Advances in the study of efficacy prediction and optimal treatment of chronic hepatitis B
Although there are several options for the treatment of chronic hepatitis B, due to differences in host (age, gender, family history, degree of liver inflammation, etc.), virus, and other factors, a significant number of patients still have poor outcomes even when patients with the same treatment indications receive the same standard treatment regimen. There is a consensus on how to optimize current antiviral drugs and how to make efficacy predictions in order to improve the overall efficacy of antiviral therapy, reduce the occurrence of drug resistance, thereby slowing disease progression, reducing the incidence of cirrhosis, hepatocellular carcinoma and end-stage liver disease, and ultimately reducing mortality associated with liver disease.
I. Optimization strategies for interferon-based (IFN) drugs.
(i) Guiding treatment according to baseline index characteristics (BGT): interferon therapy can be started when the organism breaks the immune tolerance state and enters the immune clearance phase. Grasp the right time to start interferon therapy is the key to BGT.
1, HBeAg positive chronic hepatitis B patients: baseline ALT level is a reliable indicator to predict HBeAg serological conversion. Higher indicators of liver inflammatory activity (HAI), low levels of HBVDNA quantification, and genotype A or B HBV infection become able to predict long-term outcome indicators.
2, HBeAg-negative chronic hepatitis B patients: baseline ALT levels and HBVDNA quantification are predictors of durable response to interferon therapy. Patients treated with pegylated interferon with pre-treatment baseline HBV DNA <107 IU/ml and ALT >3×ULN had a better sustained response rate after discontinuation. A Meta-analysis evaluating the efficacy of receiving 1 year of treatment with pegylated interferon alone or in combination with concomitant lamivudine showed that subjects with baseline ALT > 500 U/L had a 3.69-fold higher sustained response rate than those with ALT ≤ 500 U/L.
(ii) Guiding treatment according to the response of serological and virological indicators during interferon therapy (RGT)
The dynamic changes of serological and virological indicators during interferon therapy can predict its long-term efficacy, so the optimal treatment plan can be formulated by monitoring the changes of these indicators during the course of treatment. Currently, the main indicators include: HBsAg quantification, HBeAg quantification, and HBVDNA quantification. There is evidence that HBsAg level can human reflect the transcription level of cccDNA in hepatocytes and can be used as a serum marker to evaluate the level of viral replication. Some experts believe that the measurement of HBsAg and HBV DNA levels during treatment can be combined to evaluate the long-term efficacy.
Optimization strategy of nucleoside (acid) analogues
There are currently five nucleoside (acid) analogues approved for the treatment of chronic hepatitis B worldwide: lamivudine (LAM), adefovir (ADV), telbivudine (L-dT), entecavir (ETV), and tenofovir (TDF) (TDF is undergoing registration clinical studies in China). Most patients treated clinically with nucleoside (acid) analogs require long-term or even lifelong medication, and viral drug resistance has become one of the most difficult clinical challenges, so it is necessary to optimize the antiviral regimens of different drugs to improve the long-term treatment process and the sustained response rate after drug discontinuation, and to reduce the occurrence of drug resistance
(i). Selection of initial therapeutic agents. In the course of nucleoside (acid) analogue therapy, early viral response is closely related to its long-term efficacy and the development of drug resistance, so the choice of which nucleoside (acid) analogue to use in initial therapy is crucial. Current guidelines for the treatment of hepatitis B in Europe and the United States recommend the selection of nucleoside (acid) analogs that have the ability to efficiently inhibit viral replication and a high genetic resistance barrier for initial treatment. However, this recommendation cannot be fully implemented in clinical practice yet due to the different national conditions in China.
(ii). Selection of the timing of initial treatment. The timing of nucleoside (acid) analogue therapy is similar to that of interferon. Selection of the immune clearance phase (ALT ≥ 2 × ULN) to start nucleoside (acid) analogue antiviral therapy is an important aspect of optimal treatment. In addition, for patients with more severe hepatitis activity or who develop decompensated cirrhosis, nucleoside (acid) analogue therapy may be preferred considering their higher risk of interferon use.
(iii). Selection by response status during treatment. The virological index of each nucleoside (acid) analogue during treatment is closely related to its long-term efficacy. Among them, the response status of early HBV DNA is related to the efficacy. Patients with good early HBV DNA response have better long-term efficacy and lower incidence of viral resistance, while patients with slow early HBV DNA decline tend to predict poor long-term efficacy and are more likely to develop viral resistance.
III. Outlook
(i) Predictive indicators in terms of
1, virology: HBV DNA load is currently the more concerned about the predictive index, but its predictive efficacy still has some limitations, and more and more clinical experiments are studying the joint application with HBsAg quantitative and HBeAg quantitative testing in order to improve the predictive efficacy.
2. Immunological aspects: chronic hepatitis B is not only a viral infection, but also an immunological disease. Exploring immunological predictive indicators, such as specific antibodies produced by the host against HBV or non-specific immunological indicators of the body, is one of the most important aspects to improve predictive efficacy.
3. Genomics: Genetic factors of the host are one of the most important factors affecting disease progression, antiviral efficacy and whether adverse drug reactions occur. Exploring the value of genomics in predicting the efficacy of hepatitis B treatment will bring the development of individualized optimal treatment strategies for hepatitis B in China to a new level.
(ii) Optimization of treatment regimens.
1. Combination with therapeutic hepatitis B vaccine.
2. Combination with cell biology treatment protocols.
3. Combination with immunomodulators.