RECAP OF 1996's XI INTERNATIONAL VANCOUVER CONFERENCE ON AIDS

by Dr. Patricia Salvato

as written in the 9/96 issue of "Positively"

The following article consists of excerpts from a speech presented by Dr. Patricia Salvato as a review of her participation at the International Conference on AIDS in Vancouver. Dr. Salvato has graciously permitted us to use this material. As one of the preeminent HIV medical practitioners in Houston, we are grateful for her perspectives on the conference.

The Wall Street journal reflected the mood of the conference best stating, "The mood of the previous conference (in Berlin) reflected depression, the mood at this conference was one of mania."

This was one of the largest conferences ever attended for HIV with 15,000 participants; 125 countries were represented and 5,380 abstracts presented.

The largest number of participants were from the developing countries, and the theme of the conference, 'One World, One Hope' was not exactly representative as 90% of patients with HIV are in developing countries, where they don't have access to many of the newer therapies that we have here. The Global AIDS Policy Commission projected that by the end of the year 2000 there will be between 60 and 70 million adults who have been infected with HIV.

In the United States, the annual rate of new infections is still on the upswing. This was a little bit surprising. In fact, heterosexual transmission accounts for the highest yearly infection rate, 15-20%. In San Francisco, where the predominant infect is still among homosexuals, the number peaked at 8000 annually in the 1980s -- 1000 are infected every year. The epidemic in the United States is not decreasing; it is as if we were in the words of one presenter, "running in place." So the sobering news was that even with widespread education we are still seeing an increase in the number of infections, not only worldwide but in the United States.

Three-quarters of infected US. residents are still undiagnosed, so the epidemic will run for a long time, even if we could stop all future infections today. In spite of this, there is a great deal of optimism regarding the containment of the disease. Anti-retrovirals were the focus of the conference. Comparatively, there were few abstracts presented on opportunistic infections; however, there were many more abstracts on drug combination "cocktails." There were an increased number of abstracts concerned with social issues, particularly in developing countries, and regarding women.

New Approaches Bring Optimism

The once merely 'observational' approach to HIV has turned, in the last eleven to twelve years, into a very proactive course of preventing infections and of early antiviral therapy. Under ideal conditions, if treatment is started early using certain drug combinations (especially in patients who have never been treated, or get on a new combination of drugs), HIV replication in many patients can be reduced to levels which are completely undetectable by any known test for prolonged periods. We were never able to say that at any previous update, so there are a lot of factors that merit closer scrutiny.

Now, if viral replication can be completely suppressed for extended periods, is it possible that the virus remaining in the body would eventually die? Does this mean that HIV could be eliminated, drug therapy stopped, and the patient cured? This is the central question. It is significant in that researchers at the conference are now daring to think that we can use the "cure" word. We must be very careful -- it would be a big mistake to think we are at the point where we can cure HIV, but never before could we even attempt to use that word. There is a lot of hope precipitated by the events of the last eight months, and what happens over the next 18 months will be crucial.

David Ho of the Aaron Diamond Research Center in New York suggests that a 1.5 to 3 year course of combination therapy may completely eliminate infected macrophages and CD4 cells. (Macrophages are 'scavenger' cells that specialize in the ingestion and processing of large particulate matter, especially harmful bacteria. They are thought to be a reservoir for HIV.)

This research applies to patients treated very early, within 90 days of infection. The "cure" word (if we can use it at all) applies to people with a very early diagnosis and then eliminating the virus as quickly as possible. Early intervention can lower viral load. Of twenty patients now enrolled in this study, those patients treated with AZT, 3TC and a protease inhibitor have produced undetectable viral levels as measured by both the RNA and plasma culture. After nine months of continued aviremia (where no virus is detected), these patients will receive a biopsy to see if viruses exist in the lymph nodes. If none is present we may be at the starting point to eradicate HIV infection in man for the first time. So that is very dramatic news, but this data is specific to patients infected within 90 days. People need to be assessed in terms of risk factors, identified early and started on antiviral therapy. When these factors are met there is a chance that those patients may be rid of the virus forever. This is in direct contrast to the discussion regarding antiviral therapy for patients infected with HIV for a long time. There is even evidence that the protease inhibitors can do wonders in patients with extremely low T-cell counts and high viral loads. [Remember, viral load measures the activity of the virus, T-cells measure the activity of the immune system.] Currently we can see a patient go from 20 T-cells to 200, or from 150 to 300. We have never seen this before, so change is definitely occurring.

The elements of a cure are within our frame of reference, or at least in sight. I am so happy to be able to say that -- at every update I always have to say that I don't think we can say the 'cure' word, we can only say 'prolonging survival.' On a cautionary note, it would be terribly premature to send the message that HIV is under control. If anything, now is the time we need to work the hardest on antiviral therapies and immune boosters.

New Opportunities, New Challenges

Even though we may be on the brink of effectively dealing with HIV, there is a vast difference between clearing the first person of the disease and turning it into a practice strategy that will apply to hundreds of thousands of people. Even with these tremendous advances, it will be a long time before we can effectively cure patients. Challenges remain, and the one you will probably hear the most about is resistance. It is our foremost consideration, especially with older drug therapies (now commonly used) and an issue with the new protease inhibitors as well. However, these new agents offer real hope for the first time that viral replication may be suppressed so quickly and so completely that the virus cannot mutate. (It is important to remember that mutation occurs only when the virus is replicating.) This may solve the problem of increased mutations that occur as patients have HIV longer. Catching infection early can control replication as well as mutation. HIV infection is now being viewed as a manageable chronic disease rather than a terminal one.

AIDS and Disease Progression

AIDS is one of the most complex medical problems that we have ever faced, and there is much about the disease that is not fully known. There have been great strides in viral dynamics within the last 18 months, much of that work has been done by Dr. Ho. In the past there have been differing opinions regarding treatments; now that we have ways to measure viral loads with increased accuracy, methods are becoming slightly more standardized (and we can monitor results more effectively).

At the time of infection the virus begins reproducing almost immediately, and it creates billions of copies of itself (called 'replication') in a few weeks. Each of those copies is capable of reproducing 140 generations in a year beginning from the minute of infection. Taking this into consideration, the damage done to immune systems over the last 15 years to those with HIV has been substantial.

Recently published results of a follow-up study demonstrated that clearance and reduction of the virus, as well as production of the virus, is actually much greater than previously reported. At that time we reported that there may be a billion viruses produced per day, now we know it is approximately ten billion, with a half life of just six hours. The immune depletion of AIDS results from the rapid loss of the actively virus-producing T-cells, half of which are replaced every 36 hours. Fifty percent of the HIV virus present in the blood is cleared and replenished in the body every six hours. This new knowledge indicates great progress in the field of viral dynamics that has enabled us to treat patients more effectively. Not only is treatment progressing, but our knowledge of viral replication is increasing substantially.

An asymptomatic patient (somebody who has no symptoms at all) can carry a multitude of genetically distinct variants of HIV and not appear ill. At the same time, patients who have full-blown AIDS carry even more variants, which are already inherently drug resistant. As a result, patients can pass drug-resistant virus to a partner. Cases have been reported of patients who have never even been on any drug therapy having strains of HIV that are already resistant to the new classes of protease inhibitors. These patients have acquired drug resistant strains from others. These strains are a source of real worry to the medical community, especially when they appear in patients who have never even had drug therapy of any kind! Given the exponential number of mutations that can occur, statistically, the medical implications are severe.

Viral Load and Disease Progression

According to work presented by Dr. Miller, viral load varies considerably among individual patients. There is evidence that individuals who experience rapid disease progression have high viral loads soon after they are infected. This gives us a way to determine treatment when a person is initially infected (or diagnosed) and what their disease course would be over the next ten years. This would, in turn, determine how aggressive we need to be.

In adults we know the average time of disease progression is about ten years. However not every patient follows this course. We have all seen patients who progress very rapidly to AIDS, in about five years after infection. At the other extreme, we know that some patients, even untreated, never develop full blown AIDS. These infected individuals may remain free of AIDS for twenty years without treatment.

We know that people, when initially infected, experience a drop in their T-cells very early, and then levels will return and in general stabilize over time. We previously believed that there was an initial burst of viral activity followed by a long latent period. We now know (by the HIV RNA viral load test) that the 'latent' period is really one of ongoing very active viral inflammation and replication, not a latent period at all. This is the time that the macrophages, the T-cells, and the lymph nodes are all getting infected with HIV. So we now know there is a long asymptomatic period, but not a long latency period where the viral load is low.

If HIV infection is a war between the virus and the immune system, then T-cells estimate the number of casualties and the viral load estimates the strength of the enemy. However, we shouldn't use only T-cell count as a prognostic indicator: a patient with 7 T-cells might be with us seven years, and a patient with 200 T-cells might die next week. We never could explain that phenomenon previously, but that is becoming clearer to us as our knowledge increases. The HIV/RNA viral load test could be an early predictor of rapid progression to AIDS, and indeed it is, although there is no known key threshold that predicts rapid progression. In the very broadest terms, a viral load of 100,000 can predict increased time to disease progression while levels below 10,000 are associated with a more favorable course. The whole theme of the conference was to get the viral load as low as we can, to undetectable levels, and keep it there as long as possible. So we are aiming for levels below 10,000 at the very least, if undetectability is not possible.

TREATMENT INDICATIONS AND OPTIONS

If a patient is symptomatic, no matter what their T-cells or viral loads are, combination therapy should be started. If a patient has thrush, night sweats, or weight loss, I don't care if their T-cells are at 700, therapy should be started. If they are asymptomatic and they have T-cells less than 500, therapy is usually recommended for these patients as well. If they are asymptomatic with their T4 count greater than 500, then we look at their viral load. If the viral load level is greater than 30,000 or if they have a rapidly declining CD-4 (T-cell) count, we should start therapy. This should be considered, even with high T-cells, if the viral load level is greater than 5,000 to 10,000. This is the most aggressive approach. High viral loads irrespective of T-cell count should trigger initial antiviral therapy

Viral Loads and Logs - A Brief Explanation

Viral load measurements are written as 'logs' which are a kind of shorthand for expressing very large numbers. These measurements can express a positive or negative change; for our purposes we will assume we are expressing them in terms of decrease in viral loads, the primary focus of this discussion. A 'log' indicates a 90% reduction in some measurement, in this case, viral load, i.e., concentration of virus in the blood. In real terms one 'log' equates to a reduction of viral load from 100,000 to 10,000 (90%). A two log reduction would be a viral load reduction from 100,000 to 1,000 (99%). Three 'logs' indicates a reduction from 100,000 to 100 (99.9%). Sometimes these numbers are confusing but it is important to know and understand their meaning.

How log reductions relate to disease progression is simple: A one log reduction in viral load results in an 80% reduction in the risk of disease progression.

This reinforces the use of combination drug 'cocktails' to reduce viral load. If the viral load returns to baseline (where it was at the onset of drug therapy) it indicates drug failure, and mandates a change.

Conference Recommendations for Drug Therapy

Recommended again by an international conference panel of experts, any patient with fewer than 350 T-cells regardless of viral load should be on two nucleoside drugs (AZT, ddI, ddC, or d4t) plus a protease inhibitor (Invirase [saquinavir], Crixivan (indinavir) [indinavir], Norvir [ritonavir], or Virasept [nelfinavir]). If we had the same T-cell count but a less than 5,000 or 10,000 viral load, we could get away at that time with ddI or d4T monotherapy, or new nucleoside analogues.

The data strongly suggest that antiviral treatment should consist of the most effective viral inhibitors, given at the highest tolerable doses, to achieve the most complete viral suppression possible. This is where we are talking about 'trying to cure the patient.' A few comments with regard to general treatment for anybody with HIV -- who is initially instituting treatment.

The Delta trial and the ACTG (AIDS Clinical Trial Group) 175 trial, shows for the first time a survival benefit of starting combination antivirals, and that monotherapy with AZT is basically unacceptable, especially if other drugs are available. In fact in light of all the new information, there is not much reason for a person to be on any single drug by itself at this point. The recommendations are strong for at least two therapies. The only exception might be in patients with fairly low viral loads and 300-500 T-cells where therapy with ddI and d4T might be acceptable but never AZT alone. AZT and 3TC have looked very good in clinical trials, and the benefit has been shown at this conference to persist over 76 weeks of therapy without increasing that load.

Specific Protease Inhibitors and Their Characteristics

One of the major concerns is, "Are the protease inhibitors best used for very early treatment, or should the most aggressive regiment be "saved" for when the HIV disease progresses?" We already know the recommendations for a patient with recent infection. There are new striking results just reported for Norvir (ritonavir) in end stage AIDS, and this supports the belief that it is never too late to try aggressive therapy. So -- early in disease, when you are first infected, and late in disease -- there are definite indications to use protease inhibitors at both of these times. Some of the drugs approved so far are Invirase (saquinavir), Norvir (ritonavir) and Crixivan (indinavir), and very soon Virisept. In spite of possible cross resistance, there are lots of drugs in development.

Some of the highlights of the protease inhibitors: Invirase (saquinavir) has the lowest bioavailability (bioavailability determines what amount of any given drug is absorbed and circulated in the body) around 4%, but it is the best tolerated. The dosages required also mean that people will be taking a lot of capsules, an inconvenience at the very least. We will talk about ongoing combination studies that may raise those levels. Both Nizoral and grapefruit juice raise Invirase (saquinavir) levels. So it would make sense that a patient who is on Invirase (saquinavir) might have grapefruit juice or Nizoral instead of Diflucan for instance, and that would give them more of the drug and still be very well tolerated. When administered with AZT, Invirase (saquinavir) results in an approximate one log (90%) decrease in HIV RNA levels resulting in an 80% decrease in progression to HIV. So, even with a poorly bioavailable drug there is still a striking response, and they are making new ways to get Invirase (saquinavir) more bioavailable through a new formulation of the drug. There have also been good results with Invirase (saquinavir) used in combination with ritonavir.

Norvir (ritonavir) is the most poorly tolerated of the protease inhibitors. Gastrointestinal side effects and tingling are very common, especially around the mouth; although, I have had patients who have had total body tingling on it, especially during the first two weeks of therapy. Because of this it is recommended that we get that dose up gradually, unlike other protease inhibitors. This is a very powerful drug, but there is lots of intolerance to it. If you can kind of withstand it for a few weeks you might get through it.

AZT, 3TC, and Crixivan (indinavir) is the most potent combination reported at the conference. Fifty-nine percent of the patients in the triple drug combination had undetectable viral loads (below 500). A reduction to two logs (99.9%) seen at eight weeks and 2.3 logs at twenty-four weeks. Ninety-one percent of the patients remain below the level of detection at this point in the study. One caveat that patients should be aware of: If you are using Crixivan (indinavir), the maximum point of RNA reduction is seen at eight to twelve weeks, rather than two to three weeks, as seen in most of the other combination studies. You've got to give Crixivan (indinavir) a little more time to take effect some patients may take even longer than twelve weeks and therefore, we need to be careful about making drug therapy decisions too quickly. Patients taking Crixivan (indinavir) should drink large amounts of fluid to prevent kidney stones which are a possible complication; it should be given at least two hours after or one hour before eating, but you can take a light snack (skim milk and cereal) for patients who cannot tolerate it on an empty stomach.

Norvir (ritonavir), on the other hand is best taken with fatty foods: peanut butter, chocolate milk, or steak increases absorption. The combination of ritonavir and saquinavir, the first reported study of a drug combination with two protease inhibitors, reduced levels of the HIV virus in 60 patients by an significant amount, 99.6%. The six week data on this combination study that was released at the Vancouver conference showed that it reduced viral load by over two logs, and boosted T-cell counts by as much as 98. This is one first studies of protease inhibitors showing effective combination action, but this is only the first double protease regimen studied. The test tube studies showed that ritonavir also increases the level of Crixivan (indinavir). There are several cautions in the use of protease inhibitors -- very importantly, underdosing is likely to lead to rapid resistance, so if the patient can't take the full dose they should not take the drug at all. Patients are encouraged to take the protease inhibitors regularly. An almost religious approach to proper dosing is necessary to maintain the effectiveness of these drugs. No drug holidays. Stopping a protease inhibitor will enable the virus to replicate (and consequently, mutate) 'like crazy.'

New Basic Rules for Treatment

Never use, monotherapy. Don't add a protease inhibitor to a failing regimen. Always add at least two new agents at a time to prevent resistance. Those are the new recommendations. Now in patients initial viral loads that we talked about in the greater than 30,000 range, really we don't start everybody the first time on a protease inhibitor. We start with AZT and ddI or AZT and ddC if patients cannot tolerate ddI. Then we switch to AZT and 3TC when we add a protease inhibitor. This treatment is based on resistance patterns that are now well identified. It is not entirely unreasonable to use a protease inhibitor early, especially if viral load is very high. If viral load is not very high we could start with still our traditional nucleosides. If a patient becomes intolerant or resistant we could switch to AZT with 3TC and then add a protease inhibitor. In doing this we have already, even before the conference, seen dramatic decreases in viral loads, decreases as dramatic as 700,000 to less than 500. You sometimes feel compelled to send the work back to the lab because you think it is an error, but when it happens over and over drug therapy is obviously working.

Resistance Patterns

Now, the main problem we are going to be dealing with for the year to come andyears to come is resistance and cross resistance. (Strictly defined as 'the ability of some disease producing organism to grow and multiply even in the presence of drugs that would normally kill them'). This it does by changing its genetic material. Now, cross resistance is a new word to many people here. That occurs when resistance to one drug confers similar resistance to another drug, usually in the same family, even if the person had never used that second drug before. That is what we are seeing a great deal of right now with protease inhibitors.

Now, treatment with a drug does not induce resistance. That is a fallacy. It does however, select for resistant mutations of the virus that preexist in the variants already. These resistant viruses are already present as the result of generations of mutation. (Especially in light of the replicating ability of HIV). What that drug does is it selects specifically for those viruses it doesn't kill. Those variants then become more profound, or essentially 'stronger.' This is what resistance really means.

Using 3TC as a specific example, one single genetic mutation that leads to a change in amino acid of the reverse transcriptase enzyme (one of the enzymes that plays a crucial role in the life cycle of HIV) can produce a new version of HIV that is a thousand times less susceptible to 3TC. Resistance appears to be common and develops more rapidly with advanced disease and low CD4 counts and high viral loads. This is more likely to happen when the HIV RNA levels are high, and when the CD4 counts are low. As previously discussed, other factors also contribute to increased resistance: suboptimal drug dosing, and patients noncompliance in taking medications at the prescribed levels and times. Physicians and the patients share equal responsibility in these combination therapies. Doctors must prescribe correctly and patients must take them as directed for drug therapy to be effective.

The responsibility of determining a patient's resistance to drugs rests with the physician. This is one of the most complicated problems associated with care of the HIV positive patient. We need to be able to put patients on drugs they are least likely to be resistant to. Only Invirase (saquinavir), Crixivan (indinavir), and 3TC have been reported thus far to delay AZT resistance. It makes sense that you would like to use one of those drugs on anybody who is on AZT.

Invirase (saquinavir) is not resistant to Crixivan (indinavir) or Norvir (ritonavir). So, Invirase (saquinavir) could be used first until it is no longer effective, followed by a switch to either of the other two drugs. Invirase (saquinavir) resistant virus generally remains sensitive to Crixivan (indinavir) and Norvir (ritonavir), but the reverse is not necessarily true.

As you can see, the order in which we use drugs is crucial as the result of specific resistance patterns. Obviously it would not be wise to use Crixivan (indinavir) and Norvir (ritonavir) sequentially as they are cross resistant to each other - they may also be cross resistant to some of the drugs now in development, but there is no proof of that at this point.

There was some interesting late breaking news just prior to the start of the conference regarding the new protease inhibitor, Nelfinavir. The research reports thus far have reported no known cross resistance so far.

Potentially there is a choice of 153 approved dual drug combinations to treat HIV and AIDS. If you take the drugs and look at them- all approved at this point, you will find out that that's true. So, it's a very select, specific way that we have to treat patients.

Long Range Planning and Management of HIV

Even with advances in current therapy it is unrealistic to expect indefinite maintenance of decreases in viral load. They could stay down for six months, or a year, we don't know. However, following the initial decline (in studies of combination therapy) there is a second, slower decline in the viral load that may represent the long-lived populations of cells. These are macrophages or the lymphocytes, where virus tends to be 'stored' rather than the 'free' (that virus that has escaped from the T-cells). We have recognized that the target of antiviral drugs and vaccines is not the virus itself, but rather the relationship that the virus establishes with the host; that is the crucial issue.

When we reduce viral load to 'undetectable' levels, that means the 'free' virus. That doesn't say anything about the infected T-cells still in the blood, lymph nodes or macrophages, where estimates say there are 250 billion infected cells. Killing the virus at these sites will help us toward a cure. When the AIDS virus attacks the T-cell it turns it into an AIDS producing 'factory' that dies later, but while it's living it continues to be a reservoir that produces viruses. None of the antiretrovirals have shown any effect on those infected cells, a very important concept.

Chemokines

There was also exciting news on research that is currently being done regarding some cell secretions known as chemokines. Chemokines are small soluble molecules secreted by immune cells that are responsible for attracting other immune cells to sites of inflammation. There has been some new information at the conference regarding these secretions that can inhibit HIV replication. These proteins, known as beta chemokines, were found to be potent suppressants in blocking HIV from entering into cells. And this coincides with the discovery of a specific receptor area on the immune cells known as 'fusion' where the virus actually binds to the T-cell. It's the cofactor for HIV entry into cells and it's related to these beta chemokines. This should be a new focus for possible therapies used that tend to help this HIV inhibitor.

Vaccination Research

Remune is the first vaccine currently in development for patients who are infected to be used in widespread clinical trials in the United States. Previously called the Salk vaccine, it consists of the HIV virus stripped of certain proteins (GTM- 1 20). The stripping of this protein 'inactivates' the virus . This is then mixed with an 'adjuvant' (a substance that enhances the immune stimulating properties of substances that might help kill viruses). By including most of the HIV proteins, unlike some of the other vaccines in trial, Remune may be able to help the body learn to respond more broadly to HIV Remune is basically, the entire HIV virus minus the GTM- 120 protein, which is radiated, chemically killed, mixed with an adjuvant, and then injected into the body. This drug has been in trial since 1987 in more than 300 patients, and has found to be a very safe additional therapy for patients.

Now, it is different from AZT, ddI, and ddC, which work at inhibiting replication of the virus. The Salk vaccine, or Remune, was designed to work in a different manner. It stimulates the immune system so that the individual's own defenses can attack the virus and the virally infected cells. Rather than attack the virus, it boosts the immune system.

Additional New Therapies and Other Approaches

I had the privilege of going to the FDA to present some of our data from a study we did on a drug that has been around for years: Ampligen. This drug has been studied in over 300 patients; so far it has shown promising results with CD4 count stabilization. The FDA is interested in trying to give accelerated approval to this drug. If approved we may have another therapy to help kill the virus and infected cells.

There was a study presented at the conference a survey of the plant and herbal material because Cornell - a well respected university - did a study they reviewed all the studies that have been published over the last 18 months of plants and herbs screened; 70 compounds, and 76 crude extracts from 123 species from common food and drink, from tropical rain forest specimens, and reportedly exhibited HIV inhibitory activity. Seventy-six compounds in 76 crude extracts demonstrated HIV activity in the literature.

Only a handful of such active extracts and compounds have been formally assessed in clinical studies, so that merits caution when adding holistic therapy. We really ought to look at the data in terms of the controlled studies. Most of the studies presented were observational and controlled. SPV30, a drug that I recommend, has had mixed results. A French study showed minimum effectiveness while another showed that nearly half the participants reported 50% less fatigue, and 44% decrease in night sweats and thrush. So, it's still a nice supplement to be added. Plants and herbs are also excellent prospects in the search for potential treatment of HIV. And, I think this is important, especially in the developing countries where this may be the only type of antivirals they can have access to -- they cannot afford the protease inhibitors.

News from the conference regarding micronutrients: subjects with low B12 levels had an approximate two-fold increase in their risk of AIDS. This would indicate that B12 shots are not just a placebo, and I recommend them. Subjects with increased serum vitamin E levels had greater than a 30% decrease in progression to AIDS. B12 and vitamin E certainly seem to play an important part in the management of HIV

Some Concluding Comments

All of the previous comments highlight a continuing recurring theme: Most HIV training is the result of experience. HIV is peculiar in that no single treatment provides a cure. We have a bewildering array of therapy, with no one strategy for the treatment of any specific patient. As a result, patient treatment should be made in close consultation with a physician knowledgeable about HIV in general, and protease inhibitors in particular. According to a New England Journal of Medicine article, 'Lack of physician experience leads to early death. The risk of dying on any particular day is 30% less for AIDS patients whose physicians have lots of AIDS experience.' HMO's without HIV experienced doctors should be pressured to add them or allow enrollees to seek care outside the group at no extra cost. It must be done. There's too much to keep up with unless the doctors in those groups are studying the resistance patterns very closely.

We've got to utilize state-of-the-art HIV RNA levels to ensure the highest quality of care for patients. So, truly we can say it's time to shed the extreme cynicism and hopelessness of the whole past decade. We are entering a more hopeful era characterized by incremental, but very tangible advances in the treatment of HIV and AIDS.

I always like to end with Project Informs' Martin Delaney quote regarding the need for' hope. I keep it on my desk:

"For many, hope is a precious commodity that must be guarded jealously for now hope is perhaps the most potent therapy available against AIDS, while hopelessness remains its most destructive pathogen. When the spirit goes up, the body follows."