Being Alive; December 1996
Jim Stoecker

Antiviral Therapy

Dr. Scott Hitt of the Pacific Oaks Medical Group began the evening by discussing the current and future state of antiviral therapy. It is in the area of antiviral therapy that we have seen the largest changes over the last ten or so years. The work of antiviral researchers has been to focus on targets where the virus might be interfered with. Thus, we began with reverse transcriptase inhibitors and have now moved on to protease inhibitors as well. In the future, we anticipate fusion inhibitors and integrase inhibitors to add to the antiviral arsenal.

As Dr. Hitt noted, we still don't know everything there is to know about hiv. New targets for antiviral therapy may yet be discovered. What we do know now is that antivirals should not be taken in isolation; monotherapy is no longer the accepted way to go. The challenge is to find the right antiviral combination for each individual.

For combination therapy ultimately to be successful, however, the drugs used need to work for a long period of time. The issue of hiv developing resistance to antivirals is crucial and must be dealt with if we are to have long term efficacy from antivirals.

Dr. Hitt concluded his remarks by asserting that he believes a cure for aids will ultimately be found. The possibility for a cure, not just long term management, exists, but it may takes us years to find that cure.

Immune System Restoration

Dr. Michael Gottlieb of the Gottlieb Medical Group addressed the issues around restoring the immune system damaged by hiv infection. To better illustrate these issues, Dr. Gottlieb used the analogy of a sink. The immune system is the sink and the CD4 cells are the water in the sink. From the open tap new CD4 cells are being added to the immune system. The open drain is the effect of hiv. You can readily understand that you are never going to fill the sink with water as long as the drain is open. In fact, left alone, the sink will eventually empty since the tap cannot keep up with the water draining out.

The central problem with hiv infection has been this open drain, i.e. the virus's ability for uncontrolled replication. Recently, we have seen that new combinations of reverse transcriptase and protease inhibitors have had a remarkable effect on plugging this drain. Under such a regimen, we would expect the sink to fill up. In fact, early tests of protease inhibitors indicated that the CD4 arm of the immune system has a strong regenerative capacity even in advanced hiv disease. We are also seeing, however, that the sink does not fill up for everyone and this has been a major disappointment. CD4 cell counts do not move back up to normal.

In the last year or so, we have been focusing on viral load to track the progression of hiv disease. After years of monitoring CD4 counts, physicians seem to have abandoned this marker. Yet CD4 counts remain important in monitoring the health of the immune system. It may very well be that there are negative consequences to long term stable, but subnormal, CD4 counts. Thus, to use our sink analogy once again, we need to focus on the tap. Can we find ways to open the tap even wider, to stimulate CD4 cell production? This is the central challenge of immune system restoration.

Where do new CD4 cells in the blood come from? In very simplified terms, they begin in the stem cells of the bone marrow which create precursors that migrate to the thymus gland. Dr. Gottlieb calls this the Thymus University. Here is where the unschooled stem cells learn to recognize various invaders and to fight infections. They migrate out to the blood as fully functioning CD4 cells. The problem is that the thymus atrophies as the individual ages and is also heavily damaged in its functioning by hiv itself. Another source of new CD4 cells is the proliferation of existing CD4 cells in the lymph nodes. These cells eventually migrate out to the blood. This is where the immune boosting quality of interleukin-2 (IL2) has its effect.

Any immune booster has to target one of the two sources of CD4 production. At the same time, we need to keep in mind that a healthy immune system is very delicately balanced. Any intervention to stimulate this system must proceed with great caution.

Opportunistic Infections

Dr. David Hardy of Pacific Oaks Medical Group discussed advances in preventing opportunistic infections (OIs). Two recent advances, triple combination therapy and viral load tests, have had an impact on preventing opportunistic infections from developing. OIs result if hiv disease progresses; triple combination therapy is helping to significantly slow, if not stop, that progression. Monitoring of hiv disease allows us to know when to begin prophylaxis against OIs; viral load tests allow for more accurate monitoring.

The U.S. incidence of PCP among people with aids has dropped from a high of about 60% in the early years of the epidemic to a low of about 30% today. With people living longer with hiv, we do see a rise in incidence of CMV. Now a CMV viral load test is being developed. This test will help predict those at risk for CMV and will identify those for whom oral ganciclovir may be an effective prophylaxis. Finally, both clarithromycin and azithromycin are proving to be effective prophylaxis against MAC; tests show almost 70% effectiveness for these drugs (vs the 50% effectiveness rate of rifobutin). What we need in the future is one pill to prevent all opportunistic infections.

KS and Other Malignancies

Dr. Alexandra Levine, USC's eminent aids and cancer researcher, brought both bad and good news about the future of aids-related malignancies. The bad news is that we may be facing a proliferation of aids-related cancers. As Dr. Gottlieb mentioned, long term subnormal CD4 cells may be dangerous; such a situation may open up the risk of new and different cancers attacking people with hiv. Dr. Levine mentioned oral and anal cancers, Hodgkin's disease, melanoma, and testicular cancer as future threats to PWAs.

On the other hand, there is some good news. Researchers' experience with KS has taught the medical profession a good deal; we have learned more about what causes cancer. And with this knowledge come better ways to treat and possibly prevent the disease.

First, we now know that there has to be a genetic disposition to cancer. Certain people are at risk for certain types of cancer. Second, there are hormonal factors to be considered, as well as lifestyle factors. In the case of KS, we have now identified a virus (KSHV or KS herpes virus) that is a necessary cofactor for the disease.

Overall, to prevent the growth of aids-related cancers, we need long-term, effective antiviral therapy and we need to do a better job of rebuilding damaged immune systems. Meanwhile, we continue our research into the causes and, one hopes, the prevention of aids-related malignancies.

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