Chapter 36 — Antiviral Pharmacology — Module 1 — HIV Pharmacology Part 1: NRTIs and NNRTIs
1. A 58-year-old man on a tenofovir disoproxil fumarate (TDF)-based regimen has a declining estimated glomerular filtration rate (eGFR), now 52 mL/min/1.73m2, and worsening bone mineral density. He remains virologically suppressed. Which change in his nucleotide component is most appropriate?
A) Discontinue all tenofovir-containing agents and rely on the remaining drugs
B) Switch from tenofovir disoproxil fumarate to tenofovir alafenamide (TAF), which achieves antiviral efficacy at much lower plasma tenofovir exposure and causes less renal and bone toxicity
C) Double the tenofovir disoproxil fumarate dose to overcome reduced clearance
D) Add a loop diuretic to increase tenofovir renal elimination
E) Replace tenofovir with high-dose zidovudine
ANSWER: B
Rationale:
TAF delivers tenofovir into lymphocytes efficiently while keeping plasma tenofovir roughly ten-fold lower than TDF; because systemic tenofovir exposure drives the renal and bone toxicity, switching to TAF is the appropriate response to declining eGFR and bone loss in a suppressed patient, preserving antiviral efficacy.
Option A: Option A is incorrect: simply dropping the tenofovir component leaves an incomplete backbone and risks loss of suppression and (in HBV co-infection) a flare; an active replacement is needed.
Option C: Option C is incorrect: increasing TDF raises systemic tenofovir exposure, worsening the very toxicities of concern.
Option D: Option D is incorrect: tenofovir nephrotoxicity is a proximal tubular accumulation problem; a loop diuretic does not protect the tubule and adds volume and electrolyte risk.
Option E: Option E is incorrect: zidovudine carries marrow and mitochondrial toxicity and is not a rational substitute for managing tenofovir-associated renal and bone effects.
2. A treatment-experienced patient with virologic failure has a resistance report showing an isolated M184V mutation (methionine to valine at reverse transcriptase codon 184). How should this single finding be interpreted when redesigning the backbone?
A) The entire NRTI class is lost and no NRTI should be used
B) Tenofovir must be avoided because M184V confers tenofovir resistance
C) Zidovudine and tenofovir are now resistant while lamivudine remains fully active
D) Lamivudine and emtricitabine are compromised, but the mutation increases susceptibility to zidovudine and tenofovir and reduces viral fitness, so a tenofovir-based backbone remains useful
E) The patient should be switched to NNRTI monotherapy
ANSWER: D
Rationale:
M184V causes high-level resistance to lamivudine and emtricitabine, but it simultaneously increases susceptibility to zidovudine, tenofovir, and abacavir and lowers replicative fitness; a tenofovir-based backbone therefore remains valuable, and many regimens deliberately retain lamivudine or emtricitabine for the fitness cost even when M184V is present.
Option A: Option A is incorrect: a single M184V does not abolish the whole class; tenofovir activity is in fact enhanced.
Option B: Option B is incorrect: M184V increases tenofovir susceptibility rather than conferring resistance.
Option C: Option C is incorrect: it is lamivudine and emtricitabine that are compromised, while zidovudine and tenofovir are favored.
Option E: Option E is incorrect: any monotherapy, including NNRTI alone, would rapidly select further resistance and is never appropriate.
3. A patient starting efavirenz has a history of well-controlled major depression. Two weeks in, he reports vivid dreams and low mood. Which management principle applies most directly to this drug's central nervous system (CNS) effects?
A) Efavirenz CNS toxicity is concentration-dependent and often improves over weeks; bedtime dosing reduces perceived severity, but a psychiatric history makes efavirenz a relative contraindication and favors switching to an agent with a cleaner CNS profile
B) The symptoms indicate an allergic reaction requiring permanent avoidance of all NNRTIs
C) The dose should be increased to push past the adverse-effect threshold
D) These effects are unrelated to efavirenz and require no regimen consideration
E) The patient should stop the entire regimen immediately and remain off all ART
ANSWER: A
Rationale:
Efavirenz CNS effects (vivid dreams, insomnia, dizziness, mood changes) are plasma concentration-dependent, usually improve over the first weeks, and are mitigated by bedtime dosing; however, in a patient with a psychiatric history efavirenz is a relative contraindication, and an agent such as rilpivirine, doravirine, or an integrase inhibitor with a cleaner CNS profile is preferred.
Option B: Option B is incorrect: this is a concentration-dependent neuropsychiatric effect, not an NNRTI-class allergy.
Option C: Option C is incorrect: raising the dose increases concentration-dependent toxicity.
Option D: Option D is incorrect: the symptoms are characteristic of efavirenz and do warrant a regimen decision.
Option E: Option E is incorrect: abruptly stopping all ART risks rebound and resistance; the correct step is to switch the offending agent, not abandon therapy.
4. A patient co-infected with HIV and hepatitis B virus (HBV), currently on tenofovir/emtricitabine plus a third agent, needs a regimen change because of an unrelated intolerance to the third agent. What is the critical safety consideration in executing the switch?
A) HBV-active agents may be stopped freely because HIV suppression also suppresses HBV indirectly
B) Only the tenofovir need be retained; emtricitabine can be dropped without consequence
C) The patient should be switched entirely to an integrase inhibitor with no NRTI backbone
D) HBV testing is unnecessary once HIV therapy is established
E) The tenofovir plus emtricitabine backbone (both HBV-active) must be continued or replaced with equally HBV-active agents simultaneously, because abruptly removing anti-HBV coverage can precipitate a severe, potentially fatal HBV flare
ANSWER: E
Rationale:
Tenofovir and emtricitabine/lamivudine are active against HBV; in a co-infected patient, abrupt withdrawal of effective anti-HBV therapy can cause rebound HBV replication and severe hepatic flare. Any regimen change must continue these agents or substitute equally HBV-active coverage at the same time; only the intolerable third agent should be altered.
Option A: Option A is incorrect: HIV suppression does not independently maintain HBV control once the active anti-HBV drugs are removed.
Option B: Option B is incorrect: the backbone's HBV activity should be preserved as a unit, and dropping coverage risks a flare.
Option C: Option C is incorrect: removing the NRTI backbone strips HBV coverage and is exactly what must be avoided here.
Option D: Option D is incorrect: HBV status is precisely what governs safe regimen changes and must be known.
5. A virologically suppressed patient on a rilpivirine-based regimen is started on omeprazole by another provider for reflux. Weeks later his HIV viral load becomes detectable. What is the most likely explanation and the appropriate corrective action?
A) Omeprazole increased rilpivirine levels to toxic concentrations, so the rilpivirine dose should be reduced
B) The detectable viral load is unrelated to omeprazole and reflects nonadherence only
C) Proton pump inhibitor (PPI)-induced gastric acid suppression reduced rilpivirine absorption to subtherapeutic levels; the PPI is contraindicated with rilpivirine and should be stopped, using an alternative acid-suppression strategy or a different antiretroviral
D) The patient should simply take the omeprazole and rilpivirine at the same time each morning to align their effects
E) Rilpivirine should be doubled to compensate for the omeprazole interaction
ANSWER: C
Rationale:
Rilpivirine absorption depends on gastric acidity; PPIs suppress acid throughout the day, lower rilpivirine dissolution and absorption to subtherapeutic levels, and are contraindicated with rilpivirine regardless of timing. The detectable viral load is a predictable consequence, and the corrective action is to stop the PPI, substituting an appropriately timed H2 blocker or antacid, or changing the antiretroviral.
Option A: Option A is incorrect: PPIs lower, not raise, rilpivirine levels.
Option B: Option B is incorrect: the interaction is a well-defined pharmacologic cause and should not be dismissed as adherence alone.
Option D: Option D is incorrect: co-timing does not rescue the interaction because PPIs raise gastric pH for many hours, so they are contraindicated outright.
Option E: Option E is incorrect: dose-doubling is not an approved strategy and does not reliably overcome the absorption defect.
6. A woman of childbearing potential on efavirenz uses a combined oral contraceptive as her only method of birth control. What counseling follows from efavirenz's enzyme effects?
A) Efavirenz induces CYP3A4 and can reduce contraceptive hormone concentrations, so an additional or alternative reliable contraceptive method should be advised
B) Efavirenz inhibits CYP3A4 and raises contraceptive levels, so the contraceptive dose should be lowered
C) Efavirenz has no effect on hormonal contraception and no counseling is needed
D) The contraceptive will increase efavirenz levels and cause toxicity, so efavirenz should be stopped
E) Efavirenz only affects injectable contraceptives, so the oral pill is unaffected
ANSWER: A
Rationale:
Efavirenz is a CYP3A4 inducer and accelerates metabolism of numerous co-medications, including combined oral contraceptive hormones, which can reduce contraceptive reliability; patients should be counseled to add or substitute a reliable method, for example a non-hormonal or long-acting method less dependent on hepatic metabolism.
Option B: Option B is incorrect: efavirenz induces rather than inhibits CYP3A4, lowering hormone levels.
Option C: Option C is incorrect: the interaction is clinically relevant and does require counseling.
Option D: Option D is incorrect: the contraceptive does not drive efavirenz toxicity; the concern runs the other way.
Option E: Option E is incorrect: oral hormonal contraceptives are specifically affected by CYP3A4 induction.
7. A patient on a doravirine-based regimen is diagnosed with active tuberculosis (TB) and a rifampin-based regimen is planned. What is the correct antiretroviral consideration?
A) Doravirine and rifampin are fully compatible and require no change
B) Rifampin will raise doravirine levels, so the doravirine dose should be reduced
C) The TB therapy should be withheld until HIV therapy is complete
D) Rifampin is a strong CYP3A4 inducer that reduces doravirine exposure by roughly 88%, making the combination contraindicated; the antiretroviral regimen must be changed, or a rifamycin-sparing TB approach considered
E) Doravirine should simply be taken several hours apart from rifampin to avoid the interaction
ANSWER: D
Rationale:
Doravirine is a CYP3A4 substrate; rifampin's strong induction lowers doravirine area under the curve by approximately 88%, driving it subtherapeutic, so the combination is contraindicated and the regimen must be altered to an antiretroviral compatible with rifampin, or a rifamycin-sparing strategy used.
Option A: Option A is incorrect: the interaction is severe, not negligible.
Option B: Option B is incorrect: rifampin lowers, not raises, doravirine.
Option C: Option C is incorrect: active TB requires prompt treatment and should not be deferred for HIV therapy.
Option E: Option E is incorrect: temporal separation does not overcome enzyme induction, which suppresses doravirine exposure regardless of dosing interval.
8. Zidovudine is now rarely part of routine first-line regimens but retains a defined clinical niche. Which use, and which monitoring concern, are correctly paired?
A) First-line backbone in all newly diagnosed adults; monitor for nephrotoxicity
B) Prevention of mother-to-child transmission during labor and delivery and neonatal prophylaxis; monitor for bone marrow suppression with macrocytic anemia and neutropenia
C) Preferred agent in advanced chronic kidney disease; monitor for hypersensitivity
D) Treatment of hepatitis B co-infection; monitor for QT prolongation
E) Salvage NNRTI therapy; monitor for CNS toxicity
ANSWER: B
Rationale:
Zidovudine's principal modern use is in prevention of mother-to-child transmission during labor and delivery and in neonatal post-exposure prophylaxis; its characteristic toxicity is mitochondrial and marrow suppression producing macrocytic anemia and neutropenia through inhibition of mitochondrial DNA polymerase gamma, which must be monitored.
Option A: Option A is incorrect: zidovudine is not a routine first-line backbone, and its hallmark toxicity is marrow suppression, not nephrotoxicity.
Option C: Option C is incorrect: abacavir, not zidovudine, is the renally sparing choice, and zidovudine's concern is not hypersensitivity.
Option D: Option D is incorrect: zidovudine is not an anti-HBV agent and QT prolongation is not its signature; that concern belongs to rilpivirine at supratherapeutic levels.
Option E: Option E is incorrect: zidovudine is an NRTI, not an NNRTI, and CNS toxicity is an efavirenz feature.
9. A patient who started abacavir 10 days ago develops fever, rash, malaise, and gastrointestinal symptoms. Abacavir is stopped and symptoms resolve. Several weeks later, another clinician considers restarting abacavir. What is the correct guidance?
A) Rechallenge is acceptable if the patient is premedicated with antihistamines and corticosteroids
B) Rechallenge is acceptable provided HLA-B*57:01 testing is now performed
C) The reaction was unrelated to abacavir, so rechallenge carries no special risk
D) Rechallenge is acceptable at a lower starting dose with gradual escalation
E) Rechallenge after a clinically suspected abacavir hypersensitivity reaction is contraindicated because re-exposure can cause rapid, potentially fatal hypotension
ANSWER: E
Rationale:
The presentation is a classic abacavir hypersensitivity reaction (HSR), which typically occurs within the first six weeks. Once an HSR is clinically suspected, rechallenge is contraindicated because re-exposure can provoke rapid, severe, potentially fatal hypotension.
Option A: Option A is incorrect: premedication does not make rechallenge safe, as the reaction can be lethal regardless.
Option B: Option B is incorrect: testing after a clinical reaction does not license rechallenge; the prohibition stands once HSR is suspected.
Option C: Option C is incorrect: the timing and constellation are characteristic of abacavir HSR, not an unrelated event.
Option D: Option D is incorrect: no dose-escalation strategy renders rechallenge safe after a suspected HSR.
10. A patient stable on a tenofovir disoproxil fumarate (TDF) regimen is changed to a regimen that includes cobicistat as a pharmacokinetic booster. What renal consideration follows?
A) Cobicistat lowers plasma tenofovir, so renal monitoring can be relaxed
B) Cobicistat has no effect on tenofovir handling and changes nothing
C) Cobicistat raises plasma tenofovir concentrations by inhibiting transporter-mediated tubular secretion, so renal function should be monitored more closely even though no automatic dose change is mandated
D) Cobicistat causes immediate intrinsic nephrotoxicity independent of tenofovir and the regimen must be stopped
E) Cobicistat converts tenofovir into a renally inert metabolite, eliminating the need for monitoring
ANSWER: C
Rationale:
Boosting agents ritonavir and cobicistat inhibit transporter-mediated tubular secretion of tenofovir, raising plasma tenofovir by roughly 30%; this does not by itself require a dose change but does warrant closer renal monitoring because higher tenofovir exposure increases proximal tubular toxicity risk.
Option A: Option A is incorrect: cobicistat raises, not lowers, tenofovir exposure.
Option B: Option B is incorrect: there is a meaningful pharmacokinetic interaction.
Option D: Option D is incorrect: the concern is potentiation of tenofovir's renal effect through increased exposure, not an independent intrinsic nephrotoxin requiring automatic discontinuation.
Option E: Option E is incorrect: cobicistat does not inactivate tenofovir; it increases its exposure.
11. A treatment-naive patient's baseline genotype shows both K103N and E138K, two of the most common transmitted NNRTI resistance mutations. If an NNRTI-based regimen is desired, which agent is best supported by its resistance profile?
A) Doravirine, whose resistance profile is largely non-overlapping with K103N and E138K, so it generally retains activity against these common transmitted mutations
B) Efavirenz, because K103N does not affect it
C) Nevirapine, because it has the highest genetic barrier of the class
D) Rilpivirine, because E138K increases its potency
E) No NNRTI can ever be used once any resistance mutation is present
ANSWER: A
Rationale:
Doravirine's resistance profile is largely non-overlapping with K103N and E138K, so it typically retains activity where these common transmitted mutations would compromise older agents, supporting its use when an NNRTI is desired in this setting.
Option B: Option B is incorrect: K103N confers high-level resistance to efavirenz.
Option C: Option C is incorrect: nevirapine has a very low genetic barrier and is compromised by K103N.
Option D: Option D is incorrect: E138K confers resistance to rilpivirine rather than increasing its potency.
Option E: Option E is incorrect: the presence of specific mutations guides agent selection rather than excluding the class entirely, and doravirine remains an option here.
12. A patient with chronic kidney disease and an estimated glomerular filtration rate (eGFR) of 35 mL/min/1.73m2 is on a lamivudine-containing regimen. Which statement about NRTI renal handling applies?
A) Lamivudine and emtricitabine are hepatically eliminated and never require renal dose adjustment
B) Abacavir requires the most aggressive renal dose reduction of all NRTIs
C) Only tenofovir is renally cleared; all other NRTIs are renally inert
D) Lamivudine and emtricitabine are renally cleared and require dose reduction at reduced eGFR, so the lamivudine dose should be adjusted at this level of renal function
E) Renal function has no bearing on NRTI dosing in any patient
ANSWER: D
Rationale:
Most NRTI parent drugs and metabolites are renally cleared; lamivudine and emtricitabine in particular require dose reduction as eGFR falls, with lamivudine adjustment needed below roughly 50 mL/min, so at an eGFR of 35 the lamivudine dose should be reduced.
Option A: Option A is incorrect: lamivudine and emtricitabine are renally cleared, not hepatically eliminated.
Option B: Option B is incorrect: abacavir is the NRTI that does NOT require renal adjustment because it is hepatically metabolized.
Option C: Option C is incorrect: several NRTIs besides tenofovir are renally cleared and dose-adjusted.
Option E: Option E is incorrect: renal function directly governs dosing of most NRTIs.
13. A patient on stable methadone maintenance is about to begin efavirenz. What proactive management best reflects the expected interaction?
A) No interaction is expected, so methadone dosing can be left unchanged without monitoring
B) Anticipate that efavirenz will lower methadone concentrations through CYP3A4 induction, warn the patient about possible opioid withdrawal, and coordinate methadone dose escalation with the methadone program
C) Reduce the methadone dose preemptively because efavirenz will raise methadone levels
D) Add naloxone to counteract expected methadone accumulation
E) Switch the patient from methadone to a higher fixed efavirenz dose to balance the effect
ANSWER: B
Rationale:
Efavirenz induces CYP3A4 and lowers methadone plasma concentrations by roughly 50 to 60%, often precipitating opioid withdrawal within one to two weeks; proactive management is to warn the patient, monitor for withdrawal, and coordinate methadone dose escalation with the prescribing program.
Option A: Option A is incorrect: a clinically important interaction is expected and requires monitoring.
Option C: Option C inverts the direction: efavirenz lowers methadone levels, so reducing methadone would worsen withdrawal.
Option D: Option D is incorrect: the problem is reduced methadone exposure, not accumulation, so naloxone is inappropriate and dangerous here.
Option E: Option E is incorrect: efavirenz dose changes do not address the methadone interaction, and abandoning effective opioid agonist therapy is not the management.
14. A treatment-naive patient presents with a pretreatment plasma HIV RNA of 280,000 copies/mL and a CD4 count of 150 cells/microL. The team is considering a rilpivirine-based regimen. What is the correct decision?
A) Rilpivirine is preferred here because high viral loads respond especially well to it
B) Rilpivirine is acceptable if simply taken on an empty stomach
C) Rilpivirine dosing should be doubled to match the high viral load
D) Rilpivirine is appropriate as long as a proton pump inhibitor is added for absorption
E) Rilpivirine is not recommended as initial therapy in this patient because virologic failure rates are higher when the pretreatment viral load exceeds 100,000 copies/mL or the CD4 count is below 200 cells/microL
ANSWER: E
Rationale:
Rilpivirine is contraindicated as initial therapy when the pretreatment viral load exceeds 100,000 copies/mL or the CD4 count is below 200 cells/microL because of higher virologic failure rates; this patient meets both exclusion criteria, so an alternative agent should be chosen.
Option A: Option A inverts the criterion: high viral load argues against rilpivirine.
Option B: Option B is incorrect: rilpivirine must be taken with food, and food timing does not address the viral-load and CD4 contraindication.
Option C: Option C is incorrect: dose-doubling is not an approved strategy and does not overcome the failure-rate concern.
Option D: Option D is incorrect: proton pump inhibitors are contraindicated with rilpivirine because they reduce its absorption, the opposite of helping.
15. A patient on long-term tenofovir disoproxil fumarate (TDF) develops glucosuria with normal serum glucose, low serum phosphate, and new proteinuria. Which complication does this pattern indicate, and what is the appropriate response?
A) Diabetic nephropathy from hyperglycemia; intensify glucose control
B) NNRTI hypersensitivity; discontinue the NNRTI component
C) Proximal renal tubular dysfunction (Fanconi syndrome) from tenofovir; consider switching from TDF to tenofovir alafenamide (TAF) or an alternative and monitor renal indices
D) Abacavir hypersensitivity reaction; avoid all future abacavir
E) Mitochondrial lactic acidosis; administer intravenous bicarbonate as definitive therapy
ANSWER: C
Rationale:
Glucosuria with normal blood glucose, hypophosphatemia from phosphate wasting, and proteinuria is the classic picture of TDF-associated proximal tubulopathy (Fanconi syndrome); the appropriate response is to switch from TDF to TAF or another agent with lower systemic tenofovir exposure and to monitor renal function.
Option A: Option A is incorrect: glucosuria with normal serum glucose specifically argues against diabetic glucosuria and points to tubular dysfunction.
Option B: Option B is incorrect: this is a tenofovir tubular effect, not an NNRTI hypersensitivity.
Option D: Option D is incorrect: the renal tubular pattern is not abacavir hypersensitivity, which presents as a systemic reaction within weeks.
Option E: Option E is incorrect: the picture is a proximal tubulopathy, not lactic acidosis, and bicarbonate is not the definitive management.
16. Before initiating antiretroviral therapy in a newly diagnosed, treatment-naive patient, which step is required to ensure each regimen component will actually be active, and why?
A) Baseline HIV genotype resistance testing, because transmitted resistance mutations can silently inactivate one or more components and reduce a regimen to functional monotherapy or dual therapy
B) Routine therapeutic drug monitoring of NRTI plasma levels, because plasma levels predict intracellular activity
C) Empiric avoidance of all NRTIs until the CD4 count normalizes
D) HLA-B*57:01 testing alone, which is sufficient to confirm full regimen activity
E) No pretreatment testing, because modern regimens are universally active against all circulating virus
ANSWER: A
Rationale:
Baseline HIV genotype resistance testing is required before starting or changing ART because transmitted or archived resistance can render a component inactive without obvious clinical signs, effectively reducing the regimen to functional monotherapy or dual therapy with predictable virologic failure.
Option B: Option B is incorrect: NRTI plasma levels do not reflect intracellular triphosphate activity, so routine monitoring is not the safeguard.
Option C: Option C is incorrect: delaying NRTIs until CD4 normalizes is not standard and does not address resistance.
Option D: Option D is incorrect: HLA-B*57:01 testing addresses abacavir hypersensitivity risk only and says nothing about viral drug susceptibility.
Option E: Option E is incorrect: transmitted resistance does occur, so pretreatment genotype testing remains necessary.
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