June 29, 2011

Articles in Press

F. Violia, S. Basilia, V. Raparellia, P. Chowdaryb, A. Gattb, A.K. Burroughsc

Received 28 February 2011; received in revised form 20 June 2011; accepted 21 June 2011. published online 29 June 2011.
Accepted Manuscript

Abstract

Patients with cirrhosis can have abnormalities in laboratory tests reflecting changes in primary haemostasis, including bleeding time, platelet function tests, markers of platelet activation and platelet count. Such changes have been considered particularly relevant in the bleeding complications that occur in cirrhosis.

However, several studies have shown that routine diagnostic tests, such as platelet count, bleeding time, PFA-100, thrombelastography are not clinically useful to stratify bleeding risk in patients with cirrhosis. Moreover, treatments used to increase platelet count or to modulate platelet function could potentially do harm. Consequently the optimal management of bleeding complications is still a matter of discussion.

Moreover, in the last two decades there has been an increased recognition that not only bleeding but also thrombosis complicates the clinical course of cirrhosis. Thus, we performed a literature search looking at publications studying both qualitative and quantitative aspects of platelet function to verify which primary haemostasis defects occur in cirrhosis. In addition, we evaluated the contribution of qualitative and quantitative aspects of platelet function to the clinical outcome in cirrhosis and their therapeutic management according to the data available in the literature.

From the detailed analysis of the literature it appears clear that primary haemostasis may not be defective in cirrhosis, and a low platelet count should not necessarily be considered as an automatic index of an increased risk of bleeding. Conversely, caution should be observed in patients with severe thrombocytopenia where its correction is advised if bleeding occurs and before invasive diagnostic and therapeutic procedures.

Keywords: Liver Disease, Thrombocytopenia, Thrombocytopathy, Bleeding, Platelets

No full text is available. To read the body of this article, please view the PDF online.

a Divisione di I Clinica Medica, Sapienza- University of Rome, Rome, Italy
b Haemophilia Centre & Thrombosis Unit, Royal Free Hospital Hampstead NHS Trust, London, UK
c The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery UCL London, UK

PII: S0168-8278(11)00499-5
doi:10.1016/j.jhep.2011.06.008
© 2011 Published by Elsevier Inc.

Source
Articles in Press

Mauricio F. Silvaa, Morris Shermanb

Received 11 April 2011; received in revised form 17 May 2011; accepted 18 May 2011. published online 28 June 2011.
Accepted Manuscript

Abstract

Liver transplantation is a well-established treatment in a subset of patients with cirrhosis and hepatocellular carcinoma. The Milan criteria (single nodule up to 5cm, up to 3 nodules none larger than 3cm, with no evidence of extrahepatic spread or macrovascular invasion) have been traditionally accepted as standard of care. However, some groups have proposed that these criteria are too restrictive, and exclude some patients from transplantation who might benefit from this procedure. Transplanting patients with tumors beyond the established criteria falls into two categories, those whose tumors are beyond the Milan criteria at presentation without the use of treatment prior to transplantation (expanded criteria), and those in whom treatment allows the MC to be fulfilled (down-staging). Currently, however, there is no international consensus regarding these approaches in clinical practice. The purpose of this systematic review is to clarify this debate through a critical analysis of available data. Finally, some comments on predictive factors apart from morphological characteristics are also addressed.

Keywords: Hepatocellular carcinoma, Liver transplantation, Expanded criteria, Down-staging, Milan criteria, Systematic review, Evidence based medicine

No full text is available. To read the body of this article, please view the PDF online.

a Department of HBP Surgery and Transplantation, Santa Casa General Hospital, Porto Alegre, Brazil
b University of Toronto, University Health Network Toronto, ON, Canada

PII: S0168-8278(11)00495-8
doi:10.1016/j.jhep.2011.05.012
© 2011 Published by Elsevier Inc.

Source

Viral Load Tied to Vertical Transmission of Hepatitis C

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Genetic variation in IL28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV infected children

"In view of the data presented, we believe it is necessary to make a clear distinction between the risk factors of HCV-VT and of chronic infection. We confirm that viral load and HIV co-infection are the only risk factors involved in HCV-VT. On the other hand, the viral genotype non-1 and the infant's IL28B CC Rs12979860 polymorphism are associated with HCV spontaneous clearance. Our data are the first to account for HCV virus clearance and may provide important information about protective immunity to HCV."

Last Updated: May 23, 2011.

Hepatology

Accepted Article (Accepted, unedited articles published online for future issues)

High maternal viral load is associated with vertical transmission of hepatitis C virus, but polymorphisms in interleukin 28B are not, according to a study published online March 16 in Hepatology.

MONDAY, May 23 (HealthDay News) -- High maternal viral load is associated with vertical transmission of hepatitis C virus (HCV-VT), but polymorphisms in interleukin 28B (IL28B) are not, according to a study published online March 16 in Hepatology.

Angeles Ruiz-Extremera, M.D., from San Cecilio University Hospital in Granada, Spain, and colleagues assessed the role of a single nucleotide polymorphism on IL28B in HCV-VT and the spontaneous clearance of HCV among infected infants. Mothers recruited for the study included 112 who were HCV-RNA positive/HIV negative and 33 HCV-RNA negative/HCV-antibody positive with 142 and 43 children, respectively. Children underwent testing for HCV-RNA at birth and regularly until the age of 6 years. Single nucleotide polymorphism at IL28B was determined in mothers and children. The occurrence of HCV-VT was assumed when children presented HCV-RNA positive in two subsequent blood samples.

The investigators found that 61 percent of the 31 mothers with the CC polymorphism and 82 percent of the 68 mothers with non-CC polymorphism were HCV-RNA positive. Among infants born to HCV-RNA positive mothers, 20 percent acquired HCV infection, but only 9 percent were chronically infected. No HCV-VT was seen in HCV-RNA negative women, and the rate was increased in mothers with higher HCV viremia. Neither maternal nor child IL28B status was correlated with increased risk of HCV-VT. Genotype non-1 and genotype CC of the IL28B were the factors influencing viral clearance among the infected children. Child CC polymorphism was the sole predictor of HCV clearance in HCV genotype-1.

"High maternal viral load is the only predictive factor of HCV-VT. IL28B plays no role in HCV-VT," the authors write.

Abstract

The vertical transmission of Hepatitis C Virus (HCV-VT) is a major route of HCV infection in children, but the risk factors remain incompletely understood. This study analyses the role of IL28B in HCV-VT and in the spontaneous clearance of HCV among infected infants. Between 1991 and 2009, 145 mothers were recruited to this study: 100 were HCV-RNA+ve/HIV-ve, with 128 children, and 33 were HCV-RNA-ve/HCV antibody+ve, with 43 children. The infants were tested for HCV-RNA at birth and at regular intervals until the age of 6 years. IL28B (single nucleotide polymorphism rs12979860) was determined in the mothers and children. HCV-VT was assumed when children presented HCV-RNA+ve in two subsequent blood samples. HCV-VT infected infants were categorized as: (A) transient viremia with posterior HCV-RNA-ve and without serum-conversion; (B) persistent infection with serum-conversion. Of the 31 mothers with CC polymorphism, 19(61%) were HCV-RNA+ve whereas among the 68 mothers with non-CC polymorphism, 56(82%) were HCV-RNA+ve. 26 of 128(20%) infants born to the HCV-RNA+ve mothers acquired HCV infection, but only 9(7%) were chronically infected. The rate of HCV-VT was higher among the mothers with higher HCV viremia. No HCV-VT was detected in the HCV-RNA-ve women. Neither the mothers' nor the children's IL-28 status was associated with an increased risk of HCV-VT. The factors influencing viral clearance among the infected children were genotype non-1 and genotype CC of the IL28B. In logistic regression, child CC polymorphism was the only predictor of HCV-clearance in HCV genotype-1.

CONCLUSIONS:

High maternal viral load is the only predictive factor of HCV-VT. IL28B plays no role in HCV-VT, but IL28B CC child polymorphism is associated independently with the spontaneous clearance of HCV genotype-1 among infected children. (HEPATOLOGY 2011.)

Discussion

Vertical transmission of Hepatitis C Virus represents the mayor cause of paediatric HCV infection today, and in industrialized countries it is the most common cause of chronic liver disease in children. About 10-15% of those who are chronically infected might develop cirrhosis and eventually hepatocellular carcinoma (16, 17). HCV prevalence in pregnant women is similar to that of the general population and in general, most HCV-infected pregnant women do not have obstetric complications. At present, there are no antiviral treatment recommendations for HCV-infected women during pregnancy, or guidelines for the prevention of vertical transmission (18). Although persistent transmission of HCV from infected mothers to their infants is reported in 4-8% of cases (chronic HCV children), transient HCV perinatal infection also occurs, with a prevalence of about 14-17% (19, 20). Moreover, the maternal-infant transmission of HCV is more frequent than is generally reported, taking into account that spontaneous HCV-RNA clearance among children is more common than among adults and that in many studies the follow up of infants is incomplete; moreover, in many cases only limited data, corresponding to the first years of life, are presented (21). IFNα is currently the approved drug for hepatitis C treatment for the paediatric population. Combination therapy with IFNα or pegylated IFNα plus ribavirin has recently been approved by the US FDA-EMEA for children older than 3 years with chronic HCV infection, and clinical trials are in progress (3, 22). Although most children are asymptomatic and the associated liver damage appears to be less severe in children than in adults, they have a significantly poorer health status than community controls (23), which suggests there is a need for the services currently available for adult HCV patients to be extended to support the families of children with HCV.

Conflicting data have been reported regarding the possible role of the level of maternal HCV viremia. Some studies have shown that a high concentration of serum HCV-RNA is associated with a higher risk of transmission, although no specific cut-off value predicting or excluding transmission has been defined (11). However, other studies have found no such association, with a considerable overlap in concentrations of HCV-RNA between transmitting and non-transmitting mothers (1, 24). Moreover, maternal co-infection with HCV and human immunodeficiency virus (HIV) is associated with high maternal HCV-RNA and with a higher risk of transmission (18, 25). In the present study, we found that both the HCV-RNA concentration (over 600,000 UI/mL) and maternal co-infection with HIV were associated with a higher risk of HCV-VT. The infected infants were not HCV-RNA positive at birth but all became so within 2-4 months. These data indicate that HCV maternal-foetal transmission did not occur during gestation and, therefore, that the infants were infected during the birth. Most of the infected children were asymptomatic despite high levels of alanine transaminase, compatible with acute hepatitis. The infants that cleared the HCV virus recovered normal alanine aminotransferase levels. With respect to the type of birth, there was no significant decrease in HCV-VT among the mothers who gave birth by caesarean section versus those who did not. The data on the effect of caesarean section on the risk of HCV perinatal transmission are heterogeneous and high-quality studies of this question have not been reported. A recent meta-analysis including 8 studies and 641 mother-infant pairs suggests that caesarean section does not decrease perinatal HCV transmission from HCV-RNA+ve/HIV-ve mothers to infants (8). No relationship between HCV-VT and the maternal HCV genotype has been found. On the other hand, when we studied spontaneous clearance (children with transient viremia) vs chronic infection in infected infants, the HCV viral genotype was associated with a higher risk of chronic infection. Thus, the rate of HCV chronicity was higher for infants with viral genotype 1 than for those with genotype non-1, a finding that is in accordance with the results of Bortolotti et al. (6). The role of viral genotype and its association with HCV spontaneous clearance and chronic infection should be explored further.

The HCV-VT risk factors that have been most intensively studied, to date, are viral factors, maternal characteristics and birth mode. However, immunogenetic influence has been poorly investigated and mainly confined to HLA-class II serological polymorphisms, because of their central role in the adaptive response. Nevertheless, it has been suggested that the role of the immune defence system, as well as the relevance of the genetic background, could better explain the pathogenesis of HCV infection, and these factors have been examined (10, 11). In adult patients, genetic variations in the interleukin 28B (IL28B) gene, an innate cytokine, have been associated with the response to interferon-alpha/ribavirin therapy and spontaneous clearance in HCV genotype 1 (26-28). For this reason, we evaluated the role of IL28B polymorphism in HCV genotype 1 vertical transmission, transient viremia and chronic infection in infants. This is the first study that attempts to describe both HCV-VT and the spontaneous clearance of HCV, taking into account the influence of IL28B polymorphism in mothers and children. The data obtained indicate that the IL28B genotype of mothers and children does not influence HCV-VT. Nevertheless, in the chronic infection study, 83% of the infants with the CC genotype exhibited spontaneous clearance (transient viremia) versus only 22% of the children with a non- CC genotype. On the other hand, the maternal IL28B genotype did not influence HCV chronic infection. Multivariate analysis identified the infant's Rs12979860 CC IL28B genotype as the only factor independently associated with the spontaneous clearance of HCV. To the best of our knowledge, the present study is the first one to identify IL28B Rs12979860 polymorphism as a predictor of HCV spontaneous clearance in infants infected with HCV genotype 1 by vertical transmission. More information is now needed to understand the mechanisms that underlie this association, as well as the clinical impact of IL28B polymorphisms on HCV infection.

The multivariate analysis performed clearly shows the distinction between the risk factors in HCV-VT and in chronic infection. In HCV-VT, a high HCV viral load was independently associated with HCV-VT, thus confirming the bivariate analysis and the data previously published, by ourselves and by others. These data suggest that the maternal characteristics are more important in HCV-VT than are those of the infants. However, in the chronic HCV infection study, the multivariate analysis showed that the only factor independently associated with HCV clearance was the infants' IL28B genotype, which confirmed our hypothesis that in infected infants, the host's immunogenic influence is crucial to the HCV viral response.

Finally, all retrospective analyses have inherent limitations, but we have tried to minimize their effects. The standard method of HCV determination changed during the patient inclusion period but this factor was controlled by using the same PCR technique on all the patients studied, using a stored blood sample. Furthermore, the standard care of HIV and HCV patients also changed during the patient inclusion period; however, in this study the risk factors among the HIV negative mothers (Study Cohort) were identified. According to standard protocols for VHC pregnant women, no VHC treatment should be applied during the pregnancy, and thus the changes in standard care for HCV patients do not affect our study. In view of the data presented, we believe it is necessary to make a clear distinction between the risk factors of HCV-VT and of chronic infection. We confirm that viral load and HIV co-infection are the only risk factors involved in HCV-VT. On the other hand, the viral genotype non-1 and the infant's IL28B CC Rs12979860 polymorphism are associated with HCV spontaneous clearance. Our data are the first to account for HCV virus clearance and may provide important information about protective immunity to HCV.

Source
K. Ellingson; D. Seem; M. Nowicki; D. M. Strong; M. J. Kuehnert

Posted: 06/27/2011; American Journal of Transplantation. 2011;11(6):1201-1208. © 2011 Blackwell Publishing

Abstract and Introduction

Abstract

To prevent unintentional transmission of bloodborne pathogens through organ transplantation, organ procurement organizations (OPOs) screen potential donors by serologic testing to identify human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection. Newly acquired infection, however, may be undetectable by serologic testing. Our objective was to estimate the incidence of undetected infection among potential organ donors and to assess the significance of risk reductions conferred by nucleic acid testing (NAT) versus serology alone. We calculated prevalence of HIV and HCV—stratified by OPO risk designation—in 13 667 potential organ donors managed by 17 OPOs from 1/1/2004 to 7/1/2008. We calculated incidence of undetected infection using the incidence-window period approach. The prevalence of HIV was 0.10% for normal risk potential donors and 0.50% for high risk potential donors; HCV prevalence was 3.45% and 18.20%, respectively. For HIV, the estimated incidence of undetected infection by serologic screening was 1 in 50 000 for normal risk potential donors and 1 in 11 000 for high risk potential donors; for HCV, undetected incidence by serologic screening was 1 in 5000 and 1 in 1000, respectively. Projected estimates of undetected infection with NAT screening versus serology alone suggest that NAT screening could significantly reduce the rate of undetected HCV for all donor risk strata.

Background

Transmission of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) can occur through solid organ transplantation.[1–4] Strategies to reduce transmission of these bloodborne pathogens from donor to recipient include assessing donor medical and behavioral risk, and laboratory testing for anti-HIV and anti-HCV seroreactivity in all potential organ donors. For most laboratory tests, there are window periods during which infection cannot be detected in donors with newly acquired infection. Compared with serologic testing, nucleic acid-amplification tests (NAT) shorten the window period through detection of the virus in plasma. In 2007 a donor, who was found to be nonreactive for HIV and HCV by routine serologic screening, was later found to be NAT-positive after four organ recipients were infected with HIV and HCV.[5] This incident underscored the need for a better understanding of the prevalence of HIV and HCV among potential organ donors and for evaluation of more sensitive screening tests to reduce the risk of undetected infection.

Estimates of HIV and HCV infection rates during the window period for serologic testing (i.e. undetected infection) were recently reported in US blood and tissue donors but have not been estimated for organ donors. For first-time blood donors, 1 in 3.1 million donations for HIV and 1 in 270 000 for HCV were nonreactive by serology assays, but positive by NAT.[6] The estimated risk of undetected infection among tissue donors for serologic testing is much higher: 1 in 55 000 for HIV and 1 in 42 000 for HCV.[7] The US Food and Drug Administration (FDA) currently mandates NAT screening for all blood and tissue donors for HIV and HCV, but no government agency mandates NAT screening for organ donors.[8] As of 2008, approximately one-half of the 58 US organ procurement organizations (OPOs) voluntarily performed HIV and HCV NAT on all or at least some subset of their potential donors.[9]

When transplant centers decide whether to accept an organ for transplantation, they rely on serologic test results as well as the 'high risk' designation assigned by OPOs during donor evaluations. OPOs are required to document the potential donor's infectious risk status utilizing risk criteria for HIV transmission outlined in the PHS 1994 guidelines.[10] Many OPOs have also used these criteria to evaluate risk for hepatitis virus transmission, as indicated by donor medical-behavioral history questionnaires (Appendix 1). A 2008 survey of US OPOs reported that, on average, 7.7% of an OPO's donors with organs recovered for transplantation, were designated as high risk, ranging from 2.3 to 26.1%.[11] Because transplants can be life saving, recipients and transplant surgeons may accept organs from high risk donors due to the shortage of available organs for transplantation; in 2008, 9465 candidates died or became too ill to benefit from transplantation while waiting for an available organ.[12] Organ acceptance may be influenced by type of organ needed, type of risk factor identified, medical health status of the candidate and laboratory testing results.

To appropriately weigh the risk of unintentional infection with HIV or HCV against the risk of delayed transplant, providers and patients must be able to reasonably assess risk. Currently there are no published studies that estimate the risk of undetected infection among potential organ donors by serologic testing in the United States. The objectives of this study were to (1) calculate the prevalence of HIV and HCV among a large subset of potential organ donors in the United States; (2) estimate the incidence of HIV and HCV among potential organ donors during the window periods for serologic and NAT screening.

Materials and Methods

Study Population

A sample of 17 of the 58 OPOs in the United States participated voluntarily in this study; these 17 OPOs manage over half of US organ donors.[12] Participating OPOs constituted a convenience sample of OPOs that submitted serologic screening results through three large reference laboratories to the CDC for the designated study period. Serologic tests were performed at local OPO, hospital or reference laboratories. The geographic distribution of participating OPOs was concentrated in the northeast, mid-Atlantic and western states, including Alaska (Figure 1). Nucleic acid testing results were not available for the majority of participating OPOs and were available for only a fraction of donors within OPOs performing NAT; thus NAT results were not considered for analysis in this study.


Figure 1.
Geographic distribution of the 17 organ procurement organizations (OPOs) participating in the study; participating OPOs fully covered states shaded dark gray and partially covered states shaded light gray, representing over 50% of all US organ donors.

Demographic and serologic data from January 2004 to July 2008 were requested from participating OPOs for all potential organ donors, including those who were consented but subsequently had no organs recovered. Serologic data collected from participating OPOs included anti-HIV and anti-HCV test results. Western blot (WB) confirmatory testing results for anti-HIV and recombinant immunoblot assay (RIBA) confirmatory tests for anti-HCV were also collected when available. Data on high risk designation, as determined by the OPO based on criteria presented in Appendix I, were collected. Participating OPOs also submitted information on the assay and generation of the specific tests used over the study period. All potential donors for whom data were requested had legal consent for organ donation and serologic test results. This study was determined to be exempt from human subjects review by the institutional review board at the Centers for Disease Control and Prevention in August, 2008.

Prevalence of Bloodborne Pathogens Among Potential Organ Donors

To calculate crude prevalence for HIV and HCV among potential donors, the number of positive results for a given serologic test was divided by the total number of potential donors tested. To account for false positive serologic results, adjustment factors were created directly from data submitted by OPOs from subsets of donors with WB or RIBA confirmatory tests available. For example, within the subset of HIV-positive serologic tests with WB availability, the number of positive anti-HIV serologies with positive WB results was divided by the number of all HIV-positive serologies with WB positive, negative or indeterminate results to calculate a conservative adjustment factor; a more liberal adjustment factor using both positive and indeterminate WB results as the numerator was calculated. The same process was followed for HCV, using available RIBA testing to create conservative and liberal adjustment factors. For HIV, there were 11 antibody-reactive cases for which confirmatory WB tests were available; 4 (0.36) had positive WB results, and 2 (0.18) had indeterminate results. For HCV, there were 183 antibody-reactive cases with RIBA confirmatory tests available; 142 (0.78) were RIBA positive, and 11 (0.06) were RIBA indeterminate. The adjustment factors were determined to be the midpoint of the conservative and liberal estimates: 0.45 for HIV and 0.81 for HCV.

The prevalence of HIV and HCV among potential organ donors was calculated for all potential donors and for donors stratified by OPO risk designation. Designations included 'normal risk' (i.e. actively designated as not 'high risk'), 'high risk' and 'missing risk' (i.e. risk status was either not recorded or not available for this study). The raw prevalence was multiplied by an adjustment factor (described above) to reflect prevalence adjusted for false positive serologic tests. Credible intervals surrounding the prevalence estimates were generated using Monte Carlo simulations for each pathogen and risk category. For the simulations, the number of tests reactive by serology was assigned a Poisson distribution. The adjustment factors were assigned triangular distributions with minimum and maximum values reflecting the conservative and liberal adjustment factor calculations: (0.36–0.55) for HIV and (0.78–0.84) for HCV. Values were drawn from these probability distributions for 10 000 repetitions, resulting in 95% credible intervals.

Estimating Incidence of Undetected Infection Among Potential Organ Donors

Incidence of undetected HIV and HCV infection in potential organ donors was calculated using the incidence-window period model originally developed for blood donors, which involves multiplying the incidence of infection (i.e. the yearly rate of newly acquired infection) in the donor population by the length of the window period.[13–16] The infectious window period is defined as the time after infectivity when the virus reaches a sufficient level in plasma to be transmissible up to the time of detection by NAT or serologic screening methods.[14,16,17] The incidence-window period model was recently modified for estimation of undetected infection in the tissue donor population in the United States and to organ and tissue donor populations in Canada.[7,16] Incidence in the blood donor population can be determined by examining seroconversion in repeat blood donors.[4] Since there are no repeat donations in the deceased potential organ donor population, incidence must be estimated by extrapolating from blood donor data.

Estimating the yearly incidence of HIV and HCV among potential organ donors required making projections from incidence estimates in blood donors during the same time period. It was assumed that prevalence differences between the organ donors in this study and blood donors in published literature would reflect differences in incidence. Thus, the ratio of organ donor prevalence to published blood donor prevalence was multiplied by the published incidence in blood donor population to attain the incidence in the study population of organ donors. Published incidence and prevalence rates from a population of blood donors who had donated to Red Cross Blood Services from 2007 and 2008 were used to make this calculation.[18]

To create ranges around incidence calculations, Monte Carlo simulations were used to reflect the combined variation in input parameters, including organ donor prevalence as calculated in this study, blood donor prevalence and incidence as reported in the literature, and window periods for serologic and NAT tests (Table 2). Since the variability surrounding window period inputs was unknown, triangular distributions with 50% variation were assigned to reflect unknown (and thus conservative) distribution and variance parameters. Ranges around incidence estimates were generated from 10 000 repeated calculations resulting in a 95% credible interval around the incidence estimates. All analyses were calculated with SAS 9.2 and in Crystal Ball software applications.

Results

Serologic data were submitted for 13 677 potential donors (n = 13 607 for anti-HIV and n = 13 349 for anti-HCV) (Table 1). For anti-HIV, overall adjusted prevalence was 0.21% with a credible interval (CI) of 0.15–0.29%. Prevalence was lowest for normal risk donors (n = 11 245) at 0.10% (CI = 0.06–0.16%) and highest for donors with missing risk status (n = 1182) at 1.00% (CI = 0.57–1.54%). For high risk donors (n = 1180), prevalence was 0.50% (CI = 0.21–0.86%). The overall adjusted prevalence for anti-HCV was 5.58% (CI = 5.15–6.06%). The adjusted anti-HCV prevalence was lowest for normal risk donors at 3.45% (CI = 3.10–3.85), and highest for high risk donors at 18.20% (CI = 15.74–20.91%). For donors with missing risk status, the adjusted HCV prevalence was 12.88% (CI = 10.83–15.08).

Out of all potential organ donors tested, 11.3% (n = 1538) did not have any organs recovered. Out of the 64 anti-HIV-positive donors, 58 (90.6%) did not have any organs recovered. Of the six HIV-positive donors with organs recovered, five were designated as normal risk and one was missing risk status; none were transplanted. Of 924 anti-HCV-positive potential donors, 36.0% (n = 332) did not have any organs recovered. Of the 591 anti-HCV-positive donors who did have organs recovered, 32.3% were considered high risk donors, 63.1% were considered normal risk donors and 4.6% were missing risk status.[1]

Yearly incidence estimates for HIV among all potential organ donors was approximately 61 per 100 000 person-years; for normal risk, high risk and missing risk donors the incidence was 29, 142 and 283 per 100 000 person-years, respectively. The overall incidence estimate for HCV was approximately 168 per 100 000 person-years; for normal risk, high risk and missing risk donors, incidence was 104, 547 and 387 per 100 000 person-years, respectively.

For normal risk donors, the estimated incidence of undetected HIV infection during the 22-day window period for serologic testing was approximately 1.72 per 100 000 person-years, and 0.55 per 100 000 person-years for the 7-day window period for NAT screening. For high risk donors, undetected HIV incidence per 100 000 person-years during the window periods for serologic and NAT screening were 8.54 and 2.72, respectively. The 95% credible intervals for undetected HIV infection during serologic and NAT window periods overlapped all donor risk strata (Table 2).

For normal risk donors, the estimated incidence of undetected HCV infection during the 70-day window period for serologic testing was approximately 19.91 per 100 000 person years, and 1.99 per 100 000 person-years for the 7-day window period for NAT testing. For high risk donors, undetected HCV incidence per 100 000 person-years during the window periods for serologic and NAT screening were 104.94 and 10.49, respectively. The 95% credible intervals for undetected HCV infection during serologic and NAT window periods did not overlap for any risk strata, indicating significant potential reductions conferred by NAT screening as compared to serology alone for HCV.

1Authors were not able to obtain information about whether recovered HCV-positive organs were transplanted.

Discussion

In our prevalence study of over 13 000 potential organ donors, approximately 1 in 500 were positive for anti-HIV after adjusting for false-positive serologic testing, with higher prevalence among high risk donors (1 in 200) versus normal risk donors (1 in 1000). One in 18 of all potential donors were positive for anti-HCV after adjusting for false-positive serologic testing; the prevalence among high risk donors was striking (1 in 5), and that among normal risk donors was substantial (1 in 30).

Findings suggest that organ donors are at higher risk of undetected infection by serologic screening (i.e. incident infection during the window period) compared to tissue donors. In 2004, tissue donors were reported to have a 1 in 55 000 risk of undetected HIV and 1 in 42 000 risk of undetected HCV infection by serologic screening.[7] In this study, normal risk organ donors had an estimated 1 in 60 000 risk of undetected HIV infection by serologic screening, which is similar to tissue donors; however, high and missing risk organ donors were at substantially higher risks of undetected HIV infection (1 in 12 000 and 1 in 6000, respectively). Organ donors of all risk strata had a higher risk of undetected HCV infection by serologic testing compared to tissue donors. In this study, normal risk organ donors had an estimated 1 in 5000 risk of undetected HCV infection by serologic testing, and high risk donors had a 1 in 1000 risk. For HCV, reduction in the window period for NAT screening decreased the risk by 90% of undetected infection to 1 in 50 000 for normal risk donors and 1 in 10 000 for high risk donors. Credible intervals for HCV incidence during the window period for serologic versus NAT screening did not overlap for any of the risk strata, suggesting significant risk reductions conferred by NAT screening (vs. serology alone) for HCV. Credible intervals for HIV incidence during serologic and NAT window periods do overlap for all risk strata; this is potentially a result of low HIV prevalence and incidence rates, wide variation in input parameters, and a smaller change in the window period for serology versus NAT for HIV compared with HCV (i.e. a 15 day difference vs. a 63 day difference).

The prevalence estimates of anti-HCV in high risk and normal risk donors demonstrated in this study are similar to those reported in a nation-wide analysis of donors reported to UNOS during the same time period.[9] Rates of anti-HIV in this study are higher, likely because most HIV-positive potential donors do not have organs recovered, and thus may not be reported to UNOS. This study included potential donors who had consent for testing, but who had no organs recovered likely because of their HIV status. Both this study and the nation-wide UNOS study are likely to underestimate the true prevalence of HIV among potential organ donors because HIV-positive persons are excluded from donation by law; therefore, known HIV positive persons are less likely to be consented for testing.

A nontrivial proportion (approximately 9%) of donors tested for anti-HIV and anti-HCV were missing risk status designations by OPOs. This phenomenon was not limited to one or few OPOs; 13 of the 17 participating OPOs submitted serologic testing results for donors with missing risk status. Donors with 'missing risk' status had a high prevalence of HIV (1.0%). A possible explanation is that this study included all potential donors who received serologic testing including those whose organs were not recovered due to HIV positivity. Donors no longer considered for transplantation are rarely reported to UNOS, which requires that the OPO report the risk designation, and thus OPO may not assign risk designations for these donors.

Differences in regulatory restrictions for organ donation versus blood and tissue donation may be attributed to differences in the degree of risk acceptable for the respective recipient group of each allograft. Allowing organs from high risk donors to be transplanted is one of several policies aimed at increasing the availability for life-saving organs; increasingly, organs are transplanted from donors with underlying chronic illnesses as well as donation after circulatory determination of death. Transplanting organs from these clinically suboptimal donors is presumably accepted because of the potential life years gained by the recipient or recipients.[20] In contrast, donors with behavioral risk factors are routinely excluded from the blood and tissue supply.

Decisions to recover and transplant organs are made based on several factors. Donors designated as high risk may not have their organs recovered or transplanted because of their high risk designation or because of other known medical or anatomical issues. However, because organs are in such high demand, the high risk designation may or may not dissuade a transplant center from accepting an organ. A recent survey of transplant surgeons showed that NAT screening enhanced surgeons' comfort in accepting organs from high risk donors, presumably because concerns about undetected infection were allayed.[11] Still, a recently published expert consensus concluded that there exists insufficient evidence to recommend routine NAT because the benefit may not outweigh the possibility of disqualifying organs for transplantation because of false-positive NAT results.[20] Our study suggests that adoption of NAT screening for HCV could significantly reduce the incidence of undetected infection during the window period with a particularly high yield for high risk donors; thus NAT screening could potentially improve organ acceptance from high risk donors with negative results. The question remains as to whether expanding the donor pool through enhanced acceptance of NAT-negative organs would balance or exceed organ loss from false-positive NAT. False-positive rates for NAT screening are poorly understood. False-positive NAT screening could be detrimental to the organ supply if noninfected organs are rejected. Given the concerns about false-positive NAT results, more research on the frequency and causes of false-positives is needed and protocols for NAT screening should promote maximum specificity. While this study was not designed to assess the rate of false-positive NAT screens, we do believe this phenomenon should be considered in parallel with the results from this study when making policy decisions related to NAT screening.

This study is subject to a number of limitations. Importantly, the geographic distribution of OPOs participating in this study is focused mainly on the areas of highest population density, so that results may not be generalizable nationally. Also, interpretation of the results should be predicated on the fact that most of the serologic tests used in this study (between 2004 and 2008) were third-generation tests. The introduction of more sensitive fourth-generation serologic assays would also shorten window periods and thus may be a suitable alternative to NAT screening for purposes of reducing window periods if approved by FDA. Additionally, when considering the validity of serology results, differences may exist between large reference labs and smaller production labs and may influence the relative rate of false-positive results.

The results of our study suggest that undetected infection, and potentially transmission, can occur with current testing methods, although relatively few transmission events have been reported. There may be several reasons for this discrepancy. First, it is possible that transmissions occur unnoticed because a recipient dies before the infection is detected. Under-reporting may also occur because a transplant physician is unable to identify the donor as the source of recipient infection, particularly if discovered months after the transplant. Finally, reporting of suspected disease transmissions to UNOS was not part of OPTN policy until 2005, and that policy has remained voluntary.

This study is also subject to the inherent limitations of the incidence window-period methodology in which the incidence of undetected infection among potential organ donors is estimated from incidence in the blood donor population multiplied by an organ-to-blood donor prevalence ratio. This methodology assumes that the organ-to-blood donor prevalence ratio accurately reflects the organ-to-blood donor incidence ratio. This limitation was minimized by using prevalence and incidence estimates from the same time period; all estimates used to calculate the probability of undetected infection of HIV and HCV among potential organ donors—blood donor incidence data, blood donor prevalence data and organ donor prevalence data—were collected from 2004 through 2008.

Although recent surveys indicate that NAT is feasible, as it is performed by many OPOs on some donors for at least one bloodborne pathogen, the practice is variable (11). This is of particular concern as high risk donor recovery also is highly variable, and may not be correlated with use of NAT. Because the risk of transmitting bloodborne infections through transplantation is unlikely to be completely eliminated and can be difficult to predict for each individual donor, recipients and providers should have a clear understanding of the risk and benefits through standardized informed consent at appropriate points in the transplantation listing and offering process.[21] Through ongoing collection and analysis of donor testing results as performed in our study, a better definition of transmission risk is possible, resulting in a decision process that allows for most effective use of a limited organ supply.

The Organ Procurement Organization Nucleic Acid Testing Yield Project Team

Tiffany Arrington, The Living Legacy Foundation of Maryland; Nicole Berry, LifeNet Health; James Bradley, New England Organ Bank; Benjamin Chau, California Transplant Donor Network; Claudia Chinchilla-Reyes, Mendez National Institute of Transplantation; Stephanie Cozby, LifeCenter Northwest; Wayne Dunlap, LifeCenter Northwest; A. Bradley Eisenbrey, Gift of Life Michigan; Patricia Harris, New Jersey Organ and Tissue Sharing Network; Richard Hasz, Gift of Life Donor Program; Emily Johnson, Washington Regional Transplant Community; Curt Kandra, Pacific Northwest Transplant Bank; David Marshman, LifeNet Health; Thomas Mone, OneLegacy; Helen Nelson, Golden State Donor Services; Patricia Niles, New Mexico Donor Services; Kevin O'Connor, LifeCenter Northwest; Eugene Osborne, California Transplant Donor Network; Joseph Roth, New Jersey Organ and Tissue Sharing Network; Deborah Savaria, LifeChoice Donor Services; Edwin Serna, Nevada Donor Network; Lisa Stocks, Lifesharing—A Donate Life Organization; Katrina Tanner, Gift of Life Michigan; Waheed Tajik, New York Organ Donor Network; Sharon West, Gift of Life Donor Program.

References

1.Tugwell BD, Patel PR, Williams IT et al. Transmission of hepatitis C virus to several organ and tissue recipients from an antibodynegative donor. Ann Intern Med 2005; 143: 648–654.

2.Pereira BJ, Milford EL, Kirkman RL, Levey AS. Transmission of hepatitis C virus by organ transplantation. N Engl J Med 1991; 325: 454–460.

3.Simonds RJ, Holmberg SD, Hurwitz RL et al. Transmission of human immunodeficiency virus type 1 from a seronegative organ and tissue donor. N Engl J Med 1992; 326: 726–732.

4.CDC. Human Immunodeficiency virus infection transmitted from an organ donor screened for HIV antibody—North Carolina. Morbid Mortal Week Rep 1987; 36: 306–308.

5.Ison et al. Transmission of human immunodeficiency virus and hepatitis C virus from an organ donor to four transplant recipients. Am J Transplant, in press.

6.Stramer SL, Glynn SA, Kleinman SH et al. Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing. N Engl J Med 2004; 351: 760–768.

7.Zou S, Dodd RY, Stramer SL, Strong DM. Probability of viremia with HBV, HCV, HIV, and HTLV among tissue donors in the United States. N Engl J Med 2004; 351: 751–759.

8.FDA. Tissue and tissue products compliance and regulation. http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/default.htm.

9.Kucirka LM, Alexander C, Namuyinga R, Hanrahan C, Montgomery RA, Segev DL. Viral nucleic acid testing (NAT) and OPO-level disposition of high-risk donor organs. AmJ Transplant 2009; 9: 620–628.

10.CDC. Guidelines for preventing transmission of human immunodeficiency virus through transplantation of human tissue and organs. Morbid Mortal Week Rep 1994; 43: 1–17.

11.Kucirka LM, Namuyinga R, Hanrahan C, Montgomery RA, Segev DL. Provider utilization of high-risk donor organs and nucleic acid testing: Results of two national surveys. Am J Transplant 2009; 9: 1197–1204.

12.United Network for Organ Sharing. Latest Data. (Assessed December 7, 2009 at http://optn.transplant.hrsa.gov/latestData/rptData.asp).

13.Yao F, Seed C, Farrugia A et al. The risk of HIV, HBV, HCV and HTLV infection among musculoskeletal tissue donors in Australia. Am J Transplant 2007; 7: 2723–2726.

14.Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted viral infections. The retrovirus epidemiology donor study. N Engl J Med 1996; 334: 1685–1690.

15.Busch MP, Lee LL, Satten GA et al. Time course of detection of viral and serologic markers preceding human immunodeficiency virus type 1 seroconversion: Implications for screening of blood and tissue donors. Transfusion 1995; 35: 91–97.

16.Zahariadis G, Plitt SS, O'Brien S, Yi QL, Fan W, Preiksaitis JK. Prevalence and estimated incidence of blood-borne viral pathogen infection in organ and tissue donors from northern Alberta. Am J Transplant 2007; 7: 226–234.

17.Janssen RS, Satten GA, Stramer SL et al. New testing strategy to detect early HIV-1 infection for use in incidence estimates and for clinical and prevention purposes. JAMA 1998; 280: 42–48.

18.Zou S, Dorsey KA, Notari EP et al. Prevalence, incidence, and residual risk of human immunodeficiency virus and hepatitis C virus infections among United States blood donors since the introduction of nucleic acid testing. Transfusion 2010; 50: 1408–1412.

19.Schnitzler MA, Whiting JF, Brennan DC et al. The life-years saved by a deceased organ donor. Am J Transplant 2005; 5: 2289–2296.

20.Humar A, Morris M, Blumberg E et al. Nucleic acid testing (NAT of organ donors: Is the 'best' test the right test? A consensus conference report. Am J Transplant 2010; 10: 889–899.

21.Halpern SD, Asch DA, Shaked A, Stock PG, Blumberg E. Determinants of transplant surgeons' willingness to provide organs to patients infected with HBV, HCV or HIV. Am J Transplant 2005; 5: 1319–1325.

Source

Programs may curb hepatitis C in drug users

By Amy Norton
NEW YORK Wed Jun 29, 2011 12:01am IST

NEW YORK (Reuters Health) - Programs that give injection drug users clean needles or safer drug substitutes may help cut their odds of contracting the liver infection hepatitis C, a new study suggests.

The hepatitis C virus is passed through contact with infected blood. Health care workers are particularly vulnerable, as are people who get tattoos in unclean environments. But in the U.S., most of the roughly 18,000 new infections each year occur when people who inject opiates, like heroin, share tainted needles or syringes.

Studies have found that clean-needle programs do reduce needle-sharing, and they seem to curb drug users' risk of infection with HIV, the virus that causes AIDS. The same appears true of programs that get addicts into treatment with opiate "substitutes" like methadone, which is taken orally instead of injected.

But there has been little evidence that these programs help cut the spread of hepatitis C.

A problem with the hepatitis C virus is that it's much easier to transmit than HIV. Even a faint amount of blood on a shared needle, for example, might be enough to infect another person.

But the new findings, published in the journal Addiction, suggest that needle and opiate-substitution programs can make a difference in hepatitis C risk, according to senior researcher Matthew Hickman, a professor of public health at the University of Bristol in the UK.

Combining the results from six previous studies of UK programs, Hickman's team found that drug users with the highest "coverage" from clean-needle programs were about half as likely to contract hepatitis C as other users.

Among users who said they got enough clean needles to cover all of their injections, just under 4 percent tested positive for hepatitis C during the studies, which lasted up to a year. That compared with 7 percent of drug users who didn't get clean needles for all their injections.

Similarly, the rate of new hepatitis C infection was 3 percent among drug users who were currently taking an opiate substitute (usually oral methadone), versus 7 percent among those not on treatment.

Drug users participating in both types of programs fared best of all, with a new infection rate of 2 percent.

"The implication is that hepatitis C transmission can be reduced by opiate substitution therapy and needle and syringe programs, especially their combination," Hickman told Reuters Health in an email.

While the study looked only at UK programs, it's likely the results would be similar in other countries, he said.

The study has its limits. It combined the results of several observational studies, where researchers "observed" groups of injection drug users who chose to use or not use the needle and opiate substitution programs.

Leaving the choice to the individual makes it hard to show that the programs are what caused hepatitis C infection rates to go down. There may be other differences between people who used the programs and those who didn't that would explain the results.

The findings are also based on small numbers, Hickman's team points out. The researchers had usable information on 919 program participants across the six study sites, and there were 40 cases of new hepatitis C infection.

Still, Hickman said the study starts to fill a gap in the knowledge of how well injection drug use programs are working.

In the U.S., new cases of hepatitis C infection have fallen sharply since the 1980s, according to Centers for Disease Control and Prevention. In the early 1990s, doctors found a way to detect the virus in blood, which meant they could make sure it wasn't transmitted in blood transfusions.

But chronic hepatitis C infection, the agency says, remains a major public health problem.

Between 75 and 85 percent of people infected with hepatitis C develop chronic infection, which can eventually cause serious liver diseases like cirrhosis (scarring of the liver) and liver cancer. Hepatitis C presently accounts for about a third of the liver transplants done in the U.S. each year.

An estimated 3.2 million Americans have chronic hepatitis C, about half of whom are unaware of it. (The initial infection most often causes no symptoms.)

There are medications for treating chronic hepatitis C, although they are not effective for everyone and have side effects like fatigue, nausea, headache and sleep problems.

According to Hickman, one question for future studies is whether treating chronic hepatitis C in injection drug users helps reduce transmission.

SOURCE: bit.ly/lMvRUW Addiction, online May 25, 2011.

Source
Published on: 2011-06-29

Chronic hepatitis C (CHC) Patients, infected with genotype (GT) 2 or 3 are treated with Peg-IFN and ribavirin (RBV) (800 mg/day) for 24 weeks. Treatment duration can be shortened to 12-16 weeks if a higher dose of RBV (1.000/1.200 mg/day) was used without considerable loss of responsiveness or increased risk of relapse.

Previously we have shown that in patients with CHC, GT 2/3 RBV can be reduced to 400 mg/day if administered for 24 weeks without an increase in relapse rates. Therefore we investigated the efficacy of a reduced RBV dosage of 400 mg/day with shorter treatment duration (16 weeks).

Methods: Treatment naive patients with CHC, GT 2/3 were randomized to receive 180mug peginterferonalpha2a/week in combination with either 800 (group C) or 400 mg/d (group D) for 16 weeks.

The primary endpoint was SVR.

Results: 12 months after the first patient was randomized a inferior outcome of group D as compared to group C was noted, therefore the study was terminated. At study termination 89 patients were enrolled (group C: 31, D: 51).

The SVR rate was statistically different in the two study groups with 51.6% in group C and 28.4% in group D (p=0.038). Patients with low viral load had higher SVR rates (C: 67%, D: 33%) than those with high viral load (C: 33%, D: 21%).

Conclusion: Both treatment duration and the dose of RBV play a major role to optimize outcome of patients with GT3.

If one intends to shorten the treatment weight based RBV dose should be used, if lower RBV doses are used patients should be treated for at least 24 weeks as. A treatment regimen with a reduced RBV dosage and shortened treatment duration is associated with low SVR rates due to high relapse rates.Trial registration: NCT01258101

Author: Andreas MaieronSigrid Metz-GercekThomas-Matthias ScherzerHermann LaferlGabriele FischerMartin BischofMichael GschwantlerPeter Ferenci

Credits/Source: BMC Research Notes 2011, 4:220
 
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