Simply Medical: Antimicrobial Agents and Chemotherapy
Highlights of the 38th Interscience Conference
More than 12,000 physicians, infectious disease specialists, research scientists, and other healthcare professionals from around the world gathered in San Diego in November to hear the latest findings in the diagnosis, treatment, and control of infection with HIV/AIDS. Particular emphasis at this 38th Interscience Conference on Antimicrobial Agents and Chemotherapy was placed on new antiretroviral agents, improved treatment regimens, and methods for improving the overall physical health of HIV-infected persons. Here are some highlights.
New Antiretroviral Agent Shows Promise
Adefovir dipivoxil (Preveon®, Gilead Sciences) is a new nucleoside reverse transcriptase inhibitor with activity against HIV and suitable for once-a-day dosing when administered with any approved anti-HIV combination treatment regimen. It resulted in a significant decline in HIV viral load and a modest benefit to CD4 cells at 24 weeks, according to Dr. J. Kahn of the AIDS Program at San Francisco General Hospital. In addition, data from this study pointed out that treatment with adefovir dipivoxil was associated with a marked reduction in HIV RNA, even in patients infected with strains of HIV known to have developed resistance to lamivudine (3TC, Epivir®, Glaxo Wellcome) or zidovudine (ZDV, Retrovir®, Glaxo Wellcome).
In this study, 442 patients were randomly assigned to receive either adefovir dipivoxil 120 mg once daily or placebo along with their standard antiretroviral therapy for up to 48 weeks, provided the patient had been on a stable regimen for at least eight weeks. At week 24, all patients were offered open-label adefovir dipivoxil.
At weeks 24 and 48, adefovir dipivoxil, as part of combination regimens, was associated with sustained decreases in levels of HIV RNA, with a -0.4 log10 median decrease in the adefovir dipivoxil group versus no change in placebo. At 24 weeks, the placebo group showed an average decline of five CD4 cells compared to an average increase of five CD4 cells in the active treatment group.
Major side effects of adefovir dipivoxil included significantly increased gastrointestinal effects, including nausea, vomiting, and loss of appetite, weight loss, and increases in liver transamineses. In all studies, the drug was coadministered with L-carnitine, a nutrition supplement. Study drug discontinuations, for any purpose, were comparable in both treatment arms, with 17 percent in the placebo group and 21 percent in the adefovir dipivoxil group.
Twice-Daily Nelfinavir as Effective as Three-Times-a-Day Dosing
The 48-week results from a large-scale, ongoing, 96-week, multinational phase III clinical trial show that twice daily dosing with the potent protease inhibitor nelfinavir (Viracept®, Agouron), in combination with standard doses of stavudine (d4T, Zerit®, Bristol Meyers Squibb) and lamivudine (3TC Epivir®, Glaxo Wellcome), has proven to be as safe and effective as the currently approved three-times-a-day dosing. This is according to Dr. Ann Katrin Petersen, director and head of international clinical research of Agouron Pharmaceuticals, Inc., in LaJolla, California.
"It is generally acknowledged," Dr. Petersen noted, "that adherence is better when drugs can be taken fewer times per day. These data, if confirmed, may help improve antiretroviral drug regimen adherence, which in turn may enhance the likelihood of effective long-term suppression of HIV."
In this study, a trial was designed to compare two dosing regimens of nelfinavir 1,250 mg twice daily or 750 mg three times daily in combination with the two nucleoside analog reverse transcriptase inhibitors d4T and 3TC for a treatment duration of up to two years in a total of 360 patients (180 persons per group). Patients were all HIV-positive, with mean baseline CD4+ cell counts of 268 cells/mm3 and mean baseline viral load of 5.0 log copies HIV RNA/ml.
In preliminary results from 288 patients, over 80 percent of patients in both treatment groups achieved undetectable viral loads (under 400 copies/ml) initially. Furthermore, of those persons who responded, approximately 90 percent had viral loads that remained undetectable at up to 48 weeks of nelfinavir therapy. In addition, 68 percent of patients in the twice-daily dosing group and 64 percent of those receiving nelfinavir three times daily achieved viral loads below the limit of ultrasensitive assay detection (less than 50 copies/ml) at 48 weeks.
Amprenavir Combo Provides Excellent Antiretroviral Suppression
Amprenavir (AgeneraseTM, Vertex/Glaxo Wellcome), a new and potent protease inhibitor, in combination with zidovudine (ZDV, Retrovir®, Glaxo Wellcome) and lamivudine (3TC, Epivir®, Glaxo Wellcome) has been shown to produce superior antiretroviral activity compared to only ZDV and 3TC alone, while being equally as safe and as well tolerated as the dual therapy, according to Dr. Jeff Goodgame, associate professor of medicine at the University of Central Florida, Orlando, Florida.
In an ongoing randomized, double-blind, placebo-controlled, international, multicenter phase III clinical trial, 232 HIV-infected patients, all antiretroviral naïve, were randomly assigned to either amprenavir 1200 mg, ZDV 300 mg, and 3TC 150 mg, all twice daily, or ZDV 300 mg plus 3TC 150 mg, twice daily, for sixteen weeks. At that time, all patients received open-label amprenavir plus ZDV and 3TC continuing through 48 weeks.
At sixteen weeks, the triple combination with amprenavir was far superior to dual ZDV plus 3TC therapy, with 88 percent of patients in the amprenavir group having achieved undetectable viral loads (less than 400 copies/ml) versus only 19 percent of those on dual therapy alone. Furthermore, using a conservative intent-to-treat analysis, 59 percent of patients receiving triple therapy had HIV RNA levels below ultrasensitive assay detection (less than 50 copies/ml) compared to only 10 percent of persons on ZDV and 3TC only.
With regard to safety, amprenavir generally was well tolerated, with a low incidence of severe adverse events. In addition, this new protease inhibitor does not produce elevated total cholesterol or triglycerides, potential metabolic problems with existing protease inhibitor therapy that are linked to lipodystrophy and development of heart disease.
Pneumococcal Vaccine Safe for HIV-Infected Adults
While some earlier studies have suggested that pneumococcal polysaccharide vaccine may increase viral load, in this study no rise in viral load was observed after administration of pneumococcal vaccination. These results lead to the conclusion that such vaccination should not be discouraged because of concern about a potential rise in viral load levels in HIV-infected adults, according to Dr. Catherine A. Fleming of the Adult AIDS Program at Boston Medical Center.
Infections with the bacterial organism Pneumococcus occur frequently in HIV-infected adults and may occur at all stages of HIV infection, and it would therefore be prudent for all HIV-infected adults to be immunized against this bacterium. As noted, some earlier findings have caused concern about the safety of this practice, and a study was designed to assess this problem and develop definitive practice guidelines.
A total of 25 HIV-infected adults received pneumococcal vaccine (Pneumovax®) and had viral loads measured at baseline and at seven to 88 days post-vaccination (mean 24 days). Antibody response to the vaccine was also evaluated. Baseline plasma viral load levels were a mean 143,693 copies/ml.
Follow-up HIV viral load testing did not demonstrate any significant rise in viral load in any of the 25 persons who received the pneumococcal vaccine. In point of fact, in eight individuals who started on HIV medications in the time between receiving the vaccine and follow-up viral load testing, there was a significant reduction in viral loads, indicating a response to appropriate therapy. In addition, a number of the patients showed a significant antibody response to the pneumococcal vaccine (defined as a twofold or greater rise in the mean titer), strongly suggesting that the vaccine should not be withheld because of concerns about effect on viral load.
This article was provided by Body Positive. It is a part of the publication Body Positive.