We investigated occurrence of and risk factors for severe COVID-19 outcomes in people with HIV (PWH) in the Netherlands. An ongoing prospective nationwide HIV cohort study. COVID-19 diagnoses and outcomes with other relevant medical information were prospectively collected from electronic medical records in all HIV treatment centers in the Netherlands, from the start of the COVID-19 epidemic until December 31, 2021. Risk factors for COVID-19 related hospitalization and death were investigated using multivariable logistic regression, including demographics, HIV-related factors, and comorbidities. The cohort comprises 21 289 adult PWH, median age 51.2 years, 82% male, 70% were of Western origin, 12.0% were of sub-Saharan African and 12.6% Latin American/Caribbean origin, 96.8% had HIV-RNA less than 200 copies/ml, median CD4 + cell count 690 (IQR 510-908) cells/μl. Primary SARS-CoV-2 infections were registered in 2301 individuals, of whom 157 (6.8%) required hospitalization and 27 (1.2%) ICU admission. Mortality rates were 13 and 0.4% among hospitalized and nonhospitalized individuals, respectively. Independent risk factors for severe outcomes (COVID-19-related hospitalization and death) were higher age, having multiple comorbidities, a CD4 + cell count less than 200 cells/μl, uncontrolled HIV replication, and prior AIDS diagnosis. Migrants from sub-Saharan Africa, Latin America, and the Caribbean were at an increased risk of severe outcomes independently of other risk factors. In our national cohort of PWH, risk of severe COVID-19 outcomes was increased in individuals with uncontrolled HIV replication, low CD4 + cell count, and prior AIDS diagnosis, independently of general risk factors such as higher age, comorbidity burden and migrants originating from non-Western countries.

aModena HIV Metabolic Clinic bDepartment of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia cDepartment of Infectious Diseases, Azienda Ospedaliero-Universitaria, Policlinico of Modena, Modena, Italy. Correspondence to Giovanni Guaraldi, MD, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Largo del Pozzo 71, 41124 Modena, Italy. Tel: +39 059 422 5318; fax: +39 335 33 34 34; e-mail: [email protected] Received 13 January, 2023 Accepted 8 February, 2023

Laurent, Clémencea; Hentzien, Maximea,b; Pavel, Simonac; Didier, Kévina; Bermejo, Messalinea; N’Guyen, Yohana,d; Bani-Sadr, Firouzéa,d Author Information

aAIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan bDepartment of Biomedicine, University of Basel, Basel, Switzerland. Correspondence to Hiroyuki Yamamoto, MD, PhD, AIDS Research Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama City, Tokyo 208-0011, Japan. Tel: +81 42 848 7154; fax: +81 42 848 7155; e-mail: [email protected] Received 18 January, 2023 Accepted 24 January, 2023

aCentre for Inflammatory Diseases, School of Clinical Sciences, Monash University and Monash Infectious Diseases, Monash Health, Clayton, Victoria, Australia bSorbonne Universite, GRC n°22 (C2MV-Complications Cardiovasculaires et Metaboliques chez les patients vivant avec le Virus de l’immunodeficience humaine), Inserm UMR_S 938, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire de Cardio-metabolisme et Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Service de Cardiologie, Paris, France. Correspondence to Franck Boccara, Hôpital St Antoine, Service de Cardiologie, 184 rue du Fbg St Antoine 75012 Paris, France. Fax: +33 149282683; E-mail: [email protected] Received 12 December, 2022 Accepted 14 December, 2022

We developed an ad hoc method to estimate the number of excess deaths among persons with HIV (PWH) during the coronavirus disease 2019 (COVID-19) pandemic in the United States. Using this method, we estimated approximately 1448 excess deaths from COVID-19 among PWH in 2020 in the United States. We also developed an Excel workbook for use as a tool to quickly assess excess deaths among PWH in settings with limited surveillance data.

Depression and substance use (SU) disorders are prevalent among people with HIV (PWH) and impact health outcomes despite successful antiretroviral therapy (ART). We explored quality of life, functional ability and associated factors among PWH screened positive for depression and/or SU. This cross-sectional study recruited adult PWH during routine follow-up at five HIV clinical sites in the Asia-Pacific region. Participants were screened for depression using Patient Health Questionnaire-9 and SU using Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). Quality of life (QoL) was assessed with WHOQOL-HIV BREF and functional ability with World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Factors associated with mean QoL and disability scores were analysed using linear regression. Of 864 PWH enrolled, 753 screened positive for depression or SU. The median (interquartile range, IQR) age was 38 (31-47) years and 97% were on ART. Overall mean WHOQOL-HIV BREF and WHODAS scores indicated greater impairment with increasing depressive symptom severity and SU risk. In multivariate analysis, PWH reporting previous trauma/stress (difference = 2.7, 95% confidence interval [CI] 1.5-3.9, P < 0.001) and past mental health diagnosis (difference = 5.0, 95% CI 2.9-7.1, P < 0.001) were associated with greater disability and poorer QoL scores across multiple domains ( P < 0.01 for all). Higher CD4 T-cell counts was also associated with better QoL scores and functional ability. PWH with depression/SU experienced poorer QoL and function despite routine engagement in HIV care. Efforts to integrate mental health services and interventions addressing disability into HIV management should be prioritized in the region.

To reduce health inequalities, the creatinine-based chronic kidney disease epidemiology collaboration 2021 formula for estimated glomerular filtration rate (eGFR) is replacing the 2009 formula, which required adjustment specifically for Black individuals. We compared the 2021 and 2009 creatinine-based formulae with cystatin C-based eGFR in Black people on antiretroviral therapy (ART) with HIV RNA <200 c/ml. Cross-sectional analysis of paired serum creatinine and cystatin C measurements. Bias, imprecision, accuracy, and performance for identifying individuals with eGFR cystatin C <60 (units: ml/min per 1.73 m 2 ) were determined. The effects of ART with no, mild-moderate, or marked effect on tubular creatinine secretion on the performance of the 2021 formula was assessed. We included 362 individuals (mean age 51 years, 56% female, mean eGFR-cystatin C 88.3). Overall, the 2021 (vs. the 2009 race-adjusted) formula was less biased and had improved imprecision and accuracy compared with eGFR-cystatin C but underestimated eGFR-cystatin C in those with eGFR ≥90 and overestimated eGFR-cystatin C in those with eGFR <60. The 2021 (vs. the 2009) formula had high specificity (95% vs. 97%) and negative predictive value (97% vs. 96%), but low sensitivity (56% vs. 52%) and positive predictive value (44% vs. 54%) for identifying individuals with eGFR-cystatin C <60 ( P > 0.25). Performance at the eGFR <60 cut-off was minimally affected by ART exposure group. The CKD-EPI 2021 creatinine-based formula was better aligned with eGFR-cystatin C than the 2009 formula. eGFR-cystatin C may provide clinically useful information in Black people with eGFR <60 irrespective of ART regimen.

Infectious Diseases Pharmaceutical Medicine, Shahin Gharakhanian MD Consulting LLC, CIC: Cambridge Innovation Center, Cambridge, Massachusetts, USA. Correspondence to Shahin Gharakhanian, Infectious Diseases Pharmaceutical Medicine, Shahin Gharakhanian MD Consulting LLC, CIC: Cambridge Innovation Center, Cambridge, MA 02138, USA; E-mail: [email protected] Received 7 October, 2022 Accepted 18 October, 2022

The human endogenous protein galectin-9 (Gal-9) reactivates latently HIV-infected cells in vitro and ex vivo , which may allow for immune-mediated clearance of these cells. However, Gal-9 also activates several immune cells, which could negatively affect HIV persistence by promoting chronic activation/exhaustion. This potential 'double-edged sword' effect of Gal-9 raises the question of the overall impact of Gal-9 on HIV persistence in vivo . We used the BLT (bone marrow, liver, thymus) humanized mouse model to evaluate the impact of Gal-9 on HIV persistence in vivo during antiretroviral therapy (ART). Two independent cohorts of ART-suppressed HIV-infected BLT mice were treated with either recombinant Gal-9 or phosphate-buffered saline control. Plasma viral loads and levels of tissue-associated HIV DNA and RNA were measured by qPCR. Immunohistochemistry and HIV RNAscope were used to quantify CD4 + T, myeloid, and HIV RNA+ cells in tissues. T cell activation and exhaustion were measured by flow cytometry, and plasma markers of inflammation were measured by multiplex cytokine arrays. Gal-9 did not induce plasma markers of inflammation or T cell markers of activation/exhaustion in vivo . However, the treatment significantly increased levels of tissue-associated HIV DNA and RNA compared to controls ( P = 0.0007 and P = 0.011, respectively, for cohort I and P = 0.002 and P = 0.005, respectively, for cohort II). RNAscope validated the Gal-9 mediated induction of HIV RNA in tissue-associated myeloid cells, but not T cells. Our study highlights the overall adverse effects of Gal-9 on HIV persistence and the potential need to block Gal-9 interactions during ART-suppressed HIV infection.