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The Body Covers: The 6th Conference on Retroviruses and Opportunistic Infections
Abstract No. 331: Viral Fitness in Patients with Discordant CD4 and Plasma HIV RNA following Protease Inhibitor Failure

February 2, 1999

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

The authors begin with the observation that discordant evolution of CD4 counts and plasma viral RNA is observed in patients following protease inhibitor therapy. They offer several hypotheses:

  1. The fall in CD4 is only delayed with regard to the increase in HIV.

  2. Resistance is not fully established at the early stages of virologic failure in treatments. Therefore, since the virus is still partially sensitive, a partial CD4 response can persist.

  3. The resistant virus has lost part of its replicative and pathogenic potential: "resistance-associative loss of fitness."

This study was designed to evaluate the role of protease inhibitor resistance and associated loss of viral fitness in patients with discordant CD4 and viral failure to PI therapy. Patients with high CD4 counts displaying a virologic failure with antiviral therapy including at least one PI were followed over a mean period of 20 months. Six patients with dual failure, that is a low CD4 and low viremia, were also studied. Combinant virus carrying gag NPR sequences from plasma virus were reconstructed by a rapid transfection method. A single cycle infectious titer was measured with several dilutions of virus and the slope of the resulting linear curve was calculated. In each patient, viral fitness was measured on sequential plasma samples obtained during the course of viral escape and expressed as a percentage of that parental pre-PI therapy virus.

The first graph primarily looked at the change in log of plasma HIV RNA over 20 months after starting protease inhibitor.

While initially there was up to a -3.5 log change, as time went on the orders of magnitude became significantly lower and at 20 months there was no patient with even a -1.0 log change observed. Similarly, calculations were made looking at the change in CD4 cells, as compared to months after a start of a PI therapy. In this graph, there was a sustained rise in T cell counts, ranging from below 100 to above 300 in 20 months. While there was some scatter along the slope of the graph, it was a fairly consistent grouping.

Next, the authors looked at viral fitness versus months after PI was started. While there was a significant scatter along the slope of this line, there was a clear decrease in viral fitness over time, ranging from somewhere above 100% at the start of therapy to a mean of about 40 at 18 months. Taking this fitness index, the authors looked at that number for each patient, as compared to HIV RNA copies. Here the slope was basically clad, showing no real correlation with fitness index with measurable HIV RNA copies. However, despite the stability in viral load, when looking at CD4 changes at three months as compared to the fitness index, there was a general trend downward, going from an average of 300 CD4 cells to an average just below 200 CD4 cells, demonstrating a discordance between the viral load which remained unchanged and the CD4 counts. The authors then analyzed the values to look at the PR mutations and found that fitness is correlated to the number of resistant mutations in PR sequences. They then looked at loss of fitness as a function of phenotypic resistance, measuring maximum PR resistance index against fitness index. This demonstrated as mutations were accumulated, and as there was increase in phenotypic resistance there was a loss of fitness. In other words, there was a cost to the virus exacted in developing phenotypic resistance, decreasing the virus' ability to survive.

The results are as follows. In all tests the patients' level of viral fitness decreased over time during the course of viral escape. No significant difference in viral fitness was observed between patients with discordant failure and patients with dual failure, with dual failure meaning a rise in viremia and decrease in CD4 count. A loss of viral fitness significantly correlates with the number of resistant mutations to protease inhibitors, or a loss of viral fitness significantly correlates with the level of phenotypic maximal resistance to protease inhibitors. There is no correlation between viral fitness and viral load. In discordant patients, the loss of viral fitness correlates with the change in CD4 counts, evaluated in three months following fitness measurement.

In the discussion, the authors posed several questions. Firstly, why does the loss of fitness increase the number of CD4 cells? The conjecture that the loss of viral fitness slows the rate of infection of CD4 cells. In addition, when virus fitness decreases, the rate of replenishment of the CD4 cell population can outpace the rate of reinfection. Why then does loss of fitness not decrease viremia? They conjecture that the viremia is a function of the number of infected cells and of virus output by infected cells. Virus output by infected cells is not affected by protease fitness. The increase in the number of CD4 cells eventually compensates for the decrease in the rate of their infection, and maintains a number of productively infected cells. Accordingly, current models predict that moderate loss of fitness should not reduce viremia. Why is viral fitness also low in dual failure patients? The authors hypothesize that, unlike in discordant cells, dual failure patients carry a defect in the replenishment rate of their CD4 cells, which is unresponsive to loss of viral fitness, thus invoking a multifactorial cause for this observation.

This particular poster generated tremendous interest as evidenced by crowds 4-5 deep encircling the board. All of us involved with treating HIV disease are familiar with this particular phenomenon, namely that there is discordance between CD4 counts and plasma viral RNA. Incorporation of this data, in terms of patient management and antiretroviral regimens, remains to be worked out. However, it is important to understand the mechanism that explains why we can see this unusual phenomenon; rising viremia with rising CD4 counts. The fact that this relates to the fitness of the virus again points to the effectiveness of antiretroviral therapy, even when it is not completely successful; and, the need for the development of other modalities to supplement HAART including more effective protease inhibitors, more effective reverse transcriptase inhibitors, and immunological means of manipulation. In heavily pre-treated patients, the implication would be that one should not jump ship just because one sees a lack of virologic response. A beneficial clinical response in terms of CD4 count may be more significant in this setting. Indeed, it may be a caution to not burn one's bridges by throwing in single or double agents that may be only remaining possibly effective agents, into an otherwise failing regimen. This of course remains a personal decision that has to be made in the considered partnership between the health provider and the patient.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Abstract: Viral Fitness in Patients with Discordant CD4 and Plasma HIV RNA following Protease Inhibitor Failure
Authored by: A. Faye, et al.

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