1. Meeting Public health challenges for controlling HCV infection WHO informal consultation with VHPB Geneva, May 13-14, 2002 Prof Alessandro Zanetti Institute of Virology – University of Milan

2. Hepatitis C: a major worldwide public health problem 170 million chronic carriers In developed countries the incidence has progressively declined for: improvment of general standard of living and hygiene introduction of general public health mea- sures (screening for safe blood, use of disposable syringes and needles, universal precautions in medical settings, etc)

3. Strategies for primary prevention of HCV Identification of carriers and acutely infected individuals (counselling, treatment) Interruption of the viral chain of transmission

4. Measures to prevent hepatitis C transmission through: Transfusion Transfusion I. V. drug use and other parenteral exposures I. V. drug use and other parenteral exposures Nosocomial Nosocomial Sexual Sexual Household contact and daily life Household contact and daily life Vertical/perinatal Vertical/perinatal

5. Blood transfusion safety: prevention strategies Selection of periodic, volunteer, unremunerated donors Evaluation of medical and personal history Confidential unit exclusion Implementation of donors screening Viral inactivation Proper use of blood, blood components and derivates

6. Residual risk of transfusion-transmitted viral infections lMostly related to the pre-seroconversion window period. lThe probability of transmitting HCV through transfusion of screened blood is related to the length of the pre-seroconversion window phase and the incidence of HCV infection among donors. lThe magnitude of residual risk may differ within countries depending on the sensitivity of the assays used for screening and on the level of HCV endemicity.

7. Residual risk of transfusion-associated HCV infection in Italy (Transfusion 2002, in press) Methods MethodsMatematical model (incidence/ window-period model) Study populationSite: Study populationSite: Lombardy Period: Period: Jan 1996-Dec 2000 n° records examined for periodic, volunteer, unpaid donors: 2, 411, 800 Mean donors per year: 223,500 Donation index: 2.1 Laboratory Laboratory3rd generation EIA supplemental assays

8. Estimated residual risk of transmitting HCV/HIV by transfusion of antibody-screened blood Year Residual risk Estimated donations + ve during the window + ve during the window HCV HIV phase x 10 6 donations HCV HIV phase x 10 6 donations (95%CI) (95%CI) HCV HIV (95%CI) (95%CI) HCV HIV 1996 1: 90,909 1:357,142 11 2.8 1997 1: 100,000 1:370,370 10 2.7 1998 1 : 163,934 1:1,000,000 6.1 1 1999 1 : 158,730 1:400,000 6.3 2.5 2000 1 : 181,818 1:400,000 5.5 2.5 Total 1 : 126,582 1:434,782 7.9 2.3 (100,000-175,438) (333,333-588,235) (5.7-10) (1.7-3)

9. Estimated residual risk to the blood supply in Europe and in the USA 0 2 4 6 8 10 12 14 16 18 1 Couroucé (1996); 2 Schreiber (1996); 3 Allain (1997) 15.0 3 15.0 3 9.7 2 9.7 2 4.48 1 4.48 1 7.97.9 HCV 2.03 2 2.03 2 1.75 1 1.75 1 0.58 3 0.58 3 2.32.3 Lombardy HIV Cases per 10 6 donations

10. Residual risk of transfusion-transmitted HCV It is currently very small in developed countries. The safety of blood supply remains a major source of public concern, requiring a continous effort to reach zero-risk. NAT can shorten the window period and, consequently, further reduce the residual risk of HCV transmission.

11. Declining time to detection of HCV/HIV markers during the window phase following infection Infection HCV RNA HCV Ag EIA 3.0 EIA 2.0 EIA 1.0 0 13 1470 80150 (days) Infection HIV RNA p24 Ag EIA 3.0 0 11 1622 (days) HCV HIV

12. Estimated window Estimated window %Reduction Project yeld (infected Estimated phase period phase reduction unit detected x10 6 Residual Risk (days) (days) units) x10 6 donationsHCV: NAT 13 57 81.4 6.4 1.5 cAg 14 56 80 6.3 1.6HIV: NAT 11 11 50 1.15 1.15 p24 16 6 28 0.6 1.7 Estimated reduction of the residual risk of transfusion- transmitted HCV (7.9 x 10 6 donations) and HIV (2.3 x 10 6 donations) by using direct viral detection assays in combination with the existing serologic assays Estimated reduction of the residual risk of transfusion- transmitted HCV (7.9 x 10 6 donations) and HIV (2.3 x 10 6 donations) by using direct viral detection assays in combination with the existing serologic assays

13. Measures to reduce risk of transfusion-associated hepatitis C Solvent/detergent treatment of plasma and derivates (utilized with success against enveloped viruses). Photochemical decontamination using psoralen and UV light (effective to inactivate a wide range of viruses). The possibility to inactivate also agents whose genomic sequences are unknown (not detectable by NAT) offers the potential for approaching of zero risk associated to transfusion.

14. HCV transmission by i.v. drug use In many developed countries, drug use is the major source of HCV infection. In Europe up to 60-70% of IVDUs living in urban areas of the major cities, are anti-HCV positives. The rate of infection depends on the lenght of the time of drug abuse (25% of infection during the first year of addiction, 50% after 5 years and up to 90% for more than 5 years of use).

15. Prevention of HCV transmission by i.v. drug use (1) Need of extensive education campaigns aimed: to prevent initiation of drug use to reduce harm-behaviours to avoid sharing of syringes and needles, water or drug preparation equipments.

16. Prevention of HCV transmission by i.v. drug use (2) For IVDUs who cannot or will not stop injecting drugs: Easy access to sterile syringes* (syringe exchange program), accompanied by counselling and health education. Safe disposal of used syringes (to reduce the chance of re-use of blood-contamined syringes and to assure the community about the risk of discarded syringes in the neighborhoods). * some countries have legal restrictions on the sale and distribution of sterile syringes

17. Piercing, tatooing Education on the potential risk of acquiring blodd-borne viruses through indequates sterilized equipment, including needles. Tattoing makers must follow infection-control procedures ( i.e. using gloves, cleaning and disinfecting surfaces, etc ).

18. Nosocomial and occupational exposure Nosocomial transmission of HCV through unsafe injections and other medical practices or through unscreened blood remains a major problem in developing countries. In developed countries, HCV spread is mainly related to non-strict observance of universal precaution measures (indequate disinfection/ sterilization, sharing of medication vials and supplies and contamined equipment).

19. Modalities of acquiring blood-borne viruses in health-care settings  Nosocomial  Nosocomial from the environment to the patient or from patient-to-patient  Occupational  Occupational from an infected patient to the HCW   From an HCW to the patient

20. Nosocomial transmission of HCV Anedoctical cases as well as outbreaks of HCV are documented, especially in hemodialysis and in haematologic settings. Out patients facilities ( i.e. endoscopic services and dentist’s surgery ) also represent high-risk settings.

21. Measures to control and prevent nosocomial transmission of HCV Strict observance of universal precautions. Education and training of HCWs to the proper use of standard precautions including vaccination against HBV. Hemodialysis setting Precautions should be even more stringents. Patients should have assigned specific dialysis stations. Clean and contamined areas should be separated. Isolation of HCV infected patients is not recommended.

22. Occupational risk of acquiring HCV in health- care settings and measures to prevent it Risk is low. Follow-up studies of needlestick from HCV+ sources indicate a 1-10% seroconversion rate in recipients (mean risk of 1.8%). From an Italian study carried out on 3,795 expo- sures to HCV, the rate of transmision was 0.4% (0.9% in cases of exposures to hollow needles and 0.3% for conjunctival exposure) *. Standard barrier precautions and engineering controls should be implemented to prevent infection. * Eurosurveillance 1999; 4:33.

23. Transmission of HCV from HCWs to patients and measures to prevent it Transmission can occur but is very rare. To date, six reports of confirmed transmission of HCV from HCWs to patients have been published, including a Spanish anesthesiologist addicted to oppioids who infected nearly 200 patients. Look back of 2,286 women who had been operated between January ’93 and March 2000 by an HCV infected gynecologist, showed that only one (0.04%) woman acquired infection by the surgeon (Arch Intern Med 2002; 162: 805).

24. HCV-Provider-to-Patient Transmission Published Cases Case 1 An HCV-positive surgeon infected a patient during valve replacement surgery. Case 2 A highly viremic cardiothoracic surgeon infected five of his patients intraoperatively between 1988 and 1993. Cases 3 and 4 HCV provider-to-patient transmissions by two gynecologists. Case 5 An HCV-positive anesthesiologist transmitted the virus during a cardiothoracic operation. Case 6 A Spanish anesthesiologist addicted to opioids infected almost 200 of his patients intentionally. Esteban et al., 1996; Duckworth et al., 1999; UK Health Department, 2000; Bosch, 2000; Garfein, 2000

25. Management of HCV infected HCWs No need to screen HCWs and no recommendations (CDC, EASL) exist to restrict professional activities of infected HCWs who, hovewer, must follow strict aseptic tecniques and universal precautionary measures. According to a Consensus Conference held at the ISS in Rome*, HCV infected (RNA+) HCWs should abstain from directly performing invasive (exposure prone) procedures while no other limitations in their activities are necessary. * Digest Liver Dis 2001; 33:795.

26. Sexual transmission of HCV It occurs but the virus is inefficiently transmitted through this route. Sex is a common behaviour and the existence of a large reservoir of HCV carriers provides multiple opportunities for exposure to potentially infected partners. Adolescents and young adults, individuals with multiple partners, prostitutes and their clients, patients with STDs, partners of HCV and HIV co- infected persons are at the increased risk of acquiring HCV sexually. No reliable HCV markers (i.e. genotype or HCV load) can predict transmission.

27. Prevention of sexual transmission of HCV Individuals in long-term monogamous relationship should be informed of the low risk of transmission and encouraged to discuss the risk and the use of barrier protections with sexual partners. The use of condom is strongly recommended for individuals with multiple partners, with STDs and for IVDUs. Counselling and education ( especially for adole- scents ). There is n There is no clear evidence that prophylaxis with Ig can event sexual transmission of HCV.

28. Prevention of HCV transmission (Household contacts and “daily life”) HCV can be percutaneously transmitted within families. Infected persons should be informed on preventive measures. Prevention includes avoiding shared use of razors, toothbrushers and any item that pierces the skin. Sharing meals or eating utensiles is not a known risk factor. “Daily life” is not a risk factor. There is no evidence to justify exclusion of anti-HCV + individuals from partecipation in social, educational or employment activities.

29. Hepatitis C and pregnancy Pregnancy is not contraindicated in women with HCV. Maternal infection does not appear to affect pregnancy adversely nor does pregnancy have adverse effects on the course of the liver disease. A woman with HCV infection should not be counselled against becoming pregnant. The major issue raised by HCV infection during pre- gnancy is how to decrease the risk of viral transmis- sion to the newborn. Available drugs cannot be used in pregancy since they are teratogenic (Ribavirin) or have adverse effects on fetal growth (Interferon).

30. Mother-to-child transmission of HCV (1) Risk is less than 5% but is higher for babies born to woman with HIV co-infection. Transmission is restricted to infants whose mothers are viremic (RNA+). Risk of infection increases with increasing maternal viral load, but a specific cut-off value which predicts transmission cannot be defined. Transmission is not related to specific genotypes.

31. Mother-to-child transmission of HCV (2) There is no evidence to support that caesarean delive- ry may reduce risk of HCV transmission compared to vaginal delivery. The role of obstetric variables such as type of vaginal delivery (spontaneous, induced, operative), duration of rupture membranes and timing of caesarean section (before, during labour) remains largely unexplored. The safety of obstetric procedures (use of monitoring devices and different instruments) during pregnancy in mothers HCV+ is not well documented. Caution should be recommended in using any invasive procedures (i.e. chorionic villous sampling, amniocente- sis, cord blood sampling) that may expose the fetus or the neonate to maternal blood.

32. Mother-to-infant transmission of HCV HCV can be detectable in colostrum and milk but breastfeeding appears to be safe and is not contraindicated. Factors that might modify the risk of viral trans- mission by breastfeeding (i.e. duration of lacta- tion, levels of HCV-RNA in colostrum and milk, exposure to chapped nipples) require further studies.

33. Assisted reproductive techniques There are insufficient data on the interaction between HCV infection and ART to make recommendations. If the woman is infected, the couple should counselled on the potential risk of mother-to-child transmission. If the male is infected, there is a potential risk of transmission to female if semen contains HCV. Over 1400 intrauterine inseminations attempts with processed semen of males HCV+ have been perfor- med without a case of transmission to the uninfected partner (1). There is no report of HCV transmission through heterologous gametes by individuals infected with HCV, but is recommended to select uninfected donors. 1. 1. Semprini AE - personal communication

34. Persons who should be screened for HCV infection Persons who received transfusion or solid trasplants prior to donor screening (1991) Haemophiliacs HCWs after percutaneous or mucosal exposure to anti-HCV+ blood IVDUs Hemodialyzed patients Donors of blood, organ or tissue transplantation Children born to mothers with hepatitis C

35. HCV screening Screening should be accompained by pre and post-counselling. Screening is not recommended for general po- pulation as well as for pregnant woman (or limi- ted to woman undergoing prenatal invasive procedures?) and HCWs (except those involved in exposure prone procedures). Future availability of effective drugs to treat infections and of a protective vaccine might change our current strategy for screening.