Application for WHO Model List of Essential Medicines: Entecavir

Application to add entecavir to the Essential List of Medicines as an essential medicine for the treatment of chronic B virus infection

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Contents 1. Summary statement of the proposal for inclusion ...... 3 2. Name of the focal point in WHO submitting or supporting the application (where relevant) ...... 3 3. Name of the organization(s) consulted and/or supporting the application ...... 3 4. International Nonproprietary Name (INN, generic name) of the medicine ...... 3 5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) ...... 3 6. International availability - sources, if possible manufacturers and trade names ...... 4 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group ...... 4 8. Information supporting the public health relevance ...... 4 9. Treatment details ...... 6 10. Summary of comparative effectiveness in a variety of clinical settings: ...... 12 11. Summary of comparative evidence on safety: ...... 14 12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group: ...... 16 13. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well) ...... 18 14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopoeia) ...... 18 15. Proposed (new/adapted) text for the WHO Model Formulary ...... 18 References: ...... 19

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Application for WHO Model List of Essential Medicines: Entecavir

1. Summary statement of the proposal for inclusion

Hepatitis B virus (HBV) infection is a significant contributor to global burden of disease, accounting for an estimated 786 000 deaths each year. Effective medicines exist that can suppress HBV replication, slow or even reverse the degree of fibrosis, and thereby reduce the risk of death from hepatocellular carcinoma (HCC) and and prolong life. Despite this, the number of persons with HBV infection who receive treatment is very low. One of the reasons for this is the lack of WHO guidelines for the treatment of HBV infection. To fill this gap, WHO’s Global Hepatitis Programme (GHP) is finalizing the development of treatment guidelines. These guidelines, which will be released in March 2015, will recommend that HBV infection be treated with either tenofovir or entecavir. Currently, tenofovir (TDF) is included in the 18th edition of WHO Model List of Essential Medicines (EML), but entecavir is not included. Entecavir is highly effective and relatively inexpensive, and having this medicine on the EML will help to facilitate the scale-up of HBV treatment.

2. Name of the focal point in WHO submitting or supporting the application (where relevant)

Dr Philippa Easterbrook,

Global Hepatitis Programme, Department of HIV/AIDS, World Health Organization Geneva, Switzerland [email protected]

3. Name of the organization(s) consulted and/or supporting the application

World Hepatitis Alliance Médecins sans Frontières Coalition to end in the Western Pacific (CEVHAP) Asia and Pacific Alliance to Eliminate Viral Hepatitis (APAVH) Hepatitis B Foundation Bristol-Meyers Squibb Corporation

4. International Nonproprietary Name (INN, generic name) of the medicine

Entecavir

5. Formulation proposed for inclusion; including adult and paediatric (if appropriate)

Entecavir: Oral tablets of 0.5mg and 1mg Entecavir: Oral solution of 0.05 mg/mL

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Application for WHO Model List of Essential Medicines: Entecavir

6. International availability - sources, if possible manufacturers and trade names

Sources Entecavir (Baraclude™) was originally manufactured by Bristol-Meyers Squibb (BMS). According to BMS, entecavir is licensed for use in over 60 countries.

Entecavir is available in generic formulations and several generic manufactures produce the medicine (Table 1). As of August 2014, the only generics manufacturer of entecavir that has received U.S. Food and Drug Administration (FDA) approval is TEVA PHARMS USA.1

There are many generic medicines available in mainly Asia (Table 1).

Table 1: Generics manufacturers of entecavir: Trade name, manufactures and country Trade name Manufacturers Country Baraclude Bristol-Myers Squibb (Originator) Entecavir TEVA PHARMS USA India Entehep Zydus Cadila Healthcare Ltd India Entaliv DrReddyLaboratories India Enteca Ranbaxy Malaysia Entegard Inogen Pharma Philippines Teneir Lab Dosa Argentina Entikawei Chia Tai Taiqing Pharmaceutical Limited China Raymos Dawnrays Pharmaceutical Limited China Leiyide Counster Pharmaceutical Co., LTD China Weiliqing Qingfeng Pharmaceutical Group China Enganding Anhui Biochem Pharmaceutical Co., LTD China Beishuangding Shangdong Lukang Pharmaceutical Co., LTD China Many Generics Multiple manufacturers Vietnam

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group

As an individual medicine, to be including in the section 6 -- Anti-infective medicines of the WHO EML.

8. Information supporting the public health relevance

Epidemiological information on disease burden

Hepatitis B virus (HBV) infection is a major cause of acute and chronic liver disease (e.g., cirrhosis and primary liver cancer) globally with an estimated 786 000 deaths annually1. It is estimated that a third of the world’s population (more than 2 billion people) have been infected with HBV and that 240 million people are living with chronic HBV infection2, 3, placing them at risk for serious illness and death from cirrhosis and (HCC). Worldwide, 30% of cirrhosis and 53% of all HCC deaths are attributable to HBV infection4.

The burden of HBV remains disproportionately high in low- and middle- income countries. Approximately

1 (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApp roved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm414067.htm. Accessed 14 August 2014

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Application for WHO Model List of Essential Medicines: Entecavir

60% of the world's population lives in areas where HBV infection is highly endemic, particularly Asia and Africa. Additionally, even in low prevalence areas certain subpopulations such as indigenous populations, migrants, HIV-infected individuals, men who have sex with men (MSM) and persons who inject drugs (PWID) experience high levels of HBV infection.

Acute HBV infection typically lasts two to four months. Approximately 30-50% of children aged ≥5 years and most adults are symptomatic5; infants, children <5 years, and immunosuppressed adults are more likely to be asymptomatic. Fulminant hepatitis occurs in 0.5% of cases6. Antiviral treatment is not indicated during acute infection as more than 95–99% of adults with acute HBV infection will recover spontaneously without antiviral therapy7. Fewer than 5 percent of adults acutely infected with HBV progress to chronic infection. Chronic HBV (CHB) infection (defined as hepatitis B surface antigen ([HBsAg] detectable for >6 months) is the most common cause of HCC in the world, increasing the risk of HCC compared with non-carriers by 100 fold8. The risk of complications associated with chronic HBV infection increases in co-infection with hepatitis C (HCV) 9, 10, hepatitis D (HDV) 11, 12, or HIV13.

Chronic HBV infection is diagnosed by the presence of HBsAg in the serum. The HBsAg test is widely used for HBV screening, given its availability, low-cost and acceptability as a key marker of chronic HBV infection. HBV DNA test is crucial for initiation of treatment and monitoring drug efficacy.

Several interventions have the potential to dramatically reduce the burden of HBV infection. The three-dose series of HBV vaccine for children, including a HBV birth dose plus at least two additional doses, is the most effective tool for preventing HBV infection and the chronic sequelae of cirrhosis and liver cancer. WHO recommended routine use of this vaccine in national immunization programs in 1992. By 2011, a total of 180 countries had introduced the HBV vaccine and rates of 3-dose hepatitis B vaccine coverage now reach 79%, and have lowered the incidence of chronic infection, most dramatically in Asia14. Efforts to improve the safety of blood transfusions and injections have reduced the risk of infection through these procedures.

Despite these advances, in most countries, viral hepatitis is not being addressed in a systematic manner. Hepatitis surveillance programs are weak or non-existent, laboratory capacity is poor, testing facilities are few, and prevention programmes have low coverage. Furthermore as mentioned, 240 million persons have chronic HBV infection, and very few of these persons, particularly those living people in low- and middle- income countries have access to HBV treatment. This is because most people remain undiagnosed and there are no large publicly-funded hepatitis B treatment programmes in low- and middle-income countries.

Assessment of current use

Hepatitis B is a complex disease: the disease frequently transitions through several phases during which there may be a transition from little or minimal hepatic necroinflammation and fibrosis to active phases of disease with increased necroinflammation and more rapid progression of hepatic fibrosis. These disease phases can be characterized by serological conversion from hepatitis B e-Antigen (HBeAg) to anti-HBe or conversely seroreversion from anti-HBe to HBeAg with fluctuations in serum aminotransferases and HBV DNA concentrations.

The “immune tolerant phase” of the disease is marked by HBeAg positivity and high levels of HBV replication but normal or low levels of aminotransferases. Patients are highly infectious during this stage but will have little or no liver necroinflammation and very slow progression to fibrosis. In later phases of disease, patients will enter the immune reactive, HBe positive phase with continuing HBeAg positively. During this phase, the risk of fibrosis progression will be much higher. In this phase, a proportion of patients with CHB may undergo spontaneous seroconversion from HBeAg to anti-HBe, with an accompanying reduction in viral load and reduction in serum alanine aminotransferase (ALT) concentration. If seroconversion occurs at a relatively young age, and before the onset of marked hepatic fibrosis, the disease progresses slowly if at all. HBV treatment is not recommended for these patients as their disease does not progress11, 15.

At present, chronic hepatitis B cannot be cured in the majority of persons, and therefore the goal of treatment

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Application for WHO Model List of Essential Medicines: Entecavir

is to suppress which reduced (or reverses) progression of liver fibrosis and cirrhosis, thereby reducing the risk of liver failure, HCC, and death.

For evaluation of the necessity to treat, it is important to ascertain determinants of hepatic inflammation and fibrosis that indicate disease progression or the phase of disease. Decisions regarding HBV treatment are usually made based on clinical features, levels of serum ALT and HBV DNA, and when available, liver histology. In the draft of WHO HBV guideline, presence of cirrhosis, age, ALT level, HBV DNA and HBeAg status are used as criteria for treatment initiation.

Nucleoside analogues and (IFN)-alpha have been widely used for the treatment of chronic HBV since the 1990’s. Nucleoside analogues are potent inhibitors of HBV DNA replication, and over the last decade, four additional nucleos(t)ide analogues (NUCs) have been licensed (, , , tenofovir and entecavir), as well as two formulations of pegylated IFN (PEG-IFN) allowing weekly dosing. The primary limitation of most oral antiviral agents is the development of viral resistance because of mutations in the viral DNA during replication. This limitation applied primarily to adefovir, lamivudine and telbivudine, which have a low barrier to resistance. Fortunately, the newer medicines, tenofovir and entecavir have a high barrier to resistance and remain effective even after years of use. In fact, long-term treatment (three years or five years) with entecavir or tenofovir in patients with cirrhosis result in approximately 30-50% reduction in the risk on hepatic events, HCC, liver -related mortality and all-cause mortality comparing to untreated patients.

Target population

Deciding who needs HBV treatment is complicated as treatment decisions require evaluation of age, the presence of cirrhosis, ALT levels, HBV DNA and HBeAg status. The draft WHO HBV guidelines recommend the use of entecavir or tenofovir, because of their high barrier to resistance and recommend against the use of other drugs (e.g. lamivudine and telbivudine) because of their low barrier to resistance. Furthermore, HBV treatment is recommended for the following populations:

 All adults, adolescents, and children with evidence of decompensated cirrhosis or cirrhosis.  In the absence of cirrhosis, treatment is recommended for adults aged 30 years or older, with persistently abnormal ALT levels and/or evidence of ongoing HBV replication  For adults, adolescent and children aged 12 years who need treatment, entecavir or tenofovir are equally recommended. In children aged 2-11 years, only entecavir is recommended.

9. Treatment details

Dosage regimen:

Recommended dosage in adults  For compensated liver disease, the recommended dose of entecavir in nucleoside-inhibitor-treatment- naïve adults and adolescents 16 years of age and older is 0.5 mg once daily.

 For adults and adolescents with a history of hepatitis B viraemia while receiving lamivudine, or with known lamivudine or telbivudine resistance, the recommended dose is 1 mg once daily.

 For decompensated liver disease, the recommended dose in adults is 1 mg once daily.

Recommended dosage in pediatric patients For pediatric patients, the following table describes the recommended dose for patients 2 years of age or older and weighting at least 10kg. The oral solution should be used for patients with body weight up to 30 kg (Table 2).

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Application for WHO Model List of Essential Medicines: Entecavir

Table 2: Dosing Schedule for Pediatric Patients Recommended Once-daily Dose of Oral Solution (mL) Body Weight (kg) Treatment-Naïve Lamivudine-Experienced Patientsa Patientsb 10 to 11 3 6 Greater than 11 to 14 4 8 Greater than 14 to 17 5 10 Greater than 17 to 20 6 12 Greater than 20 to 23 7 14 Greater than 23 to 26 8 16 Greater than 26 to 30 9 18 Greater than 30 10 20 a Children with body weight greater than 30 kg should receive 10mL (0.5 mg) of oral solution or one 0.5 mg tablet once daily. b Children with body weight greater than 30 kg should receive 20mL (1.0 mg) of oral solution or one 1 mg tablet once daily.

Dose Adjustment:

For patients with renal impairment, dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) and shown in the following table. The once-daily dosing regimens are preferred (Table 3).

Table 3: Recommended Dosage in Adult Patients with Renal Impairment Creatinine Clearance Usual Dose Lamivudine-Refractory (mL/min) (0.5 mg) or Decompensated Liver Disease (1mg) 50 or greater 0.5 mg once dailya 1 mg once daily 30 to less than 50 0.25 mg once daily 0.5 mg once daily OR OR 0.5 mg every 48 hours 1 mg every 48 hours 10 to less than 30 0.15 mg once dailya 0.3 mg once dailya OR OR 0.5 mg every 72 hours 1 mg every 72 hours Less than 10 0.05 mg once dailya 0.1mg once dailya Hemodialysis b or CAPD OR OR 0.5 mg every 7 days 1 mg every 7 days a For doses less than 0.5 mg, oral Solution is recommended. b If administered on a hemodialysis day, administer entecavir after the hemodialysis session..

For the patients with hepatic impairment, no dosage adjustment is necessary.

Duration of therapy

All patients with chronic hepatitis B who have cirrhosis require lifelong treatment, and should not discontinue antiviral therapy, because of the risk of reactivation causing severe acute on chronic liver injury.

Most patients who do not have cirrhosis will also require life-long therapy. However existing guidelines propose that treatment discontinuation can be considered for patients without cirrhosis in the following situations:

National Institute for Health and Care Excellence (NICE) Guideline (2013) 16: Treatment sequence in adults with HBeAg-positive chronic hepatitis B and compensated liver disease: “1.5.21 Consider stopping nucleoside or analogue treatment 12 months after HBeAg seroconversion in people without cirrhosis.”

Treatment sequence in adults with HBeAg-negative chronic hepatitis B and compensated liver disease

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Application for WHO Model List of Essential Medicines: Entecavir

“1.5.27 Consider stopping nucleoside or nucleotide analogue treatment 12 months after achieving undetectable HBV DNA and HBsAg seroconversion in people without cirrhosis.”

WHO HBV guideline drafts: Treatment duration - When to stop treatment “Discontinuation of nucleos(t)ide analogue therapy may be considered on a case by case basis in persons without evidence of cirrhosis and who can be followed carefully long-term for reactivation, in the following situations: o Where HBV DNA not available: Persons who were initially HBeAg positive or negative, who have evidence of persistent HBsAg loss for at least 6 months on treatment Or o Where HBV DNA available: Persons who were initially HBeAg positive, who have evidence of HBeAg seroconversion for at least one year and have persistently undetectable HBV DNA level on treatment (Conditional recommendation, low quality of evidence)

Reference to existing WHO and other clinical guidelines

WHO guideline As mentioned above, there are no existing WHO guidelines on HBV treatment. The first such guidelines are nearly finalized. A Guidelines Development Group (GDG) met in July 2014 and developed the following treatment recommendations:

Treatment should be initiated with either entecavir or tenofovir because of their efficacy, safety, and a high barrier to resistance.

Treatment is recommended for: • As a priority, all adults, adolescents, and children with evidence of decompensated cirrhosis or cirrhosis (based on clinical criteria or non-invasive tests (APRI score >2 for adults), regardless of ALT levels, HBeAg status, or HBV DNA levels, to prevent further progression of the disease. (Strong recommendation, moderate quality of evidence)

• Adults without evidence of cirrhosis (based on clinical criteria or non-invasive tests, APRI score <2) and aged 30 years or older, with persistently abnormal ALT levels and/or evidence of ongoing HBV replication, based on: o Where HBV DNA available: HBV DNA >20,000 IU/mL, regardless of HBeAg status o Where HBV DNA not available: HBeAg positivity (in persons who are HBeAg positive or negative, persistently raised ALT levels) (Strong recommendation, moderate quality of evidence)

• Antiviral treatment can be deferred in persons without evidence of cirrhosis (based on clinical criteria or non-invasive tests, APRI score <2) and the following: o Where HBV DNA not available: Persons who are HBeAg positive and under the age of 30 years with persistently normal ALT levels, regardless of HBV DNA level o Where HBV DNA available: Persons who are HBeAg negative with persistently normal ALT levels and low levels of HBV replication (HBV DNA < 2000 IU/mL)) (Strong recommendation, low quality of evidence)

First-line treatment of chronic hepatitis B infection is recommended:

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Application for WHO Model List of Essential Medicines: Entecavir

• In all adults, adolescents and children aged 12 years or older in whom antiviral treatment with high barrier to resistance (tenofovir or entecavir, or entecavir in children aged 2-11 years) is recommended. (Strong recommendation, moderate quality of evidence)

• Treatment with nucleos(t)ide analogues with a low barrier to resistance (lamivudine, adefovir or telbivudine) can lead to drug resistance and is not recommended. (Strong recommendation, moderate quality of evidence)

Second-line treatment for management of treatment failure is recommended: • In persons with evidence of resistance to lamivudine, entecavir, adefovir or telbivudine, a switch to tenofovir is recommended. (Strong recommendation, low quality of evidence)

• In persons with suspected resistance (i.e. history of prior exposure or primary non-response) to adefovir*, entecavir or telbivudine, a switch to tenofovir is suggested. (Conditional recommendation, low quality of evidence)

*For adefovir resistance, a switch to tenofovir or entecavir can be considered

Stopping treatment can be considered in patients without cirrhosis under the following circumstances: Time to stop treatment is recommended: • All patients with chronic hepatitis B and cirrhosis require lifelong treatment with nucleos(t)ide analogue therapy, and should not discontinue antiviral therapy, because of the risk of reactivation causing severe acute on chronic liver injury. (Strong recommendation, low quality of evidence)

• Discontinuation of nucleos(t)ide analogue therapy may be considered on a case by case basis in persons without evidence of cirrhosis (clinical criteria or non-invasive tests, APRI score <2) and who can be followed carefully long-term for reactivation, in the following situations: o Where HBV DNA not available: Persons who were initially HBeAg positive or negative, who have evidence of persistent HBsAg loss for at least 6 months on treatment Or o Where HBV DNA available: Persons who were initially HBeAg positive, who have evidence of HBeAg seroconversion for at least one year and have persistently undetectable HBV DNA level on treatment (Conditional recommendation, low quality of evidence)

• Re-treatment is recommended if signs of reactivation (HBsAg or HBeAg become positive, raised ALT level or HBV DNA becomes detectable again (where HBV DNA available)) (Strong recommendation, low quality of evidence)

Other clinical guidelines There are four clinical guidelines from major professional associations.  American Association for the Study of Liver Disease (AASLD) 2009: AASLD Practice Guidelines, Chronic Hepatitis B: update 200917. Hepatology, September 2009  Asia Pacific Association for the Study of the Liver: (APASL) 2012: Asian-Pacific Consensus Statement on the Management of Chronic hepatitis B: a 2012 update18. Hepatol Int (2012) 6:531–561  European Association for the Study of the Liver (EASL) 2012: EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection7. Journal of Hepatology 2012 vol. 57 j 167–185  NICE 2013: National institute for Health and Care Excellence (NICE) clinical

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Application for WHO Model List of Essential Medicines: Entecavir

guideline 165. Hepatitis B (chronic) Diagnosis and management of chronic hepatitis B in children, young people and adults16.

Table 4 summarizes the recommendations from these guidelines documents.

Table 4: Comparison of HBV treatment recommendations from major clinical guidelines

AASLD 2009 APASL 2012 EASL 2012 NICE 2013 Indication Non-cirrhotic HBeAg positive Treat* >20,000 and ≥20,000 and >2,000 and/or >20,000 and HBV DNA (IU/mL) >2x >2x >1x and >1x ALT (ULN) biopsy or non- invasive assessment ≥A2 or ≥F2 HBV DNA (IU/mL) >20,000 and ≥20,000 and >2,000 and ALT (ULN) 1-2x or any >1x and Age >40 or >40 ≥30 Treat if mod/ severe Family history of then If age <30 then inflammation or fibrosis HCC Biopsy or non- Biopsy or liver then invasive stiffness >6 kPa Biopsy assessment Non-cirrhotic HBeAg negative Treat >20,000 and ≥2,000 and >2,000 >20,000 and HBV DNA (IU/mL) >2x >2x >1x >1x ALT (ULN) + biopsy or non- invasive assessment ≥A2 or ≥F2 HBV DNA (IU/mL) >2,000 and ≥2,000 and >20,000 and >2,000 and ALT (ULN) 1-2x Any value and Any or >1x and Age then ≥40 >30 or ≥30 Treat if mod/ severe Biopsy then Family history of If age <30 then inflammation or fibrosis Biopsy or non- HCC then Biopsy or liver invasive Biopsy or non- stiffness >6 kPa assessment invasive assessment

Compensated cirrhosis HBV DNA (IU/mL) >2,000 and ≥2,000 and detected detected ALT (ULN) any any any any HBeAg + or - + or - + or - + or - HBV DNA (IU/mL) <2,000 and ALT (ULN) >1x Decompensated cirrhosis HBV DNA (IU/mL) any any any any ALT (ULN) any any any any HBeAg + or – + or – + or – + or – Refer for liver transplant yes yes yes yes First-line treatment IFN PEG-IFN (not for IFN (conventional PEG-IFN (not for PEG-IFN 1st line for decompensated or PEG) preferred decompensated HBeAg+ or HBeAg- cirrhosis, caution in young patients cirrhosis) for compensated disease with compensated and HBeAg+ patients with high cirrhosis) OR patients with ALT ALT and low HBV >5x ULN DNA NUC ETV or ETV or ETV or TDF (2nd line) TDF TDF TDF ETV (alternative) Time to stop treatment HBeAg+ HBeAg HBeAg HBeAg HBeAg seroconversion and seroconversion and seroconversion+ 6- seroconversion + 12 undetectable HBV undetectable HBV 12 months months DNA + ≥6 months DNA ≥12 months consolidation consolidation consolidation HBeAg- HBsAg loss HBsAg loss or HBsAg loss 12 months after HBV DNA HBsAg undetectable ≥2 seroconversion and years undetectable HBV DNA Cirrhosis Compensated: DO NOT STOP DO NOT STOP HBsAg loss, Decompensated: DO NOT STOP

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Application for WHO Model List of Essential Medicines: Entecavir

*after 3-6 months monitoring, ALT ULN: 30 (male) and 19 (female), 40 or per lab IFN: interferon, PEG-IFN: pegylated IFN, NUC: nucleos/tide analogue, ETV: entecavir, TDF: tenofovir

Need for special diagnosis, treatment or monitoring facilities and skills

Deciding who needs HBV treatment is complicated as eligibility is based on assessing the degree of liver fibrosis, presence of HBe-Ag, elevation of liver transaminases, and level of HBV DNA. To assess these parameters, a number of diagnostic tests are needed before treatment initiation.

Fibrosis and cirrhosis are assessed by various means. Liver biopsy has been considered the gold standard method for assessing the degree of fibrosis, but it is not widely used in low-income countries because of its high cost and invasiveness, patient discomfort, risk of complications, as well as the need for expert histological interpretation. Another option is to assess liver fibrosis with transient elastography, which is an ultrasound-based technique. Use of this method is limited by the high cost (US$ 50 000/machine) and maintenance requirements. Fortunately, several non-invasive fibrosis tests based on serum indices (APRI, Fibrotest, and FIB4) are now available. The simplest of these, APRI is calculated based on platelet and transaminase levels. These tests are widely available, even in low- income countries.

Although treatment can be initiated without assessing HBV DNA level, having this result improves the accuracy of treatment-eligibility decisions. HBV DNA measurement is based on nucleic acid testing (NAT) which requires sophisticated laboratories, expensive equipment and reagent, and trained laboratory technicians. In many low- and middle-income countries, these tests are available only in large cities.

During treatment, ALT level, HBsAg, HBeAg/anti-HBe, and HBV DNA level should be monitored to assess toxicity and response to therapy. Testing to detect early cases of HCC (called cancer surveillance) should be performed by ultrasonography and serum alpha-fetoprotein testing every six months. Prior to initiating therapy, it is recommended to assess renal function in order to assess the risk of renal toxicity.

Table 5: Diagnostic tests and facility requirements for initiation and monitoring of HBV treatment Special tests for treatment Equipment and facility requirements Liver biopsy or non-invasive Equipment for biopsy Before initiation of treatment fibrosis test Fibroscan apparatus, etc. ALT Serum chemistry analyzer HBV DNA Molecular testing equipment, dedicated laboratory space, trained laboratory technicians HBeAg ELISA system, etc. Renal function Serum chemistry analyzer During treatment ALT level Serum chemistry analyzer HBV DNA Molecular testing equipment, dedicated laboratory space, trained laboratory technicians HBsAg, HBeAg/anti-HBe ELISA system, etc. Renal function Serum chemistry analyzer Ultrasonography (US) Ultrasound machine and trained operator Alpha-fetoprotein Electro-chemiluminescence immunoassay (ECLIA) system

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Application for WHO Model List of Essential Medicines: Entecavir

10. Summary of comparative effectiveness in a variety of clinical settings:

1. Identification of clinical evidence

Search strategy In 2014, the GHP Team commissioned systematic reviews for the development of WHO HBV guideline named “Guidelines for Prevention, Care and Treatment of Persons with Hepatitis B Virus Infection.” The reviews included those focusing on the effectiveness and safety of the medicines for hepatitis B. To identify information from existing studies regarding entecavir, relevant guidelines, existing systematic reviews, meta-analyses or randomized trials were searched in the following sources: AHRQ National Guideline Clearinghouse, NHS Evidence Search, AHRQ Effective Health Care Program, The Cochrane Library, MEDLINE, EMBASE, LILACS, and CENTRAL. The searches were performed up to June 2014. The studies that were found compared entecavir to pre-existing medicines such as adefovir and lamivudine.

For this application, we summarized information from these systematic reviews regarding evidence related to entecavir.

2. Summary of available data and summary of estimates of comparative effectiveness

Since entecavir was developed after other HBV drugs, all effectiveness evaluations were done comparing it to those drugs. Thus, there are few data on its use compared with placebo. The outcomes of the selected studies are presented in the Appendices and are summarized below.

Comparative trials in adult naïve patients with chronic hepatitis B comparing (Entecavir vs. adefovir, or vs lamivudine, or vs. lamivudine + adefovir):

Entecavir versus adefovir: A systematic review of six randomized clinical trials (RCTs) in HBeAg-positive naïve Asian patients19 showed that a higher percentage of entecavir treated patients attained undetectable HBV DNA levels (RR 1.73; 95% CI 1.38 to 2.17; moderate quality of evidence) and normalized serum AL levels (low quality of evidence), but there were no differences in HBeAg clearance or HBeAg seroconversion.

Entecavir vs. lamivudine: A systematic review of 8 randomized trials 20 showed that entecavir had a greater improvement in liver histology (RR 1.16; 95% CI 1.07 to 1.26), normalization of serum ALT (RR 1.15; 95% CI 1.11 to 1.2; moderate quality of evidence), and HBV-DNA loss (RR 1.65; 95% CI 1.37 to 1.98; low quality of evidence) than those treated with lamivudine. There were no differences in loss of serum HBeAg, HBeAg seroconversion or incidence of adverse effects.

Entecavir vs. lamivudine and adefovir: A systematic review of one trial21 and four cohort studies22, showed no differences in rates of undetectable HBV DNA levels, normalization of ALT levels, but entecavir increased the likelihood of HBeAg seroconversion at 48 weeks (3 studies; RR 2.83; 95% CI 1.27 to 6.33).

Impact in decompensated liver disease (Entecavir vs. lamivudine, and entecavir vs. lamivudine and adefovir): A similar effectiveness of entecavir has been shown in a review of 13 trials in adult treatment-naive patients with decompensated cirrhosis23. Compared with lamivudine, entecavir significantly increased the

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Application for WHO Model List of Essential Medicines: Entecavir

rate of HBV undetectability (RR 1.24; 95% CI 1.16 to 1.33), and HBeAg seroconversion (RR 1.42; 95% CI 1.15 to 1.75; and reduced bilirubin levels, Child-Turcotte-Pugh scores and drug resistance (RR 0.10; 95% CI 0.04 to 0.24), but there were no differences in mortality. The quality of evidence for the former four outcomes was very low23. The combination therapy of lamivudine plus adefovir increased serum creatinine levels compared with entecavir (very low quality of evidence due to imprecision). A systematic review of seven trials of entecavir vs. lamivudine and adefovir showed that entecavir significantly improved Child-Turcotte-Pugh scores (Peng and others, 2013) (moderate quality of evidence), but there were no differences for the other outcomes of undetectable HBV DNA, ALT and AST normalization, HBeAg loss, HBeAg seroconversion, or mortality (low quality of evidence).

Impact on liver histology and reversion of fibrosis: In the systematic review of 8 randomised trials of entecavir vs. lamivudine conducted by Liang20, the rate of histological improvement was higher among patients receiving entecavir (RR 1.16; 95% CI 1.07 to 1.26) and a normalization of serum ALT (RR 1.15; 95% CI 1.11 to 1.2), based on moderate quality of evidence because of limitations in study design. In an open-label extension of the trial comparing tenofovir with adefovir conducted by Marcelin 24, 54% of patients treated with entecavir had histologic improvement and 51% had regression of fibrosis after five years of open-label follow-up. In addition, 51% of patients with cirrhosis at baseline, no longer had cirrhosis25.

Long-term effectiveness of entecavir in adult naïve patients with chronic hepatitis B Studies of the long-term (three and/or five years) effectiveness of entecavir and tenofovir in adult naive patients were based on seven studies reporting long-term follow-up with entecavir (including prospective cohorts derived from a series of phase 2 and 3 trials comparing entecavir with lamivudine (ETV-01426, ETV-01527, ETV-02228, ETV-02629, ETV-02730, Tenney and others31), and other studies32-37 and five studies for tenofovir (included data from three studies based on long-term follow-up of open-label extension of the Marcellin 2008 trial comparing tenofovir with adefovir24, 25, 38-40, and two other open-label cohort studies34, 41.

Wong reported the five-year cumulative probability of complications of cirrhosis including HCC and mortality in a cohort of 1,446 entecavir treated patients (0.5 mg/day) for at least 12 months and compared results with a historical cohort of 424 untreated patients. The cohorts did not show differences in the cumulative probabilities of hepatic events between treated or untreated patients in those without liver cirrhosis. However, for the subgroup of 551 patients with liver cirrhosis, adjusted analyses showed that entecavir-treated patients had a reduced risk of all clinical outcomes when compared with naïve patients with cirrhosis35. Hosaka compared the incidence of HCC in a cohort of 472 entecavir treated patients to that in a retrospective cohort of non-treated patients using a propensity score to minimize significant differences between groups. Patients treated with entecavir were less likely to develop HCC than untreated HBV patients, and the treatment effect was greater in patients at higher risk of HCC33.

After three and five years of treatment with entecavir or tenofovir the data showed low cumulative rates of mortality (3% and 3.8%, entecavir; 0.7% and 1.4%, tenofovir), and hepatocellular carcinoma (3.9% and 6.6%, entecavir; 1.4% and 2.4% tenofovir) (low quality of evidence due to study design). The cumulative probability of developing genotypic resistance to entecavir was low at 3 years (1.2% to 3.3%) and 5 years of treatment (0.8% to 1.2%) in this and other studies32, 34, 36, 37. Results from three prospective studies on tenofovir showed similar results, with low rates at 5 years (1.2%).

Effectiveness of entecavir in children with chronic hepatitis B

A smaller body of evidence is available from two trials in children42. These include a placebo-controlled RCT of tenofovir in adolescents, which showed a high virological response (89%) and normalization in serum ALT at 72 weeks treatment, and no observed viral resistance42, and a placebo-controlled trial of entecavir in children (AI463189 trial) which is still on-going. Based on data reported for the FDA New

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Application for WHO Model List of Essential Medicines: Entecavir

Drug Application process, entecavir was superior to placebo at reducing HBV DNA to <50 IU/mL and HBeAg seroconversion (24% vs. 2%) and in normalization of serum ALT levels (67% vs. 27%, p <0.0001) at week 48 of treatment.

Network meta-analysis (NMA)

To estimate the relative efficacy and ranking of different antiviral treatments, a network meta-analysis (NMA) was undertaken using all the relevant RCT data (both indirect and direct treatment comparisons; single, combination and sequential therapy) and from a systematic review. The NMA analysis was used to enable direct comparison of the commonly used treatments - tenofovir and entecavir that have not been compared to each other in the context of an RCT. The systematic review included studies published prior to October 2012, and was limited to systematic reviews or phase III clinical trials with a minimum of 50 included patients and 1-year duration of the treatment15, 24, 25, 28, 43-71 . Patients with advanced, decompensated cirrhosis, inactive liver disease, or with co-infections with HCV, HDV and HIV were excluded. For HBeAg positive nucleoside naïve patients, a total of 21 RCTs from the original (pair-wise comparisons) comprising 5,073 patients were included for the network of undetectable HBV DNA (standardised threshold <300 copies/mL). For HBeAg negative nucleoside-experienced patients, there were 16 trials compromising 2604 patients; 11 comparisons of monotherapies or combination therapy, with most comparisons having one trial. The analyses focused on the proportion of HBeAg positive or negative patients who achieved undetectable HBV DNA (less than 300 copies/mL) as an indication of viral suppression and the proportion of HBeAg-positive patients undergoing HBeAg seroconversion. Based on the RCT evidence available, the NMA showed that tenofovir monotherapy had the highest probability of achieving undetectable HBV DNA (<300 copies/ml) at the end of one year of treatment in both HBeAg positive (95.9%) and negative (97.6%; 95% C.I. 56.7 to 99.9) patients, followed by entecavir (64.5%) and 91.9 %; 95% C.I. 87.3 to 95.1) respectively. All the other antiviral treatments were found to have very low probability of being the best treatments at achieving this outcome. The quality of the direct evidence was rated from high to very low, based on NICE Technical Unit checklist for assessing NMA.

11. Summary of comparative evidence on safety:

Estimate of total patient exposure to date

Baraclude (branded, originator form of entecavir) has been available in the market since March 2005. Cumulatively, over 17,141 subjects have been randomized across entecavir clinical trials with an estimated 9,249 patients exposed to ETV. Bristol-Myers Squibb Company, the developer of entecavir, estimates that 1,749,709 patients have been treated with entecavir (Personal communication, BMS representative).

Description of adverse effects/reactions A detailed summary studies with adverse-reactions data is presented in the Appendices and summarized below.

Assessment of adverse reactions is reported form four clinical studies (ETV-01426, ETV-02228, ETV-02629, ETV-02730, Tenney and others31) in which patients with chronic hepatitis B infection and compensated liver disease received double-blind treatment with entecavir or lamivudine for up to 107 weeks. In these studies, the most frequent adverse events, occurring in 10% of patients in either treatment group, were upper respiratory tract infection, headache, fatigue, upper abdominal pain, cough, nausea, nasopharyngitis, and increased ALT. These events generally occurred with comparable frequency in the entecavir and lamivudine groups. However one study (ETV-02730) reported two exceptions: increased ALT occurred more frequently in the lamivudine group (10% vs 4% in the entecavir group), and upper respiratory tract infection occurred more frequently in the entecavir group (18% vs 11% in the lamivudine group). Most adverse events were mild to moderate in severity.

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Application for WHO Model List of Essential Medicines: Entecavir

Cases of lactic acidosis have been reported, often in association with hepatic decompensation or other serious medical conditions or drug exposures.

Treatment beyond 48 weeks: continued treatment with entecavir for a median duration of 96 weeks did not reveal any new safety concerns.

Identification of variation in safety due to health systems and patient factors

Pregnancy There are no data regarding the use of entecavir in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for pregnant women is unknown; thus, entecavir should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits. There are no data on the effect of entecavir on transmission of HBV from mother to newborn infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.

Patients with renal impairment The clearance of entecavir decreases with decreasing creatinine clearance. Dose adjustment is recommended for patients with creatinine clearance < 50 ml/min, including those on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A reduction of the daily dose using entecavir oral solution, as detailed in Table 3, is recommended. The proposed dose modifications are based on extrapolation of limited data, and their safety and effectiveness have not been clinically evaluated. Therefore, virological response should be closely monitored.

Although there are insufficient data to recommend a specific dose adjustment of entecavir in pediatric patients with renal impairment, a reduction in the dose or an increase in the dosing interval similar to adjustments for adults should be considered.

Summary of comparative safety against comparators

Entecavir vs. tenofovir Entecavir or tenofovir are the two preferred antiviral treatments for hepatitis B in view of their safety, effectiveness, and high barrier to resistance. Tenofovir is principally eliminated via the kidney and has a side effect profile characterized by proximal tubular cell dysfunction with a range of severity from mild renal tubular dysfunction and hypophosphatemia with subclinical decline in renal function to classical Fanconi syndrome and impaired glomerular filtration. Tenofovir is also associated with risk of hypophosphatemia, bone mineral loss, and osteopenia.

Entecavir is also principally eliminated via the kidney but has little side effect on renal function as reported for tenofovir. Of six long-term (3 to 5 years treatment) effectiveness studies of entecavir31-37, adverse effects outcomes were reported in three32, 34, 36, 37, but without specific reporting of laboratory abnormalities in renal function. In one RCT comparing entecavir monotherapy to entecavir plus tenofovir, 3 (1.6%) of those receiving entecavir monotherapy had an increase in serum creatinine above baseline values by 0.5 mg/dl through 96 weeks61.

There is no evidence of comparative safety on entecavir and tenofovir because no RCT comparing efficacy and safety of entecavir to those of tenofovir has been reported. Therefore the evidence for differential renal toxicity of entecavir versus tenofovir was not considered in detail.

In the WHO HBV guideline draft, recommendations for monitoring for tenofovir and entecavir toxicity are the following:  Measurement of baseline renal function and assessment of baseline risk of renal dysfunction should be considered in all patients prior to initiation of antiviral treatment.  Renal function should be monitored around annually in persons on long-term tenofovir therapy (Conditional recommendation, very low quality of evidence)

The relevant implementation consideration is the following.  Consider either avoidance of tenofovir and use of entecavir instead, or dose reduction of tenofovir

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Application for WHO Model List of Essential Medicines: Entecavir

(guided by table 6), if the estimated GFR is <50 ml/min, or with long-term diabetes, or uncontrolled hypertension. The use of TDF is not recommended in children aged 2 to 11 years, or in any children with renal impairment.

Entecavir vs. lamivudine Lamivudine is not recommended to treatment for chronic HBV infection because of its low barrier to resistance. But comparative safety profile against lamivudine was reported form four clinical studies (ETV-01426, ETV-02228, ETV-02629, ETV-02730, Tenney and others31). The most common adverse reactions of entecavir is comparable to those of lamivudine, but in one study (ETV-02730), increased ALT occurred more frequently in the lamivudine group (10% vs 4% in the entecavir group), and upper respiratory tract infection occurred more frequently in the entecavir group (18% vs 11% in the lamivudine group).

12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group:

Range of costs of the proposed medicine

Comparative cost data is available from India. The cost for generic entecavir is almost one-third lower than originator-branded formulation of entecavir (Table 7).

Table 7: Range of costs of entecavir in India

Name Manufacturer : Constituent/Unit Price/Unit (USD) Cadila Healthcare (Zydus Cadila Entehep (0.5 mg) Entecavir-0.5 mg 1.22 Healthcare Ltd) Entaliv (0.5 mg) Dr Reddy Laboratories Ltd Entecavir-0.5 mg 1.22 Cadila Healthcare (Zydus Cadila Entehep (1 mg) Entecavir-1 mg 1.95 Healthcare Ltd) Baraclude (0.5 mg) Bristol Myers Squibb India Pvt Ltd Entecavir-0.5 mg 3.58 Baraclude (1 mg) Bristol Myers Squibb India Pvt Ltd Entecavir-1 mg 5.71

Resource use and comparative cost-effectiveness presented as range of cost per routine outcome

Five studies assessed the cost-effectiveness of entecavir compared to any alternative 72-76 (Table 8). All studies showed that entecavir was either cost-effective or the preferred strategy.

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Application for WHO Model List of Essential Medicines: Entecavir

Table 8: Outline of economic evaluations included

Study ID Lee 2012 Orlewska 2008 Veenstra 2007 Wei 2013 Yuan 2008 Comparison Entecavir Entecavir or 2 year treatment with Entecavir Entecavir lamivudine entecavir daily versus (adding adefovir (nucleoside-naive lamivudine daily. if patients and either hepatitis Adefovir daily was developed B e antigen positive added for patients resistance) or negative patients) who developed Adefovir dipivoxil resistance. Lamivudine (lamivudine Adefovir plus no treatment; Lamivudine resistant patients) lamivudine entecavir (short (adding adefovir Entecavir or combination therapy treatment duration); if patients adefovir was also compared 5-year treatment developed (lamivudine with entecavir with either daily resistance) refractory patients) monotherapy for lamivudine , previously untreated telbivudine, or patients. adefovir Country Hong Kong Poland USA China USA WHO Region Western European Americas Western Pacific Americas Pacific Setting Hospital Secondary care Secondary care Secondary care Secondary care Perspective Public health Healthcare payer Healthcare payer Healthcare payer US third-party care provider Patients’ out-of- payer pocket costs Design Cost- Cost-utility analysis Cost-utility analysis Cost-effectiveness Cost-utility effectiveness Cost-effectiveness analysis analysis analysis Cost- effectiveness analysis Analytical Decision Decision analytic Markov model Markov model Decision tree approach analytic mode model model Time horizon 10 years 10 years Lifetime 35 years 10 years Measure of QALY QALY QALY QALY QALY benefit LYS LYS Costs US dollars Polish zloty US dollars US dollars US dollars (conversion from Chinese Renminbi) Reference year 2008 2006 2006 2010 2006 Conclusions Entecavir was Entecavir was the Entecavir was a cost- 5-year entecavir A treatment of considered preferred strategy effective alternative showed a up to 10 years cost-effective to lamivudine with favourable HBV with entecavir compared with adefovir salvage or to outcome and had was a cost- lamivudine in combination therapy the desired value effective treating CHB for previously compared with their alternative to in Hong Kong untreated patients alternatives lamivudine for when long the treatment of term medical HBeAg-positive consequences patients were considered. Validity + ++ ++ + ++ (model Funded by Bristol- Funded by Bristol- (Not all sources of Funded by adapted from Myers Squibb Myers Squibb data are clear) Bristol-Myers other study, Funded by Bristol- Squibb not all sources Myers Squibb of data clear) Funded by BMS Hong Kong

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Application for WHO Model List of Essential Medicines: Entecavir

13. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well)

Entecavir is has been approved for treatment in adult patients with chronic hepatitis B with compensated liver disease and evidence of active viral replication, persistently elevated serum ALT level and histological evidence of active inflammation and/or fibrosis in US FDA since 2005 and in European Medicines Agency (EMA) of the European Union since 2006. The FDA approved entecavir for treatment in adult patients with the decompensated indication in 2010 and EMA in 2011. The FDA and EMA approved entecavir for treatment in nucleoside-naive children 2 to 17 years of age with compensated liver disease and the same qualification listed for adults.

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopoeia)

British Pharmacopoeia, Yes International Pharmacopoeia, No United States Pharmacopoeia, Yes European Pharmacopoeia, Yes

15. Proposed (new/adapted) text for the WHO Model Formulary Entecavir Tablet: 0.5mg, 1mg Oral solution: 0.05 mg/mL

Hepatitis B is a major contributor to global morbidity and mortality. Safe and effective medicines exist to treat persons with chronic hepatitis B infection. Despite this, few persons with chronic HBV infection who need treatment receive it. One of the reasons is the lack of recommendations for the treatment of hepatitis B infection from WHO and the fact that entecavir, one of the two preferred medicines, is not included in the WHO List of Essential Medicines.

Entecavir is a safe and effective medicine that suppresses the replication of HBV, and thereby slows, or even reverses, liver damage caused by HBV. This leads to a reduction in risk of death from HCC and cirrhosis. The medicine has low toxicity and a high barrier to viral resistance. It is available in generic formulations. As treatment is life-long for most persons, drug cost is a critical factor. At present, the treatment costs between US$ 1 -2/day. However, this relatively high price is a result of low levels of demand because there are no large-scale treatment programs for hepatitis B. If treatment were scale-up, the price of this medicine would likely decline.

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Application for WHO Model List of Essential Medicines: Entecavir

References: 1 Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380: 2095-128. 2 World Health Organization. Hepatitis B. July 2014. Available at: http://www.who.int/mediacentre/factsheets/fs204/en/. Last Accessed: November 26, 2013. 3 Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 2012;30: 2212-9. 4 Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. Journal of hepatology. 2006;45: 529-38. 5 Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports / Centers for Disease Control. 2006;55: 1-33; quiz CE1-4. 6 Bianco E, Stroffolini T, Spada E, et al. Case fatality rate of acute viral hepatitis in Italy: 1995- 2000. An update. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2003;35: 404-8. 7 EASL Clinical Practice Guidelines: management of chronic hepatitis B. Journal of hepatology. 2009;50: 227-42. 8 Ganem D, Prince AM. Hepatitis B virus infection--natural history and clinical consequences. The New England journal of medicine. 2004;350: 1118-29. 9 Crockett SD, Keeffe EB. Natural history and treatment of hepatitis B virus and hepatitis C virus coinfection. Annals of clinical microbiology and antimicrobials. 2005;4: 13. 10 Sagnelli E, Pasquale G, Coppola N, et al. Influence of chronic coinfection with hepatitis B and C virus on liver histology. Infection. 2004;32: 144-8. 11 Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. Journal of hepatology. 2008;48: 335-52. 12 Govindarajan S, De Cock KM, Redeker AG. Natural course of delta superinfection in chronic hepatitis B virus-infected patients: histopathologic study with multiple liver biopsies. Hepatology (Baltimore, Md). 1986;6: 640-4. 13 Thio CL, Seaberg EC, Skolasky R, Jr., et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360: 1921-6. 14 WHO UNICEF. Global immunization data. 2014. Available at: http://www.who.int/immunization_monitoring/Global_Immunization_Data.pdf. Last Accessed: November 22, 2013. 15 Marcellin P, Castelnau C, Martinot-Peignoux M, Boyer N. Natural history of hepatitis B. Minerva gastroenterologica e dietologica. 2005;51: 63-75. 16 Hepatitis B (chronic) Diagnosis and management of chronic hepatitis Bin children, young people and adults. NICE clinical guideline 165. 2013: http://guidance.nice.org.uk/cg165. 17 Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology (Baltimore, Md). 2009;50: 661-2. 18 Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int. 2012;6: 531.

19 Zhao P, Liu W, Zhao J, Guan Q. Comparison of the 48-week efficacy between entecavir and adefovir in HBeAg-positive nucleos(t)ide-naive Asian patients with chronic hepatitis B: a meta- analysis. Virology journal. 2011;8: 75. 20 Liang J, Tang YF, Wu FS, Deng X. Entecavir versus lamivudine for the treatment of chronic hepatitis B: a systematic review. Die Pharmazie. 2012;67: 883-90. 21 JC Z. De novo combination therapy with lamivudine and adefovir dipivoxii versus entecavir monotherapy for naive chronic hepatitis B patients with high viral loads. Zhong Hua Lin Chuang Gan Ran Bing Xue Za Zhi. 2012;3: 142–4. 22 Liu F, Wang X, Wei F, et al. Efficacy and resistance in de novo combination lamivudine and

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Application for WHO Model List of Essential Medicines: Entecavir

adefovir dipivoxil therapy versus entecavir monotherapy for the treatment-naive patients with chronic hepatitis B: a meta-analysis. Virology journal. 2014;11: 59. 23 Ye XG, Su QM. Effects of entecavir and lamivudine for hepatitis B decompensated cirrhosis: meta-analysis. World journal of gastroenterology : WJG. 2013;19: 6665-78. 24 Marcellin P, Heathcote EJ, Buti M, et al. fumarate versus adefovir dipivoxil for chronic hepatitis B. The New England journal of medicine. 2008;359: 2442-55. 25 Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381: 468-75. 26 Chang TT, Gish RG, Hadziyannis SJ, et al. A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients. Gastroenterology. 2005;129: 1198-209. 27 Tenney DJ, Rose RE, Baldick CJ, et al. Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrobial agents and chemotherapy. 2007;51: 902-11. 28 Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg- positive chronic hepatitis B. The New England journal of medicine. 2006;354: 1001-10. 29 Sherman M, Yurdaydin C, Sollano J, et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006;130: 2039-49. 30 Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. The New England journal of medicine. 2006;354: 1011-20. 31 Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology (Baltimore, Md). 2009;49: 1503-14. 32 Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology (Baltimore, Md). 2010;51: 422-30. 33 Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology (Baltimore, Md). 2013;58: 98-107. 34 Seto WK, Lam YF, Fung J, et al. Changes of HBsAg and HBV DNA levels in Chinese chronic hepatitis B patients after 5 years of entecavir treatment. Journal of gastroenterology and hepatology. 2014;29: 1028-34. 35 Wong GL, Chan HL, Mak CW, et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology (Baltimore, Md). 2013;58: 1537-47. 36 Yokosuka O, Takaguchi K, Fujioka S, et al. Long-term use of entecavir in nucleoside-naive Japanese patients with chronic hepatitis B infection. Journal of hepatology. 2010;52: 791-9. 37 Yuen MF, Seto WK, Fung J, Wong DK, Yuen JC, Lai CL. Three years of continuous entecavir therapy in treatment-naive chronic hepatitis B patients: VIRAL suppression, viral resistance, and clinical safety. The American journal of gastroenterology. 2011;106: 1264-71. 38 Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140: 132-43. 39 Kitrinos KM, Corsa A, Liu Y, et al. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology (Baltimore, Md). 2014;59: 434- 42. 40 Snow-Lampart A, Chappell B, Curtis M, et al. No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus. Hepatology (Baltimore, Md). 2011;53: 763-73. 41 de Vries-Sluijs TE, Reijnders JG, Hansen BE, et al. Long-term therapy with tenofovir is effective for patients co-infected with human immunodeficiency virus and hepatitis B virus. Gastroenterology. 2010;139: 1934-41. 42 Murray KF, Szenborn L, Wysocki J, et al. Randomized, placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B. Hepatology (Baltimore, Md). 2012;56: 2018-26. 43 Yao G, Chen C, Lu W, et al. Efficacy and safety of entecavir compared to lamivudine in nucleoside-naive patients with chronic hepatitis B: a randomized double-blind trial in China.

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Application for WHO Model List of Essential Medicines: Entecavir

Hepatol Int. 2007;1: 365-72. 44 Akarca US, Ersoz G, Gunsar F, et al. Interferon-lamivudine combination is no better than lamivudine alone in anti-HBe-positive chronic hepatitis B. Antiviral therapy. 2004;9: 325-34. 45 Barbaro G, Zechini F, Pellicelli AM, et al. Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter, randomized trial. Journal of hepatology. 2001;35: 406-11. 46 Chan HL, Heathcote EJ, Marcellin P, et al. Treatment of hepatitis B e antigen positive chronic hepatitis with telbivudine or adefovir: a randomized trial. Annals of internal medicine. 2007;147: 745-54. 47 Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. The New England journal of medicine. 1999;341: 1256-63. 48 Dikici B, Bosnak M, Kara IH, et al. Lamivudine and interferon-alpha combination treatment of childhood patients with chronic hepatitis B infection. The Pediatric infectious disease journal. 2001;20: 988-92. 49 Dikici B, Bosnak M, Bosnak V, et al. Combination therapy for children with chronic hepatitis B virus infection. Journal of gastroenterology and hepatology. 2002;17: 1087-91. 50 Dikici B, Ozgenc F, Kalayci AG, et al. Current therapeutic approaches in childhood chronic hepatitis B infection: a multicenter study. Journal of gastroenterology and hepatology. 2004;19: 127-33. 51 Kansu A, Doganci T, Akman SA, et al. Comparison of two different regimens of combined interferon-alpha2a and lamivudine therapy in children with chronic hepatitis B infection. Antiviral therapy. 2006;11: 255-61. 52 Fung J, Lai CL, Yuen J, et al. Randomized trial of lamivudine versus entecavir in entecavir-treated patients with undetectable hepatitis B virus DNA: outcome at 2 Years. Hepatology (Baltimore, Md). 2011;53: 1148-53. 53 Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365: 123-9. 54 Jonas MM, Block JM, Haber BA, et al. Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options. Hepatology (Baltimore, Md). 2010;52: 2192-205. 55 Jonas MM, Kelly D, Pollack H, et al. Safety, efficacy, and of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B. Hepatology (Baltimore, Md). 2008;47: 1863-71. 56 Jonas MM, Kelly D, Pollack H, et al. Efficacy and safety of long-term adefovir dipivoxil therapy in children with chronic hepatitis B infection. The Pediatric infectious disease journal. 2012;31: 578-82. 57 Jonas MM, Little NR, Gardner SD. Long-term lamivudine treatment of children with chronic hepatitis B: durability of therapeutic responses and safety. Journal of viral hepatitis. 2008;15: 20- 7. 58 Jonas MM, Mizerski J, Badia IB, et al. of lamivudine in children with chronic hepatitis B. The New England journal of medicine. 2002;346: 1706-13. 59 Lai CL, Chien RN, Leung NW, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. The New England journal of medicine. 1998;339: 61-8. 60 Izzo F, Cremona F, Ruffolo F, Palaia R, Parisi V, Curley SA. Outcome of 67 patients with hepatocellular cancer detected during screening of 1125 patients with chronic hepatitis. Annals of surgery. 1998;227: 513-8. 61 Lok AS, Trinh H, Carosi G, et al. Entecavir (ETV) monotherapy for 96 weeks in compatible to combination therapy with ETV plus tenofovir (TDF) in nucleos(t)ide-naive patients with chronic hepatitis B (CHB): The below study. Hepatology (Baltimore, Md). 2011;54: 471A. 62 Liaw YF, Gane E, Leung N, et al. 2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology. 2009;136: 486-95. 63 Marcellin P, Asselah T. Resistance to adefovir: a new challenge in the treatment of chronic hepatitis B. Journal of hepatology. England 2005; 920-3. 64 Marcellin P, Asselah T, Boyer N. Treatment of chronic hepatitis B. Journal of viral hepatitis.

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2005;12: 333-45. 65 Marcellin P, Cadranel JF, Fontanges T, et al. High rate of adefovir-lamivudine combination therapy in nucleoside-naive patients with chronic hepatitis B in France: results of a national survey in 1730 patients. European journal of gastroenterology & hepatology. 2010;22: 1290-6. 66 Marcellin P, Chang TT, Lim SG, et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology (Baltimore, Md). 2008;48: 750-8. 67 Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. The New England journal of medicine. 2003;348: 808-16. 68 Peters MG, Andersen J, Lynch P, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology (Baltimore, Md). 2006;44: 1110-6. 69 Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology (Baltimore, Md). 2007;45: 307-13. 70 Suh DJ, Um SH, Herrmann E, et al. Early viral kinetics of telbivudine and entecavir: results of a 12-week randomized exploratory study with patients with HBeAg-positive chronic hepatitis B. Antimicrobial agents and chemotherapy. 2010;54: 1242-7. 71 Zheng MH, Shi KQ, Dai ZJ, Ye C, Chen YP. A 24-week, parallel-group, open-label, randomized clinical trial comparing the early antiviral efficacy of telbivudine and entecavir in the treatment of hepatitis B e antigen-positive chronic hepatitis B virus infection in adult Chinese patients. Clinical therapeutics. 2010;32: 649-58. 72 Lee KK, Wu DB, Chow PY, Lee VW, Li H. Economic analysis between entecavir and lamivudine for the treatment of chronic hepatitis B in Hong Kong. Journal of gastroenterology and hepatology. 2012;27: 1167-74. 73 Orlewska E, Zammit D, Yuan Y, et al. The cost-effectiveness analysis of entecavir in the treatment of chronic hepatitis B (CHB) patients in Poland. Experimental and Clinical Hepatology. 2008;4: 20-8. 74 Veenstra DL, Sullivan SD, Clarke L, et al. Cost effectiveness of entecavir versus lamivudine with adefovir salvage in HBeAg-positive chronic hepatitis B. PharmacoEconomics. 2007;25: 963-77. 75 Wei L, Hu S, Hou J, et al. A novel estimation of the impact of treatment with entecavir on long- term mortality, morbidity, and health care costs of chronic . . Value in Health Regional Issues. 2013;2: 48-56. 76 Yuan Y, Iloeje UH, Hay J, Saab S. Evaluation of the cost-effectiveness of entecavir versus lamivudine in hepatitis BeAg-positive chronic hepatitis B patients. Journal of managed care pharmacy : JMCP. 2008;14: 21-33.

22

Appendix A: EVIDENCE PROFILES 1. Entecavir versus adefovir in naïve patients with chronic hepatitis B (Zhao 2011) Bibliography: Zhao P, Liu W, Zhao J, Guan Q. Comparison of the 48‐week efficacy between entecavir and adefovir in HBeAg‐positive nucleos(t)ide‐naïve Asian patients with chronic hepatitis B: a meta‐analysis. Virol J. 2011;8:75. doi: 10.1186/1743‐422X‐8‐75.

Quality assessment No of patients Effect

Quality Importance

No of Risk of Other Relative Design Inconsistency Indirectness Imprecision Entecavir Adefovir Absolute studies bias considerations (95% CI)

Attainment of undetectable levels of serum HBV DNA (follow‐up 48 weeks; assessed with: not stated)

4 randomised serious1 no serious no serious no serious none 105/161 54/148 RR 1.73 (1.38 266 more per 1000 (from +++ CRITICAL trials inconsistency2 indirectness imprecision (65.2%) (36.5%) to 2.17) 139 more to 427 more) MODERATE

Normalisation of serum alanine aminotransferase level (follow‐up 48 weeks; assessed with: not stated)

4 randomised serious1 no serious no serious serious3 none 93/131 76/136 RR 1.25 (1.06 140 more per 1000 (from 34 ++ CRITICAL trials inconsistency4 indirectness (71%) (55.9%) to 1.49) more to 274 more) LOW

HBeAg clearence (follow‐up 48 weeks; assessed with: not stated)

5 randomised serious1 no serious no serious very serious3 none 17/152 21/154 RR 0.77 (0.44 31 fewer per 1000 (from 76 + CRITICAL trials inconsistency5 indirectness (11.2%) (13.6%) to 1.35) fewer to 48 more) VERY LOW

HBeAg seroconversion (follow‐up 48 weeks; assessed with: not stated)

3 randomised serious1 no serious no serious very serious3 none 6/101 8/106 RR 0.74 (0.28 20 fewer per 1000 (from 54 + CRITICAL trials inconsistency indirectness (5.9%) (7.5%) to 1.94) fewer to 71 more) VERY LOW

1 The trials included in the review had limitation in the randomisation sequence generation and its allocation. 2 I‐square: 39% 3 Very low event rate, resulting from the from the small sample sizes in the included studies. For HBeAg clearence and seroconversion the imprecision we rate down two points the quality of evidence. 4 I‐square: 48% 5 I‐square:17.8%

23

2. Entecavir versus lamivudine in naïve patients with chronic hepatitis B (Liang 2012) Bibliography: Liang J, Tang YF, Wu FS, Deng X. Entecavir versus lamivudine for the treatment of chronic hepatitis B: a systematic review. Pharmazie. 2012;67(11):883‐90.

Quality assessment No of patients Effect

Quality Importance

No of Risk of Other Relative Design Inconsistency Indirectness Imprecision Entecavir Lamivudine Absolute studies bias considerations (95% CI)

Improvement of liver histology (follow‐up 48 weeks)

2 randomised serious1 no serious no serious no serious none 434/610 369/601 RR 1.16 (1.07 98 more per 1000 (from +++ CRITICAL trials inconsistency indirectness imprecision (71.1%) (61.4%) to 1.26) 43 more to 160 more) MODERATE

Loss of serum HBV‐DNA (follow‐up 48 to 96 weeks)

8 randomised serious2 very serious3 no serious no serious none 1183/1555 647/1368 RR 1.65 (1.37 307 more per 1000 (from + CRITICAL trials indirectness imprecision (76.1%) (47.3%) to 1.98) 175 more to 463 more) VERY LOW

Normalisation of serum ALT (follow‐up 48 to 96 weeks)

8 randomised serious2 no serious no serious no serious none 1267/1558 958/1369 RR 1.15 (1.11 105 more per 1000 (from +++ CRITICAL trials inconsistency indirectness imprecision (81.3%) (70%) to 1.2) 77 more to 140 more) MODERATE

Loss of serum HBeAg (follow‐up 48 weeks)

4 randomised serious1 no serious no serious Serious4 none 153/743 135/686 RR 1.03 (0.83 6 more per 1000 (from 33 ++ CRITICAL trials inconsistency indirectness (20.6%) (19.7%) to 1.26) fewer to 51 more) LOW

HBeAg seroconversion

6 randomised serious2 no serious no serious Serious4 none 156/1075 153/937 RR 0.92 (0.75 13 fewer per 1000 (from ++ CRITICAL trials inconsistency indirectness (14.5%) (16.3%) to 1.12) 41 fewer to 20 more) LOW

Incidence of drug‐related adverse events

24

Application for WHO Model List of Essential Medicines: Entecavir

6 randomised serious2 no serious no serious Serious4 none 1113/1484 1014/1395 RR 1.09 (0.92 65 more per 1000 (from ++ CRITICAL trials inconsistency indirectness (75%) (72.7%) to 1.3) 58 fewer to 218 more) LOW

HBsAg loss

05 No evidence none‐ 0%‐ ‐ CRITICAL available

1 The trials included in the review had limitation in the randomisation sequence generation, its allocation, and blinding. 2 Six trials were rated as having unclear randomisation. 3 Significant heterogeneity (I‐square: 86%) 4 Limited event rate, resulting in imprecise estimates. Results suggest a beneficial effect for both the intervention and the comparison. 5 This outcome was not reported.

25

3. Entecavir versus telbivudine in naïve patients with chronic hepatitis B (Su 2012) Bibliography: Su QM, Ye XG. Effects of telbivudine and entecavir for HBeAg‐positive chronic hepatitis B: a meta‐analysis. World J Gastroenterol. 2012;18(43):6290‐301.

Quality assessment No of patients Effect

Quality Importance

No of Risk of Other Relative Design Inconsistency Indirectness Imprecision Telbivudine Entecavir Absolute studies bias considerations (95% CI)

Undetectable HBV DNA (follow‐up 4‐72 weeks; assessed with: Not stated )

13 randomised serious1 no serious no serious no serious none 1314/2137 1270/2088 RR 1.02 (0.98 12 more per 1000 (from +++ CRITICAL trials inconsistency indirectness imprecision (61.5%) (60.8%) to 1.06) 12 fewer to 36 more) MODERATE

Alanine aminotransferase normalisation levels (follow‐up 4‐72 weeks; assessed with: Not stated)

13 randomised serious1 no serious no serious no serious none 1000/1411 1049/1475 RR 1.01 (0.96 7 more per 1000 (from 28 +++ CRITICAL trials inconsistency indirectness imprecision (70.9%) (71.1%) to 1.05) fewer to 36 more) MODERATE

HbeAg loss (follow‐up 4‐52 weeks; assessed with: Not stated)

9 randomised serious1 no serious no serious no serious none 338/1305 194/1278 RR 1.68 (1.35 103 more per 1000 (from +++ CRITICAL trials inconsistency indirectness imprecision (25.9%) (15.2%) to 2.09) 53 more to 165 more) MODERATE

HBaAg seroconversion (follow‐up 4 to 72 weeks; assessed with: Not stated)

10 randomised serious1 no serious no serious no serious none 351/1837 183/1750 RR 1.81 (1.55 85 more per 1000 (from +++ CRITICAL trials inconsistency indirectness imprecision (19.1%) (10.5%) to 2.13) 58 more to 118 more) MODERATE

Drug resistance (assessed with: Not stated)

6 randomised serious1 no serious no serious very serious2 none 14/307 2/297 RR 3.76 (1.28 19 more per 1000 (from 2 + CRITICAL trials inconsistency indirectness (4.6%) (0.67%) to 11.01) more to 67 more) VERY LOW

26

Application for WHO Model List of Essential Medicines: Entecavir

Adverse events (increased creatine kinase) (assessed with: Not stated)

5 randomised serious1 no serious no serious very serious2 none 28/220 3/211 RR 5.58 (2.22 65 more per 1000 (from + CRITICAL trials inconsistency indirectness (12.7%) (1.4%) to 13.98) 17 more to 185 more) VERY LOW

1 Only 2/13 trials described as blinded, and few details randomisation methods (4/13). 2 Very low event rate, resulting from the from the small sample sizes in the included studies

27

4. Entecavir versus lamivudine in decompensated HBV cirrhosis (Ye 2013) Bibliography: Ye XG, Su QM. Effects of entecavir and lamivudine for hepatitis B decompensated cirrhosis: meta‐analysis. World J Gastroenterol. 2013;19(39):6665‐78.

Quality assessment No of patients Effect

Quality Importance

No of Risk of Other Relative Design Inconsistency Indirectness Imprecision Entecavir Lamivudine Absolute studies bias considerations (95% CI)

Mortality (follow‐up 48 to 52 weeks)

5 randomised serious1 no serious no serious serious2 none 10/157 12/152 RR 0.81 (0.37 15 fewer per 1000 (from 50 ++ CRITICAL trials inconsistency indirectness (6.4%) (7.9%) to 1.8) fewer to 63 more) LOW

HBV DNA undectability (follow‐up 12 to 48 weeks; assessed with: not stated)

8 randomised serious1 no serious no serious no serious none 717/958 560/968 ‐ 579 fewer per 1000 (from +++ CRITICAL trials inconsistency indirectness imprecision (74.8%) (57.9%) 579 fewer to 579 fewer) MODERATE

HBeAg seroconversion (follow‐up 12 to 48 weeks; assessed with: not stated)

7 randomised serious1 no serious no serious serious2 none 137/429 97/452 RR 1.42 (1.15 90 more per 1000 (from 32 ++ CRITICAL trials inconsistency indirectness (31.9%) (21.5%) to 1.75) more to 161 more) LOW

Alanine aminotransferase levels (follow‐up 12 and >48 weeks; measured with: not stated; Better indicated by lower values)

7 randomised serious1 very serious3 no serious serious2 none 442 475 ‐ MD 5.11 lower (7.71 to 2.5 + CRITICAL trials indirectness lower) VERY LOW

Albumin levels (follow‐up 12 and > 48 weeks; measured with: not stated; Better indicated by lower values)

5 randomised serious1 very serious4 no serious serious2 none 316 346 ‐ MD 1.84 higher (0.47 lower + CRITICAL trials indirectness to 4.15 higher) VERY LOW

28

Application for WHO Model List of Essential Medicines: Entecavir

Total bilirrubin levels (follow‐up 12 and > 48 weeks; measured with: not stated; Better indicated by lower values)

5 randomised serious1 Serious5 no serious serious2 none 300 330 ‐ MD 7.43 lower (9.73 to 5.13 + CRITICAL trials indirectness lower) VERY LOW

Prothrombin time activity levels (follow‐up 12 and > 48 weeks; measured with: not stated; Better indicated by lower values)

4 randomised serious1 no serious no serious serious2 none 362 359 ‐ MD 1.95 higher (0.81 to ++ CRITICAL trials inconsistency indirectness 3.08 higher) LOW

Child‐Turcotte‐Pugh score (follow‐up 12 and >48 weeks; measured with: not stated; Better indicated by lower values)

7 randomised serious1 Serious6 no serious no serious none 914 880 ‐ MD 0.15 lower (0.75 to 0.26 ++ CRITICAL trials indirectness imprecision lower) LOW

Drug resistance (assessed with: not stated)

9 randomised serious1 no serious no serious serious2 none 1/325 47/328 RR 0.10 (0.04 129 fewer per 1000 (from + CRITICAL trials inconsistency indirectness (0.31%) (14.3%) to 0.24) 109 fewer to 138 fewer) VERY LOW

1 Jadad scale between 2 and 3. Altough the Jadad score is no longer endorsed, it provides an indication of the main limitations from randomised trials. Results ≤3 in this score indicate limitations in the design. 2 Low event rate, resulting from the from the small sample sizes in the included studies 3, 4, 5, 6 Significant heterogeneity (3I‐squared: 89%; 4 I‐squared: 91%; 5 I‐squared: 75%; 6 I‐squared: 72%)

29

5. Entecavir versus combined lamivudine and adefovir in decompensated HBV cirrhosis (Peng 2013) Bibliography: Peng H, Liu J, Yang M, Tong S, Yin W, Tang H, Hu P, Hu H, Ren H. Efficacy of lamivudine combined with adefovir dipivoxil versus entecavir monotherapy in patients with hepatitis B‐associated decompensated cirrhosis: A meta‐analysis. J Clin Pharmacol. 2013 Sep 16. doi: 10.1002/jcph.181.

Quality assessment No of patients Effect

Quality Importance

No of Risk of Other Lamivudine plus Relative Design Inconsistency Indirectness Imprecision Entecavir Absolute studies bias considerations adefovir (95% CI)

Mortality (follow‐up 48 weeks)

7 randomised serious1 no serious no serious Serious2 none 8/205 5/206 RR 1.20 (0.43 5 more per 1000 (from ++ CRITICAL trials inconsistency indirectness (3.9%) (2.4%) to 3.32) 14 fewer to 56 more) LOW

Adverse event (increased serum creatinine levels) (follow‐up 48 weeks)

7 randomised Serious1 no serious no serious Serious2 none 10/205 1/206 RR 4.76 (1.11 18 more per 1000 (from ++ CRITICAL trials inconsistency indirectness (4.9%) (0.49%) to 20.33) 1 more to 94 more) LOW

HBV DNA undetectable (follow‐up 48 weeks; assessed with: not stated)

6 randomised Serious1 no serious no serious serious3 none 122/175 137/176 RR 0.93 (0.83 54 fewer per 1000 (from ++ CRITICAL trials inconsistency indirectness (69.7%) (77.8%) to 1.05) 132 fewer to 39 more) LOW

Child‐Turquette‐Pugh score (follow‐up 48 weeks; Better indicated by lower values)

7 randomised Serious1 no serious no serious no serious none 205 206 ‐ MD 0.33 higher (0.21 to +++ CRITICAL trials inconsistency indirectness imprecision 0.44 higher) MODERATE

HBV DNA levels (follow‐up 48 weeks; Better indicated by lower values)

3 randomised Serious1 no serious no serious serious3 none 108 109 ‐ MD 0.09 higher (0.02 ++ CRITICAL trials inconsistency indirectness lower to 0.2 higher) LOW

30

Application for WHO Model List of Essential Medicines: Entecavir

HBeAg loss (follow‐up 48 weeks)

3 randomised Serious1 no serious no serious serious2, 3 none 43/74 44/80 RR 1.09 (0.84 50 more per 1000 (from ++ CRITICAL trials inconsistency indirectness (58.1%) (55%) to 1.41) 88 fewer to 225 more) LOW

HBeAg conversion (follow‐up 48 weeks)

5 randomised Serious1 no serious no serious serious2, 3 none 22/75 21/70 RR 0.95 (0.58 15 fewer per 1000 (from ++ CRITICAL trials inconsistency indirectness (29.3%) (30%) to 1.55) 126 fewer to 165 more) LOW

Alanine aminotransferase normalisation (follow‐up 48 weeks)

2 randomised Serious1 no serious no serious serious2, 3 none 51/75 40/61 RR 1.03 (0.81 20 more per 1000 (from ++ CRITICAL trials inconsistency indirectness (68%) (65.6%) to 1.31) 125 fewer to 203 more) LOW

Alanine aminotransferese levels (follow‐up 48 weeks; Better indicated by lower values)

4 randomised Serious1 no serious no serious serious2, 3 none 108 109 ‐ MD 1.05 higher (4.83 ++ CRITICAL trials inconsistency indirectness lower to 6.47 higher) LOW

1 Jadad score ranging between 2 and 3, all were unblinded. Altough the Jadad score is no longer endorsed, it provides an indication of the main limitations from randomised trials. Results ≤3 in this score indicate limitations in the design 2 Low event rate, resulting from the from the small sample sizes in the included studies 3 Limited event rate, resulting in imprecise estimates. Absolute estimates suggest a beneficial effect for both the intervention and the comparison.

31

6. Entecavir versus combined lamivudine and adefovir in naïve patients with chronic hepatitis B (Liu 2014) Bibliography: Liu F, Wang X, Wei F, Hu H, Zhang D, Hu P1, Ren H. Efficacy and resistance in de novo combination lamivudine and adefovir dipivoxil therapy versus entecavir monotherapy for the treatment‐naive patients with chronic hepatitis B: a meta‐analysis. Virol J. 2014;11:59.

Quality assessment No of patients Effect

Quality Importance

No of Other Lamivudine and Relative Design Risk of bias Inconsistency Indirectness Imprecision Entecavir Absolute studies considerations adefovir (95% CI)

Attainment of undetectable levels of HBV DNA (follow‐up 12 weeks; assessed with: )

4 randomised very serious1 no serious no serious very none 75/140 70/147 RR 1.08 (0.87 38 more per 1000 (from + CRITICAL trials inconsistency2 indirectness serious3 (53.6%) (47.6%) to 1.34) 62 fewer to 162 more) VERY LOW

Attainment of undetectable levels of HBV DNA (follow‐up 24 weeks; assessed with: < 1000 copies/ml)

4 randomised very serious1 no serious no serious very none 101/140 94/145 RR 1.09 (0.93 58 more per 1000 (from + CRITICAL trials inconsistency2 indirectness serious3 (72.1%) (64.8%) to 1.26) 45 fewer to 169 more) VERY LOW

Attainment of undetectable levels of HBV DNA (follow‐up 48 weeks; assessed with: < 1000 copies/ml)

4 randomised very serious1 no serious no serious very none 126/140 116/147 RR 1.14 (1.03 110 more per 1000 (from + CRITICAL trials inconsistency2 indirectness serious3 (90%) (78.9%) to 1.26) 24 more to 205 more) VERY LOW

Attainment of undetectable levels of HBV DNA (follow‐up 96 weeks; assessed with: not stated)

3 randomised very serious1 very serious4 no serious very none 102/106 87/105 RR 1.13 (0.93 108 more per 1000 (from + CRITICAL trials indirectness serious3 (96.2%) (82.9%) to 1.38) 58 fewer to 315 more) VERY LOW

32

Application for WHO Model List of Essential Medicines: Entecavir

Alanine aminotransferase normalisation levels (follow‐up 12 weeks; assessed with: not stated)

4 randomised very serious1 no serious no serious very none 37/102 42/110 RR 0.91 (0.65 34 fewer per 1000 (from + CRITICAL trials inconsistency2 indirectness serious3 (36.3%) (38.2%) to 1.29) 134 fewer to 111 more) VERY LOW

Alanine aminotransferase normalisation levels (follow‐up 24 weeks; assessed with: not stated)

4 randomised very serious1 no serious no serious very none 69/102 79/110 RR 0.83 (0.47 122 fewer per 1000 (from + CRITICAL trials inconsistency5 indirectness serious3 (67.6%) (71.8%) to 1.49) 381 fewer to 352 more) VERY LOW

Alanine aminotransferase normalisation levels (follow‐up 48 weeks; assessed with: not stated)

4 randomised very serious1 serious6 no serious serious3 none 128/140 120/147 RR 1.09 (0.95 73 more per 1000 (from + CRITICAL trials indirectness (91.4%) (81.6%) to 1.25) 41 fewer to 204 more) VERY LOW

Alanine aminotransferase normalisation levels (follow‐up 96 weeks; assessed with: not stated)

3 randomised very serious1 no serious no serious serious3 none 104/108 91/105 RR 1.11 (1.02 95 more per 1000 (from + CRITICAL trials inconsistency7 indirectness (96.3%) (86.7%) to 1.21) 17 more to 182 more) VERY LOW

HBeAg seroconversion (follow‐up 48 weeks; assessed with: HBeAg disappearance)

3 randomised very serious1 no serious no serious very none 19/91 11/93 RR 1.79 (0.9 93 more per 1000 (from + CRITICAL trials inconsistency2 indirectness serious3 (20.9%) (11.8%) to 3.54) 12 fewer to 300 more) VERY LOW

HBeAg seroconversion (follow‐up 96 weeks; assessed with: HBeAg disappearance)

3 randomised very serious1 no serious no serious very none 39/91 20/93 RR 2.00 (1.26 215 more per 1000 (from + CRITICAL trials inconsistency8 indirectness serious3 (42.9%) (21.5%) to 3.18) 56 more to 469 more) VERY LOW

33

Application for WHO Model List of Essential Medicines: Entecavir

Viral breakthrough (assessed with: increase in serum HBV DNA by 1 log10 copies/ml above a nadir on two or more consecutive occasions at least 1 month apart)

2 randomised very serious1 no serious no serious very none 0/89 6/85 RR 0.14 (0.02 61 fewer per 1000 (from + CRITICAL trials inconsistency2 indirectness serious3 (0%) (7.1%) to 1.14) 69 fewer to 10 more) VERY LOW

Attainment of undetectable levels of HBV DNA (follow‐up 12 weeks; assessed with: not stated)

1 randomised no serious no serious no serious very none 24/35 20/35 RR 1.20 (0.83 114 more per 1000 (from ++ CRITICAL trials risk of bias inconsistency indirectness serious3 (68.6%) (57.1%) to 1.73) 97 fewer to 417 more) LOW

Attainment of undetectable levels of HBV DNA (follow‐up 24 weeks; assessed with: < 1000 copies/ml)

1 randomised no serious no serious no serious very none 28/35 22/33 RR 1.20 (0.9 133 more per 1000 (from ++ CRITICAL trials risk of bias inconsistency indirectness serious3 (80%) (66.7%) to 1.61) 67 fewer to 407 more) LOW

Attainment of undetectable levels of HBV DNA (follow‐up 48 weeks; assessed with: < 1000 copies/ml)

1 randomised no serious no serious no serious very none 31/35 24/35 RR 1.29 (1 to 199 more per 1000 (from ++ CRITICAL trials risk of bias inconsistency indirectness serious3 (88.6%) (68.6%) 1.67) 0 more to 459 more) LOW

Attainment of undetectable levels of HBV DNA (follow‐up 96 weeks; assessed with: not stated )

1 randomised no serious no serious no serious very none 33/35 27/35 RR 1.22 (1 to 170 more per 1000 (from ++ CRITICAL trials risk of bias inconsistency indirectness serious3 (94.3%) (77.1%) 1.49) 0 more to 378 more) LOW

Alanine aminotransferase normalisation levels (follow‐up 12 weeks; assessed with: not stated)

1 randomised no serious no serious no serious very none 21/35 19/35 RR 1.11 (0.74 60 more per 1000 (from ++ CRITICAL trials risk of bias inconsistency indirectness serious3 (60%) (54.3%) to 1.66) 141 fewer to 358 more) LOW

Alanine aminotransferase normalisation levels (follow‐up 24 weeks; assessed with: not stated)

1 randomised no serious no serious no serious very none 26/35 21/35 RR 1.93 (0.7 558 more per 1000 (from ++ CRITICAL trials risk of bias inconsistency indirectness serious3 (74.3%) (60%) to 5.32) 180 fewer to 1000 more) LOW

34

Application for WHO Model List of Essential Medicines: Entecavir

Alanine aminotransferase normalisation levels (follow‐up 48 weeks; assessed with: not stated)

1 randomised no serious no serious no serious very none 30/35 23/35 RR 1.30 (0.99 197 more per 1000 (from ++ CRITICAL trials risk of bias inconsistency indirectness serious3 (85.7%) (65.7%) to 1.72) 7 fewer to 473 more) LOW

Alanine aminotransferase normalisation levels (follow‐up 96 weeks; assessed with: not stated)

1 randomised no serious no serious no serious very none 34/35 27/35 RR 1.26 (1.04 201 more per 1000 (from ++ CRITICAL trials risk of bias inconsistency indirectness serious3 (97.1%) (77.1%) to 1.52) 31 more to 401 more) LOW

HbeAg seroconversion (follow‐up 48 weeks; assessed with: HBeAg disappearence)

1 randomised no serious no serious no serious very none 7/35 3/35 RR 2.33 (0.66 114 more per 1000 (from ++ CRITICAL trials risk of bias inconsistency indirectness serious3 (20%) (8.6%) to 8.3) 29 fewer to 626 more) LOW

HbeAg seroconversion (follow‐up 96 weeks; assessed with: HBeAg disappearence)

1 randomised no serious no serious no serious very none 17/35 6/35 RR 2.83 (1.27 314 more per 1000 (from ++ CRITICAL trials risk of bias inconsistency indirectness serious3 (48.6%) (17.1%) to 6.33) 46 more to 914 more) LOW

1 This pool is composed by 3 cohort studies and 1 randomised clinical trial 2 I‐squared: 0% 3 Limited event rate, resulting in imprecise estimates. Results suggest a beneficial effect for both the intervention and the comparison 4 I‐squared: 82% 5 I‐squared: 37% 6 I‐squared: 68% 7 I‐squared: 43% 8 I‐squared: 51%

35

7. Long term studies on entecavir

No of Quality assessment Effect patients

Quality Importance Entecavir No of Risk of Other Relative Design Inconsistency Indirectness Imprecision Absolute studies bias considerations (95% CI)

Mortality at 3 years of follow up

1 Cohort serious1 no serious no serious no serious none All‐cause Data from the All‐cause ++ CRITICAL study inconsistency indirectness imprecision entecavir arm LOW 3.0% 3.0% (2.5 to 3.5)

(2.5 to 3.5)

HCC at 3 years of follow up

1 Cohort serious1 no serious no serious no serious none 3.9% Data from the 3.9% ++ CRITICAL study inconsistency indirectness imprecision entecavir arm LOW (3.3 to 4.5) (3.3 to 4.5)

Resistance at 3 years of follow up

3 Cohort serious1 no serious no serious no serious none Range Data from the Range ++ CRITICAL study inconsistency indirectness imprecision entecavir arm LOW 1.2 % to 1.7% 1.2 % to 17%

Mortality at 5 years of follow up

3 Cohort serious1 no serious no serious no serious none Range Data from the Range ++ CRITICAL study inconsistency indirectness imprecision entecavir arm LOW 0.9 % to 3.4% 0.9 % to 3.4%

HCC at 5 years of follow up

36

4 Cohort serious1 no serious no serious no serious None Range Data from the Range ++ CRITICAL study inconsistency indirectness imprecision entecavir arm LOW 3.6 % to 6.6% 3.6 % to 6.6%

Resistance at 5 years of follow up

3 Cohort serious1 no serious no serious no serious none Range Data from the Range ++ CRITICAL study inconsistency indirectness imprecision entecavir arm LOW 0.8 % to 1.2% 0.8 % to 1.2%

1 Data from entecavir treated arms from cohort studies without any condition to consider to grade up the quality of evidence

37

8. Entecavir versus placebo in children AI463189 trial, data obtained from FDA New Drug Application reports

Quality assessment No of patients Effect

Quality Importance

No of Other Relative Design Risk of bias Inconsistency Indirectness Imprecision Entecavir Placebo Absolute studies considerations (95% CI)

Composite of the proportion of patients with HBV DNA (follow‐up 48 weeks)

1 randomised serious1 no serious no serious serious2 none 20/82 1/41 RR 10 (1.39 to 220 more per 1000 (from 10 CRITICAL trials inconsistency indirectness (24.4%) (2.4%) 71.93) more to 1000 more) LOW

HBV DNA < 50 IU/mL (follow‐up 48 weeks)

1 randomised no serious risk no serious no serious serious2 none 38/82 1/41 RR 19 (2.7 to 439 more per 1000 (from 41 CRITICAL trials of bias inconsistency indirectness (46.3%) (2.4%) 133.53) more to 1000 more) MODERATE

Normalized ALT (follow‐up 48 weeks)

1 randomised no serious risk no serious no serious serious2 none 55/82 9/41 RR 3.06 (1.68 452 more per 1000 (from CRITICAL trials of bias inconsistency indirectness (67.1%) (22%) to 5.55) 149 more to 999 more) MODERATE

1 Unpublished trial, but primary outcome was composite 2 Low sample size, resulting in imprecise results.

38

Appendix B: Drug information

Entecavir

Tablets: 0.5 mg; 1 mg

Oral solution: 0.05 mg/mL

WARNING:

Severe acute exacerbation of hepatitis B, patients co-infected with HIV and HBV, and lactic acidosis and hepatomegaly

 Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely for at least several months after discontinuation. Initiation of anti-hepatitis B therapy may be warranted.  Entecavir is not recommended for patients co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) who are not also receiving highly active antiretroviral therapy (HAART), because of the potential for the development of resistance to HIV nucleoside inhibitors.  Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of inhibitors.

Indications:

Patients with chronic hepatitis B virus infection in adults and children at least 2 years of age with evidence of persistent elevations in serum aminotransferase (ALT or AST) or histologically active disease.

Contraindications

None.

Precautions:

 Severe acute exacerbations of hepatitis B virus infection after discontinuation: Monitor hepatic function closely for at least several months.  Co-infection with HIV: entecavir is not recommended unless the patient is also receiving HAART.  Lactic acidosis and severe hepatomegaly with steatosis: If suspected, treatment should be suspended.

Dosage

 Timing of administration

Entecavir should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).

 Recommended dosage in adults

Compensated liver disease

The recommended dose in nucleoside-inhibitor-treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily. The recommended dose in adults and adolescents with a history of hepatitis B viraemia in while receiving lamivudine or known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once 39

daily.

Decompensated liver disease

The recommended dose in adults is 1 mg once daily.

 Dose adjustment

Paediatric patients

The following table describes the recommended dose for paediatric patients 2 years of age or older and weighting at least 10kg. The oral solution should be used for patients with body weight up to 30 kg.

Table 1: Dosing Schedule for Pediatric Patients Recommended Once-daily Dose of Oral Solution (mL) Body Weight (kg) Treatment-Naïve Lamivudine-Experienced Patientsa Patientsb 10 to 11 3 6 Greater than 11 to 14 4 8 Greater than 14 to 17 5 10 Greater than 17 to 20 6 12 Greater than 20 to 23 7 14 Greater than 23 to 26 8 16 Greater than 26 to 30 9 18 Greater than 30 10 20 a Children with body weight greater than 30 kg should receive 10mL (0.5 mg) of oral solution or one 0.5 mg tablet once daily. b Children with body weight greater than 30 kg should receive 20mL (1.0 mg) of oral solution or one 1 mg tablet once daily.

Renal impairment

Dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) and shown in the following table. The once-daily dosing regimens are preferred.

Table 2: Recommended Dosage in Adult Patients with Renal Impairment Lamivudine-Refractory Creatinine Clearance Usual Dose or Decompensated (mL/min) (0.5 mg) Liver Disease (1mg) 50 or greater 0.5 mg once dailya 1 mg once daily 30 to less than 50 0.25 mg once daily 0.5 mg once daily OR OR 0.5 mg every 48 hours 1 mg every 48 hours 10 to less than 30 0.15 mg once dailya 0.3 mg once dailya OR OR 0.5 mg every 72 hours 1 mg every 72 hours Less than 10 0.05 mg once dailya 0.1mg once dailya Hemodialysis b or CAPD OR OR 0.5 mg every 7 days 1 mg every 7 days a For doses less than 0.5 mg, oral Solution is recommended. b If administered on a hemodialysis day, administer entecavir after the hemodialysis session.

Hepatic impairment

No dosage adjustment is necessary.

Duration of therapy

40

The optimal duration of treatment with entecavir for patients with chronic hepatitis B virus infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.

Adverse effect

Most common adverse reactions (≥3 %, all severity grades) are headache, fatigue, dizziness, and nausea.

Interaction with other medicine

Since entecavir is primarily eliminated by the kidneys, co-administration of entecavir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the co-administered drug. Co-administration of entecavir with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate did not result in significant drug interactions. The effects of co-administration of entecavir with other drugs that are renally eliminated or are known to affect renal function have not been evaluated, and patients should be monitored closely for adverse events when entecavir is co-administered with such drugs.

41