The delta in management of HDV/HBV coinfection: Lessons from a case

Abstract

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CASE PRESENTATION

A 41-year-old woman from Mongolia presented to the clinic for routine follow-up for HBV-HDV coinfection. She had a longstanding HBV infection, likely acquired through multiple blood transfusions for an acute illness when she was 3 years old. She was diagnosed with HDV in Mongolia after screening due to endemic risk. She was initially treated for HBV due to low-level HBV replication and increased liver enzymes with tenofovir disoproxil fumarate and then tenofovir alafenamide due to superior tolerability. She presented to our center to establish care for her HBV-HDV coinfection. Serologic evaluation at that time revealed positive HbsAg, negative HbsAb, negative HbeAg, positive HbeAb, HBV DNA of 227 IU/mL, HDV RNA of 185,900 IU/mL, and positive HDV IgG antibody. These studies indicated chronic HBV infection with likely chronic HDV superinfection due to the presence of HbeAb and HDV IgG Ab. Serum studies were also notable for aspartate aminotransferase and alanine aminotransferase 33 U/L and 59 U/L, respectively, with platelet level 130 10⁹ U/L. The rest of the comprehensive metabolic panel was normal.

Question 1: What is the next best step in management?

1. Liver biopsy

2. Noninvasive liver fibrosis assessment

3. Quantitative immunoglobulin assessment

4. MRI of the liver

HDV/HBV coinfection has a much higher rate of disease progression, which is why fibrosis assessment is appropriate at the time of HDV diagnosis. At this point, invasive assessment of histological activity and fibrosis through liver biopsy (A) is not indicated. While quantitative immunoglobulin measurement can be a useful diagnostic tool, further evaluation is needed to determine disease progression, not disease etiology. Finally, MRI of the liver would be recommended if there were suspected hepatic lesions, but the first step would be hepatic ultrasound.

Fibrosis assessment with elastography was done in the office, which revealed a fibrosis score of 12.2 kPa [kilopascal (IQR)] and Controlled Attenuation Parameter score of 295, indicating severe fibrosis and steatosis. With concern for advanced disease, an ultrasound was performed, showing irregular liver surface, heterogeneous parenchymal density and enhancement, along with hyperdense and hypodense nodules in both lobes. Due to the hypodense nodules, she had a contrast-enhanced liver MRI confirming cirrhotic appearance of the liver with 2 nodular lesions, 0.5 cm and 0.9 cm, respectively, described as Liver Reporting and Data System (LI-RADS) 3. Laboratory studies at this time showed total bilirubin 0.6 μmol/L, alanine aminotransferase 46 U/L, aspartate aminotransferase of 35 U/L, albumin of 3.9 g/dL, and a slightly elevated alpha fetoprotein (AFP) at 12 U/L. HBV DNA at this time was< 10 IU/mL. Repeat imaging was planned for 3 months with MRI and AFP. Given her well-controlled HBV, the progression in her disease was felt to be secondary to her active HDV.

Question 2: What is the best next step regarding the patient’s HDV?

1. Treat with pegylated interferon alpha (PEG-INFα)

2. Treat with bulevirtide

3. Liver transplant

4. No treatment

The patient was offered therapy with PEG-IFN. However, she declined the treatment after weighing the risk of side effects of PEG-INFα and anticipated efficacy of newer treatments and elected to join a clinical trial for an investigative new therapy for chronic HDV. Subsequent repeat MRI of the abdomen showed a stable LI-RADS 3 hepatic lesion thought to be consistent with perfusion-related changes.

DISCUSSION

Hepatitis D and Hepatitis B coinfection: Epidemiology

HDV is a satellite RNA virus that depends on HBsAg, a viral protein from HBV, for propagation. HDV and HBV infection are both transmitted through blood and bodily fluids, including perinatally through mother-to-child transmission and through exposure to blood products in the health care setting. In areas where HBV is endemic, vertical transmission is the most common mode of acquisition. HDV is not commonly acquired through mother-to-child transmission and is more commonly acquired as superinfection.

At least 12 million people, or about 5%–10% of patients with chronic HBV, are estimated to be chronically infected by HDV worldwide, but due to historically inaccurate testing, limited awareness of the disease, and varied guideline recommendations, this number is probably underestimated. There is dramatic variation in HDV prevalence by region, with the highest concentrations found in Mongolia, with a prevalence rate of anti-HDV antibody testing of 36.9% among chronic patients with hepatitis B, and prevalence rates > 10% in the Republic of Moldova and in regions of Western and Southern Africa.¹ The prevalence of HDV is also much higher in populations with certain risk factors, including injection drug use, men who have sex with men, migrants and refugees, and patients with cirrhosis.^2–5 Historically, guidelines only recommended screening for HDV in patients at high risk for coinfection. The AASLD 2018 guidelines recommend one-time screening in patients with HBV at high risk.⁶ However, low screening rates in this population have led to an evolution in recently published screening recommendations. The US HBV algorithm recommends HDV screening in all patients with positive HBsAg.⁷ The 2023 HDV guidelines by the European Association for the Study of the Liver (EASL) also recommend universal screening for HDV in those infected with hepatitis B.⁸ Our patient had several risk factors that warranted HDV screening, including being born in an area of high prevalence (Figure 1), having persistently elevated liver enzymes despite well-controlled HBV, and having advanced disease at an early age.

FIGURE 1.

Prevalence of anti-HDV among HBsAg-positive people in the general population. Reprinted from Stockdale et al, 2020¹ under the CC BY license creativecommons.org/licenses/by/4.0.

Presentations of patients infected with both HBV and HDV can include coinfection and superinfection. HBV/HDV coinfection, defined by simultaneous infectious of both HBV and HDV, may spontaneously clear, while superinfection is defined by HDV infection in a patient already chronically infected with HBV. Superinfection can lead to a hepatitis flare in patients with known chronic hepatitis B infection. Both HDV/HBV coinfection and superinfection can result in more severe liver disease than HBV infection alone, including a higher risk of cirrhosis, liver failure, and HCC. One study found the average time of progression of untreated HDV infection to cirrhosis and HCC is 5 years and 10 years, respectively.⁹ Our patient’s disease progression history is more consistent with coinfection rather than superinfection.

Cancer screening in chronic hepatitis D infection

Patients with chronic HDV infection carry an increased risk of HCC, even compared to patients with HBV monoinfection, a known oncogenic virus. The AASLD guidelines recommend screening for HCC in patients at a higher risk for HCC, including those with Child’s A or B cirrhosis and patients with HBV infection without cirrhosis but with other risk factors for HCC. The PAGE-B score is used by these guidelines to stratify risk. Included in the Page-B score calculator are points related to sex, age, and platelet counts, with scores ≤ 9, 10–17, and ≥ 18 equating to low, intermediate, and high risk of HCC, respectively.¹⁰ These risk factors include active hepatitis and/or high viral load, a family history of HCC, Asian descent and male over the age of 40 years, Asian descent and female over the age of 50 years, and Africans and African Americans. The standard of screening is ultrasonography with or without serum AFP at 6-month intervals.^6,11 In hepatitis D, because of the rapidly progressive course of the disease, it is recommended to start screening once HDV and HBV coinfection is established.

At treatment initiation, our patient had serum AFP 12 ng/mL and an abdominal ultrasound that showed hypodense nodules. Positive screening, defined by a hepatic lesion ≥ 10 mm or serum AFP > 20 ng/mL, should lead to further diagnostic imaging for HCC with multiphase CT or MRI. Each observation detected should then be radiographically categorized according to the LI-RADS to determine the need for further testing. The LI-RADS system allows for evidence-based categorization of lesions documented on CT or MRI in patients at risk for HCC. Classifications range from LI-RADS 1 (definite benign) to LI-RADS-5 (definite HCC). LI-RADS 3, the classification of our patient’s lesions, is considered intermediate risk, while LI-RADS 4 lesions carry a high but variable risk of progression to HCC. Patients with lesions classified as LI-RADS 3 progress to HCC ~one-third of the time, while over two-thirds of patients with LI-RADS 4 lesions progress to HCC.¹² In her case, repeat or alternative diagnostic imaging is recommended every 3–6 months. Her imaging has remained stable, and lesions were thought to be from perfusion-related changes. Lesions categorized as LI-RADS 4 require further diagnostic workup, and multidisciplinary discussion is recommended.¹³

Promising new therapies

Treatment options for HDV are an emerging area of research, and current approved therapies are limited. In the United States of America, only Peg-IFNα therapy is approved for HDV treatment. A systematic review found that one-third of patients treated for HDV with PEG-INF α for at least 48 weeks underwent sustained virologic response. However, in pooled analysis, at least 16% of patients included had to discontinue treatment early because of safety concerns.¹⁴ Our patient elected not to pursue this therapy after a risk-benefit analysis.

However, several emerging therapies are being studied for the treatment of HDV. The closest to approval in the USA is bulevirtide, a first-in-class entry inhibitor that targets a polypeptide hepatocyte receptor for HBV and HDV. After its conditional approval in the European Union, multinational studies have shown that it is well-tolerated and have high rates of virological response both alone and in combination with PEG-INFα therapy.¹⁵ A large phase 3 trial examining ritonavir-boosted lonafarnib with or without PEG-IFNα has been completed that showed significant virologic response at 24 weeks and a well-tolerated treatment regimen compared to placebo.¹⁶ A phase II trial of REP 2139, a nuclear acid polymer that inhibits the release of HBsAg, also showed promising results after 1 year of treatment.¹⁷ Additionally, an interferon-based immunomodulator that has shown efficacy in HCV and HBV, pegylated interferon-λ, showed cautiously optimistic phase II results for chronic HDV.¹⁸ Research is needed to determine whether these new antiviral agents will slow the rate of HDV progression to cirrhosis and/or HCC. Additionally, newly invigorated efforts to use innovations in antiviral treatment towards a functional cure for HBV should also be considered as part of HDV treatment.

TEACHING POINTS

• HDV infection can lead to a more aggressive disease course than HBV infection alone.

• It is recommended that all patients with chronic HBV be screened for HDV.

• Patients found to be positive for HDV antibody need to be tested for active HDV with HDV RNA.

• HBsAg-HDV–positive patients are at higher risk for disease progression and should be screened for advanced disease.

• HBsAg-HDV patients are at higher risk for liver cancer and should undergo regular screening for HCC.

• While current Food and Drug Administration-approved treatment options in the United States are limited, innovative antiviral treatments are showing promise.