Subject: GMHC Treatment Issues Vol. 6 No. 2 Date: Feb 1992 (1153 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T I S S U E S && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& GMHC Treatment Issues, Volume 6, Number 2 February 1992 CONTENTS: [items are separated by "*****" for this display] High-Dose Acyclovir AIDS Dementia Complex Treatment Briefs AZT and ddC Combination Glossary ***** HIGH-DOSE ACYCLOVIR CONTROVERSY by Spencer Cox Newly released data from Britain about the ability of acyclovir to prevent cytomegalovirus (CMV) recently caused a stir both in the U. S. and abroad. The British study showed that acyclovir (Zovirax) extends life for persons with HIV, but does not prevent symptomatic cytomegalovirus (CMV) disease. These findings were met with skepticism by several prominent scientists, including Dr. Anthony Fauci of the National Institutes of Health (NIH).[1] Additionally, Burroughs Wellcome, maker of Zovirax, disagrees with British scientists about what exactly the data indicate. Treatment Issues spoke with several leading HIV/AIDS community and research physicians about the study and about acyclovir-use in persons with HIV. Background Acyclovir is a nucleoside analogue (one class of general antiviral drugs) which has activity against viruses in the herpes family, including herpes simplex I & II; herpes zoster (chicken pox or shingles), Epstein-Barr Virus (EBV), and cytomegalovirus (CMV).[2] The drug is approved for the treatment of herpes simplex and herpes zoster, and for prevention of herpes simplex. In addition, it has been suggested that very large doses of the drug may prevent reactivation of latent CMV infections in persons who have a compromised immune system.[3] It has recently been hypothesized that since acyclovir acts against herpes viruses, the drug may work against the newly- discovered human herpesvirus-6 (HHV-6), a virus which may play an important role in the deterioration of the immune system. HHV-6 has been found in the saliva of HIV-infected individuals,[4] and has been found in high concentrations among individuals with primary CMV infection.[5] CMV Infection, Disease, and Prophylaxis CMV is a herpes virus that is generally benign in persons with healthy immune function. Many people in the general population (60-90%) have been exposed to the virus, but are able to build antibodies against it and stave off CMV illness. In other words, many people have "latent" or inactive CMV infection. However, in people with AIDS and other immune-compromising conditions, in newborns, and organ transplant patients, latent CMV can become reactivated and cause serious diseases including retinitis, colitis, pneumonia, ulcers in the stomach and esophagus, hepatitis, and other organ-system diseases.[6] Additionally, new infections of CMV in persons with weak immune systems can cause severe flu-like symptoms including swollen glands, fever, and a sore throat. Infection with CMV is fairly common in the U. S. CMV is transmitted through sexual contact, from CMV-infected mother to fetus, and by organ transplants. The virus has been found in about 5% of donated blood. The probability of infection seems to-rise with age: about 20% of 20-year-olds are infected with CMV, and about 70% of 60-year-olds.[7] Gay men may be at particular risk for CMV infection. One study of men attending an STD clinic in San Francisco found that 94% of gay men were infected with CMV as opposed to 54% of heterosexual men.[8] Similar findings have been reported from Houston, Germany and the Netherlands.[9] Following infection with CMV, the virus usually enters a period of latency, which means it does not actively cause illness. However, the virus is susceptible to reactivation and when activated can be transmitted by what is called viral "shedding." When the patient is shedding virus, CMV can be detected in bodily fluids such as saliva, urine, and semen. Shedding seems to be correlated with immunosuppression: one study found CMV shedding in 100% of gay men with under 100 T4 cells; 83% of men with T4 cells from 100-199; and 75% of men with 200-300 T4 cells.[10] Several studies have found evidence of symptomatic CMV disease in about 50% of autopsies performed in persons with AIDS. [11] One study suggested that CMV was the immediate cause of death in 12% of persons with AIDS. [12] Recent evidence points out that CMV infection is a significant co-factor for HIV disease progression. In a study of 108 HIV-positive hemophiliac patients, the risk of developing AIDS was 2.5 times higher in CMV-infected persons compared to people who did not have CMV infection.[13] There are many proposed reasons for this possible correlation. First, active CMV infection is thought to cause immune suppression.[14] CMV is also believed to stimulate the production of a growth-causing protein called tumor necrosis factor (TNF), which has been shown to increase HIV reproduction in infected cells. Furthermore, in cells infected with both CMV and HIV, reproduction of both viruses is thought to be enhanced.[15] CMV-related Illness CMV is the most frequent cause of blindness and retinal damage. Retinitis occurs in 5%-10% of AIDS patients. Gastrointestinal disease due to CMV is seen in about 10% of AIDS patients, and may be a significant cause of weight-loss, malabsorption, and diarrhea. Other CMV diseases seem to occur less frequently in AIDS. Treatment for CMV Ganciclovir (DHPG; brand name Cytovene) and foscarnet (brand name Focavir) are standard treatments for CMV disease. However, these drugs are inconvenient for preventing CMV in patients who have not been previously exposed, since the drugs require a catheter and have significant toxicities. Several studies of acyclovir, administered intravenously and orally, found that the drug caused significant reductions in the occurrence of CMV disease and improved survival in organ transplant patients.[16] It should be noted, though, that there is some conflicting evidence concerning the effectiveness of oral acyclovir in preventing CMV disease.[17] Some studies seem to indicate that acyclovir might be more effective at preventing CMV infection in persons who have not been exposed, than in preventing a reactivation in persons who have been exposed and have a latent, or asymptomatic infection.[18] In a recent study by Dr. Craig Metroka, a New York physician, found no evidence of CMV disease in 51 patients with under 150 T4 cells who were taking high-dose oral acyclovir. Additionally, 15 patients of another group of 51 who did not take the treatment, developed CMV retinitis.[19] Acyclovir is relatively non-toxic, but occasionally produces headaches or nausea. At high doses, it can sometimes cause toxicity to the kidneys. Controversial Recent Findings The controversial British study followed 300 patients with T4 cell counts under 150. Half of the participants took 3200 mg per day of oral acyclovir and half took placebo. Results showed that the drug did not reduce the probability of CMV disease[20] After one year, it was clear that just as many people receiving acyclovir were developing CMV infection as those who were not receiving the drug. Burroughs Wellcome, stopped the trial for this reason. It was incidentally noted, upon preliminary analysis of the data, that participants receiving acyclovir had a better survival rate than those not receiving the drug. The survival benefit shown by high dose acyclovir did not depend on whether or not participants took AZT, ddI, ddC, or had no anti- HIV therapy.[21] It should be noted, that this study was not designed to compare survival rates, and full analysis of the data is needed. In a phone interview, one British investigator stated clearly that the study was too small and the patients were too healthy to detect a significant effect of the drug on CMV disease. For the most part, CMV disease is found in patients with under 100 T4 cells. According to this investigator, the researchers involved believe that the difference in survival was due to the effect of acyclovir on latent CMV infection, and deserves further investigation. Physicians' Views on Wide-Spread Use Dr. Joseph Sonnabend, the Medical Director of the Community Research Initiative on AIDS (CRIA) is adamant about the value of high-dose acyclovir for the prevention of latent CMV infections. "There is an entire body of evidence that the herpes viruses are co-factors for HIV disease progression," says Dr. Sonnabend. "DHPG, foscarnet, and now acyclovir have been shown to extend survival." Sonnabend believes that the herpes viruses, through a variety of mechanisms, can speed up HIV disease. CMV and EBV have clear immune-suppressing effects, he says. "Acyclovir may not provide comprehensive protection against symptomatic CMV," he asserts, "but there are clear benefits to long-term, high-dose acyclovir therapy in people with AIDS. " Dr. Sonnabend prescribes acyclovir for patients with less than 300 T4 cells, or patients with less than 500 T4 cells if they are declining rapidly. The standard dose he prescribes is one 800 mg pill every four waking hours or four grams of acyclovir a day. Dr. Howard Grossman, a prominent physician in private practice in New York City, is a bit more conservative about prescribing acyclovir. "I used to try to put whoever wanted [the treatment] on high-dose acyclovir," explains Dr. Grossman. "Then people started to talk about CMV retinitis that was resistant to DHPG, and there were indications that people were getting retinitis in spite of acyclovir prophylaxis." Now Dr. Grossman prescribes lower doses -- 400 mg of acyclovir a day in 200 mg pills. This dose is standard for the suppression of herpes. "If T4 cells go below 75, then I put patients on high-dose acyclovir. I give those patients 3200 mg a day, which is four 800 mg pills." Dr. Grossman states that there have been few side effects. "I've seen some abdominal upset and diarrhea, but we're not even sure it's drug related." Dr. Donald Abrams of the Community Consortium in San Francisco claims that he has never seen any toxicities with acyclovir. "Almost all of our patients are taking it," he said. "Our observational data base found that 270 of 300 patients were on some dose of acyclovir, and the mean dose was about 1 gram per day." Dr. Abrams routinely prescribes acyclovir, "for no particular reason." "It's a benign drug," he explains, "I tell my patients that obviously HIV will have a harder time attacking the immune system without the help of a herpes virus." Dr. Abrams routinely prescribes 3200 mg of acyclovir for patients at risk for CMV disease. The Jury's Still Out? While high-dose acyclovir seems to be a common addition to HIV regimens, there is some evidence that using acyclovir may be of little benefit to persons with HIV/ AIDS. An early ACTG study found neither added benefit nor added toxicity by adding high dose acyclovir to AZT therapy.[22] It should be noted that this trial studied only 67 patients for a short 12-week period. However, the same no-benefit conclusion was drawn from a similar but larger European-Australian study of 200 ARC patients.[23] Some researchers and doctors are skeptical of the benefit, and are conservative about prescribing high-dose acyclovir until conclusive scientific evidence indicates a clear benefit to the drug in HIV treatment. Toxic to the Pocketbook The main toxicity to high-dose acyclovir is a pain in the wallet. One bottle of 100 pills (200 mg per pill) routinely costs $60 - $85. The price is unlikely to be reduced. In fact, each time Burroughs Wellcome has reduced the price of AZT, it has also increased the price of acyclovir. Since high doses of acyclovir are not approved for the prevention of CMV, there may be difficulty with insurance reimbursement. The New York State AIDS Drug Assistance Program (ADAP) has refused to pay for high- dose acyclovir, and private insurers are notoriously conservative about reimbursing the use of unapproved drugs. References: 1. "Skepticism on AIDS Report," New York Times, December 31,1991. 2. Physicians Desk Reference, Vol. 44,1990, p. 816. 3. V Int'l Conf on AIDS, Abstract # M. B. P. 126, Montreal, June 1989. 4. Levy JA et al. Characterization of a new strain of HHV-6 recovered from the saliva of an HIV-infected individual. 178: 113-21, 1990. 5. Irving WL et al. Dual antibody rises in CMV and HHV-6: frequency of occurrence in CMV infections and evidence for genuine reactivity to herpes viruses. The Journ of Infect Dis 161:910-916, 1990. 6. Drew et al. Herpes virus infections caused by CMV, HSV, and VZV: in The Medical Management of AIDS, ed Sande & Volberding (Philadelphia: W. B. Saunders Co., 1988), p. 271. 7. Wentworth BB & Alexander ER. Seroepidemiology of infections due to members of the herpes virus group. Journ of Epidem 94: 496-507, 1971. 8. Drew WL et al. Prevalence of CMV in homosexual men. Journ Infect Dis 143:188-192, 1981. 9. Greenberg SB et al. Lymphocyte subsets and urinary excretion of CMV among heterosexual men attending a clinic for STDs. Journ of Infect Dis 150:330-333, 1984; Coutinho RA et al. Infection with CMV in homosexual men. Brit Journ of Vener Dis 60:249- 252, 1984; and Doldi K et al. Proliferative responses to human CMV in lymphocyte cultures of male homosexuals. Journ of Clin Lab Immun 17:111-114, 1985. 10. VIIth Int'l Conf on AIDS, Poster Presentation # W. B .2277, Florence, June 1991. 11. Klatt EL. Diagnostic findings in patients with AIDS. Journ of AIDS 1:459-465, 1988; and VII Int'l Conf on AIDS, Abstract # M. B. 81, Florence, June 1991. 12. Klatt EL. Diagnostic findings in patients with AIDS. Journ of AIDS 1:459-465, 1988. 13. Webster A. Cytomegalovirus a possible cofactor in HIV disease progression. Journ AIDS 4 [suppl]:S47-52, 1991. 14. Rinaldo CR Cytomegalovirus as a cofactor, in HIV infection and AIDS in Cofactors in HIV Infection and AIDS (Boca Raton: CRC Press, 1990) pp. 151-85. 15. Skolnik et al. Bidirectional interactions between HIV type-1 and CMV. Journ of Infect Dis 157:508-514, 1988. 16. Meyers et al. Acyclovir for prevention of CMV infection and disease after allogenic marrow transplantation. NEJM 318:70- 75, 1988; Gluckman E et al. Prophylaxis of herpes infection after bone marrow transplantation by oral acyclovir. Lancet (ii):706-8, 1983; and Balfour et al. A randomized placebo- controlled trial of oral acyclovir for the prevention of CMV disease in recipients of renal allografts. NEJM 320:1381-7, 1989. 17. Wade JC et al. Oral acyclovir for prevention of herpes virus reactivation after marrow transplantation Ann of Intern Med 100:823, 1984; and Prentice HG et al. Use of prophylaxis of herpes infection in severely immunocompromised patients. Journ of Antimicrob Cherno 12 [suppl. B]:153-159, 1983. 18. Gluckman E et al. Prophylaxis of herpes infection after bone marrow transplantation by oral acyclovir. Lancet (ii): 706-8, 1983; and Balfour et al. A randomized placebo-controlled trial of oral acyclovir for the prevention of CMV disease in recipients of renal allografts. NEJM 320:1381-7, 1989. 19. V Int'l Conf on AIDS, Abstract # M. B. P. 126, Montreal, June 1989. 20. Youle, M. Personal Communication, January 3, 1992. 21. Ibid. 22. Collier AC et al. A pilot study of low dose zidovudine in HIV infection. NEJM 323:1015-21, 1990. 23. Cooper DA et al. The efficacy and safety of AZT with ot without acyclovir in the treatment of patients with ARC. AIDS 5(8):933-43, 1990. ***** AIDS DEMENTIA COMPLEX by Derek Link Dementia is an organic mental disorder defined as a loss of intellectual abilities interfering with a person's social or occupational function. AIDS dementia complex (ADC) is a complicated syndrome made up of different nervous system and mental symptoms found somewhat commonly in people with HIV- disease. The frequency of ADC increases with advancing disease. In fact, it is thought to be fairly uncommon in persons with early HIV disease,[1] but is found more commonly in AIDS patients with system-wide symptoms.[2] ADC consists of many progressive conditions which can be mistaken for other problems, such as depression, drug-induced side effects, or specific opportunistic infections which affect the brain, like toxoplasmosis or lymphoma. Symptoms of ADC may include: poor concentration, forgetfulness, loss of short- or long-term memory, social withdrawal, slowed thinking, short attention span, irritability, apathy, weakness, poor coordination, impaired judgement, and personality change, to name a few. Because there are many different manifestations of ADC, the syndrome is poorly understand poorly understood and has been reported and described in a variety of conflicting ways. This article will attempt to illuminate some of the complicated issues surrounding AIDS-related dementia in adults, as well as the treatment options which are available. BACKGROUND AND SYMPTOMS Nervous system and mental diseases thought to be associated with, or caused by, HIV have been reported since the earliest days of the epidemic. Such manifestations were given a variety of names and descriptions by many different researchers. "HIV encephalopathy or encephalitis," "multifocal giant-cell encephalitis," "subacute encephalitis," and "progressive dementia" are all names once used to describe this syndrome. In 1985, Drs. Navia and Price coined the name"AIDS dementia complex."[3] Since that time, the condition has been added to the list of AIDS-defining illnesses and has been further refined for surveillance purposes by the Centers for Disease Control (CDC). In May, 1991, Dr. Janssen and colleagues published the most recent working definition of ADC,[4] which includes only the most debilitating manifestations and leaves out some of the more common, but harder to detect symptoms, such as irritability and moodiness. As an AIDS-defining condition, ADC is characterized by severe changes in cognition, behavior, motor coordination, or mood that are directly attributable to HIV. s Cognition is the process of acquiring knowledge. It is defined as awareness, perception, judgement, and memory. In ADC, "cognitive impairment" is often characterized by memory loss, speech problems, inability to concentrate, and poor judgement. Behavioral changes in ADC are the least understood and least defined. They can best be characterized as impairments in the ability to perform common tasks and activities of daily living. Such changes are found in 30%-40% of patients with early ADC. [6] Motor impairment is often characterized by incontinence, paralysis and loss of control of the legs, and stiff, awkward, or markedly slow movements. Mood (also called affect) impairments are defined as changes in emotional responses to experiences. In ADC, affect impairment is characterized by severe mental conditions, such as depression, psychosis, and mania. Although the definition of ADC has been refined over the last few years, diagnosing the illness is still dependent on the keen judgement of doctors. It is easy to imagine how difficult it might be to determine impairments in mood and behavior. Consequently, the debate about the categories and usefulness of the ADC definition remains vigorous. Incidence At present, there is no reliable data concerning the percentage of people with AIDS who may eventually develop ADC. Several studies were conducted in the mid-1980s, but together they found that between 10%-70% of people with AIDS may develop ADC. [7] The reason for this wide range in percentage is two- fold: These studies were conducted 1) without a uniform definition of ADC, and 2) prior to the availability of AZT treatment for a-symptomatic HIV-positive people. Anecdotal reports indicate that there are fewer patients with ADC since AZT therapy has become standard, and that patients who do have the syndrome tend to be sicker. One scientific study from England corroborates this theory. The British study found that only 2% of patients with AIDS taking AZT developed ADC between 1982 and 1988, compared to 20% of patients not taking AZT. The incidence of ADC has dropped from 53% in 1987 (prior to the introduction of AZT) to 3% in 1988 (after the introduction of AZT).8 Early in the epidemic, a significant percentage of new AIDS diagnoses were attributed to ADC. 9 These newly-diagnosed people often had ADC, but no other AIDS-related condition. Many clinicians report that they are no longer seeing people who have just ADC. ADC has increasingly become a disease of late stage AIDS where people suffer from multiple infections. Natural history and epidemiological studies are needed now to confirm the observations of clinicians. These studies are necessary not only to define the rate of ADC among people with AIDS, but also to define what factors, if any, correlate with progression. Diagnosis The main way to detect and evaluate ADC is a test called the mental status examination. The examination is designed to reveal problems such as short- or long-term memory loss, problems with orientation, concentration, and abstract thinking, as well as swings in mood. In addition, certain laboratory tests can be useful. These include examination of cerebrospinal fluid (CSF) which is obtained by a spinal tap. Research shows that most patients with ADC have mild elevations of certain proteins and of white blood cells, which are detected by CSF examination.'x Additionally, the amount of HIV in CSF seems to correlate with progressive dementia in children.[11] Other tests which may help in the detection of ADC are CT scans, MRI scans and SPECT scans. CT scans are x-rays which use special beams to produce detailed images of organs and structures within the body. In ADC-affected patients these scans usually show signs of atrophy of brain tissue. MRI, or Magnetic Resonance Imaging, is an expensive sensitive brain scan that is used when CT findings are inconclusive. MRIs usually detect white matter disease in the brain. SPECT scars (single photon emission computed tomograms) are the latest technology in the diagnosis of ADC. SPECT uses a radioactive material to measure blood flow in the brain, and may be useful to detect early HIV dementia.[12] SPECT scans can also follow response of senses to antiviral therapy. The scan is able to show if anti-HIV therapy improves the blood flow of the brain. In order to diagnose ADC accurately, mental status exams, a spinal tap and one of the standard scans are required (CT, MRI, or SPECT). These tests may also help differentiate ADC from other brain disorders such as cryptococcal meningitis, toxoplasmosis, lymphoma, or PML. How Does HIV Cause ADC? While it is clear that HIV can cause serious nervous system disease in people with AIDS, the direct role of the virus in causing AIDS-related dementia is unclear.[13] In general, such central nervous system and mental disorders as described above are caused by the death of nerve cells. While it has been demonstrated that HIV does not directly infect nerve cells, it is thought that the virus is somehow able to kill them indirectly. Macrophages, white cells which are prevalent in the brain and act as HIV reservoirs, appear to be HIV's primary cell target in the central nervous system. HIV-infected macrophages can transport HIV into the brain from the blood stream. These macrophages then harbor large amounts of virus in the brain, where they are the primary source of indirect injury to nerve cells.[14] Test tube studies offer the following three hypotheses about the way in which macrophages may cause nerve cell destruction: 1.) A particle on HIV's outer coat, called gp120, may be shed by an infected macrophage in the brain, causing damage to nerve cells.[15] 2.) The HIV TAT gene, a protein that helps in the production of new virus, detaches from HIV and circulates in the blood, causing toxic effects in nerve cells.[16] 3.) The macrophage itself releases a toxic substance called quinolinic acid into the brain.[17] The substance binds to nerve cells and causes cell death. Recent research has found elevated levels of quinolinic acid in the spinal and brain fluid of persons with ADC. [18] More research is needed to further characterize the role of HIV in ADC. Such research is critical to the future success of efforts to develop treatments for AIDS dementia complex. AIDS Dementia in Early HIV? Recent reports of subtle nervous system symptoms in persons with early HIV-illness have understandably caused a great amount of concern. Several small, scientifically-questionable studies indicated that asymptomatic HIV infected people had subtle neurologic deficits.[19] While it is important to note that mild neurologic deficits are distinct and possibly unrelated to ADC, such findings are disturbing. However, these studies have been forcefully refuted by the work of many other researchers. Data from several large studies of persons with asymptomatic HIV have found no neurological deficits.[20] AZT, ddI & ddC as Treatment for ADC Treatments for ADC have been extremely slow in coming, especially compared to treatments for other AIDS-related conditions. The reasons for this include: a lack of understanding of the cause of ADC; a lack of reliable data on the incidence of ADC; and, not insignificantly, a dearth of research funding and initiative in this area. Despite these obstacles several agents have been identified as useful in treating ADC. The best therapies to treat ADC seem to be anti-HIV drugs. To date, AZT is the best understood and, perhaps, most effective treatment available for ADC. Several groups have reported an improvement in cognitive functioning with AZT.[21] Larger doses (1,000 mg compared to the now standard 600 mg per day) of AZT appear to be necessary for treatment of ADC. The high dose of AZT may present problems, since many people with AIDS, particularly those who are the sickest, are often unable to tolerate the high doses of the drug. Another approach to treatment is direct injections of AZT into the spinal canal. One study found that of eight patients receiving AZT injections, five showed neurological improvements.[22] ddI and ddC (both drugs work in ways similar to AZT) have not been studied sufficiently for the treatment of ADC. Several small studies[23] and numerous anecdotal reports from clinicians suggest that ddI and ddC are less effective than AZT for treating AIDS dementia. It seems that ddI and ddC do not penetrate into the brain and spinal fluid as well as AZT does. In fact, it is estimated that only about 20% of ddI crosses the blood/brain barrier. However, ddI and ddC should be studied and considered for people who are unable to tolerate high doses of AZT. Many people with AIDS have begun to use ddI or ddC in combination with AZT for the treatment of overall HIV infection. While the results are highly promising at this time for the treatment of overall HIV infections, nothing is known about their usefulness in treating ADC. This question needs to be rigorously addressed by pharmaceutical and government researchers. Treating the Symptoms of ADC The full range of psychoactive drugs is often used to treat the signs and symptoms of persons with ADC. These drugs include: antipsychotics, antidepressants, anxiolytics, psychostimulants, antimanics, and anticonvulsants.[24] These drugs do not affect the underlying cause of ADC, or stop its progression. However, they may well alleviate some of its symptoms. Haloperidol (Haldol), an effective drug for Alzheimer's Disease, is often indicated for alleviating ADC symptoms. It should be noted that the drug, however, has many side effects. Patients with ADC are extremely sensitive to Haldol. Small doses (0.5 -1 mg) should be used to avoid severe side effects. Ritalin (methylphenidate) has been used with success in patients with ADC to alleviate apathy and to increase energy, concentration, and appetite. Doses of 5 -10 mg per day are often sufficient.[25] In cases of severe behavior disorders, antipsychotics such as thorazine and mellaril can be used to control agitation. Ativan and Valium may also be used for sedation and anxiety- control. Other psychiatric drugs which are used include: perphenazine (Trilafon); thiothixene (Navane); molindole (Moban); and fluoxetine (Prozac) with bupropion (Wellbutrin). Promising New Treatments Nimodipine, a calcium blocker, is one of the few agents under development specifically for treating ADC. Nimodipine is commercially available as a pill, manufactured by Miles Pharmaceuticals under the brand name Nimotop. The drug is prescribed for treatment of cerebral hemorrhages. In test tube studies, nimodipine counteracts the toxic effects of the HIV protein gp120.[26] Testing of nimodipine in persons with ADC has been delayed for over a year because of various bureaucratic problems. However, because of its potential, some people with ADC have been prescribed nimodipine by their doctors. Since there is no data, it is impossible to recommend an appropriate dose level. It is notable that physicians prescribing the drug use 30-120 mg per day. There is no scientific basis, however, to support choosing these doses. Nimodipine can cause hypotension (lowered blood pressure) and careful monitoring is required. A note of caution is warranted: the drug verapamil, a compound closely related to nimodipine, has been shown to increase HIV replication in test tube studies.[27] It is not known whether nimodipine increases HIV replication in the test tube or in humans. Additionally, Peptide T, a very non-toxic drug made up of amino acids, has demonstrated ability to improve neuropsychologic symptoms in persons with AIDS. [28] Peptide T is believed to block the toxic effect of gp120 in brain cells. Evidence from a small study of 15 AIDS and ARC patients, reported in Florence, suggest that Peptide T protects brain cells from the effects of gp 120 and helps nerve cells survive.[29] Conclusion Scientific research of new treatments for ADC is desperately needed. It is important that new anti-HIV drugs, like ddI and ddC, be thoroughly evaluated for their usefulness in treating ADC. At the same time, other promising drugs which may work to treat the underlying causes of ADC need investigation. References 1. Goethe KE et al. Neuropsychological and neurological function of the human immunodeficiency virus seropositive asymptomatic individuals. Arch Neurol 46:129-33, 1989. 2. Grant I et al. Evidence for early central nervous system involvement in AIDS and other HIV infections. Studies with neuropsychologic testing and magnetic resonance imaging. Ann Intern Med 107:828-36, 1987. 3. Navia BA and Price RW. AIDS Dementia Complex I. Clinical Features. Ann Neurol 19:517-24, 1986. 4. American Academy of Neurology. Nomenclature and research case definition for neurologic manifestations of HIV-1 infection. 41:778-785, 1991. 5. Navia BA and Price RW. The AIDS dementia complex as the presenting or sole manifestation of HIV infection. 44:65-69, 1988. 6. Barlow 1. Dementing illness in HIV. BETA, May 1991. 7. Navia BA et al. The AIDS Dementia Complex. Clinical Features. Annals of Neurology 19:525-530, 1986; and Navia BA and Price RW The AIDS dementia complex as the presenting or sole manifestation of HIV infection. 44:65-69, 1988. 8. Portegies P et al. Declining evidence of ADC after introduction of zidovudine therapy. Br Med Journ 299:819-22, 1989. 9. Navia BA and Price RW. The AIDS dementia complex as the presenting or sole manifestation of HIV infection. 44:65-69, 1988. 10. Ho D et al. The AIDS dementia complex. Ann Intern Med 111: 400-410, 1989. 11. Epstein LG et al. Expression of HIV in CSE of children with progressive encephalopathy. Ann Neurol 21 (4):397-401,1987. 12. Masdeo I et al. SPECT in HIV encephalopathy. Journ Nucl Med 32:1471-75, 1991. 13. Tillman M, Wigdahl B. Neuropathogenesis of HIV infection. Seminars in the Neurosciences 3:131-139, 1991. 14. Koenig S et al. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233:1098-1093, 1987. 15. Kaiser PK et al. Neruonal injury due to HIV-1 envelope protein is blocked by anti-gp120 antibodies but not by anti-CD4 antibodies. Neurology 40:1757-1761, 1990. 16. Sabatier lM et al. Evidence for neurotoxic activity of tat from HIV-1. Journal of Virology 65:961-967, 1991. 17. Giulian D et al. Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science 250:1593-1596, 1990. 18. Heyes MP et al. Quinolinic acid in cerebrospinal fluid and serum in HIVC-1 infection: relationship to clinical and neurological status. Neural 29:202-209, 1991. 19. Grant I et al. Evidence for early CNS involvement in AIDS and other HIV infections. Ann Intern Med 107:828-836, 1987. 20. Miller et al. Neuropsychological performance in HIV-1 infected homosexual men. Neurology 40:197-203, 1990; Miller et al. Computerized and con- ventional neuropsychological assessment of HIV-1-infected homosexual men. Neurology 41: 1608-1616, 1991; and Seline OA et al. HIV-1 infection: no evidence of cognitive decline during the asymptomatic stages. 40:204-208, 1990. 21. Price RW et al. Zidovudine treatment of the AIDS dementia complex: results of a placebo controlled, multicentered therapeutic trial. 22. VIIth Int'l Conf on AIDS, abstract # MB 2050, Florence, June 1991. 23. Yarchoan. R. Long-term toxicity/activity profile of 2/, -dideoxyinosine in AIDS or AIDS-related complex. Lancet 336(8714):526-9, 1990. 24. Barlow I. Dementing illness in HIV. BETA, May 1991. 25. VIIth Int'l Conf on AIDS, abstract # MB 2053, Florence, June 1991. 26. Dreyer EB et al. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science 248:364-7, 1990; and Lipton SA. Calcium channel antagonists and HIV coat protein mediated neruonal injury. Ann of Neur 30:110-114, 1991. 27. Harbison MA et al. Effect of the calcium channel blocker verapamil on HIV-1 replication in lymphoid cells. Journ of Infect Dis 164:tk-tk, 1991. 28. VIIth Int'l Conf on AIDS, abstract # TH. B. 90, Florence, June 1991. 29. VIIth Int'l Conf on AIDS, abstract # M. B. 2049, Florence, June 1991. ***** COMBINATION AZT AND ddC: A PROMISING STUDY REPORTED by Gabriel Torres, M. D. A growing body of evidence indicates that treatment for HIV infection will require a combination of more than one anti-HIV drug. Often the use of only one drug leads to the rapid development of resistance. Resistance occurs when an organism, such as a bacteria or virus, develops a way to avoid or counteract the effects of a useful drug. When resistance occurs, an organism continues to reproduce and renders treatment useless. So seems the case with AZT and HIV. In fact, after six months of treatment, AZT generally seems to lose its activity against HIV (usually reflected by a decline in T4 cell counts). Such a decline may translate into a deterioration in the health of the patient. Combining AZT with other drugs is one promising strategy to prevent resistance from developing, and to prolong the period of the drug's ability to sustain T4 cell counts. Combination strategies may also allow for the use of smaller doses of each drug, which may lower toxic side effects. Recent test tube studies confirm that AZT and ddC work well together against HIV without additive toxic side effects.[1] This article will focus on the use of AZT and ddC together as a first choice anti-HIV therapy and as a secondline anti-HIV therapy for patients with AZT resistance. New Data Released From Combination Study The first promising study of AZT and ddC combination therapy was reported early this new year in the Annals of Internal Medicine.[2] The study conducted at the University of Miami and the University of California at San Diego, was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). Fifty-six patients with AIDS or ARC, and with T4 cells under 200, were studied from July 1989 to May 1990. None of them had ever taken anti-retroviral drugs, such as AZT, ddI, or ddC. All patients received aerosolized pentamidine to prevent PCP. The participants were assigned to one of several dose combinations of AZT and ddC. The doses of AZT included: 150 mg, 300 mg, and 600 mg/ day. The doses of ddC were 0.03 mg and 0.015 mg/kilogram/day. One additional group of participants received AZT alone at a dose of 150 mg/day. T4 cell counts increased in participants in each of the groups. However, patients receiving 600 mg of AZT and either 0.015 or 0.03 mg/kg of ddC were better able to sustain T4 increases than what would be expected from either drug alone. A decline in p24 antigen levels, indicating a decrease in HIV activity, was noted in all groups, except in the group of participants receiving AZT alone at 150 mg/day. Not surprisingly, the group on low-dose AZT alone had the fastest drop in T4 cell counts and a shorter suppression p24 antigen production. In the group receiving ddC and lowdose AZT declines in T4 cell counts were slower. This implies that the addition of ddC to AZT therapy may have had a synergistic effect in humans. Synergism is when two drugs have a stronger effect together than is expected when combining the drugs (i.e. 2+2 = 5). This synergistic effect of AZT and ddC occurred originally in test tube studies.[3] Toxicity In the study reported above, 17.9% of the patients had declines in white or red blood cell counts. However, there seemed to be no difference in toxicity among the different groups. Only two patients developed peripheral neuropathy, a common side effect of ddC. These peripheral neuropathies manifested as pain and numbness in the legs and feet. Several patients did develop opportunistic infections and lymphoma during the study. One patient died. Unfortunately very little information regarding the clinical outcomes of the patients after prolonged follow-up (40.6 weeks of observation after the trial) on the combination therapy was reported. Notable strategies to reduce toxicity include using alternating or intermittent combinations of the two drugs. In alternating AZT/ddC therapy, patients switch from one drug to another every week or month. The theory is that time off of AZT should allow AZT-related bone marrow toxicity to recover and the time off ddC should allow ddC-related nerve toxicity to recover. Schedules of alternating AZT and ddC have been studied in patients with AIDS or ARC who have toxic side effects from AZT. The drugs were given either every other week or every other month to 109 patients in a federally funded human study.[4] A preliminary report showed that alternating the drugs on a weekly basis caused less blood toxicity than alternating them on a monthly basis.[5] However peripheral neuropathy occurred more commonly in patients alternating the drugs on a weekly basis.[2] A second toxicity-reducing strategy is intermittent regimens, which means taking the drugs together followed by a period of no drug at all. However, it should be noted that intermittent regimens run the risk of virus reproduction during the time off of antiretroviral agents. CONCLUSION The authors of the study conclude that combination therapy using higher doses of AZT (300 mg or 600 mg) along with ddC produces higher rises in T4 cell counts than had previously been observed in studies of either AZT or ddC alone. One of the study collaborators, Dr. Margaret Fischl, stated that "the emergence of drug-resistant strains of HIV may have been diminished by the use of AZT and ddC together." Despite such optimistic conclusions, an accompanying editorial by Anthony Fauci, Director of NIAID, expressed caution in early interpretation of these results. Fauci also warned against using this combination until larger- scale trial data are available.[6] A federally-funded human trial of combination therapy,[7] hopes to enroll more than 1000 participants. Trial #155 is designed to compare the combination use of AZT and ddC to AZT alone or ddC alone. The doses chosen for that trial are 600 mg of AZT and 0.03 mg/kg of ddC, and were based on the results of the trial reported above from the Annals. Practicing physicians and persons with HIV are not likely to wait for the results of ACTG trial #155 before trying the combination. It is expected that if ddC is approved, many physicians will begin prescribing the combination of AZT and ddC as initial therapy (for people who haven't had previous AZT therapy), and may reserve ddI for persons who are intolerant or failing AZT. In the meantime, ddC is available for patients who are intolerant, ineligible, or failing AZT though an expanded access program from Hoffman-LaRoche. Doctors can call 1-800-DDC-21-HIV. References: 1. VIIth Int'l Conf on AIDS. Abstract #W. B. 2110, Florence, June 1991. 2. Meng TC et al. Combination therapy with AZT and ddC on patients with advanced HIV infection. Ann Intern Med 116:13- 20, 1992 3. Ibid. 4. AIDS Clinical Trials Group (ACTG) Trial #050. 5. VIth Int'l Conf on AIDS, Abstract # S. B. 425, San Francisco, June 1990. 6. Fauci AS. Combination therapy for HIV infection: Getting closer. Ann Intern Med 116:85-86, 1992 ***** GLOSSARY Anti-viral: A substance that stops or suppresses the activity of a virus. Antibodies: Proteins produced by plasma cells in response to a specific foreign organism. Anticonvulsant drugs: Agents which prevent or arrest convulsions. Antidepressant drugs: Agents which prevent or arrest depression. Antimanic drugs: Agents which prevent or arrest mania. Antipsychotic drugs: Agents which prevent or arrest symptoms of psychosis, a severe behavior disorder. Anxiolytic drugs: Agents which prevent or reduce anxiety. Central Nervous System (CNS): The brain and spinal cord. Cerebrospinal fluid (CSF): The fluid in the brain and spinal cord. Cognition: The ability to think. Colitis: Inflammation of the colon; a condition which causes stomach pain and diarrhea. Encephalitis: Inflammation of the brain. Encephalopathy: Any disease of the brain. Expanded access: Systems for distributing experimental drugs for free to patients who are unable to participate in human trials. Herpes simplex virus (HSV): A virus which causes a variety of disorders, including a severe rash in the mouth, anus and genitals. Lesions are usually small clusters of blisters on a base of red skin. Herpes zoster: A painful rash, also called shingles, which is a reactivation of the virus which causes chicken pox in children. Immunosuppression: A state when the body 's immune system defenses are lowered, and the body is less able to fight off infections and tumors. Lymphoma: Cancer of the lymphocyte; the cell that is responsible for normal immune function. Macrophages: A scavenger cell that specializes in the ingestion of harmful organisms. Mycobacterium avium Complex (MAC): A serious opportunistic infection in HIV, which causes symptoms including night sweats, high fevers, cough, weight loss, general fatigue, malabsorption of food and diarrhea. Neurologic: Relating to the brain and spinal cord. Neuropsychologic: Concerning the relationship between the brain and behavior. p24 antigen levels: A level which can be measured in blood and other body fluids with a test that detects the presence of a core protein fragment (p24) on HIV. Pneumocystis carinii pneumonia (PCP): An illness caused by a common parasite which grows rapidly in the lungs of people with AIDS and is the leading cause of death in AIDS. Prophylaxis: Treatment intended to preserve health and prevent the onset of a first case of disease. Psychostimulant drugs: Agents which speed up or increase responsiveness of the mind. Resistance: The condition of a bacteria or organism to mutate and avoid or counteract the effects of a useful treatment. Retinitis: Damage or inflammation of the retina of the eye, possibly leading to blindness. Secondline: A description of a therapy which is used after the first choice treatment has failed. For instance, ddC may be secondline therapy for HIV, after AZT therapy fails. Toxicity: A measure of what quantity of a medicine is poisonous. Toxoplasmosis: A specific infection of an organ, usually the brain, or the whole body. Treatment IND: A program to provide experimental treatment free of charge to patients who have no other available treatment options. Tumor necrosis factor (TNF): A natural cell substance which plays a role in many bio]ogical functions and may be implicated in stimulating HIV activity. ***** TREATMENT BRIEFS RIFABUTIN Adria Labs, maker of rifabutin, has applied to the Food and Drug Administration (FDA) for a Treatment IND to make its drug available as a prophylactic treatment for Mycobacterium avium complex (MAC). The proposed Treatment IND would provide rifabutin free of charge to virtually any HIV-infected individual with T4 cell counts under 200 and a negative MAC blood culture. Adria hopes to begin the program on February 3, and claims to have enough drug to supply up to 5,000 patients. To obtain the drug, doctors should call 1-800-552-7228. Many doctors and researchers believe that MAC becomes a threat only when T4 counts drop below 100. Data from Adria's trials should help evaluate the relationship between T4 count and MAC onset. Although the supporting data have not yet been made public, it is clear that Adria believes that their trials indicate substantial efficacy. CLARITHROMYCIN UPDATE AIDS activists have been negotiating with Abbott Labs for the past two months, urging the company to simplify its burdensome clarithromycin expanded access paperwork. Currently, Abbott plans to close the two existing expanded access protocols as soon as there are enough "evaluable" data to allow the company to apply for an FDA new drug application. Abbott claims it will offer an incentive payment to doctors of $500.00 per patient in order to further enrollment. This is the first time such a payment has been offered. It is important to note that patients already enrolled in one of the two existing protocols will continue to receive the drug from Abbott. MAC TRIALS According to Abbott Labs, interim data from the AIDS Clinical Trials Group (ACTG) study of clarithromycin for MAC treatment ( 1000 mg vs 2000 mg per day) show the drug is able to reduce the amount of mycobacteria in blood and to alleviate some symptoms. Both drug levels seem to be equally safe and effective. Development of resistant organisms has been found in up to one-third of patients by the 1 2th week of treatment. Although the meaning of this resistance is not yet determined, it seems likely that clarithromycin will be most effective when used in combination with other anti-MAC agents for MAC treatment. The long proposed ACTG study of clarithromycin as a MAC prophylaxis has recently been cancelled. Nonetheless, Abbott plans to proceed with a prophylaxis study either through the CPCRA or privately financed centers. If the data on rifabutin as a MAC prophylaxis are positive, studies using placebo will become unethical, and all new treatments will need to be compared to rifabutin. MICHAEL WRIGHT OF PROJECT INFORM (1953-1992) We are saddened to report the death of Michael Wright of Project Inform and ACT UP/Golden Gate. Michael's work on opportunistic infections was among the most impressive treatment activism in the country. "The Opportunistic Infections Chart," which Michael wrote for Pl Perspectives, has been extremely useful to both PWA's and health care providers. On a more personal note, Michael was a person who was especially kind and easy to work with. His presence will be sorely missed. PROMISING CD8 THERAPY PLUS IL-2 Activists are excited about reports of a promising anti-HIV and Kaposi's sarcoma therapy, which reactivates T8 cells. The treatment uses a device, developed by Applied Immune Science, which removes blood from the patient, activates T8 cells and infuses the blood back into the body along with Interleukin-2. In Phase I trials in Miami and Pittsburgh, the therapy was shown to be well tolerated and demonstrated renewed T8 cell activity. Patients had significant remissions of AIDSrelated symptoms such as Kaposi's sarcoma lesions. Phase ll trials are to begin in Miami in March, 1992. It is hoped that these trials will proceed without delay. CORRECTION: p24 ANTIGEN TESTS p24 antigen tests are not available through the New York City or State Departments of Health, and Wadsworth Labs by any formal mechanism, as was implied in last month's newsletter. Treatment Issues came to understand that doctors are sometimes able to get the test free for patients by requesting it along with an HlV-antibody test leven for patients who are known to be HlV-positive) at certain Health Department Laboratories. However, this is not a formal practice, and is apparently not widely available. ***** EXECUTIVE EDITOR David Gold EDITOR Mary Beth Caschetta MEDICAL CONSULTANT Gabriel Torres, M. D. TECHNICAL COORDINATOR Griffin Meyer COPY EDITOR Gary Schmidgall WRITERS Spencer Cox Derek Link DESIGNER Stephen de Francesco PRODUCTION MANAGER Val Hoskins PROOFREADERS Sara Hertz Terrence Kiernan OFFICE VOLUNTEERS Edward Friedel Eric Goldsborough Gary Schmidgall Frank Schramm Treatment Issues is GMHC's newsletter devoted to providing reliable information on experimental therapies. Describing an experimental therapy should not be construed as recommending it. All new treatments should be conducted under a physician's care. Treatment issues is published ten times yearly. All rights reserved. Non-commercial reproduction is encouraged. Subscription lists are kept confidential. Treatment Issues is supported in part by contributions made to the Richard Dunne Memorial Fund. Medical Information 129 West 20th street, New York, NY 10011 (c) 1991 Gay Men's Health Crisis, Inc. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display