Subject: BETA #11 Date: Nov 1992 (2611 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Bulletin of Experimental Treatments for AIDS &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& B-E-T-A (Bulletin of Experimental Treatments for AIDS) A publication of the San Francisco AIDS Foundation November 1992 CONTENTS: [items are separated by "*****" for this display] Treatment For Anogenital Warts And Molluscum Conta Giosum Human Papillomavirus Infection In Women With HIV Guidelines For Treatment Of HIV Infection In Adults On The Matter Of Survival Is It Possible To Prove A Survival Benefit From Early Treatment? AIDS Clinical Trials Information Service Research Notes MAC Prophylaxis Drug Recommended for Approval D4T: Promising Anti-HIV Drug Available Through Parallel Track ddI (Videx) Approved For Broader Use Mepron: New Second-Line Treatment for PCP Proposed New AIDS Definition Trimetrexate for PCP Oral Prednisone Therapy For Esophogeal Ulcers Sinusitis and HIV Infection Cytokine Effects on HIV Replications A Review Of The Epidemiology Of Kaposi's Sarcoma (KS) Combination Treatment for CMV Promising Preliminary Results of Passive Immune Therapy Results of PHT for Individuals with 50-200 T-helper Cells over Advances in the Use of Polymerase Chain Reaction (PCR) Technology Available PCR Tests for the Diagnosis of Infectious Diseases The 32nd Interscience Conference On Antimicrobial Agents And Chemotherapy: AZT and Clarithromycin Interaction Immediate Use of High Dose AZT in Early HIV Infection Low T-Helper Cell Counts Predictive of Survival Clarithromycin Effective Against MAC Reverse Transcriptase Antibodies Help to Prevent and Treat Disease Intraconazole Safe and Effective Drug for Histoplasmosis PCR Tests Detect Hidden Candida and Chlamydia Immunosuppression Without HIV: An Update Corrections Patient Drug Assistance Programs Sponsored By Pharmaceutical Companies Glossary ***** TREATMENT FOR ANOGENITAL WARTS AND MOLLUSCUM CONTA GIOSUM Mark L. Illeman, RN, FNP Mark Illeman is Associate 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 discusses strategies for the treatment of anogenital warts and molluscum, 2 dermatological conditions that frequently occur in people with HIV infection. An aggressive approach in treating life-threatening opportunistic infections such as Pneumocystis carinii pneumonia (PCP), toxoplasmosis and cytomegalovirus (CMV) disease has contributed significantly to improving survival among individuals infected with HIV. Certain other infections are more difficult to manage and have limited treatment options. This discussion focuses on 2 particularly difficult viral skin infections often found in patients with HIV disease -- condyloma acuminata (anogenital warts) and molluscum contagiosum, commonly called molluscum. This discussion includes treatment strategies used in our practice in San Francisco to manage these serious skin conditions. ANOGENITAL WARTS Anogenital warts are caused by infection with the human papillomavirus (HPV), a member of the papova virus group. There are at least 55 types of HPV, which cannot be cultured in vitro. Anogenital warts occur in 0.1% of the general population and in more than 0.5% of young men aged 20-24 years. Various studies suggest that up to 27% of people with AIDS have anogenital warts, and that approximately 2% of people with AIDS and ARC have "aggressive" variants of genital warts. Transmission of HPV is almost always sexual, with an infection rate estimated at 60%, and an incubation period that ranges from 2 weeks to 8 months. Genital warts typically present as multiple lesions that flourish in the warm, moist conditions of the anogenital region, especially if a discharge or another infectious process is present. Large perianal lesions are common, but warts also occur on other surfaces in people with AIDS, including the face, hands and feet. Individual lesions in an HIV positive patient do not usually differ morphologically from those of HIV negative individuals, but the number and size of lesions may be increased. Despite frequent, aggressive treatment, anogenital warts may recur in patients with HIV infection. While the incidence of warts appears to be no greater among patients coinfected with HIV, the response to therapy is generally poorer. The importance of frequent screening and aggressive management of genital warts has been well-documented in recent studies. Researchers are seeing a high incidence of anal intraepithelial neoplasia (AIN), bowenoid papulosis and anorectal carcinoma in patients co- infected with HPV and HIV. Several recent papers have described a variety of changes in the anogenital area of young men and women. Collectively referred to as "bowenoid papulosis," this is a recently recognized disease involving a wide spectrum of clinical features including thick pink or reddish brown papules or raised bumps, flat reddened skin, or a leukoplakia-like lesion in the genital area. Bowenoid papulosis is now associated with various HPV types (HPV 16, 18, 34, 39), most commonly with HPV 16. Bowenoid papulosis may be an early stage of dysplasia (abnormal tissue development), and may predispose the patient to squamous cell carcinoma, a serious form of skin cancer. A paper presented by Dr. Annemiek de Ruiter and her group from the Middlesex School of Medicine in London documents a clear association between HIV infection, anal condyloma and AIN. At a central London STD clinic, HIV antibody-positive and -negative gay and bisexual men were assessed for the presence of anal condyloma and AIN, using anoscopy and biopsy. Thirty-one of the 60 HIV positive patients had anal condyloma, 14 of whom had evidence of AIN. Only 3 of the 29 without anal condyloma manifested AIN, which is statistically significant. Twenty-one of the 28 HIV negative patients had anal condyloma, 7 of whom had biopsy-proven AIN. None of the patients without anal condyloma had AIN, which is not statistically significant. More advanced cases of AIN were seen in patients with advanced HIV infection. These studies point out the importance of frequent screening for subtle changes that may appear in the anogenital area. The exam should include anoscopy and pelvic exams for women, and biopsies of any suspicious-looking lesions. DIAGNOSIS Small or flat warts in the genital area are often difficult to see with the naked eye. Application of a gauze pad soaked in distilled vinegar (acetic acid) to the area in question for 5 to 10 minutes helps to distinguish affected tissue from the surrounding skin. When the gauze pad is removed, warty tissue appears white in color. This technique can be used on the penis, on the labia and around the perirectal area. TREATMENT Treatment typically involves mechanical removal of visible warts by electrodesiccation, cryotherapy or any number of topical acid solutions. Internal rectal or vaginal warts can be removed through disposable anoscopes or vaginal speculae. Once the visible warts have been removed, the surrounding normal skin is painted with 25% podophyllin solution to treat non-visible warts and to prevent the potential emergence of new warts. The painted area is then dried with a hair dryer and has talc applied to it. The patient is instructed to wash the area in approximately 2 hours to remove all of the podophyllin. Antibiotic ointments are then applied to prevent infection of open sores (Bactroban (R), Polysporin (R), Cleocin-T (R), etc.). Follow-up visits occur in 2-week intervals, and treatment is repeated until the area is clear. Several visits and aggressive management are often required in order to remove all visible warts. Once the area is clear, the patient is instructed to apply a topical chemotherapeutic agent -- 5-FU cream (Fluroplex (R) or Effudex (R)) every night or every other night as tolerated to discourage the growth of new warts. MOLLUSCUM CONTAGIOSUM Molluscum contagiosum has become one of the most common and most difficult skin conditions that we manage in our patients with HIV infection. We see large numbers of new cases daily. The lesions of molluscum contagiosum usually occur as flesh- colored, pearly, raised but firm, non-tender nodules. A typical early lesion is 2-5 mm in diameter, with a characteristic small umbilication (depression) or dimple in the center. Some lesions may become quite large, and may form disfiguring, giant nodules on the face or scalp. Lesions occur most commonly on the face, neck, arms, legs and anogenital regions. Molluscum contagiosum is a large, unclassified poxvirus that cannot be grown in tissue culture in the laboratory. At the center of each individual lesion or nodule is a firm white "molluscum body" or a collection of "molluscum bodies" that contain the active virus. These look like small firm beads, singly or in clusters. Most adults in the general population have been exposed to the molluscum contagiosum virus. Since approximately 90% of adults have antibodies to the virus, most people exposed do not develop clinical lesions. Lesions are most commonly observed in children and adolescents with a body-wide distribution pattern. Occasionally there are small epidemics in schools or other institutions. Lesions may persist for months, but usually resolve spontaneously, within 3-12 months, without the development of widespread cutaneous disease. Patients infected with HIV have an increased incidence of molluscum contagiosum, which is probably due to reactivation of viral infection from childhood or early sexual exposure, rather than a recent infection with the virus. Lesions are often widely distributed. The entire face and neck can be covered with small discreet papules or large raised nodules called "giant molluscum." Lesions on the eyelids may be associated with afollicularconjunctivitis ("pink-eye"). In immunosuppressed individuals, reexposure or reactivation of these infections may result in the first clinically apparent lesions. This pattern is similar to many other infectious organisms, including protozoal, fungal and bacterial as well as other viral infections that may lead to severe disease in HIV-positive patients. As with other opportunistic organisms, molluscum contagiosum may be difficult or impossible to eradicate in advanced stages of HIV disease. A recent report in the Archives of Dermatology reveals some distressing findings: changes suggestive of viral infection with molluscum contagiosum in the skin were detected up to 1 centimeter away from an obvious clinical lesion. Although these areas appeared to be clinically free of visible lesions, viral evidence of infection was visible on electron microscopy. In the cases of molluscum contagiosum in non-HIV infected patients, evidence of the molluscum contagiosum virus was not found by electron microscopy in the epidermis adjacent to the lesions. The findings in this study may help explain both the severity of molluscum contagiosum in HIV-infected patients and the difficulty of eradicating the disease by the usual methods. TREATMENT Treatment options are numerous but, unfortunately, not often successful in eliminating this potentially disfiguring condition. In our experience, the mechanical removal of the core or "molluscum body" of the lesion is essential to eradicate individual lesions. We have found that electrodesiccation [cautery] with a small epilating needle to the top of the lesion, followed by curetting or expressing the "molluscum body" with a comedo extractor (a device used to remove comedones or black heads for acne surgery) seems most effective. Larger lesions occasionally require local anaesthetic followed by aggressive curettage or scraping in order to remove multiple "molluscum bodies." Other techniques that we have found successful include application of a small drop of Verrusol (R) solution to the top of each lesion. Verrusol (R) solution contains a combination of three strong acids: salicylic acid, podophyllim resin and cantharidin. Cantharidin is ground-up "blister beetle" or "Spanish Fly," a blistering agent which causes a definite blister to appear over the site within 24 hours. The process of blistering and bringing the molluscum body to the surface, facilitating the growth of new skin beneath it, is another successful approach to removing the center of the lesion. Clear instructions are given to the patient to wash off the small crust that develops over the molluscum within 1 to 2 hours after applying the Verrusol (R) solution. Once the surgery has been completed or the lesions have blistered, it is important to apply an antibiotic ointment or gel (Bactroban (R), Cleocin-T (R), Polysporin (R), etc.) to prevent secondary bacterial infection in the surgical sites. Shaving often autoinoculates facial lesions, so we advise patients to use electric shavers and to avoid using straight blades. Patients are seen at 2-week intervals as long as necessary, and any new lesions are mechanically removed. An acceptable cosmetic result often can be accomplished with this aggressive management. Other less successful approaches include cryotherapy (the use of liquid nitrogen to freeze the tissue, leading to blister formation) or the use of stronger peeling agents such as cantharidin cream, 5-FU cream or RetinA (R) cream. These techniques may cause local inflammation and burning at the surface, but fail to remove the underlying putative virus core, and are therefore of little benefit. SELECTED SOURCES de Ruiter A and others. HIV, anal condylomata and anal intraepithelial neoplasia. VII International Conference On AIDS. Florence, June 1991. TuB 86. Ficarra G and GagIioti D. Facial molluscum contagiosum in HIV- infected patients. International Journal of Oral and Maxillofacial Surgery 18(4):200-201. August 1989. Koopman RJ and others. Molluscum contagiosum: a marker for advanced HIV infection. Letter. British Journal of Dermatology 126(5):528-529. May 1992. Petersen CS and Gerstoff J. Molluscum contagiosum in HIV- infected patients. Dermatology 184(1):19-21. 1992. Smith KJ and others. Molluscum contagiosum. Ultrastructural evidence for its presence in skin adjacent to clinical lesions in patients with human immunodeficiency virus type I. Military Medical Consortium for Applied Retroviral Research. Archives of Dermatology 128(2):223-227. February 1992. Thompson CH and others. Clinical and molecular aspects of molluscum contagiosum infection in HIV positive patients. International Journal of STD and AIDS 3(2):101-106. March-April 1992. Williams HR and Webster G. Warts and molluscum contagiosum. Clinics in Dermatology 9(1):87-93. January-March 1991. ***** HUMAN PAPILLOMAVIRUS INFECTION IN WOMEN WITH HIV by Teryl Nuckols Teryl Nuckols is a volunteer for the San Francisco AIDS Foundation and the Shanti Project. She is a graduate of Cornell University, and lives and works in San Francisco. A major cause of morbidity in women with HIV infection is co-infection with the human papillomavirus (HPV), the probable cause of cervical cancer. The Centers for Disease Control (CDC) recently proposed adding invasive cervical cancer, in the presence of HIV infection, to its definition of AIDS. This article will focus on treatment strategies for HPV-related conditions in women co-{nfected with HIV, including anogenital warts, cervical dysplasia and cervical cancer. THE INCIDENCE OF HUMAN PAPILLOMAVIRUS (HPV) Approximately 20% of adults in the general population in the U. S. carry HPV in their bodies. HPV is usually spread sexually, with transmission rates of approximately 6075% between partners. Some studies report HPV infection in women who have never had intercourse, suggesting that sexual activity is not the only means of transmitting HPV. It is unclear if HPV occurs more frequently among women who are HIV positive than among those who are HIV negative. Some sources cite an HPV incidence of 31-95% in HIV positive women, compared to 4-25% in HIV negative women. Another study found a correlation between lower T-helper cell counts and an increased rate of infection with HPV. Other researchers argue that the disparity in HPV infection between HIV positive and HIV negative women may be attributable to socioeconomic factors or behavioral patterns rather than to HIV serostatus. HPV AND CERVICAL CANCER In both the general population and among women with HIV infection, HPV is believed to be a major cause of cervical cancer and, less commonly, cancer of the anus and oral cavities. HPV infection may also cause considerable morbidity among HIV positive men (see article by M. Illeman on page 5 in this issue). Certain strains of HPV cause genital warts (condyloma acuminata), which may progress to precancerous cervical lesions (dysplasia), and ultimately to cervical cancer. HPV strains 16 and 18 are considered most dangerous, while strains 31, 33 and 35 have somewhat lower associated risks. Cigarette smoking and poor nutrition are other risks associated with HPV and cervical cancer. Results of a recent study of women with HPV cervical infection and their male sex partners suggest that HPV may be sexually transmitted (The Lancet, May 1992). None of the men had any penile skin changes associated with HPV during the study period, yet PCR tests detected HPV 16 in the men's semen. Cervical infection is associated with precancerous lesions and cervical cancer. Cervical dysplasia due to HPV occurs with much greater frequency in women with HIV than it does in the general population. It is not known whether precancerous cervical lesions progress more rapidly to cervical cancer in HIV positive women. Research in this area is ongoing. DETECTION OF PRECANCEROUS AND CANCEROUS LESIONS OF THE CERVIX Precancerous lesions of the cervix (squamous intraepithelial lesions) are initially detected by Pap smears, which involve the collection and examination of cells from the opening of the cervix (the os). The reliability of Pap smears is highly variable, however, depending on the screening laboratory. Generally, Pap smear results are 70-80% reliable. There is also a higher rate of false negative Pap smears reported in women who are immunosuppressed, such as women with HIV infection. Pap smears are recommended annually for women in the general population and biannually for those with HIV infection. Pap smears may reveal information about possible abnormal cell growth, but not about the presence or absence of HPV. In order to test for HPV specifically, or to identify the strain of HPV present, the ViraPap test is required. The ViraPap test uses Polymerase Chain Reaction (PCR) techniques to identify minute fragments of HPV DNA in a woman's cervix. If HPV-positive, the specific strain of HPV is then identified by comparing results to HPV genetic codes on file. If a Pap smear suggests the presence of precancerous lesions, colposcopy is immediately recommended. Colposcopy is the examination of cells of the vagina and cervix under magnification, using an endoscope. This procedure allows the physician to identify the location and extent of any lesions. Applying a solution of 5% acetic acid to HPV affected tissue whitens it, making it more visible during the colposcopic examination. Punch or cone biopsies (cervical conization) are recommended when colposcopy confirms the presence of precancerous lesions. Either procedure may be performed at the time of the colposcopy. Punch biopsies remove about 1 square centimeter of cervical tissue, and usually do not require an anaesthetic. If a local anaesthetic is necessary, lidocaine (Xylocaine) is often applied a few minutes before the procedure. Cone biopsy may be appropriate if cervical lesions are large and obvious. During this procedure, a scalpel or laser is used to cut a large cone-shaped wedge out of the bottom of the cervix and around the os. The procedure provides a biopsy for examination and simultaneously removes the lesion. Biopsies performed with a scalpel have the potential disadvantage of narrowing the os, making it more difficult for the woman to carry a child. Extensive hemorrhaging after the treatment occurs in about 5% of women who undergo either laser or cone biopsy. Loop diathermy is occasionally used for the same purpose as cone biopsy. Loop diathermy uses a heated wire loop that seals off blood vessels as it cuts. The site of the biopsy heals much more rapidly with loop diathermy, and the procedure itself is much quicker than other forms of biopsy. TREATMENT FOR WARTS, PRECANCEROUS LESIONS AND CANCER Alpha interferon, a substance the body produces naturally in response to viral and other infections, has been approved for treatment of genital warts, but not for lesions that have been identified as precancerous. The drug is injected into the wart tissue. Other drugs directly applied to warts or precancerous lesions are salicylic acid, podophyllum resin and 5-Fluorouracil (5-FU). Treatment with 5-FU stimulates an immune response and causes an inflammatory reaction. Unfortunately, higher efficacy of treatment with 5-FU is associated with a higher level of discomfort for the patient. In addition, up to 10% of women treated with 5-FU suffer afterwards from persistent vaginal ulcers. If these ulcers do not heal over the course of a few months, they may require surgical excision. Cryotherapy destroys warts, precancerous lesions and cancer by freezing the affected tissue. The instrument used is a metal probe with a cooled tip. Cervical lesions may be treated by insertion of the probe into the os. Cryotherapy can be performed in a doctor's office within 1015 minutes, and usually does not require anaesthesia. Cramping and watery discharge may occur for a few weeks after treatment. Because cryotherapy can also narrow the os, the procedure may make it more difficult for the woman to conceive or deliver a child. Electrocautery, also called electrodesiccation, involves burning away cancerous tissue with a heated metal probe. As with cryotherapy, the procedure can be completed in 10-15 minutes in a doctor's office, provided the lesions are not too extensive. Laser therapy vaporizes lesion tissue, and usually requires only about 10-15 minutes. Hospitalization is sometimes necessary, and local or general anesthesia may be appropriate. All persons in the treatment room during laser therapy must take special precautions, including the wearing of protective goggles by the doctor, nurse and patient. Although laser therapy may produce extensive bleeding, the long-term effects on the cervix are less severe than with other procedures, due to the precision possible with a laser. Laser therapy is most appropriate for smaller precancerous or cancerous lesions. When cervical cancer involves underlying cervical or uterine tissue or other organs, surgery may be recommended. Radiation treatment and other types of drug treatments may also be recommended, particularly if the cancer has spread to the lymph nodes. CLINICAL TRIALS For information on open clinical studies of HPV disease in women, call 1-800-TRIALS-A (1-800-874-2572), Monday through Friday, 9 a.m. to 7 p. m. Eastern Time. SELECTED SOURCES Allen JR and Setlow VP. Heterosexual transmission of HIV. Journal of the American Medical Association 265:2971-2975. 1991. Byrne M and others. The common occurrence of human papillomavirus and intraepithelial neoplasia in women infected by HIV. AIDS 3:39-82. 1989. Carpenter C and Flanigan T. HIV infection in women. AmFAR AIDS/HIV Treatment Directory 5(4):5-10. Spring 1992. Feingold AR and others. Cervical cytologic abnormalities and papillomavirus in women infected with human immunodeficiency virus. Journal of Acquired Immune Deficiency Syndrome 3:896. 1990. Franke-Ruta G. HIV and cervical cancer. Treatment Issues 6(7): 22-25. Summer/Fall 1992. Hayes B. Women and HIV disease: an interview with Constance Wofsy, M. D. Bulletin of Experimental Treatments for AIDS (BETA). 1-6. November 1991. Krown S. Treatment of AIDS-associated malignancy. Cancer Detection & Prevention 14(3):405-409. 1990. ***** GUIDELINES FOR TREATMENT OF HIV INFECTION IN ADULTS NOTE: The appropriate daily dose of these drugs may vary widely from person to person depending on different factors, including drug history, body weight or side effects. Always consult your physician about drug dose and schedule. [Display note: the following table is too wide for most screens, and that is the reason for the apparent jumble. It has been left intact, in the expectation that some callers will want to print it out on a wide printer. You may want to send for the original hardcopy, to the address of the AIDS Foundation, 25 Van Ness, San Francisco CA 94102.] -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- - | | Individual | | | | Drug | Indication | Daily Dose | Toxicity | Monitoring | Comments | -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- - AZT | Less than 500 | 500-600 mg | Anemia. | CBC | First-line treatment. | | T-helper cells or | | Neutropenia. | CPK | Only drug FDA- | | symptomatic | | Myopathy. | | approved for initial | | (e.g. thrush, | | Nausea. | | treatment of HIV. | | neuropathy, | | Lethargy. | | | | unexplained fever) | | Headache. | | | -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- - ddl | AZT failure or | 250-600 mg | Neuropathy. | Amylase. | Second-line | | intolerance | (determined by | Pancreatitis. | Neurological | treatment. Now | | | body weight) | Rash. | exam. | available by | | | | Diarrhea. | | prescription. | -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- - ddC/AZT | AZT monotherapy | 1.12-2.25 mg ddC| ddC: | ddC: | ddC now available | combination| failure | plus | Neuropathy. | Amylase. | by prescription. | | | 500-600 mg AZT | Pancreatitis. | Neurological. | ddC/AZT | | | | Oral ulcers. | exam. | combination is | | | | AZT: | AZT: | FDA-approved. | | | | See above. | see above. | ddC monotherapy | | | | | | not recommended. | | | | No synergistic | | | | | | toxicity observed | | | | | | in early studies. | | | -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- - ddI/AZT | AZT monotherapy | 250-600 mg ddl | No synergistic | Same as for | Experimental | combination| failure | plus | toxicity observed | monotherapy. | | | | 500-600 mg AZT | in early studies. | | | -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- - ***** ON THE MATTER OF SURVIVAL by Donald I. Abrams, MD Donald Abrams is Professor of Clinical Medicine at UCSF, Chairman of the Community Consortium in San Francisco and a member of the FDA Antiviral Advisory Committee. Dr. Abrams has an extensive background in HIV clinical research, including evaluations of new antiretroviral therapies, alternative therapies and therapies to prevent HIV related opportunistic infections. Sometimes I begin to feel like a broken record. It seems like every time I am asked to comment on the results of a clinical trial, I always wind up with the same mantra, "Okay, but what about survival?" At the most recent [October 1992] FDA Antiviral Advisory Committee meeting where rifabutin was ultimately recommended for approval for prophylaxis against Mycobacterium avium Complex infection, one after another of those at the microphone during the open session urged the committee not to focus on survival. So what if there was no difference in survival between patients on rifabutin and those on placebo-the treatment still appeared to have some activity and should be approved. But why, I wondered. Why should we keep loading up people with HIV infection with all these various treatments that are certainly not without toxicities and very likely to interact with each other in the body if they have no impact on the ultimate goal -- the prolongation of life? Am I off base in being so constant in my demand to find therapies that increase survival? When did survival become a dirty word? A lot of paradigms have shifted, as they say, over our first decade of fighting HIV. The movement to reject survival as an endpoint gained momentum back in 1986 upon the early termination of the placebo-controlled AZT trial in patients with AIDS and advanced AIDS-related complex (ARC). In this landmark study, patients receiving AZT benefitted in all possible parameters. Weight and performance status improved, CD4 lymphocyte [T-helper cell] counts rose, even skin test anergy went in the right direction. To top it off, opportunistic infections were significantly reduced in the AZT recipients. The clincher, of course, was the lopsided "body count." Nineteen placebo recipients died prior to study termination compared to only one patient receiving AZT. With all of the other clues that the drug was beneficial, how could any ethical investigator wait for such an imbalance in mortality to stop the trial and make the drug available to all? And yet, this is the study which demonstrated that AZT prolonged survival, and it is cited in all subsequent literature as the one trial to conclusively demonstrate that advantage. The authors (Fischl, et al.) of that pivotal study remarked that "these data demonstrate that AZT administration can decrease mortality and the frequency of opportunistic infections in a selected group of subjects with AIDS or AIDS-related complex, at least over the 8 to 24 weeks of observation in this study" (my emphasis). Does a decrease in mortality automatically translate into the prolonged survival that the trial has been credited with demonstrating? The population of patients with AIDS enrolled in the study had experienced a first episode of Pneumocystis carinii pneumonia within the previous 120 days. Only 10% of those enrolled completed the intended 24 week trial; the mean duration of participation was 120 days. Therefore, the AIDS patients enrolled had received initial diagnoses of PCP only 4-8 months prior to the end of the study. Eighteen more patients in the AZT-treated cohort reached this landmark, compared to the placebo group. In 1986, the average life span of a patient in San Francisco after PCP diagnosis was 13.2 months, making it a bit premature to truly claim survival prolongation on the basis of this study alone. Decreased mortality, yes, during the 8 to 24 weeks of observation -- but prolonged survival? At least to me, that still remained to be proven. Following termination of the placebo-controlled part of this milestone study, numerous updates on how the cohort was faring, as well as reports on the aggregate experience of patients on the treatment IND, seemed to support improved survival -- but the gold standard of the controlled clinical trial as the yardstick was absent. Moving clinical trials into patients in earlier stage(s) of disease helped to take the heat off the survival endpoint issue. When ACTG 016 and ACTG 019 evaluated populations with mildly symptomatic ARC or totally asymptomatic disease, evidence of activity of drug compared to placebo was apparent way before any significant number of deaths occurred. Benefits with regard to CD4 cell increases and decreased disease progression were significant in ACTG 016 after a mean duration of 9 months of treatment; only 2 of the 711 patients enrolled had died. The same benefits were appreciated in the 1,434 asymptomatic patients with CD4 cell counts <500/mm3 enrolled in ACTG 019 after a mean of 55 weeks of follow-up. The authors (Volberding, et al.) cautioned, however: "it is possible that even if AZT persistently delays the onset of AIDS, it may not have an ultimate effect on survival." To many that would seem counterintuitive. How could disease progression be forestalled without prolongation in survival? The concept of disease-free survival is well known to the oncologist. In October 1991, I spent a week at an oncology review course at Harvard. Although I am a certified cancer specialist, I spend most of my time being an AIDSologist, so I figured a little brushing up on what was new in the world of cancer medicine couldn't hurt. That's when I had a revelation. For 5 days, 8 hours a day, I sat in an auditorium hearing lecture after lecture about treatment of every different type of cancer -- lung, stomach, colon, breast -- all of them. In each case, there are many different therapies available -- either single modality or combinations of chemotherapy, radiation and/or surgery. And day after day, slide after slide of survival curves were flashed on the screen. Many treatment options were shown to be able to shrink the tumor -- for a time, that is. But, if these new therapies did nothing when compared to the old therapy, or to no therapy, to prolong overall survival, they are most often cast aside, and felt to be of little therapeutic value. As a medical specialty, oncology is a new field. Although still in its infancy, oncology has made great strides in curing some malignancies and in significantly prolonging survival in others. Much of this progress has come at the cost of relinquishing treatments that are not impacting overall survival. The much maligned study of early versus late antiretroviral therapy conducted by the Veterans Administration further confuses the survival issue in patients with HIV disease. This study in patients with symptomatic ARC followed 338 patients for just over 2 years. Those assigned to early treatment received AZT immediately, while the late treatment group received placebo until their CD4 count dropped below 200/mm3 or until they developed an AIDS defining event. Once again, although disease progression was halved in the early treatment group, overall survival was the same. Patients on the early treatment arm tended to develop more AIDS-related events in a shorter time than those who were in the late treatment group. Granted, many would prefer to have a longer period of disease-free survival to enjoy and, hopefully, to suffer less once an AIDS-defining event has occurred, but it still seems disappointing that benefits in CD4 count increases and disease progression decreases are not translating into prolonged survival. Are these laboratory and clinical markers accurate substitutes? Can they serve as surrogates for survival in studies of therapies for HIV infection? Obviously, these are difficult questions that will not be answered here and now. But it is worth noting, as more and more antiviral agents are approved early in their development, that it will take some time for us to determine what they really do and when best to use them. The more we use currently available treatments in wider populations and the more we try to correlate the emergence of viral resistance to clinical outcome, the more unclear we become about appropriate treatment strategies. In a recent review entitled "Zidovudine [AZT]: Five Years Later," the authors (McLeod and Hammer) remind us that "the effects of early therapy on survival and the optimal time to initiate therapy remain controversial" even for "the cornerstone of antiretroviral therapy." It is certainly difficult, and a bit unsettling, to face the uncertainties that still remain in the field of treatment of HIV infection. Most of us would feel much more comfortable if there were more absolutes and fewer questions. Progress has been made, and will continue to be made in the upcoming years. But we really must face the critical issue and not pooh-pooh survival in favor of modest transient increases in CD4 counts, or even significantly decreased short-term disease progression. The ultimate progression of HIV disease, unfortunately, continues to be towards death as an endpoint. At a recent meeting, I discovered a number of people wearing lapel buttons extolling, "All I Want Is The Cure And My Friends Back." Wouldn't we all! But with just a little more reality testing, we should be demanding treatments that will prolong survival. I, for one, don't think we should settle for less! ***** IS IT POSSIBLE TO PROVE A SURVIVAL BENEFIT FROM EARLY TREATMENT? by Paul A. Volberding, MD Paul Volberding is Professor of Medicine at the University of California, San Francisco, Chief of the AIDS Program and Clinical Oncology Division at San Francisco General Hospital and Director of the Center for AIDS Research in San Francisco. He is the most recent past-President of the International AIDS Society. Dr. Volberding is actively involved in the provision of care to people with AIDS and undertakes clinical research in the treatment of HIV infection and Kaposi's sarcoma. Prolonging the survival of people with HIV disease is undoubtedly the primary objective of all of our efforts in developing and testing new drugs and new drug combinations. This is true whether we are considering the treatment of HIV infection itself or the prophylaxis or therapy for HIV-related infections and malignancies. Ideally, each element in the overall treatment strategy for a patient would prolong survival without interfering with the benefits of other treatments. Also, each new treatment would show an ability to prolong survival compared with the drug it sought to replace. Finally, such information could be collected in an efficient and timely research effort that was ethical and attractive to both patient and physician. In a practical world, however, many ideals are impossible to achieve, and compromises must be made. In HIV disease, for example, it has proven increasingly difficult to expect clinical trials to demonstrate an overall survival advantage. HIV therapy is a complex field with long-term therapeutic strategies that involve not just the use of one treatment, but many. Furthermore, the long course of HIV disease makes it difficult to identify the end results of therapies applied early in the disease, since it is impossible to control all of the treatments used in later disease stages. Because subsequent therapies might substantially alter the course of disease and affect survival, it may be impossible to demonstrate a survival advantage of an early treatment strategy, even if this advantage were real and substantial. Another significant difficulty in trying to identify the survival advantage of a given therapy centers on ethical perceptions of the patient and the physician. If, for example, a clinical trial demonstrates that a new drug is more successful in controlling CMV retinitis than a previous drug, or that an antiretroviral treatment is more effective in preventing progression of clinical disease than placebo, is it fair to require volunteers to continue to take placebo or the inferior drug in order to demonstrate differences in overall death rates? Also problematic is the issue of quality of life. If one treatment is more effective than another, but also more expensive, more toxic or more difficult to administer, how do we judge which treatment is truly superior? Even in the field of oncology, where questions of clinical trial endpoints have long been debated, consensus is lacking. While there, too, survival is the goal, many drugs approved and commonly used drugs have demonstrated a superiority in tumor response alone, without providing a clear survival benefit. In oncology and in AIDS, questions of quality of life are also extremely important. In both fields, treatments are often complex, toxic and incapable of curing the disease process. Perhaps some sense of direction can be provided by the oncologists' experiences. Here, a commonly used endpoint of clinical trials is what is termed the "disease-free survival," the interval from the response of the tumor to treatment until relapse. While there is rarely anything in HIV that we could call a "complete remission," perhaps a period free of opportunistic infection recurrence or of other pre-defined symptoms of disease progression might suffice. If so, the AIDS literature in clinical trial experience is not quite so bad. Numerous clinical trials have certainly demonstrated a decrease in the relapse of specific opportunistic infections following initial therapy or a delay in onset with prophylaxis or a delay in disease progression with the use of antiretroviral drugs. Benefit in "disease free survival," while not meeting the gold standard of overall duration of survival, may be a more satisfactory compromise, especially if combined with measures of quality of life. Other options also exist. In some situations, for example, the so-called large, simple trial design may be able to provide information on survival. In these trials, particularly if nontoxic and easily administered therapies are used, survival can be the primary study endpoint. Such trials involve very large groups of volunteers with a small amount of data collected from each patient. Another approach is to analyze the treatment experience of ongoing epidemiologic studies to compare the survival in those receiving a given treatment versus those not receiving that treatment. Although subject to many biases, such information may, when combined with clinical trial results, increase our confidence in survival benefits. The real answer is that all of the above approaches must be used in HIV disease. For new agents and combination treatment regimens, smaller trials focused on laboratory or disease progression endpoints will still be required. In other settings, large, simple trials or epidemiologic analysis may be more feasible. Hopefully, we can resist any inclination to repeat all of our previous trials, as the limitations in their design are likely to continue in future research as well. ***** AIDS CLINICAL TRIALS INFORMATION SERVICE Need the latest information on clinical trials for HIV and AIDS? Call the AIDS Clinical Trials Information Service: (1-800-874-2572) Monday through Friday, 9 a.m. to 7 p. m. eastern time. * Free up-to-date information about more than 200 federally and privately sponsored HIV and AIDS clinical trials and the drugs used in the trials. * Personalized assistance from English- and Spanish-speaking health specialists. * TTY/TDD access: 1-800-243-7012. A service of the U. S. Department of Health and Human Services, Public Health Service. The Centers for Disease Control, Food and Drug Administration, National Institute of Allergy and Infectious Diseases, and National Library of Medicine have collaborated to provide this service. ***** RESEARCH NOTES by Ronald A. Baker, PhD Ronald Baker is editor of BETA and co-author of Early Care for HIV Disease, a book for people living with HIV infection. ==== MAC Prophylaxis Drug Recommended for Approval The FDA AntiviraI Drug Advisory Committee on September 24 recommended approval of rifabutin (Mycobutin) to prevent Mycobacterium avium complex (MAC) in people with advanced HIV disease. The FDA almost always follows the recommendations of this committee, and the drug should be available by prescription before the end of the year. Mycobutin is currently available free through an expanded access program (Treatment IND) to HIV positive individuals with fewer than 200 T-helper cells. To enroll patients, physicians may call the drug's manufacturer, Adria Laboratories, at 800-552-7228. MAC organisms are found almost everywhere in the environment (in dust, soil and water), and pose no threat to individuals with normal immunity. In PWA, however, MAC may cause wasting syndrome, a condition characterized by fatigue, severe diarrhea, persistent fever, night sweats and weight loss. MAC infects about 25% of all PWA within 21 / 2 years following their diagnosis. Although studies suggest that Mycobutin may lower the number of colonies (counts) of MAC, and may delay the onset of the disease, the drug does not appear to improve survival. Side effects of Mycobutin may include fever, headache, rash, gastrointestinal disorders and joint and muscle pain. It is unlikely that any single agent currently available can completely prevent MAC or effectively treat the disease. Antibiotics such as rifabutin (Mycobutin), rifampin (Rifadin, etc.) , ethambutol (Myambutol), clarithromycin (Biaxin), azithromycin (Zithromax) and ciproflaxin (Cipro) have been used in various combinations to reduce MAC symptoms, but thus far, no combination regimen has eradicated the infection. Bouract-Letarte H and others. Clinical tolerance of daily oral rifabutin, an investigational antimycobacterial drug, in AIDS patients. VIII International Conference on AIDS. Amsterdam, July 1992. PoB 3146. Gordin F and others. Rifabutin monotherapy prevents or delays Mycobacterium avium complex (MAC) bacteremia in patients with AIDS. VIII International Conference on AIDS. Amsterdam, July 1992. PoB 3081. Siegel F P and others. Clinical manifestations of M. avium complex (MAC) bacteremia in patients with AIDS. VIII International Conference on AIDS. Amsterdam, July 1992. PoB 3256. Sullivan P and others. Safety profile of rifabutin for the prevention of M. avium complex (MAC) bacteremia in patients with AIDS and CD4 <200. VIII International Conference on AIDS. Amsterdam, July 1992. PoB 3265. ==== D4T: Promising Anti-HIV Drug Available Through Parallel Track The FDA on October 4 approved use of the new anti-HIV drug d4T (stavudine) in people with AIDS who are intolerant to or fail on AZT and ddI. Individuals who qualify can receive d4T free from Bristol-Meyers Squibb through their physicians. d4T is the first drug to become available through the new FDA "parallel track" program, which makes certain experimental drugs available to people with limited treatment options, even while the drug is still under study in clinical trials. Individuals enrolled in this double-blinded, parallel track program will take either "high" or "low" doses of d4T, according to the following schedule: Body Weight Dose 132 lbs or greater 20 mg or 40 mg twice a day 88-131 lbs 15 mg or 30 mg twice a day 87 lbs or less 10 mg or 20 mg twice a day Physicians may enroll patients by calling Bristol-Meyers Squibb and requesting registration kits and applications (1-800- 842-8036). People who want general information about d4T may call this same toll-free number 8:30 am -- 5:00 pm Eastern Time. d4T belongs to the same family of drugs as AZT, ddI and ddC (nucleoside analogues). Like these compounds, d4T inhibits HIV replication by stopping the production of the reverse transcriptase enzyme of HIV. The virus needs to produce this enzyme in order to replicate. d4T is not a cure for HIV disease, and although the drug can prevent HIV infection of uninfected cells, it has no effect on cells already infected with the virus. Early studies show that people with AIDS taking d4T experience T-helper cell increases (20-50%), significant declines in p24 antigen levels and weight gain. d4T crosses the blood- brain barrier, an important advantage of the drug for people with HIV-related neurological abnormalities. The body absorbs d4T well, and the drug can be taken with or without food. There are overlapping and different side effects of the nucleoside analogue drugs. As with ddC and ddl, the dose- limiting toxicity ofd4T is peripheral neuropathy (PN). For this reason, combining d4T with either ddC or ddI would not be advisable, since both these drugs may also cause PN, according to Bristol-Meyers Squibb. The company also recommends against combining c14T with AZT. d4T interferes with the mechanism of action of AZT in a way that might significantly reduce the effectiveness of both drugs, according to a spokesperson for Bristol-Meyers Squibb. Several drugs currently in development, such as 3TC and the TAT and proteinase inhibitors, may be excellent candidates for combination with d4T, but these compounds are currently available only to individuals enrolled in clinical trials of these drugs. HIV positive individuals interested in participating in a clinical trial comparing the effectiveness and safety of d4T to AZT may call 1-800TRIALS-A for trial site locations and for inclusion and exclusion information. Cimons M. Wider use of new AIDS drug foreseen. The New York Times. September30, 1992. A-19. Yaren SJ and Sigler EM. Bristol-Meyers Squibb makes experimental AIDS drug d4T available to patients in critical need. Press release from Bristol-Meyers Squibb Company. August 26, 1992. ==== ddI (Videx) Approved For Broader Use The FDA has broadened the licensing of ddI to include its use by adults with advanced HIV disease who have received prolonged AZT treatment (more than 16 weeks). When the FDA first approved ddI in October 1991, the agency restricted the drug's use to individuals intolerant to or failing AZT treatment. Results of a recent study (ACTG 116B/117) suggest that individuals who have taken AZT for 4 months or longer benefit more from switching to ddI (500 mg/day) than from continuing AZT. (For more details about this study, see BETA. August 1992. 1.) The results of trials evaluating the use of ddI plus AZT compared to ddl monotherapy and AZT monotherapy are expected by the end of 1992. The latter study may show whether ddI is superior to AZT as first-line treatment in people with little or no prior AZT therapy. For a complete review of ddI toxicity, dosing, drug interaction and information on financial assistance programs, see BETA. November 1991.28-30. Yarin SJ and Sigler EM. Bristol-Meyers Squibb's Videx [ddl] approved by FDA for broader use. Press release from Bristol- Meyers Squibb Company. New York. September 28, 1992. Baker RA. FDA approval of ddl (Videx). Bulletin of Experimental Treatments for AIDS (BETA). November 1991.28-30. ==== Mepron: New Second-Line Treatment for PCP The FDA Antiviral Advisory Committee on September 24 recommended approval of the Burroughs Wellcome antimicrobial drug Mepron (a.k.a. atovaquone, 566, 566C, 566C80). The committee recommended the drug as second-line treatment for mild to moderate PCP in individuals who cannot tolerate or fail on trimethoprim-sulfamethozaxazole (TMP-SMX), more commonly known by the brand names Septra and Bactrim. TMP-SMX is the preferred therapy for preventing PCP and for the treatment of acute disease, but many HIV positive individuals cannot tolerate the drug's sometimes severe adverse effects, even after rechallenging. Mepron offers an effective and less toxic option for these individuals. The side effects of Mepron may include headache, nausea, diarrhea, rash, fever and elevated liver enzymes. The FDA advisory committee noted that Mepron may not be appropriate for individuals with chronic gastrointestinal disorders that cause persistent diarrhea. The drug has a low bioavailability that increases when it is taken after eating food high in fat. Mepron may also be used as secondary prophylaxis against recurrent PCP in TMP-SMX intolerant individuals. Mepron also shows strong activity against Toxoplasma gondii, the organism that causes toxoplasmosis. Until Mepron becomes available by prescription, physicians may obtain the drug free for their patients with mild to moderate PCP who cannot tolerate or fail on TMP-SMX by calling Burroughs Wellcome 1-800755-2020. The line is open 24 hours daily to accommodate emergency registration. Bartlett KS. FDA advisory committee recommends approval of atovaquone [Mepron] as treatment for PCP. News release from Burroughs Wellcome Company. September 24, 1992. Hughes WT. A new drug [Mepron] for the treatment of Pneumocystis carinii pneumonia. Annals of Internal Medicine 116(11):953-954. June 1, 1992. Ingersoll B. FDA panel backs approval of AIDS drug. Wall Street Journal. September 25, 1992. B-12. ==== Proposed New AIDS Definition After months of equivocation, the U. S. Centers for Disease Control (CDC) has proposed expanding the definition of AIDS. The proposed new definition, scheduled for implementation in January 1993, would add 3 illnesses -- cervical cancer, pulmonary tuberculosis and recurrent pneumonia -- to the list of diseases that, in the presence of HIV infection, comprise an AIDS diagnosis. In addition, if an HIV positive individual has 200 or fewer T-helper cells, he or she would receive a diagnosis of AIDS, regardless of the presence of any AIDS-associated disease. ==== Trimetrexate for PCP At the Amsterdam AIDS Conference, Dr. Judith Feinberg of Johns Hopkins University presented results of the Treatment IND study of intravenous trimetrexate in combination with Leucovorin for the treatment of PCP. For individuals who cannot tolerate or fail standard PCP treatments (Bactrim, I.V. pentamidine), trimetrexate is an effective alternative. The drug's toxicity is primarily hematologic (neutropenia, thrombocytopenia). These adverse effects become readily manageable by changing the dose schedules of trimetrexate and leucovorin, according to Dr. Feinberg. Work is underway on an oral formulation of the drug. Feinberg J and others. Trimetrexate salvage therapy for PCP in AIDS patients with limited therapeutic options. VIII International Conference on AIDS. August 1992. PoB 3297. ==== Oral Prednisone Therapy For Esophogeal Ulcers A majority of HIV positive individuals with esophogeal ulcers of unknown cause appear to benefit from treatment with oral prednisone, according to the results of a small study at Emory University School of Medicine. Researchers evaluated the effects of a daily oral dose of 40 mg prednisone (tapering to 10 mg / week) for 1 month in 12 individuals. Ten had an AIDS diagnosis. Within the first week of therapy, 11 of the 12 study participants (92%) had a complete resolution of symptoms. Difficulty swallowing (dysphagia) was the most frequently presenting symptom. Wilcox CM and others. A pilot study of oral corticosteroid therapy for idiopathic esophageal ulcerations associated with human immunodeficiency virus infection. American Journal of Medicine 93(2):131-134. August 1992. ==== Sinusitis and HIV Infection Two recently published studies suggest that individuals with advanced HIV disease commonly develop sinusitis, especially those with fewer than 100 T-helper cells. Sinusitis is an inflammation or infection of the sinuses, cavities in the skull bone that contain air and communicate with the nostrils. Both studies report that sinusitis in individuals with HIV infection is often severe and difficult to treat. Typical symptoms include mucosal thickening, fever, nasal congestion or discharge and headache. The mean T-helper count in one study was 276. 43% of the group (32 people) had T-helper counts below 100. Only 31% (23 people) received antibiotic treatment for their sinusitis. CT or MRI scans helped researchers diagnose posterior sinus involvement in some individuals that went undetected by radiography. Researchers said their data reveal that sinusitis is a frequent problem in individuals with HIV-infection. They call for larger studies to determine: (1) the true incidence of sinusitis among HIV positive individuals; (2) the precise association of sinusitis with immunosuppression; (3) the appropriate drug treatment and the proper course of therapy; and (4) the role of surgery. Although we know of no controlled studies on the incidence of sinusitis in individuals taking TMPSMX (Bactrim, Septra, etc.), anecdotal reports suggest a reduced incidence of this infection among individuals taking the drug for prevention of PCP. Godofsky EW and others. Sinusitis in HIV-infected patients: a clinical and radiographic review. American Journal of Medicine. (93)2:163-170. August 1992. Zurlow JL and others. Sinusitis in HIV infection. American Journal of Medicine 93(2):157162. August 1992. ==== Cytokine Effects on HIV Replications and on the Anti-HIV Activity of AZT, ddC and ddI Several studies have shown that recombinant (genetically engineered) granulocyte macrophage colony stimulating factor (GM-CSF) stimulates HIV replication, but that this cytokine also enhances the anti-HIV effect of AZT. A recent laboratory study looked at the effects of other bone marrow stimulating cytokines on HIV replication and their effect on the anti-HIV activity of AZT, ddC and ddI in monocyte/macrophages (white blood cells). The researchers reported the following results: (1) Like GM-CSF, macrophage-CSF(M-CSF) stimulated HIV replication. (2) Granulocyte CSF (G-CSF) and erythropoietin (EPO) did not stimulate HIV replication. These 2 recombinant cytokines are frequently used to alleviate the anemia and neutropenia, respectively, associated with AZT treatment. (3) GM-CSF increased the anti-HIV effect of AZT. (4) M-CSF did not influence the anti-HIV activity of AZT. (5) M-CSF and GM-CSF had a slightly diminishing effect on the anti-HIV activity of ddC and ddI. Perno C. Effects of bone marrow stimulatory cytokines on human immunodeficiency virus replication and the antiviral activity of dideoxynucleosides in cultures of monocyte/ macrophages. Blood 80(4):995-1003. August 15, 1992. ***** A REVIEW OF THE EPIDEMIOLOGY OF KAPOSI'S SARCOMA (KS) The cause(s) of AIDS-related Kaposi's sarcoma remain unknown 11 years after clinicians first noted its presence among gay white males in New York and California. The almost exclusive confinement of KS cases in certain HIV positive gay or bisexual men is puzzling to researchers. Epidemiologists have proposed 3 major theories to explain the occurrence of KS in HIV-infected individuals: (1) a strain of HIV causes KS; (2) another infectious agent acts as a cofactor (e.g., mycoplasma); and (3) an environmental agent (e.g. inhalant nitrites) acts as a co-factor. The first theory has been disproven. The remaining 2 theories have sufficient evidence to support them so that neither one can be rejected. ==== KS and Inhaled Nitrites (Poppers) Why do researchers continue to look at nitrites as a possible co-factor for developing KS? For one, despite extensive research, no sexually transmitted agent has been identified as the cause of KS. In addition, the pattern of the AIDS-associated KS epidemic does not fit that of any other sexually transmitted disease (STD). All STD epidemics in the U. S. are prominent among urban African Americans and Hispanics. In contrast, KS is most prominent among middle-class white gay and bisexual males. Several studies published from 1985-1989 have found a strong association between popper use and the development of KS (see references below). Other studies have found no such association, including a 1990 study by Alan Lifson and other researchers who examined KS in men enrolled in the San Francisco City Clinic Cohort Study. A small study published in 1991 concluded that nitrite inhalation frequently affected lymphocyte (white blood cell) function in HIV negative men. The researchers also noted that popper use "causes cycles of modest immune suppression, followed by gradual recovery when the drug is not inhaled for several days." ==== KS and Insertive Rimming Professor Valerie Beral of Oxford has suggested that fecal- oral contact in insertive rimming is the main route of transmission for the causative agent of KS among gay men. However, the Sydney AIDS Prospective Study, a cohort of 1,075 gay and bisexual men, found no significant difference between the proportion of men with and without KS who practiced insertive rimming. The AIDS-related KS agent or cofactor may be sexually transmitted. The highest rates are observed in gay/bisexual men with HIV. The second highest rates are in the HIV positive female sex partners of bisexual men. In further decreasing order of frequency, AIDS-related KS has also been observed in injection drug users, people who received blood transfusions before 1985 and people with blood clotting disorders, including hemophiliacs. ==== KS and Human Papillomavirus (HPV) Two reports in the February 1992 issue of The Lancet suggest an HPV association with HIV-related KS, non HIV-related KS in gay men, and with classical, non-AIDS-related KS in elderly men and women (see BETA, May 1992. 24). To confirm these findings, Robert Biggar and colleagues examined tissue from 14 individuals with KS who resided in widely separate geographic areas. The researchers found no evidence of HPV in any of the KS samples. Polymerase Chain Reaction (PCR) tests were all negative for any trace of HPV. Archibald CP and others. Evidence for a sexually transmitted cofactor for AIDS-related Kaposi's sarcoma in a cohort of homosexual men. Epidemiology 3(3):203-209. May 1992. Baker RA. New studies on Kaposi's sarcoma. BETA, May 1992. 25- 26. Beral V and others. Risk of Kaposi's sarcoma and sexual practices associated with faecal contact in homosexual and bisexual men with AIDS. The Lancet 339:632-635. March 14, 1992. Beral V and others. Kaposi's sarcoma among persons with AIDS: a sexually transmitted infection? The Lancet 335:123-128. 1990. Dax EM and others. Amyl nitrite alters human in vitro immune function. Immunopharmacology and Immunotoxicology 13(4): 577587. 1991. Friedman-Kien AE and others. Kaposi's sarcoma in HIV negative homosexual men. The Lancet 335:168-169. 1991 Haverkos HW. Nitrite inhalant abuse and AIDS-related Kaposi's sarcoma. Journal of Acquired Immune Deficiency Syndrome 3(1):54750. 1990. Haverkos HW and others. Disease manifestation among homosexual men with acquired immunodeficiency syndrome: a possible role of nitrites in Kaposi's sarcoma. Sexually Transmitted Diseases 12: 203-206. 1985. Haverkos HW. Epidemiologic studies -- Kaposi's sarcoma vs. opportunistic infection among homosexual men with AIDS. In Health Hazards of Nitrite Inhalants. NIDA Research Monograph 83. Ruckville, Maryland. U. S. Dept. of Health and Human Services. 1988. Huang YQ and Friedman-Kien AE. HPV-16 related DNA sequences in Kaposi's sarcoma. The Lancet 339:515-518. February 29, 1992. Lowy DR and Ju WD. Pathophysiology of cutaneous viral infections: papilloma virus. In Pathophysiology of Dermatologic Diseases. New York. McGraw-Hill. 441-452. 1991. Nickoloff BJ, Huang YQ and Friedman-Kien AE. Immunohistochemical detection of papillomavirus antigens in Kaposi's sarcoma. Letter. The Lancet 339:548. February 29, 1992. ==== Combination Treatment for CMV The combination of ganciclovir (Cytovene) and Foscarnet (Foscavir) appears to have a synergistic effect, and is more effective against CMV retinitis than either agent used alone, according to results of a Phase I study at San Francisco General Hospital. The combination of Cytovene and Foscavir at lower doses also produced less toxicity than when each drug was used alone at a higher dose. In the UCSF study, 27 people with CMV retinitis were assigned to 1 of 2 groups, after first taking intravenous Cytovene for 2 weeks. Those in the first group took Cytovene and Foscavir together. The second group took each drug separately on alternate days. Those taking the 2 drugs together used lower doses than individuals in the second group. Researchers found that people in the group taking the drugs on alternate days showed a slightly better response. "With both combination regimens, there is less Foscavir toxicity than when we use Foscavir alone and in higher doses," said Mark Jacobson, principal investigator of the UCSF study. Adverse side effects from the use of Cytovene may include severe neutropenia. Foscavir may cause a severe kidney toxicity and nausea. Jacobson M. Combination treatment with ganciclovir and Foscarnet for CMV retinitis. Annual Meeting of the American Society for Microbiology. Anaheim, CA. October 14, 1992. Trinkl A. Combined drug treatment looks promising for treatment of CMV retinitis. Press release from SFGH/UC San Francisco News Service. October 12, 1992. ==== Promising Preliminary Results of Passive Immune Therapy Dr. Joshua Levy presented preliminary results of a 12-month, double-blinded, controlled trial of passive hyperimmune therapy (PHT) at the 5th National AIDS Update Conference held in San Francisco on October 9, 1992. Dr. Levy maintains that the study results show that PHT stabilized T-helper counts and improved survival in individuals who started treatment with a T-helper count of at least 50 (see chart below). PHT did not benefit people who entered the study with fewer than 50 Thelper cells. PHT involves receiving monthly infusions of plasma with high levels of anti-HIV antibodies (p24 antibodies) derived from HIV positive, asymptomatic individuals. All 219 study participants were also taking antiviral drugs, including AZT, ddC, ddI or combinations of these treatments, as well as prophylaxis for opportunistic infections. Individuals in the study were randomized to 3 groups. The first group received 500 cc of plasma; the second group received 250 cc of plasma plus 250 cc of 5% albumin; the third group received 500 cc of 5% albumin as placebo. The table below summarizes study results, which suggest a dose related survival benefit and stabilization of T-helper cells in the 2 groups receiving PHT. ==== Results of PHT for Individuals with 50-200 T-helper Cells over 12 months. (n=number of participants) 500 cc plasma 250 cc plasma 500 cc albumin Deaths 1 (5%) 3 (16%) 5 (21%) n=20 n=18 n=24 T-helper cell -2% -25% -35% changes n=20 n=18 n=24 These results have not yet been published and therefore should be viewed as preliminary. After further data analysis, HemaCare Corporation, the manufacturer of PHT, will submit an application to test PHT in up to 1,000 individuals (Phase III Investigational New Drug). ==== Advances in the Use of Polymerase Chain Reaction (PCR) Technology Both the reliability of PCR testing and its practical applications have expanded dramatically since BETA first reported on its use in 1989 as a diagnostic tool in the context of HIV infection. PCR is fast emerging as a revolutionary and powerful new method for detecting infectious diseases, and may also soon become a significant tool in guiding the course of treatment for HIV infection and other diseases. PCR is an extraordinarily simple, sensitive and fast technique that can detect minute genetic fragments (DNA) and amplify them so that researchers can identify the source. Within a few hours, source DNA can be amplified a billionfold so that scientists can recognize it. The ability of the PCR test to directly identify DNA independent of an antibody response means that an infectious agent, such as a virus or other microorganism, can be identified from blood or tissue samples before any signs of disease develop. A potential benefit of early identification of a pathogen is earlier treatment. PCR has several important potential applications to HIV disease, including the ability to identify the virus in infants born to HIV positive mothers, in people with indeterminate HIV status and in health care workers who may be infected from HIV- contaminated needles or other instruments. PCR can quickly determine whether HIV infection has indeed occurred in these situations. In the near future, PCR may also be used routinely to determine HIV "viral load" in HIV positive individuals. This information can then be used to decide when to begin antiviral treatment, or to determine whether a particular drug is working well against HIV (or some other pathogen). Thus, PCR potentially could become a significant tool in selecting the timing and type of treatment appropriate for individuals with HIV infection, as well as helping to monitor the effectiveness of a particular treatment regimen. The rapid detection of M. tuberculosis is now possible using PCR. This new PCR test, available from Roche Biomedical Laboratories, can detect as many as 13 different species of Mycobacteria. Because results can be available within 48 hours of specimen receipt in the laboratory, the PCR test enables clinicians to rapidly diagnose and treat new cases of tuberculosis, rather than waiting weeks for the results of traditional laboratory tests for the disease. PCR tests have also been developed recently for determining human papillomavirus (HPV) in clinical specimens. ==== Available PCR Tests for the Diagnosis of Infectious Diseases * Human immunodeficiency virus (HIV) types 1 and 2 * Human T-celllymphotrophicvirus(HTLV) types I and II * Cytomegalovirus (CMV) * Borrelia burgdorferi (Lyme disease) * Mycobacterium * Papillomavirus * Hepadnavirus * Adenovirus * Herpes simplex virus * Human parvovirus * Hepatitis A, B, C and delta * Clostridium difficile * Typhus * Enterotoxigenic Escherichia coli * Legionella pneumophila * Trypanisoma cruzi * Toxoplasma gondii The above tests are not equally sensitive and specific. In addition, not all PCR tests (e.g. CMV) are useful for making a clinical diagnoses. In the case of CMV, diagnosis is based on tissue biopsy or a particular clinical appearance (e.g. retinitis). ***** THE 32ND INTERSCIENCE CONFERENCE ON ANTIMICROBIAL AGENTS AND CHEMOTHERAPY: SUMMARY OF AIDS-RELATED PRESENTATIONS The following are summaries of selected oral and poster sessions presented by researchers at the 32nd Interscience Conference held October 11-14 in Anaheim, California. The Conference was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). ==== AZT and Clarithromycin Interaction Physicians who prescribe the antibiotic clarithromycin (Biaxin) and AZT (Retrovir) to their HIV positive patients may want to modify the dosage schedule. In a study of 22 individuals, researchers found that clarithromycin (commonly used to treat MAC) may interfere with the absorption of AZT when the 2 drugs are taken at the same time. The investigators found that clarithromycin will not interfere with AZT absorption if it is taken 4 or more hours earlier than AZT. "Pharmacokinetic Assessment of Clarithromycin plus Zidovudine [AZT] in HIV-infected Patients." Petty B and others. #24 Oral. ==== Immediate Use of High Dose AZT in Early HIV Infection A study of macaque monkeys infected with simian immunodeficiency virus (SIV) suggests that immediate and consistent use of high dose AZT may be effective in treating early HIV infection. Higher, less frequent AZT doses were as or more effective than smaller, more frequent doses. In humans, the currently recommended dose and schedule is 200 mg 3 times a day. "Effect of Dosing Frequency on AZT Prophylaxis Against Simian Immunodeficiency Virus (SIV) in Macaca foscicularis." Che-Chung Tsai DVM and others. #58 Oral. ==== Low T-Helper Cell Counts Predictive of Survival The differences in survival among HIV positive individuals with 100 or fewer T-helper cells are significant, and have relevance for the design of clinical trials. Researchers followed 923 HIV positive individuals for 1 year. They noted a significant variation in death rates during this time, ranging from 14.6% among 94 people with 81-100 T-helper cells to 35.1% of 378 people with 20 or fewer Thelper cells. "Very Low CD4 [T-Helper] Counts -- Are They Meaningful?" Sacks LV and others. #595 Oral. ==== Clarithromycin Effective Against MAC The antibiotic clarithromycin (Biaxin) is a very active agent against the bacterial infection Mycobacterium avium complex (MAC). However, resistance to the drug may develop, and to treat active MAC effectively, clarithromycin should be used in combination with other drugs commonly used to treat the infection. The highest doses used in the study (2,000 mg clarithromycin twice daily) was the most effective dose, but also produced the most adverse side effects, primarily gastrointestinal distress and diarrhea. "Clarithromycin Therapy for Disseminated Mycobacterium avium Complex (MAC) in AIDS." Chaisson RE and others. #891 Oral. ==== Reverse Transcriptase Antibodies Help to Prevent and Treat Disease Antibodies to the reverse transcriptase, an enzyme needed by HIV to replicate, may be useful as a marker for HIV disease progression. In a study of 52 gay men, researchers found that as the levels of reverse transcriptase antibodies increase, the number of HIV-infected cells decline. In addition, only 25% of the men with the highest number of HIV-infected cells had this antibody, compared to 100% of the men with a low number of HIV- infected cells. The investigators concluded that the reverse transcriptase antibody may be protective against HIV infection. "Correlations Between Reverse Transcriptase Inhibiting Antibody and Low Numbers of HIV-I Infected Cells." Javier BJ and others. #1347 Poster. ==== Intraconazole Safe and Effective Drug for Histoplasmosis The antifungal drug itraconazole is a safe and effective alternative to amphotericin B as a treatment for mild to moderately severe histoplasmosis, a fungal disease commonly found in people with AIDS. Study participants with histoplasmosis took 300 mg itraconazole twice daily for 3 days, then 200 mg twice daily for 12 weeks. Individuals who responded to this regimen (51 of 61 enrolled) took 200 mg itraconazole daily for at least 1 year. Clearance of the fungal infection and clinical improvement occurred within 1 week of beginning of treatment. "Itraconazole is Effective Treatment for Histoplasmosis in AIDS: Prospective Multicenter Non-Comparative Trial." Wheat LJ and others. #1206 Oral. ==== PCR Tests Detect Hidden Candida and Chlamydia Polymerase Chain Reaction tests have been developed that can diagnose infections of the yeast Candida and the bacteria Chlamydia pneumoniae that other tests fail to detect. Candida normally does not cause disease in people with normal immunity, but in HIV positive individuals, this fungal infection may cause serious illness. Chlamydia pneumoniae is a bacterium that is difficult to detect. The new PCR test could become an important tool in isolating this infection, which can cause pneumonia, bronchitis, sore throat and asthma. "Polymerase Chain Reaction (PCR) for Deep Candidiasis." Kan V and Bennett J. #1627 Poster. "Detection of Chlamydia pneumoniae by PCR-EIA in an Immunosuppressed Population." Gaydos CA and others. #1632 Poster. ***** IMMUNOSUPPRESSION WITHOUT HIV: AN UPDATE As of October 1992, the CDC has received reports of 68 persons within the U. S. who meet the definition of "Idiopathic CD4+ T-Lymphocytopenia" (ICL), or low CD4+ (T-helper) lymphocyte count of unknown cause. All 68 have at least 2 negative blood tests for HIV-I antibodies; all 68 are also negative for antibodies to HIV-2 and HTLV. There are approximately 30 additional cases reported from around the world. The first 31 cases reported to the CDC include 6 men whose only behavioral risk factor for HIV infection was gay male contact. In July 1992, Newsweek reported on several puzzling cases of immunosuppression in HIV negative individuals. In Amsterdam a few days later, researchers presented the first cases of ICL during a specially convened session at the VIII International Conference on AIDS. The CDC published an interim definition of ICL syndrome later in July (see Table 1). On August 14, 1992, the CDC held a meeting in Atlanta to discuss the reported cases and related research in more detail. Dr. James Curran from the CDC and Dr. Anthony Fauci from the National Institutes of Allergy and Infectious Diseases (NIAID) each headed sections at the meeting. Leading HIV/AIDS scientists, researchers and clinicians in Atlanta reported 47 people living in 20 different states who met the interim case definition. Approximately 68% of the 47 ICL cases discussed at the CDC Conference had no known HIV behavioral risk factors. However, 14% had histories of blood-clotting disorders, 13% had gay male sexual contact, 9% had histories of blood transfusions and 2% had heterosexual contact. Twenty-five percent of ICL cases were asymptomatic and felt normal, about 56% had various non-AIDS defining illnesses, and another 19% had AIDS-defining illnesses, including PCP. Twenty household, sexual and blood donor contacts of the ICL cases interviewed felt normal and had normal immune function tests. Another 21 cases of ICL have been identified since the Atlanta meeting. Ninety-four percent of the 68 ICL cases reported to date are alive; 6% have died. Men comprise 56% and women comprise 44% of ICL cases, whereas men and women respectively comprise 89% and 11% of U. S. AIDS cases. The median (average) age of the 68 ICL cases is 43; the median age for U. S. AIDS cases is thirty-six. ICL race-ethnic composition is 78% Caucasian, 9% Hispanic, 7% Asian and 6% Black. Dr. Sudhir Gupta from the University of California at Irvine School of Medicine reported a case of ICL in a 66-year-old woman with PCP who had a blood transfusion in 1949 (subsequently published in the Proceedings of the National Academy of Sciences). Her 38-year-old daughter is well without symptoms and, although her CD4+ T-lymphocytes display functional anormalities, they are normal in number. Dr. Gupta's finding of "human intracisternal retroviral particles" in both the mother and her daughter has not been corroborated by other ICL cases. An editorial from the medical journal The Lancet suggests that the cause of illness in Dr. Gupta's patients may be MTV, "media- transmitted virus" (August 1, 1992). A report from the Atlanta conference referred to the Multi- AIDS Cohort Study (MACS) of approximately 5,000 gay/bisexual men from 4 U. S. cities. Among this group, none of the 2,288 men with 4 consecutive negative HIV blood tests met the definition of ICL. Dr. Scott Holmberg from the CDC reported on 780 HIV negative gay/bisexual men being followed in cohort studies from San Francisco, Denver and Chicago; none of these met the ICL case definition, either. However, Dr. William Mosley from the University of Southern California School of Medicine reported that 14 of 4,018 transfusion recipients (0.4%) being followed in the Transfusion Safety Study have repeated low CD4+ lymphocyte counts and meet the ICL case definition. Of 965 injection drug users followed by Dr. Stanley Wise and coworkers from the New Jersey Medical School, 106 of the men and 74 of the women are persistently HIV antibody-negative. Two of the 180 antibody-negative individuals meet the case definition of ICL. (Dr. Wise's report has been published in the September 15, 1992 of The Lancet.) Several preliminary conclusions were established at the Atlanta ICL Conference. Based on the cases presented to CDC thus far, there does not appear to be a common link or cause among the group. They are probably a heterogeneous group. Nor does there appear to be any case "clustering" associated with a transmittable infection. ICL cases are reported in over 20 states, whereas the first AIDS cases 10 years ago were from just 2 states, New York and California. While it is possible that some of the ICL cases ultimately may be linked to a new infectious agent, it is unlikely that all will. Then what is the cause of ICL? Some may be due to uncommon HIV variants that differ significantly from the HIV strains used to make the HIV antibody and PCR tests currently administered. Some reported cases of ICL may be due to Common Variable Immunodeficiency (CVI). With an onset as late as mid-life, CVI is a disease that involves various abnormalities of immune dysfunction. Low CD4+ lymphocyte counts occur in some cases. However, persons with CVI often have low blood immune globulins, while those reporting ICL had normal or low immune globulins. In this regard, both CVI and ICL differ significantly from AIDS, in which elevation of immune globulins is common. Certain infections can also cause low CD4+ lymphocyte counts (as described by Dr. V. Soriano and coworkers in the September 5, 1992 issue of The Lancet: see Table 2). For example, up to 6% of HIV negative persons with pulmonary TB have low CD4+ lymphocyte counts. There may also be some HIV negative individuals with "low" CD4+ counts who remain well for years; testing of lymphocyte subsets in the general population has not been done on a wide scale. Widespread use of these tests first began with the onset of the AIDS epidemic, and most testing has been done on persons with HIV. Another problem is that CD4+ lymphocyte test results vary from lab to lab. There is also a "diurnal variation" in blood CD4+ lymphocyte counts in HIV negative persons. Counts are highest in the late afternoon, and lower in the morning. This effect is blunted in HIV-infected individuals. Furthermore, testing for the amount of lymphocytes present in the blood does not reflect the sum or total of lymphocytes in the body; at any one time, large numbers of CD4+ cells may be found in tissues other than blood, such as the lymph organs (especially the lymph glands) and the spleen. In response to infections, including HIV and others, many CD4+ cells move transiently or permanently from the blood "compartment" and into these other tissues. Studies of persons with ICL are ongoing. The number of cases appears to be small, however. Only 100 or so cases worldwide have been identified from 1985 through October 1992. Compare this to the "...5,000 new HIV infections every day...on this planet," said Dr. Michael Merson, director of the World Health Organization (WHO) Global Program on AIDS, at the Atlanta ICL Conference. Finally, although 62% of reported ICL cases in the U. S. had no HIV risk factors for a blood-borne or sexually transmitted agent, 38% did. This is yet another prudent reason to recommend safer sex practices -- even among HIV negative individuals who do not perceive themselves to be at risk. ==== TABLE 1 -- CDC INTERIM DEFINITION OF IDIOPATHIC CD4+ T- LYMPHOCYTOPENIA (ICL)* 1. CD4+ T-cell count under 300 per microliter, OR less than 20% of lymphocytes (either of the above on 2 or more tests) 2. Negative laboratory tests for HIV (antibodies, and if done, HIV p24 antigen, PCR, and viral culture) 3. No other cause of immunodeficiency or therapy known to cause lowCD4+ T-cell counts. *Low T-helper cell count, cause unknown. ==== TABLE 2 -- INFECTIONS AND OTHER CAUSES OF A FALL IN THE CD4+ T-LYMPHOCYTE COUNT (Without HIV-I or HIV-2 Infections) Infections Viral HTLV-1 hepatitis B virus adenoviruses (cause of the "common cold") herpesviruses (CMV, varicella zoster ["shingles" & "chicken pox"], human herpes 6 measles virus human papillomaviruses (wart viruses) Fungal (histoplasmosis, cryptococcus, and coccidiomycosis) Protozoal (leishmaniasis) Mycobacterial (tuberculosis) Other Malnutrition Protein deficiency Zinc deficiency pyridoxine (vitamin B6) deficiency Drugs (corticosteroids) Congenital Immune Disorders Autoimmune disorders Proliferative disorders (thymoma) Common Variable Immunodeficiency Pregnancy Old age Adapted from V. Soriano and others. The Lancet 340:607-608. 1992. ==== Selected Sources anon. AIDS minus HIV? Editorial. The Lancet 340:280. 1992. CDC. Meeting on CD4+ T-lymphocyte depletion in persons without evident HIV infection. Transcript. U. S. Dept. of Health and Human Services. 1-268. August 14, 1992. CDC. Unexplained CD4+ T-lymphocyte depletion in persons without evident HIV infection-United States. Morbidity and Mortality Weekly Report 41:541-545. 1992. CDC. Update: CD4+ T-lymphocyte depletion in persons without evident HIV infection United States. Morbidity and Mortality Weekly Report 41:578-579. 1992. CDC. Update: CD4+ T-lymphocyte depletion in persons without evident HIV infection United States. E-mail. September 29, 1992. Gupta S and others. Detection of a human intracisternal retroviral particle associated with CD4+ T-cell deficiency. Proceedings of the National Academy of Sciences USA 89:7831 7835. 1992. Hoover DR and others. Effect of CD4+ cell count measurement variability on staging HIV-I infection. Journal of Acquired Immune Deficiency Syndrome 5:794-800. 1992. Kaczmarski RS and others. Letter. The Lancet 340:609. 1992. Laurence J and others. Acquired immunodeficiency without evidence of infection with human immunodeficiency virus types 1 and 2. The Lancet 340:273-4. 1992. Laurence J. Letter. The Lancet 340:609. 1992. Misbah S and others. Letter. The Lancet 340:609. 1992. Moore JP and others. HIV-negative AIDS. The Lancet 340:475. 1992. Navarro M. Immune disease mystery leaves patients in limbo. The New York Times. CXLII (49, 126):Al, A17. October 21, 1992. Soriano V and others. Idiopathic CD4+ T-lymphocytopenia. The Lancet 340:607-608. 1992. Stites D and Terr A, eds. Basic and Clinical Immunology, 7th ed. Norwalk: Appleton & Lange. 1991. Weiss S and others. Letter. The Lancet 340:608609. 1992. ***** CORRECTIONS It is a policy of BETA to correct factual errors. We regret these errors, and any misunderstanding they may have caused. In the August 1992 issue (page 29) Intron A was listed as a product of Hoffman-La Roche, Inc. and Roferon A was listed as a product of Schering Plough Corporation. In fact, the opposite is true: Hoffman-La Roche manufactures Roferon A, and Schering- Plough manufactures Intron A. In the May 1992 issue (page 26), BETA incorrectly referred to a device from Applied Immune Services as the Collector. The correct name is the Cellector. ***** PATIENT DRUG ASSISTANCE PROGRAMS SPONSORED BY PHARMACEUTICAL COMPANIES Some pharmaceutical companies offer programs to help physicians find a source of payment for their patients' prescription drugs, or provide them free to individuals who cannot pay. The programs outlined below have varying eligibility requirements and methods for providing assistance. In most cases it is necessary for the treating physician to contact the appropriate program and provide information about the individual's financial status and prescription drug needs. (Compiled by David Strickland) [Display note: the following table is too wide for most screens, and that is the reason for the apparent jumble. It has been left intact, in the expectation that some callers will want to print it out on a wide printer. You may want to send for the original hardcopy, to the address of the AIDS Foundation, 25 Van Ness, San Francisco CA 94102.] DRUG NAME INDICATION COMPANY PROGRAMS TELEPHONE Foscarnet CMV disease, acyclovir-resistant Astra Pharmaceuticals (Foscavir) herpes simplex Foscavir Assistance and Information on Reimbursement 800-488-3247 ddl HIV infection Bristol-Myers Squibb Co. (Videx) Videx Reimbursement Assistance and Temporary Assistance Programs 800-788-0123 AZT HIV infection Burroughs Wellcome Co. (Retrovir) HIV Patient Assistance Program 800-722-9294 Trimethoprim/sulfamethoxazole PCP prophylaxis Burroughs Wellcome Co. (Sopfro) Acute PCP HlV Patient Assistance Program 800-722-9294 (Bactrim) Hoffmann-La Roche, Inc, Oncoline (Reimbursement Assistance) 800-443-6676 Pyrimethamine Toxoplasmosis Burroughs Wellcome Co. (Daraprim) HIV Patient Assistance Program 800-722-9294 Acyclovir Herpes simplex, herpes zoster Burroughs Wellcome Co. (Zovirax) HlV Patient Assistance Program 800-722-9294 Aerosolized pentamidine PCP prophylaxis Fuiisawa Pharmaceuticals (Nebupent) Nebupent Reimbursement Service 800-366-6323 ddC HIV infection Hoffmann-La Roche, Inc, (Hivid) Assist Program (ddC) 800-285-4484 Interferon alfa-2b, recombinant Kaposi's Sarcoma Hoffmann-La Roche, Inc. (Roferon-A) (> 200 T-helper cells), Oncoline (Reimbursement Assistance) 800-443-6676 anogenital neoplasms Cost Assistance Program 800-227-7448 Indigent Patient Program 800-526-6367 Interferon alfa-2a recombinant Kaposi's Sarcoma Schering-Plough Corp. (Intron A) (> 200 T-helper cells), Interactive Reimbursement anogenital neoplasms Information Services 800-521-7157 Erythropoietin AZT-related anemia. Ortho Biotech (Procrit) Procritline (Reimbursement Assistance) 800-553-3851 Cost Sharing Program 800-441-1366 Financial Assistance Program 800-447-3437 Fluconazole Fungal infections (cryptococcal Pfizer Inc. (Diflucan) meningitis, esophageal candidiasis, etc) Diflucan Patient Assistance Program 800-869-9979 Ganciclovir CMV disease Syntex Laboratories (Cytovene) Provisional Assistance Programs 800-444-4200 ***** GLOSSARY ACYCLOVIR (ZOVIRAX): an antiviral drug used in the treatment of herpes simplex virus 1 (HSV-1, fever blisters, cold sores), herpes simplex virus 2 (HSV-2, anal and genital herpes) and herpes zoster (shingles). ADENOVIRUSES: the cause of the "common cold," adenoviruses are a family of double-stranded DNA viruses that develop in the nuclei of infected cells. ALLOPATHIC: refers to a therapeutic system in which an illness is treated by producing a second condition that is antagonistic or incompatible with the first. ALPHA INTERFERON: one type of small protein, produced by infected host cells, that protects uninfected cells from viral infection. In people who are HIV positive, elevated levels of "acid labile" alpha interferon may indicate disease progression. Genetically-engineered alpha interferon is an FDA-approved treatment for AIDS-associated KS, hepatitis B, hepatitis C and warts. The drug is being studied at low doses in combination with AZT and ddC as an anti-HIV therapy. Brand names of recombinant alpha interferon include Roferon A, Intron A and Wellferon. AMPHOTERICIN B: an antifungal drug approved for treatment of progressive, disseminated fungal infections. Toxicities may include fever, chills, nausea, kidney toxicity and anemia. ANAL INTRAEPITHELIAL NEOPLASIA (AIN): abnormal rectal cell growth, observed with a microscope, that suggests possible malignancy. ANEMIA: a condition marked by an abnormally low number of red blood cells. ANERGY: lack of a response to the injection of a certain foreign substance. This may indicate the inability of the immune system to mount a normal allergic response. ANOGENITAL: denoting the area of the anus and the genitals. ANORECTAL: pertaining to the area around the anus and rectum. ANOSCOPY: examination of the anal canal and lower rectum using a short speculum. ANTIBODY: a protein substance, developed in response to an antigen, that destroys or neutralizes bacteria, viruses or other harmful toxins. This antigen/ antibody reaction forms the basis of immunity (see also p24 antigen and autoimmune response). AUTOIMMUNE RESPONSE: a response caused by the immune system mistakenly attacking the body's own tissues. AUTOINOCULATION: spread of infection from one part of the body to another part; transmission usually occurs by means of the hands or fingers. AZITHROMYCIN (ZITHROMAX): a macrolide-class antibiotic, similar to Erythromycin, approved for the treatment of chlamydia and other common bacterial infections. The drug is available to certain people on a compassionate use basis for toxoplasmosis and MAC. Ask your physician to call Pfizer Pharmaceuticals for enrollment information (1-203-441-5941 for MAC; 1203-441-5701 for toxoplasmosis). AZT (RETROVIR): azidothymidine; also called zidovudine. A nucleoside analog (genetic building block) that suppresses replication of HIV. AZT is FDA-approved for the treatment of HIV infection. Adverse side effects may include anemia, leukopenia, muscle fatigue, muscle wasting, nausea and headaches. BACTEREMIA: the abnormal presence of bacteria in the blood. BACTRIM: one of the brand names for trimethoprim- sulfamethoxazole (TMP-SMX), a drug used in the treatment of PCP and other infections. SEPTRA is another brand name for this drug. BIOPSY: surgical removal of a small piece of tissue for microscopic examination. BLOOD-BRAIN BARRIER: a barrier between the blood and the brain. It only allows some substances to pass from the blood to the brain. This barrier presents a problem in treating HIV infection because treatments must cross it to stop HIV infection in the brain. BOWENOID PAPULOSIS: a papillomavirus-associated disease involving changes in tissue in the anogenital region. CANDIDA (CANDIDA ALBICANS): a yeast or fungus that can infect any system of the body, particularly the skin, nails and mucous membranes throughout the body, including the throat, vagina, intestines and lungs. Oral and/or vaginal candidiasis are often an early sign of an impaired immune system in HIV positive individuals. CANTHARIDIN: ground-up form of "blister beetle" or "Spanish Fly," an agent that causes the formation of a blister with 24 hours. CARCINOGENESIS: the origin, cause and/or production of cancer. CARCINOMA: a malignant tumor that may spread throughout the body. CATHETER: a narrow tubular instrument, usually made of plastic or rubber, that allows fluid to pass from or into a body cavity or blood vessel; e.g. one designed to pass through the urethra into the bladder to drain it of retained urine; also, a semi- permanently installed venous line used to inject fluids into the body. CAUTERIZE: to burn, scar or cut tissue by means of heat, electric current or chemicals. CD4: a protein embedded in the cell surface of T-helper cells (a.k.a. T4 cells) and certain other cells. HIV invades these cells by first attaching to the CD4 receptor. CD4 is also the name of an experimental, genetically-engineered anti-HIV drug. CERVIX: the cylindrical, lower part of the uterus leading to the vagina. CHEMOTHERAPEUTIC: refers to the treatment of disease with drugs or other chemical substances. CHEMOTHERAPY: the use of chemical agents in the treatment of a disease. CIPROFLOXACIN (CIPRO): an oral antibiotic approved for the treatment of common bacterial infections. Under study for the treatment of MAC in combination with other drugs. Side effects may include GI distress and rash. CLARITHROMYCIN (BIAXIN): a macrolide-class antibiotic like Erythromycin approved for the treatment of common bacterial infections in non-immunocompromised patients. Under study for the treatment of MAC, alone and in combination with other drugs; also under study for the treatment of toxoplasmosis. High doses may cause abdominal pain. COCCIDIOMYCOSIS: a disease acquired by inhalation of dust particles containing bacterial spores that can cause lesions to develop in the upper respiratory tract and lungs; sometimes disseminates to visceral organs, bones, skin and other tissues. COFACTOR: a substance, microorganism or environmental factor that activates or furthers the action of a disease-causing agent. Some possible cofactors in the progression to AIDS are parasites and the herpes group viruses (herpes simplex virus, Epstein-Barr virus, cytomegalovirus, varicella zoster virus, human herpes 6), parasites and advanced age. COHORT: a group of individuals sharing a statistical factor. COLITIS: inflammation of the colon. COLPOSCOPY: examination of the cervical surface under magnification to identify location and extent of abnormal lesions. COMEDO EXTRACTOR: a metal device used to remove comedones or blackheads. COMEDONE: a small, round hard, abnormal collection of bacteria, oil and their breakdown products in the skin; the primary lesion of acne. COMMON VARIABLE IMMUNODEFICIENCY (CVI): a disease involving various abnormalities of immune function. People with CVI often have low blood immune globulins, whereas AIDS usually involves elevation of immune globulins. CONDYLOMA ACUMINATA: anogenital warts, caused by infection with the human papillomavirus (HPV); a common sexually transmitted disease. CONE BIOPSY: removal of a large cone-shaped wedge from the bottom of the cervix and around the os (cervical opening) to remove lesion(s) and provide tissue for biopsy. CONJUNCTIVITIS: inflammation or infection of the conjunctiva of the eye, the thin protective membrane of the interior of the eyelids, and the white part of the eye. CORTICOSTEROID: any of a number of steroid substances obtained from the cortex of the adrenal gland, or any synthetic substitute. Corticosteroids are immunosuppressive, and HIV- infected individuals should be cautious in using them. CRYOTHERAPY: the use of liquid nitrogen to freeze and treat an abnormal lesion which then often forms a blister after treatment (removing the lesion). CRYPTOCOCCAL MENINGITIS (CM): a fungal infection of the layers (membranes) surrounding the brain and spinal cord. Symptoms may include headache, confusion, blurred vision, fever and speech difficulties. Left untreated, CM can lead to coma and death. CRYPTOCOCCUS: yeast-like fungi that can cause cryptococcal meningitis, a life-threatening disease that affects the central nervous system. CT: computerized axial tomography-a way to visualize the soft tissues of the body by X-rays. CURETTE: to scrape for the removal of new growth or abnormal tissue. CUTANEOUS: pertaining to skin. CYTOKINES: soluble proteins released by various cells to act as chemical messengers between cells. CYTOMEGALOVIRUS (CMV): a sexually-transmitted virus in the herpes family. CMV infection can occur without causing symptoms. In people with advanced HIV disease, CMV may reactivate to cause blindness, pneumonia, colitis, nerve inflammation and/or death. CMV infection of a woman during pregnancy often leads to congenital abnormalities in the newborn, even without HIV infection. D4T (STAVUDINE): an anti-HIV drug FDA-approved for people with AIDS who are intolerant to or fail on ddI. Like AZT, ddI and ddC, d4T belongs to the nucleoside analog family of drugs. D4T inhibits production of the reverse transcriptase enzyme of HIV needed for the virus to replicate. DAPSONE: the brand name for an antibiotic drug sometimes used in the treatment of PCP and other infections. ddC (dideoxycytodine, trade name HIVID): a nucleoside analog that inhibits replication of HIV. Adverse side effects may include peripheral neuropathy, pancreatitis (rare) and oral ulcers. FDA-approved for the treatment of HIV when used in combination with AZT. ddI (dideoxyinosine, trade name VIDEX): a nucleoside analog which inhibits replication of HIV. Side effects may include peripheral neuropathy and/or pancreatitis. FDA-approved for individuals intolerant to or failing on AZT, and for people who have taken AZT for 16 weeks or more. DIURNAL: twice a day. DOUBLE-BLINDED STUDY: a method of medical investigation in which neither the subject nor the investigator knows what treatment, if any, the subject is receiving. At the end of the experiment, the "code" is broken and data are analyzed with respect to the various treatments used. This method attempts to eliminate observer and subject bias. DRUG RESISTANCE: if an organism develops the ability to overcome the inhibiting effects of a drug, it is said to be "resistant" to that drug. DYSPLASIA: abnormal growth of tissue, possibly precancerous. ELECTRODESICATION: destroying lesions or sealing off blood vessels using high frequency electric current. ENDOSCOPIC: relating to an endoscope, an instrument used to examine the interior of a small bodily canal or hollow organ (usually the esophagus, stomach and upper GI tract). EPIDEMIOLOGY: study of the frequency, distribution and behavior of a disease in a defined population. EPIDERMIS: the outer layers of the skin. ETHAMBUTOL (MYAMBUTOL): an oral drug used in combination with other drugs to treat tuberculosis; under study, in combination with other drugs, as a treatment for MAC; side effects may include decreased or distorted vision. EXPANDED ACCESS (Open Label Study): an FDA program that distributes experimental drugs free to people who cannot participate in clinical trials, and who have no other treatment options. FIVE-FLUOROURACIL (5-FU): a chemotherapeutic medication in cream form used to treat abnormal growths on the skin or skin cancers. FLUCONAZOLE (DIFLUCAN): an oral antifungal drug approved for treatment of cryptococcal meningitis and esophageal candidiasis. Side effects may include nausea, rash, abdominal pain and headache. FOSCARNET (FOSCAVIR): an antiviral drug FDA-approved for the treatment of acyclovir-resistant herpes virus infection and CMV disease, usually with co-existent HIV infection; adverse side effects may include kidney toxicity, muscle twitching, nausea and genital ulcers. GANCICLOVIR (CYTOVENE): an antiviral drug FDA-approved to treat CMV retinitis, CMV colitis, CMV esophagitis, AIDS-related meningoencephalitis and AIDS-related polyradiculopathy. Side effects may include some neutropenia. GASTRITIS: inflammation of the mucosal lining of the stomach. GLOBULINS: proteins found in the blood and cerebrospinal fluid. GRANULOCYTE: a type of white blood cell that fights bacterial infections. HEMORRHAGE: bleeding through ruptured or unruptured vessel walls. HEPATITIS B: a viral liver disease that can be acute or chronic and even life-threatening, particularly in people with poor immune resistance. Like HIV, the hepatitis B virus can be transmitted by sexual contact, contaminated needles or contaminated blood or blood products. Unlike HIV, it is also transmissible through close casual contact. HERPES VIRUS: a group of viruses that includes herpes simplex type 1 (HSV-1), herpes simplex type 2 (HSV2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV) and human herpes virus type 6 (HSV-6). HISTOPLASMOSIS: a disease caused by a fungal infection acquired from inhaling spores of the fungus Histoplasma capsulatum present in soil or dust. In individuals with suppressed immune systems, the disease may be life-threatening. HIV-I: human immunodeficiency virus type 1. The retrovirus recognized as the causative agent of AIDS. HIV-2: human immunodeficiency virus type 2. A virus similar to HIV-I that is found primarily among Africans. HTLV: Human T-cell Leukemia Virus. HUMAN PAPILLOMAVIRUS (HPV): a member of the papova family of viruses. HPV causes warts or nipple-like protrusions. HPV has also been associated with cervical cancer in women and with anal cancer in men. IDIOPATHIC: denoting a disorder whose cause is unknown. IDIOPATHIC CD4+ T-LYMPHO- CYTOPENIA (ICL): a disorder of unknown cause characterized by low CD4+ (T-helper cell) count. IMMUNOSUPPRESSION: reduced function of one component of the body's immune system. HIV infection causes immunosuppression and other immune dysfunctions. INOCULATION: the introduction of a pathogen or antigen into the body to stimulate antibody production or other immune responses. INTRACISTERNAL: within a body cavity or enclosed space that contains fluid, usually with reference to those in the brain that contain cerebrospinal fluid. INTRAEPITHELIAL: within or among the cells composing various tissues types that cover free surfaces in the body, line cavities, ducts and vessels (skin, mucosa, etc.) . KAPOSI'S SARCOMA (KS): a tumor of the walls of lymph vessels. KS usually appears as pink to purple painless spots, flat or raised, on the surface of the skin, but it can also occur internally. KS is commonly found among people with AIDS, especially gay and bisexual men. The specific cause of KS in association with AIDS is likely to be multifactorial (yet unknown). KETOCONAZOLE: an oral medication used to treat fungal or yeast infections. It is available in pill, pastille (lozenge) or topical cream form. LABIA: lips; rounded folds of skin (majora and minora) that surround the vestibule into which the vagina and urethra open. LEISHMANIASIS: an infection caused by a parasite that takes various forms; generally characterized by lesions that appear on exposed parts of the body; may be fatal if left untreated. LESIONS: any abnormal change in tissue caused by disease or injury. LEUCOVORIN CALCIUM: a calcium salt of folic acid (a member of the vitamin B complex). Leucovorin is used to treat severe anemias. The effectiveness of leucovorin calcium as a supplement to TMP-SMX is not well understood, but it has been shown to reduce the toxicity of other drugs, e.g. trimetrexate. LEUKOPLAKIA: a white lesion appearing on the tongue or in the mouth, often the first symptom of the immunosuppression associated with HIV disease. The lesion is strongly associated with Epstein-Barr virus (EBV), the cause of mononucleosis. LOOP DIATHERMY: utilization of a heated wire loop to remove a large cone-shaped wedge from the bottom of the cervix and around the os for biopsy; the loop seals off blood vessels as it cuts. LYMPHOCYTE: a type of white blood cell. T-helper cells are lymphocytes. LYMPHOCYTOPENIA: reduced levels of lymphocytes (white blood cells) in the bloodstream. LYMPHOMA: any of a group of malignant diseases originating in the lymph nodes. MACROPHAGE: a large scavenger cell which ingests degenerated cells, blood tissue and foreign particles. Macrophages exist in large numbers throughout the body, and are key to the development of immunity to a variety of organisms. They are a major reservoir of HIV infection, along with their precursor blood cell, the monocyte. MEPRON (atoquavone, 566, 566C, 566C80): an antimicrobial drug FDA-approved as second-line treatment for PCP for individuals who cannot tolerate or fail on TMP-SMX (Bactrim, Septra). Mepron has also shown strong activity against Toxoplasma gondii, the organism that causes toxoplasmosis. MOLLUSCUM CONTAGIOSUM: a small, round, raised lesion of the skin due to the pox virus, usually appearing on the face, neck, arm, legs and anogenital region. MONOCYTE: a type of white blood cell which may be a reservoir for HIV. MORBIDITY: affected by disease. MRI: magnetic resonance imaging -- an extremely sensitive method for viewing inside soft tissues of the body. MUCOSAL TISSUES: the tissues lining the moist cavities of the body that open to the body surface, in particular the mouth, vagina and rectum. MYCOBACTERIUM AVIUM COMPLEX (MAC): a disease caused by a bacterium found in the soil. In PWA, it can spread through the bloodstream to infect lymph nodes, bone marrow, liver, spleen, spinal fluid, lungs and intestinal tract. Symptoms of MAC include prolonged wasting, fever, fatigue and enlarged spleen. NEUTROPENIA: an abnormally low number of neutrophils, a type of white blood cell that helps to defend the body against bacterial infection. NODULE: a rounded lump, knot or swelling of the skin. ODNOPHAGIA: painful swallowing. OS: the opening of the uterus (at the cervix) into the vagina. p24 ANTIGEN: a protein component of the core of HIV. The p24 antigen test measures the amount of this viral protein present in the blood, or other body fluids. A positive result for the p24 antigen suggests active HIV replication. PAP SMEAR (PAPANICOLAOU SMEAR): a specimen of cervical cells examined for abnormal development. PAPULE: a small raised bump of any color (but often red) on the skin (smaller than a nodule); papules occur individually or in clusters. PARALLEL TRACK: an FDA program that expands access to a promising drug that has not yet been approved. PATHOGEN: any microorganism capable of causing disease. PERIPHERAL NEUROPATHY: a disorder of the nerves, usually involving the feet or hands, and sometimes the legs and arms. Symptoms may include numbness, a tingling or burning sensation, sharp pain, weakness and abnormal reflexes. In some cases, paralysis may result. PHASE I STUDY: the first step in human testing of a drug. Designed to evaluate toxicity at different dose levels. Phase I studies involve only a small number of participants. PHASE II TRIAL: the second step in the evaluation of a drug in humans. Phase II trials are designed to evaluate drug effectiveness, and involve more study participants than Phase I studies. Phase II trials proceed only if 1 or more Phase I trials have shown the drug's toxicity to be acceptable within a given dose range. PHASE III TRIAL: expansion of Phase II trial up to 3,000 volunteers; designed to support information gathered in Phase I and II; Phase III trials also compare the drug to other agents, either alone or in combination. PLACEBO-CONTROLLED STUDY: a method of investigation of drugs in which an inactive substance (the placebo) is given to 1 group of patients, while the drug being tested is given to another group. The results obtained in the 2 groups are then compared. PNEUMOCYSTIS CARlNIl PNEUMONIA (PCP): a life-threatening form of pneumonia that occurs in people with suppressed immune systems. It is a common opportunistic infection in AIDS. Its onset can be prevented or delayed by treatment with drugs such as Dapsone, TMP-SMX (Bactrim, Septra), atoquavone (Mepron) and aerosolized pentamidine (Nebupent). PODOPHYLLIN: the acidic resin from the May Apple plant that is painted on warts to dissolve them from the skin or mucus membranes. POLYMERASE CHAIN REACTION (PCR): a highly sensitive test that can detect minute amounts of DNA fragments of viruses or other infections in blood or tissue. POXVIRUS: any of a large family of viruses that typically cause skin eruptions. PREDNISONE: a synthetic corticosteroid sometimes used in the treatment of neuropathies, or to decrease inflammation in the body. Like all corticosteroids, it is immunosuppressive and should be used with caution in people with HIV disease. PROPHYLAXIS: treatment that helps to prevent a disease or condition before it occurs (primary prophylaxis) or recurs (secondary prophylaxis). PROTEINASE INHIBITOR: a promising experimental drug under study for treatment of HIV infection. This drug inhibits HIV replication by blocking the function of the proteinase enzyme. PULMONARY: relating to the lungs. PUNCH BIOPSY: removal of a small round piece of abnormal-looking tissue for biopsy, from the skin or mucous membrane layers, including the cervix. PUTATIVE: assumed to exist now or in the past; also used to mean causative. PYRIDOXINE: Vitamin B6. PYRIMETHAMINE: a drug used in combination with sulfadiazine to treat toxoplasmosis. Side effects may include bone marrow suppression and allergic skin reactions. RECOMBINANT: produced in the laboratory by genetic engineering. RENAL: relating to the kidneys. RETINITIS: inflammation of the retina, on the back part of the eyeball. RETROVIRAL: referring to a retrovirus. RIFABUTIN (MYCOBUTIN): an oral drug FDA-approved as a preventive treatment for Mycobacterium avium complex (MAC). Side effects may include rash, fever, gastrointestinal distress and leukopenia. SHINGLES: a skin condition characterized by painful blisters that generally dry and scab, leaving minor scarring. Shingles is caused by the reactivation of a previous infection with the varicella-zoster virus that causes chicken pox, usually early in life. Shingles may be a symptom of HIV disease progression. Early treatment with acyclovir usually helps to control the spread of shingles lesions or accelerates their drying to form scabs. Shingles may recur in people with poor immunity. SINUSITIS: inflammation or infection of the sinuses, cavities behind the forehead or cheekbone. SPECULUM: an instrument for enlarging the opening of any canal or cavity in order to facilitate inspection of its interior, e.g. rectal, ear, nasal or vaginal speculum. SQUAMOUS: flat, thin cells that comprise the surface of the skin and the lining of the vaginal walls. TAT GENE INHIBITOR: the tat gene is the gene in HIV that regulates the rate of replication of the virus; when the tat gene is "turned off" or inhibited, HIV remains inactive and will not produce new virus nor infect other cells. The TAT gene inhibitor is an anti-HIV drug currently being tested in Phase I/II studies at 4 U. S. medical centers. Hoffman-LaRoche is the manufacturer of the drug. 3TC: an experimental drug (nucleoside analogue) under study for the treatment of HIV infection. The drug's manufacturer is Glaxo, Inc. THROMBOCYTOPENIA: an abnormally low number of platelets, blood cells that facilitate blood clotting. THYMOMA: tumor of the thymus; thymomas are usually benign, in contrast to malignant lymphoma such as Hodgkin's disease (which should not be regarded as thymoma). TMP-SMX (BACTRIM, SEPTRA): trimethoprim-sulfamethoxazole; the preferred drug for prophylaxis and treatment of PCP. TOXOPLASMOSIS: an opportunistic infection caused by a microscopic parasite (Toxoplasma gondii) found in uncooked meat and cat feces. Symptoms may be so mild as to be barely noticeable or may be more severe with lymphadenopathy, malaise, muscle pain and fever. Diagnosis is made by identification of a biopsy of the organism, by the manifestation of lesions that become smaller with treatment, and by serologic testing. Toxoplasmosis may lead to brain inflammation, coma and death in people with suppressed immune systems. If an HIV negative woman becomes infected with toxoplasmosis while pregnant, congenital malformations may occur in the newborn. TREATMENT IND: Treatment Investigational New Drug. An FDA classification that allows U. S. physicians to prescribe a promising drug before it has been approved for marketing. TRICHLOROACETIC ACID: a strong acid solution used to dissolve venereal and other warts. TUBERCULOSIS: an infectious disease caused by Mycobacterium tuberculosis (M. Tuberculosis) that typically affects the lungs, but which may occur in other organs. Treatments include isoniazid and rifampin. ULCER: a break in skin or mucous membrane, with loss of surface tissue. UMBILICATION: a navel-like depression usually located in or near the center of a lesion. VARICELLA ZOSTER VIRUS (VZV): a virus in the herpes family that causes chicken pox during childhood and may reactivate later in life to cause herpes zoster (shingles). VERRUSOL: a solution made of salicylic acid, podophyllum resin and cantharidin (Spanish fly), used to dissolve and blister skin growths such as warts and molluscum contagiosum. ***** BETA -- SUBSCRIPTION INFORMATION Editorial Office 25 Van Ness Avenue, Suite 700 San Francisco, CA 94102 415-864-5855 X 2092 Subscription Office P. O. Box 2189 Berkeley, CA 94702 To charge by phone with Visa or MasterCard, Call 1-800-327-9893 If you have questions about your paid subscription, call 510-549-4300. BETA Scholarship Program P. O. Box 426182 San Francisco, CA 94142 415-863-2437 &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display