Publications by authors named "Stephane de Wit"

163 Publications

A public health value-based healthcare paradigm for HIV.

BMC Health Serv Res 2022 Jan 2;22(1):13. Epub 2022 Jan 2.

Division of Infectious Diseases, Saint Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium.

Background: HIV patients face considerable acute and chronic healthcare needs and battling the HIV epidemic remains of the utmost importance. By focusing on health outcomes in relation to the cost of care, value-based healthcare (VBHC) proposes a strategy to optimize quality of care and cost-efficiency. Its implementation may provide an answer to the increasing pressure to optimize spending in healthcare while improving patient outcomes. This paper describes a pragmatic value-based healthcare framework for HIV care.

Methods: A value-based HIV healthcare framework was developed during a series of roundtable discussions bringing together 16 clinical stakeholder representatives from the Belgian HIV reference centers and 2 VBHC specialists. Each round of discussions was focused on a central question translating a concept or idea to the next level of practical implementation: 1) how can VBHC principles be translated into value-based HIV care drivers; 2) how can these value-based HIV care divers be translated into value-based care objectives and activities; and 3) how can value-based HIV care objectives and activities be translated into value-based care indicators. Value drivers were linked to concrete objectives and activities using a logical framework approach. Finally, specific, measurable, and acceptable structure, process and outcomes indicators were defined to complement the framework.

Results: Our framework identifies 4 core value areas where HIV care would benefit most from improvements: Prevention, improvement of the cascade of care, providing patient-centered HIV care and sustaining a state-of-the-art HIV disease management context. These 4 core value areas were translated into 12 actionable core value objectives. For each objective, example activities were proposed. Indicators are suggested for each level of the framework (outcome indicators for value areas and objectives, process indicators for suggested activities).

Conclusions: This framework approach outlines how to define a patient- and public health centered value-based HIV care paradigm. It proposes how to translate core value drivers to practical objectives and activities and suggests defining indicators that can be used to track and improve the framework's implementation in practice.
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http://dx.doi.org/10.1186/s12913-021-07371-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722062PMC
January 2022

Hypersensitivity reactions, hepatotoxicity, and other discontinuations in persons receiving integrase strand transfer inhibitors: results from the EuroSIDA study.

HIV Res Clin Pract 2021 Dec 15;22(6):160-168. Epub 2021 Nov 15.

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

Hypersensitivity reaction (HSR) and hepatotoxicity are rare, but potentially serious side-effects of antiretroviral use. To investigate discontinuations due to HSR, hepatotoxicity or other reasons among users of dolutegravir (DTG) vs. raltegravir (RAL) or elvitegravir (EVG) in the EuroSIDA cohort. We compared individuals ≥18 years and starting combination antiretroviral therapy (ART, ≥3 drugs) with DTG vs. RAL or EVG, with or without abacavir (ABC), between January 16, 2014 and January 23, 2019. Discontinuations due to serious adverse events (SAEs) were independently reviewed. Altogether 4366 individuals started 5116 ART regimens including DTG, RAL, or EVG, contributing 9180 person-years of follow-up (PYFU), with median follow-up 1.6 (interquartile range 0.7-2.8) years per treatment episode. Of these, 3074 (60.1%) used DTG (1738 with ABC, 1336 without) and 2042 (39.9%) RAL or EVG (286 with ABC, 1756 without). 1261 (24.6%) INSTI episodes were discontinued, 649 of the DTG-containing regimens (discontinuation rate 115, 95% CI 106-124/1000 PYFU) and 612 RAL or EVG-containing regimens (173, CI 160-188/1000 PYFU). After independent review, there were five HSR discontinuations, two for DTG (one with and one without ABC, discontinuation rate 0.35, CI 0.04-1.28/1000 PYFU), and three for RAL or EVG without ABC (0.85, CI 0.18-2.48/1000 PYFU). There was one hepatotoxicity discontinuation on DTG with ABC (discontinuation rate 0.18, CI 0.00-0.99/1000 PYFU). During 5 years of observations in the EuroSIDA cohort independently reviewed discontinuations due to HSR or hepatotoxicity were very rare, indicating a low rate of SAEs.
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December 2021

Contemporary antiretrovirals and body-mass index: a prospective study of the RESPOND cohort consortium.

Lancet HIV 2021 11 20;8(11):e711-e722. Epub 2021 Sep 20.

ViiV Healthcare, Research Triangle, NC, USA.

Background: Weight gain effects of individual antiretroviral drugs are not fully understood. We investigated associations between a prespecified clinically significant increase (>7%) in body-mass index (BMI) and contemporary antiretroviral use.

Methods: The International Cohort Consortium of Infectious Diseases (RESPOND) is a prospective, multicohort collaboration, including data from 17 well established cohorts and over 29 000 people living with HIV. People with HIV under prospective follow-up from Jan 1, 2012, and older than 18 years were eligible for inclusion. Each cohort contributed a predefined minimum number of participants related to the size of the specific cohort (with a minimum of 1000 participants). Participants were required to have CD4 cell counts and HIV viral load measurement in the 12 months before or within 3 months after baseline. For all antiretroviral drugs received at or after RESPOND entry, changes from pre-antiretroviral BMI levels (baseline) were considered at each BMI measurement during antiretroviral treatment. We used logistic regression to identify individual antiretrovirals that were associated with first occurrence of a more than 7% increase in BMI from pre-antiretroviral BMI. We adjusted analyses for time on antiretrovirals, pre-antiretroviral BMI, demographics, geographical region, CD4 cell count, viral load, smoking status, and AIDS at baseline.

Results: 14 703 people were included in this study, of whom 7863 (53·5%) had a more than 7% increase in BMI. Compared with lamivudine, use of dolutegravir (odds ratio [OR] 1·27, 95% CI 1·17-1·38), raltegravir (1·37, 1·20-1·56), and tenofovir alafenamide (1·38, 1·22-1·35) was significantly associated with a more than 7% BMI increase, as was low pre-antiretroviral BMI (2·10, 1·91-2·31 for underweight vs healthy weight) and Black ethnicity (1·61, 1·47-1·76 vs White ethnicity). Higher CD4 count was associated with a reduced risk of BMI increase (0·97, 0·96-0·98 per 100 cells per μL increase). Relative to lamivudine, dolutegravir without tenofovir alafenamide (OR 1·21, 95% CI 1·19-1·32) and tenofovir alafenamide without dolutegravir (1·33, 1·15-1·53) remained independently associated with a more than 7% increase in BMI; the associations were higher when dolutegravir and tenofovir alafenamide were used concomitantly (1·79, 1·52-2·11, and 1·70, 1·44-2·01, respectively).

Interpretation: Clinicians and people with HIV should be aware of associations between weight gain and use of dolutegravir, tenofovir alafenamide, and raltegravir, particularly given the potential consequences of weight gain, such as insulin resistance, dyslipidaemia, and hypertension.

Funding: The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences.
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http://dx.doi.org/10.1016/S2352-3018(21)00163-6DOI Listing
November 2021

Remdesivir Versus Standard-of-Care for Severe Coronavirus Disease 2019 Infection: An Analysis of 28-Day Mortality.

Open Forum Infect Dis 2021 Jul 26;8(7):ofab278. Epub 2021 May 26.

Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom.

Background: Remdesivir is approved by the US Food and Drug Administration for the treatment of patients hospitalized with coronavirus disease 2019 (COVID-19) and has been shown to shorten time to recovery and improve clinical outcomes in randomized trials.

Methods: This was the final day 28 comparative analysis of data from a phase 3, randomized, open-label study comparing 2 remdesivir regimens (5 vs 10 days, combined for this analysis [remdesivir cohort]) and a real-world retrospective longitudinal cohort study of patients receiving standard-of-care treatment (nonremdesivir cohort). Eligible patients, aged ≥18 years, had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), oxygen saturation ≤94% on room air or required supplemental oxygen, with pulmonary infiltrates. Propensity score matching (up to 1:10 ratio) was used to ensure comparable populations. We assessed day 14 clinical recovery (determined using a 7-point ordinal scale) and day 28 all-cause mortality (coprimary endpoints).

Results: A total of 368 (remdesivir) and 1399 (nonremdesivir) patients were included in the matched analysis. The day 14 clinical recovery rate was significantly higher among the remdesivir versus the nonremdesivir cohort (65.2% vs 57.1%; odds ratio [OR], 1.49; 95% confidence interval [CI], 1.16-1.90; = 0.002). The day 28 mortality rate was significantly lower in the remdesivir cohort versus the nonremdesivir cohort (12.0% vs 16.2%; OR, 0.67; 95% CI, 0.47-.95;  = .03).

Conclusions: Remdesivir was associated with significantly higher rates of day 14 clinical recovery, and lower day 28 mortality, compared with standard-of-care treatment in hospitalized patients with COVID-19. These data, taken together, support the use of remdesivir to improve clinical recovery and decrease mortality from SARS-CoV-2 infection.
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http://dx.doi.org/10.1093/ofid/ofab278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244650PMC
July 2021

Primary antibiotic resistance of Helicobacter pylori isolates is twofold more frequent in HIV-positive than HIV-negative individuals: A descriptive observational study.

Microbiologyopen 2021 06;10(3):e1184

Department of Infectious Diseases, CHU Saint Pierre Université Libre de Bruxelles, Bruxelles, Belgium.

The antimicrobial susceptibility of Helicobacter pylori strains isolated from HIV-positive individuals is not well characterized. This study aimed to measure the prevalence and long-term trends associated with primary H. pylori antibiotic resistance, evaluate correlations with antibiotic consumption, and compare predictors for H. pylori antibiotic resistance between HIV-positive and HIV-negative individuals. In this longitudinal registry study, we evaluated consecutive adults with and without HIV infection, naïve to H. pylori treatment, who underwent upper gastrointestinal endoscopy and had a positive H. pylori culture, with susceptibility testing available, between 2004 and 2015. Outpatient antibiotic consumption data were based on nationwide aggregated numbers. H. pylori was isolated from gastric biopsies of 3008/8321 patients, 181/477 (37.9%) were HIV-positive and 2827/7844 (36.0%) HIV-negative. Overall cohort mean prevalence of H. pylori primary antibiotic resistance was 11.1% for clarithromycin, 17.8% levofloxacin, and 39.4% metronidazole. The prevalence of H. pylori primary resistance was significantly higher for these three drugs in HIV-positive individuals across the study period. Linear regression showed that the prevalence of clarithromycin and levofloxacin resistance correlated with the country aggregate daily dose consumption of macrolides and quinolones, respectively. Multivariable regression analysis showed that HIV infection is a strong independent risk factor for multiple H. pylori antibiotic resistance. In summary, HIV infection is a risk factor for carrying multi-resistant H. pylori strains and this is correlated with antibiotic consumption. Empirical therapies should be avoided in HIV-positive individuals. These data highlight the need to implement ongoing monitoring of H. pylori antimicrobial susceptibility among HIV-positive individuals. The study is registered at ISRCTN registry, number 13466428: https://www.isrctn.com/ISRCTN13466428.
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http://dx.doi.org/10.1002/mbo3.1184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166256PMC
June 2021

Switching from boosted PIs to dolutegravir decreases soluble CD14 and adiponectin in high cardiovascular risk people living with HIV.

J Antimicrob Chemother 2021 08;76(9):2380-2393

Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain.

Background: Switching from boosted PIs to dolutegravir in people living with HIV (PLWH) with high cardiovascular risk improved plasma lipids at 48 weeks in the NEAT022 trial. Whether this strategy may have an impact on cardiovascular biomarkers is unknown.

Methods: We assessed 48 week changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury, and glomerular and tubular kidney injury.

Results: Of 415 PLWH randomized in the NEAT022 study, 313 (75.4%) remained on allocated therapy and had paired samples available. Soluble CD14 (-11%, P < 0.001) and adiponectin (-11%, P < 0.001) significantly declined and high-sensitive C-reactive protein (-13%, P = 0.069) and oxidized LDL (-13%, P = 0.084) tended to decrease with dolutegravir. Switching to dolutegravir remained significantly associated with soluble CD14 and adiponectin reductions after adjustment for baseline variables. There were inverse correlations between soluble CD14 and CD4 count changes (P = 0.05), and between adiponectin and BMI changes (P < 0.001).

Conclusions: Switching from boosted PIs to dolutegravir in PLWH with high cardiovascular risk led to soluble CD14 and adiponectin reductions at 48 weeks. While decreasing soluble CD14 may entail favourable health effects in PLWH, adiponectin reduction may reflect less insulin sensitivity associated with weight gain.
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http://dx.doi.org/10.1093/jac/dkab158DOI Listing
August 2021

No need for secondary Pneumocystis jirovecii pneumonia prophylaxis in adult people living with HIV from Europe on ART with suppressed viraemia and a CD4 cell count greater than 100 cells/µL.

J Int AIDS Soc 2021 06;24(6):e25726

Department of Infectious Diseases, Bern University Hospital, Inselspital, University of Bern, Bern, Switzerland.

Introduction: Since the beginning of the HIV epidemic in resource-rich countries, Pneumocystis jirovecii pneumonia (PjP) is one of the most frequent opportunistic AIDS-defining infections. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) has shown that primary Pneumocystis jirovecii Pneumonia (PjP) prophylaxis can be safely withdrawn in patients with CD4 counts of 100 to 200 cells/µL if plasma HIV-RNA is suppressed on combination antiretroviral therapy. Whether this holds true for secondary prophylaxis is not known, and this has proved difficult to determine due to the much lower population at risk.

Methods: We estimated the incidence of secondary PjP by including patient data collected from 1998 to 2015 from the COHERE cohort collaboration according to time-updated CD4 counts, HIV-RNA and use of PjP prophylaxis in persons >16 years of age. We fitted a Poisson generalized additive model in which the smoothed effect of CD4 was modelled by a restricted cubic spline, and HIV-RNA was stratified as low (<400), medium (400 to 10,000) or high (>10,000copies/mL).

Results: There were 373 recurrences of PjP during 74,295 person-years (py) in 10,476 patients. The PjP incidence in the different plasma HIV-RNA strata differed significantly and was lowest in the low stratum. For patients off prophylaxis with CD4 counts between 100 and 200 cells/µL and HIV-RNA below 400 copies/mL, the incidence of recurrent PjP was 3.9 (95% CI: 2.0 to 5.8) per 1000 py, not significantly different from patients on prophylaxis in the same stratum (1.9, 95% CI: 0.1 to 3.7).

Conclusions: HIV viraemia importantly affects the risk of recurrent PjP. In virologically suppressed patients on ART with CD4 counts of 100 to 200/µL, the incidence of PjP off prophylaxis is below 10/1000 py. Secondary PjP prophylaxis may be safely withheld in such patients. While European guidelines recommend discontinuing secondary PjP prophylaxis only if CD4 counts rise above 200 cells/mL, the latest US Guidelines consider secondary prophylaxis discontinuation even in patients with a CD4 count above 100 cells/µL and suppressed viral load. Our results strengthen and support this US recommendation.
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http://dx.doi.org/10.1002/jia2.25726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196713PMC
June 2021

Immunogenicity and duration of protection after yellow fever vaccine in people living with human immunodeficiency virus: a systematic review.

Clin Microbiol Infect 2021 Jul 1;27(7):958-967. Epub 2021 Apr 1.

Infectious Diseases Department, Centre Hospitalier Universitaire Saint-Pierre-Université Libre de Bruxelles, Brussels, Belgium; Institute for Medical Immunology, Université Libre de Bruxelles, Brussels, Belgium; Environmental Health Research Centre, Public Health School, Université Libre de Bruxelles, Brussels, Belgium.

Background: We lack the rationale on which to base the development of a yellow fever (YF) vaccination schedule for people living with human immunodeficiency virus (PLWHIV).

Objectives: To report on the current evidence regarding the seroconversion rate and the duration of humoral protection after YF vaccine, as well as the impact of revaccination in PLWHIV.

Data Sources: MEDLINE, Google Scholar, LILACS and Cochrane CENTRAL were searched.

Methods: We selected studies on PLWHIV of all ages (including perinatally HIV-infected patients) and all settings (YF endemic and non-endemic zones). Intervention investigated was vaccination against YF, at least once after the HIV diagnosis. The research questions were the seroconversion rate, duration of humoral immunity after YF vaccine and impact of revaccination in PLWHIV. Selected studies were assessed for quality using the Newcastle-Ottawa scale.

Results: Ten, six and six studies were selected for the systematic review of each question, respectively. Only one study addressed the first question in perinatally HIV-infected children. The quality of the studies was assessed as Poor (n = 16), Fair (n = 2) or Good (n = 4). A meta-analysis demonstrated that 97.6% (95% CI 91.6%-100%) of the included population seroconverted. Between 1 and 10 years after YF vaccine, reported persistence of neutralizing antibodies was 72% (95% CI 53.6%-91%), and it was 62% (95% CI 45.4%-78.6%) more than 10 years after YF vaccine. No conclusions could be drawn on impact of revaccination because of the small number of patients.

Conclusions: The current evidence regarding seroconversion rate, duration of humoral protection after YF vaccine and impact of revaccination in PLWHIV is limited by the low number and quality of studies. Based on the presently available data, it is difficult to rationally develop yellow fever vaccination guidelines for PLWHIV.
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http://dx.doi.org/10.1016/j.cmi.2021.03.004DOI Listing
July 2021

Cost-effectiveness of statins for primary prevention of atherosclerotic cardiovascular disease among people living with HIV in the United States.

J Int AIDS Soc 2021 03;24(3):e25690

Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: Expanding statin use may help to alleviate the excess burden of atherosclerotic cardiovascular disease in people living with HIV (PLHIV). Pravastatin and pitavastatin are preferred agents due to their lack of substantial interaction with antiretroviral therapy. We aimed to evaluate the cost-effectiveness of pravastatin and pitavastatin for the primary prevention of atherosclerotic cardiovascular disease among PLHIV in the United States.

Methods: We developed a microsimulation model that randomly selected (with replacement) individuals from the Data-collection on Adverse Effects of Anti-HIV Drugs study with follow-up between 2013 and 2016. Our study population was PLHIV aged 40 to 75 years, stable on antiretroviral therapy, and not currently using lipid-lowering therapy. Direct medical costs and quality-adjusted life-years (QALYs) were assigned in annual cycles and discounted at 3% per year. We assumed a willingness-to-pay threshold of $100,000/QALY gained. The interventions assessed were as follows: (1) treating no one with statins; (2) treating everyone with generic pravastatin 40 mg/day (drug cost $236/year) and (3) treating everyone with branded pitavastatin 4 mg/day (drug cost $2,828/year). The model simulated each individual's probability of experiencing atherosclerotic cardiovascular disease over 20 years.

Results: Persons receiving pravastatin accrued 0.024 additional QALYs compared with those not receiving a statin, at an incremental cost of $1338, giving an incremental cost-effectiveness ratio of $56,000/QALY gained. Individuals receiving pitavastatin accumulated 0.013 additional QALYs compared with those using pravastatin, at an additional cost of $18,251, giving an incremental cost-effectiveness ratio of $1,444,000/QALY gained. These findings were most sensitive to the pill burden associated with daily statin administration, statin costs, statin efficacy and baseline atherosclerotic cardiovascular disease risk. In probabilistic sensitivity analysis, no statin was optimal in 5.2% of simulations, pravastatin was optimal in 94.8% of simulations and pitavastatin was never optimal.

Conclusions: Pravastatin was projected to be cost-effective compared with no statin. With substantial price reduction, pitavastatin may be cost-effective compared with pravastatin. These findings bode well for the expanded use of statins among PLHIV in the United States. To gain greater confidence in our conclusions it is important to generate strong, HIV-specific estimates on the efficacy of statins and the quality-of-life burden associated with taking an additional daily pill.
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http://dx.doi.org/10.1002/jia2.25690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982504PMC
March 2021

Risk for Non-AIDS-Defining and AIDS-Defining Cancer of Early Versus Delayed Initiation of Antiretroviral Therapy : A Multinational Prospective Cohort Study.

Ann Intern Med 2021 06 16;174(6):768-776. Epub 2021 Mar 16.

University Hospital Basel and University of Basel, Basel, Switzerland (F.C., H.C.B.).

Background: Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non-AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. However, most HIV-positive persons initiate ART when their CD4 count decreases below 500 × 10 cells/L. Consequences of delayed ART on risk for non-AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear.

Objective: To estimate the long-term risk difference for cancer with the immediate ART strategy.

Design: Multinational prospective cohort study.

Setting: The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States.

Participants: 8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016).

Measurements: The parametric g-formula was used, with adjustment for baseline and time-dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non-AIDS-defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts <350 and <500 × 10 cells/L) ART initiation strategies.

Results: During 64 021 person-years of follow-up, 231 cases of non-AIDS-defining cancer and 272 of AIDS-defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non-AIDS-defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500 × 10 cells/L and less than 350 × 10 cells/L were 0.12 percentage point (CI, -0.01 to 0.26 percentage point) and 0.29 percentage point (CI, -0.03 to 0.73 percentage point), respectively, for non-AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer.

Limitation: Potential residual confounding due to observational study design.

Conclusion: In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non-AIDS-defining cancer.

Primary Funding Source: Highly Active Antiretroviral Therapy Oversight Committee.
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http://dx.doi.org/10.7326/M20-5226DOI Listing
June 2021

Tetanus seroprotection in people living with HIV: Risk factors for seronegativity, evaluation of medical history and a rapid dipstick test.

Vaccine 2021 04 11;39(14):1963-1967. Epub 2021 Mar 11.

Department of Infectious Diseases, Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium; Institute for Medical Immunology, Université Libre de Bruxelles (ULB), Brussels, Belgium; Centre for Environmental Health and Occupational Health, School of Public Health, Université libre de Bruxelles (ULB), Belgium. Electronic address:

Objectives: Tetanus is a vaccine-preventable disease. Booster immunization is required in order to induce long-lived tetanus-toxoid (TT) specific antibody response. We investigated the prevalence and risk factors of TT seronegativity in a cohort of people living with HIV (PWH) in Belgium along with the respective performance of vaccine history and a rapid dipstick test (Tetanus Quick Stick ® or TQS) compared to ELISA testing.

Methods: PWH were prospectively enrolled and answered a questionnaire. ELISA was performed on serum or plasma using a commercial kit. A TT antibody level ≥ 0.15 IU / mL was considered protective. The TQS test was performed on a limited number of subjects.

Results: Three-hundred forty-four subjects were included. The prevalence of tetanus seroprotection was 84,9%. Median age was 46.7 and 68% were born outside Belgium. Antiretroviral therapy coverage was almost universal (98.5%). After multivariable analysis, two risk factors were independently associated with TT seronegativity: an education level equivalent or below than secondary school and being born outside Europe. Vaccine history was shown to be unreliable (sensitivity: 43.8%; specificity: 76.5%; positive predictive value: 91.4% and negative predictive value :19.3%). The correlation between vaccine history and tetanus seroprotection was low (kappa coefficient = 0.09). The TQS performances were good (sensitivity 86.4%, specificity 96.0%, positive predictive value 99.3%, negative predictive value 52.17%). The correlation between TQS and tetanus seroprotection was substantial (kappa coefficient = 0.61).

Conclusions: In this cohort of PWH with a high proportion of migrants, socio-demographic and educational factors were associated with TT seronegativity while HIV-related factors were not, indicating that vaccine information should be tailored to cultural and educational background. As vaccine history is not reliable, TQS could represent an efficient tool for screening of TT-seronegativity.
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http://dx.doi.org/10.1016/j.vaccine.2021.02.062DOI Listing
April 2021

Bictegravir/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed People with HIV Aged ≥ 65 Years: Week 48 Results of a Phase 3b, Open-Label Trial.

Infect Dis Ther 2021 Jun 9;10(2):775-788. Epub 2021 Mar 9.

Gilead Sciences, Foster City, CA, USA.

Introduction: We report the 48-week results of an ongoing study to assess the efficacy and safety of switching older people with HIV to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF).

Methods: This was a 96-week, phase 3b, open-label, single-arm study (GS-US-380-4449; NCT03405935). Virologically suppressed individuals aged ≥ 65 years receiving elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or a tenofovir disoproxil fumarate-based regimen were switched to B/F/TAF. Primary endpoint was the percentage of participants with HIV-1 RNA < 50 copies/ml at week 24.

Results: Eighty-six participants (median age 69 [range 65-80] years; 87% male; 95% white) were enrolled and treated in five European countries. Rates of virologic suppression were 97.7% at week 24 and 90.7% at week 48; none had HIV-1 RNA ≥ 50 copies/ml, and 100% had virologic suppression by missing = excluded analysis at both time points. No treatment-emergent resistance was observed. There were no grade 3-4 study drug-related adverse events (AEs) or study drug-related serious AEs or deaths. Three AEs led to premature discontinuation; one (moderate abdominal discomfort) was attributed to the study drug by the investigator. At week 48, median changes from baseline in weight and estimated glomerular filtration rate were + 0.1 kg (interquartile range [IQR] - 1.0, 2.3) and - 6.0 ml/min (IQR - 10.2, 0.0), respectively. There were no clinically relevant changes from baseline to week 48 in fasting lipid parameters. Treatment satisfaction improved, and health-related quality of life was maintained from baseline through week 48. Median adherence to the study drug was 98.6% (IQR 96.0, 100).

Conclusions: Switching to B/F/TAF was effective and well tolerated through 48 weeks in virologically suppressed adults aged ≥ 65 years.

Trial Registration: ClinicalTrials.gov identifier, NCT03405935.
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http://dx.doi.org/10.1007/s40121-021-00419-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116430PMC
June 2021

Clinical characteristics and outcomes of COVID-19 in people living with HIV in Belgium: A multicenter, retrospective cohort.

J Med Virol 2021 05 9;93(5):2971-2978. Epub 2021 Feb 9.

Division of Infectious Diseases, Saint-Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium.

The aim of this study was to describe the clinical characteristics and outcomes of coronavirus disease 2019 (COVID-19) among people living with HIV (PLWH) in Belgium. We performed a retrospective multicenter cohort analysis of PLWH with either laboratory-confirmed, radiologically diagnosed, or clinically suspected COVID-19 between February 15, 2020 and May 31, 2020. The primary endpoint was outcome of COVID-19. Secondary endpoints included rate of hospitalization and length of hospital stay and rate of Intensive Care Unit (ICU) admission and mechanical ventilation. One hundred and one patients were included in this study. Patients were categorized as having either laboratory-confirmed (n = 65), radiologically-diagnosed (n = 3), or clinically suspected COVID-19 (n = 33). The median age was 51.3 years (interquartile range [IQR] 41.3-57.3) and 44% were female. Ninety-four percent of patients were virologically suppressed and 67% had a CD4 cell count more than or equal to 500 cells/µl. Overall, 46% of patients required hospitalization and the median length of hospital stay was 6 days (IQR 3-15). Age more than or equal to 50 years, Black Sub-Saharan African patients, and being on an integrase strand transfer inhibitor-based regimen were associated with being hospitalized. ICU admission and mechanical ventilation was required for 15% and 10% of all patients respectively. Overall, 9% of patients died while 78 (77%) patients made a full recovery. HIV patients with COVID-19 experienced a high degree of hospitalization despite having elevated CD4 cell counts and a high rate of virologic suppression. Matched case-control studies are warranted to measure the impact that HIV may have on patients with COVID-19.
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http://dx.doi.org/10.1002/jmv.26828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014531PMC
May 2021

Virologic and immunologic outcomes of treatment with integrase inhibitors in a real-world setting: The RESPOND cohort consortium.

PLoS One 2020 31;15(12):e0243625. Epub 2020 Dec 31.

The Australian HIV Observational Database (AHOD), UNSW, Sydney, Australia.

Objectives: To compare virologic and immunologic outcomes of integrase inhibitor (INSTI)-containing, contemporary boosted protease inhibitor (PI/b)-containing and non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens in a real-life setting.

Methods: Using logistic regression, virologic and immunologic outcomes of INSTI use were compared to outcomes of PI/b or NNRTI treatment 12 months after treatment start or switch, for participants in the RESPOND cohort consortium. A composite treatment outcome (cTO) was used, defining success as viral load (VL) <200 copies/mL and failure as at least one of: VL ≥200 copies/mL, unknown VL in the time window, any changes of antiretroviral therapy (ART) regimen, AIDS, or death. In addition, on-treatment analysis including only individuals with known VL and no regimen changes was performed. Favorable immunologic response was defined as a 25% increase in CD4 count or as reaching ≥750 CD4 cells/μL.

Results: Between January 2012 and January 2019, 13,703 (33.0% ART-naïve) individuals were included, of whom 7,147 started/switched to a regimen with an INSTI, 3,102 to a PI/b and 3,454 to an NNRTI-containing regimen. The main reason for cTO failure in all treatment groups were changes in ART regimen. Compared to INSTIs, the adjusted odds ratio (aOR) of cTO success was significantly lower for PI/b (0.74 [95% confidence interval, CI 0.67-0.82], p <0.001), but similar for NNRTIs (1.07 [CI 0.97-1.17], p = 0.11). On-treatment analysis and sensitivity analyses using a VL cut-off of 50 copies/mL were consistent. Compared to INSTIs, the aORs of a 25% increase in CD4 count were lower for NNRTIs (0.80 [CI 0.71-0.91], p<0.001) and PI/b (0.87 [CI 0.76-0.99], p = 0.04).

Conclusion: In this large analysis of a real-world population, cTO and on-treatment success were similar between INSTIs and NNRTIs, but lower for PI/b, though residual confounding cannot be fully excluded. Obtaining favorable immunologic outcomes were more likely for INSTIs than the other drug classes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243625PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774984PMC
February 2021

Clinical Outcomes of 2-Drug Regimens vs 3-Drug Regimens in Antiretroviral Treatment-Experienced People Living With Human Immunodeficiency Virus.

Clin Infect Dis 2021 10;73(7):e2323-e2333

Gilead science, Foster City, California, USA.

Background: Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus.

Methods: Antiretroviral treatment-experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012-1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression.

Results: Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7-59.0] vs 47.7 [39.7-54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27 159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU; 95% confidence interval [CI]: 20.7-24.5) on 3DRs and 79 (30.9/1000 PYFU; 95% CI: 24.8-38.5) on 2DRs. The most common events were death (7.5/1000 PYFU; 95% CI: 6.5-8.6) and non-AIDS cancer (5.8/1000 PYFU; 95% CI: 4.9-6.8). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio, 0.92; 95% CI: .72-1.19; P = .53).

Conclusions: This is the first large, international cohort to assess clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes. Further research on resistance barriers and long-term durability of 2DRs is needed.
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http://dx.doi.org/10.1093/cid/ciaa1878DOI Listing
October 2021

Effect of Changes in Body Mass Index on the Risk of Cardiovascular Disease and Diabetes Mellitus in HIV-Positive Individuals: Results From the D:A:D Study.

J Acquir Immune Defic Syndr 2021 04;86(5):579-586

The Kirby Institute, UNSW Sydney, Sydney, Australia.

Background: Weight gain is common among people with HIV once antiretroviral treatment is commenced. We assess the effect of changes in body mass index (BMI), from different baseline BMI levels, on the risk of cardiovascular disease (CVD) and diabetes mellitus (DM).

Methods: D:A:D participants receiving antiretroviral treatment were followed from their first BMI measurement to the first of either CVD or DM event, or earliest of January 2, 2016 or 6 months after last follow-up. Participants were stratified according to their baseline BMI, and changes from baseline BMI were calculated for each participant. Poisson regression models were used to assess the effects of changes on BMI on CVD or DM events.

Results: There were 2104 CVD and 1583 DM events over 365,287 and 354,898 person-years [rate: CVD 5.8/1000 (95% confidence interval: 5.5 to 6.0); DM 4.5/1000 (95% confidence interval: 4.2 to 4.7)]. Participants were largely men (74%), baseline mean age of 40 years, and median BMI of 23.0 (IQR: 21.0-25.3). A risk of CVD by change in BMI from baseline, stratified by baseline BMI strata showed little evidence of an increased risk of CVD with an increased BMI in any baseline BMI strata. An increase in BMI was associated with an increased risk of DM across all baseline BMI strata.

Conclusions: Although increases in BMI across all levels of baseline BMI were not associated with an increased risk of CVD, such changes were consistently associated with an increased risk of DM. There was also some evidence of an increased risk of CVD with a decrease in BMI.
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http://dx.doi.org/10.1097/QAI.0000000000002603DOI Listing
April 2021

Single-tablet regimen of emtricitabine/tenofovir disoproxil fumarate plus cobicistat-boosted elvitegravir increase adherence for HIV postexposure prophylaxis in sexual assault victims.

Sex Transm Infect 2021 08 26;97(5):329-333. Epub 2020 Oct 26.

Infectious Diseases, CHU Saint-Pierre, Bruxelles, Belgium.

Background: Postexposure prophylaxis (PEP) is a recommended public health intervention after a sexual assault to prevent HIV infection.

Methods: We conducted a retrospective case-control study on how use of a single-tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (Stribild) affected adherence to PEP and attendance of a follow-up visit to the STI clinic compared with those who received a multitablet regimen (MTR). Data from sexual assault victims consulting for PEP were prospectively recorded between January 2011 and December 2017. Data were systematically collected on patient demographics, time of medical contact, source risk factors, type of exposure, attendance to follow-up visit, reported completion of PEP and adherence based on pharmacy records.

Results: A total of 422 patients received PEP following a sexual assault, of whom 52% had documented completion of a 28-day PEP regimen and 71% attended a follow-up clinic visit. Patients who received an elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF)-based STR had a similar likelihood of attending their first follow-up visit (OR: 0.97; 95% CI: 0.64 to 1.48, p=0.90) but were more likely to complete the PEP regimen (OR: 1.70; 95% CI: 1.16 to 2.50, p=0.007). After adjusting for confounders, those who were prescribed an STR regimen were more likely to complete the PEP regimen (OR: 1.66, 95% CI: 1.09 to 2.53, p=0.019) than those who were prescribed an MTR such as stavudine/lamivudine/lopinavir/ritonavir or zidovudine/lamivudine/indinavir/ritonavir.

Conclusions: Sexual assault victims who were prescribed an STR based on EVG/COBI/FTC/TDF were more likely to complete PEP than those who were prescribed an MTR.
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http://dx.doi.org/10.1136/sextrans-2020-054714DOI Listing
August 2021

Remdesivir for Severe Coronavirus Disease 2019 (COVID-19) Versus a Cohort Receiving Standard of Care.

Clin Infect Dis 2021 12;73(11):e4166-e4174

Gilead Sciences, Foster City, California, USA.

Background: We compared the efficacy of the antiviral agent, remdesivir, versus standard-of-care treatment in adults with severe coronavirus disease 2019 (COVID-19) using data from a phase 3 remdesivir trial and a retrospective cohort of patients with severe COVID-19 treated with standard of care.

Methods: GS-US-540-5773 is an ongoing phase 3, randomized, open-label trial comparing two courses of remdesivir (remdesivir-cohort). GS-US-540-5807 is an ongoing real-world, retrospective cohort study of clinical outcomes in patients receiving standard-of-care treatment (non-remdesivir-cohort). Inclusion criteria were similar between studies: patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, were hospitalized, had oxygen saturation ≤94% on room air or required supplemental oxygen, and had pulmonary infiltrates. Stabilized inverse probability of treatment weighted multivariable logistic regression was used to estimate the treatment effect of remdesivir versus standard of care. The primary endpoint was the proportion of patients with recovery on day 14, dichotomized from a 7-point clinical status ordinal scale. A key secondary endpoint was mortality.

Results: After the inverse probability of treatment weighting procedure, 312 and 818 patients were counted in the remdesivir- and non-remdesivir-cohorts, respectively. At day 14, 74.4% of patients in the remdesivir-cohort had recovered versus 59.0% in the non-remdesivir-cohort (adjusted odds ratio [aOR] 2.03: 95% confidence interval [CI]: 1.34-3.08, P < .001). At day 14, 7.6% of patients in the remdesivir-cohort had died versus 12.5% in the non-remdesivir-cohort (aOR 0.38, 95% CI: .22-.68, P = .001).

Conclusions: In this comparative analysis, by day 14, remdesivir was associated with significantly greater recovery and 62% reduced odds of death versus standard-of-care treatment in patients with severe COVID-19.

Clinical Trials Registration: NCT04292899 and EUPAS34303.
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http://dx.doi.org/10.1093/cid/ciaa1041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454434PMC
December 2021

The Impact of Immunosuppression on Chronic Kidney Disease in People Living With Human Immunodeficiency Virus: The D:A:D Study.

J Infect Dis 2021 02;223(4):632-637

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

Background: Relations between different measures of human immunodeficiency virus-related immunosuppression and chronic kidney disease (CKD) remain unknown.

Methods: Immunosuppression measures included baseline, current, time-lagged and nadir CD4, years and percentage of follow-up (%FU) with CD4 ≤200 cells/μL, and CD4 recovery. CKD was defined as confirmed estimated glomerular filtration rate <60 mL/minute/1.73 m2.

Results: Of 33 791 persons, 2226 developed CKD. Univariably, all immunosuppression measures predicted CKD. Multivariably, the strongest predictor was %FU CD4 ≤200 cells/μL (0 vs >25%; incidence rate ratio [IRR], 0.77 [95% confidence interval [CI], .68-.88]), with highest effect in those at low D:A:D CKD risk (IRR, 0.45 [95% CI, .24-.80]) vs 0.80 [95% CI, .70-.93]).

Conclusions: Longer immunosuppression duration most strongly predicts CKD and affects persons at low CKD risk more.
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http://dx.doi.org/10.1093/infdis/jiaa396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904289PMC
February 2021

Malaria in HIV-infected patients in a nonendemic setting.

AIDS 2020 07;34(9):1359-1365

Infectious Diseases Department, Centre Hospitalier Universitaire (CHU) Saint-Pierre - Université Libre de Bruxelles (ULB).

Background: The impact of HIV infection on malaria is unclear in nonendemic areas. In endemic territories, HIV has been reported to be a risk factor for higher morbidity. Nowadays, as HIV-infected patients travel more, it is important to assess the impact of HIV at the individual level on imported malaria.

Material And Methods: This retrospective case-control study collected data on HIV-infected patients diagnosed with malaria (2000-2017) and matched them with two controls based on age, sex and ethnicity. Clinical and biological parameters were collected and compared.

Results: We identified 47 cases and matched them with 94 controls. Comparing each of the WHO 2014 severity criteria, hyperparasitemia above 10% (P = 0.006; 12.8 versus 1.1%), icterus (P = 0.042; 14.9 versus 4.3%), acute renal failure (P = 0.022; 25.5 versus 9.6%) and bacteraemia (P = 0.014; 6.4 versus 0%) were significantly more present in HIV-infected patients with a trend to more cerebral malaria (12.8 versus 6.4%). HIV- infected patients were hospitalized more frequently and for longer periods. We observed a higher number of severity criteria when CD4 T-cell count was lower, especially below 200 cells/μl. The difference in occurrence of severe malaria disappeared when patients with CD4 T-cell count more than 500 cells/μl and undetectable viral load (n = 9) were compared with controls. De-novo HIV diagnosis was made during the malaria episode in 17% of cases.

Conclusion: HIV infection has an impact on the imported malaria profile, although it is unclear whether well controlled HIV-infected patients have a higher risk of severe malaria. HIV-infected patients should be particularly targeted for pretravel advice.
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http://dx.doi.org/10.1097/QAD.0000000000002568DOI Listing
July 2020

Withholding Primary Pneumocystis Pneumonia Prophylaxis in Virologically Suppressed Patients With Human Immunodeficiency Virus: An Emulation of a Pragmatic Trial in COHERE.

Clin Infect Dis 2021 07;73(2):195-202

Department of Infectious Diseases, Bern University Hospital, Inselspital, University of Bern, Bern, Switzerland.

Background: Using data from the COHERE collaboration, we investigated whether primary prophylaxis for pneumocystis pneumonia (PcP) might be withheld in all patients on antiretroviral therapy (ART) with suppressed plasma human immunodeficiency virus (HIV) RNA (≤400 copies/mL), irrespective of CD4 count.

Methods: We implemented an established causal inference approach whereby observational data are used to emulate a randomized trial. Patients taking PcP prophylaxis were eligible for the emulated trial if their CD4 count was ≤200 cells/µL in line with existing recommendations. We compared the following 2 strategies for stopping prophylaxis: (1) when CD4 count was >200 cells/µL for >3 months or (2) when the patient was virologically suppressed (2 consecutive HIV RNA ≤400 copies/mL). Patients were artificially censored if they did not comply with these stopping rules. We estimated the risk of primary PcP in patients on ART, using the hazard ratio (HR) to compare the stopping strategies by fitting a pooled logistic model, including inverse probability weights to adjust for the selection bias introduced by the artificial censoring.

Results: A total of 4813 patients (10 324 person-years) complied with eligibility conditions for the emulated trial. With primary PcP diagnosis as an endpoint, the adjusted HR (aHR) indicated a slightly lower, but not statistically significant, different risk for the strategy based on viral suppression alone compared with the existing guidelines (aHR, .8; 95% confidence interval, .6-1.1; P = .2).

Conclusions: This study suggests that primary PcP prophylaxis might be safely withheld in confirmed virologically suppressed patients on ART, regardless of their CD4 count.
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http://dx.doi.org/10.1093/cid/ciaa615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516510PMC
July 2021

Effectiveness of dolutegravir-based antiretroviral therapy in a real-world setting in a Belgian cohort of 4101 HIV patients.

AIDS 2020 07;34(8):1151-1159

Saint-Pierre University Hospital, Université Libre de Bruxelles, Brussels.

Objective: To describe the treatment outcomes of patients receiving dolutegravir (DTG) in a 'real-world setting' in Belgium.

Design: Retrospective, observational, multicenter cohort.

Methods: Inclusion criteria: HIV-1 patients at least 18 years old having received DTG as part of their combined antiretroviral therapy (cART) between 1 April 2014 and 1 December 2017. Primary endpoint: rate of virologic suppression, defined as plasma HIV-1 viral load less than 50 copies/ml, at weeks 24, 48, and 96. Secondary endpoints: durability, expressed as probability of experiencing loss of virologic suppression by week 96 (defined as two consecutive HIV-1 viral load measurements of at least 200 copies/ml after having initially achieved virologic suppression); immunological response at weeks 24, 48, and 96; incidence of and reasons for DTG discontinuation; and change in weight at week 96.

Results: Four thousand, one hundred and one patients were included. Through 96 weeks, virologic suppression rate was 96% (on-treatment analysis), probability of experiencing loss of virologic suppression was 7%, and mean increase in CD4 cell count was 100 cells/μl (SD 220). There were 785 (19.1%) discontinuations of DTG (8.9 discontinuations per 100 patient-years). The most common cause of discontinuation was an adverse drug reaction (ADR; 9.5%) with neuropsychiatric toxicity being the most prevalent (5.2%; 2.4 discontinuations per 100 patient-years). By week 96, the median change in weight for the study population was +2.0 kg (IQR -1 to 5).

Conclusion: In this large cohort, DTG showed excellent virologic efficacy and was generally well tolerated. Whether DTG results in undesirable weight gain or rather statistically significant results, remains a debate.
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http://dx.doi.org/10.1097/QAD.0000000000002533DOI Listing
July 2020

Five-year follow-up of patients enrolled in the NEAT 001/ANRS 143 randomized clinical trial: NEAT 001/ANRS 143 LONG TERM study.

J Antimicrob Chemother 2020 06;75(6):1618-1622

Division of Infectious Diseases, Saint Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium.

Background: Few long-term data are available in subjects having initiated ART with an NRTI-sparing regimen.

Objectives: Outcomes of subjects enrolled in the NEAT 001/ANRS 143 randomized clinical trial (comparing ritonavir-boosted darunavir + raltegravir versus ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine) were retrospectively collected, through anonymized electronic case report forms, up to 6 years post-enrolment.

Methods: The last NEAT 001 visit (Week 96) was conducted in 745/805 randomized subjects (363/401 ritonavir-boosted darunavir + raltegravir and 382/404 ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine). Of these, 430 were enrolled in NEAT 001/ANRS 143 LONG TERM (NLT) study (201 raltegravir, 229 tenofovir disoproxil fumarate/emtricitabine), with a median follow-up of 44.4 months.

Results: During NLT follow-up, the proportion of AIDS, non-AIDS events, virological rebound and serious adverse events, discontinuation for virological failure and for adverse events did not differ between groups; discontinuations for virological failure since NEAT 001 inclusion were more frequent in subjects with baseline CD4 <200 cells/mm3 (11.9% versus 5.3%; P = 0.077). At last follow-up, a quarter of subjects (22.2% for ritonavir-boosted darunavir + raltegravir and 29.7% for ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine) were still receiving their initial regimen. Integrase inhibitor exposure was not associated with weight gain (P = 0.48), while tenofovir disoproxil fumarate exposure was associated with a trend to higher creatinine increase (P = 0.067).

Conclusions: After a median of 5.6 years, subjects initiating ritonavir-boosted darunavir + raltegravir or ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine experienced few serious clinical adverse events. Most discontinuations were for reasons unrelated to adverse events or virological failure.
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http://dx.doi.org/10.1093/jac/dkaa056DOI Listing
June 2020

Rapid viral rebound after analytical treatment interruption in patients with very small HIV reservoir and minimal on-going viral transcription.

J Int AIDS Soc 2020 02;23(2):e25453

Departments of Clinical and Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

Introduction: Viral remission after analytical treatment interruption (ATI), termed post-treatment control, has been described in a small proportion of HIV-positive patients. This phenomenon has been separately associated to both low levels of HIV-1 proviral DNA as well as cell-associated RNA. We investigated whether the combination of both parameters could help predict delayed viral rebound after treatment interruption (TI).

Methods: We conducted an open single-arm ATI study in four Belgian HIV reference centres from January 2016 to July 2018. Eligible participants were adults who had fewer than 50 HIV-1 RNA copies/mL for more than two years, more than 500 CD4 cells/µL for more than three months, and were in general good health. Consenting participants who had fewer than 66 copies total HIV-1 DNA (t-DNA) and fewer than 10 copies cell-associated HIV-1 unspliced RNA (US-RNA) per million peripheral blood mononuclear cells (PBMCs), interrupted therapy and were monitored closely. Antiretroviral therapy (ART) was resumed after two consecutive viral loads exceeding 1000 copies or one exceeding 10,000 copies/mL. The primary outcome was the proportion of participants with fewer than 50 HIV-1 RNA copies/mL 48 weeks after TI. Secondary outcomes were time to viral rebound, the frequency of serious adverse events (AEs) and evolution of t-DNA and US-RNA after TI.

Results: All 16 consenting participants who interrupted therapy experienced rapid viral rebound two to eight weeks after TI. No serious AEs were observed. Levels of t-DNA and US-RNA increased after TI but returned to pre-ATI levels after treatment restart. None of the studied demographic, clinical and biological parameters were predictive of time of viral rebound.

Conclusions: The combination of low levels of t-DNA and US-RNA in PBMCs, corresponding respectively to a small and transcriptionally silent viral reservoir, is not predictive of viral remission after TI in patients on ART.
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http://dx.doi.org/10.1002/jia2.25453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046528PMC
February 2020

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs.

Front Microbiol 2019 24;10:3060. Epub 2020 Jan 24.

Service of Molecular Virology, Department of Molecular Virology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.

One of the most explored therapeutic approaches aimed at eradicating HIV-1 reservoirs is the "shock and kill" strategy which is based on HIV-1 reactivation in latently-infected cells ("shock" phase) while maintaining antiretroviral therapy (ART) in order to prevent spreading of the infection by the neosynthesized virus. This kind of strategy allows for the "kill" phase, during which latently-infected cells die from viral cytopathic effects or from host cytolytic effector mechanisms following viral reactivation. Several latency reversing agents (LRAs) with distinct mechanistic classes have been characterized to reactivate HIV-1 viral gene expression. Some LRAs have been tested in terms of their potential to purge latent HIV-1 in clinical trials, showing that reversing HIV-1 latency is possible. However, LRAs alone have failed to reduce the size of the viral reservoirs. Together with the inability of the immune system to clear the LRA-activated reservoirs and the lack of specificity of these LRAs, the heterogeneity of the reservoirs largely contributes to the limited success of clinical trials using LRAs. Indeed, HIV-1 latency is established in numerous cell types that are characterized by distinct phenotypes and metabolic properties, and these are influenced by patient history. Hence, the silencing mechanisms of HIV-1 gene expression in these cellular and tissue reservoirs need to be better understood to rationally improve this cure strategy and hopefully reach clinical success.
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http://dx.doi.org/10.3389/fmicb.2019.03060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993040PMC
January 2020

Infections due to carbapenemase-producing bacteria, clinical burden, and impact of screening strategies on outcome.

Med Mal Infect 2020 Nov 5;50(8):658-664. Epub 2020 Feb 5.

Infectious Diseases Department, Saint-Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium. Electronic address:

Objectives: To characterize the risk factors, impact of screening, and clinical burden of colonization and/or infection by carbapenemase-producing bacteria (CPB) in hospitalized patients.

Method: Retrospective study in a tertiary care hospital between 2008 and 2016.

Results: Among 88 included patients, 41% were colonized, 59% developed an infection, and 69% of all cases were hospital-acquired. Risk factors for CPB contamination included recent invasive medical device (94% of patients), antibiotic therapy (82%), travel abroad (17%), and hospitalization (>50%) with 80% of all patients with underlying chronic condition. Intestinal carriage represented 89% of all colonization cases and 50% of infections were located in the urinary tract. The recent use of mechanical ventilation devices was significantly more observed in infected patients than colonized patients. The most frequent CPB was Klebsiella pneumoniae and the most frequent carbapenemase was OXA-48. Overall mortality rate was 19%. Prevalence of CPB detection in intensive care units (ICU) based on systematical rectal screen swab upon admission remained <0.5%. The infected/colonized ratio (CPB colonization cases evolving into an infection) was 23%. The time between CPB infection diagnosis and start of appropriate antimicrobial therapy increased from 1 day in previously screened patients with positive CPB to 4 days in patients with previous negative or absent screening.

Conclusion: Our results emphasize the importance of CPB screening in all ICU patients and in at-risk patients hospitalized in other units, to allow earlier adequate antibiotic therapy in case of infection which occurred in 23% of the colonized patients.
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http://dx.doi.org/10.1016/j.medmal.2019.12.011DOI Listing
November 2020

Uptake and Discontinuation of Integrase Inhibitors (INSTIs) in a Large Cohort Setting.

J Acquir Immune Defic Syndr 2020 03;83(3):240-250

Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, University College London, London, United Kingdom.

Background: Despite increased integrase strand transfer inhibitor (INSTI) use, limited large-scale, real-life data exists on INSTI uptake and discontinuation.

Setting: International multicohort collaboration.

Methods: RESPOND participants starting dolutegravir (DTG), elvitegravir (EVG), or raltegravir (RAL) after January 1, 2012 were included. Predictors of INSTI used were assessed using multinomial logistic regression. Kaplan-Meier and Cox proportional hazards models describe time to and factors associated with discontinuation.

Results: Overall, 9702 persons were included; 5051 (52.1%) starting DTG, 1933 (19.9%) EVG, and 2718 (28.0%) RAL. The likelihood of starting RAL or EVG vs DTG decreased over time and was higher in Eastern and Southern Europe compared with Western Europe. At 6 months after initiation, 8.9% (95% confidence interval: 8.3% to 9.5%) had discontinued the INSTI (6.4% DTG, 7.4% EVG, and 14.0% RAL). The main reason for discontinuation was toxicity (44.2% DTG, 42.5% EVG, 17.3% RAL). Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% DTG, 23.4% EVG, 6.6% RAL). Overall, treatment simplification was highest on RAL (2.7% DTG, 1.6% EVG, and 19.8% RAL). Factors associated with a higher discontinuation risk included increasing year of INSTI initiation, female gender, hepatitis C coinfection, and previous non-AIDS-defining malignancies. Individuals in Southern and Eastern Europe were less likely to discontinue. Similar results were seen for discontinuations after 6 months.

Conclusions: Uptake of DTG vs EVG or RAL increased over time. Discontinuation within 6 months was mainly due to toxicity; nervous system toxicity was highest on DTG. Discontinuation was highest on RAL, mainly because of treatment simplification.
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http://dx.doi.org/10.1097/QAI.0000000000002250DOI Listing
March 2020

Efficacy and Safety of Switching to Dolutegravir/Lamivudine Fixed-Dose 2-Drug Regimen vs Continuing a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen for Maintenance of Virologic Suppression in Adults Living With Human Immunodeficiency Virus Type 1: Phase 3, Randomized, Noninferiority TANGO Study.

Clin Infect Dis 2020 11;71(8):1920-1929

ViiV Healthcare, Research Triangle Park, North Carolina, USA.

Background: The 2-drug regimen dolutegravir (DTG) + lamivudine (3TC) is indicated for treatment-naive adults with human immunodeficiency virus type 1 (HIV-1). We present efficacy and safety of switching to DTG/3TC in virologically suppressed individuals.

Methods: TANGO is an open-label, multicenter, phase 3 study that randomized adults (1:1, stratified by baseline third agent class) with HIV-1 RNA <50 copies/mL to switch to once-daily fixed-dose DTG/3TC or remain on a tenofovir alafenamide (TAF)-based regimen. The primary end point was proportion of participants with HIV-1 RNA ≥50 copies/mL at week 48 (US Food and Drug Administration Snapshot algorithm) in the intention-to-treat-exposed population (4% noninferiority margin).

Results: 743 adults were enrolled; 741 received ≥1 dose of study drug (DTG/3TC, N = 369; TAF-based regimen, N = 372). At week 48, proportion of participants with HIV-1 RNA ≥50 copies/mL receiving DTG/3TC was 0.3% (1/369) vs 0.5% (2/372) with a TAF-based regimen (adjusted treatment difference [95% confidence interval], -0.3 [-1.2 to .7]), meeting noninferiority criteria. No participants receiving DTG/3TC and 1 receiving a TAF-based regimen met confirmed virologic withdrawal criteria, with no emergent resistance at failure. Drug-related grade ≥2 adverse events and withdrawals due to adverse events occurred in 17 (4.6%) and 13 (3.5%) participants with DTG/3TC and 3 (0.8%) and 2 (0.5%) with a TAF-based regimen, respectively.

Conclusions: DTG/3TC was noninferior in maintaining virologic suppression vs a TAF-based regimen at week 48, with no virologic failure or emergent resistance reported with DTG/3TC, supporting it as a simplification strategy for virologically suppressed people with HIV-1.

Clinical Trials Registration: NCT03446573.
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http://dx.doi.org/10.1093/cid/ciz1243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643745PMC
November 2020

Microglial Cells: The Main HIV-1 Reservoir in the Brain.

Front Cell Infect Microbiol 2019 24;9:362. Epub 2019 Oct 24.

Université de Strasbourg, EA7292, FMTS, IUT Louis Pasteur, Schiltigheim, France.

Despite efficient combination of the antiretroviral therapy (cART), which significantly decreased mortality and morbidity of HIV-1 infection, a definitive HIV cure has not been achieved. Hidden HIV-1 in cellular and anatomic reservoirs is the major hurdle toward a functional cure. Microglial cells, the Central Nervous system (CNS) resident macrophages, are one of the major cellular reservoirs of latent HIV-1. These cells are believed to be involved in the emergence of drugs resistance and reseeding peripheral tissues. Moreover, these long-life reservoirs are also involved in the development of HIV-1-associated neurocognitive diseases (HAND). Clearing these infected cells from the brain is therefore crucial to achieve a cure. However, many characteristics of microglial cells and the CNS hinder the eradication of these brain reservoirs. Better understandings of the specific molecular mechanisms of HIV-1 latency in microglial cells should help to design new molecules and new strategies preventing HAND and achieving HIV cure. Moreover, new strategies are needed to circumvent the limitations associated to anatomical sanctuaries with barriers such as the blood brain barrier (BBB) that reduce the access of drugs.
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http://dx.doi.org/10.3389/fcimb.2019.00362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821723PMC
June 2020

Predictors of Ischemic and Hemorrhagic Strokes Among People Living With HIV: The D:A:D International Prospective Multicohort Study.

EClinicalMedicine 2019 Aug 11;13:91-100. Epub 2019 Aug 11.

Institute for Global Health, UCL, London, United Kingdom.

Background: Hypertension is a stronger predictor of hemorrhagic than ischemic strokes in the general population. We aimed to identify whether hypertension or other risk factors, including HIV-related factors, differ in their associations with stroke subtypes in people living with HIV (PLWHIV).

Methods: HIV-1-positive individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed from the time of first blood pressure (BP) measurement after 1/1/1999 or study entry until the first of a validated stroke, 6 months after last follow-up or 1/2/2014. Stroke events were centrally validated using standardized criteria. Hypertension was defined as one systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg. Poisson and Cox proportional hazards regression models determined associations of established cerebro/cardiovascular disease and HIV-related risk factors with stroke and tested whether these differed by stroke subtype.

Findings: 590 strokes (83 hemorrhagic, 296 ischemic, 211 unknown) occurred over 339,979 person-years (PYRS) (incidence rate/1000 PYRS 1.74 [95% confidence interval (CI) 1.60-1.88]). Common predictors of both hemorrhagic and ischemic strokes were hypertension (relative hazard 3.55 [95% CI 2.29-5.50] and 2.24 [1.77-2.84] respectively) and older age (1.28 [1.17-1.39] and 1.19 [1.12-1.25]). Male gender (1.62 [1.14-2.31] and 0.60 [0.35-0.91]), previous cardiovascular events (4.03 [2.91-5.57] and 1.44 [0.66-3.16]) and smoking (1.90 [1.41-2.56] and 1.08 [0.68-1.71]) were stronger predictors of ischemic then hemorrhagic strokes, whereas hypertension, hepatitis C (1.32 [0.72-2.40] and 0.46 [0.30-0.70]) and estimated glomerular filtration rate < 60 mL/min/1.72 m (4.80 [2.47-9.36] and 1.04 [0.67-1.60]) were stronger predictors of hemorrhagic than ischemic strokes. A CD4 count < 200 cells/μL was associated with an increased risk of hemorrhagic stroke only.

Interpretation: Risk factors for stroke may differ by subtype in PLWHIV, emphasizing the importance of further research to increase the precision of stroke risk estimation.
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http://dx.doi.org/10.1016/j.eclinm.2019.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737207PMC
August 2019
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