Chapter 36 — Antiviral Pharmacology — Module 3 — HIV Pharmacology Part 3: ARV Drug Interactions, Toxicity, and Special Populations
1. A patient is started on a cobicistat-boosted regimen and takes several chronic medications. Integrating the concept that interaction magnitude scales with fraction metabolized by CYP3A4 (fm CYP3A4) and inhibitor potency, which co-medication will show the greatest proportional rise in exposure?
A) A drug eliminated almost entirely unchanged by the kidney
B) A drug with an fm CYP3A4 of approximately 0.2
C) A drug with an fm CYP3A4 greater than 0.9
D) A drug cleared predominantly by UGT2B7 glucuronidation
E) A drug that is a substrate of CYP2C9 only
ANSWER: C
Rationale:
Option C is correct. Because the proportional change in exposure during CYP3A4 inhibition is governed by how much of the drug's clearance depends on CYP3A4, a substrate with an fm CYP3A4 greater than 0.9 loses nearly its entire elimination pathway when a potent inhibitor such as cobicistat is present, producing the largest fold-rise in exposure.
Option A: Option A is incorrect. A renally eliminated drug has minimal CYP3A4-dependent clearance, so cobicistat has little effect on its exposure.
Option B: Option B is incorrect. A substrate with an fm CYP3A4 of about 0.2 retains most of its clearance through other routes, so the proportional rise is modest.
Option D: Option D is incorrect. A drug cleared mainly by UGT2B7 is not a primary CYP3A4 substrate and is relatively spared by a CYP3A4 inhibitor.
Option E: Option E is incorrect. A pure CYP2C9 substrate is not appreciably affected by CYP3A4 inhibition.
2. A patient on a ritonavir-boosted protease inhibitor (PI) needs lipid lowering. Integrating both the CYP3A4 and the hepatic uptake transporter (OATP1B1) interaction pathways, which statin strategy is safest?
A) Pravastatin, which avoids both significant CYP3A4 metabolism and major boosted-PI exposure increases
B) Simvastatin at standard dose
C) Lovastatin at standard dose
D) Rosuvastatin at maximum dose without regard to transporter effects
E) Atorvastatin at maximum dose
ANSWER: A
Rationale:
Option A is correct. Pravastatin is minimally dependent on CYP3A4 and is among the safest statins with boosted PIs, making it an appropriate low-interaction choice. Integrating both pathways matters: even a non-CYP3A4 statin can interact through OATP1B1, so pravastatin's overall favorable profile makes it the safest listed strategy.
Option B: Option B is incorrect. Simvastatin is highly CYP3A4-dependent and is contraindicated with boosted PIs due to myopathy and rhabdomyolysis risk.
Option C: Option C is incorrect. Lovastatin is likewise CYP3A4-dependent and contraindicated with boosted PIs.
Option D: Option D is incorrect. Rosuvastatin is reasonable but its concentrations roughly double through OATP1B1 inhibition, so maximum dosing without dose attention is unsafe.
Option E: Option E is incorrect. Atorvastatin may be used only at reduced dose with boosted PIs; maximum dosing is inappropriate.
3. A patient with tuberculosis must receive rifampin and cannot switch to rifabutin. Integrating rifampin's effect across drug classes, which antiretroviral strategy is both pharmacologically viable and correctly adjusted?
A) Continue a ritonavir-boosted protease inhibitor at standard dose
B) Continue elvitegravir/cobicistat unchanged
C) Use standard once-daily dolutegravir without adjustment
D) Use dolutegravir increased to 50 mg twice daily
E) Use rilpivirine at standard dose
ANSWER: D
Rationale:
Option D is correct. Rifampin induces both UGT1A1 and CYP3A4, reducing dolutegravir exposure by roughly half; doubling dolutegravir to 50 mg twice daily restores adequate troughs and is the viable, correctly adjusted strategy when rifampin cannot be replaced.
Option A: Option A is incorrect. Rifampin reduces protease inhibitor exposure by 75 to 90% regardless of boosting, so boosted PIs are contraindicated with rifampin.
Option B: Option B is incorrect. The cobicistat boost is overwhelmed by rifampin induction, so elvitegravir/cobicistat is not viable unchanged.
Option C: Option C is incorrect. Standard once-daily dolutegravir provides inadequate exposure with rifampin; dose-doubling is required.
Option E: Option E is incorrect. Rifampin markedly lowers rilpivirine concentrations, and the combination is contraindicated.
4. A patient on a cobicistat-containing regimen shows a stable serum creatinine rise of 0.2 mg/dL shortly after starting therapy, with no proteinuria, glucosuria, or electrolyte abnormalities. Integrating the difference between a secretion artifact and true tubular injury, which interpretation and action is correct?
A) This indicates early tenofovir Fanconi syndrome; stop the regimen immediately
B) This reflects inhibition of tubular creatinine secretion, not a true fall in glomerular filtration; continue and confirm with cystatin C if needed
C) This represents acute interstitial nephritis; add corticosteroids
D) This is prerenal azotemia; the regimen must be permanently discontinued
E) This is true progressive renal failure requiring urgent dialysis planning
ANSWER: B
Rationale:
Option B is correct. Cobicistat inhibits the tubular transporter that secretes creatinine, producing a small early rise in serum creatinine and a fall in estimated glomerular filtration rate without any true reduction in filtration. The absence of proteinuria, glucosuria, and electrolyte disturbance fits this benign artifact; the regimen can be continued and, if confirmation is needed, cystatin C-based estimation or measured GFR documents preserved true filtration.
Option A: Option A is incorrect. Tenofovir Fanconi syndrome would show glucosuria, phosphaturia, and tubular proteinuria, which are absent here.
Option C: Option C is incorrect. There is no evidence of interstitial nephritis, so corticosteroids are not indicated.
Option D: Option D is incorrect. The picture is a secretion artifact, not prerenal azotemia warranting permanent discontinuation.
Option E: Option E is incorrect. True progressive renal failure is not supported by a small, stable, isolated creatinine rise without other findings.
5. A patient is on tenofovir disoproxil fumarate (TDF) together with a cobicistat-boosted regimen. Integrating TDF's proximal tubular handling with the effect of boosters on tubular efflux, why is the nephrotoxicity risk amplified beyond that of TDF alone?
Option E is correct. TDF is taken into proximal tubular cells and is normally pumped out by the apical efflux transporter MRP2 (multidrug resistance-associated protein 2). Boosters such as cobicistat and ritonavir inhibit MRP2, so TDF accumulates to higher intracellular concentrations in the proximal tubule, compounding mitochondrial injury and amplifying nephrotoxicity beyond TDF alone.
Option A: Option A is incorrect. Increased uptake with unchanged efflux would not describe the booster effect, and the net result of booster co-administration is higher, not lower, tubular TDF.
Option B: Option B is incorrect. Boosters do not convert TDF into tenofovir alafenamide; these are distinct prodrugs.
Option C: Option C is incorrect. Cobicistat does not induce polymerase gamma or protect the tubule.
Option D: Option D is incorrect. Boosters do not accelerate TDF renal clearance; impaired efflux increases tubular exposure.
6. A patient who requires continuous proton pump inhibitor (PPI) therapy for severe reflux is being switched from a rilpivirine-based regimen. Integrating which antiretrovirals depend on gastric acidity and how PPIs differ from histamine-2 receptor antagonists, which redesign is most appropriate?
A) Switch to a dolutegravir-based regimen, whose absorption is acid-independent, and continue the PPI
B) Switch to unboosted atazanavir and continue the PPI
C) Keep rilpivirine but separate it from the PPI by four hours
D) Replace the PPI with a high-dose PPI taken at bedtime alongside rilpivirine
E) Switch to boosted atazanavir with a standard-dose PPI taken simultaneously
ANSWER: A
Rationale:
Option A is correct. Both rilpivirine and unboosted atazanavir require gastric acidity for absorption and cannot be combined with a continuous PPI. Dolutegravir absorption does not depend on gastric pH, so switching to a dolutegravir-based regimen lets the patient keep the needed PPI without compromising antiretroviral exposure.
Option B: Option B is incorrect. Unboosted atazanavir is also acid-dependent and cannot be paired with a PPI.
Option C: Option C is incorrect. Because PPIs suppress acid throughout the day, dose separation does not rescue rilpivirine absorption, unlike the situation with H2 receptor antagonists.
Option D: Option D is incorrect. Increasing the PPI worsens the acid-dependent absorption problem for rilpivirine.
Option E: Option E is incorrect. Even boosted atazanavir tolerates only low-dose, carefully timed acid suppression, not a standard-dose PPI taken simultaneously.
7. A pregnant patient with HIV who is also chronically infected with hepatitis B virus (HBV) needs an antiretroviral regimen. Integrating the preferred pregnancy backbone, the need for HBV coverage, and the preferred integrase inhibitor at conception, which regimen best satisfies all three considerations?
A) Abacavir/lamivudine plus raltegravir
B) Tenofovir alafenamide/emtricitabine plus cabotegravir long-acting injectable
C) Tenofovir disoproxil fumarate/emtricitabine plus dolutegravir
D) Zidovudine/lamivudine plus efavirenz
E) Tenofovir disoproxil fumarate/emtricitabine plus elvitegravir/cobicistat
ANSWER: C
Rationale:
Option C is correct. Tenofovir disoproxil fumarate/emtricitabine is the preferred pregnancy backbone and provides dual anti-HBV coverage, while dolutegravir is now recommended throughout pregnancy including at conception. This regimen simultaneously satisfies the preferred backbone, HBV coverage, and preferred integrase inhibitor.
Option A: Option A is incorrect. Abacavir/lamivudine lacks the robust HBV coverage that tenofovir provides, so it does not meet the HBV requirement as well.
Option B: Option B is incorrect. Cabotegravir long-acting injectable is not recommended in pregnancy because of absent safety data and an unmanageable pharmacokinetic tail.
Option D: Option D is incorrect. Efavirenz is a non-preferred agent when alternatives exist, and zidovudine/lamivudine is not the preferred backbone here.
Option E: Option E is incorrect. Cobicistat-boosted regimens have reduced and variable exposures in pregnancy and are not preferred.
8. A woman maintained on methadone and using a combined oral contraceptive pill is started on an efavirenz-containing regimen. Integrating efavirenz's enzyme-inducing effects across both co-treatments, which combined consequence should be anticipated?
A) Rising methadone levels causing sedation, and increased contraceptive efficacy
B) No change in methadone, with reduced contraceptive efficacy only
C) Reduced methadone levels causing withdrawal, with increased contraceptive efficacy
D) Reduced methadone levels causing withdrawal, and reduced contraceptive efficacy from lower ethinyl estradiol
E) Rising methadone and ethinyl estradiol levels from enzyme inhibition
ANSWER: D
Rationale:
Option D is correct. Efavirenz is an enzyme inducer. It lowers methadone concentrations by 50 to 60%, precipitating opioid withdrawal, and it reduces ethinyl estradiol concentrations by roughly 40 to 55%, compromising contraceptive efficacy. Both consequences flow from the same induction mechanism, so the patient needs methadone dose coordination and an alternative or additional contraceptive method.
Option A: Option A is incorrect. Induction lowers rather than raises methadone, and contraceptive efficacy is reduced rather than increased.
Option B: Option B is incorrect. Methadone is meaningfully reduced, so the methadone effect cannot be dismissed as unchanged.
Option C: Option C is incorrect. Contraceptive efficacy falls rather than rises with efavirenz-driven estrogen reduction.
Option E: Option E is incorrect. Efavirenz induces rather than inhibits these pathways, so concentrations fall rather than rise.
9. A patient co-infected with HIV and hepatitis B virus (HBV) on a tenofovir-containing regimen develops a reason to change therapy. Integrating the risk of HBV flare on tenofovir withdrawal with the resistance pitfall of HBV monotherapy, which switch strategy is safest?
A) Stop tenofovir and add entecavir alone for HBV coverage
B) Maintain an anti-HBV-active agent (tenofovir or, if tenofovir must change, another HBV-active drug) within a fully suppressive regimen throughout the switch
C) Stop all HBV-active agents and rely on the new HIV regimen alone
D) Replace tenofovir with abacavir and provide no other HBV coverage
E) Briefly interrupt all therapy, then restart a new regimen after two weeks
ANSWER: B
Rationale:
Option B is correct. Because withdrawing tenofovir without alternative HBV coverage can precipitate a severe HBV flare, an anti-HBV-active agent must be maintained within a fully suppressive antiretroviral regimen throughout any switch, integrating both the flare risk and the requirement to avoid HBV monotherapy.
Option A: Option A is incorrect. Entecavir used without a suppressive HIV regimen selects for the M184V resistance mutation in HIV and does not safely replace tenofovir as monotherapy.
Option C: Option C is incorrect. Stopping all HBV-active agents risks an HBV flare and is unsafe.
Option D: Option D is incorrect. Abacavir lacks anti-HBV activity, leaving the patient without HBV coverage.
Option E: Option E is incorrect. Interrupting all therapy risks both HBV flare and loss of HIV control and is not a safe strategy.
10. A patient with severe hepatic impairment (Child-Pugh C) needs a regimen built from individually hepatically-acceptable components. Integrating the hepatic limits of the protease inhibitor, integrase inhibitor, and nucleoside classes, which combination is most appropriate?
A) Darunavir/ritonavir plus dolutegravir plus abacavir/lamivudine
B) Tipranavir/ritonavir plus raltegravir plus tenofovir alafenamide/emtricitabine
C) Lopinavir/ritonavir plus elvitegravir/cobicistat plus abacavir/lamivudine
D) Darunavir/ritonavir plus raltegravir plus abacavir/lamivudine
E) Raltegravir plus tenofovir alafenamide/emtricitabine
ANSWER: E
Rationale:
Option E is correct. In Child-Pugh C, raltegravir is the preferred integrase inhibitor because its pharmacokinetics are minimally altered, and a tenofovir alafenamide/emtricitabine backbone avoids the hepatically problematic agents. Combining raltegravir with this backbone yields a regimen whose components are each acceptable in severe hepatic impairment.
Option A: Option A is incorrect. Darunavir is contraindicated in Child-Pugh C, dolutegravir is not recommended there, and abacavir is contraindicated in moderate to severe hepatic impairment.
Option B: Option B is incorrect. Tipranavir/ritonavir is contraindicated in clinically significant hepatic impairment because of hepatotoxicity risk.
Option C: Option C is incorrect. Lopinavir is contraindicated in Child-Pugh C, and abacavir is contraindicated in moderate to severe hepatic impairment.
Option D: Option D is incorrect. Although raltegravir is appropriate, darunavir is contraindicated in Child-Pugh C and abacavir is contraindicated in moderate to severe hepatic impairment.
11. A patient newly diagnosed with HIV and active tuberculosis has a CD4 count of 30 cells/mm3 and is beginning tuberculosis treatment. Integrating the relationship between CD4 count, timing of antiretroviral initiation, and immune reconstitution inflammatory syndrome (IRIS) risk, what is the recommended approach?
A) Start tuberculosis treatment first, then initiate antiretroviral therapy within about 2 weeks because of the very low CD4 count
B) Delay antiretroviral therapy until tuberculosis treatment is complete to avoid IRIS entirely
C) Start antiretroviral therapy and tuberculosis treatment on the same day regardless of CD4
D) Withhold antiretroviral therapy for at least 6 months in all co-infected patients
E) Start antiretroviral therapy first and delay tuberculosis treatment until viral suppression
ANSWER: A
Rationale:
Option A is correct. With a CD4 count below 50 cells/mm3, antiretroviral therapy is initiated within about 2 weeks of starting tuberculosis treatment. Although early initiation carries some IRIS risk, the very low CD4 count means the mortality benefit of prompt antiretroviral therapy outweighs that risk; patients with higher CD4 counts can wait 8 to 12 weeks.
Option B: Option B is incorrect. Delaying antiretroviral therapy until tuberculosis treatment is complete would dangerously prolong profound immunodeficiency at this CD4 level.
Option C: Option C is incorrect. Same-day initiation regardless of CD4 is not the recommended approach; tuberculosis treatment is established first.
Option D: Option D is incorrect. A blanket 6-month delay is not recommended and would be especially harmful at a CD4 of 30.
Option E: Option E is incorrect. Tuberculosis treatment is started first; deferring it until viral suppression is not appropriate.
12. A 68-year-old person living with HIV takes 11 chronic medications and has age-related declines in renal and hepatic function. Integrating the effects of aging, polypharmacy, and a boosted regimen, which statement best captures the dominant pharmacologic concern?
A) Aging eliminates the need for interaction checking because metabolism slows uniformly
B) Polypharmacy lowers interaction risk by diluting any single drug effect
C) A boosted regimen layered onto extensive polypharmacy and reduced organ reserve markedly raises the probability of clinically significant interactions and adverse effects
D) Reduced hepatic blood flow protects against CYP3A4-mediated interactions
E) Renal decline is irrelevant because modern antiretrovirals are never renally cleared
ANSWER: C
Rationale:
Option C is correct. The combination of a CYP3A4-inhibiting booster, a high pill burden, and diminished renal and hepatic reserve compounds interaction and toxicity risk: each added CYP3A4 substrate is more affected, and reduced clearance widens exposure swings. This is why older patients on boosted regimens with polypharmacy require careful interaction screening.
Option A: Option A is incorrect. Aging increases, rather than removes, the need for interaction vigilance.
Option B: Option B is incorrect. Polypharmacy raises, not lowers, the probability of clinically relevant interactions.
Option D: Option D is incorrect. Reduced hepatic blood flow tends to increase exposure to hepatically metabolized agents rather than protect against interactions.
Option E: Option E is incorrect. Several antiretrovirals and fixed-dose components are renally cleared, so renal decline is clinically relevant.
13. A patient with a 10-year cardiovascular risk above 20% is on a boosted protease inhibitor regimen with abacavir and now needs lipid lowering. Integrating the abacavir myocardial infarction signal, the lipid effects of boosted protease inhibitors, and statin interaction safety, which combined plan is most appropriate?
A) Continue abacavir, add simvastatin at high dose
B) Continue abacavir, add lovastatin
C) Continue abacavir and add no statin because the regimen itself lowers risk
D) Replace abacavir with a tenofovir-based backbone if feasible, and use rosuvastatin or pravastatin with attention to transporter interactions
E) Keep the boosted protease inhibitor and abacavir and add maximum-dose atorvastatin
ANSWER: D
Rationale:
Option D is correct. In a high-cardiovascular-risk patient, abacavir is best avoided when an alternative backbone is available, given its myocardial infarction signal; rosuvastatin and pravastatin are the safest statins with boosted protease inhibitors, with attention to the OATP1B1 transporter interaction that can raise rosuvastatin levels. This plan integrates backbone selection, the regimen's lipid effects, and statin safety.
Option A: Option A is incorrect. Simvastatin is contraindicated with boosted protease inhibitors, and retaining abacavir ignores the cardiovascular signal.
Option B: Option B is incorrect. Lovastatin is likewise contraindicated with boosted protease inhibitors.
Option C: Option C is incorrect. Withholding indicated lipid lowering and keeping abacavir does not reduce the elevated cardiovascular risk.
Option E: Option E is incorrect. Atorvastatin must be dose-limited with boosted protease inhibitors, and keeping abacavir disregards the cardiovascular signal.
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