Novel combined single dose anti-hepatitis C therapy: a pilot study

Abstract

The new anti-hepatitis C virus (HCV) molecules improve treatment regimens and outcomes, but there are drawbacks. New combinations should target the HCV infectious cycle and be effective against all HCV genotypes. We developed the novel formulation Catvira, composed of epigallocatechingallate (EGCG) + sofosbuvir + ribavirin. Here, we compared Catvira to sofosbuvir + ribavirin tablets in patients with CHC genotype 4 in a randomized open-label efficacy and safety study. Treatment-naïve and treatment-experienced patients (n = 80) were randomly assigned to receive a single daily fixed dose of Catvira or sofosbuvir + ribavirin for 12 or 24 weeks. Both Catvira and sofosbuvir + ribavirin yielded similar outcomes of viral load (p < 0.001). Patients receiving Catvira had a significantly more rapid rate of viral load decline with sustained virologic response (SVR12) achieved by 90% of patients receiving 12 weeks of treatment. Catvira did not impact hemoglobin levels while sofosbuvir + ribavirin showed significant decline in hemoglobin levels after 24 weeks (p < 0.05). In this clinical trial (ClinicalTrials.gov Identifier NCT02483156), we found that Catvira administered daily for 12 or 24 weeks is safe, effective, and well-tolerated in both naïve and treatment-experienced patients with HCV genotype 4.

Conflict of interest statement

Gamal Shiha has been a Principal Investigator for Gilead and Abbvie. Reham Soliman has been an Investigator for Gilead and Abbvie. Mohamed Elbasiony has been an Investigator for Gilead. Shaker A Mousa has no conflict of interest other than helping HCV patients in underdeveloped countries have access to treatment at low to no cost. Noureldien H. E. Darwish declares no competing interests.

Figures

Figure 1

Effects on the viral load (IU/ml) of Catvira treatment versus sofosbuvir (SOF) + ribavirin (RBV) individual tablets treatment in treatment-experienced patients with HCV through (a) 12 and (b) 24 weeks, n = 80. One-way ANOVA was used followed by the Newman-Keuls post-test, *p < 0.001 represents comparison of both groups SOF + RBV (*) and Catvira (+) versus their baseline. There was a significant trend for rapid lowering of HCV viral load in both groups (SOF + RBV and Catvira) versus their baseline (p < 0.001).

Figure 2

Effects on hematological parameters of Catvira treatment versus sofosbuvir (SOF) + ribavirin (RBV) individual tablets treatment in treatment-experienced patients with HCV (24 weeks treatment). (a) Fold changes in hemoglobin levels. (b) Fold changes in RBC counts. Values are expressed as mean ± SEM. There was a significant trend for hematological improvement (*p < 0.05) in patients treated with Catvira when compared to the SOF + RBV treatment group.

Figure 3

Effects on liver enzymes of Catvira treatment versus sofosbuvir (SOF) + ribavirin (RBV) individual tablets treatment in treatment-experienced patients with HCV (24 weeks treatment). (a) Effect on alanine transaminase (ALT) enzymes. (b) Effect on aspartate transaminase (AST) enzymes. Values are expressed as mean ± SEM. A significant difference (***p < 0.001) was observed in patients treated with Catvira and SOF + RBV when compared to control patients with HCV who were not treated.

Figure 4

Catvira interferes with HCV entry into human hepatocytes. Cell entry involves an interaction between the extracellular virion that is associated with lipoproteins and several receptors on the host cell membrane. These include scavenger receptor type B class 1 (SR-B1), epidermal growth factor receptor (EGF-R), CD81, and possibly low-density lipoprotein receptor (LDL-r). It has been suggested that the lipoprotein receptors SR-B1 and LDL-r act before CD81. These interactions induce travelling of the virus-receptor complex along the cell surface from the basolateral (blood-side) surface of the hepatic epithelium where LDL-r, SR-B1, and CD81 are localised. These events, stimulated by virion-mediated activation of receptor tyrosine kinase signaling like EGF-R, result in clathrin-dependent endocytosis of the virion. Catvira is a single tablet composed of sofosbuvir (400 mg), ribavirin (1000 mg), and epigallocatechin gallate (EGCG) (400 mg). Catvira is suggested to act on the virus particle and inhibits virus entry by impairing virus binding to the cell surface.