Antiviral Therapy 2015; 20: (doi: /IMP2878)

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1 Antiviral Therapy 2015; 20: (doi: /IMP2878) Short communication Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study Bisher Akil 1, Gary Blick 2, Debbie P Hagins 3, Moti N Ramgopal 4, Gary J Richmond 5, Rafik M Samuel 6, Naomi Givens 7, Cindy Vavro 8, Ivy H Song 8, Brian Wynne 9, Mounir Ait-Khaled 7 *, the VIKING-4 study team 1 Chelsea Village Medical, PC, New York, NY, USA 2 CIRCLE CARE Center, Norwalk, CT, USA 3 Chatham County Health Department, Savannah, GA, USA 4 Midway Immunology and Research Center, Fort Pierce, FL, USA 5 Broward Health, Fort Lauderdale, FL, USA 6 Temple University, Philadelphia, PA, USA 7 GlaxoSmithKline, London, UK 8 GlaxoSmithKline, Research Triangle Park, NC, USA 9 GlaxoSmithKline, Philadelphia, PA, USA *Corresponding author mounir.c.ait-khaled@gsk.com Background: The Phase III VIKING-3 study demonstrated that dolutegravir (DTG) 50 mg twice daily was efficacious in antiretroviral therapy (ART)-experienced subjects habouring raltegravir- and/or elvitegravir-resistant HIV-1. VIKING-4 (ING116529) included a placebo-controlled 7-day monotherapy phase to demonstrate that shortterm antiviral activity was attributable to DTG. Methods: VIKING-4 is a Phase III randomized, doubleblind study in therapy-experienced adults with integrase inhibitor (INI)-resistant virus randomized to DTG 50 mg twice daily or placebo while continuing their failing regimen (without raltegravir or elvitegravir) for 7 days (clinicaltrials.gov identifier NCT ). At day 8, all subjects switched to open-label DTG 50 mg twice daily and optimized background therapy including 1 fully active drug. The primary end point was change from baseline in plasma HIV-1 RNA at day 8. Results: The study population (n=30) was highly ARTexperienced with advanced HIV disease. Patients had extensive baseline resistance to all approved antiretroviral classes. Adjusted mean change in HIV-1 RNA at day 8 was log 10 copies/ml for the DTG arm and 0.10 log 10 copies/ml for the placebo arm (treatment difference log 10 copies/ml [-1.52, -0.80]; P<0.001). Overall, 47% and 57% of subjects had plasma HIV-1 RNA <50 and <400 copies/ml at week 24, and 40% and 53% at week 48, respectively. No discontinuations due to drug-related adverse events occurred in the study. Conclusions: The observed day 8 antiviral activity in this highly treatment-experienced population with INIresistant HIV-1 was attributable to DTG. Longer-term efficacy (after considering baseline ART resistance) and safety during the open-label phase were in-line with the results of the larger VIKING-3 study. Introduction Dolutegravir (DTG) is an integrase inhibitor (INI) recently approved in the United States and European Union for the treatment of HIV-1 infection [1,2]. This was based on several Phase III studies showing the safety and efficacy of DTG 50 mg once daily in INI-naive subjects [3 5] and DTG 50 mg twice daily in INI-resistant adults [6]. In the VIKING-3 study of adults with INI-resistant HIV-1 infection, the majority of subjects experienced a rapid and substantial virological response to DTG 50 mg twice daily with failing background therapy through day 8 and long-term efficacy with an optimized background regimen (OBR) through week 48. The efficacy of DTG in VIKING-3 was lower in subjects habouring baseline virus with 2015 International Medical Press (print) (online) 343

2 B Akil et al. Q secondary mutations. However, due to the lack of placebo-controlled data in VIKING-3, shortterm antiviral activity fully attributable to DTG was not known. The current study, VIKING-4, included a double-blind, placebo-controlled, functional monotherapy phase designed to answer this question. This approach would control for a failing regimen s potential antiviral activity and better estimate the antiviral activity of DTG. Methods Study design VIKING-4 (ING116529; clinicaltrials.gov identifier NCT ) is a Phase III, randomized, doubleblind, placebo-controlled superiority study conducted at 20 sites in the United States. Subjects received DTG 50 mg twice daily or placebo (PCB) with their previous failing background antiretroviral therapy (ART) for 7 days, followed by a single-arm, open-label DTG 50 mg twice daily with an optimized ART regimen comprising at least one fully active drug according to baseline resistance data (Figure 1). Study visits were at screening (up to 35 days prior to randomization), days 1 (randomization) and 8, and weeks 4, 8, 12, 16, 24, 32, 40, 48 and every 12 weeks thereafter. Prior written consent was obtained from each subject who participated in the study. This study was conducted in accordance with the principles outlined in the 2008 Declaration of Helsinki. Subjects Eligible subjects were 18 years old, ART-experienced and DTG-naive with plasma HIV-1 RNA 1,000 copies/ml at screening. Subjects had to be currently taking either raltegravir or elvitegravir with documented virological failure and INI genotypic resistance at screening. In addition, subjects had to have screening or historical evidence of resistance to a drug from 2 other ART classes, but at least one identified fully active drug option. Key exclusion criteria included pregnancy or breastfeeding, active US Centers for Disease Control and Prevention (CDC) category C disease except for Kaposi s sarcoma or CD4 + T-cell count <200 cells/mm 3, moderate to severe hepatic impairment (Child-Pugh classification), anticipated need for HCV therapy during the first 24 weeks, or predefined laboratory values or medical conditions. Efficacy, virology and safety assessments The primary and secondary efficacy and safety analyses were based on the randomized study population who received at least 1 dose of study drug. The primary end point was the day 8 change from baseline in plasma HIV-1 RNA using the Abbott RealTime HIV-1 Polymerase Chain Reaction assay (Abbott Molecular, Des Plaines, IL, USA). Secondary end points included proportion of subjects with plasma HIV-1 RNA <400 copies/ml and <50 copies/ml and change in CD4 + T-cell count over time. Descriptive efficacy analyses by DTG fold change (FC), derived integrase (IN) mutation group and overall susceptibility score (OSS) of the OBR were performed. The baseline IN mutation group (that is, no Q148, Q148+1 or Q148+ 2) was derived from ING data, which showed that subjects habouring HIV-1 without the Q148 mutation had the best antiviral response, whereas subjects habouring virus with Q148 substitutions had decreased response rates with increasing number of secondary mutations of G140A/C/S, L74I or E138A/K/T [6]. Genotypic and phenotypic assays were performed as previously described [6]. Safety assessments included adverse events (AEs) and laboratory parameters, such as haematology, fasting lipid profile, blood chemistries and urinalysis (including urine microalbumin/creatinine ratio). Laboratory samples were analysed using a central laboratory and sites were notified of subjects with abnormal results. Pharmacokinetic analyses Predose DTG concentrations (C0) were obtained at day 8 in the DTG arm and weeks 4 and 24 for all subjects and analysed as described elsewhere [7]. Statistical analysis A sample size of 30 subjects (15 per arm) had 91% power to detect the mean difference (standard deviation) in day 8 change from baseline in plasma HIV-1 RNA between the DTG and placebo arms, assuming the mean (sd) difference would be 1 (0.8) log 10 copies/ ml. For the primary comparison, point estimates, 95% CIs and P-value of the difference in mean change from baseline in plasma HIV-1 RNA at day 8 between the two arms were presented using an analysis of covariance (ANCOVA) model adjusting for baseline plasma HIV-1 RNA, DTG FC and OSS of the failing regimen. Longer term antiviral response was evaluated for the combined arm as all subjects entered the active DTG 50 mg open-label phase post-day-8. The proportions of subjects (combined arm) with HIV-1 RNA <50 copies/ ml and <400 copies/ml over time at week 24 and week 48 were derived using the FDA s Snapshot algorithm. Results Demographics and baseline characteristics Figure 1 shows the initial randomization of subjects during the 8-day primary analysis phase and subsequent reallocation during the open-label phase, which International Medical Press

3 DTG vs placebo in subjects with INI-resistant HIV-1: 48-week results Figure 1. Study design and disposition for VIKING-4 Screening visit ~28 days Assessed for eligibility (n=75) Screening period (up to 35 days) Excluded (n=45) Screening failure (n=45) Day 1 Randomized (n=30) Randomized, placebocontrolled monotherapy phase Allocated to DTG 50 mg twice daily + remaining components of failing regimen (n=14) Received (n=14) Allocated to PCB twice daily + remaining components of failing regimen (n=16) Received (n=16) Primary analysis (day 8) Open-label, optimized phase a Completed week 48 (n=7) Lost to follow-up (n=0) Completed week 48 (n=13) Lost to follow-up (n=1) Incarceration (n=1) Week 48 analysis Discontinued intervention (n=7) Adverse event (n=2) Lack of efficacy (n=4) - Virological failure (n=4) Withdrew consent (n=1) Discontinued intervention (n=3) Adverse event (n=0) Lack of efficacy (n=2) - Virological failure (n=2) Withdrew consent (n=0) a On day 8, both arms received dolutegravir (DTG) 50 mg twice daily + optimized background regimen (OBR; overall susceptibility score [OSS] 1) during the open-label phase. PCB, placebo. extended to 48 weeks. Overall, the study population was balanced across the DTG and PCB/DTG arms (Table 1). The study population had advanced disease and was highly treatment-experienced with multiclass resistance: 63%, 53% and 67% of subjects had 3 NRTI, 2 NNRTI and 2 PI major mutations, respectively. All subjects were currently experiencing raltegravir failure and discontinued raltegravir by day 1 before dosing with DTG or PCB. IN mutation Q148 was detected in 16/30 (53%) subjects at baseline. Four subjects harboured virus with Q secondary INI resistance mutations. Day 8 OBR activity was relatively low, with 18/30 (60%) subjects having an OSS 1. When only new ARVs never received by the subjects prior to day 8 (OSS New) were considered, 27/30 (90%) had an OSS New 1 (Table 1). Efficacy DTG antiviral response at day 8 (-1.06 log 10 copies/ ml) was superior to that of placebo (0.10 log 10 copies/ml); adjusted mean treatment difference was log 10 copies/ml (P<0.001; Table 2). Plasma HIV-1 RNA <50 copies/ml was achieved by 47% and 40% of subjects and plasma HIV-1 RNA <400 copies/ml was achieved by 57% and 53% of subjects at week 24 and week 48, respectively. The median increase in Antiviral Therapy

4 B Akil et al. Table 1. Demographics and disease characteristics a DTG 50 mg twice Placebo/DTG 50 mg Combined arms Parameter daily (n=14) twice daily (n=16) (n=30) Median age (range), years 49.5 (19 66) 48.0 (32 63) 48.5 (19 66) Male, n (%) 12 (86) 12 (75) 24 (80) Race, n (%) White 5 (38) 7 (44) 12 (41) African American/African heritage 8 (62) 8 (50) 16 (55) Other/missing 0/1 (7) 1 (6)/0 1 (3)/1 (3) Median baseline CD4 + T-cell count (IQR), cells/mm ( ) 91 (46 268) 160 (59 231) Median baseline plasma HIV-1 RNA level (IQR), log 10 copies/ml 4.38 ( ) 4.52 ( ) 4.42 ( ) CDC category C, n (%) 9 (64) 10 (63) 19 (63) Hepatitis coinfection HBsAg/HCV-antibody-positive b, n (%) 2 (14)/2 (14) 2 (13)/1 (6) 4 (13)/3 (10) Median duration of prior ART (IQR), years 14.9 (2 23.5) 12.7 (1 27.8) 13.3 (1 27.8) Median number of prior ART Prior ART FTC/TDF, n (%) 14 (100) 12 (75) 26 (87) ENF, n (%) 7 (50) 4 (25) 11 (37) DRV/r, n (%) 12 (86) 11 (69) 23 (77) ETR, n (%) 8 (57) 8 (50) 16 (53) Baseline genotypic primary INI resistance detected, n (%) 14 (100) 15 (94) c 29 (97) Derived IN mutations groups at baseline No Q148 d, n (%) 5 (36) 9 (56) 14 (47) Q e, n (%) 6 (43) 6 (38) 12 (40) Q e, n (%) 3 (21) 1 (6) 4 (13) Median baseline DTG FC (range) 4.4 ( ) 2.9 ( ) 3.3 ( ) Median baseline RAL FC (range) ( ) ( ) ( ) OSS of day 8 OBR, all/no prior use f 0, n (%) 1 (7)/11 (79) 2 (13)/8 (50) 3 g (10)/19 (63) 1, n (%) 8 (57)/3 (21) 7 (44)/5 (31) 15 (50)/8 (27) 2, n (%) 4 (29)/0 4 (25)/3 (19) 8 (27)/3 (10) >2, n (%) 1 (7)/0 3 (19)/0 4 (13)/0 Most frequently used active ARV in OBR h Any active ARV, n (%) 13 (100) 14 (100) 27 (100) TDF, n (%) 5 (38) 6 (43) 11 (41) DRV/r, n (%) 4 (31) 4 (29) 8 (30) ETR, n (%) 2 (15) 2 (14) 4 (15) ZDV, n (%) 2 (15) 2 (14) 4 (15) ENF, n (%) 1 (8) 2 (14) 3 (11) ATV/r, n (%) 0 1 (7) 1 (4) LPV/r, n (%) 1 (8) 0 1 (4) TPV/r, n (%) 1 (8) 0 1 (4) a Subjects in each arm received either dolutegravir (DTG) 50 mg twice daily or placebo alone during days 1 7. Subsequently, all subjects received DTG 50 mg twice daily + optimized background regimen (OBR) during the open-label phase, beginning on day 8. b No subjects had hepatitis B surface antigen (HBsAg) and HCV coinfection. c Virus in one subject had mutations L74L/M, T97T/A and Y143Y/C at screening that were no longer detected at baseline. d Included primary integrase resistance mutations N155H, Y143C/H/R, T66A and E92Q or historical evidence of resistance. e Secondary mutations from G140A/C/S, E138A/K/T and L74I. f Only antiretroviral (ARV) never taken prior to day 8 considered for activity measurement (overall susceptibility score [OSS] new). g Three subjects had a day 8 OBR of zero as the active agents identified for eligibility were not selected by the investigator for the OBR. h The three subjects with OBR OSS=0 were excluded from the calculation of frequency of active ARV. ART, antiretroviral therapy; ATV/r, atazanavir/ritonavir; CDC, Centers for Disease Control and Prevention; DRV/r, darunavir/ritonavir; ENF, enfuvirtide; ETR, etravirine; FC, fold change (in 50% inhibitory concentration); FTC, emtricitabine; IN, integrase; INI, integrase inhibitor; LPV/r, lopinavir/ritonavir; RAL, raltegravir; TDF, tenofovir disoproxil fumarate; TPV/r, tipranavir/ritonavir; ZDV, zidovudine. CD4 + T-cell counts at week 48 (n=21) was 125 cells/ mm 3. At weeks 24 and 48, subjects with no Q148 mutation at baseline had a better virological response (64% and 57%, respectively) than did those with a Q mutations (25% at both time points). Safety Safety and tolerability data (median follow-up of 55 weeks) were consistent with those from previous DTG studies [3 5], including those in subjects with INI-resistant virus [6], with no new concerns International Medical Press

5 DTG vs placebo in subjects with INI-resistant HIV-1: 48-week results Table 2. Comparison of DTG 50 mg twice daily versus PCB for change in BL HIV-1 at day 8 and antiviral efficacy of open-label DTG 50 mg twice daily with OBR at weeks 24 and 48 by BL characteristics a DTG 50 mg twice daily change PCB 50 mg twice daily change Combined arms, HIV-1 RNA from BL b at day 8 a (n=14) from BL b at day 8 a (n=16) <50 copies/ml a (%) (n=30) Subgroup n Mean (sd) n Mean (sd) Week 24 Week 48 Overall c 14 d (0.17) (0.18) 14/30 (47) 12/30 (40) DTG FC (0.82) (0.34) 6/11 (55) 5/11 (45) > (0.65) (0.28) 3/5 (60) 3/5 (60) > (0.65) (0.22) 2/9 (22) 1/9 (11) > /2 (50) 1/2 (50) > /2 (50) 1/2 (50) Missing /1 (100) 1/1 (100) Derived IN mutation group No Q148 e (0.745) (0.325) 9/14 (64) 8/14 (57) Q f (0.587) (0.182) 4/12 (33) 3/12 (25) Q f (0.758) /4 (25) 1/4 (25) OSS g of background ART 0 2/3 (67) 2/3 (67) 1 6/15 (40) 5/15 (33) 2 3/8 (38) 3/8 (38) >2 3/4 (75) 2/4 (50) a Subjects in each arm received either dolutegravir (DTG) 50 mg twice daily or placebo (PCB) alone during days 1 through 7. Subsequently, all subjects received DTG 50 mg twice daily + optimized background regimen (OBR) during the open-label phase, beginning on day 8. b Log 10 copies/ml. c Mean adjusted for baseline (BL) plasma HIV-1 RNA (log 10 copies/ml), baseline DTG fold change (FC; in 50% inhibitory concentration), overall susceptibility score (OSS) of failing regimen and the interaction between DTG FC and treatment. d One subject had no result for BL DTG FC and was excluded from primary end point analysis. e Includes primary integrase (IN) resistance mutations N155H, Y143C/H/R, T66A and E92Q or historical evidence of resistance. f Secondary mutations from G140A/C/S, E138A/K/T and L74I. g Calculated as the sum of the net assessment scores of antiretrovirals (ARVs) comprising the subject s day 8 OBR (only fully active ARVs are assigned a value of 1). ART, antiretroviral therapy. identified. The most common drug-related AEs were nausea (13%), diarrhoea (10%) and dizziness (7%). Two subjects (7%) were withdrawn from the study due to fatal AEs (cardiovascular-related and cardiac arrest) that were not judged to be drug-related. Both of these subjects had past medical histories of cardiovascular events, including stroke. Nine subjects experienced a serious AE (including the two fatal events); none were considered reasonably attributable to DTG by the reporting investigator. Grade 3 and 4 clinical chemistry abnormalities were reported for 13% and 3% of subjects, respectively. Pharmacokinetics The geometric mean and between-subject coefficient of variation (CV%) of the DTG pharmacokinetic parameter estimate C0 of the entire cohort was 1.80 mg/ml (123%; n=27) at day 28 and 2.05 mg/ml (127%; n=24) at week 24, comparable to those observed in VIKING-3 at week 4 (1.90 mg/ml [113%]; n=161) and week 24 (2.14 mg/ml [93%]; n=134). Virology Through 48 weeks, protocol-defined virological failure (PDVF) was observed in 7 (23%) subjects, all had paired baseline and time point of virological failure resistance results. Six of the seven PDVFs occurred in subjects with Q148 virus at baseline. INI treatment-emergent resistance was detected for five of seven subjects. Four of the five subjects with treatment-emergent INI resistance had Q148 mutations at baseline. Treatment-emergent mutations consisted of previously identified INI mutations: L74L/M (n=1), T97A (n=3), E138E/K (n=1), E138K (n=1), S147G (n=1) and N155N/H (n=1). Discussion VIKING-4 demonstrates the greater antiviral activity of DTG 50 mg twice daily compared with placebo when administered with failing background therapy for 7 days in HIV-infected subjects with current INI resistance. These results provide further evidence of the antiviral activity of DTG 50 mg twice daily against INIresistant virus. The safety and pharmacokinetic profile was similar to previous DTG studies [6]. Week 48 virological response in this study was lower than that observed in VIKING-3 (63% of subjects with plasma HIV-1 RNA <50 copies/ml at week 48) [8]. This can be partly explained by the higher proportion of subjects with Q148 virus and with extensive multiclass baseline resistance in the current study (illustrated by the low new drug OSS [OSS New] scores in the day 8 OBR; Table 1). Antiviral Therapy

6 B Akil et al. As in VIKING-3, the best antiviral responses were observed in patients with no Q148 virus with lower responses in patients habouring Q148 virus. Seven (23%) subjects experienced PDVF while on study. As was seen in VIKING-3, treatment-emergent mutations leading to decreased DTG susceptibility were mostly seen in virus with Q148 mutations at study start. Given the small sample size of the study and the small number of subjects with PDVF, no other clear discernible factor could be identified. In summary, the superiority of DTG versus PCB at day 8 supports the conclusion that the antiviral activity observed in patients with INI resistance following 7 days of functional monotherapy is attributable to DTG. Longer-term efficacy after considering baseline ART resistance (including INI) during the openlabel phase was in-line with the results of the larger VIKING-3 study. Acknowledgements This study was funded by ViiV Healthcare. Portions of the data from this study have been presented previously at the 14th European AIDS Conference (16 19 October 2013, Brussels, Belgium). We thank everyone who has contributed to the success of this study, including all study participants and their families, the VIKING-4 clinical investigators and their staff, and the other members of the GSK and ViiV Healthcare study team, including Franco Felizarta, Robert Grossberg, Charles Hicks, Chiu-Bin Hsiao, Alyssa Shon, Thomas T Jefferson, Princy Kumar, Anthony Mills, Cheryl Newman, Paul Sax, Louis M Sloan, Douglas Ward, David Wheeler, Timothy J Wilkin and David Wright. All listed authors meet the criteria for authorship set forth by the International Committee of Medical Journal Editors. The authors also wish to acknowledge the following individuals: Jenny Huang for statistical support and guidance, Annie Cameron for study operational support, Shirley Williams for data management, and Jeffrey Stumpf and Clint Smith of MedThink SciCom for editorial assistance. The authors also recognize Chandrakala Avatapally and Ruolan Wang for clinical virology support. Disclosure statement BA has received contract, consultant and speaker fees from ViiV Healthcare. GB has received grants for his work as a speaker and for participation in advisory boards for ViiV Healthcare. DPH has worked as a principal investigator in clinical trials and participated in speaker s bureaus and advisory boards for Glaxo- SmithKline, ViiV Healthcare, Gilead Sciences and Merck. MNR has participated in speaker s bureaus for ViiV Healthcare, Gilead Sciences and Abbott Laboratories. GJR has received grants and personal fees from GlaxoSmithKline, Boehringer Ingelheim and Forest Pharmaceuticals and grants from ViiV Healthcare, Gilead Sciences, Ikaria, Abbott Laboratories, Novartis, EMD Serono and Salix Pharmaceuticals. RMS has received grants from GlaxoSmithKline both to support work on this study and for work outside the submitted work. CV, NG and IHS are employees of GlaxoSmithKline. BW and MA-K received grants from ViiV Healthcare to support work on this study and are employees of GlaxoSmithKline. References 1. Tivicay (dolutegravir). Package insert ViiV Healthcare, Research Triangle Park, NC, USA. 2. Tivicay (dolutegravir). Summary of product characteristics ViiV Healthcare UK Ltd, Middlesex, UK. 3. Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 2013; 381: Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integraseinhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet 2013; 382: Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir lamivudine for the treatment of HIV-1 infection. N Engl J Med 2013; 369: Castagna A, Maggiolo F, Penco G, et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis 2014; 210: Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a Phase 1 study among healthy subjects. J Acquir Immune Defic Syndr 2013; 62: Vavro C, Huang J, Avatapally C, et al. Durable efficacy and limited integrase resistance in subjects receiving dolutegravir after failing a prior INI regimen: week 48 results from VIKING-3. 12th European Workshop on HIV & Hepatitis Treatment Strategies & Antiviral Drug Resistance March 2014, Barcelona, Spain. Abstract O_10. Accepted 29 September 2014; published online 16 October International Medical Press