Infectious Diseases: Hepatitis B and C Transmission and Treatment

Introduction

The chronic infections caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) represent major global public health concerns, contributing significantly to morbidity and mortality associated with liver disease, cirrhosis, and hepatocellular carcinoma. HBV is a partially double‑stranded DNA virus that infects hepatocytes and establishes persistent infection through integration of covalently closed circular DNA. HCV, an enveloped positive‑sense RNA virus, exerts its pathogenicity via chronic inflammation and cellular injury, ultimately leading to fibrosis. Historically, both viruses have posed challenges for prevention and treatment; HBV was recognized in the 1960s as a bloodborne pathogen, and HCV was identified in the 1980s following the discovery of non‑A, non‑B hepatitis. The advent of antiviral agents has transformed the therapeutic landscape, yet disparities in access and the emergence of drug resistance remain obstacles. Understanding the mechanisms of transmission, the pharmacologic interventions, and their clinical implications is essential for pharmacy and medical professionals engaged in patient care and public health initiatives.

Learning objectives for this chapter include:

• Clarify the virologic and epidemiologic features of HBV and HCV that influence transmission dynamics.
• Describe the pharmacologic classes employed in the treatment of chronic HBV and HCV, including mechanisms of action and pharmacokinetic considerations.
• Identify factors that affect therapeutic response, such as viral genotype, host genetics, and drug interactions.
• Apply clinical reasoning to optimize treatment regimens in diverse patient populations.
• Recognize public health strategies that reduce transmission and improve outcomes.

Fundamental Principles

Core Concepts and Definitions

HBV is classified as a member of the Hepadnaviridae family, characterized by a unique reverse transcription cycle within the nucleus of infected hepatocytes. HBV surface antigen (HBsAg) presence denotes active infection, while the core antibody (anti‑HBc) indicates prior exposure. HCV belongs to the Flaviviridae family; its single‑stranded RNA genome encodes a polyprotein that is cleaved into structural and non‑structural proteins essential for viral replication. The HCV core antibody (anti‑HCV) confirms exposure, but confirmatory RNA testing is required for active infection.

Key terminology includes:

• Viral load – quantity of viral RNA or DNA copies per milliliter of blood.
• Seroconversion – transition from seronegative to seropositive status following infection.
• Resistance‑associated substitutions (RAS) – mutations that diminish drug efficacy.
• Steady‑state concentration (C_ss) – equilibrium plasma concentration achieved after repeated dosing.

Theoretical Foundations

Transmission of HBV and HCV is predominantly parenteral, involving contact with infected blood or body fluids. The basic reproduction number, R₀, for HBV varies between 5 and 10 among high‑risk groups, whereas HCV R₀ ranges from 1.1 to 2.5 in similar settings. The effective reproductive number, R_e, is modulated by interventions such as vaccination, needle‑exchange programs, and antiviral prophylaxis. Pharmacologically, viral replication kinetics can be approximated by first‑order differential equations. For instance, the decline in viral load during antiviral therapy may be represented as C(t) = C₀ × e^-kt, where k denotes the viral clearance rate constant. The area under the concentration–time curve (AUC) is calculated as AUC = Dose ÷ Clearance, underscoring the importance of renal and hepatic elimination pathways.

Detailed Explanation

Mechanisms of Transmission

HBV and HCV share several risk factors, including intravenous drug use, unsafe sexual practices, perinatal transmission, and exposure to contaminated medical equipment. HBV possesses a higher infectivity per exposure event, attributable to its ability to establish covalently closed circular DNA in hepatocyte nuclei, enabling persistence even when serum viral load is low. HCV, while less infectious per exposure, achieves substantial transmission through repeated low‑level exposures, particularly in healthcare settings with inadequate aseptic techniques.

Mathematical modeling of transmission often incorporates the force of infection (λ), expressed as λ = β × I/N, where β is the transmission coefficient, I denotes infectious individuals, and N represents the total population. Intervention strategies reduce β by decreasing contact rates or by enhancing protective measures such as vaccination for HBV (coverage rate, c). The effective reproduction number then becomes R_e = R₀ × (1 – c), illustrating the impact of immunization coverage on epidemic control.

Pathophysiology and Host–Virus Interactions

HBV infection triggers a robust innate immune response, mediated by interferon‑α and natural killer cells, followed by a chronic adaptive response characterized by T‑cell exhaustion. The persistence of covalently closed circular DNA results in continued viral antigen production, sustaining low‑grade inflammation. HCV infection elicits a similar innate response but is more adept at evading immune detection through rapid mutation and suppression of interferon signaling pathways. Chronic HCV infection leads to continuous hepatocyte turnover, fibrosis, and eventually cirrhosis, with an estimated 1–2% annual progression to hepatocellular carcinoma in untreated individuals.

Pharmacologic Treatment Landscape

For HBV, nucleos(t)ide analogues (NAs) such as entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide constitute first‑line therapy. These agents inhibit reverse transcriptase activity, reducing viral replication and lowering serum HBV DNA levels. Treatment is typically lifelong due to the risk of viral rebound upon discontinuation. Resistance development, particularly with lamivudine, is mitigated by the high genetic barrier of entecavir and tenofovir compounds.

HCV therapy has undergone a paradigm shift with the introduction of direct‑acting antivirals (DAAs), targeting non‑structural proteins NS3/4A protease, NS5A, and NS5B polymerase. Regimens such as sofosbuvir/ledipasvir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir are pan‑genotypic, offering sustained virologic response rates exceeding 95% in most patient populations. Pharmacokinetic profiles of DAAs are optimized for once‑daily dosing, with minimal drug–drug interactions when metabolized via hepatic transporters rather than cytochrome P450 enzymes.

Factors Influencing Treatment Efficacy

• Viral genotype – HCV genotype 1 historically required longer therapy, whereas genotype 3 remains less responsive to some regimens.
• Host genetics – IL28B polymorphisms influence interferon‑based therapy response; these genetic markers are less predictive for DAA regimens.
• Comorbidities – Renal dysfunction limits the use of tenofovir disoproxil fumarate; hepatitis B reactivation risk necessitates monitoring during immunosuppressive therapy.
• Adherence – Sub‑optimal adherence compromises sustained virologic response; patient education and simplified dosing schedules are crucial.

Clinical Significance

Relevance to Drug Therapy

Understanding the pharmacodynamics and pharmacokinetics of HBV and HCV therapies enables clinicians to tailor regimens that maximize efficacy while minimizing toxicity. For HBV, monitoring serum creatinine, bone mineral density, and virologic suppression informs decisions regarding drug choice and duration. In HCV, baseline liver function tests, renal function, and viral genotype guide the selection of DAA combinations and dosing intervals.

Practical Applications

Clinicians routinely manage drug interactions between DAAs and concomitant medications. For example, sofosbuvir/ledipasvir should not be co‑administered with strong CYP3A inducers such as rifampin, due to reduced plasma concentrations and diminished efficacy. Conversely, a patient on warfarin may require dose adjustment when taking ritonavir‑boosted protease inhibitors, which inhibit CYP2C9. These interactions underscore the necessity of comprehensive medication reconciliation prior to initiating antiviral therapy.

Clinical Examples

A 42‑year‑old male with chronic HBV infection and chronic kidney disease stage 3A presents for antiviral therapy. Tenofovir disoproxil fumarate is contraindicated; therefore, tenofovir alafenamide is preferred due to its lower renal burden. Monitoring of serum creatinine and phosphate levels is recommended every 3–6 months. The patient’s adherence is reinforced by a once‑daily dosing schedule and supportive counseling.

In a separate scenario, a 55‑year‑old female with genotype 2 HCV and compensated cirrhosis (Child‑Pugh A) requires therapy. A glecaprevir/pibrentasvir regimen is indicated, offering a 12‑week course with an anticipated sustained virologic response >95%. Baseline hepatitis B surface antigen negativity is confirmed to rule out co‑infection, thereby preventing inadvertent HBV reactivation during DAA therapy.

Clinical Applications/Examples

Case Scenario 1: HBV in a Transplant Recipient

A 30‑year‑old kidney transplant recipient with resolved HBV infection (HBsAg negative, anti‑HBc positive) is scheduled for immunosuppressive therapy. The risk of HBV reactivation is significant; prophylactic tenofovir alafenamide is initiated pre‑transplant. Regular HBV DNA monitoring ensures early detection of breakthrough infection. Should viral rebound occur, escalation to a higher potency NA or addition of interferon may be considered, recognizing the immunosuppressive milieu.

Case Scenario 2: HCV and Hepatocellular Carcinoma Screening

A 68‑year‑old patient with chronic HCV genotype 1a presents for routine follow‑up. Elevated alpha‑fetoprotein (AFP) levels and a 3‑cm hepatic nodule on ultrasound raise suspicion for hepatocellular carcinoma. The patient is started on sofosbuvir/velpatasvir, achieving virologic cure within 12 weeks. Post‑therapy surveillance continues as per guidelines, with imaging every 6 months, given the residual risk of tumor development.

Problem‑Solving Approach to Drug–Drug Interactions

1. Identify all concomitant medications and their metabolic pathways.
2. Consult interaction databases to determine potential CYP or transporter involvement.
3. Adjust antiviral dosing or select alternative agents with minimal overlap.
4. Monitor therapeutic drug levels and clinical response.
5. Re‑evaluate interactions if new medications are introduced.

Summary/Key Points

• HBV and HCV remain leading causes of chronic liver disease; their transmission is predominantly parenteral and influenced by behavioral and healthcare practices.
• HBV treatment relies on nucleos(t)ide analogues with high genetic barriers; lifelong therapy is generally required to prevent relapse.
• HCV therapy has evolved to pan‑genotypic DAAs with superior efficacy, minimal resistance, and simplified regimens.
• Clinical decision‑making must account for viral genotype, host genetics, comorbidities, and potential drug interactions.
• Public health initiatives, including vaccination, harm reduction, and screening, are essential for reducing incidence and improving outcomes.

Clinical pearls include the importance of monitoring renal function when prescribing tenofovir disoproxil fumarate, the necessity of screening for HBV reactivation in immunosuppressed patients, and the utility of once‑daily dosing schedules to enhance adherence. By integrating virologic knowledge with pharmacologic principles, pharmacy and medical professionals can optimize patient care and contribute to broader public health goals.

References

1. Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Philadelphia: Elsevier; 2019.
2. Waller DG, Sampson AP. Medical Pharmacology and Therapeutics. 6th ed. Edinburgh: Elsevier; 2022.
3. Bennett PN, Brown MJ, Sharma P. Clinical Pharmacology. 12th ed. Edinburgh: Elsevier; 2019.
4. Feather A, Randall D, Waterhouse M. Kumar and Clark's Clinical Medicine. 10th ed. London: Elsevier; 2020.
5. Loscalzo J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL. Harrison's Principles of Internal Medicine. 21st ed. New York: McGraw-Hill Education; 2022.
6. Ralston SH, Penman ID, Strachan MWJ, Hobson RP. Davidson's Principles and Practice of Medicine. 24th ed. Edinburgh: Elsevier; 2022.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.