JAIDS Journal of Acquired Immune Deficiency Syndromes:
Noninvasive Diagnosis of Hepatic Fibrosis in HIV/HCV-Coinfected Patients
Larrousse, María MD*; Laguno, Montserrat MD*; Segarra, Marta PhD†; De Lazzari, Elisa‡; Martínez, Esteban MD*; Blanco, José Luis MD*; León, Agathe MD*; Deulofeu, Ramón PhD§; Miquel, Rosa MD∥; Milinkovic, Ana MD*; Lonca, Montserrat MD*; Miró, José María MD*; Biglia, Alejandra MD*; Murillas, Javier MD*; Gatell, José María MD*; Mallolas, Josep MD*
From the *Infectious Diseases Unit, †Biochemistry, ‡Biostatistics and Epidemiology, §Biochemical Service, and ∥Pathology Service, Hospital Clínic Universitari de Barcelona-IDIBAPS, University of Barcelona, Barcelona, Spain.
Received for publication January 23, 2007; accepted July 13, 2007.
Dr. Larrousse was supported in part by the Spanish Ministry of Health (FIS 2006).
Presented at Interscience Conference on Antimicrobial Agents and Chemotherapy (ICCAC), December 2005.
Correspondence to: María Larrousse, MD, Infectious Diseases Unit, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain (e-mail: firstname.lastname@example.org, email@example.com).
Background: Several serum markers reflecting extracellular matrix status have been correlated with liver fibrosis in non-HIV-infected patients with chronic hepatitis C infection. These indexes have been less examined in HIV/HCV-coinfected individuals.
Objective: We aimed to evaluate the predictive value of serum markers for liver fibrosis in HIV-infected patients with chronic hepatitis C virus (HVC).
Methods: Serum levels of metalloproteinases 1 and 2 (MMP-1 and -2), tissue inhibitors of matrix metalloproteinases (TIMP-1), procollagen type III N-terminal peptide (PIIINP), and hyaluronic acid (HA) were measured in HIV-infected patients with chronic hepatitis C at the time of obtaining a liver biopsy and before the consideration of anti-hepatitis C therapy.
Results: One hundred and nineteen consecutive HIV-HVC coinfected patients were included. TIMP-1 (r = 0.6; P < 0.001), TIMP-1/MMP-1 ratio (r = 0.5; P < 0.001), TIMP-1/MMP-2 ratio (r = 0.3; P < 0.001), MMP-2 (r = 0.2; P = 0.044), PIIINP (r = 0.4; P < 0.001), and HA (r = 0.5; P < 0.001) were positively and significantly correlated with the fibrosis stage. In the multivariate analysis, TIMP-1 (odds ratio [OR] = 1.004, 95% confidence interval [CI]: 1.002 to 1.006, P = 0.001) and HA >95 μg/dL (OR = 6.041, 95% CI: 1.184 to 30.816, P = 0.031) were independently associated with liver fibrosis. The area under the curve of score to discriminate mild (F0-F1) from significant (F2-F4) fibrosis in the received-operating analysis using the variables TIMP-1 and HA was 0.84, with a sensitivity of 72.9% and a specificity of 83.1%.
Conclusion: TIMP-1 and HA were quite sensitive and specific for predicting the degree of liver fibrosis in HIV-infected patients with chronic hepatitis C. These parameters may become a noninvasive alternative to liver biopsy when the degree of liver fibrosis needs to be estimated.
Liver disease caused by chronic hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among HIV-infected patients in the developed world, because HIV-related opportunistic events have declined dramatically as a result of the widespread use of highly active antiretroviral therapy.1,2 Chronic hepatitis C progresses more quickly to liver fibrosis in HIV-infected patients than in HIV-seronegative, immunocompetent individuals.3 In addition, HIV infection accelerates the occurrence of decompensated HCV-related cirrhosis which in turn increases morbi-mortality.4,5 Therefore, an adequate management of HCV-related chronic liver disease constitutes a priority in the care of coinfected patients.
Liver biopsy remains the gold standard for assessing the degree of liver fibrosis. Unfortunately, liver biopsy is an invasive procedure requiring a short hospital admission.6-8 The degree of liver fibrosis determines the evolution of liver disease, the indication for therapy, and the probability of response. Several efforts have been made to evaluate noninvasive markers.9 Platelet counts10 and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio11 have been used, but their results have been disappointing. Although some specific individual scores were promising in detecting cirrhosis in HCV-infected patients,12,13 their diagnostic accuracy has been lower in HIV/HCV-coinfected patients.14
Liver fibrosis is considered a dynamic process characterized by an imbalance between the deposition and the degradation of the extracellular matrix.15 Among the most extensively studied noninvasive markers of liver fibrosis in chronic hepatitis C are procollagen type III-N-terminal peptide (PIIINP), a cleavage product of collagen precursor that is a marker of fibrogenesis, and hyaluronic acid (HA), a proteoglycan of connective tissue.16,17
Markers of connective tissue matrix remodeling such as metalloproteinases (MMPs) and the specific tissue inhibitors of metalloproteinases (TIMPs) have been shown to correlate with the development of cirrhosis in patients with chronic hepatitis C,18-21 but there are few reports in HIV-infected patients with chronic hepatitis C.
The aim of this study was to measure the serum levels of MMP-1, MMP-2, TIMP-1, PIIINP, and HA serum levels in a cohort of HIV-infected patients with chronic hepatitis C who had concomitant liver biopsy available; to correlate them with the degree of liver fibrosis; and to assess their predictive value for the stage of liver fibrosis compared with other reported scores.
Consecutive HIV-infected patients with chronic hepatitis C who gave informed consent for a liver biopsy as part of their routine assessment before the consideration of anti-hepatitis C therapy were eligible. Inclusion criteria were previously untreated chronic hepatitis C with measurable plasma HCV RNA, alanine aminotransferase (ALT) >1.5-fold the upper limit of normal, a CD4 cell count 250 × 106 cells/L, and a plasma HIV-1 RNA <200 copies/mL in response to a stable antiretroviral treatment. Exclusion criteria were causes of liver disease other than hepatitis C, decompensated cirrhosis, autoimmune disease, cardiovascular disease, pregnancy, and any symptomatic intercurrent infection.
Serum HCV and HIV Markers
Anti-HCV antibodies were measured using a third-generation enzyme-linked immunosorbent assay (ELISA). Serum HCV RNA levels were measured by a quantitative polymerase chain reaction (PCR) assay at baseline (Cobas AmpliPrep/Cobas Amplicor HCV Monitor Test version 2.0; sensitivity 500 copies/mL; Roche Molecular Systems, Branchburg, NJ). HCV genotyping was carried out as described previously.22 HIV-1 RNA (Amplicor Monitor; Roche) and CD4 cell counts (dual-color flow cytometry) were measured at the time of the liver biopsy. For the purpose of the analysis, HIV RNA measurements below the limit of detection (2.30 log10 copies/mL) were assigned the detection limit's value.
Ultrasonographic-guided liver biopsy was performed in all the patients using a 16-gauge needle. The biopsies were fixed, paraffin-embedded, and stained with hematoxylin-eosin and Masson's trichrome. All biopsy samples were analyzed by an experienced pathologist, blinded to clinical information, who graded each sample according to Scheure's23 classification: no fibrosis (F0), portal fibrosis without septa (F1), portal fibrosis with few septa (F2), portal fibrosis with numerous septa without cirrhosis (F3), and cirrhosis (F4). Liver biopsy samples were considered to be insufficient for appropriate analysis in 31 patients of the 150 patients evaluated.
A serum sample from each patient was collected at the time of the liver biopsy and subsequently stored at −80°C. The measurements of TIMP-1, MMP-1, and MMP-2 serum levels were based on a 2-site ELISA sandwich format (Amersham Biosciences, Piscataway, NJ) according to manufacturer instructions. AST, ALT, platelet counts, and prothrombin time were measured by autoanalyzer (Hitachi 917 Automate) and reagents (Roche Diagnostics, Mannheim, Germany). Albumin was assessed by the bromocresol green method.
Serum levels of HA was determined by ELISA using a kit from Corgenix (Westminster, CO) and following the instructions of the manufacturer. Serum HA concentrations in healthy subjects have been reported to be within the range of 10 to 95 μg/mL.17 For the purpose of the study, we considered serum HA values higher than 95 μg/mL as abnormal values. PIIINP were assayed using an immunoradiometric assay with monoclonal antibodies (Type III procollagen Intact PIIINP RIA; Orion Diagnostica, Espoo, Finland).
Descriptive statistics of the baseline variables were expressed as medians and interquartile ranges (IQRs) for quantitative variables and as absolute frequencies and percentages for qualitative variables. Wilcoxon rank-sum and χ2 tests (or Fisher's exact test when appropriate) were used for comparisons among continuous and categorical variables, respectively. In particular, demographic, epidemiologic, clinical, and biochemical characteristics were compared at baseline, with the aim of ensuring equality among groups. Spearman's correlation coefficient (r) was used to estimate the correlation between fibrosis index stages and serum markers.
Because F2 is generally chosen as a threshold for treatment recommendation of chronic HVC infection,24 the fibrosis index was arbitrarily dichotomized into significant (F2-F4) and no significant (F0-F1) fibrosis, and a logistic regression model was applied to identify factors associated with significant fibrosis. Area under receiver operating characteristic (ROC) curve was reported as a measure of the predictive power of the adjusted model. Sensitivity, specificity, and positive and negative predictive values for different cut-offs were calculated. Area under ROC curves using previously reported scores12,13,25 and our own score were compared using an algorithm26 based on a χ2 distribution.
All analysis was performed using STATA software version 8.0 (Stata Corp., College Station, TX) at the biostatistics unit of the hospital.
Baseline characteristics of the 119 patients included in the study are shown in Table 1. Most patients were male (66%). Their median age was 39 years, and 77% had a history of injection drug use. The mean time of known HCV infection was 19 years. The most common HCV genotypes in our series were 1 and 3 (56% and 29%, respectively). Fifty-two percent of the study participants had a fibrosis index of grade 2 or above, and one third had a bridging fibrosis or cirrhosis in the liver biopsy. The stage of fibrosis was distributed as follows: F0, n = 22 (19%); F1, n = 36 (30%); F2, n = 24 (20%); F3, n = 19 (16%); F4, n = 18 (15%).
The median (IQR) values of different laboratory parameters were ALT 89 U/L (62 to 142), AST 67 U/L (147 to 92), albumin 44 g/L (42 to 46), platelet counts 198 × 809/L (156 to 231), TIMP-1 774 ng/mL (640 to 1005), MMP-1 4.8 ng/mL (3.9 to 6), MMP-2 740 ng/mL (538 to 860), PIIINP 5.6 ng/mL (4.6 to 6.8), and HA 25 μg/mL (14.7 to 45).
Degree of Liver Fibrosis Versus Demographic and Biochemical Markers
In our series, the patients with lower degree of fibrosis were younger than those with a more severe liver disease. We did not find correlations between any antiretroviral treatment and the degree of fibrosis (Table 1). AST and ALT plasma levels were higher in patients with significant fibrosis, but this correlation disappeared after adjustment by the other factors included in the study (Table 2).
Serum Levels of MMP-1, MMP-2, TIMP-1, PIIINP, and HA Versus Liver Fibrosis
Serum levels of TIMP-1 (r = 0.6, P < 0.001), MMP-2 (r = 0.2; P = 0.044), PIIINP (r = 0.4, P < 0.001), and HA (r = 0.5, P < 0.001) were positively and significantly correlated with degree of fibrosis (Fig. 1), but MMP-1 was not. Moreover, TIMP-1/MMP1 (r = 0.5, P < 0.001) and TIMP-1/MMP2 (r = 0.3, P < 0.001) were also positively correlated with the degree of fibrosis.
Increased serum levels of TIMP-1 (odds ratio [OR] = 1.005, 95% confidence interval [CI]: 1.003 to 1.007, P < 0.001), TIMP-1/MMP-1 ratio (OR = 4.475, 95% CI: 2.240 to 8.938, P < 0.001), TIMP-1/MMP-2 ratio (OR = 2.020, 95% CI: 1.239 to 3.292, P < 0.05), PIIINP (OR = 1.433, 95% CI: 1.186 to 1.731, P < 0.001), AST (OR = 1.019, 95% CI: 1.007 to 1.032, P = 0.002), and decreased transformed square platelet count (OR = 0.765, 95% CI: 0.635 to 0.922, P = 0.005) were significantly associated with fibrosis in the univariate analysis. In the multivariate model that included HA as a categorical variable (HA >95 μg/mL; HA ≤95 μg/mL), the independent factors predicting a degree of liver fibrosis were TIMP-1 (OR = 1.004, 95% CI: 1.002 to 1.006, P = 0.001) and HA >95 (OR = 6.041, 95% CI: 1.184 to 30.816, P = 0.031) over a sample of 119 patients with completed data (Table 2). In the multivariable model, when HA was considered as a continuous variable, TIMP-1 (OR = 1.003, 95% CI: 1.000 to 1.005, P = 0.021) and HA (OR = 1.022, 95% CI: 1.002 to 1.042, P = 0.032) were independently associated with fibrosis. Nine patients were excluded from the latter model because they had extremely elevated values of HA. It is important to emphasize that these patients, as expected, had a high degree of liver fibrosis in their biopsy. Necroinflammatory activity was also significantly associated with fibrosis in the multivariate analysis (OR = 1.945, 95% CI: 1.307 to 2.893, P < 0.001).
Liver Fibrosis Prediction With MMP-1, MMP-2, TIMP-1, PIIINP, and HA
Area under ROC curve was used to determine the ability of each serum marker to discriminate fibrosis stages F2/F3/F4 from F0/F1. TIMP-1 was the best marker to discriminate moderate fibrosis (F2, F3, F4) from stages below F2, with an area under the ROC curve of 0.82. Using a cut-off value of 908.5 ng/mL, the sensitivity was 65% and the specificity was 85%. The next most useful test was HA, with an area under the ROC curve of 75. Using a cut-off value of 39 μg/mL, the sensitivity was 60% and the specificity 88%. Two biochemical parameters were found to be independently associated with fibrosis F2/F3/F4 stage in the multivariate analysis: TIMP-1 (OR = 1.004, 95% CI: 1.002 to 1.006, P = 0.001) and HA >95 μg/mL (OR = 6.041, 95% CI: 1.184, 30.816; P = 0.031). The area under the ROC curve of both parameters was 0.84 (Fig. 2). The sensitivity, specificity, and negative and positive predictive value are shown in Table 3. The correlation between the score index and the estimated probability of significant fibrosis can be seen in Figure 3.
Liver Fibrosis Prediction in Our Cohort Versus APRI, Forns, and SHASTA
The Forns,12 AST to platelet ratio index (APRI),13 and serum testing for HA, albumin, and AST (SHASTA)25 scoring systems were applied to our sample in 85 patients who had all the parameters. For Forns score, the area under the ROC curve was 0.67 and the positive predictive value 63%. With APRI score, the area under the ROC curve was 0.71, the specificity 100%, and the positive predictive value 63%. Using the SHASTA index, the area under the ROC curve result was better than the others (0.79), but it should be noted that albumin levels in all of our patients were >3.5 mg/mL (Fig. 4).
We have shown that there is a correlation between the degree of liver fibrosis and several serum markers of extracellular matrix remodeling and fibrogenesis. The serum levels of TIMP-1 reflect the expression of TIMP-1 in the liver in HCV-monoinfected patients, and both measurements are related to the severity of the liver disease.27-29 In fact, an increased amount of TIMP-1 in liver tissue is considered to promote matrix accumulation by slowing down collagen breakdown. The ratio between TIMPs and MMPs, an essential determinant for the development of liver fibrosis,30 was also correlated with the degree of liver fibrosis in our cohort.
In contrast to monoinfected patients, there are few data on the usefulness of these markers in the progression of fibrosis in the HIV/HCV-coinfected patients. To our knowledge, only 1 study showed higher levels of serum TIMP-1 in HIV/HCV-coinfected patients compared to HIV patients without HCV infection,31 but the number of patients was small and liver biopsy was not done. In addition, HIV infection seems to be modulating in vivo the expression of MMPs, decreasing dramatically the levels of mRNA of these proteolytic enzymes.32
Our results also confirm that HA and PIIINP are correlated with the degree of fibrosis in HIV/HCV-coinfected patients,20,33 but HA was more correlated with liver fibrosis than PIIINP was.
Liver biopsy is an invasive procedure, and several complications can occur.6-8 Additionally, the information provided by the liver biopsy is static and does not reflect either the ongoing balance between extracellular matrix production and degradation or the rate of progression towards cirrhosis. For this reason, the markers we used were based on the physiopathology of liver fibrosis. We hypothesized that detection of soluble markers of matrix remodeling would offer additional information to liver biopsy and would be useful to detect the progression or regression of fibrosis and the response to changes in lifestyle or antiviral therapies.34-37 In fact, noninvasive markers of fibrosis might be more accurate than biopsy, as recently suggested.38 The authors concluded that liver biopsy was responsible for most of the significantly discordant results (18%, as opposed to 2% due to fibrosis markers), mainly as a result of sampling error.
In accordance with other reports, in our study HIV/HCV-coinfected patients were younger and had a higher progression to fibrosis compared with monoinfected HCV patients.4 This emphasizes the need to develop and validate specific scores to know the degree of fibrosis in this population.
We were interested in finding predictors for septal fibrosis (F2-F4), a point at which interferon and ribavirin therapy is generally recommended.24 For this reason we investigated the diagnostic potential of PIIINP, HA, MMPs, and TIMP-1 serum levels as noninvasive markers of liver fibrosis. We developed a score from the multivariate analysis combining TIMP-1 and HA serum levels, because they were identified as the best markers of liver fibrosis in our series, and we obtained good results, with an area under the curve of 0.84. Similar results were found in the international cohort of the European Liver Fibrosis (ELF) study with surrogate serum markers of liver fibrosis and fibrosis stage in liver biopsies of HCV-infected patients.21
Few studies have evaluated the potential of biochemical serum markers to differentiate mild from significant fibrosis. Among these studies, Fibrotest is the most validated test for noninvasive assessments of liver fibrosis. Fibrotest uses 5 or 6 indirect biomarkers of fibrosis, including apolipoprotein A1, haptoglobin, alfa2 macroglobulin, gamma-glutamyl transpeptidase (GGT) and total bilirubin, and gamma globulin, to differentiate F0-F1 from F2-F4, obtaining an area under the curve of 0.82 in the estimation group to 0.85 in the validation group.9 Fibrotest has been studied in a cohort of HIV/HCV-coinfected patients39 that also found that Fibrotest was able to distinguish between F2-F4 and F0/F1 with an area under the curve of 0.85. A potential limitation for Fibrotest may be the impact that antiretroviral therapy may have on several of the parameters used to calculate the score, such as GGT, total bilirubin, and lipoprotein A1. No data are given on the antiretroviral drugs used in the recent publication of Fibrotest in HIV-infected patients. This potential limitation with Fibrotest in HIV-infected patients should not be expected with the laboratory parameters used in our study, although controlled studies are needed to confirm this contention.
A model to predict liver fibrosis has been recently developed with data from the AIDS Pegasys (peginterferon alfa-2a) Ribavirin International Co-infection Trial (APRICOT) study with an area under the curve from 0.76.40 The groups of patients and the degree of fibrosis were classified differently than in our cohort, and for this reason we have been unable to test the APRICOT score in our cohort. Other authors25 have also found a good predictive value for hyaluronic acid in accordance with our results, but they recognize some limitations, such as that the cohort was chiefly composed of African American males of relatively low body weight who were mainly infected with genotype 1 HCV.
In summary, our study suggests that an index of serum markers, including TIMP-1 and HA, may be clinically useful for detecting fibrosis in HIV/HCV-coinfected individuals. The combination serum levels of TIMP-1 and HA results were well correlated with the stages of liver fibrosis. In the routine care of HIV/HCV-coinfected patients, it could be used for establishing priorities in the management of HCV. Although this score needs to be prospectively validated in further studies of coinfected patients, we believe it deserves further attention for determining the stage of fibrosis without requiring a liver biopsy.
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