Antiviral activity and safety of aplaviroc, a CCR5 antagonist, in combination with lopinavir/ritonavir in HIV-infected, therapy-naïve patients: results of the EPIC study (CCR100136).

BACKGROUND: This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist aplaviroc (APL) in antiretroviral-naïve patients harbouring R5- or R5X4-tropic virus. METHODS: A total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed. RESULTS: This study was terminated prematurely because of APL-associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent-to-treat (M-ITT) population]; of these, 133 completed the 12-week treatment phase. The proportion of subjects in the M-ITT population with HIV-1 RNA <400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4-tropic virus (n=17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability. CONCLUSIONS: While target plasma concentrations of APL were achieved, the antiviral activity of APL+LPV/r did not appear to be comparable to that of 3TC/ZDV+LPV/r.

Antibiotic regimens for endometritis after delivery.

BACKGROUND: Postpartum endometritis, which is more common after cesarean section, occurs when vaginal organisms invade the endometrial cavity during labor and birth. Antibiotic treatment is warranted. OBJECTIVES: The effect of different antibiotic regimens for the treatment of postpartum endometritis on failure of therapy and complications was systematically reviewed. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's trials register (30 January 2004). SELECTION CRITERIA: Randomized trials of different antibiotic regimens for postpartum endometritis, after cesarean section or vaginal birth, where outcomes of treatment failure or complications were reported were selected. DATA COLLECTION AND ANALYSIS: We abstracted data independently and made comparisons between different types of antibiotic regimen based on type of antibiotic and duration and route of administration. Summary relative risks were calculated. MAIN RESULTS: Thirty-eight trials with 3983 participants were included. Fifteen studies comparing clindamycin and an aminoglycoside with another regimen showed more treatment failures with the other regimen (relative risk (RR) 1.44; 95% confidence interval (CI) 1.15 to 1.80). Failures of those regimens with poor activity against penicillin resistant anaerobic bacteria were more likely (RR 1.94; 95% CI 1.38 to 2.72). In three studies that compared continued oral antibiotic therapy after intravenous therapy with no oral therapy, no differences were found in recurrent endometritis or other outcomes. In four studies comparing once daily with thrice daily dosing of gentamicin there were fewer failures with once daily dosing. There was no evidence of difference in incidence of allergic reactions. Cephalosporins were associated with less diarrhea. REVIEWERS' CONCLUSIONS: The combination of gentamicin and clindamycin is appropriate for the treatment of endometritis. Regimens with activity against penicillin- resistant anaerobic bacteria are better than those without. There is no evidence that any one regimen is associated with fewer side effects. Once uncomplicated endometritis has clinically improved with intravenous therapy, oral therapy is not needed.

Multilaboratory comparison of proficiencies in susceptibility testing of Helicobacter pylori and correlation between agar dilution and E test methods.

Susceptibility testing was performed at seven Canadian microbiology laboratories and the Helicobacter Reference Laboratory, Halifax, Nova Scotia, Canada, to assess susceptibility testing proficiency and the reproducibility of the results for clarithromycin and metronidazole and to compare the Epsilometer test (E test) method to the agar dilution reference method. Control strain Helicobacter pylori ATCC 43504 (American Type Culture Collection) and 13 clinical isolates (plus duplicates of four of these strains including ATCC 43504) were tested blindly. The National Committee for Clinical Laboratory Standards (NCCLS) guidelines for agar dilution testing were followed, and the same suspension of organisms was used for agar dilution and E test. Antimicrobials and E test strips were provided to the investigators. Methods were provided on a website (www.Helicobactercanada.org). Each center reported MICs within the stated range for strain ATCC 43504. Compared to the average MICs, interlaboratory agreements within 2 log(2) dilutions were 90% (range, 69 to 100%) for clarithromycin by agar dilution, with seven very major errors [VMEs], and 85% (range, 65 to 100%) by E test, with three VMEs. Interlaboratory agreements within 2 log(2) dilutions were 83% (range, 50 to 100%) for metronidazole by agar dilution, with six VMEs and eight major errors (MEs), and 75% (range, 50 to 94%) by E test, with four VMEs and four MEs. At lower and higher concentrations of antibiotic, E test MICs were slightly different from agar dilution MICs, but these differences did not result in errors. When a standardized protocol based on NCCLS guidelines was used, most participants in this study correctly identified clarithromycin- and metronidazole-susceptible and -resistant strains of H. pylori 93% of the time by either the agar dilution or E test method, and the numbers of errors were relatively equivalent by both methods.

Antibiotic regimens for endometritis after delivery.

BACKGROUND: Post-partum endometritis, which is more common after cesarean section, occurs when vaginal organisms invade the endometrial cavity during labour and birth. Antibiotic treatment is warranted. OBJECTIVES: The effect of different antibiotic regimens for the treatment of postpartum endometritis on failure of therapy and complications was systematically reviewed. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's trials register and the Cochrane Controlled Trials Register. Date of last search: June 2001. SELECTION CRITERIA: Randomised trials of different antibiotic regimens for postpartum endometritis, after cesarean section or vaginal birth, where outcomes of treatment failure or complications were reported were selected. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by the reviewers. Comparisons were made between different types of antibiotic regimen, based on type of antibiotic and duration and route of administration. Summary relative risks were calculated. MAIN RESULTS: Forty-seven trials were included. Overall the studies were methodologically poor. In the intent-to-treat analysis, fifteen studies comparing clindamycin and an aminoglycoside with another regimen showed more treatment failures with another regimen (relative risk (RR) 1.32; 95% confidence interval (CI) 1.09-1.60). Failures of those regimens with poor activity against penicillin resistant anaerobic bacteria were more likely (RR 1.53; 95% CI 1.10-2.13). In four studies that compared continued oral antibiotic therapy after intravenous therapy, no differences were found in recurrent endometritis or other outcomes. There was no evidence of difference in incidence of allergic reactions. Cephalosporins were associated with less diarrhea. REVIEWER'S CONCLUSIONS: The combination of gentamicin and clindamycin is appropriate for the treatment of endometritis. Regimens with activity against penicillin resistant anaerobic bacteria are better than those without. There is no evidence that any one regimen is associated with fewer side effects. Once uncomplicated endometritis has clinically improved with intravenous therapy, oral therapy is not needed.

Implications of antibiotic resistance in the management of Helicobacter pylori infection: Canadian Helicobacter Study Group.

Eradication of Helicobacter pylori from the gastric and duodenal mucosa is an important clinical goal in the treatment of infected patients with peptic ulcer disease and other H pylori-associated conditions. Although several oral drug combination regimens are associated with eradication rates of approximately 85% in controlled trials, the success rate in patients infected with a resistant strain of H pylori is closer to 75%. Resistance to metronidazole and clarithromycin, which are common components of combination treatment regimens, is of greatest concern. Reported rates of H pylori resistance to various antibiotics vary considerably. In Canada, the data documenting H pylori susceptibility are limited but suggest that resistance to these antibiotics varies geographically and within specific treatment groups. Although susceptibility testing is not a prerequisite for initial treatment of individual patients infected with H pylori, formal efforts to identify and monitor both the causes and prevalence of antibiotic resistance across Canada are a much needed step in the ongoing management of this important infection. Recommended treatment regimens may be useful, even for treating apparently resistant H pylori strains. However, it is important to understand the mechanisms of the development of resistant strains to manage patients with treatment failure better.

An outbreak of influenza A in a neonatal intensive care unit.

OBJECTIVES: Investigation of an outbreak of influenza A in a neonatal intensive care unit (NICU) with examination of risk factors for infection and outcomes. DESIGN: Retrospective cohort study of infants admitted to the unit during the outbreak period. Prospective survey of NICU staff and mothers of infants in the cohort study. SETTING: Level III nursery in a university-affiliated tertiary referral center. RESULTS: Nineteen infants in the NICU were infected with influenza A There were six symptomatic cases and one death who had evidence of virus-associated hemophagocytic syndrome at autopsy. Amantadine prophylaxis was offered to the NICU staff, and amantadine therapy was given to five of the six symptomatic infants. Mechanical ventilation, gestational age, birth weight, Clinical Risk Index for Babies score, and twin pregnancy were associated with acquisition of influenza A on univariate analysis. Mechanical ventilation (odds ratio [OR], 6.2; P=.02) and twin pregnancy (OR, 7.0; P=.04) remained as significant risk factors for infection on multiple logistic regression analysis. Only 15% of respondents to the NICU staff survey were vaccinated against influenza. There was no association between a history of an influenza-like illness during pregnancy and acquisition of influenza A by infants of mothers who responded to the maternal survey (OR, 0.91; P=1.0). CONCLUSIONS: Influenza A is an important pathogen in the neonatal population and is readily transmissible in the NICU setting.

Factors contributing to the lack of human immunodeficiency virus type 1 (HIV-1) transmission in HIV-1-discordant partners.

Correlates of resistance to infection by human immunodeficiency virus type 1 (HIV-1) are important for defining potential therapeutic interventions and for prophylactic vaccination. In this study, 11 couples discordant in their HIV-1 infection status were prospectively evaluated for the presence of protective factors. Behavioral characteristics of all subjects entailed a high risk of transmission. Cytotoxic T lymphocyte (CTL) responses against viruses isolated from the infected partner, and against laboratory virus isolates, were detected in 5 (45%) of 11 HIV-negative partners, including a CCR5Delta32-homozygous and a heterozygous subject. No CTL responses were observed in 6 control unexposed subjects. Marked variation in lymphocyte susceptibility to viral infection was noted. Resistance attributable to major histocompatibility complex discordance or anti-major histocompatibility complex antibodies was not identified. These results suggest that a combination of factors, including cellular immunity, viral characteristics, and coreceptor integrity, may be involved in the persistent nontransmission of HIV.

Antibiotic regimens for endometritis after delivery.

BACKGROUND: Post-partum endometritis, which is more common after cesarean section, occurs when vaginal organisms invade the endometrial cavity during labour and delivery. Antibiotic treatment is warranted. OBJECTIVES: The effect of different antibiotic regimens for the treatment of postpartum endometritis on failure of therapy and complications was systematically reviewed. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's trials register and the Cochrane Controlled Trials Register. Date of last search: August 1999. SELECTION CRITERIA: Randomised trials of different antibiotic regimens for postpartum endometritis, after cesarean section or vaginal delivery, where outcomes of treatment failure or complications were reported were selected. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by the reviewers. Comparisons were made between different types of antibiotic regimen, based on type of antibiotic and duration and route of administration. Summary relative risks were calculated. MAIN RESULTS: Forty-one trials were included. Overall the studies were methodologically poor. In the intent-to-treat analysis, fifteen studies comparing clindamycin and an aminoglycoside with another regimen showed more treatment failures with another regimen (relative risk (RR) 1.37; 95% confidence interval (CI) 1.10 - 1.70). Failures of those regimens with poor activity against penicillin resistant anaerobic bacteria were more likely (RR 1.73; 95% CI 1.14 - 2.63). In four studies that compared continued oral antibiotic therapy after intravenous therapy, no differences were found in recurrent endometritis or other outcomes. There was no evidence of difference in incidence of allergic reactions. Cephalosporins were associated with less diarrhea. REVIEWER'S CONCLUSIONS: The combination of gentamicin and clindamyin is appropriate for the treatment of endometritis. Regimens with activity against penicillin resistant anaerobic bacteria are better than those without. There is no evidence that any one regimen is associated with fewer side effects. Once uncomplicated endometritis has clinically improved with intravenous therapy, oral therapy is not needed.

Isoniazid for preventing tuberculosis in non-HIV infected persons.

BACKGROUND: Although isoniazid (INH) is commonly used for treating tuberculosis (TB), it is also effective as preventive therapy. OBJECTIVES: The objective of this review was to estimate the effect of 6 and 12 month courses of INH for preventing TB in HIV-negative people at increased risk of developing active TB. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase and reference lists of articles. We hand-searched Science Citation Index and Index Medicus. SELECTION CRITERIA: Randomised trials of INH preventive therapy for 6 months or more compared with placebo. Follow-up for a minimum of 2 years. Trials enrolling patients with current or previously treated active TB, or with known HIV infection, were excluded. Criteria were applied by two reviewers independently. DATA COLLECTION AND ANALYSIS: Trial quality was assessed by two reviewers independently, and data extracted by one reviewer using a standardized extraction form. MAIN RESULTS: Eleven trials involving 73,375 patients were included. Trials were generally of high quality. Treatment with INH resulted in a relative risk (RR) of developing active TB of 0.40, (95% confidence interval ¿CI¿ 0.31 to 0.52), over two years or longer. There was no significant difference between 6 and 12 month courses (RR of 0.44, 95% CI 0.27 to 0.73 for six months, and 0.38, 95% CI 0.28 to 0.50 for 12 months). Preventive therapy reduced deaths from TB, but this effect was not seen for all cause mortality. INH was associated with hepatotoxicity in 0.36% of people on 6 months treatment and in 0.52% of people treated for 12 months. REVIEWER'S CONCLUSIONS: Isoniazid is effective for the prevention of active TB in diverse at-risk patients, and six and 12 month regimens have a similar effect.

Predictors of survival and eradication of Mycobacterium avium complex bacteremia (MAC) in AIDS patients in the Canadian randomized MAC treatment trial. Canadian HIV Trials Network Protocol 010 Study Group.

OBJECTIVE: To assess the importance of baseline characteristics including medical history, indicators of current disease status, therapeutic drug use, in vitro drug susceptibility, immune status and mycobacterial load on bacteriologic response and survival in HIV-positive patients with Mycobacterium avium complex (MAC) bacteremia. DESIGN: An observational substudy of an open-label randomized controlled trial of two alternative therapeutic regimens for MAC. SETTING: Twenty-four hospital-based HIV clinics in 16 Canadian cities. MAIN OUTCOME MEASURES: The main outcome measures were survival and bacteriologic response, defined by consecutive negative blood cultures for MAC at least 2 weeks apart within 16 weeks of study entry. RESULTS: Prior AIDS diagnosis, low Karnofsky score, active unstable AIDS-related conditions, absence of antiretroviral therapy and absence of Pneumocystis carinii pneumonia prophylaxis were associated with shorter survival by univariate regression using the proportional hazards model. On multivariate analysis, antiretroviral therapy was not an independent predictor of mortality, and previous rifabutin prophylaxis was independently associated with poor survival outcomes, a result consistent across study treatment. Using a logistic regression model, baseline quantitative mycobacterial load [relative odds of clearing, 1.97 for a decrease of 1 log10 colony forming count; 95% confidence interval (CI), 1.36-2.87; P < 0.001] and Karnofsky score were the only statistically significant univariate predictors of clearance, although previous prophylaxis with rifabutin was also a significant predictor in a multivariate model (relative odds of clearing, 0.39; 95% CI, 0.17-0.88; P < 0.05). CONCLUSIONS: This study indicates that although the level of MAC bacteremia is an important predictor of clearance, it is not associated with survival.

Evaluation of salivary antibodies to detect infection with Helicobacter pylori.

Helicobacter pylori infection is an important cause of peptic ulcer disease and chronic gastritis. Infection with this bacterium stimulates the production of immunoglobulin (Ig) G antibody. Salivary IgG antibody tests to detect H pylori infection offer a convenient and noninvasive method of diagnosis. To evaluate an IgG salivary antibody kit, saliva was collected from 157 out-patients with dyspepsia referred for endoscopy to a tertiary centre. A salivary IgG ELISA antibody assay was performed using the Helisal Helicobacter pylori (IgG) assay kit, and at least four gastric biopsies were obtained. H pylori infection was confirmed by demonstration of the organism on Warthin-Starry silver stain (sensitivity 85%, specificity 55%). The prevalence of infection with H pylori was 30%. When the analysis was redone, excluding those treated with eradication therapy, the results were similar (sensitivity 86%, specificity 58%). The positive predictive value of the assay was 45% and the negative predictive value was 90%. Despite the ease of sampling, the assay used has limited diagnostic utility, lacking the predictive value to indicate which patients referred with dyspeptic symptoms to a tertiary care setting are infected with H pylori.

CD8+ T cell-mediated suppression of HIV long terminal repeat-driven gene expression is not associated with improved clinical status.

OBJECTIVES: To determine the associations between the suppression of HIV-1 long terminal repeat (LTR)-mediated gene expression by CD8+ T-cell supernatants and clinical correlates of well-being, including CD4+ and CD8+ T-cell counts, beta-chemokine production and clinical stage of disease. METHODS: Culture supernatants of activated CD8+ T cells derived from a panel of HIV-1-infected subjects were assessed for their ability to suppress HIV-1 LTR-mediated chloramphenicol acetyl transferase (CAT) expression. The percentage suppression of gene expression was correlated with CD4+ and CD8+ T-cell counts and clinical stage of infection. Some individuals within this group were followed at 2-3 month intervals over time to assess the consistency of the suppression. Selected CD8+ T-cell culture supernatants of diverse suppressive ability were screened for the levels of the beta-chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta and RANTES. RESULTS: The ability of CD8+ T cells of HIV-1 infected subjects to suppress HIV-1 LTR-mediated gene expression did not show a dependence upon high CD4+ T-cell counts or on the clinical stage or duration of infection. The ability to suppress gene expression did show a relationship with higher CD8+ T-cell counts and correlated with the levels of beta-chemokines in the culture supernatants. In contrast, strong suppression was mediated by CD8+ T-cell supernatants from some subjects with very low CD8+ T-cell counts and relatively low chemokine levels. CONCLUSIONS: Although the suppression of gene expression by CD8+ T-cell culture supernatants showed statistical correlation with beta-chemokine levels and with higher CD8+ T-cell count, no correlation could be found with correlates of clinical well-being.

Cytotoxic T-lymphocytes from HIV-infected individuals recognize an activation-dependent, non-polymorphic molecule on uninfected CD4+ lymphocytes.

OBJECTIVES: Correlation of lysis of autologous CD4+ target cells by cytotoxic lymphocytes from HIV-seropositive patients to target activation, viral replication, and major histocompatibility complex (MHC) restriction. DESIGN: Twenty-two HIV-infected patients were evaluated for lysis of activated CD4+ cells, concurrent with measurement of proliferation of the target cells, and with viral replication. METHODS: Titrated standard 51Cr-release assays for specific effector-to-target cell recognition, blocking antibodies and cell depletion for cell characterization, incorporation of [3H]-thymidine for proliferation, and p24 antigen capture assays for viral replication. RESULTS: HIV-infected patients had cytotoxic lymphocytes capable of recognizing activated CD4+ target cells in a non-MHC-restricted manner. The lysis depended on the degree of target activation, and was independent of viral replication. CONCLUSIONS: This cytolytic activity is unique to HIV-infected patients, and is suggestive of activation-induced cell death that may contribute to the progressive depletion of CD4+ lymphocytes during HIV pathogenesis.

Inhibition of HIV replication by CD8+ T cells correlates with CD4 counts and clinical stage of disease.

We sought to evaluate the relationship of CD8+ T cell-mediated inhibition of autologous HIV replication in vitro to disease stage in HIV+ individuals. Depletion of CD8+ T cells from peripheral blood lymphocytes of 16 HIV+ subjects increased the percentage of virus-producing cultures from 56% to 81%. CD4+ T cells were purified from 52 HIV+ individuals and cultured alone or in the presence of autologous CD8+ T cells. In 13 (25%) subjects HIV replication was only detected in the absence of CD8+ T cells (inhibition positive); in 26 (50%) viral replication occurred both in the absence and presence of CD8+ cells (inhibition negative). In the remaining 13 (25%) subjects, CD8+ T cell-mediated inhibitory activity could not be evaluated because stimulation of their purified CD4+ T cells did not result in p24 production. In some virus culture-negative individuals, the inability to demonstrate HIV replication was due to the presence of low numbers of CD8+ T cells that co-purified with CD4+ T cells. Detection of inhibitory CD8+ T cells was associated with significantly higher CD4 counts and better clinical status compared with inhibition-negative subjects. These results demonstrate that CD8+ T cell-mediated inhibition of HIV replication correlates with disease stage, and thus may play a role in preventing disease progression. CD8+ T cells did not inhibit autologous HIV replication across a semipermeable membrane. Further, the ability of CD8+ T cells to prevent HIV replication did not correlate with lysis of autologous CD4+ T cells. Thus, CD8+ T cells inhibited autologous HIV replication in vitro through a contact-mediated non-lytic mechanism.

Use of immune globulin to prevent symptomatic cytomegalovirus disease in transplant recipients--a meta-analysis.

The objective of this meta-analysis was to review the evidence for the use of immune globulin in the prevention of symptomatic cytomegalovirus (CMV) disease in transplant recipients. A computerized search of Medline from 1980 to October 1991 was conducted using the textword "cytomegalo:" and the subheading "prevention and control" for studies in all languages. Reference lists, a manual search of relevant literature and communication with internationally recognized experts were used to locate additional studies. Of the studies identified, 18 met the inclusion criteria (population: transplant recipients; intervention: immune globulin; outcome: symptomatic cytomegalovirus disease; study design: randomized controlled trial). The meta-analysis of the 18 studies showed a reduction in the incidence of symptomatic CMV disease in the group receiving immune globulin as compared to the untreated group. The common odds ratio was 0.58 (95% C.I. 0.42 to 0.77). Analyses of combining trials by subgroups of polyvalent immune globulin, hyperimmune globulin, bone marrow recipients and solid organ recipients resulted in common odds ratios comparable to the overall common odds ratio. Common odds ratios for the trials reporting cytomegalovirus interstitial pneumonia, cytomegalovirus death, overall death and graft loss ranged from 0.47 to 0.69. Common odds ratios for the effect of immune globulin prophylaxis analyzed by pre-transplant patient/donor cytomegalovirus antibody status ranged from 0.32 to 0.50. In conclusion, the use of immune globulin as passive immunization for the prevention of symptomatic cytomegalovirus disease in the transplant population is supported by this meta-analysis. The response is similar in both bone marrow and solid organ transplant recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

Lysis of CD4+ lymphocytes by non-HLA-restricted cytotoxic T lymphocytes from HIV-infected individuals.

Individuals infected with HIV have elevated numbers of total and activated CD8+ lymphocytes in peripheral blood. CD8+ lymphocytes from HIV-infected individuals have been shown to mediate non-human histocompatibility-linked antigen (HLA)-restricted suppression of viral replication, HLA-restricted killing of cells expressing HIV antigens, and killing of uninfected lymphocytes. We studied CD8+ T lymphocytes that lysed autologous CD4+ lymphocytes. heterologous CD4+ lymphocytes from HIV-infected individuals and uninfected CD4+ lymphocytes. Killing in all cases required T cell receptor (TCR)-mediated recognition or triggering. However, these CD8+ cytotoxic T lymphocytes (CTL) killed HLA class I mismatched CD4+ lymphocytes and CD4+ lymphocytes treated with a MoAb against HLA-A, B and C antigens (PA2.6) which blocks HLA class I-restricted killing. HLA class II-negative CD4+ T lymphoma cells (CEM.NKR) were also killed by anti-CD3 inhibited CTL. Stimulation of peripheral blood lymphocytes (PBL) from HIV-infected individuals, but not uninfected controls, with concanavalin A (Con A) and IL-2, induced non-HLA-restricted TCR alpha beta+, CD8+ CTL which lysed CD4+ lymphocytes. Activation of CD4+ lymphocytes increased their susceptibility to CD8+ CTL-mediated lysis. In HIV infection, a population of non-HLA-restricted CTL which lyse activated CD4+ lymphocytes is expanded. The expansion of CTL with unusual characteristics is interesting, because the stimulus for this expansion is unknown. CTL which recognize activated CD4+ cells could play a role in immune regulation and the pathogenesis of AIDS.

Changes in the cytotoxic T-cell repertoire of HIV-1-infected individuals: relationship to disease progression.

The repertoire of antigen-specific receptors expressed on T lymphocytes is shaped by fixed genetic and variable environmental selective pressures. Recent technological advances have enabled the analysis of T-cell receptor (TCR) expression in the context of selective pressures arising through normal immune system development and also through pathological features of disease. The pathological features of acquired immune deficiency syndrome (AIDS) are reflected by selective depletion of particular T lymphocyte subsets and expansion of others. An important question concerning the immunopathogenesis of AIDS is whether or not the perturbation of the CD4+ and CD8+ T-cell subsets following infection with human immunodeficiency virus (HIV) is selective based on TCR variable (V) region gene expression. To address this question, we have functionally analyzed TCR V gene expression on CD8+ cytotoxic T lymphocytes from HIV-1-infected individuals. This was done using monoclonal antibodies against individual TCR V regions to trigger redirected cytolysis in 51Cr release assays. The percent specific lysis induced by each antibody functionally measures the representation of the TCR V region gene product it is specific for. Relative to non-HIV-infected controls and asymptomatic HIV-infected individuals with only moderate CD4 lymphocyte depletion, HIV-infected individuals with low CD4 lymphocyte counts exhibited skewed patterns of TCR V region representation. Therefore, the perturbation within the CD8+ cytotoxic T lymphocyte repertoire in HIV infection appears to be selective based on TCR V region usage, increasingly so as disease progresses. The TCR V genes affected varied between different HIV-infected individuals and skewing detected in functional assays was not always apparent by flow cytometric analysis. These results suggest that HIV infection causes generalized effects on the T-cell repertoire, which are reflected in the relative TCR V gene representation of the CD8+ cytotoxic T lymphocyte population in peripheral blood.

The influence of lymphocyte counts and disease progression on circulating and inducible anti-HIV-1 cytotoxic T-cell activity in HIV-1-infected subjects.

OBJECTIVE: To evaluate specific anti-HIV cytotoxic T-lymphocyte (CTL) activity in relation to basic clinical and laboratory parameters used to follow HIV infection. METHODS: Lymphocytes from HIV-1-infected subjects with different clinical and immunologic features of HIV infection were tested for circulating and inducible anti-HIV CTL activity using autologous B-lymphoblastoid cells infected with recombinant vaccinia viruses expressing the HIV gag, pol and env genes as targets. Anti-HIV CTL were induced by stimulation with HIV-infected autologous lymphoblasts in vitro. RESULTS: We detected circulating anti-HIV CTL in asymptomatic subjects exclusively and found a significant association (P < 0.01) between CD8+ lymphocyte counts > or = 900/microliters blood and detectable levels of circulating anti-HIV CTL. Subjects with circulating anti-HIV CTL also had a higher mean CD8+ lymphocyte count than those without detectable circulating activity (P < 0.001), but there was no significant difference in mean CD4+ lymphocyte count. CD8+ human histocompatibility leukocyte antigen (HLA) class I-restricted anti-HIV CTL were induced in all HIV-infected subjects tested following stimulation with HIV-infected autologous lymphoblasts in vitro. In subjects without detectable circulating anti-HIV CTL, circulating HLA-DR+ cells contributed to anti-HIV CTL activity induced by stimulation with HIV or concanavalin A in vitro. CONCLUSIONS: Circulating anti-HIV CTL activity is associated with CD8+ lymphocyte counts > or = 900/microliters. Anti-HIV CTL retain proliferative and functional capacity following in vitro stimulation with HIV and interleukin-2 through all stages of HIV infection. Persistent inducible anti-HIV CTL activity in subjects with advanced HIV disease and without circulating CTL suggests impaired activation and/or proliferation of the CTL in vivo.

Subclavian vein catheterisation for haemodialysis.

Immediate access to the circulation for haemodialysis may be necessary in patients with acute renal failure or when end stage renal disease presents acutely. Vascular access may be required in patients treated by continuous ambulatory peritoneal dialysis if that technique is interrupted or, following failure of an arteriovenous fistula in patients on maintenance haemodialysis. Haemodialysis via a catheter in the subclavian vein meets these needs. Our experience with 67 patients over two years confirmed the safety and reliability of this means of access. Benefits included easy, rapid catheter placement, full patient mobility, allowing outpatient dialysis where appropriate, and the sparing of peripheral vessels for future access. With careful attention to technique by experienced personnel complications are largely preventable.