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The Impact of Genotypic Antiretroviral Resistance Testing (GART) in Patients Failing Antiretroviral Therapy: CPCRA 046 (The GART Study)
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written by Michelle E. Roland, M.D.
published on HIVresistanceWeb: April 1, 1999
As genotypic antiretroviral resistance assays move from research laboratories into the clinic, it is important that clinicians, patients and policy makers understand both the potential clinical utility and the limitations of resistance testing. Many questions remain about the clinical impact of specific mutations, interactions between various combinations of mutations, and the relationship between genotypic mutations and phenotypic resistance assay results. The Genotypic Antiretroviral Resistance Testing (GART) study conducted by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and by the Walter Reed Army Medical Center was designed to ask a very basic clinical question: In patients failing antiretroviral therapy, does the availability of genotypic resistance test results combined with expert interpretation and advice regarding the choice of salvage antiretroviral regimens result in superior HIV-1 RNA suppression compared with standard clinical care?
The GART study was a randomized, multicenter trial in patients with viral load rebound (three-fold increase in HIV-1 RNA) after > 16 weeks of triple drug therapy. Randomization to the GART arm involved genotyping of the reverse transcriptase (RT) and protease genes by sequencing plasma HIV-1 isolates to detect drug resistance mutations. The results were reviewed by the protocol virologist in conjunction with the subject's antiretroviral treatment history, and one or more potential treatment regimens were suggested to the clinician. The standard of care/No-GART group also underwent genotyping. "Suggested regimens" were recorded, but the assay results and treatment suggestions were not released to the clinicians. The clinicians in both groups recorded their proposed regimens at baseline, but drugs were not changed until the GART reports were available. CD4 counts and HIV-1 RNA levels were determined at 4, 8 and 12 weeks after randomization. The primary end-point of the study was the change in plasma HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels. Secondary analyses evaluated the impact of the prescribed vs recommended treatment regimen, and the number of active drugs added, on HIV-1 RNA levels.
The preliminary results of this study were presented by Dr. Douglas Mayers in a late-breaker session at the 6th Conference on Retroviruses and Opportunistic Infections in Chicago (31 January-4 February 1999). A total of 153 subjects were randomized: 78 to the GART group and 75 to the No-GART group. The mean baseline CD4 count was 230 cells/mm3. The median HIV-1 RNA level at baseline was 28,085 copies/mL. The proportion of subjects who had taken only a single PI was slightly but not significantly higher in the GART group (53%) compared to the No-GART group (44%). The two groups were otherwise well matched in terms of baseline treatment regimens, with 44% using AZT and 3TC, 40% using d4T and 3TC, 54% using indinavir, 33% using nelfinavir, 7% using ritonavir and 6% using saquinavir.
The GART group had statistically superior HIV-1 RNA reductions at 4, 8 and 12 weeks compared to the No-GART group (see Figure 1). The average RNA decrease at 4 and 8 weeks was -1.17 log10 copies/mL in the GART group and -0.62 log10 copies/mL in the No-GART group (P = 0.0001). The difference in viral load reduction between groups was still significant at 12 weeks (P=0.02), but both groups showed an increase in HIV-1 RNA levels compared to weeks 4 and 8. The percentages of patients with HIV RNA levels below 500 copies/mL (bDNA) at 4, 8, and 12 weeks were 45% versus 23% (P = 0.005), 51% versus 25% (P = 0.001), and 29% versus 17% (P = 0.15) for the GART versus No-GART groups, respectively (see Figure 2).
Figure 1. Mean HIV RNA Levels by Study Week.
Figure 2. Percent of Patients with Undetectable HIV RNA Levels by Study Week.
For all patients, regardless of treatment group, the number of active drugs prescribed was associated with the magnitude of change in HIV-1 RNA levels from baseline. For both groups combined, the log10 HIV RNA change was -0.10 for patients given one or fewer active drugs, -0.58 for those given 2 active drugs, -1.02 for those given 3 active drugs, and -1.25 for those given 4 or more active drugs (see Figure 3).
Figure 3. HIV RNA Changes by Number of Active Drugs Prescribed.
During his oral presentation, Dr. Mayers attributed the larger reduction in HIV-1 RNA at 4, 8, and 12 weeks in the GART group to the larger number of active drugs prescribed in that group. He also explained that the subgroup of individuals in the GART arm for whom a regimen recommended by the study virologists was prescribed (54%) had a superior virologic response compared to the subgroup who were prescribed a regimen differing from that or those recommended, and suggested that the GART group may have had an even better virologic response had more subjects received a suggested regimen.
Final publication of these results is pending and many important questions about this study are likely to be addressed in the final report. However, the preliminary analysis suggests that the availability of GART and expert interpretation of the test results, in conjunction with the subject's clinical history, enabled the clinician to select an antiretroviral treatment regimen containing more active drugs than he or she may have been able to select without GART. It is important to recognize that the expert advice may have played a significant role in optimizing the clinical utility of the genotypic resistance assay. Finally, this study only followed virologic response for 12 weeks, and it is possible that the differences seen may not be sustained beyond this time frame.
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