Chapter 36 — Antiviral Pharmacology — Module 1 — HIV Pharmacology Part 1: NRTIs and NNRTIs
1. A 61-year-old man with HIV on tenofovir disoproxil fumarate (TDF)/emtricitabine plus dolutegravir for four years presents with fatigue and bone pain. Labs show serum creatinine risen from 0.9 to 1.4 mg/dL, serum phosphate 1.9 mg/dL, glucosuria on urinalysis with a normal serum glucose, and new low-grade proteinuria. He is virologically suppressed and hepatitis B virus (HBV) surface antigen negative. What is the most appropriate next step?
A) Discontinue dolutegravir, as integrase inhibitors are the likeliest cause of this renal picture
B) Stop all antiretroviral therapy until renal function fully normalizes
C) Add a thiazide diuretic to correct the hypophosphatemia
D) Switch tenofovir disoproxil fumarate to tenofovir alafenamide (TAF), since the findings indicate tenofovir-associated proximal tubulopathy (Fanconi syndrome) and TAF produces far lower systemic tenofovir exposure
E) Increase oral phosphate and continue the current regimen unchanged
ANSWER: D
Rationale:
Glucosuria with normal serum glucose, hypophosphatemia from renal phosphate wasting, proteinuria, and a creatinine rise are the classic signature of TDF-induced proximal tubulopathy (Fanconi syndrome). Because the patient is HBV-negative and suppressed, switching TDF to TAF, which delivers tenofovir at roughly one-tenth the plasma exposure, addresses the cause while preserving the regimen's potency.
Option A: Option A is incorrect: this tubular pattern is characteristic of tenofovir, not dolutegravir.
Option B: Option B is incorrect: stopping all ART risks rebound and resistance; the correct move is to replace the offending agent.
Option C: Option C is incorrect: a thiazide does not treat tubular phosphate wasting and adds volume and electrolyte risk without addressing the cause.
Option E: Option E is incorrect: continuing TDF perpetuates the tubular injury, and phosphate repletion alone ignores the underlying drug toxicity.
2. A 34-year-old woman started an abacavir/lamivudine/dolutegravir regimen 12 days ago. She presents with fever to 38.7°C, a diffuse maculopapular rash, malaise, myalgias, nausea, and abdominal discomfort. Her pre-prescription chart shows no documented HLA-B*57:01 result. What is the correct immediate management and the binding long-term instruction?
A) Continue abacavir and add an antihistamine, since the rash is likely a benign drug exanthem
B) Stop abacavir now and permanently prohibit any future abacavir rechallenge, because the presentation is a hypersensitivity reaction and re-exposure can cause fatal hypotension
C) Hold abacavir for 48 hours, then resume at a reduced dose with corticosteroid cover
D) Send HLA-B*57:01 testing and continue abacavir while results are pending
E) Switch only the dolutegravir, since the integrase inhibitor is the most likely trigger
ANSWER: B
Rationale:
Fever, rash, and constitutional plus gastrointestinal symptoms within the first six weeks of abacavir are a clinical hypersensitivity reaction (HSR). Abacavir must be stopped immediately, and rechallenge must be permanently prohibited because re-exposure after a suspected HSR can precipitate rapid, potentially fatal hypotension.
Option A: Option A is incorrect: treating this as a benign exanthem and continuing abacavir is dangerous.
Option C: Option C is incorrect: no dose reduction or steroid cover makes rechallenge safe after a suspected HSR.
Option D: Option D is incorrect: a missed pre-prescription test does not justify continuing abacavir during an active reaction; the drug must be stopped on clinical grounds.
Option E: Option E is incorrect: the timing and syndrome point to abacavir, not dolutegravir, as the trigger.
3. A 47-year-old man on stable methadone maintenance (no recent dose changes) is initiated on an efavirenz-based regimen. Ten days later he reports yawning, rhinorrhea, diffuse myalgias, abdominal cramping, anxiety, and craving. His HIV labs are otherwise unremarkable. What is the most likely explanation and the appropriate response?
A) Efavirenz has inhibited methadone metabolism, raising methadone levels; reduce the methadone dose
B) The symptoms are unrelated to efavirenz and represent a primary anxiety disorder; refer to psychiatry only
C) Methadone has induced efavirenz clearance, causing efavirenz withdrawal; increase efavirenz
D) Efavirenz has caused central nervous system toxicity that mimics withdrawal; lower the efavirenz dose
E) Efavirenz has induced CYP3A4 and lowered methadone concentrations, precipitating opioid withdrawal; coordinate a methadone dose increase with the methadone program
ANSWER: E
Rationale:
The constellation is classic opioid withdrawal arising about one to two weeks after starting efavirenz. Efavirenz is a CYP3A4 inducer and lowers methadone plasma concentrations by roughly 50 to 60%, so the appropriate response is to anticipate withdrawal and coordinate a methadone dose increase with the prescribing program.
Option A: Option A inverts the mechanism: efavirenz induces rather than inhibits, lowering methadone levels, so reducing methadone would worsen withdrawal.
Option B: Option B is incorrect: the temporal link to efavirenz and the somatic features point to a pharmacologic interaction, not a primary anxiety disorder.
Option C: Option C reverses the interaction: efavirenz lowers methadone, not the other way around.
Option D: Option D is incorrect: efavirenz CNS effects are not opioid-withdrawal symptoms like rhinorrhea and cramping, and lowering efavirenz does not address the methadone deficit.
4. A 29-year-old treatment-naive man is newly diagnosed with HIV. His pretreatment plasma HIV RNA is 420,000 copies/mL and his CD4 count is 140 cells/microL. A clinic colleague suggests a rilpivirine-based single-tablet regimen because of its tolerability. What is the most appropriate response to this suggestion?
A) Avoid rilpivirine as initial therapy in this patient, because virologic failure rates are higher when the baseline viral load exceeds 100,000 copies/mL or the CD4 count is below 200 cells/microL, and select a regimen better suited to high baseline viremia
B) Proceed with rilpivirine but double the dose to match the high viral load
C) Proceed with rilpivirine and add a proton pump inhibitor to improve absorption at high viral loads
D) Proceed with rilpivirine because tolerability outweighs efficacy concerns in all patients
E) Defer all therapy until the CD4 count rises above 200 on its own
ANSWER: A
Rationale:
Rilpivirine is not recommended 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 in these groups; this patient meets both criteria, so an alternative (for example an integrase inhibitor-based regimen) is appropriate.
Option B: Option B is incorrect: dose-doubling is not an approved strategy and does not address the failure-rate concern.
Option C: Option C is incorrect: proton pump inhibitors are contraindicated with rilpivirine because they reduce its absorption, the opposite of helping.
Option D: Option D is incorrect: tolerability does not override a defined efficacy-based exclusion at this viral load and CD4 count.
Option E: Option E is incorrect: current guidance is to initiate ART promptly in all patients regardless of CD4, not to defer therapy.
5. A 52-year-old woman co-infected with HIV and hepatitis B virus (HBV) is maintained on tenofovir alafenamide (TAF)/emtricitabine plus an integrase inhibitor and is fully suppressed. She develops an intolerance to the integrase inhibitor. A covering clinician proposes switching her to a regimen that drops the tenofovir/emtricitabine backbone in favor of two entirely different agents. What is the critical safety issue with this plan?
A) Dropping the backbone is fine because integrase inhibitors independently control HBV
B) The plan is acceptable as long as the new agents are taken with food
C) Removing tenofovir and emtricitabine eliminates her only HBV-active therapy, and abrupt withdrawal of anti-HBV agents can trigger a severe, potentially fatal HBV flare; HBV-active coverage must be maintained or replaced simultaneously
D) The plan poses no HBV risk because HIV suppression keeps HBV permanently suppressed
E) Only emtricitabine needs to be retained; tenofovir can be dropped without HBV consequence
ANSWER: C
Rationale:
Tenofovir and emtricitabine are this patient's anti-HBV therapy. Abruptly removing effective HBV coverage can cause rebound HBV replication and a severe, potentially fatal hepatic flare, so any switch must continue these agents or substitute equally HBV-active drugs at the same time; only the intolerable agent should be changed.
Option A: Option A is incorrect: integrase inhibitors have no anti-HBV activity.
Option B: Option B is incorrect: food timing is irrelevant to the HBV-flare risk created by removing active agents.
Option D: Option D is incorrect: HIV suppression does not maintain HBV control once the active anti-HBV drugs are withdrawn.
Option E: Option E is incorrect: dropping tenofovir while keeping only emtricitabine weakens HBV coverage and risks resistance and flare.
6. A 38-year-old man on a doravirine/tenofovir alafenamide (TAF)/lamivudine single-tablet regimen is diagnosed with smear-positive pulmonary tuberculosis (TB). The TB service plans to start a standard rifampin-containing regimen. He is currently HIV-suppressed. What is the most appropriate antiretroviral action?
A) Continue doravirine unchanged, since rifampin has no meaningful effect on it
B) Continue doravirine but separate it from rifampin by eight hours each day
C) Reduce the doravirine dose, since rifampin will raise its concentration
D) Delay TB treatment until HIV therapy is complete to avoid the interaction
E) Change the antiretroviral regimen because rifampin is a strong CYP3A4 inducer that lowers doravirine exposure by roughly 88%, making the combination contraindicated; use a rifampin-compatible regimen or coordinate a rifamycin-sparing TB approach
ANSWER: E
Rationale:
Doravirine is a CYP3A4 substrate, and rifampin's strong induction reduces its area under the curve by approximately 88%, driving it subtherapeutic; the combination is contraindicated. With active TB requiring prompt treatment, the antiretroviral regimen should be switched to one compatible with rifampin (for example an appropriately dosed integrase inhibitor-based regimen) or a rifamycin-sparing TB approach coordinated.
Option A: Option A is incorrect: the interaction is severe, not negligible.
Option B: Option B is incorrect: temporal separation does not overcome enzyme induction.
Option C: Option C inverts the effect: rifampin lowers, not raises, doravirine.
Option D: Option D is incorrect: active TB must be treated promptly and cannot be deferred for HIV therapy.
7. A 25-year-old treatment-naive woman has a baseline HIV genotype showing isolated K103N (lysine to asparagine at codon 103). Her viral load is 38,000 copies/mL and CD4 is 480 cells/microL. For patient-preference reasons an oral NNRTI-containing regimen is being considered. Which choice is best supported by her resistance profile?
A) Efavirenz, because K103N does not reduce its activity
B) Doravirine, because it generally retains activity against isolated K103N, whereas efavirenz and nevirapine are compromised by this mutation
C) Nevirapine, because K103N selectively spares it
D) Any first-generation NNRTI, since K103N affects only second-generation agents
E) No NNRTI is possible, so an NNRTI-containing regimen must be abandoned outright
ANSWER: B
Rationale:
K103N confers high-level resistance to efavirenz and nevirapine but generally spares doravirine, whose resistance profile is largely non-overlapping with K103N; doravirine is therefore the rational NNRTI choice here, and her viral load and CD4 do not preclude it.
Option A: Option A is incorrect: K103N confers high-level efavirenz resistance.
Option C: Option C is incorrect: nevirapine is also compromised by K103N.
Option D: Option D inverts the relationship: K103N affects first-generation agents while later-generation doravirine is spared.
Option E: Option E is incorrect: an NNRTI regimen remains feasible because doravirine retains activity against isolated K103N.
8. A 31-year-old woman who is 9 weeks pregnant is newly diagnosed with HIV and needs to start antiretroviral therapy. She asks specifically about efavirenz because she read older warnings about birth defects. Based on the current evidence regarding efavirenz in pregnancy, what is the most accurate counseling and plan?
A) Efavirenz is absolutely contraindicated in the first trimester because it reliably causes neural tube defects
B) Efavirenz must be stopped immediately if already taken, and the pregnancy monitored as high risk solely due to efavirenz exposure
C) Efavirenz should be combined with high-dose folate as the sole mitigation, with no other regimen considerations
D) Larger epidemiologic data, including a meta-analysis of more than 2,000 first-trimester exposures, did not show a significant increase in neural tube defects above the background rate, so efavirenz is acceptable in pregnancy, though integrase inhibitor-based or rilpivirine-based regimens are generally preferred for their cleaner data
E) Efavirenz is the single preferred agent in all pregnant patients and alternatives should not be offered
ANSWER: D
Rationale:
Early case reports prompted a neural tube defect concern and a prior restrictive classification, but subsequent larger epidemiologic data, including a meta-analysis of more than 2,000 first-trimester exposures, found no significant increase above the background rate; current guidance considers efavirenz acceptable in pregnancy, while integrase inhibitor-based or rilpivirine-based regimens are generally preferred for their cleaner data profiles.
Option A: Option A is incorrect: the feared reliable teratogenicity was not borne out by larger data.
Option B: Option B is incorrect: abrupt discontinuation is not warranted, and exposure does not by itself mark the pregnancy as high risk.
Option C: Option C is incorrect: folate alone is not the framework, and regimen selection still matters.
Option E: Option E is incorrect: efavirenz is acceptable but not the universally preferred agent, and alternatives are in fact generally favored.
9. A 67-year-old man with HIV and advanced chronic kidney disease (estimated glomerular filtration rate 22 mL/min/1.73m2, not on dialysis) needs an NRTI backbone component that avoids tenofovir. He is hepatitis B virus surface antigen negative. His HLA-B*57:01 test is negative. Which NRTI is best suited to his renal status, and what made it usable here?
A) Abacavir, because it is primarily hepatically metabolized with minimal renal excretion and requires no renal dose adjustment, and the negative HLA-B*57:01 result makes hypersensitivity risk acceptably low
B) Tenofovir disoproxil fumarate at a reduced dose, because renal adjustment fully neutralizes its toxicity
C) Zidovudine at full dose, because it is renally inert
D) Full-dose lamivudine, because it does not depend on renal clearance
E) Tenofovir alafenamide, because it has no renal handling whatsoever
ANSWER: A
Rationale:
Abacavir is metabolized mainly by alcohol dehydrogenase and glucuronyl transferase with less than 2% renal excretion of unchanged drug and does not require renal dose adjustment, making it well suited to advanced chronic kidney disease; the negative HLA-B*57:01 result lowers hypersensitivity risk, which is what makes abacavir usable here.
Option B: Option B is incorrect: dose reduction does not eliminate tenofovir's proximal tubular toxicity, and the goal was to avoid tenofovir.
Option C: Option C is incorrect: zidovudine is not renally inert and carries marrow and mitochondrial toxicity.
Option D: Option D is incorrect: lamivudine is renally cleared and requires dose reduction in renal impairment, so full dose is inappropriate.
Option E: Option E is incorrect: tenofovir alafenamide still undergoes renal handling and dose considerations and remains a tenofovir prodrug, which the case sought to avoid.
10. A 44-year-old woman with HIV had an undetectable viral load for two years on a rilpivirine-based single-tablet regimen. Three months ago a gastroenterologist started omeprazole for erosive esophagitis. Today her HIV RNA is 6,500 copies/mL and her adherence to the antiretroviral tablet appears reliable by pharmacy refill records. What is the most likely cause and the best corrective action?
A) Spontaneous rilpivirine resistance unrelated to any medication; switch to a protease inhibitor immediately without further assessment
B) Laboratory error; repeat the viral load in six months with no other change
C) Proton pump inhibitor-induced acid suppression reduced rilpivirine absorption to subtherapeutic levels; stop the omeprazole, substitute a compatible acid-suppression strategy with appropriate timing or change the antiretroviral, and reassess the viral load
D) Omeprazole raised rilpivirine to toxic levels causing paradoxical viral rebound; lower the rilpivirine dose
E) The rebound reflects normal viral blips and requires no action
ANSWER: C
Rationale:
Rilpivirine absorption depends on gastric acidity, and proton pump inhibitors are contraindicated because sustained acid suppression lowers rilpivirine absorption to subtherapeutic levels regardless of timing. With reliable adherence and a temporally linked omeprazole start, the rebound is best explained by this interaction; the corrective action is to stop the omeprazole (using a timed H2 blocker or antacid, or changing the antiretroviral) and reassess.
Option A: Option A is incorrect: jumping to assumed resistance and an immediate protease inhibitor switch ignores the obvious, reversible interaction and skips resistance assessment.
Option B: Option B is incorrect: a viral load of 6,500 copies/mL is not a lab artifact to defer for six months.
Option D: Option D inverts the interaction: proton pump inhibitors lower, not raise, rilpivirine levels.
Option E: Option E is incorrect: 6,500 copies/mL exceeds transient blip range and demands action.
11. A 39-year-old man with intermittent adherence has virologic failure (HIV RNA 18,000 copies/mL) on a lamivudine-containing regimen. Genotype shows isolated M184V (methionine to valine at codon 184) with no other resistance mutations. The team designs a new regimen anchored by a high-barrier integrase inhibitor plus tenofovir alafenamide and is debating whether to keep lamivudine despite the M184V call. Which reasoning best supports retaining lamivudine?
A) M184V will revert once lamivudine is restarted, so lamivudine regains full activity
B) Lamivudine acts at a different viral enzyme, so reverse transcriptase resistance is irrelevant to it
C) Retaining lamivudine removes the need for the integrase inhibitor in the new regimen
D) M184V increases lamivudine potency, so keeping it strengthens the backbone directly
E) M184V imposes a viral fitness cost and sustains increased susceptibility to tenofovir, so maintaining lamivudine preserves selective pressure that keeps the virus less fit and the companion agents more effective, even though lamivudine itself is no longer fully active
ANSWER: E
Rationale:
M184V reduces viral replicative fitness and is associated with sustained increased susceptibility to tenofovir, zidovudine, and abacavir. Retaining lamivudine maintains selective pressure for M184V, keeping the virus less fit and the companion agents (here tenofovir alafenamide) more effective, which is the accepted rationale for keeping lamivudine or emtricitabine despite the resistance call when the rest of the regimen is fully active.
Option A: Option A is incorrect: M184V does not revert while drug pressure continues.
Option B: Option B is incorrect: lamivudine acts at reverse transcriptase, so its resistance there is directly relevant.
Option C: Option C is incorrect: a fully active regimen still requires the integrase inhibitor; the retained lamivudine does not substitute for it.
Option D: Option D is incorrect: M184V reduces lamivudine activity rather than increasing its potency; the benefit is the fitness cost and companion-drug resensitization, not direct lamivudine potency.
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