Interview with Professor Chen Enqiang: Clinical Cure of Chronic Hepatitis B

Hepatitis B virus (HBV) infection is a serious global public health problem, the existing chronic HBV infection base is huge, to achieve chronic hepatitis B (CHB) cure is a long-term academic barrier difficult to overcome, the current clinical cure is the ideal endpoint
of CHB treatment.
Yimaitong is honored to invite Professor Chen Enqiang from the Center for Infectious Diseases, West China Hospital of Sichuan University, to share
the concept, adaptation and exploration progress of CHB clinical cure.

Professor Chen Enqiang

• Associate researcher and master tutor of West China Hospital of Sichuan University

• Reserve candidate for academic and technical leaders in Sichuan Province

• Vice Chairman of the Youth Committee of the Infectious Diseases Branch of the Chinese Medical Association

• Member of the Drug-induced Hepatology Group of the Hepatology Branch of the Chinese Medical Association

• Member of the Viral Hepatitis Group of the Infectious Diseases Branch of the Chinese Medical Association

• Member of the Clinical Virology Group of the Virology Branch of the Chinese Medical Association

• Member of the Youth Committee of the Evidence-Based Medicine Branch of the Chinese Medical Doctor Association

• Vice Chairman of the Youth Committee of the Infection Special Committee of Sichuan Medical Association

• Member of the Liver Cancer Committee of Sichuan Cancer Society

• Member of the Standing Committee of the Rare Disease Committee of Sichuan Medical Association

Professor Chen Enqiang: Clinical cure is an emerging concept in recent years, which is very suitable for CHB patients in China, because China is a large country of hepatitis B, and many patients face the problem of long-term medication, so the concept of clinical cure is also proposed in a sense to meet the needs
of some patients to stop taking drugs.

Clinical cure is not the same as complete cure
.
Clinical cure, or functional cure, refers to the disappearance of hepatitis B surface antigen (HBsAg) obtained by some patients after treatment, with or without hepatitis B surface antibody (HBsAb), accompanied by alanine aminotransferase (ALT) persistent normal, peripheral blood HBV DNA below undetectable levels, no obvious inflammation or fibrosis in liver histology, and more importantly, no recurrence after the patient stops the drug, which is the real clinical cure
.

At present, many clinicians simply define functional cure or clinical cure as the disappearance of HBsAg, which is actually inaccurate
.
Some patients may have progressed to severe liver fibrosis, cirrhosis, or liver cancer when HBsAg disappears, in which case the disappearance of HBsAg does not mean that they have achieved clinical cure
.
Therefore, clinical cure not only refers to the disappearance of HBsAg, but also needs to be accompanied by normal biochemical indicators of liver function and no obvious inflammatory or fibrotic changes
in liver histology.
The above requirements can only be achieved in order to achieve a so-called clinical or functional cure
.

The benefits of achieving clinical cure are mainly as follows: First, the risk of progression to cirrhosis, hepatocellular carcinoma, etc.
is significantly reduced, and this risk reduction may be better
than in patients who only obtain a virologic response.
Second, after achieving clinical cure, patients can consider stopping the drug, which can save costs for patients on the one hand, and on the other hand, they do not have to worry about the adverse reactions
caused by long-term medication.

Prof.
Enqiang Chen: That's a very good
question.
In recent years, Chinese scholars have carried out many related researches, including the Everest Project, all of which aim to maximize the clinical cure
of patients.
But in fact, not all patients can easily obtain a clinical cure
.
At present, some doctors in the clinic simply believe that as long as the HBsAg level is low enough (such as HBsAg< 1500 or 1000 IU/ml), patients can achieve clinical cure through interferon-based treatment regimens, which is actually a very one-sided understanding<b23>.

So, which patients are likely to achieve HBsAg disappearance after receiving current antiviral regimens (including oral antivirals and interferon therapy) and thus achieve clinical cure? There are many relevant indicators, and it is not only possible to screen out advantageous patients by HBsAg quantification, and a number of indicators are required for comprehensive judgment
.
At present, the recognized dominant population meets the following conditions: hepatitis B e antigen (HBeAg)-positive "big three positive" patients before treatment, and HBeAg-negative "small three positive" patients who have been transformed into HBeAg-negative after long-term oral antiviral treatment, while peripheral blood HBV DNA continues to be undetectable, ALT continues to be normal, and peripheral blood HBsAg quantitatively drops below
1500 IU/ml.
In such cases, patients are more likely to achieve clinical cure
by achieving HBsAg disappearance with an optimized regimen (e.
g.
, in combination with interferon therapy).

In addition, there are many new indicators to help screen advantageous populations, including peripheral blood HBV RNA levels, Hepatitis B core-related antigen (HBcrAg) levels, complexity of HBV species, family history of cirrhosis or liver cancer, and length of disease
.
In short, determining the dominant population of clinical cure is a difficult topic in clinical practice, which needs to be further explored in order to make a more comprehensive and objective assessment of patients and screen out the real dominant population
.
Current indicators can help screen advantageous patients, but they cannot be determined by a single indicator, and need to be considered in a combination of indicators, including the patient's previous treatment and the use of antiviral drugs
.

Finally, I would like to emphasize that the screening of the dominant population cannot be judged only based on the peripheral blood HBsAg level, and it is not that the HBsAg level is low enough to belong to the dominant population
.
HBeAg is still positive for HBeAg in patients with "big three positives", and it is not easy for such patients to achieve HBsAg negative conversion even if they are treated with existing optimized protocols
.

Professor Chen Enqiang: This is a very cutting-edge topic
.
At present, many new hepatitis B drugs are under research, and there will definitely be more drugs to choose from in the future to help patients achieve clinical cure
.
However, at this stage, hepatitis B treatment drugs mainly include two categories, one is oral antiviral drug nucleoside (acid) analogues, and the other is subcutaneous injection of long-acting interferon
.
Whether these two types of drugs are monotherapy or combination therapy, it is difficult to achieve HBsAg disappearance and clinical cure
for the vast majority of the population.
However, in recent years, more and more patients have achieved HBsAg disappearance and clinical cure
through combination with long-acting interferon therapy.
Most of these patients have a characteristic that long-term oral drug treatment (such as oral entecavir, tenofovir oxil, or tenofovir propofovir) can significantly deplete intrahepatic HBV cccDNA, and then combined with new drugs, such as immunomodulators (including long-acting interferon), can indeed increase the probability
of HBsAg disappearing.

At present, the main clinical treatment strategy is: after long-term oral antiviral treatment, the patient's HBV cccDNA is reduced, so as to obtain immune control, on this basis, combined with new regimens (such as oral drugs combined with interferon therapy) can help patients improve the HBsAg negative conversion rate; Alternatively, in combination with other regimens, such as PD-1/PD-L1 antibodies or other immunomodulators, may be helpful
in the treatment of the disease.
However, the improvement of the clinical cure rate of these programs is based on the dominant population, and it is difficult for the general population to easily achieve clinical cure
through the above programs.
Therefore, as mentioned earlier, it is necessary to screen out the dominant population through relevant indicators and then use the existing regimen for treatment in order to help some patients achieve clinical cure
.
For non-dominant populations, clinical cure
is difficult to achieve based on current treatment regimens.

In summary, current treatment options for CHB are very limited, and combination regimens based on long-acting interferon can only benefit
a small number of patients.
In the future, in order to expand the number of beneficiaries, more new drugs need to be developed, such as immunomodulators or combination therapy
that acts on different parts of the HBV life cycle.
It is believed that in this case, the overall clinical cure rate
of the majority of hepatitis B patients can be truly improved.

Professor Chen Enqiang: The first is to clarify the concept of
clinical cure.
If the concept is not clear, it may lead to clinical overtreatment
.
In addition to the disappearance of HBsAg, it needs to be accompanied by continuous relief or disappearance of liver inflammation, persistent normal ALT, undetectable HBV DNA, and no obvious inflammation and fibrosis
on liver histology.
The second is to clarify which patients can achieve HBsAg disappearance and clinical cure
.
The screening of the dominant population cannot only be judged based on HBsAg titers, but also needs to be based on HBV RNA levels, the patient's immune function status, and the status of other viral markers
.
If clinical cure is blindly pursued without identifying the dominant population, patients may be subjected to overtreatment, resulting in increased treatment costs and drug side effects
.
Third, clinical cure does not mean complete cure, does not mean that there will be no recurrence after stopping the drug, which needs to be clarified
.
After clinical cure, HBV may rebound and reactivate in exceptional circumstances, and patients still require regular follow-up
.
Finally, the duration after clinical cure is also a matter of great clinical concern at present
.

For the possible controversy of clinical cure, in addition to the need to clarify the definition of clinical cure mentioned above, the other is the choice of treatment regimen, can only long-acting interferon combination therapy help patients achieve clinical cure? Can it be treated with longer oral medications? In this regard, different experts have also put forward some different opinions
.
Moreover, what are the criteria for clinical cure? Does the disappearance of HBsAg have to be considered as one of the important criteria for clinical cure? Are patients with unnegative HBsAg but low levels necessarily excluded from clinical cure? These are also controversial points
at the moment.
Many experts called for the inclusion of more comprehensive assessments, including HBV RNA levels, HBcrAg levels, and the complexity of virus species
.
These issues and controversies need to be further resolved
in the future.