STEP PERSPECTIVE, Volume 8, No. 3 - Winter/1996; A Publication of the Seattle Treatment Exchange Project e-mail: step@eskimo.com
Brian Coppedge

Clinical Benefit of 3TC Studied

Dr. Julio Montaner of Saint Paul's Hospital in Vancouver B.C. presented results of the CAESAR (Canada, Australia, Europe and South Africa) study which sought to compare the efficacy and safety of adding 3TC, 3TC plus Loviride, (an experimental non-nucleoside reverse transcriptase inhibitor under development in Europe but not yet available in the US), or a placebo to the participants current antiretroviral regimen. The CAESAR trial was a large trial of 1800 participants with CD4 counts between 25 and 250. All trial participants were already receiving either zidovudine (AZT) monotherapy, or AZT plus didanosine (ddI), AZT plus zalcitabine (ddC). Trial participants were separated into three separate arms. After 52 weeks of the trial all participants were offered open-label 3TC plus Loviride.

The study was stopped and unblinded following a Data Safety Monitoring Board analysis on July 5, 1996, because the trial data showed a significant difference between the three arms and it was determined no further data would change the results. The rate of disease progression to an AIDS-defining illness was: 17% for the placebo arm; 9% for the 3TC group, and 8% for the 3TC plus loviride group. Death rates in the trial were: 4.6% for the placebo arm: 2.4% for the 3TC arm, and 2.7% for the 3TC plus loviride group. This study determined that adding 3TC to these existing treatments led to a 54% reduction in AIDS-defining illnesses, and a 53% reduction in the risk of death for the trial participants. Adding 3TC to already existing combination therapy did not appear to increase toxicity and seemed to be well-tolerated by the participants. The addition of loviride did not appear to add any benefit to the 3TC enhanced treatments. The purpose of this trial was not to measure the clinical benefit of loviride. Further trials are necessary to evaluate loviride's efficacy.

Ritonavir and Saquinavir in Combination

In Vancouver, early data (only six weeks on trial) was presented that hinted to the possible advantages of using ritonavir and saquinavir in combination. The two protease inhibitors are being studied in combination because ritonavir can increase the blood levels of saquinavir up to 40 times. Additionally they have different toxicity's, and may have different resistance mutation patterns.

The study was an uncontrolled, open-label study which allowed participants to know which therapy they were receiving. Participants had CD4 counts between 100 and 500 and none were allowed to have taken any protease inhibitors previously. In addition, to be included in the trial, people had to discontinue all antiretroviral therapy for at least two weeks before starting on the new combination. The study divided the 136 volunteers into four arms: 400 mg ritonavir plus 400 mg saquinavir twice daily; 600 mg ritonavir plus 400 mg saquinavir twice daily; 400 mg of ritonavir plus 400 mg of saquinavir three times a day; 600 mg of ritonavir plus 600 mg of saquinavir twice daily.

After 12 weeks, the first two arms had a combined median reduction in viral load of 2.97 logs (a 99.9% reduction) and CD4 increase of 95. 75% of the participants in the first two arms saw their viral loads decrease to undetectable level ( below 200 copies). This same group of participants had been reported as having a 2.4 log (99.6%) drop after six weeks of the combination therapy. Only four people from these two arms had to discontinue therapy because of side effects ( one in the first arm and three in the second).

The third and fourth arms of the trial (which used high dosages) were started only after the initial lower dosage trials proved to be safe. After 6 weeks of the higher dosages, the median viral load dropped by 2.14 logs (99.3) and the median CD4 counts increased by 75 cells. The arm which received 400 mg of both ritonavir and saquinavir three times a day was not well-tolerated; eight of the participants in this arm had to discontinue treatment due to adverse side effects. The arm with 600 mg of ritonavir plus 600 mg of saquinavir was well tolerated and none of the participants in this arm had to discontinue therapy.

141W94 (Glaxo Wellcome): A New Protease Inhibitor

Glaxo Wellcome is developing a new protease inhibitor, 141W94, which it has licensed from the biotech firm Vertex. The initial study was aimed at determining the safety and maximal antiviral activity of different dosages of 141W94. This new drug seems quite promising for a few reasons: Initial data shows that it is synergistic with reverse transcriptase inhibitors, it is water soluble and therefore quite well-absorbed into the blood system, and in animals models, higher levels of the drug were seen in brain tissue than in the blood.

Antiretroviral activity was seen in the trial which was relatively small, enrolling 42 people in four separate arms. Participants CD4 counts ranged from 150 to 400 cells/ mm3 and had a median viral load of 483,000 viral copies/ml. Each arm consisted of about ten people who received either 300 mg of 141W94 twice a day, 300 mg three times a day, 900 mg twice a day or 1,200 mg twice a day. The study offered 141W94 monotherapy only, and none of the participants were allowed to have taken any protease inhibitors previously. The highest dose group saw a median increase in CD4 counts of 110 cells and a decrease in viral load of 1.95 log. The 900 mg group had a median CD4 increase of only 35 cells, had a decrease in viral load of 1.69 logs. The results of the lower dose arms were not quite as impressive. Volunteers taking 300 mg of 141W94 twice a day experienced only a .53 log reduction in viral load and an increase of 64 CD4 cells. Those who took 300 mg three times a day had CD4 increases of 84 cells and a viral load reduction of 1 log. 141W94 was generally well-tolerated, although about 10% of the participants reported side effects which included, headaches, loose stools and nausea.

Information presented at ICAAC continues to provide encouragement for people living with HIV/AIDS. The CAESAR study results confirm the clinical benefits of adding 3TC to existing antiretroviral treatments, ritonavir and saquinavir appear to be another strong combination that can be used to slow the replication of the virus and 141W94 is just one of many anticipated new protease inhibitors in development. Although the news from New Orleans was not as dramatic as that from Vancouver, important new information was made available.

Brian Coppedge is the Treatment Information Specialist for STEP.

These articles were provided by the Seattle Treatment Education Project - Copyright (c) 1997 - Seattle Treatment Education Project. Noncommercial reproduction encouraged. Distributed by AEGIS - http://www.aegis.com
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Copyright © 1996 - Seattle Treatment Education Project (STEP) - All rights reserved. Noncommercial reproduction is encouraged. STEP is published four times a year by the Seattle Treatment Education Project, 127 Broadway East, 3rd Floor, Seattle, WA 98102.    Email: step100@aol.com  STEP web page