Subject: GMHC Treatment Issues vol. 5 no. 7 Date: Oct 1991 (1229 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T I S S U E S && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& GMHC Treatment Issues vol. 5 no. 7, October 1991 Contents: [items are separated by "*****" for this display] Non-Hodgkin's Lymphoma An Ounce of Prevention: Update on Fungal Infection A Review of Fungal Infections in HIV Disease NAC Update Drug Resistant Tuberculosis In Brief Glossary TREATMENT ISSUES BULLETIN (new feature) ***** "Non-Hodgkin's Lymphoma" by Mary Beth Caschetta In 1990, the media reported an increased incidence of non- Hodgkin's Lymphoma (NHL) in people with AIDS. Lymphomas are cancerous tumors of the lymph nodes, which are usually solid and made up of abnormally fast-growing clusters of B-cells. Tumors may appear anywhere along the lymph system -- the series of vessels that transport clear fluids containing various types of white blood cells throughout the body and into the blood. Other types of NHL are characterized by the kinds of cells involved and the size of the tumor. In HIV-related NHL, tumors also commonly occur outside of the lymph system. Common sites for lymphomas in HIV-infected patients include the stomach, bone marrow, liver, and lungs. Tumors can also occur in the brain, where serious neurological damage can take place and symptoms are sometimes mistaken for AIDS dementia complex (ADC) or toxoplasmosis. Other unusual, but not altogether uncommon sites for lymphoma have been reported, including the heart, the gums, the urethra, earlobes, and rectum. It is important to carefully assess HIV-positive patients with signs or symptoms of lymphoma, in order to diagnose and treat the disease when tumors occur in unusual sites. BACKGROUND The clustering of high-grade non-Hodgkin's B-cell lymphomas, as NHL is formally called, was found to occur with frequency in HIV-infected people several years after the discover of AIDS. NHL was a relatively late manifestation of HIV disease, according to researchers, instead of one that was merely overlooked. In any case, NHL was not added to the Centers for Disease Control (CDC) definition of AIDS-defining illnesses until 1985.[1] Most recently, an increased incidence of cancers, especially lymphomas, has been observed in people at all stages of HIV infection. In 1990, the media ran a blitz of stories regarding a rise in HIV-related lymphomas, and at the international conference in Florence this year, there were several reports confirming the increased incidence. It is interesting to note that NHL has increased in the total U.S. population and not just in people with AIDS. In the past 17 years, in fact, NHL has increased in the general population by more than 50%.[2] The cause of this increase is unknown, but the National Cancer Institute projects that as many as 10% of AIDS patients will develop cancer, and that in 1992, approximately 5,000 patients will develop non-Hodgkin's lymphoma in the United States.[3] Not much is known in general about non-Hodgkin's lymphoma. Researchers believe that both congenital and acquired immunosuppression substantially increase the risk for developing NHL.[4] The condition is about 60 times more common in AIDS patients than in the general U.S. population. [5] This article will overview different aspects of non- Hodgkin's lymphoma and some of the treatments available. CLINICAL FINDINGS Widely disseminated lymphoma sometimes occurs at the time of initial diagnosis of AIDS, with tumors found outside of the lymph system in 65%-98% of patients. It is thought to be unusual to find lymphoma only in the lymph nodes in patients with HIV. Lymphoma involving the bone marrow occurs in approximately 20%- 30% of all HIV-related cases: gastrointestinal tumors in 15%-45%; and approximately 1/3 of patients with HIV-related lymphoma have brain involvement. Patients with brain involvement are usually the most ill of all patients with HIV-related lymphoma.[8] Many patients with HIV-related lymphoma have fever as an initial symptom, which may mimic other infections, such as PCP. Only a few patients with HIV infection have developed low- grade lymphoma, which is known to be fairly responsive to treatment.[9] These are not considered to be AIDS-defining events, but they are thought to occur by chance or simply to co- exist with HIV. Six patients at the University of Southern California (USC) have done very well, using minimal therapies, as is the usual prognosis for patients without HIV.[10] Single-agent chemotherapy, such as chlorambucil, or multi-agent regimens such as CVP (cyclophosphamide, vincristine, prednisone), may be well tolerated. It cannot be ruled out, however, that these lymphomas may be related in some way to HIV-induced immunosuppression. The symptoms of brain lymphoma (sometimes called lymphoma of the central nervous system, CNS) are headaches, seizures, abnormal gait or speech, or change in personality and behavior.[11] In an observation of eleven patients with brain lymphoma treated at USC, the median survival time was 2.5 months.[12] These patients had very advanced disease and T cell counts below 30. Often times, brain lymphoma is diagnosed at the time of autopsy, and seems to have occurred more frequently in patients with disseminated or widespread lymphoma. Lymphomas usually appear as single lesions on the brain, always larger than 3 cm.[13] Since NHL lesions are sometimes mistaken for toxoplasmosis, a brain biopsy may be warranted for definitive diagnosis. However, since brain biopsy is difficult, it is common practice to treat an HIV-infected patient with CNS mass lesions for toxoplasmosis for a period of one week. After a repeat CT scan is performed, if the lesion is not significantly improved, a brain biopsy is conducted.[14] Thought many people fear brain biopsies, they can be performed safely by experienced neurosurgeons without major complications. CO-FACTORS The Epstein-Barr virus (EBV) has been implicated in a majority of lymphomas associated with immunodeficiency and in transplant patients with induced immunosuppression.[15] EBV is the virus which causes mononucleosis. There has been little concrete information concerning the role of EBV in HIV-related lymphoma. The theoretical connection is that EBV can create an environment suitable for gene rearrangement that may lead to a cancerous event.[16] Cytomegalovirus infection, low T4/T8 ratios, and Kaposi's sarcoma (KS) may also be potential risk factors for the development of lymphoma in AIDS.[17] Oral hairy leukoplakia (OHL), which is thought to be caused by EBV, may also be associated with the development of NHL.[18] Additionally some studies indicate that many HIV-positive patients with lymphoma have a history of injecting drugs. However, it is not possible to predict definitively who will develop NHL based on HIV transmission factors. LYMPHOMA AND AZT A 1990 study, published in the Annals of Internal Medicine, reported an increase in HIV-related NHL in long-term survivors and raised much concern about the role of AZT in the development of NHL.[19] Specifically, the authors found that increases in NHL were found most commonly in people with AIDS who were long- term survivors taking AZT. From this study, some have concluded that long-term use of AZT actually causes NHL. Many professionals, however, have questioned that theory, since the occurrence of cancers, including NHL, in immunosuppressed patients has long been recognized.[20] Still others suggest that the increased frequency of lymphoma is most likely due to the fact that AIDS patients today live longer and, therefore, prolonged immunosuppression may contribute to the development of lymphoma. A more recent study by Richard Moore of Burroughs Wellcome, maker of AZT, was reported in the Journal of the American Medical Association.[21] To further investigate the incidence of NHL and risk factors associated with the development of lymphomas, the authors of this study analyzed data from a group of 1,030 persons with AIDS or ARC who received AZT in 1987 and early in 1988. Patients were observed two years after the initiation of AZT therapy. NHL developed after initiating therapy in 24 (2.3%) of the 1,030 patients. Development of NHL was determined to be possibly associated with a prior diagnosis of other conditions, but the direct role of AZT therapy was found to be difficult to evaluate. The incidence of NHL found in this study was consistent with the incidence found in earlier studies of persons with HIV infection who did not receive antiretroviral therapy.[22] No association between NHL and the average daily dose of AZT or the length of time on AZT was found. However, it should be noted that all patients in the study received AZT, therefore, there was no control group of patients who did not receive [the] drug. TREATMENT FOR LYMPHOMA Optimal therapy for AIDS lymphoma has not yet been found. Data in print is conflicting, and participants in studies are not all known toe HIV-positive. Deciding how aggressively to treat a patient with NHL is difficult, and may depend on clinical judgement and patient preference. Toxicities from treatment can be extensive, and dose modification is often called for. For the most part chemotherapy, which consists of an intravenous (IV) administration of several different drugs, is the treatment of choice. Although it should be noted that lymphoma involving the whole brain (or other specific sites of disease) often calls for radiotherapy, as well as intrathecal chemotherapy. Some of the chemotherapeutic regimens for lymphoma include the following: 1. Cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP). [23] 2. Cyclophosphamide, methyl-GAG, bleomycin, prednisone, doxorubicin, vincristine (NHL-7).[24] 3. Cyclophosphamide, vincristine intrathecal methotrexate, doxorubicin and prednisone induction (L-17).[25] 4. Methotrexate, bleomycin, doxorubicin, cyclophosphamide, dexamethasone (m-BACOD).[26] This particular regimen is considered standard therapy, and has been shown to demonstrate a complete remission rate in approximately 50% of patients.[27] MANAGING TOXICITY Innovations in dose scheduling, such as split-course or short and long-term continuous infusions, have alleviated the toxic side-effects of several chemotherapeutic agents.[28] Additionally, new trends seem to indicate that less may be better. In fact, a recent study reported that low-dose multi- agent chemotherapy along with CNS prophylaxis and antiretroviral therapy achieved remission in 18 (51%) of 42 patients.[29] Toxicities were also reduced. A study at the National Cancer Institute reported on the efficacy of combining chemotherapy with AZT and granulocyte- macrophage colony-stimulating factor (GM-CSF), a drug used to combat neutropenia and bone marrow damage from chemotherapy.[30] Pluda et al studied 11 patients with high grade systemic NHL. Treatment consisted of 21 day cycles of cyclophosphamide, VP-16, doxorubicin, vincristine, methotrexate and leucovorin. AZT was given at 500 mg/day and GM-CSF in doses of 10 microg/kg/day. Patients were given radiation and received aerosolized pentamidine to prevent PCP. Of the patients enrolled, five had ARC, three AIDS and three were asymptomatic. No patients experienced OIs [Opportunistic Infections], and three patients (43%) of the seven who were evaluable achieved a complete response. The authors conclude that although blood toxicity was observed, AZT and GM-CSF can safely be administered with chemotherapy. However, a modified protocol is in the works, which may cut back on toxicity. It should also be noted that the recently FDA approved GM- CSF, manufactured by Immunex Corporation, is expensive and may stimulate HIV (as opposed to G-CSF, which does not act on macrophages, HIV reservoirs). Additionally, reimbursement for the drug may be complicated when used for HIV-related conditions, since licensing of the drug is specifically for cancer patients. CONCLUSION NHL remains an illness to be reckoned with, especially as people with HIV live longer and receive better medical care for OIs. It is clear that better antiretroviral and/or immunorestorative therapy, as well as more optimal chemotherapy, will be required in order to impact upon the expected survival of patients with HIV-related lymphoma. However, early diagnosis and modified treatment regimens, especially those which use lower doses of chemotherapy drugs, may be promising options for the future. REFERENCES [Note: the source material for the following references contains a number of cosmetic errors, implying that numeric citations may also be inaccurate. Therefore, readers searching the literature may wish to be prepared for secondary or cross-referenced searches.] 1. Centers for Disease Control. Revision of the case definition of acquired immunodeficiency syndrome for national reporting -- United States. MMWR 34:373-5, 1985. 2. The Surveillance Program, Division of Cancer Prevention and Control, National Cancer Institute. Summary of 15 year trends. In: Ries LA et al. eds. Cancer Statistics Review, II:4, Bethesda, Md., 1973-1987. 3. Foreman J. Cancer risk in AIDS patients is said to rise as they live longer, Boston Globe, Wednesday, June 19, 1991. 4. Kinlen LJ. Immunosuppressive therapy and cancer. Cancer Surv 1:567-83, 1982. 5. Beral V et al. AIDS-associated non-Hodgkin [sic] lymphoma. Lancet 337(8745); 805-9, 1991. 6. Penn I. Lymphomas complicating organ transplantation. Transplant proc 15:2790-97, 1983. 7. Editorial. Lymphoma in organ transplant recipients. Lancet i:601-603, 1984. 8. Levine AM: Reactive and neoplastic lymphoproliferative disorders and other miscellaneous cancers associated with HIV infection, in DeVita VT et al (eds): AIDS: Etiology, Diagnosis, Treatment and prevention. Philadelphia, PA, Lippincott, pp. 263-276, 1988. 9. Ziegler JL et al. Non-Hodgkin's lymphomas in 90 homosexual men: Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med 311:565-570, 1984; and Oksenhendler E et al. Reversal of polyclonal hypoimmunoglobulinemia after HIV infection in a patient with myeloma. N Engl J Med 318:1540, 1988; and Levine AM: Reactive and neoplastic lymphoproliferative disorders and other miscellaneous cancers associated with HIV infection, in DeVita VT et al (eds): AIDS: Etiology, Diagnosis, Treatment and prevention. Philadelphia, PA, Lippincott, pp. 263-276, 1988. 10. Levine AM: Reactive and neoplastic lymphoproliferative disorders and other miscellaneous cancers associated with HIV infection, in DeVita VT et al (eds): AIDS: Etiology, Diagnosis, Treatment and Prevention. Philadelphia, PA, Lippincott, pp. 263-276, 1988. 11. Levine AM. Therapeutic approaches to neoplasms in AIDS. Review of Infect Dis 12(5);938-943, 1990. 12. ibid. 13. ibid. 14. ibid. 15. Hanto DW et al. Clinical spectrum of lymphproliferative disorders in renal transplant recipients and evidence for the role of Epstein-Barr virus. Cancer Res 41:4253-4261; HO M et al. Epstein-Barr virus infections and DNA hybridization studies in post-transplantation lymphoma and lymphoproliferative lesions: The role of primary infection. J Infect Dis 152:876-886, 1985; Purtilo DT et al. Documentation of Epstein-Barr virus infection in immunodeficient patients with life-threatening lymphproliferative diseases by clinical, virological, and immunopathological studies. Cancer Res 41:4226-4236, 1981. 16. Frizzera G et al. Lymphoreticural disorders in primary immunodeficiency. Cancer 48:692-699, 1980; and Ziegler JL et al. High-grade non-Hodgkin's lymphoma in patients with AIDS. Ann NY Acad Sci 437:412-419, 1984. 17. Beckhardt R et al. Increased incidence of malignant lymphoma in AIDS: A comparison of risk groups and possible etiologic factors. The Mount Sinai Journ of Med 55(5):383-389, 1988. 18. Moore RD et al. Non-hodgkin's lymphoma in patients with advanced HIV infection treated with zidovudine. JAMA 265(17);2208-2211. 19. Pluda et al. Development of non-hodgkins lymphoma in a cohort of patients with severe HIV infection on long-term antiretroviral therapy. Annals of Intern med 113:276-282, 1990. 20. Beral V et al. AIDS-associated non-Hokgkin lymphoma. Lancet 337(8745); 805-9, 1991. 21. Moore RD et al. Non-hodgkin's lymphoma in patients with advanced HIV infection treated with zidovudine. JAMA 265(17);2208-2211. 22. Harnly ME et al. Temporal trends in the incidence of non- Hodgkin's lymphoma and selected malignancies in a population with a high incidence of acquired immunodeficiency syndrome. Am J Epidemiol 128:261-267, 1988; Bernstein L et al. AIDS-related secular trends in cancer in Los Angeles county men: a comparison by marital status. Cancer Res 49:466-470, 1989; and Centers for Disease Control. Revision of the case definition of acquired immunodeficiency syndrome for national reporting -- United States. MMWR 34:373-5, 1985. 23. Elias L et al. Combination chemotherapy of diffuse histiocytic lymphoma with cyclophosphamide, adriamycin vincristine, and prednisone (CHOP). Cancer 42:1705-1710, 1978. 24. Lowenthal DA et al. The NHL-7: Alternating non-cross resistant, combination chemotherapy (CT) containing methyl-GAG (MG for diffuse (D) non-Hodgkin's lymphoma (NHL) (Abst). Proc Am Soc Clin Oncol 6:197, 1987. 25. Slater DE et al. Lymphoblastic lymphoma in adults. J Clin Oncol 4:57-67, 1986. 26. Skarin A et al. Moderate dose methotrexate (M) combined with bleomycin (B), andriamycin (A), cyclophosphamide (C), oncovin (O), and dexamethasone (D), mBACOD in advanced diffuse histiocytic lymphoma (DHL) (abst). Proc Am Soc clin Oncol 2:220, 1983. 27. Levine AM. Therapeutic approaches to neoplasms in AIDS. Reviews of Infect dis 12(5):938-943, 1990. 28. Braverman AS. Medical oncology in the 1990s. Lancet 337:901, 1991. 29. Levine AM et al. Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance in AIDS-related lymphoma. JAMA 266(1):84-88, 1991. 30. VIIth Internat Conf on AIDS, abstract #2368, Florence, 1991. ***** "An Ounce of Prevention: Update on Prophylaxis for Fungal Infection" by Gabriel Torres, M.D. The primary prevention of fungal infections remains a controversial area of treatment in HIV disease. Many health professionals fear that the cost of treatment, potential side effects, and development of resistance may outweigh the potential benefits of prophylaxis in many patients. However, fungal infections are very common and potentially very serious in HIV- infected individuals[.] Preventing an initial episode and subsequent recurrence of fungal infection is a worthy effort. PROPHYLAXIS FOR CRYPTOCOCCAL MENINGITIS A few studies were presented at the International Conference on AIDS in Florence, Italy to support the use of the anti-fungal drugs, fluconazole (Diflucan) and ketoconazole (Nizoral), as means for preventing widespread fungal infection in HIV-positive individuals. One study by Peterson and others from the University of Texas Southwestern Medical School reported promising results by comparing patients taking fluconazole to an historical control group of patients. The study compared 289 HIV-positive patients with T4 counts under 68 who received fluconazole (100 mg/day) to 366 patients, who did not receive fluconazole prophylaxis.[1] One fungal infection (disseminated cryptococcosis) developed in the fluconazole patients, and 20 infections (14 cryptococcosis and 6 histoplasmosis) occurred in the control patients. Another study from Brazil compared a group of 78 AIDS patients who received ketoconazole (200 mg/day) to 95 patients who received no antifungal therapy.[2] During the follow-up period, there were no cases of cryptococcal meningitis (CM) in the patients taking ketoconazole, but eight cases of CM in control patients. No patient had to discontinue ketoconazole due to toxicity. The most frequent complaints of patients taking [the] drug, included nausea during the first month of therapy and a rise in liver enzymes which proved to be reversible. Twenty-one patients died in the ketoconazole group, but of the 15 on whom autopsies were performed, none had fungal organisms. This suggest that death was probably not due to fungal infection. In the group that did not receive ketoconazole, there were 32 deaths. Of the 21 patients on whom autopsies were performed, three had fungal organisms. The authors postulate that even though ketoconazole does not penetrate well into the cerebrospinal fluid (CSF) and directly affect the brain, it may still prevent dissemination of fungus from the lungs. An earlier study presented by Dr. Howard Aronow suggested that ketoconazole was effective in preventing cryptococcosis.[3] Of the 210 HIV-infected men who were given ketoconazole in this study, none developed infection, whereas 11 of 91 patients, who were not receiving prophylaxis, developed disease. In addition, only five patients experienced toxicities which required withdrawal of the drug. PROPHYLAXIS FOR THRUSH Oral thrush is a very frequent condition, which generally occurs early in HIV infection in persons with relatively high T4 cell counts. However, widespread thrush, including involvement of the esophagus, trachea and bloodstream, tends to occur in patients with more advanced disease and lower T4 counts. Involvement of the esophagus often leads to ulcerations, painful swallowing and marked weight loss. The treatment of thrush often depends on the severity of the infection. Thrush of the esophagus usually requires systemic therapy with ketoconazole (Nizoral), fluconazole (Diflucan) or amphotericin B. A recent randomized double-blind trial compared fluconazole (100 mg/day) to ketoconazole (200 mg/day) in 143 patients with thrush in the esophagus.[4] The fungus was eradicated in 91% of the patients on fluconazole, as compared to only 52% of patients on ketoconazole. Symptoms such as difficulty swallowing and chest pain resolved in 85% of the fluconazole patients compared to 65% of the ketoconazole patients. It is noteworthy that most physicians continue prophylaxis with either ketoconazole or fluconazole therapy in patients who have sustained a bout of esophageal thrush, in order to prevent a relapse. In another placebo-controlled study oral thrush was prevented by fluconazole (100 mg/day) among patients with a history of recurrent thrush.[5] Thrush occurred in none of the patients on fluconazole compared to eight of 13 patients who received a placebo. Other agents which may be useful for prophylaxis of oral thrush are clotrimazole troches (Mycelex), Nystatin suspension or tablets and Peridex mouth rinses. PROPHYLAXIS FOR HISTOPLASMOSIS A report from Texas showed that fluconazole was not effective in preventing histoplasmosis in two patients with AIDS.[6] Whether itraconazole, a new anti-fungal drug for preventing relapse of disease, will prove effective in preventing initial bouts of histoplasmosis among patients in endemic areas remains to be seen. RESISTANCE Uncontrolled studies suggest that either fluconazole or ketoconazole may be beneficial in preventing initial fungal infections. However, Many professional are still concerned that widespread use of these drugs may lead to the development of resistant strains of fungi. Resistance means that new forms of fungus will develop in the body which are not killed by the drug usually used to control infection. Two studies presented in Florence demonstrated that the fungus which causes thrush became resistant to fluconazole after prolonged therapy. In a study from France, of the 28 patients with AIDS or ARC, 17.85% developed relapses of oral thrush while on fluconazole (50 mg/day).[7] Another report from Scotland studied three patients who had persistent signs and symptoms of oral thrush, despite treatment with fluconazole (150 mg/day, for one year). None of the three responded to higher doses of drug (200 mg/day) and all patients required treatment with amphotericin B and flucytosine (another anti-fungal treatment regiment). These cases illustrate that resistance can develop in patients maintained on long-term anti-fungal therapy, and such resistance impairs the use of the drugs when needed for treatment of acute infection. FUNGAL INFECTION AND T4 COUNTS Most prophylactic regimens can claim success when the OIs for which they are prescribed can be definitively linked to T4 counts. For example, it is now standard therapy to use PCP prophylaxis when an HIV-positive individual's T4 counts reach about 200 cells. Occurrences of PCP have been found to be clearly related to T4 counts under 200. However, when other OIs occur in relation to T4 cell counts, they are not as clearly defined. One Australian study published in the Journal of AIDS reviewed the occurrences of OIs in a retrospective study of 185 patients. [8] According to the study, esophageal thrush and cryptococcal meningitis occurred in patients with T4 counts between 75-125. According to a different study, cryptococcal pneumonia occurred in patients with T4 counts under 200.[9] Another French study by Isabel Lacomte, presented in San Francisco in 1990, showed that systemic cryptococcal disease almost always occurred in patients with T4 counts under 100. It is therefore reasonable to assume that most cases of systemic fungal infection will occur when T4 counts fall below 100, and that prophylaxis should be considered at this point. However, when to begin antifungal prophylaxis will remain controversial until more studies of resistance to antifungal drugs, cost-effectiveness of prophylaxis, and naturally [sic] history of OIs are completed. REFERENCES 1. VIIth Internat Conf on AIDS, abstract #W.B. 2279, Florence, June 1991. 2. VIIth Internat Conf on AIDS, abstract #W.B. 2307, Florence, June 1991. 3. Aronow H et al. Neurological manifestations of HIV infection. In AIDS 90 Summary, Philadelphia Sciences Group, Richmond, VA, 244. 4. VIIth Internat Conf on AIDS, abstract #W.B. 2317, Florence, June 1991. 5. VIth Internat Conf on AIDS, abstract #2165, San Francisco, June 1990. 6. VIIth Internat Conf on AIDS, abstract #W.B. 2360, Florence, June 1991. 7. VIIth Internat Conf on AIDS, abstract #W.B. 2357, Florence, June 1991. 8. Crow SM et al. Predictive value of CD4 lymphocyte numbers for the development of opportunistic infections and malignancies in HIV-infected persons. J AIDS 4:770, 1991. 9. Masur H et al. CD4 counts as predictors of opportunistic pneumonias in HIV infection. Ann Intern Med 111:223, 1989. ***** A Review of Fungal Infections in HIV Disease THRUSH: Candida albicans is a fungus that causes thrush, a condition otherwise known as candidiasis. This condition can appear in a variety of places in the body. Oral thrush appears as creamy white or yellow patches in the mouth, red splotches on the roof of the mouth, or cracks at the corners of the mouth. Candidiasis can also occur in the vagina in women, and appear as an odorous, white, creamy infection, and around the anal area in both men and women. CRYPTOCOCCUS: Cryptococcus meoformans is a one-celled yeast which can cause infection that can lead to inflammation of the lining of the brain, a serious condition known as cryptococcal meningitis (CM). CM occurs in approximately 10% of all AIDS patients and is fatal in nearly 60% of those infected. The usual symptoms may include headaches, altered mental status, fever and seizures. HISTOPLASMOSIS: Histoplasma capsulatum is the yeast that causes histoplasmosis, an infection which may affect many parts of the body, including lungs, lymph nodes and bone marrow. Symptoms include cough, fever and general malaise. This infection seems to occur more commonly in the southeastern, mid- atlantic and midwestern states in the U.S. and in the Caribbean. (For more information on fungal infection and prophylaxis see Treatment Issues, Vol. 5, No. 2.) ***** NAC: Efficacy Questions Remain Unanswered by Dave Roche Since initial reports in September, 1989, that the drug n- acetylcysteine (NAC) exhibited strong anti-HIV properties in laboratory experiments, new information has come to light confirming and expanding these findings. To date, all published work in this are is from test tube studies. Human drug trials have only just begun. Naturally, the nearly two-year delay in initiating a federally sponsored human study is hard to understand and enormously frustrating, especially since the drug looks so promising and is readily available through buyers' groups and elsewhere. PRE-CLINICAL TRIALS In September, 1989, two Stanford University microbiologists, Drs. Leonard and Leonore Herzenberg, announced at a conference in Switzerland that NAC inhibits HIV activity in test tube studies. NAC, currently prescribed to treat bronchitis and Tylenol overdoses, works by raising blood levels of a substance called glutathione. This substance has been found in levels well below the average in many HIV-infected individuals.[1] It is thought that glutathione is necessary to moderate the effects of tumor necrosis factor (TNF), a naturally-occurring protein which may trigger HIV activity in the body. TNF has been found in elevated levels in people with AIDS.[2] The Herzenbergs published other findings in June, 1990, showing that TNF stimulation of HIV activity can be inhibited by adding NAC to HIV-infected cells. These results were later confirmed in another study.[3] In fact, low levels of glutathione appear to correlate with over-sensitivity to TNF, implying that keeping glutathione at a normal level may prevent HIV activation.[4] In February, 1991, work by NIAID scientists, including Dr. Anthony Fauci, who has conducted much research with TNF and HIV, revealed that NAC suppresses TNG-triggered HIV activity. Additional test tube work published in June, 1991, indicates that NAC works in both recently-infected and chronically-infected T-cells and monocyte cells.[5] This is a potentially important finding, considering the immune function of T-cells and the fact that monocytes are reservoirs for HIV in the body. CLINICAL TRIALS The first of a total of twelve HIV-infected participants have enrolled in a NIAID study of NAC in Bethesda, Maryland in May, 1991. This phase I study is designed to last approximately one year and will test the safety and pharmacokinetics of the drug. Patients with T4 cells under 500 will be divided into three four-person groups. Both oral NAC (administered at home) and intravenous (IV) NAC (administered three times weekly at a clinic) will be given for a period of six weeks. Oral doses are 150 mg, 300 mg or 600 mg every 6 hours in the form of an effervescent tablet dissolved in water. The first of the three groups is now being completed, and so far no changes in surrogate markers (T4 cells, etc.) have been noted.[6] Patient recruitment is currently in progress for the second group but cost constraints limit it to people living within a 100-mile radius of Bethesda. Recruitment is still open, and more information can be obtained by contacting Chris Boenning, RN at 1-800-772-5464 ext. 401. ANECDOTAL INFORMATION Additional results of NAC are, for the most part, anecdotal and can lead to widely divergent conclusions. One patient featured in a December 10, 1989 New York Newsday article who had been taking NAC since January, 1989, died recently of lymphoma. However, another long-term NAC recipient, taking the drug for almost three years, has seen T4 cells increase from 300 to 450 and p24 levels drop sharply to near zero.[7] NAC is available through various buyers' groups that import different brands from Europe. One common brand, Fluimucil, is available in a 600 mg tablet. In general, Fluimucil is taken two or three times daily by many PWAs experimenting with the drug. Treatment Issues has also heard that some people are taking doses as low as 90 mg per day. It is unclear whether this dosing will result in levels comparable to those which were necessary to inhibit HIV in the test tube. The number of people taking NAC remains fairly high. The PWA Health Group in New York indicates that the drug is their second-highest seller (after ddC), with about 150 customers monthly. The approximate cost of taking NAC three times daily is approximately $2.25-$3.50 per day. To buy the drug or get more information, call the PWA Health Group at (212) 532-0280. Side effects and toxicity of NAC appear to be low but may involve infrequent allergic reactions, nausea, vomiting and fevers. There have been reports that NAC is also available through certain health food companies. However, it is likely that drugs produced under supervision at a pharmaceutical company may result in better quality control. It is believed NAC must be wrapped in foil (as Fluimucil is) to prevent potentially damaging exposure to air. ADDITIONAL THOUGHTS NAC has a relatively brief half-life of 5-6 hours in the body, implying frequent dosing to maintain appropriate levels of drug in the blood. Twenty to 25% of oral and intravenous NAC is eliminated unchanged in urine, raising questions about the degree to which the drug is absorbed in the body. Trials of another TNF-inhibiting drug, pentoxifylline, are in development at the NIH. A recent report has emerged that the FDA has granted the go-ahead to Clintec Nutrition Co. for a phase I trial of a glutathione-raising substance called Procysteine. Clintec reports that this trial will begin immediately. REFERENCES 1. Eck, HP et al. Low concentrations of acid soluble thiol (cysteine) in the blood plasma of HIV-1 infected patients. Biol Chem Hoppe-Seyler 370:101-108, Feb 1989. 2. Lahdevirta J et al. Am J Med 85:289-291, 1988. 3. Roederer M et al. Cytokine-stimulated human innumodeficiency virus is inhibited by N-acetyl-L-cysteine. Proc of Nat Acad of Sciences 87 (12):4884-8, 1990; and Staal et al. Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human innumodeficiency virus. Proc Nat Acad of Sciences 87(24):9943-7, 1991. 4. Kalebic et al. Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proc of Nat Acad of Sciences 88(3):986-990, 1991. 5. Roederer at al. N-acetylcysteine inhibits latent HIV expression in chronically infected cells. AIDS Research and Human Retroviruses 7(6):563-567, 1991. 6. Personal communication, Dr. R. Walker. 7. Personal communication, Dr. Leonore Herzenberg. ***** Outbreak of Drug-Resistant TB by Gabriel Torres, M.D. The Centers for Disease Control (CDC) reported several outbreaks of multi-drug-resistant tuberculosis (TB) among both patients with ANDS and HIV-positive health care workers (HCWs). The report was printed in the August 30th issue of Morbidity and Mortality Weekly Report (MMWR). In the first outbreak in a New York City hospital, 29 patients were diagnosed with TB, which was resistant to two common antibiotics used for treatment (isoniazid and rifampin). Nine of these patients also had resistance to ethambutol. Of the 29 patients, 93% were HIV-infected and 23 had AIDS. Within seven weeks of diagnosis, 72% of the patients with TB died. A year later, another 36 patients were diagnosed with resistant TB, 35 of whom were HIV-positive. Eighteen patients had TB strains resistant to isoniazid and streptomycin, and 12 patients were also resistant to rifampin and ethambutol. Strikingly similar incidences of drug-resistant TB cases have occurred in three other hospitals, two in New York and one in Miami, according to reports by the MMWR. Genetic typing identified that the TB strains were similar among many of the patients, suggesting that the tuberculosis was transmitted from one patient to another in the same ward. In all four hospitals, patients were not placed in isolation until they were already uninfectious. Of all the cases reported, eight were HCWs, five of whom had known exposure to TB-infected patients. Because TB was not detected during its infectious stage, most HCWs and hospital visitors did not wear masks. These outbreaks confirm that HIV-infected patients with advanced immunosuppression are more susceptible to tuberculosis. The CDC has recommended that patients who are suspected of having TB should be placed under respiratory isolation until they are treated and become non-infectious. Additionally, increased infection control precautions such as the use of tight-fitting masks, air exchanges in patients' rooms, and ultraviolet lights should be enforced. Routine screening of health care workers with skin tests and prophylactic therapy should be conducted to curb transmission in the workplace. The alarming report of TB outbreaks does not come as a surprise to many in New York , who have witnessed the emergence of drug resistance in the past several years among persons with HIV and tuberculosis. In fact, many on the front-lines have urged city officials to wage a more serious and effective preventive campaign. It is hoped that the publicity of these cases will strengthen the argument and urge local health officials to enforce stricter infection control in hospitals, clinics and other setting in New York City where patients with HIV congregate. Homelessness must be addressed as well, since non-compliancy with TB therapies is closely linked to unstable living situations. Transmission of TB is also well-documented within shelters for the homeless. These controls will ensure better treatment for HIV-infected individuals with TB, as well as protection for others. Screening with skin tests provides one mechanism to detect the infection prior to illness and should be utilized more often among patients, visitors, and others in close contact. ***** IN BRIEF ---------------------------------- COMBINATION DRUGS TO DECREASE TOXICITY OF AZT A report from a group of investigators in Los Angeles claims success in preventing low red blood cell counts (anemia) and low white blood cell counts (neutropenia) related to AZT by using the combination of erythropoeiten (EPO) and granulocyte-colony stimulating factor (G-CSF). Twenty-two anemic and neutropenic patients with AIDS or ARC interrupted their AZT therapy and received recombinant EPO (product name, EPOGEN) and G-CSF. Patients had increases in both red and white blood counts within two to eight weeks. Once AZT was restarted, six patients developed anemia, requiring blood transfusions and another interruption of AZT therapy; however, the remainder were able to tolerate large doses of the drug without recurrence of anemia or neutropenia. Opportunistic infections occurred in 14 patients, yet were treated successfully (many with ganciclovir) without recurrence of neutropenia. This small study, reported in a recent issue of Blood, suggests that the combination seems safe and is effective in counterbalancing the main hematologic side effects of AZT. Unfortunately, both of these drugs are administered by injections and both are very costly. HEPATITIS A OUTBREAK IN NEW YORK The New York City Department of Health has issued a warning to inform health care providers and others that an increase in cases of Hepatitis A virus (HAV) has been reported in gay and bisexual men in Manhattan. HAV is the least serious of all the hepatitis illnesses, with a low mortality rate of 0.06%. It is spread through intimate person-to-person contact (intrahousehold or sexual), and has all the symptoms of a flu. It is most infectious in the two-week period before the onset of jaundice (skin and urine turns a darkish yellow). The most effective way to prevent the spread of HAV is through careful handwashing with soap and water after using the toilet. Infected persons should also be advised not to handle food during the contagious period of the virus. Finally, household members and sexual partners of infected persons should be given a single intramuscular dose (0.02 ml/kg) of immune globulin (IG) as soon after exposure as possible. For more information consult a physician or call the Department of Health at (212) 566-1503. WHATEVER HAPPENED TO RIBAVIRIN? For a long while the answer to this question was simply, "Not much." Studies repeatedly showed that ribavirin failed to inhibit HIV, except at levels that proved to be too toxic. Additionally, it was discovered a few years ago that in the test tube ribavirin was antagonistic to AZT. However, in an August 17 letter appearing in Lancet, a Belgian doctor noted that in the test tube ribavirin greatly enhances the anti-HIV activity of ddI without increasing toxicity of the infected cell. The PWA Health Group will contest to the quickness with which good news travels; ribavirin is back in demand, according to a representative of the New York City underground buyers' group. For more information contact PWA Health Group at (212) 532-0280. ddI RESISTANCE Dr. Michael Bach of Maine Medical Center, reported in Florence that six patients who had AZT-resistant strains of HIV were treated with ddI for 12-15 months. Four patients had dramatic responses to ddI with drops in p24 antigen levels. The virus, however, became increasingly resistant to ddI, and four patients eventually deteriorated and died. But after 12-15 months off AZT, virus obtained from these patients had recovered sensitivity to AZT. This implies that AZT may still be beneficial to patients who develop resistance, since the virus may eventually be able to regain sensitivity to the drug. L-DRUG SUPPORT Bill Bahlman of New York City is starting a support group for people in clinical trials, taking the drug L-661. For more information about the drug or group, write to: 496-A Hudson Street, Suite J-11, NYC 10014, or call Bill at 929-4952. INSURANCE OUTRAGE In just weeks, hundreds of thousands of individuals may be forced off of private insurance and on to Medicaid because Empire Blue Cross Blue Shield, a major insurer of PWAs and HIV-positive people, is proposing drastic increases in its premiums. Blue Cross insurance companies in New York City, as well as the counties of Nassau, Suffolk, Westchester, and Rockland are facing insolvency, and therefore applying to the State Insurance Department to increase premiums by 50% for all individual coverage in October, 1991. This plan also calls for small businesses of three to 49 people to have employees fill out individual medical questionnaires. If any employee has "health problems," the premiums for the entire group increase by 50%. Blue Cross is claiming financial troubles in part due to their open enrollment plan, and the fact that other insurers have successfully lured away "good risk" (meaning healthy) customers by offering medical insurance at lower rates. Needless to say the impact of this plan will be disastrous, causing many to lose the means for access to reasonable health care. For more information, call the Insurance and Health Care Access Committee of ACT-UP, 135 W. 29th St., New York, NY 10001 at (212) 564- 2437. ***** Glossary AIDS dementia complex: A condition caused by HIV involvement of the brain which can lead to a loss of mental capacity. Anemia: A decrease in red blood cells. A condition which is often caused by AZT, as well as other drugs and conditions. Antiviral activity: The action of an agent that stops or suppresses the activity of a virus. Asymptomatic: An infection, or phase of an infection, without symptoms (i.e.: carrying antibodies to HIV but not displaying any of the symptoms of HIV infection). B cells: Type of white blood cell throughout the body that is able to detect the presence of foreign agents. Once exposed to the foreign agent, cells differentiate into plasma cells to produce antibodies. Bone Marrow: Soft tissue located in the cavities of bones and is responsible for producing blood cells. Brain biopsy: The surgical removal and examination of a small amount of tissue from the brain. Bronchitis: A disease marked by inflammation of the bronchial tubes in the lungs. Buyers' groups: A group that imports drugs that have been approved for use in other countries but have not yet been approved by the FDA for use in the United States. Central nervous system (CNS): The brain, spinal cord, and its covering called the meninges. Cerebrospinal fluid (CSF): Fluid which bathes the brain and the spinal cord. A sample of this fluid is often removed from the body for diagnosis purposes by a lumbar puncture (spinal tap). Co-factors: Conditions which must be present in order for a disease to flourish in the body. For instance, Epstein-Barr virus is a possible co-factor for non-Hodgkin's lymphoma. Congenital: Existing at or dating from birth. CT (also CAT) scan: Computerized Tomography, or CT, is a form of x-ray that uses a special beam to produce detailed images of internal organs and structures within the body. Cytomegalovirus (CMV): A virus related to the herpes family that can cause fever, fatigue, enlarged lymph glands aching, and a mild sore throat. In AIDS, CMV infections can produce hepatitis, pneumonia, retinitis and colitis. It can sometimes lead to blindness, chronic diarrhea, and death. Effervescent tablet: A tablet that fizzes to dissolve when placed in water; i.e., Alka Seltzer comes in effervescent tablets. Efficacy: Effective at the dose tested and against the illness for which it is prescribed. Epstein-Barr virus (EBV): A virus that causes mononucleosis. It is spread by respiratory tract secretions, such as saliva. EBV has been associated with lymphoma, a cancer of the lymph glands. Erythropoeiten (EPO): A drug recently approved as a treatment for HIV-related anemia. Produced by Ortho-Biotech. Esophagus: The conduit between the mouth and the stomach. Fluconazole: An antifungal drug (manufactured by Pfizer Pharmaceuticals) that has been approved by the FDA for oral candidiasis and cryptococcal meningitis (CM). It is still being studied for vaginal candidiasis and other fungal infections. Fungal infection: A range of distinct diseases caused by one- celled organisms, called fungi. Histoplasmosis, oral and vaginal thrush, and cryptococcal meningitis are all examples of fungal infections. Glutathione: An amino acid made by, and found in cells. The molecule is important to the ability of cells to metabolize. Granulocyte colony stimulating factory [sic] (G-CSF): A synthetic hormone that stimulates growth of both granulocytes, a specific white blood cell. The drug is used to alleviate the neutropenia caused by certain drugs and conditions. Granulocyte-macrophage colony-stimulating factor (GM-CSF): A synthetic hormone that stimulates growth of both granulocytes and macrophages (cells which can be reservoirs for HIV) and is also used as a treatment for neutropenia. Half-life: The time required for half of a substance to be excreted from the body. Historical control group: A group of people used for comparison in a clinical trial, but did not participate directly in that trial. Intrathecal: Administered directly into the spinal canal. Kaposi's sarcoma: A rare form of skin cancer, recognized as raised non-tender red or purplish spots on the skin. It may also occur internally (in the stomach or lungs, etc.) in addition to or independent of skin lesions. Lesions: A wound or injury, or a raised area on the skin. Lymph node: Small bean-sized organs of the immune system, widely distributed throughout the body, containing white blood cells, lymphocytes and macrophages. Lymphocyte cells: A type of white blood cell which are responsible for normal immune function. Monocytes: A large white blood cell which acts as a scavenger, capable of destroying invading bacteria or other foreign material. Multi-agent: Treatment with more than one drug. Oral hairy leukoplakia (OHL): A white lesion appearing on the tongue in patients with HIV; the lesion appears raised with a corrugated or "hairy" surface. p24 antigen levels: A marker of HIV replication which can be measured in the blood and represents a core protein fragment (p24) on HIV. Pneumocystis carinii pneumonia (PCP): A common parasite which infects the lungs of people with HIV infection and low T4 cell counts (usually under 200). Sometimes, PCP infections may occur elsewhere in the body (skin, eye, spleen, liver, or heart). Prophylaxis: Treatment intended to prevent the onset of an infection of disease. Refractory: Severe and recurring. Remission: Abatement or lessening in severity of the symptoms of a disease, or the period in which the abatement occurs. Resistance: Diminished effectiveness of a drug on a certain infectious organisms, which is able to change enough to avoid the drug's action against it. Sputum test: A way to diagnose tuberculosis by analyzing the mucus matter which collects in the air passage and upper food passage and is expelled by coughing. T4 counts: A type of T-lymphocyte. The T4 cell enhance the immune response to an infection through a complex series of interactions with other types of lymphocytes (B cells, T8 cells), macrophages, antibody producing cells and infectious organisms. T4/T8 ratios: The existence and complicated action of two types of white blood cell, one which naturally suppresses the immune system and the other which naturally mediate immune reaction. Together these T-cells keep the immune system in balance. Toxoplasmosis: Wide spread infection of an organ or the whole body with the parasite Toxoplasma gondii. Trachea: Windpipe; the passage in the throat. Tuberculosis (TB): A specific disease caused by a bacteria Mycobacterium tuberculosis which may affect almost any tissue or organ of the body. Tb is transmitted when the inhaled bacteria is coughed back into the environment by an infected person. Tumor necrosis factor (TNF): A natural cell substance which plays a role in many biological functions and may be implicated in stimulating HIV activity. ***** BULLETINS [insert to main issue] Editor's Note: This is the first in a series of TI Bulletins which will be enclosed with Treatment Issues each month. With these timely supplements, we will attempt to keep our readers informed of late breaking stories and updates which could not be included in Treatment Issues due to press deadlines. * Less Costly/Better PCP Prevention: Trimethoprim/sulfamethoxazole (brand names, Bactrim or Septra) is a drug for preventing Pneumocystis carinii pneumonia (PCP) which has recently been deemed superior to the standard (and significantly more expensive) treatment, aerosolized pentamidine (AP). This news comes from the results of a federally-funded study (ACTG #021), in which the risk of recurrent PCP was found to be 3.25 times greater in patients taking AZT with AP than in patients taking AZT with Bactrim or Septra. Some people experience severe allergies to Bactrim or Septra, as they are similar sulfa drugs both made of trimethoprim/sulfamethoxazole (TMP/SMX). For those without sulfa allergies, the savings from taking Bactrim or Septra may reach $3,000 per patient per year. * Sexual Precautions against Hepatitis A: The primary means of sexual transmission of the hepatitis A virus is by oral-fecal contact. Individuals are advised to practice safer sex by using a latex barrier between the mouth and the rectum when "rimming," and to wash with soap and water after coming into contact with feces. (For more information see In Brief in this issue.) * Rumors about New Swiss Treatment: A Hungarian physician, Dr. Roka has attracted widespread attention among U.S. AIDS patients and their physicians with a new drug derived from 18 plants and herbs. The substance is extracted from medicinal plants, a procedure which removes the toxic components of the plants, leaving a compound which is said to have antiviral and immune-boosting activities. One such extract (Calciviren) is administered by intravenous and intramuscular injections over a three day period in conjunction with ozone therapy (a procedure by which blood is mixed with ionized oxygen and then reinfused). The other extract (Rovital) is administered by either drops mixed with juice or a gel taken orally. A cream form of Rovital is also available to be applied directly to KS lesions. Roka has been administering the extracts in Switzerland for about a year. Dr. Roka reports treating 136 HIV+ patients in Tanzania in an uncontrolled experiment between July 1988 and April 1989. He reports a resolution in symptoms such as fevers, cough, diarrhea and a regression of swollen glands in a majority of patients. In Switzerland, Dr. Roka reports successful treatment of approximately 70 patients, 20 of whom were Americans travelling abroad for the treatment. Discontinuation of antiretroviral therapy (AZT, ddI, or ddC) and therapies for CMV or herpes is required. The cost of the therapy is approximately 4600-5300 Sfr. (about $3,000), which includes consultation and the extracts, but not cost of travel or accommodations in Europe. A corporation based in Salt Lake City, called Advanced Biological systems, Inc., is interested in testing the drug and has financed some preliminary toxicology tests in Kingston, Jamaica. A double-blind clinical study is planned in Jamaica under the direction of Dr. Patricia Burke. The sponsor claims that clinical protocols have been designed to meet FDA and World Health Organization guidelines. There is no evidence that these substances have anti-HIV activity or immune boosting effects, since laboratory tests using HIV-infected cell lines have not been conducted. The substances have not been tested in standard animal models to assess effects on different organs and body tissues. Likewise the safety and efficacy in humans have not been demonstrated, nor have toxicities been ascertained. Withdrawal of antiretroviral and other antiviral therapies should not be done without consulting with a physician. Treatment Issues, along with researchers at NYU Medical Center, has requested that Dr. Roka allow his compounds to be tested in a New York laboratory. We are awaiting a reply. Given the nature of the information we have available, at this point, PWAs are advised to proceed with caution when pursuing this treatment. (See "How to Evaluate New Treatments" in TI, Vol. 5, No. 3.) * More "L" Drugs to Come: AIDS treatment activists from GMHC, ACT UP/NY, and Project Inform met with executives from Merck & Co, Inc. on September 20, 1991 to discuss the company's plans for continued development of its reverse transcriptase compounds, the so called "L" drugs. L-679-661 is already in phase II trials at sites in Maryland and Alabama. Merck officials told activists that preliminary analysis of efficacy results should be available by February 1991, and that, barring unforeseen developments, large scale testing of the "L" drugs, in mono- and combination-therapy should begin during the first three months of 1992. Officials also disclosed plans to test L-697-661 in combination with AZT in Germany. Test tube studies show that another promising "L" compound, L-229 may be more easily absorbed and less toxic; though, so far no major toxicity has been observed in L-661 in human trials. It should be noted that Merck is developing a whole range of "L" drugs, and even if L-661 shows efficacy from these initial trials, other "L" compounds may also go into large scale trials. Activists have urged Merck to make clinical trials and other access programs available simultaneously with the initiation of any large scale trials to insure the drug is available to all PWAs who have failed nucleoside analogue therapy. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display