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Module 1909 lessonsRxPrep 2023 HIV NNRTI material, reconciled with NIH Adult and Adolescent Antiretroviral Guidelines and current FDA labeling through August 2026

Non-Nucleoside Reverse Transcriptase Inhibitors

Connect allosteric reverse transcriptase inhibition to resistance, oral absorption, long-acting delivery, CYP interactions, agent-specific toxicity, and current regimen selection.

01

Distinguish NNRTI allosteric inhibition from NRTI activation, substrate competition, and chain termination.

02

Interpret the low resistance barrier and cross-resistance of the class using cumulative treatment and genotype history.

03

Select doravirine using resistance, interaction, organ, and complete-regimen data.

04

Protect oral rilpivirine exposure through meal counseling, acid-suppressant management, and initial-therapy criteria.

05

Explain the eligibility, scheduling, and pharmacokinetic-tail requirements of long-acting rilpivirine with cabotegravir.

06

Recognize efavirenz neuropsychiatric, metabolic, QT, and administration considerations.

07

Use etravirine in treatment-experienced care only after mutation-pattern and bidirectional interaction review.

08

Recognize nevirapine as a legacy safety lesson and delavirdine as discontinued in current U.S. practice.

09

Build an NNRTI plan that integrates resistance, HBV, food, gastric acidity, interactions, toxicity, adherence, and monitoring.

190.01

Lesson

Distort Reverse Transcriptase Without Becoming DNA

NNRTIs bind a hydrophobic allosteric pocket near the reverse transcriptase active site. The resulting conformational change impairs polymerase function without phosphorylation or incorporation into viral DNA.

What to learn
  • Allosteric pocket
  • Noncompetitive inhibition
  • Reverse transcription
  • No phosphorylation
  • No chain incorporation
Allosteric pharmacologyDistort the polymerase
01EnterNo phosphorylation

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02Bind pocketNear active site

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03Shift shapeNoncompetitive

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04Stop DNABefore integration

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Bind beside the active site

NNRTIs occupy a hydrophobic pocket within HIV-1 reverse transcriptase. They do not compete with a natural nucleotide at the catalytic site. Instead, binding changes the geometry and motion required for polymerase activity.

Act as the administered molecule

Unlike nucleoside analogs, NNRTIs do not require host kinases to create an active triphosphate. Exposure therefore depends directly on absorption, distribution, metabolism, and persistence of the parent drug.

Interrupt reverse transcription

The class acts while viral RNA is being converted into DNA, before integrase inserts proviral DNA into the host genome. NNRTIs do not block entry, integration, assembly, or proteolytic maturation.

Preserve combination therapy

Direct target binding does not make NNRTIs suitable monotherapy. Their resistance barrier is generally lower than that of recommended high-barrier integrase regimens, so every component of the regimen must remain active.

Quick check

0 of 1 answered
01Which statement correctly distinguishes NNRTIs from NRTIs?
Answer every question to submit.
190.02

Lesson

Treat the Binding Pocket as a Resistance System

A small number of substitutions can alter the shared NNRTI pocket, making baseline genotype and cumulative treatment history central to safe selection.

What to learn
  • Low barrier
  • Cross-resistance
  • Baseline genotype
  • Cumulative history
  • Complete regimen
Pocket resistanceRead the complete genotype
01HistoryEvery exposure

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02MutationPocket geometry

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03Cross-resistanceAgent specific

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04Active regimenProtect all drugs

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Expect rapid selection

Ongoing replication under NNRTI pressure can select a dominant mutation quickly. High-level resistance to several older agents may result from one substitution, especially when adherence or companion-drug activity is weak.

Map cross-resistance

Efavirenz and nevirapine share substantial cross-resistance. Doravirine and etravirine can retain activity against some patterns, but neither should be assumed active without formal interpretation.

Test before starting

Current guidance recommends resistance testing before antiretroviral initiation. A transmitted mutation can turn an apparently complete regimen into one with a compromised anchor before the first dose.

Read every historical result

Mutations may become less visible after drug pressure is removed. Review all prior genotypes, regimens, failures, prevention exposure, adherence patterns, and viral-load trajectories before choosing an NNRTI.

Quick check

0 of 1 answered
01Why is baseline resistance testing especially important before an NNRTI regimen?
Answer every question to submit.
190.03

Lesson

Use Doravirine as a Current, Context-Specific Option

Doravirine offers once-daily oral dosing, no food requirement, and fewer neuropsychiatric and lipid concerns than efavirenz, but CYP3A induction and resistance still determine whether it fits.

What to learn
  • Doravirine
  • Once daily
  • CYP3A substrate
  • Strong inducer
  • Severe skin reaction
Current oral optionFit doravirine to the regimen
01GenotypeVerify activity

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02CYP3AAvoid strong inducers

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03Daily doseWith or without food

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04MonitorRNA and safety

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Position the regimen

Doravirine is used with other antiretrovirals in people starting treatment or in selected virologically suppressed switches. Unlike oral rilpivirine, it has no initial viral-load or CD4 prerequisite.

Simplify administration

Doravirine 100 mg is taken once daily with or without food. The fixed-dose product combines doravirine with lamivudine and TDF, so renal, bone, and HBV considerations extend beyond the anchor.

Protect exposure from induction

Doravirine is a CYP3A substrate. Strong inducers can reduce concentrations enough to cause failure and resistance. Review rifamycins, anticonvulsants, supplements, and recent inducer exposure.

Monitor agent-specific safety

Nausea, dizziness, headache, fatigue, abnormal dreams, rash, and liver-test abnormalities can occur. Current labeling also warns about serious skin reactions, so systemic or mucosal findings require prompt evaluation.

Quick check

0 of 1 answered
01Which medication history most directly threatens doravirine exposure?
Answer every question to submit.
190.04

Lesson

Engineer Oral Rilpivirine Absorption

Oral rilpivirine is effective only when meal, gastric acidity, resistance, and pretreatment disease criteria are protected together.

What to learn
  • Meal
  • Gastric acidity
  • PPI contraindication
  • H2 blocker separation
  • Initial criteria
Absorption pathwayProtect oral exposure
01MealReal food

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02AcidNo PPI

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03ThresholdsRNA and CD4

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04AdherenceDaily continuity

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Require a real meal

Take oral rilpivirine once daily with a meal. A protein drink alone does not provide the absorption support described in labeling and guideline tables. Assess meal reliability rather than offering a vague take-with-food instruction.

Keep the stomach acidic

Proton pump inhibitors are contraindicated with oral rilpivirine. Give H2 receptor antagonists at least 12 hours before or 4 hours after, and antacids at least 2 hours before or 4 hours after.

Respect initial-therapy criteria

For initial treatment, rilpivirine-based therapy is limited to people with pretreatment HIV RNA below 100,000 copies per mL and CD4 count above 200 cells per mm3 because failure and resistance are more likely outside those conditions.

Screen mood, liver, and QT risk

Depressive disorders, insomnia, headache, hepatotoxicity, severe skin reactions, and QT prolongation at excessive exposure inform selection and counseling. Serum creatinine can rise through altered tubular secretion without a true fall in filtration.

Quick check

0 of 1 answered
01Which acid-suppressant plan is compatible with oral rilpivirine?
Answer every question to submit.
190.05

Lesson

Protect the Long-Acting Regimen and Its Tail

Long-acting rilpivirine is administered with cabotegravir to eligible patients. The depot improves dosing frequency but creates visit, interaction, and discontinuation responsibilities.

What to learn
  • Cabotegravir
  • Virologic suppression
  • Injection schedule
  • Pharmacokinetic tail
  • Oral bridge
Depot pharmacologyPlan every injection and exit
01SuppressVerify eligibility

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02InjectTwo active drugs

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03ScheduleProtect visits

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04BridgeCover the tail

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Verify candidacy

Confirm sustained suppression, no known or suspected resistance to cabotegravir or rilpivirine, no active HBV requiring omitted therapy, and no interacting drugs. Review pregnancy context and the person's ability to attend scheduled visits.

Use two active long-acting agents

The regimen is not rilpivirine monotherapy. Both gluteal injections are administered according to the approved monthly or every-two-month schedule after an optional oral lead-in when clinically chosen.

Manage missed visits prospectively

Planned and unplanned delays use specific oral bridging or re-initiation instructions. Contact the patient, identify the last administration date, and use the current label rather than improvising a new interval.

Cover the pharmacokinetic tail

Rilpivirine can persist for many months after the final injection. If the regimen stops, begin an alternative fully suppressive regimen within the recommended window so falling concentrations do not create functional monotherapy.

Quick check

0 of 1 answered
01What is the central resistance risk after stopping long-acting cabotegravir and rilpivirine without replacement ART?
Answer every question to submit.
190.06

Lesson

Control Efavirenz Exposure and Neurotoxicity

Efavirenz remains an effective but less favored option because its CNS, psychiatric, metabolic, interaction, and resistance burdens complicate routine use.

What to learn
  • Empty stomach
  • Bedtime
  • CNS effects
  • Psychiatric symptoms
  • CYP induction
CNS exposureLower avoidable neurotoxicity
01Empty stomachLimit exposure

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02BedtimeReduce disruption

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03ScreenMood and QT

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04ReassessFunction and safety

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Reduce avoidable exposure

Food, especially a high-fat meal, increases efavirenz exposure and CNS effects. Take it on an empty stomach, preferably at bedtime. Counsel against driving or hazardous work until the individual understands the effect.

Distinguish common from dangerous

Dizziness, abnormal dreams, impaired concentration, somnolence, and insomnia often improve within several weeks. Severe depression, suicidality, psychosis, seizures, or delayed ataxia and encephalopathy require prompt assessment.

Map metabolic consequences

Efavirenz can raise total cholesterol and triglycerides. It is a CYP substrate and inducer with broad interactions, and QT prolongation deserves attention when susceptibility or interacting drugs are present.

Interpret tests carefully

Selected cannabinoid and benzodiazepine immunoassays can produce false-positive results. Confirm unexpected screening results with a specific method instead of assigning substance exposure from one assay.

Quick check

0 of 1 answered
01Why is efavirenz preferably taken on an empty stomach at bedtime?
Answer every question to submit.
190.07

Lesson

Use Etravirine Through Mutation and Interaction Expertise

Etravirine can retain activity against some NNRTI-resistant viruses, but its twice-daily dosing, food requirement, mutation pattern, and bidirectional CYP effects demand careful use.

What to learn
  • Treatment experienced
  • Weighted mutations
  • After meal
  • Twice daily
  • Bidirectional interactions
Experienced-care optionJoin genotype to interaction
01MutationsWeighted pattern

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02MealAfter food

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03Twice dailyAdherence

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04CYP mapBoth directions

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Interpret the pattern

Etravirine activity cannot be predicted by the presence or absence of one familiar mutation. Multiple weighted NNRTI substitutions can progressively reduce response, so cumulative genotype and phenotype data matter.

Protect administration

Take etravirine 200 mg twice daily after a meal. When swallowing is difficult, tablets may be dispersed in water using the exact label method and the entire mixture consumed.

Map both interaction directions

Etravirine is metabolized by CYP pathways and can induce CYP3A while inhibiting CYP2C9 and CYP2C19. Another drug may change etravirine, and etravirine may change the other drug.

Recognize hypersensitivity

Rash, severe cutaneous reactions, hypersensitivity, nausea, and liver injury require symptom-based counseling. Stop and evaluate promptly when rash is accompanied by systemic or mucosal findings.

Quick check

0 of 1 answered
01What is the safest way to count etravirine activity in a treatment-experienced regimen?
Answer every question to submit.
190.08

Lesson

Carry Legacy NNRTI Lessons Into Current Care

Nevirapine and delavirdine appear in older learning resources, but current U.S. care rarely uses nevirapine and delavirdine is discontinued. Their history remains valuable for toxicity and source appraisal.

What to learn
  • Nevirapine
  • Lead-in
  • Hepatotoxicity
  • SJS and TEN
  • Delavirdine
Historical safetyRecognize early severe injury
01Lead-inLegacy protocol

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02RashMucosa and systemic

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03LiverEarly vigilance

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04Current optionsPrefer safer agents

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Recognize the highest-risk window

Nevirapine can cause fatal hepatotoxicity and severe skin reactions. The first 18 weeks require close clinical and laboratory vigilance, with the first six weeks especially important for rash and systemic symptoms.

Understand the lead-in

Immediate-release therapy historically began once daily for 14 days before escalation when no rash occurred. A prolonged interruption can require re-initiation instructions. This safety process does not make nevirapine a routine current initial choice.

Stop for systemic danger

Rash with mucosal involvement, fever, facial edema, hepatitis, eosinophilia, or organ symptoms demands immediate evaluation. Do not continue simply because the rash began as a limited eruption.

Reconcile old sources

Delavirdine is discontinued, and nevirapine is no longer commonly used in the United States. Older charts should teach historical mechanism and toxicity, not silently populate a modern regimen.

Quick check

0 of 1 answered
01How should delavirdine be represented in a current U.S. NNRTI module?
Answer every question to submit.
190.09

Lesson

Construct the NNRTI Plan Around the Whole Patient

The final choice joins viral susceptibility with companion activity, HBV, food, gastric acidity, interactions, mental health, liver status, QT risk, access, and follow-up.

What to learn
  • Complete regimen
  • HBV
  • Drug interactions
  • Safety baseline
  • Monitoring ownership
Clinical synthesisBuild one accountable plan
01VirusResistance

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02RegimenComplete activity

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03PersonFood, organs, access

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04Follow-upRNA and toxicity

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Start with virologic activity

Review every genotype and regimen. Confirm that the NNRTI and companion drugs are active and that any rilpivirine initial-therapy prerequisites are satisfied. Do not add one active agent to uncontrolled replication.

Protect comorbid treatment

Establish HBV status before choosing or simplifying a regimen because many NNRTI combinations depend on an NRTI backbone for HBV activity. Assess liver disease, mental health, QT susceptibility, pregnancy context, and organ function.

Reconcile every exposure condition

Document meals, acid reducers, CYP inducers and inhibitors, supplements, swallowing, injection attendance, refill access, and transportation. An interaction or administration mismatch can function like nonadherence.

Own response and toxicity

Monitor HIV RNA according to current guidance and obtain agent-specific safety data. Give clear instructions for rash, mucosal disease, fever, mood change, neurologic symptoms, jaundice, and missed long-acting visits.

Quick check

0 of 1 answered
01Which approach best selects an NNRTI regimen?
Answer every question to submit.

Module test

Check the connections.

Each attempt draws 10 questions from the complete 104 question bank.

104 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 NNRTI Drug Characteristics
  2. NIH NNRTI Drug Interactions
  3. NIH What to Start: NNRTI Regimens
  4. NIH Initial Combination Regimens
  5. FDA Pifeltro Prescribing Information
  6. FDA Intelence Prescribing Information
  7. FDA Viramune XR Prescribing Information
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