Patient-Reported Outcomes After Switching to a 2-Drug Regimen of Fixed-Dose Combination Dolutegravir/Lamivudine: 48-Week Results from the SALSA Study.

Patient-reported outcomes (PROs) facilitate communication between patients and providers, enhancing patient-centered care. We report PROs for virologically suppressed people living with HIV-1 who switched to dolutegravir/lamivudine (DTG/3TC) or continued their 3- or 4-drug current antiretroviral regimen (CAR) in the phase 3 SALSA study. Secondary endpoints included change from baseline in HIV Treatment Satisfaction Questionnaire (status version; HIVTSQs) and HIV Symptom Distress Module (HIV-SDM) at Weeks 4, 24, and 48. A post hoc analysis assessed change in HIVTSQs and HIV-SDM by age (≥ 50 and < 50 years). Higher HIVTSQs scores represent greater treatment satisfaction (range, 0-60); lower HIV-SDM scores indicate less symptom bother (range, 0-80). Participants in the DTG/3TC (n = 246) and CAR (n = 247) groups reported comparable baseline HIVTSQs total scores (mean [SD], 55.2 [6.5] and 55.8 [5.5], respectively). Beginning at Week 4, mean HIVTSQs scores in the DTG/3TC group further increased vs. CAR and were sustained through Week 48. Baseline mean (SD) HIV-SDM symptom bother scores were comparable between the DTG/3TC (9.0 [9.9]) and CAR (7.9 [9.3]) groups. Small improvements in HIV-SDM scores favoring DTG/3TC were observed at Weeks 4 and 24 and sustained through Week 48 (though not significant between groups). Participants aged ≥ 50 and < 50 years who switched to DTG/3TC reported higher satisfaction and less symptom distress vs. CAR; these results were generally comparable between age groups. Participants who switched to DTG/3TC reported rapid and sustained improvements in treatment satisfaction compared with those who continued CAR, reinforcing the benefits of DTG/3TC beyond virologic suppression (NCT04021290; registration date, 7/11/2019).

Efficacy and safety of switching to dolutegravir/lamivudine in virologically suppressed people with HIV-1 aged ≥ 50 years: week 48 pooled results from the TANGO and SALSA studies.

BACKGROUND: As the population of people with HIV ages, concerns over managing age-related comorbidities, polypharmacy, immune recovery, and drug-drug interactions while maintaining viral suppression have arisen. We present pooled TANGO and SALSA efficacy and safety results dichotomized by age (< 50 and ≥ 50 years). METHODS: Week 48 data from the open-label phase 3 TANGO and SALSA trials evaluating switch to once-daily dolutegravir/lamivudine (DTG/3TC) fixed-dose combination vs continuing current antiretroviral regimen (CAR) were pooled. Proportions of participants with HIV-1 RNA ≥ 50 and < 50 copies/mL (Snapshot, intention-to-treat exposed) and safety were analyzed by age category. Adjusted mean change from baseline in CD4 + cell count was assessed using mixed-models repeated-measures analysis. RESULTS: Of 1234 participants, 80% of whom were male, 29% were aged ≥ 50 years. Among those aged ≥ 50 years, 1/177 (< 1%) DTG/3TC participant and 3/187 (2%) CAR participants had HIV-1 RNA ≥ 50 copies/mL at 48 weeks; proportions with HIV-1 RNA < 50 copies/mL were high in both treatment groups (≥ 92%), consistent with overall efficacy and similar to observations in participants aged < 50 years (≥ 93%). Regardless of age category, CD4 + cell count increased or was maintained from baseline with DTG/3TC. Change from baseline in CD4 + /CD8 + ratio was similar across age groups and between treatment groups. One CAR participant aged < 50 years had confirmed virologic withdrawal, but no resistance was detected. In the DTG/3TC group, incidence of adverse events (AEs) was similar across age groups. Proportions of AEs leading to withdrawal were low and comparable between age groups. Although drug-related AEs were generally low, across age groups, drug-related AEs were more frequent in participants who switched to DTG/3TC compared with those who continued CAR. While few serious AEs were observed in both treatment groups, more were reported in participants aged ≥ 50 years vs < 50 years. CONCLUSIONS: Among individuals with HIV-1, switching to DTG/3TC maintained high rates of virologic suppression and demonstrated a favorable safety profile, including in those aged ≥ 50 years despite higher prevalence of concomitant medication use and comorbidities. TRIAL REGISTRATION NUMBER: TANGO, NCT03446573 (February 27, 2018); SALSA, NCT04021290 (July 16, 2019).

Efficacy and Safety of Switching to the 2-Drug Regimen Dolutegravir/Lamivudine Versus Continuing a 3- or 4-Drug Regimen for Maintaining Virologic Suppression in Adults Living With Human Immunodeficiency Virus 1 (HIV-1): Week 48 Results From the Phase 3, Noninferiority SALSA Randomized Trial.

BACKGROUND: In TANGO, switching to dolutegravir/lamivudine (DTG/3TC) demonstrated long-term noninferior efficacy vs continuing tenofovir alafenamide-based regimens in treatment-experienced adults with HIV-1. The phase 3 SALSA study evaluated efficacy and safety of switching to DTG/3TC compared with continuing various 3-/4-drug current antiretroviral regimens (CARs). METHODS: Adults with HIV-1 RNA <50 copies/mL and no previous virologic failure were randomized (1:1, stratified by baseline third agent class) to switch to once-daily fixed-dose combination DTG/3TC or continue CAR (primary endpoint: proportion of participants with HIV-1 RNA ≥50 copies/mL at week 48; Snapshot, intention-to-treat-exposed population, 5% noninferiority margin). RESULTS: Overall, 493 adults (39% women; 39% aged ≥50 years; 19% African American/African heritage; 14% Asian) were randomized to switch to DTG/3TC (n = 246) or continue CAR (n = 247). At week 48, 1 (0.4%) participant in the DTG/3TC group and 3 (1.2%) in the CAR group had HIV-1 RNA ≥50 copies/mL (Snapshot), demonstrating noninferiority (adjusted difference, -0.8%; 95% CI, -2.4%, .8%). Zero participants met confirmed virologic withdrawal criteria; therefore, no resistance testing was performed. Drug-related adverse events were more frequent with DTG/3TC (20%) than CAR (6%) through week 48 but comparable post-week 24 (5% vs 2%, respectively). Proximal tubular renal function and bone turnover biomarkers improved with DTG/3TC. Both groups had generally minimal changes in lipids and inflammatory biomarkers. CONCLUSIONS: Switching to DTG/3TC was noninferior to continuing CAR for maintaining virologic suppression at week 48 with no observed resistance, supporting the efficacy, good safety, and high barrier to resistance of DTG/3TC. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov, NCT04021290.

Pharmacokinetic and pharmacokinetic/pharmacodynamic characterization of the dolutegravir/rilpivirine two-drug regimen in SWORD-1/-2 phase 3 studies.

AIM: SWORD-1 and SWORD-2 phase 3 studies concluded that switching virologically suppressed participants with HIV-1 from their current three- or four-drug antiretroviral regimen (CAR) to the two-drug regimen of once-daily dolutegravir (DTG, 50 mg) and rilpivirine (RPV, 25 mg) was safe, well tolerated and noninferior for maintaining HIV-1 suppression at week 48 and highly efficacious to week 148. A secondary objective was to characterize drug exposure and exposure-efficacy/safety relationships. METHODS: Adults with plasma HIV-1 RNA <50 copies/mL were randomized to switch to once-daily DTG + RPV on day 1 or to continue CAR for 52 weeks before switching. Trough plasma concentrations (C0) of DTG and RPV, the proportion of participants with HIV-1 RNA <50 copies/mL and adverse events to week 100 were summarized and subjected to exposure-response analyses in the overall population, in the subset of participants who switched from CAR containing enzyme-inducing drugs and by age category (≥50 and <50 years). The relationship between C0avg (individual average C0 across visits) and efficacy/safety was investigated. RESULTS: Although week 2 DTG and RPV C0 were lower in participants switching from enzyme-inducing antiretroviral drugs, C0 and C0avg stayed above in vitro antiviral protein binding-adjusted IC90 and to week 100 with viral suppression >89%. DTG or RPV C0avg showed no relationship with virologic failures or safety. Participants ≥50 years had similar C0avg and safety response to younger participants. CONCLUSION: No clinically relevant relationship between DTG or RPV exposures and virologic or safety response was observed, confirming the DTG + RPV switch for participants as a safe and effective treatment.

Efficacy and Safety of Switching to Dolutegravir/Lamivudine Versus Continuing a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen for Maintenance of Virologic Suppression in Adults Living With Human Immunodeficiency Virus Type 1: Results Through Week 144 From the Phase 3, Noninferiority TANGO Randomized Trial.

BACKGROUND: Switching to dolutegravir/lamivudine (DTG/3TC) was noninferior to continuing tenofovir alafenamide (TAF)-based regimens for maintaining virologic suppression at week 48 of the TANGO study. Here we present week 144 outcomes (efficacy, safety, weight, and biomarkers). METHODS: TANGO is a randomized (1:1, stratified by baseline third agent class), open-label, noninferiority phase 3 study. Virologically suppressed (>6 months) adults with human immunodeficiency virus type 1 (HIV-1) switched to once-daily DTG/3TC or continued TAF-based regimens. RESULTS: A total of 741 participants received study treatment (DTG/3TC, n = 369; TAF-based regimen, n = 372). At week 144, the proportion of participants with an HIV-1 RNA level ≥50 copies/mL (primary end point, Snapshot; intention-to-treat-exposed population) after switching to DTG/3TC was 0.3% (1 of 369) versus 1.3% (5 of 372) for those continuing TAF-based regimens, demonstrating noninferiority (adjusted treatment difference, -1.1 [95% confidence interval, -2.4 to .2), with DTG/3TC favored in the per-protocol analysis (adjusted treatment difference, -1.1 [-2.3 to -.0]; P = .04). Few participants met confirmed virologic withdrawal criteria (none in the DTG/3TC and 3 in the TAF-based regimen group), with no resistance observed. Drug-related adverse events were more frequent with DTG/3TC (15%; leading to discontinuation in 4%) than TAF-based regimens (5%; leading to discontinuation in 1%) through week 144, but rates were comparable after week 48 (4%; leading to discontinuation in 1% in both groups). Changes from baseline in lipid values generally favored DTG/3TC; no clinical impact on renal function and comparable changes in inflammatory and bone biomarkers across groups were observed. CONCLUSIONS: Switching to DTG/3TC demonstrated noninferior and durable efficacy compared with continuing TAF-based regimens in treatment-experienced adults with HIV-1, with good safety and tolerability, and no resistance through 144 weeks.

Integrase Inhibitor Resistance Mechanisms and Structural Characteristics in Antiretroviral Therapy-Experienced, Integrase Inhibitor-Naive Adults with HIV-1 Infection Treated with Dolutegravir plus Two Nucleoside Reverse Transcriptase Inhibitors in the DAWNING Study.

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 <400 copies/mL (5 achieved <50 copies/mL) before CVW. Treatment-emergent G118R was detected in 5 participants, occurring with ≥2 other integrase substitutions, including R263R/K, in 3 participants and without other integrase substitutions in 2 participants. G118R or R263K increased the rate of dolutegravir dissociation from integrase-DNA complexes versus wild-type but retained prolonged binding. Overall, among treatment-experienced adults who received dolutegravir in DAWNING, 6 of 314 participants developed treatment-emergent INSTI resistance-associated substitutions, with a change in in vitro dolutegravir resistance 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.).

Efficacy and Safety of Switching to Dolutegravir/Lamivudine Fixed-Dose 2-Drug Regimen vs Continuing a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen for Maintenance of Virologic Suppression in Adults Living With Human Immunodeficiency Virus Type 1: Phase 3, Randomized, Noninferiority TANGO Study.

BACKGROUND: The 2-drug regimen dolutegravir (DTG) + lamivudine (3TC) is indicated for treatment-naive adults with human immunodeficiency virus type 1 (HIV-1). We present efficacy and safety of switching to DTG/3TC in virologically suppressed individuals. METHODS: TANGO is an open-label, multicenter, phase 3 study that randomized adults (1:1, stratified by baseline third agent class) with HIV-1 RNA <50 copies/mL to switch to once-daily fixed-dose DTG/3TC or remain on a tenofovir alafenamide (TAF)-based regimen. The primary end point was proportion of participants with HIV-1 RNA ≥50 copies/mL at week 48 (US Food and Drug Administration Snapshot algorithm) in the intention-to-treat-exposed population (4% noninferiority margin). RESULTS: 743 adults were enrolled; 741 received ≥1 dose of study drug (DTG/3TC, N = 369; TAF-based regimen, N = 372). At week 48, proportion of participants with HIV-1 RNA ≥50 copies/mL receiving DTG/3TC was 0.3% (1/369) vs 0.5% (2/372) with a TAF-based regimen (adjusted treatment difference [95% confidence interval], -0.3 [-1.2 to .7]), meeting noninferiority criteria. No participants receiving DTG/3TC and 1 receiving a TAF-based regimen met confirmed virologic withdrawal criteria, with no emergent resistance at failure. Drug-related grade ≥2 adverse events and withdrawals due to adverse events occurred in 17 (4.6%) and 13 (3.5%) participants with DTG/3TC and 3 (0.8%) and 2 (0.5%) with a TAF-based regimen, respectively. CONCLUSIONS: DTG/3TC was noninferior in maintaining virologic suppression vs a TAF-based regimen at week 48, with no virologic failure or emergent resistance reported with DTG/3TC, supporting it as a simplification strategy for virologically suppressed people with HIV-1. CLINICAL TRIALS REGISTRATION: NCT03446573.

Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials.

BACKGROUND: Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. METHODS: We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of -10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. FINDINGS: Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -2·6%, 95% CI -6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -0·7%, 95% CI -4·3 to 2·9), showing non-inferiority at a -10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference -1·7%, 95% CI -4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. INTERPRETATION: The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. FUNDING: ViiV Healthcare.

Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies.

BACKGROUND: Lifelong HIV antiretroviral therapy (ART) has prompted an interest in two-drug regimens to minimise cumulative drug exposure and toxicities. The safety, tolerability, and efficacy of dolutegravir and rilpivirine suggest potential compatibility and effectiveness as a two-drug regimen. We aimed to investigate this two-drug regimen in a phase 3 study. METHODS: We identically designed SWORD-1 and SWORD-2, which were open-label, parallel-group, multicentre, phase 3, randomised, non-inferiority studies in 12 countries evaluating efficacy and safety of once-daily dolutegravir 50 mg plus rilpivirine 25 mg versus current ART regimen (CAR). We included participants aged 18 years or older who were on first or second ART with stable plasma HIV-1 RNA (viral load <50 copies per mL) for 6 months or longer at screening. We randomly assigned participants (1:1) with stratification by third-agent class, age, and planned participation in a bone mineral density substudy. The primary endpoint was proportion of participants with viral load lower than 50 copies per mL at week 48 among those individuals who received one or more doses of study medication. Investigators monitored adverse events to assess safety. These trials are registered with ClinicalTrials.gov, numbers NCT02429791 (SWORD-1) and NCT02422797 (SWORD-2). FINDINGS: We screened for participants from April 14, 2015, to Oct 15, 2015, for SWORD-1 and from April 21, 2015, to Sept 25, 2015, for SWORD-2. We randomly assigned 516 participants to dolutegravir-rilpivirine and 512 to continue with CAR. At week 48 (last patient visit was Nov 22, 2016), in the pooled analysis of the intention-to-treat population, 95% of participants had viral loads lower than 50 copies per mL in each group (486 of 513 in the dolutegravir-rilpivirine group vs 485 of 511 in the CAR group), with an adjusted treatment difference of -0·2% (95% CI -3·0 to 2·5) and showed non-inferiority with a predefined margin of -8%. 395 (77%) of 513 participants in the dolutegravir-rilpivirine group and 364 (71%) of 511 participants in the CAR group reported adverse events. The most common adverse events were nasopharyngitis (49 [10%] for dolutegravir-rilpivirine vs 50 [10%] for CAR) and headache (41 [8%] vs 23 [5%]). More participants taking dolutegravir-rilpivirine (17 [3%]) reported adverse events leading to withdrawal than did participants taking CAR (three [<1%]). INTERPRETATION: Dolutegravir-rilpivirine was non-inferior to CAR over 48 weeks in participants with HIV suppression and showed a safety profile consistent with its components. Results support the use of this two-drug regimen to maintain HIV suppression. FUNDING: ViiV Healthcare and Janssen Pharmaceutica NV.

Bioequivalence of a Fixed-Dose Combination Tablet of the Complete Two-Drug Regimen of Dolutegravir and Rilpivirine for Treatment of HIV-1 Infection.

A complete 2-drug regimen of dolutegravir at 50 mg and rilpivirine at 25 mg was approved to treat HIV-1 infection in virologically suppressed patients after demonstrating acceptable efficacy and tolerability. This study investigated the bioequivalence and pharmacokinetics of the fixed-dose combination tablet compared with those of separate tablets. Secondary endpoints were the tolerability and safety of the fixed-dose combination tablet. In this open-label, randomized-sequence, 2-way crossover trial, single doses of the fixed-dose combination tablet (the test treatment) and the combination of separate tablets (the reference treatment) were administered to healthy adults after a moderate-fat meal, with a 21-day washout between treatments. Pharmacokinetic samples were collected through 12 days after dosing. The primary endpoints were the area under the plasma concentration-time curve (AUC) and the maximum concentration of drug in plasma (Cmax). The study employed a prespecified sample size reestimation based on a blind midpoint review of Cmax variability to update the enrollment size to achieve statistical power. Of 118 participants enrolled, 113 received both treatments and underwent pharmacokinetic assessment. The 90% confidence intervals for the geometric least-squares mean ratios for the AUC from 0 h to infinity, the AUC from 0 h to the last quantifiable measurement, and Cmax (test treatment versus reference treatment) were within the bioequivalence range of 0.80 to 1.25 for both drugs, indicating bioequivalence. In this study, a single dose of either treatment was well tolerated overall, with 4% (n = 5) and 3% (n = 3) of participants reporting adverse events considered related to the test and reference treatments, respectively. The dolutegravir-rilpivirine fixed-dose combination tablet is bioequivalent to a combination of separate tablets, and no new safety signals emerged. (This study has been registered at ClinicalTrials.gov under identifier NCT02741557.).

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 .).

No clinically significant pharmacokinetic interactions between dolutegravir and daclatasvir in healthy adult subjects.

BACKGROUND: Daclatasvir (DCV) is an NS5A replication complex inhibitor recently approved for chronic hepatitis C virus treatment. METHODS: To assess drug interactions between the HIV integrase strand transfer inhibitor dolutegravir (DTG) and DCV, subjects were randomized into 1 of 2 sequences in an open-label, 3-period, crossover study. Subjects received either DTG 50 mg once daily or DCV 60 mg once daily for 5 days in periods 1 and 2 and DTG 50 mg plus DCV 60 mg once daily for 5 days in period 3, with no washout between periods 2 and 3. Between periods 1 and 2, there was a washout period of at least 7 days. RESULTS: The geometric least-squares mean ratios (90 % confidence intervals) of DCV area under the concentration-time curve over a dosing interval (AUC0-τ), maximum observed concentration (Cmax), and concentration at the end of the dosing interval (Cτ) were 0.978 (0.831-1.15), 1.03 (0.843-1.25), and 1.06 (0.876-1.29), respectively, when DCV was administered with DTG compared with DCV alone. Compared with DTG alone, coadministration of DTG with DCV increased DTG AUC0-τ, Cmax, and Cτ by approximately 33, 29, and 45 %, respectively. CONCLUSIONS: DCV plasma exposure was not meaningfully affected by DTG. Coadministration of DTG with DCV resulted in slight increases in DTG AUC0-τ, Cmax, and Cτ. Accumulated safety and tolerability data in humans receiving DTG to date suggests this effect is not considered clinically significant. DTG and DCV can be coadministered without dose adjustment. TRIAL REGISTRATION: Registered on March 6, 2014 with ClinicalTrials.gov; registration number: NCT02082808 and as Study ID: 201102 on the ViiV Clinical Study Registry.

Effect of carbamazepine on dolutegravir pharmacokinetics and dosing recommendation.

PURPOSE: Dolutegravir (DTG) is primarily metabolized by UGT1A1 with CYP3A as a minor route. Carbamazepine (CBZ) is a potent inducer of these enzymes; thus, the effect of oral extended-release CBZ on DTG pharmacokinetics (PK) was evaluated to provide dose recommendation when co-administered. METHODS: This was a single-center, open-label, fixed-sequence, crossover study in healthy adults. Subjects received three treatments: DTG 50 mg every 24 h (q24h) × 5 days in period 1, followed by CBZ 100 mg every 12 h (q12h) × 3 days, then 200 mg q12h × 3 days, then 300 mg q12h × 10 days in period 2, and DTG 50 mg q24h + CBZ 300 mg q12h × 5 days in period 3. No washout intervals occurred. Each dose was administered with a moderate-fat meal. Serial PK samples for DTG were collected on day 5 of periods 1 and 3. Plasma DTG PK parameters were determined with non-compartmental analysis. Geometric least-squares mean ratios (GMRs) and 90 % confidence intervals (CIs) were generated by the mixed-effect model for within-subject treatment comparisons. Safety assessments were performed throughout the study. RESULTS: Sixteen subjects enrolled; 14 completed the study. CBZ significantly reduced DTG exposure: GMRs (90 % CI) for DTG + CBZ versus DTG alone were 0.51 (0.48-0.549), 0.67 (0.61-0.73), and 0.27 (0.24-0.31) for area under the curve from time zero to the end of the dosing interval (AUC(0-τ)), maximum observed plasma concentration (Cmax), and plasma concentration at the end of the dosing interval (Cτ), respectively. DTG alone and co-administered with CBZ was well tolerated. CONCLUSION: Integrase strand transfer inhibitor-naive subjects taking CBZ should receive DTG 50 mg twice daily versus once daily, as is recommended with other potent UGT1A/CYP3A inducers. ClinicalTrials.gov: NCT01967771.

Effects of boceprevir and telaprevir on the pharmacokinetics of dolutegravir.

AIMS: The aim was to evaluate the effect of boceprevir and telaprevir on dolutegravir pharmacokinetics (PK); the effect of dolutegravir on boceprevir and telaprevir PK was assessed through comparison with historical data for each hepatitis C virus (HCV) drug's prescribing information alone. METHODS: This was a single-centre, randomized, open-label, two-cohort, two-period, one-way study in healthy adult subjects. Dolutegravir 50 mg once daily was administered for 5 days in Period 1, and dolutegravir 50 mg once daily was coadministered with either boceprevir 800 mg every 8 h (Cohort 1) or telaprevir 750 mg every 8 h (Cohort 2) for 10 days in Period 2. RESULTS: No deaths or serious adverse events were reported during the study. Four subjects were withdrawn from the study because of adverse events (elevated alanine aminotransferase, cellulitis, increased serum creatinine and dizziness). One subject became pregnant during the study. Coadministration of dolutegravir with boceprevir had no effect on dolutegravir area under the plasma concentration-time curve (AUC) and maximal plasma concentration (Cmax ) and caused a small increase in concentration at the end of the dosing interval (Cτ ; 8%). Coadministration of dolutegravir with telaprevir resulted in increased dolutegravir plasma exposures compared with those after administration of dolutegravir alone; AUC0- τ , Cmax and Cτ increased by 25, 19 and 37%, respectively. Coadministration of boceprevir or telaprevir with dolutegravir had no clinically significant effect on dolutegravir PK. Plasma boceprevir and telaprevir PK data for either combined treatment were similar to historical data, indicating no effect of dolutegravir on boceprevir or telaprevir exposure. CONCLUSIONS: Dolutegravir can be coadministered with boceprevir or telaprevir in patients coinfected with HIV and HCV with no dose adjustment.

Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Genetic fallout in biocultural landscapes: molecular imperialism and the cultural politics of (not) seeing transgenes in Mexico.

This article explores the trajectory of the global controversy over the introgression (or not) of transgenes from genetically modified maize into Mexican indigenous maize landraces. While a plurality of knowledge-making processes were deployed to render transgenes visible or invisible, we analyze how a particular in vitro based DNA-centered knowledge came to marginalize other forms of knowledge, thus obscuring other bio-cultural dimensions key to the understanding of gene flow and maize diversity. We show that dominant molecular norms of proof and standards of detection, which co-developed with the world of industrial monocropping and gene patenting, discarded and externalized non-compliant actors (i.e. complex maize genomes, human dimensions of gene flow). Operating in the name of high science, they hence obscured the complex biological and cultural processes that maintain crop diversity and enacted a cultural-political domination over the world of Mexican landraces and indigenous communities.

Efficacy and Safety of Switching to Dolutegravir/Lamivudine Versus Continuing a Tenofovir Alafenamide-Based Regimen in Virologically Suppressed Adults With Human Immunodeficiency Virus Type 1: Subgroup Analysis of Participants With Elvitegravir as Baseline Third Agent From the TANGO Study.

TANGO results have established the durable efficacy of dolutegravir/lamivudine in virologically suppressed individuals who switched from 3- or 4-drug tenofovir alafenamide (TAF)-based regimens. In this post hoc subgroup analysis, 144-week efficacy and tolerability of dolutegravir/lamivudine in participants who switched from elvitegravir/cobicistat/emtricitabine/TAF were consistent with the overall switch population. Clinical Trials Registration: NCT03446573.

Population Pharmacokinetic Analysis of Dolutegravir in Treatment-Experienced Adults Living with HIV-1.

The World Health Organization has recommended the use of dolutegravir (DTG) for both first and second-line antiretroviral treatment in both adults and children down to 4 weeks of age. We developed a population pharmacokinetic(PopPK) model following oral administration of DTG 50 mg QD and 50 mg BID in HIV-infected treatment-experienced adults (607) based on pooled data from four phase 2/3 trials. DTG population pharmacokinetics are described by a one-compartment model with first-order absorption, absorption lag-time, and first-order elimination. The PopPK parameter estimates were apparent oral clearance (CL/F) = 1.00 L/h, apparent volume of distribution (V/F) = 18.9 L, absorption rate constant (Ka) = 1.99 per hour, and absorption lag time = 0.333 h, respectively. The final model included inter-individual and inter-occasion variability on apparent clearance (CL/F). Weight, smoking status, use of metabolic inducers as part of background antiretroviral therapy (ART) classified by their level of induction, use of atazanavir or atazanavir-ritonavir as part of background ART, and albumin level were predictors of CL/F; weight and albumin level were predictors of V/F; and sex and concomitant use of metal cation-containing vitamin/mineral supplements were predictors of relative bioavailability (F). The current model-based analysis suggests that the DTG dose adjustment is not required based on the demographics, laboratory values, smoking status, concomitant use of mild metabolic inducers or inhibitors in the background therapy, or use of metal cation-containing vitamin/mineral supplements because these covariate effects are not predicted to have a clinically relevant impact on safety and efficacy.

Integrated Population Exposure-Response of Dolutegravir in HIV-1 Supports Bridging of Clinical Response Influenced by Relevant Intrinsic and Extrinsic Patient Characteristics.

Dolutegravir (DTG) is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric subjects aged at least 4 weeks. The present work aimed to characterize the viral response based on a pooled analysis of exposure-response (E-R) from five studies in treatment-experienced and integrase-resistant (INI-r) patients infected with HIV-1. Importantly, model-based simulations of the E-R relationships with DTG provided insight into the clinical relevance of known intrinsic (e.g., sub-population with Q148-driven integrase mutation) and extrinsic (food, enzyme inducers, and metal cation-containing products) factors expected to influence the DTG E-R relationship. Model-based post hoc exposure metrics (C min and C avg) were incorporated into a mechanistic population viral dynamic model describing the short-term effect of DTG on log10 HIV-1 RNA viral load over 8 or 10 days. In addition, the impact of DTG in combination with background ARTs on the 24-week HIV RNA response was also assessed using logistic regression. There was good concordance between model-based predictions and observed virologic response on day 10 and week 24. The E-R model-based simulations exploring the potential impact of a higher dose (100 mg b.i.d.) of DTG in subpopulations experiencing exposure changes due to covariates did not show clinically relevant changes in virological response compared with the approved 50 mg b.i.d. clinical dose. Overall, our study confirmed the current recommendation of dolutegravir 50 mg b.i.d. in the integrase inhibitor-resistant (INI-r) population.