Subject: Dementia; IMREG-1; ddC; Dextran Date: June 1 1988 (1033 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Volume 2 Number 4 June 1, 1988 In this issue: Dementia and HIV-Infection IMREG-1 ddC Dextran Sulfate Update New Studies In Brief Dementia and HIV-Infection by J. David Seaman, Ph.D. The term "AIDS dementia complex" (ADC) was definitively introduced into the scientific literature in 1986 (1), and has recently appeared in the lay press as well (2,3). The simultane- ous use of the term in two very different contexts bears enormous potential for confusion not only because of the complexity of AIDS but also because of the complexity of dementia. This arti- cle seeks to dispel some of the potential for confusion and to moderate some of the resulting fear associated with the term "AIDS-dementia" by examining the term and by critically reviewing published scientific reports about the phenomena to which the term refers. The arguments advanced in this article are that the incidence of ADC has been overestimated by researchers and by the general public and, further, that diagnoses of ADC are being made on the basis of inadequate and often faulty data. Definition of Dementia and ADC Psychological Parameters: As the word dementia is used in a medical context today, it refers to a "loss of intellectual abil- ities of sufficient severity to interfere with social or occupa- tional functioning" (4). Memory, reasoning, judgment, and language-use, among other abilities, may be impaired. The defin- ition of the dementia syndrome is quite broad, and may include impairment in one, several, or all of these intellectual func- tions. Researchers, however, usually attempt to specify those intellectual functions that are impaired in a given form of dementia. The dementia associated with Alzheimer's disease, for example, differs significantly from that associated with multi- ple, small, cerebral strokes (multi-infarct dementia). ADC is a particular form of dementia: some researchers, therefore, have attempted to specify the particular intellectual functions adversely affected in ADC. Most frequently cited as intellectual functions impaired in ADC are memory and concentration (l,5); also cited as impairments characteristic of ADC are confusion (l,6), and mental slowing (l,7). Other investigators, however, accept impairment in any area of intellectual functioning as evi- dence of ADC. Grant (8), for example, accepts a low score on any one of nine different psychological test measures as adequate evidence of a dementing disorder. Thisinconsistency in defining the psychological parameters of ADC is compounded by inconsisten- cies at other levels. Organic Parameters: It is important to note that whatever the impairment in intellectual functioning, it does not lead automatically to a diagnosis of dementia. A diagnosis of demen- tia is made only when intellectual impairment can be attributed to a currently ongoing dysfunction of the physical organism (specifically, the brain). Examples of organic dysfunction that can lead to dementia include tumors, medication effects, infec- tious processes, and trauma. In ADC, dementia is not due to these factors; dementia due to these factors has been variously described as AIDS-related dementia, AIDS-encephalitis, and AIDS encephalopathy.ADC is believed to be due to a "direct effect of the virus on the brain" (7). This viral effect constitutes the organic dysfunction that leads to intellectual impairment, thereby justifying a diagnosis of dementia. There is little con- sistency, however, in the various reports concerning the brain dysfunction presumed to be caused by the virus. In some cases of ADC, there is shrinking of the cortex of the brain (cortical atrophy) and accompanying enlargment of fluid-filled cavities (ventricular enlargment); but, in other cases, there are no such findings: brain structure appears normal (l). Similar discrepan- cies have been reported using other indicators of central nervous system involvment such as electroencephalogram (EEG) (5) and cerebrospinal fluid (CSF) (l,5,9). Motor Parameters: Motor dysfunction has been associated with ADC, but these reports are likewise inconsistent: some indi- viduals reportedly demonstrate gait problems or a loss of fine motor control in picking up objects; many, however, have no such difficulties, yet all are diagnosed as ADC. These inconsistencies in defining the psychological, motor, and organic parameters of ADC are not necessarily indictments of the concepts that generate them and may reflect the fact that the disorder itself lacks pre- cision. Which intellectual or motor functions are impaired may vary as a function of the areas of the brain attacked by the virus. But such all-inclusive definitions do present the danger of being catch-alls for any impairment in intellectual function. These reported differences in presumed characteristics of ADC have led one group of observers to conclude that AIDS as a diagnostic entity rests on criteria that are "variable" and "vaguely defined" (10). They, too, have charged that as a conse- quence of this very broad definition of ADC the incidence of ADC is overestimated. Diagnosis of ADC If the literature on ADC is replete with vagueness in cri- teria, this vagueness is overshadowed by the willingness of some investigators to accept relatively scant and unreliable evidence to diagnose ADC. Navia (l), for example, accepts as adequate evidence of mild dementia a simple notation in hospital records of "complaints of cognitive impairment" made by individuals withHIV-related disorders who, at the time of Navia's survey, were already deceased and not available for objective assessment. Similarly, though most researchers rely on a patient's subjective report of memory deficit as the single most important and charac- teristic deficit of ADC, formal memory testing reveals no deficit (7,8). The reliability of a patient's subjective complaint is brought into question by these findings and so, too, are diag- noses that are based on these unverified reports. Further, nei- ther Grant nor other investigators of ADC have reported test results or other indicators of premorbid adjustment; that is, no one has shown that a given individual's performance has gotten worse since HIV-infection. In the absence of such information, one would need considerably more subjects than have been tested by current investigators to make the group norms they report sta- tistically meaningful. Inadequate assessment, questionable data, and incomplete histories will necessarily lead to false estimates of a disorder's frequency. Differential Diagnosis: Beyond these criticisms, researchers and clinicians know that a diagnosis of ADC should only be made when all other possible organic causes of an intellectual disorder in an HIV-infected individual have been ruled out. Cytomegalovirus, herpes simplex virus, and toxo- plasmosis are examples of agents that cause dementia in individu- als with HIV-disorders; they are typically ruled out by profes- sionals. Nonorganic or "psychological" causes should, of course, also be ruled out. Yet few researchers, in arriving at a final diagnosis of ADC, have applied sufficiently rigorous stan- dards to do so; depression and anxiety and other psychological variables are rarely ruled out in individual cases and, indeed, are rarely even mentioned in reports. An intellectual dysfunction resulting from a psychological cause is nearly indistinguishable from an intellectual dysfunc- tion caused organically. The former dysfunction is referred to as a "pseudodementia" (4); differentiating it from a true demen- tia is a difficult task even for the neurologists, neuropsycholo- gists, and psychiatrists who are frequently called upon to make such judgments. The potential for confusion here is clear: When there is evidence of intellectual dysfunction, to which factor or factors does one attribute that dysfunction? If mild intellectual dys- function (forgetting, for example) is experienced by an indivi- dual who is asymptomatic, HIV-seropositive, should one attribute that dysfunction to anxiety, depression, or stress in the face of a catastrophic illness or should one simply attribute it to a direct effect of HIV and diagnose it as dementia? Also, there is no theoretical reason why a pseudodementia cannot coexist with a true dementia. One can, for example, become depressed about an experienced memory loss resulting from a brain infection; the infection-caused memory loss can be worsened by the superimposed depression. These putative causes do not exhaust the possibili- ties, all of which need to be ruled out or ruled in. The need for a team of various health professions to cooperate in the diag- nosis and to minimize the risk of overdiagnosisis underscored. Estimates of Frequency There are no upper limits to the number of individuals who allegedly suffer from or who are at risk for dementia. Some writers contend that greater than 66% of all AIDS patients show some degree of ADC (l,9) and they caution that significant numbers ofindividuals who are HIV-infected but asymptomatic like- wise show some evidence of ADC. Formal and comprehensive studies of the frequency of ADC among individuals with HIV-related disorders have not yet been done. But, at a recent meeting of 48 experts in clinical research, psychiatry, neurology, and health policy held by the World Health Organization in Geneva, estimates of a high percentage of ADC among asymptomatic HIV-seropositive individuals were rejected as baseless (11). Selected vs. Random Samples: The high, informal estimates of ADC are offered primarily by neurologists who, as a rule, see patients on a consulting basis; that is, individuals have been referred to them because the patient and/or the primary care phy- sician has already noted a deterioration in the patient's cogni- tive functioning. The patients seen by neurologists, therefore, are prescreened; they are not representative of the larger popu- lation of HIV-infected individuals whom the neurologists never see. (Navia (l), however, believes that among the latter group are many individuals with mild forms of dementia that are discer- nible only to neurologists; they present no evidence to support this contention.) In a recent study by Bruhn (10), individuals with AIDS were chosen randomly and then assessed by neuropsychological testing,The incidence of psychological impairment in this group was considerably lower than estimates given by others: of l6 patients, only l showed evidence of intellectual impairment suf- ficient to warrant a diagnosis of dementia. Overestimation of ADC by the Public The definition of dementia includes a reference to the severity of the intellectual impairment: there must be a loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. But, the degree to which these intellectual abilities may be impaired can vary tremen- dously, still within the confines of the medical definition. A person may be presumed to have "mild dementia" even with very slight impairment of intellectual functioning and, as a conse- quence, only slight interference in occupational or social func- tioning. In some research uses, as noted above, a presumptive diagnosis of dementia is made given slight intellectual impair- ment even in the absence of demonstrated occupational or social dysfunction, e.g., on the basis of a single psychological test (8) or on the basis of a patient's single complaint (l). In general usage, however, dementia is defined (as it is in a non-medical dictionary (12)) as "severe impairment or loss of intellectual capacity and personality integration" (emphasis added). Such a definition necessarily implies gross disruption in social and occupational functioning. Given this difference in meanings, it is understandable that excessive fear and confusion are widespread; when researchers write of HIV-related diagnoses and dementia, where dementiais seen as a continuum from very slight to severe intellectual dysfunction, dementia may be comprehended by a wider audience as severe dysfunction only. The incidence of dementia associated with HIV-infection (possibly already exaggerated by researchers) may be exaggerated even further by a lay audience that perceives all dementiaas severe. Again, anxiety is needlessly heightened. Prognosis and Treatment. Given that there are multiple possible causes for dementia (and multiple possible treatments), it follows that the disorder has multiple possible paths. But this fact seems also to escape general notice. Dementia (mild, severe, or otherwise) may pro- gress or reverseor it may remain relatively unchanged. If a dementia is caused by medication, the course of the dementia may be reversed by altering the medication regimen. If a dementia is caused by an infectious process, appropriate treatment of the infection may resolve the intellectual impairment. Dementia is not always progressive. Even if one mistakenly assumes that one's inability to remember someone's name at a party is a sure sign of dementia, one need not compound that error by assuming further that the so-called dementia will progress unalterably to greater intellectual impairmentand to total physical dependence on others. Again: reasonable assessment of suspected intellectu- aldysfunction needs to be made by a team of health professionals working with the individual to establish the extent of the disorder (if any), its cause (or causes), its likely path, and potentially effective treatment. Treatment is dictated in good measure by diagnosis. When all other possible causes of an intellectual dysfunction have been ruled out or ruled in and appropriate treatments considered, tried, or rejected, options for treatment of ADC can be weighed. Recent reports of effective treatment contradict a prevalent view that there is nothing to be done for dementia. Some success in alleviating dementia has been obtained with zidovudine (AZT) (13); methylphenidate and dextroamphetamine have also been useful (14). Any of the as yet unapproved alternate substances that cross the blood-brain barrier could also be effective. Obtaining accurate assessment of an intellectual impairment and adequate treatment for it are ultimately the responsibility of the individual. It is an awesome responsibility that must be met while overcoming fear and anxiety. Health care professionals and researchers also have a responsibility not only to sound clinical practice and to sound scientific method but to the pub- lic they serve; they need always to be mindful of the implica- tions of their work and sensitive to the larger meanings of the concepts and terms they use. "Dementia" is a term loaded with frightening meaning for the general public. The responsibility of clinicians and investigators to deal with the phenomena cau- tiously and sensitively is also awesome; any divergence from sound clinical practice and from the strictest of scientific methods has implications that extend far beyond the office or the laboratory to the realm of social policy where advocates of ignorance and hatred are prepared to make a tragic situation much the worse. IMREG-1 by Karen Dennis Imreg, Inc., a small biomedical company in New Orleans, has been discreetly conducting tests of their drug IMREG-1 for almost three years. They recently announced (March 8, 1988) the results of "preliminary analysis" of their double-blind placebo- controlled study of IMREG-1, which is classified as an immunomo- dulator (immune booster). The reported results are promising, although sketchy and indicate that the therapy may retard the progression to full-blown AIDS in people with ARC. The year-long study was begun in January 1987, and involved a total of 158 volunteers, treated at eight medical centers around the country. According to press reports and findings presented previously, IMREG-1 can enhance immunological function in PWAs and PWARCs, and it has been associated with clearing of chronic oral candida infections, as well as prevention of weight loss. No toxicity has been observed in tests of IMREG-1 in three years of clinical tri- als, and there are no reported side effects. Pending formal presentation of their results in a scientific forum, and licens- ing by the FDA, the company is withholding further publication of their data. However, the results of earlier studies not involv- ing the double-blind or placebo controls provide some information about this potential new therapy. Background IMREG-1 is a leukocyte (white blood cell)-derived immunomo- dulator isolated from serum of "healthy" (i.e., HIV- negative) individuals. Studies had shown that leukocyte extracts could sti- mulate the production of interleukin-2 (IL-2) -- one of the "mes- senger" agents (lymphokines) with which white blood cells communi- cate, and which is known to be deficient in AIDS patients. These extracts had also been associated with improvements in "skin testing", or delayed-type hypersensitivity (DTH, sometimes referred to as DHR). DTH is a crude but readily available meas- ure of immunoreactivity. IMREG-1 was isolated and tested in the test tube, where it was also found to enhance the production of two other lymphokines, MIF (macrophage inhibiting factor) and LIF (leukocyte inhibiting factor) in "normal" blood samples, and of IL-2 and gamma interferon in cells from subjects with AIDS or ARC. Clinical trials These results lead to preliminary clinical testing of IMREG-1. 16 PWAs, 9 of whom had no prior therapy, received injec- tions of 0.1 cc IMREG-1 intradermally (in the skin), at four-week intervals, for a period of three months. 9 of the subjects had a diagnosis of KS, 3 had both KS and an associated opportunistic infection, and 4 had had an opportunistic infection without KS. All had negative DTH skin tests to tetanus, candida, and mumps, and 10 of 16 had below-normal T-cell responses; all had total white blood cell counts far below normal levels, and T4/T8 (helper/suppressor) ratios between .04-.85. All 16 patients com- pleted at least two cycles of treatment, and 5 completed all three. White blood cell counts and T4/T8 ratios showed no improvement. Improvement on all skin test challenges was gra- dual, with the maximum effect occurring after dose 2; however, after the third dose, 7 subjects had positive DTH responses, and 50% of those with below-normal responses had reached a normal level (15); 2 more had improved, but remained below normal. One patient showed a decrease in response, a result not discussed further in the report available. Of the 12 PWAs who had KS, 9 stabilized, but three experienced some progression of the disease. No side effects or toxicity was noted in any of the subjects (16). In a separate trial that involved 6 biweekly injections of IMREG-1, 9 of 16 subjects (12 PWARCs, 4 PWAs) experienced loss of fever and night sweats, and none had any weight loss. 9 of the 10 PWARCs regained full skin test reactivity, as did 2 of the 4 PWAs (17). Next, studies were undertaken to determine the efficacy of different ways of administering IMREG-1. People with AIDS or ARC were enrolled in three studies of 16 subjects each, receiving injections as follows: (A) once every four weeks, subcutaneously (under the skin); (B) once every two weeks, subcutaneously; or (C) once every two weeks, intradermally (within the skin). Again, no toxicity attributable to the drug was observed, blood cell measures showed stabilization, and previously resistant candida infections began to respond to treatment. For the three groups, skin test reactivity (DTH) returned or increased in (A) 47%, (B) 57%, and (C) 75% of subjects; average numbers of T-cells increased or were unchanged in (A) 31%, (B) 44%, and (C) 81%, respectively, suggesting that the optimal treatment is (C), intradermal injections. In an effort to establish optimal dosing of IMREG-1, another study was carried out. 29 PWAs received IMREG-1 at either 14-day or 28-day intervals, 15 in the former group and 14 in the latter. About half of both groups had a return of skin test reactivity (DTH); 60-70% of both groups also showed increased IL-2 (interleukin) production. The monthly group had no overall weight loss, while the bi-weekly group gained an average of 4 lbs. In both groups, candida cleared or improved in most sub- jects who had experienced infection. Clinical improvement overall seemed better in those subjects treated bi-weekly, although both groups had lower levels of opportunistic infections as compared to six months previous to therapy (18,19). Based on the results of this study, further trials of IMREG-1 have used the 14-day interval. It is important to note that these studies (which now serve as the basis for "optimal" IMREG-1 dosing) were extremely short in duration and were not double-blind, which would be the authoritative basis for clinical application. The results, however, were sufficiently encouraging to lead to further studies, with larger numbers of volunteers at a number of medical centers. 400,000 cell equivalents of IMREG-1 were admin- istered to more than 50 PWAs/PWARCs over a three month period, at either 14-day or 28-day intervals. Again, no consistent change was seen in T4/T8 ratios, although about half showed increases in the numbers of T4 cells. Subjects with a 10% or greater increase in T-cells began to show significant improvements over their baseline conditions at 7-14 days following treatment; those with smaller increases in T-cells reacted more slowly, and with smaller changes in the levels of IL-2 production. The research- ers observed the best overall effects in people having at least 100 T4 cells. More than 60% of the subjects who had had totally non-reactive skin tests (DTH) regained some response. Some patients experienced weight gain, clearing of chronic candida infections, but numbers are not noted in the report available (20). The recent results The outcome of these clinical tests led to the establishment of a large, double-blind, placebo-controlled trial. The results of this trial were the subject of the announcement by Imreg, Inc. that is mentioned at the beginning of this article. 102 volunteers at eight medical centers received bi-weekly intrader- mal injections of 400,000 cell equivalents of IMREG-1, and 56 received a placebo, for up to a year (six months at most of the centers). Eligible volunteers had to have T-cell counts of at least 100 but less than 400; systemic symptoms of ARC; and/or candidiasis (thrush). Among the results announced in the Imreg, Inc. press release on March 8, were indications that the drug can slow or prevent the appearance of PCP. Resistance to opportunistic infections (specifically, candida) and prevention of weight loss have also been observed, along with resolution of fever and night sweats. According to this report, skin test reactivity has been restored, and qualitative tests of T-cell function (mitogen responses) improved. Production of at least three lymphokines increased (IL-2, MIF, and LIF), and in some subjects, T-cell counts improved. The best results were seen in those subjects with the highest initial white blood cell counts, but some signs of improvement were seen even in those people with full-blown AIDS. It must be emphasized that their actual data has not yet been released, and this is all based on a press release. Summary These results suggest that IMREG-1 may have the potential to bolster immunological function in people with ARC, slowing the progression to AIDS without observable side effects, and is easily administered. Unfortunately, the data behind this latest report are not yet available, pending their presentation in a recognized scientific forum. Imreg, Inc. has applied to the FDA for a license for IMREG-1, and the company hopes to avoid a repetition of the controversy that surrounded the press release by ICN Pharmaceuticals, another small biotechnology company, of results of their studies on Ribavirin. IMREG-1 seems to be purely an immunomodulating agent, as no antiviral effects have been noted. And since the effective therapy of AIDS will probably involve both antiviral drugs and immunomodulator drugs, a combination trial of IMREG-1 and AZT seems warranted (and is now on the drawing board). Until further information is released by Imreg, Inc., detailing the results of the current trial, it will remain difficult to judge the true value of therapy with IMREG-1. Nevertheless, the potential existence of a drug which slows or halts progression to AIDS in PWARCs, and which appears to have no toxic side effects, is of compelling interest. Availability Dr. Gottlieb can be reached at 1430 Tulaine Avenue, New Orleans LA 70112 for information on ongoing clinical trials. ddC (dideoxycytidine) With the accumulation of knowledge about both the usefulness and the limitations of AZT as a weapon against AIDS came the hope of finding substances similar to it that would prove to be even more effective therapeutic agents, either through greater antiviral activity or reduced toxicity. Chemically speaking, both AZT and 2',3'-dideoxycytidine (ddC, for short) are members of a family of substances known as "nucleoside analogs". It was found that ddC is about ten times more potent than AZT against HIV in the test tube (21), a discovery that raised the hope that ddC might be likewise effective in humans. Background Both AZT and ddC attack the virus at the same point in its replication cycle, when the viral RNA is being converted (tran- scribed) into DNA. This process involves the stringing together of substances known as nucleosides to form a DNA chain. Nucleo- sides are the building blocks of DNA and are ubiquitous in the body. Cells draw on the pool of nucleosides to synthesize DNA every time they reproduce. For HIV, the Human Immunodeficiency Virus, this reaction is accomplished by an enzyme (present in the virus) known as reverse transcriptase. Drugs such as AZT and ddC act as "counterfeit" nucleosides. The key viral enzyme reverse transcriptase cannot distinguish these drugs from thymidine (a true nucleoside) and mistakenly incorporates them into the grow- ing DNA chain. However, AZT and ddC lack the ability to attach to the next nucleoside, thus prematurely terminating the DNA chain and resulting in a defective DNA molecule. Results to Date An initial phase I (dose-finding) study of ddC was conducted by the National Institutes of Health in 1987, in which ddC was administered to 20 male patients (8 AIDS with prior PCP, 8 AIDS with Kaposi's Sarcoma, and 4 ARC) in five escalating dose regi- mens (0.03 - 0.25 milligrams per kilogram of body weight) (22). The ddC was given intravenously for 2 weeks, then orally for an additional 4 weeks. Those patients who tolerated the 6-week regimen could opt to continue oral ddC for 6-8 more weeks. While two-thirds of those who received the middle three dose levels experienced significant rises in T4 counts by week 2 (average increase 38%), these gains were not sustained in the majority of cases through week 6 (an observation also seen with AZT). Of 13 patients with detectable p24 antigen during the study, 11 had substantial decline by the end of week 2, with 7 of these sus- taining the improvements through week 6. While a majority of patients benefitted at least transiently from ddC, the drug-related toxicities were formidable. All 10 of the patients who continued treatment beyond week 6 experienced a painful peripheral neuropathy (inflammation of nerves in the legs and feet) that frequently required morphine for relief. Most subsided after the drug was stopped, but many appear permanent. In addition, almost all patients suffered from a temporary "symp- tom complex" shortly after the start of treatment, including rashes, mouth sores, fevers and malaise. No cardiac, liver, kid- ney or bone marrow toxicity was observed. In other words, anemia and low white cell counts were not a problem as with AZT. ddC was found to penetrate into the sanctuary of the brain ("cross the blood-brain barrier"), an important requirement for any antiviral therapy. ddC in combination with AZT Because ddC appeared to exhibit an anti-HIV effect with a set of toxicities different from that of AZT, an approach con- sisting of a regimen alternating ddC and AZT weekly was tested in 6 patients (2 AIDS with prior PCP, 4 ARC) as part of the study cited earlier. 200 mg AZT and 0.03 mg/kg ddC was given every 4 hours for 7 days each. Two patients discontinued the regimen -- one due to an opportunistic infection and one due to ddC toxi- city. By the time the study was published, the remaining 4 patients had continued to complete 28 weeks of therapy with nei- ther neuropathy nor bone marrow toxicity noted. The 5 patients who completed 9 weeks of treatment had consistent increases in T4 cells during that period (mean increase of 48), and the 3 who had detectable p24 antigen at the outset of the study all experienced substantial drops in antigen over 9 weeks, indicating good antiviral effect. Information recently obtained on 15 patients on an alternat- ing weekly AZT-ddC regimen, including 6 patients who have under- gone treatment for 6 months and 1 patient for 10 months (23), reveals very substantial reductions in the toxicity of both drugs relative to the aforementioned ddC toxicity and to the toxicity normally ascribed to AZT when continuously administered over a comparable time period. T-cell increases have reportedly been sustained. Next Steps While these reports of reduced toxicity can definitely be regarded as good news, it is important to note that it is still too early to draw any conclusions on the efficacy of the AZT-ddC alternating regimen. In fact, since ddC has been tested for relatively brief periods in humans, the long-term safety of even very low doses of ddC is not yet known. While it has been reported that p24 antigen suppression can occur at a minimum active dose of 0.005 mg/kg (24), it is not understood what the optimal dosages are for either drug in this combination therapy setting, or even if alternating ddC and AZT at any dose is actu- ally more effective than continuously or intermittently admin- istered AZT alone. In an attempt to begin to answer these important questions, a large (200 patient) phase II multicenter trial will be starting in May through the AIDS Clinical Trial Group (ACTG) (formerly known as ATEUs). The study is divided into 7 "arms": (1-2) High-dose ddC and low-dose ddC alternating weekly with standard dose AZT weekly; (3-4) high-dose ddC and low-dose ddC alternating monthly with standard dose AZT; (5) high-dose ddC given alone (1 week on, 1 week off); (6) standard dose AZT given alone (1 week on, 1 week off); and (7) standard dose AZT given continuously. Patients who have never taken AZT or have failed it for any rea- son are eligible. The only concurrent medication allowed is aerosolized pentamidine. Patients on long-term Zovirax, anti- Toxoplasmosis drugs or DHPG are not eligible. The following medical centers will be participating in the study: University of Miami School of Medicine, Miami, FL (305) 549-7323. University of California at San Diego, CA (619) 543-6447. Stanford University School of Medicine, Stanford, CA (415) 723- 6231. Massachusetts General Hospital, Boston, MA (617) 726-5596. Tulane University Medical Center, New Orleans, LA (504) 587-7316. Washington University School of Medicine, St. Louis, MO (314) 454-0058. USC Medical Center, Los Angeles, CA (213) 226-5225. University of Minnesota Health Center, Minneapolis, MN (612) 625-1462. University of Washington, Seattle, WA (206) 223-4756. Johns Hopkins University, Baltimore, MD (301) 955-2898. Robert Wood Johnson Medical School, New Brunswick, NJ (201) 937- 7710. Interested individuals can contact the ACTG at these insti- tutions, but should bear in mind that the various centers will begin screening patients at different times. Summary While ddC represents the potential to both minimize the tox- icity of AZT and to enhance its effectiveness, substantial work obviously lies ahead to prove both of these hypotheses. As a single agent, it appears that its toxicity outweighs its thera- peutic benefit as a viable long-term drug. But while ddC should not be construed as a "quick fix" solution for anyone right now, since not only is it insufficiently tested but also unavailable to the general public, it does at least offer hope -- particu- larly to the AZT-sensitive -- of a more tolerable and durable anti-viral program. We will be issuing follow-up reports on the upcoming AZT/ddC trial. More on Dextran Sulfate Yet another report has appeared in the scientific literature indicating that Dextran sulfate blocks the binding of HIV to T- cells and prevents cell-to-cell transmission "at concentrations that may be clinically attainable in human beings." (25) With this report (which is out of the National Cancer Institute), it is likely that more vigorous efforts will be made to get a federally-funded clinical trial going. "Vigorous effort" when speaking of federally-sponsored research may mean several more months of delay. It's still too early to comment on the informal monitoring activities taking place in the offices of community physicians in New York. Meanwhile, there were some scares regarding continued avai- lability of Dextran sulfate. Recently, a shipment of 2 kilos of dextran sulfate shipped from Canada to the United States was seized. Buyers returning from Japan related stories of being refused large quantities of Dextran sulfate by wholesalers. This seemed pretty grim. However, more recent reports indicate that it is still possible to obtain large quantities in Japan, and that for the individual traveller/buyer, Dextran sulfate has not disappeared from the shelves of Japanese pharmacies, selling for about $130 for a 3-month supply. The most widely-distributed brand is "Kowa MDS 300." Other buyers have found that Dextran sulfate is also available in Hong Kong as well. Informal conversations with FDA officials have indicated that they will allow importation by mail and will not confiscate the drug; however, this has not been placed in writing. Project Inform (800-822-7422 or 415-558-9051) keeps abreast of sources of Dextran sulfate and have recently published an excellent fact sheet on the drug. (Incidentally, they have recently moved. Their new address: 347 Dolores St., Suite 301, San Francisco, CA 94110.) Other community-based PWA groups usu- ally have some information on availablility. AIDS Treatment News by John James recently listed a list of brand names and suppliers (issue #50) and has interviewed researcher Donald Abrams about the drug (issue #54, 55, and 56). New Studies Beth Israel Medical Center is conducting a study of erythro- poietin (EPO) for people with AIDS or ARC who are anemic. Anemia may have been caused by AZT or as a result of HIV infection itself. Candidates must be HIV positive and have a hematocrit of 30% or less. They may not be taking other experimental drugs or chemotherapy. The study will be double-blind placebo-controlled for a period of 12 weeks. This will be followed by a six-month open-label period where everyone will receive drug. In studies conducted thus far, there is a strong suggestion that EOP works in improving anemia in patients who have required multiple transfusions in the past (26). It is non-toxic. Thus, for anemic patients, this drug is definitely worth pursuing. 12 weeks is a short time, after which one is guaranteed of receiving an apparantly effective, expensive drug. Contact Carol Berkowicz, study nurse, at (212) 420-4519. An identical study of erythro- poietin will be conducted at The Mount Sinai Medical Center. Call John Schalhoub or a member of their research nurse team at (212) 241-3927 for more information. Mount Sinai is also making plans for a preliminary, phase I study of the immunomodulator drug AS-101. Published results of the drug in the test tube are promising (27), and the manufacturer claims that 5 AIDS patients with low T-cells (average of 68) had significant T-cell increases after 24 weeks of therapy (average of 189). Other parameters of T-cell function also improved (28). Toxicity has been minimal: some nausea and vomiting have been observed. This may hold promise in the frustrating search for drugs that can augment the damaged immune system in AIDS. A third study of erythropoietin will be conducted by the Community Research Initiative, subject to the Board's approval. The proto- col is identical to the two described above. It is liberal, allowing for a variety of medications taken concurrently. This is a large study -- 100 patients. Anyone with full-blown AIDS who is anemic (whether or not they are taking AZT) is eligible. Contact the CRI at (212) 463-8981. Another study of aerosolized pentamidine for prevention of recurrence of PCP is being conducted at the Stuyvesant Polyclinic in New York City. Anyone with AIDS and prior history of PCP within the last 6 months is eligible. Three different doses will be used: 5, 60, or 90 milligrams every 2 weeks using the Fison nebulizer (a good machine with small droplet size). The 5 milli- gram dose is essentially a placebo and is not thought to offer protection against PCP; however, patients will be followed very closely and any episodes of PCP will be caught early and treated aggressively. Although the ethics of this type of study can be debated, 100 patients who would not otherwise be receiving aero- solized pentamidine can receive it in this study which lasts 9 months. Furthermore, the Stuyvesant Polyclinic offers excellent general medical care for PWAs and accepts Medicaid. Finally, the Community Research Initiative's (CRI) study of aerosolized pen- tamidine is fully enrolled. For more information on this study, call Michael Fraich at (212) 674-0220. For more information on aerosolized pentamidine in preventing PCP, see Treatment Issues, Vol. 1 no. 1. St. Vincent's Hospital is conducting a study of the AIDS Dementia Complex (see related article on page 1). They will be looking at AZT versus the combination of AZT plus acyclovir (Zovirax). The only exclusions are patients with active oppor- tunistic infection or malignancy of the brain. It should be noted that this study is not a placebo-controlled study whereas other studies of the effects of AZT on AIDS Dimentia are. Patients to be screened for this protocol should be referred to Josh Torgovnick, M.D. in the Department of Neurology at (212) 790-7759. In Brief A Texas judge has issued an injunction against Parkland Hos- pital to stop practices which interfered with delivery of appropriate drugs to PWAs in the hospital. Parkland has been maintaining a waiting list of patients who need AZT, and was not allowing delivery of pentamidine to treat PCP. According to officials at the hospital, AZT was provided to a limited number of patients because of a lack of hospital staff to monitor reac- tions to the drug. Aerosol pentamidine was not allowed to treat PCP because it "is not an FDA approved treatment". However, the 23 PWARCs who were on the waiting list for AZT have been con- tacted, and aerosol pentamidine will now be administered if prescribed by a staff member of the hospital. Striking a sym- pathetic note, Judge John Marshall wrote in his opinion: "To whom must the victim turn? Obviously, the public must intervene or else adopt a policy that says: 'Let them die because we can't afford them'. Such a result is not tolerable in a society that for over 200 years has prided itself on placing human values first." This decision represents an important precedent in an area of the law that is yet unchartered and guarantees effective, life-saving therapies for people who need them. The Fourth International Conference on AIDS will take place in Stockholm from June 12-16. This well attended event gathers together most of the world's significant researchers and doctors treating HIV infection. Significant developments may include results of the half-dose AZT trial, the AZT/Acyclovir trial, vac- cine development, data on Naltrexone and possibly Carrisyn. Spe- cialized workshops have been planned to provide a forum in which to discuss the many AIDS related issues being dealt with world- wide by agencies such as GMHC. GMHC will staff a literature booth at the conference, and overall, many thousands of abstracts will be presented during the five day conference. Let's hope that the conference yields some encouraging news. Treatment Issues will report on any significant developments. Correction We have previously reported that Memorial Sloane Kettering Cancer Center and Beth Israel Hospital are coordinating a study of AL721 in PWARCs with persistent generalized lymphadenopathy (PGL). We incorrectly listed the criteria for inclusion into the study. Participants must have more than 200 T4 cells to be eligi- ble. Call Cynthia Vassallo, RN at MSKCC at (212) 794-7164. Dr. Donna Mildvan is coordinating the study at Beth Israel: (212) 420-4005. Other Resources American Foundation for AIDS Research (AmFAR) has updated their catalog of trials involving experimental drugs. The "AIDS/HIV Experimental Treatment Directory" also includes several glos- saries and information about the federal clinical trials efforts and licensing of drugs. Write to AMFAR at 40 West 57th St., New York, N.Y. 10019, or call (212) 333-3118. "AIDS Treatment News" is a short, biweekly report which chroni- cles current developments in experimental and alternative treat- ments and deals with public policy issues. Contact John S. James at P.O. Box 411256, San Francisco,CA 94141 or call (415) 282-0110. "PWA Coalition Newsline", published "by and for people with AIDS and AIDS Related Conditions," is a grass-roots news magazine that appears monthly. The publication reports news developments deal- ing with the health crisis as well as alternative treatments. Editorials and literary contributions add another interesting dimension to this excellent source of information. Write PWA Coalition Inc., 263A West 19th St., Room 125, New York, N.Y. 10011, or call (212) 627-1810. Ask about their other publica- tion, "Surviving and Thriving with AIDS". The Universal Fellowship of Metropolitan Community Churches pub- lishes a monthly newsletter called "Alert", covering AIDS related legislation, education, research and treatment. Write to Rev. Steve Pieters, UFMCC, 5300 Santa Monica Blvd., Suite 304, Los Angeles, CA 90029. "ATIN" (AIDS Targeted Information Newsletter) performs a monthly search of hundreds of medical journals worldwide. Definitely aimed at doctors and researchers, it is the best ongoing litera- ture search available. It has an impressive cast of editors who comment on the significance of the studies cited. Published by Williams & Wilkins, P.O. Box 23291, Baltimore, MD 21203 or phone 1-800-638-6423. Project Inform publishes an excellent newsletter called "PI Per- spective" which deals with experimental treatments and focuses special attention on drug regulatory issues and public policy. Another valuable resource is their up-to-date drug hotline. Call them at 1-800-822-7422. Body Positive is a new organization established by and for HIV- antibody-positive people to exchange information, advocate research, fight discrimination, andp rovide mutual emotional sup- port. They publish a monthly newsletter called "The Body Posi- tive". Write to: 263A West 19th Street, New York, NY 10011 or call 212-633-1782. Northern Lights Alternatives ("NLA") is an organization that was created to help PWAs channel their energy in positive, healing directions. The cornerstone of NLA is a program of weekend retreats called AIDS Mastery Workshops. The main goal of these workshops is to teach NLA's central philosophy: PWAs can improve the quality of their lives through self-empowerment. NLA dissem- inates material through the telecommunications network of GayCom. Anyone with a personal computer and modem can access this ser- vice. NLA Online has launched, as of September 1987, an AIDS Bibliographic and Abstract Service (ABAS). This database gathers together over 2000 medical articles from a variety of sources. For more information on NLA Online and ABAS, contact Bob Morse at 718-565-0087. For more information about NLA in general and the AIDS Mastery Workshops, contact Chuck Baier or Victor Phillips at 212-877-4846. "Healing AIDS" is a monthly magazine which focuses on holostic approaches to AIDS and ARC including diet and nutrition, relaxa- tion and visualization techniques, and stress reduction. It regu- larly lists other resources. Subscriptions are $10/year for peo- ple with AIDS/ARC/low income, and $15 for others. Write: 3835 20th Street, San Francisco, CA 94114 or Phone: (415) 821-7646. The AIDS Health Project at the University of California San Fran- cisco publishs a monthly newsletter called "Focus" written "to place data and medical reports in a context that is meaningful and useful to its readers." It provides easy-to-understand prac- tical information on AIDS research. Contact UCSF AIDS Health Pro- ject, Box 0884 San Franciso CA 94143 or phone (415) 476-6430. Treatment Issues is GMHC's newsletter devoted to experimental AIDS therapies, particularly those therapies which are available to PWAs. However, describing an experimental therapy should not be construed as recommending it. All new treatments should be done under a physician's care. Treatment Issues is published ten times yearly. Copyright 1988 Gay Men's Health Crisis, Inc. All rights reserved. Non-commercial reproduction is encouraged. Subscription lists are kept confidential. Editor: Barry Gingell, M.D. Associate Editor: Kevin Armington GMHC, Department of Medical Information, 132 West 24th Street, Box 274, New York, NY 10011 From the Editor This is our sixth issue of Treatment Issues. The response from our audience has been gratifying and supportive. Our mail- ing list is now over 5,000 strong, and the total number of copies printed is now 10,000. Your generous support has made this enor- mous growth possible. During the past few months we have also been fortunate to enjoy the volunteer services of a number of excellent writers who will enhance our publication even further. It is an enormous job to maintain our mailing lists (which are always kept confidential). Inevitably, duplications occur on our lists. If you receive more than one copy of Treatment Issues, please pass it along or let us know of the duplication. Thanks. Footnotes: 1 Navia BA et al. The AIDS dementia complex. I. Clinical features. Ann Neurol l9:5l7, 1986. 2 Joyce C Assault on the brain. Psychology Today, pp38-44, March 1988. 3 Helquist M. A sobering look at AIDS dementia complex. The Advocate, p34, April 26, l988. 4 American Psychiatric Association, Committee on Nomenclature and Statistics: Diagnostic and Statistical Manual of Mental Disord- ers, ed. 3. Washington, D.C., American Psychiatric Association, l980. 5 McArthur JC. Neurologic manifestations of AIDS. Medicine 66:407, l987. 6 Levy RM et al. Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): Experience at UCSF and review of the literature. J Neurosurg 62:475, 1985. 7 Price RW et al. The brain in AIDS: Central nervous system HIV-1 infection and AIDS dementia complex. Science 239:586 (5 February), 1988. 8 Grant I et al. Evidence for early central nervous system involvement in the acquired immunodeficiency syndrome (AIDS) and other human immunodeficiency virus (HIV) infections. Ann Int Med 107:828, 1987. 9 Hollander H and Levy JA. Neurologic abnormalities and recovery of human immunodeficiency virus from cerebrospinal fluid. Ann Intern Med. 106:692,1987. 10 Bruhn P et al. AIDS and dementia: a quantitative neuropsycho- logical study of unselected Danish patients. Acta Neurol Scand 76:443, 1987. 11 No neuropsychological abnormalities in healthy HIV-positive people. Report of a World Health Organisation consultation. Lancet:1008, 4/30/88. 12 The Random House Dictionary of the English Language. Una- bridged Edition. Random House: New York, l966. 13 Yarchoan R et al. Response of human immunodeficiency-virus- associated neurological disease to 3'-azido-3' deoxythymidine. Lancet 1:132, 1987. 14 Fernandez F et al. Cognitive impairment due to AIDS related complex and its response to psychostimulants. Psychosomatics 29:38, 1988. 15 Gottlieb, A. Arthur, et al. Observations on clinical and immunological parameters in AIDS/ARC patients treated with IMREG-1. III International Conference on AIDS, Washington, 1987, MP.218. 16 Gill, Parkash S. et al. 1984. Use of leukocyte derived endogenous immuno-modulator (IMREG-1) in patients with AIDS. paper presented to the 6th Annual Meeting of the American Society of Hematology. 17 Landesman, S. et al. Clinical and immunological response to IMREG with ARC/AIDS patients. III International Conference on AIDS, Washington, TP.228. 18 Gottlieb, A. Arthur, et al. Restoration of delayed hypersensi- tivity in patients with AIDS by a leukocyte derived immunomodula- tor, IMREG-1. II International Conference on AIDS, Paris, 1986, #604. 19 Gottlieb, A. Arthur, et al. Observations on treatment of patients with the Acquired Immunodeficiency Syndrome with IMREG- 1. II International Conference on AIDS, Paris, 1986, #603. 20 Gottlieb, A. Arthur, et al. Clinical and immunological improvement in AIDS/ARC patients treated with IMREG-1, an immu- nosupportive agent. III International Conference on AIDS, Wash- ington, 1987, THP.241. 21 Mitsuya H et al. Inhibition of the in vitro infectivity and cytopathic effect of HTLV-III/LAV by 2',3'-dideoxynucleosides. Proc Natl Acad Sci USA 82:7096, 1985. 22 Yarchoan R et al. Phase I studies of 2',3'-dideoxycytidine in severe HIV infection as a single agent and alternating with zido- vudine (AZT). Lancet:76, 1/16/88. 23 Broder S. Personal communication. 24 Merrigan T. Personal communication. 25 Mitsuya H et al. Dextran sulfate suppression of viruses in the HIV family: Inhibition of virion binding to CD4+ cells. Sci- ence 240:646, 1988. 26 Starrett, B. Personal communication. 27 Sredni et al. A new immunomodulating compound with potential therapeutic application. Nature 330(12):173, 1987. 28 Sredni B et al. A new immunomodulating compound AS101 with potential therapeutic spplication. 71st Annual Meeting of the Federation of American Societies for Experimental Biology, Wash- ington, DC, 1987. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display