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 toxicities is fundamental for constructing effective and durable treatment regimens, a practice known as antiretroviral therapy (ART). The clinical goal of ART is to achieve and maintain viral suppression, typically defined as a plasma HIV-1 RNA level below 50 copies/mL, thereby preserving immune function and preventing transmission.

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 profiles of key agents, including absorption, distribution, metabolism, and elimination pathways.
• Evaluate the clinical applications, major adverse effect profiles, and significant drug interactions associated with contemporary antiretroviral regimens.
• Apply knowledge of special considerations, such as use in organ impairment or pregnancy, to optimize therapeutic outcomes and minimize toxicity.

Classification

Antiretroviral drugs are categorized primarily by their mechanism of action and their specific molecular target within 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 prevent resistance.

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 adjacent to the active site of 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. Examples are atazanavir, darunavir, fosamprenavir, and lopinavir. They are almost always administered with a pharmacokinetic enhancer or “booster” (ritonavir or cobicistat) to improve their bioavailability and prolong half-life.

Integrase Strand Transfer Inhibitors (INSTIs)

INSTIs block the integrase enzyme, preventing the insertion of viral DNA into the host genome. This class, which forms the backbone of most modern first-line regimens, includes bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir.

Entry Inhibitors

This category encompasses drugs that interfere with viral entry into the host CD4+ T-cell. It is subdivided into:

• CCR5 Antagonists: Maraviroc, which blocks the CCR5 co-receptor.
• Fusion Inhibitors: Enfuvirtide, which inhibits gp41-mediated fusion of viral and cellular membranes.
• Post-attachment Inhibitors: Ibalizumab-uiyk, a monoclonal antibody that binds CD4.

Pharmacokinetic Enhancers

Although not antiviral themselves, ritonavir and cobicistat are crucial adjuncts. They potently inhibit cytochrome P450 3A4 (CYP3A4) and drug transporters like P-glycoprotein, thereby increasing systemic exposure to co-administered PIs and elvitegravir.

Mechanism of Action

The pharmacodynamic actions of antiretroviral drugs are defined by their specific interference with the sequential steps of the HIV-1 replication cycle. Successful inhibition halts the production of new virions.

Inhibition of Reverse Transcription

NRTIs act as chain terminators. Once phosphorylated to their active triphosphate form (e.g., lamivudine-triphosphate), they compete with natural deoxynucleoside triphosphates (dNTPs) for incorporation into the growing viral DNA chain by reverse transcriptase. Upon incorporation, the absence of a 3′-hydroxyl group on the sugar moiety prevents the formation of the next phosphodiester bond, resulting in premature chain termination. The selectivity for the viral enzyme over host DNA polymerases is relative, not absolute, which underlies some mitochondrial toxicities.

NNRTIs exert allosteric inhibition. By binding to a specific pocket on the p66 subunit of reverse transcriptase, they induce a conformational change that distorts the enzyme’s catalytic site. This non-competitive inhibition reduces the enzyme’s ability to convert viral RNA into proviral DNA. The binding site is highly specific to HIV-1 reverse transcriptase, conferring no activity against HIV-2 or host enzymes.

Inhibition of Viral Protease

Protease Inhibitors are designed to mimic the natural peptide substrate (Phe-Pro or Tyr-Pro) of the HIV-1 protease enzyme. They bind with high affinity to the enzyme’s active site, competitively inhibiting its function. This enzyme is responsible for cleaving the Gag and Gag-Pol polyprotein precursors into individual functional proteins (e.g., matrix, capsid, nucleocapsid, reverse transcriptase, integrase). Inhibition results in the production of immature, non-infectious viral particles.

Inhibition of Integration

Integrase Strand Transfer Inhibitors selectively inhibit the strand transfer step of integration. They chelate the divalent metal ions (Mg²⁺ or Mn²⁺) within the active site of the integrase enzyme. This binding blocks the nucleophilic attack by which the 3′-ends of viral DNA are inserted into the host chromosome, preventing the establishment of the permanent provirus. INSTIs do not inhibit the earlier 3′-processing step as potently.

Inhibition of Viral Entry

The CCR5 antagonist maraviroc acts as a negative allosteric modulator of the human CCR5 chemokine receptor, inducing a conformational change that prevents its interaction with the viral gp120 envelope protein, thereby blocking viral entry. Its use requires prior tropism testing to confirm CCR5-tropic virus. The fusion inhibitor enfuvirtide is a synthetic peptide that binds to the heptad repeat 1 (HR1) region of gp41, preventing the conformational change needed for fusion of viral and cellular membranes. Post-attachment inhibitors like ibalizumab bind to domain 2 of the CD4 receptor, inhibiting the conformational changes in gp120 required for coreceptor binding and entry.

Pharmacokinetic Enhancement

Ritonavir and cobicistat inhibit CYP3A4 metabolism in the gut wall and liver. This inhibition significantly reduces the first-pass metabolism and systemic clearance of co-administered drugs, leading to increased area under the curve (AUC), higher trough concentrations (C_trough), and extended elimination half-life (t_1/2). This allows for less frequent dosing and improved virologic efficacy of the boosted agent.

Pharmacokinetics

The pharmacokinetic properties of antiretroviral drugs are highly variable between classes and individual agents, profoundly influencing dosing schedules, food requirements, and potential for drug interactions.

Absorption

Oral bioavailability ranges widely. For instance, the absorption of rilpivirine and atazanavir is significantly enhanced by a meal, particularly one with high fat content, while dolutegravir absorption is reduced by polyvalent cation-containing supplements. Tenofovir alafenamide (TAF) is a prodrug designed for improved lymphatic absorption and reduced plasma levels compared to tenofovir disoproxil fumarate (TDF), which correlates with its improved renal and bone safety profile. The long-acting injectable formulations of cabotegravir and rilpivirine represent a paradigm shift, offering sustained systemic delivery from intramuscular depot sites over monthly or bimonthly intervals.

Distribution

Distribution into sanctuary sites, such as the central nervous system (CNS) and genital tract, is a critical determinant of a drug’s ability to suppress virus in these compartments and potentially reduce transmission. Distribution is influenced by factors such as molecular size, lipophilicity, and protein binding. Agents with higher CNS penetration-effectiveness (CPE) scores, like zidovudine and efavirenz, achieve better CSF concentrations. Most PIs and INSTIs are highly protein-bound (>85%), primarily to albumin and alpha-1-acid glycoprotein, which can limit free drug concentrations.

Metabolism

Metabolic pathways are a major source of drug interactions. NNRTIs exhibit variable effects on CYP enzymes: efavirenz is an inducer, nevirapine is an inducer, while etravirine and rilpivirine are inhibitors. PIs are predominantly metabolized by CYP3A4, making them susceptible to interactions with other substrates, inhibitors, or inducers of this pathway. INSTIs have more favorable profiles: dolutegravir is metabolized via UGT1A1 with some CYP3A involvement, raltegravir is glucuronidated by UGT1A1, and bictegravir undergoes both CYP3A and UGT1A1 metabolism. NRTIs are generally not metabolized by CYP enzymes but are activated via intracellular phosphorylation.

Excretion

Renal excretion of parent drug or metabolites is a key route for many NRTIs (e.g., emtricitabine, tenofovir, lamivudine) and requires dose adjustment in renal impairment. Tenofovir, particularly the TDF formulation, is actively secreted by renal proximal tubule cells via organic anion transporters, a process linked to its nephrotoxic potential. Biliary and fecal excretion are significant for drugs like atazanavir and rilpivirine. Elimination half-lives vary considerably, from approximately 9 hours for raltegravir to over 40 hours for doravirine and dolutegravir, informing dosing frequency.

Therapeutic Uses/Clinical Applications

The primary indication for all antiretroviral drugs is the treatment of HIV-1 infection. Clinical application is guided by treatment guidelines, which recommend initiating ART in all persons with HIV regardless of CD4 count, a strategy known as “Treat All.”

First-Line Therapy

Contemporary first-line regimens are typically two-drug or three-drug combinations with high efficacy, favorable tolerability, and a high genetic barrier to resistance. The most common backbone consists of two NRTIs (e.g., tenofovir alafenamide/emtricitabine or abacavir/lamivudine) paired with a third agent from a different class. Currently, INSTIs like bictegravir, dolutegravir, or raltegravir are preferred as the third agent due to their potency and safety. NNRTI-based (e.g., doravirine) or boosted PI-based regimens are alternative options, often used in specific clinical scenarios.

Treatment-Experienced Patients

For patients with virologic failure or drug resistance, regimen selection must be guided by a thorough treatment history and, crucially, genotypic resistance testing. Regimens may include drugs with activity against resistant virus, such as darunavir/ritonavir, etravirine, or the second-generation INSTI dolutegravir (often at a twice-daily dose). In cases of extensive multi-class resistance, newer agents with novel mechanisms, like the attachment inhibitor fostemsavir or the capsid inhibitor lenacapavir, may be utilized.

Pre-Exposure Prophylaxis (PrEP)

Antiretroviral drugs are used for prevention in HIV-negative individuals at substantial risk. Oral PrEP typically involves a fixed-dose combination of tenofovir disoproxil fumarate/emtricitabine or tenofovir alafenamide/emtricitabine taken daily or on-demand. Long-acting injectable cabotegravir administered every two months is also an approved option for PrEP, offering an alternative to daily oral dosing.

Post-Exposure Prophylaxis (PEP)

A 28-day course of ART is recommended for individuals with a recent high-risk exposure to HIV (e.g., occupational needlestick, sexual assault). Regimens usually consist of a three-drug combination, such as tenofovir/emtricitabine plus raltegravir or dolutegravir, initiated as soon as possible, ideally within 2 hours of exposure.

Prevention of Perinatal Transmission

Administration of ART to pregnant persons with HIV dramatically reduces the risk of mother-to-child transmission during pregnancy, delivery, and breastfeeding. The goal is to achieve and maintain viral suppression throughout pregnancy. Preferred regimens include dual-NRTI backbones combined with an INSTI like dolutegravir or a boosted PI like atazanavir/ritonavir, selected based on safety and resistance profiles.

Adverse Effects

Adverse effects are common with ART and represent a major cause of treatment discontinuation and non-adherence. Profiles are class- and agent-specific.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

Class effects are often linked to inhibition of mitochondrial DNA polymerase gamma, leading to mitochondrial toxicity. Manifestations can include lactic acidosis with hepatic steatosis (rare but serious), peripheral neuropathy, lipoatrophy, and pancreatitis. Zidovudine is associated with bone marrow suppression (anemia, neutropenia) and myopathy. Abacavir can cause a potentially fatal hypersensitivity reaction, strongly associated with the HLA-B*5701 allele; genetic screening is mandatory prior to use. Tenofovir disoproxil fumarate (TDF) is linked to renal tubular dysfunction (Fanconi syndrome) and reduced bone mineral density, risks that are substantially lower with tenofovir alafenamide (TAF).

Non-Nucleoside Reverse Transcriptase Inhibitors

Adverse effects are highly variable. Efavirenz is associated with central nervous system effects (dizziness, vivid dreams, insomnia), rash, and dyslipidemia. Nevirapine carries a risk of severe hepatotoxicity and life-threatening rash, including Stevens-Johnson syndrome, particularly during the lead-in dosing period. Rilpivirine can cause depressive disorders and has a lower virologic efficacy in patients with baseline viral load >100,000 copies/mL. Doravirine generally has a more favorable neuropsychiatric and lipid profile.

Protease Inhibitors

Metabolic complications are prominent. These include insulin resistance and new-onset or exacerbation of diabetes mellitus, dyslipidemia (elevated triglycerides and LDL cholesterol), and lipodystrophy (peripheral fat loss and central fat accumulation). Gastrointestinal intolerance (nausea, diarrhea) is common. Atazanavir frequently causes unconjugated hyperbilirubinemia (benign, reversible) and may lead to nephrolithiasis. Darunavir is associated with rash.

Integrase Strand Transfer Inhibitors

INSTIs are generally well-tolerated. The most common class effect is insomnia and headache, typically transient. Weight gain, particularly when combined with tenofovir alafenamide/emtricitabine, has been observed as a longer-term effect. Raltegravir has been rarely associated with creatine kinase elevation and myopathy. Dolutegravir use at conception has been linked to a small increased risk of neural tube defects, influencing its use in individuals of childbearing potential.

Entry Inhibitors

Maraviroc may cause hepatotoxicity, cough, and dizziness. Enfuvirtide administration is limited by injection site reactions in nearly all patients. Ibalizumab can cause immune reconstitution inflammatory syndrome (IRIS) and rash.

Black Box Warnings

Several agents carry black box warnings, the strongest FDA-mandated safety alert. Abacavir carries a warning for fatal hypersensitivity reactions. Nevirapine is warned for severe hepatotoxicity and skin reactions. Efavirenz is contraindicated in pregnancy due to teratogenic risk observed in primate studies. Injectable cabotegravir/rilpivirine carries a warning for the risk of virologic failure if injections are delayed or discontinued, due to the long tail of subtherapeutic drug concentrations.

Drug Interactions

Drug-drug interactions are a paramount concern in antiretroviral therapy due to the extensive use of metabolic enzyme inhibition/induction and the narrow therapeutic index of many agents.

Pharmacokinetic Interactions

Interactions mediated by CYP450 enzymes are most prevalent. Boosted PIs and cobicistat are potent CYP3A4 inhibitors, increasing levels of co-administered substrates such as certain statins (simvastatin, lovastatin), sedatives (midazolam, triazolam), and ergot alkaloids, which can lead to toxicity. Conversely, NNRTIs like efavirenz and nevirapine are CYP3A inducers, potentially reducing the efficacy of co-administered drugs like methadone, oral contraceptives, and other antiretrovirals. Elvitegravir/cobicistat and some PIs also inhibit drug transporters like P-glycoprotein, affecting drugs such as digoxin.

Antacids, calcium, iron, and multivitamin supplements containing polyvalent cations (Ca²⁺, Mg²⁺, Al³⁺, Fe^2+/3+) can chelate INSTIs (dolutegravir, raltegravir, bictegravir) in the gut, significantly reducing their absorption. Administration should be staggered, typically by 2 hours before or 6 hours after the cation-containing product.

Pharmacodynamic Interactions

Additive toxicities can occur. Combining two NRTIs with mitochondrial toxicity potential (e.g., didanosine and stavudine) is contraindicated due to excessive risk. Concurrent use of nephrotoxic agents (aminoglycosides, NSAIDs, high-dose TDF) may amplify renal injury. The combined dyslipidemic effects of PIs and certain NRTIs can exacerbate cardiovascular risk.

Contraindications

Absolute contraindications are specific and critical. Abacavir is contraindicated in patients who test positive for HLA-B*5701 or who have a history of abacavir hypersensitivity. Efavirenz is contraindicated in pregnancy and with certain drugs metabolized by CYP3A4 where elevated levels are dangerous (e.g., terfenadine, cisapride). Nevirapine is contraindicated in patients with moderate-to-severe hepatic impairment or as initial therapy in women with CD4 counts >250 cells/mm³ or men with CD4 counts >400 cells/mm³ due to heightened hepatotoxicity risk. Elvitegravir/cobicistat is contraindicated with drugs highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious events (e.g., alfuzosin, rifampin, ergot derivatives).

Special Considerations

The management of HIV infection requires tailoring ART to individual patient characteristics and comorbidities.

Pregnancy and Lactation

The goal of therapy is maximal viral suppression to prevent perinatal transmission. Regimen selection balances efficacy with teratogenic risk. Dolutegravir is now a preferred agent due to high efficacy and a more recent evaluation showing the neural tube defect risk to be lower than initially estimated. Efavirenz is generally avoided in the first trimester but can be used thereafter if needed. Zidovudine has an extensive safety record in pregnancy. Most antiretrovirals are present in breast milk; in resource-rich settings where safe alternatives exist, breastfeeding by individuals with HIV is not recommended due to a residual risk of transmission.

Pediatric Considerations

Dosing is based on body surface area or weight, requiring careful calculation and adjustment as the child grows. Formulation availability (e.g., liquid suspensions, dispersible tablets) is a key practical concern. Pharmacokinetics can differ from adults due to developmental changes in metabolism and renal function. Certain drugs, like efavirenz, may have different neuropsychiatric side effect profiles in children.

Geriatric Considerations

Older adults with HIV often have multiple comorbidities (cardiovascular disease, renal impairment, osteoporosis) and take numerous concomitant medications (polypharmacy), increasing the risk of drug interactions and additive toxicities. Regimens with fewer side effects and lower interaction potential (e.g., INSTI-based regimens) are often favored. Renal and hepatic function must be monitored closely, and doses of renally excreted drugs (e.g., tenofovir, emtricitabine) may require adjustment.

Renal Impairment

NRTIs eliminated renally (tenofovir, emtricitabine, lamivudine) require dose adjustment based on creatinine clearance. Tenofovir alafenamide (TAF) is preferred over TDF in renal impairment due to its lower systemic tenofovir exposure. Cobicistat inhibits tubular secretion of creatinine, causing a benign, reversible increase in serum creatinine without affecting glomerular filtration rate, which must be distinguished from true renal injury.

Hepatic Impairment

Metabolism of many PIs and NNRTIs is hepatic. Use of nevirapine is contraindicated in moderate-to-severe impairment. Efavirenz levels may be increased in severe impairment. Dose adjustments for most PIs and NNRTIs are recommended in hepatic impairment, though data are often limited. NRTIs and INSTIs generally require less adjustment, though caution is advised with severe impairment due to risk of lactic acidosis or altered metabolism.

Summary/Key Points

• Antiretroviral therapy (ART) involves combination regimens from at least two different drug classes to suppress HIV replication, restore immune function, and prevent transmission.
• The six major drug classes—NRTIs, NNRTIs, PIs, INSTIs, Entry Inhibitors, and Pharmacokinetic Enhancers—target distinct stages of the viral life cycle: reverse transcription, integration, protease-mediated maturation, and cellular entry.
• Pharmacokinetic properties, particularly metabolism via CYP450 enzymes and renal excretion, are central to understanding dosing schedules, food effects, and the extensive drug interaction profiles that characterize ART.
• First-line regimens are typically anchored by an INSTI or an NNRTI combined with a dual-NRTI backbone, selected for efficacy, tolerability, and genetic barrier to resistance.
• Adverse effects are class-specific: mitochondrial toxicity (NRTIs), CNS effects and rash (NNRTIs), metabolic complications (PIs), and weight gain/insomnia (INSTIs). Recognition and management of these toxicities are crucial for adherence.
• Major drug interactions are primarily pharmacokinetic, involving CYP3A4 inhibition (boosted PIs, cobicistat) or induction (efavirenz, nevirapine), and chelation of INSTIs by polyvalent cations.
• Special populations require tailored approaches: avoidance of teratogens in pregnancy, weight-based dosing in pediatrics, vigilance for polypharmacy in geriatrics, and dose adjustment in renal/hepatic impairment.

Clinical Pearls

• Always perform HLA-B*5701 testing before considering abacavir therapy to avoid hypersensitivity reactions.
• Stagger the administration of INSTIs (dolutegravir, raltegravir, bictegravir) by at least 2 hours from calcium/iron supplements or antacids to prevent chelation and absorption failure.
• Interpret serum creatinine changes in patients on cobicistat with caution, as it inhibits tubular secretion of creatinine without affecting actual glomerular filtration.
• In treatment failure, obtain a genotypic resistance test while the patient is still on the failing regimen to best identify resistance mutations.
• Consider long-term metabolic and cardiovascular risks, such as dyslipidemia from PIs or bone density loss from TDF, when selecting a regimen for a young patient initiating lifelong therapy.

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