Publications by authors named "Franco Maggiolo"

131 Publications

Time spent with viral load≤200 copies/mL in a cohort of people with HIV seen for care in Italy during the U=U prevention campaign era.

AIDS 2021 01 29. Epub 2021 Jan 29.

Unit of Infectious Diseases, Department of Medical, Surgical and Experimental Sciences, University of Sassari; Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME) Institute for Global Health UCL, London, UK; Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy; Division of Infectious Diseases, ASST Papa Giovanni XXIII, Bergamo, Italy; Department of Laboratory Medicine, Unit of Microbiology and Immunology, IRCCS Children Hospital Bambino Gesù, Rome, Italy; HIV/AIDS Clinical Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy; ASST Santi Paolo e Carlo, University of Milan, Clinic of Infectious and Tropical Diseases, Department of Health Sciences, Milan, Italy; Department of Infectious Diseases, Policlinic Hospital, University of Bari 'Aldo Moro', Bari, Italy; Clinical Epidemiology Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.

Objective: Zero risk of linked HIV transmission in sero-discordant couples when the HIV-infected partner had viral load (VL) <200 copies/mL ('U status') was found in observational studies. We aimed at estimating the proportion of time in which 'U status' was maintained and identifying factors associated with the risk of losing it.

Design: Observational cohort study.

Methods: We included participants in the ICONA cohort who had reached an established 'U status' (VL≤200 copies/mL for >6 months) as of December 2010. The outcome was the number of person-days of follow up (PDFU) above a VL>200 copies/ml, relative to the total number of PDFU observed. A logistic regression model was used to identify factors independently associated with the risk of losing 'U status'.

Results: 8,241 persons living with HIV were included in the analysis who contributed 12,670,888 PDFU. Of these, 1,648 (20%) were female, 768 (9%) were people who inject drugs (PWID), and 2,066 (25%) were foreing-born. The median of VL measurements was 9 (IQR: 4-15). Overall, only 3.1% of PDFU were observed when VL was >200 copies/mL. The proportion of PDFU with VL>200 cp/ml was higher than average in females (5.3%), unemployed (5.4%), PWID (4.7%), and in people with>3 previous virologic failures (6.3%). These variables were significant predictors of losing 'U status' in the multivariable logistic regression.

Conclusions: Our results reinforce the validity of the U=U message in real-world setting. However, we identified subsets of our study population at higher risk of losing the 'U status' for whom additional efforts are needed.
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http://dx.doi.org/10.1097/QAD.0000000000002825DOI Listing
January 2021

High rates of sustained virological response despite premature discontinuation of directly acting antivirals in HCV-infected patients treated in a real-life setting.

J Viral Hepat 2021 Mar 2;28(3):558-568. Epub 2021 Jan 2.

U.O. Malattie Infettive e Tropicali, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

In routine clinical practice, hepatitis C virus-infected patients can prematurely discontinue the prescribed regimen for several reasons. The aim of our study was to investigate sustained virological response (SVR12) rates in patients who prematurely discontinued directly acting antiviral (DAA) regimens and to assess the shortest effective duration of DAA able to lead to SVR12. We retrospectively collected the SVR rates of patients, registered in the NAVIGATORE-Lombardia Network database from January 2015, who discontinued DAAs before the predefined end of treatment. Overall, we included 365 patients, males were the majority (213, 58.4%), mean age was 60.5 years, and 53 (14.5%) patients were HIV-co-infected. Liver cirrhosis was observed in 251 (68.8%) subjects, and the most represented genotypes were 1b (n = 168, 46%) and 3 (n = 59, 16.2%). DAA was discontinued a median of 1 (IQR 1-4) weeks before the predefined EOT, with 164 (44.9%) patients stopping DAAs at least 2 weeks before the planned schedule. In patients with F0-F3 liver fibrosis, lower rates of SVR12 were observed in patients treated for <4 weeks: 50% (n = 2/4) vs. 99.1% (n = 109/110) for ≥4 weeks, p = 0.003. In patients with liver cirrhosis, lower rates of SVR12 were observed in patients treated <8 weeks: 83.3% (n = 25/30) vs. 94.6% (n = 209/221) for ≥8 weeks, p = 0.038. Despite premature discontinuation of DAA, high SVR12 rates were observed in a real-life setting for treatment lasting at least 4 weeks in patients with liver fibrosis F0-F3 and 8 weeks in those with liver cirrhosis. On this basis, feasibility of reducing DAA treatment duration should be explored in randomized clinical trials.
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http://dx.doi.org/10.1111/jvh.13454DOI Listing
March 2021

Enhancing care for people living with HIV: current and future monitoring approaches.

Expert Rev Anti Infect Ther 2020 Oct 15:1-14. Epub 2020 Oct 15.

Infectious Diseases Clinic, San Martino Hospital - IRCCS, Genoa, Italy - Department of Health Sciences, University of Genoa , Genova, Italy.

Introduction: Antiretroviral therapy (ART) is the most significant advance in the medical management of HIV-1 infection. Given the fact that HIV cannot be eradicated from the body, ART has to be indefinitely maintained. New approaches need to be defined for monitoring HIV-infected individuals (PLWHIV), including clinical, virologic, immunological parameters and also ways to collect individual points of view and quality of life.

Areas Covered: We discuss which tests may be used to improve the management of PLWHIV and respond to a comprehensive health demand.

Expert Opinion: Viral load and CD4 counts are well-validated outcome measures and we still need them, but they do not completely depict the health status of PLWHIV. We need to better understand and to apply to clinical practice what happens in sanctuaries, what is the role of HIV DNA, what is the meaning of low-level viremia. Most of these questions do not yet have a definitive response. Further, we need to understand how to modify these variables in order to improve outcomes. Similar points may be raised for immunological measures and for tests exploring the tolerability of drugs. The goal must be the evolution from a viro/immunologic-based to a comprehensive quality-of-health-based evaluation of PLWHIV.
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http://dx.doi.org/10.1080/14787210.2021.1823217DOI Listing
October 2020

Marked decrease in acquired resistance to antiretrovirals in latest years in Italy.

Clin Microbiol Infect 2020 Sep 23. Epub 2020 Sep 23.

Department of Biomedical and Clinical Sciences 'L. Sacco', University of Milan, Milan, Italy.

Objectives: The aim of this study was to evaluate acquired drug resistance in Italy in the 2009-2018 period.

Methods: We analysed 3094 patients from the Italian ARCA database who had failed antiretroviral treatment and who had received a genotypic test after 6 months of treatment. Drug resistance mutations were identified using International AIDS Society (IAS)-USA tables and the Stanford HIVdb algorithm. The global burden of acquired resistance was calculated among all subjects with antiretroviral failure. Time trends and correlates of resistance were analysed using standard statistical tests.

Results: Patients of non-European origin and non-B subtypes increased significantly from 11.5% (103/896) to 19.2% (33/172) and from 13.1% (141/1079) to 23.8% (53/223), respectively, over time. Overall, 14.5% (448/3094), 12.1% (374/3094) and 37.8% (1169/3094) of patients failed first, second and later lines, respectively. According to both IAS and HIVdb, in the study period resistance to any class, nucleoside reverse inhibitor, non-nucleoside reverse inhibitor, and protease inhibitors (PIs) declined significantly. Integrase strand transfer inhibitor (INSTI) resistance declined significantly from 31% (36/116) to 20.8% (41/197) according to HIVdb but not to IAS. Divergent data were highlighted regarding the proportion of non-European patients carrying any, PI and INSTI resistance using IAS tables compared with the Stanford HIVdb algorithm, as the former failed to detect a decrease in resistance while the latter indicates a reduction of 1.6-, 5- and 1.8-fold resistance for such drug classes. In the multivariate analysis, the risk of resistance increased in patients with a larger number of treatment lines and higher viraemia and decreased in those starting therapy in the last biennium of the study.

Discussion: A marked reduction in drug resistance was observed over 10 years, compatible with higher genetic barrier and potency of new antiretrovirals. Nonetheless, concerns remain for subjects with non-B subtypes when using mutation lists instead of interpretation systems because of the extensive polymorphism of the protease region.
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http://dx.doi.org/10.1016/j.cmi.2020.09.028DOI Listing
September 2020

Evaluation of virological response and resistance profile in HIV-1 infected patients starting a first-line integrase inhibitor-based regimen in clinical settings.

J Clin Virol 2020 09 11;130:104534. Epub 2020 Jul 11.

Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy. Electronic address:

Background: Virological response and resistance profile were evaluated in drug-naïve patients starting their first-line integrase inhibitors (INIs)-based regimen in a clinical setting.

Study Design: Virological success (VS) and virological rebound (VR) after therapy start were assessed by survival analyses. Drug-resistance was evaluated at baseline and at virological failure.

Results: Among 798 patients analysed, 38.6 %, 27.1 % and 34.3 % received raltegravir, elvitegravir and dolutegravir, respectively. Baseline resistance to NRTIs, NNRTIs, PIs and INIs was: 3.9 %, 13.9 %, 1.6 % and 0.5 %, respectively. Overall, by 12 months of treatment, the probability of VS was 95 %, while the probability of VR by 36 months after VS was 13.1 %. No significant differences in the virological response were found according to the INI used. The higher pre-therapy viremia strata was (<100,000 vs. 100,000-500,000 vs. > 500,000 copies/mL), lower was the probability of VS (96.0 % vs. 95.2 % vs. 91.1 %, respectively, P < 0.001), and higher the probability of VR (10.2 % vs. 15.8 % vs. 16.6 %, respectively, P = 0.010). CD4 cell count <200 cell/mm was associated with the lowest probability of VS (91.5 %, P < 0.001) and the highest probability of VR (20.7 %, P = 0.008) compared to higher CD4 levels. Multivariable Cox-regression confirmed the negative role of high pre-therapy viremia and low CD4 cell count on VS, but not on VR. Forty-three (5.3 %) patients experienced VF (raltegravir: 30; elvitegravir: 9; dolutegravir: 4). Patients failing dolutegravir did not harbor any resistance mutation either in integrase or reverse transcriptase.

Conclusions: Our findings confirm that patients receiving an INI-based first-line regimen achieve and maintain very high rates of VS in clinical practice.
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http://dx.doi.org/10.1016/j.jcv.2020.104534DOI Listing
September 2020

SARS-CoV-2 infection in persons living with HIV: A single center prospective cohort.

J Med Virol 2021 02 8;93(2):1145-1149. Epub 2020 Oct 8.

Department of Laboratory, Biobanking Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.

Information about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in HIV-infected individuals is scarce. In this prospective study, we included HIV (human immunodefeciency virus)-infected individuals (people living with HIV [PLWHIV]) with confirmed SARS-CoV-2 infection and compared them with PLWHIV negative for SARS-CoV-2. We compared 55 cases of SARS-CoV-2 infection with 69 asymptomatic PLWHIV negative for SARS-CoV-2 reverse transcription-polymerase chain reaction and/or serology. There was no significant difference between SARS-CoV-2 positive or negative patients for age distribution, gender, time with HIV infection, nadir CD4-cell counts, type and number of co-morbidities, current CD4 and CD8 counts and type of anti-HIV therapy. Positive patients presented with a median of three symptoms (interquartile range, 1-3). Most common symptoms were fever (76%), dyspnea (35%), anosmia (29%) non-productive cough (27%), fatigue 22%), and ageusia (20%). Ten patients (18%) were completely asymptomatic. Four (7.2%) subjects died of coronavirus disease 2019. Factors significantly (P < .05) associated with death included age and number of co-morbidities, while time from HIV infection and lower current CD4 counts were significant only in univariate analysis. HIV-infected individuals are not protected from SARS-CoV-2 infection or have a lower risk of severe disease. Indeed, those with low CD4 cell counts might have worse outcomes. Infection is asymptomatic in a large proportion of subjects and this is relevant for epidemiological studies.
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http://dx.doi.org/10.1002/jmv.26352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404443PMC
February 2021

Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials.

Lancet HIV 2020 06;7(6):e389-e400

Department of HIV Clinical Research, Gilead Sciences, Foster City, CA, USA.

Background: In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies.

Methods: We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov, NCT02607930 and NCT02607956.

Findings: 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference -2·6%, 95% CI -8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference -1·9%, -7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (-0·1 vs -0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study.

Interpretation: These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2352-3018(20)30099-0DOI Listing
June 2020

In vitro susceptibility to fostemsavir is not affected by long-term exposure to antiviral therapy in MDR HIV-1-infected patients.

J Antimicrob Chemother 2020 09;75(9):2547-2553

IRCCS San Raffaele Scientific Institute, Milan, Italy.

Objectives: Fostemsavir is the prodrug of the HIV-1 attachment inhibitor temsavir and is currently under clinical assessment in heavily treatment-experienced patients with limited therapeutic options. We evaluated the genotypic and phenotypic susceptibility to temsavir in a panel of samples collected from patients harbouring MDR strains enrolled in the Italian PRESTIGIO Registry.

Methods: Plasma samples from 24 patients were used for HIV-1 gp120 sequencing, while viral tropism and susceptibility to temsavir were assessed through a homemade phenotypic assay with pseudotyped viruses expressing patient-derived Env protein.

Results: Of the 24 patients enrolled, 18 (75%) were male, median (IQR) age was 55 years (52-61), time since HIV-1 diagnosis was 27 years (24-30), time on ART was 26 years (23-27) and 11 (46%) had a previous AIDS diagnosis. Exposure to entry inhibitors (maraviroc and/or enfuvirtide) had occurred in 19 (79%) patients. Among 23/24 gp120 sequences obtained, temsavir resistance-associated mutations (RAMs) were detected in three cases (two M426L and one S375N). Pseudotyped viruses were obtained from 23/24 samples and viral tropism was CXCR4-tropic, CCR5-tropic and dual/mixed-tropic in six, nine and eight cases, respectively. Phenotypic susceptibility to temsavir was comparable to the reference WT viruses NL4-3 and AD8 in all samples, irrespective of RAMs. Viral tropism and exposure to entry inhibitors did not impact temsavir susceptibility.

Conclusions: These data support the use of fostemsavir as a valuable therapy option in patients harbouring MDR virus. The role of laboratory testing in optimal screening of patients eligible for fostemsavir treatment remains to be investigated.
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http://dx.doi.org/10.1093/jac/dkaa178DOI Listing
September 2020

Brief Report: Virologic Response by Baseline Viral Load With Dolutegravir Plus Lamivudine vs Dolutegravir Plus Tenofovir Disoproxil Fumarate/Emtricitabine: Pooled Analysis.

J Acquir Immune Defic Syndr 2020 05;84(1):60-65

ViiV Healthcare, Brentford, United Kingdom.

Background: To investigate antiviral potency of the 2-drug regimen (2DR) dolutegravir plus lamivudine vs the 3-drug regimen (3DR) dolutegravir plus tenofovir disoproxil fumarate/emtricitabine, we performed a post-hoc analysis assessing antiviral response rates in the phase III GEMINI-1 and GEMINI-2 studies by baseline viral load (VL).

Setting: One hundred ninety-two centers in 21 countries.

Methods: Treatment-naive HIV-1-infected participants with screening VL ≤500,000 copies/mL were randomized 1:1 to once-daily dolutegravir plus lamivudine or dolutegravir plus tenofovir disoproxil fumarate/emtricitabine. Median change from baseline was determined for log10-transformed VL in the overall study population and the subpopulation with baseline VL >100,000 copies/mL. Proportion of participants achieving plasma VL <50 copies/mL (Snapshot algorithm) or <40 copies/mL (Abbott RealTime HIV-1 assay) and target not detected was assessed through week 48 by baseline VL. Time to viral suppression was determined (nonparametric Kaplan-Meier method).

Results: For 293 participants with baseline VL >100,000 copies/mL, median change from baseline at week 4 was -3.38 and -3.40 log10 copies/mL in the 2DR and 3DR groups, respectively; reduction was sustained throughout 48 weeks. Time to VL <50 copies/mL was longer in participants with baseline VL >100,000 copies/mL than the overall study population (57 [week 8] vs 29 days [week 4]) and similar between the 2DR and 3DR groups. Proportion of participants with VL <50 or <40 copies/mL and target not detected was similar between groups, irrespective of baseline VL, at all tested visits throughout 48 weeks.

Conclusion: Dolutegravir plus lamivudine demonstrates high antiviral potency in treatment-naive HIV-1-infected individuals across baseline VL strata.
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http://dx.doi.org/10.1097/QAI.0000000000002302DOI Listing
May 2020

Virological response and retention in care according to time of starting ART in Italy: data from the Icona Foundation Study cohort.

J Antimicrob Chemother 2020 03;75(3):681-689

HIV/AIDS Clinical Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.

Objectives: To describe: (i) factors associated with rapid and delayed ART initiation; (ii) rates of 12 week virological response; and (iii) virologically controlled retention in care by 1 year from ART initiation according to timing of start in a real-life setting.

Methods: All individuals in the Icona cohort diagnosed with HIV in 2016-17 who initiated ART were grouped according to the time between HIV diagnosis and ART initiation: Group 1, ≤7 days; Group 2, 8-14 days; Group 3, 15-30 days; Group 4, 31-120 days; and Group 5, >120 days. Multivariable logistic regression models were used to identify factors associated with: (i) the probability of rapid (Group 1) and very delayed (Group 5) ART initiation; (ii) the 12 week virological response (by a modified snapshot algorithm); and (iii) the probability of retention in care at 1 year (on ART with HIV-RNA <50 copies/mL).

Results: A total of 1247 individuals were included [82 (6.6%) in Group 1, 115 (9.2%) in Group 2, 267 (21.4%) in Group 3, 641 (51.4%) in Group 4 and 142 (11.4%) in Group 5]. Main predictors of rapid ART start (Group 1) were low CD4 cell count and high HIV-RNA at first contact with the infectious diseases centre. There was no association between probability of virological response and timing of ART initiation. Overall, 90% of individuals remained on ART after 1 year, 91% with undetectable HIV-RNA. Participants of Italian nationality, those with higher CD4 cell count and lower HIV-RNA at ART initiation were more likely to be retained in care after 1 year.

Conclusions: In our high-income observational setting, we did not observe differences in the 1 year rate of virological response and retention in care according to timing of ART initiation.
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http://dx.doi.org/10.1093/jac/dkz512DOI Listing
March 2020

Renal safety in 3264 HCV patients treated with DAA-based regimens: Results from a large Italian real-life study.

Dig Liver Dis 2020 02 6;52(2):190-198. Epub 2019 Dec 6.

ASST Papa Giovanni XXIII, Bergamo HCV Network, Bergamo, Italy.

Background: Sofosbuvir (SOF)-based regimens have been associated with renal function worsening in HCV patients with estimated glomerular filtration rate (eGFR) ≤ 45 ml/min, but further investigations are lacking.

Aim: To assess renal safety in a large cohort of DAA-treated HCV patients with any chronic kidney disease (CKD).

Methods: All HCV patients treated with DAA in Lombardy (December 2014-November 2017) with available kidney function tests during and off-treatment were included.

Results: Among 3264 patients [65% males, 67% cirrhotics, eGFR 88 (9-264) ml/min], CKD stage was 3 in 9.5% and 4/5 in 0.7%. 79% and 73% patients received SOF and RBV, respectively. During DAA, eGFR declined in CKD-1 (p < 0.0001) and CKD-2 (p = 0.0002) patients, with corresponding rates of CKD stage reduction of 25% and 8%. Conversely, eGFR improved in lower CKD stages (p < 0.0001 in CKD-3a, p = 0.0007 in CKD-3b, p = 0.024 in CKD-4/5), with 33-45% rates of CKD improvement. Changes in eGFR and CKD distribution persisted at SVR. Baseline independent predictors of CKD worsening at EOT and SVR were age (p < 0.0001), higher baseline CKD stages (p < 0.0001) and AH (p = 0.010 and p < 0.0001, respectively).

Conclusions: During DAA, eGFR significantly declined in patients with preserved renal function and improved in those with lower CKD stages, without reverting upon drug discontinuation.
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http://dx.doi.org/10.1016/j.dld.2019.11.006DOI Listing
February 2020

No impact of previous NRTIs resistance in HIV positive patients switched to DTG+2NRTIs under virological control: Time of viral suppression makes the difference.

Antiviral Res 2019 12 17;172:104635. Epub 2019 Oct 17.

III Infectious Disease Unit, ASST-FBF-Sacco, Milan, Italy; Department of Biomedical and Clinical Sciences DIBIC L. Sacco, University of Milan, Milan, Italy.

The accumulation of drug-resistance mutations on combined antiretroviral regimens (ART) backbone could affect the virological efficacy of the regimen. Our aim was to assess the impact of previous drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) on the probability of virological failure (VF) in patients, under virological control, who switched to dolutegravir (DTG)+2NRTIs regimens. All HIV-1 positive drug-experienced patients who started a regimen composed by DTG+2NRTIs [abacavir/lamivudine or tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)/emtricitabine (FTC)] in the ARCA collaborative group with HIV-RNA <50 cp/mL were included in the analysis. Patients with a previous VF to integrase inhibitors were excluded. The impact of single and combined NRTIs mutations on the probability of VF (defined as 2 consecutive HIV-RNA >50 copies/mL or one HIV-RNA >1000 copies/mL) was assessed by Kaplan Meier curves. A multivariable Cox regression analysis was constructed to assess factors potentially related to VF. Five hundred and eighty-eight patients were included in the analysis with a median time of viral suppression before the switch of 37 months (IQR 12-78), of whom 148 (25.2%) had at least one previous NRTIs resistance mutation. In the multivariable model no association was observed between NRTIs mutations and VF. Conversely, the duration of viral suppression before switch resulted associated with a lower risk of VF (for 1 month increase, adjusted Hazard Ratio 0.98, 95%CI 0.96-0.99; p=0.024). Previous NRTIs mutations appeared to have no impact on the risk of VF in patients switched to DTG+2NRTIs, whereas a longer interval on a controlled viremia decreased significantly the risk of VF.
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http://dx.doi.org/10.1016/j.antiviral.2019.104635DOI Listing
December 2019

Impact of NRTI resistance mutations on virological effectiveness of antiretroviral regimens containing elvitegravir: a multi-cohort study.

J Antimicrob Chemother 2020 01;75(1):194-199

Infectious Diseases, IRCCS San Raffaele, Via Olgettina 60, 20132, Milan, Italy.

Background: Antiretroviral drug resistance mutations remain a major cause of treatment failure.

Objectives: To evaluate the impact of NRTI resistance mutations on virological effectiveness of elvitegravir-containing regimens.

Materials And Methods: We selected treatment-experienced HIV-1-infected patients starting elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), with at least one protease/reverse transcriptase genotype available before switching and at least one HIV-1 RNA viral load (VL) measurement during follow-up. The primary endpoint was virological failure (VF), defined as one VL value of ≥1000 copies/mL or two consecutive VL values of >50 copies/mL.

Results: We included 264 ART regimens: 75.6% male, median (IQR) age 47 years (39-53), 7 years (3-16) of HIV infection, nadir CD4+ 247 cells/mm3 (105-361), 81.5% with VL ≤50 copies/mL and 11.7% with at least one NRTI mutation at baseline. Eleven (5.2%) VFs occurred in virologically suppressed patients versus eight (15.1%) in viraemic patients. The estimated probability of VF at 48 weeks with versus without any NRTI mutation was 7.4% (95% CI 2.3-12.5) versus 3.8% (2.1-5.5) in virologically suppressed patients and 66.7% (39.5-93.9) versus 11.2% (6.5-15.9) (P<0.001) in viraemic patients. The only predictor of VF was time on therapy (per 1 year more, adjusted HR 1.14, 95% CI 1.02-1.27, P=0.024) in viraemic patients.

Conclusions: A switch to E/C/F/TDF or E/C/F/TAF is safe for virologically suppressed patients without documented NRTI resistance, but not recommended in viraemic patients with a history of NRTI resistance. Although we did not detect a detrimental effect of past NRTI resistance in virologically suppressed patients, a fully active regimen remains preferred in this setting due to possible rebound of drug-resistant virus in the long term.
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http://dx.doi.org/10.1093/jac/dkz424DOI Listing
January 2020

Lipid profile changings after switching from rilpivirine/tenofovir disoproxil fumarate/emtricitabine to rilpivirine/tenofovir alafenamide/emtricitabine: Different effects in patients with or without baseline hypercholesterolemia.

PLoS One 2019 11;14(10):e0223181. Epub 2019 Oct 11.

Infectious Disease Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.

Tenofovir alafenamide (TAF) has similar efficacy compared to tenofovir disoproxil fumarate (TDF), but a less favorable effect on lipids. Aim of this retrospective multicentre study was to evaluate the impact on lipids of switching from rilpivirine (RPV)/ emtricitabine (FTC)/TDF to RPV/FTC/TAF in a cohort of HIV-1 infected patients. Total cholesterol (TC), high density lipoproteins (HDL) and low density lipoproteins (LDL) were compared at the moment of the switch and at the first following evaluation, by using paired t-test. Overall, 573 patients were considered, 99% with HIV-RNA <50 copies/ml, with mean age of 49.7 (±0.4) years and median 13.4 (6.9-22.5) years of HIV infection. In the study population with available data (431/573, 75%), mean TC changed from 173 ±1.7 to 188 ±1.8 mg/dl; mean HDL from 46 ±0.7 to 51± 0.7 mg/dl; mean LDL from 111 ±1.5 to 120 ±1.8 mg/dl (p<0.0001 for all). Neither LDL/HDL nor TC/HDL ratio changed significantly, with LDL/HDL from 2.6 ±0.5 to 2.5 ±0.5 (p = 0.12) and TC/HDL from 4.0 ±0.6 to 3.9 ±0.6 (p = 0.11). In patients with baseline diagnosis of hypercholesterolemia (TC>200 mg/dl, N = 87), there was no significant change in TC (224 ±2.2 to 228 ±3.4 mg/dl, p = 0.286) or LDL (150±2.5 to 151±3.2 mg/dl, p = 0.751), while HDL increased from 51 ±1.6 to 55 ±1.7 mg/dl (p<0.0001) and both LDL/HDL and TC/HDL ratio decreased significantly, from 3.2±0.1 to 3.0 ±0.1 (p = 0.025) and from 4.7±0.1 to 4.4 ±0.1 (p = 0.004). In this real life study, a slight increase in lipids was found after switching from RPV/FTC/TDF to RPV/FTC/TAF, but these results were not confirmed in people with hypercholesterolemia, in which lipids did not change and LDL/HDL and TC/HDL ratio decreased.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223181PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788691PMC
March 2020

Bone mineral density in virologically suppressed people aged 60 years or older with HIV-1 switching from a regimen containing tenofovir disoproxil fumarate to an elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide single-tablet regimen: a multicentre, open-label, phase 3b, randomised trial.

Lancet HIV 2019 10;6(10):e655-e666

Gilead Sciences, Foster City, CA, USA. Electronic address:

Background: Tenofovir alafenamide is associated with less renal and bone toxicity than tenofovir disoproxil fumarate and might improve the long-term safety of antiretroviral therapy. We aimed to investigate the effect on bone mineral density of switching from a regimen containing tenofovir disoproxil fumarate to one containing tenofovir alafenamide in participants aged 60 years and older.

Methods: We did a prospective, open-label, multicentre, randomised trial in 36 European centres. Participants were virologically suppressed (HIV-1 RNA <50 copies per mL), aged 60 years or older, on a tenofovir disoproxil fumarate-containing regimen and were randomly assigned (2:1) via an interactive web-response system to open-label elvitegravir (150 mg), cobicistat (150 mg), emtricitabine (200 mg), and tenofovir alafenamide (10 mg) daily or continued therapy containing tenofovir disoproxil fumarate (300 mg). Participants were stratified by spine and hip bone mineral density categories. Primary endpoints were change from baseline to week 48 in spine and hip bone mineral density with a null hypothesis of zero between-group difference tested at a significance level of 0·05. This study was registered with ClinicalTrials.gov, NCT02616783.

Findings: Between Dec 22, 2015, and March 21, 2018, 167 participants were randomly assigned to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (n=111 [66%]) or tenofovir disoproxil fumarate (n=56 [34%]). One participant in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group did not receive treatment and was excluded from all analyses. At week 48, the mean percentage change in spine bone mineral density was 2·24% (SD 3·27) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and -0·10% (3·39) in the tenofovir disoproxil fumarate group (between-group difference 2·43% [95% CI 1·34-3·52]; p<0·0001), and mean percentage change in hip bone mineral density was 1·33% (2·20) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and -0·73% (3·21) in the tenofovir disoproxil fumarate group (difference 2·04% [1·17-2·90]; p<0·0001). The most common adverse events were nasopharyngitis (12 [11%]), back pain (nine [8%]), and diarrhoea (eight [7%]) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group; and bronchitis (six [11%]), vitamin D deficiency (four [7%]), and arthralgia (four [7%]) in the tenofovir disoproxil fumarate group. 22 (20%) participants in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and one (2%) participant in the tenofovir disoproxil fumarate group had an adverse event that was considered to be related to treatment. No treatment-related serious adverse events were observed. The proportions of adverse events leading to premature treatment discontinuation were similar between groups (four [4%] in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group; and one (2%) in the tenofovir disoproxil fumarate group).

Interpretation: The significantly improved bone mineral density, overall safety, and efficacy data show the feasibility of switching from a regimen containing tenofovir disoproxil fumarate to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed people living with HIV aged 60 years or older.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2352-3018(19)30195-XDOI Listing
October 2019

A prospective randomized trial on abacavir/lamivudine plus darunavir/ritonavir or raltegravir in HIV-positive drug-naïve patients with CD4<200 cells/uL (the PRADAR study).

PLoS One 2019 27;14(9):e0222650. Epub 2019 Sep 27.

Department of Infectious Diseases, Bergamo Hospital, Bergamo, Italy.

Background: Very few data are available on treatment in HIV Late presenter population that still represents a clinical challenge.

Methods: Prospective, multicenter, randomized open-label, 2 arm, phase-3 trial comparing the 48-week virological response of two different regimens: abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir in antiretroviral naive with CD4+ counts < 200/mm3 and a viral load (VL)<500,000 copies/mL. The primary Endpoint was the proportion of patients with undetectable viremia (VL<50 copies/mL) after 48 weeks. The planned sample size for this trial was 350 patients.

Results: In 3 years, 53 patients were screened and 46 enrolled: 22 randomized to raltegravir and 24 to darunavir/r; 7 patients were excluded, 4 because of a VL >500,000 copies/mL and 3 for HLAB5701 positivity. The snapshot analysis at 48 weeks showed a virologic success of 77.3% in raltegravir and 66.7% in darunavir/r. Time to starting treatment was 34.5 days in raltegravir and 53 days in darunavir/r. At the as treated analysis, the median CD4 counts at 48 weeks was 297 cells/μL in raltegravir and 239 cells/μL in darunavir/r. No difference in total cholesterol, while triglycerides were higher in the darunavir/r arm. No statistical analyses were performed due to the low number of patients enrolled.

Conclusions: Late presenter patients are frequent but very difficult to enroll in clinical trials, especially in western countries. These regimens and the conditions of many patients could not allow the test and treat strategy. The rate of virologic success was higher than 65% in both arms with a median CD4 cell count >200/μL at week 48.

Trial Registration: EUDRACT number: 2011-005973-21.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222650PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764686PMC
March 2020

Real-life effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients with previous DAA failure.

J Hepatol 2019 12 6;71(6):1106-1115. Epub 2019 Aug 6.

Bergamo HCV Network, ASST Papa Giovanni XXIII, Italy.

Background & Aims: Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting.

Methods: All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment.

Results: A total of 179 patients were included: median age 57 (18-88) years, 74% males, median HCV-RNA 1,081,817 (482-25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%).

Conclusions: SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting.

Lay Summary: This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure.
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http://dx.doi.org/10.1016/j.jhep.2019.07.020DOI Listing
December 2019

Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial.

Lancet HIV 2019 06 5;6(6):e364-e372. Epub 2019 May 5.

Department of HIV Clinical Research, Gilead Sciences, Inc, Foster City, CA, USA.

Background: The single-tablet regimen consisting of bictegravir, emtricitabine, and tenofovir alafenamide is recommended for treatment of HIV-1 infection on the basis of data from 48 weeks of treatment. Here, we examine the longer-term efficacy, safety, and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with dolutegravir plus co-formulated emtricitabine and tenofovir alafenamide at week 96.

Methods: This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 126 outpatient centres in ten countries. We enrolled treatment-naive adults (aged ≥18 years) with HIV-1 infection who had an estimated glomerular filtration rate of at least 30 mL/min and sensitivity to emtricitabine and tenofovir. People with chronic hepatitis B or C infection, or both, and those who had used antivirals previously for prophylaxis were allowed. We randomly assigned participants (1:1) to receive treatment with either co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or dolutegravir 50 mg with co-formulated emtricitabine 200 mg and tenofovir alafenamide 25 mg (the dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. This study was registered with ClinicalTrials.gov, number NCT02607956.

Findings: Between Nov 13, 2015, and July 14, 2016, we screened 742 individuals, of whom 657 were enrolled. 327 participants were assigned to the bictegravir group and 330 to the dolutegravir group. Of these, 320 in the bictegravir group and 325 in the dolutegravir group received at least one dose of study drug. At week 96, HIV-1 RNA less than 50 copies per mL was achieved by 269 (84%) of 320 participants in the bictegravir group and 281 (86%) of 325 in the dolutegravir group (difference -2·3%, 95% CI -7·9 to 3·2), demonstrating non-inferiority of the bictegravir regimen compared with the dolutegravir regimen. Both treatments continued to be well tolerated through 96 weeks; 283 (88%) of 320 participants in the bictegravir group and 288 (89%) of 325 in the dolutegravir group had any adverse event and 55 (17%), and 33 (10%) had any serious adverse event. The most common adverse events were diarrhoea (57 [18%] of 320 in the bictegravir group vs 51 [16%] of 325 in the dolutegravir group) and headache (51 [16%] of 320 vs 48 [15%] of 325). Deaths were reported for three (1%) individuals in each group (one cardiac arrest, one gastric adenocarcinoma, and one hypertensive heart disease and congestive cardiac failure in the bictegravir group and one unknown causes, one pulmonary embolism, and one lymphoma in the dolutegravir group); none were considered to be treatment related. Adverse events led to discontinuation in six (2%) participants in the bictegravir group and five (2%) in the dolutegravir group; one of these events in the bictegravir group versus four in the dolutegravir group occurred between weeks 48 and 96. Study drug-related adverse events were reported for 64 (20%) participants in the bictegravir group and 92 (28%) in the dolutegravir group.

Interpretation: These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with chronic HIV.

Funding: Gilead Sciences, Inc.
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http://dx.doi.org/10.1016/S2352-3018(19)30080-3DOI Listing
June 2019

Prevalence of predicted resistance to doravirine in HIV-1-positive patients after exposure to non-nucleoside reverse transcriptase inhibitors.

Int J Antimicrob Agents 2019 Apr 12;53(4):515-519. Epub 2019 Feb 12.

Clinical Department, Istituto Nazionale per le Malattie Infettive 'Lazzaro Spallanzani', IRCCS, Rome, Italy.

This study investigated the prevalence of doravirine (DOR) resistance mutations in non-nucleoside reverse transcriptase inhibitor (NNRTI)-experienced patients. DOR resistance was assessed in samples from NNRTI-experienced patients who underwent genotypic testing for virological failure from the Antiretroviral Response Cohort Analysis (ARCA) database. Intermediate DOR resistance was defined as detection of any of V106A/M, Y188C/H, V108I, and K103N+P225H. High-level DOR resistance was defined as detection of any of Y188L, M230L, G190E, V106A/M+F227L, and V106A/M+L234I. Overall, 6893 patients were included in the study: 64.2% had experienced efavirenz (EFV), 54.4% nevirapine (NVP), 6.8% etravirine (ETR), 7.7% rilpivirine (RPV) and 0.7% delavirdine. Among NNRTI-experienced patients, 12.7% and 6.1% of subjects had intermediate and high-level DOR resistance, respectively. The most common DOR resistance mutation was Y188L. In multivariable analysis, previous EFV use (OR = 1.52, 95% CI 1.15-2.02) and ETR use (OR = 1.91, 95% CI 1.34-2.73) were associated with detection of high-level DOR resistance, whilst RPV use was associated with a lower probability of high-level DOR resistance (OR = 0.39, 95% CI 0.22-0.71). Moreover, EFV use (OR = 1.76, 95% CI 1.19-2.58) and ETR use (OR = 1.72, 95% CI 1.10-2.68) were associated with detection of the Y188L mutation, whereas RPV use was not (OR = 0.16, 95% CI 0.05-0.50). In Italy, DOR resistance is uncommon among NNRTI-experienced patients, confirming a distinguishing resistance pattern within NNRTIs. However, previous EFV and ETR experience poses a higher risk of DOR resistance. These results support the use of DOR in NNRTI-experienced patients.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.02.007DOI Listing
April 2019

Effectiveness of dolutegravir-based regimens as either first-line or switch antiretroviral therapy: data from the Icona cohort.

J Int AIDS Soc 2019 01;22(1):e25227

Clinic of Infectious and Tropical Diseases, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy.

Introduction: Concerns about dolutegravir (DTG) tolerability in the real-life setting have recently arisen. We aimed to estimate the risk of treatment discontinuation and virological failure of DTG-based regimens from a large cohort of HIV-infected individuals.

Methods: We performed a multicentre, observational study including all antiretroviral therapy (ART)-naïve and virologically suppressed treatment-experienced (TE) patients from the Icona (Italian Cohort Naïve Antiretrovirals) cohort who started, for the first time, a DTG-based regimen from January 2015 to December 2017. We estimated the cumulative risk of DTG discontinuation regardless of the reason and for toxicity, and of virological failure using Kaplan-Meier curves. We used Cox regression model to investigate predictors of DTG discontinuation.

Results: About 1679 individuals (932 ART-naïve, 747 TE) were included. The one- and two-year probabilities (95% CI) of DTG discontinuation were 6.7% (4.9 to 8.4) and 11.5% (8.7 to 14.3) for ART-naïve and 6.6% (4.6 to 8.6) and 7.6% (5.4 to 9.8) for TE subjects. In both ART-naïve and TE patients, discontinuations of DTG were mainly driven by toxicity with an estimated risk (95% CI) of 4.0% (2.6 to 5.4) and 2.5% (1.3 to 3.6) by one year and 5.6% (3.8 to 7.5) and 4.0% (2.4 to 5.6) by two years respectively. Neuropsychiatric events were the main reason for stopping DTG in both ART-naïve (2.1%) and TE (1.7%) patients. In ART-naïve, a concomitant AIDS diagnosis predicted the risk of discontinuing DTG for any reason (adjusted relative hazard (aRH) = 3.38, p = 0.001), whereas starting DTG in combination with abacavir (ABC) was associated with a higher risk of discontinuing because of toxicity (aRH = 3.30, p = 0.009). TE patients starting a DTG-based dual therapy compared to a triple therapy had a lower risk of discontinuation for any reason (adjusted hazard ratio (aHR) = 2.50, p = 0.037 for ABC-based triple-therapies, aHR = 3.56, p = 0.012 for tenofovir-based) and for toxicity (aHR = 5.26, p = 0.030 for ABC-based, aHR = 6.60, p = 0.024 for tenofovir-based). The one- and two-year probabilities (95% CI) of virological failure were 1.2% (0.3 to 2.0) and 4.6% (2.7 to 6.5) in the ART naïve group and 2.2% (1.0 to 3.3) and 2.9% (1.5 to 4.3) in the TE group.

Conclusions: In this large cohort, DTG showed excellent efficacy and optimal tolerability both as first-line and switching ART. The low risk of treatment-limiting toxicities in ART-naïve as well as in treated individuals reassures on the use of DTG in everyday clinical practice.
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http://dx.doi.org/10.1002/jia2.25227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340053PMC
January 2019

Real-world effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C.

J Hepatol 2019 03 23;70(3):379-387. Epub 2018 Nov 23.

Bergamo HCV Network, ASST Papa Giovanni XXIII, Italy.

Background And Aims: The efficacy and safety of glecaprevir/pibrentasvir (G/P) for patients infected with hepatitis C virus (HCV) have only been investigated in clinical trials, with no real-world data currently available. The aim of our study was to investigate the effectiveness and safety of G/P in a real-world setting.

Methods: All patients with HCV consecutively starting G/P between October 2017 and January 2018 within the NAVIGATORE-Lombardia Network were analyzed. G/P was administered according to drug label (8, 12 or 16 weeks). Fibrosis was staged either histologically or by liver stiffness measurement. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks after the end of treatment.

Results: A total of 723 patients (50% males) were treated with G/P, 89% for 8 weeks. The median age of our cohort was 58 years, with a median body mass index of 23.9 kg/m, and median liver stiffness measurement of 6.1 kPa; 84% were F0-2 and 16% were interferon-experienced. Median HCV-RNA was 1,102,600 IU/ml, and 49% of patients had HCV genotype 1 (32% 1b), 28% genotype 2, 10% genotype 3 and 13% genotype 4. The median estimated glomerular filtration rate was 90.2 ml/min, platelet count 209x10/mm and albumin 4.3 g/dl. The SVR rates were 94% in intention-to-treat and 99.3% in per protocol analysis (8-week vs. 12 or 16-week: 99.2% vs. 100%). Five patients failed therapy because of post-treatment relapse; a post-treatment NS5A resistance-associated substitution was detected in 1 case. SVR rates were lower in males (p = 0.002) and in HCV genotype-3 (p = 0.046) patients treated for 8 weeks, but independent of treatment duration, fibrosis stage, baseline HCV-RNA, HIV co-infection, chronic kidney disease stage and viral kinetics. Mild adverse events were reported in 8.3% of the patients, and 0.7% of them prematurely withdrew treatment. Three patients died of drug-unrelated causes.

Conclusions: In a large real-world cohort of Italian patients, we confirmed the excellent effectiveness and safety of G/P administered for 8, 12 or 16 weeks.

Lay Summary: A large number of patients with hepatitis C virus have been treated with glecaprevir/pibrentasvir (G/P) within the NAVIGATORE-Lombardia Network, in Italy. This is the first real-world study evaluating effectiveness and safety of G/P in patients with hepatitis C virus treated according to international recommendations. This study demonstrated excellent effectiveness (with sustained virological response rates of 99.3%) and safety profiles.
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http://dx.doi.org/10.1016/j.jhep.2018.11.011DOI Listing
March 2019

Impact of the M184V Resistance Mutation on Virological Efficacy and Durability of Lamivudine-Based Dual Antiretroviral Regimens as Maintenance Therapy in Individuals With Suppressed HIV-1 RNA: A Cohort Study.

Open Forum Infect Dis 2018 Jun 15;5(6):ofy113. Epub 2018 May 15.

Infectious Diseases Unit, AOU Senese, Siena, Italy.

Background: Dual therapy (DT) with boosted protease inhibitors (bPIs) plus lamivudine has been shown to be superior to bPI monotherapy in virologically suppressed patients despite previous selection of the lamivudine resistance M184V mutation. We compared the virological efficacy of lamivudine-based DT in patients with and without a history of M184V detection.

Methods: We retrospectively analyzed patients with HIV-RNA ≤50 copies/mL switching to DT with at least 1 previous resistance genotype in the ARCA database. Time to virological failure (VF; HIV-RNA ≥200 copies/mL or 2 consecutive HIV-RNA >50 copies/mL) and to treatment discontinuation (TD) was analyzed by survival analysis.

Results: Four hundred thirty-six patients switching to lamivudine plus bPIs (70%) or integrase inhibitors (30%) were included. Patients with M184V (n = 87) were older, had lower nadir CD4+ cell count, longer duration of antiretroviral therapy and of virologic suppression, and higher rate of hepatitis C virus infection compared with patients without M184V. The 3-year probability of remaining free from VF was 91.9% (95% confidence interval [CI], 86.6-97.2) without M184V and 87.8% (95% CI, 78.4-97.2) with M184V ( = .323). The time to TD did not differ between groups. Multivariate analysis adjusting for baseline variables differing between groups also did not detect M184V as being associated with VF or TD; however, the 3-year probability of remaining free of viral blips (isolated HIV-RNA 51-199 copies/mL) was 79.8% (95% CI, 67.8%-91.8%) with M184V vs 90.1% (95% CI, 84.0%-96.2%) without M184V ( = .016).

Conclusions: Previous selection of M184V did not increase the risk of VF or TD with lamivudine-based DT but was associated with a higher probability of viral blips.
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http://dx.doi.org/10.1093/ofid/ofy113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016422PMC
June 2018

Patient-Reported Symptoms Over 48 Weeks Among Participants in Randomized, Double-Blind, Phase III Non-inferiority Trials of Adults with HIV on Co-formulated Bictegravir, Emtricitabine, and Tenofovir Alafenamide versus Co-formulated Abacavir, Dolutegravir, and Lamivudine.

Patient 2018 10;11(5):561-573

Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA, 94404, USA.

Background: Integrase strand transfer inhibitors (INSTIs) are recommended for first-line antiretroviral therapy in combination with two nucleos(t)ide reverse transcriptase inhibitors. Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF), a novel, INSTI-based regimen, is currently approved in the US and EU for the treatment of HIV-1 infection and recommended as first-line treatment in current guidelines. In our current analysis, we aimed to determine changes in patient-reported symptoms over time among HIV-1-infected adults who initiated or switched to B/F/TAF versus another INSTI-based regimen, co-formulated abacavir, dolutegravir, and lamivudine (ABC/DTG/3TC).

Methods: A planned secondary analysis of patient-reported outcomes was conducted for two double-blind, randomized, phase III studies in HIV-1-infected adults comparing B/F/TAF with ABC/DTG/3TC: one in treatment-naïve individuals (GS-US-380-1489, ClinicalTrials.gov NCT02607930) and the other in virologically suppressed participants (GS-US-380-1844, ClinicalTrials.gov NCT02603120). In both studies, the HIV symptoms distress module (HIV-SI) was administered at baseline (BL) and weeks 4, 12, and 48. Responses to each of the 20 items were dichotomized as bothersome or not bothersome. Treatment differences were assessed using unadjusted and adjusted logistic regression models (adjusted for BL HIV-SI count, age, sex, BL Veterans Aging Cohort Study [VACS] Index, medical history of serious mental illness, BL Short Form [SF]-36 Physical Component Summary [PCS], BL SF-36 Mental Component Summary [MCS], and, for virologically suppressed participants only, years since HIV diagnosis). We conducted longitudinal modeling of bothersome symptoms using a generalized mixed model including treatment, time, time-by-treatment, and additional covariates from the adjusted logistic regression model as described above. The Pittsburgh Sleep Quality Index (PSQI) was administered at the same frequency as the HIV-SI, and the total score was dichotomized as good or poor sleep quality. Similar models to those used for HIV-SI were applied, using BL sleep quality and BL SF-36 MCS as covariates. Statistical significance was assessed using p < 0.05.

Results: Across both studies, bothersome symptoms were reported by fewer participants on B/F/TAF than those on ABC/DTG/3TC. In treatment-naïve adults, fatigue/loss of energy, nausea/vomiting, dizzy/lightheadedness, and difficulty sleeping were reported significantly less with B/F/TAF at two or more time points. Fatigue and nausea were also significantly less common for those receiving B/F/TAF in longitudinal models. In virologically suppressed participants, nausea/vomiting, sad/down/depressed, nervous/anxious, and poor sleep quality (from the PSQI) were reported significantly less with B/F/TAF at two or more time points, as well as in longitudinal models.

Conclusions: B/F/TAF was associated with lower prevalence of bothersome symptoms than ABC/DTG/3TC in both treatment-naïve and virologically suppressed adults.
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http://dx.doi.org/10.1007/s40271-018-0322-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132439PMC
October 2018

Biochemical and inflammatory modifications after switching to dual antiretroviral therapy in HIV-infected patients in Italy: a multicenter retrospective cohort study from 2007 to 2015.

BMC Infect Dis 2018 06 25;18(1):285. Epub 2018 Jun 25.

Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Background: Triple-drug regimens are the gold standard for HIV therapy. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) reducing regimens are used to decrease drugs toxicity, exposure and costs. Aim of our study was to evaluate trends of biochemical and inflammatory indices in patients switching to dual therapy (DT).

Methods: We included patients that a) switched to a DT from 2007 to 2015 from a tenofovir/abacavir-based triple regimen b) previously maintained a triple and c) subsequently a dual regimen for 12 months with virological suppression. We retrieved data measured at 5 points (at the switch, 6 and 12 months before and after switch). We used platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and CD4/CD8 ratio as inflammatory indices. We assessed temporal trends of viro-immunological, biochemical and inflammatory parameters.

Results: Overall, 364 and 65 patients switched from a tenofovir- and an abacavir-triple regimen, respectively. In the tenofovir-reducing group, creatinine clearance and lipids raised after the switch. There was a significant increase in both CD4+ cells and CD4/CD8. CD8+ cells rose after the switch, while opposite trend was found for PLR. In the abacavir-reducing group total lipids showed a decrease during the first 6 months after the switch and then stabilized. An increase of CD4+ and a decrease of CD8+ cells was observed during the study period, although not statistically significant. While CD4/CD8 remained stable after simplification, PLR decreased significantly after 6 months, then returning to baseline. CD8+ cells increased in the tenofovir-reducing group despite a viro-immunological response. Intriguingly, PLR decreased, maintaining this trend for 12 and 6 months after tenofovir and abacavir interruption respectively.

Conclusions: Increased PLR has been linked to hypercholesterolemia and metabolic-syndrome, while high CD8+ cells count to increased risk of non-AIDS-related events regardless of CD4 T-cell recovery and to virological failure. Whether these findings may have clinical implications, and which role DT plays on the immune system and on inflammation should be further investigated.
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http://dx.doi.org/10.1186/s12879-018-3198-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020212PMC
June 2018

A Comprehensive Development Agenda on Tenofovir Alafenamide in Clinical Practice.

AIDS Rev 2018 Apr-Jun;20(2):75-82

Division of Infectious Diseases, ASST Papa Giovanni XXIII, Bergamo, Italy.

The introduction of tenofovir (TFV) alafenamide (TAF) into clinical practice will be a further revolution in antiretroviral therapy. Currently available HIV-1 regimens are wide enough to allow diversified usage in different settings. Despite the fact that TAF is not capillary accessible, even in industrialized countries, ultimate International Guidelines have already included TAF in backbone or in single-tablet regimens. Due to a better safety profile, TAF will progressively replace TFV disoproxil fumarate, both in naïve and experienced patients. However, therapeutic innovations have to deal with budget constraints and different global spending-review patterns. The aim of this article is to give a comprehensive agenda of TAF use in naïve and experienced HIV-1 infected patients, providing a full review of the studies present in the literature and contextualizing these findings into daily clinical practice.
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http://dx.doi.org/10.24875/AIDSRev.M18000017DOI Listing
October 2018

Post-treatment controllers after treatment interruption in chronically HIV-infected patients.

AIDS 2018 03;32(5):623-628

Virology Laboratory, ASST PG-23, Bergamo, Italy.

Objective: Control HIV replication requires continuous combined antiretroviral therapy (cART) as discontinuation of cART results in a rapid viral rebound. However, a few individuals exist who took cART for several years and did not show the expected viral rebound after treatment cessation. Most post-treatment controllers (PTCs) are early treated individuals. We report three cases who started cART during chronic infection.

Design: Patients were treated and monitored according to Italian guidelines. For the description of cases, the percentage of CD8CD38HLA*DR cells, CD8CD38HLA*DR cells, major histocompatibility complex genotyping, total HIV-DNA and plasma levels of anti-retroviral (ARV) drugs were performed.

Results: Patients started therapy during chronic infection. Patient 26636 started her first ARV drug two years after diagnosis and patients 93016 and 50293 started cART with high viral loads and low CD4 cell counts. Time without cART was 13, 11 and 1.5 years, respectively. None presented any of the protective class I HLA alleles and patient 93016 has the HLA-B*35 allele that appears to be enriched in PTCs. Patients 93016 and 50293 had very low levels of CD8CD38HLA*DR cells (<5%) much lower than those of patient 26636 (27%). T-cell-associated HIV-DNA was 3.78, 3.48 and 3.13 log copies/10 CD4, respectively.

Conclusion: Patients like ours may advance our understanding of the characteristics for which individuals may be more likely to achieve ART-free remissions. Furthermore, our patients are among the few so far described who started cART during chronic infection extending the hope that a functional cure is possible even in this setting.
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http://dx.doi.org/10.1097/QAD.0000000000001743DOI Listing
March 2018

Active HCV Replication but Not HCV or CMV Seropositive Status Is Associated With Incident and Prevalent Type 2 Diabetes in Persons Living With HIV.

J Acquir Immune Defic Syndr 2017 08;75(4):465-471

*Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena;†UOC Malattie Infettive Universitarie ed Epatologia, Dipartimento di Medicina Interna e Specialistica, Azienda Ospedaliera Universitaria Senese, Siena, Italy;‡National Institute for Infectious Diseases "L Spallanzani, Roma, Italy;§Division of Infectious Diseases, Hospital San Raffaele, Milan, Italy;‖Division of Infectious Diseases, Niguarda Hospital, Milan, Italy;¶Department of Infectious Diseases, University of Brescia, Brescia, Italy;#Division of Infectious Diseases, AO Giovanni XXIII, Bergamo, Italy;**Division of Infectious Diseases, University La Sapienza, Polo Pontino, Latina, Italy;††INMI "L Spallanzani," Rome, Italy;‡‡Division of Infectious Diseases, University of Modena and Reggio Emilia, Modena, Italy;§§Division of Infectious Diseases, University La Sapienza, Polo Pontino, Latina, Italy; and‖‖Division of Infectious Diseases, University of Milan, San Paolo Hospital, Milan, Italy.

Objective: To analyze the association between chronic hepatitis C virus (HCV) and cytomegalovirus (CMV) infections with type 2 diabetes in HIV-infected patients.

Methods: HIV-1-infected patients enrolled in ICONA, a prospective cohort study involving 42 tertiary care centers in Italy, were selected with the following characteristics: for the diabetes incidence analysis, all patients with available CMV IgG results (first available test = baseline) and without type 2 diabetes were followed until onset of type 2 diabetes, last available clinical follow-up, death or September 30, 2014, whichever occurred first; for the prevalence analysis, all ICONA patients were analyzed at their last follow-up visit. Main outcome measures were the new onset of type 2 diabetes (incidence analysis) and the prevalence of type 2 diabetes at last follow-up.

Results: During 38,062 person-years of follow-up (PYFU) in 6505 individuals, we observed 140 cases of incident type 2 diabetes (Incidence rate 3.7, 95% CI: 3.1 to 4.3, per 1000 PYFU). In a multivariable Poisson regression model, HCV-antibody (Ab)+/HCV RNA+ patients [adjusted relative rate versus HCV-Ab negative 1.73 (95% CI: 1.08 to 2.78)] but not HCV Ab+RNA- or CMV IgG+ patients, had a higher risk of diabetes. Among 12,001 patients, 306 (2.5%) prevalent cases of type 2 diabetes were detected. HCV Ab+RNA+ status was independently associated with prevalent diabetes (adjusted Odds Ratio vs HCV Ab- 2.49; 95% CI: 1.08 to 5.74), whereas HCV-Ab+/HCV RNA- and CMV IgG+ status were not.

Conclusion: In HIV-infected individuals, active HCV replication but not prior HCV exposure or latent CMV infection is associated with incident and prevalent type 2 diabetes.
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http://dx.doi.org/10.1097/QAI.0000000000001443DOI Listing
August 2017

Reduced adherence to antiretroviral therapy is associated with residual low-level viremia.

Pragmat Obs Res 2017 26;8:91-97. Epub 2017 May 26.

USC of Infectious Diseases.

The source and significance of residual low-level viremia (LLV) during combinational antiretroviral therapy (cART) remain a matter of controversy. It is unclear whether residual viremia depends on ongoing release of HIV from the latent reservoir or if viral replication contributes to LLV. We examined the relationship between adherence and LLV. Adherence was estimated by pharmacy refill and dichotomized as ≥95% or <95%. Plasma HIV-RNA was determined, with an ultrasensitive test having a limit of detection of 3 copies/mL at least 2 times over the follow-up period. Patients were grouped according to HIV-RNA over time as K<3: constantly <3 copies/mL; V<3: sometimes below or above the cutoff limit but always <50 copies/mL; K>3: constantly between 3 and 50 copies/mL; and V>50: a measure of >50 copies/mL minimum. Overall, 2789 patients were included. At each time point approximately 92% of the patients presented an HIV-RNA <50 copies/mL and two-thirds of those <3 copies/mL, 34.6% of patients had <3 copies/mL constantly, 32.7% sometimes below or above the cutoff limit but always <50 copies/mL, 9.5% constantly between 3 and 50 copies/mL, and 23.2% a measure of >50 copies/mL minimum. The mean adherence rate was 92.1% (95% confidence interval [CI] from 91.1% to 93.1%) in K<3 patients, similar in V<3 patients (91.9%), but lowered to 88.8% in K>3 patients and to 88.4% in V>50 patients (<0.0001). Approximately 55% of patients in groups K<3 and V<3 showed an adherence rate ≥95%; this proportion lowered to ~51% in K>3 and to 48% in V>50. Moreover, 34% of patients with a steady adherence <95% were categorized as K>3, whereas 21.7% of those with a drug holiday (21.7%) were observed in the V>50 group (=0.002). A steady viral suppression can occur despite moderate cART non-adherence, but reduced adherence is associated with low-level residual viremia, which could reflect new rounds of HIV replication. However, a detectable HIV-RNA could also be detected in patients with optimal cART adherence, indicating additional mechanisms favoring HIV persistence.
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http://dx.doi.org/10.2147/POR.S127974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457149PMC
May 2017

Efficacy and safety of emtricitabine/tenofovir alafenamide (FTC/TAF) vs. emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as a backbone for treatment of HIV-1 infection in virologically suppressed adults: subgroup analysis by third agent of a randomized, double-blind, active-controlled phase 3 trial.

HIV Clin Trials 2017 05 17;18(3):135-140. Epub 2017 Mar 17.

g Departments of Biometrics, Virology, Clinical Operations, and Clinical Research , Gilead Sciences Inc. , Foster City , CA , USA.

Background: FTC/TAF was shown to be noninferior to FTC/TDF with advantages in markers of renal and bone safety.

Objective: To evaluate the efficacy and safety of switching to FTC/TAF from FTC/TDF by third agent (boosted protease inhibitor [PI] vs. unboosted third agent).

Methods: We conducted a 48-week subgroup analysis based on third agent from a randomized, double blind study in virologically suppressed adults on a FTC/TDF-containing regimen who switched to FTC/TAF vs. continued FTC/TDF while remaining on the same third agent.

Results: We randomized (1:1) 663 participants to either switch to FTC/TAF (N = 333) or continue FTC/TDF (N = 330), each with baseline third agent stratifying by class of third agent in the prior treatment regimen (boosted PI 46%, unboosted third agent 54%). At week 48, significant differences in renal biomarkers and bone mineral density were observed favoring FTC/TAF over FTC/TDF (p < 0.05 for all), with similar improvements in the FTC/TAF arm in those who received boosted PI vs. unboosted third agents. At week 48, virologic success rates were similar between treatment groups for those who received a boosted PI (FTC/TAF 92%, FTC/TDF 93%) and for those who received an unboosted third agent (97% vs. 93%).

Conclusions: In virologically suppressed patients switching to FTC/TAF from FTC/TDF, high rates of virologic suppression were maintained, while renal and bone safety parameters improved, regardless of whether participants were receiving a boosted PI or an unboosted third agent. FTC/TAF offers safety advantages over FTC/TDF and can be an important option as an NRTI backbone given with a variety of third agents.
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http://dx.doi.org/10.1080/15284336.2017.1291867DOI Listing
May 2017

Lamivudine/dolutegravir dual therapy in HIV-infected, virologically suppressed patients.

BMC Infect Dis 2017 03 16;17(1):215. Epub 2017 Mar 16.

Division of Infectious Diseases, University of Modena, Modena, Italy.

Background: Little is known about the applicability of dual treatments based on integrase inhibitors. We explored the combination of lamivudine + dolutegravir as an option when switching from standard cART in virologically suppressed patients.

Methods: In this prospective cohort we enrolled patients previously switched to 3TC + DTG who were 18 years or older, with no previous resistance mutations to the used drugs, having a HIV-RNA <50 copies/ml for 6 months or longer, negative for HBsAg and on a stable (>6 months) cART.

Results: Ninety-four individuals were included. They were mostly men (77.7%) with a mean age of 53 years. They presented 159 co-morbidities including cardiovascular, bone, hepatic, kidney, and CNS diseases. Because of these pathologies, they took 207 non-ARV drugs (mean 2.2 per patient). Median duration of viral suppression was 77.5 months (IQR 61). All subjects were prospectively followed up to week 24 and all remained on dual therapy during the whole period. Neither virological failure, nor viral blip was detected. The median CD4 count rose from 658 cells/mcl (IQR 403) to 724 cells/mcl (IQR 401) (P = 0.006) without a significant (P = 0.44) change in the CD4/CD8 ratio. A significant (P < 0.0001) increment of median creatinine from 0.87 mg/dl (IQR 0.34) to 0.95 mg/dl (IQR 0.29) was observed in the first 2 months but thereafter leveled on these values (1.00 mg/dl; IQR 0.35) (P = 0.111 compared to 2 months). The lipid profile slightly improved. The daily cost of cART was significantly (P < 0.0001) reduced of 6.89 euros (SD 6.10).

Discussion: Switching to a dual cART regimen based on lamivudine + dolutegravir maintains virological efficacy up to week 24, and is associated to slight improvements of the immunologic and metabolic status. The strategy allows to freely using concomitant medications for associated pathologies. The dual therapy is less expensive in economic terms.

Conclusion: Although still limited evidence exists, a dolutegravir-based dual therapy in combination with lamivudine shows promising results to be confirmed in larger controlled trials.
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http://dx.doi.org/10.1186/s12879-017-2311-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356275PMC
March 2017