1. A 34-year-old man with advanced acquired immunodeficiency syndrome (AIDS) and a cluster of differentiation 4 (CD4) count of 18 cells per microliter has progressively enlarging, deep perioral ulcers that have not healed after 12 days of adequate intravenous acyclovir. Adherence and dosing have been confirmed appropriate, and a lesion swab confirms herpes simplex virus (HSV). What is the most appropriate next step?
A) Increase the acyclovir dose, since a partial thymidine kinase defect can be overcome with higher drug exposure in all cases.
B) Switch to intravenous foscarnet, because a non-healing HSV lesion despite adequate acyclovir in a profoundly immunocompromised patient indicates likely thymidine kinase (TK)-null acyclovir resistance, and foscarnet inhibits the viral DNA polymerase without requiring viral TK.
C) Switch to oral valacyclovir, because improved oral bioavailability will overcome the resistance.
D) Add famciclovir to acyclovir, since combining two TK-dependent agents restores activity against TK-null virus.
E) Discontinue all antiviral therapy and treat the lesions with topical care alone.
ANSWER: B
Rationale:
Option B is correct. A progressive, non-healing HSV lesion despite adequate acyclovir in a profoundly immunocompromised patient is the classic picture of TK-null acyclovir-resistant HSV. Because acyclovir activation requires viral TK, the appropriate pivot is foscarnet, which directly inhibits the viral DNA polymerase and does not need viral TK.
Option A: Option A is incorrect. A TK-null phenotype cannot be overcome by dose escalation because the activating enzyme is absent.
Option C: Option C is incorrect. Valacyclovir is a prodrug of acyclovir and still depends on viral TK, so better bioavailability does not overcome TK-null resistance.
Option D: Option D is incorrect. Famciclovir (via penciclovir) is also TK-dependent, so combining two TK-dependent agents does not restore activity against TK-null virus.
Option E: Option E is incorrect. Stopping antiviral therapy abandons treatable resistant infection in a high-risk patient; an effective TK-independent agent is available.
2. A 58-year-old lung transplant recipient on valganciclovir for cytomegalovirus (CMV) viremia has a plasma CMV viral load that has not declined by at least 1 log10 after two weeks of adequately dosed therapy. Genotyping returns an isolated UL97 (CMV phosphotransferase) mutation at codon 594 with no UL54 (CMV DNA polymerase) mutation. Drug levels and adherence are confirmed adequate. What is the most appropriate management?
A) Switch to an agent that does not require UL97 for activation — foscarnet or cidofovir — or use maribavir, which inhibits UL97 at a distinct site and retains activity against many UL97 mutations; do not simply increase the ganciclovir dose.
B) Continue valganciclovir unchanged, since UL97 mutations do not reduce ganciclovir efficacy.
C) Double the valganciclovir dose, because UL97 codon 594 mutations are overcome by higher exposure.
D) Stop all CMV therapy, because UL97 mutations confer pan-resistance to every available CMV agent.
E) Switch to oral acyclovir, which is active against ganciclovir-resistant CMV.
ANSWER: A
Rationale:
Option A is correct. An isolated UL97 mutation impairs ganciclovir activation, conferring ganciclovir resistance while leaving foscarnet and cidofovir fully active (neither requires UL97). Maribavir inhibits UL97 through a binding site distinct from ganciclovir and retains activity against many UL97 mutations, including at codon 594-region positions, so it is also an option. Dose escalation does not overcome impaired activation.
Option B: Option B is incorrect. A UL97 mutation reduces ganciclovir activation, so continuing unchanged is inappropriate.
Option C: Option C is incorrect. Impaired UL97-mediated activation is not overcome by higher ganciclovir exposure.
Option D: Option D is incorrect. UL97-only mutations do not confer pan-resistance; foscarnet, cidofovir, and maribavir remain options.
Option E: Option E is incorrect. Acyclovir is not effective therapy for ganciclovir-resistant CMV disease.
3. A 27-year-old woman is newly diagnosed with HIV and has never taken antiretroviral therapy. A baseline genotype performed before starting treatment reveals the K103N (lysine-to-asparagine at position 103) mutation. How should this result be interpreted and acted upon?
A) The result is a laboratory artifact, because a treatment-naive patient cannot harbor any resistance mutation.
B) K103N is irrelevant to regimen choice because it affects only nucleoside reverse transcriptase inhibitors.
C) An efavirenz-based regimen should still be started, since K103N does not affect first-generation non-nucleoside reverse transcriptase inhibitors.
D) This represents transmitted resistance — the patient acquired a virus already carrying K103N — and a first-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) such as efavirenz or nevirapine should be avoided; an integrase-inhibitor-based regimen is a preferred alternative.
E) The mutation can be ignored because it will disappear once therapy is started.
ANSWER: D
Rationale:
Option D is correct. K103N detected in a treatment-naive patient reflects transmitted resistance — the patient was infected with a virus already carrying the mutation. K103N confers high-level resistance across first-generation NNRTIs, so efavirenz and nevirapine should be avoided; a regimen built on an integrase strand transfer inhibitor (or another fully active anchor) is preferred. This is precisely why baseline genotyping at diagnosis is recommended.
Option A: Option A is incorrect. Transmitted resistance occurs in roughly 10% to 15% of newly diagnosed patients, so the result is not an artifact.
Option B: Option B is incorrect. K103N is an NNRTI binding-pocket mutation, not an NRTI mutation.
Option C: Option C is incorrect. K103N confers high-level resistance to first-generation NNRTIs, so an efavirenz-based regimen would likely fail.
Option E: Option E is incorrect. The mutation will not disappear; under NNRTI pressure it would be selected, not eliminated.
4. A 41-year-old man on tenofovir disoproxil fumarate, emtricitabine, and efavirenz (TDF/FTC/EFV) with documented intermittent adherence has a confirmed plasma HIV ribonucleic acid (RNA) of 14,000 copies per milliliter. A genotype is obtained while he is still on the failing regimen. Which resistance pattern is most consistent with this clinical picture?
A) Integrase mutations N155H and Q148H, since these are the expected mutations on an efavirenz-containing regimen.
B) Protease inhibitor mutations only, because TDF/FTC/EFV exerts selective pressure exclusively on the protease gene.
C) M184V (from emtricitabine pressure) together with an NNRTI mutation such as K103N (from efavirenz pressure), reflecting the low-barrier components of this regimen.
D) No detectable mutations, because resistance never emerges on a tenofovir-containing regimen.
E) The hepatitis B virus rtM204V/I mutation, since emtricitabine selects that change in HIV reverse transcriptase.
ANSWER: C
Rationale:
Option C is correct. The low-barrier components of TDF/FTC/EFV are emtricitabine and efavirenz. Under intermittent adherence, emtricitabine pressure readily selects M184V, and efavirenz pressure readily selects a first-generation NNRTI mutation such as K103N. This combination is the expected genotype on this failing regimen.
Option A: Option A is incorrect. N155H and Q148H are integrase mutations; this regimen contains no integrase inhibitor and exerts no integrase pressure.
Option B: Option B is incorrect. The regimen contains no protease inhibitor, so protease pressure is not exerted.
Option D: Option D is incorrect. Resistance can and does emerge on tenofovir-containing regimens, particularly through the low-barrier emtricitabine and efavirenz components.
Option E: Option E is incorrect. rtM204V/I is the hepatitis B virus lamivudine-resistance mutation, not an HIV mutation selected by emtricitabine in HIV reverse transcriptase.
5. A 49-year-old woman re-engages in care after stopping all antiretroviral therapy four months ago. Her record documents prior virologic failure with M184V and K103N. A new genotype, drawn now while she is off all therapy, reports wild-type virus with no resistance mutations. How should this new "wild-type" result be used in planning her next regimen?
A) Restart efavirenz and emtricitabine, since the current genotype confirms full susceptibility has returned.
B) Disregard all prior genotypes, because only the most recent result reflects the true virus.
C) Conclude the earlier genotypes were erroneous, since resistance mutations cannot fall below detection.
D) Delay any regimen until the mutations reappear on a repeat genotype, since absent mutations cannot be planned around.
E) Treat the previously documented M184V and K103N as archived resistance still present below the detection threshold off-therapy, and avoid relying on emtricitabine/lamivudine and first-generation NNRTIs as if those mutations were active.
ANSWER: E
Rationale:
Option E is correct. Off therapy, fitter wild-type virus outcompetes resistant variants, which can fall below the standard genotype detection threshold; however, the mutations persist as archived resistance and re-emerge rapidly if the relevant class is reintroduced. Planning must therefore incorporate all prior genotypes and treat M184V and K103N as still present.
Option A: Option A is incorrect. Apparent wild-type off-therapy does not mean susceptibility has returned; archived resistance remains.
Option B: Option B is incorrect. Prior genotypes remain essential precisely because archived mutations are not erased.
Option C: Option C is incorrect. Resistance mutations can fall below detection without the selecting drug, so the earlier results were not erroneous.
Option D: Option D is incorrect. There is no need to wait for mutations to reappear; the documented history already informs the regimen.
6. A 52-year-old man with chronic hepatitis B virus (HBV) infection has been on lamivudine monotherapy for four years. His HBV deoxyribonucleic acid (DNA) level, previously suppressed, has risen by 2 log10 over three months, accompanied by an alanine aminotransferase (ALT) flare. Which interpretation and management is most appropriate?
A) This is expected hepatitis B surface antigen seroconversion, and lamivudine should be continued unchanged.
B) This is virologic breakthrough from lamivudine resistance, most likely the rtM204V/I mutation (often with compensatory rtL180M); switch to tenofovir, which retains the highest resistance barrier with no confirmed clinical resistance.
C) The flare reflects lamivudine toxicity, so the drug should be stopped and no antiviral substituted.
D) Add a second L-nucleoside analog such as telbivudine, since combining L-nucleoside analogs overcomes rtM204V/I.
E) Increase the lamivudine dose, because rtM204V/I resistance is dose-dependent and reversible with escalation.
ANSWER: B
Rationale:
Option B is correct. Rising HBV DNA with an ALT flare after sustained lamivudine monotherapy is classic virologic breakthrough from lamivudine resistance, most often the rtM204V/I mutation with compensatory rtL180M. The appropriate response is to switch to tenofovir, the highest-barrier agent with no confirmed clinical resistance, rather than continuing a failing low-barrier drug.
Option A: Option A is incorrect. Rising viral load with an ALT flare is breakthrough, not surface antigen seroconversion, which would be accompanied by declining viral markers.
Option C: Option C is incorrect. The flare reflects viral breakthrough, not drug toxicity, and stopping antiviral therapy without substitution risks severe hepatitis.
Option D: Option D is incorrect. Telbivudine is an L-nucleoside analog cross-affected by rtM204V/I, so it does not overcome the resistance.
Option E: Option E is incorrect. rtM204V/I is not overcome by dose escalation; this contradicts the resistance mechanism.
7. A 60-year-old man with hepatitis C virus (HCV) genotype 1a relapsed after a prior NS5A-inhibitor-containing direct-acting antiviral regimen. He is now being evaluated for re-treatment. Which testing strategy most appropriately guides his salvage regimen?
A) Obtain NS5A resistance-associated substitution (RAS) testing, because NS5A substitutions can persist for years after failure and influence both the choice of salvage regimen and its duration.
B) Skip all resistance testing and simply repeat the identical regimen, since relapse is always due to nonadherence.
C) Test for the hepatitis B virus rtM204V/I mutation, because it predicts HCV NS5A inhibitor failure.
E) Measure UL97 genotype, since it guides HCV NS5A inhibitor re-treatment.
ANSWER: A
Rationale:
Option A is correct. After failure of an NS5A-inhibitor-containing regimen, NS5A RASs can persist for years and meaningfully affect re-treatment. NS5A RAS testing therefore guides selection of an appropriate salvage regimen (for example, one incorporating a high-barrier combination such as sofosbuvir-velpatasvir-voxilaprevir) and its duration.
Option B: Option B is incorrect. Repeating the identical failed regimen without resistance testing ignores persistent NS5A RASs; relapse is not always nonadherence.
Option C: Option C is incorrect. rtM204V/I is an HBV mutation and does not predict HCV NS5A inhibitor outcomes.
Option D: Option D is incorrect. Co-receptor tropism testing applies to HIV maraviroc use, not HCV.
Option E: Option E is incorrect. UL97 is a cytomegalovirus gene and is irrelevant to HCV re-treatment.
8. A 46-year-old hematopoietic stem cell transplant (HSCT) recipient on long-term acyclovir prophylaxis develops progressive verrucous, hyperkeratotic skin nodules that do not follow a dermatomal pattern and have failed to evolve through the usual vesicular stages despite continued acyclovir. Varicella-zoster virus (VZV) is confirmed. What is the best interpretation and next step?
A) This is typical dermatomal zoster; simply continue the current acyclovir prophylactic dose.
B) These lesions indicate disseminated bacterial superinfection, so antiviral therapy is unnecessary.
C) This atypical presentation suggests acyclovir-resistant VZV arising through a thymidine kinase (TK) gene mutation; confirm with TK gene sequencing and switch to foscarnet, which does not require viral TK.
D) Escalate the oral acyclovir dose, since hyperkeratotic VZV lesions are always due to underdosing rather than resistance.
E) Switch to oral valacyclovir, which bypasses viral TK and is active against TK-mutant VZV.
ANSWER: C
Rationale:
Option C is correct. Atypical, progressive verrucous/hyperkeratotic VZV lesions lacking the usual vesicular evolution and dermatomal distribution in an immunocompromised patient on prolonged acyclovir are the recognized presentation of acyclovir-resistant VZV, which arises through the same TK gene mutation mechanism as resistant HSV. Confirmation is by TK gene sequencing, and management is a switch to foscarnet, which does not require viral TK.
Option A: Option A is incorrect. The presentation is atypical and progressive, not typical dermatomal zoster, and continuing the same therapy abandons resistant disease.
Option B: Option B is incorrect. VZV is confirmed; this is viral resistance, not bacterial superinfection.
Option D: Option D is incorrect. A TK mutation is not overcome by dose escalation, since the activating enzyme is defective.
Option E: Option E is incorrect. Valacyclovir is a prodrug of acyclovir and still depends on viral TK, so it does not bypass the defect.
9. A 55-year-old man with B-cell depletion from prior rituximab therapy has persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. After repeated and prolonged courses of nirmatrelvir-ritonavir, his viral load rebounds, and sequencing identifies a mutation in the viral main protease (Mpro) gene. Which interpretation best fits this scenario?
A) The mutation is irrelevant, because SARS-CoV-2 never develops clinically meaningful antiviral resistance.
B) Resistance must have been transmitted from a vaccinated contact, since vaccine antibodies select Mpro mutations.
C) The finding reflects laboratory contamination, because Mpro mutations cannot arise during nirmatrelvir therapy.
D) This is treatment-emergent nirmatrelvir resistance arising in a severely immunocompromised host, where the inability to clear virus immunologically plus sustained drug selection pressure from prolonged or repeated courses favors emergence of Mpro resistance mutations.
E) The mutation proves the patient was never infected with SARS-CoV-2, since Mpro is not a coronavirus gene.
ANSWER: D
Rationale:
Option D is correct. Nirmatrelvir targets the SARS-CoV-2 main protease (Mpro), and treatment-emergent Mpro resistance mutations have been described in severely immunocompromised patients receiving prolonged or repeated courses. This mirrors the herpesvirus pattern: sustained drug selection pressure in a host who cannot clear virus immunologically favors emergence of resistance.
Option A: Option A is incorrect. SARS-CoV-2 can develop clinically meaningful resistance to some antivirals, including nirmatrelvir, in this setting.
Option B: Option B is incorrect. Vaccine-induced antibodies target the spike protein, not the Mpro drug target, and do not select nirmatrelvir resistance.
Option C: Option C is incorrect. Mpro mutations can and do arise under nirmatrelvir selection; this is not contamination.
Option E: Option E is incorrect. Mpro (the main protease) is a SARS-CoV-2 gene and the target of nirmatrelvir.
10. A 63-year-old kidney transplant recipient on oral valganciclovir for CMV viremia shows a viral load that is not declining as expected. Before attributing this to ganciclovir resistance, review reveals that she has had significant vomiting and reduced oral intake for the past two weeks, and an inadvertent dose reduction was made during a recent hospitalization. What is the most appropriate immediate step?
A) Switch directly to foscarnet, since failure to respond always indicates true ganciclovir resistance regardless of drug exposure.
B) First confirm adequate drug exposure and adherence — addressing the poor absorption and dosing error, for example by switching to intravenous ganciclovir and correcting the dose — because inadequate drug levels and true resistance produce clinically identical pictures but require different responses, so pharmacokinetic failure must be excluded before genotyping or changing agents for presumed resistance.
C) Immediately order UL97 and UL54 genotyping and change therapy based on the result without addressing the absorption problem.
D) Stop all CMV therapy and observe, since the viral load will likely clear once the patient resumes eating.
E) Add cidofovir empirically while continuing the under-dosed oral valganciclovir, without correcting the exposure problem.
ANSWER: B
Rationale:
Option B is correct. A unifying principle is that inadequate drug exposure (poor absorption, dosing errors, interactions) and true resistance can look identical, so pharmacokinetic failure must be excluded first. Here, vomiting/poor intake and an erroneous dose reduction are clear causes of inadequate exposure; correcting them — for example by switching to intravenous ganciclovir at the proper dose — is the appropriate immediate step before invoking resistance.
Option A: Option A is incorrect. Non-response does not always mean resistance; exposure must be assessed before switching agents.
Option C: Option C is incorrect. Genotyping is reasonable later, but changing therapy for presumed resistance without correcting an obvious exposure problem is premature.
Option D: Option D is incorrect. Stopping CMV therapy in a transplant recipient with active viremia risks progression; the issue is exposure, not a reason to discontinue.
Option E: Option E is incorrect. Adding cidofovir while leaving the under-dosing uncorrected fails to address the actual cause and adds nephrotoxicity risk.
11. A 58-year-old man with multi-drug-resistant HIV and an extensive treatment history has documented resistance across NRTIs and NNRTIs, two primary protease inhibitor mutations, and no documented integrase mutations. You are assembling a salvage regimen aiming for two to three fully active agents. Which combination best applies salvage regimen principles?
A) Two recycled NRTIs plus efavirenz, since reusing prior agents restores their activity.
B) Lamivudine monotherapy, since its low fitness cost keeps the virus suppressed.
C) A first-generation integrase inhibitor alone, because integrase inhibitors are unaffected by any prior resistance.
D) Three drugs all targeting reverse transcriptase, to concentrate pressure on one enzyme.
E) A second-generation integrase inhibitor (dolutegravir, counted fully active given no integrase mutations) plus ritonavir-boosted darunavir (retaining substantial activity with only two primary protease mutations) plus a novel agent such as fostemsavir or lenacapavir, achieving an optimized regimen with at least two fully active agents.
ANSWER: E
Rationale:
Option E is correct. Salvage principles aim for two to three fully active agents. With no documented integrase mutations, a second-generation INSTI (dolutegravir) counts as fully active; boosted darunavir retains substantial activity unless three or more primary protease mutations are present (only two here); and a novel agent (fostemsavir, lenacapavir, or ibalizumab) adds another fully active drug. Together these achieve an optimized background regimen with an activity score of at least two, associated with virologic suppression.
Option A: Option A is incorrect. Recycled NRTIs and efavirenz are already compromised by documented NRTI and NNRTI resistance, so they are not fully active.
Option B: Option B is incorrect. Lamivudine monotherapy in a resistant virus will not suppress; low fitness cost of M184V does not equate to viral suppression.
Option C: Option C is incorrect. A first-generation integrase inhibitor alone is both insufficient (single agent) and lower-barrier; integrase inhibitors are not immune to resistance.
Option D: Option D is incorrect. Concentrating three drugs on one already-compromised enzyme does not provide multiple fully active agents and ignores documented reverse transcriptase resistance.
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