ABSTRACT
Treatment of hepatitis C (HCV)-mixed cryoglobulinemia (MC) may target either the viral trigger (HCV) or the downstream B-cell clonal expansion. Prospective cohort study of 38 HCV-MC patients who received a combination of rituximab (375 mg/m(2)) once a week for 1 month followed by Peg-interferon-alpha (Peg-IFN-alpha; 2a, 180 microg or 2b, 1.5 microg/kg) weekly plus ribavirin (600-1200 mg) daily for 48 weeks were compared with 55 HCV-MC patients treated by Peg-IFN-alpha/ribavirin with the same modalities. In the whole population of HCV-MC patients (n = 93), a complete clinical response was achieved in 73.1% (68 of 93), cryoglobulin clearance in 52.7% (49 of 93), and a sustained virologic response in 59.1% (55 of 93). Compared with Peg-IFN-alpha/ribavirin, rituximab plus Peg-IFN-alpha/ribavirin-treated patients had a shorter time to clinical remission (5.4 +/- 4 vs 8.4 +/- 4.7 months, P = .004), better renal response rates (80.9% vs 40% of complete response, P = .040), and higher rates of cryoglobulin clearance (68.4% vs 43.6%, P = .001) and clonal VH1-69(+) B-cell suppression (P < .01). Treatment was well tolerated with 11% of discontinuation resulting from antiviral therapy and no worsening of HCV RNA under rituximab. Our findings indicate that rituximab combined with Peg-IFN-alpha/ribavirin is well tolerated and more effective than Peg-IFN-alpha/ribavirin in HCV-MC.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antiviral Agents/administration & dosage , Cryoglobulinemia/drug therapy , Cryoglobulinemia/etiology , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Interferon-alpha/administration & dosage , Polyethylene Glycols/administration & dosage , Ribavirin/administration & dosage , Aged , Antibodies, Monoclonal, Murine-Derived , Cohort Studies , Cryoglobulinemia/immunology , Drug Therapy, Combination , Female , Hepatitis C, Chronic/virology , Humans , Interferon alpha-2 , Male , Middle Aged , Prospective Studies , RNA, Viral/blood , Recombinant Proteins , Remission Induction , Rituximab , Treatment OutcomeABSTRACT
OBJECTIVES: To study, in asymptomatic HIV-1-infected (HIV+) patients, whether peripheral blood hematopoietic progenitor/stem cells (PBPC) mobilized by granulocyte colony stimulating factor (G-CSF), can be used as a source of cells for retroviral gene therapy. DESIGN: PBPC from two groups of HIV+ patients (treated or untreated by highly active antiretroviral therapy) and from seronegative donors were mobilized with G-CSF. METHODS: PBPC collected by leukapheresis were enriched for CD34 cells, immunophenotypically and functionally characterized, cultured and infected with retroviral vectors. HIV proviral integration was studied on fresh and cultured cells. RESULTS: G-CSF moderately and transiently increased the viral load in untreated patients only, and induced in both groups of HIV+ patients mobilization of percentages and numbers of CD34 cells comparable to those of seronegative volunteers. The most immature CD34 cell subset, the clonogenic progenitor and long-term culture initiating cells were significantly decreased in leukapheresis products and CD34-enriched fractions from untreated HIV+ patients but not in those from treated HIV+ patients. Cell cycle activation and growth factor responses of CD34 cells from both groups of HIV+ patients were not different from those of the control group. Culture and retroviral infection of CD34 cells from HIV+ patients did not enhance HIV replication, and yielded transduction levels similar to those obtained using CD34 cells from seronegative donors. CONCLUSIONS: G-CSF-mobilized PBPC can be safely used for HIV retroviral gene therapy in asymptomatic treated patients while highly active antiretroviral therapy would control the G-CSF-induced increase in viral load and correct the defective hematopoiesis observed in untreated patients, without inhibiting the retroviral transduction of PBPC.
