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Treatment of Hepatitis B
Abbreviations
ALT
alanine aminotransferase
anti-HBc
hepatitis B core antibody
anti-HBe
hepatitis B e antibody
anti-HBs
hepatitis B surface antibody
Cas9
clustered regularly interspaced short palindromic repeats–associated 9
CHB
chronic hepatitis B
CRISPR
clustered regularly interspaced short palindromic repeats
HBeAg
hepatitis B e antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HIV
human immunodeficiency virus
IFN
interferon
NUC
nucleoside/nucleotide analog
PEG-IFN
pegylated interferon
TDF
tenofovir disoproxil fumarate
Introduction
Hepatitis B virus (HBV) infection is a major public health problem. Approximately 350 million people are long-term carriers of HBV, and every year 0.5 million to 1.2 million people die of the long-term sequelae of chronic liver disease, such as liver cirrhosis and hepatocellular carcinoma (HCC).
A hepatitis B vaccine was developed in the 1970s, making hepatitis B a preventable disease. In its effort to eliminate chronic hepatitis B (CHB) infection, the World Health Organization passed a resolution to recommend global vaccination against hepatitis B in 1992. Widespread use of the hepatitis B vaccine has already markedly reduced HBV-related morbidity and mortality, including prevention of HCC in countries such as Taiwan, where nearly all infants are vaccinated. Globally, the vaccination coverage increased from 3% in 1992 to 81% in 2013. Nonetheless, new HBV infections continue to occur, in part because of the lack of knowledge of the general population of the mode of transmission and failure to vaccinate those at risk, and the difficulty to deliver the hepatis B vaccine in remote regions of the world.
In the past nearly 3 decades, antiviral treatment of CHB has been revolutionized, first with conventional interferon (IFN) and then with pegylated IFN (PEG-IFN) and, more recently, with the availability of nucleoside/nucleotide analogs (NUCs). Currently, seven antiviral agents (lamivudine, adefovir, entecavir, telbivudine, tenofovir, standard IFN, and PEG-IFN) are available for the treatment of CHB, and have been shown to delay the progression of cirrhosis, reduce the incidence of HCC, and improve long-term survival.
Indications for Treatment
Currently approved treatment options are unable to eradicate HBV infection. Furthermore, they are expensive, and it is unclear whether they are safe and effective in maintaining viral suppression over decades in the light of antiviral drug resistance. Therefore assessment of the phase of infection and the risk of liver disease progression is essential to identify those patients who may benefit from antiviral therapy.
Natural History
Phases of Chronic Hepatitis B Virus Infection
The natural course of chronic HBV infection involves four phases, although not all patients go through all phases ( Fig. 33-1 ).
In the immunotolerant (high replicative carrier) phase of infection, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) are present, serum HBV DNA levels are greater than 10 7 IU/mL, the levels of serum aminotransferases are normal, and there is no or minimal necroinflammation on liver histology. In patients with perinatally acquired HBV infection, this phase may last for 1 to 4 decades. By contrast, the immunotolerant phase is short or absent in patients who acquire HBV infection in late childhood or during adulthood. The second phase is the immune-active phase. It is characterized by the presence of HBsAg and HBeAg, high or fluctuating serum HBV DNA levels, persistent or intermittent elevation of aminotransferase levels, and active necroinflammation on liver histology. In this phase, spontaneous and sustained HBeAg seroconversion occurs at a rate of approximately 10% per year, and it is estimated that up to 65% of patients undergo spontaneous HBeAg seroclearance. Frequently, a flare of aminotransferases precedes this important event, reflecting immune-mediated lysis of infected hepatocytes. However, flares may also only result in transient decreases in serum HBV DNA levels without loss of HBeAg. The frequency and severity of these flares are associated with an increased risk of progression to cirrhosis and HCC. The phase that follows HBeAg seroconversion is called the immune-control phase or inactive carrier state . It is characterized by the absence of HBeAg, the presence of hepatitis B e antibody (anti-HBe), persistently normal aminotransferase levels, and low serum HBV DNA levels. The prognosis for those who remain in this phase is excellent, with an incidence of delayed HBsAg seroconversion of 1% per year to 2% per year in Western countries and 0.05% per year to 0.8% per year in Asia. After spontaneous HBeAg seroconversion, approximately 60% of patients will have a sustained remission and low risk of cirrhosis and HCC. However, up to 17% will have HBeAg seroreversion, and 15% to 24% will go on to develop HBeAg-negative active chronic hepatitis. This fourth phase, HBeAg-negative chronic hepatitis, is characterized by the absence of HBeAg, the presence of anti-HBe, elevated serum HBV DNA levels, elevated aminotransferase levels, and active necroinflammation on liver histology. Most patients harbor HBV variants with mutations in the precore or core promoter region. The most common precore mutation, G1896A, creates a premature stop codon in the precore region with loss of HBeAg synthesis. Patients with HBeAg-negative chronic hepatitis are usually older, have more advanced liver disease, and tend to have lower serum HBV DNA levels compared with patients with HBeAg-positive chronic hepatitis.
Progression to Cirrhosis and Hepatocellular Carcinoma
The incidence of progression to cirrhosis is 1.3% to 3.8% for patients with HBeAg-positive chronic hepatitis and 2.8% to 9.7% for patients with HBeAg-negative chronic hepatitis. The higher rate of cirrhosis among patients with HBeAg-negative chronic hepatitis is associated with older age and is likely related to longer duration of infection. Factors associated with an increased rate of progression to cirrhosis include older age, male sex, high serum HBV DNA levels, presence of HBeAg, coinfection with hepatitis C virus, hepatitis delta virus, or human immunodeficiency virus (HIV), alcohol abuse, and HBV genotype (C > B). In untreated patients there appears to be a direct association between the level of viremia and the risk of developing HCC; the higher the level of HBV DNA at presentation, the higher the risk of developing HCC during follow-up. Hepatic decompensation occurs at an annual rate of 3% in cirrhotic patients. The annual incidence of HCC is approximately 0.21% for noncirrhotic inactive carriers, 0.6% for patients without cirrhosis but with active hepatitis and 3% to 4% for patients with cirrhosis. Even higher incidence rates have been reported in Asian and African populations. Nevertheless, approximately 30% of HBV-associated HCC occurs in noncirrhotic livers. HCC and liver failure are the main causes of death in liver disease. In patients in whom compensated CHB has been newly diagnosed, the 5-year survival rate is 99% to 100%. For patients with compensated cirrhosis, the survival rate is 86% at 5 years. Once an episode of decompensation occurs, prognosis is very poor in the absence of antiviral therapy, with survival rates of only 14% to 28% at 5 years.
Treatment Indication
The primary indication of treatment initiation is elevated HBV DNA levels in the presence of significant liver injury, as reflected by elevated alanine aminotransferase (ALT) levels, or necroinflammatory activity and/or fibrosis on histology. In general, this means that patients in the immune-active or reactivation phase are candidates for antiviral treatment, whereas patients in the immunotolerant or inactive phase do not need antiviral therapy, and can be closely monitored. Normal ALT values of healthy adults are 30 U/L or less for males and 19 U/L or less for females. The HBV DNA levels used to define immune-active disease (>2000 IU/m [European Association for the Study of the Liver] or >20,000 IU/mL [American Association for the Study of Liver Diseases] for HBeAg-positive patients and >2000 IU/mL for HBeAg-negative patients) are based on historical cutoffs of clinical trials and long-term follow-up studies. Large population-based cohort studies demonstrated an increased risk of progression to cirrhosis and development of HCC in adults with HBV DNA levels greater than 2000 IU/mL. Still, one should keep in mind that some patients are currently in the gray zone for HBV DNA and ALT criteria for treatment versus observation. As CHB is a dynamic disease characterized by periods of immune activity and quiescence, longitudinal assessment is of vital importance for correct determination of the phase of infection and the stage of liver disease. Liver biopsy can be helpful in patients who lack these clear-cut indications for treatment initiation.
Initial Evaluation
The initial evaluation should include history taking and physical examination with special attention paid to alcohol use and family history of HBV infection and HCC ( Table 33-1 ). Laboratory tests include assessment of liver disease activity and function, markers of HBV replication, and tests for coinfection with hepatitis C virus, hepatitis delta virus, and HIV. Noninvasive assessment of the stage of disease includes not only abdominal ultrasonography but also aspartate aminotransferase to platelet ratio index, fibrosis-4 score, FibroTest, and transient elastography. Liver biopsy is necessary only in select patients ( Fig. 33-2 ).
TABLE 33-1
Initial Evaluation of the Hepatitis B Surface Antigen–Positive Patient
| History/Physical Examination | Routine Laboratory Tests | Serology/Virology | Imaging/Staging Studies | |
|---|---|---|---|---|
| All patients |
|
CBC, AST level, ALT level, GGT, total bilirubin level, alkaline phosphatase level, albumin level, INR |
|
|
| Select patients | Tests to rule out other causes of chronic liver diseases |
|
Liver biopsy |
ALT, Alanine aminotransferase; anti-HAV, hepatitis A virus antibody; anti-HBe, hepatitis B e antibody; anti-HCV, hepatitis C virus antibody; anti-HDV, hepatitis delta virus antibody; APRI, aspartate aminotransferase to platelet ratio index; AST, aspartate aminotransferase; CBC, complete blood count; FIB-4, fibrosis-4; GGT, γ-glutamyl transpeptidase; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma; INR, international normalized ratio.
Treatment End Points
Complete eradication of HBV from host hepatocytes can probably not be achieved with currently available drugs because of persistence of HBV covalently closed circular DNA in the nucleus of the cell and because of integration into host DNA. The main goal of therapy is therefore to slow, halt, or even reverse progression of liver inflammation to fibrosis, (decompensated) cirrhosis, or HCC. Because most of these events do not transpire until after several decades of infection, various surrogate end points are used to evaluate treatment efficacy in CHB. Frequently used end points of therapy are loss of HBeAg from serum with or without the appearance of anti-HBe (serologic response), return of ALT levels to the normal range (biochemical response), a reduction of HBV DNA levels to low or undetectable levels (virologic response), and improvement of liver histologic features. Complete remission of disease is defined by a loss of HBsAg from serum accompanied by the appearance of hepatitis B surface antibody (anti-HBs), because the HBsAg-negative state is associated with an excellent prognosis with very low relapse rates in immunocompetent patients.
PEG-IFN and the NUCs differ in their modes of antiviral action. PEG-IFN is an immunomodulator that also has a modest direct antiviral effect, whereas NUCs impede viral polymerase activity and thus prohibit viral replication without directly influencing the host immune response to the virus. These differences are reflected in the definitions used to classify response to therapy. Because the aim of PEG-IFN therapy is to induce an off-treatment sustained remission of disease, response to PEG-IFN is assessed at 6 to 12 months after therapy discontinuation, as opposed to on-treatment assessments of virologic suppression used during NUC therapy.
The ultimate end point of PEG-IFN therapy is HBsAg clearance but this is achieved in only a limited number of patients. Therefore clinical guidelines have defined response to PEG-IFN on the basis of serologic and virologic characteristics associated with long-term off-treatment sustained disease remission. In HBeAg-positive patients, response to PEG-IFN is defined as the combined achievement of HBeAg loss (or seroconversion) with low levels of HBV DNA (<2000 IU/mL) at 6 months after treatment. In patients with HBeAg-negative CHB, the presence of HBV DNA levels lower than 2000 IU/mL combined with normalization of ALT levels at 6 months to 12 months after treatment is used as the definition of response to PEG-IFN. Achievement of off-treatment sustained viral suppression after IFN-based therapy is associated with increased rates of subsequent HBsAg seroclearance and an excellent prognosis.
In contrast to PEG-IFN therapy, complete viral suppression during treatment is an essential part of NUC-based therapy, because persistent viral replication is associated with a higher risk of antiviral resistance development, particularly for drugs with a low barrier to resistance. The HBV DNA patterns during NUC therapy may have clinical consequences, in particular for drugs with a lower threshold to resistance. HBV DNA response to NUCs is typically classified as nonresponse (<1 log decline after 3 months), partial response (>1 log decline but still detectable HBV DNA after at least 6 months), or complete virologic response (undetectable HBV DNA). Development of resistance is frequently indicated by virologic breakthrough, defined as a 1 log increase of HBV DNA levels above the nadir in an adherent patient. The clinical relevance of a partial response to entecavir or tenofovir disoproxil fumarate (TDF) is generally limited because most patients will achieve undetectable HBV DNA with prolonged therapy. The importance of serologic responses during NUC therapy, especially HBeAg seroconversion, remains to be determined because achievement of HBeAg seroconversion during NUC therapy does not always appear to signify immune control in NUC-treated patients as it does with PEG-IFN therapy or during the natural history of disease because HBeAg seroreversion and progression to HBeAg-negative CHB is frequent. As a result, only HBsAg clearance or seroconversion constitutes the most definitive immune control in treated patients.
Nucleoside/Nucleotide Analogs
Introduction
The discovery of NUC-based therapy provided a safe, effective, and well-tolerated alternative to PEG-IFN. In general, NUCs target the reverse transcriptase of HBV and are potent inhibitors of viral replication. After intracellular phosphorylation they act as an analog of natural nucleotides and compete for incorporation into the viral DNA chain. As they lack a hydroxyl group, formation of a covalent bond with an adjacent nucleotide is not possible, and so they prohibit further chain elongation ( Fig. 33-3 ). Current international treatment guidelines recommend TDF or entecavir as a first-line treatment option. Characteristics of the different approved NUCs are shown in Table 33-2 .
TABLE 33-2
Characteristics of Approved Treatment Options for Chronic Hepatitis B
| Drug | Drug Class | Dosage in Adults * | Pregnancy Category | Potential Side Effects † | Resistance Mutations | Monitoring on Treatment † |
|---|---|---|---|---|---|---|
| Pegylated interferon-α 2a | Interferon | 180 µg weekly | C | Flulike symptoms, fatigue, mood disturbances, cytopenias, autoimmune disorders | None |
|
| Lamivudine | l -Nucleoside | 100 mg daily | C |
|
|
|
| Telbivudine | l -Nucleoside | 600 mg daily | B |
|
|
|
| Entecavir | d -Cyclopentane | 0.5 mg or 1 mg daily ‡ | C | Lactic acidosis |
|
Lactic acid level if clinical concern |
| Adefovir | Acyclic phosphonate | 10 mg daily | C |
|
|
|
| Lactic acidosis |
|
|||||
| Tenofovir | Acyclic phosphonate | 300 mg daily | B |
|
|
CBC, Complete blood count; TSH, thyroid-stimulating hormone.
* Doses need to be adjusted in people with renal dysfunction.
‡ Entecavir dosage in adults is 1 mg daily if lamivudine or telbivudine experienced and there is decompensated cirrhosis.
The probability of undetectable HBV DNA for different NUCs and PEG-IFN after 1 year of therapy is given in Figs. 33-4 and 33-5 for HBeAg-positive and HBeAg-negative patients. With prolonged treatment, more than 90% of patients treated with TDF or entecavir will have virologic suppression.
Tenofovir
Tenofovir belongs to a class of acyclic phosphonate nucleotide analogs. Its antiviral activity was first described in 1993, and is restricted to retroviruses and hepadnaviruses. TDF was licensed for the treatment of HIV infection in 2001, and continues to be an important component of many anti-HIV regimens. The efficacy of TDF in HBV therapy was first described in several studies including mainly patients coinfected with HBV and HIV-1, and some receiving combination therapy with lamivudine. It was licensed for the treatment of CHB in 2008.
Clinical Response
The excellent efficacy of TDF in CHB has been established in two phase III randomized clinical trials and long-term follow-up studies, in which HBeAg-positive and HBeAg-negative CHB patients were treated with either TDF or adefovir monotherapy. After 48 weeks, all eligible patients were switched to open-label TDF monotherapy for up to an additional 7 years. Seventy-six percent of HBeAg-positive TDF-treated patients demonstrated undetectable HBV DNA (<400 copies per milliliter) after 48 weeks of treatment. Among the HBeAg-negative patients, 93% demonstrated HBV DNA levels lower than 400 copies per milliliter at week 48. For all patients receiving treatment at year 7, 99% maintained undetectable HBV DNA (HBV DNA level <69 IU/mL), 80% achieved serum ALT level normalization, and in HBeAg-positive patients, 55% and 12% achieved HBeAg and HBsAg loss respectively. In the HBeAg-negative patients, only 0.3% achieved HBsAg loss. Moreover, a subgroup analysis of patients who underwent a follow-up liver biopsy after 5 years of TDF treatment demonstrated regression of fibrosis in 54% of patients. Of the patients with cirrhosis at the baseline, 74% no longer had liver cirrhosis.
The efficacy of TDF has also been clearly demonstrated in nucleoside/nucleotide-experienced HBV patients. In one randomized clinical trial of lamivudine-resistant HBV patients who were treated either with TDF alone or with TDF in combination with emtricitabine, 89% of patients in the TDF group and 86% in the emtricitabine-TDF group had levels of HBV DNA lower than 69 IU/mL at week 96 of treatment. Another randomized trial showed that TDF is highly effective in adefovir-resistant HBV patients as well. In patients infected with entecavir-resistant HBV, TDF monotherapy for 48 weeks provided a virologic response comparable to that of TDF and entecavir combination therapy. Furthermore, the efficacy of TDF in both nucleoside/nucleotide-naïve and nucleoside/nucleotide-experienced HBV patients has been confirmed in several large cohort studies derived from real-life clinical practice.
Resistance
Resistance to TDF has not been observed in any patient with CHB so far despite extensive resistance surveillance. The purported resistance mutation, A194T, was seen in addition to lamivudine resistance (rtL180M and rtM204V) in two patients coinfected with HIV and HBV receiving tenofovir therapy, yet a decrease in susceptibility of the mutant virus to TDF has not been confirmed in other studies. Some cohort studies suggested a decreased efficacy of TDF in patients with genotypic adefovir resistance. Small decreases in susceptibility to rtN236T HBV mutants have been shown in in vitro studies as well Yet the observed susceptibility shifts are smaller than for adefovir, and together with the significantly higher dose, TDF is able to effectively suppress viral replication in patients with genotypic adefovir resistance.
Safety
As TDF is also one of the most widely prescribed antiretroviral agents, information on the safety profile of TDF comes from its use in both HBV-infected patients and HIV-infected patients. TDF is generally well tolerated, with few side effects. There have been concerns about the risk of renal toxicity with TDF. The renal proximal tubule is the main target of toxicity. Mild and subclinical proximal tubule dysfunction (defined as persistent presence of 2 or more of the following: glucosuria, hyperaminoaciduria, hyperphosphaturia, hyperuricosuria, and β 2 -microglobulinuria) is observed in up to 20% of patients. The incidence of severe cases leading to Fanconi syndrome or acute kidney injury is probably less than 1%. Large observational cohort studies have reported that TDF exposure is associated with a small but significantly increased risk of development of chronic kidney disease (estimated glomerular filtration rate <60 mL/min). An increase in serum creatinine level to more than 2 mg/dL was observed in 0.6% of patients in a large cohort of more than 10,000 TDF-treated subjects. Most of the decline in renal function occurs within the first 3 months, followed by a stable clearance rate thereafter. In the long-term follow-up studies of the phase III registration trials, no significant decline in mean serum creatinine levels was demonstrated among 437 TDF-treated HBV patients, and 1.7% of patients experienced elevations of serum creatinine level of more than 0.5 mg/dL above the baseline. Some studies suggest that the change in serum creatinine level is due to impaired proximal tubule creatinine secretion rather than true alteration of the glomerular filtration rate. Withdrawal of TDF treatment may result in complete recovery from Fanconi syndrome and substantial improvement in kidney function. Decrease in bone mineral density has also been associated with TDF, and most likely is caused by reduced absorption of phosphate in the proximal tubule, leading to urine phosphate wasting. No significant change in bone mineral density was observed in the long-term follow-up studies of the phase III registration trials. In a large population-based cohort study, exposure to nucleotide analogs, compared with nucleoside analogs, increased the risk of hip fracture, yet the overall fracture risk was less than 1% during a median follow-up of approximately 5 years. It is recommended that in patients at risk of renal impairment, creatinine clearance, serum phosphate level, urine glucose level, and protein levels should be monitored at least annually. In individuals with a history of fracture or risk of osteopenia, a bone density study should be considered at the baseline and during treatment (see Table 33-2 ).
Tenofovir alafenamide is a recently developed prodrug of TDF designed to resist rapid metabolism in the plasma (common with the first-generation prodrug TDF), thereby more efficiently delivering active drug (TDF diphosphate) to infected hepatocytes. Tenofovir alafenamide is considered to have efficacy similar to that of TDF. The administration in smaller doses (10 times lower dose) and the lack of systemic effects may lead to less renal and bone toxicity. Recent data from ongoing clinical trials suggests noninferiority compared with TDF concerning viral suppression.
Entecavir
Entecavir is a cyclopentyl guanosine nucleoside analog, and is a highly selective inhibitor of HBV replication. It was licensed for the treatment of CHB in 2006. Although it was initially thought that entecavir exerted no anti-HIV activity, drops in HIV RNA level were observed in patients coinfected with HIV and HBV who received entecavir therapy. In one patient even a lamivudine-resistant M184V HIV variant was selected. Entecavir should therefore not be used as monotherapy in viremic patients coinfected with HIV and HBV.
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