- Email: [email protected]
HCV-coinfected patients: A validation study
Journal of Infection (2011) 63, 402e405
www.elsevierhealth.com/journals/jinf
LETTER TO THE EDITOR Diagnostic accuracy of the APRI, FIB-4, and the Forns index for predicting liver fibrosis in HIV/HCVcoinfected patients: A validation study
Identification of liver fibrosis is essential for an adequate clinical management of hepatitis C virus (HCV)-infected patients providing prognostic information and influencing therapeutic decisions.1 When liver biopsy demonstrates lower grades of liver fibrosis (F0-1), regardless of HCVgenotype, HCV-therapy can be deferred in human immunodeficiency virus (HIV)/HCV-coinfected patients.1 Liver biopsy has been considered the gold standard for the diagnosis and quantification of fibrosis, but several drawbacks have been described and patients are reluctant to undergo repeated biopsies to monitor disease progression.2,3 These limitations have led to the development of non-invasive alternatives, including serum markers, some imaging technologies and transient elastography.4 Aspartate aminotransferase (AST) to platelet ratio (APRI),5 FIB4,6 and the Forns index7 are non-invasive fibrosis indices which include data from routine biochemical and haematological analyses (indirect markers). The variables included in these indices are easily accessible and the calculations are relatively easy. However, these variables used to calculate these indices may be more problematic in HIV/HCVcoinfected patients because their values could be affected by factors associated with HIV infection. Among these factors, we highlight haematological abnormalities and antiretroviral therapy, which can lead to an increase in transaminases or cholesterol in the blood. The aim of this study was to evaluate the diagnostic performance of three simple fibrosis indices based on routine analytical parameters (APRI, FIB-4, and the Forns index) in order to discriminate significant fibrosis (F 2), advanced fibrosis (F 3) and cirrhosis (F4) a in cohort of 356 HIV/HCV-coinfected patients previously described.8 Each index had similar receiver operating characteristic curves (AUC-ROC) values for F 2 and F 3 which were lower than 0.80, and higher than 0.80 for cirrhosis (Table 1). Furthermore, adjusted AUC-ROC values of the three indices by the Obuchowski method were higher than unadjusted AUC-ROC values (p < 0.05); but there were no statistical differences. Four clinical situations were studied (Table 2):
- For discarding significant fibrosis (F < 2), APRI was a better test than the Forns index. - For confirming significant fibrosis (F 2), the Forns index achieved the best specificity (Sp), positive predictive values (PPV) and positive likelihood ratios (LRþ) values, which were significantly higher than those of APRI and FIB-4. - For confirming advanced fibrosis (F 3), the three indices achieved a Sp higher than 90%, specially the Forns index that also presented the better LRþ. - For confirming cirrhosis (F4), the three indices achieved a Sp and negative predictive values (NPV) higher than 85% and 90% respectively; while sensitivity (Se) and PPV were relatively low (<60% and <50% respectively). SDC 1 shows the percentage of biopsies that could have been avoided in the three following clinical situations: - For the diagnosis of significant fibrosis (F 2), APRI would have avoided a higher number of biopsies than FIB-4 and the Forns index (p < 0.05). Table 1 AUC-ROC curves illustrating the diagnostic values of APRI, FIB-4, and the Forns index for prediction of significant fibrosis (F 2), advanced fibrosis (F 3) and cirrhosis (F4). AUC-ROC (95%CI) F2 APRI FIB-4 Forns F3 APRI FIB-4 Forns F4 APRI FIB-4 Forns
0.790 (0.744; 0.837) 0.766 (0.718; 0.815) 0.731 (0.680; 0.783)
Adjusted AUC-ROC (95%CI)a (*)
0.862 (0.831; 0.891) 0.846 (0.814; 0.876) 0.823 (0.789; 0.855)
0.788 (0.735; 0.841) 0.783 (0.726; 0.840) 0.773 (0.717; 0.829)
0.888 (0.861; 0.914) 0.885 (0.856; 0.914) 0.880 (0.851; 0.908)
0.828 (0.773; 0.883) 0.843 (0.774; 0.912) 0.825 (0.756; 0.895)
0.956 (0.954; 0.957) 0.960 (0.942; 0.977) 0.955 (0.937; 0.972)
*Significant differences between APRI and the Forns index. a AUC-ROC was adjusted by Obuschowski method; which was calculated by the package “nonbinROC” developed for R software (GNU General Public Licence; http://www.r-project.org/).
0163-4453/$36 ª 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2011.07.017
Letter to the Editor
Table 2
Diagnostic performance values of APRI, FIB-4, and the Forns index in HIV/HCV-coinfected patients. Cut-off
TP
FP
TN
FN
*Se
To rule out significant fibrosis (F < 2) (Low cut-off) APRI 0.5 182 92 63 19 90 (85; 94) FIB-4 0.6 197 146 9 4 98 (95; 99) Forns 4.2 128 44 111 73 64 (57; 70) p-values a, b, c To detect significant fibrosis (F 2) (High cut-off) APRI 1.5 78 10 145 123 38 (32; 45) FIB-4 1 180 103 52 21 89 (84; 93) Forns 6.9 25 1 154 176 12 (9; 17) p-values a, b, c To detect advanced fibrosis (F 3) (High cut-off) APRI 2 37 26 234 59 38 (29; 48) FIB-4 3.25 35 15 245 61 36 (27; 46) Forns 6.9 20 6 254 76 21 (14; 30) p-values b, c To detect cirrhosis (F4) (High cut-off) APRI 2 19 44 274 19 50 (35; 65) FIB-4 3.25 21 29 289 17 55 (40; 70) Forns 6.9 12 14 304 26 32 (19; 47) p-values
*Sp
*PPV
*NPV
**LRþ
**LRe
**DOR
41 (33; 48) 6 (3; 11) 72 (64; 78) a, b, c
66 (60; 71) 57 (52; 62) 74 (67; 80) a, c
77 (67; 85) 69 (42; 87) 60 (53; 67) b
1.5 (1.3; 1.7) 1.1 (0.9; 1.1) 2.2 (1.7; 2.9) a, b, c
0.2 (0.1; 0.4) 0.3 (0.1; 0.9) 0.5 (0.4; 0.6) b
6.5 (3.7; 11.6) 3.1 (0.9; 10.0) 4.4 (2.8; 6.9)
93.5 (88.5; 96.5) 33.5 (26.6; 41.3) 99.4 (96.4; 99.9) a, b, c
88.6 (80.3; 93.7) 63.6 (57.9; 69.0) 96.2 (81.1; 99.3) a, c
54.1 (48.1; 60.0) 71.2 (60.0; 80.3) 46.7 (41.4; 52.1) a, c
6.1 (3.2; 11.2) 1.3 (1.2; 1.5) 19.2 (2.6; 140) a, c
0.6 (0.6; 0.7) 0.3 (0.2; 0.5) 0.9 (0.8; 0.9) a, b, c
9.19 (4.56; 18.5) 4.32 (2.46; 7.58) 21.8 (2.92; 163)
90 (86; 93) 94 (91; 96) 97 (95; 99) b
58 (46; 70) 70 (56; 81) 77 (58; 89)
80 (75; 84) 80 (75; 84) 77 (72; 81)
3.8 (2.5; 6) 6.3 (3.6; 11) 9.1 (3.7; 22) b
0.7 (0.6; 0.8) 0.7 (0.6; 0.8) 0.8 (0.7; 0.9)
5.6 (3.2; 10.0) 9.4 (4.8; 18.2) 11.1 (4.3; 28.7)
86 (82; 89) 91 (87; 94) 95 (93; 97) b, c
30 (20; 42) 42 (29.4; 55) 46 (29; 64)
93 (90; 96) 94 (91; 96) 92 (88; 95)
3.6 (2.4 5.5) 6.1 (3.8; 9.5) 7.2 (3.6; 14.3)
0.6 (0.4; 0.8) 0.5 (0.3; 0.7) 0.7 (0.6; 0.9)
6.2 (3.1; 12.6) 12.3 (5.84; 25.9) 10 (4.2; 23.8)
Abbreviations: TP, true positive cases (correct diagnosis); FP, false positive cases (over-diagnosis); TN, true negative cases (correct diagnosis); FN, false negative cases (missed cases). Se, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value; LR, likelihood ratio; DOR, diagnostic odds ratio. p-values: Statistical significance (p < 0.05): a, APRI vs. FIB-4; b, APRI vs. the Forns index; c, FIB-4 vs. the Forns index. Statistical analysis was performed by SPSS version 15.0 (SPSS INC, Chicago, IL, USA). *Values as percentage and 95% of confidence interval. **Values as ratio value and 95% of confidence interval.
403
404 - For discarding significant fibrosis (F < 2) and confirming advanced fibrosis (F 3), 37% of patients were correctly classified and biopsy would have been correctly avoided in 86% of patients. - For discarding significant fibrosis (F < 2) and confirming cirrhosis (F4), 35% of patients were correctly classified and biopsy would have been correctly avoided in 95% of patients. The non-invasive fibrosis indices represent an important tool for the management of HCV-infected patients, especially when there is no access to a liver biopsy. APRI, FIB-4, and the Forns index include readily available laboratory tests which are routine in the evaluation of HCVmonoinfected, and have shown a good diagnostic accuracy for the non-invasive assessment of hepatic fibrosis and cirrhosis.5,7,9,10 In our study, the diagnostic performance of APRI, FIB-4, and the Forns index was slightly lower in HIV/ HCV-coinfected patients than that found in the original studies performed on HCV-monoinfected patients,5,7,9 although it was consistent with that obtained by other authors in HIV/HCV-coinfected patients.11e14 Moreover, some experts would regard non-invasive indices as good as a liver biopsy for staging fibrosis when AUC-ROC is higher than 0.85.15 Therefore, except for the diagnosis of cirrhosis, APRI, FIB-4, and the Forns index could be considered as relatively inaccurate to diagnose significant and advanced fibrosis in HIV/HCV-coinfected patients. We also evaluated AUC-ROC using the Obuchowski method16 that achieved surprisingly high levels for the three serum biomarkers, especially for the diagnosis of cirrhosis (AUC-ROC >0.950). An advantage of this measure over the AUC-ROC is the possibility to eliminate the bias related to the distribution of fibrosis stages and correct the type I error that is due to the spectrum effect.16 However, we cannot interpret the Obuchowski measure as the unadjusted AUC-ROC because they are not equivalent as it is an accuracy weighted as a function of the fibrosis stage.16 Until now, the Obuchowski measure has not been very extensively used in this research field, with very few scientific publications using it for the analysis of patients’ results.16,17 According to this measure, the three indices (APRI, FIB-4, and the Forns index) have a similar diagnostic performance for each fibrosis stage. The cut-off points chosen for a hepatic fibrosis marker depend on their clinical utility to discriminate between different fibrosis stages. APRI and the Forns index were developed to differentiate mild from significant fibrosis in HCV-monoinfected patients while the FIB-4 was proposed to differentiate mild/moderate from advanced fibrosis in HIV/HCV-coinfected patients.5e7 In our study, we found that classical cut-off points of APRI, FIB-4, and the Forns index had a low global diagnostic performance. Moreover, our study adds some relevant clinical information related to the possibility of avoiding the biopsy procedures depending on the results of these three serum indices. For the indication of avoiding biopsy, the greatest utility of these three indices was to discard significant fibrosis and confirm advanced fibrosis or cirrhosis; especially for the Forns index, that showed the higher percentage of successfully avoided biopsies in a higher percentage of correctly classified patients. However, there is a risk of influence incorrectly in the
Letter to the Editor clinical management of the patients not correctly classified (FP þ FN). For the rest of patients who were not considered in this analysis (non-invasive indices between the upper and lower cut-off point), the biopsy should be performed as it is usually done in the clinical practise. In conclusion, APRI, FIB-4, and the Forns index values increase gradually with the fibrosis stage on HIV/HCVcoinfected patients, but their diagnostic accuracies were relatively acceptable only for the diagnosis of cirrhosis. Even though all these indices have already been validated, the present study gives some important information regarding how to use them. Thus, these three indices cannot be proposed to replace biopsy but they contribute to appropriately select patients in whom biopsy could be avoided.
Acknowledgements Potential conflicts of interest: The authors do not have commercial relationships or other associations that might pose a conflict of interest. Sources of financial support: This work has been supported by grants from the “Instituto de Salud Carlos III” (ISCIII) (PI08/0738) to SR; and from ISCIII (Ref. ISCIII-RETIC n para la InvesRD06/006, PI08/0928) and the “Fundacio n y la Prevencio n del Sida en Espan ~a” (FIPSE) tigacio (Ref. 36443/03; Ref. 361020/10) to JB. Besides, JB is n supported by a grant from the "Programa de Intensificacio de la Actividad Investigadora en el SNS" (I3SNS). Writing assistance: Ana Garcıa-Moreno provided writing assistance for this manuscript
Supplementary data Supplementary data related to this article can be found online at doi:10.1016/j.jinf.2011.07.017.
References 1. Pol S, Soriano V. Management of chronic hepatitis C virus infection in HIV-infected patients. Clin Infect Dis 2008;47(1):94e101. 2. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38(6):1449e57. 3. Dienstag JL. The role of liver biopsy in chronic hepatitis C. Hepatology 2002;36(5 Suppl. 1):S152e60. 4. Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology 2008;134(6):1670e81. 5. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38(2):518e26. 6. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43(6):1317e25. 7. Forns X, Ampurdanes S, Llovet JM, Aponte J, Quinto L, Martinez-Bauer E, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology 2002;36(4 Pt 1):986e92. 8. Resino S, Seoane JA, Bellon JM, Dorado J, Martin-Sanchez F, Alvarez E, et al. An artificial neural network improves the
Letter to the Editor
9.
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13.
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non-invasive diagnosis of significant fibrosis in HIV/HCV coinfected patients. J Infect 2011;62(1):77e86. Cales P, de Ledinghen V, Halfon P, Bacq Y, Leroy V, Boursier J, et al. Evaluating the accuracy and increasing the reliable diagnosis rate of blood tests for liver fibrosis in chronic hepatitis C. Liver Int 2008;28(10):1352e62. Poynard T, Morra R, Ingiliz P, Imbert-Bismut F, Thabut D, Messous D, et al. Biomarkers of liver fibrosis. Adv Clin Chem 2008;46:131e60. Trang T, Petersen JR, Snyder N. Non-invasive markers of hepatic fibrosis in patients co-infected with HCV and HIV: comparison of the APRI and FIB-4 index. Clin Chim Acta 2008; 397(1e2):51e4. Macias J, Giron-Gonzalez JA, Gonzalez-Serrano M, Merino D, Cano P, Mira JA, et al. Prediction of liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfected patients by simple non-invasive indexes. Gut 2006;55(3):409e14. Loko MA, Castera L, Dabis F, Le Bail B, Winnock M, Coureau G, et al. Validation and comparison of simple noninvasive indexes for predicting liver fibrosis in HIV-HCV-coinfected patients: aNRS CO3 Aquitaine cohort. Am J Gastroenterol 2008;103(8): 1973e80. Tural C, Tor J, Sanvisens A, Perez-Alvarez N, Martinez E, Ojanguren I, et al. Accuracy of simple biochemical tests in identifying liver fibrosis in patients co-infected with human immunodeficiency virus and hepatitis C virus. Clin Gastroenterol Hepatol 2009;7(3):339e45. Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol 2004;99(6):1160e74. Lambert J, Halfon P, Penaranda G, Bedossa P, Cacoub P, Carrat F. How to measure the diagnostic accuracy of noninvasive liver fibrosis indices: the area under the ROC curve revisited. Clin Chem 2008;54(8):1372e8. Poynard T, Munteanu M, Ngo Y, Castera L, Halfon P, Ratziu V, et al. ActiTest accuracy for the assessment of histological activity grades in patients with chronic hepatitis C, an overview using Obuchowski measure. GastroenterolClin Biol 2010; 34(6e7):388e96.
405 Salvador Resino* Laboratory of Molecular Epidemiology of Infectious Diseases, National Centre of Microbiology, Instituto de Salud Carlos III, Carretera Majadahonda - Pozuelo, Km 2.2, 28220 Majadahonda, Madrid, Spain E-mail address: [email protected]. Cristina Asensio Agency for Health Technology Assessment, Instituto de Salud Carlos III, Madrid, Spain Marıa Bello n Jose Biomedical Research Foundation, Hospital General Universitario “Gregorio Maran~on”, Madrid, Spain Rocıo Carmona Agency for Health Technology Assessment, Instituto de Salud Carlos III, Madrid, Spain Pilar Miralles pez Juan Carlos Lo Jaime Cosın Infectious Diseases-HIV Unit, Hospital General Universitario “Gregorio Maran~on”, Madrid, Spain Emilio Alvarez Pathology Department, Hospital General Universitario “Gregorio Maran~on”, Madrid, Spain Juan Berenguer Infectious Diseases-HIV Unit, Hospital General Universitario “Gregorio Maran~on”, Madrid, Spain Accepted 29 July 2011 Available online 3 August 2011
* Corresponding author. Tel.: þ34 918 223 266; fax: þ34 918 223 269.
www.elsevierhealth.com/journals/jinf
LETTER TO THE EDITOR Diagnostic accuracy of the APRI, FIB-4, and the Forns index for predicting liver fibrosis in HIV/HCVcoinfected patients: A validation study
Identification of liver fibrosis is essential for an adequate clinical management of hepatitis C virus (HCV)-infected patients providing prognostic information and influencing therapeutic decisions.1 When liver biopsy demonstrates lower grades of liver fibrosis (F0-1), regardless of HCVgenotype, HCV-therapy can be deferred in human immunodeficiency virus (HIV)/HCV-coinfected patients.1 Liver biopsy has been considered the gold standard for the diagnosis and quantification of fibrosis, but several drawbacks have been described and patients are reluctant to undergo repeated biopsies to monitor disease progression.2,3 These limitations have led to the development of non-invasive alternatives, including serum markers, some imaging technologies and transient elastography.4 Aspartate aminotransferase (AST) to platelet ratio (APRI),5 FIB4,6 and the Forns index7 are non-invasive fibrosis indices which include data from routine biochemical and haematological analyses (indirect markers). The variables included in these indices are easily accessible and the calculations are relatively easy. However, these variables used to calculate these indices may be more problematic in HIV/HCVcoinfected patients because their values could be affected by factors associated with HIV infection. Among these factors, we highlight haematological abnormalities and antiretroviral therapy, which can lead to an increase in transaminases or cholesterol in the blood. The aim of this study was to evaluate the diagnostic performance of three simple fibrosis indices based on routine analytical parameters (APRI, FIB-4, and the Forns index) in order to discriminate significant fibrosis (F 2), advanced fibrosis (F 3) and cirrhosis (F4) a in cohort of 356 HIV/HCV-coinfected patients previously described.8 Each index had similar receiver operating characteristic curves (AUC-ROC) values for F 2 and F 3 which were lower than 0.80, and higher than 0.80 for cirrhosis (Table 1). Furthermore, adjusted AUC-ROC values of the three indices by the Obuchowski method were higher than unadjusted AUC-ROC values (p < 0.05); but there were no statistical differences. Four clinical situations were studied (Table 2):
- For discarding significant fibrosis (F < 2), APRI was a better test than the Forns index. - For confirming significant fibrosis (F 2), the Forns index achieved the best specificity (Sp), positive predictive values (PPV) and positive likelihood ratios (LRþ) values, which were significantly higher than those of APRI and FIB-4. - For confirming advanced fibrosis (F 3), the three indices achieved a Sp higher than 90%, specially the Forns index that also presented the better LRþ. - For confirming cirrhosis (F4), the three indices achieved a Sp and negative predictive values (NPV) higher than 85% and 90% respectively; while sensitivity (Se) and PPV were relatively low (<60% and <50% respectively). SDC 1 shows the percentage of biopsies that could have been avoided in the three following clinical situations: - For the diagnosis of significant fibrosis (F 2), APRI would have avoided a higher number of biopsies than FIB-4 and the Forns index (p < 0.05). Table 1 AUC-ROC curves illustrating the diagnostic values of APRI, FIB-4, and the Forns index for prediction of significant fibrosis (F 2), advanced fibrosis (F 3) and cirrhosis (F4). AUC-ROC (95%CI) F2 APRI FIB-4 Forns F3 APRI FIB-4 Forns F4 APRI FIB-4 Forns
0.790 (0.744; 0.837) 0.766 (0.718; 0.815) 0.731 (0.680; 0.783)
Adjusted AUC-ROC (95%CI)a (*)
0.862 (0.831; 0.891) 0.846 (0.814; 0.876) 0.823 (0.789; 0.855)
0.788 (0.735; 0.841) 0.783 (0.726; 0.840) 0.773 (0.717; 0.829)
0.888 (0.861; 0.914) 0.885 (0.856; 0.914) 0.880 (0.851; 0.908)
0.828 (0.773; 0.883) 0.843 (0.774; 0.912) 0.825 (0.756; 0.895)
0.956 (0.954; 0.957) 0.960 (0.942; 0.977) 0.955 (0.937; 0.972)
*Significant differences between APRI and the Forns index. a AUC-ROC was adjusted by Obuschowski method; which was calculated by the package “nonbinROC” developed for R software (GNU General Public Licence; http://www.r-project.org/).
0163-4453/$36 ª 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2011.07.017
Letter to the Editor
Table 2
Diagnostic performance values of APRI, FIB-4, and the Forns index in HIV/HCV-coinfected patients. Cut-off
TP
FP
TN
FN
*Se
To rule out significant fibrosis (F < 2) (Low cut-off) APRI 0.5 182 92 63 19 90 (85; 94) FIB-4 0.6 197 146 9 4 98 (95; 99) Forns 4.2 128 44 111 73 64 (57; 70) p-values a, b, c To detect significant fibrosis (F 2) (High cut-off) APRI 1.5 78 10 145 123 38 (32; 45) FIB-4 1 180 103 52 21 89 (84; 93) Forns 6.9 25 1 154 176 12 (9; 17) p-values a, b, c To detect advanced fibrosis (F 3) (High cut-off) APRI 2 37 26 234 59 38 (29; 48) FIB-4 3.25 35 15 245 61 36 (27; 46) Forns 6.9 20 6 254 76 21 (14; 30) p-values b, c To detect cirrhosis (F4) (High cut-off) APRI 2 19 44 274 19 50 (35; 65) FIB-4 3.25 21 29 289 17 55 (40; 70) Forns 6.9 12 14 304 26 32 (19; 47) p-values
*Sp
*PPV
*NPV
**LRþ
**LRe
**DOR
41 (33; 48) 6 (3; 11) 72 (64; 78) a, b, c
66 (60; 71) 57 (52; 62) 74 (67; 80) a, c
77 (67; 85) 69 (42; 87) 60 (53; 67) b
1.5 (1.3; 1.7) 1.1 (0.9; 1.1) 2.2 (1.7; 2.9) a, b, c
0.2 (0.1; 0.4) 0.3 (0.1; 0.9) 0.5 (0.4; 0.6) b
6.5 (3.7; 11.6) 3.1 (0.9; 10.0) 4.4 (2.8; 6.9)
93.5 (88.5; 96.5) 33.5 (26.6; 41.3) 99.4 (96.4; 99.9) a, b, c
88.6 (80.3; 93.7) 63.6 (57.9; 69.0) 96.2 (81.1; 99.3) a, c
54.1 (48.1; 60.0) 71.2 (60.0; 80.3) 46.7 (41.4; 52.1) a, c
6.1 (3.2; 11.2) 1.3 (1.2; 1.5) 19.2 (2.6; 140) a, c
0.6 (0.6; 0.7) 0.3 (0.2; 0.5) 0.9 (0.8; 0.9) a, b, c
9.19 (4.56; 18.5) 4.32 (2.46; 7.58) 21.8 (2.92; 163)
90 (86; 93) 94 (91; 96) 97 (95; 99) b
58 (46; 70) 70 (56; 81) 77 (58; 89)
80 (75; 84) 80 (75; 84) 77 (72; 81)
3.8 (2.5; 6) 6.3 (3.6; 11) 9.1 (3.7; 22) b
0.7 (0.6; 0.8) 0.7 (0.6; 0.8) 0.8 (0.7; 0.9)
5.6 (3.2; 10.0) 9.4 (4.8; 18.2) 11.1 (4.3; 28.7)
86 (82; 89) 91 (87; 94) 95 (93; 97) b, c
30 (20; 42) 42 (29.4; 55) 46 (29; 64)
93 (90; 96) 94 (91; 96) 92 (88; 95)
3.6 (2.4 5.5) 6.1 (3.8; 9.5) 7.2 (3.6; 14.3)
0.6 (0.4; 0.8) 0.5 (0.3; 0.7) 0.7 (0.6; 0.9)
6.2 (3.1; 12.6) 12.3 (5.84; 25.9) 10 (4.2; 23.8)
Abbreviations: TP, true positive cases (correct diagnosis); FP, false positive cases (over-diagnosis); TN, true negative cases (correct diagnosis); FN, false negative cases (missed cases). Se, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value; LR, likelihood ratio; DOR, diagnostic odds ratio. p-values: Statistical significance (p < 0.05): a, APRI vs. FIB-4; b, APRI vs. the Forns index; c, FIB-4 vs. the Forns index. Statistical analysis was performed by SPSS version 15.0 (SPSS INC, Chicago, IL, USA). *Values as percentage and 95% of confidence interval. **Values as ratio value and 95% of confidence interval.
403
404 - For discarding significant fibrosis (F < 2) and confirming advanced fibrosis (F 3), 37% of patients were correctly classified and biopsy would have been correctly avoided in 86% of patients. - For discarding significant fibrosis (F < 2) and confirming cirrhosis (F4), 35% of patients were correctly classified and biopsy would have been correctly avoided in 95% of patients. The non-invasive fibrosis indices represent an important tool for the management of HCV-infected patients, especially when there is no access to a liver biopsy. APRI, FIB-4, and the Forns index include readily available laboratory tests which are routine in the evaluation of HCVmonoinfected, and have shown a good diagnostic accuracy for the non-invasive assessment of hepatic fibrosis and cirrhosis.5,7,9,10 In our study, the diagnostic performance of APRI, FIB-4, and the Forns index was slightly lower in HIV/ HCV-coinfected patients than that found in the original studies performed on HCV-monoinfected patients,5,7,9 although it was consistent with that obtained by other authors in HIV/HCV-coinfected patients.11e14 Moreover, some experts would regard non-invasive indices as good as a liver biopsy for staging fibrosis when AUC-ROC is higher than 0.85.15 Therefore, except for the diagnosis of cirrhosis, APRI, FIB-4, and the Forns index could be considered as relatively inaccurate to diagnose significant and advanced fibrosis in HIV/HCV-coinfected patients. We also evaluated AUC-ROC using the Obuchowski method16 that achieved surprisingly high levels for the three serum biomarkers, especially for the diagnosis of cirrhosis (AUC-ROC >0.950). An advantage of this measure over the AUC-ROC is the possibility to eliminate the bias related to the distribution of fibrosis stages and correct the type I error that is due to the spectrum effect.16 However, we cannot interpret the Obuchowski measure as the unadjusted AUC-ROC because they are not equivalent as it is an accuracy weighted as a function of the fibrosis stage.16 Until now, the Obuchowski measure has not been very extensively used in this research field, with very few scientific publications using it for the analysis of patients’ results.16,17 According to this measure, the three indices (APRI, FIB-4, and the Forns index) have a similar diagnostic performance for each fibrosis stage. The cut-off points chosen for a hepatic fibrosis marker depend on their clinical utility to discriminate between different fibrosis stages. APRI and the Forns index were developed to differentiate mild from significant fibrosis in HCV-monoinfected patients while the FIB-4 was proposed to differentiate mild/moderate from advanced fibrosis in HIV/HCV-coinfected patients.5e7 In our study, we found that classical cut-off points of APRI, FIB-4, and the Forns index had a low global diagnostic performance. Moreover, our study adds some relevant clinical information related to the possibility of avoiding the biopsy procedures depending on the results of these three serum indices. For the indication of avoiding biopsy, the greatest utility of these three indices was to discard significant fibrosis and confirm advanced fibrosis or cirrhosis; especially for the Forns index, that showed the higher percentage of successfully avoided biopsies in a higher percentage of correctly classified patients. However, there is a risk of influence incorrectly in the
Letter to the Editor clinical management of the patients not correctly classified (FP þ FN). For the rest of patients who were not considered in this analysis (non-invasive indices between the upper and lower cut-off point), the biopsy should be performed as it is usually done in the clinical practise. In conclusion, APRI, FIB-4, and the Forns index values increase gradually with the fibrosis stage on HIV/HCVcoinfected patients, but their diagnostic accuracies were relatively acceptable only for the diagnosis of cirrhosis. Even though all these indices have already been validated, the present study gives some important information regarding how to use them. Thus, these three indices cannot be proposed to replace biopsy but they contribute to appropriately select patients in whom biopsy could be avoided.
Acknowledgements Potential conflicts of interest: The authors do not have commercial relationships or other associations that might pose a conflict of interest. Sources of financial support: This work has been supported by grants from the “Instituto de Salud Carlos III” (ISCIII) (PI08/0738) to SR; and from ISCIII (Ref. ISCIII-RETIC n para la InvesRD06/006, PI08/0928) and the “Fundacio n y la Prevencio n del Sida en Espan ~a” (FIPSE) tigacio (Ref. 36443/03; Ref. 361020/10) to JB. Besides, JB is n supported by a grant from the "Programa de Intensificacio de la Actividad Investigadora en el SNS" (I3SNS). Writing assistance: Ana Garcıa-Moreno provided writing assistance for this manuscript
Supplementary data Supplementary data related to this article can be found online at doi:10.1016/j.jinf.2011.07.017.
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405 Salvador Resino* Laboratory of Molecular Epidemiology of Infectious Diseases, National Centre of Microbiology, Instituto de Salud Carlos III, Carretera Majadahonda - Pozuelo, Km 2.2, 28220 Majadahonda, Madrid, Spain E-mail address: [email protected]. Cristina Asensio Agency for Health Technology Assessment, Instituto de Salud Carlos III, Madrid, Spain Marıa Bello n Jose Biomedical Research Foundation, Hospital General Universitario “Gregorio Maran~on”, Madrid, Spain Rocıo Carmona Agency for Health Technology Assessment, Instituto de Salud Carlos III, Madrid, Spain Pilar Miralles pez Juan Carlos Lo Jaime Cosın Infectious Diseases-HIV Unit, Hospital General Universitario “Gregorio Maran~on”, Madrid, Spain Emilio Alvarez Pathology Department, Hospital General Universitario “Gregorio Maran~on”, Madrid, Spain Juan Berenguer Infectious Diseases-HIV Unit, Hospital General Universitario “Gregorio Maran~on”, Madrid, Spain Accepted 29 July 2011 Available online 3 August 2011
* Corresponding author. Tel.: þ34 918 223 266; fax: þ34 918 223 269.