Accession No. 00411 AN 00411 TI hiv Therapeutics, An Update From Berlin SO Seminar Handout AU Paul J. Cimoch, MD, FACP, Director of Medical Services, Center for Special Immunology, 2918 Fifth Avenue, Suite 300, San Diego, CA 92103, 619.291.1122 TX The IXth International Conference on aids brought nearly 15,000 scientists, clinicians, health care workers, and people living with hiv infection to Berlin to discuss the past year's progress in the fight against aids. Although this congress produced some of the most important work to date, there was initially a sense of disappointment and gloom among the attendees as a result of the publicity surrounding the Concorde Trial. However, these negative emotions were later replaced with a great deal of excitement and enthusiasm after presentations showed continued advances in hiv therapeutics. This renewal of positive feelings stemmed from several important highlights. First, our understanding of hiv infection and the body systems that it affects, has increased dramatically over the past few years. In addition, several therapies discussed at previous conferences have moved from in vitro to human trials, and have shown encouraging results in phase I toxicity trials. Among these therapies are several compounds that work by different mechanisms than the currently available nucleoside analogues. Finally, promising new therapies were presented this year, including for the first time, research in the area of immune reconstitution. Our greater understanding of the pathophysiology of this disease continues to drive the research and intervention strategies. It has become clear that hiv infection is a multifactorial, multiphasic and multipathogenic process. Physicians will need to substratify patients by their stage of pathophysiology and individualize therapies accordingly. I will begin by summarizing our current understanding of hiv pathophysiology Eloquent plenary sessions were delivered on this topic by Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), and by Dr. Jay Levy, head of the Cancer Research Institute at the University of California, San Francisco. I will then review the multiple antiviral workshops and posters including presentations on mono- and combination therapies, in addition to the new antiretroviral agents. I will conclude by summarizing the gene therapy and immunotherapeutic sessions. IMMUNOPATHOGENESIS We know that the virus remains active and continuously replicates from the moment it enters the body. There is no virologic latency as previously theorized. The major reservoir of the virus within the body is the lymphatic system which consists of the intestines, the spleen and the lymph nodes. Low-level viral replication is probably stimulated by endogenous cytokines, which are highly concentrated in the micro-environment of the lymphoid tissues. Cytokines such as tumor necrosis factor (TNF), granulocyte/monocyte-colony stimulating factor (GM-CSF), various interleukins, and others, appear to induce hiv expression. Activation of the CD4+ T-lymphocytes in response to various cytokines actually makes these activated cells more susceptible to hiv infection. Also anergy or apoptosis (programmed cell death) can occur even without direct cellular infection when CD4+ T-lymphocytes are activated by viral components. In other words, as the body tries to fight the virus it may actually increase viral activity, and through the release of various cytokines and viral components cause immune system dysfunction. Additionally, these processes lead to an increase of viral burden within the body. Gradually the virus destroys the lymphoid architecture with subsequent destruction of the immune system culminating in immune system devastation. Dr. Levy reviewed the cell mediated immune mechanisms used by the body to control hiv replication. Two subtypes of CD4+ T-lymphocytes known as TH1 and TH2 lymphocytes have now been identified. The TH1 cells guide the CD8+ T-lymphocyte response (cytotoxic lymphocytes [CTL]) to antigens such as hiv while the TH2 cells deactivate the CTL response and stimulate antibody production. In long-term survivors of aids, the TH1 subtype remains dominant over time. They also have a strong anti-hiv neutralizing antibody response in addition to a strong CTL response. The CTL responses include major histocompatibility complex (MHC)-dependant cell cytolysis and non-MHC-directed, non-lytic, anti-hiv suppression mediated in part by a secreted novel cytokine. Dr. Levy continues to search for this elusive cytokine. The anti-hiv suppression is associated with an activated CD8+ cell with the cytotoxic phenotype, CD28+ HLA-DR+ CD38+. Understanding these immune factors could eventually lead to methods of modifying the immune system, allowing the body itself to control hiv infection. Another contributor of pathogenesis is the ability of the virus to cause CD4+ lymphocytes to form syncytium (clumps of dysfunctional cells). Over time, the virus is able to mutate into syncytium-inducing (SI) strains, thereby speeding the destruction of CD4+ T-cells. Differences in an individual's immune response in preventing non-SI strains from mutating into SI strains may also explain why some individuals respond better to antiretrovirals than others. Our clearer understanding of hiv pathophysiology has lead Dr. Fauci to propose stage specific treatment interventions. In the earliest stages of hiv infection, paradoxic selective suppression of the immune system in combination with antiretrovirals may prove beneficial. In support of this concept are studies of hiv-infected organ transplant patients. The patients who received immune suppressing medications and zidovudine (ZDV or AZT) showed a slower progression to aids than those who did not. In the moderate stages of hiv-infection, antiretrovirals in combination with cytokine blocking agents or immunomodulators may prove useful. Studies have already been done utilizing interleukin infusions in combination with antiretroviral agents. Finally, in the immune devastated category, antiretrovirals will still be necessary to control viral burden while immune restorative therapies are implemented. ANTIVIRAL AGENTS - MONOTHERAPY Of the antiviral monotherapy workshops, the study that received the most media attention was the Concorde Trial. This three-year study enrolled 1,749 asymptomatic patients in the United Kingdom, France and Ireland. The average follow-up was three years. At enrollment, 57% had CD4+ lymphocyte counts of less than 500 cells/mm3 (7% were less than 200 cells/mm3) and 13% were p24-antigen positive. The patients were randomized to either begin ZDV treatment immediately upon enrollment or to start ZDV only after they had developed an AIDS-defining event. The dose of ZDV was 250 mg four times a day. The researchers concluded that there was no survival benefit in the immediate-treatment group versus the delayed-treatment group. The data did show, however, that the immediately treated patients showed an improvement in their immune system response, in particular their CD4+ T-cells, for at least the first 15 months. These findings were very similar to those of the aids Clinical Trials Group (ACTG) studies that led to the FDA approval of ZDV. The Concorde trial, therefore, showed that continuing ZDV monotherapy for as long as three years may not be beneficial. The Concorde trial, although recognized as a remarkable research project, was widely criticized at the congress. Most clinicians do not feel that the study represents current state-of-the-art treatment. Critics point out that many patients continued receiving ZDV despite evidence of its failure. By current practice standards, such patients would usually be switched to an alternative antiretroviral agent. Also, due to the approval of DZV in the United States for patients with CD4+ T-cells below 500/mm3, many Concorde patients initially randomized to receive delayed treatment actually started taking ZDV halfway through the trial. Therefore, by the end of the trial, the distinction between the two groups was less clear. Finally, the dosage of ZDV used in the trial was higher than is currently recommended. We have learned over the last couple of years from ZDV resistance studies that the earlier one starts taking ZDV, the less chance resistance will develop. In fact, several years may elapse before ZDV-resistant restrains of hiv are detected in people who start ZDV with high numbers of CD4+ T-0lymphocytes or before they develop aids. However, patients who start ZDV after the development of aids can develop ZDV-resistant hiv strains within as little as four months. This year Dr. Paul Volberding from the University of California at San Francisco presented extended clinical follow-up on the ACTG-019 study (abstract WS-B24-6). This study now provides a strong clinical correlate to the previously reported ZDV-resistance studies. Dr. Volberding concluded that ZDV definitely slows down the progression to aids. In ASTG-019, the clinical duration of ZDV benefit depended on patients' initial CD4+ T-lymphocyte counts. In patients who started ZDV with CD4+ T-cells below 300/mm3, the clinical benefit lasted approximately 18 months. However, in patients who started ZDV with above 300/mm3, the duration of clinical benefit lasted for over 2.2 years. A greater benefit was also seen with a dosage of 500 mg per day rather than with a dosage of 1500 mg per day. There were several presentations on studies of monotherapy with didanosine (ddI) or zalcitabine (ddC), almost all of which were begun after ZDV failure or compared treatment to continued ZDV use. Dr. Tony Pinching presented the work of the Coordinating Committee for the European/Australian Alpha trial of ddI (WS-B24-3). Eligibility criteria were symptomatic hiv disease and intolerance to ZDV. Patients were randomized to receive 200 mg or 750 mg of ddI per day., The results showed no significant difference in the progression of aids or survival between the two groups. Toxicity was greater in the high dose group. An important ddI trial was reported by Dr. Rafael Dolin for the ACTG (WS-B24-1). This randomized, double-blind study compared two different doses of ddI (500 mg/day or 750 mg/day) to ZDV in patients with advanced disease and no prior therapy or less than 16 weeks of prior ZDV therapy. The researchers found that ZDV appeared to be more efficacious than ddI among patients who were ZDV-naive, while ddI appeared more efficacious than ZDV among patients who previously received ZDV for 8 to 16 weeks. The two doses of ddI appeared to be similarly effective, although the toxicities were higher in the 750 mg/day dose. The CPCRA 002 study (WS-B24-4) was a comparative trial of ddC versus ddI in patients who had already taken ZDV and were either ZDV intolerant or failed therapy with ZDV. A total of 467 patients were followed for a mean of 15 months. Two-thirds of the patients had an aids diagnosis. The median CD4+ lymphocyte count was 37 cells/mm3. Equal numbers of patients reported adverse experiences within the two groups, although peripheral neuropathy was reported twice as frequently with ddC. This trial showed that overall, ddI and ddC were equivalent with respect to efficacy and toxicity as monotherapies for patients who had failed or were intolerant to ZDV. A trend toward improved survival in the ddC group was observed. Based on these results and several other oral and ;poster presentations, the general consensus about monotherapy among clinicians could be summarized as follows. Antiretroviral therapy should be individualized based on serial immune system assessments and patient tolerance. Zidovudine delays progression of hiv disease in asymptomatic patients. This response will vary from person to person, but appears to last longer when ZDV is instituted at higher CD4+ lymphocyte counts. Zidovudine prolongs survival in symptomatic patients. It appears to be more efficacious in these patients than ddC or ddI as initial therapy, but ddI appears to be better than ZDV in patients who have already taken ZDV for over 8 weeks. COMBINATION ANTIVIRALS The results of the ACTG-155 trial of the safety and efficacy of using ZDV with ddC versus ZDV alone were reported (WS-B-25-1). A total of 1,001 patients were enrolled; 83% had symptomatic disease, the median CD4+ lymphocyte count was 119 cells/mm3, and the median duration of prior ZDV therapy was 18 months. Patients were randomly assigned to ZDV alone (600 mg/day), ddC alone (*2.25 mg/day) or combination therapy., Overall, the researchers found no statistical differences between the groups except in patients with greater than 150CD4+ T-cells/mm3. In this subgroup, the patients who received combination ZDV and ddC were less likely to develop a new aids-related condition or die than patients taking ZDV alone. A small German study involving 44 patients was presented by Dr. S. Mauss from Duesseldorf (WS-B25-6). Patients who had taken ZDV for six months with declining immune parameters were either randomized to add ddI (*200 mg/bid) or ddC (*0.75 md/tid) to the regimen. An increase in the absolute CD4+ T-cell count occurred in both groups, with a trend towards a higher increase in the CD4+ T-cell counts in the patients taking ZDV and ddI than in those taking ZDV with ddC. There was no difference between the groups in the occurrence of aids-defining events. This trial is ongoing. An interesting study by Dr. Shafer from Stanford University compared the effects of combination theray with ZDV and ddI versus monotherapy with ZDV on viral load and on the development of in vitro ZDV-resistance in asymptomatic patients with 200-500 CD4+ lymphocytes.mm3 (WS-B-25-3). These researchers found that patients receiving combination therapy experienced a greater suppressive effect on viral load than patients on monotherapy with ZDV. However, ZDV resistance was greater in the combination therapy group. Seven posters on combination therapy with RTI and interferon by injection were presented. All were small trials with mixed results. As previously demonstrated, the effect on surrogate markers was greatest when the combination was employed in the stages of better immunocompetence. Definitive research on oral interferon concluded that it provided no immunologic or clinical benefit over a placebo. A new approach to combination therapy is of convergent therapy. Knowing that the virus is able to mutate and develop resistance to antiretroviral compounds over time, it is postulated that using selected multi-drug regimens directed against the same viral target (for example, reverse transcriptase) may prevent the development of multi-drug resistant virus. Also, this approach may cause the virus to mutate into a nonviable or a more benign form. Previous in vitro work has been released on the combination of ZDV, ddI and nevirapine leading to this convergent demise of the virus. Additional in vitro research was presented orally and in posters at the conference from the Harvard University group. These three drugs, in addition to using various combinations of ZDV, ddI, interferon, foscarnet, and many other compounds were discussed. This approach appears very promising in vitro. However, whether or not this approach will be successful in humans remains to be seen. Remember that the viral burden in humans is heterogenous. Even though certain strains of the virus may mutate into nonviable irions, conceptually, other strains would become the more predominant population. Human trials with convergent therapies are anticipated to start soon. At the present time, no consensus exists regading combination therapy. Multi-drug regimens appear to be more effective in inhibiting viral replication in vitro than single agents, as shown by the Harvard group. This inhibitory effect increases with the number of drugs in the regimen, and is effective by both convergent or divergent combinations. Although alternating drug regimens are effective, they are less effective than simultaneous drug regimens. Patients with progressive immune system dysfunction or destruction despite monotherapy may benefit from combination therapy. Treatment-naive patients with poor prognostic markers may wish to pursue combination therapy from the start. Many combination trials are ongoing, and current decisions regarding combination treatments must be individualized. ANTIVIRALS - OTHERS Other antiviral workshops concentrated on agents that have been discussed over the last few years. I am pleased to report that many of these compounds have now gone from the test tube stage into phase I human toxicity trials. Research on L-drugs (pyridinones), nevirapine (BI-RG-587), protease inhibitors and the tat antagonists was presented. Several of the protease inhibitors have completed multiple phase I/II trials. Dr. Sven Danner of Amsterdam reported on Abbott's A-77003 protease inhibitor (WS-B-26-6). This compound requires intravenous administration due to poor oral bioavailability. Unfortunately, phlebitis was found to be the dose-limiting toxicity. It was impossible to further escalate the medication in this trial due to this adverse event. More exciting was the report on the Roche protease inhibitor, Ro 31-8959. Three phase I/II trials were presented. These studies concluded that a dosage of 600 mg orally three times a day was extremely well tolerated. There were no serious adverse events. An improvement in CD4+ lymphocytes was noted with decreases in p24-antigen levels. This compound will soon enter phase II efficacy trials and appears to be a promising medication. The results of a tat antagonist trial with Ro 24-7429 was presented by Dr. R.H. Haubrich for the ACT-213 team (WS-B26-5). Ninety-six patients with between 50-500 CD4+ T-cells/mm3 were randomized to various doses of the tat antagonist or ZDV or ddI. Seventy-eight percent of the patients completed twelve weeks. Unfortunately, the compound did not exhibit antiviral activity at doses between 75-300 mg per day. Dose related rashes were a limiting factor in this phase I trial. Patients receiving ZDV or ddI showed an average increase of 20 CD4+ T-cells/mm3 as compared to their baseline levels. All the patients on the tat antagonist, however, showed an average decrease of 20 C4+ T-cells/mm3. These researchers will institute another study with further dose escalations. There is some question about the oral bioavilability of this compound. Plasma levels of the drug are pending on the above-mentioned study. A new nucleoside compound, 3TC, is produced by Glaxo, Inc. This medication is known to be synergistic in vitro with ZDV, ddI and ddC. There were three open-label, phase I/II trials reported at the congress. One of these trials reported on by Dr. T. Cooley, studied doses between 0.5 to 20 mg per kilogram per day (WS-B26-2). The mean CD4+ lymphocyte count of the patients was 132 cells/mm3. Dose-related neutropenia occurred in 16% of the patients. No evidence of anemia was noted, although megaloblastosis was seen at all dose levels. Insomnia, rash, increased appetite, headache and nausea were the most common side effects. The majority of the patients showed stable immune parameters at dosages between 4-12 mg per kilogram per day. Forty-three of the patients who were noted to be p24-antigen positive had a diminution in their antigen level which was not sustained. Resistance developed to the agent in 12 of 42 patients within 6 months. Larger phase II trials should be beginning in the United States this summer. The results of ACTG 164 and 168 on nevirapine (NVP) were presented by Dr. Diane Havlir from the University of California, San Diego (WS-B26-1). The dosage studied was 400 mg per day, which achieved greater than 50% of the mean inhibitory concentration (MIC) of resistant strains. Patients had less than 400 CD4+ T-cells/mm3, and were off antiretrovirals for four weeks. Forty-eight percent of the patients developed a rash which was the dose limiting toxicity. It was noted that the rash could be minimized by starting with a dose of 200 mg per day for two weeks, then increasing to 400 mg per day. Headaches and gastrointestinal side effects were other adverse events reported. The serum half-life of the compound was 24 hours, and a steady state level of 4.2 micrograms per milliliter was achieved. This level was four times higher than the 50% MICs of resistant virus. Eight out of 10 patients had a sustained reduction in p24-antigen levels at 8 weeks and viral burden was diminished by quantitative polymerase chain reaction (PCR). There was a transient increase in CD4+ T-cells, which then stabilized. These researchers concluded that NVP was safe and well tolerated with dose escalation. It was noted that resistance rapidly emerges to this compound, but that sustained antiviral effect could be achieved with continued use. A phase I trial on the non-nucleoside reverse transcriptase inhibitor, L697,661 (pyridinone) was also presented (WS-B26-4). This compound has poor oral bioavailability that increases 10 fold when taken with food. The major side effect was fatigue (30%), especially for patients receiving combination therapy with pyridinone and ZDV. In addition, nausea and vomiting were reported as major sid effects. All patients developed low-level resistance to the L-drug that was thought to be possibly overcome by increasing the dose. It was found that a mutation at codon #181, led to hiv strains highly resistant to pyridinone. These researchers concluded that long-term therapy with this compound was well tolerated but that L-drugs should not be used as monotherapy. Multiple new antiretroviral compounds were discussed, including topotecan (TPT), humic acid (polyhydroxylate), triterpene, SC-49483 (BuDNJ) and MKC-442. All these compounds in vitro are effective against hiv. Animal studies are underway or have been completed. A new non-reverse transcriptase inhibitor called atevirdine (ATV), has completed pharmacokinetic prfiles and will soon enter phase I toxicity trials. GENE THERAPY Gene therapy was a major topic of discussion at the conference. Advances in this arena would provide clinicians with a quantum leap in therapeutic interventions. An entire basic science workshop was devoted to this treatment modality. Presentations were given on tRNA-ribozymes, virion-specific interfering molecules (VSIM), and antisense genes. An extremely interesting agent making an important impression at the conference was the antisense oligonucleotide, GEM 91. GEM stands for Gene Expressing Modulator. In principal, this antisense nucleotide attaches to viral specific nucleic acids through Watson-Crick base pairing, specifically suppressing hiv expression. This attachment can occur at two different points in the viral life cycle; initially after viral penetration into the host cell and later during transcription of viral RNA components. Dr. Sudhir Agrawal, chief scientific officer of Hybridon, Inc., reviewed the tremendous amount of work that has already been done with this agent (WS-A17-4). In collaboration with Dr. Gallo's lab at the National Institutes of Health, six years of numerous in vitro and animal studies have been completed. The nucleotide has been altered through the attachment of a sulfa-moiety, preventing degradation by cellular enzymes. The compound is specifically complimentary to the initiation codon of the gag gene of hiv-1 RNA, which has been found to be conserved among hiv isolates. GEM 91 has been shown to have excellent inhibitory effects in acute and chronically infected cell lines at 1-2 micromolar concentrations. Toxicity and pharmacokinetic studies have been performed in animals. The plasma half-life is up to 50 hours in monkeys. Dr. Agrawal has already submitted a treatment IND to the FDA. He is hopeful that within weeks this compound will enter human phase I trials. The development of this type of genetic therapy could alter the course of this epidemic. IMMUNOTHERAPEUTICS Other extremely exciting therapies discussed at the conference were immunotherapeutics and immune restoration. Once the immune system is damaged, it is not believed that it has the ability to spontaneously regenerate. The immune system is very capable of initially suppressing the virus and, perhaps, the immune system can be therapeutically manipulated in order to assist pharmacologic interventions. Immunotherapeutics can be divided in active and passive immunotherapy. Numerous papers on active immunotherapy with vaccines were presented. One that received extensive media attention was the Salk vaccine. Many studies were also presented on the gp 120, gp 160, and gp 160/p24 vaccines. The major companies involved in vaccine research include Genentech and Microgenesys. Numerous papers indicated that the vaccines were immunogenic in humans. Many investigators are experimenting with different adjuvants in hopes of eliciting even greater immune responses. In order for an immune response to theoretically occur, a patient must be relatively immunocompetent. Therefore, all the studies are dealing with earlier stage patients where the natural incidence of clinical events and immune system decline is low. Whether or not these immunogenic responses will translate into clinical benefit remains to be seen. The vaccine furthest along in clinical use is gp 160 (Vaxsyn). A phase I/II trial concluded that this vaccine was safe and well tolerated. Immunogenicity was observed in all patients with 200-500 CD4+ T-cells/mm3. All individuals remained clinically asymptomatic with statistically significant improvements in CD4+ cell counts. The Salk vaccine research, in addition to noting immunogenicity claimed to diminish the slope of the increase in viral burden over time when compared to a placebo. Numerous vaccine trials are underway, but it may be several years before definitive results are available. Another area of immunotherapeutics presented was cryopreservation. The concept is to take lymphocytes, perhaps from patients in earlier stages of the illness, and freeze these cells so that they can later be given back to the patient. Researchers from Hamburg, Germany presented work on cryopreservation and subsequent in vitro expansion of T-lymphocytes (WS-B28-4). They showed that these cells could be preserved for up to a year, remaining viable after being thawed out. There was little evidence of increased viral activity when the cells were thawed and expanded. Another area which is receiving a great deal of attention is the CD8+ cell expansion studies. At last years conference, Dr. Nancy Klimas from the V.A. Medical Center in Miami, presented the initial landmark research with this technology, the ex-vivo expansion and reinfusion of CD8+ lymphocytes. The lymphocytes are removed from a patient by plasmapheresis, expanded in the test tube, and then reinfused into the body, followed by an interleukin-2 infusion. Based on her initial work, which showed that this therapy could be carried out safely, this year Dr. Klimas presented results of a trial on eight Kaposi's sarcoma patients. This therapy produced a 50 to 70 percent response rate. She continues to be very encouraged by these results, and anticipates pursuing other disease processes with the CD8+ cell expansion therapy, such as cytomegalovirus (CMV) infections or Epstein-Barr associated lymphomas. The expanded cytotoxic lymphocytes may be very effective in controlling those types of opportunistic processes. One of the bright spots at the conference for those people living with immune system devastation is the area of immune reconstitution. Passive hyperimmune therapy (PHT), which consists of taking plasma or antibodies from patients at earlier stages and infusing them into later-stage patients, has been increasingly discussed over the past several years. Conceptually, the problem with PHT, especially in later-stage illness, is that there may not be enough effector lymphocytes to assist the infused antibodies. Therefore, research has pursued the transfer of HIV-negative lymphocytes via transfusions. Dr. R. Walker, from the NIAID, presented research on immune reconstitution with lymphocyte transfers from 6 sets of hiv-discordant twins. Lymphocytes from the non-infected twin were obtained by lymphapheresis, stimulated and expanded ex vivo, then transfused into the hiv- infected twin. Other than mild systemic side effects of fevers, aches and pains, the tranfusions were well-tolerated. Baseline CD4+ lymphocyte counts ranged from 145 to 493 cells/mm3. After the transfusion, CD4+ lymphocyte counts increased up to 47%, but over the course of about 50 days, diminished back to baseline. These researchers concluded that adoptive transfer of expanded and activated unfractionated lymphocytes was safe. An oral presentation on immune reconstitution with broader implications was presented by Dr. Robert Keller from the Center for Special Immunology-Fort Lauderdale, Florida (WS-B28-5). Sixteen aids patients with multiple prior opportunistic infections. failing other therapies, participated in this salvage protocol. The mean patient CD4+ T-cell count was 25 cells/mm3. The patients received monthly transfusions of PHT followed by hiv-negative, haplotype-matched lymphocytes, usually obtained from family members. A total of 67 transfusions were administered. Side effects of the therapy consisted of flu-like symptoms, low grade fever, and painful lymphadenopathy. One patient had a serious adverse event related to the therapy, which resolved after treatment without sequela. Two patients died during the study, but neither death was thought to be related to the salvage protocol No graft-versus-host reactions were noted. The researchers concluded that this type of adoptive immune reconstitution was feasible and an acceptably-tolerated procedure. The use of haplotype-matched lymphocytes, rather than identical-matched lymphocytes, will make this type of therapy available to a much larger group of patients. The advances in gene therapies, immunotherapeutics and immune reconstitution offer great hope for people living with hiv infection. SUMMARY Certainly there was some dismay expressed at the congress and in the United States regarding the Concorde Trial results. However, most scientists believe that no single drug is going to be the answer; combination therapies are increasingly being utilized, and treatments must be individualized. Our better understanding of hiv pathophysiology allows for the potential of stage-dependent therapeutic interventions. Early-stage patients may, in fact, receive immunosuppressive therapy, whereas later-stage patients certainly will require immune restorative treatments. New drugs that work by different mechanisms than the currently available antiviral agents have been tested in humans and are entering efficacy trials. Creative antiviral combinations are being actively investigated. Human trials of gene therapy should start this year and, if successful, alter the course of the epidemic. Finally, the exciting area of immunotherapeutics and immune restorative therapies is coming of age. --- oOo --- * Origin: AEGIS/San Juan Capistrano * 714.248.2836 (CASAN) (1:103/927) * Provided as a service of THE BACKROOM - NYC * 718-951-8256