Anti-hepatitis B virus (HBV) drug resistance is a serious problem.
(1) Most patients with chronic hepatitis B require long-term treatment. HBeAg-negative patients account for about 40% of patients with chronic hepatitis B, and they all require long-term treatment; HBeAg-positive patients account for about 60% of patients, 20% of whom can undergo HBeAg conversion or transformation after short-term treatment, but 80% of patients do not convert HBeAg at 1 year of treatment, and they also require long-term treatment. Long-term antiviral therapy inevitably results in drug resistance. For example, the incidence of drug resistance at 1, 2, 3, 4, and 5 years of treatment with lamivudine is 24%, 38%, 49%, 67%, and 65%, respectively.
(2) Currently, nucleoside (acid) analogs against hepatitis B virus have only one antiviral target, namely the reverse transcriptase region, and do not work on other processes of viral replication.
(3) With the exception of interferon, only one class of nucleoside (acid) analogs is an antiviral drug.
(4) Although the current nucleoside (acid) analogues can be divided into three categories: (i) L-nucleoside analogues such as lamivudine and telbivudine; (ii) acyclic phosphates such as adefovir and tenofovir; and (iii) cyclopentane/alkene analogues such as entecavir. However, they have common resistance mutation sites, for example, rtA181T/V mutation can produce resistance to lamivudine, telbivudine, adefovir and tenofovir; rtM204V/I mutation can produce resistance to lamivudine, telbivudine, tenofovir and entecavir, etc.
(5) Lamivudine was first used for the treatment of chronic hepatitis B in China and abroad, and its resistance rate is high, thus affecting the therapeutic effect of other nucleoside (acid) analogues in the future.
(6) There is a problem of abuse of antiviral drugs in China, such as treatment of hepatitis B virus carriers in the immune tolerance period and antiviral drugs for pregnant women to prevent mother-to-child transmission.
(7) Irregular treatment, such as some doctors or patients blindly reducing the dosage of drugs or treating on alternate days.
(8) Poor patient compliance, such as patients do not adhere to the treatment, see the “good” to accept, eat and stop, or change their own drugs, etc.
(9) Doctors do not know enough about antiviral treatment and cannot standardize treatment.
(10) Lack of simple and sensitive methods to monitor drug resistance, and failure to monitor the occurrence of drug resistance in a timely and effective manner.
(11) What is more serious is that drug-resistant strains can also be spread in the population, and once an epidemic occurs, especially a multi-drug-resistant strain, treatment will be more difficult.
I. Prevention of antiviral resistance.
Prevention of antiviral resistance includes.
(1) avoiding unnecessary treatment.
(2) Application of drugs with high resistance genetic barrier and high antiviral power.
(3) switching to other antiviral drugs if early response is suboptimal
(4) Avoid sequential monotherapy.
(5) Applying combination therapy, if possible.
(6) standardization of treatment (standardized regimens and doses and treatment by route maps, etc.).
(7) Improving patient compliance with treatment.
(8) Strengthening drug resistance monitoring (including pre-treatment monitoring).
II. Monitoring of antiviral drug resistance.
(i) The indications for the emergence of drug-resistant strains of HBV are.
(1) elevated viral load (31.0 log IU/mL).
(2) Elevated serum alanine aminotransferase (ALT) levels.
(3) Clinical exacerbation.
(4) Detectable drug resistance gene variants in the viral polymerase region.
(ii) Nomenclature of antiretroviral therapy resistance.
(1) Primary Antiviral Treatment Failure (or Nonresponse)]: serum HBV DNA does not decrease to 31 log10 IU/ml 6 months after initiation of nucleoside (acid) analogue therapy.
(2) Secondary Antiviral Treatment Failure (or Virologic Breakthrough)]: Patients who were compliant with antiviral treatment and achieved Initial Response, but were maintained on treatment, but after 2 serum HBV DNA increased by 3 1 log10 IU/ml from the nadir after a 1-month interval.
(3) Biochemical Breakthrough: Patients who are compliant with antiviral therapy and whose ALT has returned to normal, but whose serum ALT is elevated despite maintenance therapy.
(4) Genotypic Resistance: amino acid substitutions in the reverse transcriptase region of the HBV genome are detected in the viral population during antiviral therapy, indicating resistance to antivirals in phenotypic tests; these variants are generally detectable in patients with virologic breakthrough but can also be present in patients with persistent viremia without virologic breakthrough.
(5) Phenotypic resistance (PVR): reduced susceptibility of HBV polymerase to antiviral therapy in vitro.
(6) Cross Resistance (Cross Resistance): decreased sensitivity to more than one antiviral drug due to substitution of the same amino acid or combined substitution of 2 or more amino acids.
(c) Detection methods for drug resistance site variation include.
(1) Direct PCR sequencing method: the least sensitive, with a minimum detection limit of 20%; can detect new variant sites and can be used as a test for new treatments or to detect new resistance-associated site variants of current treatments.
(2) Restriction Fragment Length Polymorphism (RFLP): sensitive with a minimum detection limit of 5%; can detect only known resistance loci.
(3) INNO-LiPA: sensitive, with a minimum detection limit of 5%; only known resistance loci can be detected.
III. Rescue treatment of antiviral resistance.
(i) Lamivudine resistance.
(1) Addition of adefovir.
(2) Switching to entecavir.
(3) Switch to Truvada (a combination of emtricitabine and tenofovir).
(4) Addition of tenofovir.
(ii) Adefovir resistance.
(1) Addition of lamivudine.
(2) Addition of entecavir.
(3) Switch to entecavir.
(4) Switch to Truvada.
(iii) Entecavir resistance.
(1) Addition of adefovir.
(2) Switch to adefovir.
(3) Addition of tenofovir.
(4) Switch to tenofovir.
IV. Treatment according to the roadmap to prevent the occurrence of drug resistance.
Predictors affecting prognosis at 2 years of treatment by applying stepwise logistic regression analysis were.
(1) Baseline factors: including age, geographic region, HBV DNA level, Knodell HAI score, BMI, years since diagnosis, previous IFN treatment history race, HBV genotype, ALT level, cirrhosis, weight, likely source of infection, and treatment.
(2) On-treatment factors: including serum viral load and ALT levels at 24 weeks.
(i) Evaluation of initial response (Initial Response) at 12 weeks.
If the patient’s serum HBV DNA decreases by 31 log at 12 weeks of treatment, the patient is considered to have an initial response and treatment can be continued. If serum HBV DNA decreases <1 log, the patient is considered to be in initial non-response. If the initial non-response is due to poor patient compliance, try to improve patient compliance; if patient compliance is good, the treatment regimen should be changed.
(ii) Early Response at 24 weeks.
Early response at 24 weeks correlates with serum HBV DNA level, drug resistance rate, and disease regression at 2 years.
(1) Complete Response: That is, serum HBV DNA is reduced to <60 IU/mL or <300 cp/mL, and treatment can be continued with follow-up every 6 months, or once every 3 months or more frequently if the patient is sicker.
(2) Partial Response: i.e., serum HBV DNA is reduced to 60~2000 IU/mL or 300~104 cp/mL, and treatment can be continued with non-cross-resistant drugs or followed up every 3 months.
(3) Inadequate Response: serum HBV DNA >2000 IU/mL or >104 cp/mL, can be added with non-cross-resistant drugs and followed up once every 3 months.
(iii) Follow-up of partial responders.
Follow up every 3 months when treatment is started. If the patient has a complete response at 36 weeks, follow up once every 6 months; if the patient’s viral load continues to decrease within 36 weeks but does not have a complete response at 36 weeks, continue to follow up once every 3 months; if the patient’s viral load increases or stops moving, treat as under-responder; if the patient is in serious condition, increase the frequency of follow up (decided by the physician).
(iv) Future of the hepatitis B treatment roadmap.
Future hepatitis B treatment roadmap may include HBV genotype testing, screening for pre-existing variants to help select treatment regimens, and maintaining treatment continuity through early detection of drug resistance and adjustment of treatment regimens; future roadmap should focus on prevention of drug resistance, i.e., application of roadmap and combination therapy to avoid drug resistance.