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When Does An Individual Initiate Therapy?
Dr. Coombs is suggesting, that once your viral load is at a certain level or "threshold" (which, he advises, we have not yet been able to establish, and it is suggested from various sources that it could be 20,000, 5,000 or 10,000 again depending also on the assay being used; or, below "detectability" is suggested as a goal by some researchers--which can be below 500, 200 or 25 depending on the test used), then lowering your viral load even more should be weighed by the costs and potential benefits. The cost of lowering your viral load can include using up treatment options, financial, and side effects. He is suggesting, it may be beneficial to save treatment options, rather than lowering viral load to "as low as possible"?
However, let me make reference to a commentary from below, but relevant to this discussion: "... in patients with more advanced disease (median CD4 cell count, 89/ul), disease progression occurred in up to 30% of patients with fewer than 10,000 HIV RNA copies/ml." --Saag et al, Nature Medicine, vol 2, number 6, June 1996. This progression rate, of 30% appears to be greater than for individuals with under 10,000 RNA copies but higher CD4 counts. Additionally, with reference to the Upjohn study data, the reason that for individuals in the lowest viral load group (under 100,000--or as Upjohn says, the equivalent of 20,000 RT-PCR), there may not be this linear relationship (whereby, those with greatest RNA reduction received the most benefit to clinical progression), is because this arm of the study had fewer participants, their CD4 counts were probably higher, there RNA levels were lower --therefore, they have less risk of progression, less endpoints have so far been accumulated and it should take more time to detect progression and the possibility of development of the linear relationship. Despite what Dr. Coombs says, this may leave open to question, his assertion that it may not be beneficial (cost/benefit ratio) for individuals with RNA below a certain level, say 5-10,000, to initiate protease inhibitor therapy. Research needs to address these type of questions, so we can try to better utilize viral load technology and protease inhibitors. Considering these factors, Dr. Coombs still suggests the cost/benefit ratio factor may limit treatment to individuals in the lower viral load levels.
The more "conservative," cautious, or less aggressive approach, put forward by Dr. Coombs, of when to initiate therapy, represents one school of thinking. Some other leading AIDS researchers are suggesting that the better approach may be to "hit hard and hit early". That is, treat with the most potent therapy and possibly treat as early as possible in an individual's disease stage, unless perhaps if your viral load is already very low (under 5,000 or 10,000) and/or your CD4 may be relatively high. Although, a more aggressive wing of this group may be supporting the notion of "hit hard and hit early" as soon as possible, even soon after sero-conversion--during primary or new infection (after contracting the virus)-- for the purpose of rendering an individual's viral load "undetectable" or as low as possible for as long as possible.
This approach is based in part on early or preliminary data discussed below, which was presented publicly at the Vancouver Int'l. AIDS Conference in July; in these 2 small pilot studies, suppressing virus to "undetectable" levels (in the 2 studies discussed, "undetectable" viral load was defined as below 25 RNA equiv/ml in one study and below 100 RNA equiv/ml in the other--as measured by bDNA) has kept viral replication in check, thereby prevented resistance from emerging, and permitting viral RNA to remain undetectable for a still ongoing period for all study subjects remaining in the trials; (see the NATAP paper Can HIV be eradicated" from the infectedindividual?)
Other trials' results have contributed to this thinking, including: Merck's trial of indinavir/AZT/3TC in AZT-experienced individuals; Abbott's trial of ritonavir/AZT/ddC in treatment-naive individuals. Also a basis for this most aggressive approach to treatment is the Boehringer Ingelheim 1046 study of treatment-naive individuals, which was only recently (June 7) publicly presented (see Nevirapine article; 80% of the individuals in the group receiving the 3-drug combination of AZT/ddI and nevirapine had their viral load rendered "undetectable" (which in this case was below 200 RNA copies/ml--as measured by PCR); additionally, there is some follow-up out to 18 months where some individuals are still undetectable. In addition, treatment of a small number newborns with potent 3-drug therapy has resulted in similar results. However, it may be advisable to be circumspect about this new information (see discussion below).
There are some differences of opinion about which viral load level is low enough, is it under 25, 100, 200, 5,000 or 10,000? Despite the preliminary results from the pilot studies that are discussed below, researchers need to conduct further studies to confirm which viral load levels should be targeted with therapy. If your viral load is 5,000, should you initiate protease inhibitor therapy now or should you wait? The answer to this question is more clear if your viral load is over 20,000; and, becomes more clear the higher one's viral load climbs; the IAS interim guidelines (discussed below) recommend driving one's viral load as low as possible or to "undetectable levels"; while Dr. Coombs is not convinced that is necessary, for him 5,000 may be acceptable.
This relates directly to the question--when should an individual initiate therapy, and with which drugs?? If your viral load is 5,000, should you initiate protease inhibitor (or nevirapine) therapy now or should you wait? The IAS guidelines described below recommend initiating therapy if your viral load is above 5-10,000 and your CD4 status suggests progression. In light of the new data revealed in Vancouver, the authors of the IAS guidelines may or may not revise their recommendations. I think that for doctors and their patients, there will be no clear recommendations forthcoming, because the interpretation of this data will probably remain controversial for a good while.
The subject of cross-resistance between protease inhibitors is relevant to this discussion. Will treatment with a particular protease inhibitor cause any or significant cross-resistance to another protease inhibitor? We do not yet adequately understand the cross-resistance relationships between different protease inhibitors. If your viral load is relatively low, by waiting until we better understand cross-resistance between protease inhibitors, you may be better able to optimize your results from therapy. But, we may not have information for a good while (1 year maybe), that is adequate to understand cross-resistance sufficiently to answer these questions (see Pre-Vancouver Protease Inhibitor Update for a discussion of ACTG 333, the first study of protease cross-resistance). Also, there are many individual and theoretical factors that can be considered in making these decisions. Does one want to use the best available therapy early in their disease stage, rather than save it for later? The aggressive treaters say yes, and some of the underpinning for their thinking is discussed below. They say, there will be other therapies available. Other treaters are more cautious about spending options. The answers to many of these questions are not yet clear.
The 2 studies presented in Vancouver are ongoing small pilot trials meant to test specific hypothesis'. Twelve therapy-naive individuals were recruited who were chronically infected (HIV+ for a while with some progression), and were treated with open-label nelfinavir (750 mg 3x/day) and AZT/3TC. In the 2nd study, 12 individuals who had recently sero-converted were recruited and treated with open-label ritonavir/AZT/3TC. The principal investigators of both studies, David Ho and Martin Markowitz of the Aaron Diamond AIDS Research Center in New York City, wanted to explore the extent to which these therapies in these populations could turn off viral replication and the longer-term implications of that. In the sero-converter, trial the investigators also wanted to explore the possibility of "eradicating" HIV-1 in a recently infected person with a relatively intact immune system.
In Vancouver, only 4 months of data was available for presentation for the treatment-naive, chronically infected group treated with nelfinavir/AZT/3TC; and, the data so far available and presented in Vancouver, for the sero-converter study of ritonavir/AZT/3TC, extends only to between 4 and 10 months for the study subjects. Again, all study subjects, in both trials, remaining on therapy had their viral load rendered "undetectable."
The meaning and interpretation of these study results, and their potential application has created much controversy in the AIDS research and medical community. Many feel it is pre-mature to draw strong conclusions from these preliminary results; and that it is pre-mature to begin treating sero-converters and treatment-naive individuals in this way, i.e. "hit hard and early" with the most potent therapy at the earliest possible time of intervention. However, some researchers disagree and expressed that we should treat individuals with this "hit hard and early" approach to therapy.
The potential benefits of a potent 3 or 4 drug therapy may be different for individuals who have extensive prior drug experience with nucleosides (AZT, ddI, ddC, 3TC, d4T). These individuals may not be as responsive as those who are treatment-naive, and of course as those who are recently infected. If you merely add a protease inhibitor to other drugs you have been taking for a while, you may not be able to reduce your viral load to undetectable; or, if you are able to reduce it to undetectable, it may not be as likely to remain at that level and it could begin to rebound. For this group of individuals, the set of issues are considerably different, more difficult and cannot be bunched together in a discussion with treatment-naive or newly infected. However, there are promising treatment approaches that can be utilized by this group. Protease inhibitors now in human trials that are not yet approved are Agouron's nelfinavir and Glaxo Wellcome's141W94; as well, Glaxo Wellcome's 1592U89 is a potent NRTI (nucleoside reverse transcriptase inhibitor) which is also in early human trials. There are real prospects for sequencing from one of the currently approved protease inhibitors onto a different one after they become available. Other antiretroviral drugs are in either available or in human studies, including DMP-266 (NNRTI), nevirapine, (NNRTI), and delavirdine (NNRTI), which will be useful in designing treatment strategies for those who are drug-experienced. I am just concerned that all the attention appears to me to be focused on the treatment-naive and newly infected populations without adequate attention to those who are treatment-experienced.
Clearly, there are many remaining questions: how durable will the responses be of the individuals in the 2 aforementioned studies (treatment-naive and newly infected)? What will the findings be of residual virus in other "compartments"--CSF, lymph nodes, testes, etc.? Only a small number of individuals (24) were studied, what follow-up studies do we need? Individuals with advanced HIV (low CD4s) may not respond as well to treatment as those who are seroconverters or treatment-naive. What treatment strategies will be best for individuals with moderate or advanced disease who may have exhausted most if not all previously available treatment options? How will protease inhibitor cross-resistance effect treatment strategies for all of these different types of individuals?
A number of discussions are onging to devise future studies to address some of these remaining questions. Studies are being planned for individuals with greater than 500 CD4. Four-drug combination studies are being planned, to begin shortly, for treatment-naive and possibly for treatment-experienced individuals. One proposal currently under discussion is devising a study to allow individuals to begin stopping part or all of their therapy after being "undetectable" for a prolonged period of time, to see if they remain undetectable. Other unique approaches to study design are being discussed and planned.
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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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