1. [CASE 1 — QUESTION 1]
A 58-year-old man with newly diagnosed HIV, coronary artery disease, hyperlipidemia, and recently treated latent tuberculosis is started on a boosted darunavir-based regimen (darunavir/ritonavir) because of concern about future adherence and a desire for a high genetic resistance barrier. His clinic visit today is to review several medications prescribed by other providers. As a foundation for the decisions that follow, which statement best describes how the protease inhibitor component of his regimen renders virus non-infectious?
A) It chelates two magnesium ions in the integrase active site, blocking insertion of viral DNA into the host genome
B) It is incorporated into nascent viral DNA by reverse transcriptase and terminates chain elongation
C) It blocks cleavage of the Gag and Gag-Pol polyproteins, so that virions still bud from the cell but are morphologically immature and non-infectious
D) It binds the host CCR5 (C-C chemokine receptor type 5) co-receptor, preventing the conformational change needed for membrane fusion
E) It binds the viral capsid protein, disrupting capsid assembly and nuclear import of the pre-integration complex
ANSWER: C
Rationale:
Protease inhibitors act late in the replication cycle: HIV-1 protease cleaves the Gag and Gag-Pol polyproteins, and when this cleavage is blocked the particle still buds but is morphologically immature and non-infectious.
Option C: Option C states this maturation mechanism, the basis for the rest of this case.
Option A: Option A describes the integrase strand transfer inhibitor mechanism.
Option B: Option B describes a nucleoside reverse transcriptase inhibitor acting as a chain terminator.
Option D: Option D describes the CCR5 antagonist maraviroc acting on a host co-receptor.
Option E: Option E describes the capsid inhibitor lenacapavir. Only Option C correctly localizes the protease inhibitor to post-budding maturation.
2. [CASE 1 — QUESTION 2]
Continuing with the same patient. His cardiologist's note lists simvastatin 40 mg daily, started last week for his hyperlipidemia, and he has not yet taken a dose. Which action is most appropriate regarding this statin in the context of his boosted protease inhibitor regimen?
A) Advise against simvastatin because it is contraindicated with boosted protease inhibitors—ritonavir potently inhibits CYP3A4 (cytochrome P450 3A4), the enzyme that clears simvastatin, raising its concentration dramatically and risking myopathy and rhabdomyolysis—and recommend a minimally CYP3A4-metabolized statin such as pravastatin or rosuvastatin
B) Continue simvastatin 40 mg, since statin selection is unaffected by boosted protease inhibitors
C) Continue simvastatin but at 80 mg daily to ensure efficacy despite the interaction
D) Replace the protease inhibitor regimen so that simvastatin can be retained
E) Add a fibrate to simvastatin to offset the interaction
ANSWER: A
Rationale:
Simvastatin is heavily CYP3A4-dependent, and ritonavir potently inhibits CYP3A4; together they raise simvastatin concentrations dramatically and risk rhabdomyolysis, so simvastatin (and lovastatin) are contraindicated with boosted protease inhibitors. The correct action is to avoid simvastatin and select a minimally CYP3A4-metabolized statin such as pravastatin or rosuvastatin. Option A is correct. Option B is wrong because statin choice is critical in this setting. Option C is dangerous because raising the dose worsens the interaction. Option D needlessly disrupts an effective regimen when safer statins exist.
Option E: Option E is incorrect because adding a fibrate increases myopathy risk rather than offsetting the interaction.
3. [CASE 1 — QUESTION 3]
Continuing with the same patient. He develops new atrial fibrillation, and a covering physician prescribes rivaroxaban for stroke prevention. Considering his boosted protease inhibitor regimen, what is the most appropriate response?
A) Continue rivaroxaban unchanged, because boosted protease inhibitors do not interact with direct oral anticoagulants
B) Continue rivaroxaban but double the dose to overcome any interaction
C) Add a second direct oral anticoagulant to stabilize anticoagulant levels
D) 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 use an anticoagulant whose levels are not raised by the booster, such as appropriately monitored warfarin
E) Stop the antiretroviral regimen so that rivaroxaban can be continued
ANSWER: D
Rationale:
Rivaroxaban is a substrate of both CYP3A4 and P-glycoprotein, and 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 monitored warfarin.
Option D: Option D is correct.
Option A: Option A is wrong because the interaction is significant.
Option B: Option B is dangerous because a higher dose compounds bleeding risk.
Option C: Option C increases bleeding rather than stabilizing levels.
Option E: Option E needlessly disrupts effective HIV therapy when a safer anticoagulant can be selected.
4. [CASE 1 — QUESTION 4]
Continuing with the same patient. Months later he develops active pulmonary tuberculosis, and the treating team proposes a rifampin-based antimycobacterial regimen while he remains on darunavir/ritonavir. What is the correct pharmacological judgment?
A) Rifampin is fully compatible with boosted protease inhibitors and requires no change
B) Rifampin is contraindicated with boosted protease inhibitors because it is a potent CYP3A4 (cytochrome P450 3A4) inducer that reduces protease inhibitor exposure by roughly 75 to 90% and defeats the boosting strategy; rifabutin, a far weaker inducer, is the preferred rifamycin and is used with a reduced rifabutin dose
C) Rifampin should be combined with a second booster to neutralize its effect on the protease inhibitor
D) The protease inhibitor dose should simply be tripled to ride through rifampin induction
E) Rifampin inhibits CYP3A4, so the protease inhibitor concentration will rise to toxic levels
ANSWER: B
Rationale:
Rifampin is a potent CYP3A4 inducer that reduces boosted protease inhibitor exposure by roughly 75 to 90%, undermining the boosting strategy, so it is contraindicated with boosted PIs; rifabutin is a much weaker inducer, is the preferred rifamycin in this setting, and is given at a reduced dose because the boosted PI raises rifabutin levels. Option B is correct. Option A is wrong because the interaction is severe.
Option C: Option C is incorrect because a second booster does not overcome rifampin's potent induction. Option D is unsafe and not an approved strategy for boosted PIs with rifampin.
Option E: Option E inverts the mechanism: rifampin induces rather than inhibits CYP3A4, so PI levels fall rather than rise.
5. [CASE 2 — QUESTION 1]
A 31-year-old woman of African ancestry is newly diagnosed with HIV and started on bictegravir/tenofovir alafenamide/emtricitabine (a single-tablet integrase strand transfer inhibitor [INSTI]-based regimen). She has no prior treatment and no baseline resistance. As the team explains the regimen, which statement best captures why a second-generation INSTI is preferred first-line for a treatment-naive patient like her?
A) Second-generation INSTIs are preferred only because they are inexpensive, with no pharmacological advantage
B) Second-generation INSTIs require pharmacokinetic boosting, which simplifies her drug interactions
C) Second-generation INSTIs act on viral protease and therefore share the resistance barrier of darunavir
D) Second-generation INSTIs are active only against CXCR4 (C-X-C chemokine receptor type 4)-tropic virus, sparing the need for tropism testing
E) Second-generation INSTIs such as bictegravir combine a very high genetic resistance barrier—so that treatment-naive patients essentially do not select integrase resistance at virologic failure—with rapid virologic suppression, good tolerability, and a limited interaction profile
ANSWER: E
Rationale:
Second-generation INSTIs (bictegravir, dolutegravir) have a very high genetic resistance barrier such that treatment-naive patients essentially do not select integrase resistance at failure, and they offer rapid suppression, good tolerability, and a limited interaction profile—the basis for first-line preference. Option E is correct. Option A reduces the choice to cost and denies the pharmacological advantages. Option B is wrong because bictegravir and dolutegravir do not require boosting. Option C misassigns the mechanism to protease; these are integrase inhibitors.
Option D: Option D is incorrect because INSTIs act independent of co-receptor tropism, and tropism testing concerns the CCR5 antagonist maraviroc.
6. [CASE 2 — QUESTION 2]
Continuing with the same patient. After initial suppression she has a low-level viral rebound with a subtherapeutic bictegravir trough, yet pharmacy refill data and pill counts confirm excellent adherence. She recently began an over-the-counter calcium plus iron supplement, which she takes at the same time as her morning medication. What is the most likely explanation?
A) The supplement induced CYP3A4 (cytochrome P450 3A4), accelerating bictegravir metabolism
B) The supplement raised gastric pH, ionizing bictegravir so it could not be absorbed
C) Polyvalent cations (calcium and iron) chelated bictegravir in the gut when taken simultaneously, reducing its absorption and lowering the trough despite genuine adherence; separating the supplement in time, or taking bictegravir with food and the calcium or iron appropriately, prevents this
D) Iron supplementation directly mutated the integrase gene, generating resistance
E) Calcium displaced bictegravir from plasma proteins, increasing its renal clearance
ANSWER: C
Rationale:
INSTIs chelate polyvalent cations, so calcium and iron taken simultaneously with bictegravir bind it in the gut and reduce absorption, producing subtherapeutic troughs and possible rebound even with perfect adherence; appropriate timing (and taking bictegravir with food as labeled) prevents this. Option C is correct. Option A is wrong because the mechanism is gut chelation, not CYP3A4 induction. Option B invokes a pH-ionization mechanism that does not describe cation chelation. Option D is biologically incorrect; supplements do not mutate viral genes, and the trough is low from reduced absorption, not resistance.
Option E: Option E misattributes the effect to protein-binding displacement and increased renal clearance rather than decreased absorption.
7. [CASE 2 — QUESTION 3]
Continuing with the same patient. After the chelation issue is corrected and she is again suppressed, she returns at 48 weeks having gained about 4 kg and asks whether her regimen is responsible. Integrating the INSTI weight-gain literature with her specific regimen and demographics, which statement is most accurate?
A) INSTI-based regimens are associated with weight gain that tends to be greater when combined with tenofovir alafenamide (TAF) than with tenofovir disoproxil fumarate (TDF), and the gain appears larger in women and in persons of African ancestry, so her regimen and demographics are consistent with the observed gain and this should be discussed and monitored
B) INSTIs reliably cause weight loss, so her weight gain must be from another cause entirely
C) The weight change is purely transient fluid retention and will fully reverse within one week
D) Only protease inhibitors cause weight gain, so her INSTI regimen cannot be contributing
E) Weight change on INSTIs is identical regardless of the tenofovir prodrug and is unrelated to sex or ancestry
ANSWER: A
Rationale:
INSTI-based regimens are associated with weight gain that is greater with TAF than TDF, with apparently larger effects in women and persons of African ancestry; her regimen and demographics fit the observed gain, which should be discussed and monitored. Option A is correct.
Option B: Option B inverts the direction, since INSTIs are associated with gain, not loss. Option C mischaracterizes the gain as one-week fluid retention, whereas it accrues over months.
Option D: Option D incorrectly excludes INSTIs from the weight signal. Option E contradicts the observed TAF-versus-TDF difference and the demographic modifiers.
8. [CASE 2 — QUESTION 4]
Continuing with the same patient. At a routine visit her serum creatinine is noted to have risen slightly and stably since starting bictegravir, with no proteinuria, normal electrolytes, and sustained virologic suppression. What is the best interpretation?
A) This indicates tenofovir alafenamide proximal tubulopathy and mandates urgent regimen change
B) This is the expected effect of bictegravir's weak inhibition of the renal cation transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1), which reduces tubular secretion of creatinine and raises serum creatinine while true glomerular filtration is preserved; continue and monitor
C) This signals progressive chronic kidney disease and requires stopping all antiretrovirals
D) This reflects rhabdomyolysis and requires immediate dialysis
E) This is contrast nephropathy and requires intravenous hydration
ANSWER: B
Rationale:
Bictegravir weakly inhibits the renal cation transporters OCT2 and MATE1, reducing tubular secretion of creatinine and producing a small, stable rise in serum creatinine while true glomerular filtration is unchanged—analogous to the cobicistat and dolutegravir creatinine artifacts. With no proteinuria, normal electrolytes, and sustained suppression, the regimen should be continued with monitoring.
Option B: Option B is correct.
Option A: Option A wrongly attributes the finding to tenofovir alafenamide tubulopathy, which would show proteinuria, phosphate wasting, or glycosuria.
Option C: Option C overreads a benign artifact as progressive kidney disease.
Option D: Option D invokes rhabdomyolysis and dialysis without supporting features.
Option E: Option E is irrelevant because no contrast was administered and the pattern is not contrast nephropathy.
9. [CASE 3 — QUESTION 1]
A 34-year-old man on a boosted atazanavir regimen presents distressed by yellow eyes. Examination shows scleral icterus; total bilirubin is 3.0 mg/dL with a predominantly unconjugated fraction, while aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase are all normal, and he is otherwise well. What is the best explanation for his presentation?
A) Acute viral hepatitis, requiring immediate cessation of all antiretrovirals pending serologies
B) Hemolytic anemia, requiring transfusion and corticosteroids
C) Biliary obstruction, requiring urgent endoscopic retrograde cholangiopancreatography
D) Benign unconjugated hyperbilirubinemia from atazanavir inhibition of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), which impairs bilirubin conjugation; the finding is benign and reversible, and reassurance is appropriate
E) Drug-induced hepatocellular necrosis, with the normal transaminases disregarded
ANSWER: D
Rationale:
Atazanavir inhibits UGT1A1, the enzyme that conjugates bilirubin, producing benign unconjugated hyperbilirubinemia with scleral icterus while transaminases and alkaline phosphatase remain normal. The finding does not reflect liver injury, and reassurance is appropriate. Option D is correct. Option A is wrong because an isolated unconjugated bilirubin rise with normal transaminases is not acute hepatitis.
Option B: Option B is incorrect because there is no evidence of hemolysis and the mechanism is impaired conjugation. Option C is wrong because the unconjugated pattern with normal alkaline phosphatase argues against obstruction.
Option E: Option E is incorrect because hepatocellular necrosis would elevate transaminases, which are explicitly normal.
10. [CASE 3 — QUESTION 2]
Continuing with the same patient. Six weeks later he reports he has been taking an over-the-counter proton pump inhibitor (PPI) twice daily for reflux, and his viral load now shows low-level rebound. Integrating atazanavir's absorption pharmacology with this history, what is the most accurate assessment and action?
A) The PPI has no effect on atazanavir, so the rebound is from nonadherence alone
B) The PPI increases atazanavir absorption, so the rebound is unrelated to it
C) A higher PPI dose should be used because it improves atazanavir absorption
D) Atazanavir must be abandoned permanently because no acid-suppressing therapy can ever be combined with it
E) Atazanavir absorption depends on an acidic gastric environment, so acid suppression by the PPI can lower atazanavir concentrations enough to permit rebound; review the need for acid suppression and manage per label (unboosted atazanavir is contraindicated with PPIs, and even boosted atazanavir requires strict PPI dose limits and timing separation)
ANSWER: E
Rationale:
Atazanavir requires an acidic gastric environment for adequate absorption, so PPIs can lower its concentration and permit virologic rebound. The correct response is to recognize the 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 wrongly dismisses a real interaction.
Option B: Option B inverts the effect, since acid suppression decreases atazanavir absorption.
Option C: Option C is incorrect because a higher PPI dose worsens the absorption problem.
Option D: Option D overstates the restriction, since boosted atazanavir can sometimes be co-managed with limits rather than abandoned.
11. [CASE 3 — QUESTION 3]
Continuing with the same patient. After the PPI issue is addressed, he presents a few months later with acute right flank pain radiating to the groin and microscopic hematuria; imaging shows a urinary tract stone. Which mechanism most likely accounts for this stone in a patient on long-term atazanavir?
A) Atazanavir induces hyperuricemia, producing classic uric acid stones unrelated to the drug itself
C) Atazanavir can precipitate as drug-containing crystals in the urinary tract, producing atazanavir nephrolithiasis in a small percentage of patients with long-term use
D) Atazanavir chelates dietary calcium, producing calcium oxalate stones through gut binding
E) Atazanavir has no association with nephrolithiasis, so another etiology must be sought exclusively
ANSWER: C
Rationale:
Beyond its UGT1A1-mediated hyperbilirubinemia, atazanavir can precipitate as drug-containing crystals in the urinary tract, causing nephrolithiasis in a small percentage of patients with long-term use; this is a recognized, distinct atazanavir effect. Option C is correct. Option A is wrong because the stones are atazanavir crystals, not urate from drug-induced hyperuricemia.
Option B: Option B incorrectly attributes the stones to renal tubular acidosis. Option D invokes a gut-chelation calcium oxalate mechanism that does not describe atazanavir crystal nephrolithiasis.
Option E: Option E is incorrect because atazanavir is specifically associated with nephrolithiasis.
12. [CASE 3 — QUESTION 4]
Continuing with the same patient. Given his bothersome jaundice, the PPI absorption conflict, and now nephrolithiasis—all linked to atazanavir—the team decides a different protease inhibitor would serve him better while preserving a high resistance barrier. Which switch is most appropriate?
A) Switch to a boosted darunavir regimen, because darunavir offers an exceptionally high genetic resistance barrier without the UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1)-mediated hyperbilirubinemia, the acid-dependent absorption requirement, or the crystal nephrolithiasis characteristic of atazanavir
B) Switch to lopinavir/ritonavir, because it has the most favorable lipid and tolerability profile of all protease inhibitors
C) Switch to unboosted atazanavir, which eliminates all of the problems seen so far
D) Discontinue protease inhibitors entirely and use low-dose ritonavir alone as maintenance
E) Switch to tipranavir as a preferred first-choice agent for its mild adverse-effect profile
ANSWER: A
Rationale:
Darunavir provides an exceptionally high genetic resistance barrier and does not share atazanavir's distinctive problems—UGT1A1-mediated hyperbilirubinemia, the requirement for an acidic gastric environment, and crystal nephrolithiasis—so a boosted darunavir regimen directly addresses this patient's issues while preserving a high barrier. Option A is correct. Option B is wrong because lopinavir/ritonavir has one of the least favorable metabolic and tolerability profiles among PIs.
Option C: Option C is incorrect because unboosted atazanavir worsens absorption issues (notably with acid suppression) and does not eliminate hyperbilirubinemia or stones. Option D is unsound because ritonavir is a booster with no useful antiviral activity at booster doses and is never used as maintenance monotherapy.
Option E: Option E is incorrect because tipranavir is a salvage agent with substantial toxicity, not a preferred first-choice PI.
13. [CASE 4 — QUESTION 1]
A 49-year-old man with extensive prior treatment is being evaluated for a maraviroc-containing salvage regimen. Before maraviroc can be prescribed, which step is mandatory, and why?
A) Therapeutic drug monitoring of maraviroc troughs, because the drug has a narrow therapeutic index
B) A validated co-receptor tropism assay must confirm exclusively CCR5 (C-C chemokine receptor type 5)-tropic virus, because maraviroc has no activity against CXCR4 (C-X-C chemokine receptor type 4)-using virus and any detectable X4 population predicts virologic failure
C) HLA-B*57:01 testing, because maraviroc causes a hypersensitivity reaction in carriers
D) UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) genotyping, because maraviroc is cleared by glucuronidation
E) Glucose-6-phosphate dehydrogenase activity measurement, because maraviroc causes oxidative hemolysis
ANSWER: B
Rationale:
Maraviroc blocks only the CCR5 co-receptor and has no activity against CXCR4-using virus, so a validated tropism assay confirming exclusively R5 tropism is mandatory before prescribing; any detectable X4 population predicts failure. Option B is correct. Option A is wrong because routine maraviroc trough monitoring is not the required pre-prescribing step.
Option C: Option C describes abacavir hypersensitivity and HLA-B*57:01, not maraviroc.
Option D: Option D is incorrect because maraviroc is a CYP3A4 substrate, and UGT1A1 genotyping is not required.
Option E: Option E describes a glucose-6-phosphate dehydrogenase concern unrelated to maraviroc.
14. [CASE 4 — QUESTION 2]
Continuing with the same patient. The 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 conclusion about maraviroc for him?
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 combined with an approved CXCR4 antagonist to broaden coverage
D) Do not use maraviroc, because it has no activity against CXCR4-using virus and any X4 or dual/mixed population predicts virologic failure
E) Repeat the assay indefinitely and defer therapy until it returns exclusively R5
ANSWER: D
Rationale:
Because maraviroc lacks activity against CXCR4-using virus, a dual/mixed-tropic result means any X4 component predicts failure, so maraviroc is inappropriate. Option D is correct. Option A misinterprets dual/mixed tropism as predicting 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 E needlessly defers effective therapy when active tropism-independent agents exist.
15. [CASE 4 — QUESTION 3]
Continuing with the same patient. For teaching purposes, the attending poses a hypothetical: if this patient instead had exclusively R5-tropic virus and maraviroc were used, how should the maraviroc dose be adjusted according to the other agents in the regimen?
A) Maraviroc dose is fixed at 300 mg twice daily regardless of co-administered drugs
B) Maraviroc should be reduced when given with a potent CYP3A4 (cytochrome P450 3A4) inducer and increased when given with a potent inhibitor
C) Maraviroc requires no adjustment with any antiretroviral because it is renally cleared unchanged
D) Maraviroc should be doubled whenever it is combined with any other antiretroviral
E) Maraviroc, a CYP3A4 (cytochrome P450 3A4) substrate, is reduced to 150 mg twice daily with potent CYP3A4 inhibitors such as boosted protease inhibitors and increased to 600 mg twice daily with potent CYP3A4 inducers such as efavirenz or rifampin, with 300 mg twice daily as the standard otherwise
ANSWER: E
Rationale:
Maraviroc is a CYP3A4 substrate, so its dose depends on co-administered CYP3A4 modulators: the standard 300 mg twice daily is reduced to 150 mg twice daily with potent inhibitors (such as boosted protease inhibitors) and increased to 600 mg twice daily with potent inducers (such as efavirenz, rifampin, or rifabutin). Option E is correct. Option A is wrong because the dose is not fixed.
Option B: Option B inverts the adjustments: inhibitors raise exposure (dose down) and inducers lower it (dose up).
Option C: Option C is incorrect because maraviroc is CYP3A4-metabolized, not renally cleared unchanged.
Option D: Option D is incorrect because dose doubling applies specifically to potent inducers, not to any co-administration.
16. [CASE 4 — QUESTION 4]
Continuing with the same patient, whose virus is dual/mixed-tropic. Given that maraviroc is unsuitable, which approach provides genuine entry-class or novel-mechanism activity that does not depend on co-receptor tropism?
A) Re-use a previously failed boosted protease inhibitor at a higher dose
B) Add efavirenz, relying on dose escalation to overcome non-nucleoside resistance
C) Select a tropism-independent active agent such as ibalizumab (a post-attachment CD4 [cluster of differentiation 4] domain-2 monoclonal antibody), fostemsavir (a gp120 attachment inhibitor), or lenacapavir (a capsid inhibitor), combined with any remaining active background drugs
D) Add a second CCR5 (C-C chemokine receptor type 5) antagonist alongside maraviroc
E) Withhold therapy until the virus spontaneously reverts to exclusively R5 tropism
ANSWER: C
Rationale:
Because maraviroc fails against CXCR4-using virus, activity must come from agents whose mechanism does not depend on co-receptor tropism. Ibalizumab (post-attachment CD4 domain-2 monoclonal antibody), fostemsavir (gp120 attachment inhibitor), and lenacapavir (capsid inhibitor) all act independent of tropism and are used with any remaining active background drugs. Option C is correct. Option A is wrong because re-using a failed PI does not overcome established resistance.
Option B: Option B is incorrect because non-nucleoside resistance is not overcome by dose escalation. Option D is futile because a second CCR5 antagonist shares maraviroc's inactivity against X4 virus.
Option E: Option E is incorrect because the virus does not reliably revert to exclusive R5 tropism, and effective tropism-independent agents are available now.
17. [CASE 5 — QUESTION 1]
A 55-year-old woman with multi-drug-resistant HIV has genotypic resistance across the nucleoside, non-nucleoside, protease, and integrase classes and a persistently detectable viral load. The team plans a salvage regimen built around agents with novel mechanisms. Which statement correctly describes lenacapavir, the first agent they are considering?
A) Lenacapavir is a capsid inhibitor that disrupts HIV-1 capsid function—including capsid assembly and nuclear import of the pre-integration complex—and is given by subcutaneous injection every six months in combination with an optimized background regimen for heavily treatment-experienced adults with multi-drug-resistant HIV-1
B) Lenacapavir is an integrase strand transfer inhibitor given intramuscularly every month
C) Lenacapavir is a non-nucleoside reverse transcriptase inhibitor taken orally once daily
D) Lenacapavir is a CCR5 (C-C chemokine receptor type 5) antagonist requiring tropism testing before use
E) Lenacapavir is a boosted protease inhibitor with the highest resistance barrier in its class
ANSWER: A
Rationale:
Lenacapavir is a first-in-class capsid inhibitor that disrupts the HIV-1 capsid, including capsid assembly and nuclear import of the pre-integration complex, and is given subcutaneously every six months with an optimized background regimen for heavily treatment-experienced adults with multi-drug-resistant HIV-1. Option A is correct. Option B misclassifies it as a monthly intramuscular integrase inhibitor like cabotegravir. Option C wrongly labels it an oral daily non-nucleoside reverse transcriptase inhibitor.
Option D: Option D confuses it with the CCR5 antagonist maraviroc.
Option E: Option E incorrectly calls it a protease inhibitor.
18. [CASE 5 — QUESTION 2]
Continuing with the same patient. The team next considers ibalizumab as a second active agent. Which statement correctly characterizes ibalizumab?
A) It is a subcutaneously injected peptide that mimics gp41 and blocks six-helix bundle formation
B) It is a humanized monoclonal antibody that binds domain 2 of the host CD4 (cluster of differentiation 4) receptor, blocking the post-attachment conformational change required for co-receptor engagement, and is given by intravenous infusion every two weeks; because it targets a host protein, resistance arises atypically through gp120 variable-loop changes rather than through a drug-binding-site mutation
C) It is an oral capsid inhibitor dosed once daily
D) It is a small-molecule CCR5 (C-C chemokine receptor type 5) antagonist taken orally twice daily
E) It is a boosted protease inhibitor used as preferred first-line therapy
ANSWER: B
Rationale:
Ibalizumab is a humanized monoclonal antibody that binds domain 2 of the host CD4 receptor, blocking the post-attachment conformational change required for co-receptor engagement without impairing CD4's immune function; it is given intravenously every two weeks, and because it targets a host protein, resistance arises atypically through gp120 variable-loop (V5) changes rather than a drug-binding-site mutation. Option B is correct.
Option A: Option A describes enfuvirtide, a gp41 fusion inhibitor.
Option C: Option C describes lenacapavir, a capsid inhibitor (and it is not oral daily).
Option D: Option D describes maraviroc, a small-molecule CCR5 antagonist.
Option E: Option E incorrectly labels it a first-line boosted protease inhibitor.
19. [CASE 5 — QUESTION 3]
Continuing with the same patient. An older fusion inhibitor, enfuvirtide, is discussed as a possible component. Which statement best describes enfuvirtide and the practical limitation that has largely relegated it to salvage use?
A) It is an oral integrase inhibitor limited by hepatotoxicity
B) It is an intravenous monoclonal antibody limited by infusion reactions every two weeks
C) It is a capsid inhibitor limited by its six-month dosing interval
D) It is a subcutaneously injected peptide fusion inhibitor that binds the gp41 HR1 (heptad repeat 1) region to block six-helix bundle formation, given twice daily, and is limited in practice by near-universal injection site reactions
E) It is an oral CCR5 (C-C chemokine receptor type 5) antagonist limited by the need for tropism testing
ANSWER: D
Rationale:
Enfuvirtide is a synthetic peptide fusion inhibitor that binds the gp41 HR1 region to block six-helix bundle formation and membrane fusion; it must be given by subcutaneous injection twice daily, and near-universal injection site reactions are the practical limitation that has largely confined it to salvage regimens. Option D is correct. Option A is wrong because enfuvirtide is not an oral integrase inhibitor.
Option B: Option B describes ibalizumab's route and schedule, not enfuvirtide.
Option C: Option C describes lenacapavir, a capsid inhibitor.
Option E: Option E describes maraviroc, an oral CCR5 antagonist.
20. [CASE 5 — QUESTION 4]
Continuing with the same patient, who will receive lenacapavir as part of her salvage regimen. Which pharmacological property of lenacapavir most warrants attention to concomitant medications?
A) Lenacapavir is eliminated entirely unchanged by the kidney, so all interactions are renal
B) Lenacapavir has no metabolic interactions of any kind because it is an injectable
C) Lenacapavir potently induces CYP3A4 (cytochrome P450 3A4), lowering the concentrations of co-administered substrates
D) Lenacapavir is a P-glycoprotein (P-gp) inducer that lowers digoxin levels as its principal interaction
E) Lenacapavir is both a substrate and a moderate inhibitor of CYP3A4 (cytochrome P450 3A4), so strong CYP3A4 inducers can lower its levels while lenacapavir itself can raise concentrations of sensitive CYP3A4 substrates—warranting review of concomitant medications
ANSWER: E
Rationale:
Lenacapavir is both a CYP3A4 substrate and a moderate CYP3A4 inhibitor: strong CYP3A4 inducers can reduce lenacapavir exposure, and lenacapavir can raise concentrations of sensitive CYP3A4 substrates, so concomitant medications must be reviewed. Option E is correct. Option A is wrong because lenacapavir is not eliminated unchanged by the kidney, and its key interactions are CYP3A4-related.
Option B: Option B is incorrect because being injectable does not exempt it from metabolic interactions.
Option C: Option C inverts its effect: lenacapavir is a moderate inhibitor, not a potent inducer, of CYP3A4. Option D mischaracterizes it as a P-gp inducer with a digoxin-centered interaction, which is not its principal interaction concern.
21. [CASE 6 — QUESTION 1]
A 40-year-old man who is virologically suppressed on a daily oral integrase-based regimen, with no history of resistance to integrase or non-nucleoside agents, expresses strong interest in long-acting injectable cabotegravir plus rilpivirine (CAB+RPV) to avoid daily pills. Which statement best describes his eligibility and the standard initiation approach?
A) CAB+RPV is appropriate for treatment-naive patients with high baseline viral loads as initial therapy
B) CAB+RPV should be started only after virologic failure with documented resistance to its components
C) He is an appropriate candidate because he is virologically suppressed without resistance to the regimen's components; the standard approach is an oral lead-in (oral cabotegravir plus rilpivirine for about four weeks to assess tolerability) followed by intramuscular injections monthly or every two months
D) CAB+RPV requires lifelong ritonavir boosting to maintain adequate levels
E) CAB+RPV is given as a single subcutaneous injection once every six months
ANSWER: C
Rationale:
Long-acting CAB+RPV is indicated for virologically suppressed adults without resistance to its components, and the standard initiation uses an oral lead-in (oral cabotegravir plus rilpivirine for about four weeks to assess tolerability) before switching to intramuscular injections monthly or every two months. This patient fits that profile, so Option C is correct. Option A is wrong because CAB+RPV is for suppressed patients, not high-viral-load naive initiation.
Option B: Option B inverts eligibility, since documented resistance to the components is a contraindication, not a prerequisite.
Option D: Option D is incorrect because CAB+RPV does not require ritonavir boosting.
Option E: Option E describes lenacapavir's six-month subcutaneous schedule, not CAB+RPV.
22. [CASE 6 — QUESTION 2]
Continuing with the same patient, now established on intramuscular CAB+RPV. He asks how the injections keep working for weeks between visits. Which statement best explains the pharmacokinetics of the long-acting formulations?
A) After intramuscular injection, both drugs are absorbed slowly from the depot at the injection site, producing sustained plasma concentrations across the dosing interval; this slow, prolonged absorption is what allows monthly or every-two-month dosing
B) The drugs are absorbed and eliminated within hours, and efficacy between injections depends on an active oral component taken daily
C) The injections work by forming permanent crystals in the bloodstream that never clear
D) The formulations are rapidly cleared by the kidney, requiring weekly dose adjustment
E) Each injection delivers a prodrug that must be reactivated daily by hepatic metabolism
ANSWER: A
Rationale:
After intramuscular injection, cabotegravir and rilpivirine are absorbed slowly from the injection-site depot, producing sustained plasma concentrations throughout the dosing interval; this slow, prolonged absorption is precisely what permits monthly or every-two-month dosing. Option A is correct. Option B is wrong because the drugs are not cleared within hours and no daily oral component is required once on injections.
Option C: Option C is incorrect because the depot is a slow-release reservoir, not permanent bloodstream crystals. Option D is wrong because the formulations are not rapidly renally cleared and do not need weekly adjustment.
Option E: Option E is incorrect because these are not daily-reactivated prodrugs.
23. [CASE 6 — QUESTION 3]
Continuing with the same patient. He now wishes to stop the injections because of a job relocation that will interrupt his clinic access. What is the correct plan to prevent resistance after his last injection?
A) Simply stop; the drugs clear within a day, so no bridging therapy is needed
B) Continue injections indefinitely with no oral coverage, since the tail protects forever
C) Wait until both drugs are fully undetectable before considering any further therapy
D) Begin a fully suppressive oral antiretroviral regimen promptly—about when the next injection would have been due—because the slowly declining depot concentrations (cabotegravir for months, rilpivirine for up to years) create a prolonged functional monotherapy window that can select resistance if left uncovered
E) Switch to single-agent oral rilpivirine during the gap
ANSWER: D
Rationale:
After the last injection, cabotegravir and rilpivirine decline slowly—cabotegravir detectable for months and rilpivirine for up to years—so the patient passes through a subtherapeutic range that constitutes functional monotherapy and can select resistance. The correct plan is to start a fully suppressive oral regimen promptly, around when the next injection would have been due. Option D is correct. Option A is wrong because the drugs do not clear within a day.
Option B: Option B ignores the eventual decline below therapeutic levels. Option C leaves the patient uncovered during the exact window when resistance is selected. Option E provides inadequate single-agent coverage, itself a setup for resistance.
24. [CASE 6 — QUESTION 4]
Continuing with the same patient. After he is bridged to oral therapy, he asks—on behalf of his partner, who is living with HIV, taking long-acting CAB+RPV, and now planning pregnancy—what the guidance is for the rilpivirine component in pregnancy. What is the most accurate response?
A) Long-acting CAB+RPV is the preferred regimen in pregnancy because of its convenience
B) Long-acting CAB+RPV is not recommended in pregnancy because of insufficient safety data and the prolonged pharmacokinetic tail that would persist if therapy needed to be stopped; transition to a recommended oral regimen should be planned
C) The rilpivirine component is unaffected by baseline resistance and may be used regardless of pre-treatment mutations
D) Long-acting CAB+RPV may be continued in pregnancy at half the usual dose with no other considerations
E) Rilpivirine requires an acidic gastric environment for absorption, so antacids must be added in pregnancy
ANSWER: B
Rationale:
Long-acting CAB+RPV is not recommended in pregnancy because of insufficient safety data and the prolonged pharmacokinetic tail that would persist if therapy required discontinuation; a recommended oral regimen should be planned instead. Option B is correct. Option A is wrong because convenience does not make it preferred in pregnancy given the data gap and tail.
Option C: Option C is incorrect because rilpivirine does impose baseline requirements—patients with pre-treatment rilpivirine resistance mutations are ineligible.
Option D: Option D is incorrect because there is no validated half-dose pregnancy strategy and the safety concern is not addressed by dose reduction. Option E mistakenly assigns atazanavir's acid-dependent absorption property to rilpivirine.
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