1. Protease inhibitors (PIs) act at a distinct point in the HIV (human immunodeficiency virus) replication cycle compared with reverse transcriptase and integrase inhibitors. Which statement best describes the pharmacological mechanism by which a protease inhibitor reduces the production of infectious virus?
A) It chelates two magnesium ions in a viral enzyme active site, blocking insertion of viral DNA into the host genome
B) It binds a host cell co-receptor, preventing the conformational change required for viral membrane fusion
C) It blocks cleavage of the Gag and Gag-Pol polyproteins, so that virions released from the cell are morphologically immature and non-infectious
D) It is incorporated into the growing viral DNA chain, terminating reverse transcription
E) It binds the viral capsid protein, disrupting assembly and nuclear import of the pre-integration complex
ANSWER: C
Rationale:
HIV-1 protease is a homodimeric aspartyl protease that cleaves the Gag polyprotein (yielding matrix, capsid, nucleocapsid, and p6) and the Gag-Pol polyprotein (yielding reverse transcriptase, integrase, and protease itself). Because this cleavage is required for virion maturation after the particle buds from the cell, inhibiting protease produces release of immature, non-infectious virions rather than blocking intracellular replication outright. Option C correctly captures this maturation-inhibition mechanism.
Option A: Option A describes the integrase strand transfer inhibitor (INSTI) mechanism (magnesium chelation in the integrase active site), not protease inhibition.
Option B: Option B describes a CCR5 (C-C chemokine receptor type 5) antagonist such as maraviroc acting on a host co-receptor, not a protease inhibitor.
Option D: Option D describes a nucleoside reverse transcriptase inhibitor acting as a chain terminator, a different drug class.
Option E: Option E describes the capsid inhibitor lenacapavir, not a protease inhibitor.
2. A boosted protease inhibitor regimen pairs the active PI with low-dose ritonavir, for example darunavir/ritonavir. What is the pharmacological role of the ritonavir component at the low doses (100 to 200 mg) used in these regimens?
A) It inhibits cytochrome P450 3A4 (CYP3A4), raising plasma concentrations and prolonging the half-life of the co-administered protease inhibitor, while contributing little antiviral activity of its own
B) It provides the principal antiviral effect of the regimen, with the partner PI acting only to widen the resistance barrier
C) It induces CYP3A4, lowering the partner PI concentration to reduce its toxicity
D) It blocks intestinal absorption of the partner PI to delay its peak concentration
E) It neutralizes the unconjugated hyperbilirubinemia caused by the partner PI
ANSWER: A
Rationale:
Ritonavir was originally developed as an antiviral PI but is now used almost exclusively as a pharmacokinetic enhancer (booster). At sub-therapeutic doses of 100 to 200 mg it produces near-complete inhibition of CYP3A4 (and inhibits P-glycoprotein), which raises the area under the concentration-time curve (AUC) of the partner PI several-fold and extends its half-life, enabling lower and less frequent PI dosing. At these doses ritonavir contributes no meaningful antiviral activity itself, so Option A is correct. Option B is wrong because the partner PI, not ritonavir, supplies the antiviral effect.
Option C: Option C inverts the mechanism: ritonavir inhibits rather than induces CYP3A4, and boosting raises rather than lowers partner concentrations.
Option D: Option D is incorrect because boosting works through metabolic enzyme inhibition, not by blocking absorption.
Option E: Option E is incorrect; ritonavir does not counteract hyperbilirubinemia, which is an atazanavir effect mediated by UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) inhibition.
3. A patient started on a cobicistat-boosted regimen shows a serum creatinine rise of about 0.15 mg/dL within the first weeks, with no other evidence of kidney injury. Which explanation best accounts for this finding?
A) Cobicistat causes acute tubular necrosis, and the regimen should be stopped immediately
B) Cobicistat triggers an immune-mediated interstitial nephritis requiring corticosteroids
C) Cobicistat reduces the true glomerular filtration rate by constricting the afferent arteriole
D) Cobicistat inhibits renal tubular secretion of creatinine via the multidrug and toxin extrusion protein 1 (MATE1) transporter, raising serum creatinine without lowering the true glomerular filtration rate
E) Cobicistat displaces creatinine from plasma protein binding, transiently increasing its measured level
ANSWER: D
Rationale:
Cobicistat is a pharmacokinetic booster that, like ritonavir, potently inhibits CYP3A4 but lacks intrinsic antiviral activity. It also inhibits MATE1, the transporter responsible for tubular secretion of creatinine. Blocking this secretory pathway raises serum creatinine by approximately 0.1 to 0.2 mg/dL and lowers estimated creatinine clearance, but the true glomerular filtration rate (GFR) is unchanged because filtration itself is not impaired. Recognizing this as an artifact prevents unnecessary regimen discontinuation, so Option D is correct.
Option A: Option A is incorrect because acute tubular necrosis is a genuine form of kidney injury that does not explain a small isolated creatinine rise without other findings.
Option B: Option B is incorrect because interstitial nephritis is likewise a true injury process that would present with additional features rather than an isolated minor creatinine increase.
Option C: Option C is incorrect because cobicistat does not reduce true GFR or alter afferent arteriolar tone.
Option E: Option E misstates the mechanism; the effect is transporter inhibition of tubular secretion, not protein-binding displacement.
4. Among the protease inhibitors, one agent is preferred in current guidelines when a PI-based regimen is indicated, in large part because of its resistance characteristics. Which statement best describes this agent?
A) Lopinavir/ritonavir is preferred because a single protease mutation cannot reduce its activity
B) Darunavir is preferred because no single mutation confers high-level resistance; at least three major protease resistance mutations must accumulate simultaneously for clinical failure
C) Atazanavir is preferred because it has no drug interactions and requires no pharmacokinetic boosting
D) Tipranavir is preferred for treatment-naive patients because of its favorable lipid profile
E) Saquinavir is preferred because it can be given without regard to gastric pH
ANSWER: B
Rationale:
Darunavir is the preferred PI when a protease inhibitor-based regimen is chosen. It binds the protease active site with very high affinity and forms an extensive hydrogen bond network with the protease backbone, so no single mutation produces high-level resistance; clinical failure requires simultaneous accumulation of at least three of the defined major resistance-associated mutations. This high genetic barrier is the basis for Option B.
Option A: Option A is incorrect because lopinavir/ritonavir has only a moderate resistance barrier.
Option C: Option C misstates atazanavir, which is typically boosted and carries meaningful interactions (and proton pump inhibitor restrictions).
Option D: Option D is incorrect because tipranavir is a salvage agent with substantial toxicity, not a preferred naive-patient drug, and is associated with dyslipidemia rather than a favorable lipid profile.
Option E: Option E is incorrect; gastric pH independence is not the basis for preferring saquinavir, which is not a current preferred agent.
5. A patient on a boosted protease inhibitor develops scleral icterus and a mild rise in unconjugated bilirubin, but liver enzymes are normal and the patient feels well. Which protease inhibitor most characteristically produces this picture, and by what mechanism?
A) Lopinavir, by causing intrahepatic cholestasis with conjugated hyperbilirubinemia
B) Darunavir, by direct hepatocellular toxicity reflected in markedly elevated transaminases
C) Tipranavir, by inducing hemolysis that overwhelms hepatic conjugation
D) Saquinavir, by obstructing the biliary tree with drug crystals
E) Atazanavir, by inhibiting uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), the enzyme that conjugates bilirubin, producing benign and reversible unconjugated hyperbilirubinemia
ANSWER: E
Rationale:
Atazanavir inhibits UGT1A1, the hepatic enzyme responsible for bilirubin conjugation. The result is unconjugated hyperbilirubinemia in most patients, with visible scleral icterus or jaundice in up to about 10%, while transaminases remain normal and the finding is benign and reversible on discontinuation. This matches the vignette, so Option E is correct.
Option A: Option A is incorrect because the picture is unconjugated, not a conjugated cholestatic pattern, and is characteristic of atazanavir rather than lopinavir.
Option B: Option B is incorrect because darunavir does not characteristically cause this benign hyperbilirubinemia, and the scenario explicitly lacks the transaminase elevation that hepatocellular toxicity would produce.
Option C: Option C is incorrect; the mechanism is impaired conjugation, not hemolysis.
Option D: Option D is incorrect because the finding is a conjugation defect, not biliary obstruction by crystals (atazanavir can cause nephrolithiasis, a separate and distinct effect).
6. Integrase strand transfer inhibitors (INSTIs) such as dolutegravir act on the HIV enzyme integrase. Which description best captures how these drugs block integration of viral DNA into the host genome?
A) They prevent removal of two nucleotides from the viral DNA ends in the cytoplasm during 3-prime processing
B) They competitively block the active site of a viral aspartyl protease, preventing polyprotein cleavage
C) They chelate two magnesium ions in the integrase active site, blocking the metal coordination required for the strand transfer step that inserts viral DNA into host DNA
D) They bind a host cell co-receptor required for membrane fusion before entry
E) They terminate the growing viral DNA strand after incorporation by reverse transcriptase
ANSWER: C
Rationale:
Integrase performs two sequential reactions: 3-prime processing (trimming the viral DNA ends in the cytoplasm) and strand transfer (inserting the processed viral DNA into host chromosomal DNA in the nucleus). INSTIs contain a pharmacophore that chelates the two magnesium ions in the integrase active site, blocking the metal coordination required specifically for strand transfer; this is why they are named strand transfer inhibitors. Option C is therefore correct.
Option A: Option A describes the 3-prime processing step, which INSTIs do not primarily target.
Option B: Option B describes protease inhibition, a different class and enzyme.
Option D: Option D describes an entry/fusion mechanism (for example a CCR5 antagonist), not integrase inhibition.
Option E: Option E describes a nucleoside reverse transcriptase inhibitor acting as a chain terminator.
7. First-generation and second-generation integrase strand transfer inhibitors (INSTIs) differ importantly in their resistance barriers. Which statement correctly characterizes the second-generation INSTIs dolutegravir and bictegravir?
A) They have a high genetic resistance barrier, such that treatment-naive patients essentially do not develop treatment-emergent integrase resistance at virologic failure in registrational trials
B) They have a lower resistance barrier than raltegravir, so a single mutation readily abolishes their activity
C) They require pharmacokinetic boosting with cobicistat to achieve any antiviral effect
D) They are active only against CXCR4-tropic virus and require tropism testing before use
E) They work by inhibiting viral protease rather than integrase
ANSWER: A
Rationale:
Dolutegravir and bictegravir are second-generation INSTIs whose flexible binding allows them to retain activity despite minor integrase conformational changes caused by first-generation resistance mutations. Their genetic resistance barrier is high enough that treatment-naive patients essentially do not select treatment-emergent integrase resistance at virologic failure, as seen in their registrational trials. Option A is correct.
Option B: Option B inverts the truth: their barrier is higher than that of first-generation raltegravir, which can be defeated by a single signature mutation.
Option C: Option C is incorrect for these agents; dolutegravir and bictegravir do not require cobicistat boosting (elvitegravir does).
Option D: Option D confuses INSTIs with the CCR5 antagonist maraviroc, which requires tropism testing; INSTIs act regardless of co-receptor tropism. Option E misassigns the mechanism to protease rather than integrase.
8. Maraviroc is a CCR5 (C-C chemokine receptor type 5) antagonist. Which step is required before maraviroc can be appropriately prescribed, and why?
A) Therapeutic drug monitoring of maraviroc trough levels, because the drug has a narrow therapeutic index
B) Confirmation of UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) genotype, because the drug is cleared by glucuronidation
C) HLA-B*57:01 testing, because maraviroc causes a hypersensitivity reaction in carriers
D) A validated co-receptor tropism assay confirming exclusively CCR5 (R5)-tropic virus, because maraviroc has no activity against CXCR4-using virus and any detectable X4 virus predicts virologic failure
E) Measurement of glucose-6-phosphate dehydrogenase activity, because maraviroc causes oxidative hemolysis
ANSWER: D
Rationale:
Maraviroc blocks the conformational change in the host CCR5 co-receptor required for membrane fusion, so it works only against R5-tropic virus. HIV can also use the CXCR4 (C-X-C chemokine receptor type 4) co-receptor, and maraviroc has no activity against CXCR4-using (X4) or dual/mixed-tropic virus. A validated tropism assay (for example, the Trofile assay or genotypic inference from the V3 loop) must confirm exclusively R5 tropism before prescribing, because any detectable X4-using virus predicts failure. Option D is therefore correct.
Option A: Option A is incorrect; routine maraviroc trough monitoring is not the required pre-prescribing step.
Option B: Option B is incorrect because UGT1A1 genotyping is not required for maraviroc, which is a CYP3A4 substrate.
Option C: Option C describes abacavir hypersensitivity and HLA-B*57:01, not maraviroc.
Option E: Option E describes a glucose-6-phosphate dehydrogenase deficiency concern unrelated to maraviroc.
9. Enfuvirtide occupies an unusual niche among antiretrovirals because of both its mechanism and its route of administration. Which description is correct?
A) It is an oral capsid inhibitor that blocks nuclear import of the pre-integration complex
B) It is a subcutaneously injected fusion inhibitor that mimics the HR2 (heptad repeat 2) region of gp41 and blocks formation of the six-helix bundle required for viral membrane fusion
C) It is an oral CCR5 antagonist used as a first-line agent in treatment-naive patients
D) It is an intravenous integrase inhibitor given once every two weeks
E) It is a boosted protease inhibitor preferred in salvage regimens for its high resistance barrier
ANSWER: B
Rationale:
Enfuvirtide is a 36-amino-acid synthetic peptide that mimics the HR2 region of the viral envelope glycoprotein gp41. By binding the heptad repeat 1 (HR1) region, it prevents formation of the six-helix bundle that drives fusion of the viral and cell membranes. It must be given by subcutaneous injection twice daily, which—together with near-universal injection site reactions—largely restricts it to salvage regimens. Option B is correct.
Option A: Option A describes lenacapavir, a capsid inhibitor, not enfuvirtide.
Option C: Option C is incorrect because enfuvirtide is not an oral CCR5 antagonist and is not a first-line agent.
Option D: Option D describes the intravenous monoclonal antibody ibalizumab dosing pattern, not enfuvirtide.
Option E: Option E describes a boosted protease inhibitor, a different class entirely.
10. A patient on a ritonavir-boosted protease inhibitor regimen needs a statin for hyperlipidemia. Which statin is absolutely contraindicated in this setting, and why?
A) Pravastatin, because it is heavily metabolized by CYP3A4 and accumulates to toxic levels
B) Rosuvastatin, because the booster eliminates it through CYP3A4 induction, rendering it ineffective
C) Atorvastatin, because it cannot be used at any dose with a boosted PI
D) All statins are equally safe, so the choice does not matter
E) Simvastatin, because CYP3A4 inhibition by the booster raises its plasma concentration dramatically, producing a high risk of myopathy and rhabdomyolysis
ANSWER: E
Rationale:
Simvastatin (and lovastatin) are extensively metabolized by CYP3A4. When a boosted PI strongly inhibits CYP3A4, simvastatin plasma concentrations rise dramatically—up to roughly 50-fold—creating a high risk of myopathy and rhabdomyolysis, so these agents are absolutely contraindicated. Option E is correct. Option A is wrong because pravastatin is minimally CYP3A4-metabolized and is actually a preferred statin in this setting.
Option B: Option B inverts the mechanism: rosuvastatin is not eliminated by CYP3A4 induction, and the booster inhibits rather than induces CYP3A4.
Option C: Option C overstates the atorvastatin restriction; atorvastatin may be used cautiously at the lowest effective dose with monitoring, not absolutely contraindicated.
Option D: Option D is incorrect because statins differ markedly in their interaction risk with boosted PIs.
11. Most protease inhibitors are not given alone but are combined with a booster such as ritonavir or cobicistat. What underlying pharmacokinetic problem makes this boosting strategy necessary?
A) Unboosted PIs are too potent, and the booster is required to lower their concentrations into the therapeutic range
B) Unboosted PIs are renally cleared too slowly, and the booster accelerates their elimination
C) Without enhancement, oral bioavailability of most PIs is low and variable and plasma concentrations are insufficient for sustained viral suppression; the booster inhibits CYP3A4 and P-glycoprotein to raise and sustain PI levels
D) Unboosted PIs cannot cross cell membranes, and the booster acts as a transport carrier into infected cells
E) The booster is required to convert an inactive PI prodrug into its active form
ANSWER: C
Rationale:
All currently used PIs are extensively metabolized by CYP3A4 and are substrates of P-glycoprotein (P-gp) in the gut wall and liver. As a result, their oral bioavailability is low and variable, and without enhancement plasma concentrations are insufficient for sustained viral suppression. Low-dose ritonavir or cobicistat inhibits CYP3A4 and P-gp, raising the PI area under the concentration-time curve and prolonging its half-life so that lower, less frequent doses work. Option C is correct.
Option A: Option A inverts the rationale; boosting raises rather than lowers PI concentrations.
Option B: Option B is incorrect because the limiting problem is metabolic clearance and poor bioavailability, not slow renal elimination, and boosting slows rather than accelerates clearance.
Option D: Option D is incorrect; the booster acts through enzyme and transporter inhibition, not as a membrane carrier.
Option E: Option E is incorrect because boosted PIs are not prodrugs requiring metabolic activation by the booster.
12. Raltegravir was the first integrase strand transfer inhibitor (INSTI) approved. Which pair of features distinguishes it from the second-generation agents dolutegravir and bictegravir?
A) A relatively low genetic resistance barrier, such that a single signature mutation confers significant resistance, together with twice-daily dosing due to a short plasma half-life
B) A higher resistance barrier than any other INSTI, together with once-monthly injectable dosing
C) An absolute requirement for cobicistat boosting, together with strong CYP3A4 inhibition
D) Activity restricted to CXCR4-tropic virus, together with mandatory tropism testing
E) Elimination entirely by the kidney, requiring dose reduction in renal impairment
ANSWER: A
Rationale:
Raltegravir has a short plasma half-life (about 9 hours) and is dosed twice daily, and it has a low genetic resistance barrier: a single mutation in one of its signature pathways (such as Q148, N155, or Y143) can confer significant resistance. These two features distinguish it from the high-barrier, once-daily second-generation agents, so Option A is correct.
Option B: Option B is incorrect because raltegravir's barrier is lower, not higher, and raltegravir is oral, not a monthly injectable.
Option C: Option C is incorrect; raltegravir does not require boosting (elvitegravir does) and does not strongly inhibit CYP3A4.
Option D: Option D confuses raltegravir with a CCR5 antagonist; INSTIs act independent of tropism.
Option E: Option E is incorrect because raltegravir is eliminated mainly by UGT1A1-mediated glucuronidation, not renal excretion, and does not require renal dose reduction.
13. A patient taking an integrase strand transfer inhibitor (INSTI) has unexpectedly low trough drug concentrations despite reporting good adherence. Which commonly overlooked interaction should be suspected first?
A) Grapefruit juice strongly induces INSTI metabolism, lowering drug levels
B) Polyvalent cation-containing products (calcium, magnesium, iron, or aluminum supplements and antacids) bind the INSTI in the gut and reduce its absorption when taken together
C) Concurrent acetaminophen displaces the INSTI from plasma proteins, increasing its clearance
D) A high-fat meal completely blocks absorption of all INSTIs
E) Vitamin C acidifies the urine and accelerates renal elimination of the INSTI
ANSWER: B
Rationale:
INSTIs chelate divalent and trivalent metal cations as part of their mechanism, and the same property makes them vulnerable to gastrointestinal chelation by calcium, magnesium, iron, and aluminum found in supplements and antacids. Taken together, these products markedly reduce INSTI absorption and can produce subtherapeutic troughs in an otherwise adherent patient; appropriate dose separation (or taking certain agents with food) prevents this. Option B is correct.
Option A: Option A is incorrect because the cation interaction, not grapefruit-mediated induction, is the classic missed cause (grapefruit inhibits rather than induces CYP3A4).
Option C: Option C is incorrect; the mechanism is gut chelation, not protein-binding displacement.
Option D: Option D overstates food effects—food does not completely block INSTI absorption and in some cases improves it.
Option E: Option E is incorrect because INSTIs are not cleared predominantly by pH-dependent renal elimination.
14. Which option correctly describes the cabotegravir plus rilpivirine (CAB+RPV) long-acting regimen for HIV?
A) Two oral integrase inhibitors taken together once daily for treatment-naive patients with high viral loads
B) A single subcutaneous capsid inhibitor injection given once every six months
C) An intravenous monoclonal antibody infusion given every two weeks
D) An intramuscular injectable regimen combining a second-generation integrase strand transfer inhibitor (cabotegravir) with a non-nucleoside reverse transcriptase inhibitor (rilpivirine), given monthly or every two months after an oral lead-in
E) A boosted protease inhibitor combination requiring ritonavir for pharmacokinetic enhancement
ANSWER: D
Rationale:
Cabotegravir is a second-generation INSTI and rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI); together they form the first complete long-acting injectable ART. The regimen uses an oral lead-in to assess tolerability, then intramuscular injections given once monthly or every two months, and is indicated for virologically suppressed patients. Option D is correct.
Option A: Option A is incorrect because the regimen is injectable, contains an NNRTI (not two integrase inhibitors), and is for suppressed rather than high-viral-load naive patients.
Option B: Option B describes lenacapavir, a capsid inhibitor.
Option C: Option C describes ibalizumab, an intravenous monoclonal antibody.
Option E: Option E is incorrect because CAB+RPV does not contain a protease inhibitor and is not ritonavir-boosted.
15. Dyslipidemia is a recognized class effect of protease inhibitors. Which statement best reflects the relative metabolic burden among PIs?
A) Dyslipidemia is most pronounced with darunavir and essentially absent with lopinavir/ritonavir
B) All protease inhibitors raise lipids to an identical degree, so agent choice has no metabolic consequence
C) Protease inhibitors lower triglycerides and LDL (low-density lipoprotein) cholesterol as a class
D) The dyslipidemia is purely a laboratory artifact with no real change in circulating lipids
E) Dyslipidemia is most pronounced with lopinavir/ritonavir, with marked triglyceride and LDL (low-density lipoprotein) elevations, whereas darunavir-based regimens produce substantially less
ANSWER: E
Rationale:
Protease inhibitor-associated dyslipidemia varies by agent: it is most pronounced with lopinavir/ritonavir and older PIs, with triglyceride elevations several-fold above baseline and meaningful rises in LDL cholesterol, while darunavir-based regimens produce substantially less. Option E captures this gradient correctly.
Option A: Option A inverts the relationship, attributing the worst effect to darunavir.
Option B: Option B is incorrect because PIs differ markedly in their lipid effects.
Option C: Option C is incorrect because PIs as a class raise rather than lower triglycerides and LDL.
Option D: Option D is incorrect because the lipid changes are real circulating elevations, not a laboratory artifact (the creatinine artifact, a separate phenomenon, belongs to cobicistat).
16. A patient on a ritonavir-boosted protease inhibitor regimen is found to need treatment for active tuberculosis, and rifampin is proposed. What is the principal pharmacological problem with combining rifampin and a boosted PI?
A) Rifampin and boosted PIs together cause additive QT-interval prolongation, risking arrhythmia
B) Rifampin inhibits CYP3A4, raising PI concentrations to toxic levels
C) Rifampin is a potent CYP3A4 inducer that markedly lowers protease inhibitor concentrations, defeating the boosting strategy and risking virologic failure; it is contraindicated with boosted PIs
D) Rifampin chelates the protease inhibitor in the gut, preventing its absorption
E) Rifampin and boosted PIs compete for renal tubular secretion, causing PI accumulation
ANSWER: C
Rationale:
Rifampin is a potent inducer of CYP3A4. Because boosted PIs depend on CYP3A4 inhibition to maintain therapeutic exposures, co-administering rifampin induces the enzyme and reduces PI area under the concentration-time curve by roughly 75 to 90%, undermining the entire boosting strategy and risking virologic failure and resistance; rifampin is therefore contraindicated with boosted PIs. Option C is correct.
Option B: Option B inverts the mechanism—rifampin induces rather than inhibits CYP3A4, so concentrations fall rather than rise.
Option A: Option A is incorrect because the defining problem is loss of PI exposure through induction, not additive QT prolongation.
Option D: Option D is incorrect; the mechanism is enzyme induction, not gut chelation.
Option E: Option E is incorrect because the interaction is hepatic metabolic induction, not competition for renal secretion.
17. Current guidelines recommend integrase strand transfer inhibitor (INSTI)-based regimens as preferred initial therapy for most treatment-naive adults. Which option is an example of such a preferred first-line regimen?
A) Bictegravir co-formulated with tenofovir alafenamide (TAF) and emtricitabine (FTC) as a single-tablet once-daily regimen
B) Enfuvirtide plus ibalizumab given by injection twice daily
C) Ritonavir monotherapy
D) Maraviroc as a single agent without tropism testing
E) Lopinavir/ritonavir plus enfuvirtide as a preferred naive-patient regimen
ANSWER: A
Rationale:
Guideline-preferred initial therapy for most treatment-naive adults is built on a second-generation INSTI. Bictegravir/TAF/FTC (a single-tablet, once-daily regimen) pairs the high-barrier INSTI bictegravir with the preferred tenofovir prodrug and emtricitabine, has no significant CYP interactions, and suits most patients starting ART, so Option A is correct.
Option B: Option B describes salvage-only injectable agents, not first-line therapy.
Option C: Option C is incorrect because ritonavir is a booster with no useful antiviral activity at booster doses and is never used as monotherapy.
Option D: Option D is incorrect both because maraviroc requires documented R5 tropism and because single-agent therapy is never appropriate. Option E pairs an older moderate-barrier PI with a salvage injectable and is not a preferred naive-patient regimen.
18. Lenacapavir introduced a mechanism not represented by older antiretroviral classes. Which description is correct?
A) A non-nucleoside reverse transcriptase inhibitor given orally once daily
B) A capsid inhibitor that disrupts HIV-1 capsid function—including capsid assembly and nuclear import of the pre-integration complex—formulated for subcutaneous injection every six months and used in heavily treatment-experienced patients with multi-drug-resistant HIV-1
C) A CCR5 (C-C chemokine receptor type 5) antagonist requiring tropism testing before use
D) A boosted protease inhibitor with the highest resistance barrier in its class
E) An integrase strand transfer inhibitor given by monthly intramuscular injection
ANSWER: B
Rationale:
Lenacapavir is a first-in-class capsid inhibitor. It disrupts the HIV-1 capsid protein through several actions, including interfering with capsid assembly and with nuclear import of the pre-integration complex. It is given subcutaneously every six months—the longest dosing interval among approved antiretroviral injectables—in combination with an optimized background regimen for heavily treatment-experienced adults with multi-drug-resistant HIV-1. Option B is correct.
Option A: Option A is incorrect; lenacapavir is not an NNRTI and is not a daily oral agent.
Option C: Option C describes maraviroc, a CCR5 antagonist.
Option D: Option D is incorrect because lenacapavir is not a protease inhibitor.
Option E: Option E describes cabotegravir, the injectable INSTI, not lenacapavir.
19. Ibalizumab differs from most antiretrovirals because it targets a host cell protein rather than a viral enzyme. Which description is correct?
A) An oral capsid inhibitor that prevents nuclear import of the pre-integration complex
B) A peptide fusion inhibitor that mimics gp41 and is injected subcutaneously twice daily
C) A small-molecule CCR5 antagonist taken orally
D) A humanized monoclonal antibody that binds domain 2 of the CD4 (cluster of differentiation 4) receptor, blocking the post-attachment conformational change needed for co-receptor engagement, and is given by intravenous infusion every two weeks
E) A boosted protease inhibitor preferred for treatment-naive patients
ANSWER: D
Rationale:
Ibalizumab is a humanized monoclonal antibody that binds domain 2 of the host CD4 receptor. It blocks the post-attachment conformational change required for co-receptor engagement without interfering with the domain 1-mediated immune functions of CD4, and it is administered as an intravenous infusion every two weeks for treatment-experienced adults with multi-drug-resistant HIV-1. Option D is correct.
Option A: Option A describes lenacapavir, a capsid inhibitor.
Option B: Option B describes enfuvirtide, a subcutaneously injected gp41 fusion inhibitor.
Option C: Option C describes maraviroc, an oral small-molecule CCR5 antagonist.
Option E: Option E describes a boosted protease inhibitor, an unrelated class and indication.
20. Rifampin induces the glucuronidation and CYP3A4 pathways that eliminate dolutegravir, lowering its concentration. When dolutegravir and rifampin must be co-administered, what is the approved management strategy?
A) Substitute cobicistat boosting of dolutegravir to overcome the induction
B) Reduce the dolutegravir dose to avoid accumulation
C) Add ritonavir to inhibit the rifampin effect
D) No adjustment is needed because rifampin does not affect dolutegravir
E) Double the dolutegravir dose from 50 mg once daily to 50 mg twice daily to restore adequate plasma exposure
ANSWER: E
Rationale:
Rifampin induces UGT1A1 and CYP3A4, the pathways that clear dolutegravir, reducing its area under the concentration-time curve by roughly half. The approved strategy is to double dolutegravir from 50 mg once daily to 50 mg twice daily, which restores adequate exposures confirmed in pharmacokinetic studies. Option E is correct.
Option A: Option A is incorrect because dolutegravir is not managed by adding cobicistat boosting, and boosting would not counter potent enzyme induction.
Option B: Option B inverts the needed direction: induction lowers exposure, so the dose is increased, not reduced.
Option C: Option C is incorrect because adding ritonavir is not the approved approach and would introduce its own interactions.
Option D: Option D is incorrect because rifampin clearly does reduce dolutegravir exposure and requires dose adjustment (note that bictegravir, by contrast, is contraindicated with rifampin).
21. A clinically important observation has emerged since integrase strand transfer inhibitors (INSTIs) became preferred first-line therapy. Which statement best describes it?
A) INSTIs reliably cause weight loss, useful in patients with obesity
B) INSTIs cause a dose-dependent QT prolongation that limits their use
C) INSTI-based regimens are associated with weight gain (commonly 2 to 4 kg over the first year or two), with greater gain when combined with tenofovir alafenamide (TAF) and apparently greater effect in women and persons of African ancestry
D) INSTIs cause unconjugated hyperbilirubinemia as a class effect
E) INSTIs require pretreatment tropism testing because of a weight-related interaction
ANSWER: C
Rationale:
Switch and initiation data show that INSTI-based regimens are associated with weight gain, commonly on the order of 2 to 4 kg over the first 48 to 96 weeks, with greater gain when the regimen includes tenofovir alafenamide rather than tenofovir disoproxil fumarate, and apparently larger effects in women and in persons of African ancestry. Option C is correct.
Option A: Option A inverts the finding—weight gain, not loss, is observed.
Option B: Option B is incorrect because dose-dependent QT prolongation is not the characteristic INSTI concern.
Option D: Option D misattributes atazanavir's UGT1A1-mediated hyperbilirubinemia to the INSTI class.
Option E: Option E is incorrect because tropism testing relates to the CCR5 antagonist maraviroc and has nothing to do with INSTI weight effects.
22. A patient on a boosted protease inhibitor regimen needs a statin and the team wants to minimize the risk of a serious drug interaction. Which statins are generally preferred in this setting, and why?
A) Pravastatin and rosuvastatin, because they are minimally metabolized by CYP3A4 and therefore are not raised to dangerous concentrations by the CYP3A4-inhibiting booster
B) Simvastatin and lovastatin, because their extensive CYP3A4 metabolism makes them safest with a booster
C) Any statin at maximum dose, because boosted PIs lower all statin concentrations
D) No statin can be used safely, so lipid-lowering therapy must be withheld entirely
E) Only fibrates, because statins of every kind are absolutely contraindicated with boosted PIs
ANSWER: A
Rationale:
Because boosted PIs strongly inhibit CYP3A4, statins that depend on CYP3A4 for clearance accumulate to dangerous concentrations. Pravastatin and rosuvastatin are minimally metabolized by CYP3A4, so they are not raised to hazardous levels and are the preferred choices (rosuvastatin rises only modestly via OATP1B1 inhibition and remains manageable). Option A is correct. Option B is dangerously wrong: simvastatin and lovastatin are the agents whose CYP3A4 metabolism makes them contraindicated, not safest.
Option C: Option C is incorrect because boosting raises CYP3A4-dependent statin levels rather than lowering all statins, and maximum dosing would worsen risk.
Option D: Option D is incorrect because effective lipid-lowering can be achieved safely with the preferred statins.
Option E: Option E overstates the restriction; statins as a class are not all contraindicated, and preferred agents exist.
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