Subject: New Labeling for OTC Products Date: Feb 1993 (393 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Project Inform P E R S P E C T I V E &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Permission granted for non-commercial use. New Labeling for OTC Products In June of 1992, the FDA approved the nonprescription sale of creams and suppositories for the treatment of vaginal candidiasis. These products include Monistat-7, Gyne-Lotrimin, FemCare and Mycelex-7. These products contain a warning that states that recurrent yeast infections may result from hormonal changes or use of oral contraceptives or antibiotics. The activist community has been actively lobbying the FDA and the pharmaceutical manufacturers to add an additional warning to the label concerning the risk of HIV infection in women with chronic or recurring yeast infections. After much resistance we have won a victory. The FDA has asked manufacturers to add the following additional warning to the package insert: In women with frequently recurrent vaginal yeast infections, especially infections that do not clear up easily with proper treatment, the vaginal yeast infections may also be the result of serious medical conditions, including infection with HIV, that can damage the body's normal defenses against infection. This new label will reach packages on the shelves within the next month or two. The importance of alerting women that chronic yeast infections could be a sign of HIV infection can not be overstressed. In one study it was reported that 38% of women diagnosed with HIV- related immunosuppression suffered recurrent or persistent cases of vaginal candidiasis as their first symptom. The same study indicated that the principle reason that women were tested for the presence of HIV antibodies was their own perception of risk. This was true for all categories of transmission, with half of all heterosexual transmission testing being driven by self perception. Since most studies looking at survival differences in women and men conclude that if women are tested and then treated in the earlier stages of infection they will survive as long, perhaps longer, than men, it is imperative that women with chronic or recurrent yeast infections seriously consider anonymous HIV testing and seeking primary care if found to be HIV positive. Elsewhere in this issue is a short article on the new CDC Case Definition of AIDS. ***** Vaccine Progress by Brenda Lein and Jesse Dobson AIDS vaccines are being studied in two ways: first for their potential to prevent HIV infection, as prophylactic or preventative vaccines, and second for their ability to stop or slow disease progression in people who are HIV-positive, as therapeutic vaccines. If successful, these vaccines will offer the possibility of controlling HIV, perhaps without the need for toxic drugs. Therapeutic vaccines may be the first therapy available for people with greater than 500 CD4 cells. A vaccine is a preparation intended to produce or increase the immune system's ability to respond to a particular disease. Vaccines are typically prepared through the use of a damaged virus, part of a virus, a weakened or "attenuated" virus, or through the use of a full virulent virus. The possible uses of vaccines for AIDS are varied and many. Influenza vaccines, for example, are recommended for people who are HIV-positive to prevent flu infections.[1] Work is being done on the development of a type of cytomegalovirus (CMV) vaccine which could potentially prevent relapses of CMV infection.[2] Extensive effort is being put into the development of a vaccine that targets the underlying cause of AIDS, HIV infection. AIDS vaccines currently in development are being studied for their ability to prevent HIV infection in people who are HIV-negative and for their ability to stop or delay progression of HIV-disease in persons who are HIV-positive. The AIDS vaccine furthest along in development in HIV-positive persons is MicroGeneSys' gp160. Other products, such as Genentech's gp120 vaccine, have been tested less extensively in HIV-positive persons but are demonstrating results similar to the MicroGeneSys product. AIDS vaccine products appear to be safe, toxicities noted thus far are minor, including pain at injection site and very mild flu-like symptoms. While none of the products currently being tested are a cure, therapeutic AIDS vaccines may become an important component in the management of HIV-disease, especially in early stages of disease while CD4 cells are above 400. Most of the AIDS vaccines in development are envelope vaccines, using part of the viral envelope, for example, gp160 or gp120, in order to elicit an immune response. gp 160 and gp120 are proteins on the envelope of HIV. Other vaccines utilize proteins from the HIV core, such as p17 or p24. Once the virus infects the DNA of immune cells, the immune system has difficulty recognizing the infected cells, which enables HIV to replicate despite the initial natural immune response. It is hoped that by introducing a synthetic viral protein into the system, the production of antibodies to neutralize the virus and cells directed at killing HIV infected cells will be stimulated to enhance the body's ability to detect HIV and keep the virus in check. It may be that the best use of any of these vaccine products will be in combination with antivirals, such as AZT and ddI and other types of immune based therapies, such as IL-2 and pentoxifylline. What Does The Research Show? There are numerous AIDS vaccine products being tested in HIV-positive individuals. How some of these products compare to one another is being studied in a clinical trial about to start in the AIDS Clinical Trials Group. An open label study of MicroGeneSys' gp160 vaccine, conducted by Robert Redfield of the Walter Reed Army Institute, suggests that by utilizing vaccine therapy it is possible to redirect the immune system and create new responses against HIV. This is a critical first step in the development of a therapeutic vaccine that can effectively create an immune response capable of neutralizing the virus. In Redfield's initial dose escalating study of 30 patients with CD4 cells greater than 400, volunteers were randomized to receive two different dose schedules of gp160. Nineteen of 30 people developed new immune responses to HIV.[3] Twenty-eight of the original thirty volunteers reenrolled in a continuation trial and the original "non-responders" received a series of higher dose injections of gp 160 (640 micrograms). All but one trial participant have since developed new immune responses to HIV. It is unknown if these responses are beneficial. The duration of vaccine-induced immune responses varies between people, however. Study participants have demonstrated proliferation of HIV-specific cytotoxic lymphocytes, cells that specifically target and destroy HIV infected cells as well as a trend toward CD4 cell percentage stabilization.[4] In the course of researching therapeutic vaccines it has been noted that the immune system is much more resilient than previously believed. Even persons with low CD4 cell counts are developing responses to vaccination and demonstrating increased immune response and trends toward CD4 cell percent stabilization. Because this is not a controlled study, however, it cannot be said for certain that this is a real response to the vaccine. Some of Dr. Redfield's patients have been on the study drug for over three years and thus far there have been only minor side effects which include pain at injection site and mild malaise.[5] In an open label Canadian study, 21 volunteers were randomized to receive one of two doses of MicroGeneSys' gp160 [160 or 320 micrograms), monthly for 5 months to evaluate the safety and toxicity of the product. All volunteers tested positive for HIV-1, had CD4 cells greater than 500, were aymptomatic and p24-negative. People were not allowed to be on antiviral therapy or other immune based therapies. Ninety percent of study volunteers developed new and broadened immune responses to HIV. Of those who responded, all demonstrated absolute CD4 cell count and percentage stabilization or increases over time. After two years of follow-up, volunteers have shown a mean absolute CD4 cell increase of 117 and a mean increase in CD4/CD8 percentage of 2. Side effects of gp160 were limited to transient pain at the site of injection.[6] In a randomized controlled trial conducted through the NIH, 52 HIV- positive asymptomatic volunteers with CD4 cells greater than 400 received either placebo (hepatitis B vaccine) or one of four doses of the MicroGeneSys' gp160, regardless of dose, demonstrated increased cellular recognition of HIV and increased cellular anti-HIV activity. Some volunteers developed cellular recognition of a number of strains of HIV. Side effects were minimal and limited to pain at the site of injection.[7] In an open label study of 30 HIV-positive people receiving MicroGeneSys' gp160 envelope and p24 core vaccines, analysis was conducted with respect to CD4 cell count. The study was open to anyone, regardless of stage of disease. Fourteen volunteers had CD4 cell counts less than 200 and sixteen volunteers had counts greater than 200. Trial participants with greater than 200 CD4 cells have demonstrated a progressive increase in CD4 cells that peaked at month 5 with a mean increase of 108 over baseline which at twelve months remain 42 above baseline. Of the fourteen volunteers with less than 200 CD4 cells, eight died while on study. Of the remaining six volunteers, there was no significant stabilization of disease or immune response. There were individuals, however, within this group who showed signs of clinical stability, CD4 cell count improvements and the development of new immune responses.[8] While these studies look promising, they were not designed to look for effectiveness, and the majority were not controlled trials. Many healthy asymptomatic people are stable or have increasing CD4 cell levels. In ACTG O19, for example, asymptomatic volunteers who received placebo had a mean CD4 cell rise over a two year period. It is important not to draw too many conclusions about the benefit of vaccine therapy based on CD4 cell levels at this time. Larger trials designed to look at efficacy will better answer the question of whether or not vaccine therapy has an effect on CD4 cell counts. A double blind placebo controlled trial of Genentech's gp 120, randomized 42 volunteers to receive one of three doses (100, 300 or 600 micrograms) of Genentech's product or placebo. Preliminary results of the trial show that volunteers receiving higher doses had stronger responses to the vaccine and respondents demonstrated cross reactivity to a variety of laboratory strains of HIV.[9] In an early animal study, vaccinated chimps who failed to resist challenge with HIV were further studied. The infected animals, when inoculated with a host of different vaccines, including AIDS vaccines, demonstrated high viral activity after each inoculation.[10] This study suggested that antivilal therapy should be administered with vaccine therapy. Preliminary results of a Swedish trial of MicroGeneSys' gp160 demonstrated that volunteers given vaccine plus placebo did clinically better than volunteers receiving vaccine plus AZT. In the forty person study, three volunteers demonstrated an increase in viral load after being administered vaccine. Two of these volunteers were receiving vaccine with AZT and one was not.[11] These early results may change with the continuation of the study and will need to be confirmed with further research. Access and Availability Therapeutic vaccines are only available through small clinical trials. Trials enrolling throughout the country. Most of these trials are only open to people with greater than 500 CD4 cells. Some will be open to people with as low as 50 CD4 cells, but there will be limited space. Most trials of vaccines for people with less than 500 CD4 cells will allow concurrent use of antiviral therapy. At this point there are no expanded access or compassionate use programs established for people who do not qualify for trials or for people who live in areas where there are no clinical trials for vaccines. Commentary There are a number of vaccine products currently in human testing, including products from MicroGeneSys, Genentech, Immuno AG, and Chiron. Many questions remain unanswered about the effectiveness of therapeutic vaccines, despite the enthusiasm of some researchers. Researchers are looking for a number of immune markers, including antibody production, increases in T-cell specific response, decreases in viral load and increases in absolute CD4 cell counts in order to determine the benefit of vaccine therapy . Potential risks of vaccine therapy include activating cells and potentially making them targets for infection, activating HIV infection, and enhancing autoimmune reactions. Results of current studies, demonstrating absolute CD4 cell stabilization and increases, CD4 cell percentage stabilization and increases and stabilization in disease progression are clearly encouraging, but are short term, and show no evidence of the feared problems. Testing AIDS vaccine products in people with less than 500 CD4 cells is long overdue. A few companies have agreed to add arms to existing trials in order to begin to get some answers about the benefit of vaccines for people with low CD4 cells. "Salvage" protocols, or studies which make these vaccines available to people with low CD4 cells are necessary in order to give people with HIV more options as well as real answers about vaccine therapy in the spectrum of HIV disease. By conducting studies in people with lower CD4 cell levels, it is possible that answers about the benefits of vaccine therapy will be achieved more quickly, and if successful could lead to earlier approval of vaccine therapies. In October, the Senate Armed Services committee appropriated $20 million to the Army to conduct an efficacy trial of therapeutic vaccines. This appropriation was advanced by the successful lobbying efforts of ex-Senator Russell Long, who was hired by MicroGeneSys, the company which is developing the gp160 product tested in the trials described above. The legislation stipulated that if the heads of the NIH, the FDA and the Department of Defense could not agree that such a trial was currently scientifically justifiable, the money would revert to DoD's HIV research program. The FDA and NIH held a series of meetings to develop a recommended design for such a trial. The Army held a separate meeting on this subject. After much work, the NIH/FDA panel has written a concept sheet for the study. The design calls for a comparison of three vaccine candidates and a placebo arm in 12,000 patients with between 200 and 500 CD4 cells. The candidate vaccines have not yet been identified, but products from MicroGeneSys, Chiron and Genentech are leading contenders. The group decided this was the best use of the limited resources, since a study in those with >500 CD4 cells would take at least five years and would probably be interrupted by the development of new therapies. The majority of patients will only be followed for changes in survival on the drugs, while a smaller group (about 500 patients/arm) will be followed for clinical disease progression and surrogate markers such as CD4 or viral load changes. While Project Inform applauds increasing moneys for the study of therapies for HIV, we question the methods by which this appropriation was made. It is probably unwise to bring Congress into the setting of scientific priorities, especially since it is obvious by this example that these priorities are easily influenced by outside interests. The trial as designed will definitely further the understanding of how these vaccines work and help determine if they have therapeutic benefit. Therefore, we support the trial, since we have no input into what the Army would come up with on its own. The Army has not committed to execute the trial. The panel also felt it was critical that the manufacturers of the products should donate them for study. The trial would be conducted in a variety of settings, including community doctors' offices. The smaller clinical progression studies would be carried out in existing HIV research networks. More aggressive and innovative strategies for vaccine development are necessary in order to fully realize the best uses of vaccine therapy in HIV disease. The development of AIDS vaccines puts a magnifying glass on the need for increased research into the basic science of HIV disease. It remains unclear which immune responses are beneficial to enhance and which are harmful, which types of responses should be stimulated and which should be suppressed. While these concerns highlight the need for further research into HIV disease, vaccine development must move forward with these concerns unanswered. Several issues need to be kept in mind when deciding whether or not to participate in a vaccine study. Vaccine trials typically require numerous visits to the trial site for injections and follow-up lab work after each injection. Some trial sites have transportation services and childcare availability, others do not. Making arrangements beforehand and planning for appointments can make it easier to stay in these trials. Many of these trials are placebo controlled and there is no guarantee that participants will receive vaccine. Also, trial participants should be aware that participation in trials of existing vaccines may prevent them from being eligible for future anti-HIV trials. As with any trial, you can stop participating at any time. References 1. Steinhoff, M and others Letters -H Influenzae vaccines in HIV. New England Journal of Medicine, v. 3226, n. 28, pp 1569- 1571, June 4, 1992. 2. Cino, T and others. Prevention of The Cylomegalovirus Infection With The Early Administration of Anti-CMV Human Immunoglobulin in HIV Positive Patients. VIII International AIDS Conference, Amsterdam, Netherlands, abstract POs 8267, July, 1992. 3. Redfield, R and others. A Phase I Evaluation Of The Safety and Immunogenicity of Vaccination With Recombinant gp160 In Patients With Early Human Immunodeficiency virus Infection. The New England Journal of Medicine, v 324, n. 24, pp 1677-1684, June, 1991. 4. Redfield, R. Active Vaccination. Project Inform's Immune Restoration Think Tank, oral presentation, April 25, 1992. 5. Redfield, R and others. HIV Vaccine Therapy: Phase I Safety and Immunogenicity Using gp160 VIII International AIDS Conference, Amsterdam, Netherlands, abstract TuB0563, July, 1992. 6. Tsoukas, C and others. Specific Active Immunotherapy in Asymptomatic HIV-Disease Using Recombinant gp160. VIII International AIDS Conference, Amsterdam, Netherlands. abstract TuB0560. July, 1992. 7. Valentule, F and others. A Randomized Controlled Study of gp160 Vaccine in HIV-Infected Subjects. VIII International AIDS Conference, Amsterdam, Netherlands, abstract TuB0561, July, 1992. 8. Blick G and others. A Phase 1/ 11 Study of the Toxicity, Immunogenicity and Efficacy of Recombinant gp160 and p24 Vaccines (Vaxsyn) in HIV-infected Individuals Regardless of CD4+ Cell Count. VIII International AIDS Conference, Amsterdam, Netherlands, abstract TuB0562, July, 1992. 9. Bird, DL and others. Immunogenicity and Safety of rgp120 (lai) in Early Stage HIV Positive Patients. VIII International AIDS Conference, Amsterdam, Netherlands, abstract TuB0564, July, 1992. 10. Fultz, PN and others. Transient Increases in Numbers of Infectious Cells in an HIV-infected Chimpanzee Following Immune Stimulation. AIDS Research and Human Retroviruses, v. 8, n.2, pp 313-317, 1992. 11. Wahrell, B and others. High Affinity and Cellular Immunity By Post exposure HIV Vaccination. NCI's Tumor Cell Biology Laboratory Meeting. Bethesda, MD. oral presentation, August, 1992. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display