AbbVie's 3D hepatitis C regimen containing paritaprevir (ABT-450),
ombitasvir, and dasabuvir was generally well-tolerated in the phase 3
SAPPHIRE trials, according to a pooled analysis presented at the 54th
Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) earlier this month in Washington, DC. While most participants in the study experienced some adverse
events, serious side-effects were rare and few people discontinued
treatment early for this reason.
Direct-acting antiviral agents (DAAs) that target different steps of
the hepatitis C virus (HCV) lifecycle have brought about a revolution in
treatment, especially with the advent of all-oral regimens that omit
interferon and its difficult side-effects, which can include flu-like
symptoms and depression. While the first-generation DAAs used with
interferon added their own side-effects, the new generation of hepatitis
C drugs have few adverse effects.
Tolga Baykal from AbbVie, Donald Jensen from the University of Chicago
Medical Center, and colleagues performed a combined analysis of adverse
events in the SAPPHIRE-I and SAPPHIRE-II trials. SAPPHIRE-I enrolled
previously untreated participants, while SAPPHIRE-II enrolled prior
non-responders to interferon-based therapy. Participants in both studies
had HCV genotype 1 – including a majority with harder-to-treat subtype
1a – and did not have liver cirrhosis.
Both trials evaluated a 12-week interferon-free regimen consisting of
the HCV protease inhibitor ABT-450 boosted with ritonavir, the NS5A
replication complex inhibitor ombitasvir (formerly ABT-267; 25 mg), the
non-nucleoside NS5B polymerase inhibitor dasabuvir (formerly ABT-333),
Unlike many recent hepatitis C treatment trials, the SAPPHIRE studies
included a placebo arm, allowing direct comparison of adverse event
rates. This is important because a proportion of people randomly
assigned to receive placebo in clinical trials also report side-effects
or adverse events unrelated to treatment; the difference between the
active drug and placebo arms gives a better idea of which effects are
actually attributable to the drugs being studied. Overall, 770 of
participants in the combined SAPPHIRE trials were randomised to receive
the active 3D regimen plus ribavirin, while 255 received placebo.
As previously reported, sustained virological response rates at 12 weeks post-treatment (SVR12) were 96% in both SAPPHIRE I and SAPPHIRE-II.
Overall, 89% of study participants receiving the 3D + ribavirin
regimen reported adverse events compared with 77% of those receiving
placebo in a pooled analysis.
Most adverse events were mild or moderate in severity. Sixteen participants (2.1%) taking the 3D + ribavirin regimen and only 1
person (0.4%) taking placebo experienced serious adverse events. Three people (0.4%) taking 3D + ribavirin, but none taking placebo,
experienced serious adverse events considered possibly related to the
Drug discontinuation due to adverse events was uncommon and occurred
with similar frequency in the 3D + ribavirin and placebo groups (0.8% vs
The most common adverse events – headache and fatigue – were
reported by approximately 30% of participants across study arms. Approximately twice as many 3D + ribavirin recipients as placebo recipients
reported insomnia (14 vs 8%, respectively), asthenia or weakness (14
vs 7%), and rash (10 vs 6%). The symptom with the greatest difference between the two groups was pruritis or itching (16 vs 4%, respectively).
Despite the use of ribavirin, serious anaemia was rare.
"The 3D + ribavirin regimen demonstrated a favourable adverse event
profile as evidenced by low rates of study drug discontinuation,
drug-related serious adverse events, and generally mild adverse events,"
the researchers concluded.
"Previous exposure to treatment did not influence the safety profile."