What is hepatitis delta? Viral hepatitis D: what it is and how to avoid it. Symptoms of Hepatitis A

Hepatitis D is an acute or chronic infectious liver infection with a parenteral mechanism of infection, caused by the hepatitis D virus (HDV).

A specific feature of the disease is its secondary nature. Infection with HDV is possible only against the background of prior infection with the hepatitis B virus (HBV). About 5% (according to other sources - up to 10%) of HBV carriers are simultaneously infected with HDV. Chronic viral hepatitis, caused by exposure to HBV and HDV, is currently confirmed in approximately 15–30 million people, according to information provided by the World Health Organization.

Liver damage due to hepatitis D

HDV was first obtained in 1977 by a group of Italian scientists from liver cell biopsies of patients suffering from viral hepatitis B. An erroneous assumption was made that a fundamentally new marker of HBV had been isolated, but further studies showed that the detected particles were independent pathogens, defective viruses ( viroids). Later, a fundamentally new type of hepatitis caused by these viruses was classified, called viral hepatitis D.

The prevalence of the disease in different regions varies significantly: from isolated cases to affecting 20–25% of those infected with the hepatitis B virus.

According to the spread of viral hepatitis D, all regions are conventionally divided as follows:

• highly endemic – the frequency of HDV infection exceeds 60%;
• regions of medium endemicity – incidence rate 30–60%;
• low-endemic – HDV is detected in 10–30% of cases;
• regions of very low endemicity - the frequency of detection of antibodies to HDV is not higher than 10%.

The Russian Federation belongs to areas of low endemicity, although some researchers attribute such positive statistics to the lack of mandatory diagnosis of antibodies to HDV in patients with HBV.

Synonyms: hepatitis delta, viral hepatitis D, HDV infection, HDV infection.

Causes and risk factors

Currently, 8 genotypes of HDV have been identified, which have specific distribution and differ in clinical and laboratory manifestations (for example, genotype 1 is common in European countries, genotype 2 is common in East Asia, genotype 3 is found mainly in Africa and tropical Asia , in the Amazon basin, etc.).

The main route of infection is blood contact (transmission through blood):

• during therapeutic and diagnostic procedures (including dental);
• for cosmetic and aesthetic procedures (tattooing, manicure, piercing);
• with blood transfusions;
• when using injecting drugs.

Less common are vertical transmission of the virus (from mother to child during pregnancy) and sexual transmission. Infection within the same family is possible through close household contact (the formation of family foci of chronic hepatitis D is often observed in highly endemic regions).

Forms of the disease

In combination with viral hepatitis B there are:

• co-infection (parallel infection);
• superinfection (attached against the background of existing chronic hepatitis B).

Depending on the severity of the process:

• acute hepatitis D;
• chronic hepatitis D.

Acute hepatitis delta usually resolves within 1.5–3 months; chronicity of the disease occurs no more than in 5% of cases.

Both acute and chronic disease can occur in a manifest form with a detailed clinical and laboratory picture or in the form of a latent (latent) HDV infection, when the only sign of hepatitis is a change in laboratory parameters (there are no active symptoms in this case).

According to the severity, the following forms of hepatitis D are distinguished:

• easy;
• moderate severity;
• heavy;
• fulminant (malignant, rapid).

Stages of the disease

There are the following stages of hepatitis D:

• incubation (from 3 to 10 weeks);
• pre-icteric (on average about 5 days);
• icteric (several weeks);
• convalescence.

Symptoms

During the incubation period, there are no symptoms of the disease; despite this, the patient is a virus shedding agent.

The pre-icteric period debuts acutely:

• intoxication symptoms - headache, fatigue, decreased tolerance to usual physical activity, drowsiness, muscle and joint pain;
• dyspeptic symptoms - loss of appetite up to anorexia, nausea, vomiting, bitterness in the mouth, bloating, pain and a feeling of fullness in the right hypochondrium;
• increase in body temperature to 38 ºС and above (noted in approximately 30% of patients).

Symptoms of the icteric period:

• characteristic coloring of the skin and mucous membranes, icterus of the sclera;
• enlarged and painful liver;
• low-grade body temperature;
• weakness, loss of appetite;
• urticarial rashes similar to urticaria on the skin;
• discoloration of stool, dark urine.

More than half of the patients experience a two-wave course: after 2–4 weeks from the onset of the icteric stage of the disease, as the symptoms of the disease subside, general health and laboratory parameters sharply deteriorate.

Acute hepatitis delta usually resolves within 1.5–3 months; chronicity of the disease occurs no more than in 5% of cases.

Acute superinfection is more severe than co-infection, it is characterized by a violation of the protein-synthetic function of the liver, the outcome of the disease is usually unfavorable:

• death (in the fulminant form, developing in 5–25% of patients, or in the severe form with the formation of subacute liver dystrophy);
• the formation of chronic viral hepatitis B + D (in approximately 80%) with high activity of the process and rapid transformation into cirrhosis of the liver.

Diagnostics

The main laboratory diagnostic method to confirm the presence of HDV infection is testing HBsAg-positive patients (persons who have detected hepatitis B virus antigens) for the presence of HDV antibodies in the blood serum.

Methods for diagnosing viral hepatitis D:

• analysis of data on previous contact with possibly infected blood, medical and other manipulations;
• characteristic clinical manifestations of the icteric form of the disease;
• determination of IgM and IgG to HDV in HBsAg-positive patients;
• detection of HDV RNA (HDV-RNA) by polymerase chain reaction;
• specific changes in biochemical blood test (increased levels of liver enzymes AST and ALT, positive thymol test, hyperbilirubinemia, possible decrease in sublimate test and prothrombin index).

A specific feature of the disease is its secondary nature. Infection with HDV is possible only against the background of prior infection with the hepatitis B virus (HBV).

Treatment

Combined therapy for hepatitis D + B is carried out, during which the following are prescribed:

• interferons (including PEG-interferon);
• antiviral drugs (there are no specific drugs that specifically target the hepatitis D virus);
• immunomodulators;
• hepatoprotectors;
• detoxification therapy;
• desensitizing agents;
• vitamin therapy;
• enzyme preparations.

The duration of antiviral therapy is not determined; the question of its termination is decided depending on the patient's condition. (Can last a year or more.)

For patients with fulminant hepatitis and advanced liver cirrhosis, liver transplantation is considered.

Possible complications and consequences

Complications of hepatitis D may include:

• cirrhosis of the liver;
• hepatocellular carcinoma;
• acute liver failure;
• hepatic encephalopathy;
• bleeding from varicose veins of the esophagus;
• hepatic coma, death.

Forecast

The prognosis for acute HDV co-infection is favorable: most patients are cured, the disease becomes chronic in 1–5% of cases.

Superinfection has an unfavorable prognosis: chronic hepatitis is observed in 75–80% of patients, cirrhosis quickly develops, often followed by malignancy.

The prevalence of the disease in different regions varies significantly: from isolated cases to affecting 20–25% of those infected with the hepatitis B virus.

Prevention

Basic preventive measures:

• compliance with safety precautions when working with blood;
• refusal of casual unprotected sexual contacts;
• refusal to take narcotic drugs;
• receiving medical and cosmetology services in official licensed institutions;
• carrying out systematic medical examinations in cases of occupational contact with blood.

Video from YouTube on the topic of the article:

Hepatitis D is a non-independent form of liver pathology. Delta virus (HDV) is able to reproduce only in the presence of a “stimulator”, which is a virus. Because of this, the severity of this dual disease increases significantly. The only thing that is a little reassuring is the rarity of this form of hepatitis in our country.

Due to the specific nature of the transmission of the disease from person to person (through blood and sexual contact), the risk group is mainly the younger generation.

The important thing is that the acute form can be cured within a few months. However, if you miss the initial stage of the disease, the process turns into a latent chronic form. In its chronic form, the virus is destructive to the liver, gradually destroying it.

Viral hepatitis D belongs to the group of VH (viral hepatitis), characterized by contact transmission of an infectious agent. At the same time, the reproduction of viral particles in the liver tissue is possible only if the patient has the hepatitis B virus.

For reference. In patients without concomitant hepatitis B, hepatitis D (delta hepatitis) is not registered due to the defectiveness of the pathogen itself.

The course of viral hepatitis D is always severe, and the prognosis for recovery is often unfavorable (the disease is often complicated by hepatic coma). The most unfavorable prognosis for hepatitis D is in patients with concomitant HIV infection.

Important. The combination of HIV and hepatitis D is often accompanied by a fulminant course of infection with the development of cirrhotic degeneration of liver tissue and hepatic coma.

Viral hepatitis D code according to ICD10 classification:

• B16.0 for a combination (co-infection) of hepatitis D and B if the course of the disease is complicated by hepatic comas;
• B16.1 for co-infections D and B, not accompanied by the addition of hepatic comas;
• B17.0 for the addition of acute hepatitis D if the patient is a carrier of hepatitis B viruses.

Etiological factors of the disease

Hepatitis D viruses were discovered in 1977. Since the virus was isolated from a patient with hepatitis B, scientists assumed that it was the fourth genotype of hepatitis B and named it delta (D is the fourth letter in the Greek alphabet).

Subsequently, studies showed that the pathogen belongs to a new genus of hepadnaviruses - deltaviruses.

A specific feature of the infectious agent is the inferiority of its genome. That is, this virus is not capable of causing disease on its own, since there are no regions in its genome capable of encoding envelope proteins.

In this regard, hepatitis D cannot develop on its own. However, if the patient has hepatitis B, the addition of delta agents (hepatitis D virus) contributes to the development of severe damage to the liver tissue.

For reference. The ability of the hepatitis D virus to interact with the hepatitis B pathogen is determined by the high ribonucleic activity of the pathogen (pronounced ability to bind to other ribonucleic viral particles).

The hepatitis D virus is highly resistant to environmental factors. The pathogen is able to easily tolerate high temperatures, freezing, exposure to acids and ultraviolet radiation.

The virus can be inactivated using disinfectants based on proteases and concentrated alkalis.

Hepatitis D - how is it transmitted?

For reference. Viral hepatitis D belongs to anthroponotic infectious diseases, that is, the main source of pathogens is a sick person. Most often, patients with chronic viral hepatitis B and D pose an epidemic threat.

The transmission routes for hepatitis D are similar to those for hepatitis B.

Infection occurs:

• parenterally (surgery, aseptic (criminal) abortions, injections of narcotic drugs, constant hemodialysis, constant need for donor blood (the patient has hemophilia), etc.);
• through the sexual tract (acute hepatitis D is often recorded in patients who frequently change sexual partners, as well as in homosexuals);
• transplacentally (transmission of infection occurs from a pregnant woman to the fetus).

For reference. It should be noted that transplacental transmission of the pathogen occurs less frequently. At the same time, the risk of infection of a child increases significantly if a woman has HIV infection.

The main risk groups for hepatitis D infection are:

• injection drug addicts;
• patients with severe kidney pathologies requiring regular hemodialysis;
• persons with severe coagulopathies (patients with hemophilia), who often require donor blood transfusions;
• homosexuals;
• patients who frequently change sexual partners.

Attention! Also, the disease can be transmitted in tattoo and piercing parlors, nail salons, when using other people's razors at home, etc. accessories.

Hepatitis D is reported less frequently in children than in adults.

D is considered a defective microorganism because it does not have its own membrane and the enzymes necessary for reproduction. The main condition for its development in the human body is the presence of the hepatitis B virus, which facilitates the penetration of the delta virus into cells after infection.

The delta virus is a single strand of ribonucleic acid (RNA), covered with a protein coat on top. Penetrating into hepatocyte cells, the virus loses its capsule and begins to multiply, creating new microorganisms. The vital activity of the virus disrupts the functioning of liver cells and leads to the deposition of fat droplets in them, which ends in necrosis and death of hepatocytes. Having coped with one cell, delta viruses move on to others.

The pathogenesis of hepatitis D is not only cell death, but also the immune response. Viral infection and disruption of the organ leads to activation of the immune system, it begins to produce antibodies. The antibodies produced by the body mainly fight the pathogens of hepatitis type B, but if it is completely destroyed, then the conditions conducive to the reproduction and development of the delta virus disappear.

The causative agent of the hepatitis D virus is significantly different from the more well-known microorganisms that lead to hepatitis. The delta virus is considered the most contagious of them and has several genotypes that are divided along racial lines.

• The genotype of the first type is mostly detected in European residents.
• The second type genotype was identified in residents of Taiwan and Japan. In Russia, this genotype affects the population of Yakutia.
• The third type genotype is characteristic of residents of Africa and Asia.

People infected with hepatitis B are considered the main group in which hepatitis D can also be detected. You can become infected with the delta virus through blood and unprotected sexual contact.

Causes and methods of infection

Hepatitis D is transmitted from a sick person to a healthy person. The source of infection is patients with acute and chronic forms of infection, as well as carriers, that is, those people who do not have signs of the disease, but the delta virus itself is present in the body. If the delta virus enters the body of a person who does not have viral hepatitis D, then the microorganism will not multiply, that is, the disease is excluded. The etiology, that is, the causes of infection, is associated with infection with the blood and biological fluids of a sick person; this can happen in several ways:

In rare cases, infection is detected when the same hygiene items are used by family members. These could be scissors, toothbrushes, razors. The risk of infection among medical workers is increased, since blood from a sick person getting on healthy skin leads to infection.

The delta virus is not transmitted through sneezing, kissing, dishes or water. Therefore, a person sick with the D virus does not pose any danger to others during normal communication.

Symptoms

Diet

For viral hepatitis, patients are prescribed diet No. 5. The main purpose of its use is to improve the functioning of the digestive tract and reduce the secretion of digestive juices. The following principles must be followed:

• Food intake should be in minimal portions at least 4 times a day.
• Dishes must be warm, cold and hot are excluded.
• You should not eat foods containing large amounts of spices and essential oils.

All fatty fish and meats, smoked meats, chocolate, fresh baked goods, pickled preparations, and too salty and spicy dishes are excluded from the diet. The emphasis should be on plant and dairy foods, cereals. A sufficient amount of liquid in the form of compotes and rosehip decoctions will help free the body of toxins.

Consequences and prevention

Complications of viral hepatitis D include the development of cirrhosis, liver failure, and malignant neoplasms. If the disease is detected early, complete restoration of liver function is possible, but it may take several months.

There are two main methods of preventing hepatitis D. The specific method is to administer a vaccine against hepatitis B. Since this protects a person from the B virus, the possibility of the delta virus multiplying in the body is eliminated.

Non-specific methods of prevention include the use of only disposable instruments during medical and other manipulations, condom-protected sexual intercourse, and abstinence from drugs.

Good day, dear readers!

In today's article we will continue to consider hepatitis in all its aspects and next in line - hepatitis D, or as it is also called - viral hepatitis D, as well as its causes, symptoms, diagnosis, treatment and prevention. So…

What is hepatitis D?

Hepatitis D (hepatitis D)– an inflammatory infectious disease of the liver, the cause of which is infection of the body with the hepatitis D virus (HDV).

HDV (Hepatitis delta virus), translated into Russian it sounds like this - hepatitis delta virus. Due to the fact that the cause of this disease is a virus (HDV), it is also called viral hepatitis D, or delta hepatitis.

Antiviral drugs aimed at stopping HBV and HDV infections are:

• Alpha interferon group— “Alfaferon”, “Interferon”;
• Nucleoside analogues- “Adefovir”, “Lamivudine”.

The course of taking these medications ranges from 6 months to several years.

1.2. Therapy aimed at maintaining liver health

To protect liver tissue from pathological processes caused by its infection with hepatitis viruses, as well as to accelerate the regeneration of cells (hepatocytes) of this organ from infection, hepatoprotectors are prescribed: "", "Ursonan", "Legalon", "Lipoic acid", "Hepatosan" ", "Silymarin", "".

The effectiveness of liver restoration increases with the simultaneous use of hepatoprotectors and ursodeoxycholic acid (UDCA): Ursodex, Ursor.

1.3. Detoxification therapy

The infection, entering the body, poisons it with its waste products, which can often poison the body, causing symptoms such as nausea, general weakness, lack of appetite, elevated body temperature and other symptoms. To stop such processes that poison the body, detoxification therapy is prescribed. These drugs adsorb the waste products of the infection and promote its rapid elimination from the human body.

Among the detoxification drugs, the following products can be distinguished: “Atoxil”, “Albumin”, glucose solution (5%), “Enterosgel”.

1.4. Supporting the patient's immune system

The immune system is the body's defense mechanism against various infections. If an infection gets inside a person, and the immune system is unable to overcome it, in many cases immunostimulants are prescribed, which not only help improve overall health, but also increase the effectiveness of fighting the infection that already exists inside the person.

Among the immunostimulants we can highlight: Vilozen, Zadaxin, Thimalin, Timogen.

A natural immunostimulant is, large amounts of which are found in cranberries and many other products.

1.5. Relief of symptoms of viral hepatitis D;

To alleviate the course of the patient’s illness, symptomatic medications are prescribed during treatment.

Against nausea and vomiting:" ", "Pipolfen", " ".

Against insomnia, anxiety– sedatives: “Valerian”, “Tenoten”.

2. Diet for hepatitis D

For hepatitis D, a therapeutic nutrition system developed by M.I. is usually prescribed. Pevzner - which is also prescribed for the treatment of liver cirrhosis and.

The basis of the diet consists of drinking plenty of fluids - 2-3 liters of liquid/day, fresh fruit juices, gentle soups, steamed porridge.

For hepatitis B and D, the consumption of alcohol, as well as spicy, salty, fried, fatty, canned and smoked foods, fast food, chips, crackers and other unhealthy foods is strictly prohibited. It is also necessary to stop smoking and using drugs.

3. Good rest

Adequate rest helps the body accumulate energy to fight a viral infection, so you need to allocate the necessary time for it. The lack of proper rest, including healthy sleep, work/rest/sleep modes leads the body to constant tension and... In such situations, the activity of the body's immune system is suppressed, and the person becomes more susceptible to various diseases. Moreover, in this state it is more difficult for the body to cope with the disease already present within it.

4. Dosed physical activity

Morning exercises bother few people. When a person moves, his blood flow increases, and along with it, his metabolism accelerates, his organs are more quickly saturated with oxygen and nutrients. This contributes to a faster process of recovery of the body from various diseases, as well as speed up the processes of recovery of the body after illnesses.

Treatment prognosis

With adequate treatment, the positive prognosis for recovery from acute forms of hepatitis B and D is up to 95%, and the liver is able to fully recover.

The recovery rate from chronic forms of hepatitis B and D is about 15%, and largely depends on timely consultation with a doctor, as well as strict compliance with all his instructions, including following a diet and completely abstaining from alcoholic beverages and smoking.

If doctors do not give a positive prognosis for recovery, try not to despair, turn to the Lord Jesus Christ. There are an incredible number of miraculous healings of people not only from hepatitis, but also cancer on the Internet and the Holy Scriptures. To do this, you don’t have to run somewhere, just at home, with a sincere heart, ask God for forgiveness for everything that you may have done wrong in your life, and also ask Him for complete healing. May the Lord help you! And when it helps, don’t forget to thank Him, and try to change your lifestyle and worldview.

Cost of treatment for hepatitis D and B

The cost of hepatitis D treatment, depending on the clinic and the manufacturer of antiviral drugs, can range from 6,000 to 30,000 USD. in year.

Important! Before using traditional methods of treatment, be sure to consult your doctor!

Folk remedies against hepatitis D are aimed only at maintaining the liver during drug therapy for hepatitis, as well as at restoring liver cells during the recovery period.

Elecampane. Take 1-1.5 g (at the tip of a knife) of root powder 2 times a day with water, 30 minutes before meals. This remedy is also effective for other diseases of the gastrointestinal tract, chicory, knotweed, and buckthorn bark. Mix them. Next, 4 tbsp. spoons of the mixture, pour 500 ml of cold water and leave the product to infuse overnight. In the morning, boil the product, boil it for 5 minutes, then leave the decoction to infuse and cool for about 25 minutes. You need to take the decoction half a glass, 3 times a day, 30 minutes before meals.

Corn silk. Pour 200 ml of boiling water over 1 tablespoon of corn silk, cover the container and set it aside to steep for 2 hours. You need to take this medicine for hepatitis 2-3 tbsp. spoons, 4 times a day, until complete recovery.

Calendula. Calendula should be consumed in the form of tea and non-alcoholic infusion until complete recovery.

Prevention of hepatitis D and B includes the following preventive measures:

• Compliance ;
• Do not use other people's personal hygiene items;
• Refusal of services from beauty salons and medical institutions, including dental clinics of dubious nature;
• Refusal of tattoos, piercings;
• Quitting drugs, especially injection drugs;
• Quitting alcoholic drinks (and low-alcohol drinks too) and smoking;
• For injections, use only disposable syringes, and it is better to take medications orally;
• If a person infected with the hepatitis virus lives in the family, separate dishes, bedding, body care items and other things with which the person has contact for personal use;

Hepatitis D virus (HDV, delta, or hepatitis D virus), a defective infectious virus that causes hepatitis D in humans, is a small RNA virus that was originally described in patients with more severe chronic hepatitis B. This virus was first introduced discovered more than 35 years ago.

A distinctive feature of this infectious agent is that it shares a number of properties with both plant viroids and plant viroid-like satellite RNAs, using hepatitis B virus envelope proteins (HBsAg) to package its genome.

Evolution and epidemiology

As a rule, only humans are carriers of hepatitis D disease. Research data suggests the African origin of the virus. HDV is characterized by a high degree of genetic heterogeneity. It is believed that the evolution of HDV is driven by 3 main mechanisms: mutation, editing and recombination.
It should also be noted that the mutation rate of HDV is higher than that of most RNA viruses, and therefore it is assumed that HDV circulates within a single infected host as a number of quasispecies.

Initially, 3 genotypes of this virus were described (I-III). Genotype I has been isolated in Europe, North America, Africa and some regions of Asia. Genotype II is found in Japan, Taiwan, and also in Yakutia. Genotype III is known exclusively in South America (Peru, Colombia and Venezuela). It is now known that there are at least 8 genotypes of hepatitis delta virus (HDV-1 - HDV-8). All of them, with the exception of HDV-1, are confined to strictly defined geographic regions. HDV-2 (formerly known as HDV-IIa, found in Japan, Taiwan and Yakutia; HDV-4 (HDV-IIb) - in Japan and Taiwan; HDV-3 - in the Amazon region; HDV-5, HDV- 6, HDV-7 and HDV-8 - in Africa
Around 20 million people are infected with hepatitis delta virus worldwide, making it an important public health issue.

Clinical features

Replication (multiplication) of the hepatitis B virus does not harm a person in itself. Liver damage occurs due to the host's immune system's response to this infection. The immune system kills liver cells infected with the virus. The same is probably true for the hepatitis D virus. However, there are experimental situations where the replication of the hepatitis delta virus led to the death of liver cells - hepatocytes.

The symptoms of hepatitis D are the same as those of hepatitis B, but their severity is much higher. The distinctive features of chronic hepatitis D include its high cirrhosis. In addition, the possibility of the participation of the hepatitis delta virus in the development of autoimmune diseases of the liver and thyroid gland has been shown.

The course of the disease may also depend on the genotype of the hepatitis D virus: infection caused by genotype 1 virus is characterized by a more severe course than those caused by viruses of genotypes 2 and 4. In addition, the large delta antigen (L-HDAg) can cause changes in the cell proteome, which contribute to their malignant degeneration; thus, hepatitis D may underlie hepatocellular carcinoma.

In some regions, such as the Amazon, the risk of developing fulminant hepatitis delta is very high.

Main markers of hepatitis D:

• IgM anti-HDV - class M antibodies to the hepatitis D virus mark HDV replication in the body and correlate with histological activity and long-term course of the disease;
• IgG anti-HDV - class G antibodies to the hepatitis virus indicate possible HDV infection or past infection.
• HDAg antigen of the HDV virus - a marker of the presence of HDV in the body, can only be detected in liver tissue.
• HDV-RNA - RNA of the HDV virus is a marker for the presence and replication of HDV.

Features of the disease and treatment of hepatitis D

Acute delta hepatitis, as a result of co-infection with the hepatitis B virus, is quite rare, but in some cases it can lead to fulminant hepatitis, for which there is no treatment. Chronic delta hepatitis (CDH) primarily results from superinfection of hepatitis delta virus (HDV) into a hepatitis B surface antigen (HBsAg) carrier. As with other viral infections, therapy must be tailored to the dominant virus, which in the vast majority of cases is HDV. However, changes in the dominant virus may occur over time. In rare cases, hepatitis B virus (HBV) may become dominant, at which time treatment with nucleos(t)ide analogues is required.

The only method of control and treatment of chronic delta hepatitis is interferon alpha, which must be administered in doses used to treat hepatitis B for at least 1 year. Virologic response within 24 weeks of treatment is the most widely used surrogate marker of treatment response, but does not represent sustained virologic response (so-called SVR) as is the case with hepatitis C. Late relapses are common. Anti-HDV-IgM is also an easy-to-use serological test that has been found to correlate with histological inflammatory activity and clinical long-term course; however, this test does not have the same sensitivity and specificity as HDV RNA in assessing response to treatment.

There are currently no evidence-based guidelines or recommendations for the treatment of CGD. The duration of treatment should be individualized based on the virological response at the end of treatment/observation. Effective treatment can reduce the risk of liver-related complications such as decompensated cirrhosis, HCC, and death. In patients with decompensated cirrhosis, interferons are contraindicated for use and the only option for them is liver transplantation. Finding alternative treatment options is an urgent need. Unlike HBV and HCV infection, direct inhibition of HDV replication is not possible. HDV replicates by a double rolling circle mechanism and also uses cellular RNA polymerase II, with contributing functions of RNA polymerase I and III, all of which are host polymerases and therefore should not be affected by antiviral agents.

HDV is becoming a less common pathogen despite being endemic, mainly affecting areas of the world with low socioeconomic status. Low financial support, unfortunately, is a likely explanation for the lack of interest on the part of major pharmaceutical companies in the development of drugs for the treatment of CGD, and the problem of developing promising areas currently depends more on academic institutions. However, new treatment guidelines are likely to be adopted as new treatment strategies are emerging that target different stages of the HDV life cycle, such as viral particle entry inhibitors, prenylation inhibitors, or HBsAg release inhibitors.

Treatment of acute hepatitis D

Acute hepatitis D (AHD) resembles typical self-limited hepatitis, which is clinically and histologically indistinguishable from hepatitis B or other types of viral hepatitis. This may, however, result in a biphasic type of hepatitis, possibly due to the sequential expression of two viruses.
The acute process can clinically vary from mild hepatitis to fulminant, leading to the death of the patient. Early studies conducted in both the United States and Europe clearly demonstrated that HBV/HDV coinfection was more likely to result in more severe hepatitis compared with HBV monoinfected patients. However, a recent study from Spain reported the development of fulminant HDV hepatitis in only two (1.7%) of 115 patients, suggesting that acute fulminant hepatitis D is still rare. This is good news, since there is no therapy for OGD with proven effectiveness.

Treatment of chronic hepatitis D

The only therapy with proven effectiveness is treatment with interferons. Over the years, various drugs have been used in the treatment of CGD, but none have proven effective. The first studies with interferons were conducted in the late 1980s. Several studies in the late 1980s and early 1990s suggested that the duration of treatment should probably be no less than 1 year, and that interferon-alpha (IFN-α)-2a or IFN-α-2b should be given at a dose 9-10 million units three times a week.

Response to treatment is assessed in most publications at week 24 of treatment, and patients who exhibit negative HDV RNA at this time point are considered virologic responders. Interferon therapy for 1 year results in a virological response in about 25% of patients, which clearly emphasizes the need to optimize treatment and search for alternative options.

Important points regarding the treatment of CGD:

• 
  To evaluate treatment effectiveness, a reliable surrogate marker of treatment success is needed. The best treatment outcome is clearance (or loss) of HBsAg; however, this goal is very rarely achieved in clinical practice. A surrogate marker of treatment effectiveness is a sustained virological response, that is, a decrease and maintenance of HDV-RNA levels at undetectable levels. Unfortunately, there is currently no standardized assay to quantify HDV RNA. Lack of standardization is a serious problem. Even in reference laboratories, discrepant results were observed with the same serum samples. To some extent, this may explain the differences in rates of sustained virologic responses reported in past studies.
• How durable and reliable is the sustained virological response? As described above, in most studies, sustained virological response is the absence of detectable viral RNA for 24 weeks after therapy, similar to the approach for chronic hepatitis C. However, the reliability of this treatment endpoint as an indicator of long-term HDV control has not been confirmed. Some patients may become HDV RNA negative even after interferon therapy (Niro et al., 2006; Wedemeyer et al., 2011, 2014). Notably, HDV can remain infectious at very low titers, well below detectable levels using current tests (sensitivity threshold 10 copies/ml). HDV was transmitted to HBsAg carriers (chimpanzees) using serum diluted 11 times, which is the highest infectious potential. Therefore, if HBsAg remains detectable, residual very small amounts of HDV latent in the liver may reactivate the HDV infection and repeat liver damage.
• In chronic hepatitis C, accumulating evidence suggests differences in response to treatment between previously untreated and previously treated patients. In a study from Italy, the worst outcome of hepatitis D treatment was an independent predictor of subsequent treatment success (Niro et al., 2006). However, the two largest studies (HIDIT-1 and HIDIT-2) found no difference in virological response between treatment-naïve and treated patients (Wedemeyer et al., 2011, 2014).

  Treatment with pegylated interferon should last at least 1 year, although the optimal duration of treatment is not yet known. In several clinical studies, 2 years of treatment did not appear to provide a higher rate of viral response compared with 1 year (Di Marco et al., 1996; Günşar et al., 2005; Yurdaydin et al., 2007; Örmeci et al. . 2011). However, these were small clinical studies, and any conclusion based on these studies risks being misleading. The recent HIDIT-2 trial, in which interferon-based therapy was administered for 2 years, did not appear to increase the likelihood of response after treatment and was associated with high rates of relapse after discontinuation (Wedemeyer et al., 2014). However, according to experts, data, although limited, suggest that individual patients may require treatment durations exceeding 1 year (Lau et al., 1999a; Kabaçam et al., 2011; Heller et al., 2014), but the duration will likely be determined on a case-by-case basis. Cumulative treatment durations of up to 10 or 12 years have been reported (Lau et al. 1999a; Kabaçam et al. 2011). A recent study showed that interferon can delay the entry of HDV into hepatocytes (Han et al., 2011). This suggests that the effectiveness of interferon therapy may lie in blocking the spread of HDV to other hepatocytes rather than acting as a direct antiviral agent, further rationalizing the need for long-term treatment.

• Can other parameters be used to evaluate the effectiveness of treatment? HBsAg quantification could theoretically provide additional information. This is supported by data that show that successful interferon treatment is associated with a decrease not only in HDV RNA, but also in quantitative levels of HBsAg (Manesis et al., 2007). Additionally, a correlation was observed between serum HDV RNA levels and HBsAg levels, but not with HBV DNA levels (Zachou et al., 2010). However, quantitative HBsAg levels were not an independent predictor of treatment response (O Keskin, H Wedemeyer, A Tüzün, et al., Unpubl.).
• Combination regimens for treating INF with nucleos(t)ide analogues have been studied in hopes of increasing response rates. However, these attempts were disappointing. No increase in virological response was observed when INFα was combined with lamivudine. Similarly, combinations of conventional and Peg-INF with ribavirin, and more recently the combination of adefovir with Peg-IFN, did not increase virological response compared with INF or Peg-INF monotherapy. However, combination therapy was more effective than Peg-INF monotherapy in terms of the rate of reduction in HBsAg levels. More encouraging results were observed in patients with CGD coinfected with human immunodeficiency virus (HIV); A significant reduction in HDV RNA was observed in 13 of 16 patients treated with tenofovir for 6 years. Since a direct effect of tenofovir on HBsAg production cannot be expected, long-term therapy must be required for it to have an effect on HBsAg synthesis.

Several algorithms for treating CGD with interferon have been proposed, one of them is shown below:

New drugs targeting HDV infection

Myrcludex B

The recognition that NTCP is the entry receptor for HBV and HDV into hepatocytes has led to the study of several drugs in vitro and in animal models to determine their ability to inhibit this receptor and prevent HBsAg entry into the liver cell. Irbesartan, ezetimibe, ritonavir, cyclosporine, cyclosporine derivatives SCY446 and SCY45O17 and proanthocyanidin as well as its analogues were found to inhibit the binding of HBsAg in vitro. The first subcutaneous drug used in the treatment of HDV is Myrcludex B (MyrB), a myristoylated synthetic N-acylated HBV preS1 domain peptide. A safety study (Blank et al) determined that the concentration of MyrB that blocks HBV and HDV entry is 100 times lower than that required to inhibit bile acid transport. High doses of MyrB (up to 20 mg) were administered to 36 healthy volunteers. The drug was well tolerated with no signs of toxicity; Moderate and transient elevations of amylase and lipase were observed in seven patients, but clinically resolved spontaneously without treatment adjustment.

Lonafarnib

Critical to HDV morphogenesis is the process of L-HDAg prenylation; This step is required to facilitate the interaction of L-HDAg with HBsAg within the cell, and inhibition of this process provides the basis for new therapeutic strategies. Following demonstration in vitro and in mouse models, various farnesyltransferase inhibitors reduced HDV replication. Lonafarnib (LNF), a tricyclic carboxamide derivative initially tested as an antitumor agent, was developed as a prototype farnesyltransferase inhibitor for clinical trials in the treatment of HDV.

Nucleic acid polymers (NAPs)

NAPs are negatively charged molecules composed of single-unit phosphorothioid oligonucleotides that interfere with the initial nonspecific adsorption of viruses to the cell surface; Studies in ducks infected with hepatitis B virus (DHBV) have suggested that various NAPs are able to block DHBV entry into duck hepatocytes and reduce HBsAg secretion. In a first-in-human study, NAP REP 2055 and NAP REP 2139 (REP 2139) were conducted in patients with HBeAg positive CHB who experienced a significant decrease in serum HBsAg. With this premise, REP-2139 was selected for a pilot study to evaluate the safety and efficacy in combination with Peg IFN in the treatment of HDV.

results

Myrcludex B and Lonafarnib

Myrcludex B monotherapy (Bogomolov et al) evaluated MyrB in the treatment of HDV to provide evidence that blocking HBsAg entry can prevent de-novo HBV infection of yet uninfected liver cells, thereby reducing the population of HDV-positive cells, allowing hepatocytes , which does not contain HDV, regenerate and ultimately lead to the destruction of the virus. Accordingly, the primary endpoint of the study was HBsAg response, defined as a decrease in serum HBsAg of at least 0.5 log IU/mL. The drug was administered to seven patients at a dose of 2 mg daily subcutaneously for 24 weeks. Treatment for 6 months was associated with a >1 log10 reduction in HDV-RNA in four patients receiving MyrB alone; treatment resulted in normalization of alanine aminotransferase (ALT) in six patients. However, MyrB did not reduce serum HBsAg titer; HDV-RNA levels recovered in all patients after treatment.

Lonafarnib: (Koh et al) studied the drug for the treatment of patients with Ishak fibrosis score 3, all HBeAg negative, with borderline serum HBV DNA levels and HDV RNA levels of at least 10^5 IU/ml. Patients were randomized into two groups, which received oral LNF for 28 days and were observed for 6 months after therapy. Eight patients were enrolled in group 1; six of them received LNF 200 mg per day and two received placebo. Six patients were classified into group 2; four of them received LNF 400 mg per day and two received placebo. After completion of therapy, two patients receiving placebo in group 1 were transferred to group 2 and received 400 mg LNF. By the end of therapy, HDV RNA levels decreased by 0.73 log10 IU/ml with the lower dose and by 1.54 log10 IU/ml with the higher dose; the reduction was significantly higher than in the placebo group (0.12 log10 IU/ml). Serum HBsAg and ALT levels did not change, and HDV RNA returned to baseline levels in all patients after discontinuation of therapy. Tolerance was poor; the most important side effects occurred with the 400 mg dose and were gastrointestinal side effects (intermittent vomiting in 50%) and weight loss (average 4 kg).

Because LNF is metabolized by cytochrome P450-3A4,35, the CPY3A4 inhibitor ritonavir has been added to LNF therapy to reduce side effects and achieve higher drug levels at a lower dosage. Research under the acronym LOWR HDV (LOnafarnib With Ritonavir for HDV) is ongoing and has so far been presented in abstract form. In LOWR HDV-2, LNF was given to three patients for 8 weeks at a dose of 100 mg BD along with ritonavir 100 mg daily. Compared with the 100 mg dose and the 300 mg dose without ritonavir, LNF plus ritonavir produced the best antiviral response, resulting in a 3.2 log10 IU/mL reduction in HDV-RNA after 8 weeks of therapy; serum LNF levels in patients treated with ritonavir were 4 to 5 times higher than LNF without ritonavir. Side effects were similar to monotherapy, but to a lesser extent.

In LOWR HDV-4, 15 patients were prescribed 50 mg LNF with ritonavir 100 mg daily; ritonavir was maintained at 100 mg regardless of LNF dose. The mean reduction from baseline in HDV-RNA levels was 0.98 log10 IU/mL at week 24, and this decreased to >-1.5 log10 IU/mL in 58% of patients. Most patients had diarrhea; grade 3 diarrhea and asthenia occurred in three patients. Decreased HDV RNA was associated with HBV DNA relapse in patients who did not receive antiviral therapy against HBV, indicating an inhibitory effect of HDV on HBV replication. The reduction in HDV did not persist after cessation of therapy, and viremia recovered; serum HBsAg did not change.

Thus, both MyrB and LNF transiently reduced HDV RNA levels, but their antiviral effect did not prevail. No HDV mutations to the study drugs were detected; both therapies demonstrate a high genetic barrier. MyrB normalized ALT and had excellent clinical effect; LNF had no effect on this enzyme. The serum HBsAg titer did not decrease either; this was unexpected for MyrB, since the study's postulated mechanism of action required HBsAg response to be the primary endpoint of the study.

REP-2139 in combination with Peg IFN

Results from a phase 2 proof-of-concept study of REP 2139 in combination with Peg IFN were recently published. The study included 12 patients aged 18 to 55 years from Moldova with HDV-RNA genotype 1; the infection had been identified for more than 17 months. All were HBeAg negative, had negative or low HBV DNA levels, and were reported to have chronic hepatitis without cirrhosis; Cirrhosis was excluded by hepatic and hematological parameters, abdominal ultrasound (US) and liver stiffness (KPa<10 у семи пациентов,>10 in five patients). Serum HBsAg concentration at baseline was >1000 IU/ml. Patients received 500 mg IV REP 2139 once weekly for 15 weeks, followed by 250 mg IV REP 2139 combined with 180 mcg subcutaneous Peg IFN once weekly for 15 weeks, followed by Peg IFN monotherapy 180 mcg once weekly. week for 33 weeks. They were monitored for 1 year after therapy. Eleven patients became HDV-RNA negative during treatment, with HDV-RNA decreasing sharply from the first weeks of REP monotherapy; nine were negative at the end of treatment and seven at the end of follow-up.

At the end of follow-up, nine patients had normal serum aminotransferase (ALT) levels. In six, the HBsAg level decreased to<0,05 МЕ / мл к концу лечения; пять пациентов поддерживали ответ по HBsAg в конце наблюдения.

Various side effects have been reported, mainly related to the toxicity of PEG IFN. Pyrexia, chills and asthenia were observed in 100%, 75%, 67% of patients, respectively. Eight patients had neutropenia (67%), 10 patients had thrombocytopenia (83%), requiring Eltrombopag in two patients. In 5 patients (42%), ALT increased during therapy; the enzyme elevation was reported to be clinically uneventful.

No serious adverse events were described during the REP 2139 studies. Six patients developed antibodies to HBsAg (anti-HBs), titers exceeding 7681 mIU/mL after administration of Peg IFN; five still had antibodies at the end of follow-up.

conclusions

New drugs targeting HDV will likely lead to better control of hepatitis D in the coming years. Preliminary data for REP 2139/Peg IFN are most promising. If confirmed in larger, well-designed, randomized trials, this therapeutic strategy would provide a breakthrough over IFN-α-based therapy; however, the biological background of REP 2139 therapy is currently poorly understood, and the molecular mechanism by which the drug exerts its therapeutic effect must be elucidated to provide a rationale for optimizing therapy. With new drugs, we hope to increase the number of patients cured of hepatitis D. However, management of patients who do not respond to HDV or who do not lose HBsAg, regardless of HDV RNA kinetics, will remain challenging. The proportion of patients with negative HDV RNA and HBsAg can be expected to increase compared with treatment with IFN monotherapy; the dilemma is how long these patients should be treated and whether HDV/HBsAg can ultimately be eradicated by expanding therapy. If HDV RNA becomes undetectable but HBsAg remains unchanged, long-term clinically unprecedented follow-up is required to conclude that treatment has eradicated HDV: how long follow-up is required needs to be determined, in the meantime, virological relapses have occurred years after, a seemingly virological response. Long-term treatment will increase the issue of tolerance and safety, particularly when combined with poorly tolerated IFN-α; IFN-λ may serve as an alternative, as this cytokine is thought to cause fewer side effects than IFN-α and may be more suitable for long-term treatments. Ongoing and future trials will show whether new drugs can further increase the chances of HDV eradication within reasonable treatment periods.