Secondary Logo

Journal Logo

Clinical Science

Determinants of Liver Complications Among HIV/Hepatitis B Virus–Coinfected Patients

Lo Re, Vincent III MD, MSCEa,b,c; Newcomb, Craig W. MSa; Carbonari, Dena M. MSa,b; Roy, Jason A. PhDa,b; Althoff, Keri N. PhDd; Kitahata, Mari M. MD, MPHc; Reddy, K. Rajender MDc; Lim, Joseph K. MDf; Silverberg, Michael J. PhD, MPHg; Mayor, Angel M. MD, MSh; Horberg, Michael A. MD, MASi; Cachay, Edward R. MD, MASj; Kirk, Gregory D. MD, MPH, PhDd; Hull, Mark MDk; Gill, John MB, ChB, MScl; Sterling, Timothy R. MDm; Kostman, Jay R. MDn; Peters, Marion G. MDo; Moore, Richard D. MDp; Klein, Marina B. MD, MScq,r; Kim, H. Nina MD, MSce; for the North American AIDS Cohort Collaboration on Research and Design of IeDEA

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: September 1, 2019 - Volume 82 - Issue 1 - p 71-80
doi: 10.1097/QAI.0000000000002094

Abstract

INTRODUCTION

Hepatitis B virus (HBV) infection is a leading cause of liver-related mortality worldwide. Many countries that have high HBV endemicity also carry an increased burden of HIV infection.1 HIV accelerates progression of HBV-related liver fibrosis.2 HIV/HBV-coinfected patients have a higher risk of cirrhosis and death from end-stage liver disease (ESLD) than those with HIV or HBV alone,2–6 and higher rates of hepatocellular carcinoma (HCC) than those with HIV alone.7 Consequently, ESLD and HCC have emerged as major causes of mortality among HIV/HBV-coinfected patients.8 Rates of liver complications remain higher for HIV/HBV than HIV/hepatitis C virus (HCV)-coinfected patients, even with antiretroviral therapy (ART) that includes HBV-active medications [ie, tenofovir disoproxil fumarate (TDF), lamivudine, emtricitabine].9

The impact of HIV-related factors, such as HIV viremia and low CD4 cell count, and other potential determinants of liver disease, such as heavy alcohol use, diabetes mellitus, and HCV coinfection, remain unclear in HIV/HBV-coinfected patients, primarily because large-scale, population-representative longitudinal studies specifically in this group have not yet been conducted. Identification of these contributing factors could help define the major determinants for the high rates of liver complications among HIV/HBV patients and guide interventions to reduce the risk of these events in this population.

We evaluated HIV-related and host factors associated with the development of liver complications, defined as a composite of first ESLD or HCC diagnosis, among HIV/HBV-coinfected patients in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).10 We examined the risk of liver complications associated with HBV-active ART compared with use of ART without an HBV-active agent. We also determined whether longer duration of HIV suppression with HBV-active ART reduced the risk of liver complications among HIV/HBV patients.

METHODS

Study Design and Data Source

We performed a retrospective cohort study of HIV/HBV-coinfected patients enrolled in 10 United States (US) and Canadian cohorts of the NA-ACCORD that had access to both inpatient and outpatient electronic medical records to permit validation of ESLD and HCC diagnoses from 1996 to 2010 (see Table 1, Supplemental Digital Content, https://links.lww.com/QAI/B334). The NA-ACCORD is the largest consortium of interval and clinic-based HIV cohorts from the US and Canada and is the North American region of the International Epidemiologic Databases to Evaluate AIDS.10 At scheduled intervals, cohorts securely transfer demographic, diagnostic, medication, social–behavioral, laboratory, and vital status information to the Data Management Core (University of Washington), which performs quality control for completeness and accuracy before harmonization of data files by the Epidemiology/Biostatistics Core (Johns Hopkins University). NA-ACCORD research has been approved by the institutional review boards of each cohort. This study also was approved by the University of Pennsylvania and University of Washington Institutional Review Boards.

Study Patients

All HIV-infected patients aged ≥18 years were included if they had active HBV coinfection [defined by at least one of the following: positive HBV surface antigen (HBsAg), positive HBV e antigen (HBeAg), or detectable HBV DNA] and were members of an NA-ACCORD cohort that participated in the validation of ESLD and HCC diagnoses between January 1, 1996 and December 31, 2010. Patients were excluded if they had: (1) ESLD or HCC before start of follow-up (defined below), (2) no follow-up time, or (3) received care at a site within a cohort that did not participate in ESLD or HCC validation.

Follow-up began at NA-ACCORD enrollment, start of ESLD and HCC observation windows for the patient's cohort (time period during which these events were ascertained9), or January 1, 1996, whichever occurred last. Follow-up continued until the first occurrence of: ESLD, HCC, death, cohort-specific end date for reporting validated ESLD/HCC diagnosis, date lost to follow-up (defined by NA-ACCORD as the earlier of the last CD4 count or HIV RNA plus 540 days), or December 31, 2010.

Main Study Outcomes

The primary outcome was an incident liver complication, defined as a composite of first occurrence of an ESLD or HCC diagnosis. We chose to examine a composite of ESLD or HCC, because these events equally represent important liver complications.

ESLD and HCC events were confirmed using a method we previously described.11,12 Patients were centrally screened for possible ESLD or HCC from 1996 to 2010 based on: (1) relevant hospital or outpatient diagnoses (ie, ascites, spontaneous bacterial peritonitis, variceal hemorrhage, hepatic encephalopathy, end-stage liver disease, hepatorenal syndrome, HCC) or procedures (ie, paracentesis, transjugular intrahepatic portosystemic shunt, liver transplant), or (2) presence of significant liver fibrosis determined by ≥2 measurements of aspartate aminotransferase (AST)-to-platelet ratio index (APRI) >1.513 or ≥2 measurements of Fibrosis-4 Index for Liver Fibrosis (FIB-4) >3.2514,15 >180 days apart plus ≥2 laboratory results indicating impaired hepatic function (ie, total bilirubin ≥5.0 mg/dL, albumin ≤2.0 mg/dL, or international normalized ratio ≥1.7) >180 days apart. APRI was calculated using AST and platelet count: (AST [U/L]/upper limit of normal [considered as 40 U/L])/(platelet count [109/L] × 100).13 APRI >1.5 identifies significant liver fibrosis (METAVIR stages F2-F4). FIB-4 was determined using AST, alanine aminotransferase (ALT), platelet count, and age: (age [years] × AST [U/L])/(platelet count [109/L]) × (ALT [U/L])1/2).14,15 FIB-4 >3.25 indicates advanced hepatic fibrosis/cirrhosis (METAVIR stages F3-F4).

Patients who screened positive for possible ESLD or HCC had all medical records reviewed by a clinician in each cohort. ESLD was defined by a clinical complication of cirrhosis (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, or hepatic encephalopathy). HCC was determined by review of medical records and pathology reports or by cancer registry linkage.12 The earliest date of ESLD or HCC diagnosis represented the liver complication date.

Data Collection

We collected age at start of follow-up, sex, race/ethnicity, HIV transmission risk factors, diabetes mellitus, heavy alcohol use, and use of ART. Sex, race/ethnicity, and HIV risk factors were determined via self-report at enrollment. Diabetes was assessed throughout observation and defined by: (1) hemoglobin A1c ≥6.5%, (2) prescription of certain antidiabetic medications, or (3) diabetes diagnosis plus prescription of certain anti-diabetic medications.16 Heavy alcohol use was defined as ever having had while under observation: (1) inpatient or outpatient International Classification of Diseases, Ninth Revision (ICD-9) diagnosis of alcohol dependence/abuse; (2) ≥3 drinks/day or ≥7 drinks/week for females; ≥4 drinks/day or ≥14 drinks/week for males on the self-reported Alcohol Use Disorders Identification Test-Consumption questionnaire17; or (3) documentation of alcohol intoxication, dependence, or abuse identified during medical record review to confirm ESLD or HCC diagnosis.9 ART was defined as use of 3 antiretrovirals from at least 2 classes18 or a triple nucleoside/nucleotide reverse transcriptase inhibitor regimen (previously accepted as ART19). We determined exposure to ART, HBV-active antiretrovirals (TDF, lamivudine, emtricitabine), or entecavir throughout observation.

All HIV RNA, CD4 cell count, HBsAg, HBeAg, and HBV DNA results before and during follow-up were collected. Owing to changes in the sensitivity of HIV RNA assays over time, HIV suppression was defined as ≤500 copies/mL. HCV coinfection was defined by detectable HCV RNA or available HCV genotype recorded at any time during observation. HCV treatment before or during follow-up was ascertained. FIB-4 was determined using the closest AST, ALT, and platelet counts within 24 months before or after start of follow-up.

Statistical Analysis

We calculated unadjusted incidence rates of liver complications, overall and by ART era (1996–2001, 2002–2005, 2006–2010). We used multivariable Cox regression to examine adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of liver complications associated with risk factors of interest. HIV-related factors included time-updated HIV viremia (>500 copies/mL) and time-updated lower CD4 cell count. Traditional liver disease risk factors included age ≥40 years, male sex, black/non-Hispanic race/ethnicity (versus non-black/non-Hispanic and Hispanic), time-updated diabetes status, heavy alcohol use, HCV coinfection, and advanced liver fibrosis by FIB-4. Analyses were adjusted for year of start of follow-up. We did not include ART as a covariate, because of its effects on HIV RNA and CD4 count and collinearity with both variables. HBV DNA and HBeAg were measured too infrequently in clinical practice to be evaluated as determinants of liver complications.

We performed 4 sensitivity analyses to assess the robustness of our results. First, we repeated our analysis accounting for death as a competing risk.20 Second, as our definition of HBV infection might have misclassified some patients with acute HBV infection as having chronic HBV, we repeated our analysis after excluding patients who had an ALT or AST >1000 U/L within ±30 days of their qualifying HBV laboratory test (since aminotransferase elevations of this degree are typically observed during acute HBV infection21). Third, as duration of diabetes may affect the risk of liver complications, we determined the time since the first observed diabetes diagnosis for each patient and repeated the primary analysis, replacing time-updated diabetes with duration of diabetes diagnosis. We determined the aHR of liver complications for every 12 months of diabetes. Finally, as the accuracy of FIB-4 among HIV/HBV-coinfected patients is unclear, we repeated our analysis substituting FIB-4 first with platelet count at start of follow-up (<150,000 versus ≥150,000/µL) and then with both AST (per 10 U/L increase) and platelet count (per 20,000/µL decrease), because both variables were associated with advanced hepatic fibrosis in a recent analysis of HIV/HBV patients in the Hepatitis B Research Network.22

Next, we examined the effect of HBV-active ART on the risk of liver complications. Among patients who received ART, we examined the aHRs of liver complications with use of ART that included: (1) an HBV-active antiretroviral, or (2) either TDF or entecavir, compared with ART use without an HBV-active antiretroviral, adjusting for all variables in the above risk factor analysis.

We then performed multivariable Cox regression to examine whether increasing consecutive time with suppressed HIV RNA (≤500 copies/mL) during HBV-active ART was associated with a lower risk of HBV-related liver complications. We restricted the cohort to patients who received HBV-active ART to determine the effect of HIV suppression during treatment for both HIV and HBV infections. We evaluated consecutive, rather than cumulative, months of HIV suppression because the latter measure may include periods of interruption in HIV suppression, which could attenuate the beneficial effects of HIV suppression on risk of liver complications. HIV suppression was evaluated as a time-updated variable. Once a patient had suppressed HIV, consecutive months were counted until an HIV RNA result of >500 copies/mL was identified, at which time the patient was classified as unsuppressed. If HIV suppression was again achieved, the consecutive months suppressed was restarted at one month. In an initial model (model #1), we evaluated HRs of liver complications with increasing categories of HIV suppression (<6 months; 6–11 months; 12–17 months; 18–23 months; ≥24 months) compared with persons with unsuppressed HIV, adjusting for all other variables in our previous risk factor analyses. Because aHRs of liver complications for categories of HIV suppression of ≥6 months were not statistically different, in a subsequent model (model #2), we dichotomized our results at 6 months (<6 months; ≥6 months). Analyses were repeated accounting for death as a competing risk.

We implemented multiple imputation using chained equations to address the potential bias of missing risk factor data, by means of 10 imputations using all variables in Table 1.23 For laboratory covariates, we imputed values that were not measured at baseline and carried those forward until first measurement. Results across the 10 datasets were combined to arrive at CIs that accounted for within- and across-dataset variances.24 Data were analyzed using SAS 9.4 (SAS Institute, Inc., Cary, NC).

T1
TABLE 1.:
Characteristics of HIV/Hepatitis B Virus–Coinfected Patients Within the North American AIDS Cohort Collaboration on Research and Design (1996–2010) at Start of Follow-up
table1-a
TABLE 1-A.:
Characteristics of HIV/Hepatitis B Virus–Coinfected Patients Within the North American AIDS Cohort Collaboration on Research and Design (1996–2010) at Start of Follow-up

RESULTS

Patient Characteristics

Among 54,415 HIV-infected patients in the 10 cohorts, 5134 (9.4%) were HBV-coinfected. Of these, 1561 were excluded because they did not meet eligibility (Fig. 1), leaving 3573 HIV/HBV-coinfected patients in the sample.

F1
FIGURE 1.:
Selection of HIV/HBV-coinfected patients within the North American AIDS Cohort Collaboration on Research and Design (January 1996–December 2010) for inclusion in the study. NA-ACORD, North American AIDS Cohort Collaboration on research and Design. *Includes data from 10 cohorts that participated in validation of ESLD and HCC diagnoses: HIV Research Network; Johns Hopkins HIV Clinical Cohort; Kaiser Permanente Northern California; Montreal Chest Institute Immunodeficiency Service Cohort; Southern Alberta Clinic Cohort; University of Alabama at Birmingham 1917 Clinic Cohort; University of North Carolina at Chapel Hill HIV Clinical Cohort; University of Washington HIV Cohort; Vanderbilt-Meharry Center for AIDS Research Cohort; Veteran's Aging Cohort Study 8-Site Study. †HBV coinfection determined by ever positive for HBV surface antigen, HBV e antigen, or HBV DNA. ‡Patients at a site within a cohort that did not participate in ESLD or HCC validation. §Patients with no observation time did not have follow-up during the period in which ESLD/HCC events were ascertained.

This cohort was predominantly <40 years, male, and non-white/non-Hispanic (Table 1). The most common risk factor for HIV transmission included men who have sex with men (51.6%). Heavy alcohol use was reported in 25.1%, and 17.9% had HCV coinfection. Among HCV-infected individuals, only 3.7% were treated for HCV during the study period. At start of follow-up, 53.7% had HIV RNA >500 copies/mL, and 29.1% had a CD4 count <200 cells/mm3. Advanced hepatic fibrosis/cirrhosis by FIB-4 was present in 9.3%.

At start of follow-up, 35.9% were on ART with lamivudine or emtricitabine as the only HBV-active antiretroviral, 21.2% received TDF-based ART, and 6.8% were on ART without an HBV-active antiretroviral. Notably, 36.0% (n = 1287) were not on ART at start of follow-up; of these, 742 (57.7%) started ART during follow-up. Among 1530 patients not on an HBV-active antiretroviral at study entry, 916 (59.9%) received HBV-active ART during follow-up (613 TDF-based; 303 with lamivudine or emtricitabine alone). Twelve patients received entecavir during follow-up.

Within the cohort, 3227 (90.3%) had HBsAg status determined, 1163 (32.6%) had HBV DNA assessed, and 1152 (32.2%) had HBeAg tested at any time before or during follow-up. HBV DNA was detectable in 741 (63.7%) of those assessed. Among those who had HBeAg tested, 783 (68.0%) had a positive result.

Liver Complications

Among the 3573 patients, 111 (3.0%) developed a liver complication (90 with ESLD only; 11 with HCC only; 10 with both) during 13,790 person-years of follow-up [incidence rate = 8.0 (95% CI: 6.6 to 9.7) events/1000 person-years]. The median (interquartile range) duration of follow-up was 3.0 (1.8–5.0) years. The incidence rate of ESLD was 7.2 (95% CI: 5.9 to 8.8) events/1000 person-years. The most frequent first ESLD event was ascites (n = 74, 74%), followed by variceal hemorrhage (n = 17, 17%), hepatic encephalopathy (n = 13, 13%), and spontaneous bacterial peritonitis (n = 4, 4%). Four patients had concurrent ascites and hepatic encephalopathy at presentation, 3 had ascites and spontaneous bacterial peritonitis, and one had ascites and variceal hemorrhage. There were no differences in types of ESLD events by ART era. The incidence rate of HCC was 1.5 (95% CI: 0.9 to 2.3) events/1000 person-years. Rates of liver complications during follow-up did not significantly differ in magnitude by ART era (Fig. 2; see Table 2, Supplemental Digital Content, https://links.lww.com/QAI/B334).

F2
FIGURE 2.:
Incidence rates and 95% confidence intervals of liver complications (composite of first occurrence of ESLD or HCC diagnosis), ESLD, and HCC among HIV/HBV-coinfected patients in the North American AIDS Cohort Collaboration on Research and Design (January 1996–December 2010), by antiretroviral therapy era (1996–2001, 2002–2005, 2006–2010).

Determinants of Liver Complications

Non-black/non-Hispanic race, time-updated diabetes, heavy alcohol use, lower time-updated CD4 count, and higher FIB-4 at start of follow-up were significant determinants of liver complications (Table 2). Analyses accounting for the competing risk of death showed similar results (see Table 3, Supplemental Digital Content, https://links.lww.com/QAI/B334). Results were also similar after patients with ALT or AST >1000 U/L within ±30 days of their qualifying HBV laboratory test (n = 95) were excluded (see Table 4, Supplemental Digital Content, https://links.lww.com/QAI/B334). When duration of diabetes was examined in place of time-updated diabetes, the risk of liver complications was increased with longer diabetes duration [aHR, 1.12 (95% CI: 1.05 to 1.20) per 12 months of diabetes]. When platelet count at start of follow-up was substituted for FIB-4, platelets <150,000/µL were associated with an increased risk of liver complications [aHR, 5.78 (95% CI: 3.61 to 9.24)]. When FIB-4 was replaced with both AST and platelet count at start of follow-up, the risk of liver complications was increased with higher AST [aHR, 1.04 (95% CI: 1.02 to 1.05) per 10 U/L increase] and lower platelet count [aHR, 1.25 (95% CI: 1.16 to 1.33) per 20,000/µL decrease].

T2
TABLE 2.:
Factors Associated With Liver Complications, Defined by First Occurrence of End-Stage Liver Disease or Hepatocellular Carcinoma, Among HIV/Hepatitis B Virus–Coinfected Patients Within the North American AIDS Cohort Collaboration on Research and Design (1996–2010; n = 3573)

The risk of liver complications was reduced with use of ART that included an HBV-active antiretroviral [aHR, 0.47 (95% CI: 0.16 to 1.36)] or ART that included either TDF or entecavir [aHR, 0.36 (95% CI: 0.12 to 1.03)] compared with those receiving ART without an HBV-active antiretroviral, but results were not statistically significant.

Association Between HIV RNA Suppression and Liver Complications

Among 3385 HIV/HBV-coinfected persons who received HBV-active ART during follow-up, HIV suppression for ≥6 months was associated with a lower risk of liver complications compared with those with unsuppressed HIV (Table 3). Results were similar in analyses accounting for competing risk of death (see Table 5, Supplemental Digital Content, https://links.lww.com/QAI/B334).

T3
TABLE 3.:
Adjusted Hazard Ratios of Liver Complications Associated With Increasing Consecutive Months of HIV Suppression Compared With Persons With Unsuppressed HIV Among HIV/Hepatitis B Virus–Coinfected Patients Who Received HBV-Active Antiretroviral Therapy Within the North American AIDS Cohort Collaboration on Research and Design (1996–2010; n = 3385)

DISCUSSION

This is the first population-representative cohort study to evaluate rates and determinants of liver complications exclusively among HIV/HBV-coinfected individuals from North America. We observed high rates of liver complications in our cohort. Non-black/non-Hispanic race, diabetes, heavy alcohol use, lower CD4 cell count, and higher FIB-4 were significant risk factors for liver complications. Importantly, maintaining HIV suppression for ≥6 months with HBV-active ART significantly decreased the risk of liver complications.

The high rate of liver complications among coinfected individuals in this study may have been driven by lack of receipt of HBV-active ART during the observation period. By end of follow-up, 5.3% of patients had not received HBV-active ART, despite guidelines recommending that all HIV/HBV patients be considered for dual therapy.18 Some of these patients may have had contraindications to HBV-active ART (eg, underlying nephrotoxicity or HIV mutations conferring antiretroviral resistance). The risk of liver complications was reduced with ART that included an HBV-active antiretroviral, particularly TDF, though these results did not achieve statistical significance, likely because of the short (median, 3.0 years) duration of follow-up. Future studies with longer follow-up should evaluate the extent to which HBV-active and TDF-based ART decrease the risk of liver complications.

We found that coinfected patients with ≥6 months of HIV suppression during HBV-active ART were significantly less likely to develop liver complications, highlighting the importance of HIV control to limit progression of liver disease. HIV viremia has been linked with hepatic fibrogenesis.25 Early and late HIV suppression with ART is associated also with lower cancer incidence, though to a greater degree for AIDS-defining cancers.26 Our study shows that initiation of ART and maintenance of HIV suppression should remain key goals for HIV/HBV patients to reduce the risk of ESLD and HCC.

Lower CD4 cell count was a strong determinant of liver complications. This finding is consistent with a previous study in the Multicenter AIDS Cohort Study that found that liver-related death was associated with lower CD4 counts among HIV/viral hepatitis-coinfected patients.27 However, it remains unclear whether the association between low CD4 count and increased risk of liver complications is due to immunosuppression or if the low CD4 count is a marker of advanced liver disease, because cirrhosis-induced portal hypertension can lead to low CD4 counts via splenic sequestration.28 Additional studies are needed to determine the effects of immunosuppression on risk of liver complications among HIV/HBV-coinfected persons.

We identified non-black/non-Hispanic race as a determinant of liver complications. No studies have examined racial/ethnic differences in HBV-related liver complications in HIV. Recent studies among HIV/HCV-coinfected patients reveal that persons of non-black race have a higher risk of hepatic decompensation29 and liver-related death.30 More research is needed to determine the impact of race/ethnicity on risk of liver complications in HIV/HBV coinfection.

Diabetes, as well as increasing duration of diagnosis, were independently associated with an increased risk for liver complications. Previous cohort studies show that diabetes increases risk of ESLD among HCV-monoinfected31 and HIV/HCV-coinfected patients.29 Diabetes can promote hepatic steatosis, which contributes to hepatic fibrosis.32 Diabetes may also induce hepatic fibrosis independent of steatosis via stimulation of hepatic stellate cells by insulin.33 Cirrhosis can further promote development of glucose intolerance and diabetes,34 making it difficult to interpret associations between diabetes and ESLD, especially in cross-sectional and case–control studies. The longitudinal design of our study and time-updated manner in which diabetes was evaluated overcomes this limitation.

Higher FIB-4, a noninvasive index of hepatic fibrosis, was also a determinant of liver complications. Cirrhosis is a well-recognized risk factor for hepatic decompensation and HCC.35 HIV providers could calculate FIB-4 for their HIV/HBV patients, particularly when transient elastography or other modalities for assessing hepatic fibrosis are unavailable. Increased FIB-4 should prompt clinicians and patients to address modifiable risk factors for ESLD and identify those who should be followed closely for this outcome.

We also examined the effects of heavy alcohol use and HCV coinfection on liver complications among HIV/HBV patients. Similar to findings in HBV-monoinfected patients,36 heavy alcohol use was an important determinant of ESLD/HCC. Interestingly, HCV coinfection was associated with a modest, but nonsignificant, increase in risk of liver complications. Among HIV-uninfected persons, HCV coinfection increases rates of cirrhosis and HCC compared with HBV monoinfection.37 However, interference between HBV and HCV in coinfected patients resulting in suppression of viral replication has been described,38 which could have resulted in attenuation of the effect of HCV coinfection in our analysis. Additional studies should examine the risk of liver complications with HCV coinfection among HIV/HBV patients.

This study has a number of strengths. It included a large, representative sample of HIV/HBV patients from across the US and Canada; evaluated previously unexamined determinants of ESLD/HCC among HIV/HBV patients; accounted for time-varying covariates; and ascertained validated ESLD and HCC endpoints using standardized criteria across the participating sites. Results were robust in sensitivity analyses.

The study has several potential limitations. First, ESLD and HCC diagnoses were validated through 2010, which prevented inclusion of HIV/HBV patients receiving more modern ART and HBV treatment regimens. However, the greater variability in HIV suppression during the study period enhanced statistical power to evaluate associations between HIV suppression and liver complication risk. Second, by allowing patients with only one measurement of HBsAg, HBeAg, or HBV DNA into the cohort, we may have included some patients with acute HBV infection. However, we performed a sensitivity analysis excluding those with concomitant liver aminotransferases >1000 U/L, who might have had acute HBV and did not progress to chronic infection, and results were similar to the primary analysis. Third, the accuracy of FIB-4 among HIV/HBV-coinfected patients, particularly during HBV-active ART, is unclear and has not been validated compared with liver biopsy. Liver fibrosis may have been misclassified by FIB-4 because of conditions that decrease platelets or increase liver aminotransferases. Finally, data on body mass index and hepatitis delta virus were unavailable, and HBV DNA and HBeAg were measured too infrequently to be examined as determinants of liver complications. Future studies should evaluate these variables and examine whether there is a biological gradient of risk for liver complications with increasing HBV DNA.

In summary, HIV/HBV-coinfected patients in the NA-ACCORD experienced high rates of ESLD and HCC events. In addition to non-black/non-Hispanic race, diabetes, heavy alcohol use, and higher FIB-4, lower cell CD4 count and longer consecutive time with HIV suppression were important HIV-related determinants of liver complications. Initiation of HBV-active ART and sustained HIV suppression should be a focus for HIV/HBV patients to reduce the risk of ESLD and HCC. Future studies should evaluate how HBV DNA and different HBV-active ART regimens have an impact on liver complications among HIV/HBV-coinfected patients.

ACKNOWLEDGMENTS

The authors would like to acknowledge the assistance of Ms. Brenna Hogan in the development of the analytic datasets in addition to the following NA-ACCORD collaborating cohorts and representatives: AIDS Clinical Trials Group Longitudinal Linked Randomized Trials: Constance A. Benson and Ronald J. Bosch. AIDS Link to the IntraVenous Experience: Gregory D. Kirk. Fenway Health HIV Cohort: Stephen Boswell, Kenneth H. Mayer, and Chris Grasso. HAART Observational Medical Evaluation and Research: Robert S. Hogg, P. Richard Harrigan, Julio S.G. Montaner, Benita Yip, Julia Zhu, Kate Salters, and Karyn Gabler. HIV Outpatient Study: Kate Buchacz and John T. Brooks. HIV Research Network: Kelly A. Gebo and R.D.M. Johns Hopkins HIV Clinical Cohort: R.D.M. John T. Carey Special Immunology Unit Patient Care and Research Database, Case Western Reserve University: Benigno Rodriguez. Kaiser Permanente Mid-Atlantic States: M.A.H. Kaiser Permanente Northern California: M.J.S. Longitudinal Study of Ocular Complications of AIDS: Jennifer E. Thorne. Multicenter Hemophilia Cohort Study–II: Charles Rabkin. Multicenter AIDS Cohort Study: Joseph B. Margolick, Lisa P. Jacobson, and Gypsyamber D'Souza. Montreal Chest Institute Immunodeficiency Service Cohort: M.B.K. Ontario HIV Treatment Network Cohort Study: Sean B. Rourke, Anita R. Rachlis, and Patrick Cupido. Retrovirus Research Center, Bayamon Puerto Rico: Robert F. Hunter-Mellado and A.M.M. Southern Alberta Clinic Cohort: M. John Gill. Study of the Consequences of the Protease Inhibitor Era: Steven G. Deeks and Jeffrey N. Martin. Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy: Pragna Patel and John T. Brooks. University of Alabama at Birmingham 1917 Clinic Cohort: Michael S. Saag, Michael J. Mugavero, and James Willig. University of California at San Diego: William C. Mathews. University of North Carolina at Chapel Hill HIV Clinic Cohort: Joseph J. Eron and Sonia Napravnik. University of Washington HIV Cohort: M.M.K., Heidi M. Crane, and H.N.K. Vanderbilt Comprehensive Care Clinic HIV Cohort: T.R.S., David Haas, Peter Rebeiro, Megan Turner, Sally Bebawy, Ben Rogers, Trisha Pahawa, and Kamaria Wilson. Veterans Aging Cohort Study: Amy C. Justice, Robert Dubrow, and David Fiellin. Women's Interagency HIV Study: Stephen J. Gange and Kathryn Anastos.

NA-ACCORD Study Administration:Executive Committee: R.D.M., Michael S. Saag, Stephen J. Gange, M.M.K., K.N.A, Michael A. Horberg, M.B.K., Rosemary G. McKaig and Aimee M. Freeman. Administrative Core: R.D.M., Aimee M. Freeman and Carol Lent. Data Management Core: MM.K, Stephen E. Van Rompaey, Heidi M. Crane, H.N.K., Liz Morton, Justin McReynolds, and William B. Lober. Epidemiology and Biostatistics Core: Stephen J. Gange, K.N.A., Bin You, Brenna Hogan, Elizabeth Humes, Jinbing Zhang, Jerry Jing, Bin Liu, Mark Riffon, and Fidel A. Desir.

REFERENCES

1. Hoffmann CJ, Thio CL. Clinical implications of HIV and hepatitis B co-infection in Asia and Africa. Lancet Infect Dis. 2007;7:402–409.
2. Colin JF, Cazals-Hatem D, Loriot MA, et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology. 1999;29:1306–1310.
3. Hoffmann CJ, Seaberg EC, Young S, et al. Hepatitis B and long-term HIV outcomes in coinfected HAART recipients. AIDS. 2009;23:1881–1889.
4. Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS. 2005;19:593–601.
5. Puoti M, Spinetti A, Ghezzi A, et al. Mortality for liver disease in patients with HIV infection: a cohort study. J Acquir Immune Defic Syndr. 2000;24:211–217.
6. Thio CL, Seaberg EC, Skolasky R Jr, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360:1921–1926.
7. Franceschi S, Lise M, Clifford GM, et al. Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study. Br J Cancer. 2010;103:416–422.
8. Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006;166:1632–1641.
9. Klein MB, Althoff KN, Jing Y, et al. Risk of end-stage liver disease in HIV-viral hepatitis coinfected persons in North America from the early to modern antiretroviral therapy eras. Clin Infect Dis. 2016;63:1160–1167.
10. Gange SJ, Kitahata MM, Saag MS, et al. Cohort profile: the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Int J Epidemiol. 2007;36:294–301.
11. Kitahata MM, Drozd DR, Crane HM, et al. Ascertainment and verification of end-stage renal disease and end-stage liver disease in the North American AIDS Cohort Collaboration on Research and Design. AIDS Res Treat. 2015;2015:923194.
12. Silverberg MJ, Lau B, Achenbach CJ, et al. Cumulative incidence of cancer among persons with HIV in North America: a cohort study. Ann Intern Med. 2015;163:507–518.
13. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–526.
14. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–1325.
15. Kim BK, Kim do Y, Park JY, et al. Validation of FIB-4 and comparison with other simple noninvasive indices for predicting liver fibrosis and cirrhosis in hepatitis B virus-infected patients. Liver Int. 2010;30:546–553.
16. Crane HM, Kadane JB, Crane PK, et al. Diabetes case identification methods applied to electronic medical record systems: their use in HIV-infected patients. Curr HIV Res. 2006;4:97–106.
17. Bush K, Kivlahan DR, McDonell MB, et al. The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test. Arch Intern Med. 1998;158:1789–1795.
18. Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2018;320:379–396.
19. Yeni PG, Hammer SM, Carpenter CC, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA. 2002;288:222–235.
20. Fine J, Gray RJ. A proportional hazards model for the subdistribution of competing risk. J Am Stat Assoc. 1999;94:496–509.
21. Trepo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet. 2014;384:2053–2063.
22. Sterling RK, Wahed AS, King WC, et al. Spectrum of liver disease in hepatitis B virus (HBV) patients co-infected with human immunodeficiency virus (HIV): results of the HBV-HIV Cohort Study. Am J Gastroenterol. 2019;114:746–757.
23. Royston P. Multiple imputation of missing values: update. STATA J. 2005;5:188–201.
24. Freedman VA, Wolf DA. A case study on the use of multiple imputation. Demography. 1995;32:459–470.
25. Kim HN, Nance R, Van Rompaey S, et al. Poorly controlled HIV infection: an independent risk factor for liver fibrosis. J Acquir Immune Defic Syndr. 2016;72:437–443.
26. Park LS, Tate JP, Sigel K, et al. Association of viral suppression with lower AIDS-defining and non-AIDS-defining cancer incidence in HIV-infected veterans: a prospective cohort study. Ann Intern Med. 2018;169:87–96.
27. Falade-Nwulia O, Seaberg EC, Rinaldo CR, et al. Comparative risk of liver-related mortality from chronic hepatitis B versus chronic hepatitis C virus infection. Clin Infect Dis. 2012;55:507–513.
28. McGovern BH, Golan Y, Lopez M, et al. The impact of cirrhosis on CD4+ T cell counts in HIV-seronegative patients. Clin Infect Dis. 2007;44:431–437.
29. Lo Re V III, Kallan MJ, Tate JP, et al. Hepatic decompensation in antiretroviral-treated patients co-infected with HIV and hepatitis C virus compared with hepatitis C virus-monoinfected patients: a cohort study. Ann Intern Med. 2014;160:369–379.
30. Sarkar M, Bacchetti P, French AL, et al. Lower liver-related death in African-American women with human immunodeficiency virus/hepatitis C virus coinfection, compared to Caucasian and Hispanic women. Hepatology. 2012;56:1699–1705.
31. Huang YW, Yang SS, Fu SC, et al. Increased risk of cirrhosis and its decompensation in chronic hepatitis C patients with new-onset diabetes: a nationwide cohort study. Hepatology. 2014;60:807–814.
32. Lo Iacono O, Venezia G, Petta S, et al. The impact of insulin resistance, serum adipocytokines and visceral obesity on steatosis and fibrosis in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2007;25:1181–1191.
33. Paradis V, Perlemuter G, Bonvoust F, et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology. 2001;34(4 pt 1):738–744.
34. Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA, et al. Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical implications and management. World J Gastroenterol. 2009;15:280–288.
35. Fattovich G, Pantalena M, Zagni I, et al. Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients. Am J Gastroenterol. 2002;97:2886–2895.
36. El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology. 2014;60:1767–1775.
37. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol. 2008;48:335–352.
38. Bini EJ, Perumalswami PV. Hepatitis B virus infection among American patients with chronic hepatitis C virus infection: prevalence, racial/ethnic differences, and viral interactions. Hepatology. 2010;51:759–766.
Keywords:

hepatitis B; HIV; end-stage liver disease; hepatocellular carcinoma; coinfection

Supplemental Digital Content

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.