Protease Inhibitors and Integrase Inhibitors (Anti‑HIV)

Introduction/Overview

Human immunodeficiency virus (HIV) remains a significant global health challenge, with antiretroviral therapy (ART) transforming a once fatal disease into a manageable chronic condition. Within the ART armamentarium, protease inhibitors (PIs) and integrase strand transfer inhibitors (INSTIs) play pivotal roles in suppressing viral replication and preventing disease progression. PIs target the viral aspartyl protease enzyme, thereby disrupting the maturation of viral particles, whereas INSTIs inhibit the integrase enzyme essential for the incorporation of viral DNA into the host genome. The synergistic use of these drug classes, often in combination with nucleoside reverse transcriptase inhibitors and non‑nucleoside reverse transcriptase inhibitors, constitutes the backbone of contemporary HIV therapy.

Understanding the pharmacological nuances of PIs and INSTIs is essential for clinicians and pharmacists engaged in HIV management. Their distinct mechanisms of action, pharmacokinetic profiles, resistance patterns, and adverse effect spectra necessitate careful patient selection, dosing, and monitoring. This chapter provides a comprehensive review aimed at medical and pharmacy students, elucidating key concepts and practical considerations.

• Learning Objectives
• Describe the chemical classification and mechanism of action of protease inhibitors and integrase strand transfer inhibitors.
• Explain the pharmacokinetic characteristics influencing dosing and drug interactions.
• Identify approved therapeutic indications and common off‑label uses.
• Recognize the spectrum of adverse effects and special populations requiring modification of therapy.
• Apply knowledge of drug interactions to anticipate and manage clinically significant events.

Classification

Protease Inhibitors

Protease inhibitors are chemically diverse, yet they share a common functional motif that chelates the active site of the HIV aspartyl protease. They are typically large, hydrophobic molecules with multiple ring systems, and are classified into first‑generation and second‑generation agents based on their potency and resistance profiles.

Agent	Generation	Key Features
Indinavir	First	Early PI, high resistance risk
Saquinavir	First	High hepatic metabolism
Lopinavir/ritonavir	First (boosted)	Ritonavir boosts plasma levels
Darunavir/ritonavir	Second	Broad resistance coverage
Atazanavir	Second	Lower lipodystrophy risk

Integrase Strand Transfer Inhibitors

INSTIs target the integrase enzyme’s strand transfer activity, preventing the insertion of viral cDNA into the host genome. They are generally small, highly lipophilic molecules, and are grouped according to their chemical scaffold: dolutegravir, bictegravir, and raltegravir among the most widely used agents.

Agent	Class	Key Features
Raltegravir	First‑generation	Requires twice‑daily dosing
Elvitegravir	First‑generation (boosted)	Boosted with cobicistat
Dolutegravir	Second‑generation	High barrier to resistance
Bictegravir	Second‑generation	Once‑daily dosing, high potency

Mechanism of Action

Protease Inhibitors

HIV protease is an aspartyl protease that cleaves the Gag and Gag‑Pol polyproteins into functional viral proteins, a critical step in virion maturation. PIs are peptidomimetic inhibitors that bind to the active site, forming a stable complex that prevents substrate access. This inhibition results in the release of immature, noninfectious viral particles. The potency of a PI is influenced by its affinity for the protease active site, resistance mutations, and the degree of protease inhibition required for viral suppression. Because protease is a viral enzyme with no human homolog, PIs exhibit high selectivity, though off‑target effects arise from the modulation of host protease‑like pathways.

Integrase Strand Transfer Inhibitors

Integrase catalyzes two sequential reactions: 3′ processing of viral cDNA and subsequent strand transfer into host DNA. INSTIs target the strand transfer step, chelating divalent metal ions essential for catalysis. By occupying the catalytic core, they preclude integration of viral DNA, thereby halting the establishment of proviral DNA and subsequent viral replication. The high affinity of INSTIs for the integrase active site, coupled with their resistance barriers, underpins their efficacy. Residual integrase activity is suppressed to a degree that cannot be compensated by viral mutation without significant fitness loss, which explains the lower emergence of resistance compared with earlier drug classes.

Pharmacokinetics

Protease Inhibitors

Absorption of PIs is generally good when administered with food, as the lipid‑rich matrix enhances solubility. Food effects vary among agents; for example, lopinavir/ritonavir requires a high‑fat meal for optimal absorption. The oral bioavailability of unboosted PIs is often low (<10%), necessitating the use of pharmacokinetic boosters such as ritonavir or cobicistat. Boosters inhibit cytochrome P450 3A4 (CYP3A4), thereby reducing first‑pass metabolism and increasing plasma concentrations of the co‑administered PI.

Distribution of PIs is characterized by extensive plasma protein binding (typically >95%) and large volumes of distribution due to lipophilicity. Tissue penetration, particularly into lymphoid tissues and the central nervous system, varies among agents and may influence virologic control in sanctuary sites.

Metabolism is predominantly hepatic, mediated by CYP3A4 and, to a lesser extent, CYP2D6 and CYP2C9. Concomitant use of strong CYP3A4 inducers (e.g., rifampin) can markedly reduce PI plasma levels, while inhibitors (e.g., ketoconazole) may increase toxicity. Excretion is primarily biliary, with minimal renal clearance.

Half‑lives differ substantially; for instance, lopinavir exhibits a half‑life of ~5 hours, necessitating twice‑daily dosing, whereas darunavir has a half‑life of ~10 hours, allowing once‑daily administration when boosted. Dosing schedules are tailored to maintain therapeutic concentrations while minimizing peak‑to‑trough variability.

Integrase Strand Transfer Inhibitors

INSTIs are absorbed rapidly, with peak plasma concentrations reached within 1–2 hours post‑dose. Food may enhance absorption for some agents (e.g., elvitegravir), but the effect is less pronounced than for PIs. Oral bioavailability ranges from moderate to high (e.g., dolutegravir ~74% without food). The lack of significant food interaction simplifies dosing regimens.

Distribution is characterized by moderate plasma protein binding (e.g., dolutegravir ~32%) and limited penetration into the central nervous system. Tissue distribution is sufficient to achieve therapeutic concentrations in peripheral blood mononuclear cells, the primary replication niche of HIV.

Metabolism of INSTIs occurs primarily via UGT1A1 (dolutegravir) and CYP3A4 (elvitegravir). Consequently, co‑administration with potent CYP3A4 inhibitors or inducers can alter drug exposure. For example, dolutegravir exposure increases ~30% with strong CYP3A4 inhibitors, whereas elvitegravir exposure is markedly reduced by rifampin.

Excretion is predominantly via fecal routes for dolutegravir and via renal routes for elvitegravir, with a half‑life of ~12–15 hours for dolutegravir, permitting once‑daily dosing. Bictegravir, a newer agent, has a half‑life exceeding 50 hours, enabling once‑daily dosing with a robust safety profile.

Therapeutic Uses/Clinical Applications

Protease Inhibitors

Protease inhibitors are integral components of first‑line, salvage, and pre‑exposure prophylaxis (PrEP) regimens, depending on resistance profiles. Their use is typically embedded within fixed‑dose combinations (FDCs) that improve adherence. Indinavir, saquinavir, and lopinavir/ritonavir were historically first‑line options; however, newer agents such as darunavir/ritonavir and atazanavir/ritonavir have supplanted them due to improved tolerability and resistance barriers.

In treatment‑naïve patients, PIs are commonly combined with nucleoside reverse transcriptase inhibitors (NRTIs) to achieve maximal viral suppression. In treatment‑experienced individuals, PIs are valuable salvage agents, particularly when resistance to other classes exists. The high genetic barrier of darunavir/ritonavir is advantageous in regimens requiring durable virologic control.

Off‑label uses include the management of HIV‑associated lymphoma and prophylaxis of opportunistic infections in severely immunocompromised patients. PIs are also employed in certain pre‑exposure prophylaxis protocols, although integrase inhibitors have largely supplanted them in this context.

Integrase Strand Transfer Inhibitors

INSTIs have become the preferred class for initial ART due to their favorable resistance profiles, once‑daily dosing, and lower adverse effect burden. Dolutegravir and bictegravir are frequently incorporated into first‑line regimens, often as part of three‑drug combinations with NRTIs. Raltegravir and elvitegravir, while effective, are more commonly used in salvage settings or in patients with specific resistance patterns.

INSTIs also serve in PrEP strategies, with dolutegravir‑based regimens demonstrating superior efficacy compared with tenofovir‑based options in certain populations. Off‑label indications include the treatment of HIV‑associated neurocognitive disorders, where INSTIs penetrate the central nervous system more effectively than some PIs.

Adverse Effects

Protease Inhibitors

Common adverse effects associated with PIs encompass gastrointestinal disturbances (nausea, vomiting, diarrhea), metabolic derangements (hyperlipidemia, insulin resistance), and dermatologic manifestations (rash). Lipodystrophy, characterized by central adiposity and peripheral lipoatrophy, is a notable issue, particularly with older agents such as indinavir and saquinavir. Hepatotoxicity may occur, especially when combined with other hepatotoxic drugs or in patients with pre‑existing liver disease.

Serious adverse reactions include pancreatitis, severe hypertriglyceridemia, and, rarely, nephrolithiasis. Black box warnings focus on the risk of serious hepatotoxicity, pancreatitis, and lipid abnormalities. Dose adjustments or discontinuation are recommended in patients with hepatic impairment or significant renal dysfunction.

Integrase Strand Transfer Inhibitors

INSTIs are generally well tolerated, with common side effects comprising headache, nausea, and mild gastrointestinal upset. Raltegravir may induce transient creatine phosphokinase elevations, while elvitegravir has been associated with mild increases in hepatic transaminases. Serious adverse events are uncommon but may include hypersensitivity reactions and, rarely, bone marrow suppression.

Dolutegravir has been linked to neuropsychiatric symptoms such as insomnia, mood disturbances, and insomnia, although the incidence is low. Bictegravir, with its novel scaffold, has a favorable safety profile, and no black box warnings have been issued to date. Nonetheless, vigilance remains essential, particularly in patients with pre‑existing psychiatric conditions.

Drug Interactions

Protease Inhibitors

PIs interact extensively with drugs that influence CYP3A4 activity. Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) markedly reduce PI plasma concentrations, potentially compromising virologic suppression. Conversely, strong inhibitors (e.g., ketoconazole, clarithromycin) can elevate PI levels, increasing toxicity risk. Concomitant use of PIs with other drugs that undergo CYP3A4 metabolism may necessitate dose adjustments or alternative therapies.

Boosted PIs (ritonavir or cobicistat) further potentiate these interactions due to their CYP3A4 inhibitory effects. For instance, ritonavir can increase the exposure of drugs such as warfarin, leading to bleeding risk. Conversely, ritonavir can reduce the efficacy of medications metabolized by CYP3A4, such as certain antipsychotics.

Integrase Strand Transfer Inhibitors

Dolutegravir is a substrate of UGT1A1 and a minor substrate of CYP3A4. Strong CYP3A4 inducers can reduce dolutegravir exposure by up to 50%, while inhibitors may increase it modestly. Raltegravir is metabolized via glucuronidation; co‑administration with potent UGT1A1 inducers (e.g., rifampin) can lower plasma levels. Elvitegravir is highly dependent on CYP3A4; rifampin can reduce its concentration by >90%, necessitating alternative regimens.

Boosting agents such as cobicistat, used with elvitegravir, inhibit both CYP3A4 and P-glycoprotein, potentially increasing the exposure of drugs that are substrates of these pathways. Consequently, co‑administration with drugs like digoxin or certain antiepileptics requires caution. Bictegravir, metabolized via CYP3A4, is similarly susceptible to interactions with strong inducers or inhibitors.

Special Considerations

Pregnancy and Lactation

Protease inhibitors have been classified as pregnancy category C; however, data suggest that lopinavir/ritonavir and atazanavir/ritonavir are relatively safe, providing a reduction in vertical transmission risk. Nonetheless, the potential for teratogenicity or fetal toxicity mandates careful risk–benefit analysis. Counsel patients regarding the importance of maintaining viral suppression throughout pregnancy to minimize perinatal transmission.

Dolutegravir, initially categorized as category B, has emerged as a preferred agent in pregnancy due to its robust safety data and low risk of neural tube defects. Raltegravir and elvitegravir have limited pregnancy data but are generally considered acceptable when benefits outweigh risks. Lactation is not contraindicated for most PIs and INSTIs, but drug transfer into breast milk varies; monitoring infant growth and development is advisable.

Pediatric Considerations

In pediatric populations, weight‑based dosing and formulation availability are critical. Indinavir and atazanavir have pediatric formulations, yet dosing adjustments are required due to developmental pharmacokinetic differences. Darunavir/ritonavir is approved for children ≥3 years, with dosing guided by pharmacokinetic modeling. INSTIs such as dolutegravir have established pediatric dosing guidelines, with weight‑based adjustments ensuring therapeutic exposure. Growth, neurodevelopment, and bone mineral density should be monitored, particularly with prolonged PI exposure.

Geriatric Considerations

The elderly may experience altered drug metabolism due to hepatic and renal impairment, as well as polypharmacy. PIs with extensive hepatic metabolism (e.g., indinavir) may warrant dose reductions or avoidance in advanced liver disease. INSTIs with minimal renal clearance (e.g., dolutegravir) are preferable in geriatric patients with renal dysfunction. Cognitive impairment and polypharmacy heighten the risk of drug interactions, necessitating comprehensive medication reconciliation.

Renal and Hepatic Impairment

Protease inhibitors are predominantly hepatically cleared; therefore, moderate to severe hepatic impairment requires dose adjustment or selection of agents with more favorable hepatic metabolism. Darunavir/ritonavir, for instance, can be used with caution in Child‑Pugh B cirrhosis, whereas lopinavir/ritonavir may be contraindicated in severe hepatic disease.

Renal impairment affects INSTIs differently; dolutegravir exposure increases modestly in renal failure, but clinical significance is limited. Elvitegravir requires dose reduction in patients with renal impairment due to increased exposure. Bictegravir shows moderate accumulation in severe renal disease, but no dose adjustment is typically necessary. Monitoring renal function is essential to prevent accumulation and toxicity.

Summary/Key Points

• Protease inhibitors suppress HIV maturation by blocking the protease enzyme, whereas integrase strand transfer inhibitors prevent viral DNA integration into host genomes.
• PIs exhibit extensive hepatic metabolism and are subject to potent food and drug interactions; boosting agents are essential for optimal plasma exposure.
• INSTIs offer once‑daily dosing, high barrier to resistance, and favorable safety profiles, making them first‑line choices in many regimens.
• Adverse effect spectra differ: PIs are associated with metabolic complications and lipodystrophy; INSTIs are generally well tolerated, with occasional neuropsychiatric symptoms.
• Drug interactions, particularly involving CYP3A4 and UGT1A1, necessitate vigilant medication review, especially in patients on CNS agents, antiepileptics, or antibiotics.
• Special populations—pregnant women, infants, elderly, and patients with organ dysfunction—require individualized dosing and monitoring strategies.
• Continued surveillance for resistance mutations and emerging safety data is essential for maintaining optimal therapeutic outcomes.

References

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