Since the introduction of HAART in 1996, the incidence of most opportunistic illnesses has declined sharply 
, while HCV-related liver disease has become a leading cause of morbidity and mortality in HIV-1-infected individuals. Bica et al. 
and Monga et al. 
demonstrated that end-stage liver disease was the leading cause of death in the HIV-1 seropositive population after HAART was introduced. In China, most of HIV-1 infected individuals (including FBDs) have received the first-line HAART regimes consisting of two NRTIs and one NNRTI since 2003. Preliminary data from a survey (still ongoing, unpublished) in our laboratory indicated that HCV infections also accounted for up to 50% of mortality in co-infected FBD individuals.
Several studies 
have investigated the distribution and correlation of HCV RNA positivity or negativity among HCV-seropositive populations. In our present study, the percentage of HCV RNA negative patients among anti-HCV seropositive patients was a little higher in HIV-1 seronegative (33.51%) than HIV-1 seropositive (30.99%) subpopulations () in enrolled participants (more than 90% of subjects having a history of blood donation) while this difference did not reach statistical significance. However, it's hard to draw a conclusion that HCV self-recovery rate has no association with HIV-1 infection since it is difficult to determine if HCV infection occurs before or after HIV-1 infection. If acute HCV infection and self-recovery occur before HIV-1 infection, there should be no association between HCV self-recovery and HIV-1 infection. Since transmission of HCV is more efficient than HIV-1 through unsanitary blood or blood products, it is most possible that HCV self-recovery occurred before HIV-1 infection in the majority of FBDs with HIV-1/HCV coinfection.
A number of cross-sectional studies have investigated the predictors of elevated liver enzymes in HIV-infected patients without HCV infection 
. However, the effects of HIV-1 virus per se
or of HAART on the progression of hepatic damage in HCV infected patients are not well understood. Our results indicated that HIV-associated factors may contribute to the elevated signals (ALT and AST) of liver function since the HIV-infected SVC group showed higher serum ALT (P
0.05) and AST (P
<0.001) than the HIV-noninfected SVC group (). In our study, 80% (35/44) of HIV-infected SVC patients (including patients with elevated ALT/AST) were taking HAART treatment, regularly or intermittently. HAART regimes consisted of two NRTIs (AZT/ddI or d4T/3TC), and one NNRTI (NVP). Usage of NRTIs might slightly worsen liver function with very low frequency and NVP might be associated with hepatitis on the background of high baseline CD4+ T cell counts 
. It is understandable that the effect of HIV-associated factors on liver disorders may be mild-to-moderate because no differences were found between CHC groups with and without HIV-1 coinfection. However, it is difficult to definitely conclude which factor played a major role in aggravating liver damage when considering chronic hepato-toxicity related to HAART, incomplete immune recovery, and other possible factors from our current data.
Our data showed that the S/CO ratio of anti-HCV Abs in HCV RNA-positive patients with or without HIV-1 co-infection was significantly higher than that of the patients with HCV RNA seronegativity (<0.001), which is consistent with the hypothesis that active HCV intrahepatic replication and stimulation is crucial for the maintenance of higher levels of serum anti-HCV responses. Theoretically, the clearance or extreme decline of HCV intrahepatic replication would result in the gradual decrease of HCV specific antibodies due to the loss of constant stimulation by HCV viral components. Once the virus was cleared away, the titer of serum HCV antibodies would drop gradually and spontaneous seroconversion would finally occur.
Previous studies reported that HCV core Ag quantification by ELISA method such as Lumipulse Ortho HCV Ag (Lumipulse-Ag) (Ortho Clinical Diagnostics) with a detection limit of 50 fmol/l can be used in the various indications of viral load monitoring, including the evaluation of baseline viral load before therapy and the study of early viral kinetics during therapy 
. Recently, a highly sensitive assay for HCV core antigen using a fully automated CMIA technique has become commercially available. The reactive cut-off for this assay was set at 3 fmol/l (S/CO
1.0) for maximum specificity, although the limit of detection has been calculated to be 0.83–1.24 fmol/l 
. A number of potential clinical uses for this assay have been described, including significantly shorten the diagnostic window period for detection of acute infection, as a tool to monitor the incidence/course of disease in various patient groups such as hemodialysis patients and injection drug users, as a rapid test for confirmation of active infection in anti-HCV positive cases, and as an independent parameter to predict response to treatment 
. In the present study, both of serum concentration of HCV core antigen and HCV viral load were significantly lower in HCV mono-infection than HCV/HIV-1 co-infection. Of note, quantitation of the CMIA HCV core antigen assay is highly correlated with the corresponding HCV viral load in CHC with or without HIV-1 infection (). Furthermore, HCV core antigen had a detection rate comparable to using HCV RNA testing. In contrast, serum anti-HCV titer in HCV mono-infection was significantly higher than in co-infection. As shown in , low S/CO ratios (less than 10) of serum anti-HCV antibodies were apparent in a minority of plasma HCV-RNA positive HCV/HIV-1 co-infected patients (approximately 10%). However, this value is notably higher than the percentage with low S/CO ratios (less than 1%) in that of plasma HCV RNA positive HCV mono-infected patients, indicating an increased risk of false negativity of HCV infection only judged by presence of positive anti-HCV antibody in HIV-1 coinfected patients. indicated that an undetectable anti-HCV antibody (0.09 S/CO) occurred in one HIV-infected CHC patient (HCV viral load: 4.11 log10
IU/ml; HCV core concentration: 16.03 fmol/l; CD4+ T cells count: 346/µl). As a result, it should be valuable to evaluate the HCV infectious status of an HIV-1 positive population by detecting HCV antigen or RNA. Of note, we demonstrated that a significant positive correlation was found between S/CO ratio of anti-HCV antibodies and peripheral CD4+ T cell counts in HCV/HIV-1 coinfection. Importantly, HCV core antigen concentration was shown to negatively correlate with CD4+ T cell counts (r
0.0083), while no correlation was found between HCV viral load and CD4+ T cell counts in HIV-coinfected CHC patients (). These findings could be interpreted as a hint that HCV core antigen testing was more sensitive to reflect immune pressure than HCV RNA testing. A possible interpretation was that the half-life of HCV core protein was relatively shorter under the regular human immune condition than under the immunodeficiency condition, whereas the breakdown of serum HCV RNA was less sensitive to immune clearance compared with HCV core protein. This interpretation may be also partially responsible for the higher ratio of HCV RNA to core antigen found in HIV-noninfected CHC patients compared to HIV-infected CHC individuals ().
In this study, we suggested that HCV core antigen could be used as a marker of HCV replication in anti-HCV antibody positive, treatment-naïve population, with or without HIV-1 coinfection. It is well known that the application of HCV core antigen testing on HCV diagnosis has several advantages. First, no sophisticated equipments are needed for HCV core antigen testing and the performance is time-saving in comparison with HCV RNA testing. Second, the expected price of HCV core antigen testing is cheaper than HCV RNA detection. Final, HCV core antigen was shown to be much more stable in serum and plasma than HCV RNA 
. It was demonstrated that the concentration of HCV core antigen was reproducible and stable even after incubation at room temperature for one week, while the concentration of HCV RNA dropped dramatically after incubation at 25°C for 24 hours 
. Therefore, HCV core antigen testing may act as an useful alternative marker for quantitative analysis of HCV replication and monitoring anti-HCV therapy.
In total, our findings demonstrated that there were distinctive serological and virological characteristics of serum HCV RNA positive and negative hepatitis C patients with or without HIV-1 coinfection. Importantly, there was an excellent correlation between plasma HCV viral load and the concentration of HCV core protein not only in the HCV mono-infected population but also in the HCV/HIV-1 coinfected population. The HCV antigen assay detected the vast majority of HCV RNA positives with or without HIV-1 infection (97.96% and 96.9%, respectively). Considering HCV, core antigen testing has a comparable sensitivity to HCV RNA qPCR. HCV core antigen concentration, but not HCV RNA level, was negatively correlated with CD4+ T cell counts. Our data suggested that quantitative detection of plasma HCV core antigen may be a novel and alternative indicator of peripheral HCV level than HCV RNA level when evaluating the association between HCV replication and host immune status in HCV/HIV-1 coinfected patients.