To the Editor:

HCV therapy in patients co-infected with HIV/HCV shows worse responses than in patients infected with HCV, and often exhibits higher discontinuation rates.1–3 Therefore, a careful patient selection before antiviral therapy is advisable, usually reserving treatment for those with significant hepatic fibrosis. Liver biopsy is considered the gold standard method to assess fibrosis in chronic liver disease. However, it is an invasive technique with associated morbidity.4 Accurate noninvasive tests to predict liver fibrosis would be particularly useful in HIV/HCV patients in whom a more advanced liver disease is commonly observed.5, 6

Table 1. Diagnostic Accuracy of FIB-4 in Predicting Significant Liver Fibrosis (F3-4) in 111 HIV/HCV Patients
FIB-4F0-2 (%) (n = 83)F3-4 (%) (n = 28)Sensitivity (%)Specificity (%)PPV (%)NPV (%)
  1. Abbreviations: PPV, positive predictive value; NPV, negative predictive value.

<2.648 (58)3 (11)89584294
≥2.635 (42)25 (89)    
<5.077 (93)11 (39)    
≥5.06 (7)17 (61)61937488

We read with interest the article by Sterling et al.7, in which they developed the FIB-4 index, a model that uses age and routine tests such as AST, ALT, and platelet count (PLT) for the prediction of significant liver fibrosis in HIV/HCV patients, giving an important contribution to our knowledge in this field. However, these authors used AST and ALT levels expressed as International Units per liter. Considering that reference ranges for these tests exhibit considerable interlaboratory variability, we believe that the proposed cutoff for FIB-4 may show different sensitivities, specificities, and accuracies among medical centers using distinct limits of normality. Hence, it is possible that this method of expressing aminotransferases activity can limit the applicability of this index.

We sought to validate FIB-4 using data retrospectively collected from treatment-naive HIV/HCV patients. The original model was adapted in order to use AST and ALT levels expressed as times the upper limit of normality (×ULN), as follows: (age [yr] × AST [×ULN]) × 10/((PLT [109/l]) × (ALT [×ULN])1/2). We evaluated 111 patients (males, 73%; mean age, 40.2 ± 7.8 years). Mean CD4+ cell count was 431 ± 225 cells/ml and 58% of patients had undetectable HIV viral load under antiretroviral therapy. All patients showed HCV viremia and underwent liver biopsy, irrespective of ALT levels. A single pathologist analyzed all liver biopsy slides using the METAVIR group scoring system.

Advanced liver fibrosis, defined by the presence of F3 or F4 METAVIR stages, was observed in 28 patients (25%). To discriminate these subjects, the area under the receiver operating characteristic curve (ROC) of FIB-4 was 0.846 ± 0.046. Based on the ROC, 2 cutoffs were chosen: <2.6 and ≥5.0. Among patients with scores <2.6 or ≥5.0, concordant results were found in 88% (65/74). If biopsy indication was based only on FIB-4 results and restricted to scores in the intermediate range (≥2.6 and <5.0), 67% of liver biopsies could have been avoided.

Overall, our results are similar to the data presented by Sterling et al. (Table 1). In fact, even higher sensitivities and positive and negative predictive values were achieved. The use of different histological scoring systems (i.e., METAVIR versus Ishak score) and the evaluation of our cohort by a single pathologist could be responsible for these differences. Nevertheless, in both studies the FIB-4 index could reliably predict the severity of liver fibrosis in about 70% of patients with HIV/HCV co-infection, possibly avoiding the requirement for a liver biopsy in those patients.

Finally, we would like to suggest the use of AST and ALT levels as times the upper limit of normality in the calculation of FIB-4, which can expand its applicability to populations with different reference ranges for aminotransferases.


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  • 1
    Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A, et al; APRICOT Study Group. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351: 438450.
  • 2
    Chung RT, Andersen J, Volberding P, Robbins GK, Liu T, Sherman KE, et al; AIDS Clinical Trials Group A5071 Study Team. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; 351: 451459.
  • 3
    Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al; ANRS HCO2 RIBAVIC Study Team. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 2004; 292: 28392848.
  • 4
    Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001; 344: 495500.
  • 5
    Soto B, Sanchez-Quijano A, Rodrigo L, del Olmo JA, Garcia-Bengoechea M, Hernandez-Quero J, et al. Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis. J Hepatol 1997; 26: 15.
  • 6
    Rockstroh JK, Spengler U, Sudhop T, Ewig S, Theisen A, Hammerstein U, et al. Immunosuppression may lead to progression of hepatitis C virus-associated liver disease in hemophiliacs coinfected with HIV. Am J Gastroenterol 1996; 91: 25632568.
  • 7
    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: 13171325.

Leonardo L. Schiavon M.D.*, Roberto J. Carvalho Filho M.D.*, Janaína L. Narciso M.D.*, Juliana P. Sampaio*, Valéria P. Lanzoni M.D.*, Maria Lucia G. Ferraz M.D.*, Antonio Eduardo B. Silva M.D.*, * Division of Gastroenterology, Hepatitis Section, Federal University of São Paulo, São Paulo, Brazil.