Limited Fibrosis Progression but Significant Mortality in Patients Ineligible for Interferon-Based Hepatitis C Therapy.

BACKGROUND: Individuals ineligible for interferon-based hepatitis C therapy may have a worse prognosis than patients who have failed or not received treatment. AIMS: To provide information about the limitations of medical treatment of hepatitis C in real-world patients. METHODS: We studied 969 treatment-ineligible patients and 403 treated patients enrolled between 1/1/01 and 6/30/06; data were collected until 3/31/13. Treatment barriers were grouped into five categories and classified as health-related or health-unrelated. Fibrosis stage was assessed initially and at the end of follow-up. Mortality was determined by search of the Social Security database. Death certificates of treatment-ineligible patients were reviewed. RESULTS: Initially, 288 individuals had advanced fibrosis and compensated disease; 87 untreated patients developed advanced fibrosis during follow-up. Health-related treatment barriers were more commonly associated with fibrosis progression and worse survival. During follow-up, 247 untreated patients died: 47% of liver-related and 53% of liver-unrelated causes. Patients with significant comorbid illness had the worst five- (70%) and ten-year (50.5%) survival. Despite high mortality (47%) in persons with decompensated liver disease, no treatment barrier was associated with a greater incidence of liver-related death. Only significant comorbid medical illness was an independent predictor of disease progression; however, it was not associated with a greater incidence of liver-related death. Furthermore, treated patients had better 10-year survival than untreated patients on Kaplan-Meier analysis (80.3% vs. 74.5%, P = 0.005). CONCLUSION: Many patients with hepatitis C will die of non-liver-related causes and may not be helped by anti-viral treatment.

Efficacy of levofloxacin in the treatment of BK viremia: a multicenter, double-blinded, randomized, placebo-controlled trial.

BACKGROUND AND OBJECTIVES: BK virus reactivation in kidney transplant recipients can lead to progressive allograft injury. Reduction of immunosuppression remains the cornerstone of treatment for active BK infection. Fluoroquinolone antibiotics are known to have in vitro antiviral properties, but the evidence for their use in patients with BK viremia is inconclusive. The objective of the study was to determine the efficacy of levofloxacin in the treatment of BK viremia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Enrollment in this prospective, multicenter, double-blinded, placebo-controlled trial occurred from July 2009 to March 2012. Thirty-nine kidney transplant recipients with BK viremia were randomly assigned to receive levofloxacin, 500 mg daily, or placebo for 30 days. Immunosuppression in all patients was adjusted on the basis of standard clinical practices at each institution. Plasma BK viral load and serum creatinine were measured monthly for 3 months and at 6 months. RESULTS: At the 3-month follow-up, the percentage reductions in BK viral load were 70.3% and 69.1% in the levofloxacin group and the placebo group, respectively (P=0.93). The percentage reductions in BK viral load were also equivalent at 1 month (58% versus and 67.1%; P=0.47) and 6 months (82.1% versus 90.5%; P=0.38). Linear regression analysis of serum creatinine versus time showed no difference in allograft function between the two study groups during the follow-up period. CONCLUSIONS: A 30-day course of levofloxacin does not significantly improve BK viral load reduction or allograft function when used in addition to overall reduction of immunosuppression.

Genomics of BK viremia in kidney transplant recipients.

BACKGROUND: This study aimed to investigate global gene expression profiles of BK viremia and nephropathy (BKVN) samples using microarrays to investigate the immunologic response to BK virus. METHODS: Patients were monitored for BK viremia in the blood monthly for 6 months, then at 9 and 12 months after kidney transplantation. BKVN and normal transplant kidney biopsy samples, and whole blood samples of patients with and without BK viremia were analyzed by Affymetrix Human Gene 1.0 ST Arrays. RESULTS: During a mean follow-up of 917±325 days, 61 of the 289 patients (21%) developed BK viremia at a median 149 (27, 1,113) days after transplantation with a median peak PCR titers of 35,900 (1,000, 2,677,000). The only significant risk factor for development of BK viremia was induction with anti-thymocyte globulin (P=0.03). Only four patients developed BKVN (1.3%). Pathogenesis-based transcript analysis revealed a significant increased expression of interferon-gamma and rejection induced (GRIT), quantitative cytotoxic T-cell (QCAT), quantitative constitutive and alternate macrophage, B-cell and natural killer cell-associated transcripts (NKAT), indicating an active inflammatory immune response in BKVN biopsies (n=3) compared to normal transplant kidney biopsies with (n=3) and without BK viremia (n=11). The whole blood gene expression profiles of 19 BK viremia patients revealed significant increased expression of GRIT, QCAT, and NKAT compared to 14 patients without viremia. CONCLUSIONS: The results showed increased activity of cytotoxic T cells and natural killer cells in BKVN and viremia samples resembling acute rejection and suggested the involvement of both adaptive and innate immunity.

Pretransplant anti-HLA-Cw and anti-HLA-DP antibodies in sensitized patients.

We investigated the prevalence and the strength of anti-HLA-Cw and DP antibodies and clinical outcomes in kidney transplant recipients with isolated donor-specific anti-HLA-Cw antibodies. Patients on the waiting list were screened by Luminex single antigen beads (One Lambda). The strength of antibodies was determined by mean fluorescence intensity (MFI) values of the beads. Of the 1069 patients on the waiting list, 251 (24%) were sensitized with calculated panel reactive antibody >0%. The frequency and the median MFI values of anti-HLA antibodies to Cw (56%, 4955) and DP (35%, 2945) were lower than anti-HLA-A (79%, 10,194), B (86%, 11,235), DR (66%, 7866) and DQ (69%, 8283) (p<0.01). Among three major sensitizing events, only previous transplant was associated with development of all anti-HLA antibodies and history of pregnancy was associated only with development of anti-HLA-A antibodies. Eight patients with donor-specific anti-HLA-Cw antibodies received transplantation. During a median 6 months of follow-up (range 3-24 months), patient and graft survival was 100% without any acute rejection. In summary, the prevalence and the strength of anti-HLA-Cw and HLA-DP were lower compared to anti-HLA-A, B, DR, and DQ antibodies and previous organ transplantation was the main sensitizing event in our cohort of patients.