INTRODUCTION: HIV replication leads to a change in lymphocyte phenotypes that impairs immune protection against opportunistic infections. We examined current HIV replication as an independent risk factor for tuberculosis (TB). METHODS: We included people living with HIV from 25 European cohorts 1983-2015. Individuals <16 years or with previous TB were excluded. Person-time was calculated from enrolment (baseline) to the date of TB diagnosis or last follow-up information. We used adjusted Poisson regression and general additive regression models. RESULTS: We included 272,548 people with a median follow-up of 5.9 years (interquartile range [IQR] 2.3-10.9). At baseline, the median CD4 cell count was 355 cells/μL (IQR 193-540) and the median HIV-RNA level 22,000 copies/mL (IQR 1,300-103,000). During 1,923,441 person-years of follow-up, 5,956 (2.2%) people developed TB. Overall, TB incidence was 3.1 per 1,000 person-years (95% confidence interval [CI] 3.02-3.18) and was four times higher in patients with HIV-RNA levels of 10,000 compared with levels <400 copies/mL in any CD4 stratum. CD4 and HIV-RNA time-updated analyses showed that the association between HIV-RNA and TB incidence was independent of CD4. The TB incidence rate ratio for people born in TB-endemic countries compared with those born in Europe was 1.8 (95% CI 1.5-2.2). CONCLUSIONS: Our results indicate that ongoing HIV replication (suboptimal HIV control) is an important risk factor for TB, independent of CD4 count. Those at highest risk of TB are people from TB-endemic countries. Close monitoring and TB preventive therapy for people with suboptimal HIV control is important.

Africa Health Research Institute School of Laboratory Medicine and Medical Sciences College of Health Sciences University of KwaZulu Natal KwaZulu Natal South Africa

Amsterdam UMC location University of Amsterdam Global Health and Amsterdam Institute for Global Health and Development Amsterdam The Netherlands

Centre for Infectious Disease Epidemiology and Research Faculty of Health Sciences University of Cape Town Cape Town South Africa

Centre of Excellence for Health Immunity and Infections Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

CHU de Montpellier Université de Montpellier Montpellier France

CIBERINFEC Instituto de Salud Carlos 3 Madrid Spain

Clinic of Infectious Diseases University of Modena and Reggio Emilia Modena Italy

Department of Clinical Research London School of Hygiene and Tropical Medicine London United Kingdom

Department of Infectious Diseases Bern University Hospital University of Bern Bern Switzerland

Department of Infectious Diseases Institut Fournier Paris France

Department of Infectious Diseases IRCCS San Raffaele Scientific Institute Milan Italy; Vita Salute San Raffaele University Milan Italy

Department of Infectious Diseases Location University of Amsterdam Amsterdam Institute for Immunology and Infectious Diseases Infectious Diseases Program Amsterdam UMC Amsterdam The Netherlands

Department of Infectious Diseases Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Infectious Diseases Saint Pierre University Hospital Université Libre de Bruxelles Brussels Belgium

Department of Mathematics and Statistics Masaryk University Brno Czech Republic

Department of Public Health and Epidemiology AP HP Bicêtre Hospital INSERM CESP U1018 Paris Saclay University Le Kremlin Bicêtre France

Department of Respiratory and Infectious Diseases Copenhagen University Hospital Bispebjerg Denmark

Infectious Diseases Division Washington University School of Medicine in St Louis St Louis MO United States of America

Infectious Diseases Service Hospital Clinic IDIBAPS University of Barcelona Barcelona Spain

Institute for Global Health University College London London United Kingdom

Institute of Social and Preventive Medicine University of Bern Bern Switzerland

ISPED INSERM Bordeaux Population Health Research Center Team PHARes UMR 1219 University of Bordeaux Bordeaux France

Population Health Sciences Bristol Medical School University of Bristol Bristol United Kingdom

Service de Médecine Interne et Maladies Infectieuses Centre Hospitalier Universitaire de Bordeaux Bordeaux France

Stichting HIV Monitoring Amsterdam The Netherlands

University General Hospital Attikon School of Medicine National and Kapodistrian University of Athens Athens Greece

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