ION-3
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Clinical Question
In patients with Hepatitis C without cirrhosis, what is the optimal duration of ledipasvir/sofosbuvir to achieve sustained virologic response (SVR)? Does ribavirin need to be included to maximize the effect?
Bottom Line
Patients who are treated with 8 weeks of ledipasvir/sofosbuvir have similar rates of sustained virologic response to patients treated with 12 weeks of ledipasvir/sofosbuvir and 8 weeks of ledipasvir/sofosbuvir plus ribavirin. Adverse events were more common in the group who received ledipasvir/sofosbuvir plus ribavirin.
Major Points
Previously, the drug of choice for hepatitis C genotype 1 infection was sofosbuvir, an oral nucleotide analogue inhibitor of the HCV-specific NS5B polymerase. It was used in conjunction with peginterferon alfa and ribavirin for 12 weeks, or with ribavirin alone for 24 weeks. Many patients cannot tolerate interferon therapy and/or ribavirin therapy. Ledipasvir is a novel HCV NS5A inhibitor which has demonstrated antiviral activity against hepatitis genotypes 1A and 1B. It has been combined with sofosbuvir for the treatment of hepatitis C.
Prior to this trial, treatment with ledipasvir/sofosbuvir for a duration of 12 weeks was shown to be effective at achieving a high rate of sustained virologic response (SVR). Researchers wondered if treatment at a shorter duration could achieve similarly high rates of SVR. The ELECTRON trial showed that treatment with ledipasvir/sofosbuvir for a duration of only 6 weeks resulted in low SVR as well as a high relapse rate post-treatment.
In the ION-3 trial, investigators sought out to find the optimal duration of treatment for ledipasvir/sofosbuvir. In addition, they wanted to look at the effect on SVR from adding ribavirin to the ledipasvir/sofosbuvir regimen. 647 patients underwent randomization and were assigned in a 1:1:1 ratio to ledipasvir/sofosbuvir for 8 weeks, ledipasvir/sofosbuvir for 12 weeks, and ledipasvir/sofosbuvir plus ribavirin for 8 weeks. The primary endpoint of SVR was defined as an HCV RNA level of less than 25 IU per milliliter at 12 weeks after the end of therapy. The key secondary endpoint was the noninferiority of 8 weeks of ledipasvir/sofosbuvir to the other treatment regimens.
At 12 weeks after the end of treatment, the ledipasvir/sofosbuvir group had an SVR of 94% (202/215) and 95% (206/216) for the 8-week and 12-week groups, respectively. The ledipasvir/sofosbuvir plus ribavirin group had an SVR of 93% (201/216). These results indicated that treatment with ledipasvir/sofosbuvir for 8 weeks was non-inferior to the other two treatments.
A higher rate of adverse events was shown in the group treated with ledipasvir/sofosbuvir plus ribavirin group (76%, 165/216) than the ledipasvir/sofosbuvir groups for 8 weeks (67%, 145/215) and 12 weeks (69%, 149/216).
These findings showed that the optimal duration of treatment with ledipasvir/sofosbuvir was 8 weeks. It also showed that co-administering ribavirin provided no additional benefit in SVR, and actually led to an increase in adverse events.
Design
- Multicenter, randomized, open-label trial
- N=647
- Ledipasvir/sofosbuvir:for 8 weeks: 215
- Ledipasvir/sofosbuvir for 12 weeks: 216
- Ledipasvir/sofosbuvir plus ribavirin for 8 weeks: 216
- Setting: 58 sites in the United States
- Enrollment: May 20, 2013--June 19, 2014
- Mean follow-up: 12 weeks
- Analysis: Kruskal-Wallis test used to test for overall differences in continuous data between treatment groups. Cochran-Mantel-Haenszel test used to test for overall differences in categorical data between treatment groups.
- Primary endpoint: HCV RNA level of less than 25 IU per mL at 12 weeks after the end of therapy
- Secondary endpoint: non-inferiority of 8 weeks of ledipasvir/sofosbuvir to the other treatment groups
Population
Inclusion Criteria
- 18+ years of age
- Chronic HCV Genotype 1 Infection
- HCV RNA level of at least 104 IU per milliliter at the time of screening
- ALT and AST no more than 10x ULN
- Platelet count greater than 90,000 per cubic millimeter
- Hemoglobin level of at least 11 g/dL in females and 12 g/dL in males
Exclusion Criteria
- Liver cirrhosis
- Previous treatment for HCV infection
Baseline Characteristics
Presented in order of LDV/SOF 8 weeks, LDV/SOF 12 weeks, LDV/SOF+RIB 8 weeks
- Age (Means): 53, 53, 51
- BMI (Means): 28, 28, 28
- Male (%): 60, 59, 54
- White Race (%): 76, 77, 81
- Black Race (%): 21, 19, 17
- HCV Genotype 1A (%): 80, 80, 80
- HCV Genotype 1B (%): 20, 20, 20
- HCV RNA log10IU/mL: 6.5 ± 0.8, 6.4 ± 0.8, 6.4 ± 0.7
- HCV RNA > 800,000 IU/mL (%): 84, 80, 79
- IL28B genotype CC (%): 26, 26, 28
- IL28B genotype CT (%): 56, 57, 59
- IL28B genotype TT (%): 18, 17, 13
- ALTs > 1.5x ULN (%): 40, 46, 44
- Fibrosis Score F0-F3 (%): 73, 72, 63
- Fibrosis Score F0-F2 (%): 59, 59, 50
- Fibrosis Score F3 (%): 13, 13, 13
- Eligible for Interferon (%): 94, 94, 94
Interventions
- Randomization to a group:
- Ledipasvir/Sofosbuvir 90/400 mg daily for 8 weeks
- Ledipasvir/Sofosbuvir 90/400 mg daily for 12 weeks
- Ledipasvir/Sofosbuvir 90/400 mg daily plus Ribavirin BID for 8 weeks
- Ribavirin TDD 1000 mg if TBW <75 kg, TDD 1200 mg if TBW ≥ 75 kg
Outcomes
Primary Outcomes
- HCV RNA level of less than 25 IU per mL at 12 weeks after the end of therapy
- All treatment groups met this outcome. SVRs were as follows:
- Ledipasvir/sofosbuvir for 8 weeks: 94%, (95% CI 90% - 97%)
- Ledipasvir/sofosbuvir for 12 weeks: 95%, (95% CI 92% - 98%)
- Ledipasvir/sofosbuvir plus ribavirin for 8 weeks: 93%, (95% CI 89% - 96%)
Secondary Outcomes
- Secondary analysis of noninferiority
- Rate of SVR among patients who received 8 weeks of ledipasvir/sofosbuvir was noninferior to the SVR in the two other treatment groups.
- Lower boundaries of the confidence intervals for the difference in proportions between the groups were greater than the predetermined noninferiority margin of -12 percentage points.
Other Outcomes
Presented in order of LDV/SOF 8 weeks, LDV/SOF 12 weeks, LDV/SOF+RIB 8 weeks
- Virologic Failure During Treatment (%): 0, 0, 0
- Relapse in patients with HCV RNA <25 IU/mL at end of treatment (%): 5, 1, 4
- Lost to follow up (number): 1, 7, 5
- Withdrew consent (number): 1, 0, 1
Adverse Events
Presented in order of LDV/SOF 8 weeks, LDV/SOF 12 weeks, LDV/SOF+RIB 8 weeks
- Discontinuation due to adverse event (%): 0, 1 <1
- Serious adverse event (%): 2, 2, <1
- Any adverse event (%): 67, 69, 76
- Common adverse events
- Fatigue (%): 21, 23, 35
- Headache (%): 14, 15, 25
- Nausea (%): 7, 11, 18
- Insomnia (%): 5, 7, 12
- Irritability (%): 1, 4, 13
- Diarrhea (%): 7, 4, 6
- Arthralgia (%): 4, 7, 5
- Constipation (%): 4, 4, 6
- Dizziness (%): 3, 4, 6
- Rash (%): 1, 2, 9
- Pruritis (%): 1, 2, 7
- Cough (%): 1, 3, 6
- Anemia (%): 1, 1, 8
- Muscle Spasms (%): 1, 3, 5
- Dyspnea (%): 0, <1, 5
- Hematologic Abnormalities
- Hemoglobin levels < 10 g/dL (%): 0, <1, 5
- Lymphocyte count 350 to <500 per mm3 (%): 0, 0, <1
- Neutrophil count 500 to <750 per mm3 (%): 0, <1, <1
Criticisms
- The study did not include patients with cirrhosis. Current treatment guidelines may indicate a need for increased treatment durations in this patient population.
- In the past, patients with Hepatitis C have been treated with pegylated interferon and ribavirin. It is unknown whether conclusions of this study can be extended to patients who are treatment-experienced with these medications.
- Allocation concealment unclear.
- Gilead Sciences, the maker of the drug, funded the study and was considered the main sponsor. Gilead was also instrumental in the study design and conduction. The drug company also created the study protocol, collected data, and performed statistical analyses.
Further Reading
1. Afdhal, N et al. Ledipasvir and Sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014. 370(20): 1889-1898.
2. Afdhal, N et al. Ledipasvir and Sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014. 370(16): 1483-1493.