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Careful evaluation of the aetiology and severity of liver cirrhosis is necessary prior to initiation of anticancer treatment. Modifiable causal factors (eg, alcohol, liver toxins including drugs with known hepatotoxicity, diabetes) should be corrected in order to prevent worsening of the liver disease. Additionally, patients should be screened for portal hypertension and its complications and undergo adequate management if present,111 ,112 especially those patients whose prognosis is mainly determined by the liver disease (ie, very advanced/decompensated cirrhosis, potential curative cancer treatment).179

Reactivation of viral hepatitis

In general, reactivation of viral hepatitis during chemotherapy can be divided into three different stages.242–247 First, chemotherapy-induced immunosuppression facilitates viral replication by reducing immune response that controls viral infection. The second stage is characterised by an ‘immunological rebound’ after cessation of chemotherapy, characterised by restored immune function and rapid destruction of viral-infected hepatocytes leading to increased liver inflammation and hepatocellular injury. The ‘recovery phase’ represents the final stage and is characterised by normalisation of viral markers and clinical symptoms of hepatitis.242–247

Reactivation of HBV infection during chemotherapy can lead to fulminant hepatitis resulting in liver failure or even death (mortality rate, 5–52%); the risk is especially increased in patients receiving rituximab and/or high-dose steroids.243 ,246 ,248–254 HBV reactivation is defined by an abrupt increase in HBV DNA levels (>1 log10 copies/mL higher than before treatment start or absolute increase >6 log10 copies/mL) among patients with positive hepatitis B surface antigen (HBsAg) or the reappearance of HBV DNA in patients with resolved infection and is usually accompanied by an elevation of serum liver aminotransferases (hepatitis).246 ,253 ,255 All patients should be screened for HBsAg and hepatitis B core antibodies (anti-HBc) before initiation of treatment.113 ,179 ,212 ,252 ,254 ,256 HBV seronegative patients should undergo vaccination.113 ,246 table 3 summarises treatment indications before chemotherapy as recommended by the EASL guidelines for HBV management.113

Table 3

Pre-emptive hepatitis B treatment before chemotherapy

HBsAg-positive patients (regardless of HBV DNA levels) and HBsAg-negative, anti-HBc positive individuals with detectable serum HBV DNA should be treated with a nucleoside analogue during anticancer therapy and for at least 12 months after the last cycle of chemotherapy.113 ,246 Lamivudine might be sufficient in candidates with low HBV DNA levels (<2000 IU/mL) and short duration of immunosuppression113 ,246 ,257 ,258 while nucleoside analogues with higher potency and barrier to resistance (ie, entecavir, tenofovir) are recommended for patients with high viral load and/or long-lasting chemotherapeutic therapy.113 ,246

HBsAg-negative, anti-HBc positive candidates with undetectable serum HBV DNA levels should be monitored carefully during chemotherapy with alanine aminotransferase (ALT) and HBV DNA testing (every 1–3 months) and undergo antiviral treatment with a nucleoside analogue if HBV reactivation occurs.113 ,246 It was recently reported that high titres of anti-HBs were protective for HBV reactivation during rituximab-based chemotherapy.259 Prophylaxis should be given in special indications (ie, bone marrow or stem cell transplantation, rituximab and/or combined regimens for hematological diseases).113 ,246 ,249 ,260–263

Reactivation of HCV infection can also occur during chemotherapy245 ,264 ,265 but is less common and usually less severe than HBV reactivation.246 ,266–268 However, mortality rates seem to be similar between HCV-infected and HBV-infected patients once severe hepatitis due to viral reactivation occurs.246 ,269 ,270 HCV reactivation is characterised by an at least threefold increase in serum ALT levels not explained by other causes (ie, tumour infiltration of liver, hepatotoxic drugs, recent blood transfusions, other systemic infections except HCV) which can be accompanied by reappearance or abrupt increase of HCV RNA levels. In patients with chronic HCV infection an increase of HCV RNA of more than 1 log10 IU/mL might indicate HCV reactivation since these patients usually have stable RNA values (variations by about 0.5 log10 IU/).246 ,271

No specific prophylaxis is established for HCV patients undergoing chemotherapy.114 ,246 Once chemotherapy is started, an individualised approach with close monitoring of serum ALT (every 1–2 weeks) and HCV RNA (every 4 weeds) until 3 months after treatment cessation is recommended. In patients with elevated ALT levels, viral reactivation should be confirmed by HCV RNA measurement (>1 log10 IU/mL compared to baseline). Discontinuation of chemotherapy should be considered if increasing ALT levels preclude its use.246

Historically, anti-HCV agents such as interferon and ribavirin have been avoided during chemotherapy due to potential drug interactions and aggravation of hematological side effects.179 ,246 ,272 ,273 Hence, management of HCV reactivation has traditionally been only supportive including dose reduction or cessation of chemotherapy or switching to an alternative chemotherapy regimen.246 ,273 Borchardt and Torres273 recently recommended to start HCV treatment in cancer survivors without evidence of metastatic disease not before 6 months after cancer remission. In general, antiviral treatment is not recommended in patients with limited life expectancy due to non-liver related comorbidities like cancer,114 but survival for many cancers treated medically has improved so much that antiviral therapy might be warranted. The recent advances in HCV treatment including the development of the new, almost side effect-free direct-acting antivirals and the establishment of interferon-free regimens114 ,274 may change the therapeutic approach to HCV infection in patients with cancer, depending on costs and drug-interaction profiles of available and future treatment regimens.

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