Treatment Issues - Vol. 9, No. 7 - July 1995 -------------------------------------------- Published by Gay Men's Health Crisis, New York, NY -------------------------------------------- Contents The Changing Treatment Options for CMV Retinitis Testing for CMV in the Central Nervous System Finding Support for AIDS-Related Vision Problems CDC Report on Waterborne Cryptosporidiosis Treatment Briefs New Developments in Kaposi's Sarcoma Liposomal Chemotherapies KS Virus Controversy X-Rays for Monitoring Opportunistic Infection Washington Watch CDC Recommends HIV Testing for All Pregnant Women ************************************************ The Changing Treatment Options for CMV Retinitis by Dave Gilden Cytomegalovirus (CMV) is a major opportunistic infection of people with advanced AIDS, affecting a fifth of those with helper T-cell counts below 50. CMV's most common target is the retina -- the light-sensitive tissue at the back of the eyes that sends what we see to the brain. If left untreated, CMV infection of the retina ("CMV retinitis") causes blindness in the affected eye 90 percent of the time. The standard therapies for CMV retinitis are very burdensome for patients. They involve expensive one- or two-hour infusions through a tube (catheter) permanently inserted into a chest or arm vein. The two medications used -- ganciclovir and foscarnet -- are both very toxic. Ganciclovir suppresses the bone marrow's production of red blood cells, neutrophils and platelets, leaving patients prone to anemia, bacterial infections and bleeding. Foscarnet commonly impairs kidney function, and this disrupts the body's electrolyte balance. The consequent low calcium levels can provoke nerve malfunction (tingling and numbness) and, occasionally, seizures. There is also a danger of outside bacteria spreading along the catheter and into the bloodstream. The rate of infection was 0.2 per 100 days on catheter in one survey.[1] During the first, or induction, phase of therapy, infusions take place two or three times daily. This suppresses but does not eliminate the CMV. A life-long maintenance phase is then necessary, which involves once-a-day infusions. But the CMV lesions in the eye inevitably start spreading again after three or four months. The current medical response to renewed CMV is to return to induction therapy, possibly switching to the other drug. "Everybody pretends that we have therapies for CMV, but they are not working. Despite ganciclovir, people are going blind. There is progression within a few months," said Kevin Frost in summing up the current situation. Frost, a long-time activist on issues related to CMV retinitis, is director of the Community Based Clinical Trials Network at the American Foundation for AIDS Research. This is the old paradigm, which is set to change radically. Within the next twelve months, companies expect to file for FDA approval of four new anti-CMV medications, and these will radically alter the treatment landscape. Reflecting the new expectations, Claudette Lajam, trials coordinator at a New York City ophthalmology practice, says, "If your T-cell count gets near 100, go and get screened for CMV by an ophthalmologist rather than wait until you notice visual deterioration. Before there was no need to screen because all it would mean is that you would be catheterized three months early for some itty-bitty infection that wasn't sight-threatening. Now, no one need go blind from CMV if we catch it early enough and control it. We have new tools every day, and if one stops working, we can switch to another." These therapies unfortunately have to work with less and less help from the immune system and therefore threaten to be less and less effective with passing time. Each therapy also brings with it a set of specific issues ranging from side effects to drug resistance that limit its usefulness and can interfere with succeeding or concurrent treatments. What works in one patient may not work in another. The evolving complex treatment mosaic will require skillful manipulation by physicians and people with AIDS. Below, we examine the pros and cons of the new developments in CMV and see how they fit together. Ganciclovir Implants One of the inherent problems of systemic therapy for CMV retinitis is that the blood-retina barrier, which is similar to the blood-brain barrier, allows only a small amount of medication to attain its target in the eye. One study examining how much ganciclovir reached the eye after intravenous infusions[2] found that the concentration in the eye's vitreous humor (the jelly-like region between the retina and the lens) was below that needed to inhibit CMV replication. This was true even with twice a day infusions. The investigators commented that the suboptimal level of ganciclovir in the eye may explain the drug's borderline efficacy. It may also explain the frequent emergence of ganciclovir-resistant CMV during treatment: In another study, 38 percent of patients receiving ganciclovir for more than three months were found to have resistant CMV.[3] The way to get more drug to the eye is through localized therapy. Intraocular injections of ganciclovir directly into the vitreous humor have been tried for some time, but their usefulness is limited because they require a twice a week regimen likely to irritate the eye. A better way is the time-release implant, which Treatment Issues described in December, 1994 (page 1-2) and March, 1995 (pages 4-5). Chiron Vision, the implants' developer, filed for FDA approval of the devices on July 5. In the trials, a single implant delayed CMV retinitis progression (as defined by growth of the lesions on the retina) by six to eight months, compared to a delay of only two months for intravenous ganciclovir. Some recipients have now gone for up to eighteen months without reactivation of their CMV by receiving repeat implants. Until the implants are approved, those who are failing or intolerant of the traditional CMV therapies can obtain them through an open- label protocol. For details, call Chiron at 800/244-7668. The implants seem like a great advance, but as more experience is obtained through the open-label protocol, some of their drawbacks have become more evident. Joseph Eviatar, M.D., a New York City ophthalmologist with a large AIDS practice, commented, "I hoped the implants would be revolutionary, but there are too many complications. But we're using them 'on the late side,' with very advanced patients." The first problem is that the implants do not work at all with a few people, probably due to ganciclovir-resistant CMV bred by prolonged exposure to intravenous ganciclovir. In more patients, progression returns after only five or six months. The early relapse may be due to the implants running out of drug earlier than expected. Frequent eye exams are still necessary for individuals who have implant. Possibly too, those with sight-threatening lesions (near the center of the retina) should have their implants replaced at intervals shorter than the current norm of eight months. The objection to earlier replacements is that the procedure is a delicate operation. Installing an implant requires making a small slit through the white part of the eye (sclera) and stitching the plastic capsule onto the inside wall. The risk is that the procedure might cause retinal detachment by disturbing the vitreous humor's support of the retina. The implant trials did record a number of such incidents (in eighteen percent of eyes with implants during one study), but those with CMV retinitis frequently experience spontaneous detachments due to the disease. According to one of the investigators, Daniel Martin, M.D., of Emory University in Atlanta, "The retinal detachment issue remains unresolved." He holds out the hope that "the reduced CMV progression may offset the risk of detachment from the implants because a smaller surface of the retina will be diseased." The installation procedure nonetheless is a significant insult to an already weakened eye, and the threat of retinal detachment must be taken seriously, even though it is treatable. A more mild symptom of the disruption caused by the procedure is the vision blurring that persists for several weeks afterward. This blurriness makes it impossible to put implants in both eyes at the same time. A longer-lasting (eighteen months to two years) version of the implant is under development which presumably would minimize many of these problems. As Dr. Martin put it, "Eliminating a surgical procedure would be a kinder thing for the eye." Another issue would persist, though. That is the question as to whether local therapy alone is enough to control CMV, which not only can infect the other eye but also many other parts of the body. For example, one recent paper noted that upon autopsy, half the people with retinal CMV also have detectable CMV in their brains.[4] In the largest study of the implant, extraocular CMV disease occurred in twelve percent of the people receiving the implants compared to none of the people in the intravenous comparison arm.[5] There also was a high rate of CMV spread to initially uninvolved eyes during the trial, with those on the implant tending to have a worse experience than those on IV ganciclovir here too. Chiron Vision itself now warns that people receiving its implants should have concurrent systemic therapy. But if systemic intravenous therapy is needed to control breakthrough infections, is there a point to the implants? Well, yes because the existing retinitis is clearly better suppressed, but part of the quality of life and economic advantages to the implants are nonetheless lost. Oral Ganciclovir An alternative to intravenous therapy is the new oral form of ganciclovir, which was approved by the FDA last winter as a maintenance therapy between courses of intravenous induction therapy. "The implant plus oral ganciclovir would be an advance," said Dr. Eviatar. Indeed, there is just such a trial under way, comparing the implant plus oral ganciclovir to the implant alone to intravenous ganciclovir in people with stable, early (less than six months) CMV retinitis in one eye. (This trial is still enrolling. Interested parties should contact Roche Bioscience -- formerly Syntex Laboratories -- at 800/526- 6367.) Oral ganciclovir faces the hurdle of reaching the bloodstream from the digestive tract, which absorbs it very poorly. As a consequence, blood levels are somewhat lower and time to CMV progression is less than with intravenous ganciclovir. In the one published trial6 comparing the oral and intravenous formulations, mean time to progression was about twenty percent less for the oral group. Interestingly, the incidence of extraocular CMV (almost zero in this twenty week study) or CMV appearing in the uninvolved eye (eleven to twelve percent) was about the same in both groups. Oral ganciclovir alone might be worthwhile therapy only in those with inactive, CMV outside the all-important central retina zone, but it might be of greater use when combined with the implants. (Oral ganciclovir might also be more effective at a higher dose, if the digestive tract can tolerate it. Such studies are now underway. One, a European study comparing daily doses of three grams and six grams, is now having its data analyzed.) In May, Syntex (now Roche Bioscience) submitted a supplemental application to the FDA for clearance to market oral ganciclovir as a CMV preventive for people with AIDS. To support this prophylactic indication, Syntex submitted results from a trial that found that over eighteen months, oral ganciclovir reduced the rate of CMV retinitis from 39 percent to eighteen percent. (The detected occurrence of other CMV disease was only a few percent, and the effect of oral ganciclovir on the rate of extraocular infection was not statistically significant. See Treatment Issues, October 1994, page 9 for details on this trial and a related, problem-plagued trial sponsored by the Community Programs for Clinical Research on AIDS (CPCRA), which found no difference between oral ganciclovir and placebo in preventing CMV retinitis.) Why so many trial participants on oral ganciclovir developed CMV retinitis is a matter of debate. Many observers are afraid that suboptimal blood levels of the drug are encouraging the evolution of resistant virus. Kevin Frost is probably most opposed to the use of ganciclovir as prophylaxis. He said, "Oral ganciclovir is my worst nightmare. It is a resistance breeder. Only 20 percent in trial got a benefit from drug. Why treat everybody then? Widespread CMV resistance will be a devastating problem for HIV and organ transplant communities." Physicians such as Daniel Martin are worried that popular use of prophylactic ganciclovir will reduce the effectiveness of ganciclovir implants. Lawrence Drew, M.D., a San Francisco investigator who contributed to the Syntex trial, grants that drug resistance is a real concern with oral ganciclovir. Drug resistance data from the trial are now being analyzed and may be presented at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this September. Dr. Drew argues, though, "The breakthrough infections were most likely due to either lack of compliance on the patient's part or poor absorption. Resistance was probably not the reason." (Since February, Syntex/Roche Bioscience has made available an open label safety study that provides free oral ganciclovir for preventing CMV in HIV-positive, CMV-positive individuals with CD4 counts less than 50 and no active CMV disease. Enrollment has been very slow. As of July, just 132 of the 5,000 allotted slots had been filled. Oral ganciclovir is available at pharmacies, officially only for maintenance therapy, and physicians apparently prefer simply to prescribe the drug for prophylaxis and avoid the study's paper work. Third-party payers are reimbursing for this off-label use even though the price is a hefty one -- $39 a day wholesale. Those who cannot afford this expensive product can call the Roche Bioscience Study Center at 800/569-4630 for information on enrolling in the open-label study, which will continue until ganciclovir is approved for primary CMV prevention.) Cidofovir (HPMPC) One way to avoid ganciclovir overuse is to try another drug. William Freeman, M.D., of the University of California San Diego believes that he has found just such a method using intraocular injections of the highly active experimental antiviral drug cidofovir (HPMPC). Dr. Freeman has pioneered this field by himself. He now injects tiny amounts -- twenty micrograms -- of the long- lasting cidofovir every six weeks into the vitreous humor of patients' eyes. The results, he says, "are unbelievably good." Freeman claims that he has seen no progression of CMV retinitis in his patients, now numbering more than 70 persons who have received a total of 223 injections. The patient treated the longest has had ten injections, amounting to 60 weeks of treatment. Originally there were problems with eye irritation (vitritis) and loss of pressure in the eyeball (hypotony), but Dr. Freeman reports that the present low dose avoids most of these events. There remains the issue of cidofovir-resistant CMV -- and this resistance could be due to foscarnet as well as previous exposure to cidofovir. Strains with mutations rendering the virus cross-resistant to foscarnet and cidofovir occur, so prior foscarnet therapy might sometimes make the cidofovir injections ineffective. Dr. Freeman says that he has not had any problem with resistance. In the eye, "we hit the virus with an overwhelming amount of drug," he claimed. While Dr. Freeman waxes enthusiastic over his discovery, other experts are more cautious. The words "little data" come quickly to everyone's lips. Dr. Freeman is the only person in the world now treating CMV retinitis with intraocular cidofovir. He has just published the results from the first 52 injections in 33 patients.[7,8] The lack of available data is hardly Dr. Freeman's fault. The owner of U.S. rights to cidofovir, Gilead Sciences, located south of San Francisco, has consistently refused to support the San Diego research. (Freeman's supply of cidofovir comes from an independent European source.) Now, in the aftermath of the published articles, Gilead says it will undertake a preliminary dose-ranging trial of intraocular cidofovir. Dr. Freeman, meanwhile, is scrambling for funds to launch a pivotal randomized trial with 30 to 40 volunteers, which would provide enough data by itself, he says, to apply to the FDA for marketing clearance. Dr. Freeman is also working on a more stable version of the therapy in which the cidofovir is encapsulated in liposomes (fat globules). Such a formulation might allow for thrice yearly injections and be clearly superior to the present ganciclovir implants. Gilead in the past few years has preferred to concentrate on investigating cidofovir's use as a systemic, intravenous therapy. Howard Jaffe, M.D., Gilead's director of research, says, "We are a small company with no revenue. Our intraocular studies were delayed because we gave priority to developing a systemic drug for the systemic aspect of CMV." Cidofovir lasts so long in cells that infusions for systemic therapy can be relatively infrequent. Intravenous cidofovir is infused once weekly for the first two weeks and every other week thereafter. Doses used are on the order three to five mg per kilogram of body weight. (The total intravenous dose of several hundred milligrams is easier than the intraocular version's mere twenty micrograms to market at a profitable price, note the cynics.) Systemic therapy may be important, but intravenous cidofovir turned out to have life-threatening kidney toxicities that delayed research. This spring, two reports demonstrated that intravenous cidofovir could be more safely administered along with probenecid, which modulates kidney function but has its own side effects, and intravenous prehydration.[9,10] These measures did not interfere with cidofovir's dramatic reduction of CMV shedding in the urine, the investigators said. Right now, intraocular cidofovir is only available through Dr. Freeman's clinic in San Diego. His patients must be off systemic therapy and come in every two weeks for evaluation. Dr. Freeman argues these restrictions are necessary to clearly document the injections' effect, but they represent a serious obstacle to those desiring the injections for their personal treatment. In a month or two, Gilead finally will commence an intraocular dose-ranging trial, largely repeating Dr. Freeman's work. It will take place at five sites: three University of California campuses (Irvine, Los Angeles and San Francisco), Emory University in Atlanta and Georgetown University in Washington, D.C. Once again, participants may not have extraocular CMV and will not receive systemic therapy. Gilead expects to apply to the FDA for marketing approval of intravenous cidofovir by the end of the year. At present, the IV formulation can be obtained in three ways. There are two on-going randomized trials: the government-sponsored ACTG 281 and Gilead's own phase II/III trial. Both of these trials are for people with early CMV retinitis without prior therapy and include a comparison arm whose treatment is deferred until the CMV retinitis lesions progress. The trials' goal is to measure the extent to which cidofovir delays progression. There is also a study for people with relapsing CMV retinitis who have failed or are intolerant of ganciclovir and/or foscarnet in which everyone receives immediate cidofovir. The company is also working with the FDA to initiate a TIND (expanded access) program for cidofovir in people who have failed the standard treatments and cannot participate in a clinical trial. More information on access to cidofovir can be obtained by calling Gilead at 415/573-4700. The company also will soon commence trials on a less toxic variant of cidofovir, and an oral version of this variant is under development, too. ISIS 2922 Another new intraocular option is ISIS 2922, produced by the Isis Pharmaceuticals outside of San Diego. 2922 is a novel sort of drug that involves "antisense" RNA technology. It consists of RNA made of sequences complementary to those produced by the CMV genes integrated into an infected cell's genetic material. CMV messenger RNA directs the cell's metabolic machinery to produce new virus particles, but 2922 locks onto a specific portion of that RNA, rendering it inoperative. ISIS 2922 is given by intraocular injection once per week for the first three weeks and then biweekly thereafter. A year ago, Isis reported the initial successful results with its drug (see Treatment Issues, May, 1994, page 5), and the company seemed to be charging ahead, with ISIS 2922 set to become the first commercial antisense medication. Phase III trials commenced last December, and Isis had hoped to file for FDA approval sometime in 1996. Unfortunately, the development of 2922 has hit a snag. As many as five of the participants already enrolled in trials have developed a stippling, or spotting, on their retinal surface. Four of 23 treated eyes also suffered losses in peripheral vision. These effects could be due to some previously unnoticed drug toxicity. Isis temporarily halted enrollment in two of its trials while it reviewed the situation. A third trial has remained open. It is an open- label protocol for people who have failed on previous therapies. In July, the company announced that it was preparing to resume its trial in people with early CMV retinitis without prior treatment. The biweekly injections of ISIS 2922 were being reduced to 75 micrograms from 300 micrograms and would be increased as the drug's safety was established. The company also was considering redesigning a second trial, which tested ISIS 2922 in combination with ganciclovir in more advanced patients, to also include a gradual dose escalation -- and the use of oral ganciclovir as well. The company reportedly is betting heavily on the effectiveness of the combination of intraocular 2922 and systemic oral ganciclovir in preventing CMV relapse. Further information on the trials' status may be obtained by calling the Isis hotline at 619/929-3898. (Note that a call to this number produced a response that there is no "compassionate use" program for ISIS 2922. Ask about trial CS7 for treatment failures with advanced disease.) ISIS 2922 has been a particularly interesting drug because it attacks CMV by a wholly different method than other CMV treatments (which attempt to terminate replication of the viral DNA gene set within infected cells). Because of its unique character, the Isis compound is not subject to the same type of resistance as the other drugs. CMV resistant to 2922 has not emerged in laboratory tests, although it is possible in principle. Claudette Lajam says that her office has seen real vision improvement in some, but not all, patients on the drug. This clinical improvement may be due to reduced nerve membrane swelling as the CMV infection subsides or perhaps new synaptic connections that compensate for dead tissue. She says that the drug is "best for smoldering CMV [i.e., not too advanced and only very slowly progressing]. It is very promising, especially as an adjunct therapy. There is probably a need for systemic treatment. We haven't had enough follow-up yet to see how it works on its own." Another Type of Systemic Backup ISIS 2922 is not a candidate for systemic therapy because of the compound's cost and instability in the bloodstream. Cidofovir would seem a better candidate, but its present form, at least, has some serious side effects that make many people hesitant. There is also a risk that CMV resistant to either therapy will emerge, ruining that drug's usefulness for local therapy. To have a more complete arsenal against CMV requires a relatively nontoxic systemic drug that preferably acts in a different manner than the localized therapy. An attractive alternative systemic treatment under development is MSL 109, a human monoclonal antibody against CMV. Monoclonal antibody treatment consists of a purified concentrate of a single human-type antibody that has strong neutralizing activity against a particular virus. It is produced in laboratory culture by a special hybrid cell fused with a human B lymphocyte found to produce an antibody with the desired properties. MSL 109 is about to undergo testing in two extensive human trials (ACTG 266 and ACTG 294) involving a total of nearly 500 persons. These trials will try out the antibody in combination with approved CMV treatments, i.e., ganciclovir, foscarnet and, when approved, ganciclovir implants. Observation of participants will continue for a year. (For more information, call the government trials hotline at 800/TRIALS-A.) Decisive data on MSL 109 will not be available for several years. This wait may be unavoidable, but it represents yet another holdup in the long development of the antibody, which was originally created by Sandoz Pharmaceuticals back in the eighties. Sandoz sponsored initial human trials of MSL 109 some six years ago. It then decided to get out of this area of research and eventually sold its experimental line of antiviral monoclonal antibodies to Protein Design Labs, a small company located south of San Francisco, in April of 1993. Protein Design Labs has spent the last two years revamping the manufacturing process for MSL 109 in preparation for further human testing. Four years have been lost because of Sandoz's pullout. In one Sandoz trial conducted in 1991,11 seventeen persons received a combination of MSL 109 and either foscarnet or ganciclovir as maintenance therapy. The time until recurrence of CMV progression was 200 days or twice as long as historically observed with either ganciclovir or foscarnet monotherapy. MSL 109, which was administered intravenously every two weeks, was well tolerated, and it did not seem to provoke any immune response against it (this was a problem with earlier versions of monoclonal antibodies, which were mouse- rather than human-based). The 200-day delay in CMV progression was achieved despite the fact that the MSL 109 was discontinued after at most 112 days. The effect of prolonged therapy, to be evaluated in the current trials, remains unknown, but according to Richard Pollard, M.D., the principal investigator for ACTG 266, MSL 109-resistant strains of CMV have not appeared in his extensive laboratory attempts to breed such a viral strain (although one other lab did find reduced sensitivity to the drug after exposure). Dr. Pollard, who works at the University of Texas at Galveston concluded, "If there is no escape mutant and the agent is nontoxic, it will be a good candidate for long-term systemic therapy," at least in combination with other compounds. Monoclonal antibodies' ability to cross from the blood to the retina and the brain remains undetermined and may be relatively poor due to their large molecular size. But their lack of toxicity and unique mode of action make them seem a potential candidate for supplementing localized eye therapy so as to prevent breakthrough CMV infections elsewhere. Whether a monoclonal could be used without ganciclovir or foscarnet also remains to be determined. Towards Better Medical Management The outlines of a "kinder, gentler" combination treatment regimen that effectively manages CMV in people with AIDS is gradually emerging. It would include some type of direct therapy for the eyes that requires only occasional reapplication. Meanwhile, a systemic therapy would protect against infection outside the affected eye, and that therapy should be less onerous and more effective than the present ganciclovir and foscarnet intravenous regimens. But the path of research is never a straight one. Corporate strategies (ganciclovir, cidofovir, MSL 109) as well as scientific mishap (ISIS 2922) are impeding achievement of optimal therapeutic strategies. The only treatment now easily obtainable for people with refractory CMV is intravenous ganciclovir and foscarnet combined. Administering both these drugs requires that patients spend most of their day connected to an infusion pump and suffer the combined side effects of both drugs. This unpleasant but more active therapy is now the subject of ACTG trial 228. In the next article Gary Ranum describes what the delays in developing better CMV treatments mean in personal terms. 1 Stanley HD et al. Journal of Acquired Immune Deficiency Syndromes. Mar 1994; 7(3):272-8. 2 Kupperman BD et al. The Journal of Infectious Diseases. Dec 1993; 168(6):1506-9. 3 Drew WL et al. The Journal of Infectious Diseases. Apr 1990; 163(4):716-9. 4 Blysma SS et al. Archives of Ophthalmology. Jan 1995; 113(1):89-95. 5 Chiron Vision/Hoffmann La Roche press release. July 5, 1995. 6 Oral Ganciclovir European and Australian Cooperative Study Group. AIDS. May 1995; 9(5):471-7. 7 Kirsch LS et al. Ophthalmology. Apr 1995; 102(4):533-43. 8 Kirsch LS et al. American Journal of Ophthalmology. Apr 1995; 119(4):466-76. 9 Lalezari JP et al. Journal of Infectious Diseases. Apr 1995; 171(4):788-96. 10 Polis MA et al. Antimicrobial Agents and Chemotherapy. Apr 1995; 39(4):882-6. 11 Toplin M et al. Ninth International Conference on AIDS. Jun 6-11 1993; I(abstract WS-B11-2):54. ********************************************* Testing for CMV in the Central Nervous System CMV can involve both the brain (encephalitis) and the spinal nerves (polyradiculopathy). Two European studies recently reported that using polymerase chain reaction (PCR) to measure CMV's DNA in the cerebrospinal fluid (CSF) was helpful in making the diagnosis and following the response to treatment in patients with CMV neurological disease. In a French study, the presence of CMV DNA in the CSF correlated with a clinical diagnosis of CMV neurological disease and was associated with an increased risk of death (J. Gozlan et al. AIDS. March,1995; 9(3): 253-60). In the second study, conducted in Sweden, seven AIDS patients with CMV disease of the central nervous system were treated with ganciclovir for three weeks (P. Cinque et al. The Journal of Infectious Diseases, June, 1995; 171(6): 1603-6). After treatment, all the Swedish patients had either a reduction or disappearance of CMV DNA viral load in the CSF. Four had neurological improvement. Three of four patients who had autopsies done were found to have other pathogens in the brain. All four had evidence of CMV brain infection. The authors concluded that despite the reduction in CMV viral load in the CSF after ganciclovir therapy, the treatment was unable to completely suppress replication of the virus in the brain, possibly because of the low levels of the drug reaching brain tissue. The Swedish investigators also felt that quantitative PCR assay could be used reliably to monitor the response to therapy of CMV infections of the central nervous system and to evaluate the severity of the disease. -- GT CMV Drugs: Why They Work and How the Virus Evades Them Drug: Ganciclovir Mechanism of Action: A nucleoside analog, a defective copy of the DNA building block guanine. It requires activation through addition of a phosphate group by a viral enzyme within infected cells. This phosphorylated ganciclovir is taken up by a viral DNA polymerase that builds DNA replicates of the CMV gene set. Ganciclovir prevents further extension of the DNA chain, blocking creation of a new virus. Resistance: 1) A single mutation in the UL97 gene, which governs the structure of the viral enzyme that phosphorylates ganciclovir. This prevents creation of the active ganciclovir molecule. 2) Rarely, a mutational change in the viral DNA polymerase enzyme reduces ganciclovir incorporation into viral DNA. This change creates moderate resistance to ganciclovir. There is potential cross-resistance to cidofovir. Drug: Foscarnet Mechanism of Action: An analog of the phosphate groups added to nucleosides before they link up to form DNA. It binds to CMV's DNA polymerase within infected cells and blocks this enzyme's role in CMV replication. Resistance: A mutational change in the viral DNA polymerase obstructs binding with foscarnet. Foscarnet-resistant CMV may also be resistant to cidofovir. Drug: Cidofovir Mechanism of Action: Nucleotide analog, differs from nucleoside analogs in that it is pre-phosphated and does not depend on phosphorylation by a CMV enzyme. It is taken up by CMV's DNA polymerase, and prevents further extension of the DNA chain forming the new viral DNA. Resistance: A mutational change in CMV's DNA polymerase reduces cidofovir incorporation into viral DNA. Cidofovir- resistant CMV may be cross-resistant to foscarnet. Drug: ISIS 2922 Mechanism of Action: An antisense sequence of nucleotides complementary to a messenger RNA sequence produced by the CMV genes in an infected cell. CMV's messenger RNA coordinates the production of new viral protein in the infected cell's cytoplasm. ISIS 2922 binds to a messenger RNA from CMV's IE2 gene, which produces proteins that regulate expression of other viral genes. Resistance: None observed so far. In principle, a simple change in the IE2 gene sequence would protect its messenger RNA from binding with ISIS 2922. Because of ISIS 2922's unique mechanism of action, CMV resistant to this compound would not be cross-resistant to other medications. Drug: MSL 109 Mechanism of Action: A laboratory-produced monoclonal antibody that binds to a surface protein on a CMV virus particle. It neutralizes the virus, probably by preventing entry of the virus into uninfected cells. MSL 109 may also bind to the viral protein on the surface of CMV-infected cells, signaling the immune system to kill them. Resistance: Changes in CMV surface protein could reduce the virus's susceptibility to MSL 109, but the extent of resistance seems low from laboratory tests. There would be no cross-resistance to other CMV treatments. ************************************************ Finding Support for AIDS-Related Vision Problems by Gary Ranum M.A., M.Ed., Ed.D. People do not realize that getting a drug for CMV will not make the disease go away. The drugs just hold the line for a little while, then your vision continues to decline as your immunity worsens. I first had CMV in my colon two years ago, and six months later, the virus struck one of my eyes. I have had intravenous infusions of ganciclovir for these last two years. Now, I am legally blind in one eye and have one sight-threatening CMV lesion in my other eye. I currently get infusions of foscarnet and ganciclovir each day and I get weekly injections of ganciclovir in each eye. I also had ganciclovir implants installed in both eyes this spring and now all the old lesions in both eyes are dormant, but there is that new and growing sight-threatening lesion in the central area of my good eye's retina. As I write this, I am planning to up the dose of my Tuesday ganciclovir intraocular injection and add a Thursday injection of foscarnet. Unfortunately, the number of pages devoted to support services for those of us who are becoming blind, or those of us who are already blind, is limited indeed. Most articles published in the AIDS community are about the medical conditions of vision loss rather than the psychological or sociological aspects -- what does one do, and where does one go, when vision loss is inevitable? In Manhattan, where I live, there are three agencies specifically designed to help the blind and those becoming blind. They are: The Jewish Guild for the Blind, The Lighthouse Inc. and The Helen Keller Institute. At the Jewish Guild, for example, there are case workers who work only with AIDS-related blindness. After receiving information about the medical condition of vision loss, these case workers help the person fill out the necessary paperwork to submit to the city's Commission for the Blind and Visually Handicapped (CBVH) to see which services are appropriate and available for that individual. One needs to establish relationships with agencies early on with vision loss, so that services will already be in place when your impairment increases. It will be more difficult psychologically to make the necessary connections after the vision loss has become severe. Another step is to involve oneself in a support group. For me, it has been the one thing at GMHC that got me through retiring and going on disability. It also was the first place I could discuss my vision impairment, but sighted people have a different perspective than we do. My vision loss required a different kind of support. Encroaching blindness causes extreme anxiety, fear, depression and isolation more than AIDS by itself. AIDS plus blindness is a doubly difficult diagnoses to cope with. We have different issues than just dealing with AIDS and particular opportunistic infections. We are faced with a multitude of questions: Who can sit with us? Who will maintain care of medical matters, such as the infusions, injections and pills we are taking? Who will go to the doctor's with us and fill out the paper work? What happens if we are home alone and need help -- and cannot find the phone? What about daily life -- preparing meals, bathing, shaving, buying food, going out to eat, enjoying spare time, transportation, bad weather, losing something in the apartment, to name just a few. In May of 1994, I submitted a proposal to GMHC outlining the rationale for establishing a support group to assist those with vision problems. This would be the agency's first program for its visually impaired clients. GMHC listened, and understood, and now there are fliers posted around the agency giving the details about the group. (Further information about the GMHC group may be obtained from Mark Thomas, the group's facilitator, at 212/337-3515.) But the first support has to be you. People going through the experience have to reach out and educate themselves. After I realized the inevitable, it became apparent that there are things one can do when one loses vision. There are computers designed to assist blind people; there are books on tape; there is a radio station at the Jewish Guild which broadcasts readings of daily newspapers. Last but not least, in New York the Metropolitan Museum of Art has a collection of art objects specifically for the visually impaired. One of the curators will take you to the collection and allow you to touch the various objects. Being blind is not the end of life, there are still things we can do. Even though we are losing vision, we can still "see," and the business of life continues. Because of the interventions in my case, and because I have sought help, I am coping with my progressive loss of vision. I could not have made it this far without my wonderful partner, though, who stands by me as I confront my condition. My going blind is very different for the two of us, as he becomes more and more "my eyes." As people with AIDS live longer, more and more will lose sight. Here are some tips for those of you who are suddenly called upon to be the eyes for someone who is visually impaired or blind: 1) if the person asks for help across the street, let them grab your arm, please do not pull them around; 2) when entering a room, introduce yourself to the person and tell them where you will be sitting if necessary; 3) never leave a sightless person standing in a room without guiding him or her to a chair or table (a safe area); 4) describe the room to let the person know what is in the room; 5) avoid "throw rugs," as they can trip those with limited vision. ****************************************** CDC Report on Waterborne Cryptosporidiosis This June, the Centers for Disease Control and Prevention issued a report based on a meeting of outside experts to examine the safety of public water supply in regards to cryptosporidiosis. This parasitic disease causes life- threatening diarrhea in people with AIDS. The experts concluded that the magnitude of the risk of cryptosporidiosis remains uncertain. Whether or not a waterborne crypto outbreak is occurring in a given locality, people with immune deficiencies such as AIDS can protect themselves by consistently drinking only water that has been: 1) boiled for one minute, or 2) filtered with a one micron microstraining filter meeting industry standards or 3) bottled by a commercial firm that has passed it through such a filter or treated it by distillation or reverse osmosis. For more information on this issue, see Treatment Issues, September, 1994, pages 5-6 and October, 1994, page 15. -- DG **************** Treatment Briefs by Gabriel Torres, M.D., and Theo Smart Merck's Protease Inhibitor Expanded Access Program Now Open Phone registration is now underway for the expanded access program of Merck's protease inhibitor, indinavir sulfate (Crixivan) -- formerly known as MK-639 and L-735,524. The program will offer drug to 1,100 selected with less than 50 CD4 cells who will be selected in a lottery. To participate in the selection process, patients or their care providers must call 800/497-8383 before 11 p.m. on August 11, 1995. Callers will be sent a one page "qualification form" which must be filled out and returned to the company before September 8, 1995. The earlier these forms are returned to the company the better, since drug recipients will be chosen on August 15. People who aren't in the first 1,100 selected will be placed upon a waiting list and may receive drug should more become available. 3TC Compassionate Use Protocol Improved By the end of August, Glaxo Wellcome plans to increase the weekly quota for its 3TC compassionate use protocol from 300 to 650 new enrollments. Although patients with fewer than 100 CD4 cells will be given priority, anyone with less than 300 CD4 cells may now apply for the program, which now distributes the experimental drug 3TC to 24,000 people. In April, Glaxo Wellcome reduced access to 3TC through its compassionate use program because demand had outstripped drug supply. This move followed wide publicity concerning the improved CD4 and viral load responses seen when combining 3TC with AZT. Glaxo limited the weekly enrollment and lowered the entry criteria from 300 to 100 CD4 cells. This announcement follows Glaxo Wellcome's June 30 filing for FDA approval of 3TC in combination with AZT as a first line therapy in people with HIV and less than 500 CD4 cells. Call for information: Treatment Issues would like to hear from any people with HIV or their doctors who have observed unusual declines in white blood cells, lymphocytes or CD4 cell counts while on 3TC. We have heard of several cases in which people starting the AZT/3TC combination have experienced such drops, at least temporarily (although they may also have had concurrent reductions in viral load). Glaxo Wellcome claims that it has received no reports of this phenomenon. New Non-nucleoside Reverse Transcriptase Inhibitor Eli Lilly Co. has announced that LY30046-HCL, the first of a new class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), has entered phase I clinical trials. The new class of inhibitors, called the PETT series, were discovered when Lilly researchers dismantled TIBO derivatives (another class of NNRTI) into simple structural elements, and screened their organic compound library to find substances with similar structures. Viral resistance is the biggest obstacle to an NNRTI. HIV resistant to the NNRTI nevirapine also exhibits reduced susceptibility to the PETT compounds. However, the company reports that LY30046-HCL is more potent than nevirapine and that elevated concentrations of this new compound should be able to inhibit nevirapine-resistant virus. When exposed to LY30046-HCL in the test tube, HIV develops resistance by making multiple mutations different from the mutations that confer resistance to nevirapine. Lilly's announcement comes as a surprise. A year and a half ago, Carlos Lopez, the company's Executive Director of Infectious Disease Research, announced that Lilly had halted in-house research on HIV treatments, as part of their plan to "focus resources in areas where we feel we have a competitive advantage." Subsequently, the company dropped out of the Inter-Company Collaborative on AIDS, a network of pharmaceutical companies involved in developing treatments for AIDS. Plasma Viremia Predicts Clinical Outcome A recent French study suggests that plasma HIV viremia may predict clinical outcome during AZT therapy (A. Ruffault et al. Journal of AIDS. April, 1995; 9(4): 330-4). Plasma viremia is a measurement of culturable virus in the fluid of the blood, it is not to be confused with viral load. The study involved 28 asymptomatic or mildly symptomatic people with HIV and CD4 counts below 350. Their plasma viremia, p24 antigen levels and CD4 counts were measured before and during the course of treatment. "Responders" were defined as patients who had positive plasma virus cultures that turned negative during treatment or that were negative at the outset and remained so during therapy. During the mean follow-up period of 21 months, 73 percent of the non-progressors were "responders," whereas all of the thirteen patients who progressed in their illness were plasma viremia "non-responders." A significant and stable decrease in plasma viremia was observed only in the nonprogressors. The persistence, increase or reappearance of viral replication appeared to be an important predictor of poor clinical outcome in this small group of patients undergoing AZT therapy. There were significant discrepancies between clinical outcome and the response rates in terms of p24 antigen levels and CD4 counts. The authors concluded that plasma viremia is a more sensitive surrogate marker, and may precede the decline in CD4 counts, predicting disease progression earlier. Thalidomide for Microsporidiosis A small British study has reported positive effects using thalidomide for the treatment of gastrointestinal infection with Enterocytozoon bieneusi (microsporidiosis), one of the most common causes of diarrhea in persons with AIDS. (D. Sharpstone et al. AIDS. June 1995 9(6):6589) The rationale for the use of this agent comes from its effects against tumor necrosis factor, a cytokine that has been found at high levels in the stool of persons with microsporidiosis. Twelve gay men with microsporidiosis and chronic diarrhea were treated with thalidomide (100 mg per day for three weeks). All had previously been treated with albendazole, but had failed to improve. Following the first three days of thalidomide treatment, all the men had improved, with a decrease in bowel movements and decreased utilization of antidiarrheal agents. Stools became semi-solid. After three weeks of therapy, the patients had gained an average of 1.2 kilograms of body weight. The only reported side effects were a generalized rash in one patient and drowsiness in three, requiring a dose reduction to 50 mg per day. One week after the dose was lowered, one patient relapsed. These encouraging results indicate that an expanded trial, possibly including albendazole, should be set up immediately. Rifabutin Induces Rifampin-Resistant TB The first case of tuberculosis resistant to the antibiotic rifampin has been reported in an HIV-positive patient using rifabutin for Mycobacterium avium complex (MAC) prophylaxis (A Weltman et al.The Lancet. June 10, 1995; 345:1513). Rifampin and rifabutin come from the same family of antibiotics and there has been a growing concern that the widespread use of rifabutin for MAC prophylaxis would result in emergence of Mycobacterium tuberculosis resistant to rifampin, one of the most important drugs in the treatment of TB. The case was in an HIV-positive prison inmate who had a CD4 count under 100 and negative results on three skin tests for TB (PPD skin tests). He had been placed on rifabutin for MAC prophylaxis seven months prior to the onset of symptoms of TB (cough, fever, night sweats). A sputum analysis revealed a strain of TB mycobacterium resistant to both rifampin and rifabutin. The resistance was documented by genetic analysis of the bacterial DNA through a technique called restriction fragment polymorphism (RFLP) analysis. This case raises concern about use of rifabutin in populations such as prisoners, homeless persons and injection drugs users that have a high rate of latent TB and yet do not react to the PPD skin test. Such "anergy" makes the diagnosis of the latent TB impossible. Persons to be placed on rifabutin should first have active TB ruled out by a chest x- ray and three negative sputum analyses prior to starting the drug. Clarithromycin-Induced Mania The antibiotic clarithromycin is commonly used in people with AIDS to treat or prevent disseminated Mycobacterium avium complex (MAC) infections. A report from New Mexico described two patients with AIDS who became psychotic possibly due to therapy with clarithromycin (S. Nightingale et al. Clinical Infectious Diseases, June 1995; 20(6):1563-4). Both became agitated and psychotic within 48 to 72 hours after starting the drug at a high dose (1000 mg twice daily) to fight MAC. Symptoms included anxiety and delusions of grandeur, which resolved after the drug was discontinued but recurred when the drug was restarted. One patient also was taking fluconazole, which can interact with clarithromycin. A drug-drug interaction phenomenon could not be excluded. The relatively high doses of clarithromycin in these underweight individuals nonetheless is thought to have contributed to this reversible alteration of mental status. ************************************ New Developments in Kaposi's Sarcoma by Theo Smart Kaposi's sarcoma (KS) was one of the earliest, most visible manifestations of AIDS in the gay community. Although a number of debatable studies have claimed that the percentage of gay men contracting KS is declining, the total number of cases is definitely increasing. Also, now that treatments and prophylaxis for life threatening opportunistic infections have improved, KS, which normally progresses slowly, has the opportunity to cause greater suffering and death. Meanwhile, efforts to explain why KS develops and to find more effective regimens for KS have lacked direction and support from the National Institutes of Health. One year ago, the Treatment Action Group (TAG) published a report on treatment and research policy issues pertaining to KS. Largely at TAG's prompting, the National Cancer Institute (NCI) sponsored the first conference devoted to KS this past June. It was an opportune time to hold such a conference since there have been a number of major advances recently in our understanding of what causes the KS disease process and how to treat it. We summarize here some of the major findings presented at the conference. Clinical Features A number of speakers focused on the features and causes of Kaposi's sarcoma. AIDS-related KS is much more aggressive than other subtypes such as classical KS. Its lesions start as small purple or reddish marks (macules), frequently on the tip of the nose or soles of the feet, and become papules, nodules or plaques that can be scattered across the body, commonly in mucosal tissues. In about 50 percent of people with AIDS-related KS, lesions form in the lungs and gastrointestinal tract. KS in the lungs is most life- threatening, causing pulmonary fluid buildup, obstruction of airways, bleeding with resultant coughing and difficult breathing. Wherever, and whenever KS occurs, it can be compounded by inflammation, ulceration and secondary infections of the surrounding tissues. KS involvement of the lymph tissues leads to a particularly poor prognosis as the disease rapidly spreads to other organs. It is still undecided whether KS is a true cancer or merely a skin growth in reaction to infection by an unknown agent. Cancers are generally characterized by one type of cell that mutates and begins to proliferate without control. Although many of the cells that compose a KS lesion are spindle shaped like fibroblasts, they are derived at first from various cell types. But as the lesion advances, one cell line might become dominant, making the KS growth resemble a cancerous tumor. Steven Miles, M.D, of the University of California Los Angeles, has proposed a simple working model for the development and spread of KS. He believes that cells are initially transformed somehow, perhaps by a virus. When these transformed cells are exposed to certain molecules present in abundance during HIV infection -- immune system cytokines (especially IL-6), various other growth factors that promote cell growth and HIV's tat protein -- they replicate and spread. Eventually, the cells begin producing their own growth factors, some of which stimulate angiogenesis -- the development of new blood vessels that help feed the growing lesion. Kathryn O'Connell of Johns Hopkins University presented data at the conference that seemed to support this model. By infecting endothelial cells from nude mice with a virus (SV40), she was able to produce tumors quite similar to KS. These lesions were easily stimulated by many of the growth factors common in AIDS-related KS. Yuan Chang gave the conference an update on the data behind her theory that KS is caused by a previously unknown herpes virus popularly, and perhaps prematurely, referred to as KSHV (see page 17). There is as yet no definitive proof that KSHV (also dubbed HHV8) causes KS, though. Other researchers, such as Barbara Ensoli and colleague Valeria Fiorelli (visiting Italian scientists at the NCI), argued that no one agent, viral or otherwise, is necessary for the development of KS. Instead, the presence of HIV's tat protein plus the inflammatory cytokines and, in particular, basic fibroblast growth factor (bFGF), may by themselves transform normal cells and lead to the formation of lesions. In cell cultures, they have induced normal endothelial cells (from umbilical cord tissue) to acquire spindle cell characteristics by exposing them to both bFGF and tat. These cells cause KS-like lesions after injection into mice. According to the Ensoli model, the synergy between tat and bFGF is responsible for the virulence of AIDS-related KS. If there is no contagious microbe involved, why is AIDS-KS more common in gay or bisexual men than in other HIV-positive populations? Valerie Fiorelli thinks that there may be a number of environmental factors to blame -- for example, the immune cytokine profile in gay men may be somewhat altered. Gay men's immune systems are more activated, Fiorelli claims, perhaps because they are exposed to a greater variety of infectious agents. Potential Therapeutic Approaches Whatever the initial cause, everyone agrees that cytokines and other growth factors play a primary role in the development, growth and spread of KS. The list of these growth factors is quite long and, besides bFGF and tat, includes a host of other fibroblast growth factors: PDGF (platelet derived growth factor), IL-1, IL-6, TNF-alpha, oncostatin-M, scatter factor and others. Inhibitors of any of these factors may hold potential as treatments for KS. Many such therapeutic strategies were discussed at the NCI conference. Angiogenesis Inhibitors: Angiogenesis (new blood vessel formation) is necessary for the growth and metastasis of tumors, so it is not surprising that much current anticancer research concerns angiogenesis inhibitors. James Pluda and David Roberts of the NCI reported on the status of research with these compounds, which include IL-12, TNP-470, recombinant platelet factor 4 (rPF4), tecogalan (SP-PG), pentosan polysulfate (which failed in its clinical trials) and thalidomide. IL-12 has been shown to inhibit angiogenesis and primary tumor growth in mice with Lewis lung carcinomas. Plans for a phase II study in patients with cancer are under consideration at the NCI. TNP-470 is in a phase I study at the NCI. It is administered as a one-hour infusion every other day. The investigators have seen very little toxicity, but no major responses yet at the doses currently being studied. Thrombospondin is a naturally occurring glycoprotein that plays a role in platelet aggregation. It appears to have the capacity both to stimulate and inhibit cell motility and proliferation. Generally, its expression is associated with decreased metastic potential, and it may inhibit bFGF. Researchers at the NCI have investigated the complex activity of thrombospondin and have found a specific peptide sequence that appears responsible for its anti-angiogenic activities. They are currently devising analogs of these peptides that may work as drugs (peptides are notorious for being metabolized too quickly). Phil Browning of Vanderbilt University's Cancer Center presented data suggesting that depletion of a naturally occurring protein that inhibits angiogenesis aids the development of KS. Apolipoprotein E (ApoE) is a protein complexed with lipids in high and low density lipoproteins that helps transport cholesterol from blood plasma to tissues. Reduced plasma levels are associated with arteriosclerosis. ApoE appears to play a role in the regulation of vascular cell growth. Levels of the protein become depleted early in the course of HIV infection and people with HIV have an increased risk of arteriosclerosis. In the test tube, ApoE inhibits KS cell growth and migration and lowers the permeability of blood vessels. It has blocked angiogenesis in mice. This naturally occurring substance may be a novel and safe way to inhibit angiogenesis as it has no known toxicity in animals. Analogs of ApoE are currently being designed for clinical development. Liposomal Anthracyclines: Two of these are very near FDA approval. (See box, page 13.) Cytokines: As noted before, many cytokines and growth factors are involved both in the proliferation of KS spindle cells and the vascular structures that support them. Many cytokine inhibitors may also be angiogenesis inhibitors, and much of angiogenesis inhibitors' activity may actually involve the inhibition of cytokines and growth factors. Peter Polverini of the University of Michigan presented data at the conference on "scatter factor" and its potential inhibitors. Scatter factor is a cytokine that causes endothelial cells to become spindle shaped and scatter or spread out. KS cells both produce it and have receptors for it, setting up a potential endless loop of auto-stimulation. Antibodies to scatter factor markedly reduce growth of KS lesions in lab experiments, as does an inactive variant of scatter factor, which probably competes with the active molecule for receptor sites. Dr. Miles of UCLA presented clinical data on a dose ranging study of IL-4. IL-4 may increase CD4 cells and suppress IL-6, which Dr. Miles believes is one of the critical cytokines stimulating KS proliferation. IL-4 does inhibit KS cells in tissue culture studies. In nine patients at the lowest dose, of 0.5 mg/kg of body weight per day, just one patient showed a partial transient response, and five had progressive disease. In the six patients at the next dose level of 1.5 mg/kg per day, there were three cases of neutropenia, headaches and fever were common, and only two patients had a partial response. Dr. Miles saw no effect upon IL-6 or TNF alpha levels, but he did note a 72 percent reduction in HIV levels as measured by bDNA. IL-4 may have an antiviral effect through its modulation of the immune system. Its side effects, which are related to that modulation, are severe, though. Georgia Vogelsang of Johns Hopkins gave a presentation on thalidomide -- which not only reduces levels of TNF alpha, one of the inflammatory cytokines that may stimulate KS, it also inhibits angiogenesis due to bFGF and perhaps other growth factors. Thalidomide has shown anti-tumor activity in animal models. In one study, dogs treated with thalidomide experienced a stabilization and shrinkage of tumors. Clinical trials for KS are now under consideration. Barbara Ensoli presented work on an "antisense" compound that locks onto the cellular RNA directing production of bFGF. This compound inhibits bFGF production and KS cell growth in a dose dependent manner. It appears to work in a mouse model without any deleterious effects. Because of her belief that bFGF and the HIV tat protein synergistically stimulate KS, she also argued in favor of developing tat inhibitors to treat KS. Retinoids: Retinoids are derivatives of vitamin A that may reduce IL-6 levels and have other immune stimulatory activity. Robert Yarchoan of the NCI presented data from a small study (in twelve evaluable patients) of oral all trans retinoic acid (ATRA), one derivative of vitamin A. ATRA is absorbed erratically, and continuous administration seems to produce ever decreasing plasma levels. To circumvent the absorption problems, it was administered every other week in the study. Even with this precaution, researchers saw no benefit, and ten of the twelve patients had progressive disease. Steven Miles reviewed data from an ongoing study of topical ATRA in forty patients with KS. Each patient had to have at least six previously untreated lesions. Three were treated with ATRA and three served as controls. Dr. Miles' group is seeing some responses in treated lesions. The time to response seems to be dependent on size. They are seeing more improvement in patients who have received previous systemic treatment. However, the big problems are that local absorption appears erratic, responses seem to depend upon site of lesion, and new lesions appear elsewhere on the body. So there is clearly a need to use systemic therapy. Dr. Miles also believes that there may be better derivatives of ATRA. 9-cis retinoic acid is one that has a high level of activity in the test tube. It and derivatives of it appear to have much less complex pharmacokinetics. Novel Mechanisms: Bill Thorpe of the University of Texas Southwestern Medical Center may have improved on the angiogenesis strategy by finding ways to attack the established blood vessels in tumors and KS lesions, cutting off their entire blood supply rather than simply the formation of new blood vessels that sustains tumor growth. He has found at least one protein, endoglin, that is present only in replicating endothelial cells in tumor vessels, but not in normal resting tissues. Administration of TEC-11, a combination antibody/toxin that binds to endoglin, kills cells containing the protein, triggering massive blood clots in the vessels feeding the tumor. Dr. Thorpe was able to essentially starve mouse tumors to death with this strategy. It is too early to tell whether Dr. Thorpe's tumor- eradicating strategy will work on human KS. There are also serious safety concerns about causing strokes and heart attacks as a side effect. Dr. Thorpe is quick to say that even if the present antibody/toxin proves too dangerous, he has a better protein target and antibody that he is fairly certain will be safe. He plans to publish information on the alternative treatment scheme in the next few months (as soon as it is patented). Bruce Dezube presented data from a small study of SCHAL-1, a cream containing clotrimazole. Clotrimazole has been shown to be an inhibitor of cell proliferation, probably by inhibiting the calcium signals that bFGF and other growth factors use to induce cell growth. In a mouse model, clotrimazole was able to decrease metastases in SCID-hu mice with melanoma. Eleven patients with AIDS-related KS enrolled in Dr. Dezube's study, and nine were evaluable through week four. Half of the patients' lesions were randomized to treatment, half to placebo. The treatment was very safe but after four weeks, there were no differences between treated and untreated lesions. There was, in fact, a slight increase in the size of all the lesions, except perhaps in a subset of small lesions. The SCHAL-1 cream contains a very low concentration of clotrimazole, and there did not seem to be much penetration into the lesions. Dr. Dezube's team is presently working on a more potent formulation. Clotrimazole is an established antifungal medication. Since it is relatively cheap and safe, it represents an attractive treatment possibility. Robert Yarchoan reported on clinical results from a study of Taxol in 29 AIDS patients with advanced KS (six had KS in the lungs) with a median CD4 count of sixteen (an interim analysis of this study was published in The Lancet, July 1, 1995; 346(8966):26-8). Taxol, derived from the yew tree, has established activity against other cancers, although its mechanism of action is unclear (it may affect the formation of microtubules -- the cellular skeleton -- in proliferating cells). The drug was administered in one three-hour infusion every 21 days, at doses of 135, 155 and 175 mg per square meter of body surface. Patients were given anti-inflammatory steroids before administration, (but no G-CSF -- a therapy that helps alleviate low white blood cell counts due to bone marrow toxicity). Fatigue, hair loss and fever were the most common side effects, and rash, fever, psoriasis, bone marrow suppression and high levels of eosinophils (a type of white blood cell) were also seen. There was one case of cardiac dysfunction that led to death -- but that may not have been drug-related. As for the clinical response, one patient had a complete response and nineteen had partial responses. It took eight months for the KS to start progressing again in the responders. Of the 29 patients who entered the study, eleven have died -- the median survival is only fifteen months, and there were fourteen concurrent major opportunistic infections -- so these patients were severely immune compromised. Future studies of Taxol will include longer infusion times and co-administration with G-CSF. The Elusive Standard of Care Very little of the conference dealt with standard of care treatments. This was disappointing given the absence of guidelines on what treatments should be used and when. The one standard of care treatment that was discussed was radiation therapy in a presentation by Patrick Swift of the University of California San Francisco. Radiation therapy may be particularly useful for cosmetic purposes and for painful lesions that interfere with functions like walking, or lesions that are associated with bleeding or pain. But these were broad observations for one modality of treatment when there are many types of treatment and many types of clinical presentations. When people with KS have different types of lesions that progress at different rates (and this is compounded by concurrent opportunistic infections and different states of immune dysfunction) what is a doctor to do? Much of the published clinical information is often inconsistent and confusing. ABV (the chemotherapeutic combination of adriamycin, bleomycin and vincristine) is probably the agreed-upon standard of care for widespread systemic and internal disease. But Michael Marco of TAG presented data that showed that over the years, the response rates to ABV, reported in clinical trials, appeared to be dropping dramatically, going from a response rate of 88 percent down to 30 percent. One explanation for this decrease would be that participants in earlier trials had less severe disease, and were therefore more likely to benefit. Ron Mitsuyasu of UCLA listed a number of reasons why it is difficult to assess the clinical improvement reported in clinical trials over time. For one, treatment has changed for primary infection of HIV and for opportunistic infections. But the biggest problems concern methodology: 1) there is no clear evidence that improved survival is associated with tumor reduction; 2) there is no agreed upon system of staging the disease; 3) different studies assess responses differently -- for example, one study may define a partial response as a 25 percent reduction in tumor size (even though new tumors are cropping up everywhere), while in another study, only a greater than 50 percent reduction in lesion size with no new lesions qualifies as a partial response; 4) few studies assess how treatments effect quality of life; and 5) there simply have not been any large randomized comparative clinical trials. Michael Marco noted, too, that the availability of G-CSF and improvements in antinausea medications make chemotherapy not as horrible as in the past. Even so, as Susan Krown, M.D., of Sloan-Kettering concluded, "The future treatment of KS will probably rely on combination approaches that address all the various factors that contribute to the development of KS." The focus is shifting from the standard anti-cancer chemotherapies. ************************ Liposomal Chemotherapies by Theo Smart Just two days after the KS conference concluded, the Food and Drug Administration (FDA) Oncology Drugs Advisory Committee recommended that the agency approve DaunoXome (liposomal daunorubicin) for the treatment of patients with systemic KS. This was the second time that Vestar had filed for approval of the drug. The last time the company's data were so disputed that the drug was rejected out of hand. Data from a large phase III trial were now available, but it was a close call even so. "It was a relief -- five years of work came to a good end," said Parkash Gill who served as investigator on a number of the DaunoXome studies. The phase III trial involved 227 participants with advanced systemic KS (more than 25 lesions, visceral/internal disease, or severe edema). Patients were randomized to receive intravenous DaunoXome, (40 mg/m2 of body area) or a low dose intravenous ABV (adriamycin ten mg/m2, bleomycin fifteen U, and vincristine one mg) that permitted concurrent administration of antiviral drugs. Earlier studies in people with AIDS have shown low-dose ABV to be as efficacious as higher doses. The results were not remarkable. Overall the response rates for both arms were lower than expected. By the FDA's assessment, 23 percent responded on DaunoXome and 30 percent responded on ABV. Time to progression was slightly in favor of ABV, but not significantly, while there was an insignificant trend to prolonged survival on DaunoXome. Oddly, there also seemed to be a trend toward increased opportunistic infections on DaunoXome. There were no fewer cases of neutropenia or cardiac abnormalities, as was expected with DaunoXome. On the contrary, there seemed to be slightly more neutropenia. There were differences in toxicity, just not the types of toxicity that, according to Gill, "seemed to matter to the review panel," (for example, the incidence of hair loss, fatigue and neuropathy was significantly lower on DaunoXome). Dr. Gill notes, "If there is no hair loss and people can go back to work without everyone knowing they are on chemotherapy, that makes a large difference to patients." Overall quality-of- life scores were somewhat better on DaunoXome, and patients also could continue treatment for a longer period of time. One other liposomal anthracycline, Doxil (liposomal doxorubicin), has also been recommended for approval. Is one better than the other? Doxil certainly has its promoters. Its developer, Sequus (formerly Liposome Technology), claims that a component of Doxil's liposome, PEG (or polyethylene glycol), makes that liposome superior to other liposomes, because it increases the liposome's life circulating in the blood stream. This does not, however, mean that more drug gets into the tumor, and even if it does, doxorubicin may not be the equal of daunorubicin. Of DaunoXome versus Doxil, Dr. Gill says "it would be great to compare them head to head. It is clear that liposomal delivery is going to make a difference in quality of life." Human Chorionic Gonadotropin by Theo Smart The pregnancy hormone human chorionic gonadotropin, (HCG) is one of the most intriguing experimental treatments for KS (see Treatment Issues, August 1994, pages 4-5). Interest in HCG stems from anecdotal reports of remission of KS in women who became pregnant, and published reports of an anti-KS effect in mice.1 A recent letter in The Lancet, and ongoing clinical studies of HCG are likely to generate even more interest in the compound. In the Lancet letter, Pamela Harris of Washington, D.C. reported treating six of her AIDS-related KS patients with HCG.2 Two patients had only one lesion; two had extensive cutaneous disease; and two had cutaneous and internal KS. She started them on a low dose of intramuscular HCG, and escalated the dose to 150,000 IU (and higher), three times a week. These doses are comparable to the extremely high ones used in mice. The only side effects were a sensation of skin retraction around the lesions and tolerable pain at the site of the injections. Side effects seen in other studies of HCG include phallic and testicular enlargement in boys. Breast enlargement has also been observed, but safety of chronic use is unknown. All the patients had significant tumor regression. When treatment was delayed or if patients were treated with less than 100,000 IU, the tumors started growing back. Regression lasted until treatment was discontinued due to cost. These doses are expensive, particularly without insurance reimbursement. At the 150,000 IU dose Harris is using, the retail cost of Serono Laboratories' brand name version, Profasi HP, is $10,800 per month ($60 per 10,000 IU vial). The generic HCG is cheaper, at about $3,150 per month ($35 for one 20,000 IU vial). Meanwhile, Parkash Gill, M.D., of the University of Southern California, has finished his 24-person dose escalation study of intralesional HCG (250, 500, 1,000, and 2,000 IU). Dr. Gill cannot yet release the results, which have been submitted for publication. They apparently are at least good enough to justify commencing a follow-up study of HCG.3 The new study tries out systemic HCG therapy. The hormone will be injected subcutaneously, starting at a dose of 2,500 IU once a day, escalating to 10,000 IU and perhaps more. Besides evaluating HCG's safety and anti-tumor effect, Dr. Gill plans to monitor the patients' viral load as HCG has an anti-HIV effect in the test tube. (This effect could be part of the reason why so few HIV-positive infants are born to HIV-positive mothers.4) 1 Lunardi-Iskander Y et al. Nature. May 4, 1995; 375(6526):64-8. 2 Harris P. Lancet. Jul 8, 1995; 346(89667):118-9. 3 Personal Communication. July 13, 1995. 4 Bourinbaiar AS and Nagorny R. FEBS Letters. Aug 31, 1992; 309(1):82-4. ******************** KS Virus Controversy by Theo Smart The causal role of the new herpes virus (popularly known as KSHV) in the development of KS was called into question by some researchers, including Robert Gallo, M.D., at the KS conference. The genetic footprints of this virus were discovered in tissue from AIDS-related KS lesions by Patrick Moore and Yuan Chang, of Columbia Presbyterian Hospital in New York. (See Treatment Issues, January 1995, pages 11-12.) Traces of the virus were isolated by comparing genes present in diseased tissue to genes in healthy tissue. Since then other researchers have duplicated and extended their findings. Yuan Chang reviewed her group's research to date at the conference. The researchers have isolated sixteen genes from this virus, fifteen of which bear striking similarities to genes from herpesvirus saimiri, a monkey virus, and the Epstein-Barr Virus (EBV). These are both viruses of the gamma herpes sub-family that have been associated with tumors. "KSHV" also is detectable in body cavity lymphomas (BCL), a rare type of non-Hodgkins lymphoma. In blinded case-controlled studies, Chang, Moore and other investigators have found the virus in tissue from patients with all subtypes of KS, but not in healthy tissues from these patients, and generally not in other types of tumors or carcinomas other than BCL (although there were exceptions to this rule in patients from Africa). With the help of Alvin Friedman-Kien, M.D., of New York University, the Columbia group has detected virus in the lesions of HIV-negative gay men with KS. Dr. Chang feels that the group has nearly fulfilled the epidemiological criteria for establishing KSHV as the cause of KS because 1) the virus is found in KS lesions of all sub- types; 2) the virus is not found in other tumors except for BCL; 3) there is a biologic gradient since virus is found in the lesion and in tissues close to the lesion, but not in tissues farther away; 4) there is a temporal association -- the virus appears in the white blood cells of some patients before they develop the lesions; 5) these findings have been reproduced by several labs; and 6) there is a biologic plausibility since the virus belongs to a family of organisms that is thought to cause cancers. Other researchers criticized these conclusions. Dr. Gallo, who calls the virus human herpes virus 8 (HHV8), claimed that his lab has been unable to find the virus in one of his KS cell lines. A recent article in Science reports that Parkash Gill, M.D., also has had trouble finding the virus in some of his KS cell lines, but the article adds that frequently when cell lines are grown for a long time in culture, they begin to lose resemblance to the original tissue. In one presentation at the conference, Robert Biggar, M.D., an epidemiologist from the NCI, cited a paper by Rady, et al. in The Lancet1 which he believes indicates that this virus may not be the cause of KS. The researchers reported finding KSHV in 82 percent of 33 lesions taken from four organ- transplant patients on immunosuppressive drugs. The lesions included basal cell carcinomas, squamous cell carcinomas, actinic and seborrheic keratosis and verruca vulgaris -- the common wart. The researchers concluded that the herpes virus may be involved in all sorts of proliferative lesions in immune-compromised people. But Biggar thinks that this research shows the virus is not specific to KS which weakens the case for it being the causative agent. Could it be, mocked Biggar, that this is "the cause of all cancers?" Dr. Friedman-Kien, in contrast, is not so troubled by the idea that the virus may indeed be involved in the development of many types of lesions. There is precedent for this: the closely related EBV is also associated with a number of tumors, for example. Dr. Friedman-Kien says that his lab has also found the virus in a number of different neoplasms. Accordingly, he agrees that the virus should be named HHV8. Foscarnet for KS If KS is indeed caused by a herpes virus, there is a possibility that an antiviral drug may have a therapeutic effect. Foscarnet may be the available treatment with the greatest potential as it has activity against all known herpes viruses. Even before the discovery of HHV8, there had been anecdotal reports that people taking foscarnet experienced remission in their KS lesions. Dr. Friedman-Kien, of NYU, has reported on a few such cases. His patients had remissions and developed no new lesions for up to a year. One open-label study of five people with KS treated with foscarnet was published last year.2 Three of these patients experienced regression and even clearance of external (and in one case, internal) lesions for more than a year after just one or two brief courses of foscarnet. The authors noted that the two patients who did not respond had advanced disease and concurrent opportunistic infections. Also, a retrospective analysis of 20,228 patients with HIV/AIDS found that patients who were treated with foscarnet for any reason were 70 percent less likely to develop KS than people who did not receive foscarnet.3 Ganciclovir and acyclovir had no effect, but foscarnet has a different mechanism of action than these drugs. Some researchers remain skeptical of this approach. Robert Gallo, M.D., who has conducted extensive KS treatment research at the National Cancer Institute, in particular is unconvinced that HHV8 is the cause of KS. In contrast, Dr. Friedman-Kien and others contend that KS could become a malignancy in later stages as a result of cellular changes induced early on as a result of infection by the virus. Delaying antiviral treatment could rob it of its benefit. The reports cited above and other anecdotal accounts are nonetheless cause enough to investigate foscarnet. And even if the proposed mechanism of action turns out to be nonsense, there may be other ways that this drug could have an effect, perhaps simply through foscarnet's anti-HIV activity. For several months, Dr. Friedman-Kien has wanted to launch a formal study of the drug in patients with early KS at the NYU AIDS-Related Malignancy Clinic. He received approval from his Institutional Review Board back in December, but he only just received drug the first week of July. The hold-up? It took him considerable time to convince Astra Pharmaceuticals in Sweden that the study was worth running. Also, the FDA gave the him approval only fairly recently. The study will be an open label trial for 25 people with early KS, who seem to have the most chance of benefiting from antiviral treatment. Trial participants will receive the standard loading dose of foscarnet, (180 mg/kg in two divided doses -- twice a day -- for fourteen days) in three two-week cycles separated by two weeks off drug. Patients will be administered with treatment at home, and all blood will be drawn in the home. Patients will need to go into the clinic for baseline check-ups. Recruitment has already begun (anyone interested should call Clare Kenny or Lorrie Jondreau at 212/263-5244). If the trial goes well, a multicenter study (probably placebo-controlled) will follow. 1 Rady et al. Lancet. 345(8961);1339-40, May 27, 1995. 2 Morfeldt L and Torssander J. Scandinavian Journal of Infectious Diseases. 26:749-52, 1994. 3 Jones JL et al. Science. 267:1088-1089, February 24, 1995. ********************************************* X-Rays for Monitoring Opportunistic Infection by David Pieribone, R.T. Regular diagnostic x-ray exams as well as specialized x-ray procedures are routinely used in the diagnosis of secondary infections and cancers associated with HIV infection. These exams can give a physician a great deal of information about a patient's condition, information that in many cases could only be obtained otherwise with increased risk. Some people worry about the harmful effects of x-ray radiation, but the need for accurate diagnosis generally outweighs the minimal risk of inducing cancer or damaging the immune system. Modern x-ray technology provides detailed images of the body while exposing the person to a relatively small amount of radiation. Understanding what an x-ray exam entails and what, if any, steps a patient should accomplish before or after an exam can make the exam a success or a failure. While not much patient preparation is necessary for a routine chest x-ray, a gastrointestinal (GI) x-ray exam or a computed tomography (CT scan) can be a complicated procedure. Gastrointestinal Exams X-ray examinations of the gastrointestinal (GI) tract are used in the diagnosis of a number of complications associated with HIV and AIDS. There are three basic GI tract exams: the upper GI exam focusing on the esophagus and stomach, the lower GI exam used for the small intestine and the barium enema exam, which is used for the examination of the large intestine or colon. All GI exams require the use of a contrast agent. A contrast agent blocks x-rays and thereby silhouettes (outlines) the body parts of interest, allowing their visualization. Contrast agents used for the GI tract are usually composed of a barium sulfate liquid suspension, but iodine and non-iodine based contrast agents are also used. The barium mixture has a thick milky consistency and is either swallowed or introduced into the rectum by an enema while the x-rays are taken. The contrast agent and not the x-rays generally cause the complications arising from the exam. Because constipation can occur with barium sulfate, patients need to drink plenty of water after the exam and if conditions allow, they should increase the amount of fiber in their diet for the next several days. Stools will be white or very light-colored until all the barium is expelled. Some physicians will prescribe a laxative to promote bowel movement. A dose of mineral oil can help propel the barium through the bowels. A physician should be notified immediately if a bowel movement does not occur within 24 hours after the exam or there is any of the following: rectal bleeding, faintness, weakness, abdominal pain, inability to pass gas, polyuria (excessive urination), nocturia (excessive urination at night) or abdominal distention (extension of the abdomen with pressure). In rare instances, barium contrast agents can obstruct the intestines. This blockage can be life threatening if not caught in time. Upper GI Exams An upper GI exam, also known as a barium swallow, aids in the diagnosis of candidiasis, herpes, cytomegalovirus (CMV) and Mycobacterium avium complex (MAC) infections of the esophagus. An upper GI exam can also detect ulcerations of the stomach and other gastric (stomach) problems as well as Kaposi's sarcoma (KS) of the throat and stomach. Individuals undergoing an upper GI exam should have nothing to eat for the eight hours prior to the examination. Smoking and chewing gum before the exam is discouraged because they stimulate stomach secretions that can dilute the contrast agent. Most medications are also restricted for eight hours prior to the examination, but always consult with a doctor before stopping or altering a medication regime. An upper GI exam requires that patients drink the contrast agent (barium sulfate) while the x-rays are taken. Often a second contrast agent, usually granulated like Alka-seltzer, is added. These secondary agents are quickly swallowed and produce a gas (carbon dioxide), which allows the radiologist to better visualize the mucosal surface of the throat and stomach. When both liquid and gas contrast agents are used, the procedure is called a double contrast exam. Lower GI Exams A small bowel exam is used to visualize the small intestine. This exam is generally combined with an upper GI exam but can be done alone. It is needed for diagnosing CMV, Cryptosporidium, and MAC infections as well as intestinal KS and lymphoma. As with the upper GI exam, the patient drinks a contrast agent. A barium enema is used for x-ray images of the large intestine, which are needed for detecting CMV colitis, aphthous ulcers, and KS. Careful preparation is necessary for a barium enema. If time allows, patients should eat foods low in residue for several days prior to the exam. A low residue diet excludes fresh fruits, and vegetables, fatty and fried foods, whole grain cereals and breads. Increasing fluid intake for two to three days prior to the exam also is recommended. This helps clear the large intestine of waste before the examination. Twenty-four hours before the examination, a clear liquid diet should be consumed. Clear liquids include coffee or tea with sugar but no milk, clear gelatin, clear broth, and carbonated beverages. The afternoon before the barium enema, a laxative is prescribed -- the type and amount governed by the patient's condition. A cleansing enema is usually prescribed to remove any additional residue on night or the morning before the exam. A barium enema exam will be canceled if the lower bowel is not properly cleaned. The barium sulfate is given via an enema. The mixture is administered through a tube placed in the rectum. Taking in short breaths while the tip is being inserted will be more comfortable. The exam can last up to 45 minutes and requires the patient to assume a number of different positions while lying on the x-ray table. Patients cannot evacuate their bowels (go to the bathroom) during the exam period. It is often routine, though, to have a final x-ray taken after the patient goes to the bathroom and evacuates as much of the barium as possible. Because x-ray exam procedures vary from institution to institution and from patient to patient, patients should ask their doctors for specific instructions. CT Scan A CT scan is actually many x-ray images taken in rapid succession. Each image is a thin slice very much like the way you would slice a loaf of bread. Unlike standard x-ray machines, a CT scan requires the patient to lie on a bed that is moved in and out of a gantry with a hole in the center as the x-rays are being taken. CT scan images provide a high degree of accuracy and detail not obtained with traditional x-ray techniques. CT scans are used more and more to aid in a better diagnosis of tuberculosis (TB), pneumocystis carinii pneumonia (PCP), infections of the brain and spinal cord (i.e., encephalitis, toxoplasmosis, meningitis and progressive multifocal leukoencephalopathy (PML). CT scans are also used to guide needle biopsies, allowing the doctor to accurately position the needle at the desired site. Breathing in the course of some types of scans is very critical, and the radiographer will instruct the patient when to breathe. As with other special x-ray exams, contrast agents may be used in CT scanning. The contrast agents normally used contain iodine, though more expensive non-iodinated contrast agents are available. The contrast agent is administered by way of an intravenous (IV) drip but can be taken orally as in GI exams. Special contrast CT scans involve the automatic intravenous injection of contrast agent that is activated as the scan begins. Contrast Reactions Allergic reaction is a major consideration when using any contrast agent. Allergic reactions are rare and usually consist of mild itching, rash, hives and sometimes nausea. But reactions can be severe enough to cause death if not caught in time. Patients should tell the radiographer (person performing the x-ray exam) immediately if they feel sudden itching, see a rash developing or experience any trouble breathing. Contrast reactions happen more often with IV administered contrast. It is very important that patients who have a history of asthma or have allergies to seafood (which also contain iodine) or previous contrast agents inform the doctor or radiographer of this before the exam. The administration of drugs such as benadryl or epinephrine are used to control allergic reactions. These drugs can be given prophylactically (to prevent the reactions from arising) in persons with known allergies to contrast agents. Special Note for Women Because x-radiation can be dangerous to a fetus, women should tell their radiographers or doctors if they even suspect that they are pregnant. If it does not interfere with the exam, shielding should be provided, usually in the form of a lead apron. References Radiology of AIDS, Michael P. Federle, Alec J. Megibow, David P. Naidich. Raven Press, New York 1988. Basic Medical Techniques and Patient Care for Radiographers, Lillian S. Torres, J.B. Lippincott Company, Philadelphia 1989. **************** Washington Watch by Rich Lynn Reviewing the Research Agenda Until 1993, the federal government's AIDS research monies were allocated to the various institutes making up the National Institutes of Health (NIH). The institutes then dispersed the money to programs of their choice. Many community activists and even the National Academy of Science called for more coordination. At the urging of a coalition of AIDS organizations and researchers, the Congress overhauled the way the NIH managed its AIDS research programs in the NIH Revitalization Act of 1993. This legislation gave budgetary and coordination authority for all NIH AIDS spending to the Office of AIDS Research (OAR) at the NIH. Congress also mandated that the OAR conduct a comprehensive review of the NIH's AIDS research programs to help determine the Institutes' AIDS priorities. As this review was to be the government's first overall analysis of the NIH's AIDS efforts, the recommendations of the review committee were expected to have far-reaching effects. The OAR was forced to spend most of its early months fighting for staff positions and asserting its power with entrenched NIH bureaucrats who resented the OAR's new role. The review finally started this spring in preparation for the planning for fiscal year 1998 that will occur next year. The OAR was given no power over funds that had already been committed, so the OAR only gains control of funds when existing commitments expire. Since most grant and contract awards last for multiple years, the first year in which the OAR will control a substantial amount of funds is fiscal year 1998. (The director of the OAR does have a modest discretionary budget that he can use to fill in gaps identified by the review before 1998.) The OAR divided the work of the review amongst an oversight and coordinating committee called the Evaluation Working Group and six Area Review Panels. The panels have each been assigned one of the following areas: 1) Drug Discovery, 2) Etiology and Pathogenesis, 3) Natural History, Epidemiology and Prevention, 4) Behavioral, Social Science and Prevention, 5) Vaccine Research and Development, and 6) Clinical Trials. Each panel contains fifteen to twenty members, with each member expected to devote a substantial amount of time to the panel's work. Members of the panels include activists and community representatives (this writer among them) in addition to prominent researchers and industry representatives. There are some vocal critics of government programs, too -- scientists who supported NIH reform at a time when it was professionally risky for them to do so. In addition, younger researchers are represented on the panels. Such researchers would benefit the most from an intelligent, sweeping redesign of government AIDS research. Most of the area review panels have met at least twice. The panelists have grappled with two issues in these early meetings: what is the true mission of this committee and how are we going to find the information we need to do our work? None of the scientists had ever participated in an effort of this kind before. All the participants have reviewed grant proposals or another's research and some have even analyzed a department or a major program, but none have been asked to dissect a billion dollar endeavor. Members of the committees are clearly intimidated by the scope of their mandate. Uncovering which programs and personnel are successful and which are failures or merely redundant, and determining how to establish new programs and attract new, more insightful investigators threatens to upset well-established fiefdoms. Among these is the large in-house effort at the National Cancer Institute's own laboratories, which consumes one-tenth of the national AIDS research budget. Participants have discussed the temptation to focus on specific grants instead of the bigger picture. The purpose of the review is not to critique individual research, but to decide if suitable research is progressing in the right areas. They must decide what mechanisms are needed to insure that such research does get done. Without a set of mechanisms for keeping research priorities and funding mechanisms current, AIDS research will ossify as researchers compete with each other to answer the same questions over and over. Still, nothing will happen if the committees have insufficient information. Unfortunately, obtaining data from the NIH is a logistical nightmare. All of the NIH's policies, procedures and information systems have been designed to support an arcane budgeting process, not to assist anyone actually trying to analyze NIH spending. As one member of my panel stated, "Government budgeting and accounting systems are designed to provide reports that are crystal clear and completely wrong." The majority of institutes can provide a summary of their total spending and not much more. Congressional mandates have made the situation with AIDS marginally better. We can obtain listings of all grants in the area of AIDS research. But these reports only include the title of an application, the amount, the area of research and in some cases, the abstract that accompanied the investigator's original application. As investigators realize that their abstracts will be a matter of public record, they become extremely vague so as not to provide competing scientists with specifics of their research. Some of the abstracts are so unspecific, that it is not even apparent how the proposed research relates to AIDS. Nonetheless, the starting material for all the committees consisted of intimidating stacks of printouts of these grant abstracts as well as some program summaries and requests that were used to solicit applications. It took the NIH staff two months to disgorge this disjointed muddle. Conspicuously absent from the stack were investigator progress reports, the specific objectives section from investigator applications, and information about grants that went unfunded. Such information would have provided a clearer sense of what the NIH's priorities have been over the past years. But providing information on individual projects would violate the confidentiality of the grant review process, says the NIH, which has deemed that data beyond the scope of the review. Instead, the review panelists will be allowed only to interview the various NIH officials who coordinate grant reviews and funding initiatives. Having to resort to this roundabout strategy will lengthen and complicate the review. If the program officers turn out to be forthcoming, though, it may be more helpful than trying to sort through piles of uncategorized information. The review will only be as good as the information available to work with. And besides the challenge of finding the relevant information, panelists will have to devise new ways to organize and measure what they expose to enable them to reach some reasonable conclusions. Many committees will find it difficult just to connect specific initiatives with specific results. For example, the drug discovery panel must determine the effectiveness of the NIH's drug discovery programs when there is no clear way to figure out which compounds were discovered with NIH resources. The obstacles to an effective review are formidable and many in the research and activist communities have been quick to criticize the review of research projects. Indeed, in its current understaffed state, the OAR has not been able to move as quickly as its supporters had hoped. But perpetually sniping at the OAR and its review effort plays right into the hands of the right-wingers in Congress who would just as soon strip the OAR of its power and then defund AIDS research entirely as the institute heads bicker among themselves. Our best defense against this onslaught is a coherent plan that would lay out the research, drug discovery and prevention efforts that must proceed for a cure to be found. The OAR review must produce this strategy for AIDS research to continue. Without a strategy for researchers and our remaining allies in Congress to rally around, it will be impossible to protect AIDS research -- particularly if we are faced with a Republican president as well as Republican Congress after 1996. Alert -- AIDS Research Budget in Danger! On July 11, the House of Representative's Subcommittee of Appropriations for Labor, Health and Human Services took steps to eliminate the OAR's authority to direct the NIH's AIDS research budget. More importantly, the committee removed the budgetary requirement that the NIH allocate a certain amount of its funds to AIDS research. As Treatment Issues went to press, this measure had been approved by the full House Appropriations Committee, but not the House floor or the Senate, and its future is uncertain. The fact that it has gotten this far, though, underscores the importance of the need for strong leadership from the OAR to create a cohesive and respected AIDS research agenda. The review process mentioned on these pages is central to this effort. -- TS ************************************************* CDC Recommends HIV Testing for All Pregnant Women by Dave Gilden On July 7, the Centers for Disease Control and Prevention (CDC) issued new guidelines urging "voluntary" HIV testing for all pregnant women. The agency report stated, "Because specific services must be offered to HIV-infected women to prevent perinatal transmission, PHS [the Public Health Service] is recommending routine HIV counseling and voluntary testing of all pregnant women so that interventions to improve the woman's health and the health of her infant can be offered in a timely and effective manner." Several factors have contributed to the CDC announcement. Most immediately, several states and Congress are considering proposals to institute mandatory HIV testing of all newborn babies. At Treatment Issues' press time, the House Commerce Committee had just defeated one attempt to impose such testing, the Coburn amendment to the Ryan White CARE Act (which provides funding for AIDS services). Nonetheless, some measure mandating HIV testing of all infants seems likely to pass Congress this year. Testing of newborns is in reality testing of mothers: The usual HIV test checks for antibodies against HIV, not the virus itself. Babies carry their mothers' antibodies for up to eighteen months. Although all babies born to HIV-positive mothers test HIV-positive themselves, only about a quarter of them have actually contracted the virus from their mothers. The CDC estimates that 7,000 HIV-infected U.S. women give birth annually, resulting in one to two thousand babies with HIV. Based on scattered studies, the agency also estimates that under the old 1985 guidelines, which promulgated a testing strategy that targeted women who report high risk behaviors, half or more of the HIV-positive pregnant women were never identified. Until recently, more comprehensive testing of expectant mothers would not have had much of an impact on the number or health of babies with HIV. But the results of ACTG 076, a trial using AZT during pregnancy and in the early weeks of a baby's life to impede HIV transmission from mother to child, have wrought a sharp change in official attitudes. The 076 regimen achieved a two-thirds reduction in such "vertical" transmission. (See Treatment Issues, March, 1994, pages 15- 16.) According to Martha Rogers, M.D., chief of the epidemiology branch of the CDC's Division of HIV/AIDS Prevention and main author of the testing guidelines, "The guidelines were sparked by the AZT trial, which increased the need to test women who don't know their HIV status before pregnancy." There are many limitations to the 076 study. Among them are: the women tested were relatively healthy (half had CD4 counts over 500) and had not had extensive prior AZT therapy; it is unclear what phase of the AZT treatment was effective -- the capsules during the last two-thirds of pregnancy, the intravenous AZT during labor or the syrup given to the baby for six weeks after birth; and the treatment's long-term effects on the children (including birth defects, cancer, damage to muscle and heart tissue) will not be known definitively for several decades. Besides, there are several other potential treatments that are probably safer and may be more effective. The wide range of possibilities include the anti-HIV drug nevirapine, HIVIG (concentrated HIV antibodies extracted from other people), vitamin A, and vaginal cleansing (lavage) just prior to birth. There also are studies suggesting that only women with relatively high HIV levels transmit the virus to their babies. (See Treatment Issues, March 1995, pages 2-3.) Pregnant women with high viral loads may be the only ones in need of therapy to prevent transmission. Excessive use of AZT increases the likelihood of needlessly breeding AZT-resistant virus, making the drug useless to women when they might need it later on to ameliorate their own medical condition. These lingering questions did not stop the CDC from issuing a set of guidelines last August that strongly favored following the 076 therapy schedule as much as possible in all women with HIV. Defending the AZT guidelines, Dr. Rogers of the CDC said, "AZT is what we have right now. Other things are not proven, but sound scientific study shows that women with the trial characteristics were benefited by AZT. The AZT guidelines make clear that our information is limited and that counseling should make clear the risks and benefits." Changes in the standards for care for babies exposed to HIV have also increased the urgency around the testing issue. On April 23, the CDC issued a revised set of guidelines for prevention of Pneumocystis carinii pneumonia (PCP) in infants "exposed" to HIV. Citing the tendency for babies with HIV to suddenly develop catastrophic cases of PCP accompanied by precipitous drops in CD4 count, the CDC wants pediatricians to institute PCP prophylaxis, primarily with Bactrim, in all infants six weeks to a year old who are born to HIV-positive mothers and in whom HIV infection cannot yet be excluded. Advances in testing technology have made the PCP prophylaxis guidelines more practical by making it easier to determine which babies really have HIV. This fall, the Hoffmann-La Roche drug company plans to seek FDA approval for using its diagnostic polymerase chain reaction (PCR) test in newborns. The PCR test is a very sensitive one that directly detects HIV, not antibodies. Still, it is not very accurate until the baby is one month old. It is also rather expensive (about $200 per test). For the purposes of ending needless PCP prophylaxis, the CDC recommends performing two PCR tests on the baby, at one month and four months. If both are negative, the baby is considered uninfected. The three-part AZT therapy, the PCR tests, the Bactrim: this all amounts to a complicated medical regimen with high potential for side effects that require further medical management. This is the reason why the testing should be voluntary, asserts Dr. Rogers. "The women enter into a whole process for better health of mother and baby. Women want what's best for the baby, but if you take a mandatory approach, you set the wrong atmosphere," Dr. Rogers said. Perhaps, though, the wrong atmosphere is already set by focusing on women as carriers of babies. It is best to know that you have HIV as soon as possible, regardless of whether you are pregnant or not. Pregnancy, with all its other stresses, is a bad time to find out you are HIV-positive, points out Marion Banzhaf, director of the New Jersey Women's AIDS Network. "The shock and denial have a particularly negative impact then," she observed. The obstetrics establishment is not known for its patience with pregnant women. It is noteworthy that one of the biggest proponents of mandatory infant testing on Capitol Hill, newly elected Rep. Tom Coburn (R-OK) is an obstetrician by profession. If the health care system's entire approach to the HIV testing issue is set up out of concern for the babies and not the mothers, Banzhaf warned, "The pressure will build an antagonism into the mother-child relationship. Women want to do what's best for their babies, but this becomes an issue of state control of reproduction." Many women will find reasons to reject the 076 regimen. All pregnant women with HIV will be urged to follow the course of AZT treatments even though it will make a difference in outcome in only one out of six babies. The doubts about the treatment's safety have yet to be resolved. And AZT's side effects, such as nausea, fatigue, weakness and anemia, are likely to be especially intolerable to someone already enduring the effects of pregnancy. If women reject their care providers' advice at any point, they will find out how voluntary the system is. The HIV Law Project in New York City says that it already has two clients whose doctors reported them to child welfare authorities when they refused to give AZT to their infants. The CDC advocates training medical professionals to be able to counsel women in a more supportive and sensitive manner, although the effectiveness of such training has yet to be established. Now comes Congress (and several the state legislatures) trying to force testing of babies whose mothers refuse HIV testing before their birth. For women with HIV, such measures add to the threat of coercive medical care without providing any protection at all against abuse of power by medical practitioners. ------------------------------------------------------- Distributed by AEGIS, your online gateway to a world of people, information and resources. 714.248.2836 * 8N1/Full Duplex * v.34