文章基本信息

标题：Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine
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作者：Malvika Verma ; Jacqueline N. Chu ; John A. F. Salama 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：22
页码：11987-11994
DOI：10.1073/pnas.2004746117
出版社：The National Academy of Sciences of the United States of America
摘要：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. Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide ( 1 ⇓ – 3 ). One forecast predicted that mortality from chronic hepatitis would exceed the mortality caused by HIV, tuberculosis (TB), and malaria combined by 2040 ( 4 ). Accordingly, the World Health Organization has called for elimination of HCV infection by 2030 ( 5 , 6 ). Encouragingly, the development of direct-acting antiviral (DAA) therapy for HCV has revolutionized the field. The high cure rate of DAA therapies, with rates of sustained virologic response (SVR) of greater than 95%, short duration of treatment, and tolerability, has greatly expanded the number of patients being cured of chronic HCV ( 1 , 2 , 7 , 8 ). However, due to factors such as cost, limited access to medical care, and inconsistent follow-up, less than half of those infected are actually treated ( 3 , 8 ⇓ – 10 ). People who inject drugs (PWID) have especially low HCV treatment uptake, despite being a large reservoir for chronic HCV infection (50% of all PWID globally) and the leading population infected with acute HCV ( 9 , 11 ). Particular challenges facing the PWID population include homelessness, which can make storage of oral medications difficult; comorbid psychiatric conditions; limited access to healthcare; and distrust of the medical system ( 3 ). Modeling studies have suggested that expanding treatment to PWID can reduce transmission of HCV, even with poor rates of adherence and SVR ( 12 ). Studies utilizing methadone programs to deliver HCV treatment show promise, with high rates of treatment completion and SVR ( 3 ). However, such programs require significant infrastructure and cost and do not capture PWID who do not engage in other opioid agonist therapies such as buprenorphine or who may engage only intermittently ( 3 , 13 ). Challenges that all populations face with regard to oral therapies include forgetfulness, low priority, pill phobia, dysphagia, and pill burden ( 14 ); rates of adherence to chronic medications in general are, at most, 50%, though higher for short courses of therapy such as DAAs ( 14 ). Thus, there is a clear need for alternative strategies to deliver HCV treatment, and long-acting treatment delivery systems are one of the innovative strategies that have been endorsed, including recently by Unitaid ( 15 , 16 ). A long-acting DAA system (LA-DAAS) has the potential to safely and consistently deliver DAA therapy to patients with good adherence and quality of life by decreasing the frequency of dosing, with the goal of ultimately providing single dosing ( 14 , 15 ). We have previously described a coil-shaped gastric resident system (GRS) which, due to its dimensions and mechanical properties, can remain resident in the gastric cavity and deliver multigram levels of drugs for TB, which has similar treatment challenges as HCV with frequent and daily dosing ( 17 ⇓ – 19 ). Here, we describe the development of a LA-DAAS inspired by the multigram GRS with evaluation in a swine model of chronic HCV. We developed additional features, including integration of ethanol, temperature, and Bluetooth sensors, to enable patient engagement via wireless communication with the LA-DAAS. Such tools have improved patient adherence to HCV therapy in other preliminary devices ( 20 , 21 ). We then evaluated the cost-effectiveness of the LA-DAAS in general and PWID populations. Results Design of the LA-DAAS. The LA-DAAS design was inspired by a previous multigram GRS used for monthly treatment of TB ( SI Appendix ) ( 17 ). The LA-DAAS consists of drug–polymer pills strung along a superelastic nitinol wire ( 22 ). It can be administered via a nasogastric tube and forms a cylindrical coil upon reaching the stomach. During its residence in the gastric cavity, the LA-DAAS continually releases grams of drugs and is retrieved back through a nasogastric tube ( Fig. 1 A and B ). Electronic sensors were added to each end of the LA-DAAS to provide information on alcohol intake and body temperature, and to engage patients during their treatment. As alcohol use can cause further liver injury and accelerate disease progression, it is important for patients and clinicians to be aware of alcohol intake. However, patients may underestimate or underreport alcohol use due to stigma, and physicians frequently fail to screen adequately for excessive alcohol intake ( 23 , 24 ). An intragastric sensor can provide an objective measure of alcohol consumption and identify patients in need of therapy directed toward alcohol cessation ( 23 ). Additionally, patients with chronic liver disease—particularly PWID with chronic liver disease—are at higher risk of infection. To this end, a temperature sensor was also incorporated into the LA-DAAS in order to alert patients and physicians of fever or hypothermia that may signal a serious infection. Finally, patient engagement with treatment has been shown to improve adherence ( 20 , 21 , 25 , 26 ). To this end, a Bluetooth and temperature sensor to confirm continual functional device status combined with a mobile software application was incorporated into the LA-DAAS. Messages could be sent to a patient’s mobile device to remind them of clinic appointments or to return for repeat LA-DAAS administration and/or removal. In PWID or other high-risk populations where communication can be a challenge, a built-in device could improve outreach to patients. The physical dimensions of the LA-DAAS can be personalized to each patient, depending on the target drug load and duration of therapy ( SI Appendix , Fig. S2 ).