The treatment of the most severe form of hepatitis with the novel drug Boulevirtide was initiated in Russia in February 2020. This is the only treatment option for patients with hepatitis D (hepatitis B with a delta agent). Other drugs can only inhibit the virus in about 10% of cases. Liver transplantation, as an alternative treatment, is practically unavailable. According to the results of clinical trials, Boulevirtide in combination with pegylate d interferon leads to a significant reduction in viral load until the disease is cured. The drug starts the reverse process in all pathological changes, prevents the progression of fibrosis and the development of liver cirrhosis.
What is hepatitis D?
Hepatitis D is an acute or chronic liver disease caused by the hepatitis D virus (HDV). Hepatitis D virions are spherical and consist of an outer coat, a nucleocapsid and delta antigen. HDV has a circular negative-sense, single-stranded RNA genome and possesses genotypes I, II, III and IV, among which genotype 1 is the most prevalent globally and has two subtypes Ia and Ib. HDV is a defective virus dependent on the helper function of Hepatitis B virus (HBV) for its replication and expression. The envelope of HDV particles contains the Hepatitis B surface antigen (HBsAg). The production and transmission of HDV are entirely dependent on HBV to provide HBsAg. Thus, HDV is considered a satellite virus of HBV.
At least 5% of people with chronic HBV infection are co-infected with HDV, resulting in a total of 15 – 20 million persons infected with HDV worldwide. In different countries, among people infected with HBV, the proportion of infected with HDV varies from 0.1% to 20-30%.
Transmission
Hepatitis D virus is transmitted by parenteral route, via blood. Other ways of transmission include transfusion of unsafe blood, use of insufficiently sterilized medical instruments or their reuse, use of injectable drugs with non-sterile instruments. It can also pass through sexual contact. Vertical transmission from infected mother to child is possible but rare.
Who is at risk?
Due to the nature of replication, HDV-infected patients are more likely to be people infected with HBV or those, who are not immune to HBV (either by natural disease or immunization with the hepatitis B vaccine). Persons who inject drugs, not using personal disposable syringes, and sex workers are also at risk for HBV/HDV infection. High prevalence of HDV is in contaminated blood transfusion receivers and professionals who are exposed to blood contact.
How to protect your family and friends from infection?
Firstly, after the diagnosis has been confirmed, it is recommended to inform your family and friends about the infection and get vaccinated immediately. As soon as you build up immunity to HBV, the risk of acquiring this infection virtually disappears.
Nevertheless, it will be worthwhile to adhere to a number of general recommendations in everyday life: do not share your toothbrush, razor, manicure scissors. If a patient, infected with hepatitis, gets an injury or a cut and he needs help in treating a wound, care must be taken with all the precautions, always wearing gloves to avoid contact with blood. All small wounds and cuts of the patient must be sealed with a band-aid. For injections, the HDV carrier must use individual disposable syringes and dispose of needles and cotton with extreme caution.
Symptoms
HBV/HDV co-infection, i.e. when an individual is simultaneously infected by HBV and HDV, is the most severe form of viral hepatitis and can lead to a mild-to-severe or fulminant hepatitis. The incubation period is similar to that of HBV and lasts 1.5-6 months. The prodromal period is short and is characterized by fever, which is not typical for HBV. Other symptoms include pain in the liver area, joint pain and jaundice. HBV is actively replicating during the icteric phase, and HDV starts replicating 2-4 weeks later during the post-icteric phase. The icteric phases are characterized by subfebrile temperature, pain in the right hypochondrium, enlarged liver, edematous-ascitic syndrome and rashes.
Most cases of HBV/HDV infection resolve spontaneously without specific therapy. However, patients with acute HBV/HDV co-infection have a higher risk of developing severe and fulminant hepatitis, with mortality rate of 13%. 2-5% of individuals develop chronic illness.
Superinfection occurs when chronic HBV carriers are infected with HDV. The incubation period is 1-2 months. The pre-icteric phase is 3-5 days, characterized by weakness, irritability, digestive dysfunction. Fever occurs in the first 3-5 days during the icteric phase. Severe edematous-ascitic and hemorrhagic syndromes are typical of severe acute hepatitis. Superinfection is associated with the fulminant form of viral hepatitis, characterized by acute hepatic encephalopathy or development of chronic illness, progressing to liver cirrhosis. The mortality rate for superinfection is 5-20%. Chronic illness develops in 80% of patients.
Diagnosis
There are several tests for the diagnosis of hepatitis D infection. Type D hepatitis should be considered in individuals who are HBsAg positive or who have evidence of recent HBV infection.
At the end of the pre-icteric phase Hepatitis D virus antigen ( HDAg ) is detected in blood serum by ELISA and is present in blood serum for 1-2 weeks. During the acute and chronic phases HDAg is primarily expressed in the liver cell nuclei where it can be detected by immunofluorescence. The hepatitis D virus’s RNA can be identified by PCR that detects the presence of the virus in the body and its replication in the liver cells.
The diagnosis scheme is as follows. A patient infected with HBV is tested for specific HDAg antibodies . If the test is negative, there is no HDV infection. If the test is positive, you are advised to have a test again. IgM anti -HDV antibodie s are detected in patients with acute hepatitis D and are typical of an acute phase of the disease. The presence of IgG anti-HDV antibodies show evidence of current or past infection.
Treatment. Prognosis
The search for the effective method of treating hepatitis D virus has been an pressing problem for a long time. The treatment aims at suppresing HDV RNA replication and normalizing liver enzyme activity. The results of the clinical trials of Myrcludex B were obtained at the end of 2018. Myrcludex B is a drug for the treatment of hepatitis B and D, which was developed by Russian scientists together with their German colleagues at Hannover Medical School.
The scientists explained the mechanism of action of the new drug: it blocks the penetration of hepatitis B and D viruses into liver cells. Thus, the life cycle of the virus is disrupted, which enables to control the disease successfully.
During clinical trials, a decrease in viral load was observed in all groups of subjects. After six months of treatment, hepatitis D virus disappeared in 25% of patients who were administered the new drug. In patients who received the therapy of Myrcludex and pegylated interferon, viruses were not detected in 72% of patients.
Since late 1980s and 90s, interferon alfa (IFN-α) has been administered for patients with hepatitis D. IFN- α therapy resulted in normalization of ALT levels in 20-50% of patients (although in some cases the improvement was temporary). The improvement of efficacy was achieved with higher doses and a longer duration of IFN-α therapy. The absence of HDV RNA was observed in 25-40% of patients treated with pegylated interferon. Some cases documented the resumption of HDV RNA replication in patients who responded to the treatment 24 weeks after peg-interferon was discontinued. PegIFN-α and Ribavirin or Adefovir Combination Therapy did not show sustained virological response (SVR). Nucleoside and nucleotide analogues (NUCs) targeting hepatitis D virus are capable of inhibiting HDV replication by decreasing HBsAg and HBV DNA levels.
“ Myrcludex B has shown a very good safety profile and antiviral activity. Currently, the results of the study are widely discussed in scientific and medical circles, ”said Alexander Alexandrov, Medical director of the biotech company. His colleague Heiner Wedemeyer, professor at Hannover Medical School , said: “There is every reason to hope that the drug “has a potential to become a new option” for the treatment of chronic hepatitis D. What vaccinations do I need if I have hepatitis D?
If you were diagnosed with HDV, it means that you have been infected with HBV. In this case, it is too late to get vaccinated for HDV and HBV. A vaccine for hepatitis D virus does not currently exist. However, it is important to protect yourself from the complications associated with other infections. Therefore, patients should receive two doses of hepatitis A vaccines at an interval of 6-12 months, and three doses of pneumococcal vaccine at an interval of 0-1-6 months.
Treatment and efficacy
In 2019 study results were presented at the International Conference on Liver Diseases (ILC 2019) that showed that the new drug boulevirtide ( Myrcludex B) is effective and safe for patients with chronic hepatitis B/D virus (HBV/HDV) coinfection. When used in combination with peg-interferon-α 2a (PEG-IFN-α), above 50% of study participants who received bulevirtide (Myrcludex B) had undetectable HDV RNA after 48 weeks of treatment, which was sustained off-treatment in the majority of individuals.
In 2016 Journal of Hepatology published an article Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib / IIa study by Russian scientists P. Bogomolov, A. Alexandrov, N. Voronkova et al, which presented the outcome of Myrcludes B therapy in patients with CGD.
The study was conducted in 2014-2016 and included 24 participants. They were divided into three groups: in group A patients received a 24-week boulevirtide therapy at a dose of 2 mg / day, and a further 48-week peg-interferon-α 2a therapy at a dose of 180 μg / week; in group B patients received a 24- week boulevirtide and peg-interferon- α 2a combination therapy and a further 24-week peg-interferon- α 2a monotherapy; in (control) group C patients received peg-interferon- α 2a monotherapy.
The results showed that the drug is well-tolerated and does not cause serious side effects. At the same time, the virological response achieved with Myrcludex B therapy, is sustained and accompanied by normalization of biochemical parameters, as well as stabilization or degradation of fibrosis. After 24- week Myrcludex B and/or peg-interferon -alfa 2a therapy, the level of HDV RNA decreased in all patients with chronic hepatitis B/ D virus. HDV RNA was undetectable in two out of eight participants who received Myrcludex B and/or peg-interferon-alfa 2a consecutively and five out of seven participants who received both drugs simultaneously.
Boulevirtide is a novel drug, a linear 47-amino acid chemically synthesized peptide. As a first-in-class agent it inhibits the entry of HDV and HBV into hepatocytes. In the UK it became “a promising treatment for chronic HDV infection” and in the USA “a breakthrough therapy”. Earlier EMA and FDA classified it as “orphan drug”.
Examinations to be done before treatment
The list of examinations for the patient before visiting a specialist includes:
Complete blood count (CBC)
Comprehensive Metabolic Panel (CMP) -ALT, AST, bilirubin
Detection of IgM and IgG Antibodies in serum, PCR that detects the presence of the HDV RNA (for patients infected with HBV and HBsAg positive)
Liver and abdominal ultrasound
Observation during treatment
Patients diagnosed with HDV should be registered at the early treatment clinics. Clinical observation includes diagnostic and clinical assessment at least once in 3 months, abdominal ultrasound once in 6 months. During basic therapy, a test for the presence of HDV1 markers should be performed every 12 months. While patients undergo the drug therapy laboratory tests are performed monthly in order to monitor the patients’ condition and evaluate the effectiveness of the treatment.
Where to be treated
Myrcludex B is a novel drug, which appeared in 2019. It is the first drug in the world for previously incurable hepatitis D. The efficiency and safety of the therapy were proven during studies in leading clinics in Russia and Germany.
By blocking the receptor through which the virus enters the liver cells, Myrcludex B prevents viral inflammation and the development of life-threatening complications. When protein is blocked, viruses remain outside the cells and can be eradicated by the immune system.
Under current plans, treatment is provided in Russian Federation.
You can make an appointment with a hepatologist and get comprehensive information about treatment by calling 8 800 775-19-96 (for citizens of the Russian Federation) and +7 495 324-40-00 (for foreign citizens).