الفهرس 
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Abstract
Egypt has one of the highest global burdens of hepatitis C virus (HCV) infection. Hepatitis C virus is the primary contributor to chronic liver diseases in Egypt, including cirrhosis and Hepatocellular carcinoma (HCC), those comorbidities has been ranked by the WHO among Egypt’s top 10 causes of death. However, a rapid change in the situation took place in Egypt after the introduction of the oral direct-acting antiviral (DAA) drugs and the conduction of multiple national programs to screen and treat HCV.
Although DAAs offer a short‐term treatment with high rates of sustained virologic response (SVR), a comprehensive review of the safety and the adverse event (AE) profile of DAAs is lacking. Few serious adverse drug reactions (ADRs) were observed and reported in the clinical trials performed on the DAAs, this returns to the limited ability of the pre-authorization clinical trials to detect ADRs that occur in a ‘real-world’ setting. Hence, post-marketing surveillance through pharmacovigilance activities -as spontaneous reporting of ADRs- is essential to identify potential safety and efficacy concerns associated with drugs.
Previous studies conducted in Egypt evaluating the safety and efficacy of DAAs, were only concerned with descriptive data analysis without computing the disproportionalities in reports or performing more statistical models that can figure out some important drug-AE associations.
This study aimed to evaluate the safety profile of the DAA regimens; sofosbuvir/ribavirin (SOF/RBV), sofosbuvir/daclatasvir (SOF/DCV), ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) and sofosbuvir/ledipasvir (SOF/LDV) on the local population in Egypt, through describing the pattern of adverse events and detecting the signals of disproportionate reporting (SDRs) defining the statistical associations between the DAAs and the reported adverse events.
This is a cross-sectional pharmacovigilance study conducted using data from VigiBase - the World Health Organization global database of individual case safety reports (ICSRs) that was developed and maintained by Uppsala Monitoring Centre (UMC).
Out of 3670 ICSRs in Egypt were extracted with the designated DAA regimens, 2925 reports were eligible for descriptive and disproportionality analyses. SOF/RBV (n=671), SOF/DCV (n=2032), OBV/PTV/r (n=171) and SOF/LDV (n=51).
Descriptive analysis was performed to summarize patients’ and reactions’ characteristics. A disproportionality analysis using Bayesian and frequentist signal indicators -Information components (ICs) and proportional reporting ratios (PRRs)- was conducted to identify signals of disproportionate reporting. Also, logistic regression analysis was performed to identify the DAAs association with specific serious events -HCV/HBV reactivation, anaemia, renal impairment (including acute kidney injury (AKI), renal insufficiency, and elevated blood creatinine), and hepatic complications (composite endpoint including hepatocellular carcinoma and hepatic encephalopathy)- while adjusting for the covariates; age, gender, pre-existing cirrhosis, and ribavirin use.
Most of the ADRs were deemed mild (49.5%) per the Hartwig’s severity assessment scale, while serious ADRs comprised (38.7%). The most commonly reported ADRs were anaemia (21.3%), hepatitis C relapse (14.5%), headache (14%), fatigue (12.9%), dizziness (12.2%) and pruritus (4.8%).
Concerning OBV/PTV/r, the disproportionality analysis showed that the highest signal was for drug-drug interactions (DDIs). It was also associated with serious and potentially fatal ADRs including anaemia and renal impairment. The observed number of reports of renal impairment with OBV/PTV/r were two-folds higher than the expected number of reports (IC: 2.12, 95% CrI: 0.7-3.03). the logistic regression analysis revealed a nearly 9 folds risk of anaemia with OBV/PTV/r, which was independent of ribavirin use (ROR: 8.97, 95% CI: 4.91–17.29). Despite the heightened risk of anaemia and renal impairment, OBV/PTV/r was superior to all other studied DAA combinations in terms of lower risk of HCV/HBV reactivation, progression to hepatic encephalopathy and HCC, and being the regimen associated with the lowest severity index (0.58%), seriousness (7.02%) and no fatal outcomes.
A signal of disproportionate reporting of anaemia was also reported with SOF/RBV (IC: 4.73, 95% CrI: 4.56-4.85), SOF/LDV (IC: 1.87, 95% CrI: 0.312 – 2.86) and with SOF/DCV (IC: 2.25, 95% CrI: 2.02-2.42), with nearly 1.5 folds higher risk of anaemia (OR: 1.42, CI: 1.12–1.81) independently of RBV use.
Beside anaemia, SOF/DCV regimen was also associated with SDRs of hepatic nature; a SDR of HCC (IC: 3.46, 95% CrI: 2.62-4.04) and a SDR of HCV relapse (IC: 3.65, 95% CrI: 3.47-3.79) were reported.
The highest signal of HCV relapse among the four regimens was reported with SOF/RBV (IC: 3.69, 95% CrI: 3.37-3.92) which is possibly related to the efficacy of regimen. This regimen also reported the highest severity index (4.02%) and seriousness (85.7%)
This study concluded that although the credible safety margin and tolerability of the DAAs in Egypt, these reported signals of renal impairment and anaemia with OBV/PTV/r and HCC with SOF/DCV need clinical validation through further population-based studies and to be considered in monitoring HCV patients on DAA treatment.