Short communication Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96

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1 Antiviral Therapy : (doi: /IMP1301) Short communication Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96 Keikawus Arastéh 1 *, Patrick Yeni 2, Anton Pozniak 3, Beatriz Grinsztejn 4, Dushyantha Jayaweera 5, Afsoon Roberts 6, Jennifer Hoy 7, Sandra De Meyer 8, Tony Vangeneugden 8 and Frank Tomaka 9 1 EPIMED, Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany 2 Hôpital Bichat and University of Paris, Paris, France 3 Chelsea and Westminster Hospital, London, UK 4 Instituto de Pesquisa Clinica Evandro Chagas-FIOCRUZ, Rio de Janeiro, Brazil 5 University of Miami, Miami, FL, USA 6 George Washington University Medical Center, Washington, DC, USA 7 The Alfred Hospital, Melbourne, VIC, Australia 8 Tibotec BVBA, Mechelen, Belgium 9 Tibotec Inc., Yardley, PA, USA *Corresponding author: keikawus.arasteh@vivantes.de Background: Long-term (96-week) efficacy and safety of the protease inhibitor (PI) darunavir coadministered with low-dose ritonavir (DRV/r) was evaluated in HIV type-1 (HIV-1)-infected patients with extensive prior treatment experience in the POWER 1, 2 and 3 trials. Methods: Patients with HIV-1 RNA 1,000 copies/ml and 1 primary PI mutation were randomized to receive either DRV/r 600/100 mg twice daily plus an optimized background regimen (OBR), or an investigator- selected control PI (CPI) plus OBR (POWER 3 was a DRV/r 600/100 mg twice daily single-arm study). The proportion of patients with HIV-1 RNA<50 copies/ml at week 96 was assessed (intent-to-treat [ITT], time-to-loss of virological response algorithm). Results: In total, 467 patients received DRV/r 600/100 mg twice daily; 124 patients received CPI(s). At week 96, 39% of DRV/r patients in POWER 1 and 2 (pooled analysis) versus 9% of CPI patients achieved HIV-1 RNA<50 copies/ml (ITT, time-to-loss of virological response algorithm; P<0.001). A similar proportion of DRV/r patients (42%) in POWER 3 achieved HIV-1 RNA<50 copies/ml at week 96. Mean absolute CD4 + T-cell count increase for DRV/r at 96 weeks was 133 cells/mm 3 in POWER 1 and 2 and 103 cells/mm 3 in POWER 3. Grade 2 4 treatmentemergent adverse events at least possibly related to DRV/r ( 2% incidence, excluding laboratory abnormalities) were diarrhoea (3%), vomiting (3%), nausea (2%) and headache (2%). Conclusions: Treatment with DRV/r 600/100 mg twice daily was well tolerated and led to sustained virological and immunological responses in treatment-experienced HIV-1-infected patients over 96 weeks. Introduction The protease inhibitor (PI) darunavir coadministered with low-dose ritonavir (DRV/r) has demonstrated efficacy and tolerability in a broad range of HIV type-1 (HIV-1)-infected patients from those who are treatment-naive and early treatment-experienced through to the highly treatment-experienced population [1 7]. The POWER (Performance Of TMC114/r When evaluated in highly treatment-experienced patients with PI Resistance) studies are Phase IIb, 144-week trials evaluating the efficacy and safety of DRV/r in triple- class (PI-, nucleoside reverse transcriptase inhibitor [NRTI]- and non-nrti [NNRTI])-experienced patients [1 5]. POWER 1 and 2 are randomized trials comparing DRV/r with investigator-selected control PIs (CPIs). POWER 3 is an open-label analysis in a larger set of similarly experienced patients. Data from these studies up to week 48 have demonstrated excellent efficacy and tolerability in these highly treatment International Medical Press (print) (online) 859

2 K Arastéh et al. experienced patients, with 45 46% of DRV/r patients achieving HIV-1 RNA<50 copies/ml in pooled POWER 1 and 2 analysis, and POWER 3 (compared with only 10% of CPI patients) [4,5]. DRV/r 600/100 mg twice daily was generally well tolerated up to week 48 in all POWER studies, with a lower or similar rate of adverse events (AEs) compared with CPIs. Longer-term data are needed to evaluate the sustainability of the antiviral effects observed previously with DRV/r and to confirm its continued tolerability. In this communication, we present the 96-week efficacy and safety of DRV/r 600/100 mg twice daily in the POWER 1, 2 and 3 trials. Methods Patient population Inclusion and exclusion criteria have been described previously [1 3]. In brief, patients were HIV-1- infected adults with plasma HIV-1 RNA>1,000 copies/ml, prior experience of 1 NRTI, NNRTI and PI, and 1 primary PI mutation [8,9]. All patients gave written informed consent and protocols were approved by the appropriate institutional ethics committees and/or health authorities and conducted in accordance with the Declaration of Helsinki. Study design POWER 1 (TMC114-C213), 2 (TMC114-C202) and 3 (TMC114-C215) are registered with ClinicalTrials. gov (numbers NCT , NCT and NCT , respectively). Study design has been described previously [1 3]. Briefly, POWER 1 and 2 were randomized partially-blinded controlled trials comparing DRV/r with investigator-selected CPI(s), with an initial 24-week dose-finding phase [1,2]. Only patients receiving the DRV/r 600/100 mg twice-daily dose from baseline were included in the current analysis. POWER 3 comprised two similar non-randomized open-label trials (TMC114-C215 and -C208), with all patients receiving DRV/r 600/100 mg twice daily from baseline [3]. Only data from study TMC114-C215 were included in this pre-planned 96-week efficacy analysis. All patients in POWER 1 3 received an investigator-selected optimized background regimen (OBR) from baseline. Efficacy and safety assessments and statistical analyses Efficacy data for DRV/r are reported pooled for POWER 1 and 2 and separately for POWER 3, but safety data for all trials were combined to provide a more robust evaluation. Data for CPI(s) from POWER 1 and 2 were included in the present efficacy analysis but safety was not evaluable because of the high rate of treatment discontinuation, mainly as a result of virological failure. Efficacy and safety were assessed as previously described, with further evaluations at 12-week intervals between weeks 48 and 96 [1 3]. Cumulative toxicity effects were determined by recording the incidence of AEs at 24-week intervals. Statistical analyses were conducted as previously described [1 3]. Results Baseline demographics and characteristics The 96-week analysis included 467 patients who initiated treatment with DRV/r 600/100 mg twice daily in POWER 1 (n=65), POWER 2 (n=66) and POWER 3 (n=336), and 124 CPI patients. Demographics and baseline disease characteristics have been reported previously and were well balanced across treatment arms [1 3]. Overall, patients had advanced HIV-1 disease (mean HIV-1 RNA 4.59 log 10 copies/ml for DRV/r and 4.49 log 10 copies/ml for CPI; median CD4 + T-cell count 129 cells/mm 3 and 163 cells/mm 3, respectively) and extensive prior treatment experience. Mean duration of treatment was 90.5 weeks for DRV/r (POWER 1 3) compared with 39.8 weeks for CPI (POWER 1 and 2). At the time of the week-96 analysis, 32% of DRV/r patients had discontinued therapy compared with 87% of patients receiving CPI(s). Virological failure was the main reason for discontinuation (72% CPI and 13% DRV/r patients). Virological response At week 96, 39% of DRV/r patients in POWER 1 and 2 achieved HIV-1 RNA<50 copies/ml, compared with 9% for CPI patients (P<0.001; intent-to-treat, time-to-loss of virological response algorithm; Figure 1). The difference between treatment arms was maintained regardless of subgroup (number of primary PI mutations, enfuvirtide use in the OBR and baseline HIV-1 RNA; results not shown). Of the 45% of DRV/r patients in POWER 1 and 2 with HIV-1 RNA<50 copies/ml at week 48, 80% maintained this response to week 96. In the CPI group, 11% achieved HIV-1 RNA<50 copies/ ml at week 48, with 79% maintaining the response to week 96. In POWER 3, 42% DRV/r patients achieved HIV-1 RNA<50 copies/ml at week 96, and 86% of those with undetectable viral load at week 48 maintained this response to week 96. Immunological response The mean absolute CD4 + T-cell count increase from baseline to week 96 in POWER 1 and 2 was 133 cells/ mm 3 for DRV/r and 15 cells/mm 3 for CPI (P<0.001). The mean difference in CD4 + T-cell count between treatment arms increased from 86 cells/mm 3 at week 48, to 118 cells/mm 3 at week 96 (ITT, last observation carried forward). In POWER 3 the mean increase from baseline International Medical Press

3 Long-term DRV/r in ARV-experienced patients Figure 1. Proportion of patients with HIV type-1 RNA<50 copies/ml from baseline to week Proportion of patients with viral load <50 copies/ml, % DRV/r POWER 1 and 2 600/100 mg twice daily DRV/r POWER 3 600/100 mg twice daily CPI(s) POWER 1 and 2 42% 39% 9% Time, weeks Data are means ±se. Treatment is darunavir combined with low-dose ritonavir (DRV/r) for POWER 1 and 2 and POWER 3 and control protease inhibitors (CPIs) for POWER 1 and 2 by intent-to-treat, time-to-loss of virological response algorithm. to week 96 was 103 cells/mm 3 (ITT, last observation carried forward). Safety analysis The majority of AEs that occurred in DRV/r patients in POWER 1 3 reported to week 96 were grade 1 or 2 in severity, consistent with the week 48 findings [4,5]. The most commonly reported treatment-emergent AEs were diarrhoea, nausea, nasopharyngitis and headache (Table 1). The majority of rash-related AEs were also grade 1 or 2 in severity, with the exception of one grade 3 drug-related skin eruption that led to treatment discontinuation. Grade 2 4 treatment-emergent AEs considered at least possibly related to DRV/r and observed in 2% of patients were diarrhoea, vomiting, nausea and headache (Table 1). A total of 20 (4%) patients receiving DRV/r died during the treatment period, with all deaths considered to be unrelated or doubtfully related to study medication. The overall mortality rate was 2.5 per 100 patient-years of exposure and did not increase over the treatment period. The majority of deaths (75%) occurred in patients with baseline CD4 + T-cell counts of <50 cells/mm 3, a factor known to be associated with a higher mortality risk. The majority of laboratory abnormalities in DRV/rtreated patients were grade 1 or 2 in severity. Mean triglyceride levels decreased over time (-0.59 mmol/l [ mg/dl] from baseline to week 96); whereas slight increases were observed for mean low-density lipoprotein (0.53 mmol/l [20.49 mg/dl]), high-density lipoprotein (0.08 mmol/l [3.09 mg/dl]), and total cholesterol (0.46 mmol/l [17.79 mg/dl]). These changes occurred mainly within the first 12 weeks of treatment. The most commonly reported grade 2 4 laboratory abnormalities, observed in 2% of DRV/r patients, were increased total cholesterol, increased low-density lipoprotein and increased triglycerides (Table 1). The majority of treatment-emergent liver-related laboratory abnormalities of interest were of grade 1 or 2 seventy. The changes in treatment-emergent grade 2 4 laboratory parameters between baseline and week 96 were generally consistent with earlier analyses [4,5]. Overall, there was minimal change in the type and incidence of AEs observed over time. No cumulative toxicity effects were evident with long-term use of DRV/r 600/100 mg twice daily (Table 2). Gastrointestinal disorders, which included diarrhoea, nausea and abdominal pain, decreased during the study (Table 2). Discussion The efficacy results of the present analysis support and extend the findings of POWER 1 3 at 24 and Antiviral Therapy

4 K Arastéh et al. Table 1. Safety analysis: treatment-emergent AEs and laboratory abnormalities observed in POWER 1, 2 and 3 DRV/r patients at week 96 AE or laboratory abnormality type Incidence in DRV/r-treated patients, n (%) Any AE 455 (97) AEs reported in 10% of patients regardless of severity and causality Diarrhoea 118 (25) Nasopharyngitis 75 (16) Nausea 75 (16) Headache 74 (16) Bronchitis 63 (13) Sinusitis 63 (13) Cough 54 (12) Herpes simplex 51 (11) Influenza 50 (11) Fatigue 49 (10) Arthralgia 49 (10) Pyrexia 47 (10) Rash (all types) a 47 (10) Grade 2 4 AEs at least possibly related to DRV/r ( 2% of patients) b Diarrhoea 16 (3) Vomiting 12 (3) Nausea 10 (2) Headache 10 (2) Most commonly reported serious AEs, regardless of severity and causality ( 1% of patients) At least one serious AE 125 (27) Pneumonia 9 (2) Acute renal failure 6 (1) Vomiting and pyrexia 5 (1) Grade 2 4 laboratory abnormalities ( 2% of patients) Total cholesterol 115 (25) Increased LDL 103 (22) Increased triglycerides 99 (21) Hyperglycaemia 80 (17) Pancreatic amylase 75 (16) Decreased neutrophils 63 (13) Increased AST 49 (10) Increased ALT 43 (9) Pancreatic lipase 40 (9) Decreased white blood cell count 37 (8) Increased partial thromboplastin time 36 (8) Decreased platelet count 30 (6) Increased creatinine 27 (6) Increased ALP 22 (5) Decreased haemoglobin 18 (4) Increased prothrombin time 11 (2) Hyperbilirubinaemia 10 (2) Darunavir with low-dose ritonavir (DRV/r) 600/100 mg twice daily. Total n=467. a All rash-related adverse events (AEs) were grade 1 or 2 in severity, except for one case of grade 3 drug-related skin eruption, which led to permanent treatment discontinuation. b Excluding laboratory abnormalities reported as AEs. ALP, alkaline phosphatise; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDL, low-density lipoprotein. 48 weeks [1 5], and show that DRV/r 600/100 mg twice daily provides sustained virological and immunological responses in treatment-experienced patients following 96 weeks of treatment. These responses were significantly greater for DRV/r than for CPI(s) in POWER 1 and 2, with responses of a similar magnitude observed in a larger set of patients in POWER 3. Recent Phase III studies, DUET-1, DUET-2 and BENCHMRK 1 and 2 [10 13], suggest that when DRV/r is coadministered with newer antiretroviral drugs, virological response could be further enhanced in highly treatment-experienced patients. This approach is in line with current treatment guidelines for this group of patients, recommending the use of at least two fully active drugs with an OBR [14] International Medical Press

5 Long-term DRV/r in ARV-experienced patients Table 2. Cumulative toxicity effects: the rate of adverse events over time reported in >10% of DRV/r-treated patients in POWER 1, 2 and 3 studies Prevalence in DRV/r-treated patients, n (%) System organ class Week 0 24 Week Week Week Gastrointestinal disorders 199 (43) 143 (33) 128 (32) 115 (32) General disorders and administration site conditions 163 (35) 136 (31) 125 (31) 120 (33) Infections and infestations 256 (55) 207 (47) 184 (46) 162 (45) Musculoskeletal and connective tissue disorders 94 (20) 94 (21) 93 (23) 92 (25) Nervous system disorders 111 (24) 88 (20) 73 (18) 67 (18) Psychiatric disorders 60 (13) 60 (14) 59 (15) 65 (18) Respiratory, thoracic and mediastinal disorders 75 (16) 60 (14) 51 (13) 42 (12) Darunavir with low-dose ritonavir (DRV/r) 600/100 mg twice daily. Total n=467. The long-term safety and tolerability of antiretroviral therapies are of particular importance. A robust comparison of safety data between DRV/r and CPI was not possible in this study at 96 weeks because of high levels of treatment discontinuation in CPI patients in POWER 1 and 2. However, the type and incidence of AEs in the DRV/r arms were consistent across POWER 1 3 studies at 24, 48 and 96 weeks [1 5]. Indeed, the majority of AEs reported in this 96-week analysis were grade 1 or 2 in severity, with DRV/r 600/100 mg twice daily generally very well tolerated by patients, and with no new safety concerns identified. In conclusion, these data support the use of DRV/r 600/100 mg twice daily for robust, long-term treatment of patients with advanced HIV-1 infection and extensive prior antiretroviral experience. As new agents become available, greater and more durable viral suppression can be expected, helping more patients with multidrug-resistant HIV-1 infections to reach undetectable HIV-1 RNA and to achieve longterm treatment success. Acknowledgements We thank the patients and their families for their participation and support during this study. Special thanks go to Sandra De Meyer, Martine De Pauw, Frederic Godderis, Richard Hoetelmans, Koen De Backer, Marie-Pierre de Béthune, Jasmine Kestemont, Eric Lefebvre, Vanitha Sekar, Ben Van Baelen, Hilde Walgraeve, Andreas Koester, Wim Parys, Monika Peeters, Tony Vangeneugden, Els De Paepe and the TMC114 study team for their contributions. We acknowledge Julia Woodman (Medical Writer, Gardiner-Caldwell Communications, Macclesfield, UK), for her assistance in drafting this short communication and collating author contributions, and for her assistance in collating author responses to peer review comments. Financial assistance to support these services was provided by the study sponsor, Tibotec. Disclosure statement KA, PY, BG and JH have all been members of Tibotec advisory boards and have all received research funding from Tibotec. DJ has been a member of a Tibotec advisory board, received consultancy fees from Tibotec and has received research funding from Tibotec. AP has been a member of a Tibotec advisory board and received consultancy fees from Tibotec. AP is also a member of a department that has received research funding from Tibotec. AR has been a principal investigator for several Tibotec-funded trials. SDM, TV and FT are employed by Tibotec and all own Johnson & Johnson stocks. References 1. Katlama C, Esposito R, Gatell JM, et al. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS 2007; 21: Haubrich R, Berger D, Chiliade P, et al. Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients. AIDS 2007; 21:F11 F Molina J-M, Cohen C, Katlama C, et al. Safety and efficacy of darunavir (TMC114) with low-dose ritonavir in treatment-experienced patients: 24-week results of POWER 3. J Acquir Immune Defic Syndr 2007; 46: Saag M, Falcon R, Lefebvre E. Efficacy and safety results of darunavir/ritonavir in treatment-experienced patients: POWER 3. 44th Annual Meeting of the Infectious Diseases Society of America October 2006, Toronto, ON, Canada. Poster Clotet B, Bellos N, Molina J-M, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet 2007; 369: Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet 2007; 370: Ortiz R, DeJesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. 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6 K Arastéh et al. 10. Haubrich R, Cahn P, Grinsztejn B, et al. DUET-1: week 48 results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 612 treatment-experienced HIV-1 infected patients. 15th Conference on Retroviruses and Opportunistic Infections. 3 6 February 2008, Boston, MA, USA. Abstract Johnson M, Campbell T, Clotet B, et al. DUET-2: week 48 results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 591 treatment-experienced HIV-1 infected patients. 15th Conference on Retroviruses and Opportunistic Infections. 3 6 February 2008, Boston, MA, USA. Abstract Cooper DA, Gatell J, Rocktroh J, et al. 48-Week results from BENCHMRK-1, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV-1. 15th Conference on Retroviruses and Opportunistic Infections. 3 6 February 2008; Boston, MA, USA. Abstract Steigbigel R, Kumar P, Eron J, et al. 48-week results from BENCHMRK-2, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV. 15th Conference on Retroviruses and Opportunistic Infections. 3 6 February 2008, Boston, MA, USA. Poster Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1- infected adults and adolescents. US Department of Health and Human Services. November 3, 2008 (Updated 3 November Accessed 9 April 2009.) Available from nih.gov/contentfiles/adultandadolescentgl.pdf Accepted for publication 25 May International Medical Press