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Research Letters

Aspartate aminotransferase-to-platelet ratio index increases significantly 3 years prior to liver-related death in HIV-hepatitis-coinfected men

Price, Jennifer C.a; Seaberg, Eric C.b; Stosor, Valentinac; Witt, Mallory D.d; Lellock, Carling D.e; Thio, Chloe L.f

Author Information
doi: 10.1097/QAD.0000000000001977

Abstract

Liver disease, primarily because of hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection, is a leading cause of non-AIDS mortality among people living with HIV [1]. Identifying patients at highest risk of adverse outcomes is critical for reducing liver-related events in this population. The aspartate aminotransferase-to-platelet-ratio index (APRI), a noninvasive surrogate for liver fibrosis, utilizes routinely obtained serum markers and is especially useful when alternative noninvasive options are unavailable [2]. Studies validating APRI have primarily been cross-sectional [3–5]. We performed a nested case–control study in the Multicenter AIDS Cohort Study (MACS) to determine whether APRI changes are associated with liver-related death in viral hepatitis-infected men with or without HIV infection.

The MACS is an ongoing cohort study of HIV-infected and HIV-uninfected MSM with cohort details described elsewhere [6,7]. Men with chronic HCV or HBV followed between 1 January 1984 and 31 December 2010 were eligible. Cases were participants who experienced liver-related death during follow-up and had stored serum available at specified timepoints before death. Liver-related deaths were determined from death certificates with primary or contributing International Classification of Diseases, 9th Revision, diagnosis codes for HBV, HCV, viral hepatitis, hepatic failure, chronic hepatitis, cirrhosis, liver failure, chronic liver disease, hepatocellular carcinoma, hepatic coma, or hepatorenal syndrome. Randomly selected HCV-infected or HBV-infected controls were matched 1 : 1 to cases by age, HIV, HBV and HCV status, and race. APRI was calculated at years 9, 6, 3, 2, and 1 prior to death for cases, and at visits matched by calendar year for controls. HCV, HBV, and HIV status were defined at the visit closest to death for cases and the calendar-matched visit for controls.

We used a paired t-test to compare natural-log-transformed (ln)APRI by case status. We evaluated APRI changes using multilevel linear regression models with ln(APRI) as the dependent variable and included random effects to account for clustering within each case–control pair. Time interval was categorized from 9 to more than 3 years and 3–1 years before death based on graphical exploration indicating a precipitous APRI increase 3 years before death. Coefficients were exponentiated to produce relative APRI differences. The model included HIV status, race, age, CD4+ count, and use of HBV medication. Analyses were performed using Stata, version 12.1 (College Station, Texas, USA).

Most of the 57 cases were HIV-infected (91%) and white (88%), with a median age of 44 years [interquartile range (IQR) 37–51]. Chronic HBV was more common than HCV, as expected in MSM (38 vs. 23 men, including 4 HBV/HCV/HIV-coinfected). Among HIV-infected cases and controls, median CD4+ counts were 206 (IQR 109–342) and 431 (IQR 315–679), respectively (P < 0.001). Only 33% and 38% of HIV-infected cases and controls, respectively, were on combination antiretroviral therapy (ART) at the visit closest to death (or calendar year-matched visit for controls; P = 0.61). For deaths after 2001, these numbers increased to 62% and 78% (P = 0.33). There were no differences in ART use by case/control status at any timepoint. Forty-seven percent of liver-related deaths occurred before 1996. Among those with chronic HBV, 26% of cases and 28% of controls received an anti-HBV medication. Two HCV-infected cases and no HCV-infected controls received HCV treatment.

The proportion of cases with APRI greater than 1.5 (consistent with cirrhosis) steadily rose during follow-up from 31% to 75% whereas it remained stable among controls (6–9%; Supplemental Figure 1, https://links.lww.com/QAD/B335). Mean APRI, which was higher in cases than controls at all timepoints, was stable among controls but increased among cases, particularly in the 3 years preceding death (Table 1, Supplemental Figure 2, https://links.lww.com/QAD/B335). Among cases, the adjusted APRI increased 4.6%/year between 9 and 3 years before death (P = 0.10 compared with no change) and 30%/year within 3 years of death (P < 0.001). The annual APRI change among cases was significantly higher in the 3–1-year interval compared with the 9- to more than 3-year interval (P = 0.01). On multivariable analysis, lower CD4+ counts were also independently associated with significantly higher APRI. Compared with CD4+ counts of at least 500 cells/μl, CD4+ counts of 300–499 cells/μl and less than 300 cells/μl were associated with 36% (P = 0.005) and 51% (P < 0.001) higher APRI, respectively.

T1-22
Table 1:
Aspartate aminotransferase-to-platelet-ratio index by timepoint and adjusted annual percentage change in aspartate aminotransferase-to-platelet-ratio index.

As HIV and/or ART can affect both platelets and aspartate aminotransferase (AST), we evaluated whether APRI changes were primarily driven by either of these values. The mean platelet count (in APRI denominator) was lower in cases than controls and declined at each timepoint. Conversely, mean AST (in APRI numerator) was higher in cases than in controls and increased longitudinally, suggesting that APRI changes were driven by both these parameters.

In summary, APRI was consistently higher and increased more rapidly in men who died a liver-related death over the 9 years before death. This increase was most precipitous in the 3 years preceding death, likely reflecting the rapid reduction in hepatic function observed in cirrhosis once decompensation occurs. These data are consistent with a study demonstrating that baseline APRI predicted 3-year liver morality in a cohort of HCV-monoinfected and HIV/HCV-coinfected individuals [8] and another study showing that baseline APRI predicted liver complications in a cohort of HIV-monoinfected and HIV/HCV-coinfected patients followed for a median of 4.6 years [9]. Additionally, lower CD4+ counts were associated with higher APRI, regardless of case status. This is consistent with a prior cross-sectional analysis in which we found an independent association of lower CD4+ count and higher APRI in the MACS [10]. Studies in other HIV cohorts have similarly found an inverse association of CD4+ count and fibrosis stage [11–14].

The unique features of our study include the prospective design, APRI testing at discrete timepoints predeath, use of liver-related death as the outcome, and inclusion of matched controls. We recognize that the relatively small sample limited our ability to control for all potential factors associated with liver-related mortality, that death certificates have limitations, and that the all-male cohort limits generalization to women. These data suggest that increasing APRI, especially when the baseline APRI is elevated, heralds the onset of an adverse liver-related outcome in HIV–viral hepatitis coinfection and underscores the urgency of aggressive treatments in this population. Further examination in large prospectively followed cohorts is needed to determine specific APRI values and trajectories with the highest predictive value for liver-related death.

Acknowledgements

Funding/support: This work was funded by the National Center for Research Resources (NCRR) (1KL2RR025006-01 to J.C.P.) and the National Institute on Drug Abuse (NIDA) (5R03DA026094-02 to C.L.T.). Data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS). MACS (Principal Investigators): Johns Hopkins University Bloomberg School of Public Health (Joseph Margolick), U01-AI35042; Northwestern University (Steven Wolinsky), U01-AI35039; University of California, Los Angeles (Roger Detels), U01-AI35040; University of Pittsburgh (Charles Rinaldo), U01-AI35041; the Center for Analysis and Management of MACS, Johns Hopkins University Bloomberg School of Public Health (Lisa Jacobson), UM1-AI35043. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by UL1-TR001079 (JHU ICTR) from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research and the Los Angeles Biomedical Research Institute at Harbor-UCLA CTSI, UL1TR000124. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH), Johns Hopkins ICTR, or NCATS.

Author contributions: J.C.P., study concept and design, acquisition of data, analysis and interpretation of data, drafting of manuscript; E.C.S., study concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content; V.S., analysis and interpretation of data, critical revision of the manuscript for important intellectual content; M.D.W., analysis and interpretation of data, critical revision of the manuscript for important intellectual content; C.D.L., analysis and interpretation of data, critical revision of the manuscript for important intellectual content; C.L.T., study concept and design, acquisition of data, analysis and interpretation of data, critical revision of the manuscript for important intellectual content.

Conflicts of interest

J.C.P. discloses grant support from Gilead Sciences and Merck and ownership interest in Bristol-Myers Squibb, Johnson and Johnson, Merck, and Abbvie. C.L.T. discloses grant support paid to her university from Gilead Sciences. All other authors have nothing to disclose.

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