Hepatitis B Treatment & Management

Updated: May 26, 2017
  • Author: Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP, AGAF; Chief Editor: BS Anand, MD  more...
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Treatment

Approach Considerations

The primary treatment goals for patients with hepatitis B (HBV) infection are to prevent progression of the disease, particularly to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). [2, 37, 53] Risk factors for progression of chronic HBV include the following [2, 37, 53] :

  • Persistently elevated levels of HBV DNA and, in some patients, alanine aminotransferase (ALT), as well as the presence of core and precore mutations seen most commonly in HBV genotype C and D infections
  • Male sex
  • Older age
  • Family history of HCC
  • Alcohol use
  • Elevated alpha-fetoprotein (AFP)
  • Coinfection with hepatitis D (delta) virus (HDV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)

A synergistic approach of suppressing viral load and boosting the patient’s immune response with immunotherapeutic interventions is needed for the best prognosis. [33] The prevention of HCC often includes the use of antiviral treatment using pegylated interferon (PEG-IFN) or nucleos(t)ide analogues. [34]

HBV infection can be self-limited or chronic. [39] No specific therapy is available for persons with acute hepatitis B; treatment is supportive. [39]

Therapy is currently recommended for patients with evidence of chronic active hepatitis B disease (ie, abnormal aminotransferase levels, positive HBV DNA findings, positive or negative hepatitis B e antigen [HBeAg]). Various algorithms have been proposed, such as that by the American Association for the Study of Liver Diseases (AASLD), [37, 54] the European Association for the Study of the Liver (EASL), [55] the Asian Pacific Association for the Study of the Liver (APASL), [56] the Canadian Association for the Study of the Liver (CASL), [57] the National Institute for Health and Clinical Excellence (NICE), [58] Kuo and Gish, [19] and Keeffe et al. [59]

National Institutes of Health recommendations

The National Institutes of Health (NIH) recommends nucleos(t)ide therapy for the treatment of patients with acute liver failure, as well as cirrhotic patients who are HBV DNA positive and those with clinical complications, cirrhosis or advanced fibrosis with positive serum HBV DNA, or reactivation of chronic HBV during or after chemotherapy or immunosuppression. [2] In addition, immunoglobulin and vaccination should be administered to newborns born to women positive for hepatitis B surface antigen (HBsAg). [2, 41, 60]

In general, for hepatitis B e antigen (HBeAg)-positive patients with evidence of chronic HBV disease, treatment is advised when the HBV DNA level is at or above 20,000 IU/mL (105 copies/mL) (or, per the EASL, >2,000 IU/mL [55] ) and when serum ALT is elevated for 3-6 months. [2, 37, 53]

For HBeAg-negative patients with chronic hepatitis B disease, treatment can be administered when the HBV DNA is at or above 2,000 IU/mL (104 copies/mL) and the serum ALT is elevated (ALT levels >20 U/L for females; 30 U/L for males) for 3-6 months.

In patients coinfected with HBV and HIV, initiate therapy against HBV and administer antiretroviral therapy (ART) as well. [41]

The NIH also indicates that immediate therapy is not routinely indicated for patients who have the following [2] :

  • Chronic hepatitis B with high levels of serum HBV DNA but normal serum ALT levels or little activity on liver biopsy (immune-tolerant phase)
  • Low levels of or no detectable serum HBV DNA and normal serum ALT levels (inactive chronically infected/low replicative phase)
  • Positive serum HBV DNA but not HBsAg (latent HBV infection), unless the patient is undergoing immunosuppression

World Health Organization (WHO) recommendations

The 2015 WHO guidelines for the prevention, care, and treatment of persons with chronic hepatitis B infection indicates treatment priority for individuals of all ages who have chronic hepatitis B infection and clinical evidence of compensated/decompensated cirrhosis (or cirrhosis based on APRI [aspartate aminotransferase (AST)-to-platelet ratio index] score >2 in adults), regardless of their levels of ALT or HBV DNA, or their HBeAg status. [53]  (Strong recommendation)

Treatment is recommended for adults with chronic hepatitis B infection without clinical evidence of cirrhosis (or based on APRI score ≤2 in adults), but who have all of the following features , and regardless of HBeAg status (strong recommendation) [53] :

  • Are older than 30 years (in particular)
  • Have persistently abnormal ALT levels
  • Have evidence of high-level HBV replication (HBV DNA >20,000 IU/mL). (If HBV DNA testing is unavailable, consider treatment based on persistently abnormal ALT levels alone, regardless of HBeAg status. [Conditional recommendation])

In individuals with HBV/human immunodeficiency virus (HIV) coinfection, the AASLD recommends initiating ART in (1) all those with evidence of severe chronic liver disease, regardless of CD4 count, as well as (2) those with a CD4 count of 500 cells/mm3 or below, regardless of their liver disease stage. [53] (Strong recommendation)

However, the AASLD does not recommend  antiviral therapy, indicating it can be deferred, in individuals with all of the following , regardless of HBeAg status or age (strong recommendation) [53] :

  • No clinical evidence of cirrhosis (or based on APRI score ≤2 in adults)
  • Persistently normal ALT levels
  • Low levels of HBV DNA replication (HBV DNA <2,000 IU/mL). (If HBV DNA testing is unavailable, treatment can be deferred in HBeAg-positive individuals aged 30 years or younger who have persistently abnormal ALT levels. (Conditional recommendation)]

American Association for the Study of Liver Diseases (AASLD) recommendations

The 2016 AASLD guidelines for the treatment of chronic hepatitis B [37]  are outlined below.

Adults with immune-active chronic hepatitis B infection (ie, ALT >2 times the upper limit of normal [ULN] or  significant histologic disease and HBeAg negative [HBV DNA >2,000 IU/mL] or HBeAg positive [HBV DNA >20,000 IU/mL]) (Strong recommendations)

Administer antiviral therapy to lower the risk of morbidity and mortality associated with chronic hepatitis B infection.

The recommended initial agent for adults is PEG-IFN, entecavir, or tenofovir. 

Adults with immune-tolerant chronic hepatitis B infection (ie, ULNs: ALT levels ≤30 U/L for men and ≤19 U/L for women)

Antiviral therapy is not recommended. (Strong recommendation)

The AASLD suggests obtaining ALT levels at least every 6 months to monitor for potential transition to immune-active or -inactive chronic hepatitis B. (Conditional recommendation)

For select patients older than 40 years, the AASLD suggests antiviral therapy in the setting of normal ALT levels, elevated HBV DNA (≥1,000,000 IU/mL), and significant necroinflammation or fibrosis on liver biopsy specimens. (Conditional recommendation)

Adults with HBeAg-positive immune-active chronic hepatitis B who seroconvert to anti-HBe on nucleos(t)ide analog (NA) therapy (Conditional recommendations)

After a period of treatment consolidation (treatment for ≥12 months in the setting of persistently normal ALT levels and undetectable serum HBV DNA), consider discontinuing NA therapy in noncirrhotic HBeAg-positive adults who seroconvert to anti-HBe while on NA treatment. If antiviral therapy is stopped, monitor the patient every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, seroreversion, and clinical decompensation.

For cirrhotic HBeAg-positive adults who seroconvert to anti-HBe on NA therapy, the AASLD suggests indefinite antiviral therapy owing to the potential for clinical decompensation and death, unless a strong competing rationale for treatment discontinuation exists. If antiviral therapy is stopped, closely monitor these patients for recurrent viremia, ALT flares, seroreversion, and clinical decompensation.

Adults with HBeAg-negative immune-active chronic HBV infection

The AASLD suggests indefinite antiviral therapy for adults with HBeAg-negative immune-active chronic hepatitis B infection, unless there is a competing rationale for treatment discontinuation. (Conditional recommendation) If antiviral therapy is stopped, monitor the patient every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, and clinical decompensation.

Antiviral therapy is not recommended for noncirrhotic individuals who are HBeAg negative and who have normal ALT activity and low-level viremia (<2,000 U/mL; “inactive chronic hepatitis B”).

Children with chronic hepatitis B infection

For HBeAg-positive children aged 2 years up to 18 years who have both elevated ALT and detectable HBV DNA levels, the AASLD suggests antiviral therapy (IFN-alpha-2b: age ≥1 year; lamivudine, entecavir: age ≥2 year), with the goal of achieving sustained HBeAg seroconversion. (Conditional recommendation) If antiviral therapy is stopped, monitor the child every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, and clinical decompensation.

Antiviral therapy is not recommended for HBeAg-positive children aged 2 years up to 18 years who have persistently normal ALT (conservative value: 30 U/L), regardless of the HBV DNA level. (Strong recommendation)

Inpatient care

Patients with hepatitis B disease and fulminant hepatic failure should be hospitalized in the intensive care unit (ICU) and be considered as liver transplant candidates in the event that they do not recover. Any patient with acute HBV disease needs to be treated with first-line oral therapy, such as tenofovir disoproxil fumarate (TDF) or entecavir (ETV).

Patients with acute hepatitis should be monitored with blood tests in order to document biochemical improvement (see Workup).

Dietary limitations

Patients with acute or chronic hepatitis without cirrhosis have no dietary restrictions. For individuals with decompensated cirrhosis (signs of portal hypertension or encephalopathy), the following dietary limitations are indicated:

  • A low-sodium diet (1.5 g/day)
  • High-protein diet (ie, white-meat protein, such as chicken, turkey, or fish)
  • Fluid restriction (1.5 L/day) in cases of hyponatremia
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Pharmacologic Management

Currently, pegylated interferon alfa (PEG-IFN-a), entecavir (ETV), and tenofovir disoproxil fumarate (TDF) are the first-line agents in the treatment of hepatitis B disease. These are the main treatment drugs approved globally for this disease, although ongoing trials are investigating new types of medications, such as tenofovir disoproxil in combination with emtricitabine (FTC). Encapsidation inhibitors, entry inhibitors, TLR7 agonists, and therapeutic vaccines are all in development.

In 2009, international phase III trials with clevudine (l-FMAU) for the treatment of chronic hepatitis B virus (HBV) infection were halted owing to a very high risk of myopathy. [61]

Lamivudine (3TC), telbivudine, and adefovir are of historical interest. These agents are currently considered second- or third-line therapy, or “nonpreferred” treatment. [62]

Approved antiviral therapies

The following are medications approved for the treatment of chronic hepatitis B in pediatric and adult patients (adjust all dosing in the setting of renal dysfunction)  [37] :

  • Pegylated interferon (PEG-IFN)-2a (adults) or IFN-alpha-2b (children) – Adult dose 180 μg weekly; pediatric dose (age ≥1 year): 6 million IU/m 2 three times weekly
  • Telbivudine – Adult dose only: 600 mg daily
  • Entecavir – Adult dose: Daily 0.5 mg (lamivudine-/telbivudine-naive persons) or 1.0 mg (those with lamivudine/telbivudine experience or decompensated cirrhosis); pediatric dose (age ≥2 years): Weight-based to 10-30 kg; for children weighing more than 30 kg, use 0.5 mg daily
  • Lamivudine – Adult dose: 100 mg daily; pediatric dose (age ≥2 years): 3 mg/kg daily (maximum: 100 mg)
  • Adefovir – Adult and pediatric dose (age ≥12 years): 10 mg daily
  • Tenofovir – Adult and pediatric (age ≥12 years) dose: 300 mg daily

World Health Organization (WHO) recommendations

First-line antiviral treatment (Strong recommendations)

All individuals aged 12 years or older who are eligible for antiviral therapy are recommended to receive therapy with tenofovir or entecavir, the nucleos(t)ide analogs (NAs) with a high barrier to drug resistance. Entecavir is recommended in children aged 2-11 years.

NAs with a low barrier to drug resistance (lamivudine, adefovir, or telbivudine) are not recommended owing to their potential for drug resistance.

In HBV/human immunodeficiency virus (HIV)-coinfected indviduals aged 3 years or older, a fixed-dose combination of tenofovir/lamivudine (or emtricitabine)/efavirenz is the preferred option for initiation of ART.

Second-line antiviral treatment for managing treatment failure (Strong recommendation)

For individuals with confirmed or suspected antiviral resistance (ie, history of prior exposure or primary nonresponse) to lamivudine, entecavir, adefovir, or telbivudine, the WHO recommends switching to tenofovir.

Specific considerations

Special attention must be given to patients on liver transplantation lists. Initiation of treatment with entecavir or tenofovir is of cardinal importance before and after liver transplantation to achieve viral suppression and to prevent recurrence of the disease after the procedure. Combination therapy with ETV and TDF or, more rarely, TDF with FTC or 3TC can be considered if drug-resistant mutants are present or for patients with failing first-line therapy.

Caution must also be used with long-term and high-dose administration of adefovir or tenofovir therapy in patients with chronic HBV disease. In a National Institutes of Health (NIH) study, 15% of patients on adefovir or tenofovir for 2-9 years developed proximal renal tubular dysfunction, defined as de novo incidence of 3 of the following 5 features [63] :

  • Hypophosphatemia
  • Hypouricemia
  • Elevated serum creatinine level
  • Proteinuria
  • Glycosuria

Switching to other antiviral agents in the study allowed for partial reversal of the renal tubular dysfunction. [63]

ETV was associated with lactic acidosis in a study of 5 patients with liver failure who had Model for End-Stage Liver Disease (MELD) scores of greater than 20. [64]

In patients with HBV who are coinfected with human immunodeficiency virus (HIV), it may be possible to simplify treatment regimens with agents that have dual effectiveness against both viruses. [41] Hepatitis D (delta) virus (HDV) infection is best treated with PEG-IFN therapy.

Interferon alfa

Interferons are proteins that have antiviral, antiproliferative, and immunomodulatory effects. Published reports indicate that after IFN-a treatment with 5 million U/day or 10 million U 3 times per week subcutaneously (SC) for 4 months, HBV DNA levels and HBeAg become undetectable in 30-40% of patients. [65] In addition, 10% of patients seroconvert from hepatitis B surface antigen (HBsAg) to hepatitis B surface antibody (anti-HBs). Unfortunately, 5-10% of patients relapse after completion of treatment. A transient "flare," (ie, increased serum alanine aminotransferase [ALT] levels during the beginning of treatment) can be identified, and this represents the impact of the activated cytolytic T cells on the infected hepatocytes.

High levels of aminotransferases, a low viral load, and infection with the wild type virus are good prognostic factors for response to IFN-a treatment. However, Asian patients and patients with the precore mutant virus tend to not have a clinical response to IFN-a treatment.

Loss of HBsAg indicates resolution of the HBV infection, acute or chronic, but it is rare in chronic infection. A study by Tseng et al that followed Taiwanese patients with chronic hepatitis B infection who developed spontaneous HBeAg loss (seroconversion) showed that patients with low levels of HBsAg 1 year after their HBeAg seroconversion had a higher probability of loss of HBsAg. [66]

Glomerulonephritis

IFN-a therapy has been successful in treating HBV-related glomerulonephritis. A regimen of 5 million units of IFN-a subcutaneously (SC) daily for 4 months has achieved HBsAg seroconversion with improvement of glomerulonephritis. It has also been reported that IFN-a given at a dose of 3 million units 3 times per week led to improvement of proteinuria only in patients with mesangial proliferative glomerulonephritis, not in those with membranoproliferative glomerulonephritis (MPGN).

Finally, a single case report described the resolution of this complication after liver transplantation. In addition to interferon, antiviral therapy with lamivudine (3TC) has not only been shown to significantly increase the incidences of proteinuria remission and of HBeAg seroconversion but also cause a decline in levels of HBV-DNA in adult patients with HBV-related glomerulonephritis relative to controls. [67]

Polyarteritis nodosa

Small and medium-sized arteries and arterioles are affected in polyarteritis nodosa (PAN). Although corticosteroids and immunosuppressive agents may be beneficial for treating vasculitis, they may potentially have a deleterious effect on the course of hepatitis B liver disease due to viral reactivation, particularly after the withdrawal of treatment.

The antiviral drug adenine arabinoside and IFN-a have been used in conjunction with plasmapheresis and a short course of corticosteroids, with promising results.

The combination of short-term corticosteroids accompanied by plasmapheresis and lamivudine, as used in one study, resulted in 100% clinical recovery and 66% seroconversion, although the number of patients in the trial was relatively small. [68]

Precautions

Special attention must be given to patients with HBV-decompensated cirrhosis (eg, ascites, encephalopathy) who are taking IFN-a, owing to the fact that, although they occasionally may have a treatment response, these individuals can also deteriorate further.

The adverse effects of IFN-a treatment can sometimes be severe, even devastating. Some patients cannot complete the treatment. A flulike syndrome, myelosuppression (eg, leukopenia, thrombocytopenia), nausea, diarrhea, fatigue, irritability, depression, thyroid dysfunction, and alopecia are among the adverse effects that may occur.

Pegylated IFN-a 2a

PEG-IFN-a 2a has an enhanced half-life relative to the standard INF-a. Pegylation lowers the rate of absorption following subcutaneous (SC) injection, reduces renal clearance, and decreases the immunogenicity of the interferon.

A 48-week regimen of PEG-IFN-a 2a may induce a 27% rate of HBeAg seroconversion and a 25% rate of loss of HBV DNA. [69] In a study by Lau et al involving a 48-week regimen, after 24 weeks of follow-up the HBeAg seroconversion rate with PEG-IFN-a 2a monotherapy was 32%, compared with 27% in those receiving combination therapy with 3TC and 19% in those receiving 3TC monotherapy. [69]

It appears that patients infected with HBV genotype A or B have a better response to IFN treatment than do patients infected with genotype C or D. This therapy also appears to be more appealing, especially for patients with increased ALT levels.

PEG-IFN-a 2a is also indicated for treatment of chronic hepatitis C, alone or in combination with ribavirin, in patients not previously treated with IFN-a, with compensated liver disease, or with HDV infection. At most, 17% of patients have durable suppression of the virus as defined by undetectable HBV DNA at 5 years posttreatment. [69, 70]

Telbivudine

Telbivudine, a cytosine nucleoside analogue, is a second-line agent (not preferred) used in HBV therapy. [19]  This drug is a potent inhibitor of HBV DNA polymerase. Although telbivudine appears to have slightly more potent antiviral activity than do adefovir and lamivudine, it is more expensive and plays a limited role in primary therapy.

HBeAg-positive patients

The results of the phase III GLOBE Trial that tested the administration of 600 mg of telbivudine versus 100 mg of 3TC over a 2-year period showed that in the HBeAg-positive population, therapeutic response (defined as HBV DNA < 10,000 copies/mL, with either ALT normalization or HBeAg loss) was 75% for the patients treated with telbivudine and 67% for the patients treated with 3TC. [71, 72]

Of the patients receiving telbivudine, 26% lost the e antigen, versus 23% of the patients receiving 3TC. [71, 72]  In addition, a 6.5-log reduction of the HBV DNA was noted for the patients receiving telbivudine versus a 5.5-log reduction for the patients receiving 3TC.

HBeAg-negative patients

In the HBeAg-negative patients in the phase III GLOBE Trial, the response rates at 1 year were 75% for the telbivudine group and 77% in the 3TC group, whereas 88% of the telbivudine-treated patients and 71% of the lamivudine-treated patients had nondetectable HBV DNA. The HBV DNA log reduction was 5.2 (telbivudine group), compared with 4.4 (lamivudine group). [71, 72]

Regarding treatment resistance, a major issue in hepatitis B disease, the reported resistance rates at 1 year were 2.6% for patients on telbivudine and 8.2% for patients on lamivudine. [71, 72]

Entecavir

Entecavir is a first-line agent in the treatment of hepatitis B. [19] This drug is a potent guanosine analogue inhibitor of the viral polymerase with 1.2% resistance in patients who have no history of previous treatment with nucleos(t)ide analogues and almost 56% resistance in 3TC-resistant patients during a 6-year treatment period. [73]

Advantages of therapy with this agent include potent antiviral activity and a low drug resistance rate, [19] although entecavir has less of a role than other agents in the treatment of 3TC-resistant hepatitis B.

A retrospective study demonstrated that HBV DNA responses at 12 months can potentially be used to evaluate entecavir therapy in nucleos(t)ide analogue ̶ naïve, HBV-infected patients. [74] Investigators reported 3 independent predictors for maintenance of viral suppression among patients on entecavir treatment at 3 years—lower baseline HBV DNA, undetectable HBV DNA at month 12, and negative HBeAg—as well as for the probability of HBeAg-seroconversion and the risk of drug resistance. [74]

HBeAg-positive patients

With regard to the HBeAg-positive population, administration of 0.5 mg of entecavir in patients who were naïve to nucleoside analogues relative to patients who received 100 mg of 3TC for a duration of 48 weeks resulted in histologic improvement in 72% of the entecavir group compared with 62% of the 3TC group. [75] Undetectable serum HBV DNA levels were reported in 67% of entecavir-treated patients, compared with 36% of 3TC-treated patients.

In addition, normalized ALT levels were achieved in 68% of the entecavir group, versus 60% of the 3TC group. [75] The mean reduction in serum HBV DNA from baseline to week 48 was 6.9 log copies/mL (on a base-10 scale) in the entecavir-treated patients, relative to 5.4 log copies/mL in the 3TC-treated patients. HBeAg seroconversion occurred in 21% of patients treated with entecavir and in 18% of patients treated with 3TC. [75]

HBeAg-negative patients

In an HBeAg-negative population, administration of 0.5 mg of entecavir in patients who were naïve to nucleoside analogues compared with patients who received 100 mg of 3TC for a duration of 48 weeks resulted in histologic improvement in 71% of the entecavir group, versus 61% of the 3TC group. [73] Undetectable serum HBV DNA levels were found in 90% of the entecavir-treated patients, versus 72% of the 3TC-treated patients.

Normalized ALT levels were achieved in 78% of the entecavir group, compared with 71% of the 3TC group. [73] The mean reduction in serum HBV DNA levels from baseline to week 48 was 5.0 log copies/mL (on a base-10 scale) in the entecavir-treated patients, versus 4.5 log copies/mL in the 3TC-treated patients. [73]

Long-term (5- and 6-y) data

After up to 5 years (240 wk) of continuous entecavir therapy (1.0 mg qDay) for HBeAg-positive patients, 94% of patients had less than 300 copies/mL of HBV DNA, and 80% had normal ALT levels. [76] An additional 23% of patients achieved HBeAg seroconversion, and 1.4% lost HBsAg. Only 1 patient demonstrated treatment resistance with entecavir through 5 years. [76]

In another study, Schiff et al reported that long-term treatment with entecavir (about 6 y of cumulative therapy [range, 267-297 wk]) in nucleoside-naïve chronic hepatitis B patients with advanced fibrosis or cirrhosis resulted in durable virologic suppression, continued histologic improvement, and reversal of fibrosis/cirrhosis. [77] The patients received entecavir for at least 3 years and had evaluable biopsies at baseline and after long-term treatment.

Lamivudine

A nucleoside analogue, 3TC inhibits the viral polymerase. It appears to be effective in patients who do not have a treatment response to IFN-a (eg, patients infected by the precore mutant virus). However, its role in hepatitis B treatment is diminishing as alternate therapies become available [19] ; thus, this agent is a third-line therapy and not preferred.

Other agents, except for adefovir, are superior to 3TC in suppression of viral replication. Another disadvantage to this therapy includes its high rate of drug resistance. [19] Relative to other oral treatments, however, 3TC is lower in cost.

Therapy with 3TC has been associated with a 4-log reduction of viral load. [62, 78, 79, 80] Treatment (100 mg/day) has also been associated with the following:

  • 16-18% seroconversion rate from HBeAg to anti-HBe
  • 30-33% rate of HBeAg loss
  • 40-50% normalization of the value of the aminotransferases
  • 1-2% HBsAg seroconversion rate

The HBeAg seroconversion rate has been shown to possibly increase to 27% after 2 years, 40% after 3 years, and 47% after 4 years of treatment in patients with a viral load of less than 104 pg/mL.

Histologic improvement (ie, reduction of the histologic activity index by >2 points) has been noticed in approximately 50% of patients taking 3TC. The adverse effects are negligible, although a transient elevation of aminotransferases can be noticed shortly after starting treatment.

Treatment with 3TC has also been shown to dramatically improve the condition of patients with decompensated disease due to HBV reactivation. Patients with HIV infection and fulminant hepatic failure due to active HBV infection may receive 3TC-only treatment. [41] Those with HIV/HBV coinfection who are eligible for antiretroviral therapy and have less severe hepatic injury should defer the antiretroviral treatment until resolution of the liver injury. [41]

Polyarteritis nodosa

As previously mentioned, the combination of short-term corticosteroids accompanied by plasmapheresis and lamivudine, as used in one study, resulted in 100% clinical recovery and 66% seroconversion in patients with HBV-associated PAN, although the number of patients in the trial was relatively small. [68]

HBV infection prophylaxis in HIV

In patients infected with HIV, antiretroviral therapy regimens containing 3TC or TDF may be prophylactic for HBV infection. A recent analysis examined stocked serum samples from 354 men with HIV who had not been vaccinated against hepatitis B and whose initial serum samples showed no signs of HBV. [81]

All of the patients in the study were men who had sex with men, a population in which hepatitis B infection in the presence of HIV is particularly common. An analysis of the final stocked samples from these patients found that sometime after their first serum samples were obtained, 43 of the 354 men had become infected with HBV. [81]

The investigators found that the rate of incident HBV infections was lower during periods when antiretroviral regimens using 3TC or TDF were used (0.669 incident infections in 100 person-years) than it was during periods when no antiretroviral therapy was used or when antiretroviral therapy employed neither 3TC or TDF (6.726 and 5.263 incident infections in 100 person-years, respectively). [81]

Complications

The emergence of viral variants is the major complication in hepatitis B disease. [82, 83] Approximately 15-30% of patients develop a mutation of the viral polymerase gene (the YMDD variants) after 12 months of treatment with 3TC; approximately 50% develop a mutation after 3 years of treatment with the drug, and as many as 70-100% develop a mutation with long-term therapy. However, continued treatment after the breakthrough with the variant type has been associated with lower HBV DNA levels, less aminotransferase activity, and histologic improvement. For these patients, discontinuation of treatment is accompanied by a reversion to a wild type of HBV and a flare of the disease.

Adefovir dipivoxil

Adefovir is another third-line agent (not preferred) that is indicated for the treatment of chronic hepatitis B disease with evidence of active viral replication, including patients with 3TC-resistant hepatitis B. [19] This agent is a nucleoside analogue, a potent inhibitor of the viral polymerase. The efficacy of adefovir dipivoxil has been tested in HBeAg-positive, HBeAg-negative, and 3TC-resistant patients with encouraging results.

The optimal dose seems to be 10 mg/day [84, 85] ; higher doses are nephrotoxic. The estimated rate of resistance to adefovir and the development of mutations (rtN236T and rtA181V) are approximately 4-6% after 3 years and approximately 30% after 5 years of treatment. [86, 87, 88, 89]

The results of 2 multicenter trials that used adefovir for 48 weeks noted that in HBeAg-positive patients who received 10 mg of adefovir daily, there was a median 3.52-log reduction of the viral load (HBV DNA) level. [84, 85] In 48% of the patients, normalized aminotransferase levels were reported, and histologic improvement was seen in 53% of the patients who received this regimen. [84] The HBeAg seroconversion rate was 12%.

Furthermore, of the HBeAg-negative population, 64% experienced histologic improvement after receiving 10 mg of adefovir for 48 weeks, and 72% had normalized aminotransferase levels. [84, 85] The serum HBV DNA level was decreased in 51% of subjects. The outcomes were maintained if treatment was continued for 44 weeks, but the benefits were lost if treatment was discontinued at 44 weeks. [84, 85] The development rate for the resistant mutations rtN236T and rtA181V has been estimated to be around 6%. [85]

Tenofovir

Tenofovir may be used as the first-line therapy for treatment-naïve patients. [19] This agent is preferred as an additional therapy in patients with resistance to 3TC, telbivudine, or entecavir. Tenofovir provides more potent antiviral therapy than adefovir, and it can be used as a substitute in patients who do not have an adequate response to adefovir.

Tenofovir is a nucleotide analogue (adenosine monophosphate) reverse transcriptase and HBV polymerase inhibitor.

HBeAg-positive naïve patients

In a study that randomized patients to receive either tenofovir (300 mg once daily) or adefovir (10 mg once daily) for 48 weeks—with the adefovir-treated patients then switched to tenofovir—79% of the patients who received tenofovir were found to have a viral load below 400 copies/mL, whereas 76% of patients who received adefovir before switching to tenofovir were found to have a viral load below 400 copies/mL. [90]

In addition, 72% of patients in the adefovir arm who were found to have a viral load greater than 400 copies/mL achieved viral suppression after they were switched to tenofovir. For patients who achieved viral suppression on adefovir alone, the effect was maintained after they were switched to tenofovir. [90] Biochemical response was reported in 77% of patients in the tenofovir arm at week 72 and in 61% of those switching from adefovir to tenofovir.

With regard to seroconversion, 26% of patients who received tenofovir seroconverted at week 64, while in the adefovir arm, the observed seroconversion rate was reported as 21%. [90] It is noteworthy to mention that 5% of patients in the tenofovir arm experienced loss of the s antigen.

HBeAg-negative patients

In another report involving patients who were randomized to receive either tenofovir (300 mg once daily) or adefovir (10 mg once daily), with all eligible adefovir-treated patients being switched to tenofovir after 48 weeks, 91% of patients receiving tenofovir at 72 weeks of treatment were found to have a viral load below 400 copies/mL, [91] compared with 88% of patients in the adefovir-to-tenofovir arm. All of the adefovir-treated patients who had a viral load below 400 copies/mL at week 48 maintained a viral load below this level after switching to tenofovir. [91] Of the patients in the adefovir arm who did not achieve optimal viral response (that is, those with a viral load >400 copies/mL) by the time they switched to tenofovir, 94% had a viral load below 400 copies/mL by week 72.

Normal ALT levels at week 72 were observed in 79% of patients who initiated therapy with tenofovir and in 77% of patients who switched from adefovir to tenofovir. [91]

HBeAg-negative or -positive patients with chronic HBV

In 2 double-blind, phase III studies in which patients with HBeAg-negative or HBeAg-positive chronic hepatitis B were randomized to receive tenofovir (300 mg) or adefovir (10 mg) (ratio, 2:1) once daily for 48 weeks, Marcellin et al concluded that among patients with chronic hepatitis B, tenofovir at a daily dose of 300 mg had superior antiviral efficacy and a similar safety profile to adefovir at a daily dose of 10 mg through week 48. [92]

At week 48 in both studies, a significantly higher proportion of patients receiving tenofovir than those receiving adefovir had reached the primary end point (plasma HBV DNA level < 400 copies/mL [69 IU/mL]), and viral suppression occurred in more HBeAg-negative patients in the tenofovir group (93%) than in the adefovir group (63%), as well as in more HBeAg-positive patients receiving tenofovir (76%) than in those receiving adefovir (13%). [92]

Furthermore, significantly more HBeAg-positive patients in the tenofovir group (68%) not only had normalized ALT levels relative to those in the adefovir group (54%), but these individuals also had loss of HBsAg (3% tenofovir group vs 0% adefovir group). [92]

At the end of 48 weeks, none the patients had developed the amino acid substitutions within HBV DNA polymerase that are associated with phenotypic resistance to tenofovir or other drugs used to treat hepatitis B. Tenofovir produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The 2 treatments in both studies had similar safety profiles. [92]

5-Year data

Marcellin et al reported that patients who received tenofovir continuously for 240 weeks had sustained suppression of HBV DNA levels below 400 copies/mL (HBeAg-negative patients: 83%; HBeAg-positive patients: 65%). [58] Patients who were randomized to adefovir and then, at week 48, rolled over to tenofovir for the subsequent 192 weeks also maintained viral suppression (HBeAg-negative patients: 84%; HBeAg-positive patients: 66%).

Of the HBeAg-positive patients who received tenofovir through 240 weeks, 9% experienced s-antigen loss, and 7% seroconverted. The HBeAg loss rate was 46%, and the HBeAg seroconversion rate was 40%. No evidence of resistance to tenofovir emerged over the treatment period. [58]

In addition, 87% of the 348 patients who had paired biopsies at baseline and week 240 experienced an improvement in the overall liver histology, as measured by an improvement of a minimum of 2 points in the Knodell necroinflammatory score without worsening in the Knodell fibrosis score. Of the 96 patients who had cirrhosis (Ishak fibrosis score ≥5) at the start of therapy, 74% experienced regression of cirrhosis. [58]

HBV infection prophylaxis in HIV

As previously mentioned, in patients infected with HIV, antiretroviral therapy regimens containing 3TC or TDF may be prophylactic for HBV infection.

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Surgical Intervention

Orthotopic liver transplantation (OLT) is the treatment of choice for patients with fulminant hepatic failure who do not recover and for patients with end-stage liver disease due to hepatitis B disease. The implementation of hepatitis B immunoglobulin (HBIG) during and after the OLT period, and of lamivudine (3TC) or adefovir in the pre- and post-OLT periods, dramatically reduces the recurrence rate of hepatitis B. The current standard is to use HBIG and tenofovir disoproxil fumarate (TDF) or entecavir (ETV). At some centers, HBIG is being stopped at approximately 12 months or sooner; at other centers, HBIG is no longer being used, with the focus on first-line therapy.

For more information, see the Medscape Drugs & Diseases articles Liver Transplants, Liver Transplantation, Transfusion Requirements in Liver Transplantation, and Imaging of Liver Transplantation Complications.

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Hepatitis B and Pregnancy

The American College of Obstetricians and Gynecologists (ACOG) and the US Preventive Services Task Force (USPSTF) recommend routine prenatal screening for hepatitis B surface antigen (HBsAg) in all pregnant women—during every pregnancy—regardless of previous test results or vaccinations. [93, 94] Pregnant women at risk for hepatitis B infections should be specifically targeted for vaccination. [93] The risk of transmission of hepatitis B associated with amniocentesis is low.

For newborns born to mothers with chronic hepatitis B infection, administer combined immunoprophylaxis with hepatitis B immune globulin (HBIG) and hepatitis B vaccine within 12 hours of birth. [93, 94] Thereafter, these infants should follow the hepatitis B vaccine series as part of the recommended childhood immunization schedule.

Breastfeeding is not contraindicated in women chronically infected with hepatitis B if the infant receives HBIG passive prophylaxis and vaccine active prophylaxis. [93] Mothers with chronic hepatitis B infection are often treated in the third trimester if the serum hepatitis B virus (HBV) DNA level is greater than 106 -108 copies/mL, especially if she is positive for the hepatitis B e antigen (HBeAg).

The 2016 American Association for the Study of Liver Diseases (AASLD) has similar guidelines for the treatment of chronic hepatitis B in pregnant women. [37]  The AASLD suggests antiviral therapy to reduce the risk of perinatal HBV transmission in HBsAg-positive pregnant women with an HBV DNA level above 200,000 IU/mL. (Conditional recommendation) Infants of these mothers should receive immunoprophylaxis according to current World Health Organization and Centers for Disease Control and Prevention recommendations.

Therapy for pregnant women with immune-active hepatitis B should be based on the same recommendations as for their nonpregnant counterparts.

Antiviral therapy is not recommended to reduce the risk of perinatal HBV transmission in HBsAg-positive pregnant women whose HBV DNA level is at or below 200,000 IU/mL. (Strong recommendation)

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Vaccination

Universal hepatitis B vaccination programs are ongoing in endemic areas, with encouraging results. The hepatitis B vaccine consists of recombinant hepatitis B surface antigen (HBsAg) produced in yeast. A series of 3 injections may achieve HBsAg antibody (anti-HBs) levels greater than 10 million IU/mL in approximately 95% of vaccinated individuals. Vaccination with a single dose must be repeated every 5-10 years.

All newborns must be vaccinated against hepatitis B. For infants born to mothers with active hepatitis B, a passive-active approach (hepatitis B immunoglobulin [HBIG] and vaccination) is recommended.

Healthcare workers should be vaccinated against HBV. Individuals who have had a needle-stick accident from a patient with active hepatitis B infection must receive active-passive immunization (HBIG and the first dose of the vaccine at the same time). These individuals must be monitored with blood tests.

Current guidelines recommend that all previously unvaccinated adults aged 19 through 59 years with diabetes mellitus (types 1 and 2) be vaccinated against hepatitis B as soon as possible after a diagnosis of diabetes is made. Clinicians may use their discretion in determining whether to vaccinate elderly diabetic patients (age ≥60 y). [95]

The New York State Department of Health recommends vaccination with the hepatitis B vaccine series in patients infected with human immunodeficiency virus (HIV) who are negative for anti-HBs, unless they have chronic infection. [41, 60]

In a report that collected data from 2 studies assessing the 5- and 10-year persistence of anti-HBs and immune response to a hepatitis B virus (HBV) vaccine challenge in children and adolescents who had received the HBV 3-dose vaccine series in infancy, German investigators demonstrated that this routine practice induced long-term anti-HBs persistence for 10 years and immune memory against HBV—even with waning anti-HBs levels. [96]

Low response rates and nonresponders

Low vaccination response rates have been associated with obesity, smoking, immunosuppression, and advanced age. Approximately 25-50% of persons who initially do not have a vaccine response will show a response to 1 additional vaccine dose, and 50-75% of individuals will have a response to a second 3-dose series.

It is recommended that testing for anti-HBs be obtained 4-12 weeks following vaccination. [41, 60] Revaccinate nonresponders, (HBsAb levels < 10 IU/L) with another series of 3-dose hepatitis B vaccine. Consider delaying revaccination for several months after initiation of antiretroviral therapy in patients with CD4 counts below 200 cells/mm3 or those with symptomatic HIV disease. The delay in these individuals is an attempt to maximize the antibody response to the vaccine. [41, 60]

Do not defer vaccination in pregnant patients or patients who are unlikely to achieve an increased CD4 count. [41, 60] Individuals at increased risk of severe complications due to HBV infection include those unlikely to achieve CD4 counts of 200 cells/mm3 or above after antiretroviral therapy (eg, HBV/hepatitis C virus [HCV] coinfection) and HIV-infected pregnant women. [41]

A combined hepatitis A virus (HAV)/HBV vaccine is licensed in many countries and offers the advantage of protection against both of these viruses at the same time. The vaccine seems to be safe, although some questions exist regarding neurologic complications.

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Long-Term Monitoring

Individuals with inactive chronic infection with the hepatitis B virus (HBV) should have routine blood tests at least annually to check their aminotransferase levels. Patients with chronic active hepatitis should also undergo blood tests (ie, to evaluate aminotransferase levels, antigen-antibody HBV profile, viral load, and alpha-fetoprotein [AFP] levels). In rare cases, patients may be considered for liver biopsy.

Current guidelines recommend monitoring of HBV DNA and alanine aminotransferase (ALT) levels at least annually; however, a study conducted by Juday et al suggests that adherence falls below recommendations. [97] Expert opinion supports that following the recommended guidelines reduces the risk of disease progression.

Patients with cirrhosis must be monitored for hepatocellular carcinoma (HCC) by having their AFP levels checked every 6-12 months and undergoing surveillance with abdominal ultrasonography. [98]  Note, however, that AFP levels have been eliminated from the American Association for the Study of Liver Diseases (AASLD) guidelines. [37, 54]

Monitoring considerations

Physicians should keep the following in mind when managing a patient with hepatitis B:

  • Identify cases of fulminant hepatic failure, and list the patient as a candidate for liver transplantation
  • Monitor individuals with inactive chronic infection for probable disease reactivation
  • Inform the patients' spouse/sexual partners about the infectivity of hepatitis B and their need for screening, possible linkage to care, and possible need for vaccination
  • Monitor patients with cirrhosis and perform HCC surveillance studies (ie, liver ultrasonography) every 6-12 months
  • Place patients with cirrhosis on liver transplantation list when needed
  • Identify hepatitis D (delta) virus (HDV) superinfection in patients with HBV infection
  • Screen for human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV) coinfection
  • Assess for hepatitis A virus (HAV) immunity; if the patient is not immune, provide immunization

Viral reactivation

Hepatitis B virus (HBV) may persist in the blood for decades after clinical recovery from acute hepatitis despite the presence of serum antibodies. Immunosuppressive conditions or drugs may allow dormant HBV to flare or reactivate. Additionally, genetic factors (eg, genetic mutations) may influence the risk for reactivation by affecting hepatitis B core antibody (anti-HBc) response. [99]

Close monitoring during and for several months after therapy with immunosuppressive drugs is appropriate. If reactivation of hepatitis B occurs, stopping the agent and initiating antiviral therapy may be warranted. Various national organizations including the AASLD and the National Institutes of Health (NIH) recommend the use of prophylactic antiviral therapy in inactive HBsAg carriers who are to undergo antineoplastic or immunosuppressive therapy. [2, 54, 99]

Medications that may increase the risk for hepatitis B reactivation include:

  • Anti-CD20 antibodies: Ofatumumab (Arzerra), rituximab (Rituxan)
  • Antineoplastic agents (including methotrexate) [100, 101]
  • Glucocorticoids, especially with abrupt discontinuation [102, 103]
  • Interleukin receptor antagonists: Ustekinumab (Stelara), [104] anakinra (Kineret), tocilizumab (Actemra)
  • Nucleoside and nucleotide therapy, due to immune reconstitution syndrome or discontinuation of antiviral therapy with anti-HBV properties
  • T-cell regulator: Abatacept (Orencia) [105]
  • Tumor necrosis factor (TNF) inhibitors: Infliximab (Remicade), [104] etanercept (Enbrel), [104] adalimumab (Humira), [104] certolizumab pegol (Cimzia), golimumab (Simponi, Simponi Aria)
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