Understanding etravirine susceptibility: new weighted genotype score and phenotypic cut-offs

30 August 2008. Related: Conference reports, Drug resistance, Intl Drug Resistance Workshop 17 Sitges 2008.

Simon Collins, HIV i-Base

Although etravirine (ETR) was approved in the US in January 2008, [1] the indication to not rely on ETR with only two new RTIs, and its interaction profile with other ARVs, have limited its use, other than with darunavir as in the DUET registrational studies.

The workshop included several studies addressing both genotypic and phenotypic resistance, that will hopefully help interpret a patients susceptibility to this new NNRTI.

Johan Vingerhoets and colleagues from Tibotec presented a new and updated weighted list of mutations associated with reduced virological response from the DUET studies.

Until now, presence of three or more mutations from the 13 key mutations V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S, indicated likely high-level resistance. This year, four additional mutations were added to this list: K101H, E138A, V179T and M230L. Virologic responses still decreased with increasing numbers of mutations, with 77%, 61%, 56% and 38% patients achieving <50 copies/mL in the presence of 0, 1, 2 and >3 of mutations respectively.

However, V179F, G190S and Y181V had the greatest impact with only approximately 12%, 20% and 32% of patients with only one of each these single mutations achieving <50 copies/mL, indicating the importance of developing a weighting score.

Relative weighting was determined using random forest and linear model techniques, applied to matched phenotypic/genotypic samples and a panel of recombinant isolates. A multivariate analysis adjusted for baseline viral load, darunavir fold-change (FC) and NRTI sensitivity.

A new weighted score of 0-2, 2.5-3.5 and >4 corresponded to 74%, 52% and 38% virological response rates. This significantly improved the correction between genotype score and etravirine phenotypic sensitivity, especially at lower scores, shown in Table 1.

Table 1: Genotypic weighting scores and associated phenotypic sensitivity to etravirine

Phenotypic sensitivity cut-offs for etravirine were evaluated by Monika Peeters and colleagues from Tibotec who looked at samples from almost 600 patients from the DUET studies to determine clinical cut-offs for the Virco Antivirogram phenotypic assay. Excluding patients who discontinued before week 24 or who used T-20 as a new drug, this left 403 patient samples for this analysis which looked at a continuum of responses. [3]

Baseline etravirine EC50 was a significant predictor of response at week 24 and data mining techniques set a lower cut-off a < 3.0 fold change. However, the data set could not establish an upper cut-off with > -1.0 log reductions seen at 13 fold changes, leading the researchers to call this ‘intermediate’ rather than an ‘upper cut-off. At baseline, 67%, 18% and 15% of patients had etravirine fold-changes of < 3, 3-13 and >13 fold; with 71%, 50% and 37% of patients in the same groups respectively, achieving viral suppression <50 copies/mL at week 24.

Eoin Coakley presented the results from the Monogram clinical cut-offs for etravirine, derived from evaluating week 2, 4, 8 and 24 viral responses from the DUET studies in relation to baseline fold change in 200 samples from patients not starting new T-20. Although they arrived at a similar lower clinical cut-off of 2.9, they failed to report an upper cut-off due to a limited number of sample with higher phenotypic resistance.

They reported that from their analysis of the DUET data, median etravirine fold change at baseline was 0.75 (range 0.06-200), with a third of sample showing hypersensitivity (<0.04 FC).

Lee Batchelor and colleagues from Virco, classified phenotype responses as maximal (MA), reduced (RR) or minimal (Min) for the VircoTYPE vitual phenotype, using clinical cut-offs of 1.6, 5.0 and 27.6 fold change for IC50 (associated respectively with 20%, 50% and 80% losses of predicted wild-type response). [5]

In a subset of routine clinical samples from the Virco database, the percentage associated with MA, RR or Min was 73%, 24% and 2.4% respectively, with 38% of samples having at least one NNRTI-associated mutation. When just looking at this subset of NNRTI-resistant samples, 48%, 46% and 6% had etravirine values classified as MA, RR or Min.

The percentage of patients achieving <50 copies/mL by fold change in the DUET studies were found to be 69% (FC<1.6), 59% (FC 1.6-<5.0), 49% (FC 5.0-27.6) and 44% (FC >27.6).

Comment

Workshop organiser John Mellors commenting on the new etravirine data emphasised that clinicians just want an easy way to know whether a drug will work, and collaboration between research groups would help his situation as an expert responsible for interpreting these results.

Several clinicians at the meeting, including Jonathan Shapiro found the upper cut-off levels unconvincing as an aid for clinical decisions.

In the UK, where phenotype tests are used less frequently, the new genotypic weighed score analysis will be of most relevance.

References:

1. See HIV Treatment Bulletin, Jan/Feb 2008.
   http://www.i-base.info/htb/v9/htb9-1-2/Etravirine.html
2. Vingerhoets J et al. An update on the list of NNRTI mutations associated with decreased viralogical response to etravirine: multivariate analysis on the pooled DUET-1 and DUET-2 clinical trial data. XVII IHDRW 2008, Sitges. Abstract 24.
3. Peeters M et al. Determination of phenotypic clinical cut-offs for etravirine: pooled week 24 results of the DUET-1 and DUET-2 trials. XVII IHDRW 2008, Sitges. Abstract 121.
4. Coakley E et al. Biological and clinical cut-off analyses for etravirine
5. Bacheler L et al. Exploring etrivirine resistance among recent routine clinical samples submitted for resistance testing. XVII IHDRW 2008, Sitges. Abstract 110.