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Non-Invasive Liver Tests Studies Disappoint at CROI in Coinfection Studies
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The results of studies at CROI on using non-invasive liver tests to discriminate the stage of fibrosis a Hiv-coinfected patients yielded negative findings. I think liver biopsy remains the gold standard; A study from the federal government found that in the future genetic testing may play an important role in predicting fibrosis stage.
Reported by Jules Levin
CROI 2007
Improving Non-invasive Discrimination of Fibrosis Stage in HIV/HCV-co-infected Patients.... "Most current noninvasive indices are not ready for routine clinical use.... Overall misclassification rate was 45%.
Norah Shire*1, M Rao1, J Andersen2, A Butt3, R Chung4, K Sherman1, and The ACTG 5178 Study Group
1Univ of Cincinnati, OH, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Univ of Pittsburgh, PA, US; and 4Massachusetts Gen Hosp, Boston, US
Background: Liver fibrosis progression is a significant health concern in those with HCV/HIV co-infection. Biopsy is costly and invasive, however, the utility of existing fibrosis prediction models developed with non-invasive biomarkers is suboptimal in co-infected patients. We aimed to assess predictive capacity of current models in the AIDS Clinical Trials Group 5178 and improve discriminatory capacity with novel statistical methods.
Methods: Pre-treatment data from 210 of the first 218 study entries were available, including demographics, laboratory values, and METAVIR stage from biopsy. Current models tested were the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), age-platelet index (API), AST/platelet ratio index (APRI), ordinally scored platelet count/AAR/INR, and FIB-4. Area under the ROC curve (AUROC) was assessed using pre-defined cut-points. Individual covariates were assessed using ordinal logistic regression, then entered into a classification and regression tree (CART) model to predict specific METAVIR stages. The CART model was "boosted" to decrease classification error. Boosting weights incorrectly classified samples with iterative resampling so that they have a greater chance of being resampled on the next iteration.
Results: The cohort consisted of subjects with well-compensated HIV (median CD4 503, range 135 to 2162; 85% on ART). Of these, 31.2% had significant fibrosis (METAVIR F3/F4) and 14% had cirrhosis (F4). Differences between those with and without F3/F4 were seen for CD4+ count, platelet count, and INR. For current models, FIB-4 performed best. At a cutoff ≥3.25 it had 88% specificity for F4 and >86% negative predictive values for F3/F4, but AUROCs were low (0.58±0.05 and 0.56±0.03) as were sensitivities. Similar trends were seen for predicting absence of F3/F4. After univariable ordinal regression, age, gender, CD4+, HCV/HIV viral loads, INR, platelets, ALT/AST, bilirubin, and ART or PI alone were chosen for inclusion in CART models. Training sets included 75% of the data; 25% was for cross-validation. Overall misclassification rate was 45%. After boosting, it was 1.31%. AUROC for predicting each individual fibrosis stage (F1-F4) for training/validation sets were 93/89, 93/90, 94/84, and 97/91%.
Conclusions: Current models for fibrosis assessment have poor discriminatory capacity in HCV/HIV-co-infected patients. Statistical methods such as boosting have potential to substantially improve stage-wise predictive ability, thus discriminating mild, moderate, and severe fibrosis. Further studies will be required to validate these models in HCV-monoinfected patients and to assess predictive capacity over time.
Most current noninvasive indices are not ready for routine clinical use
Normal classification methods may prove inadequate for stagewise fibrosis assessment in coinfected patients.
Failure of Transient Elastometry (Fibroscan) to Differentiate Mild from Significant Liver Fibrosis in HIV/HCV-co-infected Patients.... "Fibroscan fails to discriminate mild from significant liver fibrosis in a substantial number of HIV/HCV-co-infected patients... as many as 27% of individuals carrying F ≥2 would not receive therapy."
Salvador Vergara*1, J Mac’as1, A Rivero2, L L—pez-Cortes3, J Garc’a-Garc’a1, D Merino4, M Gonz‡lez5, M Rios-Villegas6, J de la Torre2, and J Pineda1
1Hosp de Valme, Seville, Spain; 2Hosp Reina Sofia, Cordoba, Spain; 3Hosp Virgen del Rocio, Seville, Spain; 4Hosp Juan Ramon Jimenez, Huelva, Spain; 5Hosp Virgen de la Victoria, Malaga, Spain; and 6Hosp Virgen Macarena, Seville, Spain
Background: Liver biopsy is frequently used for establishing the prognosis and the need of therapy against hepatitis C virus (HCV) in co-infected patients. Transient elastometry (Fibroscan), a new non-invasive method to measure liver stiffness, has been validated to evaluate liver fibrosis in HCV-mono-infected patients. However, while it has been reported to be highly accurate in detecting advanced liver fibrosis and cirrhosis (F = 4), there are contradictory data regarding the discrimination of significant (F ≥2) from mild liver fibrosis. In addition, liver stiffness has been insufficiently validated in HIV/HCV co-infection. Our aim was to assess the reliability of reported cutoff values of liver stiffness to discriminate F = 4 and F ≥2 in HIV/HCV-co-infected subjects.
Methods: Liver stiffness was measured in HIV/HCV-co-infected subjects who met the following inclusion criteria: liver biopsy within 12 months of liver stiffness measurement; and no therapy for HCV infection between liver biopsy and liver stiffness measurement. Patients diagnosed with clinical cirrhosis were included, and a F4 fibrosis stage was assumed. Accuracy of liver stiffness to assess liver fibrosis was tested by the area under the receiver operating characteristic curves (AUROC).
Results: The inclusion criteria were met by 101 patients, 37 of whom (37%) had F = 4, and 20 of those (54%) with clinical diagnosis of cirrhosis. AUROC (95% confidence interval CI) for liver stiffness were 0.95 (0.91 to 0.99) for F = 4 and 0.88 (0.82 to 0.95) for F ≥2. For the diagnosis of F = 4, cutoff values = 14.6 kPa, positive predictive value 79%, negative predictive value 93%; cutoff values = 17.6 kPa, positive predictive value 81%, negative predictive value 89%. For the diagnosis of liver fibrosis ≥2, a cutoff value of 7.2 showed a positive predictive value of 86% and a negative predictive value of 73%; 19 (19%) patients were incorrectly classified according to a cutoff value of 7.2. Thus, 10 (27%) of 37 patients with a liver stiffness value <7.2 showed F ≥2 in liver biopsy (9; 24%) with F = 2 and 1 (3%) with F = 3; and 9 (14%) of 64 subjects with a liver stiffness value ≥7.2 showed F<2 in liver biopsy (6 [9 %] with F = 1).
Conclusions: Fibroscan fails to discriminate mild from significant liver fibrosis in a substantial number of HIV/HCV-co-infected patients. If a decision to start HCV therapy were based on the presence of a liver stiffness ≥7.2 kPa, as many as 27% of individuals carrying F ≥2 would not receive therapy.
Biochemical Scores for Liver Fibrosis in HIV/HBV-co-infected Patients: Accuracy in Detecting Cirrhosis but Not Mild or Bridging Fibrosis: "...No score had enough power to differentiate the F1 from the F2 stage, which is an indicator for treatment. Liver biopsy may still be the "gold standard" to assess fibrosis in HIV/HBV-co-infected patients".
Karine Lacombe*1,2, Karine Lacombe*1,2, V Massari2, J Guechot1, D Wendum1, M Chevallier3, P Callard4, L Serfaty1, G Pialoux4, J M Molina5, and P M Girard1
1Hosp St Antoine, Paris, France; 2INSERM U707, Univ Pierre and Marie Curie, Paris, France; 3Hotel-Dieu, Lyon, France; 4Hosp Tenon, Paris, France; and 5Hosp St Louis, Paris, France
Background: Surrogate markers to assess liver fibrosis, such as biochemical scores, might be useful in patients with chronic hepatitis. However, the accuracy of such tools has not been evaluated in HIV/hepatitis B virus (HBV) -co-infected patients.
Evaluation of liver fibrosis is essential in patients with chronic liver disease in order to guide therapeutical management.
Liver biopsy is still the gold standard for fibrosis assessment but presents many drawbacks (invasive procedures, sample variability, etc).
Simple non invasive tests have been recently developed using serum biochemical markers.
Most of them have been validated only in HCV and HBV mono-infections ( from Jules: I question this, how well they have been validated in momoinfected patients. In the USA I do not think these tests are widely used or accepted, but in Europe it is my understanding use of the tests are more widely accepted).
Few of them have also been validated in HIV-HCV coinfected patients.
However, none specifically adressed the issue of HIV-HBV co-infection.
Roughly 7-9% of HIV infected patients are also infected with chronic hepatitis B.
The complex drug management of HIV-HBV co-infection involves an acccurate evaluation of liver fibrosis before starting a treatment.
It is therefore important to determine if liver biopsy can be efficiently replaced by non invasive procedures such as biochemical markers.
Methods: A cross-sectional analysis on a panel of biochemical markers, measured at the time of liver biopsy, was performed in HIV/HBV-co-infected patients recruited in an HIV/HBV French cohort study. Patients with hepatitis-C-co-infection were excluded. In this study population, 10 published scores validated in HBV- or HCV-mono-infected patients or HIV/HVC-co-infected patients were calculated (Fibrotest, SHASTA, Hepascore, Zeng, Forns, Apri, hyaluronic acid, AST/ALT, FIB4, SNIFF7). For each biochemical score and liver biopsy, the level of fibrosis was dichotomized as follows: no or very mild fibrosis (Metavir F0-F1) vs mild/bridging fibrosis/cirrhosis (Metavir F2-F3-F4); and no or mild or bridging fibrosis (F0-F1-F2-F3) vs cirrhosis (F4). The area under the curve (AUC) was calculated for each test and the corresponding confidence intervals were calculated by a bootstrap procedure. AUC were compared using non-parametric tests.
Results: We included in the study, 55 patients with a mean age of 40.5 years, of whom 23 were classified F0-F1 vs 32 with F2-F3-F4, and 43 were classified with F0-F1-F2-F3 vs 12 with F4. Cirrhosis was accurately diagnosed with, by increasing performance, Forns (AUC = 0.80), hyaluronic acid (AUC = 0.82), Zeng (AUC = 0.83), Hepascore (AUC = 0.83), SHASTA (AUC = 0.88), and SNIFF7 (AUC = 0.88). All other tests had an AUC <0.80 (eg, Fibrotest, AUC = 0.75). However, no test could accurately differentiate F0-F1 from F2-F3-F4 (all AUC <0.75).
No test could accurately differentiate F0-F1 from F2-F3-F4 (all AUC < 0.75).
Five tests could accurately discriminate patients with cirrhosis :
-- Fibrometer, Hepascore, ZengŐscore, FornsŐs score, Hyaluronic acid.
-- Fibrometer was the only test with a significantly higher AUROC.
Four tests could accurately discriminate F0-F1-F2 from F3-F4
--Fibrometer, Hepascore, ZengŐs score, Fibrotest
-- Fibrometer and Hepascore were the two tests with significantly higher AUROCs.
Conclusions: In HIV/HBV-co-infected patients, 6 biochemical scores accurately diagnosed cirrhosis. However, no score had an AUC significantly higher than that of hyaluronic acid, an easy-to-measure, single marker. No score had enough power to differentiate the F1 from the F2 stage, which is an indicator for treatment. Liver biopsy may still be the "gold standard" to assess fibrosis in HIV/HBV-co-infected patients.
In HIV-HBV patients, Fibrometer and Hepascore were the two tests with the highest diagnostic performance for distinguishing bridging fibrosis with many septa and cirrhosis.
More simple tests such as APRI or AST/ALT failed to differentiate fibrosis stages in general.
The influence of HIV infection and antiretroviral therapy on some biochemical markers such as haptoglobine, bilirubine, AST or ALT might explain the failure of simple tests to accurately evaluate the level of fibrosis.
The use of scores including markers reflecting the matrix degradation (hyaluronic acid, metalloprotease inhibitor) increased the diagnostic performance.
The performance of a simple and costless marker such as the hyaluronic acid was good in detecting cirrhosis.
Those results need to be confirmed on a validation sample.
Biochemical Scores for Liver Fibrosis in HIV/HBV-co-infected Patients: Accuracy in Detecting Cirrhosis but Not Mild or Bridging Fibrosis.... "In HIV/HBV-co-infected patients, 6 biochemical scores accurately diagnosed cirrhosis.....No score had enough power to differentiate the F1 from the F2 stage, which is an indicator for treatment. Liver biopsy may still be the "gold standard" to assess fibrosis in HIV/HBV-co-infected patients."
Karine Lacombe*1,2, Karine Lacombe*1,2, V Massari2, J Guechot1, D Wendum1, M Chevallier3, P Callard4, L Serfaty1, G Pialoux4, J M Molina5, and P M Girard1
1Hosp St Antoine, Paris, France; 2INSERM U707, Univ Pierre and Marie Curie, Paris, France; 3Hotel-Dieu, Lyon, France; 4Hosp Tenon, Paris, France; and 5Hosp St Louis, Paris, France
Background: Surrogate markers to assess liver fibrosis, such as biochemical scores, might be useful in patients with chronic hepatitis. However, the accuracy of such tools has not been evaluated in HIV/hepatitis B virus (HBV) -co-infected patients.
Methods: A cross-sectional analysis on a panel of biochemical markers, measured at the time of liver biopsy, was performed in HIV/HBV-co-infected patients recruited in an HIV/HBV French cohort study. Patients with hepatitis-C-co-infection were excluded. In this study population, 10 published scores validated in HBV- or HCV-mono-infected patients or HIV/HVC-co-infected patients were calculated (Fibrotest, SHASTA, Hepascore, Zeng, Forns, Apri, hyaluronic acid, AST/ALT, FIB4, SNIFF7). For each biochemical score and liver biopsy, the level of fibrosis was dichotomized as follows: no or very mild fibrosis (Metavir F0-F1) vs mild/bridging fibrosis/cirrhosis (Metavir F2-F3-F4); and no or mild or bridging fibrosis (F0-F1-F2-F3) vs cirrhosis (F4). The area under the curve (AUC) was calculated for each test and the corresponding confidence intervals were calculated by a bootstrap procedure. AUC were compared using non-parametric tests.
Results: We included in the study, 55 patients with a mean age of 40.5 years, of whom 23 were classified F0-F1 vs 32 with F2-F3-F4, and 43 were classified with F0-F1-F2-F3 vs 12 with F4. Cirrhosis was accurately diagnosed with, by increasing performance, Forns (AUC = 0.80), hyaluronic acid (AUC = 0.82), Zeng (AUC = 0.83), Hepascore (AUC = 0.83), SHASTA (AUC = 0.88), and SNIFF7 (AUC = 0.88). All other tests had an AUC <0.80 (eg, Fibrotest, AUC = 0.75). However, no test could accurately differentiate F0-F1 from F2-F3-F4 (all AUC <0.75).
Conclusions: In HIV/HBV-co-infected patients, 6 biochemical scores accurately diagnosed cirrhosis. However, no score had an AUC significantly higher than that of hyaluronic acid, an easy-to-measure, single marker. No score had enough power to differentiate the F1 from the F2 stage, which is an indicator for treatment. Liver biopsy may still be the "gold standard" to assess fibrosis in HIV/HBV-co-infected patients.
Genomics- and Proteomics-based Approach to Develop Novel Serum Markers in HIV/HCV-co-infected Individuals
"....We identified....2 genes (alanyl amino peptidase and mitogen activated protein) with the highest significance....genomic and protein profiling offer additional accuracy and provide novel markers for correctly predicting fibrosis. Future research will focus on identifying the functional role of these novel genetic markers in patients with liver fibrosis..."
Daniel Suzman*1, M McLaughlin1, D Kliener2, A Suffredini3, S Kern3, K Reitano1, D Gonzales3, R Lempicki4, M Polis1, and S Kottilil1
1Lab of Immunoregulation, NIAID, NIH, Bethesda, MD, US; 2NCI, NIH, Bethesda, MD, US; 3NIH, Bethesda, MD, US; and 4SAIC-Frederick/NCI-Frederick, MD, US
Background: The degree of liver fibrosis is a determinant for initiation of therapy for hepatitis C virus (HCV). Liver biopsy is invasive, risky, and costly, but is required to assess fibrosis. The purpose of this study was to develop a model incorporating both previously validated serum markers, as well as genomic and proteomic fingerprinting to accurately assess fibrosis in HIV/HCV-co-infected patients.
Methods: Fibrosis was assessed in 59 liver biopsies obtained from 31 HIV/HCV co-infected patients. Age, sex, CD4+ T cell count, ART and nevirapine (NVP) use, gene expression profiles and 11 serum markers identified using Affymetrix U133A also determined. Markers of highest importance in distinguishing biopsies with Ishak fibrosis scores <3 and _3 were identified using Radom Forest analysis and then used in a logistic regression analysis to generate a predictive model. In addition, serum protein profiling on these patients pre- and post-HCV therapy was also performed and protein peaks that were differentially expressed between the those with mild and advanced fibrosis were identified.
Results: We identified 2 serum markers (_2-macroglobulin and haptoglobin) and 2 genes (alanyl amino peptidase and mitogen activated protein) with the highest significance using Random Forest analysis and included them in the model. Using these 4 markers, the area under the ROC curve was 0.92. Univariate analysis also revealed 20 protein peaks that were differentially expressed in mild vs advanced fibrotic biopsies (p <0.01).
Conclusions: Our model using 4 markers accurately predicted fibrosis in HIV/HCV-co-infected patients. We scored 78% of biopsies as either above or below our cut-off points, which could thus be classified as having either mild or advanced fibrosis. In these biopsies, classification was 91% accurate. Thus, biopsies could have been avoided in the majority of these patients. In addition, genomic and protein profiling offer additional accuracy and provide novel markers for correctly predicting fibrosis. Future research will focus on identifying the functional role of these novel genetic markers in patients with liver fibrosis. Validating this model on larger cohorts of HIV/HCV-co-infected patients is necessary to develop non-invasive markers for liver fibrosis and avoid liver biopsies.
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