Showing papers on "Dolutegravir published in 2012"

Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial

Abstract: Summary Background Dolutegravir (S/GSK1349572) is a new HIV-1 integrase inhibitor that has antiviral activity with once daily, unboosted dosing. SPRING-1 is an ongoing study designed to select a dose for phase 3 assessment. We present data from preplanned primary and interim analyses. Methods In a phase 2b, multicentre, dose-ranging study, treatment-naive adults were randomly assigned (1:1:1:1) to receive 10 mg, 25 mg, or 50 mg dolutegravir or 600 mg efavirenz. Dose but not drug allocation was masked. Randomisation was by a central integrated voice-response system according to a computer-generated code. Study drugs were given with either tenofovir plus emtricitabine or abacavir plus lamivudine. Our study was done at 34 sites in France, Germany, Italy, Russia, Spain, and the USA beginning on July 9, 2009. Eligible participants were seropositive for HIV-1, aged 18 years or older, and had plasma HIV RNA viral loads of at least 1000 copies per mL and CD4 counts of at least 200 cells per μL. Our primary endpoint was the proportion of participants with viral load of less than 50 copies per mL at week 16 and we present data to week 48. Analyses were done on the basis of allocation group and included all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00951015. Findings 205 patients were randomly allocated and received at least one dose of study drug: 53, 51, and 51 to receive 10 mg, 25 mg, and 50 mg dolutegravir, respectively, and 50 to receive efavirenz. Week 16 response rates to viral loads of at most 50 copies per mL were 93% (144 of 155 participants) for all doses of dolutegravir (with little difference between dose groups) and 60% (30 of 50) for efavirenz; week 48 response rates were 87% (139 of 155) for all doses of dolutegravir and 82% (41 of 50) for efavirenz. Response rates between nucleoside reverse transcriptase inhibitor subgroups were similar. We identified three virological failures in the dolutegravir groups and one in the efavirenz group—we did not identify any integrase inhibitor mutations. We did not identify any dose-related clinical or laboratory toxic effects, with more drug-related adverse events of moderate-or-higher intensity in the efavirenz group (20%) than the dolutegravir group (8%). We did not judge that any serious adverse events were related to dolutegravir. Interpretation Dolutegravir was effective when given once daily without a pharmacokinetic booster and was well tolerated at all assessed doses. Our findings support the assessment of once daily 50 mg dolutegravir in phase 3 trials. Funding Shionogi-GlaxoSmithKline Pharmaceuticals, LLC, now Shionogi-ViiV Healthcare, LLC.

Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

Abstract: Integrase (IN) strand transfer inhibitors (INSTIs) have been developed to inhibit the ability of HIV-1 integrase to irreversibly link the reverse-transcribed viral DNA to the host genome. INSTIs have proven their high efficiency in inhibiting viral replication in vitro and in patients. However, first-generation INSTIs have only a modest genetic barrier to resistance, allowing the virus to escape these powerful drugs through several resistance pathways. Second-generation INSTIs, such as dolutegravir (DTG, S/GSK1349572), have been reported to have a higher resistance barrier, and no novel drug resistance mutation has yet been described for this drug. Therefore, we performed in vitro selection experiments with DTG using viruses of subtypes B, C, and A/G and showed that the most common mutation to emerge was R263K. Further analysis by site-directed mutagenesis showed that R263K does confer low-level resistance to DTG and decreased integration in cell culture without altering reverse transcription. Biochemical cell-free assays performed with purified IN enzyme containing R263K confirmed the absence of major resistance against DTG and showed a slight decrease in 3' processing and strand transfer activities compared to the wild type. Structural modeling suggested and in vitro IN-DNA binding assays show that the R263K mutation affects IN-DNA interactions.

Effect of Food on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir

Abstract: Healthy subjects received dolutegravir at 50 mg in a single-dose crossover study while they were in the fasted state or with low-, moderate-, or high-fat meals. Food increased dolutegravir exposure and reduced the rate of absorption. The area under the concentration-time curve from 0 h to infinity (AUC(0-∞)) increased by 33%, 41%, and 66% when administered with low-, moderate-, or high-fat meals, respectively, compared with fasting. This increase in dolutegravir exposure is not anticipated to impact clinical safety, and therefore dolutegravir can be taken with or without food and without regard to fat content.

The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults.

Abstract: Background Dolutegravir (DTG, S/GSK1349572) is an integrase inhibitor with low nanomolar potency. Susceptibility to dolutegravir and raltegravir was determined for raltegravir-resistant clinical isolates.

Evolution of HIV integrase resistance mutations.

Abstract: Purpose of review Integrase strand transfer inhibitors (INSTIs) have become a key component of antiretroviral therapy since the approval of twice-daily raltegravir in 2007 and the more recent approval of elvitegravir in 2012. At the same time, a third compound, dolutegravir, is in late-phase clinical trials, being tested as part of a multidrug once-daily formulation comprising this INSTI and two other antiretroviral (ARV) drugs. This review focuses on the factors leading to the development of drug resistance mutations (DRMs) against INSTIs, evidence of cross-resistance among them, and the results of regimen simplification in regard to this topic. Recent findings Sequencing data show that DRMs are highly dynamic in patients failing INSTI therapy. Considerations of viral fitness and drug resistance can together determine the evolution of drug resistance mutations, and in this regard the Y143 and Q148 pathways are superior to the N155 pathway in the promotion of resistance. Preventing the emergence of DRMs requires that effective reverse transcriptase or other inhibitors be used together with INSTIs and that high-level adherence to treatment be maintained. Summary Because of the susceptibility to drug resistance, INSTIs should always be used together with other effective ARV drugs.

Novel therapeutic strategies targeting HIV integrase.

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.

C URRENT OPINION Emerging patterns and implications of HIV-1 integrase inhibitor resistance

Abstract: Purpose of review This review highlights recent data on the pathways of resistance that impact the clinical activity of firstgeneration and second-generation integrase inhibitors. Recent findings Raltegravir (RAL) and elvitegravir (EVG) are highly efficacious in first-line antiretroviral therapy, with small numbers of virological failures observed in clinical trials. Durable activity in treatment-experienced patients requires a fully supportive background regimen. RAL and EVG show a low-to-moderate genetic barrier to resistance and extensive cross-resistance, which preclude their sequential use. Resistance to dolutegravir

Dolutegravir for the treatment of HIV

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...

Once-daily single-tablet regimens: a long and winding road to excellence in antiretroviral treatment.

Abstract: Once-daily single-tablet regimens represent the paramount simplification of antiretroviral treatment achieved so far. They include drugs with favorable pharmacokinetics that allow once-daily administration, that do not need dose adjustments, have no additional toxicities, and do not require dissimilar intake conditions. Co-formulated efavirenz/tenofovir disoproxil fumarate/emtricitabine has been a gold standard of initial therapy since its approval in 2006. Galenic research and industry patent agreements may allow availability of single-tablet regimens with HIV-1 nonnucleoside reverse transcriptase inhibitors (efavirenz or rilpivirine), integrase inhibitors (cobicistat-boosted elvitegravir or dolutegravir), and protease inhibitors (cobicistat-boosted darunavir), combined with either tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine. The introduction of the new phamacoenhancer cobicistat as a potential substitution for ritonavir and the investigational agent GS-7340, with one-tenth the tenofovir mass, is a breakthrough in antiretroviral drug development. Many HIV-1-infected patients who are treatment-naive or treatment-experienced with susceptible virus will potentially have more options to reduce pill burden and optimize dosage schedules with one pill once-daily regimens.

Pharmacology of HIV integrase inhibitors.

Abstract: Purpose of reviewThe purpose of this study is to review recent and relevant pharmacology data for three HIV integrase inhibitors: raltegravir (marketed), dolutegravir, and elvitegravir (both in phase III drug development).Recent findingsData from January 2011 to April 2012 were evaluated. These data

Tolerability of HIV integrase inhibitors.

Abstract: PURPOSE OF REVIEW This review discusses the available safety data for three integrase strand transfer inhibitors (INSTIs)--raltegravir, elvitegravir and dolutegravir--derived from studies in both HIV-infected and HIV-uninfected cohorts. RECENT FINDINGS Phase 2 and 3 clinical trials show that all three INSTIs are well tolerated in treatment-naive and treatment-experienced patients with headache and gastrointestinal effects being the most commonly reported adverse events. Other nervous system (including neuropsychiatric) effects are often reported with INSTIs but are milder and less frequent than with efavirenz. Limited data suggest that effects upon lipid metabolism with raltegravir and dolutegravir are favourable compared with efavirenz and protease inhibitors, with more variable findings for elvitegravir because of coadministration with the boosting agent cobicistat. Cobicistat and dolutegravir have effects upon proximal renal tubular function causing mild-to-moderate creatinine elevation. Rare and severe events possibly related to INSTIs include systemic hypersensitivity reactions and rhabdomyolysis. SUMMARY INSTIs are an important recent addition to the antiretroviral armamentarium, with good short-term and medium-term safety. Long-term data from ongoing clinical studies are needed for a definitive assessment of their safety profile.

Development of an AlphaScreen-based HIV-1 integrase dimerization assay for discovery of novel allosteric inhibitors.

Abstract: In recent years, HIV-1 integrase (IN) has become an established target in the field of antiretroviral drug discovery. However, its sole clinically approved inhibitor, the integrase strand transfer inhibitor (INSTI) raltegravir, has a surprisingly low genetic barrier for resistance. Furthermore, the only two other integrase inhibitors currently in advanced clinical trials, elvitegravir and dolutegravir, share its mechanism of action and certain resistance pathways. To maintain a range of treatment options, drug discovery efforts are now turning toward allosteric IN inhibitors, which should be devoid of cross-resistance with INSTIs. As IN requires a precise and dynamic equilibrium between several oligomeric species for its activities, the modulation of this equilibrium presents an interesting allosteric target. We report on the development, characterization, and validation of an AlphaScreen-based assay for high-throughput screening for modulators of HIV-1 IN dimerization. Compounds identified as hits in thi...

Molecular dynamics approaches estimate the binding energy of HIV-1 integrase inhibitors and correlate with in vitro activity.

Abstract: The design of novel integrase (IN) inhibitors has been aided by recent crystal structures revealing the binding mode of these compounds with a full-length prototype foamy virus (PFV) IN and synthetic viral DNA ends. Earlier docking studies relied on incomplete structures and did not include the contribution of the viral DNA to inhibitor binding. Using the structure of PFV IN as the starting point, we generated a model of the corresponding HIV-1 complex and developed a molecular dynamics (MD)-based approach that correlates with the in vitro activities of novel compounds. Four well-characterized compounds (raltegravir, elvitegravir, MK-0536, and dolutegravir) were used as a training set, and the data for their in vitro activity against the Y143R, N155H, and G140S/Q148H mutants were used in addition to the wild-type (WT) IN data. Three additional compounds were docked into the IN-DNA complex model and subjected to MD simulations. All three gave interaction potentials within 1 standard deviation of values estimated from the training set, and the most active compound was identified. Additional MD analysis of the raltegravir- and dolutegravir-bound complexes gave internal and interaction energy values that closely match the experimental binding energy of a compound related to raltegravir that has similar activity. These approaches can be used to gain a deeper understanding of the interactions of the inhibitors with the HIV-1 intasome and to identify promising scaffolds for novel integrase inhibitors, in particular, compounds that retain activity against a range of drug-resistant mutants, making it possible to streamline synthesis and testing.

Treatment of HIV infection with once-daily regimens.

Abstract: Introduction: Treatment for HIV infection requires a lifetime antiretroviral therapy. In order to improve adherence, once daily (OD) is thus a preferred regimen. Areas covered: Evidence-based information and most recent guidelines recommendation, both from resource-rich and resource-limited settings, on antiretroviral regimens that can be administered OD will be reviewed. Sources of evidences were from the late clinical development studies (Phase III and II) published in Medline or major international conferences. Expert opinion: Nine OD US FDA-approved regimens and one new integrase inhibitor OD regimen have been shown to be efficient and well tolerated. For the fixed-dose single-tablet regimens (STRs), there are two currently approved regimens: Atripla® and Complera®. Another STR elvitegravir/cobicistat/emtricitabine/tenofovir (QUAD, Stribild®) is recently approved by the US FDA (August 20, 2012), whereas two additional SRTs, including abacavir/lamivudine/dolutegravir and darunavir/cobicistat/emtricitab...

Antiviral activity of dolutegravir in subjects with failure on an integrase inhibitor-based regimen: week 24 phase 3 results from VIKING-3

Abstract: Background : VIKING-3 aimed to examine efficacy and safety of dolutegravir (DTG) 50 mg twice daily in patients with resistance to multiple ARV classes, including integrase inhibitors (INI). Methods : RAL and/or EVG-resistant (current or historical) adult subjects with screening plasma HIV-1 RNA ≥500 c/mL and resistance to ≥2 other ART classes received open-label DTG 50 mg BID while continuing their failing regimen (without RAL/EVG). At Day 8 the background regimen was optimised and DTG continued. Activity of the optimized background regimen (OBR) was determined by Monogram Net Assessment. Primary endpoints were antiviral efficacy at Day 8 and Week 24. Results : 183 subjects enrolled, 124 with INI-resistance at screening and 59 with historical (but no screening) resistance. Population was advanced: at BL, median CD4 140, prior ART 13 yrs, 56% CDC Class C; 79% had >2 NRTI, 75% >1 NNRTI, and 70% >2 PI resistance-associated mutations, and 61% had non-R5 HIV detected. Of the 114 subjects who had the opportunity to complete 24 weeks on study before data cutoff, 72 (63%) had 2, respectively. Discontinuations due to adverse events were uncommon (6/183, 3%); the most common drug-related AEs were diarrhoea, nausea and headache, each reported in only 5% of subjects. Conclusion : A majority of the highly treatment-experienced subjects in VIKING-3 achieved suppression with DTG-based therapy. Responses were associated with Baseline IN genotype but not OSS, highlighting the importance and independence of DTG antiviral activity. DTG had a low rate of discontinuation due to adverse events at 50 mg BID in this advanced patient population. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Nichols G et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18112 http://www.jiasociety.org/index.php/jias/article/view/18112 | http://dx.doi.org/10.7448/IAS.15.6.18112

Amorphous form of dolutegravir

Abstract: The present invention provides an amorphous form of dolutegravir sodium, pharmaceutical compositions comprising same, methods for its preparation and use thereof as an antiretroviral agent.

The elvitegravir Quad pill: the first once-daily dual-target anti-HIV tablet

Abstract: Anti-HIV combination therapies in a single formulation currently target only HIV-1 reverse transcriptase via two different mechanisms of action by associating a nucleoside and a non-nucleoside reverse transcriptase inhibitor. These combination therapies are therefore referred to as multi-class combination products. The elvitegravir Quad pill (Gilead Sciences), when approved by the Food and Drug Administration for the treatment of HIV/AIDS, will become the first once-daily dual-target anti-HIV tablet. This “4 in 1” tablet targets HIV-1 integrase by elvitegravir boosted by the pharmaco-enhancer cobicistat and HIV-1 reverse transcriptase by the two nucleoside reverse transcriptase inhibitors emtricitabine + tenofovir disoproxil fumarate. A second pill referred to as the 572-Trii pill (Shionogi-ViiV Healthcare, LLC), also based on the dual inhibition of integrase and reverse transcriptase, is currently in late-phase clinical trials. The availability of these novel once-daily anti-HIV tablets will improve trea...

New and investigational antiretroviral drugs for HIV infection: mechanisms of action and early research findings.

Abstract: Numerous investigational antiretroviral agents are in clinical development. Among them are festinavir (BMS986001), a thymidine analogue similar to stavudine with reduced potential for toxicity; GS-7340, a prodrug of tenofovir that achieves greater intracellular concentrations; MK-1439, a nonnucleoside analogue reverse transcriptase inhibitor (NNRTI) that retains activity against common NNRTI-associated resistance mutations; and albuvirtide, a long-acting parenteral fusion inhibitor. Investigational integrase strand transfer inhibitors (InSTIs) include elvitegravir, recently approved by the US Food and Drug Administration (FDA) as part of a once-daily, single-tablet formulation with cobicistat/tenofovir/emtricitabine; dolutegravir, which maintains some activity against raltegravir- and elvitegravir-resistant mutants; and S/GSK1265744, which also maintains some activity against resistance mutations in the integrase gene and is being developed as a long-lasting parenteral agent. Novel 2-(quinolin-3-yl)acetic acid derivatives (LEDGINs), agents that were originally thought to inhibit the interaction of integrase with its cofactor lens epithelium-derived growth factor p75 (LEDGF/p75), be active against InSTI-resistant mutants and to have additive activity when combined with InSTIs. This article summarizes a presentation by Michael S. Saag, MD, at the IAS-USA live Improving the Management of HCV Disease continuing medical education program held in New York in October 2012.

Multiple choices for HIV therapy with integrase strand transfer inhibitors

Abstract: Two integrases inhibitors, raltegravir and elvitegravir, have now been approved by regulatory agencies for use in the treatment of HIV-infected patients; and the approval of a third such drug, dolutegravir, is expected during 2013 on the basis of several phase 3 clinical trials. The advent of this new class of antiretroviral (ARV) medications represents a major advance in the management of HIV infection, and each of these three drugs can be expected to continue to be an important component of ARV combination regimens.

Effect of a single supratherapeutic dose of dolutegravir on cardiac repolarization.

Abstract: Study Objective To assess the effect of a supratherapeutic dose of the integrase inhibitor dolutegravir on the QT and corrected QT (QTc) interval. Design Randomized, partial-blind, placebo-controlled, single-dose, 3-period, balanced crossover study. Setting Clinical research unit. Subjects Forty-two healthy subjects were randomized; of these subjects, 38 completed the study, three withdrew early because of protocol violations, and one was lost to follow-up. Intervention Subjects were randomized to receive three single doses of the following treatments: dolutegravir 250-mg suspension, moxifloxacin 400-mg tablet, and placebo suspension; each treatment was separated by a 14-day washout period. Treatment with the dolutegravir and placebo suspension was blinded, whereas treatment with moxifloxacin was open label. Measurements and Main Results The pharmacokinetic exposure at a supratherapeutic dose of dolutegravir 250 mg was 2–4 times higher than the pharmacokinetic exposure at clinically relevant dosages (50 mg once or twice/day). The upper limit of the 90% confidence interval (CI) for the placebo-adjusted mean change from baseline of the QTc interval (ΔΔQTcF) using Fridericia's formula was less than 10 msec at all time points. The sensitivity of the study to detect modest increases in QT interval was established with moxifloxacin, a positive control for QT-interval prolongation. The maximum ΔΔQTcF values for dolutegravir and moxifloxacin were observed at 4 hours: 1.99 msec (90% CI −0.55–4.53 msec) and 9.58 msec (90% CI 7.05–12.11 msec), respectively. Conclusion This pharmacokinetic-pharmacodynamic model demonstrates no relationship between dolutegravir plasma concentration and ΔΔQTcF. Furthermore, a supratherapeutic dose of dolutegravir was generally well tolerated without any serious or severe adverse events. As such, dolutegravir does not affect cardiac repolarization.

Genetic Barrier to the Development of Resistance to Integrase Inhibitors in HIV-1 Subtypes CRF01_AE and B

Abstract: Objective: The genetic barrier for the evolution of integrase inhibitors (INIs) including raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) resistance

The use of HIV-1 integrase inhibitors in antiretroviral naive patients.

Abstract: PURPOSE OF REVIEW: In this review we will discuss recent findings on the use of inhibitors of the HIV-1 integrase enzyme for the treatment of antiretroviral naive patients. We will also discuss differences between integrase inhibitors, and comment on the use of this class of drugs in the future. RECENT FINDINGS: Raltegravir when taken twice daily is as effective and well tolerated as efavirenz. Once daily dosing of raltegravir is virologically inferior to raltegravir taken twice daily. A novel nucleoside-free regimen of raltegravir in combination with a once daily ritonavir-boosted protease inhibitor did not produce adequate viral suppression, although raltegravir with a twice daily protease inhibitor yielded better results. Subset analyses have demonstrated a favorable impact of raltegravir on lipid levels and body fat composition. Two once daily integrase inhibitors not yet Food and Drug Administration-approved, elvitegravir and dolutegravir, have completed phase-2 testing and are also virologically noninferior to efavirenz. SUMMARY: Integrase inhibitors provide potent antiretroviral activity, little short-term toxicity and excellent tolerability. For patients with preexisting atherosclerosis or cardiac risk factors this class of therapy is a logical preferred treatment choice. Raltegravir is a preferred option for those in whom therapy for hepatitis C virus infection is anticipated.

Selection in culture of HIV resistance to dolutegravir by mutations at integrase positions R263K and H51Y that diminish viral replication fitness

Abstract: Purpose of the study : We selected for resistance in tissue culture against dolutegravir (DTG), a second-generation HIV integrase strand transfer inhibitor, which is now in phase 2/3 clinical trials, in order to try to characterize the resistance profile of this compound. Methods : HIV-1 of different subtypes was grown in both MT-2 cells and peripheral blood mononuclear cells over protracted periods, with the concentration of DTG being incrementally increased from an initial concentration of 0.05 nM, i.e. 4 times less than the EC 50 . After a total of 6 months of growth, a final drug concentration of 50-100 nM was achieved, beyond which virus could no longer be grown. Viral DNA was then sequenced to reveal the presence of mutations that might confer resistance to DTG. The biological relevance of these mutations was confirmed through site-directed mutagenesis experiments in which individual mutations or combinations of mutations were studied in comparison with wild-type (wt) virus in tissue culture and with recombinant HIV integrase enzyme in biochemical assays. Summary of results : The most common integrase resistance mutation to arise in subtype B and recombinant A/G viruses was R263K followed by H51Y. In the case of subtype C viruses, the most common mutation was G118R followed by H51Y. The presence of R263K alone conferred an approximate 3-6-fold level of resistance to DTG in culture, a 30% drop in levels of recombinant integrase strand transfer activity, as well as an approximate 20-30% loss in viral replicative capacity. Biochemical experiments indicated that the t ½ residency times of DTG for subtype B and C viruses for wt integrase were 26 h and 38 h, respectively, and for R263K, 16h and 22h, respectively. In contrast, H51Y by itself did not significantly affect either strand transfer activity or resistance to DTG. However, the combination of R263K together with H51Y led to an increase in levels of DTG resistance to about 15-fold accompanied by an ~50% loss in both viral replication capacity and integrase strand transfer activity. Conclusions : R263K and H51Y can combine to augment levels of resistance to DTG yet result in a more severe attenuation of viral replication capacity and integrase strand transfer activity than R263K alone. These data suggest that viruses containing both mutations may be at a severe replicative disadvantage and help to explain why primary resistance to DTG is so rare to arise in clinical studies performed to date. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Mesplede T et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18113 http://www.jiasociety.org/index.php/jias/article/view/18113 | http://dx.doi.org/10.7448/IAS.15.6.18113

Combinational therapies for HIV: a focus on EVG/COBI/FTC/TDF.

Abstract: Introduction: The co-formulation of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) is a new, investigational, once-daily (q.d.) drug, currently undergoing Phase II and III clinical trials. Next to the nucleotide/nucleoside reverse transcriptase inhibitors FTC and TDF, it contains EVG, the second member of the HIV-1 integrase strand transfer inhibitor class, together with its pharmacokinetic booster COBI. Areas covered: In this article, the authors review EVG/COBI/FTC/TDF, in addition to discussing the single-tablet regimens (STRs) containing EFV/FTC/TDF or RPV/FTC/TDF, and the investigational combination pill containing dolutegravir, lamivudine and abacavir (DTG/3TC/ABC, 572-Trii pill). A Medline review was conducted of Phase II and III trials, as well as a review of abstracts from major HIV and infectious disease conferences from 2010 to 2012, involving EVG/COBI/FTC/TDF. Expert opinion: Next to the combination of EFV/FTC/TDF or RPV/FTC/TDF, the co-formulation of EV...

Dolutegravir treatment response by baseline viral load and NRTI backbone in treatment-naïve HIV-infected individuals

Abstract: Background : In two 48-week studies in naive subjects, dolutegravir with NRTI of choice has shown non-inferiority to raltegravir and, with ABC/3TC, superiority to Atripla. Factors that influenced choice of NRTIs included viral load, resistance and safety. Methods : We analysed response rates and time to virologic failure by NRTI backbone and baseline viral load in the pivotal DTG-naive studies. SPRING-2 randomized participants to DTG 50 mg QD or RAL 400 mg BID, each in combination with investigator-selected NRTIs (TDF/FTC or ABC/3TC). SINGLE randomised participants to DTG 50 mg + ABC/3TC QD or TDF/FTC/EFV (Atripla) QD. In SPRING-2, changes in serum creatinine were examined by INI and NRTI backbone. Results : The two studies randomized and treated 1655 subjects, of whom 249 (15%) were female, 388 (23%) non-white, 495 (30%) had HIV-1 RNA >100,000 c/ml, and 224 (14%) had CD4+ count <200 cells/mm 3 . Primary analyses demonstrated non-inferiority of DTG to RAL in SPRING-2 (Δ=2.5%; 95% CI: -2.2% to +7.1%, excluding -10%), and superiority of the DTG regimen in SINGLE (7.4%; +2.5% to +12.3%). In SPRING-2, response rates by NRTI backbone were comparable in each viral load stratum. In SINGLE, a 7% difference in response (favoring DTG + ABC/3TC) was observed in each viral load stratum. Exploratory analyses examining time-to-virologic failure showed no difference in response rates between the NRTIs irrespective of baseline viral load or study. Resistance to INIs or NRTIs was not demonstrated in any subject on DTG-based therapy through 48 weeks. Withdrawals due to AEs on DTG-based regimen were few (2%) in both studies. In SPRING-2, no significant differences were observed in serum creatinine change from baseline to Week 48 by NRTI backbones. Conclusions :In SPRING-2 and SINGLE, DTG was effective with both ABC/3TC and TDF/FTC, and in subjects with high and low viral load. DTG was well tolerated in both studies. Renal safety also was similar by NRTI backbone. DTG is a once-daily, unboosted INI that can be used with either TDF/FTC or ABC/3TC backbone in treatment-naive, HIV-infected individuals. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Eron Jr J et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18264 http://www.jiasociety.org/index.php/jias/article/view/18264 | http://dx.doi.org/10.7448/IAS.15.6.18264

Trial watch: HIV integrase inhibitor-based regimen beats market leader.

Abstract: Shionogi-ViiV Healthcare has announced positive results from the Phase III SINGLE trial of their investigational HIV integrase inhibitor, dolutegravir, in treatment-naive adults with HIV-1. The dolutegravir-based regimen demonstrated superiority over the most widely prescribed HIV combination therapy, Atripla (Gilead/BMS).