Worldwide, 2 billion people are infected with hepatitis B virus (HBV) – seropositive – and 400 million of them are HBsAg positive, that is, people with chronic HBV infection. While some of them are being followed up with the diagnosis of inactive HBsAg carrier (more precisely, inactive HBV Infection), 15-40% of the total pool will develop cirrhosis and/or hepatocellular carcinoma (HSC) over years and decades, most of which are among patients with chronic hepatitis. (one). The aim is to prevent bad outcome with medical treatment and/or liver transplantation in this population with chronic hepatitis B.
Hepatitis B has not been alone for the past 15 years. Besides the hepatitis D (delta) virus (HDV), which is debatable whether it is a helper or a parasite, it has had to share its great dominance in this field with the hepatitis C virus (HCV). Nevertheless, the most common cause of cirrhosis and hepatocellular carcinoma in a significant part of the world, primarily in Asia, Africa, Middle East countries, Southeast Europe and Mediterranean countries, and some parts of South America, and most importantly in Turkey, is the most common cause of cirrhosis alone and partially HDV. with the contribution of HBV infection (1-3). The participation of HCV in the game increases the risk of cirrhosis and HCC many times and creates a caliper that accelerates the bad end for human beings (4). The struggle is to get rid of this game, to win the war of mankind against viral hepatitis. Universal vaccination, which was started two decades ago and has been applied more than 100 times in the last 10 years, including Turkey, is the first victory in this field. Positive results are reported (5). However, the treatment of HBV-infected people for whom the vaccine is of no use is at least as important as primary prophylaxis and is the most important area of concern for us hepatologists.
Important information in due diligence;
There are 2 billion HBV seropositive and 400 million HBsAg positive people.
-HBV is the most common cause of cirrhosis and HCC in the world.
– The most common cause of cirrhosis and HCC in Turkey is HBV infection.
-Universal vaccination program is effective, should be expanded.
People with chronic HBV infection should be treated.
Purpose of treatment
The ideal goal of chronic hepatitis B treatment is to eradicate HBV infection. In other words, it is to make the person HBsAg negative and anti-HBs positive. With today’s drugs, this is possible in a very small number of patients, which we cannot predict. It is not an achievable goal in general. Therefore, the main goal of treatment is to prevent HBV replication-related disease progression, hence the development of liver cirrhosis and/or HCC, as a result of permanent complete inhibition or suppression of HBV replication to a certain degree (“permanent HBV DNA negativity or suppression”). The result of this will naturally be a decrease in morbidity and mortality due to HBV infection. There are large epidemiological and clinical studies showing that HBV DNA level is the single most important criterion both in predicting the prognosis of liver disease, that is, its progression to cirrhosis and HCC, and in determining the response to treatment (6-13). The results of these studies are summarized in Table-1.
As a treatment goal, HBV DNA is required to be negative with sensitive PCR tests. If this cannot be achieved, the targeted HBV DNA level in suppression therapy should be <60 IU/ml (<300 copies/ml) (14-16).
At these levels, HBV replication will be easily controlled by the immune system and liver damage will be prevented.
1. HBV DNA indicates active viral replication, that is, disease.
2. Damage to the liver and its consequences (cirrhosis, HCC) are the result of the disease.
3. There is a direct and strong relationship between HBV DNA level and the development of cirrhosis and HCC.
4. Suppression and prevention of the disease, namely HBV replication, reduces the risk of cirrhosis and HCC.
5. Persistent viral response (HBV DNA negativity or suppression) is associated with good prognosis.
6. Permanent HBeAg/anti-HBe seroconversion is associated with persistent HBV DNA negativity or suppression.
7. The HBV DNA value, which poses a risk for cirrhosis and HCC complications, is defined as 10,000 copies/ml and above. It is information that needs to be verified.
8. HBV DNA level alone is the most important risk factor for HCC, independent of HBeAg/anti-HBe status and ALT level.
9. In HBeAg positive patients, the HBV DNA value is almost always above 100,000 copies/ml.
10. The differential HBV DNA value between inactive HBV infection and HBeAg negative chronic B hepatitis is unknown (30,000 and 10,000 copies/ml recommended).
11. The effectiveness of the treatment is measured by the HBV DNA level.
12. Resistance to treatment and detection of mutations are determined by HBV DNA level monitoring.
Can we achieve this goal with existing drugs? If we consider the standard interferon (sIFN) alpha preparations, which are the drugs that have been used for the longest time in the treatment of chronic hepatitis B, from this perspective; It has been reported that cirrhosis and HCC development is less common in patients with a persistent viral response, although it is not very evident, and survival is increased (17). The studies of Lin et al. (18) including 233 patients with HBeAg positive chronic B hepatitis and receiving IFN-alpha therapy and 233 control patients showed the most striking results in this regard (Table-2). In multivariate analysis, IFN alpha therapy, HBeAg seroconversion, and genotype B are indicators of better long-term prognosis.
Long-term follow-up results similar to IFN have not yet emerged in treatments with oral antiviral drugs. However, lamivudine and adefovir dipivoxil combined treatment with an add-on approach in long-term lamivudine or lamivudine-resistant patients in the treatment of patients with cirrhosis, both in clinical improvement (improvement in Child-Pugh score) and in the prevention of cirrhosis complications (variceal bleeding, encephalopathy, ascites infection, etc.). It has been stated that it is effective, but no data can be obtained regarding a decrease in the risk of HCC (19-21). The development of lamivudine resistance is an unfavorable prognostic factor, a risky condition that should be avoided especially in decompensated patients and transplant recipients. Primary treatment with both adefovir and entecavir has been found to be cost-effective in patients with cirrhosis and is superior to lamivudine in terms of resistance profile (22). Rescue therapy with adefovir is more cost-effective in lamivudine-resistant patients.
Definitions-terminology related to treatment:
The terminology on this subject is changing rapidly. According to recent data, definitions of response to chronic hepatitis B treatment can be summarized as follows (14, 15, 23);
Definitions of response to treatment
Virological response
HBeAg positive patients HBeAg loss
HBeAg/anti-HBe seroconversion
HBV DNA <20,000 copies/ml
HBeAg negative patients HBV DNA <10,000 copies/ml
Biochemical response ALT normalization
Histological response At least 2 points decrease in necro-inflammatory score compared to pretreatment biopsy (without worsening fibrosis score)
Complete (“complete”) response Additional HBsAg/anti-HBs
seroconversion
Definitions of timing of response
Response during treatment Virological response while on treatment
Response at the end of treatment Virological response status at the end of treatment
Response at follow-up Virological response status at the time of end of treatment
Sustained response (“sustained response”) After what period of time can a sustained response be mentioned for hepatitis B treatment? This is not exactly known…
“Breakthrough” Presence of virologic relapse (HBV DNA increase and/or HBeAg/anti-HBe reversion) and/or ALT elevation while on therapy
Additional definitions of oral antiviral therapy
Complete virological response HBV DNA negative or <60 IU/ml (<300 copies/ml) at week 24
Partial virological response At least 2 log10 decrease in HBV DNA or <20,000 IU/ml (<100,000 copies/ml) at week 24
(No complete or partial viral response should be defined as primary non-response*).
Virological “breakthrough” 1 log10 IU/ml increase in serum HBV DNA level in a patient with complete or partial response during treatment (for example, >10,000 IU/ml from 1000 IU/ml)
Genotypic resistance Detection of HBV polymerase mutations by direct HBV DNA analysis
Phenotypic resistance Demonstration of drug resistance of mutation “in vitro” in cell culture
*primary unresponsiveness to antiviral therapy according to some authors HBV after the first 3 months
If the decrease in DNA remains below 1 log 10 IU/ml, secondary unresponsiveness
1 log 10 IU/ml increase in sufficiently low or negative HBV DNA induced by treatment
(24).
Treatment indications
Below are the latest literature information (1, 14, 15, 21, 23, 25) and algorithms related to the treatment of chronic hepatitis B within the framework of the experiences of the branch of science I am a member of.
1) HBeAg positive chronic hepatitis B
HBV DNA ALT (U/L) Decision
<105 copies/ml normal Monitor without treatment
ALT and virology every 3-6 months
Less viral if histology is severe (≥F2)
even at high load (HBV DNA ≥10,000 copies/ml)
consider treatment
≥105 copies/ml normal Young patient-immunotolerance period-watch
≥40 years, biopsy ≥F2 fibrosis; Consider treatment
≥105 copies/ml high Consider treatment. Peg IFN, lamivudine,
entecavir, adefovir may be the first choice…
Oral antivirals may be the first choice if HBV DNA is very high (>1 million copies/ml)
-Peg IFN alpha should be the first choice in genotypes A and B. The difference between genotypes for oral antivirals is unknown. (The genotype is nearly 100% D in Turkey.)
2) HBeAg negative chronic B hepatitis
HBV DNA ALT Decision
<104 copies/ml normal Monitor without treatment-inactive HBsAg may be carrier
ALT every 3 months (HBV DNA when ALT rises)
≥F2 fibrosis on biopsy; Even at low viral load
(If HBV DNA >1000 k/ml) consider treatment
≥104 copies/ml normal Probably chronic B with fluctuating ALT
hepatitis – monitor with ALT or consider biopsy,
If ≥F2 fibrosis on biopsy, consider treatment.
≥104 copies/ml high ≥F2 fibrosis on biopsy; Consider treatment, more
in mild histology, the decision should be individual…
Treatment with oral antivirals is prolonged, perhaps
should be for life. First choice peg IFn alpha
preparations or oral antivirals (entecavir,
adefovir) may occur. Lamivudine?
-Lamivudine treatment should not be considered in this patient group, because both peg IFN alfa and entecavir are more effective and lamivudine resistance is very common in this group and has a negative effect on treatment.
3) Treatment in compensated cirrhosis (HBeAg positive or negative)
HBV DNA ALT Decision
If <103 copies/ml high HBV DNA positive treat
<103 copies/ml normal ALT/HBV DNA monitoring every 3-6 months
≥103 copies/ml high treat-first choice entecavir or adefovir
or may be. Resistance is common with lamivudine…
normal Peg IFN may be present in well-selected cases.
-Pay attention should be paid to peg IFN treatment in patients with clinically evident cirrhosis (hypersplenism and prominent esophageal varices).
HBeAg positive patients will almost always have high levels of HBV DNA. The problem is the difficulty of decision making in HBeAg negative and ALT normal cases.
– There are groups that prefer lamivudine as the first treatment option and suggest that adding adefovir (“add on”) will be the most effective treatment when genotypic resistance develops with HBV DNA monitoring every 3 months.
4) Treatment in decompensated cirrhosis (HBeAg positive or negative)
Patients with detectable HBV DNA (qualitatively or quantitatively positive) should be treated with oral antivirals (antecavir, adefovir, lamivudine) regardless of ALT level.
HBeAg positive patients will almost always have high levels of HBV DNA. The problem is the difficulty of decision making in HBeAg negative and ALT normal cases.
– There are groups that prefer lamivudine as the first treatment option and suggest that adding adefovir (“add on”) will be the most effective treatment when genotypic resistance develops with HBV DNA monitoring every 3 months.
1) Chronic Hepatitis B
-HBeAg positive (“wild” type) 9-10 MU/hüg ≥6 months
-HBeAg negative (mutant type) 9-10 MU/hüg ≥12 months
2) Compensated cirrhosis variable variable
3)Decompensated cirrhosis contraindicated (treatment in special cases)
4)Extrahepatic tables (Glomerulonephritis, Vasculitis etc.)
Pegylated IFN-alpha
1) Chronic hepatitis B
-HBeAg positive (“wild” type) 180 ug/week 12 months
1.5 ug/kg//week 12 months
-HBeAg negative (mutant type) 180 ug/week 12 months
1.5 ug/kg/week 12 months
2) Compensated cirrhosis is like chronic hepatitis B.
3)Decompensated cirrhosis contraindicated (treatment in special cases)
4)Extrahepatic tables not enough experience
lamivudine
1) Chronic Hepatitis B
-HBeAg positive 100mg/day ≥ 12 months
-HBeAg negative 100mg/day ≥ 12 months
– Viral load is very high (HBV DNA >1,000,000 copies/ml and above) HBeAg positive and
Patients with markedly high ALT levels (>4-5 times) constitute the group in which it is most effective.
-HBeAg/anti-HBe seroconversion in HBeAg positive cases
Then it should be continued for another 6-12 months.
-The duration of treatment is uncertain in anti-HBe positives, it may be lifelong (his histology is serious-
should be preferred in those with significant fibrosis?). Therefore, the risk of developing resistance
is high (>50% at 3 years) and is no longer recommended as first-line therapy.
– Preferably adefovi and entecavir as a second choice in patients who develop resistance
treatment can be done. There is no native experience with Peg IFN.
2)Compensated or Decompensated Cirrhosis 100 mg/day ≥ 12 months
In fact, the treatment is lifelong. Adefovir Dipivoxil (“add on”) therapy should be initiated if virological and biochemical breakage (as determined by ALT elevation during treatment and HV DNA positivity) develops.
3) Acute Liver Failure 100mg/day 12 months ?
4) Preemptive-prophylactic treatment in HBsAg-positive patients who will receive immunosuppressive (especially corticosteroid-containing) treatment: 100mg/day for 6-12 months
-Immunosuppressive therapy should be continued for at least 3-6 months after completion.
5) Pre- and postoperative HBV prophylaxis in transplant recipients is variable
6) To prevent perinatal transmission in the last month in pregnant women with high viremia
7) To prevent transmission from healthcare personnel with high viremia to the patient
Dose adjustment is required in hemodialysis patients, renal transplant recipients, or liver patients with impaired renal function.
Adefovir Dipivoxil 10mg/day ≥ 12 months
1) Lamivudine-resistant chronic hepatitis B (HBeAg positive/HBeAg negative)
2) Lamivudine-resistant HBV-cirrhosis (compensated/decompensated) – “add on” treatment should be done, that is, adefovir should be added and used together without discontinuing lamivudine.
3) Hepatitis B treatment in lamivudine-resistant transplant recipients
4) “Naive” chronic hepatitis B with severe histology (stage 3-4 fibrosis)
5) “Naive” HBV-cirrhosis (compensated/decompensated) patients
-Adefovir dipivoxil dose should be adjusted according to renal function. More care should be taken in terms of nephrotoxicity in patients with decompensated cirrhosis.
Entecavir
1) “Naive” chronic hepatitis B with severe histology (stage 2-4 fibrosis)
2) “Naive” HBV-cirrhosis (compensated/decompensated) patients
3) Lamivudine-resistant chronic hepatitis B (HBeAg positive/HBeAg negative)
4) Lamivudine-resistant HBV-cirrhosis (compensated/decompensated)
5) Hepatitis B treatment in lamivudine-resistant transplant recipients
-Entecavir is the antiviral drug with a high antiviral effect and the lowest risk of resistance development in naive patients. To date, resistance characterized by virological and biochemical breakage in naïve patients has been negligible (<1% at 3 years). However, resistance may develop (18% in 3 years) in patients who are resistant to lamivudine (25).
