Drug Classification · Questions 1–6
Identify the pharmacological class or categorical label for each drug or receptor. Vocabulary preparation is sufficient to answer every question in this section.
Question 1
Which of the following protease inhibitors is classified as characteristically causing unconjugated hyperbilirubinemia as a distinctive class effect?
Correct Answer
C — Atazanavir
Rationale
Atazanavir is classified as the protease inhibitor that characteristically causes unconjugated hyperbilirubinemia. This is a distinctive feature of atazanavir among protease inhibitors and results from its inhibition of the bilirubin-conjugating enzyme UGT1A1. Darunavir, lopinavir, and tipranavir do not share this classification feature.
Question 2
Which of the following integrase strand transfer inhibitors is classified as requiring a pharmacokinetic booster for adequate plasma concentrations?
Correct Answer
C — Elvitegravir
Rationale
Elvitegravir is the only integrase strand transfer inhibitor classified as requiring a pharmacokinetic booster — it is always co-formulated with cobicistat, which inhibits CYP3A4 and raises elvitegravir concentrations to therapeutic levels. Dolutegravir, raltegravir, and bictegravir do not require boosting. Raltegravir is eliminated by glucuronidation. Dolutegravir and bictegravir are second-generation agents with sufficient oral bioavailability and half-lives to permit once-daily unboosted dosing.
Question 3
Which of the following non-nucleoside reverse transcriptase inhibitors is classified as carrying the highest risk of severe hepatotoxicity when initiated in women with CD4 counts above 250 cells per cubic millimeter?
Correct Answer
D — Nevirapine
Rationale
Nevirapine is classified as the NNRTI carrying the highest risk of severe hepatotoxicity, with risk specifically concentrated in women with CD4 counts above 250 cells per cubic millimeter and men with CD4 counts above 400 cells per cubic millimeter at initiation. This CD4-dependent risk pattern is a distinctive classification feature of nevirapine not shared by efavirenz, rilpivirine, or doravirine, and is the primary reason nevirapine is rarely used in resource-rich settings today.
Question 4
Which of the following non-nucleoside reverse transcriptase inhibitors is classified as the only agent in its class acceptable for co-administration with rifampin?
Correct Answer
B — Efavirenz
Rationale
Efavirenz is classified as the only NNRTI acceptable for co-administration with rifampin. Efavirenz maintains adequate plasma concentrations despite approximately 26% reduction in exposure because its therapeutic window accommodates this degree of induction. Rilpivirine and doravirine concentrations are reduced to subtherapeutic levels by rifampin and are contraindicated. Nevirapine, while also a CYP3A4 inducer itself, has insufficient data to support use with rifampin and is not classified as acceptable in this combination.
Question 5
Which of the following integrase strand transfer inhibitors is classified as the preferred agent throughout pregnancy, including at conception, per current guidelines?
Correct Answer
A — Dolutegravir
Rationale
Dolutegravir is classified as the preferred integrase strand transfer inhibitor throughout pregnancy, including at conception, following reassessment of the initial neural tube defect signal from Botswana surveillance data. Current DHHS and WHO guidelines recommend dolutegravir in this setting. Elvitegravir requires cobicistat boosting, which alters drug pharmacokinetics during pregnancy and is not preferred. Cabotegravir-rilpivirine long-acting injectable ART is not recommended in pregnancy due to absent safety data and the prolonged pharmacokinetic tail. Bictegravir has insufficient pregnancy safety data to support a preferred classification at this time.
Question 6
Which of the following nucleoside reverse transcriptase inhibitors is classified as a guanosine analog?
Correct Answer
B — Abacavir
Rationale
Abacavir is classified as a guanosine analog — it mimics the nucleoside guanosine and is converted intracellularly to carbovir triphosphate, which is incorporated into viral DNA by reverse transcriptase. Zidovudine is a thymidine analog. Emtricitabine is a cytosine analog. Tenofovir disoproxil fumarate is an adenosine analog and is additionally classified as a nucleotide rather than a nucleoside reverse transcriptase inhibitor because it already contains a phosphonate group.
Core Pharmacology · Questions 7–14
Apply your understanding of drug mechanisms, pharmacokinetics, and adverse effects. Each question requires one reasoning step.
Question 7
All protease inhibitor-based antiretroviral regimens are contraindicated with rifampin, even when the protease inhibitor is pharmacokinetically boosted with ritonavir or cobicistat. Which of the following best explains why pharmacokinetic boosting cannot overcome this interaction?
Correct Answer
D — Rifampin induces CYP3A4 to such a degree that it reduces protease inhibitor exposure by 75 to 90 percent even with boosting, producing subtherapeutic concentrations that cannot be corrected by dose escalation
Rationale
Rifampin is the most potent CYP3A4 inducer in clinical use. Co-administration reduces protease inhibitor plasma exposure by 75 to 90 percent regardless of pharmacokinetic boosting, because rifampin-driven induction overwhelms the CYP3A4 inhibitory effect of ritonavir or cobicistat. The resulting protease inhibitor concentrations are subtherapeutic and cannot be restored by dose escalation within safe limits. The preferred antiretroviral strategy with rifampin is dolutegravir 50 mg twice daily, or efavirenz when an NNRTI is required. Rifabutin, a weaker CYP3A4 inducer, can be used with boosted protease inhibitors at a reduced dose of 150 mg every other day.
Question 8
Nevirapine-associated hepatotoxicity occurs most commonly in women with CD4 counts above 250 cells per cubic millimeter at the time of antiretroviral initiation. Which of the following best explains why higher CD4 counts at initiation are associated with greater hepatotoxicity risk?
Correct Answer
B — Nevirapine hepatotoxicity is immune-mediated; patients with better-preserved immune function mount a more vigorous hypersensitivity response directed at nevirapine-modified hepatic proteins
Rationale
Nevirapine hepatotoxicity occurs through an immune-mediated hypersensitivity mechanism rather than direct mitochondrial or metabolic toxicity. Patients with higher CD4 counts at initiation have more intact immune function and mount a stronger immune response against nevirapine or nevirapine-modified hepatic proteins, producing more severe hepatic injury. This explains the paradox that healthier patients are at greater risk — the toxicity is driven by the immune system, not by direct drug effect. This CD4-dependent pattern is the primary reason nevirapine is contraindicated at higher CD4 thresholds and is rarely used in resource-rich settings where INSTI-based regimens are preferred.
Question 9
A patient taking atazanavir develops visible jaundice. Laboratory evaluation shows elevated unconjugated bilirubin but normal alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Which of the following best explains this finding?
Correct Answer
A — Atazanavir inhibits the hepatic enzyme responsible for conjugating bilirubin, causing unconjugated bilirubin to accumulate without hepatocellular injury
Rationale
Atazanavir inhibits UGT1A1, the glucuronosyltransferase that conjugates bilirubin to make it water-soluble for biliary excretion. Inhibition allows unconjugated bilirubin to accumulate in plasma, producing jaundice and scleral icterus. Because this is an enzyme inhibition effect rather than hepatocyte injury, liver enzymes remain normal. This finding is benign and does not represent true hepatotoxicity. No dose adjustment or drug discontinuation is required for isolated unconjugated hyperbilirubinemia on atazanavir, though some patients request a regimen change for cosmetic reasons.
Question 10
A patient with advanced HIV infection and a CD4 count of 18 cells per cubic millimeter begins antiretroviral therapy for the first time. Three weeks later he develops worsening respiratory symptoms, new lymphadenopathy, and radiographic findings consistent with expansion of a previously identified pulmonary cryptococcal lesion. Which of the following best explains this clinical deterioration?
Correct Answer
C — Rapid immune reconstitution following antiretroviral initiation produces an exaggerated inflammatory response directed at previously sub-clinical or inadequately treated pathogens
Rationale
Immune reconstitution inflammatory syndrome (IRIS) occurs when recovering immune function generates an exaggerated inflammatory response against opportunistic pathogens — either previously undiagnosed infections that become unmasked, or treated infections that paradoxically worsen as immunity recovers. Patients with the lowest CD4 counts at antiretroviral initiation are at highest risk because the degree of immune reconstitution is greatest. Cryptococcal IRIS is among the most dangerous forms and is one reason antiretroviral initiation is typically deferred for two to ten weeks after starting antifungal therapy for cryptococcal meningitis. The presentation described — worsening despite viral suppression — is characteristic of paradoxical IRIS rather than treatment failure.
Question 11
Tenofovir disoproxil fumarate nephrotoxicity risk is substantially amplified when it is co-administered with cobicistat or a ritonavir-boosted protease inhibitor. Which of the following best explains why these pharmacokinetic boosters increase the renal risk of tenofovir disoproxil fumarate?
Correct Answer
D — Cobicistat and ritonavir inhibit the renal transporters responsible for tenofovir elimination, increasing tenofovir accumulation in proximal tubular cells and amplifying local mitochondrial toxicity
Rationale
Cobicistat and ritonavir inhibit renal drug transporters — including P-glycoprotein and multidrug resistance-associated protein transporters — that are involved in tenofovir elimination from proximal tubular cells. Transporter inhibition impairs tenofovir efflux from these cells, leading to higher intracellular tenofovir concentrations at the site of mitochondrial toxicity. The amplified local tenofovir accumulation increases the risk of Fanconi syndrome and renal injury. This is an important clinical consideration when selecting tenofovir prodrug formulations in patients on boosted regimens; tenofovir alafenamide, with its far lower plasma tenofovir concentrations, substantially reduces this interaction-driven risk.
Question 12
A patient with HIV infection requires anticonvulsant therapy for a new seizure disorder. The neurology consultant recommends carbamazepine. Which of the following best explains why carbamazepine is problematic in this patient and identifies the preferred anticonvulsant alternatives?
Correct Answer
B — Carbamazepine induces CYP3A4 and UGT1A1, reducing antiretroviral plasma concentrations to subtherapeutic levels; levetiracetam, lacosamide, and pregabalin are preferred because they have minimal cytochrome P450 interactions
Rationale
Carbamazepine, phenytoin, phenobarbital, and oxcarbazepine are all potent inducers of CYP3A4 and UGT1A1. Co-administration reduces plasma concentrations of nearly all antiretroviral agents — protease inhibitors, NNRTIs, and integrase strand transfer inhibitors — to a clinically meaningful degree, risking virologic failure. When anticonvulsant therapy is needed in patients on antiretroviral therapy, non-inducing agents are strongly preferred: levetiracetam, lacosamide, and pregabalin have minimal cytochrome P450 interactions. Lamotrigine may be used with caution in patients on boosted PI regimens because its UGT1A1-mediated clearance is accelerated by enzyme inducers. Valproate and phenytoin carry their own interaction concerns and are not the preferred choice.
Question 13
A patient with HIV infection and Child-Pugh C hepatic cirrhosis requires an integrase strand transfer inhibitor as part of his antiretroviral regimen. Which of the following best explains why raltegravir is preferred over dolutegravir in this clinical setting?
Correct Answer
A — Raltegravir is eliminated primarily by glucuronidation without meaningful CYP3A4 contribution, and its pharmacokinetics are not substantially altered by severe hepatic impairment
Rationale
Raltegravir's elimination depends primarily on UGT1A1 glucuronidation with minimal CYP3A4 involvement. Because UGT1A1 activity is relatively preserved in hepatic impairment compared with CYP-mediated pathways, raltegravir pharmacokinetics are not substantially altered even in Child-Pugh C disease, making it the preferred integrase strand transfer inhibitor in severe hepatic impairment. Dolutegravir exposure increases approximately 1.5-fold in moderate hepatic impairment and is not recommended in Child-Pugh C due to limited data. Raltegravir is not renally eliminated and is not hepatotoxic through mitochondrial mechanisms; option D incorrectly attributes mitochondrial toxicity to dolutegravir.
Question 14
Efavirenz is the only non-nucleoside reverse transcriptase inhibitor acceptable for co-administration with rifampin, despite rifampin reducing efavirenz plasma exposure by approximately 26 percent. Which of the following best explains why efavirenz remains effective at this reduced exposure while rilpivirine and doravirine do not?
Correct Answer
C — Efavirenz has a wide enough therapeutic window that a 26 percent reduction in exposure still maintains concentrations above the threshold required for antiviral efficacy, unlike rilpivirine and doravirine whose therapeutic windows are narrower
Rationale
The key difference between efavirenz and other NNRTIs in the context of rifampin co-administration is the therapeutic window. Efavirenz plasma concentrations remain above the minimum effective threshold despite the approximately 26 percent reduction in exposure caused by rifampin-mediated CYP3A4 induction. Rilpivirine and doravirine have narrower therapeutic windows and narrower margins above their minimum effective concentrations; rifampin-mediated reductions bring their concentrations to subtherapeutic levels and are contraindicated. Efavirenz does not compensate by producing active metabolites, and while efavirenz is itself a CYP3A4 inducer, this does not meaningfully counteract rifampin co-induction at the pharmacokinetic level.
Clinical Correlations · Questions 15–18
Apply pharmacological knowledge to clinical scenarios. Each vignette presents a patient situation; the question tests mechanism of action or drug selection.
Question 15
A 29-year-old woman with HIV infection presents for preconception counseling. She is currently on an efavirenz-based regimen with an undetectable viral load and wishes to become pregnant within the next three months. Her physician recommends switching her antiretroviral regimen before conception. Which of the following integrase strand transfer inhibitors is the preferred choice throughout pregnancy, including at the time of conception, per current guidelines?
Correct Answer
B — Dolutegravir
Rationale
Dolutegravir is the preferred integrase strand transfer inhibitor throughout pregnancy, including at conception, following reassessment of the initial neural tube defect signal. Current DHHS and WHO guidelines recommend dolutegravir in this setting based on its high resistance barrier, excellent tolerability, and accumulating pregnancy safety data. Efavirenz is now a non-preferred option in pregnancy. Cabotegravir-rilpivirine long-acting injectable therapy is not recommended in pregnancy due to absent safety data and the inability to rapidly discontinue if needed. Elvitegravir requires cobicistat boosting, which alters pharmacokinetics during pregnancy and is not preferred. Bictegravir lacks sufficient pregnancy safety data for a preferred classification.
Question 16
A 36-year-old man is diagnosed with pulmonary tuberculosis and HIV infection simultaneously. His CD4 count is 32 cells per cubic millimeter. Tuberculosis treatment is initiated today. Which of the following best describes the recommended timing for initiating antiretroviral therapy in this patient?
Correct Answer
D — Antiretroviral therapy should be initiated within two weeks of starting tuberculosis treatment, because a CD4 count below 50 cells per cubic millimeter identifies patients in whom early antiretroviral therapy reduces mortality
Rationale
Clinical trial data establish that in HIV/tuberculosis co-infected patients with CD4 counts below 50 cells per cubic millimeter, initiating antiretroviral therapy within two weeks of tuberculosis treatment start reduces mortality compared with deferred initiation. The benefit of early immune reconstitution outweighs the increased risk of immune reconstitution inflammatory syndrome in this severely immunocompromised group. For patients with CD4 counts above 50 cells per cubic millimeter, antiretroviral initiation can be deferred to 8 to 12 weeks after tuberculosis treatment begins, allowing the tuberculosis regimen to establish pathogen control before immune reconstitution occurs and reducing immune reconstitution inflammatory syndrome risk.
Question 17
A 31-year-old woman with HIV infection is 36 weeks pregnant and has been maintained on an atazanavir-based antiretroviral regimen throughout her pregnancy. Her obstetrician asks about the specific neonatal risk associated with atazanavir use near term. Which of the following best explains the mechanism underlying this neonatal concern?
Correct Answer
A — Atazanavir crosses the placenta and inhibits the neonatal enzyme responsible for bilirubin conjugation, impairing conjugation in the newborn and risking severe hyperbilirubinemia and kernicterus
Rationale
Atazanavir inhibits UGT1A1, the enzyme responsible for conjugating bilirubin. When atazanavir crosses the placenta near delivery, it can inhibit neonatal UGT1A1. Neonates already have physiologically immature bilirubin conjugation capacity; further impairment from atazanavir can produce severe unconjugated hyperbilirubinemia with risk of kernicterus. Neonatal bilirubin monitoring is required when atazanavir is used near term. This risk is the reason atazanavir is not the preferred protease inhibitor in pregnancy when alternatives are available. Options B, C, and D describe neonatal toxicities that are not attributable to atazanavir's pharmacological mechanism.
Question 18
A 58-year-old man with HIV infection has been on a tenofovir disoproxil fumarate-containing regimen for five years. His estimated glomerular filtration rate has declined to 45 mL per minute per 1.73 square meters over the past year. His viral load remains undetectable. His physician wishes to maintain a tenofovir-based backbone while minimizing further renal risk. Which of the following best supports this decision?
Correct Answer
C — Tenofovir disoproxil fumarate should not be initiated or continued when estimated glomerular filtration rate falls below 60 mL per minute; tenofovir alafenamide is preferred and may be used down to an estimated glomerular filtration rate of 15 mL per minute
Rationale
Current guidelines recommend against initiating or continuing tenofovir disoproxil fumarate when estimated glomerular filtration rate falls below 60 mL per minute per 1.73 square meters, due to the risk of proximal tubular toxicity and Fanconi syndrome from tenofovir accumulation. This patient's estimated glomerular filtration rate of 45 mL per minute falls below this threshold. Tenofovir alafenamide achieves high intracellular antiviral concentrations at far lower plasma tenofovir exposure than tenofovir disoproxil fumarate, substantially reducing renal and bone toxicity. Tenofovir alafenamide may be used down to an estimated glomerular filtration rate of 15 mL per minute, making it the appropriate switch in this patient who wishes to maintain tenofovir-based therapy.