Chapter 36 — Antiviral Pharmacology — Module 3 — HIV Pharmacology Part 3: ARV Drug Interactions, Toxicity, and Special Populations
1. A 44-year-old man with HIV has been virologically suppressed for two years on a rilpivirine-based single-tablet regimen. He is newly diagnosed with erosive gastroesophageal reflux disease and his gastroenterologist wants to start daily omeprazole. What is the most appropriate antiretroviral action?
A) Continue rilpivirine and start omeprazole, separating the two doses by four hours
B) Switch to a dolutegravir-based regimen because rilpivirine absorption is impaired by proton pump inhibitors
C) Continue rilpivirine and substitute an over-the-counter proton pump inhibitor
D) Continue rilpivirine and add a once-daily H2 receptor antagonist taken at the same time
E) Continue rilpivirine and reassure that proton pump inhibitors do not affect it
ANSWER: B
Rationale:
Option B is correct. Rilpivirine requires gastric acidity for absorption, and proton pump inhibitors reduce its concentrations by roughly 76% all day, making the combination contraindicated with no workaround. Because this patient needs continuous proton pump inhibitor therapy, switching to a dolutegravir-based regimen, whose absorption is acid-independent, preserves both reflux control and virologic suppression.
Option A: Option A is incorrect. Proton pump inhibitors suppress acid throughout the day, so dose separation does not rescue rilpivirine absorption.
Option C: Option C is incorrect. Switching the proton pump inhibitor brand does not change the class effect on gastric pH.
Option D: Option D is incorrect. H2 receptor antagonists can be used with rilpivirine only with strict timing (at least 12 hours before or 4 hours after), not taken simultaneously, and they do not address the need for daily acid suppression here.
Option E: Option E is incorrect. Proton pump inhibitors clearly impair rilpivirine absorption, so reassurance is incorrect.
2. A 39-year-old woman on stable methadone maintenance is started on an efavirenz-containing regimen. Ten days later she develops yawning, rhinorrhea, myalgias, abdominal cramps, and craving consistent with opioid withdrawal. What is the most appropriate explanation and management?
A) Efavirenz inhibits methadone metabolism, causing toxicity; reduce the methadone dose
B) She has developed methadone tolerance unrelated to efavirenz; no change is needed
C) Efavirenz displaced methadone from opioid receptors; switch to buprenorphine immediately
D) Efavirenz induced CYP3A4 and CYP2B6, lowering methadone concentrations; coordinate a methadone dose increase with her clinic
E) The symptoms are efavirenz central nervous system toxicity; stop methadone
ANSWER: D
Rationale:
Option D is correct. Efavirenz is an enzyme inducer that lowers methadone concentrations by 50 to 60% through CYP3A4 and CYP2B6 induction, precipitating withdrawal within days to weeks. The correct response is to coordinate a methadone dose increase with the methadone clinic; this interaction is predictable and should ideally be anticipated before starting efavirenz.
Option A: Option A is incorrect. Efavirenz induces rather than inhibits methadone metabolism, so withdrawal rather than toxicity results, and lowering the dose would worsen it.
Option B: Option B is incorrect. The timing and symptoms point to the efavirenz interaction, not coincidental tolerance.
Option C: Option C is incorrect. Efavirenz does not act at opioid receptors, and abrupt switching is not the indicated response to a manageable interaction.
Option E: Option E is incorrect. The picture is opioid withdrawal from reduced methadone exposure, not efavirenz central nervous system toxicity, and stopping methadone would intensify withdrawal.
3. A 57-year-old man on tenofovir disoproxil fumarate (TDF) plus a cobicistat-boosted regimen for three years presents with fatigue and bone pain. Labs show normoglycemic glucosuria, hypophosphatemia with phosphaturia, low-molecular-weight proteinuria, and a creatinine rise. What is the most likely diagnosis?
A) Tenofovir-associated proximal tubular injury (Fanconi syndrome)
B) Diabetic nephropathy
C) Benign cobicistat-related creatinine elevation alone
Option A is correct. The combination of normoglycemic glucosuria, phosphaturia with hypophosphatemia, low-molecular-weight tubular proteinuria, and a rising creatinine is the classic picture of tenofovir disoproxil fumarate proximal tubular injury (Fanconi syndrome). The risk is heightened here because the cobicistat booster raises proximal tubular tenofovir concentrations by inhibiting tubular efflux.
Option B: Option B is incorrect. Diabetic nephropathy produces glucosuria only with hyperglycemia and does not characteristically cause the full proximal tubular wasting pattern seen here.
Option C: Option C is incorrect. The benign cobicistat creatinine artifact is an isolated creatinine rise without glucosuria, phosphaturia, or tubular proteinuria.
Option D: Option D is incorrect. Atazanavir hyperbilirubinemia is an unconjugated bilirubin elevation, not a tubular wasting syndrome.
Option E: Option E is incorrect. Post-infectious glomerulonephritis presents with hematuria, red cell casts, and hypertension rather than proximal tubular solute wasting.
4. A 33-year-old man with HIV is diagnosed with pulmonary tuberculosis and started on rifampin-based therapy. His clinician wants to use a dolutegravir-based antiretroviral regimen and rifampin cannot be replaced with rifabutin. What is the correct dolutegravir strategy?
A) Dolutegravir 50 mg once daily, unchanged
B) Dolutegravir 25 mg once daily
C) Dolutegravir 50 mg twice daily
D) Hold dolutegravir until rifampin completes
E) Dolutegravir 50 mg once weekly
ANSWER: C
Rationale:
Option C is correct. Rifampin induces UGT1A1 and CYP3A4 and reduces dolutegravir exposure by approximately 54%. Doubling the dose to dolutegravir 50 mg twice daily restores adequate trough concentrations and is the recommended strategy when rifampin must be used with dolutegravir.
Option A: Option A is incorrect. Standard once-daily dosing leaves dolutegravir exposure inadequate during rifampin co-administration.
Option B: Option B is incorrect. Reducing the dose would deepen the induction-driven loss of exposure.
Option D: Option D is incorrect. Both infections require concurrent treatment; dolutegravir is dose-adjusted rather than withheld.
Option E: Option E is incorrect. Once-weekly dosing is not a recognized regimen and would not maintain adequate troughs.
5. A 48-year-old woman starts an elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine single-tablet regimen. Four weeks later her serum creatinine has risen from 0.8 to 1.0 mg/dL and is stable, with no proteinuria, no glucosuria, normal electrolytes, and normal blood pressure. What is the best next step?
A) Stop the regimen immediately for nephrotoxicity
B) Start empiric corticosteroids for interstitial nephritis
C) Switch to a tenofovir disoproxil fumarate regimen to protect the kidney
D) Order a renal biopsy
E) Continue the regimen and, if confirmation is needed, assess true filtration with cystatin C
ANSWER: E
Rationale:
Option E is correct. Cobicistat inhibits tubular creatinine secretion, producing a small, stable rise in serum creatinine without a true fall in glomerular filtration. With no proteinuria, glucosuria, or electrolyte disturbance, this is the expected benign artifact; the regimen is continued, and cystatin C-based estimation or measured filtration can confirm preserved true function if needed.
Option A: Option A is incorrect. An isolated, stable creatinine rise without other findings does not indicate nephrotoxicity requiring discontinuation.
Option B: Option B is incorrect. There is no evidence of interstitial nephritis to justify corticosteroids.
Option C: Option C is incorrect. Switching to tenofovir disoproxil fumarate would increase, not decrease, the risk of true tubular injury.
Option D: Option D is incorrect. A renal biopsy is unwarranted for an expected benign creatinine artifact.
6. A 29-year-old woman who is 9 weeks pregnant is newly diagnosed with HIV and is also chronically infected with hepatitis B virus (HBV). She is antiretroviral-naive. Which regimen best meets the needs of pregnancy, HBV coverage, and integrase inhibitor selection at this gestational age?
A) Abacavir/lamivudine plus raltegravir
B) Tenofovir disoproxil fumarate/emtricitabine plus dolutegravir
C) Zidovudine/lamivudine plus efavirenz
D) Tenofovir alafenamide/emtricitabine plus cabotegravir long-acting injectable
E) Lamivudine monotherapy until after delivery
ANSWER: B
Rationale:
Option B is correct. Tenofovir disoproxil fumarate/emtricitabine is the preferred pregnancy backbone and provides dual anti-HBV activity, and dolutegravir is recommended throughout pregnancy including in the first trimester. This regimen simultaneously secures the preferred backbone, HBV coverage, and a preferred integrase inhibitor.
Option A: Option A is incorrect. Abacavir/lamivudine lacks the strong HBV coverage that tenofovir provides.
Option C: Option C is incorrect. Efavirenz is non-preferred when alternatives exist, and zidovudine/lamivudine is not the preferred backbone.
Option D: Option D is incorrect. Cabotegravir long-acting injectable is not recommended in pregnancy because of absent safety data and an unmanageable pharmacokinetic tail.
Option E: Option E is incorrect. Lamivudine monotherapy is never appropriate for HIV and risks resistance and HBV undertreatment.
7. A 51-year-old man with HIV and chronic hepatitis B virus (HBV) co-infection is on tenofovir disoproxil fumarate/emtricitabine plus dolutegravir. Because of declining renal function, the team plans to change his backbone. What is the most important principle in making this switch safely?
A) Maintain an anti-HBV-active agent throughout the switch to prevent an HBV flare
B) Stop all HBV-active agents to reduce the pill burden
C) Replace tenofovir with abacavir and provide no other HBV coverage
D) Add entecavir as the sole HBV agent without a suppressive HIV regimen
E) Interrupt all therapy for two weeks before starting the new regimen
ANSWER: A
Rationale:
Option A is correct. Withdrawing tenofovir without alternative HBV coverage can precipitate a severe HBV flare with hepatic decompensation. The key principle is to maintain an anti-HBV-active agent, such as switching to tenofovir alafenamide (usable to a lower estimated glomerular filtration rate) or otherwise ensuring HBV coverage, throughout the change.
Option B: Option B is incorrect. Stopping HBV-active agents risks a dangerous HBV flare.
Option C: Option C is incorrect. Abacavir has no anti-HBV activity, leaving the patient without HBV coverage.
Option D: Option D is incorrect. Entecavir without a suppressive HIV regimen selects for the M184V resistance mutation in HIV.
Option E: Option E is incorrect. Interrupting all therapy risks both an HBV flare and loss of HIV control.
8. A 41-year-old man with advanced AIDS (CD4 28 cells/mm3) and culture-confirmed tuberculosis was started on standard tuberculosis therapy, then began antiretroviral therapy two weeks later. Five weeks after starting antiretrovirals, while adherent and showing a falling HIV viral load, he develops enlarging, tender cervical lymphadenopathy and recurrent fevers. Mycobacterial cultures from the nodes are now negative. What is the most likely explanation?
A) Tuberculosis treatment failure from drug resistance
B) A new opportunistic infection unrelated to immune recovery
C) Paradoxical immune reconstitution inflammatory syndrome (IRIS)
D) Antiretroviral hypersensitivity reaction
E) Lymphoma arising from immunodeficiency
ANSWER: C
Rationale:
Option C is correct. Worsening of an already-treated infection weeks after starting antiretroviral therapy in a patient with very low CD4 and a falling viral load, with now-negative mycobacterial cultures, is the hallmark of paradoxical immune reconstitution inflammatory syndrome. The recovering immune response drives inflammation against residual mycobacterial antigen rather than uncontrolled infection.
Option A: Option A is incorrect. Negative node cultures and the temporal link to immune recovery argue against treatment failure from resistance.
Option B: Option B is incorrect. The picture reflects an exaggerated response to the known, treated tuberculosis, not a separate new infection.
Option D: Option D is incorrect. Antiretroviral hypersensitivity would not produce localized worsening of treated tuberculous lymphadenitis with negative cultures.
Option E: Option E is incorrect. The acute inflammatory worsening tied to immune reconstitution fits IRIS rather than lymphoma.
9. A 60-year-old woman with HIV and decompensated cirrhosis (Child-Pugh C) needs an antiretroviral regimen that includes an integrase strand transfer inhibitor (INSTI). Which INSTI is preferred in this degree of hepatic impairment?
A) Elvitegravir boosted with cobicistat
B) Bictegravir in a fixed-dose combination
C) Dolutegravir at a doubled dose
D) Raltegravir
E) Cabotegravir long-acting injectable
ANSWER: D
Rationale:
Option D is correct. 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. Cobicistat-boosted elvitegravir is not preferred in severe hepatic impairment because of altered metabolism of the boosted components.
Option B: Option B is incorrect. Bictegravir is supplied in fixed-dose combinations not suited to severe hepatic impairment and lacks raltegravir's favorable hepatic profile.
Option C: Option C is incorrect. Dolutegravir is not recommended in Child-Pugh C due to insufficient data, and dose-doubling is a strategy for enzyme induction, not hepatic impairment.
Option E: Option E is incorrect. Cabotegravir long-acting injectable is not the preferred agent here and carries a prolonged pharmacokinetic tail that limits flexibility.
10. A 62-year-old man with HIV is on an abacavir/lamivudine plus dolutegravir regimen. He is a smoker with hypertension and a calculated 10-year cardiovascular risk of 26%. His renal function is normal and he is HLA-B*57:01-negative. What antiretroviral change is most appropriate?
A) Continue abacavir because the myocardial infarction association is not proven causal
B) Replace abacavir with a tenofovir-based backbone, since abacavir is best avoided in high cardiovascular risk when alternatives exist
C) Stop dolutegravir and continue abacavir alone
D) Add low-dose ritonavir to boost the regimen
E) No change is needed because dolutegravir lowers cardiovascular risk
ANSWER: B
Rationale:
Option B is correct. Abacavir has been associated with increased myocardial infarction risk, most pronounced in patients with high baseline cardiovascular risk. With a 10-year risk of 26%, normal renal function, and available alternatives, replacing abacavir with a tenofovir-based backbone is the appropriate step while aggressive risk-factor modification, including smoking cessation, continues.
Option A: Option A is incorrect. Regardless of the causality debate, guidance is to avoid abacavir in high cardiovascular risk when alternatives are available.
Option C: Option C is incorrect. Dolutegravir is an effective, low-interaction anchor and should not be stopped; the issue is the abacavir backbone.
Option D: Option D is incorrect. Adding ritonavir provides no benefit here and could worsen the lipid profile.
Option E: Option E is incorrect. Dolutegravir does not offset the abacavir cardiovascular signal, so no change is not appropriate.
11. A 26-year-old woman with HIV relies on a combined oral contraceptive pill for pregnancy prevention. She is about to start an efavirenz-containing regimen and does not currently wish to become pregnant. What counseling and contraceptive recommendation is most appropriate?
A) The combined oral contraceptive will work better on efavirenz, so no change is needed
B) Double the dose of the combined oral contraceptive pill while on efavirenz
C) Switch to an etonogestrel implant, which is unaffected by enzyme inducers
D) Rely on the combined oral contraceptive plus an additional progestin-only pill
E) Advise that efavirenz lowers ethinyl estradiol concentrations and recommend a more reliable method such as a copper or levonorgestrel intrauterine device, with an additional barrier method
ANSWER: E
Rationale:
Option E is correct. Efavirenz induces metabolism and reduces ethinyl estradiol concentrations by roughly 40 to 55%, compromising combined oral contraceptive efficacy. The appropriate counsel is that efficacy is reduced and that a more reliable, induction-resistant method such as a copper or levonorgestrel-releasing intrauterine device is preferred, with an additional barrier method for added protection.
Option A: Option A is incorrect. Efavirenz reduces, rather than improves, contraceptive hormone concentrations.
Option B: Option B is incorrect. Doubling the pill is not a validated or reliable strategy to overcome the interaction.
Option C: Option C is incorrect. The etonogestrel implant depends on metabolism that enzyme inducers accelerate, so it may have reduced efficacy and is not a reliable choice here.
Option D: Option D is incorrect. Adding a progestin-only pill does not reliably overcome the induction effect, whereas an intrauterine device provides dependable protection.
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