A Story of HDV Coinfection, the Often Missed Diagnosis

Patient Case
A 38-year-old woman from Mongolia was referred to my practice with slightly elevated liver enzymes, normal liver function, low platelets (10⁹ cells/L), positive serology for hepatitis B surface antigen (HBsAg) and anti–hepatitis B e antigen (HBeAg), and a serum HBV DNA level of 1600 IU/mL. Serology for hepatitis C virus and HIV was negative. The patient denied alcohol use or consumption of potentially hepatotoxic medicines. Married for 16 years with a conational, she had a 10-year old son, and both her spouse and son were in good health. Family history revealed an uncle who had died of liver cancer a year before, which had led her to a medical checkup looking for evidence of liver disease. Serum iron, ferritin, fasting glucose, lipid profile, serum protein electrophoresis, and α-1-antitrypsin and ceruloplasmin were within the normal ranges. Serum creatinine was 43 μmol/L, phosphates were 1.10 mmol/L, estimated glomerular filtration rate was 112 mL/min, and α-fetoprotein was 2.9 μg/L. Ultrasound examination of the upper abdomen revealed a dysmorphic liver, with hypertrophy of segment 1, and an enlarged spleen. A percutaneous liver biopsy confirmed the clinical suspicion of cirrhosis without steatosis.

Treatment Recommendation
Before performing any additional diagnostic tests, the patient should be offered treatment for her hepatitis B virus (HBV)–associated cirrhosis, where antiviral therapy is recommended regardless of HBV DNA levels and biochemical alterations. The European Association for the Study of the Liver (EASL) recommendations stipulate that she may benefit from a nucleoside or nucleotide analogue (NA), choosing between indefinite treatment with entecavir, tenofovir disoproxil (TDF), or tenofovir alafenamide, or 48 weeks of treatment with peginterferon-α (pegIFN). 

The Missing Diagnostic Piece
However, the diagnostic workup was not complete. The patient needed testing for antibodies against the hepatitis D virus (HDV), and indeed she turned out to be positive. Subsequent testing confirmed the active HDV infection, as the HDV RNA level was 1.3 x 10⁶ copies/mL. Thus, the final diagnosis was cirrhosis associated with dual HBV and HDV infection, a very frequent occurrence in migrants born in Mongolia.

Selecting Treatment
According to the EASL recommendations, the recommended treatment option for patients coinfected with HDV/HBV and with compensated liver disease is pegIFN (currently available only in its α2a formulation) 180 μg SC once weekly for at least 48 weeks, as it is the only authorized treatment that has demonstrated some antiviral efficacy against HDV infection and clinical benefit in the long-term by reducing the incidence of liver-related unfavorable events and improving mortality. The pegIFN treatment should be continued until Week 48 regardless of on-treatment virologic response, provided that this is well tolerated. In patients with concomitant, ongoing HBV DNA replication >2000 IU/mL, the addition of NA therapy to pegIFN treatment should be considered. In cases of cirrhosis, such as this patient, I would recommend adding NA therapy regardless of the HBV DNA level. This patient was already started on NA therapy for her HBV therapy, so she should continue her NA therapy and add pegIFN upon HDV diagnosis.

The endpoint for HDV treatment that is currently accepted is the undetectable HDV RNA in serum 24 weeks after the end of therapy; this is achieved in approximately 25% of cases. There are no factors unequivocally predicting this pattern of response. Analogous to hepatitis C therapy terminology, this endpoint has been termed “sustained virologic response,” but the use of “sustained” has been challenged. One study from Germany reported that 9 of 16 patients who originally achieved sustained virologic response presented with a virologic HDV relapse, some as late as 9 years after the end of therapy. Thus, long-term follow-up of patients treated with pegIFN is recommended, with yearly HDV RNA determinations. Loss of HBsAg with or without seroconversion to anti-HBs is rare and inconsistent across different studies. Patients with cirrhosis at baseline must continue surveillance every 6 months to detect early hepatocellular carcinoma, the incidence of which is increased up to 3-fold compared with HBV moninfection.

Alternative Treatment Options?
A prolonged duration of pegIFN treatment beyond the recommended 48 weeks has been tested in some studies, without consistent results. A single study from Turkey, where patients were treated with repeated courses of pegIFN, reported impressive rates of HDV RNA response and HBsAg loss, with improved clinical outcomes, but an independent confirmation of these encouraging results is lacking. In addition, pegIFN is not an option for all patients, as it is contraindicated in patients with decompensated liver disease, and these patients should instead be evaluated for liver transplantation. Finally, tolerability is generally low, making prolonged treatments poorly accepted. As said above, NA therapy should be included whenever clinically indicated to better treat HBV, but it has no effect on HDV.

In the transplant setting, NA therapy in combination with hepatitis B immunoglobulins (HBIg) effectively reduces the risk of graft reinfection. The aim is to achieve anti-HBs levels of 50-100 IU/L. In selected patients (eg, HBV DNA negative at liver transplantation), NA prophylaxis without HBIg can be safe and effective in preventing posttransplant recurrence. However, combination therapy should be given without interruptions to patients at high risk for recurrence, including those who are HBeAg or HBV DNA positive at the time of liver transplantation, those who have HCC, and those with HIV coinfection.

Emerging Options
Daily SC administration of bulevirtide, a lipopetide inhibiting HBV and HDV entry into hepatocytes, is an emerging therapeutic option. This drug has been granted Conditional Marketing Authorization by the European Commission and PRIority MEdicines (PRIME) eligibility by the European Medicines Agency and has been granted Breakthrough Therapy Designation and Orphan Drug status by the FDA. The dose authorized is 2 mg/day, with or without TDF, for as long as it is tolerated. The results of a phase II study show that after 24 weeks of therapy with 2 mg bulevirtide and TDF, 46% of patients had undetectable HDV RNA or >2 log decline and 43% had alanine aminotransferase normalization compared with 4% and 7%, respectively, among controls treated with TDF alone. The currently accepted endpoint is at least a 2 log decline of HDV RNA. This endpoint is based on a previous study using high-dose standard pegIFN, in which survival was associated with an average on-treatment HDV RNA decline of 2 logs. Interim results from a phase III study demonstrated that HBV/HDV co-infected patients receiving 2 mg or 10 mg bulevirtide SC daily for 24 weeks achieved significant viral load suppression and improvements in liver enzyme levels compared to patients not yet receiving antiviral treatment. The safety profile of these interim phase III study results is consistent with previous studies; no serious adverse events or study discontinuations related to bulevirtide were reported. Given the fact that bulevirtide is not yet fully approved in the United States, patients may, as an alternative, be enrolled on clinical trials using this and other experimental antivirals like lonafarnib and REP 2139-Mg or REP 2165-Mg.

Your Thoughts?
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