Birmingham UK Drug Therapy Conference -- Early Report

The important 3rd International Congress on Drug Therapy in HIV Infection took place in Birmingham, UK, November 3-7; we could not attend and are still gathering information as we go to press November 12. There was much interest in studies relevant to the complete suppression of HIV replication by drugs.

A small but widely discussed study at the University of Amsterdam found that antiviral treatment which reduced viral load to undetectable levels in the blood, also reduced viral load to undetectable levels in lymph tissue. This was found in six out of six patients in a substudy of a larger trial. The lymph tissue was taken by a biopsy of the tonsils (which is much less invasive than the conventional procedure of removing a lymph node), before starting treatment and again after six months of treatment.

Researchers at the University of Minnesota developed the methodology to measure HIV in lymph tissue from tonsils; see recent paper by Haase AT, Henry K, Zupancic M and others, "Quantitative Image Analysis of HIV-1 Infection in Lymphoid Tissue," SCIENCE, November 8, 1996, pages 985-989.

Undetectable HIV viral load in the lymph nodes does NOT mean that the virus has been eradicated -- only that it is not actively reproducing. This viral load test only looks for viral particles; it does not detect the viral DNA that is still in the patients' cells -- ready to start up the infection again if the drugs are stopped. No one knows whether or not all these cells will eventually be eliminated by the body, if replication can be stopped for long enough.

While the growth of the virus is being completely suppressed, drug resistance apparently does not develop. The virus develops resistance when it is able to reproduce to some degree in the presence of the drugs, since then the viral variants which happen to be resistant to those drugs have a selective advantage, and can replace the more susceptible virus.

These results are not surprising, as there have long been indications that if viral replication is being suppressed in the blood by antiretroviral drugs, it is also suppressed in the lymph nodes (where there is much more HIV than in the blood, and where the virus is more important in the development of disease). And no one would expect the drug resistance of the virus to increase if the virus is not reproducing. But it is important to get direct evidence, since these questions are central to the interpretation of viral load tests and the management of therapy.

Note: The drug combination used in this University of Amsterdam study was ritonavir, AZT, and 3TC, in volunteers who had not used any antiretroviral before. However, there is nothing special about this particular combination; all evidence suggests that what is important is reducing the viral replication essentially to zero and keeping it there, using whatever drugs can do so for a particular patient. Similar suppression of replication has also been achieved with other combinations using a different protease inhibitor -- or even no protease inhibitor at all.

The main problem now is that some patients are more difficult to treat -- especially those with more advanced HIV disease, those who have already developed resistance to existing antiretrovirals, and those who cannot tolerate the drugs. This is why the problem of HIV treatment is not solved, despite the good results in some people. We need continuing development of better drugs -- with stronger and more durable antiviral effects, and/or less toxicity, and/or different resistance profiles than existing treatments, and/or drugs which may not be superior on the average but do work for some people when others treatments do not. And then of course there are still the economic barriers of getting effective treatments to those who need them.

More work is also needed on measurement of HIV in lymph tissue, since the most sensitive tests are quite difficult to do at this time.

There has long been an ongoing debate about the importance of aiming specifically for complete suppression of viral replication, vs. being willing to compromise on partial suppression due to practical concerns of toxicity, cost, and onerous compliance with regimens of three drugs or more. Professional opinion now seems to be moving more strongly toward the importance of complete suppression whenever antiviral therapy is used, because of the danger that otherwise the patients' virus will develop resistance to the drugs one by one, and each drug in turn will be lost for that person. This probably means that when therapy is begun, it will usually be with three or more drugs started together (instead of starting with one or two, then adding other drugs when the first ones fail); those who have already used antivirals will need to start or add combinations of at least two new drugs they have not seen before. What counts is keeping the viral load essentially at zero, whatever treatment that requires, because otherwise the virus will eventually escape the control of the drugs.

Extending and applying these principles to the treatment of many different patients in different situations, given the limitations of the drugs available and the practical limitations imposed by the difficulties of therapy, will be a central challenge in AIDS medicine for the next several years.