The Activity of the Integrase Inhibitor Dolutegravir Against HIV-1 Variants Isolated From Raltegravir-Treated Adults

*Infectious Diseases Therapy Area Unit, Medicines Discovery & Development, GlaxoSmithKline, Research Triangle Park, NC †Medicinal Research Laboratories, Shionogi & Co., Ltd, Osaka, Japan ‡Department of Epidemiology and Biostatistics. University of California, San Francisco, San Francisco, CA §Positive Health Program, Department of Medicine, San Francisco General Hospital, San Francisco, San Francisco, CA ‖Global Development, Shionogi & Co., Ltd, Osaka, Japan.
JAIDS Journal of Acquired Immune Deficiency Syndromes (Impact Factor: 4.56). 08/2012; 61(3):297-301. DOI: 10.1097/QAI.0b013e31826bfd02
Source: PubMed


: Dolutegravir (DTG, S/GSK1349572) is an integrase inhibitor with low nanomolar potency. Susceptibility to dolutegravir and raltegravir was determined for raltegravir-resistant clinical isolates.
: Genotypic and phenotypic susceptibility to integrase inhibitors was examined using 39 clinical isolate samples obtained from 18 adults who had exhibited incomplete viral suppression on a raltegravir-based regimen.
: Of 39 samples evaluated, 30 had genotypic and phenotypic resistance to raltegravir. All samples lacking raltegravir resistance retained complete susceptibility to dolutegravir. Of the 30 samples with genotypic evidence of raltegravir resistance, the median level of phenotypic resistance to raltegravir was high (median fold change in inhibitory concentration at 50%, >81; range, 3.7 to >87), while the level of resistance to dolutegravir was close to that of wild-type variants (median fold change, 1.5; range, 0.9-19.0). Longitudinal samples from 5 subjects collected during long-term failure of raltegravir revealed time-dependent general decreases in phenotypic susceptibility to raltegravir, with minimal changes in phenotypic susceptibility to dolutegravir. The median fold change to dolutegravir for isolates containing changes at G140S + Q148H, G140S + Q148R, T97A + Y143R, and N155H (thus including raltegravir signature resistance codons) were 3.75, 13.3, 1.05, and 1.37, respectively.
: Dolutegravir retained in vitro activity against clinical isolates obtained from subjects who failed raltegravir-based therapy at near wild-type levels for variants containing the Y143 and N155 resistance mutations. Isolates with Q148 plus additional integrase mutations possessed a broader range of and more reduced susceptibility to dolutegravir.

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    • "Dolutegravir (DTG) is an investigational integrase inhibitor (INI) for treatment of HIV infection which has demonstrated safety and efficacy in Phase 3 trials [1–3]. Its unique resistance profile supports its antiviral activity in patients who have previously failed treatment with the INI raltegravir [4]. "
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    ABSTRACT: Dolutegravir (DTG), an unboosted HIV integrase inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment on the PK of DTG. This was an open-label, single-dose study of oral DTG 50 mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] <30 mL/min; not on dialysis) and to healthy controls (CLcr >90 mL/min) matched for gender, age and body mass index (8 subjects per group). Serial PK samples were collected up to 72 h post-dose for determination of DTG and DTG-glucuronide (DTG-Gluc) concentrations in plasma. DTG unbound fraction in plasma was determined at 3 and 24 h. PK parameters were determined by non-compartmental methods and compared between groups by analysis of covariance. DTG was well tolerated with a low incidence of Grade 1 adverse events. DTG PK parameters showed significant overlap between groups. DTG mean exposure was lower in subjects with severe renal impairment compared to healthy, matched subjects: AUC(0-∞) and Cmax were 40 % and 23 % lower, while mean DTG-Gluc was increased. Renal impairment did not affect DTG fraction unbound in plasma. The modest reductions in mean PK exposures for DTG and increases for DTG-Gluc in the severe renal impairment group are not considered clinically significant. DTG does not require dose adjustment in patients with renal impairment.
    Preview · Article · Oct 2013 · European Journal of Clinical Pharmacology
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    • "Nanomolar concentrations of RAL, DTG and EVG efficiently inhibit the integration process [47,48]. We found that, although RAL, DTG and EVG in the micromolar range inhibit 3′-processing to different extents both in vitro and in the virological context, none of these compounds inhibit 3′-processing in infected cells at submicromolar concentrations that fully inhibit integration (e.g. "
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    ABSTRACT: HIV-1 DNA is found both integrated in the host chromosome and unintegrated in various forms: linear (DNAL) or circular (1-LTRc, 2-LTRc or products of auto-integration). Here, based on pre-established strategies, we extended and characterized in terms of sensitivity two methodologies for quantifying 1-LTRc and DNAL, respectively, the latter being able to discriminate between unprocessed or 3[prime]-processed DNA. Quantifying different types of viral DNA genome individually provides new information about the dynamics of all viral DNA forms and their interplay. For DNAL, we found that the 3[prime]-processing reaction was efficient during the early stage of the replication cycle. Moreover, strand-transfer inhibitors (Dolutegravir, Elvitegravir, Raltegravir) affected 3[prime]-processing differently. The comparisons of 2-LTRc accumulation mediated by either strand-transfer inhibitors or catalytic mutation of integrase indicate that 3[prime]-processing efficiency did not influence the total 2-LTRc accumulation although the nature of the LTR-LTR junction was qualitatively affected. Finally, a significant proportion of 1-LTRc was generated concomitantly with reverse transcription, although most of the 1-LTRc were produced in the nucleus. We describe the fate of viral DNA forms during HIV-1 infection. Our study reveals the interplay between various forms of the viral DNA genome, the distribution of which can be affected by mutations and by inhibitors of HIV-1 viral proteins. In the latter case, the quantification of 3[prime]-processed DNA in infected cells can be informative about the mechanisms of future integrase inhibitors directly in the cell context.
    Full-text · Article · Aug 2013 · Retrovirology
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    • "Patients showing N155H and Y143CR pathways did achieve successful suppression of the virus, but only a third of those with Q148H/K/R mutations had a sustained virologic response.62 These findings were supported by recent data demonstrating that dolutegravir has essentially wild-type levels of activity against N155H and T97A + Y143R mutants, whereas its susceptibility was diminished by isolates containing G140S + Q148H, and was further diminished by those carrying G140S + Q148R.50,63 "
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    ABSTRACT: The viral integrase enzyme has recently emerged as a primary alternative target to block HIV-1 replication, and integrase inhibitors are considered a pivotal new class of antiretroviral drugs. Dolutegravir is an investigational next-generation integrase inhibitor showing some novel and intriguing characteristics, ie, it has a favorable pharmacokinetic profile with a prolonged intracellular half-life, rendering feasible once-daily dosing without the need for ritonavir boosting and without regard to meals. Moreover, dolutegravir is primarily metabolized via uridine diphosphate glucuronosyltranferase 1A1, with a minor component of the cytochrome P450 3A4 isoform, thereby limiting drug-drug interactions. Furthermore, its metabolic profile enables coadministration with most of the other available antiretroviral agents without dose adjustment. Recent findings also demonstrate that dolutegravir has significant activity against HIV-1 isolates with resistance mutations associated with raltegravir and/or elvitegravir. The attributes of once-daily administration and the potential to treat integrase inhibitor-resistant viruses make dolutegravir an interesting and promising investigational drug. In this review, the main concerns about the efficacy and safety of dolutegravir as well as its resistance profile are explored by analysis of currently available data from preclinical and clinical studies.
    Full-text · Article · Feb 2013 · HIV/AIDS - Research and Palliative Care
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