Hepatitis B: Who and when to treat?

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1 Received: 7 November 2017 Accepted: 8 November 2017 DOI: /liv REVIEW ARTICLE Hepatitis B: Who and when to treat? Jiannis Vlachogiannakos George V. Papatheodoridis Department of Gastroenterology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens, Greece Correspondence George V. Papatheodoridis, MD, Department of Gastroenterology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens, Greece. gepapath@med.uoa.gr Handling Editor: Mario Mondelli Abstract As current treatment options almost never achieve eradication of hepatitis B virus (HBV), the most realistic goal for HBV treatment is persistent inhibition of viral replication and ALT normalization. Thus, the decision to start treatment should be based on careful patient selection and individualized decisions. Treatment is generally indicated in chronic hepatitis B patients with HBV DNA >2000 IU/mL, elevated ALT and/or at least moderate histological lesions, while all patients with cirrhosis and detectable HBV DNA should be treated. Patients with HBV DNA > IU/mL and ALT >2xULN (upper limit of normal), HBV DNA >2000 IU/mL and liver stiffness >9 or >12 kpa in case of normal or 5xULN, HBV DNA >2000 IU/mL and a family history of cirrhosis and/or HCC as well as HBeAgpositive patients with HBV DNA > IU/mL and over 30 years old can begin treatment whatever the liver histology. Moreover, patients with HBV DNA >2000 IU/mL and at least moderate histological lesions can begin treatment whatever the ALT levels. Prophylactic treatment is indicated in HBV- related liver transplantation patients to prevent recurrence, in the last trimester of pregnancy in women with high viraemia to prevent vertical transmission and in patients receiving immunosuppression/chemotherapy to prevent the reactivation of HBV. Treatment is also indicated in patients with co- infections, extrahepatic manifestations and severe acute hepatitis B, or healthcare workers with viraemia. These treatment indications can only change if HBV eradication or at least HBsAg clearance can be achieved in the future in a significant proportion of patients. KEYWORDS cirrhosis, HBsAg, HBV DNA, hepatitis B, hepatocellular carcinoma, treatment indications 1 INTRODUCTION Chronic hepatitis B virus (HBV) infection is a global public health problem, because persistent viraemia is associated with increased morbidity and mortality. 1 Approximately 240 million people are chronic HBV surface antigen (HBsAg) carriers, with large regional variations between low (<2%) and high (>8%) endemic areas. 2 The number of HBV- related deaths from cirrhosis and/or hepatocellular carcinoma (HCC) has significantly increased in the last 20 years and more than people die every year. 3 Abbreviations: ALT, alanine aminotransferase; CHB, chronic hepatitis B; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; NA, nucleos(t)ide analogue; Peg-IFNa, pegylated interferon-alpha; TDF, tenofovir disoproxil fumarate; ULN, upper limit of normal. This review describes the current therapeutic indications for chronic HBV infection, including the natural history of the disease, the realistic goals of therapy and the specific patient subgroups that require treatment. 2 NATURAL HISTORY: FROM CHRONIC HBV INFECTION TO HEPATOCELLULAR CARCINOMA The natural history of chronic HBV infection is determined by a complex relationship between the virus and the host immune system. It has been schematically divided into five phases whose durations vary, distinguished by the presence of the hepatitis Be antigen (HBeAg) or Liver International. 2018;38(Suppl. 1): wileyonlinelibrary.com/journal/liv 2018 John Wiley & Sons A/S. 71 Published by John Wiley & Sons Ltd

2 72 its antibody (anti- HBe) in serum, serum HBV DNA and aminotransferases levels, and the presence or absence of liver inflammation. 4 HBeAg- positive chronic HBV infection (phase 1), previously called the immune- tolerant phase, is characterized by the presence of serum HBeAg, very high viraemia, normal serum aminotransferases and minimal histological changes. 4,5 HBeAg- positive chronic hepatitis B (CHB) (phase 2) is characterized by the presence of serum HBeAg, high levels of HBV DNA and elevated alanine aminotransferases (ALT). There is moderate or severe liver necroinflammation, and the progression of fibrosis is accelerated. 4,6 The outcome of this phase varies. Many patients achieve HBeAg seroconversion. They then enter the HBeAg- negative phase, which may be classified as (a) HBeAg- negative chronic HBV infection (phase 3), previously called the inactive carrier phase and characterized by low levels of viral replication, normal aminotransferases and minimal histological lesions, or (b) HBeAg- negative CHB (phase 4), characterized by high viral replication, elevated aminotransferases and active liver necroinflammation and fibrosis. 4,7 Finally, the HBsAg- negative phase (phase 5) may also develop and is characterized by negative serum HBsAg and positive antibodies to HBV core antigen (anti- HBc), with or without detectable antibodies to HBsAg (anti- HBs). This phase is also known as occult HBV infection. Patients in this phase have normal ALT values and usually, but not always, undetectable serum HBV DNA. 4 In general, chronic HBV infection has a dynamic natural course with periodic activation of the host immune system against infected hepatocytes to eradicate the virus, but which usually causes disease exacerbations and progressively accumulating fibrosis and ultimately, the development of cirrhosis. 8 Approximately 8%- 20% of untreated patients develop cirrhosis within 5 years, while 15% of patients with compensated cirrhosis and >60% of those with decompensated cirrhosis die within 5 years. 9 It is important to note that, all patients with chronic HBV infection have a greater risk of developing HCC than the general population and that the risk increases significantly in patients with prolonged high viraemia and cirrhosis. 10,11 3 THERAPEUTIC TARGETS AND END- POINTS The ideal goal of therapy in patients with chronic HBV infection should be viral eradication corresponding to clearance of HBsAg from serum and of covalently closed circular HBV DNA from hepatocytes. 12 Because this goal is rarely, if ever achieved with available anti- HBV agents, a more realistic goal is persistent inhibition of HBV replication and normalization of ALT activity. 9,13 Inhibition of viral replication by antiviral treatment has been shown to result in elimination of chronic HBV- induced necroinflammatory activity and progressive fibrosis in most patients. Thus, inhibition of HBV replication successfully achieves the ultimate goal of HBV therapy by improving survival and quality of life by preventing disease progression and the development of HCC. 14,15 The goal of antiviral therapy is also to prevent mother- to- child transmission, HBV reactivation during immunosuppression or chemotherapy as well as the prevention and treatment of HBV- associated extrahepatic manifestations. 4 Key points The most realistic goal for HBV treatment is persistent inhibition of viral replication with ALT normalization. Treatment is generally indicated in patients with HBV DNA >2000 IU/mL, elevated ALT and/or at least moderate histological lesions. HBV cirrhosis should be treated with any detectable HBV DNA. Prophylaxis is indicated to prevent HBV recurrence in liver transplant patients, vertical transmission from pregnant mothers with high viraemia and HBV reactivation in patients receiving immunosuppression/chemotherapy. HBV treatment is also indicated in patients with co-infections, viraemic healthcare workers, patients with extrahepatic manifestations and those with severe acute hepatitis B. Several studies in HBeAg- positive CHB have shown that treatment- induced HBeAg loss and seroconversion to anti- HBe leads to a low replicative phase of chronic HBV infection with long- term benefits to survival. 4 Thus, inducing HBeAg to anti- HBe seroconversion and undetectable HBV DNA is considered to be a valuable end- point in patients with HBeAg- positive CHB. 4,16 In addition, maintenance of virological and biochemical remission after stopping pegylated interferon- alfa (Peg- IFNa) or effective long- term (>4 years) therapy with a nucleos(t)ide analogue (NA; >3 years on- NA virological remission) is considered to be a treatment end- point in non- cirrhotic HBeAg- negative CHB. 4,16 Although HBsAg loss is the optimal treatment end- point and is called a functional cure, it cannot be achieved in most patients with CHB. On the other hand, HBeAg seroconversion is not always a durable end- point because HBeAg seroreversion or the development of HBeAg- negative CHB may occur. 16 Similarly, relapses are common when Peg- IFNa or long- term NA therapy is stopped in patients with HBeAg- negative CHB. Thus, the continuation of NA therapy until HBsAg loss is an alternative strategy, whatever the HBeAg status. 4 Spontaneous HBsAg seroreversion with reactivation of the inflammatory process in the liver is rare after HBsAg loss but may occur in patients with significant impairment to the immune function. 17,18 The main advantage of HBsAg loss is that it allows antiviral treatment to be safely discontinued. It should be noted that HCC may develop even after spontaneous HBsAg loss (annual rate 0.55%) TREATMENT INDICATIONS 4.1 Chronic hepatitis B The current indications to begin treatment are not different in HBeAgpositive and HBeAg- negative CHB. The decision is based on serum HBV DNA and ALT levels as well as the severity of liver disease. All

3 73 patients without cirrhosis who have HBV DNA levels >2000 IU/mL, serum ALT levels above the upper limit of normal (ULN: 40 IU/mL) and at least moderate necroinflammation and/or at least moderate fibrosis should be evaluated for treatment (Table 1). 4 Liver biopsy is still considered to be the gold standard to estimate disease activity in CHB. 20 However, it is invasive and treatment decisions may be based on non- invasive markers of fibrosis in patients who cannot or are reluctant to undergo liver biopsy. Elastography is the most extensively studied non- invasive technique, and it seems to have the highest diagnostic accuracy for the detection of advanced fibrosis. 21 The results of elastography should be interpreted with caution in patients with severe inflammation and high ALT levels. 21 In general, patients with chronic HBV infection, normal ALT and liver stiffness >9 kpa, or ALT that are elevated but below 5xULN and liver stiffness >12 kpa on transient elastography can be considered to have severe fibrosis or cirrhosis and can begin treatment if HBV DNA >2000 IU/mL (Figures 1-3). 21 Equivalent cut- offs for other elastography or serological techniques for the assessment of liver fibrosis may also used once they have been validated in patients with chronic HBV. 4 Patients with HBV DNA levels > IU/mL and ALT >2xULN can begin treatment without a liver biopsy because usually the results will not change the decision for treatment (Figure 1). 4 A non- invasive technique is recommended in these cases to confirm or exclude cirrhosis in patients who begin treatment without a liver biopsy. 21 TABLE 1 Indications for treatment or prophylaxis in chronic infection with hepatitis B virus in clinical practice. In addition, treatment is usually recommended in severe acute hepatitis B with coagulopathy or protracted course HBV DNA > IU/mL and ALT >2xULN (regardless of liver histology) HBV DNA >2000 IU/mL and liver stiffness >9 kpa, if normal ALT, or liver stiffness >12 kpa, if elevated ALT 5xULN HBV DNA >2000 IU/mL and at least moderate histological lesions (regardless of ALT) HBV DNA detectable and compensated or decompensated cirrhosis HBeAg positive, HBV DNA > IU/mL and age >30 y (regardless of ALT and liver histology) HBV DNA >2000 IU/mL and family history of cirrhosis and/or HCC (regardless of ALT and liver histology) HBV-related liver transplant recipients HBsAg-negative liver transplant recipients of organs from anti-hbc-positive donors HBV and HDV co-infected patients with HBV DNA persistently >2000 IU/mL HBV and HIV co-infection HBV and HCV co-infected patients receiving HCV direct-acting antivirals HBsAg-positive healthcare workers with HBV DNA >200 IU/mL Third trimester of pregnancy and HBV DNA > IU/mL or HBsAg >4 log 10 IU/mL HBsAg-positive patients under immunosuppression/chemotherapy HBsAg-negative, anti-hbc-positive subjects under immunosuppression/chemotherapy at high risk of HBV reactivation HBV-related extrahepatic manifestations Treatment may be begun in patients with HBV DNA levels >2000 IU/mL and at least moderate fibrosis, even if ALT levels are normal (Figure 1). In addition, patients with HBeAg- positive chronic HBV infection (persistently normal ALT and high HBV DNA levels) may be treated if they are >30 years old whatever the severity of histological lesions in the liver (Figure 2). 4 It should be noted that the decision to begin treatment should also take into account many other co- factors that could influence disease progression and the risk of HCC such as the patient s age and health status (lower threshold for patients >40 years old), a family history of HCC or cirrhosis, occupational requirements (eg, healthcare providers that participate in exposureprone procedures) and the presence of extrahepatic manifestations. 4 As the course of chronic HBV infection fluctuates, patients who do not fulfil the indications for antiviral therapy should be carefully monitored with periodic assessment of serum ALT and HBV DNA levels as well as for the severity of liver fibrosis by non- invasive markers (Figures 2 and 3). Patients with HBeAg- positive chronic HBV infection who are <30 years old and not being treated should undergo ALT tests every 3 months at least, HBV DNA every 6-12 months and assessment of liver fibrosis every 12 months (Figure 2). 4 Patients with HBeAg- negative chronic HBV infection and HBV DNA <2000 IU/mL should be monitored with ALT measurements every 6-12 months and periodic HBV DNA and liver fibrosis tests every 2-3 years. 22 Recent data suggest that quantitative HBsAg testing can be helpful in deciding on the frequency of follow- up in such patients. 23 Patients with HBsAg levels <1000 IU/ ml should undergo ALT measurements every 12 months and have HBV DNA and liver fibrosis tests every 3 years, while those with HBsAg levels 1000 IU/mL should receive ALT measurements every 6 months and HBV DNA and liver fibrosis tests every 2 years at least (Figure 3). 4,20,23 Patients with HBeAg- negative chronic HBV infection, normal ALT and HBV DNA 2000 IU/mL should be closely followed with ALT measurements every 3 months for the first year and every 6 months at least thereafter. Moreover, annual evaluation of HBV DNA levels and a non- invasive liver fibrosis test should be performed for at least 3 years (Figure 3). If they do not fulfil any indications for treatment during the first 3 years of follow- up, these patients should be monitored for life, like all other patients in this phase of disease Cirrhosis Patients with any detectable HBV DNA and compensated or decompensated cirrhosis should be treated whatever the ALT values. 4 NAs are the best treatment option, while Peg- IFNa is contraindicated in patients with decompensated liver disease. 24,25 Patients with decompensated cirrhosis should also be referred for liver transplantation, but treatment with NAs must be begun as early as possible for rapid and complete viral suppression. The main goal of NAs treatment in patients with decompensated liver disease is to achieve clinically compensated disease and avoid liver transplantation. 26 Approximately

4 74 FIGURE 1 Management of chronic HBV patients with increased baseline ALT levels. Patients should be initially followed with monthly ALT determinations, unless they have signs of cirrhosis for which immediate treatment is recommended. HBeAg- positive or HBeAg- negative patients with ALT >2xULN and HBV DNA > IU/mL should start therapy even without a liver biopsy. HBeAg- positive patients with ALT 1-2 xuln and/or HBV DNA < IU/mL can continue to be followed with *ALT every 3 mo and # HBeAg and # HBV DNA every 6 mo for 6-12 mo. Patients with increasing or even stable HBV DNA need to undergo biopsy for therapeutic decisions, while patients with decreasing HBV DNA may just remain under follow- up. HBeAg- negative patients with ALT 1-2xULN and/or HBV DNA < IU/mL may better undergo biopsy for therapeutic decisions FIGURE 2 Management of HBeAg- positive chronic HBV patients with normal baseline ALT levels. These patients should be followed with monthly ALT for 3 mo. Patients with ALT elevations or any sign of advanced disease should be managed according to the algorithm of Figure 1. Patients with ALT persistently <ULN and HBV DNA > IU/mL may better continue to be followed with *ALT every 3 mo and # HBeAg and # HBV DNA every 6-12 mo for 6-12 mo. If they remain in the same status, only follow- up is required for patients 30 y, unless they have liver stiffness >9 kpa at elastography, while treatment may be initiated in all such patients >30 y old. Patients with ALT persistently <ULN and HBV DNA < IU/mL may better continue to be followed with ALT and HBeAg every 6 mo and periodical!hbv DNA determinations

5 75 FIGURE 3 Management of HBeAg- negative chronic HBV patients with normal baseline ALT levels. These patients should be followed with ALT every 3-4 mo for 1 y. Patients with ALT elevations or HBV DNA > IU/mL or any sign of advanced disease should be managed according to the algorithm of Figure 1. Patients with ALT persistently <ULN and HBV DNA IU/mL may be treated, if liver stiffness exceeds 9 kpa. The latter cases with liver stiffness 9 kpa may be better continue to be followed with *ALT every 3-4 mo and # HBV DNA every 12 mo for 2 additional years and with ALT every 6 mo and # HBV DNA every 12 mo thereafter, if they remain in the same status. Patients with ALT persistently <ULN and HBV DNA <2000 IU/mL need only to be followed with ALT every 6 mo and periodical!hbv DNA determinations. Patients in the last subgroup may be followed with ALT even every 12 mo in case they have HBsAg levels <1000 IU/mL 35% of treated patients can be taken off the list for liver transplantation, and an improvement in the Child- Pugh score 2 has been observed in at least 40%- 50%. 27 Despite a high overall safety profile, close monitoring for adverse events is recommended in patients with decompensated cirrhosis receiving NAs, especially those with a MELD score >22 and impaired kidney function. 9 All patients with decompensated disease should receive antiviral treatment for life. However, the risk of developing HCC remains high in this specific group, thus careful long- term HCC monitoring must be performed Liver transplantation All HBsAg- positive candidates for liver transplantation should be treated with a NA to obtain undetectable HBV DNA. NA therapy is continued following liver transplantation in combination with HBV immunoglobulin (HBIG) to prevent graft infection. A short course of HBIG or prophylaxis with NA alone can be considered in selected patients with a low risk of recurrent HBV. On the other hand, a lifelong combination of NA and HBIG should be given to patients who are at a high risk of HBV recurrence, as well as to patients who are HBV DNA positive at liver transplantation, HBeAg positive, have HCC, and HDV or HIV co- infection. 4 Lifelong prophylaxis with NAs, often lamivudine, is recommended in HBsAg- negative liver transplant recipients of organs from anti- HBcpositive donors. 4.4 Co- infections All patients with HBV and HIV co- infection should begin antiretroviral therapy for HIV whatever the CD4 cell count. All such patients should be treated with a tenofovir- based antiretroviral regimen. 4 HBV and HDV co- infected patients with compensated liver disease can usually be treated with Peg- IFNa. NA therapy can be used in this group with ongoing HBV DNA replication and serum HBV DNA >2000 IU/mL. 4 Recent data suggest that treatment of HCV with directly acting antivirals (DAAs) may cause HBV reactivation in patients with HBV- HCV co- infection. Thus, NA therapy is recommended not only in patients fulfilling the standard indications for HBV treatment but in all HBsAgpositive cases. If prophylactic NA therapy is indicated, it should be given during DAAs and until 12 weeks after the end of DAAs therapy. HBsAg- negative, anti- HBc- positive patients receiving DAAs therapy should be monitored and tested for HBV reactivation in the presence of elevated ALT Healthcare workers Even if they do not fulfil the typical indications for treatment, healthcare workers may require antiviral therapy to reduce direct transmission to patients during exposure- prone procedures. Thus, healthcare workers, including surgeons, gynaecologists and dentists, who are

6 76 HBsAg- positive with HBV DNA >200 IU/mL may be treated with a potent NA to obtain undetectable or at least <200 IU/mL HBV DNA levels before resuming exposure- prone procedures. 4,29 Practicing surgeons should be monitored for adherence and efficacy. 4.6 Pregnancy Treatment of CHB during pregnancy should take into consideration both the mother s health and the safety of the fetus. Women should be informed about the safety of HBV drugs during a possible pregnancy. 4,30 Peg- IFNa is contraindicated during pregnancy. If pregnancy is being considered in the near future, it may be advisable to delay therapy if possible. In a woman of childbearing age with advanced fibrosis or cirrhosis who agrees to a planned pregnancy, Peg- IFNa should be the first- line treatment because it is the only finite short- term treatment with a chance of an off- therapy sustained virological response. 4,30 It should be noted that contraception is required during treatment. Treatment options should be re- evaluated if a woman becomes pregnant during treatment for CHB. The same treatment indications apply to women who are first diagnosed with CHB during pregnancy. Patients with advanced fibrosis or cirrhosis should definitely continue treatment, but with tenofovir disoproxil fumarate (TDF) due to its safety profile. 4,31 The prevention of vertical transmission of HBV is based on administering a combination of HBIG and a vaccination within 12 hours after delivery. However, this strategy may not be entirely effective in these women who are usually HBeAg- positive with high HBV DNA levels (> IU/mL) and/or HBsAg levels >4-4.5 log 10 IU/mL. Available data suggest that beginning treatment for HBV in the third trimester (around weeks of gestation) may be sufficient to prevent mother- to- child transmission of HBV in the latter group. 4 Although lamivudine, telbivudine or TDF prophylaxis has been used, TDF is now considered to be the best option. 4,32,33 The duration of NAs therapy for the prevention of perinatal transmission has not been well defined, but it is usually advised to continue treatment until 12 weeks after delivery. 4 Although HBsAg can be detected in breastmilk, breastfeeding is not contraindicated in HBsAg- positive mothers. The safety of NAs therapy during lactation is uncertain, but TDF may be used. 4.7 Immunosuppressive therapy, chemotherapy The risk of HBV reactivation in patients with chronic HBV infection who are candidates for chemotherapy or immunosuppressive therapy is increased 4 and may be classified as high (>10%), moderate (1%- 10%) or low (<1%). 18,34 Therefore, these patients should be screened for HBsAg, anti- HBs and anti- HBc before beginning immunosuppressive treatment. HBV- seronegative patients should be vaccinated. 4,35 Candidates for chemotherapy and immunosuppressive therapy who are HBsAg positive should be evaluated to determine the phase of HBV infection. All these patients should receive a potent NA (entecavir, TDF or tenofovir alafenamide) for treatment or prophylaxis. 4,34,36 NAs administration should be continued for at least 12 months (or 18 months with rituximab- based regimens) after immunosuppressive treatment is stopped and only discontinued if the underlying disease is in remission. 4 Monitoring is necessary during prophylactic treatment (every 3 6 months) and for at least 12 months after NAs withdrawal because most HBV reactivation develops after NAs are discontinued. 4,37 The risk of HBV reactivation in HBsAg- negative, anti- HBc- positive subjects depends on the virological profile, the underlying disease and the type and duration of the immunosuppressive regimen. 4,34,36 These patients should be tested for serum HBV DNA before immunosuppression. Viraemic patients should be treated in the same way as HBsAgpositive patients. 4,34,36 Antiviral prophylaxis is recommended in the high- risk group (>10%), including anti- HBc- positive subjects who require rituximab or those undergoing stem cell transplantation. 38 Prophylaxis should continue for at least 18 months after stopping immunosuppression, and patients should be monitored for at least 12 months after prophylaxis is discontinued. 4 In HBsAg- negative, anti- HBc- positive subjects with a moderate (<10%) or low (<1%) risk of HBV reactivation, preemptive therapy rather than prophylaxis, is generally recommended. 37 Treatment is based upon monitoring HBsAg and/or HBV DNA every 1-3 months during and after immunosuppression, and beginning treatment in the presence of detectable HBV DNA or HBsAg seroreversion Extrahepatic manifestations HBV infection is frequently associated with extrahepatic manifestations including polyarteritis nodosa, arthralgia, peripheral neuropathy, glomerulonephritis or purpura. Patients with extrahepatic manifestations and active HBV replication may respond to antiviral therapy. 4 Peg- IFNa should not be administered because it can worsen certain immune- mediated manifestations. A few reports have suggested that NAs are safe and effective in these cases while they can also be combined with plasmapheresis, corticosteroids or other immunesuppressive drugs for better efficacy Acute hepatitis B Adult patients with acute hepatitis B recover clinically and virologically with seroconversion to anti- HBs without antiviral therapy in more than 95% of cases. Thus, the main goal of potential treatment in these patients should be the prevention of acute or subacute liver failure. 40 Several cohort studies have reported that early antiviral therapy with highly potent NAs can prevent progression to acute liver failure and liver transplantation or mortality. 4,35 Thus, only patients with severe acute hepatitis B, characterized by coagulopathy (INR > 1.5) or a protracted course (ie, persistent symptoms or marked jaundice for >4 weeks) or signs of acute liver failure should be treated with NA and considered for liver transplantation. 4,35 5 CONCLUSIONS HBV is the most common cause of chronic viral infection in the world and represents a serious public health issue. Chronic HBV

7 77 infection is characterized by a complex interplay between the virus and the host immune system. Patients with CHB have an increased risk of progressing to cirrhosis and HCC. Because available treatments can only eradicate the virus in a minority of patients, the most realistic goal of treatment is persistent inhibition of viral replication and normalization of transaminases. To increase the number of patients who can benefit from treatment and minimize the risk of adverse events, treatment should be optimized by careful patient selection and individualized treatment decisions. Thus, treatment is indicated in patients with HBV DNA >2000 IU/mL, elevated ALT and/or at least moderate histological lesions, while all patients with cirrhosis and detectable HBV DNA should be treated. Moreover, prophylactic HBV treatment is indicated in HBV- related liver transplant patients to prevent recurrent HBV, in pregnant women with high viraemia to prevent mother- to- child vertical transmission and in patients who require immunosuppression or chemotherapy to prevent HBV reactivation. HBV treatment is also indicated in patients with co- infections, healthcare workers with viraemia, patients with extrahepatic manifestations or those with severe acute hepatitis B. Future therapeutic approaches may result in HBV eradication or at least clearance of HBsAg and seroconversion in a significant proportion of patients. This could lead to a functional cure and eliminate the risk of virological relapse, further decreasing the risk of HCC. CONFLICTS OF INTEREST J Vlachogiannakos advisor/lecturer for Abbvie, Bristol- Myers Squibb, Gilead, Merck Sharp & Dohme, Novartis, Roche. GV Papatheodoridis advisor/lecturer for Abbvie, Boehringer Ingelheim, Bristol- Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, Roche; research grants Abbvie, Bristol- Myers Squibb, Gilead, Janssen, Roche; consultant for Roche; Data Safety Management Board for Gilead. REFERENCES 1. Papatheodoridis GV, Manolakopoulos S, Dusheiko G, Archimandritis AJ. Therapeutic strategies in the management of patients with chronic hepatitis B. Lancet Infect Dis. 2008;8: Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and Lancet. 2015;386: Stanaway JD, Flaxman AD, Naghavi M, et al. The global burden of viral hepatitis from 1990 to 2013: findings from the global burden disease study Lancet. 2016;388: European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. 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