HCV in Pregnancy Overview | HCV Screening in Pregnancy | HCV: Antepartum, Intrapartum and Postpartum Management | HCV Treatment in Pregnancy and Postpartum | HCV Professional Resources
Review the latest recommendations with
Alex Miller, MD and Katherine S. Kohari, MD, FACOG
Dr. Miller is a Maternal-Fetal Medicine fellow at the Yale School of Medicine
Dr. Kohari, a Maternal-Fetal Medicine specialist, is an Assistant Professor and the Medical Director for MFM Outpatient Services in the Department of Obstetrics and Gynecology at the Yale School of Medicine in New Haven, CT
Learning Objectives
Upon completion of this activity, participants should be better able to:
- Evaluate a patient prior to the initiation of treatment for HCV
- Demonstrate the ability to identify current recommendations for treatment of HCV including management during pregnancy and lactation
- Identify potential pregnancy and lactation impacts of common medications currently used to treat HCV
Contents
- Current guidance
- Medications used in Treatment of HCV
- Treatment during Pregnancy and Lactation
- Current Guidelines for Treatment During Pregnancy
- Key Points
- Learn More – Primary Sources
SYNOPSIS:
Current Guidance
Rationale of Treatment of HCV
- The rate of acute HCV has been steadily increasing over the past decade in the setting of the nation’s opioid crisis
- In 2018, the prevalence of acute HCV nationwide was 0.12% with rates disproportionately higher among 20 to 39-year-olds (0.31% and 0.26% in ages 20 to 29 and 30 to 39, respectively) (CDC Surveillance 2018)
- Acute HCV progresses to chronic HCV in >50% of patients
- Chronic HCV is associated to progression to fibrosis and cirrhosis in approximately 10 to 20% of patients within 20 to 30 years
- Treatment results in decrease in liver inflammation and a reduction in the rate of progression of liver fibrosis
- Treatment may also improve cirrhosis, portal hypertension, splenomegaly, and other advanced manifestations of HCV associated liver disease and reduces risk of HCC and need for liver transplant
Initial Steps (adapted from AASLD/IDSA guidelines 2021)
- Education about behaviors associated with transmission
- Alcohol screening with recommended abstinence from alcohol
- Evaluate for other conditions that may accelerate liver fibrosis (Hepatitis B, HIV)
- Evaluate for advanced fibrosis using noninvasive tests (serum panels, elastography) or liver biopsy
- ALT, AST, albumin, bilirubin, INR, CBC with platelet count
- Serum fibrosis marker panels (i.e. FIB-4 index, AST to platelet ratio index [APRI])
- Transient elastography via ultrasound (i.e. Fibroscan)
- Liver imaging (US or CT)
- Levels concerning for cirrhosis: FIB-4>3.25, APRI >2, Platelet count <150,000/mm3, Fibroscan stiffness >12.5kPa
- Appropriate vaccinations
- Hepatitis A and B if not previously performed | Can be safely administered during pregnancy
- Pneumococcal vaccination in the setting of cirrhosis is recommended | Can be safely administered during pregnancy
- TDAP and influenza vaccination should be administered in accordance with standard obstetric care
- Depression screening and evaluation of history of psychiatric disorders and substance use disorders
- Avoidance of hepatotoxic or nephrotoxic medications if concerned for liver fibrosis (ie acetaminophen for postpartum pain control)
Pretreatment Assessment (adapted from AASLD/IDSA guidelines 2021)
- Medication reconciliation (including OTC/supplements) with drug-drug interaction assessment
https://www.hep-druginteractions.org/- Labs prior to initiation of Direct Antiviral Agents (DAAs)
- Within 6mo: CBC, INR, ALT, AST, alkaline phosphate levels, eGFR
- Anytime: HCV viral load (HCV RNA), HCV genotype and subtype (if not using a pan-genotypic medication), HBV assessment (HBsAg, anti-HbC, anti-HBs), HIV
- Potential testing for resistance-associated substitutions based on planned medication regimen
- If receiving HCV NS3 protease inhibitor, assess for history of decompensated liver disease and liver disease severity using Child-Turcotte-Pugh score
- In pregnant individuals, consider timing of assessment to limit delay in initiation of treatment in the postpartum period
Treatment (adapted from AASLD/IDSA guidelines 2021)
- Treat all non-pregnant patients with chronic HCV except those with a short life expectancy that will not be improved with HCV treatment, liver transplant, or other therapy
- Historic treatment strategies relied on interferon (IFN) and ribavirin (later combined with first generation DAAs).
- Newer generation DAAs allow for IFN-free and generally ribavirin-free treatment regimens with improved side effect profiles
- DAAs impair HCV replication via action as protease inhibitors, nucleoside polymerase inhibitors, non-nucleoside polymerase inhibitors, and NS5A inhibitors
- Use DAAs targeting different proteins in combination (2-3 medications) to improve viral clearance rates (>95% with current regimens)
Simplified HCV treatment in treatment-naïve adults without cirrhosis
- Exclusion Criteria
- prior HCV treatment, HIV, Hepatitis B
- Cirrhosis or hepatocellular carcinoma
- History of liver transplantation
- Pregnancy
- Regimens
- Glecaprevir (300mg) / pibrentasvir (120mg) for 8 weeks
- Sofosbuvir (400mg) / velpatasvir (100mg) for 12 weeks
- No drug monitoring required
Simplified HCV treatment for treatment-naïve adults with compensated cirrhosis
- Exclusion Criteria
- Prior HCV treatment, HIV, or Hepatitis B
- Current or prior decompensated cirrhosis or hepatocellular carcinoma
- History of liver transplantation
- Pregnancy
- End stage renal disease
- Regimens
- Genotype 1-6: Glecaprevir (300mg) / pibrentasvir (120mg) for 8 weeks
- Genotypes 1, 2, 4, 5, or 6: Sofosbuvir (400mg) / velpatasvir (100mg) for 12 weeks
- Genotype 3: Perform NS5A resistance-associated substitution testing | If Y93H not found, treat wit h12 weeks of sofosbuvir/velpatasvir
- Drug monitoring
- Consider monitoring hepatic function due to risk of hepatic decompensation
Special Considerations for Treatment (See AASLD/IDSA guidelines for other clinical situations)
- Patients with diabetes on medication have a risk of hypoglycemia during treatment
- Patients on warfarin may need close monitoring of INR to adjust dosing
Treatment Follow-up (adapted from AASLD/IDSA guidelines 2021)
Success defined as absence of detectable HCV RNA for at least 12 weeks after completion of therapy
- Failed Treatment
- Retreat based on AASLD/IDSA retreatment guidelines
- Reassess disease progression every 6 to12 months with hepatic function panel, CBC, and INR
- In patients with cirrhosis, HCC surveillance is recommended with ultrasound every 6mo, and endoscopic surveillance is recommended for varices
- Successful Treatment
- Patients without cirrhosis do not require HCV specific follow-up unless there is ongoing risk of exposure to HCV
- Test with quantitative HCV RNA test annually if concern for ongoing risk of exposure or in the setting of unexplained hepatic dysfunction
- In patients with cirrhosis, surveillance is recommended for HCC and varices
- Assess other causes of liver disease if persistently abnormal liver tests despite sustained viral clearance
Historical Treatment Strategies
- Historic treatment strategies relied on interferon (IFN) and ribavirin (later combined with first generation DAAs)
- Ribavirin is embryocidal/teratogenic in animal studies and contraindicated in pregnancy or within 6mo of planned pregnancy, including use in male partners.
- Newer generation DAAs allow for IFN-free and generally ribavirin-free treatment regimens. However, minimal pregnancy and lactation data exists to guide counseling (see below)
Review of Common Medications Used in Treatment of HCV
Common medications used for treatment of HCV have minimal human studies with
- Elbasvir inhibits HCV NS4A phosphoprotein | No current human studies | LactMed link https://www.ncbi.nlm.nih.gov/books/NBK500816/
- Glecaprevir inhibits HCV NS3/4A protease | No current human studies | LactMed Link https://www.ncbi.nlm.nih.gov/books/NBK525494/
- Grazoprevir inhibits HCV NS3/4A protease | No human studies | LactMed link https://www.ncbi.nlm.nih.gov/books/NBK500819/
- Ledipasvir inhibits HCV NS5A phosphoprotein | Phase 1 pilot study complete (combined with sofosbuvir) | LactMed https://www.ncbi.nlm.nih.gov/books/NBK525494/
- Pibrentasvir inhibits HCV NS5A phosphoprotein | No human studies | LactMed link https://www.ncbi.nlm.nih.gov/books/NBK525500/
- Sofosbuvir is a nucleoside analog inhibitor of HCV NS5B RNA-dependent RNA polymerase | Multiple phase 1 pilot studies underway | LactMed Link https://www.ncbi.nlm.nih.gov/books/NBK500824/
- Phase 1 pilot study complete (combined with ledipasvir)
- Phase 1 pilot study ongoing (combined with velpatasavir)
- Velpatasvir inhibits HCV NS5A phosphoprotein | Phase 1 pilot study (combined with sofosbuvir) | Lactmed link https://www.ncbi.nlm.nih.gov/books/NBK500838/
- Voxilaprevir is a non-covalent, reversible inhibitor of HCV NS3/4a protease | No human studies | LactMed link https://www.ncbi.nlm.nih.gov/books/NBK500919/
- Ribavirin is a guanine analog nucleotide inhibitor that disrupts viral RNA synthesis and mRNA clapping | Contraindicated in pregnancy, within 6 months of pregnancy, or in male partner of patient within 6 months of pregnancy | LactMed link https://www.ncbi.nlm.nih.gov/books/NBK500613/
- Animal pregnancy studies show teratogenic and embryocidal effects include malformations of the skull, palate, eye, jaw, limbs, skeleton, and GI tract
- Pregnancy registry data insufficient to identify drug-associated risks
- No lactation data, but ribavirin used in infants to treat RSV
Note: Ribavirin is the only drug currently with known teratogenic effects and is contraindicated in pregnancy or within 6 months of pregnancy
Treatment During Pregnancy and Lactation
Potential Benefits of Treatment
- HCV is often transmitted following the onset of labor
- Treatment may help reduce transmission rates by reducing both antepartum and intrapartum transmission
Current Status of Human Research
Completed Trials
- Phase 1 evaluation of ledipasvir/sofosbuvir treatment for 12 weeks in 2nd/3rd trimester in 9 women (genotypes 1, 4, 5, and 6) (Chappell et al. Lancet Microbe, 2020)
- KEY FINDINGS:
- Pharmacokinetic parameters for sofosbuvir and ledipasvir were not significantly different than nonpregnant reference group
- All participants had undetectable viral load by 33 to 35 weeks
- All infants were HCV negative
- No neonatal or maternal safety concerns were identified
- KEY FINDINGS:
Ongoing Trials Involving Pregnancy and Postpartum
- Treatment of Chronic HCV During Pregnancy with Sofosbuvir/Velpatasvir at Magee Womens Hospital at UPMC (NCT04382404)
- Single-arm, single-center, open label Phase 1 evaluation
- 12-week course of Sofosbuvir/Velpatasvir during the second trimester in 10 pregnant women with chronic HCV
- Sofosbuvir/Velpatasvir in Postpartum Women with Opiod Use Disorder and Chronic HCV Infection at Magee Womens Hospital of UPMC (NCT 03057847)
- Single-arm, single-center, open label, prospective observational cohort study
- Identifying candidates for treatment during pregnancy then initiating 12 weeks of treatment starting 2 weeks postpartum
- Exclusion criteria includes lactation
- Transmission of Chronic HCV in Pregnancy (NCT03570112)
- Multicenter, non-comparative, observational study to determine natural history of chronic HCV in pregnancy and the rate of vertical transmission to their infants
- Treatment offered following delivery and the cessation of breastfeeding
- Observational Study of HCV in Pregnancy (NCT01959321)
- Multi-center observational study examining risk factors for HCV transmission from mother to baby
Note: More information on the above trials can be found at the NIH site ‘ClinicalTrials.gov’ (see link below in ‘Learn More – Primary Resources)
Current Guidelines for Treatment During Pregnancy
AASLD (2021)
DAA treatment not recommended for pregnant women due to lack of safety, goal to treat prior to pregnancy
USPTF (2020)
Antiviral therapy is not generally considered during pregnancy because of the lack of data on the safety during pregnancy and breastfeeding
CDC (2020)
DAAs are not yet approved, safety data during pregnancy is preliminary and larger studies are required
SMFM (2021)
We recommend that DAA regimens should be initiated only in the setting of a clinical trial during pregnancy and that people who become pregnant while taking a DAA should be counseled in a shared decision-making framework about the risks and benefits of continuation (GRADE 1C)
KEY POINTS:
- Medications should be used in combination (2 or 3 DAAs) with different protein targets to yield higher rates of cure
- Treatment results in cure in >95% of patients
- Resistance testing is only indicated prior to use of certain DAAs
- Treatment during pregnancy or lactation outside of a clinical trial is currently not recommended due to lack of safety data
- Ribavirin is contraindicated in pregnancy, therefore delay of pregnancy for 6 months following completion of ribavirin containing treatment in patient or male partner
Learn More – Primary Sources
CDC Viral Hepatitis Surveillance Report 2018 – Hepatitis C
DailyMed Elbasvir and Grazoprevir
DailyMed Glecaprevir and Pibrentasvir
DailyMed Ledipasvir and Sofosbuvir
DailyMed Sofosbuvir, Velpatasvir, and Voxilaprevir
CDC Recommendations for Hepatitis C Screening Among Adults – United States, 2020
SMFM: Consult Series #56: Hepatitis C in pregnancy—updated guidelines
Commercial Support
This educational activity is supported by an independent educational grant from Gilead Sciences
Faculty Disclosures
Dr. Miller has no relevant financial relationships to disclose
Dr. Kohari has no relevant financial relationships to disclose