[Electronic distribution for GayCom by the Backroom 718 951-8256] Volume 7 no. 6 June, 1993 Gay Men's Health Crisis: Treatment Issues > The Collapse of Early Intervention at the Ninth Int'l AIDS Conference > AZT/ddI/ddC recommendations > Viral Skin Disorders in AIDS > Issues in CMV Drug Development > Treatment Briefs >> Vaginal Douching Increases PID Risk >> FDA To Regulate Vitamins, Minerals; Public Comments Sought >> FDA Committee Rejects Potential KS Drug >> Two AIDS Gene Therapy Trials Approved >> Doctors' Group Votes For Gay Rights >> Intralesional GM-CSF for Kaposi's Sarcoma? >> NIAID Announces TB Agenda > Washington Watch ============================ ============================ The Collapse of Early Intervention at the Ninth International AIDS Conference by Derek Link (Editor's Note: Treatment Issues will present coverage of the Ninth International Conference on AIDS in Berlin in both the July and August editions. In this issue, we will present an overview of the data on nucleoside analogue therapy (AZT, ddI and ddC) from the International Conference and the recommendations of the recent "State of the Art" conference in Washington. In the August issue we will present comprehensive coverage and analysis of the Berlin meeting.) The Ninth International AIDS Conference in Berlin was one of the bleakest moments since the AIDS crisis began. Large, definitive studies prove that treatment with the nucleoside analogs (AZT, ddI and ddC), the cornerstone of current HIV treatment, is, at best, only marginally effective for a brief moment of time. Other large studies prove that early AZT use does not delay progression and prolong survival in asymptomatic patients for up to three years, and that combination AZT/ddC treatment is clearly no better, and perhaps even worse, than monotherapy. The belief that AIDS could somehow be transformed into a "chronic and manageable" condition through the right mix of nucleoside treatments was shattered in Berlin. In response, the National Institutes of Health (NIH) convened a panel of experts for a "State of the Art Conference on Antiretroviral Therapy for HIV-Infected Patients" on June 23 to 25 in an attempt to make sense of the data and draft new treatment recommendations. After three days of intense scientific discussion, the panel made specific recommendations which address two critical themes in HIV clinical care: When should patients start AZT? How should ddI and ddC be used? Although these recommendations have not been finalized, it is unlikely they will change considerably since they have already been distributed nationwide. The final recommendations will be submitted to a peer-reviewed journal later this summer. In writing its draft recommendations, the panel was forced to deal in matters of belief and faith, not data. Virtually all the information upon which the recommendations are based is negative or conflicting. The panel had an extraordinarily difficult time reconciling studies which point in different directions, or demonstrate no benefit to the drugs. Dr. John Hamilton, an AIDS researcher at the Veterans Administration in North Carolina, summed up the meeting best when he commented that the data "extend the scope of our ignorance." In this article, we review the specific recommendations of the panel in regard to particular subgroups of patients. An overall analysis of the specific studies which support each recommendation reveals that the panel relied heavily on judgement calls and negative data in its deliberations. Recommendations for INDIVIDUALS considering AZT who have not taken any antiretroviral treatment before AZT vs. ddI vs. AZT/ddC First and foremost, the panel reaffirmed that AZT is first-line therapy, based on data from two studies which agree with each other, ACTG 119 and 116A. ACTG 119 showed that AZT is superior to ddC for initial therapy; ACTG 116A showed AZT is superior to ddI for initial therapy. The panel recommends AZT monotherapy 500 to 600mg per day as initial therapy for all patients. Although combination therapy has been proposed as initial treatment, little data exist to support this theory. ACTG 106 demonstrated higher CD4 cell rises in combination AZT/ddC regimens. However, ACTG 106 was very small (n=56) and did not collect clinical data. Data from studies designed to answer this question, most notably ACTG 175, will not be available until 1995. (However, one significant limitation of ACTG 175, in light of the Concorde study, is the trial's lack of a placebo arm. In other words, the trial only compares combination therapy to monotherapy, and not to "deferred" or no therapy). Asymptomatic, Above 500 CD4 cells In patients with above 500 CD4 cells, the panel recommended monitoring, but not AZT. This decision is based on information from two studies. The Concorde study team analyzed 710 people who entered the study with greater than 500 CD4 cells. At three years, early AZT neither reduced disease progression nor improved survival. A European-Australian study of early AZT in people with greater than 400 CD4 cells also showed no improvement in progression and survival at 93 weeks. Finally, the greater than 500 CD4 subgroup of ACTG 019 is still ongoing; the study will close this December. Data are expected in 1994. Asymptomatic, 200 to 500 CD4 cells For asymptomatic patients with 200 to 500 CD4 cells, the panel recommended consideration of two options: AZT or continued monitoring. Two studies were presented which show that AZT does not improve disease progression and survival in this group up to three years: Concorde and the long-term follow-up of ACTG 019. Concorde evaluated immediate versus deferred AZT in 1749 patients followed for three years. Long-term follow up of ACTG 019 followed 1565 patients for an average of 2.6 years. Both studies proved that early AZT does not delay progression beyond one year or improve survival overall. [See Treatment Issues (May 1993) for a review of Concorde.] Furthermore, a European-Australian study of AZT in asymptomatic patients with 200 to 400 CD4 cells showed no difference in disease progression at two years. In short, it is hard to know what data the panel recommends front-line physicians consider when evaluating AZT treatment for this patient group. Symptomatic, 200 to 500 CD4 Cells For symptomatic patients with 200 to 500 CD4 cells, the panel recommended AZT. Two studies support AZT's ability to delay progression in this patient group. ACTG 016 and the VA Cooperative study both examined AZT in mildly symptomatic HIV-infected people with 200 to 500 CD4 cells. ACTG 016 enrolled 513 patients in this group and followed them for an average of eleven months. The VA study enrolled 338 patients in this group. AZT did not prolong survival in the VA study; survival information is not available from ACTG 016. Therefore, the panel recommended AZT treatment in this patient group despite data which show no survival advantage to the drug. Recommendations for individuals who are tolerating AZT Above 300 CD4 cells For patients who "appear stable" on AZT with CD4 counts above 300, the panel recommends continuing AZT. There are no data describing what to do in this specific group of patients. This recommendation was based on the clinical judgement of the panelists that "if it ain't broke, don't fix it" (again, this seems to rely on a presumption that therapy should be used, rather than the reverse). Below 300 CD4 Cells For patients with CD4 cells below 300, the panel recommends consideration of two options: continue AZT or switch to ddI. While there are no data which specifically address this question, there are several factors to consider. Advocates for a switch to ddI cite data from ACTG 116B/117, a study of AZT versus ddI in 913 patients who received, on average, thirteen months of prior AZT. In this study, ddI delayed progression of disease in asymptomatic and ARC patients, but not in people with AIDS. ddI did not improve survival in any study group. Those who support continued AZT emphasize their reluctance to place patients tolerating AZT on ddI, a drug with an entirely different set of serious toxicities. RECOMMENDATIONS FOR INDIVIDUALS WHO ARE INTOLERANT TO OR HAVE FAILED AZT AZT-Intolerant, 50 to 500 CD4 cells For AZT-intolerant patients between 50 and 500 CD4 cells, the panel recommends switching to ddI monotherapy. This recommendation is based on CPCRA 002 which compared ddI with ddC in AZT-intolerant patients with under 200 CD4 cells. The median CD4 cell count of those who enrolled in the study was under 50. This study demonstrated that ddI and ddC are equivalent in this group. However, there may be a slight survival advantage to ddC in this group, based on the CPCRA study. No other data exist which define the optimal time to switch treatments. AZT-Intolerant, Below 50 CD4 Cells For AZT-intolerant patients with under 50 CD4 cells, the panel recommends consideration of three options: ddI monotherapy, ddC monotherapy, or discontinuing antiretroviral treatment altogether. This group has few clearly defined treatment options. In fact, there is no proof that ddI or ddC is better than no treatment in this patient group. CPCRA 002, a study of ddI versus ddC in 467 AZT-intolerant or failed patients with under 50 CD4 cells, demonstrated a marginal survival benefit to ddC monotherapy. However, the difference in this study is so small that consideration must also be given to differential drug toxicities. Furthermore, the panel did not recommend combination in this group. Data from ACTG 155, the first definitive combination efficacy study, demonstrated that patients with under 50 CD4 cells may have had faster progression, lower survival, and more toxicities, when placed on combination AZT/ddC treatment. ACTG 155 included 991 patients who had received an average of eighteen months of prior AZT therapy. Furthermore, the ddC monotherapy arm had the fewest toxicities. Failed AZT, 50 to 500 CD4 Cells For patients with 50 to 500 CD4 who experience clinical progression while on AZT, the panel recommends switching to ddI monotherapy or combination treatment with either AZT/ddI or AZT/ddC. This recommendation is based entirely on speculation and hope. Although a switch to ddI monotherapy may be suggested by ACTG 116B/117, combination therapy is harder to understand. ACTG 155 demonstrated no delay in progression or improvement in survival in patients placed on AZT/ddC combination compared with those continued on AZT or switched to ddC alone. This recommendation rests on the hope that future combination therapy regimens will demonstrate clinical benefit, and a subgroup analysis from ACTG 155 which showed a possible benefit to combination AZT/ddC in patients with 150 to 300 CD4 cells. Failed AZT, Below 50 CD4 Cells For AZT failures with under 50 CD4 cells, the panel recommends switching to ddI or ddC monotherapy. This recommendation was based on reasoning similar to that for the recommendation to AZT- intolerant patients with under 50 CD4 cells. Conclusion Rapid changes in our understanding of nucleoside analog therapy occurred at the International AIDS Conference in Berlin. The treatment guidelines issued by the NIH-convened panel of experts are limited by lack of data supporting the efficacy of nucleoside therapy in virtually all patient groups. Also, the studies were designed to obtain approval of the drugs, not address questions in clinical care. The impact of the new data and treatment recommendations on clinical care, research, and drug approval will likely be enormous. ============================ ============================ Viral Skin Disorders in AIDS by John Chism The skin and mucosa are the body's first defense against countless microbial threats, such as bacteria, fungi, protozoa, and viruses. But this line of defense depends on a functional immune system. When the immune system is suppressed, disorders of the skin may appear. Organ transplant and cancer patients who undergo immune suppressive therapies can develop skin disorders, such as Kaposi's sarcoma or herpes outbreaks. In HIV infection, skin disorders often occur early in disease and may recur or become chronic. In HIV-infected people, skin disorders caused by viruses are common. This article reviews viral skin diseases in AIDS and emphasizes that early detection and treatment are the best course of action. MOLLUSCUM CONTAGIOSUM Molluscum contagiosum is caused by a poxvirus. Molluscum are benign, pimple-like lesions which occur in both children and adults; the primary sites of involvement for adults are the face, buttocks and genitals. In appearance, molluscum are smooth translucent bumps, sometimes flesh-colored, sometimes yellowish or pearly. The lesions have a sack-like core of viral material. They may cause mild discomfort and cosmetic frustration, but are neither acutely painful nor life-threatening. Molluscum is believed to be transmitted by both sexual and nonsexual routes, although epidemiological data are inconclusive. Since molluscum usually goes away on its own in healthy people, those with it often do not see a doctor. Furthermore, molluscum is not reported to public health authorities like other sexually transmitted diseases. Before AIDS, molluscum was primarily regarded as a childhood disease transmitted through ordinary child's play. Strong indirect evidence from studies of prostitutes and those attending STD clinics supports the belief that molluscum is transmitted sexually.[1] Other reports suggest that it may be spread by nonsexual routes such as baths, swimming pools, sharing towels, and contact with infected family members. Nonsexual transmission is uncommon in North America and Europe, though, except among children. The limited epidemiologic data which do exist indicate that reported molluscum infections have increased eleven-fold since 1966,[2] are five times more likely to occur in men than women, and two to four times more frequent in whites than blacks. In HIV-infected people, molluscum lesions can number in the hundreds or thousands,[3] which is uncharacteristic of molluscum in those uninfected with HIV. In uninfected people, or those with few lesions, molluscum is treated by physical destruction of each lesion. Several techniques are used, although none has been evaluated in controlled studies. Scraping or scooping the lesion off the skin through minor surgery is a common method. Cryotherapy, freezing the lesion with liquid nitrogen, is another method of direct physical destruction. Often, the affected area is treated with chemicals (such as phenol, silver nitrate, trichloroacetic acid, or iodine) or cauterization after physical removal of the lesion. However, physical removal of each lesion is often impractical in people with AIDS because multiple lesions may cover the face or genital areas. When surgical techniques are impractical, there are no effective drugs to treat and cure molluscum in people with AIDS. Topical treatment with podophyllin, canthraradin, retin-A, silver nitrate, phenol, or trichloroacetic acid may be effective to a very limited degree. Systemic treatment with oral isoprinosine, a purported immunomodulator available in some buyers' clubs, does not appear effective for molluscum, despite encouraging preliminary results from Sweden. HERPES SIMPLEX VIRUS Herpes Simplex Virus (HSV) can produce recurrent, painful lesions on the genitals, anus, mouth, and face in people with HIV. HSV is sexually transmitted. It enters the body through broken skin or the mucosa. Although serologic tests are available to determine if you have been infected by HSV, the vast majority of people with AIDS are already infected. HSV infections have a fundamental connection to AIDS: chronic HSV lesions on the skin and mucosa are an AIDS-defining diagnosis and HSV genital lesions are believed to be a risk factor for subsequent or concurrent HIV infection.[4] Once HSV enters the body, it remains latent in the nervous system for the life of the individual. Periodically, HSV may reactivate and produce painful lesions which can last several weeks. The lesions are blister-like ulcers on outer layers of reddened skin or mucosa. The lesions can be extremely painful. HIV-infected people have a much higher rate of HSV recurrences; often HSV outbreaks may become chronic. Additionally, HSV lesions in HIV-infected people can grow much larger than those in healthy people. A lesion can grow to cover the entire buttocks, for example, or two thirds of a patient's face.[5] Sometimes the entire body is covered with small ulcers.[6] Although HSV skin lesions are not life-threatening, the pain and suffering they cause can be substantial. (HSV can also cause life-threatening infections of the brain, lungs, and GI tract.) Acyclovir (Zovirax, Burroughs Wellcome) is an effective, approved therapy to treat and prevent HSV lesions. The drug comes in several forms: the topical, cream form is used for milder outbreaks and the pill or intravenous forms are used for more severe illness. Many people with HIV are placed on chronic, suppressive oral acyclovir therapy to prevent HSV outbreaks. Recently, HSV strains resistant to acyclovir have emerged. In these cases, foscarnet (Foscavir, Astra) is an effective, but more toxic, alternative. Foscarnet is given intravenously. In addition, research is underway to find better treatment options for HSV and acyclovir-resistant HSV. HERPES ZOSTER: "SHINGLES" Shingles is another viral skin disorder that occurs in HIV-positive people. It is caused by the Varicella Zoster Virus (VZV), the herpes virus responsible for childhood chicken pox. After a childhood episode of chicken pox, VZV is not eliminated from the body. It remains latent for years in the nervous system. Although VZV remains in the body through adulthood, most adults never experience a reactivation of the virus. However, reactivation occurs in approximately 10 to 20 percent of adults who had childhood chicken pox. Reactivation of latent VZV is more common in HIV-positive people. A small number go on to experience three or more outbreaks of shingles. Early detection and treatment of shingles often resolve the problem in a matter of days, but delays in treatment can extend treatment to more than three weeks, and increase the likelihood of residual pain. The classic symptom of shingles begins as a slight sunburn-like feeling on the skin, often around the upper torso, upper arms, or face, which progresses within a day or two to a painful outbreak of reddened skin and fluid-fulled red sores. The pattern of the outbreak on the skin may delineate the track of the affected nerve. In HIV-negative people, the outbreak is usually confined to a small area of the body and often affects just one side of the body. In HIV-positive people, the outbreak can affect both sides and be much more extensive. HIV-related shingles is extremely painful. While skin manifestations of VZV are not life-threatening, the virus can involve the eye, resulting in blindness. Also, VZV can spread to the lungs or the central nervous system, although this is rare.[7] Treatment for shingles is oral or intravenous acyclovir. Axsair or Zostrix creams can be applied topically to alleviate pain and infection with bacteria.8 Intravenous foscarnet can be used in acyclovir-resistant VZV. Furthermore, experimental drugs, most notably Bv-ara-U and 882C, have shown preliminary success against VZV. HAIRY LEUKOPLAKIA Oral hairy leukoplakia (OHL), once thought unique to HIV-positive people, occurs in other patients who are immune-suppressed, such as renal transplant patients. The disease was discovered in 1984 and manifests itself as white, plaque-like growths on the sides of the tongue or raised lesions with a corrugated texture.[9] The tongue isn't the only site of occurrence, but it is the most common. OHL can also occur in other parts of the oral mucosa, but it is never found on other mucous membranes outside the mouth. Although the exact cause of OHL is not yet determined, the Epstein-Barr Virus (EBV), another herpes virus, plays a critical role. The presence of EBV in a OHL lesion is a requirement for diagnostic purposes. However, diagnosis of EBV in OHL lesions requires in situ hybridization, a technique not routinely available. While OHL is not life-threatening, nearly all patients with HIV who come down with it are likely to develop other AIDS-related symptoms later.[10] There is controversy among treating physicians whether to treat OHL. Since OHL is usually painless and not life- threatening, patients often request treatment for cosmetic reasons. Systemic antiviral treatment with acyclovir or ganciclovir has been suggested. Often physicians are reluctant to begin systemic antiviral treatment for OHL alone. Other reports suggest the use of topical treatment, such as retin-A and podophyllin in cases where systemic antiviral therapy is unwarranted.[11] GENITAL WARTS There are at least 50 related Human Papilloma Viruses, three groups of which lead to various diseases of the genital area. HPV 6 and 11 cause anal and genital warts; HPV 16 and 18 are highly associated with invasive cervical cancer; HPV 31, 33, and 35 have a lower, but still significant, connection to cervical cancer. [Editor's note: See Treatment Issues Vol. 6, No. 7, the special issue on women and AIDS, for a review of HPV.] [12] HPV genital warts can occur on virtually any part of the vagina, penis, or anus, and are usually visible, cone-like, flesh-colored growths. Warts can also grow inside the vagina, anus, or urethra, making detection more difficult. Genital warts may also be subclinical -- that is, they are invisible until painted with acetic acid. Individuals with subclinical warts are infectious, despite the absence of obvious growths. Therefore, individuals who have had sex with someone with genital warts should be examined by a physician, even if they have no obvious signs of infection. Genital warts are treated by surgical removal, topical treatment, or by local injections of alpha-interferon. HIV-infected people often have multiple warts, making surgical removal difficult. Therefore, alpha-interferon injections are increasingly common. However, warts can recur despite treatment. Optimal treatment to prevent or reduce recurrences in HIV-infected people has not yet been defined. CONCLUSION While many viral skin disorders common in HIV-infected people are not ordinarily life-threatening, they can cause significant pain, illness, and cosmetic frustration. In some cases, viral skin diseases can spread to infect other parts of the body, possibly resulting in life-threatening conditions, like HSV encephalitis. The early detection, prophylaxis, and treatment of skin diseases is clearly the best approach to take. 1 Postlethwaite R. Archives of Environmental Health. 1970. 21:432. 2 Becker TM, et al. Sexually Transmitted Disease. 1986. 13:18. 3 Stone MS, Lynch PJ. in Principles and Practice of Dermatology. Editors: W. Mitchell Sams Jr.and Peter J. Lynch. Churchill Livingstone. 1990. 4 Holmberg SD, Stewart JA, et al. JAMA. 1988, 259(7):1048-51. 5 Cockerell CJ. in AIDS and Other Manifestations of HIV Infection. Editor: Gary P. Wormser. Raven Press. 1992. 6 Corey L. in Sexually Transmitted Agents. Editors: Holmes KK, et al. McGraw-Hill. 1990. 7 Cockerell CJ. in AIDS and Other Manifestations of HIV Infections. Editor: Gary P. Wormser. Raven Press. 1992. 8 Seattle Treatment Education Project. Skin Manifestations Associated with HIV Infection. [chart]. 9 Greenspan D, et al. Lancet. 1984;2:831-4 10 Greenspan JS, Greenspan D. in AIDS and Other Manifestations of HIV Infection. Editor: Gary P. Wormser. Raven Press. 1992. 11 Greenspan JS, Greenspan D. Oral Surgery, Oral Medicine, Oral Pathology. 1989; 67:396-403. 12 Shah KV. in Sexually Transmitted Agents. Editors: Holmes KK, et al. McGraw-Hill. 1990. ============================ ============================ Issues in CMV Drug Development Developing effective and relatively nontoxic treatments for Cytomegalovirus (CMV) is among the most critical needs in AIDS research and drug development. However, the testing of promising CMV treatments raises a number of difficult and complex issues. Derek Link, editor of Treatment Issues, interviewed Dr. David Feigal, M.D., Ph.D., director of the Division of Antiviral Drug Products at the Food and Drug Administration (FDA), and Sandy Kweder, M.D., the division's CMV medical officer, for their thoughts on CMV drug development. TI: Describe what a model CMV New Drug Application (NDA) would be. How has the foscarnet NDA contributed to the understanding of how CMV should be studied? FEIGAL: You have to look at the options in terms of how you study patients. One model is for acute treatment and the other would be for prophylaxis. For acute treatment, one of the options is to find patients who have peripheral disease that is not sight-threatening, follow them closely, and consider a treatment vs. placebo, double- blind design. That would be one option. The other option is to induce everybody with the new drug or with the old drug, put them on maintenance, and compare time to a second episode. There are variations, too. You can induce everyone with standard therapy, but randomize patients in the maintenance phase to remain on the old drug or switch to the new drug. There's many different ways it could go. I think it depends a little on how certain you are that you've got an active drug. There two situations where I think you can ethically study drugs where one of the arms may not be as effective as the other. One is in the area of peripheral disease, because it's not life-threatening or sight-threatening. The other is looking at recurrences, since we currently don't have a drug that will prevent them. We can look at things like number of re-treatments and duration of maintenance as a way of assessing drug activity. KWEDER: No, I think Dave's right. I mean, a lot depends on the individual drug. We're trying to look at a general model here. One of the models that Dave talked about was the small placebo-controlled trial for retinitis patients. And really, that was the cornerstone at NEI. That was the data that best established the activity of the drug. The other studies that they submitted all had problems of their own. FEIGAL: One of the things that creates a logistic problem in these studies is the retinal photos and the ability to have somebody review them who was unaware of the drug assignment. Reviewing the retinal photos can be very, very subjective, and if you've got a treating ophthalmologist who knows the study assignment, it's just human nature that affects your judgement in close calls. So that creates a little bit of a problem for these studies, in that they probably are going to have to be done in centers that can manage to do fundus photographs and that have the resources to pay for the coding and the scoring. There aren't many centers which can do this. The Wisconsin Center that has been used by the Eye Institute for a number of studies -- not just for CMV but for other retinal diseases -- is an excellent center. But it does mean that early testing of these drugs will probably have to be done in specialized centers, rather than a community-based trial, for example. KWEDER: On the other hand, every study doesn't need to have retinal photos. You have to realize that we certainly recognize the costs of doing that, and the need to have the drug used and studied in environments other than specialized, academic, ophthalmology centers, which is not where most patients get treated. FEIGAL: That's true. There may be the options in some of those kinds of studies to get some longer-term follow-up and experience. For example, progression of CMV into the parts of the eye that have the best vision isn't the only way that you get blindness with this disease. You also get it from retinal detachment. It might be possible with future CMV studies to combine a well-controlled photographic study of the slow march of peripheral disease with a larger program that can show whether or not any of these drugs are superior in terms of saving sight. We really don't know how much these drugs preserve vision. It's an extrapolation from the observation that you can slow things down with peripheral disease. TI: The use of peripheral lesion designs has been controversial among community organizations. Since these designs use either a deferred treatment arm or, in some cases, a placebo, people are uncomfortable about giving essentially no treatment to very sick patients. However, I was surprised that in several discussions I've had with CMV researchers, there was almost complete unanimity that a peripheral lesion study would be critical to do first -- to establish that there was activity and some initial efficacy of a new CMV agent before it was put into larger Phase III studies that compares it head to head in patients with sight-threatening disease. What's your perspective on that issue? KWEDER: Really, the only study that there's any data from that's been useful is the Foscarnet study done at the National Eye Institute. And there's not a difference in visual acuity. You know, by the end of that study, the patients in the control group and the deferred treatment group were usually off treatment within some short period of time, and there's no difference in visual acuity. Now, in all fairness, we're talking about small numbers. It's not likely that we'd be able to tell a significant difference in visual acuity in these patients. It's an interesting question, because since I've been dealing with CMV drugs, which has been a few years now, the pendulum has swung. NEI basically did that amidst cries of "no way -- you can't do this kind of study." And Pete Nolan was interested in doing that sort of study. No ophthalmologist anywhere except these guys at the NEI at the time would do it -- and there was a lot of concern as to whether they'd be able to enroll all patients, etc., etc. And I've been surprised to see, and I mean, happy to see, that the pendulum has swung, and ophthalmologists, as they've become more experienced in managing this disease, have become much more comfortable with that sort of a design, provided that they can follow their patients closely. It's been surprising to us as well, but I think it will help some of these drugs in the long run. I mean, you've probably been at the same meetings where I have where you sort of hear all the testimonials from ophthalmologists who say, "Listen, I have patients who all the time just tell me they want to wait -- they're not ready to start treatment when they have peripheral disease." And they go "X" amount of time with not much change in what I can see on ophthalmologic exam. FEIGAL: It could be more of an issue if we had a well-tolerated oral drug. I think the thing that many patients are very aware of what a cramp it puts in your lifestyle to have to have an infusional medication -- even aside from the financial burdens. The morbidity from in-dwelling catheters when you don't have a normal immune system isn't trivial. TI: There are many people who have come to the conclusion that future CMV agents are going to need equivalence studies done before approval to see how the new drugs will fit into the clinical management of CMV. What's your perspective on the use of equivalence studies as a necessary part of an NDA? FEIGAL: There's a lot of room for improvement on the existing drugs, so I hope that the new drugs coming down the pipeline are superior. And the more superior they are, the quicker you can figure it out, because it takes smaller sample sizes and smaller studies to convince you. Strict equivalence really only applies in drug regulation to generics. There's a very set, defined hard-nosed -- it's-got-to-be-this-close- to-the-original-product-or-else -- because of the philosophy behind generics. On the other hand, for approving new drugs, equivalence really isn't the goal. The goal is to show that it's active, and they have some sense of how the drug fits in, compared to other things that are currently the standard of practice. Though it is common to ask for a comparison of the new drug to the current best regimen, we have examples of drugs that are very useful -- fluconazole is probably not as good for cryptococcal meningitis as amphotericin-B. But it's good enough, and it has an important role as a therapeutic option in that disease and probably a nice role in maintenance. Aerosolized Pentamidine is not as good as trimethoprim-sulfa, but for the trimethoprim-sulfa-intolerant patients, it's an alternative that should be available. When there's another drug out there the fear often is, "Oh, gee, you've got to get into these gigantic equivalence trials." These trials can get really large when the existing therapy is very good. Then you don't have very many failures. But when you've got drugs like these where you've got a continuous outcome measure -- for example, duration of disease free interval after induction -- the studies can be considerably smaller, and still get you a result that shows it's about the same or that it may even be superior. Or if it's worse, exactly how much worse is it. So I think with CMV, this is one area where it's less of a concern. It's much more of a problem with acute pneumocystis treatment, where you probably have to have 400 or 500 patient trials to decide how good the drug is compared to trimethoprim-sulfa. I don't know the sample size off the top of my head, but to get an idea of how a new drug stacks up to foscarnet or ganciclovir doesn't take those kinds of sample sizes. The CMV Drug Pipeline by Barclay Dunne Foscarnet (Foscavir, Astra Pharmaceuticals) and ganciclovir (Cytovene, Syntex), the two drugs approved to treat CMV retinitis, are effective, but toxic. Both require long, daily intravenous infusions through a catheter implanted in the chest. In addition to the risk of serious blood infections associated with catheters, they are also physically uncomfortable and emotionally traumatic. For these reasons, the search for new CMV drugs which are not intravenous is a top priority. Several compounds in development may help improve CMV treatment in the near future. New Oral Formulations of both ganciclovir and foscarnet are under investigation for CMV treatment and prophylaxis. Although the oral forms of both drugs are not absorbed well, the companies remain confident that blood levels sufficient to inhibit CMV can be achieved. Oral ganciclovir is further along than foscarnet. Intravitreal implants (Chiron Intraoptics) are small pellets surgically sewn to the inside wall of the eye which release drug directly to the site of infection. The procedure is done in twenty to thirty minutes on an out-patient basis under local anesthesia. The implants release drug directly into the eye for four or eight months. At the end of that period, the old device is removed and a new one implanted. Possible drawbacks include unknown safety risks and no drug delivered to other parts of the body where CMV may be a problem, like the colon and esophagus. Several compounds may be appropriate to use in the implants, particularly ganciclovir and HPMPC. New CMV Prophylaxis: In addition to oral ganciclovir, valacyclovir (BW 256; Burroughs-Wellcome) is in studies which examine its ability to prevent the development of CMV. BW256 is metabolized into acyclovir in the body,reaching drug levels higher than could be achieved by taking acyclovir directly. Trials are under way to determine BW256's potential as a CMV prophylaxis. HPMPC (GS 504; Gilead Sciences) is a nucleotide analog, a new class of antiviral compounds distinct from the familiar nucleoside analogs. HPMPC has broad antiviral activity, especially against CMV. The drug is being developed in both sub-cutaneous and IV forms. Although HPMPC may ultimately be an IV drug, Gilead scientists hope HPMPC will require only once-a-week, or perhaps even once-every- other-week dosing, removing the need for a catheter. Preliminary results from Phase I safety studies indicate that the drug causes significant kidney toxicities which might be reduced with probenicid. Phase II/III efficacy studies are in development. Cyclobut-G (BMS 180-194; Bristol-Myers Squibb) is an oral antiviral drug nearing completion in a 40 patient Phase I bioavailability study at Johns Hopkins. Preliminary results from this study are expected within a few weeks. Monoclonal Antibodies: MSL-109 is a monoclonal anti-CMV antibody. Although monoclonal antibodies were originally dismissed for AIDS- related uses, a phase I study presented at the Berlin AIDS Conference suggested that MSL-109, when combined with either ganciclovir or foscarnet, may delay progression to CMV disease. ============================ ============================ Treatment Briefs by Derek Link Vaginal Douching Increases PID Risk A recent study in Obstetrics & Gynecology (April 1993) suggests that vaginal douching increases the risk of pelvic inflammatory disease (PID), a serious infection of the upper genital tract in women. The study compared 131 women with PID with a large control group. Forty-two percent of women with PID, but only 25 percent of controls, reported recent douching. While the need to douche may be increased among women with PID, the study found a significantly greater incidence of PID among women who douched. Moreover, women who douched most frequently had the greatest risk of PID. Women with HIV have a substantially higher risk of developing PID, and when they do develop the condition, it is often serious and difficult to treat. Women with HIV should be aware that there is increasing evidence that douching may increase the chances of developing PID. FDA To Regulate Vitamins, Minerals; Public Comments Sought The Food and Drug Administration announced in the Federal Register, June 17, new regulations to govern the labeling, content, safety, and health claims made for vitamins, minerals, amino acids, and other diet supplements commonly sold in health food stores and pharmacies. The new regulations would require these products to carry the same sort of labeling now found on processed foods. Health claims for these products would be permitted, but only if FDA "finds significant agreement among qualified experts that these claims are scientifically valid." The proposed regulations also originate from serious safety concerns associated with some of these products, particularly amino acids. A few years ago, 38 people died and hundreds were injured by dietary supplements containing the amino acid L-tryptophan. FDA seeks public comments on its proposal. Written comments should be submitted by August 17 to: Dockets Management Branch, HFA-305, Food and Drug Administration, Room 1-23, 12420 Parklawn Dr., Rockville, MD 20857. FDA Committee Rejects Potential KS Drug DaunoXome (liposomal daunorubicin), an experimental treatment for Kaposi's sarcoma made by Vestar, Inc. of California, was rejected for approval by the FDA Oncology Advisory Committee on June 17. The FDA Committee rejected the application because Vestar scientists offered little data in support of safety and efficacy claims. Vestar scientists presented data from only 39 patients to support their application. Furthermore, only 18 percent (seven patients) had a confirmed partial response to DaunoXome treatment. Two AIDS Gene Therapy Trials Approved Viagene, a California-based biotechnology firm, and Gary Nabel, M.D. of the University of Michigan each obtained approval from the Recombinant DNA Advisory Committee (RAC) of the NIH to proceed with their gene therapy experiments in HIV-infected people. Both trials are small phase I studies which seek to insert genes into the cells of HIV-infected people to ameliorate the course of disease. The RAC must approve all gene therapy experiments conducted at institutions which receive NIH money. In practice, virtually all institutions receive some NIH money. Doctors' Group Votes For Gay Rights The American Medical Association, the nation's largest organization of physicians, voted June 15 to prohibit discrimination based on sexual orientation in its membership policies. Although the AMA rejected a similar proposal four times in the past, John L. Crowe, M.D., AMA president, said "Édiscrimination based on sexual orientation is improper and unacceptable by any part of medicine." Intralesional GM-CSF for Kaposi's Sarcoma? A group of researchers report that local injections of GM-CSF may be effective in treating KS lesions. In a letter to The Lancet (May 1, 1993; 341:1154) the researchers described the case of a 46-year- old man with KS. After three months of treatment with standard KS drugs, vinblastine and vincristine, the lesions continued to grow. GM-CSF (400ug) was injected at the site of a large KS lesion and ten days later the researchers describe the lesion as having "disappeared." GM-SCF (leukine) is a manufactured version of a natural human protein which stimulates the growth of certain white blood cells from the bone marrow. No adverse effects were seen from the treatment. NIAID Announces TB Agenda The National Institute of Allergy and Infectious Diseases (NIAID) will spend $20.7 million on tuberculosis research in fiscal year 1993, a six-fold increase over fiscal year 1991. This increase occurs during a rapid rise in tuberculosis cases worldwide. In April, the World Health Organization declared the resurgence of tuberculosis an international public health emergency. Furthermore, tuberculosis is the leading cause of death of people with AIDS worldwide. NIAID outlined the eight ways it wants to spend the money: more studies on TB epidemiology and natural history, more basic research into TB biology, development of new diagnostics, development of new drugs or drug delivery systems, new clinical studies of anti-TB drugs, new vaccines to prevent TB, training for TB researchers, and education campaigns about TB prevention. ============================ ============================ Washington Watch by Derek Hodel May and June are busy months in our nation's capital, as legislators race to finish summer business before their August recess. Here's a look at some of their machinations: NIH reforms become law After months of delay, the House/Senate conference committee charged with hammering out the differences between two versions of the National Institutes of Health (NIH) Revitalization Act of 1993 filed its report at the end of May. President Clinton signed the bill into law on June 10 at a Rose Garden ceremony. A hybrid of the House and Senate versions of TITLE XVIII, which strongly enhances the authority and mandate of the Office of AIDS Research (OAR) and provides long-sought reforms to the AIDS Research Program at the NIH, is included in the report. The final bill contains the following provisions: - The Director of the Office of AIDS Research will be appointed by the Secretary of Health and Human Services, and will direct the NIH's AIDS research program. The OAR Director will report to the Director of the NIH, as do the directors of the national research institutes. Secretary Shalala has expressed her commitment to making a rapid appointment. - The Director is charged with developing a comprehensive plan for AIDS research throughout the institutes of the NIH. Based upon the plan, the Director will submit a consolidated, bypass budget directly to the President. (The National Cancer Institute has employed a bypass budget since 1972.) Following Congressional appropriations, the Director will receive all monies for the AIDS research programs, and will distribute funding to the research institutes in accordance with the strategic plan. - An advisory council, comprised of leading scientists from the field, will be formed to advise the Director. - A discretionary fund, authorized at $100 million, is established for the Director to address emerging or breakthrough opportunities, critical research gaps, or emergency research needs. Following the appointment of a director, the Office will have to work at breakneck speed to get the FY95 research plan in place before the October, 1993 beginning of the FY94 fiscal year. MONEY FOR AIDS The House Appropriations subcommittee on Labor/HHS/Education has been trying to figure out how to satisfy President Clinton's request for $227 million in additional AIDS research funding. (The problem: the rest of the programs at NIH were either flat funded or cut, prompting furious lobbying to spread the AIDS monies around.) In testimony before the committee, Dr. Anthony S. Fauci, Director of NIAID and Associate NIH Director for AIDS Research, was asked by Rep. Stokes (D/OH) whether the President's request for AIDS research was scientifically justified and whether the NIH could absorb such an increase. Fauci testified that the amount was not only scientifically justified, but that the agency had a surplus of projects just waiting to be funded, and that the money would be well spent. Stokes then noted that he had received letters requesting $1.6 billion (See! Your letters do have an impact!) in AIDS research funding, $300 million more than the President's request, and inquired as to whether that amount would also be justified. Fauci testified that indeed, the NIH would be perfectly capable of absorbing that amount of increase, and that that amount, too, would be money well spent. Meanwhile, at the same hearing, Dr. Samuel Broder, director of the National Cancer Institute, was asked whether it was fair to treat AIDS differently than other diseases, like cancer. His response: As a nation, we have a responsibility to treat AIDS differently, because it is an infectious disease that is spreading rapidly, because it strikes primarily young people in the prime of their lives, and because it disproportionately affects disenfranchised communities. Not news to us, perhaps, but beautifully said, courageously put, and right on the mark. No thanks to Rep. John Edward Porter (R/IL), who took it upon himself to lead the charge against the AIDS increase by drawing unfair comparisons between what we spend per patient on AIDS research versus heart disease research, etc. On June 24, the House voted to recommend the full $227 million increase and found another $268 million for other NIH programs. BUYERS' CLUBS The FDA finally wrote to a number of AIDS buyers' clubs expressing governmental concern about "certain" activities. The letter, as usual a master stroke of government double talk, represents the first time the agency has made a stab at formally defining its relationship with the intrepid, so-called buyers' clubs, some of which are neither clubs nor comprised of buyers. FDA notes that it has, in the past, articulated a policy regarding personal use importation of drugs under which it may exercise what it euphemistically refers to as "enforcement discretion" -- their answer to don't ask, don't tell. (It means that they can bust you if they really want to. They just don't want to. ) They note further that many buyers' clubs have taken the position (on their own, presumably) that their activities fall under the policy. Concerning the clubs' activities, the letter reiterates the agency's long-standing concerns about "the lack of physician involvement in the medical care of [buyers' club] clients; the sale of injectable products of unknown purity, sterility and strength; the sale of products with unknown sources of manufacture (foreign and domestic); and the promotion, distribution and commercialization of unproven and potentially dangerous products." Most strikingly, FDA articulates for the first time several courses of action designed to "explore the feasibility of allowing continuation of the beneficial aspects of the personal use importation policy while, at the same time, preventing serious abuses of this policy..." The agency claims it will intensify communications with interested parties in an effort to catalog those products which may have the greatest potential for benefit to people with HIV, and which are not yet legally available in the United States. They then promise to explore alternatives. Buyers' clubs were designed as guerrilla activity, intended to spark systemic reform. In this light, FDA inaction is inexcusable. As we have learned over the years, access questions are most appropriately addressed by creating legitimate access channels. (It is much preferable, for example, for people with HIV to secure genuine drug through an expanded access program than it is for them to secure bootleg drug via the underground.) Furthermore, insofar as it is the government's responsibility to protect people with HIV (and other people, too) from being taken advantage of, it is conceivable that regulation -- even in this arena -- is appropriate and welcome. Of course, people will argue that this particular line is especially difficult to draw, and of course, it is. To make matters worse, FDA is not known for being overly sensitive in this area. Nevertheless, an increasing number of businesses engaged in nothing more palatable than health fraud have cloaked their activities in the language of buyers' clubs, and have specifically targeted people with AIDS. It is time to find that line. >>Derek Hodel is Treatment Issues Director at AIDS Action Council, a Washington, D.C.-based lobbying group. Hodel updates Treatment Issues readers every other month on AIDS related developments in Washington.<<