced herpes labialis by sunscreen.    
Lancet, 1991 Dec 7, 338(8780):1419-22.                     

Abstract: 
Sunlight exposure is reported by some patients to precede onset of 
recurrent herpes labialis. Ultraviolet (UV) B light is known to be a      
stimulus for the reactivation of herpes simplex virus (HSV) infections. 
We assessed the effect of a sunblocking agent on UV-light-induced 
reactivation of recurrent herpes labialis in a double-blind, placebo-
controlled crossover trial. 38 patients were exposed on two separate 
occasions to four minimum erythema doses of UV light at an area of 
previous labial herpes recurrence. A solution containing sunscreen was 
applied to the lips before one exposure and a matched placebo before the 
other. After placebo and UV exposure, herpes labialis developed in 27 
(71%) of the 38 patients, with a mean time to recurrence of 2.9 (SEM 
0.2) days. In contrast, when sunscreen was applied before UV exposure, 
no lesions developed, but 1 of the 35
patients shed virus at the exposure site. We conclude that UV light is a
potent stimulus for inducing reactivation of herpes labialis, and that
application of sunscreen may be effective in the prevention of sunlight-
induced recurrent infection.

   The following excerpt is from Chapter 15, "Psoriasis and AIDS" 
written by Andrew P. Lazar and Henry H. Roenigk, Jr., Northwestern 
University Medical School, Chicago, Illinois.  The chapter is included 
in the text PSORIASIS edited by Henry H. Roenigk, Jr., and Howard I. 
Maibach, University of California School of Medicine, San Francisco, 
California.

PAGES 164-165:
   "Our next step in the non-AIDS or AIDS patient with increasingly 
difficult to treat psoriasis would be to initiate ultraviolet therapy. 
We often employ a modified Goeckerman-2% crude coal tar applied each 
evening, washed off in the morning, UVB therapy, then full body 
lubrication with the use of a mildly potent corticosteroid to lesions. 
We have found, however, that most HIV infected patients tend not to 
respond to the regimen. They often are over sensitive to UV radiation 
and burn, koebnerizing with resultant pustulation or erythrodermic 
results. These types of severe reactions in a HIV patient can often 
accentuate their already debilitated status.

   "Traditionally, PUVA has been our next line of therapy in psoriatics. 
However in HIV patients there are theoretical as well as practical 
concerns in using this modality. Immunosuppression of lymphocytes and 
Langerhans' cell has long been a concern to dermatologists (29), and 
further immunosuppression of any degree in HIV patients should probably 
be avoided. Some authors have utilized PUVA in their HIV patients and 
have noticed an increase in the number of lesions of Kaposi sarcoma 
(28). Whether this represents a cause and effect relationship or merely 
a natural progression of their AIDS as their immune function fails is 
unclear. Like UVB, PUVA burns can cause flares of psoriasis. Other 
considerations regarding the use of PUVA in HIV patients include the 
risk of developing skin cancers and cataracts. In these immunosuppressed 
patients these skin cancers are more likely to be aggressive and 
metastasize. Though most HIV patients are not living long enough for 
this to happen, we hope that the future will allow these patients to 
live a longer time, and thus this might be a concern. Cataracts are not 
usually a problem with the use of PUVA unless the patient fails to 
exercise proper eye protection. In our experience this lack of 
compliance is seen in HIV patients with, again, in the short term will 
not lead to any problems, but as our ability to treat and control AIDS 
improves, the problem of cataracts may become a practical one."

REFERENCES
28.  Duvic, M., Johnson, T.M., Rapini, R.P., et al. (1987). AIDS-
       associated psoriasis and Reiter's syndrome. Arch. Dermatol. 
      123:1622-1633.
29.  Freidman, P.S. (1981). Disappearance of epidermal Langerhans 
       cells during PUVA therapy. Br. J. Dermatol. 105:219-221.
************************************************************************
The following is an excerpt from "The Skin and HIV Infection" by Mark 
Illeman, RN, FNP, in the February, 1991, edition of the Bulletin of 
Experimental Treatment for AIDS (BETA) published by the San Francisco 
AIDS Foundation.

   "Mark Illeman is Associated Medical Director of Dr. Marcus Conant's 
San Francisco Medical Group, where he specializes in dermatology and HIV 
primary care. Mark has written and lectured extensively on medical care 
for people with HIV disease. In the following article, he describes the 
most common dermatologic manifestations of HIV infection and reviews his 
and Dr. Conant's treatment recommendations for these conditions."

PSORIASIS-Page 8
   "Psoriasis, a common chronic skin condition characterized by patches 
of thick scaling on the scalp, elbow, knees and occasionally the entire 
body, is more common in people with HIV infection than in the general 
population. It is often an inherited condition, but it may be that HIV 
induces its appearance or triggers more frequent eruptions.

   "Adequate treatment is often difficult. Traditional use of topical 
steroid creams, or zinc shampoos and UV light may be effective. In our 
experience, zidovudine (AZT) has been effective at reducing the number 
and severity of plaques in at least 50% of cases. Using AZT in 
combination with traditional therapies, we have had good success in 
controlling this condition."

From: Billi Goldberg <[email-masked]>

                AZT, CYCLOSPORINE AND PSORIASIS
                       Billi Goldberg

Four studies that appear to tie together AZT, cyclosporine, and 
psoriasis. Both AZT and cyclosporine work by interfering with helper T 
cell proliferation and its cytokine production to control psoriasis.  
Corticosteroids also interfere with IL-1 production of antigen 
presenting cells thus inhibiting helper T cell proliferation. That is 
probably why corticosteroids has shown such efficacy in the treatment of 
psoriasis. Therefore AZT, cyclosporine and corticosteroids appear to be 
the most effective drugs in controlling psoriasis.

The immunosuppressive drugs azathioprine, methotrexate, 
cyclophosphamide, and corticosteroids interfere with proliferation of  
cytotoxic T cells and B cells.                                         
***********************************************************************
1. The study by Heagy et al. shows that AZT interferes with helper T  
   cell proliferation and may contribute to the immune deterioration 
   observed in patients following prolonged use of AZT.

Heagy W; Crumpacker C; Lopez PA; Finberg RW. Inhibition of immune 
functions by antiviral drugs.  Journal of Clinical Investigation, 1991 
Jun, 87(6):1916-24.     

Abstract: Immune functions were evaluated in vitro for PBMC isolated 
from healthy donors and cultured with the antiviral agents,
3'-azido-3'-deoxythymidine (AZT), ribavirin, ganciclovir,
2'3'-dideoxyinosine (ddI), or acyclovir. To identify methods for 
assessing the effects of antiviral drugs on immune cells, the PBMC 
response to mitogens, Con A, or phytohemagglutinin was evaluated from 
measurements of [3H]thymidine and [14C]-leucine incorporation, cell 
growth, cellular RNA, DNA, and protein levels, and the PBMC 
proliferative cycle (i.e., progression from G0----G1----S----G2 + M). At 
clinically relevant concentrations, AZT, ribavirin, or ganciclovir 
diminished PBMC responsiveness to mitogen. The numbers of proliferating 
cells in G1, S, and G2 + M phases of the cell cycle, DNA content, and 
[3H]thymidine uptake were decreased in cultures treated with AZT, 
ribavirin, or ganciclovir. AZT or ribavirin but not ganciclovir reduced 
RNA and protein in the cultures and inhibited cell growth. Whereas AZT, 
ribavirin, or ganciclovir were antiproliferative, ddI or acyclovir had 
little, if any, effect on PBMC mitogenesis. The inhibitory effects of 
antivirals on immune cells may contribute to the immune deterioration 
observed in patients following prolonged use of the drugs.

2. The study by Kaplan et al. shows that AZT controls psoriasis.      

Kaplan MH; Sadick NS; Wieder J; Farber BF; Neidt GW. Antipsoriatic 
effects of zidovudine in human immunodeficiency virus-associated 
psoriasis. Journal of the American Academy of Dermatology, 
1989:20(1):76-82.      

3. In Goodman and Gilman's "The Pharmacological Basis of Therapeutics,"
   eighth edition published in 1990 by Pergamon Press states on page 
   1265: 

   "Classical cytotoxic immunosuppressants such as methotrexate, 
   azathioprine, and cyclophosphamide [including corticosteroids] act by 
   inhibiting the synthesis of DNA, thereby thwarting the stimulus for 
   proliferation." This thwarting is accomplished by interfering with 
   the proliferation/differentiation of cytotoxic T cells and B cells. 
   Corticosteroids also interfere with IL-1 secretions of antigen 
   presenting cells such as macrophages and LC/DC.

   "Another consequence of the activation of helper T cells is the 
   synthesis and release of variety of cytokines that control both the 
   cellular and humoral arms of the immune response." These cytokines 
   are undoubtedly gamma interferon and IL-2 for Th1, and IL-4, IL-5, 
   IL-6 and IL-10 for Th2. "It is this step in the activation of T cells 
   that is exquisitely sensitive to cyclosporine and FK-506."

4. In the study by Griffiths et al., it is shown that cyclosporine    
   suppresses the cutaneous manifestations of psoriasis.              

   "When psoriasis is treated with systemically administered           
   cyclosporine a large reduction in CD4+ and CD8+ T cells occurs within 
   the plaques but only a small decrease in the DR+CD4+ T cells subset.
   This observation implies that, although activated DR+CD4+ T cells are 
   still present, they are in effect paralyzed and unable to produce 
   cytokines capable of perpetuating the psoriatic process."

   "Cyclosporine [and FK-506] has a mechanism of action directed mainly 
   at the CD4+ T lymphocyte and is known to inhibit its production of 
   IL-2 and Interferon-gamma."

Griffiths CEM; Voorhees JJ. Immunological mechanisms involved in 
psoriasis. Springer Seminars in Immunopathology, 1992;13:441-454.