1. A 54-year-old man on darunavir/ritonavir for HIV is seen by a new primary care provider who, unaware of his regimen, prescribes simvastatin 40 mg daily for hyperlipidemia. He returns to your clinic before filling it and asks whether it is safe. What is the most appropriate action?
A) Approve simvastatin 40 mg, since statin choice does not matter with boosted protease inhibitors
B) Approve simvastatin but reduce the dose to 10 mg daily, which is safe with any booster
C) Advise against simvastatin because it is contraindicated with boosted protease inhibitors—CYP3A4 (cytochrome P450 3A4) inhibition by ritonavir raises simvastatin concentrations dramatically and risks rhabdomyolysis—and recommend a minimally CYP3A4-metabolized statin such as pravastatin or rosuvastatin instead
D) Switch the antiretroviral regimen off darunavir so that simvastatin can be used
E) Add a second statin to balance the interaction
ANSWER: C
Rationale:
Ritonavir potently inhibits CYP3A4, and simvastatin is heavily CYP3A4-dependent; together they raise simvastatin concentrations dramatically and risk myopathy and rhabdomyolysis, so simvastatin (and lovastatin) are contraindicated with boosted protease inhibitors. The correct action is to avoid simvastatin and choose a minimally CYP3A4-metabolized statin such as pravastatin or rosuvastatin. Option C is correct. Option A is wrong because statin choice matters greatly in this setting. Option B is unsafe because even reduced-dose simvastatin remains contraindicated with a potent CYP3A4 inhibitor. Option D needlessly disrupts an effective antiretroviral regimen to accommodate a statin when safer statins exist.
Option E: Option E is incorrect and dangerous, as adding a second statin does not offset the interaction and compounds myopathy risk.
2. A 38-year-old woman with HIV is virologically suppressed on a dolutegravir-based regimen when she is diagnosed with active pulmonary tuberculosis, and the treatment plan includes rifampin. How should her dolutegravir be managed during rifampin co-therapy?
A) Continue dolutegravir but double the dose to 50 mg twice daily to offset rifampin induction of its UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) and CYP3A4 (cytochrome P450 3A4) clearance pathways
B) Stop dolutegravir entirely for the duration of tuberculosis therapy
C) Continue dolutegravir at the standard 50 mg once daily with no change, because rifampin does not affect it
D) Halve the dolutegravir dose to prevent accumulation caused by rifampin
E) Replace rifampin with no antimycobacterial coverage to protect the dolutegravir level
ANSWER: A
Rationale:
Rifampin induces UGT1A1 and CYP3A4, the pathways that clear dolutegravir, reducing its exposure by roughly half. The established management is to double dolutegravir to 50 mg twice daily, which restores adequate plasma concentrations and allows the combination. Option A is correct. Option B is unnecessary because dose adjustment maintains efficacy. Option C is wrong because rifampin clearly lowers dolutegravir exposure and standard once-daily dosing would be subtherapeutic.
Option D: Option D inverts the needed direction; induction lowers exposure, so the dose is increased, not decreased. Option E is unacceptable because withholding tuberculosis treatment to protect a drug level endangers the patient and ignores the validated dose-doubling strategy.
3. A 45-year-old man started on elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine has a serum creatinine that rose from 0.9 to 1.05 mg/dL at week 4 and has been stable since. He is asymptomatic, has no proteinuria, normal electrolytes, and an undetectable viral load. What is the most appropriate interpretation and action?
A) This represents progressive renal failure; stop the regimen immediately
B) This is contrast nephropathy and requires aggressive intravenous hydration
C) This reflects tenofovir alafenamide proximal tubulopathy and mandates an urgent switch
D) This is the expected cobicistat effect from inhibition of creatinine tubular secretion via the multidrug and toxin extrusion protein 1 (MATE1) transporter, with preserved true glomerular filtration; continue the effective regimen and monitor
E) This indicates rhabdomyolysis and requires immediate creatine kinase-guided dialysis
ANSWER: D
Rationale:
Cobicistat inhibits MATE1 and thereby blocks tubular secretion of creatinine, producing a small, early, and stable rise in serum creatinine without a true fall in glomerular filtration. The asymptomatic course, absent proteinuria, normal electrolytes, and virologic suppression all fit this benign artifact, so the regimen should be continued with monitoring.
Option D: Option D is correct.
Option A: Option A misreads the artifact as progressive failure and discards an effective regimen.
Option B: Option B is irrelevant because no contrast was given and the pattern is not contrast nephropathy.
Option C: Option C wrongly attributes the change to tenofovir alafenamide tubulopathy, which would show proteinuria, phosphate wasting, or glycosuria rather than an isolated creatinine bump.
Option E: Option E invokes rhabdomyolysis and dialysis with no supporting features.
4. A 29-year-old man on a boosted atazanavir regimen is distressed by yellowing of his eyes. Examination confirms scleral icterus. Total bilirubin is 2.8 mg/dL with predominantly unconjugated fraction; aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase are all normal, and he is otherwise well. What is the best explanation and management?
A) Acute viral hepatitis; stop all antiretrovirals and obtain hepatitis serologies before any further dosing
B) Benign unconjugated hyperbilirubinemia from atazanavir inhibition of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), which impairs bilirubin conjugation; reassure the patient, and switch only if the cosmetic effect is unacceptable to him
C) Hemolytic anemia; transfuse and begin corticosteroids
D) Obstructive biliary disease; order urgent endoscopic retrograde cholangiopancreatography
E) Drug-induced hepatocellular necrosis; the normal transaminases can be disregarded
ANSWER: B
Rationale:
Atazanavir inhibits UGT1A1, the enzyme that conjugates bilirubin, producing benign and reversible unconjugated hyperbilirubinemia with scleral icterus while transaminases and alkaline phosphatase remain normal. The finding does not reflect liver injury; reassurance is appropriate, and a regimen switch is warranted only if the cosmetic jaundice is unacceptable to the patient. Option B is correct. Option A is wrong because normal transaminases and an isolated unconjugated bilirubin rise are not consistent with acute hepatitis, and stopping therapy is unwarranted.
Option C: Option C is incorrect because there is no evidence of hemolysis, and the mechanism is impaired conjugation. Option D is wrong because the unconjugated pattern with normal alkaline phosphatase argues against biliary obstruction.
Option E: Option E is incorrect; hepatocellular necrosis would elevate transaminases, which are explicitly normal here.
5. A 60-year-old woman with extensive treatment experience needs a new active agent, and the team considers maraviroc. A validated tropism assay returns dual/mixed-tropic virus, indicating both CCR5 (C-C chemokine receptor type 5)- and CXCR4 (C-X-C chemokine receptor type 4)-using populations. What is the correct decision?
A) Start maraviroc, because dual/mixed tropism confirms it will be active
B) Start maraviroc at an increased dose to cover the CXCR4-using virus
C) Start maraviroc together with a CXCR4 antagonist to broaden coverage, using maraviroc as the anchor
D) Repeat the tropism assay indefinitely and defer all therapy until it returns pure R5
E) Do not use maraviroc, because it has no activity against CXCR4-using virus and any X4 or dual/mixed population predicts failure; choose an agent active regardless of tropism, such as lenacapavir, ibalizumab, or fostemsavir, with any remaining active drugs
ANSWER: E
Rationale:
Maraviroc blocks only the CCR5 co-receptor and has no activity against CXCR4-using virus; when the tropism assay shows a dual/mixed population, any X4-using virus predicts virologic failure, so maraviroc is inappropriate and a tropism-independent active agent (lenacapavir, ibalizumab, or fostemsavir) should be selected with any remaining active background drugs. Option E is correct. Option A misinterprets dual/mixed tropism as predicting maraviroc success. Option B is wrong because dose escalation does not confer activity against X4 virus.
Option C: Option C is incorrect because there is no approved CXCR4 antagonist for routine antiretroviral therapy, and maraviroc would still fail against the X4 component. Option D needlessly defers effective therapy when active tropism-independent agents are available now.
6. A 52-year-old man with multi-drug-resistant HIV has genotypic resistance across the nucleoside, non-nucleoside, protease, and integrase classes, and his viral load remains detectable on his current regimen. The team wants to add an agent with a mechanism outside the exhausted classes that also offers an extended dosing interval. Which choice best fits?
A) Re-introduce a previously failed boosted protease inhibitor at a higher dose
B) Add efavirenz, since non-nucleoside resistance can be overcome by dose escalation
C) Add lenacapavir, a capsid inhibitor given by subcutaneous injection every six months, combined with an optimized background regimen, because its target lies outside the classes to which the virus is resistant
D) Add a second integrase strand transfer inhibitor to the regimen despite documented integrase resistance
E) Stop all therapy and observe, since no active agent exists
ANSWER: C
Rationale:
When resistance spans the conventional classes, activity must come from an agent whose target lies outside them. Lenacapavir is a capsid inhibitor—mechanistically distinct from nucleoside, non-nucleoside, protease, and integrase inhibitors—and is given subcutaneously every six months in combination with an optimized background regimen for heavily treatment-experienced patients with multi-drug-resistant HIV, satisfying both the novel-mechanism and extended-interval requirements. Option C is correct. Option A is wrong because re-using a failed PI at higher dose does not overcome established high-level resistance.
Option B: Option B is incorrect because non-nucleoside resistance is not overcome by dose escalation. Option D adds a drug to which the virus is already resistant, providing no real activity. Option E is unacceptable because effective novel-mechanism agents exist for exactly this scenario.
7. A 34-year-old man maintained on long-acting injectable cabotegravir plus rilpivirine informs you he is moving abroad next week and will not be able to receive his scheduled injections for several months. He is currently virologically suppressed. What is the most appropriate plan to protect against resistance?
A) Start a fully suppressive oral antiretroviral regimen promptly—about the time the next injection would have been due—because the slowly declining depot concentrations of cabotegravir (months) and rilpivirine (up to years) create a functional monotherapy window during which resistance can be selected if left uncovered
B) Reassure him that no further therapy is needed, since the long-acting injection protects him indefinitely
C) Simply skip the missed injections and resume the injectable schedule whenever he returns, with no interim coverage
D) Give a single extra injection now at double dose to cover the entire absence
E) Switch him to oral rilpivirine monotherapy during the gap
ANSWER: A
Rationale:
After the last injection, cabotegravir and rilpivirine concentrations decline slowly—cabotegravir detectable for months and rilpivirine for up to years—so the patient passes through a prolonged subtherapeutic range that constitutes functional monotherapy and can select resistance. The correct plan is to begin a fully suppressive oral regimen promptly, around when the next injection would have been due, to maintain complete coverage. Option A is correct. Option B is wrong because protection is not indefinite once injections stop. Option C leaves the patient uncovered during the exact window when resistance is selected.
Option D: Option D is incorrect because a double-dose injection does not safely extend coverage across months and is not how the regimen is managed. Option E provides inadequate single-agent coverage, itself a setup for resistance.
8. A 67-year-old woman on lopinavir/ritonavir develops atrial fibrillation, and a cardiologist starts rivaroxaban for stroke prevention. She mentions this at her HIV visit. What is the most appropriate response regarding the anticoagulant choice?
A) Continue rivaroxaban unchanged, since boosted protease inhibitors do not affect direct oral anticoagulants
B) Advise against rivaroxaban with this regimen, because ritonavir inhibits both CYP3A4 (cytochrome P450 3A4) and P-glycoprotein (P-gp), markedly raising rivaroxaban exposure and bleeding risk; coordinate with cardiology to select an anticoagulant whose levels are not raised by the booster, such as appropriately managed warfarin
C) Double the rivaroxaban dose to overcome an expected interaction
D) Add a second direct oral anticoagulant to balance the levels
E) Stop the antiretroviral regimen so rivaroxaban can be continued
ANSWER: B
Rationale:
Rivaroxaban is a substrate of both CYP3A4 and P-glycoprotein. Ritonavir inhibits both, so a boosted protease inhibitor markedly increases rivaroxaban exposure and bleeding risk; combined CYP3A4/P-gp-inhibiting boosted PIs are therefore generally contraindicated with rivaroxaban (and apixaban). The appropriate step is to coordinate with cardiology and choose an anticoagulant not raised by the booster, such as carefully managed warfarin with international normalized ratio monitoring. Option B is correct. Option A is wrong because the interaction is significant. Option C is dangerous, as raising the dose compounds bleeding risk.
Option D: Option D is incorrect because adding a second anticoagulant increases bleeding rather than balancing levels. Option E needlessly disrupts effective HIV therapy when a safer anticoagulant can be chosen instead.
9. A 47-year-old man on a raltegravir-based regimen experiences virologic failure, and integrase genotyping reveals an isolated N155H (asparagine-155-histidine) mutation. The team asks whether switching to dolutegravir is reasonable. What is the best assessment?
A) Switching to dolutegravir is pointless because integrase resistance always extends fully across the class
B) Switching to dolutegravir is contraindicated because dolutegravir and raltegravir are identical molecules
C) Dolutegravir should be avoided and the patient moved off integrase inhibitors entirely, as no integrase inhibitor can act once raltegravir has failed
D) Switching to dolutegravir is reasonable because its flexible binding mode preserves activity against isolated first-generation signature mutations such as N155H (which reduce dolutegravir susceptibility only minimally), ideally as part of an optimized regimen with twice-daily dolutegravir dosing and adherence support
E) Switching to dolutegravir requires adding cobicistat boosting to be effective against the mutant virus
ANSWER: D
Rationale:
Dolutegravir's flexible binding mode adapts to the small active-site conformational changes produced by isolated first-generation signature mutations such as N155H, which reduce dolutegravir susceptibility only minimally. Switching to dolutegravir is therefore reasonable after raltegravir failure with an isolated N155H, ideally with twice-daily dolutegravir dosing in an optimized regimen and adherence support. Option D is correct. Option A is wrong because resistance does not uniformly extend across the class for isolated first-generation mutations.
Option B: Option B is incorrect because dolutegravir and raltegravir are distinct molecules with different resistance barriers.
Option C: Option C overstates the situation, since a second-generation integrase inhibitor can retain activity against isolated first-generation mutations.
Option E: Option E is incorrect because dolutegravir does not require cobicistat boosting to act against such virus.
10. A 41-year-old man on an atazanavir-based regimen is found to be taking an over-the-counter proton pump inhibitor (PPI) twice daily for reflux, started a month ago. His most recent viral load shows low-level rebound. Integrating atazanavir's absorption pharmacology with this history, what is the most appropriate assessment and action?
A) The PPI has no effect on atazanavir, so the rebound must be from nonadherence alone
B) The PPI increases atazanavir absorption, so the rebound is unrelated to the PPI
C) Atazanavir should be stopped permanently because no acid-suppressing therapy can ever be combined with it
D) Switch the PPI to a higher dose, which improves atazanavir absorption
E) Atazanavir absorption depends on an acidic gastric environment, and acid suppression by the PPI can lower atazanavir concentrations enough to permit rebound; review the indication for acid suppression and manage the interaction per label (unboosted atazanavir is contraindicated with PPIs, and even boosted atazanavir requires strict dose limits and timing separation of the PPI)
ANSWER: E
Rationale:
Atazanavir requires an acidic gastric environment for adequate absorption, so acid-suppressing drugs—PPIs in particular—can lower atazanavir concentrations and allow virologic rebound. The correct response is to recognize this interaction, review whether acid suppression is truly needed, and manage per label: unboosted atazanavir is contraindicated with PPIs, and even boosted atazanavir requires strict PPI dose limits and timing separation. Option E is correct. Option A is wrong because the PPI does interact and should not be dismissed.
Option B: Option B inverts the effect; acid suppression decreases, not increases, atazanavir absorption.
Option C: Option C overstates the restriction, since boosted atazanavir can sometimes be co-managed with limits rather than abandoned.
Option D: Option D is incorrect because a higher PPI dose worsens, not improves, the absorption problem.
11. A 27-year-old woman who hopes to conceive needs to start antiretroviral therapy and has read online about a possible link between dolutegravir and birth defects. She asks whether dolutegravir is safe for her. Integrating the evolution of the neural tube defect data with current guidance, what is the most accurate counseling?
A) Dolutegravir is absolutely contraindicated in any woman who might conceive and must never be used
B) Dolutegravir must be stopped the moment pregnancy is confirmed regardless of viral suppression
C) An early signal from the Tsepamo surveillance study suggested a small increase in neural tube defects with dolutegravir at conception, but larger subsequent analyses found rates close to background, and current guidelines support dolutegravir throughout pregnancy including at conception; counsel her that it is an appropriate choice while discussing the evolving evidence
D) Only protease inhibitors are safe in pregnancy, so dolutegravir should be replaced with a boosted protease inhibitor in all cases
E) Neural tube defects from dolutegravir occur in the third trimester, so first-trimester use is the concern of no consequence
ANSWER: C
Rationale:
An early signal from the Tsepamo surveillance study suggested a small excess of neural tube defects with dolutegravir exposure at conception, but larger follow-up analyses showed rates close to background, and current guidelines support dolutegravir use throughout pregnancy, including at conception. Appropriate counseling reassures the patient that dolutegravir is a suitable choice while transparently discussing the evolving evidence. Option C is correct.
Option A: Option A overstates the data as an absolute contraindication. Option B is wrong because abruptly stopping effective therapy in pregnancy risks rebound and is not recommended.
Option D: Option D incorrectly restricts pregnancy options to protease inhibitors and ignores current guidance.
Option E: Option E misstates the biology, because neural tube defects relate to the periconception and early first-trimester window of neural tube closure, not the third trimester.
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