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Objectives: Women represent >50% of people with HIV globally but have historically been underrepresented in clinical trials. We evaluated the efficacy and safety of switching to dolutegravir/lamivudine (DTG/3TC) vs continuing their current antiretroviral regimen (CAR) by sex assigned at birth (female and male) in virologically suppressed adults with HIV‐1 without prior virological failure in a pooled analysis of two randomized controlled trials. Methods: This analysis included 48‐week data from the phase 3 TANGO and SALSA studies. Primary and key secondary endpoints included proportions of participants with HIV‐1 RNA ≥50 and <50 copies/mL at week 48, respectively. Safety was also assessed. Results: Of 1234 participants, 250 (DTG/3TC, n = 133; CAR, n = 117) were female at birth. Week 48 proportions of participants with Snapshot HIV‐1 RNA ≥50 copies/mL were similar regardless of sex at birth (DTG/3TC vs CAR: female, <1% [1/133] vs 2% [2/117]; male, <1% [1/482] vs <1% [3/502]). Proportions with HIV‐1 RNA <50 copies/mL were high across sexes and treatment groups (DTG/3TC vs CAR: female, 91% [121/133] vs 89% [104/117]; male, 94% [455/482] vs 94% [471/502]). Immunological response with DTG/3TC was slightly higher in female participants. Incidences of adverse events leading to withdrawal and serious adverse events were low and comparable between treatment groups and across sexes. Weight gain was higher with DTG/3TC than with CAR among female participants aged ≥50 years (treatment difference 2.08 kg [95% confidence interval 0.40–3.75]). Conclusions: Results confirm the robustness of DTG/3TC as a switch option in virologically suppressed females with HIV‐1, with outcomes similar to those in males. [ABSTRACT FROM AUTHOR]

Background: TANGO demonstrated non-inferior virological efficacy (HIV-1 RNA >50 copies/mL, Snapshot) of switching to DTG/3TC versus continuing TBR in HIV-1-infected, virologically suppressed adults at 96 weeks. Abbott RealTime HIV-1 assay [...]

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK, Background S/GSK1349572 is a new integrase inhibitor (INI) with in‐vitro activity against INI‐resistant HIV. Before dosing a large number of subjects in pivotal clinical trials, in‐vitro findings were validated in [...]

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK, Background S/GSK1349572(572) showed potent activity in Phase 2 studies in INI‐naive HIV‐infected subjects and limited cross‐resistance to raltegravir (RAL) and elvitegravir in vitro. VIKING is an ongoing 24‐week Phase 2b [...]

Qualitative and competitive-quantitative nested polymerase chain reaction (PCR) assays were developed for human herpesvirus 7 (HHV-7). These assays amplify a DNA sequence encoding part of the HHV-7 homologue of the human herpesvirus 6 (HHV-6) U42 gene. The PCR assays were used to analyze peripheral blood DNA (pbDNA) and saliva from 24 healthy volunteers. The prevalence of HHV-7 in saliva was 96%, with a median virus load of 1.1 x 10(6) copies/mL. Longitudinal analysis revealed sustained virus load, suggesting continued active viral replication. Analysis of 1 microgram of pbDNA showed the prevalence of HHV-7 to be 83%, with a median virus load of 40 copies (267 copies/10(6) cells). Analysis of sequential pbDNA samples showed individuals to have stable levels of HHV-7 virus load. These data demonstrate persistence of HHV-7 at two distinct sites and provide baseline data allowing comparisons with HHV-7 load in immunocompromised patients. [ABSTRACT FROM AUTHOR]

Background: Dolutegravir (DTG; S/GSK1349572), a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. This phase IIb study assessed the activity of DTG in HIV-1-infected subjects with genotypic evidence of RAL resistance.Methods: Subjects received DTG 50 mg once daily (cohort I) or 50 mg twice daily (cohort II) while continuing a failing regimen (without RAL) through day 10, after which the background regimen was optimized, when feasible, for cohort I, and at least 1 fully active drug was mandated for cohort II. The primary efficacy end point was the proportion of subjects on day 11 in whom the plasma HIV-1 RNA load decreased by ≥0.7 log(10) copies/mL from baseline or was <400 copies/mL.Results: A rapid antiviral response was observed. More subjects achieved the primary end point in cohort II (23 of 24 [96%]), compared with cohort I (21 of 27 [78%]) at day 11. At week 24, 41% and 75% of subjects had an HIV-1 RNA load of <50 copies/mL in cohorts I and II, respectively. Further integrase genotypic evolution was uncommon. Dolutegravir had a good, similar safety profile with each dosing regimen.Conclusion: Dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen. These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL. [ABSTRACT FROM AUTHOR]

TANGO study demonstrated that switching to DTG/3TC fixed dose combination (FDC) 2-Drug Regimen (2DR) was non-inferior to continuing a TAF-based 3-drug regimen (TBR, 3DR) in maintaining virologic suppression in HIV-1 infected, ART-experienced adults through Week 48. The impact of pre-existing, HIV-1 drug resistance on virologic outcomes through Week 48 was assessed. (367) 방법 Participants with historical IAS major NRTI or INSTI resistance associated mutations (RAMs) were excluded from the study. Pro-viral DNA genotyping was conducted retrospectively on baseline samples from randomized participants by Monogram Bioscience using GenoSure Archive assay. Virologic outcomes based on IAS major NRTI, NNRTI, PI and INSTI RAMs were determined by last available on-treatment HIV-1 RNA through Week 48 in order to assess pure virologic responses by censoring discontinuations due to non-efficacy reasons. This was repeated on the FDA Snapshot Algorithm at Week 48 as a sensitivity analysis. (609) 결과 322 (87%) of participants in the DTG/3TC arm and 321 (86%) in the TBR arm had both pro-viral genotype data and at least one on-treatment HIV-1 RNA result. Archived major NRTI, NNRTI, PI and INSTI RAMs were observed in 42 (7%), 90 (14%), 43 (7%) and 6 (1%) participants, respectively across both arms , and 474 (74%) participants were without any major RAMs at the baseline. The frequencies of NRTI RAMs M184V/I (n=7, 1%), K65E/N/R (n=2, <1%) and thymidine analog mutations (TAMs, n=14, 2%) were low. Through Week 48, 322 (100%) of participants on DTG/3TC and 319 (>99%) on TBR were virologically suppressed (last on-treatment HIV-1 RNA <50 c/mL). For participants with any major NRTI, INSTI, NNRTI or PI RAMs, all were virologically suppressed. The results of a sensitivity analysis using the FDA Snapshot algorithm were consistent with those using last available on-treatment HIV-1 RNA. One participant in the TBR arm without any archived RAMs met the protocol-defined, confirmed Virologic withdrawal criterion (CVW) with no emergent resistance. None in the DTG/3TC arm met CVW criteria through Week 48. (1114) 결론 In TANGO, archived major NRTI (e.g., M184V/I, K65E/N/R and TAMs) and INSTI (e.g., Q148R, Y143C/H, R263K) RAMs were infrequent. High rates of virologic suppression were maintained in participants on both treatment arms through Week 48. The presence of pre-existing, archived RAMS did not appear to impact virologic outcomes through Week 48. [ABSTRACT FROM AUTHOR]

Amprenavir (APV) is a highly active and selective HIV protease inhibitor (PI) that is used for the treatment of HIV infection in adults and children. In this review we present data from extensive resistance studies undertaken during the development of amprenavir. These include in vitro and clinical studies where the phenotype and genotype of HIV protease was determined after treatment with amprenavir either as the single PI [alone or with nucleoside reverse transcriptase inhibitors (NRTIs)] or in combination with other PIs. In addition, cross-resistance with other PIs has been examined to help position use of amprenavir in the clinic. The key signature amino acid substitution associated with amprenavir resistance that was identified from in vitro and subsequent in vivo studies was isoleucine to valine at position 50 (I50V) in HIV protease. This was a new mutation not observed as a natural variant or in PI-experienced patients. Additional mutations including M46I/L and I47V were required to produce high level resistance. Cross-resistance was limited and observed only with ritonavir. In amprenavir/zidovudine/lamivudine combination therapy in PI-naive and lamivudine-naive patients, therapy failure is associated frequently with the reverse transcriptase M184V mutation, and not with amprenavir resistance. However, when amprenavir was added to NRTI therapy in NRTI-experienced and PI-naive patients where treatment was compromised by baseline NRTI resistance, failure was more frequently associated with the development of amprenavir resistance. From these studies, four pathways of amprenavir resistance were identified, with the I50V pathway associated with the highest levels of resistance. Alternative pathways to amprenavir resistance involved key substitutions, either V32I + I47V, or I54L/M, or more rarely I84V. Limited cross-resistance was observed to other PIs with each of these genetic mechanisms. Similarly, in PI-experienced patients, cross-resistance to amprenavir is markedly lower than for the other four approved PIs. Markers of cross-resistance to amprenavir include the above mutations but not L90M or V82A/T/Y as observed for other PIs. These data suggest that amprenavir may have an important part to play in rescue therapy regimens. In combination with other PIs, resistance development may be suppressed and key signature mutations, such as I50V (amprenavir), D30N (nelfinavir) and V82A/T/Y (ritonavir, indinavir) have not been observed in vitro. In addition, passage with saquinavir may resensitise amprenavir-resistant variants to amprenavir. Hypersensitivity to amprenavir has been reported for N88S variants occasionally observed after nelfinavir therapy. Differences in the resistance profile of amprenavir from that of other PIs suggest that amprenavir may add value to HIV combination therapy, particularly in PI combinations and in rescue therapy. [ABSTRACT FROM AUTHOR]

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., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Background: Cabotegravir + rilpivirine long-acting (CAB + RPV LA) dosed every 2 months (Q2M) is a complete regimen for the maintenance of HIV-1 virologic suppression. In this study, we report month 12 clinical outcomes in patient study participants (PSPs) in the CAB and RPV Implementation Study in European Locations (CARISEL) study., Setting: CARISEL is a phase 3b implementation-effectiveness study., Methods: CARISEL was designed as a 2-arm, unblinded study with centers randomized to either enhanced or standard implementation arms. For PSPs, this study is single arm, unblinded, and interventional; all PSPs switched from daily oral therapy to CAB + RPV LA dosed Q2M. The primary objective was to evaluate the perceived acceptability, appropriateness, and feasibility of CAB + RPV LA implementation for staff participants (presented separately). Clinical secondary endpoints assessed through month 12 included the proportion of PSPs with plasma HIV-1 RNA ≥50 and <50 copies/mL (Snapshot algorithm), incidence of confirmed virologic failure (CVF; 2 consecutive plasma HIV-1 RNA levels ≥200 copies/mL), adherence to injection visit windows, and safety and tolerability., Results: Four hundred thirty PSPs were enrolled and treated; the mean age was 44 years (30% ≥50 years), 25% were women (sex at birth), and 22% were persons of color. At month 12, 87% (n = 373/430) of PSPs maintained HIV-1 RNA <50 copies/mL, with 0.7% (n = 3/430) having HIV-1 RNA ≥50 copies/mL. One PSP had CVF. The safety profile was consistent with previous findings. Overall, the results were similar between implementation arms., Conclusion: CAB + RPV LA Q2M was well tolerated and highly effective in maintaining virologic suppression with a low rate of virologic failure., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2024, The American College of Clinical Pharmacology.)

Background: Drug resistance testing aids in appropriate antiretroviral therapy selection to improve treatment success but may not be readily available. We evaluated the impact of switching to dolutegravir/lamivudine (DTG/3TC) using pooled data from the TANGO and SALSA trials in adults who were virologically suppressed with or without historical resistance results at screening., Methods: Adults who were virologically suppressed (HIV-1 RNA <50 copies/mL for >6 months) with no prior virologic failure were randomized to switch to DTG/3TC (TANGO, n = 369; SALSA, n = 246) or continue their current antiretroviral regimen (CAR; TANGO, n = 372; SALSA, n = 247). Week 48 HIV-1 RNA ≥50 and <50 copies/mL (Snapshot algorithm, Food and Drug Administration; intention-to-treat exposed), CD4+ cell count, and safety were analyzed by availability of historical resistance results., Results: Overall, 294 of 615 (48%) participants in the DTG/3TC group and 277 of 619 (45%) participants in the CAR group had no historical resistance results at screening. At week 48, proportions with Snapshot HIV-1 RNA ≥50 copies/mL were low (≤1.1%) and similar across treatment groups and by historical resistance results availability. High proportions (91%-95%) maintained virologic suppression through week 48, regardless of results availability. Across both subgroups of results availability, greater increases in CD4+ cell count from baseline to week 48 occurred with DTG/3TC vs CAR. No participants taking DTG/3TC had confirmed virologic withdrawal, regardless of historical resistance results availability. One participant undergoing CAR without historical resistance results had confirmed virologic withdrawal; no resistance was detected. Overall, DTG/3TC was well tolerated; few adverse events led to withdrawal., Conclusions: Findings support DTG/3TC as a robust switch option for adults who are virologically suppressed with HIV-1 and no prior virologic failure, regardless of historical resistance results availability., Clinical Trial Registration: TANGO: NCT03446573, https://clinicaltrials.gov/study/NCT03446573. SALSA: NCT04021290, https://clinicaltrials.gov/study/NCT04021290., Competing Interests: Potential conflicts of interest. S. S. has received honoraria from PPD/GSK for participation in the TANGO study and has received grants and/or personal fees for consultancy, lectures, and congress support from AbbVie, Cepheid, Gilead, Janssen, Merck Sharp and Dohme, Theratechnologies, and ViiV Healthcare. P. C. has received consulting fees from Gilead, Merck, and ViiV Healthcare and has participated in data safety monitoring/advisory boards for Gilead, Janssen, Merck, Moderna, and ViiV Healthcare. J. P. has received grants, personal fees, and nonfinancial support from Gilead, Janssen-Cilag, and ViiV Healthcare. F. B. has participated in advisory boards for Gilead and is the president of AusPATH. S. H. has participated in advisory boards for Gilead, Merck, and ViiV Healthcare; her institution has received support from Merck and ViiV Healthcare. P. R. has received support for speaking/advisory activities from Gilead and ViiV Healthcare. B. R. W., C. Y. M., R. G., R. W., B. J., M. A.-K., M. K., and C. O. are employees of ViiV Healthcare or GSK and may own stock in GSK. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Cabotegravir plus rilpivirine (CAB + RPV) is the first complete long-acting (LA) regimen recommended for maintaining HIV-1 virological suppression. Cabotegravir And Rilpivirine Implementation Study in European Locations (CARISEL) is an implementation-effectiveness study examining the implementation of CAB+RPV LA administered every 2 months (Q2M) in European HIV centres. We present staff study participant (SSP) perspectives on the administration of CAB+RPV LA over 12 months., Methods: Eighteen clinics were randomized to one of two implementation support packages: standard arm (Arm-S) or enhanced arm (Arm-E). Arm-S included video injection training and provider/patient toolkits. Additionally, Arm-E included skilled wrap-around team meetings, face-to-face injection training and continuous quality improvement (CQI) calls. SSPs completed surveys on the acceptability, appropriateness and feasibility of CAB+RPV LA as an intervention and its implementation into their clinics, as well as barriers and facilitators to implementation. All surveys were completed at Month (M)1 (baseline), M5 and M12; data collection was completed by February 2022. Qualitative data were obtained from semi-structured interviews at M1, M5 and M12. The primary objective was assessed via formal statistical comparisons between study arms of the Acceptability of Implementation Measure, Implementation Appropriateness Measure and Feasibility of Implementation Measure surveys (1-5 Likert scale ranging from 1 = "completely disagree" to 5 = "completely agree"). Equivalent measures anchored to CAB+RPV LA as a therapy were also assessed., Results: Seventy SSPs completed surveys and interviews at M1, 68 at M5 and 62 at M12. Mean acceptability/appropriateness/feasibility scores were ≥3.8 (out of 5) at M12 for implementation- and intervention-based measures. An analysis of covariance showed no significant differences between study arms for these outcomes. Although barriers were noted, most SSPs were not overly concerned that these would impact implementation; concern about these anticipated barriers also decreased over time. At M12, 90.3% (n = 56/62) of SSPs held a positive opinion about CAB+RPV LA implementation. Qualitative interviews and CQI calls highlighted three top practices that supported implementation: implementation planning; education about CAB+RPV LA clinical efficacy; and education around administering injections and managing pain/discomfort after injections., Conclusions: CARISEL demonstrated that CAB+RPV LA dosed Q2M was successfully implemented across a range of European locations, with SSPs finding implementation highly acceptable, appropriate and feasible., Gov Number: NCT04399551., (© 2024 ViiV Healthcare and The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

A fixed-dose combination (FDC) of 50 mg dolutegravir and 300 mg lamivudine is indicated for the treatment of HIV-1 infection. This analysis aimed to characterize the population pharmacokinetics (PK) of dolutegravir and lamivudine based on data from a phase 3 study (TANGO) in virologically suppressed adults living with HIV-1 switching to dolutegravir/lamivudine FDC. These analyses included 362 participants who contributed 2,629 dolutegravir and 2,611 lamivudine samples collected over 48 weeks. A one-compartment model with first-order absorption and elimination parameterized by apparent oral clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (Ka) described dolutegravir PK. Covariate search yielded body weight, bilirubin, and ethnicity as predictors of CL/F, and weight was predictive for V/F. The estimates of CL/F, V/F, and Ka were 0.858 L/h, 16.7 L, and 2.15 h -1 , respectively. A two-compartment model with first-order absorption and elimination parameterized by CL/F, apparent intercompartmental clearance (Q/F), apparent central volume of distribution (V2/F), apparent peripheral volume of distribution (V3/F), and Ka described lamivudine PK. Covariate search yielded eGFR and race as predictors of CL/F, and weight was predictive for V2/F. The estimated parameter values were CL/F = 19.6 L/h, Q/F = 2.97 L/h, V2/F = V3/F = 105 L, and Ka = 2.30 h -1 . The steady-state prediction suggested that the effect of covariates dolutegravir and lamivudine exposures was small (<20%) and not clinically relevant. Therefore, no dose adjustments are recommended based on these analyses. The results support the use of dolutegravir/lamivudine FDC in the treatment of HIV-1 infection in adults.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03446573., Competing Interests: H.C. is an employee of GSK and owns stock in GSK. T.P.D. and R.S. were employees of GSK at the time the study was conducted and may own stock in the company. M.A.-K. and K.A. are employees of ViiV Healthcare and own stock in GSK.

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)., (© 2024. The Author(s).)

Background: Switching to the 2-drug regimen dolutegravir/lamivudine demonstrated durable non-inferior efficacy vs continuing 3- or 4-drug tenofovir alafenamide-based regimens for maintaining virologic suppression in people with HIV-1 through Week 144 in TANGO., Setting: 134 centers, 10 countries., Methods: Adults with HIV-1 RNA <50 copies/mL for >6 months and no history of virologic failure were randomized to switch from stable tenofovir alafenamide-based regimens to dolutegravir/lamivudine on Day 1 (early-switch group) for 196 weeks. Those randomized to continue tenofovir alafenamide-based regimens on Day 1 who maintained virologic suppression at Week 144 switched to dolutegravir/lamivudine at Week 148 (late-switch group). Efficacy, safety, and tolerability (including weight and biomarker changes) of dolutegravir/lamivudine in early-switch and late-switch groups were assessed through Week 196., Results: Overall, 369 participants switched to dolutegravir/lamivudine on Day 1 (early-switch) and 298 switched at Week 148 (late-switch). In the early-switch group, 83% (306/369) maintained virologic suppression through Year 4, and 3% (11/369) reported new adverse events between Weeks 144 and 196. The late-switch group at Week 196 and early-switch group at Week 48 had comparable proportions with virologic suppression (93% each) and similar safety profiles. No late-switch participants and 1 early-switch participant met confirmed virologic withdrawal criteria through Week 196, with no resistance-associated mutations observed. Treatment continued to be well tolerated long-term., Conclusion: Switching from tenofovir alafenamide-based regimens to dolutegravir/lamivudine showed durable efficacy, high barrier to resistance, and good tolerability through 4 years. These results support dolutegravir/lamivudine as a robust treatment for maintaining virologic suppression., Competing Interests: Conflicts of Interest and Source of Funding: SDW has received funding from ViiV Healthcare paid to his institution. FBonnet has served as a consultant, invited speaker, and/or received grants from Gilead and ViiV Healthcare. OO has served as a consultant for Gilead and ViiV Healthcare and received honoraria from ViiV Healthcare. FBisshop has participated in advisory boards for Gilead. JOlalla has served as a consultant, invited speaker, and/or received grants from Gilead, GSK, Janssen, Merck, and ViiV Healthcare. J-PR has served as a consultant, invited speaker, and/or received grants from AbbVie, Gilead, GSK, Merck, and ViiV Healthcare. CW has no conflicts to disclose. RM, KP, RW, JOyee, EL, BW, BJ, KYS, and MA-K are employees of ViiV Healthcare or GSK and own stock in GSK. PS is a complimentary worker on behalf of GSK. This study was funded by ViiV Healthcare., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: CARISEL is an implementation-effectiveness "hybrid" study examining the perspectives of people living with HIV-1 (patient study participants [PSPs]) on cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) dosed every 2 months (Q2M) across 5 European countries., Methods: PSPs completed questionnaires on acceptability (Acceptability of Intervention Measure), appropriateness (Intervention Appropriateness Measure), and feasibility (Feasibility of Intervention Measure) at their first (Month [M] 1), third (M4), and seventh (M12) injection visits. Semistructured qualitative interviews were also conducted., Results: Overall, 437 PSPs were enrolled, of whom 430 received treatment. Median (interquartile range) age was 44 (37-51) years, 25.3% (n = 109/430) were female (sex at birth), and 21.9% (n = 94/430) were persons of color. Across time points, PSPs found CAB + RPV LA highly acceptable, appropriate, and feasible (mean scores ≥4.47/5). Qualitative data supported these observations., Conclusions: PSPs found CAB + RPV LA Q2M to be an acceptable, appropriate, and feasible treatment option., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CAG, RM, RT, JS, MP-B, MA-K, BH, AdR, PM and MC are employees of ViiV Healthcare and may be stockholders of GSK. MvdV has received research grants and fees for participation in advisory boards from ViiV, MSD and Gilead. JP reports grants from Gilead and ViiV Healthcare and payments from lectures from Gilead and Janssen. EJ has received speaking fees or consulting activities from ViiV and Gilead laboratories and hospitality and congress registrations from ViiV, Gilead, MSD and Pfizer laboratories. LB and TL have no conflicts of interest to report. SBA, ELL, MH and NB are employees of Evidera who were paid by GSK/ViiV Healthcare to conduct the CARISEL study. NS is the director of London Safety and Training Solutions Ltd, which offers training and improvement and implementation solutions to healthcare organisations and the pharmaceutical industry.

Background: We compared proportions of participants with target detected, target not detected (TND), and elevated viral load (VL) and assessed baseline variables associated with week 144 inflammatory biomarker levels between dolutegravir-lamivudine (DTG/3TC) and tenofovir alafenamide-based regimens (TBRs) in the TANGO study (post hoc)., Methods: TANGO is an open-label, multicenter, phase 3 study that randomized adults with VL <50 copies/mL to switch to once-daily fixed-dose DTG/3TC or continue TBR. At baseline and each study visit, the VL was measured. Elevated VL event frequencies were assessed, including "blips." Interleukin 6, D-dimer, high-sensitivity C-reactive protein, soluble CD14, and soluble CD163 were measured at baseline and at week 144. Log e -transformed week 144 biomarker levels were compared between treatment groups using an analysis of covariance model adjusting for baseline variables., Results: High, comparable proportions of participants had VL <40 copies/mL and TND at week 144 (DTG/3TC, 279 of 369 [76%]; TBR, 267 of 372 [72%], intention-to-treat exposed Snapshot analysis; adjusted difference, 3.9% [95% confidence interval, -2.5% to 10.2%]), with similar TND proportions at all postbaseline visits (123 of 369 [33%] vs 101 of 372 [27%], respectively). Similar proportions of DTG/3TC participants had ≥1 postbaseline VL ≥50 copies/mL (28 of 369 [8%] vs 42 of 372 [11%] for TBR), primarily blips (18 of 369 [5%] and 26 of 372 [7%], respectively). Week 144 inflammatory biomarker levels were low and comparable between groups and associated with multiple demographic and baseline characteristics, including baseline biomarker levels, indicating a multifactorial inflammatory response., Conclusions: Week 144 biomarker levels were low and generally comparable between treatment groups, reflecting similar, robust, and durable viral suppression observed using the stringent TND end point. Trial registration:  ClinicalTrials.gov, NCT03446573., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Competing Interests: E.F., C.M., J.S., A.Z., B.W., J.v.W., and M.A.-K. are employees of ViiV Healthcare and own stock in GSK. N.E. has received grants from Merck; honoraria for participation in presentations or educational events from Merck, Gilead, Janssen, and GSK; and travel support from Gilead, Janssen, and GSK; and has participated in data safety monitoring or advisory boards for Merck, Gilead, and GSK. RGulminetti has received grants from Gilead and ViiV Healthcare, which were paid to his institution; received consulting fees from AbbVie, Gilead, ViiV Healthcare, and Merck Sharp & Dohme; received honoraria from Gilead, ViiV Healthcare, and Merck Sharp & Dohme; provided expert testimony for Gilead and ViiV Healthcare; and received travel support from Gilead. D.H. has served as a principal investigator through her institution, received honoraria for participation in speakers bureaus, and received travel support from GSK/ViiV Healthcare; has participated in advisory boards for ViiV Healthcare; and serves on the Georgia ADAP committee. RGrove is an employee of and owns stock in GSK. J.S.M. and H.-C.T. have no conflicts of interest to disclose.

Background: Cardiometabolic outcomes were investigated 3 years after switching to the 2-drug regimen dolutegravir/lamivudine (DTG/3TC) vs continuing 3-/4-drug tenofovir alafenamide (TAF)-based regimens in a multicenter phase 3 noninferiority study based on an open-label randomized design., Method: Adults with virologically suppressed HIV-1 switched to once-daily DTG/3TC (n = 369) or continued TAF-based regimens (n = 372). Cardiometabolic health parameters were assessed through week 144 via mixed-model repeated measures or logistic regression analyses, adjusting for baseline variables., Results: At week 144, 13% (42/316) of the DTG/3TC group and 12% (37/303) of the TAF-based regimen group had ≥10% weight gain from baseline (adjusted odds ratio, 1.11; 95% CI, .68-1.80). Adjusted change from baseline in serum leptin, a surrogate marker of adiposity, was similar between groups (treatment ratio, 1.00; 95% CI, .89-1.13). The lipid profile generally favored DTG/3TC in the baseline boosted subgroup. Adjusted odds revealed no clinically meaningful differences between groups: homeostatic model assessment of insulin resistance ≥2 (adjusted odds ratio, 0.79; 95% CI, .50-1.26), metabolic syndrome (International Diabetes Federation criteria, 0.99; .59-1.68), hepatic fibrosis (fibrosis-4 index score ≥1.45, 1.39; .63-3.06), and coronary artery disease risk (Framingham risk score ≥10%, 0.92; .56-1.49). Baseline variables and characteristics associated with odds of each cardiometabolic parameter outcome were consistent with known risk factors, including age, sex, race, and some disease characteristics., Conclusions: Cardiometabolic health 3 years after switching to DTG/3TC was comparable to that for individuals continuing TAF-based regimens, further supporting DTG/3TC as a robust switch option with a stable metabolic profile., Trial Registration: ClinicalTrials.gov NCT03446573., Competing Interests: Potential conflicts of interest. R. L. B. has provided educational sessions or attended advisory boards (institutional and personal) for Novo Nordisk, International Medical Press, ViiV Healthcare, Pfizer, Gila Therapeutics Ltd, and Eli Lilly, and her institution has received research grant support or funding for clinical trials from Novo Nordisk and Fractyl. N. E. has received grants from Merck; honoraria for participation in presentations or educational events from Merck, Gilead, Janssen, and GSK; and travel support from Gilead, Janssen, and GSK. N. E. has also participated in data safety monitoring or advisory boards for Merck, Gilead, and GSK. C. K. has received grants and/or personal fees from ViiV Healthcare, Gilead, and MSD. M. M. has participated in the safety monitoring committee for the Adolescent Medicine Trials Network for HIV/AIDS Intervention and scientific advisory boards for Merck. S. S. has received grants and/or personal fees from PPD/GSK, ViiV Healthcare, AbbVie, Gilead, and Janssen. D. E. S. has received consulting fees and honoraria from ViiV Healthcare, Gilead, and Janssen and travel/meeting support from Gilead. M. A.-K., N. G., J. W., L. A. G, R. M., B. W., and J. v. W. are employees of ViiV Healthcare or GSK and own stock in GSK., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The TANGO study (ClinicalTrials.gov, NCT03446573) demonstrated that switching to dolutegravir/lamivudine (DTG/3TC) was non-inferior to continuing tenofovir alafenamide-based regimens (TBR) through week 144. Retrospective baseline proviral DNA genotypes were performed for 734 participants (post-hoc analysis) to assess the impact of archived, pre-existing drug resistance on 144-week virologic outcomes by last on-treatment viral load (VL) and Snapshot. A total of 320 (86%) participants on DTG/3TC and 318 (85%) on TBR had both proviral genotype data and ≥1 on-treatment post-baseline VL results and were defined as the proviral DNA resistance analysis population. Archived International AIDS Society-USA major nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, and integrase strand transfer inhibitor resistance-associated mutations (RAMs) were observed in 42 (7%), 90 (14%), 42 (7%), and 11 (2%) participants, respectively, across both groups; 469 (74%) had no major RAMs at baseline. M184V/I (1%), K65N/R (<1%), and thymidine analogue mutations (2%) were infrequent. Through week 144, >99% of participants on DTG/3TC and 99% on TBR were virologically suppressed (last on-treatment VL <50 copies/mL) regardless of the presence of major RAMs. Results from the sensitivity analysis by Snapshot were consistent with the last available on-treatment VL. In TANGO, archived, pre-existing major RAMs did not impact virologic outcomes through week 144.

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., Competing Interests: Potential conflicts of interest. O. O. has received personal fees from ViiV Healthcare, Gilead, and Merck; has received financial support for meeting attendance/travel from GlaxoSmithKline and Merck; and owns stock in Gilead, Pfizer, and GlaxoSmithKline. S. D. W. has received financial support or grants paid to his institution from ViiV Healthcare, Gilead, Merck Sharpe & Dohme, and Janssen and has participated in data safety monitoring or advisory boards for ViiV Healthcare and Curevac. F. B. has participated in advisory boards for Gilead and is the president of AusPATH. J. P. 
has received grants, personal fees, and nonfinancial support from ViiV Healthcare, Gilead, and Janssen-Cilag. C. W. has received personal fees from AbbVie, AstraZeneca, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharpe & Dohme, Roche, Theratechnologies, and ViiV Healthcare for speaking at educational events or participating in advisory boards. M. A. -K., 
P. L., K. A. P., R. W., B. W., M. A., J. v. W., and K. Y. S. are employees of ViiV Healthcare and own stock in GlaxoSmithKline. J. W. and N. G. are employees of and own stock in GlaxoSmithKline. F. A. and J. -P. R. report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: GEMINI-1 and GEMINI-2 (ClinicalTrials.gov, NCT02831673 and NCT02831764, respectively) are double-blind, multicenter, phase III studies that demonstrated the non-inferiority of once-daily dolutegravir + lamivudine to dolutegravir + tenofovir disoproxil fumarate/emtricitabine in achieving HIV-1 RNA <50 copies/mL at 48, 96, and 144 weeks in treatment-naive adults with HIV-1 infection. Objective: We present a post hoc analysis of the impact of treatment adherence on Week 48 virologic response. Methods: Adherence was estimated using pill counts and categorized as ≥90% vs <90%. Unadjusted treatment differences with exact 95% CIs were derived for the proportion of participants with HIV-1 RNA <50 copies/mL within each adherence category, using Snapshot algorithm and last available on-treatment viral load through Week 48. Results: In each treatment group, 5% of participants had <90% adherence (dolutegravir + lamivudine group, 35/716; dolutegravir + tenofovir disoproxil fumarate/emtricitabine group, 34/717). The proportion of participants with HIV-1 RNA <50 copies/mL (Snapshot) at Week 48 in the <90% adherence group was 69% in the dolutegravir + lamivudine group and 65% in the dolutegravir + tenofovir disoproxil fumarate/emtricitabine group (analysis by last on-treatment viral load: 91% and 85%, respectively). Corresponding proportions in the ≥90% adherence group were 93% and 96% (analysis by last on-treatment viral load: 97% and 99%, respectively). Conclusions: Decreased adherence resulted in lower Week 48 virologic efficacy outcomes that were comparable between treatment groups. These results indicate that the robust antiviral activity and regimen forgiveness of dolutegravir + lamivudine is similar to dolutegravir-containing 3-drug regimens (see graphical abstract).

Background: In TANGO, switching to dolutegravir/lamivudine was noninferior at 48 weeks to continuing 3-/4-drug tenofovir alafenamide-based regimens in virologically suppressed individuals with HIV-1. Antiretroviral agents have been associated with weight gain and metabolic complications., Setting: One hundred thirty-four centers; 10 countries., Methods: We assessed weight; fasting lipids, glucose, and insulin; and prevalence of insulin resistance and metabolic syndrome at baseline and week 48 in TANGO participant subgroups by boosting agent use in baseline regimens (boosted and unboosted)., Results: In each treatment group, 74% of participants used boosted regimens at baseline. In boosted and unboosted subgroups, weight and fasting glucose changes at week 48 were small and similar between treatment groups. Overall and in the boosted subgroup, greater decreases from baseline were observed with dolutegravir/lamivudine in fasting total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P < 0.001), triglycerides (P < 0.001), total cholesterol/high-density lipoprotein cholesterol ratio (overall, P = 0.017; boosted, P = 0.007), and insulin (boosted, P = 0.005). Prevalence of HOMA-IR ≥2 was significantly lower at week 48 with dolutegravir/lamivudine overall [adjusted odds ratio (aOR), 0.59; 95% confidence interval (CI), 0.40 to 0.87; P = 0.008] and in the boosted subgroup [aOR, 0.56; 95% CI, 0.36 to 0.88; P = 0.012] but not in the unboosted subgroup [aOR, 0.70; 95% CI, 0.31 to 1.58; P = 0.396]. Prevalence of metabolic syndrome at week 48 was low and consistent between treatment groups overall, with differences trending to favor dolutegravir/lamivudine in the unboosted subgroup [aOR, 0.41; 95% CI, 0.15 to 1.09; P = 0.075]., Conclusion: Generally, switching from 3-/4-drug tenofovir alafenamide-based regimens to dolutegravir/lamivudine improved metabolic parameters, particularly when switching from boosted regimens. Because of smaller sample size in the unboosted subgroup, results warrant further investigation., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The concurrent treatment of tuberculosis and human immunodeficiency virus (HIV) is challenging, owing to drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). The efficacy and safety of dolutegravir (DTG) were assessed in adults with HIV and drug-susceptible tuberculosis., Methods: International Study of Patients with HIV on Rifampicin ING is a noncomparative, active-control, randomized, open-label study in HIV-1-infected antiretroviral therapy-naive adults (CD4+ ≥50 cells/mm3). Participants on rifampicin-based tuberculosis treatment ≤8 weeks were randomized (3:2) to receive DTG (50 mg twice daily both during and 2 weeks after tuberculosis therapy, then 50 mg once daily) or efavirenz (EFV; 600 mg daily) with 2 nucleoside reverse transcriptase inhibitors for 52 weeks. The primary endpoint was the proportion of DTG-arm participants with plasma HIV-1-RNA <50 copies/mL (responders) by the Food and Drug Administration Snapshot algorithm (intent-to-treat exposed population) at Week 48. The study was not powered to compare arms., Results: For DTG (n = 69), the baseline HIV-1 RNA was >100 000 copies/mL in 64% of participants, with a median CD4+ count of 208 cells/mm3; for EFV (n = 44), 55% of participants had HIV-1 RNA >100 000 copies/mL, with a median CD4+ count of 202 cells/mm3. The Week 48 response rates were 75% (52/69, 95% confidence interval [CI] 65-86%) for DTG and 82% (36/44, 95% CI 70-93%) for EFV. The DTG nonresponses were driven by non-treatment related discontinuations (n = 10 lost to follow-up). There were no deaths or study drug switches. There were 2 discontinuations for toxicity (EFV). There were 3 protocol-defined virological failures (2 DTG, no acquired resistance; 1 EFV, emergent resistance to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors). The tuberculosis treatment success rate was high. Tuberculosis-associated IRIS was uncommon (4/arm), with no discontinuations for IRIS., Conclusions: Among adults with HIV receiving rifampicin-based tuberculosis treatment, twice-daily DTG was effective and well tolerated., Clinical Trials Registration: NCT02178592., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The Phase III VIKING-3 study demonstrated that dolutegravir (DTG) 50 mg twice daily was efficacious in antiretroviral therapy (ART)-experienced subjects harbouring raltegravir- and/or elvitegravir-resistant HIV-1. VIKING-4 (ING116529) included a placebo-controlled 7-day monotherapy phase to demonstrate that short-term antiviral activity was attributable to DTG., Methods: VIKING-4 is a Phase III randomized, double-blind study in therapy-experienced adults with integrase inhibitor (INI)-resistant virus randomized to DTG 50 mg twice daily or placebo while continuing their failing regimen (without raltegravir or elvitegravir) for 7 days (clinicaltrials.gov identifier NCT01568892). At day 8, all subjects switched to open-label DTG 50 mg twice daily and optimized background therapy including ≥1 fully active drug. The primary end point was change from baseline in plasma HIV-1 RNA at day 8., Results: The study population (n=30) was highly ART-experienced with advanced HIV disease. Patients had extensive baseline resistance to all approved antiretroviral classes. Adjusted mean change in HIV-1 RNA at day 8 was 
-1.06 log10 copies/ml for the DTG arm and 0.10 log10 copies/ml for the placebo arm (treatment difference -1.16 log10 copies/ml [-1.52, -0.80]; P<0.001). Overall, 47% and 57% of subjects had plasma HIV-1 RNA <50 and <400 copies/ml at week 24, and 40% and 53% at week 48, respectively. No discontinuations due to drug-related adverse events occurred in the study., Conclusions: The observed day 8 antiviral activity in this highly treatment-experienced population with INI-resistant HIV-1 was attributable to DTG. Longer-term efficacy (after considering baseline ART resistance) and safety during the open-label phase were in-line with the results of the larger VIKING-3 study.

Background: The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the 50 mg twice daily (BID) dose., Methods: VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued. The primary efficacy endpoints were the mean change from baseline in plasma HIV-1 RNA at day 8 and the proportion of subjects with HIV-1 RNA <50 c/mL at week 24., Results: Mean change in HIV-1 RNA at day 8 was -1.43 log10 c/mL, and 69% of subjects achieved <50 c/mL at week 24. Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced in subjects with Q148 + ≥2 resistance-associated mutations. DTG 50 mg BID had a low (3%) discontinuation rate due to adverse events, similar to INI-naive subjects receiving DTG 50 mg once daily., Conclusions: DTG 50 mg BID-based therapy was effective in this highly treatment-experienced population with INI-resistant virus., Clinical Trials Registration: www.clinicaltrials.gov (NCT01328041) and http://www.gsk-clinicalstudywww.gsk-clinicalstudyregister.com (112574)., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)