Publications by authors named "Alessandro Cozzi-Lepri"

161 Publications

Development and validation of a prediction model for tocilizumab failure in hospitalized patients with SARS-CoV-2 infection.

PLoS One 2021 23;16(2):e0247275. Epub 2021 Feb 23.

Department of Infectious Diseases, Azienda Ospedaliero-Universitaria, Policlinico of Modena, Modena, Italy.

Background: The aim of this secondary analysis of the TESEO cohort is to identify, early in the course of treatment with tocilizumab, factors associated with the risk of progressing to mechanical ventilation and death and develop a risk score to estimate the risk of this outcome according to patients' profile.

Methods: Patients with COVID-19 severe pneumonia receiving standard of care + tocilizumab who were alive and free from mechanical ventilation at day 6 after treatment initiation were included in this retrospective, multicenter cohort study. Multivariable logistic regression models were built to identify predictors of mechanical ventilation or death by day-28 from treatment initiation and β-coefficients were used to develop a risk score. Secondary outcome was mortality. Patients with the same inclusion criteria as the derivation cohort from 3 independent hospitals were used as validation cohort.

Results: 266 patients treated with tocilizumab were included. By day 28 of hospital follow-up post treatment initiation, 40 (15%) underwent mechanical ventilation or died [26 (10%)]. At multivariable analysis, sex, day-4 PaO2/FiO2 ratio, platelets and CRP were independently associated with the risk of developing the study outcomes and were used to generate the proposed risk score. The accuracy of the score in AUC was 0.80 and 0.70 in internal validation and test for the composite endpoint and 0.92 and 0.69 for death, respectively.

Conclusions: Our score could assist clinicians in identifying, early after tocilizumab administration, patients who are likely to progress to mechanical ventilation or death, so that they could be selected for eventual rescue therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247275PLOS
February 2021

Prevalence and Outcomes for Heavily Treatment-Experienced (HTE) Individuals Living with Human Immunodeficiency Virus in a European Cohort.

J Acquir Immune Defic Syndr 2021 Feb 11. Epub 2021 Feb 11.

Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, University College London, London, UK, Department of Infectious Diseases Immunology, Statens Serum Institut, Copenhagen, Denmark, Centre for Health and Infectious Disease Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, Department of Infectious Diseases, Odense University Hospital, Odense, Denmark, Sjællands Universitetshospital, Roskilde, Denmark, St. Mary's Hospital, London, UK, CHU Nice Hopital de l' Archet 1, Nice, France, University Clinic Hamburg Eppendorf, Hamburg, Germany, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Skåne University Hospital, Malmö, Sweden, Faculty of Medicine, University of Iceland, Reykjavik, Iceland, Medical University of Warsaw, Warsaw, Poland, Clinic of Infectious Diseases and Hepatology, Medical University of Lodz, Lodz, Poland, Poznan University of Medical Sciences, Poznan, Poland, Victor Babes Clinical Hospital for Infectious and Tropical Diseases, Bucharest, Romania, Lviv Regional Public Health Center, HIV Unit, Lviv, Ukraine, Kharkov State Medical University, Kharkov, Ukraine, University Hospital for Infectious Diseases Dr. Fran Mihaljević, Zagreb, Croatia, Infectious Diseases Department, Karolinska University Hospital, Infectious Diseases Department, Stockholm, Sweden, ViiV Healthcare, London, UK.

Background: Although antiretroviral treatments have improved survival of persons living with HIV, their long-term use may limit available drug options. We estimated the prevalence of heavily treatment-experienced (HTE) status and the potential clinical consequences of becoming HTE.

Setting: EuroSIDA, a European multicentre prospective cohort study.

Methods: A composite definition for HTE was developed, based on estimates of antiretroviral resistance and prior exposure to specific antiretroviral regimens. Risks of progressing to clinical outcomes were assessed by Poisson regression, comparing every HTE individual with three randomly-selected controls who never became HTE.

Results: Of 15,570 individuals under follow-up in 2010-2016, 1617 (10.4%, 95% CI 9.9-10.9%) were classified as HTE. 1093 individuals became HTE during prospective follow-up (HTE incidence rate 1.76, CI 1.66-1.87 per 100 person-years of follow-up). The number of HTE individuals was highest in West/Central Europe (636/4019 persons, 15.7%) and lowest in East Europe (26/2279 persons, 1.1%). Although most HTE individuals maintained controlled viral loads (<400 copies/ml), many had low CD4 counts (≤350 cells/µl). After controlling for age, immunological parameters and pre-existing comorbidities, HTE status was not associated with the risk of new AIDS (adjusted incidence rate ratio, aIRR 1.44, CI 0.86-2.40, p = 0.16) or non-AIDS clinical events (aIRR 0.96, CI 0.74-1.25, p = 0.77).

Conclusions: HTE prevalence increased with time. After adjusting for key confounding factors, there was no evidence for an increased risk of new AIDS or non-AIDS clinical events in HTE. Additional therapeutic options and effective management of comorbidities remain important to reduce clinical complications in HTE individuals.
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http://dx.doi.org/10.1097/QAI.0000000000002635DOI Listing
February 2021

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

HBcAb Positivity Increases the Risk of Severe Hepatic Fibrosis Development in HIV/HCV-Positive Subjects From the ICONA Italian Cohort of HIV-Infected Patients.

Open Forum Infect Dis 2021 Jan 18;8(1):ofaa566. Epub 2020 Nov 18.

University of Rome Tor Vergata, Rome, Italy.

Background: The aim of this study was to investigate the impact of anti-HBc (HBcAb) positivity on the progression of liver fibrosis (Fibrosis-4 score >3.25) in the Italian cohort of HIV-infected individuals naïve to antiretroviral treatment (ICONA).

Methods: All patients with FIB-4 <3.25 at baseline were evaluated prospectively: 6966 people with HIV (PWH) were screened and classified based on hepatitis B virus (HBV) and hepatitis C virus (HCV) serology.

Results: Patients who were HBcAb+/HCV-/HBs antigen (HBsAg)- and HCV+/HBcAb+/HBsAg- or HBsAg+/HBcAb+/HCV- had CD4+ cell counts below the nadir and significantly higher prevalence of AIDS diagnosis at baseline than the other groups ( < .0001). A Cox regression model adjusted for age, HIV transmission mode, country of birth, and alcohol consumption showed a higher relative risk (HR) of progression to FIB-4 >3.25 in HCV+/HBcAb+/HBsAg- patients (HR, 7.2; 95% CI, 3 8-13.64).

Conclusions: HBcAb+ contributes to liver damage in HIV+/HCV+/HBcAb+/HBsAg- subjects. A careful monitoring for signs of previous HBV infection is needed in this kind of patients.
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http://dx.doi.org/10.1093/ofid/ofaa566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781466PMC
January 2021

Better prognosis in females with severe COVID-19 pneumonia: possible role of inflammation as potential mediator.

Clin Microbiol Infect 2021 Jan 20. Epub 2021 Jan 20.

Department of Infectious Diseases, Azienda Ospedaliero-Universitaria Policlinico of Modena, Modena, Italy; Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Italy.

Objectives: Sex differences in COVID-19 severity and mortality have been described. Key aims of this analysis were to compare the risk of invasive mechanical ventilation (IMV) and mortality by sex and to explore whether variation in specific biomarkers could mediate this difference.

Methods: This was a retrospective, observational cohort study among patients with severe COVID-19 pneumonia. A survival analysis was conducted to compare time to the composite endpoint of IMV or death according to sex. Interaction was formally tested to compare the risk difference by sex in sub-populations. Mediation analysis with a binary endpoint IMV or death (yes/no) by day 28 of follow-up for a number of inflammation/coagulation biomarkers in the context of counterfactual prediction was also conducted.

Results: Among 415 patients, 134 were females (32%) and 281 males (67%), median age 66 years (IQR 54-77). At admission, females showed a significantly less severe clinical and respiratory profiles with a higher PaO/FiO (254 mmHg vs. 191 mmHg; p 0.023). By 28 days from admission, 49.2% (95% CI 39.6-58.9%) of males vs. 31.7% (17.9-45.4%) of females underwent IMV or death (log-rank p < 0.0001) and this amounted to a difference in terms of HR of 0.40 (0.26-0.63, p 0.0001). The area under the curve in C-reactive protein (CRP) over the study period appeared to explain 85% of this difference in risk by sex.

Discussion: Our analysis confirms a difference in the risk of COVID-19 clinical progression by sex and provides a hypothesis for potential mechanisms leading to this. Specifically, CRP showed a predominant role to mediate the difference in risk by sex.
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http://dx.doi.org/10.1016/j.cmi.2020.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816626PMC
January 2021

Tocilizumab in COVID-19: finding the optimal route and dose - Authors' reply.

Lancet Rheumatol 2020 Dec 17;2(12):e739-e740. Epub 2020 Sep 17.

Department of Infectious Diseases, Azienda Ospedaliero-Universitaria Policlinico of Modena, Modena 41124, Italy.

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http://dx.doi.org/10.1016/S2665-9913(20)30333-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498220PMC
December 2020

The importance of patients' case-mix for the correct interpretation of the hospital fatality rate in COVID-19 disease.

Int J Infect Dis 2020 Nov 17;100:67-74. Epub 2020 Sep 17.

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

Objective: We aimed to document data on the epidemiology and factors associated with clinical course leading to death of patients hospitalised with COVID-19.

Methods: Prospective observational cohort study on patients hospitalised with COVID-19 disease in February-24th/May-17th 2020 in Milan, Italy. Uni-multivariable Cox regression analyses were performed. Death's percentage by two-weeks' intervals according to age and disease severity was analysed.

Results: A total of 174/539 (32.3%) patients died in hospital over 8228 person-day follow-up; the 14-day Kaplan-Meier probability of death was 29.5% (95%CI: 25.5-34.0). Older age, burden of comorbidities, COVID-19 disease severity, inflammatory markers at admission were independent predictors of increased risk, while several drug-combinations were predictors of reduced risk of in-hospital death. The highest fatality rate, 36.5%, occurred during the 2nd-3rd week of March, when 55.4% of patients presented with severe disease, while a second peak, by the end of April, was related to the admission of older patients (55% ≥80 years) with less severe disease, 30% coming from long-term care facilities.

Conclusions: The unusual fatality rate in our setting is likely to be related to age and the clinical conditions of our patients. These findings may be useful to better allocate resources of the national healthcare system, in case of re-intensification of COVID-19 epidemics.
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http://dx.doi.org/10.1016/j.ijid.2020.09.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497732PMC
November 2020

Tocilizumab for severe COVID-19 pneumonia - Authors' reply.

Lancet Rheumatol 2020 Nov 17;2(11):e660-e661. Epub 2020 Aug 17.

Department of Infectious Diseases, Azienda Ospedaliero-Universitaria Policlinico of Modena, Modena 41124, Italy.

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http://dx.doi.org/10.1016/S2665-9913(20)30285-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431126PMC
November 2020

Tocilizumab in patients with severe COVID-19: a retrospective cohort study.

Lancet Rheumatol 2020 Aug 24;2(8):e474-e484. Epub 2020 Jun 24.

Department of Infectious Diseases, Azienda Ospedaliero-Universitaria Policlinico of Modena, Modena, Italy.

Background: No therapy is approved for COVID-19 pneumonia. The aim of this study was to assess the role of tocilizumab in reducing the risk of invasive mechanical ventilation and death in patients with severe COVID-19 pneumonia who received standard of care treatment.

Methods: This retrospective, observational cohort study included adults (≥18 years) with severe COVID-19 pneumonia who were admitted to tertiary care centres in Bologna and Reggio Emilia, Italy, between Feb 21 and March 24, 2020, and a tertiary care centre in Modena, Italy, between Feb 21 and April 30, 2020. All patients were treated with the standard of care (ie, supplemental oxygen, hydroxychloroquine, azithromycin, antiretrovirals, and low molecular weight heparin), and a non-randomly selected subset of patients also received tocilizumab. Tocilizumab was given either intravenously at 8 mg/kg bodyweight (up to a maximum of 800 mg) in two infusions, 12 h apart, or subcutaneously at 162 mg administered in two simultaneous doses, one in each thigh (ie, 324 mg in total), when the intravenous formulation was unavailable. The primary endpoint was a composite of invasive mechanical ventilation or death. Treatment groups were compared using Kaplan-Meier curves and Cox regression analysis after adjusting for sex, age, recruiting centre, duration of symptoms, and baseline Sequential Organ Failure Assessment (SOFA) score.

Findings: Of 1351 patients admitted, 544 (40%) had severe COVID-19 pneumonia and were included in the study. 57 (16%) of 365 patients in the standard care group needed mechanical ventilation, compared with 33 (18%) of 179 patients treated with tocilizumab (p=0·41; 16 [18%] of 88 patients treated intravenously and 17 [19%] of 91 patients treated subcutaneously). 73 (20%) patients in the standard care group died, compared with 13 (7%; p<0·0001) patients treated with tocilizumab (six [7%] treated intravenously and seven [8%] treated subcutaneously). After adjustment for sex, age, recruiting centre, duration of symptoms, and SOFA score, tocilizumab treatment was associated with a reduced risk of invasive mechanical ventilation or death (adjusted hazard ratio 0·61, 95% CI 0·40-0·92; p=0·020). 24 (13%) of 179 patients treated with tocilizumab were diagnosed with new infections, versus 14 (4%) of 365 patients treated with standard of care alone (p<0·0001).

Interpretation: Treatment with tocilizumab, whether administered intravenously or subcutaneously, might reduce the risk of invasive mechanical ventilation or death in patients with severe COVID-19 pneumonia.

Funding: None.
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http://dx.doi.org/10.1016/S2665-9913(20)30173-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314456PMC
August 2020

Epidemiology and Outcomes of Bloodstream Infections in HIV-Patients during a 13-Year Period.

Microorganisms 2020 Aug 8;8(8). Epub 2020 Aug 8.

Infectious Disease Clinic, Azienda Ospedaliero-Universitaria di Modena, 41125 Modena, Italy.

No data on antibiotic resistance in bloodstream infection (BSI) in people living with HIV (PLWH) exist. The objective of this study was to describe BSI epidemiology in PLWH focusing on multidrug resistant (MDR) organisms. A retrospective, single-center, observational study was conducted including all positive blood isolates in PLWH from 2004 to 2017. Univariable and multivariable GEE models using binomial distribution family were created to evaluate the association between MDR and mortality risk. In total, 263 episodes (299 isolates) from 164 patients were analyzed; 126 (48%) BSI were community-acquired, 137 (52%) hospital-acquired. At diagnosis, 34.7% of the patients had virological failure, median CD4 count was 207/μL. Thirty- and 90-day mortality rates were 24.2% and 32.4%, respectively. Thirty- and 90-day mortality rates for MDR isolates were 33.3% and 46.9%, respectively ( < 0.05). Enterobacteriaceae were the most prevalent microorganisms (29.8%), followed by Coagulase-negative staphylococci (21.4%), and (12.7%). In BSI due to MDR organisms, carbapenem-resistant and methicillin-resistant were associated with mortality after adjustment for age, although this correlation was not confirmed after further adjustment for CD4 < 200/μL. In conclusion, BSI in PLWH is still a major problem in the combination antiretroviral treatment era and it is related to a poor viro-immunological status, posing the question of whether it should be considered as an AIDS-defining event.
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http://dx.doi.org/10.3390/microorganisms8081210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463563PMC
August 2020

Effectiveness of hydroxychloroquine in COVID-19 disease: A done and dusted deal?

Int J Infect Dis 2020 10 29;99:75-76. Epub 2020 Jul 29.

Centre for Clinical Research, Epidemiology, Modelling and Evaluation, Institute for Global Health, University College London, London, UK.

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http://dx.doi.org/10.1016/j.ijid.2020.07.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388856PMC
October 2020

Machine learning can identify newly diagnosed patients with CLL at high risk of infection.

Nat Commun 2020 01 17;11(1):363. Epub 2020 Jan 17.

Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Infections have become the major cause of morbidity and mortality among patients with chronic lymphocytic leukemia (CLL) due to immune dysfunction and cytotoxic CLL treatment. Yet, predictive models for infection are missing. In this work, we develop the CLL Treatment-Infection Model (CLL-TIM) that identifies patients at risk of infection or CLL treatment within 2 years of diagnosis as validated on both internal and external cohorts. CLL-TIM is an ensemble algorithm composed of 28 machine learning algorithms based on data from 4,149 patients with CLL. The model is capable of dealing with heterogeneous data, including the high rates of missing data to be expected in the real-world setting, with a precision of 72% and a recall of 75%. To address concerns regarding the use of complex machine learning algorithms in the clinic, for each patient with CLL, CLL-TIM provides explainable predictions through uncertainty estimates and personalized risk factors.
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http://dx.doi.org/10.1038/s41467-019-14225-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969150PMC
January 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

Is physician assessment of alcohol consumption useful in predicting risk of severe liver disease among people with HIV and HIV/HCV co-infection?

BMC Public Health 2019 Oct 15;19(1):1291. Epub 2019 Oct 15.

Institute of Global Health, University College London, Royal Free Hospital, London, UK.

Background: Alcohol consumption is a known risk factor for liver disease in HIV-infected populations. Therefore, knowledge of alcohol consumption behaviour and risk of disease progression associated with hazardous drinking are important in the overall management of HIV disease. We aimed at assessing the usefulness of routine data collected on alcohol consumption in predicting risk of severe liver disease (SLD) among people living with HIV (PLWHIV) with or without hepatitis C infection seen for routine clinical care in Italy.

Methods: We included PLWHIV from two observational cohorts in Italy (ICONA and HepaICONA). Alcohol consumption was assessed by physician interview and categorized according to the National Institute for Food and Nutrition Italian guidelines into four categories: abstainer; moderate; hazardous and unknown. SLD was defined as presence of FIB4 > 3.25 or a clinical diagnosis of liver disease or liver-related death. Cox regression analysis was used to evaluate the association between level of alcohol consumption at baseline and risk of SLD.

Results: Among 9542 included PLWHIV the distribution of alcohol consumption categories was: abstainers 3422 (36%), moderate drinkers 2279 (23%), hazardous drinkers 637 (7%) and unknown 3204 (34%). Compared to moderate drinkers, hazardous drinking was associated with higher risk of SLD (adjusted hazard ratio, aHR = 1.45; 95% CI: 1.03-2.03). After additionally controlling for mode of HIV transmission, HCV infection and smoking, the association was attenuated (aHR = 1.32; 95% CI: 0.94-1.85). There was no evidence that the association was stronger when restricting to the HIV/HCV co-infected population.

Conclusions: Using a brief physician interview, we found evidence for an association between hazardous alcohol consumption and subsequent risk of SLD among PLWHIV, but this was not independent of HIV mode of transmission, HCV-infection and smoking. More efforts should be made to improve quality and validity of data on alcohol consumption in cohorts of HIV/HCV-infected individuals.
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http://dx.doi.org/10.1186/s12889-019-7608-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794785PMC
October 2019

Incidence and risk factors for liver enzyme elevation among naive HIV-1-infected patients receiving ART in the ICONA cohort.

J Antimicrob Chemother 2019 11;74(11):3295-3304

Department of Health Sciences, Clinic of Infectious and Tropical Diseases, University of Milan, Milan, Italy.

Objectives: To evaluate the incidence and risk factors for liver enzyme elevations (LEE) in patients initiating first-line ART in the ICONA prospective observational cohort, between June 2009 and December 2017.

Patients And Methods: In total, 6575 ART-naive patients were selected, initiating two NRTIs with the third drug being a boosted PI (n=2436; 37.0%), an NNRTI (n=2384; 36.3%) or an integrase strand transfer inhibitor (INSTI) (n=1755; 26.7%). HBV surface antigen and HCV RNA were detected in 3.9% and 5.8% of the study population. Inverse probability weighted Cox regression analysis was used to calculate the HRs, according to first-line regimen, for LEE, defined as ALT or AST increases of ≥2.5× upper limit of normal (ULN) for patients with normal baseline values or ≥2.5× baseline for patients with higher baseline values.

Results: One hundred and eighty-three LEE occurred over 20722 patient-years of follow-up. After adjusting for the main confounders, the risk of LEE halved with INSTIs compared with NNRTIs (HR 0.46, 95% CI 0.25-0.86), with a significant reduction in the raltegravir group (HR 0.11, 95% CI 0.02-0.84 using the NNRTI class as reference). HRs for LEE were significantly higher in subjects with HBV or HCV coinfection, in patients with poorly controlled HIV infection and in those who acquired HIV through homosexual transmission.

Conclusions: In our study, INSTI use almost halved the risk of LEE compared with other regimens. This finding could be particularly important for choosing ART in patients with risk factors for liver toxicity such as HCV and HBV coinfections.
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http://dx.doi.org/10.1093/jac/dkz353DOI Listing
November 2019

Impact of diabetes on the risk of serious liver events and liver-related deaths in people living with HIV and hepatitis C co-infection: data from the ICONA Foundation Cohort Study.

Eur J Clin Microbiol Infect Dis 2019 Oct 22;38(10):1857-1865. Epub 2019 Jun 22.

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

To investigate the association between diabetes and HCV infection in persons living with HIV and to determine the impact of diabetes on the occurrence of serious liver events (SLEs) and liver-related deaths (LRDs) among HIV/HCV-co-infected patients. Patients were included if they had at least one follow-up visit. In a cross-sectional analysis among all HIV patients, we have investigated the association between diabetes and HCV infection. A further longitudinal analysis was performed in the population of HIV/HCV-co-infected free from SLE with FIB-4 index < 3.25 at baseline, using the following endpoints: (A) first event between SLE and LRD; (B) liver fibrosis progression defined as the first of two consecutive FIB-4 > 3.25; (C) first event between SLE, LRD, and liver fibrosis progression. Data from 15,571 HIV patients were analyzed: 2944 (18.9%) were HCV-Ab positive, and 739 (4.7%) presented a diagnosis of diabetes at their last follow-up. Among HIV/HCV-co-infected population, 107 patients had a diagnosis of diabetes. Viremic HCV-co-infected patients had 3-fold risk of diabetes onset than HCV-uninfected patients. On HIV/HCV-co-infected population, 85 SLEs/LRDs occurred over 20,410 person-years of follow-up (PYFU), for an incidence rate of 4.2/1000 PYFU (95%CI 3.4-5.2). Diabetic patients had 3-fold risk of pooled SLE and LRD than patients without diabetes. Furthermore, viremic HCV infection was independently associated with a higher risk of SLE/LRD (aIRR 3.35 [95%CI 1.14-9.83]). In HIV-infected patients, viremic HCV co-infection is a strong predictor of diabetes. Among HIV/HCV-co-infected population, diabetic patients showed an increased risk of SLE/LRD compared with those without diabetes.
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http://dx.doi.org/10.1007/s10096-019-03618-8DOI Listing
October 2019

Durability of different initial regimens in HIV-infected patients starting antiretroviral therapy with CD4+ counts <200 cells/mm3 and HIV-RNA >5 log10 copies/mL.

J Antimicrob Chemother 2019 09;74(9):2732-2741

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

Objectives: Our aim was to investigate the durability of different initial regimens in patients starting ART with CD4+ counts <200 cells/mm3 and HIV-RNA >5 log10 copies/mL.

Methods: This was a retrospective study of HIV-infected patients prospectively followed in the ICONA cohort. Those who started ART with boosted protease inhibitors (bPIs), NNRTIs or integrase strand transfer inhibitors (InSTIs), with CD4+ <200 cells/mm3 and HIV-RNA >5 log10 copies/mL, were included. The primary endpoint was treatment failure (TF), a composite endpoint defined as virological failure (VF, first of two consecutive HIV-RNA >50 copies/mL after 6 months of treatment), discontinuation of class of the anchor drug or death. Independent associations were investigated by Poisson regression analysis in a model including age, gender, mode of HIV transmission, CDC stage, HCV and HBV co-infection, pre-treatment HIV-RNA, CD4+ count and CD4+/CD8+ ratio, ongoing opportunistic disease, fibrosis FIB-4 index, estimated glomerular filtration rate, haemoglobin, platelets, neutrophils, calendar year of ART initiation, anchor drug class (treatment group) and nucleos(t)ide backbone.

Results: A total of 1195 patients fulfilled the inclusion criteria: 696 started ART with a bPI, 315 with an InSTI and 184 with an NNRTI. During 2759 person-years of follow up, 642 patients experienced TF. Starting ART with bPIs [adjusted incidence rate ratio (aIRR) (95% CI) 1.62 (1.29-2.03) versus starting with NNRTIs; P < 0.001] and starting ART with InSTIs [aIRR (95% CI) 0.68 (0.48-0.96) versus starting with NNRTIs; P = 0.03] were independently associated with TF.

Conclusions: In patients starting ART with <200 CD4+ cells/mm3 and >5 log10 HIV-RNA copies/mL, the durability of regimens based on InSTIs was longer than that of NNRTI- and bPI-based regimens.
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http://dx.doi.org/10.1093/jac/dkz237DOI Listing
September 2019

Is the rate of virological failure to cART continuing to decline in recent calendar years?

J Clin Virol 2019 07 3;116:23-28. Epub 2019 May 3.

University College London, UK.

Background: Despite the high rate of virological success of combined antiretroviral therapy (cART), HIV infected individuals continue to fail. In this contest, it is unclear whether having previously experienced virological failure (VF) of cART remains an important predictor of future risk of VF in people receiving cART in modern times. We investigated the rate of VF and factors potentially associated with this event in 9220 HIV-1 infected patients enrolled in the Icona Cohort who showed a stable viral suppression on modern cART regimens after January 1, 2006.

Methods: We investigated two main exposure factors: current calendar period (2006-2009; 2010-2013; 2014-2017) and number of VFs (0; 1-3; >3) prior to baseline. Relative rates of VF were estimated from fitting a Poisson regression model.

Results: Seven-hundred-seventy-nine patients experienced VF over follow-up for an overall rate of 2.08 per 100 person years of follow-up (PYFU, 95%CI: 1.93-2.22). The rate of VF increased with higher numbers of previous VFs: patients with >3 previous VFs had a rate of 4.87 (4.10-5.78), 2.75-fold higher than that observed in patients without any previous VF (p < 0.001). The rate of VF was lower in recent years: 3.81 (3.36, 4.32) in 2006-2009; 1.36 (1.20-1.53) in 2014-2017 (p < 0.001). Other factors independently associated with lower risk of VF were Italian origin, longer history of virological suppression, and university education level.

Conclusions: In HIV-infected patients virologically suppressed after January 2006, the rate of VF continues to show a decline even in the most recent years. Previous VFs should be carefully considered.
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http://dx.doi.org/10.1016/j.jcv.2019.04.009DOI Listing
July 2019

Very high pre-therapy viral load is a predictor of virological rebound in HIV-1-infected patients starting a modern first-line regimen.

Antivir Ther 2019 ;24(5):321-331

Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy.

Background: Pre-cART (combined antiretroviral therapy) plasma viral load >500,000 copies/ml has been associated with a lower probability of achieving virological suppression, while few data about its role on maintenance of virological suppression are available. In this study we aimed to clarify whether high levels of pre-cART viraemia are associated with virological rebound (VR) after virological suppression.

Methods: HIV-infected individuals who achieved virological suppression after first-line cART were included. VR was defined as the first of two consecutive viraemia >50 copies/ml (VR50) or, in an alternative analysis, >200 copies/ml (VR200). The impact of pre-cART viraemia on the risk of VR was evaluated by survival analyses.

Results: Among 5,766 patients included, 59.2%, 31.4%, 5.2% and 4.2% had pre-cART viraemia ≤100,000, 100,001-500,000, 500,001-1,000,000 and >1,000,000 copies/ml, respectively. Patients with pre-cART viraemia levels >1,000,000 copies/ml had the highest probability of VR (>1,000,000; 500,000-1,000,000; 100,000-500,000; <100,000 copies/ml; VR50: 28.4%; 24.3%; 17.6%; 13.8%, P<0.0001; VR200: 14.4%; 11.1%; 7.2%; 7.6%; P=0.009). By Cox multivariable analyses, patients with pre-cART viraemia >500,000 and >1,000,000 copies/ml showed a significantly higher risk of VR regardless of the VR end point used. No difference in the risk of VR was found between patients with pre-cART viraemia ranging 500,000-1,000,000 copies/ml and those with pre-cART viraemia >1,000,000 copies/ml, regardless of the VR end point used.

Conclusions: Pre-cART plasma viral load levels >500,000 copies/ml can identify fragile patients with poorer chance of maintaining virological control after an initial response. An effort in defining effective treatment strategies is mandatory for these patients that remain difficult to treat.
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http://dx.doi.org/10.3851/IMP3309DOI Listing
July 2020

Durability of first-line regimens including integrase strand transfer inhibitors (INSTIs): data from a real-life setting.

J Antimicrob Chemother 2019 05;74(5):1363-1367

HIV/AIDS Department, INMI 'L. Spallanzani' IRCCS, Rome, Italy.

Objectives: To evaluate the durability of three integrase strand transfer inhibitors (INSTIs) and two NRTIs in ART-naive individuals.

Methods: The study design was observational. Patients were HIV-positive, ART-naive subjects starting raltegravir, elvitegravir/cobicistat or dolutegravir with two NRTIs. The primary endpoint was time to treatment failure, i.e. occurrence of virological failure (first of two consecutive plasma HIV RNAs  ≥200 copies/mL after 24 weeks) or INSTI discontinuation for any reason apart from simplification. Secondary endpoints were INSTI discontinuation due to toxicity/intolerance and CD4 count response. Survival analysis was done using Kaplan-Meier and Cox regression.

Results: Two thousand and sixteen patients were included: 310 (15.4%) started raltegravir-based regimens, 994 (49.3%) started dolutegravir-based regimens and 712 (35.3%) started elvitegravir/cobicistat-based regimens. Over a median of 11 months, 167 patients experienced treatment failure; the 1 year probability of treatment failure was 6.5% for raltegravir, 5.4% for dolutegravir and 6.7% for elvitegravir/cobicistat (P = 0.001). Sixty-eight patients (3.4%) discontinued INSTIs owing to toxicity/intolerance. By multivariable analysis, patients starting raltegravir had a 2.03-fold (95% CI = 1.2-3.2) higher risk and patients on elvitegravir/cobicistat a 1.88-fold (95% CI = 1.2-2.9) higher risk of treatment failure versus dolutegravir; there was no difference in risk of discontinuation due to toxicity/intolerance when comparing dolutegravir and raltegravir and marginal evidence for a difference when comparing elvitegravir/cobicistat and dolutegravir (adjusted relative hazard = 1.94 for elvitegravir/cobicistat versus dolutegravir, 95% CI = 1.00-3.76, P = 0.05).

Conclusions: In our real-life setting, INSTI-based regimens showed high potency and durability. Among regimens currently recommended in Europe, those including dolutegravir are associated with a lower risk of treatment failure.
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http://dx.doi.org/10.1093/jac/dky566DOI Listing
May 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

Inflammatory effects of atazanavir/ritonavir versus darunavir/ritonavir in treatment naïve, HIV-1-infected patients.

HIV Clin Trials 2018 08 13;19(4):158-162. Epub 2018 Nov 13.

j Clinica di Malattie Infettive , San Paolo Hospital, University of Milan , Milan , Italy.

Background: Limited studies have compared the impact of different antiretroviral regimens on soluble markers of inflammation with discordant results.

Methods: In this prospective study, treatment naïve HIV-1-infected patients were included if they started their current regimen with atazanavir/ritonavir (ATV/r) (N = 73, Group 1) or darunavir/ritonavir (DRV/r) (N = 85, Group 2) plus tenofovir/emtricitabine. The analysis of IL-6, MCP-1, sCD163, VCAM-1, ox-LDL, and adiponectine was performed on two stored plasma samples, the first prior to antiretroviral therapy initiation and the second one year after initiation.

Results: The results of our analysis show a difference in ox-LDL between the two groups with higher mean (SD) values in ATV/r based group 608.5 ± 137.4 versus 519.1 ± 119.6 in DRV/r group, after controlling for baseline levels of ox-LDL as well as other potential confounding factors controlled by means of matching design or linear regression modelling.

Conclusions: Our analysis provides further data examining the association between the modulation of vascular inflammatory and of activation markers with specific protease inhibitors-based treatments over one year of exposure to these drugs. The data show little evidence for an association, supporting the notion that antiretroviral regimens has generally poor efficiency in downregulating these soluble markers.
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http://dx.doi.org/10.1080/15284336.2018.1488453DOI Listing
August 2018

The effect of primary drug resistance on CD4+ cell decline and the viral load set-point in HIV-positive individuals before the start of antiretroviral therapy.

AIDS 2019 02;33(2):315-326

Clinic of Infectious Diseases, 'S. Gerardo de' Tintori' Hospital, ASST Monza-Brianza, Monza, Italy.

Objective: To evaluate the effect of primary resistance and selected polymorphic amino-acid substitutions in HIV reverse transcriptase and protease on the CD4 cell count and viral load set point before the start of antiretroviral treatment.

Design: Prospective cohort study.

Methods: A total of 6180 individuals with a resistance test prior to starting antiretroviral treatment accessing care in HIV clinics across Europe who had at least one viral load and one CD4+ test available were included in the analysis. The impact of amino-acid substitutions variants on viral load and CD4+ trends was investigated using linear mixed models. Clusters of mutations were studied using principal component analysis.

Results: Overall, the detection of any primary resistance was not associated with either the speed of CD4+ cell decline or the viral load set point. However, transmitted nucleoside reverse transcriptase inhibitor and protease inhibitor resistance appeared to be weakly associated with lower viral load set points, as were the polymorphic G16E or Q92K protease mutations. There was some evidence suggesting that these effects varied according to HIV subtype, with the effects of transmitted nucleoside reverse transcriptase inhibitor and protease resistance being particularly marked among individuals with a subtype B virus. A cluster of five polymorphic protease substitutions at position 20, 13, 36, 69 and 89 was associated with less steep CD4+ cell declines and lower viral load set points.

Conclusion: Although we found little evidence for an association between primary resistance and CD4+ speed of decline and viral load set point, the potential role of polymorphic protease (alone or in clusters) and their interplay with HIV subtype needs to be further evaluated.
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http://dx.doi.org/10.1097/QAD.0000000000002046DOI Listing
February 2019

Pre-ART HIV-1 DNA in CD4+ T cells correlates with baseline viro-immunological status and outcome in patients under first-line ART.

J Antimicrob Chemother 2018 12;73(12):3460-3470

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

Objectives: We evaluated the association between pre-ART HIV DNA and HIV-infected participant characteristics at baseline as well as with their response to first-line ART.

Methods: Four hundred and thirty-three patients from the ICONA cohort, starting first-line ART after the year 2000, were analysed. Pre-ART HIV DNA was quantified with the modified COBAS TaqMan HIV-1 Test and normalized by CD4+ T cells. Linear correlation between pre-ART HIV DNA and other continuous markers (HIV RNA, CD4 count, markers of inflammation and coagulation) at baseline was evaluated by means of Pearson correlation coefficient and a linear regression model. Survival analyses and Cox regression models were used to study the association between pre-ART HIV DNA and time to viro-immunoclinical events.

Results: Pre-ART HIV DNA [median (IQR): 10 702 (3397-36 632) copies/106 CD4+ T cells] was correlated with pre-ART HIV RNA [R2 = +0.44, (P < 0.0001)], CD4+ T cells [R2 = -0.58, (P < 0.0001)] and CD4/CD8 ratio [R2 = -0.48, (P < 0.0001)], while weaker correlations were observed with CD8+ T cells (R2 = -0.20, P = 0.01), IL-6 (R2 = +0.16, P = 0.002) and soluble CD14 (R2 = +0.09, P = 0.05). Patients with higher pre-ART HIV DNA showed lower rate and delayed virological response (defined as HIV RNA ≤50 copies/mL), compared with those having lower HIV DNA (67.2% for >10 000, 81.1% for 1000-10 000 and 86.4% for 10-1000 copies/106 CD4+ T cells; P = 0.0004). Higher pre-ART HIV DNA was also correlated with increased risk of virological rebound (defined as HIV RNA >50 copies/mL) by 24 months (17.2% for >10 000, 7.4% for 1000-10 000 and 4.3% for 10-1000 copies/106 CD4+ T cells; P = 0.0048). Adjusted HRs of all virological rebound definitions confirmed these findings (P ≤ 0.02).

Conclusions: Pre-ART HIV DNA, along with HIV RNA and CD4+ T cell count, should be considered as a new staging marker to better identify people at lower (or higher) risk of viral rebound following achievement of virological suppression (≤50 copies/mL).
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http://dx.doi.org/10.1093/jac/dky350DOI Listing
December 2018

Switching to dual/monotherapy determines an increase in CD8+ in HIV-infected individuals: an observational cohort study.

BMC Med 2018 05 29;16(1):79. Epub 2018 May 29.

Clinic of Infectious Diseases, Department of Health Sciences San Paolo Hospital, DIBIC Luigi Sacco, University of Milan, Milan, Italy.

Background: The CD4/CD8 ratio has been associated with the risk of AIDS and non-AIDS events. We describe trends in immunological parameters in people who underwent a switch to monotherapy or dual therapy, compared to a control group remaining on triple antiretroviral therapy (ART).

Methods: We included patients in Icona who started a three-drug combination ART regimen from an ART-naïve status and achieved a viral load ≤ 50 copies/mL; they were subsequently switched to another triple or to a mono or double regimen. Standard linear regression at fixed points in time (12-24 months after the switch) and linear mixed model analysis with random intercepts and slopes were used to compare CD4 and CD8 counts and their ratio over time according to regimen types (triple vs. dual and vs. mono).

Results: A total of 1241 patients were included; 1073 switched to triple regimens, 104 to dual (72 with 1 nucleoside reverse transcriptase inhibitor (NRTI), 32 NRTI-sparing), and 64 to monotherapy. At 12 months after the switch, for the multivariable linear regression the mean change in the log CD4/CD8 ratio for patients on dual therapy was -0.03 (95% confidence interval (CI) -0.05, -0.0002), and the mean change in CD8 count was +99 (95% CI +12.1, +186.3), taking those on triple therapy as reference. In contrast, there was no evidence for a difference in CD4 count change. When using all counts, there was evidence for a significant difference in the slope of the ratio and CD8 count between people who were switched to triple (points/year change ratio = +0.056, CD8 = -25.7) and those to dual regimen (ratio = -0.029, CD8 = +110.4).

Conclusions: We found an increase in CD8 lymphocytes in people who were switched to dual regimens compared to those who were switched to triple. Patients on monotherapy did not show significant differences. The long-term implications of this difference should be ascertained.
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http://dx.doi.org/10.1186/s12916-018-1046-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972434PMC
May 2018

Factors Associated With Persistence of Plasma HIV-1 RNA During Long-term Continuously Suppressive Firstline Antiretroviral Therapy.

Open Forum Infect Dis 2018 Feb 3;5(2):ofy032. Epub 2018 Feb 3.

Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.

Background: Persistence of plasma HIV-1 RNA during seemingly effective antiretroviral thereapy (ART) is incompletely understood. Using an ultrasensitive assay, this cross-sectional study investigated residual plasma HIV-1 RNA in subjects maintained on firstline ART with continuous viral load suppression <50 copies/mL for ≤15 years without recognized viral load blips or treatment interruptions and explored its relationship with the duration of suppressive ART, efavirenz concentrations in plasma, 2-LTR circular HIV-1 DNA (2-LTRc DNA) in peripheral blood mononuclear cells, and cellular (CD4 plus CD26/CD38/CD69; CD8 plus CD38/HLA-DR/DP/DQ) and soluble (sCD14, sCD27, sCD30, IL-6) markers of immune activation in peripheral blood.

Methods: Residual plasma HIV-1 RNA, total HIV-1 DNA and 2-LTRc DNA were quantified by real-time and digital droplet PCR. Cellular (CD4 plus CD26/CD38/CD69; CD8 plus CD38/HLA-DR/DP/DQ) and soluble (sCD14, sCD27, sCD30, IL-6) markers of immune activation were measured by flow cytometry and ELISA.

Results: Residual plasma HIV-1 RNA and 2-LTRc DNA were detected in 52/104 (50%) and 24/104 (23%) subjects, respectively. Among subjects with detectable HIV-1 RNA, 50/52 showed levels ≤11 copies/mL. In adjusted analyses, HIV-1 RNA levels were 0.37 log copies/mL higher with each log U/mL increase in sCD27 (95% confidence interval, 0.01-0.73; = .02). No significant association was found between residual plasma HIV-1 RNA and other explored parameters.

Conclusions: These findings point to an ongoing relationship between plasma HIV-1 RNA and selected markers of immune activation during continuously suppressive ART. The novel direct association with levels of sCD27 warrants further investigation.
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http://dx.doi.org/10.1093/ofid/ofy032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825920PMC
February 2018

Durability and tolerability of first-line regimens including two nucleoside reverse transcriptase inhibitors and raltegravir or ritonavir boosted-atazanavir or -darunavir: data from the ICONA Cohort.

HIV Clin Trials 2018 04 1;19(2):52-60. Epub 2018 Mar 1.

b HIV/AIDS Clinical Department , National Institute for Infectious Diseases "Lazzaro Spallanzani" , Rome , Italy.

Background We aimed to mimic the ACTG 5257 trial, comparing raltegravir (RAL), ritonavir-boosted atazavavir (ATV/r) and ritonavir-boosted darunavir (DRV/r) in the observational setting. Methods All the ICONA patients starting a first cART with 2NRTI + ATV/r, DRV/r or RAL were included. Primary end-point was treatment failure, i.e. virological failure (confirmed HIV-RNA > 200copies/mL > 6 months therapy) or discontinuation for any reason of the third drug. Secondary end-points: virological failure50 (50 copies/mL threshold), and discontinuation of the third drug due to intolerance/toxicity. Cox regression analyses were run to compare the risk of outcomes between the three regimens. Results 2249 patients were included, 985 (44%) initiated ATV/r, 1023 (45%) DRV/r and 241 (11%) RAL; median follow-up of 3.6 years (IQR: 2.3-5.2). After controlling for baseline confounding factors, patients given ATV/r showed a 26% higher risk of treatment failure (TF) vs. DRV/r (AHR 1.26, 95%CI 1.11-1.43); patients on RAL had a lower risk of TF vs. ATV/r (AHR 0.81, 95%CI 0.66-0.99). The probability of virological failure50 was significantly lower for people initiating RAL vs. DRV/r (AHR 0.46, 95%CI 0.24-0.87) or ATV/r (AHR 0.52, 95%CI 0.27-0.99). In addition, RAL was associated to a lower risk of discontinuation for toxicity vs. both DRV/r (AHR: 0.37, 95%CI: 0.19-0.72) and ATV/r (AHR: 0.18, 95%CI: 0.09-0.34). ATV/r was associated with a higher risk of discontinuing due to toxicity (AHR 2.09, 95%CI 1.63-2.67) vs. DRV/r. Conclusions In our observational study, we confirmed higher risk of treatment failure and lower tolerability of ATV/r-based regimens as compared to those including DRV/r or RAL.
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http://dx.doi.org/10.1080/15284336.2018.1440691DOI Listing
April 2018

Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial.

Lancet Respir Med 2018 03 8;6(3):183-192. Epub 2018 Jan 8.

Centre of Excellence in Immunity and Infection/Centre of Excellence for Personalised Medicine of Infectious Complications in Immune Deficiency, Department of Infectious Diseases, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark; Respiratory Medicine Division, Department of Internal Medicine, Herlev and Gentofte Hospital, Hellerup, Denmark. Electronic address:

Background: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock.

Methods: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America. Inclusion criteria for patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg, mechanical ventilation in an ICU, age at least 50 years, predicted length of stay in the ICU at least 24 h, and recruitment into the study within 6 h of fulfilling inclusion criteria. Exclusion criteria were uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission. We randomly allocated patients 1:1 (with variable block sizes ranging from four to eight; stratified by predictors of mortality, age, Acute Physiology and Chronic Health Evaluation II score, and study site) to routine thermal management or 24 h of induced hypothermia (target 32-34°C) followed by 48 h of normothermia (36-38°C). The primary endpoint was 30 day all-cause mortality in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention). Patients and health-care professionals giving the intervention were not masked to treatment allocation, but assessors of the primary outcome were. This trial is registered with ClinicalTrials.gov, number NCT01455116.

Findings: Between Nov 1, 2011, and Nov 4, 2016, we screened 5695 patients. After recruitment of 436 of the planned 560 participants, the trial was terminated for futility (220 [50%] randomly allocated to hypothermia and 216 [50%] to routine thermal management). In the hypothermia group, 96 (44·2%) of 217 died within 30 days versus 77 (35·8%) of 215 in the routine thermal management group (difference 8·4% [95% CI -0·8 to 17·6]; relative risk 1·2 [1·0-1·6]; p=0·07]).

Interpretation: Among patients with septic shock and ventilator-dependent respiratory failure, induced hypothermia does not reduce mortality. Induced hypothermia should not be used in patients with septic shock.

Funding: Trygfonden, Lundbeckfonden, and the Danish National Research Foundation.
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http://dx.doi.org/10.1016/S2213-2600(18)30004-3DOI Listing
March 2018

HIV-1 co-receptor tropism and liver fibrosis in HIV-infected patients.

PLoS One 2018 11;13(1):e0190302. Epub 2018 Jan 11.

Clinic of Infectious and Tropical Diseases, Department of Health Sciences, San Paolo H, University of Milan, Milan, Italy.

Background: In vitro, gp120 of both X4 and R5 HIV-1 strains activates human hepatic stellate cells, but if it can promote liver fibrosis in vivo is unknown. We aimed to evaluate if patients carrying X4 or R5 strains have a different liver fibrosis (LF) progression over time.

Methods: A total of 1,137 HIV-infected patients in ICONA cohort (21% females, 7% HCV co-infected) with an available determination of HIV-1 co-receptor tropism (CRT), a Fibrosis-4 Index for Liver Fibrosis (FIB-4) <3.25 and at least one-year follow-up were included. CRT was assessed by gp120 sequencing on plasma RNA and geno2pheno algorithm (10% false positive rate) or by Trofile. LF was assessed by means of FIB-4. LF progression was defined as an absolute score increase or a transition to higher fibrosis stratum and/or occurrence of liver-related clinical events.

Results: A total of 249 (22%) patients carried X4 strains, which were associated with older age, lower CD4 count, lower nadir CD4, and intravenous drug use. Overall, X4 and R5 patients had similar baseline FIB-4 scores and similar mean FIB-4 slope after a median follow-up of 35 months. There was no difference between X4 and R5 for time to LF progression (p = 0.925). Estimated risk of LF at 24 months (95% CI) after baseline in X4 and R5 was 10.6% (8.3-12.9) and 9.9% (5.9-14.0), respectively. Age, HCV co-infection, diabetes, HIV-duration, HIV-RNA>100.000 cp/mL, antiretroviral therapy exposure were associated with LF progression at multivariate analysis.

Conclusions: A slight LF progression over time was observed in HIV-infected patients. No difference was demonstrated for X4 and R5 HIV-1 strains in accelerating LF evolution.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764264PMC
February 2018

Incidence and predictors of single drug discontinuation according to the presence of HCV coinfection in HIV patients from the ICONA Foundation Cohort Study.

Eur J Clin Microbiol Infect Dis 2018 May 9;37(5):871-881. Epub 2018 Jan 9.

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

To evaluate incidence rates of and predictors for any antiretroviral (ART) drug discontinuation by HCV infection status in a large Italian cohort of HIV infected patients. All patients enrolled in ICONA who started combination antiretroviral therapy (cART) containing abacavir or tenofovir or emtricitabine or lamivudine plus efavirenz or rilpivirine or atazanavir/r or darunavir/r (DRV/r) or lopinavir/r or dolutegravir or elvitegravir or raltegravir were included. Multivariate Poisson regression models were used to determine factors independently associated with single ART drug discontinuation. Inverse probability weighting method to control for potential informative censoring was applied. Data from 10,637 patients were analyzed and 1,030 (9.7%) were HCV-Ab positive. Overall, there were 15,464 ART discontinuations due to any reason in 82,415.9 person-years of follow-up (PYFU) for an incidence rate (IR) of 18.8 (95% confidence interval [95%CI] 18.5-19.1) per 100 PYFU. No difference in IR of ART discontinuation due to any reason between HCV-infected and -uninfected patients was found. In a multivariable Poisson regression model, HCV-infected participants were at higher risk of darunavir/r discontinuation due to any reason (adjusted incidence rate ratio = 1.5, 95%CI 1.01-2.22, p value = 0.045) independently of demographics, HIV-related, ART and life-style factors. Among DRV/r treated patients, we found that HCV-viremic patients had twice the risk of ART discontinuation due to any reason than HCV-aviremic patients. In conclusion, HIV/HCV coinfected patients had a marginal risk increase of DRV/r discontinuation due to any reason compared with those without coinfection.
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http://dx.doi.org/10.1007/s10096-017-3180-8DOI Listing
May 2018