Chapter 36 — Antiviral Pharmacology — Module 4 — Hepatitis B and C Pharmacology
1. A 59-year-old man with chronic hepatitis B has been on lamivudine monotherapy for nine years. Over the past six months his HBV DNA has risen from undetectable to 240,000 IU/mL and his ALT is now twice the upper limit of normal. Genotypic resistance testing reports rtM204V plus rtL180M. His eGFR is 84 mL/min/1.73m² and he has no bone disease. What is the most appropriate change in therapy?
A) Continue lamivudine and add entecavir at the standard dose
B) Discontinue lamivudine and switch to tenofovir-based therapy
C) Switch to entecavir monotherapy
D) Add adefovir dipivoxil to the lamivudine
E) Switch to peginterferon alfa-2a for a finite course
ANSWER: B
Rationale:
The rtM204V plus rtL180M pattern with rising HBV DNA confirms lamivudine resistance with virologic breakthrough. Tenofovir disoproxil fumarate or tenofovir alafenamide retains full activity against lamivudine-resistant HBV and is the appropriate switch; with a normal eGFR and no bone disease, either formulation is reasonable.
Option A: Option A is incorrect: the lamivudine-resistance mutations sharply lower the entecavir resistance barrier, so adding standard-dose entecavir on this background risks rapid entecavir resistance, and continuing lamivudine maintains failed selective pressure.
Option C: Option C is incorrect: entecavir monotherapy is specifically contraindicated on a lamivudine-resistant background for the same reason.
Option D: Option D is incorrect: adefovir has a low resistance barrier and dose-limiting nephrotoxicity and is no longer a preferred salvage agent; tenofovir is superior.
Option E: Option E is incorrect: switching a patient with active virologic breakthrough to finite peginterferon is not the indicated maneuver; potent suppressive therapy with tenofovir is needed.
2. A 48-year-old woman with genotype 1 hepatitis C virus infection is scheduled to begin sofosbuvir/velpatasvir next week. Pretreatment testing returns hepatitis B surface antigen (HBsAg) positive, hepatitis B e antigen (HBeAg) negative, and an HBV deoxyribonucleic acid (DNA) of 900 IU/mL. She is currently on no hepatitis B therapy. What is the most appropriate management before and during her HCV treatment?
A) Proceed with the direct-acting antiviral and recheck HBV DNA only if her ALT rises
B) Delay HCV therapy indefinitely until HBsAg clears spontaneously
C) Give hepatitis B immune globulin once at the start of HCV therapy
D) Treat the hepatitis C and withhold any hepatitis B therapy unless jaundice develops
E) Start tenofovir-based therapy with or before the direct-acting antiviral and continue it for at least 12 weeks after HCV treatment ends
ANSWER: E
Rationale:
She is HBsAg-positive and not on HBV-active therapy, placing her at risk of HBV reactivation — potentially acute liver failure — when HCV is cleared. The correct approach is to start tenofovir disoproxil fumarate or tenofovir alafenamide with or before the DAA and continue it for at least 12 weeks after completing HCV treatment.
Option A: Option A is incorrect: waiting for an ALT rise risks reactivation hepatitis or acute liver failure; preemptive HBV therapy is required.
Option B: Option B is incorrect: HCV should be treated with concurrent HBV coverage, not deferred indefinitely.
Option C: Option C is incorrect: hepatitis B immune globulin is not the strategy for preventing reactivation during DAA therapy; suppressive antiviral therapy is.
Option D: Option D is incorrect: a HBsAg-positive patient needs preemptive HBV-active therapy rather than watchful waiting for jaundice.
3. A 54-year-old man with genotype 3 hepatitis C virus infection has compensated cirrhosis (Child-Pugh A) confirmed on elastography. He is treatment-naive and has never received an NS5A inhibitor. His renal function is normal. Recognizing that this is among the most difficult contemporary HCV scenarios, which regimen offers him the best chance of cure where it is available?
A) Sofosbuvir/velpatasvir for 8 weeks
B) Ledipasvir/sofosbuvir for 12 weeks
C) Sofosbuvir/velpatasvir/voxilaprevir for 12 weeks
D) Elbasvir/grazoprevir for 16 weeks with ribavirin
E) Peginterferon plus ribavirin for 24 weeks
ANSWER: C
Rationale:
Genotype 3 with cirrhosis is the most challenging contemporary HCV scenario, where sofosbuvir/velpatasvir alone achieves only about 88 to 91% sustained virological response. Adding the protease inhibitor voxilaprevir — sofosbuvir/velpatasvir/voxilaprevir for 12 weeks — is preferred in NS5A-inhibitor-naive genotype 3 cirrhotic patients where available, maximizing the chance of cure.
Option A: Option A is incorrect: 8 weeks of sofosbuvir/velpatasvir is inadequate for genotype 3 with cirrhosis.
Option B: Option B is incorrect: ledipasvir/sofosbuvir has limited activity against genotype 3 and is inappropriate here.
Option D: Option D is incorrect: elbasvir/grazoprevir covers genotypes 1 and 4, not genotype 3.
Option E: Option E is incorrect: interferon-based therapy is obsolete, more toxic, and inferior to modern direct-acting antivirals for this patient.
4. A 61-year-old man with genotype 2 hepatitis C virus infection has end-stage renal disease and receives maintenance hemodialysis three times weekly. He has no cirrhosis. He takes no statins and has no significant drug interactions. Which regimen is preferred for him, and on what pharmacologic basis?
A) Glecaprevir/pibrentasvir, because both components are biliary-excreted and avoid the renal accumulation that limits sofosbuvir in dialysis
B) Sofosbuvir/velpatasvir, because sofosbuvir is safely dialyzed at every session
C) Ledipasvir/sofosbuvir, because ledipasvir compensates for impaired sofosbuvir clearance
D) Sofosbuvir monotherapy, because a single agent minimizes dialysis-related interactions
E) Peginterferon plus ribavirin, because neither requires renal dosing
ANSWER: A
Rationale:
In a dialysis patient, glecaprevir/pibrentasvir is preferred because both components are primarily biliary-excreted and neither depends on renal elimination, avoiding the metabolite-accumulation concern that limits sofosbuvir below an eGFR of 30 mL/min/1.73m². It is approved at standard doses across genotypes, including in hemodialysis, with high sustained virological response rates.
Option B: Option B is incorrect: sofosbuvir's renally eliminated metabolite raises accumulation concerns at very low eGFR, and reliance on dialysis to clear it is not the basis for preferring this regimen.
Option C: Option C is incorrect: ledipasvir does not correct impaired sofosbuvir clearance, and this combination still contains sofosbuvir.
Option D: Option D is incorrect: sofosbuvir is never used as monotherapy and is renally cleared, making it inappropriate here.
Option E: Option E is incorrect: ribavirin is renally eliminated and causes hemolytic anemia in dialysis patients, and interferon-based therapy is obsolete.
5. A 66-year-old woman with genotype 1 hepatitis C virus infection has decompensated cirrhosis (Child-Pugh class C) with ascites and prior hepatic encephalopathy. She is being evaluated for liver transplantation. Her renal function is adequate. Which antiviral approach is appropriate, and which must be avoided?
A) Glecaprevir/pibrentasvir for 8 weeks
B) Sofosbuvir/velpatasvir/voxilaprevir for 12 weeks
C) Elbasvir/grazoprevir for 12 weeks
D) Sofosbuvir/velpatasvir with or without ribavirin for 12 to 24 weeks, avoiding protease-inhibitor-containing regimens
E) Any pangenotypic protease-inhibitor regimen, since decompensation does not affect drug levels
ANSWER: D
Rationale:
In decompensated cirrhosis (Child-Pugh B or C), NS3/4A protease inhibitors are contraindicated because their plasma concentrations rise dramatically in hepatic impairment, increasing toxicity. The preferred approach is sofosbuvir/velpatasvir with or without ribavirin for 12 to 24 weeks, with transplant evaluation proceeding in parallel.
Option A: Option A is incorrect: glecaprevir is a protease inhibitor and is contraindicated in decompensated cirrhosis.
Option B: Option B is incorrect: voxilaprevir is also a protease inhibitor, so this triple regimen is contraindicated here.
Option C: Option C is incorrect: grazoprevir is a protease inhibitor and likewise contraindicated in Child-Pugh C disease.
Option E: Option E is incorrect: hepatic decompensation markedly raises protease inhibitor concentrations, so these regimens are not safe in this setting.
6. A 43-year-old man with HIV/hepatitis C virus (HCV) co-infection has an undetectable HIV viral load on atazanavir boosted with ritonavir plus tenofovir/emtricitabine. He is genotype 1 HCV without cirrhosis, and the team plans glecaprevir/pibrentasvir. The pharmacist flags a contraindication with his antiretroviral regimen. What is the most appropriate next step before starting HCV therapy?
A) Halve the glecaprevir/pibrentasvir dose to compensate for the interaction
B) Switch the boosted atazanavir to an integrase inhibitor such as dolutegravir, keeping the tenofovir backbone, then start glecaprevir/pibrentasvir
C) Continue atazanavir/ritonavir and monitor liver enzymes weekly during HCV therapy
D) Stop the tenofovir backbone for the duration of HCV treatment
E) Add ribavirin to neutralize the antiretroviral interaction
ANSWER: B
Rationale:
Glecaprevir is a sensitive CYP3A4 substrate, and ritonavir-boosted atazanavir raises glecaprevir exposure roughly 6-fold, making the combination contraindicated. Switching to an integrase inhibitor such as dolutegravir (which has minimal interaction) while keeping the tenofovir/emtricitabine backbone — which also covers any HBV — allows glecaprevir/pibrentasvir to be used safely.
Option A: Option A is incorrect: glecaprevir/pibrentasvir is a fixed-dose combination not designed for dose reduction, and halving it would not reliably correct the interaction.
Option C: Option C is incorrect: the interaction is formally contraindicated, so continuing it with monitoring is unsafe.
Option D: Option D is incorrect: stopping the tenofovir backbone removes HBV protection and does not address the protease-inhibitor interaction.
Option E: Option E is incorrect: ribavirin does not alter this pharmacokinetic interaction.
7. A 31-year-old woman with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B has HBV genotype A, an alanine aminotransferase (ALT) three times the upper limit of normal, a relatively low HBV deoxyribonucleic acid (DNA) level, and no cirrhosis. She wishes to avoid indefinite oral therapy and asks about a finite-duration option with a chance of lasting off-treatment control. Which therapy best fits her profile, and why?
A) Lamivudine, because its low resistance barrier suits short courses
B) Tenofovir alafenamide indefinitely, because finite therapy is never appropriate in HBeAg-positive disease
C) Adefovir dipivoxil, because it favors HBeAg seroconversion
D) Entecavir for 12 weeks, then stop, because its triple mechanism allows finite dosing
E) Peginterferon alfa-2a, because her favorable predictors make durable off-treatment HBeAg seroconversion achievable with a finite course
ANSWER: E
Rationale:
She has multiple favorable predictors of peginterferon response — genotype A, high baseline ALT, low baseline HBV DNA — and no contraindication such as cirrhosis. Peginterferon alfa is the only HBV therapy capable of inducing durable off-treatment responses including HBeAg seroconversion, making a finite course a reasonable, profile-matched choice.
Option A: Option A is incorrect: lamivudine's low resistance barrier is a liability, not a rationale for short courses, and it does not provide durable immune-mediated control.
Option B: Option B is incorrect: finite peginterferon therapy is in fact appropriate for selected HBeAg-positive patients with favorable predictors.
Option C: Option C is incorrect: adefovir is an outdated low-barrier nucleotide analogue and is not an immune-based finite therapy.
Option D: Option D is incorrect: entecavir is a suppressive nucleoside analogue requiring continued use; stopping at 12 weeks would allow viral rebound, and its mechanism does not enable finite cure.
8. A 29-year-old man who injects drugs achieved sustained virological response at 12 weeks (SVR12) after treatment of genotype 1a hepatitis C virus 14 months ago. At a routine visit his HCV ribonucleic acid (RNA) is again detectable, and genotyping now identifies genotype 3. He has ongoing injection exposure. How should this be interpreted and managed?
A) This is reinfection with a new strain; the prior SVR12 still stands, and he should be retreated following treatment-naive principles
B) This represents failure of the original regimen, which should be permanently abandoned
C) This is relapse of the original genotype 1a infection requiring resistance testing of the prior strain
D) This indicates the original SVR12 was invalid and must be retracted
E) This means HCV cure is no longer possible and he requires indefinite suppressive therapy
ANSWER: A
Rationale:
Detectable HCV RNA after a genuine SVR12 in a person with ongoing exposure — especially with a different genotype — is reinfection with a genetically distinct strain, not relapse or treatment failure. The earlier SVR12 remains valid, and retreatment follows treatment-naive principles, with a pangenotypic regimen appropriate for the new genotype 3 infection.
Option B: Option B is incorrect: a new-genotype infection reflects reinfection, not failure of the regimen that cured the original strain.
Option C: Option C is incorrect: a different genotype indicates reinfection rather than relapse of the genotype 1a strain.
Option D: Option D is incorrect: a true SVR12 is not invalidated by subsequent reinfection.
Option E: Option E is incorrect: HCV reinfection remains curable with standard finite direct-acting antiviral therapy.
9. A 50-year-old woman with genotype 1a hepatitis C virus infection and stage 4 chronic kidney disease is being considered for elbasvir/grazoprevir, which is attractive because both components are hepatically eliminated. Before prescribing, baseline nonstructural protein 5A (NS5A) resistance-associated substitution (RAS) testing returns positive at position 93. What does this finding require?
A) Switching to sofosbuvir monotherapy because RAS abolishes elbasvir activity
B) No change, because NS5A RAS do not affect elbasvir/grazoprevir outcomes
C) Extending treatment to 16 weeks and adding ribavirin to preserve efficacy against the resistant virus
D) Abandoning all direct-acting antiviral therapy because cure is no longer achievable
E) Immediately reducing the grazoprevir dose to account for the resistant strain
ANSWER: C
Rationale:
In genotype 1a, baseline NS5A RAS at positions such as 28, 30, 31, or 93 reduce the efficacy of elbasvir/grazoprevir because NS5A inhibitors have a lower resistance barrier. When relevant RAS are present, guidelines call for extending treatment to 16 weeks and adding ribavirin to preserve the chance of cure.
Option A: Option A is incorrect: a single NS5A RAS does not abolish activity, and sofosbuvir monotherapy is never used and would be problematic in stage 4 chronic kidney disease.
Option B: Option B is incorrect: NS5A RAS meaningfully affect elbasvir/grazoprevir in genotype 1a, which is exactly why testing is required.
Option D: Option D is incorrect: cure remains achievable with the extended-duration, ribavirin-containing regimen.
Option E: Option E is incorrect: the response to baseline RAS is extended duration with ribavirin, not a grazoprevir dose reduction.
10. A 38-year-old man is newly diagnosed with HIV, chronic hepatitis B virus (HBV), and hepatitis C virus (HCV) infection. His CD4 count is 130 cells/mm³ and he is antiretroviral-naive. The team must decide what to prioritize. What is the most appropriate initial sequencing strategy?
A) Begin HCV direct-acting antiviral therapy first and defer all HIV treatment until HCV is cured
B) Treat HBV alone first and withhold both HIV and HCV therapy until HBV DNA is undetectable
C) Start peginterferon to address HIV, HBV, and HCV together
D) Start antiretroviral therapy to suppress HIV and allow immune reconstitution first — using a tenofovir-based backbone that simultaneously covers HBV — then treat HCV with a compatible regimen
E) Cure HCV, then switch to an HBV-inactive antiretroviral regimen to simplify therapy
ANSWER: D
Rationale:
With advanced immunodeficiency (CD4 below 200 cells/mm³), antiretroviral therapy should be optimized and HIV suppressed first, allowing immune reconstitution, which itself improves HCV outcomes. A tenofovir-based backbone simultaneously suppresses HBV. Once HIV is controlled, HCV is treated with an antiretroviral-compatible regimen, and the HBV-active backbone is continued indefinitely.
Option A: Option A is incorrect: deferring HIV therapy at a CD4 of 130 cells/mm³ is unsafe; HIV suppression takes priority.
Option B: Option B is incorrect: HBV is covered by the antiretroviral backbone alongside HIV therapy, so isolating HBV treatment while withholding HIV therapy is inappropriate.
Option C: Option C is incorrect: peginterferon is not a unified therapy for all three viruses and is not the correct sequencing strategy.
Option E: Option E is incorrect: switching to an HBV-inactive regimen after HCV cure is the classic catastrophic error that precipitates HBV reactivation.
11. A 57-year-old man with genotype 2 hepatitis C virus infection is starting sofosbuvir/velpatasvir. He takes omeprazole 40 mg twice daily for severe gastroesophageal reflux disease and is reluctant to stop it. What is the most appropriate way to manage his acid suppression during HCV therapy?
A) Continue omeprazole 40 mg twice daily and take it 4 hours after the antiviral
B) Reduce omeprazole to an omeprazole-equivalent of 20 mg once daily and take it simultaneously with sofosbuvir/velpatasvir
C) Switch to a higher proton pump inhibitor dose to ensure adequate absorption of velpatasvir
D) Stop all acid suppression permanently before initiating the antiviral
E) Replace the proton pump inhibitor with continuous intravenous acid suppression during treatment
ANSWER: B
Rationale:
Velpatasvir absorption is pH-dependent and is reduced when gastric pH rises. The recommended management is to limit the proton pump inhibitor to an omeprazole-equivalent of 20 mg and take it simultaneously with sofosbuvir/velpatasvir, which preserves adequate velpatasvir exposure without abandoning needed reflux control.
Option A: Option A is incorrect: high-dose omeprazole produces sustained acid suppression across the day, so taking it hours apart does not restore the acidity needed for velpatasvir absorption.
Option C: Option C is incorrect: raising the proton pump inhibitor dose further reduces velpatasvir absorption, the opposite of what is needed.
Option D: Option D is incorrect: acid suppression need not be stopped permanently; a limited, simultaneously dosed proton pump inhibitor is acceptable.
Option E: Option E is incorrect: intravenous acid suppression still raises gastric pH and does not solve the absorption problem; dose limitation with simultaneous administration is the correct approach.
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