**4. Evaluating the Response to the Hepatitis D Treatment**

The only recognized available and effective drug against HDV is interferon alfa (IFNa), and it is recommended for patients with detectable HDV RNA and active liver disease (elevated serum aminotransferase and/or chronic hepatitis on liver biopsy) [43]. The treatment of chronic hepatitis D remains unsatisfactory and the eradication of HDV and HBV and prevention of the long-term sequelae of chronic hepatitis, such as cirrhosis, liver decompensation, and HCC are still not commonly achieved. Since the primary endpoint of treatment is suppression of HDV RNA, the standard of therapeutic success was defined as negative HDV RNA at 6 months (24 weeks) or more after treatment, known as a sustained virological response (SVR) [9,44]. Detectable HDV RNA at 6 months of treatment might be a predictor for a failed virological response [45]. Although achieving a negative HDV viremia is still considered a hallmark of treatment efficacy, several studies have shown that the only robust endpoint might differently be the clearance of the HBsAg [46,47]. It finally seems that the ideal goal of HDV treatment should be both the clearance of HBsAg and the sustained HDV virological response at least 6 months after stopping the treatment, and the attainment of both the aforementioned aims is truly challenging [48]. Moreover, together with a negative HDV viremia, a successful treatment is also associated with amelioration of necroinflammatory activity, defined as a sustained biochemical response (normalization of ALT and/or AST levels at six months or more after treatment) or histological response (improvement of inflammatory activity confirmed by liver biopsy). These goals are commonly considered as secondary outcomes measures in the available trials [45]. Taking these into account, Yurdaydin et al. recently proposed the evaluation of HDV treatment success based on the improvement of liver function rather than the virologic response. Relying on this unorthodox method, a decline of two or more logs of HDV RNA even without achieving a negative HDV RNA test might be sufficient, if ALT are normalized [7].

Therapeutic targets remain generally similar in the older and newer studies assessing the efficacy of HDV treatment. In any case, depending on the treatment aim (HDV-RNA long-term suppression, ALT normalization, etc.) and the degree of hepatic impairment, these novel regimens might potentially be successful, even more if additional strategies, as the combination of drugs, are implemented. Our expert opinion is that the primary goal would be, first of all, the functional cure of HBV.

#### **5. Finite Nucleos(t)ide Analog Therapy**

Long-term therapy with NA is effective in achieving viral suppression; however, this is not indicative of HBV eradication [49]. As highlighted by Papatheodoridi et al., several reasons have driven the emergent proposal to stop long-term NA therapy: the futility of continuing a therapy that does not offer any further benefit; the unknown safety of a lifetime NA therapy; the cumulative cost; the undoubted risk to occur through a decline of treatment adherence [50]. Despite the lack of a well-defined endpoint for HBV treatments, international guidelines unanimously consider HBsAg loss as the most important one [6]. However, Dusheiko et al. reported that HBsAg loss rates were <1% per year during NA treatment [6,51]. With this in mind, over the past 5–10 years, the finite NA treatment became a very interesting topic [6], and since 2016, the international guidelines have begun accepting finite NA therapy as an option in a specific subset of patients.

Although the approach of finite NA treatment is not completely uniform, there is a consistent agreement among different guidelines: finite NA therapy was suggested in not-cirrhotic patients with undetectable levels of HBV DNA(on three separate occasions, 6 months apart) after 12–18 months from HBeAb seroconversion (consolidation therapy) [52]. The Asian guidelines, in contrast to EASL and AASLD, consider finite NA treatment also in patients with cirrhosis [4,53–55]. After discontinuation, virological relapse is quite common; however, not all patients necessarily have a biochemical relapse, which means that not all patients require retreatment [53]. Although several studies have focused on identifying factors that might predict relapse after treatment discontinuation, at present, there is no reliable marker able to predict such a response [53]. Liu Y et al. performed a meta-analysis to evaluate those factors and data showed that older age, high levels of quantitative HBsAg (>1000 IU/mL) at baseline and at the end of treatment, and shorter duration of consolidation therapy result as factors predictive of relapse after NA discontinuation in HBeAg-negative CHB patients [56]. Certain viral markers have gained interest, such as the hepatitis B core-related antigen (HBcrAg), which seemed to serve as a useful marker on patients who are planning finite NA therapy. In particular, a decrease in HBcrAg levels was reported during NA therapy; Matsumoto et al. reported an experience from CHB patients treated with lamivudine where HbcrAg levels > 4.9 log U/mL at the time of NA discontinuation were correlated to clinical relapse. In contrast, HbcrAg levels < 3.4 log U/mL were the only independent predictive factor without relapse after NA cessation [57].

Moreover, immunological studies have highlighted the role of the host immune response as a pathobiological basis to facilitate HBsAg decline towards HBsAg loss [58]. Considering that, investigators have progressed to exploring immune biomarkers [53], such as soluble isoform of growth stimulation expressed gene 2 (ST2), which belongs to the Toll-like/interleukin-1 receptor superfamily. Xie et al. showed that ST2 was correlated with HBsAg, HBV DNA, ALT and anti-HBc levels. Although baseline levels of ST2 were not associated to clinical relapse, after 12 weeks after NA cessation, the level of ST2 was able to predict the clinical relapse [59].
