Browsing by Author "Diero L"
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Item Association of cardiovascular disease risk with liver steatosis and fibrosis in people with HIV in low- and middle-income countries.(2025-Jan-01) Kuniholm MH; Murenzi G; Shumbusho F; Brazier E; Plaisy MK; Mensah E; Wandeler G; Riebensahm C; Chihota BV; Samala N; Diero L; Semeere AS; Chanyachukul T; Borse R; Nguyen DTH; Perazzo H; Lopez-Iniguez A; Castilho JL; Maruri F; Jaquet A; Department of Infectious Diseases, Inselspital, Bern University Hospital.; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.; Research for Development (RD Rwanda).; Department of Epidemiology and Biostatistics, University at Albany, State University of New York, Rensselaer, New York, USA.; Espoir Vie-Togo, Lome, Togo.; AMPATH, Moi University, Eldoret, Kenya.; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City, Mexico.; Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.; Department of Infectious Diseases, National Hospital for Tropical Diseases, Hanoi, Vietnam.; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, Indiana, United States of America.; B.J. Government Medical College & Sassoon General Hospitals, Pune, Maharashtra, India.; Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda.; Evandro Chagas National Institute of Infectious Diseases -Oswaldo Cruz Foundation (INI/FIOCRUZ), Rio de Janeiro, Brazil.; TREAT Asia/amfAR - The Foundation for AIDS Research, Bangkok, Thailand.; Graduate School of Public Health and Health Policy, City University of New York, New York, New York, USA.; Rwanda Military Hospital, Kigali, Rwanda.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Institute for Implementation Science in Population Health.; National Institute for Health and Medical Research (INSERM) UMR 1219, Research Institute for Sustainable Development (IRD) EMR 271, University of Bordeaux, Bordeaux Population Health Centre, Bordeaux, France.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)OBJECTIVE: The aim of this study was to understand the relationship between cardiovascular disease (CVD) risk and liver steatosis and fibrosis among people with HIV (PLWH) at least 40 years of age on antiretroviral therapy (ART) in low and middle-income countries (LMIC). DESIGN: We used cross-sectional behavioral and clinical data collected during study enrollment visits in 2020-2022 for the Sentinel Research Network of International epidemiology Databases to Evaluate AIDS (SRN of IeDEA). METHODS: Ten-year CVD risk was calculated using 2019 WHO nonlaboratory and laboratory models. Transient elastography was used to assess liver disease. Presence of steatosis and significant fibrosis were defined by controlled attenuation parameter (CAP) at least 248 dB/m and liver stiffness measurement (LSM) at least 7.1 kPa, respectively. Participants with viral hepatitis, hazardous alcohol consumption, and unsuppressed HIV viral load were excluded from the analysis. Logistic regression was used to estimate odds ratios, adjusting for study site, CD4 + T cell count, stavudine and didanosine exposure, and in models stratified by sex and geographic region. RESULTS: There were 1750 participants from nine LMIC. Median CVD risk was 3% for both nonlaboratory and laboratory-based models. Adjusted odds ratios (ORs) for steatosis and significant fibrosis associated with laboratory CVD risk (≥10 vs. <5%) were OR = 1.83 [95% confidence interval (95% CI) = 1.21-2.76; P = 0.004] and OR = 1.62 (95% CI = 0.85-3.07; P = 0.14), respectively. Associations of CVD risk with steatosis were stronger in men and among participants at study sites outside Africa. CONCLUSION: Higher CVD risk was associated with steatosis but not with significant fibrosis in PWH in our LMIC cohort.Item Detection and management of drug-resistant tuberculosis in HIV-infected patients in lower-income countries.(2014-Nov) Ballif M; Nhandu V; Wood R; Dusingize JC; Carter EJ; Cortes CP; McGowan CC; Diero L; Graber C; Renner L; Hawerlander D; Kiertiburanakul S; Du QT; Sterling TR; Egger M; Fenner L; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.; Centre Intégré de Recherches Biocliniques, Abidjan, Côte d'Ivoire.; United States Agency for International Development Academic Model Providing Access to Healthcare, Eldoret, Kenya.; Vanderbilt University School of Medicine, Nashville, Tennessee, USA.; Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.; Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Children's Hospital, Ho Chi Minh City, Viet Nam.; Women's Equity in Access to Care & Treatment, Kigali, Rwanda.; Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa.; University of Ghana Medical School, Accra, Ghana.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; University of Chile School of Medicine, Santiago, Chile.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)SETTING: Drug resistance threatens tuberculosis (TB) control, particularly among human immunodeficiency virus (HIV) infected persons. OBJECTIVE: To describe practices in the prevention and management of drug-resistant TB under antiretroviral therapy (ART) programs in lower-income countries. DESIGN: We used online questionnaires to collect program-level data on 47 ART programs in Southern Africa (n = 14), East Africa (n = 8), West Africa (n = 7), Central Africa (n = 5), Latin America (n = 7) and the Asia-Pacific (n = 6 programs) in 2012. Patient-level data were collected on 1002 adult TB patients seen at 40 of the participating ART programs. RESULTS: Phenotypic drug susceptibility testing (DST) was available in 36 (77%) ART programs, but was only used for 22% of all TB patients. Molecular DST was available in 33 (70%) programs and was used in 23% of all TB patients. Twenty ART programs (43%) provided directly observed therapy (DOT) during the entire course of treatment, 16 (34%) during the intensive phase only, and 11 (23%) did not follow DOT. Fourteen (30%) ART programs reported no access to second-line anti-tuberculosis regimens; 18 (38%) reported TB drug shortages. CONCLUSIONS: Capacity to diagnose and treat drug-resistant TB was limited across ART programs in lower-income countries. DOT was not always implemented and drug supplies were regularly interrupted, which may contribute to the global emergence of drug resistance.Item Increased prevalence of pregnancy and comparative risk of program attrition among individuals starting HIV treatment in East Africa.(2018) Holmes CB; Yiannoutsos CT; Elul B; Bukusi E; Ssali J; Kambugu A; Musick BS; Cohen C; Williams C; Diero L; Padian N; Wools-Kaloustian KK; Masaka Regional Hospital, Masaka, Uganda.; National Institute of Allergies and Infectious Diseases, Bethesda, Maryland, United States of America.; Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya.; University of California San Francisco, San Francisco, California, United States of America.; University of California, Berkeley, California, United States of America.; Academic Model Providing Access to Health Care (AMPATH), Eldoret, Kenya.; Georgetown University School of Medicine, Washington, DC, United States of America.; Indiana University School of Medicine, Indianapolis, Indiana, United States of America.; Mailman School of Public Health, Columbia University, ICAP at Columbia University, New York, New York, United States of America.; Infectious Diseases Institute, Kampala, Uganda.; Indiana University R.M. Fairbanks School of Public Health, Indianapolis, Indiana, United States of America.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)BACKGROUND: The World Health Organization now recommends initiating all pregnant women on life-long antiretroviral therapy (ART), yet there is limited information about the characteristics and program outcomes of pregnant women already on ART in Africa. Our hypothesis was that pregnant women comprised an increasing proportion of those starting ART, and that sub-groups of these women were at higher risk for program attrition. METHODS AND FINDINGS: We used the International Epidemiology Databases to Evaluate AIDS- East Africa (IeDEA-EA) to conduct a retrospective cohort study including HIV care and treatment programs in Kenya, Uganda, and Tanzania. The cohort consecutively included HIV-infected individuals 13 years or older starting ART 2004-2014. We examined trends over time in the proportion pregnant, their characteristics and program attrition rates compared to others initiating and already receiving ART. 156,474 HIV-infected individuals (67.0% women) started ART. The proportion of individuals starting ART who were pregnant women rose from 5.3% in 2004 to 12.2% in 2014. Mean CD4 cell counts at ART initiation, weighted for annual program size, increased from 2004 to 2014, led by non-pregnant women (annual increase 20 cells/mm3) and men (17 cells/mm3 annually), with lower rates of change in pregnant women (10 cells/mm3 per year) (p<0.0001). There was no significant difference in the cumulative incidence of program attrition at 6 months among pregnant women starting ART and non-pregnant women. However, healthy pregnant women starting ART (WHO stage 1/2) had a higher rate of attrition rate (9.6%), compared with healthy non-pregnant women (6.5%); in contrast among women with WHO stage 3/4 disease, pregnant women had lower attrition (8.4%) than non-pregnant women (14.4%). Among women who initiated ART when healthy and remained in care for six months, subsequent six-month attrition was slightly higher among pregnant women at ART start (3.5%) compared to those who were not pregnant (2.4%), (absolute difference 1.1%, 95% CI 0.7%-1.5%). CONCLUSIONS: Pregnant women comprise an increasing proportion of those initiating ART in Africa, and pregnant women starting ART while healthy are at higher risk for program attrition than non-pregnant women. As ART programs further expand access to healthier pregnant women, further studies are needed to better understand the drivers of loss among this high risk group of women to optimize retention.Item The long-term impact of the COVID-19 pandemic on tuberculosis care and infection control measures in anti-retroviral therapy (ART) clinics in low- and middle-income countries: a multiregional site survey in Asia and Africa.(2025-Mar-24) Ballif M; Banholzer N; Perrig L; Avihingsanon A; Nsonde DM; Obatsa S; Muula G; Komena E; Uemura H; Lelo P; Otaalo B; Huwa J; Gouéssé P; Kumarasamy N; Brazier E; Michael D; Rafael I; Ramdé R; Somia IKA; Yotebieng M; Diero L; Euvrard J; Ezechi O; Fenner L; City University of New York, Institute for Implementation Science in Population Health, New York, NY, USA.; Pediatric Hospital of Kalembelembe, Kinshasa, Democratic Republic of the Congo.; Centre for Reproduction and Population Health Studies, Nigerian Institute of Medical Research, Lagos, Nigeria.; HIV-NAT / Thai Red Cross AIDS Research Centre and Center of Excellence in Tuberculosis, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.; Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.; Centre for Microbiology and Research, Kenya Medical Research Institute, Kisumu, Kenya.; School of Public Health, University of Cape Town, Cape Town, South Africa.; Division of General Internal Medicine, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.; CHU Sourô Sanou, Bobo-Dioulasso, Burkina Faso.; PAC-CI program, Abidjan, Côte d'Ivoire.; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland lukas.fenner@unibe.ch.; Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland.; CART Clinical Research Site, Voluntary Health Services, Chennai, India.; SolidarMed, Chiure, Mozambique.; Lighthouse Trust, Lilongwe, Malawi.; Kisesa Observation Cohort study, National Institute for Medical Reseach, Mwanza, Tanzania.; Faculty of Medicine, Udayana University, Ngoerah Hospital, Bali, Indonesia.; Centre de Traitement Ambulatoire, Brazzaville, Republic of Congo.; Department of Medicine, Moi University, AMPATH Program / Moi Teaching and Referral Hospital, Eldoret, Kenya.; CePReF, Abidjan, Côte d'Ivoire.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)BACKGROUND: The COVID-19 pandemic challenged healthcare systems, particularly in settings with high infectious disease burden. We examined the postpandemic long-term impacts of COVID-19 on tuberculosis (TB) services at anti-retroviral therapy (ART) clinics in lower-income countries. METHODS: Using standardised online questionnaires, we conducted a cross-sectional site survey among ART clinics providing TB services in Africa and Asia from July to September 2023 (site-level information and number of TB diagnoses and tests). RESULTS: Of 45 participating ART clinics, 32 (71%) were in Africa and 13 (29%) in Asia. During the COVID-19 pandemic (2020-2022), 43 (96%) clinics reported implementing social distancing or separation measures, 39 (87%) personal protections for staff members and 32 (71%) protections for patients. Infection control measures were in place in 45% of the clinics before the pandemic (until 2019), 23% introduced measures during the pandemic and 15% maintained them after the pandemic (after 2022). Service provision was affected during the pandemic in 33 (73%) clinics, including TB services in 22 (49%) clinics. TB service restrictions were addressed by introducing changes in directly observed therapy provision in 8 (18%) clinics, multimonth TB drug dispensing in 23 (51%), telehealth services in 25 (56%) and differentiated service delivery in 19 (42%). These changes were sustained after the pandemic at 4 (9%), 11 (24%), 17 (38%) and 12 (27%) clinics, respectively. Compared with 2018-2019, the number of TB diagnoses decreased sharply in 2020-2021 and improved after the pandemic. CONCLUSIONS: COVID-19 affected TB care services in ART clinics in Africa and Asia. This was paralleled by a reduction in TB diagnoses, which partly resumed after the pandemic. Infection control measures and alternative modes of service delivery were adopted during the pandemic and only partially maintained. Efforts should be made to sustain the lessons learnt during the COVID-19 pandemic, particularly approaches that reduce the risk of transmission of infectious diseases, including TB, in ART clinics.Item The Tuberculosis Sentinel Research Network (TB-SRN) of the International epidemiology Databases to Evaluate AIDS (IeDEA): protocol for a prospective cohort study in Africa, Southeast Asia and Latin America.(2024-Jan-09) Enane LA; Duda SN; Chanyachukul T; Bolton-Moore C; Navuluri N; Messou E; Mbonze N; McDade LR; Figueiredo MC; Ross J; Evans D; Diero L; Akpata R; Zotova N; Freeman A; Pierre MF; Rupasinghe D; Ballif M; Byakwaga H; de Castro N; Tabala M; Sterling TR; Sohn AH; Fenner L; Wools-Kaloustian K; Poda A; Yotebieng M; Huebner R; Marcy O; Vanderbilt Institute of Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.; Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.; Division of General Internal Medicine, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.; Duke Global Health Institute, Duke University, Durham, North Carolina, USA.; Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Indiana University Center for Global Health Equity, Indianapolis, Indiana, USA.; Mbarara University of Science and Technology Faculty of Medicine, Mbarara, Uganda.; Department of Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland.; Center for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia.; Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.; The Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince, Haiti.; The Kirby Institute, UNSW, Sydney, New South Wales, Australia.; Health Economics and Epidemiology Research Office, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Centre Hospitalier Universitaire Sourô Sanou, Bobo Dioulasso, Burkina Faso.; TREAT Asia/amfAR - The Foundation for AIDS Research, Bangkok, Thailand.; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.; Kinshasa School of Public Health, University of Kinshasa, Kinshasa, Democratic Republic of the Congo.; The Ryan White Center for Pediatric Infectious Diseases and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA lenane@iu.edu.; Vanderbilt Tuberculosis Center, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.; Centre de Prise en Charge de Recherche et de Formation (Aconda-CePReF), Abidjan, Côte d'Ivoire.; Université de Bordeaux, Bordeaux, France.; Department of Medicine, Moi University College of Health Sciences, Eldoret, Kenya.INTRODUCTION: Tuberculosis (TB) is a leading infectious cause of death globally. It is the most common opportunistic infection in people living with HIV, and the most common cause of their morbidity and mortality. Following TB treatment, surviving individuals may be at risk for post-TB lung disease. The TB Sentinel Research Network (TB-SRN) provides a platform for coordinated observational TB research within the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. METHODS AND ANALYSIS: This prospective, observational cohort study will assess treatment and post-treatment outcomes of pulmonary TB (microbiologically confirmed or clinically diagnosed) among 2600 people aged ≥15 years, with and without HIV coinfection, consecutively enrolled at 16 sites in 11 countries, across 6 of IeDEA's global regions. Data regarding clinical and sociodemographic factors, mental health, health-related quality of life, pulmonary function, and laboratory and radiographic findings will be collected using standardised questionnaires and data collection tools, beginning from the initiation of TB treatment and through 12 months after the end of treatment. Data will be aggregated for proposed analyses. ETHICS AND DISSEMINATION: Ethics approval was obtained at all implementing study sites, including the Vanderbilt University Medical Center Human Research Protections Programme. Participants will provide informed consent; for minors, this includes both adolescent assent and the consent of their parent or primary caregiver. Protections for vulnerable groups are included, in alignment with local standards and considerations at sites. Procedures for requesting use and analysis of TB-SRN data are publicly available. Findings from TB-SRN analyses will be shared with national TB programmes to inform TB programming and policy, and disseminated at regional and global conferences and other venues.Item Trends in hepatitis B virus testing practices and management in HIV clinics across sub-Saharan Africa.(2017-Nov-01) Coffie PA; Egger M; Vinikoor MJ; Zannou M; Diero L; Patassi A; Kuniholm MH; Seydi M; Bado G; Ocama P; Andersson MI; Messou E; Minga A; Easterbrook P; Anastos K; Dabis F; Wandeler G; Centre for Infectious Disease Epidemiology and Research (CIDER), University of Cape Town, Cape Town, South Africa.; Service de Médecine Interne, CNHU Hubert Maga, Cotonou, Benin.; Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA.; Programme PACCI, CHU Treichville, Site de Recherche ANRS, Abidjan, Côte d'Ivoire. ahuatchi@gmail.com.; Service des Maladies Infectieuses et de Pneumologie, CHU Sylvanus Olympio, Lomé, Togo.; INSERM U1219, Bordeaux Population Health, Bordeaux, France.; Department of Infectious Diseases, Fann University Hospital, Dakar, Senegal.; ISPED, Université de Bordeaux, Bordeaux, France.; Département de Dermatologie et d'Infectiologie, UFR des Sciences Médicales, Université Félix Houphouët Boigny, Abidjan, Côte d'Ivoire. ahuatchi@gmail.com.; Hôpital de Jour, Service des Maladies Infectieuses et Tropicales, CHU Souro Sanou, Bobo Dioulasso, Burkina Faso.; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.; Department of Medicine, Moi University, College of Health Sciences, School of Medicine, Eldoret, Kenya.; Global Hepatitis Programme, HIV Department, World Health Organization, Geneva, Switzerland.; Department of Infectious Diseases, Fann University Hospital, Dakar, Senegal. gilles.wandeler@ispm.unibe.ch.; Infectious Diseases Institute, Kampala, Uganda.; Department of Medicine at University of Alabama, Birmingham, AL, USA.; Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland. gilles.wandeler@ispm.unibe.ch.; Centre de Prise en charge de Recherche et de Formation. CePReF-Aconda-VS, Abidjan, Côte d'Ivoire.; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. gilles.wandeler@ispm.unibe.ch.; Department of Epidemiology and Biostatistics, University at Albany, State University of New York, Rensselaer, NY, USA.; Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.; Division of Medical Virology, Department of Pathology, University of Stellenbosch and Tygerberg Academic Hospital, Cape Town, South Africa.; Centre Médical de Suivi de Donneurs de Sang/ CNTS/PRIMO-CI, Abidjan, Côte d'Ivoire.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Département de Dermatologie et d'Infectiologie, UFR des Sciences Médicales, Université Félix Houphouët Boigny, Abidjan, Côte d'Ivoire.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)BACKGROUND: Approximately 8% of HIV-infected individuals are co-infected with hepatitis B virus (HBV) in sub-Saharan Africa (SSA). Knowledge of HBV status is important to guide optimal selection of antiretroviral therapy (ART) and monitor/prevent liver-related complications. We describe changes in testing practices and management of HBV infection over a 3-year period in HIV clinics across SSA. METHODS: A medical chart review was conducted in large urban HIV treatment centers in Côte d'Ivoire (3 sites), Benin, Burkina Faso, Cameroon, Kenya, Senegal, South Africa, Togo, Uganda and Zambia (1 site each). Of the patients who started ART between 2010 and 2012, 100 per year were randomly selected from each clinic. Demographic, clinical and laboratory information as well as individual treatment histories were collected using a standardized questionnaire. We examined changes over time in the proportion of patients screened for HBV infection (HBV surface antigen [HBsAg]-positivity), identified predictors of HBV testing using logistic regression, and assessed the proportion of patients initiating a tenofovir (TDF)-containing ART regimen. RESULTS: Overall, 3579 charts of patients initiating ART (64.4% female, median age 37 years) were reviewed in 12 clinics. The proportion of patients screened for HBsAg increased from 17.8% in 2010 to 24.4% in 2012 overall, and ranged from 0.7% in Kenya to 96% in South Africa. In multivariable analyses, age and region were associated with HBsAg screening. Among 759 individuals tested, 88 (11.6%; 95% confidence interval [CI] 9.4-14.1) were HBV-infected, of whom 71 (80.7%) received a TDF-containing ART regimen. HBsAg-positive individuals were twice as likely to receive a TDF-containing first-line ART regimen compared to HBsAg-negative patients (80.7% vs. 40.3%, p < 0.001). The proportion of patients on TDF-containing ART increased from 57.9% in 2010 to 90.2% in 2012 in HIV/HBV-co-infected patients (Chi-2 test for trend: p = 0.01). Only 114 (5.0%) patients were screened for anti-HCV antibodies and one of them (0.9%, 95% CI 0.02-4.79) had a confirmed HCV infection. CONCLUSIONS: The systematic screening for HBV infection in HIV-positive patients before ART initiation was limited in most African countries and its uptake varied widely across clinics. Overall, the prescription of TDF increased over time, with 90% of HIV/HBV-coinfected patients receiving this drug in 2012.