Among an urban, predominantly black study population of HCV-monoinfected persons and HIV-HCV–coinfected persons, liver stiffness measurement was well tolerated and had diagnostic accuracy for staging fibrosis and cirrhosis that was comparable to histologic methods. Because of the high acceptability, safety, and potential to repeat the test, the procedure holds promise to markedly expand liver disease screening and monitoring, particularly among IDUs.
For detection of fibrosis, elastography diagnostic performance in our study was comparable to prior validation studies involving HCV-monoinfected patients from Europe [10
]. In early validation studies, the AUC-ROC for detecting significant fibrosis ranged from 0.79 to 0.83 [10
There are limited data on elastography for HIV-HCV–coinfected persons. In a multisite study from hospital-based hepatology clinics in France, de Ledinghen et al. [26
] reported an AUC-ROC of 0.72 (95% CI, 0.60–0.84) for liver stiffness measurement in predicting fibrosis, compared with concurrent examination of a liver biopsy specimen, among 72 HIV-HCV–coinfected patients. Among 169 HIV-HCV–coinfected patients from 6 hospital-based infectious diseases clinics in Spain, the AUC-ROC for significant fibrosis was notably higher (0.87; 95% CI, 0.84–0.93) than that in the French study [27
]. The diagnostic accuracy of liver stiffness measurement for fibrosis in our HIV-HCV–coinfected subset was higher than that in the French study and similar to that in the Spanish study.
Consistent with observations in HCV-monoinfected patients [10
], both prior studies of HIV-HCV–coinfected patients reported excellent ability to discriminate cirrhosis (AUC-ROC, >0.95) [26
]. In contrast, we did not observe substantially greater diagnostic accuracy of liver stiffness measurement for diagnosis of cirrhosis, compared with diagnosis of fibrosis. There are several probable reasons to explain observed differences in diagnostic accuracy between studies. First, the spectrum of liver disease stages within the study populations affects the diagnostic accuracy [28
]. In our study, we had a relatively large proportion of participants with minimal fibrosis (59%) and a relatively small proportion with cirrhosis (25%). By comparison, the prevalence of minimal fibrosis was only 26%–36% in the HIV-uninfected study populations of Castera and Ziol [10
]. Likewise, the studies involving HIV-HCV–coinfected patients had less representation of patients with a fibrosis score of F0 or F1 (38%–39%) and an increased proportion of patients with cirrhosis (31%–38%) [26
]. The reduced prevalence of advanced disease in our population diminishes the predictive value for cirrhosis.
Technical differences in application of new technology such as elastography could affect the estimated accuracy of liver stiffness measurement. In our study, we had 3 trained operators perform elastography with use of a single machine at a single site and included only examinations that exceeded specified performance criteria. Of importance, we did not detect lower elastography performance measures in participants with liver stiffness measurement values that were discordant with results of examination of a biopsy specimen.
Discordant classification of participants by elastography could simply represent overdiagnosis of fibrosis, compared with examination of a biopsy specimen. However, the accuracy of the biopsy itself will impact the estimated diagnostic accuracy of liver stiffness measurement [29
]. One recognized error of staging fibrosis by liver biopsy testing is sampling error, resulting in an underrepresentation of fibrosis [4
], which is most likely to occur with small samples of liver tissue [31
]. Overestimation of fibrosis on examination of a biopsy sample occurs much less frequently, because it essentially occurs as a result of reader error. However, similar to prior findings [25
], biopsy sample quality did not appear to explain discordance in our study. Although we cannot precisely parse out the reasons for discrepancies among the available data, we consistently found that individuals classified as having significant fibrosis or cirrhosis by liver stiffness measurement but not by histologic examination displayed elevated markers of liver disease (increased AST level, ALT level, and AST-to-platelet ratio index) or other liver pathology (steatosis and hepatic iron). Additional studies will need to determine whether liver stiffness measurement may be better than liver biopsy for detection of fibrosis or whether liver stiffness measurement “overstaged” these discordant cases (), potentially reflecting the contribution of other disease processes, such as hepatic inflammation. Of note, in contrast to transient increases in liver stiffness measurement reported in persons with acute hepatitis or with acute liver damage [32
], all of our participants were chronically infected with HCV, with modest abnormalities of liver enzymes or synthetic function (). Furthermore, compared with hepatology clinic–based studies, liver enzyme elevations in our community-recruited cohort were notably less frequent or less severe [34
]. These findings suggest that clinicians should consider using multiple methods to stage liver disease, and as with other medical tests, they should interpret the findings in light of the pretesting disease probability and the inherent limitations of the tests.
Distribution of the severity of liver fibrosis, based on histologic findings (by Metavir fibrosis score; A) and on liver stiffness measurements (B), stratified by study group and HIV status.
Of importance, inaccuracies related to fibrosis staging will be amplified in patient subgroups in which the true disease prevalence is high. In subgroup analyses, we observed diminished liver stiffness measurement accuracy, compared with accuracy of examination of a biopsy sample, among individuals with HIV infection, specifically among community-based, out-of-treatment ALIVE participants with low CD4 cell counts. To our knowledge, no other study has directly compared elastography accuracy among HIV-infected patients and HIV-uninfected patients with chronic HCV infection. However, because HIV-related CD4 cell count decreases are associated with increased odds of having significant fibrosis, lower apparent accuracy may merely reflect more frequent underrepresentation of fibrosis by histologic findings among this subset with a higher prevalence of disease. Likewise, greater discordance was observed among patients with higher AST-to-platelet ratio index scores.
As a reflection of the aforementioned limitations, diagnostic accuracy will also be reduced when greater proportions of persons have mid-stage disease, compared with when greater proportions of patients have low-stage or high-stage disease [28
]. This principle might also explain differences in apparent accuracy noted within subsets of our 2 cohorts. ALIVE HIV-infected participants with more advanced immunosuppression demonstrated a more advanced spectrum of underlying liver disease (), compared with the more bimodal distribution in the ALIVE HIV-infected group or with JHHCC participants.
Racial differences have been detected for some HCV clinical outcomes, such as natural recovery from HCV infection and IFN-α responsiveness [17
]. Although we did not observe any racial differences, our assessment of race was limited because we included relatively few participants who were not black. We are not aware of other studies that have assessed elastography performance by race.
In summary, elastography is a safe method for detection of fibrosis and cirrhosis in HCV-monoinfected persons and HIV-HCV–coinfected persons. Additional investigations will need to establish elastography effectiveness among populations with varying disease severity and in the presence of other disease processes. The broad acceptability of elastography makes the test potentially attractive for use in large-scale clinical research studies, especially those including IDUs. In clinical practice, liver stiffness measurement results, liver biopsy examination results, and all medical test results should be interpreted on the basis of a full understanding of their accuracy and limitations, as well as on the basis of the level of suspicion for the outcome (pretesting probability). In liver disease staging in particular, caution should be used when assuming that disease stage is low on the basis of a single test result, especially when the probability of significant disease is high (such as in HIV-HCV–coinfected patients with advanced immunosuppression).