Prevalence of resistance mutations related to integrase inhibitor S/GSK1349572 in HIV-1 subtype B raltegravir-naive and -treated patients
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.
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[Show abstract] [Hide abstract] ABSTRACT: This review focuses on the topic of HIV integrase inhibitors that are potent antiretroviral drugs that efficiently decrease viral load in patients. However, emergence of resistance mutations against this new class of drugs represents a threat to their long-term efficacy. Here, we provide new information about the most recent mutations identified and other mutations that confer resistance to several integrase inhibitors, such as new resistance mutations-for example, G118R, R263K, and S153Y-that have been identified through in vitro selection studies with second-generation integrase strand transfer inhibitors (INSTIs). These add to the three main resistance pathways involving mutations at positions Y143, N155, and Q148. Deep sequencing, structural modeling, and biochemical analyses are methods that currently help in the understanding of the mechanisms of resistance conferred by these mutations. Although the new resistance mutations appear to confer only low levels of cross-resistance to second-generation drugs, the Q148 pathway with numerous secondary mutations has the potential to significantly decrease susceptibility to all drugs of the INSTI family of compounds.0Comments 20Citations
- "In contrast, the presence of Q148HKR mutations did lead to further mutations and >100 FC for DTG susceptibility relative to wild type in subtype B viruses [123, 125]. Interestingly, Q148HKR mutations did not affect susceptibility to DTG in HIV-1 subtype C and HIV-2 isolates [125, 134, 135]. An ongoing trial termed SPRING-2 will evaluate the use of once-daily DTG versus twice-daily RAL in treatment-naïve patients. "
[Show abstract] [Hide abstract] ABSTRACT: Integration of the viral genome into host cell chromatin is a pivotal and unique step in the replication cycle of retroviruses, including HIV. Inhibiting HIV replication by specifically blocking the viral integrase enzyme that mediates this step is an obvious and attractive therapeutic strategy. After concerted efforts, the first viable integrase inhibitors were developed in the early 2000s, ultimately leading to the clinical licensure of the first integrase strand transfer inhibitor, raltegravir. Similarly structured compounds and derivative second generation integrase strand transfer inhibitors, such as elvitegravir and dolutegravir, are now in various stages of clinical development. Furthermore, other mechanisms aimed at the inhibition of viral integration are being explored in numerous preclinical studies, which include inhibition of 3' processing and chromatin targeting. The development of new clinically useful compounds will be aided by the characterization of the retroviral intasome crystal structure. This review considers the history of the clinical development of HIV integrase inhibitors, the development of antiviral drug resistance and the need for new antiviral compounds.0Comments 42Citations
- "In contrast, the presence of Q148HRK mutations did lead to further mutations and > 100 FC for DTG susceptibility relative to wild-type in subtype B viruses [63,65]. Interestingly, Q148HRK mutations did not affect susceptibility to DTG in HIV-1 subtype C and HIV-2 isolates [65,75,76]. An ongoing trial termed SPRING-2 will evaluate the use of once-daily DTG versus twice-daily RAL in treatment-naïve patients. "
- [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.0Comments 24Citations
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