To the Editors:
The response rate to treatment for hepatitis C virus (HCV) infection with interferon-α (IFN-α) and ribavirin (RBV) has been associated with viral factors, host factors, and factors that might interfere with therapy.1 IFN-γ-inducible protein 10 (IP-10/CXCL10) could play an important role in the pathogenesis of chronic HCV infection through the recruitment of effector Th1 lymphocytes to the liver parenchyma,2 potentially contributing to the host immune response against the virus and to disease progression. Recently, serum IP-10 levels, before HCV therapy, have been associated with treatment response in HCV-infected patients.3-7 Only 2 reports were done in HIV/HCV-coinfected patients with a small number of patients and different HCV genotypes.6,7
The aim of this study was to analyze the association between baseline plasma IP-10 levels and virologic response to IFN-α + RBV therapy in HIV/HCV-coinfected patients who harboured HCV genotype 1 (difficult-to-treat patients) in a retrospective study. Of 264 patients treated in our unit, we included 68 patients in an on-treatment analysis. Patients were treated for 48 weeks with the combination of IFN-α + RVB. For the purpose of this study, we excluded patients who; harboured HCV genotypes 2, 3, or 4, did not have a serum sample taken at baseline, had previously received IFN-α + RBV, had received HCV treatment for less than 24 weeks or prematurely interrupted HCV treatment due to adverse events, abandonment, or loss of follow-up.
The HCV viral load was measured by polymerase chain reaction (Cobas Amplicor HCV Monitor Test, Branchburg, NJ) and results were reported in IU/mL. Virologic response was defined as an undetectable plasma HCV RNA level (<50 IU per milliliter). Virologic failure was defined as either failure to achieve a drop of 2 log10 in HCV RNA from baseline levels at week 12 after initiation of therapy, detectable plasma HCV RNA level at week 24, or HCV viral rebound during therapy in subjects with prior undetectable viremia. To evaluate virologic response, we determined baseline plasma HCV RNA at weeks 12, 24, 48, and 72. Sustained virologic response (SVR) was defined as an undetectable plasma HCV RNA level at 24 weeks after the end of treatment.
A plasma sample before the initiation of IFN-α + RBV therapy was used to measure γIP10 (CXCL10) using the Multiplex kit (Panomics Afymetrix, Inc; Procarta Protein Profiling Assays, Fremont, CA) and a Luminex 100 analyzer (Luminex Corporation, Austin, TX).
Comparisons between groups were made using the T test according to Levene test for equality of variances for continuous variables and the χ2 test or Fisher exact test for categorical variables. Multivariate logistic regression was used to evaluate the association between baseline IP-10 and virologic response (at weeks 12, 24, 48, and 72) to HCV therapy adjusted according to gender, age, insulin resistance, HCV viral load, nadir CD4 T-cell count, and advanced liver fibrosis (F ≥ 3). Statistical analysis was performed using SPSS 15.0 software (SPSS INC, Chicago, IL).
The majority of the patients were male (75%), acquired HIV infection by intravenous drug use (82.4%), were on highly active antiretroviral therapy (82.4%), had a Metavir fibrosis stage of F2-F3 (72.4%), and had plasma HIV viral load <50 copies per milliliter (63.2%). Nine patients (13%) received standard interferon (IFN) and 59 (87%) received either 2a or 2b pegylated IFN.
Plasma IP-10 values before anti-HCV therapy were higher among patients who did not achieve a virologic response than among those with virologic response at weeks 12, 24, 48, and 72, although at week 72, the difference was not significant (P = 0.054) (Fig. 1A). Next, we selected a cut-off for IP-10 near the 75th percentile (1200 pg/mL). Patients with IP-10 <1200 pg/mL had higher rates of virologic response than patients with IP-10 ≥1200 pg/mL at weeks 12, 24, 48, and 72 after starting HCV therapy (Fig. 1B). Overall, patients with IP-10 <1200 pg/mL had virologic response rates of ≥40%, and patients with IP-10 ≥1200 pg/mL had virologic response rates off less than 20%. Moreover, we found a positive association between plasma IP-10 levels that were <1200 pg/mL before HCV therapy and virologic responses at weeks 12, 24, 48, and 72 (Figure 1C). Patients with IP-10 <1200 pg/mL had an odds ratio >4 for SVR and odds ratio >7 for the other virologic responses during therapy at weeks 12, 24, and 48.
In our study, serum IP-10 was found to be a predictive marker of virologic response in difficult-to-treat HIV/HCV-coinfected patients. We found that baseline IP-10 levels before HCV therapy were significantly higher in nonresponder patients at weeks 12, 24, 48, and 72 after starting treatment. Our study not only is in concordance with previous reports in HCV patients3-7 but provides additional information on virologic response rates during and after HCV therapy in difficult-to-treat HIV/HCV-coinfected patients with HCV genotype 1. Using an IP-10 cut-off of 1200 pg/mL, we found that IP-10 <1200 pg/mL before HCV-therapy was associated with virologic response to HCV-therapy.
IP-10 is the agonist of CXCR3 expressed in Th1 cells and is an antagonist of CCR3 expressed in Th2 cells. Therefore, IP-10 may be indirectly involved in the antiviral effect of therapy when HCV-infected hepatocytes secrete IP-10 and recruit mononuclear cells to the liver.8 IP-10 values found in HCV-infected patients with genotype 1 may also indicate a change in the IFN network. Greater IFN-stimulated gene induction in SVRs compared with nonresponders after in vitro IFN stimulation of the liver has been reported.9 Furthermore, low response to HCV therapy indicates preactivation of the IFN system and results in some defects at steps downstream of IFN-sensitive gene (ISG) expression, making them refractory to both endogenous IFN-α and IFN-α therapy.9 IFN-α activates the Jak-STAT pathway, and most nonresponders had nuclear phospho-STAT1 already present in pretreatment biopsies, and ISG transcripts were seen to be up-regulated.9 The IP-10 gene is activated via the Jak-STAT pathway resulting in secretion of IP-10 by the cell. This could be the cause of why we and other authors have found elevated IP-10 in peripheral blood.
In conclusion, plasma IP-10 levels before HCV-therapy may predict virologic response during and after HCV-therapy in difficult-to-treat HIV/HCV-coinfected patients with genotype 1.
Ana Vargas, Msc*
Juan Berenguer, MD, PhD†
Pablo Ryan, MD†
Pilar Catalán, PharmD‡
Juan Carlos López, MD, PhD†
Jaime Cosín, MD, PhD†
Pilar Miralles, MD†
Salvador Resino, PhD*
*Laboratory of Molecular Epidemiology of Infectious Diseases, National Centre of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
†Infectious Diseases-HIV Unit; Hospital General Universitario “Gregorio Marañón”, Madrid, Spain
‡Microbiology Department, Hospital General Universitario “Gregorio Marañón”, Madrid, Spain
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