Phenotypic resistance testing improves response to therapy: final analysis of VIRA3001

16 July 2000. Related: Conference reports, Drug resistance, Intl Drug Resistance Workshop 4 Sitges 2000.

VIRA3001 is an open-label, randomised, multicentre study evaluating the clinical benefit of prospective phenotypic resistance testing (PRT). Virologic response to a treatment switch guided by PRT versus no access to resistance testing was compared in subjects who failed to maintain virologic suppression on their first PI-containing regimen.

A total of 273 subjects with plasma HIV RNA >2,000 copies/mL were randomised to treatment guided by the results of PRT (Virco Antivirogram™ assay) or to clinician choice without the results of resistance testing and followed for 16 weeks.

Calvin Cohen of the Community Research Initiative presented the final analysis of this trial at the Resistance Workshop [1]. Significant differences in numbers of NRTIs, PIs and total antiretrovirals to which virus was still sensitive (<4-fold resistance) were observed between the arms. Similarly, significantly greater numbers of NRTIs with reduced susceptibility (>4-fold resistance) were used in the non-PRT arm than in the PRT arm.

Table 1

	PRT	No PRT	p value
Median no. of drugs initiated	3.4	3.4
>= 2 active NRTI initiated	63%	40%	<0.001
>= 1 active PI initiated	60%	47%	0.059
>= 2 active NNRTI initiated	38%	49%	0.108
>= 2 active all classes	92%	77%	0.003

(active = < 4-fold resistance)

There was a statistically significant difference in virological response at week 16 between the two arms. Various analyses revealed the following – see Table 2. The presenter concluded that therapy choice guided by PRT appears to be associated with improved virological outcome in this patient population. PRT had affected the physicians choice of antiretrovirals with a significantly greater number of ‘active’ drugs used in the PRT arm. This was despite the increased use of NNRTIs in the non-PRT arm in this mostly NNRTI-naive population (33% less use of NNRTIs in the PRT arm.

Access to resistance testing does not affect virological response in heavily treatment experienced patients: The NARVAL trial.

Table 2

		Phenotypic testing	No phenotypic testing	p value
Median decrease in VL (log copies/mL)	ITT Observed LOCF	-1.23	-0.87	0.004
Median decrease in VL (log copies/mL)	ITT Observed LOCF	-0.89	-0.52	0.026
% <400 copies/mL	ITT observed – ITT (M=F)	59%	42%	0.033
% <400 copies/mL	ITT observed – ITT (M=F)	41%	32%	0.132

NARVAL is a prospective randomised trial of phenotypic and genotypic resistance testing versus no access to resistance testing for guiding the choice of antiretroviral regimen in heavily pre-treated patients.

Data were presented at this meeting by Pierre Marie Girard of the H™pital Rothschild, Paris [2]. A total of 541 patients were enrolled and virological response by trial arm analysed at week 12 (the primary endpoint). A week 24 evaluation was also available for 427 patients with a full year of follow-up planned. It should be cautioned, however, that interpretation after week 12 is complex as subjects who were not <200 copies/mL in the history only arm were able to access resistance testing at this time-point.

At study entry 82% of participants had received at least four nucleoside analogues, 67% were failing on their second PI-based regimen, and 26% had prior treatment with more than two protease inhibitors. Median CD4 count for all subjects was 280 cells/mm3. In addition to resistance testing drug level monitoring for PIs and NNRTIs was performed across all arms.

At 12 weeks there was no difference in the numbers of patients in each arm who had achieved an HIV RNA level <200 copies/mL (41% genotyping, 33% phenotyping, 34% treatment history only, p=0.249). Week 24 results on 427 subjects again showed no difference between the arms in numbers <200 copies/mL. The only detectable difference between the groups was found in those who were below 200 copies/mL at both week 12 and week 24, 29% had received genotyping while only 17% were in the treatment history only group (p=0.008). Phenotyping did not confer this advantage in maintained undetectability.

An analysis of antiretroviral drug utilisation across the study arms revealed that the treatment history only group received more drugs to which they were na•ve than either of the resistance testing arms. There was a much higher tendency to recycle drugs if resistance testing was available with drugs only being changed if resistance was detected. Differences across the arms were also apparent for the institution of dosage adjustment based on the results from therapeutic drug monitoring (TDM). 8% of the phenotypic and 7% of the genotypic testing groups had dosages adjusted compared to 16% of the treatment history only group. It is unclear why these differences based on TDM occurred.

The primary end-point of this trial clearly reveals no benefit for resistance testing in opposition to results from other studies. Possible reasons for this are discussed below (see comments box).

Comment

The results of the NARVAL study have been controversial as they initially seem to contradict results from other prospective studies of resistance testing. However heavily pre-treated patients may be expected to benefit less from resistance testing as there will be limited choices anyway. There was also a tendency for resistance testing to push prescribers towards selection of ddI and d4T due to resistance being less frequently detected and phenotype tending to show low levels of fold change in sensitivity.

Resistance testing therefore encouraged recycling of these drugs which may not be appropriate in this patient population. We do not know if resistance testing in this trial had any benefit for toxicity management, quality of life, or drug costs. These may be an issue in salvage situations where testing may help keep clearly non-contributory drugs from being used.

Finally, virological response rates were similar across the arms despite less new drugs being used in the resistance testing groups. This would seem to indicate that ‘a more economical’ use of drugs was able to achieve similar levels of virologic response when resistance testing was available.

References:

Cohen C, Kessler H, Hunt S et al. Phenotypic resistance testing significantly improves response to therapy: final analysis of a randomised trial (VIRA3001). 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 84.
Meynard JL, Vray M, Morand-Joubert L et al. Impact of treatment guided by phenotypic or genotypic resistance on the response to antiretroviral therapy: a randomised trial (NARVAL, ANRS 088). 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 84.