&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Copyright 1993 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS Issue #168, February 5, 1993 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: [items are separated by "*****" for this display] Sulfadiazine Shortage: Buyers' Club Has Drug TP-5: Thymus Hormone Trial Suggests Benefit Clinton: Setting New Directions on AIDS Political Action Proposal: Cultural Change for Grassroots Electronic Democracy New CDC Definition Now in Effect, But Confidentiality Questions Remain CMV Experimental Treatment Overview, Part II Announcements ***** Sulfadiazine Shortage: Buyers' Club Has Drug by John S. James Due to a production shutdown at the only U. S. manufacturer, a critical shortage of the drug sulfadiazine has developed in New York, Boston, and many other parts of the U. S. Sulfadiazine is part of the first-line treatment for toxoplasmosis, and a shortage could become life-threatening to patients. The U. S. Centers for Disease Control (CDC) has obtained a small supply (enough for fewer than 70 patients), and is rationing it for emergency use, especially for infants with congenital toxoplasmosis. The CDC is seeking FDA permission to import more from Canada; but even when it obtains an adequate emergency supply, release of the drug will require considerable paperwork for each patient, which is usually impossible for public clinics. It could take up to a year for regular commercial supplies to be re-established. The good news is that the shortage is only in the U. S. ; elsewhere, the same drug is plentiful and inexpensive. The products available abroad have not been explicitly approved by the FDA for U. S. sale, and there is no available procedure to give emergency permission for their importation. Physicians and patients should know that sulfadiazine from Europe is available through the PWA Health Group, a New York "buyers' club" which has helped people import personal-use quantities of AIDS medications not available in the U. S. The organization will ship the drug. It requires a prescription, and the use of its own order form. For more information, call the PWA Health Group at 212/255-0520. Trying to Fix the Problem Similar shortages have recently occurred with other critical drugs: streptomycin for multi-drug-resistant tuberculosis, and nitroglycerine tablets for certain heart conditions. On January 12 the New York Times quoted FDA Commissioner David Kessler as saying that all three problems had been solved. But on January 29 and February 1 AIDS TREATMENT NEWS found that the CDC believed that it had submitted all necessary documents and was waiting for FDA action, while the FDA believed that it needed more documents from the CDC before it could process the application. Each agency appears to be waiting for the other. The mechanism the agencies are using to allow the CDC to obtain more supplies for its emergency program (which distributes the drug free) is the "treatment IND," an FDA procedure intended to allow early access to experimental drugs; it is being used here for a drug approved for 40 years, simply because no other mechanism is available. The problem is that this procedure will only provide the drug on a patient-by-patient basis, with considerable paperwork each time. Many physicians, especially those not familiar with AIDS or those practicing in understaffed public clinics for underserved populations, will not use this method for getting sulfadiazine specially shipped from the CDC, and instead will prescribe other drugs which are less desirable. The PWA Health Group is trying to find a way for the CDC to release bulk supplies of the dg directly to hospitals andlinics. Comment The obvious solution would be for the FDA commissioner to give emergency permission to allow the usual commercial distributors of the drug to import sulfadiazine which has been approved for sale in certain countries known by the FDA to have adequate quality standards. We do not know what regulations or laws, if any, would need to be changed to permit the FDA to do this. But similar shortages have already occurred with several drugs, and the problem potentially threatens patients with many different diseases -- important reasons to make the changes required to respond effectively to present and future shortages as they happen. ***** TP-5: Thymus Hormone Trial Suggests Benefit by Dave Gilden Evidence that the thymus gland suffers extensive damage during HIV infection has led to research on using thymus hormone replacement therapy as a means to counteract the damage. Thymus hormones are proteins that affect the development of immune system T-cells in the thymus gland. They also enhance immune function in mature T-cells in the blood and lymph. While their exact role in AIDS therapy is unclear, various experiments suggest that injecting thymus hormones can increase the numbers of the various T-cell subpopulations. By enhancing the activity of the immune system's killer cells, they may increase these cells' ability to seek out and destroy cells infected by HIV. Three injectable thymus hormone derivatives are now in formal trials as AIDS therapies -- TP-5 (thymopentin), THF-g2 (thymic humoral factor) and thymosin-alpha1. No toxic effects have been noted for any of them. Despite years of interest in using thymus hormones for AIDS, hard data has been lacking. Now, investigators claim they have data showing that injecting TP-5 three times a week confers some protection against progression of HIV disease. "In my mind, there is very strong evidence that the drug prevents progression to AIDS-related conditions," said Marcus Conant, M. D., a San Francisco AIDS physician and researcher. The latest TP-5 study, conducted by Dr. Conant and others, compared the drug against a placebo for 48 weeks in 354 asymptomatic HIV-positive persons. This study was double blind -- no one knew who was getting TP-5 and who the placebo. All the study participants took AZT, and they started out with T-helper cell counts of between 200 and 500. A close review of the data by AIDS TREATMENT NEWS verified that something useful does seem to be happening: For those study volunteers who had been on AZT for longer than six months, protection against early symptoms of HIV infection was apparent, though hard to quantify exactly. In this 235- person subgroup, 14 volunteers on placebo developed symptoms versus only four of those on TP-5. But major questions persist as to the extent of TP-5's beneficial action. An attempt by Johnson & Johnson, TP-5's sponsor, to accelerate FDA approval of the substance was rebuffed when the company sat down with agency officials in December. The corporate push began when the study was terminated four months early by an independent, ad hoc Data and Safety Monitoring Board (DSMB) reviewing the interim figures. Early termination by a DSMB usually occurs because a study has already yielded decisive results. The DSMB's decision on TP-5 sparked loose talk of an impending step forward in AIDS care, similar to the introduction of AZT for early HIV infection. But no dramatic statistical observations underlie the DSMB's reasoning. The board simply noted that the TP-5 trial was dragging on for no reason. It would take another four months to collect the final five percent of the data without any chance that the study's conclusions could be significantly altered. The DSMB noted that the data could be considered unreliable in several respects: % The drop-out rate was rather high, 20 percent in both the placebo and treatment arms. High drop-out rates distort study findings because the volunteers who are doing poorly or who suffer adverse effects from the experimental drug are most likely to be the ones who quit. One of the FDA's requests to Johnson & Johnson was to perform an "intent to treat analysis" on the data. Using this statistical method, the company will have to include the drop outs' experience over the 48 weeks as if they actually continued with the study. We will then have a better picture of how well TP-5 would perform under real conditions, in which patients frequently fail to follow prescribed treatments. % The clinical symptoms used to judge progression of HIV disease were limited and subjective. The criteria required two of the following: 10 percent weight loss, temperature of 38!C for five consecutive days or any 10 days out of any 30, unexplained diarrhea for seven out of any 30 days, just one episode of oral candidiasis, a single localized eruption of herpes zoster, or oral hairy leukoplakia. Confirmation of symptoms was by clinical examination and patient report only; it is possible that some signs of immune decline were misdiagnosed or missed entirely. And other disease episodes not on the trial's list would not be counted, even if they were severe. % There was also a T-helper cell criterion for progression of HIV disease -- to be counted as progressing, an individual's count had to drop below 200. However, there was no difference at all in T-helper cell trends between the study arms. Even in those with more than six months' use of AZT, T-helper cell counts held steady on average throughout the 48 weeks, no matter whether volunteers were on TP-5 or not. Such a finding is at odds with the previous study of TP-5 as an AIDS therapy (published in AIDS, November 1992, pages 1335-1339). That small study did find indications of T-helper cell protection using TP-5, but its volunteers did not use AZT or any other antiviral medication. It may be that the effect of AZT in the current trial overwhelmed and hid any direct support TP-5 gives to T-helper cells. When looking at a summary of the symptoms volunteers developed, we were struck by how much TP-5's observed benefit depends on differences in the rate of occurrence of thrush and oral hairy leukoplakia. This limited difference has led to some criticism in the AIDS activist community that TP-5 merely represents an unnecessary alternative to simpler treatments for these two diseases of the mouth. But there is no reason to believe that TP-5 has any direct activity against these conditions; therefore, if it reduced their incidence, it probably did so by strengthening the immune system, implying that the drug did work as intended. TP-5 seemed to make the biggest difference for people who had used AZT for more than six months. Howard Grossman, M. D., a New York City physician who participated in the TP-5 trial, commented, "Even if TP-5 only does a little, everybody with HIV will be on it if the price is low." (Pricing is an issue because the effective dose of TP-5 costs about $100 per week in Italy, where the substance is legally sold.) According to Robert Kniffen, a Johnson & Johnson spokesperson, the company is now putting together an expanded access program (which will probably be free for those eligible). Dr. Grossman noted that there really is no reason why anyone eligible shouldn't participate since TP-5 has no record of adverse side effects. While the expanded access program is in operation, a confirmatory study involving up to 1,000 people taking antiretroviral therapy together with TP-5 or a placebo will be carried out. Two years will go by before TP-5 can be approved. Robert Kniffen summarized TP-5's current status in this manner: "Details of the confirmatory study and an interim expanded access program are being worked out in consultation with the FDA and the principal investigators. The status of the drug reflects the study data, which are unclear. The trick is to get clear-cut, definitive data." Another Thymus Derivative Trials of other thymus hormone derivatives will also need to show clear data on clinical improvement or viral load, since these substances' effect on T-helper cell counts may not reflect their total activity. At Stanford University, Thomas Merigan, M. D., is conducting a federally-sponsored (ACTG) trial combining thymosin-alpha1 (a thymus hormone derivative), IL-2 (a substance used by the body to stimulate T-cell growth), and the anti-viral drug AZT. Dr. Merigan will use his quantitative polymerase chain reaction (PCR) technique to detect changes in volunteers' HIV levels. Thymosin-alpha1 attracted Dr. Merigan's interest because one preliminary trial in people with chronic hepatitis B provided evidence that thymosin cleared that virus from the body. "Both thymosin and IL-2 affect lymphocyte maturation, but thymosin works at an earlier point, so it may potentiate IL- 2's action," Dr. Merigan explained. Dr. Merigan's study raises the possibility that thymus hormone derivatives may work better in combination with other immune modulators. ***** Clinton: Setting New Directions on AIDS by Keith Griffith What are influential voices in the AIDS community expecting from the Clinton Administration? To help answer this question, AIDS TREATMENT NEWS spoke with a diverse segment of the national AIDS leadership -- from a Nobel prize-winning scientist to one of the most outspoken activists in the United States, from insiders in the Clinton transition team to front-line physicians. Everyone agreed that a Clinton Administration would be more responsive than its predecessors; for some, this was more an indictment of the Reagan/Bush years rather than an endorsement of Bill Clinton. Melanie Thompson, M. D., principal investigator for AIDS Research Consortium of Atlanta, echoed many others interviewed when she said, "Not only is this a significant opportunity, I think it is the only opportunity we have really had in the twelve years of this epidemic." Campaign Themes During the campaign the Clinton team issued a lengthy position paper entitled, "Bill Clinton on AIDS. " Less than a week before the November election, the candidate delivered a speech to a group in Jersey City, New Jersey, on the subject. Both of these publicly delivered documents are at the centerpiece of any discussion about what the new administration is expected to deliver. Among policy moves we may see from Clinton: (1) "Loud, clear, and consistent" leadership on all AIDS issues. To carry this out, the president will appoint one person, an AIDS czar as he phrased it, "to oversee and coordinate all federal efforts related to this issue, a person with my ear, my attention and my support, with the power to cut through red tape and the mandate to get results as quickly as possible." (2) He will appoint a "high-level AIDS task force in the White House to coordinate a federal 'Manhattan Project,'" (referring to the intense scientific/technological project which developed the atomic bomb). (3) "Increase funding both for AIDS-specific and general biomedical research." Furthermore, he stated, "I will not tolerate a business-as-usual attitude towards AIDS research." He called for an expansion of clinical trials including community-based trials and for the National Institutes of Health infrastructure to "be reorganized to streamline its AIDS research efforts, and to increase planning, efficiency, and communication." (4) Finally, the campaign promised a whole series of changes in the delivery of health care which will directly impact people living with HIV. This included guaranteed access to prescription drugs and improved access to experimental therapies. Transition Plans To outline the often-mysterious transition process before Clinton's inauguration, AIDS TREATMENT NEWS spoke with Steve Morin, Ph.D., long-time assistant to Congresswoman Nancy Pelosi (Democrat, San Francisco) and one of the handful of people on Capitol Hill working full time on AIDS. During the transition, Dr. Morin was assigned to the Health and Human Services Transition Cluster Group. While AIDS was not the focus of the group, it was a top priority. Morin offered this explanation of what his group was charged to do regarding AIDS: "First, we had to identify issues that would require high-level attention in the rst 90 to 180 days of the inistration. There are a number of policy issues that need to be reversed from the Reagan/Bush years. Then there were emerging controversies which needed to be identified along with options available in dealing with them. All of this was followed up with other groups on the transition team such as the personnel department in selecting people for posts or the budget group in revising numbers that will replace the 1994 Bush budget." Morin told AIDS TREATMENT NEWS that this work was some of the most satisfying he has experienced in public service. "There is a level of commitment in these people that would have been unthinkable under Reagan or Bush. This administration is determined to address AIDS as promised." The AIDS "Czar" The administration is now referring to this new position as the Special Assistant to the President for AIDS. Transition member Steve Morin confirmed for AIDS TREATMENT NEWS that a decision has been reached to keep this position in the White House. Morin says that the job description is under review. The key issue right now in administration discussions is over whether the Special Assistant will be primarily a policy position or more a public spokesperson. Dr. Thompson believes, as do many in the community, that this job must not be reduced to "a public relations figure, a mere figurehead. The choice for this position will reflect the kind of direction Clinton intends to offer in this epidemic." President Clinton pledged to appoint an AIDS czar who would oversee all components of AIDS, not a scientist who would dole out research grants. This person will probably spend at least as much time dealing with prevention campaigns and other pieces of the AIDS agenda as with research. Dr. Morin sees the Special Assistant as someone who will facilitate cutting across government agencies, for instance getting Immigration and Naturalization talking with Health and Human Services. He says that "this doesn't mean this person is in charge of running all AIDS programs in every branch of government. It is a problem- solving, leadership position." One additional appointment that should be announced by mid- February is the position of Assistant Secretary for Health and Human Services (HHS). Candidates were being interviewed as we went to press. Morin believes that ultimately the person chosen for this post will coordinate many critical AIDS programs at HHS. Funding Levels According to an article in Nature (No. 356, April 16, 1992, page 555), the federal government spends $70 billion annually on science and technology, weighted heavily toward military research and development. The President agreed during the campaign that this country's investment in research and development needed to shift more towards civilian needs, including AIDS research. Activists, taking their cue from the administration, are taking a new approach to funding issues. AIDS activists have begun demanding major increases in all biomedical research at NIH, with a special recognition of extra funding needs for all life- threatening diseases. For the 1994 fiscal year activists and lobbyists are calling upon Clinton to double the entire NIH budget, including a sizable increase for AIDS. The Clinton administration will not release details of possible changes in the 1994 budget until the State of the Union address in mid- February. We asked Terry Beswick, AIDS Research Policy Analyst for the Human Rights Campaign Fund and one of only three people in Washington paid to lobby for research money on behalf of the AIDS community, what to expect from Congress. "Budget issues are going to get worse. Over the last two years, we saw congressional funding for NIH drop below what even Bush requested." Beswick believes that Congress is going to be a major obstacle not only in funding, but also in other AIDS issues. "Congress has long been our obstacle. They have moved far too slowly, and leadership hasn't come unless they were dragged into it by sheer necessity." Beswick added, "What we need now is a groundswell of support for our position that there even is a problem." Larry Kramer, one of the founders of AIDS street activism, believes that what is most needed is not just more money, but a greater willingness to take risks: "To be gutsy doesn't cost a lot of money. Far from it. But just to do things in ways that haven't been done before tends to scare everybody." [Part 2 of this article will examine ideas for improving the organization of AIDS biomedical research.] ***** Political Action Proposal: Cultural Change for Grassroots Electronic Democracy by John S. James AIDS activist organizations could make a major contribution to correcting a serious political weakness which is hurting the fight against AIDS in federal, state, and local issues. The problem can best be illustrated with a non-AIDS issue in the headlines last week: whether openly gay soldiers should be allowed in the U. S. military. Opinion polls consistently showed that the public was about equally divided on that issue, yet phone calls to congressional offices were as much as 100 to one against; this is why Congress has been hostile to the gay soldier. Clearly one side was far better than the other in getting its supporters to contact their representatives. It is striking that the gay community, so excellent in getting to the polls to vote in elections, is so poor in calling their representatives when necessary. Since last year's presidential campaign and election, U. S. political observers have noted an accelerating move toward a kind of electronic plebiscite -- with talk-show formats which bypass reporters, and instant "voting" through phone calls and other means, becoming more important. In this fast-moving forum, issues may come and go in days, leaving lasting traces behind them even as they are replaced by new issues. This kind of direct democracy is not necessarily good or necessarily bad. But both the gay and AIDS communities have had a serious cultural weakness in this political forum -- the widespread reluctance of people to contact representatives and other officials to make their desires known. We believe that political success will increasingly require all of the following: (1) Being right on the merits of the issues. This includes integrating one's efforts with the public interest, so that one is genuinely pulling for the public interest, not only for one's own; (2) Successfully explaining and communicating the issues -- including through coalitions with other groups which agree; and (3) Getting out the vote -- both at the ballot box (which is still the most important), and through phone calls and other contact with officials, as electronic plebiscites develop. Why are people reluctant to pick up the phone and tell their public officials what they want? There are several reasons: (1) In some localities such as San Francisco, many politicians already agree with the AIDS community on most issues, so people think calling is unnecessary. That is a mistake; their representatives need to count the calls which support them, not only those on the other side. The same logic applies in reverse when representatives seem unalterably opposed. (2) People feel they do not know enough to speak publicly on the issues. But their representatives need their vote -- yes or no on a current question -- not a speech or analysis for the busy telephone receptionist. You need only state your position clearly enough so that the receptionist does not accidentally count you on the wrong side. (3) The gay community has a history of needing to be inconspicuous or secretive. This style persists even when not necessary. What to Do Before writing this article, we asked several gay friends and associates if they had called the White House public-comment line (202/456-1111) or called or faxed any of their representatives about the gay-military issue. The results were interesting. No one had called; some were uncomfortable with the thought of doing so. We believe we would have had to ask many more before finding anyone who had made any call on this issue. We suggest that people experiment, as appropriate issues arise, with asking others to make calls (or write letters) in support of the fight against AIDS. Try doing it only when it feels right. If it doesn't feel right, explore why. The White House comment line (number above) may be a good one to start with to help people overcome old habits of reluctance to pick up the phone and make a political call. (The only drawback at this time is that so many people are calling that the number is usually busy. Still, it is important to try, because, statistically, the calls that are completed will represent the ones attempted.) There is usually no problem getting through to the local or Washington offices of your congressional representatives. Any member of Congress can be reached through the Capitol switchboard (202/224-3121), and each also has an individual number in Washington, as well as a local office number in their home district. On federal issues, calls to your three representatives in Congress are usually the most important political calls you can make. AIDS activist organizations should consider the project of training a cadre to not only make the calls themselves, but also to gently confront others they know and get them to start doing so. It might help to print business cards with the numbers most likely to be needed for local and national issues; people can carry the cards so they can call any time. Budget issues (local, state, and federal) will be especially important to address in this way over the coming months and years. But organize first; don't wait for an issue to come along, because when it does, there may be only a few days to respond. The goal is to spark a widespread cultural change in the AIDS and gay communities, so that most people will call or otherwise contact their representatives several times a year or more, for the rest of their lives, as important issues arise. Cultural changes are always difficult, but this one is feasible, since the communities are already political, already very good at voting, and already phone and fax oriented (and note the "phone zap" already in activist use). Some have said that the AIDS community could never turn out political calls and letters as well as the religious right, with its television and radio networks, and its ideology of people doing what they are told in sending contributions of both money and political influence. We do not need to do equally well, but we need to do much better than we have until now. And potentially the AIDS community could respond powerfully indeed. Almost three years ago, a nationwide survey by the Boston Globe (July 17, 1990) found that one American in five personally knew somebody who had AIDS or was HIV positive; undoubtedly many more do today. While AIDS does not have its own television networks to turn out mass responses for an instant issue, we can mobilize in a decentralized way instead, if enough people independently follow the news and spread the word to others when important. A few organizations and committed individuals could help spark a community change to eliminate the greatest political weakness we now have, and help greatly to mobilize the U. S. and the world against AIDS. ***** New CDC Definition Now in Effect, But Confidentiality Questions Remain By Nancy Solomon The new U. S. Centers for Disease Control (CDC) criteria for an AIDS diagnosis -- which now add pulmonary tuberculosis, recurrent bacterial pneumonia and invasive cervical cancer to the previous list of 23 opportunistic infections needed for an official diagnosis -- took effect January 1. The new criteria also include anyone with less than 200 T-helper cells. The CDC definition is important because it affects whether someone with HIV is eligible for social services and also because it alerts doctors to test for HIV when someone has a condition on the official list. While most government and non-government agencies use the CDC definition to determine whether or not they provide services, the Social Security Administration will not change its requirement that an applicant for disability benefits must show actual physical disability. Activists had pushed for the change because the former list excluded many of the opportunistic infections common among women, injection drug users and poor people. The changes represent a compromise between the activists and the CDC. The new definition is expected to double the number of AIDS cases in the United States. But several thorny legal and political issues have made the long sought changes more of a mixed blessing. The new criteria are expected to send some state public health officials rummaging through patient records to boost their caseload statistics so that their states can receive more federal funds. This pr, legal advocates say, willdermine patient confidentiality, leading to fewer people seeking testing and an eroding of HIV confidentiality standards. "Despite extensive advocacy directed at the CDC requesting a bar on name-based lab reporting of low (T-helper cell) counts, we find that we are forced to fight this battle on a state-by-state basis," says a memorandum from the AIDS Legal Referral Panel in San Francisco. Legal advocates are asking that activists fight name-based reporting of T-helper cell counts at the local level. The new definition also raises questions about access to T- helper cell testing, which can cost $100-$200, beyond the means of most people without health insurance. Lack of access to testing will continue to perpetuate undercounting of the epidemic and lack of HIV services among women, people of color, and the poor. Legal advocates also ask that activists pressure local government agencies to provide anonymous T- helper cell testing to all who need it. For a copy of the new definition, contact the CDC National AIDS Clearinghouse, 800/458-5231; or for more information about the legal and political impact, call the AIDS Legal Referral Panel, 415/291-5454. ***** CMV Experimental Treatment Overview, Part II by Giacomo Palazzolo Note: Part I of this article, published in AIDS TREATMENT NEWS #167 (January 15, 1993), looked at ganciclovir in combination with G-CSF or GM-CSF, at ganciclovir eye implants, and at oral ganciclovir. Foscarnet Foscarnet (brand name Foscavir) was the second drug approved for treating CMV retinitis in persons with AIDS. In the U. S., government approval came only after much work by AIDS treatment activists; in Europe, however the drug had long been used often as first-line therapy. Foscarnet is also active against other herpes viruses, and to a limited degree against HIV. It is currently being tested in clinical trials as a treatment for CMV colitis, acyclovir-resistant herpes simplex, and herpes zoster infections. Risks of foscarnet include kidney toxicity, electrolyte abnormalities, anemia, and penile ulcerations. Individuals taking foscarnet must be carefully monitored by an HIV-knowledgeable physician for these side effects. One of the advantages of treatment with foscarnet is that there seems to be a survival benefit greater than treatment with ganciclovir. This may be due to its antiviral activity against HIV. In one study of 234 people with CMV retinitis, average survival was 12.6 months compared to an average survival time of 8.5 months for those treated with ganciclovir. ("Mortality in Patients with the Acquired Immunodeficiency Syndrome Treated with Either Foscarnet or Ganciclovir for Cytomegalovirus Retinitis." Studies of Ocular Complications of AIDS Research Group, in collaboration with the AIDS Clinical Trials Group. New England Journal of Medicine, January 23, 1992, volume 326 number 4, pages 213- 220.) Currently, foscarnet is given intravenously. An oral form has been developed, and a single-dose pharmacokinetic study has been completed in Europe. A phase II trial in Europe is expected to start this spring. Combination Therapy with Foscarnet and Ganciclovir Ganciclovir- and foscarnet-resistant strains of CMV eventually develop when these drugs are used, and disease progression takes place. Combination use of the two drugs is now being tested to see if it can delay these problems. AIDS TREATMENT NEWS spoke with Mark Jacobson, M. D., Clinical Professor of Medicine at the University of California in San Francisco, who is conducting a phase I clinical trial of this combination. He told us that the study is for maintenance therapy, after an initial occurrence of CMV retinitis has been treated with an induction therapy of ganciclovir. The 30 patients enrolled in this trial were randomized to maintenance therapy with either daily alternating regimens of ganciclovir and foscarnet, or concurrent therapy with both drugs. According to Dr. Jacobson, "the time to progression of CMV retinitis in the interim analysis was similar in the two groups -- ganciclovir and foscarnet combined vs. ganciclovir and foscarnet alternating. Based on our data, and we are still following a number of these patients, it looks like the alternating regimen may be better than the combined one because there is not a big difference in time to progression; therefore the simpler regimen with only one infusion per day would require less infusion time than the combination regimen." One German study presented at the VIII International Conference on AIDS in Amsterdam reported on the treatment of several patients with CMV retinitis who received both drugs (B. Salzberger and others, abstract #PoB3253). IVIG (Intravenous Immune Globulin) Gamma globulin is a blood product containing antibodies pooled from various blood donors. It gives the recipient a passive immunity by increasing the amount of antibodies to CMV (or other infections). There are many different preparations of IVIG, including some prepared specifically for CMV. Side effects of IVIG rarely occur, although there may be pain at the infusion site, headache, and malaise. Standard IVIG preparations, although not made for anti-CMV use, may have varying amounts of anti-CMV antibodies, depending on the donors of the blood used in each batch. A representative of Baxter Pharmaceuticals we spoke with said that a physician could request a preparation of Gammagard (Baxter's brand of IVIG) with higher than average concentration anti-CMV antibodies. A clinical trial is presently being conducted at Georgetown University Medical Center comparing the efficacy of ganciclovir plus IVIG to that of ganciclovir alone. In this pilot study, 20 people with CMV retinitis were given IVIG five times during the ganciclovir induction. During maintenance therapy they received IVIG weekly. According to Princy Kumar, M. D., the treatment "was extremely well tolerated. Nobody had to be withdrawn because of any complications related to the IVIG. " The efficacy data is still being analyzed and will probably be available early in 1993. While it is unknown whether or not IVIG can penetrate the blood-retinal barrier (to reach the retina and the CMV infection there), it penetrates into the cerebral-spinal fluid well and this is an indication that it may also cross the blood- retinal barrier. CMVIg CMVIg [Cytomegalovirus Immune Globulin Intravenous (Human), brand name Cytogam] is an IVIG preparation which is specially made to contain high concentrations of antibodies against CMV. It is manufactured by the state of Massachusetts, and is approved by the FDA for use in the prevention of CMV disease in kidney transplant patients. Unfortunately, it was not studied in HIV- infected individuals until recently, so it is only available off label, by prescription, from the American Red Cross. CMVIg is currently being studied for preventing CMV disease in persons with HIV. A phase I safety study for HIV-infected individuals with positive CMV blood cultures is being conducted at the National Institutes of Health in Bethesda, Maryland. The dose used in this trial is 150 mg per kilogram of body weight every two weeks or every four weeks. This trial has enrolled nine persons to date. One volunteer may have developed CMV colitis on the trial. CMVIg is generally well tolerated, though side effects include chills, muscle cramps, and fever. Unfortunately this treatment is expensive, and because HIV use of this preparation is off label, patients are unlikely to be reimbursed by Medicaid or by their insurance companies. The cost for 2.5 grams of this preparation is approximately $300 per vial, so a person of average weight who used the same dose as in the above trial would need to spend about $1000 per intravenous infusion, not including the cost of administration. MSL-109 MSL-109 is a genetically engineered monoclonal antibody against CMV. A small phase I/II of ganciclovir with MSL-109 is being conducted at Massachusetts General Hospital. The study began in early 1990 and so far has enrolled seven individuals with CMV retinitis. There is still one more slot for someone recently diagnosed with CMV retinitis who has done induction therapy with either foscarnet or ganciclovir. MSL-109 seems well tolerated, although it is unclear whether the combination is effective at slowing the time to progression in CMV retinitis patients. TI-23 TI-23 as another anti-CMV monoclonal antibody. Results of a small human trial at the University of Arizona were presented at the 1991 International Conference on AIDS [abstract #W. B. 2291]. The researchers concluded that the treatment was well tolerated, and that CMV retinitis progression data was favorable compared with historical controls. We do not have recent information. HPMPC HPMPC is a broad spectrum antiviral active against many herpes viruses, including CMV. It is presently in phase I/II testing in San Francisco, and at the National Institute of Health in Bethesda, Maryland. The current trials are with HIV-infected individuals who have no symptoms of CMV disease, but are at risk for developing it because they have positive CMV urine cultures. Gilead Sciences, the pharmaceutical company developing HPMPC, announced on December 1, 1992, that preliminary data showed evidence of anti-CMV activity in the phase I/II trial. According to Jay Lalezari, M. D., who is conducting the trial at Mt. Zion Hospital in San Francisco, "HPMPC has shown unprecedented efficacy in reducing titers of CMV in urine and semen. Our only concern is its potential for kidney toxicity. We are currently recruiting ten more individuals to study the role of probenecid, a drug we believe will protect the kidneys from toxicity. Assuming we have a therapeutic window [a dose which is effective but not too toxic to use], we should have a treatment protocol available by this summer." Persons interested in volunteering for this study can call Dr. Jay Lalezari, Mt. Zion Hospital HIV Clinical Research, 415/476-6356. [Note: AIDS TREATMENT NEWS is preparing a longer article on HPMPC, and on PMEA, a potential drug which is chemically related to HPMPC but has both anti-CMV and anti-HIV effects.] Acyclovir; BW256 Acyclovir has very little effect against CMV, but some HIV- infected individuals with low T-helper cells have tried to prevent CMV disease with high-dose acyclovir. A major clinical trial at 19 centers in Europe and Australia for individuals at risk for developing CMV disease has found that taking 800 mg of acyclovir four times a day failed to stop progression to CMV disease. However, there appeared to be a survival benefit for the group treated with acyclovir. (There is some controversy among physicians about this conclusion, since no one is sure how the drug might be working.) According to Kenneth Mayer, M. D., Director of the Brown University AIDS Program and Research Director of the Fenway Community Health Center, the "acyclovir may be acting in several ways that may preserve life. Laboratory tests have shown that if you add herpes simplex or CMV to cells which were previously latently infected with HIV, the co-infected cells can be activated and produce HIV. " A new drug being developed by Burroughs-Wellcome, BW256, is rapidly turned into acyclovir when metabolized by the body. Blood levels of BW256 reach three to four times that of oral acyclovir, making it a better candidate than acyclovir for CMV prophylaxis. A phase I safety trial using this drug in HIV-infected individuals with less than 150 T-helper cells is currently underway at Johns Hopkins, and a protocol for an efficacy trial is being developed. At this time it is not certain whether the possible anti-CMV efficacy or a possible survival benefit will be studied. Etoposide (VePesid or VP-16) Etoposide is an agent approved for use as a cancer chemotherapy; it is currently being tested for treating AIDS- associated Kaposi's Sarcoma (KS), and with other chemotherapies for treating AIDS-associated non-Hodgkin's lymphoma. Side effects of this drug include severe bone marrow suppression, nausea, vomiting and hair loss. In the test tube this drug can "turn off" the CMV virus by inhibiting an enzyme (topoisomerase- 2) found in the cells. Nobody knows what dose might be used to achieve the drug level which showed anti-CMV effect in the test tube studies. AIDS TREATMENT NEWS interviewed one person with AIDS who tried, with his physician, to find an effective dose. This person had no CMV disease, but was at risk because of low T- helper cell count and positive blood and urine cultures for CMV. After taking etoposide, he lost all of his hair, and his hematocrit level fell dangerously. He felt very ill from the toxic effects of the drug, and went off etoposide after about one month. In his case the blood culture and urine culture for CMV remained positive. Despite this one anecdotal case where the treatment appears to have failed, this drug should be studied further for possible use in treating CMV. Perhaps data collected in the clinical trials of etoposide for KS and for lymphoma d be analyzed to see if t is any anti- CMV effect in these patients, who will be taking the drug anyway. Hypericin Hypericin is a compound derived from the herb St. John's wort, and in test tube studies shows activity against both HIV and CMV. A synthetic form of hypericin has also been manufactured. There have been no clinical trials using hypericin for CMV disease, and we have not heard of anyone trying it for this purpose. An early trial of hypericin as an HIV treatment is underway. [Note: for more information about hypericin as an experimental antiviral, see AIDS TREATMENT NEWS # 146, February 1992]. Notes: (1) Other CMV drugs are in preclinical development. We did not include them in this article because they are not yet in human use, and we have little information about them at this time. (2) For background on CMV, see "CMV Infection," by Douglas Dieterich, M. D., in PAACNOTES, October 1992. This article includes 34 literature references. It only covers the FDA- approved CMV treatments, ganciclovir and foscarnet. ***** Correction: ddI vs. AZT In our last issue (#167), in the article, "ddI vs. AZT: New Results, No Press," the fourth paragraph on page two should have read: "However, among 118 people with 8-16 weeks of prior AZT use, one year progression rates were 11 percent for 500 mg of ddI, 17 percent for 750 mg, but 33 percent with AZT -- a statistically significant advantage for ddI. " The phrase '500 mg of ddI' erroneously appeared as '500 mg of AZT'. The error was not the fault of the author, but was introduced later during editing. ***** Announcements ** Therapeutic Vaccine Conference, New York, February 11-12 About a dozen leading AIDS vaccine researchers will gather on February 11-12 for The 2nd Annual Forum on HIV Vaccine and Immune Therapies, cosponsored by the Gay Men's Health Crisis (GMHC) and the Community Research Initiative on AIDS (CRIA). Scheduled speakers include Robert Redfield, M. D., Fred Valentine, M. D., Allan Goldstein, Ph.D., Ronald Desrosiers, Ph.D., Martha Eibl, M. D., and Bernadine Healy, M. D. The conference will be at The Marriott Marquis Hotel, Westside Ballroom, 45th and Broadway, New York City. For more information, call CRIA, 212/924-3934. ** Liposomal Daunorubicin for Advanced KS: Limited Expanded Access Program Liposomal daunorubicin, a treatment which may be a significant advance over other chemotherapy for treatment of Kaposi's sarcoma, is currently in phase III clinical trials, and will also be offered without charge to patients with advanced KS who are not eligible for the trials and who have failed other chemotherapy, through designated physicians in New York, Los Angeles, and San Francisco, and possibly also in Miami and Chicago. This program is limited because of short supplies of the drug. Conventional daunorubicin is approved for treating leukemia, but has severe toxicities and can damage the heart and other organs. In the liposomal form of the drug, the daunorubicin is trapped in microscopic spheres composed of certain fats. In this form, the drug is selectively absorbed by the abnormal cells in the KS lesions, allowing high doses to be used with little toxicity. According to information released by Vestar, of 75 patients with advanced KS who had failed conventional therapy, 60 percent improved on liposomal daunorubicin, and most of the rest remained stable; fewer than five percent of the patients got worse. Liposomal daunorubicin (brand name DaunoXome() is also being tested as a treatment for certain solid-tumor cancers not related to HIV. The developer, Vestar, Inc., of San Dimas, California, worked with ACT UP/Golden Gate in San Francisco, and with ACT UP/New York, in setting up this program. Andy Zysman, M. D., of ACT UP/Golden Gate commented: "It has been very gratifying for us to be able to work so cooperatively with a company to achieve our common goal: namely, for patients to gain access to a new drug as soon as its efficacy has been demonstrated in clinical trials. Vestar's role in this process has been a model for the industry, and we're looking forward to weaving a close partnership among physicians, patients, and the company. The limited drug supply remains a problem, and we hope that the company can expand the program as the need becomes evident." For more information, contact the DaunoXome Study Center, 800/247-3303. ** Sarasota Clinic Seeks Medical Director The Comprehensive Care Clinic, Inc., in Sarasota, Florida, is seeking a medical director. Full-time responsibilities include medical examinations, clinical drug trials, and ARNP supervision. Internal medicine, family practice, or infectious disease specialist preferred. Send resume to: Comprehensive Care Clinic, 150 East Ave. So., Sarasota, FL 34237, phone 813/366- 0461. ***** AIDS TREATMENT NEWS Published twice monthly Subscription and Editorial Office: P. O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U. S. and Canada 415/255-0588 regular office number 415/255-4659 fax Editor and Publisher: John S. James Medical Reporters: Jason Heyman John S. James Nancy Solomon Reader Services and Business: David Keith Thom Fontaine Tadd Tobias Rae Trewartha Statement of Purpose: AIDS TREATMENT NEWS reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $230/year. Nonprofit organizations: $115/year. Individuals: $100/year, or $60 for six months. Special discount for persons with financial difficulties: $45/year, or $24 for six months. If you cannot afford a subscription, please write or call. Outside North, Central, or South America, add air mail postage: $20/year, $10 for six months. Back issues available. Fax subscriptions, bulk rates, and multiple subscriptions are available; contact our office for details. Please send U. S. funds: personal check or bank draft, international postal money order, or travelers checks. VISA, Mastercard, and purchase orders also accepted. ISSN # 1052-4207 Copyright 1993 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used. -- ben@maggadu.QueerNet.ORG AIDS Info BBS 415)_626-1246 free since July 25, 1985