Antiviral boosters

Introduction

• Antiviral boosters are pharmacological agents used in combination with certain antiviral drugs to enhance their efficacy, usually by increasing systemic drug exposure and prolonging half-life.

• They work by inhibiting drug-metabolizing enzymes or transporters that would otherwise reduce antiviral concentrations.

• Primarily used in HIV therapy and some HCV regimens to maintain optimal plasma levels of protease inhibitors or polymerase inhibitors.

• Boosters have minimal or no direct antiviral activity; their primary role is pharmacokinetic enhancement.

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Rationale for Use

• Many potent antivirals, especially protease inhibitors, are rapidly metabolized by hepatic enzymes (notably CYP3A4) and cleared from the body.

• Subtherapeutic drug levels can lead to:

  • Loss of efficacy.

  • Viral breakthrough.

  • Development of resistance.

• By co-administering a booster, the metabolism of the main antiviral is slowed, allowing for:

  • Higher plasma concentrations.

  • Less frequent dosing.

  • Improved adherence.

  • Potentially lower doses of the main drug, reducing pill burden and cost.

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Mechanism of Action

CYP3A4 Inhibition

• Most boosters inhibit the cytochrome P450 3A4 enzyme in the liver and intestines, the primary metabolic pathway for many antivirals.

• Results in reduced first-pass metabolism and slower clearance.

P-glycoprotein (P-gp) Inhibition

• Some boosters also inhibit efflux transporters such as P-gp, increasing absorption and bioavailability.

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Main Antiviral Boosters

1. Ritonavir

• Originally developed as an HIV protease inhibitor.

• At full doses: antiviral effect; at low doses: potent CYP3A4 inhibitor with minimal direct antiviral use.

• Also inhibits CYP2D6 and P-gp.

• Used extensively in combination with other protease inhibitors for HIV (e.g., lopinavir, atazanavir, darunavir).

2. Cobicistat

• Designed solely as a pharmacokinetic enhancer without intrinsic antiviral activity.

• Potent CYP3A4 inhibitor and P-gp inhibitor.

• Does not have the metabolic side effects (e.g., lipid abnormalities) seen with ritonavir.

• Used in fixed-dose combinations with HIV drugs such as atazanavir and darunavir, and with elvitegravir (an integrase inhibitor).

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Examples of Antiviral Drugs Requiring Boosting

HIV Protease Inhibitors

• Atazanavir.

• Darunavir.

• Lopinavir (fixed with ritonavir as lopinavir/ritonavir).

HIV Integrase Strand Transfer Inhibitor

• Elvitegravir (requires boosting with cobicistat).

Hepatitis C Virus NS3/4A Protease Inhibitors

• Some early-generation HCV protease inhibitors (e.g., paritaprevir boosted with ritonavir).

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Clinical Advantages of Boosting

• Achieves higher trough concentrations, improving antiviral coverage throughout dosing interval.

• Extends drug half-life, allowing once-daily dosing for many regimens.

• Improves barrier to resistance by maintaining inhibitory concentrations.

• Reduces dosing requirements of primary antiviral drug.

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Limitations and Risks

• Significant potential for drug–drug interactions due to potent CYP3A4 inhibition.

• May increase concentrations of co-administered drugs metabolized by CYP3A4 to toxic levels.

• Side effects from booster itself (e.g., ritonavir: gastrointestinal upset, lipid elevations, taste disturbances).

• Requires careful patient medication review before initiation.

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Adverse Effects

Ritonavir

• Gastrointestinal: nausea, diarrhea, abdominal pain.

• Metabolic: hypertriglyceridemia, hypercholesterolemia, insulin resistance.

• Hepatic: elevated liver enzymes.

• Others: paresthesia, taste changes.

Cobicistat

• Gastrointestinal: nausea, diarrhea.

• Renal: increase in serum creatinine due to inhibition of tubular secretion (no change in actual GFR).

• Generally better tolerated metabolically compared to ritonavir.

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Contraindications

• Concomitant use with drugs highly dependent on CYP3A4 for clearance and where elevated levels cause serious adverse events (e.g., amiodarone, certain benzodiazepines, ergot derivatives, rifampin).

• Known hypersensitivity to the booster or its components.

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Precautions

• Perform a comprehensive drug interaction check before starting therapy.

• Monitor liver function tests periodically.

• In patients with renal impairment on cobicistat: monitor renal function closely.

• Educate patients about potential interaction with over-the-counter medications and herbal supplements (e.g., St. John’s wort reduces efficacy by inducing CYP3A4).

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Drug Interaction Considerations

• Strong CYP3A4 inhibitors: may lead to excessive drug levels (e.g., clarithromycin, ketoconazole).

• Strong CYP3A4 inducers: reduce antiviral and booster concentrations (e.g., rifampin, carbamazepine, phenytoin).

• Drugs with narrow therapeutic index: warfarin, digoxin, certain antiarrhythmics require close monitoring or alternative therapy.

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Fixed-Dose Combinations (FDCs) Including Boosters

HIV

• Darunavir/cobicistat (Prezcobix).

• Atazanavir/cobicistat (Evotaz).

• Elvitegravir/cobicistat/emtricitabine/tenofovir (Genvoya, Stribild).

• Lopinavir/ritonavir (Kaletra).

HCV

• Paritaprevir/ritonavir/ombitasvir ± dasabuvir (Viekira Pak, no longer widely used).

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Special Populations

• Pregnancy: Ritonavir-boosted regimens often preferred due to more data on safety; cobicistat less studied.

• Pediatrics: Dose adjustments required; some FDCs not approved for young children.

• Hepatic impairment: Use with caution; avoid in severe impairment (Child-Pugh C).

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Future Directions

• Development of next-generation boosters with more selective enzyme inhibition and fewer drug–drug interactions.

• Exploration of boosting for long-acting injectable antivirals to extend dosing intervals to months.

• Potential expansion of boosting concept to antivirals in other diseases beyond HIV and HCV.