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Pharmacokinetics, safety, and tolerability of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg were assessed in this phase 1, single‐arm, open‐label, single‐dose study in fasted healthy male (n = 4) and female (n = 8) participants of Japanese heritage. Participants received a single dose of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg after an 8‐hour fast, with safety assessments and blood samples for pharmacokinetic parameters collected through 72 hours after dosing. Geometric mean maximum plasma concentrations were 5.22 μg/mL (time to maximum concentration [tmax], 1.01 hours) for abacavir, 4.13 μg/mL (tmax, 3.50 hours) for dolutegravir, and 3.35 μg/mL (tmax, 2.98 hours) for lamivudine. Geometric mean area under the concentration‐time curve values were 18.20, 71.60, and 16.60 μg • h/mL for abacavir, dolutegravir, and lamivudine, respectively. No adverse events were reported, and no clinically significant findings were observed in laboratory values, physical examinations, or 12‐lead electrocardiographic parameters. Single‐tablet administration of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg was well tolerated in Japanese participants. Exposure to abacavir and lamivudine was comparable with that seen in previous studies. A modest increase in exposure to dolutegravir vs previous clinical studies was observed but is not expected to impact the clinical management of HIV‐1 or increase the risk for adverse events.

At week 48 in the phase IIIb DAWNING study, the integrase strand transfer inhibitor (INSTI) dolutegravir plus 2 nucleoside reverse transcriptase inhibitors demonstrated superiority to ritonavir-boosted lopinavir in achieving virologic suppression in adults with HIV-1 who failed first-line therapy. Here, we report emergent HIV-1 drug resistance and mechanistic underpinnings among dolutegravir-treated adults in DAWNING. Population viral genotyping, phenotyping, and clonal analyses were performed on participants meeting confirmed virologic withdrawal (CVW) criteria on dolutegravir-containing regimens. Dolutegravir binding to and structural changes in HIV-1 integrase-DNA complexes with INSTI resistance-associated substitutions were evaluated. Of participants who received dolutegravir through week 48 plus an additional 110 weeks for this assessment, 6 met CVW criteria with treatment-emergent INSTI resistance-associated substitutions and 1 had R263R/K at baseline but not at CVW. All 7 achieved HIV-1 RNA levels of 10-fold and reduced viral replication capacity versus baseline levels. This study demonstrates that the pathway to dolutegravir resistance is a challenging balance between HIV-1 phenotypic change and associated loss of viral fitness. (This study has been registered at ClinicalTrials.gov under identifier NCT02227238.)

Doubts exist regarding optimal second-line treatment options for HIV-1-infected patients in resource-limited settings. We assessed safety and efficacy of dolutegravir compared with ritonavir-boosted lopinavir, plus two nucleoside reverse transcriptase inhibitors (NRTIs) in adults in whom previous first-line antiretroviral therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two NRTIs has failed.DAWNING is a phase 3b, open-label, parallel-group, non-inferiority, active-controlled trial done at 58 sites in 13 countries. Eligible adults were aged at least 18 years and, during at least 6 months of treatment with a first-line treatment containing an NNRTI and two NRTIs, had virological failure (confirmed HIV-1 RNA ≥400 copies per mL). Participants were randomly assigned by a central randomisation system to receive oral dolutegravir (50 mg once daily) or ritonavir-boosted lopinavir (800 mg lopinavir plus 200 mg ritonavir once daily or 400 mg plus 100 mg twice daily), plus two investigator-selected NRTIs (at least one fully active based on resistance testing at screening). The primary outcome was the proportion of participants achieving viral suppression (defined as plasma HIV-1 RNA50 copies per mL) at week 48 using the snapshot algorithm and a non-inferiority margin of -12%. The primary analysis was done in an intention-to-treat-exposed (ITT-E) population of participants who received at least one dose of study medication, according to original group assignment. Safety was analysed in all participants who received at least one dose of study drug, according to which drug was received. The study was registered at ClinicalTrials.gov, number NCT02227238, and viiv-studyregister.com, number 200304.Between Dec 11, 2014, and June 27, 2016, 968 adults were screened and 627 were randomly assigned to the dolutegravir group (n=312) or the ritonavir-boosted lopinavir group (n=315). Three patients in the ritonavir-boosted lopinavir group did not receive study medication and so 624 were included in the ITT-E population. At week 48, 261 (84%) of 312 participants in the dolutegravir group achieved viral suppression compared with 219 (70%) of 312 in the ritonavir-boosted lopinavir group (adjusted difference 13·8%; 95% CI 7·3-20·3). Non-inferiority was achieved on the basis of the 95% CI of the adjusted treatment difference having a lower bound greater than -12% (prespecified non-inferiority margin). Because the lower bound of the 95% CI is greater than zero (7·3%), superiority of dolutegravir was also concluded (p0·0001). The safety profile for dolutegravir was favourable compared with that of ritonavir-boosted lopinavir. More grade 2-4 drug-related adverse events occurred with ritonavir-boosted lopinavir than dolutegravir (44 [14%] of 310 with ritonavir-boosted lopinavir vs 11 [4%] of 314 with dolutegravir), mainly driven by gastrointestinal disorders.When administered with two NRTIs, dolutegravir was superior to ritonavir-boosted lopinavir at 48 weeks and can be considered a suitable option for second-line treatment.ViiV Healthcare.

Background In the DAWNING study, dolutegravir + 2 nucleoside reverse transcriptase inhibitors (NRTIs) demonstrated superior efficacy at Week 48 and a favourable safety profile compared with lopinavir/ritonavir + 2 NRTIs in adults with HIV-1 failing first-line therapy of a non-nucleoside reverse transcriptase inhibitor + 2 NRTIs. Methods Participants at 58 centres in 13 countries were randomised (1:1) to 52 weeks of open-label treatment with dolutegravir or lopinavir/ritonavir combined with 2 investigator-selected NRTIs, including at least one fully active NRTI based on screening resistance testing. The primary endpoint was the proportion of participants achieving HIV-1 RNA Results Of 624 participants randomised and treated, 499 (80%) received Conclusions Response rates were high in participants receiving dolutegravir + 2 NRTIs as second-line treatment regardless of pre-existing resistance to one of the NRTIs, including in participants using lamivudine or emtricitabine in the presence of M184V/I.

Background Some observational studies and randomized controlled trials (RCTs) have suggested an association between abacavir (ABC) use and myocardial infarction (MI), whereas others have not. Methods This pooled analysis of 66 phase II–IV RCTs estimates exposure-adjusted incidence rates (IRs) and relative rates (RRs) of MI and cardiovascular events (CVEs) in participants receiving ABC- and non-ABC-containing combination antiretroviral therapy (cART). The primary analysis of MI included ABC-randomized trials with ≥48-week follow-up. Sensitivity analyses of MI and CVEs included non-ABC-randomized and Results In 66 clinical trials, 13 119 adults (75% male, aged 18–85 years) were on ABC-containing cART and 7350 were not. Exposure-adjusted IR for MI was 1.5 per 1000 person-years (PY; 95% confidence interval [CI], 0.67–3.34) in the ABC-exposed group and 2.18 per 1000 PY (95% CI, 1.09–4.40) in the unexposed group. The IR for CVEs was 2.9 per 1000 PY (95% CI, 2.09–4.02) in the exposed group and 4.69 per 1000 PY (95% CI, 3.40–6.47) in the unexposed group with studies of ≥48 weeks of follow-up, with an RR of 0.62 (95% CI, 0.39–0.98). The inclusion of nonrandomized and shorter-duration trials did not significantly change the RR for MI or coronary artery disease. Conclusions This pooled analysis found comparable IRs for MI and CVEs among ABC-exposed and -unexposed participants, suggesting no increased risk for MI or CVEs following ABC exposure in a clinical trial population. Modifiable risk factors for MI and CVEs should be addressed when prescribing ART.

Background Several observational studies and randomized controlled trials (RCTs) have suggested an association between abacavir (ABC) use and myocardial infarction (MI) but others, including meta-analyses of clinical trial data, have not. Methods This updated meta-analysis estimates exposure-adjusted incidence rate (IR) and relative rate (RR) of MI and coronary artery disease (CAD) in subjects receiving ABC and non ABC-containing combination antiretroviral therapy (cART). Summary data from 52 Phase II-IV RCTs from a previous meta-analysis were combined with aggregate data from 14 new RCTs. Subjects were either randomized to ABC cART vs. other cARTs, or ABC was prescribed as a background medication. Primary analyses included ABC-randomized trials with a follow-up of ≥48 weeks and focused on MI. Secondary analyses included shorter duration trials and non-ABC-randomized trials and estimated IR and RR for both MI and CAD. Results In 66 clinical trials (75% male, aged 18–85 years), 13,119 adults were on ABC-containing cART and 7,350 were not. Exposure-adjusted IR for MI was 1.5 per 1,000 person-years (PY) [95% Confidence Interval (CI) 0.67–3.34] in the ABC-exposed group, and 2.18 per 1,000 PY (95% CI 1.09–4.40) in the unexposed group with a RR of 0.69 (95% CI 0.24–1.98). RR for MI was 0.69 (95% CI 0.24–1.99) with inclusion of shorter duration studies, and 0.83 (95% CI 0.44–1.60) with inclusion of ABC non-randomized studies. The IR for CAD was 2.9 per 1,000 PY (95% CI 2.09–4.02) in the ABC-exposed group and 4.69 per 1,000 PY (95% CI 3.4–6.47) in the unexposed group with studies of ≥48 weeks of follow-up, with a RR of 0.62 (95% CI 0.39–0.98). With inclusion of studies of