Outcomes and predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection

Ossama A Ahmed,1 Mohamed A Elsebaey,2 Mohamed Hassan A Fouad,1 Heba Elashry,3 Ahmed I Elshafie,1 Ahmed A Elhadidy,2 Noha E Esheba,2 Mohammed H Elnaggar,2 Shaimaa Soliman,4 Sherief Abd-Elsalam3 1Department of Internal Medicine, Ain Shams University, Faculty of Medicine, Cairo, Egypt; 2Department of Internal Medicine, Tanta University, Tanta, Egypt; 3Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt; 4Department of Public Health and Community Medicine, Menoufia University, Shbeen El-koum, Egypt Background and aims: Treatment of hepatitis C virus (HCV) changed dramatically with the introduction of oral direct-acting antiviral drugs due to their high antiviral potency and safety profile. Sofosbuvir plus daclatasvir combination therapy was extensively investigated in HCV genotypes 1, 2, and 3, while published data regarding its real-life application in the treatment of genotype 4 is lacking. Therefore, we conducted this study to assess the outcomes and predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection. Patients and methods: This prospective study included 300 Egyptian patients with chronic genotype 4 HCV, treated with sofosbuvir plus daclatasvir with or without ribavirin for 12–24 weeks. Primary outcome was the number of patients who achieved sustained virologic response (SVR12), and secondary outcome was the occurrence of adverse events. Results: A total of 92.67% of all patients achieved SVR12. SVR12 rates of 96.55% and 84.54% were reported in non-cirrhotic and cirrhotic patients, respectively. SVR12 in treatment-naïve and treatment-experienced patients were 94.12% and 87.01%, respectively. A total of 19.7% of patients experienced mild adverse events. Older age, cirrhosis, and low platelet count were the predictors of treatment non-response. Conclusion: Based on this multi-center prospective study, sofosbuvir plus daclatasvir with or without ribavirin for 12–24 weeks appears to have favorable outcomes in the treatment of genotype 4 HCV-infected Egyptian patients. Older age, cirrhosis, especially Child–Pugh class B, and low platelet count are independent risk factors of treatment non-response. Keywords: hepatitis C virus, genotype 4, sofosbuvir plus daclatasvir, sustained virologic respons

Concurrent triplication and uniparental isodisomy: evidence for microhomology-mediated break-induced replication model for genomic rearrangements

Whole-genome oligonucleotide single-nucleotide polymorphism (oligo-SNP) arrays enable simultaneous interrogation of copy number variations (CNVs), copy neutral regions of homozygosity (ROH) and uniparental disomy (UPD). Structural variation in the human genome contributes significantly to genetic variation, and often has deleterious effects leading to disease causation. Co-occurrence of CNV and regions of allelic homozygosity in tandem involving the same chromosomal arm are extremely rare. Replication-based mechanisms such as microhomology-mediated break-induced replication (MMBIR) are recent models predicted to induce structural rearrangements and gene dosage aberrations; however, supportive evidence in humans for one-ended DNA break repair coupled with MMBIR giving rise to interstitial copy number gains and distal loss of heterozygosity has not been documented. We report on the identification and characterization of two cases with interstitial triplication followed by uniparental isodisomy (isoUPD) for remainder of the chromosomal arm. Case 1 has a triplication at 9q21.11–q21.33 and segmental paternal isoUPD for 9q21.33-qter, and presented with citrullinemia with a homozygous mutation in the argininosuccinate synthetase gene (ASS1 at 9q34.1). Case 2 has a triplication at 22q12.1–q12.2 and segmental maternal isoUPD 22q12.2-qter, and presented with hearing loss, mild dysmorphic features and bilateral iris coloboma. Interstitial triplication coupled with distal segmental isoUPD is a novel finding that provides human evidence for one-ended DNA break and replication-mediated repair. Both copy number gains and isoUPD may contribute to the phenotype. Significantly, these cases represent the first detailed genomic analysis that provides support for a MMBIR mechanism inducing copy number gains and segmental isoUPD in tandem