Anti‑Herpes Virus Drugs

Introduction / Overview

Herpes simplex viruses (HSV‑1 and HSV‑2) and varicella‑zoster virus (VZV) are ubiquitous pathogens that establish lifelong latency following primary infection. Reactivation of these viruses can lead to mucocutaneous lesions, ophthalmic disease, neonatal herpes, and, in immunocompromised hosts, severe disseminated infections. Because of their prevalence and potential morbidity, antiviral therapy targeting the herpesviridae family occupies a pivotal role in contemporary clinical practice. A systematic understanding of the pharmacology of anti‑herpes agents is essential for clinicians and pharmacists to optimize therapeutic regimens, anticipate complications, and counsel patients accurately.

Learning objectives for this chapter include:

• Identify the major classes of anti‑herpes agents and their chemical characteristics.
• Describe the pharmacodynamic mechanisms through which nucleoside analogues inhibit viral replication.
• Explain the pharmacokinetic profiles of key drugs and their implications for dosing in special populations.
• Recognize the approved therapeutic indications, off‑label uses, and safety concerns associated with anti‑herpes therapy.
• Apply knowledge of drug interactions and special patient considerations to formulate individualized treatment plans.

Classification

Drug Classes and Categories

Anti‑herpes agents are primarily grouped into two pharmacologic families: nucleoside analogues and non‑nucleoside analogues. Within the nucleoside analogue class, the most widely used agents are acyclovir, valacyclovir, famciclovir, and penciclovir. Non‑nucleoside agents, though less common, include cidofovir and ganciclovir (the latter is also classified as a nucleoside analogue due to its structure but displays unique properties). Recent advances have introduced oral agents such as letermovir for VZV prophylaxis in stem cell transplant recipients, which represent a distinct class of viral DNA polymerase inhibitors.

Chemical Classification

Most anti‑herpes agents share a common structural motif: a nucleoside backbone modified at the 5‑position of the ribose ring or at the base. Acyclovir and penciclovir retain the guanosine base but possess a 2,6‑dimethyl substitution that confers selective activation by viral thymidine kinase. Valacyclovir and famciclovir are prodrugs that release acyclovir and penciclovir, respectively, upon hydrolysis by intestinal esterases. The molecular weight and lipophilicity of these compounds influence absorption and tissue distribution, with acyclovir exhibiting a low log P (−1.5) and famciclovir possessing a modestly higher lipophilicity facilitating better skin penetration.

Mechanism of Action

Pharmacodynamics

The central pharmacologic action of nucleoside analogues lies in their selective incorporation into viral DNA. Following cellular uptake, the agents are phosphorylated by viral thymidine kinase (TK) to the monophosphate form, then by cellular kinases to the active triphosphate. The triphosphate competes with deoxyguanosine triphosphate for incorporation by viral DNA polymerase. Once incorporated, chain termination occurs due to the absence of a 3′‑hydroxyl group, halting further elongation. This mechanism ensures a high degree of specificity for virus‑infected cells, sparing normal host DNA synthesis.

Receptor Interactions

Although not mediated through classical cell surface receptors, the activation of viral TK represents a critical step in drug specificity. TK is induced upon viral entry and is markedly expressed in infected cells, thereby conferring a therapeutic window. In contrast, cellular TK facilitates the phosphorylation of prodrugs, a process that may be less efficient in certain tissues, influencing drug distribution and efficacy.

Molecular and Cellular Mechanisms

In addition to chain termination, some agents exhibit secondary effects. For example, ganciclovir has been shown to interfere with host mitochondrial DNA polymerase γ, contributing to its myelosuppressive profile. Cidofovir, a nucleotide analogue, is phosphorylated by host cellular kinases and directly inhibits viral DNA polymerase through competitive inhibition. Letermovir binds to the DNA polymerase processivity factor UL54, preventing phosphodiester bond formation. These diverse mechanisms highlight the importance of understanding each drug’s unique interaction with viral and host enzymes.

Pharmacokinetics

Absorption

Oral bioavailability varies markedly among agents. Acyclovir demonstrates limited absorption (<20 %) due to poor permeability and efflux by P‑glycoprotein. Valacyclovir overcomes this limitation by exploiting amino acid transporters, achieving oral bioavailability of approximately 55 %. Famciclovir has a bioavailability of ~30 % and is partly converted to penciclovir before systemic absorption. Cidofovir is not absorbed orally and is administered intravenously. Letermovir shows moderate oral absorption (~25 %) and is taken with food to enhance bioavailability.

Distribution

Distribution volumes (V_d) range from 0.8 L/kg for acyclovir to 1.5 L/kg for famciclovir. Penetration into ocular fluid and cerebrospinal fluid is limited for acyclovir but improved for valacyclovir due to higher plasma concentrations. The ability to cross biological barriers is critical for treating herpes zoster ophthalmicus and central nervous system (CNS) manifestations. Tissue distribution is often influenced by the drug’s lipophilicity and protein binding, which is generally low (<10 %) for acyclovir and famciclovir, facilitating rapid clearance.

Metabolism

Metabolism is predominantly limited for acyclovir and famciclovir, with most of the dose excreted unchanged. Valacyclovir undergoes rapid hydrolysis by intestinal esterases to acyclovir. Ganciclovir is metabolized by deoxycytidine kinase to its active form, but also undergoes glucuronidation. Cidofovir is not metabolized significantly. Letermovir is metabolized by CYP3A4 and hydroxylation, generating inactive metabolites.

Excretion

Renal excretion via glomerular filtration is the primary elimination pathway for acyclovir, famciclovir, and valacyclovir. Elimination half‑lives (t_½) are 2.5–3.5 h for acyclovir, 1.5–2 h for famciclovir, and 2–3 h for valacyclovir, necessitating dosing adjustments in renal impairment. Cidofovir and ganciclovir have longer half‑lives (5–10 h) and require renal monitoring. Letermovir has a half‑life of ~12 h, allowing once‑daily dosing for prophylaxis.

Dosing Considerations

Dosing regimens are tailored to the route of administration, severity of disease, and patient characteristics. For uncomplicated genital HSV, valacyclovir 500 mg orally twice daily for 7 days is common, whereas severe disseminated disease may necessitate intravenous acyclovir at 5 mg/kg every 8 h. In patients with creatinine clearance (CrCl) <50 mL/min, dose reduction or extended dosing intervals are recommended to avoid accumulation. Ganciclovir dosing in severe CMV retinitis often begins at 2 mg/kg IV every 12 h, with adjustment based on marrow suppression.

Therapeutic Uses / Clinical Applications

Approved Indications

Acute and suppressive therapy for HSV‑1 and HSV‑2 mucocutaneous disease, HSV‑2 neonatal infection, and recurrent genital herpes is well established for acyclovir, valacyclovir, famciclovir, and penciclovir. VZV infections, including zoster, are treated with acyclovir, valacyclovir, famciclovir, and cidofovir for severe or disseminated disease. Ganciclovir is approved for cytomegalovirus (CMV) retinitis and opportunistic CMV infections in immunocompromised hosts. Letermovir is specifically indicated for VZV prophylaxis in hematopoietic stem cell transplant recipients. Cidofovir is reserved for refractory CMV retinitis and certain adenoviral infections.

Off‑Label Uses

Off‑label applications include the treatment of oral or ocular HSV infections with topical acyclovir or penciclovir preparations. Intramuscular or intrathecal administration of acyclovir has been employed for refractory CNS infections, albeit with limited evidence. Oral valacyclovir and famciclovir are occasionally used in prophylaxis of HSV infection in organ transplant recipients, especially when intravenous therapy is impractical. Ganciclovir and valganciclovir (the oral prodrug) are also used for CMV prophylaxis in transplant and HIV‑positive patients, despite their higher cost.

Adverse Effects

Common Side Effects

Gastrointestinal upset, headache, and mild rash are frequently reported with all nucleoside analogues. Oral formulations may cause nausea or dysgeusia. Topical preparations can induce local irritation or contact dermatitis. These effects are generally self‑limited and may be mitigated by taking the drug with food.

Serious / Rare Adverse Reactions

Nephrotoxicity, manifested as crystalluria or acute tubular necrosis, is a recognized complication of intravenous acyclovir and particularly of cidofovir. Renal impairment is dose‑dependent and can be exacerbated by concomitant nephrotoxic agents (e.g., aminoglycosides, NSAIDs). Hematologic toxicity, including leukopenia, thrombocytopenia, and anemia, is associated with ganciclovir and valganciclovir due to inhibition of host DNA polymerase γ. Neurotoxicity, presenting as paresthesias or seizures, has been reported rarely with high doses of ganciclovir. Cidofovir may trigger hypersensitivity reactions, including fever, rash, and eosinophilia.

Black Box Warnings

Ganciclovir carries a black box warning for bone marrow suppression, especially in patients with pre‑existing cytopenias. Cidofovir is associated with a black box warning for nephrotoxicity and requires baseline renal function assessment. Valacyclovir and famciclovir have no black box warnings but are cautioned in severe renal impairment.

Drug Interactions

Major Drug–Drug Interactions

Valacyclovir and famciclovir may compete with other substrates for P‑glycoprotein, potentially altering the pharmacokinetics of agents such as digoxin or amphotericin B. Ganciclovir can potentiate the myelosuppressive effects of zidovudine and other nucleoside reverse transcriptase inhibitors. Cidofovir has a well‑documented interaction with probenecid, which can reduce its clearance and amplify nephrotoxicity. Letermovir is metabolized by CYP3A4; strong inhibitors (e.g., ketoconazole) can raise its plasma concentration, while strong inducers (e.g., rifampin) may decrease efficacy.

Contraindications

Absolute contraindications include severe renal impairment (CrCl <15 mL/min) for intravenous acyclovir and cidofovir, and hypersensitivity to any component of the formulation. Ganciclovir is contraindicated in patients with severe neutropenia or thrombocytopenia. Valacyclovir and famciclovir should be avoided in patients with known hypersensitivity to the parent nucleoside analogues. Letermovir is contraindicated in patients receiving concomitant strong CYP3A4 inducers.

Special Considerations

Pregnancy / Lactation

Animal studies have not demonstrated teratogenicity for acyclovir, valacyclovir, famciclovir, or penciclovir. Consequently, these agents are generally considered acceptable for use in pregnancy when the benefits outweigh potential risks. Ganciclovir and cidofovir have limited human data but are often reserved for life‑threatening CMV disease in pregnancy. Lactation is not contraindicated; however, excretion of the drug into breast milk is low, and infants typically exhibit no adverse effects when exposed to maternal therapy.

Pediatric / Geriatric Considerations

Children require weight‑based dosing, with adjustments for renal function. Neonates with HSV infection are treated with high‑dose intravenous acyclovir (20 mg/kg every 8 h) for 21 days. Geriatric patients often present with reduced renal clearance; dose reduction or extended dosing intervals are recommended. Age‑related changes in plasma protein binding are minimal for these agents but should be considered when polypharmacy is present.

Renal / Hepatic Impairment

Renal impairment mandates dose adjustment for all nucleoside analogues due to primarily renal excretion. Ganciclovir’s half‑life is prolonged in renal failure, increasing the risk of myelosuppression. Hepatic impairment has limited impact on pharmacokinetics for most agents, except for ganciclovir, which may undergo hepatic metabolism; caution is advised in severe liver disease. Monitoring of serum creatinine and complete blood counts is essential during therapy.

Summary / Key Points

• Anti‑herpes drugs primarily act by selective inhibition of viral DNA polymerase, exploiting viral thymidine kinase for activation.
• Oral prodrugs such as valacyclovir and famciclovir achieve higher bioavailability by engaging intestinal esterases, thereby enhancing therapeutic levels.
• Renal clearance is the dominant elimination pathway; dose adjustments are mandatory in patients with impaired kidney function.
• Nephrotoxicity and myelosuppression are the most significant adverse effects; monitoring renal function and blood counts is essential.
• Drug–drug interactions involving P‑glycoprotein, CYP3A4, and probenecid can alter drug exposure and should be anticipated in polypharmacy settings.
• Special populations—including pregnant patients, neonates, the elderly, and those with hepatic or renal disease—require individualized treatment strategies to balance efficacy and safety.
• Clinical pearls: ensuring adequate hydration before intravenous therapy mitigates nephrotoxicity; using topical preparations for localized lesions reduces systemic exposure; and prophylactic dosing in transplant recipients can prevent severe disseminated disease.

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