Article

Prevalence of resistance mutations related to integrase inhibitor S/GSK1349572 in HIV-1 subtype B raltegravir-naive and -treated patients

Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Paris 06, INSERM U943, Paris, France.
Journal of Antimicrobial Chemotherapy (Impact Factor: 5.44). 07/2011; 66(7):1481-3. DOI: 10.1093/jac/dkr152
Source: PubMed

ABSTRACT To compare the frequency of previously in vitro-selected integrase mutations (T124A, T124A/S153F, S153Y, T124A/S153Y and L101I/T124A/S153Y) conferring resistance to S/GSK1349572 between HIV-1 subtype B integrase inhibitor (INI)-naive and raltegravir-treated patients.
Integrase sequences from 650 INI-naive patients and 84 raltegravir-treated patients were analysed.
The T124A mutation alone and the combination T124A/L101I were more frequent in raltegravir-failing patients than in INI-naive patients (39.3% versus 24.5%, respectively, P = 0.005 for T124A and 20.2% versus 10.0%, respectively, P = 0.008 for T124A/L101I). The S153Y/F mutations were not detected in any integrase sequence (except for S153F alone, only detected in one INI-naive patient).
T124A and T124A/L101I, more frequent in raltegravir-treated patients, could have some effect on raltegravir response and their presence could play a role in the selection of other mutations conferring S/GSK1349572 resistance. The impact of raltegravir-mediated changes such as these on the virological response to S/GSK1349572 should be studied further.

Download full-text

Full-text

Available from: Slim Fourati, Oct 01, 2014
1 Follower
 · 
247 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Changing antiretroviral regimens and the introduction of new antiretroviral drugs have altered drug resistance patterns in human immunodeficiency virus type 1 (HIV-1). This review summarizes recent information on antiretroviral drug resistance. As tenofovir and abacavir have replaced zidovudine and stavudine in antiretroviral regimens, thymidine analog resistance mutations have become less common in patients failing antiretroviral therapy in developed countries. Similarly, the near universal use of ritonavir-boosted protease inhibitors (PI) in place of unboosted PIs has made the selection of PI resistance mutations uncommon in patients failing a first-line or second-line PI regimen. The challenge of treating patients with multidrug-resistant HIV-1 has largely been addressed by the advent of newer PIs, second-generation non-nucleoside reverse transcriptase inhibitors and drugs in novel classes, including integrase inhibitors and CCR5 antagonists. Resistance to these newer agents can emerge, however, resulting in the appearance of novel drug resistance mutations in the HIV-1 polymerase, integrase and envelope genes. New drugs make possible the effective treatment of multidrug-resistant HIV-1, but the activity of these drugs may be limited by the appearance of novel drug resistance mutations.
    12/2011; 1(6):582-9. DOI:10.1016/j.coviro.2011.10.020
  • [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION: Development of new antiretroviral drugs which are highly potent, tolerable over the long term and with a high genetic barrier to resistance is essential for the treatment of a chronic viral disease that requires life-long therapy with near-perfect medication adherence. Integrase inhibitors (INI) are a new class of antiretroviral drugs that block the action of HIV integrase, which catalyses several key steps in the virus life cycle which are essential for insertion of the viral genome into the DNA of host cell. AREAS COVERED: Dolutegravir (DTG), a second-generation INI currently in the late stage of clinical development, is an effective orally available drug with a long half-life that does not need to be pharmacologically enhanced, is effective as a once daily drug in the absence of INI resistance mutations and twice daily in presence of INI resistance mutations. EXPERT OPINION: DTG, as other drugs in the INI class, appears safe and well tolerated. Results from ongoing large Phase III studies will bring more generalizable and robust information on the long-term effects of DTG.
    Expert Opinion on Investigational Drugs 03/2012; 21(4):523-30. DOI:10.1517/13543784.2012.661713 · 5.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The genetic barrier for the evolution of integrase inhibitors (INIs) including raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) resistance was compared between HIV-1 subtypes CRF01_AE and B. Analysis of 66 substitutions associated with INI resistance at 41 amino acid positions in 144 nucleotide sequences (109 HIV-1 subtype CRF01_AE and 35 HIV-1 subtype B) of integrase-coding region of polymerase gene derived from INI-naive patients. 28/41 studied amino acid positions were conserved, leading to a similar genetic barrier between the two subtypes. At six codon positions with different genetic barriers, six mutations (V72I, L101I, A124T, T125K, and G140C/S) displayed a higher genetic barrier and one mutation (V201I) showed a lower genetic barrier in subtype CRF01_AE than subtype B. Most studied amino acid positions including all corresponding to RAL and EVG primary mutations show a high level of conservation, indicating the same genetic barrier between subtypes CRF01_AE and B. Nevertheless, different genetic barriers were observed in two mutations described to be associated with DTG resistance (L101I, A124T) and other five RAL and EVG secondary mutations (V72I, T125K, G140C/S, V201I), which could have an impact on the development of resistance to RAL, EVG, and DTG.
    Intervirology 03/2012; 55(4):287-95. DOI:10.1159/000336658 · 1.77 Impact Factor
Show more