Good afternoon, everybody. Welcome to today's webinar on hepatitis C virus in pregnancy, an opportunity to screen and treat. My name's Julie Kmic and I'll be your moderator for this session. Today, we have Dr. Catherine Chappell as our presenter. Dr. Chappell is an academic obstetrician gynecologist who completed fellowships in reproductive infectious diseases and family planning, and is board certified in addiction medicine. She provides perinatal addiction medical care at McGee Women's Hospital at the University of Pittsburgh Medical Center. Her research focuses on evaluating the safety and efficacy of cefosbuvir-based treatments for hepatitis C treatment in pregnancy. So welcome Dr. Chappell. Thank you so much for that introduction. Does my, do my slides look okay? Switch your view. I switched it wrong. Okay, how about this? It's good now, thank you. Okay, good, thank you so much. Well, I really appreciate the opportunity to talk about our work on how we can improve management of hepatitis C during pregnancy. And we are not quite yet at a test and treat strategy, but we are making great strides in that direction. And I'm going to talk to you a little about, a bit about where we've come for both screening and a treatment perspective and where we're going to go in the future. So I have to show this, and then I just want to disclose that I'm going to present to you some data that was funded by Gilead Sciences, who is the maker of cefosbuvir-valpatavir. So the newly reported cases of hepatitis C most recently present with a bimodal distribution, meaning that we've really seen a significant shift in the epidemiology, and this is due to the opioid crisis. So first, historically, hepatitis C was thought to be a disease of the baby boomer generation. This was primarily due to healthcare-related exposures prior to our being able to test for hepatitis C. But most recently, due to the opioid epidemic, we've seen an increasing prevalence among persons of reproductive age. And so now that we have this bimodal distribution, where we see actually that the people of reproductive age have overcome the baby boomer generation, we still do see that men outnumber women with the reported hepatitis C cases, but there may be some reporting bias there. And I'm personally practicing, as mentioned, in Pittsburgh and Pennsylvania, and there are some states where we may actually see more similar distribution among men and women, especially in that younger generation. And epidemiologists are concerned because of this epidemic among persons of reproductive age, and because women of reproductive age do get pregnant, that we may, in the future, see a trimodal distribution of hepatitis C, where we see an epidemic that also is occurring in children due to perinatal transmission of hepatitis C. So I'm gonna present to you a case along the way of this that's very similar to many cases that I see in my practice, to kind of put a personal face to the data that I'm gonna present. So TJ is a 33-year-old gravitative two pair one, meaning she's had one previous child at term. She's at 14 weeks, she comes in for routine antenatal care. She has a history of opioid use disorder. She's been in recovery for two years since the birth of her previous child, and she was not screened for hepatitis C in her previous pregnancy. Should she be screened for hepatitis C in this pregnancy? All of the questions are rhetorical, so I will be answering them, and the answer is absolutely yes, and it's not because she has a history of substance use disorder or opioid use disorder. It is only because she is pregnant. Universal hepatitis C screening is now recommended in pregnancy. It was initially recommended by AASLD in 2018. It was supported by the US Preventative Task Force in 2019, and then in April of 2020, which was a wonderful time to roll out new healthcare guidelines, the CDC recommended universal hepatitis C screening, and then somewhat late to the game, ACOG and SMFN joined to support universal hepatitis C screening. At the University of Pittsburgh, we rolled out universal hepatitis C screening in June of 2020, but we got some pushback for this because there were a lot of concerns that we were doing some screening in pregnancy where we couldn't actually do anything during pregnancy according to routine clinical management at that time other than refer for treatment postpartum, and there was no really clear pathway identified for cases that we identified, and then there was a lot of concern among providers that hepatitis C, about those patients that were hepatitis C antibody positive but RNA negative, how would we talk to patients about this result? So I started a perinatal hepatitis C clinic at McGee Women's Hospital, really to address this specific concern, but also to facilitate treatment of hepatitis C in the pregnant population. So really the argument for hepatitis C screening in pregnancy is that this test was really two for the price of one. During pregnancy, women have a unique high engagement in healthcare. It's like a part-time job attending antenatal care, unique motivation, because not only are they care about their own physical health, but they also care about the health of the developing fetus. It's an opportunity for linkage for hepatitis C care and treatment, and hepatitis C treatment can prevent cirrhosis. And this test will identify all infants that were exposed, which can lead to early detection of perinatal hepatitis C transmission, and linkage to hepatitis C care and treatment and prevent cirrhosis. Just as a reminder of the recommended testing sequence for hepatitis C, the first test in the sequence is the hepatitis C antibody. If that test is positive, it does not necessarily mean somebody has hepatitis C, it just means that they've been exposed to hepatitis C. So if that's reactive, it's recommended that a hepatitis C RNA test or viral load is done ideally on the same sample. And then if hepatitis C RNA or the actual hepatitis C virus is detected, then that means that they have current hepatitis C infection and they should be linked to care. One caveat is that if somebody has a recent diagnosis, they may not have formed an antibody response yet or a recent risk factor for infection, and you're concerned about acute hepatitis C infection, you may want to get a hepatitis C RNA test instead. So I mentioned ideally hepatitis C antibody with reflex RNA test is ideal, and that's what we have done at UPMC with the rollout of universal hepatitis C screening among pregnant persons. What that means is that if that hepatitis C antibody test is positive, then the hepatitis C RNA test will automatically be done in the laboratory on the same sample, so the patient doesn't have to get a repeat blood draw. So this is really facilitated diagnosis of active hepatitis C. So I just want to tell you about our experience, but first I need to define what actually was going on during risk-based versus universal hepatitis C screening in pregnancy. Risk-based screening was screening of patients with only with risk factors in pregnancy, and this was done just by getting the hepatitis C antibody and then the RNA test would have to be done on a separate blood draw, but some providers didn't do even the RNA test, so they would just say somebody is hepatitis C positive based on the antibody result. Universal hepatitis C screening is now done on all pregnant patients with the reflex test. So we looked at what happened when we rolled out universal hepatitis C screening. So we collected a year of data on patients in 2019 that underwent risk-based screening. We excluded the disaster time period of the early COVID pandemic, because we were worried about low healthcare utilization, and then we compared the result from the risk-based screening to the universal screening, which started in July of 2020 and went on for a year. Universal screening, it was again initiated in June of 2020, and it was utilizing a best practice alert that would pop up if a provider ordered a new OB panel, but didn't also include a hepatitis C test. And so we reviewed records for nine months before and after the initiation of prenatal care, and we compared these using the Fisher's exact test. So this table shows what was the bang for our buck, changing from risk-based screening to universal screening. So as you can see, we had a similar number. These were all the same practices of new OB patients in the risk-based period versus the universal screening period. We had an increase from 23% to 81% of total people being tested for hepatitis C with antibody testing. We had an increase of 1.2% of being positive during risk-based, and we found an additional 0.7% in the universal screening, so it went up to 1.9. And this was the kind of, I think the most important finding is we really increased the number of hepatitis C RNA tests done on the hep C antibody positive results from 22% to 95%. So that was critically important. And that way we were able to find an increase of 0.09% to 0.68% or sevenfold increase in detection of active hepatitis C. So universal screening resulted in a significant increase in hepatitis C detection in our population. And it really goes to show that risk-based screening for things, especially things that are where you ask patients, you know, that are stigmatized things like injection drug use, it just really is not a great strategy. It's also a stigmatizing strategy, and I really think universal hepatitis C screening is really a step forward from a public health perspective. So back to our case. So as you know, in her previous pregnancy, she was not screened, but her current testing results show that she has hepatitis C antibody positivity and hepatitis C RNA detectable as well. These are pretty typical results here. So for chronic hepatitis C infection. And so she asked you, you know, what really are the implications of having hepatitis C? And just as a reminder, hepatitis C is a virus that infects the liver, but just because you are exposed to hepatitis C does not mean you will always get it. There is about a 40 or so percent rate of clearance, spontaneous clearance, and then your results would look like hepatitis C antibody positivity, RNA negativity. Now, if the, now, if you do go on to acquire chronic hepatitis C, meaning your hepatitis C RNA test is positive for greater than six months, then you by definition have chronic hepatitis C. It takes about 20 or 30 years for it really to impact the liver. And the sequelae of that are cirrhosis, and then with cirrhosis, the risk of cirrhosis is really hepatocellular carcinoma, a risk of one to 4% per year, or end-stage liver disease, requiring transplantation in two to 5% per year. And so this, although oftentimes patients are completely asymptomatic, this infection does have significant health consequences. It is still a frequent cause of liver transplantation despite the advent of DAAs. So what is the impact of hepatitis C on pregnancy? What about specifically maternal health? There's been a number of studies trying to get at this. I will say it is a challenge because the control group is a question. So should the control group of the impact of hepatitis C be persons just without hepatitis C, or perhaps there's some confounding variables like poverty, substance use that may impact the findings. But what we know is that it may or may not have an increased risk of gestational diabetes. So we don't know that much about that. But what is more convincing is that there is an increased risk of intrapartic cholestasis of pregnancy. And I definitely see this clinically. Hepatitis C is a certain risk factor for this. And clinically, it does make sense. It at least doubles the increased risk of intrapartic cholestasis of pregnancy. And cholestasis of pregnancy is actually quite dangerous. It is associated with a two and a half fold increase in stillbirth. Cholestasis of pregnancy, how I'd like to explain it to patients is that the liver stops processing the bile and the bile acids build up in the blood system. And that can actually be quite dangerous. It causes itching in the palms of the hands and the soles of the feet. And usually we see it later in pregnancy in the third trimester, but I have seen earlier cases, especially in the setting of hepatitis C. Recently, Tatyana Kushner did a nice analysis comparing hepatitis C antibody positive RNA negativity cohort to hepatitis C RNA positivity cohort and found that there was an increased risk of postpartum hemorrhage with hepatitis C, active hepatitis C by remia. What about the impact of hepatitis C on the neonate? Again, there's some data that can be quite confounded, but some of the studies indicate that preterm birth is certainly higher in persons with active hepatitis C. Fetal growth restriction is higher, which is associated with low birth weight. There has also been published reports of admission to NICU, mechanical ventilation and congenital anomalies, but this may be more related to confounding. But I suspect that chronic viremia leads to immune activation, which can certainly increase your risk of preterm birth and fetal growth restriction. Again, I just want to mention that the caveat with any of these findings in these observational studies is that it's really difficult to know with certainty if the adverse fetal outcome is actually due to viral effect or potential confounders in the population being studied. So there's, but it seems the more we're gathering data, the more it seems like the preterm birth and fetal growth restriction with appropriate controls does seem to be consistent. I think one of the most significant consequences that patients have concerns about regarding hepatitis C is the frequency of perinatal hepatitis C transmission. I will say relative to other viral infections, the transmission rate is quite low. There are two big studies. One was published in 2014 and the other published in 2022 that looked at the rate of perinatal hepatitis C transmission in both patients with HIV infection, HIV co-infection and without HIV co-infection. And overall what they have found in the blue is the total rate of perinatal transmission. And then in the red is what is actually chronic hepatitis C infection that is lasting that will require treatment. So oftentimes, so overall perinatal transmission occurs six to 7% of the time, plus or minus in a HIV negative cohort, but that infection is cleared. And so chronic infection only occurs in about three to 4%. And that's, some of this is like based on follow-up of the cohorts, they may not have no, that's why there's some variability in these rates, but if you put it all together and both of these were MAD analysis showing these transmission rates, so. So what are the risk factors of perinatal hepatitis C transmission? And this is also hard to study because again, transmission doesn't occur like all that often relatively speaking and follow-up is a little bit challenging, but it does seem that prolonged rupture membranes may increase the risk. And then any obstetric procedures that lead to intrapartum maternal to fetal blood exchange such as internal fetal monitoring, vaginal lacerations or operative delivery may increase that risk as well. And then there's some data that active injection drug use that may lead to higher levels of viremia may increase the risk of perinatal transmission. I unfortunately didn't update this slide, but there was a recent study that showed that antenatal bleeding also may increase the risk of transmission. And then there was that study that was published in 2022 about perinatal transmission, tried to get at when transmission occur, comparing those births that happen via elective cesarean delivery or non-elective cesarean delivery and also trying to do some viral kinetics to figure out when transmission occurred. And what's interesting is that relative to another virus like HIV, hepatitis C transmission actually occurs earlier. It may occur more in the second trimester than HIV does, in the late and in the third trimester, but less common at delivery. There's some assumptions in this paper that may be a little bit overstated, but this is the best data that we got about when it happens. So, and I'll talk a little bit more about that. And I apologize, I could not get this slide to look any different from this, but how do we assess for maternal to child hepatitis C transmission or perinatal transmission? Historically, it was recommended that the antibody testing occur at 18 months, and then the earliest time that you could do hepatitis C treatment for infants would be, for children would be three years old. And so that is the time when confirmatory test can happen. There's some data that actually indicates that patients make clear even after three years old, and it's really hard to get a three-year-old to take medications, as I have a almost three-year-old in my house right now. But the moral of the story of this slide is really that oftentimes screening for perinatal hepatitis C transmission has not been done. It's only done about 11 to 30% of the time with that hepatitis C antibody test. So back in October, very recently, the CDC came forward and recommended that testing occur earlier, more when we have the minds, we're thinking about perinatal transmission that occurred so closer to the birth is maybe the time where we should be testing. So they changed their recommendations to test all perinatal exposed infants with nucleic acid amplification tests between two and six months. And those that are exposed is defined by the hepatitis C RNA test. So it's critically important for everyone that has hepatitis C antibody tests to also get the hepatitis C antibody positivity to also get the hepatitis C RNA test. If there's no RNA test, then they just recommend going ahead and screening. So with this recommendation, it's actually more critically important to do hepatitis C screening in pregnancy also because those testing results drive how we screen the infants. I will say that in our recent experience, we have had some perinatal transmissions that have occurred where the hepatitis C RNA test was undetectable. Now, what that says to me probably happened is that there was a reinfection that occurred during pregnancy. So we also have to think about re-screening patients close to delivery that have active risk factors. And that is actually very challenging to do. So what are the interventions that we do currently to prevent perinatal hepatitis C infection? Are there lessons that we've learned from HIV? What about elective cesarean delivery? Now, there's really no randomized clinical trials of this, but there is one relatively large meta-analysis that showed that there was no change in transmission. So for that reason, elective cesarean delivery is not recommended based on just maternal hepatitis C status. What about avoidance of breastfeeding? Actually, there is no or very little hepatitis C RNA found in the breast milk, and there is no increased risk of transmission in breast versus bottle feeding. So breastfeeding is considered safe for patients with active hepatitis C infection. The caveat is if there is over blood bleeding or cracked nipples where, and this doesn't occur too often, where there's concern about blood exposure because of viremia, then the mom should consider pumping and dumping until she is no longer having active blood in the breast milk. What about, so what we actually do is something that's not very, in the guidelines is not very helpful. We avoid procedures that may increase maternal to infant blood exchange. And I will say that we, as an obstetrician, despite what you may hear from your all natural health influencers, we often do not do procedures, invasive procedures, without significant indication. So we only do fetal scalp monitoring if we cannot monitor the baby. We only do amniocentesis if there's an indication. We do operative delivery in urgent scenarios where we're concerned about the fetal wellbeing. And some people also recommend delayed cord clamping. I think we've kind of loosened that up now at the McGee, at McGee, but that is based on only theoretic concerns. So fortunately, there was a very recent revolution in hepatitis C treatment with the advent of DAs who offers an opportunity to consider, to really eradicate hepatitis C if you can get the treatment to the people that need it. The Lidipazivir, Cepasivir was the first DA regimen that was FDA approved in 2014, followed by Cepasivir, Velpatazivir, and then Proventazivir, Goklapavir. That one is even worse than those previous ones, but they all work extremely well, over 95% cure rate with eight to 12 weeks of treatment. These are oral medication taken once a day. They're extremely well-tolerated. So because we don't have many chronic viral infections that have cures, I tell my patients that if I were to choose any chronic viral infection, it would absolutely be hepatitis C. And I really think that stigma is what drives this negativity around hepatitis C in this era where we really do have excellent treatments. So right now, the only way to treat patients with hepatitis C who we identify during pregnancy is with postpartum hepatitis C treatment. So I'm going to present a few studies that have happened in different time periods and in different ways to show you how well or not well we've done that. So this was a- Sorry, excuse me. Do you mind to be clear? We did have a question that came in. Yeah, sure. Sure. And so it says, in our area, all babies get RNA checked at the two to four month visit, including moms who've had a negative viral load because they thought that they might have had varying levels. Thoughts on this? Should I fight back or just be happy that anyone is getting tested? I think I would prefer the latter, honestly. I'm a gynecologist, so I don't want to talk too much about pediatric screening recommendations, but if a lot of people are getting tested, but if more babies are getting screened, I do think that's better. I mean, the problem is a lot of times the hepatitis C RNA tests require venipuncture, which is hard. Logistically, it's very hard. So I'm impressed. A lot of patients don't actually go get that test done. And I do have a little bit of concern, especially for very high risk patients that may have had a recurrence of use during pregnancy, that they have active hepatitis C infection, and we may miss actually diagnosing this in pregnancy. And those babies, because the patient had an active hepatitis C infection with high viremia and active substance use, may have an increased risk of transmission. So I don't think that, I wouldn't fight more screening personally, but I hope that answers the question. All right, so moving on to postpartum treatment. This was a retrospective cohort study done of almost 800 pregnant people with opioid use disorder at McGee Women's Hospital in the era before DAAs. And so I'm actually impressed that anyone was treated, but we had a pretty high rate of new hepatitis C diagnosis in pregnancy, and this was done during risk-based screening. We had a liver function test that were done really well. We rarely did a hepatitis C viral load during that time period, because my old OB attendings would tell me, well, what are you going to do with that result? Other than know that they had hepatitis C and prefer them for treatment, but they argued that there was nothing that you could actually do in pregnancy. We did pretty well with referral to hepatology, but very few patients attended the hepatology consultation. I think this gets at the importance of co-located care. And then a whopping just above 1% of patients were treated for hepatitis C within the year. So this was like worst case scenario. And then a more recent, this is different type of data. It was an analysis of pooled Medicaid data. So all the caveats that go on with pooled Medicaid data, looking at postpartum treatment for patients with opioid use disorder in several states. And at 60 days and at six months, we found at six months only, we got up to almost 6% that were treated with postpartum. So not great. And then recently we published a study that was actually more of a clinical trial looking at co-located integrated care of hepatitis C care with opioid use disorder care in our Pregnancy and Women's Recovery Center at McGee Women's Hospital. So we, I'm sorry, this is a little bit small, but we enrolled 32 women of who 21 or about half initiated treatment. And of those 76% completed treatment. And then we always have trouble with SVR, but presumably most people, unless they were reinfected were cured. So, and this is really kind of ideal conditions where we are, we have co-located care, we're offering substance use treatment in the same, like in the same space. And this is the treatment was provided through the study. So ideal, this was ideal scenario. And about half of participants completed hepatitis C treatment. So we got a lot of room for improvement in the postpartum period. And I really kind of get it as a person that has young children myself. I, you know, I barely can make it. I actually, I don't make it to the dentist very often. I need to get an eye exam. They keep calling me. I mean, it's just like this, there's just so many other things going on. And even if you have something significant like a chronic viral infection, if you have no symptoms and there's really no pressing reason for you to get, for you to be treated, it's really a very busy time. But what are things that we can do to increase postpartum linkage? So, you know, pregnancy and the antenatal care time, it's very busy, but people are used to coming in for the doctor. So an antenatal consult with a hepatitis C provider may increase the likelihood that somebody may come back in the postpartum period. At least they know the person, maybe they liked the person they wanted, and maybe they might come back. At least they know the number to call. Co-located care is always helpful if you can get postpartum or pediatric care or opioid use disorder care in the same location, a one-stop shop is really helpful. And honestly, hepatitis C treatment is really easy. You don't even need to have people come into the office at all. You can have somebody do their labs. They can actually do their labs while they're being delivered at the hospital, or you can send them their labs in the mail and they can do their labs. And then you can just mail them their hepatitis C treatment to their house and then hope that they will also do their SVR at the same time. So they don't even have to come in for hepatitis C treatment. And really the postpartum period is also maybe an ideal time because depending on what state you are, you have a time of extended insurance coverage that's associated with pregnancy. The caveat is the postpartum period is kind of a disaster. You're not sleeping and all that that I discussed earlier. So let's just take a step back. Let's talk about the woman in that like throughout the reproductive time of women of reproductive age. And we'll talk about when hepatitis C treatment is available. So what about, why don't we just treat everybody before pregnancy? I mean, if you can get treatment that happens before pregnancy, that would be ideal. It would have to probably occur with something else. So in a substance use treatment center, in jail, because oftentimes, women often come to the gynecologist for contraception or sometimes like that, but gynecologists are not doing hepatitis C treatment. A lot of young women do not have a PCP. So there's really no clear pathway to screen and treat women before they conceive unless it occurs because they're receiving treatment for something else. And then I talked about in the postpartum period, there's like this significant loss to follow up. So what I'm saying is that pregnancy really may be the ideal window of time for treatment when a woman is really engaged in care. The arguments in favor of hepatitis C treatment is that it would reduce that loss to follow up and they have insurance coverage. And it might, because treatment during pregnancy might decrease the risk of perinatal hepatitis C transmission and then children affected by perinatal hepatitis C develop cirrhosis at a younger age than children that acquire it through other ways. So there may be really prevention of perinatal transmission may not only just reduce the risk of infection, it may also reduce the risk of significant sequelae of hepatitis C infection that may be worse if transmitted perinatally. And then surveys indicate that the majority of women with hepatitis C would be interested in hepatitis C treatment in pregnancy, but they're really wanted, they only, many want it only if it could also decrease the perinatal transmission. So they really want also there to be some fetal benefit. Now, why we're not just doing this is because there are few data on the safety of hepatitis C treatment in pregnancy or in the safety of treatment with breastfeeding women. I will say that, and this is not quite updated in the slides, that AASLD and IDSA came forward with very bold recommendations of offering hepatitis C treatment during pregnancy in an individual basis through shared decision-making. So it opens the door for the potential of hepatitis C treatment during pregnancy in clinical care. I just want to talk just briefly as an OBGYN about the harms of evidence gaps. I see this in all aspects of my career. The problem is that historically pregnant women were considered vulnerable because they had this presence of a third party, the fetus, that was unable to give consent. It feels a little icky. I think this was an overreaction to the thalidomide disaster that happened where we really had no data and we just rolled out a medication. We had no human data and rolled out a medication in a pregnant population. And so that was, I mean, we way overcorrected though. So we, for a long time, excluded pregnant women from participating in research, which led to significant harms because there was really no unknown adverse consequences of medications until a lot more. Pregnancies had been exposed. There was also limited access to studies with direct benefit. We saw this in the early days when there were only trials of the COVID vaccination occurring. And then there was also, because if there's no studies done in pregnancy and there's significant physiologic changes that occur during pregnancy, we didn't know if the doses that we use for a non-pregnant adult should be the same in pregnant adults, but we didn't have studies. So we just kind of assumed that that was the right dose. So really we have not, we really should not be protecting pregnant people from research. We should be protecting them through research. And so that's what we've really been trying to do with DAAs in pregnancy. So just to remind everybody that Lidipasvir-Cifosvir was the first DAA. We did a study and this DAA only covered genotypes one, four, five, and six. We study it between 2017 and 2019. That study was called HIP-1. This is, and then HIP-2 was the Cifosvir-Velpatisvir. It was pan-genotypic and we studied it between 2020 and 2023. This is called HIP-2. So these two studies really were getting at, is the dose appropriate for pregnancy? So our primary objective was to define the pharmacokinetics. Of course, we also looked at the safety and virologic response, but it was a very small sample. This is our study design. We enrolled patients between 23 and 25 weeks gestation. They completed a 12 week course. Everybody completed their treatment course before they delivered. And then 12 weeks after they completed their treatment, we got their final viral load to see if they were cured. We followed the babies for an entire year, really looking for any adverse events that could be due to their antenatal DAA exposure. We did growth neurodevelopmental assessments. We also assessed for perinatal transmission. So these were small studies really getting at the pharmacokinetics. We enrolled nine to HIP-1. It took a long time to recruit those nine participants. And then we enrolled 11. One participant in HIP-2 discontinued because she had hyperemesis. She probably was not a great candidate, but hindsight is always 20-20. She discontinued after taking two doses of her study medication and that worsened her hyperemesis. And then so 10 completed the study medication delivered. And even between delivery and like that 12-week assessment, we lost two to follow up. One moved out of state. The other one had a recurrence of use and would not answer her phone. And so we had eight complete her SVR assessment. I don't want to spend a whole lot of time looking at this PK data, but I just want you to understand what we found. So what this shows is the drug. And then on the left, it shows what we found in pregnancy, what we found in non-pregnant women with hepatitis C that were historic control. And then what I really look at is the percent geometric mean ratio, this right-hand side. If it crosses 100, that means it was equal in pregnant versus non-pregnant women. So sofosbuvir in HIP1 was the same in HIP2 was slightly increased. This could have been due to increased adherence in our study versus the control. This GS331007 is a metabolite of sofosbuvir that's inactive. It's renally excreted. It was significantly lower because in pregnancy, our renal clearance is so much higher. And so that is actually to be expected. And then lidipasvir and valpatasvir were similar. So we were a little bit concerned about this inactive metabolite, even though it was inactive, that it was lower. So we actually, for HIP2, looked at the active form of sofosbuvir, which is actually an intracellular form of sofosbuvir. We looked at both in dried blood spots as well as peripheral blood mononuclear cells. Dried blood spots, and we see this with other drugs too, are actually more diluted because of hemodilution in pregnancy. So we saw a significant decrease in the dried blood spot sofosbuvir concentrations compared to the control group. But reassuringly, in peripheral blood mononuclear cells, which are not impacted by hemodilution in pregnancy, the concentrations were either the same or higher. And even more important, after patients started the treatment regimen, we saw a very rapid decline in viremia. In fact, everybody was undetectable by the third PK visit. We had one participant that had a slightly detectable viral load at delivery, but she went on to cure. And all participants that returned for their SVR12 visit were cured. This is not surprising. These medications are highly effective. And so we do see that they seem to be just as effective in pregnancy in this small sample. These are delivery and neonatal outcomes. We saw about a 55% rate of related maternal adverse events, meaning some sort of side effect that they thought could be due to the study medication. So these medications, the sofosbuvir-based DAAs, they can cause fatigue, some headache, nausea. We also see all these symptoms commonly in pregnancy. So it's really hard to tease those apart. We definitely saw a lot more GI side effects with this treatment in pregnancy compared to what was reported in the package insert and whatnot. But that could all be pregnancy related. We only had one related adverse event that was greater than grade two. That was that poor woman who had a hyperemesis that got worse after she started her treatment. She discontinued her treatment, 60% rate of vaginal delivery. Most patients delivered it at term. Our earliest delivery was at 35 weeks, so not terribly preterm, but we did have three preterm births out of the full cohort of 20 participants. And so that, but that's in line with what we see with hepatitis C in general. Birth weights were normal. We had varying lengths of hospitalization. Some of that was due to an observation period for neonatal opioid withdrawal syndrome. We had no adverse events that could be related to this study medication, and then we had no perinatal transmissions. And what was really rewarding for me is our participants seem to really enjoy, really appreciate being treated in pregnancy. They said that it increased their self-esteem, their sense of well-being, and they thought it might be protected against relapse. And they were really grateful for this opportunity. They even said it was life-saving. And so the conclusions from these early studies, PK studies of hepatitis C treatment in pregnancy is that there's really no clinically significant PK changes, so we could use that dose, you know, moving forward in pregnancy. And we had reassuring preliminary safety and efficacy data, but we have to really do a larger study to support safety and efficacy of antenatal treatment so that, you know, we can really change the guidelines and to incorporate hepatitis C treatment in pregnancy. So that's what we're doing now. We've opened a larger study called the STORC study, whose primary outcome is really to look at treatment efficacy, the impact of treatment on gestational age timing at delivery, and then we're also looking at safety just really in a descriptive way, looking at maternal and neonatal safety as well as perinatal transmission. This slide is just to show that we've really loosened up the inclusion-exclusion criteria from our previous study. We are including people that have HIV as well, those that have had previous treatment and have documented SVR but have reinfections can enroll too, and then we've really widened the gestational age window of enrollment to between 20 and 30 weeks. And our study design is very similar to HIP2, except for we don't have all that PK, so we have study visits every four weeks, so that's helpful. And then we're following the infants again for a year. These are our study sites. You'll notice a lot of sites in the Appalachian Mid-Atlantic region, you know, where we have high prevalence of hepatitis C. We're hoping to get 100 participants, and that will allow us to at least show that the SVR rate is not below 92 percent, and the preterm birth rate is not increased by 13 percent. It's unclear if this number is large enough to really change guidelines, but we are hopeful for that. So I presented this at AASLD last year, our interim analysis. We had 26 participants enrolled, and thus far 100 percent of those that have completed their SVR assessment have been cured, and we've had no perinatal transmissions thus far. We're currently at 48 participants enrolled. It's a very hard study to enroll, but we hope to get this data out in 2026. I do want to let people know that there is a hepatitis C treatment exposure registry that's ongoing. This is critically important to really understand, like, the clinical implications of a first trimester exposure, because we're not going to study that. So if somebody has an accidental exposure in the first trimester, it would be really important to register the pregnancy outcome here. And then also for any people that may be doing antenatal treatment off-label in clinical practice, you can report those outcomes here in this registry. And you'll have these slides, and so if you personally or anyone you know is treating people in pregnancy, then I would strongly encourage them to become part of the registry. So back to our clinical case with some key takeaways. So the guidelines recommend that really we only need labs only once. This is just kind of a reminder for the obstetricians in the room. Because of that increased risk of fetal growth restriction, a third trimester growth ultrasound is recommended. Maybe watch out for gestational diabetes, but definitely watch out for cholestasis of pregnancy, which is increased for those that have hepatitis C. Vaginal deliveries and breastfeeding are okay. Try to avoid invasive procedures that we don't do electively if you can. And I'm really hopeful about the possibility of DAAs eliminating hepatitis C, but we have to get the patients that need them the treatment. And whether that is improving linkage to postpartum care or someday soon, maybe testing and treatment of hepatitis C during pregnancy will be a reality. And this could cure maternal hepatitis C and prevent perinatal transmission while somebody is engaged in care, antenatal care. This is it. I thank you very much for again, letting me talk to you about this. And I'm happy to take any questions, any other questions. Great. Thank you so much. That was so informative and so interesting. We do have a couple of questions here. Let's see. Since pregnancy carries a 10% increase in cure just by being pregnant, would you wait a certain amount of time before testing viral load again or just treat? Oh, you're talking about postpartum clearance. Is that? I'm thinking so. Yeah. You know, those data are not well established in our population. I personally, in my practice for postpartum treatment, and this is great question. I do try to check it again, if it's been a while, if it's like something that we facilitate, like at delivery, that it's logistically not really possible to recheck it before we get, you know, so before we get medications to them, if we facilitate getting medications at the time at delivery, but with their labs, you know, and it's occurred too quickly. But I don't want to create barriers for, because of the somewhat theoretical, it may not occur that often potential for clearance. So no, I don't, I don't really, I don't really do that. So, but it's a good question. The guidelines say that you should potentially check it, but sometimes that's not logistically possible. Uh, another question was, are you still accepting patients? I believe that this was to the STORC study. Oh yeah. And she would love to get in on this. So, uh, yes. Uh, send me an email. There's my email address. I, I didn't put up our STORC, like, uh, like, uh, number, our research office number, but just email me and I'm happy to, yeah, we are about half enrolled almost, and it's been a struggle. So any, if you, it's like, it's like wonderful every time every single patient is such a, it's like, we are so thankful for it. So if you send us one patient, we would be so indebted to you. And so. Great. Um, we have another question here. Really great presentation. Can totally appreciate this would be a difficult study to recruit for us. So many patients we see who are pregnant with hepatitis C tend to present for prenatal care so late in gestation, often close to the time of delivery. Very interested in these results as we have many patients who would be interested in the treatment during pregnancy and also during breastfeeding. Yeah, I, I, I didn't include this, but maybe I should have, uh, we did a very small, tiny for patient PK study that we presented at CROI that I'm, uh, going to write up now where it showed that there was very small amounts of sofosbuvir and vilpatasvir in, in the breast milk. Um, so I do, I do like talk to, I do more shared decision-making during breastfeeding because breastfeeding is so important. I don't, and, but people are often motivated to get when, when somebody is motivated to be treated, I want to try to treat them. So I do shared decision-making about treatment, um, uh, in, in breastfeeding. Um, so, uh, so, you know, but not everybody's comfortable doing that. Um, and then, uh, I, I just want to also reiterate that we, our eligibility criteria was between 20 and 30 weeks. So yes, it was, it's hard to recruit, but we wanted to make sure that each participant that, that did the study gave enough, like had enough exposure, um, to really say like, oh, they, their pregnancy, the fetus was exposed to the DAAs enough to say that, uh, to really draw conclusions. If we enrolled patients and like, and they got like two days of treatment, I'm not sure we could really say anything. Right. So, um, and we also were giving them the maximum benefit of potential for a reduction of perinatal transmission, which I think is an important outcome, uh, at least for patients. So, you know, I did have a question too, when I was, you were describing the HIP one study and you had your inclusion criteria and how many people enrolled and everything. I was looking at how many people declined to enroll, uh, like the screen fails. And I was wondering if you had any data with, cause this was the postpartum treatment, I believe. Right. Um, where you offered it or not, sorry, it wasn't the HIP one. It was when you offered postpartum treatment and the women didn't want to enroll after they gave birth. Yeah. Yeah. So really the crux of that study was, um, they had to be engaged at our treatment clinic. And so a lot, some in Pittsburgh, I mean, this is the hard truth in Pittsburgh. We have a lot of clinics that, I mean, our, our clinic is located at McEwen's hospital and then parking lot is a disaster. And there's a lot of other clinics that were, um, uh, that are like easier to get to for our patient population. I think patients like to come to McGee during pregnancy, but afterwards they would rather go somewhere else. So that was a lot of it. They didn't want to come back to the study site. They didn't want to come back to the clinic that we had. So there's, so we may, the truth is we may be able to do a little better than what I, I presented as an ideal circumstance, if that makes any sense. Do you, do you happen to notice too, like if those women had babies that actually that had the, um, transmission during pregnancy, if they tested positive, were those women more motivated to be engaged in the treatment or did more of them participate in the treatment versus say no. So, uh, not for, uh, for postpartum treatment or for. Yeah. For the postpartum, if they, if there was the perinatal transmission that happened in their infants. So I think oftentimes it was so early when they participate in the study that they did not know if their babies, because at that time during that they weren't tested until 18 months. I am not aware that any of the other, any of the patients that, I mean, honestly, testing rates are so low. I'm not aware of any of the patients that had, uh, had perinatal transmission, um, in the, in the study. Um, what I will say for people that present that, that participated in our HIP one and two studies, um, there was, uh, there were, there was one patient who did have perinatal transmission for one of her child, and that didn't motivate her. And there was another participant who actually had perinatal transmission herself. Um, uh, her mom had a knee surgery back in the seventies. She didn't know she had hepatitis C until she tried to donate blood at 18 and had hepatitis C and she was highly motivated. So, you know, I do think that there are some, um, extrinsic motivators that are, are, are due to perinatal transmission that may, that may come about, but we have to do a better job of testing infants to really get at that. Okay. Thank you. Actually, we don't have any more questions and it is, and I'm past time. So yeah, 6.01. So I want to thank you again for sharing your experience and your research with us. Um, and, um, if you do have anybody to, uh, refer to for her research study, she's got her email up there. And so thank you so much, Dr. Chappell. And then our next and last webinar for this series is going to be next week at five o'clock Eastern. And it's Dr. Aisha Appa, who's going to be talking about drugs and bugs, case-based pearls for integrated substance use substance use disorder, infectious disease care in the hospital. So please join us again for our next and last webinar. Thank you everybody for attending. And thank you again, Dr. Chappell. Thank you.

Hepatitis C

Pregnancy

Screening

Treatment

Epidemiology

Opioid crisis

Perinatal transmission

DAAs

Postpartum care

Antenatal care