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A dual regimen of ritonavir/darunavir plus dolutegravir for rescue or simplification of rescue therapy: 48weeks’ observational data

A dual regimen of ritonavir/darunavir plus dolutegravir for rescue or simplification of rescue... Background: Dolutegravir (DTG) plus darunavir/ritonavir (DRV/r) is a simple combination of drugs that has the best genetic barrier to HIV-1 resistance and may be fit for salvage therapy. Methods: All HIV-1-infected subjects treated with DTG plus DRV/r between March 2014 and September 2015 in eight Italian centres were included in the analysis. The main metabolic data, efficacy parameters and safety data routinely collected were provided. This observational study is aimed to assess the efficacy of such approach. The primary end- point was the proportion of subjects achieving or maintaining virologic suppression <50 copies/mL at week 24. Secondary end points were maintaining virologic suppression in the follow-up (weeks 48 and 96) and safety. Results: One hundred and thirty subjects were followed for a median of 56 months. Reasons for switching were simplification (44.6%), viral failure (30%), toxicity (16.9%), non-adherence (4.6%), persistent low-level viremia (3.1%), and drug-drug interaction (0.8%). At baseline, 118 subjects had documented resistance to 1 to 5 antiretroviral classes while 12 had viral rebound at a time when genotypic tests were not yet available. Seventeen and 14 subjects took DRV/r and DTG twice daily, respectively. One subject was lost to follow-up, one discontinued for liver enzymes’ elevation, one died of illicit drug abuse and one of cancer-related complications. The proportion of subjects with ongoing HIV replication dropped from 40% to 6.1%. Those with undetectable viral load increased from 38.5% to 76.2%. At week 48, 17.7% had HIV RNA between 1 and 49 copies/mL. The number of subjects with altered serum glucose, creatinine, ALT, AST, total-, HDL- and LDL-cholesterol, triglycerides and MDRD <90 mL/min decreased by week 48, while those having MDRD <60 mL/min remained 4.6%. Overall 90/283 baseline laboratory alterations returned to normality. Conclusions: Switching to DTG plus DRV/r proved to be safe, suppressing viral replication without metabolic impact. Keywords: Dolutegravir, Darunavir, Ritonavir, Switch, Dual, Salvage, Simplification * Correspondence: amedeo.capetti@unimi.it Data from this work have been presented at the 14th European Meeting on HIV & Hepatitis, 25–27 May 2016, Rome, Italy, at the HIV Drug Therapy Congress, 24–26 October 2016 Glasgow, UK and to the 9th Italian Conference on AIDS and Antiviral Research, 12–14 June 2017, Siena, Italy. 1st Division of Infectious Diseases, ASST Fatebenefratelli-Sacco, Via Giovanni Battista Grassi, 74, pavillion 56, Malattie Infettive, 2nd floor, 20157 Milan, Italy Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Capetti et al. BMC Infectious Diseases (2017) 17:658 Page 2 of 7 Background by Ethics Committees (EC) no further enrolment was The present work is the 48-week update of a previously allowed. Since the last publication two centres that were reported study [1], concerning a retrospective-prospective waiting for EC approval joined the group, increasing the follow-up of subjects who had been switched for any population size. For homogeneity no data were collected reason to a dual combination of dolutegravir (DTG) plus after week 48 (plus 8 weeks’ window as observational stud- darunavir/ritonavir (DRV/r). A randomized clinical trial ies do not dictate strict timelines). The follow-up was cen- comparing the switch to this regimen towards the con- sored at November, 30, 2016. Subjects were not required tinuation of DRV/r plus 2 nucleoside analogues is still to be naive to DRV or DTG, but regimens containing both recruiting patients [2]. When we started this strategy of drugs were not included. dual rescue therapy or simplification of more complex res- Participating subjects have signed an informed consent cue regimens, the OPTIONS study, the first randomized according to local procedures, the study has been ap- trial to utilize a web utility in combination with central- proved by the coordinating centre and by all participat- ized expert opinion to guide the selection of salvage anti- ing centres and conducted according to the Good retroviral therapy was published [3]. The 413 participants Clinical Practice (GCP) Guidelines. had antiretroviral (ARV) experience or resistance to The aim of the study is to assess the efficacy of this nucleoside reverse transcriptase inhibitors (NRTI) and approach. The primary end-point was the proportion non-NRTI (NNRTI), were taking a protease inhibitor (PI)- of subjects achieving or maintaining virologic sup- containing regimen for at least 8 weeks prior to study pression <50 copies/mL at week 24. Secondary end entry, and had plasma HIV RNA ≥1000 copies/mL. points were maintaining virologic suppression in the Enfuvirtide (ENF), etravirine (ETR), DRV, maraviroc follow-up (weeks 48 and 96) and safety, as proportion (MVC), raltegravir (RAL), and tipranavir (TPV) plus rito- of drop-outs for any reason and grade 3–4adverse navir booster allowed 20 potential ARV regimens. Fifty- events. three subjects had obliged regimen choice due to poor phenotypic sensitivity score while 360 were randomized to add or not NRTIs. The resulting regimens were rather Safety data and laboratory standards complex, with 3 to 6 drugs and twice-daily dosing, and In this update it was decided to document the impact of generally contained DRV and RAL. The proportion of pa- the switch on some routine safety analyses. Investigators tients achieving viral suppression at 48 weeks (<50 HIV-1 retrospectively reported to the coordinating center serum RNA copies/mL) was 70.2% and 74.1% for the Omit NRTI glucose, alanine aminotransferase (ALT), aspartate amino- and for the Add NRTI arms, respectively [4]. Prescribers transferase (AST), total cholesterol (TC), high density were generally oriented to prefer simpler regimens. lipoprotein (HDL-C), low density lipoprotein (LDL-C) The combination of elvitegravir/cobicistat/tenofovir and triglycerides (TG). The estimated glomerular filtration alafenamide/emtricitabine plus 800 mg DRV (two pills rate (e-GFR) was calculated at baseline and at follow-up once daily) demonstrated superiority towards the con- according to the Modification of Diet in Renal Disease tinuation of baseline therapy in a randomized (2:1), (MDRD) equation [7]. Plasma viral suppression status was open-label, switch trial in treatment-experienced viro- classified as harbouring ≥50 HIV-1 RNA copies/mL, or logically suppressed subjects [5]. The baseline regimens detectable below 50 copies/mL, or undetectable (no virus contained in median 5 pills per day and the primary detected, NVD = 0 copies/mL). endpoint was maintaining <50 HIV-1 RNA copies/mL. Viremia was measured depending on centers with In this context some authors were looking forward for Abbot HIV-1 RT-PCR, threshold 37 copies, COBAS nucleoside-sparing regimens in the long-term care of TaqMan HIV-1 test, threshold 20 copies, and Single HIV infection, welcoming the possible positive contribu- Copy Assay. TruGene™ was used for resistance testing, tion of DTG [6]. validated on the Stanford Algorithm, and cumulative The present study reports what the clinical practice data was considered. Data were collected from electronic had already realised, aiming for convenience, simplicity, or hand-written patients’ case record forms, according to potency and high genetic barrier, prescribing this com- each centre’s organization and sent as pre-specified excel bination to several patients and controlling them closely files. Available data from routine therapeutic monitoring until viral suppression was achieved. of darunavir and dolutegravir trough plasma concentra- tion were analysed. Methods For the toxicity analyses the Common Terminology All subjects who had started DTG plus DRV/r between Criteria for Adverse Events (CTCAE, Version 4.03, June March 1, 2014 and September 30, 2015 were included in 14, 2010) was considered [8]. Adverse clinical events and an Italian observational multicenter cohort named Tivista deaths were reported to the local Ethics Committees and (Tivicay plus Prezista Observational cohort). After approval authorities as required by the law. Capetti et al. BMC Infectious Diseases (2017) 17:658 Page 3 of 7 Statistical analysis and drug-drug interaction, 0.8% (n = 1). The algorithm The statistical analysis was limited to routine parameters of the study population is represented in Fig. 1. (median, mean and standard error) and to the paired t- At baseline 118 subjects had documented resistance to test for the comparison between the baseline and 48- 1 to 5 ARV classes. For the remaining 12 patients, viral week metabolic and immunologic values. The virologic failure was not accompanied by a genotypic test. Twenty- response is reported as the number of patients in each three subjects (17.7%) had never experienced virologic viral suppression category and as the median and inter- failure but had transmitted drug resistance mutations. quartile range of log copies/mL in those who do not One hundred and sixteen patients (89.2%) had NRTI reach suppression at each time point. The other analyses resistance-associated mutations (RAMs) at baseline, 98 consider the on-treatment population. The sample size (75.4%) had NNRTI RAMs, 91 (70%) had PI RAMs and was obtained from the participants’ adhesion. 12 (10.6%) had integrase strand transfer inhibitors (INSTI) RAMs (See Table 1). Results Twenty subjects had reduced baseline sensitivity to One hundred and thirty subjects were followed for a me- darunavir (Stanford median score 15, range 15–40), and dian of 56 months, mean 64 months. The median age 12 had reduced sensitivity to INSTIs (Stanford median was 52 years, females were 25.4% and non-Caucasians score 10, range 10–25) but none rebounded. None de- 8.9%. The median baseline CD4+ T-cell count was 526/ veloped new drug resistance mutations during the study. mmc (IQR 329–718). Fifty-nine subjects had been ex- Of those subjects who had resistance to 3–4 drug clas- posed to INSTIs and all had been exposed to PIs. ses (n = 70), 35 were not failing at baseline, but rather Eighty-one had darunavir in their pre-switch regimen simplified from raltegravir and boosted darunavir-based and one had dolutegravir. The main risk factor for three- (n = 31) or four-drugs regimens (n = 9). acquiring HIV was being male homosexual, 48.5% One hundred and thirteen have started the combination (n = 63), followed by drug abuse, 26.9% (n = 35) and of DRV 800 mg plus RTV 100 mg plus DTG 50 mg every heterosexual intercourse, 24.6% (n = 32). Reasons that 24 h, 3 DRV 600 mg plus RTV 100 mg every 12 h and 14 led to the switch were simplification, 44.6% (n = 56), DRV 600 mg plus RTV 100 mg plus DTG 50 mg every viral failure 30% (n = 39) toxicity 16.9% (n = 22, of 12 h. All of those who were on BID therapy had active which 11 for osteopoenia/osteoporosis, 3 each for HIV-1 replication at baseline (range 5.46–6.16 log HIV- lipodystrophy and cardiovascular problems, 2 for renal 1 RNA copies/mL). All of them suppressed viremia to <50 toxicity and one each for gastrointestinal toxicity, dia- copies/mL during the follow-up. betes and creatine kinase elevation), non-adherence, Between week 24 and 48 one subject was lost to 4.6% (n = 6), persistent low-level viremia, 3.1% (n = 4), follow-up, one interrupted the regimen for liver Fig. 1 Algorithm of the study population. DTG = dolutegravir; DRV/r = darunavir boosted with ritonavir; AST = aspartate aminotransferase; ALT = alanine aminotransferase Capetti et al. BMC Infectious Diseases (2017) 17:658 Page 4 of 7 Table 1 Baseline HIV-1 drug resistance mutations in the study population Primary resistance mutations (Wensing, 2017) are underlined enzymes’ elevation, one died of illicit drug abuse and as 3 with high baseline viral load and 3 with extensive one of cancer-related complications. baseline resistance, had still very low but detectable The proportion of subjects harboring active HIV repli- viremia, while in those who started with 0–49 copies/ cation dropped from 40% at baseline to 6.1% by week mL the success rate was 97.4% as in this group two 48, while those who had NVD at real-time polymerase subjects were not on therapy on the sampling day, as de- chain reaction (RT-PCR) increased from 38.5% to 76.2%. scribed above. Of interest, both were in the subgroup Overall, at baseline 78 subjects had <50 HIV-1 RNA starting with 1–49 copies/mL, as some authors suggest copies/mL (60%) and this proportion increased at week that this low but persistent viremia may sometime hide 48 to 90,8% (n = 118) At week 48, 19 subjects (14,6%) adherence problems. The mean viral load in this popula- had HIV RNA between 1 and 49 copies/mL and eight tion at week 48 was 1.89 log copies/mL (range 1.70– subjects (6,1%) had ≥50 HIV-1 RNA copies/mL. Of the 2.57, Fig. 2). The CD4+ T-cell absolute count and latter, 3 had a slow but constant decay from median proportion increased by 27 cells/mm , +5%, not reaching baseline 5.12 to 2.30 log HIV-1 RNA copies/mL, 3 had statistical significance. at least three-class drug resistance with a Stanford DRV A single-point pharmacokinetic analysis in a subgroup score > 60 and median viral decay from 4.39 to 1.75 of 32 subjects confirmed the safety of the association: log HIV-1 RNA copies/mL, and 2 had dropped out of DTG median C was 579 ng/mL (range 275–5036), 10 trough therapy 4 and 7 days before blood sampling. Considering while DRV median C was 3007 ng/mL (range 678– trough separately two populations, those who started with active 8053) and no values were found to be below the safety HIV replication (≥ 50 copies/mL) and those who started threshold. Five subjects were taking DRV 600 mg twice with 0–49 copies/mL, at week 48 the success rate was daily and had C above the threshold for resistant min 88.5% in those who had started with active replication, strains, and three were taking DTG twice daily. Capetti et al. BMC Infectious Diseases (2017) 17:658 Page 5 of 7 Fig. 2 Virologic and immunologic response. a n. of patients by HIV-1 RNA, copies/mL; b HIV-1 replication decay in the population with ongoing viral replication, log copes/mL; c CD4+ T-lymphocytes/mmc; d CD4+ T-lymphocytes, %. eGFR = estimated Glomerular Filtration Rate, calculated on the Modified Diet for Renal Disease (MDRD) score; AST = aspartate aminotrasferase; ALT = alanine aminotrasferase; TC = total cholesterol; HDL-C = HDL cholesterol; LDL-C = LDL cholesterol The proportion of subjects having any metabolic Discussion alterations at baseline decreased for serum glucose, While awaiting the results of the randomized DUALIS creatinine, MDRD <90 mL/min, ALT, AST, total-, study [2], our data suggest that the combination of DTG HDL- and LDL-cholesterol and triglycerides. The pro- plus DRV/r may be considered reliable in salvage or sim- portion of subjects having MDRD <60 remained plification of salvage regimens. The pharmacokinetic stable at 4.6%. Overall 84/175 (48%) baseline labora- interaction between the two drugs [9] did not seem to im- tory alterations returned to normality. Considering pact neither causing subtherapeutic C in the subjects min each parameter in the whole population, none varied tested nor leaving space for plasma HIV-1 RNA rebound significantly (Fig. 3). in any subject. In particular, 70% of our patients would In particular, the median variation in serum cre- not have been suitable for the combination of DTG plus atinine was −0,03 and the eGFR decrease on average atazanavir, which has a favourable interaction profile [10] by 2.66 mL/min. None of the subjects who had al- due to baseline resistance to the latter and it should be tered serum creatinine at baseline showed progres- said that clinical experience with this combination is still sion and 6 out of 8 improved, having discontinued limited though promising. Moreover, we have not re- tenofovir. ported significant neurological side effects, as suggested Overall this strategy yielded mean savings for € by Hoffman et al. [11] Possible reasons may be the com- 169,428.00 considering the whole population, the obser- bination, which does not include abacavir, the fact that vation period and the dropouts. The figure was gener- many of our patients had received the indication to take ated only from the cost of the previous and current the drug in the morning and the relatively small number antiretroviral regimen. of other at risk subjects (15 elderly and 33 women). Capetti et al. BMC Infectious Diseases (2017) 17:658 Page 6 of 7 Fig. 3 Metabolic profile during the follow-up. a Number of subjects with any laboratory abnormality at baseline, week 24 and week 48. b Variation of metabolic indicators from baseline, mean values; c Variation in triglycerides (different scale). AST = Aspartate Aminotransferase; ALT = Alanine Aminotransferase; HDL-C = High-Density Lipoprotein - Cholesterol; LDL-C = Low-Density Lipoprotein - Cholesterol; MDRD = Modified Diet for RenalDisease;TC=TotalCholesterol The study limitations include poor patient selection (the Additional file only two inclusion criteria were being HIV-1 antibody Additional file 1: Tivista Study Week 48 database. (TIFF 31 kb) positive and having started DTG plus DRV/r by the end of September 2015), leading to the inclusion of a heteroge- Abbreviations neous population, made out of failures and simplification, ALT: Alanine aminotransferase; ARV: Antiretroviral; AST: Aspartate once- and twice-daily regimens, adherent and poorly aminotransferase; CD4: Cluster difference 4; CTCAE: Common Terminology adherent subjects and subjects harbouring treatment- Criteria for Adverse Events; C : Trough concentration; DRV/r: Darunavir trough boosted with ritonavir; DTG: Dolutegravir; EC: Ethics Committee; resistant and treatment-sensitive strains. The set of meta- eGFR: Estimated glomerular filtration rate; ENF: Enfivirtide; ETV: Etravirine; bolic parameters furthermore reflects standard follow-up GCP: Good clinical practice; HDL: High-density lipoprotein; HIV-1: Human data shared by centres and does not include bone density immunodeficiency virus type 1; LDL: Low density lipoprotein; MDRD: Modified diet for renal disease; MVC: Maraviroc; NNRTI: Non- measures nor inflammatory markers. nucleoside reverse transcriptase inhibitor; NRTI: Nucleoside reverse transcriptase inhibitor; NVD: No virus detected; PI: Protease inhibitor; Conclusions RAL: Raltegravir; RNA: Ribonucleic acid; RT-PCR: Real-time Polymerase Chain Reaction; TPV: Tipranavir Switching to DTG plus DRV/r provided a simple and safe rescue regimen to all subjects, controlling viral replication Acknowledgements in a high proportion of patients. The metabolic impact We acknowledge Mrs. Maureen Naomi Quinn for reviewing this text as native american health worker. was favourable in a proportion of subjects who had base- line alterations, while no significant modifications were Funding observed in mean and median values when also normal This research did not receive any specific grants from funding agencies from baseline values were included. funding agencies in the public, commercial or not-for-profit sectors. Capetti et al. BMC Infectious Diseases (2017) 17:658 Page 7 of 7 Availability of data and materials 2. Dual Therapy With Boosted Darunavir + Dolutegravir (Dualis) https://clinicaltrials. The study database is attached as Additional file 1. gov/ct2/show/NCT02486133 Accessed 4 April, 2017. 3. Tashima KT, Mollan KR, Na L, Gandhi RT, Klingman KL, Fichtenbaum CJ, et al. Regimen selection in the OPTIONS trial of HIV salvage therapy: drug Authors’ contributions resistance, prior therapy, and race–ethnicity determine the degree of AFC planned and proposed the study, contributed participants’ data, regimen complexity. HIV Clin Trials. 2015;16(4):147–56. analyzed them and drafted the paper. MVC clinically followed, enrolled and 4. Tashima KT, Smeaton LM, Fichtenbaum CJ, Andrade A, Eron JJ, Gandhi RT, contributed patients’ data, coordinated the team and in particular dealt with et al. HIV salvage therapy does not require nucleoside reverse transcriptase Ethics’ Committees and revised the paper with minor comments. GCO, GC, inhibitors: a randomized trial. Ann Intern Med. 2015;163(12):908–17. AMC, NR, GMB, FPPN and GB clinically followed, enrolled and contributed 5. Huhn GD, Tebas P, Gallant J, Wilkin T, Cheng A, Yan M, et al. A randomized, patients’ data and revised the paper with minor comments. GS, GVDS, AS, SR open-label trial to evaluate switching to elvitegravir/cobicistat/emtricitabine/ contributed data and revised the draft, providing substantial improvement. tenofovir alafenamide plus darunavir in treatment-experienced HIV-1 infected GR supervised the team’s work and contributed clinical advice during the adults. J Acquir Immune Defic Syndr. 2017;74(2):193–200. follow-up. All authors read and approved the final manuscript. 6. Pasquau J, Hidalgo-Tenorio C. Nuke-Sparing Regimens for the Long-Term Care of HIV Infection. AIDS Rev. 2015;17:220–30. Ethics approval and consent to participate 7. Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, et al. Chronic The study was approved by the coordinating centre’s Ethics Committee and Kidney Disease Epidemiology Collaboration. Expressing the Modification of subsequently by all the ECs of the participating centres. Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate List of the Ethics’ Committees: with Standardized Serum Creatinine Values. Clin Chem. 2007;53(4):766–72. Comitato Etico Interaziendale Milano Area A (Protocol n. 6926/2016). 8. CTCAE website. Available: http://evs.nci.nih.gov/ftp1/CTCAE/About.html. Comitato Etico delle Aziende Sanitarie dell’Umbria, Perugia. Accessed 21 February 2017. Comitato Etico della ASL To/2 di Torino. 9. Cottrell ML, Hadzic T, Kashuba ADM. Clinical Pharmacokinetic, Comitato Etico per la Sperimentazione dell’Azienda Ospedaliera di Padova. Pharmacodynamic and Drug-Interaction Profile of the Integrase Inhibitor Comitato Etico Regionale Regione Liguria. Dolutegravir. Clin Pharmacokinet. 2013;52(11):981–94. Comitato Etico Sperimentazione Clinica Azienda Ospedaliera-Universitaria 10. Cattaneo D, Minisci D, Cozzi V, Riva A, Meraviglia P, Clementi E, et al. Careggi, Firenze. Dolutegravir plasma concentrations according to companion antiretroviral Comitato Etico dell’Università Cattolica del Sacro Cuore - Policlinico drug: unwanted drug interaction or desirable boosting effect? Antivir Ther. Universitario Agostino Gemelli, Roma. 2016; doi: 10.3851/IMP3119. [Epub ahead of print] Comitato Etico IRCCS Policlinico San Matteo, Pavia. 11. Hoffmann C, Welz T, Sabranski M, et al. Higher rates of neuropsychiatric Comitato Etico Brianza. adverse events leading to dolutegravir discontinuation in women and older The patients signed a general privacy agreement for data management and an patients. HIV Med. 2017;18(1):56–63. informed consent for accepting a non-conventional regimen in accordance with local procedures. Since the data collection was retrospective-prospective, no study-specific informed consent exist since at the time of the switch no study was planned. Consent for publication Not applicable Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details 1st Division of Infectious Diseases, ASST Fatebenefratelli-Sacco, Via Giovanni Battista Grassi, 74, pavillion 56, Malattie Infettive, 2nd floor, 20157 Milan, Italy. 1st Division of Infectious Diseases Amedeo di Savoia Hospital, Torino, Italy. 3 4 Division of Infectious Diseases, “Careggi” Hospital, Firenze, Italy. Division of Infectious Diseases, Ospedali Galliera, Genova, Italy. Infectious Diseases Clinic, Azienda Ospedaliero-Universitaria di Perugia, Perugia, Italy. Infectious and Tropical Diseases, Azienda Ospedaliera-Universitaria di Padova, Padova, Italy. Clinic of Infectious Diseases, San Gerardo Hospital, ASST Monza, University of Milano-Bicocca, Monza, Italy. Infectious Diseases Clinic, DIBIC Luigi Sacco, University of Milano, Milano, Italy. Infectious Diseases Clinic, Submit your next manuscript to BioMed Central “San Martino” Hospital, Genova, Italy. 2nd Division of Infectious Diseases, Università Cattolica del Sacro Cuore, Rome, Italy. 2nd Division of Infectious and we will help you at every step: Diseases, “Policlinico San Matteo” Hospital, Pavia, Italy. Whitwaterstrand University, Johannesburg, South Africa. • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal Received: 21 June 2017 Accepted: 21 September 2017 � We provide round the clock customer support � Convenient online submission References � Thorough peer review 1. Capetti AF, Sterrantino G, Cossu MV, Cenderello G, Cattelan AM, De Socio � Inclusion in PubMed and all major indexing services GV, et al. Correction: Correction: Salvage therapy or simplification of salvage � Maximum visibility for your research regimens with dolutegravir plus ritonavir-boosted darunavir dual therapy in highly cART-experienced subjects: an Italian cohort. Antivir Ther. 2017;22(3): Submit your manuscript at 273–5. doi: 10.3851/IMP3109. Epub 2016 Nov 28 www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Infectious Diseases Springer Journals

A dual regimen of ritonavir/darunavir plus dolutegravir for rescue or simplification of rescue therapy: 48weeks’ observational data

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Springer Journals
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Copyright © 2017 by The Author(s).
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Medicine & Public Health; Infectious Diseases; Parasitology; Medical Microbiology; Tropical Medicine; Internal Medicine
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1471-2334
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10.1186/s12879-017-2755-4
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28964268
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Abstract

Background: Dolutegravir (DTG) plus darunavir/ritonavir (DRV/r) is a simple combination of drugs that has the best genetic barrier to HIV-1 resistance and may be fit for salvage therapy. Methods: All HIV-1-infected subjects treated with DTG plus DRV/r between March 2014 and September 2015 in eight Italian centres were included in the analysis. The main metabolic data, efficacy parameters and safety data routinely collected were provided. This observational study is aimed to assess the efficacy of such approach. The primary end- point was the proportion of subjects achieving or maintaining virologic suppression <50 copies/mL at week 24. Secondary end points were maintaining virologic suppression in the follow-up (weeks 48 and 96) and safety. Results: One hundred and thirty subjects were followed for a median of 56 months. Reasons for switching were simplification (44.6%), viral failure (30%), toxicity (16.9%), non-adherence (4.6%), persistent low-level viremia (3.1%), and drug-drug interaction (0.8%). At baseline, 118 subjects had documented resistance to 1 to 5 antiretroviral classes while 12 had viral rebound at a time when genotypic tests were not yet available. Seventeen and 14 subjects took DRV/r and DTG twice daily, respectively. One subject was lost to follow-up, one discontinued for liver enzymes’ elevation, one died of illicit drug abuse and one of cancer-related complications. The proportion of subjects with ongoing HIV replication dropped from 40% to 6.1%. Those with undetectable viral load increased from 38.5% to 76.2%. At week 48, 17.7% had HIV RNA between 1 and 49 copies/mL. The number of subjects with altered serum glucose, creatinine, ALT, AST, total-, HDL- and LDL-cholesterol, triglycerides and MDRD <90 mL/min decreased by week 48, while those having MDRD <60 mL/min remained 4.6%. Overall 90/283 baseline laboratory alterations returned to normality. Conclusions: Switching to DTG plus DRV/r proved to be safe, suppressing viral replication without metabolic impact. Keywords: Dolutegravir, Darunavir, Ritonavir, Switch, Dual, Salvage, Simplification * Correspondence: amedeo.capetti@unimi.it Data from this work have been presented at the 14th European Meeting on HIV & Hepatitis, 25–27 May 2016, Rome, Italy, at the HIV Drug Therapy Congress, 24–26 October 2016 Glasgow, UK and to the 9th Italian Conference on AIDS and Antiviral Research, 12–14 June 2017, Siena, Italy. 1st Division of Infectious Diseases, ASST Fatebenefratelli-Sacco, Via Giovanni Battista Grassi, 74, pavillion 56, Malattie Infettive, 2nd floor, 20157 Milan, Italy Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Capetti et al. BMC Infectious Diseases (2017) 17:658 Page 2 of 7 Background by Ethics Committees (EC) no further enrolment was The present work is the 48-week update of a previously allowed. Since the last publication two centres that were reported study [1], concerning a retrospective-prospective waiting for EC approval joined the group, increasing the follow-up of subjects who had been switched for any population size. For homogeneity no data were collected reason to a dual combination of dolutegravir (DTG) plus after week 48 (plus 8 weeks’ window as observational stud- darunavir/ritonavir (DRV/r). A randomized clinical trial ies do not dictate strict timelines). The follow-up was cen- comparing the switch to this regimen towards the con- sored at November, 30, 2016. Subjects were not required tinuation of DRV/r plus 2 nucleoside analogues is still to be naive to DRV or DTG, but regimens containing both recruiting patients [2]. When we started this strategy of drugs were not included. dual rescue therapy or simplification of more complex res- Participating subjects have signed an informed consent cue regimens, the OPTIONS study, the first randomized according to local procedures, the study has been ap- trial to utilize a web utility in combination with central- proved by the coordinating centre and by all participat- ized expert opinion to guide the selection of salvage anti- ing centres and conducted according to the Good retroviral therapy was published [3]. The 413 participants Clinical Practice (GCP) Guidelines. had antiretroviral (ARV) experience or resistance to The aim of the study is to assess the efficacy of this nucleoside reverse transcriptase inhibitors (NRTI) and approach. The primary end-point was the proportion non-NRTI (NNRTI), were taking a protease inhibitor (PI)- of subjects achieving or maintaining virologic sup- containing regimen for at least 8 weeks prior to study pression <50 copies/mL at week 24. Secondary end entry, and had plasma HIV RNA ≥1000 copies/mL. points were maintaining virologic suppression in the Enfuvirtide (ENF), etravirine (ETR), DRV, maraviroc follow-up (weeks 48 and 96) and safety, as proportion (MVC), raltegravir (RAL), and tipranavir (TPV) plus rito- of drop-outs for any reason and grade 3–4adverse navir booster allowed 20 potential ARV regimens. Fifty- events. three subjects had obliged regimen choice due to poor phenotypic sensitivity score while 360 were randomized to add or not NRTIs. The resulting regimens were rather Safety data and laboratory standards complex, with 3 to 6 drugs and twice-daily dosing, and In this update it was decided to document the impact of generally contained DRV and RAL. The proportion of pa- the switch on some routine safety analyses. Investigators tients achieving viral suppression at 48 weeks (<50 HIV-1 retrospectively reported to the coordinating center serum RNA copies/mL) was 70.2% and 74.1% for the Omit NRTI glucose, alanine aminotransferase (ALT), aspartate amino- and for the Add NRTI arms, respectively [4]. Prescribers transferase (AST), total cholesterol (TC), high density were generally oriented to prefer simpler regimens. lipoprotein (HDL-C), low density lipoprotein (LDL-C) The combination of elvitegravir/cobicistat/tenofovir and triglycerides (TG). The estimated glomerular filtration alafenamide/emtricitabine plus 800 mg DRV (two pills rate (e-GFR) was calculated at baseline and at follow-up once daily) demonstrated superiority towards the con- according to the Modification of Diet in Renal Disease tinuation of baseline therapy in a randomized (2:1), (MDRD) equation [7]. Plasma viral suppression status was open-label, switch trial in treatment-experienced viro- classified as harbouring ≥50 HIV-1 RNA copies/mL, or logically suppressed subjects [5]. The baseline regimens detectable below 50 copies/mL, or undetectable (no virus contained in median 5 pills per day and the primary detected, NVD = 0 copies/mL). endpoint was maintaining <50 HIV-1 RNA copies/mL. Viremia was measured depending on centers with In this context some authors were looking forward for Abbot HIV-1 RT-PCR, threshold 37 copies, COBAS nucleoside-sparing regimens in the long-term care of TaqMan HIV-1 test, threshold 20 copies, and Single HIV infection, welcoming the possible positive contribu- Copy Assay. TruGene™ was used for resistance testing, tion of DTG [6]. validated on the Stanford Algorithm, and cumulative The present study reports what the clinical practice data was considered. Data were collected from electronic had already realised, aiming for convenience, simplicity, or hand-written patients’ case record forms, according to potency and high genetic barrier, prescribing this com- each centre’s organization and sent as pre-specified excel bination to several patients and controlling them closely files. Available data from routine therapeutic monitoring until viral suppression was achieved. of darunavir and dolutegravir trough plasma concentra- tion were analysed. Methods For the toxicity analyses the Common Terminology All subjects who had started DTG plus DRV/r between Criteria for Adverse Events (CTCAE, Version 4.03, June March 1, 2014 and September 30, 2015 were included in 14, 2010) was considered [8]. Adverse clinical events and an Italian observational multicenter cohort named Tivista deaths were reported to the local Ethics Committees and (Tivicay plus Prezista Observational cohort). After approval authorities as required by the law. Capetti et al. BMC Infectious Diseases (2017) 17:658 Page 3 of 7 Statistical analysis and drug-drug interaction, 0.8% (n = 1). The algorithm The statistical analysis was limited to routine parameters of the study population is represented in Fig. 1. (median, mean and standard error) and to the paired t- At baseline 118 subjects had documented resistance to test for the comparison between the baseline and 48- 1 to 5 ARV classes. For the remaining 12 patients, viral week metabolic and immunologic values. The virologic failure was not accompanied by a genotypic test. Twenty- response is reported as the number of patients in each three subjects (17.7%) had never experienced virologic viral suppression category and as the median and inter- failure but had transmitted drug resistance mutations. quartile range of log copies/mL in those who do not One hundred and sixteen patients (89.2%) had NRTI reach suppression at each time point. The other analyses resistance-associated mutations (RAMs) at baseline, 98 consider the on-treatment population. The sample size (75.4%) had NNRTI RAMs, 91 (70%) had PI RAMs and was obtained from the participants’ adhesion. 12 (10.6%) had integrase strand transfer inhibitors (INSTI) RAMs (See Table 1). Results Twenty subjects had reduced baseline sensitivity to One hundred and thirty subjects were followed for a me- darunavir (Stanford median score 15, range 15–40), and dian of 56 months, mean 64 months. The median age 12 had reduced sensitivity to INSTIs (Stanford median was 52 years, females were 25.4% and non-Caucasians score 10, range 10–25) but none rebounded. None de- 8.9%. The median baseline CD4+ T-cell count was 526/ veloped new drug resistance mutations during the study. mmc (IQR 329–718). Fifty-nine subjects had been ex- Of those subjects who had resistance to 3–4 drug clas- posed to INSTIs and all had been exposed to PIs. ses (n = 70), 35 were not failing at baseline, but rather Eighty-one had darunavir in their pre-switch regimen simplified from raltegravir and boosted darunavir-based and one had dolutegravir. The main risk factor for three- (n = 31) or four-drugs regimens (n = 9). acquiring HIV was being male homosexual, 48.5% One hundred and thirteen have started the combination (n = 63), followed by drug abuse, 26.9% (n = 35) and of DRV 800 mg plus RTV 100 mg plus DTG 50 mg every heterosexual intercourse, 24.6% (n = 32). Reasons that 24 h, 3 DRV 600 mg plus RTV 100 mg every 12 h and 14 led to the switch were simplification, 44.6% (n = 56), DRV 600 mg plus RTV 100 mg plus DTG 50 mg every viral failure 30% (n = 39) toxicity 16.9% (n = 22, of 12 h. All of those who were on BID therapy had active which 11 for osteopoenia/osteoporosis, 3 each for HIV-1 replication at baseline (range 5.46–6.16 log HIV- lipodystrophy and cardiovascular problems, 2 for renal 1 RNA copies/mL). All of them suppressed viremia to <50 toxicity and one each for gastrointestinal toxicity, dia- copies/mL during the follow-up. betes and creatine kinase elevation), non-adherence, Between week 24 and 48 one subject was lost to 4.6% (n = 6), persistent low-level viremia, 3.1% (n = 4), follow-up, one interrupted the regimen for liver Fig. 1 Algorithm of the study population. DTG = dolutegravir; DRV/r = darunavir boosted with ritonavir; AST = aspartate aminotransferase; ALT = alanine aminotransferase Capetti et al. BMC Infectious Diseases (2017) 17:658 Page 4 of 7 Table 1 Baseline HIV-1 drug resistance mutations in the study population Primary resistance mutations (Wensing, 2017) are underlined enzymes’ elevation, one died of illicit drug abuse and as 3 with high baseline viral load and 3 with extensive one of cancer-related complications. baseline resistance, had still very low but detectable The proportion of subjects harboring active HIV repli- viremia, while in those who started with 0–49 copies/ cation dropped from 40% at baseline to 6.1% by week mL the success rate was 97.4% as in this group two 48, while those who had NVD at real-time polymerase subjects were not on therapy on the sampling day, as de- chain reaction (RT-PCR) increased from 38.5% to 76.2%. scribed above. Of interest, both were in the subgroup Overall, at baseline 78 subjects had <50 HIV-1 RNA starting with 1–49 copies/mL, as some authors suggest copies/mL (60%) and this proportion increased at week that this low but persistent viremia may sometime hide 48 to 90,8% (n = 118) At week 48, 19 subjects (14,6%) adherence problems. The mean viral load in this popula- had HIV RNA between 1 and 49 copies/mL and eight tion at week 48 was 1.89 log copies/mL (range 1.70– subjects (6,1%) had ≥50 HIV-1 RNA copies/mL. Of the 2.57, Fig. 2). The CD4+ T-cell absolute count and latter, 3 had a slow but constant decay from median proportion increased by 27 cells/mm , +5%, not reaching baseline 5.12 to 2.30 log HIV-1 RNA copies/mL, 3 had statistical significance. at least three-class drug resistance with a Stanford DRV A single-point pharmacokinetic analysis in a subgroup score > 60 and median viral decay from 4.39 to 1.75 of 32 subjects confirmed the safety of the association: log HIV-1 RNA copies/mL, and 2 had dropped out of DTG median C was 579 ng/mL (range 275–5036), 10 trough therapy 4 and 7 days before blood sampling. Considering while DRV median C was 3007 ng/mL (range 678– trough separately two populations, those who started with active 8053) and no values were found to be below the safety HIV replication (≥ 50 copies/mL) and those who started threshold. Five subjects were taking DRV 600 mg twice with 0–49 copies/mL, at week 48 the success rate was daily and had C above the threshold for resistant min 88.5% in those who had started with active replication, strains, and three were taking DTG twice daily. Capetti et al. BMC Infectious Diseases (2017) 17:658 Page 5 of 7 Fig. 2 Virologic and immunologic response. a n. of patients by HIV-1 RNA, copies/mL; b HIV-1 replication decay in the population with ongoing viral replication, log copes/mL; c CD4+ T-lymphocytes/mmc; d CD4+ T-lymphocytes, %. eGFR = estimated Glomerular Filtration Rate, calculated on the Modified Diet for Renal Disease (MDRD) score; AST = aspartate aminotrasferase; ALT = alanine aminotrasferase; TC = total cholesterol; HDL-C = HDL cholesterol; LDL-C = LDL cholesterol The proportion of subjects having any metabolic Discussion alterations at baseline decreased for serum glucose, While awaiting the results of the randomized DUALIS creatinine, MDRD <90 mL/min, ALT, AST, total-, study [2], our data suggest that the combination of DTG HDL- and LDL-cholesterol and triglycerides. The pro- plus DRV/r may be considered reliable in salvage or sim- portion of subjects having MDRD <60 remained plification of salvage regimens. The pharmacokinetic stable at 4.6%. Overall 84/175 (48%) baseline labora- interaction between the two drugs [9] did not seem to im- tory alterations returned to normality. Considering pact neither causing subtherapeutic C in the subjects min each parameter in the whole population, none varied tested nor leaving space for plasma HIV-1 RNA rebound significantly (Fig. 3). in any subject. In particular, 70% of our patients would In particular, the median variation in serum cre- not have been suitable for the combination of DTG plus atinine was −0,03 and the eGFR decrease on average atazanavir, which has a favourable interaction profile [10] by 2.66 mL/min. None of the subjects who had al- due to baseline resistance to the latter and it should be tered serum creatinine at baseline showed progres- said that clinical experience with this combination is still sion and 6 out of 8 improved, having discontinued limited though promising. Moreover, we have not re- tenofovir. ported significant neurological side effects, as suggested Overall this strategy yielded mean savings for € by Hoffman et al. [11] Possible reasons may be the com- 169,428.00 considering the whole population, the obser- bination, which does not include abacavir, the fact that vation period and the dropouts. The figure was gener- many of our patients had received the indication to take ated only from the cost of the previous and current the drug in the morning and the relatively small number antiretroviral regimen. of other at risk subjects (15 elderly and 33 women). Capetti et al. BMC Infectious Diseases (2017) 17:658 Page 6 of 7 Fig. 3 Metabolic profile during the follow-up. a Number of subjects with any laboratory abnormality at baseline, week 24 and week 48. b Variation of metabolic indicators from baseline, mean values; c Variation in triglycerides (different scale). AST = Aspartate Aminotransferase; ALT = Alanine Aminotransferase; HDL-C = High-Density Lipoprotein - Cholesterol; LDL-C = Low-Density Lipoprotein - Cholesterol; MDRD = Modified Diet for RenalDisease;TC=TotalCholesterol The study limitations include poor patient selection (the Additional file only two inclusion criteria were being HIV-1 antibody Additional file 1: Tivista Study Week 48 database. (TIFF 31 kb) positive and having started DTG plus DRV/r by the end of September 2015), leading to the inclusion of a heteroge- Abbreviations neous population, made out of failures and simplification, ALT: Alanine aminotransferase; ARV: Antiretroviral; AST: Aspartate once- and twice-daily regimens, adherent and poorly aminotransferase; CD4: Cluster difference 4; CTCAE: Common Terminology adherent subjects and subjects harbouring treatment- Criteria for Adverse Events; C : Trough concentration; DRV/r: Darunavir trough boosted with ritonavir; DTG: Dolutegravir; EC: Ethics Committee; resistant and treatment-sensitive strains. The set of meta- eGFR: Estimated glomerular filtration rate; ENF: Enfivirtide; ETV: Etravirine; bolic parameters furthermore reflects standard follow-up GCP: Good clinical practice; HDL: High-density lipoprotein; HIV-1: Human data shared by centres and does not include bone density immunodeficiency virus type 1; LDL: Low density lipoprotein; MDRD: Modified diet for renal disease; MVC: Maraviroc; NNRTI: Non- measures nor inflammatory markers. nucleoside reverse transcriptase inhibitor; NRTI: Nucleoside reverse transcriptase inhibitor; NVD: No virus detected; PI: Protease inhibitor; Conclusions RAL: Raltegravir; RNA: Ribonucleic acid; RT-PCR: Real-time Polymerase Chain Reaction; TPV: Tipranavir Switching to DTG plus DRV/r provided a simple and safe rescue regimen to all subjects, controlling viral replication Acknowledgements in a high proportion of patients. The metabolic impact We acknowledge Mrs. Maureen Naomi Quinn for reviewing this text as native american health worker. was favourable in a proportion of subjects who had base- line alterations, while no significant modifications were Funding observed in mean and median values when also normal This research did not receive any specific grants from funding agencies from baseline values were included. funding agencies in the public, commercial or not-for-profit sectors. Capetti et al. BMC Infectious Diseases (2017) 17:658 Page 7 of 7 Availability of data and materials 2. Dual Therapy With Boosted Darunavir + Dolutegravir (Dualis) https://clinicaltrials. The study database is attached as Additional file 1. gov/ct2/show/NCT02486133 Accessed 4 April, 2017. 3. Tashima KT, Mollan KR, Na L, Gandhi RT, Klingman KL, Fichtenbaum CJ, et al. Regimen selection in the OPTIONS trial of HIV salvage therapy: drug Authors’ contributions resistance, prior therapy, and race–ethnicity determine the degree of AFC planned and proposed the study, contributed participants’ data, regimen complexity. HIV Clin Trials. 2015;16(4):147–56. analyzed them and drafted the paper. MVC clinically followed, enrolled and 4. Tashima KT, Smeaton LM, Fichtenbaum CJ, Andrade A, Eron JJ, Gandhi RT, contributed patients’ data, coordinated the team and in particular dealt with et al. HIV salvage therapy does not require nucleoside reverse transcriptase Ethics’ Committees and revised the paper with minor comments. GCO, GC, inhibitors: a randomized trial. Ann Intern Med. 2015;163(12):908–17. AMC, NR, GMB, FPPN and GB clinically followed, enrolled and contributed 5. Huhn GD, Tebas P, Gallant J, Wilkin T, Cheng A, Yan M, et al. A randomized, patients’ data and revised the paper with minor comments. GS, GVDS, AS, SR open-label trial to evaluate switching to elvitegravir/cobicistat/emtricitabine/ contributed data and revised the draft, providing substantial improvement. tenofovir alafenamide plus darunavir in treatment-experienced HIV-1 infected GR supervised the team’s work and contributed clinical advice during the adults. J Acquir Immune Defic Syndr. 2017;74(2):193–200. follow-up. All authors read and approved the final manuscript. 6. Pasquau J, Hidalgo-Tenorio C. Nuke-Sparing Regimens for the Long-Term Care of HIV Infection. AIDS Rev. 2015;17:220–30. Ethics approval and consent to participate 7. Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, et al. Chronic The study was approved by the coordinating centre’s Ethics Committee and Kidney Disease Epidemiology Collaboration. Expressing the Modification of subsequently by all the ECs of the participating centres. Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate List of the Ethics’ Committees: with Standardized Serum Creatinine Values. Clin Chem. 2007;53(4):766–72. Comitato Etico Interaziendale Milano Area A (Protocol n. 6926/2016). 8. CTCAE website. Available: http://evs.nci.nih.gov/ftp1/CTCAE/About.html. Comitato Etico delle Aziende Sanitarie dell’Umbria, Perugia. Accessed 21 February 2017. Comitato Etico della ASL To/2 di Torino. 9. Cottrell ML, Hadzic T, Kashuba ADM. Clinical Pharmacokinetic, Comitato Etico per la Sperimentazione dell’Azienda Ospedaliera di Padova. Pharmacodynamic and Drug-Interaction Profile of the Integrase Inhibitor Comitato Etico Regionale Regione Liguria. Dolutegravir. Clin Pharmacokinet. 2013;52(11):981–94. Comitato Etico Sperimentazione Clinica Azienda Ospedaliera-Universitaria 10. Cattaneo D, Minisci D, Cozzi V, Riva A, Meraviglia P, Clementi E, et al. Careggi, Firenze. Dolutegravir plasma concentrations according to companion antiretroviral Comitato Etico dell’Università Cattolica del Sacro Cuore - Policlinico drug: unwanted drug interaction or desirable boosting effect? Antivir Ther. Universitario Agostino Gemelli, Roma. 2016; doi: 10.3851/IMP3119. [Epub ahead of print] Comitato Etico IRCCS Policlinico San Matteo, Pavia. 11. Hoffmann C, Welz T, Sabranski M, et al. Higher rates of neuropsychiatric Comitato Etico Brianza. adverse events leading to dolutegravir discontinuation in women and older The patients signed a general privacy agreement for data management and an patients. HIV Med. 2017;18(1):56–63. informed consent for accepting a non-conventional regimen in accordance with local procedures. Since the data collection was retrospective-prospective, no study-specific informed consent exist since at the time of the switch no study was planned. Consent for publication Not applicable Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details 1st Division of Infectious Diseases, ASST Fatebenefratelli-Sacco, Via Giovanni Battista Grassi, 74, pavillion 56, Malattie Infettive, 2nd floor, 20157 Milan, Italy. 1st Division of Infectious Diseases Amedeo di Savoia Hospital, Torino, Italy. 3 4 Division of Infectious Diseases, “Careggi” Hospital, Firenze, Italy. Division of Infectious Diseases, Ospedali Galliera, Genova, Italy. Infectious Diseases Clinic, Azienda Ospedaliero-Universitaria di Perugia, Perugia, Italy. Infectious and Tropical Diseases, Azienda Ospedaliera-Universitaria di Padova, Padova, Italy. Clinic of Infectious Diseases, San Gerardo Hospital, ASST Monza, University of Milano-Bicocca, Monza, Italy. Infectious Diseases Clinic, DIBIC Luigi Sacco, University of Milano, Milano, Italy. Infectious Diseases Clinic, Submit your next manuscript to BioMed Central “San Martino” Hospital, Genova, Italy. 2nd Division of Infectious Diseases, Università Cattolica del Sacro Cuore, Rome, Italy. 2nd Division of Infectious and we will help you at every step: Diseases, “Policlinico San Matteo” Hospital, Pavia, Italy. Whitwaterstrand University, Johannesburg, South Africa. • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal Received: 21 June 2017 Accepted: 21 September 2017 � We provide round the clock customer support � Convenient online submission References � Thorough peer review 1. Capetti AF, Sterrantino G, Cossu MV, Cenderello G, Cattelan AM, De Socio � Inclusion in PubMed and all major indexing services GV, et al. Correction: Correction: Salvage therapy or simplification of salvage � Maximum visibility for your research regimens with dolutegravir plus ritonavir-boosted darunavir dual therapy in highly cART-experienced subjects: an Italian cohort. Antivir Ther. 2017;22(3): Submit your manuscript at 273–5. doi: 10.3851/IMP3109. Epub 2016 Nov 28 www.biomedcentral.com/submit

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