Chapter 36 — Antiviral Pharmacology — Module 1 — HIV Pharmacology Part 1: NRTIs and NNRTIs
1. [CASE 1 — QUESTION 1]
A 27-year-old man is newly diagnosed with HIV during a routine screening visit. He is asymptomatic with a CD4 count of 510 cells/microL and a plasma HIV RNA of 62,000 copies/mL. He is otherwise healthy, takes no medications, and has no hepatitis B virus (HBV) co-infection. He asks why he cannot simply take a single effective drug rather than a three-drug regimen. Which statement best explains the pharmacological basis for obligatory combination antiretroviral therapy (ART)?
A) A single agent cannot be dosed high enough to reach therapeutic plasma concentrations
B) Combination therapy is required only to reduce the cost of individual drugs
C) HIV replicates at an enormous daily rate using an error-prone reverse transcriptase that lacks proofreading, so mutants resistant to any single drug pre-exist and are rapidly selected; multiple active drugs make simultaneous resistance to all components statistically improbable
D) Host antibodies neutralize single agents, so several drugs are needed to overwhelm them
E) Combination therapy is needed because each drug treats a different organism
ANSWER: C
Rationale:
Untreated HIV produces on the order of 10 billion virions per day, and reverse transcriptase lacks proofreading, generating roughly one mutation per genome per replication cycle; mutants resistant to any single drug therefore pre-exist and are rapidly selected by monotherapy. Using multiple active agents makes it statistically improbable that a single virion carries resistance to all of them, which is why combination ART is obligatory.
Option A: Option A is incorrect: monotherapy fails by resistance selection, not by inability to reach therapeutic plasma levels.
Option B: Option B is incorrect: cost is not the pharmacological basis for combination therapy.
Option D: Option D is incorrect: antibody neutralization does not explain monotherapy failure, which is driven by viral genetic diversity.
Option E: Option E is incorrect: all components treat the same virus; the rationale is resistance prevention, not different organisms.
2. [CASE 1 — QUESTION 2]
Continuing with the same patient, the team prepares to initiate therapy. Before selecting specific agents, which step is required to ensure each component will actually be active against his virus, and why?
A) Baseline HIV genotype resistance testing, because transmitted resistance mutations can silently inactivate one or more components and reduce a nominal three-drug regimen to functional dual or monotherapy
B) Therapeutic drug monitoring of NRTI plasma levels, because plasma levels reliably predict intracellular antiviral activity
C) Empiric avoidance of all NNRTIs until the CD4 count exceeds 700 cells/microL
D) HLA-B*57:01 testing alone, which is sufficient to confirm that the entire regimen will be active
E) No pretreatment testing, because transmitted resistance does not occur in newly diagnosed patients
ANSWER: A
Rationale:
Baseline HIV genotype resistance testing is recommended before initiating ART because transmitted resistance can render a component inactive without obvious clinical signs, effectively reducing the regimen to functional dual or monotherapy with predictable failure.
Option B: Option B is incorrect: NRTI plasma levels do not reflect intracellular triphosphate activity, so routine therapeutic drug monitoring is not the safeguard.
Option C: Option C is incorrect: there is no CD4 threshold that justifies empirically avoiding NNRTIs, and therapy should not be delayed.
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 in treatment-naive patients, which is precisely why baseline genotyping is advised.
3. [CASE 1 — QUESTION 3]
Continuing with the same patient, his baseline genotype returns showing transmitted K103N (lysine to asparagine at codon 103). A colleague nonetheless suggests an efavirenz-based regimen because efavirenz is inexpensive and once-daily. What is the predicted consequence of using efavirenz here?
A) Improved virologic response, because K103N enhances efavirenz binding
B) No change in outcome, because transmitted mutations are clinically irrelevant
C) Efavirenz toxicity rather than failure, because K103N raises efavirenz plasma levels
D) Full suppression, because three drugs were prescribed regardless of the mutation
E) A higher risk of virologic failure, because K103N confers high-level resistance to efavirenz, inactivating that component and reducing the regimen to two active drugs
ANSWER: E
Rationale:
K103N confers high-level resistance to efavirenz (and nevirapine); if efavirenz is used, that component is inactive, leaving only two active drugs and raising the risk of virologic failure and further resistance.
Option A: Option A inverts the effect: K103N reduces, not enhances, efavirenz activity.
Option B: Option B is incorrect: transmitted mutations are clinically important and directly affect drug selection.
Option C: Option C is incorrect: K103N causes loss of efavirenz activity, not elevated levels or toxicity.
Option D: Option D is incorrect: the count of prescribed drugs is irrelevant if one is inactive against the patient's virus.
4. [CASE 1 — QUESTION 4]
Continuing with the same patient with transmitted K103N, if an NNRTI-containing regimen is still desired for patient-specific reasons, which NNRTI is best supported by his resistance profile, and why?
A) Nevirapine, because it retains the highest genetic barrier in the class
B) Doravirine, because its resistance profile is largely non-overlapping with K103N, so it generally retains activity where efavirenz and nevirapine are compromised
C) Efavirenz, because K103N does not affect it at standard doses
D) Any first-generation NNRTI, because K103N affects only later-generation agents
E) No NNRTI can be used once any mutation is present, so the class must be abandoned
ANSWER: B
Rationale:
Doravirine's resistance profile is largely non-overlapping with K103N, so it generally retains activity against isolated K103N, whereas efavirenz and nevirapine are compromised; doravirine is therefore the rational NNRTI choice if an NNRTI regimen is desired.
Option A: Option A is incorrect: nevirapine has a very low genetic barrier and is compromised by K103N.
Option C: Option C is incorrect: K103N confers high-level efavirenz resistance.
Option D: Option D inverts the relationship: K103N affects first-generation agents while later-generation doravirine is spared.
Option E: Option E is incorrect: doravirine remains active against isolated K103N, so the class need not be abandoned.
5. [CASE 2 — QUESTION 1]
A 59-year-old woman with HIV has been on tenofovir disoproxil fumarate (TDF)/emtricitabine plus a cobicistat-boosted third agent for five years. She is hepatitis B virus surface antigen negative and virologically suppressed. Over the past year her serum creatinine has risen from 0.8 to 1.5 mg/dL, and today she has a serum phosphate of 1.8 mg/dL, glucosuria with a normal serum glucose, and new low-grade proteinuria. Which process best explains this constellation?
A) Immune-complex glomerulonephritis from chronic HIV infection
B) Prerenal azotemia from volume depletion that will fully reverse with fluids
C) Diabetic nephropathy, given the glucosuria
D) Tenofovir-associated proximal renal tubular dysfunction (Fanconi syndrome), in which proximal tubular tenofovir accumulation causes phosphate wasting, glucosuria with normal serum glucose, and proteinuria
E) Abacavir hypersensitivity reaction affecting the kidney
ANSWER: D
Rationale:
Glucosuria with normal serum glucose, hypophosphatemia from renal phosphate wasting, proteinuria, and a rising creatinine are the classic signature of TDF-induced proximal tubulopathy (Fanconi syndrome), driven by tenofovir accumulation in proximal tubular cells.
Option A: Option A is incorrect: the pattern is tubular, not a glomerulonephritis with an immune-complex picture.
Option B: Option B is incorrect: the chronic creatinine rise with tubular wasting is not simple reversible prerenal azotemia.
Option C: Option C is incorrect: glucosuria with a normal serum glucose specifically argues against diabetic glucosuria and points to tubular dysfunction.
Option E: Option E is incorrect: this is a tenofovir tubular effect; abacavir hypersensitivity is a systemic reaction within weeks of starting abacavir, not a chronic tubulopathy.
6. [CASE 2 — QUESTION 2]
Continuing with the same patient, the team reviews why her tenofovir toxicity may have been potentiated. How did the cobicistat in her regimen contribute to the proximal tubular injury?
A) Cobicistat is directly nephrotoxic to glomeruli independent of tenofovir
B) Cobicistat inhibits transporter-mediated tubular secretion of tenofovir, raising plasma tenofovir exposure and thereby increasing proximal tubular accumulation and toxicity
C) Cobicistat lowers plasma tenofovir, so it actually protects the tubule and is not contributory
E) Cobicistat has no pharmacokinetic interaction with tenofovir
ANSWER: B
Rationale:
Boosting agents such as cobicistat and ritonavir inhibit transporter-mediated tubular secretion of tenofovir, raising plasma tenofovir exposure (by roughly 30%) and increasing proximal tubular accumulation, which potentiates tenofovir nephrotoxicity.
Option A: Option A is incorrect: the mechanism is potentiation of tenofovir's tubular effect through increased exposure, not an independent glomerular nephrotoxin.
Option C: Option C inverts the effect: cobicistat raises, not lowers, tenofovir exposure.
Option D: Option D is incorrect: cobicistat does not interconvert the two tenofovir prodrugs.
Option E: Option E is incorrect: there is a meaningful pharmacokinetic interaction that increases tenofovir exposure.
7. [CASE 2 — QUESTION 3]
Continuing with the same patient, what is the most appropriate change to her nucleotide component, given that she is HBV surface antigen negative and virologically suppressed?
A) Switch tenofovir disoproxil fumarate to tenofovir alafenamide (TAF), which delivers tenofovir at roughly one-tenth the plasma exposure and substantially reduces renal and bone toxicity while preserving antiviral efficacy
B) Continue tenofovir disoproxil fumarate but add oral phosphate and proceed unchanged
C) Discontinue all tenofovir and leave the backbone with a single NRTI
D) Double the tenofovir disoproxil fumarate dose to overcome reduced clearance
E) Replace tenofovir with high-dose zidovudine
ANSWER: A
Rationale:
Because systemic tenofovir exposure drives the renal and bone toxicity, switching from TDF to TAF, which achieves efficacy at far lower plasma tenofovir exposure, addresses the cause while preserving regimen potency; she is HBV-negative and suppressed, so the switch is straightforward.
Option B: Option B is incorrect: continuing TDF perpetuates tubular injury, and phosphate repletion alone ignores the cause.
Option C: Option C is incorrect: dropping tenofovir to a single-NRTI backbone risks incomplete therapy and loss of suppression.
Option D: Option D is incorrect: increasing TDF raises systemic tenofovir exposure and worsens toxicity.
Option E: Option E is incorrect: zidovudine adds marrow and mitochondrial toxicity and is not a rational substitute for managing tenofovir renal effects.
8. [CASE 2 — QUESTION 4]
Continuing with the same patient, suppose instead that she had been hepatitis B virus (HBV) surface antigen positive. How would that change the safe approach to modifying her tenofovir-containing backbone?
A) HBV status would not matter, because the renal issue takes absolute priority and tenofovir could be stopped outright
B) She could safely drop both tenofovir and emtricitabine, since HIV suppression independently controls HBV
C) She would simply continue tenofovir disoproxil fumarate unchanged, since HBV co-infection precludes any tenofovir formulation change
D) Only emtricitabine would need to be retained; tenofovir could be dropped without HBV consequence
E) Because tenofovir and emtricitabine are her HBV-active therapy, the backbone must be maintained or replaced with equally HBV-active coverage simultaneously (for example switching to tenofovir alafenamide rather than removing tenofovir), since abrupt withdrawal of anti-HBV agents can precipitate a severe, potentially fatal HBV flare
ANSWER: E
Rationale:
In HBV co-infection, tenofovir plus emtricitabine constitute the anti-HBV therapy; abrupt withdrawal can cause a severe, potentially fatal HBV flare, so the backbone must be maintained or replaced with equally HBV-active coverage at the same time. Switching TDF to TAF preserves HBV activity while reducing renal exposure, making it the safe route.
Option A: Option A is incorrect: HBV status critically constrains the change; tenofovir cannot simply be stopped.
Option B: Option B is incorrect: HIV suppression does not maintain HBV control once active agents are removed.
Option C: Option C is incorrect: a formulation change to TAF is exactly what preserves HBV coverage while lowering toxicity, so co-infection does not preclude it.
Option D: Option D is incorrect: dropping tenofovir while keeping only emtricitabine weakens HBV coverage and risks resistance and flare.
9. [CASE 3 — QUESTION 1]
A 45-year-old man is newly diagnosed with HIV. Screening labs reveal he is also hepatitis B virus (HBV) surface antigen positive with detectable HBV DNA, indicating chronic HBV co-infection. His estimated glomerular filtration rate is normal. As his initial NRTI backbone is selected, which principle governs the choice?
A) Any two NRTIs are acceptable as long as a third agent is added for HIV
B) The backbone should specifically avoid tenofovir to prevent additive hepatotoxicity
C) The backbone should contain tenofovir (TDF or TAF) plus emtricitabine or lamivudine, because these agents are active against both HIV and HBV and treat the co-infection simultaneously
D) HBV should be treated with a separate non-antiretroviral agent while any HIV backbone is used
E) Lamivudine monotherapy for HBV is sufficient alongside the HIV regimen
ANSWER: C
Rationale:
In HIV/HBV co-infection, the backbone should contain tenofovir (TDF or TAF) plus emtricitabine or lamivudine because these agents are active against both viruses, treating the co-infection simultaneously and avoiding the pitfalls of inadequate HBV coverage.
Option A: Option A is incorrect: not any two NRTIs suffice; HBV-active agents are specifically required.
Option B: Option B is incorrect: tenofovir is specifically wanted here for its anti-HBV activity, not avoided.
Option D: Option D is incorrect: the same NRTI agents treat HBV, so a separate non-antiretroviral agent is unnecessary and the backbone choice is directly relevant.
Option E: Option E is incorrect: lamivudine alone risks HBV resistance, and effective dual-active coverage (tenofovir plus emtricitabine or lamivudine) is preferred.
10. [CASE 3 — QUESTION 2]
Continuing with the same patient, he is counseled never to stop his backbone abruptly. What is the pharmacological basis for the warning that abrupt discontinuation of emtricitabine or lamivudine is dangerous in his situation?
A) These agents accumulate to toxic levels if stopped suddenly
B) Stopping them precipitates an HIV integrase inhibitor withdrawal syndrome
C) These agents have no anti-HBV effect, so stopping them is actually harmless
D) Abrupt discontinuation triggers an abacavir hypersensitivity reaction
E) Emtricitabine and lamivudine suppress HBV replication, and abrupt withdrawal allows rapid rebound of HBV replication, which can cause a severe hepatitis flare and potentially fatal hepatic decompensation
ANSWER: E
Rationale:
Emtricitabine and lamivudine (and tenofovir) suppress HBV; abrupt withdrawal removes that suppression and allows HBV replication to rebound rapidly, which can produce a severe hepatitis flare and potentially fatal hepatic decompensation in a co-infected patient.
Option A: Option A is incorrect: the danger is loss of HBV suppression, not drug accumulation.
Option B: Option B is incorrect: there is no integrase inhibitor withdrawal syndrome; the risk is an HBV flare.
Option C: Option C is incorrect: these agents are anti-HBV active, so stopping them is far from harmless.
Option D: Option D is incorrect: the flare risk relates to loss of HBV suppression, not an abacavir hypersensitivity reaction.
11. [CASE 3 — QUESTION 3]
Continuing with the same patient, two years later he develops an intolerance to his third (non-backbone) agent and a regimen change is planned. What is the safe approach to the switch with respect to his HBV co-infection?
A) Stop the entire regimen for two weeks to washout before starting the new one
B) Replace the backbone with two agents that lack HBV activity, since only the third agent is the problem
C) Drop emtricitabine and continue tenofovir alone permanently
D) Change only the intolerable third agent while continuing the HBV-active tenofovir-plus-emtricitabine backbone uninterrupted, or substitute equally HBV-active coverage simultaneously, so HBV suppression is never lost
E) Switch entirely to an integrase inhibitor with no NRTI backbone
ANSWER: D
Rationale:
The safe approach is to alter only the intolerable third agent while continuing the HBV-active backbone uninterrupted (or substituting equally HBV-active coverage at the same time), so HBV suppression is never lost and a flare is avoided.
Option A: Option A is incorrect: a washout interrupts both HIV and HBV suppression and risks a flare and HIV rebound.
Option B: Option B is incorrect: replacing the backbone with non-HBV-active agents removes HBV coverage.
Option C: Option C is incorrect: dropping emtricitabine weakens HBV coverage and risks resistance.
Option E: Option E is incorrect: an integrase inhibitor alone provides no HBV coverage, so removing the NRTI backbone is exactly what must be avoided.
12. [CASE 3 — QUESTION 4]
Continuing with the same patient, several years later his estimated glomerular filtration rate declines to 48 mL/min/1.73m2 on a tenofovir disoproxil fumarate (TDF)-based backbone. He remains HBV co-infected and suppressed. What modification best preserves HBV coverage while reducing renal risk?
A) Switch from tenofovir disoproxil fumarate to tenofovir alafenamide (TAF), retaining tenofovir's anti-HBV activity while markedly lowering systemic tenofovir exposure and renal risk
B) Stop all tenofovir and rely on emtricitabine alone for HBV coverage
C) Replace tenofovir with abacavir, which provides equivalent HBV coverage with no renal handling
D) Continue tenofovir disoproxil fumarate unchanged because HBV co-infection forbids any change
E) Discontinue the backbone entirely and treat HBV with a separate course later
ANSWER: A
Rationale:
Switching TDF to TAF retains tenofovir's anti-HBV activity (preserving HBV suppression) while delivering tenofovir at far lower systemic exposure, reducing renal risk; this is the preferred maneuver in a co-infected patient with declining renal function.
Option B: Option B is incorrect: emtricitabine alone is inadequate HBV coverage and risks resistance and flare.
Option C: Option C is incorrect: abacavir is not an anti-HBV agent, so it cannot replace tenofovir's HBV coverage.
Option D: Option D is incorrect: a formulation change to TAF is exactly what preserves HBV coverage while reducing renal exposure, so co-infection does not forbid change.
Option E: Option E is incorrect: discontinuing the backbone removes HBV suppression and risks a severe flare.
13. [CASE 4 — QUESTION 1]
A 50-year-old man on long-standing, stable methadone maintenance is newly started on an efavirenz-based antiretroviral regimen. About ten days later he develops yawning, rhinorrhea, lacrimation, diffuse myalgias, abdominal cramping, and craving, without fever or rash. What is the most likely explanation for his symptoms?
A) Efavirenz central nervous system toxicity, which characteristically produces rhinorrhea and abdominal cramping
B) Efavirenz induction of CYP3A4 has lowered methadone plasma concentrations, precipitating opioid withdrawal in a patient previously stable on methadone
C) Efavirenz inhibition of CYP3A4 has raised methadone levels, causing opioid toxicity
D) An abacavir hypersensitivity reaction, presenting with withdrawal-like features
E) Methadone has induced efavirenz metabolism, causing efavirenz withdrawal symptoms
ANSWER: B
Rationale:
Efavirenz is a CYP3A4 inducer and lowers methadone plasma concentrations by roughly 50 to 60%, typically precipitating opioid withdrawal within one to two weeks in a patient previously stable on methadone; the somatic withdrawal features fit this timing and mechanism.
Option A: Option A is incorrect: efavirenz CNS effects are neuropsychiatric (vivid dreams, dizziness), not opioid-withdrawal features like rhinorrhea and cramping.
Option C: Option C inverts the mechanism: efavirenz induces rather than inhibits CYP3A4, lowering methadone levels.
Option D: Option D is incorrect: there is no fever or rash and the picture is opioid withdrawal, not abacavir hypersensitivity.
Option E: Option E reverses the interaction: efavirenz lowers methadone, not the other way around.
14. [CASE 4 — QUESTION 2]
Continuing with the same patient, what is the most appropriate management of the methadone interaction?
A) Discontinue methadone and rely on the antiretroviral regimen to manage his symptoms
B) Reduce the methadone dose, since efavirenz raises methadone concentrations
C) Add naloxone to counteract presumed methadone accumulation
D) Anticipate the interaction, counsel the patient about withdrawal symptoms, and coordinate a methadone dose increase with the prescribing methadone program
E) Stop efavirenz permanently and place the patient on no antiretroviral therapy
ANSWER: D
Rationale:
Because efavirenz lowers methadone concentrations through CYP3A4 induction, the appropriate response is to anticipate the interaction, counsel the patient, and coordinate a methadone dose increase with the prescribing program to restore adequate opioid agonist effect.
Option A: Option A is incorrect: discontinuing methadone abandons effective opioid agonist therapy and worsens withdrawal.
Option B: Option B inverts the direction: efavirenz lowers methadone, so reducing it would intensify withdrawal.
Option C: Option C is incorrect: the problem is reduced methadone exposure, not accumulation, so naloxone is inappropriate and dangerous.
Option E: Option E is incorrect: while switching to a non-inducing regimen is reasonable, leaving the patient on no antiretroviral therapy is not; therapy should be maintained and the methadone managed.
15. [CASE 4 — QUESTION 3]
Continuing with the same patient, the team also reviews his other medications and considers switching him to a regimen with fewer enzyme interactions. To illustrate the breadth of efavirenz's enzyme effects, which additional interaction is correctly characterized?
A) Efavirenz raises plasma concentrations of co-administered protease inhibitors, requiring dose reduction
B) Efavirenz inhibits CYP3A4 and increases combined oral contraceptive hormone levels
C) Efavirenz induces CYP3A4 and can reduce concentrations of combined oral contraceptive hormones and many protease inhibitors, so co-medications metabolized by CYP3A4 may require dose adjustment or alternatives
D) Efavirenz has no effect on protease inhibitor or contraceptive concentrations
E) Efavirenz selectively inhibits renal clearance of co-medications without affecting hepatic metabolism
ANSWER: C
Rationale:
Efavirenz is a CYP3A4 inducer and lowers concentrations of many co-medications metabolized by CYP3A4, including combined oral contraceptive hormones (reducing contraceptive reliability) and several protease inhibitors (often requiring dose adjustment); this breadth of induction is the core of its interaction profile.
Option A: Option A inverts the effect: efavirenz lowers, not raises, protease inhibitor concentrations.
Option B: Option B inverts the mechanism: efavirenz induces rather than inhibits CYP3A4, lowering hormone levels.
Option D: Option D is incorrect: efavirenz materially affects both protease inhibitors and contraceptives.
Option E: Option E is incorrect: the dominant effect is hepatic CYP3A4 induction, not selective inhibition of renal clearance.
16. [CASE 4 — QUESTION 4]
Continuing with the same patient, to avoid ongoing methadone dose instability, the team decides to replace the efavirenz component. Which replacement strategy best eliminates the CYP3A4-induction problem driving his withdrawal?
A) Switch to nevirapine, another first-generation NNRTI
B) Increase the efavirenz dose to stabilize its enzyme effect
C) Add a CYP3A4 inhibitor to counteract the induction while keeping efavirenz
D) Switch to a second efavirenz-containing co-formulation at a different time of day
E) Switch to a regimen without CYP-inducing activity, such as an integrase strand transfer inhibitor (INSTI)-based regimen or a non-inducing NNRTI like rilpivirine or doravirine, which removes the induction effect on methadone
ANSWER: E
Rationale:
The withdrawal is driven by efavirenz's CYP3A4 induction; switching to a regimen without CYP-inducing activity, such as an INSTI-based regimen or a non-inducing NNRTI (rilpivirine or doravirine), removes the inductive effect on methadone and stabilizes opioid agonist levels.
Option A: Option A is incorrect: nevirapine is also a CYP3A4 inducer and would not solve the problem.
Option B: Option B is incorrect: increasing efavirenz intensifies, not stabilizes, the induction.
Option C: Option C is incorrect: layering a CYP3A4 inhibitor onto an inducer creates an unpredictable interaction rather than a clean solution.
Option D: Option D is incorrect: another efavirenz formulation retains the same induction regardless of timing.
17. [CASE 5 — QUESTION 1]
A 36-year-old woman started an abacavir-containing regimen 9 days ago. She now presents with fever to 38.8°C, a diffuse rash, fatigue, myalgias, nausea, and vomiting. Review of her chart shows the abacavir was started without a documented HLA-B*57:01 result. What is the most likely diagnosis?
A) Abacavir hypersensitivity reaction (HSR), a systemic reaction typically occurring within the first six weeks of abacavir therapy and associated with the HLA-B*57:01 allele
B) Efavirenz central nervous system toxicity
C) Tenofovir-induced Fanconi syndrome
D) Immune reconstitution inflammatory syndrome unrelated to any specific drug
E) Nevirapine-induced Stevens-Johnson syndrome
ANSWER: A
Rationale:
Fever, rash, and constitutional plus gastrointestinal symptoms within the first six weeks of starting abacavir are the classic features of abacavir hypersensitivity reaction (HSR), which is associated with the HLA-B*57:01 allele.
Option B: Option B is incorrect: efavirenz CNS toxicity is neuropsychiatric, not a febrile systemic reaction with rash.
Option C: Option C is incorrect: tenofovir Fanconi syndrome is a proximal tubulopathy with electrolyte and urinary findings, not an acute febrile rash illness.
Option D: Option D is incorrect: the timing and features point specifically to abacavir HSR rather than a nonspecific immune reconstitution syndrome.
Option E: Option E is incorrect: although nevirapine can cause severe cutaneous reactions, this patient is on abacavir and the syndrome described is abacavir HSR.
18. [CASE 5 — QUESTION 2]
Continuing with the same patient, abacavir is stopped and her symptoms resolve over several days. What is the binding long-term instruction regarding future abacavir use?
A) Abacavir may be cautiously restarted after a negative HLA-B*57:01 test
B) Abacavir may be restarted at a reduced dose with antihistamine and corticosteroid premedication
C) Abacavir rechallenge is permanently contraindicated after a clinically suspected hypersensitivity reaction, because re-exposure can cause rapid, potentially fatal hypotension
D) Abacavir may be restarted once at least six months have elapsed
E) Abacavir may be restarted if the reaction is later attributed to another drug without further testing
ANSWER: C
Rationale:
Once an abacavir hypersensitivity reaction is clinically suspected, rechallenge is permanently contraindicated because re-exposure can precipitate rapid, severe, potentially fatal hypotension.
Option A: Option A is incorrect: a subsequent negative test does not license rechallenge after a clinical reaction; the prohibition stands.
Option B: Option B is incorrect: no premedication or dose reduction makes rechallenge safe.
Option D: Option D is incorrect: elapsed time does not remove the contraindication.
Option E: Option E is incorrect: rechallenge after a suspected HSR is unsafe and should not proceed on the basis of informal reattribution.
19. [CASE 5 — QUESTION 3]
Continuing with the same patient, the team reviews how this event could have been prevented. What is the correct role of HLA-B*57:01 screening in abacavir prescribing?
A) It is an optional test ordered only after a reaction occurs
B) It predicts abacavir efficacy rather than safety
C) It identifies CYP2B6 slow metabolizers at risk of abacavir neurotoxicity
D) It detects the K65R resistance mutation that would render abacavir ineffective
E) Prospective HLA-B*57:01 screening before initiation identifies patients at high risk of hypersensitivity, and avoiding abacavir in allele-positive patients reduces clinically suspected hypersensitivity reactions to near zero; screening is mandatory before abacavir use
ANSWER: E
Rationale:
Prospective HLA-B*57:01 screening before abacavir initiation identifies patients at high risk for hypersensitivity; avoiding abacavir in allele-positive patients reduces clinically suspected HSR to near zero, and screening is mandatory before prescribing abacavir.
Option A: Option A is incorrect: screening must be done before initiation, not only after a reaction.
Option B: Option B is incorrect: the test predicts hypersensitivity risk (safety), not efficacy.
Option C: Option C is incorrect: CYP2B6 slow-metabolizer status relates to efavirenz CNS toxicity, not abacavir HSR.
Option D: Option D is incorrect: K65R is a resistance mutation affecting drug activity, not the pharmacogenetic safety screen for abacavir.
20. [CASE 5 — QUESTION 4]
Continuing with the same patient, a replacement NRTI backbone must now be chosen. Abacavir is permanently excluded after her hypersensitivity reaction. She also has moderately reduced renal function (estimated glomerular filtration rate 45 mL/min/1.73m2) and is hepatitis B virus surface antigen negative. Which approach to the backbone is most appropriate?
A) Rechallenge abacavir at a low dose since it spares the kidney
B) Use a tenofovir alafenamide (TAF)-based backbone with emtricitabine, since abacavir is now excluded and TAF provides effective coverage with much lower renal exposure than tenofovir disoproxil fumarate, with dose attention to her renal function
C) Use high-dose tenofovir disoproxil fumarate (TDF) to ensure potency despite her renal function
D) Use zidovudine plus didanosine to avoid both abacavir and tenofovir
E) Withhold all NRTIs and treat with a single agent
ANSWER: B
Rationale:
With abacavir permanently excluded and moderately reduced renal function, a TAF-based backbone with emtricitabine provides effective coverage at far lower systemic tenofovir exposure than TDF, with appropriate attention to renal dosing; this best balances efficacy and renal safety.
Option A: Option A is incorrect: abacavir rechallenge is permanently contraindicated after her HSR regardless of renal advantage.
Option C: Option C is incorrect: high-dose TDF increases systemic tenofovir exposure and renal risk, the wrong direction for her renal function.
Option D: Option D is incorrect: zidovudine and didanosine carry high mitochondrial toxicity (didanosine is largely withdrawn) and are not appropriate.
Option E: Option E is incorrect: dropping to single-agent therapy is functional monotherapy and would select resistance.
21. [CASE 6 — QUESTION 1]
A 41-year-old man with a history of inconsistent adherence is on a lamivudine-containing regimen and is found to have virologic failure with an HIV RNA of 24,000 copies/mL. A genotype shows isolated M184V (methionine to valine at codon 184) with no other resistance mutations. How should this single finding be interpreted?
A) The entire NRTI class is lost and no NRTI can be used
B) Tenofovir is now resistant because M184V confers tenofovir resistance
C) Zidovudine and tenofovir are resistant while lamivudine remains fully active
D) Lamivudine and emtricitabine are compromised by M184V, but the mutation increases susceptibility to zidovudine and tenofovir and reduces viral replicative fitness
E) M184V confers resistance to integrase inhibitors
ANSWER: D
Rationale:
M184V causes high-level resistance to lamivudine and emtricitabine but simultaneously increases susceptibility to zidovudine, tenofovir, and abacavir and reduces viral replicative fitness, so a tenofovir-based backbone remains useful.
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 inverts the effect: M184V increases tenofovir susceptibility rather than conferring resistance.
Option C: Option C inverts the relationship: it is lamivudine and emtricitabine that are compromised, while zidovudine and tenofovir are favored.
Option E: Option E is incorrect: M184V is a reverse transcriptase mutation and does not confer integrase inhibitor resistance.
22. [CASE 6 — QUESTION 2]
Continuing with the same patient, the new regimen is anchored by a high-barrier integrase inhibitor plus tenofovir alafenamide, and the team debates whether to retain lamivudine despite the M184V call. Which reasoning best supports keeping lamivudine?
A) M184V imposes a viral fitness cost and sustains increased susceptibility to companion agents such as tenofovir, so retaining lamivudine preserves selective pressure that keeps the virus less fit and the partner drugs more effective, even though lamivudine itself is no longer fully active
B) M184V reverts to wild type once lamivudine is restarted, restoring full lamivudine activity
C) Lamivudine acts at a different viral enzyme, so reverse transcriptase resistance does not affect it
D) Retaining lamivudine eliminates the need for the integrase inhibitor
E) M184V increases lamivudine potency, directly strengthening the backbone
ANSWER: A
Rationale:
M184V reduces viral replicative fitness and sustains increased susceptibility to tenofovir, zidovudine, and abacavir; retaining lamivudine maintains selective pressure for M184V, keeping the virus less fit and companion agents more effective, which is the accepted rationale for keeping lamivudine or emtricitabine when the rest of the regimen is fully active.
Option B: Option B is incorrect: M184V does not revert while drug pressure continues.
Option C: Option C is incorrect: lamivudine acts at reverse transcriptase, so its resistance there is directly relevant.
Option D: Option D is incorrect: a fully active regimen still requires the integrase inhibitor; retained lamivudine does not substitute for it.
Option E: Option E is incorrect: M184V reduces lamivudine activity rather than increasing potency; the benefit is the fitness cost and resensitization, not direct potency.
23. [CASE 6 — QUESTION 3]
Continuing with the same patient, suppose that an alternative regimen had instead been built on rilpivirine, and that he had achieved suppression. Months later, after a gastroenterologist started omeprazole for reflux, his viral load became detectable despite reliable tablet adherence by pharmacy records. What is the most likely cause?
A) Spontaneous rilpivirine resistance independent of any medication
B) Proton pump inhibitor (PPI)-induced gastric acid suppression reduced rilpivirine absorption to subtherapeutic levels, because rilpivirine absorption is acid-dependent and PPIs are contraindicated with it
C) Omeprazole raised rilpivirine to toxic levels, paradoxically causing viral rebound
D) The detectable viral load is a laboratory artifact requiring no action
E) Omeprazole induced rilpivirine metabolism through CYP3A4
ANSWER: B
Rationale:
Rilpivirine absorption depends on gastric acidity, and PPIs are contraindicated because sustained acid suppression lowers rilpivirine absorption to subtherapeutic levels regardless of timing; with reliable adherence and a temporally linked omeprazole start, this interaction is the most likely cause of rebound.
Option A: Option A is incorrect: the reversible, temporally linked interaction is the obvious explanation rather than assumed spontaneous resistance.
Option C: Option C inverts the interaction: PPIs lower, not raise, rilpivirine levels.
Option D: Option D is incorrect: a detectable viral load in this context is not a mere artifact.
Option E: Option E is incorrect: the dominant mechanism is reduced acid-dependent absorption, not CYP3A4 induction by omeprazole.
24. [CASE 6 — QUESTION 4]
Continuing with the same patient on the rilpivirine-based regimen, what is the most appropriate corrective action for the interaction that caused his rebound?
A) Double the rilpivirine dose to overcome the proton pump inhibitor effect
B) Continue the omeprazole but separate it from rilpivirine by two hours
C) Stop the proton pump inhibitor and manage his reflux with a compatible strategy (an appropriately timed histamine-2 receptor antagonist or antacid) or switch the antiretroviral regimen to one not dependent on gastric acidity, then reassess the viral load
D) Switch immediately to a protease inhibitor without any resistance assessment
E) Take no action, since the viral load will normalize on its own
ANSWER: C
Rationale:
Because the rebound stems from PPI-induced loss of acid-dependent rilpivirine absorption, the correct action is to stop the PPI and manage reflux with a compatible strategy (a timed H2 blocker or antacid) or switch to an antiretroviral not dependent on gastric acidity, then reassess the viral load.
Option A: Option A is incorrect: dose-doubling is not an approved strategy and does not reliably overcome the absorption defect.
Option B: Option B is incorrect: PPIs are contraindicated regardless of timing because they raise gastric pH for many hours, so temporal separation does not rescue absorption.
Option D: Option D is incorrect: switching blindly to a protease inhibitor without resistance assessment skips appropriate evaluation of a reversible cause.
Option E: Option E is incorrect: a sustained detectable viral load requires corrective action, not observation alone.
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