Research Initiative Treatment Action (RITA!); Vol 5, No. 5 December 1999
At the end of November, Abbott Laboratories announced that it had broadened the entry criteria in the United States for its early access program to ABT-378/r. Under the new criteria patients with up to 200 CD4 T cells who have failed multiple antiretroviral therapy regimens will have access to the new drug. Abbott plans to expand further the program by February 2000. At that time, any patient who cannot construct a viable treatment regimen with currently approved antiretrovirals will have access ABT-378/r without regard for viral load levels, CD4 T cell counts or previous protease inhibitor use. For more information call 888.711.7193.
A letter appearing in the October 5, 1999 issue of the Annals of Internal Medicine reported on four men with HIV infection who sustained myocardial infarction after 24 to 29 months of protease inhibitor therapy. Two of the subjects died. The men were ages 35 to 44 and were smokers. Two developed increased triglycerides and cholesterol related to protease inhibitor use. One had high lipids before starting the therapy. All patients were of the Kalamazoo Center for Medical Studies of Michigan State University School of Medicine.
The US Food & Drug Administration (FDA) has approved the twice-daily dosing of nelfinavir (Viracept). The decision was based on interim results of a phase III trial comparing the antiviral effects and safety of 1,250 mg twice daily versus the previously approved 750 mg, three times a day dose of nelfinavir. Moderate to severe diarrhea was reported in 14 to 18% of the patients receiving either dosing regimen.
Bristol-Meyers Squibb, the makers of didanosine, sent health care providers a revised warning letter that expands the number of patients at risk of fatal and nonfatal pancreatitis associated with the drug. The original warning on the drug labeling was of a 1 to 10% risk of didanosine-related pancreatitis based on the phase III experience with patients with advanced HIV infection who were taking higher than recommended doses of didanosine. The new warning comes as a result of pancreatitis deaths in patients participating in a trial of stavudine (Zerit) and didanosine, with or without hydroxyurea (Hydrea). Two treatment-naïve patients died of pancreatitis about seven months after starting a regimen consisting of stavudine, didanosine and a protease inhibitor. Two other deaths occurred in patients participating in ACTG 5025, which involved a regimen of didanosine, stavudine, indinavir and hydroxyurea. The two patients were hospitalized for pancreatitis within three months of trial enrollment and died between one and 10 weeks of diagnosis. ACTG 5025 has been cancelled due to these toxicities. Bristol-Meyers Squibb and the FDA have requested that all cases of pancreatitis occurring in patients treated with didanosine be reported to Bristol-Meyers Squibb at 800.426.7644 and to the FDA via:
Researchers reported in the Journal of Medical Virology (59, p. 364, 1999) on a prospective trial involving nineteen HIV-infected pregnant women were given either zidovudine (Retrovir) (14 women) or zidovudine and lamivudine (Epivir) (5 women). The dual drug regimen was given to women with more advanced disease. Viral load reductions were seen in both groups, but the women who received the dual combination had greater reductions in viral load and greater increases in CD4 T cells. However, four of the five women on the dual therapy developed the M184V mutation (indicative of resistance to lamivudine) as early as 8 weeks after treatment began. Researchers concluded that resistance to lamivudine has important implications for future management of the mothers and as such, when possible other therapies should be given.
For the first time ever the Antiviral Drugs Advisory Committee of the FDA rejected the application for accelerated approval of an AIDS drug. Gilead Sciences's application for accelerated approval of their nucleotide, adefovir dipivoxil, as a second-line therapy for patients who have not responded to highly active antiretroviral therapy (HAART) was rejected by a vote of thirteen to one. It was noted that the antiviral activity of adefovir was modest, at best. The determining issue was one of safety. In the view of many, Gilead had failed to establish sufficient data to determine the safety of its proposed 60 mg dose. At the higher dose of 120 mg patients had experienced kidney toxicities. Gilead had proposed the lower dose as safe but the committee found the data insufficient to establish long-term safety. Approximately nine thousand patients have taken adefovir under the company's expanded access program. According to company's press release these patients will have continued access to the drug, but no new patients will be accrued.
Scientists at the National Eye Institute report in the November 3 issue of the Journal of the American Medical Association (282, p. 282, 1999), on patients with stable cytomegalovirus (CMV) retinitis who experience increases in CD4 T cell counts as a result of highly active antiretroviral therapy (HAART), and conclude that these patients may safely discontinue CMV treatment. The researchers studied fourteen patients who had stable CMV retinitis and were treated with anti-CMV medications and HAART. Patients had a median of 25 CD4 T cells at the time of diagnosis of retinitis. At the time of the study the patients's CD4 T cell counts were greater than 150 cells. CMV medications were discontinued and the patients were followed. At a mean follow-up of 16.4 months none of the patients had experienced CMV retinitis reactivation or extraocular CMV disease.
Using an ultrasensitive viral load assay that measures HIV RNA levels down to five copies, researchers at Thomas Jefferson University measured the HIV RNA levels in the plasma and genital fluids of 22 patients who had viral load of less than 50 copies by convention viral load tests. All 22 patients showed viral RNA with a mean level of 17 copies. Ten of the 22 patients had detectable virus in genital fluids, although the levels were generally lower than in the plasma. (See "Why the fat lady hasn't sung: The limits of HAART" on page 8 of this issue.)
Participants in the Virology Quality Assurance Program have confirmed a recommendation that has generally been accepted in current clinical practice: patients should have at least two viral load tests done prior to starting antiretroviral therapy. In a retrospective study, plasma samples from 663 members of the Adult and Pediatric AIDS Clinical Trials Groups and the Women and Infants Transmission Study were analyzed for inter-assay and intra-assay variation, along with biological variation within each subject. The results, published in the November 12 issue of AIDS (13, p. 2269, 1999), showed a total variation of 0.26 log. Biological variation accounted for about 56 to 80% of total variation. Inter- and intra-assay variation was estimated to be about 0.08 to 0.12 log.
Current theory holds that in the course of sexual transmission HIV first invades macrophages or dendritic cells and it is subsequently transmitted to activated and propagating CD4 T cells. Ashley T. Haase, MD, of the University of Minnesota Medical School and colleagues have observed that at least in a monkey model, infection was propagated not only in activated and proliferating cells at the point of entry, but also in resting CD4 T cells. The report appears in the November 12 issue of Science (298, p. 1353, 1999). The scientists studied monkeys that had been inoculated intravaginally with SIV, expecting that macrophages and dendritic cells would be the first to show signs of infection. To their surprise, they found that in the earliest stages of infection most of the infected cells were CD4 T cells and further that contrary to expectation, these CD4 T cells were resting cells. When the researchers looked at HIV they found similar results with a substantial population of resting CD4 T cells carrying infection. Finally, they found that these resting cells were capable of supporting viral replication, whether they were activated or not and the bulk of resting cells persisted even after the introduction of antiretroviral therapies.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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