Recurrent Viremia Research Articles

Alemtuzumab Induction in Pediatric Kidney Transplantation

Introduction: Recipient parenchymal lymphatic cells are crucial for semidirect and indirect pathways of allorecognition and development of chronic rejection. We and others proposed that alemtuzumab, being infused several weeks pretransplant could eradicate peripheral lymphatic cells and promote donor-specific tolerance. Method: 107 children (54 boys, 53 girls; age 0,7 to 18 years) received living related kidney transplant in Russian Scientific Center of Surgery from September 2006 to January 2011. The major causes for recipients' ESRD were reflux nephropathy (29 %) and dysplasia (23%). Diseases that recur in the graft represented a small portion of our patients (5% primary FSGS). The average HLA mismatch was 2.5±1.0. Immunosupression (IS) protocol included two 30 mg doses of alemtuzumab: first given 12-29 days prior to transplantation and second on day of transplant. Maintenance IS was based on combination of low dose CNI and mycophenolate. Steroids were discontinued after achievement of target CNI level, usually by Day 5. IS was decreased in cases of BK viruria above 107 copies/ml, repeated BK or EBV viremia and recurrent CMV viremia. Patients were followed for 1192±470 days and protocol biopsies were taken 1 month, 1 and 3 year post transplant. Results: The Kaplan-Meier graft and patient survival was 95% and 97% for one year, 88% and 93% for three years, 84% and 90% for five years. Delayed graft function occurred in 7 patients. Biopsy proven acute rejection (BPAR) developed in 26% patients at one year and in 35% at two years, no rejections occurred behind 2 years. BANFF scores were borderline in 59%, 1a in 34%, 1b in 0.5%, 2a in 5% and 2b in 1% of all rejections. Among 93 patients with functioning grafts the decline of graft function by estimated GFR and degree of proteinuria between discharge and last control were not significant: 92±34 and 82±37 ml per min; 220±260 and 189±149 mg per day. Infections: All patients received prophylaxis with Valgancyclovir for 3 weeks after transplantation. CMV, EBV and BK viremia were monitored monthly during first post-transplant year, thereafter every 3 months. In case of detectable CMV-viremia preemptive therapy with Valgancyclovir was re-introduced. CMV and BKV viremia were noticed in 30% and 25% of all patients correspondingly during first 3 months and in less than 10 and 5% after first year. Prevalence of EBV viremia was reaching 20% at 2 years. We have not detected any cases of PTLD in our population; however 2 kids had lymphadenopathy associated with EBV-viremia that improved after discontinuation of CNI. At last follow up 53 patients was receiving combination of CNI+MMF, 15 MMF+PSI, 10 CNI+MMF+steroids, 6 mycophenolate alone, 3 CNI alone, 2 MMF+steroids, 2 CNI+steroids, 1 PSI+MMF+steroids and 1 CNI+Aza+steroids. Free of steroids remain 83% of patients. Conclusion: Alemtuzumab pretreatment prior to LRD kidney transplantation allows to reach satisfactory middle-term results and maintain steroid-free immunosuppressive protocol in the majority of pediatric patients.

Frequent Longitudinal Sampling of Hepatitis C Virus Infection in Injection Drug Users Reveals Intermittently Detectable Viremia and Reinfection

Detection of hepatitis C virus (HCV) reinfection and intercalation (ie, intermittent recurrent bouts of viremia with homologous virus interspersed with aviremic periods) requires extensive and frequent evaluation and viral sequencing. HCV infection outcomes were studied prospectively in active injection drug users with recurrent HCV RNA-positive tests after serial negative results. HCV viremia and viral sequences (Core/E1) were assessed from monthly blood samples. Viral clearance, reinfection, and intercalating infection were all detected. Among 44 participants with apparently resolved HCV (26 incident HCV clearers and 18 enrolled with already resolved infection), 36 (82%) remained persistently HCV RNA negative, but 8 demonstrated intermittent recurrent viremia. Four of these (50%) had confirmed reinfection with a heterologous virus; 3 demonstrated viral intercalation, and 1 was not classifiable as either. Estimated incidence of first reinfection was 5.4 per 100 person-years (95% confidence interval, 2.0-14.5). Six (75%) participants, including 3 of 4 with reinfection, demonstrated sustained viral clearance for a median of 26 months since last HCV RNA test. These results show that frequent monitoring and viral sequencing are required to correctly assess HCV outcomes and estimate incidence of reinfection (which was previously overestimated). Sustained clearance may take many months and occur after episodes of reinfection and viral intercalation. Three of 4 subjects who had confirmed reinfection showed evidence of long-term clearance. Viral intercalation occurs with significant frequency. Further studies of these events, especially immunological, are needed to inform HCV clinical care and vaccine development.

Reduction in Hepatic Inflammation Is Associated With Less Fibrosis Progression and Fewer Clinical Outcomes in Advanced Hepatitis C

During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation. Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥ 2-point difference in HAI or Ishak fibrosis score between biopsies. Among 657 patients who received full-dose peginterferon/ribavirin "lead-in" therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P<0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3-4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups. Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.

RNA Interference: A Promising Approach for the Treatment of Viral Hepatitis

Hepatitis viruses are the leading cause of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. The hepatitis C virus (HCV), together with the hepatitis B virus (HBV), accounts for 75% of all cases of liver disease around the world, with chronic hepatitis, cirrhosis, and HCC causing 500,000 to 1.2 million deaths per year [1][2][3]. More than 170 million people worldwide have chronic HCV infection. According to the 2002 WHO report, chronic liver diseases were responsible for 1.4 million deaths, including 796,000 deaths due to cirrhosis and 616,000 deaths due to primary liver cancer. At least 20% of these deaths (more than 280,000 deaths) are probably attributable to HCV infection [4]. With the WHO officially recognizing hepatitis as a global health issue, more research needs to be conducted to develop new therapeutic interventions. Current antiviral therapies for chronic viral hepatitis are effective only in approximately half of the patients [5]. The most widely available agents for the treatment of chronic hepatitis are interferon-α (IFN-α) and nucleoside analogs such as lamivudine or adefovir [6][7]. However, treatment with these agents has some disadvantages, including possible serious adverse effects in the case of interferon treatment or recurrence of viremia after discontinuation of therapy and development of resistant mutants after prolonged lamivudine treatment [8][9][10][11]. Moreover, nucleoside analogs such as 3TC-lamivudine only interfere with viral replication and do not induce cessation of the process. The low efficacy of these agents, their adverse effects, and development of resistant viral mutations are major impediments to the clinical application of these agents for the treatment of viral hepatitis [6]. These shortcomings necessitate the development of alternative treatment strategies. Sequence-specific gene silencing using RNA interference (RNAi) is a Nobel prize-winning technology that represents a promising new approach to overcome viral infections [5][12][13][14]. RNA interference is an evolutionary mechanism for protecting the genome against invasion by mobile genetic elements such as transposons and viruses [6]. It is a process by which small interfering RNA (siRNA) with specific target sequences induce silencing of homologous genes by binding to their complementary mRNA and inducing the elimination of the mRNA molecule [15]. This process occurs post-transcriptionally in the cytoplasm and is mediated by small RNA molecules (21 to 25 nucleotides in length) that bind to their complementary mRNA targets and silence the expression of these targets [6]. The phenomenon of RNA interference (RNAi) was first described by Fire et al. They observed that in the nematode Caenorhabditis elegans, the presence of double-stranded RNA (dsRNA) resulted in sequence-specific gene silencing at the post-transcriptional level. The RNAi pathway has since been recognized as a conserved biological pathway, and several experimental models have contributed to the understanding of this process [15][16].

High Rate of Recurrent Hepatitis B Viremia Following Treatment-Induced Hepatitis B E Antigen (HBeAg) Seroconversion

Purpose: In patients with HBeAgpositive chronic hepatitis B (CHB), one of the primary endpoints of therapy is HBeAg seroconversion; however, there is inconsistent data on the durability of HBeAg seroconversion following consolidation therapy. Our goal is to investigate the rate of recurrent HBV viremia in CHB patients after HBeAg seroconversion. Methods: We retrospectively studied 88 consecutive CHB patients who achieved treatment-induced HBeAg seroconversion among the 458 HBeAg-positive patients treated with various antiviral regimens at 3 GI and liver clinics in the U.S. between 3/1998 and 9/2010. HBeAg seroconversion was defined as loss of HBeAg and development of hepatitis B e antibody (anti-HBe). Recurrent HBV viremia was defined as reappearance of detectable HBV DNA (>100 IU/mL) from nadir in two consecutive laboratory tests. Results: Patients were stratified into two groups: Group I 49 patients who remained on therapy, and Group II 39 patients who discontinued therapy following HBeAg seroconversion. In both groups, the majority of patients were Asian (94-95%) and male (62-69%). Antiviral medications in which patients achieved HBeAg seroconversion included: lamivudine (23%), adefovir (34%), entecavir (36%), tenofovir (4%), adefovir+lamivudine (1%), and entecavir+tenofovir (2%). Median treatment duration before HBeAg seroconversion was similar in Group I and Group II (18 [1-86] vs. 21 [5-63] months, p=0.99). At the time of HBeAg seroconversion, compared to Group I, Group II was younger (37±10 vs. 41±12 years), had lower mean HBV DNA levels (0.27±0.78 vs. 0.95±1.69 log10 IU/mL), and median ALT levels (24 [8-60] vs. 30 [593] U/L). In Group II, the median duration of consolidation therapy before treatment discontinuation was 12 months (range, 1-55), in which 10 completed <6 months, 10 completed 6-11 months, and 19 completed ≥12 months. At time of treatment discontinuation, all patients in Group II had undetectable HBV DNA. The rate of recurrent HBV viremia was significantly higher in Group II compared to Group I (90% vs. 0%, p<0.0001). After a median of 3 (1-42) months off therapy, the mean HBV DNA level detected at time of recurrent HBV viremia was 4.11±1.92 log10 IU/mL. Conclusion: The majority of patients (90%) who discontinued therapy after achieving HBeAg seroconversion with undetectable HBV DNA by PCR experienced recurrent HBV viremia. Patients who remained on therapy achieved and maintained undetectable level of HBV DNA. Patients should be monitored closely for recurrent HBVwhen therapy is discontinued, despite achieving HBeAg seroconversion.

Markers of Microbial Translocation Are Elevated in Hepatitis B (HBV) and Hepatitis C (HCV) Infection; A Window Into Biology and Surrogate Markers for Detecting Disease Progression

Purpose: In patients with HBeAgpositive chronic hepatitis B (CHB), one of the primary endpoints of therapy is HBeAg seroconversion; however, there is inconsistent data on the durability of HBeAg seroconversion following consolidation therapy. Our goal is to investigate the rate of recurrent HBV viremia in CHB patients after HBeAg seroconversion. Methods: We retrospectively studied 88 consecutive CHB patients who achieved treatment-induced HBeAg seroconversion among the 458 HBeAg-positive patients treated with various antiviral regimens at 3 GI and liver clinics in the U.S. between 3/1998 and 9/2010. HBeAg seroconversion was defined as loss of HBeAg and development of hepatitis B e antibody (anti-HBe). Recurrent HBV viremia was defined as reappearance of detectable HBV DNA (>100 IU/mL) from nadir in two consecutive laboratory tests. Results: Patients were stratified into two groups: Group I 49 patients who remained on therapy, and Group II 39 patients who discontinued therapy following HBeAg seroconversion. In both groups, the majority of patients were Asian (94-95%) and male (62-69%). Antiviral medications in which patients achieved HBeAg seroconversion included: lamivudine (23%), adefovir (34%), entecavir (36%), tenofovir (4%), adefovir+lamivudine (1%), and entecavir+tenofovir (2%). Median treatment duration before HBeAg seroconversion was similar in Group I and Group II (18 [1-86] vs. 21 [5-63] months, p=0.99). At the time of HBeAg seroconversion, compared to Group I, Group II was younger (37±10 vs. 41±12 years), had lower mean HBV DNA levels (0.27±0.78 vs. 0.95±1.69 log10 IU/mL), and median ALT levels (24 [8-60] vs. 30 [593] U/L). In Group II, the median duration of consolidation therapy before treatment discontinuation was 12 months (range, 1-55), in which 10 completed <6 months, 10 completed 6-11 months, and 19 completed ≥12 months. At time of treatment discontinuation, all patients in Group II had undetectable HBV DNA. The rate of recurrent HBV viremia was significantly higher in Group II compared to Group I (90% vs. 0%, p<0.0001). After a median of 3 (1-42) months off therapy, the mean HBV DNA level detected at time of recurrent HBV viremia was 4.11±1.92 log10 IU/mL. Conclusion: The majority of patients (90%) who discontinued therapy after achieving HBeAg seroconversion with undetectable HBV DNA by PCR experienced recurrent HBV viremia. Patients who remained on therapy achieved and maintained undetectable level of HBV DNA. Patients should be monitored closely for recurrent HBVwhen therapy is discontinued, despite achieving HBeAg seroconversion.

Dendritic cell vaccination in an allogeneic stem cell recipient receiving a transplant from a human cytomegalovirus (HCMV)-seronegative donor: induction of a HCMV-specific Thelper cell response

In the absence of a protective immune response, human cytomegalovirus (HCMV) infection remains a life-threatening complication after allogeneic stem cell transplantation (SCT), especially in recipients of grafts from HCMV-seronegative donors. After allogeneic SCT from a seronegative donor, prolonged and severe immune deficiency often leads to infectious complications. Vaccination with antigen-loaded dendritic cells (DC) has been shown to be a potent approach for the induction of antigen-specific cytotoxic T-cell responses in vivo. For protection from subsequent HCMV reactivation, a sustained immune response is necessary, including antigen-specific CD4(+) T cells. We report the case of an 18-year-old girl with high-risk acute lymphoblastic leukemia that received an allogeneic SCT in CR2. After an HCMV infection, the graft was rejected and she received a second transplant from an HLA-mismatched, HCMV-seronegative family donor. She was treated with pp65-pulsed monocyte-derived DC at day 200 post-SCT, using a recombinant pp65 protein. Until day 200 post-SCT, HCMV reactivated six times with emerging viral resistance to antiviral chemotherapy. After vaccination with protein-pulsed DC, an induction and expansion of HCMV-specific T(helper) cells and cytotoxic T lymphocytes was observed, associated with a sustained clearance of the HCMV viremia. Antiviral treatment could be tapered without recurrence of viremia within the first year post-SCT. pp65-pulsed DC could induce antigen-specific T-cell responses even after a SCT from an HCMV-seronegative donor. After vaccination with pp65-pulsed DC, a sustained antigen-specific T-cell response prevented concurrent HCMV viremia. Emergence of antigen-specific T(helper) cells may be essential for a sustained, functional T-cell response post-SCT.

Preemptive Retransplant for BK Virus Nephropathy Without Concurrent Transplant Nephrectomy

Preemptive Retransplant for BK Virus Nephropathy Without Concurrent Transplant Nephrectomy

Preemptive therapy for cytomegalovirus based on real-time measurement of viral load in liver transplant recipients

Background Real-time PCR has emerged as the preferred diagnostic assay for CMV. However, its utility as a preemptive therapy tool for CMV disease and related outcomes in liver transplant recipients has not been fully defined. Methods Patients comprised 117 consecutive liver transplant recipients who underwent CMV surveillance monitoring using real-time PCR. Preemptive therapy with valganciclovir was employed upon detection of viremia. Baseline viral load was considered high based on log values (median). Results CMV viremia developed in 54% (63/117) of the patients, including 77% of R−/D+, 63% of R+/D+, 43% of R+/D−, and 10% of R−/D− patients. Overall, 23% (15/63) of the patients had recurrent viremia; R− serostatus ( p = 0.065) but not initial viral load correlated with recurrent viremia ( p = 0.80). At 12 months post-transplant, CMV disease occurred in 0.85% (1/117) of the patients (R+/D + recipient). None (0/30) of the R−/D + patients had CMV disease. Patients with CMV viremia treated preemptively did not differ significantly from those who never developed CMV viremia with regards to bacterial or fungal infections, rejection, graft loss, mortality rate, and probability of survival at 12 months ( p > 0.05 for all variables). The above outcomes also did not differ for patients with high (> 1.9 logs) vs. low viral load (< 1.9 logs) ( p > 0.05 for all outcomes). Conclusions Preemptive therapy guided by real-time PCR based monitoring led to outcomes in all patients or in those with high viral loads that were comparable to outcomes in patients who never developed viremia or had low viral loads, respectively. Late-onset CMV disease at 12 months was observed in < 1% of all patients.

A Review of Oral Antiretroviral Therapy for the Treatment of Chronic Hepatitis B

To describe the current evidence for the use of oral antiretroviral (ARV) agents in the treatment of chronic hepatitis B (CHB). A search from 1950 to April 2010 was conducted using the databases PubMed and MEDLINE with the search terms chronic hepatitis B, lamivudine, entecavir, adefovir, telbivudine, tenofovir, emtricitabine, clevudine, and pradefovir. The search was limited to trials conducted in humans that were published in the English language. Studies were included if they evaluated the use of oral ARVs in patients with CHB infection who were not coinfected with hepatitis C, hepatitis D, or HIV. Oral ARVs have revolutionized the treatment of CHB. Studies conducted comparing ARVs have favored entecavir and tenofovir with respect to their ability to decrease hepatitis B virus DNA viral load while minimizing the development of resistance. However, low seroconversion rates, recurrent viremia when ARV therapy is discontinued, and increased resistance rates with longer treatment durations limit the benefit of oral ARVs in the treatment of CHB. Combination therapy has been a suggested solution; however, studies have yet to prove additional benefit over currently recommended monotherapy. Oral ARVs should continue to be used in the treatment of CHB; however, research is needed to define the optimal duration of therapy, evaluate the utility of combination therapy, and explore novel targets within the hepatitis B life cycle.

Sites of feline coronavirus persistence in healthy cats

Feline coronavirus (FCoV) is transmitted via the faecal-oral route and primarily infects enterocytes, but subsequently spreads by monocyte-associated viraemia. In some infected cats, virulent virus mutants induce feline infectious peritonitis (FIP), a fatal systemic disease that can develop in association with viraemia. Persistently infected, healthy carriers are believed to be important in the epidemiology of FIP, as they represent a constant source of FCoV, shed either persistently or intermittently in faeces. So far, the sites of virus persistence have not been determined definitely. The purpose of this study was to examine virus distribution and viral load in organs and gut compartments of specified-pathogen-free cats, orally infected with non-virulent type I FCoV, over different time periods and with or without detectable viraemia. The colon was identified as the major site of FCoV persistence and probable source for recurrent shedding, but the virus was shown also to persist in several other organs, mainly in tissue macrophages. These might represent additional sources for recurrent viraemia.

CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency

We report on two patients with no active GVHD and on moderate doses of immunosuppressive drugs who unexpectedly developed fatal CMV meningoencephalitis after umbilical cord blood transplantation. A review of these two cases along with nine other cases of CMV central nervous system (CNS) disease after allogeneic SCT that were mostly reported within the last 8 years suggests that this severe complication of CMV infection may be increasing. CMV CNS disease after allogeneic SCT is a late-onset disease (median time of onset, 210 days) and is usually manifested as encephalitis in the absence of other sites of CMV disease. The development of CMV CNS disease is associated with risk factors (T-cell depletion, anti-thymocyte globulin, umbilical cord blood transplantation) that cause severe and protracted T-cell immunodeficiency (8 of 11 cases), a history of recurrent CMV viremia treated with multiple courses of preemptive ganciclovir or foscarnet therapy (11 of 11 cases), and ganciclovir-resistant CMV infection (11 of 11 cases). Despite therapy with a combination of antiviral drugs (ganciclovir, foscarnet and cidofovir), mortality is high (10 of 11 cases). Given this high mortality, extended prophylaxis with current or novel antiviral drugs and strategies to enhance CMV immunity need to be considered in high-risk patients.

Dominance of highly divergent feline leukemia virus A progeny variants in a cat with recurrent viremia and fatal lymphoma

BackgroundIn a cat that had ostensibly recovered from feline leukemia virus (FeLV) infection, we observed the reappearance of the virus and the development of fatal lymphoma 8.5 years after the initial experimental exposure to FeLV-A/Glasgow-1. The goals of the present study were to investigate this FeLV reoccurrence and molecularly characterize the progeny viruses.ResultsThe FeLV reoccurrence was detected by the presence of FeLV antigen and RNA in the blood and saliva. The cat was feline immunodeficiency virus positive and showed CD4+ T-cell depletion, severe leukopenia, anemia and a multicentric monoclonal B-cell lymphoma. FeLV-A, but not -B or -C, was detectable. Sequencing of the envelope gene revealed three FeLV variants that were highly divergent from the virus that was originally inoculated (89-91% identity to FeLV-A/Glasgow-1). In the long terminal repeat 31 point mutations, some previously described in cats with lymphomas, were detected. The FeLV variant tissue provirus and viral RNA loads were significantly higher than the FeLV-A/Glasgow-1 loads. Moreover, the variant loads were significantly higher in lymphoma positive compared to lymphoma negative tissues. An increase in the variant provirus blood load was observed at the time of FeLV reoccurrence.ConclusionsOur results demonstrate that ostensibly recovered FeLV provirus-positive cats may act as a source of infection following FeLV reactivation. The virus variants that had largely replaced the inoculation strain had unusually heavily mutated envelopes. The mutations may have led to increased viral fitness and/or changed the mutagenic characteristics of the virus.

Parvovirus B19 in Solid Organ Transplant Recipients

Parvovirus B19 is a common, ubiquitous human pathogen.It is a small, single-stranded linear, nonenveloped DNAvirus classified into three different genotypes (genotype1, Au and Wi strains; genotype 2, LaLi and A6 strains; andgenotype 3, V9 strains). Its worldwide genetic variability islow, and there is no clear correlation between genotypeand distinctive clinical manifestation. Parvovirus B19 repli-cates most efficiently and preferentially in human erythro-cyte precursors; thus, the virus is classified as a memberof the Erythrovirus genus of the Parvoviridae family. Mostpeople are infected between the ages of 5 and 15 years;by adulthood, up to 80% are seropositive (1). Infection ap-pears to confer lifelong immunity to immunocompetenthosts, but reinfection is possible in a minority of cases(2). It has been hypothesized that Parvovirus B19 can per-sist in the bone marrow and other tissues (3), support-ing possible reactivation rather than reinfection in certainseropositive patients. Parvovirus B19 infection can be ei-ther symptomatic or asymptomatic, depending on the age,hematologic and immunologic status of the host. Whilemostpatientsrecollectonlynonspecificflu-likesymptoms,distinctive clinical entities have been associated with Par-vovirus B19 infection in both immunocompetent hosts (4)and solid organ transplant (SOT) recipients (5). The mostcommonclinicalmanifestationsofParvovirusB19aresum-marizedinTable1.Although large, prospective surveillance studies are lack-ing, earlier studies reported an incidence of Parvovirus B19disease of

This Month in Gastroenterology

This Month in Gastroenterology

Management of chronic hepatitis C treatment failures: role of consensus interferon

Management of chronic hepatitis C treatment failures: role of consensus interferon Stevan A Gonzalez1, Emmet B Keeffe21Division of Hepatology, Baylor Regional Transplant Institute, Baylor All Saints Medical Center, Fort Worth and Baylor University Medical Center, Dallas, TX, USA; 2Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USAAbstract: A significant proportion of patients with chronic hepatitis C virus (HCV) infection who undergo antiviral therapy have persistent or recurrent viremia and fail to achieve a sustained virologic response (SVR). Factors associated with treatment failure include HCV genotype 1 infection, high serum HCV RNA levels, and advanced fibrosis. Consensus interferon (CIFN) is a synthetic type I interferon derived from a consensus sequence of the most common amino acids found in naturally occurring alpha interferon subtypes. Several prospective clinical studies have demonstrated that CIFN may be a treatment option in patients who have failed prior interferonbased therapy, including those who have failed combination therapy with standard interferon or peginterferon plus ribavirin. Daily CIFN in combination with ribavirin may be an effective regimen in this setting; however, optimal dose and treatment duration of CIFN therapy have not been well established. Patients who achieve viral suppression during prior interferon-based therapy and those who do not have advanced fibrosis have a greater likelihood of achieving a SVR with CIFN retreatment. Individualized therapy targeting specific patient groups will be an important consideration in the successful management of prior treatment failures. Additional prospective studies are required in order to identify optimal treatment strategies for the use of CIFN in these patients.Keywords: consensus interferon, hepatitis C, interferon, nonresponder, relapser

Management of chronic hepatitis C treatment failures: role of consensus interferon

A significant proportion of patients with chronic hepatitis C virus (HCV) infection who undergo antiviral therapy have persistent or recurrent viremia and fail to achieve a sustained virologic response (SVR). Factors associated with treatment failure include HCV genotype 1 infection, high serum HCV RNA levels, and advanced fibrosis. Consensus interferon (CIFN) is a synthetic type I interferon derived from a consensus sequence of the most common amino acids found in naturally occurring alpha interferon subtypes. Several prospective clinical studies have demonstrated that CIFN may be a treatment option in patients who have failed prior interferon-based therapy, including those who have failed combination therapy with standard interferon or peginterferon plus ribavirin. Daily CIFN in combination with ribavirin may be an effective regimen in this setting; however, optimal dose and treatment duration of CIFN therapy have not been well established. Patients who achieve viral suppression during prior interferon-based therapy and those who do not have advanced fibrosis have a greater likelihood of achieving a SVR with CIFN retreatment. Individualized therapy targeting specific patient groups will be an important consideration in the successful management of prior treatment failures. Additional prospective studies are required in order to identify optimal treatment strategies for the use of CIFN in these patients.

T-Cell Large Granular Lymphocyte Leukemia of Donor Origin Following Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation for Acute Myeloid Leukemia.

Lymphoproliferative disorders are a recognized complication of allogeneic hematopoietic cell transplantation (HCT). Most are B-cell disorders, often associated with Epstein-Barr virus infection. We report the fourth case of T-cell, large granular lymphocyte leukemia. In May 2005, a 63-year-old woman with acute myeloid leukemia in first relapse underwent reduced intensity, myeloablative, allogeneic peripheral blood HCT from her HLA-genotypically matched brother. Three months later, she received a donor-lymphocyte infusion (DLI) for recurrent leukemia. She developed acute graft-versus-host disease (GvHD) and remission of leukemia. GvHD was controlled with high-dose steroids. Multiple episodes of asymptomatic cytomegalovirus viremia were treated with pre-emptive valganciclovir. In June 2006, 10 months post-DLI, PCR-based chimerism studies revealed 100% donor peripheral blood cells. One month later, immunophenotyping of peripheral blood to evaluate neutropenia and lymphocytosis, revealed expansion of CD3+, CD8+, CD2+, CD11c+ and HLA-DR+ lymphocytes with clonally rearranged T-cell receptor genes, consistent with the diagnosis of large granular lymphocyte (LGL) leukemia. Evaluation of her donor, including bone marrow aspiration and biopsy, showed normal hematopoiesis with no evidence of LGL expansion. PCR of donor peripheral blood mononuclear cells was negative for TCRγ rearrangements. During the year since diagnosis of T-cell LGL leukemia the CBC has been stable, without specific treatment, and AML remains in remission.Discussion: lymphocytosis due to expansion of T-cell large granular lymphocytes is a rare occurrence after allogeneic HCT. Non-clonal expansion is more common, with 6 cases described in a series of 201 patients (Mohty et al. Leukemia 2002; 16:2129–33). To our knowledge, this is the fourth documented case of donor-derived T-cell LGL leukemia (clonal expansion) after allogeneic HCT. The course of post-transplant LGL leukemia appears to resemble de novo disease. Of the previously reported cases, 2 patients were alive 6 and 18 months (Chang et al. Am J Clin Pathol 2005; 123:196–9), and 1 died 7 months post-LGL leukemia diagnosis (Au et al. Am J Clin Pathol 2003; 120:626–30). Our patient is 12 months since diagnosis without therapy. Etiologic factors responsible for post-transplant LGL leukemia have not been identified. In all cases tested, the leukemia arose in donor cells, but was not transmitted from the donor. An association between long-term antigenic stimulation due to GvHD or viral infection has been proposed. Our patient had both GvHD and recurrent CMV viremia before developing T-cell LGL leukemia. Of interest, our patient experienced long-lasting complete remission of AML after DLI. Whether the T-cell LGL leukemia, which developed almost one year after DLI, has any impact on maintaining remission (graft-versus-leukemia effect) is unknown, but has been suggested by other authors.

Intravenous interferon during the anhepatic phase of liver retransplantation and prevention of recurrence of cholestatic hepatitis C virus

Cholestatic hepatitis C virus (HCV) infection post orthotopic liver transplantation is associated with a poor prognosis. We describe 2 patients who received interferon and ribavirin for cholestatic HCV infection with clearance of HCV RNA from the serum. Both developed signs of graft failure necessitating repeat orthotopic liver transplantation, and at surgery, interferon was administered during the anhepatic phase to prevent graft reinfection. Both patients are doing well with no evidence of recurrent viremia at 36 and 24 months of follow-up after repeat transplantation, respectively. Our results suggest that in those with cholestatic HCV infection, repeat transplantation after viral clearance is feasible and can occur without reinfection of the graft, challenging the current practice of denying retransplantation for patients with cholestatic HCV. The role of anhepatic administration of interferon deserves further examination, and this combination may provide a solution in a subset of patients with an otherwise poor prognosis.

Risk Factors for HCV Relapse in HIV-Infected Patients

Although combination therapy with pegylated interferon and ribavirin clears hepatitis C virus (HCV) infection in some HIV-infected patients, many experience recurrent viremia or relapse after therapy is stopped. To determine the risk factors for relapse, investigators in Spain studied 256 HIV/HCV-coinfected patients who had undetectable HCV RNA at the end of pegylated interferon/ribavirin therapy. Twenty-four percent of study participants — including 33% of those with genotype 1 HCV — suffered …