Michael Aboud

Cardiovascular risk evaluation and antiretroviral therapy effects in an HIV cohort: implications for clinical management: the CREATE 1 study

Aims:u2002 The aim of this study is to determine the cardiovascular disease (CVD) risk profile of a large UK HIV cohort and how highly active antiretroviral therapy (HAART) affects this.

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

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

Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label, Phase IIIb study

BACKGROUNDnSimplified dosing regimens are important for patients who face challenges in adhering to HIV-1 therapy. We investigated the safety and virological efficacy of switching to once-daily abacavir/dolutegravir/lamivudine (ABC/DTG/3TC).nnnMETHODSnThe STRIIVING study was a randomized, open-label, Phase IIIb study in adults with HIV-1 RNA <50 copies/ml on antiretroviral therapy (ART) at enrolment (ClinicalTrials.gov identifier, NCT02105987). Subjects were randomly assigned to switch to ABC/DTG/3TC once daily for 48 weeks (early-switch group) or continue current ART for 24 weeks and then switch to ABC/DTG/3TC (late-switch group). The primary end point was the proportion of subjects with HIV-1 RNA <50 copies/ml at week 24.nnnRESULTSnOf 553 subjects enrolled, 275 were randomly assigned to switch immediately to ABC/DTG/3TC and 278 continued on current ART. At week 24, 85% and 88% of subjects who switched to ABC/DTG/3TC or remained on current ART, respectively, were virologically suppressed, indicating that ABC/DTG/3TC was non-inferior (difference in proportion, -3.4%; 95% CI -9.1, 2.4). At week 48, 83% and 92% were virologically suppressed in the early- and late-switch groups, respectively. Adverse events were reported more frequently with ABC/DTG/3TC (66%) than with current ART (47%) by week 24, and in the late-switch group, 60% of subjects reported adverse events post-switch. Pharmacokinetic data supported immediate switch. HIV Treatment Satisfaction Questionnaire scores improved in participants switching to ABC/DTG/3TC versus current ART.nnnCONCLUSIONSnData demonstrating non-inferiority of switching to ABC/DTG/3TC versus continuing current ART support ABC/DTG/3TC as an option when considering switch regimens in HIV-1-infected adults with stable viral suppression.

The assessment of metabolic syndrome in UK patients with HIV using two different definitions: CREATE 2 study.

Abstract Objective: To determine the prevalence and clinical associations of the metabolic syndrome (M-IRS) in an HIV cohort. Methods and design: Data was collected prospectively on demographics, anthropometry, HIV disease, drug regimens and cardiometabolic risk factors using a two-centre cross-sectional cohort study design. M-IRS was diagnosed by National Cholesterol Education Program (NCEP) and International Diabetes Federation (IDF) criteria. Results: The prevalence of M-IRS in 678 subjects was 14% by NCEP and 10% by IDF. One feature of the M-IRS was present in 68%, while 37% had two or more features. Increased waist circumference was found in 32% by NCEP or by IDF criteria, hypertriglyceridaemia in 32%, reduced HDL-C in 27%, 18% had raised systolic blood pressure and 13% had dysglycaemia. Protease inhibitor (PI) usage was similar in both M-IRS categories (43 vs. 38%; pu2009=u20090.38) but increased use of efavirenz was seen in M-IRS (47 vs. 36%; pu2009=u20090.07) and nevirapine in the non-M-IRS groups (10 vs. 20%; pu2009=u20090.05). Multiple drug therapies were associated with raised triglyceride levels while nevirapine therapy was associated with raised HDL-C and abacavir with dysglycaemia. Conclusions: The prevalence of M-IRS in this HIV cohort was similar to the general population and independent of current or previous highly active antiretroviral therapy (HAART) or its duration. Given the relationship between individual drugs and features of M-IRS its significance must be interpreted in the light of probable accrual bias in prescribing. Prospective studies are required to ascertain the cardiometabolic risk factors to include in a prognostically useful HIV disease-specific definition of M-IRS.

Switch from tenofovir disoproxil fumarate combination to dolutegravir plus rilpivirine improves parameters of bone health

Objective: Bone mineral density (BMD) loss, a risk factor for osteoporosis, has been attributed to HIV infection and antiretroviral therapy (ART), including regimens containing tenofovir disoproxil fumarate. Design: Study 202094 is an open-label, parallel-group, sub-study of the phase III SWORD-1 and SWORD-2 studies (ClinicalTrials.gov identifier, NCT02478632). Methods: HIV-1-infected adults with HIV-1 RNA less than 50 copies/ml who received ART containing tenofovir disoproxil fumarate for at least 6 months were randomized to receive dolutegravir with rilpivirine or continue current ART regimen. Total hip and lumbar spine BMD were measured by dual-energy X-ray absorptiometry (DXA) scans. The primary endpoint was percentage change from baseline in total hip BMD. Results: DXA scans were evaluable for 81 participants at baseline and Week 48. Percentage increase in total hip BMD was significantly greater in participants who switched to dolutegravir with rilpivirine (1.34%) compared with participants who continued current ART (0.05%; treatment difference, +1.29%; 95% CI 0.27–2.31; Pu200a=u200a0.014). Lumbar spine BMD significantly increased in the dolutegravir with rilpivirine group by 1.46% (95% CI 0.65–2.28) compared with 0.15% (95% CI –0.79 to 1.09) in the current ART group (treatment difference, 1.32; 95% CI 0.07–2.57; Pu200a=u200a0.039). Participants in the dolutegravir with rilpivirine group experienced significantly greater reductions in bone formation and resorption biomarkers compared with the current ART group. Conclusion: Switch to dolutegravir with rilpivirine was associated with significant improvement in BMD and bone turnover markers compared with tenofovir-based three-drug regimens, providing a robust option for preserving bone health while continuing suppressive ART.

Sword 1 and 2: Subgroup Analysis of 48 Week Results by Age, Race and Gender

Abstract Background Switching to the 2-drug regimen (2DR) of DTG+RPV was proven non-inferior to continuing a suppressive PI-, INI- or NNRTI- based current antiretroviral regimen (CAR) at Week 48. This analysis evaluated the efficacy and safety of switching from CAR to DTG+RPV by age, race and gender subgroups. Methods Two identically designed, open-label, multicenter, global, phase III, non-inferiority studies compared the efficacy and safety of switching from a 3 or 4-drug CAR to DTG + RPV once daily in HIV-1-infected adults, with HIV-1 RNA<50 c/mL. Primary endpoint was proportion of patients with VL<50 c/mL at Wk48 using FDA Snapshot. Additional analysis were performed to summarize efficacy base on age, race and gender subgroups for each individual study and pooled. Results 1024 patients were randomized and exposed (DTG+RPV 513; CAR 511), across both studies. Treatment arms were well matched for demographic and baseline characteristics. Median age across both arms was 43.4 years, with 29% and 28% ≥ 50 years in DTG+RPV and CAR, respectively. 23% and 21% were female while 18% and 22% were non-white for DTG+RPV and CAR. For the pooled studies and for SWORD-1 and SWORD-2 individually, switching to DTG+RPV was non-inferior to CAR at Wk48. Similar response rates were observed in the DTG+RPV arm compared with CAR across subgroups (Table 1). More AEs were reported in the DTG+/RPV arm across all subgroups except Asian race; no unexpected AEs were identified for either drug.Table 1. Proportion of patients with HIV-1 RNA <50 c/mL at Week 48 (snapshot): pooled SWORD studies population DTG/RPV, N = 513, n/N (%) CAR, N = 511, n/N (%) Overall 486/513 (95) 486/511 (95) Age <50 years 350/366 (96) 348/369 (94) ≥50 years 136/147 (93) 137/142 (96) Gender Male 375/393 (95) 387/403 (96) Female 111/120 (93) 98/108 (91) Race White 395/421 (94) 378/398 (95) African heritage 36/37 (97) 44/47 (94) Other 17/17 (100) 14/16 (88) Asian 38/38 (100) 49/50 (98) Conclusion Switch to a novel, once daily 2DR of DTG+RPV in patients with a suppressed viral load, was an effective and well tolerated treatment option across age, race, and gender subgroups which were consistent with overall results. Disclosures S. Walmsley, Merck: Board Member, Consultant, Grant Investigator, Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Grant recipient, Research grant and Speaker honorarium; ViiV Healthcare: Board Member, Consultant, Grant Investigator, Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Grant recipient, Research grant and Speaker honorarium; Gilead Sciences: Board Member, Consultant, Grant Investigator, Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Grant recipient, Research grant and Speaker honorarium; GSK: Board Member, Consultant, Grant Investigator, Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Grant recipient, Research grant and Speaker honorarium; Janssen: Board Member, Consultant, Grant Investigator, Investigator, Scientific Advisor and Speaker’s Bureau, Grant recipient, Research grant and Speaker honorarium; BMS: Grant Investigator, Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Grant recipient, Research grant and Speaker honorarium; G. Richmond, Viiv Healthcare: Investigator, Research support; u2028 F. Bredeek, ViiV Healthcare: Investigator and Scientific Advisor, Consulting fee and Research support; M. Ramgopal, viiv: Investigator, Consulting fee; C. C. Hung, Gilead Sciences: Board Member and Speaker’s Bureau, Consulting fee and Speaker honorarium; ViiV: Board Member and Investigator, Consulting fee and Research support; Abbvie: Board Member and Investigator, Consulting fee and Research grant; Bristol-Myers Squibb: Investigator, Research support; Jassen: Board Member and Investigator, Consulting fee and Research support; E. Blair, ViiV Healthcare: Employee and Shareholder, Salary; L. Kahl, ViiV Healthcare: Employee and Shareholder, Salary; M. Underwood, ViiV Healthcare: Employee, Salary; K. Angelis, GlaxoSmithKline: Employee, Salary; K. Vandermeulen, Jansen: Employee, Salary; B. Wynne, ViiV Healthcare: Employee, Salary; M. Aboud, ViiV Healthcare: Employee, Salary

VIH-17 - Le switch d’une trithérapie de 2 inti associés à un IP, un INNTI ou un INI par DTG/ABC/3TC maintient la suppression virologique à 24 semaines

Introduction La mise à disposition de l’association fixe DTG/ABC/3TC permet de simplifier le traitement ARV, prévenir certaines toxicités à long terme et éviter des interactions médicamenteuses tout en maintenant une suppression virologique. Cette étude a évalué l’efficacité et la tolérance du switch d’une trithérapie (2 INTI + 3 agent parmi IP, INNTI ou INI) par DTG/ABC/3TC QD. Matériels et méthodes Essai de non-infériorité (marge – 10 %) randomisé en ouvert multicentrique nord-américain évaluant l’efficacité, la tolérance, la pharmacocinétique et la satisfaction des patients liés au switch d’une trithérapie par DTG/ ABC/3TC chez des adultes infectés par le VIH, contrôlés (CV < 50 copies/ml). Les participants étaient randomisés 1:1 entre switch DTG/ABC/3TC et maintien du traitement. Le critère principal était la réponse virologique (CV < 50 copies/ml) à 24S en analyse snapshot. Résultats 551 adultes ont été randomisés et traités (DTG/ABC/3TC N = 274 ; maintien du traitement N = 277). La non-infériorité a été démontrée à S24 en ITTe [85 % vs 88 % (différence ajustée – 3,4 % ; IC95 % – 9,1 ; 2,3)] et en per protocole [93 % vs 93 % (IC95 % – 4,9 ; 4,4)]. Aucun échec virologique (défini par le protocole) ni mutation de résistance n’ont été observés. Les arrêts pour effets indésirables ont été de 4 % (n = 10) sous DTG/ABC/3TC versus 0 en maintien du traitement. Les données pharmacocinétiques permettaient un switch immédiat. La satisfaction des patients a augmenté significativement dans le bras DTG/ABC/ 3TC vs le bras maintien du traitement (différence ajustée 2,4 ; IC95 % 1,3 ; 3,5 ; p < 0,001). Conclusion Chez des patients contrôlés, le switch de DTG/ABC/3TC QD était non-inférieur au maintien du traitement, sans échec virologique ni mutation de résistance. Un taux d’arrêts pour EI a été plus fréquent chez les patients switchés sous DTG/ABC/3TC, mais le taux de satisfaction était supérieur par rapport au maintien d’une trithérapie (2 INTI + 3 agent parmi IP, INNTI ou INI). Liens d’intérêts déclarés : J.K. ViiV Healthcare employee