Subject: Passive Immunotherapy; CMV; Clinical Trials; AL721 Date: Dec 12 1988 (1050 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Volume 2 Number 8 December 12, 1988 In this issue: Passive Immunotherapy Cytomegalovirus (CMV) Clinical Trials Guide Is it Time to Retire AL721? In Brief New Studies Passive Immunotherapy by Victoria Nott Results of small, uncontrolled trials suggest that infusions of antibody-rich plasma may be a treatment possibility -- not a cure -- for AIDS. In an experiment by George G. Jackson and oth- ers reported in the Lancet (1), six patients with advanced AIDS received single infusions (one received two infusions) of plasma from one of two donors. The donors were healthy HIV seroposi- tives who were selected because they had high concentrations of antibody to p24, a core protein of the virus. The recipients' blood acquired the antibody profile of the donors. Western blot tests after infusion showed antibodies against p24 and other HIV viral proteins. p24 antigen (viral protein) immediately disap- peared from their blood. During the next weeks, HIV could be cultured much less often than before. Recipients gained weight, experienced fewer symptoms, and developed significantly fewer opportunistic infections compared with the periods before infu- sion and after the beneficial effects wore off. T-cell counts also rose. The mean number of T4 and T8 cells increased more than 50%. The positive effects lasted from four to eleven weeks, depending on the amount of plasma infused. Amounts ranging from 55 ml to 500 ml were tried. As the effects wore off, evidence of the virus reappeared in the patients' blood, T-cell counts fell to their original levels or below, and syptoms returned. No adverse effects from the infusions were noted. Of the six patients, one, who was very ill at the time of infusion, did not improve and died nine weeks later, and a second patient died 12 weeks after infusion from a recurrence of PCP (he had been receiving aerosolized pentamidine prophylaxis). Two other patients died five and eight months after infusion. Background - Plasmapheresis, p24 Plasma is the fluid remaining from blood after all the cells have been separated out. Plasmapheresis, a routine procedure used in blood banking, separates the cells and returns them to the donor. Donors can replace plasma much more rapidly than cells, allowing for frequent donation. The procedure is harmless to the donor and may be be beneficial by removing unwanted immune complexes seen with HIV infection. In the Jackson study, six weeks after plasmapheresis, the donors had antibody levels twice as high as before donation. Originally a more time consuming procedure, the new plasmapheresis machines require only 30-40 minutes. With regard to p24, previous studies have shown that HIV seropositives with high levels of antibody against the core pro- tein p24 remain healthy. With time, most seropositives seem to lose the ability to produce p24 antibodies, which fall to undetectable levels. Subsequently, about 70% of patients develop p24 antigenemia, meaning that the p24 viral protein can be detected in blood. Patients with high levels of p24 antigen are more likely to progress to ARC or AIDS, but some AIDS patients do not show the p24 antigen. Two such nonantigenemic patients were included in the Jackson study. These two patients had the same favorable clinical response as the others. Thus, effects of the infusion seemed to extend beyond elimination of p24 antigen. Researchers attending Dr. Jackson's presentation at the Stockholm conference (abstract #3064) expressed surprise during the ques- tion period, not at the disappearance of p24 antigen after infu- sion of anti-p24 antibodies -- which would be expected -- but by the clinical improvement and evidence of HIV neutralization. It had been thought that a core antibody had no site at which it could neutralize virus. While Jackson focused on the role of p24, a number of other antibodies were transferred in the plasma infusions. Western blot tests showed new or enhanced bands against several viral proteins (p18, 24 and 51; also p32, 38, 61 and gp41). However, the patients had antibodies against the surface (envelope) pro- teins gp120 and 160 before and after receiving plasma infusions; thus, these two antibodies would seem ineffective in neutralizing HIV. Most efforts to produce a vaccine have been concentrating on these envelope antibodies. One possible conclusion suggested by the Jackson experiment is that core antibodies can indeed neu- tralize HIV. Related Trials In another trial, Dr. Michael Youle of St. Stephen's Hospi- tal, London, has been infusing ten AIDS and ARC patients with antibody-rich plasma monthly for up to eight months. Results of this teams's investigation will be published in December (2). Plasma donors were selected for high amounts of whole HIV neu- tralizing antibodies (rather than for high anti-p24 antibodies, as in Jackson's trial). Patients were infused with 500 ml plasma each month, some- times reduced to 250 ml. p24 antigen disappeared from the blood right after the first infusion in all patients and remained undetectable in all except one, who subsequently developed PCP, lymphoma, and CMV retinitis. The amount of neutralizing antibo- dies increased approximately two fold. However, T4 and T8 cell counts did not increase (3). Two patients left the study -- one after improving, one after worsening. Of the eight original patients remaining, four are very well, three stable but rather unwell, and one as men- tioned developed three opportunistic infections. Those who were sickest at the start tended to remain sicker than those who were relatively well at the start, Dr. Youle said. Most patients gained significant weight, and three who were transfusion depen- dent before no longer need them. There were no adverse effects from the infusions, except for one patient with type A blood early in the study who had headache, nausea, cold extremities and joint pain after receiving plasma from a donor with type B blood. Since this time, plasma has been cross matched. (In the Jackson trial, it was not found necessary to cross-match.) Dr. Youle plans to continue all patients on a monthly infusions, and to add more patients. He emphasized that this was an uncontrolled trial basically to assess possible toxicity, with encouraging but inconclusive results. A controlled trial comparing antibody-rich plasma to AZT is planned. Another controlled trial of passive immunotherapy is being set up at the Bronx VA Hospital in New York. Dr. Neville Colman, in charge of screening donors and collecting plasma, says they are recruiting asymptomatic HIV seropositives. Donors will be selected for high amounts of neutralizing antibodies, as in the Youle trial. Control patients will receive HIV negative plasma (that is, without antibodies). The therapeutic arm of the trial will be under the direction of Dr. Jeff Jacobsen, Chief of Infec- tious Diseases. The protocol and numbers of patients are not yet final. They hope to have some preliminary data by the middle of 1989. Dr. Fred Prinz and associates at the New York Blood Center have been working for the past three to four years on developing an immune globulin (that is, purified antibodies) from HIV posi- tive plasma. The original aim was to try to prevent viral transmission, especially from infected mothers to their unborn babies. With the recent reports of apparent success in using plasma to treat individuals with AIDS, their focus is changing to include treatment, and they will be involved in making and test- ing immune globulin, or plasma, or both. The project which is "in the discussion stage" with the National Institutes of Health (NIH) has the potential to expand significantly. Dr. Prinz is unconvinced that p24 or any other particular component of HIV is critical, or even if the neutralizing antibody amount is meaning- ful. Although only donors in the top 10% of antibody amounts are accepted, he stresses good health as a criterion for seropositive donors. If new materials are to be developed and larger trials to take place, Dr. Prinz says, greater numbers of healthy seropo- sitives will have to volunteer for testing and plasmapheresis. At present, the New York Blood Center has a panel of only 12 accepted donors. People interested in donating can call Dr. Lou Baker at (212) 570-3248. Cytomegalovirus by William Byne, Ph.D. Cytomegalovirus (CMV) is a member of the herpesvirus family, and like its relatives, the herpes simplex viruses, it is capable of causing primary, latent and persistent infections. CMV is the most common viral cause of life-threatening opportunistic infec- tion in patients with AIDS and is the primary cause of death in approximately 10 percent of these patients (,5). Except in newborns and immunocompromized patients, the initial CMV infec- tion is usually asymptomatic. After the initial infection, infectious virus particles are shed from body fluids (i.e. are detectable), often for several years. If the virus establishes a latent infection, it may reactivate with renewed shedding of virus, years after the primary infection. CMV has several modes of transmission including sexual contact and many, perhaps most, gay men with HIV infection also have evidence of recently acquired or reactivated CMV infection (6). CMV infection is immunosuppressive and strongly associated with inverted T- helper:T-suppressor cell ratios, even in the absence of con- current HIV infection (7). Thus, CMV has been suspected of being a cofactor in the development of AIDS. However, many people with AIDS have no evidence of CMV infection. CMV may also be involved in the development of Kaposi's sarcoma: It behaves as a cancer-causing virus in the test tube, and studies have associ- ated it with this common malignancy of gay men with AIDS. Manifestations of CMV Disease While disseminated CMV infection is one criterion for an AIDS diagnosis, CMV-related symptoms are very rarely the first manifestations. Even in patients with AIDS, asymptomatic infec- tion is much more common than life-threatening disease. In a review of 164 AIDS autopsy cases, 81 had evidence of CMV infec- tion, but CMV was the probable cause of death in only 17 . In the 81 patients with CMV infection, the most common organs affected were the adrenal glands (75%), the lungs (58%), the digestive system (30%), the nervous system (20%) and the eyes (10%). Mul- tiple sites were infected in 62 percent. The most severe man- ifestations of CMV disease in AIDS patients usually involve the retina, colon, esophagus, or stomach. Less commonly, severe man- ifestations involve the lungs or liver. CMV Retinitis CMV retinitis was rarely seen prior to the AIDS pandemic. Patients with this disorder usually complain of blurred or par- tially blocked vision or decreased visual acuity. The condition is painless but progressive, and if untreated it inevitably leads to blindness in patients with AIDS. CMV retinitis is usually discovered in patients with a prior diagnosis of AIDS, but the frequency with which it is the initial AIDS diagnosis is increasing as is awareness of the disorder (8). Several other disease entities may present a similar clini- cal picture. Because differentiating among these may be diffi- cult, and because treatment of CMV retinitis is expensive, time- consuming and toxic, the diagnosis should usually be confirmed by an ophthamologist. Therapy must usually be started before diag- nosis is confirmed. Cultures are primarily useful for confirming the diagnosis and monitoring the effectiveness of therapy. Tissue destruction occurs in areas of active CMV retinitis, leading to scar formation, which can set the stage for retinal detachment. Retinal detachment often occurs during healing, and may result in total loss of sight in the affected eye. This can occur even in patients whose retinitis is controlled with antiviral therapy. While antiviral therapy may allow the retin- itis to resolve, life-long maintenance therapy is currently necessary to prevent recurrence. Digestive tract disease CMV causes severe inflammation of blood vessels in the stomach, esophagus and colon. Gastrointestinal CMV disease is often the first opportunistic infection diagnosed in AIDS. Untreated patients tend to have progressive symptoms, and per- foration of the affected organ is not uncommon. The typical presenting symptoms of CMV colitis are severe cramp-like abdomi- nal pain and diarrhea. A biopsy of the rectum or colon is required to confirm the diagnosis. Stool cultures are not help- ful because they rarely yield virus even in patients with CMV disease. Furthermore, because of the high prevalence of asymp- tomatic CMV infection in the general population, the presence of virus in stool samples is of uncertain significance. CMV gastritis and esophagitis may mimic peptic ulcer disease or the reflux of stomach contents (regurgitation) into the eso- phagus. Affected patients usually complain of pain in the chest or abdomen, or of difficulty or pain during swallowing. A biopsy is required to confirm the diagnosis. CMV gastritis may be con- fused with candida esophagitis and herpes esophagitis. Patients presenting with the symptoms and x-ray evidence of esophagitis may be given trials of empiric (trial and error) therapy: If the symptoms improve with ketoconazole, a presumptive diagnosis of candida esophagitis may be made. If the symptoms fail to respond to ketoconazole, a response to acyclovir suggests a diagnosis of herpes esophagitis. Empiric treatment with ganciclovir (dis- cussed later in this article) is probably never warranted. CMV Pneumonia CMV is rarely the primary cause of pneumonia in patients with AIDS. Although one study detected CMV in 17 percent of AIDS patients with active pneumonia, other pathogens were present in all but 4 percent. Thus, the isolation of CMV from the respira- tory tract is usually of unknown significance. One study, how- ever, has associated coexistent CMV infection with respiratory failure and death in PCP (9). The most common symptoms of CMV pneumonia are fever, shortness of breath and nonproductive cough. Clinical findings can range from asymptomatic viral shedding to rapidly fatal pneumonia. Other Manifestations of CMV in AIDS Encephalitis (infection of the brain) with evidence of CMV infection has been described, but coinfection with other oppor- tunistic pathogens makes a syndrome of CMV encephalitis difficult to describe. Further complicating this matter is the widespread prevalence of HIV infection of the central nervous system (brain and spinal cord). A progressive course of altered mental status, fever and confusion has been described in six patients in which evidence at autopsy suggested that CMV was the only pathogen infecting the central nervous system (10). Neither CT scans nor analysis of the cerebrospinal fluid gave specific clues that could have established the diagnosis prior to death. Autopsy studies have shown that the liver is involved in approximately a third of patients with CMV infection elsewhere. In one report, 4 of 20 patients with retinitis and 8 of 16 with gastrointestinal involvement had abnormal liver function tests. Adrenal gland involvement is one of the most frequent autopsy findings. While this was previously thought to have lit- tle, if any, clinical importance, more recent evidence suggests that patients with symptomatic CMV disease should be monitored for evidence of adrenal hormonal deficiencies. Treatment of CMV Disease Ganciclovir (DHPG): This antiviral was the first drug shown to be effective against CMV in vivo (in people) (11). It is also known as DHPG or Cytovene (the trade name). Ganciclovir is very similar to acyclovir, which has been highly publicized as a treatment for herpes simplex infections. Both drugs inhibit herpesvirus DNA polymerase, an enzyme that is necessary for the replication of herpesviruses. The antiviral effect appears to be highly specific for CMV. In cell culture, ganciclovir has been shown to be at least 10 times more active by weight than acyclovir in inhibiting CMV replication, and as effective as acyclovir in inhibiting the herpes simplex viruses and the herpes zoster virus (the virus that causes chicken pox and shingles). Ganciclovir for CMV disease is usually administered in two phases. The initial, or "induction," phase consists of ganciclo- vir given intravenously every 8 to 12 hours over a 10 to 14 day period. Because relapse has been documented after the induction phase in every clinical series published on AIDS patients, life- long maintenance is required. Maintenance therapy is usually administered as a single daily intravenous dose given 5-7 days per week. While the blood levels of ganciclovir achieved with oral administration are not adequate for the induction phase of therapy, oral administration may prove to be an alternative for the maintenance phase (12). Ganciclovir was available early in the AIDS pandemic and many patients have received it on an experimental basis. The majority of studies have focused on the use of ganciclovir for induction therapy in CMV retinitis. The results of these studies are summarized in the recent review by Jacobson and Mills. Briefly, CMV retinitis can be expected to stabilize or improve in the majority of patients after a 10-20 day induction course of 5-14 mg/kg/day. In one study, when maintenance therapy was not initiated, the average length of time before the symptoms of retinitis began to progress was 16 days. The effectiveness of maintenance therapy appears to be dose-related (e.g. higher doses are better). Specifically, in one study reviewed by Jacobson and Mills, 2.5 mg/kg 2-5 times a week did not prevent relapse, while in another study relapse occured within 3 weeks in 4 of 10 patients receiving 5 mg/kg, 5 days a week. In a third study, all patients receiving mainte- nance therapy of 10-15 mg/kg per week had progression of retin- itis compared to 5 of 10 patients who received 30 mg/kg/week. In the latter study, CMV could be cultured from 9 percent of patients while on maintenance therapy, compared with 40 percent off therapy. Thus, it appears that ganciclovir suppresses active CMV infection but does not cure the latent infection. The efficacy of ganciclovir in the treatment of the gas- trointestinal manifestations of CMV is less well documented and no randomized studies have been published. In the largest study published to date, 30 out of 41 patients with gastrointestinal manifestations showed improvement with ganciclovir induction therapy. Thirty-three of these patients were evaluated for relapse, 13 of whom had relapse at a median of 9 weeks from the start of induction therapy (13). The data reviewed by Jacobson and Mills suggest that induction and maintenance therapy with ganciclovir reduce the pain and diarrhea associated with gas- trointestinal disease. There are few data pertaining to the efficacy of ganciclovir therapy in AIDS patients with CMV pneumonia. While ganciclovir therapy does not appear to alter the mortality rate (90 percent) of CMV pneumonia, one study found that 64 percent of patients with CMV pneumonia had some favorable response. Perhaps one reason for the apparent inefficacy of ganciclovir for CMV pneu- monia is that, because of the drug's toxicity and the often ques- tionable significance of the presence of CMV in the respiratory tract, ganciclovir may be withheld until the oxygen content of the patient's blood becomes low. A paper given at the recent meetings in Stockholm reported long disease-free survival in 18 patients with mild CMV pneumonia who were treated with ganciclo- vir (5mg/kg intravenously, twice daily for 14 days): 2 years for 3 patients; 18 months for 5; 12 months for 3, and 6 months for 2 (14). No reports on ganciclovir therapy for other manifestations of AIDS have been published. Jacobson and Mills, however, noted that neurological findings consistent with encephalitis resolved in several patients who received ganciclovir for CMV retinitis or gastrointestinal disease. This observation is consistent with the fact that ganciclovir is known to enter the cerebrospinal fluid, and suggests that ganciclovir may be effective in treating CMV infections of the central nervous system. The most common adverse side effect of ganciclovir therapy is a decrease in the ability of the bone marrow to produce white blood cells. Other side effects include disorientation, rashes, blood clots, thrombocytopenia (decreased blood platelets), nausea and vomiting, and pain or phlebitis at the infusion site. Perhaps the most serious drawback to the use of ganciclovir is that it cannot be administered systemically to patients who are taking AZT, the only drug that has been documented to prolong the lives of AIDS patients. This is because AZT also frequently reduces the white blood cell count. Two recent reports by Con- tril and associates, however, suggest that patients with CMV retinitis who are ineligible for intravenous ganciclovir therapy, may be successfully treated by injecting the drug directly into the eye (15,16). Induction therapy by this method requires two injections per week, while maintenance therapy requires one or more injections per week. A physician may obtain ganciclovir by calling Syntex at 415-855-5924. Ganciclovir has been available on a "compassionate use" basis for quite some time. This means that Syntex provides the drug free of charge to patients who meet certain criteria. Syn- tex cannot afford this generosity indefinitely, but the FDA has been scrupulously critical of data submitted to demonstrate ganciclovir's efficacy. About one year ago, the FDA refused to license ganciclovir, contending that the data on maintenance therapy was insufficient. To obtain this data, officials at the FDA are obstinately structuring a new, stricter protocol for access to this life-saving drug. It appears that patients with less serious CMV infections will be forced to participate in a placebo controlled trial if they want ganciclovir. Given the limited options for such patients, restricted access to ganciclo- vir is not justified on the grounds of exploring the efficacy of maintenance dose. Foscarnet: This is a newer drug than ganciclovir and, consequently, it has been less well studied. Like ganciclovir, it inhibits her- pesvirus DNA polymerase. It has two potential advantages over ganciclovir. First, it does not suppress the production of white blood cells and, therefore, it can be administered concurrently with AZT. Second, in addition to inhibiting CMV, it inhibits the replication of HIV by interfering with the enzyme reverse tran- scriptase (17). The ability of foscarnet to inhibit HIV in patients with ARC or AIDS has been demonstrated in several stu- dies, two of which were presented at the recent meetings in Stockholm (18,19,20). While foscarnet and AZT appear to be simi- lar in their ability to inhibit HIV, foscarnet offers at least four potential advantages. First, foscarnet is active against CMV. Second, it is not associated with the severe blood abnor- malities now being seen in people receiving AZT. Third, foscar- net penetrates the blood brain barrier and achieves levels in the cerebrospinal fluid that are high enough to inhibit HIV in the test tube (21). Fourth, foscarnet also inhibits HIV in macro- phages at concentrations achievable in vivo, while AZT does not (22). In certain cells, but not macrophages, the effect of administering AZT and foscarnet concurrently is greater than the effect of administering either drug alone in higher doses (23). Foscarnet is largely eliminated by the kidneys, with the remainder passing into bone (24). The drug markedly increases urine output and fluid intake, and can be associated with malaise, nausea, vomiting, fatigue and headache. Decreased kid- ney function is the most common toxicity attributed to foscarnet, and its incidence increases with the severity and chronicity of HIV infection. Dosing modifications must be made in patients with decreased renal function. Other side effects include mild anemia, reversible tremor, seizures, irritability and decreased blood calcium levels. Pentamidine, a drug used to treat Pneumo- cystis carinii pnuemonia has also been associated with low cal- cium levels. At the Stockholm meetings, M. Youle and associates reported administering foscarnet and pentamidine to 4 patients, all of whom developed hypocalcemia (low blood calcium) and neuro- logical signs indicative of low calcium (25). Thus, care should be taken when prescribing these drugs concurrently. Foscarnet has been studied for the treatment of CMV retin- itis with results comparable to those of ganciclovir (26,27). In the largest study published to date 13 patients were treated for 14-21 days and followed for one month after the cessation of treatment. Six patients showed evidence of kidney toxicity, and the drug was stopped in 3. Retinitis resolved partially or com- pletely in all patients; however, during the follow-up period relapses occurred in 10 of the 11 surviving patients. The patients that relapsed had favorable responses to subsequent courses of foscarnet. While foscarnet is generally given by con- tinuous infusion, a study presented at Stockholm suggests that intermittent infusion (60 mg/kg over 2 hours, repeated every 8 hours) is as effective but better tolerated. The effective dose for maintenance therapy with foscarnet has yet to be established. In another paper presented at Stockholm, 5 of 6 patients relapsed on maintenance therapy of 70mg/kg/day by 2 hour infusion, sug- gesting that higher dose maintenance therapy should be tried. Foscarnet is currently only available by joining a clinical trial, but many people think it will receive FDA approval before ganciclovir. Clinical Trials Guide by Lisa Nielsen One of the many difficult decisions that PWAs face today is whether or not to particpate in a clinical trial. Entrusting one's care to an establishment that many PWAs view with suspicion is an understandably daunting endeavor. However, it is possible to reach a common ground where the meticulous needs of "good sci- ence" and the right of desperately ill patients to responsible, humane health care converge. This article seeks to decipher the issues and language of scientific medical research and to empower PWAs with the tools necessary to make an informed decision about entering a clinical trial. People interested in participating in an experimental drug trial face many uncertainties. Not the least of these is the rather exclusive vocabulary of experimentation itself, a jargon that can be unnecessarily anxiety-producing. Take, for example, the phrase: "A randomized, double-blind, placebo controlled study." This is a typical title for a drug trial. The purpose of this article is to provide definitions, in understandable language, of these and other unfamiliar phrases. The general features of the experimental method will also be addressed. It is of utmost importance that experimental subjects (the people who volunteer for a scientific study) have a good grasp of the "terms" of their participation. Only then can they give truly "informed" consent. With the help of this article, pros- pective participants can hope to make a clearer choice, with a stronger grasp on the language of clinical trials. A drug trial's protocol, or written plan of action, should make clear to the participant the procedures involved. Unfor- tunately, procedures are phrased as codified messages between scientists. It is helpful to consider the reasoning underlying these cold, calculated terms. There are a number of conditions necessary for experimental results to have scientific value. First, the process of drug testing must be orderly. Before the drug is tested in living things (in vivo), it must show efficacy (be seen to work) in a non-living container or environment like a test tube. This is called in vitro (literally "in the glass"). Good in vitro results do not necessarily lead to experiments in people. Many substances which can kill the AIDS virus, say, in a test tube are poisonous to the human body -- an example is household bleach. The step after in vitro studies is a toxicity (poisonousness) trial in animals. Animals are tested to see how well a living thing can tolerate the new substance. In vitro and animal stu- dies together are called preclinical trials. Finally, a clinical (people) trial can be planned. Researchers need to gather a group of participants who are very similar, especially as far as their type and severity of illness, other medications they have taken or are taking at present, phy- sical weaknesses, and other details. A protocol speaks of inclu- sion criteria, those aspects of a person's condition which make him or her eligible to participate in the specific study because they "match" the description of other people in the experimental design. Likewise, exclusion criteria turn away unlikely sub- jects. This is done for a number of reasons, one of which is to protect the subjects if the drug would pose a known danger to them, like probable damage to a pregnant woman's fetus. Another critical reason is that scientific trials must be designed so that they eliminate variables, things about the subjects that make them different. Experimenters ideally want the only vari- able in their study to be the drug treatment they give. This would leave the drug as the only "reason" for a change in a subject's illness state. An experiment must come up with objective results, ones that are not biased or prejudicial. One way to do this is to include a large number of participants so that individual differences do not count for quite so much when the results of all the patients are examined statistically. Objective data may be readily col- lected from a controlled experiment. This plan separates sub- jects into two different groups. The people in the control group either may get no drug (as in a placebo study, explained below) or may receive "standard treatment" for their disease. They form the basis for comparison with the people in the experimental group who are treated with the drug under investigation. Sub- jects are often randomized (assigned by chance) to one of these two types of groups. This is a nonjudgmental distribution, and participants are subject to the "luck of the draw." Volunteers have no say over where they are placed in the study, and every one of them is led to believe that they are getting the experi- mental treatment. (It should be noted that an uncontrolled experiment does not mean chaos! It means that there is no con- trol group, everyone in the study gets the drug. Some synonyms for "uncontrolled" are open-label and open-trial because everyone knows they are getting the drug and how much of it.) The control group may receive a placebo, a substance that looks like the real drug and is given as if it were the real drug, but which contains no active ingredients. It is, in effect, a zero dosage. Placebo studies are very valuable scien- tifically because fewer subjects are needed for the trial to pro- duce significant results. Also, effects and side effects not due to the drug in question ("the placebo response") may be recog- nized by the researchers and properly "weeded out" of a final report. Of course, giving inactive treatment to ill subjects raises serious ethical and moral issues. Many AIDS activists feel that is is acceptable to structure protocols that include a placebo control for people with asymptomatic HIV infection, but that it is completely unethical to ask people who are ill to risk taking a sugar pill. Placebo usage in a trial of Dextran sul- fate, or other drugs that are readily available through the underground network is illogical. Some studies have attempted to be fair by promising the drug to people getting placebo if their condition worsens and/or planning a crossover in which the con- trol group and experimental group(s) switch treatment regimens after a prearranged amount of time. Researchers can consciously or unconsciously influence drug recipients, communicating their personal prejudice for or against the drug. Because patients tend to respond in the way they think they "should," another objective method is to make an experiment double-blinded. In this plan neither the people who directly administer the treatment nor the subjects who receive it know who is getting the drug and who is getting placebo. (In a blinded study only the patient does not know.) We can now take another look at the sample protocol title given at the beginning of this article: "A randomized, double- blind, placebo controlled study." In order, as written, this means: in this study participants will be assigned by chance to an experimental subgroup. Neither the subjects nor the people who administer the treatment to them will know who is getting the investigational drug and who is getting an inactive substitute. Having established this background, let us turn to the specific ways in which trials are designed in the drug approval process. Phases of Testing Clinical trials proceed in phases numbered I, II, III, and beyond. A phase I or pilot study investigates the toxicity of the drug in a small number of humans. Controlled, phase I stu- dies usually do not involve placebos; everyone receives the drug. The subjects in such a trial may be the very first people ever to take the new drug. They are truly on the cutting edge of drug research. A phase I study may also be called a safety/pharmacokinetic study. Pharmacokinetics means how the drug is absorbed and goes to work in the body , which dose seems most appropriate, and any toxic effects in subjects who are ill. It may also reveal the consequences of mixing medications. It is important for physicians to know, as well, the bioavailability of the drug, the amount of it which is active and useful in the body for a given dose. Phase I studies are typically short-term. Patients are usually not guaranteed to be continued on the tested drug after the study is over, but they may be assured a spot in a phase II trial if the drug continues on the testing track. A phase II study, involving a larger number of participants, seeks to determine if a drug actually works and what short-term side effects it causes. A protocol in this phase commonly uses a double-blind design with placebo and will usually promise a con- tinuation of treatment to subjects when the study is finished. Some trials do not guarantee indefinite access to an experimental drug after the conclusion of the trial. This issue is critical when the investigational drug may cause a "rebound effect", i.e. the patient's condition may deteriorate when therapy is discon- tinued. Trials examining drugs with this potential effect should ensure indefinite access to the drug if the participant desires it. Phase III studies are large, long-term trials that are con- trolled but usually do not involve placebo. Phase III studies may go on for years. FDA recently adopted Commissioner Frank Young's plan to eliminate the phase III stage and grant New Drug Application (NDA) status earlier to drugs for life-threatening diseases such as AIDS. Candidate drugs would need to have con- vincingly navigated the first two phases, and proved to be safe and possibly effective. This relaxed approach has great appeal, but initiative is still left entirely to pharmaceutical com- panies. The greatest weakness of this plan is that it is not man- datory. It remains to be seen if the regulations are implemented, and the now largely unused treatment-IND (explained later) regu- lations do not set an impressive precendent for another FDA "early release" program. Large numbers of subjects , generally hundreds, are recruited for phase III studies which examine long term side effects and search for optimal dosing. It is important to include many participants to achieve meaningful statistical data, as mentioned earlier. A multicenter study provides such numbers by running the same drug trial at several different research facilities at the same time. Though such studies reach eligible patients around the country, they do have a drawback: more than one physician is interpreting the participant's physi- cal findings -- and clinicians do differ. Experiments cannot be perfect, but there is a striving for balance and validity. Early Access to Drugs If one is unable to participate in a drug trial there are two alternative means of obtaining experimental drugs. These are through the Treatment IND (investigational new drug) program and a request for access to the drug on a compassionate use basis. Either way may be attempted through one's physician, who should know the proper methods of enquiry. Under a Treatment IND a pharmaceutical company makes its drug available to those patients with severe or immediately life-threatening disease if no other satisfactory treatment is available. The trend has been to do so free of charge, though this is not required; companies may charge to recoup research and development costs only. An inference was made earlier about this program's ineffectiveness. Although the regulations published in June 1987 state that candidate drugs "may" be effective, the FDA has commanded much higher standards of efficacy in approving this status for candidate drugs, making the program largely a failure. Under compassionate use distribu- tion, drug companies are forbidden to bill patients for the treatment. Both methods may demand that follow-up information on the patient's condition be sent to the pharmaceutical company. This means that even those patients who are not subjects in a drug trial per se can contribute to a growing wealth of knowledge about specific experimental medicines. There are a number of subjective issues that deserve atten- tion here as well. For instance, investigators monitoring a clinical trial should interrupt treatment for a patient whose condition deteriorates. Provisions for such termination should be a part of the trial's written protocol. Patients should report any worsening or new symptoms immediately to the doctors running the trial. Also, patients should be extremely wary of trials that charge money for anything. Participation alone in a clinical trial is compensation for any related costs. Is It Time To Retire AL721? by Barry Gingell, M. D. Two years ago, Max Navarre wrote an editorial for the PWA Coalition Newsline regarding AL721. At the time, there was no such thing as AZT, and people were understandably desperate for a treatment. Several prominent researchers published a tiny arti- cle in the New England Journal of Medicine which caught the eye of patients and entrepreneurs alike. Within months, an AL721 industry sprung up, eventually becoming a million-dollar busi- ness. It seemed that everyone with ARC or AIDS, even many sero- positives, were buying the lipids and embarking on the incon- venient and rather expensive AL721 ritual. Max was very insight- ful in his article. He realized that the evidence supporting AL721 was totally theoretical; that there were no substantial results in patients who were ill. He warned about putting too much faith in an unproved drug, about putting all one's eggs in one basket. AL721 was just as likely to be a washout as a suc- cess. Since that time, after countless tons of AL721 have been sold in the United States, the mystique of AL721 remains. Treat- ment Issues ran an article on AL721 (Vol. 2 no. 1) which tried to be neutral on recommending the drug: it just didn't seem that enough clinical data had been accumulated, and very little was published to venture some kind of opinion about the drug. I feel that this situation has changed. Two unimpressive studies were presented at the Stockholm AIDS conference which did not show convincing improvement in people taking the drug. The St. Luke's study of AL721 in patients with lymphadenopathy has recently been published (28). Although only 8 patients were studied, there were no significant improvements in T-cell numbers or p24 antigen levels. Although 4 of 8 had reductions in reverse transcriptase, this test is no longer considered a reliable indi- cator of the amount of HIV in the body. 4 out of the 8 patients have progressed to AIDS over the subsequent 14 months. The numbers of patients followed on AL721 by local physicians total much more than the St. Luke's study. When asked whether they felt that AL721 had any positive clinical effect on patients, physicians consistently answer "No. " Few doctors will forbid a patient from taking AL721, but only a handful recommend it. How has the AL721 mystique survived? In large part, it seems to be a result of the negative press that AZT continually receives, especially in local, less-than-informed publications. Sure, AZT is not perfect. But the body of evidence supporting it is overwhelming. It does not appear wise to discard it for a substance which has no proven clinical value. I suspect that this article will generate some debate, and no one should take one person's opinion as the final word on AL721. I do feel, however, that this opinion should be expressed so that patients can make a more informed decision about taking AL721 and generic forms of "lipids." Although the final word is not yet in, the evidence to date suggests that it may be time to retire AL721. Finally, the CRI study of AL721 is still underway. Treat- ment Issues will report on this study as data becomes available. In Brief Alpha-interferon: The FDA last week approved the use of Alpha-interferon for treatment of Kaposi's sarcoma. This is an incredible, unexpected decision that will help a large number of PWAs. Two companies, Hoffman-LaRoche and Schering, manufacture Alpha-interferon. Both have issued statements about pricing of this expensive drug. They have assured us that no patient will pay more than $9,800 per year for the drug. The drug will be supplied at no cost for any indigent patient. This is a generous gift, considering that the retail price of the drug in quantities sufficient for treatment of KS would be over $30,000 per year. Up until now patients with rapidly progressive Kaposi's sarcoma, who failed mild chemotherapy, had two options: severe toxic chemoth- erapy or joining a clinical trial of Alpha-interferon. Although Alpha-interferon has some side effects, they are generally much less severe than with chemotherapy such as adriamycin or VP-16. For information regarding KS and treatment with Alpha- interferon, see our last issue. CD4: Treatment Issues has learned that another Phase I trial of this new antiviral is underway. The Biogen Company, based in Cambridge Mass., has been conducting a dose ranging trial for about one month. The trial is open and still recruit- ing at Massachusetts General Hospital (617-726-3819) and Cedars Sinai in Los Angeles (213-855-5000). The 28-day trial is open to patients with AIDS who have had one opportunistic infection (that is not active) or PWARCs who meet other criteria. According to company researchers, participants have tolerated the first dose level well. We also have an update on the NIH sponsored Phase I CD4 trial. The drug has been well tolerated to date. Halfway through this 6-month dose escalation trial, patients have just begun tak- ing 100 mg of CD4. According to Dr. Sam Broder, head of the National Cancer Institute, this is the minimum dose that probably will be effective. Unconfirmed rumors have indicated that patients have had significant rises in T4 cells. We must emphasize that the drug is in very early stages of testing, and that no claims can be made yet about its efficacy. Two CD4 trials will be opening soon in New York, at NYU Med- ical Center and St. Luke's-Roosevelt. We will be reporting more information when it is available. On a related note, researchers in New Orleans have been working with a modified version of the synthetic CD4 molecule. This molecule has a toxic particle attached that kills HIV- infected cells. Initial results from test tube work look very promising. However, trials in people are a long way off. Stay tuned for the continuing CD4 saga. Imreg: The FDA recently denied Treatment-IND status (early release) to the Imreg Company for their experimental immunomodu- lator Imreg-1. The company has been quite enthusiastic about results seen to date, but the FDA reviewers concluded that the drug does not delay the course of AIDS. Nebulizers: Two recent decisions by Medicaid have limited the options of people at risk for PCP who are using aerosolized pentamidine as a preventive measure. Officials in the New Rochelle office, stating that Medicaid does not pay for experi- mental therapy, have decided that patients outside of New York City will no longer be reimbursed for nebulizers. For poor patients who cannot tolerate other, standard PCP prophylactic medications which are sulfa based (i.e. Bactrim, Dapsone, Fansi- dar), this decision is a serious setback. Reimbursement claims for nebulizers in the five boroughs of New York City will still be honored, but only for one machine (the Pulmosonic). On a related note, Medicaid will not pay claims in New York City for a new, more efficient nebulizer that has come to market. The Porto-Sonic, which is produced by the DeVilbiss Company, delivers a higher percentage of drug to the lungs, making this somewhat more expensive machine a wise investment choice in the long run. Such a posture is inconsistent with Medicaid's origi- nal decision to pay for this indispensible preventive measure and seems to indicate that the agency is willing to saddle patients with inferior technology. Hazelden Educational Materials has published a book of daily meditations for PWAs entitled: The Color of Light: Meditations for All of Us Living with AIDS. The book, which is based on the 12-step philosophy that has helped many people recover from add- ictions, is authored by Peter Tilleraas. To place orders for The Color of Light, call 1-800-328-9000 outside of Minnesota, or 1- 800-257-0070 within the state. New Studies St. Luke's-Roosevelt Hospital is still recruiting for a phase I/II dose ranging study of Dextran sulfate in seroposi- tives, PWAs and PWARCs. Researchers will be administering very high doses (3600, 5400 or 7200 mg/day) of the drug. While some people have been able to tolerate these dose levels, severe toxic reactions (bloody diarrhea above 2700 mg/day, liver abnormalities above 5400) are possible. We advise readers to be very cautious before joining this trial. More information can be obtained by calling Brenda Kolatch at (212) 523-6722. The National Eye Institute has opened a trial of foscarnet in patients with CMV retinitis (for more information on this drug, see our article on CMV in this issue). The trial is not open to anyone who has had previous foscarnet or ganciclovir (DHPG) treatment, or who has a history of intolerance to AZT. Patients must have non-sight threatening CMV retinitis, and will be randomized to three arms: IV foscarnet alone, IV foscarnet plus AZT and AZT alone. Those receiving foscarnet will be hospi- talized for the first 3 weeks of the trial. After the trial, all participants will have access to the drug on a compassionate use basis. Participants will also be given aerosolized pentamidine every other week as a preventive treatment for PCP. For more information, call Dr. Judith Rabin at (301) 496-1243. Our Apologies... Regarding the long time lapse between our previous two issues (Vol. 2, Nos. 6 & 7), the Treatment Issues staff would like to extend sincere apologies to everyone who was affected. We have had serious problems with mailing services, resulting in very late mailings. We are changing our mailing procedure to eliminate this problem in the future. Treatment Issues is GMHC's newsletter devoted to providing reli- able information on experimental AIDS therapies. Describing an experimental therapy should not be construed as recommending it. All new treatments should be done under a physician's care. Treatment Issues is published ten times yearly. Copyright 1988 Gay Men's Health Crisis, Inc. All rights reserved. Non-commercial reproduction is encouraged. Subscription lists are kept confidential. Editor: Barry Gingell, M. D. Managing Editor: Kevin Armington GMHC, Department of Medical Information, 129 West 20th Street, New York, NY 10011. Footnotes: 1 Jackson GG et al. Passive Immunoneutralization of human immuno- deficiency virus in patients with advanced AIDS. Lancet ii:647, 1988. 2 Karpas A et al. Effects of passive immunization in patients with the AIDS related complex and immune deficiency syndrome. Proc Nat Acad Sci. Dec 1988. 3 Youle M. Personal Communication. 4 Klatt EC et al. Cytomegalovirus infection in the acquired immunodeficiency syndrome. Arch Pathol Lab Med 112:540, 1988. 5 Jacobson MA et al. Serious cytomegalovirus disease in the acquired immunodeficiency syndrome. ann Int Med 108:585, 1988. 6 Pass RF. Epidemiology and transmission of cytomegalovirus. J. Infect Dis 152(2):243, 1985. 7 Drew LW et al. Cytomegalovirus infection and abnormal T- lymphocyte subset ratios in homosexual men. Ann Int Med 103:61, 1985. 8 Walmsley et al. Treatment of cytomegalovirus retinitis with trisodius phosphonoformate. J Infect dis 157(3)569, 1988. 9 Pass HI et al. Thoracic manifestations of the acquired immuno- deficiency syndrome. J Thorac Cardiovasc Surg 88:654, 1984. 10 Post MJ et al. Cytomegalic inclusion virus encephalitis in patients with AIDS: CT, clinical and pathologic correlation. AJR 146:1299, 1986. 11 Shepp DH et al. Activity of 9-(2Hydroxymethylethoxymethyl) guanine in the treatment of cytomegalovirus pneumonia. Ann Int Med 103:368, 1985. 12 Jacobson MA et al. Oral ganciclovir: human pharmacokinetics and tolerence. Third International Conference on AIDS, Washing- ton, 1987, #WP. 231. 13 Chachoua A et al. 9-(1,3-2-propoxymethyl) guanine (gancyclo- vir) in the treatment of cytomegalovirus gastrointestinal disease with acquired immunodeficiency syndrome. Ann Int Med 107:133, 1987. 14 Finaud M et al. Long disease free survival after DHPG cure for cytomegalovirus (CMV) pneumonitis in AIDS. Fourth International Conference on AIDS, Stockholm, 1988, #7505. 15 Contril HL et al. Treatment of CMV retinitis with intravitreal ganciclovir - long term results. Fourth International Conference on Aids, Stockholm, 1988 #7188. 16 Contril HL et al. Use of intravitreal ganciclovir (dihydroxy propoxy methyl guanine) for cytomegalovirus retinitis in a patient with AIDS. Am J Ophthamol 103:17, 1987. 17 Gaub J et al. The effect of foscarnet (phosphonoformate) on human immunodeficiency virus isolation, T-cell subsets and lym- phocyte function in AIDS patients. AIDS 1:27, 1987. 18 Farthing CF et al. Phosphonoformate (foscarnet): a pilot study in AIDS and AIDS related complex. AIDS 1:21, 1987. 19 Jacobson MA et al. Beneficial effect of intermittent intravenous (IV) foscarnet (PFA) therapy on HIV infection in patients with AIDS. Fourth International Conference on AIDS, Stockholm, 1988, #3586. 20 Bergdahl S et al. Antiviral effect against HIV in patients with AIDS-related complex given intermittent IV foscarnet. Fourth International Conference on AIDS, Stockholm, 1988, #3588. 21 Bergdahl S et al. Declining levels of HIV P24 antigen in serum during treatment with foscarnet. Lancet 1:1052, 1988. 22 Crowe S et al. Contrasting antiretroviral efficacy of zido- vudine (AZT) and phosphonoformate (PFT) in HIV-infected macro- phages. Fourth International Conference on AIDS, Stockholm, 1988, #3132. 23 Eriksson BFH et al. Combination of 3'-azido-3'deoxythymidine (AZT) or its 5'-triphosphate and phosphonoformate (PFA) against HIV-1 replication and reverse transcriptase. Fourth Interna- tional Conference on Aids, Stockholm, 1988, #3624. 24 Sjvall (sp? ) J et al. Distribution to CSF and pharmacokinetics after IV infusion of foscarnet to patients with HIV-infection. Fourth International Conference on Aids, Stockholm, 1988, #3585. 25 Youle M et al. Possible drug interaction between foscarnet and pentamidine in AIDS patients. Fourth International Conference on AIDS, Stockholm, 1988, #3590. 26 Katlama C et al. Phosphonoformate (foscarnet (R)): treatment and maintenance therapy in CMV retinitis. Fourth International Conference on AIDS, Stockholm, 1988, #7180. 27 Jacobson MA et al. Tolerance and efficacy of intermittent intravenous (IV) foscarnet (PFA) therapy for cytomegalovirus (CMV) retinitis in AIDS patients. Fourth International Confer- ence on AIDS, Stockholm, 1988, #7179. 28 Grieco MH et al. Open study of AL721 treatment of HIV- infected subjects with generalized lymphadenopathy syndrome: An eight week open trial and follow-up. Antiviral Research 9:177, 1988. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display