I11010
I11010 The effect of Maraviroc on serum markers
van der Pas V.
Date of approval: 9 February 2011
Background: With the increased life expectancy of human immunodeficiency virus (HIV) infected individuals due to highly active antiretroviral therapy (HAART) one of the potential long-term complications, end-stage liver disease, has become the third most important causes of death1. The majority of these deaths are due to hepatitis B (HBV) or hepatitis C (HCV) related decompensated liver cirrhosis1. A co-infection with HIV accelerates the development of liver fibrosis caused by these chronic viral hepatitides and increases the risk of developing cirrhosis2, 3. The Hepatic Stellate Cells (HSC) appear to play an important role in this process. These cells express the chemokine receptor-5 (CCR5) 4; recent research has suggested that inhibition of this receptor might slow down or even reverse the process of liver fibrosis5.
Besides its function on the HCS, this receptor plays an important role in the fusion of a specific HIV-subgroup with its host cell. The entry inhibitor Maraviroc (MVC) specifically blocks the CCR5 receptor. This leads to the hypothesis that treatment with MVC in HIV-infected patients might slow down or reverse liver fibrosis in this group, by inhibiting the CCR5-receptor on HCS. The preferred method to asses this effect would be invasive liver biopsy. However, in this study we used the non-invasive makers APRI (AST to Platelets Ratio Index) and FIB-4 to asses a possible effect of MVC on the progression of liver fibrosis.
Methods: The database of the Stichting HIV Monitoring (SHM) was evaluated for HIV-infected individuals using MVC for 6 months or longer between January 2007 and February 2011. Of these patients the demographic, clinical and biochemical characteristics were obtained. Since Maraviroc is a relatively new drug, the expected number of patients was low and thus all HIV-positive individuals were included.
The degree of liver fibrosis was quantified by the APRI and the FIB-4. The APRI was calculated using the formula as described in the original article of Wai et al6 with the AST’s upper limit of normal (ULN) being 40 IU/L.
|
APRI =AST (IU/L) / ULN x 100 |
Liver fibrosis was classified into 3 classes with class 1 indicating that no clinically significant fibrosis is present, in class 2 the presence of fibrosis cannot be excluded and in class 3 were clinically significant fibrosis or cirrhosis is present. Cut-off values as described in the literature were used with class 1 ≤ 0,50, class 2 from 0,50 to 1,50 and class 3 > 1,50 6.
The FIB-4 was calculated using the formula described in the original article7. A cut-off value of ≤1,45 was used for class 1, class 2 from 1,45 to 3,25 and class 3 >3,2.
FIB-4 = AST (IU/L) / ULN x 100
Platelet count(x 109/L)
The APRI and the FIB-4 were calculated at 3 moments in time: a year before treatment with MVC was initiated (t=-1), when MVC was initiated (t=0) and a year thereafter (t=+1). Biochemistry from a 3 month period before or after the ideal moment in time was considered acceptable. Since the transaminases and the platelet counts are not specific for liver fibrosis, both markers were also calculated a year before treatment to assess the naturals fluctuations.
Results: Of the 143 patients using MVC during the study period, 95 satisfied the inclusion criteria. From only 27 patients sufficient biochemistry was available to calculate the APRI and the FIB-4 at all 3 moments in time. Four patients were HIV/HCV-coinfected, there were no HBV/HCV coinfections.
Spontaneous improvement of the APRI and FIB-4 markers occurred in a major part of the patients in the year before the start of MVC. This trend persisted in the first year of MVC-treatment (table 1). However, univariate analysis showed no significant effects of MVC-treatment on the non-invasive markers.
Concordance between the two invasive markers was calculated showing a kappa value of 0.053, indicating moderate concordance.
|
|
Year before start MVC |
Start MVC |
Year after start MVC |
|||
|
|
APRI |
FIB-4 |
APRI |
FIB-4 |
APRI |
FIB-4 |
|
Class 1 |
16 |
10 |
20 |
15 |
24 |
17 |
|
Class 2 |
10 |
15 |
7 |
12 |
2 |
9 |
|
Class 3 |
1 |
2 |
0 |
0 |
1 |
1 |
Conclusion: Using the non-invasive serum markers APRI and FIB-4, no protective effect of MVC on the progression of liver fibrosis could be demonstrated in HIV-infected patients. However, the small sample size as well as the variability between the APRI and FIB-4, warrant further investigation on the effects of MVC on liver fibrosis in a larger subset of patients.
Decursus: As mentioned above, only in a limited number of patients enough laboratory data were available to calculate the non-invasive serum markers at three time points. Therefore, it is not possible to make concrete statements about the effect of MVC on the progression of liver fibrosis. We are currently evaluating on different methods to extend this number and thereby increasing the power of this study.
References:
1. Fang CT, Chang YY, Hsu HM, Twu SJ, Chen KT, Lin CC, et al. Life expectancy of patients with newly-diagnosed HIV infection in the era of highly active antiretroviral therapy. QJM 2007; Feb;100(2):97-105.
2. Monga HK, Rodriguez-Barradas MC, Breaux K, Khattak K, Troisi CL, Velez M, et al. Hepatitis C virus infection-related morbidity and mortality among patients with human immunodeficiency virus infection. Clin Infect Dis 2001; Jul 15;33(2):240-7.
3. Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology 1999; Oct;30(4):1054-8.
4. Moreira RK. Hepatic stellate cells and liver fibrosis. Arch Pathol Lab Med 2007; Nov;131(11):1728-34.
5. Hellier S, Frodsham AJ, Hennig BJ, Klenerman P, Knapp S, Ramaley P, et al. Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection. Hepatology 2003; Dec;38(6):1468-76.
6. 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; Aug;38(2):518-26.
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; Jun;43(6):1317-25.