Chapter 36 — Antiviral Pharmacology — Module 3 — HIV Pharmacology Part 3: ARV Drug Interactions, Toxicity, and Special Populations
1. For a victim drug co-administered with a ritonavir-boosted regimen, which property most determines how sensitive that drug is to a clinically significant interaction?
A) Its volume of distribution
B) Its fraction metabolized by cytochrome P450 3A4 (fm CYP3A4)
C) Its degree of renal tubular secretion
D) Its oral bioavailability in the fasted state
E) Its plasma elimination half-life
ANSWER: B
Rationale:
Option B is correct. The magnitude of a CYP3A4-mediated interaction scales with both the potency of the inhibitor or inducer and the fraction of the victim drug cleared by CYP3A4 (fm CYP3A4). Drugs with a high fm CYP3A4 (greater than 0.9) lose nearly their entire clearance pathway when CYP3A4 is inhibited, so their concentrations rise the most; drugs with a low fm CYP3A4 are relatively spared because alternative pathways remain.
Option A: Option A is incorrect. Volume of distribution influences loading and tissue distribution but does not determine the proportional change in exposure caused by enzyme inhibition or induction.
Option C: Option C is incorrect. Renal tubular secretion governs renal elimination and is irrelevant to the magnitude of a hepatic CYP3A4 interaction.
Option D: Option D is incorrect. Fasted bioavailability reflects absorption conditions, not sensitivity to CYP3A4 modulation.
Option E: Option E is incorrect. Half-life is a derived parameter and does not itself dictate how much exposure changes when the CYP3A4 pathway is inhibited.
2. Cobicistat and ritonavir are both used as pharmacokinetic boosters. Which statement correctly discriminates cobicistat from ritonavir?
A) Cobicistat is a potent CYP3A4 inducer, whereas ritonavir is an inhibitor
B) Cobicistat has greater intrinsic antiretroviral activity than ritonavir
C) Cobicistat must always be dosed twice daily, whereas ritonavir is once daily
D) Cobicistat has no antiretroviral activity of its own and functions purely as a CYP3A4 inhibitor for boosting
E) Cobicistat does not raise serum creatinine, whereas ritonavir does
ANSWER: D
Rationale:
Option D is correct. Cobicistat is a dedicated pharmacokinetic enhancer with no intrinsic antiretroviral activity; it boosts co-administered agents solely by inhibiting CYP3A4. Ritonavir, although now used almost exclusively as a booster, is itself a protease inhibitor with antiretroviral activity at higher (no longer used) doses.
Option A: Option A is incorrect. Both agents act as CYP3A4 inhibitors for boosting; neither is used clinically as an inducer.
Option B: Option B is incorrect. The opposite is true: cobicistat has no antiretroviral activity, while ritonavir is a protease inhibitor.
Option C: Option C is incorrect. Dosing frequency depends on the partnered agent and does not reliably distinguish the two boosters.
Option E: Option E is incorrect. Cobicistat characteristically raises serum creatinine by inhibiting tubular creatinine secretion, so this statement is reversed.
3. Rosuvastatin concentrations roughly double when given with lopinavir/ritonavir even though rosuvastatin is not appreciably metabolized by CYP3A4. Which mechanism explains this interaction?
A) Inhibition of hepatic uptake transporter OATP1B1
B) Inhibition of CYP3A4-mediated rosuvastatin oxidation
C) Induction of UGT1A1-mediated rosuvastatin glucuronidation
D) Displacement of rosuvastatin from plasma albumin
E) Inhibition of renal OCT2-mediated rosuvastatin secretion
ANSWER: A
Rationale:
Option A is correct. Rosuvastatin depends on the organic anion transporting polypeptide 1B1 (OATP1B1) for hepatic uptake. Lopinavir/ritonavir inhibits OATP1B1, reducing hepatic extraction and raising rosuvastatin plasma concentrations approximately two-fold independently of CYP3A4. This is the prototypical transporter-mediated statin interaction.
Option B: Option B is incorrect. Rosuvastatin is minimally CYP3A4-metabolized, so the interaction cannot be explained by CYP3A4 inhibition.
Option C: Option C is incorrect. The interaction raises concentrations through reduced uptake, not through changes in glucuronidation, and induction would lower rather than raise levels.
Option D: Option D is incorrect. Protein-binding displacement is not the mechanism of this statin interaction.
Option E: Option E is incorrect. The relevant transporter is the hepatic uptake transporter OATP1B1, not the renal cation transporter OCT2.
4. Zidovudine (ZDV) and stavudine (d4T) should never be combined. What is the basis for this prohibition?
A) Additive proximal tubular nephrotoxicity
B) Competition for the same plasma protein binding sites
C) Pharmacodynamic antagonism from competition for the same intracellular phosphorylation pathway
D) Additive QTc prolongation
E) Mutual induction of each other's hepatic metabolism
ANSWER: C
Rationale:
Option C is correct. Zidovudine and stavudine are both thymidine analogues that compete for the same intracellular phosphorylation (thymidine kinase) pathway required to generate their active triphosphate forms. The competition reduces formation of active drug, producing pharmacodynamic antagonism, so the combination is contraindicated.
Option A: Option A is incorrect. The problem is intracellular activation antagonism, not additive renal toxicity.
Option B: Option B is incorrect. Plasma protein displacement is not the basis for the prohibition.
Option D: Option D is incorrect. QTc prolongation is a concern with certain protease inhibitors, not the reason ZDV and d4T are not combined.
Option E: Option E is incorrect. The interaction is pharmacodynamic competition for activation, not reciprocal enzyme induction.
5. Which constellation of laboratory findings is most characteristic of tenofovir disoproxil fumarate (TDF)-associated proximal tubular injury (Fanconi syndrome)?
A) Hyperglycemia, hyperphosphatemia, and metabolic alkalosis
B) Isolated unconjugated hyperbilirubinemia with normal renal indices
C) Hyperkalemia, hyperphosphatemia, and preserved urine concentrating ability
D) Hypernatremia with concentrated urine and absent glucosuria
E) Normoglycemic glucosuria, phosphaturia with hypophosphatemia, aminoaciduria, and tubular proteinuria
ANSWER: E
Rationale:
Option E is correct. TDF proximal tubular injury produces the classic Fanconi pattern: normoglycemic glucosuria (glucose in the urine despite normal blood glucose), phosphaturia with hypophosphatemia, aminoaciduria, uricosuria, and low-molecular-weight tubular proteinuria, sometimes with a declining estimated glomerular filtration rate.
Option A: Option A is incorrect. Fanconi syndrome causes phosphate wasting with hypophosphatemia, not hyperphosphatemia, and glucosuria occurs with normal blood glucose.
Option B: Option B is incorrect. Isolated unconjugated hyperbilirubinemia describes the benign atazanavir effect, not TDF tubular injury.
Option C: Option C is incorrect. Proximal tubular dysfunction causes urinary losses and impaired reabsorption, not hyperphosphatemia with preserved function.
Option D: Option D is incorrect. The hallmark is glucosuria and solute wasting, not hypernatremia with concentrated urine and absent glucosuria.
6. Which statement best describes the pharmacologic basis for tenofovir alafenamide (TAF)'s improved renal and bone safety relative to tenofovir disoproxil fumarate (TDF)?
A) TAF is a different nucleotide that does not require intracellular phosphorylation
B) TAF delivers tenofovir diphosphate efficiently to target cells while producing about 90% lower plasma tenofovir concentrations
C) TAF is eliminated unchanged in bile and never undergoes intracellular activation
D) TAF achieves its effect through far higher plasma tenofovir concentrations than TDF
E) TAF acts on a viral target entirely distinct from that of TDF
ANSWER: B
Rationale:
Option B is correct. TAF is a prodrug that remains intact in plasma and is converted to the active metabolite tenofovir diphosphate predominantly inside target lymphocytes. This delivers adequate intracellular active drug while producing roughly 90% lower plasma tenofovir exposure than TDF, reducing proximal tubular and bone exposure and improving renal and bone safety.
Option A: Option A is incorrect. TAF still yields tenofovir, which requires intracellular phosphorylation to tenofovir diphosphate for activity.
Option C: Option C is incorrect. TAF is activated intracellularly to tenofovir diphosphate rather than eliminated unchanged in bile.
Option D: Option D is incorrect. TAF produces lower, not higher, plasma tenofovir concentrations than TDF.
Option E: Option E is incorrect. Both TAF and TDF deliver tenofovir, which inhibits HIV reverse transcriptase; the viral target is the same.
7. A clinician must distinguish benign atazanavir-associated hyperbilirubinemia from true atazanavir hepatotoxicity. Which feature correctly identifies the benign UGT1A1-mediated effect?
A) Marked transaminase elevation with synthetic dysfunction
B) Conjugated (direct) hyperbilirubinemia with cholestatic enzyme pattern
C) Hyperbilirubinemia accompanied by eosinophilia and rash
D) Unconjugated (indirect) hyperbilirubinemia with normal transaminases
E) Hyperbilirubinemia only in the presence of hepatitis C co-infection
ANSWER: D
Rationale:
Option D is correct. Atazanavir inhibits UGT1A1, impairing bilirubin conjugation and producing an unconjugated (indirect) hyperbilirubinemia with normal transaminases, analogous to Gilbert syndrome. It is benign, reflects no hepatocellular injury, and does not require discontinuation.
Option A: Option A is incorrect. Transaminase elevation with synthetic dysfunction indicates true hepatocellular injury, not the benign bilirubin effect.
Option B: Option B is incorrect. The benign effect is unconjugated hyperbilirubinemia from impaired conjugation, not a conjugated cholestatic pattern.
Option C: Option C is incorrect. Eosinophilia and rash suggest a hypersensitivity reaction rather than the isolated benign hyperbilirubinemia of UGT1A1 inhibition.
Option E: Option E is incorrect. The benign effect occurs from UGT1A1 inhibition regardless of hepatitis C status and is not defined by co-infection.
8. Among the non-nucleoside reverse transcriptase inhibitors (NNRTIs), which agent is the acceptable choice for co-administration with rifampin, tolerating only a modest exposure reduction?
A) Efavirenz
B) Rilpivirine
C) Doravirine
D) Etravirine
E) Nevirapine
ANSWER: A
Rationale:
Option A is correct. Efavirenz is the acceptable NNRTI with rifampin: its area under the concentration-time curve falls by only about 26%, and standard 600 mg dosing maintains adequate concentrations in most patients despite rifampin's induction.
Option B: Option B is incorrect. Rilpivirine concentrations are markedly reduced by rifampin, and the combination is contraindicated.
Option C: Option C is incorrect. Doravirine exposure is substantially reduced by strong inducers such as rifampin, making the pairing inappropriate without specific dose strategies not equivalent to efavirenz.
Option D: Option D is incorrect. Etravirine is not an established acceptable partner for rifampin co-treatment.
Option E: Option E is incorrect. Nevirapine combined with rifampin gives unpredictable, often subtherapeutic concentrations and added hepatotoxicity risk, so it is not the acceptable choice.
9. A patient on rilpivirine needs intermittent acid suppression. Which approach correctly reflects how histamine-2 receptor antagonists (H2RAs) differ from proton pump inhibitors (PPIs) in this setting?
A) Both PPIs and H2RAs are absolutely contraindicated with rilpivirine
B) Both PPIs and H2RAs may be taken at the same time as rilpivirine without restriction
C) H2RAs may be used if given at least 12 hours before or at least 4 hours after rilpivirine, whereas PPIs are contraindicated
D) PPIs may be used with dose separation, whereas H2RAs are absolutely contraindicated
E) Neither agent affects rilpivirine because rilpivirine absorption is acid-independent
ANSWER: C
Rationale:
Option C is correct. Because H2RAs raise gastric pH only transiently, they can be combined with rilpivirine if separated by at least 12 hours before or at least 4 hours after the rilpivirine dose, preserving an acidic window for absorption. PPIs suppress acid throughout the day, so the rilpivirine-PPI combination is contraindicated with no workaround by separation.
Option A: Option A is incorrect. Only PPIs are contraindicated; H2RAs are usable with appropriate timing.
Option B: Option B is incorrect. H2RAs require strict timing rather than unrestricted concurrent dosing, and PPIs are not allowed at all.
Option D: Option D is incorrect. The relationship is reversed: PPIs are contraindicated and H2RAs are the agents usable with separation.
Option E: Option E is incorrect. Rilpivirine absorption is acid-dependent, which is precisely why these acid-suppression interactions matter.
10. Nevirapine carries a distinctive hepatotoxicity profile that sets it apart from other non-nucleoside reverse transcriptase inhibitors. Which description is correct?
A) Dose-dependent direct hepatocellular toxicity that worsens at lower CD4 counts
B) Immune-mediated hepatotoxicity concentrated at higher CD4 counts (women above 250, men above 400 cells/mm3)
C) Cholestatic injury seen only in patients without viral hepatitis
D) Benign unconjugated hyperbilirubinemia identical to the atazanavir effect
E) Mitochondrial hepatotoxicity from inhibition of DNA polymerase gamma
ANSWER: B
Rationale:
Option B is correct. Nevirapine hepatotoxicity is an immune-mediated hypersensitivity reaction that is concentrated in patients with higher CD4 counts at initiation, with the highest risk in women above 250 cells/mm3 and men above 400 cells/mm3. This pattern is why nevirapine is avoided as initial therapy in those groups.
Option A: Option A is incorrect. The risk rises at higher CD4 counts and reflects immune-mediated injury, not dose-dependent toxicity worsening at low CD4.
Option C: Option C is incorrect. Underlying viral hepatitis amplifies the risk; the injury is not limited to patients without hepatitis.
Option D: Option D is incorrect. Benign unconjugated hyperbilirubinemia is the atazanavir UGT1A1 effect, not nevirapine hepatotoxicity.
Option E: Option E is incorrect. Mitochondrial toxicity from DNA polymerase gamma inhibition is a nucleoside analogue mechanism, not the basis of nevirapine hepatotoxicity.
11. Observational cohort data associate abacavir with an increased relative risk of myocardial infarction of approximately 1.7 to 1.9-fold. How should this finding influence backbone selection?
A) Abacavir should be preferred in all patients because the association is not causal
B) Abacavir is mandated in patients with low cardiovascular risk to reduce renal toxicity
C) Abacavir should replace tenofovir whenever any cardiac history exists
D) The finding has no bearing on regimen choice
E) Abacavir is best avoided in patients with high cardiovascular risk when alternative backbones are available
ANSWER: E
Rationale:
Option E is correct. The increased myocardial infarction signal is most pronounced in patients with high baseline cardiovascular risk, so the practical application is to avoid abacavir in high-cardiovascular-risk patients (for example, 10-year risk above 20%) when an alternative backbone can be used.
Option A: Option A is incorrect. The signal cautions against, rather than favors, abacavir in higher-risk patients, regardless of ongoing debate about causality.
Option B: Option B is incorrect. There is no mandate to use abacavir in low-risk patients to spare the kidney; that misapplies the data.
Option C: Option C is incorrect. The concern is concentrated in high cardiovascular risk, not triggered by any cardiac history, and abacavir is not a routine tenofovir replacement.
Option D: Option D is incorrect. The finding does inform backbone selection by prompting avoidance in high-risk patients.
12. Immune reconstitution inflammatory syndrome (IRIS) is classically divided into two forms. Which pairing correctly defines them?
A) Unmasking IRIS = a previously subclinical infection becomes clinically apparent as immunity recovers; paradoxical IRIS = a known, treated infection worsens despite effective antimicrobial therapy
B) Unmasking IRIS = worsening of a treated infection; paradoxical IRIS = emergence of a new subclinical infection
C) Unmasking IRIS = an allergic drug reaction to antiretrovirals; paradoxical IRIS = direct antiretroviral hepatotoxicity
E) Both terms describe the same phenomenon with no meaningful distinction
ANSWER: A
Rationale:
Option A is correct. In unmasking IRIS, a previously subclinical opportunistic infection becomes clinically apparent as immune function recovers on antiretroviral therapy. In paradoxical IRIS, a known and already-treated infection clinically worsens despite effective antimicrobial therapy, driven by the recovering inflammatory response.
Option B: Option B is incorrect. The definitions are reversed; unmasking refers to a newly apparent subclinical infection and paradoxical to worsening of a treated one.
Option C: Option C is incorrect. IRIS is an inflammatory response to recovering immunity, not a drug allergy or direct hepatotoxicity.
Option D: Option D is incorrect. IRIS is not defined by relapse after stopping therapy or by primary virologic failure.
Option E: Option E is incorrect. The two forms are distinct and clinically meaningful.
13. Entecavir is an oral hepatitis B virus (HBV) antiviral without anti-HIV activity. Why must it never be used as HBV monotherapy in a person with HIV who lacks a fully suppressive antiretroviral backbone?
A) It precipitates an immediate HBV flare in all HIV-positive patients
B) It causes severe lactic acidosis specific to HIV co-infection
C) It is nephrotoxic only in the presence of HIV
D) It selects for the M184V resistance mutation in HIV when used without a suppressive regimen
E) It induces CYP3A4 and lowers all antiretroviral concentrations
ANSWER: D
Rationale:
Option D is correct. Although marketed for HBV, entecavir has enough activity against HIV reverse transcriptase to select for the methionine-to-valine substitution at codon 184 (M184V) when used without a suppressive antiretroviral regimen, compromising future lamivudine- and emtricitabine-based therapy. It must therefore only be used alongside a fully suppressive HIV regimen.
Option A: Option A is incorrect. The concern is HIV resistance selection, not a universal HBV flare from entecavir itself.
Option B: Option B is incorrect. Lactic acidosis is not the entecavir monotherapy concern in this setting.
Option C: Option C is incorrect. The issue is HIV resistance selection, not HIV-specific nephrotoxicity.
Option E: Option E is incorrect. Entecavir is not a clinically significant CYP3A4 inducer of antiretrovirals.
14. A patient on antiretroviral therapy needs an anticonvulsant. Which choice minimizes clinically significant interactions with the antiretroviral regimen?
A) Carbamazepine
B) Phenytoin
C) Levetiracetam
D) Phenobarbital
E) Oxcarbazepine
ANSWER: C
Rationale:
Option C is correct. Levetiracetam has minimal cytochrome P450 interaction potential and does not meaningfully alter antiretroviral concentrations, making it a preferred anticonvulsant in patients on antiretroviral therapy (along with agents such as lamotrigine, lacosamide, and pregabalin).
Option A: Option A is incorrect. Carbamazepine is a potent CYP3A4 and UGT1A1 inducer that markedly reduces antiretroviral exposure.
Option B: Option B is incorrect. Phenytoin is a strong enzyme inducer that lowers antiretroviral concentrations.
Option D: Option D is incorrect. Phenobarbital is a potent inducer and reduces antiretroviral exposure.
Option E: Option E is incorrect. Oxcarbazepine is an enzyme inducer that reduces antiretroviral concentrations and is not preferred.
15. Regarding bone mineral density (BMD), how do tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) compare?
A) TAF causes substantially greater BMD loss than TDF
B) TDF is associated with greater BMD loss than TAF, and switching from TDF to TAF typically improves BMD
C) Both cause identical BMD loss because both deliver tenofovir
D) Neither agent affects BMD
E) TDF improves BMD while TAF reduces it
ANSWER: B
Rationale:
Option B is correct. TDF is consistently associated with greater bone mineral density loss than TAF, mediated in part by proximal tubular phosphate wasting and secondary effects on bone turnover. Switch trials show an average BMD gain of roughly 1 to 2% at the spine and hip when patients change from a TDF-based to a TAF-based regimen.
Option A: Option A is incorrect. The relationship is reversed; TDF, not TAF, causes greater BMD loss.
Option C: Option C is incorrect. Despite both delivering tenofovir, the much lower plasma exposure with TAF produces less bone loss, so the effects are not identical.
Option D: Option D is incorrect. Tenofovir-containing regimens, especially TDF, do affect BMD.
Option E: Option E is incorrect. TDF does not improve BMD; it is the agent associated with greater bone loss.
16. In a patient with severe hepatic impairment (Child-Pugh C), which statement about antiretroviral selection is correct?
A) Darunavir and lopinavir are preferred because hepatic metabolism is reduced
B) Tipranavir/ritonavir is the safest protease inhibitor in this setting
C) Dolutegravir is the recommended integrase inhibitor in Child-Pugh C
D) Abacavir is preferred because it bypasses hepatic metabolism
E) Darunavir and lopinavir are contraindicated in Child-Pugh C, and raltegravir is the preferred integrase inhibitor
ANSWER: E
Rationale:
Option E is correct. Darunavir and lopinavir are extensively hepatically metabolized and are contraindicated in severe hepatic impairment (Child-Pugh C) due to elevated, unpredictable exposures, whereas raltegravir pharmacokinetics are minimally altered by hepatic impairment, making it the preferred integrase inhibitor in Child-Pugh C disease.
Option A: Option A is incorrect. Reduced hepatic metabolism raises exposures to dangerous levels, which is why these protease inhibitors are contraindicated, not preferred.
Option B: Option B is incorrect. Tipranavir/ritonavir carries a high hepatotoxicity risk and is contraindicated in clinically significant hepatic impairment.
Option C: Option C is incorrect. Dolutegravir is not recommended in Child-Pugh C due to insufficient data; raltegravir is preferred.
Option D: Option D is incorrect. Abacavir depends on hepatic metabolism and is contraindicated in moderate to severe hepatic impairment.
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