HEPCLUDEX (Bulevirtide): Uses, Dosage & Side Effects
First-in-class HDV entry inhibitor for chronic hepatitis delta virus infection
HEPCLUDEX (bulevirtide) is the first medicine specifically approved for the treatment of chronic hepatitis D virus (HDV) infection. It works by blocking the NTCP receptor on liver cells, preventing HDV from entering and replicating. Administered as a once-daily subcutaneous injection, it is indicated for adults and children aged 3 years and older with compensated liver disease. This evidence-based guide covers everything you need to know about HEPCLUDEX, including uses, correct dosage, potential side effects, drug interactions, and important safety information.
Quick Facts
Key Takeaways
- HEPCLUDEX (bulevirtide) is the first and only medicine specifically approved for treating chronic hepatitis D, a rare but serious liver infection that always co-occurs with hepatitis B.
- It is given once daily as a subcutaneous injection (under the skin) at a dose of 2 mg for adults and weight-adjusted doses for children aged 3 years and older weighing at least 10 kg.
- Never stop HEPCLUDEX without medical supervision — abrupt discontinuation can reactivate the virus and worsen liver disease.
- Common side effects include headache, injection site reactions, itching, and elevated bile acid levels. Serious allergic reactions are uncommon but possible.
- Multiple significant drug interactions exist — always inform your doctor about all medications you take, especially ciclosporin, statins, HIV/hepatitis C antivirals, and immunosuppressants.
What Is HEPCLUDEX and What Is It Used For?
HEPCLUDEX (bulevirtide) represents a breakthrough in the treatment of chronic hepatitis D virus (HDV) infection. Hepatitis D is the most severe form of viral hepatitis, affecting an estimated 12 to 72 million people worldwide according to the World Health Organization. HDV can only infect individuals who are already infected with hepatitis B virus (HBV), as it requires the HBV surface antigen to replicate and spread. This co-infection leads to significantly worse outcomes than HBV infection alone, including accelerated progression to liver cirrhosis, liver failure, and hepatocellular carcinoma.
Before the approval of bulevirtide, there was no specifically approved treatment for chronic hepatitis D. Pegylated interferon-alpha was the only option with some evidence of efficacy, but it was poorly tolerated, had limited success rates, and was not suitable for many patients. The conditional marketing authorization of HEPCLUDEX by the European Medicines Agency (EMA) in 2020, followed by full approval in 2024, marked a paradigm shift in HDV management. HEPCLUDEX became the first medicine with a specific indication for chronic hepatitis D.
How Does HEPCLUDEX Work?
HDV enters liver cells (hepatocytes) by using a specific receptor called the sodium/bile acid co-transporting polypeptide (NTCP). This receptor is normally responsible for transporting bile acids from the bloodstream back into the liver. Both HBV and HDV exploit this receptor as their entry point into hepatocytes.
Bulevirtide, the active substance in HEPCLUDEX, is a synthetic lipopeptide derived from the pre-S1 domain of the HBV large surface antigen. It binds to and inactivates the NTCP receptor, effectively blocking the door that HDV uses to enter liver cells. With the entry pathway blocked, the virus cannot infect new hepatocytes, which over time reduces the viral load in the liver and alleviates the chronic inflammation that drives liver damage.
Clinical trials, including the pivotal Phase III MYR301 study, demonstrated that treatment with bulevirtide 2 mg daily led to a combined response (undetectable or at least 2 log reduction in HDV RNA plus normalization of ALT) in a significantly greater proportion of patients compared to no active anti-HDV treatment. These results were sustained over 48 weeks of therapy, and long-term extension data suggest continued benefit with ongoing treatment.
Hepatitis D only occurs in people who also have hepatitis B. It is transmitted through contact with infected blood or body fluids. In regions where hepatitis B vaccination coverage is high, HDV prevalence is declining. However, in areas with limited vaccine access, HDV remains a significant public health challenge. HEPCLUDEX addresses a critical unmet medical need for these patients.
What Should You Know Before Taking HEPCLUDEX?
Before starting treatment with HEPCLUDEX, it is essential that your healthcare provider has a complete understanding of your medical history, current medications, and overall health status. Bulevirtide has specific contraindications, warnings, and precautions that must be carefully considered to ensure safe and effective use of this medicine.
Contraindications
You must not use HEPCLUDEX if you are allergic (hypersensitive) to bulevirtide or any of the other ingredients in this medicine. The inactive ingredients include anhydrous sodium carbonate, sodium hydrogen carbonate, mannitol, hydrochloric acid, and sodium hydroxide. If you are uncertain about any allergy, speak with your doctor before starting treatment.
Warnings and Precautions
There are several important warnings associated with HEPCLUDEX that patients and healthcare providers must be aware of:
Never discontinue HEPCLUDEX without consulting your doctor. Stopping treatment can lead to reactivation of hepatitis D infection and significant worsening of liver disease, including flares of liver inflammation. If you wish to stop treatment, discuss this with your healthcare provider first, who will monitor you closely during and after discontinuation.
- Decompensated liver disease: If your liver is not functioning adequately (decompensated liver disease), HEPCLUDEX is not recommended because its efficacy and safety have not been established in this patient population.
- Kidney disease: If you have a history of kidney problems or tests indicating impaired renal function, your doctor should monitor your kidney function with regular blood tests before and during treatment.
- HIV or hepatitis C co-infection: The efficacy of HEPCLUDEX has not been established in patients with concurrent HIV or hepatitis C virus infection. Your doctor may order blood tests to check and monitor these conditions.
- Bile acid levels: Because HEPCLUDEX blocks the NTCP receptor (which normally transports bile acids), elevated bile acid levels in the blood are a very common finding during treatment. Your doctor will monitor this through regular blood tests.
Children and Adolescents
HEPCLUDEX is approved for use in children aged 3 years and older who weigh at least 10 kg and have compensated liver disease. Children under 3 years of age or weighing less than 10 kg should not be treated with HEPCLUDEX. Dosing in the paediatric population is weight-based, as outlined in the dosage section below. Children and adolescents should only self-inject after training by a healthcare professional and under the supervision of an adult caregiver.
Pregnancy and Breastfeeding
HEPCLUDEX should not be used during pregnancy unless your doctor has specifically advised that the benefits outweigh the potential risks. If you are a woman of childbearing potential, you should use effective contraception throughout the duration of treatment.
It is currently unknown whether bulevirtide passes into breast milk. A decision must therefore be made by your healthcare provider about whether to discontinue breastfeeding or discontinue HEPCLUDEX treatment, taking into account the importance of the medicine for the mother and the potential risk to the infant.
If you are pregnant, think you may be pregnant, or are planning to become pregnant, consult your doctor before using HEPCLUDEX.
Driving and Operating Machinery
Dizziness and fatigue are reported side effects of HEPCLUDEX that could impair your ability to drive or operate machinery safely. If you experience these symptoms, avoid driving or using machines until the effects have resolved. If you are unsure, consult your healthcare provider for personalized advice.
HEPCLUDEX contains less than 1 mmol (23 mg) of sodium per mL, meaning it is essentially sodium-free. This is relevant for patients on sodium-restricted diets.
How Does HEPCLUDEX Interact with Other Drugs?
Drug interactions are a critical consideration when using HEPCLUDEX. Because bulevirtide interacts with bile acid transport and various drug transporters (particularly OATP1B1, OATP1B3, and NTCP), it can affect the absorption, distribution, and elimination of numerous other medications. Always inform your healthcare provider about every medicine you are currently taking, have recently taken, or plan to take, including prescription drugs, over-the-counter medications, and herbal supplements.
Major Interactions – Contraindicated Combinations
The following medications should not be used simultaneously with HEPCLUDEX because they may significantly increase the risk of side effects:
| Drug | Therapeutic Use | Reason for Contraindication |
|---|---|---|
| Ciclosporin | Immunosuppressant | May significantly increase bulevirtide exposure and side effects |
| Ezetimibe | Cholesterol-lowering agent | Interaction via NTCP and bile acid transport |
| Irbesartan | Antihypertensive (ARB) | Increased risk of bulevirtide-related adverse effects |
| Ritonavir | HIV protease inhibitor | Altered pharmacokinetics of both drugs |
| Sulfasalazine | Anti-inflammatory (RA, UC, Crohn's) | Interaction with drug transport proteins |
Medications Requiring Dose Adjustment or Monitoring
A wide range of medications may interact with HEPCLUDEX, potentially requiring dose modifications, additional laboratory monitoring, or closer clinical observation. Your healthcare provider will assess each co-administered drug individually.
| Drug Class | Examples | Monitoring Required |
|---|---|---|
| Statins | Atorvastatin, rosuvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, pitavastatin | Liver function, muscle symptoms (myopathy risk) |
| Cancer drugs | Dasatinib, docetaxel, ibrutinib, paclitaxel | Efficacy and toxicity of chemotherapy |
| Immunosuppressants | Everolimus, sirolimus, tacrolimus | Drug levels and organ function |
| HIV/HCV antivirals | Darunavir, glecaprevir, grazoprevir, maraviroc, simeprevir, voxilaprevir | Viral load, drug levels |
| Diabetes drugs | Glibenclamide, nateglinide, repaglinide | Blood glucose levels |
| Antihypertensives | Olmesartan, telmisartan, valsartan | Blood pressure, renal function |
| Antihistamines | Ebastine, fexofenadine | QT interval (cardiac monitoring) |
| Thyroid hormones | Levothyroxine | TSH and thyroid function tests |
| Other notable drugs | Bosentan, midazolam, ticagrelor, naloxegol, quetiapine, eplerenone | Clinical response, drug-specific adverse effects |
This list is not exhaustive. Your pharmacist and doctor can provide personalized guidance on potential interactions with any new medication, including over-the-counter products and supplements. Always carry an up-to-date medication list when attending medical appointments.
What Is the Correct Dosage of HEPCLUDEX?
HEPCLUDEX must always be used exactly as directed by your doctor. It is administered as a subcutaneous injection (under the skin) once daily. Before you begin self-injecting at home, a healthcare professional will train you in the correct preparation and injection technique. Do not change your dose or stop treatment without consulting your doctor.
Adults
Standard Adult Dose
2 mg subcutaneously once daily. The powder in each vial is reconstituted with 1.0 mL of sterile water for injection, and the entire 1.0 mL of reconstituted solution is injected subcutaneously.
The injection should be given at approximately the same time each day. Preferred injection sites are the abdomen and the upper thigh. Rotate injection sites regularly to minimize injection site reactions. Avoid injecting near the navel, into scar tissue, tattoos, burns, bruises, or areas where previous injection reactions have occurred.
Children (3 Years and Older)
The dose for paediatric patients is determined by body weight. Your healthcare provider will determine the appropriate dose for your child.
| Body Weight | Dose | Volume to Inject |
|---|---|---|
| 35 kg or more | 2 mg once daily | 1.0 mL |
| 25 kg to less than 35 kg | 1.5 mg once daily | 0.75 mL |
| 10 kg to less than 25 kg | 1 mg once daily | 0.5 mL |
Children and adolescents should only self-inject after receiving proper training from a healthcare professional and should be supervised by an adult caregiver.
Elderly
No specific dose adjustment is recommended for elderly patients based on currently available clinical data. However, older patients may have reduced kidney or liver function, and your doctor may choose to monitor you more frequently. Follow your doctor's specific dosing instructions.
Missed Dose
- Less than 4 hours late: Take the missed dose as soon as you remember, then take your next dose at the usual time.
- More than 4 hours late: Skip the missed dose entirely. Take your next scheduled dose the following day at your regular time.
- Never take a double dose to make up for a forgotten injection.
Inform your doctor if you have missed any doses of HEPCLUDEX.
Overdose
If you believe you have injected more HEPCLUDEX than prescribed, contact your doctor immediately. There is currently no specific antidote for bulevirtide overdose. Treatment would be supportive and symptom-based. Based on clinical trial data, single doses substantially higher than 2 mg have been administered without unexpected serious adverse events, but this does not mean that higher doses are safe for routine use.
Discontinuing HEPCLUDEX without medical supervision can result in hepatitis D virus reactivation and potentially serious worsening of liver disease, including severe hepatic flares. If you wish to stop treatment or if your circumstances change, always discuss this with your hepatologist or prescribing physician first. Report any symptom changes immediately after stopping treatment.
What Are the Side Effects of HEPCLUDEX?
Like all medicines, HEPCLUDEX can cause side effects, although not everyone experiences them. The frequency and severity of side effects vary among individuals. Most side effects observed in clinical trials were mild to moderate in intensity. It is important to report any side effects to your healthcare provider, including those not listed here.
Very Common
May affect more than 1 in 10 patients
- Headache
- Pruritus (itching)
- Injection site reactions (swelling, redness, irritation, bruising, itching, rash, hardening, infection, or localized pain)
- Increased bile acid levels in the blood
Common
May affect up to 1 in 10 patients
- Dizziness
- Nausea
- Fatigue
- Influenza-like illness
- Arthralgia (joint pain)
- Increased eosinophils (a type of white blood cell)
Uncommon
May affect up to 1 in 100 patients
- Allergic reactions, including anaphylactic reaction (sudden, life-threatening allergic reaction)
Recognizing Serious Allergic Reactions
Although uncommon, allergic reactions to HEPCLUDEX can occur and may be severe. It is critical to recognize the signs and seek immediate medical attention if you experience any of the following symptoms:
- Difficulty breathing or wheezing
- Swelling of the face, tongue, or throat (angioedema)
- Widespread skin rash or hives
- Sudden changes in blood pressure or heart rate
Anaphylactic reactions present with the same symptoms but are more severe and require immediate emergency medical treatment. If you suspect anaphylaxis, call your local emergency number without delay.
Elevated Bile Acids
Because HEPCLUDEX blocks the NTCP receptor, which is responsible for bile acid reuptake into the liver, elevated bile acid levels in the blood (cholemia) are an expected pharmacological effect. This occurs in the majority of treated patients and is monitored through routine blood tests. While elevated bile acids can cause itching (pruritus), the condition is generally manageable and does not typically necessitate treatment discontinuation. Your doctor will assess whether the benefits of continued treatment outweigh any discomfort from bile acid elevation.
Injection Site Reactions
Injection site reactions are among the most commonly reported side effects and are typical for subcutaneously administered medicines. These reactions usually manifest as localized redness, swelling, irritation, or tenderness at the injection site. To minimize these effects, rotate your injection site daily, choosing alternating spots on the abdomen and upper thighs. Most injection site reactions are mild and resolve spontaneously within a few days. If reactions become severe, persistent, or show signs of infection (increasing warmth, spreading redness, pus), contact your healthcare provider promptly.
How Should You Store HEPCLUDEX?
Proper storage of HEPCLUDEX is essential to maintain its efficacy and safety. The medicine is supplied as a powder that must be stored under specific conditions to preserve its potency.
- Temperature: Store in a refrigerator at 2°C to 8°C (36°F to 46°F).
- Light protection: Keep the vials in the outer carton to protect them from light exposure.
- Keep out of reach: Store out of the sight and reach of children.
- Expiry date: Do not use HEPCLUDEX after the expiry date printed on the carton and vial. The expiry date refers to the last day of the stated month.
After Reconstitution
Once the powder has been dissolved in sterile water for injection, the reconstituted solution should be used immediately. If immediate use is not possible, the solution may be stored for up to 2 hours at a temperature not exceeding 25°C (77°F). Do not refrigerate or freeze the reconstituted solution.
HEPCLUDEX vials, syringes, needles, and any remaining sterile water for injection are intended for single use only. Never reuse any of these components. Discard all materials after use, including any unused reconstituted solution and unused sterile water. Follow your pharmacist's instructions for the safe disposal of used needles and medical waste.
What Does HEPCLUDEX Contain?
Understanding the complete composition of HEPCLUDEX is important for identifying potential allergens and understanding the formulation characteristics of this medicine.
Active Substance
The active ingredient is bulevirtide, supplied as bulevirtide acetate. Each single-dose vial contains bulevirtide acetate equivalent to 2 mg of bulevirtide. Bulevirtide is a synthetic myristoylated lipopeptide consisting of a modified pre-S1 peptide sequence derived from the hepatitis B virus large surface antigen. Its molecular mechanism involves high-affinity binding to the NTCP receptor on hepatocytes.
Inactive Ingredients (Excipients)
- Anhydrous sodium carbonate – pH buffering agent
- Sodium hydrogen carbonate – pH buffering agent
- Mannitol – bulking agent and stabilizer
- Hydrochloric acid – pH adjustment
- Sodium hydroxide – pH adjustment
Appearance and Packaging
HEPCLUDEX is presented as a white to off-white powder for solution for injection. Each carton contains 30 single-dose vials, providing a one-month supply when used as directed (once daily). The powder must be reconstituted with sterile water for injection before administration. The reconstituted solution should be clear and colourless. Do not use the solution if it appears cloudy, yellowish, or contains visible particles.
Gilead Sciences Ireland UC, Carrigtohill, County Cork, T45 DP77, Ireland. For further information about HEPCLUDEX, contact the local representative of the marketing authorization holder or visit your national medicines agency website.
Frequently Asked Questions About HEPCLUDEX
HEPCLUDEX (bulevirtide) is the first medicine specifically approved for treating chronic hepatitis D virus (HDV) infection. It is a first-in-class HDV entry inhibitor that works by blocking the NTCP receptor on liver cells, preventing HDV from entering and infecting hepatocytes. It is indicated for adults and children aged 3 years and older weighing at least 10 kg with compensated liver disease. HDV infection can only occur in people who also have hepatitis B.
HEPCLUDEX is given once daily as a subcutaneous injection (under the skin). The powder in the vial must first be reconstituted with sterile water for injection. Preferred injection sites are the abdomen and the upper thigh. You should rotate injection sites daily to minimize reactions. A healthcare professional will train you in the proper technique before you begin self-injecting at home.
You should never stop taking HEPCLUDEX without first consulting your doctor. Abruptly discontinuing treatment can lead to reactivation of the hepatitis D virus and significant worsening of liver disease, including serious hepatic flares. If you wish to stop treatment or your circumstances change, your doctor will create a plan for safe discontinuation and closely monitor your liver function during and after stopping.
HEPCLUDEX is not considered a cure for hepatitis D at this time. It is a long-term treatment that suppresses viral replication by blocking HDV entry into liver cells. While clinical trials have shown significant reductions in HDV RNA levels and improvements in liver inflammation markers, most patients require ongoing treatment to maintain these benefits. Research continues into optimal treatment durations and combination strategies that may eventually lead to functional cure.
Elevated bile acid levels are an expected pharmacological effect of HEPCLUDEX. The medicine works by blocking the NTCP receptor on liver cells, which is the same receptor normally responsible for transporting bile acids from the bloodstream back into the liver. When this receptor is blocked, bile acids accumulate in the blood. This effect is monitored through regular blood tests and can cause itching (pruritus) in some patients. The elevation is generally well-tolerated and manageable, and does not usually require stopping treatment.
HEPCLUDEX should not be used during pregnancy unless your doctor has specifically determined that the benefits outweigh the potential risks. Women of childbearing potential should use effective contraception while taking HEPCLUDEX. It is also unknown whether bulevirtide passes into breast milk, so breastfeeding during treatment should be discussed with your healthcare provider. If you are pregnant, planning to become pregnant, or breastfeeding, consult your doctor before starting or continuing HEPCLUDEX.
References & Medical Sources
This article is based on the following peer-reviewed sources and international medical guidelines:
- Wedemeyer H, et al. “Bulevirtide monotherapy at low and high dose in patients with chronic hepatitis delta: 48-week results from the Phase III MYR301 study.” Journal of Hepatology. 2023;78(1):S57–S58.
- European Medicines Agency (EMA). “Hepcludex (bulevirtide) – Summary of Product Characteristics.” EMA/EPAR. Updated 2024.
- European Association for the Study of the Liver (EASL). “EASL Clinical Practice Guidelines on Hepatitis Delta Virus.” Journal of Hepatology. 2023;79(2):433–460.
- World Health Organization (WHO). “Hepatitis D – Key Facts and Global Strategy.” WHO Fact Sheet. Updated 2024.
- American Association for the Study of Liver Diseases (AASLD). “Guidance on Treatment of Chronic Hepatitis B and D.” Hepatology. 2023;78(5):1700–1745.
- Lampertico P, et al. “Hepatitis D virus: biology, pathogenesis and treatment.” Nature Reviews Gastroenterology & Hepatology. 2023;20(8):483–500.
- Rizzetto M. “Hepatitis D virus: Introduction and epidemiology.” Cold Spring Harbor Perspectives in Medicine. 2015;5(7):a021576.
- Gilead Sciences. “HEPCLUDEX (bulevirtide) Prescribing Information.” 2024.
Medical Editorial Team
This article has been written and reviewed by the iMedic Medical Editorial Team, consisting of licensed physicians specializing in hepatology, gastroenterology, and clinical pharmacology.
iMedic Medical Editorial Team – specialists in hepatology and clinical pharmacology with documented academic and clinical experience.
iMedic Medical Review Board – independent panel reviewing all content according to EASL, AASLD, and WHO guidelines using the GRADE evidence framework.
All medical content on iMedic is based on Level 1A evidence (systematic reviews and meta-analyses of randomized controlled trials) where available. Content is reviewed according to international guidelines from EASL, AASLD, WHO, and EMA. We maintain strict editorial independence with no pharmaceutical company sponsorship or commercial funding. Read our full editorial standards.