1. Four agents used against CMV are letermovir, ganciclovir, foscarnet, and cidofovir. Three of them ultimately act on the same molecular target, while one acts on a target entirely distinct from that shared pathway. Which statement correctly identifies the agent with the distinct target?
A) Foscarnet is the outlier, acting on the terminase complex while the others inhibit the DNA polymerase
B) Letermovir is the outlier, inhibiting the viral terminase complex, while ganciclovir, foscarnet, and cidofovir all converge on the viral DNA polymerase
C) Cidofovir is the outlier, acting on the terminase complex while the others inhibit the DNA polymerase
D) Ganciclovir is the outlier, inhibiting the terminase complex while the others act on the DNA polymerase
E) All four agents act on the viral DNA polymerase; none targets the terminase
ANSWER: B
Rationale:
Discriminating among anti-CMV targets is foundational to selecting therapy and predicting cross-resistance. Option B is correct: letermovir inhibits the viral terminase complex (UL56/UL89/UL51), which packages viral DNA into procapsids, whereas ganciclovir (after UL97 activation), foscarnet (directly), and cidofovir (after host-cell phosphorylation) all inhibit the viral DNA polymerase. The shared polymerase target is why polymerase-region (UL54) mutations can produce cross-resistance among the latter three but not letermovir.
Option A: Option A is incorrect: foscarnet inhibits the polymerase, not the terminase.
Option C: Option C is incorrect: cidofovir inhibits the polymerase.
Option D: Option D is incorrect: ganciclovir inhibits the polymerase after activation; it does not target the terminase.
Option E: Option E is incorrect: letermovir does target the terminase, so the premise that none does is false.
2. Genotypic resistance testing on a CMV isolate reveals a mutation at UL97 codon 594 with a wild-type UL54 gene. Which interpretation and consequence is correct?
A) The isolate is resistant to foscarnet but susceptible to ganciclovir
B) The isolate carries high-level multidrug resistance to ganciclovir, foscarnet, and cidofovir
C) The mutation affects the DNA polymerase and predicts cidofovir failure
D) The isolate is resistant to ganciclovir because UL97-mediated activation is impaired, but typically retains susceptibility to foscarnet and cidofovir
E) The mutation confers letermovir resistance and mandates a switch to terminase-independent therapy
ANSWER: D
Rationale:
UL97 versus UL54 genotype directly governs which agents remain usable. Option D is correct: UL97 phosphotransferase mutations (commonly at codons 460, 594, 595) impair phosphorylation/activation of ganciclovir, producing ganciclovir resistance, while foscarnet (no activation required) and cidofovir (host-cell activation) usually retain activity when UL54 is wild-type.
Option A: Option A is incorrect: it reverses the pattern — ganciclovir is the affected drug, not foscarnet.
Option B: Option B is incorrect: high-level multidrug resistance requires UL54 (polymerase) involvement, often combined with UL97; an isolated UL97 mutation does not confer it.
Option C: Option C is incorrect: UL97 encodes the phosphotransferase, not the polymerase, and cidofovir is generally retained.
Option E: Option E is incorrect: letermovir resistance is mediated by UL56 mutations, not UL97. The rational next step for isolated UL97 resistance is to switch to foscarnet.
3. A patient with refractory CMV disease has genotyping showing a UL54 DNA polymerase mutation. Compared with an isolated UL97 mutation, what is the principal clinical concern raised specifically by a UL54 mutation?
A) UL54 mutations target the shared DNA polymerase and can produce cross-resistance among ganciclovir, foscarnet, and cidofovir depending on the specific substitution
B) UL54 mutations impair only ganciclovir activation and are overcome by raising the ganciclovir dose
C) UL54 mutations selectively abolish foscarnet activity while leaving ganciclovir fully effective
D) UL54 mutations confer resistance exclusively to letermovir through terminase alteration
E) UL54 mutations affect drug uptake transporters rather than any viral enzyme
ANSWER: A
Rationale:
The defining feature of UL54 resistance is that it strikes the common target of three agents. Option A is correct: UL54 encodes the viral DNA polymerase — the shared target of ganciclovir, foscarnet, and cidofovir — so specific UL54 substitutions can confer cross-resistance across these agents (the pattern depending on which residues are mutated), and combined UL97 plus UL54 mutations produce high-level multidrug resistance.
Option B: Option B is incorrect: that describes UL97 (activation) resistance, which dose escalation does not overcome.
Option C: Option C is incorrect: UL54 mutations do not selectively spare ganciclovir; ganciclovir acts on the same polymerase.
Option D: Option D is incorrect: letermovir resistance is a UL56 (terminase) phenomenon, unrelated to UL54.
Option E: Option E is incorrect: UL54 is a viral polymerase gene, not a transporter gene. Management of multidrug-resistant CMV may involve combination foscarnet plus ganciclovir, reduced immunosuppression, and investigational agents such as maribavir.
4. A clinician must choose between ganciclovir and foscarnet for a CMV infection and is weighing their characteristic dose-limiting toxicities. Which pairing of agent to its principal toxicity is correct?
B) Both agents share myelosuppression as the dominant dose-limiting toxicity
C) Ganciclovir causes myelosuppression (neutropenia, thrombocytopenia); foscarnet causes nephrotoxicity and electrolyte wasting (hypocalcemia, hypomagnesemia, hypokalemia)
D) Foscarnet causes myelosuppression; ganciclovir causes QT prolongation as its primary toxicity
E) Neither agent has clinically significant organ toxicity at therapeutic doses
ANSWER: C
Rationale:
Matching each agent to its signature toxicity drives monitoring and patient selection. Option C is correct: ganciclovir (and valganciclovir) characteristically cause myelosuppression — neutropenia and thrombocytopenia — which limits use in already-cytopenic transplant patients; foscarnet characteristically causes nephrotoxicity and electrolyte wasting (hypocalcemia, hypomagnesemia, hypokalemia), the latter from its chelation of divalent cations, requiring electrolyte repletion before each infusion.
Option A: Option A is incorrect: it reverses the two profiles.
Option B: Option B is incorrect: foscarnet is not primarily myelosuppressive; this is the key reason it is chosen in neutropenic patients.
Option D: Option D is incorrect: foscarnet is not principally myelosuppressive, and QT prolongation (via hypomagnesemia/hypocalcemia) is a downstream foscarnet electrolyte effect, not a primary ganciclovir toxicity.
Option E: Option E is incorrect: both agents have well-defined dose-limiting toxicities. This contrast is why foscarnet is often preferred when marrow reserve is poor despite its nephrotoxicity and infusion burden.
5. Letermovir is approved for CMV prophylaxis in seropositive HSCT recipients but is not recommended as treatment for active, high-level CMV replication. What property of letermovir resistance best explains this restriction?
A) Resistance requires combined UL97 and UL54 mutations that accumulate only over months
B) Letermovir resistance never develops, but the drug is simply less potent against established disease
C) Resistance is mediated by UL54 polymerase mutations shared with ganciclovir, making cross-resistance the limiting issue
D) Letermovir loses activity at low viral loads, so it works only when replication is brisk
E) Resistance arises rapidly through UL56 terminase mutations when letermovir is exposed to active high-level replication, owing to its low barrier to resistance
ANSWER: E
Rationale:
The low genetic barrier of letermovir dictates its appropriate use niche. Option E is correct: letermovir has a low barrier to resistance, and UL56 (terminase) mutations are selected rapidly when the drug encounters active, high-level CMV replication; in the low-replication prophylactic setting this selection pressure is minimized, which is why letermovir is positioned for prophylaxis rather than treatment of established disease.
Option A: Option A is incorrect: letermovir resistance arises from single UL56 mutations and does not require combined UL97/UL54 changes.
Option B: Option B is incorrect: resistance does develop and is the central concern.
Option C: Option C is incorrect: letermovir resistance is a UL56 (terminase) phenomenon, not UL54, so it is not cross-resistant with polymerase inhibitors.
Option D: Option D is incorrect: the issue is rapid resistance selection under high replication, not a loss of activity at low viral loads. This is also why letermovir, acting on a unique target, lacks cross-resistance with ganciclovir, foscarnet, and cidofovir.
6. Maribavir and ganciclovir both interact with the CMV UL97 kinase but in opposite ways. Which statement correctly captures that relationship and its practical prescribing consequence?
A) Both drugs require UL97 to phosphorylate them, so combining them doubles activation and is encouraged
B) Maribavir inhibits the UL97 kinase, whereas ganciclovir requires UL97 to activate it; co-administration is counterproductive because maribavir blocks the kinase ganciclovir needs
C) Maribavir and ganciclovir both inhibit the DNA polymerase directly, so they are interchangeable
D) Maribavir is activated by UL97 just as ganciclovir is, making them fully cross-resistant
E) Maribavir inhibits the terminase while ganciclovir inhibits UL97, so the two are synergistic
ANSWER: B
Rationale:
Recognizing the inverted UL97 relationship prevents a pharmacodynamic antagonism. Option B is correct: ganciclovir depends on UL97 phosphorylation for activation, while maribavir directly inhibits the UL97 kinase; consequently, giving maribavir alongside ganciclovir impairs ganciclovir activation, so the combination is antagonistic and not used. Maribavir binds UL97 at a site distinct from the codons of common ganciclovir-resistance mutations, which is why it retains activity against most ganciclovir-resistant strains.
Option A: Option A is incorrect: maribavir is not a UL97 substrate; it inhibits the enzyme.
Option C: Option C is incorrect: maribavir targets UL97, not the polymerase, and the two are not interchangeable.
Option D: Option D is incorrect: maribavir does not depend on UL97 for activation and is not broadly cross-resistant with ganciclovir.
Option E: Option E is incorrect: maribavir does not target the terminase (that is letermovir), and the pairing is antagonistic, not synergistic.
7. A transplant recipient with disseminated adenovirus is to receive cidofovir. Which statement about cidofovir's nephrotoxicity and its mitigation is correct?
A) Nephrotoxicity arises from glomerular deposition and is prevented by alkalinizing the urine
B) Cidofovir is nephroprotective and may be given without renal precautions in any patient
C) Probenecid worsens cidofovir nephrotoxicity by increasing tubular uptake and is contraindicated
D) Cidofovir accumulates in proximal tubular cells via OAT1-mediated uptake; oral probenecid plus intravenous saline reduces this, and the drug is contraindicated below a defined creatinine-clearance threshold
E) The drug is renally inert and is contraindicated only in hepatic failure
ANSWER: D
Rationale:
Cidofovir's toxicity mechanism dictates a specific, testable mitigation protocol. Option D is correct: cidofovir is taken into proximal tubular cells by the organic anion transporter OAT1, where accumulation causes tubular injury; probenecid competitively blocks OAT1 uptake and saline hydration limits exposure, so each infusion is given with oral probenecid (before and after) plus pre-infusion IV normal saline, and cidofovir is contraindicated when creatinine clearance falls below the defined threshold (about 55 mL/min).
Option A: Option A is incorrect: the injury is proximal tubular via OAT1, not glomerular, and urinary alkalinization is not the protective measure.
Option B: Option B is incorrect: cidofovir is nephrotoxic, not nephroprotective.
Option C: Option C is incorrect: probenecid reduces, not increases, tubular uptake and is part of the standard protocol.
Option E: Option E is incorrect: cidofovir is renally cleared and nephrotoxic, with a renal — not hepatic — contraindication. Brincidofovir avoids OAT1 uptake and thereby this toxicity.
8. Brincidofovir was developed to overcome the chief limitation of cidofovir. Which statement correctly distinguishes brincidofovir from cidofovir?
A) Brincidofovir is a lipid conjugate that enters cells by lipid-mediated endocytosis rather than OAT1-mediated tubular uptake, sparing the proximal tubule while delivering active cidofovir diphosphate intracellularly
B) Brincidofovir is a wholly new pharmacophore that does not yield cidofovir or any cidofovir metabolite
C) Brincidofovir requires viral kinase activation, narrowing its spectrum compared with cidofovir
D) Brincidofovir is more nephrotoxic than cidofovir and therefore requires intensified probenecid dosing
E) Brincidofovir acts on the CMV terminase, unlike cidofovir which acts on the polymerase
ANSWER: A
Rationale:
The structural change explains both the benefit and the retained mechanism. Option A is correct: brincidofovir is a lipid (hexadecyloxypropyl) conjugate of cidofovir that enters cells via lipid endocytosis, bypassing OAT1-mediated proximal tubular uptake; intracellular phospholipases release active cidofovir diphosphate, so the antiviral mechanism is preserved while the characteristic nephrotoxicity is largely avoided.
Option B: Option B is incorrect: brincidofovir is a prodrug that delivers the active cidofovir species intracellularly.
Option C: Option C is incorrect: like cidofovir, it is activated by host (not viral) kinases, preserving broad dsDNA-virus coverage.
Option D: Option D is incorrect: the entire design rationale is reduced renal toxicity, not increased.
Option E: Option E is incorrect: brincidofovir works through the cidofovir/polymerase pathway, not the terminase. Despite its renal advantage, a phase 3 adenovirus trial in HSCT recipients did not show a survival benefit.
9. Ganciclovir and acyclovir are ineffective for established EBV-driven PTLD. Which statement precisely identifies the molecular reason?
A) PTLD B cells overexpress an efflux pump that exports both drugs before activation
B) EBV in PTLD has mutated its DNA polymerase to a drug-resistant form
C) PTLD is driven by latently infected B cells that do not express the viral thymidine kinase required to activate these nucleoside analogues, which act only on lytically replicating virus
D) The drugs penetrate lymphoid tissue poorly and never reach therapeutic concentrations
E) EBV uses an RNA genome, so DNA polymerase inhibitors are irrelevant
ANSWER: C
Rationale:
The latency-versus-lytic distinction is the crux of antiviral failure in PTLD. Option C is correct: acyclovir and ganciclovir require phosphorylation by a virally encoded thymidine kinase expressed only during lytic replication; PTLD is sustained by B cells in the latency program, which do not express viral thymidine kinase, so the drugs are never activated and cannot act — PTLD is fundamentally an immunological proliferation, not a lytic infection.
Option A: Option A is incorrect: efflux-pump export is not the mechanism.
Option B: Option B is incorrect: polymerase mutation is not why these drugs fail in PTLD; the failure is upstream at activation.
Option D: Option D is incorrect: tissue penetration is not the limiting factor.
Option E: Option E is incorrect: EBV is a double-stranded DNA herpesvirus, not an RNA virus. This is why therapy targets the B-cell reservoir and the immune deficit rather than the viral polymerase.
10. Which sequence correctly represents the standard escalation of therapy for EBV-positive PTLD, from first intervention to treatment of aggressive monomorphic disease?
A) Rituximab first, then reduction of immunosuppression, then ganciclovir
B) Ganciclovir first, then rituximab, then reduction of immunosuppression
C) R-CHOP first for all PTLD, with reduction of immunosuppression reserved for relapse
D) Reduction of immunosuppression first, then ganciclovir, then splenectomy
E) Reduction of immunosuppression first, then rituximab if inadequate, then rituximab plus chemotherapy (R-CHOP) for monomorphic disease resembling diffuse large B-cell lymphoma
ANSWER: E
Rationale:
The ordered hierarchy is a high-yield discrimination point. Option E is correct: reduction of immunosuppression is the first intervention wherever feasible (allowing EBV-specific cytotoxic T-cell recovery), rituximab (anti-CD20) is added when reduction alone is insufficient or disease progresses, and aggressive monomorphic PTLD resembling diffuse large B-cell lymphoma is treated with rituximab plus chemotherapy (R-CHOP).
Option A: Option A is incorrect: it places rituximab before reduction of immunosuppression and includes ganciclovir, which is ineffective for established PTLD.
Option B: Option B is incorrect: ganciclovir is not a PTLD treatment and reduction of immunosuppression is first, not last.
Option C: Option C is incorrect: R-CHOP is not first-line for all PTLD; early polymorphic disease often responds to reduction of immunosuppression alone.
Option D: Option D is incorrect: ganciclovir and splenectomy are not steps in the standard hierarchy. Antivirals may have a preventive role against lytic EBV in high-risk seronegative recipients but not against established PTLD.
11. A clinician relies on a negative blood CMV PCR to exclude CMV in three immunocompromised patients presenting with colitis, pneumonitis, and encephalitis respectively. Which statement about this approach is correct?
A) A negative blood CMV PCR reliably excludes tissue-invasive CMV at all sites
B) Blood CMV PCR can be negative in tissue-invasive CMV; definitive diagnosis requires site-directed sampling — colonoscopic biopsy for colitis, bronchoalveolar lavage for pneumonitis, and CSF PCR for encephalitis
C) Tissue sampling is unnecessary because serum CMV IgG confirms active disease
D) A negative blood PCR specifically rules out colitis but not pneumonitis or encephalitis
E) Antiviral therapy should always be withheld until blood PCR turns positive in these patients
ANSWER: B
Rationale:
Knowing the limits of blood PCR prevents missed tissue-invasive CMV. Option B is correct: in CMV colitis, pneumonitis, and encephalitis the virus can replicate locally without detectable viremia, so a negative blood PCR does not exclude disease; definitive diagnosis is by site-directed sampling — colonoscopy with biopsy (colitis), bronchoalveolar lavage (pneumonitis), and CSF PCR (encephalitis).
Option A: Option A is incorrect: this is precisely the dangerous assumption being tested.
Option C: Option C is incorrect: CMV IgG reflects prior exposure, not active tissue disease, and does not substitute for tissue diagnosis.
Option D: Option D is incorrect: the false-negative limitation applies across these tissue-invasive sites, not selectively to colitis.
Option E: Option E is incorrect: in a deteriorating patient with a compatible presentation, antiviral therapy should not be withheld solely while awaiting tissue results. The corollary in HSCT is distinguishing CMV colitis from GVHD before escalating corticosteroids.
12. In CMV pneumonitis complicating allogeneic HSCT, standard practice combines IV ganciclovir with intravenous immunoglobulin (IVIG) rather than using ganciclovir alone. What is the rationale for adding IVIG?
A) IVIG supplies CMV-specific neutralizing antibody that augments antiviral activity at the pulmonary mucosal surface, and combination therapy outperforms antiviral monotherapy in observational HSCT data
B) IVIG directly inhibits the CMV DNA polymerase, doubling the antiviral mechanism
C) IVIG reverses ganciclovir-induced neutropenia, permitting higher ganciclovir doses
D) IVIG eradicates latent CMV reservoirs, preventing all future reactivation
E) IVIG replaces ganciclovir entirely, since antibody alone clears established pneumonitis
ANSWER: A
Rationale:
The immunologic rationale for combination therapy is the testable point. Option A is correct: CMV pneumonitis is the most lethal CMV manifestation in allogeneic HSCT, and adding IVIG provides CMV-specific neutralizing antibodies that augment the antiviral response at the alveolar/mucosal surface; observational HSCT data show combination ganciclovir plus IVIG outperforming antiviral monotherapy, with reduction of immunosuppression as an important adjunct.
Option B: Option B is incorrect: IVIG is antibody, not a polymerase inhibitor.
Option C: Option C is incorrect: IVIG does not reverse myelosuppression (that role belongs to growth factors such as G-CSF).
Option D: Option D is incorrect: IVIG does not eradicate latent reservoirs or guarantee against reactivation.
Option E: Option E is incorrect: IVIG augments but does not replace antiviral therapy; ganciclovir remains essential. Diagnosis still requires bronchoalveolar lavage because blood CMV PCR may be negative.
13. A kidney transplant recipient with rising plasma BK viral load and biopsy-proven BK nephropathy is contrasted with a recipient who has CMV viremia. Which statement correctly distinguishes the pharmacological management of BK virus from that of CMV?
A) Both BK virus and CMV have FDA-approved first-line antivirals, differing only in dosing
B) BK virus is treated with ganciclovir while CMV is managed by reducing immunosuppression
C) Letermovir is first-line for BK virus, while CMV requires reduction of immunosuppression
D) BK virus has no approved or reliably effective antiviral, so management centers on reducing immunosuppression to restore BK-specific T-cell control, whereas CMV has effective antivirals (ganciclovir, valganciclovir, foscarnet, letermovir)
E) Both viruses are managed solely by reducing immunosuppression, with no role for antivirals in either
ANSWER: D
Rationale:
The presence or absence of effective antivirals is the defining contrast. Option D is correct: there is no FDA-approved or reliably effective antiviral for BK virus, so BK nephropathy is managed chiefly by reducing immunosuppression to restore BK-specific cytotoxic T-cell control (guided by serial plasma BK PCR), whereas CMV has multiple effective agents (ganciclovir/valganciclovir, foscarnet, cidofovir, letermovir for prophylaxis).
Option A: Option A is incorrect: BK virus lacks an approved first-line antiviral.
Option B: Option B is incorrect: ganciclovir is not active against BK virus, and CMV is not managed primarily by immunosuppression reduction alone.
Option C: Option C is incorrect: letermovir is CMV-specific and has no role against BK virus.
Option E: Option E is incorrect: CMV very much has effective antiviral therapy. Low-dose cidofovir or leflunomide are used only in refractory BK cases on limited observational evidence.
14. A patient on natalizumab for multiple sclerosis develops progressive multifocal leukoencephalopathy (PML). Which statement correctly pairs the mechanism of natalizumab-associated PML risk with the appropriate management principle?
A) Natalizumab depletes CD20 B cells, and PML is treated with high-dose cidofovir, which is proven effective for JC virus
B) Natalizumab inhibits the JC virus polymerase, and management is to increase the dose to overcome resistance
C) Natalizumab blocks alpha-4 integrin (VLA-4), preventing JC virus-specific T cells from entering the CNS; management centers on restoring immune surveillance — discontinuing natalizumab (with plasma exchange to hasten clearance) — because no antiviral, including cidofovir, has proven effective
D) Natalizumab causes marrow suppression, and PML resolves spontaneously once blood counts recover, with no need to stop the drug
E) Natalizumab directly lyses oligodendrocytes, and the treatment is intrathecal foscarnet
ANSWER: C
Rationale:
PML management is governed by immune restoration, not antiviral therapy. Option C is correct: natalizumab is an anti-alpha-4 integrin antibody that blocks VLA-4/VCAM-1 binding, preventing lymphocyte trafficking into the CNS and removing JC virus-specific cytotoxic T-cell surveillance; because no antiviral (cidofovir included) has proven effective against JC virus, management centers on restoring immunity — discontinuing natalizumab, often with plasma exchange to accelerate clearance — while watching for immune reconstitution inflammatory syndrome.
Option A: Option A is incorrect: natalizumab is not a B-cell depleter, and cidofovir is not effective for JC virus.
Option B: Option B is incorrect: natalizumab is not a polymerase inhibitor.
Option D: Option D is incorrect: natalizumab is not marrow-suppressive, and PML does not resolve spontaneously without restoring immune surveillance.
Option E: Option E is incorrect: natalizumab does not lyse oligodendrocytes, and intrathecal foscarnet is not a therapy. PML risk rises with JC virus antibody index, duration beyond 24 months, and prior immunosuppressant use.
15. A transplant recipient has a persistently very high plasma HHV-6 DNA level exceeding one million copies per milliliter that is stable across samples and unchanged by antiviral therapy, without clinical encephalitis. Which test best distinguishes inherited chromosomally integrated HHV-6 (iciHHV-6) from active HHV-6 replication?
A) Serum HHV-6 IgM titer, which is elevated only in integration
B) Repeat plasma HHV-6 PCR, since integration produces a fluctuating viral load
C) Cerebrospinal fluid HHV-6 PCR, which is negative in integration and positive in viremia
D) Plasma HHV-6 viral load trend over 48 hours, since integration declines rapidly
E) HHV-6 DNA quantification in hair follicle cells; integration is present in every nucleated cell, so hair follicles are positive in iciHHV-6 but not in true active viremia
ANSWER: E
Rationale:
The discriminating test follows directly from the biology of chromosomal integration. Option E is correct: in iciHHV-6 the viral genome is integrated into host chromosomes and is therefore present in every nucleated cell, so testing a non-blood host tissue such as hair follicle cells reveals HHV-6 DNA in integration but not in true active viremia; iciHHV-6 produces constitutively very high, treatment-unresponsive plasma DNA that mimics active replication.
Option A: Option A is incorrect: IgM serology does not distinguish integration from active infection.
Option B: Option B is incorrect: integration produces a stable, not fluctuating, high load, and repeating plasma PCR cannot separate the two.
Option C: Option C is incorrect: CSF PCR addresses CNS disease, not the integration-versus-viremia question, and may be misleading given high systemic DNA.
Option D: Option D is incorrect: integrated DNA does not decline over hours and is treatment-independent. Recognizing iciHHV-6 prevents unnecessary antiviral treatment of an asymptomatic carrier state.
16. A patient with HIV and CMV retinitis begins antiretroviral therapy. Over the next weeks the CMV viral load falls markedly and the CD4 count rises, yet the retinitis worsens with new intraocular inflammation. Which interpretation is correct, and how does it differ from treatment failure?
A) This is immune reconstitution inflammatory syndrome (IRIS): a paradoxical inflammatory worsening of a known infection as recovering immunity reacts to residual antigen — distinguished from treatment failure by the improving virologic markers (falling viral load, rising CD4), whereas failure would show a rising or non-responding viral load
B) This is antiviral resistance, confirmed by the rising CD4 count
C) This is primary treatment failure, indicated by the falling viral load
D) This is a new, unrelated opportunistic infection, since IRIS cannot affect a previously treated site
E) This is direct antiretroviral retinal toxicity and is unrelated to immune status
ANSWER: A
Rationale:
Separating IRIS from true failure changes management entirely. Option A is correct: IRIS is a paradoxical worsening of an existing or subclinical infection driven by recovering immune function reacting to residual antigen; the discriminating feature is the trajectory of virologic and immunologic markers — in IRIS the viral load falls and CD4 rises (good control) while inflammation worsens, whereas treatment failure shows a rising or non-responding viral load. CMV IRIS classically presents as worsening retinitis or uveitis and may need coordinated CMV therapy, continued antiretroviral therapy, and sometimes short-course corticosteroids.
Option B: Option B is incorrect: a rising CD4 count is not evidence of antiviral resistance.
Option C: Option C is incorrect: a falling viral load argues against, not for, treatment failure.
Option D: Option D is incorrect: IRIS characteristically flares a previously treated or subclinical site.
Option E: Option E is incorrect: the picture is immune-mediated inflammation tied to immune recovery, not direct drug toxicity. The same principle explains unmasking of EBV, adenovirus, or HHV-6 when transplant immunosuppression is reduced.
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