Chapter 36 — Antiviral Pharmacology — Module 3 — HIV Pharmacology Part 3: ARV Drug Interactions, Toxicity, and Special Populations
1. Which single drug-metabolizing enzyme is responsible for the metabolism of the majority of currently approved antiretroviral drugs and a large proportion of all drugs used in clinical medicine?
A) Uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1)
B) Cytochrome P450 2B6 (CYP2B6)
C) Cytochrome P450 3A4 (CYP3A4)
D) Organic anion transporter 1 (OAT1)
E) Cytochrome P450 2C9 (CYP2C9)
ANSWER: C
Rationale:
Option C is correct. Cytochrome P450 3A4 (CYP3A4) metabolizes the majority of currently approved antiretrovirals and a vast proportion of drugs used across clinical medicine, which is why it is the single most important enzyme for predicting antiretroviral drug interactions. Inhibition of CYP3A4 by ritonavir or cobicistat is the basis of pharmacokinetic boosting, and induction by efavirenz, nevirapine, or rifampin lowers the concentrations of CYP3A4 substrates.
Option A: Option A is incorrect. UGT1A1 is the primary elimination pathway for raltegravir and contributes to dolutegravir and bictegravir clearance, but it handles a narrow range of substrates rather than the majority of antiretrovirals.
Option B: Option B is incorrect. CYP2B6 contributes to efavirenz metabolism but is not the dominant pathway for most antiretrovirals.
Option D: Option D is incorrect. OAT1 is a renal proximal tubular transporter that mediates tenofovir uptake, not a metabolizing enzyme.
Option E: Option E is incorrect. CYP2C9 has only a minor role in antiretroviral metabolism and is not the principal enzyme for the drug class.
2. Ritonavir and cobicistat are used as pharmacokinetic "boosters" in many antiretroviral regimens. By what mechanism do they raise the plasma concentrations of co-administered antiretrovirals?
A) They inhibit cytochrome P450 3A4 (CYP3A4), slowing metabolism of the boosted drug
B) They induce cytochrome P450 3A4 (CYP3A4), accelerating metabolism of the boosted drug
C) They increase renal tubular reabsorption of the boosted drug
D) They displace the boosted drug from plasma protein binding sites
E) They enhance intestinal P-glycoprotein efflux of the boosted drug
ANSWER: A
Rationale:
Option A is correct. Ritonavir and cobicistat are potent CYP3A4 inhibitors. By slowing the metabolism of co-administered CYP3A4 substrates, they raise and sustain plasma concentrations of the boosted antiretroviral, which is the entire basis of the pharmacokinetic boosting strategy. The same mechanism unavoidably raises concentrations of any other CYP3A4 substrate the patient takes, producing many clinically important interactions.
Option B: Option B is incorrect. Induction would accelerate metabolism and lower concentrations, the opposite of boosting; induction is the action of efavirenz, nevirapine, and rifampin.
Option C: Option C is incorrect. Boosting is a hepatic and intestinal metabolic effect, not a change in renal tubular reabsorption.
Option D: Option D is incorrect. Protein-binding displacement is not the mechanism of pharmacokinetic boosting.
Option E: Option E is incorrect. Ritonavir and cobicistat inhibit, rather than enhance, P-glycoprotein efflux; enhanced efflux would reduce absorption and lower concentrations.
3. Raltegravir is eliminated principally through a single metabolic pathway, which also contributes to the clearance of dolutegravir and bictegravir. Which pathway is this?
A) Cytochrome P450 3A4 (CYP3A4) oxidation
B) Renal tubular secretion by organic cation transporter 2 (OCT2)
C) Cytochrome P450 2B6 (CYP2B6) oxidation
D) Glucuronidation by uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1)
E) Hepatic alcohol dehydrogenase metabolism
ANSWER: D
Rationale:
Option D is correct. Raltegravir is eliminated primarily by UGT1A1-mediated glucuronidation, and UGT1A1 also contributes substantially to dolutegravir and bictegravir clearance. This is why UGT1A1 inducers such as rifampin lower integrase inhibitor concentrations and why UGT1A1 inhibitors such as atazanavir raise raltegravir concentrations.
Option A: Option A is incorrect. CYP3A4 is the dominant pathway for most protease inhibitors and many other antiretrovirals, but raltegravir is not principally a CYP3A4 substrate.
Option B: Option B is incorrect. OCT2 mediates renal secretion of creatinine and is relevant to the cobicistat and dolutegravir creatinine artifact, not to raltegravir elimination.
Option C: Option C is incorrect. CYP2B6 contributes to efavirenz metabolism, not to raltegravir clearance.
Option E: Option E is incorrect. Alcohol dehydrogenase participates in abacavir metabolism, not raltegravir elimination.
4. Which agent is the most potent clinically available inducer of cytochrome P450 3A4 (CYP3A4) and reduces the exposure of most protease inhibitors by 75 to 90%, effectively negating pharmacokinetic boosting?
A) Cobicistat
B) Rifampin
C) Atazanavir
D) Omeprazole
E) Ritonavir
ANSWER: B
Rationale:
Option B is correct. Rifampin is the strongest clinically available CYP3A4 inducer. It reduces the area under the concentration-time curve of most protease inhibitors by 75 to 90% regardless of boosting, which is why all protease inhibitor-based regimens are contraindicated with rifampin and why rifabutin or alternative strategies are used for HIV/tuberculosis co-treatment.
Option A: Option A is incorrect. Cobicistat is a CYP3A4 inhibitor used for boosting, not an inducer.
Option C: Option C is incorrect. Atazanavir inhibits UGT1A1 and is itself a substrate that requires boosting; it is not a potent enzyme inducer.
Option D: Option D is incorrect. Omeprazole raises gastric pH and affects acid-dependent drug absorption but is not a potent CYP3A4 inducer of antiretrovirals.
Option E: Option E is incorrect. Ritonavir is a CYP3A4 inhibitor used as a booster; although it has weak inductive effects on some pathways, its net clinically exploited action is inhibition.
5. A patient started on a cobicistat-containing regimen shows a modest rise in serum creatinine without other signs of kidney injury. What best explains this finding?
A) True glomerular filtration rate (GFR) decline from cobicistat nephrotoxicity
B) Tenofovir-associated proximal tubular injury
C) Acute interstitial nephritis from cobicistat
D) Prerenal azotemia from volume depletion
E) Inhibition of tubular creatinine secretion (MATE1), not a true fall in GFR
ANSWER: E
Rationale:
Option E is correct. Cobicistat inhibits the multidrug and toxin extrusion protein 1 (MATE1) transporter that secretes creatinine into the renal tubule. This raises serum creatinine and lowers estimated GFR without any true reduction in glomerular filtration. When the distinction matters clinically, cystatin C-based estimation or measured GFR confirms preserved true filtration. Dolutegravir produces the same benign creatinine artifact.
Option A: Option A is incorrect. The creatinine rise is an artifact of secretion blockade, not true GFR loss or cobicistat nephrotoxicity.
Option B: Option B is incorrect. Tenofovir disoproxil fumarate proximal tubular injury produces glucosuria, phosphaturia, and tubular proteinuria, not an isolated benign creatinine rise.
Option C: Option C is incorrect. Acute interstitial nephritis would typically present with additional findings such as pyuria, eosinophiluria, or rash and is not the expected mechanism here.
Option D: Option D is incorrect. Prerenal azotemia from volume depletion would not be the explanation for an isolated creatinine rise attributable to starting cobicistat.
6. Tenofovir disoproxil fumarate (TDF) nephrotoxicity targets a specific nephron segment because of the transporter that concentrates the drug there. Which segment is preferentially injured?
A) Glomerular capillary endothelium
B) Proximal tubule
C) Thick ascending limb of the loop of Henle
D) Collecting duct
E) Distal convoluted tubule
ANSWER: B
Rationale:
Option B is correct. TDF is taken up into proximal tubular cells by organic anion transporter 1 (OAT1), where it inhibits mitochondrial DNA polymerase gamma and impairs mitochondrial function, producing proximal tubule injury. The resulting Fanconi syndrome features normoglycemic glucosuria, phosphaturia, aminoaciduria, uricosuria, and tubular proteinuria.
Option A: Option A is incorrect. TDF toxicity is tubular, not a primary glomerular endothelial process.
Option C: Option C is incorrect. The thick ascending limb is the site of loop diuretic action, not the focus of TDF accumulation.
Option D: Option D is incorrect. The collecting duct is not the segment that concentrates TDF via OAT1.
Option E: Option E is incorrect. The distal convoluted tubule is the site of thiazide action and is not preferentially injured by TDF.
7. Compared with tenofovir disoproxil fumarate (TDF), why is tenofovir alafenamide (TAF) associated with less nephrotoxicity and less bone mineral density loss?
A) TAF achieves much lower plasma tenofovir concentrations while delivering adequate active metabolite to target cells
B) TAF is not an antiretroviral and has no antiviral activity
C) TAF is eliminated entirely by biliary excretion and never reaches the kidney
D) TAF blocks organic anion transporter 1 (OAT1), preventing tubular uptake of all drugs
E) TAF is given at a far higher dose, saturating renal transporters
ANSWER: A
Rationale:
Option A is correct. TAF delivers the active metabolite tenofovir diphosphate to lymphocytes while producing roughly 90% lower plasma tenofovir concentrations than TDF. The lower systemic and proximal tubular exposure translates into significantly less nephrotoxicity and bone mineral density loss in head-to-head trials, which is why TAF is preferred over TDF in patients with chronic kidney disease when available.
Option B: Option B is incorrect. TAF is an active antiretroviral prodrug of tenofovir with potent antiviral activity.
Option C: Option C is incorrect. TAF does reach systemic circulation and is not eliminated solely by biliary excretion; the key difference is its lower plasma tenofovir exposure.
Option D: Option D is incorrect. TAF does not work by globally blocking OAT1.
Option E: Option E is incorrect. TAF is given at a much lower milligram dose than TDF, not a higher one.
8. A patient on atazanavir develops jaundice with elevated unconjugated bilirubin but normal transaminases and no other evidence of liver injury. What is the most likely explanation?
A) Atazanavir-induced acute hepatocellular necrosis
B) Hemolytic anemia from atazanavir
C) Inhibition of UGT1A1 producing benign unconjugated hyperbilirubinemia
D) Biliary obstruction from atazanavir crystals
E) Immune-mediated hepatotoxicity similar to nevirapine
ANSWER: C
Rationale:
Option C is correct. Atazanavir inhibits UGT1A1, the enzyme that conjugates bilirubin, producing an unconjugated hyperbilirubinemia that resembles Gilbert syndrome. It is benign, does not reflect hepatotoxicity, and does not require discontinuation in the absence of true liver injury.
Option A: Option A is incorrect. Hepatocellular necrosis would elevate transaminases and reflect conjugated injury, which is not described here.
Option B: Option B is incorrect. Although hemolysis raises unconjugated bilirubin, atazanavir hyperbilirubinemia is due to UGT1A1 inhibition, not red cell destruction.
Option D: Option D is incorrect. The picture is unconjugated hyperbilirubinemia from impaired conjugation, not obstructive cholestasis.
Option E: Option E is incorrect. Immune-mediated hepatotoxicity is characteristic of nevirapine and would present with transaminase elevation and systemic features, not isolated benign unconjugated hyperbilirubinemia.
9. According to current Department of Health and Human Services (DHHS) and World Health Organization (WHO) guidance, which integrase strand transfer inhibitor (INSTI) is recommended throughout pregnancy, including at the time of conception, following reassessment of the neural tube defect signal?
A) Elvitegravir/cobicistat
B) Cabotegravir long-acting injectable
C) Bictegravir
D) Dolutegravir
E) Efavirenz
ANSWER: D
Rationale:
Option D is correct. Current DHHS and WHO guidelines recommend dolutegravir throughout pregnancy, including at conception, after the Tsepamo data showed periconceptional neural tube defect rates of approximately 0.19%, not significantly different from background in most analyses. This reassessment reversed earlier caution about the neural tube defect signal.
Option A: Option A is incorrect. Cobicistat-boosted regimens such as elvitegravir/cobicistat have reduced and variable exposures in pregnancy and are not preferred.
Option B: Option B is incorrect. Cabotegravir long-acting injectable is not recommended in pregnancy because safety data are absent and the prolonged pharmacokinetic tail prevents rapid discontinuation.
Option C: Option C is incorrect. Bictegravir has less pregnancy data and is not the guideline-recommended INSTI at conception.
Option E: Option E is incorrect. Efavirenz is a non-nucleoside reverse transcriptase inhibitor, not an INSTI, and is a non-preferred agent when alternatives exist.
10. A patient on a ritonavir-boosted protease inhibitor (PI) regimen is diagnosed with tuberculosis and needs rifampin. What is the correct assessment of combining rifampin with a boosted PI?
A) Rifampin can be added safely because ritonavir boosting overcomes the interaction
B) The combination is contraindicated because rifampin reduces PI exposure by 75 to 90%
C) Rifampin doubles PI concentrations and the PI dose must be halved
D) No interaction occurs because PIs are not metabolized by CYP3A4
E) Rifampin only affects integrase inhibitors and is safe with PIs
ANSWER: B
Rationale:
Option B is correct. Rifampin reduces the area under the concentration-time curve of most protease inhibitors by 75 to 90% regardless of pharmacokinetic boosting, driving concentrations to subtherapeutic levels and risking treatment failure and resistance. All PI-based regimens are therefore contraindicated with rifampin; rifabutin or an alternative regimen is used instead.
Option A: Option A is incorrect. Boosting does not overcome the magnitude of rifampin induction on PIs.
Option C: Option C is incorrect. Rifampin induces rather than inhibits metabolism, lowering rather than raising PI concentrations.
Option D: Option D is incorrect. Protease inhibitors are extensively CYP3A4-metabolized, which is exactly why rifampin affects them so strongly.
Option E: Option E is incorrect. Rifampin affects integrase inhibitors as well, but it is far from safe with PIs.
11. When dolutegravir must be used together with rifampin for HIV/tuberculosis co-treatment, how is the dolutegravir regimen adjusted to maintain adequate exposure?
A) Dolutegravir is reduced to 25 mg daily
B) Dolutegravir is held until rifampin is stopped
C) Dolutegravir is increased to 50 mg twice daily
D) Dolutegravir is given once weekly at 100 mg
E) No adjustment is needed because rifampin does not affect dolutegravir
ANSWER: C
Rationale:
Option C is correct. Rifampin reduces dolutegravir exposure by approximately 54% through UGT1A1 and CYP3A4 induction. Doubling the dose to dolutegravir 50 mg twice daily restores adequate trough concentrations, making this the preferred integrase inhibitor strategy for HIV/tuberculosis co-treatment.
Option A: Option A is incorrect. Lowering the dose would worsen the induction-driven loss of exposure.
Option B: Option B is incorrect. Both infections require treatment; dolutegravir is dose-adjusted rather than held.
Option D: Option D is incorrect. Once-weekly dosing is not a recognized strategy and would not maintain adequate troughs.
Option E: Option E is incorrect. Rifampin clearly reduces dolutegravir exposure, so adjustment is required.
12. Rilpivirine has a critical interaction with proton pump inhibitors (PPIs). Which statement correctly describes it?
A) PPIs reduce rilpivirine absorption by about 76% and the combination is contraindicated
B) PPIs and rilpivirine can be combined freely if separated by two hours
C) PPIs raise rilpivirine concentrations and the rilpivirine dose must be reduced
D) Rilpivirine requires an alkaline gastric environment, so PPIs enhance its absorption
E) The interaction is avoided simply by taking rilpivirine on an empty stomach
ANSWER: A
Rationale:
Option A is correct. Rilpivirine requires an acidic gastric environment for dissolution and absorption. PPIs raise gastric pH throughout the day, reducing rilpivirine absorption by roughly 76% regardless of dose timing, so the combination is absolutely contraindicated with no workaround by dose separation.
Option B: Option B is incorrect. Because PPIs suppress acid all day, separating doses does not rescue the interaction, unlike the situation with H2 receptor antagonists.
Option C: Option C is incorrect. PPIs lower, not raise, rilpivirine concentrations.
Option D: Option D is incorrect. Rilpivirine needs an acidic environment; raising pH impairs its absorption.
Option E: Option E is incorrect. Taking rilpivirine with a meal actually supports absorption; an empty stomach does not solve the PPI interaction.
13. A methadone-maintained patient is started on an efavirenz-containing regimen and develops opioid withdrawal symptoms within two weeks. What is the mechanism?
A) Efavirenz inhibits methadone metabolism, causing accumulation and toxicity
B) Efavirenz displaces methadone from opioid receptors
C) Efavirenz raises methadone concentrations, causing sedation then rebound
D) Efavirenz blocks methadone absorption in the gut
E) Efavirenz induces CYP3A4 and CYP2B6, lowering methadone concentrations by 50 to 60%
ANSWER: E
Rationale:
Option E is correct. Efavirenz is an enzyme inducer that lowers methadone plasma concentrations by 50 to 60% through CYP3A4 and CYP2B6 induction, precipitating opioid withdrawal within days to weeks. The interaction is predictable, so the methadone clinic should be contacted and dose escalation coordinated before efavirenz is started; dolutegravir-based regimens avoid the interaction.
Option A: Option A is incorrect. Efavirenz induces rather than inhibits methadone metabolism, so withdrawal rather than accumulation results.
Option B: Option B is incorrect. Efavirenz does not act at opioid receptors.
Option C: Option C is incorrect. Methadone concentrations fall rather than rise with efavirenz.
Option D: Option D is incorrect. The interaction is metabolic induction, not impaired gut absorption.
14. In a patient co-infected with HIV and hepatitis B virus (HBV) whose regimen includes tenofovir, what is the principal danger of discontinuing tenofovir without substituting another anti-HBV agent?
A) Immediate HIV resistance to all integrase inhibitors
B) Acute tenofovir withdrawal nephrotoxicity
C) Rapid loss of HIV viral suppression only, with no hepatic consequence
D) Severe HBV flare with possible acute hepatic decompensation
E) Permanent loss of HBV surface antibody
ANSWER: D
Rationale:
Option D is correct. Tenofovir (as TDF or TAF) has potent anti-HBV activity. Stopping it in an HBV co-infected patient without simultaneous coverage by another anti-HBV agent can precipitate a severe HBV flare with acute hepatic decompensation and, rarely, liver failure. HBV-active coverage must be maintained through any regimen switch.
Option A: Option A is incorrect. Discontinuing tenofovir does not immediately confer pan-integrase-inhibitor resistance.
Option B: Option B is incorrect. The danger of stopping tenofovir is hepatic flare, not a withdrawal nephrotoxicity syndrome.
Option C: Option C is incorrect. The hepatic consequence is exactly the concern; it is not limited to loss of HIV suppression.
Option E: Option E is incorrect. The risk is a hepatitis flare from uncontrolled viral replication, not loss of surface antibody.
15. Nevirapine-associated hepatotoxicity is concentrated in a specific group of patients, which limits its use as initial therapy. Which patients are at highest risk?
A) Patients with very low CD4 counts and advanced immunodeficiency
B) Patients with higher CD4 counts at initiation (women above 250, men above 400 cells/mm3)
C) Patients with undetectable viral loads only
D) Patients with no hepatitis co-infection
E) Patients older than 60 years regardless of CD4 count
ANSWER: B
Rationale:
Option B is correct. Nevirapine hepatotoxicity is an immune-mediated hypersensitivity reaction concentrated in patients with higher CD4 counts at initiation: women with CD4 above 250 cells/mm3 and men with CD4 above 400 cells/mm3 are at highest risk, which is why nevirapine is avoided as initial therapy in these patients.
Option A: Option A is incorrect. The risk is highest at higher CD4 counts, not in advanced immunodeficiency with low CD4.
Option C: Option C is incorrect. Risk is defined by CD4 strata at initiation, not by viral load suppression status.
Option D: Option D is incorrect. Underlying viral hepatitis amplifies hepatotoxicity risk; absence of co-infection does not define the high-risk group.
Option E: Option E is incorrect. The defining risk factor is the CD4 threshold by sex, not age above 60.
16. Which statins are contraindicated in a patient receiving a ritonavir-boosted protease inhibitor (PI) regimen because of the high risk of toxic statin accumulation?
A) Simvastatin and lovastatin
B) Rosuvastatin and pravastatin
C) Atorvastatin and rosuvastatin
D) Pravastatin and atorvastatin
E) Rosuvastatin alone
ANSWER: A
Rationale:
Option A is correct. Simvastatin and lovastatin are highly dependent on CYP3A4 metabolism, so a boosted PI raises their concentrations to dangerous levels, risking myopathy and rhabdomyolysis; both are contraindicated with boosted PI regimens.
Option B: Option B is incorrect. Rosuvastatin and pravastatin are actually the safest choices with boosted PIs and are not contraindicated.
Option C: Option C is incorrect. Rosuvastatin is among the preferred agents, and atorvastatin may be used at reduced dose rather than being contraindicated.
Option D: Option D is incorrect. Pravastatin is preferred and atorvastatin is allowed at reduced dose; neither is contraindicated.
Option E: Option E is incorrect. Rosuvastatin is a recommended choice, not a contraindicated one.
17. A patient with severe gastroesophageal reflux disease requires daily proton pump inhibitor (PPI) therapy and is starting antiretroviral treatment. Applying the acid-suppression interactions reviewed earlier, which regimen is the most appropriate choice?
A) A rilpivirine-based regimen
B) An unboosted atazanavir-based regimen
C) A dolutegravir- or bictegravir-based regimen
D) A regimen requiring the patient to stop the PPI entirely
E) A boosted atazanavir regimen with high-dose omeprazole
ANSWER: C
Rationale:
Option C is correct. Dolutegravir and bictegravir absorption does not depend on gastric acidity, so they are unaffected by PPIs and are the most appropriate choice for a patient who must remain on a PPI. This applies the principle that PPI-dependent patients should avoid acid-dependent antiretrovirals.
Option A: Option A is incorrect. Rilpivirine absorption falls about 76% with PPIs and the combination is contraindicated.
Option B: Option B is incorrect. Unboosted atazanavir also requires gastric acidity and cannot be combined with PPIs.
Option D: Option D is incorrect. Stopping the PPI is not necessary or appropriate when acid-independent antiretrovirals are available.
Option E: Option E is incorrect. Even boosted atazanavir tolerates only low-dose acid suppression with strict timing, making it inferior to an acid-independent regimen for a patient needing daily high-dose PPI.
18. In a resource-rich setting, a patient on a boosted protease inhibitor regimen needs tuberculosis treatment, and the team wants to preserve the existing antiretroviral regimen. Applying the rifamycin interaction principles, which choice best allows this?
A) Use standard rifampin and continue the boosted PI unchanged
B) Use standard rifampin and double the PI dose
C) Stop all antiretrovirals until tuberculosis treatment is complete
D) Substitute rifabutin, a weaker CYP3A4 inducer, at a reduced dose
E) Use rifampin with an added second booster
ANSWER: D
Rationale:
Option D is correct. Rifabutin is a weaker CYP3A4 inducer than rifampin and can be combined with boosted PI regimens at a reduced dose (such as 150 mg every other day or three times weekly), preserving antiretroviral flexibility. This applies the earlier principles that rifampin strongly induces CYP3A4 and is contraindicated with PIs.
Option A: Option A is incorrect. Standard rifampin would drop PI exposure by 75 to 90% and cannot be combined with a boosted PI.
Option B: Option B is incorrect. PI dose-doubling does not reliably overcome rifampin induction and is not a recommended strategy.
Option C: Option C is incorrect. Stopping antiretrovirals risks loss of viral control and resistance and is not appropriate.
Option E: Option E is incorrect. Adding a second booster does not overcome rifampin's powerful induction of PIs.
19. A patient with chronic kidney disease has an estimated glomerular filtration rate (eGFR) of 28 mL/min/1.73m2. Applying what you know about tenofovir formulations and proximal tubular injury, which approach to the nucleoside backbone is most appropriate?
A) Initiate tenofovir disoproxil fumarate (TDF) at full dose
B) Avoid TDF and favor tenofovir alafenamide (TAF) or a non-tenofovir backbone with appropriately adjusted agents
C) Use TDF but add a boosted protease inhibitor to protect the kidney
D) Use high-dose TDF to overcome reduced clearance
E) Avoid all antiretrovirals until eGFR normalizes
ANSWER: B
Rationale:
Option B is correct. TDF should not be initiated at low eGFR because of its proximal tubular toxicity, whereas TAF achieves much lower plasma tenofovir exposure and can be used down to an eGFR of 15 mL/min/1.73m2, making TAF or a non-tenofovir backbone with dose-adjusted components the appropriate choice. This applies the OAT1-mediated TDF toxicity and the lower-exposure TAF advantage covered earlier.
Option A: Option A is incorrect. Full-dose TDF is inappropriate and is not initiated below an eGFR of 60 mL/min/1.73m2.
Option C: Option C is incorrect. Adding a booster raises proximal tubular tenofovir concentrations and worsens, rather than protects against, TDF toxicity.
Option D: Option D is incorrect. Higher TDF dosing increases tubular exposure and toxicity rather than compensating for reduced clearance.
Option E: Option E is incorrect. Antiretroviral therapy should not be withheld; an appropriate renally-tolerant regimen is selected instead.
20. A patient with severe hepatic impairment (Child-Pugh C) needs an integrase strand transfer inhibitor (INSTI). Applying the hepatic-impairment principles for this drug class, which INSTI is preferred?
A) Elvitegravir boosted with cobicistat
B) Dolutegravir at a doubled dose
C) Bictegravir in a fixed-dose combination
D) Cabotegravir long-acting injectable
E) Raltegravir
ANSWER: E
Rationale:
Option E is correct. Raltegravir pharmacokinetics are not substantially altered by hepatic impairment, making it the preferred INSTI in Child-Pugh C disease. This applies the principle that hepatic impairment most affects agents with high hepatic extraction and extensive first-pass metabolism.
Option A: Option A is incorrect. Cobicistat-boosted elvitegravir is not preferred in severe hepatic impairment because of altered metabolism of the boosted components.
Option B: Option B is incorrect. Dolutegravir is not recommended in Child-Pugh C due to insufficient data, and dose-doubling is a rifampin strategy, not a hepatic-impairment one.
Option C: Option C is incorrect. Bictegravir is delivered in fixed-dose combinations not suited to severe hepatic impairment and lacks the favorable hepatic profile of raltegravir.
Option D: Option D is incorrect. Cabotegravir long-acting injectable is not the preferred agent in Child-Pugh C and carries a prolonged pharmacokinetic tail that limits flexibility.
21. A patient stable on methadone maintenance is beginning antiretroviral therapy, and the team wants to avoid precipitating opioid withdrawal. Applying the opioid-interaction principles, which regimen is the best choice?
A) A dolutegravir-based regimen
B) An efavirenz-based regimen
C) A nevirapine-based regimen
D) A lopinavir/ritonavir-based regimen
E) A regimen requiring an immediate 50% methadone dose reduction
ANSWER: A
Rationale:
Option A is correct. Dolutegravir has minimal interaction with methadone, so a dolutegravir-based regimen avoids the induction-driven fall in methadone concentrations and the resulting withdrawal. This applies the earlier principle that enzyme-inducing antiretrovirals lower methadone exposure.
Option B: Option B is incorrect. Efavirenz lowers methadone concentrations by 50 to 60% and commonly precipitates withdrawal.
Option C: Option C is incorrect. Nevirapine reduces methadone concentrations by about 46% and can also cause withdrawal.
Option D: Option D is incorrect. Lopinavir/ritonavir reduces methadone exposure by roughly 50% and is not the best choice for avoiding withdrawal.
Option E: Option E is incorrect. The goal is to choose a non-interacting regimen; a preemptive 50% dose cut would itself risk withdrawal and is not the appropriate strategy.
22. A patient with a high 10-year cardiovascular risk (above 20% by Framingham criteria) needs a nucleoside backbone, and alternatives are available. Applying the cardiovascular-risk data reviewed earlier, which agent is best avoided?
A) Lamivudine (3TC)
B) Emtricitabine (FTC)
C) Abacavir (ABC)
D) Tenofovir alafenamide (TAF)
E) Zidovudine (ZDV)
ANSWER: C
Rationale:
Option C is correct. Abacavir has been associated with an increased risk of myocardial infarction (relative risk roughly 1.7 to 1.9-fold) in several large observational studies, most pronounced in patients with high baseline cardiovascular risk. Current guidance is to avoid abacavir in patients with high cardiovascular risk when alternative backbones are available, which applies the cardiovascular-risk principles covered earlier.
Option A: Option A is incorrect. Lamivudine is not the agent linked to elevated myocardial infarction risk.
Option B: Option B is incorrect. Emtricitabine is not associated with the increased cardiovascular risk that abacavir carries.
Option D: Option D is incorrect. Tenofovir alafenamide-based regimens have a relatively favorable cardiovascular profile and are not the agent to avoid here.
Option E: Option E is incorrect. Zidovudine is limited by hematologic and mitochondrial toxicity rather than the abacavir cardiovascular signal, and is not the best answer for cardiovascular-risk avoidance.
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