AIDS TREATMENT NEWS Issue #210, November 4, 1994
John S. James

Many researchers agree with this kind of strategy. But the mainstream is not yet ready to move. Instead, it wants to first do other trials to prove beyond a doubt that HIV RNA testing is useful for testing drugs. These trials will take years -- if they can be conducted at all.

Yet it is already clear that HIV RNA is a much better measure of the virus in the bloodstream than any other test we have. It is also becoming clear that this viral load in the blood reflects viral reproduction in the lymph nodes and elsewhere. Reducing the level of virus in the blood does NOT mean that it has been removed from the lymph nodes or other tissues; but usually it does mean that the virus throughout the body has become, at least temporarily, less active.

We need to learn how to use combinations of drugs and other treatments to keep HIV inactive indefinitely. It will probably be hard to do this. But we now have tests that open doors to creativity by researchers, physicians, and patients, because they can tell rapidly and reliably whether a treatment is working for a patient to reduce the virus -- and how long it is working. When it stops working, new approaches can be tried. As experience develops and knowledge is exchanged -- in research settings, and also in physicians' offices -- we will learn what strategies are most likely to work, and how to deliver better care to patients in all stages of HIV disease.

Examples: Approved Antiretrovirals

What drugs should be tested in this way? One good place to start is with the drugs already approved by the FDA as antiretrovirals -- AZT, d4T, ddI, ddC -- and combinations of those drugs. First, establish a baseline value of HIV RNA for an individual patient, while the patient is on a stable treatment regimen. If that value is low, and the patient is otherwise doing well, the decision might be to leave well enough alone -- but to watch the test in the future. If the value is high, then switch to (or add) other regimens which make sense for that patient; within about two weeks the test will show whether the new regimen is working to reduce the virus. If it is not, other options can be tried.

What is "low" and what is "high"? This is still being learned, but a rule of thumb is that anything under 10,000 copies of RNA per milliliter of plasma is fairly low, and anything over 100,000 copies is fairly high. [Note that some testing companies report the number of copies for other than one milliliter of plasma; in this case the number on the lab report needs to be multiplied by 20, or by some other factor, to get the number per milliliter.] Some researchers believe that it may be good enough to keep the HIV RNA under some threshold amount, probably somewhere between 10,000 and 100,000; others suspect that it may be important to keep the value as low as possible. At this time no one knows for sure.

Example: Acyclovir

Besides the four approved antiretrovirals, many other treatments can be tested this way. For example, two major trials and one epidemiological study have unexpectedly suggested that acyclovir may substantially improve survival of persons with advanced HIV disease. But none of these studies was planned in advance to test that possibility, and none has given definitive answers, so this issue remains controversial. There are at least four unpublished studies with additional information; but it is clear that at least three of the four, and perhaps all of them, will not give definitive answers either.

Acyclovir does NOT inhibit HIV directly; but it might help indirectly by inhibiting certain herpes viruses, which are believed to make HIV more active. If so, this indirect benefit might be indicated by a decrease in HIV RNA. If such a decrease is seen -- and a small, rapid trial would be enough to find out -- then physicians might be more confident about using acyclovir for improving survival of people with AIDS, and targeting the treatment to those most likely to benefit.

Small trials measuring viral load could help to answer questions which are unlikely to be answered in any other way. (1) Is AZT necessary to get this possible benefit from the acyclovir? No one knows, since the previous trials which suggested this benefit all used AZT in addition. (2) If acyclovir is found to (indirectly) lower HIV in late-stage disease, would it also help in earlier stage HIV infection? None of the previous studies have shown such a benefit. But they would probably not have found it even if it was there, because people with early infection either were not included in the studies, or would not have had time to get sick during the period that the studies were run. (3) Which patients benefit? Only those who have been infected with herpes (which includes much of the general U.S. population, including a large majority of gay men)? Only (or mainly) those who have active herpes outbreaks? Or could those who have never been infected also benefit, perhaps because the acyclovir suppressed unknown viruses which might activate HIV?

Definitive answers to these questions would require trials with hundreds of people, lasting for years. Obviously such trials will never be run. But it would be easy to find out if the amount of virus in the blood goes down after the treatment is started. And this information -- which would strongly suggest that the treatment is beneficial, although it would not prove that -- would be useful for physicians and patients making treatment decisions.

Example: "Alternative" Treatments

Dozens of herbs, nutritional supplements, and other treatments without commercial or government sponsors have come into substantial use by persons with HIV. Some -- for example, certain herbs used in traditional medicine as anti- infectives -- have shown anti-HIV activity in laboratory tests. But conventional drug development, which costs an average of over $100,000,000 per new drug approved, will never be done for them.

It is quite possible that some "alternative" treatments do in fact reduce viral load in people. They could then be tested in combination trials with approved antivirals, protease inhibitors, or other treatments, to help design better antiviral regimens. But others, which are being taken in the hope of an antiviral effect, will be found to have none. Persons who are using those treatments clearly need to know this information.

Recently a small underground trial tested the combination of Ro 24-7429 (the abandoned Hoffmann-La Roche tat inhibitor) plus pentoxifylline, a prescription drug, using blood tests to detect changes in viral load. Laboratory experiments had suggested that the two drugs might work very well together. But in people, the combination was found to be completely ineffective as an antiviral. Viral load went up, sometimes greatly, in four of the five patients; in the fifth, the viral load was down at four weeks, but the decrease was so small that it was well within the error of the test. This result has not previously been published; AIDS TREATMENT NEWS is seeking more information and preparing a more complete report.

There is no evidence of any benefit from Ro 24-7429; this small trial answered the one remaining question, of whether the combination with pentoxifylline would have antiviral activity. If modern viral testing had been available when Ro 24-7429 was first tried in people, several years of wasted effort could have been avoided.

The Obstacles Today

Testing for HIV RNA is now being incorporated in most new trials of antiretrovirals -- not to prove that the drugs work, but to help in understanding their action. We agree this is appropriate. What, then, is the issue?

The central issue is not about technology, but about professional, commercial, and political will. The small, exploratory trials of available drugs are not being done today for the same reasons they have not been done in the past. These reasons include lack of commercial incentive, excessive influence of industry over professional and governmental agendas, and pervasive neglect of treatment and research by the leadership of AIDS organizations. This is why the trials we need are not being done -- despite the new technology which would make them faster, cheaper, and more reliable then ever before.

Perhaps the basic problem in AIDS research is that the interest we share in saving lives does not translate into the institutional arrangements necessary for doing so.

941104
ATN21003

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 1994. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .