Brian Wynne

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.

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.

Relative Bioavailability of a Dolutegravir Dispersible Tablet and the Effects of Low- and High-Mineral-Content Water on the Tablet in Healthy Adults

Dolutegravir (DTG) is approved in the United States to treat HIV‐1‐infected patients weighing ≥30 kg. A dispersible DTG tablet formulation was recently developed for pediatric patients. This study compares the pharmacokinetics (PK) of the dispersible tablet with that of a previously evaluated granule formulation. In this randomized, open‐label, crossover study, 15 healthy adults received single oral doses of DTG 20 mg every 7 days across 5 treatment arms: granules consumed immediately after mixture with purified water, dispersible DTG consumed immediately after reconstitution in low‐mineral‐content (LMC) or high‐mineral‐content (HMC) water, and dispersible DTG consumed 30 minutes after dispersal in LMC or HMC water. Primary endpoints were bioavailability of immediately consumed dispersible tablet in LMC water relative to granule formulation reconstituted in purified water and PK of the dispersible tablet. Secondary endpoints included tolerability and palatability. The DTG dispersible tablet showed equivalent exposures to the granule formulation with geometric least‐squares mean treatment ratios of 1.06 and 1.12 for AUC0‐∞ and Cmax, respectively. DTG PK parameters were unaffected by mineral content or the 30‐minute delay. Adverse events were mild; only nausea (n = 1) was considered drug related. DTG exposure observed with the dispersible tablet supports evaluation of this formulation for further development.

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