SHOULD ANTENATAL SCREENING FOR HEPATITIS C VIRUS SHOULD BE MADE PART OF ROUTINE CARE IN THE UK?

The West London Medical Journal 2010 Vol 2 1 pp 1-11 SHOULD ANTENATAL SCREENING FOR HEPATITIS C VIRUS SHOULD BE MADE PART OF ROUTINE CARE IN THE UK? Krupa Pitroda Screening has the potential to save lives or improve quality of life through early diagnosis of serious conditions.(1) The plethora of benefits of screening is highlighted through the success of various screening programmes already instituted worldwide. However, despite these advantages, it is neither practical nor sensible to screen for all known conditions; there are certain criteria that need to be satisfied before a screening programme can be implemented. This article will focus on the issue of antenatal screening for hepatitis C virus (HCV) infection. I will begin by defining screening and the criteria for a successful screening programme. I will then proceed to focus on how these criteria can be applied to HCV, by discussing the course of infection from mother to child and, simultaneously, analysing the implications for screening. In order to complete the article, I will summarise the current situation in the UK and discuss areas of ongoing research. The National Screening Committee define screening as the systematic application of a test or enquiry, to identify individuals at sufficient risk to benefit from further investigation or direct preventative action, amongst persons who have not sought medical attention on account of symptoms of that disorder. The infectious diseases in pregnancy screening programme aims to reduce the risk of in-utero or intrapartum mother-to-infant transmission of four conditions, which could be carried (asymptomatically) by the mother, namely: Hepatitis B, HIV, Rubella and Syphilis. The transmission of these conditions from mother to child can have serious consequences for the fetus and antenatal screening aims to reduce the likelihood of these occurring. Screening is carried out early in gestation, where a blood sample is taken from the mother, having obtained consent, and tested for markers of infection of the four mentioned conditions. Upon analysing the test results, appropriate measures can be taken and guidance provided. For various reasons, reasons, there are some infectious diseases for which antenatal screening is currently not recommended, including cytomegalovirus, toxoplasmosis, and HCV. There are certain criteria which need to be satisfied before the establishment of a successful screening programme, namely that: 1. The condition being screened for is an important health problem; 2. The natural history of the condition is understood; 1

THE WEST LONDON MEDICAL JOURNAL 2009 2, 1 3. There is treatment or intervention of proven effectiveness available; 4. Early detection and treatment has benefit over later detection and treatment; and 5. The screening test is safe, acceptable, has justifiable costs, and the risk of both physical and psychological harm is less than the chance of benefit. It is important to remember that screening is targeting apparently healthy people and therefore has numerous ethical implications. Therefore, in order to evaluate the usefulness of routine antenatal screening in the UK, it is important to analyse the mentioned criteria, with specific focus on HCV and the situation in the UK. It is not appropriate to introduce routine antenatal screening for HCV infection in the UK at this time, in the light of the evidence currently available.(2) A critical analysis of the screening criteria and the data available regarding HCV infection may shed light onto the rationale behind this decision. HCV infection is a major public health problem.(3) Hepatitis encompasses inflammation of the liver, caused by immunological abnormalities, toxic substances or viral infection. Five major viruses are implicated: hepatitis A, B, C, D and E. The HCV is a small enveloped single-stranded RNA virus of the Flaviviridae family. It has been classified into 6 major genotypes, with over 50 different subtypes. It is a blood-borne virus and transmission therefore generally occurs through infected blood, via intravenous drug abuse and other percutaneous exposures, such as tattooing and body piercing. The acquisition of the virus through contaminated blood transfusions has been virtually eliminated through the routine screening of donor blood, introduced in 1992. It is important to note that sometimes risk factors for HCV infection can not be identified in those infected and this may have implications for other modes of acquisition of the virus, including horizontal and sexual transmission. The presence of HCV infection in adults can be diagnosed by the identification of anti-hcv antibodies in the serum by enzyme immunoassay. Detection of HCV RNA by Polymerase Chain Reaction (PCR) is the gold standard of identification of presence of infection; however, this technique is mainly used to monitor its course, by measuring viraemia. Recently, a test measuring HCV core antigen has been devised, which can also qualify and quantify infection, and studies are being carried out to monitor its efficacy. Following the introduction of vaccination against Hepatitis B, HCV has become the most important cause of chronic hepatitis and end-stage liver disease worldwide.(4) In adults, the infection can be acute or progress to chronicity. The acute stage is generally asymptomatic or mildly symptomatic, however, 85% of individuals go on to develop chronic infection, of which 20% will develop liver cirrhosis and 1-4% will progress to hepatocellular carcinoma. 2

SHOULD ANTENATAL SCREENING FOR HEPATITIS C VIRUS SHOULD BE MADE PART OF ROUTINE CARE IN THE UK? The World Health Organisation estimates that 3% of the world s population is chronically infected with HCV, although the prevalence is much higher (70-90%) in certain groups, such as intravenous drug users (IVDUs).(5) HCV is also more common in those infected with HIV, due to the shared routes of acquisition of these infections. In the UK, however, HCV/HIV co-infection is rare. The overall prevalence amongst pregnant women in the UK is estimated to be below 1%, although this is based on limited data. A study carried out in inner London, where there is a high prevalence of IVDUs, reported the antenatal prevalence to be 0.8%.(6) However, it is not clear whether this value can be extrapolated to the general antenatal population, due to the wide variation in prevalence according to the characteristics of the population studied. Regarding paediatric HCV infection, following the introduction of routine blood screening prior to transfusion, vertical transmission from mother-tochild is the most common cause. The risk of transmission is approximately 5%, ranging from 3-7%,(7) and there are various factors that affect transmission. A higher maternal viral load is associated with an increased risk of vertical transmission; however, a threshold has not been identified above which transmission always occurs, or below which transmission never occurs. It is important to note that transmission is almost always restricted to those who are HCV RNA positive (i.e. are viraemic) and rarely occurs in those who are HCV RNA negative (but anti-hcv antibody positive). Transmission is more commonly associated with HCV genotypes 1b and 3a. HIV co-infection with HCV is associated with a 15% risk of transmission.(3) This increased rate is thought to be due to the higher maternal viral load, as a result of maternal immunosuppression. This persistent viraemia is also thought to be responsible for the increased rate of transmission seen in IVDUs. The effect of mode of delivery, other obstetric procedures and breastfeeding is uncertain. Table 1 summarises the potential risk factors for transmission. Risk Factor Maternal HCV viraemia/ maternal viral load Findings Very low risk in from nonviraemic women. In viraemic women, a high viral load increases risk. Strength of the evidence (strong> sufficient> insufficient) Sufficient Potentially modifiable? Guidelines 3

THE WEST LONDON MEDICAL JOURNAL 2009 2, 1 Risk Factor Maternal HIV coinfection Obstetric procedures Mode delivery of Rupture of membranes Prematurity Findings 2-3 fold increased risk in co-infected women. Amniocentesis is unlikely to increase the risk. Use of forceps during vaginal delivery is associated with a 3-fold increased risk. evidence for a protective effect of Caesarean section in women infected only with HCV. An increased duration of rupture of membranes may increase the risk of transmission. evidence to say that gestational age is significantly associated with HCV transmission. Strength of the evidence (strong> sufficient> insufficient) Strong Potentially modifiable? Guidelines Insufficient Yes Prudent to avoid these procedures whenever possible Sufficient Yes Current evidence does not support the recommendation of elective Caesarean for HCV infection without HIV. Insufficient Sufficient 4

SHOULD ANTENATAL SCREENING FOR HEPATITIS C VIRUS SHOULD BE MADE PART OF ROUTINE CARE IN THE UK? Risk Factor Gender Infant feeding Findings Girls are twice as likely to be infected as boys. evidence of increased risk of transmission through breastfeeding in women infected solely with HCV. Strength of the evidence (strong> sufficient> insufficient) Sufficient Potentially modifiable? Guidelines Sufficient Yes The avoidance of breastfeeding is NOT recommended in HCV infected women. Table 1: The risk factors potentially associated with vertical transmission of HCV from mother-to-infant. Guidelines based on the findings are also shown, as well as the strength of the evidence available.(7) Regarding the timing of transmission, it has been estimated that between a ⅓ to ½ of infected children acquired the infection in utero. Intrapartum transmission is not as common and postpartum transmission is rare. This has various implications for intervention, discussed later. In contrast to adult HCV infection, early paediatric HCV infection can not be diagnosed based solely on the presence of anti-hcv antibodies in the serum; this is due to the transplacental passage of antibodies during pregnancy, so all infants born to HCV positive mothers will be seropositive at birth. These antibodies are generally cleared by 15-18 months age in uninfected children. Earlier diagnosis therefore requires detection of viraemia via PCR monitoring of HCV RNA. Following studies of sensitivity (the ability of a test to pick up true positives) and specificity (the ability of a test to pick up true negatives) of this technique, the ideal schedule of follow-up of children born to HCV positive mothers was suggested (Figure 2). Overall, it has been estimated that, in the UK, 69 vertically acquired paediatric HCV infections occur each year, giving a UK antenatal prevalence of 0.16%.(3) Following the vertical acquisition of the virus, the natural history of paediatric HCV infection is not completely understood. It has been shown that there are few clinical consequences of HCV infection in the short and medium term, where the infection is relatively benign. At birth, children are asymptomatic and they develop few clinical signs in the first 5-10 years of 5

THE WEST LONDON MEDICAL JOURNAL 2009 2, 1 life. Mild hepatomegaly is seen is some children, and there may be variations in the alanine aminotranferase (ALT) levels. It is important to note that ALT Figure 2: The recommended follow-up schedule for early diagnosis of infection in infants born to HCV positive mothers. te that testing is delayed till 2 months age due to the low sensitivity of the technique at birth.(7) elevation does not correlate well with histological severity. The ALT levels start to decrease from the second year of life and liver histology shows features of mild hepatitis. The long term consequences of HCV infection in children are unknown, although it seems likely that serious symptoms of infection may not occur for many years in vertically infected children. In addition to symptoms of chronic liver disease, they may also develop autoimmune symptoms. 6

SHOULD ANTENATAL SCREENING FOR HEPATITIS C VIRUS SHOULD BE MADE PART OF ROUTINE CARE IN THE UK? Children infected with HCV can be broadly classified into 3 categories, based on their outcome;(3) those who clear the virus (20%), generally occurring before 3 years of age, reflecting acute infection; those with chronic asymptomatic infection (50%), characterised by intermittent viraemia, normal ALT levels and rare hepatomegaly; and those with chronic active infection (30%), characterised by persistent viraemia, frequently abnormal ALT levels and hepatomegaly in some cases. In adults, spontaneous clearance of the virus is associated with the MHC class II alleles, DRB1*1101 and DQB1*0301, and they could also be implicated in children. Knowledge of the natural history of the condition concerned is vital for the institution of treatment and intervention. At present, regarding paediatric HCV infection, there are currently no interventions of proven safety and efficacy for the prevention of mother-tochild transmission of HCV (3) (see Table 1). Treatment of adult HCV infection comprises combination therapy of interferon α (IFN α) and ribavirin, and this is generally effective in decreasing viral load. It would, therefore, be ideal to use this treatment regime in pregnancy, as a decrease in viral load would decrease the risk of transmission. However, the use of IFN α is contraindicated in pregnancy due to potential deleterious effects on the fetus; IFN α is an anti-proliferative cytokine and therefore affects fetal growth. This feature also limits its use in the treatment of early paediatric HCV, and its use is not recommended in children less than 3 years old. In children older than 3 years, with compensated liver disease and no previous treatment with IFN α, combination therapy of IFN α and ribavirin is recommended. One of the main drawbacks of treatment in children is the requirement for injection 3 times a week. This could, potentially, be overcome by the use of pegylated interferon, which requires less frequent injections, in combination with ribavirin, as this regime in adults has proven to be effective. There are limited studies on the use of pegylated interferon in children; however, its use should be considered in those older than 5 years who are persistently viraemic and have persistently elevated ALT. It is important to note that the benefits of treating children earlier, as opposed to later in life, had not been sufficiently evaluated. If early treatment of exposed infants or children, confirmed as being vertically infected was found to be more beneficial than later treatment, this would strengthen the case for routine antenatal screening.(3) Regarding the actual screening process, a safe, valid and reliable screening test is available. The presence of HCV infection is determined by the detection of anti-hcv antibodies in a maternal blood sample, using enzyme immunoassays (EIA) or enzyme-linked immunosorbant assays (ELISA). If the result is positive, a second ELISA or confirmatory recombinant immunoblot assay (RIBA) is carried out on the same blood sample. If positive again, the woman is informed of the result, and another blood sample taken for a repeat ELISA test, to confirm the diagnosis. 7

THE WEST LONDON MEDICAL JOURNAL 2009 2, 1 HCV prevalence (%) 1 st blood sample and ELISA test With 100% sensitivity:. of truly infected women (prevalence multiplied by the total number of pregnant women) (all identified by the screening test). of truly uninfected women (total number of pregnant women minus the number of truly infected women) With 96% specificity, 4 % of the truly uninfected women will be identified as positive by the screening test (false positive) Another ELISA or RIBA on the same sample for all that were positive (true positives+ false positives) With 100% sensitivity and 96% specificity: True positives (1 multiplied by the no. of truly infected women) False positives (0.04 multiplied by the no. of truly uninfected women identified as positive by the first ELISA test) Positive Predictive Value (PPV) (%) 700 000 pregnant women per year in the UK tested by ELISA (approximately 8 per test) 0.80 5600 694 400 0.25 1750 698 250 0.09 630 699 370 27 776 27 975 5600 + 27 776 = 33 376 5600 1111 83 1750 + 27 930 = 29 680 1750 1117 61 630 + 27 975 =28 605 630 1119 36 2 nd blood sample and ELISA test Total number of women undergoing a 2 nd sample With 100% sensitivity and 96% specificity: True positives False positives 6711 5600 44 2867 1750 45 1749 630 45 Table 2: The effect of sensitivity and specificity in determining the presence or absence of infection, according to the prevalence of infection. The table considers the upper, middle and lower limits of estimated prevalence in the UK, to show how prevalence affects the proportion of cases correctly and incorrectly identified; with a higher prevalence, there are fewer false positives. PPV= positive predictive value (i.e. the number of people identified as positive who truly are positive). te that this value decreases as the prevalence decreases. Modified from the Working party report on screening for Hepatitis C in the UK, 2002. 8

SHOULD ANTENATAL SCREENING FOR HEPATITIS C VIRUS SHOULD BE MADE PART OF ROUTINE CARE IN THE UK? The sensitivity and specificity of ELISA, specifically used in anti-hcv antibody assays in pregnant women, are estimated to be 100% and 96% respectively. Table 2 summarises the effects of sensitivity and specificity in determining the presence or absence of infection, according to the prevalence of infection. The cost of screening all the pregnant women in the UK (estimated to be 700 000 a year) each year would be between 5 700 000 and 5 900 000, when considering only the cost of the ELISA and not the personnel involved. Following a positive result, the woman is offered post-test counselling, advising her about the implications of HCV infection for her and her infant, and the subsequent management of the pregnancy. Pre-natal diagnosis to confirm potential fetal infection is not performed and there are no known interventions that can prevent transmission: considerable anxiety is therefore involved with a positive result during pregnancy, in both women with false positive results and women correctly identified. Therefore, before the introduction of a routine antenatal screening programme for HCV infection, several criteria must be met, and, at present, a large proportion of these are not. Whilst HCV infection is a major public health problem and can lead to serious sequelae such as cirrhosis and hepatocellular carcinoma, the natural history of paediatric HCV infection remains to be elucidated; children are generally asymptomatic in early life, but may go on to develop the sequelae mentioned above in their teen or adult years. In addition, there are no known interventions proven to reduce transmission from mother-to-infant, and once infection has occurred, treatment is not suitable for those less than 3 years of age. The benefits of early versus late treatment are also yet to be revealed, although children are thought to be ideal candidates for anti-hcv treatment, as they have milder disease, with absence of both cirrhosis and co-morbidity. Despite the fact that a safe and reliable screening test is available, and it is generally accepted by pregnant women, it is still associated with a certain proportion of women who will have false positive results.(5) This, combined with the fact that, even in those correctly identified, there is no intervention possible to decrease the risk of maternal-fetal transmission or opportunity for treatment of the mother during pregnancy, may result in a great deal of anxiety. It is important to note that the antenatal screening programme is aimed to decrease the risk of paediatric infection, but it may have indirect benefits for the mother, such as the new discovery of asymptomatic infection, allowing treatment and lifestyle modifications. In addition, the test can be performed on the same sample of blood taken for the screening of Hepatitis B, HIV, Rubella and Syphilis, therefore causing no extra inconvenience to the mother. Table 3 provides a summary of the current situation. At present, much research is being carried out to try and satisfy the criteria. The work carried out by large, multicentre prospective studies, such as those within the European Paediatric HCV Network, as well as the data collected by the National HCV Register in the UK, will be of great benefit. 9

THE WEST LONDON MEDICAL JOURNAL 2009 2, 1 Research still needs to be carried out to clarify the natural history of vertically acquired HCV. If effective interventions to decrease maternal-fetal transmission are unattainable, then the development of therapies for paediatric HCV will be particularly important. Criteria Evidence regarding HCV Satisfied in the context of antenatal HCV screening? The condition is an Global prevalence of 3%, with an important health antenatal prevalence of Yes problem approximately 1% in the UK The natural history is well understood Treatment or intervention of proven effectiveness is available A safe, valid and reliable screening test is available which is acceptable to those being tested. The risk of harm, both physical and psychological is less than the chance of benefit. The natural history of paediatric HCV infection is poorly classified The available treatment is contraindicated in pregnancy and there are no known interventions available The ELISA tests used have a high sensitivity (100%), satisfactory specificity (96%), but a low positive predictive value A positive result in pregnancy is associated with considerable anxiety. There is no benefit of diagnosis during pregnancy as there are no interventions Yes Table 3: To summarise whether HCV infection satisfies the criteria for the introduction of routine antenatal screening. (7). Hence, while, at present, it is not possible to routinely screen for HCV in pregnant women, and it is not advisable to just screen at-risk individuals (due to the absence of, or denial of, risk factors by many), it is important to address the fact that there are no national guidelines. Routine antenatal screening takes place in some centres in the UK, selective screening in others and some do not offer either. Therefore, in order to make practical use of the knowledge and data available, it is vital to develop guidelines for the management of women infected with, or at high risk of being infected with, HCV. 10

SHOULD ANTENATAL SCREENING FOR HEPATITIS C VIRUS SHOULD BE MADE PART OF ROUTINE CARE IN THE UK? To conclude, it is my point of view that, once areas of uncertainty have been clarified via research, routine antenatal screening of HCV should be introduced in the UK, as it has the potential to benefit both mother and child. REFERENCES 1. http://www.nsc.nhs.uk/whatscreening_ind.htm. 2. National Screening Committee, Working party report on screening for Hepatitis C in the UK, January 2002. 3. Pembrey L, Newell ML, Peckham C; Is there are case for Hepatitis C infection screening in the antenatal period?; Journal of Medical Screening; 2003; 10; 4; 161-168. 4. Syriopoulou V et al; Mother to child transmission of hepatitis C virus: rate of infection and risk factors; Scandinavian Journal of Infectious Disease; 2005; 37; 5; 350-353. 5. Ciommo VD, Russo P, Ravà L, Caprino L; Interferon α in the treatment of chronic hepatitis C in children: a metanalysis; Journal of Viral Hepatitis; 2005; 10; 210. 6. Ward C, Tudor-Williams G, Cotzias T, Hargreaves S, Regan L, Foster GR; Prevalence of hepatitis C among pregnant women attending an inner London obstetric department: uptake and accessibility of named antenatal testing; Gut; 2000; 47; 277-280. 7. Pembrey L, Newell ML, Tovo PA, EPHN Collaborators; The management of HCV infected pregnant women and their children; European Paediatric HCV Network; Journal of Hepatology; 2005; 43; 515-525. 8. Mok J, Pembrey L, Tovo PA, Newell ML, for the European Paediatric HCV Network; When does mother to child transmission of hepatitis C virus occur?; Archives of Disease in Childhood Neonatal and Fetal Edition; 2005; 90; 156-160. 9. Resti et al; Clinical features and progression of perinatally acquired Hepatitis C virus infection; Journal of Medical Virology; 2003; 70; 373-377 10. European Paediatric HCV Network; Three broad modalities in the natural history of vertically acquired hepatitis C virus infection; Clinical Infectious Disease; 2005; 41; 45-51. 11