gilbert@tce.COM (Gilbert Cornilliet) (03/14/91)
================================================================ FOSCARNET EXPANDED ACCESS PROGRAM by Wade Richards On Wednesday, January 30, Astra Pharmaceuticals held a meeting at the Beverly Hilton to inform physicians and community representatives about the expanded access program for foscarnet (brand name, Foscavir), a treatment for cytomegalovirus (CMV) infection and acyclovir-resistant herpes simplex virus (HSV). About forty people attended, but as far as I could tell, I was the only person there who wasn't a doctor. Since this program was sponsored by the manufacturer, I was prepared for the presentation to be fairly one-sided. ABOUT CMV RETINITIS CMV retinitis is the leading cause of loss of vision among PWAs. A member of the herpes family, CMV is a chronic viral infection that healthy individuals can carry for a lifetime without symptoms. Currently, 80% of all healthy adults carry antibodies to CMV, indicating some exposure to it. Current estimates of CMV retinitis among PWAs vary, but is thought to be about 20%. One projection estimated that as many as 45% of PWAs will develop CMV retinitis. The only fully-approved treatment for CMV infection is DHPG (Ganciclovir) which some patients cannot take because of its high toxicity; in addition, it cannot be taken with AZT because it causes anemia and a low white blood cell count. HISTORY OF ACTIVISM AROUND FOSCAVIR The announcement of the expanded access program on July 19, 1990 concluded fifteen months of negotiations between Astra Pharmaceuticals of Westborough, Mass. and ACTUP/Boston. A year earlier, in June of 1989, ACTUP/Boston was joined by members of ACTUP/Rhode Island and ACTUP/New York City in a demonstration at Astra headquarters in Westborough. Over a hundred people participated and fifteen were arrested. For months, Astra officials in their meetings with ACTUP/Boston cited supply problems as the reason for their failure to release Foscavir on a compassionate use basis. As early as mid-summer of 1989, Astra assured ACTUP/Boston that they were working diligently to create an adequate supply by 1990, but foot-dragging and corporate haggling delayed the process. At the same time, other Astra officials were stating their intention of getting Foscavir approved in record time by avoiding the "distraction" of a wide-scale compassionate use program. Negotiations between the two organizations had broken down completely in the fall of 1989, when it became clear that Astra was not sincere in its stated desire rapidly to secure an American manufacturer to correct the supply shortage, and ACTUP/Boston began a series of demonstrations at the home of Astra's CEO. Finally, in the spring of 1990, Astra and ACTUP/Boston resumed negotiations, and expanded access came six months later. BACKGROUND ON FOSCAVIR Sarah Martin-Munley, Director of Clinical Research for Astra, began the meeting with some general background on Foscavir. She said that the US research program for this drug began in November of 1988, and concluded with submission to the FDA of a New Drug Application (NDA) in September of 1990. Astra hopes that full approval will be granted by June of 1991. Foscavir is already approved in seven European countries. Martin-Munley said that one study (called FOS-03) showed that Foscavir has in vitro activity against herpes viruses, CMV, hepatitis-B, and HIV. It works by inhibiting virus-specific enzymes without blocking cellular DNA, so that it does not produce the same serious side effects of much broader spectrum drugs like AZT. The CMV trials found that Foscavir delayed the time to progression of retinitis, and that the delay was dose-related. Foscavir also suppresses systemic CMV infection. In FOS-03, Foscavir was administered at a dose of 60 mg/kg of body weight, intravenously three times a day for an induction period; after that time, the dose was changed to 90 or 120 mg/kg once a day. The trial contained a placebo arm, with patients receiving no treatment until progression of CMV infection; at that time, they were then given Foscavir. The study found that the median time to progression for those receiving no treatment was three weeks; by contrast, the median time for those on treatment was eight weeks. Another result was that CMV in viral cultures became negative, and that p24 decreased in recipients. Following Martin-Munley's remarks, Dr. Myles Lippe, a San Francisco physician who treats PWAs, discussed the results of another Foscavir trial (called FOS-06) that had similar results to FOS-03. SIDE EFFECTS Dr. Stephen Follansbee of the Institute for HIV Research and Treatment in San Francisco reported on some of the side effects of Foscavir that he recorded in his study of Foscavir for CMV retinitis and acyclovir-resistant herpes. The study compared the 90 and 120 mg daily doses of Foscavir. The most significant toxicity seems to be impairment of renal (kidney) function, which was experienced by 27% of patients. Dr. Follansbee stressed that adequate hydration is important when taking Foscavir. The drug has synergistic toxicity with IV pentamidine, amphotericin, amikacin, and ciprofloxacin, meaning that the side effects of the two drugs together is greater than simply the combined side effects of the two drugs. Foscavir and aerosolized pentamidine seems to be okay, as does concomitant use of GMCSF, EPO, and alpha-interferon. A Foscavir/ddI combination study is currently underway. Hematological changes from Foscavir include: changes in serum calcium and magnesium, low hemoglobin (especially with concurrent AZT), leukopenia, granulo-cytopenia, and thrombocytopenia (low platelets, also especially with AZT). 3% of patients experienced seizures. Others experienced nausea, vomiting, headache, or irritation at the infusion site. All side effects seem reversible, meaning that they subside when the drug is stopped. After a period, the drug can be resumed at a lower dose. Dr. Follansbee concluded his remarks by stressing that administration of Foscavir requires meticulous patient follow-up by the physician. DIAGNOSIS AND TREATMENT OF CMV RETINITIS. Fred Ussery III of Park Plaza Hospital in Houston noted that the incidence of CMV infection in HIV disease is about 30% and on the rise because patients are living longer. Both retinitis and systemic CMV infection are end-stage manifestations, and retinitis almost never happens with a T4 count over 200; with a T4 under 50, it is common. The length of time from detection of CMV infection to retinitis varies widely, but has been as rapid as four months when untreated. Symptoms include hundreds of floating black dots in the visual field, but generally there is no acute inflammation, because by the time retinitis develops, the immune system is already in bad shape. 50% of PWAs have retinitis in both eyes at the time of diagnosis. Dr. Ussery stressed the need for doctors to look at both eyes and compare them to each other. "Cotton wool spots" on the retina may be a precursor to widespread CMV infection. Retinal toxoplasmosis, retinal candidiasis, and cryptococcal meningitis can all look like CMV retinitis. He believes that all people with a T4 count under 100 should be tested for CMV retinitis, and doctors should ask patients about floaters in their vision. When examining patients, physicians need to look at the retina, especially if the patient has no regular ophthalmologist; most doctors can catch 25% of cases early through this kind of inspection. It is important to refer retinal abnormalities to an ophthalmologist within 24 hours. Blood cultures and titers may be unreliable indicators for rapid progression to disease because some PWAs with CMV infection do not culture CMV in their blood or urine and viral cultures take too long. THE EXPANDED ACCESS PROGRAM Ms. Martin-Munley concluded the formal remarks with a discussion of the expanded access program. It differs from some other expanded access programs in that it is "automatic" it does not require case-by-case approval by the FDA, the way the expanded access program for ddC does. 600 patients received the drug through expanded access in 1990, while another 300 are currently enrolled in clinical trials. Astra will submit a supplemental NDA for acyclovir-resistant herpes by the end of 1991, and plans to undertake a study of Foscavir for gastrointestinal HIV disease. In conclusion, it is clear that Foscavir offers new hope to those who are at risk for losing their sight from CMV infection, and that it can greatly reduce the symptoms of acyclovir-resistant herpes infections. In addition, its side effects are manageable and much less severe than the only other alternative, Ganciclovir. Given these favorable results, it is sad that the expanded access program is so late in getting started. (Wade Richards is facilitator for the Treatment & Data Committee of ACTUP/Los Angeles. He thanks ACTUP/Boston for some of the information contained in this article.) ================================================================ L.A. PHYSICIANS AIDS FORUM: NEW TREATMENT FOR PCP by Walt Senterfitt This month the Being Alive Newsletter begins coverage of the presentations to the L. A. Physicians AIDS Forum, a bimonthly meeting of area physicians involved in direct HIV-related care. Dr. John Black, a professor at the Indiana University Medical School and a private practitioner in Indianapolis, described his recent studies of Clindamycin and Primaquine as an alternative to Bactrim/Septra or pentamidine in the treatment of acute episodes of Pneumocystis carinii pneumonia (PCP). He was driven, he said, by the fact that acute PCP remains a serious problem despite widespread use of prophylaxis; 15-30% "breakthrough" has been reported in recent studies and at least one leading researcher predicts 62,000 new episodes nationwide in 1991. Also, the two standard regimens are typically effective, but each carries a significant risk of toxic side effects so that 50-60% of all patients are unable to complete a full three-week treatment regimen. Another drug regimen is needed, preferably with less toxicity. Why these two particular drugs? Primaquine has long been used in the treatment of acute malaria, which is a protozoan not unlike Pneumocystis. Clindamycin, an antibiotic well known for a number of uses, had been reported to enhance the effect of Primaquine alone in the treatment of malaria. Finally, the investigators felt that since each drug was already approved and well known, it would be easier to get FDA approval for study than with novel agents. Initial studies in laboratory and in animals showed efficacy. Previous use of the two drugs for other reasons indicated the advantages of oral rather than intravenous administration, concentration at the site of infection, and relatively few serious side effects. On these bases, the AIDS Clinical Trial Group and the FDA approved a pilot study in PWAs. They enrolled 22 persons with mild-to-moderate cases of PCP. For 20 of these, it was their first episode. They were given Clindamycin 900 mg IV every 8 hours for 10 days, then 450 mg by mouth every 6 hours for 11 more days (providing they had improved), plus Primaquine 30 mg by mouth once a day. These doses for the first study were estimated as the highest likely to be tolerated. After seven days, 20 of the 22 (91%) had responded positively to treatment. Overall, 16 of the 21 (73%) were able to complete the treatment. Only 4 had to stop because of toxic reactions; overall survival was 21 or 95% (the person who died was apparently coinfected with H. influenza pneumonia as well which did not respond to treatment). Based on this success, the researchers felt they could continue and could modify the regimen to an entirely oral one. Among other advantages, this could permit outpatient treatment of mild cases. The second phases enrolled 38 persons, all with mild PCP only; virtually all were treated as outpatients. The regimen consisted of Clindamycin 600 mg every 8 hours and Primaquine 30 mg every day. Continued prophylaxis with another anti-PCP drug was allowed (unlike the first study, which wanted to isolate the effect of the two study drugs). The results: 92% showed a positive response to treatment, whereas 3 individuals (8%) did not. The entire course was completed by 79% of those who started it, 13% discontinued treatment because of side effects. Everyone survived. Combining the two studies, 55/60 (92%) showed a therapeutic response, 46/60 (77%) completed three weeks of therapy on these two drugs, and 59/60 (98%) survived the PCP episode. The most common side effect was a rash (usually beginning about day 10) which usually disappeared after 2-4 days and was much milder than rashes typically seen with Septra/Bactrim. There were a few cases of fever, nausea, and diarrhea and two instances of decreased white blood cell counts. A third study explored the regimen as so-called salvage therapy, after the clinical failure or intolerance of the standard treatments. Thirty-two patients were enrolled in this phase; for 59% it was the first PCP episode, for 31% the second, and for 9% the third or more. The results showed that 88% (28/32) were able to complete the treatment successfully. Of the other four, three failed to respond and one had to discontinue because of toxicity. All 32 survived. Other investigators, including here at USC, have also tried this regimen in about 100 more individuals with comparable results. Dr. Black concluded that the Clindamycin/Primaquine combination is: 1) effective as primary treatment for mild to moderately severe PCP; 2) an inexpensive, conventional, oral treatment; 3) may also be effective as salvage treatment; and 4) is relatively well tolerated. Looking ahead, controlled randomized clinical trials have been initiated comparing this regimen to Septra/Bactrim. Dr. Black would like to see studies begun investigating effectiveness as prophylaxis, and would like to look at other analogues of the two drugs to see if something else is even better. One problem is the availability of Primaquine. It is no longer manufactured in the U.S. and the CDC has doled out its limited supply for malaria cases only. However, the British manufacturer has started up production again, and supplies should be widely available by June. ================================================================ NIH BEGINS PHASE I STUDY OF ADVANCED REVERSE TRANSCRIPTASE INHIBITORS Last month's Newsletter included a discussion of a new set of antivirals called advanced or second generation reverse transcriptase inhibitors. These drugs inhibit the same enzyme as AZT, but do so in a much more specific way. The new generation of RT inhibitors have shown considerable potency against HIV in the test tube. Now we have word that the National Institutes of Health are beginning a Phase I study of one such RT inhibitor, L-697,639. Phase I testing is used both to determine the proper dosage and to detect any possible early side effects. The NIH is seeking study participants who are asymptomatic HIV+ with a T cell count greater than 500. Participants must not be taking any other anti-retroviral or experimental drugs. To be a part of the study, you need to travel to Bethesda, Maryland, for two outpatient evaluations and then be admitted to the National Institute of Allergy and Infectious Diseases inpatient unit for two separate 48-hour hospitalizations. The two hospital stays must be at least ten days apart. Except for the initial outpatient screening, the NIAID will cover the cost of travel, hotel accommodations, and hospital stays during the course of the study. If you are interested in participating in this NIH study, contact Marilyn Decker, R.N., at 1.800.772.5464, ext, 306. Ms. Decker is the Study Coordinator and can provide further information about this protocol. ================================================================ NEWS AND VIEWS by Fran McDonald, Social Services Editor RENTER'S CREDIT It's almost tax time again and I want to remind those who rent that persons who are of low income and/or disabled can claim a California Renter's Credit of $60 per year for an individual or $l20 for married couples, even if no taxes are payable. The qualifications are: - You must be a California resident; - You must have paid rent for at least 6 months on a property that was your principal residence; - That property was not exempt from property taxes; - You are not claimed on another person's income tax return. You may also apply for a renter's credit for the past four-year period and therefore could be eligible for a retroactive payment of up to $240. To get an application, call toll-free l.800.852.87ll and ask them to include California Short Form 540A. CALIFORNIA CHEATING SSI RECIPIENTS As many of you may know, the federal government gave a cost-of-living increase to the nation's SSI recipients. However, the increase received by California from Washington which is then combined with state money to be given to the SSI recipients (SSI is a combination of federal and state money) is instead being applied to the state's budget shortfall. The amount in question is $l7 per month. In addition, the state is not granting a cost-of-living increase on its share of the SSI sum, approximately $l2. So, the 849,000 SSI recipients in California will continue to receive a maximum of $630 per month, instead of $659 per month. Very seldom do I state an opinion here, but I feel that this action is inexcusable and irresponsible on the part of our ex-governor and legislature. It seems to me bad enough for the state to cancel its own COL increase, but to take the money from the federal government intended for the poor and use it to balance the budget appears to me to be outright stealing. I am not familiar with this area of law, but I would surely appreciate hearing from any of you out there who are can this act truly be legal? In the meantime, make your voice heard on this and every other matter that gets your dander up. Only when enough of us kick up a fuss and make it clear to our elected representatives that unless government business is conducted with conscience and compassion they will never again receive our votes. Only then will we see change, fairness, and an end to the shameful tradition of running this country on the backs of the working- and middle-class. End of sermon. Now, fetch the paper, pen, and stamps and get busy! `HIPP' INCOME LIMIT INCREASES I'm happy to tell you that effective February l, the share-of-cost limit in the HIPP program of Medi-Cal was raised to $200 from the previous figure of $l50 (Medi-Cal currently figures the share-of-cost at an income of $600, the so-called maintenance need level. This figure hasn't had a cost-of-living increase, either, and is good reason for a letter as suggested above). Earlier the same day that I learned about this from Sacramento, I had spoken to a man who was $2 over the limit to be so close, yet so far and understandably crestfallen. I immediately called him back with the good news. Was he one happy man! So, with the new increase in mind, if you think that there is any chance that you might qualify for HIPP, please call me. Remember, nothing ventured, nothing gained. CAN'T TOLERATE MILK? A nice lady named Claire called me in response to the item in my January column about milkless pancakes and told me that she cooks for a friend who cannot digest milk products. She has a suggestion for our readers with that problem: scald the milk first, then proceed with the recipe. Her friend has no difficulty if the milk is scalded first. True, this may not work for everyone but it may well be worth your while to give it a try. Thanks, Claire! (Fran McDonald has been in Social Services for 20 years and welcomes your calls at 213.664.4772.) ================================================================ HIV SYSTEM OF CARE by David Smith Efficient linkage between HIV testing, medical evaluation, medical treatment, and social services programs at the Los Angeles Gay and Lesbian Community Services Center have created a new "HIV System of Care." This program will significantly increase the availability of HIV-related services in Los Angeles County and relieve the pressure and subsequent waiting lists for HIV+ individuals at Los Angeles County's four medical facilities. With the acquisition of the West Hollywood HIV Center from Los Angeles County in December 1990, LA/GLCSC can now provide treatment and prophylactic therapies to HIV+ patients whose T-cells generally fall between 500 and 200. This window of opportunity provides the best chances for treatments such as AZT to effectively stall the decline of the immune system and ward off preventable opportunistic infections that lead to an AIDS diagnosis. Services and treatments are provided regardless of a patient's ability to pay. The Edelman Health Care Center currently operates both Los Angeles County's largest HIV anonymous test site and the Philip Mandelker AIDS Prevention Clinic which provides medical evaluations and T-cell testing that monitor the status of the patient's immune system. In addition, a bilingual and culturally sensitive triage clinic has begun at the Edelman Center. Patients who are HIV+ are first evaluated by a registered nurse and tested for their T-cell count and other indications of HIV activity. If the T-cell count is above 500 and other tests do not indicate HIV activity, the patient is re-evaluated every six months. If the patient's T-cells are below 500, they are sent to the West Hollywood HIV Health Care Center where treatments will be prescribed by the staff physician. If the patient's T-cells are below 200, treatment continues at WHHHC, while case workers place the patient in Los Angeles County system at one of the four facilities. "The missing links in the system were expeditious triage and early intervention treatments," said Torie Osborn, Executive Director of The Los Angeles Gay and Lesbian Community Services Center. "In regards to HIV, our message is twofold: 1 Get tested. If you're negative, get tested again every three months for approximately one year to make sure. Always practice safe sex and NEVER share needles, and 2 If you're positive get evaluated and seek treatment.For many, HIV can be managed if it's caught early. We have the system in place to take care of you." ================================================================ PEOPLE WITH HIV/AIDS AND SEX by Ferd Eggan I think we who are HIV+/PWAs need to revisit all the controversial and difficult questions of love, physical intimacy and sex. Many have decided that sexual contact is not appropriate, but our office receives hundreds of calls each month from people, particularly gay men, who want to meet others and develop relationships that would include sex. Of course, safe sex should be a standard operating procedure for all of us who wish to engage in sex. We know how terrible it is to deal with the news that one is HIV+ or is now diagnosed with an AIDS-defining opportunistic infection. And we don't wish that on anyone else. But there's another set of issues not addressed by efforts to prevent transmission of HIV to the uninfected population. These issues revolve around the question of what is safe for those of us whose immune systems are debilitated? In a sexual encounter where both partners are HIV+, are there precautions that are necessary to prevent further transmission of HIV? Is reinfection a factor in AIDS? Is oral sex or anal sex any more or less safe? Do we need to use condoms? I believe the last question must be answered yes, unequivocally; condoms certainly will prevent the transmission of other dangerous microbes from one person to another through sexual contact. It is known that hepatitis and CMV and Epstein-Barr virus are sexually transmissible, and condoms may minimize the possibility of transmission. Other microbes are known to be even more transmissible, and may complicate practices considered "safe" for HIV. And what about all the problems of sexual functioning when one is taking a number of drugs? A friend takes eight different drugs and he says he has no sexual interest in his lover any more. The lover, also diagnosed with AIDS, wants to make love and my friend always says no. They both wonder if there are any tactics whereby they can sneak up on their sexual energies and enjoy some of the physical intimacy that used to be so important for both of them. One of the most serious problems for people with HIV/AIDS in relation to intimacy and sex is psychological. Another friend says when he lost his lover, he had to start dating again and found it very difficult. He just couldn't get ready; he couldn't face disclosing his HIV status and he couldn't make himself feel attractive. He wants to stick to HIV+ men now, so he doesn't have to face the very real possibility that someone will turn him down if they learn he has AIDS. It's true that even our friends, who care for us when we are sick, are sometimes not willing to build a relationship with a PWA. There are many reasons, many of them understandable, fears of bereavement or of personal illness, but none of the reasons makes the rejection any more bearable. I think of another friend who is a long term survivor, veteran of many bouts with devastating illness. He is single because his lover died. He needs someone to love him and care for him as he experiences a little dementia and disorientation. He has good friends, but he deserves somebody to hold him, to offer him a little sexual healing on occasion. I've been asking other groups that do safe sex education for information about all these issues, both physical and psychological, and I found that almost all efforts are directed toward prevention. The common directive of safe sex education is "know your partner's HIV status," meaning avoid HIV+ partners. This is obviously unacceptable for us. Very little is available to inform or to support people actually living with immune system disease who want to maintain physical intimacy in their lives. We are, by now, a bank of important experience on this issue. I invite your comments and research on this difficult and exciting terrain. Once again, it is up to us to break this new ground. ================================================================ REMINDER: DOCTORS ARE NOT PERFECT by Todd Husted To all of you who think that the doctors at a well known, local medical center, specializing in HIV, walk on water, read on. My lover was diagnosed with toxoplasmosis three years ago. At that time, he was being treated by one of their doctors. The toxo cleared up and things seemed to be going along fine. Craig started to complain about always being thirsty and having pain behind his eyes. His limbs were becoming thin. These are signs of a diabetic. Each week he had blood drawn, and each week he complained to the doctor about the above signs becoming even more intense. After we reviewed Craig's medical records we found out that his trigliceride level was 1200 (normal 20-150) and his blood sugar level was 800 (normal is 80-120). Now why the doctor was not looking at the results every week is a mystery, especially since Craig kept telling him about these complaints. This finally lead to pancreatitis. Craig was hospitalized for a week. It could have been prevented had the doctor been looking at the test results. Craig fired this doctor and he was replaced by another. Again, the doctor seemed to be fine. Then Craig started to complain about a pain inside his rectum. The doctor checked Craig and said there was nothing wrong. Month after month he complained about the pain and discomfort, but the doctor again looked up his rectum and said he saw nothing. Later when Craig was hospitalized for PCP and a relapse of toxo, the areas on his rear which Craig was complaining about looked like a large blister. Finally, surgery was needed. The doctor who performed the surgery said he had never seen anything like it before. Because of the closeness of the herpes "blister" to the opening of the anus, the herpes would not heal, causing a great deal of pain. The only way for the herpes to clear up was to have a colostomy. This article is to remind you that even the "finest" doctors are not perfect. Check your chart, ask questions, even though this can lead to a doctor becoming defensive. Let's face it, some of the doctors are more concerned about how many patients they can see and how much money can be made than they are in providing good patient care. ============================================================================== End of Being Alive Newsletter (March 1991 - part 2/2)