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Published in the Bulletin of Experimental Treatments for AIDS 1999 Year-End issue, by the San Francisco AIDS Foundation.
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Conference Notes -- HAART and Experimental Approaches to TreatmentHarvey S. Bartnof, MD Can highly active antiretroviral therapy (HAART) be stopped without risk?At the 39th ICAAC, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), described an experimental trial whereby successful HAART was discontinued. Dr. Fauci's plenary presentation was entitled "Host Factors in the Pathogenesis of HIV Disease." He reported on 18 HIV positive people who had had undetectable HIV viral loads for one to three years due to successful HAART. Twelve of the 18 also had taken interleukin 2 (IL-2, or Proleukin) in the past, as part of an experimental anti-HIV therapy to boost CD4 cell counts and to "flush out" the reservoir of immune cells latently infected with HIV. In a highly experimental study, HAART was discontinued in all 18 persons. Not unexpectedly, all 18 experienced rapid viral rebound. Dr. Fauci and his colleagues were somewhat surprised by two of the 12 volunteers who had taken IL-2: Dr. Fauci was unable to culture any HIV from over 150 million of their blood mononuclear cells. He thought the IL-2 had "flushed out" this HIV reservoir, but the IL-2 apparently had not eradicated HIV from every reservoir. On a positive note, when HAART was restarted, all 18 volunteers quickly achieved an undetectable viral load. These people will be followed with additional analyses to better understand the human immune response to HIV. Stopping HAART involves significant risks, including rapid viral load rebound within days to weeks and the possibility of developing resistance to the drugs that were stopped. Do not stop medication without discussing the issue with a physician. Researcher proposes that HIV viral load be neither too high nor too lowAccording to Franco Lori, MD, of the Research Institute of Genetic and Human Therapy (RIGHT) in Washington, DC, the key to individual control of HIV infection lies in inducing HIV viral load levels that are neither too high nor too low. In his oral presentation at the 39th ICCAC, Dr. Lori indicated that in almost all untreated persons with HIV infection, a high viral load overwhelms the immune system, thereby limiting a favorable immune response. HAART drives the viral load too low, he continued, allowing too little of an antigenic (foreign) stimulus for the immune system to respond. Dr. Lori presented a graph showing what he believes is the optimal viral load range that would lead to an immune response likely control HIV infection. He arrived at his theory after observing "controlled" HIV infection in a few people who had pulsed (i.e., started, stopped, restarted, then restopped) anti-HIV therapy. All had started taking HAART-specifically hydroxyurea (Hydrea)- and ddI (Videx)-containing regimens-within three months after first being infected. Most also took a protease inhibitor (PI). The first person to experience the phenomenon was Dr. Lori's so-called Berlin patient. Dr. Lori believes that pulsed therapy shows benefits due to what he calls autoimmunization. That is, when the person's own HIV strain is allowed to grow, an increased viral load acts as an immunogen, like a vaccine. Specifics and details have not been fully elucidated, however. This is demonstrated by the fact that when almost all HIV positive persons discontinue HAART, viral load rebounds and usually remains high. One in three HIV positive U.S. adults taking HAART has a viral load of 20,000 copies/mL or greaterAt the 39th ICAAC, Julio S.G. Montaner, MD, from the University of British Columbia announced the following during his presentation: "Preliminary and unpublished estimates from HCSUS, which used [a] probability sampling to represent all adults in regular HIV care across the entire U.S. at the start of the HAART era are that, as of [autumn 1998], one-third of all such people on three or more antiretroviral drugs had viral loads of 20,000 [copies/mL] by the new Gen-Probe assay." These results underscore the fact that HAART is not effective for a significant proportion of HIV positive persons, mostly due to poor adherence, drug resistance, or both. Experimental therapy eliminates latent HIV reservoir in the laboratoryAn interesting study was presented at the 39th ICAAC by C. McCoig, MD, from the University of Texas Southwestern Medical Center. Latent reservoirs of HIV-infected cells represent the roadblock to eradicating HIV after successful HAART. Dr. McCoig described an experimental therapy called anti-CD45 RO immunotoxin. "RO" refers to the memory subset of mononuclear immune cells. "CD45" represents a cellular surface marker associated with these latent memory cells. When the immunotoxin was added to cells in the laboratory, HIV growth was reduced more than 90%. The authors concluded that the immunotoxin therapy "eliminates in vitro latently-infected cells." They added, "Future studies will be required to determine whether the anti-CD45 RO immunotoxin can also eliminate latently infected cells from HIV-infected individuals." Experimental once-daily dosing of PIsAccording to Alfred Saah, MD, of Merck & Co., an experimental regimen of indinavir (Crixivan) and ritonavir (Norvir) may be taken once daily. When compared with the standard indinavir dose (800 mg three times daily) without ritonavir, each of the following once-daily doses gave equal or better total 24-hour indinavir exposure (area under the curve, or AUC): indinavir 800 mg plus ritonavir 200 mg or indinavir 1,200 mg plus ritonavir 100 mg. Healthy volunteers had only mild to moderate gastrointestinal side effects. There were no reported kidney stones during the 14-day period in Study 089. In his presentation at the 39th ICAAC, Dr. Saah concluded that once-daily dosing should be tested for clinical benefits. A similar poster at the 39th ICAAC was authored by David M. Burger, MD, from the University of Nijmegen, The Netherlands. Dr. Burger concluded that the optimal once-daily dosing was indinavir 1,200 mg plus a "baby" dose (200 mg) of ritonavir. He said that an initial ritonavir dose of 400 mg starting on day 1 may be necessary, however. In Dr. Saah's study, dosing was once daily for two weeks, while Dr. Burger's study evaluated drug levels during a three-week period when the test dose was given once on days 1, 15, 18 and 21. At the 39th ICAAC, an experimental once-daily dosing of saquinavir (Fortovase) plus ritonavir was presented by Michael Saag, MD, from the University of Alabama at Birmingham. In his study of 41 healthy volunteers, Dr. Saag concluded that the optimal once-daily dose for future studies in HIV positive persons is saquinavir 1,600 mg plus ritonavir 100 mg. Concentration profiles for saquinavir were much more favorable than with the standard three times daily dosing of saquinavir without ritonavir. Concentration measurements included area under the curve (AUC), minimum concentration (C-min), and maximum concentration (C-max). A higher dose of ritonavir may be necessary when combined with a once-daily dosing of saquinavir 1,600 mg. A popular and effective dosing of the two PIs when used in a four-drug combination has been 400 mg of each every 12 hours. Page last updated 8 January 2000 |
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