The 2015 American Association for the Study of Liver Diseases (AASLD) annual meeting published the 2015 AASLD Guidelines: Treatment of Chronic Hepatitis B. The guidelines focus on antiviral treatment options for chronic HBV infection, and issues related to disease screening, prevention and surveillance and diagnosis, monitoring and treatment of special populations are not addressed in detail, with the following guideline recommendation highlights.
Treatment of CHB in the immune active phase
Recommendation 1A: AASLD recommends antiviral therapy for patients with immunologically active CHB (HBeAg-negative or HBeAg-positive) to reduce the risk of liver-related complications. (Quality of evidence/certainty: moderate; strength of recommendation: strong)
Recommendation 1B: AASLD recommends Peg-IFN, entecavir, or tenofovir therapy as the first choice for initial treatment in adult patients with immunoreactive CHB. (Quality of evidence/certainty: low Strength of recommendation: strong)
1, Immunologically active CHB is defined as elevated ALT levels >2 ULN (upper limit of normal) or evidence of significant histologic disease and elevated HBV DNA levels >2,000 IU/mL (HBeAg negative) or >20,000 IU/mL (HBeAg positive).
2, The ULN of ALT in healthy adults is 30 U/L for men; 19 U/L for women.
3, There is insufficient evidence to support or oppose the use of ALT criteria, except for ALT ≥ 2 ULN. Treatment is recommended for ALT levels > ULN, but <2 hbv="" dna="">2,000 IU/mL, regardless of their ALT levels.
4. Other factors to consider in the treatment of immunologically active CHB patients with ALT levels <2 ULN and HBV DNA levels below the threshold include.
Age > 40 years with a higher likelihood of significant histological disease
Family history of HCC
History of treatment.
-Peg-IFN serologic benefit (disappearance of HBeAg and HBsAg) may occur months to years after treatment interruption (delay).
Trans-NA treatment is a risk for drug resistance
Extrahepatic manifestations are present: there are indications for treatment independent of the severity of liver disease
5. HBV DNA levels should be consistent with immunologically active disease, and recommended thresholds should be well-documented, not absolute, and not a therapeutic necessity.
6, Head-to-head comparisons of antiviral therapy do not demonstrate an advantage of one treatment regimen in reducing the risk of liver-related complications. However, in recommending Peg-IFN, tenofovir and entecavir as the preferred treatment
the most important factor considered was the absence of drug resistance with long-term use. Patient-specific factors to consider when choosing between Peg-IFN, tenofovir, and entecavir include
Desire for short-term treatment
Comorbidities: Peg-IFN is contraindicated in patients with autoimmune disease, uncontrolled psychiatric disease, hemocytopenia, severe cardiac disease, uncontrolled seizures and decompensated cirrhosis
History of lamivudine resistance (entecavir is not recommended as a first choice)
HBV genotype: genotypes A and B are more likely to achieve HBeAg and HBsAg disappearance with Peg-IFN therapy than non-A/B types
Cost of drug therapy
7. Peg-IFN treatment is superior to non-pegylated forms from a simplified treatment perspective
8. For patients treated with Peg-IFN, a 48-week treatment period was used in most studies and was preferred. The HBeAg serologic conversion rate for this treatment cycle is 20-31%, and approximately 65% of patients with HBeAg serologic conversion to anti-HBe have sustained HBV DNA suppression <2,000 IU/mL after treatment. serologic or virologic response rates after Peg-IFN in combination with NAs are not high and are not recommended.
9. Duration of NA-based regimens is a variable influenced by HBeAg status, duration of HBV DNA suppression, and decompensated cirrhosis. Dose adjustment is required for all NAs in patients with creatinine clearance <50 mL/min.
10. Assessment of disease stage or biopsy with noninvasive tests is necessary to guide treatment decisions including duration of therapy.
11. Antiviral drug therapy does not eliminate the risk of HCC, and HCC surveillance should be performed in high-risk patients.
Treatment of CHB in the immune tolerant phase
Recommendation 2A: AASLD does not recommend antiviral therapy for adult patients with immune-tolerant CHB. (Quality of evidence/certainty: moderate; strength of recommendation: strong)
1. Immune-tolerant CHB is defined as a ULN with an ALT level ≤ 30 U/L in men and an ALT level ≤ 19 U/L in women, rather than the local laboratory index ULN.
Recommendation 2B: AASLD recommends that adult patients with immune-tolerant CHB be tested for ALT levels at least every 6 months to monitor the potential transition from immune tolerance to immune activity or inactivity. (Quality of evidence/certainty: very low; strength of recommendation: conditional)
Recommendation 2C: AASLD recommends that the select group of adults aged >40 years with normal ALT levels and elevated HBV DNA levels (≥1,000,000 IU/mL) and liver biopsies suggestive of significant necrotizing inflammation or fibrosis should be treated with antiviral therapy. (Quality of evidence/certainty: very low; strength of recommendation: conditional)
1. After excluding other causes of liver disease, liver biopsy showing moderate to severe necrotizing inflammation or fibrosis may be considered for initiation of antiviral therapy.
Treatment of HBeAg-positive immunoreactive CHB patients after seroconversion to anti-HBe after NA therapy
Recommendation 3A: AASLD recommends discontinuation of NAs after a period of consolidation therapy in HBeAg-positive adult CHB patients without cirrhosis who seroconvert to anti-HBe.(Quality of evidence/certainty: very low; strength of recommendation: conditional)
1, During consolidation therapy, ALT levels need to remain normal and serum HBV DNA levels undetectable for at least 12 months.
2. It is unclear whether a longer duration of consolidation therapy will result in a lower rate of virologic relapse. Therefore, it is hoped that alternative treatment regimens will result in the disappearance of HBsAg.
3. Decisions about the duration of treatment and the duration of consolidation therapy before stopping treatment require careful consideration of the risks and benefits to health prognosis, including.
1. the risk of virologic relapse, liver failure, hepatocellular carcinoma and death.
2. the burden of continuing antiviral therapy, the cost of drugs and the financial implications of long-term testing, patient compliance, and the potential for drug resistance and treatment discontinuation
3. the preferred choice of patients and physicians. These considerations apply to HBeAg-positive adult patients with (or without) cirrhosis who are seroconverting to anti-HBe on treatment.
4. Patients who discontinue antiviral therapy should be monitored every 3 months for relapse of viremia, ALT surge, seroconversion, and clinical failure to compensate for at least 1 year.
Recommendation 3B: The AASLD recommends that adult CHB patients with cirrhotic HBeAg-positive disease receive long-term antiviral therapy after seroconversion to anti-HBe on NA therapy based on considerations of potential clinical failure and death unless there is a strong reason to discontinue therapy. (Quality of evidence/certainty: very low; strength of recommendation: conditional)
1. Patients with cirrhosis who discontinue antiviral therapy should be monitored closely (e.g., monthly for the first 6 months and every 3 months thereafter) for relapse of viremia, ALT surge, seroconversion, and clinical failure .
2. Patients with confirmed disappearance of HBsAg should be considered for treatment discontinuation. However, there is insufficient evidence to definitively guide treatment decisions in this population.
Duration of treatment in HBeAg-negative immunoreactive CHB patients
Recommendation 4: The AASLD recommends that adult patients with HBeAg-negative immunoreactive CHB should be placed on long-term antiviral therapy unless there is a strong reason to discontinue treatment. (Quality of evidence/certainty: low; strength of recommendation: conditional)
1, HBeAg-negative adult patients without cirrhosis need to be cautious about the risks and benefits to their health prognosis when discontinuing treatment, including: 1, the risk of virologic relapse, liver failure, hepatocellular carcinoma and death; 2, the burden of continuing antiviral therapy, the economic burden of drug costs and long-term monitoring, patient compliance, the likelihood of drug resistance and treatment discontinuation; and 3, patient and physician preference.
2, discontinuation of therapy in patients with cirrhosis is not recommended, so that liver failure and death may occur, although relevant data are limited.
3, Patients with proven disappearance of HBsAg may be considered for discontinuation of therapy. However, there is insufficient evidence to clearly guide treatment decisions in this population.
4, Patients who discontinue antiviral therapy should be monitored every 3 months for relapse of viremia, ALT surge, seroconversion, and clinical failure to compensate for at least 1 year.
5. Antiviral therapy is not recommended for patients without cirrhosis who are HBeAg-negative, have normal ALT activity, and have low levels of viremia (< 2,000 U/mL; "inactive chronic hepatitis B").
Renal and orthopedic complications in NA-treated patients
Recommendation 5: The AASLD recommends no difference between entecavir and tenofovir in terms of potential long-term risk of renal and orthopedic complications, (quality of evidence/certainty: very low [bone], low [renal]; strength of recommendation: conditional)
1. In patients with HBV infection treated with tenofovir or entecavir, the available studies showed no significant differences in the development of renal insufficiency, hypophosphatemia, or altered bone mineral density. However, renal adverse events, such as acute renal failure or hypophosphatemia, have been reported in tenofovir-treated patients.
2. For tenofovir-treated patients, renal safety testing, including serum creatinine, phosphorus, urinary glucose and urinary protein, should be performed regularly (at least annually if renal insufficiency is preexisting or at high risk of occurrence) prior to initiation of therapy.
3, In the absence of other risk factors for osteoporosis/osteochondrosis, there is insufficient evidence to support or oppose bone density monitoring in HBV-infected patients treated with tenofovir.
4, Tenofovir should be discontinued when tenofovir-associated renal insufficiency and/or osteoporosis/osteochondrosis is suspected and replaced with alternative NA based on prior resistance history.
5. The dose of NAs should be adjusted based on renal function and creatinine clearance.
Management of patients with persistent low-level viremia on NA therapy
Recommendation 6A: The AASLD recommends that patients on entecavir or tenofovir monotherapy with persistent low-level viremia (<2,000 IU/mL) continue monotherapy regardless of ALT level. (Quality of evidence/certainty: very low; strength of recommendation: conditional)
Recommendation 6B: The AASLD recommends that patients who experience virologic breakthrough with entecavir or tenofovir monotherapy choose one of two strategies: switch to monotherapy with another antiviral with a high resistance barrier or add a second antiviral without cross-resistance. (Quality of evidence/certainty: very low; strength of recommendation: conditional)
1. It is important to understand patient medication adherence, especially for patients with persistent viremia on antiviral therapy.
2. Persistent viremia has been defined as detectable HBVDNA even after 48 weeks of treatment. this time point is based on the results of virologic response in clinical trials and reflects a period of antiviral therapy with ineffective antiviral, high resistance rate drugs. With entecavir and tenofovir becoming the current first therapy, persistent viremia is defined as a plateau period in which HBVDNA levels decline and/or remain detectable after 96 weeks of treatment. When continuing monotherapy replacement, there is currently insufficient comparative evidence regarding the addition of a second drug or switching to another drug. If viral levels are low, drug resistance testing may not be technically feasible at this time. Clinicians should ensure patient compliance at the time of treatment.
3. Viral breakthrough is defined as previously undetectable HBVDNA (<10 hbv="">1 log or HBV DNA ≥100 IU/mL. Confirmatory testing should be performed prior to changing treatment regimens. Drug resistance testing may be helpful for relevant follow-up therapy. A confirmed virologic breakthrough may be a reason to switch to another high genetic resistance barrier anti
viral monotherapy or add a second antiviral with a complementary resistance profile (Table 8). The long-term comparative evidence for advocating one regimen over the other is not sufficient. Based on virologic principles, the risk of viral resistance is predicted to be somewhat lower with antiviral drug combinations than with monotherapy.
4, Although the optimal frequency of HBV DNA testing has not been fully evaluated, testing every 3 months until undetectable and every 3-6 months thereafter is recommended to detect persistent viremia and virologic breakthrough.
5. For patients treated with NAs other than tenofovir or entecavir, switching to another antiviral monotherapy with a high genetic resistance barrier or adding a second antiviral with a complementary resistance profile will definitely achieve virologic breakthrough (Table 8).
Management of adult patients with cirrhosis and low-level viremia
Recommendation 7A: The AASLD recommends antiviral therapy for adult patients with compensated cirrhosis and low-level viremia (< 2,000 IU/ml), regardless of ALT level, to reduce the risk of liver failure. (Quality of evidence/certainty: very low; strength of recommendation: conditional)
1. Tenofovir and entecavir are preferred based on efficacy and minimal risk of drug resistance. Antivirals with low genetic resistance barriers should not be used because resistance can be hepatic decompensation.
2, Peg-IFN is contraindicated in patients with compensated cirrhosis, but NAs are relatively safe.
3. If patients with compensated cirrhosis and low-level viremia are not receiving treatment, they must be closely monitored (every 3-6 months) for elevated HBV DNA levels and/or clinical decompensation. If these occur, treatment should be initiated.
4, these patients have generally normal or <2>2 ULN) ALT levels should be considered for other causes of ALT elevation, and if none are found, antiviral therapy is strongly indicated.
5, The available evidence does not provide an optimal length of time for treatment. If treatment is discontinued, close monitoring (at least every 3 months for at least 1 year) should be performed for early detection of virologic rebound that can lead to decompensation.
6, For patients with compensated cirrhosis and high HBV DNA levels (>2,000 U/mL), receive treatment as recommended for HBeAg-positive and HBeAg-negative immunoreactive CHB patients (Recommendation 1A/B).
7. Antiviral drug therapy does not eliminate the risk of HCC and HCC monitoring should be continued.
Recommendation 7B: AASLD recommends long-term antiviral therapy in adult patients with decompensated cirrhosis who are HBsAg positive, regardless of their HBV DNA level, HBeAg status, or ALT level, to reduce the risk of worsening liver-related complications. (Quality of evidence/certainty: moderate; strength of recommendation: high)
1, Entecavir and tenofovir are the drugs of choice.
2.Peg-IFN is contraindicated in patients with decompensated cirrhosis for safety reasons.
3, Also consider suitable population for liver transplantation.
4.Some NAs have been reported to cause lactic acidosis, and patients with advanced decompensated cirrhosis are at higher risk. Close follow-up of laboratory tests and clinical status is necessary.
5. Antiviral drug therapy does not eliminate the risk of HCC and HCC monitoring should be continued.
Treatment of CHB during pregnancy
Recommendation 8A: AASLD recommends antiviral therapy for HBsAg-positive pregnant women with HBV DNA levels >200,000 IU/mL to reduce the risk of perinatal hepatitis B transmission. (Quality of evidence/certainty: low; strength of recommendation: conditional)
1, All infants of HBsAg-positive women should receive immunoprophylaxis (HBV vaccination ± hepatitis B immunoglobulin, as recommended by WHO/Center for Disease Control and Prevention).
2. The only antiviral drugs studied in pregnant women were lamivudine, telbivudine and tenofovir.
3. In most studies, antiviral therapy was initiated at 28-32 weeks of gestation.
4. In most studies, antiviral therapy was discontinued between birth and 3 months postpartum. During discontinuation of treatment, ALT surges should be monitored every 3 months for 6 months.
5. Data on HBV DNA levels for routinely recommended antiviral therapy are limited. Conservative recommendations for HBV DNA levels >200,000 IU/mL (1 million copies/mL).
6, For pregnant women with immunologically active hepatitis B, treatment should be based on the recommendations for non-pregnant women.
7. Breastfeeding is not a contraindication. These antivirals are rarely excreted through breast milk and are unlikely to cause significant toxicity. The unknown risk of low viral level exposure in infants should be communicated to the mother.
8. Long-term safety data for infants born to mothers taking antivirals during pregnancy and lactation are inadequate.
9. Cesarean section is not indicated because the relevant data supporting benefit are insufficient.
Recommendation 8B: AASLD does not recommend antiviral medications for pregnant women who are HBsAg positive with HBV DNA ≤ 200,000 IU/mL
to reduce the risk of perinatal hepatitis B transmission. (Quality of evidence/certainty: low; strength of recommendation: strong)
Treatment of CHB in children
Recommendation 9A: The AASLD recommends antiviral therapy for HBeAg-positive pediatric patients (2-18 years of age) with elevated ALT levels and measurable HBV DNA levels to achieve the goal of sustained HBeAg serologic conversion. (Quality of evidence/certainty: moderate; strength of recommendation: conditional)
1. ALT elevation (>1.3 ULN) for at least 6 months with elevated HBV DNA was included in most studies. Considering that HBV DNA levels are usually high in childhood (>106 IU/mL), there is no basis for recommending a lower treatment-related limit. However, if HBV DNA levels <106 IU/mL are found, treatment may be delayed until other causes of liver disease and spontaneous HBeAg serologic conversion are ruled out.
2. IFN-α-2b is approved for use in children 1 year and older, while lamivudine and entecavir are approved for use in children 2 years and older. Peg- IFN-α-2a (180 μg/1.73 m2 body surface area, maximum 180 μg once a week) is not approved for use in children with CHB, but is approved for the treatment of chronic hepatitis C in children 5 years and older. Clinicians may consider using this drug for the treatment of children with chronic HBV infection.
3. Entecavir treatment has a lower risk of viral resistance compared to lamivudine.
4, Tenofovir is approved for use in children 12 years of age and older.
5, The duration of treatment with IFN-alpha-2b is 24 weeks.
6. The duration of treatment with studied oral antivirals is 1-4 years. When taking oral antivirals, it may be prudent to continue consolidation therapy for 12 months as recommended for adults with HBeAg serologic conversion as a treatment endpoint. It is unclear whether a longer duration of consolidation therapy will reduce the chance of virologic relapse.
7. Children who discontinue antiviral therapy should be monitored for virologic relapse, ALT surges, and clinical loss of compensation every 3 months for at least 1 year.
Recommendation 9B: AASLD does not recommend antiviral drugs for HBeAg-positive pediatric patients (2-18 years of age) with persistently normal ALT, regardless of their HBV DNA levels. (Quality of evidence/certainty: very low; strength of recommendation: high)
1, Normal ALT in children is not clearly defined, but based on clinical trial definitions and limited literature, a conservative value is 30 U/L.
2. Although some IFN studies include children with normal ALT values, studies of oral antivirals do not include children with normal ALT values