A French study of the impact of changing treatment based on information from phenotypic or genotypic resistance tests has shown 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 guesswork based on a patient's treatment history.
The NARVAL study, conducted by France's Agence Nationale de Recherche sur le SIDA (ANRS), randomised 541 individuals to change their therapy on the basis of either genotypic test results, phenotypic test results or treatment history (the control group). People were eligible to join the study if their viral load was above 1,000 copies on existing treatment, but participants in NARVAL had an average viral load of 4.3 log (just short of 20,000 copies). Eighty-two per cent had received at least four nucleoside analogues when they entered the study, 67% were currently experiencing the failure of their second PI-based regimen, and 26% had received more than two protease inhibitors. In effect, this group of patients could be classified as eligible for `salvage therapy'.
Patients were randomised on the basis of baseline viral load and prior treatment experience:
- Patients with viral load below 5,000 copies
- Patients with viral load greater than 5,000 copies with no prior experience of abacavir, any NNRTI, and amprenavir, OR ritonavir/saquinavir
- Patients with viral load greater than 5,000 copies with prior experience of at least one of the drugs listed above.
The study evaluated the impact of resistance test information by looking at the response to treatment after three months on a new regimen, and at the proportion of participants who experienced a viral load fall of greater than 1 log after three months.
After three months follow-up, there was no significant difference in response between those who had switched on the basis of resistance test results and those who switched on the basis of treatment history. Between 30% and 41% of patients across the three arms had viral load below 200 copies at this point, and between 51% and 59% had experienced a viral load fall of greater than 1 log.
Disappointing results at six months in all arms
However, in the 427 patients who had completed six months of a new treatment regimen, switches based on genotypic test results had been significantly more successful than switches based on the phenotypic resistance test or on treatment history. However, 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.
The investigators have put forward a number of explanations for the comparatively poor responses:
- Those in the control group were more likely to receive nucleoside analogues they had not taken before when they were prescribed a new regimen, and this was 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. Sixteen per cent of the control group had dosage adjustments or changes in treatment as a result of monitoring, compared with 8% of the phenotypic group and 7% of the genotypic group.
These factors may have biased the outcome somewhat in favour of the control group, according to investigators.
At a press conference called to release the results, ANRS director Dr. Michel Kazatchkine questioned whether resistance testing provides sufficient additional benefit to justify its widespread use. However, study co-ordinator Dr. Pierre-Marie Girard noted that in the NARVAL study, treatment switches in the control group were carried out on the basis of a full treatment history, and where such information is unavailable, resistance testing may be an important tool despite the disappointing results of this particular study.
Should we be surprised by these results?
"Broadly speaking, the results of this study aren't out of line with the results of Viradapt, GART or VIRA 3001 in terms of the proportions with undetectable viral load" said Dr Graeme Moyle, Associate Director of Research at the Chelsea and Westminster Hospital in London. "In a way it doesn't surprise me that the results of phenotypic testing may be less good, because we know that minor changes in the protease gene and minor NNRTI-related polymorphisms can reduce drug sensitivity."
He warned that the apparent failure of resistance testing should not be blamed for the poor viral load responses in this study. "You have to have new drugs to give third line therapy!", he said. "I think that the level of cross-resistance between nucleoside analogues is often under-appreciated. While it may be adequate to give three drugs as first line therapy, it may be necessary to give four as second line therapy and five or even six as third line therapy in order to overcome this problem".
Further data will be available at the Sitges International Workshop on HIV Drug Resistance in June, and at ICAAC in September, and the study will continue to follow patients for a further six months to assess the longer-term impact of resistance test-driven treatment switches.