From: Billi Goldberg RESPONSE TO POST ON ANTIVIRALS Billi Goldberg In post <07-22-92 11:48:00 rpetsche@mrg.tmc.edu (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 The study medication was withdrawn if unacceptable toxic effects or a neoplasm requiring therapy developed.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 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.