December 14, 2011

Obesity and diabetes epidemics spur increase in nonalcoholic steatohepatitis

Public release date: 14-Dec-2011

Contact: Dawn Peters

Liver transplantations for NASH-cirrhosis grew more than 600 percent over past decade

Nonalcoholic steatohepatitis (NASH) occurs when fat builds up in the liver. This accumulation of fat damages the liver and leads to cirrhosis. NASH is rapidly increasing in the U.S. mainly related to the epidemics of obesity and diabetes. As a result, the proportion of liver transplantations performed for NASH cirrhosis rose dramatically from roughly 1% in 1997-2003 to more than 7% in 2010. However, according to new research published in Liver Transplantation, a peer-reviewed journal of the American Association for the Study of Liver Diseases, post-transplantation survival for NASH patients is excellent, with one-year survival rates near 88%.

Excessive fat in liver cells in the absence of alcohol is known as non-alcoholic fatty liver disease (NAFLD) and is the most common liver disease in the U.S., affecting nearly 30% of the general population experts say. Previous research found that 15% to 20% of those with NAFLD have NASH—the most severe form of fatty liver causing inflammation and fibrosis. Primary risk factors for both NAFLD and NASH are central obesity, insulin resistance, and diabetes, all of which are increasingly prevalent and could impact the future demand for liver transplantation. In fact, prior studies suggest that by 2025 more than 25 million Americans may have NASH, which may progress to cirrhosis, liver cancer, and liver failure in 20% of these cases. This influx of new cases has the potential to dramatically worsen the shortage of organs available for transplantation.

In the current study, Dr. Anita Afzali and colleagues from the University of Washington in Seattle investigate the proportion of liver transplantations of NASH-related cirrhosis in the U.S. and estimate survival rates of those patients following transplantation. "With the epidemics of obesity and diabetes giving rise to cases of NAFLD and NASH, it is important to understand the impact of these metabolic conditions on the outcomes after liver transplantation," says Dr. Afzali.

The researchers used data collected by the United Network for Organ Sharing (UNOS) for all liver transplants performed in the U.S. from January 1, 1997 to October 31, 2010. A total of 53,738 transplant patients 18 years of age or older were included in the analysis. The team collected data on primary diagnosis for all study patients, categorizing those as NASH, cryptogenic cirrhosis, hepatitis C virus (HCV), alcohol-related cirrhosis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, autoimmune hepatitis, acute hepatic necrosis, and hepatocellular carcinoma (HCC).

The research found that only 279 transplantations for NASH-cirrhosis (1.2%) were performed between 1997 and 2003, but increased dramatically to 1,531 (7.4%) between 2004 and 2010. The team found that by the end of the study period NASH was the fourth most common indication for transplantation behind HCC (34%), HCV (22%), and alcohol-related liver disease (11%). Survival was excellent among patients with NASH with 88% surviving at one year, 82% at three years, and 77% at five years following liver transplantation.

Patients with NASH had higher survival rates than patients with HCC, HCV, alcoholic liver disease, acute hepatic necrosis, hemochromatosis and cryptogenic liver disease, but were lower than those with PBC, PSC, autoimmune hepatitis and HBV. Post-transplantation survival was similar in NASH patients compared to non-NASH patients, despite being older, more obese, and more likely to have diabetes. Their analysis shows deaths caused by recurrent disease occurred in roughly 9% of NASH patients compared to 17% of patients without NASH. The authors believe this is likely due to a greater frequency of recurrence of diseases such as HCV in those without NASH.

"Our study confirms post-transplantation survival in recipients transplanted for NASH is excellent and comparable to patients with other liver diseases," concludes Dr. Afzali. "With the shortage of available donor organs, appropriate allocation of livers is an important concern for transplant centers and our findings indicate NASH-cirrhosis patients are potentially good candidates for liver transplantation. However, careful screening for cardiovascular disease prior to transplantation and monitoring of underlying cardiac and metabolic conditions following transplantation is recommended to ensure optimal survival for patients with NASH."


This study is published in Liver Transplantation. Media wishing to receive a PDF of the article may contact

Full citation: "Excellent Post-Transplantation Survival in Patients with Non-Alcoholic Steatohepatitis in the United States." Anita Afzali, Kristin Berry, George N. Ioannou. Liver Transplantation; (DOI: 10.1002/lt.22435) Print Issue Date: January 2012.

Author Contact:To arrange an interview with Dr. Afzali, please contact Carrie Silverman with the University of Washington at or at 206-235-3223.

About the Journal

Liver Transplantation is published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society . Since the first application of liver transplantation in a clinical situation was reported more than twenty years ago, there has been a great deal of growth in this field and more is anticipated. As an official publication of the AALSD and the ILTS, Liver Transplantation delivers current, peer-reviewed articles on surgical techniques, clinical investigations and drug research — the information necessary to keep abreast of this evolving specialty. For more information, please visit Liver Transplantation.

About Wiley-Blackwell

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit or our new online platform, Wiley Online Library (, one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.


Headaches May Plague Many With HIV/AIDS

Migraines worse in patients with more advanced disease, study finds

December 14, 2011

WEDNESDAY, Dec. 14 (HealthDay News) -- Headache affects 50 percent of HIV/AIDS patients in the United States, and many of those headaches are severe, a new study says.

About 27.5 percent of the 200 HIV/AIDS patients in the study suffered "chronic migraine," a rare condition in which a person has migraine symptoms (with or without other headaches) for 15 or more days a month. This condition occurs in only 2 percent of the general population.

"This translates into a 13-fold increased risk of chronic migraine among patients with HIV disease," study author Todd Smitherman, an assistant professor of psychology at the University of Mississippi, said in a university news release.

"The strongest predictor of headache was the severity of HIV disease, such that patients with more advanced disease had more frequent, more severe and more disabling migraines," he added.

For the study, the researchers interviewed Montgomery, Ala., clinic patients who have HIV or AIDs and reviewed their medical records to look for any other cause of headache.

The findings, recently published online in the journal Headache, could help lead to improved treatment and reduced medical costs for HIV patients who suffer headaches, the researchers said.

"This research is of interest to clinicians and physicians for several reasons," Smitherman said. "Recent research from the U.S. Centers for Disease Control and Prevention shows that, despite the availability of medications that effectively slow disease progression, most Americans with HIV do not have the disease under control. Our study shows that patients with poorly controlled HIV/AIDS are most prone to suffer also from frequent, severe migraines at rates that far exceed those of the general population."

The authors said theirs is the first study since highly active antiretroviral therapy (HAART) became widely available to find that having HIV/AIDS is associated with a very high risk of headache, particularly migraines.

Doctors need to regularly monitor immune system functioning in HIV/AIDS patients and pay close attention to headache symptoms in those with more advanced disease, the researchers said.

More information

The U.S. National Institute of Neurological Disorders and Stroke has more about headache.


Alarming Incidence of Hepatitis C Virus Re-infection After Treatment of Sexually Acquired Acute Hepatitis C Virus Infection in HIV-infected MSM

Femke A.E. Lambers; Maria Prins; Xiomara Thomas; Richard Molenkamp; David Kwa; Kees Brinkman; Jan T.M. van der Meer; Janke Schinkel

Posted: 12/13/2011; AIDS. 2011;25(17):F21-F27. © 2011 Lippincott Williams & Wilkins

Abstract and Introduction


Background: Recent data indicate that seroprevalence of sexually transmitted hepatitis C virus (HCV) infection among MSM is stabilizing in Amsterdam. However, little is known about the incidence of HCV re-infection in MSM who have cleared their HCV infection. We, therefore, studied the incidence of re-infection in HIV-infected MSM who were HCV RNA-negative following HCV treatment of acute primary infection.
Methods: Our study population comprised HIV-infected MSM at two large HIV outpatient clinics in Amsterdam, who were previously diagnosed with a sexually transmitted acute HCV infection and tested HCV RNA-negative at the end of treatment. We defined HCV re-infection as detectable HCV RNA in individuals with an undetectable HCV RNA at the end of treatment accompanied by a switch in HCV genotype or clade. Person–time methods were used to calculate the incidence of re-infection.
Results: Fifty-six persons who became HCV RNA-negative during primary acute HCV treatment were included. Five of the 56 cases relapsed and were not analysed. Eleven persons were re-infected. The incidence of HCV re-infection in this group was 15.2 per 100 person-years (95% confidence interval 8.0–26.5). The cumulative incidence was 33% within 2 years.
Discussion: An alarmingly high incidence of HCV re-infection was found in this group. This high re-infection rate indicates that current prevention measures should be discussed, frequent HCV RNA testing should be continued after successful treatment and, in case of possible relapse, clade typing should be performed to exclude re-infection.


In the last decade, the sudden increase in incidence of acute hepatitis C virus infection (HCV) among HIV-infected MSM in Europe, Australia and the United States has led to a substantial number of studies on this new public health problem. It has become clear that transmission takes place in specific clusters of HIV-infected MSM engaging in high-risk sexual behaviour.[1–3] Subsequently, targeted prevention messages have been developed, focusing on sexual risk behaviour, recreational drug use and regular testing for HCV. Furthermore, treatment of HCV co-infection in this population has proven to be very successful in the acute phase, and recommendations on treatment have been published.[4,5]

The response to this epidemic has clearly been extensive, and a recent study in Amsterdam has suggested that the prevalence of new primary HCV infections may no longer be increasing (A.T. Urbanus et al., presented at AIDS Conference 2010, abstract WEPDC 104). The question remains, however, whether prevention messaging and early testing and treatment also prevents HCV re-infection in MSM co-infected with HCV and HIV who have cleared their infection.

HCV re-infection occurs frequently among IDUs who continue high-risk behaviour.[6] Incidence rates of re-infection vary depending on population, definition of re-infection and methods and frequency of testing.[6–10] Reports on HCV re-infection by sexual transmission among MSM have been published only rarely[11,12] (H.-J. Stellbrink et al., presented at CROI 2011, poster 645; presented at International Congress on Drug Therapy in HIV Infection 2010, poster 200; and J. Sasadeusz et al., presented at EASL 2011, poster presentation), and no specific incidence rates have been presented yet.

Therefore, the objective of the current study was to examine the incidence of HCV re-infection among HIV-infected MSM attending two HIV outpatient clinics in Amsterdam, who were HCV RNA-negative at the end of treatment for their initial acute HCV infection.

Study Population

We included 56 HIV-infected MSM at the HIV outpatient clinics of two major hospitals in Amsterdam, who had been previously diagnosed with and treated for an acute HCV infection between 2003 and 2011; none had detectable HCV RNA at the end of their HCV treatment. All patients had been treated with weekly injections of peg-interferon and daily doses of ribavirin, the majority for a duration of 24 weeks.[13] In the majority of the cases, no HCV parental transmission routes were identified by clinical history and sexual transmission was the most likely mode of transmission.

Data Collection

Sociodemographic, clinical and virological data, such as age, use of HAART, CD4 cell counts, HIV RNA levels, levels of alanine aminotransferase (ALT) and genotype of primary HCV infection were collected from medical files. A subset of the MSM at risk of re-infection (n = 21) was included in a prospective study of acute infection with HCV in MSM (MSM Observational Study of Acute Infection with hepatitis C, MOSAIC study). For these patients, additional data on risk behaviour are presented. Data collection exists of an extensive self-administered questionnaire regarding classic risk factors for HCV transmission, such as IDU and sexual risk behaviour, collected at baseline and follow-up visits.

Virological Testing

All plasma samples available after the end of treatment were tested for HCV RNA with the Siemens VERSANT transcription-mediated amplification (TMA) assay which has a detection limit of 5 IU/ml. Genotyping of the first TMA-positive sample after the end of treatment was performed by amplifying and sequencing a 389 base pair fragment of NS5B, as described by Murphy et al.[14] If the genotype was similar to that in the treated primary infection, a 573 base pair fragment of E2 including the hypervariable 1 region (HVR1) was amplified and sequenced directly to identify clade shifts and differentiate between relapse or re-infection.

Definition of Re-infection and Relapse

Re-infection was defined as having detectable HCV RNA following an undetectable level at the end of treatment, with demonstration of the presence of a different genotype compared with primary infection or, if genotype was similar, a different clade compared with primary infection, as indicated by phylogenetic analysis of the E2/HVR1 region. If in the phylogenetic pretreatment and posttreatment sequences from the same viral subtype (e.g. 1a) large genetic distances were present, as indicated by distinct clustering, this was defined as a clade switch and, therefore, as a re-infection with the same viral subtype. Relapse was defined as a positive HCV TMA after a negative HCV TMA at the end of treatment and no genotype or clade switch compared with the primary infection.

Phylogenetic Analysis

Sequences were aligned using Clustal X version 2.[15] Phylogenetic trees were inferred using maximum-likelihood methods, using a Generalized Time Reversible Model with a gamma distribution of mutations (GTR + Γ) as implemented in MEGA software package version 5.[16] Bootstrap values were determined from 500 bootstrap resamplings of the original.

Statistical Analysis

The incidence rate of re-infection was estimated by dividing the number of re-infections by the total duration of follow-up. The individuals who had relapses were excluded from this calculation. The cumulative incidence was estimated by Kaplan–Meier methods.

In case of re-infection, follow-up time was calculated as the time between the end of treatment and the date of re-infection; the latter was estimated by taking the midpoint between the last negative HCV RNA test and first positive HCV RNA test. If no re-infection occurred, the censor date for follow-up was the date of the last HCV RNA test.

We compared sociodemographic, clinical, virological and behavioural characteristics, including peak ALT levels during follow-up between patients with and without re-infection. Risk behaviour was compared between MSM with and without re-infection for whom risk questionnaires were available. Differences between the two groups were tested with the χ2-test or Fisher's exact test for categorical variables and Student's t-test or Mann–Whitney U-test for continuous variables. Analyses were performed using SPSS (version 17.0; SPSS Inc., Chicago, Illinois, USA). The incidence rate and its confidence interval (CI) were calculated with OpenEpi[17] and are given per 100 person-years.


In total, follow-up was obtained for 56 HIV-infected MSM treated for acute HCV infection who were HCV RNA-negative at the end of treatment. Patients were treated between 2003 and 2011. Patient and virological characteristics are shown in Table 1.

Five of the 56 experienced relapse, as evidenced by sequencing of the E2/HVR1 region, and were excluded from the incidence calculations.

According to our definition, 11 of the remaining 51 persons became re-infected. The total follow-up time for the 51 persons was 72.2 years [median 1.3 years, interquartile range (IQR) 0.5–1.6]. The incidence of HCV re-infection was 15.2 per 100 person-years (95% CI 8.0–26.5). Among the 11 individuals with a re-infection, the median time until re-infection was 8.4 months (IQR 3.6–19.2). The majority of re-infected patients switched from genotype 4 to 1.

Three persons became re-infected with the same genotype (clade switch). Figure 1 shows the phylogenetic tree of pretreatment and posttreatment E2-HVR1 sequences of these patients together with pretreatment and posttreatment sequences of relapse patients. Pretreatment and posttreatment sequences from patients O1, O2, O3, P06 and P44 clearly cluster together and they were, therefore, classified as 'true' relapsers, corresponding with the clinical observation of RNA rebound at the first time point available after treatment withdrawal. In contrast, pretreatment and posttreatment sequences from patients P01, P31 and P48 do not cluster and they were, therefore, considered re-infections. Although patients P01 and P31 became HCV RNA-positive again within 6 months after the end of treatment, the first sample taken at 4 weeks was negative, supporting our phylogenetic evidence of re-infection.


Figure 1.

Phylogenetic tree of relapsers and patients with a re-infections with the same genotype.Phylogenetic tree of sequences before and after treatment from relapsers and patients with a re-infection with the same genotype. Relapsers are presented by filled symbols and re-infections are presented by open symbols. Each patient is presented by a unique symbol. The numbers in the labels indicate sampling dates. Note: re-infections with a different genotype are not presented in this tree.

The cumulative incidence of re-infection is demonstrated in Fig. 2; after 2 years, the cumulative incidence of re-infection was 33% (95% CI 16–50).


Figure 2.

Cumulative incidence of hepatitis C virus (HCV) re-infection after In order to examine whether ALT levels are useful for indicating a new infection, we compared peak ALT levels during follow-up in patients with and without re-infection. The peak ALT levels were in general low (with a maximum of 160 U/l), although the median ALT peak during follow-up was higher in individuals with a re-infection than in those without a re-infection (P = 0.01). Interestingly, in four cases with a re-infection, no increased ALT levels were observed, whereas in individuals without evidence of re-infection, ALT levels were elevated frequently (Fig. 3).successful treatment of primary HCV infection.

In order to examine whether ALT levels are useful for indicating a new infection, we compared peak ALT levels during follow-up in patients with and without re-infection. The peak ALT levels were in general low (with a maximum of 160 U/l), although the median ALT peak during follow-up was higher in individuals with a re-infection than in those without a re-infection (P = 0.01). Interestingly, in four cases with a re-infection, no increased ALT levels were observed, whereas in individuals without evidence of re-infection, ALT levels were elevated frequently (Fig. 3).


Figure 3.

Peak alanine aminotransferase levels during follow-up.Peak alanine aminotransferase (ALT) levels in units per litre during the observation period (end of treatment until last negative or first positive time point). The dotted line represents the maximum normal ALT value.

CD4 cell counts did not differ between patients with and without re-infection (Table 1). In addition, analysis of HIV load data from the eight of nine patients with a re-infection, who were on combination antiretroviral therapy (cART), showed that all patients had undetectable HIV loads around the time of HCV re-infection. From one re-infected patient on cART, no HIV load data were available.

Analysis of the 21 MSM with behavioural data revealed that re-infected MSM (n = 7) significantly more often reported noninjecting recreational drug use at inclusion than MSM without re-infection (n = 14) (P = 0.048). In this small study population, no statistically significant differences in sexual risk behaviour were found.

Of the 11 re-infected patients, four were treated for their re-infection; of those four, two achieved a sustained virologic response (SVR), one had a relapse, and one is still in follow-up for SVR time.


With this study, we demonstrate an alarmingly high incidence rate of sexually transmitted HCV re-infection among HIV-infected MSM previously successfully treated for primary HCV infection.

Most importantly, these findings stress the importance of repeated risk counselling for HCV transmission which should be provided not only before and during treatment but also after its completion. MSM re-infected with HCV showed higher rates of noninjecting recreational drug use. Sexual risk behaviour, including recreational drug use during sex, was highly prevalent (data not shown). Unfortunately, because of our relatively small study population with behavioural data, we were not able to examine risk behaviour more precisely and longitudinally.

The high incidence rate in this study implies that ALT levels, which can be elevated during an acute HCV infection, should be measured regularly in this population. Because these levels are not always elevated during acute infection or might not coincide with the test moment, as shown in Fig. 3, subsequent HCV RNA testing, especially in cases of high-risk behaviour, should be performed regularly, as antibodies remain in general present after successful treatment.

Along with risk behaviour, the role of biological susceptibility to HCV re-infection, although still unclear, is an important consideration. Importantly, discussion is ongoing whether previous infection with HCV can generate partial protective immunity to re-infection or increase the chance of clearance of re-infection.

Several studies that compared incidence rates of primary infection and re-infection among IDUs have presented results that argue both for[8,18,19] and against[6,7,10] this phenomenon. Differences between these studies are probably due to variations in intervals of testing, age of the participants, frequency of ongoing drug use and adjustment for behaviour in the analyses. The higher incidence of re-infection in our study compared with the incidence of primary infection in Amsterdam[2,20] and elsewhere[3] indicates that, as expected, there is no complete protection. Yet, the finding that most re-infections in this study occurred with a different genotype compared with the primary infection suggests that genotype-specific immunity may develop in some individuals.

Additionally, underlying a persons' ability to develop protective immunity, genetic profiles may play a role in susceptibility to HCV re-infection. The association of genetic variations near the interleukin-28B (IL28B) region with spontaneous HCV clearance and treatment-induced clearance has been well described for HCV-mono-infected patients.[21–28] Similar results have been found regarding HCV treatment response in persons co-infected with HIV, although in this population the association is less clear for those treated during the acute infection.[29–34] The effect of IL28B polymorphisms on HCV re-infection has not been described. In accord with the effects in primary infection, one would expect the responder genotype to be at least more likely to allow clearance of re-infection than the nonresponder genotype. Whether initial partial protective immunity is also more established in individuals with a beneficial IL28B genotype remains undetermined.

Apart from HCV-specific immune responses, HIV co-infection may play an important role. The exact role of HIV co-infection in primary sexually transmitted HCV infection is not well known. CD4 cell depletion in the gut may diminish the immune response against HCV sexual transmission.[35] Nevertheless, CD4 cell counts did not differ between patients with and without re-infection, indicating that the level of immune suppression caused by HIV co-infection does not influence the risk of re-infection following successful HCV treatment.

The results of this study may lead to a change in the current definitions of HCV relapse and re-infection. When no further genotyping or sequencing is performed, a recurrent HCV viraemia within 6 months after a negative test at the end of the treatment is currently considered a relapse.[36] Our study demonstrates that early recurrence of HCV could well be a re-infection with another genotype or strain. This distinction has important clinical ramifications and should, therefore, be recognized by clinicians. The definition of relapse or re-infection, especially in population with a high incidence of infection, should, therefore, always be based on virological characteristics and not on a specific interval between the end of treatment and recurrence of HCV RNA in the serum.

Finally, from a clinical and cost-effective perspective, the results of this study will encourage discussion about the validity of repetitive HCV treatment in patients with numerous subsequent re-infections owing to continued risk behaviour.

Apart from small numbers, this study has other limitations. We have not studied the possible existence of HCV-mixed infections during primary infection. Therefore, we cannot entirely exclude the possibility that re-infections were previously existing infections that became detectable after a dominant strain had been cleared.[37] However, the fact that the median interval from the first HCV RNA-negative test to the first HCV RNA-positive test after treatment was 8 months, with several negative results in between, strongly suggests that all re-infections were recently transmitted infections.

Furthermore, as this was not a prospective study, time between tests was not similar for all patients, and a re-infection followed by a quick, spontaneous clearance might have been missed. Nevertheless, as the median time between tests was 3 months, we do not expect this to have significantly influenced the incidence rate.

In conclusion, a high incidence rate of HCV re-infection among HIV-infected MSM in Amsterdam was demonstrated in this study, emphasizing the need for more extensive risk behaviour counselling and secondary prevention by regular and frequent HCV testing in this population. Future research should focus on the reasons for continuing high-risk sexual behaviour in order to improve targeted prevention. In addition, research should try to elucidate the virological and host factors associated with re-infection and its outcome in HIV-infected individuals.


  1. Danta M, Brown D, Bhagani S, Pybus OG, Sabin CA, Nelson M, et al. Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours. AIDS 2007; 21:983–991.
  2. van de Laar TJ, van der Bij AK, Prins M, Bruisten SM, Brinkman K, Ruys TA, et al. Increase in HCV incidence among men who have sex with men in Amsterdam most likely caused by sexual transmission. J Infect Dis 2007; 196:230–238.
  3. van de Laar TJ, Matthews GV, Prins M, Danta M. Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection. AIDS 2010; 24:1799–1812.
  4. Albert M, Benito J, Bhagani S, Boesecke C, Deterding K, Dominguez S, et al. Acute hepatitis C in HIV-infected individuals: recommendations from the European AIDS Treatment Network (NEAT) consensus conference. AIDS 2011; 25:399–409.
  5. Vogel M, Dominguez S, Bhagani S, Azwa A, Page E, Guiguet M, et al. Treatment of acute HCV infection in HIV-positive patients: experience from a multicentre European cohort. Antivir Ther 2010; 15:267–279.
  6. van de Laar TJ, Molenkamp R, van den Berg C, Schinkel J, Beld MG, Prins M, et al. Frequent HCV reinfection and superinfection in a cohort of injecting drug users in Amsterdam. J Hepatol 2009; 51:667–674.
  7. Aitken CK, Lewis J, Tracy SL, Spelman T, Bowden DS, Bharadwaj M, et al. High incidence of hepatitis C virus reinfection in a cohort of injecting drug users. Hepatology 2008; 48:1746–1752.
  8. Grebely J, Conway B, Raffa JD, Lai C, Krajden M, Tyndall MW. Hepatitis C virus reinfection in injection drug users. Hepatology 2006; 44:1139–1145.
  9. Grebely J, Knight E, Ngai T, Genoway KA, Raffa JD, Storms M, et al. Reinfection with hepatitis C virus following sustained virological response in injection drug users. J Gastroenterol Hepatol 2010; 25:1281–1284.
  10. Micallef JM, Macdonald V, Jauncey M, Amin J, Rawlinson W, van Beek I, et al.High incidence of hepatitis C virus reinfection within a cohort of injecting drug users. J Viral Hepat 2007; 14:413–418.
  11. den Hollander JG, Rijnders BJ, van Doornum GJ, van der Ende ME. Sexually transmitted reinfection with a new hepatitis C genotype during pegylated interferon and ribavirin therapy. AIDS 2005; 19:639–640.
  12. Jones R, Brown D, Nelson M, Low E, Bhagani S, Atkins M, et al. Re-emergent hepatitis C viremia after apparent clearance in HIV-positive men who have sex with men: reinfection or late recurrence?. J Acquir Immune Defic Syndr 2010; 53:547–550.
  13. Lambers FA, Brinkman K, Schinkel J, Spijkerman IJ, Molenkamp R, Coutinho RA, et al. Treatment of acute hepatitis C virus infection in HIV-infected MSM: the effect of treatment duration. AIDS 2011; 25:1333–1336.
  14. Murphy DG, Willems B, Deschênes M, Hilzenrat N, Mousseau R, Sabbah S. Use of sequence analysis of the NS5B region for routine genotyping of hepatitis C viru with reference to C/E1 and 5' untranslated region sequences. J Clin Microbiol 2007; 45:1102–1112.
  15. Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, et al. Clustal W and Clustal X version 2.0. Bioinformatics 2007; 23:2947–2948.
  16. Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 2011. [Epub ahead of print]
  17. Dean AG, Sullivan KM, Soe MM. OpenEpi: Open Source Epidemiologic Statistics for Public Health, Version 2.3.1.
  18. Currie SL, Ryan JC, Tracy D, Wright TL, George S, McQuaid R, et al. A prospective study to examine persistent HCV reinfection in injection drug users who have previously cleared the virus. Drug Alcohol Depend 2008; 93:148–154.
  19. Mehta SH, Cox A, Hoover DR, Wang XH, Mao Q, Ray S, et al. Protection against persistence of hepatitis C. Lancet 2002; 359:1478–1483.
  20. Urbanus AT, van de Laar TJ, Stolte IG, Schinkel J, Heijman T, Coutinho RA, et al. Hepatitis C virus infections among HIV-infected men who have sex with men: an expanding epidemic. AIDS 2009; 23:F1–F7.
  21. Ahlenstiel G, Booth DR, George J. IL28B in hepatitis C virus infection: translating pharmacogenomics into clinical practice. J Gastroenterol 2010; 45:903–910.
  22. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461:399–401.
  23. Grebely J, Petoumenos K, Hellard M, Matthews GV, Suppiah V, Applegate T, et al. Potential role for interleukin-28B genotype in treatment decision-making in recent hepatitis C virus infection. Hepatology 2010; 52:1216–1224.
  24. Rauch A, Kutalik Z, Descombes P, Cai T, Di IJ, Mueller T, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010; 138:1338–1345.1345.e1–e7.
  25. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009; 41:1100–1104.
  26. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009; 41:1105–1109.
  27. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461:798–801.
  28. Tillmann HL, Thompson AJ, Patel K, Wiese M, Tenckhoff H, Nischalke HD, et al. A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice. Gastroenterology 2010; 139:1586–1592.1592.e1.
  29. Aparicio E, Parera M, Franco S, Perez-Alvarez N, Tural C, Clotet B, et al. IL28B SNP rs8099917 is strongly associated with pegylated interferon-alpha and ribavirin therapy treatment failure in HCV/HIV-1 coinfected patients. PLoS One 2010; 5:e13771.
  30. Clausen LN, Weis N, Astvad K, Schonning K, Fenger M, Krarup H, et al. Interleukin-28B polymorphisms are associated with hepatitis C virus clearance and viral load in a HIV-1-infected cohort. J Viral Hepat 2011; 18:e66–e74.
  31. Labarga P, Barreiro P, Mira JA, Vispo E, Rallon N, Neukam K, et al. Impact of IL28B polymorphisms on response to peginterferon and ribavirin in HIV-hepatitis C virus-coinfected patients with prior nonresponse or relapse. AIDS 2011; 25:1131–1133.
  32. Nattermann J, Vogel M, Nischalke HD, Danta M, Mauss S, Stellbrink HJ, et al. Genetic variation in IL28B and treatment-induced clearance of hepatitis C virus in HIV-positive patients with acute and chronic hepatitis C. J Infect Dis 2011; 203:595–601.
  33. Pineda JA, Caruz A, Rivero A, Neukam K, Salas I, Camacho A, et al. Prediction of response to pegylated interferon plus ribavirin by IL28B gene variation in patients coinfected with HIV and hepatitis C virus. Clin Infect Dis 2010; 51:788–795.
  34. Rallon NI, Soriano V, Naggie S, Restrepo C, Goldstein D, Vispo E, et al. IL28B gene polymorphisms and viral kinetics in HIV/hepatitis C virus-coinfected patients treated with pegylated interferon and ribavirin. AIDS 2011; 25:1025–1033.
  35. Guadalupe M, Reay E, Sankaran S, Prindiville T, Flamm J, McNeil A, et al. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol 2003; 77:11708–11717.
  36. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49:1335–1374.
  37. Smith JA, Aberle JH, Fleming VM, Ferenci P, Thomson EC, Karayiannis P, et al. Dynamic coinfection with multiple viral subtypes in acute hepatitis C. J Infect Dis 2010; 202:1770–1779.


Study: Hep C Doesn’t Impair Women’s Cognitive Faculties

December 12, 2011

Infection with the hepatitis C virus (HCV) doesn't damage women's cognitive function—mental tasks such as attention, memory and the abilities to solve problems and make decisions—according to Women's Interagency HIV Study (WIHS) data published in the Journal of Acquired Immune Deficiency Syndromes and reported by aidsmap. The researchers confirmed, however, that HIV infection alone is independently associated with cognitive impairment.

Previous studies have indicated that HCV increases the risk of neurocognitive impairment, possibly because the virus can migrate to the brain. And while researchers have indicated that coinfection with both HCV and HIV—another chronic viral infection that has been linked to central nervous system problems—may further increase the risk of cognitive deficits, this theory has not been definitively proved, notably in women.

To shed light on this lingering question, researchers analyzed data involving 1,338 women, 18 percent of whom had detectable levels of HCV and 67 percent of whom were HIV positive. The participants were divided into six groups based on their HCV infection status, HIV infection status and immune system health.

After controlling for properties known to have a negative impact on cognitive function—age, liver disease status, drug or alcohol abuse, etc.—the researchers found no connection between diminished cognitive function and HCV infection. However, the research showed that HIV infection was correlated with cognitive impairments, notably processing information and perceptual-motor ability (hand-eye coordination).

The researchers said that larger studies, including both men and women, would be required to gain a definitive answer regarding the effect of HCV on cognitive processes.


Can Transplant Recipients Be Weaned Off Their Immunosuppresive Drugs?

Article Date: 13 Dec 2011 - 1:00 PST

Transplant surgeons live in the hope that one day they will be able to wean at least some of their patients off the immunosuppressive drugs that must be taken to prevent rejection of a transplanted organ. A team of researchers led by Alberto Sánchez-Fueyo, at the University of Barcelona, Spain, has now identified markers that might make this possible for liver transplant recipients.

Transplant recipients must take immunosuppressive drugs for the rest of their lives to prevent rejection of their transplanted organ; this has serious negative health consequences. It would be helpful if it were possible to determine what would happen if a patient was weaned from their immunosuppressive drugs: would they reject their transplanted organ or would their immune system be sufficiently tolerant of the transplant that it would not be rejected?

Sánchez-Fueyo and colleagues determined that liver transplant recipients with higher blood levels of proteins involved in handling iron (hepcidin and ferritin) could tolerate weaning from their immunosuppressive drugs. Moreover, measuring expression in the liver of genes involved in handling iron enabled Sánchez-Fueyo and colleagues to predict the outcome of immunosuppressive-drug withdrawal in an independent set of patients. They therefore suggest that they have identified a way to accurately pick out those liver transplant recipients who would be good candidates for drug-weaning protocols.

TITLE: Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation


Cost Effectiveness of Fibrosis Assessment Prior to Treatment for Chronic Hepatitis C Patients

Shan Liu1*, Michaël Schwarzinger2, Fabrice Carrat3, Jeremy D. Goldhaber-Fiebert4

1 Department of Management Science and Engineering, Stanford University, Stanford, California, United States of America, 2 Equipe ATIP-AVENIR/UMR-S 738 INSERM, Paris Diderot University, Paris, France, 3 UMR-S 707 INSERM, Pierre et Marie Curie University, Paris, France, 4 Department of Medicine, Center for Health Policy and Center for Primary Care and Outcomes Research, Stanford University, Stanford, California, United States of America


Background and Aims

Chronic hepatitis C (HCV) is a liver disease affecting over 3 million Americans. Liver biopsy is the gold standard for assessing liver fibrosis and is used as a benchmark for initiating treatment, though it is expensive and carries risks of complications. FibroTest is a non-invasive biomarker assay for fibrosis, proposed as a screening alternative to biopsy.


We assessed the cost-effectiveness of FibroTest and liver biopsy used alone or sequentially for six strategies followed by treatment of eligible U.S. patients: FibroTest only; FibroTest with liver biopsy for ambiguous results; FibroTest followed by biopsy to rule in; or to rule out significant fibrosis; biopsy only (recommended practice); and treatment without screening. We developed a Markov model of chronic HCV that tracks fibrosis progression. Outcomes were expressed as expected lifetime costs (2009 USD), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICER).


Treatment of chronic HCV without fibrosis screening is preferred for both men and women. For genotype 1 patients treated with pegylated interferon and ribavirin, the ICERs are $5,400/QALY (men) and $6,300/QALY (women) compared to FibroTest only; the ICERs increase to $27,200/QALY (men) and $30,000/QALY (women) with the addition of telaprevir. For genotypes 2 and 3, treatment is more effective and less costly than all alternatives. In clinical settings where testing is required prior to treatment, FibroTest only is more effective and less costly than liver biopsy. These results are robust to multi-way and probabilistic sensitivity analyses.


Early treatment of chronic HCV is superior to the other fibrosis screening strategies. In clinical settings where testing is required, FibroTest screening is a cost-effective alternative to liver biopsy.

Citation: Liu S, Schwarzinger M, Carrat F, Goldhaber-Fiebert JD (2011) Cost Effectiveness of Fibrosis Assessment Prior to Treatment for Chronic Hepatitis C Patients. PLoS ONE 6(12): e26783. doi:10.1371/journal.pone.0026783

Editor: Ravi Jhaveri, Duke University School of Medicine, United States of America

Received: June 27, 2011; Accepted: October 4, 2011; Published: December 2, 2011

Copyright: © 2011 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: Ms. Liu was supported by a Stanford Graduate Fellowship. Dr. Goldhaber-Fiebert was supported in part by a U.S. National Institutes of Health National Institute on Aging Career Development Award (K01 AG037593-01A1: PI; Goldhaber-Fiebert). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

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