AIDS TREATMENT NEWS Issue #197, April 15, 1994 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: Topotecan, CPT-11 (Irinotecan), Camptothecin, and Other Topoisomerase I Inhibitors Itchy Skin in HIV Announcements: AIDS Federal Lobbying: Washington, May 22-24; Local Districts May 29 - June 6 California: AIDS Budget Lobby Day, May 16 NAC, Glutathione and HIV -- San Francisco, May 7 ***** Topotecan, CPT-11 (Irinotecan), Camptothecin, and Other Topoisomerase I Inhibitors by John S. James We sent the following memos to the National Task Force on AIDS Drug Development, for their meeting on April 14 and 15. They describe a new class of potential drugs, which are not well known in the AIDS world but are being actively developed for cancer. Because a major meeting on this subject occurred on April 13 in San Francisco, we send a last-minute update memo to the National Task Force, and we also delayed the printing of this issue of AIDS TREATMENT NEWS. We will continue to follow this subject, and would appreciate any information about it. * * * The following is a revised version of the memo we sent on April 11 to the National Task Force on AIDS Development: A new class of anti-cancer compounds, generating wide interest in cancer research and already in human trials with hundreds of patients, also shows major promise for treating HIV. But almost nothing is being done to test or develop this possibility; there are no plans for any HIV clinical trial anywhere in the world, as far as we can determine. The main obstacle seems to be that some of the key information is new, and almost all of the work has been done by cancer, not AIDS, researchers; therefore the HIV medical/scientific community is not yet aware of the promise. The National Task Force should pay attention and make sure that an important opportunity for immediate, practical progress in treating HIV disease is not delayed or overlooked. While no one knows if topoisomerase I inhibitors will prove successful in treating HIV disease, these drugs do have the following advantages: * Laboratory tests have suggested that the doses required for HIV inhibition may be a small fraction of those needed for treating cancer. One laboratory study found 80 percent inhibition of HIV at a dose 200 times less than cancer patients have tolerated; another found an anti-HIV concentration 400 times less than that required to kill cells. Therefore, the toxicity seen in cancer trials might be greatly reduced, if much lower doses can be used for treating HIV disease. * These drugs have been found to be highly active against HIV in both acutely and chronically infected cells -- unlike drugs now in use. * They have been found to be equally active against HIV strains which are highly resistant to AZT, as against susceptible strains. (See reference in Li, Wang, and Pardee, below.) * Although no long-term resistance studies have yet been done, theory suggests that the development of viral drug resistance may be much slower with these drugs than with other antivirals. * The mechanism of action of these substances is entirely different from that of any other anti-HIV agents -- either treatments in use, or potential treatments in trials or in laboratory testing. A new class of drugs would open new worlds of therapeutic options -- for example, new kinds of combinations to target different steps in the HIV life cycle. * These potential drugs are also effective against at least some other retroviruses -- a finding which may offer a number of research and clinical advantages. * Because of the large cancer trials, the problems of manufacture and quality control have been largely worked out; and extensive human pharmacokinetics and toxicity data is already available. This means that clinical trials to test for anti-HIV activity in people could start almost immediately. All that is needed would be to give a low dose to a handful of people, and measure virological and clinical markers (HIV RNA, T-helper counts, etc.) before, during, and after the treatment. To the best of our knowledge, no person with HIV has ever taken any of these drugs. Therefore, it is possible that a very important advance is being overlooked. (Note: drugs which inhibit the closely-related enzyme topoisomerase II do not have anti-HIV activity.) We should also point out that these are not underground drugs. Topoisomerase I inhibitors can be very toxic, and difficult to dissolve and administer in an effective form. The first known compound, camptothecin, was abandoned as an experimental cancer treatment about 20 years ago, although it recently re-entered human cancer testing in the U.S. (Although camptothecin was discovered in a Chinese tree, it was never used in traditional Chinese medicine.) These obstacles could easily be overcome by qualified researchers, however, due to the human experience in the cancer trials. What is needed is serious mainstream attention -- and moving quickly on a small, practical trial to measure anti-HIV activity in humans. Some Potential Topoisomerase I Inhibitors * Topotecan. A camptothecin derivative being developed by SmithKline Beecham, topotecan is now in phase II trials in a number of countries as a potential treatment for many kinds of cancers. It might be the most feasible drug to test against HIV. Laboratory work showed that it inhibited HIV at a concentration 200 times lower than cancer patients have tolerated. * CPT-11. This drug has now been approved in Japan, for certain cancers. * Camptothecin. A major review published in 1993 (see below) noted that the sodium salt of camptothecin, which was abandoned 20 years ago, is now known to be poorly effective, because of the open-ring structure used to make the drug soluble. The article also reported that a new phase I trial of camptothecin in the lactone form, as an oral preparation, was being planned. [Note: based on the results of that trial, a U.S. phase II trial has recently been approved.] * There are a number of other camptothecin derivatives in early development. * Some topoisomerase I inhibitors (for example, b-lapachone) are not camptothecin derivatives, and may have different mechanisms of action. Drug Resistance In cancer, resistance to topoisomerase I inhibitors is already well known. In AIDS, there is no data on resistance. However, the two situations are entirely different. In cancer, the drug is used to kill cells, so resistant cells tend to survive and multiply. In AIDS, the drug appears to target cellular, not viral, proteins. Cellular genes mutate far less rapidly than HIV. Perhaps more importantly, supporting HIV replication is hardly a survival advantage for the cell, so the selective pressures are to remove, not preserve, any cells resistant to the drug's antiviral action. And in any case, the occasional resistant cell is not multiplying, so its impact on the disease process is likely to be negligible. Independently, the fact that topoisomerase I inhibitors appear to be broadly effective against retroviruses, not only HIV, suggests that we are unlikely to see the very rapid resistance found with drugs highly targeted against HIV-1 gene products. (Priel, Showalter, and Blair, reference below, "found that camptothecin inhibits equine infectious anemia virus (EIAV) replication in chronically infected cells and Moloney murine leukemia virus replication [manuscript in preparation], suggesting that camptothecin may act at a common, but as yet unidentified, step in the life cycle of retroviruses.") In addition, the finding, published only last month, that camptothecin inhibits the Tat pathway of LTR (long terminal repeat) activation of HIV, recalls the case of Ro 24-7429, the Hoffmann-La Roche Tat inhibitor, to which HIV developed no resistance at all despite a two-year-long attempt to create such resistance in laboratory cultures (see reference, below). Annotated Bibliography The information above is based on the following articles: * Li CJ, Zhang LJ, Dezube BJ, Crumpacker CS, and Pardee AB. Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication. Proceedings of the National Academy of Sciences, USA. March 1993; volume 90, pages 1839-1842. This paper described the use of a well-known research test to screen for LTR inhibitors as a new class of potential AIDS drugs. Three LTR inhibitors were identified: topotecan (the most powerful), b-lapachone, and curcumin (the least powerful). The results of the screening were confirmed by live-virus tests. "For comparison, topotecan can be tolerated in cancer patients at a plasma concentration that is 200 times the concentration that inhibits 80% of p24 antigen production in chronically infected cells." * Li CJ, Wang C, and Pardee AB. Camptothecin inhibits Tat- mediated transactivation of type 1 human immunodeficiency virus. The Journal of Biological Chemistry. March 11, 1994; volume 269, number 10, pages 7051-7054. This research, using engineered cells but not live HIV, found that camptothecin worked as an LTR inhibitor at a very low concentration -- about 0.03 micromolar, an order of magnitude lower than for the Roche Tat inhibitor Ro-7429. Camptothecin seemed to work as a Tat inhibitor: "Experiments with HIV-1 LTR mutants suggest that transactivation response sequence but not NF-kB is responsible for the inhibition by camptothecin. The target for camptothecin may be a cellular factor that is important for the activation of HIV-1 LTR by Tat and thus may offer a potential target for therapy of HIV- 1 infection." The Tat mechanism of action is important. The other main mechanism for inhibiting activation of the HIV LTR (namely, NF-kB), is (1) already achievable by readily available drugs, for example, pentoxifylline, and (2) can only be partially inhibited in any case, because cellular activation by NF-kB is needed by the body. Effective inhibition of HIV through the LTR (to keep the virus in latency) will probably require inhibition of both the Tat and the NF-kB mechanisms of LTR activation; but of the two, Tat-inhibitor drugs are most needed now. * Priel E, Showalter SD, and Blair DG. Inhibition of human immunodeficiency virus (HIV-1) replication in vitro by noncytotoxic doses of camptothecin, a topoisomerase I inhibitor. AIDS Research and Human Retroviruses. 1991; volume 7, number 1, pages 65-72. This early paper showed inhibition of live HIV by camptothecin, at concentrations of 0.01 to 0.02 micromolar when H9 cells were treated for one hour at the time of infection. This is important in providing live-virus confirmation of the work by Li, Wang, and Pardee (cited above), which used a screening test for LTR inhibitors, but did not use live HIV in their study of camptothecin. "The results suggest that the inhibitory effect of camptothecin on HIV replication is due to its effect on the virus replication and is not a result of its cytotoxic character. Moreover, the anti-HIV doses are 400 times lower than the cytotoxic doses of camptothecin." Also, this paper reported that two topoisomerase II inhibitors (m-Amsa, and VP-16) had no effect on HIV replication. * Slichenmyer WJ, Rowinsky EK, Donehower RC, and Kaufmann SH. The current status of camptothecin analogues as antitumor agents. Journal of the National Cancer Institute. February 17, 1993; volume 85, number 4, pages 271-291. This article reviews clinical and pre-clinical research with camptothecin itself, and with its derivatives, especially topotecan and CPT-11. "...The previous clinical trials assessing the efficacy of sodium camptothecin as an antitumor agent were probably inadequate. The insolubility of camptothecin lactone makes it difficult to devise a suitable formulation for further clinical testing. Nonetheless, the decision to reopen a limited clinical trial of camptothecin lactone (a single- institution phase I trial of an oral preparation) represents an interesting first step in re-evaluating camptothecin." * Wall ME and Wani MC. Camptothecin. In Anticancer Agents Based on Natural Product Models, Academic Press, 1980. This paper describes the discovery of camptothecin, as a result of screening thousands of plants by the U.S. National Cancer Institute in the late 1950s. Only one of the plants screened in that program, C acuminata, a small tree native to China, showed significant activity. The article also noted that the plant had not been used in Chinese traditional medicine. China, however, has done considerable research with camptothecin since its anticancer activity was discovered. * Hsu MC, Dhingra U, Earley JV, and others. Inhibition of type 1 human immunodeficiency virus replication by a tat antagonist to which the virus remains sensitive after prolonged exposure in vitro. Proceedings of the National Academy of Sciences, USA. July 15, 1993; volume 90, number 14, pages 6395-6399. This paper reported that HIV developed no resistance to Ro 24-7429, the Hoffmann-La Roche Tat inhibitor. "After 2 years of continued weekly passage of the virus in fresh CEM cells grown in the presence of the compound at 1 or 10 micromolar, the virus did not develop resistance to the drug. These results indicate that the compound's action might involve a cellular factor." * * * We sent the following update to the National Task Force on AIDS Drug Development, on April 14, 1994. Update on topoisomerase I inhibitors Here is more information on topoisomerase I inhibitors -- some from papers we had missed, some from a major symposium on the subject yesterday, at the American Association for Cancer Research annual conference in San Francisco. * CPT-11 (also called irinotecan; like topotecan, it is a camptothecin derivative, with the molecule modified to make it water-soluble) was approved in Japan on January 18, 1994, for lung, cervical, and ovarian cancers. This is the first topoisomerase I inhibitor approved anywhere. CPT-11 is a pro- drug with a long half life in humans, which can simplify administration; the active form of all the compounds has a shorter half life. Also, Dr. Arthur Pardee's group at the Dana Farber Cancer Institute has tested CPT-11 (using their HIV LTR screening system, not live HIV), and found results comparable to those for the similar drugs, topotecan and camptothecin (private communication). * Camptothecin has recently been approved for a phase II cancer trial in the U.S. * In animal tests, camptothecin prevented the development of two different retroviral diseases, when given one, two, or sometimes three days after exposure to the infection. (E. Priel and others, Inhibition of Retrovirus-Induced Disease in Mice by Camptothecin, Journal of Virology, June 1993, pages 3624-3629.) * An Australian group failed to find anti-HIV activity of camptothecin, except at doses that killed cells (D Jardine and others, Cellular Topoisomerase I Activity Associated with HIV-1, AIDS Research and Human Retroviruses, December 1993, p 1245-1250). At this time, two separate groups (Pardee's in Boston, and Esther Priel and others at Ben-Gurion University in Israel) did find anti-HIV activity at doses hundreds of times less than the cell-killing dose, in tests with live HIV (with topotecan in Boston, and with camptothecin in Israel). We do not know why the Australian finding is different. In any case, the risk and cost of a small, low-dose trial is slight; and the need for a new class of HIV drug is great. Unless a specific antiviral effect can be largely ruled out, a low dose of one of the three drugs (CPT-11, topotecan, or camptothecin) should be given to a few people, with careful monitoring of viral and clinical markers such as HIV RNA, to see if there is anti-HIV activity in humans. ***** Itchy Skin in HIV by Michelle Roland [Michelle Roland, a 4th-year medical student, is starting Internal Medicine residency at the University of California San Francisco/San Francisco General Hospital in June.] Introduction [Note: Much of the clinical and research information contained in this article was provided by physician investigators in the Dermatology department at San Francisco General Hospital. We would like to thank Toby Maurer, M.D., and Tim Berger, M.D., for their help in educating us and contributing to the research cited in this article. Appointments for evaluation and treatment of HIV-associated skin problems can be made at the San Francisco General Hospital Dermatology Clinic by calling 415/206-4470.] Itchy skin rashes are very common in people with HIV infection. The medical term for itch is pruritus. The specific cause of the itch may be related to HIV-induced immunosuppression or, less commonly, to specific organ disease resulting from opportunistic infections, cancer, or non-HIV related illness. The incidence of many of the diseases which cause itch increases as the T-helper cell (CD4) count decreases, thus itch is often associated with more severe immunocompromise. Doctors Toby Maurer and Tim Berger, researchers at San Francisco General Hospital, examined many people with HIV who had itchy skin and found that a diagnosis could be made with a relevant clinical history, physical examination, and sometimes a skin biopsy or other studies, in approximately 90% of their patients. Once diagnosed, the majority of these conditions can be treated. Some are quite responsive to therapy, while others may be resistant to currently available treatment options. The most common causes of itch in HIV infection can be divided into the following categories: 1) scabies and insect bite reactions, 2) inflammation of the hair follicles including either eosinophilic or bacterial (staph) folliculitis, 3) drug reactions, 4) dry skin, 5) a group of scaly skin disorders including seborrheic dermatitis and psoriasis, and 6) photosensitivity dermatitis. These terms will be described in non-medical language in the body of this article. Systemic illnesses including renal (kidney), hepatic (liver), endocrinologic (various hormone systems), hematologic (blood or bone marrow), neurologic (nervous system) and psychiatric disorders, may also be associated with itchy skin. The previously held theory of a "pruritic eruption of HIV," which proposed that HIV itself caused itch associated with a rash, has not been supported by investigations at San Francisco General Hospital. A cause for itchy skin, which is often extremely distressing, should be aggressively pursued. Referral should be made to a dermatologist with experience in this area if the primary care physician has been unable to make a diagnosis. Unfortunately, in some cases, no cause or syndrome will be identified and the patient and health care provider will be left with the challenge of symptomatic management. Scabies Scabies are very common and should always be looked for. Scabies infections in people with HIV may take one of the following forms: 1) typical, 2) exaggerated or atypical or 3) crusted (Norwegian) scabies.(1) Typical scabies cause small itchy bumps, especially between the fingers, with visible thin white lines representing burrows. These bumps (also called papules) can often be found in the genital and skin fold areas as well. In exaggerated or atypical scabies, there may be widespread infection with itchy bumps in atypical areas and none in the more common locations. In some cases, especially in more immunocompromised individuals, the scabies infection may become crusted (sometimes called Norwegian scabies). The lesions are unusual: there are no bumps, but rather widespread thick crusts, especially on the scalp, face, back, and under the nails. The crusts contain very high concentrations of mites and are extremely contagious. The skin may or may not be itchy. Serious systemic bacterial infections may occur in people with crusted scabies as cracks in the skin serve as a portal of entry into the blood stream for bacteria that normally inhabit the skin or for hospital-acquired bacteria. Diagnosis requires (non-painful) skin scrapings and microscopic identification of the mites or eggs. If the scrapings do not show evidence of scabies, a skin biopsy from an area which has not been scratched may be necessary to confirm the diagnosis. Initial treatment may employ Lindane (Kwell) cream or lotion(2) or Permethrin (Elimite) cream.(3) Patients with crusted scabies should be followed carefully for signs and symptoms of systemic bacterial infection and treated appropriately with oral or intravenous antibiotics. Scabies which do not respond to standard treatment, including crusted scabies, may require an extensive approach such as the three week regimen advocated by Dr. Timothy Berger at the San Francisco General Hospital Dermatology Clinic. Permethrin (Elimite) cream is applied on day one. On day two, Lindane (Kwell) cream or lotion is used. On days three through seven, Crotamiton (Eurax) cream or lotion is applied. This entire three drug course is repeated three times, for a total of three weeks. According to Dr. Berger, this approach is approximately 75% effective in eliminating persistent scabies. After the full three week treatment, if subsequent skin scrapings show no mites or eggs, the entire home must be thoroughly cleaned, including vacuuming of all floors and furnishings, dry cleaning of drapes or curtains, and flea bombing. Household members should also be treated monthly with standard anti-scabies medication if they are not immunosuppressed. Itch may persist for several weeks after successful eradication of scabies. The dead mites, eggs, and feces left in the skin appear to elicit an on-going allergic-type reaction. If the itch persists beyond several weeks, either the scabies were not completely eradicated, there has been a re-infestation, or there may be a second process involved. Insect Bites Flea and mosquito bites may be more extensive in people with HIV infection, eliciting a more severe allergic reaction than usual. Itchy hive-like bumps on the legs may be insect bite reactions. Sometimes these bumps will develop into small or large blisters; a skin biopsy may be required to confirm that the insect bite reaction is the cause of the lesions.(2) Treatment of animals in the home, application of insect repellents, and symptomatic treatment of itch are indicated. Standard oral anti-itch medications such as the antihistamines diphenhydramine (benadryl) and hydroxyzine (atarax or vistaril) may be effective but are sedating. The most potent anti-itch medication is Doxepin (Sinequan), an antidepressant used for its potent anti-histamine side effect. 25-50 mg at night relieves itch and is sedating, promoting a good night's rest. Topical steroids such as triamcinalone 0.1% cream or hydrocortisone 1% cream may also be helpful. Eosinophilic Folliculitis (EF) EF is a skin disease which is unique to HIV and is being recognized more frequently as it is discussed more in the medical literature. It is an itchy hive-like bumpy rash; each bump occurs around a hair follicle. The cause of EF is unknown, but does not seem to be bacterial, fungal, or related to the common skin mite, Demodex. EF has a characteristic clinical presentation as well as recently defined skin biopsy findings.(4) The lesions occur on the scalp, face, neck, upper trunk and upper arms in people with advanced HIV infection (fewer than 250-300 T-helper cells). The skin has often been scratched. The clinical presentation of itchy bumps around the hair follicles on the face and trunk appears to be very specific for EF, thus some experienced clinicians do not believe that a skin biopsy is necessary to make the diagnosis, particularly if the patient has failed to respond to systemic antibiotic treatment. When a skin biopsy is indicated, it is important that a primary lesion (one which has not been scratched or secondarily infected) be identified. Initial standard treatment strategies for EF used to employ astemizole (Hismanal), a non-sedating antihistamine, or ultraviolet B (UVB) light therapy. (Note: astemizole should not be used in combination with the anti-fungal agents ketoconazole or intraconazole). Although UVB is often effective, maintenance treatment is required as relapses are common after termination of treatment.(5) In addition, people with HIV appear to be at an increased risk for photosensitivity reactions, including reactions caused by UVB.(6) Fortunately, a relatively new anti-fungal drug, itraconazole, has recently been demonstrated to be effective in EF.(7) The mechanism of its action is believed to be distinct from its anti-fungal properties, as no fungus has been consistently identified in EF. The authors of the itraconazole paper suggest that a clinical diagnosis should be confirmed by skin biopsy (although if the lesions are characteristically located, are centered around follicles, and have not responded to systemic antibiotics, this may not be necessary). They recommend initiating itraconazole at 200 mg a day. This dosage may be increased to 300 or 400 mg daily if there has not been a significant response after two weeks. Note that itraconazole should be ingested with food. [The Conant Medical Group recommends taking itraconazole with an acidic beverage, for example a Coke or orange juice, followed by a meal. Patients taking ddI may have inadequate absorption of itraconazole because of the buffer required with ddI.] As with the some other anti-fungals, it has many important drug interactions and must be prescribed carefully and monitored closely.(8) Staphylococcal Skin Infections Another cause of folliculitis in HIV is Staphylococcus aureus (staph aureus), a common bacteria which infects the skin. Some people normally carry staph aureus in their noses, where it does not cause disease but may re-infect the skin and other parts of the body. In HIV, staph aureus commonly causes several skin infections, some of which may be itchy. Folliculitis is the most common infection caused by staph in people with HIV.(9) It may be confused with EF and should always be ruled out before a clinical diagnosis of EF is made. The lesions are usually red bumps containing pus which are centered around a hair follicle. Sometimes they appear as small hive-like bumps. The folliculitis occurs most commonly on the upper trunk or back, legs, and groin. The infection may become more widespread and form abscesses, boils or carbuncles. Alternatively, an atypical form of staph folliculitis which occurs on the scalp, under the arms, or in the groin appears as large raised deeply red or purple lesions studded with pus-filled bumps.(2) Diagnosis requires culture of pus from the lesion. In uncomplicated cases of staph folliculitis, a short course of a single oral antibiotic should suffice. The more involved lesions may require longer courses of antibiotics and the addition of rifampin (600 mg a day for five to ten days). Staph aureus may also be involved in secondary infections of other itchy skin diseases, increasing the itch. It can also cause a blistering skin infection called bullous impetigo, which may be mildly itchy. Diagnosis and treatment of bullous impetigo are the same as for uncomplicated folliculitis. Drug Reaction Allergic reactions to prescription and over the counter drugs are extremely common in people with HIV. The reactions involve the skin and may be intensely itchy. They most commonly occur seven to fourteen days after the initiation of a new drug and start out as small, flat or slightly raised, red bumps which coalesce into larger red bumps and may become completely generalized. The skin eruption may be associated with fever and malaise. People with HIV are particularly likely to react to trimethoprim-sulfamethoxazole (TMP-SMX, Septra, Bactrim) used for the prevention and treatment of pneumocystis pneumonia, and to penicillins. In any generalized skin eruption, a drug reaction must be considered. All those drugs which are either suspected or unnecessary should be discontinued if possible; over the counter drugs, herbal remedies, compounds obtained from buyers' clubs, etc. should be included in this consideration. Some rashes will resolve while the patient continues on TMP- SMX, others will require discontinuation. [Note: In many cases, it is possible to desensitize patients to TMP-SMX, so that this prophylactic (preventive) treatment for pneumocystis, and probably also for toxoplasmosis, can be continued; for more information, see AIDS TREATMENT NEWS, issues #180, August 6, 1993, and #161, October 16, 1992; or contact Chris King (see footnote #7, below).] Dry Skin Dry skin (also called xerosis or xerotic eczema) is very common in people with HIV, and is usually associated with itch. Often the intensity of itch, which may be resistant to oral antihistamines, seems out of proportion to the visible dryness. Dry skin is most common on the front of the lower legs, but may also be seen on the back of the lower legs and arms, or in a generalized distribution. There may be a fine scale with occasional red bumps and/or discrete areas of thickening of the skin secondary to rubbing or scratching. People with dry skin are at risk for secondary bacterial and viral infections. Some patients with dry skin may have a history of allergic conditions such as asthma, hay fever or atopic dermatitis. However, many have no such history.(10) Treatment includes minimizing time in the shower or bath and avoiding very hot water, using mild soap (for example, Dove) and avoiding deodorant soaps, and application of moisturizing creams after bathing and before going to bed. Potent oral antihistamines such as doxepin may be helpful. Mild topical steroid ointments (for example, 1% hydrocortisone) can also be used. Unfortunately, dry skin tends to worsen as HIV-associated immunosuppression progresses. Seborrheic Dermatitis and Psoriasis Seborrheic dermatitis is a common mild skin disorder which includes dandruff and mild flaking in the eyebrows, behind the ears and in the area between the nose and the cheeks in HIV-negative individuals. It is extremely common in people with HIV, occurring in 30-80% of studied populations. It often presents very early in the disease, before any other signs of immunosuppression. It may be mild or quite severe, involving the eyelashes, inside the ears, central chest, upper back, under arms, and groin, in addition to the more common distribution. The rash varies from a very indistinct light pink slightly raised lesion with very mild, fine, white scale, to intensely red widespread lesions with profuse, loose, waxy, yellowish scale. Itch is usually minimal. Seborrheic dermatitis is a chronic condition with variable response to treatment. It is believed that an allergic reaction to the yeast Pityrosporum ovale or Pityrosporum obicularis may contribute to the development of this disorder. Treatment includes a topical steroid cream combined with an anti-fungal cream applied to the affected areas twice a day. Anti-fungal, tar or selenium shampoos may also be used. In severe cases, oral anti-fungals may be more effective. Ultraviolet phototherapy has also been used in cases which did not respond to other treatments. Psoriasis is another relatively common flaking skin disorder with an increased incidence in people with HIV infection. Approximately 1/3 of patients with psoriasis had it prior to their HIV infection, while the remaining 2/3 developed it after they became HIV positive. It is not unusual to see psoriasis develop in people who previously had seborrheic dermatitis, and these disorders are often seen as being on a continuum of severity in people with HIV. Some patients have a combination of these conditions, referred to as sebopsoriasis. When people initially develop psoriasis lesions, which are pink to red with a silvery scale, they commonly appear on the knees, elbows and lower back. Initially, they may be very itchy. As they thicken and become more typical of psoriasis, the itch usually resolves. Treatment of psoriasis includes tar preparations, exposure to natural sunlight, ultraviolet light therapy, and an oral medication called etretinate. Oral steroids (prednisone) are not used for the treatment of psoriasis. The Conant Medical Group has had success with high-dose AZT for treating severe psoriasis; for more information, contact Chris King (see footnote #7, below). Photodermatitis People with HIV infection appear to be at increased risk for the development of skin reactions in areas which are exposed to either sunlight or ultraviolet B (UVB) therapy. Although the reason is unknown, there are many drugs commonly used by people with HIV which make them more sensitive to sunlight, including Bactrim/Septra and non-steroidal anti- inflammatories (for example ibuprofen, feldene, etc). The rash is typically itchy and bumpy or scaly and occurs only in areas exposed to sunlight or light therapy. It may be confused with seborrheic dermatitis on the face, except the distribution is reversed: photodermatitis involves the nose and the area above the eyebrows but spares the crease between the nose and the cheeks and the eyebrows themselves. There is also a clear area under the chin. Phototherapy with UVB has been shown to be helpful in people with HIV who have psoriasis.(11,12) and eosinophilic folliculitis.(5) There are theoretical concerns that phototherapy may be immunosuppressive; it has been shown to activate HIV replication in the test tube and in mice. In a study of 6 people over a period of 42 treatments, UVB did not appear to have a negative effect on the immune system as measured by lab markers (CD-4 cell count, beta-2- microglobulin, and p24 antigen) or occurrence of new opportunistic infection or malignancy.(11) There also remains some concern that phototherapy may enhance the development of Kaposi's sarcoma or skin cancers. A recent study at San Francisco General documented the development of photosensivity dermatitis in three people with HIV infection who were being treated with UVB (one for EF, one for EF and psoriasis, and one for pruritic/itchy eczematous dermatitis).(6) The authors of this study made the following recommendations when considering phototherapy in people with HIV-associated skin disorders: 1) make sure that the patient does not already have a photodermatitis, 2) document photosensitizing medications, previous photosensitivity reactions, and history of KS and skin cancer, 3) discuss the potential immunosuppressive effects of phototherapy with the patient, and 4) use the minimal UV dose required, utilizing additional therapy which enables reduction in the UVB dose when available (e.g. retinoids in psoriasis). Treatment for photodermatitis is usually very successful. It includes sun avoidance, sunscreens and topical steroids. In severe cases, oral steroids may be used for a short time. Systemic Disease Rarely, people with HIV infection will have itch without any primary skin lesions.(13) (There may be secondary lesions due to scratching.) Although occasionally no cause other than the effects of HIV itself can be found,(14) there are a wide variety of systemic illnesses associated with itch. The laboratory evaluation of a specific patient will be directed by the symptoms, past history, and physical examination and may include a variety of blood tests, urinalysis, skin biopsy, radiological/x-ray studies, etc. Following is a list of systemic illnesses associated with itch: 1) infectious diseases including hepatitis (especially hepatitis B), tuberculosis and syphilis; 2) kidney disease; 3) other liver dysfunction, including obstructive biliary disease; 4) blood disorders including polycythemia vera, thrombocytosis, chronic lymphocytic leukemia and lymphoma; 5) other malignancies including breast cancer and occult malignancy; 6) hormone dysfunction including hypo- or hyperthyroidism and diabetes mellitus; 7) heart disease including congestive heart failure and arrhythmias; 8) central nervous system disorders including tumors, Huntington's chorea and Parkinson's disease; 9) peripheral nervous system disorders including peripheral neuropathies; 10) nutritional deficiencies including vitamin B12 and niacin (pellagra); 11) substance use including alcohol, amphetamines and cocaine; 12) psychiatric illness including depression, anxiety, obsessive-compulsive disorder and delusional parasitosis and 13) medications. Very infrequently, a person may have a false belief of infestation, called delusional parasitosis (DP). This is usually an isolated delusion, but it may be associated with other mental illness. Sometimes the delusion is shared by a family member or friend.(15) There is an effective medication for DP called pimozide (Orap). It has some potentially serious side effects and is contraindicated in people with specific heart problems, thus it should be administered under careful supervision. Relapses of DP do occur when pimozide is discontinued. Research into the Mechanisms of Itch and Immunocompromise Studies are on-going at San Francisco General Hospital and elsewhere to try to determine the mechanisms involved in various forms of itchy skin eruptions. An initial study compared IgE (the allergy related antibody) levels in patients with eosinophilic folliculitis and those with HIV- related skin disorders which did not involve itch. This study documented elevated levels of IgE in patients with clinical and biopsy proven EF. Current studies are assessing IgE levels in patients with non-EF associated itch, with the theory that HIV may be associated with atopy (the tendency to have allergic-type disorders such as asthma and hay fever). A second theory, which is also being examined, was spurred by the observation that an increasing incidence of itch appears to be associated with declining T-helper cell levels. It is thought that a change in T-helper cells may occur at around 200, the point at which the incidence of itch appears to increase, and that the new cells may produce chemicals which are associated with allergy and itch. Thus, researchers at San Francisco General Hospital are trying to determine if the symptom of itch can be used as a marker for disease progression, in areas where monitoring T-helper cell counts is neither feasible nor affordable. Conclusion Itchy skin can be debilitating in people with HIV infection. Although it has been tempting in the past to attribute this symptom to HIV itself, it has recently been recognized by experienced clinicians and researchers that a specific diagnosis can often be made. Careful diagnosis is essential for successful treatment. Patients, primary care physicians and dermatologists must work together in difficult cases of itchy skin to establish a diagnosis and devise a reasonable treatment approach. Multiple therapeutic trials and repeated visits to the physician may be necessary to find an effective regimen. References and Notes 1. Orkin M. Scabies in AIDS. SEMINARS IN DERMATOLOGY. 1993; volume 12, number 1, pages 9-14. 2. Odom RB and Berger TG. The cutaneous manifestations of AIDS. CURRENT CONCEPTS (Upjohn). 1990. 3. Orkin M and Maibach HI. Scabies therapy -- 1993. SEMINARS IN DERMATOLOGY. 1993; volume 12, number 1, pages 22-25. 4. McCalmont TH, Altemus D, Maurer T, and Berger TG. Eosinophilic folliculitis: the histologic spectrum. In press. Timothy McCalmont, M.D., dermatopathologist at UCSF, is willing to consult on cases of suspected EF. He may be reached by telephone at 415/476-1543 or by fax at 415/476- 4190 to arrange viewing of skin biopsy specimens. 5. Buchness MR, Lim HW, Hatcher VA, Sanchez M, and Soter NA. Eosinophilic pustular folliculitis in the acquired immunodeficiency syndrome. Treatment with ultraviolet B phototherapy. NEW ENGLAND JOURNAL OF MEDICINE. 1988; volume 318, number 18, pages 1183-1186. 6. Thieberg MD and Berger TG. Iatrogenic photodermatitis in patients with acquired immunodeficiency syndrome. In press. 7. Berger TG, Heon V, King C, Schulze K, and Conant MA. Itraconazole therapy for HIV-associated eosinophilic follicultis. In press. Note that one of the authors of this study, Christopher King, Assistant Director of Research, Conant Medical Group, has prepared an extensive written summary of eosinophilic folliculitis. For more information, you may write to him at 1635 Divisadero St., Suite 601, San Francisco 94115, or fax him at 415/923-0337. He includes additional treatment suggestions for patients who do not respond to itraconazole, including Accutane and/or intermittent low dose systemic prednisone. Also, an aggressive topical management program is used. 8. Itraconazole. THE MEDICAL LETTER. 1993; volume 35, number 888, pages 7-9. 9. Berger TG, Obuch ML, and Goldschmidt RH. Dermatologic manifestations of HIV infection. AMERICAN FAMILY PHYSICIAN. 1990; volume 41, number 6, pages 1729-1742. 10. Cockerell CJ. Seborrheic dermatitis-like and atopic dermatitis-like eruptions in HIV-infected patients. CLINICS IN DERMATOLOGY. 1991; volume 9, number 1, pages 49-51. 11. Meola T, Soter NA, Ostreicher R, Sanchez M, and Moy JA. The safety of UVB phototherapy in patients with HIV infection. JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY. 1993; volume 29, number 2 part 1, pages 216-220. 12. Pardo RJ, Bogaert MA, Penneys NS, Byrne GE, and Ruiz P. UVB phototherapy of the pruritic papular eruption of the acquired immunodeficiency syndrome. JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY. 1992; volume 26, number 3 part 2, pages 423-428. 13. Berger TG. Evaluation and treatment of pruritus in the HIV-infected patient. In Volberding P and Jacobson M. AIDS CLINICAL REVIEW. 1989; pages 205-220. 14. Hoover WD Jr and Lang PG. Pruritus in HIV infection. JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY. 1991; volume 24, number 6 part 1, pages 1020-1021. 15. Driscoll MS, Rothe MJ, Grant-Kels JM, and Hale MS. Delusional parasitosis: a dermatologic, psychiatric and pharmacologic approach. JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY. 1993; volume 29, number 6, pages 1023-1033. ***** Announcements ** AIDS Federal Lobbying: Washington, May 22-24; Local Districts May 29-June 6 This year's AIDSWatch lobby days "is dedicated to securing greater AIDS program funding in Congress during the appropriations cycle, with a focus on health care reform that will be beneficial for people living with HIV disease. The goal is to have representation from every Congressional district." Those who cannot go to Washington for the May 22-24 events can help locally by lobbying their U.S. Representative and Senators during the Congressional recess, May 29 - June 6. For more information about either the Washington or the local district efforts, call Lisa Ragain, National Association of People With AIDS, 202/898-0414; or, if you are affiliated with one of the groups below, call them directly. This project is coordinated by NAPWA, and sponsored by: AIDS Action Council; AIDS National Interfaith Network; AIDS Policy Center for Children, Youth, and Families; AIDS Project Los Angeles; American Foundation for AIDS Research; CAEAR Coalition; Housing Works; Human Rights Campaign Fund; Mobilization Against AIDS; Mothers' Voices; National Alliance of State and Territorial AIDS Directors; National Community AIDS Partnership; National Hemophilia Foundation; National Minority AIDS Council; National Native American AIDS Prevention Center; Project Inform; San Francisco AIDS Foundation; Treatment Action Group; and the Whitman Walker Clinic. ** California: AIDS Budget Lobby Day, May 16 California's 4th annual AIDS Budget Lobby Day, consisting of a briefing on the California AIDS budget, a rally on the Capitol steps, and meetings with legislators and legislative staffs, will be Monday, May 16, from 10 a.m. to 4 p.m. at the State Capitol in Sacramento. This event is sponsored by major AIDS organizations in both Northern and Southern California, and by Planned Parenthood Affiliates of California. For more information, call 415/864-5855 x2537 (Northern California) or 213/993-1374 (Southern California). ** NAC, Glutathione and HIV -- San Francisco, May 7 Leonore Herzenberg, Ph.D., a member of the Genetics Department at Stanford University, will speak on recent research regarding N-acetylcysteine (NAC) as a potential treatment for HIV. The rationale for using NAC is that glutathione levels inside the cells are known to be abnormally low in many persons with HIV disease; this may impair the cells' antioxidant defenses, and the resulting oxidative stress may also stimulate the growth of HIV. NAC has been proposed as an efficient way to raise glutathione levels, but it remains controversial, with some researchers questioning whether it is adequately absorbed. [The Herzenberg Laboratory at Stanford is currently coordinating a trial, in San Francisco, to see whether high doses of NAC can restore glutathione levels if they are deficient. The main entry criteria are: T-helper count of 500 or less, no acute opportunistic infections (those under control are OK), and a low glutathione level (volunteers will be tested). For more information about volunteering for the trial, call Bill Clawson or Laura Goldbaum, at 415/863-8090.] Dr. Herzenberg's talk, sponsored by ACT UP/San Francisco, will be Saturday, May 7, at 1:00 p.m. at the Davies Medical Center (Gazebo Room), Castro and Duboce Streets. Admission is free. ***** AIDS TREATMENT NEWS Published twice monthly Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number fax: 415/255-4659 Internet: aidsnews.igc.apc.org Editor and Publisher: John S. James Reader Services and Business: David Keith Thom Fontaine Tadd Tobias Rae Trewartha Statement of Purpose: AIDS TREATMENT NEWS reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $230/year. Nonprofit organizations: $115/year. Individuals: $100/year, or $60 for six months. Special discount for persons with financial difficulties: $45/year, or $24 for six months. If you cannot afford a subscription, please write or call. 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