Darunavir/ritonavir monotherapy at a low dose (600/100 mg/day) in HIV-1-infected individuals with suppressed HIV viraemia

Darunavir/ritonavir monotherapy at a low dose (600/100 mg/day) in HIV-1-infected individuals... Abstract Background Darunavir/ritonavir is a potent PI with a high genetic barrier and pharmacological robustness favourably investigated as monotherapy. Whether darunavir could be dose reduced in the context of monotherapy deserves investigation. Methods Patients with HIV suppressed viraemia (plasma viral load <50 copies/mL for 12 months) under ART who had switched to darunavir/ritonavir monotherapy at 600/100 mg/day between 2013 and 2015 were included in this observational 48 week single-centre study. The primary outcome was the proportion of patients with virological success (defined as plasma viral load <50 copies/mL) at week 24. Secondary outcomes included treatment strategy success and resistance. Results Thirty-one patients were included with the following baseline characteristics [median (IQR)]: age 52 years (47–57), CD4+ 649 cells/mm3 (463–813), ART duration 16.3 years (9.2–22.3), nadir CD4+ 195 cells/mm3 (144–261) and duration of HIV suppression 7.8 years (4.8–9.7). Prior to switch, ART consisted of PI monotherapy for 28 of 31 patients [darunavir/ritonavir 800/100 mg/day (n = 26), lopinavir/ritonavir (n = 1) and atazanavir/ritonavir (n = 1)] and a triple drug regimen for 3 of 31 patients. Within the 48 weeks of follow-up, no virological failure occurred and two patients discontinued 600/100 mg of darunavir/ritonavir due to side effects at week 16 and 40, leading to a virological suppression rate of 100% (95% CI = 89–100) at weeks 24 and 48. Strategy success rates were 96.8% (95% CI = 83.3–99.9) at week 24 and 93.5% (95% CI = 78.6–99.2) at week 48. Median (IQR) Ctrough values of 800/100 mg of darunavir/ritonavir and 600/100 mg of darunavir/ritonavir were 1537 ng/mL (1286–1724) and 1255 ng/mL (873–2161), respectively. Conclusions A lower dose of darunavir/ritonavir used as monotherapy (600/100 mg/day) was highly effective in virologically suppressed HIV-infected patients. Further studies are needed to confirm these data. Introduction The need for long-term HIV replication suppression on ART is mandatorily required to minimize deleterious consequences of HIV replication, such as disease progression, occurrence of non-AIDS defining events1 and prevent sexual transmission.2 Universal ART recommended to all HIV-infected patients has enlarged the number and the heterogeneity of patients on ART including patients at an early stage of HIV disease, late presenters or patients with several years of viral suppression. Currently, triple drug strategy remains the standard recommended antiretroviral strategy for any of those situations.2–4 There is a growing interest for lighter antiretroviral strategies using fewer drugs or lower dosages without derogating to the objective of viral suppression, as multiple long-term drug exposure, increased cost and potential higher cumulative toxicities5,6 may not be necessary. Darunavir is a recommended PI with a high virological potency, a good safety profile and, among the different classes of antiretroviral drugs, one with the highest genetic barrier to resistance together with an acceptable tolerability.7,8 Switching strategies with darunavir/ritonavir monotherapy have shown in MONOI, MONET trials a high efficacy reaching up to 94% of virological success and no emergence of drug resistance.8,9 While the recommended dose of darunavir/ritonavir is 800/100 mg once daily in naive patients or 600/100 mg twice daily in patients with darunavir resistance mutations, lower doses of darunavir/ritonavir such as 400/100 mg with an NRTI dual backbone regimen were effective in the POWER 1 and 2 trials10,11 among patients with fully susceptible HIV strains. PIs have been associated with an increase in lipids, metabolic disorders,12 mostly related to drug dosage and associated with increased cardiovascular risk; it is therefore important to evaluate the lower dosage of this major drug class, as suggested by a pilot experience with a low darunavir/ritonavir dose.13 We report here our experience of using darunavir/ritonavir monotherapy at a low dose of 600/100 mg once daily in antiretroviral suppressed HIV-1-infected individuals. Patients and methods This observational single-centre study included HIV-1-infected patients followed at the HIV Clinical Unit, Infectious Diseases Department, Pitié-Salpêtrière Hospital (Paris, France) in whom ART was switched between 2013 and 2015 from a suppressive antiretroviral regimen to a low-dose darunavir/ritonavir monotherapy (600/100 mg once daily). Patients had to have a plasma viral load <50 copies/mL for at least 12 months on ART before switching. As part of routine follow-up, after ART modification, plasma viral load was assessed within 4–8 weeks, week 12, week 24 and then every 12–24 weeks up to 48 weeks according to each physician’s practice. Rebound in plasma viral load >50 copies/mL was confirmed within 2–4 weeks. Two consecutive values of plasma viral load ≥50 copies/mL 2–4 weeks apart or one value >200 copies/mL defined virological failure. In case of confirmed rebound, genotypic resistance test and drug plasma concentrations were performed. Strategy failure was defined as either discontinuation of darunavir/ritonavir monotherapy (600/100 mg once daily) for drug-related adverse events, patient’s or investigator’s decision, or lost to follow-up (defined as at least two missing clinical visits). Darunavir plasma concentrations were determined in routinely frozen samples 24 h after the last drug intake (Ctrough) at weeks 4–8, 12, 24, 32 and 48 (LC coupled with tandem MS; Acquity UPLC-TQD Waters Corp., Milford, MA, USA; lower limit of quantification = 5 ng/mL)14 for patients who switched from monotherapy with darunavir/ritonavir at 800/100 mg/day to darunavir/ritonavir at 600/100 mg/day. The primary outcome was the virological response defined as the proportion of individuals who remained virally suppressed (plasma viral load <50 copies/mL) at week 24. Secondary outcomes included virological response at week 48, treatment response rate (proportion of patients virally suppressed on 600/100 mg of darunavir/ritonavir once daily), resistance profile in case of virological failure and tolerability. Continuous and nominal variables were expressed as median (IQR) and percentages, respectively. Wilcoxon signed rank test was used for pairwise comparisons. Statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, NC, USA). Ethics All patients gave their written informed consent for using their medical chart recorded in the electronic medical record system NADIS (Fedialis Medica, France, CNIL number: 1171457, 2006), designed for the medical follow-up of HIV-infected patients, and oral consent for treatment modification. Results Thirty-one HIV-1-infected individuals were enrolled from May 2013 to September 2015. All patients were followed up to week 48. Patients were mostly male (71%) with a median age of 52 years (IQR = 47–57), a median antiretroviral duration of 16.3 years (IQR = 9.2–22.3) and a median duration of virological suppression of 7.8 years (IQR = 4.8–9.7) (Table 1). They switched to monotherapy with 600/100 mg of darunavir/ritonavir mostly from PI monotherapy (28 of 31, 90%) that consisted mainly of 800/100 mg of darunavir/ritonavir once daily (26 of 31, 84%) for a median time (IQR) of 2.4 years (0.2–0.2). Main reasons reported for switching antiretroviral strategy were a request for simplification to avoid potential long-term antiretroviral toxicity. From the 13 patients with available HIV RNA genotype resistance profiles, only one had major PI resistance mutations including darunavir (84V). Table 1. Demographic and clinical characteristics of the study population; N = 31 Male, n (%)  22 (71)  Age (years), median (IQR)  52 (47–57)  ART duration (years), median (IQR)  16.3 (9.2–22.3)  Duration of virological suppression (years), median (IQR)  7.8 (4.8–9.7)  Nadir CD4+ T cell count (cells/mm3), median (IQR)  195 (144–261)  Current CD4+ T cell count (cells/mm3), median (IQR)  649 (463–813)  ART regimen prior to switch, n (%)     PI monotherapy  28 (90)    darunavir/ritonavir  26 (84)    atazanavir/ritonavir  1 (3)    lopinavir/ritonavir  1 (3)  triple drug regimen  3 (10)    2 NRTIs + PI  2 (7)    2 NRTIs + NNRTI  1 (3)  Male, n (%)  22 (71)  Age (years), median (IQR)  52 (47–57)  ART duration (years), median (IQR)  16.3 (9.2–22.3)  Duration of virological suppression (years), median (IQR)  7.8 (4.8–9.7)  Nadir CD4+ T cell count (cells/mm3), median (IQR)  195 (144–261)  Current CD4+ T cell count (cells/mm3), median (IQR)  649 (463–813)  ART regimen prior to switch, n (%)     PI monotherapy  28 (90)    darunavir/ritonavir  26 (84)    atazanavir/ritonavir  1 (3)    lopinavir/ritonavir  1 (3)  triple drug regimen  3 (10)    2 NRTIs + PI  2 (7)    2 NRTIs + NNRTI  1 (3)  The proportion of patients with plasma viral load <50 copies/mL was 100% (95% CI = 89–100) at weeks 24 and 48. Two patients discontinued the strategy without virological failure due to potentially drug-related side effects including persistence of abdominal discomfort at week 16 and abdominal fat gain at week 40. Overall, treatment response rates were 96.8% (95% CI = 83.3–99.9) at week 24 and 93.5% (95% CI = 78.6–99.2) at week 48. Among the 16 patients who switched from darunavir/ritonavir monotherapy at 800/100 to 600/100 mg once daily with available measurement of darunavir concentration, median (IQR) darunavir Ctrough values were 1537 ng/mL (1286–1724) and 1225 ng/mL (873–2161), respectively (P = 0.84) (Figure 1). All darunavir plasma concentrations values exceeded the 10-fold in vitro protein-binding corrected median effective concentration required to induce a 50% response (EC50) of 550 ng/mL (resistant HIV).15 Figure 1. View largeDownload slide DRV/r Ctrough among DRV/r-treated patients and with available drug dosage (n = 16). DRV/r, darunavir/ritonavir. Figure 1. View largeDownload slide DRV/r Ctrough among DRV/r-treated patients and with available drug dosage (n = 16). DRV/r, darunavir/ritonavir. Discussion In patients with long-term virological suppression, mostly on boosted PI monotherapy, the switch to monotherapy with darunavir/ritonavir at 600/100 mg once daily is effective to maintain virological suppression over 48 weeks. The majority of our patients had a long history of ART and a long duration of viral suppression. They were on a PI monotherapy regimen (90%) with a long time of exposure to darunavir/ritonavir monotherapy at 800/100 mg once daily (2.2 years) prior to switch. Darunavir is highly effective against both WT virus and viruses with PI mutations7,8 and currently represents one of the antiretroviral drugs with the highest genetic barrier to resistance. Its virological potency, in a triple antiretroviral regimen, has been reported starting from a lower dose of 400/100 mg of darunavir/ritonavir with a significantly higher virological success rate compared with other PIs.10 In addition, the virological suppression rate of darunavir/ritonavir at 400/100 mg once daily reached 43%, close to the 48% virological suppression rate of darunavir/ritonavir at 800/100 mg in the POWER 1 trial.10 A reduced dose of darunavir/ritonavir at 600/100 mg once daily was similar in terms of efficacy as compared with the maintenance of darunavir/ritonavir at 800/100 mg once daily in combination with two NRTIs among 100 virologically suppressed HIV-infected patients (with 50 individuals in each arm).13 There is currently a pilot study in virally suppressed patients treated with 400/100 mg of darunavir/ritonavir with two NRTIs.16 Inadequate drug exposure leading to virological rebound is one major concern when evaluating lower doses of antiretroviral drugs. In our experience, similar to the Molto et al.13 study, the plasma concentration remained largely above the 10-fold EC50 threshold needed to control either susceptible or even partially resistant viruses. Ageing of the HIV population with cumulative toxicity under poly-pharmacy and comorbidities will prompt clinical researchers to evaluate lower dosage of potent drugs. Darunavir (800 mg) is now co-formulated with cobicistat,17 which may induce fewer drug interactions and less toxicity, but does not allow dose reduction. After years of viral suppression, one question remains whether the same amount of drugs and the same antiretroviral potency is needed to control HIV replication and, consequently, whether a triple drug therapy is not indispensable to control viral replication in all patients.18,19 PIs offer the unique characteristic to be safely used as monotherapy in contrast with other classes due to their virological robustness linked to their high genetic barrier to resistance. Several studies have investigated darunavir monotherapy as maintenance therapy in western countries and overall have demonstrated either non-inferiority7 or slightly less efficacy ∼85%8,20 compared with 90% in case of maintaining a triple drug therapy and no emergence of resistance in case of rebound. From a medico-economic perspective, the annual cost reduction from 800 to 600 mg of darunavir once daily was estimated to be €1000 per successfully treated patient. We acknowledge that our study has a limited number of patients in a single centre with an observational design. However, we think that these data can help to enlarge the portfolio of reduced drug strategies and should be considered for larger controlled trials. Acknowledgements This work was presented in part at the AFRAVIH, Brussels, Belgium, 2016 (Oral Presentation PS 4/4).  We acknowledge Fiona Mac Brearty for helping with English language in the final version of the manuscript. We are grateful to Christine Blanc who helped collect the clinical data and to Rachid Agher who helped collect the clinical data and helped to analyse and interpret the data. Funding This study was carried out as part of our routine work. Transparency declarations G. P. has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies including Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Janssen and Merck. C. K. has served on advisory boards for Merck Sharp & Dohme (MSD) and Janssen, and has been a clinical investigator for MSD, Janssen and ViiV Healthcare. All other authors: none to declare. Author contributions C. K., L. S., G. P. and L. A. contributed to the conception and design of the study. C. K., M.-A. V., R. T., L. S. and F. C. included the patients in the study. L. S. and S. S. collected the clinical data. C. K., G. P., T. N., L. S., R. C., R. A., M. P. L., S. S., A. G.-M. and L. A. analysed and interpreted the data. T. N. and C. S. performed the virology analysis. M. P. L. and G. P. performed the pharmacology analysis. C. K., L. S., S. S., G. P. and L. A. wrote the manuscript. All of the authors reviewed, revised and approved the final version of this paper. References 1 INSIGHT START Study Group, Lundgren JD, Babiker AG et al.   Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med  2015; 373: 795– 807. Google Scholar CrossRef Search ADS PubMed  2 Cohen MS, Chen YQ, McCauley M et al.   Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med  2016; 375: 830– 9. Google Scholar CrossRef Search ADS PubMed  3 European AIDS Clinical Society Guidelines, Version 8.2. 2017. http://www.eacsociety.org/files/guidelines_9.0-english.pdf. 4 WHO Guidelines. 2016. http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1. 5 Bunupuradah T, Kiertiburanakul S, Avihingsanon A et al.   Low-dose versus standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai adults with HIV (LASA): a randomised, open-label, non-inferiority trial. Lancet HIV  2016; 3: e343– 50. Google Scholar CrossRef Search ADS PubMed  6 ENCORE1 Study Group, Carey D, Puls R et al.   Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study. Lancet Infect Dis  2015; 15: 793– 802. Google Scholar CrossRef Search ADS PubMed  7 Arribas JR, Clumeck N, Nelson M et al.   The MONET trial: week 144 analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load < 50 HIV-1 RNA copies/mL at baseline. HIV Med  2012; 13: 398– 405. Google Scholar CrossRef Search ADS PubMed  8 Katlama C, Valantin MA, Algarte-Genin M et al.   Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS  2010; 24: 2365– 74. Google Scholar PubMed  9 Pulido F, Arribas JR, Hill A et al.   Analysis of drug resistance during HIV RNA viraemia in the MONET trial of darunavir/ritonavir monotherapy. Antivir Ther  2011; 16: 59– 65. Google Scholar CrossRef Search ADS PubMed  10 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: 395– 402. Google Scholar CrossRef Search ADS PubMed  11 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– 8. Google Scholar CrossRef Search ADS PubMed  12 Ledergerber B, Furrer H, Rickenbach M et al.   Factors associated with the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV Cohort Study. Clin Infect Dis  2007; 45: 111– 9. Google Scholar CrossRef Search ADS PubMed  13 Molto J, Valle M, Ferrer E et al.   Reduced darunavir dose is as effective in maintaining HIV suppression as the standard dose in virologically suppressed HIV-infected patients: a randomized clinical trial. J Antimicrob Chemother  2015; 70: 1139– 45. Google Scholar PubMed  14 Jung BH, Rezk NL, Bridges AS et al.   Simultaneous determination of 17 antiretroviral drugs in human plasma for quantitative analysis with liquid chromatography-tandem mass spectrometry. Biomed Chromatogr  2007; 21: 1095– 104. Google Scholar CrossRef Search ADS PubMed  15 Boffito M, Miralles D, Hill A. Pharmacokinetics, efficacy, and safety of darunavir/ritonavir 800/100 mg once-daily in treatment-naïve and -experienced patients. HIV Clin Trials  2008; 9: 418– 27. Google Scholar CrossRef Search ADS PubMed  16 Molina JM, El Abassi EM, Gallien S et al.   Efficacy and safety of darunavir dose reduction from 800 to 400 mg daily with ritonavir and TDF/FTC or ABC/3TC in virologically suppressed HIV-1-infected adults: an open-label study (ANRS-165 Darulight). International AIDS Society 2017; MOPEB0313. http://programme.ias2017.org//PAGMaterial/eposters/1075.pdf. 17 Tashima K, Crofoot G, Tomaka FL et al.   Cobicistat-boosted darunavir in HIV-1-infected adults: week 48 results of a phase IIIb, open-label single-arm trial. AIDS Res Ther  2014; 11: 39. Google Scholar CrossRef Search ADS PubMed  18 Katlama C, Ghosn J, Murphy RL. Individualized antiretroviral therapeutic approaches: less can be more. AIDS  2017; 31: 1065– 71. Google Scholar CrossRef Search ADS PubMed  19 Baril JG, Angel JB, Gill MJ et al.   Dual therapy treatment strategies for the management of patients infected with HIV: a systematic review of current evidence in ARV-naive or ARV-experienced, virologically suppressed patients. PLoS One  2016; 11: e0148231. Google Scholar CrossRef Search ADS PubMed  20 Paton NI, Stohr W, Arenas-Pinto A et al.   Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial. Lancet HIV  2015; 2: e417– 26. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Darunavir/ritonavir monotherapy at a low dose (600/100 mg/day) in HIV-1-infected individuals with suppressed HIV viraemia

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Abstract

Abstract Background Darunavir/ritonavir is a potent PI with a high genetic barrier and pharmacological robustness favourably investigated as monotherapy. Whether darunavir could be dose reduced in the context of monotherapy deserves investigation. Methods Patients with HIV suppressed viraemia (plasma viral load <50 copies/mL for 12 months) under ART who had switched to darunavir/ritonavir monotherapy at 600/100 mg/day between 2013 and 2015 were included in this observational 48 week single-centre study. The primary outcome was the proportion of patients with virological success (defined as plasma viral load <50 copies/mL) at week 24. Secondary outcomes included treatment strategy success and resistance. Results Thirty-one patients were included with the following baseline characteristics [median (IQR)]: age 52 years (47–57), CD4+ 649 cells/mm3 (463–813), ART duration 16.3 years (9.2–22.3), nadir CD4+ 195 cells/mm3 (144–261) and duration of HIV suppression 7.8 years (4.8–9.7). Prior to switch, ART consisted of PI monotherapy for 28 of 31 patients [darunavir/ritonavir 800/100 mg/day (n = 26), lopinavir/ritonavir (n = 1) and atazanavir/ritonavir (n = 1)] and a triple drug regimen for 3 of 31 patients. Within the 48 weeks of follow-up, no virological failure occurred and two patients discontinued 600/100 mg of darunavir/ritonavir due to side effects at week 16 and 40, leading to a virological suppression rate of 100% (95% CI = 89–100) at weeks 24 and 48. Strategy success rates were 96.8% (95% CI = 83.3–99.9) at week 24 and 93.5% (95% CI = 78.6–99.2) at week 48. Median (IQR) Ctrough values of 800/100 mg of darunavir/ritonavir and 600/100 mg of darunavir/ritonavir were 1537 ng/mL (1286–1724) and 1255 ng/mL (873–2161), respectively. Conclusions A lower dose of darunavir/ritonavir used as monotherapy (600/100 mg/day) was highly effective in virologically suppressed HIV-infected patients. Further studies are needed to confirm these data. Introduction The need for long-term HIV replication suppression on ART is mandatorily required to minimize deleterious consequences of HIV replication, such as disease progression, occurrence of non-AIDS defining events1 and prevent sexual transmission.2 Universal ART recommended to all HIV-infected patients has enlarged the number and the heterogeneity of patients on ART including patients at an early stage of HIV disease, late presenters or patients with several years of viral suppression. Currently, triple drug strategy remains the standard recommended antiretroviral strategy for any of those situations.2–4 There is a growing interest for lighter antiretroviral strategies using fewer drugs or lower dosages without derogating to the objective of viral suppression, as multiple long-term drug exposure, increased cost and potential higher cumulative toxicities5,6 may not be necessary. Darunavir is a recommended PI with a high virological potency, a good safety profile and, among the different classes of antiretroviral drugs, one with the highest genetic barrier to resistance together with an acceptable tolerability.7,8 Switching strategies with darunavir/ritonavir monotherapy have shown in MONOI, MONET trials a high efficacy reaching up to 94% of virological success and no emergence of drug resistance.8,9 While the recommended dose of darunavir/ritonavir is 800/100 mg once daily in naive patients or 600/100 mg twice daily in patients with darunavir resistance mutations, lower doses of darunavir/ritonavir such as 400/100 mg with an NRTI dual backbone regimen were effective in the POWER 1 and 2 trials10,11 among patients with fully susceptible HIV strains. PIs have been associated with an increase in lipids, metabolic disorders,12 mostly related to drug dosage and associated with increased cardiovascular risk; it is therefore important to evaluate the lower dosage of this major drug class, as suggested by a pilot experience with a low darunavir/ritonavir dose.13 We report here our experience of using darunavir/ritonavir monotherapy at a low dose of 600/100 mg once daily in antiretroviral suppressed HIV-1-infected individuals. Patients and methods This observational single-centre study included HIV-1-infected patients followed at the HIV Clinical Unit, Infectious Diseases Department, Pitié-Salpêtrière Hospital (Paris, France) in whom ART was switched between 2013 and 2015 from a suppressive antiretroviral regimen to a low-dose darunavir/ritonavir monotherapy (600/100 mg once daily). Patients had to have a plasma viral load <50 copies/mL for at least 12 months on ART before switching. As part of routine follow-up, after ART modification, plasma viral load was assessed within 4–8 weeks, week 12, week 24 and then every 12–24 weeks up to 48 weeks according to each physician’s practice. Rebound in plasma viral load >50 copies/mL was confirmed within 2–4 weeks. Two consecutive values of plasma viral load ≥50 copies/mL 2–4 weeks apart or one value >200 copies/mL defined virological failure. In case of confirmed rebound, genotypic resistance test and drug plasma concentrations were performed. Strategy failure was defined as either discontinuation of darunavir/ritonavir monotherapy (600/100 mg once daily) for drug-related adverse events, patient’s or investigator’s decision, or lost to follow-up (defined as at least two missing clinical visits). Darunavir plasma concentrations were determined in routinely frozen samples 24 h after the last drug intake (Ctrough) at weeks 4–8, 12, 24, 32 and 48 (LC coupled with tandem MS; Acquity UPLC-TQD Waters Corp., Milford, MA, USA; lower limit of quantification = 5 ng/mL)14 for patients who switched from monotherapy with darunavir/ritonavir at 800/100 mg/day to darunavir/ritonavir at 600/100 mg/day. The primary outcome was the virological response defined as the proportion of individuals who remained virally suppressed (plasma viral load <50 copies/mL) at week 24. Secondary outcomes included virological response at week 48, treatment response rate (proportion of patients virally suppressed on 600/100 mg of darunavir/ritonavir once daily), resistance profile in case of virological failure and tolerability. Continuous and nominal variables were expressed as median (IQR) and percentages, respectively. Wilcoxon signed rank test was used for pairwise comparisons. Statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, NC, USA). Ethics All patients gave their written informed consent for using their medical chart recorded in the electronic medical record system NADIS (Fedialis Medica, France, CNIL number: 1171457, 2006), designed for the medical follow-up of HIV-infected patients, and oral consent for treatment modification. Results Thirty-one HIV-1-infected individuals were enrolled from May 2013 to September 2015. All patients were followed up to week 48. Patients were mostly male (71%) with a median age of 52 years (IQR = 47–57), a median antiretroviral duration of 16.3 years (IQR = 9.2–22.3) and a median duration of virological suppression of 7.8 years (IQR = 4.8–9.7) (Table 1). They switched to monotherapy with 600/100 mg of darunavir/ritonavir mostly from PI monotherapy (28 of 31, 90%) that consisted mainly of 800/100 mg of darunavir/ritonavir once daily (26 of 31, 84%) for a median time (IQR) of 2.4 years (0.2–0.2). Main reasons reported for switching antiretroviral strategy were a request for simplification to avoid potential long-term antiretroviral toxicity. From the 13 patients with available HIV RNA genotype resistance profiles, only one had major PI resistance mutations including darunavir (84V). Table 1. Demographic and clinical characteristics of the study population; N = 31 Male, n (%)  22 (71)  Age (years), median (IQR)  52 (47–57)  ART duration (years), median (IQR)  16.3 (9.2–22.3)  Duration of virological suppression (years), median (IQR)  7.8 (4.8–9.7)  Nadir CD4+ T cell count (cells/mm3), median (IQR)  195 (144–261)  Current CD4+ T cell count (cells/mm3), median (IQR)  649 (463–813)  ART regimen prior to switch, n (%)     PI monotherapy  28 (90)    darunavir/ritonavir  26 (84)    atazanavir/ritonavir  1 (3)    lopinavir/ritonavir  1 (3)  triple drug regimen  3 (10)    2 NRTIs + PI  2 (7)    2 NRTIs + NNRTI  1 (3)  Male, n (%)  22 (71)  Age (years), median (IQR)  52 (47–57)  ART duration (years), median (IQR)  16.3 (9.2–22.3)  Duration of virological suppression (years), median (IQR)  7.8 (4.8–9.7)  Nadir CD4+ T cell count (cells/mm3), median (IQR)  195 (144–261)  Current CD4+ T cell count (cells/mm3), median (IQR)  649 (463–813)  ART regimen prior to switch, n (%)     PI monotherapy  28 (90)    darunavir/ritonavir  26 (84)    atazanavir/ritonavir  1 (3)    lopinavir/ritonavir  1 (3)  triple drug regimen  3 (10)    2 NRTIs + PI  2 (7)    2 NRTIs + NNRTI  1 (3)  The proportion of patients with plasma viral load <50 copies/mL was 100% (95% CI = 89–100) at weeks 24 and 48. Two patients discontinued the strategy without virological failure due to potentially drug-related side effects including persistence of abdominal discomfort at week 16 and abdominal fat gain at week 40. Overall, treatment response rates were 96.8% (95% CI = 83.3–99.9) at week 24 and 93.5% (95% CI = 78.6–99.2) at week 48. Among the 16 patients who switched from darunavir/ritonavir monotherapy at 800/100 to 600/100 mg once daily with available measurement of darunavir concentration, median (IQR) darunavir Ctrough values were 1537 ng/mL (1286–1724) and 1225 ng/mL (873–2161), respectively (P = 0.84) (Figure 1). All darunavir plasma concentrations values exceeded the 10-fold in vitro protein-binding corrected median effective concentration required to induce a 50% response (EC50) of 550 ng/mL (resistant HIV).15 Figure 1. View largeDownload slide DRV/r Ctrough among DRV/r-treated patients and with available drug dosage (n = 16). DRV/r, darunavir/ritonavir. Figure 1. View largeDownload slide DRV/r Ctrough among DRV/r-treated patients and with available drug dosage (n = 16). DRV/r, darunavir/ritonavir. Discussion In patients with long-term virological suppression, mostly on boosted PI monotherapy, the switch to monotherapy with darunavir/ritonavir at 600/100 mg once daily is effective to maintain virological suppression over 48 weeks. The majority of our patients had a long history of ART and a long duration of viral suppression. They were on a PI monotherapy regimen (90%) with a long time of exposure to darunavir/ritonavir monotherapy at 800/100 mg once daily (2.2 years) prior to switch. Darunavir is highly effective against both WT virus and viruses with PI mutations7,8 and currently represents one of the antiretroviral drugs with the highest genetic barrier to resistance. Its virological potency, in a triple antiretroviral regimen, has been reported starting from a lower dose of 400/100 mg of darunavir/ritonavir with a significantly higher virological success rate compared with other PIs.10 In addition, the virological suppression rate of darunavir/ritonavir at 400/100 mg once daily reached 43%, close to the 48% virological suppression rate of darunavir/ritonavir at 800/100 mg in the POWER 1 trial.10 A reduced dose of darunavir/ritonavir at 600/100 mg once daily was similar in terms of efficacy as compared with the maintenance of darunavir/ritonavir at 800/100 mg once daily in combination with two NRTIs among 100 virologically suppressed HIV-infected patients (with 50 individuals in each arm).13 There is currently a pilot study in virally suppressed patients treated with 400/100 mg of darunavir/ritonavir with two NRTIs.16 Inadequate drug exposure leading to virological rebound is one major concern when evaluating lower doses of antiretroviral drugs. In our experience, similar to the Molto et al.13 study, the plasma concentration remained largely above the 10-fold EC50 threshold needed to control either susceptible or even partially resistant viruses. Ageing of the HIV population with cumulative toxicity under poly-pharmacy and comorbidities will prompt clinical researchers to evaluate lower dosage of potent drugs. Darunavir (800 mg) is now co-formulated with cobicistat,17 which may induce fewer drug interactions and less toxicity, but does not allow dose reduction. After years of viral suppression, one question remains whether the same amount of drugs and the same antiretroviral potency is needed to control HIV replication and, consequently, whether a triple drug therapy is not indispensable to control viral replication in all patients.18,19 PIs offer the unique characteristic to be safely used as monotherapy in contrast with other classes due to their virological robustness linked to their high genetic barrier to resistance. Several studies have investigated darunavir monotherapy as maintenance therapy in western countries and overall have demonstrated either non-inferiority7 or slightly less efficacy ∼85%8,20 compared with 90% in case of maintaining a triple drug therapy and no emergence of resistance in case of rebound. From a medico-economic perspective, the annual cost reduction from 800 to 600 mg of darunavir once daily was estimated to be €1000 per successfully treated patient. We acknowledge that our study has a limited number of patients in a single centre with an observational design. However, we think that these data can help to enlarge the portfolio of reduced drug strategies and should be considered for larger controlled trials. Acknowledgements This work was presented in part at the AFRAVIH, Brussels, Belgium, 2016 (Oral Presentation PS 4/4).  We acknowledge Fiona Mac Brearty for helping with English language in the final version of the manuscript. We are grateful to Christine Blanc who helped collect the clinical data and to Rachid Agher who helped collect the clinical data and helped to analyse and interpret the data. Funding This study was carried out as part of our routine work. Transparency declarations G. P. has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies including Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Janssen and Merck. C. K. has served on advisory boards for Merck Sharp & Dohme (MSD) and Janssen, and has been a clinical investigator for MSD, Janssen and ViiV Healthcare. All other authors: none to declare. Author contributions C. K., L. S., G. P. and L. A. contributed to the conception and design of the study. C. K., M.-A. V., R. T., L. S. and F. C. included the patients in the study. L. S. and S. S. collected the clinical data. C. K., G. P., T. N., L. S., R. C., R. A., M. P. L., S. S., A. G.-M. and L. A. analysed and interpreted the data. T. N. and C. S. performed the virology analysis. M. P. L. and G. P. performed the pharmacology analysis. C. K., L. S., S. S., G. P. and L. A. wrote the manuscript. All of the authors reviewed, revised and approved the final version of this paper. References 1 INSIGHT START Study Group, Lundgren JD, Babiker AG et al.   Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med  2015; 373: 795– 807. Google Scholar CrossRef Search ADS PubMed  2 Cohen MS, Chen YQ, McCauley M et al.   Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med  2016; 375: 830– 9. Google Scholar CrossRef Search ADS PubMed  3 European AIDS Clinical Society Guidelines, Version 8.2. 2017. http://www.eacsociety.org/files/guidelines_9.0-english.pdf. 4 WHO Guidelines. 2016. http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1. 5 Bunupuradah T, Kiertiburanakul S, Avihingsanon A et al.   Low-dose versus standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai adults with HIV (LASA): a randomised, open-label, non-inferiority trial. Lancet HIV  2016; 3: e343– 50. Google Scholar CrossRef Search ADS PubMed  6 ENCORE1 Study Group, Carey D, Puls R et al.   Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study. Lancet Infect Dis  2015; 15: 793– 802. Google Scholar CrossRef Search ADS PubMed  7 Arribas JR, Clumeck N, Nelson M et al.   The MONET trial: week 144 analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load < 50 HIV-1 RNA copies/mL at baseline. HIV Med  2012; 13: 398– 405. Google Scholar CrossRef Search ADS PubMed  8 Katlama C, Valantin MA, Algarte-Genin M et al.   Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS  2010; 24: 2365– 74. Google Scholar PubMed  9 Pulido F, Arribas JR, Hill A et al.   Analysis of drug resistance during HIV RNA viraemia in the MONET trial of darunavir/ritonavir monotherapy. Antivir Ther  2011; 16: 59– 65. Google Scholar CrossRef Search ADS PubMed  10 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: 395– 402. Google Scholar CrossRef Search ADS PubMed  11 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– 8. Google Scholar CrossRef Search ADS PubMed  12 Ledergerber B, Furrer H, Rickenbach M et al.   Factors associated with the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV Cohort Study. Clin Infect Dis  2007; 45: 111– 9. Google Scholar CrossRef Search ADS PubMed  13 Molto J, Valle M, Ferrer E et al.   Reduced darunavir dose is as effective in maintaining HIV suppression as the standard dose in virologically suppressed HIV-infected patients: a randomized clinical trial. J Antimicrob Chemother  2015; 70: 1139– 45. Google Scholar PubMed  14 Jung BH, Rezk NL, Bridges AS et al.   Simultaneous determination of 17 antiretroviral drugs in human plasma for quantitative analysis with liquid chromatography-tandem mass spectrometry. Biomed Chromatogr  2007; 21: 1095– 104. Google Scholar CrossRef Search ADS PubMed  15 Boffito M, Miralles D, Hill A. Pharmacokinetics, efficacy, and safety of darunavir/ritonavir 800/100 mg once-daily in treatment-naïve and -experienced patients. HIV Clin Trials  2008; 9: 418– 27. Google Scholar CrossRef Search ADS PubMed  16 Molina JM, El Abassi EM, Gallien S et al.   Efficacy and safety of darunavir dose reduction from 800 to 400 mg daily with ritonavir and TDF/FTC or ABC/3TC in virologically suppressed HIV-1-infected adults: an open-label study (ANRS-165 Darulight). International AIDS Society 2017; MOPEB0313. http://programme.ias2017.org//PAGMaterial/eposters/1075.pdf. 17 Tashima K, Crofoot G, Tomaka FL et al.   Cobicistat-boosted darunavir in HIV-1-infected adults: week 48 results of a phase IIIb, open-label single-arm trial. AIDS Res Ther  2014; 11: 39. Google Scholar CrossRef Search ADS PubMed  18 Katlama C, Ghosn J, Murphy RL. Individualized antiretroviral therapeutic approaches: less can be more. AIDS  2017; 31: 1065– 71. Google Scholar CrossRef Search ADS PubMed  19 Baril JG, Angel JB, Gill MJ et al.   Dual therapy treatment strategies for the management of patients infected with HIV: a systematic review of current evidence in ARV-naive or ARV-experienced, virologically suppressed patients. PLoS One  2016; 11: e0148231. Google Scholar CrossRef Search ADS PubMed  20 Paton NI, Stohr W, Arenas-Pinto A et al.   Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial. Lancet HIV  2015; 2: e417– 26. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Feb 1, 2018

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