AIDS TREATMENT NEWS #216, February 12, 1995

With no International Conference on AIDS this year (in the future, that meeting will occur only in even-numbered years), the Second National Conference on Human Retroviruses and Related Infections, January 29 - February 2 in Washington, D.C., with about 2300 people attending, was probably the largest conference on AIDS basic science and clinical trials to occur in 1995. Many felt that this was a better conference than most, with a higher quality of work presented and a more consistent focus on important research issues, reflecting improvements in the research today. There was more sense of optimism, based on a growing understanding of HIV, and growing agreement on some of the important research directions.

Lack of access by persons with HIV was a serious problem, however. The conference was expensive -- $425 on-site registration. The absence of corporate advertising booths may have been a welcome contribution to the focused scientific atmosphere, but also meant that the considerable expenses of the meeting had to be paid largely by those who attended. And there were no HIV scholarships, which meant that few people with AIDS could go unless they could register as press. Because many people were not there, AIDS TREATMENT NEWS is expanding its coverage of the information presented.

We urge organizers of future AIDS conferences to re-think the entire project in view of the development of computer communication. As much as possible of the information to be presented -- in writing, slides, and eventually video -- should be released on the Internet BEFORE the conference, and made freely copyable so that it will be immediately available to AIDS physicians and other service providers throughout the world. Future conferences will focus less on formal, mass lectures, and more on working groups of people who need to meet face to face to discuss and extend the information already released.

Highlights These are some of the areas we found most memorable and important: * Protease inhibitors. This new class of HIV treatments -- not yet widely available to patients -- is getting the most research and public attention today. It is fairly clear that protease inhibitors will be an important advance in AIDS treatment, but will not be the answer. They will need to be used in combination -- with each other, and with other drugs. Their development is one of a number of incremental steps toward better treatment. The new information presented at the conference was about as expected -- neither more nor less optimistic. More information should become available next week at the protease meeting of the National Task Force on AIDS Drug Development.

* 3TC plus AZT. This treatment is more widely available, at least to U.S. patients who are failing other treatments. Data from U.S. trials presented at the Human Retroviruses meeting basically confirmed the data from European trials presented in Glasgow last November (see AIDS TREATMENT NEWS #212, December 2, 1994). But as at the Glasgow meeting, most of the data now available is only for the first 24 weeks of the trial, and is only from blood tests; also, there was a fairly high dropout rate from both the European and U.S. trials. And, as expected, the results are less dramatic for people who have already used AZT extensively. The apparent benefit of this combination is not enough to keep skeptics from arguing that it may be no better than other combinations already available; for example, both 3TC plus AZT and ddC plus AZT caused comparable reductions in viral load (almost 10 fold) sustained at least for 24 weeks and perhaps beyond 48 weeks, when they were compared head to head in the same trial. But the general sense is that the AZT plus 3TC combination appears to give better and especially more sustained blood-work improvement than more standard combinations, and probably to be safer as well.

* Long-term non-progressors. It is now generally believed that not everyone with HIV disease will eventually become ill. About five percent are "long-term non-progressors" -- defined in one study as persons who have had HIV for at least seven years, have stable CD4 counts over 600, and no HIV- related illnesses. (Although the definition specified seven years, most of the people studied have been HIV-positive and stable for over ten years.) While this information is not new, an important report appeared in the NEW ENGLAND JOURNAL OF MEDICINE on January 26, just before the Human Retroviruses conference -- and the conference seems to have marked a change in the "conventional wisdom" about HIV, the general assumptions that pass unthinkingly into newspaper stories, etc. In the past, the conventional wisdom had been that everyone would probably progress to AIDS eventually. Now the conventional wisdom is that, as far as we know today, about five percent of people with HIV will never become ill as a result.

Another study presented at the Human Retroviruses conference used statistical methods to project AIDS-free survival, based on data from the MACS project, which includes a large cohort of men with HIV who have been followed for many years. This study predicted that about 13 percent of people with HIV would be AIDS-free 20 years after they became HIV positive.

There is no contradiction between the five percent estimated by one study, and the 13 percent estimated by the other. This is because there are many kinds of long-term survivors, not all of whom fit the above definition of "long-term non- progressor." The 13 percent probably includes the five percent who may never get sick as a result of HIV infection, and others who will develop AIDS but very slowly, after 20 years or more -- unless better treatments are found by then.

Neither figure includes another group, who are HIV negative but whose immune systems show that they have been exposed to HIV in the past. This group may have recovered from HIV infection, or may have had a small exposure which did not result in infection.

It is clearly important to study all kinds of long-term survivors, to find out what is different about them and/or about their virus. This information might lead to new ways to treat HIV disease, whether or not it has already progressed to AIDS.

* Clinical trial design. There were signs of movement toward consensus on this controversial issue -- perhaps more in the hallway conversations and overall atmosphere of the meetings than in the formal sessions on this topic. And it was encouraging to see that seemingly obscure meetings on clinical trials could pack large lecture halls.

The general professional opinion is clearly accepting viral load as a useful measure, and wants to see it used in small, rapid trials (the position we have long advocated in AIDS TREATMENT NEWS), while also acknowledging that there is much to be learned about how well viral load reduction translates into clinical benefit to patients. A minority does not argue that viral load is useless, but rather that it is unproven. These people are concerned that we could be making a mistake -- that "treating the marker" (blood test value) may not mean that we are "treating the patient" -- in other words, that the strategy of lowering viral load might not prove helpful. They point to the Concorde trial, which showed that early use of AZT raised the T-helper count but did not lead to longer survival, as an example of the need for caution in judging drugs by blood-test results. They want to see a large trial to test the strategy of changing drugs to lower viral load, compared with changing drugs by other criteria without using viral load, to prove that viral load is superior for this purpose.

The practical controversy is between those who emphasize small, rapid, data-intensive trials generally using blood tests, and those who emphasize large, long-lasting trials with "clinical endpoints" -- statistics on how many people progress to more serious illness or death. But a working compromise seems to be developing. Those who want the large trials know that there can be very few of them (because of the limited number of qualified patients, as well as limited money, trained personnel, and other resources); therefore, rapid small trials will be needed to find the best treatments to put into the large trials. And those who emphasize small trials know that large trials will also be necessary, and that these large trials will help to define the appropriate use of viral load and other blood tests for studying new drugs in the future, and for managing patient care.

* New immune-function tests. Even with viral load tests in addition to T-cell counts, doctors are missing something important -- measures of how well the T-cells are working. Specialized research tests can measure immune function, but they have been labor intensive, expensive, and inherently imprecise. They are not suitable for widespread use, and even research use can be problematic.

Now there is a new kind of immune-function test, based on an "early activation" marker called CD69; this test is becoming commercially available for research use (but not for routine patient care) this month. The new test has many advantages. It uses whole blood at body temperature, greatly simplifying the procedure and leaving the cells in their natural environment, so that the test result will better reflect how the cells behave in the body. The entire procedure takes a few hours, compared to two weeks for earlier methods; only a few minutes of labor is required, and no radioactivity is used. Also, the cells are typed and measured individually, while previous methods gave bulk answers; variations of the technique can even show the production of certain substances, such as IL-2, within each cell. And the new test is inexpensive -- probably well under $100 for reagents and labor. An expensive flow cytometer is required, but many laboratories have one already; they can begin running these tests at little start-up cost, only a few thousand dollars for reagents. The major barrier to widespread use is conceptual; this new technology makes possible many different immune tests, and doctors do not know what tests to order or how to interpret the results.

Different patients can have the same disease status by all conventional measures, but have different results on immune function tests, predicting different disease outcomes. As more becomes known, these tests will be used not only to study the pathogenesis of HIV disease, but also to see if treatment or lifestyle changes are correcting the immune defects they find. Much research will be necessary before this technology can become part of routine care; but existing AIDS research organizations, including specialized medical practices, can begin this research now.

The Human Retroviruses conference had only one poster involving this technology, which has been developed by Beckton-Dickinson Immunocytometry Systems and is being marketed under the name FastImmune (TM) (see poster #174, "Diminished V-Beta T Cell Subset Responses to Superantigen in HIV+ Individuals as Determined by Multiparameter Flow Cytometry," VC Maino, JJ Ruitenberg, MA Suni, L Mole, and M Holodniy; also see abstract #504A from the Yokohama conference, "Rapid Flow Cytometry Detection of T Cell Subset Activation in AIDS," by the same research group). We will continue to report on these and other immune-function tests as we learn more about them.

[Part II of this article will continue our report from the Human Retroviruses conference.]