Important note: Information in this article was accurate in January 1997. The state of the art may have changed since the publication date.I arrived in Washington D.C. with high exceptions, remembering it was at this conference the year before that much of the good news around Protease Inhibitors had been presented. It quickly became apparent that this year's conference would not be a watershed event. Primarily, additional data was presented about ongoing trials and a few new antiretrovirals were discussed. In this article I am going to give brief reviews of some of the more interesting developments in antiretroviral therapies and discuss some the general themes covered at the conference.
Starting on January 22 shortly before Dr. Ho's opening presentations, several activists and people living with AIDS (PLWA) tried to register for the conference. Organizers had limited enrollment at this year's conference turning away hundreds of doctors and PLWAs during the initial enrollment period. It was explained to the community members seeking enrollment that they would not be allowed to register, as that would not be fair to the hundreds of other people who had been denied enrollment during the official enrollment period.
After lengthy discussions and negotiations it was agreed that community members would not attend the opening presentations, but if they returned in the morning they might be allowed to register for the remaining presentations. It was stressed several time by activists that they expected to be admitted the following day, and that seemed to be agreeable to the conference organizers. The following morning all of the community members seeking admission were denied entry. It seems that this conference once again forces community members and activists to address issues of access to and participation in the research process.
During the course of the conference several broad themes seemed to emerge. One of the most pressing questions in many peoples mind was how to prevent the development of resistance to therapies that include protease inhibitors. It seemed widely agreed that resistance occurs in two ways: failure of people to be compliant with their dosing routine, and the failure of the therapy to completely suppress viral replication. Several presenters discussed the importance of total viral suppression, stressing that if the virus is allowed to reproduce in the presence of drugs. Resistance will eventually occur. This follows the strong push for the "hit early, hit hard" theme that emerged from the Vancouver conference.
Dr. Joep Lange presented a lively presentation on the future of drug trials. In his presentation Dr. Lange encouraged researchers to stop reproducing studies which have already been performed and addressed the issues of suboptimal therapy arms in trials. He stated that it is now longer acceptable to create a study that forces some participants to accept suboptimal therapy. He also chastised the pharmaceutical industry for its continued practice of only allowing their products to be tested in combinations with other drugs they manufacture. Hopefully GlaxoWellcome was listening.
The most encouraging information presented revolved around various reports of the impact that the new antiretroviral therapies have had on quality of life. The City of New York released data showing a 30% decrease in the number of AIDS related deaths in 1996. In was generally agreed that introduction of the new therapies was the greatest reason for this decline. Several studies also discussed the decline in the number of illness that required hospitalization and in the duration of stay for those admitted. The obvious result of these declines was a reduction in cost to care for someone living with HIV/AIDS. Although the data was not presented at the conference, the CDC has released information supporting this decline in the death rate. Nationally there was a 13% decline in the AIDS related death rate for the first six months of 1996, but the CDC reported increases for women and people of color. The CDC data clearly points to the importance of guaranteeing access to these drugs for everyone living with HIV/AIDS.
In this section I want to present new data on combinations that are currently available. Many people are currently taking a combination of Saquinavir and Ritonavir, and we now have data from week 24 of this study. In the ongoing study, 71 people were randomized to arms using either 400 mg of ritonavir plus 400 mg of saquinavir, or 600 mg of ritonavir plus 600 mg of saquinavir twice daily. At 24 weeks the median viral load had seen a decrease of more than 99.9%, and CD4 increases of 114 cells. The double protease treatment suppressed the viral load to less than 200 copies for over 80% of the people in the trial. A second group of 70 people were randomized to receive the same dose, but three times a day instead of twice. After 20 weeks of treatment, median viral RNA had decreased by 99.8%, and the median CD4 had increased by 100 cells. One of the most important pieces of information reported in this study showed that the viral suppression seen at 12 weeks was very predictive of what happened at 24 weeks, which may help identify people who require more aggressive therapy.
A University of Ottawa study found that the combination of saquinavir plus ritonavir may potentially help restore immune functions damaged by HIV. It analyzed 43 people who were part of another study, and determined that their blood cells had partial restoration of previously suppressed immune responsiveness.
The last interesting piece on the two protease combinations involves the role the two drug therapy might play for people with advanced HIV infection who have failed other treatments. In evaluating 10 people who were treated for 1-10 months, investigators saw an increase in CD4 cells for nine of the ten people (the mean percentage increase was 275% from baseline). Five of the ten participants had viral loads that were undetectable (under 500 copies), sustained for three months or longer. During the study no opportunistic infections developed, and no adverse effects of the treatment were reported.
It seems that many people are struggling to understand what role nevirapine might play in their antiretrorial therapy and some data presented might help provide some answers. The manufactures of nevirapine are stressing the importance of its ability to cross the blood brain barrier. The Institut Pasteur in Paris presented information suggesting that a decrease in plasma RNA might not coincide with a decrease of the virus in the Central Nervous System (CNS). The one person studied had very low CD4 counts (20/mm3) and a high viral load (5 log) when he began a triple combination that included Indinavir. On this therapy his CD4 count increased to 105 and his viral load in plasma was under 200 copies but his CSF viral load was 1,262,653 (6.1 log). This data adds strength to the argument that combination therapies need to include an agent with strong CNS penetration.
A study conducted by Boehringer Ingelheim, the manufacturer of nevirapine showed that nevirapine was extremely effective at penetrating the blood brain barrier in vitro in both animals and in human CSF. Using an in vitro process, they were able to show that the levels of nevirapine that were detectable were twice as high as with the next closest antiretrovial (AZT). Also, information was presented to community members that suggested that nevirapine could be used in combination with protease inhibitors with certain restrictions, since nevirapine reduces the amount of saquinavir and indinavir that get absorbed into into the blood stream. It seems that any reduction in the amount of saquinavir in the plasma is risky but the reduction of Indinavir can be corrected with an increase in dosage.
This article provides a brief review of only a small part of studies presented at the conference. Many new agents in development were discussed and we will continue to follow their development as significant data is presented.
Brian Coppedge is the Treatment Information Specialist at STEP
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