Hepatol Commun. 2018 Nov 15;3(1):8-19. doi: 10.1002/hep4.1281. eCollection 2019 Jan.
Hepatitis B Treatment: What We Know Now and What Remains to Be Researched.
Suk-Fong Lok A1.
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Abstract
Chronic hepatitis B virus (HBV) infection remains a major global health burden. Currently, two types of treatment, interferons (IFNs) and nucleos(t)ide analogues (NAs), have been approved. These treatments are effective in suppressing HBV replication and in decreasing the risk of developing cirrhosis, liver failure, hepatocellular carcinoma (HCC), and death. However, these treatments do not eliminate the virus, and the risk of HCC remains. This review article summarizes current knowledge about the safety, efficacy, and clinical indications of hepatitis B treatment. It also discusses limitations of existing treatment, gaps in knowledge, and feasibility of a hepatitis B cure.
Recent studies suggest paradoxically that, for patients who are HBeAg‐negative who had been virally suppressed for >2 to 3 years, withdrawal of an NA may be associated with a higher rate of HBsAg loss compared to those who continued the NA.39-41 This has led the APASL and EASL guidelines to include a provision for such an approach as long as patients agree to close monitoring after treatment is discontinued. However, outcomes, including risks of hepatic decompensation, frequency of monitoring, and criteria for resuming treatment, need to be studied in larger cohorts before this approach is widely adopted.
The reason for a higher rate of HBsAg loss after NA withdrawal is unclear. It has been postulated that viral relapse after a long duration of virus suppression may mimic acute hepatitis B, provoking a rigorous immune response to HBV leading to HBsAg loss. Among patients who experienced clinical relapse, one study found that those who did not resume treatment had a higher rate of HBsAg loss than those who did, suggesting that HBsAg loss is more likely to occur if immune clearance is allowed to proceed and not be curbed too soon. However, overly rigorous or prolonged immune lysis of infected hepatocytes can result in liver failure. Moreover, this same study showed that patients who had no viral relapse and those who had viral but not clinical relapse had higher rates of HBsAg loss than those who had clinical relapse, indicating that hepatitis flares are not required for HBsAg loss.40
最近的研究表明，对于HBeAg阴性且病毒被抑制超过2至3年的患者，与继续使用NA的患者相比，撤销NA可能与较高的HBsAg丢失率相关.39-41这导致APASL和EASL指南包括这种方法的规定，只要患者同意在停止治疗后进行密切监测。然而，在广泛采用这种方法之前，需要在更大的队列中研究结果，包括肝功能失代偿的风险，监测频率和恢复治疗的标准。
The availability of a simple, safe, and highly effective cure for hepatitis C has reenergized the search for a cure for hepatitis B. However, as described earlier, a sterilizing cure with elimination of both cccDNA and integrated HBV DNA may not be possible. Instead, experts agree that a functional cure akin to spontaneous HBsAg loss in patients with chronic HBV infection may be a realistic goal.3 The endpoint would be HBsAg loss accompanied by HBeAg loss and undetectable HBV DNA in serum, but HBV DNA may persist in the liver as integrated HBV DNA and as transcriptionally inactive cccDNA. Progression of liver disease would be halted, and over time fibrosis would regress and the incidence of HCC would decrease. Whether seroconversion to hepatitis B surface antibody is necessary to prevent HBsAg seroreversion remains to be determined. This functional cure is currently achievable in a small percentage (<10%) of patients after IFN or NA therapy. The vision for the future is to deploy a combination of antiviral drugs directed against new targets and immunomodulatory therapies to restore innate as well as adaptive immune responses with the goal of achieving HBsAg loss in a higher percentage (>50%) of patients after a finite course (≥2 years) of treatment. These new strategies may or may not include IFN or NAs.
New antiviral drugs in clinical trials include entry receptor inhibitors, capsid assembly modifiers, RNA interference, and nucleic acid polymers.3 To date, capsid assembly modifiers have shown promising results, but the effect on HBsAg levels has been modest and there is a concern for antiviral drug resistance. RNA interference has been shown to result in >1 log decrease in HBsAg levels, but it has to be administered as injections and there is a concern for off‐target effects. Studies of nucleic acid polymers have shown a high rate of HBsAg loss, but the design of those studies is complex, the exact mechanism of action of nucleic acid polymers is unclear, and marked ALT flares were observed in a high percentage of patients; thus, safety needs to be established and efficacy needs to be confirmed. To date, studies of immune modulatory therapies, including therapeutic vaccines to stimulate T‐cell response and toll‐like receptor agonists to enhance innate immune response, have had limited success. Given the recent success of immune therapies in oncology, enthusiasm for immune modulatory therapies, including check‐point inhibitors and engineered T cells, remains high. A major concern of immune modulatory therapies is uncontrolled immune activation leading to fatal hepatitis flares or extrahepatic organ damage.
Major challenges with developing new drugs for hepatitis B include safety (given the excellent safety profile of NAs), ease of administration (NAs are taken as pills once a day), and cost (ETV and TDF are both off patent). However, given the high global burden of hepatitis B, the desire to achieve a “cure” with a finite course of therapy, and the need to effectively control HBV replication at an early stage of chronic HBV infection, it is hoped that there will be sufficient interest and commitment from the pharmaceutical industry and the scientific community to work together to make an HBV cure a reality in the not too distant future.
HBV治疗的未来