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Sustiva-AZT-3TC Combo May Offer New Option There's a promising new drug on the horizon that could give people with AIDS yet another drug combination option for initial treatment of HIV. Interestingly enough, the combo in question does not contain a protease inhibitor. DuPont Pharmaceuticals, Wilmington, DE, announced 24-week data from a study of its investigational drug Sustiva, showing that a combination of the drug with two nucleoside analogues can suppress HIV-RNA levels to below quantifiable levels (BQL, or less than 400 copies/mL). In fact, the company said, the Sustiva combination therapy reduced these levels in a greater percentage of patients than a current standard of care regimen containing a protease inhibitor. The Sustiva data was presented at the 12th World AIDS Conference in Geneva. Findings were presented from the ongoing Phase III study in which the following therapies are being compared for antiretroviral activity and tolerability: Sustiva (600 mg, once daily) in combination with two nucleoside analoguesAZT (300 mg, twice daily) and 3TC (150 mg, twice daily); Sustiva (600 mg, once daily) in combination with the protease inhibitor Crixivan (1,000 mg, every eight hours); and Crixivan (1,000 mg, every eight hours) in combination with AZT (300 mg, twice daily) and 3TC (150 mg, twice daily). Some of the study findings using observed data at 24 weeks:
Sustiva also appeared to be well tolerated, researchers reported. When Sustiva is combined with either AZT/3TC or Crixivan, the most commonly reported side effects were nausea, dizziness, fatigue, impaired concentration, headache, diarrhea, rash, insomnia and dyspepsia. Severe rashes were reported in less than one percent of patients receiving Sustiva in this study. A second study from DuPont showed long-term durability of the Sustiva/Crixivan combo. Eighty-five percent of patients taking the combo maintained HIV-RNA BQL for 72 weeks, using observed data. If Sustiva wins FDA approval, it will almsot certainly have at least some impact on the current HIV treatment market. "Typically, we have recommended that all highly active antiretroviral therapy (HAART) combinations include a protease inhibitor. However, the availability of a new initial HIV therapy with Sustiva that does not include a protease inhibitor, but achieves a higher level of efficacy, may provide us with a promising new alternative," announced Schlomo Staszewski, M.D., director of the Outpatient Clinic for HIV-infected Patients, and of the research unit at Johann Wolfgang Goethe University, Frankfurt am Main, Germany. HIV Reservoirs May Sustain Infection A new theory of the dynamics of HIV infection argues that reservoirs of dormant virus found in the immune systems of infected individuals play a critical role in sustaining active infection. The new hypothesis could explain "recent findings regarding the persistence of HIV reservoirs, and evidence of replicating HIV, in individuals whose viral loads have been driven to undetectable levels with anti-HIV drugs," said Anthony Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID). This theory of HIV replication deserves future study, he added. This model of HIV infection was published in a report by William E. Paul, M.D., chief of NIAID's laboratory of immunology, and his colleagues, in the May 26 issue of the Proceedings of the National Academy of Sciences. It is based on a process called proximal activation and transmission, or PAT, in which it is believed that reservoirs of dormant HIV cells hidden in the lymphoid tissues of the immune system spark local bursts of infection when CD4+ T-cells in their immediate vicinity become activated. Such activation events are local and transient, according to the researchers, and occur in microscopic lymphoid tissues in the form of cell proliferation bursts. These bursts last several days, then subside. "Studies have shown that T-cells activated in the presence of a cellular source of HIV are much more likely to become infected than are activated cells simply exposed to the ambient HIV in extracellular fluid," explained Paul. "This would be particularly true when viral burdens are low, since contact between virus and activated cells would be less likely." Current theory is that HIV propagates itself through rapid, continuous cycles of infection and death of activated CD4+ T-cells, the virus' primary target. The model suggested by Paul and his co-authors, Zvi Grossman, Ph.D., of Tel Aviv University in Israel, and Mark Feinberg, M.D., of Emory University in Atlanta, however, argues that two types of fuel are essential to maintaining active infection: the fast-burning productively infected CD4+ T-cells as well as the slower-burning latently and chronically infected cells. The authors hypothesized that during acute HIV infection, the lymphoid tissues of the immune system are seeded with chronically and latently infected cells, setting the stage for the PAT process in the future. "Given what we know about the interaction of HIV with its target cells, we believe PAT provides the most plausible explanation of HIV propulgation during chronic infection," argued Paul. PAT could have implications in HIV vaccine research, too, he suggested. "If the initial seeding of tissues with latently infected cells is essential for a sustained chronic infection," he said, "then a major focus in developing vaccines should be on those parameters and molecular events that facilitate latent infection. These parameters are presently poorly understood." Lodenosine, an experimental, novel anti-retroviral agent from U.S. Bioscience, West Conshohocken, PA, showed promising results in a recent Phase I clinical trial sponsored by the National Cancer Institute, Bethesda, MD. The purine-based reverse transcriptase inhibitor (RTI) has shown activity against clinical isolates that are resistant to other comercially available agents. The drug showed anti-HIV activity even in patients who had failed with other anti-retroviral therapies such as AZT, 3TC and d4T. Two abstracts on the NCI trial of Lodenosine were presented at the 12th World AIDS Conference in Geneva. The first abstract, presented by Richard Little, M.D., reported trial results for 25 patients with symptomatic HIV infection and CD4 counts less than 500 cells/mm3 who were treated with 12 weeks of lodenosine monotherapy. (Nineteen of these people had received prior anti-retroviral therapy for more than six months.) The 25 patients were assigned to five dose levels of lodenosine ranging from 0.2 to 3.2 mg/kg twice daily. At week six, eight patients tested to date on the highest doses (1.6 and 3.2 mg/kg) had a median decrease in viral load of 10.42 log10 copies/mL. Patients receiving 0.4 and 0.8 mg/kg doses also experienced a downward trend in viral load. In addition, patients taking lodenosine during the 12 weeks tolerated the drug well. The second abstract, presented by James Kelley, Ph.D., scrutinized oral bioavailability of lodenosine. At 1.6 and 3.2 mg/kg, the drug's capsules were 75 percent bioavailable during fasting and 65 percent bioavailable when administered with food. "Lodenosine's anti-HIV activity in these patients, most of whom have had extensive prior therapy, is consistent with its unique resistance profile," noted Robert Yarchoan, M.D., NCI principal investigator. He explained lodenosine even had activity against clinical isolates with "mutations at codon 151, which usually results in multi-drug resistance." Based on the results shown by lodenosine to date, the NCI and the drug's manufacturer have begun testing the drug as part of triple combination therapy. U.S. Bioscience is collaborating with NCI on the drug's development under a "Cooperative Research and Development Agreement." Gene therapy advanced by study of twins A study of 30 sets of identical twinsin which one twin was infected with HIV and the other was notmay have shed some light on the future of gene therapy in fighting HIV infection. In the study, conducted by the National Institute of Allergy and Infectious Diseases (NIAID) and led by Robert Walker, M.D., HIV-fighting T-cells were taken from the uninfected twin and genetically altered to produce an extra receptor for finding HIV-infected cells. Transfers of these altered T-cells into the infected twins were found to be safe and well-tolerated. A mix of altered CD4+ and CD8+ T-cells proved best, surviving and proliferating in the bloodstream for at least 100 days after infusion. "This was an unexpected finding," Walker said. "Transferred cells were assumed to be short-lived. The fact that they live for weeks to months provides a rational basis for transfusing genetically altered cells to fight HIV infection." Walker cautioned that the results were preliminary. Still, he added they were still "encouraging enough for us to take the next steps in studying this approach." Altered cells were marked with a marker gene called neomycin phosphotransferase, which allowed the cells to be tracked in the bloodstreams of the infected twins. Research was conducted in collaboration with Cell Genesys Inc., Foster City, CA. The company's scientists developed methods for transferring receprot-producing genes into T-cells. Results were presented in a paper presented at the 12th World AIDS Conference in Geneva, Switzerland in July. There's sobering news in the fight against AIDS. A new study is the first to show that patients previously treated with multiple HIV drugs can develop full resistance to all available treatment options. The research report by scientists at Stanford University School of Medicine, Stanford, CA, was published in the June 1 issue of the Annals of Internal Medicine. "There is a problem with drug resistance, and we can't fool ourselves," said Dr. Robert Shafer, clinical assistant professor of medicine at Stanford and lead author of the study. In the study, Shafer conducted detailed genetic analyses of viral samples taken from four patients infected with HIV-1, who had been on HIV drug treatment between four and nine years. He also tested 11 different drugs against the viral samples to determine if they were susceptible to treatment. All of the patients had experienced similar changes in drug regimen over the course of their treatment:
Shafer performed genetic sequencing of the sampled viruses and found that the samples from all four patients shared seven recognized mutations in the protease gene that are associated with resistance. He checked gene sequences three times during a six-month period, and the results remained consistent over time. Shafer found a high level of resistance to five drugs, including three protease inhibitors, and a lower level of resistance to three drugs, all reverse transcriptase inhibitors. "These four patients represent thousands of patients," he argued. "They don't represent an oddity at all. They represent something very common." Since the study's completion, Shafer said he has sequenced viral samples from some 400 patients in the San Francisco area, with much the same results. He has found 20 percent have "a genetic profile consistent with resistance to the majority of anti-HIV drugs." Shafer's contention is that people with AIDS now fall into two distinctly different groupsnewly infected patients who have benefited from powerful new drug combinations that can shut down viral replication, and people with HIV strains resistant to one or more drugs [either through transmission or medication]. New approaches are needed for the latter group, Shafer argued, because current drug combinations may not work for them. "There is so much cross resistance that while there may be 11 approved drugs, and three to four in the pipeline, there really aren't 14 or 15 different options," he said. It is up to the academic community to make pharmaceutical manufacturers cognizant of this fact, Shafer contended. "Unless we recognize the fact that certain things aren't going to work, there won't be the incentive to go back and develop new drugs," he explained. Shafer's study was funded by the AIDS Clinical Trial Group within the National Institutes of Health and the J.M. Kaplan Fund. His co-authors were: research associate Mark Winters, postdoctoral fellow Sarah Palmer and Dr. Thomas Merigan, director of the Center for AIDS Research at Stanford. More information on the study and on the HIV gene sequences tracked by Shafer can be found on his Website at http://hivdb.stanford.edu. Drug "Holidays" Common Amoung HIV Population People with HIV are not adhering to the medication regimens prescribed by their physicians. Worse yet, such noncompliance appears to increase with prolonged use of anti-HIV drugs. These findings were part of a study sponsored by DuPont Merck Pharmaceutical Co., Wilmington, DE, and published in the May issue of the Journal of the International Association of Physicians in AIDS Care. The study was based on telephone interviews with 665 HIV-positive people. Among the specific findings:
The study's lead author, Joel E. Gallant, M.D., M.P.H., associate professor of medicine, Johns Hopkins University School of Medicine, explained that "inadequate drug combinations or inadequate adherence to therapy," can lead to quick resistance to HIV medications. "Even mild degrees of noncompliance can lead to resistance. Once resistant strains of HIV are present, the patient's treatment options are narrowed and sometimes entirely exhausted," he said. Asked for suggestions on how to improve adherence, 74 percent of physicians identified simplification of the dosing regimen as most important, as did 24 percent of patients. Simplifications included using medications without food restrictions, once-daily dosing regimens or medications requiring fewer doses per day. Drugs with fewer side effects were mentioned by 15 percent. In the same study, physicians who treat HIV populations estimated that 54 percent of their patients do not properly adhere to medication regimens. Sixty-two percent of physicians said they became aware of this noncompliance when they observed an increase in patients' viral loads, 42 percent learned from patients admitting noncompliance without prompting, and 12 percent found out by asking patients about noncompliance. Agouron Acquires Protease Inhibitor Agouron Pharmaceuticals, Inc. announced it has acquired rights to develop and commercialize JE-2147, a new novel HIV protease inhibitor discovered by Japan Energy Corp., Tokyo, Japan. Agouron plans to initiate clinical studies of JE-2147, formerly known as KNI-764, in 1999. Agouron will have have exclusive rights to the development and commercialization of JE-2147 in North America, Europe and many other countries, while Japan Energy will supply compound for development and maintain commercialization rights in Japan, Korea and Taiwan. "There is an urgent and growing need for a new HIV protease inhibitor capable of acting on virus that has become resistant to currently available compounds," said Peter Johnson, Agouron's president and chief executive officer. "A comprehensive review of preclinical data convinced us that JE-2147 has unique potential to meet this need." Data presented at the 12th World AIDS Conference in Geneva by Japan Energy scientists demonstrated that JE-2147 is fully active against a battery of virus strains representing the predominant resistance mutations produced by currently available protease inhibitors. JE-2147 also demonstrated synergistic anti-viral activity [ital]in vitro[ital] when combined with nelfinavir, indinavir, ritonavir, saquinavir or amprenavir. Under the agreement with Agouron, Japan Energy will receive license fees of up to $26 million, including an initial $6 million license fee as well as additional milestone payments. In addition, Agouron will pay Japan Energy royalties based on sales of JE-2147. Agouron Pharmaceuticals is an integrated pharmaceutical company committed to the discovery, development, manufacturing and marketing of innovative therapeutic products engineered to inactive proteins that play key roles in cancer, aids[sc] and other serious diseases. Japan Energy Corp., established in 1929, is an organization with main business in petroleum resource development, oil refining and marketing, optics and electronics and pharmaceuticals and biotechnology. They may not be Supermen warding off super-villains, but X-rays are now coming to the rescue of researchers battling against a mortal foethe HIV virus. X-ray images have revealed the detailed structure of the protein docking mechanism that HIV uses to infect immune cells, according to an article in the June 18 issue of Nature and the June 19 issue of Science. And now, with a greater understanding of the protein's structures, researchers are encouraged about the possibility of finding new treatment options and vaccines. The docking mechanism is made of a sugar-coated protein called gp120. The images of the protein's structure show that is has developed an assortment of strategies for evading destruction at the hands of the body's defenses. The following were reported in the studies:
The researchers are encouraged about the findings, as the images also show that vaccines made of gp120 particles do not appear to work effectively because they stimulate the immune to attack gp120 without compensating for the proteins's ability to hide its key binding regions until the last instant. Viramune Combo Proves Simple, Effective Twice-daily drug regimens including the non-nucleoside reverse transcriptase inhibitor Viramune (nevirapine, Boehringer Ingelheim)) have been proven to achieve undetectable levels of HIV in the blood while increasing infection-fighting immune cells. Dr. Francois Raffi, professor at Centre Hospitalier Regional et Universitaire de Nantes, presented data at the 12th World AIDS Conference showing that starting anti-HIV therapy with Viramune, d4T (Zerit, stavudine) and ddI (Videx, didanosine) dramatically reduces virus in the blood to undetectable levels. This treatment combination is twice-daily and requires seven to eight pills daily. Plus, it has no cross-resistance with protease inhibitors, which is useful in helping people infected with HIV strains that are resistant to those medications. The Viramune combination is also an attractive treatment option because it is less complicated than some drug cocktails with protease inhibitors, which can require as many as 18 pills daily. Raffi presented the folowing data at the conference: n Sixty-two percent of patients taking Viramune in combination with ddI and d4T (24 of 39) achieved undetectable HIV levels at week four of the study. n Eighty-five percent of patients at week 16 of the study (17 of 20) also achieved an undetectable viral load. "Although more anti-HIV agents are available than ever before, resistance remains a problem," said Raffi. "Because inability to adhere to treatment is often a cause of resistance, we're continually looking for highly effective therapies that are also easy for patients to take." Raffi continued that Viramune is "an obvious choice" because "it rapidly supresses the HIV virus, and is taken twice a day with or without food." Viramune is generally well tolerated. It's most common side effect is rash. Data was also presented on how the Viramune combo worked in treatment-naive patients and in patients who had to stop protease inhibitor therapy due to adherence issues or intolerance. Dr. Cathy Pell of the Taylor Square Private Clinic, Sydney, Australia, noted that 100 percent of patients with no prior treatment (8 of 8) achieved undetectable viral loads using the Viramune-d4T-ddI combo, while 75 percent maintained those undetectable loads fr the 26-week followup period. A total of 39 patients switched from protease inhibitor therapy to the Viramune combo. Of these, 24 had detectable viral load at baseline and 15 had undetectable viral load at baseline. In the baseline-detectable group, 54% (13 of 24) achieved undetectable viral load during the 26-week period; of the 10 evaluable patients in the baseline-undetectable group at 26 weeks, 70 percent remained undetectable. |
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