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New Ways To Keep the Virus In Check

Spring 1996

Product: Company: The Protease Inhibitors:
Saquinavir (Invirase) Hoffmann-la Roche Approved by the FDA last December for use in combination with standard AIDS drugs.
Indinavir (Crixivan) Merck Reported to have caused an unprecedented thousand-fold drop in level of virus found in the blood.
Ritonavir (Norvir) Abbot Scientists reported survival benefit in 500 people with advanced AIDS. Recently FDA approved.

The new generation of antiviral drugs (d4T-Zerit, 3Tc-Epivir) and the newly approved protease inhibitors look promising, indeed. With the promise of widespread availability of the PCR tests for measuring viral load, HIV-infected people may benefit greatly from new insights about the nature of the disease. (The quantitative PCR or "Q-PCR" test can measure actual viral particles, informing people as to how much virus is present. This test may prove to be significant in helping PWAs decide when to take medication or when to switch. T-cell counts are a surrogate marker and indicate the damage that HIV has caused. The P24 antigen test may give you some idea of how active the virus is.)

We now have a far better understanding of how quickly the virus replicates, where it is reproduced, & how it responds to treatment. This implies new strategies for slowing down the virus and delaying the onset of AIDS. AIDS research is on the brink of finding new approaches in the way we use drugs and the timing of therapies. Timing may be at least as important as the drugs and therapies themselves.

This may allow us to reach new levels of effectiveness in fighting HIV infection. These approaches focus on new strategies and processes rather than new products or drugs. Therefore, the pharmaceutical companies may not show much interest in sponsoring treatments since they are most interested in marketing new drugs.

The Basic Concept

Timely Use Of Combinations

The almost universal practice of medicine today is based on producing and prescribing new drugs or products. Doctors and patients alike tend to think in product terms: use or don't use AZT, switch from AZT to ddI, etc.. Once a person begins taking a drug, current practice keeps the person on it until there is clinical evidence of failure or intolerance. (clinical failure may be indicated by the onset of an OI; intolerance may include persistent headaches or neuropathy). If people stay on a drug long enough, it is certain that their virus will become resistant to it. The drug will not be effective because the virus will become used to it and mutate.

One way to delay or avoid the problems of resistance and toxicity is to assume from the beginning that it will be necessary to change therapy on a routine basis.

A new generation of "strategy" trials will soon begin testing various ways to do this. In this approach, study volunteers or individuals acting with their doctors will begin therapy using an agreed upon first step. Most likely this will be a well-understood combination such as AZT + 3Tc. If a drug or combination doesn't result in a significant reduction in HIV levels (measured with the PCR viral load test) within a month, it probably never will. Physicians and people with HIV/AIDS can reach a decision point within 30 days to either continue therapy or switch to something else. Viral load (Q-PCR) and CD4+ cell (T-cell) testing will give guidance about what to do next.

Timing Therapies

Change To A Different Drug or Combination On A Timed Basis

Every six months may be a good time to switch based on data from studies which show how quickly resistance develops. On average, drug resistance occurs within 6 months. One limitation of this approach is that the "average" time to resistance may not apply to every individual situation. Some people using this approach might stay on a therapy longer than they should, while others may switch too quickly, shortening the duration of benefit from the drug. However, even with these risks, this approach seems likely to work better than simply waiting for people to fail on any given drug.

Swith Based On Viral Load

When Viral Load Increases

This approach relies upon viral load testing to give the "signal to switch" therapies. Many scientists favor this method. The viral load test is the most direct measure of viral quantity which indicates viral activity. It's a direct measure of the drug's effect on HIV.

One possible weakness of this approach has to do with protease inhibitor drugs. Recent studies show that these drugs appear to provide sustained improvements in T-cells even after PCR testing shows that viral load is beginning to increase. It is not clear whether this says something about the limitations of PCR testing, or whether virus produced after using a protease inhibitor is somehow weakened and less likely to cause damage to the immune system. Whatever the answer, this method offers the most precise way to determine the value of a therapy used for suppressing virus levels. Additional studies will help answer the question.

Switch When T-Cells Fall

But Before Clinical Changes Occur

While T-cell tests are only one measure of the health of the immune system, they correlate well with clinical symptoms and the risk of opportunistic infections. The main risk of using this approach, however, is that it may not give the "signal-to-switch" until after the damage is done and a significant loss of T-cells has occurred.

It is not clear which "switching" strategy will produce the best clinical and survival benefits. Any of them are likely to be superior to staying on a drug or combination until clinical signs of failure become evident. Any of them will reduce the risk of developing long-term cumulative side effects from the individual drug or combinations. A likely fourth strategy will simply be to take all 3 points into consideration and make a reasonable judgment about when to switch therapies.

Using any of these strategies will require careful monitoring and access to a wide array of drugs as well as access to viral load testing.

There are now five approved antivirals (AZT, ddI, ddC, d4T, 3Tc). There is one available drug targeted at cellular activity, hydroxyurea, (ask your doctor about this therapy.), and two protease inhibitors, saquinavir, (now called "Invirase") and ritonavir. Several drugs are waiting approval, including nevi-rapine, delavirdine, and other protease inhibitors (Indinavir, also known as "Crixivan," is the latest hopeful).

Practical Considerations

Unfortunately, physicians and their patients are largely on their own when trying to figure out how best to use such strategies. The goal of clinical trials studying these approaches will be to determine standards of care, not to meet FDA licensing requirements. Therefore, a person could join such a clinical trial without fear of using an "experimental drug".

The responsibility for this type of testing falls to the federal government's AIDS research establishment. But at the moment, the National Institute of Health is reducing the amount of funding devoted to AIDS clinical trials. At a time when there is a rapidly growing critical need for trials, there is less money being allocated to fund them.


No matter how good antiviral drugs become, it is unrealistic to hope that it will be possible to use them for a person's entire normal life span. Even the best therapies may still encounter problems with long-term toxicity, tolerance, and resistance. Yet, it might at least be possible to greatly reduce the total body burden of HIV in hopes of adding many years to life expectancy. The key might be to determine the best time and way to use the available drugs to make the greatest possible impact.

TAG (Treatment Action Group) reports that at least one study showed that staying on AZT or switching to d4T made no difference in survival time. Much more needs to be learned about switching therapies. Clearly more clinical trials need to be done.

For more on treatment approaches call Woman Alive 800-554-4876. For the original article, call Project Inform 800-822-7422. TAG newsletter, 200 E. 10th St. #6601, NY, NY 10003.

This Article summarized from PI Perspective, Dec. '95.
Original article Title: "New Concepts for Combating HIV Infection"

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This article was provided by Women Alive. It is a part of the publication Women Alive Newsletter.
See Also
Archived Material on Treatment Strategies