translation agency

Being Alive
Can We Eradicate HIV from the Body?
Walt Senterfitt
September 5, 1996
Being Alive 1996 Sep 5: 5

This question dominated the news from the Vancouver International aids Conference this summer. The very asking of it is controversial for fear that it raises cruelly false hopes, distracts attention from more pressing research or ignores those with advanced disease and years of drug therapy already. Once posed, however, (by some of the smartest and most productive aids researchers) it won't go away until we know the answer. Its hint of possibility of total victory, of cure, is too exciting to be ignored.

Even the most optimistic proponents of "The Eradication Hypothesis," as it's come to be known, argue for caution in the discussion. Their provisional answer is "who knows?" The most they can say right now is that for the first time we can raise the question and design experiments and clinical trials to answer it. The answer may be "no." Or it may be: "only in comparatively few people." Or it may be: "no, but we can eliminate it from everywhere but small reservoirs and can keep it quietly hidden there if people can stay on the drugs indefinitely." Why Can We Raise the Question Now and Not Before? The new viral amplification techniques (commonly know as "viral load tests" or "PCR tests," though not all of them actually use PCR technology) allow direct measurement of whether or not and how much virus is in the blood and in any other tissues (such as lymph nodes) that can be accurately biopsied and tested. These procedures amplify any hiv or hiv fragments in the tissues tested more than a million times. It's rather like a huge photographic enlargement or electron microscopy that allows us to see things that were in earlier times too tiny to detect. As these tests get more refined, we can be fairly confident that if they can find no virus in the specimen, that means there's no virus there to be found. So, one key fact is that we have vastly better measurement tools.

Second, the newly available drug combinations are more powerful than what we had to work with before. Specifically, they are powerful enough in many people tested to shut down any detectable reproduction of hiv (known as replication) in the body. When reproduction is shut down, it is believed that no drug resistance can emerge. Drug resistance happens, it is now thought, not because hiv mutates in response to an antiviral drug, but rather because it occurs spontaneously as a result of hiv's extremely rapid rate of turnover. If one stops viral replication, no new mutations occur and thus no new drug-resistant mutations occur.

Third, Drs. David Ho and George Shaw showed last year that the rate of virus replication and T-cell turnover is very, very fast. Half of all hiv in the blood and half of all CD4 or T-cells die and are replaced every 36 hours or so. If the new potent drug combinations are used to stop replication, there's no hiv floating around to infect the new T-cells being made continuously. A whole new crop of T-cells that are uninfected can replace the old infected T-cell population within two to three weeks, theoretically.

This is not enough for a knockout blow, however, because other cells that hiv infects do not die off and get replaced as rapidly as CD4 or T-cells. Macrophages, lymph node tissues and other immune system cells in the lining of the skin and mucous membranes live longer. No one seems to know yet how long each of these types of cells live. Dr. Ho hypothesizes that at least most of these cells turn over within a few weeks to months. He bases this on his observations in a small number of patients he has studied intensively.

The viral load of these people all came down to undetectable levels within a few months, but did so in two phases. The first phase was very rapid and probably represented the clearing of infected T-cells from the bloodstream; that brought the viral load down to a quite low but still detectable level. Then, it came down the rest of the way more gradually, over three or four months. Dr. Ho deduced that this slower second phase represents the replacement of the macrophages, lymph node tissues and other cells that act as the reservoirs for hiv and which can "re-seed" the bloodstream if they are not also replaced with uninfected cells. However, it is not yet clear if all of the infected cells in these "compartments" of the immune system were in fact replaced. Some may remain latently infected, only to become activated as little hiv-producing powerhouses at some future point. (Cells which make and release new hiv viral particles are known as "productively" as opposed to latently infected.) Small Experiments Support an Answer of "Maybe" Several small and still ongoing experiments designed to help answer this big question reported preliminary results in Vancouver. Two were conducted by Dr. Ho and his collaborator, Dr. Marty Markowitz, in New York City. One of the studies is of AZT plus 3TC plus ritonavir in 12 newly infected people; all had evidence of having been infected within one to four months of starting triple combination drug therapy. Two of the 12 withdrew and one was dropped; one for intolerable side effects and two for non-compliance. In the remaining nine, viral loads became undetectable by three months, using the most sophisticated tests available which detects hiv RNA down to 25 copies/ml.

Similar results were achieved in another Ho/Markowitz study of AZT/3TC/nelfinavir in 12 people with much more advanced hiv infection but who had never taken antiviral drugs before. This group started with an average CD4 count of 258 (range 37 to 557) and a mean viral load of 209,000 copies/ml (the median, i.e., half above and half below this number, was 81,270 copies/ml). One person withdrew at 6 weeks with intolerable side effects (diarrhea and abdominal cramping). The remaining 11 had all reached undetectable viral loads by week 12. In both studies, after 12 months participants will be invited to have a lymph node biopsy. If the biopsies show no hiv, people will be offered the opportunity to stop taking the drugs and then watched closely to see if hiv comes back, in which case they would start drugs again. If there is evidence of hiv in the lymph nodes, individuals will continue on the drug regimen, though perhaps with a reduction in dose.

Dr. Julio Montaner of Vancouver reported achieving almost as good results in a group of about 80 patients in Canada who had intermediate to advanced hiv infection and who had never taken antivirals before. He used the combination of AZT, 3TC and nevirapine-the first study of this type to use a combination that did not include a protease inhibitor. More than 80% of his study participants became viral load undetectable.

In all three of these studies, the profound suppression (and perhaps total cessation) of viral replication has been maintained indefinitely since being first attained. Finally, Dr. John Sullivan of the University of Massachusetts Medical School has reported on two babies born with definite hiv infection, i.e., virus was cultured from their blood after birth. Both of these babies achieved undetectable viral loads quickly and have maintained that state. Indeed, they both show a pattern of losing hiv antibody; they appear to be headed for becoming definitely HIV negative.

The Big "Ifs" and Doubts One big uncertainty, mentioned already, is the lifespan of the infected macrophages, lymph nodes and tissues in the "second compartment" of the immune system. Have they all been replaced with new uninfected versions of themselves? Or have at least some of them remained latently infected, and perhaps will for a lifetime, so that their quiescence will always have to be maintained with some kind of maintenance drug therapy? Related, and even harder to assess with biopsies, is the possibility of hiv-infected cells in the CNS (central nervous system, especially the brain) or the reproductive organs serving as latent but potentially active reservoirs of hiv infection. It is known that hiv infects some nervous system cells directly, as well as cells in the testes, and that this happens fairly early. Drugs don't easily penetrate the brain, so the suppression achieved elsewhere in the body is probably much harder to achieve in the brain. No one yet knows whether or not these infected CNS or reproductive cells are capable of serving as reservoirs that could re-seed body organs otherwise cleared of all hiv. Needless to say, it is very difficult to get people to agree to brain biopsies when they are well and even so it is not certain that one would biopsy the right spot. More broadly we might say that just because we have sensitive tools to measure hiv doesn't mean that we can deploy that tool in all the right places.

This possibility of unreachable reservoirs, of infected cells that live as long as the person, is probably the central problem with the eradication hypothesis. As a main proponent, Dr. Doug Richman of UC San Diego, acknowledged in a press conference after the June meeting which first brought media attention to eradication: "If hiv is like herpes, we'll never be able to 'eradicate' the infection. In other words, herpes infects a type of cell that is life-long, so that we can only suppress herpes. We can't eradicate it. hiv may fall into that category, but it may not. If it doesn't, we can still credibly aim for suppressing it permanently; it's just a matter of potency and duration of therapy." Other studies are being planned on a fast track that will try to help answer the question of what happens when one stops drug treatment after a prolonged period of suppression. In one study, for example, some people would be randomized to complete stoppage of drugs coupled with frequent follow up tests, some to a lower maintenance regimen and some to continuing the full dose regimen. Even if eradication could be achieved, it is not clear how long it would take. Some of Ho's mathematical calculations suggest an average period of three years might be necessary to eradicate it from all the possible reservoirs. These studies may also help answer another related question: how far along the pathway of disease progression and immune system damage is it possible to achieve eradication, or even permanent suppression? In other words, at what approximate T-cell count is it even theoretically impossible, unless we find effective ways to restore the damaged immune system? Skeptics of the eradication hypothesis believe that it is very probable that hiv will turn out to be like herpes, in that it exists integrated within cells that live as long as the person does and which cannot be killed without irreparable harm to the body. Some of them argue, therefore, that all this talk about eradication is a diversion with possibly negative consequences on morale, on risk reduction and on the pace of research into more pressing questions.

Comment Practical problems abound as well, principally the difficult problems of high cost and thus unequal access as well as difficult compliance requirements. In continuing the search for answers to the questions described above, it is urgent not to slow down the search for easier methods of taking these drugs and the campaign to vastly reduce cost and increase equity of access.

It is also important not to focus solely on those who most easily show dramatic results -the newly infected, the previously untreated and the babies. The majority of people who know of their hiv infection have already undergone drug treatment, often for years. The immune systems of many are already, alas, severely damaged. As activists and as the broad hiv community, we must demand that research be balanced and give emphasis to those who need its results the fastest.

It is important that research devoted to testing this hypothesis be conducted among a broad range of people, including, of course, women, all ethnicities and all lifestyles. It is not wrong to start studying a new hypothesis in small groups that are easiest to access and which promise the most likely positive effects. It is wrong to end there, or to promulgate drugs or treatments as generally beneficial when they have only been tried out in limited and atypical groups.

With these cautions, I think the thought and the work behind this new possibility is defensibly exciting. It should benefit all of us to know much more about the life span and life cycles of all the cells infected or affected by HIV.

www.aegis.org