Lamivudine

INDICATIONS AND USAGE Lamivudine tablets (HBV) are indicated for the treatment of chronic hepatitis B virus (HBV) infection associated with evidence of hepatitis B viral replication and active liver inflammation [ see Clinical Studies ( 14.1 , 14.2 ) ]. The following points should be considered when initiating therapy with lamivudine tablets (HBV): Due to high rates of resistance development in treated patients, initiation of treatment with lamivudine tablets (HBV) should only be considered when the use of an alternative antiviral agent with a higher genetic barrier to resistance is not available or appropriate. Lamivudine tablets (HBV) have not been evaluated in patients co-infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis delta virus. Lamivudine tablets (HBV) have not been evaluated in liver transplant recipients or in patients with chronic hepatitis B virus infection with decompensated liver disease. Lamivudine tablets (HBV) are a nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of chronic hepatitis B virus (HBV) infection associated with evidence of hepatitis B viral replication and active liver inflammation. (1)

DOSAGE AND ADMINISTRATION Adults: 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily. (2.1) Pediatric Patients Aged 3 Months and Older: Administered twice daily. Dose should be calculated on body weight (kg) and should not exceed 300 mg daily. (2.2) Patients with Renal Impairment: Doses of LAMIVUDINE must be adjusted in accordance with renal function. (2.3) 2.1 Recommended Dosage for Adult Patients The recommended dosage of LAMIVUDINE in HIV-1-infected adults is 300 mg daily, administered as either 150 mg taken orally twice daily or 300 mg taken orally once daily with or without food. If lamivudine is administered to a patient infected with HIV-1 and HBV, the dosage indicated for HIV-1 therapy should be used as part of an appropriate combination regimen [see Warnings and Precautions (5.2) ]. 2.2 Recommended Dosage for Pediatric Patients The recommended dosage of EPIVIR oral solution in HIV-1-infected pediatric patients aged 3 months and older is 4 mg per kg taken orally twice daily (up to a maximum of 300 mg daily), administered in combination with other antiretroviral agents. Once daily dosing in pediatric patients 3 months of age and older in combination with other antiretroviral agents for the treatment of HIV-1 infection. LAMIVUDINE scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Before prescribing LAMIVUDINE scored tablets, pediatric patients should be assessed for the ability to swallow tablets. For patients unable to safely and reliably swallow LAMIVUDINE tablets, the oral solution formulation should be prescribed [see Warnings and Precautions (5.6) ] . The recommended oral dosage of LAMIVUDINE tablets for HIV-l-infected pediatric patients is presented in Table 1. Table 1. Dosing Recommendations for LAMIVUDINE Scored (150-mg) Tablets in Pediatric Patients Weight (kg) Twice-daily Dosing Regimen Using Scored 150-mg Tablet AM Dose PM Dose Total Daily Dose 14 to <20 ½ tablet (75 mg) ½ tablet (75 mg) 150 mg ≥20to <25 ½ tablet (75 mg) 1 tablet (150 mg) 225 mg ≥25 1 tablet (150 mg) 1 tablet (150 mg) 300 mg Additional pediatric use information for patients aged 3 months and above is approved for ViiV Healthcare Company’s EPIVIR® (lamivudine) tablets and oral solution. However, due to ViiV Healthcare Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.3 Patients with Renal Impairment Dosing of LAMIVUDINE is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2 [see Clinical Pharmacology (12.3) ] . Table 2. Adjustment of Dosage of LAMIVUDINE in Adults and Adolescents (Greater than or Equal to 25 kg) in Accordance with Creatinine Clearance Creatinine Clearance (mL/min) Recommended Dosage of ≥50 150 mg twice daily or 300 mg once daily 30-49 150 mg once daily 15-29 150 mg first dose, then 100 mg once daily 5-14 150 mg first dose, then 50 mg once daily <5 50 mg first dose, then 25 mg once daily No additional dosing of LAMIVUDINE is required after routine (4-hour) hemodialysis or peritoneal dialysis. Although there are insufficient data to recommend a specific dose adjustment of LAMIVUDINE in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered. 2.1 Recommended Dosage for Adult Patients The recommended dosage of LAMIVUDINE in HIV-1-infected adults is 300 mg daily, administered as either 150 mg taken orally twice daily or 300 mg taken orally once daily with or without food. If lamivudine is administered to a patient infected with HIV-1 and HBV, the dosage indicated for HIV-1 therapy should be used as part of an appropriate combination regimen [see Warnings and Precautions (5.2) ]. 2.2 Recommended Dosage for Pediatric Patients The recommended dosage of EPIVIR oral solution in HIV-1-infected pediatric patients aged 3 months and older is 4 mg per kg taken orally twice daily (up to a maximum of 300 mg daily), administered in combination with other antiretroviral agents. Once daily dosing in pediatric patients 3 months of age and older in combination with other antiretroviral agents for the treatment of HIV-1 infection. LAMIVUDINE scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Before prescribing LAMIVUDINE scored tablets, pediatric patients should be assessed for the ability to swallow tablets. For patients unable to safely and reliably swallow LAMIVUDINE tablets, the oral solution formulation should be prescribed [see Warnings and Precautions (5.6) ] . The recommended oral dosage of LAMIVUDINE tablets for HIV-l-infected pediatric patients is presented in Table 1. Table 1. Dosing Recommendations for LAMIVUDINE Scored (150-mg) Tablets in Pediatric Patients Weight (kg) Twice-daily Dosing Regimen Using Scored 150-mg Tablet AM Dose PM Dose Total Daily Dose 14 to <20 ½ tablet (75 mg) ½ tablet (75 mg) 150 mg ≥20to <25 ½ tablet (75 mg) 1 tablet (150 mg) 225 mg ≥25 1 tablet (150 mg) 1 tablet (150 mg) 300 mg Additional pediatric use information for patients aged 3 months and above is approved for ViiV Healthcare Company’s EPIVIR® (lamivudine) tablets and oral solution. However, due to ViiV Healthcare Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.3 Patients with Renal Impairment Dosing of LAMIVUDINE is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2 [see Clinical Pharmacology (12.3) ] . Table 2. Adjustment of Dosage of LAMIVUDINE in Adults and Adolescents (Greater than or Equal to 25 kg) in Accordance with Creatinine Clearance Creatinine Clearance (mL/min) Recommended Dosage of ≥50 150 mg twice daily or 300 mg once daily 30-49 150 mg once daily 15-29 150 mg first dose, then 100 mg once daily 5-14 150 mg first dose, then 50 mg once daily <5 50 mg first dose, then 25 mg once daily No additional dosing of LAMIVUDINE is required after routine (4-hour) hemodialysis or peritoneal dialysis. Although there are insufficient data to recommend a specific dose adjustment of LAMIVUDINE in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered.

WARNINGS AND PRECAUTIONS Co-infected HIV-1/HBV Patients: Emergence of lamivudineresistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. (5.2) Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving interferon and ribavirin-based regimens. Monitor for treatment-associated toxicities. Discontinue LAMIVUDINE as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.3) Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. (5.4) Immune reconstitution syndrome and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy. (5.5, 5.7) Lower virologic suppression rates and increased risk of viral resistance were observed in pediatric subjects who received LAMIVUDINE oral solution concomitantly with other antiretroviral oral solutions compared with those who received tablets. (5.6) 5.1 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering LAMIVUDINE to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors. Treatment with LAMIVUDINE should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 5.2 Patients with and Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. Important Differences among Lamivudine-containing Products LAMIVUDINE tablets contain a higher dose of the same active ingredient (lamivudine) than LAMIVUDINE-HBV tablets. LAMIVUDINE-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in LAMIVUDINE-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. If treatment with LAMIVUDINE-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment. If a decision is made to administer lamivudine to patients co-infected with HIV-1 and HBV, LAMIVUDINE tablets, or another product containing the higher dose of lamivudine should be used as part of an appropriate combination regimen. Emergence of Lamivudine-resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV (see full prescribing information for LAMIVUDINE-HBV). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. 5.3 Use with Interferon- and Ribavirin-based Regimens In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients [see Clinical Pharmacology (12.3) ] , hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and LAMIVUDINE should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of LAMIVUDINE should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). See the full prescribing information for interferon and ribavirin. 5.4 Pancreatitis In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, LAMIVUDINE should be used with caution. Treatment with LAMIVUDINE should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1) ] . 5.5 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including LAMIVUDINE. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.6 Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution Pediatric subjects who received LAMIVUDINE oral solution concomitantly with other antiretroviral oral solutions at any time in the ARROW trial had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving LAMIVUDINE tablets [see Clinical Pharmacology (12.3) , Microbiology (12.4) , Clinical Studies (14.2) ]. LAMIVUDINE scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Consider more frequent monitoring of HIV-1 viral load when treating with LAMIVUDINE oral solution. 5.7 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.1 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and othe

CONTRAINDICATIONS Lamivudine tablets (HBV) are contraindicated in patients with a previous hypersensitivity reaction to lamivudine. Lamivudine tablets (HBV) is contraindicated in patients with previous hypersensitivity reaction to lamivudine. ( 4 )

DRUG INTERACTIONS Sorbitol: Coadministration of lamivudine and sorbitol may result in decreased lamivudine concentrations; when possible, avoid chronic coadministration. Consider more frequent monitoring of HBV viral load when chronic coadministration cannot be avoided. ( 7.2 ) 7.1 Drugs Inhibiting Organic Cation Transporters Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim) [see Clinical Pharmacology ( 12.3 )] . No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine. 7.2 Sorbitol Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine [see Clinical Pharmacology ( 12.3 )] . Consider more frequent monitoring of HBV viral load when chronic coadministration cannot be avoided.

ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions ( 5.1 )]. • Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions ( 5.2 )]. • Pancreatitis [see Warnings and Precautions ( 5.3 )]. • Immune reconstitution syndrome [see Warnings and Precautions ( 5.4 )]. • The most common reported adverse reactions (incidence greater than or equal to 15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. ( 6.1 ) • The most common reported adverse reactions (incidence greater than or equal to 15%) in pediatric subjects were fever and cough. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Clinical Trials Experience in Adult Subjects Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety profile of lamivudine in adults is primarily based on 3,568 HIV-1-infected subjects in 7 clinical trials. The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea, and cough. Selected clinical adverse reactions in greater than or equal to 5% of subjects during therapy with lamivudine 150 mg twice daily plus RETROVIR 200 mg 3 times daily for up to 24 weeks are listed in Table 3. Table 3. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) Adverse Reaction LAMIVUDINE 150 mg Twice Daily plus RETROVIR (n = 251) RETROVIR a (n = 230) Body as a Whole Headache 35% 27% Malaise & fatigue 27% 23% Fever or chills 10% 12% Digestive Nausea 33% 29% Diarrhea 18% 22% Nausea & vomiting 13% 12% Anorexia and/or decreased appetite 10% 7% Abdominal pain 9% 11% Abdominal cramps 6% 3% Dyspepsia 5% 5% Nervous System Neuropathy 12% 10% Insomnia & other sleep disorders 11% 7% Dizziness 10% 4% Depressive disorders 9% 4% Respiratory Nasal signs & symptoms 20% 11% Cough 18% 13% Skin Skin rashes 9% 6% Musculoskeletal Musculoskeletal pain 12% 10% Myalgia 8% 6% Arthralgia 5% 5% a Either zidovudine monotherapy or zidovudine in combination with zalcitabine. Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received lamivudine in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007 [see Warnings and Precautions ( 5.4 )]. Lamivudine 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for 48 weeks were similar. Selected laboratory abnormalities observed during therapy are summarized in Table 4. Table 4. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Trial (NUCB3007) Test (Threshold Level) 24-Week Surrogate Endpoint Trials a Clinical Endpoint Trial a LAMIVUDINE plus RETROVIR RETROVIR b LAMIVUDINE plus Current Therapy c Placebo plus Current Therapy c Absolute neutrophil count (<750/mm 3 ) 7.2% 5.4% 15% 13% Hemoglobin (<8.0 g/dL) 2.9% 1.8% 2.2% 3.4% Platelets (<50,000/mm 3 ) 0.4% 1.3% 2.8% 3.8% ALT (>5.0 x ULN) 3.7% 3.6% 3.8% 1.9% AST (>5.0 x ULN) 1.7% 1.8% 4.0% 2.1% Bilirubin (>2.5 x ULN) 0.8% 0.4% ND ND Amylase (>2.0 x ULN) 4.2% 1.5% 2.2% 1.1% a The median duration on study was 12 months. b Either zidovudine monotherapy or zidovudine in combination with zalcitabine. c Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine. ULN = Upper limit of normal. ND = Not done. The frequencies of selected laboratory abnormalities reported in subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar. Clinical Trials Experience in Pediatric Subjects Lamivudine oral solution has been studied in 638 pediatric subjects aged 3 months to 18 years in 3 clinical trials. Selected clinical adverse reactions and physical findings with a greater than or equal to 5% frequency during therapy with lamivudine 4 mg per kg twice daily plus RETROVIR 160 mg per m 2 3 times daily in therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 5. Table 5. Selected Clinical Adverse Reactions and Physical Findings (Greater than or Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG300 Adverse Reaction LAMIVUDINE plus RETROVIR (n = 236) Didanosine (n = 235) Body as a Whole Fever 25% 32% Digestive Hepatomegaly 11% 11% Nausea & vomiting 8% 7% Diarrhea 8% 6% Stomatitis 6% 12% Splenomegaly 5% 8% Respiratory Cough 15% 18% Abnormal breath sounds/wheezing 7% 9% Ear, Nose, and Throat Signs or symptoms of ears a 7% 6% Nasal discharge or congestion 8% 11% Other Skin rashes 12% 14% Lymphadenopathy 9% 11% a Includes pain, discharge, erythema, or swelling of an ear. Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric subjects receiving lamivudine alone or in combination with other antiretroviral agents. In an open-label dose-escalation trial (NUCA2002), 14 subjects (14%) developed pancreatitis while receiving monotherapy with lamivudine. Three of these subjects died of complications of pancreatitis. In a second open-label trial (NUCA2005), 12 subjects (18%) developed pancreatitis. In Trial ACTG300, pancreatitis was not observed in 236 subjects randomized to lamivudine plus RETROVIR. Pancreatitis was observed in 1 subject in this trial who received open-label lamivudine in combination with RETROVIR and ritonavir following discontinuation of didanosine monotherapy [see Warnings and Precautions ( 5.4 )]. Paresthesias and Peripheral Neuropathies: Paresthesias and peripheral neuropathies were reported in 15 subjects (15%) in Trial NUCA2002, 6 subjects (9%) in Trial NUCA2005, and 2 subjects (less than 1%) in Trial ACTG300. Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 6. Table 6. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Pediatric Subjects in Trial ACTG300 Test (Threshold Level) LAMIVUDINE plus RETROVIR Didanosine Absolute neutrophil count (<400/mm 3 ) Hemoglobin (<7.0 g/dL) Platelets (<50,000/mm 3 ) ALT (>10 x ULN) AST (>10 x ULN) Lipase (>2.5 x ULN) Total Amylase (>2.5 x ULN) 8% 4% 1% 1% 2% 3% 3% 3% 2% 3% 3% 4% 3% 3% ULN = Upper limit of normal. Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): The safety of once-daily compared with twice-daily dosing of lamivudine was assessed in the ARROW trial. Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. Neonates: Limited short-term safety information is available from 2 small, uncontrolled trials in South Africa in neonates receiving lamivudine with or without zidovudine for the first week of life following maternal treatment starting at Week 38 or 36 of gestation [see Clinical Pharmacology ( 12.3 )] . Selected adverse

Mechanism of Action Lamivudine is an antiviral agent with activity against HBV [ see Microbiology ( 12.4 ) ] .