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.

A proposed modification to Hy's law and Edish criteria in oncology clinical trials using aggregated historical data.

PURPOSE: Identifying drug-induced liver injury is a critical task in drug development and postapproval real-world care. Severe liver injury is identified by the liver chemistry threshold of alanine aminotransferase (ALT) >3× upper limit of normal (ULN) and bilirubin >2× ULN, termed Hy's law by the Food and Drug Administration. These thresholds require discontinuation of the causative drug and are seldom exceeded in most patient populations. However, because maintenance of therapy is critical in the treatment of advanced cancer, customized thresholds may be useful in oncology patient populations, particularly for those with baseline liver chemistries elevations. METHODS: Liver chemistry data from 31 aggregated oncology clinical trials were modeled through a truncated robust multivariate outlier detection (TRMOD) method to develop the decision boundary or threshold for examining liver injury in oncology clinical trials. RESULTS: The boundary of TRMOD identified outliers with an ALT limit 5.0× ULN and total bilirubin limit 2.7× ULN. In addition, TRMOD was applied to the aggregated oncology data to examine fold-baseline ALT and total bilirubin, revealing limits of ALT 6.9× baseline and bilirubin 6.5× baseline. Similar ALT and bilirubin threshold limits were observed for oncology patients both with and without liver metastases. CONCLUSIONS: These higher liver chemistry thresholds examining fold-ULN and fold-baseline data may be valuable in identifying potential severe liver injury and detecting liver safety signals of clinical concern in oncology clinical trials and postapproval settings while helping to avoid premature discontinuation of curative therapy.

Truncated robust distance for clinical laboratory safety data monitoring and assessment.

Laboratory safety data are routinely collected in clinical studies for safety monitoring and assessment. We have developed a truncated robust multivariate outlier detection method for identifying subjects with clinically relevant abnormal laboratory measurements. The proposed method can be applied to historical clinical data to establish a multivariate decision boundary that can then be used for future clinical trial laboratory safety data monitoring and assessment. Simulations demonstrate that the proposed method has the ability to detect relevant outliers while automatically excluding irrelevant outliers. Two examples from actual clinical studies are used to illustrate the use of this method for identifying clinically relevant outliers.

Three-year durable efficacy of dolutegravir plus lamivudine in antiretroviral therapy - naive adults with HIV-1 infection.

OBJECTIVE: To assess efficacy and safety of dolutegravir (DTG) + lamivudine (3TC) vs. DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive adults with HIV-1 in the prespecified 144-week secondary analyses of GEMINI-1 and GEMINI-2. DESIGN: Identical, multicenter, phase III, randomized, non-inferiority studies (double-blind through 96 weeks). METHODS: Participants with HIV-1 RNA ≤500 000 copies/ml and no major viral resistance mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors were randomized 1:1 to once-daily DTG + 3TC or DTG + TDF/FTC. RESULTS: At week 144, DTG + 3TC (N = 716) was noninferior to DTG + TDF/FTC (N = 717) in proportion of participants achieving HIV-1 RNA <50 copies/ml (Snapshot algorithm) in the pooled analysis (82% vs. 84%, respectively; adjusted treatment difference [95% confidence interval (CI)], -1.8% [-5.8, 2.1]), GEMINI-1 (-3.6% [-9.4, 2.1]), and GEMINI-2 (0.0% [-5.3, 5.3]). Twelve DTG + 3TC participants and nine DTG + TDF/FTC participants met protocol-defined confirmed virologic withdrawal (CVW) criteria; none developed treatment-emergent resistance. One DTG + 3TC participant who did not meet CVW criteria developed M184V at week 132 and R263R/K at week 144, conferring a 1.8-fold change in susceptibility to DTG; non-adherence to therapy was reported. Significantly fewer drug-related adverse events occurred with DTG + 3TC vs. DTG + TDF/FTC (20% vs. 27%; relative risk [95% CI], 0.76 [0.63-0.92]). Renal and bone biomarker changes favored DTG + 3TC. CONCLUSIONS: Three-year durable efficacy, long-term tolerability, and high barrier to resistance support first-line use of DTG + 3TC for HIV-1 treatment (see Supplemental Digital Content 1, http://links.lww.com/QAD/C297; video abstract).

Incident type 2 diabetes mellitus after initiation of common HIV antiretroviral drugs.

OBJECTIVES: To describe the prevalence and incidence of prediabetes and type 2 diabetes mellitus (T2DM) among people living with HIV (PLHIV) and evaluate the association between antiretroviral therapy (ART) initiation with dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), raltegravir (RAL), or boosted darunavir (bDRV) and incident T2DM. DESIGN: Longitudinal study based on electronic health records of 29 674 PLHIV from the Observational Pharmaco-Epidemiology Research and Analysis (OPERA) cohort. METHODS: Calculate prevalence of prediabetes and T2DM at regimen initiation. Among PLHIV without prevalent disease, estimate prediabetes and T2DM incidence (Poisson regression) and association between regimen and incident T2DM (multivariate Cox proportional hazards regression). Analyses stratified by ART experience. RESULTS: Among ART-naive and ART-experienced/suppressed PLHIV, the estimated prevalence of prediabetes was 8 and 11%; that of T2DM was 4 and 10%, respectively. The T2DM incidence rate was 9 per 1000 person-years [95% confidence interval (CI): 8-11] among ART-naive and 13 per 1000 person-years (95% CI: 12-15) among ART-experienced/suppressed PLHIV, with no statistically significant differences between regimens. Compared with DTG, no statistically significant association between T2DM risk and regimen was observed among ART-naive on EVG/c [adjusted hazard ratios: 0.70 (95% CI: 0.47-1.05)] or bDRV [0.53 (0.26-1.04)] and ART-experienced/suppressed on EVG/c [0.96 (0.70-1.33)], RAL [1.17 (0.70-1.96)] or bDRV [0.90 (0.57-1.42)]. CONCLUSION: No increased risk of T2DM was observed with EVG/c, RAL or bDRV compared with DTG in ART-naive and experienced PLHIV. However, despite a large cohort, there was a small number of events and differential risk cannot be excluded.

Hypersensitivity reactions, hepatotoxicity, and other discontinuations in persons receiving integrase strand transfer inhibitors: results from the EuroSIDA study.

Background: Hypersensitivity reaction (HSR) and hepatotoxicity are rare, but potentially serious side-effects of antiretroviral use.Objective: To investigate discontinuations due to HSR, hepatotoxicity or other reasons among users of dolutegravir (DTG) vs. raltegravir (RAL) or elvitegravir (EVG) in the EuroSIDA cohort.Methods: We compared individuals ≥18 years and starting combination antiretroviral therapy (ART, ≥3 drugs) with DTG vs. RAL or EVG, with or without abacavir (ABC), between January 16, 2014 and January 23, 2019. Discontinuations due to serious adverse events (SAEs) were independently reviewed.Results: Altogether 4366 individuals started 5116 ART regimens including DTG, RAL, or EVG, contributing 9180 person-years of follow-up (PYFU), with median follow-up 1.6 (interquartile range 0.7-2.8) years per treatment episode. Of these, 3074 (60.1%) used DTG (1738 with ABC, 1336 without) and 2042 (39.9%) RAL or EVG (286 with ABC, 1756 without). 1261 (24.6%) INSTI episodes were discontinued, 649 of the DTG-containing regimens (discontinuation rate 115, 95% CI 106-124/1000 PYFU) and 612 RAL or EVG-containing regimens (173, CI 160-188/1000 PYFU). After independent review, there were five HSR discontinuations, two for DTG (one with and one without ABC, discontinuation rate 0.35, CI 0.04-1.28/1000 PYFU), and three for RAL or EVG without ABC (0.85, CI 0.18-2.48/1000 PYFU). There was one hepatotoxicity discontinuation on DTG with ABC (discontinuation rate 0.18, CI 0.00-0.99/1000 PYFU).Conclusion: During 5 years of observations in the EuroSIDA cohort independently reviewed discontinuations due to HSR or hepatotoxicity were very rare, indicating a low rate of SAEs.

Brief Report: Weight Gain Following ART Initiation in ART-Naïve People Living With HIV in the Current Treatment Era.

OBJECTIVES: Evaluate differences in weight change by regimen among people living with HIV (PLWH) initiating antiretroviral therapy (ART) in the current era. METHODS: Between 2012 and 2019, 3232 ART-naïve PLWH initiated ≥3-drug ART regimens in 8 Centers for AIDS Research Network of Integrated Clinical Systems sites. We estimated weight change by regimen for 11 regimens in the immediate (first 6 months) and extended (all follow-up on initial regimen) periods using linear mixed models adjusted for time on regimen, interaction between time and regimen, age, sex, race/ethnicity, hepatitis B/C coinfection, nadir CD4, smoking, diabetes, antipsychotic medication, and site. We included more recently approved regimens [eg, with tenofovir alafenamide fumarate (TAF)] only in the immediate period analyses to ensure comparable follow-up time. RESULTS: Mean follow-up was 1.9 years on initial ART regimen. In comparison to efavirenz/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), initiating bictegravir/TAF/FTC {3.9 kg [95% confidence interval (CI): 2.2 to 5.5]} and dolutegravir/TAF/FTC [4.4 kg (95% CI: 2.1 to 6.6)] were associated with the greatest weight gain in the immediate period, followed by darunavir/TDF/FTC [3.7 kg (95% CI: 2.1 to 5.2)] and dolutegravir/TDF/FTC [2.6 kg (95% CI: 1.3 to 3.9)]. In the extended period, compared with efavirenz/TDF/FTC, initiating darunavir/TDF/FTC was associated with a 1.0 kg (95% CI: 0.5 to 1.5) per 6-months greater weight gain, whereas dolutegravir/abacavir/FTC was associated with a 0.6-kg (95% CI: 0.3 to 0.9) and dolutegravir/TDF/FTC was associated with a 0.6-kg (95% CI: 0.1 to 1.1) per 6-months greater gain. Weight gain on dolutegravir/abacavir/FTC and darunavir/TDF/FTC was significantly greater than that for several integrase inhibitor-based regimens. CONCLUSIONS: There is heterogeneity between regimens in weight gain following ART initiation among previously ART-naïve PLWH; we observed greater gain among PLWH taking newer integrase strand transfer inhibitors (DTG, BIC) and DRV-based regimens.

Antiretroviral therapy and liver disorders in the OPERA® cohort.

INTRODUCTION: A comprehensive assessment of liver disorders was conducted among people living with HIV (PLWH) on a new antiretroviral regimen based on common core agents. METHODS: Treatment-naïve and experienced PLWH first initiating dolutegravir (DTG), elvitegravir (EVG), raltegravir (RAL), or darunavir (DRV) in the OPERA® cohort were included if they had ⩾1 liver chemistry test performed both within 12 months before regimen start and over follow-up. Liver disorders were defined as a diagnosis of drug-induced liver injury (DILI) or moderate/severe liver chemistry elevations (LCE). History of liver disorders experienced within 12 months of initiation was summarized. Liver disorders occurring during follow-up were described as prevalent (all disorders) or incident (disorders occurring among PLWH without a history of liver disorders or advanced liver fibrosis). RESULTS: Out of 16,024 PLWH, 38% initiated DTG, 43% EVG, 5% RAL, and 14% DRV. EVG users were younger and had a lower likelihood of comorbidities or lipid-lowering agent use than DTG users. EVG users were significantly less likely to have a history of moderate/severe LCE or to have prevalent moderate LCE. RAL users were older and had a higher likelihood of comorbidities or lipid-lowering agent use than DTG users. RAL users were significantly more likely to have a history of advanced liver fibrosis and prevalent moderate/severe LCE during follow-up. DRV users were older and had a lower likelihood of lipid-lowering agent use than DTG users. There was no difference in history of LCE, nor in prevalent or incident LCE between DRV and DTG users. No DILI diagnoses were recorded. Discontinuation following a liver disorder was rare (<1%) across all groups. CONCLUSION: While PLWH with comorbidities may have been channeled away from EVG and toward DTG and RAL, the incidence of moderate/severe LCE did not differ between DTG and EVG, RAL, and DRV. PLAIN LANGUAGE SUMMARY: Liver disorders and HIV treatment A comprehensive assessment of liver disorders was conducted using data from the OPERA® cohort, which provides anonymous patient-level clinical data from electronic health records. People living with HIV (PLWH) who were starting a new HIV treatment regimen that included one of four common HIV drugs were included in this study. Liver disorders included drug-induced liver injury (DILI) and moderate or severe liver chemistry elevations. History of a disorder was defined as liver disorders that occurred before starting the new treatment. Prevalent disorders were those that occurred after starting the new treatment in the whole population. Incident disorders were those that occurred after starting the new treatment, but only among PLWH without any history of liver disorders.Out of 16,024 PLWH, 38% initiated dolutegravir (DTG), 43% elvitegravir (EVG), 5% raltegravir (RAL), and 14% darunavir (DRV). EVG users were younger and less likely to have other diseases or use cholesterol lowering drugs compared to DTG users. They were also less likely to have a history of moderate/severe liver chemistry elevations or to have prevalent moderate liver chemistry elevations. RAL users were older and more likely to have other diseases or use cholesterol lowering drugs compared to DTG users. They were also more likely to have prevalent moderate/severe liver chemistry elevations than DTG users. DRV users were older and less likely to use cholesterol lowering agents compared to DTG users. There was no difference in history of liver chemistry elevations, or in prevalent, or incident liver chemistry elevations between DRV and DTG users. There were no DILI diagnoses and discontinuation of treatment following liver disorders was rare across all groups. Overall, the incidence of liver disorders after starting a new HIV treatment regimen did not differ between four common antiretroviral drugs.

Psychiatric outcomes observed in patients living with HIV using six common core antiretrovirals in the Observational Pharmaco-Epidemiology Research and Analysis database.

BACKGROUND: Psychiatric outcomes are common among people living with HIV and may be associated with specific antiretroviral use. We evaluated the occurrence of psychiatric outcomes in patients taking dolutegravir (DTG)-containing regimens compared with five other core agents. METHODS: Patients in the OPERA database prescribed regimens based on DTG, efavirenz (EFV), raltegravir (RAL), darunavir (DRV), rilpivirine (RPV), or elvitegravir (EVG) for the first time between 1 January 2013 and 31 December 2015 were analyzed. Psychiatric outcomes included diagnoses of anxiety, depression, insomnia, or suicidality during core agent exposure. Multivariable Cox analysis models were used to assess time to psychiatric outcomes between core agents stratified by psychiatric history, with DTG as the referent. RESULTS: A total of 13,261 patients initiated a regimen of interest (DTG: 2783; RAL: 979; EVG: 3895, EFV: 1746, RPV: 1921, DRV: 1937). Psychiatric history was common, with varied prevalence across groups (DTG 38%, EFV 24%, RAL 40%, DRV 34%, RPV 29%, EVG 31%). Among patients without a psychiatric history, the likelihood of a psychiatric outcome during follow up did not differ between DTG and the other core agents. Among patients with a psychiatric history, risk during follow up for patients taking DTG was equivalent (versus RPV), marginally reduced (versus RAL and EFV), or reduced (versus EVG and DRV). CONCLUSIONS: In a large cohort of HIV+ patients in care, patients with a psychiatric history appeared channeled towards drugs with known favorable psychiatric safety profiles, including DTG. Despite this, DTG exposure was not associated with an increased risk of psychiatric outcomes during follow up in patients with or without a psychiatric history.

Psychiatric Symptoms in Patients Receiving Dolutegravir.

INTRODUCTION: Psychiatric symptoms (PSs) are reported to occur frequently in people living with HIV and may be associated with specific antiretrovirals. We analyzed PSs observed with dolutegravir (DTG) and other frequently prescribed anchor drugs. METHODS: Selected PSs (insomnia, anxiety, depression, and suicidality) occurring in HIV-positive patients during DTG treatment across 5 randomized clinical trials (3 double-blind), in the Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, and among cases spontaneously reported to ViiV Healthcare were analyzed. RESULTS: In clinical trials, PSs were reported at low and similar rates in patients receiving DTG or comparators [atazanavir, darunavir, efavirenz, or raltegravir (RAL)]. Insomnia was most commonly reported. The highest rates were observed in SINGLE (DTG 17%, efavirenz 12%), with consistently lower rates in the other trials (DTG: 3%-8% versus comparator: 3%-7%). More efavirenz-treated patients withdrew because of PSs than patients treated with other anchor drugs. In OPERA, history of PSs at baseline was lowest in efavirenz-treated patients compared with patients treated with DTG, RAL, or darunavir. Despite baseline differences, prevalence and incidence during treatment were similar across the 4 anchor drugs. Withdrawal rates for PSs were lowest for DTG (0%-0.6%) and highest for RAL (0%-2.5%). Spontaneously reported events were similar in nature to clinical trial data. CONCLUSIONS: Analysis of 3 different data sources shows that, similar to other frequently prescribed anchor drugs to treat HIV infection, PSs are also reported in DTG-treated patients. These events are reported with low frequency and rarely necessitate DTG discontinuation.

Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects.

BACKGROUND: Recently, the Data collection of Adverse events of Anti-HIV Drugs Group (D:A:D) described results from their international observational cohort of 33,347 HIV-1-infected individuals, suggesting unexpected increased risk of myocardial infarction (MI) associated with abacavir (ABC) therapy [relative rate 1.9, 95% confidence interval (CI): 1.47 to 2.45; P = 0.0001]. To contribute to the scientific question, we summarized GlaxoSmithKline HIV clinical trial data to determine if a similar signal emerged. METHODS: We compiled data from GlaxoSmithKline-sponsored clinical trials with > or = 24 weeks of combination antiretroviral therapy comprising 14,174 HIV-infected adults who received ABC (n = 9502; 7641 person-years) or not (n = 4672; 4267 person-years). FINDINGS: Baseline demographics and HIV disease characteristics, including lipids and glucose values, were similar. MI rates were comparable among subjects exposed [n = 16 (0.168%; CI: 0.096 to 0.273; 2.09 per 1000 person-years)] or not [n = 11 (0.235%; CI: 0.118 to 0.421; 2.57 per 1000 person-years)] to ABC-containing therapy. Results of 12 trials with randomization to ABC or not were consistent (2.15 per 1000 person-years vs. 4.10 per 1000 person-years). INTERPRETATIONS: In this pooled summary, we observed few MI events overall and no excess risk of MI with ABC therapy. It is unclear why results from this data set seem discrepant to the Data collection of Adverse events of Anti-HIV Drugs data set, particularly, as the non-ABC MI event rate is similar. Further data are needed to evaluate any association between ABC and increased risk of MI.