Genotype vs phenotype vs treatment history

One of the largest studies to date, the CERT study, randomised 450 individuals to change treatment on the basis of treatment history, genotypic or phenotypic testing. In the genotyping group, treatment selection based on algorithm was replaced by treatment selection based on Virtual Phenotype in 52 of 124 individuals. In 99 individuals with prior NNRTI experience, time to virologic failure was significantly longer in the phenotyping group when compared with the genotyping group and the treatment history group. In individuals who had taken at least four drugs prior to randomisation, both phenotyping and genotyping were associated with superior virological outcomes. 1

The difference between the two sub-groups may be explained by the greater accuracy of phenotyping in determining sensitivity to protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) in individuals with a greater degree of treatment experience.

Phenotypic testing was not found to be useful in the NARVAL study, first reported in 2000. This study examined a group of 541 individuals with an average viral load of about 20,000 copies/ml, and investigated the impact of changing treatment based on information from phenotypic or genotypic resistance tests or patient history. Results showed no added benefit from using the more sensitive phenotypic resistance test, and only a marginal benefit to switching treatment based on genotypic test results when compared to doctor assessment based on a patient's treatment history. The number of those who maintained undetectable viral load after six months was disappointing in all three groups: 29% in the genotypic testing group, compared with 22% in the phenotypic testing group and 17% in the control group. 2

Several explanations for the comparatively poor responses have been proposed:

  • Those in the control group were more likely to have received NRTIs they had not taken before when they were prescribed a new regimen. This may have been more significant than the total number of new drugs prescribed or the new protease inhibitor prescribed in determining outcome.
  • Those in the control group were more likely to have their drug dosage adjusted as a result of therapeutic drug monitoring.
  • Treatment switches in the control group were carried out on the basis of a full treatment history, which is often unavailable in the clinical setting.

These factors may have biased the outcome somewhat in favour of the control group, according to investigators.

The VIHRES study randomised 144 individuals who had experienced failure of at least two antiretroviral therapy regimens to undergo genotypic or phenotypic testing with a subsequent switch in therapy based on an expert panel's interpretation of this result. After 24 weeks, the proportions with viral load below 200 copies/ml did not differ between the two arms. 3

In summary, these studies indicate that selecting a regimen on the basis of resistance testing results in a greater viral load reduction after 16 weeks, but many people who receive a resistance test still fail to achieve undetectable viral load after switching a regimen, particularly if they have few remaining treatment options.

The ERA study found no additional benefit to performing a phenotypic test if genotypic data were already being used.4

References

  1. Wegner S et al. Long-term clinical efficacy of resistance testing: results of the CERT trial. Antiviral Therapy 7: S170, 2002
  2. Meynard JL et al. Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure. AIDS 16: 727-736, 2002
  3. Blanco JL et al. A prospective randomized study on the usefulness of genotypic resistance tests versus real phenotypic resistance tests in heavily pretreated patients with virological failure (VIHRES Study). 14th International AIDS Conference, Barcelona, abstract TuPeB4624, 2002
  4. Loveday C et al. A randomized controlled trial of phenotypic resistance testing in addition to genotypic resistance testing: the ERA trial. Antiviral Therapy 8 (suppl 1): S188, 2003
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