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Responsible Inclusion of Pregnant
Individuals in Eradicating Hepatitis C Virus
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Hepatology 20 March 2021
Abstract
Hepatitis C virus (HCV) infections have increased in recent years due to injection drug use and the opioid epidemic. Simultaneously, HCV cure has become a reality, with the advent of direct‐acting antivirals (DAAs) and expansion of treatment programs. As a result, HCV screening recommendations now include all adults, including pregnant individuals, and many countries have endorsed widespread DAA access as a strategy to achieve HCV eradication. However, almost universally, pregnant individuals have been systematically excluded from HCV clinical research and treatment programs. This omission runs counter to public health strategies focused on elimination of HCV but is consistent with a historical pattern of exclusion of pregnant individuals from research. Our systematic review of publications on HCV treatment with DAAs in pregnancy revealed only one interventional study, which evaluated sofosbuvir/ledipasvir in 8 pregnant individuals.
Given the paucity of research on this issue of great public health importance, we aimed to appraise the current landscape of HCV research/treatment and analyze the ethical considerations for responsibly including pregnant individuals.
We propose that pregnancy may be an opportune time to offer HCV treatment given improved access, motivation, and other health care monitoring occurring in the antenatal period. Moreover, treatment of pregnant individuals may support the goal of eliminating perinatal HCV transmission and overcome the established challenges with transitioning care after delivery. The exclusion of pregnant individuals without justification denies them and their offspring access to potential health benefits, raising justice concerns considering growing data on DAA safety and global efforts to promote equitable and comprehensive HCV eradication. Finally, we propose a path forward for research and treatment programs during pregnancy to help advance the goal of HCV elimination.
The currently recruiting sofosbuvir/velpatasvir in pregnancy study is a necessary first step to accelerate the inclusion of pregnant individuals in HCV treatment programs, but with only 10 patients, it will not address the unresolved questions of safety that require larger scale studies. What is needed is a clinical trial to study the current HCV pan-genotypic DAA regimens with the National Institutes for Health (NIH) as the sponsor. Ideally, NIH could lead a public-private partnership, in coordination with the FDA, which is designed to study the 2 most common pan-genotypic regimens using the same study infrastructure, the same enrollment criteria and the same clinical outcomes. Study sites should be part of an established network accustomed to performing clinical studies during pregnancy related to maternal infectious diseases (e.g. International Maternal Pediatric Adolescent AIDS Clinical Trials Network [IMPAACT]). Since most trials used for initial licensure of DAAs were open-label and enrolled 100-300 individuals, a target of 100 pregnant individuals could receive each regimen. If the safety and efficacy are consistent with those seen in non-pregnant individuals and in the phase 1 trial in pregnancy, the FDA label would be expanded for use during pregnancy.(28)
Since initial studies do not identify rare adverse events, mandatory pregnancy registry should be established for post-approval treatment to evaluate effectiveness and safety in a real-world setting. Treatment could be linked to data registry enrollment and reporting requirements, and private payors would be required to cover treatment in the same manner as for non-pregnant patients. A safety monitoring committee would review all outcomes of HCV treatment during pregnancy and immediately alert providers of any sentinel events. After several years of data were collected and major safety concerns abate, the registry would then shift to a post-marketing model like the Vaccine Adverse Events Reporting System (VAERS).
The Global Goal of HCV Eradication
While HCV treatment once consisted of a year-long, partially efficacious regimen requiring subcutaneous injection with many side effects, it now involves 6-8 weeks of a once-daily oral regimen that cures >95% patients with HCV infection.(7-9) These highly efficacious direct-acting antivirals (DAAs) have enabled public health authorities globally to employ different strategies for “microelimination” of HCV.(10) Such strategies generally involve first expanding screening efforts to identify all patients with HCV then streamlining treatment access to achieve cure. A lower prevalence of people with HCV would translate to reduced transmission, which ultimately will lead to eradication of HCV. The World Health Organization has embraced this approach, setting global targets for HCV elimination by 2030, and these goals are aligned with U.S. Health and Human Services Healthy People 2030 targets.(11-13)
Various strategies can achieve eradication. For example, Iceland and Egypt have enacted national plans for widespread testing and “universal” access to DAAs,(14) and persons living with HCV in Egypt have declined substantially.(15) In the US, many states have lifted insurance restrictions on publicly-funded access to DAAs and have attempted “universal” access after simple criteria for testing and evaluation are met. Louisiana and Washington are implementing novel strategies for financing universal DAA access, negotiating fixed-price agreements with pharmaceutical companies regardless of how many patients are treated (or “Netflix models”).(16-18) Australia has used this model to great effect across the country to dramatically reduce the population burden of HCV.(19) Nevertheless, these efforts all systematically exclude one population with a potentially high prevalence of HCV infection: pregnant individuals.
Pregnant Individuals and HCV Screening
Pregnant individuals have been part of the wave of HCV infections among young adults primarily related to the opioid epidemic.(20-23) A high prevalence within pregnant individuals has been documented in many states in which the opioid epidemic has been rampant, prompting Kentucky to mandate universal screening for HCV during pregnancy.(20-26)
This changing epidemiology of HCV first drove the American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA) in 2018 to recommend universal screening of all pregnant individuals(27), which was ultimately taken up by both the USPSTF and CDC in their recommendation for universal screening of all adults.(5, 6) However, recommendations still defer treatment for pregnant individuals with HCV until after giving birth, a strategy that captures only a fraction of those who could benefit. While there may be some off-label treatment of pregnant patients being undertaken by providers, no individual or group has reported their experience and only the AASLD/IDSA include discussion on a case by case basis among existing professional guidelines regarding HCV treatment in pregnancy.
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