Subject: AZT; Passive Immunotherapy; Compound Q Date: June 1989 - Issue #3 (1887 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Bulletin of Experimental Treatments for AIDS &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& This display has 1887 lines. You can't back up, it has to come in sequence. B-E-T-A (Bulletin of Experimental Treatments for AIDS) A publication of the San Francisco AIDS Foundation -- June 1989 Table of Contents [main topics separated here by *****] AZT Update AZT Studies Show Benefit and Toxicity HIV Develops Resistance to AZT AZT May Improve Neurological Functions New AZT Drug Erythropoietin for AZT Related Anemia AZT and Acyclovir Newly Reported Toxicities AZT Treatment Among Injection Drug Users AZT and HIV Related Thrombocytopenia (ITP) HIV Related Neuropathy Plasmapheresis for HIV Related Neuropathy Passive Immunotherapy Do You Remember CD4? The Early Promise of Compound Q The Dextran Sulfate Story: An Interview with Dr. Donald Abrams Directory of Open HIV Trials in the S.F. Bay Area Stanford Clinical Trials Group Treatment Resources Glossary ***** AZT UPDATE by Ron Baker "Zidovudine [AZT] is now the standard of care for persons with ARC and AIDS and should be given whenever possible." -- John Bartlett, MD 0*0* Clinical Research Director, AIDS Clinical Trial Unit, Duke University Medical Center. HIV Therapeutics, An Emerging Sci- ence. Journal of the American Medical Association 260(20):3051. "AZT is not a very impressive drug for treating AIDS." -- Andrew Moss, PhD 0*0* Director of AIDS Epidemiology Group at UCSF affiliated S.F. General Hospital. Remarks to the 73 annual meeting of the Federation of American Societies for Experimental Biology, New Orleans, March, 1989. Reported by CDC Weekly , April 3, 1989, p.3.. "AZT should not be used to treat asymptomatic HIV infected patients until further data are available from clinical trials." -- Mark Jacobson, MD and John Mills, MD 0*0* Dr. Jacobson is Assistant Professor of Medicine at UCSF. Dr. Mills is Professor of Medicine at UCSF and Chief of Infectious Diseases at S.F. General Hospital. Long term consequences of azidothymidine therapy of HIV infection using Delphi technique. Archives of AIDS Research 111(1,2,3):203 216, 1989.M [Words in this article followed by an asterisk are defined in the GLOSSARY at end of this whole display -- ed.] AZT is the only drug approved by the Food and Drug Adminis- tration to treat HIV infection, and it continues to receive the lion's share of attention in the research lab and in clinical trials. This issue of BETA reviews the results of recent research on AZT. Among the topics discussed are the role of AZT in increasing survival time for people with AIDS and severe ARC, its possibly transient benefits, newly reported toxicities, and a modified form of the drug, which researchers say is more potent and less toxic. AZT STUDIES SHOW BENEFIT AND TOXICITY Increased Survival Time A U.S. multi-center trial of 4,805 people with previous bouts of PCP* suggests that beginning AZT treatment early after the AIDS diagnosis increases survival time. 0*0* Creagh Kirk T, et al. Survival experience among patients with AIDS receiving zidovudine follow up of patients in a compassionate plea program. Journal of the American Medical Association 260(20):3009 3015, November, 1988. According to the authors, "...the finding of a strong associa- tion between stage of illness at time of initiation of therapy and survival suggests the need for study in patients still ear- lier in the disease process." Some individuals responded to treatment better than others. People with hemoglobin* levels above 12 grams per deciliter (.10 liter) had a higher survival rate, for instance, while those with transfusion acquired AIDS had a lower survival time. Gender or race did not appear to be factors in survival time. "The trend toward poorer prognosis in untreated women, IDU* and minorities with AIDS, as seen in the New York natural history cohort, was not seen in the present study." 0*0* Ibid No new information about the drug's toxicity came out of this trial. Only adverse effects requiring hospitalization were reported. Almost 20% of people in the study required 1 or more blood transfusions and 8.3% developed serious depletion of the white blood cells. 0*0* Ibid Transient Benefits. A French study of 365 individuals (285 PWA*, 80 PWARC*) underscores AZT's transitory beneficial effects and emphasizes the drug's toxicity. 0*0* Dournon E, et al. Effects of zidovudine in 365 consecutive patients with AIDS or AIDS related complex: a perspective study of 2 to 12 month therapy. The Lancet , 8623:1297 1281, December 3, 1988. The French researchers concluded that AZT had short term clini- cal benefits for study participants, but that in general, weight gains and T helper cell increases disappeared after six months. 0*0* Reported in AIDS/HIV Experimental Treatment Directory 2(3):31, December, 1988. Because of blood toxicity, 214 individuals (58%) had to stop taking AZT for at least 7 days. This study did show increased survival time for those PWA who began AZT sooner after diag- nosis. Fewer Opportunistic Infections. A study of 80 PWA and 33 PWARC taking AZT reports "improved well being and reduced frequency and severity of opportunistic infections" in the first year of follow. 0*0* Pinching AJ, et al. Clinical experience with zidovudine for patients with acquired immune deficiency syndrome and acquired immune deficiency syndrome related complex. Journal of Infectious Disease , 18(1,S 1):33 40, January, 1989. The researchers also noted more rapid improvement in lung tests during recovery from PCP, and transient increases in platelet* counts. There was also a consistent decline in p24 antigen* lev- els during treatment, but the rise in T helper cell counts seen in the first few months of therapy did not continue. Individuals with low T helper counts and those using ganciclovir* or dapsone* along with AZT experienced more bone marrow toxicity than those taking AZT alone. This study also discusses the muscle toxicity that can occur with long term use of AZT and the meningoencephal- itis* associated with reducing the dose of the drug. HIV DEVELOPS RESISTANCE TO AZT Researchers have found strains of HIV that "resist" AZT. This means the drug may become less effective in blocking repli- cation of the virus. These laboratory findings may help explain why the improvement seen in some PWA and PWARC taking AZT goes away over time. The development may also have important implica- tions for the timing of AZT therapy: if HIV resists AZT in the blood of severely ill individuals, a similar outcome may develop in healthier HIV positive people taking the drug. Researchers emphasized that this discovery did not appear to affect the clinical status of the individuals, who were all severely immunocompromised. "It will be necessary to study iso- lates* from asymptomatic, seropositive individuals who have experienced prolonged zidovudine therapy to evaluate the effect of immune status on development of resistance." 0*0* Larder BA, et al. HIV with reduced sensitivity to zido- vudine (AZT) isolated during prolonged therapy. Science , 243:1733, March 31, 1989. They also said that after consulting with other AIDS experts, a consensus emerged that this new information would not require changing AZT therapy for PWA or PWARC. The present structure of clinical trials using AZT should not be altered, they concluded. "Patients who are receiving AZT and benefitting from its use should continue to take the drug," said NIAID* director Dr. Anthony Fauci. 0*0* Press release, March 20, 1989. AZT MAY IMPROVE NEUROLOGICAL FUNCTIONS HIV infection can cause several neurologic* disorders: cog- nitive problems (forgetfulness, confusion, impaired reasoning), peripheral neuropathy*, paraplegia*, poor coordination, and pro- gressive dementia*. Subtle symptoms of AIDS related dementia often appear before infections such as PCP or KS. Two hundred eighty eight people with AIDS or severe ARC par- ticipated in a study to find out if AZT therapy would improve neurologic functions. 0*0* Schmidt FA, et al. Neuropsychological outcome of zidovudine (AZT) treatment of patients with AIDS and AIDS related complex. New England Journal of Medicine , 319(24):1573 1578, December 15, 1988. Individuals taking AZT, especially PWA, showed improved cogni- tion (memory, mental speed, and visual attention) and motor func- tion compared to people who took a placebo. "Longer clinical trials may be necessary to document the positive neurologic effects of the drug in earlier stages of HIV infection," according to the researchers. "Such studies will be particularly crucial in the long term treatment of these patients, because improvement in intellectual functioning due to zidovudine [AZT] treatment has the potential to improve the qual- ity of life of patients with HIV infection. 0*0* Ibid NEW AZT DRUG Researchers at Tulane University report that in lab experi- ments with mice a modified form of AZT is 2.5 times more effec- tive than the original drug and is half as toxic to the bone mar- row cells. 0*0* Remarks at the 73 annual meeting of the Federation of American Societies for Experimental Biology in New Orleans (March, 1989). Reported by CDC AIDS Weekly , April 10, 1989, p 3. Scientists developed the new drug, DP AZT*, to help deliver AZT directly to brain cells, Dr. Dudhir Gogu told BETA. 0*0* Personal communication, April 14, 1989. To treat or prevent AIDS related dementia, an antiviral drug must penetrate into the brain cells. Most researchers agree that AZT reaches the cerebrospinal fluid, even though none or only a small amount of the drug may directly reach brain tissue. AZT's ability to enter the cerebrospinal fluid may explain how the drug improves neurological* symptoms in some individuals. ERYTHROPOIETIN FOR AZT RELATED ANEMIA. The experimental use of a genetically engineered form of erythropoietin (EPO), a natural hormone, may allow anemic HIV infected individuals to use AZT while requiring fewer or no blood transfusions. One of the major adverse side effects of AZT therapy is that it can cause severe anemia (loss of red blood cells). The drug brings on this condition by attacking the bone marrow, which pro- duces red blood cells in the body. Early studies of EPO on HIV negative individuals with kidney disease show the drug increases red blood cell production. 0*0* Winearls CG, et al. Effect of human erythropoietin derived from recombinant DNA in the anemia of patients maintained by chronic hemodialysis. The Lancet , II:1175, 1987. The March 1989 issue of Treatment Issues. 0*0* Monthly newsletter on AIDS treatments published by the Gay Men's Health Crisis in New York. reports on two ongoing EPO studies with PWA at St. Luke's Hospi- tal in New York. Researcher Randy Levine told Treatment Issues that of the 3 PWA who have completed his study, 1 has a "50% decreased need for transfusions" and the other two now have hema- tocrit levels* in the high 30's... just below normal range.". 0*0* Treatment Issues 3, March 30, 1989. A three year, half million dollar grant from the NIH* will allow scientists at Thomas Jefferson University to study the potential benefits of EPO for 64 individuals with HIV related or related anemia. The researchers hope those receiving EPO will need fewer transfusions than those taking a placebo. EPO appears to be a promising, but expensive treatment for anemic individuals who want to use AZT or other bone marrow suppressive drugs. The FDA* may make EPO available as an investigational new drug.. AZT AND ACYCLOVIR. Is the combination therapy of AZT plus acyclovir (ACV) more effective than AZT alone? Used alone, ACV shows no anti effect either in the test tube or in humans, but some researchers believe that the drug significantly increases the antiviral effect of AZT. A 10 week study of 20 asymptomatic* HIV positive individuals by researchers from Burroughs Wellcome, the San Francisco Depart- ment of Public Health and UCSF showed no antiviral effect from low dose AZT (100 mg five times a day) and high dose ACV (400 800 mg five times a day). 0*0* Hollander H, et al. 1988 IV International Conference on AIDS, Stockholm. Abstracts 3134 3136. Preliminary results of a small study (24 PWARC) showed more promising, but inconclusive results. Nine p24 antigen positive individuals taking AZT and ACV (50 or 100 mg AZT every 4 hours and 800 mg ACV every 4 hours) for 12 weeks showed significantly lower p24 antigen levels than other individuals treated with AZT alone. 0*0* Collier AC, et al. 1988 International Conference on AIDS, Stockholm. Abstracts 3137 3138. Final results of this study have not been published. Researchers from Europe and Australia report that after 24 weeks of AZT plus ACV (250 mg AZT and 800 mg ACV every 6 hours), PWA showed significantly better survival rates. They also had decreased numbers and severity of opportunistic infections when compared to those given AZT alone. 0*0* Fiddian AP, et al. Zidovudine Plus or Minus Acyclovir in Patients with AIDS or ARC. European/Australian Collaborative Study Group. Abstract, 28th Interscience Conference on Antimi- crobial Agents and Chemotherapy. Los Angeles, October, 1988. This is a large, multi center study of over 400 people with AIDS or ARC. Burroughs Wellcome is also conducting a double blind placebo controlled trial with over 400 PWA and PWARC individuals at several European medical centers. 0*0* Reported in AIDS/HIV Experimental Directory 2(3):43, December, 1988.r Preliminary results on 108 PWA and PWARC after 36 weeks of com- bination therapy (250 mg AZT every 6 hours plus 800 mg ACV a day) or AZT alone (250 mg every 6 hours) showed the following results: 11 people on combination therapy and 24 people on AZT alone had to stop treatment because of toxicity; 25 on the combination required AZT dose reduction as compared to 14 on AZT alone; 5 people died in the group using AZT plus ACV and 15 died in the group using AZT alone. 0*0* Ibid To help settle the question of the effectiveness of AZT with or without ACV, the NIH is now recruiting for a large, multi center, 2 year study of 600 individuals with early ARC. Research- ers will evaluate four groups on a 4 times a day dosing schedule with the following combinations: (1) 100 mg AZT (no ACV) (2) 100 mg AZT plus 800 mg ACV (3) 200 mg AZT plus 800 mg ACV (4) 200 mg AZT plus placebo. Some researchers believe that the herpes viruses, especially herpes simplex* and human herpes virus 6*, may play a co factor role in HIV infection. For this reason, people infected with HIV and any herpes virus may benefit from prophylaxis* with acyclo- vir, regardless of whether or not the drug increases the antiviral effect of AZT. NEWLY REPORTED TOXICITIES Liver Damage AZT can damage the liver of some individuals. 0*0* Dubin G and Braffman M. (Letter) Annals of Internal Medi- cine , January, 1989. Reported in The New York Times Gina Kolata, January 3, 1989. A 39 year old man developed jaundice* and liver dysfunction within a week after starting the drug. When he stopped taking AZT, his liver recovered. After beginning the drug for a second time, his liver dysfunction reappeared. Again his physicians stopped the drug and his liver functions returned to normal. Reaction with Pyrimethamine Laboratory tests show that AZT counters the action of pyrimethamine, one of the drugs used to treat toxoplasmosis infection. 0*0* Iraelski DM, et al. Zidovudine antagonizes the action of pyrimethamine in experimental infection with toxoplasmosis gondii AIDS Targeted Information Newsletter February, 1989, p.17. AZT also countered the beneficial effect of pyrimethamine in mice infected with Toxoplasma gondii 0*0* Ibid PWA with toxoplasmic encephalitis* taking AZT and pyrimethamine should be monitored carefully. Researchers suggest that if individuals respond poorly to the combination therapy or appear to have a relapse, AZT treatment should stop. 0*0* Ibid Bone Marrow Damage Some researchers are concerned that the bone marrow changes produced in individuals taking AZT do not always stop when treat- ment stops. 0*0* Mir N and Costello C. Zidovudine and Bone Marrow (letter). The Lancet , ii(8621):1195 1196, November 19, 1988. Dr. Naheed Mir and Dr. Christine Costello of St. Stephen's Hos- pital in London suggest that long term treatment with AZT may damage the bone marrow cell pool* and cause adverse changes in other cell lines as well. 0*0* Ibid These findings may have serious implications for using AZT in HIV positive but symptom free individuals as well as symptomatic PWA and PWARC. AZT TREATMENT AMONG INJECTION DRUG USERS AZT therapy for injection drug users (IDU) is just beginning to be studied. A recently published study begun in March 1987 looks at 40 individuals treated with AZT, 25 of whom were former or current users. 0*0* Cowan FM, et al. Use of zidovudine for drug users infected with human immunodeficiency virus. Journal of Infectious Disease , 18(1 1):59 66. January, 1989. Eighteen individuals took various kinds of narcotics either occasionally or regularly while on AZT therapy. The researchers report that no adverse clinical effects were observed from the simultaneous use of AZT and narcotics, whether used orally or by injection. "In our experience, it is possible to treat safely current and former injection drug users with zidovudine (AZT)." 0*0* Ibid NIAID AIDS program director Dr. Daniel Hoth reports that a study of the interaction of AZT with methadone is under way. 0*0* Remarks to the 73 meeting of the Federation of American Societies for Experimental Biology, New Orleans, March 1989. Reported by CDC Weekly , April 3, 1989, p.3. AZT AND HIV RELATED THROMBOCYTOPENIA (ITP) Thrombocytopenia* (also called ITP*) can be the first clini- cal sign of HIV infection. Five to ten percent of individuals infected with the virus develop this disorder, with symptoms which may include easy bruising, bleeding gums, or nosebleeds. ITP is the result of an abnormal decrease in the number of pla- telets*, which normally range from 150,000 to 300,000 per mm of blood. ITP can go away without treatment. However, some people with the disease need therapy. One study of ten people with mild cases of ITP showed that platelet counts increased in each indi- vidual while taking AZT. 0*0* Hirshel B, et al. Zidovudine for the treatment of thrombo- cytopenia associated with HIV a prospective study. Annals of Internal Medicine , 109(9): 718 721, November, 1988. While taking a placebo, these same individuals' platelet counts did not increase. Other researchers also report successfully treating HIV related thrombocytopenia with AZT. 0*0* Pottage JC, et al. Treatment of human immunodeficiency virus related thrombocytopenia with zidovudine. Reports of three cases. Journal of the American Medical Association 260(20):3045 3048, November 25, 1988. One otherwise asymptomatic individual with severe HIV related thrombocytopenia responded quickly and successfully to full dose AZT. 0*0* Neil BJ, et al. Zidovudine therapy for severe human immuno- deficiency virus related thrombocytopenia. American Journal of Medicine , 85(5):744 745, November, 1988. However, Dr. Donald Abrams 0*0* Assistant Director, AIDS Activities, UCSF affiliated San Francisco General Hospital. cautions against using AZT in people who are asymptomatic except for low platelet counts. "I generally feel that people [without bleeding complications] really don't need to be treated with any- thing just to raise their platelet counts... Running the risk that the person's virus will ultimately become resistant, this treatment [with AZT] may not be the wisest tack to take." 0*0* Interview with Ron Baker, March 29, 1989. ***** HIV-RELATED NEUROPATHY by Etienne Hafs and Ron Baker Neuropathy is the name given to a group of disorders whose symptoms may range from a tingling sensation or numbness in the toes and fingers to paralysis. Neuropathy might more accurately be called "neuropathies" because there are several types. Esti- mates indicate that 35 50% of PWA have some form of neuropathy. 0*0* Reported by UCSF researchers Dale Bredesen and Raphael Stricker at the annual meeting of the American Academy of Neurol- ogy. Chicago, April, 1989. In people with HIV infection, approximately one third of neuropathies are caused by infections such as CMV or other viruses of the herpes family. 0*0* Miller RG, et al. Peripheral Nervous System Dysfunction in AIDS. AIDS in the Nervous System 1988. p.65. If diagnosed early, some of these neuropathies may be treat- able. In other neuropathies, HIV or other pathogens* may cause the body to trigger an autoimmune response* against its own nerve tissue. Antibodies to peripheral* nerve tissue have been found in individuals with HIV related peripheral neuropathies*. The precise role of the antibodies is still unclear, but they may be important in producing these neuropathies. 0*0* Kiprov D, et al. Antibody mediated peripheral neuropathies associated with ARC and AIDS: successful treatment with plasma- pheresis. Journal of Clinical Apheresis , vol 4, p.6, 1988. Symptoms Symptoms of peripheral nervous system (PNS) disorders vary widely. Most people with peripheral neuropathy first notice numbness or tingling in the toes. Over a period of weeks or months the symptoms may gradually spread to the fingers. 0*0* Miller RG, et al. p. 65.A Individuals often report severe pain along the course of a nerve (neuralgia), especially in the feet. This can make walking dif- ficult or impossible. Muscles in the feet and calves may cramp, causing sleeplessness. As the neuropathy progresses, individuals may become tired and lose their balance. 0*0* Ibid Distal symmetric peripheral neuropathy (DSPN) is the most common syndrome among people with generalized neuropathy. The feet and lower legs may show hair loss, thinning of the skin, or redness. In most cases, weakness in the foot muscles is mild, but can be severe. Loss of feeling begins in the toes and gradu- ally spreads upward. The symptoms of chronic inflammatory demyelinating* polyrad- iculoneuropathy (CIDP) resemble those of Guillain Barr syndrome*, except that CIDP usually gets worse over time and lasts for a long time. 0*0* Ibid Individuals usually have significant weakness in muscles of the feet, legs, arms, and hands. Sensory abnormalities in hands and feet are mild compared with the muscle weakness. Mononeuritis multiplex (MM) is less common than DSPN or CIDP. Usually symptoms of MM start suddenly. Individuals experience abnormal sensations over the face, legs arms or trunk of the body. Cranial nerves are commonly affected. 0*0* Lipkin WI, et al. Inflammatory neuropathy in homosexual men with lymphadenopathy. Neurology , 35:1479 1483, 1985. Diagnosis Diagnosis is usually made by some combination of the follow- ing: 1) Patient's description of symptoms. 2) Physical examination. 3) Laboratory tests, especially of the blood and cerebrospinal fluid. 4) Electromyography (electrical stimulation of the muscles). 5) Muscle biopsy. 6) Nerve biopsy. Natural History The course of neuropathies varies widely from patient to patient and from syndrome to syndrome. Some individuals with DSPN improve or stabilize without treatment. Some people with MM go on to develop CIDP. In most cases, CIDP progresses slowly, but relentless progression is more likely in patients with severe opportunistic infections and/or wasting syndrome. Treatments Determining the most effective treatment depends on the type of neuropathy in each case. Plasmapheresis has been shown effec- tive for individuals with CIDP (see article below). There is no specific treatment for DSPN, but some antidepressants (e.g., ela- vil) can be helpful in reducing nerve pain. CMV is responsible for a progressive polyradiculopathy which is usually fatal, but a recent study suggests that if the syndrome is recognized early and treated with ganciclovir* within 12 days after the onset of symptoms, individuals can recover. 0*0* Miller RG, et al. Successful treatment of progressive polyradiculopathy in AIDS patients. Neurology , 39(1):271, March, 1989. ***** PLASMAPHERESIS FOR HIV RELATED NEUROPATHY by Ron Baker Several studies suggest that plasmapheresis is a safe, effective treatment for some individuals with HIV related peri- pheral neuropathy, specifically those with either Guillain Barr syndrome* or CIDP. The procedure has also significantly bene- fitted individuals with Guillain Barr syndrome* and CIDP who are not infected with HIV. 0*0* Humphrey JG, et al. Plasmapheresis and acute Guillain Barr syndrome. Neurology , 35:1096 1104, August, 1985. Plasmapheresis is not effective in treating HIV infected indi- viduals with DSPN. In plasmapheresis, blood is circulated outside the indivi- dual, antibodies to the nerve tissue and plasma are removed, and the blood cells are then returned to the patient along with a replacement fluid. Dr. Dobri Kiprov and colleagues at Children's Hospital in San Francisco studied 30 gay men with polyneuropathy*. 0*0* Kiprov D, et al. pp.3 Twenty one of the men had ARC and nine had AIDS. All had reduced T helper cell counts and all had antibodies to peripheral nerve tissue. Fifteen of these men with CIDP were treated with plasmapheresis because of severe progressive weakness and numb- ness. The removal of antibodies to peripheral nerve tissue pro- duced clinical improvement in 12 of 15 individuals. 0*0* Kiprov D, et al, p. 3. These men mainly had demyelinating* neuropathy (an axonal* neu- ropathy) did not respond to treatment. Three of the 4 individu- als who responded well to plasmapheresis later had relapses of peripheral neuropathy. When plasmapheresis was performed again, these individuals again showed significant clinical improvement. The researchers conclude that plasmapheresis is an effective treatment for most people with related CIDP. In one study, 6 HIV infected individuals with CIDP and 3 with Guillain Barr syndrome recovered either spontaneously or after treatment with corticosteroids* or plasmapheresis 0*0* Cornblath DR, et al. Inflammatory demyelinating peripheral neuropathy associated with HTLV III infection. Annals of Neurol- ogy , 21:32 40, 1987. Because corticosteroid therapy is immunosuppressive, it may be hazardous to use in treating HIV infected individuals. Plasmapheresis produces only mild side effects, which may include temporary lowering of blood pressure and a disturbed heart rhythm. Researchers suggest using the procedure to treat related CIDP when the clinical symptoms (weakness and numbness) start to interfere with normal functioning. Each plasmapheresis treatment costs approximately $1,000 and most individuals with CIDP require an average of 10 treatments. Many insurance carriers now cover the cost of plasmapheresis for HIV related CIDP. Physicians interested in finding out more about the pro- cedure can contact Dr. Dobri Kiprov (Plasmapheresis Unit) or Dr. Robert Miller (Department of Neurology) at Children's Hospital in San Francisco (415 8700). ***** PASSIVE IMMUNOTHERAPY by Rick Davis Two small uncontrolled* studies suggest that PWA who are infused with p24 antibody rich blood plasma* from healthy HIV positive individuals may experience at least transient clinical improvement. In a study at the University of Illinois, Dr. George Jackson and colleagues injected 6 PWA with plasma from healthy seropositives. The recipients' blood showed immediate clearing of p24 antigen. 0*0* Jackson GG, et al. Passive immunization of human immunode- ficiency virus in patients with advanced AIDS. Lancet , ii:647 652, September 17, 1988. For several weeks following the infusion, the researchers could only rarely find HIV in the recipients' blood. There were no apparent adverse side effects to donors or recipients. p24 antibody versus p24 antigen The p24 antigen test detects a protein (p24) fragment of HIV. The p24 antibody test measures the amount of antibody against the p24 antigen. Individuals with high levels of p24 antibody and undetectable levels of p24 antigen usually remain healthy. Over time, most HIV positive individu- als will have a decline in the amount of detectable p24 antibo- dies and within a short time may become p24 antigen positive. People who are p24 antigen positive are more likely to develop ARC or AIDS, although at least 1/3 of those who develop AIDS never become p24 antigen positive. 0*0* Moss, AR. Remarks to the 73 annual meeting of the Federation of American Societies for Experimental Biology, New Orleans, March, 1989. Reported by CDC Weekly , April 3, 1989, p.7. Almost all the PWA in the Jackson trial showed improvement during treatment: higher T helper and T suppressor cell counts (50% average increase), weight gain, and a significant decline in new opportunistic infections. These improvements continued for 11 weeks, and appeared to depend on the amount of plasma infused (55 500 ml). When treatment stopped, symptoms returned, cell counts fell to pre treatment levels, and p24 antigen again became positive. One of the trial participants who was severely ill at the beginning of the trial showed no improvement and died two months later. Three individuals who did show improvement during the treatment period also subsequently died. In another study (still ongoing) at London's St. Stephen's Hospital, researchers infused 10 PWA and PWARC with 250 500 ml of p24 antibody rich plasma monthly. 0*0* Karpas A, et al. Effects of passive immunization in patients with the AIDS related complex and immune deficiency syn- drome. Proceedings of the National Academy of Sciences December, 1988. In this study, researchers selected donors for high amounts of HIV neutralizing antibody rather than high amounts of p24 anti- body. As in the Jackson study, p24 antigen became negative almost immediately, and stayed negative in all but one individual who later developed CMV retinitis, lymphoma and PCP. Unlike the results of the Jackson trial, T helper and T suppressor cell counts did not increase. The researchers have noted no toxic side effects and have continued to give trial participants monthly infusions. Dr. Michael Youle of St. Stephen's Hospital told Treatment Issues plans to continue adding individuals to the London study. 0*0* Nott V. Passive Immunotherapy. Treatment Issues December 12, 1988. He emphasized that the trial was being conducted primarily "to assess toxicity," and it had produced "encouraging but incon- clusive results." Dr. Youle plans a controlled trial comparing p24 antibody rich plasma to AZT. 0*0* Ibid More complete results of the St. Stephen's Hospital team's ongoing trial will be presented at the Montreal International AIDS Conference in June 1989. These preliminary uncontrolled trials have encouraged other researchers to begin or plan controlled studies of passive immu- notherapy. A double blind study is currently under way at New York's Bronx V.A. Hospital with 50 participants Two companies, Medicorp and Immunotech, have applied to the California Food and Drug Bureau for approval of open and double blind studies. Medicorp, sponsor of the London and New York tri- als, is applying to the FDA for IND* status. Passive immunotherapy costs $700 $1,000 per treatment. An Immunotech spokesperson told BETA the company will charge study participants for treatment costs. Medicorp says it will not charge participants who enroll in its forthcoming trials. The PATH Project in San Francisco is a community based organization that closely follows developments in passive immu- notherapy. Call (415) 549 9137 for further information. ***** DO YOU REMEMBER CD4? by Ron Baker Phase I trials of soluble CD4* in Boston, Los Angeles, San Francisco and Bethesda show no toxic side effects with the doses tested. Results of earlier test tube studies demonstrated that the genetically engineered CD4 serves as a decoy that "tricks" HIV into attaching to it instead of white blood cells. Research- ers hope the drug will act the same in humans infected with HIV, soaking up free floating virus and preventing it from infecting new cells. Phase II trials (for efficacy) are currently stalled at several medical centers, including San Francisco General, N.Y.U. and Stanford. These proposed trials plan to study CD4 in combi- nation with AZT. Dr. Mamoru Watanake and colleagues report that they injected CD4 into 4 rhesus monkeys for 50 days. 0*0* Watanake M, et al. Effect of recombinant soluble CD4 in rhesus monkeys infected with simian immunodeficiency virus of macaques. Nature , 337(6204):267 270, January 19, 1989. Two of the monkeys were infected with SIV (simian immunodefi- ciency virus), which resembles HIV and causes a similar disease. After a week of treatment with CD4, SIV could not be found in the cells of the infected monkeys. When therapy was stopped, the virus reappeared. This indicates CD4 can suppress detectable SIV. The researchers hope CD4 will produce a similar effect in HIV infected humans. Although the study suggests that CD4 may temporarily reverse the bone marrow damage caused by the SIV infection, one of the 2 infected monkeys died from severe anemia a few days after the CD4 treatment stopped. Many researchers are enthusiastic about CD4, but there are several weaknesses and disadvantages to this therapy. First, the drug will probably require at least one daily injection if it is to be effective. Second, CD4 does not cross the blood brain bar- rier, and therefore may not be effective in preventing or treat- ing HIV brain infection. Laboratory experiments by Dr. Paul Clapham and colleagues indicate CD4 can stop HIV from infecting helper cells and macrophages, but not brain and muscle cells. 0*0* Clapham PR, et al. Soluble CD4 blocks the infection of diverse strains of HIV and SIV for cells and monocytes but not for brain and muscle cells. Nature , 337(6205):368 370, January 26, 1989. Finally, although CD4 may be able to block HIV infection between cells, when used alone the drug cannot kill cells already infected with the virus. As a way of possibly overcoming some of these disadvantages, scientists have developed specially designed CD4 drugs. Some of these new drugs combine CD4 with toxins that recognize and kill infected cells. More recently, researchers at National Cancer Institute, Harvard Medical School, and Genentech, Inc. have combined CD4 with an artificial human antibody molecule. In test tube stu- dies, this hybrid CD4 not only prevents the virus from infecting new cells but also actually seeks out and kills the virus and infected cells. 0*0* Capon DJ, et al. Designing CD4 immunoadhesins for AIDS therapy. Nature , 337:525 531, February 9, 1989. The CD4 hybrid also stays in the bloodstream much longer than CD4 alone. Individuals using this hybrid will probably need fewer injections per week. In tests on infected rabbits, CD4 with the artificial antibody killed infected cells and continued working in the animals' blood up to 200 times longer than the original CD4. Other possible advantages of the hybrid CD4 are its theoret- ical ability to neutralize different strains of HIV and the pos- sibility the drug can activate the immune system to attack HIV on its own. 0*0* Ibid The artificial antibody also locks onto the surface of infected macrophages and may signal uninfected macrophages to destroy them. Researchers have expressed enthusiasm for the potential of CD4. But some remain cautious. "This is a technological leap," commented Dr. Samuel Broder of the NIH*. "Whether it has clini- cal value is something we will have to examine." ***** THE EARLY PROMISE OF COMPOUND Q by Ron Baker "Its specificity is uncanny." Michael McGrath, MD, PhD 0*0* Director of the AIDS/Immunobiology Research Laboratory at UCSF affiliated S.F. General Hospital. Early Tests Promising For New AIDS Drug. Reported by Gina Kolata. New York Times , April 18, 1989, p.B6. The purified protein extract from the root tuber of a Chinese cucumber plant (Trichosanthes kirilowii) appears to kill infected macrophages and to block replication of the virus in helper cells, according to researchers at UCSF and Genelabs, Inc. 0*0* McGrath MS, et al. GLQ223: An inhibitor of human immunode- ficiency virus replication in acutely and chronically infected cells of lymphocytes and mononuclear phagocyte lineage. Proceed- ings of the National Academy of Sciences (USA) , 86(6), April 14, 1989.- In China the root has been used for centuries to induce abor- tions and, more recently, to treat malignant tumors. Dr. Michael McGrath and colleagues suggest that Compound Q (GLQ 223) shows great promise as a treatment for HIV infection because in test tube studies, the compound selectively kills HIV infected macrophages without damaging uninfected cells. 0*0* Ibid It is the only anti HIV drug known to perform in this way. Macrophages are vital to the immune system as a defense against invading organisms (they destroy infectious agents) and they play an important role in how T cells function. Dr. McGrath says his team's research proves that in HIV infected individuals, macrophages act as a reservoir for virus replication. HIV infects 2 7% of macrophages in the blood of PWA, according to the UCSF study. These infected macrophages do not die quickly and because they live in almost every body organ, they probably play a critically important role in the development of AIDS. Compound Q, by an unknown mechanism, only attacks those macrophages and T cells infected with HIV. In an interview with the Los Angeles Times , Dr. McGrath said he did not expect Com- pound Q to get rid of all HIV infected cells in the body and sug- gested the drug might be tested in combination with other antivirals such as AZT. 0*0* Toxin From China May Offer AIDS Hope. Reported by Robert Steinbrook. The Los Angeles Times Phase I safety trials of Compound Q will begin at S.F. Gen- eral Hospital in May 1989 under the supervision of Dr. Paul Vol- berding, director of the hospital's AIDS Unit. Dr. Volberding will begin injecting very low doses of the drug into 3 people with AIDS. 0*0* Personal communication, April 29, 1989. If these volunteers show no adverse side effects from the drug, dosages will be increased and more participants will be added until 20 HIV infected individuals are using Compound Q. 0*0* Ibid Phase I safety trials usually last for 6 months. Dr. Volberding and Dr. McGrath warn that people should not use the unpurified Chinese version of Compound Q because it can cause blood clots, seizures and strokes. 0*0* FDA Moves Swiftly to Approve Trials of Promising AIDS Drug. Reported by David Perlman, San Francisco Chronicle , April 28, p.A8. ***** THE DEXTRAN SULFATE STORY: AN INTERVIEW WITH DR. DONALD ABRAMS Donald Abrams, MD is the Assistant Director of AIDS Activities at San Francisco General Hospital, where he has been the principal investigator of dextran sulfate. In the following excerpts from an interview with BETA on March 29, 1989, Dr. Abrams discusses the history of studies on dextran sulfate as a possible treatment for HIV, the controversy surrounding recent press reports of its "ineffectiveness," and questions about the drug that he hopes to answer in current and future studies. Oral versus Intravenous Since the beginning of the development of dextran sulfate as a possible anti HIV drug, much confusion, skepticism and doubt has surrounded it. Part of this, should anyone need take blame, has been somewhat my fault because the original discussions I had with Ueno Fine Chemicals [a Japanese pharmaceutical firm] in 1986 indicated that they had a compound they thought worked against HIV. They wanted to bring it into clinical trials. The com- pound, they told me, was available in two forms in Japan: intravenous and oral. At that time [July 1986] my decision was to develop and investigate oral dextran sulfate as opposed to intravenous dex- tran sulfate. It is not only easier for patients participating in a trial, but it is also less labor intensive and less expen- sive. At that time, many people cautioned me that because dextran sulfate is such a large molecule, the body would be unable to absorb it through the gastrointestinal tract. If it were absorbed, it was felt a molecule of that size would not penetrate into a cell to do its work. Measuring Dextran Sulfate in the Blood As we got further into the planning, my Japanese collabora- tors brought me graphs demonstrating, in fact, that dextran sul- fate could be measured in the bloodstream a certain time after it is taken orally. It reaches a certain level, then disappears (as you would like to see with any orally absorbed drug). However, this assay, to detect the actual level of the dextran sulfate in the blood, was not reproducible in samples we sent from our patients. We cannot send HIV infected blood to Japan. It's part of their importation policies. Therefore, we had to heat inac- tivate blood specimens before we could send them. This process coagulated proteins, which made the assay they had developed for HIV negative blood not possible for the treated blood samples we sent them. So, throughout the course of our phase I study here at San Francisco General, performed in 1987, there was no direct method of measuring the level of dextran sulfate in the bloodstream. There was no conclusive evidence that dextran sulfate taken by mouth got into the bloodstream. When I began to go to NIAID with this project, suggesting that we begin to investigate dextran sulfate on a larger scale, I was asked whether any of the drug was getting into the bloodstream. I replied that patients were experiencing side effects, they got "speedy," they had abnormali- ties of their liver tests, their white blood cell counts went down. It seemed to me that something was having an effect. In the test tube, the specific molecular weight of dextran sulfate and the amount of sulphur on the molecule is critical for whether or not it has antiviral activity. Skeptics cautioned that oral dextran sulfate could be broken down into smaller subfragments which are not then anti retroviral and that these subfragments could be causing some of the side effects and laboratory abnor- malities. In the absence of an assay, there was still no direct evidence that oral dextran sulfate was absorbed. Effect on p24 Antigen and T helper Cell (T 4) Levels The phase I study we did was performed to determine the max- imally tolerated dose and to learn more about dextran sulfate's side effects in people with HIV infection. In AIDS research, it is difficult to do a study which just looks at toxicity and side effects. There is a demand to evaluate potential agents quicker, and to also get some information on effectiveness simultaneously with phase I data. Therefore, in this first study, we also looked at T 4 cell counts and p24 antigen levels. We really did not see anything very positive. 4 cells did not change in a sus- tained fashion. HIV p24 antigen positivity was not a prere- quisite for entry into the study. Those patients who were posi- tive at study entry stayed positive and those who were negative stayed negative. Dextran sulfate, for an eight week course, did not appear to have any effect. Finally, we did decide to do a larger trial of patients through the NIAID* AIDS Clinical Treatment Group mechanism. This second trial was to enroll patients who were HIV positive and p24 antigen positive so we could at least answer the question, "Is oral dextran sulfate effective in causing a decline in p24 antigen levels?" I also believe that one of the things we should now begin to question is whether p24 antigen is the only measure we have of a drug's effectiveness against the virus. AZT cer- tainly makes p24 levels decline. But can we expect a drug (such as dextran sulfate) that prevents virus attachment to cells and cell cell infection to really impact on p24 antigen levels? The phase I study gave us only a small amount of information on people with AIDS taking dextran sulfate. Most people in this trial had lymphadenopathy*. In fact, the few AIDS patients who participated could not complete the trial because of adverse side effects. It was felt, like other treatments we evaluated, that the drug might be better tolerated in patients in earlier stages of infection and less well tolerated in PWA. The current study being performed via the NIAID AIDS Clini- cal Trials Group program evaluated dextran sulfate in three patient groups: asymptomatics, ARC and AIDS. Ten patients in each group were enrolled at each dose. We started at 2700 mg and increased to 5400 mg; we were prepared to escalate to higher dosages if we hadn't reached the maximum tolerated dose by 5400 mg. If 5400 proved to be the maximum, we were planning to inves- tigate intermediate dosages (between 2700 mg and 5400 mg) as we had done in the initial phase I trial. Johns Hopkins Experiment In the middle of our trial, the pharmacology group at Johns Hopkins University reported on an experiment involving 6 healthy people. They gave them intravenous dextran sulfate followed by a single dose of oral dextran sulfate. They followed what I would have to call 'surrogate markers' for dextran sulfate activity. In Japan, the intravenous preparation of dextran sulfate is used as an anticoagulant, or blood thinner. The oral preparation is used to lower blood fats. This group looked at the activated partial thromboplastin time [PTT] which measures how thin the blood is getting, and found that after intravenous dextran sulfate, the PTT prolonged significantly. However, after a single oral dose of 1800 mg (which is what our patients on 5400 mg take three times/day) there was no prolongation, which suggested to them that there was no absorption. I objected to that reasoning because a single oral dose may not be enough to create the effect. However, I was told a single IV dose does, so if you're checking to see how much of that oral dose becomes available in the bloodstream (the so called "bio availability"), if the intravenous dose produces such an effect, then the oral dose should as well. They also measured an enzyme called lipoprotein lipase [an enzyme that promotes breakdown of blood fats]. Patients receiving the IV compound had a marked increase in the activity of this enzyme; patients after the oral single dose also had an increase but it was not as marked. This again suggested to me that there was some absorption of the oral form, but that it was very low. New Information on Absorption At about the same time, Ueno in Japan seemed again to come up with what they felt was a perfected assay to measure actual dextran sulfate directly, not using these surrogate markers for its activity [i.e., the PTT and the lipoprotein lipase]. Ueno also concurred that the oral bioavailability of dextran sulfate is probably less than 1%. That means that less than 1% of what was given orally actually gets into the bloodstream. This made people question whether or not oral dextran sulfate could ever be effective against HIV. The pharmacokinetic* data became available in January. At that time a conference call discussion among the participating centers and the central office staff at the NIAID concluded that we should explain this information to patients participating in our protocols. They could then make an informed decision as to whether they wanted to continue in the trial, or withdraw and try to participate in other studies. We held a meeting of patients participating in our dextran sulfate trial on January 23rd to tell them about this paper, which was being published on February 1st, and to inform them about the preliminary data from Johns Hopkins lab. Confusion in the Press Then the L.A. Times article appeared February 19th, alleging that the dextran sulfate investigators knew the drug was effec- tive , and were not sharing that information. We did not know the drug was not effective; we suspected it was not being absorbed. Our tack was now to collect all the available efficacy data and to run as many of the p24 antigens levels and T 4 counts as possible. We would analyze the data to see if dextran sulfate may still be effective even if it is not absorbed to any great extent. We did not want to throw the baby out with the bathwa- ter! That was our plan. What particularly upset me about the L.A. Times article was that it constantly referred to the drug as "dextran." Dextran is a completely different compound than dextran sulfate. To me, that sort of inaccuracy and sloppiness served only to perpetuate the confusion. Currently, 16 patients nationwide out of the 60 who began the study are continuing on the trial. We are hoping that by the end of April more patients will have completed the 6 months of treatment. Then we can begin to assess whether oral dextran sul- fate is worth pursuing or not. In the meantime, we know many people continue to use dextran sulfate that they obtain in many creative fashions. I received a recent letter which highlights our dilemma. This is an anonymous letter, signed only "name withheld." To me, it highlights both the need for well controlled clinical trials and some of the problems we have as clinical investigators in attempting to per- form them. Dear Dr. Abrams, I buy my dextran sulfate from one of the participants in your study. He does not take the dextran, and his lab values show it. He stays in your study to get the dextran to sell and to have free lab tests regularly. On the other hand, I do take the dextran. I take 1500 mg in three doses of 600 mg, 600 mg and 300 mg at bedtime. I have been since April of '88. My T cells have gone from 289 to 884, gradually, as a result. I understand from my friend in your study that several participants are not taking the doses you think they are. I am writing because I know personally that dextran is a valuable antiviral medication. I am hoping your test results will in some way reflect this erroneous input. Would a lie detector test be helpful? ***** DIRECTORY OF OPEN HIV TRIALS IN THE S.F. BAY AREA COMPILED BY THE SAN FRANCISCO COUNTY COMMUNITY CONSORTIUM WHO IS ELIGIBLE? | DRUG NAME AND | STUDY TITLE | SITE AND | MECHANISM OF | | CONTACT | ACTION | | | | | AIDS; greater than 2, but | Clofazimine | Randomized Treatment | Your M.D.* less than 4 months status | (Anti- | vs. No Treatment | post first episode of PCP |mycobacterial) | Study of Clofazimine | | to Prevent Myco- | | bacterium avium | | Complex Infection in | | AIDS (CCC 001) | ------------------------------------------------------------------------------- Any stage of HIV |AZT | Zidovudine (AZT) | Your M.D.* patients taking physician-|(Antiretroviral | Database (CC 002) | prescribed AZT. Excludes |Observational | patients failing AZT |study -- data | |collection only) ------------------------------------------------------------------------------- Any stage of HIV infection| Non-specified | HIV Alternative | Your M.D.* patients taking systemic | (Self admini- | Treatment Database "alternative treatment" |stered | (CCC 003) |alternative |therapy) ------------------------------------------------------------------------------- HIV + with fewer than 200 | AZT plus Vita- | Randomized, Placebo | Your M.D.* T4 cells or p24 antigen |min B12 |Controlled Trial of the positive, or diagnosis of |injection (De- |Combined Use of Zido- ARC or AIDS. No prior |creases |vudine (AZT) and history of AZT use. |hematologic |Vitamin B12 in HIV |toxicity) |Disease (CCC 004) ------------------------------------------------------------------------------- HIV +, asymptomatic (ex- | Megestrol | Phase III Double | Your M.D.* cept for weight loss) to | acetate |Blind Randomized Cross- ARC (no AIDS diagnosis), |(Anti-neoplastic|Over Study of High- | weight loss greater than |hormone) |Dose Megestrol Acetate| 5% of usual body weight. | |(Megace) vs. Placebo | |in Patients with HIV | |Infection (CCC 005) | ------------------------------------------------------------------------------- * This is a County Community Consortium clinical trial. Physicians can enroll their own patients in Consortium clinical trials. Ask your physician if he/she knows about the County Community Consortium and its clinical trials program. Physicians who would like to learn how to enroll patients in Consortium clinical trials may call (415) 821-3144. WHO IS ELIGIBLE? | DRUG NAME AND | STUDY TITLE | SITE AND | MECHANISM OF | | CONTACT | ACTION | | | | | HIV + with thrush (must be| Fluconazole or | A Randomized, Multi- | Davies evident on visual exam) | Clotrimazole | Study of the Efficacy| Dan Cox, RN | (Antifungal) | Safety and Toleration| 565-6958 | of Fluconazole tablets | or Clotrimazole Troches | in the Treatment of | | Oropharyngeal | | Candidiasis in | | Association With AIDS| ------------------------------------------------------------------------------- AIDS with Cryptococcal | Fluconazole | Fluconazole vs. Am- | Davies meningitis | versus | as Treatment For | Brian | Amphotericin B | Cryptococcal Meningi-| Christianson | (Antifungal) | tis. (Randomized | 565-6153 | 2:1). ------------------------------------------------------------------------------- AIDS with Cryptococcal | Fluconazole | Fluconazole vs. | Davies meningitis | versus | Amphotocerin B | Brian |Amphotocerin B |as Maintenance Therapy| Christianson |(Antifungal) |for Cryptococcal | 565-6153 | Meningitis. | (Randomized 1:1). ------------------------------------------------------------------------------- AIDS with Cryptococcal | Fluconazole | Efficacy of Flucona- | SFHG meningitis; failed on | (Antifungal) | zole in AIDS Patients| AIDS standard therapay |Failing Standard Treat-|Research |ment for Cryptococcal | Group |Meningitis | 821-5089 ------------------------------------------------------------------------------- AIDS with second episode | Clindamycin | An Open Study to Eva-| SFGH PCP |plus Primaquine |luate Clindamycin Plus| AIDS |(Anti-PCP) |Primaquine for the | Research |Treatment of Pneumo- | Group |cystis Pneumonia in | 821-5089 |AIDS | ------------------------------------------------------------------------------- ARC or AIDS, p24 antigen | Foscarnet | Intermittent Foscar- | SFGH positive, on full-dose AZT|(Antiretroviral)|net Therapy for Human | AIDS less than or equal to 11 | |Immunodeficiency Virus| Research weeks without serious AZT | |Infection in Patients | Group toxicity | |Receiving Long-Term | 821-5089 |Zidovudine (AZT) | |Therapy (ACTG 053) ------------------------------------------------------------------------------- HIV + with no HIV-related | AZT | Safety and Efficacy | SFGH symptoms. (May have |(Antiretroviral)|of Zidovudine (AZT) | AIDS Persistent Generalized | |for Asymptomatic HIV+ | Research Lymphodenopathy) | |Individuals (ATEU 019)| Group | 821-5089 | Mt. Zion | Lawrence | Drew, M.D. | 885-7315 ------------------------------------------------------------------------------- AIDS or ARC with fewer | AZT with or | Phase III Blinded | Davies than 200 T4 cells; unable |without Beta |Placebo-Controlled | Stephanie to tolerate full-dose AZT.|Interferon |Study of Beta Inter- | LaCarrubba, On reduced dose AZT for at|(Antiretroviral)|on in Patients with | R.N. least three weeks. | |AIDS and Advanced HIV | 565-6524 |Infection Receiving |Reduced Dose AZT. ------------------------------------------------------------------------------- AIDS with MAI infection | Ansamycin | Ansamycin for Treat- | SFGH |(Antituberculo- | ment of Disseminated | AIDS |sis) | Mycobacterium avium | Research | in AIDS Patients | Group | 821-5089 ------------------------------------------------------------------------------- AIDS with CMV Retinitis, | Foscarnet | Foscarnet Treatment | SFGH no prior DHPG therapy, no | (Antiviral | of Serious CMV | AIDS concurrent nephrotoxic | against CMV) | Retinitis Infections | Research therapy | | in Patients with | Group | AIDS (ATEU 015) | 821-5089 ------------------------------------------------------------------------------- AIDS or confirmed HIV | Gancyclovir | A Randomized, Con- | Mt. Zion infection with CMV retini-| (Antiviral |trolled Study of In- | Lawrence tis. Retinal lesions must| against CMV) |travenous Gancyclovir | Drew, M.D. be greater than 1500 microns |Therapy for Peripheral| Lawrence from the edge of the optic| |Cytomegalovirus | Mintz, M.D. disc and greater than 3000| |Retinitis in Patients | Ronald microns from the fovea | |with AIDS | Dworkin,M.D. | 885-7315 ------------------------------------------------------------------------------- AIDS or confirmed HIV | Ganciclovir | A Randomized Con- | Mt. Zion infection with CMV retini-| (Antiviral |trolled Study of Two | Lawrence tis. Patients must have | against CMV) |Doses of Intravenous | Drew, M.D. retinal lesions less than | |Ganciclovir Therapy | Lawrence 1500 microns from the op- | |for Cytomegalovirus | Ronald tic disk or less than 3000| |Retinitis in Patients | Dworkin,M.D. microns from the fovea. | |with AIDS | 885-7315 ------------------------------------------------------------------------------- AIDS with KS | Vincristine, | Phase II Study of | SFGH |Vinblastine, AZT| Weekly Alternating | AIDS |(Antitumor for |Vincristine and Vin- | Research |KS plus antire- |blastine Plus Zido- | Group |troviral) |vudine (AZT) for AIDS-| 821-5089 | |Associated Kaposi's | |Sarcoma ------------------------------------------------------------------------------- AIDS-associated Non- | Four chemothe- | A Randomized Trial of| SFGH Hodgkin's Lymphoma |rapy agents, | Chemotherapy With or | AIDS |used with or | Without Recombinant | Research |without rGMCSF | Human Granulocyte Co-| Group |(Anti-tumor for |lony Stimulating Factor 821-5089 |NHL plus hemato-|(rGMCSF) in Patients | |logic growth |with AIDS-associated | |factor) |Non-Hodgkin's Lymphoma| ------------------------------------------------------------------------------- HIV antibody or antigen | Chemotherapy | Chemotherapy and Azi-| SFGH positive, or prior diag- | plus AZT (Anti-| dothimidine (AZT) For| AIDS nosis of AIDS; with newly | tumor plus |for treating AIDS-Re- | Research diagnosed, previously un- | antiretroviral)|lated Primary CNS Lym-| Group treated primary CSN lym- | |phoma. (ATEU 009) | 821-5089 phoma. | | | ------------------------------------------------------------------------------- Initial patients must: | GLQ 223 | Single-Dose Open | SFGH 1) have AIDS | (Cytotoxic |Label Safety and Tole-| AIDS 2) be p24 antigen positive| against HIV) |rance Study of GLQ 223| Research 3) have less than 100 T4 | |Administered Intrave- | Group cells | |nously in Patients In-| 821-5089 Criteria for subsequent | |fected with HIV | patients are still in | negotiations with the FDA.| ------------------------------------------------------------------------------- HIV infection with or | Lentinan | A Phase I/II Dose | SFGH without symptoms, but |(Immunomudula- |Finding Pilot Study of| AIDS without AIDS-defining ill-|tory) |Lentinan in Patients | Research ness; 200-500 T4 lympho- | |With PGL and ARC | Group cytes | | | 821-5089 ------------------------------------------------------------------------------- AIDS-related ITP | Gamma globulin | Monthly Intravenous | St. Francis |(Immunomodula- |Gamma Globulin Treat- | Terrence |tory) |ment of Patients With | Chew, M.D. | |AIDS-Related Immune | 474-2020 | |Thrombocytopenic Purpura ------------------------------------------------------------------------------- HIV +, asymptomatic to | Thymopentin | Double Blind Study of| 1710 Scott ARC, no AIDS |(Immunomodula- |Thymopentin Effects on| St. |tory) |Infectivity of Mononu-| Leland |clear Cells in HIV-1 | Traiman, |Infected Patients | R.N.,F.N.P. | 673-3902 ------------------------------------------------------------------------------- Symptomatic HIV disease | DHEA | Phase I Study of | Children's but without AIDS diagno- |(Immunomodula- |Dehydroepiandrosterone| Jaime Geaga sis, greater than or equal|tory) |(EL-10) Therapy For | P.A. to 300 but less than 600, | |Patients With Early | 750-6529 no other antiretroviral | |HIV Disease | therapy for 60 days prior | to study entry ------------------------------------------------------------------------------- Patients with clinical | Somatostatin |Efficacy and Safety of| SFGH features of HIV infection | (Neurohormone) |Sandostatin (Somato- | Julie Hahn and uncontrolled diarrhea | |statin) in the Treat- | R.N. for at least four weeks; | |ment of Immunodefici- | 821-8822 failed on standard therapy| |ency-Related Diarrhea:| | |Open Label Study | ------------------------------------------------------------------------------- Stratified into 5 groups: | No drug -- data| AIDS-Associated Heart| SFGH, UCSF HIV +, asymptomatic |collection only |Disease Incidence and | Tom HIV +, ARC | |Etiology | Tremblay HIV +, AIDS | | | R.N. HIV -, gay men | | | 821-5973 HIV -, men with wasting illness ------------------------------------------------------------------------------- Members of groups at risk | No drug -- data| A Collaborative Study| SFGH for HIV infx. and their |collection only |of Heterosexual HIV | Heidi opposite sex partners; se-| |Transmission | Peterson ropositives with no iden- | | | M.P.H. tified risk and their | | 550-6896 opposite sex partners | ------------------------------------------------------------------------------- Diagnosed with syphilis | No drug -- data| HIV and Syphilis -- | City Clinic any type), no H/O PCN al- |collection only |Prospective Cohort | Gail Bolan lergy, no antibiotics | |Study | M.D. within 2 weeks, willing to| | 864-8100 take HIV test, no H/O | | 774-4635 other immunosuppressive | | (LRB) illness | ------------------------------------------------------------------------------- Confirmed HIV positivity | No drug -- data| Study of the Metabo- | Children's (any stage of disease) and|collection only |lic Basis of Myalgias | Robert suffering from myalgias | |in Patients with AIDS | Miller (muscle pains) | | | M.D. | 750-6040 ------------------------------------------------------------------------------- HIV +, with or without | No drug -- data|A Prospective Study of| SFGH symptoms of HIV disease |collection only |Pulmonary Complica- | Joan Turner | |tions of Human Immuno-| R.N.,M.S. |deficiency Virus In- | 821-8313 |fection | ------------------------------------------------------------------------------- Seropositive women | No drug -- data| Natural History Study| SFGH |collection only |of HIV Infection in | Lauren Poole | |Women | N.P. | Catherine | Lyons, N.P. | 476-4091 ------------------------------------------------------------------------------- ***** THE STANFORD AIDS CLINICAL TRIALS GROUP The Stanford AIDS Clinical Trials Group (ACTG) is actively recruiting patients for the following studies. For additional information about these trials or trials under development, call the Stanford AIDS Clinical Trials Unit office at (415) 723 6231. AZT for asymptomatic HIV positive individuals (019). Bactrim and aerosolized pentamidine for prophylaxis of PCP for PWA taking AZT (021). Phase I trial of AZT and IL 2 for people with persistent general- ized lymphadenopathy (024). AZT for asymptomatic, HIV positive hemophiliacs (036). Phase I/II trial of alternating and intermittent regimens of AZT and ddC for PWA and PWARC (047). Phase I/II trial of alternating and intermittent regimens of AZT and ddC for people who have experienced hematologic toxicity from AZT (050). cell mediated cytotoxicity and lymphocyte prolifera- tion responses in asymptomatic, HIV positive individuals. T-cell mediated cytotoxicity and lymphocyte proliferation responses in asymptomatic, HIV-positive individuals. Phase I dose escalating trial of a new glycosylase inhibitor (SC 48334) for people with severe ARC or AIDS (100). Randomized trial of three antipneumocystis agents plus AZT for the primary prevention of PCP (081). ***** OTHER TREATMENT RESOURCES AIDS/HIV EXPERIMENTAL TREATMENT DIRECTORY The American Foundation for AIDS Research (AmFAR) publishes this quarterly manual. It is intended primarily for physicians. $10 per issue or $30 per year (free to PWA, PWARC, and HIV+). Write to AmFAR, 1515 Broadway, Suite 3601, New York, NY 10036 8901 or call (212) 719 0033. AIDS TARGETED INFORMATION NEWSLETTER A monthly review of published studies in all areas of AIDS research. ATIN targets physicians, researchers and other medi- cally sophisticated readers. Available for $125 a year. To sub- scribe write to Williams & Wilkins, P.O. Box 23291, Baltimore, MD 21203 or call (800) 6423 except in Alaska. AIDS TREATMENT NEWS A biweekly newsletter on experimental and alternative treatments for AIDS. To subscribe send $100 per year ($30 for PWA or PWARC) to ATN Publications, P.O. Box 411256, San Francisco, CA 94141, or (415) 255 0588 anytime for information. A six month subscription is also available. For the complete set of over 70 back issues, send $75 ($18 for PWA or PWARC) to the above address. BODY POSITIVE This monthly magazine focuses on HIV related news articles and features, with information on medical, political and judicial matters. Each issue includes several pages in Spanish. To sub- scribe , send $15 ($35 foreign) to Body Positive, 208 W. 13th Street, New York, NY 10011 or call (212) 633 1782 and ask for a free sample copy and an order form. CDC WEEKLY This private publication (not affiliated with the Centers for Disease Control) offers a comprehensive weekly report of AIDS related news and research. $695 per year. Write CDC AIDS Weekly, P.O. Box 83409, Birmingham, AL 35283 0409 or call (205) 991 6920. FOCUS The UCSF AIDS Health Project publishes this monthly review of HIV related issues. FOCUS is intended primarily for health care service providers. $36 per year. Make checks payable to "UC Regents" and send to FOCUS, UCSF AIDS Health Project, Box 0884, San Francisco, CA 94143 0884. Back issues are available. Call (415) 476 6430. PI PERSPECTIVE A free quarterly newsletter with information about treatment options and access, as well as public policy. PI Perspective is published by Project Inform, which also operates a hotline. To subscribe, call the hotline at (800) 822 7422 (outside CA) or (800) 334 7422 (CA only) or write to Project Inform, 347 Dolores Street, Suite 301, San Francisco, CA 94110. TREATMENT ISSUES A free monthly newsletter on experimental and alternative AIDS therapies published by the Gay Men's Health Crisis in New York. To subscribe, write to GMHC, Inc., Department of Medical Informa- tion, 129 W. 20th Street, New York, NY 10011, or call (212) 337 3556. ***** GLOSSARY Compiled by Etienne Hafs acyclovir (zovirax): An antiviral drug used in the treatment of herpes simplex virus 1 (HSV 1), herpes simplex virus 2 (HSV and herpes zoster. anemia: A low number of red blood cells. antibody: A protein substance, developed in response to an antigen, that destroys or neutralizes bacteria, viruses or other harmful toxins. This antigen/antibody reaction forms the basis of immunity (see also p24 antigen and autoimmune response). asymptomatic seropositive: An individual who has been infected with HIV but shows no apparent symptoms. HIV positive individuals can still spread the disease even though they are asymptomatic. atrophy: A wasting or decrease in size. autoimmune response: A response caused by the immune system mistakenly attacking the body's own tissues. axon: A long structure in the nerve cell that acts as a pathway for nerve impulses. baseline: A known value with which later measurements can be compared (e.g., baseline temperature, baseline hemoglobin level.) bone marrow cell pool: Those bone marrow cells responsible for the production of blood cells. CD4: A protein embedded in the cell surface of T helper cells and certain other cells. HIV invades these cells by first attaching to the CD4 receptor. This term also refers to an experimental, genetically engineered drug that acts as a "decoy" that "tricks" HIV into attaching to it instead of infecting new cells. CPK (creatine phosphokinase): An enzyme essential to muscle contraction that is elevated in the blood in most muscle diseases. cortex: The external part of an organ, such as the brain, kidney, or adrenal gland. corticosteroid: Any of a number of steroid substances obtained from the cortex of the adrenal gland, or any synthetic substitute. Corticosteroids are immu- nosuppressive and HIV infected individuals should be cautious about taking them. cranial nerves: Twelve pair of nerves in the brain. AZT: Dihydro methyl pyridinyl carbonyl azido dideoxy- thymidine. danazol: A drug that suppresses the action of the pituitary gland. It is used in the treatment of thrombo- cytopenia (ITP). dapsone: An antibacterial drug used to treat PCP. dementia: A loss of mental capacity. AIDS related dementia may be caused by HIV or other infections. demyelinating: Having to do with destruction of the myelin sheath that surrounds and insulates the axon of some nerves. distal: Farthest from the center or from a central point of reference. double blind study: A method of medical investigation in which neither the subject nor the investigator knows what treat- ment, if any, the subject is receiving. At the end of the experiment, the "code" is broken and data are analyzed with respect to the various treatments used. This method attempts to eliminate observer and subject bias. FDA: Food and Drug Administration. Guillain Barr syndrome: An acute disease that produces bilateral weakness or paralysis, most commonly in the legs and feet. ganciclovir (DHPG): An experimental antiviral drug used in the treatment of CMV retinitis, AIDS related meningoencephalitis, and AIDS related polyradiculopathy. hematocrit: The volume percentage of red blood cells in whole blood. In men, it normally constitutes about 40 to 54% of the whole blood; in women, it normally con- stitutes about 37 to 47%. hemoglobin: The protein in red blood cells that carries oxygen to the cells. Normal hemoglobin values for women are 12 grams per liter and 14 16 grams per liter for men. These values may vary according to where the test is performed. herpes simplex virus 1 (HSV 1): A virus that can cause painful "cold" sores or blisters on the lips ("fever blisters") or in the mouth or around the eyes. The symptomatic disease stage occurs at unpredictable intervals of weeks, months or years. The latent (inactive) virus can reactivate due to emotional stress, physical trauma, other infections, or suppression of the immune system. HSV 1 responds well to treatment with acyclovir. herpes simplex virus 2 (HSV 2): A virus that can cause an inflammatory disease of the skin or mucous membrane. It is highly contagious and is usually sexually trans- mitted. Painful blisters may appear on the anus or genitals 2-12 days after infection. In healthy individuals, symptoms resolve without treatment in 2 3 weeks. In severely immunocompromised individuals, the virus is sometimes difficult to suppress. Like HSV 1, HSV 2 may lie dormant (inactive) for weeks, months or years before reactivating to produce symptoms. Treatment with acyclovir usually works well. human herpes virus 6 (HHV 6): A new herpes virus recently discovered by Dr. Robert Gallo and associates at the National Cancer Institute. Dr. Gallo has suggested that HHV 6 may play an important co factor role in the development of AIDS. IDU: Injection drug user(s). immunoglobulin: One of a family of closely related proteins that can act as antibodies. IND status: Investigational new drug status. Certain drugs are available on a case by case basis through this mechanism. isolate: Different strains of HIV. ITP: Idiopathic thrombocytopenia. Idiopathic means that the disorder is of unknown origin. (See also thrombocytopenia). jaundice: Yellow pigmentation of the skin and whites of the eyes caused by liver disease (such as hepatitis) or excessive destruction of red blood cells. KS: Kaposi's sarcoma. KS is a tumor of the walls of lymph vessels. It usually appears as pink to purple painless spots on the surface of the skin, but it can also occur internally. KS is one of the major cancers found among PWA, especially gay and bisexual men. leukopenia: An abnormally low normal number of white blood cells in the circulating blood. lymphadenopathy: Enlargement of the lymph nodes or lymph system. lymphocyte: A type of white blood cell. lymphokines: Substances that help to produce cellular immunity by stimulating macrophages and lymphocytes. macrophage: A large cell which ingests degenerated cells and blood tissue, and foreign particles. It breaks down foreign particles and displays their antigens on its surface. T cells then read these antigens, beginning the process of antibody production. Macrophages exist in large numbers throughout the body. meningoencephalitis: Inflammation of the brain and of the membranes covering the brain and spinal cord. neurologic (neurological): Concerning the central nervous system (brain and spinal cord) or the peripheral nervous system (the rest of the nervous system) and/or diseases of these systems. neuropathy: Any disease of the nervous system. neuroradiological: Pertaining to the study of the nervous system with X rays. neutropenia: A shortage of neutrophils, the most common type of white blood cells. NIAID: The National Institute of Allergy and Infectious Diseases. NIH: National Institutes of Health. p24 antigen: A protein fragment of HIV. The p24 antigen test measures this fragment. A positive result for p24 antigen suggests active HIV replication. A posi- tive test result may mean the individual has a higher chance of developing AIDS in the future. PCP (Pneumocystis Carinii Pneumonia): A type of lung infection found in immunosuppressed individuals. It is the most common opportunistic infection in AIDS. paraplegia: Paralysis of both legs and lower part of the body. pathogen: Any microorganism capable of causing disease. peripheral: Located at, or pertaining to, the periphery; occurring away from the center. peripheral neuropathy: A disorder of the nerves, usually involving the feet or hands, sometimes including legs and arms. pharmacokinetic: Concerning the study of how a drug passes through the body, the extent and rate of absorption from the stomach, its distribution, and location in tissues. placebo: An inert substance (see placebo controlled study). placebo controlled study: A method of investigation of drugs in which an inactive substance (the placebo) is given to one group of patients, while the drug being tested is given to another group. The results obtained in the two groups are then compared. plasma: A fluid in which blood cells and nutritive sub- stances are circulated in the body. It also serves to remove waste products of metabolism from organs and to facilitate chemical communication between different portions of the body. plasmapheresis: The selective removal of certain proteins or anti- bodies. This process is sometimes used in the treatment of some peripheral neuropathies. platelets: Blood cells that help normal blood clotting. polyneuropathy: A disease in which several peripheral nerves are affected at the same time. prednisone: A synthetic corticosteroid sometimes used in the treatment of neuropathies. Like all cortico- steroids, it is immunosuppressive. prophylaxis: Treatment that helps to prevent a disease before it occurs. PWA: Person with AIDS or people with AIDS. PWARC: Person with ARC or people with ARC. seropositive: Infected with HIV, or a person infected with HIV. sulfadiazine: A sulfa drug used in the treatment of K.S., toxo- plasmosis and meningitis. symmetric: Occurring in the same parts on opposite sides of the body (e.g., right leg and left leg). synergistic: Working together to produce a greater effect than with either drug alone. thrombocytopenia: An abnormally low number of platelets in the blood. toxoplasmic encephalitis: An inflammation of the brain caused by toxoplas- mosis, a parasite. uncontrolled trials: Research studies in which there are no participants taking a placebo (see also placebo controlled study). vincristine: A drug sometimes used in the treatment of K.S., ITP (thrombocytopenia), leukemias, lymphomas, and solid tumors. ***** [MASTHEAD] BETA EDITOR Ron Baker Consultants for this issue: William Lang, MD Harvey Bartnof, MD Robert Miller, MD Dobri Kiprov, MD George Rutherford, MD Editorial Assistants Etienne Hafs Isabel Auerbach Anne Goddard Editorial Production Don Frazell Design Larry Stinson Production Hunt Weber Clark Design BETA is published by the San Francisco AIDS Foundation, P.O. Box 6182, San Francisco, CA 94101 6182. Funding for this issue pro- vided by private and corporate donations. Subscription informa- tion: San Francisco residents: 415 863-AIDS &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display