Pharmacology of Antiretroviral Drugs (HIV)

Introduction/Overview

Human immunodeficiency virus (HIV) remains a major global health challenge, with antiretroviral therapy (ART) transforming a once uniformly fatal disease into a manageable chronic condition. The advent of highly active antiretroviral therapy (HAART) in the mid‑1990s revolutionised care, achieving sustained viral suppression, immune restoration, and significant reductions in morbidity and mortality. Current treatment guidelines recommend combination regimens comprising at least three antiretroviral agents from two distinct drug classes, tailored to individual virologic, immunologic, and comorbidity profiles. The evolving pharmacologic landscape—encompassing novel agents with improved potency, safety, and pharmacokinetic properties—continues to refine therapeutic strategies.

For pharmacy and medical students, a comprehensive understanding of antiretroviral pharmacology is essential. Mastery of drug mechanisms, kinetics, therapeutic uses, adverse effect profiles, and interaction potential informs clinical decision‑making, patient counselling, and medication management. The following monograph is structured to provide a systematic overview, integrating current evidence while emphasizing clinical relevance.

Learning objectives:

• Describe the major classes of antiretroviral drugs and their chemical characteristics.
• Explain the pharmacodynamic mechanisms underlying viral replication inhibition.
• Summarise key pharmacokinetic parameters that guide dosing and monitoring.
• Identify therapeutic indications, off‑label uses, and contraindications for antiretroviral agents.
• Recognise common and serious adverse reactions, as well as pivotal drug‑drug interactions.
• Apply special considerations for pregnancy, lactation, pediatrics, geriatrics, and organ impairment.

Classification

Drug Classes and Categories

Antiretroviral agents are grouped into six principal classes, each targeting a distinct stage of the HIV life cycle:

1. Reverse Transcriptase Inhibitors (RTIs)
   • Nucleoside / Nucleotide Reverse Transcriptase Inhibitors (NRTIs/NtRTIs): e.g., zidovudine, lamivudine, tenofovir alafenamide.
   • Non‑nucleoside Reverse Transcriptase Inhibitors (NNRTIs): e.g., efavirenz, rilpivirine.
2. Protease Inhibitors (PIs): e.g., lopinavir/ritonavir, darunavir, atazanavir.
3. Integrase Strand Transfer Inhibitors (INSTIs): e.g., raltegravir, dolutegravir, bictegravir.
4. Entry / Fusion Inhibitors
   • Fusion inhibitors: e.g., enfuvirtide.
   • CCR5 coreceptor antagonists: e.g., maraviroc.
5. Phosphonoformate (Phosphonate) Analogs: e.g., tenofovir disoproxil fumarate.
6. Other Agents / Novel Mechanisms: e.g., integrase inhibitors with distinct pharmacology, capsid inhibitors under investigation.

Chemical Classification

RTIs are structurally similar to natural nucleosides, facilitating incorporation into viral DNA and subsequent chain termination. NNRTIs possess a hydrophobic pocket adjacent to the catalytic site of reverse transcriptase, inducing allosteric inhibition. PIs are peptidomimetic molecules that mimic the transition state of protease cleavage. INSTIs chelate the divalent metal ions essential for strand transfer. Fusion inhibitors are short peptides that destabilise the viral envelope. CCR5 antagonists are small molecules that occupy the coreceptor binding site, preventing gp120‑gp41 interaction.

Mechanism of Action

Reverse Transcriptase Inhibitors

NRTIs and NtRTIs are phosphorylated intracellularly to their active triphosphate forms, competing with natural deoxynucleoside triphosphates for incorporation into nascent viral DNA. The resulting chain termination occurs either by immediate termination (e.g., zidovudine) or delayed termination (e.g., lamivudine). NNRTIs bind to a hydrophobic pocket near the active site of reverse transcriptase, inducing a conformational change that reduces enzymatic activity. Binding is non‑competitive and results in rapid viral replication inhibition.

Protease Inhibitors

HIV protease cleaves the Gag and Gag‑Pol polyproteins into functional viral proteins. PIs occupy the catalytic cleft, blocking substrate access. The inhibition is competitive and reversible, leading to the production of immature, non‑infectious virions. Co‑administration with ritonavir or other pharmacokinetic enhancers increases systemic exposure by inhibiting CYP3A4‑mediated metabolism.

Integrase Strand Transfer Inhibitors

INSTIs chelate the two divalent metal ions (Mg²⁺/Mn²⁺) in the active site of integrase, preventing the strand transfer step of proviral DNA integration into host chromatin. The inhibition is non‑competitive with respect to the viral cDNA substrate. As a result, replication is halted early in the viral life cycle, reducing the pool of integrated proviruses.

Entry / Fusion Inhibitors

Enfuvirtide binds to the heptad repeat region of gp41, blocking the conformational changes required for membrane fusion. Maraviroc binds to the CCR5 coreceptor on target cells, inducing a conformational shift that prevents HIV gp120 engagement. Both mechanisms prevent viral entry into host cells, thereby halting infection at the earliest stage.

Pharmacokinetics

Absorption

Oral bioavailability varies across classes. NRTIs such as abacavir and lamivudine have high absolute bioavailability (>80 %). NNRTIs exhibit moderate to high oral absorption; efavirenz shows dose‑dependent absorption with a C_max that peaks at 2–4 h post‑dose. PIs generally have lower oral bioavailability due to first‑pass metabolism, necessitating boosting with ritonavir or cobicistat. INSTIs, notably dolutegravir, have excellent oral absorption (≈ 90 %) and are not significantly affected by food.

Distribution

Volume of distribution (V_d) ranges from moderate to large. Tenofovir disoproxil fumarate distributes extensively into tissues (V_d ≈ 400 L). Raltegravir has a V_d of ~1.3 L/kg. Lipophilic agents such as ritonavir achieve high plasma protein binding (~95 %) and penetrate sanctuary sites, including the central nervous system, albeit variably. Tissue penetration is clinically relevant for virologic suppression in reservoirs.

Metabolism

Metabolic pathways differ by class. NRTIs are largely non‑metabolised; they undergo intracellular phosphorylation. NNRTIs are metabolised primarily by CYP3A4 (e.g., efavirenz) and CYP2B6 (e.g., efavirenz, nevirapine). PIs are extensively metabolised by CYP3A4; ritonavir acts as a potent CYP3A4 inhibitor. INSTIs are metabolised by UGT1A1 (dolutegravir) and CYP3A4 (bictegravir). Enfuvirtide is degraded by peptidases and is not metabolised hepatically. Maraviroc is metabolised by CYP3A4 and CYP2D6.

Excretion

Renal excretion dominates for many NRTIs (e.g., tenofovir, abacavir). Tenofovir disoproxil fumarate is cleared via glomerular filtration and tubular secretion (P‑gp, MATE1). NNRTIs and PIs are excreted via bile and feces, with negligible renal clearance. INSTIs exhibit mixed routes: dolutegravir is excreted renally (≈ 50 %) and hepatically (≈ 30 %). Enfuvirtide is eliminated by proteolytic catabolism, with no active metabolites.

Half‑Life and Dosing Considerations

Half‑life (t_1/2) influences dosing frequency. NRTIs such as zidovudine have t_1/2 ≈ 1 h, requiring twice‑daily dosing; tenofovir alafenamide has t_1/2 ≈ 17 h, enabling once‑daily administration. NNRTIs vary from 12–24 h (efavirenz) to 48 h (nevirapine). PIs have t_1/2 ≈ 1–2 h without boosting; boosted forms extend to 8–12 h. INSTIs generally have t_1/2 ≈ 12–16 h, allowing once‑daily dosing. Dose adjustments are required in renal or hepatic impairment, depending on the drug’s excretion pathway.

Therapeutic Uses / Clinical Applications

Approved Indications

All antiretroviral agents are indicated for the treatment of HIV‑1 infection, either as part of initial ART regimens or for maintenance therapy following virologic suppression. Combination therapy remains the standard to prevent resistance development. Specific class indications may be guided by resistance patterns, comorbidities, and patient preferences.

Off‑Label Uses

Certain antiretroviral agents are employed off‑label for other viral infections. For example, ribavirin (a nucleoside analogue) is used for hepatitis C and chronic viral respiratory infections. However, within HIV therapy, off‑label use is limited to compassionate use of investigational agents or adjunctive therapy in co‑infected patients (e.g., HIV/HCV co‑infection). Off‑label application of maraviroc has been explored in treatment‑naïve patients with CCR5‑tropic virus, but routine practice remains confined to approved regimens.

Adverse Effects

Common Side Effects

Adverse events vary by class. NRTIs may cause mitochondrial toxicity, manifested as lactic acidosis, hepatic steatosis, and peripheral neuropathy. NNRTIs commonly precipitate neuropsychiatric disorders (e.g., rash, vivid dreams) and hepatotoxicity. PIs are associated with hyperlipidaemia, insulin resistance, and gastrointestinal intolerance. INSTIs are generally well tolerated; dolutegravir may cause mild headache and insomnia, while bictegravir can induce dizziness. Fusion inhibitors require subcutaneous injection, causing injection site reactions. CCR5 antagonists may provoke nasal congestion and cough.

Serious / Rare Adverse Reactions

Serious complications include hypersensitivity reactions (e.g., abacavir hypersensitivity), severe cutaneous adverse reactions (e.g., Stevens‑Johnson syndrome with nevirapine), and pancreatitis (notably with abacavir). PIs may precipitate drug‑induced pancreatitis and significant hepatic dysfunction. INSTI‑associated neuropsychiatric events, although rare, may require therapy discontinuation. Enfuvirtide is associated with rare anaphylactic reactions at the injection site.

Black Box Warnings

Abacavir carries a black‑box warning for hypersensitivity, necessitating HLA‑B*5701 screening prior to initiation. Efavirenz has a black‑box warning regarding neuropsychiatric toxicity, particularly in pregnancy. Some PIs, such as ritonavir, are flagged for serious hepatic injury in patients with pre‑existing liver disease.

Drug Interactions

Major Drug‑Drug Interactions

Pharmacokinetic interactions predominate. NNRTIs induce CYP3A4, potentially reducing the efficacy of concomitant drugs metabolised by this pathway (e.g., statins, oral contraceptives). PIs, especially when boosted, inhibit CYP3A4, elevating plasma concentrations of co‑administered medications and increasing toxicity risk. INSTIs are moderate inhibitors of CYP3A4 (bictegravir) and may interact with hormonal contraceptives. Enfuvirtide is not subject to hepatic metabolism, but its peptide nature may compete for protease‑dependent drug transporters. Maraviroc is a potent inhibitor of CYP2D6 and a substrate of CYP3A4.

Contraindications

Concomitant use of certain antiretroviral agents is contraindicated with specific drugs. For instance, abacavir should not be combined with carbamazepine due to the risk of hypersensitivity. NNRTIs are contraindicated with drugs requiring activation by CYP2B6 (e.g., certain antipsychotics). PIs require avoidance of drugs that induce CYP3A4 (e.g., rifampin) without appropriate dose adjustment. INSTIs should be avoided with potent CYP3A4 inducers (e.g., phenytoin) unless therapeutic drug monitoring is available. Maraviroc contraindicates use with strong CYP3A4 inducers as well.

Special Considerations

Use in Pregnancy / Lactation

HIV treatment is essential during pregnancy to prevent vertical transmission. Preferred regimens include dolutegravir, tenofovir disoproxil fumarate, and emtricitabine, owing to favourable safety profiles. Efavirenz remains an option, but recent data suggest potential teratogenicity. Breastfeeding is generally safe with most antiretrovirals; however, drug excretion into breast milk must be considered. Tenofovir disoproxil fumarate is excreted in breast milk but at low concentrations, and infant exposure is minimal.

Pediatric / Geriatric Considerations

Pediatric dosing requires weight‑based calculations and consideration of developmental pharmacokinetics. Many pediatric formulations are available in liquid or chewable forms. Geriatric patients often present with polypharmacy, increasing interaction risk; dose adjustments based on renal clearance are critical for NRTIs and INSTIs. Age‑related changes in hepatic metabolism may alter drug exposure, necessitating careful monitoring.

Renal / Hepatic Impairment

Renal dysfunction necessitates dose reductions for NRTIs with significant renal excretion (e.g., tenofovir alafenamide, abacavir). Tenofovir disoproxil fumarate is contraindicated in creatinine clearance <30 mL/min. Hepatic impairment impacts PIs and NNRTIs; for example, ritonavir is contraindicated in severe hepatic disease (Child‑Pugh C). INSTIs require monitoring of liver enzymes during initiation, particularly in patients with pre‑existing hepatic disease.

Summary / Key Points

• Antiretroviral therapy relies on multi‑class regimens that inhibit distinct stages of the HIV life cycle.
• Pharmacokinetic properties—absorption, distribution, metabolism, excretion—dictate dosing schedules and interaction potential.
• Common adverse reactions include metabolic disturbances and neuropsychiatric effects; serious events necessitate vigilance and prompt management.
• Drug–drug interactions are frequent; routine review of concomitant medications is essential to prevent therapeutic failure or toxicity.
• Special populations—pregnant women, infants, elderly, and patients with organ impairment—require tailored regimens and dose adjustments.
• Ongoing research continues to expand the antiretroviral armamentarium, emphasizing the importance of staying current with evolving evidence.

Incorporating these pharmacologic principles into clinical practice enhances therapeutic outcomes, mitigates adverse events, and supports the overarching goal of sustained viral suppression in individuals living with HIV.

References

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