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      Anucleoside-sparing regimen of dolutegravir plus ritonavir-boosted atazanavir in HIV-1-infected patients with virological failure: the DOLATAV study

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          Abstract

          Introduction The increased exposure of dolutegravir (DTG) when given with atazanavir/ritonavir (ATV/r), as well as the acceptable safety profile, may suggest the use of this combination as a two-drug regimen both in virologically suppressed and treatment-failing subjects.1–5 This nucleoside reverse transcriptase inhibitors (NRTIs)-sparing regimen, characterized by a high genetic barrier, may represent an option in patients who have failed previous regimens and developed pharmacoresistance mutations to NRTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, no data on DTG plus boosted ATV in patients with virological failure are currently available. Therefore, the aim of the DOLATAV study was to investigate the efficacy, safety, and pharmacokinetics of ATV/r 300/100 mg once-daily plus DTG 50 mg once-daily in treatment-failing HIV-1-infected patients. Methods DOLATAV is a prospective, single-arm, monocentric, open label, pilot study (NCT02542852). It was approved by the Ethics Committee of the San Raffaele Scientific Institute, conducted in accordance with the Declaration of Helsinki, and all participants in it signed the study’s informed consent at screening. The study was conducted on HIV-infected subjects with virological failure, defined as two consecutive viral loads ≥200 copies/mL, without a history of ATV failure and ATV resistance and without any exposure to integrase strand transfer inhibitors. Patients were assessed at screening, baseline (ATV/r plus DTG initiation), day 8, weeks 4, 8, 12, 16, and 24 (or study discontinuation). Treatment failure was defined as virological failure (confirmed rebound in plasma HIV-RNA levels ≥50 copies/mL after prior confirmed suppression to <50 copies/mL or a plasma HIV-1 RNA level ≥50 copies/mL at week 24) or study discontinuation for any reason. Ctrough of ATV and DTG were evaluated at each time-point after baseline by sensitive liquid chromatography tandem mass spectrometry. Results were described as median (IQR) or frequency (%). The ANOVA for repeated measures was used to evaluate differences in laboratory parameters over time. Significant changes at each time-point were assessed by the Wilcoxon signed-rank test; the Bonferroni correction was applied. Results We screened 16 subjects (5 screening failures for HIV- RNA <200 copies/mL, 1 withdrawal of consent) and enrolled 10 participants with a median age of 47 (42–50) years. Patients had a known HIV infection of 14.4 (11.7–28.9) years and 10.7 (5.1–18.0) years of antiretroviral therapy exposure. Sixty percent of patients were on a failing boosted protease inhibitor (PI)-based regimen and 40% on a NNRTIs-based treatment; HIV-RNA was 2.77 (2.09–2.98) log10 copies/mL at baseline. In addition, 80% of the patients had NRTIs or NNRTIs mutations and one subject showed archived PIs mutations at HIV genotype screening (Table 1). At week 24, the proportion of virological efficacy (HIV-RNA <50 copies/mL) was 100% and the corresponding 95%CI extended from 68% to 100%, in both the intention-to-treat and on-treatment analyses. None of the enrolled participants discontinued the treatment regimen. Six clinical adverse events (AEs) occurred in five participants: three subjects experienced a drug-related clinical event (scleral jaundice) of grade 2 (one participant) or grade 1 (two participants); three participants had non-drug related AEs (a grade-1 pharyngitis, a grade-2 subcutaneous abscess and a grade-2 accidental nasal fracture). No clinical event was serious and no neuropsychiatric events were reported. A significant increase of total bilirubin (+1.97 mg/dL [+0.77; +3.44]; P=0.004) and a marginally significant decline in eGFR (−9.5 mL/min/1.73 m2 [−16; −2]; P=0.084) were observed during the treatment with DTG plus ATV/r. No significant variations during follow-up were found in immunological, hepatic and hematological parameters or lipid and glucose levels. ATV and DTG plasma concentrations were stable during follow-up as shown in Table 2. Discussion and conclusion To our knowledge, our study investigated for the first time the association of DTG plus ATV/r as rescue therapy in patients with virological failure. However, our trial has several limitations, such as the monocentric and single arm design of the study. In addition, given the small number of participants, mainly due to the low number of observed virological failures in our cohort during the enrollment period, another clear limitation of this study is the low statistical power. In conclusion, this pilot study showed that in HIV-infected subjects with virological failure, a long antiretroviral therapy exposure and resistance to NRTIs and NNRTIs, a dual regimen with DTG plus ATV/r may represent a novel and well-tolerated therapeutic option with excellent efficacy and a high genetic barrier. Data sharing statement Individual participant data that underlie the results reported in this article, after de-identification (text and tables) will be shared with researchers who provide a proposal, beginning 3 months and ending 5 years after article publication. Proposals may include individual participant data meta-analysis and should be directed to spagnuolo.vincenzo@hsr.it to get access to the data. The study protocol and the statistical analysis plan are available at https://clinicaltrials.gov/ct2/ show/NCT02542852.

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          Effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572.

          S/GSK1349572 is an unboosted, once daily, next generation integrase inhibitor with potent activity, low pharmacokinetic (PK) variability and a novel resistance profile. As the primary route of metabolism is via glucuronidation, the effects of atazanavir (ATV, a UGT1A1 inhibitor) and atazanavir/ritonavir (ATV/RTV) on S/GSK1349572 PK were evaluated. A randomized, open label, two period, crossover study was conducted in healthy adult subjects. Twenty-four subjects received S/GSK1349572 30 mg every 24 h for 5 days. Subjects then were administered S/GSK1349572 30 mg every 24 h in combination with either ATV/RTV 300/100 mg every 24 h (n= 12) or ATV 400 mg every 24 h (n= 12) for 14 days. Serial PK samples and safety assessments were obtained throughout the study. The combination of S/GSK1349572 with ATV/RTV or ATV was generally well tolerated. All adverse events were mild or moderate, and no subject withdrew because of an adverse event. The AE of highest frequency was ocular icterus, observed only during combination of S/GSK1349572 and ATV or ATV/RTV. Co-administration with ATV/RTV resulted in increased plasma S/GSK1349572 area under the concentration-time curve during a dosing interval (AUC(0,τ)), observed maximal concentration (C(max) ), and concentration at the end of dosing interval at steady state (C(τ) ) by 62%, 34% and 121%, respectively. Co-administration with ATV resulted in increased plasma S/GSK1349572 AUC(0,τ), C(max) , and C(τ) by 91%, 50% and 180%, respectively. Co-administration of ATV/RTV and ATV was generally well tolerated and produced a modest, non-clinically significant increase in S/GSK1349572 exposure. No dose adjustment for S/GSK1349572 is necessary when co-administered with ATV and ATV/RTV. © 2011 Viiv Healthcare. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.
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            Low dose of unboosted atazanavir plus dolutegravir as simplification strategy for HIV-infected patients receiving antiretroviral therapy

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              Dolutegravir 50 mg thrice weekly plus atazanavir 400 mg daily in a long-term virologically suppressed HIV-infected patient.

              Highly active antiretroviral therapy (HAART) has changed the natural course of HIV infection. However, the toxicities associated with long-term use of nucleoside reverse transcriptase inhibitors (NRTIs) have led to the assessment of dual-therapy approaches with less toxicity. Atazanavir and dolutegravir have antiviral potency, tolerability and favourable metabolic profile. In suppressed HIV-infected patients, with NRTIs-related toxicity effects, the association of atazanavir and dolutegravir, favoured by their positive pharmacokinetics interaction, could be used as 'maintenance' antiretroviral therapy. We report a case report about one HIV-infected patient, on HAART and with a persistent suppression of HIV RNA, switched to dolutegravir 50 mg three times weekly plus atazanavir 400 mg once daily, as 'maintenance antiretroviral therapy', with persistence of viral suppression.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2019
                24 January 2019
                : 13
                : 477-479
                Affiliations
                [1 ]Vita-Salute San Raffaele University, Faculty of Medicine and Surgery, Milan, Italy, spagnuolo.vincenzo@ 123456hsr.it
                [2 ]Clinic of Infectious Diseases, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy, spagnuolo.vincenzo@ 123456hsr.it
                [3 ]Laboratory Medicine Service, IRCCS San Raffaele Hospital, Milan, Italy
                Author notes
                Correspondence: Vincenzo Spagnuolo, Vita-Salute San Raffaele University, Faculty of Medicine and Surgery, via Stamira d’Ancona 20, 20127 Milan, Italy, Tel +39 02 2643 7907, Fax +39 02 2643 7903, Email spagnuolo.vincenzo@ 123456hsr.it
                Article
                dddt-13-477
                10.2147/DDDT.S192124
                6352870
                © 2019 Spagnuolo et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Research Letter

                Pharmacology & Pharmaceutical medicine

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