Pharmacology of Antiretroviral Drugs (HIV)

Introduction/Overview

The management of human immunodeficiency virus (HIV) infection represents one of the most significant achievements in modern therapeutics. The development of antiretroviral drugs has transformed HIV from a uniformly fatal diagnosis to a manageable chronic condition. The pharmacology of these agents is complex, involving multiple drug classes that target distinct stages of the viral replication cycle. A thorough understanding of their mechanisms, pharmacokinetics, and adverse effect profiles is essential for optimizing therapy, preventing resistance, and managing comorbidities. This chapter provides a systematic examination of the pharmacology underpinning contemporary antiretroviral therapy (ART).

Learning Objectives

• Classify the major antiretroviral drug families according to their molecular target within the HIV replication cycle.
• Explain the detailed pharmacodynamic mechanisms by which each drug class inhibits viral replication.
• Analyze the pharmacokinetic properties, including absorption, distribution, metabolism, and excretion, that influence the dosing and administration of key antiretroviral agents.
• Evaluate the common and serious adverse effects, drug interactions, and special population considerations associated with antiretroviral therapy.
• Integrate pharmacological principles to construct rational, guideline-concordant regimens for the treatment and prevention of HIV infection.

Classification

Antiretroviral drugs are categorized primarily by their mechanism of action and their specific molecular target in the HIV-1 replication cycle. This classification forms the basis for constructing combination regimens, which typically consist of agents from at least two different classes to maximize efficacy and suppress the emergence of resistant viral strains.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

NRTIs are analogues of endogenous nucleosides or nucleotides. Key agents include abacavir, emtricitabine, lamivudine, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and zidovudine. They require intracellular phosphorylation to their active triphosphate forms.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

NNRTIs are a chemically diverse group of compounds that bind non-competitively to a hydrophobic pocket on the reverse transcriptase enzyme. This class includes doravirine, efavirenz, etravirine, nevirapine, and rilpivirine.

Protease Inhibitors (PIs)

PIs are peptidomimetic compounds that inhibit the viral aspartyl protease enzyme. Commonly used agents are atazanavir, darunavir, and lopinavir, typically administered with a pharmacokinetic enhancer (cobicistat or ritonavir).

Integrase Strand Transfer Inhibitors (INSTIs)

INSTIs block the integrase enzyme, preventing the insertion of viral DNA into the host genome. First-line agents include bictegravir, dolutegravir, and raltegravir.

Entry Inhibitors

This class is subdivided based on the specific step of viral entry that is inhibited.

• Fusion Inhibitors: Enfuvirtide, which binds to gp41 and prevents fusion of viral and cellular membranes.
• CCR5 Antagonists: Maraviroc, which blocks the CCR5 co-receptor on the host CD4+ T-cell.
• Post-attachment Inhibitors: Ibalizumab-uiyk, a monoclonal antibody that binds CD4 and inhibits conformational changes required for entry.

Pharmacokinetic Enhancers

Although not antiviral themselves, cobicistat and low-dose ritonavir are crucial components of many regimens. They inhibit cytochrome P450 3A4 (CYP3A4) and drug transporters, thereby boosting the plasma concentrations of co-administered PIs and some other agents.

Mechanism of Action

The efficacy of antiretroviral therapy relies on the simultaneous inhibition of multiple, sequential steps in the HIV replication cycle. Each drug class exerts its effect at a specific, vulnerable point in this process.

Inhibition of Reverse Transcription

Reverse transcription, the conversion of viral RNA into double-stranded DNA, is a critical early step catalyzed by the reverse transcriptase enzyme. Two distinct pharmacological strategies target this process.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

NRTIs are prodrugs that must be transported into cells and phosphorylated by host cell kinases to their active 5’-triphosphate (or diphosphate for tenofovir) forms. The active moiety competes with natural deoxynucleoside triphosphates (dNTPs) for incorporation into the growing viral DNA chain by reverse transcriptase. Once incorporated, they act as chain terminators because they lack a 3’-hydroxyl group on their deoxyribose sugar moiety. This absence prevents the formation of the phosphodiester bond necessary for the addition of the next nucleotide, resulting in premature termination of DNA synthesis. The selectivity for viral over host polymerases is relative, not absolute, which contributes to some of their mitochondrial toxicities.

Non-Nucleoside Reverse Transcriptase Inhibitors

NNRTIs inhibit reverse transcriptase through a fundamentally different, allosteric mechanism. They bind to a specific, hydrophobic pocket (the NNRTI-binding pocket) located near the enzyme’s active site. This binding induces a conformational change in the enzyme that distorts the catalytic site, dramatically reducing its polymerase activity. The inhibition is non-competitive with respect to nucleoside substrates. A single amino acid mutation in the binding pocket can confer high-level cross-resistance within the class, though newer agents like doravirine and etravirine have higher genetic barriers to resistance.

Inhibition of Viral Integration

Integrase Strand Transfer Inhibitors

Following reverse transcription, the viral cDNA is transported into the nucleus as part of a pre-integration complex. The viral integrase enzyme performs a two-step reaction: 3’-processing, which cleaves two nucleotides from each 3’ end of the viral DNA, and strand transfer, where the processed ends are covalently ligated into the host chromosomal DNA. INSTIs selectively inhibit the strand transfer step. They chelate the divalent metal ions (Mg²⁺ or Mn²⁺) within the integrase active site, forming a stable drug-viral DNA-integrase complex that blocks the strand transfer reaction. This prevents the stable integration of the viral genome, halting the establishment of a permanent provirus.

Inhibition of Viral Proteolysis

Protease Inhibitors

After integration and transcription, viral polyproteins (Gag and Gag-Pol) are synthesized. The viral protease enzyme is responsible for cleaving these polyproteins into individual, functional structural proteins and enzymes (e.g., matrix, capsid, nucleocapsid, reverse transcriptase, integrase). PIs are designed to mimic the natural peptide substrate’s transition state. They bind with high affinity to the protease’s active site, competitively inhibiting its activity. This results in the production of immature, non-infectious viral particles. The use of a pharmacokinetic enhancer (ritonavir or cobicistat) is often necessary to achieve and maintain therapeutic plasma concentrations throughout the dosing interval due to extensive first-pass metabolism.

Inhibition of Viral Entry

Entry inhibitors block the multi-step process by which HIV attaches to and fuses with the host CD4+ cell.

Fusion Inhibitors

Enfuvirtide is a synthetic 36-amino acid peptide that mimics a region of the viral transmembrane glycoprotein gp41. It binds to the N-terminal heptad repeat region of gp41, preventing the formation of a six-helix bundle structure that is essential for bringing the viral and cellular membranes into close proximity for fusion.

CCR5 Antagonists

Maraviroc is a small molecule that acts as an allosteric antagonist of the CCR5 chemokine receptor, one of the two major co-receptors (alongside CXCR4) used by HIV for entry. It binds to a transmembrane pocket of CCR5, inducing conformational changes that prevent the binding of the viral envelope glycoprotein gp120, thereby blocking viral entry. Its use requires prior tropism testing to confirm the presence of CCR5-tropic virus.

Post-attachment Inhibitors

Ibalizumab-uiyk is a humanized monoclonal antibody that binds to domain 2 of the CD4 receptor. This binding does not block HIV attachment but inhibits the post-attachment conformational changes in the viral envelope and receptor that are necessary for fusion and entry.

Pharmacokinetics

The pharmacokinetic profiles of antiretroviral drugs are highly variable and critically important for dosing frequency, food requirements, and the potential for drug interactions. Therapeutic success depends on maintaining drug concentrations above the inhibitory concentration for the specific viral strain throughout the dosing interval.

Absorption

Oral bioavailability varies widely. Most NRTIs and NNRTIs have good bioavailability (≥80%), though food can significantly impact the absorption of some agents. For instance, the absorption of rilpivirine and etravirine is markedly enhanced by a meal, while the bioavailability of dolutegravir is reduced by polyvalent cation-containing supplements. Protease inhibitors generally have poor and variable oral bioavailability, necessitating pharmacokinetic enhancement. The absorption of tenofovir alafenamide (TAF) is more efficient than its predecessor TDF, leading to higher intracellular concentrations of the active tenofovir-diphosphate at much lower plasma tenofovir levels.

Distribution

Distribution into sanctuary sites, such as the central nervous system (CNS) and genital tract, is a key consideration for preventing compartment-specific viral replication. Agents vary in their ability to cross the blood-brain barrier. Zidovudine, abacavir, nevirapine, and dolutegravir achieve higher CNS penetration compared to tenofovir, most PIs, and raltegravir. Volume of distribution is generally high for lipophilic drugs like efavirenz and PIs. Protein binding is extensive for PIs and rilpivirine (>95%), which can limit their removal by dialysis and influence drug interaction potential.

Metabolism

Metabolic pathways are a major source of drug interactions. NNRTIs and PIs are primarily metabolized by the hepatic cytochrome P450 system, predominantly CYP3A4. Efavirenz is both an inducer and inhibitor of CYP enzymes, while etravirine and rilpivirine are less potent inducers. Protease inhibitors are primarily metabolized by CYP3A4 and are also potent inhibitors of this enzyme, which is the basis for their use as pharmacokinetic enhancers. NRTIs are generally not metabolized by CYP enzymes; they undergo phosphorylation intracellularly and may be substrates for renal tubular secretion. INSTIs like dolutegravir and bictegravir are metabolized via UDP-glucuronosyltransferase (UGT) 1A1 and are also substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Excretion

Renal and hepatic excretion pathways determine dosing adjustments in organ impairment. Most NRTIs (e.g., tenofovir, emtricitabine, lamivudine) are eliminated renally, primarily via glomerular filtration and active tubular secretion, requiring dose adjustment in renal impairment. In contrast, abacavir is metabolized hepatically by alcohol dehydrogenase and glucuronidation. NNRTIs, PIs, and INSTIs are largely eliminated via hepatic metabolism and biliary excretion, with minimal renal elimination of unchanged drug. Their pharmacokinetics may be altered in severe hepatic impairment.

Half-life and Dosing Considerations

Half-life influences dosing frequency and the forgiveness of the regimen regarding missed doses. Drugs with long half-lives, such as efavirenz (40-55 hours), rilpivirine (~50 hours), and dolutegravir (~14 hours), support once-daily dosing. The very long intracellular half-lives of some NRTI triphosphates (e.g., emtricitabine-triphosphate > 24 hours) also contribute to once-daily dosing. Raltegravir has a shorter plasma half-life (~9 hours), necessitating twice-daily dosing unless using the higher-dose once-daily formulation. The combination of a long-acting NNRTI (rilpivirine) and a long-acting INSTI (cabotegravir) has enabled the development of complete long-acting injectable regimens administered monthly or every two months.

Therapeutic Uses/Clinical Applications

Antiretroviral drugs are used in specific combinations to treat established HIV-1 infection and to prevent transmission in high-risk individuals.

Treatment of HIV-1 Infection

The cornerstone of HIV management is combination antiretroviral therapy (cART), historically termed highly active antiretroviral therapy (HAART). Current guidelines recommend initiating therapy in all individuals with HIV, regardless of CD4 count. Preferred regimens typically consist of two NRTIs as a backbone plus a third agent from a different class, most commonly an INSTI. Examples include bictegravir/emtricitabine/tenofovir alafenamide (a single-tablet regimen), dolutegravir plus lamivudine (a two-drug regimen), or dolutegravir/abacavir/lamivudine (provided HLA-B*5701 testing is negative). The goal is to achieve and maintain virologic suppression, defined as a plasma HIV RNA level below the limit of detection of available assays (typically < 50 copies/mL).

Prevention of Mother-to-Child Transmission

ART administered during pregnancy, delivery, and to the newborn postpartum can reduce the risk of perinatal HIV transmission to less than 1%. Regimens must be effective and safe for both the pregnant person and the fetus. Preferred regimens often include a dual-NRTI backbone with an INSTI like dolutegravir or a boosted PI.

Post-Exposure Prophylaxis

Antiretroviral drugs are used for post-exposure prophylaxis (PEP) following occupational or non-occupational (e.g., sexual, needle-sharing) exposure to HIV. A 28-day course of a three-drug regimen, initiated as soon as possible (ideally within 2 hours and not beyond 72 hours post-exposure), is standard.

Pre-Exposure Prophylaxis

Pre-exposure prophylaxis (PrEP) involves the ongoing use of antiretroviral medication by HIV-negative individuals at substantial risk of acquiring HIV. Approved regimens include daily oral co-formulated emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), emtricitabine/tenofovir alafenamide (FTC/TAF) for specific populations, and event-driven (2-1-1) dosing with FTC/TDF for men who have sex with men. Long-acting injectable cabotegravir administered every two months is also an approved option for PrEP.

Treatment-Experienced Patients

For patients with virologic failure on a regimen, therapy is guided by resistance testing (genotypic and/or phenotypic). Salvage regimens may incorporate newer agents with high barriers to resistance (e.g., dolutegravir, darunavir), drugs from newer classes (e.g., ibalizumab, fostemsavir), or agents active against resistant strains (e.g., etravirine for NNRTI-resistant virus).

Adverse Effects

Adverse effects range from mild, transient symptoms to severe, life-threatening toxicities. They are a common cause of non-adherence and regimen discontinuation.

Class-Specific Adverse Effects

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

• Mitochondrial Toxicity: Due to inhibition of human mitochondrial DNA polymerase-γ, leading to lactic acidosis, hepatic steatosis, peripheral neuropathy, myopathy, and lipoatrophy. This is more commonly associated with older NRTIs like stavudine and didanosine.
• Bone and Renal Effects (Tenofovir Disoproxil Fumarate): TDF is associated with proximal renal tubulopathy (Fanconi syndrome), reduced bone mineral density, and increased serum creatinine. Tenofovir alafenamide (TAF) has a markedly improved renal and bone safety profile.
• Hypersensitivity Reaction (Abacavir): A potentially fatal multi-organ hypersensitivity reaction is strongly associated with the HLA-B*5701 allele. Screening for this allele is mandatory prior to initiation.

Non-Nucleoside Reverse Transcriptase Inhibitors

• CNS Effects (Efavirenz): Dizziness, insomnia, abnormal dreams, impaired concentration, and rarely severe psychiatric symptoms (depression, suicidal ideation). These often subside after several weeks.
• Rash: Maculopapular rash is common, particularly with nevirapine, which can rarely progress to Stevens-Johnson syndrome or toxic epidermal necrolysis.
• Hepatotoxicity: Elevated transaminases, particularly with nevirapine, which carries a black box warning for severe, potentially fatal hepatotoxicity.

Protease Inhibitors

• Metabolic Disturbances: Insulin resistance, hyperglycemia, new-onset or exacerbation of diabetes mellitus, and dyslipidemia (elevated triglycerides and LDL cholesterol).
• Gastrointestinal Intolerance: Nausea, diarrhea, and abdominal discomfort are frequent, especially early in therapy.
• Cardiovascular Risk: May be associated with an increased risk of myocardial infarction, linked to metabolic effects.

Integrase Strand Transfer Inhibitors

• Insomnia and Headache: Common, usually mild and transient, with dolutegravir and raltegravir.
• Weight Gain: Some INSTIs, particularly dolutegravir and bictegravir, have been associated with greater weight gain compared to other drug classes, though the mechanism is not fully understood.
• Hypersensitivity Reactions: Rare but serious reactions, including rash and organ dysfunction, have been reported with dolutegravir and raltegravir.

Black Box Warnings

Several antiretrovirals carry black box warnings, the strongest FDA-mandated safety alert. These include:

• Abacavir: Risk of fatal hypersensitivity reactions in HLA-B*5701-positive patients.
• Nevirapine: Risk of severe, life-threatening hepatotoxicity and skin reactions.
• Maraviroc: Risk of hepatotoxicity with allergic-type features.
• Enfuvirtide: Increased rate of bacterial pneumonia.

Drug Interactions

Drug interactions are a paramount concern in antiretroviral therapy due to the narrow therapeutic index of many agents and their complex effects on drug-metabolizing enzymes and transporters.

Pharmacokinetic Interactions

Enzyme Inhibition and Induction

Protease inhibitors (especially ritonavir and cobicistat) are potent inhibitors of CYP3A4. They can dramatically increase plasma levels of co-administered drugs that are substrates of this enzyme, such as certain statins (simvastatin, lovastatin), sedatives (midazolam, triazolam), and ergot alkaloids, potentially leading to toxicity. Conversely, efavirenz and nevirapine are inducers of CYP3A4 and other enzymes, potentially reducing the efficacy of co-administered drugs like oral contraceptives, methadone, and certain antifungals. Doravirine and rilpivirine have minimal inducing effects.

Transporter-Based Interactions

Tenofovir (both TDF and TAF) is a substrate for renal organic anion transporters (OATs). Co-administration with drugs that inhibit these transporters, such as high-dose or multiple NSAIDs, may increase tenofovir plasma levels and the risk of nephrotoxicity. Many antiretrovirals are substrates or inhibitors of P-glycoprotein (P-gp) and BCRP.

Absorption Interactions

Polyvalent cations (Ca²⁺, Mg²⁺, Al³⁺, Fe^2+/3+) found in antacids, mineral supplements, and buffered medications can chelate INSTIs (raltegravir, dolutegravir, bictegravir) in the gut, significantly reducing their absorption. Administration should be separated by several hours.

Pharmacodynamic Interactions

Additive toxicities can occur. For example, combining two NRTIs with mitochondrial toxicity potential (e.g., stavudine and didanosine) is contraindicated due to an excessive risk of lactic acidosis and pancreatitis. Concurrent use of nephrotoxic agents (e.g., aminoglycosides, amphotericin B) with tenofovir disoproxil fumarate may increase renal injury risk.

Major Contraindications

• Abacavir in patients positive for HLA-B*5701.
• Maraviroc in patients with only CXCR4-tropic or dual/mixed-tropic virus (must have CCR5-tropic virus only).
• Simvastatin and lovastatin with potent CYP3A4 inhibitors like ritonavir or cobicistat (risk of rhabdomyolysis).
• Ergot derivatives, pimozide, and certain sedatives with potent CYP3A4 inhibitors.
• Rifampin, a potent enzyme inducer, with most PIs, NNRTIs (except efavirenz at a higher dose), and INSTIs (except dolutegravir at a doubled dose), as it can cause subtherapeutic antiretroviral levels.

Special Considerations

The pharmacological management of HIV requires careful adjustment for specific patient populations and comorbidities.

Pregnancy and Lactation

The goal is to maintain virologic suppression while minimizing fetal risk. Dolutegravir is now a preferred INSTI due to its efficacy and safety profile, though initial concerns about a potential risk of neural tube defects have been largely mitigated by subsequent data. Efavirenz, once contraindicated, can be used if necessary. Zidovudine is often included in the NRTI backbone for its extensive pregnancy data. Efavirenz and protease inhibitors like atazanavir may require dose adjustment. Most antiretrovirals are present in breast milk, and in resource-rich settings where safe alternatives exist, breastfeeding by individuals with HIV is generally not recommended due to the risk of postnatal transmission.

Pediatric Considerations

Pharmacokinetics differ significantly due to variations in absorption, metabolism, distribution, and excretion related to age and development. Dosing is typically weight-based or body surface area-based. Many drugs have pediatric-specific formulations (solutions, chewable tablets, granules). Key considerations include palatability, dosing frequency, and long-term effects on growth and development. Agents like abacavir and lamivudine are commonly used, and dolutegravir is a preferred INSTI for children over a certain age and weight.

Geriatric Considerations

Older adults with HIV often have multiple comorbidities (cardiovascular disease, osteoporosis, renal impairment) and are on polypharmacy, increasing the risk of drug interactions and adverse effects. Renal function declines with age, necessitating careful dosing of renally eliminated NRTIs (tenofovir, emtricitabine). The increased cardiovascular risk profile of some PIs may be less desirable. Regimens with fewer side effects and drug interactions, such as those based on INSTIs, are often preferred.

Renal Impairment

Dose adjustment is required for drugs eliminated renally. Tenofovir disoproxil fumarate (TDF), emtricitabine, and lamivudine require dose reduction or interval extension as glomerular filtration rate declines. Tenofovir alafenamide (TAF) is preferred in patients with moderate to severe renal impairment as it produces much lower systemic tenofovir exposure. Most NNRTIs, PIs, and INSTIs do not require adjustment in renal impairment, though accumulation of their inactive metabolites may occur. Hemodialysis can remove some drugs (e.g., emtricitabine, tenofovir), requiring post-dialysis supplementation.

Hepatic Impairment

Agents metabolized hepatically require caution. Nevirapine is contraindicated in moderate to severe impairment. Dose adjustment may be necessary for some PIs (e.g., atazanavir) and NNRTIs (e.g., rilpivirine) in severe impairment. NRTIs that are not hepatically metabolized (e.g., tenofovir, emtricitabine) are generally safe, but caution is advised with abacavir in severe impairment due to limited data. The risk of hepatotoxicity from underlying viral hepatitis co-infection (HBV, HCV) must be considered, particularly with nevirapine or high-dose ritonavir.

Summary/Key Points

• Antiretroviral therapy employs a multi-class strategy to inhibit sequential steps in the HIV replication cycle, including reverse transcription (NRTIs, NNRTIs), integration (INSTIs), proteolysis (PIs), and entry (fusion inhibitors, CCR5 antagonists).
• Pharmacokinetic properties, particularly metabolism via CYP450 enzymes and renal excretion, dictate dosing schedules, food requirements, and are the primary source of complex drug-drug interactions. Pharmacokinetic enhancers (ritonavir, cobicistat) are used to optimize the profiles of co-administered drugs.
• Modern first-line regimens typically consist of two NRTIs plus an INSTI, aiming for once-daily dosing, high efficacy, and a high genetic barrier to resistance. Single-tablet regimens improve adherence.
• Adverse effects are class-specific: mitochondrial toxicity (older NRTIs), CNS effects (efavirenz), metabolic disturbances (PIs), and weight gain (some INSTIs). HLA-B*5701 screening is mandatory before abacavir use.
• Major drug interactions occur due to enzyme inhibition (PIs boosting other drugs) or induction (efavirenz reducing levels of co-medications), and chelation with polyvalent cations (INSTIs).
• Special population management requires tailored approaches: avoidance of teratogens in pregnancy, weight-based dosing in pediatrics, renal dose adjustments for tenofovir and emtricitabine, and consideration of polypharmacy in the elderly.

Clinical Pearls

• Virologic suppression (HIV RNA < 50 copies/mL) is the primary goal of therapy and prevents clinical progression and transmission.
• Adherence to the prescribed regimen is the strongest predictor of virologic success; regimen choice should consider pill burden, side effect profile, and lifestyle.
• Resistance testing (genotypic) should guide therapy selection in treatment-naïve patients with transmitted resistance and in all patients experiencing virologic failure.
• Comprehensive management includes monitoring for and managing long-term metabolic complications of both HIV and its treatment.
• Antiretroviral drugs are also pivotal tools for prevention, both as pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP).

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