Focus
Authors: Daniel Shouval
Journal: Journal of Hepatology (2012)

The prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in patients with haematological and solid malignancies is increased compared with the general population worldwide. There is currently a consensus that immune suppressive and/or anti-neoplastic therapy in patients with overt or occult HBV pose a serious, but usually preventable threat of liver injury and failure in such patients [[1]Lalazar G. Rund D. Shouval D. Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies.Br J Haematol. 2007; 136: 699-712Crossref PubMed Scopus (279) Google Scholar]. HBV reactivation has been reported in 14–70% of patients undergoing chemotherapy and especially in those treated with corticosteroids and rituximab. Consequently, the AASLD and EASL recommend pre-treatment screening and pre-emptive protection with an anti-viral agent for HBV patients at risk [2Lok A.S. McMahon B.J. Chronic hepatitis B: update 2009.Hepatology. 2009; 50: 661-662Crossref PubMed Scopus (2371) Google Scholar, 3European Association For The Study Of The Liver EASL clinical practice guidelines: management of chronic hepatitis B virus infection.J Hepatol. 2012; 57: 167-185Abstract Full Text Full Text PDF PubMed Scopus (2645) Google Scholar]. In contrast, the definition, the risk, and consequences of HCV reactivation in such patient populations undergoing immunosuppressive and chemotherapy are less clear as reflected in a number of recent reports [4Zuckerman E. Zuckerman T. Douer D. Qian D. Levine A.M. Liver dysfunction in patients infected with hepatitis C virus undergoing chemotherapy for hematologic malignancies.Cancer. 1998; 83: 1224-1230Crossref PubMed Scopus (104) Google Scholar, 5Dizdar O. Tapan U. Aksoy S. Harputluoglu H. Kilickap S. Barista I. Liver dysfunction after chemotherapy in lymphoma patients infected with hepatitis C.Eur J Haematol. 2008; 80: 381-385Crossref PubMed Scopus (22) Google Scholar, 6Pitini V. Sturniolo G. Arrigo C. HCV genotype 2 as a risk factor for reactivation in patients with B-cell lymphoma undergoing rituximab combination chemotherapy.Br J Haematol. 2010; 150 ([letter]): 116-117PubMed Google Scholar, 7Nooka A. Shenoy P.J. Sinha R. Lonial S. Flowers CR Hepatitis C reactivation in patients who have diffuse large B-cell lymphoma treated with rituximab: a case report and review of literature.Clin Lymphoma Myeloma Leuk. 2011; 11: 379-384Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 8Coppola N. Pisaturo M. Guastafierro S. Tonziello G. Sica A. Iodice V. et al.Sagnelli E Increased hepatitis C viral load and reactivation of liver disease in HCV RNA-positive patients with onco-haematological disease undergoing chemotherapy.Dig Liver Dis. 2012; 44: 49-54Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 9Nosotti L. D'Andrea M. Pitidis A. Pimpinelli F. Dessanti M.L. Pisani F. et al.Hepatitis C virus infection prevalence and liver dysfunction in a cohort of B-cell non-Hodgkin's lymphoma patients treated with immunochemotherapy.Scand J Infect Dis. 2012; 44: 70-73Crossref PubMed Scopus (22) Google Scholar, 10Torres H.A. Davila M Reactivation of hepatitis B virus and hepatitis C virus in patients with cancer.Nat Rev Clin Oncol. 2012; 24: 156-166Crossref Scopus (133) Google Scholar]. In this context, and regardless of whether the patient has HBV or HCV, one has to distinguish between acute exacerbation of an underlying liver disease in immune suppressed patients, which is not necessarily caused by viral reactivation (i.e., infection or drug induced liver injury), and the direct or indirect effects of viral reactivation per se. Except for some anecdotal case reports with a fatal outcome, a literature search between 1996 and 2012 failed to identify large scale studies reporting severe hepatic dysfunction in HCV patients undergoing immuno or chemotherapy [[10]Torres H.A. Davila M Reactivation of hepatitis B virus and hepatitis C virus in patients with cancer.Nat Rev Clin Oncol. 2012; 24: 156-166Crossref Scopus (133) Google Scholar]. Already in 1998, Zuckerman and co-workers retrospectively evaluated 27 viremic HCV patients undergoing chemotherapy for hematologic malignancies of whom 55% developed a mild to moderate ALT flare (range 59–491 U/L) which appeared within 2–3 weeks following cessation of chemotherapy (protocols did not include anti CD20 – rituximab) while none developed liver failure [[4]Zuckerman E. Zuckerman T. Douer D. Qian D. Levine A.M. Liver dysfunction in patients infected with hepatitis C virus undergoing chemotherapy for hematologic malignancies.Cancer. 1998; 83: 1224-1230Crossref PubMed Scopus (104) Google Scholar]. The conclusion of the authors that significant hepatic dysfunction is uncommon among HCV infected patients treated with chemotherapy for hematologic malignancies seems still valid 14 years later, even after widespread incorporation of rituximab into the treatment protocols. A recent survey in Italy has followed 207 consecutive non-Hodgkin lymphoma (NHL) patients of whom 9.2% were infected with HCV and treated with CHOP with or without rituximab. The incidence of hepatitis flares, although again relatively mild, was 26.3% vs. 2.1% among HCV+ patients as compared to non-infected controls. Further case reports have been published which link the relatively mild flares observed in such HCV patients to treatment, mainly with rituximab and possibly with some other chemotherapeutic agents. Yet, in most of these cases, it is difficult if not impossible, to distinguish between acute exacerbation of liver disease (potentially due to non-viral causes) and HCV re-activation. One reason for this difficulty is the lack of prospective follow-up of the HCV viral load at fixed intervals in relation to ALT fluctuations and chemotherapeutic regimen. In reactivating HBV patients undergoing chemotherapy, enhanced viral replication usually precedes hepatocellular injury which frequently appears following withdrawal of anti-neoplastic therapy and recovery of the immune system. In contrast, conflicting data have been reported in HCV patients receiving similar chemotherapy where enhanced viral replication was documented before, during or after an ALT flare [5Dizdar O. Tapan U. Aksoy S. Harputluoglu H. Kilickap S. Barista I. Liver dysfunction after chemotherapy in lymphoma patients infected with hepatitis C.Eur J Haematol. 2008; 80: 381-385Crossref PubMed Scopus (22) Google Scholar, 6Pitini V. Sturniolo G. Arrigo C. HCV genotype 2 as a risk factor for reactivation in patients with B-cell lymphoma undergoing rituximab combination chemotherapy.Br J Haematol. 2010; 150 ([letter]): 116-117PubMed Google Scholar, 7Nooka A. Shenoy P.J. Sinha R. Lonial S. Flowers CR Hepatitis C reactivation in patients who have diffuse large B-cell lymphoma treated with rituximab: a case report and review of literature.Clin Lymphoma Myeloma Leuk. 2011; 11: 379-384Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 8Coppola N. Pisaturo M. Guastafierro S. Tonziello G. Sica A. Iodice V. et al.Sagnelli E Increased hepatitis C viral load and reactivation of liver disease in HCV RNA-positive patients with onco-haematological disease undergoing chemotherapy.Dig Liver Dis. 2012; 44: 49-54Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 9Nosotti L. D'Andrea M. Pitidis A. Pimpinelli F. Dessanti M.L. Pisani F. et al.Hepatitis C virus infection prevalence and liver dysfunction in a cohort of B-cell non-Hodgkin's lymphoma patients treated with immunochemotherapy.Scand J Infect Dis. 2012; 44: 70-73Crossref PubMed Scopus (22) Google Scholar, 10Torres H.A. Davila M Reactivation of hepatitis B virus and hepatitis C virus in patients with cancer.Nat Rev Clin Oncol. 2012; 24: 156-166Crossref Scopus (133) Google Scholar]. The similarities and differences in the risk factors, the patho-physiologic mechanisms leading to liver injury and the prognosis in HBV and HCV patients undergoing chemotherapy have captured the attention of a number of investigators in the past two years [6Pitini V. Sturniolo G. Arrigo C. HCV genotype 2 as a risk factor for reactivation in patients with B-cell lymphoma undergoing rituximab combination chemotherapy.Br J Haematol. 2010; 150 ([letter]): 116-117PubMed Google Scholar, 7Nooka A. Shenoy P.J. Sinha R. Lonial S. Flowers CR Hepatitis C reactivation in patients who have diffuse large B-cell lymphoma treated with rituximab: a case report and review of literature.Clin Lymphoma Myeloma Leuk. 2011; 11: 379-384Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 8Coppola N. Pisaturo M. Guastafierro S. Tonziello G. Sica A. Iodice V. et al.Sagnelli E Increased hepatitis C viral load and reactivation of liver disease in HCV RNA-positive patients with onco-haematological disease undergoing chemotherapy.Dig Liver Dis. 2012; 44: 49-54Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 9Nosotti L. D'Andrea M. Pitidis A. Pimpinelli F. Dessanti M.L. Pisani F. et al.Hepatitis C virus infection prevalence and liver dysfunction in a cohort of B-cell non-Hodgkin's lymphoma patients treated with immunochemotherapy.Scand J Infect Dis. 2012; 44: 70-73Crossref PubMed Scopus (22) Google Scholar, 10Torres H.A. Davila M Reactivation of hepatitis B virus and hepatitis C virus in patients with cancer.Nat Rev Clin Oncol. 2012; 24: 156-166Crossref Scopus (133) Google Scholar]. In the present issue of the Journal, Mahale and co-workers from the MD Anderson Institute in the US, retrospectively identified 33/308 cancer patients with acute exacerbation of liver dysfunction, most of them with hematologic malignancies and nine with solid tumors, infected with HCV (42% genotype 1). Diagnosis was established via detection of anti-HCV antibodies and confirmed through detection of circulating HCV-RNA by PCR [[11]Mahale P. Kontoyiannis D.P. Chemaly R.F. Jiang Y. Hwang J.P. Davila M. et al.Acute exacerbation and reactivation of chronic hepatitis C virus infection in cancer patients.J Hepatol. 2012; 57: 1177-1185Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. A control group consisted of 32 anti-HCV+ patients, negative for HCV-RNA. The investigators defined an acute exacerbation of liver disease by at least a threefold rise in ALT while HCV reactivation was defined arbitrarily through a 1log10 rise in HCV-RNA. The main findings of this survey suggest that about 11% of patients with persistent HCV infection developed an acute exacerbation of their liver disease in association with immuno/chemotherapy and particularly with administration of rituximab. The study population consisted mainly of males at a median age of 55 years. Multivariate analysis suggests that the risk for exacerbation of liver disease was proportional to an increased dosing of rituximab, but was not affected by administration of corticosteroids. Chemotherapy had to be discontinued, at least temporarily, in 45% of patients with acute exacerbation of liver dysfunction as compared to 11% in patients with preserved hepatic functions. Information on HCV viral load was only available for 22/33 patients with acute exacerbation, of whom 8 patients (36%) developed a median rise in viral load above baseline of 1.45 log10 IU/ml, which was interpreted as evidence for viral re-activation in the absence of other causes of liver dysfunction. The rates of cirrhosis (diagnosed mainly radiologically, and histologically in a minority of patients), were similar, ranging between 23% and 25% in patients with or without exacerbation, respectively. Surprisingly, in patients who discontinued chemotherapy due to acute exacerbation, cirrhosis was less frequent at baseline as compared to patients without exacerbation. A 10-fold rise in ALT levels was present in 14/33 HCV patients, of whom 10 patients were treated with protocols containing rituximab. Yet, none developed fulminant liver failure and the median peak of ALT levels was similar in both study groups. The one-year outcome as well as the median survival was similar in both groups as well (data not shown). Finally, none of the 32 anti-HCV+/HCV-RNA- patients receiving chemo or immunosuppressive treatment developed an acute exacerbation of liver disease. The results of this important study strengthen and confirm a number of sporadic observations that chemo and especially immunetherapy with rituximab and possibly with several other antineoplastic agents can indeed trigger HCV reactivation and lead to exacerbation of previously silent liver disease. At first look, this phenomenon reminds us of the by now well characterized risk of HBV reactivation in patients with persistent HBV infection treated by immuno and chemotherapy. Indeed, there are quite a number of similarities between both groups of patients at risk. These include, among others, the presence of persistent viral infection, the perceived relationship between treatment-induced impaired immunity and emerging hepatocellular injury, the overwhelming impact of rituximab treatment on B cell functions, and the disruption in treatment of the underlying tumors as a result of liver dysfunction. There are, however, a number of dissimilarities between these DNA and RNA virus infected patients. In the present study and in contrast to the situation in HBV, administration of corticosteroids was not associated with an increased risk for acute exacerbation and viral reactivation. The rates and severity of HCV reactivation seem to be much lower in patients with HCV infection as compared to HBV reactivation, which has repeatedly been linked to development of fulminant hepatitis and death. HBV reactivation can be prevented through vaccination or pre-emptive treatment with an anti-viral agent in patients at risk. In contrast, at present, HCV cannot be prevented by vaccination, and effective anti-viral treatment in heavily immune suppressed hemato-oncologic patients with reactivating HCV is not a viable option. In contrast to HBV, little is known about the pathogenesis of HCV infection in immune-suppressed patients. It has already been repeatedly hypothesized that immune suppression in HBV as well as in HCV infection may lead to enhanced viral replication, which serves as trigger for liver injury after recovery of the immune system, within weeks to months following cessation of anti-neoplastic treatment [[10]Torres H.A. Davila M Reactivation of hepatitis B virus and hepatitis C virus in patients with cancer.Nat Rev Clin Oncol. 2012; 24: 156-166Crossref Scopus (133) Google Scholar]. Yet, proof for this hypothesis is still lacking, particularly in the case of HCV infection. Regretfully, only 22 of the HCV patients, which represent 7% of the entire study cohort, were tested for HCV-RNA before and after treatment. The correlation between ALT levels and fluctuations in viral load presented for nine patients in Fig. 4, does not enable a clear conclusion whether enhanced viral replication precedes hepatocellular injury, as described for most HBV patients under similar circumstances. The study has a number of limitations as also acknowledged by the authors. The retrospective design as well as the exclusion of 261 anti-HCV+ patients from analysis may have led to a bias in assessment of HCV reactivation rates. Furthermore, asymptomatic exacerbations could have been missed. Longer follow-up is warranted in patients with reactivated HCV infection. Regardless of these limitations, the study results are a timely contribution to an increased awareness by hemato-oncologists and hepatologists alike regarding the risk of HCV reactivation among their patients. Although less frequent and less severe as compared to HBV infection, HCV reactivation can lead to serious disruption of treatment in such patients and pre-treatment screening through anti-HCV testing is a simple and low cost procedure. The results of this report justify the design of a prospective study with predefined periodic measurements of HCV-RNA and ALT in HCV patients treated with immune suppressive and cytotoxic agents. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Acute exacerbation and reactivation of chronic hepatitis C virus infection in cancer patientsJournal of HepatologyVol. 57Issue 6PreviewData on acute exacerbation and reactivation of chronic hepatitis C virus (HCV) infection following chemotherapy are very limited. We sought to characterize the episodes of acute exacerbation and viral reactivation of HCV infection in cancer patients. Full-Text PDF