**1. Introduction**

Viral hepatitis has been recognized as a health and development priority only recently [1]. Most countries have implemented neonatal vaccination programs against hepatitis B virus (HBV) and reached a reduction in HBV prevalence among children; despite this, the burden this infection places, especially on the adult population, is still huge. In 2015, an estimated 257 million people were living with chronic HBV infection (CHB) worldwide, and its complications (especially long-term consequences, i.e., cirrhosis and hepatocellular carcinoma) were responsible for the 66% of the deaths caused by viral hepatitis; future perspectives are worrying, with 17 million deaths attributable to CHB in 2030 [2,3]. It is estimated that 5% of HBV-infected persons are also coinfected with hepatitis Delta virus (HDV) and have a more severe liver disease; however, there is substantial uncertainty, as in many countries, HDV infection is not tested [2].

Currently, the recommended treatment of choice for CHB regardless of the severity of the liver disease is the long-term administration of a nucleos(t)ide analog (NA) with a high barrier to resistance, such as entecavir, tenofovir disoproxil fumarate and telbivudine; alternatively, for patients with mild to moderate CHB, a 48 week-therapy with peginterferon alfa (PegIFNa) can be considered [4]. The main endpoint of all current treatment strategies is suppression of HBV DNA levels, as it is strongly associated with disease progression; however, this does not translate to an effective and complete cure of the HBV infection. Among the several barriers to cure, the most worrying one is the covalently closed circular DNA (cccDNA), which allows the virus to permanently persist in hepatocytes and against which NAs have little effect [5]. Moreover, NAs rarely achieve the so-called "functional cure", which was defined by clinical guidelines as seroclearance of hepatitis B surface antigen (HBsAg) with or without anti-HBs. Therefore, treatment is often lifelong and often leading to the selection of resistant mutants or causing side effects [4,6]. As for HDV infection, the ideal goal of treatment is the clearance of HBsAg plus a sustained HDV virological response at least 6 months after stopping the treatment, and the attainment of both the aforementioned aims is truly challenging. Pertaining to chronic HDV infection (CHD), the treatment of choice is a one year-course of PegIFNa, usually leading to a reduction of the HDV RNA viral load, but this may prove useless if not associated with

**Citation:** Zuccaro, V.; Asperges, E.; Colaneri, M.; Marvulli, L.N.; Bruno, R. HBV and HDV: New Treatments on the Horizon. *J. Clin. Med.* **2021**, *10*, 4054. https://doi.org/10.3390/ jcm10184054

Academic Editors: Pierluigi Toniutto and Tatsuo Kanda

Received: 8 August 2021 Accepted: 6 September 2021 Published: 8 September 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

a clearance of the HBsAg [7]. When compared to other viral chronic hepatitis, there are certainly fewer data on the PegIFNa efficacy for chronic hepatitis D. To date, the largest available trial includes a total of 38 participants. Treatment success was achieved in only eight patients (21%) after 24 weeks of follow-up (all patients were maintained on PegINFa for 48 weeks) [8]. A higher virological response rate (43%) after a 12-month-follow-up was instead found in a subsequent trial. Nevertheless, it was carried out in a restricted group of 14 patients [9]. The European Association for the Study of the Liver (EASL) guidelines suggest tenofovir or entecavir treatment for those patients not eligible for interferon-based therapy with detectable HBV DNA levels in order to block residual HBV replication, mainly in patients with decompensated liver disease [4]. Unsurprisingly, rather than an ineffective drug with a well-known toxicity, we support the search for new molecules.

Although there are multiple comprehensive literature reviews on chronic hepatitis B and D treatments, there are still several critical issues, which frequently remain uncovered.

As CHB is associated with aging population, individuals often have co-morbid health concerns. Although current and investigational therapies do not carry high risks of toxicities, attention should be paid to subsets of the population called special populations, such as HIV coinfected patients, children, pregnant women, immunosuppressed patients, and patients undergoing chemotherapy and dialysis. Moreover, the futility of long-term NA therapy has become a very interesting topic, and the approach of finite NA treatment is not completely uniform.

The purpose of our study is not only to overview the different therapeutic options for chronic hepatitis B and D but to focus on those critical issues especially.

#### **2. Overview of the Drug Pipeline**

To succeed in the cure of the chronic infection, the prevailing theory at the moment is that the combination of two different strategies is required [3,10]. On the one hand, the recent progress in understanding the structure and life cycle of the virus allowed the development of novel antivirals directly targeting multiple steps in the virus replication, preventing the synthesis of new cccDNA. On the other hand, immunomodulators are also needed to subvert the state of tolerance found in the chronic phase of the disease and consequently promote the death of infected hepatocytes and neutralization of circulating virions [5]. According to the latest update, more than 50 compounds are currently being tested for CHB, and the majority of the studies are in a preclinical phase [11].

Adding to an existing class of drugs, new nucleotides analogs in development include besifovir, metacavir and two prodrugs of tenofovir (tenofovir exalidex, tenofovir disoproxil orotate). However, it is now widely recognized that an efficacious therapy should target more than one step of the virus replication cycle. For this reason, other drugs currently in development include attachment/entry inhibitors, such as bulevirtide.

Myrcludex-B (Myr), also known as bulevirtide, acts upon the sodium taurocholate cotransporting polypeptide (NTCP), a receptor of both HBV and HDV. Therefore, this new drug might block HBV and HDV entry, and it was approved in the European Union in July 2020 as the first effective drug for the treatment of chronic HDV in patients with compensated liver disease [11,12]. In a phase 2a trial, patients were treated with Myr for 72 weeks, and a follow-up was planned 6 months after the end of treatment. The estimation of efficacy parameters was planned to be performed after 24 and 48 weeks of therapy and after the end of follow-up. The results, though, were published as interim findings at week 24 and showed that all patients with measurable HDV RNA experienced a decline of HDV RNA under Myr monotherapy, while, remarkably, the combination of Myr with PegIFNα-2a profoundly enhanced this antiviral effect, achieving a decline >1 log in HDV RNA in all the subjects. Finally, ALT levels significantly declined in six of the eight patients of the Myr cohort [13]. Regarding the reduction of >0.5 log HBsAg, which we already described as an alternative therapeutic target, none of the patients achieved this endpoint. Similarly, Wedemeyer et al. showed a HDV RNA declined by 2 log and a normalization of ALT levels in patients treated with Myr and tenofovir, but regrettably, HDV RNA replication relapsed

after the end of treatment in most of the patients and HBsAg remained unaffected [14]. Moreover, recent studies showed that the effect on HBsAg seemed to be more pronounced in the HDV patients receiving lower doses of Myr in combination with IFNa, rather than higher. The reason for this observation is not currently known.

Lonafarnib (LNF) is a farnesyl transferase inhibitor, which blocks assembly and secretion of virions in the cell (IC50: 36 nM) through the hepatitis delta antigen prenylation. LNF has been more extensively studied because of its potential activity in cancer patients and its proven efficacy in Hutchinson–Gilford progeria syndrome. In a phase 2a study, 14 patients were randomly assigned to receive LNF 100 mg or 200 mg twice daily for 28 days with greater decline in HDV RNA [15]. In a subsequent study, Yurdaydin et al. explored different potential LNF regimens: different doses of LNF, LNF plus ritonavir (RTV), LNF plus PEG-INF. A better antiviral response was achieved with the addition of RTV supporting the key role of the cytochrome P450 3A4 inhibitor and the need of exploration of boosting combinations [7].

Recently, nucleic acid polymers (NAPs), such REP 2139, have also been widely studied, showing promising results, as after a follow-up of 1 year, 7 and 5 of the 12 evaluated patients were HDV RNA and HBsAg negative, respectively. Asymptomatic and transient elevation of liver enzymes have been also reported [16]. Similarly, PEG-IFN-lambda was associated with improved or similar rates of virologic response with fewer adverse events than IFNa. The primary end point was once again a reduction of >2 log or negative HDV RNA at the end of 48-week-treatment and following a 24-week observation period [17]. We underline here that therapeutic targets remain generally similar in the older and newer studies assessing the efficacy of HBV or HDV treatment. In any case, depending on the treatment aim (HBV DNA or HBsAg decline, HDV-RNA long-term suppression, ALT normalization, etc.) and the degree of hepatic impairment, these novel regimens might potentially be successful, and with additional strategies, such as drug combinations, they might work even better.

Other molecules working with different mechanisms include:


In the immunotherapy side of HBV treatment, mechanisms and molecules under study include:

• Toll-like receptor agonists (activation of innate immune system with production of IFN): GS-9620, GS9688, TQ-A3334, RO6864017. As explained above, there is also RO7020531 in combination with a capsid inhibitor (RO7049389 + RO7020531). They are mostly in phase II.

