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Taramasso, Lucia, Antonio Falletta, Elena Ricci, et al. "Trajectories of CD4+/CD8+ T-Cells Ratio 96 Weeks after Switching to Dolutegravir-Based Two-Drug Regimens: Results from a Multicenter Prospective Cohort Study." Viruses 14, no. 11 (2022): 2315. http://dx.doi.org/10.3390/v14112315.
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The aim of the present study was to evaluate CD4/CD8 dynamics in patients on dolutegravir (DTG)-based two-drug regimens (2DRs) and compare them with DTG-containing triple-drug regimens (3DRs). A prospective observational study was performed in the context of the SCOLTA cohort. Experienced PWH with HIV-RNA < 50 copies/mL were included if they were on the DTG-2DR, the DTG + tenofovir/emtricitabine (TDF/FTC) regimen, the DTG + tenofovir alafenamide (TAF)/FTC regimen, or the DTG + abacavir/lamivudine (ABC/3TC) regimen; they were followed-up for at least one year. A total of 533 PWH were enrolled, 120 in the DTG + 3TC group, 38 in the DTG + protease inhibitors (PI) group, 67 in the DTG + rilpivirine (RPV) group, 49 in the DTG + TDF/FTC group, 27 in the DTG + TAF/FTC group, and 232 in the DTG + ABC/3TC group. After one year, the CD4/CD8 ratio significantly increased in the PWH treated with DTG + 3TC (+0.08 ± 0.26), DTG + TDF/FTC (+0.1 ± 0.19), and DTG + ABC/3TC (+0.08 ± 0.25). At two years, the CD4/CD8 increase was confirmed for PWH on DTG + TDF/FTC (+0.16 ± 0.28) and DTG + ABC/3TC (+0.1 ± 0.3). In the SCOLTA cohort, PWH on 2DRs experienced a CD4/CD8 increase only in the DTG + 3TC group. Controlled studies with longer follow-up will clarify the long-term immunological and clinical impacts of DTG-2DR.
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Ward, Douglas, Steven F. Scheibel, Moti Ramgopal, et al. "2485. Real-world Experience with Dolutegravir Plus Rilpivirine Two-Drug Regimen." Open Forum Infectious Diseases 6, Supplement_2 (2019): S861. http://dx.doi.org/10.1093/ofid/ofz360.2163.
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Abstract Background Three-drug regimens (3DRs) have long been the mainstay of antiretroviral treatment (ART) for HIV. Dolutegravir-based two-drug regimens (DTG 2DRs) are now accepted alternatives to 3DRs, with the first 2DR single tablet regimen (STR), Juluca (DTG/rilpivirine [RPV]), FDA-approved in 2017. This study evaluated treatment patterns of DTG+RPV in clinical practice to understand use prior to availability of DTG/RPV STR. Methods A retrospective medical chart review was conducted across 10 US sites identified as using any DTG 2DRs. Eligible patients were adults initiated on DTG 2DR prior to July 31, 2017 and followed up to January 30, 2018. This analysis describes a subgroup who received DTG+RPV 2DR. Patient demographics, clinical characteristics and treatment history were abstracted from medical charts. Analyses were descriptive. Results From an overall sample of 278 DTG 2DR patients, 66 received DTG+RPV 2DR. In this DTG+RPV subgroup, mean age was 56 years, 79% were male and 68% were Caucasian. Most were treatment-experienced (97%), with an average 15.5 years of prior ART; 48% had received ≥ 4 prior regimens. The most common physician reported reasons for initiating DTG+RPV were avoidance of potential long-term toxicities (53%), toxicity/intolerance of ARVs (20%) and treatment simplification/streamlining (15%). Prior to initiation of DTG+RPV, 70% of patients were virologically suppressed (< 50 copies/mL); of those, 98% remained suppressed after switching to DTG+RPV. Of the 30% of patients with detectable viral load prior to DTG+RPV initiation, 60% achieved and maintained virologic suppression on DTG+RPV. Mean time on DTG+RPV was 1.6 years. Only 5 (8%) patients discontinued DTG+RPV by data cut-off, and one patient was lost to follow-up. Reasons for discontinuation were virologic failure (n = 2), treatment simplification/streamlining (n = 2) and toxicity/intolerance (n = 1). Physicians reported that most patients (91%) achieved the desired outcome from DTG+RPV use. Conclusion Prior to commercial availability of DTG/RPV STR in the United States, DTG+RPV was used primarily in treatment experienced patients, most commonly to avoid potential long-term toxicities. A high proportion of patients achieved the desired outcome and maintained virologic suppression while receiving DTG+RPV. Disclosures All authors: No reported disclosures.
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C. Ramos-Sanchez, M., F. J. Rey, M. L. Rodriguez, F. J. Martin-Gil, and J. Martin-Gil. "DTG and dta studies on typical sugars." Thermochimica Acta 134 (October 1988): 55–60. http://dx.doi.org/10.1016/0040-6031(88)85216-x.
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Ramos-Sanchez, M. C., J. A. Leal, J. Martin-Gil, and F. J. Martin-Gil. "DTG and DTA studies on fungical polysaccharides." Thermochimica Acta 134 (October 1988): 61–65. http://dx.doi.org/10.1016/0040-6031(88)85217-1.
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Rey, F. J., M. C. Ramos-Sanchez, M. L. Rodriguez-Mendez, J. Martin-Gil, and F. J. Martin-Gil. "DTG and DTA studies on sugar derivatives." Thermochimica Acta 134 (October 1988): 67–72. http://dx.doi.org/10.1016/0040-6031(88)85218-3.
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L. Rodriguez-Mendez, Ma, F. J. Rey, J. Martin-Gil, and F. J. Martin-Gil. "DTG and DTA studies on amino acids." Thermochimica Acta 134 (October 1988): 73–78. http://dx.doi.org/10.1016/0040-6031(88)85219-5.
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Taramasso, Lucia, Giancarlo Orofino, Elena Ricci, et al. "Reversibility of Central Nervous System Adverse Events in Course of Art." Viruses 14, no. 5 (2022): 1028. http://dx.doi.org/10.3390/v14051028.
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The purpose of this study is to evaluate the frequency of central nervous system adverse events (CNS-AE) on dolutegravir (DTG) and non-DTG containing ART, and their reversibility, in the observational prospective SCOLTA cohort. Factors associated with CNS-AE were estimated using a Cox proportional-hazards model. 4939 people living with HIV (PLWH) were enrolled in DTG (n = 1179) and non-DTG (n = 3760) cohorts. Sixty-six SNC-AE leading to ART discontinuation were reported, 39/1179 (3.3%) in DTG and 27/3760 (0.7%) in non-DTG cohort. PLWH naïve to ART, with higher CD4 + T count and with psychiatric disorders were more likely to develop a CNS-AE. The risk was lower in non-DTG than DTG-cohort (aHR 0.33, 95% CI 0.19–0.55, p < 0.0001). One-year follow-up was available for 63/66 PLWH with CNS-AE. AE resolution was reported in 35/39 and 23/24 cases in DTG and non-DTG cohorts, respectively. The probability of AE reversibility was not different based on ART class, sex, ethnicity, CDC stage, or baseline psychiatric disorder. At the same time, a lower rate of event resolution was found in PLWH older than 50 years (p = 0.017). In conclusion, CNS-AE leading to ART discontinuation was more frequent in DTG than non-DTG treated PLWH. Most CNS-AE resolved after ART switch, similarly in both DTG and non-DTG cohorts.
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Hauser, Anthony, Katharina Kusejko, Leigh F. Johnson, et al. "Impact of scaling up dolutegravir on antiretroviral resistance in South Africa: A modeling study." PLOS Medicine 17, no. 12 (2020): e1003397. http://dx.doi.org/10.1371/journal.pmed.1003397.
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Background Rising resistance of HIV-1 to non-nucleoside reverse transcriptase inhibitors (NNRTIs) threatens the success of the global scale-up of antiretroviral therapy (ART). The switch to WHO-recommended dolutegravir (DTG)-based regimens could reduce this threat due to DTG’s high genetic barrier to resistance. We used mathematical modeling to predict the impact of the scale-up of DTG-based ART on NNRTI pretreatment drug resistance (PDR) in South Africa, 2020 to 2040. Methods and findings We adapted the Modeling Antiretroviral drug Resistance In South Africa (MARISA) model, an epidemiological model of the transmission of NNRTI resistance in South Africa. We modeled the introduction of DTG in 2020 under 2 scenarios: DTG as first-line regimen for ART initiators, or DTG for all patients, including patients on suppressive NNRTI-based ART. Given the safety concerns related to DTG during pregnancy, we assessed the impact of prescribing DTG to all men and in addition to (1) women beyond reproductive age; (2) women beyond reproductive age or using contraception; and (3) all women. The model projections show that, compared to the continuation of NNRTI-based ART, introducing DTG would lead to a reduction in NNRTI PDR in all scenarios if ART initiators are started on a DTG-based regimen, and those on NNRTI-based regimens are rapidly switched to DTG. NNRTI PDR would continue to increase if DTG-based ART was restricted to men. When given to all men and women, DTG-based ART could reduce the level of NNRTI PDR from 52.4% (without DTG) to 10.4% (with universal DTG) in 2040. If only men and women beyond reproductive age or on contraception are started on or switched to DTG-based ART, NNRTI PDR would reach 25.9% in 2040. Limitations include substantial uncertainty due to the long-term predictions and the current scarcity of knowledge about DTG efficacy in South Africa. Conclusions Our model shows the potential benefit of scaling up DTG-based regimens for halting the rise of NNRTI resistance. Starting or switching all men and women to DTG would lead to a sustained decline in resistance levels, whereas using DTG-based ART in all men, or in men and women beyond childbearing age, would only slow down the increase in levels of NNRTI PDR.
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Acosta, Rima K., Andrew Mulato, Michelle L. D’Antoni, Stephen R. Yant, Tomas Cihlar, and Kirsten L. White. "888. In Vitro Forgiveness of INSTI-Containing Regimens at Drug Concentrations Simulating Variable Adherence." Open Forum Infectious Diseases 8, Supplement_1 (2021): S535. http://dx.doi.org/10.1093/ofid/ofab466.1083.
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Abstract Background The integrase strand transfer inhibitor (INSTI)-based regimens bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), dolutegravir (DTG)+FTC/TAF, DTG/lamivudine (3TC), and DTG/rilpivirine (RPV) are all used for treatment of HIV-infected patients. Here, relative time to in vitro viral breakthrough (VB) and resistance barrier using simulated human drug exposures at either full or suboptimal treatment adherence to each regimen were compared. Methods Wild-type HIV-1 (IIIb)-infected MT-2 cells were exposed to the combinations of BIC+FTC+TAF, DTG+FTC+TAF, DTG+3TC, or DTG+RPV for up to 35 days or until VB. Fixed drug concentrations were the human plasma-free adjusted clinical trough concentrations (Cmin) or fixed at simulated Cmin after missing 1 to 4 consecutive doses (Cmin-1 to -4), with many replicates. Drug resistance was studied by next-generation sequencing at ≥2% frequency. Results At drug concentrations corresponding to full adherence and 1 missed dose (Cmin and Cmin-1), no VB occurred with any regimen (Table). At Cmin-2, only DTG+3TC had VB, with some emergent resistance to both drugs. At Cmin-3, all regimens had VB: by day 12, 100% of DTG+3TC wells had VB; for BIC+FTC+TAF, DTG+FTC+TAF, and DTG+RPV, &lt; 15% of wells had VB which began after day 14. Emergent RT or IN resistance was seen for DTG+RPV and DTG+3TC but not for BIC+FTC+TAF or DTG+FTC+TAF. At Cmin-4, all DTG+3TC and DTG+FTC+TAF wells had VB by day 12, while DTG+RPV had 94% VB by day 25 and BIC+FTC+TAF had 50% VB by day 35. Emergent Cmin-4 drug resistance was seen for all regimens but at differing frequencies; DTG+RPV had the most wells with resistance. Cumulatively, emergent RT and/or IN resistance was found in 1.3% BIC+FTC+TAF, 2.5% DTG+FTC+TAF, 7.9% DTG+3TC, and 8.8% DTG+RPV cultures. Summary of Forgiveness and Barrier to Resistance of INSTI-Containing Regimens Conclusion Regimen forgiveness and resistance barrier are important factors in long term treatment. These INSTI-based regimens had high in vitro forgiveness and resistance barriers with concentrations simulating high adherence. When multiple missed doses were simulated in vitro, BIC+FTC+TAF had the highest forgiveness and barrier to resistance. When compared to DTG+3TC and DTG+FTC+TAF, DTG+RPV had higher forgiveness but lower resistance barrier after several simulated missed doses. Disclosures Rima K. Acosta, BS, Gilead Sciences, Inc. (Employee, Shareholder) Andrew Mulato, BS, MBA, Gilead Sciences, Inc. (Employee, Shareholder) Michelle L. D’Antoni, PhD, Gilead Sciences (Employee, Shareholder)Gilead Sciences, Inc (Employee, Shareholder) Stephen R. Yant, PhD, Gilead Sciences, Inc. (Employee, Shareholder) Tomas Cihlar, PhD, Gilead Sciences, Inc. (Employee, Shareholder) Kirsten L. White, PhD, Gilead Sciences, Inc (Employee, Shareholder)
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Ward, Douglas, Moti Ramgopal, David J. Riedel, et al. "Real-World Experience with Dolutegravir-Based Two-Drug Regimens." AIDS Research and Treatment 2020 (July 7, 2020): 1–8. http://dx.doi.org/10.1155/2020/5923256.
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Background. Dolutegravir-based 2-drug regimens (DTG 2DRs) are now accepted as alternatives to 3-drug regimens for HIV antiretroviral treatment (ART); however, literature on physician drivers for prescribing DTG 2DR is sparse. This study evaluated treatment patterns of DTG 2DR components in clinical practice in the US. Methods. This was a retrospective chart review in adult patients in care in the US with HIV-1 who received DTG 2DR prior to July 31, 2017, with follow-up until January 30, 2018. Primary objectives of the study were to determine reasons for patients initiating DTG 2DR and to describe the demographics and clinical characteristics. All analyses were descriptive. Results. Overall, 278 patients received DTG 2DR (male: 70%; mean age: 56 years). Most patients were treatment experienced (98%), with a mean 13.5 years of prior ART. DTG was most commonly paired with darunavir (55%) or rilpivirine (27%). The most common physician-reported reasons for initiating DTG 2DR were treatment simplification/streamlining (30%) and avoidance of potential long-term toxicities (20%). Before starting DTG 2DR, 42% of patients were virologically suppressed; of those, 95% maintained suppression while on DTG 2DR. Of the 50% of patients with detectable viral load before DTG 2DR, 79% achieved and maintained virologic suppression on DTG 2DR during follow-up. There were no virologic data for 8% of patients prior to starting DTG 2DR. Only 15 patients discontinued DTG 2DR, of whom 4 (27%) discontinued due to virologic failure. Conclusions. Prior to commercial availability of the single-tablet 2DRs, DTG 2DR components were primarily used in treatment-experienced patients for treatment simplification and avoidance of long-term toxicities. Many of these patients achieved and maintained virologic suppression, with low discontinuation rates.
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Fu, Cheng Guo, Shi Bang Ma, Yi Shui Tian, Dang Qin Xue, Lin Hai Zhang, and Shu Lin Hou. "Discussions of Traditional Ignition Temperature Methods with DTA Principle and a New DTG-DTA Method Establishment." Advanced Materials Research 1008-1009 (August 2014): 833–38. http://dx.doi.org/10.4028/www.scientific.net/amr.1008-1009.833.
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Ignition temperature is an important parameter in fuel combustion characteristics research. In this paper, tradition ignition temperature determination methods and their application limitations were discussed by analyzing the DTA curve. All discussions were demonstrated in sweet sorghum fermentation residue particles combustion test. As commonly-used methods were totally established with no consideration of thermal analyzing, the calculating value error were obvious. Taking account detected time tk (uV>0) and delay time() in DTG (derivative thermogravimetry)-DTA (differential thermal analyses) profile, DTG-DTA delay time method was established in this paper. The calculated values comparison has been performed between new method and TG-DTG dividing point method，the latter was recognized as the most accurate method. It was showed that new method has almost the same ignition temperature to that of TG-DTG dividing point method. While new method needs only half workloads of TG-DTG diving point method. The physical conception of new method is clear and corresponded ignition temperature is accurate. Therefore, new method is suitable for biomass ignition temperature determination.
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Hocqueloux, Laurent, François Raffi, Thierry Prazuck, et al. "Dolutegravir Monotherapy Versus Dolutegravir/Abacavir/Lamivudine for Virologically Suppressed People Living With Chronic Human Immunodeficiency Virus Infection: The Randomized Noninferiority MONotherapy of TiviCAY Trial." Clinical Infectious Diseases 69, no. 9 (2019): 1498–505. http://dx.doi.org/10.1093/cid/ciy1132.
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Abstract Background We investigated whether dolutegravir (DTG) monotherapy could be used to maintain virological suppression in people living with human immunodeficiency virus (HIV) on a successful dolutegravir-based triple therapy. Methods MONCAY (MONotherapy of TiviCAY) was a 48-week, multicentric, randomized, open-label, 12% noninferiority margin trial. Patients with CD4 nadir >100/μL, plasma HIV-1 RNA <50 copies/mL for ≥12 months, and stable regimen with DTG/abacavir (ABC)/lamivudine (3TC) were 1:1 randomized to continue their regimen or to DTG monotherapy. The primary endpoint was the proportion of patients with HIV RNA <50 copies/mL at week 24 in intention-to-treat snapshot analysis. Virologic failure (VF) was defined as 2 consecutive HIV RNA >50 copies/mL within 2 weeks apart. Results Seventy-eight patients were assigned to DTG monotherapy and 80 to continue DTG/ABC/3TC. By week 24, 2 patients in the DTG group experienced VF without resistance to the integrase strand transfer inhibitor (INSTI) class; 1 patient discontinued DTG/ABC/3TC due to an adverse event. The success rate at week 24 was 73/78 (93.6%) in the DTG arm and 77/80 (96.3%) in the DTG/ABC/3TC arm (difference, 2.7%; 95% confidence interval [CI], –5.0 to 10.8). During subsequent follow-up, 5 additional VFs occurred in the DTG arm (2 of which harbored emerging resistance mutation to INSTI). The cumulative incidence of VF at week 48 was 9.7% (95% CI, 2.8 to 16.6) in the DTG arm compared with 0% in the DTG/ABC/3TC arm (P = .005 by the log-rank test). The Data Safety Monitoring Board recommended to reintensify the DTG arm with standardized triple therapy. Conclusions Because the risk of VF with resistance increases over time, we recommend avoiding DTG monotherapy as a maintenance strategy among people living with chronic HIV infection. Clinical Trials Registration NCT02596334 and EudraCT 2015-002853-36.
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Krainova, S. I., I. V. Kryukova, N. A. Mkrtumova, Yu M. Keda, and V. I. Kandror. "Stimulation of the growth of "normal" thyrocytes by lymphocytes infiltrating the tissue of diffuse toxic goiter." Problems of Endocrinology 47, no. 3 (2001): 3–5. http://dx.doi.org/10.14341/probl11466.
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The capacity of lymphocytes isolated from diffuse toxic goiter (DTG) tissue to stimulate the proliferation of normal thyrocytes isolated from paranodular tissue adjacent to nodular euthyroid goiter was studied. Normal and DTG thyrocytes were incubated for 24 h with fetal calf serum (FCS) in various concentrations, DTG orparanodular lymphocytes, or both FCS and lymphocytes. The proliferation rate of normal thyrocytes in the presence of FCS alone increased with increase of the serum concentration, while the proliferation rate of DTG thyrocytes did not depend on the concentration of FCS. DTG lymphocytes, but not paranodular ones, stimulated the proliferation of normal thyrocytes. The growth-stimulating effect of DTG lymphocytes was paralleled by loss of normal thyrocytes sensitivity to growth factors (FCS). These data indicate a probable role of intrathyroid lymphocytes in increase of thyrocyte count characteristic of DTG and confirm a previous hypothesis on decrease in expression of surface antigens (receptors) on DTG cells under the effect of intrathyroid lymphocytes.
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Schlenker, E. H., T. Tamura, and A. M. Gerdes. "Gender-specific effects of thyroid hormones on cardiopulmonary function in SHHF rats." Journal of Applied Physiology 95, no. 6 (2003): 2292–98. http://dx.doi.org/10.1152/japplphysiol.00594.2003.
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Spontaneously hypertensive heart failure (SHHF) rats develop hypertension and heart failure. We hypothesized that induction of hyperthyroidism should accelerate development of heart failure in male SHHF rats. Male and female SHHF rats received diets containing desiccated thyroid glands (DTG) or a control diet for 8 wk. Male and female Wistar-Kyoto rats were used as normotensive controls. DTG treatment reduced body weight in male, but not female, SHHF rats but increased body temperature and heart weight-to-body weight ratio in both genders. In DTG-treated male SHHF rats, serum triiodothyronine levels doubled relative to SHHF controls, whereas O2 consumption increased in DTG-treated SHHF rats. Frequency of breathing in air increased in DTG-treated female rats, and ventilation increased in DTG-treated male rats. Ventilatory equivalents exhibited gender differences in SHHF rats, were decreased in both genders by DTG treatment, and reached levels similar to those of Wistar-Kyoto rats. DTG increased heart rate, right ventricular pressure, and contractility in both genders and increased left ventricular pressure in SHHF male rats. These results refute our hypothesis and suggest that cardiopulmonary function of SHHF male rats may be improved by DTG treatment.
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Song, Ivy H., Julie Borland, Shuguang Chen, Paul Savina, Amanda F. Peppercorn, and Stephen Piscitelli. "Effect of Prednisone on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir." Antimicrobial Agents and Chemotherapy 57, no. 9 (2013): 4394–97. http://dx.doi.org/10.1128/aac.00728-13.
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ABSTRACTPrednisone, a corticosteroid frequently used to treat common AIDS-related illnesses and comorbidities, has been shown to induce drug metabolism. This study was performed to determine whether prednisone coadministration affected the pharmacokinetics of dolutegravir (DTG). In this open-label, repeat-dose study, 12 healthy subjects were administered DTG at 50 mg daily alone for 5 days and then with concomitant prednisone for 10 days (prednisone at 60 mg daily for 5 days, followed by a 5-day taper). Serial blood sampling and safety assessments were performed during the trial. Pharmacokinetic parameters were determined using noncompartmental methods and geometric least-square mean ratios, and 90% confidence intervals were generated. Coadministration of DTG and 5-day high-dose prednisone with a 5-day taper had a modest effect on DTG exposure. The area under the DTG plasma concentration-time curve, maximum observed DTG concentration, and 24-hour postdose DTG concentration were increased by 11%, 6%, and 17%, respectively, on day 10 of the combination. Similar results were observed after 5 days of DTG and prednisone. Dolutegravir and prednisone coadministration was well tolerated. The changes in plasma exposures of DTG in healthy individuals as a result of prednisone dosing were not clinically significant. No dose adjustment is required for DTG coadministered with prednisone. (This study has been registered atClinicalTrials.govunder registration no. NCT01425099.)
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Pain, J. B., M. P. Lê, M. Caseris, et al. "Pharmacokinetics of Dolutegravir in a Premature Neonate after HIV Treatment Intensification during Pregnancy." Antimicrobial Agents and Chemotherapy 59, no. 6 (2015): 3660–62. http://dx.doi.org/10.1128/aac.00173-15.
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ABSTRACTWe describe the pharmacokinetics of dolutegravir (DTG) in a premature neonate after maternal intensification of an antiretroviral (ARV) regimen by adding DTG. During the last 2 weeks of pregnancy, the ARV was tenofovir-emtricitabine, atazanavir-ritonavir, and DTG (50 mg once daily). From the interaction between atazanavir and DTG via CYP3A4 and UGT1A1 and placental efflux transporter inhibition and considering the infant's probable enzymatic immaturity, the DTG elimination half-life was estimated to be 4-fold longer in neonates than in adults.
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Ciccullo, Arturo, Gianmaria Baldin, Vanni Borghi, et al. "Real-Life Impact of Drug Toxicity on Dolutegravir Tolerability: Clinical Practice Data from a Multicenter Italian Cohort." Viruses 14, no. 1 (2022): 163. http://dx.doi.org/10.3390/v14010163.
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Dolutegravir (DTG) is currently one of the most used Integrase inhibitors (INI) in antiretroviral therapies (ARV) in both naïve and experienced people living with HIV (PLWHIV). We analyzed a multicenter cohort of PLWHIV, both naïve and experienced, starting an ARV including DTG. We enrolled 3775 PLWHIV: 2763 (73.2%) were males, with a median age of 50 years. During 9890.7 PYFU, we observed 930 discontinuations (9.4 per 100 PYFU). Estimated probabilities of maintaining DTG at three and five years were 75.1% and 67.2%, respectively. Treatment-naïve pts showed a lower probability of maintaining DTG at three and five years compared to treatment-experienced PLWHIV (log-rank p < 0.001). At a multivariate analysis, a longer time of virological suppression (aHR 0.994, p < 0.001) and having experienced a previous virological failure (aHR 0.788, p = 0.016) resulted protective against DTG discontinuation. Most discontinuations (84.0%) happened within the first 12 months of DTG initiation, in particular, 92.2% of discontinuations due to neuropsychiatric toxicity were observed in the first year. Our data confirm the overall good tolerability of DTG in clinical practice, with a low rate of discontinuations. CNS toxicity resulted the main reason for DTG discontinuation, with most related interruptions happening in the first year from DTG introduction.
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Fusco, Jennifer, Cassidy Henegar, Evelyn Byrd Quinlivan, et al. "Integrase Inhibitor-Based Antiretroviral Therapy Among Women Living with HIV: Data from the OPERA Cohort." Current HIV Research 17, no. 4 (2019): 266–76. http://dx.doi.org/10.2174/1570162x17666190927161537.
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Background: Women face unique complexities in HIV treatment yet are underrepresented in antiretroviral therapy (ART) studies. Objective: This analysis assessed the one-year durability of the first integrase strand transfer inhibitor (INSTI)-based regimens prescribed to women in a large cohort of patients living with HIV in care. Methods: Women with HIV who initiated their first INSTI-containing regimen between 08/12/2013 and 11/30/2015 were identified in the OPERA cohort, a collaboration of 79 US outpatient clinics. Discontinuation within the first year of treatment with an INSTI was compared between dolutegravir (DTG), raltegravir (RAL) and elvitegravir (EVG), using multivariable Cox regression and Kaplan- Meier estimates. Virologic response and regimen modifications were described and compared across INSTIs. Results: A total of 537 treatment-naïve (DTG: 39%, EVG: 48%, RAL: 13%) and 878 treatmentexperienced (DTG: 57%, EVG: 29%, RAL: 13%) women were analyzed. In the first twelve months after initiation, women taking EVG or RAL were more likely to discontinue their initial INSTI than those taking DTG among both treatment-naïve (adjusted hazard ratio EVG vs. DTG: 1.59 (95% CI: 1.09, 2.39); RAL vs. DTG: 2.46 (1.49, 4.05)) and treatment-experienced women (EVG vs. DTG: 1.39 (1.02, 1.88); RAL vs. DTG: 2.17 (1.51, 3.12)). Following discontinuation of the initial INSTI, women commonly switched to a regimen containing a different drug from the INSTI class (treatment-naïve DTG: 34%, RAL: 33% EVG: 41%; treatment-experienced DTG: 23%, RAL: 19% EVG: 41%). Conclusion: In treatment-naïve and treatment-experienced women living with HIV, women taking DTG had the lowest risk for early (≤1 year) discontinuation.
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Song, Ivy, Julie Borland, Shuguang Chen, Amanda Peppercorn, Toshihiro Wajima, and Stephen C. Piscitelli. "Effect of Fosamprenavir-Ritonavir on the Pharmacokinetics of Dolutegravir in Healthy Subjects." Antimicrobial Agents and Chemotherapy 58, no. 11 (2014): 6696–700. http://dx.doi.org/10.1128/aac.03282-14.
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ABSTRACTDolutegravir (DTG) is an HIV integrase inhibitor (INI) with demonstrated activity in INI-naive and INI-resistant patients. The objective of this open-label, 2-period, single-sequence study was to evaluate the effect of fosamprenavir-ritonavir (FPV-RTV) on the steady-state plasma pharmacokinetics of DTG. Twelve healthy subjects received 50 mg DTG once daily for 5 days (period 1), followed by 10 days of 50 mg DTG once daily in combination with 700/100 mg FPV-RTV every 12 h (period 2). All doses were administered in the fasting state. Serial pharmacokinetic samples for DTG and amprenavir and safety assessments were obtained throughout the study. Noncompartmental pharmacokinetic analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated for within-subject treatment comparison. Fosamprenavir-ritonavir decreased the DTG area under the concentration-time curve, maximum concentration in plasma, and concentration in plasma at the end of the dosing interval by 35%, 24%, and 49%, respectively. Both DTG and DTG with FPV-RTV were well tolerated; no subject withdrew because of adverse events. The most frequently reported drug-related adverse events were rash, abnormal dreams, and nasopharyngitis. The modest decrease in DTG exposure when it was coadministered with FPV-RTV is not considered clinically significant, and DTG dose adjustment is not required with coadministration of FPV-RTV in INI-naive patient populations on the basis of established “no-effect” boundaries of DTG. In the INI-resistant population, as a cautionary measure, alternative combinations that do not include FPV-RTV should be considered. (This study has been registered atClinicalTrials.govunder identifier NCT01209065.)
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Qin, Zhong Bao, Guang Bin Liu, Jian Feng Guo, and Xiao Long Hu. "Modal Analysis of Dynamically Tuned Gyroscope Based on ANSYS11.0." Applied Mechanics and Materials 152-154 (January 2012): 1183–86. http://dx.doi.org/10.4028/www.scientific.net/amm.152-154.1183.
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This paper proposed a method to analyses and obtain the vibration identities of DTG(Dynamically Tuned Gyroscope) within the vibration-overloading environment based on ANSYS11.0. Finite element model of DTG was constructed by ANSYS11.0. The Natural Frequencies and vibration modals of DTG in the cases of both being stationary and rotating were studied respectively through the method of modal analysis. The influence of each-rank vibration model of DTG on its output was investigated. The result of this paper provides a stable basis for improving the design of DTG and enhancing the functions of it.
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Rolle, Charlotte-Paige M., Beth Bryant, Colton J. Tucker, et al. "2486. Clinical Outcomes of Patients Treated with Dolutegravir Functional Monotherapy or Dolutegravir plus an Active Non-cytosine Nucleoside Analog: A Retrospective Observational Cohort Study of Treatment-Experienced Patients." Open Forum Infectious Diseases 6, Supplement_2 (2019): S861—S862. http://dx.doi.org/10.1093/ofid/ofz360.2164.
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Abstract Background Dual dolutegravir (DTG)-containing regimens (DCRs) are currently approved for the treatment of antiretroviral (ARV) naïve and experienced patients with HIV-1 infection. DTG monotherapy has resulted in unacceptable rates of virologic failure and subsequent development of DTG resistance. Here, we evaluate the “real-world” efficacy and “barrier to resistance” of DCRs containing 0–1 active ARVs. Methods This is a retrospective observational study evaluating clinical outcomes of treatment-experienced patients on combination DCRs found to be on DTG functional monotherapy or DTG plus an active non-cytosine analog between 2013 and 2014. The primary endpoint was virologic suppression (HIV-1 RNA< 50 copies/mL) at week 48. Virologic failure (VF) was defined as confirmed HIV-1 RNA≥ 50 copies/mL 12 weeks after initiating DTG or any time after achieving HIV-1 RNA< 50 copies/mL. Adherence, adverse events (AEs) and laboratory parameters were analyzed throughout the study. Results Thirty-nine patients were included in the analysis, 19 (49%) were on DTG functional monotherapy and 20 (51%) were on DTG plus a non-cytosine nucleoside analog. The median age (range) was 53 (40–74) years, median baseline CD4+ count (range) was 564 (92–1217) cells/mm3, 22 (56%) had baseline HIV-1 RNA< 50 copies/mL, and 24 (62%) had previously used INSTIs (Table 1). At Weeks 48 and 96, virologic suppression was observed in 78.3% and 86% of patients respectively (Figures 1 and 2). Among 7 VFs (2 on DTG functional monotherapy, 5 on DTG plus a non-cytosine nucleoside analog), there was no evidence of treatment-emergent resistance to DTG. There was a significant median increase in CD4+ count from baseline to Week 48 (+90 cells/mm3, 95% confidence interval: [14.18, 165.9]). No significant changes in lipid parameters were observed. Treatment-related AEs occurred in 17/39 (44%) patients (all Grade 1–2) and 1 patient discontinued DCR treatment due to rash. Conclusion In this “real-world” cohort of treatment-experienced patients, we observed that DTG functional monotherapy and DTG plus a non-cytosine nucleoside analog maintained long-term virologic control and was well tolerated. These data supports use of DTG as a partner for dual DCRs given its high efficacy in patients with underlying ARV resistance. Disclosures All authors: No reported disclosures.
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Souza, Cléssius Ribeiro de, Maria das Graças Braga Ceccato, Simone Furtado dos Santos, Marcos Paulo Gomes Mol, and Micheline Rosa Silveira. "Alterações no índice de massa corporal: Coorte em indivíduos em uso de dolutegravir." Research, Society and Development 10, no. 16 (2021): e65101623189. http://dx.doi.org/10.33448/rsd-v10i16.23189.
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Goal: To assess body mass index (BMI) changes in people living with HIV (PLHIV) and using antiretroviral therapy (ART) with dolutegravir (DTG) and its associated factors. Methods: Retrospective and prospective cohorts of PLHIV who started ART with DTG or used DTG after changing the therapeutic regimen, from Belo Horizonte, between February/2017 and March/2020. Data were gathered from clinical records of the Drug Logistics and Laboratory Test Control Systems. BMI changes were analyzed in the following week intervals 1-24(t24), 25-48(t48), 49-72(t73), and 73-96(t96) using the Wilcoxon test and generalized estimation equation (GEE) model, at 5% significance level. Results: A total of 614 individuals were included and average was 38.4 years old. Most were men (85.5%) and 52.3% had started ART with DTG. These individuals, and the immunosuppressed ones, showed significant increases in BMI when compared to those who used DTG after switching therapeutics or the non-immunosuppressed ones (p-value <0.05). After 96 weeks, individuals starting ART with DTG had a mean increase in BMI of 1.02 Kg/m2, whereas those who used DTG after the therapeutic change had an increase of 0.56 Kg/m2 (p<0.05). DTG use length, ART type, immune status, baseline BMI, and age were associated (p<0.05) with BMI increases. Conclusions: We observed an increase in BMI both in individuals starting ART with DTG use and those using it after changing the therapeutic regimen.
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Wainberg, Mark A., Ying-Shan Han, and Thibault Mesplède. "Might dolutegravir be part of a functional cure for HIV?" Canadian Journal of Microbiology 62, no. 5 (2016): 375–82. http://dx.doi.org/10.1139/cjm-2015-0725.
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Antiretroviral therapy (ART) has greatly decreased HIV-related morbidity and mortality. However, HIV can establish viral reservoirs that evade both the immune system and ART. Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI) related to the first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). DTG shows a higher genetic barrier to the development of HIV-1 resistance than RAL and EVG. More interestingly, clinical resistance mutations to DTG in treatment-naïve patients have not been observed to date. This review summarizes recent studies on strategies toward a cure for HIV, explores resistance profiles of DTG, and discusses how DTG might help in finding a functional cure for HIV.
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Pepperrell, Toby, Willem Daniel Francois Venter, Kaitlyn McCann, et al. "Participants on Dolutegravir Resuppress Human Immunodeficiency Virus RNA After Virologic Failure: Updated Data from the ADVANCE Trial." Clinical Infectious Diseases 73, no. 4 (2021): e1008-e1010. http://dx.doi.org/10.1093/cid/ciab086.
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Abstract Following evidence of HIV RNA re-suppression on DTG-based regimens, we assess the re-suppressive capacity of ADVANCE participants on TAF/FTC+DTG, TDF/FTC+DTG, and TDF/FTC/EFV. Viraemic participants were able to re-suppress within 3 follow-up visits of protocol-defined virological failure (PDVF) in 77/121 (64%), 85/126 (67%), and 44/138 (32%) cases respectively (DTG regimens vs. TDF/FTC/EFV; P &lt; 0.001).
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van Wyk, Jean A., Choy Y. Man, Jörg Sievers, et al. "2842. Durable Efficacy of Two-Drug Regimen (2DR) of Dolutegravir (DTG) plus Lamivudine (3TC) in Antiretroviral Treatment-Naïve Adults with HIV-1 Infection at 96 Weeks: Subgroup Analyses in the GEMINI Studies." Open Forum Infectious Diseases 6, Supplement_2 (2019): S67—S68. http://dx.doi.org/10.1093/ofid/ofz359.147.
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Abstract Background At Weeks 48 and 96 in the GEMINI-1 and GEMINI-2 studies (Clinicaltrials.gov: NCT02831673 and NCT02831764), the 2DR of DTG+3TC was noninferior to the three-drug regimen of DTG + tenofovir/emtricitabine (TDF/FTC) in achieving plasma HIV-1 RNA < 50 c/mL in treatment-naïve adults. Methods GEMINI-1 and 2 are identical, global, double-blind, multicenter Phase III studies. Participants with screening HIV-1 RNA ≤ 500.00 c/mL were randomized to once-daily DTG+3TC or DTG+TDF/FTC, stratified by plasma HIV-1 RNA and CD4+ cell count. The primary endpoint was the proportion of participants with plasma HIV-1 RNA < 50 c/mL at Week 48 (Snapshot algorithm). We present a secondary endpoint analysis of efficacy at Week 96 by baseline disease and demographic characteristics. For the overall population, estimates and confidence intervals were based on a stratified analysis using Cochran–Mantel–Haenszel weights. Results In total, 714 and 719 adults were randomized and treated in GEMINI-1 and -2, respectively. Based on a 10% noninferiority margin, DTG+3TC was noninferior to DTG+TDF/FTC at Week 96 in both GEMINI-1 and -2 and in the pooled analysis. Response rates across baseline HIV-1 RNA subgroups were high and similar in both arms in the pooled analysis, including in participants with baseline HIV-1 RNA >100,000 c/mL (Table 1). Results were also generally consistent regardless of age, gender, or race. In the CD4+ ≤ 200 cells/mm3 subgroup, response rates were lower in the DTG+3TC group compared with DTG+TDF/FTC; most reasons for nonresponse were unrelated to virologic efficacy or treatment regimen. Across both studies, 11 participants on DTG+3TC and 7 on DTG+TDF/FTC met protocol-defined virologic withdrawal criteria through Week 96; none had treatment emergent integrase-strand-transfer-inhibitor or NRTI resistance mutations. Conclusion In GEMINI-1 and 2, DTG+3TC was noninferior to DTG+TDF/FTC in treatment-naïve adults at Week 96, demonstrating durable efficacy. The results of subgroup analyses of efficacy at Week 96 were generally consistent with overall study results, and further demonstrate that DTG+3TC is an effective initial treatment for HIV-infected patients across a spectrum of disease characteristics and patient populations. The studies are ongoing. Disclosures All Authors: No reported Disclosures.
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Yang, J., S. Kaliaguine, and C. Roy. "Improved Quantitative Determination of Elastomers in Tire Rubber by Kinetic Simulation of DTG Curves." Rubber Chemistry and Technology 66, no. 2 (1993): 213–29. http://dx.doi.org/10.5254/1.3538307.
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Abstract A method of identifying and quantifying elastomers and processing oil in tire rubber, called DTG curve simulation method, is proposed. This method is based on DTG (derivative thermogravimetry) analysis of the straight elastomers NR, BR and SBR, which produces a series of decomposition rate data and pairs of kinetic constants. DTG curves of binary elastomer systems NR/SBR, NR/BR and BR/SBR are measured. The samples are qualitatively identified following the shape of their DTG curves. Quantitative determination is achieved by DTG curve simulation using a least squares method. When correct elastomers and proper compound ratio are chosen, minimum simulation error is achieved leading to effective identification. Satisfactory results were obtained when applying the method to elastomer mixtures of known composition and to tire rubbers of unknown composition. The study advanced the capability of the TG-DTG technique for quantitative determination of elastomers and blends.
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Mendoza, Maria A., Mohammad H. Alshaer, Giovanni Roldan, et al. "Effect of Rifabutin in Dolutegravir Dosing: A Case Series." Journal of the International Association of Providers of AIDS Care (JIAPAC) 21 (January 2022): 232595822211110. http://dx.doi.org/10.1177/23259582221111077.
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Background: Tuberculosis (TB) is the leading cause of death in human immunodeficiency virus (HIV)-infected people worldwide. Currently there are no studies examining the use of Rifabutin (RBN) and Dolutegravir (DTG) in co-infected persons. This is a case series of 4 co-infected patients receiving both agents who underwent Pharmacokinetic (PK) analysis. Methods and Results: This is a retrospective chart review study of four patients diagnosed with both HIV and TB, receiving RBN and DTG and undergoing therapeutic drug monitoring. All 4 cases had lower than expected DTG concentrations at least once, including those on the current recommended dose of DTG with RBN, and even those receiving higher doses. Conclusions: Given the frequency of low DTG and RBN concentrations, therapeutic drug monitoring (TDM) for these drugs is advisable. Prospective clinical studies are needed to further determine the PK interactions between RBN and DTG, and virologic response to treatment.
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Hsu, Ricky, Jennifer Fusco, Cassidy Henegar, et al. "Psychiatric outcomes observed in patients living with HIV using six common core antiretrovirals in the Observational Pharmaco-Epidemiology Research and Analysis database." Therapeutic Advances in Drug Safety 9, no. 12 (2018): 675–86. http://dx.doi.org/10.1177/2042098618798350.
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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.
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Krainova, S. I., and V. I. Kandror. "Interaction of antibodies from the sera of autoimmune patients thyroidopathies with isolated diffuse cells toxic euthyroid nodular goiter." Problems of Endocrinology 39, no. 6 (1993): 46–50. http://dx.doi.org/10.14341/probl11950.
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Blood sera of 46 patients with diffuse toxic goiter (DTG) and of 48 ones with Hashimotos thyroiditis (HT) were tested for antibodiescomplement-mediated cytotoxicity carriers (ACMMC). ACMCC targets were isolated DTG cells and cells of euthyroid nodular goiter (ENG) perinodular tissue. Antimicrosomal antibodies were assayed in the sera by indirect immunofluorescence and antibodies to all thyrocyte surface antigens isolated from both tissue samples were determined by solid-phase enzyme immunoassay. When DTG cells were targets, DTG patients' sera detected ACMCC in 36 % of cases and HT patients sera in 73% of cases (p0.001).
 In ENG cells the sera of patients of both groups detected ACMCC equally frequently (in more than 70% of cases). Of the 27 DTG patients sera tested with both tissues app. roximately a half detected ACMCC in only ENG tissue. There was no difference in HT patients sera effects on ACMCC detection in both tissue samples. This has brought the authors to a conclusion about DTG cells deficiency for ACMCC mediating antigens. Moreover, DTG cells bound much less antibodies from sera of patients with autoimmune thyropathies, than ENG cells (p0.001), this confirming a deficiency of surface antigen on DTG cells. No correlation between the presence in the sera of antimicrosomal cells and of ACMCC was detected. A conclusion has been made about heterogeneity of antimicrosomal antibody population and about the presence of ACMCC in blood sera of patients with autoimmune thyropathies, these antibodies not belonging to antimicrosomal ones. ACMCC also may be heterogenous and differ in DTG and HT patients.
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Ciccullo, Arturo, Gianmaria Baldin, Amedeo Capetti, et al. "Cohort profile: The Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE)." BMJ Open 9, no. 12 (2019): e029960. http://dx.doi.org/10.1136/bmjopen-2019-029960.
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PurposeThe Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE) cohort was established in Italy in 2016 to evaluate the overall efficacy and tolerability of dolutegravir (DTG)-based antiretroviral (ARV) regimens in clinical practice.ParticipantsThe ODOACRE cohort enrols all adult HIV-1-infected patients, both treatment-naïve and treatment-experienced, starting a DTG-based ARV regimen, in 11 clinical centres in Italy from 2014.Findings to dateIn recent years, various works by the ODOACRE cohort have been produced, demonstrating the high efficacy and tolerability of DTG-based ARV regimens in clinical practice, both in ART-naïve (in the setting of acute HIV-1 infection and late presenters patient) and experienced patients. We confirmed the virological efficacy of DTG-based regimens and we evaluated predictors of virological failure. We investigated cause of discontinuation and evaluated tolerability and metabolic profile of the regimens. Within these investigations, we explored particularly the use of DTG in simplification in two-drug regimen with either rilpivirine or lamivudine. We also compared DTG-based regimens with other integrase inhibitors in clinical practice.Future plansTo continue to study long-term efficacy and tolerability of DTG-based regimens is the purpose of the ODOACRE cohort.
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Ngoufack Jagni Semengue, Ezechiel, Maria Mercedes Santoro, Valantine Ngum Ndze, et al. "HIV-1 integrase resistance associated mutations and the use of dolutegravir in Sub-Saharan Africa: A systematic review and meta-analysis." PLOS Global Public Health 2, no. 10 (2022): e0000826. http://dx.doi.org/10.1371/journal.pgph.0000826.
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As sub-Saharan Africa (SSA) countries are transitioning to dolutegravir (DTG)-based ART, baseline data are required for optimal monitoring of therapeutic response. In this frame, we sought to generate up-to-date evidence on the use of integrase-strand transfer inhibitors (INSTI) and associated drug resistance mutations (DRMs) within SSA. In this systematic review and meta-analysis, we included randomized and non-randomized trials, cohort-studies, cross-sectional studies, and case-reports published on INSTI or integrase DRMs in SSA. We included studies of patients exposed to DTG, raltegravir (RAL) or elvitegravir (EVG). Primary outcomes were “the rate of virological control (VC:<50copies/ml)” and “the presence of DRMs” on INSTI-based regimens among patients in SSA. We synthesised extracted data using subgroup analysis, and random effect models were used where appropriate. Additional analyses were conducted to assess study heterogeneity. We identified 1,916 articles/citations through database searches, of which 26 were included in the analysis pertaining to 5,444 patients (mean age: 37±13 years), with 67.62% (3681/5444) female. Specifically, 46.15% (12/26) studies focused on DTG, 26.92% (7/26) on RAL, 23.08% (6/26) on both DTG and RAL, and 3.85% (1/26) on EVG. We found an increasing use of DTG overtime (0% before 2018 to 100% in 2021). Median treatment duration under INSTI-based regimens was 12 [9–36] months. Overall, the rate of VC was 88.51% [95%CI: 73.83–97.80] with DTG vs. 82.49% [95%CI: 55.76–99.45] and 96.55% [95%CI: 85.7–100.00] with RAL and EVG, respectively. In univariate analysis, VC with DTG-containing vs. other INSTI-regimens was significantly higher (OR = 1.44 [95%CI: 1.15–1.79], p = 0.0014). Among reported DRMs at failure, the only DTG resistance-mutations were G118R and R263K. In SSA, DTG presents a superiority effect in VC compared to other INSTIs. Nonetheless, the early detection of INSTI-DRMs calls for sentinel surveillance for a successful transition and a sustained efficacy of DTG in SSA. PROSPERO Registration Number: CRD42019122424.
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Gerasimenko, L. V. "FEATURES OF OSTEOPOROTIC CHANGES AT THE REPRODUCTIVE AGE FEMALES WITH DIFFUSE TOXIC GOITER (literature review and own data)." Problems of Endocrine Pathology 54, no. 4 (2015): 105–10. http://dx.doi.org/10.21856/j-pep.2015.4.12.
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It was shown the modern data on the study of the risk factors which contribute to the formation of osseous tissue structural and functional disorders at the diffuse toxic goiter (DTG) patients and evaluation of the bone tissue metabolism. At the surveyed reproductive age women with DTG the bone disorders set up to 57.47 % (osteopenia — 54 %, osteoporosis — 46 %). As the result of the research it was proved the necessity of densitomertic examination for DTG patients, especially T-point determination which indicates early character of osteoporotic disorders at DTG.
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Yamada, Eiko, Ritsuo Takagi, Hiroshi Moro, Koji Sudo, and Shingo Kato. "Saliva as a potential matrix for evaluating pharmacologically active dolutegravir concentration in plasma." PLOS ONE 16, no. 2 (2021): e0246994. http://dx.doi.org/10.1371/journal.pone.0246994.
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Therapeutic drug monitoring (TDM) is used in certain clinically selected cases and in research settings to optimize the response to antiretroviral therapy. Plasma of blood is commonly used for TDM, but blood sampling is invasive and at risk for transmission of infectious agents. On the other hand, saliva sampling is noninvasive, safe, cheap, and easily performed compared to blood. Dolutegravir (DTG) is now widely prescribed as a key component of antiretroviral therapy for HIV infection. In this study, we examined the relationship between DTG concentrations in plasma and saliva of treated patients to explore the possibility of using saliva as an alternative body fluid of TDM. A total of 17 pairs of blood and saliva samples were obtained from 15 consented HIV-1-infected subjects treated with DTG containing regimens for more than one month. Both blood and saliva samples were collected within 1 h of each other. Drug concentrations were determined by liquid chromatography-tandem mass spectrometry using DTG-d5 as an internal standard. The LLOQ was 0.5 ng/mL. The calibration curves were prepared with pooled plasma or saliva containing DTG in a range of 0.5–100 ng/mL with precision of <14.4% and accuracy within ±14.7%. The DTG concentrations in the plasma and saliva were significantly correlated (Pearson’s correlation coefficient r = 0.76, p < 0.001). The median ratio of the drug concentration in saliva to those in plasma was 0.0056, which is close to the rate of non-protein-bound DTG in plasma (0.70%), suggesting that only free DTG in plasma is transported to the salivary glands and secreted into saliva. The present study demonstrates that DTG concentration in saliva reflects the pharmacologically active drug concentration in plasma and may provide an easily accessible alternative for monitoring effective antiretroviral treatment.
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Song, Ivy, Julie Borland, Sherene Min, et al. "Effects of Etravirine Alone and with Ritonavir-Boosted Protease Inhibitors on the Pharmacokinetics of Dolutegravir." Antimicrobial Agents and Chemotherapy 55, no. 7 (2011): 3517–21. http://dx.doi.org/10.1128/aac.00073-11.
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ABSTRACTDolutegravir (DTG) is an unboosted, once-daily integrase inhibitor currently in phase 3 trials. Two studies evaluated the effects of etravirine (ETR) alone and in combination with ritonavir (RTV)-boosted protease inhibitors (PIs) on DTG pharmacokinetics (PK) in healthy subjects. DTG 50 mg every 24 h (q24h) was administered alone for 5 days in period 1, followed by combination with ETR at 200 mg q12h for 14 days in period 2 (study 1) or with ETR/lopinavir (LPV)/RTV at 200/400/100 mg q12h or ETR/darunavir (DRV)/RTV at 200/600/100 mg q12h for 14 days in period 2 (study 2). PK samples were collected on day 5 in period 1 and day 14 in period 2. All of the treatments were well tolerated. ETR significantly decreased exposures of DTG, with geometric mean ratios of 0.294 (90% confidence intervals, 0.257 to 0.337) for the area under the curve from time zero until the end of the dosage interval (AUC0-τ), 0.484 (0.433 to 0.542) for the observed maximum plasma concentration (Cmax), and 0.121 (0.093 to 0.157) for the plasma concentration at the end of the dosage interval (Cτ). ETR combined with an RTV-boosted PI affected the exposure of DTG to a lesser degree: ETR/LPV/RTV treatment had no effect on the DTG plasma AUC0-τandCmax, whereas theCτincreased by 28%. ETR/DRV/RTV modestly decreased the plasma DTG AUC0-τ,Cmax, andCτby 25, 12, and 37%, respectively. Such effects of ETR/LPV/RTV and ETR/DRV/RTV are not considered clinically relevant. The combination of DTG and ETR alone should be avoided; however, DTG may be coadministered with ETR without a dosage adjustment if LPV/RTV or DRV/RTV is concurrently administered.
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Wandeler, Gilles, Marta Buzzi, Nanina Anderegg, et al. "Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis." F1000Research 7 (August 30, 2018): 1359. http://dx.doi.org/10.12688/f1000research.15995.1.
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Background: Dolutegravir-containing maintenance therapy is a promising simplification strategy for virologically suppressed HIV-infected individuals. However, most of the available data to inform this strategy come from small, uncontrolled studies. We estimated the proportion of HIV-infected patients experiencing virological failure (VF) and developing drug resistance on dolutegravir (DTG)-based maintenance therapy. Methods: We searched Medline, Embase, Cochrane Central, Web of Science, and conference abstracts for studies assessing VF on DTG-based maintenance therapy. Studies including ≥5 adults with an undetectable viral load on antiretroviral therapy (ART) who switched to a DTG-based mono- or dual therapy were included. Pooled proportions of VF were estimated using random-intercept logistic meta-regression and acquired drug resistance mutations described for each strategy. Results: Of 1719 studies considered, 21 met our selection criteria, including seven interventional and 14 observational studies. Eight studies including 251 patients assessed VF on DTG monotherapy and fourteen studies including 1670 participants VF on dual therapy. The participant’s median age ranged from 43 to 63 years, their median nadir CD4 count from 90 to 399 cells/µl, and 27.6% were female. The proportion of participants experiencing VF on DTG-monotherapy was 3.6% (95% confidence interval [CI] 1.9-6.7) at 24 weeks and 8.9% (95% CI 4.7-16.2) at 48 weeks. Resistance mutations developed in seven (3.6%) participants on DTG-monotherapy. Among patients on dual therapy, ten (0.7%, 95% CI 0.4-1.3) experienced VF by 48 weeks and none developed resistance to DTG. In adjusted analyses, VF at 24 weeks was less likely on dual therapy than on monotherapy (adjusted odds ratio: 0.10, 95% CI 0.03-0.30). Conclusions: Whereas VF is relatively common on DTG maintenance monotherapy, DTG-based dual therapy appears to be a promising simplification strategy for individuals with a suppressed HIV viral load on triple-ART.
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Wandeler, Gilles, Marta Buzzi, Nanina Anderegg, et al. "Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis." F1000Research 7 (April 3, 2019): 1359. http://dx.doi.org/10.12688/f1000research.15995.2.
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Background: Dolutegravir-containing maintenance therapy is a promising simplification strategy for virologically suppressed HIV-infected individuals. However, most of the available data to inform this strategy come from small, uncontrolled studies. We estimated the proportion of HIV-infected patients experiencing virological failure (VF) and developing drug resistance on dolutegravir (DTG)-based maintenance therapy. Methods: We searched Medline, Embase, Cochrane Central, Web of Science, and conference abstracts for studies assessing VF on DTG-based maintenance therapy. Studies including ≥5 adults with an undetectable viral load on antiretroviral therapy (ART) who switched to a DTG-based mono- or dual therapy were included. Pooled proportions of VF were estimated using random-intercept logistic meta-regression and acquired drug resistance mutations described for each strategy. Results: Of 1719 studies considered, 21 met our selection criteria, including seven interventional and 14 observational studies. Eight studies including 251 patients assessed VF on DTG monotherapy and fourteen studies including 1670 participants VF on dual therapy. The participant’s median age ranged from 43 to 63 years, their median nadir CD4 count from 90 to 399 cells/µl, and 27.6% were female. The proportion of participants experiencing VF on DTG-monotherapy was 3.6% (95% confidence interval [CI] 1.9-6.7) at 24 weeks and 8.9% (95% CI 4.7-16.2) at 48 weeks. Resistance mutations developed in seven (3.6%) participants on DTG-monotherapy. Among patients on dual therapy, ten (0.7%, 95% CI 0.4-1.3) experienced VF by 48 weeks and none developed resistance to DTG. In adjusted analyses, VF at 24 weeks was less likely on dual therapy than on monotherapy (adjusted odds ratio: 0.10, 95% CI 0.03-0.30). Conclusions: Whereas VF is relatively common on DTG maintenance monotherapy, DTG-based dual therapy appears to be a promising simplification strategy for individuals with a suppressed HIV viral load on triple-ART.
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Ford, Susan L., Elizabeth Gould, Shuguang Chen, et al. "Lack of Pharmacokinetic Interaction between Rilpivirine and Integrase Inhibitors Dolutegravir and GSK1265744." Antimicrobial Agents and Chemotherapy 57, no. 11 (2013): 5472–77. http://dx.doi.org/10.1128/aac.01235-13.
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ABSTRACTDolutegravir (DTG) and GSK1265744 are HIV integrase inhibitors (INIs) in clinical development. The oral formulation of rilpivirine (RPV), a nonnucleoside reverse transcriptase inhibitor (NNRTI), has been approved for treatment-naive HIV infection. Long-acting depot injections of GSK1265744 and RPV are also being developed. This study evaluated the potential for drug interactions between RPV and these INIs. This phase 1, open-label, two-cohort, three-period, single-sequence crossover study evaluated oral coadministration of RPV with DTG or GSK1265744. Healthy subjects received DTG (50 mg every 24 h for 5 days) or GSK1265744 (30 mg every 24 h for 12 days) in period 1 followed by a washout, RPV (25 mg every 24 h for 11 or 12 days) in period 2, immediately followed by RPV (25 mg every 24 h) plus DTG (50 mg every 24 h) for 5 days or GSK1265744 (30 mg every 24 h) for 12 days in period 3. Steady-state pharmacokinetic (PK) parameters were estimated using noncompartmental analysis of data collected on the last day of each period. The combinations of RPV and DTG (n= 16) and of RPV and GSK1265744 (n= 11) were well tolerated; no grade 3 or 4 adverse events (AEs) or AE-related discontinuations were observed. The 90% confidence intervals for the area under the curve from time zero until the end of the dosage interval [AUC0–τ] and maximum concentration of drug in serum (Cmax) geometric mean ratios were within 0.8 to 1.25. Following administration of DTG + RPV, DTG and RPVCτ increased by 22% and 21%, respectively. Following administration of GSK1265744 + RPV, RPVCτ decreased 8%. DTG and GSK1265744 can be administered with RPV without dosage adjustment for either agent. These results support coadministration of RPV with DTG or GSK1265744 as either oral or long-acting depot injection regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01467531.)
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Ramesh, K., N. Naresh, Pumlianmunga, and E. S. R. Gopal. "Shift of Glass Transition Temperature under High Pressure for Ge20Te80 Glass." Key Engineering Materials 702 (July 2016): 43–47. http://dx.doi.org/10.4028/www.scientific.net/kem.702.43.
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Amorphous solids prepared from their melt state exhibit glass transition phenomena upon heating. Derivatives of volume like viscosity, specific heat and thermal expansion coefficient show rapid changes at the glass transition temperature (Tg). In general, application f high pressure increases the Tg (a positive dTg/dP). This positive dTg/dP has been well understood with the Free Volume and Entropy models. However, there are few exceptions where a negative dTg/dP has been observed. It has been proposed that the glasses which undergo negative thermal expansion can exhibit a negative dTg/dP. In this study, electrical resistivity of semiconducting Ge20Te80 glass at high pressures as a function of temperature has been measured in a Bridgman anvil apparatus. Electrical resistivity showed a pronounced change at Tg. The pressure dependence of Tg (dTg/dP) shows a decreasing trend (-dTg/dP). Chalcogenide glasses like Se, As2Se3 and As30Se30Te40 show a positive dTg/dP in contradiction to the present observation of negative dTg/dP. A model proposed by deNeufville and Rockstad finds a linear relationship between Tg and the optical band gap (Eg) when they are grouped according to their connectivity (Zav).Application of high pressure decreases the interatomic distance which in turn decreases the separation between the valence and conduction bands (optical band gap). This reduction in optical band gap shifts the glass transition to lower values. It is also suggested that the sign of the pressure derivative of Tg can be negative (-dTg/dP) if the thermal expansion coefficient is negative. Inelastic neutron diffraction studies show a negative thermal expansion coefficient for most of the Te based chalcogenide glasses. Hence, Ge20Te80 glass is uniquethat its pressure dependence of Tgobeys both thermodynamic and the Tg-Eg-Zav models.
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van Wyk, Jean, Faïza Ajana, Fiona Bisshop, et al. "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." Clinical Infectious Diseases 71, no. 8 (2020): 1920–29. http://dx.doi.org/10.1093/cid/ciz1243.
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Abstract 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 &lt;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.
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Seki, Takahiro, Akemi Suyama-Kagitani, Shinobu Kawauchi-Miki, et al. "Effects of Raltegravir or Elvitegravir Resistance Signature Mutations on the Barrier to Dolutegravir ResistanceIn Vitro." Antimicrobial Agents and Chemotherapy 59, no. 5 (2015): 2596–606. http://dx.doi.org/10.1128/aac.04844-14.
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ABSTRACTThe recently approved HIV-1 integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) (S/GSK1349572) has overall advantageous activity when testedin vitroagainst HIV-1 with raltegravir (RAL) and elvitegravir (EVG) resistance signature mutations. We conducted anin vitroresistance selection study using wild-type HIV-1 and mutants with the E92Q, Y143C, Y143R, Q148H, Q148K, Q148R, and N155H substitutions to assess the DTGin vitrobarrier to resistance. No viral replication was observed at concentrations of ≥32 nM DTG, whereas viral replication was observed at 160 nM RAL or EVG in the mutants. In the Q148H, Q148K, or Q148R mutants, G140S/Q148H, E138K/Q148K, E138K/Q148R, and G140S/Q148R secondary mutations were identified with each INSTI and showed high resistance to RAL or EVG but limited resistance to DTG. E138K and G140S, as secondary substitutions to Q148H, Q148K, or Q148R, were associated with partial recovery in viral infectivity and/or INSTI resistance. In the E92Q, Y143C, Y143R, and N155H mutants, no secondary substitutions were associated with DTG. Thesein vitroresults suggest that DTG has a high barrier to the development of resistance in the presence of RAL or EVG signature mutations other than Q148. One explanation for this high barrier to resistance is that no additional secondary substitution of E92Q, Y143C, Y143R, or N155H simultaneously increased the fold change in 50% effective concentration (EC50) to DTG and infectivity. Although increased DTG resistance via the Q148 pathway and secondary substitutions occurs at low concentrations, a higher starting concentration may reduce or eliminate the development of DTG resistance in this pathwayin vitro.
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Sperandeo, N. R., C. V. Mattia, and Maria M. de Bertorello. "Thermal studies of isoxazolylnaphthoquinones by simultaneous DTA-TG-DTG." Journal of thermal analysis 48, no. 2 (1997): 267–76. http://dx.doi.org/10.1007/bf01979270.
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Murphy, R. A., B. Douglas-Jones, G. Mucinya, H. Sunpath, and T. Govender. "Expanding the use of dolutegravir-based antiretroviral therapy in multidrug-resistant TB." International Journal of Tuberculosis and Lung Disease 25, no. 9 (2021): 696–700. http://dx.doi.org/10.5588/ijtld.21.0125.
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The wider availability of dolutegravir (DTG) containing HIV therapy for patients living with multidrug-resistant TB (MDR-TB) presents several advantages. DTG-based antiretroviral therapy (ART) has superior potency, reduces pill burden, and may reduce overall treatment-related toxicity, giving it the potential to improve outcomes in both diseases. While the uptake of DTG-based ART in programs where drug-resistant TB is treated remains unknown, there is early evidence from three programs that uptake is increasing. The use of DTG-based ART should be scaled-up, beginning with antiretroviral-naïve or virologically suppressed patients initiating MDR-TB treatment.
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Hawkins, Kellie, Brian Montague, Sarah Rowan, et al. "1766. Sustained Viral Suppression with Dolutegravir and Boosted Darunavir Dual Therapy Among Highly Treatment-Experienced Individuals." Open Forum Infectious Diseases 5, suppl_1 (2018): S64. http://dx.doi.org/10.1093/ofid/ofy209.151.
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Abstract Background The use of antiretroviral (ARV) dual therapy for treatment of HIV is increasing; raltegravir with boosted darunavir (bDRV) is recommended in certain clinical situations in DHHS guidelines. Dolutegravir (DTG) with bDRV has not been widely studied. We sought to determine the effectiveness of DTG/bDRV in treatment experienced patients. Methods This retrospective cohort study evaluated viral suppression in patients prescribed DTG/bDRV dual therapy within a large urban health system. Data collected included demographics, cumulative ARV exposure, reasons for use, regimen start/stop dates, and viral suppression (HIV-RNA ≤200). Follow-up was defined as the number of days from start of regimen until last HIV-RNA determination on the study regimen. Results From January 1, 2013 to December 31, 2017, 60 patients received DTG/bDRV dual therapy: 15% were female, median age was 56, 83% were ≥3 class ARV-experienced, and median time since starting ARVs was 20 years. Median follow-up on DTG/bDRV was 444 days (IQR 273–808). Viral suppression was achieved by 59 of 60 (98%) patients at some point on DTG/bDRV. When stratified by baseline viral suppression, 46 of 46 (100%) who had baseline viral suppression maintained viral suppression in comparison to 11 of 14 (79%) without baseline viral suppression (table). The most common reasons for DTG/bDRV were simplification in setting of prior resistance (47%), toxicity reduction (39%), and virologic failure (15%). At study end, 53 of 60 (88%) were still on DTG/bDRV and the most common reason for stopping was drug interactions. Conclusion In a highly treatment-experienced cohort of patients, DTG/bDRV dual therapy demonstrated sustained rates of viral suppression, even in those who were failing therapy prior to initiating the regimen. Further study of this potent, simple, high-barrier dual class regimen is warranted. Disclosures S. Rowan, Gilead Sciences: Investigator, Research grant. S. C. Johnson, Viiv Healthcare: Scientific Advisor, Consulting fee.
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Klinger, Amanda E., Ryan J. Kronen, Tomer Barak, et al. "769. Mortality Among Inpatients After the Initiation of ‘Treat All’ With Dolutegravir in Botswana." Open Forum Infectious Diseases 7, Supplement_1 (2020): S429. http://dx.doi.org/10.1093/ofid/ofaa439.959.
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Abstract Background Botswana was the first African country to implement a ‘treat all’ dolutegravir (DTG)-based treatment program for all adults. We studied whether this transition made a short-term impact on inpatient mortality among people living with HIV (PLWHIV). Methods From Dec 2015-Nov 2017, data were collected prospectively on all patients admitted to the medical wards of a district hospital in Botswana. Tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV) was the first-line recommended antiretroviral treatment (ART) regimen for all ART-naïve adults with CD4 &lt; 350 until May 2016, when it was replaced by TDF/FTC/DTG without CD4 restriction (‘treat all’). Multivariable logistic regression was used to compare mortality by ART regimen. Results Of 1,969 patients admitted, 41.5% were PLWHIV and of these 62.9% were on ART prior to admission. Before ‘treat all’, 160 (58.0%) of 276 PLWHIV were on ART prior to admission, and post-implementation 354 (65.4%) of 541 PLWHIV were on ART prior to admission (p=0.01). Among 315 patients on EFV-based ART and 85 on DTG-based ART prior to admission, demographics were similar (Table 1), except for more recent ART initiation with DTG, and lower median CD4 cell count with DTG (256 vs. 339 cells/mm3). Tuberculosis (TB) and community acquired pneumonia were the leading causes of hospitalization for both regimens. Death occurred in 178 (21.8%) PLWHIV, including 29% not on ART and 19% on any ART (p=0.003). Overall, 38% who initiated ART &lt; 3 months prior to admission died (23.7% DTG, 48.8% EFV), and 36% with CD4 cell count &lt; 50 cells/mm3 died (42.9% DTG, 30.8% EFV). Fewer deaths occurred among those on EFV (18%) compared with those on DTG (27%). However, controlling for CD4 count and timing of ART start, the risk of mortality among those on DTG and EFV was similar (aRR 1.08, 95% CI 0.62, 1.87). TB was the leading cause of death (40.1% off ART, 31.8% on DTG, 22.2% on EFV). Table 1. Demographics, clinical characteristics, and outcomes of people living with HIV (PLWHIV) admitted to Scottish Livingstone Hospital, stratified by ART regimen prior to admission. Conclusion We found no improvement in inpatient mortality among PLWHIV during the shift to ‘treat all’ with DTG-based ART in Botswana. Decreasing high inpatient HIV mortality will require increased testing in the community to detect and treat PLWHIV prior to disease progression, and improved screening for opportunistic infections. Disclosures All Authors: No reported disclosures
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Pierone, Gerald, Kathy Schulman, Jennifer S. Fusco, et al. "2483. Characteristics and Outcomes Over First 12 Months of a Two-Drug Regimen (Dolutegravir/Rilpivirine) for Treatment of HIV-1 in the United States." Open Forum Infectious Diseases 6, Supplement_2 (2019): S860—S861. http://dx.doi.org/10.1093/ofid/ofz360.2161.
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Abstract Background In 2017, the first complete antiretroviral regimen (ART) containing only two drugs, dolutegravir/rilpivirine (DTG/RPV), was approved for treatment of HIV-1 in virologically suppressed (<50 copies/mL) patients on a stable ART regimen for ≥6 months with no history of treatment failure/resistance to DTG or RPV. Our objective was to characterize early utilization/outcomes of DTG/RPV in a real-world population. Methods HIV-1+ individuals initiating DTG/RPV from January 1, 2018 to December 31, 2018 were identified in the OPERA Database. Outcomes were evaluated among the virologically suppressed subgroup who initiated in the first 6 months. Discontinuation (d/c) was defined as cessation of DTG/RPV. Virologic failure (VF) was defined as either 2 consecutive HIV viral loads (VL) ≥ 200 copies/mL OR 1 VL ≥200 copies/mL + d/c. Population was observed from DTG/RPV start (index) until the first of: (a) d/c, (b) death, or (c) study end (December 31, 2018). Demographic and clinical characteristics were described at index. Kaplan–Meier methods were used to describe d/c and VF. Results A total of 880 patients were prescribed DTG/RPV in the first 12 months; demographic and clinical characteristics are described in Figures 1 and 2. Most (76%) DTG/RPV users were virologically suppressed at initiation (n = 671). Among the 197 (22%) ART experienced, viremic initiators, a third had a baseline VL ≥ 50 but <200. Few patients were ART naïve (n = 12, 1%). Index VL was unavailable for 21 (5%) initiators. Comorbidity was prevalent: 59% had ≥1 endocrine disorders; 42% hypertension, and 33% mental disorders. For the virologically suppressed at initiation, with ≥6 months of follow-up (n = 340); median (IQR) days on DTG/RPV was 248 (204–299); 88% remained on DTG/RPV at study end. Among the 42 (12.4%) discontinued patients, 41% were virologically stable (<200 copies/mL) at d/c. Median (IQR) days to d/c was 58 (29–141) (Figure 3). Most patients (n = 288, 85%) had ≥ 1 VL during follow-up; 79% (n = 270) had ≥1 VL during the first 24 weeks. Among these, VF occurred in 1.5% patients. Median (IQR) time to VF was 5.1 (2.0–9.2) months (Figure 4). Conclusion While DTG/RPV initiators were primarily ART-experienced, virologically suppressed individuals older than 50 years of age challenged by significant comorbid conditions, the frequency of d/c or VF in the first 12 months was low. Disclosures All authors: No reported disclosures.
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Yang, Guang, Xing Fei Li, Jian Yuan Zhao, and Jia Wang. "Loop Decoupling Design Based on Identification Model of DTG." Applied Mechanics and Materials 197 (September 2012): 367–71. http://dx.doi.org/10.4028/www.scientific.net/amm.197.367.
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To solve the coupling problems cause by flexible structure of Dynamic Tuned Gyroscope (DTG), solutions was proposed through the combination of loop control and decoupling within Individual Channel Design (ICD) framework during the DTG lock loop design. Firstly, theoretical model of DTG and its actual coupling property were presented. Then, the diagonal controller was designed for the diagonal elements and counter-diagonal elements of DTG transfer function matrix under the framework of ICD. The stability and coupling relationship of individual channel were also analyzed for both two cases. Finally, a validation experiment was carried out for a certain type of DTG when it works in tuned state and mistuned state with 20% perturbation of tuned speed. The experimental results show that the diagonal controller for both two cases can stabilize the loop. But in mistuned state, the coupling degree of diagonal elements case grows up to 15%.This shows that the controller robustness for counter-diagonal elements is greater.
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Ferrer, Pedro E., Mark Bloch, Norman Roth, et al. "A retrospective clinical audit of general practices in Australia to determine the motivation for switch to dolutegravir/abacavir/lamivudine and clinical outcomes." International Journal of STD & AIDS 29, no. 3 (2017): 300–305. http://dx.doi.org/10.1177/0956462417730474.
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The most common reasons for switching HIV-1 therapy in patients with virologic suppression are treatment regimen simplification and resolving tolerability issues. Single-pill regimens that include an integrase inhibitor are recommended options. A retrospective clinical audit was performed to determine the motivations for switching to dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC) at high HIV-caseload general practice clinics in Australia. The most common reasons for switching from a prior suppressive therapy to DTG/ABC/3TC were simplification of regimen, resolving toxicity/intolerance and patient preference (73%, 13% and 12%, respectively). Kaplan–Meier analysis showed that the probability of patients remaining on DTG/ABC/3TC therapy at 12 months was 95.1%. Switching to DTG/ABC/3TC from a range of other regimens was associated with a discontinuation rate of 3.2%, with 2.5% of patients discontinuing due to adverse events and no patients discontinuing due to virologic failure. Switching to DTG/ABC/3TC was a viable treatment strategy in this cohort of Australian patients.
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Brizzi, Marisa B., Thomas D. Chiampas, Sarah M. Michienzi, Jeremy D. Young, Mahesh C. Patel, and Melissa E. Badowski. "Real-world evaluation of the safety and tolerability of abacavir/dolutegravir/lamivudine in an incarcerated population." International Journal of STD & AIDS 30, no. 12 (2019): 1163–68. http://dx.doi.org/10.1177/0956462419863925.
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A trend of increased adverse effects and laboratory abnormalities was observed in patients treated at the University of Illinois Hospital and Health Sciences System (UIH) HIV Telemedicine Clinic after switching to abacavir/dolutegravir/lamivudine (ABC/DTG/3TC). Therefore, we sought to investigate if major clinical trials overestimated the safety and tolerability of DTG-based antiretroviral therapy (ART). This study was a single-center, retrospective, pre- and post-analysis of incarcerated patients receiving care at the UIH HIV Telemedicine Clinic, USA. Patients included were adults with HIV switched from previous ART to ABC/DTG/3TC. Primary endpoints included patient-reported adverse effects and changes in renal and hepatic function from baseline. A total of 95 patients were included in the study. After switching from previous ART to ABC/DTG/3TC, 20% of patients reported incidence of adverse effects. Most common were headache (7.4%), nausea (6.3%) rash (3.2%), fatigue (3.2%), and insomnia (2.1%). There were statistically significant increases in serum creatinine (SCr), in 20% of the patients (P < 0.0001), with a median increase of 0.38 mg/dl. ABC/DTG/3TC appears to have similar or fewer adverse effects in the real-world incarcerated population compared to clinical trials. DTG-based ART can cause statistically significant increases in SCr in some patients.
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Fernandes, Ana Cristina da Silva, Jorgino Júlio Cesar, Palmira de Fátima Bonolo, Clessius Ribeiro de Souza, and Maria das Graças Braga Ceccato. "Perfil lipídico em pessoas iniciando a terapia antirretroviral com regimes baseados em efavirenz ou dolutegravir em um centro de referência no Brasil: um estudo de coorte." Research, Society and Development 11, no. 5 (2022): e55811528662. http://dx.doi.org/10.33448/rsd-v11i5.28662.
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Objetivo: Comparar o impacto no perfil lipídico (PL) em pessoas iniciando a terapia antirretroviral (TARV) baseados pré e pós uso de efavirenz (EFZ) ou dolutegravir (DTG). Métodos: Coorte prospectiva onde foi estratificados dois grupos, as pessoas vivendo com HIV (PVIV) que iniciaram esquema com DTG ou EFV. A dislipidemia foi definida por critérios laboratoriais no período entre setembro de 2015 a outubro de 2017. Utilizados testes paramétrico e não paramétrico e testes de pares combinados, considerando o p <0,05 estatisticamente significativo. Resultados: estudados 468 indivíduos estratificados em dois grupos, com (n=180) ou sem (n=288) registros dos exames laboratoriais no tempo T0 (início do tratamento) ou no T48 (12 meses após a dispensação dos antirretrovirais. Entre esses 180, 60 (33,1%) estavam em uso de DTG e 113 (62,4%) em uso de EFZ. Nas comparações do nível sérico (mg/dl) do PL, pré e pós TARV, todos os valores apresentaram aumento e estaticamente significativo para o HDL (p<0,001). Foi analisado a variação do PL, pós TARV e em relação ao uso de EFV e DTG. Em relação ao EFZ, houve aumento do nível sérico de todo o PL, estaticamente significativo para o HDL. Em relação ao DTG, houve aumento do nível sérico apenas para o VLDL que não foi estaticamente significativo. Conclusão: comparando o uso do DTG com o EFV, o EFV aumentou o nível sérico do CT e frações, estaticamente significativa para o HDL. Com uso do DTG, houve um aumento do nível sérico de VLDL e diminuição do HDL, sem significância estatística.
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Hightower, Kendra E., Ruolan Wang, Felix DeAnda, et al. "Dolutegravir (S/GSK1349572) Exhibits Significantly Slower Dissociation than Raltegravir and Elvitegravir from Wild-Type and Integrase Inhibitor-Resistant HIV-1 Integrase-DNA Complexes." Antimicrobial Agents and Chemotherapy 55, no. 10 (2011): 4552–59. http://dx.doi.org/10.1128/aac.00157-11.
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ABSTRACTThe integrase inhibitor (INI) dolutegravir (DTG; S/GSK1349572) has significant activity against HIV-1 isolates with raltegravir (RAL)- and elvitegravir (ELV)-associated resistance mutations. As an initial step in characterizing the different resistance profiles of DTG, RAL, and ELV, we determined the dissociation rates of these INIs with integrase (IN)-DNA complexes containing a broad panel of IN proteins, including IN substitutions corresponding to signature RAL and ELV resistance mutations. DTG dissociates slowly from a wild-type IN-DNA complex at 37°C with an off-rate of 2.7 × 10−6s−1and a dissociative half-life (t1/2) of 71 h, significantly longer than the half-lives for RAL (8.8 h) and ELV (2.7 h). Prolonged binding (t1/2, at least 5 h) was observed for DTG with IN-DNA complexes containing E92, Y143, Q148, and N155 substitutions. The addition of a second substitution to either Q148 or N155 typically resulted in an increase in the off-rate compared to that with the single substitution. For all of the IN substitutions tested, the off-rate of DTG from IN-DNA complexes was significantly slower (from 5 to 40 times slower) than the off-rate of RAL or ELV. These data are consistent with the potential for DTG to have a higher genetic barrier to resistance, provide evidence that the INI off-rate may be an important component of the mechanism of INI resistance, and suggest that the slow dissociation of DTG may contribute to its distinctive resistance profile.