Among 6789 HIV-infected Zambian adults screened for hepatitis B virus (HBV) coinfection, estimated glomerular filtration rate (eGFR) was 50-90 mL/minute/1.73 m2 in 17.6% and <50 mL/minute/1.73 m2 in 2.5%. Human immunodeficiency virus/HBV coinfection was associated with eGFR <50 mL/minute/1.73 m2 (adjusted odds ratio, 1.96 [95% confidence interval, 1.34-2.86]), adjusted for age, sex, CD4+ count, and World Health Organization disease stag

Chi, Benjamin H.

Emge, Drew

Mulenga, Lloyd

Mweemba, Aggrey

Vinikoor, Michael J.

Wandeler, Gilles

Zanolini, Arianna

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B R I E F R E P O R TChronic Hepatitis B VirusCoinfection Is Associated WithRenal Impairment Among ZambianHIV-Infected AdultsAggrey Mweemba,1,2 Arianna Zanolini,3,4 Lloyd Mulenga,1,2,4 Drew Emge,3,4Benjamin H. Chi,4,5 Gilles Wandeler,6,7 and Michael J. Vinikoor3,41Department of Medicine, University of Zambia, and 2University Teaching Hospital,Lusaka, Zambia; 3Department of Medicine, Division of Infectious Diseases,University of North Carolina at Chapel Hill; 4Centre for Infectious Disease Researchin Zambia, Lusaka; 5Department of Obstetrics and Gynecology, University ofNorth Carolina at Chapel Hill; 6Institute of Social and Preventive Medicine,University of Bern, and 7Department of Infectious Diseases, University HospitalBern, SwitzerlandAmong 6789 HIV-infected Zambian adults screened for hep-atitis B virus (HBV) coinfection, estimated glomerular ﬁltra-tion rate (eGFR) was 50–90 mL/minute/1.73 m2 in 17.6%and <50 mL/minute/1.73 m2 in 2.5%. Human immunodeﬁ-ciency virus/HBV coinfection was associated with eGFR<50 mL/minute/1.73 m2 (adjusted odds ratio, 1.96 [95% con-ﬁdence interval, 1.34–2.86]), adjusted for age, sex, CD4+count, and World Health Organization disease stage.Keywords. HIV/AIDS; hepatitis B virus; renal dysfunction;Africa; tenofovir.Approximately 3 million human immunodeﬁciency virus(HIV)-infected individuals in sub-Saharan Africa (SSA) arechronically coinfected with hepatitis B virus (HBV) [1]. HIV/HBV coinfection is associated with increased incidence ofserum aminotransferase elevations, delayed CD4+ count recov-ery, and increased all-cause mortality during antiretroviral ther-apy (ART) compared with HIV alone [2, 3]. Another potentialcomplication of HIV/HBV coinfection is renal dysfunction.HBV monoinfection causes various forms of kidney disease[4], but little is known about HBV-related kidney disease inthe setting of HIV, particularly in SSA. Comorbid kidney dis-ease in the setting of HIV/HBV is challenging to manage clin-ically because the preferred antiretroviral agent in coinfection,tenofovir disoproxil fumarate (TDF), is potentially nephrotoxic[5]. We investigated the prevalence of renal impairment amongHIV-infected Zambian adults with and without HBV coinfec-tion at the time of enrollment in HIV care.METHODSIn their 2010 HIV treatment guidelines, the Zambian Ministryof Health recommended routine HBV screening of patients atthe time of linkage to care [6].During 2011–2013, this guidelinewas implemented among public-sector HIV care and treatmentfacilities in Zambia’s capital, Lusaka [7]. We analyzed data fromHIV-infected adults who enrolled in clinics that had the highestuptake of HBV screening during that time period. HBV testingtook place at a reference laboratory using an enzyme-linked im-munoassay (Access 2 Analyzer, Beckman Coulter) for the hep-atitis B surface antigen (HBsAg).Other enrollment procedures included World Health Orga-nization (WHO) AIDS clinical staging and the measurementof hemoglobin, CD4+ T-cell count, creatinine, and alanine ami-notransferase (ALT). For this analysis, we deﬁned an elevatedALT level as grade 2 or higher according to the Division ofAIDS criteria [8]. Using a single creatinine measurementmade at enrollment and prior to receipt of any antiretroviraldrugs (Olympus AU400 Analyzer, Beckman Coulter), we calcu-lated each patient’s estimated glomerular ﬁltration rate (eGFR)with the Chronic Kidney Disease Epidemiology Collaborationformula [9]. We deﬁned tuberculosis coinfection as havingbeen referred to HIV care during tuberculosis treatment.Using logistic regression, we modeled the factors associatedwith being screened for HBV at enrollment. We then deter-mined the proportion of HBV-screened patients with chronicHBV coinfection, deﬁned by having a single positive HBsAgtest. We compared patient characteristics using the Wilcoxonrank-sum test for continuous variables and the χ2 test forcategorical variables, according to HBV status. We categori-zed eGFR as normal (>90 mL/minute/1.73 m2) [10], mildlyimpaired (50–90 mL/minute/1.73 m2), and moderate/severelyimpaired (<50 mL/minute/1.73 m2) [11]. To explore the associ-ation between HBV coinfection and eGFR <50 mL/minute/1.73 m2—the degree of impairment where TDF is relativelycontraindicated—we ﬁt a multivariable logistic regressionReceived 7 July 2014; accepted 7 September 2014; electronically published 16 September2014.Correspondence: Michael J. Vinikoor, MD, University of North Carolina at Chapel Hill, Centrefor Infectious Disease Research in Zambia, 5032 Great North Road, PO Box 34681, Lusaka, Zam-bia (mjv@med.unc.edu).Clinical Infectious Diseases® 2014;59(12):1757–60© The Author 2014. Published by Oxford University Press on behalf of the Infectious DiseasesSociety of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.DOI: 10.1093/cid/ciu734BRIEF REPORT • CID 2014:59 (15 December) • 1757model considering HBV coinfection as the primary exposurevariable and including possible confounders including age,sex, WHO clinical stage, and CD4+ count. Under a subgroupanalysis of the HBV-coinfected individuals, we assessed wheth-er an elevated ALT level, a surrogate of liver disease, was asso-ciated with an eGFR <50 mL/minute/1.73 m2.In a sensitivity analysis, we estimated GFR using the Modiﬁ-cation of Diet in Renal Disease (MDRD) study equation [12].Prior to use, the dataset was stripped of personal identifying in-formation. We used Stata version 12 for analysis (StataCorp,College Station, Texas). The ethics committees of the Universityof Zambia and the University of North Carolina at Chapel Hillapproved our use of programmatic data in this analysis.RESULTSFrom January 2011 to December 2013, within 7 Lusaka urbandistrict facilities, 6839 of 13 138 (52.1%) HIV-infected adultswere screened for HBV at enrollment into HIV care. InitialALT level and CD4+ T-cell count were not associated withbeing screened for HBV coinfection (both P > .05), but age≥30 years (adjusted odds ratio [AOR], 1.11; 95% conﬁdence in-terval [CI], 1.03–1.20), male sex (AOR, 1.14; 95% CI, 1.06–1.23), and WHO stage 1 or 2 (AOR, 1.32; 95% CI, 1.22–1.43)were associated with an increased likelihood of HBsAg screen-ing. Patients with tuberculosis were less likely to be tested forHBsAg (AOR, 0.70; 95% CI, .62–.80).Among HBsAg-tested patients, 50 (0.7%) had unavailable re-sults due to insufﬁcient specimen volume, and the remainingpatients (N = 6789) comprised the analysis cohort. Amongthe analysis cohort, the median age was 34 years (interquartilerange [IQR], 28–40), 56% were women, and 799 (11.8%) wereHBV coinfected. Men were more likely than women to be HBVcoinfected (14.6% vs 9.5%, P < .001). HBV-coinfected patientshad lower median CD4+ counts (194 vs 252 cells/µL) andwere more likely to have tuberculosis coinfection (9.9% vs6.9%) compared to those with HIV alone (all P < .001).At enrollment, the median eGFR among those in the analysiscohort was 111 mL/minute/1.73 m2 (IQR, 94–129); 1195(17.6%) had an eGFR of 50–90 mL/minute/1.73 m2, and 172(2.5%) patients had an eGFR <50 mL/minute/1.73 m2. Factorsassociated with eGFR <50 were increased age, male sex, reducedCD4+ count, WHO stage 3 or 4, and HBV coinfection (allP < .001; Table 1). Compared to those infected with HIValone, HIV/HBV-coinfected patients had 2-fold odds ofeGFR<50 mL/minute/1.73 m2 (4.9% vs 2.2%, P < .001). Afteradjustment for age, sex, CD4+ count, and WHO stage, HBV co-infection remained associated with an eGFR <50 mL/minute/1.73 m2 (AOR, 1.96; 95% CI, 1.34–2.86; Table 1).Among HIV-HBV patients, 61 (7.7%) had an elevated ALTlevel at enrollment compared with 158 (2.7%) in the HIV-monoinfected group. Independent of age, sex, CD4+ count,and WHO stage, an elevated ALT level was associated with aneGFR <50 mL/minute/1.73 m2 among HIV/HBV-coinfectedpatients (AOR, 4.03; 95% CI, 1.60–10.13). When we repeatedanalyses using the MDRD formula, the proportion of patientswith renal impairment and the association between HBsAgand eGFR <50 mL/minute/1.73 m2 was similar (SupplementaryTable 1).DISCUSSIONAmong HIV-infected Zambian adults in this analysis, HBV co-infection was associated with increased odds of baseline eGFR<50 mL/minute/1.73 m2, the threshold at which TDF use is dis-couraged by the WHO’s HIV treatment guidelines. Interesting-ly, HIV/HBV-coinfected patients with elevated ALT levelsappeared more likely to have an eGFR <50 mL/minute/1.73m2, suggesting a possible link between HBV-related liver diseaseactivity and renal dysfunction.Strengths of our study included its relatively large size and itsexternal validity for primary care settings in SSA. We also noteseveral limitations. Our study was limited by its cross-sectionalnature. As our analysis relied on the initial eGFR at enrollment,we could not distinguish acute from chronic kidney disease. Al-though HBV is an established cause of renal disease, we wereTable 1. Risk Factors for Baseline Moderate/Severe RenalDysfunction Among 6789 HIV-Infected Zambian AdultsRiskFactorNo. (%) WithRenalDysfunctionBivariableAnalysis,OR(95% CI)MultivariableAnalysis,OR(95% CI)HBV coinfectionNo 133 (2.2) 1 1Yes 39 (4.9) 2.26 (1.57–3.25) 1.96 (1.34–2.86)Age, y16–39 80 (1.6) 1 140–49 54 (4.0) 2.59 (1.82–3.68) 2.32 (1.63–3.32)≥50 38 (8.1) 5.41 (3.63–8.06) 5.01 (3.32–7.55)SexFemale 71 (1.9) 1 1Male 101 (3.4) 1.84 (1.36–2.51) 1.34 (.97–1.84)WHO clinical stage1–2 62 (1.4) 1 13–4 110 (4.4) 3.16 (2.30–4.33) 2.07 (1.49–2.89)CD4+ count, cells/µL≥200 24 (1.2) 1 150–200 47 (4.8) 3.81 (2.62–5.52) 2.89 (1.98–4.24)<50 24 (7.7) 6.11 (3.99–9.36) 4.06 (2.60–6.34)Estimated glomerular filtration rate of <50 mL/minute/1.73 m2 was based onthe Chronic Kidney Disease Epidemiology Collaboration formula.Abbreviations: CI, confidence interval; HBV, hepatitis B virus; HIV, humanimmunodeficiency virus; OR, odds ratio; WHO, World Health Organization.1758 • CID 2014:59 (15 December) • BRIEF REPORTunable to attribute causality to HBV coinfection. We adjustedmodels for factors known to be associated with impaired renalfunction in HIV patients, but unobserved factors may have re-sulted in residual confounding. In addition, urinalysis and/orrenal biopsy data would have strengthened our study as it mayhave allowed us to differentiate HBV-associated nephropathyfrom HIV-associated kidney diseases; however, such diagnostictests are limited in settings such as ours. In the period of our anal-ysis, only 52% of HIV care enrollees were screened for HBsAg.Although a patient’s initial ALT level was not associated, theprobability of HBsAg testing increased with age, a risk factorfor eGFR <50 mL/minute/1.73 m2. Therefore, we could not ex-clude selection bias as a factor in the observed association be-tween HBV and renal dysfunction.Nevertheless, our results suggest that HBV coinfection maybe an important risk factor for renal disease in HIV-infected in-dividuals and that the degree of HBV-related liver disease maybe associated with renal dysfunction. At HIV care enrollment,the likelihood of an eGFR <50 mL/minute/1.73 m2 was doubledfor patients with HIV/HBV coinfection, and was even higher inthe subset of dually infected patients with an elevated ALT.These results support others in the medical literature. InFrance, among 137 HIV/HBV-coinfected patients in a well-characterized cohort study, investigators demonstrated thatsigniﬁcant hepatic ﬁbrosis, based on the Fibrometer score,was associated with increased risk of developing renalimpairment during ART (adjusted hazard ratio, 3.74; 95% CI,1.57–8.92) [13]. However, among 114 HIV/HBV-coinfectedparticipants in a clinical trial, despite being more likely toexperience an eGFR decline compared to those with HIValone, HBV DNA level, hyaluronic acid, AST-to-platelet ratio,and FIB-4 were not associated with the likelihood of kidney dis-ease development [14]. More investigation is needed to conﬁrmour ﬁndings and to delineate which HBV-coinfected patientsare at highest risk to develop renal disease.Although only 5% of HIV/HBV-coinfected patients hadan eGFR <50 mL/minute/1.73 m2 in our study, an estimated3 million dually infected patients live in resource-constrainedsettings. For this reason, guidelines are needed to address themanagement of this challenging clinical scenario. WheneverHIV infection is complicated by an eGFR <50 mL/minute/1.73 m2, WHO and Zambian guidelines recommend non-TDF-containing regimens that include either lamivudine oremtricitabine [11]. This is suboptimal in HIV/HBV coinfectionbecause resistant HBV viruses emerge when either is the soleHBV-active agent in the regimen. Dose adjustment of TDF isalso possible, but this is unlikely to be a widely implementablestrategy in overburdened ART programs where ﬁxed-dose com-bination pills are predominant. Unfortunately, entecavir, a drugthat is often used in such situations in upper-income settings, israrely available in SSA.In summary, in this Lusaka cohort, HBV coinfection was as-sociated with having an eGFR <50 mL/minute/1.73 m2, thethreshold at which TDF should be withheld per guidelines.Additional investigation and clinical guidance is needed for re-source-constrained settings with signiﬁcant HIV/HBV burden.Supplementary DataSupplementary materials are available at Clinical Infectious Diseases online(http://cid.oxfordjournals.org). Supplementary materials consist of dataprovided by the author that are published to beneﬁt the reader. The postedmaterials are not copyedited. The contents of all supplementary data are thesole responsibility of the authors. Questions or messages regarding errorsshould be addressed to the author.NotesDisclaimer. The funders had no role in study design, data collectionand analysis, the decision to publish, or the preparation of the manuscript.Financial support. This work was supported by the National Institutesof Health through the Fogarty Global Health Fellowship (R25TW009340);the Vanderbilt-CIDRZ AIDS International Training and Research Program(D43TW001035); an International Research Scientist Development Award(1K01TW009998); and the Doris Duke Charitable Foundation throughthe Doris Duke International Clinical Research Fellowship.Potential conﬂicts of interest. All authors: No reported conﬂicts.All authors have submitted the ICMJE Form for Disclosure of PotentialConﬂicts of Interest. Conﬂicts that the editors consider relevant to the con-tent of the manuscript have been disclosed.References1. 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Chronic Hepatitis B Virus Coinfection Is Associated With Renal Impairment Among Zambian HIV-Infected Adults

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