APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation

In the direct-acting antiviral (DAA) era for hepatitis C virus (HCV) infection, sustained virological response (SVR) is very high, but close attention must be paid to the possible occurrence of hepatocellular carcinoma (HCC) and reactivation of hepatitis B virus (HBV) in patients with co-infection who achieved SVR in short term. HCC occurrence was more often observed in patients with previous HCC history. We found occurrence of HCC in 178 (29.6%) of 602 patients with previous HCC history (15.4 months mean follow-up post-DAA initiation) but, in contrast, in only 604 (1.3%) of 45,870 patients without previous HCC history (18.2 months mean follow-up). Thus, in these guidelines, we recommend the following: in patients with previous HCC history, surveillance at 4-month intervals for HCC by ultrasonography (US) and tumor markers should be performed. In patients without previous HCC history, surveillance at 6-to 12-month intervals for HCC including US is recommended until the long-term DAA treatment effects, especially for the resolution of liver fibrosis, are confirmed. This guideline also includes recommendations on how to follow-up patients who have been infected with both HCV and HBV. When HCV was eradicated in these HBsAg-positive patients or patients with previous HBV infection (anti-HBc and/ or anti-HBs-positive), it was shown that HBV reactivation or HBV DNA reappearance was observed in 67 (41.4%) of 162 or 12 (0.9%) of 1317, respectively. For these co-infected patients, careful attention should be paid to HBV reactivation for 24 weeks post-treatment.

# Introduction
Hepatocellular carcinoma (HCC) due to hepatitis C virus (HCV) infection is one of the major causes of liver-related death [bib_ref] Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017..., Omata [/bib_ref] [bib_ref] Incidence of hepatocellular carcinoma in chronic hepatitis B and C: a prospective..., Takano [/bib_ref]. Eradication of HCV could reduce the occurrence of HCC, as demonstrated by the long-term followup of patients who achieved sustained virological response (SVR) in the interferon era [bib_ref] Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of..., Yoshida [/bib_ref] [bib_ref] Long-term effects of interferon-based therapy for chronic hepatitis C, Yu [/bib_ref] [bib_ref] Outcome of sustained virological responders with histologically advanced chronic hepatitis C, Morgan [/bib_ref]. Thus, SVR could be the goal of antiviral therapy for HCV.
In the interferon era, as the duration of interferon-based therapy was longer than that of DAA therapy, the occurrence of HCC has occasionally been observed during the Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1207 2-019-09988 -7) contains supplementary material, which is available to authorized users. treatment. But these cases were omitted from studies or ignored by regarding them as pre-existing, and they were therefore unrelated to the interferon treatment [bib_ref] Outcome of sustained virological responders with histologically advanced chronic hepatitis C, Morgan [/bib_ref] [bib_ref] APASL consensus statements and recommendation on treatment of hepatitis C, Omata [/bib_ref]. Now, in the age of DAAs, extremely high SVR rates, sometimes even 100%, have been reported [bib_ref] Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection:..., Omata [/bib_ref] [bib_ref] Ledipasvir and sofosbuvir fixeddose combination with and without ribavirin for 12 weeks..., Mizokami [/bib_ref] [bib_ref] Sofosbuvir and Velpatasvir for HCV genotype 1, 2, 4, 5, and 6..., Feld [/bib_ref] [bib_ref] Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic..., Lau [/bib_ref] [bib_ref] Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with..., Jacobson [/bib_ref] [bib_ref] Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection, Bourliere [/bib_ref] [bib_ref] Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment, Gane [/bib_ref] [bib_ref] Ledipasvir/sofosbuvir for treatment-naive and treatment-experienced Chinese patients with genotype 1 HCV: an..., Wei [/bib_ref] [bib_ref] Sofosbuvir-based interferon-free direct acting antiviral regimens for heart transplant recipients with chronic..., Liu [/bib_ref] [bib_ref] Glecaprevir/pibrentasvir treatment in liver or kidney transplant patients with hepatitis C virus..., Reau [/bib_ref] [bib_ref] Generic sofosbuvir-based direct-acting antivirals in hepatitis C virus-infected patients with chronic kidney..., Kumar [/bib_ref]. However, there have been several reports on the unexpectedly high rate of early HCC occurrence despite the virus eradication [bib_ref] The impact of direct-acting antivirals on early tumor recurrence after radiofrequency ablation..., Minami [/bib_ref] [bib_ref] Unexpected high rate of early tumor recurrence in patients with HCV-related HCC..., Reig [/bib_ref] [bib_ref] Hepatocellular carcinoma recurrence after treatment with directacting antivirals: First, do no harm..., Torres [/bib_ref] [bib_ref] Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with..., Conti [/bib_ref] [bib_ref] Hepatocellular carcinoma recurrence after direct antiviral agent treatment: A European multicentre study, Kolly [/bib_ref] [bib_ref] High incidence of hepatocellular carcinoma following successful interferon-free antiviral therapy for hepatitis..., Cardoso [/bib_ref] [bib_ref] Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype..., Calleja [/bib_ref] [bib_ref] Direct-acting antivirals decreased tumor recurrence after initial treatment of hepatitis C virus-related..., Ikeda [/bib_ref] [bib_ref] Interferon-free therapy of chronic hepatitis C with directacting antivirals does not change..., Mettke [/bib_ref] [bib_ref] Rapidly growing, moderately differentiated HCC: A clinicopathological characteristic of HCC occurrence after..., Nakao [/bib_ref] [bib_ref] Effect of interferon-based and -free therapy on early occurrence and recurrence of..., Nagata [/bib_ref] [bib_ref] Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents, Kanwal [/bib_ref] [bib_ref] HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular..., Ioannou [/bib_ref] [bib_ref] Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by..., Cabibbo [/bib_ref] [bib_ref] Prediction of the very early occurrence of HCC right after DAA therapy..., Ooka [/bib_ref] [bib_ref] Long-term follow-up of clinical trial patients treated for chronic HCV infection with..., Reddy [/bib_ref] [bib_ref] Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting..., Ogawa [/bib_ref] [bib_ref] Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting..., Calvaruso [/bib_ref]. In real-life settings, if these are actual cases, this incidence could be a shocking event to patients as well to attending physicians. This prompted us to collect data and provide a compact APASL practice guidelines.
In addition, in Asian countries, co-infections of HBV and HCV are more frequently observed. We are likely the first to elucidate the effects of DAA on the replication of HBV by such a high SVR for HCV. Therefore, we have also proposed a compact recommendation on how to follow co-infected patients.

## Part i

## Risk factors for the occurrence of hcc
These days, most patients seen at outpatient clinics are those whose HCV has been eradicated by the use of DAAs. Although more recent clinical studies and real-world studies have reported that DAA therapy decreased the risk of both de novo HCC and recurrent HCC in both cirrhotic and noncirrhotic patients with HCV infection, several preliminary studies have dealt with the risk factors for the occurrence of HCC [bib_ref] Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents, Kanwal [/bib_ref] [bib_ref] Prediction of the very early occurrence of HCC right after DAA therapy..., Ooka [/bib_ref] [bib_ref] Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting..., Ogawa [/bib_ref] [bib_ref] Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting..., Calvaruso [/bib_ref]. These studies revealed that male gender, older age, alcohol abuse, diabetes mellitus, and the existence of cirrhosis are associated with the occurrence of Risk factors and odds ratio for HCC in direct-acting antiviral (DAA) combination-treated patients [bib_ref] Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents, Kanwal [/bib_ref] [bib_ref] Prediction of the very early occurrence of HCC right after DAA therapy..., Ooka [/bib_ref] [bib_ref] Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting..., Ogawa [/bib_ref] [bib_ref] Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting..., Calvaruso [/bib_ref] AFP -fetoprotein, EOT end of treatment, n number HCC [bib_ref] Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents, Kanwal [/bib_ref] [bib_ref] Prediction of the very early occurrence of HCC right after DAA therapy..., Ooka [/bib_ref] [bib_ref] Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting..., Ogawa [/bib_ref] [bib_ref] Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting..., Calvaruso [/bib_ref]. Most of these studies were conducted 1-2 years after DAA treatment [bib_ref] Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with..., Jacobson [/bib_ref] [bib_ref] Long-term follow-up of clinical trial patients treated for chronic HCV infection with..., Reddy [/bib_ref]. Similar factors were also shown to be associated with increased HCC risk during the interferon era [bib_ref] Time-Degenerative Factors and the Risk of Hepatocellular Carcinoma after Antiviral Therapy among..., Yu [/bib_ref] [bib_ref] Long-term effect of sustained virological response on hepatocellular carcinoma in patients with..., Janjua [/bib_ref]. However, in addition to the abovementioned parameters, there is some dispute regarding the difference in occurrence of HCC between patients with and without previous HCC history [bib_ref] Unexpected high rate of early tumor recurrence in patients with HCV-related HCC..., Reig [/bib_ref] [bib_ref] Hepatocellular carcinoma recurrence after treatment with directacting antivirals: First, do no harm..., Torres [/bib_ref] [bib_ref] Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with..., Conti [/bib_ref] [bib_ref] Is the risk of neoplastic recurrence increased after prescribing direct-acting antivirals for..., Zavaglia [/bib_ref]. Thus, we conducted a literature search, investigating the occurrence of HCC in DAA-treated patients with and without previous HCC history [fig_ref] Table 2: Occurrence of hepatocellular carcinoma [/fig_ref] [bib_ref] The impact of direct-acting antivirals on early tumor recurrence after radiofrequency ablation..., Minami [/bib_ref] [bib_ref] Unexpected high rate of early tumor recurrence in patients with HCV-related HCC..., Reig [/bib_ref] [bib_ref] Hepatocellular carcinoma recurrence after treatment with directacting antivirals: First, do no harm..., Torres [/bib_ref] [bib_ref] Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with..., Conti [/bib_ref] [bib_ref] Hepatocellular carcinoma recurrence after direct antiviral agent treatment: A European multicentre study, Kolly [/bib_ref] [bib_ref] High incidence of hepatocellular carcinoma following successful interferon-free antiviral therapy for hepatitis..., Cardoso [/bib_ref] [bib_ref] Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype..., Calleja [/bib_ref] [bib_ref] Direct-acting antivirals decreased tumor recurrence after initial treatment of hepatitis C virus-related..., Ikeda [/bib_ref] [bib_ref] Interferon-free therapy of chronic hepatitis C with directacting antivirals does not change..., Mettke [/bib_ref] [bib_ref] Rapidly growing, moderately differentiated HCC: A clinicopathological characteristic of HCC occurrence after..., Nakao [/bib_ref] [bib_ref] Effect of interferon-based and -free therapy on early occurrence and recurrence of..., Nagata [/bib_ref] [bib_ref] Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents, Kanwal [/bib_ref] [bib_ref] HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular..., Ioannou [/bib_ref] [bib_ref] Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by..., Cabibbo [/bib_ref] [bib_ref] Prediction of the very early occurrence of HCC right after DAA therapy..., Ooka [/bib_ref] [bib_ref] Long-term follow-up of clinical trial patients treated for chronic HCV infection with..., Reddy [/bib_ref] [bib_ref] Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting..., Ogawa [/bib_ref] [bib_ref] Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting..., Calvaruso [/bib_ref]. A summary of the collected data is described in the following sections.

## Occurrence of hcc in patients without previous hcc history
The occurrence of HCC after SVR in patients without previous HCC history was reported in ten studies [fig_ref] Table 3: Occurrence of hepatocellular carcinoma [/fig_ref]. In those 10 studies, the total number of SVR patients ranged from 54 to 19,909 patients (mean: 4587 patients). The mean follow-up period of those studies was 18.2 months (range 9-36 months) post-DAA initiation. The overall occurrence rate of HCC after SVR in 45,870 patients without previous HCC history was 604 (1.3%) (range 0.9-7.4%) [fig_ref] Table 3: Occurrence of hepatocellular carcinoma [/fig_ref] [bib_ref] Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with..., Conti [/bib_ref] [bib_ref] High incidence of hepatocellular carcinoma following successful interferon-free antiviral therapy for hepatitis..., Cardoso [/bib_ref] [bib_ref] Interferon-free therapy of chronic hepatitis C with directacting antivirals does not change..., Mettke [/bib_ref] [bib_ref] Effect of interferon-based and -free therapy on early occurrence and recurrence of..., Nagata [/bib_ref] [bib_ref] Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents, Kanwal [/bib_ref] [bib_ref] HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular..., Ioannou [/bib_ref] [bib_ref] Prediction of the very early occurrence of HCC right after DAA therapy..., Ooka [/bib_ref] [bib_ref] Long-term follow-up of clinical trial patients treated for chronic HCV infection with..., Reddy [/bib_ref] [bib_ref] Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting..., Ogawa [/bib_ref] [bib_ref] Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting..., Calvaruso [/bib_ref]. Thus, the annual occurrence rate of SVR patients by DAA without previous HCC history is no different from that of the interferon era [bib_ref] Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of..., Yoshida [/bib_ref] [bib_ref] Long-term effects of interferon-based therapy for chronic hepatitis C, Yu [/bib_ref] [bib_ref] Outcome of sustained virological responders with histologically advanced chronic hepatitis C, Morgan [/bib_ref] [bib_ref] Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in..., Nishiguchi [/bib_ref] [bib_ref] Tenyear follow-up analysis of chronic hepatitis C patients after getting sustained virological..., Wang [/bib_ref] [bib_ref] A risk for hepatocellular carcinoma persists long-term after sustained virologic response in..., Aleman [/bib_ref]. Therefore, the same guidelines and recommendations as were present in the time of interferon may apply to patients treated by DAAs, if there is no previous experience of HCC. Of course, regular follow-ups are necessary, according to the routinely set rules of the interferon era, especially among HCV patients with advanced liver fibrosis or cirrhosis [fig_ref] Table 3: Occurrence of hepatocellular carcinoma [/fig_ref] [bib_ref] Predictors of the efficacy of interferon therapy for patients with chronic hepatitis..., Shiratori [/bib_ref] [bib_ref] Asian Pacific association for the study of the liver consensus recommendations on..., Omata [/bib_ref].

## Occurrence of hcc in patients with previous hcc history
The occurrence of HCC after DAA treatment and SVR in patients with previous HCC history was reported in six studies [bib_ref] Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with..., Conti [/bib_ref] [bib_ref] Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype..., Calleja [/bib_ref] [bib_ref] Direct-acting antivirals decreased tumor recurrence after initial treatment of hepatitis C virus-related..., Ikeda [/bib_ref] [bib_ref] Effect of interferon-based and -free therapy on early occurrence and recurrence of..., Nagata [/bib_ref] [bib_ref] Prediction of the very early occurrence of HCC right after DAA therapy..., Ooka [/bib_ref] [bib_ref] Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting..., Ogawa [/bib_ref]. The total number of SVR patients ranged from 53 to 155 patients (mean: 100 patients). The mean follow-up period of these studies was 15.4 months (range 9-28 months) post-DAA initiation. The overall occurrence rate of HCC after DAA treatment and SVR in patients with previous HCC history was [bib_ref] Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents, Kanwal [/bib_ref].6% (178/602) (range 17.1-71.6%) [bib_ref] Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with..., Conti [/bib_ref] [bib_ref] Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype..., Calleja [/bib_ref] [bib_ref] Direct-acting antivirals decreased tumor recurrence after initial treatment of hepatitis C virus-related..., Ikeda [/bib_ref] [bib_ref] Effect of interferon-based and -free therapy on early occurrence and recurrence of..., Nagata [/bib_ref] [bib_ref] Prediction of the very early occurrence of HCC right after DAA therapy..., Ooka [/bib_ref] [bib_ref] Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting..., Ogawa [/bib_ref].
The very high incidence of HCC occurrence during and right after DAA treatment suggests that very careful attention should be paid to the possible occurrence of HCC in patients with previous HCC history.

# Discussion

## Risk of hcc occurrence among patients post-daa treatment
In the interferon era, male gender, older age, and the existence of cirrhosis and other factors were shown to be associated with risk factors of HCC occurrence [bib_ref] Predictors of the efficacy of interferon therapy for patients with chronic hepatitis..., Shiratori [/bib_ref] [bib_ref] Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis..., El-Serag [/bib_ref] [bib_ref] Stagnation of histopathological improvement is a predictor of hepatocellular carcinoma development after..., Motoyama [/bib_ref]. Also in the age of DAAs, similar factors are shown to be associated with this risk. In other words, the existence of cirrhosis, no SVR, male gender, alcohol abuse, older age, and diabetes mellitus are risk factors for HCC occurrence [bib_ref] Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents, Kanwal [/bib_ref] [bib_ref] Prediction of the very early occurrence of HCC right after DAA therapy..., Ooka [/bib_ref] [bib_ref] Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting..., Ogawa [/bib_ref] [bib_ref] Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting..., Calvaruso [/bib_ref]. Surveillance is recommended for SVR patients with any histologic stage of HCV with comorbidities, such as alcohol abuse and diabetes mellitus [bib_ref] Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017..., Omata [/bib_ref].
Of note, most importantly, the current survey revealed that the existence of previous HCC history is an independent, very high-risk factor for HCC occurrence post-DAA treatment.
In the interferon era, because the treatment duration was longer than that of DAA, several studies seemed to exclude HCC occurrence during and right after interferon treatment when analyzing their data. In fact, during the interferon era, many patients with HCC or cirrhosis could not receive interferon treatment. To some extent, this might explain the lower occurrence of HCC during or right after antiviral treatment.
It has been reported that several mechanisms may exist during and after DAA treatment, such as rapid immunological changes, that could lead to HCC occurrence [bib_ref] Rapid hepatitis C virus clearance by antivirals correlates with immune status of..., Sasaki [/bib_ref] [bib_ref] Temporal dynamics of inflammatory cytokines/ chemokines during sofosbuvir and ribavirin therapy for..., Carlin [/bib_ref] [bib_ref] Direct-acting antiviral-induced hepatitis C virus clearance does not completely restore the altered..., Hengst [/bib_ref] [bib_ref] Interferon-free treatment for hepatitis C virus infection induces normalization of extrahepatic type..., Sung [/bib_ref] [bib_ref] IFN-free therapy is associated with restoration of type I IFN response in..., Carlton-Smith [/bib_ref]. Changes in cytokines and chemokines have been observed in HCC occurrence post-DAA treatment and it is possible that they may have affected tumor immunity [bib_ref] Rapid hepatitis C virus clearance by antivirals correlates with immune status of..., Sasaki [/bib_ref] [bib_ref] Temporal dynamics of inflammatory cytokines/ chemokines during sofosbuvir and ribavirin therapy for..., Carlin [/bib_ref] [bib_ref] Direct-acting antiviral-induced hepatitis C virus clearance does not completely restore the altered..., Hengst [/bib_ref] [bib_ref] Interferon-free treatment for hepatitis C virus infection induces normalization of extrahepatic type..., Sung [/bib_ref] [bib_ref] IFN-free therapy is associated with restoration of type I IFN response in..., Carlton-Smith [/bib_ref].
DAA treatment increased the serum vascular endothelial growth factor (VEGF) level which is significantly related to the serum angiopoietin-2 level. These are risk factors for HCC occurrence post-DAA treatment [bib_ref] DAAs rapidly reduce inflammation but increase serum VEGF level: a rationale for..., Villani [/bib_ref] [bib_ref] Liver angiopoietin-2 is a key predictor of de novo or recurrent hepatocellular..., Faillaci [/bib_ref]. Rapid immunological changes, including in NKG2D systems, are also observed during and after DAA treatment [bib_ref] On-treatment decrease of NKG2D correlates to early emergence of clinically evident hepatocellular..., Chu [/bib_ref] [bib_ref] Dynamic changes in innate immune responses during direct-acting antiviral therapy for HCV..., Holmes [/bib_ref]. With such drastic "environmental changes" occurring in the liver due to the very powerful DAAs, pre-existing "occult neoplastic" or "dysplastic" cells may develop into classical tumors in a short time period. Ooka et al. reported that "dysplastic" nodules detected by ultrasonography (US) might turn into hyper-vascular "classical" HCC by rapid decrease of the immune surveillance system with rapid elimination of HCV [bib_ref] Prediction of the very early occurrence of HCC right after DAA therapy..., Ooka [/bib_ref] [bib_ref] Rapid hepatitis C virus clearance by antivirals correlates with immune status of..., Sasaki [/bib_ref] [bib_ref] Impact of previously cured hepatocellular carcinoma (HCC) on new development of HCC..., Toyoda [/bib_ref]. Studies have proposed that the presence of "dysplastic" nodules by US has a much higher odds ratio (26 times) than previous HCC history [bib_ref] Prediction of the very early occurrence of HCC right after DAA therapy..., Ooka [/bib_ref] [bib_ref] Natural history of large regenerative nodules and dysplastic nodules in liver cirrhosis:..., Sato [/bib_ref].
In fact, approximately 50% of HCC occurrence and recurrence cases are observed during and 1-2 years after DAA treatment [bib_ref] Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with..., Conti [/bib_ref] [bib_ref] Long-term follow-up of clinical trial patients treated for chronic HCV infection with..., Reddy [/bib_ref]. Although it is well known that patients with mild/no fibrosis and SVR have a lower risk of developing HCC, population-based studies were different from clinical practice guidelines. So, we recommend that, for patients with SVR and risk factors of HCC, surveillance for HCC should be conducted at shorter intervals, and especially within 2 years post-DAA treatment.
How to follow these patients? Among imaging modalities (US, CT, and MRI), US might be the most cost-effective and easily available modality.
The prognosis of HCC depends on earlier-stage detection and earlier treatment [bib_ref] Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017..., Omata [/bib_ref]. In addition to US, measurement of tumor markers may play a more important role in HCC screening. Among tumor markers for the diagnosis of HCC, measurement of AFP has been performed for decades [bib_ref] Serum alpha-fetoprotein has high specificity for the early detection of hepatocellular carcinoma..., Minami [/bib_ref] [bib_ref] -fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis..., Asahina [/bib_ref] , although with some dispute regarding its significance. However, there have been numerous studies regarding multiple tests including lens culinaris agglutinin (LCA)-reactive AFP isoform (AFP-L3), which can differentiate an increase in AFP due to HCC from that in patients with benign liver disease. In addition, des--carboxy prothrombin (DCP) is a very powerful measure for detecting early and small tumors [bib_ref] Fucosylated alpha-fetoprotein as marker of early hepatocellular carcinoma, Aoyagi [/bib_ref] [bib_ref] Prognostic significance of Lens culinaris agglutinin A-reactive alpha-fetoprotein in small hepatocellular carcinomas, Yamashita [/bib_ref] [bib_ref] Serum des-gamma-carboxy prothrombin levels determined by a new generation of sensitive immunoassays..., Nomura [/bib_ref] [bib_ref] High-sensitivity Lens culinaris agglutinin-reactive alpha-fetoprotein assay predicts early detection of hepatocellular carcinoma, Kumada [/bib_ref] [bib_ref] Clinical significance of simultaneous determinations of alphafetoprotein and des-gamma-carboxy prothrombin in monitoring..., Aoyagi [/bib_ref] [bib_ref] Diagnostic accuracy of tumor markers for hepatocellular carcinoma: a systematic review, Tateishi [/bib_ref] [bib_ref] Double-and triple-positive tumor markers predict early recurrence and poor survival in patients..., Ryu [/bib_ref]. These studies are mostly from Japan, and these two tests, AFP-L3 and DCP, could not be validated as they have not been available in many countries. However, AFP, AFP-L3, and DCP tests have now become increasingly available in many Asian countries. Thus, we recommended the measurements of these markers.
Once a blood test result is abnormal, further imaging modalities [gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI and/or dynamic CT] should be performed for the potential diagnosis of HCC occurrence [bib_ref] Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017..., Omata [/bib_ref] [bib_ref] Prediction of the very early occurrence of HCC right after DAA therapy..., Ooka [/bib_ref].
Thus, in patients with previous HCC history, surveillance of shorter 4-month intervals for HCC, including US with AFP, AFP-L3, and/or DCP, should be performed [bib_ref] Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017..., Omata [/bib_ref].
After successful eradication of HCV, regular follow-up of HCC, esophageal varices, and other complications of advanced liver fibrosis will be necessary if they existed at pre-treatment [bib_ref] The course of esophageal varices in patients with hepatitis C cirrhosis responding..., Aghemo [/bib_ref] [bib_ref] Effects of eradicating hepatitis C virus Infection in patients with cirrhosis differ..., Marco [/bib_ref] [bib_ref] Effects of All-Oral Anti-Viral Therapy on HVPG and Systemic Hemodynamics in Patients..., Lens [/bib_ref].

## #1 consensus statements and recommendations on follow-up of daa-treated virus-eradicated hcv-infected patients
1. In patients without advanced liver fibrosis, or cirrhosis and without previous HCC history (1) Before, during, and approximately 2 years after the end of treatment (EOT) with DAA, surveillance at 6-month intervals for HCC, including ultrasonography (US) with or without tumor markers, should be performed (C-2). (2) After 2 years, surveillance at 12-month intervals for HCC, including US with or without AFP, could be performed (C-2).
2. In patients with advanced liver fibrosis or cirrhosis and without previous HCC history Surveillance at 6-month intervals for HCC, including by US with AFP, lens culinaris agglutinin (LCA)reactive AFP isoform (AFP-L3) and/or des--carboxy prothrombin (DCP) should be performed (A-1).

## In patients with previous hcc history
Surveillance at 4-month intervals for HCC, including by US with AFP, AFP-L3 and/or DCP, should be performed. In these cases, contrast-enhanced US (CEUS), dynamic CT, dynamic MRI or gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)enhanced MRI could be added (A-2). 4. SVR patients with alcohol abuse and/or diabetes mellitus should undergo surveillance for HCC regularly (A-1). 5. In patients with advanced liver fibrosis or cirrhosis, screening for esophageal and gastric varices by endoscopy should be performed especially if present at pretreatment (A-1). .

## Grading of evidence and recommendations are shown in

## Part ii

## Hbv reactivation in patients with hcv and hbv co-infection
HBV infection is one of the major health problems in the world, with the highest rates being in Africa and the Asia-Pacific region [bib_ref] Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015..., Sarin [/bib_ref]. Evaluation for HBV infection was also recommended for all persons with active HCV infection by the US Food and Drug Administration in 2004. However, the exact prevalence and characteristics of HBV DNA reappearance and clinical "reactivation" among patients treated by DAAs are not known in detail.
Therefore, we collected data from 14 studies on HBV DNA reappearance and clinical reactivation in HBV and HCV co-infected patients treated by DAAs [bib_ref] Ledipasvir and sofosbuvir for HCV infection in patients coinfected with HBV, Gane [/bib_ref] [bib_ref] Frequency of, and factors associated with, hepatitis B virus reactivation in hepatitis..., Doi [/bib_ref] [bib_ref] Comparing the risk of hepatitis B virus reactivation between direct-acting antiviral therapies..., Kawagishi [/bib_ref] [bib_ref] Reactivation of hepatitis B in patients of chronic hepatitis C with hepatitis..., Yeh [/bib_ref] [bib_ref] No evidence of hepatitis B virus reactivation in patients with resolved infection..., Mucke [/bib_ref] [bib_ref] Hepatitis due to reactivation of hepatitis B virus in endemic areas among..., Wang [/bib_ref] [bib_ref] Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients..., Tamori [/bib_ref] [bib_ref] Efficacy of ledipasvir and sofosbuvir treatment of HCV infection in patients coinfected..., Liu [/bib_ref] [bib_ref] Potential risk of HBV reactivation in patients with resolved HBV infection undergoing..., Ogawa [/bib_ref].

## Hbsag-positive group
Of these 14 studies, 8 reported the results of HBV DNA reappearance and clinical reactivation in HBsAg-positive patients treated by DAAs [bib_ref] Ledipasvir and sofosbuvir for HCV infection in patients coinfected with HBV, Gane [/bib_ref] [bib_ref] Frequency of, and factors associated with, hepatitis B virus reactivation in hepatitis..., Doi [/bib_ref] [bib_ref] Comparing the risk of hepatitis B virus reactivation between direct-acting antiviral therapies..., Kawagishi [/bib_ref] [bib_ref] Reactivation of hepatitis B in patients of chronic hepatitis C with hepatitis..., Yeh [/bib_ref] [bib_ref] No evidence of hepatitis B virus reactivation in patients with resolved infection..., Mucke [/bib_ref] [bib_ref] Hepatitis due to reactivation of hepatitis B virus in endemic areas among..., Wang [/bib_ref] [bib_ref] Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients..., Tamori [/bib_ref] [bib_ref] Efficacy of ledipasvir and sofosbuvir treatment of HCV infection in patients coinfected..., Liu [/bib_ref]. The number of patients enrolled in those 8 studies ranged from 4 to 109 patients (mean 20) and the mean observation period was 3 months post-EOT. The overall occurrence rate of HBV DNA reappearance and clinical reactivation among 162 patients treated by DAA was 41.4% (67/162) (range 25-100%). Thus, among HBsAg-positive patients, HBV DNA reappearance and reactivation are the frequent events through at least 12 weeks after EOT .

## Hbsag-negative group (anti-hbc-and/or anti-hbs-positive group)
Of the 14 studies , 6 studies reported results on HBV DNA reappearance and clinical reactivation in HBsAgnegative, but positivity for anti-hepatitis B core (anti-HBc) antibody and/or anti-hepatitis B surface (anti-HBs) antibody at baseline .
The number of patients enrolled in those 6 studies ranged from 57 to 765 patients (mean 219.5) and the mean observation period was 3 months post-EOT. The overall occurrence rate of HBV DNA reappearance and clinical reactivation among 1317 patients treated by DAAs was 0.91% (12/1317) (range 0-6.3%) . Thus, in HBsAg-negative patients but positive for anti-HBc antibody and/or anti-HBs antibody Hepatitis B virus (HBV) reactivation or HBV DNA reappearance in patients with HBV and hepatitis C virus (HCV) co-infection after direct-acting antiviral (DAA) treatment [bib_ref] Ledipasvir and sofosbuvir for HCV infection in patients coinfected with HBV, Gane [/bib_ref] [bib_ref] Frequency of, and factors associated with, hepatitis B virus reactivation in hepatitis..., Doi [/bib_ref] [bib_ref] Comparing the risk of hepatitis B virus reactivation between direct-acting antiviral therapies..., Kawagishi [/bib_ref] [bib_ref] Reactivation of hepatitis B in patients of chronic hepatitis C with hepatitis..., Yeh [/bib_ref] [bib_ref] No evidence of hepatitis B virus reactivation in patients with resolved infection..., Mucke [/bib_ref] [bib_ref] Hepatitis due to reactivation of hepatitis B virus in endemic areas among..., Wang [/bib_ref] [bib_ref] Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients..., Tamori [/bib_ref] [bib_ref] Efficacy of ledipasvir and sofosbuvir treatment of HCV infection in patients coinfected..., Liu [/bib_ref] [bib_ref] Potential risk of HBV reactivation in patients with resolved HBV infection undergoing..., Ogawa [/bib_ref] HBsAg hepatitis B surface antigen, anti-HBc anti-hepatitis B core antibody, anti-HBs anti-hepatitis B surface antibody, EOT end of treatment, n number a Three patients (one with cirrhosis and two without cirrhosis) began anti-HBV treatment: one entecavir (ETV) and two tenofovir disoproxil fumarate (TDF) b Three patients (one with cirrhosis and two without cirrhosis) began TDF at baseline; HBV reactivation and/or HBV DNA reappearance are rare events through 12 weeks after EOT .

# Discussion

## Clinical pictures of hbv reactivation

## Hbsag-positive group
Before the rituximab (humanized anti-CD20 monoclonal antibody) era, Lau et al. reported that among 15 HBsAgpositive patients with lymphoma treated with chemotherapy but deferred prophylactic lamivudine therapy, 8 (53%) had HBV reactivation defined as an increase of serum HBV DNA to more than 10 times of baseline [bib_ref] Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients..., Lau [/bib_ref]. Of these eight patients, seven (87.5%) had 'hepatitis', defined as a more than threefold increase of serum ALT on two consecutive determinations at least 5 days apart. Of these seven patients, anicteric and icteric hepatitis and hepatic failure were 5, 1, and 1, respectively [bib_ref] Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients..., Lau [/bib_ref]. Thus, of HBsAg-positive patients with lymphoma treated by chemotherapy without nucleos(t) ide analogs, 6.7% (1/15) had hepatic failure [bib_ref] Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients..., Lau [/bib_ref]. They also observed that, among 15 patients with lymphoma who received lamivudine 1 week before chemotherapy, none had HBV reactivation after chemotherapy [bib_ref] Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients..., Lau [/bib_ref]. Lok et al. also observed 18 HBV reactivations (67%) [6 icteric hepatitis (22%); 1 non-fatal hepatic failure (3.7%); and 1 death (3.7%)] among 27 Chinese patients who underwent induction cytotoxic therapy without prophylaxis for HBsAg-positive malignant lymphoma [bib_ref] Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy, Lok [/bib_ref]. After rituximab was introduced as a potent drug for patients with malignant lymphoma, reactivation of HBV has been repeatedly shown in HBsAg-positive patients. Wang et al. reported that rituximab/chemotherapy induced hepatic dysfunction in 13 (33%) of 40 HBsAg-positive patients with diffuse large B cell lymphoma [bib_ref] Clinical and prognostic analysis of hepatitis B virus infection in diffuse large..., Wang [/bib_ref].
HBV reactivation has also been reported in HBsAg-positive solid cancer patients who underwent chemotherapy or other molecular target therapies [bib_ref] Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015..., Sarin [/bib_ref]. Among HBsAg-positive breast cancer patients receiving chemotherapy, the rates of HBV reactivation in patients without or with prophylactic lamivudine were 28.6% and 0%, respectively [bib_ref] A single-center, prospective and randomized controlled study: can the prophylactic use of..., Long [/bib_ref]. HBV reactivation during chemotherapy occurred independently of lymphoma (odds ratio: 5.0), breast cancer (odds ratio: 4.2), steroid use (odds ratio: 2.7), and HBV DNA positive at baseline (odds ratio: 8.4) [bib_ref] Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation..., Yeo [/bib_ref].
Thus, APASL HBV guidelines have recommended that prophylactic nucleos(t)ide therapy should be given to HBsAg-positive cancer patients who receive cytotoxic and immunosuppressive therapy, regardless of HBV DNA levels for 12 months after cessation [bib_ref] Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015..., Sarin [/bib_ref].
Regarding the treatment by DAAs for those co-infected with HBV and HCV, a variety of events, ranging from asymptomatic HBV reactivation/HBV DNA reappearance to clinically symptomatic reactivation characterized by elevation in HBV DNA and ALT were reported [bib_ref] Ledipasvir and sofosbuvir for HCV infection in patients coinfected with HBV, Gane [/bib_ref] [bib_ref] Frequency of, and factors associated with, hepatitis B virus reactivation in hepatitis..., Doi [/bib_ref] [bib_ref] Comparing the risk of hepatitis B virus reactivation between direct-acting antiviral therapies..., Kawagishi [/bib_ref] [bib_ref] Reactivation of hepatitis B in patients of chronic hepatitis C with hepatitis..., Yeh [/bib_ref] [bib_ref] No evidence of hepatitis B virus reactivation in patients with resolved infection..., Mucke [/bib_ref] [bib_ref] Hepatitis due to reactivation of hepatitis B virus in endemic areas among..., Wang [/bib_ref] [bib_ref] Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients..., Tamori [/bib_ref] [bib_ref] Efficacy of ledipasvir and sofosbuvir treatment of HCV infection in patients coinfected..., Liu [/bib_ref].
Collected results of eight studies of HBsAg-positive and co-infected patients treated with DAAs for HCV infection indicated that the rates of HBV reactivation were similar to HBsAg-positive patients with malignant lymphoma and cancer patients treated with cytotoxic drugs (~ 40%) [bib_ref] Hepatitis B virus reactivation in breast cancer patients undergoing chemotherapy: a review..., Liu [/bib_ref] [bib_ref] Hepatitis B virus carriers in the treatment of malignant lymphoma: an epidemiological..., Kumagai [/bib_ref] (also see .
Regarding the severity of liver disease induced by this HBV reactivation in HBsAg-positive patients treated with DAAs, only limited data are available [bib_ref] Hepatitis due to reactivation of hepatitis B virus in endemic areas among..., Wang [/bib_ref] [bib_ref] Efficacy of ledipasvir and sofosbuvir treatment of HCV infection in patients coinfected..., Liu [/bib_ref] [bib_ref] Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis..., Bersoff-Matcha [/bib_ref] [bib_ref] Hepatitis B reactivation during or after direct acting antiviral therapy-implication for susceptible..., Holmes [/bib_ref] [bib_ref] Direct-acting antiviral treatment in adults infected with hepatitis C virus: reactivation of..., De Monte [/bib_ref]. Bersoff-Matcha et al. reported that two cases with liver failure resulted in one death and one case of liver transplantation [bib_ref] Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis..., Bersoff-Matcha [/bib_ref]. Wang et al. also reported one HBsAg-positive patient with liver failure due to HBV reactivation although most reported cases were asymptomatic increases of HBV DNA and/or ALT in the absence of concomitant liver injury [bib_ref] Hepatitis due to reactivation of hepatitis B virus in endemic areas among..., Wang [/bib_ref].
Of note, Liu et al. reported that two patients had concomitant elevation of HBV DNA level with ALT elevation > 2 times the upper limit of normal at post-treatment week 48, of whom one commenced treatment with entecavir at posttreatment week 53 following the onset of malaise, anorexia, and nausea associated with sclera jaundice [bib_ref] Efficacy of ledipasvir and sofosbuvir treatment of HCV infection in patients coinfected..., Liu [/bib_ref]. Holmes et al. reviewed two HBsAg-positive, co-infected patients who were treated by DAAs for HCV infection, and had fulminant hepatic failure and death: one was a 57-year-old female who was treated with daclatasvir plus asunaprevir, had HBV reactivation at week 8 from the start of DAAs, and she was treated with entecavir; the other was a 73-year-old female who was treated with daclatasvir plus asunaprevir, had HBV reactivation at week 7 from the start of DAAs, and she had stopped entecavir prior to the commencement of DAA therapy [bib_ref] Hepatitis B reactivation during or after direct acting antiviral therapy-implication for susceptible..., Holmes [/bib_ref].
At present, we do not know the risk factors of HBV reactivation and associated liver failure, although several factors such as HBsAg levels and HBV DNA levels have been reported [bib_ref] Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients..., Tamori [/bib_ref] [bib_ref] Hepatitis B virus reactivation in patients receiving interferonfree direct-acting antiviral agents for..., Liu [/bib_ref].
For the safety of HBsAg-positive patients treated by DAAs, we recommend that prophylactic nucleos(t)ide therapy should be given before starting DAA therapy; nonetheless, further studies may also be needed to determine the duration of prophylactic nucleos(t)ide therapy.

## Hbsag-negative, but positive for anti-hbc and/or anti-hbs group
Although the elimination of HBsAg is one of the goals in the treatment of HBV infection, HBV DNA reappeared in 15-33% patients after HBsAg seroclearance in the natural history of HBV infection and in post-anti-HBV treatment [bib_ref] Reappearance of serum hepatitis B viral DNA in patients with hepatitis B..., Nakamura [/bib_ref]. So, it is possible that HBV reactivation and/or HBV DNA reappearance may occur in patients of this group treated by DAAs, as well as patients who receive immunosuppressants or anti-cancer drugs [fig_ref] Table 6: HBV reactivation in HBsAg-negative patients treated for lymphoma and solid tumors [/fig_ref].
With the administration of rituximab without antiviral treatment, clinical HBV reactivation was estimated at 6.3% in HBsAg-negative/anti-HBc-positive patients with lymphoma [bib_ref] Hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma: a meta-analysis, Mozessohn [/bib_ref]. Prior to use of rituximab, Lok et al. also observed 10 HBV reactivations (14%) [1 icteric hepatitis (2%); 1 non-fatal hepatic failure (2%); and no death (0%)] of 72 HBsAg-negative patients with malignant lymphoma treated by chemotherapy without prophylactic treatment of nucleos(t)ide analogs [fig_ref] Table 6: HBV reactivation in HBsAg-negative patients treated for lymphoma and solid tumors [/fig_ref] [bib_ref] Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy, Lok [/bib_ref].
Thus, in the rituximab era, once HBsAg-negative patients who received rituximab including chemotherapy for malignant lymphoma had HBV reactivation (6.3-17.9%) [fig_ref] Table 6: HBV reactivation in HBsAg-negative patients treated for lymphoma and solid tumors [/fig_ref] [bib_ref] Hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma: a meta-analysis, Mozessohn [/bib_ref] [bib_ref] Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation..., Huang [/bib_ref] [bib_ref] Randomized prospective study evaluating tenofovir disoproxil fumarate prophylaxis against hepatitis B virus..., Buti [/bib_ref] , higher mortality rates (12.5-50%) were seen [bib_ref] Reactivation of hepatitis B virus following systemic chemotherapy for malignant lymphoma, Kusumoto [/bib_ref].
In breast cancer, HBV fetal reactivation was occasionally observed in HBsAg-negative patients who underwent chemotherapy [bib_ref] Hepatitis B virus reactivation in adjuvant chemotherapy for breast cancer, Ide [/bib_ref]. [bib_ref] HBV reactivation risk factors in patients with chronic HBV infection with low..., Jun [/bib_ref]. Of note, the incidence of HBV reactivation in these HBsAgnegative patients was not low (5.9%) [bib_ref] HBV reactivation risk factors in patients with chronic HBV infection with low..., Jun [/bib_ref] [bib_ref] Hepatitis B reactivation in patients receiving immunosuppressive therapy: a hidden menace, Lin [/bib_ref] , although most patients with solid cancers remained unscreened for HBV-resolved infection [bib_ref] Trends in hepatitis B virus screening at the onset of chemotherapy in..., Hwang [/bib_ref] [bib_ref] Prevention and management of hepatitis B virus reactivation in cancer patients, Cheung [/bib_ref].
A summary of six studies of HBsAg-negative cases indicates that the overall occurrence rate of HBV reactivation and/or HBV DNA reappearance is lower (0.91%) .
The prevalence rates of HBV reactivation and/or HBV DNA reappearance in patients of the HBsAg-negative/anti-HBc-positive group by DAAs seem equal to or less than those with chemotherapy for breast cancer, one of the nonhematologic malignancies.
Regarding the severity of liver disease induced by this HBV reactivation in HBsAg-negative patients treated by DAA, only limited data are available [bib_ref] Fulminant hepatitis B reactivation leading to liver transplantation in a patient with..., Ende [/bib_ref] [bib_ref] A case of acute hepatitis B in a chronic hepatitis C patient..., Hayashi [/bib_ref]. Two HBsAg-negative patients who developed hepatic failure after DAA treatment have been reported [bib_ref] Fulminant hepatitis B reactivation leading to liver transplantation in a patient with..., Ende [/bib_ref] [bib_ref] A case of acute hepatitis B in a chronic hepatitis C patient..., Hayashi [/bib_ref]. We do not know the exact risk factors of HBV reactivation in HBsAg-negative patients treated with DAAs although several factors have been reported .
There are no standard management regimens for HBV reactivation among HBsAg-negative patients, even for those treated with rituximab including chemotherapy. It has been reported that monthly monitoring of HBV DNA is useful for preventing HBV reactivation-related hepatitis among B cell non-Hodgkin lymphoma patients with resolved HBV infection following rituximab plus corticosteroid including chemotherapy [bib_ref] Monitoring of hepatitis B virus (HBV) DNA and risk of HBV reactivation..., Kusumoto [/bib_ref].
Physicians should be aware of the risk of HBV reactivation in HBsAg-negative patients. Although further studies are needed to compare the efficacy and cost effectiveness of different preventive strategies, we should at least perform careful monitoring of these patients, and if needed, we should administer nucleos(t)ide analogs against HBV DNA reactivation/reappearance. Regarding nucleos(t)ide analogs, as lamivudine and telbivudine are limited, entecavir or tenofovir would be preferred.

## #2 consensus statements and recommendations on follow-up of hbv and hcv co-infected patients treated with daa in asia-pacific region
1. Before starting DAA treatment, HBsAg should be examined in high endemic areas of HBV infection (A-1). 2. In HBsAg-positive patients with advanced fibrosis, cirrhosis or previous HCC, pre-emptive nucleos(t)ide [bib_ref] Hepatitis B virus reactivation during anti-cancer chemotherapy in patients with past hepatitis..., Kim [/bib_ref] analog treatment should be started to prevent HBV reactivation (A-1). 3. In HBsAg-positive patients without advanced fibrosis, cirrhosis or previous HCC history, pre-emptive nucleos(t)ide analog treatment is effective for HBV infection , or close monitoring should be recommended during DAA treatment and through 24 weeks after EOT (B-1). Stopping should follow APASL HBV guidelines. 4. In HBsAg-negative patients who are positive for anti-HBc antibody and/or anti-HBs antibody when abnormal liver function tests are observed during DAA treatment and after EOT, HCV RNA, HBsAg and HBV DNA should be examined. Nucleos(t)ide analogs should be used to treat HBV reactivation (B-1).
Grading of evidence and recommendations are shown in .

# Conclusion
During DAA treatment, host immunological changes may occur although DAA treatment can lead to higher SVR rates with shorter treatment duration and less serious adverse events in most patients infected with HCV [bib_ref] Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic..., Lau [/bib_ref]. First, we have created guidelines for the monitoring of HCC occurrence based on its accumulated data for it . Second, we have constructed compact guidelines for patients with HBsAg and anti-HBc and/or anti-HBs antibody .
Funding None.

## Compliance with ethical standards
Conflict of interest Dr. Tatsuo Kanda received research grants from Merck Sharp and Dohme (MSD), Chugai Pharm, and AbbVie. Prof. Masao Omata received research grants from Gilead, Eisai, and Ono Pharma. The founding sponsors played no role in the study design, data collection, analyses, interpretation, writing of the manuscript, or in the decision to publish the results. The other authors have declared that there is no conflict of interest.
Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent Not necessary, see above.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
[table] Table 2: Occurrence of hepatocellular carcinoma (HCC) in patients with direct-acting antiviral (DAA) treatment and sustained virological response (SVR)[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] [/table]
[table] Table 3: Occurrence of hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment and sustained virological response (SVR) in patients without previous HCC history[21,23,26,[28][29][30][32][33][34][35] [/table]
[table] Table 6: HBV reactivation in HBsAg-negative patients treated for lymphoma and solid tumors [/table]