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Isolated Hepatitis B Core Antibody is Associated With Advanced Hepatic Fibrosis in HIV/HCV Infection But Not in HIV Infection Alone

Year: 2016

Type: article

Abstract: To the Editors: INTRODUCTION Isolated hepatitis B virus (HBV) core antibody (HBcAb+), defined as the presence of HBcAb in the absence of HBV surface antigen (HBsAg) and surface antibody (HBsAb), occurs in up to 34% HIV–HCV-coinfected persons.1–6 Isolated HBcAb can indicate occult HBV viremia, (the presence of HBV viremia in the absence of HBsAg), resolved infection with low titers of HBsAb, a window period during acute infection, or a false-positive result. However, the relationship between isolated HBcAb pattern and liver disease remains unclear with some, but not all, studies describing an association with liver disease.3,7–10 Our objective was to characterize the prevalence of isolated HBcAb pattern among HIV- and HIV/HCV-infected veterans in the Veterans' Aging Cohort Study (VACS) and to determine whether the isolated HBcAb pattern was associated with advanced fibrosis in HIV- and HIV/HCV-coinfected veterans. METHODS Study Design and Setting We conducted a cross-sectional study among HIV-infected individuals in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC).11 Comprised electronic medical record data from all HIV-infected veterans at Veterans Affairs (VA) medical facilities in the United States, data include hospital and outpatient diagnoses, laboratory results, and pharmacy data.12 Study Patients The study sample included all HIV-infected individuals who enrolled in the VACS-VC between October 1996 and September 2010, had at least 180 days of follow-up, and who had all 3 HBcAb, HBsAg, and HBsAb serologies tested. We then searched for the first positive or negative HBcAb test and included only those who had subsequent HBsAb and HBsAg testing ± 12 months from the first positive or negative HBcAb result. We further evaluated those for whom data variables to calculate FIB-4 and aspartate aminotransferase (AST)-to-platelet ratio index (APRI) scores were available within ± 12 months of the earliest complete serologic data. The following 5 serologic patterns were assessed: Isolated HBcAb: HBsAg negative, HBcAb positive, HBsAb negative Resolved HBV infection: HBsAg negative, HBcAb positive, HBsAb positive Nonimmune HBV: HBsAg negative, HBcAb negative, HBsAb negative Immunized HBV: HBsAg negative, HBcAb negative, HBsAb positive Active HBV infection: HBsAg positive, HBcAb negative or positive, HBsAb negative. The main outcome was advanced hepatic fibrosis, defined by an FIB-4 >3.25 at the time of serologic evaluation (within 1 year of markers obtained). Secondary outcomes defining advanced hepatic fibrosis were assessed individually and included: (1) aspartate aminotransferase (AST)-to-platelet ratio index (APRI) >2.0, and (2) platelet count <140,000 per microliter. Both FIB-4 (based on age, AST, alanine aminotransferase)13 and APRI have been shown to validly identify patients with advanced hepatic fibrosis/cirrhosis.14 Similarly, platelet counts of <140,000 per microliter have been associated with advanced fibrosis/cirrhosis.15 HCV infection was defined as HCV Ab positive, HCV RNA positive, or an ICD-9 diagnosis of HCV. Age, race/ethnicity, CD4 count, log HIV viral load, diabetes, body mass index, alcohol-related disorders, drug use, smoking were collected from all patients at inclusion. Diabetes was defined by a random glucose level ≥200 mg/dL or antidiabetic medication use. Alcohol-related disorders and injection/noninjection drug use were defined by ICD-9 codes. Logistic regression was used to evaluate associations between serological patterns of HBV and advanced hepatic fibrosis for patients with and without chronic HCV infection, adjusting for age, race/ethnicity, CD4 count, log HIV RNA, diabetes, body mass index, alcohol-related disorders, injection/noninjection drug use, and smoking. As substance use can be associated with immune dysfunction,16 which in turn can be associated with the isolated HBcAb pattern, interactions between serological patterns and alcohol-related disorders, injection/noninjection drug use, and smoking were also evaluated. All analyses were performed using SAS version 9.2 (Cary, NC). RESULTS Among 44,180 HIV-infected veterans (14,568 with and 29,612 without HCV infection), 41,088 had at least 180 days of follow-up, 26,924 had all 3 serologies tested, and 23,970 veterans had all 3 serologies within 1 year of the first positive or negative HBcAb result. Among 23,970 HIV-infected veterans, 9327 with and 14,643 without HCV infection, 7290 and 12,196, respectively, had complete data allowing for calculation of FIB-4 and APRI. Complete information on persons with missing hepatitis data included race, smoking status, and age. Those who were included were more likely to be white (37% vs 30%), older (mean age 47 vs 46), and less likely to be current smokers (59% vs 64%), all P < 0.01. In this cohort, 12.3% (1504/12,196) and 37% (2707/7290) of HIV and HIV/HCV individuals, respectively, had the isolated HBcAb pattern (Table 1). Persons with isolated HBcAb were the same age or older and more likely to be nonwhite, or to have an alcohol-related disorder, than were persons with resolved HBV, nonimmune HBV, or HBsAb only. HIV-monoinfected persons with isolated HBcAb were more likely to have <200 CD4 cells per microliter and a higher median level of HIV-1 RNA copies per milliliter. In addition, coinfected persons who were nonimmune to HBV and persons who were HBsAb+ only had a higher median HIV-1 RNA copies per milliliter than did persons with isolated HBcAb. In both groups, there was not a statistically significant interaction noted between substance use and the isolated HBcAb pattern.TABLE 1: Patient Characteristics and Comparative Prevalence of Advanced Fibrosis for Isolated HBcAb Compared With Other HBV Serologic PatternsIn both HIV-monoinfected and HIV/HCV-coinfected groups, AST, FIB-4, and APRI scores were higher, whereas platelets were lower in isolated HBcAb patients, when compared with those with resolved HBV, nonimmune HBV, or HBsAb only serologic profiles. However, in multivariable analysis, when compared with HBsAg-negative groups, only HIV/HCV-coinfected patients with isolated HBcAb exhibited an association with advanced hepatic fibrosis. HIV+/HCV+ patients with isolated HBcAb had higher odds ratio (OR) for advanced hepatic fibrosis by FIB-4 than those who had resolved HBV [OR, 1.34; 95% confidence interval (CI): 1.15 to 1.58], were nonimmune (OR, 1.32; 95% CI: 1.09 to 1.60), or were HBsAb+ (OR, 1.65; 95% CI: 1.20 to 2.28). Similar results were observed when APRI and platelet counts <140,000 per microliter were evaluated. Not unexpectedly, advanced fibrosis was less in patients with isolated HBcAb than in those who were HBsAg positive. We performed a sensitivity analysis (not shown) that included HCV viremic patients which showed a similar association with HCV viremia, the isolated HBcAb profile, and advanced fibrosis, but this was not statistically significant, likely a reflection of the smaller sample size. DISCUSSION In this large cross-sectional study of isolated HBcAb patterns of both HIV-infected and HIV/HCV-coinfected veterans, we found that the isolated HBcAb pattern was associated with advanced hepatic fibrosis in HIV/HCV-coinfected patients but not in HIV infection without concomitant HCV infection. Although most clearly seen using an FIB-4 threshold of >3.25, similar results were seen with an APRI threshold of >2.0 or a platelet count of <140,000 per microliter. The fact that the isolated HBcAb pattern was associated with advanced liver disease in HIV/HCV-coinfected, but not HIV-monoinfected patients, suggests that there might be a multiplicative effect of HCV, HIV, and previous or ongoing low-grade HBV infection on the liver (as demonstrated by the isolated HBcAb pattern). Alternatively, both chronic HCV and the isolated HBcAb pattern may reflect a suboptimal immune response that facilitates HCV persistence, isolated HBcAb persistence, and ongoing liver damage, as manifested by an association with lower CD4 counts in a cohort of HIV-infected women and in this study.17 However, CD4 was incorporated into the logistic regression model for this study, suggesting that other components of the immune response may be involved. Although there were no interaction effects, an increased prevalence of substance use in those with the isolated HBcAb pattern, may be indicative of other defects in immune response, as has been seen with opiates, marijuana, and alcohol.16 Because this is a cross-sectional study, it was not possible to distinguish whether the advanced fibrosis reflected previous versus ongoing liver damage. Strengths of the current analysis included a large sample size of patients with a full panel of HBV serologies and direct comparison of HCV-infected and uninfected veterans with HIV infection. Limitations of the study include the cross-sectional nature of the analysis and missing data in those who had complete serologies, which represented 19% of the cohort. This may have led to selection bias, especially in the HCV-uninfected group where hepatitis B serologies were disproportionately not evaluated. However, as patients who did not have serologies were likely to be healthier than those who did, it is unlikely that this would have affected our results. In addition, we did not assess HBV DNA in the serum, as only a fraction of the study population had serum HBV DNA measured. Moreover, FIB-4 and APRI might not be accurate in assessing intermediate degrees of fibrosis. Finally, our study was conducted in HIV-infected veterans who may have differing risk factors, including socioeconomic factors, for liver disease than other HIV-infected cohorts potentially limiting generalizability to other cohorts. In summary, we found that the isolated HBcAb pattern was associated with advanced hepatic fibrosis in HIV/HCV-coinfected, but not HIV-monoinfected, veterans. These findings suggest that HIV- and HCV-infected persons with isolated HBcAb may be at increased risk of clinical liver complications and support the need for further studies in the longitudinal assessment of liver disease.

Source: JAIDS Journal of Acquired Immune Deficiency Syndromes

DOI: 10.1097/qai.0000000000000941