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Treatment of HBV/HCV Coinfection: Releasing the Enemy Within
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Gastroenterology Feb 2009
Stuart C. Gordona, Kenneth E. Shermanb
a Henry Ford Hospital, Detroit, Michigan
b University of Cincinnati College of Medicine, Cincinnati, Ohio
Refers to article:
Peginterferon Alfa-2a Plus Ribavirin for the Treatment of Dual Chronic Infection With Hepatitis B and C Viruses , 30 October 2008
Chun-Jen Liu, Wan-Long Chuang, Chuan-Mo Lee, Ming-Lung Yu, Sheng-Nan Lu,
Shun-Sheng Wu, Li-Ying Liao, Chi-Ling Chen, Hsing-Tao Kuo, You-Chen Chao, Shui-Yi Tung, Sien-Sing Yang, Jia-Horng Kao, Chen-Hua Liu,
Wei-Wen Su, Chih-Lin Lin, Yung-Ming Jeng, Pei-Jer Chen, Ding-Shinn Chen
Gastroenterology
February 2009
See "Peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses," by Liu CJ, Chuang WL, Lee CM, et al, on page 496.
Estimates suggest that up to 10% of anti-hepatitis C virus (HCV)-positive patients may be hepatitis B surface antigen (HBsAg) positive, and that up to 20% of hepatitis B virus (HBV)-positive individuals are coinfected with HCV. Such estimates do not account for the possibility that occult HBV infection, not detected by HBsAg testing alone, may substantially increase the true prevalence of HCV/HBV dual infection. In the present issue of Gastroenterology, Liu et al1 describe the treatment of 161 persons infected with both HBsAg and HCV RNA (HCV dominant), and 160 matched, HCV-monoinfected persons with the combination of pegylated interferon and ribavirin using currently accepted doses and durations of therapy. In contrast with other experiences described in the literature, they found that HBV/HCV dually infected patients clear HCV equally as well as HCV monoinfected individuals. The details of their findings are encouraging and intriguing, but a dark side of this therapy was also exposed.
HBV and HCV: Pathogenesis and Immune Response
Both hepatitis B and hepatitis C are hepatotropic viruses whose primary site of replication resides in the liver; however, differences exist between these viruses regarding the pattern of injury after acute infection, immune response and the underlying mechanisms that may precipitate injury.. An understanding of the potential interactions that may occur during HBV/HCV coinfection (and its subsequent treatment) necessitates a review of their similarities and differences.
Acute HBV acquisition results in a prolonged period of relatively silent infection, characterized by appearance of HBsAg. Liver injury is delayed as virus fills the replication space, and seems to be primarily the result of an immune response to infected hepatocytes. Evidence for this comes from multiple animal models and from examples of human infection in unique clinical settings, including after liver transplantation and in HBV/HIV-coinfected subjects with significant immunosuppression. For example, HBV was thought to be a relatively benign process in the pre-highly active antiretroviral therapy era of HIV infection, with high levels of replication, but little or no evidence of liver injury among coinfected patients with very low CD4 counts.2 The mechanism of HCV-associated injury is less clear. A cytopathic effect has been noted in tissue culture systems, but there is far less evidence for this in vivo. Among liver transplant recipients with recurrent HCV liver disease, the early infection is often associated with scattered apoptotic cells in mid-zonal parenchymal areas. However, in established chronic infection, most of the cellular death appears to be associated with CD8 cells surrounding hepatocytes at the bounds of the limiting plate.3, 4, 5
The immune response to HBV is strong, and can be associated with control through both humoral pathways (HBsAg:HBsAb binding) and through strong cytotoxic T-cell responses.6 In contrast, humoral antibody response to HCV is more commonly associated with a sequential selection of an ever-varying array of envelope epitopes that drive mutational display, but fail to clear the virus.7 The cytotoxic T lymphocyte response is relatively poor until the virus is actually cleared, when a strong polyclonal response is frequently observed.8 There is strong evidence that HCV can modify the infected hepatocyte's innate immune response to infection through mediation of the JAK-STAT and other pathways.9 In contrast, HBV may avoid development of an innate response-not primarily by active interference with interferon-stimulated gene response pathways, but by maintaining key elements of its transcriptional template within the isolated nuclear compartment of the cell. A key issue in coinfection is whether modulation of infection occurs in coinfected individual hepatocytes in nature or if we are seeing a broader transcellular interaction. If hepatocyte coinfection does not naturally occur, then modification of replication is more likely a result of cytokine-mediated modulation of cell populations in proximity to each other. Bortolami et al10 described differential response to FAS-L in HCV- versus HBV-related disease. Tumor necrosis factor-β, interleukin (IL)-1β, IL-6, IL-8, and transforming growth factor-β levels are all higher in HBV-HCV-coinfected individuals than with separate infections.11 Taken together, these observations may explain the more severe clinical course of acute superinfection and greater likelihood of development of hepatic failure described by Asian investigators.12
HBV/HCV Coinfection: Order of Infection and Viral Levels Over Time
Clinical literature provides a confusing mix regarding the effects of HBV on HCV and vice versa, with most reports showing that HCV suppresses HBV, but also that HBV can suppress HCV replication.13 In a report from Canada,14 a 47-year-old man with chronic hepatitis C acquired superinfection with HBV, which resulted in profound suppression and sustained loss of HCV RNA, but with subsequent development of chronic hepatitis B infection. The authors speculated that vigorous immune responses (HBV-specific and/or HBV-induced nonspecific) were sufficient to suppress active HCV infection, but insufficient to inhibit HBV. Reciprocal viral inhibition is likely, with many hypotheses to explain this finding.15 Studies of chronically HBV-infected chimpanzees subsequently infected with HCV show a drop in HBV titers after coinfection.16, 17 Several studies note that HCV core protein may suppress HBV replication in cell culture system18, 19 and suggest that the mechanism may involve suppression of the HBV enhancer 1 and 2 from 3- to 11-fold. This effect was abrogated by deletion of nucleotides 1115 to 1236 of the HBV enhancer. Furthermore, this activity was genotype dependent.19 Chen et al20 cotransfected Huh7 cells with an HBV plasmid and variations of HCV core expression constructs and demonstrated significant suppression of HBsAg and HBeAg production. This effect was mediated through direct interaction between the HBx protein and HCV core protein constructs. In addition, HCV core protein was able to complex with HBV polymerase, which prevented HBV virion formation.20 Therefore, virus-virus interaction can occur at multiple levels and further differential modulation of the immune system may be superimposed on these processes.
The notion that most HBV-/HCV-positive patients are all "coinfected," however, actually belies the "superinfection" pathogenesis of the entity, especially among Asians who acquired HBV perinatally, and were infected with HCV later in life. The epidemiology of this entity likely varies by region, and among Westerners the shared risk of injection drug use may in fact lead to near-simultaneous coacquisition of both viruses. Such is not the case for the majority of cases globally, however. Liaw et al12 reported the course of acute HCV infection (and hepatitis D virus [HDV] infection) among chronically infected HBV patients in Taiwan, and described not only a severe acute phase (often with hepatic decompensation), but also an aggressive clinical outcome. Indeed, the long-term prognosis after acute HCV superinfection was worse than HDV superinfection in this series, including higher rates of cirrhosis than among HBV monoinfected patients. Additionally, rates of subsequent hepatocellular carcinoma were higher, validating previous studies21, 22 that underscore the synergistic role of coinfection on the risk of hepatocellular carcinoma formation.
In reality, the HBV-/HCV-coinfected patient represents a dynamic rather than a static process, and the "snapshot in time" perception of such patients, particularly those in antiviral treatment regimens, may be misleading. Unlike the chronic HCV monoinfected patient, wherein viral levels generally remain static and within one-log variation over time,23 the HBeAg-negative chronic hepatitis B patient typically exhibits wide viral variation. However, when the two viruses cohabitate the liver, not only do HBV serum levels still fluctuate profoundly, but now HCV likewise exhibits wide and uncharacteristic fluctuations.24 These large and unpredictable variations in both HCV and HBV viral loads over time in an individual patient are seemingly sporadic, as the reactivation phase of one virus was independent of "any peculiar modification of the viremia levels of the other."24
Reciprocal Viral Interference and the Treatment of HBV/HCV Coinfection
Shortly after the discovery of HCV, it was realized that HCV may exert an inhibitory effect on HBV,25 and that after the subsequent acquisition of HCV among HBV carriers, this virus may "usurp" the role of HBV after its clearance, leading to the major cause of chronic hepatitis.26 Others have found, however, that HBV DNA replication actually inhibits HCV RNA replication among dually infected patients.27 Results of interferon trials for the treatment of HBV/HCV coinfection are mixed, owing in part to evolving regimens and durations, and more sensitive and reproducible HBV DNA assays. More important, many of these studies demonstrate that successful clearance of one virus may lead to reactivation of the other,28 or "reciprocal viral interference," with HBV flares most frequently described.
The report by Liu et al,1 which excluded HBeAg-positive patients, sheds further light on this phenomenon. As reported previously, coinfected patients had more advanced fibrosis than did their HCV monoinfected counterparts. After PEG/ribavirin therapy the investigators also found that among the HBV/HCV coinfected persons with nondetectable HBV DNA pretreatment, there was subsequent emergence of detectable HBV DNA in 36.3%. This hepatitis B viral resurgence was reportedly not clinically consequential in any patient in this series, and was unrelated to the overall very high HCV antiviral response (72.2% sustained viral response [SVR] in coinfected genotype 1, 77.3% SVR in monoinfected, and >80% for genotype 2/3). It remains unclear, however, whether this apparent increase in HBV replication, occasionally with ALT elevations, will alter the natural history of HBV-associated liver disease among those individuals who experienced a post-HCV clearance phenomenon. It has been suggested that prolonged low-level viremia, with very nominal ALT abnormalities, is the most likely pathway toward HBV-induced liver disease among Asian patients.29
Despite the fact that one third of those dually infected patients with nondetectable HBV DNA levels pretreatment developed HBV reactivation posttreatment, HBsAg clearance occurred in 11.2% of dual-infected patients, many with seroconversion to anti-HBs. This number is somewhat higher than both the reported spontaneous and treatment-induced surface antigen clearance rates, leading to speculation once again on the HCV inhibitory effect on HBV dynamics. The authors found that on multivariate analysis only low pretreatment serum HBsAg titers correlated with posttreatment HBsAg loss or surface antigen seroconversion. The prognostic significance of serum HBsAg levels as a predictor of surface antigen clearance during peginterferon treatment of HBeAg-negative patients has recently been reported30, 31; future studies are required to confirm the clinical relevance of baseline HBsAg serum titers.
In summary, the largest treatment trial for HCV-/HBV-dual-infected patients to date has shown an SVR of roughly 75% in genotype 1 patients. Will these results translate to the non-Asian, higher body mass index population? Are the results applicable to the HBeAg-positive (or HBV-dominant) coinfected cohort? Should we be checking HBV DNA levels on our HCV monoinfected patients? Notably, 6.3% of the HCV-monoinfected patients had occult HBV infection (detectable HBV DNA in serum despite absence of HBsAg) pretreatment, and these subjects all cleared occult HBV DNA during interferon therapy. Nevertheless, among those dually infected patients who lost HCV RNA but still had elevated ALT posttreatment, detectable HBV DNA in the serum was found in over three quarters of these patients. It has been suggested that occult HBV disease may decrease response to HCV antiviral therapy irrespective of genotype.32 Should oral nucleoside/nucleotide analogs be added preemptively to obviate HBV reactivation? Finally, as we enter a new HCV antiviral era that may include triple therapy regimens (interferon, ribavirin, and HCV protease or polymerase inhibitors), how will these new agents interact with HBV in the coinfected population? The report from Taiwan has provided us with promising answers, but still more questions.
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