With the increase in the number of anti-HBV drugs and their applications, the forms of HBV drug resistance variants will also increase. The frequent emergence of drug resistance in clinical anti-HBV treatment has become a serious and important “clinical problem” that we must face, and the new concept of moving forward the time point of drug resistance management in the process of clinical drug resistance management has gradually become a consensus among virologists and clinicians.
I. Current status of nucleoside drug resistance
1, lamivudine (LAM): the first nucleoside analogues used in the antiviral treatment of chronic hepatitis B, belongs to the levonucleoside analogues, and its resistance rate is the highest, which greatly limits the application of the drug. The cumulative incidence of genotypic resistance for 1 to 4 years of treatment is 23% to 71%.
2.Tebivudine (LdT): The same drug belongs to the levonucleoside class structure, and its ability to inhibit HBV replication is powerful. In the global clinical trial data, ITT analysis of LdT treatment for 2 years found that the proportion of HBeAg-positive and negative chronic hepatitis B patients with virological breakthrough due to genotypic resistance was 21.6% and 8.6%, respectively, with a mutation pattern of mainly rtM204I, but also a little rtM204 mixed type, and did not see the combined rtM204I/L180M mutation. However, the mutation rate was 10.5% in the first year (48 weeks) and 30% in the second year (104 weeks) in the control LAM group, and the mutation pattern included rtM204I/V, rtM204 mixed type and rtM204I/L180M 3 kinds.
3. adefovir (ADV): a non-optimal dose of 10 mg was selected at the time of marketing approval due to its potential nephrotoxicity. long-term resistance incidence of ADV is currently available only in HBeAg-negative chronic hepatitis B patients, with a cumulative genotypic resistance incidence of 0-29% at 1-5 years of treatment, and its major mutation patterns are rtA181V and rtN236T, of which rtA181 locus deserves further study.
4, entecavir (ETV): the strongest antiviral effect among the currently listed nucleoside analogues, while requiring multiple loci replacement to produce clinical resistance (high resistance gene barrier), and the lowest incidence of cumulative genotypic resistance to long-term treatment in nucleoside primary patients. 1-6 years cumulative genotypic resistance incidence of ADV treatment in nucleoside primary patients is only 0.2%~1.2%.
Also ADV resistance requires a background of LAM resistance site replacement, and when patients have LAM resistance site replacement prior to ADV treatment, only one more ADV resistance-associated site replacement is required to generate resistance (low resistance gene barrier). Therefore, the incidence of ADV resistance in patients with LAM failure is significantly increased, with a cumulative genotypic resistance incidence of 6% to 52% over 1 to 6 years.
5, Tenofovir (TFV): In long-term studies of HIV/HBV co-infected patients, most cohort studies did not find the occurrence of drug resistance. TFV has been used for those who failed LAM treatment, and no resistance has been reported so far. Therefore, TFV should also be a nucleic acid analogue with low drug resistance, which, combined with its strong viral inhibitory efficacy and good serological conversion level, shows great promise for clinical application.
Clinical management of nucleoside drug resistance
At present, the strategies of drug resistance management are mainly prevention of drug resistance and prediction of drug resistance (roadmap concept) and salvage treatment, and the new concept of clinical management of drug resistance is “management time forward”, that is, from the time point of clinical resistance (biochemical breakthrough) to the time point of virological breakthrough and then to the time point of unsatisfactory virological response (early Virological response prediction) and eventually the time point of possible future resistance should be shifted forward to the starting point of treatment, i.e., the concept of preventive resistance management. Prevention of drug resistance mainly refers to the consideration of how to reduce the risk of drug resistance and delay its occurrence at the time of initial selection of antiviral therapy, and there are currently two main treatment strategies.
(1) Initial treatment selection of antiviral monotherapy with both potent and high resistance genetic barriers and low incidence of resistance;
(2) Initial treatment with a combination of two or more antivirals without cross-resistance. Predicting resistance refers to how to adjust and change the existing treatment strategy in a timely manner based on monitoring early response in patient treatment to reduce the risk of resistance to that drug therapy when an antiviral drug with low genetic barrier and high incidence of resistance has been started, i.e., the concept of treatment roadmap.
(I) Prevention of drug resistance
Prevention of drug resistance starts with the choice of initial therapy in addition to.
(1) Rational application of antiviral therapy, i.e., selecting the right patient to start the right antiviral therapy at the right time (including the selection of the right drug and regimen);
(2) Avoid single-drug sequential therapy to prevent the risk of decreased efficacy and increased risk of resistance to subsequent therapeutic agents due to single-drug sequential therapy, which limits the options for long-term hepatitis B antiviral therapy; there is also a risk of multidrug resistance;
(3) Avoiding the selection of drugs with cross-resistance limits the choice of future treatment options.
From the perspective that long-term treatment must be considered to prevent or delay the onset of resistance, the selection of potent, low resistance drugs, so-called high resistance genetic barriers and/or low resistance incidence drugs (e.g., ADV or TFV) monotherapy is an important prevention regimen for drug resistance. Available clinical data demonstrate that the basic therapeutic goal of long-term sustained suppression of HBV replication can be achieved in 90% of patients with this regimen. Another approach to prevent or delay the onset of drug resistance is the combination therapy strategy, where the initiation of antiviral therapy is combined with two or more drugs used simultaneously.
Data from current clinical studies show that combination regimens can reduce the incidence of drug resistance. However, there is still no clear answer or standard approach to achieve the dual effect of increasing antiviral efficacy and reducing (delaying) the onset of drug resistance through combination therapy. For example, the incidence of drug resistance in LAM and pegylated interferon combination therapy for 1 year is 1-4%; the incidence of drug resistance in ADV combination therapy for 2 years is 15%; and the incidence of drug resistance in LdT combination therapy for 1 year is 10%.
Thus, in terms of resistance prevention strategy, combining an antiviral drug with a low resistance gene barrier and high resistance incidence can reduce the risk of drug resistance, but does not completely prevent the occurrence of drug resistance; and if combined with a drug with a high resistance gene barrier, there is no relevant clinical study data.
It is debatable whether it is possible to completely prevent the occurrence of drug resistance by reducing the incidence from 1% to 0. Secondly, if such combination therapy proves to be better, is it worthwhile to do such a clinical study requiring >1000 patients per group? The trial design is very difficult to assess how to increase the efficacy and decrease the incidence of drug resistance, including the combination of such drugs with interferon.
(ii) Predicting drug resistance
Recently, analysis based on the LdTGLOBE study showed that patients who achieved a complete virological response at 24 weeks of treatment had a low incidence of resistance at 2 years of treatment. When coupled with appropriate patient selection, the incidence of drug resistance can be reduced to 2%-4%. As a result, Keeffe et al. proposed the concept of a treatment roadmap to guide the next clinical treatment decision based on assessing early virological response in antiviral therapy to improve efficacy and reduce the incidence of drug resistance by adjusting and optimizing treatment regimens.
It should be noted, however, that the current treatment roadmap concept and protocols are far from a perfect and ideal optimization protocol. The relationship between early treatment response and long-term efficacy is not only present in current hepatitis B antiviral therapy, but has been observed as early as in hepatitis C treatment. However, while the long-term (only 1 year predicted course) outcome of treatment in patients with early response in hepatitis C treatment is the ability to clear HCV and be cured, there is no antiviral therapy that can clear HBV with a course-free long-term treatment.
Therefore, the current treatment roadmap concept only provides and predicts the occurrence of drug resistance for 1-2 years of treatment. How effective is the long-term improvement of efficacy and reduction and delay of drug resistance through an adapted and optimized approach needs to be refined by a large body of evidence-based medical evidence. Therefore, it has been suggested that the current treatment roadmap concept applied to drug resistance management is closer to a trial-and-error concept.
We should also note that according to the treatment roadmap concept and current clinical data, the adjusted and optimized regimens to be used vary by hepatitis B disease state and by disease stage. The treatment roadmaps used for different nucleoside (acid) analogue classes of drugs with different antiviral efficacy and different resistance genetic barriers are also inconsistent.
As mentioned earlier, different adjustment time points (12, 24, 48 weeks), different lower limit values for HBV DNA testing, and different adjustment drug regimens determine the concept of individualization and optimization in the application of treatment roadmaps. According to the concept of time-shifting of drug resistance management, the concept of treatment roadmap for managing drug resistance has shifted the current time point of drug resistance intervention by a large step, which has its practical value for drugs with low resistance genetic barrier class. Through the use of roadmaps, we can screen at least this subset of patients for such drugs, thereby reducing or delaying the onset of resistance. However, for the resistance management of drugs with high genetic resistance barriers, I am afraid it is difficult to use the concept and method of roadmap to achieve it.
(C) Early “rescue” treatment
The time point of “rescue” treatment for patients with drug resistance has also been shifted forward to the point of virological breakthrough only, rather than the point of biochemical breakthrough of clinical resistance. (1.0 mg/d, but the incidence of resistance mutation is higher than in LAM primed patients), or add TFV (not yet approved by SFDA), or switch to Truvada (TFV + emtricitabine, not yet approved by SFDA), or switch to interferon α or pegylated interferon α (evidence-based); ADV resistance can be added to LAM or LdT or ETV (good for those who have not used LAM), or Truvada or TFV (not yet approved by SFDA), or interferon α or pegylated interferon α (evidence-based); ETV resistance can be added to ADV or TFV (the latter not yet approved by SFDA), or interferon α or pegylated interferon α (evidence-based); LdT resistance is treated in the same way as LAM-R. basically the same. Treatment of multidrug resistance: multidrug resistance to LAM+ADV can be treated with Truvada or TFV+ETV (not yet approved by SFDA); multidrug resistance to LAM+ETV can be replaced with TFV or Truvada (not yet approved by SFDA).