Treatment of Hepatitis B: A Concise Review

Chronic infection with hepatitis B virus (HBV) affects 400 million people worldwide, including at least 1.25 million in the United States. Those who develop chronic hepatitis B die, on average, 22 years earlier compared with those without HBV1 owing to complications of cirrhosis, hepatocellular carcinoma, and liver failure. The burden of HBV is expected to grow in the face of immigration patterns into the United States from highly endemic countries. Despite the approval of several anti-viral agents, very few patients are actually on treatment.2, 3, 4, 5 There are many possible reasons for this, including the need for lifelong treatment, lack of education and awareness of the disease in largely immigrant, non-English-speaking groups, under screening for the condition in primary care settings, and concerns regarding the requirement for liver biopsies to determine the need for treatment in many cases. Guidelines for hepatitis B treatment have also issued variable recommendations for the treatment of some phases of the disease,6, 7, 8, 9 which can lead to confusion for practitioners. In this review, we provide practical recommendations for both primary care doctors and subspecialists on who should be treated for hepatitis B and how. The life cycle of HBV is complex. The virus enters the hepatocyte by binding to a receptor on the cell surface—the sodium taurocholate cotransporting polypeptide, a bile acid transporter.11, 12, 13 After uncoating of the viral nucleic acid, the viral genomic DNA is transferred to the cell nucleus and the partially double-stranded viral DNA is then transformed into covalently closed circular DNA (cccDNA), a highly stable intermediate that serves as a template for transcription of viral mRNAs, including the pregenomic RNA. The pregenomic RNA serves as template for translation of viral proteins, including the surface antigen, nucleocapsid, and polymerase proteins. Taken together with the nucleocapsid and polymerase proteins, the HBV pregenomic RNA is encapsidated in the virus core particle. The first step is reverse transcription and first-strand cDNA synthesis, catalyzed by the HBV polymerase—the site of action of oral anti-HBV nucleoside/nucleotide analog (NA) agents. The next step is second-strand DNA synthesis to generate a partially double-stranded viral DNA genome. The HBV polymerase lacks proofreading activity; thus, mutations of the viral genome are frequent and result in the coexistence of genetically distinct viral species in infected individuals (quasispecies). Nucleocapsids associated with the partially double-stranded HBV DNA can then either re-enter the hepatocyte nucleus to replenish the pool of cccDNA or be enveloped for secretion as complete virions via the endoplasmic reticulum. After budding into the ER lumen, the envelope proteins are secreted from the cell either as non-infectious subviral particles (HBsAg) or incorporated into infectious virions known as Dane particles. The persistence of the highly stable cccDNA accounts for the challenge in eradicating chronic HBV. In addition, error-prone replication of the HBV genome and generation of mutants in the precore region (precore mutants) are additional contributors to persistence of hepatitis B infection. HBV proteins can also target key immune cells to circumvent host anti-viral immunity. Adaptive immune responses to HBV are blunted in CHB subjects when compared with those who have resolved acute infection. Studies have demonstrated that T cells responding to HBV antigens from these subjects have an exhausted phenotype and are less responsive to HBV antigens.14 Chronic hepatitis B has a complicated natural history with three identified phases. The immune-tolerant phase is characterized by high HBV DNA (usually >1 million IU/ml) and normal alanine aminotransferase (ALT) with minimal liver disease. This phase is thought to occur most frequently in persons who are infected perinatally. The immune-active phase is marked by high HBV DNA and elevated ALT levels with active liver inflammation. Finally, the inactive phase is associated with low HBV DNA levels (<2,000 IU/ml) and normal ALT with minimal liver inflammation and fibrosis. The main aim of the anti-viral therapy are to decrease morbidity and mortality by suppressing HBV replication and hepatic inflammation and preventing progression to cirrhosis and hepatocellular carcinoma. Anti-viral treatment results in normalization of ALT, suppression of HBV DNA, possible loss of HBeAg and seroconversion to anti-HBe, possible loss of HBsAg and seroconversion to anti-HBs, and histological improvements with decreased inflammation and fibrosis. The Food and Drug Administration has approved seven anti-viral drugs for the treatment of chronic HBV: interferon-a2b, pegylated interferon-a2α (peg-IFN), lamivudine (LAM), adefovir, entecavir (ETV), telbivudine, and tenofovir (TDF). Of these, the most commonly used first-line agents are peg-IFN, TDF, and ETV. In severe acute HBV with prolonged prothrombin time and increased bilirubin, interferon failed to be effective,20, 21, 22, 23 but NAs have been shown to be effective. A randomized controlled trial of 80 patients found that early treatment with LAM leads to a greater decrease in HBV DNA levels, better clinical improvement, and mortality improvement but with a lower HBsAg and HBeAg seroconversion rate.24 Multiple randomized studies have produced results consistent with this randomized controlled trial.25, 26, 27, 28 Furthermore, most patients who died or required transplantation despite LAM therapy were started on LAM at advanced stages compared with those who survived. These findings suggest that prompt and timely anti-viral therapy is crucial. Multicenter double-blind randomized trials to compare the efficacy between LAM and ETV or even TDF in acute severe HBV cases are lacking because of the difficulty of accruing cases. However, given the safety and efficacy of these agents in other cases of acute hepatitis B (e.g., reactivation in patients receiving chemotherapy),29, 30, 31, 32, 33, 34, 35, 36, 37 the AASLD recommends treatment with an NA for fulminant and acute/symptomatic hepatitis B. In one prospective randomized trial of TDF vs. placebo in 27 patients with spontaneous reactivation of chronic hepatitis B who presented with acute on chronic liver failure, the 3-month probability of survival was higher in the TDF group compared with that in the placebo group (57% vs. 15%, P=0.03).33 Because of their anti-viral potency, ETV or TDF are the preferred agents for the treatment of acute or fulminant hepatitis B. Treatment should be continued until HBsAg clearance is confirmed or indefinitely in those who undergo liver transplantation. IFN is contraindicated and has not been shown to be effective in fulminant hepatitis B. Thus, to prevent reactivation of HBV replication, which can lead to hepatitis and liver failure, prophylactic anti-viral therapy with ETV or TDF is recommended in HBsAg+ patients who will be receiving anti-CD20 therapy (e.g., rituximab), hematopoietic cell transplantation, high-dose glucocorticoids (e.g., ≥20 mg per day for at least 4 weeks), the anti-CD52 agent alemtuzumab, cytotoxic chemotherapy without glucocorticoids, anti-TNF therapy, and antirejection therapy for solid organ transplants. Prophylactic anti-viral therapy is also recommended for patients who are HBsAg− and anti-HBc+ and who will be receiving potent immunosuppressive therapies such as rituximab or myeloablation before hematopoietic stem cell transplantation, to prevent reappearance of HBsAg. HBsAg+ individuals are at low risk of reactivation if they receive methotrexate or azathioprine and thus in these low-risk patients prophylactic therapy is not indicated but they should be monitored for possible reactivation and treated with an anti-viral should this occur.41 Given these findings, the AASLD recommends the consideration of NAs with favorable resistance and safety profiles, such as TDF, during pregnancy to reduce the risk of mother-to-infant transmission. However, there is no consensus on the cutoff HBV DNA concentration for recommending anti-viral therapy and when anti-viral therapy should be started. At our institution, we have used the algorithm shown in Figure 4. If HBV treatment is needed and TDF cannot safely be used, the alternative recommended HBV therapy is ETV in addition to a fully suppressive antiretroviral regimen (to prevent selection of the M184V mutation that confers HIV resistance to LAM and emtricitabine), or peg-IFNα monotherapy for 48 weeks, particularly in patients with HBV genotype A, high ALT, and low HBV DNA level.56 When HAART (highly active antiretroviral therapy) regimens are altered, drugs that are effective against HBV should not be discontinued without substituting another drug that has activity against HBV, unless the patient has achieved HBeAg seroconversion and has completed an adequate course of consolidation treatment. Discontinuation of agents with anti-HBV activity may cause serious hepatocellular damage resulting from reactivation of HBV. In addition, patients in the inactive carrier state (HBsAg+, HBeAg−, HBeAb+) in whom both HBV DNA levels are very low (<2,000 IU/ml) or undetectable and ALT levels are normal should not be treated but rather monitored on a biannual basis with ALT and HBV DNA levels, as well as with hepatocellular carcinoma screening in high-risk patients. Finally, those who are HBeAg− with an intermediate viral load (between 2,000 and 20,000 IU/ml) and borderline normal or minimally elevated liver function tests should not be treated but should be considered for liver biopsy and treated if there is moderate or severe necroinflammation or significant fibrosis. Overall, all NAs have an excellent safety profile across a wide spectrum of persons with chronic hepatitis B and any side effects are infrequent.61 Adverse events associated with TDF are rare and include renal insufficiency, Fanconi’s syndrome, proximal tubular acidosis, and decreased bone density, particularly in children, in whom the drug is contraindicated.61, 62, 63, 64, 65 If TDF is used in patients with renal insufficiency, the dose must be adjusted for creatinine clearance. Adverse events with ETV are mild to moderate and include headache, upper respiratory tract infection, cough, nasopharyngitis, fatigue, and upper abdominal pain.66 Severe lactic acidosis has been reported in a case series of patients with advanced cirrhosis (MELD score ≥20) and thus ETV should be used with caution in patients with decompensated liver disease. ETV should also be adjusted for creatinine clearance.67 TDF or ETV are the only therapeutic options in patients with decompensated liver disease, in patients undergoing immunosuppressive treatment, and in patients with other contraindications to or unwilling to receive peg-IFN. In HBeAg+ patients, treatment can be discontinued after a 12-month consolidation period following documented HBeAg seroconversion with undetectable HBV DNA. Close monitoring for relapse is nonetheless required following therapy discontinuation. In HBeAg− patients, long-term therapy is required until HBsAg loss is documented. Advantages of NAs include potent anti-viral effect (viral suppression in >95% of patients over 5 years with fibrosis regression and prevention of cirrhosis),68, 69, 70 good tolerability with minimal side effects, and oral administration. Disadvantages include indefinite duration of therapy, particularly in HBeAg− patients, and risk of resistance along with unknown long-term safety. Fortunately, the risk of drug resistance has thus far been minimal (1.2% with ETV after 6 years and 0% with TDF after 5 years).70, 71, 72 Lifelong treatment is recommended for all patients with recurrent hepatitis B after liver transplantation and in all cirrhotics, both compensated and decompensated, due to concerns for potential reactivation and death when treatment is stopped.73, 76, 78 In addition, there appears to be an association between quantitative level of HBsAg and relapse after anti-viral therapy for chronic HBV infection.79 All guidelines recommend peg-IFN for 48–52 weeks in both HBeAg+ and HBeAg− patients. Irrespective of the underlying liver disease and the treatment used, patients need to be closely monitored for viral relapse and ALT flares when treatment is stopped, so that treatment can be reinitiated promptly.80 Direct virologic approaches include HBV capsid inhibitors, small interfering RNA targeted to viral mRNA, and cccDNA targeting strategies. The HBV capsid is polyfunctional, as it is essential for HBV genome packaging, reverse transcription, intracellular trafficking, maintenance of cccDNA, and inhibition of host innate immune responses. Thus, it is an attractive target for HBV therapies. Several capsid inhibitors being evaluated include NVR 3-778, GLS-4, and phenylpropenamide derivatives.84 Small interfering RNAs directed against conserved HBV RNA sequences could knock down HBV RNA, proteins, and DNA levels. To this end, the HBV small interfering RNA ARC-520 is currently being evaluated in a phase 2 trial. cccDNA targeting strategies include prevention of cccDNA formation (e.g., disubstituted sulfonamide DSS), elimination of cccDNA by inhibition of viral or cellular factors contributing to cccDNA stability/formation (e.g., APOBEC3A, B agonists) or physical elimination of cccDNA (e.g., zinc-finger, transcription activator-like effector nucleases or TALEN, CRISPR/Cas9 nucleases), and silencing of cccDNA transcription.84, 85, 86, 87 Indirect acting host target inhibitors include entry inhibitors, epigenetic modifiers (sirtuin inhibitors such as sirtinol), morphogenesis inhibitors (glucosidase inhibitors), and secretion inhibitors (Rep 9AC). A promising target is the inhibition of the sodium taurocholate cotransporting polypeptide receptor by which HBV/HDV enters hepatocytes (e.g., agents include myrcludex B, cyclosporine A, and ezetimibe),12 although there may be limitations in terms of the clinical implications of inhibiting bile salt transport. Immunomodulatory approaches include targeting innate and adaptive immune responses. Innate targets include IFN-α, TLR7 agonists, and STING agonists.88, 89 Adaptive immune agents include therapeutic T-cell vaccines and PD-1/PD-L1 antagonists. Targeting the T-cell response to HBV is important because, in contrast to HCV, there is a robust T cell (CTL) that spontaneously clears natural HBV infection with high frequency in adults. Chronic HBV is associated with attenuated CTL responses (high PD-1/PD-L1 expression) and thus inhibitors of PD-1/PD-L1 could reawaken these vigorous responses. A combination of these inhibitors with directly acting anti-virals against HBV could have merit, although caution will need to be exercised regarding the risk of triggering autoimmunity and hepatic flares.90, 91, 92, 93 Chronic infection with HBV remains a major public health problem. Treatment of hepatitis B is indicated in immune-active patients, in those with cirrhosis or fulminant hepatitis B, in prevention of reactivation in HBV carriers who require immunosuppressive or cytotoxic therapies, in pregnant mothers with high viral load, and in HIV/HBV coinfection. Most of the effective anti-viral agents that are available require indefinite treatment; thus, efforts are being devoted to approaches to enhance functional cure rates and permit cessation of therapy. A true virologic cure for HBV is much more elusive, in contrast to HCV, because of its highly stable latent form (HBV cccDNA). However, a rich array of viral and host targets is being explored for manipulation. It is highly likely that a multimodality approach will be essential for the achievement of a functional and virologic cure. Guarantor of the article: Ruma Rajbhandari, MD, MPH and Raymond T. Chung, MD. Specific author contributions: RR compiled the various studies and articles for initial review, drafted the initial manuscript and was involved in all subsequent revisions. RTC was involved in critical review of the manuscript. RR and RTC have both approved the final draft of the manuscript. Financial support: Dr Ruma Rajbhandari was supported by a grant from the National Institutes of Health (T32 DK007191). Dr Raymond Chung is supported, in part, by a grant from the National Institutes of Health (K24 DK078772). Potential competing interests: Dr Raymond T. Chung receives research grant support (to institution) from Gilead Sciences and Bristol-Myers-Squibb. RR declares no conflict of interest. RTC has received research grant support from Gilead and Bristol-Myers Squibb (research grant support to institution).