17 Apr Hepatitis C: Triple DAA Plus Ribavirin Highly Effective for Genotype 1 Infections
MedicalResearch.com: What are the main findings of the study?
Dr. Feld: The SAPPHIRE 1 study was an international, large (631 patients) Phase 3 study of 3 direct acting antivirals combined with ribavirin for 12 weeks for the treatment of patients with genotype 1 hepatitis C virus (HCV) infection without cirrhosis. The antivirals used were ABT-450, which is a protease inhibitor that is boosted with ritonovir to allow for once daily dosing along with ombitasvir (formally ABT 267), a potent NS5A inhibitor and dasabuvir (formerly known as ABT 333), a non-nucleoside polymerase inhibitor. The ABT-450, ritonovir and ombitasvir were all co-formulated into a single tablet and dasabuvir was taken twice daily, as was ribavirin. The results of the study showed that the treatment is highly effective with 96% of patients achieving a sustained virological response (SVR) at 12 weeks after completing treatment. SVR is a cure of HCV infection. Importantly, patients with genotypes 1a and 1b had similar results with a rate of SVR12 of 95% in genotype 1a and 98% in genotype 1b. These results were clearly superior to a historical control treatment with telaprevir combined with peginterferon and ribavirin. Baseline factors were not predictive of outcome, including factors associated with non-response to interferon such as the IL28B genotype, baseline HCV viral load and older age.
One unique thing about this study was the inclusion of a placebo arm. Patients were randomized (3:1) to active treatment or a placebo for 12 weeks. All placebo-treated patients received active treatment for 12 weeks as soon as they completed the placebo course. The inclusion of a placebo arm allows for a true evaluation of the safety and tolerability of the treatment. The regimen proved to be very well tolerated. Although 87% of patients reported an adverse event of some type on treatment, 73% of those treated with placebo also reported at least one side effect. The most common side effects, fatigue and headache, were equally frequent in the placebo and active treatment groups. Nausea, pruritus (itch), diarrhea and insomnia were reported more frequently in the treatment arm but side effects were generally very mild with only 3 patients (0.6%) stopping therapy due to an adverse event. Some of these side effects were likely due to the inclusion of ribavirin in the regimen, however in general ribavirin was well tolerated without the addition of peginterferon, with only 5.8% of patients experiencing grade 2 anemia. Transient bilirubin elevations were seen in 2.8% of patients, likely related to inhibition of a bile transporter by ABT-450. Overall, treatment was well-tolerated and 96% achieved SVR12 with just 12 weeks of therapy, irrespective of genotype 1 subtype.
MedicalResearch.com: Were any of the findings unexpected?
Dr. Feld: The low rate of virological failure in the trial and particularly in patients with genotype 1a was somewhat surprising. In general, resistance to the 3 classes of drugs used is more common in patients with genotype 1a infection than in those with genotype 1b HCV. However, in the trial, only 1 patient experienced virological breakthrough on therapy, meaning that the virus was undetectable and then became detectable with continued treatment. In addition, 7 patients relapsed after completing therapy. All 8 patients with virological failure had at least 1 HCV variant known to confer resistance to at least one of the 3 antivirals identified. The significance of these resistant variants is unknown but the fact that a potent regimen of 3 moderate barrier drugs produces so little resistance, even in genotype 1a, is very notable.
MedicalResearch.com: What should clinicians and patients take away from your report?
Dr. Feld: This triple DAA regimen with ribavirin is highly effective for all genotype 1 infected patients. A parallel study showed that the same regimen was equally effective in patients who had failed therapy with peginterferon and ribavrin previously and another study showed that this regimen is effective in patients with compensated cirrhosis. Collectively these data suggest that a ‘one size fits all’ approach is feasible, with all patients, regardless of baseline characteristics, being very likely to achieve SVR with this combination. Tolerability and safety look very reassuring and therefore this regimen offers a great option for most genotype 1 infected patients. For those with genotype 1b infection, ribavirin does not appear to be necessary, which would allow for a better-tolerated option with a lower pill burden.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Dr. Feld: A question still remains about whether ribavirin is absolutely necessary and whether treatment duration could be shortened. A study reported elsewhere clearly showed that ribavirin is not necessary for patients with genotype 1b infection, with 99% of patients treated with the 3 DAA regimen with or without ribavirin going on to achieve SVR. With such a high percentage of patients cured with 12 weeks of therapy, one wonders whether a shorter duration of treatment might be feasible, particularly in a genotype 1b population. The 1a vs 1b issue raises the question of whether it is better to opt for a ‘one size fits all’ strategy, using the same regimen for all patients, or to customize therapy by HCV genotype 1 subtype. The simplicity of one regimen is appealing but will lead to over-treatment of a large number of patients. Sorting out the optimal approach for tailoring therapy will need to be a high priority for future research.
EASL – The International Liver Congress 2014
49th Annual Meeting of the European
Association for the Study of the Liver
London, United Kingdom April 9-13