Outcomes, infections, and immune reconstitution after double cord blood transplantation in patients with high-risk hematological diseases.

Double unrelated cord blood transplant (dUCBT) has been used to circumvent cell dose limitation of single UCBT; however, few data are available describing outcomes, infectious disease, and immune recovery. We analyzed 35 consecutive dUCBT recipients with high-risk malignant disorders (n=21) and bone marrow failure syndromes (n=14). Median follow-up was 32 months. Conditioning regimen was myeloablative in 14 and reduced intensity in 21 patients. Median infused nucleated cell dose was 4 × 10(7) /kg. Median time to absolute neutrophil count >0.5 × 10(9) /L was 25 days. Cumulative incidence (CI) of acute grade II-IV graft-versus-host disease was 47%. Estimated overall survival at 2 years was 48%. CI of first viral infections at 1 year was 92%. We observed 49 viral infections in 30 patients, 34 bacterial infections in 19 patients, and 16 fungal or parasitic infections in 12 patients. Lymphocyte subset analyses were performed at 3, 6, 9, and >12 months after dUCBT. Decreased T-cell and B-cell counts with expansion of natural killer cells were observed until 9 months post transplantation. Recovery of thymopoiesis measured by T-cell receptor excision circles was impaired until 9 months after dUCBT, when the appearance of new thymic precursors was observed. Delayed immune recovery and high incidence of infectious complications were observed after dUCBT in patients with high-risk hematological diseases.

Peripheral blood natural killer cell count is associated with clinical outcome in patients with aaIPI 2-3 diffuse large B-cell lymphoma.

BACKGROUND: Lymphocytopenia is a prognostic factor in Hodgkin's disease. In diffuse large B-cell lymphoma (DLBCL), data are much less established, in spite of numerous reports on immune system-lymphoma interactions. This study addresses the prognostic value of blood lymphocyte subsets at diagnosis in DLBCL. PATIENTS AND METHODS: Absolute values of blood lymphocyte subsets and monocytes were prospectively determined by flow cytometry in 140 patients with 2 or 3 adverse age-adjusted International Prognostic Index (aaIPI) factors included in a Groupe d'Etude des Lymphomes de l'Adulte protocol (LNH98B3). Absolute cell counts at diagnosis and aaIPI were evaluated with regard to clinical outcome. RESULTS: Low median cell counts of 337, 211, and 104/mul were evidenced for the CD4+, CD8+ T, and natural killer (NK) cells, respectively. In univariate analysis, only NK cell count [odds ratio (OR) = 1.81 (1.27, 2.57), P = 0.001] and aaIPI [OR = 2.29 (0.95, 5.45), P = 0.06] were associated with induction treatment response. Low NK cell count [Hazard ratio (HR) = 1.27 (1.06, 1.52), P = 0.01] and aaIPI 3 [HR = 1.95 (1.20, 3.16), P = 0.01] were also associated with a shorter event free survival (EFS). In multivariate analysis, NK cell count was associated with response [OR = 1.77 (1.24, 2.54), P = 0.002] and EFS [HR = 1.25 (1.04, 1.50) P = 0.02] independently of aaIPI. CONCLUSIONS: This study shows an association between circulating NK cell number and clinical outcome in DLBCL, possibly important in the context of the broadening use of rituximab, a likely NK-dependent therapy.

Treatment of refractory erosive oral lichen planus with extracorporeal photochemotherapy: 12 cases.

BACKGROUND: Case reports have suggested that extracorporeal photochemotherapy (ECP) might be beneficial for the treatment of erosive oral lichen planus (OLP) recalcitrant to conventional immunosuppressive therapies. OBJECTIVES: To evaluate over a long-term period the clinical efficacy and toxicity of ECP in a series of patients with refractory OLP, and to monitor peripheral blood lymphocyte subset counts under treatment. METHODS: Twelve patients with refractory OLP underwent a standardized protocol of ECP. Sessions were performed twice weekly for 3 weeks, and then the treatment schedule was adapted according to clinical benefit. The disease severity was evaluated monthly on a clinical basis. Complete remission was defined as the absence of any erosion and partial remission as a decrease of at least 50% of erosion surface. Blood cell counts with CD4+ and CD8+ lymphocyte subsets were evaluated every 3 months. RESULTS: All patients showed a decrease of the erosive surface; nine (75%) achieved a complete remission and three (25%) a partial remission. Seven of the eight patients followed for more than 3 years had recurrences of erosions when ECP sessions became less frequent or were stopped. After resumption of an initially accelerated regimen of ECP, all again showed partial or complete remission. Blood lymphocyte counts decreased during treatment, without statistically significant changes in CD4+/CD8+ ratio, and increased during relapse. CONCLUSIONS: ECP is an effective alternative therapy in erosive OLP showing resistance to classical treatments. The decrease in blood lymphocyte counts appears to parallel the clinical improvement under treatment.

Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients.

To evaluate the long-term immune reconstitution after allogeneic haematopoietic stem cell transplantation (SCT), we prospectively screened standard immune parameters in a series of 105 patients, at a median time of 15 months after SCT. Analysing lymphoid phenotypes, in vitro immune functions and immunoglobulin levels, we found that, more than 1 year post SCT, cellular and humoral immunity was still altered in a significant number of patients. CD4+ T cells were < 200/microl in one third of patients, and the CD4/CD8 ratio was still reversed in 78% of patients. Almost all patients showed positive T-cell responses against mitogens, but antigen-specific proliferation assays identified 20% to 80% of non-responders. B-cell counts were reconstituted in 61% of the patients, but levels of total immunoglobulins were still low in 59%. In multivariate analyses, human leucocyte antigen (HLA) disparity between donor and recipient and chronic graft-versus-host disease were the leading causes affecting immune reconstitution. Interestingly, cytomegalovirus (CMV) infections were strongly associated with normal CD8+ T-cell counts. Studying the impact of impaired immune reconstitution on the rate of infections occurring in the 6 years following screening, we identified three parameters (low B-cell count, inverted CD4/CD8 ratio, and negative response to tetanus toxin) as significant risk factors for developing such late infections.

Influence of bone marrow graft lymphocyte subsets on outcome after HLA-identical sibling transplants.

OBJECTIVE: The aim of this study was to analyze bone marrow lymphocyte subsets and CD34 cell dose and their influence on the outcomes of bone marrow transplantation. MATERIALS AND METHODS: Forty-eight patients (median age 30 years, range 5-54) receiving HLA-identical sibling bone marrow transplantation for hematologic malignancies were analyzed. RESULTS: Median number (range) of nucleated cells and CD34+ cells infused were 2.4 (0.4-6.0) x 10(8)/kg and 3.5 (0.5-13.0) x 10(6)/kg, respectively. Probability of neutrophil recovery was 97%. In a multivariate analysis, time to neutrophil recovery was shortened when a higher number of CD3/CD8 cells was infused (> or =1.0 x 10(7)/kg) (hazard ratio [HR] = 2.13, p = 0.018); when the patient was female or had negative cytomegalovirus serology (HR = 2.03, p = 0.03; HR = 0.41, p = 0.009; respectively). The incidence of grade II to IV acute graft-vs-host disease (GVHD) was 47%. Infusion of >1 x 10(7) CD4 infused/kg increased the risk of acute GVHD (HR = 2.86, p = 0.03). Nineteen of 40 patients at risk experienced chronic GVHD, the risk of which was increased by diagnosis of chronic leukemia (p = 0.03), <2.0 x 10(8) nucleated cells infused/kg (p = 0.05), and a low number of all lymphocyte subsets, except CD19. Estimated 3-year survival rate was 54%. Risk of death was increased in patients receiving <3.5 x 10(6)CD34 infused/kg (HR = 0.37, p = 0.02). Only six patients relapsed. CONCLUSIONS: A high cell dose of CD3/CD8 is associated with faster neutrophil recovery, whereas a high cell dose of CD4+ cells increases the incidence of acute GVHD. A high number of nucleated cells and CD34+ cells infused was associated with decreased risk of chronic GVHD and improved survival, respectively.

Lipodystrophic syndromes and hyperlipidemia in a cohort of HIV-1-infected patients receiving triple combination antiretroviral therapy with a protease inhibitor.

OBJECTIVES: To assess the frequency and features of lipodystrophic syndromes in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) with a protease inhibitor (PI), and examine whether clinical and biologic abnormalities are always associated in these conditions. METHODS: Retrospective-prospective single-center observational study of 175 patients. Comparisons for continuous variables by t-test and paired t-test, and Kaplan-Meier analysis of time to onset of lipodystrophy were performed. RESULTS: In all, 51 patients (29%) had morphologic changes, after a mean HAART duration of 20.0 +/- 6.1 months, and were categorized into pure lipoatrophy (n = 16), mixed syndrome (truncal fat accumulation and face or limb lipoatrophy) (n = 30) or pure truncal fat accumulation (n = 5). Because of the small number, the latter group was not analyzed statistically. No differences were found among patients with lipoatrophy, mixed syndrome, or no lipodystrophy, in terms of gender, CD4 count, and HIV RNA plasma load at time of HAART initiation, nor in response to treatment. Patients with a mixed syndrome were older. Patients with lipoatrophy had longer duration of HIV disease, pre-HAART exposure to nucleoside analog therapy, and HAART. Baseline and pre-HAART fasting triglyceride levels were higher in patients who developed lipoatrophy, whereas weight and fasting cholesterol were higher in patients who developed a mixed syndrome. After 12 and 24 months on HAART, triglycerides and cholesterol rose significantly in all patients, independently of lipodystrophy, whereas these parameters were not increased during nucleoside analog therapy. CONCLUSIONS: Nucleoside analog exposure appears as a risk factor for lipoatrophy. Age and nutritional status (reflected by baseline weight, triglycerides and cholesterol) may influence the evolution to lipoatrophy or a mixed syndrome. Hyperlipidemia is observed in the absence of lipodystrophy and depends on PI exposure.

Immune recovery under highly active antiretroviral therapy is associated with restoration of lymphocyte proliferation and interferon-gamma production in the presence of Toxoplasma gondii antigens.

The in vitro lymphocyte proliferative response (LPR) and interferon (IFN)-gamma production in the presence of Toxoplasma antigen were evaluated in 97 human immunodeficiency virus (HIV)-1-infected patients with CD4 cell counts of <100 cells/microL (group 1), currently >300 cells/microL but previously <100 cells/microL (group 2), or always >300 cells/microL (group 3) and in 28 non-HIV-infected blood donors (group 4), all seropositive to Toxoplasma. In group 2, 81% of patients had a positive LPR, versus 20% in group 1 (P<10(-3)). IFN-gamma production was greater in group 2 than in group 1 (922 vs. 0 Deltapg/mL; P=10(-4)). Multivariate analysis found a significant association between a positive LPR to Toxoplasma antigen and a CD4 count >300 cells/microL (odds ratio [OR], 16.3; 95% confidence interval [CI], 5.3-50.2) and anti-Toxoplasma IgG titer >150 IU/mL (OR, 5; 95% CI, 1.6-15.2). Immune reconstitution under highly active antiretroviral therapy was associated with a restoration of immune responses against Toxoplasma.

Interruption of prophylaxis for major opportunistic infections in HIV-infected patients receiving triple combination antiretroviral therapy.

UNLABELLED: Interruption of prophylaxis for major opportunistic infections in HIV-infected patients receiving triple combination antiretroviral therapy. OBJECTIVE: To determine whether HIV-infected patients receiving highly active antiretroviral therapy (HAART) and recovering a CD4 cell number above 200x10(6)/l may safely discontinue primary and secondary prophylaxes for major opportunistic infections. DESIGN: Retrospective study of a single-center, prospectively constituted cohort of 223 patients receiving HAART with a protease inhibitor, of whom 137 received at least one prophylaxis. METHODS: Exhaustive informations on prophylaxis use, clinical and laboratory data were used to produce descriptive statistics on infectious events, duration of HIV infection, time on HAART, time to prophylaxis interruption, length of follow-up and biological values at relevant time points. RESULTS: Fifty-one patients with a history of severe immunodepression (median CD4 nadir: 62x10(6)/l), including 16 patients with CDC stage C infection, discontinued at least one prophylaxis. Primary or secondary P. carinii pneumonia prophylaxis was discontinued in 43 patients: 1 first episode of PCP occurred after 2 months but no other episode was recorded after a median follow-up of 16 months. Toxoplasmosis primary or secondary prophylaxis, secondary cytomegalovirus prophylaxis and primary or secondary M. avium complex prophylaxes were discontinued in respectively 37, 5 and 5 patients, and no event was recorded after respective follow-ups of 16, 7 and 15 months. Nine secondary and 2 primary acyclovir prophylaxes were discontinued, and two events were observed after 1 and 19 months; no other event was noted after a follow-up of 22 months. CONCLUSION: Prophylaxis for opportunistic infections could be safely interrupted in most of these severely immunodeficient patients recovering a CD4 cell count above 200x10(6)/l on HAART. This confirms the efficiency of immune restoration and is beneficial to patients but, since 3 infectious events were recorded, caution should be taken before making a decision based on immunological and virological considerations.

Five years follow-up after 2-chloro deoxyadenosine treatment in thirty patients with hairy cell leukemia: evaluation of minimal residual disease and CD4+ lymphocytopenia after treatment.

Between March 1992 and August 1993, thirty patients with hairy cell leukemia (HCL) were treated in a single institution with 2-chlorodeoxyadenosine (2-CdA) for one course (N=27) or two courses at six month interval (N=3). Sixteen patients were previously untreated, 14 had been treated with alpha interferon (alpha IFN) (N=5), alpha IFN and splenectomy (N=8) and splenectomy, alpha IFN and Deoxycoformycin (N=1). Overall results in 29 evaluable patients were: 25 CR (86%), 3 PR (10%), one failure. The three PR patients relapsed after 18, 24 months and five years. Two were retreated successfully. Two CR patients relapsed after five years. Careful clinical survey, sequential bone marrow biopsies (BMB) with DBA44 immunostaining for assessment of response and detection of residual disease and serially evaluation of lymphocyte subsets counts were performed. Results of bone marrow biopsies study show 1) a progressive reduction in hairy cell infiltration during the first six months after therapy and not after that indicating that the best moment for the evaluation of response may be the sixth month, 2) the persistence of a very small number of DBA44+ cells (80% of BMB). There was a correlation between the presence of > 5% DBA44 positive cells on 6th month BMB and relapse. 60% had an absolute CD4+ lymphocyte count less than 0.2 10(9)/l at least on one examination after treatment. CD4+ lymphocyte level persisted less than baseline level in 8/18 patients tested after four and/or five years. Lymphopenia was less marked in splenectomized patients: 7/7 splenectomized patients tested have recovered a CD4+ lymphocyte count equal to pretherapy level compared to 3/11 non splenectomized patients (p: 0.004). Three opportunistic infections were observed early (first 6 months) after 2CdA therapy: pneumocystis pneumonia, retinitis due to toxoplasma in the patient who failed and legionella pneumonia in a patient retreated after relapse. Two patients developed a second carcinoma 6 and 12 months after therapy. Five patients died, three from a cause unrelated to HCL, one from HCL and one from infection while in second CR. At five years, overall survival is 83% and progression free survival is 66%. Our study shows 1) long-lasting response in the majority of patients after 2-CdA, 2) a correlation between persistent minimal residual disease detected with DBA44 immunostaining and occurrence of relapse and 3) a profound and persistent CD4+ lymphopenia more marked in non splenectomized patients.

Standardisation and quality assurance of lymphocyte proliferation assays for use in the assessment of immune function. European Concerted Action on Immunological and Virological Markers of HIV Disease Progression.

Lymphocyte proliferation is a widely used technique to assess immune competence. However, the technique is subject to a large degree of variation, some biological and some technical. In this study, the components of variation in whole blood proliferation assays were analysed over time, using both antibody and mitogenic stimulants. The levels of variation within individual samples, between individuals and between groups of individuals over time were examined. A method of transforming the data is proposed which reduces the coefficients of variation to an acceptable level, and which expresses individual results as a standardised count. This method overcomes the problem of different levels of absolute counts, it corrects for time sensitive errors and allows data from multiple laboratories to be pooled.

A prospective study of the influence of HIV status on the seroreversion of serological tests for syphilis.

UNLABELLED: The evolution of serological tests for syphilis (STSs) after therapy in HIV+ patients is a major point of controversy, with possible seroreactivation and illicit seroreversion in these patients. The aim of our study was to evaluate the long-term outcome of STSs in a cohort of HIV+ male homosexuals with a history of treated syphilis as compared with HIV- controls. PATIENTS AND METHODS: Sixty-nine HIV+ male homosexuals with a documented history of treated syphilis and positive baseline treponemal tests were prospectively studied between 1986 and 1993. A medical examination, HIV staging, CD4+ cell count, VDRL, FTA-Abs tests and TPHA were performed every 6 months. Controls consisted of 49 HIV- patients with similar inclusion criteria over the same period. Comparisons between subgroups were based on chi(2) and Kruskal-Wallis tests. Analysis of negativation of the STS used the failure data methods (Kaplan-Meier, log-rank and Cox's model). RESULTS: Patients had a mean age of 38 years, a baseline CD4+ cell count of 578/mm(3), elapsed time since last syphilis of 7.5 years and a median follow-up of 4.3 years. Controls had a mean age of 42 years, elapsed time since last syphilis of 5.3 years and a median follow-up of 4.7 years. Time to seroreversion was shorter in HIV+ patients for TPHA (p = 0.009, log-rank test) and FTA-Abs test (p = 0.001, log-rank test), even after adjustment for stage of syphilis, age and time since the last episode of syphilis. The decrease in VDRL titres was not different between the 2 groups (p = 0.053, log-rank test). Seroreversion of the TPHA, FTA-Abs test and VDRL test was not significantly related to stage of syphilis, time elapsed since the last episode of syphilis, age or history of STDs in both groups. Seroreversion of the TPHA and VDRL test was not related to baseline CD4+ cell count. However, seroreversion of the FTA-Abs test was related to a low baseline CD4+ cell count (p = 0. 003). In HIV+ patients, a significant decrease in titres was noticed for TPHA, FTA-Abs test and VDRL test over time, but this time effect remained only for TPHA titres after adjustment for the CD4+ cell count. CONCLUSION: TPHA may serorevert in HIV+ patients. Thus, a non-reactive TPHA does not exclude a past syphilis infection in such patients. Evolution of the VDRL test after therapy is regular in HIV+ patients. The VDRL test remains adequate for controlling the efficacy of treatment in these patients.

The influence of highly active antiretroviral therapy on AIDS-associated Kaposi's sarcoma.

To assess the clinical and biological benefit of highly active antiretroviral therapy on AIDS-associated Kaposi's sarcoma (KS), 13 patients with AIDS-associated Kaposi's sarcoma (five pulmonary KS and eight cutaneous KS) were prospectively followed for a mean duration of 12 months. Six patients were treated with specific anti-KS chemotherapy before or simultaneously with the introduction of antiretroviral therapy. Clinical response was assessed according to the AIDS Clinical Trial Group (ACTG) criteria. CD4 cell counts, plasma HIV-1 RNA and human herpesvirus 8 (HHV-8) viraemia were measured at baseline and at different points. Among patients with pulmonary KS, we observed three complete responses (CR), one partial response (PR) and one progression. The median survival time after the diagnosis of pulmonary KS was 15 months with a median duration of the response after the discontinuation of specific chemotherapy for KS of 8 months. Among patients with cutaneous KS, we observed four CR, three PR and one stable response. A complete response was significantly associated with a reversal in HHV-8 viraemia (five of six vs. one of six; P = 0.02, Mann-Whitney test).

Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial. ANRS 048 study group.

BACKGROUND: Intermittent interleukin-2 therapy for HIV-1 by continuous intravenous infusion leads to sustained increase of CD4 T cells. This method of administration is, however, inconvenient and has limiting toxic effects. We did a randomised study to compare safety and efficacy of antiviral treatment alone or combined with various interleukin-2 regimens in HIV-1-infected patients. METHODS: 94 symptom-free patients, naïve to antiretroviral treatment, with CD4-T-cell counts of 250-550 cells/microL at baseline were randomly assigned zidovudine and didanosine alone (n=26) or combined with interleukin-2 administered intravenously (12 million IU/day, n=22) or subcutaneously (3 million IU/m2 twice daily, n=24) for 5 days, or were given polyethylene-glycol-modified (PEG) interleukin-2 (2 million IU/m2 intravenous bolus, n=22) administered every 2 months from week 2 to week 50 (seven cycles). Safety and immunological and virological results were monitored until week 56. FINDINGS: CD4-T-cell count increased to higher than baseline by a mean of 564 cells/microL (subcutaneous group), 676 cells/microL (intravenous group), 105 cells/microL (PEG group), and 55 cells/microL (antiretroviral-therapy group, p=0.0001). 68% and 77% of patients in the subcutaneous and intravenous groups, respectively, achieved an 80% increase of CD4 T cells (p<0.001). In these two groups, 50% of patients restored a CD4/CD8-T-cell ratio of more than 1. The groups did not differ significantly for changes in plasma HIV-1 RNA loads throughout the study. The duration of common side-effects of interleukin-2 was shorter in the subcutaneous group, which enabled outpatient treatment. Naïve and memory CD4 T cells, CD28 expression on CD4 and CD8 T cells, and restoration of in-vitro proliferative response to mitogens and recall antigens increased in the intravenous and subcutaneous groups. INTERPRETATION: Subcutaneous interleukin-2 is a convenient regimen that, as well as intravenous therapy, improves immunological function in HIV-1-infected patients receiving two nucleosides. Larger studies are needed to show whether immunological improvements translate into clinical benefit.

Common intra-articular T cell expansions in patients with reactive arthritis: identical beta-chain junctional sequences and cytotoxicity toward HLA-B27.

Spondyloarthropathies constitute a group of autoimmune diseases of special interest because of their tight association with the MHC class I molecule HLA-B27 and the bacterial triggering of some clinical forms called reactive arthritis (ReA). One current hypothesis is the presentation by HLA-B27 of a so-called arthritogenic peptide to T cells. To better focus on the relevant T cell populations within the joint, we performed an extensive beta-chain T cell repertoire analysis of synovial fluid compared with PBL in seven patients, four of whom were characterized as having ReA triggered by Yersinia enterocolitica, Chlamydia trachomatis, or Shigella sonnei. Analysis of the size diversity of the beta-chain complementarity-determining region 3 (CDR3) allowed us to evaluate the degree of T cell clonality in the samples. Oligoclonal T cell expansions were frequently observed in the joint. In one patient, CDR3 amino acid sequences of major expansions using two different BV genes were identical. One dominant T cell expansion and several CDR3 amino acid sequences were identical in two different patients. Furthermore, one sequence was identical with a sequence reported independently in a Salmonella-induced ReA patient. Together, these data indicate a surprisingly high degree of conservation in the T cell responses in recent-onset ReA triggered by different micro-organisms. A CD8+ synovial line expressing shared clonotypes was established and reacted toward several B*2705 lymphoblastoid cell lines, therefore supporting a molecular mimicry phenomenon at the T cell level in the disease mechanism.

[6-mercaptopurine levels and study of blood lymphocyte subsets during azathioprine treatment of Crohn's disease]. / Dosage de la 6-mercaptopurine et étude des sous-populations lymphocytaires sanguines au cours du traitement par l'azathioprine dans la malaide de Crohn.

OBJECTIVES: Our aim was to study the relationships between clinical efficacy of azathioprine, 6-mercaptopurine pharmacokinetics and changes in peripheral blood lymphocyte subpopulations induced by azathioprine treatment in Crohn's disease. METHODS: Twenty-three patients were prospectively followed up for 1 year. Peripheral blood counts, total lymphocytes, CD3+, CD4+, CD8+, CD25+, CD16+CD56+, CD57+ and CD19+ lymphocyte subpopulations were carried out, using flow cytometry, during azathioprine treatment. Pharmacokinetic studies were performed at day 8 and month 3 by measuring 6-mercaptopurine plasma concentration after an oral dose of azathioprine (2 mg/kg). Results were compared in responders (no activity and no steroids) and non-responders. RESULTS: The decrease in peripheral blood leukocytes and neutrophils was significant after 1 month, reaching 49% and 48% of the pre-treatment values at 1 year; the one of lymphocytes was significant after 6 months and reached 41% at 1 year. Percentages of CD3+, CD4+, CD8+, CD57+, CD16+CD56+ and CD19+ lymphocytes remained unchanged whereas percentage of CD25+ lymphocytes increased from 10% to 28% (P < 0.01). There was a high inter and intraindividual variability of 6-mercaptopurine peak plasma concentration and area under the curve. No significant difference was found between responders (n = 14) and non responders (n = 7) for pharmacokinetic parameters and lymphocyte subpopulations; there was no correlation between lymphocyte subpopulation changes and 6-mercaptopurine pharmacokinetics. CONCLUSION: Monitoring of 6-mercaptopurine plasma concentration and blood lymphocyte subpopulations is of little value in Crohn's disease patients treated with azathioprine.

No evidence for proliferation in the blood CD4+ T-cell pool during HIV-1 infection and triple combination therapy.

OBJECTIVE: To evaluate the role of cell proliferation in peripheral blood lymphocyte (PBL) dynamics during HIV infection and potent antiretroviral therapy including protease inhibitors. DESIGN: Transverse study of 150 patients at different stages of infection. Longitudinal study of 50 patients on triple combination antiretroviral therapy with 9-month follow-up. METHODS: Ex vivo incubation of fresh PBL with the DNA biosynthetic marker bromodeoxyuridine (BrdU). Flow cytometric analysis of cell phenotypes and BrdU incorporation. Parallel determination of plasma virus load and CD4+ cell counts. RESULTS: Percentages of BrdU+ B and T lymphocytes found in patients with asymptomatic HIV infection were not different from the low values found in HIV-seronegative controls, and were not correlated with the CD4+ cell count. DNA synthesis increased significantly only during acute opportunistic infections occurring in patients with high plasma viral load and fewer than 100 x 10(6) CD4+ cells/l. Triple combination therapy induced a decrease of plasma virus load and a rise of CD4+ cell counts, whereas BrdU incorporation remained low or decreased. CONCLUSION: Proliferation of peripheral blood T cells observed at late stages of HIV infection corresponds to a response to opportunistic infections. Apart from these particular cases, proliferation in this compartment does not appear as a critical parameter of CD4+ cell kinetics during chronic HIV infection and potent therapy.

Tritherapy for human immunodeficiency virus infection does not modify replication of hepatitis C virus in coinfected subjects.

Triple antiretroviral therapy combining reverse transcriptase and protease inhibitors modifies the prognosis for human immunodeficiency virus (HIV) infection, with dramatic improvement in immune status. In an attempt to evaluate the impact of anti-HIV triple combination therapy on the course of hepatitis C virus (HCV)-related chronic hepatitis and on HCV replication, we studied the biological and virological characteristics of 22 HCV/HIV-coinfected patients who were given triple combination therapy. In comparison with baseline values, there was (1) a significant increase in the CD4 and CD8 cell counts and a decrease in the HIV RNA load and (2) no significant variation in aminotransferase activities or the HCV RNA load at 3, 6, or 9 months of tritherapy. Antiretroviral tritherapy seems to modify neither the biological activity of HCV-related chronic hepatitis nor the HCV load, despite immune restoration. Hepatic histopathologic analysis is warranted to assess the impact of immune restoration on liver lesions.