Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine

Abstract

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug-polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.

Fig. 1.

Design and in vivo retention of the LA-DAAS. (A, i) A nasogastric (NG) tube is placed in a patient to administer the LA-DAAS, and then the NG tube is removed. (A, ii) The LA-DAAS resides in the gastric cavity while releasing DAAs. (A, iii) The NG tube is once again placed in a patient to deploy a retrieval device for attachment and removal of the LA-DAAS from the gastric cavity. The LA-DAAS is compatible with communication with a personal device, such as a smart phone, engaging patients to track alcohol and temperature levels and how much drug is left, and to schedule an appointment to receive another LA-DAAS. (B) The LA-DAAS consists of a series of drug pills on a coiled superelastic nitinol wire with end protected with epoxy and a magnet for retrieval. One end of the LA-DAAS is equipped with a Bluetooth, temperature, and alcohol sensor. (C) Representative radiographs of the LA-DAAS immediately after deployment and on day 30 in a swine model (n = 3). Dashed circled indicate location of the LA-DAAS. (D) Representative endoscopic images of the LA-DAAS immediately after deployment and on day 30 in a swine model (n = 3). For scale, each pill is 5 mm. Pentax endoscope magnification is up to 35×.

Fig. 2.

Fabrication and in vitro release of DAAs from individual drug–polymer pills. (A) Drug–polymer pills are made by mixing drug with either silicone or PCL and then casting into a Petri dish or a three-dimensional (3D) printed mold. Drug–silicone pills are extracted by using a biopsy punch, and drug–PCL pills are extracted with a razor blade. Pills are then spray-coated with a pan coater. A cross-sectional image of a PCL-coated drug–PCL pill is shown. (B) In vitro release of sofosbuvir from a drug pill in water with varying molecular weights of PCL. (C) In vitro release of daclatasvir from a drug pill in water with varying molecular weights of PCL and PCL coating. (D) In vitro release of ledipasvir from a drug pill in acetonitrile with varying silicone hardness. (E) In vitro release of ribavirin from a drug pill in water with molecular weight of PCL and drug-loading percentage. Formulation compositions are available in SI Appendix, Table S2. Error bars represent SD for n = 3 samples.

Fig. 3.

In vivo applications of the LA-DAAS. (A, Left) Concentration-time profiles of the sofosbuvir metabolite GS-331007 in serum after administering a single dose of 400 mg (n = 3). (A, Right) Concentration-time profiles of the sofosbuvir metabolite GS-331007 in serum after administering the LA-DAAS, which had 11.2 g of sofosbuvir across two formulations (n = 3; SI Appendix, Fig. S11). (B) Area under the curve (AUC) and the duration of drug release for a single dose compared to the LA-DAAS administered in vivo, with the mean value and SD reported for n = 3 samples in each group. (C) Evaluation of the LA-DAAS electronic sensors (n = 3) in euthanized swine. The analog signal of the ethanol sensor, temperature, and RSSI were measured after placement of the LA-DAAS in the stomach. Ethanol was administered at the time indicated by the red point. Temperature levels are shown in blue, with the corresponding RSSI signal shown in red for the same LA-DAAS. AU, arbitrary units.

Fig. 4.

Monthly HCV treatment and cost-effectiveness of a LA-DAAS. (A) Illustration of two treatment strategies for HCV treatment: Current HCV treatment spans 12 wk and involves daily administration of DAAs. The LA-DAAS can be administered once per month for HCV treatment. (B) Schematic of the cost-effectiveness model for chronic HCV with two treatment strategies, DAA or LA-DAAS. Transition states are shown in blue. Health states in red indicate death states or liver transplant, after which patients exit the model. HCC, hepatocellular carcinoma; LRD, liver-related death; LT, liver transplant; non-LRD, non-liver-related death. Table of parameters can be found in SI Appendix, Table S1. (C) Results for the cost-effectiveness analysis of DAA versus LA-DAAS. Results for three cohorts are presented. In the base case, patients treated have average adherence to DAA and average likelihood of returning for NGT retreatment. In the PWID case, patients have lower adherence than the general population and are less likely to return for repeated NGT treatment. In the PWID:DOT case, patients in the DAA arm are PWID treated in a DOT program. Cost and ICER are in US dollars. In all cohorts, treatment with LA-DAAS was cost-effective.