HCV vertical transmission in pregnancy: New horizons in the era of DAAs
Authors: Tomi T. Kanninen, Douglas Dieterich, Stefania Asciutti
Journal: Hepatology (2015)

Potential conflict of interest: Dr. Dieterich consults, advises, and received grants from Gilead, Bristol‐Myers Squibb, Merck, and Janssen. Routine prenatal hepatitis C virus (HCV) screening is not recommended in women lacking risk factors for infection. This is partially because of the absence of options in the management of maternal to neonatal transmission and the perceived low prevalence of HCV in pregnancy. Vertical transmission rates of HCV have been reported to be as high as 8%. Reducing maternal viremia may be beneficial given its role as a requirement for vertical transmission. Recent advances in HCV infection combination therapy have made high rates of sustained virological response and HCV‐RNA clearance in nonpregnant adults achievable. Currently, there are no therapies to prevent HCV vertical transmission. However, certain direct‐acting antiviral agents (DAAs) may have substantially more favorable profiles in pregnancy in comparison to past medications. Given that maternal viremia has been linked to vertical neonatal transmission, the use of DAAs may considerably lower HCV vertical transmission in pregnancy and warrant future studies. The prevalence of HCV infection in pregnancy has been estimated to be similar to the reported 0.5%‐1.4% seropositivity in low‐risk blood donors.1 Presently, routine prenatal HCV screening is not recommended by the American College of Obstetricians and Gynecologists and Centers for Disease Control and Prevention, except for women with significant risk factors for infection.1 This policy is the result of a lack of any available pre‐ or postnatal pharmacological, immunological, or interventional measures to decrease the risk of vertical transmission. HCV vertical transmission rates have been reported between 2% and 10% and HCV chronically infects an estimated 25,000‐50,000 children with 750 new cases a year acquired through vertical transmission.1 Furthermore, though high rates of spontaneous resolution have been reported for children acquiring HCV infection at birth, many still become chronically infected. Current long‐term outcome data on these chronically infected children is significantly limited given that HCV disease morbidity in general takes longer than two decades to develop.3 Clinicians frequently delay treatment for HCV until after pregnancy given limited experience with the use of interferon (IFN) in pregnancy and the absolute contraindication for ribavirin (RBV) use.1 Recent developments in HCV infection combination therapy have made persistent normalization of transaminase levels and HCV‐RNA clearance in nonpregnant adults possible.5 Given that maternal viremia has been linked to vertical neonatal transmission, the use of DAAs for prevention of HCV transmission alone or in association with IFN warrants more‐intense future study. Maternal Viremia in HCV Present‐day evidence using quantitative polymerase chain reactions has shown a correlation between maternal viral titer of HCV and risk of neonatal infection.4 However, evidence of the effect of quantitative maternal viremia and its influence on vertical transmission is less constant in comparison to evidence on vertical human immunodeficiency virus (HIV) transmission, therefore limiting recommendations on management.1 Mothers with undetectable plasma HCV‐RNA levels rarely vertically transmit HCV. The influence of acute HCV infection on rate of vertical transmission and its rate of spontaneous resolution in pregnancy is currently not well defined. Vertical transmission in HIV patients in treatment with highly active antiviral therapy (ART) has been shown to be comparable to rates in HIV‐negative women; however, not all evidence agrees with this assertion.1 Maternal risk factors recently reported to be associated with an increased rate of vertical HCV transmission include higher maternal HCV viral titer, prolonged membrane rupture during labor (6 hours or longer), and use of internal fetal monitoring during labor.1 Route of delivery has not been shown to influence risk of vertical HCV transmission, except in one trial, and cesarean delivery is recommended only for obstetric indications in women with HCV infection.1 This situation is in contrast to HIV infection, where maternal HIV viral load is a recognized predictor of vertical transmission and has influenced current guidelines in regard to HIV in pregnancy.1 Recent developments in HCV infection combination therapy that have cleared HCV RNA in nonpregnant adults may potentially present a new therapeutic option in HCV infection in pregnancy. These new emerging therapies may present a new avenue to preventing neonatal transmission. Emerging Therapy in HCV Infection Recent advances in HCV therapy in nonpregnant adults with DAA combination therapies have demonstrated prompt and substantial suppression of serum viral levels, allowed shortened courses of therapy, and offered high (>95%) sustained response rates and relatively few toxicities.5 These new DAAs are categorized into four main groups: protease inhibitors, such as simeprevir, nucleotide analog polymerase inhibitors, such as sofosbuvir, non‐nucleotide analogs, such as dasabuvir, and nonstructural (NS)5A inhibitors, such as dacalastasvir or ledipasvir. Both the apparent safety profile and the potential RBV‐ and IFN‐free nature of these regimens make them particularly attractive for potential use in pregnancy. The side effects associated with IFN therapy have prevented many patients from undergoing treatment and advocated postponing treatment to postdelivery in pregnant women. DAAs have less severe adverse affects (e.g., headache and fatigue) and a shorter duration of therapy.8 These newer medications seem to be less influenced as well by racial ground, interleukin‐28B genotype, body mass index, and baseline HCV‐RNA level.8 Currently, a number of current phase III studies have shown the superiority of DAAs in combinations of ledipasvir and sofosbuvir or paritaprevir, ombitasvir, and dasabuvir in comparison to the standard combination of IFN, RBV, and a protease inhibitor for HCV genotype 1 infection.8 Anti‐HCV potency and the genetic barrier to development of resistant mutations were early problems contributing to DAA drug resistance in early single‐drug regimen trials. These difficulties have been superseded by the use of combination therapy.8 These trials have demonstrated a new, exciting avenue in HCV treatment that has produced substantial responses in patients. Given the success of these agents outside of pregnancy, a significant improvement in preventing the transmission of HCV to neonates and enhanced therapeutic regimens of HCV in pregnancy is conceivable. Currently, experience with any of these new DAAs in human pregnancy is greatly lacking. Many currently approved U.S. Food and Drug Administration (FDA) DAA combination therapies are with RBV and as a result category X. Sofosbuvir and ledipasvir are both category B drugs, given there was no evidence of fetal harm in animal studies. However, simeprevir is a category C medication in monotherapy. Animal studies in mice have showed significantly reduced fetal weights, increased fetal skeletal variations, in utero fetal losses, and early maternal deaths at high exposures.9 Currently, many new DAAs are in the process of approval, and, surely, a number of newer medications will emerge. The safety profiles of each one of these medications will indisputably have to be individually examined before evaluating a potential use in HCV in pregnancy (Table 1). Table 1 - Safety Profile of New DAAs in Pregnancy DAA Combination Pregnancy Category (1) Paritaprevira + (2) ombitasvira (1) B, (2) B (1) Paritaprevira + (2) dasabuvira + (3) ombitasvira (1) B, (2) B, (3) B (1) Daclatasvirb + (2) asunaprevirc (1) N/A, (2) N/A (1) Daclatasvirb + (2) asunaprevirc + (3) beclabuvir (1) N/A, (2) N/A, (3) N/A (1) Sofosbuvira + (2) ledipasvira (1) B, (2) B (1) Sofosbuvira + (2) ledipasvira + (3) vedroprevir (1) B, (2) B, (3) N/A (1) Sofosbuvira + (2) ledipasvira + (3) GS‐9669 (1) B, (2) B, (3) N/A (1) Sofosbuvira + (2) simeprevira (1) B, (2) C (1) Grazoprevir, (2) elbasvir (1) N/A, (2) N/A (1) Daclatasvirb + (2) sofosbuvira (1) N/A, (2) B (1) Sofosbuvira + (2) velpatasvir (1) B, (2) N/A (1) Grazoprevir, (2) elbasvir ± (3) MK‐3682 (1) N/A, (2) N/A, (3) N/A aFDA‐approved DAA.bApproved in Europe, Brazil, and Japan.cApproved in Japan.Abbreviation: N/A, not available. Obviously, caution is needed in regard to administering any DAA to pregnant women. However, the safety profile of certain medications, such as sofosbuvir and ledipasvir, may allow further research examining its potential in limiting neonatal transmission and maternal HCV treatment in pregnancy. The potential for this class of medication to significantly impact HCV transmission is suggested by the evidence provided by the successful prophylactic treatment of maternal‐neonatal HIV transmission, as discussed further below. Parallels With HIV Therapy in Pregnancy The most direct inference to draw upon for the potential effect of these new classes of HCV therapy is the currently used medications for HIV in pregnancy. The impact of ART on the natural history of HIV infection has resulted in dramatic reductions in disease‐associated morbidity and mortality.10 Zidovudine, a polymerase inhibitor, is routinely used in pregnancy given that it has been shown to significantly reduce the risk of vertical HIV transmission safely.10 The protease inhibitor safety profile in pregnancy, particularly in regard to the risk of preterm birth, has been raised, and hepatotoxicity and teratogenicity are the main concerns with nucleoside reverse transcriptase inhibitors.10 The majority of antiviral drugs used in HIV, with the exception of efavirenz, are safe throughout pregnancy and their benefits far outweigh any risks.10 NS5A inhibitors are not used in HIV treatment, but their profile in pregnancy is promising. Further animal and patient studies are warranted. Hopefully, further research on HCV antiviral medication will provide a similar impact as ART has had on HIV disease‐associated morbidity and mortality. Successful use of these classes of medications for HIV treatment in pregnancy suggests they may be effective and safe for HCV treatment as well. Conclusion Current screening protocols in pregnancy do not recommend universal HCV screening given the lack of effective treatments in preventing maternal‐neonatal transmission. This has led to many physicians deciding to postpone treatment of HCV until after pregnancy. However, the 2%‐10% reported vertical transmission rate of HCV and potential negative maternal outcomes in HCV infections in pregnancy is not an insignificant quantity. The emergence of these new routes of therapy offer the possibility to examine further methods of lowering these risks to maternal‐fetal outcome and may provide new support for universal HCV screening in pregnancy provided their effectiveness.