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Guidelines for using viral load testing and interpreting measurements
The discussion so far by Dr. Coombs is helpful in placing into better context the following part of his discussion. The International AIDS Society (IAS) convened a USA advisory panel, who, after careful deliberation, have assembled a list of interim recommendations related to viral load measurement and the use of test results. The panel consists of:
In fact, these recommendations have just been published (Nature Medicine, volume 2, number 6, June 1996). The recommendations are characterized as interim, because more information is important to better understanding how to use the tests, the meaning and interpretation of test results, and how to better apply these results. Currently, individuals and their doctors are utilizing the test and its results in managing HIV, and in fact it is widely believed that proper use of the test and its results can be helpful in clinical practice. These recommendations are intended to provide helpful guidelines for patients and doctors.
The following questions are addressed by the recommendations:
With each IAS recommendation, Dr. Coombs has added his own editorial, sometimes differing with the recommendation.
(1) Where to initiate therapy?
panel recommendation: More than between 5,000-10,000;
Dr. Coombs-- editorialized that 5-10,000 applies when using the bDNA test, but if using RT-PCR, he recommends greater than 20,000, because from his experience the RT-PCR can run twice as high as bDNA.
The panel strongly encourages therapy at greater than 25,000; Dr. Coombs says 25,000 by bDNA and 50,000 by RT-PCR. In clinical and natural history studies reported to date, some people with higher than 25,000 (bDNA) or 50,000 (PCR) are in the group associated with higher disease progression rates.
Dr. Coombs: Although RT-PCR and bDNA correlate well in their results, there are no common RNA assay standards; therefore, values from the bDNA assay cannot be readily translated into values from the RT-PCR assay. One common recommendation is if you are being monitored by one assay type, you should continue using it, and not switch from one assay to another, until we have common assay standards.
(2) Target level of RNA after initiating therapy
The panel recommends--"undetectable levels of plasma HIV RNA should be sought... under 5,000 would be acceptable." (Dr. Coombs says--5,000 by bDNA is the equivalent of 10,000 by RT-PCR). Panel: "It has not been shown whether plasma HIV RNA reduced to a particular level by antiretroviral therapy carries the same risk of clinical progression as that same HIV RNA level without antiretroviral therapy" having been used. "Prospective clinical trials are urgently needed to address this question."
Dr. Coombs: Under 10,000 (bDNA) or 20,000 (RT-PCR) RNA copies is probably a reasonable target, based on that individuals with these measures appear to have a very slow clinical progression rate. We don't yet know how much benefit accrues from driving the viral load much lower. Since this is a slow progressing group, establishing the clinical benefit to them from a log or more change, will take some time to sort out.
Commentary:
Commentary:
One hundred and eighty seropositive study participants enrolled in MACS in 1984 and 1985. Their blood specimens were taken at study entry and every 6 months and stored. RNA measures were taken and analyzed retrospectively, from the stored samples. Individuals were followed for progression to AIDS (1987 CDC definition) and death. Based on their retrospective baseline RNA value, individuals were divided into the following ranges of RNA: under 4,530; 4,531-13,020; 13,021-36,270; over 36,271. For this analysis, HIV-1 RNA was measured by the new 2nd generation bDNA assay; the 1st assay upon which the first MACS data analysis was based (discussed earlier in this article) is limited, in that it measures down to 10,000 RNA copies; this 2nd generation assay is more sensitive, as it measures as low as 500 copies. Since, we are discussing whether it may be beneficial to reduce one's viral load from 10,000 to 5,000 or lower, the data from this study has some relevance.
It is in context to quote from the Nature Medicine article--"Higher HIV RNA levels correlate with lower baseline CD4 counts, more rapid declines in CD4 counts, and more rapid disease progression....maintenance of plasma HIV RNA levels below 10,000 in early HIV disease appears to be associated with decreased risk of progression to AIDS. However, in patients with more advanced disease (median CD4 counts, 89/ul), disease progression occurred in up to 30% of patients with fewer than 10,000 HIV RNA copies/ml." -----The cost/benefit ratio concept is importantly relevant to this last sentence. If individuals with lower CD4 counts have more potential to progress in the under 10,000 copy range, than those with higher CD4 counts but also with under 10,000 RNA, then this may dictate a different and more aggressive approach (for individuals with lower CD4 and under 10,000 RNA) to the question---when should an individual initiate or change therapy?
***"For the 4 groups, ranging from the lowest through the highest viral load, the proportion of subjects who progressed to AIDS by 5 years after study entry were 8, 26, 49 and 62%. The median times to development of AIDS for subjects in these 4 groups were greater than 10, 7.7, 5.3, and 3.5 years. (Remember, the data collection was only out to 10 years). For the 4 groups, ranging from the lowest through the highest viral load, the proportions of subjects who died within 5 years were 5, 10, 25 and 49%. The median estimated survival times in these 4 groups, ranging from the lowest viral load to the highest were, greater than 10, 9.5, 7.4 and 5.1". These results are mostly independent of CD4 values.***
Although it is not clearly defined, you may be able to infer, from these study results, that lowering viral load from 13,021 to under 4,530 may have value. However, if you factor in the cost/benefit ratio considerations, the value of such a reduction in RNA is more complicated to determine.] end of commentary.
(3) Minimal decrease in HIV RNA indicative of antiviral activity and hopefully efficacy
Panel recommends: at least a 0.5 log reduction that is sustained (3-fold or greater), based on our understanding of factors affecting variability (biological and within-assay variability). "It is likely that the clinical benefits of antiretroviral therapy are related to the duration as well as to the magnitude of HIV suppression...., although the precise duration of HIV suppression necessary to result in measurable clinical benefits still needs to be clearly defined."
Dr. Coombs: Sustained decreases of as little as 2-fold, in clinical studies, have been associated with clinical benefit. Just looking at the amount of RNA reduction (0.5) may not be adequate to judge the prospect of clinical benefit. As discussed earlier, a 1 log decrease for an individual with a viral load of 1 million copies may be more beneficial, to that individual, than a 1 log reduction for an individual with 20,000 RNA copies. For example, a 1 log reduction for an individual with 1 million RNA copies will lower his viral load to 100,000 copies, and 1 log reduction for an individual with 20,000 RNA copies will lower their viral load to 2,000 RNA copies.
(4) Change in HIV RNA that suggests drug treatment failure
Panel: "The return of HIV RNA levels to pre-treatment (or to within 0.3-0.5 log of the pre-treatment value) values, confirmed by at least two measurements, is indicative of drug failure and should prompt considerations of alternative treatment regimens".
Dr. Coombs: A return to baseline is probably an indication that the viral load is no longer reflecting antiviral activity. Again, this change is very dependent on starting RNA level. For example, a return to baseline, if baseline is less than 10,000 (bDNA) or 20,000 (RT-PCR) may not be so bad, and addresses the issue of the cost/benefit ratio of driving viral load lower, without evidence of clinical benefit, which we urgently need to obtain.
(5) Suggested frequency of HIV RNA measurement
Panel: At baseline: 2 measurements, 2 to 4 weeks apart to assess the inherent variability. Subsequently, measurements might be obtained along with the CD4 count every 3 to 4 months, since serial determination of both markers simultaneously provide useful information. Shorter intervals may be appropriate as critical decision points--such as the return of the viral load to baseline values--are approached. RNA levels should be measured 3-4 weeks after initiating or changing therapy to determine antiviral activity, before waiting to see if the CD4 count reflects a change.
(6) Optimal methods of specimen processing
Panel: Optimal procedures for storage, handling, and processing samples have yet to be fully defined. Each provider should adopt consistent procedures for handling specimens, including using the same collection tube and anticoagulant, processing techniques, transport and storage procedures. To minimize HIV RNA degradation, all plasma specimens should be separated and frozen within 6 hours of collection. If this approach is not possible, the plasma should be removed and refrigerated. Less desirably, the whole blood could be refrigerated, but not for more than 24 hours before separation and freezing are completed. Consistent use of the same assay in an individual patient is very important.
Dr. Coombs: Use the recommended anticoagulant, as it varies, depending on which assay you are using. Prompt processing and freezing of the specimen within 2-4 hours, or at least within 6 hours of phlebotomy.
Conclusion by Dr. Coombs at the forum:
In this discussion, varying points of view on different issues are presented for the purpose of objectivity and to convey a better understanding of the issues. In the end, the intent of this paper is to assist individuals and medical care providers in making more informed treatment decisions.
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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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