PI Perspective #19

September 1996     View PDF

Eradication of HIV: Hope or Hype?

Something of a milestone was reached in June of 1996 when a group of researchers associated with the University of Amsterdam and the medical journal Antiviral Therapy convened the first ever conference addressing whether it would now or soon be possible to totally eradicate HIV infection from infected people. As recently as a year ago, any scientist suggesting such a thing would be laughed at. But this invitation-only meeting was applauded and drew an impressive crowd of researchers. This article gives an overview of the thinking and discussion which took place at the meeting and the implications it might have for the current treatment of HIV infection.

Definitions
For the sake of clarity at the meeting, it was important for researchers to define their terms. These definitions are equally useful for community discussion of the issue.

Complete Suppression of HIV is defined as a condition in which no viral replication can be measured on the best available HIV RNA tests. This may require constant use of therapy. In this state, there still may be hidden reservoirs of infected cells which are capable of rekindling the fires of infection. Complete suppression has been achieved in some people with the use of aggressive antiviral regimens for up to two years. It is too early to know whether this can be maintained for much longer periods. Researchers will soon begin to test whether it is possible to maintain complete suppression while reducing the number of drugs employed.

Eradication of HIV is defined as a condition in which all viral replication is stopped (and consequently, there is no possibility of developing drug resistance) and remains stopped even if anti-HIV therapy is discontinued, as all infected cells and infectious virus have been eliminated. Achieving eradication requires going beyond the current standard of “reduction below the limit of detection” on the commercial HIV RNA tests. The most advanced virology laboratories are able to detect the difference between the “limit of detection” on commercial tests and true viral eradication.

Scientists are debating whether a true state of viral eradication of HIV has been achieved in current experiments. It is simply too early to know for certain. However, in pediatric research, evidence suggests that eradication has taken place naturally in a few children. Researchers are referring to these pediatric cases as transient infections, meaning HIV appeared to be there but now is gone.

The prospects for eradication are somewhat different for distinct populations:

• newborns (mother-to-child transmission).
• primary or acute infection (people recently exposed to HIV, such as healthcare workers exposed to HIV via needle-stick injuries and others identified in or near the acute infection syndrome).
• chronic infection (people who have been infected for a year or longer; within this group are all the normal variants ranging from long-term non-progressors to people with more advanced HIV-disease).

Newborns
Six cases of transient infection have been reported in the U.S. These are children who appeared to be infected with HIV, as determined by multiple positive HIV RNA tests and viral cultures, but who later appear to have no evidence of infection. The initial six cases are children who appear to have cleared HIV infection without the use of therapy. Some researchers at the conference remarked that they remain unconvinced by these cases, arguing that the possibility still exists for lab error to be the explanation. The scientists reporting the cases, however, strongly disagree and believe their case is proven. What’s necessary is for the two groups to agree upon a common definition of the procedures needed to warrant the label of transient infection.

Two European groups also reported data from large studies which might show wider evidence of transient infections. In these studies, they claim a transient infection rate of 2% to 2.5%. This figure astonished the Americans at the meeting, who believe it must be too high since they have not seen a similar incidence in their own studies. They questioned the accuracy of the European tests. Nonetheless, everyone seems to agree that something is going on, whether it is a single case or dozens of them.

Another U.S. group reported the first results of a triple-drug combination treatment of very young children, using a regimen anchored by nevirapine along with two nucleoside analogs. After 6 months of treatment, the children involved appear to be as free of virus as anyone in the best adult studies. Moreover, there is immunologic evidence that makes them look more like uninfected children than non-progressors. In particular, the children are losing HIV antibodies and showing diminished levels of HIV-specific cellular immune activity. The study director’s plan is to follow the children and not make any premature announcements or conclusions. But they are obviously surprised and pleased by the results.

Primary or Acute Infection
The hope of eradication in primary infection (the period before there is any immunologic evidence of infection) is based on the assumption that the virus has not spread early on and may thus present an easier target for full clearance. In needle-stick and other healthcare environment exposures, the hope is to stop the virus from ever getting a foothold by treating with anti-HIV drugs immediately. Immediate treatment, even with AZT-alone, may greatly reduce the expected rate of infection. The plan now is to begin treatment immediately with a triple-drug combination regimen and to continue treatment for as little as six weeks to as long as six months.

Several studies are also underway for people identified in the very early, “acute” phase of infection, usually by presentation with the flu-like syndrome seen in the early weeks after exposure to HIV. Again, the goal is to arrest the infection before it has a chance to fully “seed” itself in body tissues and cells. Researchers hope to achieve one of two goals. Ideally, they would like to stop the infection altogether and reach a point where the patient no longer needs therapy of any kind. If this fails, the second goal is to establish a much lower “set-point” viral load in the patient, one associated with long-term non-progression. (Recent research has shown that the immune system stabilizes sometime after initial infection with a certain “set point” level of viral reproduction. The higher the level of that set point, the more rapidly the disease progresses.) Researchers seem cautiously optimistic that they can achieve the first goal, of shutting down the infection altogether. A small group of people, identified shortly after initial infection, has been receiving this therapy regimen for nearly a year already and all have no detectable level of virus. Researchers at the Aaron Diamond AIDS Research Center will soon begin searching for virus in their lymph nodes and tissues, and if they don’t find any, they plan to take at least some volunteers off of treatment to see if the infection has been eliminated. Only time will tell.

Chronic Infection
The most challenging target for HIV eradication is clearly that of the chronically infected population—people who have been living with HIV for a year or longer, many of whom have used existing therapies for long periods. In this group, it is almost certain that HIV has infected many types of cells and body tissue. To eradicate HIV in this setting, it will be necessary to stop viral replication at all sites long enough to wait out the death of all infected cells. Researchers aren’t sure they know all the relevant cells and tissue sites of infection, let alone how long it will take to replace the cells. Nonetheless, there is a sense that eradication in people with chronic infection is a plausible goal which should be vigorously pursued.

The notion of eradicating HIV in chronic infection represents a major paradigm shift. Researchers previously believed that once infected, it would be impossible to eradicate the virus from a person. The pediatric experience with transient infection challenges that assumption, as do recent data about viral replication rates and cell turnover times. Some scientists argue that the pediatric experience may be due to low initial viral level or weakened strains of virus, but it is possible that similar conditions might exist or could be induced by therapy in chronically infected people.

Recent studies of indinavir and ritonavir demonstrate that it is often possible to reduce viral load “below the limit of detection.” Researchers at the HIV Eradication meeting went considerably further in their description of some of these results. They argued that the companies are being directed by the FDA to use the phrase “below the limit of detection” but in fact, the level of virus, in some instances, appears to be conclusively lower than this might imply. Using an advanced version of the PCR test, virologists working on the Merck 035 study of AZT + 3TC + indinavir reported that all study participants receiving the 3-drug combination have “no signal” levels of detection. This means that their viral load measures somewhere between 0 and 20 copies. The currently approved Roche HIV RNA PCR test has a limit of detection of “under 200 copies” of viral particles. Similar results have been noted in other studies, particularly with ritonavir. Further confirmation that little or no viral replication is taking place can be found in the lack of drug resistance seen in these studies, because resistance can only occur when the virus is replicating. Most people using 3TC, for example, develop resistant mutations in a few weeks, but none have acquired the mutation in the 035 study after 48 weeks. Similarly, it now appears that almost all study participants receiving the 3-drug combination have avoided resistance to indinavir as well. This strongly suggests that no significant viral replication is occurring.

These combined study results raise many important possibilities and many questions. If replication is fully suppressed, then it appears that it will be possible to thwart or greatly delay the problem of drug resistance. Conversely, the data suggest that unless a therapy regimen can truly halt viral replication—bringing it down below the limit of detection—then drug resistance is inevitable. This gives us a powerful clue as to what the target must be for long-term effective use of the new drugs that have recently become available. It suggests that simply reducing viral levels is not enough. Even though new studies show that modest reductions in viral load (starting at about ½ log reduction) may produce important clinical benefits and reduce mortality rates, it will not present a true long-term solution to the problems of viral reproduction and drug resistance. This can be achieved only when viral replication is virtually stopped.

Researchers at the conference speculated on what made the AZT + 3TC + indinavir combination as potent and long lasting as it is. Several people in the audience noted that in community use, the combination wasn’t always producing such spectacular or lasting results. The “magic” of the study may be due to the simultaneous initiation of at least one other very potent and “fresh” drug at the same time as initiating therapy with a protease inhibitor. Although most of the participants in the 035 study were AZT resistant, all were new to both 3TC and indinavir. With the simultaneous potent onslaught of 3TC and indinavir, it’s relatively easy to see why the virus is effectively shut down. Similar results have not always been seen in people who had taken 3TC for a substantial period of time prior to starting indinavir—they were almost certainly resistant to 3TC at the outset, and therefore 3TC probably did not add its most potent punch to the 3-drug combination.

Duration of Therapy
It has been assumed that suppressing HIV replication would require lifetime therapy. This raises troubling questions of costs, long-term toxicity, and drug resistance. Even here, a new paradigm entered the discussion at the meeting. When the viral signal has completely disappeared, will it be necessary for people to remain on potent therapy for the rest of their lives? Will a time come when people can either quit therapy altogether (disease is over) or be sustained on a more modest regimen (disease suffers a major setback or is crippled)? Only longer-term studies can answer this.

Representatives from the Aaron Diamond AIDS Research Center presented new data on cell and viral dynamics in response to 3-drug therapy. They observed two stages of viral reduction in patients—a large initial drop reflecting a shut-down of virus from rapidly producing active cells, and a second, smaller drop which occurs later, from what they call the “second compartment” of viral reproduction. They believe this “second compartment” is composed of dormant, latently infected and slowly acting cells, such as macrophages and dendritic cells. Thus, if therapy could truly stop all replication, preventing all cells from producing new virus or infecting other cells, it would take about 2½ to 3 years for all the slower-acting infected cells to turn over or die. At that point, the body might be free of all potential for initiating further HIV replication. This remains a theory and it assumes that there isn’t some hidden “third compartment” of infection yet to be discovered. Nonetheless, their research goal is to keep patients at the “no-signal” level of viral reproduction for at least 2½ years and then to cautiously experiment with withdrawing therapy.

There have already been a few cases of people with “undetectable viral load” for six months or less who stopped therapy. In each case, there was a quick return of virus, though it didn’t always return to pre-study levels. Withdrawing therapy this early is obviously a mistake and physicians should not expect short-term viral suppression, however complete, to translate into a long-term eradication of virus. The effect of stopping therapy after 2 to 3 years still remains to be seen.

Other Sites of Infection
Researchers are now doing lymph node biopsies on as many people as possible to see what effect 3-drug therapy is having in lymph nodes. Dr. Pantaleo, from the National Institute of Allergy and Infectious Diseases (NIAID), showed preliminary slides from a few people. Pre-treatment lymph nodes showed a high level of viral activity and clustering of virus in the lymph tissue, as expected. In contrast, a few slides from people treated with a protease inhibitor—but not necessarily as part of a structured 3-drug regimen—showed dramatic reduction in the number of viral “spots” in the slide. Clearly, treatment had a potent effect in lymph tissue even if it had not yet cleared all virus, indicating that the effect of therapy seen in the blood stream does reflect what is happening in body tissue.

Therapeutic Implications
There are two almost conflicting messages about therapy in these new observations. One is that treatment with anything less than a “perfect” regimen will lead to drug resistance. Anytime HIV replicates, even at low levels, in the presence of a drug or combination of drugs, the development of drug-resistant virus is inevitable. The ideal goal is clear: complete suppression of viral replication, which leads to complete suppression of resistance. Achieving this appears to require, for most people, starting two or more potent anti-HIV drugs simultaneously.

Some people with low initial viral loads might be able to achieve complete suppression with lesser regimens, possibly 2-drug rather than 3-drug approaches. However, new data suggest that it would be a mistake to settle for any regimen that fails to give complete suppression below the limit of detection of the test. While it’s true that reducing the viral load alone may have a clinical benefit, the goal now is to go beyond that and begin looking at long-term solutions.

This creates a dilemma for people who have already used most of the available therapies. They rarely have access to two or more potent new inhibitors at the same time. Achieving the goal of true long-term suppression in this setting will be a greater challenge than for those just beginning therapy for the first time. The goal will be to find the regimen to which they are most sensitive. It might suggest a strategy which includes testing viral sensitivity to existing drugs and possibly holding off when new therapies are approved until more than one potent new option becomes available.

While this new information is very exciting to many people, it may make others depressed if they can’t achieve complete suppression with the regimens available to them. They may wonder if continuing to use partially effective therapy will hasten drug failure. While this is probably true in an absolute sense, it doesn’t mean they won’t benefit from using therapy. The recent Hoffman-La Roche study which employed nothing but substandard regimens shows that as long as a therapy achieves and sustains about a three to four-fold drop in virus, there is a clinical and survival benefit. The only reason studies like this aren’t met with great applause today is the hint that we now have the tools to do much better—to be able to develop longer-term solutions, or perhaps even achieve the eventual eradication of HIV from the blood, the tissues and the body overall.

As we move toward developing truly effective medical strategies for HIV infection, it has become more and more clear that the way new therapies are currently delivered often flies in the face of how such drugs should best be used. Each drug is released on its own and slowly works its way into the third party payer formularies over time. Physicians and patients get access to the drugs in a staggered fashion, causing them to add one new therapy on top of another, thus giving HIV a chance to develop resistance to each individually. It may be easiest to achieve the goal of complete suppression or eradication in people who get to choose their regimens from the entire batch of drugs, fresh and for the first time. Those who pioneered development of those therapies, in a fight to extend their own lives, now face the greatest challenge in trying to benefit from them in a medical strategy. This does not mean that people who have used therapies for a long time will see no benefit, but only that the challenges to achieve complete suppression are greater. Much work must be done to insure realistic expanded access programs to new drugs in the pipeline, which insure optimal flexibility to everyone in this situation.

11th Int'l Conference

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