Subject: GMHC Treatment Issues Vol. 6 No. 5 Date: May/June 1992 (1170 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T I S S U E S && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& GMHC Treatment Issues, Volume 6, Number 5 May/June 1992 CONTENTS: [items are separated by "*****" for this display] AZT/ddI Highlights from European AIDS Conference by Gabriel Torres, M. D. ddI in Children Comparing ddI to AZT Combining ddI and AZT New AZT Data AZT and Alpha Interferon AZT and GP160 AZT and Pregnancy AZT and Low Platelet Counts Conclusion Nucleoside Notes by David Gold New Findings AZT/ddI Combinations ACTG Reports on ddI vs. AZT New Immune Therapies by Michael Becker Cellector Therapy Early Human Trial Results Phase II Trials Push for Development Other CD-8 Therapies Gene Therapy Mail Order Pharmacies by Loren Couch How Mail Order Works Conclusion To Treatment Issues Readers Notes on Oral CMV Drugs by Mark Harrington High dose Acyclovir New Oral Drugs A Study for Science or Money? Conclusion Treatment Briefs by David Gold New theories on KS, but still no SP-PG trial CRIA to begin Pentoxifylline trial Fluctuating T-cells Fetal tissue transplant ban overturned by Senate Non-discrimination policies by Drug and Healthcare companies Oral Alpha Interferon study results Glossary ***** AZT/ddI Highlights from European AIDS Conference by Gabriel Torres, M. D. The Third European Conference on Clinical Aspects and Treatment of HIV Infection was held in Paris in March, 1992. The conference focused on treatment and prophylaxis of opportunistic infections and new research from trials using ddI and AZT. Most of the research studies presented were from Europe, Australia, and Africa. This article will describe some of the highlights of the conference and discuss the results of European studies. ddI Dr. Claude Carbon of the Bichat School of Medicine in Paris presented data from the large multicenter European study called the ALPHA trial.[1] This study compares the efficacy and safety of two doses of ddI in patients with AIDS and ARC who are intolerant of AZT. The randomized double-blind trial compares low-dose ddI (100 mg twice daily) to the standard dose (375 mg twice daily). Patient enrollment concluded in November 1991 and totalled 1,995 participants. Of those patients enrolled, 45% had ARC and 55% had AIDS. The study population received AZT therapy for a little over a year. Participants have been followed for about eight months. Of all the participants, 659 died and 146 patients with ARC progressed to AIDS. Seventy-nine patients developed HIV-related neuro-cognitive disorder (formerly referred to in Treatment Issues as AIDS dementia complex, or ADC). The most significant adverse effects of ddI included the following: 28 cases of pancreatitis (8 of which led to death); 196 cases of elevated serum amylase levels, indicating pancreatic damage; 282 cases of peripheral neuropathy; 256 cases of diarrhea; and 81 cases of neutropenia (low white blood cell count). The final results from this study should be available at the VIIIth International Conference on AIDS in Amsterdam during July 1992. A smaller ddI study from Belgium also compared a very low dose (67 mg twice daily) od ddI to a higher dose (250 mg twice daily) in patients who had failed or were intolerant of AZT.[2] Participants were followed for an average of five months. No significant differences in side-effects were caused by the different doses, except for a trend toward less pancreatitis in the lower dose group. T4 cell count elevations were seen in both groups. The range in T-cell increase was 19-36 cells after three months of treatment. A German study which was presented as an abstract in the conference also compared two doses of ddI and found more opportunistic infections and more cases of pancreatitis among patients taking the high dose rather than the low dose.[3] In a poster presentation, the same German researchers reported that serum lipase levels were the best marker for early detection of ddI-related pancreatitis and that serum amylase levels and abdominal sonography were not as useful in detecting early pancreatitis.[4] Active CMV infection was found in three of four patients who developed ddI-related pancreatitis, suggesting that CMV may play a role in the development of this side-effect. ddI resistance has also been documented in a few European patients who had switched from AZT to ddI and had taken ddI for 6 months or more.[5] Notably, four of thirteen HIV strains in patients who switched from AZT to ddI were still AZT resistant after no AZT for about eight months. These results conflict with studies in the U.S. that most viral strains regain sensitivity to AZT after a period off AZT. European ddI studies have confirmed those in the United States, though the drug is still awaiting approval for general use in Europe. Unlike Americans, Europeans have decided to gather more definitive data on efficacy before making the drug widely available. Approval will probably not be final until the results of the ALPHA trial are available. In the meantime, an expanded access program makes ddI available to patients who are failing or are intolerant of AZT in European countries. ddI In Children A ddI trial from France studied the effects of the two tested doses of ddI in 34 children with symptomatic HIV infection who had failed or developed intolerance to AZT. [6] The mean duration of treatment was eight months. No significant side effects have been observed at these doses, except for three children who have developed elevated liver levels enzymes. Comparing ddI to AZT Results from a multicenter Italian trial comparing AZT and ddI in patients with ARC who had never received AZT (a state referred to as "AZT naive") and who had T4 cell counts under 500 were presented by Dr. Stefano Vella from the Instituto di Sanita in Rome.[7] The trial was designed to enroll 300 patients in each arm by April 1992. In a early analysis, 126 patients are taking AZT and 137 are taking ddI. The average length of follow-up was approximately five months. About the same percent of the total of each group have had to discontinue taking the drug due to side-effects. Early data about T4 cell counts suggest that patients who entered the trial with more than 50 cells had a more significant increase in T4 cell counts with ddI than similar patients had with AZT. However, those who entered the trial with less than 50 T4 cells had a better response with AZT. Another Italian study is comparing AZT and ddI in patients with AIDS who have received AZT for at least six months. This study plans to enroll 200 patients in each arm. Over 50% of the patients enrolled in the Italian studies are intravenous drug users (IVDUs) and over 30% - 40% are women. This difference in populations may account for results that differ from U.S. trials that generally exclude large numbers of women. Combining ddI and AZT Dr. Margaret Ragni from the Hemophilia Center of Western Pennsylvania presented preliminary data from a Phase I-II trial which compared three dose combination regimens of AZT and ddI to ddI alone. The trial recruited asymptomatic HIV-positive patients with T4 cells between 200 to 500.[8] After a followup of 18 weeks, it was observed that the combination of AZT and ddI was well tolerated in participants. Of 126 patients enrolled, nine developed side effects (seven liver reactions, one gastrointestinal reaction, and one peripheral neuropathy). So far, no cases of pancreatitis has been reported. The T4 cell counts in all participants have increased, including an increase of 64 cells in patients taking ddI alone. After 24 weeks of observation there have been no significant efficacy differences among the four treatment areas. New AZT Data Several studies presented at the Conference focused on the use of AZT alone or in combination with interferon in different populations of patients. Interferon is a manufactured form of protein that fights off virus in infected cells. One observational study from the University of Bordeaux in France showed that AZT improved survival for persons with HIV and T4 cells under 350 for the first 12 months but not for the subsequent 24 months.[9] In the U.S., AZT has been shown to improve survival only for those with T4 cell counts under 200. The recently published Veterans Administration (VA) study of AZT failed to show a survival benefit for use of AZT in patients with T4 cells under 500.[10] A Danish study compared AZT to placebo in 335 asymptomatic participants with T4 cell counts under 400.[11] The study was terminated in December 1990 when the federally-funded trial (ACTG study #019) showed that AZT (500 mg/ day) reduced progression of disease to ARC or AIDS after 60 weeks. Only 2% of the AZT recipients developed anemia (low red blood cell counts) and 3% developed neutropenia (count of low white blood cell, called neutrophils). T4 cell counts remained increased for a longer period in those participants taking AZT than in those taking placebo. No difference in survival was noted between the treatment groups. Finally, a multicenter European and Australian study (H56- 20) funded by Burroughs Wellcome, the manufacturer of AZT, showed that the drug reduced disease progression to AIDS in asymptomatic HIV-positive participants.[12] The study compared AZT (dose 500 mg twice per day) to placebo in nearly 1000 patients from 10 countries with entry T4 cell counts greater than 400. The overall progression rate for those on AZT was 14% after two years compared to 28% for those participants taking placebo. The benefits of the drug were seen in those with entry T4 cell counts of between 400-750. There were no significant differences in severe blood toxicities between participants taking AZT and those on placebo, though more patients on AZT required dose reduction. This study must be evaluated very cautiously, for the following reasons 1) AZT was taken in a dose twice that of the recommended dose in the U.S.; 2) participants were not followed for very long to assess efficacy and toxicity; and 3) the trial was sponsored by the drug's manufacturer. AZT and Alpha Interferon An Italian study compared the use of AZT and alpha interferon to AZT alone in 202 patients with asymptomatic HIV infection and T4 cell counts between 200-500.[13] The dose of AZT was 250 mg twice daily and the dose of alpha interferon 3 million units three times per week. Over 90% of the patients in both arms were IDVUs. Of those who were initially p24-antigen positive, a greater number in the combination arm became p24- negative. Four patients on the combination regimen have progressed to AIDS compared to none in the AZT-alone arm. However, more patients (six vs. four) in the AZT-alone arm have developed minor opportunistic infections indicative of early symptoms. The group receiving combination therapy had more neutropenia and the group on AZT alone had more anemia. More follow-up studies and data are needed before conclusions can be drawn as to the possible benefits of AZT and interferon in HIV disease. AZT and GP160 A Swedish study reported on the use of gp 160 vaccine in combination with AZT in 40 asymptomatic patients with T4 cell counts over 400.[14] Subjects received six intramuscular injections of 160 micrograms of gp 160 (Vaxsyn HIV-1, MicroGenSys) in a set schedule lasting up to 26 weeks. They were also randomly assigned to receive either AZT or placebo. Though the study is still blinded, there has been a 14% increase in T4 cell counts in the entire group. T4 cell immune responses to the vaccine and an increase in the level of antibodies directed at the V3 loop (a section of the envelope protein of HIV) have been noticed. Three patients have also had a decrease in the amount of HIV detected in the blood. The only side-effects have been headaches and nausea. AZT and Pregnancy An Italian group presented a poster on the use of AZT during pregnancy.[15] Seven pregnant women were treated with AZT from 17-30 weeks of gestation until delivery. All had deliveries of infants with normal APGAR scores and neurodevelopmental measurements. After a year of follow-up none of the infants has become HIV-positive nor has evidence of HIV infection by PCR tests and viral cultures appeared. Except for mild anemia in the first week of life in two infants, no baby has developed side- effects. AZT and Low Platelet Counts Several Italian studies evaluated the effect of AZT treatment on low platelet counts (thrombocytopenia). This blood condition is defined as a platelet count of less than 150,000 and may affect women, children, and IVDUs disproportionately. Some studies have shown that relatively high doses of AZT are effective in increasing platelet counts in persons with HIV infection. One study presented compared the use of low dose AZT (500 mg per day) versus high dose (1000 mg) for thrombocytopenia.[16] After six months of treatment with AZT, 41% of the group receiving the high dose had maintained a platelet count above 100,000, compared to 12% of the group receiving the low dose. This study encourages the use of high dose AZT in conditions such as thrombocytopenia. Conclusion The European clinical trials with antiretroviral agents have been limited to the study of AZT and ddI. Most other similar drugs (ddC, d4T, 3TC, and FLT) are not available in Europe. Interpretation of these studies needs to be made in connection with results from major U.S. studies for a competent translation into actual clinical practice. (Editor's Note: A follow-up report on data from the European Conference relating to the management and prophylaxis of opportunistic infections is forthcoming in Treatment Issues.) References: 1. Carbon C, Update on the ALPHA Trial (oral presentation). Third European Conference on AIDS, Paris, March, 1992. 2. Third European Conference on AIDS. Abstract #065, Paris, March, 1992. 3. Third European Conference on AIDS. Abstract #013, Paris, March, 1992. 4. Third European Conference on AIDS. Abstract #P149, Paris, March, 1992. 5. Third European Conference on AIDS. Abstract #P278, Paris, March, 1992. 6. Third European Conference on AIDS. Abstract #043, Paris, March, 1992. 7. Third European Conference on AIDS. Abstract #066, Paris, March, 1992. 8. Ragni MV. Phase I/II Study of Combination Zidovudine and Didanosine in the Positive Asymptomatic Patients (Oral presentation) Third European Conf. on AIDS, Paris, Mar.,1992. 9. Third European Conference on AIDS. Abstract #063, Paris, March, 1992. 10. Hamilton J, Simberkoff M. get title of Veteran's study (NEJM) 11. Third European Conference on AIDS. Abstract #064, Paris, March, 1992. 12. Burroughs-Wellcome. Wellcome trial H56-020 of zidovudine in "low risk" asymptomatic HlV-positive individuals (CD4.400) 13. Third European Conference on AIDS. Abstract #021, Paris, March, 1992. 14. Third European Conference on AIDS. Abstract #068, Paris, March, 1992. 15. Third European Conference on AIDS. Abstract #P132, Paris, March, 1992. 16. Third European Conference on AIDS. Abstract #P2&9, Paris, March, 1992. ***** NUCLEOSIDE NOTES by David Gold New Findings AZT/ddI Combinations A small study conducted by Dr. Robert Yarchoan at the National Cancer Institute (NCI) compared the combination of AZT (300 mg/ day) and ddI (250 mg/day) to a regimen in which the drugs were alternated (AZT 600 mg/day for 3 weeks and then ddI 500 mg/day for three weeks).[1] Forty participants with AIDS or with symptomatic HIV infection (under 350 T4 cells) were randomly assigned to either the combination or the alternating regimen. None of the patients had a prior history of AZT or ddI use. Results showed that after 49 weeks both regimens were well tolerated. (One participant taking combination drug had to stop AZT for four weeks due to anemia.) After 18 weeks, average T4 cell counts increased by 99 cells in participants taking the combination AZT and ddI, compared to only 33 cells in participants alternating the drugs every three weeks. After 27 weeks of the therapies, increases in T4 cells were 80 for combination and 29 for alternating regimen. All study participants reported increased energy and appetite and experienced weight gain. It is hoped that this ongoing study will yield further information concerning the relative merits of combination versus alternating ddI/AZT therapy. ACTG Reports on ddI vs. AZT Data from a large AIDS Clinical Trials Group (ACTG) study of ddI versus AZT was presented at the 14th ACTG Meeting in Washington, D. C. [2] In the study, 913 participants were assigned randomly to ddI (either 500 mg/day or 750 mg/day) or AZT (500mg/ day). These participants had been on AZT for at least four months. They had AIDS, ARC (defined as symptomatic HIV infection and fewer than 300 T4 cells) or asymptomatic infection and fewer than 200 T4 cells. Study results indicate that participants who were switched to 500 mg of ddI developed fewer AIDS-related infections and yielded fewer drop-outs from the study. Additionally, those with ARC or asymptomatic infection who were switched to either dose of ddI were less likely to develop AIDS-related infections and had modestly better T4 levels than those who remained on AZT. People with AIDS had no significant differences in the effectiveness of AZT as compared to ddI. For all patient groups no significant difference in survival rates was found. The benefits of switching to ddI were not related to length of time on AZT. Two people died from pancreatitis (both on high doses of ddI) and anemia was reported by patients taking AZT. This study provides some indication that ddI may yet prove to be equal or superior to AZT as a front-line therapy in individuals with ARC and asymptomatic HIV infection. Additionally, these data suggest that a lower dose of ddI (500 mg) is preferable to the standard dose (750 mg/day). References: 1. Keystone Symposia on Molecular & Cellular Biology, Silverthorne, Co. Abstract # Q561, Washington D. C., March 1992. 2. 14th AIDS Clinical Trials Group. Oral Presentation, Washington, D. C., April, 1992. ***** NEW IMMUNE THERAPIES by Michael Becker A number of innovative therapies that attempt to stimulate the immune system are entering early stages of human testing. This article will review such immune therapies and discuss their potential role in treating HIV disease. Cellector Therapy The "Cellector" is a device made by Applied Immune Science (AIS) that stimulates immune CD8 cells (same as T8 or suppressor cells). It may be useful in treating AIDS, Kaposi's Sarcoma (KS), and other HIV-related opportunistic infections and cancers. AIS, a California-based biotechnology company, is attempting to treat disease by "harvesting" or stimulating a particular class of CD8 cells, known as cytotoxic or "killer" cells from blood or bone marrow. The device removes the blood from the patient and isolates the cytotoxic CD8 cells with Interleukin-2 (IL-2), a natural immune booster. The cells are then reintroduced into the patient's body approximately two weeks later. IL-2 is a genetically manufactured protein found naturally in the body. It is believed to stimulate the rapid growth and activity of CD8 cells. The procedure has been tested in patients with AIDS in Phase I trials in Pittsburgh and Miami. Approximately twelve patients received between five to seven treatments in escalating doses of IL-2 on a monthly basis. Published reports about the Cellector have not included mention of the infusion of low-dose IL-2 two- to-three days before the re-introduction of the treated blood. IL-2 is thought to maintain the biological activity of the reintroduced cells. Once the stimulated cytotoxic or "killer" CD8 cells are reintroduced into the body, they attack infected or malignant body cells. Theoretically, this process should help destroy not only HIV-infected cells but also otherwise damaged or malignant cells. This therapy theoretically provides immune protection against opportunistic infections such as toxoplasmosis, cytomegalovirus (CMV), and Pneumocystis carinii pneumonia (PCP). Early Human Trial Results While AIS has not yet published results from the Phase I trials, it has reported that the Cellector causes no adverse reactions or toxicities. Initial concerns about an inflammatory response or other serious side effects seem to be unfounded. No patient involved in the trial experienced any opportunistic infections while receiving Cellector therapy. Two patients with chronic wasting had significant weight gain; three patients with hairy leukoplakia had a relief in symptoms, and two patients with KS (each of whom had "failed" chemotherapy) had significant reductions in their lesions. The phase I trials were not originally designed to measure efficacy or changes in surrogate markers, so these findings must be interpreted cautiously. Phase II Trials Based on the phase I results, AIS is now developing a phase II trial for the treatment of KS. The trial plan will soon be submitted to the FDA for approval. Projections have the trials starting in late spring 1992 in San Francisco and Miami. AIS is focusing on the treatment of KS in order to prove efficacy and obtain prompt FDA approval for the therapy with appropriate speed. The company has no current plans to develop phase II trials for AIDS or HIV infection itself. AIS entered a joint venture with Caremark, an affiliate of Baxter Health Care Corp., to secure the cell-therapy and laboratory services necessary for this complicated treatment. Caremark is building a facility in San Francisco which will provide support for the phase II trials. Questions about dosing and the clinical benefit from low-dose IL-2 remain to be answered. If the therapy is effective, it is most likely that repetitive lifelong treatments will be required. Push For Development The Treatment and Data Committee of ACT UP/New York has called upon the National Institute of Allergy and Infectious Diseases (NIAID) to investigate the Cellector and, if warranted, to sponsor broader trials for AIDS and HIV infection. NIAID scientists have preliminarily suggested to Treatment Issues that cells activated by the Cellector demonstrated predominantly non specific activity and, therefore, may have minimal anti-HIV activity. Moreover, they report no effect on absolute CD4 or CD8 counts and question whether the benefits from the therapy (particularly in treating KS) were, in fact, due to the IL-2 infusion rather than the Cellector process itself. Notably, KS has been known to respond to cytokines such as IL-2. Other CD-8 Therapies Researchers are also working on the possibility of expanding HIV-CD8 cell therapy. The CD-8 cells are removed and given time to proliferate before they are re-infused into the HIV-infected individual. It is hoped that the HIV-specific CD8 cells, (cells that react to certain proteins produced by HIV) will destroy HIV-infected cells and result in significant clinical benefit to the patient. A small, 14-person, federally funded clinical trial will test both the safety and activity of reinfusing HIV-specific CD8 cells. According to the researcher designing the trial, a vigorous response may protect HIV-infected asymptomatic individuals from progressing to symptomatic disease. This researcher told Treatment Issues that HIV-specific CD8 cells have been isolated from HIV-infected individuals and stimulated. Test tube studies show that they have rigorous activity against HIV- infected cells. The chief concern of this researcher is that HIV may be able to mutate so that the CD8 cells would not be able to continue to recognize it as a target. This trial will not require IL-2 infusions, and patients will be allowed to remain on anti-viral therapy. Gene Therapy The Recombinant Advisory Committee of the NIH recently gave permission to the Targeted Genetic Corporation to begin clinical trials involving the implementation of genetically-modified cytotoxic CD8 cells into patients with AIDS. It is hoped that these altered cells will kill HIV-infected cells or AIDS-related cancer cells. Several other companies are developing similar techniques. In general, the procedure involves implanting specific genetic material into a viral envelope. Theoretically, the viral genetic material in the envelope will then "infect" targeted cells and introduce the new material into the patient's own cells. It is hoped that the new material will provide enhanced immune function. The initial gene therapy trials are intended to examine safety and to determine whether the genetic material can be implanted into the targeted cells in the body. Because we do not know the potential risks of this procedure, the newly implanted genes will contain a "suicide gene" which will make it possible to kill the altered cells if the procedure proves harmful. Conclusion It is important to note that many biotechnology companies operate with minimal capital and revenues. Often these companies depend on the favorable opinion of the stock market to fund their operations. Therefore, promising reports and public statements issued by companies should be read critically. For example, AIS was in the middle of an important public financing at the time it made public disclosures about the preliminary Cellector results. Some officials from NIAID suggest that the company may have been engaging in public hype. Reports must be carefully reviewed and verified. Nevertheless, it is encouraging to see new treatment for AIDS enter clinical trials. These therapies, like HIV-vaccine therapies, seek to stimulate a patient's own immune system to act against HIV. However, hopes must not be raised prematurely. The basis for these treatments may shed light on newer theories that suggest AIDS may be the end result of a long period of over- stimulation of the immune system. Finally, the financial cost and ultimate feasibility of these treatments remain to be addressed. ***** MAIL ORDER PHARMACIES by Loren Couch Mail order pharmacies have grown in popularity and are increasingly used by people with HIV/AIDS. Offering convenience, confidentiality, and discounted prescription drugs, these businesses provide free membership, toll-free customer service, refills, medication shipments, insurance billing, and opportunities to talk with pharmacists about specific medications. Treatment Issues has surveyed a number of mail order pharmacies to determine and describe the merits of each plan. All of the plans surveyed stress customer service and low cost. A few calls or a few orders can tell if a plan is living up to its pledge. These programs are similar in a number of ways. For instance, each classifies its members in three ways: 1) those with insurance, 2) those without insurance, and 3) those with Medicare or Medicaid. Drugs are then priced according to the ability of each member to pay, as defined by the three categories. Therefore, members with health insurance will pay the highest price, and those without insurance who must pay out-of-pocket will be charged the lowest price. Of course, every insurance policy is different, so it is important to review personal insurance policies before using a mail order pharmacy. Policies may have certain contingencies like drug limits, maximums (no reimbursement after a certain amount has been paid), or exclusions (drugs or therapies that are not reimbursable). A low lifetime maximum policy that only allows repayment at, say, $5,000, might warrant using mail order pharmacies and paying directly out-of-pocket to receive the most medication for the least cost. None of the mail order pharmacies surveyed is a non-profit organization. How Mail Order Works Mail order pharmacies bill the insurance company directly and accept whatever amount the insurance company pays. If the full cost is not covered, the pharmacy does not seek any payment from the individual member. This means no out-of-pocket costs and a 20%-30% discount on medications benefit the participating individual with insurance. Payment of the deductible (amount required out-of-pocket before the service kicks in) is still the responsibility of each member, but some plans offer different methods for making such payment. For instance, American Preferred Plan has a frequent-buyer program that awards bonus points to members. Bonus points can be applied toward payment of deductibles. My Choice Plan, Community Prescription Plan, and University Pharmacy Health Center work with the member to devise a payment plan for the deductible. For individuals without insurance, each plan seeks to provide medications at the lowest cost. It is advisable to call around for the lowest price. Each plan offers assistance for non-insured members in locating drug assistance programs, like the AIDS Drug Assistance Program (ADAP), to pay for needed medications. Finally, for participants on Medicare and Medicaid, federal and state policies do not allow use of out-of-state mail order pharmacies. o American Preferred Plan (APP), (800) 227-1195. Established in 1988 by Ron English, APP is a free membership plan. For those with insurance, APP accepts any amount the insurance company pays. Members are not obliged to pay the amount not covered. For individuals without insurance, APP will provide assistance in locating possible sources of free medication. Services provided include no-cost prescriptions, prompt free delivery (UPS), no filing of insurance forms, and 24-hour telephone service. Members can also get automatic refills. APP works with the AIDS Treatment and Data Network (ATDN), where medications may be delivered for easy pick-up. APP has a frequent buyer program that awards points to members. These points can be redeemed in the form of payment of a deductible, the purchase of merchandise, or a designated contribution to any not-for-profit organization. (Editor's Note: GMHC is one of the organizations to which members can designate a donation.) o My Choice Plan, (800) 336-7310. This program also offers free membership for prescriptions by mail. My Choice Plan has been around for over 20 years. The staff of My Choice Plan also provides assistance in helping members obtain necessary medications. If a member has no insurance, the plan will provide information on obtaining medication through compassionate use, Treatment IND's, or a manufacturer's assistance plan. Non-insured members are also able to obtain drugs at cost plus shipping charges. One unusual aspect of My Choice Plan is that it accepts New York or New Jersey Medicare. With each order, My Choice Plan sends free condoms. o Community Prescription Service (CPS), (800) 677-4323. A gay, lesbian and HIV-positive owned and operated plan that began in 1991. In addition to the convenience of a mail order pharmacy, CPS has a drug card that is good at 3,500 pharmacies around the country. With this card, a member who needs medication and cannot wait for the mail, can obtain small amounts of medication from participating pharmacy for only $4.00. Every three months, CPS also provides members with an information packet from national gay and activist publications. CPS stresses customer service. Members are encouraged to evaluate the service they receive. Pharmacists are available to answer questions about medications and related concerns. o University Pharmacy Health Center, (800) 487-7115, offers the convenience of a mail order pharmacy and a research library on drugs and nutrition from which members can request copies of specific articles. o Stadtlanders Pharmacy Lifetime Program, (800) 238-7828. This plan accepts insurance information from each customer and then verifies the coverage separately. If insurance pays 80% of the billed amount, Stadtlanders takes that amount as the total. However, for applicants with insurance plans that reimburse less than 80%, Stadtlanders offers out-of-pocket billing. Under out-of-pocket billing, members may use credit cards to pay for medications. Clients need to order $200.00 of drug per month, rendering the plan best for maintenance medications. The plan also incorporates families, so that one member needs to match the $200.00 and other family members can have prescriptions filled at any cost per month. Medication, however, has to be sent in the same package to the same address. Deductibles with Stadtlanders are handled with a billing program. The company employs a social worker for clients with financial limitations. Medicaid is accepted from the following states: Pennsylvania, Virginia, Idaho, Illinois, Indiana, Iowa, Kentucky, Nebraska, and New Mexico. New York and New Jersey Medicaid are not accepted. The pharmacy offers an automatic refill option after the first prescription is filled. If approved by a doctor, the pharmacy sends a 30 day supply. Stadtlanders has 30 pharmacists to take calls and discuss medication and doses. Conclusion It is important to assess personal insurance situations before becoming a member of any of these important optional mail order pharmacy plans. For people with HIV/AIDS, these plans may help alleviate some of the burden of treatment costs and help make financial planning more feasible. For more help with assessing insurance plans, call the GMHC financial hotline at 807-7519. ***** TO TREATMENT ISSUES READERS: o GMHC's Medical Information Program has moved to the 2nd floor of 129 West 20th Street. The new phone number is (212) 337-3505. o During the move and during an upgrade of our computer system, some damage seems to have occurred to the database that stores Treatment Issues' mailing list. If readers know of any subscriber who has not received the May/June 1992 edition, please advise him or her to call Paul Warren at (212) 337-3695 or to write to: Treatment Issues Subscriptions, GMHC, 129 W. 20th St., New York. NY 10011. o We warmly welcome Paul Warren, the new Assistant Coordinator of Medical Information, to our staff. He replaced Griffin Meyer, who moved to Los Angeles to continue his career working with PWAs. We wish Griffin well in L. A. and thank him for his enormous contribution to our program. o As readers have surely noted, this edition of Treatment Issues serves for both May and June, allowing staff to catch up after our office move. July's issue will be mailed at the beginning of the month, rather than the end. And August's edition will be the first special edition, Women's Treatment Issues. o The editor wishes to thank all of those valued readers who contributed review comments for the draft of Women's Treatment Issues. Your editorial comments were greatly appreciated. ***** NOTES ON ORAL CMV DRUGS by Mark Harrington Cytomegalovirus (CMV) infection appears to hasten the progression of HIV-associated immune suppression.[1] A member of the herpes virus, CMV can cause sickness, blindness, wasting, and death in persons with under 50 T4 cells.[2] (see the April Treatment Issues CMV Treatment Update). Prophylaxis of CMV disease in persons with AIDS may then prevent CMV retinitis and colitis, as well as, perhaps, extend life. So far, however, efforts to develop CMV prophylaxis have been impeded by the fact that the two existing anti-CMV agents, ganciclovir (DHPG) and foscarnet, are intravenously administered, requiring that a tube be inserted into the vein. Thus, the drug directly enters the blood. Intravenous administration is highly inconvenient and carries the risk of infection at the injection site (arm or chest). This article will briefly review some promising oral drugs that may prevent CMV. HIGH DOSE ACYCLOVIR Reports have suggested that high-dose oral acyclovir (Zovirax, made by Burroughs-Wellcome) may have some anti-CMV activity. Oral acyclovir, however, does not remain in the body at high enough doses to stop CMV growth.[3] A report of oral acyclovir's anti-CMV activity, conducted by Craig Metroka, a New York City physician, was not randomized. Thus, one cannot know whether the difference in CMV outcomes in participants taking the drug compared to those taking placebo was due to the use of high-dose acyclovir (4000 mg/day, or 800 mg taken every 4 waking hours), or to other uncontrolled factors. More recently, British tabloid reports about a Burroughs Wellcome study of AZT with or without high-dose acyclovir claimed that those on combination AZT and acyclovir lived longer than those on AZT alone (See Treatment Issues, February 1992, "High Dose Acyclovir Controversy"). The study found no difference in CMV-disease progression. Sixteen of the study participants taking acyclovir and nine taking placebo developed CMV and organ disease. However, it was later noted that 12 patients on the placebo died, as compared to only six on high-dose acyclovir. Whether these results are statistically significant is not known. Regardless of whether or not high-dose oral acyclovir may extend survival, it appears to lack efficacy in preventing CMV disease. Dr. Brian Gazzard, the principal investigator of this much- hyped study, spoke at a conference called "The AIDS Crossroads" presented by ABEL Health Management Services in New York City on April 16. Dr. Gazzard emphasized that despite the articles in the London Times and New York Times articles reporting his findings, data from the trial had only become available a week previous to the conference. Nonetheless, his findings markedly resembled information printed in media sources, including Treatment Issues, Vol. 6, No. 2, though Dr. Gazzard revealed new tidbits about his research. 300 patients with fewer than 150 T4 cells were randomly assigned to take either acyclovir (3200 mg/day) or placebo. Of the 151 participants evaluated for taking acyclovir, 25 developed CMV disease, compared to only 17 participants of 149 taking placebo. Therefore, it is assumed that high-dose acyclovir failed to prevent CMV disease. However, significantly fewer patients assigned to high-dose acyclovir died in the study. Twenty-seven participants taking acyclovir died, compared to 43 participants in the placebo arm. According to Dr. Gazzard of St. Stephen's Hospital in London, this difference in survival times was statistically significant. Some have speculated that the apparent survival benefit seen with high-dose acyclovir may be related to inhibition of other herpes viruses that cause immune suppression like Epstein-Barr virus (EBV). Most of the participants in this study were white men under 40 years old, many of whom had a T4 count lower than 50. Slightly more participants were taking AZT or ddI in the placebo arm than those on acyclovir. Reasons for withdrawal from the trial included episodes of herpes (participants knew then they were taking placebo and so dropped out) and deterioration of health. The probability of getting CMV in patients taking the drug was equivalent to those who were taking placebo (no drug), thus indicating that acyclovir may not prevent CMV disease. However, participants taking acyclovir had only a 23% probability of death after one year of treatment, as compared to participants taking placebo who had a 39% probability of dying. Such a finding is not completely unexpected, since AZT and acyclovir research has reported some improved survival all along. Dr. Gazzard concluded with the following notes. The data is incomplete and he and his staff will conduct at least fifty more analyses of it. He maintains that quality of life is important; that low doses of acyclovir for anti-herpes must be considered; and that the difference in mortality must be assessed for its clinical significance. Treatment Issues will report further as details become available. New Oral Drugs Two new oral anti-CMV drugs have completed preliminary phase I trails to test their safety, activity against the virus and ability to spread throughout the body. Both of these drugs are now ready for phase II clinical trials. Syntex Corporation makes the first drug, oral ganciclovir (DHPG), and Burroughs-Wellcome makes a drug called BW256. The drugs will enter phase II trials later in 1992. An intravenous form of ganciclovir was approved by the FDA in 1989 after a long struggle led by ACT UP/New York. The new oral formulation needs to be taken at high doses (3 grams daily) because it is not easily absorbed from the gut into the blood. Burroughs-Wellcome's drug is an acyclovir prodrug, BW256, that once inside the body is broken down into acyclovir. This enables the drug to be absorbed into the blood at levels three- to-four times greater than that of oral acyclovir. These higher levels seem able to prevent CMV disease in bone-marrow transplant patients. While such findings in transplant patients offer significant promise, similar findings need to be exposed in people with HIV. BW256 will be administered at doses of between 3-4 grams daily. A Study for Science or Money? The Cytomegalovirus Pathogen Study Group (CMV PSG), involved in federally-funded trial designs, has been trying for a year to persuade the sponsors of oral DHPG and BW256 to collaborate in a three-arm study. The study would enroll participants with under 100 T4 cells and would assign them randomly to receive either oral DHPG, BW256, or placebo (no drug at all). This would minimize the number of people with CMV in clinical trials who are receiving no drug. In this trial design, two-thirds of the participants would get active drug. However, if the ACTG and the companies conduct two separate studies each comparing each drug to placebo, 50% of participants would get placebo. The three-arm trials design answers three questions simultaneously: 1) Is oral DHPG better than placebo in preventing CMV? 2) Is BW256 better than placebo? 3) Which oral CMV drug is safest and most effective? Syntex has been difficult to persuade. Syntex claims that drug- manufacturing problems and limited supplies make a collaborative study impossible. Dr. Ellen Cooper, who was director of FDA's Division of Anti-Viral Drugs Products when the agency approved intravenous ganciclovir in 1989, is now the director of clinical research at Syntex - an ironic turnabout. On the other hand, Burroughs-Welcome has been cooperative. Conclusion Community activists are now working to persuade Syntex to participate in the three-arm ACTG trials and to consider opening an expanded access program for oral ganciclovir. If Syntex will be done outside the ACTG, comparing oral ganciclovir to placebo. This would force the ACTG to compare BW256 to placebo alone. The picture will become somewhat clearer later this year. In the meantime, some even newer anti-CMV drugs are slated to begin phase I trials this year, including HPMPC by Gilead Pharmaceutical Products and Cyclobut-G by Bristol-Myers Squibb. References: 1. A Webster et al. Cytomegalovirus infection and progression towards AIDS in hemophiliacs with HIV infection. Lancet i:63-66, 1989; J Laurence. Molecular interactions among herpesviruses and human immunodeficiency viruses. J. Infect. Dis. 162:338- 346,1990; A Webster. Cytomegalovirus as a possible cofactor in HIV disease progression. J AIDS 4 (Suppl):47-52,1991; and E Levy et al. Cytomegalovirus IgG and IgA Serum Antibodies in a Study of HIV Infection and HIV Related Diseases in Homosexual Men. J Med Virol 35(3):174-179,1991. 2. V Int'l Conf AIDS. Abstract #M. B. P. 126, Montreal, June, 1989. 3. Burroughs Wellcome Foundation. Unpublished letter. Zovirax Clinical Review,51-52, 1988. ***** TREATMENT BRIEFS by David Gold New Theories on KS, But Still No SP-PG Trial Two dramatically different theories about the cause of Kaposi's Sarcoma KS) have recently been published. Researchers have long been puzzled over the common occurrence of KS in HlV- positive gay men as compared to people who were exposed to HIV through injecting drugs. One theory proposes that KS is caused by a strain of the human papilloma virus (HPV). Another proposes that KS is caused by a microorganism found in feces and may be associated with oral-fecal contact (rimming). Perhaps the most promising treatment for KS is SP-PG, under development by the Japanese company, Daiichi Pharmaceuticals. A recent report in Science suggests that in laboratory cells SP-PG stops the growth of KS with little apparent toxicity. So far, however, the company has refused to meet with activists to discuss when human trials will begin. Because of the desperate need for effective and non-toxic KS therapies, continued and increased pressure must be brought to bear on Daiichi. CRIA to Begin Pentoxifylline Trial The Community Research Initiative on AIDS (CRIA) has received funding from AmFAR and PTAAA (People Taking Action Against AIDS) for a trial to study the ability of the drug pentoxifylline to reduce levels of Tumor Necrosis Factor (TNF). TNF is a protein naturally produced by the human body that is associated with wasting, anemia, and increased HIV replication. Pentoxifylline, marketed under the name "Trental," is currently prescribed for increasing blood circulation. The drug is believed to have minimal side effects. Additionally, CRIA may set up a small, quick trial of cimetidine (Tagamet) for efficacy against HIV. For information call (212) 889-1958. Fluctuating T-Cells There are many reasons for wide fluctuations in absolute T4 cell counts. Now, according to new reports, we can add two more factors: laboratories and personnel. An abstract (#P84) released by Dr. Peddecord and colleagues at the 5th National Forum on AIDS, Hepatitis and Blood Borne Infections, 1992, found a wide disparity in reported absolute T4 counts when blood samples taken from the same donor at the same time were analyzed by different commercial laboratories. Nine laboratories analyzed the same blood sample and reported a disparity of the absolute T4 count of the specimen in a range between 868 and 2401 cells. When two specimens were sent to the same laboratory under different labels the disparity in reported T4 counts ranged from 0 to 595 with an average difference of 209. An earlier ACTG survey of 60 labs found similar results with T4 counts of between 380-850 reported for the same specimen interestingly, the percentages of T4 counts reported by the laboratories were much more consistent. The range of percentages was 44% to 54%. Differences in T4 percentages found by the same laboratory varied from O% to 10%. Physicians, patients, and governmental agencies are all encouraged to use caution when basing treatment or financial assistance decisions on a single T4 test. Fetal Tissue Transplant Ban Overturned By Senate The U.S. Senate voted to overturn the ban on federally funded research that uses fetal tissue from elective abortions. Researchers believe that fetal transplant research, in which healthy fetal cells are transplanted into diseased or dead cells, is among the most promising areas for rebuilding the immune system. The research may have a beneficial impact on Parkinson's disease, diabetes, and Alzheimer's disease. The Bush Administration maintains that fetal tissue research encourages women to have abortions and so should not be funded by federal agency funds. In this respect, George Bush's dealings with the extreme right wing have had a direct and harmful impact on promising AIDS-related research. Readers are urged to follow the local elected representatives voting on this issue. In the tri- state area only Senator Alphonse D'Amato (R-N. Y), voted to keep the research ban in place. Readers may wish to comment to Senator D'Amato, who is up for re-election in 1992, about his vote on this issue. His office phone number is (212) 947-7390 or (202) 234-6542. Non-Discrimination Policies by Drug and Healthcare Companies ACT UP/Golden Gate has embarked on an important campaign to encourage pharmaceutical and healthcare companies serving HlV- infected communities to adapt formal policies and pro-active programs to prevent discrimination in the workplace on the basis of HlV-serostatus or sexual orientation. Call (415) 252-9275 for more information. Oral Alpha Interferon Study Results New reports indicate that individuals who are using or considering oral alpha interferon should be wary about claims of efficacy. The AIDS Research Advisory Committee (ARAC) of the National Institutes of Allergies and Infectious Diseases (NIAID) strongly recommend that patients seek alternatives to oral alpha interferon, specifically the version of the drug called Kemron. In 1990, the original Kemron trial in Kenya reported that people with AIDS or ARC who were given the drug had dramatic increases in T4 cells and improved symptoms. Study reports also claimed that eight people taking the drugs converted from HlV-positive to HlV-negative. The ARAC statement reports that 13 studies in the U.S. and abroad have failed to duplicate the results from the original Kenya trial. In a recent study by the Community Research Initiative of Toronto, 149 HIV-positive individuals with a T4 count under 700 were randomly assigned to receive oral alpha interferon (50 or 100IU/ day) or placebo. After eight weeks of treatment, no difference was found between patients taking drug and patients taking placebo in terms of T4 counts or symptoms. Unfortunately, the study included only one black person. The PWA Health Group, New York City's underground buyers' club, sells the drug, but makes no claim about how much drug is in the product. The Health Group has therefore decided to offer oral alpha interferon free of charge. The Health Group's number is (212) 255-2080. In a related matter, treatment activist and occasional Treatment Issues writer Derek Link has joined the PWA Health Group as Director of Quality Assurance, Research & Development. ***** SCOTT SLUTSKY 1954-1992 We mourn the loss of Scott Slutsky. As a member of ACT UP and TAG, Scott coordinated nationwide efforts to insure the rapid testing and availability of a number of important drugs. Scott will be sorely missed by friends, activists, and all people with HIV. ***** GLOSSARY Cytomegalovirus (CMV): A virus related to the herpes family that can cause fever, fatigue, enlarged lymph glands, aching, and a mild sore throat. In AIDS, CMV infections can produce hepatitis, pneumonia, retinitis, and colitis. It can sometimes lead to blindness, chronic diarrhea, and death. Efficacy: Effectiveness at the dose tested and against the illness for which it is prescribed. Nucleoside analogue: A type of anti-viral drug, like AZT, ddI, or ddC. Phase I: The classification of federally-funded trials which test experimental drugs to determine safety and find the most effective dose. Phase II: The classification of federally-funded trials which test an experimental drug to see how well it works and to study its side-effects. Phase II trials often involve several hundred participants who are randomly assigned to take either drug or a control (the standard treatment for the disease or no treatment at all, known as placebo.) These trials are usually double- blinded, which means no one knows who is getting drug until the trial is over. Pneumocystis carinii pneumonia (PCP): An AIDS-related illness caused by Pneumocystis carinii, a common parasite that infects the lungs of people with HIV infection and low T4 cell counts (usually under 200). Sometimes, PCP infections may occur elsewhere in the body (skin, eyes, spleen, liver, or heart). Prophylaxis: Treatment intended to prevent the onset of an infection or disease. Toxicity: A range of many reactions by the body when a beneficial medicine is also poisonous elsewhere in the body. ***** TREATMENT ISSUES Executive Editor: David Gold Editor: Mary Beth Caschetta Medical Consultant: Gabriel Torres, M. D. Technical Coordinator: Paul Warren Copy Editor: Gary Schmidgall Writers: Michael Becker Loren Couch David Gold Mark Harrington Gabriel Torres, M. D. Designer: Stephen Louis de Francesco Production Manager: Valerie Michele Hoskins Proofreader: Steven Humes Office Volunteers: Joseph Evans David Feiden Edward Friedel Suzanne Gilman Erik Goldsborough Gary Schmidgall Frank Schramm Student Intern: Julie Francis 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 10 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. 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