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Aliment Pharmacol Ther. 2016 Mar;43(6):674-96. doi: 10.1111/apt.13514. Epub 2016 Jan 20.

Review article: safety and tolerability of direct-acting anti-viral agents in the new era of hepatitis C therapy.

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Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA.



Direct-acting anti-virals (DAAs) licensed to treat chronic HCV infection have revolutionised treatment algorithms by drastically mitigating side effects while enhancing efficacy relative to interferon-based therapy.


To review adverse events (AEs) uniquely associated with DAA therapy across a broad spectrum of patient populations.


Searches of PubMed and FDA surveillance studies were undertaken to complete an exhaustive review. Search terms included 'DAAs', 'safety', and 'tolerability'.


While DAAs are remarkably well tolerated, they are accompanied by unique AEs. Simeprevir, an NS3/4A protease inhibitor, has been known, albeit infrequently, to cause mild hyperbilirubinemia and photosensitivity reactions; and paritaprevir boosted with ritonavir causes bilirubin and ALT elevations. Asunaprevir, another protease inhibitor, infrequently causes elevated transaminase levels. NS5A and NS5B inhibitors are well tolerated, although sofosbuvir is contraindicated in patients with severe renal impairment. Ribavirin co-administered in certain treatment regimens has been associated with cough, rash and haemolytic anaemia.


With the impending reality of a more tolerable interferon-sparing regimen, the future of DAA therapy offers shorter treatment duration, simplified disease management, and a patient-centred regimen. With advantages come drawbacks, including development of resistance to therapy and accessibility to this expensive treatment. DAA therapy continues to advance at a brisk pace with a promising trend for higher tolerability, even in difficult-to-treat subgroups such as those with cirrhosis, nonresponders to prior therapy, and transplant recipients. Subgroup-specific contraindications and safety-related limitations are active areas of research. Concerted research efforts and continuing advances lend hope to the goal of rendering HCV a routinely curable disease.

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