ESCCMID OLL. by Author. Hepatitis in immunocompromised hosts. Treviso, July 5, Saverio G Parisi

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1 Hepatitis in immunocompromised hosts Treviso, July 5, 2011 Saverio G Parisi Department of Histology, Microbiology and Medical Biotechnology Università di Padova

2 HBV

3 Virological categories Persistent HBV infection is defined as overt when the hepatitis B surface antigen (HBsAg) is present in amounts well-detectable by sensitive immune assays Occult in HBsAg-negative subjects with evidence of intrahepatic and/or serum HBV DNA. In occult carriers, HBsAg can be completely absent (real OBI) or undetectable for very low amounts or polymorphisms (false OBI).

4 Occult HBV carriers (HBsAg-negative). - the difficulty in determining HBV DNA in the liver biopsy (frequently not justified in subjects without clinical signs of hepatitis), - the rare presence of detectable viremia in serum even with sensitive techniques, - the frequent presence in occult carriers of markers of previous contact with the HBV (antihbc +/- antihbs), leads one to consider all anti-hbc (anti-core)-positive subjects as potential occult carriers. Instead there are no serum determinants in the minority (about 20%) of occult carriers who are negative for all HBV markers.

5 HBV and cancer Reactivation of HBV infection is now a well-recognized complication in infected patients who undergo cytotoxic chemotherapy for cancer. The condition ranges from asymptomatic self-limiting anicteric hepatitis to severe, potentially fatal progressive decompensated hepatitis. With the increasing use of potent cytotoxic chemotherapy, reactivation of hepatitis B in endemic regions is becoming a common clinical problem. Reactivation of HBV was first described by Wands et al.(gastroenterology 1975), who reported the condition in 20 patients with lympho- and myeloproliferative disorders. Most of the cases reported since were similar in patients with hematological malignancies in particular, lymphomas.

6 HBV and cancer The skewed observations may be due to the fact that - these patients are often subjected to intense myelosuppressive treatment regimens, -the malignancies per se are often associated with an immunocompromised state, - and the patients have been consistently reported to have a higher rate of hepatitis B surface antigen (HBsAg) seropositivity than the normal population. Over the past decade, HBV reactivation has been increasingly observed in patients with solid tumors.

7 The prevalence of positivity for hepatitis B surface antigen (HBsAg) was 8.5% among B-NHL cases and 2.8% among controls (adjusted odds ratio, 3.67; 95% confidence interval, ).

8 HBV and cancer In patients with hepatocellular carcinoma (85% of whom have chronic HBV infection in Southern China), hepatitis following systemic chemotherapy has been reported in 60%; this is mostly attributed to HBV reactivation, which has a 30% mortality rate. diseaseẹsccmid In other cancer subpopulations, the incidence of HBV reactivation ranges between 25% and 40%. In the setting of hematopoietic stem cell transplantation (HSCT) for various hematological and oncological conditions, HBV reactivation has been reported in over 50% of patients. This is linked to either the high frequency of inactive HbsAg carriers and occult B infection among oncohaematological patients, or the profound immunosuppression caused by high dose chemotherapy, monoclonal antibody therapy or auto- and allo-haematopoietic stem cell (HSC) transplantations, irradiation and the coexistence of acute graft-versushost OLL

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10 HBV and cancer In early reports, the diagnosis of HBV reactivation was based on HBsAg and hepatitis B surface antibody (anti-hbs) titers. 2 separate clinical scenarios during immunosuppressive therapy: 1) HBsAg-pos patients experiencing an increase in serum HBsAg titer 2) HBsAg-neg / anti-hbs pos patients showing anti-hbs decline associated with the reappearance of HBsAg (seroreversion). With the availability of quantitative HBV DNA assays, HBV reactivation could be tracked by the temporal relationship of the rise in HBV DNA titers with hepatitis and chemotherapy administration. The sensitivity of the HBV DNA assays is crucial

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13 HBV and cancer Reactivation may occur during or after completion of the full course of chemotherapy. Although some patients will recover from the condition spontaneously, anticancer treatment has to be interrupted due to hepatitis, and thus the patient s prognosis is jeopardized. In a study on breast cancer patients, over 70% of patients who developed HBV reactivation required premature termination of chemotherapy or disruption in treatment schedules compared with 30% in those without reactivation Some patients experience icteric hepatitis with HBV reactivation, with fatality rates ranging between 5% and 40%.

14 HBV and cancer Patients with cirrhosis are more likely to develop hepatic decompensation. This in part explains the particularly poor clinical outcome of patients who have hepatocellular carcinoma with HBVreactivation, as the majority of them have coexisting cirrhosis. Hepatic failure in patients who have cirrhosis may be complicated by sepsis, which occurs more commonly during immunosuppression. Patients with cirrhosis require more stringent monitoring. Diagnosis of cirrhosis is ideally determined via histology.

15 50 HBsAg-negative/anti-HBc-positive HSCT recipients with oncohematological diseases During 17 months of follow-up, six (12%) patients had seroreverted to HBsAg, 7 32 months after HSCT, with 1- and 5-year cumulative rates of 13 and 22%. HBsAg seroreversion was associated with serum HBeAg, higher than 8 log 10 cp HBV DNA and a 1.5 to 36 fold increase of serum alanine aminotransferase leading to HBeAg-positive chronic hepatitis B in all patients. Patients with chronic onco-hematological disease and longlasting immunosuppression following HSCT had a higher risk of HBsAg seroreversion independently of serum HBV DNA levels at HSCT.

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17 HBV Reactivation in HBsAg-Negative Patients in the Absence of Prophylactic Antiviral Therapy

18 HBV Reactivation in HBsAg-Negative Patients in Association With Rituximab or Alemtuzumab in the Absence of Prophylactic Antiviral Therapy

19 Incidence and Associated Risk Factors of HBV Reactivation in Cancer Patients Undergoing Chemotherapy

20 Chemotherapeutic Agents That Have Been Associated With Development of HBV Reactivation

21 Studies of Prophylactic Lamivudine for HBV Reactivation

22 A longer duration, at least 12 months, is suggested if the patient has received rituximab or alemtuzumab

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24 Lamivudine unfortunately has an high incidence of treatment resistance in actively replicating patients (up to 24% at 1 year and 60% at 3 years emergence of YMDD mutant strains). Regarding the incidence of lamivudine resistance in haematologic malignancies the literature has reported rates varying from 3.1% to 7.7% [42,43]. Therefore, HBV reactivation in an HBsAg inactive carrier may still occur while the patient is already on LAM, so that it is necessary to monitor HBV-DNA level of patients on LAM as elevation of HBV-DNA in the peripheral blood begins several weeks earlier than the occurrence of acute hepatitis [20] Another Achilles heel of prophylactic LAM is the risk of HBV recurrence after withdrawal of long-term prophylaxis, so that in oncohaematologic patients monitoring should continue for 1 year after cessation of therapy [44].

25 Since the efficacy of long-term LAM prophylaxis is limited by the appearance of antiviral resistance (YMDD mutant) the use of recently available potent anti-hbv agents with a different resistance profile (such as entecavir, adefovir,tenofovir) might be preferable when the drug needs to be administered for a prolonged time. These newer agents are more expensive than lamivudine and their long-term safety is less well defined; thus large prospective controlled studies are needed to address their use as first line prophylactic therapy in the oncohaematological setting.

26 Identified risk factors include - prolonged use of steroids, - HBsAb negative donors, - acute graft vs host disease, - unrelated rather than sibling donors, - the routine use of prophylactic cyclosporine and methotrexate for prevention of chronic graft vs host disease. - Some infections like CMV are also immunosuppressive and increase the risk of HBV reactivation.

27 In the transplantation setting the HBV status of the donor also needs to be considered [49]. An HBV infected donor is often the only choice: his serum HBV-DNA level before transplantation must be obtained and this donor must be started on anti-hbv therapy as early as possible. This treatment will rapidly bring down the donor s serum HBV-DNA to an undetectable level before haematopoietic stem cell donation, hence minimizing HBV transmission. Finally, immunization is recommended for all allogeneic transplants donors and recipients who are HBV naıve. [49]

28 The duration of lamivudine in the setting of stem cell transplants needs to be more prolonged. It should be continued until there is evidence of a good immune recovery, and not less than 12 months after cessation of all immunosuppression. The need for prolonged treatment even in patients off immunosuppressive drugs may have been confirmed by a recent report of an HBV reactivation 18 months after the discontinuation of immunosuppression [48]. Lamivudine must be continued in patients receiving treatment for chronic graft vs host disease: in this setting since there is a high risk of drug resistance associated with a prolonged use of lamivudine, newer anti-hbv agents with low risk of drug resistance may be suggested [50].

29 Pre-emptive therapy before immunosuppressive therapy or chemotherapy All candidates for chemotherapy and immunosuppressive therapy should be screened for HBsAg and anti-hbc antibodies prior to initiation of treatment [104,105]. Vaccination against HBV in seronegative patients is highly recommended. HBsAg-positive candidates for chemo- and immunosuppressive therapy should be tested for HBVDNA levels and receive pre-emptive NUC administration during therapy (regardless of HBVDNA levels) and for 12 months after cessation of therapy. Most experience with pre-emptive treatment has been with lamivudine, which may suffice for patients with low HBVDNA levels and a low risk of resistance [103, ]. It is however recommended that patients, especially those with a high HBVDNA level, be protected with a NUC with high antiviral potency and a high barrier to resistance, i.e. entecavir or tenofovir. (A1) HBsAg-negative patients with positive anti-hbc antibodies and undetectable HBVDNA in the serum who receive chemotherapy and/or immunosuppression should be followed carefully by means of ALT and HBVDNA testing and treated with NUC therapy upon confirmation of HBV reactivation before ALT elevation. NUC prophylaxis is also recommended in patients receiving bone marrow transplantation from a non-immune donor. Recipients of anti-hbc-positive liver grafts should receive NUC prophylaxis combined with HBIg. (A1) The optimal duration of combined prophylaxis is not known.

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34 Post Liver Ttransplant antiviral therapy In patients on treatment with lamivudine or lamivudine and adefovir at time of Liver Transplant, the same antiviral treatment should be continued after LT to prevent recurrence. D. Shouval et al. Hepatology 2000 ; 32 :

35 Lamivudine (LAM) or adefovir + HBIg versus HBIG alone after liver transplantation in patients with HBV-related liver disease L.H. Katz Cochrane Database Syst Rev ; 7 :CD

36 Anti-HBV treatment of cirrhosis Lamivudine (LAM) and/or adefovir (ADV) + HBIg versus LAM and/or ADV alone after liver transplantation in patients with HBV-related liver disease L.H. Katz Cochrane Database Syst Rev ; 7 :CD

37 HCV

38 Acute hepatitis C in HIV-infected individuals Acute HCV infection is defined as the first 6 mo after exposure to HCV. As the majority of individuals with acute HCV infection are asymptomatic, clinical diagnosis has a low sensitivity. Differentiating between acute HCV infection and an exacerbation of chronic HCV infection clinically, virologically and immunologically is difficult in the absence of recent negative HCV- RNA and antibody results. A serological test does not exist to differentiate between acute and chronic infection.

39 HIV-infected patients with chronic HCV develop hepatic flares with a rise of ALT higher than five times the upper limits of normal (ULN) in less than 2% [Cicconi 2007], minimizing the possibility of classifying chronic HCV infection as acute. The first marker of HCV infection is serum or plasma HCV-RNA detected through nucleic acid test (NAT) as early as 1 week postinfection [Marcellin 1999]. HCV antibody responses may be delayed or absent in HIV infected individuals with two-thirds positive at 3 months and 5% remaining negative up to 1 year after infection [Thomson 2009]. Fluctuations in HCV-RNA levels during the acute phase of HCV infection are characteristic in HIV-uninfected individuals and may be of value in suggesting a diagnosis of acute hepatitis C [Mc Govern 2009].

40 The prevalence of HCV infection in the HIV-infected is higher than in the uninfected population [Balogun 2002]. Within the HIV-infected population, the highest prevalence is in those with a history of intravenous drug use (IVDU) or haemophilia and other bleeding disorders. The European AIDS cohort (EuroSIDA) reported a prevalence of anti- HCV antibody or HCV-RNA positivity of 33%, ranging from 6.6% inmsm to 75% in IVDUs. Hepatitis C virus incidence among people who are HIV infected

41 Innate and adaptive immune responses. The immune response in acute hepatitis C, and correlates of spontaneous clearance, has been studied predominantly in HCV-monoinfected individuals and in chimpanzees. Single nucleotide polymorphisms near the interleukin (IL28B) gene, encoding for interferon-l (IFNl), provide strong evidence for an important role of the innate immune system in the natural defence against HCV [Thomas 2009, Rauch 2010, Ge 2009]. Individuals with the rs CC genotype were more than three times likely to clear HCV-RNA compared with individuals with C/Tand T/T genotypes. A similar association is observed in HIV/HCV-coinfected individuals [Rauch 2010]. Successful antiretroviral therapy can restore HCV-specific cellular immune responses [Valdez 2000]. The role of humoral immune responses in acute hepatitis C is not well defined [Dowd 2009, Osburn 2010, Chapel 2001].

42 Selection for early antiviral therapy. Ideally, only those who will not clear HCV spontaneously would be candidates for early antiviral treatment. However, delays in treatment could reduce efficacy. A positive HCV-RNA 12 weeks into acute hepatitis is associated with transition to chronic infection. Thus, treatment has been recommended in those with persistent HCV-RNA reactivity 12 weeks after onset of symptoms or 12 weeks after putative exposure.

43 Predictability of week 4 and 12 hepatitis C virus RNA in determining spontaneous viral clearance. If initiation of anti-hcv treatment is delayed for more than 1 year after onset, rates of sustained virological response (SVR) in HIV-uninfected persons are halved [Nomura 2004]

44 Acute hepatitis C virus treatment in HIV-infected patients.

45 Hepatitis C virus (HCV) can be transmitted in healthcare settings from healthcare workers to patients or from patient to patient. However, the vehicle of transmission is not always determined. Several cases of HCV contamination have resulted from shared medical devices such as hemodialysis machines, digestive endoscopy, mechanical ventilation for operated on patients, and injection materials or products.

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