Antiviral Pharmacology

Correct Answer

B — Emtricitabine

Rationale

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI). Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Raltegravir is an integrase strand transfer inhibitor. Darunavir is a protease inhibitor.

Correct Answer

A — Efavirenz

Rationale

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Tenofovir disoproxil fumarate is an NRTI. Dolutegravir is an integrase strand transfer inhibitor. Lopinavir is a protease inhibitor.

Correct Answer

D — Zidovudine

Rationale

Zidovudine is a thymidine analog NRTI — it mimics the nucleoside thymidine and is incorporated into viral DNA in place of thymidine, terminating chain elongation. Stavudine is the other thymidine analog NRTI. Tenofovir disoproxil fumarate is an adenosine analog (and technically a nucleotide rather than a nucleoside). Emtricitabine is a cytosine analog. Abacavir is a guanosine analog.

Correct Answer

D — Doravirine

Rationale

Doravirine is a second-generation NNRTI classified as retaining activity against HIV strains resistant to first-generation agents. Efavirenz, nevirapine, and delavirdine are all first-generation NNRTIs that share a common resistance profile; strains resistant to one are generally resistant to all three. Second-generation NNRTIs such as doravirine, etravirine, and rilpivirine were developed specifically to address this limitation.

Correct Answer

B — Tenofovir disoproxil fumarate

Rationale

Tenofovir disoproxil fumarate is classified as a nucleotide reverse transcriptase inhibitor (NtRTI) because its active moiety, tenofovir, already contains a phosphonate group — it enters cells one phosphorylation step ahead of true nucleosides. Zidovudine, abacavir, and emtricitabine are nucleoside reverse transcriptase inhibitors (NRTIs), which lack the phosphate group and require intracellular phosphorylation to the triphosphate form before they can be incorporated by reverse transcriptase. Tenofovir alafenamide is the other approved nucleotide RTI.

Correct Answer

B — Nevirapine

Rationale

Nevirapine is a first-generation NNRTI, along with efavirenz and delavirdine. Rilpivirine, doravirine, and etravirine are classified as second-generation NNRTIs with improved resistance profiles and better tolerability compared with the first-generation agents.

Correct Answer

C — The incorporated NRTI lacks the 3′-hydroxyl group required to form the phosphodiester bond needed to add the next nucleotide

Rationale

NRTIs are obligate chain terminators because they lack a 3′-hydroxyl group. In normal deoxyribonucleic acid synthesis, each incoming nucleotide forms a phosphodiester bond with the 3′-hydroxyl of the preceding nucleotide. When an NRTI is incorporated, no 3′-hydroxyl is available, so the next nucleotide cannot be added and elongation stops.

Correct Answer

A — Reduced CYP2B6 activity leads to higher plasma efavirenz concentrations, increasing central nervous system toxicity

Rationale

Efavirenz is metabolized primarily by CYP2B6. CYP2B6 slow metabolizers clear efavirenz more slowly, resulting in plasma concentrations two to three times higher than in normal metabolizers. These elevated concentrations correlate directly with central nervous system toxicity including vivid dreams, insomnia, and dizziness. Efavirenz is not a prodrug and does not require metabolic activation; options B and C do not reflect efavirenz pharmacology. Option D describes an absorption mechanism that does not apply to efavirenz.

Correct Answer

D — NRTIs impair mitochondrial deoxyribonucleic acid replication, reducing oxidative phosphorylation capacity and forcing cells to rely on anaerobic metabolism

Rationale

The class-wide mitochondrial toxicity of NRTIs results from off-target inhibition of mitochondrial deoxyribonucleic acid replication. The responsible enzyme is mitochondrial deoxyribonucleic acid polymerase gamma, which shares sufficient structural similarity with reverse transcriptase to be inhibited by NRTI triphosphates. Impaired mitochondrial deoxyribonucleic acid replication reduces the capacity for oxidative phosphorylation, forcing cells to rely on anaerobic glycolysis and producing lactic acidosis. Hepatic steatosis and peripheral neuropathy follow from energy failure in metabolically active tissues. Risk varies by agent: older agents such as stavudine carried the highest risk; tenofovir and emtricitabine have negligible mitochondrial toxicity at therapeutic concentrations.

Correct Answer

B — Certain patients carry a genetic variant that places them at risk for a potentially fatal immunologically mediated hypersensitivity reaction to abacavir; prospective screening virtually eliminates this complication

Rationale

Approximately 5 to 8 percent of patients carry the HLA-B*57:01 allele, which confers risk of a severe immunologically mediated hypersensitivity reaction to abacavir. The reaction typically occurs within the first six weeks of therapy and presents with fever, rash, and systemic symptoms including gastrointestinal and respiratory involvement. Rechallenge after a confirmed reaction is absolutely contraindicated due to risk of fatal anaphylaxis. Prospective genetic screening before prescribing abacavir identifies carriers and virtually eliminates clinically diagnosed hypersensitivity reactions — it is mandatory practice. Option A is incorrect because abacavir toxicity is not related to hepatic metabolism accumulation. Option C is incorrect because abacavir phosphorylation proceeds normally regardless of HLA genotype. Option D is incorrect because the screening targets a host genetic variant, not a viral resistance mutation.

Correct Answer

C — Rilpivirine requires an acidic gastric environment for dissolution and absorption; proton pump inhibitors suppress gastric acid throughout the day and prevent adequate drug absorption

Rationale

Rilpivirine solubility and absorption depend on gastric acidity and require co-administration with a substantial meal. Proton pump inhibitors suppress acid production throughout the day and cannot be timed around a rilpivirine dose to avoid the interaction — the suppression is persistent. This makes proton pump inhibitors an absolute contraindication with rilpivirine. H2-receptor antagonists, which have a shorter duration of acid suppression, may be used with appropriate timing separation. Rilpivirine is a CYP3A4 substrate but neither inhibits nor induces CYP3A4, making option A pharmacologically inaccurate.

Correct Answer

A — Tenofovir accumulates in renal proximal tubular cells and impairs local mitochondrial function, disrupting the energy-dependent transport processes that reabsorb glucose, phosphate, and protein

Rationale

Tenofovir disoproxil fumarate generates high plasma tenofovir concentrations, and tenofovir accumulates in renal proximal tubular cells where it inhibits mitochondrial deoxyribonucleic acid polymerase gamma. The resulting mitochondrial dysfunction impairs the energy-dependent active transport processes that normally reabsorb glucose, phosphate, amino acids, and low-molecular-weight proteins from the tubular filtrate. The clinical syndrome — glucosuria without hyperglycemia, phosphaturia, and proteinuria — is Fanconi syndrome. Tenofovir alafenamide produces far lower plasma tenofovir concentrations and substantially less renal toxicity. Options B, C, and D describe mechanisms that do not apply to tenofovir nephrotoxicity.

Correct Answer

D — Emtricitabine suppresses hepatitis B virus replication directly, and its discontinuation allows rapid viral rebound that can cause severe hepatic flare and decompensation

Rationale

Emtricitabine and lamivudine are active against both HIV and hepatitis B virus. In patients co-infected with HIV and hepatitis B virus, these agents suppress hepatitis B virus replication as part of the antiretroviral regimen. Abrupt discontinuation removes this suppression, allowing rapid viral rebound. The resulting immune response to resurging hepatitis B virus replication can cause severe hepatic flares with potentially fatal hepatic decompensation. Any planned regimen change in a co-infected patient must include a strategy to maintain hepatitis B virus suppression using agents active against hepatitis B virus, typically tenofovir-based combinations.

Correct Answer

B — NNRTIs bind a hydrophobic pocket adjacent to but distinct from the reverse transcriptase active site, inducing a conformational change that reduces polymerase activity

Rationale

NNRTIs are non-competitive inhibitors that bind a hydrophobic allosteric pocket in the p66 subunit of reverse transcriptase, positioned approximately 10 angstroms from the catalytic active site. Binding distorts the geometry of the active site and reduces the flexibility of the enzyme's thumb subdomain, slowing the rate of polymerization without blocking substrate entry directly. Because NNRTIs act at an allosteric site rather than the active site, a single point mutation at or near the binding pocket can abolish inhibition — explaining why NNRTIs have a low genetic barrier to resistance and why resistance emerges rapidly under monotherapy or in the setting of incomplete viral suppression. This contrasts with NRTIs, which act as obligate chain terminators at the active site after phosphorylation and incorporation.

Correct Answer

A — Efavirenz induces CYP3A4 and CYP2B6, increasing methadone metabolism and reducing plasma methadone concentrations

Rationale

Efavirenz is a potent inducer of CYP3A4 and CYP2B6, both of which are involved in methadone metabolism. Induction accelerates methadone clearance, reducing plasma concentrations by approximately 50 to 60 percent within one to two weeks of efavirenz initiation. This rapid fall in methadone levels precipitates opioid withdrawal in patients on stable maintenance doses. Coordination with the methadone prescriber before starting efavirenz is essential, and dose escalation is routinely required. Integrase strand transfer inhibitor-based regimens are strongly preferred in patients on methadone because they lack this interaction. Options B, C, and D describe mechanisms that do not apply to the efavirenz-methadone interaction.

Correct Answer

C — Women with CD4 counts above 250 cells per microliter face substantially increased risk of serious hepatotoxicity with nevirapine, including potentially fatal hepatic necrosis

Rationale

Nevirapine carries a well-characterized CD4-dependent hepatotoxicity risk. Women with CD4 counts above 250 cells per microliter and men with CD4 counts above 400 cells per microliter are at substantially higher risk for serious, potentially fatal hepatic reactions — including symptomatic hepatic necrosis — compared with patients initiating nevirapine at lower CD4 counts. The mechanism is believed to be immune-mediated rather than purely direct toxicity, which explains the CD4 threshold effect. This patient's CD4 count of 520 cells per microliter places her squarely in the high-risk category, making nevirapine an inappropriate choice for initial therapy regardless of viral load. Current guidelines recommend integrase strand transfer inhibitor-based regimens as preferred initial therapy, and nevirapine has largely fallen out of use in treatment-naive patients in settings where alternatives are available.

Correct Answer

D — Efavirenz has been associated with neural tube defects in animal studies and isolated human case reports, and neural tube closure occurs during the first several weeks of pregnancy when exposure has already occurred

Rationale

Efavirenz was historically classified as FDA Pregnancy Category D based on teratogenicity in primate studies and isolated case reports of neural tube defects in infants with first-trimester exposure. Neural tube closure occurs by approximately four weeks after conception — meaning that for this patient, the period of highest teratogenic risk has already passed before the pregnancy was detected. Current guidelines have moved toward permitting efavirenz continuation in women who are already pregnant and virologically suppressed, given that the data on actual human teratogenic risk are weaker than initially feared and that abrupt regimen changes risk virologic rebound. However, efavirenz is avoided in women planning pregnancy and should not be started in the first trimester. The pharmacological basis for concern is efavirenz's lipophilicity and CNS penetration, which facilitate placental transfer and fetal exposure. Options A, B, and C do not reflect the established teratogenicity concern that drives clinical decision-making with efavirenz in pregnancy.

Correct Answer

B — Tenofovir alafenamide delivers tenofovir preferentially into lymphocytes, producing high intracellular antiviral concentrations at far lower plasma tenofovir exposure than tenofovir disoproxil fumarate

Rationale

Tenofovir disoproxil fumarate generates high plasma tenofovir concentrations, and tenofovir accumulates in renal proximal tubular cells where it impairs mitochondrial function and causes Fanconi syndrome. Tenofovir alafenamide is a phosphonamidate prodrug designed to deliver tenofovir intracellularly into lymphocytes with high efficiency, achieving equivalent antiviral activity at plasma tenofovir concentrations approximately one-tenth those of tenofovir disoproxil fumarate. The reduced plasma exposure substantially lowers the amount of tenofovir reaching the proximal tubule, producing far less renal toxicity at equivalent antiviral efficacy. The other options describe mechanisms that do not reflect how tenofovir alafenamide differs from tenofovir disoproxil fumarate.