Direct antiviral agents (DAAs) and their use in pregnant women with hepatitis C (HCV)

Abstract

Introduction:

Direct-Acting Antiviral Agents (DAAs) provide safer, efficacious, tolerable, and curative therapy for women with hepatitis C. Their preferred safety and efficacy profile make them potential therapies for the elimination of perinatal transmission of hepatitis C virus (HCV). However, DAAs are not currently recommended for use during pregnancy due to limited pharmacokinetic and safety data.

Areas Covered:

This review covers the different DAA drug combinations, the available data on their pharmacodynamic and pharmacokinetic properties, how the physiology in pregnancy can potentially affect DAA drug disposition, known drug-drug interactions with DAAs, and available and planned epidemiological and pharmacokinetic studies on DAA use during pregnancy. Although no large randomized clinical trials or prospective cohort studies involving DAAs have been completed in pregnancy, the currently available studies demonstrate no significant changes in pharmacokinetics, and no major safety concerns in women with hepatitis C.

Expert Opinion:

Initial pharmacokinetic and safety data suggest that DAAs have high efficacy and a low risk of adverse events during pregnancy. As more pharmacokinetic and epidemiologic data become available, DAAs could become a preferred option for treating HCV during pregnancy and elimination of perinatal transmission of hepatitis C virus.

1.0. INTRODUCTION:

Hepatitis C virus (HCV) infection continues to be a critical public health problem. The World Health Organization (WHO) estimates that approximately 1.5 million new HCV infections occur annually [1]. In the United States, HCV is the most commonly reported bloodborne infection, with estimated new cases increasing from 24,700 in 2012 to 57,500 in 2019 [2], with the majority of these cases occurring in people aged 20–39 years [2]. This increase in HCV cases with age is seen globally, with around 21% of global HCV cases occurring in women of childbearing age [3,4]. In those who become pregnant, approximately 3–6% of infants born to HCV positive women become infected [5,6]. While approximately 20% of children with perinatally acquired HCV tend to clear the viral infection, 30% will progress to chronic liver disease [7]. Additionally, the risk of HCV vertical transmission is 4-fold higher in the setting of HIV-co-infection [8]. Hence, the risk of perinatal transmission is critically important and needs to be addressed.

Approximately 15–30% of adults with chronic HCV infection will develop cirrhosis, hepatocellular carcinoma, and death within 20 years of diagnosis of HCV infection if not treated[9]. Therefore, treatment of HCV infection becomes essential, especially in individuals with chronic infection. In the past, first-generation antiviral medications like ribavirin and interferon (INF) were the only options available for treating HCV [10,11]. Recent advancements in direct antiviral agent (DAA) therapy have made many more efficacious and tolerable treatment options available. Currently, the available DAAs are categorized into 4 classes. The NS3/4A0 protease inhibitors (PI) are also known as first-generation DAAs, while the NS5A inhibitors, NS5B nucleoside polymerase inhibitors (NPIs), and NS5B non-nucleoside polymerase inhibitors (NNPIs) are second-generation DAAs [12,13].

With the increasing cases of HCV infection in the last decade, and with these effective DAA therapeutic options, it became essential to update the HCV screening and treatment guidelines. In 2020, both the US Preventive Services Task Force (USPSTF) and the Center for Disease Control (CDC) updated their HCV screening guidelines to include at least a one-time screening in all individuals over 18 years of age [3,7,14]. However, with the increase in HCV cases in people of reproductive age [3], there became a clear need for more screening guidelines in pregnant women [15]. The CDC added specifics for pregnant women, recommending that they get tested with every pregnancy to allow for early detection [7]. Other expert committees suggest similar screening strategies for HCV during pregnancy [16–18].

While these updated HCV screening guidelines are beneficial in identifying and treating HCV cases in non-pregnant women, the use of DAA as a modality for maternal HCV treatment and prevention of vertical HCV transmission (as has proven so effective for HIV) continues to lag behind when compared to non-pregnant adults. Unfortunately, this has been the case for several years, a common theme encountered in the use of new drugs in pregnant women [19–22]. The current practice of postpartum HCV therapy involves linking HCV positive pregnant women with resources to provide postpartum care and enhance DAA adherence [23] as well as pediatric care and testing for infants. However, pregnancy represents an ideal window of opportunity for HCV therapy given that pregnancy is a time of high healthcare engagement and improved adherence to antiviral therapy. Even more critical is that there are currently no proven interventions to decrease the risk of HCV perinatal transmission, making it pertinent to study medications that could prevent vertical transmission of HCV, similar to the use of antiretroviral therapy (ART) to prevent perinatal transmission of HIV. Additionally, HCV therapy would reduce the risk of cirrhosis and other HCV-related complications in the mother. If prenatal HCV therapy is proven to be safe and effective, this strategy would be critical to the mission of HCV elimination by integrating HCV therapy into routine prenatal care and therefore, providing curative maternal HCV therapy, prevention of perinatal HCV transmission, and linking partners to HCV testing and treatment. Such studies would inform current HCV treatment guidelines.

2.0. METHODS:

This is a narrative review of direct antiviral agents and their use in pregnant women with hepatitis C virus. A literature search was conducted in the PubMed database between March 8th and July 7th, 2022 for studies of any design or in any setting, on use of direct antiviral agents in pregnant women with hepatitis C infection. The search terms included were: Hepatitis C; direct antiviral therapy (DAA); pregnancy; pharmacokinetics; pharmacodynamics, efficacy, safety, teratogenicity, and pharmacoepidemiology. Results were limited to articles in English. Other citations were identified in references of available literature and from ClinicalTrials.gov. The results and discussion of the literature review are summarized by sections: section 3 describes the fixed-dose DAA combinations currently in use; section 4 describes the chemistry and pharmacokinetic profiles of select direct HCV antiviral agents; section 5 discusses the pharmacodynamics and antiviral activity of DAA and barrier to drug resistance; section 6 discusses the physiologic changes during pregnancy relevant to DAA disposition; section 7 discusses in detail the currently available pharmacokinetic studies in pregnancy; section 8 describes the epidemiological and case-series od DAA use during pregnancy; section 9 describes DAA drug-drug interactions (DDIs) and potential adverse effects during pregnancy; section 10 discusses the risk of congenital anomalies with DAA use; section 11 is the concluding paragraph while section 12 is the expert opinion.

3.0. DIRECT ANTIVRAL AGENTS (DAA) FIXED-DOSE COMBINATIONS:

For a long time, ribavirin and INF were the only treatments available for HCV. However, the approval of the first DAA in 2011 changed the landscape for HCV therapy [24,25]. As previously discussed, the DAAs are categorized into four classes, all targeting different pathways of the HCV replication cycle. Table 1 provides a summary of the currently used DAA drug combinations. The first generation DAAs include telaprevir and boceprevir. These drugs target the non-structural serine 3 protease (NS3) on the HCV. These were followed by more effective, safer, and pan-genotypic protease inhibitors (PIs), like simeprevir (SMV) [25,26]. The second group of DAAs target the viral RNA-dependent RNA polymerase (NS5B). These are classified into two classes according to their molecular nature; nucleoside polymerase inhibitors (NIs) like Sofosbuvir, which are highly effective, and generally pan-genotypic due to the conserved structure of the polymerase [26], and non-nucleoside polymerase inhibitors (NNIs) like dasabuvir, which tend to be more genotype-specific (genotype 1) [25,26]. The last group is the NS5A inhibitors include DAAs like ledipasvir – Table 1. These target the NS5A, a protein essential for HCV replication cycle and virion assembly [26,27]. The currently FDA approved DAA regimens for treatment of HCV mostly include a NS5B inhibitor in combination with other DAAs [28,29]. For instance, the NS5B inhibitor Sofosbuvir is frequently combined with a NS5A inhibitor - Ledipasvir, Daclatasvir, Velpatasvir, or with an NS3/4A inhibitor - Voxilaprevir, or Simeprevir. Although HCV therapy guidelines rely on several factors, including patient’s HCV naïve or experienced status, presence or absence of cirrhosis, stage of HCV liver disease, viral genotype, and HCV scoring systems [30], DAAs, like ART, are used as combination to provide a high-barrier to resistance, affinity for pan-genotypic HCV virus, and good efficacy.

Table 1:

Fixed Dose Combination Direct Antiviral Agents (DAAs) used in the treatment of Hepatitis C

DAA Combination	DAA Class	Genotype	Dosing
Ledipasvir + Sofosbuvir	nucleotide NS5B inhibitor + NS5A inhibitor	1, 4, 5, and 6	Once daily
Glecaprevir + Pibrentasvir	NS3/4A PI + NS5A inhibitor	1, 2, 3, 4, 5, and 6	Three tablets, once daily
Sofosbuvir + Simeprevir	nucleotide NS5B inhibitor + NS3/4A PI	1	Once daily
Sobosbuvir + Velpatasvir	nucleotide NS5B inhibitor + NS5A inhibitor	1, 2, 3, 4, 5, and 6	Once daily
Sofosbuvir + Velpatasvir + Voxilaprevir	nucleotide NS5B inhibitor + NS5A inhibitor + NS3/4A PI	1, 2, 3, 4, 5, and 6	Once daily
Sofosbuvir + Daclatasvir	nucleotide NS5B inhibitor + NS5A inhibitor	1 or 3	Once daily

4.0. CHEMISTRY AND PHARMACOKINETIC PROFILES OF SELECT DIRECT HCV ANTIVIRAL AGENTS:

4.1: Sofosbuvir/Ledipasvir:

The first fixed-dose combination DAA that was FDA approved was Sofosbuvir/Ledipasvir (SOF/LDV). SOF/LDV combination was FDA-approved in 2014, and is manufactured in two fixed-dose tablets, a 90mg/400mg, and a 45mg/200mg for SOF and LDV respectively. Both drugs are dosed once daily. Sofosbuvir/Ledipasvir combination is effective against HCV genotypes 1, 4, 5, and 6 [31]. Following oral intake, LDV is well absorbed. SOF/LDV has a time to maximum plasma concentration after oral administration (T_max) of 0.5–2 hours for SOF and approximately 4 hours for LDV, reaching a maximum plasma concentration (C_max) of 323ng/mL, without a significant effect of food on drug absorption. Ledipasvir is highly protein-bound (approximately 99.8%) while SOF is approximately 65% bound to plasma proteins [32]. Sofosbuvir is a pro-drug that is metabolized in the liver after dosing through sequential metabolism into its tri-phosphate active metabolite, GS-461203, which accounts for most of the systemic effects of SOF [32]. However, following its absorption, it is also metabolized into an inactive metabolite, GS-331007, which does not have HCV antiviral activity [33]. Ledipasvir is minimally metabolized, as most of the originally ingested LDV account for its systemic effects. Elimination of SOF and GS-331007 occurs primarily via the renal route (approximately 80%), with minimal excretion via the biliary route, while LDV elimination occurs primarily through feces (approximately 86%) [34]. LDV has a long half-life of approximately 47 hours compared to a half-live of 0.5 hours for SOF and 27 hours for GS-331007 [34]. Although the active metabolite GS-461203 is not detected in human plasma, in-vitro studies show a half-life of about 18 hours [33,34].

4.2: Sofosbuvir/Simeprevir (SOF/SMV)

Sofosbuvir/Simeprevir (SOF/SMV) was the first approved second generation NS3/4A protease inhibitor [35]. It is available as a single fixed-dose combination capsules of 150mg dosed once daily [36], and is approved for the treatment of HCV genotype 1 [36]. Simeprevir is orally absorbed, with a T_max of approximately 4–6 hours [36]. Simeprevir demonstrates higher intestinal absorption, and longer T_max when ingested with food. Simeprevir is highly bound to plasma proteins (approximately 99.9% bound to plasma proteins), and is primarily metabolized by CYP3A and excreted via the biliary-fecal route [36]. Simeprevir has an elimination half-life of approximately 41 hours in HCV-infected patients [36].

4.3: Sofosbuvir/Velpatasvir (SOF/VEL)

Sofosbuvir/Velpatasvir (SOF/VEL) is available as a fixed dose combination of 400mg SOF with 100mg VEL, dosed once daily [37]. Velpatasvir is highly bound to plasma proteins (approximately 99.5% bound), and is metabolized by CYP2B6, CYP2C8, and CYP3A4, and primarily excreted through the biliary route. Velpatasvir has a half-life of approximately 15 hours [37]. SOF/VEL combination is also available in combination with a third drug, Voxilaprevir (VPR) as Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) [38]. The SOF/VEL/VOX regimen is highly effective against all HCV genotypes, dosed as one-tablet daily of SOF 400mg/ VEL 100mg/ and VPR 100mg [38]. Voxilaprevir has a T_max of approximately 4 hours, and is generally well absorbed following oral administration, and shows increased absorption with food (increase between 112% to 435%) [38]. Voxilaprevir is mainly metabolized by CYP3A4, and eliminated in feces with a half-life of 33 hours [38].

4.4: Sofosbuvir/Daclatasvir (SOF/DCV)

Sofosbuvir/Daclatasvir (SOF/DCV) combination is used for HCV genotypes 1 and 3 [39]. Daclatasvir is an NS5A inhibitor, and is available as a single-tablet of 60mg, administered once daily [39]. Daclatasvir is absorbed orally, with a T_max of approximately 2 hours. Daclatasvir is highly bound to plasma proteins, and primarily metabolized by CYP3A4. It is eliminated mostly via the biliary-feces route, with a half-life of approximately 12–15 hours [39].

4.5: Glecaprevir/Pibrentasvir (GLE/PIB)

Glecaprevir/Pibrentasvir (GLE/PIB) are both potent, pan-genotypic (HCV genotypes 1–6) combination of a NS3/4A protease inhibitor (GLE) and an NS5A inhibitor (PIB) [40]. Glecaprevir/Pibrentasvir is manufactured as a fixed-dose combination of 100mg/40mg tablet of GLE and PIB respectively and is dosed in a single administration per day (three tablets) [40]. This fixed-drug combination was FDA approved in 2019 for treatment of HCV, as this drug combination was noted to be effective against HCV genotypes 1–6 [40]. As a combination of a NS3/4A protease inhibitor and an NS5A inhibitor, GLE/PIB inhibits the viral replication and virion assembly [40]. Glecaprevir/Pibrentasvir is absorbed well orally when dosed with meals, with an 83–163% increase in absorption for GLE following a meal, compared with only 40–53% increase for PIB. The oral bioavailability of GLE/PIB is approximately 90% in humans, with a protein-binding of >97% [40]. Following an oral dose of GLE/PIB, drug concentrations are widely distributed, with the highest concentrations found in the liver. The T_max is approximately 5 hours, with an elimination half-life of 6 and 13 hours for GLE and PIB respectively. This might be related to the fact that, while both are primarily eliminated through the biliary-fecal route (with minimal renal excretion), GLE is secondarily metabolized by CYP3A4/5, while PIB is not [40].

5.0. PHARMACODYNAMICS AND ANTIVIRAL ACTIVITY OF DAAs AND BARRIER TO DRUG RESISTANCE:

Understanding pharmacodynamic variables are critically important in the action of DAAs. The pharmacodynamic variables of interest in measuring dose-response and HCV viral susceptibility include the minimum amount of a DAA required to produce a HCV antiviral response (potency); the maximum antiviral activity that can be produced by a DAA (efficacy); the plasma drug concentration of DAAs needed to produce 50, 90, or 95% maximum HCV antiviral activity (EC₅₀, EC₉₀ or EC₉₅); and the ability of HCV to withstand the effects of DAAs even at optimal or high doses (HCV viral resistance to DAA). Additionally, pharmacodynamic processes that drive the effects of DAAs involve mechanisms governing medication action, signal transduction stages, and processes governing receptor binding or mediator turnover. When DAAs are taken orally, the effects it has can frequently be divided into three types: direct (rapidly or slowly reversible), indirect (inhibitory or stimulatory), and irreversible [41]. Additionally, tolerance, and counter-regulation might develop [41]. The antiviral effectiveness of the HCV DAAs may be reduced by resistance-related variants (RAVs), which could result in treatment failure [42]. Therefore, employing targeted HCV antiviral medicines requires a thorough grasp of the processes behind the development of drug-resistance. These pharmacodynamic factors aid in predicting and defining the potency, effectiveness, and resistance barrier of DAAs.

Second generation DAAs generally have good efficacy, favorable pharmacodynamic profiles, and higher potency compared with first generation HCV drugs, although their potency tend to decrease with resistance polymorphisms and mutations [42]. For example, sofosbuvir, the backbone of several widely used HCV regimens, has high HCV antiviral potency [43]. Unfortunately, despite the high potency and the pan-genotypic efficacy of SOF, the low fidelity of HCV viral RNA polymerase predisposes SOF to drug resistance. As such, if sofosbuvir-velpatasvir is being considered, baseline NS5A genotype 3 resistance testing should be done, and if the Y93H resistance-associated substitution (RAS) is found, ribavirin should be added to sofosbuvir-velpatasvir [44]. Although several DAA’s have a high genetic barrier to treatment-emergent RAS, mutations such as S282T (Sofosbuvir) [45,46], NS5B L159F, V321A (Sofosbuvir/Ledipasvir)[47], Q30H/Y, L31M/L31V, M28A, Q30K/E, Y93C/H/N, Y93H (Ledipasvir)[48], Q80K, R155K, D168E, D168V (Simeprevir)[36], D186E, L31I, P58S, Y93H (Pibrentasvir, P32 gene deletion (Glecaprevir/Pibrentasvir)[49,50], and M28, Q30, L31, Y93, L31 (Velpatasvir) [51], these reduce the efficacy of DAAs. The impact of these pharmacodynamic properties of DAAs on pregnancy are currently unknown.

6.0. PHYSIOLOGIC CHANGES DURING PREGNANCY RELEVANT TO DAA DISPOSITION:

Pregnancy can affect the disposition of DAAs used for HCV therapy in several ways, including changes in drug absorption, distribution, metabolism, and elimination. A summary of the physiological effects of pregnancy and how they can affect DAA drug disposition is shown in Figure 1.

Figure 1:

Changes in pregnancy physiology that might affect the disposition of DAAs:

6.1: Drug absorption following oral intake during pregnancy:

During pregnancy, increase in plasma concentration of progesterone is usually associated with longer gastric emptying times, increased gastric pH, and longer times to achieve T_max [52,53]. The prolonged gastrointestinal emptying times during pregnancy can affect the concentration of drugs whose absorption are influenced by food, like Ombitasvir/Paritaprevir/Ritonavir/Dasbuvir (OBV/PTV/r/DSV), and SIM [36]. The increased gastric pH due to lower acid and higher mucus production affects ionization and absorption of acidic HCV drugs, leading to reduced absorption [52,54]. For instance, LDV is a weak acid, and has the potential for decreased absorption during pregnancy due to complexities with drug ionization at the gastrointestinal interphase.

Changes in drug transporter activity play significant roles in drug absorption [53]. The most extensively studied intestinal transporters belong to the ATP binding cassette (ABC) family. These include ABCB1, also known as P-glycoprotein (P-gp), ABCG2, also known as breast cancer resistance protein, and ABCC2, called multidrug resistance-associated protein 2 (MRP2)[53]. Almost all the DAA drugs are substrates of P-gp and/or other transporters whose actions can increase or decrease during pregnancy, with the potential to affect drug absorption and bioavailability. Some of these gastrointestinal and hepatic transmembrane transporters undergo changes that occur during pregnancy that can affect the disposition of HCV drugs. For example, OATP1B1/3 is a primary uptake transporter for Grazoprevir (GZR), and there is an approximately 50% decreased expression of OATP1B during pregnancy (as demonstrated in hepatocytes of pregnant rats)[53]. Therefore, it is plausible that due to the decrease in OATP1B expression in the liver/bile ducts during pregnancy, hepatic absorption of GZR would likely decrease during pregnancy. The effects of these drug transporters on HCV drugs during absorption remain unknown and is currently being studied by the International Transport Consortium (ITC).

6.2: Drug distribution in pregnancy:

Pregnancy is associated with changes in drug distribution because of a 40–50% increase in blood volume and increased body fat that occurs during pregnancy[53,55]. The increase in plasma volume results in a dilutional decrease in plasma protein concentrations, decreased protein binding ability, and increased fraction of free drug (non-protein bound pharmacologically active drug fractions during pregnancy that correlates with therapeutic and adverse effects). The pharmacokinetic consequences of increased volume of distribution during pregnancy is that hydrophilic drugs tend to be relatively minimally distributed and are limited within the plasma compartment (low volume of distribution)[53], while hydrophobic drugs generally tend to have a large volume of distribution, particularly into fatty tissues during pregnancy[53]. These physiologic changes may result in increased loading and maintenance medication dosage requirements for HCV medications, as well as the potential for sub-therapeutic drug dosing during pregnancy. Many DAAs are highly protein-bound[34,36–38]. For example, Grazoprevir/Elbasvir (GZR/EBR) are highly protein-bound (98.8% for GZR and 99.9% for EBR), with a large volume of distribution of 1,250 and 680 liters for GZR and EBR respectively[56]. It is expected that the volume of distribution of GZR/EBR would further increase during pregnancy and can have profound effects on the pharmacokinetics and pharmacodynamics of GZR and EBR. Pregnancy studies are needed.

6.3. Drug metabolism in pregnancy:

Changes in drug metabolism during pregnancy can highly impact the pharmacokinetics of HCV drugs[53]. The increase in cardiac output increases hepatic blood flow during pregnancy and can lead to increased elimination of drugs with high-extraction ratios[54], as the elimination of these drugs are dependent on hepatic blood flow (perfusion-rate dependent). The activity of the CYP family of enzymes (especially CYP3A family), one of the largest and most active phases I enzymes, generally increases during pregnancy[52,53]. This is usually accompanied by decreased plasma concentrations of CYP3A substrates, including some HCV DAAs like GZR, EBR, and PTV. Cathepsin A, which metabolizes SOF, is downregulated during pregnancy[53,57]. This might lead to higher levels of SOF during pregnancy. The impact of increased metabolism during pregnancy on these DAAs are yet to be fully determined.

6.4: Drug elimination in pregnancy:

Drug elimination generally tend to increase during pregnancy as a result of changes in renal function. Increased renal blood flow and glomerular hyper-filtration, as well as changes in tubular function; increased secretion and potentially reduced renal reabsorption, affect drug elimination[53,58]. These renal changes during pregnancy would likely impact serum clearance of DAAs that are predominantly eliminated via the kidneys[52]. For instance, SOF is mainly cleared by the kidneys, therefore, the increase in renal function during pregnancy might result to lower levels of SOF[34]. In addition to these alterations, changes in transmembrane receptor function, expression and regulation also alter the pharmacokinetics of drugs during pregnancy[53]. For example, studies in pregnant mice have demonstrated decreased renal expression of multi-drug resistance mutation 1 (MDR1), multi-drug resistance protein 4 and 5 MRP4 and MRP5, and an approximately 50–60% increase in messenger RNA (mRNA) and protein expression of MRP3[53]. The effects of these drug transporters on HCV DAAs during drug elimination remain unknown and need to be studied.

6.5. Placental drug transporters:

Placental drug transporters can greatly impact drug disposition during pregnancy. Not only does this affect the drug, but it also puts the fetus at risk for drugs that have teratogenic effects[59]. The most extensively studied placental drug transporters belong to the solute carrier family (SLC) and the ABC protein family[60]. As many DAAs are substrates of these drug transporters, diffusion through the placental membranes has been reported. For instance, SOF, VEL, VPR, LDV, and GLE are substrates of the placental efflux transporter P-gp[34,36,40]. As P-gp is one of the efflux transporters localized in the placenta, it could potentially affect trans-placental transport of DAAs[60]. In a recent in-vitro study by Pfeifer et al[61], placental P-gp and BCRP expression increased in HCV positive women. It is expected that placental efflux transporter P-gp would potentially help limit the fetal exposure[61], but more pregnancy studies are needed.

7.0. PHARMACOKINETIC STUDIES OF DAA USE DURING PREGNANCY:

7.1. Pharmacokinetic study of Sofosbuvir/Ledipasvir in pregnant women:

A 2021 pharmacokinetic study by Chappell et al[62] was the first to study SOF/LDV fixed-dose combination therapy in pregnant women with HCV. The study was a phase 1, open label study that took place at the Magee-Women’s Hospital, in Pittsburgh, PA, USA, (NCT02683005). Nine HCV positive women, with HCV genotypes 1, 4, 5, or 6 were enrolled. A 12-week regimen of once daily SOF 400mg/LDV 90mg was administered, and full pharmacokinetic profiles for SOF/LDV and their metabolites (GS-331007) were obtained by intensive pharmacokinetic visits at 3 timepoints: during 25–26 weeks, 29–30 weeks, and 33–34 weeks of gestation. For post-partum pharmacokinetic profiles, data from completed phase II and phase III studies in women on SOF/LDV were collected and compared to pregnancy data. No clinically significant changes were seen in the pharmacokinetic profile of SOF (AUC_tau GMR 91.1%, 90% CI 78.0–106.3) or with LDV (AUC_tau GMR 89.3%, 90% CI 68.7–116.1). However, GS-331007 demonstrated statistically significant lower plasma concentrations, with a 38% reduction in plasma concentrations during pregnancy compared to postpartum (AUC_tau GMR 62.0%, 90% CI 56.3–68.4). This was attributed to the increase in glomerular filtration rate (GFR) in pregnancy, as GS-331007 is renally eliminated. However, the clinical utility of this finding is unknown, as GS-331007 is an inactive metabolite with no significant effect on efficacy of SOF/LDV. Most importantly, there was a 100% HCV cure rate at completion of the 12 weeks of therapy in all 9 participants. One participant had detectable viral loads at delivery, but this was attributed potentially to medication adherence issues. No significant adverse events were reported, and no cases of HCV perinatal viral transmission occurred. Overall, the study demonstrated that SOF/LDV had high efficacy, tolerability, and safety during pregnancy, with no clinically significant changes in plasma SOF/LDV drug concentrations. Although this was a small pharmacokinetic study, it was pivotal to increasing HCV DAA pharmacokinetic studies in pregnant persons.

7.2. Pharmacokinetic study of Sofosbuvir/Velpatasvir during pregnancy in HCV positive women:

This is an on-going phase I pharmacokinetic study in pregnant women with chronic HCV[63]. The study is aiming to enroll 10 pregnant participants with detectable HCV viral load and complete a 12-week regimen of SOF/VEL during the second and third trimesters of pregnancy. The study is being conducted at the Magee Womens Hospital, Pittsburgh, PA, USA, and registered on ClinicalTrials.gov (NCT04382404)[63]. Screening visits will occur between 14- and 22-weeks of gestation, when informed consents will be obtained, and HCV viral load determined. The study will include several maternal prenatal, intrapartum, and postpartum visits, including three visits where the pharmacokinetic profiles of VEL, SOF, its inactive metabolite GS-331007, and its intracellular active metabolite GS-461203 will be evaluated. Postpartum infants follow up visits are expected to occur to assess infant outcomes following exposure to SOF/VEL. The study is estimated to be completed in December 2023.

8.0. EPIDEMIOLOGICAL STUDIES AND CASE-SERIES OF DAA USE DURING PREGNANCY:

With the increasing incidence of HCV infection in younger women, especially in women of child-bearing age, identifying potential safe treatment options for pregnant individuals is critically important[64]. Currently, no HCV therapy is approved for use in pregnant women. In addition, postpartum HCV therapies are not always possible due to poor adherence following delivery[64,65]. As a result, HCV DAA studies are currently being advocated during pregnancy because pregnant women have medical insurance coverage, and the prenatal period may be the only window to screen and treat them[66,67]. A summary of all available HCV DAA studies is as shown in Table 2.

Table 2:

Currently published and ongoing studies on DAA use during pregnancy

Author	Year of publication	Number of participants	Results	Research gap
Chappell et al.	2022	9 HCV positive women	9 women had SVR with only one having low viral load at delivery (non-adherence), no adverse events in infants. No mother to child transmission.	Low number of participants; short duration of treatment follow-up. ost-treatment follow-up preferred
Kushner et al.	2022	23 HCV positive women, of which 15 agreed to treatment in pregnancy (7 treated in pregnancy and 8 in the postpartum period)	12 out of 15 patients (80%) completed DAA therapy out of which 5 were lost to follow up, while 6 patients achieved SVR12.	High percentage of patients were lost to follow up. Strategies for recruitment and retention for HCV studies are critically important.
Chappell et al.	Estimated to be completed in 2023	Aiming to enroll 10 participants	Awaiting efficacy and safety outcomes	-
Yattoo et al.	2018	15 HCV positive women	Mothers had SVR upon treatment completion. No adverse events in the infants.	Small case series of participants who became pregnant on DAA Therapy. Small sample size; Lacks external validity.
El Sayed et al.	2019	8 HCV positive women	7 women had uneventful delivery, 1 had postpartum hemorrhage. One infant had low viral load.	Small case series of participants who became pregnant on DAA Therapy. Small sample size; Lacks external validity; Participants did not complete treatment
Zeng et al.	2022	2 HCV positive women	The 2 women had undetectable viral load after 2 weeks of treatment and achieved SVR after 12 weeks. Infants were healthy with no adverse events.	Small case series of participants who initiated their treatment while pregnant. Small sample size; lacks external validation.
AbdAllah et al.	2021	9 HCV positive women	7 women achieved SVR after treatment completion. Their deliveries were normal. 2 women were lost to follow-up.	Small case series of participants who continued their HCV treatment during pregnancy. Small sample size; 2 participants were not assessed; lacks external validation
Chappell et al.	Estimated to be completed 2025	Estimated to enroll 100 participants	Awaiting efficacy and safety outcomes	-
The Task Force for Global Health	Estimated to be completed 2023	Estimated to enroll 100 participants	Awaiting efficacy and safety outcomes	-

8.1. TiP-HepC Registry

The Treatment in Pregnancy for Hepatitis C (TiP-HepC Registry, NCT05368974) is an observational, global clinical registry supported by the Coalition for Global Hepatitis Elimination (CGHE) and the CDC [68,69]. It aims at scaling efforts for HCV screening and therapy during pregnancy, and sharing pregnancy outcomes, in an effort to encourage collaboration and gather more information for safe DAA therapies [68,69]. The study, which is currently recruiting, is collecting data on HCV positive pregnant women who are exposed to DAA during pregnancy. The primary outcome is the number of adverse pregnancy or birth outcomes, while secondary outcomes include the proportion of participants achieving sustained virological response (SVR12) – defined as undetectable viral load at 12 months following DAA therapy; and proportion of infants infected with HCV within 18 months. The TiP-HepC Registry is estimated to enroll 100 participants, and collected data will be analyzed at 6-monthly intervals.

8.2: Sofosbuvir/Velpatasvir treatment of chronic hepatitis C during pregnancy (STORC):

Safety, Tolerability, and Outcomes of Velpatasvir/SofosbuviR in Treatment of Chronic Hepatitis C Virus During Pregnancy (STORC, NCT05140941) is a phase 4 study on the use of SOF/VEL in pregnant individuals with positive HCV[70]. It is a multi-center study, aiming to enroll 100 pregnant persons with chronic HCV during the second and third trimesters of pregnancy. The study includes a screening visit, followed by the initiation of a 12-week regimen of SOF/VEL in pregnant women. The study will follow mothers (maternal visits) infants and will describe safety and adverse events. The primary outcomes include the number of pregnant participants who achieve sustained virologic response after completion of the regimen, and the prevalence of preterm birth (number of participants who deliver before 37 completed weeks of gestation). Secondary outcomes include the number of maternal and infant participants experiencing adverse events, number of participants experiencing postpartum hemorrhage, stillbirth, gestational diabetes, adverse effects in infants, and prevalence of detectable HCV in infants up to 12 months follow-up. The study is estimated to conclude in April 2025[70].

8.3. Sofosbuvir/Ledipasvir treatment of chronic hepatitis C in pregnant women (n=15):

This is one of three case series published in recent years in women on DAA regimens who were pregnant and chose to continue DAA therapy during pregnancy. The first one by Yattoo et al[71] was reported from India. Of the 15 HCV positive, non-cirrhotic, pregnant women included in the study, ten had HCV genotype 3 while four had HCV genotype 1. All participants continued on SOF/LDV during their second and early third trimesters to complete a 12-week course of therapy. The participants had SVR12 after treatment completion without safety concerns. The infants were delivered with no adverse events.

8.4. Sofosbuvir/Daclatasvir use during pregnancy (n=11):

This second study was reported by El Sayed et al in Cairo, Egypt[72]. This was a case-series of HCV positive women of child bearing age who received SOF/DCV (with or without ribavirin) for treatment of HCV. Among the cohort, eleven women receiving SOF/DCV became pregnant, among which eight were contacted for additional data and follow-up. Seven of the eight women (88%) were reported to have discontinued DAA therapy after 4 weeks, and one (12%) after 8 weeks of therapy. All women achieved term pregnancies, with only one pregnancy complicated by postpartum hemorrhage. Of the 8 infants, only one had plasma-detectable HCV at 18 months. There were no congenital anomalies reported.

8.5. Sofosbuvir-based therapy for late pregnant women and infants with severe chronic hepatitis C: A case series study (n=2)

This was a recently published case-series by Zeng et al (May 2022) involving two pregnant participants who commenced SOF/VEL and SOF/LDV at 26 weeks and 31 weeks of gestation respectively, to complete 12 weeks of therapy[73]. The participants were diagnosed with severe chronic hepatitis C with hepatic transaminases >5 times the upper limit of normal, necessitating initiation of therapy by the authors. The participants were monitored for the duration of the therapy and for 12 months post-treatment for efficacy and adverse effects of these DAAs. Both pregnant participants were cured, with undetectable HCV RNA levels after 2 weeks of therapy, and SVR upon treatment completion. No serious adverse events were reported in the follow-up period.

8.6. Direct antiviral therapy (SOF/DCV, SOF/DCV/Ribavirin, and PTV/OBV/Ribavirin/Ritonavir in an Egyptian cohort (n=9).

AbdAllah and colleagues[74] followed nine women who became pregnant on DAAs and completed 12 weeks of therapy. Seven participants (78%) achieved term pregnancies while the other two participants (12%) were lost to follow-up. All seven participants were cured, with undetectable HCV RNA levels at 12 weeks of therapy, and SVR upon treatment completion. No serious adverse events were reported in the follow-up period.

9.0. SELECT DAA DRUG-DRUG INTERACTIONS (DDIs) AND POTENTIAL EFFECTS DURING PREGNANCY:

As many of the DAAs are metabolized by the CYP450 enzymes, many DDIs occur that influence CYP450 activity, interfere with DAA concentrations, and potentially alter their activity. Further, as several of the DAAs are also substrates of similar drug transporters, changes in transporters activity can also affect the uptake or efflux of DAAs used for the treatment of HCV[75]. Many DAAs are inhibitors or activators of CYP450 enzymes or transporters, therefore they can also affect other drugs[75,76]. While the common HCV DAA DDIs are previously described in detail, some clinically significant DAA DDIs that affect pregnancy and postpartum women are discussed in section 9 of this review.

9.1: HCV/HIV co-infection –

DAA and ART use in HCV/HIV co-infection can result in significant DDIs. Sofosbuvir, though not metabolized by CYP5450, is a substrate of both P-gp and BCRP drug transporters. Ledipasvir is also a substrate, as well as an inhibitor of the same P-gp and BRCP drug transporters[34]. Co-administration of SOF/LDV with the fixed dose combination ART Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate demonstrated reduced tenofovir plasma concentrations, although not considered clinically significant[34,77]. Direct antiviral agents like SIM and DCV are all substrates of CYP3A, and have been demonstrated to interact with Efavirenz, a CYP3A and CYP3D6 substrate and inducer[36,77–79]. Ritonavir, a CYP3A inhibitor, when co-administered with Efavirenz or Rilpivirine, results in higher plasma concentrations, and potentially harmful levels of these ARTs [80]. These DDIs are important to consider in pregnant persons living with HIV and HCV who are on ART and DAAs, as reduction of viral efficacy of ART during pregnancy due to a DDI can potentially result in vertical transmission of HIV.

9.2: Interaction with antacids:

Several DAAs have pH-dependent solubility in the gastrointestinal tract following ingestion that can cause potential DDIs when co-administered with acid-suppression therapy. This becomes critically important drug in pregnancy, as gastric pH generally increases. For instance, a few studies have demonstrated reduced plasma concentrations of DCV when co-administered with Omeprazole or Famotidine, though the reduced serum levels of these DAAs were not clinically significant [78,81]. Co-administration of SOF/LDV with Omeprazole, or SOF/VEL have demonstrated significant reductions in the serum concentration of these DAAs, and are considered clinically significant, and co-administration generally avoided [34,37,81].

9.3: Interaction with contraceptives:

Many women of childbearing age use oral contraceptives (OC) while on DAA therapy to avoid unwanted pregnancies. Ethinyl-estradiol and norethindrone, the main components of OC, are metabolized by CYP3A[82,83]. Ethinyl-estradiol is also a substrate of BCRP and P-gp [82]. Therefore, potential DDIs can occur. SOF/LED has been reported not to have clinically significant DDIs with OCs[84]. Similarly, EBR/GZR and SIM can be taken with OC without dose adjustment, as co-administration of OC and these DAAs do not cause clinically significant changes in drug concentrations [85,86]. Conversely, some DAAs like OBV, PTV/r, and DSV, are not recommended to be used with OC, as DAA-induced liver injury with elevated alanine transaminases has been reported [87].

9.4: interaction with antihypertensives:

Hypertension is a common condition in pregnancy, and the commonly used antihypertensives during pregnancy are labetalol, nifedipine, and methyldopa[88]. No significant DDIs have been demonstrated between DAAs and methyldopa[89]. Labetalol is metabolized by UGT1A1[90]. Since OBV, PTV, and DSV are all inhibitors of UGT1A1, potential interactions can occur. Nifedipine is a substrate of CYP3A4[90,91], therefore co-administration with CYP3A4 inhibitors like SIM or ritonavir may increase SIM plasma concentrations[36,89]. The University of Liverpool database, dedicated to the research and study of drug-drug interactions, is an important resource[92].

10.0: DAA USE AND THE RISK OF CONGENITAL ANOMALIES:

Ribavirin has been associated with teratogenic and embryotoxic effects, therefore not currently recommended for use during pregnancy [93,94], but newer ribavirin-free DAA regimens may have promise for use during pregnancy. Until the recent SOF/LDV pharmacokinetic and safety study, there were no in-human studies demonstrating the safety and efficacy of DAAs in pregnant individuals. In pre-clinical animal studies of SOF/LDV, no serious acute or chronic toxicities were described [34]. Both LDV and SOF metabolites (GS-331007) were noted to be excreted in breast milk of animal models, with no adverse effects on neonatal and infant development [34,37]. In addition, a recent case-report of a mother who breastfed for 3 weeks while on SOF/LDV demonstrated no significant adverse events [73]. Safety data from the SOF/LDV pharmacokinetic and safety study continue to be reassuring.

Limited available data on other DAAs have been reassuring. While the FDA package insert does not mention any significant toxicity or congenital anomalies when VEL was used in pre-clinical studies [37], the European Medicine Agency (EMA) describes higher rates of visceral malformations seen in pregnant rats treated with VEL [95]. Velpatasvir was demonstrated in breast milk, but no effect on postnatal development was described [37]. Similar favorable safety profiles were noted in other DAAs, with no reproductive toxicity, adverse events on fertility, or harmful impact on postnatal development.

11.0. CONCLUSION:

Direct antiviral therapy show promise as a preferred treatment option for pregnant women with HCV, as it is curative for maternal HCV infection, and can potentially prevent vertical transmission of HCV. However, DAAs are not currently recommended for use during pregnancy due to limited pharmacokinetic and safety data. While no large randomized clinical trials or prospective cohort studies involving DAAs have been completed in pregnancy, the currently available studies demonstrate no clinically significant changes in pharmacokinetics, and no major safety concerns in pregnant women with hepatitis C exposed to DAAs. As more pharmacokinetic and epidemiologic data become available, DAAs could become a preferred option for treating HCV during pregnancy, making elimination of perinatal transmission of hepatitis C virus a reality.

12.0. EXPERT OPINION:

The lack of large clinical trials with DAA use in pregnant women has limited their use during pregnancy, but this is not surprising, as it is the unfortunate reality for most new drugs during pregnancy [19,20]. It takes a median of 8–10 years from FDA approval of a drug and its use in pregnant women. The physiologic changes that occur during pregnancy pose additional challenges to understanding the pharmacodynamics and pharmacokinetics of drugs used in pregnant women. Changes in drug absorption, distribution, metabolism and excretion can significantly alter drug disposition in pregnant women, and these changes have led to discontinuation of certain medications for use during pregnancy due to the significantly reduced plasma concentration in pregnant women [96–98]. The just concluded phase I pharmacokinetic and safety clinical study of SOF/LDV in pregnant women is a pivotal milestone for DAA HCV treatments in pregnancy and offer hope for deployment of newer DAAs for use in pregnant women. As discussed in section 7.1, no significant dosage changes were noted in LDV or SOF during pregnancy, with no adverse events seen in the participants or the infants.

Treatment of HCV during pregnancy is desirable and is justified for several reasons. First, pregnancy is a time when many women who attend prenatal care obtain health insurance for most medications used for preventive and curative therapy. This creates a window of opportunity to be screened for HCV for the first-time in pregnancy. Hepatitis C DAA can then be integrated with prenatal, intrapartum, and postpartum care to increase rates of hepatitis C cure. Second, any delay in HCV therapy results in fewer people progressing along the HCV care cascade to cure, and is an impediment to HCV elimination goals. Third, for some people with poor adherence. (e.g., due to lack of insurance or substance use disorder), the pregnancy and postpartum period may be the only window to treat them. Studies of DAAs among women living with HIV demonstrate similar rates of sustained viral response (SVR12).

The potential advantage of using DAAs during pregnancy is the ability to both treat pregnant patients with HCV while they are receiving antenatal care and lower the risk of perinatal transmission. Some studies have demonstrated that many women prefer to have DAAs commenced during pregnancy to treat HCV to potentially reduce perinatal transmission of HCV [99], However, DAAs are not recommended to be used during pregnancy due to limited safety, efficacy and pharmacokinetic data. As results from ongoing HCV DAA pregnancy studies become available, some of the newer DAAs may become incorporated into HCV pregnancy management guidelines. In the meantime, clinicians should continue to use the American Association for the Study of Liver Diseases (AASLD)[30] and the Infectious Diseases Society of America (IDSA) recommendations that individuals be treated for HCV before conception or during the postpartum period on a case-by-case basis [23].

Despite these potential advantages, large gaps remain on what we know and understand about DAA use in pregnant women with HCV infection, and there are currently no large clinical trials on DAA regimens in pregnant women. The continued interval and dearth of information about the effects of medication use during pregnancy[100–102] and the ways in which pregnancy alters pharmacokinetics and drug response that exist from when a drug receives first licensure in the adult population and when pregnancy safety, pharmacokinetic, pharmacodynamic and efficacy data become available, has been a chronic failure of several drug development pipelines and processes [96]. Like with most other drugs, pregnancy pharmacokinetic, pharmacodynamic, and pharmacogenomic data are not necessary requirements for licensure of DAAs. As such, most pregnant women are precluded from participating in early phases of drug development of these DAAs. The downstream effect of excluding pregnant women from initial phases of drug development programs is that it takes a longer time to obtain this pregnancy-specific information, which can sometimes demonstrate reduced plasma drug concentrations during the second and third trimesters of pregnancy.

The lessons learned from study of several ART pharmacokinetics during pregnancy has demonstrated the urgent need to encourage the recruitment, participation, and retention of pregnant women in drug development programs, to be involved at about the same time when such studies are being completed in non-pregnant adults [103,104]. We need to constantly develop new and efficient methods to study drug kinetics in pregnant women. Direct HCV antiviral therapy drug development programs should include pregnant women in early phases of drug development programs so that pregnancy-specific pharmacokinetic and safety data are available at time of initial approval to help guide clinicians and patients on DAA drug selection and dosing. Expanding HCV therapy to pregnant women will not only lower barriers to care and further HCC elimination goals, but may reduce perinatal transmission of hepatitis C of the incident pregnancy and will potentially eliminate vertical HCV transmission risk to subsequent pregnancies. The time to act is now.

Article highlights.

• Hepatitis C virus (HCV) infection continues to be a critical public health problem. In pregnant women, approximately 3–6% of infants born to HCV positive women become infected.

• Recent advancements in direct antiviral agent (DAA) therapy have made many more efficacious and tolerable treatment options available. However, DAAs are not currently recommended for use during pregnancy due to limited pharmacokinetic and safety data.

• Pregnancy represents an ideal window of opportunity for HCV DAA therapy given that pregnancy is a time of high healthcare engagement, enhanced insurance coverage, and improved adherence to antiviral therapy (as evidence has demonstrated with the use of antiretroviral therapy to prevent perinatal transmission of HIV)

• Despite these potential advantages, the continued interval and dearth of information about the effects of medication use during pregnancy and the ways in which pregnancy alters pharmacokinetics and drug response that exist from when a drug receives first licensure in the adult population and when pregnancy safety, pharmacokinetic, pharmacodynamic and efficacy data become available, has led to large gaps on what we know and understand about DAA use in pregnant women with HCV infection

• Expanding HCV therapy to pregnant women will not only lower barriers to care and further hepatocellular carcinoma elimination goals, but may reduce perinatal transmission of hepatitis C of the incident pregnancy, and will potentially eliminate vertical HCV transmission risk to subsequent pregnancies.