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Is there a role for etravirine in patients with Nonnucleoside reverse
transcriptase inhibitor resistance?
[RESEARCH LETTERS]
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AIDS:Volume 22(8)11 May 2008p 989-990
Scott, C; Grover, D; Nelson, M
St. Stephens Centre, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
Abstract
Etravirine is a next generation nonnucleoside reverse transcriptase inhibitor with activity against nonnucleoside reverse transcriptase inhibitor resistant HIV-1 virus. Susceptibility and virological response to etravirine is dependent on the type and number of nonnucleoside reverse transcriptase inhibitor resistance-associated mutations. We examined the predicted susceptibility of etravirine in patients experiencing virological failure secondary to nonnucleoside reverse transcriptase inhibitor resistance in our patient cohort.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in highly active antiretroviral therapy (HAART) and are recommended for use in treatment-naive HIV-1-infected patients [1]. NNRTI containing regimens have been shown to be highly efficacious in terms of potency and virological suppression [2]. A major limitation of the currently available NNRTIs is their low genetic barrier to resistance [3]. Virological failure on an efavirenz (EFV) or nevirapine (NVP)-containing regimen can result in single mutations in the reverse transcriptase gene leading to the development of high level and cross resistance to the nonnucleoside class [3].
Etravirine (ETV) is a next generation NNRTI that demonstrates activity against NNRTI resistant HIV-1 virus [4,5]. Susceptibility and virological response to ETV is dependent on the type and number of NNRTI resistance-associated mutations (RAMs) [4,5]. Patients may sequence to an ETV-containing antiretroviral regimen following NNRTI resistance if they have ETV susceptible HIV-1.
The DUET trials were large randomized double-blinded placebo controlled studies in highly treatment experienced HIV-1 infected patients [4,5]. Patients had to have at least more than one NNRTI mutation along with a minimum of four primary protease mutations before being randomized to either ETV or placebo along with an optimized background regimen. There was a trend for virological response to decrease with increasing number of NNRTI RAMs. The response rate at week 24 in the subgroup with at least three NNRTI RAMs was 52.8% and substantially greater than in the placebo group. Thirteen reverse transcriptase mutations were identified as ETV RAMs, as they affected the virological response in the ETV group. We examined the susceptibility of ETV in patients experiencing virological failure secondary to NNRTI resistance.
All patients experiencing virological failure with NNRTI resistance when taking an NNRTI-based regimen were identified from the Chelsea and Westminster Hospital HIV-1 phenotypic resistance database; a central repository of HIV resistance tests results from patients within the cohort (antivirogram/vircoTYPEHIV-1). Virological failure was defined as plasma HIV-1 RNA more than 50 copies/ml on one occasion. Data on NNRTI used in HAART at the time of failure and the number and type of NNRTI mutations were collected and retrospectively analysed.
Resistance to EFV, NVP and ETV was defined using IAS-USA 2007 drug resistance mutations [6].
The following were defined as NNRTI RAMs: V90I, A98G, L10OI, K103E/N/P, V106A/I/M, V108I, V179D/F, Y181C/I/V, Y188C/L/H, G190A/S and P225H.
ETV RAMs were defined as V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V and G190A/S.
The predicted susceptibility to ETV was defined as the acquisition of two or less ETV RAMs following NNRTI failure [4,5]. Using this definition, we calculated the percentage of patients who were predicted to have ETV susceptibility. A chi-square analysis was used to evaluate any difference between ETV susceptibility and mutation acquisition following individual NNRTI exposure.
A total of 743 patients were identified with NNRTI resistance following previous exposure to an NNRTI-containing antiretroviral regimen. Of these, 352 patients (47%) had been treated with an EFV-containing regimen and 391 patients (53%) on a regimen containing NVP. Following NNRTI exposure in this cohort, the frequency of NNRTI RAMs acquired was as follows: one mutation, 39.0%, two mutations, 31.6%, three mutations, 19.5%, four mutations, 6.9%, five or more mutations, 3.0%.
The most frequently occurring NNRTI RAMs after NNRTI exposure were K103N (55.9%) and Y181C (29.2%). K103N (66.5%), Y181C (17%) and V108I (16.8%) were most frequently seen after EFV failure. K103N (46.5%), Y181C (40.5%) and G190A (27.6%) were most frequently seen after NVP failure.
Of the 743 patients with NNRTI resistance, the prevalence of ETV-associated RAMs was as follows: zero mutations, 26.9%, one mutation, 42.8%, two mutations, 19.8%, three or more mutations, 10.5%, range: 0-6 mutations. 89.5% of patients in the Chelsea and Westminster cohort with NNRTI resistance were predicted to be susceptible to ETV. V90I, Y181C and G190A were the most prevalent ETV RAMs seen after failure on either EFV or NVP [Fig. 1].
Of the 352 patients failing on an EFV-containing regimen, the prevalence of ETV associated RAMs was found to be as follows: zero mutation, 32.4%, one mutation, 41.5%, two mutations, 16.8%, three or more mutations, 9.4%. The median number of ETV RAMs acquired following EFV exposure was one (range 0-5). 90.6% of patients with EFV resistance in the Chelsea and Westminster cohort predicted to be susceptible to ETV. For 391 patients failing on a NVP-containing regimen, the prevalence of ETV-associated RAMs was found to be as follows: zero mutation, 22.0%, one mutation, 44.0%, two mutations, 22.5%, three or more mutations, 11.5%. The median number of ETV RAMS following NVP exposure was one (range 0-6). 88.5% patients in cohort with NVP resistance predicted to be susceptible to ETV.
Using a chi-square test to compare the number of ETV RAMs acquired following NNRTI exposure, no significant statistical difference was found between patients failing EFV or NVP-containing regimens and the prevalence of more than two ETV RAMs (P = 0.408). Similarly when comparing ETV RAM acquisition following EFV and NVP treatment, significantly more patients failed with zero ETV RAMs on an EFV-containing regimen than on a NVP-containing regimen (P = 0.002).
Next generation NNRTIs, including ETV, will play an important future role in sequencing in HIV-1-infected patients who have acquired NNRTI resistant virus. Data from the cohort suggests that predicted susceptibility to ETV is not affected by previous NNRTI choice as no significant difference was shown between the acquisition of more than two ETV RAMs in patients following treatment with EFV-containing HAART or NVP-containing HAART. From this retrospective analysis of data in our cohort, we predict that the majority of patients will have ETV sensitivity after acquisition of NNRTI resistance following treatment with EFV or NVP.
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