Preexisting Hepatitis C Virus Infection Research Articles

Direct-Acting Antivirals and Organ Transplantation: Is There Anything We Can't Do?

The opioid epidemic has resulted in an increase in organ donors with hepatitis C virus (HCV) infection in the United States. With the development of direct-acting antiviral regimens that offer high sustained virologic response rates even in the setting of immunosuppression after transplantation, these HCV-viremic organs are now being offered to transplant candidates with or without preexisting HCV infection. Strategies for HCV treatment with HCV-viremic organs have included delayed and preemptive approaches. This review will discuss key studies in the different solid organ transplants, recent reports of adverse events, and ethical and regulatory considerations. The efficacy of current HCV therapies has created this important opportunity to improve survival for patients with end-organ failure through greater access to organ transplantation and decreased waitlist mortality rate.

The clinical impact of hepatitis C virus infection in Egyptian multiple myeloma patients

BackgroundMultiple myeloma (MM) is a human B cell neoplasia characterized by the clonal proliferation of malignant plasma cells in the bone marrow. Worldwide, hepatitis C virus (HCV) infection is a public health problem. For MM patients, the clinical impact of preexisting HCV infection is still unclear. We aim to assess the clinical characteristics and the prevalence of the HCV infection in Egyptian MM patients. This observational study included 81 MM patients. HCV antibody assay was performed, and positive cases were confirmed using a reverse transcription-quantitative PCR (RT-PCR) method.ResultsFifteen (18.5%) patients were anti-HCV antibody positive. Only 6/15 (7.4%) patients were HCV RNA positive by RT-PCR. Liver affection in the form of hyperbilirubinemia with grade 4 adverse events was significantly higher in the anti-HCV positive/HCV RNA positive group versus anti HCV negative group (16.7% vs. 1.5%, p value = 0.005). The median HCV-RNA before the initiation of chemotherapy was 2.5 log IU/ml with mean ± SD = 4.25 ± 1.6 with no HCV reactivation. In the univariate and multivariate analysis, HCV infection was not an independent factor related to DFS. Low hemoglobin level < 10 g/dL (HR 0.59, 95% CI, 0.36–0.97, p value = 0.037) and abnormal serum total bilirubin level (HR 1.9, 95% CI 1.03–3.5, p value = 0.039) influenced DFS in the univariate analysis. However, in the multivariate analysis, serum calcium level greater than 12 mg/dL (HR 7.04, 95% CI 1.12–44.45, p value = 0.038) and abnormal serum total bilirubin level (HR 10.9, 95% CI 2.92–41.02, p value = < 0.001) remained statistically significant worse prognostic factors.ConclusionIn conclusion, our study revealed the prevalence of HCV infection in Egyptian MM patients. Serologic tests at diagnosis are necessary to identify these patients, and confirmation of positive cases by molecular techniques should be mandatory, with regular follow-up for liver dysfunction. Finally, further larger studies explaining the molecular mechanisms linking HCV and the MM pathogenesis are warranted.

CDC issues guidance on exposure to HCV for health professionals

In late July, CDC released guidance on the testing and clinical management of health care personnel potentially exposed to hepatitis C virus (HCV). The agency noted that the incidence of acute HCV infections among patients is increasing in the United States as a result of risky behaviors such as injection drug use, placing providers at risk for HCV infections if exposed to the blood and other bodily fluids of infected patients. “Testing for occupational exposure for blood- or fluid-borne pathogens is standard practice for many years,” said Rima A. Mohammad, PharmD, FCCP, BCPS, clinical pharmacist specialist in general surgery/gastroenterology/nutrition at the University of Michigan. “This guideline outlines the steps to take specific to HCV occupational exposure, which is similar to any exposure to other blood- or fluid-borne pathogens. Baseline testing of the source patient and the health care provider should occur immediately, preferably within 48 hours of exposure. CDC notes that the source patient should be tested for HCV RNA using a nucleic acid test. However, for low-risk patients, screening for anti-HCV serology (i.e., antibodies) can be done as an alternative, followed by a nucleic acid test if the serology is positive. For providers, testing should include anti-HCV testing, and if positive, HCV RNA testing. If the HCV RNA is positive at baseline, then the provider is considered to have a preexisting HCV infection and should be referred for HCV treatment. If a patient is anti-HCV positive but HCV RNA negative, then follow-up testing for the provider is not required. However, if the patient is HCV RNA positive or if the RNA status of the patient is unknown, then the provider should have follow-up HCV RNA testing 3 to 6 weeks postexposure and a final anti-HCV test 4 to 6 months postexposure as there may be periods of aviremia during acute HCV infection. Postexposure prophylaxis for HCV is not recommended for health care providers who have occupational exposure to blood or other bodily fluids. It is estimated that only 0.2% of percutaneous exposures and 0% of mucocutaneous exposures result in HCV transmission. CDC recommends that curative antiviral regimens be reserved for treatment if confirmed HCV transmission occurs. “Compared to previous HCV treatments, HCV is much easier to treat with the newer therapies that are a shorter duration, [are] well tolerated, and have efficacy rates of more than 95% for a cure or sustained virologic response,” said Mohammad. “Therefore, we can delay HCV treatment until we confirm that the health care provider is positive for HCV. The key difference between hepatitis B virus (HBV) and HCV occupational exposure is that postexposure prophylaxis is recommended after HBV exposure in select situations. “Unfortunately, with other viruses, such as HBV, there is no ‘cure’ for the infection and health care providers may need to be on long-term treatment,” said Mohammad. “Therefore, it is important to treat providers with postexposure prophylaxis (if appropriate) as soon as we confirm that the patient has an HBV infection. Routine use of the HBV vaccination for health care providers, combined with standard precautions, has resulted in a 98% decline in HBV infections over the past 2 decades, according to CDC. For those who are exposed to HBV, CDC has specific recommendations based on the vaccination status of the provider, the anti-HBs levels of the provider (i.e., < or ≥10 mIU/mL), and the status of the source patient. Postexposure recommendations vary based on these factors, but administration of HBIG and the hepatitis B vaccines are listed as options. The HCV and HBV postexposure guidance documents are available on CDC's website. The new HCV information can be used to update procedures for postexposure testing and clinical management of providers potentially exposed to the virus.

Sexual behaviour, recreational drug use and hepatitis C co-infection in HIV-diagnosed men who have sex with men in the United Kingdom: results from the ASTRA study.

IntroductionTransmission of Hepatitis C virus (HCV) among HIV-positive men who have sex with men (MSM) in the United Kingdom is ongoing. We explore associations between self-reported sexual behaviours and drug use with cumulative HCV prevalence, as well as new HCV diagnosis.MethodsASTRA is a cross-sectional questionnaire study including 2,248 HIV-diagnosed MSM under care in the United Kingdom during 2011–2012. Socio-demographic, lifestyle, HIV-related and sexual behaviour data were collected during the study. One thousand seven hundred and fifty two (≥70%) of the MSM who consented to linkage of ASTRA and clinical information (prior to and post questionnaire) were included. Cumulative prevalence of HCV was defined as any positive anti-HCV or HCV-RNA test result at any point prior to questionnaire completion. We excluded 536 participants with clinical records only after questionnaire completion. Among the remaining 1,216 MSM, we describe associations of self-reported sexual behaviours and recreational drug use in the three months prior to ASTRA with cumulative HCV prevalence, using modified Poisson regression with robust error variances. New HCV was defined as any positive anti-HCV or HCV-RNA after questionnaire completion. We excluded 591 MSM who reported ever having a HCV diagnosis at questionnaire, any positive HCV result prior to questionnaire or did not have any HCV tests after the questionnaire. Among the remaining 1,195 MSM, we describe occurrence of new HCV diagnosis during follow-up according to self-reported sexual behaviours and recreational drug use three months prior to questionnaire (Fisher's exact test).ResultsCumulative HCV prevalence among MSM prior to ASTRA was 13.3% (95% CI 11.5–15.4). Clinic- and age-adjusted prevalence ratios (95% CI) for cumulative HCV prevalence were 4.6 (3.1–6.7) for methamphetamine, 6.5 (3.5–12.1) for injection drugs, 2.3 (1.6–3.4) for gamma hydroxybutyrate (GHB), 1.6 (1.3–2.0) for nitrites, 1.7 (1.5–2.0) for all condom-less sex (CLS), 2.1 (1.7–2.5) for CLS-HIV-seroconcordant, 1.3 (0.9–1.9) for CLS-HIV-serodiscordant, 2.0 (1.6–2.5) for group sex, 1.5 (1.2–1.9) for more than 10 new sexual partners in the past year. Among 1,195 MSM with 2.2 years [IQR 1.5–2.4] median follow-up, there were 7 new HCV cases during 2,033 person-years at risk. Incidence was 3.5 per 1,000 person-years (95% CI 1.6–7.2). New HCV was recorded in 1.3% MSM who used methamphetamine versus 0.5% MSM who did not (p=0.385); 3.7% MSM who injected recreational drugs versus 0.5% MSM who did not (p=0.148); 2.9% MSM who used GHB versus 0.4% MSM who did not (p=0.003); 1.5% MSM who used nitrites versus 0.2% MSM who did not (p=0.019); 1.1% MSM having CLS versus 0.3% MSM who did not (p=0.084); 1.7% MSM having CLS-HIV-serodiscordant versus 0.4% MSM who did not (p=0.069); 0.9% MSM who had CLS-HIV-seroconcordant versus 0.5% MSM who did not (p=0.318); 0.8% MSM who had group sex versus 0.5% MSM who did not (p=0.463); and 1.6% MSM with =10 new sexual partners in the previous year versus 0.2% MSM with no or up to 9 new partners (p=0.015).ConclusionsSelf-reported recent use of recreational and injection drugs, condom-less sex and multiple new sexual partners are associated with pre-existing HCV infection and, with the exception of injection drugs, appear to be predictive of new HCV co-infection among HIV-diagnosed MSM.

An Investigation of Bloodborne Pathogen Transmission Due to Multipatient Sharing of Insulin Pens

On January 30, 2009, nursing staff at a military hospital in Texas reported that single-patient use insulin pens were used on multiple patients. An investigation was initiated to determine if patient-to-patient bloodbome transmission occurred from the practice. Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) testing was offered to patients hospitalized from August 2007 to January 2009 and prescribed insulin pen injections. Virus from HCV-infected patients' sera was sequenced and compared for relatedness. An anonymous survey was administered to nurses. Of 2,113 patients prescribed insulin pen injections, 1,501 (71%) underwent testing; 6 (0.4%) were HIV positive, 6 (0.4%) were hepatitis B surface antigen positive, and 56 (3.7%) had HCV antibody. No viral sequences from 10 of 28 patients with newly diagnosed and 12 of 28 patients with preexisting HCV infection were closely related. Of 54 nurses surveyed, 74% reported being trained on insulin pen use, but 24% believed nurses used insulin pens on more than one patient. We found no clear evidence of bloodborne pathogen transmission. Training of hospital staff on correct use of insulin pens should be prioritized and their practices evaluated. Insulin pens should be more clearly labeled for single-patient use.

Influence of Preexisting Hepatitis C Virus Antibody Positivity in Simultaneous Pancreas-Kidney Transplant Recipients

Preexisting hepatitis C virus (HCV) infection is implicated in diminished patient and graft survivals in renal transplant recipients. The impact of HCV infection on patient and graft survival in simultaneous pancreas-kidney transplantations is unclear. We evaluated the effect of preexisting HCV infection on patient and graft survival in simultaneous pancreas-kidney transplant (SPKT) recipients in the United States. Using the Organ Procurement and Transplant Network/United Network for Organ Sharing database as of March 2009, adult primary SPKT recipients transplanted from 1995 to 2008 were studied. We stratified recipients based on pretransplant HCV status as HCV positive (HCV+) or HCV negative (HCV-). Overall kidney graft, pancreas graft, and patient survival were compared. A total of 10,809 adults received primary SPKT, of which 350 (3.2%) were HCV+. Less than 2% of the HCV+ recipients received organs from HCV+ donors. There were no significant differences in baseline donor and recipient characteristics between groups. Rates of acute kidney rejection at 1 year were similar: 22.9% for HCV+ and 23.0% for HCV- recipients (P=0.49). There was no difference in serum creatinine between groups up to 3 years. After controlling for confounding factors, HCV positivity was not associated with worsened overall kidney graft (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61-1.03), pancreas graft (HR 0.80, 95% CI 0.63-1.00), or patient survival (HR 0.78, 95% CI 0.56-1.08). Only 3.2% of SPKT recipients had preexisting HCV infection. Preexisting HCV infection had no significant impact on kidney graft, pancreas graft, or patient survival.

Hepatitis C virus infection after liver transplantation is associated with lower levels of activated CD4+ CD25+ CD45RO+ IL-7rαhigh T cells

The expression of interleukin 7 receptor alpha(high) (IL-7Ralpha(high)) discriminates between activated CD25(+)CD45RO(+)CD4(+) T cells [IL-7Ralpha(high) and forkhead box P3-negative (FoxP3(-))] and regulatory T cells (IL-7Ralpha(low) and FoxP3(+)). The IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cell population has been shown to be expanded in the blood and tissues of patients after kidney transplantation and to contain alloreactive T cells (activated T cells). In the present study, we analyzed the distribution of IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cells in the blood of 53 patients after liver transplantation. The IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cell population was significantly expanded (P < 0.0001) in stable transplant recipients versus healthy donors. However, the magnitude of the expansion was significantly higher (P < 0.0001) in liver transplant recipients with no hepatitis C virus (HCV) infection in comparison with those with a preexisting HCV infection. Interestingly, effective suppression of HCV viremia after antiviral therapy was associated with an increase in the IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cell population to levels comparable to those of liver transplant recipients not infected with HCV. The present results indicate that (1) the IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cell population is expanded after liver transplantation, (2) it is a valuable immunological marker for monitoring activated and potential alloreactive CD4 T cells in liver transplantation, and (3) a preexisting HCV infection negatively influences the expansion of this population in liver transplant recipients.

Apparently Nonspecific Enzyme Elevations After Portal Vein Delivery of Recombinant Adeno-Associated Virus Serotype 2 Vector in Hepatitis C Virus-Infected Chimpanzees

Hepatic gene transfer is envisioned as a substitute for protein replacement therapies, many of which are derived from blood products. Thus, the target populations may have a high prevalence of blood-borne pathogens, such as hepatitis C virus (HCV). We sought to determine whether the safety of recombinant adeno-associated virus serotype 2 (rAAV2) would be altered by preexisting HCV infection. Doses of approximately 1 x 10(13) vector genomes of an rAAV2-chimpanzee alpha(1)-antitrypsin (rAAV2-cAAT) vector were injected into the portal vein of each of three HCV genome-positive (HCV+) chimpanzees and three HCV-negative (HCV-) controls. Acute safety studies were performed up to 90 days after vector administration, along with analyses of the peripheral blood and liver tissue for rAAV2-cAAT genomes. Vector genome copy numbers in blood and liver tissue were similar in both groups. All animals demonstrated increases in liver and muscle enzyme levels after the pretreatment liver biopsy (5 days before vector injection) and after the vector injection. However, HCV+ animals demonstrated a substantially greater rise in aspartate aminotransferase, alanine aminotransferase, and creatinine phosphokinase values than HCV- animals. Histopathology demonstrated abnormal lipid accumulation (steatosis) in the hepatocytes of HCV+ animals, both before and after vector injection. These data indicate an increased susceptibility to subclinical liver toxicity from portal vein injection of rAAV2 in the presence of HCV infection.

Hepatitis C virus infection and incident type 2 diabetes

Although hepatitis C virus (HCV) infection is more common among adults with type 2 diabetes, it is uncertain whether HCV precedes the development of diabetes. Thus, we performed a prospective (case-cohort) analysis to examine if persons who acquired type 2 diabetes were more likely to have had antecedent HCV infection when enrolled in a community-based cohort of men and women between the ages of 44 and 65 in the United States (Atherosclerosis Risk in Communities Study [ARIC]). Among 1,084 adults free of diabetes at baseline, 548 developed diabetes over 9 years of follow-up evaluation. Incident cases of diabetes were identified by using fasting glucose and medical history and HCV antibodies were assessed at baseline. A priori, persons were categorized as low-risk or high-risk for diabetes based on their age and body mass index, factors that appeared to modify the type 2 diabetes-HCV infection incidence estimates. The overall prevalence of HCV in this population was 0.8%. Among those at high risk for diabetes, persons with HCV infection were more than 11 times as likely as those without HCV infection to develop diabetes (relative hazard, 11.58; 95% confidence interval, 1.39-96.6). Among those at low risk, no increased incidence of diabetes was detected among HCV-infected persons (relative hazard, 0.48; 95% confidence interval, 0.05-4.40). In conclusion, pre-existing HCV infection may increase the risk for type 2 diabetes in persons with recognized diabetes risk factors. Additional larger prospective evaluations are needed to confirm these preliminary findings. (H epatology 2003;38:50-56.)

Hepititis C and renal transplantation: The controversy continues

Hepatitis C virus (HCV) infection, the leading cause of posttransplant liver disease, has recently been recognized as one of the major causes of morbidity and mortality in renal transplantation. Most HCV antibody-positive recipients acquire HCV infection before or at the time of transplantation. The prevalence of HCV among patients with end-stage renal disease (ESRD) undergoing dialysis is reported between 12% to 85%, depending on the techniques used such as antibody and RNA assays [1‐ 4]. It has been shown that HCV is transmissible by organ transplantation [5, 6]. In recipients of kidneys from HCV antibody positive donors, 57 to 96% were tested positive for HCV RNA by polymerase chain reaction (PCR) and 0 to 55% developed post-transplantation liver disease [7]. There have been controversial reports on the long-term effects of HCV infection on graft and patient survival in kidney transplant recipients. In this issue of Kidney International, Pereira and colleagues analyze the impact of HCV infection on survival of kidney transplant and ESRD patients [8]. They report that the presence of HCV infection was associated with an increased risk of death in patients referred for renal transplantation, and the effect of transplantation was similar in anti-HCV positive and negative patients. They conclude that anti-HCV positive status is not a contraindication for renal transplantation, which has a beneficial effect on long-term survival in anti-HCV positive patients. The report by Pereira and associates provides new fuel to the controversy as to how HCV infection alters outcomes in ESRD and transplant population [8]. Two important infection-related outcomes are described by the authors: the relationship of infection to chronic liver disease and to transplant outcome. There have been other reports of progressive liver disease in HCVinfected renal allograft recipients. A study by Morales et al demonstrated that more than 50% of HCV positive renal transplant recipients exhibited a severe pattern including cirrhosis, chronic active hepatitis and chronic persistent hepatitis in liver biopsies indicating the seriousness of HCV infection [9]. Older age at transplant, female sex, and morphologic diagnosis of advanced chronic hepatitis were found to be associated with histologic progression to cirrhosis [10]. On the other hand, several other groups have described the absence of dire consequences of HCV infection on patient and graft survival in renal allograft recipients [11, 12]. A group of HCV-infected ESRD patients (N 5 14) was prospectively followed for up to two years with pretransplant liver biopsies, and virologic and biochemical parameters post-transplant [11]. All patients did well with functioning grafts despite enhanced viral replication and mild increase in liver enzymes. Haem and colleagues followed 62 HCV positive renal transplant recipients with liver biopsies for a mean of 72 months (range 36 to 108 months) [12]. Although they found a 42% incidence of chronic active hepatitis, patient and graft survival were not significantly different from HCV negative recipients. At our institution, we found that, despite a predisposition to post-transplant liver disease in recipients with pre-existing HCV infection, overall patient and graft survival were similar in long-term follow up (median follow-up 9 years) in the HCV positive and HCV negative recipients [12]. Irrespective of the antibody status, the outcome was poor in patients with associated liver disease. Less controversial has been the variant impact of HCV infection on patient outcomes related to forms of renal replacement. Similar to the report by Pereira et al, in a study by Knoll and colleagues, HCV-positive renal transplant recipients had a better survival compared with HCV-positive patients who were acceptable candidates for transplantation but were on dialysis [14]. The importance of these studies lies in using a cohort of dialysis patients for outcome comparison very similar to the transplant group as they were on the transplant waiting list, reducing the possibility that differences discerned were merely a consequence of selection bias. The continuing controversy of the impact of HCV infection on the transplant recipient demands further study and analysis by examining such issues as variant viral strains or geographic differences, and improving our understanding of HCV related liver disease. Nevertheless, the report by Pereira and his colleagues supports the conclusion that transplantation is the preferred mode of renal replacement therapy for HCV positive patients with end-stage renal disease [8].

Hepatitis C infection in cadaver organ donors: strategies to reduce transmission of infection and prevent organ waste.

The transmission of hepatitis C virus (HCV) by organ transplantation has been unequivocally demonstrated. Among recipients of organs from anti-HCV-positive donors, 57%-96% test positive for HCV RNA. Consequently, several organ procurement organizations have adopted a policy restricting the use of anti-HCV-positive donors to life-saving transplants (heart, liver, or lung). The differences in the rate of transmission of HCV infection by anti-HCV-positive donors could be related to the prevalence of HCV RNA among these donors. In a national collaborative study of 3,078 cadaver organ donors from eight organ procurement organizations in the United States, the prevalence of anti-HCV antibodies and HCV RNA were 4.2% and 2.4%, respectively. The sensitivity and negative predictive value of anti-HCV antibodies for HCV RNA were 100%. However, despite a specificity of 98.1%, the positive predictive value was only 55.1%. Discarding organs from enzyme-linked immunosorbent assay 2-positive donors would eliminate transmission, but organs from 1.88% of donors would be wasted. Clinical and laboratory characteristics did not distinguish anti-HCV-positive donors with and without HCV RNA. Hence, to reduce waste it is necessary to develop confirmatory tests with a higher specificity for HCV RNA than those that are currently available. Even if anti-HCV-positive but HCV RNA-negative donors could be identified and utilized, 2.4% of cadaver organ donors that test positive for serum HCV RNA would remain unsuitable for transplantation of non-life-saving organs. Hence, several authors have suggested the use of kidneys from anti-HCV-positive donors in recipients with pre-existing HCV infection.(ABSTRACT TRUNCATED AT 250 WORDS)