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Module 19110 lessonsRxPrep 2023 HIV protease inhibitor and booster material, reconciled with NIH Adult, Adolescent, and Perinatal HIV Guidelines and current FDA labeling through August 2026

HIV Protease Inhibitors

Connect protease structure and virion maturation to pharmacokinetic enhancement, resistance, darunavir and atazanavir selection, interaction engineering, toxicity, pregnancy, and current clinical positioning.

01

Explain how transition-state mimicry and competitive protease inhibition prevent infectious virion maturation.

02

Use cumulative resistance data to distinguish high barrier from guaranteed activity.

03

Select and dose boosted darunavir according to resistance, treatment history, food, booster, and product constraints.

04

Manage atazanavir food, gastric acidity, bilirubin, kidney, gallstone, and cardiac-conduction considerations.

05

Differentiate ritonavir and cobicistat as pharmacokinetic enhancers rather than interchangeable additives.

06

Interpret cobicistat-related creatinine changes and current pregnancy limitations.

07

Evaluate clinically important boosted-PI interactions using current authoritative tables.

08

Recognize metabolic, hepatic, gastrointestinal, dermatologic, renal, biliary, and cardiovascular safety issues.

09

Separate discontinued or uncommon legacy protease inhibitors from current U.S. practice.

10

Construct and monitor a complete protease-inhibitor regimen around the whole person.

191.01

Lesson

Stop Maturation at the Catalytic Pocket

HIV protease cleaves viral polyproteins after budding. Protease inhibitors occupy its catalytic site and prevent the ordered processing required to create a mature infectious virion.

What to learn
  • Aspartyl protease
  • Transition-state mimic
  • Gag-pol
  • Competitive inhibition
  • Maturation
Maturation pharmacologyStop cleavage, release an immature virion
01PolyproteinGag and gag-pol

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02ProteaseCatalytic pocket

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03Cleavage blockedUnprocessed proteins

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04NoninfectiousFailed maturation

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Start with viral polyproteins

HIV translates gag and gag-pol as long polyprotein precursors. After assembly and budding, viral protease must cleave those precursors at defined sites to generate structural proteins and enzymes in functional form.

Mimic the cleavage transition state

Protease inhibitors contain a noncleavable scaffold that resembles key geometry of peptide-bond cleavage. High-affinity occupancy of the catalytic pocket competitively excludes the natural polyprotein substrate.

Distort maturation

When cleavage fails, capsid and enzyme organization remain defective. The cell can still release particles, but those particles are immature and poorly infectious.

Place the class correctly

This is a late life-cycle effect after integration, transcription, translation, assembly, and budding. It differs from entry blockade, reverse-transcriptase inhibition, integrase inhibition, and capsid-targeted activity.

Quick check

0 of 1 answered
01What is the direct result of HIV protease inhibition?
Answer every question to submit.
191.02

Lesson

Use High Barrier Without Assuming Invulnerability

Pharmacokinetically enhanced darunavir is durable and often retains activity when other anchors are uncertain, but resistance history, exposure, and active companion drugs still determine success.

What to learn
  • High barrier
  • PI genotype
  • Darunavir RAMs
  • CAB-LA PrEP
  • Complete regimen
Barrier and activityBuild around verified susceptibility
01HistoryEvery regimen

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02GenotypePI and INSTI

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03Boosted DRVHigh barrier

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04Active partnersComplete suppression

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Define high barrier accurately

Multiple changes are usually needed to cause high-level darunavir resistance when exposure is maintained. This makes boosted darunavir valuable in selected rapid-start, resistance-uncertain, and treatment-experienced settings.

Read cumulative resistance

Review every prior PI, genotype, phenotype when available, adherence pattern, and viral-load trajectory. Archived substitutions may remain clinically important even when a current plasma genotype does not display them.

Respond to prior CAB-LA exposure

When HIV is acquired after long-acting cabotegravir PrEP and integrase susceptibility is not yet known, current guidance uses boosted darunavir plus two active NRTIs while awaiting an integrase genotype.

Protect the rest of the regimen

A high-barrier anchor is not permission to use inactive companion drugs or ignore adherence and interactions. Persistent replication can eventually accumulate enough protease substitutions to compromise future options.

Quick check

0 of 1 answered
01Why can boosted darunavir be useful while awaiting an integrase genotype after CAB-LA PrEP breakthrough?
Answer every question to submit.
191.03

Lesson

Make Darunavir Exposure and Resistance Explicit

Darunavir is the principal contemporary PI option in U.S. guidelines. Its booster, food, resistance pattern, and companion regimen are part of the prescription, not optional details.

What to learn
  • Darunavir
  • Ritonavir
  • Cobicistat
  • Food
  • Resistance substitutions
Current PI anchorMake every darunavir condition explicit
01ResistanceRAM review

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02BoosterRTV or COBI

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03FoodWith food

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04DoseOnce or twice daily

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Always identify the booster

Darunavir requires ritonavir or cobicistat. Once-daily darunavir 800 mg with ritonavir 100 mg or the darunavir 800 mg and cobicistat 150 mg product is used when no darunavir resistance substitutions are present.

Let resistance determine frequency

Treatment-experienced patients with qualifying darunavir substitutions generally use darunavir 600 mg plus ritonavir 100 mg twice daily. Once-daily cobicistat combinations should not be substituted for that resistance-informed strategy.

Administer with food

Take boosted darunavir with food. Counsel around a repeatable daily eating pattern and verify the instructions for the exact single-agent or fixed-dose product.

Interpret sulfonamide history

Darunavir contains a sulfonamide moiety. Clarify the culprit, phenotype, and severity of a prior sulfonamide reaction. Most patients with sulfonamide allergy can tolerate darunavir, but severe histories warrant caution and a clear rash plan.

Quick check

0 of 1 answered
01Which factor can make once-daily darunavir with cobicistat inappropriate?
Answer every question to submit.
191.04

Lesson

Manage Atazanavir as an Absorption and Organ System

Atazanavir has distinctive pH-dependent absorption, indirect hyperbilirubinemia, stone risk, renal effects, and PR-interval effects. It remains approved but is no longer recommended for routine initial therapy.

What to learn
  • Gastric pH
  • UGT1A1
  • Indirect bilirubin
  • Nephrolithiasis
  • PR interval
Absorption and organ effectsSeparate exposure from toxicity
01FoodRequired

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02AcidpH dependent

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03BilirubinIndirect rise

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04Kidney and rhythmStones and PR

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Protect acidic absorption

Take atazanavir with food. Acid reducers can lower exposure, and management differs by treatment history, booster, TDF use, and acid-reducer class. Use the current interaction table rather than a single memorized spacing rule.

Interpret jaundice correctly

Atazanavir inhibits UGT1A1 and commonly raises unconjugated bilirubin. Isolated indirect hyperbilirubinemia is reversible and does not require discontinuation for organ injury, although visible jaundice can affect acceptance and adherence.

Watch kidney and biliary pathways

Atazanavir can contribute to renal insufficiency, crystal or stone formation, and gallstones. Evaluate flank pain, hematuria, biliary symptoms, hydration, kidney function, and interacting nephrotoxic exposures.

Respect conduction effects

PR prolongation and symptomatic atrioventricular block have been reported. Review underlying conduction disease and other PR-prolonging medicines, and obtain an ECG when clinical risk warrants.

Quick check

0 of 1 answered
01A patient taking atazanavir has jaundice, high indirect bilirubin, and stable AST and ALT. What is the most likely explanation?
Answer every question to submit.
191.05

Lesson

Treat Pharmacokinetic Enhancement as Active Therapy

Ritonavir and cobicistat suppress CYP3A-mediated clearance so a PI reaches higher, longer-lasting exposure. Similar purpose does not make the enhancers interchangeable.

What to learn
  • Pharmacoenhancer
  • CYP3A
  • Ritonavir
  • Cobicistat
  • Exposure
Pharmacokinetic enhancementTreat the booster as part of the dose
01RTV or COBINot interchangeable

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02CYP3AClearance inhibited

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03PI exposureHigher and longer

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04Interaction mapEvery medicine

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Understand the exposure lever

Both enhancers inhibit CYP3A and increase PI area under the curve and half-life. This allows less frequent dosing and creates a more durable trough concentration.

Read ritonavir broadly

Ritonavir was developed as an active PI but is now usually used at low booster doses. It strongly inhibits CYP3A and CYP2D6 while inducing several other enzymes and transport pathways, so its effects are multidirectional.

Read cobicistat narrowly but not simply

Cobicistat has no antiretroviral activity. It inhibits CYP3A and selected transporters and can alter creatinine handling. It should never be counted as another active HIV drug.

Avoid informal substitution

The enhancers differ in enzyme induction, fixed-dose products, pregnancy evidence, renal interpretation, and interaction recommendations. Follow the selected regimen and exact label rather than swapping milligram for milligram.

Quick check

0 of 1 answered
01What is cobicistat's role in a darunavir regimen?
Answer every question to submit.
191.06

Lesson

Interpret Cobicistat Creatinine and Pregnancy Correctly

Cobicistat changes serum creatinine interpretation and loses reliable boosting during later pregnancy. Both issues require mechanism-based assessment rather than a shortcut.

What to learn
  • Tubular secretion
  • Serum creatinine
  • True GFR
  • Pregnancy
  • Viral-load monitoring
Enhancer interpretationRead creatinine and pregnancy correctly
01BaselineRenal context

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02SecretionSCr may rise

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03PregnancyExposure falls

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04AlternativeCurrent guidance

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Establish a renal baseline

Cobicistat inhibits tubular secretion of creatinine, often causing a small early rise in serum creatinine without reducing actual glomerular filtration. Document timing and the baseline before interpreting the new value.

Do not dismiss progressive injury

A known secretion effect does not protect against true kidney disease from TDF, dehydration, comorbidity, or another nephrotoxin. Evaluate the trend, urine findings, electrolytes, symptoms, and full regimen.

Recognize pregnancy underexposure

Cobicistat and the drugs it boosts have substantially lower exposure during the second and third trimesters. Current perinatal guidance does not recommend initiating cobicistat-boosted PI therapy during pregnancy.

Use a current transition plan

For a pregnant patient who presents suppressed on cobicistat, use specialist-guided shared decision-making about switching or continuing with frequent viral-load monitoring. Ritonavir remains an effective PI enhancer in pregnancy when appropriately selected.

Quick check

0 of 1 answered
01Which pattern is most consistent with cobicistat's expected creatinine effect?
Answer every question to submit.
191.07

Lesson

Engineer the Entire Interaction Network

Boosted protease inhibitors are among the most interaction-intensive regimens in pharmacotherapy. Safe use requires a current authoritative checker and route-by-route medication reconciliation.

What to learn
  • CYP3A substrate
  • CYP3A inducer
  • Transporter
  • Contraindication
  • Monitoring
Interaction engineeringMap both exposure directions
01Medication listEvery route

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02SubstrateNarrow margin

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03Inhibitor or inducerMagnitude

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04Safe planAvoid, adjust, monitor

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Identify dangerous substrates

Sensitive CYP3A substrates with narrow therapeutic margins can rise to toxic concentrations. Lovastatin and simvastatin are contraindicated; many antiarrhythmics, pulmonary-hypertension PDE5 inhibitors, sedatives, and oncology agents require avoidance or specialist adjustment.

Find every route

Inhaled, intranasal, injected, topical, and systemic corticosteroids can interact. Excess corticosteroid exposure can produce iatrogenic Cushing syndrome and adrenal suppression even when the product seems locally administered.

Reject the booster-overpowers-induction myth

Strong inducers such as rifampin, selected anticonvulsants, and St. John's wort can lower PI exposure and cause failure. Induction can persist after discontinuation, so recent history matters.

Individualize antithrombotic therapy

Direct anticoagulants and antiplatelet agents differ in CYP and transporter dependence. Use the exact PI, booster, antithrombotic, organ function, indication, and current table to avoid both bleeding and thrombosis.

Quick check

0 of 1 answered
01Why can an inhaled corticosteroid be dangerous with a boosted PI?
Answer every question to submit.
191.08

Lesson

Monitor the Longitudinal Toxicity Pattern

Current PI therapy is better tolerated than many legacy regimens, but hepatic, metabolic, gastrointestinal, dermatologic, renal, biliary, and cardiovascular concerns remain patient specific.

What to learn
  • Hepatotoxicity
  • Dyslipidemia
  • Hyperglycemia
  • GI effects
  • Cardiovascular risk
Longitudinal safetyTrack organ and metabolic burden
01LiverHepatitis risk

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02GlucoseInsulin resistance

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03LipidsASCVD context

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04SymptomsGI and rash

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Establish hepatic context

Drug-induced hepatitis and decompensation have occurred, especially with HBV, HCV, alcohol-related disease, steatosis, or advanced liver disease. Distinguish hepatocellular injury from atazanavir's isolated indirect bilirubin effect.

Measure metabolic burden

Boosted PIs can contribute to hypertriglyceridemia, LDL elevation, insulin resistance, hyperglycemia, and fat redistribution. Agent and era matter, but baseline and follow-up cardiovascular risk remain necessary.

Protect adherence from GI effects

Nausea and diarrhea can lead to missed doses, dehydration, and abandonment. Assess severity, timing, infection, other medicines, nutrition, and whether the symptom is compromising exposure.

Interpret cardiovascular evidence responsibly

Observational studies report increased cardiovascular events with some PI exposure, including darunavir in selected cohorts. Use the signal in individualized selection without presenting association as universal causation.

Quick check

0 of 1 answered
01Which monitoring set best captures boosted-PI metabolic risk?
Answer every question to submit.
191.09

Lesson

Separate Legacy Protease Inhibitors From Current Practice

Older sources list many approved protease inhibitors. Current NIH tables focus on atazanavir, darunavir, and ritonavir because other agents are discontinued or no longer commonly used.

What to learn
  • Indinavir
  • Saquinavir
  • Lopinavir-ritonavir
  • Tipranavir
  • Source date
Source reconciliationSeparate history from current practice
01DiscontinuedIDV and SQV

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02UncommonFPV, LPV/r, NFV, TPV

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03Archived toxicityResistance and harm

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04Current optionBoosted DRV

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Mark discontinued agents

Indinavir and saquinavir are discontinued in the United States. They can explain old resistance patterns, nephrolithiasis, metabolic effects, or prior intolerance, but they are not current regimen choices.

Mark uncommon agents

Fosamprenavir, lopinavir-ritonavir, nelfinavir, and tipranavir are no longer commonly used in current U.S. practice because contemporary options improve efficacy, tolerability, pill burden, or interaction burden.

Retain high-value safety history

Tipranavir carries major hepatic and intracranial hemorrhage warnings. Lopinavir-ritonavir has substantial metabolic and interaction burden. Historical exposure can still shape organ assessment and resistance interpretation.

Reconcile every source date

RxPrep appropriately tests legacy agents because they may appear on examinations and records. The learning platform must label historical knowledge clearly and pair it with current availability and guideline position.

Quick check

0 of 1 answered
01How should indinavir be presented in a current U.S. curriculum?
Answer every question to submit.
191.10

Lesson

Build One Accountable Protease Inhibitor Plan

The final regimen joins verified viral activity with booster, food, HBV, organ function, pregnancy, interaction, metabolic, access, and monitoring realities.

What to learn
  • Complete ART
  • Resistance
  • HBV
  • Medication reconciliation
  • Monitoring owner
Clinical synthesisClose the complete PI loop
01VirusResistance

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02PersonOrgans and pregnancy

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03RegimenFood and interactions

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04Follow-upRNA and safety

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Verify complete activity

Review cumulative resistance and prior treatment. Confirm the PI dose and booster, select active companion drugs, and preserve adequate HBV therapy when coinfection is present.

Fit the person and product

Integrate kidney, liver, cardiac, metabolic, pregnancy, food, swallowing, formulation, and access data. Read the complete fixed-dose product rather than evaluating the PI in isolation.

Reconcile repeatedly

Perform a full interaction review at initiation and whenever any prescription, nonprescription drug, supplement, injection, or inhaled product changes. Document safe alternatives and required monitoring.

Own virologic and safety follow-up

Monitor HIV RNA according to current guidance. Respond to persistent viremia by evaluating adherence, food, booster, access, interactions, resistance, and companion activity before making a fragmented change.

Quick check

0 of 1 answered
01Which approach best selects a boosted PI regimen?
Answer every question to submit.

Module test

Check the connections.

Each attempt draws 10 questions from the complete 144 question bank.

144 questions in this module bank10 questions per attempt

Each attempt draws a fresh set and rearranges the answer choices.

References

Current clinical foundation.

Lecture material was synthesized with the following contemporary guidance. Verify local policy and current guidance before applying clinical information.

  1. NIH Protease Inhibitor Characteristics
  2. NIH Protease Inhibitor Drug Interactions
  3. NIH Initial Protease Inhibitor Regimens
  4. NIH Initial Combination Regimens
  5. NIH Antiretroviral Adverse Effects
  6. NIH Ritonavir in Pregnancy
  7. FDA Prezcobix Prescribing Information
  8. FDA Evotaz Prescribing Information
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