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Letter to the Editor: Pregnant women and their providers want DAAs and we are missing the mark
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06 May 2021
Tatyana Kushner, Catherina A. Chappell
We read with great interest the Special Article by Jhaveri et al. entitled "Responsible Inclusion of Pregnant Individuals in Eradicating Hepatitis C virus."1 This article is timely and draws attention to pregnant women, a subpopulation that has been ignored in the study of hepatitis C (HCV) treatment. Pregnancy is an ideal window of opportunity due to the high engagement in healthcare of reproductive-aged women. The AASLD/ IDSA, USPSTF and CDC now all recommended universal HCV screening during pregnancy which will lead to increased diagnosis of HCV during pregnancy. However, the American College of Obstetrics and Gynecology (ACOG) has been hesitant to recommend universal screening due to the lack of treatment available during pregnancy.2 Jhaveri et al. identified only one pharmacokinetic study of sofosbuvir/ledipasvir, which demonstrated safety, tolerability, and effectiveness of direct-acting antiviral (DAA) therapy in nine pregnant women. Guidance from the AASLD/ IDSA suggests that "women who become pregnant while on DAA therapy should discuss the risks versus benefits of continuing treatment with their physicians."3 This "guidance" puts providers in the difficult position of providing advice with minimal published data on DAA safety in pregnancy.
CV Screening During Pregnancy Recommended by ACOG: Am Coll. of Obstetricians & Gynecologists - (05/19/21)
We agree with Jhaveri et al. that a clinical trial of HCV treatment during be sponsored by the NIH, leading a public-private partnership in coordination with the FDA. However, there is no clear funding mechanism from NIH for larger trials for HCV DAAs and no NIH network of study sites in high HCV prevalence areas. If the NIH/FDA truly supports ethical research in pregnant women then they should dedicate funding or require industry to include pregnant women in studies prior to FDA approval for medications. An alternative approach would be a larger industry sponsored study which evaluates the use of a pangenotypic DAA regimen during pregnancy. This strategy would require the pharmaceutical company to have a commitment to the health pregnant women (an honorable cause), yet could be in opposition to a successful business strategy particularly for medications that are closer to the patent expiration date. A critical first step would be to compare DAA treatment compared to the current standard of care (no treatment) on pregnancy and neonatal outcomes to convince providers that treatment is as safe as no treatment. Additionally, a registry of outcomes after first trimester DAA exposure, similar to the antiretroviral pregnancy registry (http://www.apregistry.com) is needed even with a larger study to determine the effect of exposure early in pregnancy. Pregnant women with HCV prefer to be treated during pregnancy4. Jhavari, et al. provides a strong call to action for us in the field and our NIH, FDA and industry partners to determine the best way to get the evidence that is desperately needed.
Responsible Inclusion of Pregnant Individuals in Eradicating HCV
March 2021- Hepatology - Ravi Jhaveri ,1,2 Lynn M. Yee,3 Swati Antala,1,4 Margaret Murphy,1,5 William A. Grobman,3 and Seema K. Shah1,6
• What is needed is a clinical trial to study the current HCV pan-genotypic DAA regimens with the NIH as the sponsor.
• Study sites should be part of an established network accustomed to performing clinical studies during pregnancy related to maternal infectious diseases (e.g., the International Maternal Pediatric Adolescent AIDS Clinical Trials Network).

• mandatory pregnancy registry should be established for postapproval 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 nonpregnant patients.
• A safety monitoring committee would review all outcomes of HCV treatment during pregnancy and immediately alert providers of any sentinel events
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 epidemiology and treatment of HCV infection have been transformed over the last decade. Newly identified cases have increased dramatically, driven by injection drug use and the opioid epidemic(1-3); and HCV screening recommendations have expanded to include all adults.(1, 4-6) In 2020, some guidelines in the United States have included pregnant individuals in universal HCV screening recommendations for the first time.(5, 6) However, pregnant individuals have been excluded from most HCV clinical research and treatment programs around the world. Thus, we aimed to assess data on HCV treatment in pregnancy—including through a systematic review—and analyze ethical considerations for the responsible inclusion of pregnant individuals. Finally, we offer a proposal for the responsible inclusion of pregnant individuals in research and treatment programs.
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 US 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 the number of persons living with HCV in Egypt has declined substantially.(15) In the United States, 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 US Preventive Services Task Force and the Centers for Disease Control and Prevention 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.
A Paucity of Data: Systematic Review
To evaluate the evidence on HCV DAA treatment in pregnancy, we conducted a systematic review of the literature, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Briefly, a search of the MEDLINE (PubMed), EMBASE, Cochrane Library, clinicaltrials.gov, CINAHL, and Global Health databases for relevant studies was first performed during October and November 2019 and refreshed in July 2020. A separate clinicaltrials.gov search was performed again in January 2021. The reference lists of the reports selected for inclusion were screened for further potentially relevant articles. Any comparative studies such as randomized controlled trials, quasi-experimental designs, and observational studies that assessed the effectiveness of therapy were included. No language restriction was applied. The search strategy is provided in Supplemental Table 1 and was uploaded in PROSPERO. Two investigators (S.A. and R.J.) independently screened all citations by title and abstract. The same investigators then screened the studies retrieved independently. Disagreements regarding inclusion were resolved by discussion.
Our systematic review abided by PRISMA guidelines (Supporting Fig. S1) and identified 1,987 unique references, of which 1,783 were potentially relevant. Of these, 31 references addressed treatment for HCV in pregnancy. Only one of these described an interventional treatment study, a study of sofosbuvir/ledipasvir initiated during pregnancy in 8 individuals.(28) The remaining 30 papers discussed HCV treatment during pregnancy generally and/or called for further study, including a pharmacokinetic study of sofosbuvir/velpatasvir treatment during pregnancy that is currently recruiting with a target enrollment of 10 participants and a target completion date of June 2023.(29) In summary, the scarcity of publications on this topic demonstrates the exclusion of pregnant people from research.
Ethical Considerations for the Responsible Inclusion of Pregnant Individuals These results are consistent with the historical pattern of excluding pregnant individuals from research by default.(30, 31) Perhaps the most important reason for this exclusion is the desire to protect pregnant individuals and fetuses classified as "vulnerable,"(30) which was in response to unethical studies in which researchers exploited vulnerable populations. In the 1990s, however, the HIV epidemic shifted the paradigm of research oversight away from regulatory paternalism toward greater participant access to research benefits.(32) In 1994, the National Institutes of Health's (NIH's) Office of Research on Women's Health called for pregnant individuals to be "presumed eligible" for clinical research participation, which was later echoed by international guidelines.(33) Recent guidelines now recommend that research with pregnant individuals be "promoted."(34) Moreover, the 2019 revision of the US federal regulations governing research removed pregnant individuals from the list of groups classified as vulnerable to coercion or undue influence, given that there is no reason to question the decision-making capacity of pregnant individuals as a group.(35)
Despite this increasing recognition of the importance of greater inclusion of pregnant individuals in research, change has been slow. In 2011, there were no safety data in pregnancy for 73% of drugs approved by the Food and Drug Administration (FDA) in the prior decade and "very limited" safety data in pregnancy for 19.2% of treatments.(36) Pregnant individuals also largely were excluded from trials conducted during the Ebola epidemic of 2013-2016 and in the COVID-19 pandemic.(37, 38)
Although exclusion from research may be appropriate in some cases, exclusion without justification unjustly denies pregnant individuals and fetuses access to potential health benefits. Paradoxically, while pregnant individuals are not more vulnerable to coercion or undue influence than other groups, a substantial source of vulnerability for pregnant individuals is greater exposure to risk from important interventions due to a lack of scientific knowledge.(39) Critical evidence gaps include information about pharmacokinetics, fetal safety, and maternal risks and benefits, which should be addressed through research but are often neglected.(40)
There are three generally accepted scientific considerations for inclusion of pregnant individuals in research: (1) basic clinical safety data should be available in the general population, (2) clinical efficacy should be established for the general population, and (3) sufficient preclinical and early clinical data relevant for use in pregnancy should be available.(41) The first two considerations have been met for HCV treatment as it is well-established that treatment with DAAs is both safe and efficacious for achieving sustained virologic response in nonpregnant individuals with HCV infection. Additionally, the pilot treatment study of sofosbuvir/ledipasvir has begun to satisfy the third consideration.(28)
Additionally, the US Code of Federal Regulations Section 46.204 permits approval of research in pregnancy if the research offers a prospect of direct benefit for the pregnant individual and/or the fetus and if risks are minimized. Examining the risks and benefits of HCV treatment in pregnancy reveals that research could meet these conditions.
Potential benefits and risks from HCV treatment during pregnancy
There is clear potential benefit for initiating HCV treatment during pregnancy rather than delaying it until after pregnancy. In addition to curing HCV in pregnant individuals, treatment during pregnancy could markedly reduce, if not eliminate, perinatal HCV transmission and associated risks to the fetus. Viremia is the only absolute requirement for perinatal transmission, and the current DAA regimens all rapidly reduce HCV RNA levels to undetectable within 2 weeks of initiation.(42, 43) While the precise window of transmission in unknown, it is possible that rapid and potent suppression of viremia will virtually eliminate the risk.(44)
There are potential risks from HCV treatment during pregnancy, such as possible teratogenic effects as well as unique toxicity during pregnancy. Teratogenic risks remain theoretical worries, but review of product label information with both pan-genotypic regimens did not demonstrate any notable toxicities in pregnant animals or their offspring.(45, 46) Because DAA regimens are as short as 6-8 weeks and therapy could be started in the middle of the second trimester after organogenesis is complete and still conclude before delivery, potential teratogenic effects would be minimized while using the window of opportunity for treatment in pregnancy. In the absence of teratogenicity, however, fetal exposure to DAAs could still have other long-lasting effects, requiring further research in pregnant individuals and their offspring. As for toxicity, DAAs have been exceptionally well tolerated in medically complex patients such as those with uncompensated cirrhosis, end-stage renal disease requiring dialysis, and HIV. Aside from drug–drug interactions, side effects are rare. There is no a priori reason to believe administration in pregnancy would be different. Ultimately, the best way to evaluate these largely theoretical risks of HCV treatment during pregnancy would be to conduct research to generate more evidence about the risks and benefits.
Other considerations regarding HCV treatment during pregnancy
HCV treatment during pregnancy offers many advantages compared with delaying treatment until after pregnancy is complete. Pregnancy is a window of opportunity in which current DAA regimens could be integrated into prenatal care. Studies of HIV treatment during pregnancy demonstrate comparable or higher adherence with antiretroviral therapy than treatment outside of pregnancy, and pregnancy has been established to be a period of increased engagement in care.(47)
With the lifting of Medicaid restrictions on treatment with DAAs and expansion of health care coverage to all pregnant people through at least 6 weeks postpartum, HCV treatment during pregnancy could be provided while a patient still has coverage and avoid the potential deficit in care that could arise with interruptions of coverage. Even when coverage remains available, transitioning individuals after pregnancy to providers who address nonobstetric and longer-term issues is often challenging. Indeed, several studies have documented very low follow-up rates when pregnant individuals are referred for HCV treatment after delivery.(25, 48-50)
While the high cost of DAAs is frequently mentioned as a reason against treatment during pregnancy, the cost is no different than for anyone else. A study of cost-effectiveness has demonstrated that treatment initiated during pregnancy is a high-value proposition.(51)
Finally, liability concerns may lead sponsors to avoid conducting research in pregnancy or seeking labeling for the use of their products in pregnancy.(52) Ultimately, the legal culture surrounding research in pregnancy may be a more important barrier than existing laws but may also be more flexible and easier to change.(52) For instance, public recognition of the great need for research in pregnancy and advocacy could begin to shift institutional attitudes.
Some may reflect and ask, "What do pregnant patients think?" about HCV treatment during pregnancy. Our research indicates that patients are largely supportive of these concepts and want more open discussions with their providers on the subject.(53)
Looking Forward
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 NIH as the sponsor. Ideally, the NIH could lead a public–private partnership, in coordination with the FDA, which is designed to study the two 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., the International Maternal Pediatric Adolescent AIDS Clinical Trials Network). Because 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 nonpregnant individuals and in the phase 1 trial in pregnancy, the FDA label would be expanded for use during pregnancy.(28)
Because initial studies do not identify rare adverse events, mandatory pregnancy registry should be established for postapproval 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 nonpregnant 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 are collected and major safety concerns abate, the registry would shift to a postmarketing model like the Vaccine Adverse Events Reporting System.
This proposal is one clear way to achieve equitable inclusion of pregnant patients in HCV treatment programs, and it highlights the important work remaining to be done. Until the injustice of excluding pregnant patients from HCV research and, by extension, treatment programs is addressed, we will not be able to move together equitably in a global endeavor to eliminate HCV.
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