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Cautious Approach to "New Paradigm"
It is very exciting that we can suppress virus to "undetectable" levels, and that viral levels can remain undetectable for a prolonged period, but there are reasons to consider for not rushing too quickly to accepting these new approaches to treatment of HIV, i.e. "hit hard and early" in primary infection, with treatment-naive individuals and with all others as well. It may be premature to design a new approach to treatment of HIV based on such a small body of research. Some observers say, a potential problem could be-- how long will viral load stay undetectable for some individuals, and what options remain for those individuals if and when their viral load rises? Dr. Coombs contends that these approaches, such as treating acute infection or early intervention (individuals with "higher" CD4), and using 4-drug combinations are promising theories, that need to be adequately researched before we put too much stock into them. Without more extensive studies of treatment intervention in primary (new) infection and treatment-naive individuals, doctors may not be willing to utilize such approaches to treatment. However, it may be helpful for you and your doctor to be informed and educated about these issues, and to discuss treatment strategies with a knowledgeable physician(s).
A challenge of a different sort is compliance with adhering to the regimens for taking protease inhibitor drugs in 3- or 4-drug combinations (i.e., taking the fully recommended doses, at all recommended times, and not taking reduced doses or missing doses---non-compliance can cause resistance). This challenge may be a formidable one, as many individuals are already non-compliant. If a large body of people are not compliant, we could end up with a large pool of protease inhibitor resistant people, which could be transmissable. For individuals with early disease and no signs of sickness, will they be compliant with the rigorous demands of taking 3 or 4-drug protease inhibitor therapy? Of course, this shouldn't deter researchers and doctors from recommending the utilization of protease inhibitors and multi-drug combinations in the way that will optimize benefits for individuals that will be compliant. It is the responsibility of society to devise a strategy for dealing with non-compliance: the drug companies, federal public health and research officials, the medical community, and the "activist" community.
As mentioned earlier, one of the newly suggested approaches to HIV treatment is, if an individual remains "undetectable" (below the level of detection by laboratory RNA tests capable of measuring as low as 10 RNA copies, or is under 100 or 200 copies adeaquate?) for 18 months or 2 years, can that individual begin to stop taking 1, 2 or all of the medications he was taking? Is that person's virus "eradicated"? Will their virus remain in "remission"? HIV may be present in a number of "compartments" in the body besides the blood.
The belief that the virus can be "eradicated" or that lowering viral load to "undetectable" may not be true, if the virus and its replication is driven by the "reservoir" hidden in these compartments. Does protease inhibitor or nevirapine therapy accompanied by 2 or 3 additional drugs affect the virus hidden in these compartments? Or, will this hidden virus emerge after an individual may begin to stop taking 1 or 2 drugs of their combination therapy? And of course, there is the possibility that virus can be driven from these other "compartments. Continuing studies are necessary to explore this unknown.
Despite these difficult questions and obstacles, it is important to remember we are in fact entering into a new and exciting era for the treatment of HIV. Never before have we been in a position to ask some of these questions---such as, can we "eradicate HIV from an infected person? But, we need to remain circumspect, to encourage continuing research to address the unanswered questions, and not to allow ourselves to become overconfident or complacent.
It may be however important to better understand the thinking of those who are supporting the notion of being aggressive with new approaches to HIV treatment. Aside from the early new data from these pilot trials, a reason some experts recommend "hit hard and hit early" is, because the earlier it is in an individuals disease progression, their virus has not had as much opportunity to replicate and therefore mutate. The virus will tend to be more homogenous; the contention is that a homogenous (the virus hasn't had ample opportunity yet to mutate very much) virus is more receptive to treatment and less likely to develop resistance to the treatment as quickly as an individual's virus that is more heterogenous from replication and mutation.
Additionally, it is widely accepted that disease progression and consequent sickness and death is a result of a depleted immune system. Presumably, the earlier treatment begins, the more intact an individuals immune system will be at the start of therapy; and, hopefully therapy will maintain the healthy status of the immune system, or at least maintain it for a longer period of time.
This thinking is at least partially based on the recent research developments from David Ho, George Shaw and others. Prior thinking was that there was a prolonged period of relative virus latency; this has been replaced with the thinking that ongoing, high-level viral replication takes place from the time of initial infection. This research says, as many as 10 billion new HIV virions are produced per day, with a half-life in plasma of 6 hours. CD4 cells, a principle target for the virus responsible for viral replication, are also produced in high number, and once productively infected, have a half-life of 1.6 days. The life-cycle of the virus, from infection of one cell to the production of new progeny, which infects the next cell, is 2.6 days.
Additionally, prior to now the only available drugs for treatment of HIV were of very moderate benefit (AZT, ddI, etc.). Now, we have much more potent drugs-- protease inhibitors, nevirapine--with which to treat HIV, and we've found that resistance can be suppressed for a prolonged period of time by utilizing a protease inhibitor or nevirapine as part of a potent 3-drug combination; also, we now have available the viral load test by which to measure antiviral activity. Of course, researchers are as yet uncertain of the durability of the suppression of virus resulting from potent 3-drug therapy.
Some of these experts are comparing treatment of HIV with treatment of cancer and tuberculosis, by saying the traditional or the classic approach to treatment of cancer and TB is to hit "early and hard" with combination therapy. However, can it be compared to cancer and TB? Again, they postulate, that if treated early enough in the disease with potent therapy, an individual may be better able to, in a sense, put the virus in remission; that is, lower the viral load to an adequately "undetectable" level (undetectable does not mean virus isn't present--how low is enough?), which will hopefully stop viral replication and prevent the emergence of resistance; or, possibly "eradicate" the virus from the blood or the system. The objections to pre-maturely accepting this thinking are outlined above; it may be advisable to remain at once excited, skeptical and circumspect until we have more data from studies implemented to explore and confirm these new approaches to treating HIV.
Nonetheless, the ACTG 175, Upjohn and MACS research, discussed above, appear to indicate that reductions in viral load can alter the course of clinical progression. Although, reductions in RNA were mostly modest in the 175 and Upjohn studies, the drug therapies used in the study did not include any protease inhibitors. In the group with over 1 million viral load, a 1 log or greater reduction in RNA produced the most benefit to clinical progression, when compared to individuals, in the other groups with less viral load reductions. As you know, successful protease inhibitor therapy, which utilizes effective multi-drug combinations, has produced in some instances, significantly more than 1 log decreases in viral load. Importantly, still to be confirmed, is the durability of these reductions in viral load.] end of commentary
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About the author: Jules Levin is the Executive Director of NATAP, based in New York City.
The National AIDS Treatment Advocacy Project (NATAP) is a New York State non-profit corporation dedicated to facilitating the effort for development of effective treatment for HIV.
Last modified 9/3/96
by Jules Levin
Copyright © 1996 natap
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