JAIDS Journal of Acquired Immune Deficiency Syndromes:
Basic and Translational Science
Transient Liver Injury Associated With the Early Recovery of HCV-Specific T-Cell Responses and HCV Rebound in HIV-1/HCV Coinfected Patients Undergoing Highly Active Antiretroviral Therapy
Kang, Fubiao MD*; Chen, Weiwei MD, PhD*; Zhang, Xinwei MD*; Nie, Weimin MD*; Fu, Junliang MD, PhD†; Xu, Xiangsheng MD, PhD†; Zhao, Peng MD*; Zhang, Xin MD*; Li, Wengang MD, PhD*; Wang, Fu-sheng MD, PhD†; Zhang, Zheng MD, PhD†; Zhao, Min MD*
*The Treatment and Research Center for Infectious Diseases, Beijing 302 Hospital, Beijing, China
†Research Center of Biological Therapy, Beijing 302 Hospital, Beijing, China.
Correspondence to: Min Zhao, MD, The Treatment and Research Center for Infectious Diseases, and Zheng Zhang, MD, PhD, Research Center of Biological Therapy, Beijing 302 Hospital, Beijing 100039, China (e-mail: firstname.lastname@example.org).
Supported by the National Nature Science Foundation of China Grant 81072423, the National Science Fund for Outstanding Young Scholars 81222024, the National Grand Program on Key Infectious Disease Grants 2012ZX10001006-003-003 and 2012ZX10001003-001-022, and the National Key Basic Research Program of China Grant 2012CB519005.
The authors have no conflicts of interest to disclose.
F. Kang and W. Chen contributed equally to this work.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).
Received May 16, 2012
Accepted September 19, 2012
Objectives: HIV-1/hepatitis C virus (HCV) coinfection accelerates the progression of liver disease to cirrhosis, particularly in individuals with low CD4+ T-cell counts. Highly active antiretroviral therapy (HAART) can significantly increase HCV-specific T-cell responses; however, it remains unclear whether the restoration of HCV-specific T cells by HAART is associated with liver injury in these coinfection patients.
Methods: A total of 32 HIV-1/HCV coinfected patients and 14 HCV monoinfected patients were enrolled, and 13 coinfected patients were initialized HAART and followed up for 6 months. HCV-specific interferon-γ responses to HCV core and NS3A proteins were examined by enzyme-linked immunosorbent spot.
Results: HCV-specific interferon-γ responses to HCV core and NS3A proteins were impaired in HIV-1/HCV-coinfected patients as compared with those in HCV monoinfected patients. The impaired HCV-specific T-cell responses could be efficiently restored during the early phase of HAART, independent of HCV status, and were positively associated with increased CD4 T-cell counts. In addition, this recovery of HCV-specific T-cell responses occurred simultaneously with elevated serum alanine aminotransferase levels in HCV viremic patients and in patients with HCV rebound, but not in HCV nonviremic patients after 6 months of HAART.
Conclusions: The recovery of HCV-specific T-cell responses by HAART may lead to transient liver injury in patients with HIV-1/HCV coinfection, suggesting that early anti-HCV therapy before HAART may reduce the risk of liver injury and therefore may be beneficial to HIV-1/HCV-coinfected patients.
Hepatitis C virus (HCV) and HIV-1 are often found within the same individual due to shared routes of transmission. It is estimated that HIV-1/HCV coinfected individuals account for approximately 33% of all HIV-infected persons, and this proportion increases to 85%–90% of HIV-infected injection drug users.1 HIV-1/HCV coinfection indeed accelerates the progression of liver disease to cirrhosis, particularly in individuals with low CD4+ T-cell counts.1–3 During the era of highly active antiretroviral therapy (HAART), HCV-related liver diseases are emerging as a leading cause of death in coinfected patients.2,4,5 Although some studies have indicated that nearly all antiretroviral drugs are hepatotoxic,6,7 most instances of liver injury are subclinical and spontaneously subside. Interestingly, the selective use of antiretroviral drugs with low hepatotoxicity has failed to reduce the occurrence of liver failure. Thus, the underlying mechanism of increased liver disease in coinfected individuals remains unclear.8
HCV is noncytolytic and liver injury is generally thought to be immune mediated. In this regard, HCV-specific T-cell immune responses are crucial for the control of HCV infection. However, HCV-specific CD8+ and CD4+ T-cell responses are weak in chronic HCV infection and are further impaired in HIV-1/HCV coinfected individuals,9–12 which is particularly evident in individuals with low CD4+ T-cell counts.13–15 Similarly, a correlation between higher CD4+ T-cell counts and preserved immunity exhibiting lower levels of HCV viremia has been described.16 However, the role of HCV-specific T-cell responses in treatment-induced viral clearance has yielded conflicting results in several studies, for example, one study reported that combined ART (cART) efficiently increased CD4+ T-cell counts and reduced HIV-1 load, while significantly enhancing HCV-specific T-cell responses leading to a long-term decrease in HCV RNA levels.15 By contrast, it has been reported that HCV RNA levels in plasma actually increase in the first months of HAART, particularly in individuals with low pretreatment CD4+ T-cell counts.17 Although these data suggest that HAART can significantly increase HCV specific T-cell responses, their effects on HCV RNA levels remain unclear. Furthermore, the extent to which HCV-specific T-cell responses contribute to liver damage in HIV-1/HCV coinfected patients undergoing HAART is also unclear.
The present study found that HCV-specific T-cell responses to core and NS3A proteins are severely impaired in HIV-1/HCV coinfected individuals but could be efficiently restored during the early phase of HAART. This early recovery of HCV-specific T-cell responses was associated with transient liver injury and increased HCV RNA levels in plasma in these coinfected patients. Thus, our findings suggest that early anti-HCV therapy may decrease HCV loads and subsequently reduce liver injury in HIV-1/HCV coinfected patients undergoing HAART.
A total of 32 HIV-1/HCV coinfected patients and 14 HCV monoinfected patients were enrolled in this study. There was no difference in the basic clinical characteristics of these 2 cohorts (Table 1). All of the patients lacked evidence of liver cirrhosis, as determined by liver biopsy and/or unequivocal clinical and biochemical data. Subjects with a history of interferon (IFN)-α treatment or ART were excluded from the study. The research described in this study was approved by the ethics committee of 302 Hospital and informed consent was obtained from each patient in accordance with institutional review board guidelines for the protection of human subjects. Blood samples were used for the evaluation of HIV-1 and HCV viral load, serum alanine aminotransferase (ALT) and aspartate aminotransferase levels, and peripheral blood CD4+ T-cell counts.
Among the 32 HIV-1/HCV coinfected patients, 13 well-compliant individuals with low CD4 counts (<500 cells/μL) and high HIV-1 viral loads (>10, 000 copies/mL) were offered HAART, including 2 nucleoside reverse transcriptase inhibitors (lamivudine and didanosine) and 2 protease inhibitors (lopinavir and ritinavir). Among them, 6 patients had undetectable serum HCV RNA (<100 copies/mL) and 7 patients had detectable serum HCV RNA (>5,000 copies/mL; see Table, Supplemental Digital Content 1, http://links.lww.com/QAI/A360). Peripheral blood samples were obtained from all 13 patients before the initiation of HAART and then once a month for 6 months after HAART.
IFN-γ Enzyme-Linked Immunosorbent Spot Assay
Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll–Hypaque density gradient centrifugation of heparinized blood samples and resuspended in RPMI 1640 culture media supplemented with 25 mM HEPES, 2 mM L-glutamine, 50 μg/mL of gentamicin, and 10% human serum. The cells were then seeded at a concentration of 2 × 106/mL and cultured with HCV NS3A (10 ng/mL) and core proteins (10 ng/mL) and human interleukin-2 (25 U/mL) in 96-well plates for 7 days. The cells were then transferred to enzyme-linked immunosorbent spot (ELISPOT) assay plates coated with a primary IFN-γ antibody and were restimulated with the same antigens for a further 18 hours at 37°C in a 5% CO2 atmosphere. The plates were then washed and incubated with a biotin-labeled anti–IFN-γ monoclonal antibody (1 μg/mL) for 3 hours. Subsequently, the plates were washed and incubated with an alkaline phosphatase-labeled anti-biotin secondary antibody for 2 hours at room temperature. To visualize the spots, 5-bromo-4-chloro-3-indolyl phosphate was added to the plates and the reaction was stopped by washing with distilled water after 5–10 minutes. Plates were then air dried, and the spots were counted using an automated ELISPOT reader. Responses were expressed as spot-forming cells (SFCs) per million PBMCs. PBMCs stimulated with phytohemagglutinin were used as a positive control. The assay was considered valid if the number of spots was at least 2-fold above the background level. All reactions were performed in triplicate.
All data were analyzed using SPSS software (SPSS Inc, Chicago, IL). A nonparametric Mann–Whitney U test was used for comparisons between the groups of HCV monoinfected patients and HIV-1/HCV coinfected patients. Correlations between variables were evaluated using the Spearman rank correlation test. For all statistical tests, 2-sided P < 0.05 was considered to be statistically significant.
Impaired HCV-Specific T-Cell Responses Are Dependent on CD4+ T-Cell Counts in HIV-1/HCV Coinfected Patients
The results of our ELISPOT assay demonstrated that the HCV-specific T-cell responses to both core and NS3A proteins were significantly lower in HIV-1/HCV coinfected patients, as compared with HCV monoinfected patients (Figs. 1A, B). We further compared the HCV-specific T-cell responsiveness to NS3A and core proteins between serum HCV(+) and HCV(−)-coinfected patients and found that the SFCs of NS3A, but not of core protein, were significantly lower in HCV(+)-coinfected patients than those of HCV(−) coinfected patients (Figs. 1C, D). Correlation analysis indicated that both NS3A and core-specific T-cell SFCs were positively associated with CD4+ T-cell counts in HIV-1/HCV-coinfected patients (r = 0.487, P = 0.004 for core protein, Fig. 1E; r = 0.397, P = 0.024 for NS3A protein, Fig. 1F). These data indicated that the magnitude of HCV-specific T-cell responses was impaired in HIV-1/HCV-coinfected patients as compared with HCV monoinfected patients and that the extent of impairment was dependent on the CD4+ T-cell counts of coinfected patients.
HAART Successfully Decreased HIV-1 Loads and Restored CD4+ T-Cell Counts in Both HCV(+) and HCV(−) Patients
We next investigated whether the influence of HAART on immune reconstitution was dependent on HCV status in a cohort of 13 HIV-1/HCV-coinfected patients. As shown in Figure 2A, both the HCV(−) and HCV(+)-coinfected patients displayed a significant increase in the peripheral CD4+ T-cell count at 3 months and 6 months since the onset of HAART. Accordingly, the HIV-1 RNA levels were decreased to undetectable levels (<500 copies/mL) in both HCV(−) and HCV(+)-coinfected patients (Fig. 2B). These data indicated that HAART successfully decreased HIV-1 loads and restored CD4+ T-cell counts in both HCV(+) and HCV(−) patients.
HAART Leads to a Transitory Increase in Plasma HCV Level and Liver Injury in HCV Viremic–Coinfected Patients
We further analyzed the changes in plasma HCV loads and serum ALT levels in the subgroup of 6 of HCV(−)- and 7 of HCV(+)-coinfected patients who underwent HAART. It is found that serum HCV loads were slightly but significantly increased at 3 months and maintained at high levels until 6 months of HAART in all of 7 HCV(+) patients. Contrastingly, only 1 of 6 HCV(−) patients experienced HCV rebound, with all of the other 5 patients maintaining negative HCV loads in their plasma (Fig. 2C). Notably, in those patients with elevated plasma HCV load, serum ALT levels were significantly increased at 3 months after HAART, but returned to baseline at 6 months (Fig. 2D). These data indicate that HAART has the potential to induce an HCV rebound and a transient liver injury during the early phase of treatment, particularly in HCV(+)-coinfected patients.
The Restoration of HCV-Specific T-Cell Responses by HAART Was Associated With Increased CD4+ T-Cell Counts in HIV-1/HCV-Coinfected Patients
The effect of HAART on HCV-specific T-cell responses in HIV-1/HCV coinfected patients was further investigated. We found that both core-specific and NS3A-specific T-cell responses were significantly increased at 3 and 6 months since the onset of HAART, as compared to baseline data in both HCV(−) and HCV(+) patients (Figs. 3A, B). The effect of HAART on NS3A-specific T-cell responses was particularly significant, with a further increase at 6 months as compared with 3 months in these patients (Fig. 3B). Our ELISPOT data also demonstrated that the increased core-specific T-cell SFCs were significantly associated with the elevated CD4+ T-cell counts in all patients at the 6-month time-point (Fig. 3C). We also found a positive trend between the increased NS3A-specific T-cell SFCs and the CD4+ T-cell counts at 6-month time-point in these patients (Fig. 3D). Taken together, these data indicated that HAART successfully restored HCV-specific T-cell responses in both HCV(+) and HCV(−)-coinfected patients, and this restoration was associated with increased CD4+ T-cell counts.
Time-Course Analysis of HCV-Specific T-Cell Responses in Relation to the Increased CD4+ T-Cell Counts, HCV Rebound, and Liver Injury in HIV-1/HCV-Coinfected Patients Undergoing HAART
To determine the association between increased HCV-specific T-cell responses and total CD4+ T-cell counts with HCV RNA rebound and ALT elevation, these parameters were analyzed in HIV-1/HCV-coinfected patients undergoing HAART during a 6-month follow-up period. Figure 4 shows representative data from 3 HCV(−)-coinfected patients (patients 1, 4 and 5, Fig. 4A) and 3 HCV(+)-coinfected patients (patients 8, 10, and 13, Fig. 4B). These representative patients displayed several key features: first, all patients showed a significant rise in HCV-specific T-cell responses, which occurred simultaneously with, or lagged behind the increase in peripheral CD4+ T-cell counts; second, in patients 4, 8, 10, and 13, the increase in HCV-specific T-cell responses occurred simultaneously with an elevation of serum ALT levels; and third, in patients 4, 8, 10, and 13, the increase in plasma HCV load simultaneously occurred or preceded to serum ALT elevation, whereas in patients 1 and 5, the persistent undetectable HCV RNA in serum was consistent with normal ALT levels. This comprehensive time-course analysis indicates that HCV rebound and increased HCV-specific T-cell responses, induced by HAART, are associated with early liver injury in HIV-1/HCV-coinfected patients.
Previous studies have shown that coinfection with HIV-1 substantially reduces HCV-specific immune responses,10–15 thus diminishing the immunologic control of HCV and thereby promoting liver pathogenesis.1 It has also been shown that successful cART could partially restore T-cell responses to HCV-core peptides, which occurred in parallel with decreased HCV load.15 Despite these intriguing reports, few studies have reported the effect of HAART on liver pathogenesis in HIV-1/HCV coinfected patients. The present study addresses this issue through a comprehensive analysis of HCV-specific T-cell responses and their association with liver injury in HIV-1/HCV coinfected patients, and the effect of HAART on these responses.
Our findings indicate that impaired HCV-specific immune responses are associated with peripheral total CD4+ T-cell counts. This result suggests that HIV-1 infection substantially diminishes host immune status, which is a key determinant of HCV disease progression. This observation was also supported by the fact that HAART partially restored HCV-specific T-cell responses during the early phase of treatment. Interestingly, this finding is similar to a previous longer term study in which nearly half of patients on cART produced detectable immune responses10 and is also consistent with the observation that cellular immunity is maintained in individuals who spontaneously clear their HCV infection.18 Notably, the restoration of HCV-specific T-cell responses in our study is dependent on CD4+ T-cell counts but independent of baseline plasma HCV RNA status. Future studies will be required to elucidate the extent to which in the increase of cellular immune responses during cART results in beneficial effects on liver disease progression.
In addition to the increased cellular immune responses during HAART that we observed, we also found a slight but significant increase in HCV RNA levels during the early phase of HAART. Similarly, Chung et al17 also demonstrated elevated plasma HCV RNA levels in the first months after HAART, which was particularly evident in patients with a low pretreatment CD4+ T-cell count.19 The mechanism for this increase of HCV load is unclear. It is possible that extrahepatic HCV replication in restored CD4+ T cells and that the increased hepatocyte lysis through restored T-cell immunity and decreased IFN levels during HIV-1 treatment.20 It should also be noted that these observations are contradictory to other studies. For example, a significant decrease in the level of HCV mRNA has been observed in patients undergoing long-term HAART.15 Furthermore, clearance of HCV infection during cART has also been reported in only a few cases.21–25 The temporal association between increasing HCV-specific T-cell responses and decreasing HCV RNA levels might potentially indicate immune reconstitution through successful cART, which thereby improves the control of HCV replication. Notably, a cause and effect relationship is difficult to ascertain in this scenario. It is also possible that they are 2 separately simultaneous events in such an early short-term period of HAART treatment or the increases of HCV load in the early phase of HAART treatment in HCV (+) patients may induce the restoration of HCV-specific T-cell responses, that is, HAART indeed restored the HCV-specific T-cell responsiveness. However, the persistently high levels of HCV-specific T-cell responses may finally clear HCV, but also possibly leading to liver injury. The longitudinal analysis will favor for elucidating the dynamic correlation between HCV replication and HCV–T-cell responses.
Another interesting observation in our study was that the occurrence of transient liver injury was because of the early recovery of HCV-specific T-cell responses in HIV-1/HCV coinfected patients undergoing HAART. There are 3 aspects of evidences to support the notion: (1) liver injury only occurred in plasma HCV(+) patients, or patients with HCV rebound after HAART; by contrast, no liver injury was observed in plasma HCV(−) patients, (2) the elevated serum ALT observed in these patients occurred simultaneously with increased HCV-specific T-cell responses, (3) all of these patients received the same antiviral regimen, including 2 nucleoside reverse transcriptase inhibitors (lamivudine and didanosine) and 2 protease inhibitors (lopinavir and ritinavir), but displayed various extent of liver injury or not. In addition, although nearly all antiretroviral drugs are hepatotoxic, most instances of liver injury are subclinical and spontaneously subside.6,7 Thus, we interpreted our data to indicate that HCV rebound and the increased HCV-specific T-cell responses induced by HAART were associated with the early liver injury in the HIV-1/HCV coinfected patients. These data also suggest that early initiation of anti-HCV therapy may decrease plasma HCV loads and subsequently, may reduce liver injury induced by HAART in these coinfected patients. However, our data have to be rationalized with previous studies in which a beneficial clinical effect of cART on the natural course of hepatitis C in HIV-1 infected individuals was reported.16,26 For example, Rohrbach et al15 provides evidence that the benefits of an effective treatment for HIV-1 on HCV disease could occur in part through restoration of HCV-specific immune responses. Other favorable effects of cART on liver disease include a reduction in immune activation and in bacterial translocation, and preventing adverse liver-related outcomes in HCV coinfected patients.22,27 Thus, these observed effects of treatment for HIV-1 on HCV cellular immune responses provides new insights into the mechanisms underlying HCV load and liver disease progression, which should be taken into account when treatment strategies of coinfected patients are discussed.
Our comprehensive 6-month follow-up study described the early clinical characteristics of HIV-1/HCV coinfected patients undergoing HAART. During this time frame, we were able to evaluate the impact of HAART on HCV-specific T-cell responses, observing transient liver injury in coinfected patients with increased HCV RNA levels. We are currently conducting an ongoing study designed to elucidate the long-term clinical consequences of restored HCV-specific T-cell responses in these patients.
In summary, our data indicate that the early restoration of HCV-specific T-cell responses and an increased HCV load by HAART is associated with the transitory liver injury in HIV-1/HCV coinfected patients. Our data highlights the key role of HCV-specific T-cell responses in the pathogenesis of liver injury in HIV-1/HCV coinfected patients undergoing HAART. Future studies should clarify the cause and effect relationship between the restoration of HCV-specific T-cell responses and liver injury, and determining whether early anti-HCV therapy in the course of HIV-1/HCV coinfection can reduce liver injury through decreasing HCV load.
The authors thank Wang Songshan for his excellent technical assistance in ELISPOT and all patients and volunteers who participated in the study.
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HIV-1/HCV coinfection; HARRT; HCV-specific T-cell response; liver injury
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