Hepatitis D: Symptoms, Types, Causes and Treatment

Hepatitis D, also known as hepatitis delta, is a unique and severe form of viral hepatitis that only affects people already infected with hepatitis B. Despite global efforts, hepatitis D remains a significant health concern due to its aggressive progression and limited treatment options. In this article, we’ll explore the symptoms, types, causes, and treatment strategies for hepatitis D, providing a clear and comprehensive overview for anyone seeking to understand this challenging disease.

Symptoms of Hepatitis D

Hepatitis D can present with a variety of symptoms, which may range from mild to life-threatening. Recognizing these symptoms early is crucial for diagnosis and timely medical intervention. Below we’ll introduce the main symptoms, followed by a summary table and a deeper dive into how hepatitis D manifests in affected individuals.

Symptom	Description	Severity/Progression	Source(s)
Fatigue	Persistent tiredness and lack of energy	Early and chronic	2 4
Jaundice	Yellowing of skin and eyes	Acute and/or chronic	2 4
Abdominal pain	Discomfort, especially in upper right	Acute and chronic	2 4
Nausea/Vomiting	Feeling sick and/or vomiting	Acute phase	2 4
Joint pain	Aching joints (arthralgia)	Acute phase	2
Liver failure	Rapid decline in liver function	Fulminant/late stage	2 4
Cirrhosis	Scarring and dysfunction of the liver	Chronic/long-term	2 4

Table 1: Key Symptoms of Hepatitis D

Acute vs. Chronic Symptoms

Hepatitis D symptoms can emerge suddenly (acute) or develop gradually over time (chronic). Acute infection may cause:

• Sudden onset of jaundice
• Severe abdominal pain
• Nausea and vomiting
• Fatigue and malaise
• Joint pain

While some people may recover from the acute phase, others—especially those already living with chronic hepatitis B—can develop chronic hepatitis D, which often progresses rapidly and severely 2 4.

Complications and Disease Progression

Chronic hepatitis D frequently leads to:

• Cirrhosis: Up to 70-80% of chronic cases develop cirrhosis, a condition where healthy liver tissue is replaced with scar tissue, leading to impaired liver function 2 4.
• Hepatic decompensation: The liver loses its ability to function properly, resulting in symptoms such as fluid buildup, confusion, and increased bleeding risk 1 4.
• Hepatocellular carcinoma: The risk for liver cancer is significantly increased in those with chronic hepatitis D 1 2 4.

Why Symptoms Matter

The aggressive nature of hepatitis D means that symptoms progress more rapidly than with hepatitis B alone. Prompt recognition and medical attention are vital to slow disease progression and improve outcomes 1 2 4.

Types of Hepatitis D

Understanding the types of hepatitis D is key to grasping how the disease develops and progresses. The virus can infect individuals in different ways, and these modes of infection significantly impact prognosis and disease management.

Type	Description	Chronicity Risk	Source(s)
Coinfection	Simultaneous infection with HBV and HDV	Rare (~2%)	2
Superinfection	HDV infects someone already carrying chronic HBV	High (>90%)	2
Genotypes	At least 8, each with unique geographic distribution	Variable	1

Table 2: Main Types and Patterns of Hepatitis D Infection

Coinfection vs. Superinfection

Coinfection

• Occurs when a person is infected with hepatitis B and hepatitis D at the same time.
• Usually causes an acute, sometimes severe episode of hepatitis.
• Chronic infection develops in only about 2% of these cases 2.

Superinfection

• Happens when someone already chronically infected with hepatitis B contracts hepatitis D.
• Leads to chronic hepatitis D in over 90% of cases 2.
• Tends to cause more severe and rapidly progressing liver disease.

HDV Genotypes and Their Importance

• There are at least eight described HDV genotypes, each associated with different geographic regions and clinical outcomes 1.
• Some genotypes are linked to more aggressive disease courses.
• Geographic differences affect public health strategies and treatment research.

Multiple Infections and Disease Severity

People can be infected with multiple hepatitis viruses (including hepatitis B, D, and sometimes C), or HIV, which can lead to more complex disease patterns and faster progression to liver failure or cancer 2.

Causes of Hepatitis D

Delving into the causes of hepatitis D reveals a fascinating interplay between viruses. HDV is unique in its dependence on hepatitis B, which shapes both who can get infected and how the disease is transmitted.

Cause/Factor	Description	Notes/Key Details	Source(s)
HDV (Hepatitis D virus)	Defective RNA virus requiring HBV	Cannot infect alone	1 3 4 10
HBV (Hepatitis B virus)	Provides surface antigen for HDV lifecycle	Essential “helper” virus	1 3 4 10
Parenteral exposure	Blood/blood products, injections, etc.	Main transmission route	3 5
At-risk groups	IDUs, HBsAg carriers, immigrants from endemic areas	High prevalence	3 5
Lack of HBV vaccination	Increases risk of HDV infection	Prevention possible	5 10

Table 3: Main Causes and Risk Factors for Hepatitis D Infection

Viral Dependency: What Makes HDV Unique?

• HDV is a “defective” virus. Unlike other hepatitis viruses, HDV cannot replicate or infect on its own—it needs the hepatitis B virus (HBV) to provide the surface antigen (HBsAg) necessary for its life cycle 1 4 10.
• Only those already infected with HBV can get hepatitis D. This means HDV is never found in isolation—it always accompanies hepatitis B.

Transmission Pathways

• Parenteral (blood-borne) route: The virus spreads primarily through contact with infected blood or blood products. This includes:
  • Sharing needles (especially among injecting drug users)
  • Unsafe medical procedures or transfusions
  • Tattooing or piercing with non-sterile equipment 3 5
• Sexual transmission can occur but is less common than for hepatitis B.

Populations at Risk

• Chronic hepatitis B carriers: The main group susceptible to HDV superinfection 3.
• Injecting drug users (IDUs): High risk due to needle sharing 3.
• Immigrants from endemic regions: HDV prevalence is higher in some parts of Africa, Asia, South America, and Eastern Europe 5.
• Areas with poor HBV vaccination coverage: Ongoing transmission in these regions contributes to the global burden 5 10.

The Role of HBV Vaccination

• HBV vaccination is effective prevention for hepatitis D. Since HDV cannot infect without HBV, vaccination programs against hepatitis B have dramatically reduced hepatitis D incidence in many developed countries 5 10.
• In regions where HBV remains unchecked, HDV is still a major health issue. This highlights the importance of global HBV vaccination campaigns 5 10.

Treatment of Hepatitis D

Treating hepatitis D remains a major clinical challenge. While several therapies are under investigation, options are still limited, and not all patients respond to currently available treatments. Below is an overview of the treatment landscape, including established and emerging therapies.

Therapy/Approach	Efficacy / Key Details	Side Effects / Limitations	Source(s)
Pegylated interferon-α	25–30% sustained virologic response; long-term	Poor tolerance; relapse common	1 7 8 10
Bulevirtide (entry inhibitor)	76% virologic response in real-world studies	Well-tolerated; conditional approval in EU	6 9 10
Combination therapy (PegIFN + Tenofovir)	No significant improvement over IFN alone	Adverse effects; limited benefit	7
Liver transplantation	For end-stage liver disease	Risk of reinfection present	8
Novel agents (prenylation inhibitors, antisense oligos)	In clinical development	Awaiting further data	1 8 10

Table 4: Current and Emerging Treatments for Hepatitis D

Pegylated Interferon-Alpha: The Mainstay

• Pegylated interferon-alpha (PegIFN-α) is the only approved antiviral with proven (though limited) efficacy against hepatitis D 1 7 10.
• Treatment duration: Typically administered for at least one year, sometimes longer.
• Response rates: Sustained undetectable HDV RNA achieved in about 25–30% of patients 1 7 10.
• Limitations: Many patients relapse after stopping therapy; significant side effects such as fatigue, flu-like symptoms, and psychiatric complaints are common 7 8.

Bulevirtide: A New Entry Inhibitor

• Bulevirtide is a novel drug that blocks the entry of both HBV and HDV into liver cells 9 10.
• Real-world evidence: Approximately 76% of patients show a virologic response (reduction or elimination of HDV RNA) after 24 weeks; improvement in liver inflammation is seen even in some non-responders 9.
• Approval status: Conditionally approved in Europe for chronic hepatitis D 9 10.
• Tolerability: Favorable safety profile, with few serious side effects 9.

Combination and Adjunct Therapies

• PegIFN-α with Tenofovir (TDF): Large trials found no significant increase in efficacy compared to PegIFN-α alone 7.
• Myrcludex B (another name for bulevirtide): Alone or combined with PegIFN-α, shows promise in clinical trials for reducing HDV RNA and normalizing liver enzymes 6.
• Other antivirals (lamivudine, famciclovir): Have not demonstrated meaningful benefit for hepatitis D 8.

Future and Experimental Therapies

• Prenylation inhibitors (e.g., lonafarnib): Target viral assembly, currently under investigation 1 10.
• Antisense oligonucleotides and other molecular agents: May offer new hope in disrupting HDV replication or life cycle, but remain in early clinical development 1 8 10.
• Liver transplantation: Reserved for patients with end-stage liver disease; risk of re-infection by HDV is lower with appropriate immune prophylaxis 8.

Challenges and Outlook

• No cure for all: Many patients do not achieve a complete or sustained response with current therapies.
• Urgent need for better treatments: Ongoing clinical trials and drug development are focused on expanding options and improving outcomes for this difficult disease 1 10.

Conclusion

Hepatitis D is a distinctly severe viral hepatitis that poses unique challenges in diagnosis, management, and treatment. Its dependence on hepatitis B, rapid progression, and limited therapeutic options make it a critical area for ongoing research and public health efforts.

Key points:

• Hepatitis D only infects those who are already hepatitis B positive and often leads to rapidly progressing, severe liver disease 1 2 4.
• Symptoms can range from mild fatigue to acute liver failure and chronic cirrhosis, with a high risk for liver cancer 2 4.
• Two main types of infection exist: coinfection (with a low risk of chronicity) and superinfection (with a very high risk of chronic progression) 2.
• The disease is transmitted primarily via blood, with injecting drug users and individuals from endemic regions at highest risk 3 5.
• HBV vaccination is the most effective preventive measure against hepatitis D 5 10.
• Treatment options remain limited: Pegylated interferon-alpha is the mainstay, while bulevirtide offers new hope and several novel therapies are in development 1 7 9 10.

By understanding the symptoms, types, causes, and evolving treatments, patients and clinicians can work together for earlier diagnosis, better management, and improved outcomes in the fight against hepatitis D.