Clinical application of entecavir entecavir expert consensus

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Entecavir (ETV) is one of the chronic hepatitis B (CHB) is one of the first-line drugs in patients with antiviral therapy. 2005, the U.S. Fo

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Entecavir (ETV) is one of the chronic hepatitis B (CHB) is one of the first-line drugs in patients with antiviral therapy. 2005, the U.S. Food and Drug Administration and the China National Food and drug administration has approved ETV for CHB treatment. Specification for clinical application and optimization of ETV, May 13, 2014 "Chinese Journal of Hepatology (Electronic Edition)" published in the latest issue of "guide to the clinical application of entecavir entecavir expert consensus: 2014 update", for clinical reference.

Data sources: 1, including seminars Pubmed as of October 2013 on the ETV literature; literature on ETV 2, Chinese database; 3, AASLD, EASL and APASL as the 2013 annual meeting of the conference of the personal experience and opinion; 4, experts. See Table 1 for the relevant evidence and recommendations.

1 ETV pharmacokinetics

ETV ring valeryl guanosine analogs in vivo into three phosphate active ingredient, HBV replication inhibition from 3 aspects: HBV polymerase start, pregenome RNA reverse transcription for the synthesis of HBV DNA positive and negative strand DNA chain. After oral administration of ETV, it can be absorbed rapidly. The peak concentration of plasma is about 0.5-1.5 hours, and the bioavailability of > is 70%.

Eating a standard high fat meal or a low-fat meal while taking 0.5 mg ETV will cause a slight delay in drug absorption, and therefore should be taken on an empty stomach ETV (before and after medication should not eat for 2 hours). ETV excretion through the kidneys. Pharmacokinetic studies showed that the clearance rate of ETV decreased with the decrease of endogenous creatinine clearance rate (Ccr), and patients with Ccr < 50 ml/min were required to adjust the dosage or medication interval.

If you choose to adjust the dosing interval, refer to table 2. In addition, ETV was similar to that in healthy controls in patients with decompensated liver function, so patients with decompensated liver disease did not need to adjust the ETV regimen for pharmacokinetic reasons.

Recommendation 1:ETV need fasting, you can recommend the patient before going to bed 2 hours after fasting. No need to adjust the dosage regimen in patients with decompensated liver function. Patients with renal insufficiency may adjust the dosing interval (A1) according to Ccr.

2 ETV for the treatment of chronic HBV infection

2.1 ETV used in the treatment of CHB patients with nucleoside (acid) analogs (NAs)

Results of a global registry of clinical trials and follow-up studies of patients with CHB treated with 2.1.1 ETV

1, ETV treatment of HBeAg positive CHB patients: ETV treatment of HBeAg positive patients with CHB global registration study and follow-up results show that: A, ETV: HBV DNA < for 48 weeks; 300 copies of /ml, the ratio of alanine aminotransferase (ALT) normalization rate, histological improvement rate and HBeAg seroconversion rates were 67% 68%, 72%, and 21%;

B and ETV were used for 96 weeks to accumulate HBVDNA <. The ratio of to /ml, the rate of ALT complex and the seroconversion rate of HBeAg were 80%, 87% and 31%, respectively. C and ETV were accumulated at HBVDNA for the first time in 144 weeks

< 300 copies of the /ml ratio, the recovery rate of ALT were 82%, 90% and 39% with HBeAg seroconversion; D, 146 cases of HBeAg positive patients at 240 weeks, the cumulative HBV DNA < ALT /ml 300 copy ratio and recovery rate were 94% and 80%.

2, ETV treatment of HBeAg negative CHB patients: global registration study of ETV treatment of HBeAg negative CHB patients and follow-up results: A, ETV: HBV DNA < for 48 weeks; 300 copies of the /ml ratio, the recovery rate of ALT and histological improvement rate were 90%, 78% and 70%; B, ETV for 96 weeks total HBV DNA

< 300 copy /ml ratio and ALT recurrence rate were 94% and 89%, respectively, C, relapse after stopping treatment and received ETV treatment for another 3 years, HBV

DNA< 300 copy /ml ratio was 95%.

2.1.2 ETV in the treatment of CHB patients in China

ETV treatment of CHB patients China phase III clinical study results: 1, ETV: HBV DNA < for 48 weeks; 300 copies of the /ml ratio, the recovery rate of ALT and HBeAg positive patients with HBeAg seroconversion rates were 76%, 90% and 18%; 2, ETV for 96 weeks total HBVDNA

< 300 copies of the /ml ratio, the recovery rate of ALT and HBeAg positive patients with HBeAg seroconversion rates were 79%, 96% and 21%; 3 part, poor efficacy in patients with a total of 160 cases were included in the long-term follow-up study, followed up to 144 weeks of HBVDNA < 300 copy ratio and ALT in patients with /ml recovery rate were 89% and 86%.

The results of the phase III clinical trial of patients with CHB (DNA) treated with maleic acid ETV control ETV: HBeAg (+) patients were treated with maleic acid ETV for 48 weeks, HBV

< 300/ml ratio, the recovery rate of ALT and e antigen seroconversion rates were 45%, 83% and 10%; 96 weeks of treatment, the above indexes were 66%, 86% and 12%; HBeAg (-) with maleic acid ETV for 48 weeks, HBV DNA

< 300 copy /ml ratio and ALT recurrence rate were 94% and 84%, respectively, at the end of the treatment for 96 weeks were 97% and 90%, respectively. The results showed that the efficacy and safety of maleic acid ETV and ETV in Chinese patients with CHB were similar.

Drug resistance of 2.1.3 ETV in patients with primary NAs

ETV genotype resistance is required in the HBV reverse transcriptase region rtM204V/I

On the basis of the variation of rtL180M + +, the amino acid changes of at least 1 sites of rtI169, rtT184, rtS202 or rtM250 can be combined into 4 groups. ETV treatment of NAs patients with initial treatment of first, 2, 3, 4 and the cumulative incidence of genotypic resistance were 0.2%, 0.5%, 1.2%, 1.2%, and 1.2%, respectively, in the treatment of CHB.

A study of 3 consecutive ETV patients treated with NAs in Japan for the first time in showed that the cumulative incidence of genotypic resistance was CHB. The incidence rate of ETV in the treatment of patients with CHB in China was 0%, 0.46% and 3, respectively, at the age of first, 2 and 3.8%, respectively. Based on the above studies, ETV can effectively inhibit HBV in patients with CHB, and the incidence of drug resistance is low. CHB guidelines at home and abroad are included in one of the first-line treatment of patients with CHB.

According to the China and Asia Pacific CHB guide, ETV CHB for the treatment of antiviral therapy in patients with general indications for a=HBeAg patients with positive HBV DNA load of more than 5 copies of log10 /ml, HBeAg HBV negative patients with DNA load of more than 4 copies of log10 /ml; b=ALT = 2

* the upper limit of normal (ULN); c=ALT < 2 * ULN, but liver histology showed that Knodell HAI is more than 4, or inflammation and necrosis or fibrosis than G2, more than S2.

In addition to HBV DNA positive, not up to the standard of care, but there are circumstances, should also be considered for antiviral therapy: A, ALT> ULN and > age; 40 years of age, should be carried out on antiviral therapy; B, ALT but normal older adults (> 40) should be closely follow up, the best liver biopsy; if the liver histology showed that Knodell HAI is more than 4, or more than G2 or inflammation and necrosis, fibrosis than S2, should be given antiviral treatment; C, dynamic observation as evidence of disease progression (such as splenomegaly), recommended for liver tissue biopsy, the need for antiviral therapy.

According to the China and Asia Pacific CHB guide, ETV treatment of HBeAg positive CHB patients, such as patients with HBV and DNA below the detection limit of ALT normalization and HBeAg seroconversion, and consolidation therapy for at least 1 years (after at least 2 review, the time interval of 6 months) will remain unchanged and the total course has at least 2 years. Can consider to stop drug.

However, in view of the fact that there is a considerable rate of recurrence in patients who have been discontinued by this standard, the experts suggest that the treatment should be extended as far as possible to reduce recurrence. For HBeAg negative CHB patients, ETV treatment reached HBV DNA below the detection limit and the ALT recovery after at least 1 and a half years of consolidation therapy (after at least 3 times review, the time interval of 6 months) will remain unchanged, and the total course has reached at least 2 and a half years, can consider to stop drug. The same time, considering that there is a considerable rate of recurrence in patients who have been discontinued by this standard, the experts strongly recommend extending the treatment as long as possible to reduce recurrence.

Recommendation 2:ETV can be used as one of the first choice drugs for CHB treatment of patients with antiviral therapy (A1), ETV antiviral treatment should be strictly grasp the indications. HBeAg positive and negative CHB patients are advised to prolong the course of treatment as far as possible to reduce recurrence (B1).

2.2 ETV for NAs treated patients with CHB 2.2.1 ETV (LAM) in the treatment of lamivudine and telbivudine (LdT) treated with CHB

Study ETV randomized Global Registry of patients with positive HBeAg LAM failure for 48 weeks of treatment with ETV although some patients with virologic response, but to continue receiving ETV treatment in patients with CHB LAM showed that the long-term monitoring of drug resistance in patients with genotype ETV failure resistant cumulative probability first to sixth years were 6% 15%, 36%, 47%, 51%, and 57%, the probability of drug resistance was significantly higher than that of untreated patients. Based on this, ETV monotherapy is not recommended for antiviral therapy in patients treated with LAM.

For patients with LdT failure, although the relevant evidence is not sufficient, taking into account the resistance site similar to LAM, it is not recommended that ETV monotherapy for LdT treatment of patients with antiviral therapy. Heo study showed that LAM resistant HBeAg positive CHB were treated with LAM + adefovir dipivoxil (ADV) scheme with ETV + ADV scheme to save for 96 weeks, ETV + ADV group HBV DNA load decreased 5.06 log copies /ml.

The LAMADV group decreased 4.49 log copies /ml. ETVADV group HBV DNA

< 50 IU/ml ratio was significantly higher than that of group vs (43.5% LAMADV

28.5%). Based on this, the LAM resistant patients, ETVADV salvage therapy is better than LAMADV scheme.

Recommendation 3:ETV treatment of LAM resistant CHB patients treated by high incidence rate, generally not recommended ETV monotherapy for the treatment of patients with LAM after antiviral therapy (B1), LAM resistant patients with ETV + ADV + ADV salvage therapy is more effective than LAM (B2). For patients with LdT failure, taking into account that the drug resistance site is similar to that of LAM, the application of ETV salvage therapy may refer to LAM treated patients (C2).

2.2.2 ETV for ADV treated patients with CHB

In patients with poor ADV response (including poor response, relapse after withdrawal and ADV resistance), ETV treatment could effectively inhibit the HBV DNA load. Studies have shown that patients with poor ADV response or relapse after discontinuation of treatment with ETV, 50% (8/16) and (8/9) in patients with ETV after twenty-fourth and 48 weeks to achieve HBV DNA < () copy of /ml.

In addition, the response rates were 63%, 68%, 72%, and 72 for patients with ADV partial responders who were treated with ETV at the age of 6, 12, 18, and 24 months, respectively. Patients who received ADV therapy were treated with ETV, regardless of whether the patient had ADV resistance, and 88% of the patients received virological response during 12-46 months follow-up. Therefore, ADV can not be considered for the treatment of poor efficacy of ETV as a follow-up treatment program; LAM treatment and ADV treatment is not ideal for patients with ETV + ADV regimen.

Recommendation 4:ADV early treatment effect of the poor, including patients with poor response, relapse after drug withdrawal and ADV resistant patients, can be considered as a follow-up treatment for ETV (B1); LAM treated and the effect is not ideal for the current ADV patients can be considered ETV + ADV treatment (C2).

2.3 ETV for the treatment of patients with chronic HBV infection 2.3.1

ETV in the treatment of patients with hepatitis B cirrhosis

Patients with hepatitis B liver cirrhosis (including compensatory and decompensated patients) as long as the detection of HBV DNA, regardless of the level of ALT should be considered antiviral therapy, most patients need a long course of treatment or even life-long treatment. Because of the strong inhibition of ETV and the low incidence of drug resistance, ETV should be regarded as one of the first-line antiviral drugs in patients with HBV.

ETV can not only effectively inhibit HBV, improve liver function in patients with liver cirrhosis, but also delay and reverse cirrhosis, reduce the incidence of liver cirrhosis and complications, improve the prognosis of patients with liver cirrhosis. Chang reported 10 cases of severe liver fibrosis / cirrhosis patients with long-term application of antiviral therapy of ETV (average 6 years), in patients with liver fibrosis were improved from the baseline (Ishak fibrosis score decreased more than 1 cent).

In 4 patients with liver cirrhosis, liver biopsy was restored to mild fibrosis. A long-term follow-up cohort study for Su reported 621 cases of patients with ETV cirrhosis of hepatitis B virus in Taiwan, preliminary results show that compared with non antiviral treatment history of the queue, ETV for 2.7 years can make the patients with decompensated cirrhosis risk of hepatocellular carcinoma decreased 59%.

Recommendation 5: compensatory and decompensated hepatitis B cirrhosis patients, as long as the HBV DNA can be detected, should be considered antiviral therapy; most patients require a long course of treatment or even life-long treatment. Because of the strong inhibitory effect of ETV and the low incidence of drug resistance, ETV should be regarded as one of the first-line antiviral drugs (A1) in patients with HBV.

2.3.2 ETV in patients with HBV associated hepatocellular carcinoma (HCC)

As long as the detection of HBV DNA, HBV related HCC patients should be treated with antiviral therapy. Antiviral therapy can inhibit HBV, improve liver function, reduce or delay the recurrence of HCC, prolong the survival time of patients. Taiwan, a large cohort follow-up study of HCC patients after surgical resection of tumor recurrence showed that patients receiving antiviral treatment of NAs (518 cases) 6 year recurrence rate was significantly lower than that of NAs did not receive antiretroviral treatment (4051 cases, 20.5% vs

43.6%).

NAs antiviral therapy is an independent risk factor for reducing the risk of HCC recurrence (HR= 0.68). Because of the strong inhibitory effect of ETV on HBV and the low incidence of drug resistance, it should be regarded as one of the first-line antiviral drugs (C1). In patients with HBsAg positive HCC, even if the HBV was negative in the patients with DNA, there was still HBV reactivation after liver arterial chemoembolization and systemic chemotherapy. Such patients should be given NAs to prevent HBV reactivation before receiving transcatheter arterial chemoembolization.

HBsAg positive HCC patients can be treated with ETV to prevent the reactivation of HBV infection before receiving immunosuppressive therapy such as hepatic arterial chemoembolization and systemic chemotherapy. The timing and course of treatment may refer to the following sections of ETV for immunosuppression.

Recommendation 6: HBV DNA can be detected in patients with HCC, ETV should be used as first-line antiviral drugs (C1). HBsAg positive HCC patients should be given antiviral therapy to prevent reactivation of HBV infection before receiving transcatheter arterial chemoembolization or systemic chemotherapy, and ETV should be considered as one of the first choice drugs (B1).

2.3.3 ETV for patients with HBV associated liver failure

Antiviral therapy should be given to patients with HBV related liver failure as long as HBV DNA positive. ETV inhibits HBV DNA rapidly, and should be used as first-line therapy in patients with this disease. Patients with acute and subacute liver failure should be treated with ETV until the occurrence of HBsAg seroconversion, and patients with chronic liver failure and chronic liver failure often need lifelong medication.

Zhao Hong reported that the application of ETV virus in patients with HBV related chronic liver failure in treatment can improve liver function in patients with ETV, 4 years of follow-up treatment group patients were followed up for 4 year survival rate was significantly higher than the control group (57.1% vs 17.2%), ETV related serious adverse reactions were not found during the study. ETV can be safely used in the treatment of HBV related liver failure and can effectively reduce the level of HBV DNA, improve the prognosis of patients with liver failure in early and middle stage, and improve the survival rate.

In the patients with advanced liver failure, the survival rate of the patients with liver failure is difficult to be improved due to the poor survival of the liver cells and the regeneration ability. The use of ETV in the treatment of patients with HBV related liver failure requiring liver transplantation can improve the patient's condition, improve survival and reduce the risk of hepatitis B recurrence after liver transplantation.

Recommendation 7:HBV related liver failure patients as long as HBV positive DNA antiviral therapy should be given to ETV. Patients with acute and subacute liver failure should continue to be treated with HBsAg seroconversion, and patients with chronic liver failure and chronic liver failure (CRF) are often treated with life-long medication (B1).

2.3.4 ETV for the treatment of chronic HBV infection with immunosuppressive agents

In patients with chronic HBV infection who are often treated with chemotherapy or immunosuppressive therapy, HBV replication is often repeated. Therefore, all patients receiving chemotherapy or immunosuppressive therapy should be screened for HBsAg and anti -HBc. HBsAg positive patients, regardless of the level of HBV DNA and ALT, should be treated with immunosuppressive therapy or chemotherapy before using NAs for antiviral therapy.

HBsAg negative and anti -HBc positive patients, such as HBV DNA positive, the treatment is similar to the HBsAg positive patients; HBV is DNA negative, regardless of how the anti -HBs state, application of general immunosuppressive or cytotoxic drugs should be closely monitored by the HBsAg HBV, DNA and ALT levels in the event of a HBsAg or HBVDNA positive to do may the rise in ALT before antiviral therapy.

Biological agents (including, but not limited to, anti -CD20 monoclonal antibodies and anti TNF- antibodies, etc.) that are involved in the body's immune system should also be treated with prophylactic antiviral therapy before treatment with corticosteroids. ETV should be used as one of the first choice for the prevention of reactivation of HBV infection in patients with this disease, especially for patients with high HBV DNA load, long duration of treatment, or liver dysfunction.

In recent years both at home and abroad have been reported that ETV is used for antiviral therapy before and after immunosuppressive agents and chemotherapy drugs. ETV should be applied for at least 2-4 weeks before immunosuppressive therapy or chemotherapy, such as baseline HBV DNA

Less than 5 copies of log10 /ml, 6 month discontinuation of preventive treatment at the end of immunosuppressive or cytotoxic drugs after treatment; such as baseline HBV DNA more than 5 copies of log10 /ml, to continue to reach the general treatment of HBV infection antiviral treatment discontinuation standards.

Recommendation 8: patients receiving chemotherapy or immunosuppressive therapy, HBsAg and anti -HBc screening should be carried out before treatment. ETV should be used as one of the prophylactic antiviral therapy for HBsAg positive patients receiving chemotherapy or immunosuppressive therapy (B1). ETV should be administered at least 2-4 weeks before immunosuppressive therapy or chemotherapy, and continue to be treated to achieve the standard of antiviral therapy (B1). Only -HBc positive patients should be closely monitored for the levels of HBsAg, HBV and ALT when treated with immunosuppressive agents or cytotoxic drugs. It is suggested that ETV and other drugs should be used to prevent the reactivation of HBV infection as early as possible (C2).

Application of 2.3.5 ETV before and after liver transplantation in patients with HBsAg positive

HBV infection in patients with end-stage liver disease in liver transplantation before the application of antiviral agents such as ETV HBV DNA to the lowest level, on the one hand can reduce the risk of recurrence in HBV patients after transplantation, on the other hand can make the partial loss of patients with decompensated cirrhosis have been alleviated, thus reducing the death to transplant period, and even make some patients no longer the need for liver transplantation.

Long term use of antiviral drugs combined with hepatitis B immunoglobulin (HBIG) in patients with HBV related end-stage liver disease after liver transplantation to prevent recurrence of HBV infection. The risk factors of patients with recurrent CHB, ETVHBIG scheme is LAMHBIG scheme can significantly reduce HBV reinfection after liver transplantation. A number of prospective and retrospective studies have reported the efficacy and safety of ETV in patients with CHB related liver transplantation.

In a single, open, multicenter phase B study, 65 patients with HBsAg positive end-stage liver disease were treated with ETV for at least 72 weeks after liver transplantation, with a total of 64 patients with HBIG. After 72 weeks of follow-up, the HBsAg of all the patients who were included in the analysis after transplantation was lower than the lower limit of detection, no HBV DNA positive again, and ETV combined with HBIG to prevent graft HBV reinfection was well tolerated.

Recommendations related to 9:HBV infection in patients with end-stage liver disease in liver transplantation using ETV HBV DNA to the lowest level, to reduce the patients after liver transplantation HBV the risk of recurrence, and can make the partial loss of patients with decompensated cirrhosis remission (A1). The same ETV combined with HBIG can be used to prevent graft reinfection of HBV, and there is no fixed course of treatment and long-term maintenance therapy (B1).

2.3.6 ETV for the treatment of HBV patients with human immunodeficiency virus (HIV) infection

CHB patients should be screened for HIV infection before anti HBV therapy. Most of the patients with HBV/HIV combined with the initial treatment of both HBV and HIV, should be used at the same time HBV/HIV are effective anti retroviral therapy (HAART) program, such as TDF + FTC/LAM treatment options. If HBV/HIV combined with the treatment of HAART infection does not contain a HBV inhibitory activity of the drug, can be used in the treatment of HAART inhibition of HIV on the basis of the full use of ETV for anti HBV therapy.

Among the HBV/HIV infected individuals who did not use HARRT, ETV single drug anti HBV therapy could screen out the HIV-1 resistance mutation, which led to the decrease of HIV-1 and FTC sensitivity. Therefore, HBV/HIV is not recommended for treatment of patients with HAART infection and in the near future without HAART treatment, ETV alone is not recommended for the treatment of HBV.

Recommendation 10: such as HBV/HIV infection in the HAART program does not contain HBV inhibitory activity of the drug, can be used in the treatment of HAART inhibition of HIV on the basis of the full use of ETV for anti HBV therapy (B1). HBV/HIV is not recommended for the treatment of HBV infection in patients who have not been treated with HAART and those who do not need to be treated with HAART in the near future (A1) with ETV alone.

2.3.7 ETV for pediatric patients

ETV was well tolerated in adolescents and adults over 16 years of age. A use of ETV in children with CHB in non interim randomized, open clinical study showed that NAs patients with newly diagnosed children according to the weight of the administration of ETV (0.015 mg/kg, a maximum dose of 0.5 mg) pharmacokinetic (PK) data similar to adult patients received a daily dose of 0.5 mg/.

A prospective evaluation of 24 weeks, the efficacy and safety of a previous anti HBV treatment without response to 5-17 year old children with CHB by ETV, the results suggest that ETV after 24 weeks of treatment, the total population, HBeAg positive and HBeAg negative patients with HBVDNA load and ALT level decreased. At twenty-fourth weeks, the mean serum HBV DNA load and ALT level in patients with HBeAg negative were significantly lower than those in HBeAg positive patients.

88%

The DNA of HBeAg negative patients and 23% HBeAg positive patients was lower than the detection limit of HBV. There were no adverse reactions associated with ETV therapy (AEs) during the analysis. Therefore, although ETV has not been formally approved for pediatric patients, preliminary studies have shown that ETV can effectively inhibit HBV replication in children with CHB and is well tolerated. Age > 5 years of age in patients with full communication with parents and informed consent, consider the use of ETV antiviral therapy.

Conclusion 11:ETV can effectively inhibit viral replication and well tolerated in children with CHB. Age > 5 years of age in children, can be fully informed consent to consider the use of ETV antiviral therapy (B2).

2.3.8 ETV for pregnant women

ETV is FDA class C drugs for pregnancy. Using ETV antiviral therapy during the pregnancy of patients may be considered as appropriate for the LAM, LdT or TDF to antiviral therapy is not recommended ETV for blocking vertical transmission of HBV infection, also do not recommend taking ETV mother to breastfeed.

3 monitoring of ETV treatment and drug resistance management

3.1 monitoring and follow-up of ETV therapy

Monitoring and follow-up of 3.1.1 ETV during treatment

During the ETV treatment response related indicators for regular monitoring and follow-up: A, biochemical indicators including: monitoring ALT and other indexes of liver function, should be 1 times a month after the start of treatment, continuous monitoring of 3 times, with 1 times improvement after every 3 months; B, virological markers: after the start of treatment each 3 months testing 1 HBV DNA, every 3-6 months testing 1 HBsAg, C, HBeAg and anti -HBe; monitoring of treatment should be individualized, can be adjusted according to the patient's condition.

Follow up after discontinuation of 3.1.2 ETV

ETV antiviral therapy should be careful to stop the drug, prolong the course of ETV can reduce recurrence. At least 1 months after stopping the drug, ALT, HBsAg, HBeAg, anti -HBe and HBV DNA were detected every 2 months, and every 3-6 months after the test, followed up for at least 12 months. If there is any change in the follow-up, the interval should be shortened.

3.2 management of resistance to ETV therapy

Prevention of 3.2.1 ETV resistance

ETV is one of the first-line drugs for antiviral therapy in patients with CHB. Before the start of ETV treatment should be fully assessed the patient's treatment indications, a detailed understanding of the patient's previous treatment. CHB patients with immune tolerance, unless the need for immunosuppressive therapy and other special circumstances, generally do not recommend antiviral therapy. For the first time in patients with elevated ALT, CHB should be analyzed for its possible causes, and caution should be given to antiviral therapy. LAM treatment failure patients generally do not recommend follow-up ETV monotherapy antiviral therapy.

ETV during the treatment of patients should be standardized medication, regular follow-up, as far as possible to improve patient compliance. Such as follow-up found that patients with poor virological response or virological breakthrough, should be timely to determine whether the patient compliance problems. In order to avoid the subsequent occurrence of hepatitis and liver decompensation, we should adjust the treatment plan according to the test results, and then we should adjust the treatment plan according to the results of HBV.

Recommendation 12: Anti HBV ETV therapy should be strictly grasp the indications for antiviral therapy; follow-up during treatment regularly, increase the compliance of patients; treatment of patients with good compliance, such as poor virological response or virologic breakthrough, timely genotypic resistance testing and give the salvage treatment (A1).

Treatment of 3.2.2 ETV resistance

ETV is a highly resistant gene barrier NA. Based on the existing studies, ETV resistant patients are recommended to use / replace TDF for antiviral therapy, or to consider the use of ADV for salvage therapy. In addition, it is possible to consider the use of interferon as salvage therapy.

Recommendation 13:ETV resistant patients suggest we add / change of antiviral therapy with TDF (B1), also can consider adding AD V rescue therapy (B2); also can consider change / interferon as salvage therapy (B2).

4 long term safety of ETV therapy

ETV since listing, has been applied in a large number of CHB patients, registration of clinical trials and clinical practice showed that ETV is safe and well tolerated, similar to other NAs, should closely monitor the liver function of patients with HBV, DNA, blood lactate and creatinine during ETV treatment.

Short text:

ETV:entecavir CHB:chronic hepatitis B, entecavir, chronic hepatitis B Ccr:creatinine

Clearance, creatinine clearance rate NAs:nucleoside

Analog (UE), nucleoside (acid) analogue ALT:Alanine

Aminotransferase, alanine aminotransferase ULN:upper limit of

Normal, the upper limit of normal LAM:lamivudine LdT:telbivudine ADV:adefovir dipivoxil, lamivudine, telbivudine and adefovir dipivoxil HCC:hepatocellular

Carcinom, hepatocellular carcinoma HBIG:HBV immune globulin, hepatitis B immunoglobulin HIV:Human

Immunodeficiency virus, human immunodeficiency virus HAART:highly active

Antiretroviral therapy, highly effective antiretroviral therapy PK:Pharmacokinetics, pharmacokinetics AEs:adverse events, adverse reaction

Xing Huichun Yang Song: Cheng Danying Li Yue write Expert Committee of experts (alphabetized): Chai Guangli, Cheng Danying, Jun, Hou Qingyuan, Jin Chunying, Ren Tao, Li Yousheng, Li Yao, Lv Hongmin, Luo Guanghan, Sun Wanli, Xie Wen, Pu Chunwen, Yan Jie, Yang Song, Zhang Huizhen, Zhang Ping, Zhang Wentao, Zhang Zong, Zhao Caiyan, Zhao Dougui, Zhao Yun, Zhen Zhen, Zhu Yinghua, Zou Guizhou

 

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