Chapter 36 — Antiviral Pharmacology — Module 1 — HIV Pharmacology Part 1: NRTIs and NNRTIs
1. Nucleoside reverse transcriptase inhibitors (NRTIs) terminate synthesis of the viral DNA strand once incorporated by reverse transcriptase. What structural feature of the activated NRTI is directly responsible for this chain-terminating action?
A) An extra phosphate group that the viral polymerase cannot cleave
B) A modified nitrogenous base that cannot pair with the template strand
C) Absence of a 3-prime hydroxyl group on the sugar, preventing addition of the next nucleotide
D) A bulky side chain that physically blocks the reverse transcriptase active site
E) Covalent crosslinking of the two DNA strands after incorporation
ANSWER: C
Rationale:
Activated NRTI triphosphates are recognized by HIV reverse transcriptase as substrates and incorporated into the growing viral DNA strand. Because they lack a 3-prime hydroxyl group on the ribose ring, no phosphodiester bond can form with an incoming nucleotide, so the chain cannot be extended (obligate chain termination).
Option A: Option A is incorrect: all incorporated nucleotides arrive as triphosphates, and it is the missing 3-prime hydroxyl, not an uncleavable phosphate, that halts synthesis.
Option B: Option B is incorrect: NRTIs base-pair normally with the template; termination is a sugar-backbone effect, not a base-pairing failure.
Option D: Option D describes the allosteric mechanism of NNRTIs, not NRTIs, which are incorporated into the strand rather than blocking the site sterically.
Option E: Option E is incorrect: NRTIs do not crosslink DNA strands; that is a property of certain alkylating agents, not antiretrovirals.
2. Combination antiretroviral therapy (ART), using three or more active agents, is mandatory in all treated HIV patients. What is the central pharmacological reason monotherapy invariably fails?
A) HIV's enormous daily replication combined with an error-prone reverse transcriptase means resistant mutants to any single drug already exist and are quickly selected
B) Single antiretroviral agents are too toxic to dose high enough for viral suppression
C) HIV rapidly develops enzymes that chemically inactivate any single drug
D) The blood-brain barrier prevents any one drug from reaching adequate concentration
E) Host antibodies neutralize single agents before they reach infected cells
ANSWER: A
Rationale:
Untreated HIV-1 produces on the order of 10 billion virions daily, and reverse transcriptase (the viral RNA-dependent DNA polymerase) lacks proofreading, generating roughly one mutation per genome per replication cycle. Consequently, mutants resistant to any single agent pre-exist in the viral population; a single drug that does not fully suppress replication simply selects these mutants within days to weeks. Using multiple agents simultaneously makes it statistically improbable that a single virion carries resistance to all of them.
Option B: Option B is incorrect: monotherapy fails through resistance selection, not because single agents cannot be dosed adequately.
Option C: Option C is incorrect: HIV resistance arises through mutation of drug targets, not by elaborating drug-inactivating enzymes.
Option D: Option D is incorrect: CNS penetration is a real but secondary concern and does not explain why monotherapy fails systemically.
Option E: Option E is incorrect: antibody neutralization does not account for pharmacologic monotherapy failure, which is driven by viral genetic diversity.
3. A pharmacology student notes that plasma concentrations of lamivudine do not predict its intracellular antiviral activity well. Which property of NRTIs explains this disconnect?
A) NRTIs are highly protein-bound, so only a small free fraction is ever active
B) NRTIs are rapidly metabolized by hepatic cytochrome P450 enzymes
C) NRTIs are actively pumped out of cells by efflux transporters before acting
D) NRTIs bind plasma lipoproteins that sequester them away from lymphocytes
E) NRTIs are prodrugs that must be phosphorylated inside the cell to an active triphosphate with its own, often longer, intracellular half-life
ANSWER: E
Rationale:
NRTIs enter cells as inactive prodrugs and are converted by host kinases to their active triphosphate forms. The intracellular triphosphate has a half-life independent of (and frequently longer than) the parent drug's plasma half-life; lamivudine's plasma half-life is roughly 5 to 7 hours while its intracellular triphosphate half-life is 10 to 19 hours, which is why plasma levels poorly predict activity and why once-daily dosing is feasible.
Option A: Option A is incorrect: protein binding does not explain the plasma-versus-intracellular activity gap that defines this class.
Option B: Option B is incorrect: NRTIs are notably NOT cytochrome P450 substrates, which is why they have few metabolic drug interactions.
Option C: Option C is incorrect: the governing factor is intracellular activation and triphosphate persistence, not efflux.
Option D: Option D is incorrect: lipoprotein sequestration is not the mechanism; obligate intracellular phosphorylation is.
4. Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are two prodrugs of the same active drug, tenofovir. Why is TAF generally associated with less kidney and bone toxicity than TDF?
A) TAF is a different active drug entirely and does not inhibit reverse transcriptase
B) TAF delivers tenofovir preferentially into target lymphocytes, achieving effective intracellular levels at roughly one-tenth the plasma tenofovir exposure of TDF
C) TAF is not renally cleared at all, so renal dose adjustment is never required
D) TAF includes a built-in nephroprotective agent that blocks proximal tubular uptake
E) TAF is given at a much higher milligram dose, saturating toxic transporters
ANSWER: B
Rationale:
TAF uses a phosphonamidate prodrug chemistry that delivers tenofovir into lymphocytes efficiently, producing high intracellular tenofovir diphosphate while keeping plasma tenofovir roughly ten-fold lower than TDF. Because systemic tenofovir exposure drives proximal tubular and bone toxicity, the lower plasma exposure translates into substantially less renal and bone harm at equivalent antiviral efficacy.
Option A: Option A is incorrect: both are prodrugs of the same active tenofovir and both inhibit reverse transcription.
Option C: Option C is incorrect: TAF still undergoes renal dose adjustment at low estimated glomerular filtration rate (eGFR), just at a lower threshold than TDF.
Option D: Option D is incorrect: TAF contains no separate nephroprotectant; the benefit comes from its pharmacokinetics.
Option E: Option E is incorrect: TAF is given at a far LOWER milligram dose (25 mg) than TDF (300 mg), the opposite of the statement.
5. Before prescribing abacavir, a clinician must order a specific pharmacogenetic test. What does this test identify, and why is it mandatory?
A) CYP2B6 slow-metabolizer status, which predicts abacavir neurotoxicity
B) Glucose-6-phosphate dehydrogenase deficiency, which predicts abacavir-induced hemolysis
C) Reduced kidney function, which predicts abacavir accumulation
D) The HLA-B*57:01 allele, which predicts a potentially fatal hypersensitivity reaction; screening reduces clinically suspected reactions to near zero
E) The K65R resistance mutation, which predicts abacavir treatment failure
ANSWER: D
Rationale:
Abacavir hypersensitivity reaction (HSR) occurs in roughly 5 to 8% of patients carrying the human leukocyte antigen B*57:01 (HLA-B*57:01) allele, typically within the first six weeks, and rechallenge after a confirmed reaction has caused fatal hypotension. Prospective HLA-B*57:01 screening before initiation lowers the rate of clinically suspected HSR to near zero and is therefore mandatory.
Option A: Option A is incorrect: CYP2B6 slow-metabolizer status relates to efavirenz CNS toxicity, not abacavir HSR.
Option B: Option B is incorrect: G6PD deficiency is not the relevant abacavir test; HLA-B*57:01 is.
Option C: Option C is incorrect: abacavir is primarily hepatically metabolized and does not require renal dose adjustment, so renal testing is not the gatekeeper.
Option E: Option E is incorrect: K65R is an NRTI resistance mutation affecting drug activity, not the pharmacogenetic safety screen required before abacavir.
6. The class-wide toxicities historically associated with NRTIs, including lactic acidosis, hepatic steatosis, peripheral neuropathy, and lipoatrophy, share a single mechanistic origin. What is it?
A) Off-target inhibition of mitochondrial DNA polymerase gamma (pol-gamma), impairing mitochondrial DNA replication and function
B) Induction of hepatic cytochrome P450 enzymes that generate toxic metabolites
C) Direct immune-mediated destruction of mitochondria by drug-specific antibodies
D) Chelation of intracellular magnesium required for ATP synthesis
E) Competitive inhibition of the host nuclear DNA polymerase, halting cell division
ANSWER: A
Rationale:
NRTI triphosphates have varying affinity for mitochondrial DNA polymerase gamma (pol-gamma). Inhibiting pol-gamma impairs replication of mitochondrial DNA (mtDNA), reducing mitochondrial function and producing the characteristic spectrum of lactic acidosis, hepatic steatosis, peripheral neuropathy, lipoatrophy, and cardiomyopathy; thymidine analogues such as zidovudine and stavudine have the highest affinity and risk.
Option B: Option B is incorrect: NRTIs are not cytochrome P450 substrates and do not act through P450-generated metabolites.
Option C: Option C is incorrect: the injury is biochemical inhibition of pol-gamma, not antibody-mediated.
Option D: Option D is incorrect: magnesium chelation is not the mechanism of NRTI mitochondrial toxicity.
Option E: Option E is incorrect: the relevant target is mitochondrial pol-gamma, not nuclear DNA polymerase; clinical toxicity tracks mitochondrial dysfunction, not arrested cell division.
7. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit the same enzyme as NRTIs but by a fundamentally different mechanism. How do NNRTIs act?
A) They are incorporated into the viral DNA strand and terminate elongation
B) They block the CD4 receptor, preventing reverse transcriptase from ever assembling
C) They bind an allosteric hydrophobic pocket near the reverse transcriptase active site, causing a conformational change that slows catalysis, without requiring intracellular phosphorylation
D) They competitively occupy the dNTP-binding site as nucleotide mimics
E) They inhibit integrase, preventing the proviral DNA from being made
ANSWER: C
Rationale:
NNRTIs bind a hydrophobic allosteric pocket on the p66 subunit of HIV reverse transcriptase, roughly 10 angstroms from the polymerase active site, inducing a conformational change that reduces the catalytic rate. Unlike NRTIs, they require no intracellular phosphorylation and are not incorporated into viral DNA.
Option A: Option A describes the NRTI chain-termination mechanism, not the NNRTI allosteric mechanism.
Option B: Option B is incorrect: NNRTIs do not act at the CD4 receptor; entry/co-receptor steps are a separate drug target.
Option D: Option D is incorrect: NNRTIs do NOT bind the substrate (dNTP) site as nucleotide mimics; that describes NRTIs.
Option E: Option E is incorrect: integrase inhibition is the mechanism of a different class (INSTIs), not NNRTIs, which act on reverse transcriptase.
8. A patient newly started on efavirenz reports vivid disturbing dreams, dizziness, and difficulty concentrating during the first two weeks. These symptoms represent which characteristic adverse effect of this drug?
A) Hypersensitivity reaction requiring immediate discontinuation and lifelong avoidance
B) Mitochondrial toxicity from pol-gamma inhibition
C) Lactic acidosis from impaired mitochondrial function
E) Central nervous system (CNS) toxicity, which is concentration-dependent and often improves after the first few weeks
ANSWER: E
Rationale:
Efavirenz's signature adverse effect is CNS toxicity: vivid or disturbing dreams, insomnia, dizziness, and impaired concentration, typically peaking in the first 2 to 4 weeks and improving in most patients, though persisting in roughly 10 to 15% at six months. Bedtime dosing places peak concentrations during sleep and reduces perceived severity, and effects are worse in CYP2B6 slow metabolizers.
Option A: Option A describes the abacavir HLA-B*57:01 hypersensitivity reaction, not efavirenz CNS effects.
Option B: Option B describes NRTI mitochondrial toxicity, not an NNRTI effect; efavirenz is not incorporated into DNA and does not inhibit pol-gamma.
Option C: Option C describes a downstream consequence of NRTI mitochondrial toxicity rather than an efavirenz effect.
Option D: Option D describes tenofovir (TDF) proximal tubular toxicity, not efavirenz, whose hallmark toxicity is neuropsychiatric rather than renal.
9. The M184V mutation (methionine to valine at reverse transcriptase codon 184) emerges quickly under lamivudine or emtricitabine pressure. Beyond conferring resistance to those two drugs, why is M184V paradoxically useful in backbone design?
A) It restores full susceptibility to all NNRTIs simultaneously
B) It increases viral susceptibility to zidovudine and tenofovir, partially offsetting other resistance and reducing viral fitness
C) It prevents any further resistance mutations from ever developing
D) It converts the virus to a non-replicating latent form
E) It eliminates the need for combination therapy in that patient
ANSWER: B
Rationale:
M184V confers high-level resistance to lamivudine (3TC) and emtricitabine (FTC) but simultaneously increases susceptibility to zidovudine, tenofovir, and abacavir and reduces viral replicative fitness. This resensitizing effect is part of the pharmacologic rationale for pairing tenofovir with 3TC or FTC: the resistance pathways partially antagonize one another.
Option A: Option A is incorrect: M184V is an NRTI-site mutation and does not restore NNRTI susceptibility.
Option C: Option C is incorrect: M184V does not prevent further mutations; additional resistance can still accumulate.
Option D: Option D is incorrect: M184V does not force latency; the virus continues replicating, just with altered drug susceptibility and reduced fitness.
Option E: Option E is incorrect: combination therapy remains mandatory regardless of M184V; no single mutation removes that requirement.
10. A patient co-infected with HIV and hepatitis B virus (HBV) is starting ART. Why does the choice of NRTI backbone carry special weight in this patient?
A) HBV co-infection makes all NRTIs ineffective against HIV
B) HBV co-infection mandates avoiding tenofovir because of additive liver toxicity
C) The backbone is irrelevant because HBV requires a completely separate antiviral class
D) Lamivudine, emtricitabine, and tenofovir are active against HBV as well as HIV, so the backbone should include them, and abruptly stopping them can trigger a dangerous HBV flare
E) Any NRTI backbone is acceptable as long as a protease inhibitor is added
ANSWER: D
Rationale:
Lamivudine (3TC), emtricitabine (FTC), and tenofovir (TDF or TAF) have potent anti-HBV activity in addition to anti-HIV activity. A co-infected patient should therefore receive a backbone of tenofovir plus 3TC or FTC to treat both viruses, and these agents must not be discontinued abruptly because rebound HBV replication can cause severe, potentially fatal hepatic flares.
Option A: Option A is incorrect: these NRTIs remain effective against HIV; co-infection does not nullify them.
Option B: Option B is incorrect: tenofovir is specifically wanted here for its anti-HBV activity, not avoided.
Option C: Option C is incorrect: the same NRTI agents treat HBV, so the backbone is highly relevant rather than separate.
Option E: Option E is incorrect: simply adding a protease inhibitor does not address HBV; the backbone must contain HBV-active agents and be managed to avoid withdrawal flares.
11. Tenofovir disoproxil fumarate (TDF) is taken up into renal proximal tubular cells where it can accumulate. Which clinical picture reflects this characteristic toxicity?
A) Proximal tubular dysfunction (Fanconi syndrome) with glucosuria despite normal blood glucose, phosphate wasting, and proteinuria
B) Glomerulonephritis with red-cell casts and hypertension
C) Obstructive uropathy from crystal precipitation in the collecting ducts
D) Pure prerenal azotemia that fully reverses with hydration alone
E) Papillary necrosis identical to chronic analgesic nephropathy
ANSWER: A
Rationale:
TDF is taken up by proximal tubular cells via organic anion transporter 1 (OAT1) and can accumulate to toxic levels, producing a proximal tubulopathy: Fanconi syndrome with glucosuria in the setting of normal blood glucose, hypophosphatemia from phosphate wasting, hyperuricosuria, and proteinuria, with or without a rise in serum creatinine. Boosting agents such as ritonavir or cobicistat increase intracellular accumulation and risk.
Option B: Option B is incorrect: the lesion is tubular, not a glomerulonephritis with red-cell casts.
Option C: Option C is incorrect: TDF causes a tubulopathy, not crystal-induced obstruction.
Option D: Option D is incorrect: the injury is a true tubular toxicity, not simply reversible prerenal azotemia.
Option E: Option E is incorrect: papillary necrosis is characteristic of chronic analgesic nephropathy, not tenofovir, which targets the proximal tubule.
12. Rilpivirine has two non-negotiable administration requirements that distinguish it from other NNRTIs. Which pair is correct?
A) Must be taken on an empty stomach and requires concurrent proton pump inhibitor therapy
B) Must be refrigerated and taken only at bedtime
C) Must be taken with a meal of adequate caloric content, and proton pump inhibitors (PPIs) are contraindicated because acid suppression reduces its absorption
D) Must be co-administered with grapefruit juice and avoided with any antacid for life
E) Must be given intravenously and paired with a CYP3A4 inducer
ANSWER: C
Rationale:
Rilpivirine absorption depends on gastric acidity and food. It must be taken with a meal of at least about 390 kcal (food raises its exposure by roughly 40%), and proton pump inhibitors are contraindicated because sustained acid suppression reduces rilpivirine dissolution and absorption to subtherapeutic levels. Histamine-2 receptor antagonists may be used only with strict timing separation.
Option A: Option A is incorrect on both counts: rilpivirine needs food, not an empty stomach, and PPIs are contraindicated rather than required.
Option B: Option B is incorrect: refrigeration and bedtime-only dosing are not rilpivirine requirements.
Option D: Option D is incorrect: grapefruit juice is not required, and antacids are not banned for life, only separated in time.
Option E: Option E is incorrect: rilpivirine is oral, not intravenous, and strong CYP3A4 inducers are contraindicated because they lower its levels.
13. A patient on stable methadone maintenance is started on efavirenz and develops opioid withdrawal symptoms within two weeks. What is the pharmacological basis of this interaction?
A) Efavirenz displaces methadone from plasma protein binding, lowering its activity
B) Efavirenz blocks the mu-opioid receptor competitively
C) Methadone inhibits efavirenz metabolism, causing efavirenz toxicity that mimics withdrawal
D) Efavirenz inhibits renal clearance of methadone, causing accumulation and tolerance
E) Efavirenz induces CYP3A4, accelerating methadone metabolism and reducing its plasma concentration by roughly 50 to 60%
ANSWER: E
Rationale:
Efavirenz is a CYP3A4 inducer and lowers methadone plasma concentrations by approximately 50 to 60%, precipitating opioid withdrawal in patients on previously stable methadone; the methadone dose typically must be escalated with close coordination with the methadone program.
Option A: Option A is incorrect: the mechanism is enzyme induction, not protein-binding displacement.
Option B: Option B is incorrect: efavirenz does not antagonize the mu-opioid receptor; the effect is pharmacokinetic.
Option C: Option C inverts the direction of the interaction: efavirenz induces methadone metabolism rather than methadone impairing efavirenz clearance.
Option D: Option D is incorrect: the effect is increased hepatic metabolism, not reduced renal clearance, and the clinical result is withdrawal from lower levels, not accumulation.
14. A treatment-naive patient's baseline genotype shows the K103N mutation (lysine to asparagine at codon 103). How should this finding guide NNRTI selection?
A) It mandates avoiding all NRTIs in the regimen
B) It confers high-level resistance to efavirenz and nevirapine while sparing later-generation NNRTIs such as rilpivirine and doravirine
C) It eliminates the entire NNRTI class as an option permanently
D) It indicates resistance to integrase inhibitors specifically
E) It has no effect on drug selection because it is not transmissible
ANSWER: B
Rationale:
K103N is the single most common transmitted HIV resistance mutation and confers high-level resistance to the first-generation NNRTIs efavirenz and nevirapine, while rilpivirine and doravirine generally retain activity. This is why baseline resistance testing is critical before choosing an NNRTI.
Option A: Option A is incorrect: K103N is an NNRTI-site mutation and does not by itself require avoiding NRTIs.
Option C: Option C is incorrect: the class is not eliminated; later-generation NNRTIs remain options against isolated K103N.
Option D: Option D is incorrect: K103N affects reverse transcriptase/NNRTI binding, not integrase inhibitors.
Option E: Option E is incorrect: K103N is in fact the most commonly transmitted resistance mutation and directly influences drug selection.
15. Among the commonly used NRTIs, which agent is least dependent on renal clearance and therefore often favored, after appropriate pharmacogenetic screening, in patients with advanced chronic kidney disease (CKD)?
A) Tenofovir disoproxil fumarate, because it is filtered and immediately reabsorbed intact
B) Emtricitabine, because it is fully metabolized by the liver
C) Lamivudine, because it undergoes extensive biliary excretion
D) Abacavir, because it is primarily hepatically metabolized with less than 2% renal excretion of unchanged drug and does not require renal dose adjustment
E) Zidovudine, because it has no active metabolites
ANSWER: D
Rationale:
Abacavir is metabolized primarily by alcohol dehydrogenase and glucuronyl transferase, with less than 2% of unchanged drug excreted renally, so it does not require renal dose adjustment and is often preferred (after HLA-B*57:01 screening) when kidney function is poor.
Option A: Option A is incorrect: TDF is renally handled and is associated with proximal tubular toxicity, making it less suitable in CKD.
Option B: Option B is incorrect: emtricitabine is renally cleared and requires dose reduction at low eGFR, not hepatically eliminated.
Option C: Option C is incorrect: lamivudine is renally cleared and dose-adjusted in renal impairment, not predominantly biliary.
Option E: Option E is incorrect: zidovudine undergoes glucuronidation but its active metabolite and dosing still require attention in renal impairment, and its marrow and mitochondrial toxicity, not renal independence, dominate its profile.
16. Earlier questions established that K65R is selected by tenofovir and that thymidine analogue mutations (TAMs) are selected by zidovudine. Applying that, why do tenofovir-resistance and zidovudine-resistance pathways tend not to coexist in the same virus?
A) K65R reduces the efficiency of the zidovudine-type excision (pyrophosphorolysis) reaction, so the K65R and TAM pathways are largely mutually antagonistic
B) Both mutations require the same single nucleotide change, so only one can occur
C) TAMs revert the virus to wild type, erasing K65R automatically
D) K65R and TAMs both abolish viral replication, so neither virus survives
E) The two mutations occur on different viral genes that never recombine
ANSWER: A
Rationale:
TAMs enhance reverse transcriptase's ability to excise an incorporated chain-terminating nucleotide by pyrophosphorolysis, allowing elongation to resume. K65R reduces the efficiency of this excision reaction, so a virus carrying K65R is poorly compatible with the TAM-mediated excision phenotype; the two pathways are largely mutually exclusive. This antagonism is the mechanistic basis for the earlier-noted reciprocal susceptibility between tenofovir and zidovudine resistance.
Option B: Option B is incorrect: the antagonism is functional, not a shared single nucleotide constraint.
Option C: Option C is incorrect: TAMs do not revert the genome or erase K65R.
Option D: Option D is incorrect: both viruses replicate; the issue is incompatibility of the two resistance mechanisms, not lethality.
Option E: Option E is incorrect: K65R and TAMs occur within the same reverse transcriptase gene, so separate-gene non-recombination is not the explanation.
17. Using the virologic suppression goal introduced earlier, which statement best applies that concept to a patient who has maintained a plasma HIV RNA below 50 copies/mL for two years on a stable regimen?
A) The patient can safely switch to monotherapy because the virus is now eradicated
B) The patient no longer requires baseline-active drugs because resistance can no longer develop
C) The patient is not expected to transmit HIV sexually and has near-normal life expectancy, but must remain on fully suppressive combination therapy indefinitely
D) The patient has cleared the integrated provirus and may discontinue ART
E) The patient's regimen can be reduced to a single NNRTI to limit toxicity
ANSWER: C
Rationale:
Sustained suppression below 50 copies/mL means the patient does not transmit HIV sexually (Undetectable = Untransmittable) and can expect near-normal life expectancy, but the integrated provirus persists, so fully suppressive combination therapy must continue indefinitely; stopping or reducing it permits rebound and resistance.
Option A: Option A is incorrect: suppression is not eradication, and monotherapy would select resistance.
Option B: Option B is incorrect: ongoing full suppression is precisely what prevents resistance; relaxing active-drug coverage invites it.
Option D: Option D is incorrect: ART does not clear the integrated provirus, so discontinuation leads to viral rebound.
Option E: Option E is incorrect: reducing to a single agent is functional monotherapy and would risk virologic failure.
18. Building on the CYP profiles described earlier, a patient with HIV requires rifampin-based tuberculosis (TB) therapy. Rifampin is a strong CYP3A4 inducer. Which NNRTI consideration follows correctly?
A) Rilpivirine is the ideal NNRTI here because its levels are unaffected by inducers
B) Doravirine is preferred with rifampin because rifampin barely changes its concentration
C) Nevirapine should be selected because it inhibits CYP3A4 and will counteract rifampin
D) All NNRTIs are equally unaffected by rifampin because none are CYP substrates
E) Doravirine and rilpivirine are CYP3A4 substrates whose levels are driven sharply subtherapeutic by rifampin, so they are contraindicated, whereas efavirenz can sometimes be used with a dose increase
ANSWER: E
Rationale:
Doravirine and rilpivirine are CYP3A4 substrates, so rifampin's strong induction lowers their exposure dramatically (doravirine area under the curve falls by roughly 88%), making those combinations contraindicated. Efavirenz, itself an inducer, is reduced only modestly by rifampin (about 25%) and can sometimes be continued with a dose adjustment.
Option A: Option A inverts the rilpivirine relationship: its levels are strongly reduced by inducers, and the combination is contraindicated.
Option B: Option B is incorrect: rifampin reduces doravirine markedly, which is the opposite of barely changing its concentration.
Option C: Option C is incorrect: nevirapine is a CYP3A4 inducer, not an inhibitor, and is not the answer to a rifampin interaction.
Option D: Option D is incorrect: rilpivirine and doravirine are CYP3A4 substrates and are very much affected by rifampin.
19. Lamivudine has a plasma half-life of only about 5 to 7 hours, yet it is dosed once daily. Applying the activation concept established earlier, which reasoning correctly justifies once-daily dosing?
A) Once-daily dosing is a compromise that accepts subtherapeutic troughs each evening
B) The active intracellular triphosphate has a substantially longer half-life (about 10 to 19 hours) than the parent drug in plasma, so antiviral activity persists between doses
C) Lamivudine irreversibly inactivates reverse transcriptase, so plasma levels no longer matter after the first dose
D) Lamivudine is stored in adipose tissue and released slowly into plasma overnight
E) The plasma half-life is irrelevant because lamivudine acts extracellularly on free virions
ANSWER: B
Rationale:
What matters for NRTI activity is the intracellular triphosphate, not the parent drug in plasma. Lamivudine's triphosphate persists about 10 to 19 hours intracellularly, well beyond its 5-to-7-hour plasma half-life, so once-daily dosing maintains antiviral effect; this directly applies the intracellular-activation principle established earlier.
Option A: Option A is incorrect: dosing is justified by triphosphate persistence, not by accepting subtherapeutic exposure.
Option C: Option C is incorrect: NRTIs cause chain termination during reverse transcription rather than irreversibly inactivating the enzyme for the cell's lifetime, and continued intracellular drug is what sustains activity.
Option D: Option D is incorrect: adipose storage is not the mechanism; intracellular triphosphate half-life is.
Option E: Option E is incorrect: NRTIs act inside the cell after phosphorylation, not extracellularly on free virions.
20. A student is asked to contrast the two reverse transcriptase inhibitor classes covered in this module. Which single statement correctly distinguishes NRTIs from NNRTIs across mechanism, activation, and spectrum?
A) Both classes require intracellular phosphorylation and both are active against HIV-1 and HIV-2
B) NRTIs bind an allosteric pocket while NNRTIs are incorporated into the DNA chain
C) NNRTIs require phosphorylation while NRTIs act without any activation step
D) NRTIs are incorporated into viral DNA as chain terminators and require intracellular phosphorylation, whereas NNRTIs bind an allosteric site without phosphorylation and are active only against HIV-1
E) Both classes are CYP3A4 inducers and neither is affected by reverse transcriptase mutations
ANSWER: D
Rationale:
NRTIs are prodrugs requiring intracellular phosphorylation and act by incorporation into viral DNA as obligate chain terminators; they are active against both HIV-1 and HIV-2. NNRTIs need no phosphorylation, bind an allosteric pocket on reverse transcriptase, are not incorporated into DNA, and are active only against HIV-1. Option D captures these distinctions correctly.
Option A: Option A is incorrect: NNRTIs do not require phosphorylation and are not active against HIV-2.
Option B: Option B reverses the two mechanisms.
Option C: Option C reverses the activation requirement.
Option E: Option E is incorrect: NRTIs are not CYP inducers, the first-generation NNRTIs (not NRTIs) are inducers, and both classes are very much affected by reverse transcriptase resistance mutations.
21. Applying the tenofovir transporter and toxicity concepts from earlier, a patient on tenofovir disoproxil fumarate (TDF) begins regular high-dose nonsteroidal anti-inflammatory drug (NSAID) use. Why does this combination warrant closer renal monitoring?
A) NSAIDs reduce renal perfusion through prostaglandin inhibition and compete at proximal tubular transport, both of which can potentiate tenofovir nephrotoxicity
B) NSAIDs induce CYP3A4, accelerating tenofovir activation to a toxic metabolite
C) NSAIDs displace tenofovir from plasma proteins, raising its free fraction to toxic levels
D) NSAIDs chelate tenofovir in the gut, paradoxically increasing its absorption
E) NSAIDs convert tenofovir into its more nephrotoxic alafenamide form
ANSWER: A
Rationale:
Tenofovir nephrotoxicity reflects proximal tubular accumulation; NSAIDs add insult two ways: they reduce renal perfusion via prostaglandin inhibition and they affect tubular handling, both increasing the risk of tenofovir-associated proximal tubular injury, so renal function should be watched more closely.
Option B: Option B is incorrect: tenofovir is not a CYP3A4 substrate, and the toxicity is not from a CYP-generated metabolite.
Option C: Option C is incorrect: protein-binding displacement is not the operative mechanism for tenofovir renal toxicity.
Option D: Option D is incorrect: NSAIDs do not chelate tenofovir to enhance absorption; the concern is renal, not absorptive.
Option E: Option E is incorrect: NSAIDs do not transform TDF into TAF; the formulations are distinct manufactured prodrugs.
22. A treatment-naive patient presents with a pretreatment plasma HIV RNA of 350,000 copies/mL. Applying the rilpivirine selection criteria introduced earlier, what is the correct conclusion?
A) Rilpivirine is preferred here because higher viral loads respond better to second-generation NNRTIs
B) Rilpivirine is acceptable provided it is taken on an empty stomach
C) Rilpivirine is contraindicated as initial therapy because of higher virologic failure rates when the pretreatment viral load exceeds 100,000 copies/mL (and when the CD4 count is low)
D) Rilpivirine dosing should simply be doubled to overcome the high viral load
E) Rilpivirine is contraindicated only if the patient also carries K103N
ANSWER: C
Rationale:
Rilpivirine is contraindicated as initial therapy when the pretreatment viral load is above 100,000 copies/mL or the CD4 count is below 200 cells/microL because of higher virologic failure rates in those groups; a viral load of 350,000 copies/mL falls squarely in that excluded range.
Option A: Option A inverts the criterion: high viral load argues against, not for, rilpivirine.
Option B: Option B is incorrect: rilpivirine must be taken WITH food, and food timing does not rescue the viral-load contraindication.
Option D: Option D is incorrect: dose-doubling is not an approved strategy and does not address the failure-rate concern.
Option E: Option E is incorrect: the viral-load threshold is an independent contraindication and does not require co-existing K103N (indeed rilpivirine often retains activity against isolated K103N).
This Web-based pharmacology and disease-based integrated teaching site is based on reference materials that are believed reliable and consistent with standards accepted at the time of development.
Possibility of error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete.
Users should confirm the information contained herein with other sources.
This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site.
Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals.
Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.
Medical or other information thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals.