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In addition to improved efficacy, one of the key advantages of interferon-free DAA-based regimens is markedly improved tolerability. However, adverse events that necessitate discontinuation of treatment can occur infrequently. Early recognition and intervention can help clinicians ensure patients are able to complete therapy where possible and achieve the goal of viral eradication. Although every patient will experience adverse effects to differing degrees, a systematic approach to their management can be very helpful.
The most common adverse effects seen in phase III trials evaluating use of daclatasvir in combination with other antiviral agents were fatigue, headache, and nausea.[29,42] Discontinuation of treatment for toxicity in these trials was infrequent.
Coadministration of amiodarone with sofosbuvir and another DAA, including daclatasvir, may result in serious symptomatic bradycardia and is not recommended.
The most common adverse events in patients treated with ledipasvir/sofosbuvir in phase III trials were fatigue, headache, and asthenia. Other reported adverse events included nausea, diarrhea, and insomnia. Most adverse events were mild in severity. Among patients treated with ledipasvir/sofosbuvir for 8-24 weeks in the phase III ION-1, -2, and -3 trials, ≤ 1% permanently discontinued therapy because of adverse events.[39-41]
Cases of hyperbilirubinemia were also reported in phase III trials, with higher rates in ribavirin-containing treatment arms. In the ION-1 trial, severe hyperbilirubinemia (> 2.5 times the upper limit of normal) developed in 4% of patients in the 12-week ribavirin-containing arm and 3% of patients in the 24-week ribavirin-containing arm. One patient with Gilbert’s syndrome experienced hyperbilirubinemia in the 12-week ledipasvir/sofosbuvir arm. Grade 1/2 hyperbilirubinemia developed in 32% to 41% of patients treated with ledipasvir/sofosbuvir plus ribavirin and in 1% to 7% of patients treated with ledipasvir/sofosbuvir alone in the ION-2 trial.  In the ION-3 trial, 1% of patients in the 8-week ledipasvir/sofosbuvir plus ribavirin arm developed grade 3 hyperbilirubinemia.
Coadministration of ledipasvir/sofosbuvir with amiodarone may result in serious symptomatic bradycardia. Use of ledipasvir/sofosbuvir with amiodarone is not recommended.
Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir
The FDA prescribing information states that ombitasvir/paritaprevir/ritonavir plus dasabuvir and ombitasvir/paritaprevir/ritonavir are contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C).[14,16] This contraindication is based on reports of hepatic decompensation and liver failure, including some cases requiring liver transplantation or resulting in death among patients receiving ombitasvir/paritaprevir/ritonavir-containing regimens. Patients who experienced these severe outcomes had evidence of advanced cirrhosis before beginning treatment.
The most common adverse events reported in phase III trials of ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin were fatigue, nausea, pruritus, other skin reactions, insomnia, and asthenia. In patients receiving ombitasvir/paritaprevir/ritonavir plus dasabuvir without ribavirin, the most common adverse events were nausea, pruritus, and insomnia.
Among patients treated with ombitasvir/paritaprevir/ritonavir plus dasabuvir with ribavirin for 12 weeks in the phase III SAPPHIRE-I and -II trials, ≤ 1% permanently discontinued therapy because of adverse events.
The FDA prescribing information states that elbasvir/grazoprevir is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C) based on the expectation that grazoprevir plasma concentrations would be markedly increased in this population, resulting in an increased risk for ALT elevations.
The most common adverse events in patients treated with elbasvir/grazoprevir for 12 weeks in phase III trials were fatigue, headache, and nausea. Most adverse events were mild in severity. When elbasvir/grazoprevir was administered with ribavirin for 16 weeks in clinical trials, the most common adverse events of moderate or severe grade were anemia and headache. Other reported adverse events included fatigue, dyspnea, and rash or pruritus.
Occasional late increases in ALT levels (> 5 times the upper limit of normal) after 4-10 weeks of elbasvir/grazoprevir therapy have been observed in clinical trials.[124,126] Increased ALT levels did not occur in parallel with increases in bilirubin, and the elevated ALT levels resolved after discontinuing elbasvir/grazoprevir therapy. In clinical trials, higher rates of late ALT increases occurred in women, Asian patients, and patients aged 65 years or older, but dose adjustment is not recommended for these patient groups. Hepatic laboratory testing is recommended before starting therapy, at treatment Week 8, and as clinically indicated. For patients receiving elbasvir/grazoprevir for 16 weeks, aminotransferase testing should also be performed at Week 12. Elbasvir/grazoprevir should be discontinued if the ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or international normalized ratio.
Among treatment-naive patients given elbasvir/grazoprevir for 12 weeks in the phase III C-EDGE TN study, the treatment was generally well tolerated in both cirrhotic and noncirrhotic patients, with 1% of patients discontinuing treatment due to adverse events. Treatment-experienced patients who received elbasvir/grazoprevir plus ribavirin for 16 weeks in the C-EDGE TE trial had a greater risk of anemia (incidence: 16.0% vs 0% for patients receiving elbasvir/grazoprevir alone for 12 or 16 weeks). Among patients receiving elbasvir/grazoprevir plus ribavirin, serious adverse events occurred in 3.8% of patients, and 4.7% of patients discontinued treatment for adverse events. Among patients receiving elbasvir/grazoprevir alone for 12 weeks, 3.8% also reported a serious adverse event and 1.0% discontinued treatment because of an adverse event.
The most frequent adverse events occurring in > 10% of patients treated with sofosbuvir/velpatasvir are headache and fatigue. In phase III clinical trials, few serious adverse events and discontinuations for adverse events were reported. In the ASTRAL-1 trial of sofosbuvir/velpatasvir in patients with genotype 1, 2, 4, 5, or 6 HCV infection, including 19% with cirrhosis, there was no significant difference in rates of adverse events between patients receiving sofosbuvir/velpatasvir vs placebo, and the most common adverse events were headache, fatigue, nasopharyngitis, and nausea. In the sofosbuvir/velpatasvir arm, 2% of patients reported a serious adverse event with none of these events occurring in more than 1 patient. One patient with genotype 1a HCV infection discontinued therapy because of an anxiety attack on Day 13 of treatment with sofosbuvir/velpatasvir. One percent or fewer patients experienced a hematologic abnormality with sofosbuvir/velpatasvir. One patient with genotype 5a HCV infection, no cirrhosis, and a history of dyslipidemia died 8 days posttreatment, and the cause of death was not determined.
In the ASTRAL-2 and ASTRAL-3 trials of sofosbuvir/velpatasvir in patients with genotype 2 and genotype 3 HCV infection, respectively, rates of adverse events were lower in patients receiving sofosbuvir/velpatasvir vs those receiving sofosbuvir plus ribavirin. The most common events reported were fatigue, headache, and nausea. Serious adverse events occurred in 1% of patients with genotype 2 HCV infection and 2% of patients with genotype 3 HCV infection receiving sofosbuvir/velpatasvir. One patient with genotype 2 HCV infection discontinued sofosbuvir/velpatasvir treatment because of anxiety, headache, and difficulty concentrating and no patients with genotype 3 HCV infection receiving this combination discontinued treatment for an adverse event. Two patients with genotype 2 HCV infection died during posttreatment follow-up. One woman died from cardiac arrest, and 1 man died from complications of metastatic lung cancer.
The most common adverse events reported in the ASTRAL-4 trial of patients with genotype 1-6 HCV infection and decompensated cirrhosis receiving either sofosbuvir/velpatasvir for 12 weeks, sofosbuvir/velpatasvir plus ribavirin for 12 weeks, or sofosbuvir/velpatasvir for 24 weeks were fatigue, nausea, and headache. Anemia, diarrhea, and insomnia were also common in the group receiving sofosbuvir/velpatasvir plus ribavirin. Nine patients discontinued treatment for an adverse event: 1 (1%) in the group receiving sofosbuvir/velpatasvir for 12 weeks, 4 (5%) in the group receiving sofosbuvir/velpatasvir plus ribavirin for 12 weeks, and 4 (4%) in the group receiving sofosbuvir/velpatasvir for 24 weeks. Serious adverse events were reported in 16% to 19% of patients in all arms, with the most common serious adverse events being hepatic encephalopathy and sepsis, each of which occurred in 5 patients in each arm. Reduced levels of hemoglobin, lymphocytes, and platelets were common in all arms.
The most frequent adverse events occurring in ≥ 10% of patients treated with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir are headache, fatigue, diarrhea, and nausea. In phase III clinical trials, few serious adverse events and discontinuations for adverse events were reported. In the POLARIS-1 trial of sofosbuvir/velpatasvir/voxilaprevir in patients with genotype 1-6 HCV infection previously treated with an NS5A inhibitor, including 46% with compensated cirrhosis, rates of adverse events for patients receiving sofosbuvir/velpatasvir/voxilaprevir vs placebo were 78% and 70%, respectively. The most common events reported were headache, fatigue, diarrhea, and nausea. In the sofosbuvir/velpatasvir/voxilaprevir arm, 5 of 263 (2%) patients reported 7 serious adverse events, although no specific serious adverse event occurred in more than 1 patient. One patient receiving concomitant ramipril for hypertension discontinued sofosbuvir/velpatasvir/voxilaprevir because of angioedema on Day 12. No more than 5% of patients experienced a grade 3/4 laboratory abnormality with sofosbuvir/velpatasvir/voxilaprevir, and no patients died in either arm.
In the POLARIS-4 trial of sofosbuvir/velpatasvir/voxilaprevir in patients with genotype 1-4 HCV infection previously treated with DAAs but not with NS5A inhibitors, rates of adverse events were comparable between patients receiving the triple coformulation (77%) vs those receiving only sofosbuvir/velpatasvir (74%). The most common adverse events reported were headache, fatigue, and diarrhea. Identical to POLARIS-1, serious adverse events and grade 3/4 laboratory abnormalities occurred in 2% and ≤ 5% of patients receiving sofosbuvir/velpatasvir/voxilaprevir, respectively. No patients discontinued sofosbuvir/velpatasvir/voxilaprevir treatment because of adverse events, but 1 patient died 2 days after HCV treatment completion from an illicit drug overdose.
The most frequent adverse events occurring in ≥ 5% of patients treated with 8-16 weeks of glecaprevir/pibrentasvir are headache, fatigue, and nausea, and 80% of observed events were grade 1 in severity. The type and severity of adverse events did not differ by treatment duration or presence of compensated cirrhosis. In the phase III ENDURANCE series of clinical trials in noncirrhotic patients, few serious adverse events (< 1% to 2%) and discontinuations (0% to 3%) for adverse events were reported.[130,182,183] Likewise, in patients with compensated cirrhosis, serious adverse event rates ranged from 4% to 8%, and no discontinuations for adverse events were observed.[135,136] Overall, few patients experienced laboratory abnormalities, although total bilirubin elevations ≥ 2 times the upper limit of normal were observed in 1.2% of patients across clinical trials. Because glecaprevir/pibrentasvir inhibits OATP1B1/3 and UGT1A1, bilirubin metabolism may be transiently affected during regimen administration with recovery of total bilirubin levels after therapy completion.