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Changing epidemiology, implications, and recommendations for Hepatitis C in Women of Childbearing Age and During Pregnancy
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Nov 25, 2020
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Tatyana Kushner, MD, MSCE, Icahn School of Medicine at Mount Sinai
Nancy Reau, MD, Associate Director, Solid Organ Transplantation
Rush University Medical Center
Key Points:
• 1. The incidence and prevalence of HCV infection in women of childbearing age and in pregnancy have demonstrated have increased and have been linked with injection drug use
• 2. Incidence of mother-to-child transmission of HCV may not be adequately described with retrospective studies due to incomplete follow up of infants for testing at 18 months and therefore missing data on rates of tranmission
• 3. Other than HIV suppression in HIV/ HCV co-infected women, there are no known interventions to decrease the risk of MTCT of HCV
• 4. HCV in pregnancy is associated with preterm birth and intrahepatic cholestasis of pregnancy
• 5. Universal screening during pregnancy is supported by the CDC, USPFTF and found cost-effective
"Utilizing the Healthcare Cost and Utilization Project (HCUP) from 2000-2015 the CDC found that national rate of HCV infection among women giving birth increased over 400% from 0.8 to 4.1 per 1000 deliveries. Though rates were significantly higher among women with a history of opioid use disorder, increases were also seen in women without opioid use history."
"at least in the U.S., the obstetric societies have not embraced universal screening yet. Prior to increased uptake across health settings in the U.S., it will be necessary to have endorsement of universal screening by the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal Fetal Medicine (SMFM)..........based on these findings there are limited pregnancy management interventions that can be done to decrease risk of transmission. ....... in the national response to the WHO goal, the Department of Health and Human Services National Viral Action Plan 2017-2020 specifically includes pregnant women as a priority population for HCV elimination due to the risk of perinatal HCV transmission.....testing for HCV during pregnancy is not uniform across practice settings potentially leading to significant underdiagnosis of HCV...... the United States Preventative Services Task Force (USPSTF) and the CDC both endorsed universal screening during pregnancy, with the CDC further recommending repeat screening at every pregnancy.....
.....Although previously AASLD/ IDSA guidelines recommended to strictly avoid treatment during pregnancy, current recommendations are that "treatment can be considered during pregnancy on an individual basis after a patient-physician discussion about the potential risks and benefits." .....Although ideally women should be treated prior to pregnancy, if diagnosed with HCV during pregnancy, counseling should be aimed at determining when HCV treatment would be possible. Furthermore, when women with a history of HCV seeking care at a tertiary care center in the U.S. (study conducted at University of California San Francisco liver diseases clinic) were surveyed about their preferences and views toward treatment during pregnancy, more than half stated that they would consider DAA therapy during pregnancy if it were to prevent MTCT.....
......Given reassuring animal safety data, investigation into potential treatment with DAAs during pregnancy or soon after delivery are underway. Most recently, the first trial of HCV treatment during pregnancy has been conducted in a single-center study in Pittsburgh enrolling 9 patients during second and third trimesters of pregnancy for treatment with sofosbuvir/ ledipasvir for a 12-week treatment duration, and finding that HCV treatment during pregnancy was safe, effective, and well-tolerated. However, recruitment into the trial was limited by participation, retention in the study (one patient did not complete all assessments needed), as well as exclusion of genotype 3 infected women. Ongoing studies include assessment of postpartum treatment with the use of sofosbuvir/ velpatasvir in women enrolled in an observational study in Ohio who are offered treatment after cessation of breastfeeding as well as a single arm Phase 1 Pharmacokinetic Trial of Sofosbuvir/Velpatasvir investigating the use of sofosbuvir/ velpatasvir during pregnancy. Furthermore, models of care with linkage to treatment prior to conception and after delivery/ breastfeeding are needed. Guidelines now suggest that treatment during pregnancy is a risk/benefit conversation between woman and provider, but until women are accepting of treatment this opportunity for cure (and decreased vertical/hortizontal transmission) will be lost. Demonstrating safety is only one component. Assuring women that DAA therapy during pregnancy is important for their health and the health of their unborn child will require not just patient buy in but also provider buy in. Given that obstetric guidelines don't yet advocate for universal screening in pregnancy, convincing this group of providers to navigate a care cascade will continue to be a lost opportunity.
CONCLUSION: The epidemiology of HCV has shifted over the last decade as a result of the opioid epidemic in the U.S. as well as injection drug use as well as healthcare associated exposures in other regions of the world, leading to the recognition of more women of childbearing age being infected with HCV as well as higher rates of HCV diagnosis during pregnancy. Although in a few regions a clear shift in guideline recommendation has been made to endorse universal HCV screening in pregnancy, it is yet to be determined whether these recommendations will be made more broadly internationally, and whether it will lead to a significant increase in HCV diagnosed during pregnancy. Regardless, it will be important to improve our understanding of the implications of having HCV during pregnancy, as well as role for HCV treatment in the pregnancy context. Future directions should also involve evaluating cost-effectiveness, feasibility, and effectiveness of DAA treatment during pregnancy, as well as developing models of care to optimally reduce the risk of MTCT."
AASLD: Low adherence to infant HCV testing guidelines among pregnant women with HCV cirrhosis - (11/16/20)
Ledipasvir plus sofosbuvir in pregnant women with hepatitis C virus infection: a phase 1 pharmacokinetic study - (11/24/20)
Treatment of Chronic Hepatitis C During Pregnancy With Sofosbuvir/Velpatasvir - (12/04/20)
A study of therapy for hepatitis C in pregnancy with Sofosbuvir/Velpatasvir in Australia - (12/08/20)
WOMEN AND THE 2019 HEPATITIS C CASCADE OF CARE: FINDINGS FROM THE BC-HEPATITIS TESTERS COHORT - (11/28/20)
COST-EFFECTIVENESS OF ANTENATAL RESCREENING AMONG PREGNANT WOMEN FOR HEPATITIS C IN THE UNITED STATES (11/20/20)
NAFLD AND ALCOHOL-RELATED LIVER DISEASE ARE PRIMARY DRIVERS OF CURRENT AND FUTURE CAUSES OF CIRRHOSIS AMONG WOMEN IN NORTH AMERICA - (12/03/20)
CROI: NEWBORN TESTING REVEALS HIGH HCV SEROPREVALENCE IN PREGNANT WOMEN FROM NEW YORK STATE - (03/11/20)
CROI: HCV Prevalence Almost 2% in New Mothers in 2 New York State Regions - (03/11/20)
CROI: NEWBORN TESTING REVEALS HIGH HCV SEROPREVALENCE IN PREGNANT WOMEN FROM NEW YORK STATE - (03/11/20)
Sexual Transmission of Hepatitis C for MSM & Heterosexual Women Facilitated by STDs, HIV, Unsafe Sex Practices
http://www.natap.org/2006/CROI/CROI_49.htm
HCV Sex Transmission, Early Reports from 1995/2002 Among Men, Women at Johns Hopkins STD Clinics & other Studies, HIV+ MSM from the Netherlands
http://www.natap.org/2014/HCV/022414_02.htm
Changing epidemiology, implications, and recommendations for Hepatitis C in Women of Childbearing Age and During Pregnancy
Published:November 25, 2020 Jnl of Hepatology
Brief Summary:
Despite remarkable advances in HCV treatment with DAAs, HCV remains a public health concern worldwide, and rising prevalence of HCV infection has been cited in women of childbearing age. Implications of active HCV on pregnancy include association with cholestasis of pregnancy as well as risk of mother-to-child transmission. Recent updates have increased recommendations for universal screening during pregnancy. Treatment of HCV in the pregnancy context is currently being investigated.
Hepatitis C in Women of Childbearing Age and During Pregnancy
Introduction
Hepatitis C (HCV) remains a significant public health problem with an estimated 71 million people affected worldwide as of 2015, including 5.6 million people in the World Health Organization European region, and over 2 million in the United States (US). In Africa, rates of HCV vary across countries, with the highest rates in Egypt, followed by Nigeria, and Ethiopia. HCV is spread by exposure to blood including from unsafe injection practices. In addition, with an estimated 15.6 million people who inject drugs (PWID) worldwide, with over 25% of PWID aged 25 years or younger, injection drug use (IDU) is a major risk factor for HCV internationally. HCV can also be acquired from healthcare associated risk, such as from unscreened blood products or other healthcare associated exposures, with predominant risk factors varying by region. For example, in countries such as Egypt and Pakistan, nosocomial transmission continues to lead to high rates of HCV. Fortunately, the advent of direct acting antiviral (DAA) agents has dramatically shifted the landscape of HCV, allowing the treatment and cure of over 95% of individuals with access to treatment. However, there are significant global inequities in the access to diagnosis and treatment of hepatitis C. With around 90% of those with HCV residing in low- and middle-income countries, treatment coverage is less than 10% in most countries.
There has been an increase in HCV among young adults related to IDU, including women of childbearing age and women who are being diagnosed during pregnancy, which has been well-described, particularly in the United States in parallel with the opioid epidemic. Given this shift in epidemiology, there has been an increased focus on addressing care pathways (including HCV screening during pregnancy), studying risks of HCV mother-to-child transmission, as well as beginning to investigate the role of antiviral therapy in the context of pregnancy. With the WHO plan for HCV elimination by the year 2030, addressing HCV in women, and in particular during pregnancy, is imperative. For example, in the national response to the WHO goal, the Department of Health and Human Services National Viral Action Plan 2017-2020 specifically includes pregnant women as a priority population for HCV elimination due to the risk of perinatal HCV transmission.
Here we describe key considerations in addressing HCV in women during childbearing and during pregnancy.
Epidemiology of Hepatitis C in Women and During Pregnancy
Although there has been an increase in studies dedicated to understanding HCV burden in women and during pregnancy, many of the studies are U.S. based, and data on HCV burden in this important population across other health settings internationally is needed. As a result of the opioid epidemic, there has been an increase in HCV infection among women of childbearing age, as demonstrated in U.S. based studies. National commercial laboratory data in the U.S., from 2011 to 2016, demonstrated a significant increase in HCV testing among women of childbearing age (up by 39%), as well as an increase in the proportion who were HCV antibody (Ab) positive by 36% (from 4.4% to 6.0%), with the greatest increase occurring from 2015 to 2016. Increases in HCV detection rates were also cited in women age 15-44 on a national level utilizing national Quest laboratory data from 2011-2014.
Similarly using the national notifiable disease surveillance system (NNDSS), a doubling of HCV diagnoses among women of childbearing age was seen from 2006 to 2014, with new infection diagnosed among women of childbearing age surpassing those among women in older age categories. As a result, in the U.S., there has been a shift in HCV from a predominantly male disease to one that is largely equal between men and women. Outside of the U.S., countries with high prevalence of HCV, such as Georgia, appear to have higher prevalence of diagnosed HCV among men than women, but trends over time have not been assessed, and in many assessments, such as in Africa, women are often underrepresented in prevalence estimates. Significant barriers to the prevention of HCV exist across geographical settings including low coverage of interventions to prevent the spread of HCV, inadequate policies to decrease risks for transmission, and barriers to medication access have made HCV elimination challenging to attain . Furthermore, in the setting of the recent COVID-19 pandemic, and concurrent increase in high risk drug use behaviors, as well as a disruption of worldwide hepatitis elimination programs, a further increase in HCV transmission among women at risk can be anticipated.
Rates of hepatitis C in women during pregnancy have also been evaluated through birth certificate data, national reporting systems and hospital-based assessments. A systematic review conducted of EU data, estimated prevalence of 0.1% to 0.9% in data from 2005-2015. A meta-analysis was also conducted in Africa evaluating pregnancy prevalence estimates identifying a prevalence of 3.4% (95% CI: 2.6-4.2, 58 studies) from 2003 to 2015. More recent studies with data from HCV prevalence in pregnancy are shown in Table 1. In a recent evaluation of all live births in the United States based on National Center for Health Statistics birth records, the rate of HCV infection among increased from 1.8 cases to 4.7 cases per 1000 live births. Utilizing the Healthcare Cost and Utilization Project (HCUP) from 2000-2015 the CDC found that national rate of HCV infection among women giving birth increased over 400% from 0.8 to 4.1 per 1000 deliveries. Though rates were significantly higher among women with a history of opioid use disorder, increases were also seen in women without opioid use history. Outside of the US, studies conducted in countries such as Poland (from 1998 to 2012), have also shown increased in hepatitis C prevalence diagnosed during pregnancy over time. Like in the US, these increases are largely driven by increased HCV transmission due injection drug use, with increased prevalence of IDU over time among women who tested positive for HCV.
Mother-to-child transmission of HCV
A major implication of diagnosing HCV during pregnancy is understanding the risk of mother-to-child transmission (MTCT). A 2014 meta-analysis of 109 studies of HCV-positive women from 1997 to 2012, estimated the MTCT rate as 5.8 % (95% CI, 4.2-7.8%), with transmission rates significantly higher among women who are HIV co-infected (10.8% (95% CI 7.6-15.2%). Furthermore, much lower MTCT rates in observational studies of women coinfected with HIV on treatment have demonstrated that suppressive HIV therapy is a potentially successful intervention to decrease the risk of HCV transmission. More recently, in a U.S. national cohort, a 3.6% rate of MTCT was identified and in a recent study from Spain, an estimated 7% risk of transmission was noted among mothers coinfected with HIV. However, given low rates of infant testing for MTCT and therefore limited data on true prevalence of HCV among infants born to mothers with HCV, an accurate estimate of the MTCT risk is challenging. For example, in a Philadelphia department of health study of 8119 females with HCV identified in a hepatitis registry, only 84 (16%) of their infants ever received HCV testing.Similarly, in a population-based retrospective cohort of women in Pittsburgh, only 30% of at risk infants were tested for HCV. In a prospective Egyptian study of 3000 pregnant women viral transmission was much higher than rates in the retrospective analysis. 46/3000 women were found to be HCV positive of which vertical transmission was identified in eight neonates (17.39%). High maternal viral load was identified as the only risk factor for transmission.
Although it is thought that the majority of MTCT occurs perinatally, there is likely a small risk of earlier in utero transmission (Figure 1). However, part of the challenge to understanding MTCT is the significant delay after birth to testing the infant for infection and then confirming viral infection. Current recommendations for assessment of MTCT is to test children for HCV Ab at ≥ 18 months of age, prior to which many may become lost to follow up (Figure 2). Confirmation of chronic viremia may be postponed until after age 3 due to availability of treatment starting at age 3. This again may lead to a significant loss to follow up in children who test positive. Investigation of earlier testing strategies has demonstrated that infant testing for HCV-RNA PCR at age 2-6 months demonstrated high sensitivity and specificity for mother-to-child transmission as defined by positive HCV-RNA testing or anti-HCV at age ≥24 months and negative result as those that had negative anti-HCV at age ≥18 months.[Thus, consideration should be made towards implementing revised criteria for evaluation of MTCT at an earlier infant age, as this will certainly increase the number of infants appropriately tested and diagnosed.
Pregnancy-related risk factors for MTCT have also been evaluated. In a systematic review of eighteen observational studies addressing MTCT, there was no clear association seen between mode of delivery (vaginal versus cesarean) and risk of transmission, nor was an association seen between breastfeeding and risk for transmission (Table 3). Although two studies included in the systematic review reported an association between prolonged duration of ruptured membranes and risk of transmission, based on these findings there are limited pregnancy management interventions that can be done to decrease risk of transmission. Although avoidance of certain obstetric procedures, such as amniotomy and invasive fetal monitoring, may decrease perinatal HCV transmission, evidence is lacking. Furthermore, although it has been proposed that higher HCV viral load may be associated with increased risk of MTCT, a viral load threshold for increased transmission has not been defined and interventions to reduce risk cannot be recommended based on viral load.
Implications of HCV on pregnancy outcomes
Infection with HCV during pregnancy has been associated with adverse pregnancy outcomes, as seen predominantly in large retrospective studies. In a large meta-analysis of over 4 million women with over 5000 HCV infected women, there was a significant association seen with preterm birth in women with HCV (OR 1.62 (95% CI 1.48-1.76), including after stratification for other key contributors to adverse pregnancy outcomes including smoking/ alcohol abuse, maternal drug abuse, or coinfection with HBV or HIV. Similarly a Swedish registry with over 2000 HCV births saw an association of HCV with preterm birth (aRR 1.32 (95% CI 1.08-1.60) and late neonatal death (aRR 3.79 (95% CI 1.07-13.79) when adjusting for maternal age, smoking, BMI, diabetes, and alcohol use. Perhaps the most established association of adverse pregnancy outcome with HCV is with intrahepatic cholestasis of pregnancy (ICP), with significantly higher risk of developing ICP (OR 5.76; 95% CI 1.30-25.44) in women with pre-pregnancy hepatitis C, and a pooled OR as high as 20.40 (95% CI 9.29-44.33) for ICP in HCV-infected pregnant women compared to non-HCV pregnant women. Given this significant increase in risk, and the known association of ICP with adverse fetal outcomes, women with HCV should be counseled on this potential risk during prenatal counseling. On the other hand, it is currently not known whether HCV treatment or clearance during pregnancy would decrease the risk of ICP, or other adverse pregnancy outcomes.
Considerations for DAA therapy in the pregnancy care context
Given the increased risk of adverse pregnancy outcomes associated with HCV during pregnancy, perinatal transmiaaion,as well as increased rates of HCV diagnosis during pregnancy, the question of optimal HCV treatment timing in relation to pregnancy is being evaluated (Figure 3). Although previously AASLD/ IDSA guidelines recommended to strictly avoid treatment during pregnancy, current recommendations are that "treatment can be considered during pregnancy on an individual basis after a patient-physician discussion about the potential risks and benefits." Although ideally women should be treated prior to pregnancy, if diagnosed with HCV during pregnancy, counseling should be aimed at determining when HCV treatment would be possible. Furthermore, when women with a history of HCV seeking care at a tertiary care center in the U.S. (study conducted at University of California San Francisco liver diseases clinic) were surveyed about their preferences and views toward treatment during pregnancy, more than half stated that they would consider DAA therapy during pregnancy if it were to prevent MTCT.
Safety in this population is paramount. Although real world exposure data is limited, animal reproduction studies have demonstrated DAA safety with no evidence of adverse developmental outcomes observed with sofosbuvir based therapies or glecaprevir/pibrentasvir (GP). In animal based studies, exposures to the predominant circulating metabolite of sofosbuvir (GS-331007) were approximately 4 (rats) and 10 (rabbits) times the exposure in humans at the recommended human dose. Similarly, in animal reproduction studies, no adverse developmental effects were observed when the components of GP were administered separately during organogenesis at exposures up to 53 times (rats; glecaprevir) or 51 and 1.5 times (mice and rabbits, respectively; pibrentasvir) the human exposures at the recommended dose. Furthermore, prior human safety evaluations have found DAAs safe, but therapy to effectively prevent MTCT has not been established.
Given reassuring animal safety data, investigation into potential treatment with DAAs during pregnancy or soon after delivery are underway. Most recently, the first trial of HCV treatment during pregnancy has been conducted in a single-center study in Pittsburgh enrolling 9 patients during second and third trimesters of pregnancy for treatment with sofosbuvir/ ledipasvir for a 12-week treatment duration, and finding that HCV treatment during pregnancy was safe, effective, and well-tolerated. However, recruitment into the trial was limited by participation, retention in the study (one patient did not complete all assessments needed), as well as exclusion of genotype 3 infected women. Ongoing studies include assessment of postpartum treatment with the use of sofosbuvir/ velpatasvir in women enrolled in an observational study in Ohio who are offered treatment after cessation of breastfeeding as well as a single arm Phase 1 Pharmacokinetic Trial of Sofosbuvir/Velpatasvir investigating the use of sofosbuvir/ velpatasvir during pregnancy.
Many providers are hesitant to consider DAA treatment without sufficient safety data, and larger scale studies may be needed to establish safety and efficacy of treatment with DAAs during pregnancy. Although we know that highest rates of potential teratogenicity occur during first trimester with drug exposure, safety established during 3rd trimester of treatment (and potentially breastfeeding) will be necessary. Furthermore, models of care with linkage to treatment prior to conception and after delivery/ breastfeeding are needed. Guidelines now suggest that treatment during pregnancy is a risk/benefit conversation between woman and provider, but until women are accepting of treatment this opportunity for cure (and decreased vertical/hortizontal transmission) will be lost. Demonstrating safety is only one component. Assuring women that DAA therapy during pregnancy is important for their health and the health of their unborn child will require not just patient buy in but also provider buy in. Given that obstetric guidelines don't yet advocate for universal screening in pregnancy, convincing this group of providers to navigate a care cascade will continue to be a lost opportunity.
Conclusions
The epidemiology of HCV has shifted over the last decade as a result of the opioid epidemic in the U.S. as well as injection drug use as well as healthcare associated exposures in other regions of the world, leading to the recognition of more women of childbearing age being infected with HCV as well as higher rates of HCV diagnosis during pregnancy. Although in a few regions a clear shift in guideline recommendation has been made to endorse universal HCV screening in pregnancy, it is yet to be determined whether these recommendations will be made more broadly internationally, and whether it will lead to a significant increase in HCV diagnosed during pregnancy. Regardless, it will be important to improve our understanding of the implications of having HCV during pregnancy, as well as role for HCV treatment in the pregnancy context. Future directions should also involve evaluating cost-effectiveness, feasibility, and effectiveness of DAA treatment during pregnancy, as well as developing models of care to optimally reduce the risk of MTCT.
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