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      Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection.

      The New England journal of medicine

      Young Adult, RNA, Viral, Middle Aged, Male, therapeutic use, adverse effects, Lamivudine, Humans, Heterocyclic Compounds, 3-Ring, genetics, HIV-1, drug therapy, HIV Infections, Female, Drug Therapy, Combination, Double-Blind Method, Dideoxynucleosides, Anti-Retroviral Agents, Aged, 80 and over, Aged, Adult, blood

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          Abstract

          Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen. We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily (DTG-ABC-3TC group) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily (EFV-TDF-FTC group). The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance. A total of 833 participants received at least one dose of study drug. At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (88% vs. 81%, P=0.003), thus meeting the criterion for superiority. The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group (28 vs. 84 days, P<0.001), as well as greater increases in CD4+ T-cell count (267 vs. 208 per cubic millimeter, P<0.001). The proportion of participants who discontinued therapy owing to adverse events was lower in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (2% vs. 10%); rash and neuropsychiatric events (including abnormal dreams, anxiety, dizziness, and somnolence) were significantly more common in the EFV-TDF-FTC group, whereas insomnia was reported more frequently in the DTG-ABC-3TC group. No participants in the DTG-ABC-3TC group had detectable antiviral resistance; one tenofovir DF-associated mutation and four efavirenz-associated mutations were detected in participants with virologic failure in the EFV-TDF-FTC group. Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine. (Funded by ViiV Healthcare; SINGLE ClinicalTrials.gov number, NCT01263015 .).

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          Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study.

          Dolutegravir (S/GSK1349572) is a once-daily HIV integrase inhibitor with potent antiviral activity and a favourable safety profile. We compared dolutegravir with HIV integrase inhibitor raltegravir, as initial treatment for adults with HIV-1. SPRING-2 is a 96 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began on Oct 19, 2010, at 100 sites in Canada, USA, Australia, and Europe. Treatment-naive adults (aged ≥ 18 years) with HIV-1 infection and HIV-1 RNA concentrations of 1000 copies per mL or greater were randomly assigned (1:1) via a computer-generated randomisation sequence to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily). Study drugs were given with coformulated tenofovir/emtricitabine or abacavir/lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤ 100,000 copies per mL or >100,000 copies per mL) and nucleoside reverse transcriptase inhibitor backbone. Investigators were not masked to HIV-1 RNA results before randomisation. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies per mL at 48 weeks, with a 10% non-inferiority margin. Main secondary endpoints were changes from baseline in CD4 cell counts, incidence and severity of adverse events, changes in laboratory parameters, and genotypic or phenotypic evidence of resistance. Our primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01227824. 411 patients were randomly allocated to receive dolutegravir and 411 to receive raltegravir and received at least one dose of study drug. At 48 weeks, 361 (88%) patients in the dolutegravir group achieved an HIV-1 RNA value of less than 50 copies per mL compared with 351 (85%) in the raltegravir group (adjusted difference 2·5%; 95% CI -2·2 to 7·1). Adverse events were similar between treatment groups. The most common events were nausea (59 [14%] patients in the dolutegravir group vs 53 [13%] in the raltegravir group), headache (51 [12%] vs 48 [12%]), nasopharyngitis (46 [11%] vs 48 [12%]), and diarrhoea (47 [11%] in each group). Few patients had drug-related serious adverse events (three [<1%] vs five [1%]), and few had adverse events leading to discontinuation (ten [2%] vs seven [2%] in each group). CD4 cell counts increased from baseline to week 48 in both treatment groups by a median of 230 cells per μL. Rates of graded laboratory toxic effects were similar. We noted no evidence of treatment-emergent resistance in patients with virological failure on dolutegravir, whereas of the patients with virologic failure who received raltegravir, one (6%) had integrase treatment-emergent resistance and four (21%) had nucleoside reverse transcriptase inhibitors treatment-emergent resistance. The non-inferior efficacy and similar safety profile of dolutegravir compared with raltegravir means that if approved, combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients. ViiV Healthcare. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks.

            The integrase inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) in a single tablet given once daily. We compared the efficacy and safety of EVG/COBI/FTC/TDF with standard of care-co-formulated efavirenz (EFV)/FTC/TDF-as initial treatment for HIV infection. In this phase 3 trial, treatment-naive patients from outpatient clinics in North America were randomly assigned by computer-generated allocation sequence with a block size of four in a 1:1 ratio to receive EVG/COBI/FTC/TDF or EFV/FTC/TDF, once daily, plus matching placebo. Patients and study staff involved in giving study treatment, assessing outcomes, and collecting and analysing data were masked to treatment allocation. Eligibility criteria included screening HIV RNA concentration of 5000 copies per mL or more, and susceptibility to efavirenz, emtricitabine, and tenofovir. The primary endpoint was HIV RNA concentration of fewer than 50 copies per mL at week 48. The study is registered with ClinicalTrials.gov, number NCT01095796. 700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF, 352 with EFV/FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF; 305/348 (87·6%) versus 296/352 (84·1%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 3·6%, 95% CI -1·6% to 8·8%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF (72/348 vs 48/352) and dizziness (23/348 vs 86/352), abnormal dreams (53/348 vs 95/352), insomnia (30/348 vs 49/352), and rash (22/348 vs 43/352) were less common. Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 μmol/L, IQR 5 to 20 vs 1 μmol/L, -6 to 8; p<0·001). If regulatory approval is given, EVG/COBI/FTC/TDF would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection. Gilead Sciences. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial.

               Hans Jaeger,  ,  Clare Brennan (2013)
              In the primary analysis of SPRING-2 at week 48, dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment. We present the 96 week results. SPRING-2 is an ongoing phase 3, randomised, double-blind, active-controlled, non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19, 2010. We present results for the safety cutoff date of Jan 30, 2013. Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more. Patients were randomly assigned (1:1) to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily), plus investigator-selected tenofovir-emtricitabine or abacavir-lamivudine. Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL, CD4 cell count changes from baseline, safety, tolerability, and genotypic or phenotypic resistance. We used an intention-to-treat exposed population (received at least one dose of study drug) for the analyses. Sponsor staff were masked to treatment assignment until primary analysis at week 48; investigators, site staff, and patients were masked until week 96. Of 1035 patients screened, 827 were randomly assigned to study group, and 822 received at least one dose of the study drug (411 patients in each group). At week 96, 332 (81%) of 411 patients in the dolutegravir group and 314 (76%) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 4∙5%, 95% CI -1∙1% to 10∙0%) confirming non-inferiority. Secondary analyses of efficacy such as per protocol (HIV RNA <50 copies per mL: 83% for dolutegravir and 80% for raltegravir) and treatment-related discontinuation equals failure (93% without failure for dolutegravir; 91% for raltegravir) supported non-inferiority. Virological non-response occurred less frequently in the dolutegravir group (22 [5%] patients for dolutegravir vs 43 [10%] patients for raltegravir). Median increases in CD4 cell count from baseline were similar between groups (276 cells per μL for dolutegravir and 264 cells per μL for raltegravir). Ten patients (2%) in each group discontinued because of adverse events, with few such events between weeks 48 and 96 (zero in the dolutegravir group and one in the raltegravir group). No study-related serious adverse events occurred between week 48 and week 96. At virological failure, no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir. At week 96, once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive, patients with HIV-1. Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Journal
                10.1056/NEJMoa1215541
                24195548

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