HCVAVERT: designing a trial to cure hepatitis C virus (HCV) in HCV-infected pregnant women And prevent VERTical HCV transmission

In 2015, an estimated 71 million people, or 1% of the world's population, were living with hepatitis C, including 5 million children, most of whom were infected from their mother during pregnancy. Hepatitis B and C together caused 1.34 million deaths globally in that year alone, which is comparable to the number of people dying from tuberculosis, and higher than the number for HIV. Until recently, treatment for hepatitis C involved patients having daily injections of medication, which made some of them feel poorly. Remarkable developments of direct acting antivirals (DAAs) have recently transformed this treatment, and patients now take pills which are safe and effective, and which cure nearly everyone. Because of this, the WHO would like to eliminate hepatitis C by 2030. However there is currently no treatment available for pregnant women with hepatitis C, and around 6 in every 100 will transmit it to their baby.

Pregnancy is an important opportunity to test and diagnose hepatitis C, but it is not known whether treatment of hepatitis C during pregnancy is safe and if it can be used to stop transmission from a mother to her baby. Testing and treatment in pregnancy is the foundation of treatment and control of transmission of infectious diseases such as HIV, syphilis and hepatitis B. In many low and middle income countries, pregnant women do not present to healthcare services until the third trimester, and drop out of care after delivery, highlighting the importance of this window of opportunity to engage in medical care. However as there is no recommended treatment for hepatitis C in pregnancy, currently those identified in pregnancy are told to delay treatment until after birth. This means that there is still a risk that the mother will transmit the virus to the baby, and the mother's disease may get worse during pregnancy and after birth, especially if they drop out of care.

We plan to design a trial to treat pregnant women with hepatitis C, to cure them and prevent transmission to their babies. We will probably conduct this trial in Egypt and Ukraine, which both have a large number of people with hepatitis C. However before we do this, we need to find out additional background information to help us design the trial. We would like to:

(1) contact experts about blood test results that they already have from pregnant women and their babies which can help us understand when transmission of hepatitis C is likely to occur We will put this information from different studies together to see if it helps us work out when we would need to treat pregnant women for hepatitis C (e.g. early pregnancy or late pregnancy)

(2) do a literature review to understand which DAAs seem to be the safest to give in pregnancy, to help us choose the safest treatment for our trial

(3) evaluate the benefit and cost of different ways that pregnant women could be tested for hepatitis C and treated (for example, early in pregnancy compared to later in pregnancy), to help us in terms of what we compare in our future trial

(4) ask pregnant women and doctors what they think about treatment for hepatitis C in pregnancy, and assess which clinics in Egypt and Ukraine may be suitable to participate in our trial.

Answering these questions will help us design the trial, for which we will then apply for separate funding.

O1 HCV MTCT
O1a: Assemble published/ unpublished data to inform a staged model of MTCT. Contact authors and networks for aggregated and individual patient data (IPD). Analyse IPD on a study-by-study basis in the first instance.
O1b: Construct a model of the timing of MTCT, using data from (O1a) to estimate parameters using multi-parameter evidence synthesis.

O2 DAA safety
O2a: Review published/ unpublished pre-clinical safety and availability of DAAs in high-burden LMIC.
O2b: Establish a prospective registry of women becoming pregnant on DAAs in Egypt, and their infants, and contact existing known cases, through liver units, antenatal and other clinics responsible for DAA treatment. Collect follow-up data current/ historical pregnancy outcomes. Review pharmacovigilance pregnancy registries for DAAs.

O3 Cost-effectiveness
O3a: Adapt an existing Markov model on HCV for pregnant women
O3b: Build on transmission probabilities estimated in O1b and review data (including SE Asia) to inform key model parameters
O3c: Estimate incremental cost effectiveness ratio (ICER) of screening and treatment strategies vs. SOC, across different settings, prevalence, HIV co-infection, and cost scenarios. Conduct sensitivity analyses to assess key model parameters to capture in the trial.

O4 Implementation
O4a: Conduct assessments of current practice regarding screening and care pathways. Semi-structured interviews with clinic staff will take place in 2 antenatal clinics in Egypt (Ain Shams + one other) and 2 in Ukraine (Odessa, Kiev and/or Dnipropetrovsk) to identify practice and key gaps which need strengthening for a trial.
O4b: Design and implement a DAA acceptability survey to elicit views from pregnant and post-partum women (cured and not cured) engaged in care. n=300 pregnant/post-partum women, and 20 clinicians will complete a quantitative survey. Focus groups/ roundtable discussions with patients, clinicians and key stakeholders will be held.

This study will benefit national HCV eradication programs, the WHO, healthcare workers in LMIC, and most importantly, pregnant women with HCV and their offspring.

Policymakers such as WHO will benefit from this research in several ways. Pregnant women with HCV are currently denied HCV treatment which can cure their HCV and also prevent vertical transmission, but the evidence base informing this strategy is weak, and there is an urgent need to reappraise these recommendations which lack foundation. At present there are too few voices advocating for studies investigating whether HCV treatment can be given safely in pregnancy, and a "collective view" that it is harmful, without any serious appraisal of the lack of evidence. Better evidence for the timing of HCV transmission in pregnancy, and systematic review of the evidence for safety of DAAs in pregnancy, will stimulate interest in including pregnant women in strategies to eradicate HCV.

Ministries of Health in Egypt and Ukraine will also benefit from the research. Investigation of implementation questions will lead to a better understanding of gaps in current care, and identification of strategies for improvement. Modelling of cost-effectiveness of different strategies to screen and treat pregnant women will give an indication of the likely budgetary impact of HCV treatment for pregnant women for national healthcare budgets. The model could also be adapted in the future to consider new treatments, other treatment strategies or for other high or LMIC settings.

Benefits to pregnant women include an improved evidence base on the risks and benefits of HCV treatment in pregnancy, and having their voices heard through engagement in the study regarding acceptability of treatment. Although only around 6% of women with HCV may transmit HCV to their child, this risk may seem very high to the individual and cause considerable anxiety throughout pregnancy and up to 18 months post-partum, when the infant may finally be eligible for an HCV antibody test, and subsequent PCR if positive. There are no data to date on this issue.

Manufacturers may also have increased interest in investing in this area given an emerging possibility of a market share. Intense competition between DAA manufacturers in the context of multiple drugs all with extremely high sustained virological response (SVR, equivalent to HCV cure) has served to inhibit product development in neglected populations such as pregnant women, as any negative findings could destabilise the product's total market share. However, with women taking DAAs becoming pregnant during the course of their treatment, the current scenario of a lack of data is not sustainable or ethical long-term, and indeed our research will highlight the extent of the potential market for drugs in pregnancy.

These benefits are all from the trial development grant. However, the impact of a subsequent trial which found that HCV treatment in pregnancy is safe, effective, and cost effective, could be substantial, with the principal beneficiaries being women of childbearing age who have HCV and become pregnant in the future. If benefits of the intervention arm were shown with supporting cost-effectiveness data, there would be complete u-turn in policy and practice towards the identification and treatment of HCV in pregnancy, with new clinical guidelines. Strengthening of care pathways for a trial, irrespective of the results, would lead to improved delivery of care to women and their offspring across the pregnancy and post-partum care cascade. Poor post-partum care pathways in the health system, and drug use in some HCV-infected women, causes high loss to follow-up post-partum, constituting a considerable missed opportunity to continue the care cascade through infancy.