HCV e HBV nelle malattie oncologiche

Transcription

1 INFEZIONI DA HBV E HCV PROBLEMATICHE ATTUALI Cagliari, 7 Dicembre 2018 HCV e HBV nelle malattie oncologiche Marta Muntoni, MD UOC Oncologia Medica AOBrotzu, P.O. Businco - Cagliari -

2 INTRODUCTION Ø Chemotherapy-induced immunosuppression can lead to HBV reactivation and may cause discontinuation of anticancer treatment, fulminant hepatitis with liver failure and death Torre et al, Nat. Rev Clin. Oncol Ø During immunosuppressive treatments reactivation of HBV infection is a lifethreatening complication that can occur in HBV active or inactive carriers but also in patients with occult HBV infection (OBI) Ø Many literature data showed a benefit from prophylactic antiviral treatment in cancer patients, however there is no evidence in determining the benefit of routine screening for chronic HBV infection in all patients undergoing cytotoxic and immunosuppressive chemotherapy

3 EPIDEMIOLOGY First described in the mid-1970s in the setting of cancer chemotherapy and kidney transplant In the United States, HBV reactivation-related acute liver failure increasingly is being recognized and has emerged as an important and preventable cause of acute liver failure HBV REACTIVATION Virological criteria: sudden and rapid increase in HBV-DNA level by at least a 100-fold in patients with previously detectable HBV DNA or reappearance of HBV-DNA viremia in individuals who did not have viremia before the initiation of immune-suppressive or biological therapy or cancer chemotherapy Biochemical criteria: 2- or 3- fold increase in alanine aminotransferase above the upper limit of normal Clinical criteria

4 Natural history of HBV reactivation after receiving immunosuppressive therapy

5 RISK FACTORS OF HBV REACTIVATION In patients with chronic HBV receiving chemotherapy for solid tumors without antiviral prophylaxis ranged from 4% to 68% (median 25%, in 19 studies) Sonali Paul et al, Annals of Internal Medicine, 2016 HOST FACTORS VIROLOGIC FACTORS IMMUNOSUPPRESSIVE THERAPY (and tumor subtype)

6 RISK FACTORS OF HBV REACTIVATION Virologic Factors

7 RISK FACTORS OF HBV REACTIVATION Immunosuppressive treatment (and tumor subtype) Patients undergoing chemotherapy for breast cancer have higher rate of HBV reactivation (41-56%) than other cancer patients (14-21%) Liu et al, 2015; Yeo et al., 2003 More patients with reactivation undergo permanent discontinuation or delay of treatment (76%) compared with those without evidence of reactivation (33%) Yeo et al, 2015; Yeo et al., 2003

8 Sonali Paul et al, 2016

9 Sonali Paul et al, 2016

10 > 10% 1% - 10% < 1%

11 RISK FACTORS OF HBV REACTIVATION patients with chronic HBV Risk for reactivation in patients with chronic HBV receiving chemotherapy for solid tumors without antiviral prophylaxis ranged from 4% to 68% (median 25%) Sonali Paul et al, 2016 With antiviral prophylaxis the risk was much lower, rangin from 0.9% to 31.4% (median 4.1%) in 18 studies. Sonali Paul et al, 2016

12 Sonali Paul et al, 2016

13 RISK FACTORS OF HBV REACTIVATION patients with resolved HBV infection In 3 studies of 328 patients with resolved HBV infection, the risk for reactivation without antiviral prophylaxis ranged from 0.3% to 9% (median 3%). Sonali Paul et al, 2016

14 MECHANISMS OF HBV REACTIVATION

15 HBV: to screen or not to screen There is no evidence in determining the benefit of routine screening for chronic HBV infection in patient undergoing cytotoxic and immunosuppressive chemotherapy (C. Bozza et al, 2015) The European Association for the Study of the Liver recommends that all candidates for CT should be screeneed (C. Coyle et al, 2016) American Association for the Study of Liver Disease and the ASCO guidelines recommended HBV screening only in HBV-infection high risk patients or if the immunosuppression caused by the treatment is expected to be high (Lok AS et al, 2009)

16 SCREENING: for whom and how The majority of guidelines recommended screening with HBsAg and anti-hbc C. Bozza et al, 2015 United States Centers of Disease Control and Prevention (CDCP) consider a screening also anti-hbs

17 MANAGEMENT AND PROPHYLAXIS Prescribe antiviral therapy when reactivation is detected Prescribe an antiviral therapy for high risk patients before starting immunosuppressive therapy could lead to an discontinuation of chemotherapy and it does not usually stop liver damage caused by viral reactivation (Yun et al, 2011; Yeo et al., 2004c) This finding can be explained by the biology of viral reactivation: studies suggested that viral replication occurs 1-2 weeks before hepatitis flare (Liaw, 2003; Yeo and Johnson, 2006; Yeo et al., 2001; Lau et al., 2003; Kohrt et al., 2006), so the prophylactic use of antiviral therapy have a clinical stronger rational than therapeutic strategy

18 TYPE OF ANTI-HBV REGIMEN FOR PROPHYLAXIS Previous meta-analyses have show that, in patients receiving chemotherapy, prophylactic therapy with LAMIVUDINE significantly reduced: 1. the risk of HBV reactivation and severity of HBV-related hepatitis by % 2. HBV-related acute liver failure 3. HBV-related mortality 4. the risk of interruption of CT Hsu et al., 2014; Leaw et al., 2004; Martyak et al., 2008; Loomba et al., 2008 Referring to breast cancer, Sohn et al. (2011) analyzed the efficacy of pre-emptive use of lamivudine in 169 HbsAg positive-patients receiving anthracycline-based adjuvant CT à the prophylactic lamivudine seems to reduce the severity of hepatic dysfunction and the incidence of hepatic flare-up during CT

19 TYPE OF ANTI-HBV REGIMEN FOR PROPHYLAXIS A more recent metanalysis (Liu et al., 2015) regarding HBsAg-positive breast cancer patients demonstrated that lamivudine prophylaxis had a significant reduction in the risk of HBV reactivation (RR=0.23, 95% CI: , p< ) and the rates of moderate and severe hepatitis were significantly lower then the patients group with no prophylaxis.

20 TYPE OF ANTI-HBV REGIMEN FOR PROPHYLAXIS: Lamivudine resistance mutation (YMDD-mutations) Patients developing CT-induced HBV reactivation may have a mortality rate as high as 11%, despite lamivudine (C.S. Voican et al., 2016) Lamivudine is not considered the agent of choice because it has a low barrier for the development of resistance (rate at 1 and 2 years 20% and 30% respec.) à could be ineffective to prevent HBV reactivation and hepatitis, so it is appropriate to use other ones in patients who need extended periods of CT Experts recommended: q lamivudine or telbivudine if the duration of treatment is no longer than 12 months and HBV DNA levels at baseline are low; q entecavir (Watanabe et al., 2010) or tenovir for patients who require longer duration of prophylaxis (more than 12 months) or have higher HBV DNA titers (De la Revilla et al., 2013)

21 DURATION OF ANTIVIRAL PROPHYLAXIS Ideally should be started 2-4 weeks before the initiation of immunosuppressive therapy Antiviral therapy should be continued for at least 6 months after the last dose of immunosuppressive or cancer therapy After it is stopped, patients should undergo routine testing for HBV DNA and serum ALT and AST at 3-6 months after discontinuation to monitor for an increase in HBV-DNA level, suggesting HBV reactivation after withdrawal of antiviral therapy

22 Algorithm for management of hepatitis B reactivation R. Loomba et al., 2017

23 What about HCV? HCV reactivation occurred in 23% of HCV-infected patients receiving cancer treatment, less common than HBV reactivation Is generally associated with a good outcome and less severe medical consequences Recommendations from CDCP suggest screening with a baseline anti-hcv test, detecting specific antibodies against HCV (anti-hcv) before starting CT (Hwang et al., 2014) HCV REACTIVATION at least a threefold increase in serum ALT level in a patient without liver involvement (liver metastasis or primary tumor), who does not receive hepatotoxicity drugs and have no sistemic infections with the exception of HCV (De la Revilla et al., 2013) Acute exacerbation can occur during the cytotoxic treatment but usually it was observed weeks or months after the last drug administration No clinically symptomatic acute ALT or HCV RNA levels elevation was seen in the most patients and usually liver enzymes elevation was mild and transient

24 Algorithm for management of HCV-positive patients with cancer De la Revilla et al., 2013

25 CORRELATION BETWEEN CHANGES IN HCV-RNA AND ALT Few studies demonstrated none direct correlation between transaminase elevation and increase HCV-RNA levels (suggesting that it could be related to liver toxicity caused to cytotoxic drugs) (Torres et al., 2018)

26 and then... Currently no specific drugs for the prevention of HCV reactivation are avaible in patients with solid tumors during a CT and only supportive therapy is considered Anti-HCV therapy is avoided during CT because it can worsen toxicity by cytotoxic drugs, in particular haematological adverse effects In a retrospective cohort of patients with an early breast cancer and HCV-related hepatitis, the treatment with anthracycline with or without taxane and trastuzumab was feasible even through in approximately one-half of patients it was required dose reductions and delays during the therapy 2010) (Morrow et al., Data from literature revealed that in patients with solid cancer and HCV infection, the administration of targeted therapy such as anti-her2 (trastuzumab, pertuzumab and lapatinib), mtor inhibitors (everolimus), anti-epidermal growth factor receptor therapies (cetuximab, panitumumab) seemed safe (Yazici et al.,

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30 Future Directions and Research Priorities 1) Set reseach priorities to comprehensively elucidate the mechanisms of HBV/HCV reactivation associated with various drugs and biologics 2) Establish better or improve existing animal models to study HBV/HCV immune control and thus HBV/HCV reactivation in more biologically meaningful settings 3) Invest in a public database that will allow comprehensive and timely reporting of all drugs, either new or old, in association with HBV/HCV reactivation 4) Identify and validate predictive markers, including viral markers (genotypes), biomarkers, or genetic traits, of HBV/HCV reactivation

31 Padova, Piazza della Frutta 2018