icon-    folder.gif   Conference Reports for NATAP  
  17th CROI
Conference on Retroviruses
and Opportunistic Infections
San Francisco CA
February 16-19, 2010
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Resistance Associated Mutations to Etravirine (TMC-125) in Antiretroviral Naïve Patients infected with non-B HIV-1 subtypes
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Reported by Jules Levin
CROI Feb 16-19 2010 SF
1 Almoustapha Issiaka Maïga, 2 Diane Descamps, 1 Laurence Morand-Joubert, 3 Mamadou Cisse, 4 Andre Capt, 1 Christine Katlama, 1 Dominique Costagliola, 5 Bernard Masquelier,1 Vincent Calvez and 1 Anne-Genevieve Marcelin 1 INSERM U943, Pitie-Salpetriere Hospital, Paris, France; 2 Bichat-Claude Bernard Hospital, Paris, France; 3 CESAC, Bamako, Mali; 4 Virco, Belgium; 5 CHU Bordeaux, France.
Non-B HIV-1 subtypes in naïve patients exhibit some naturally-occurring ETR RAMs (some of them considered as medium-impact ETR RAMs). The overall prevalence was 10% and this had a limited impact on ETR susceptibility.
Only 3 cases were associated with phenotypic resistance to ETR and in 2/3 cases this was in a context of Y181C transmitted drug resistance. Our results also show that V179I mutation could have an impact on ETR FC only in combination with some specific mutations such as E138A and that the concomitant presence of Y181C and H221Y, which is not considered as an ETR RAM, dramatically increases ETR FC suggesting that the role of H221Y, alone and in combination, on ETR resistance should be further investigated.
Background: Susceptibility to etravirine (ETR), a second generation non-nucleoside reverse transcriptase inhibitor (NNRTI), is dependent on the type and number of NNRTI resistance-associated mutations (RAMs). Studies have shown that some HIV-1 subtypes may have natural polymorphisms described as ETR RAMs. This study addresses the prevalence of ETR RAMs in treatment-naïve patients infected with HIV-1 non-B subtypes and its potential impact on ETR susceptibility.
Methods: The prevalence of ETR RAMs was studied in 726 antiretroviral naïve patients infected with non-B HIV-1 subtypes. ETR genotypic resistance was interpreted according to ANRS and Stanford algorithms. NNRTIs phenotypic susceptibility of samples with at least one ETR RAMs was measured. Phenotypic tests were done with a phenotypic assay (Antivirogram, VIRCO BVBA, Mechelen, Belgium). Fold changes (FC) in IC50 cut-off for normal susceptible range were 6.0, 3.3 and 3.2 for nevirapine, efavirenz and ETR, respectively.
Results: 75/726 (10.3%) of the sequences harbored at least one ETR RAM: 71 (9.8%) patients had one ETR RAM and 4 (0.5%) had two ETR RAMs (V90I+Y181C, E138A+V179E and V90I+A98G in 2 cases). None of the viruses had three or more ETR RAMs and consequently classified as resistant to ETR. All sequences with 2 ETR RAMs belong to CRF02_AG. The presence of one ETR RAM was statistically more frequent in CRF02_AG than in other non-B subtypes (p = 0.004). Among the strains harbouring at least one ETR RAM, 3 were phenotypically resistant to ETR: 1 with 2 ETR RAMs and 2 with 1 ETR RAM associated to another NNRTI resistance mutation. Indeed, these new mutations profiles showed decreased ETR phenotypic susceptibility E138A+V179I (FC = 5.2), Y181C+H221Y (FC = 11.1) and V90I+Y181C (FC = 3.3) were identified.
Conclusions: Although the prevalence of ETR RAMs in treatment-naïve patients infected with non-B HIV-1 subtypes was 10%, this had in most of cases no significant impact on ETR susceptibility. However, the transmission of drug resistant viruses with Y181C in a non-B genetic background has a potential impact on ETR susceptibility. In addition, our results suggest that mutations V179I and H221Y should be considered as ETR RAMs.
Some studies have shown that non-B subtypes may have natural polymorphisms described as etravirine (ETR) Resistance Associated Mutations (RAMs). Although ETR previously showed comparable activities against different group M subtypes (AtoH), including several CRFs, the testing was done with few strains, and few data concerning the impact of the HIV-1 subtype on the virologica response to ETR are currently available.
The aim of this study was to evaluate the prevalence of ETR RAMs in a large panel of patients infected by various non-BHIV-1 subtypes and who never received antiretroviral treatment, and to study the ETR phenotypic susceptibility of their strains.
Patients and methods
Patients: HIV-1 seropositive individuals infected with non B subtype were eligible for this study if they had never been exposed to antiretroviral drugs before the time of sampling. Briefly, samples were collected at time of HIV diagnosis or before the start of antiretroviral treatment. In total, 726 patients were included from the following centers (no. of patients): CESAC, Centre d'Ecoute, de Soins, d'Animation et de Conseils in Bamako, Mali (163); Nianankoro Fomba Hospital in Segou, Mali (118); Pitie-Salpetriere Hospital in Paris, France (192), Bichat Claude-Bernard Hospital in Paris, France (182); and Saint-Antoine Hospital in Paris, France (71). For each patient a single HIV-1 sequence was included.
Virological methods:
RT sequences were determined by bulk sequencing. We studied the prevalence of ETR RAMs according to the latest international AIDS Society (IAS)-USA panel list (www.iasusa.org, last update in December 2008): V90I, A98G, L100I, K101E, K101H, K101P, V106I, E138A, V179D, V179F, V179T, Y181C, Y181I, Y181V, G190A, G190S, and M230L. In case of presence of ETR RAMs, resistance genotypic tests were interpreted according to the last version of Agence Nationale de Recherches sur le SIDA(ANRS) (www.hivfrenchresistance.org) and Stanford algorithms (http://www.hivfrenchresistance.org/;http://hivdb6.stanford.edu/asi/deployed/hiv_central.pl?program=hivalg&action=showSequenceForm). Samples with at least one ETR RAMs were tested for phenotypic susceptibility to nevirapine (NVP), efavirenz (EFV) and ETR. Phenotypic tests were done with a commercial phenotypic assay (Antivirogram, VIRCO BVBA, Mechelen, Belgium). Fold changes (FC) in IC50 cut-off for normal susceptible range were 6.0, 3.3 and 3.2 for NVP, EFV and ETR, respectively. The definitions for resistance are those as defined by Virco: below these values samples were considered within normal susceptible range and above these values, samples were considered above normal susceptible range or resistant.

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