Marc Lipman

Protection by BCG Vaccine Against Tuberculosis: A Systematic Review of Randomized Controlled Trials

BACKGROUND Randomized trials assessing BCG vaccine protection against tuberculosis have widely varying results, for reasons that are not well understood. METHODS We examined associations of trial setting and design with BCG efficacy against pulmonary and miliary or meningeal tuberculosis by conducting a systematic review, meta-analyses, and meta-regression. RESULTS We identified 18 trials reporting pulmonary tuberculosis and 6 reporting miliary or meningeal tuberculosis. Univariable meta-regression indicated efficacy against pulmonary tuberculosis varied according to 3 characteristics. Protection appeared greatest in children stringently tuberculin tested, to try to exclude prior infection with Mycobacterium tuberculosis or sensitization to environmental mycobacteria (rate ratio [RR], 0.26; 95% confidence interval [CI], .18-.37), or infants (RR, 0.41; 95% CI, .29-.58). Protection was weaker in children not stringently tested (RR, 0.59; 95% CI, .35-1.01) and older individuals stringently or not stringently tested (RR, 0.88; 95% CI, .59-1.31 and RR, 0.81; 95% CI, .55-1.22, respectively). Protection was higher in trials further from the equator where environmental mycobacteria are less and with lower risk of diagnostic detection bias. These associations were attenuated in a multivariable model, but each had an independent effect. There was no evidence that efficacy was associated with BCG strain. Protection against meningeal and miliary tuberculosis was also high in infants (RR, 0.1; 95% CI, .01-.77) and children stringently tuberculin tested (RR, 0.08; 95% CI, .03-.25). CONCLUSIONS Absence of prior M. tuberculosis infection or sensitization with environmental mycobacteria is associated with higher efficacy of BCG against pulmonary tuberculosis and possibly against miliary and meningeal tuberculosis. Evaluations of new tuberculosis vaccines should account for the possibility that prior infection may mask or block their effects.

Outcome of HIV-associated tuberculosis in the era of highly active antiretroviral therapy

BACKGROUND The benefit of highly active antiretroviral therapy (HAART) in the treatment of patients coinfected with tuberculosis (TB) and human immunodeficiency virus (HIV) is unclear because of concerns about treatment-related complications. METHODS We compared outcomes in patients starting TB treatment during the pre-HAART era (before 1996; n=36) with those in patients starting treatment during the HAART era (during or after 1996; n=60). RESULTS During a median of 3.6 years of follow-up, 49 patients died or had an AIDS event. Compared with patients in the pre-HAART group, those in the HAART group had a lower risk of death (cumulative at 4 years, 43% vs. 22%; P=.012) and of death or having an AIDS event (69% vs. 43%; P=.023). Event risk within the first 2 months of TB treatment was exceptionally high in patients with CD4(+) cell counts <100 cells/mm(3) and declined thereafter. HAART use during follow-up was associated with a marked reduction in event risk (adjusted hazard ratio, 0.38 [95% confidence interval, 0.16-0.91]). CONCLUSIONS HAART substantially reduces new AIDS events and death in coinfected patients. Those with a CD4(+) cell count <100 cells/mm(3) have a high event risk during the intensive phase of anti-TB treatment. These data should be taken into account when deciding to delay HAART in coinfected patients with CD4(+) cell counts <100 cells/mm(3).

Increased numbers of primed activated CD8+CD38+CD45RO+ T cells predict the decline of CD4+ T cells in HIV-1-infected patients.

OBJECTIVE To look for surrogate markers in HIV-1 infection that can predict the decline of CD4+ T cells. METHODS Multiparameter flow cytometric analyses of CD8+ lymphocytes were performed. These cells were investigated for their expression of the activation marker CD38+ within the naive (CD45RA+) and primed (CD45RO+) subsets. Serial CD4 counts were plotted for each patient and the straight line that best fitted was obtained using least squares regression. Differences in rate of decline were tested using analysis of variance, after each patient was weighted by the reciprocal of the variance. RESULTS Baseline levels of percentages of CD8+CD38+ T lymphocytes predict the CD4 decline in HIV-1-infected patients. Within the CD8+ subset, the primed CD8+CD38+CD45RO+ population was responsible for this prediction. Conversely, the naive CD8+CD38+CD45RA+ population was not predictive. Patients who initially showed a percentage of CD8+CD38+ T lymphocytes above the median (> 25%) had a more marked decline in CD4+ T cells when compared to individuals with percentages of CD8+CD38+ T lymphocytes below the median value (79.3 and 21.2 x 10(6)/l mean CD4 cell decline per year, respectively). Similarly, percentages of CD8+CD38+CD45RO+ T cells above the median value (> 7%) were also associated with a more rapid decline (69.4 and 14.2 x 10(6)/l mean CD4+ cell decline per year). These results were statistically significant after adjustment for the baseline CD4 count and beta 2-microglobulin levels. CONCLUSIONS Percentages of activated CD8+ cells expressing CD38+ can predict the rate of decline (slope) of the CD4+ T cells. This resides in the CD45RO+ primed population. An early prediction of the CD4+ slope will allow the clinician to target treatment to those patients that are most likely to benefit.

MMP-1 drives immunopathology in human tuberculosis and transgenic mice

Mycobacterium tuberculosis can cause lung tissue damage to spread, but the mechanisms driving this immunopathology are poorly understood. The breakdown of lung matrix involves MMPs, which have a unique ability to degrade fibrillar collagens at neutral pH. To determine whether MMPs play a role in the immunopathology of tuberculosis (TB), we profiled MMPs and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs), in sputum and bronchoalveolar lavage fluid from patients with TB and symptomatic controls. MMP-1 concentrations were significantly increased in both HIV-negative and HIV-positive patients with TB, while TIMP concentrations were lower in HIV-negative TB patients. In primary human monocytes, M. tuberculosis infection selectively upregulated MMP1 gene expression and secretion, and Ro32-3555, a specific MMP inhibitor, suppressed M. tuberculosis-driven MMP-1 activity. Since the mouse MMP-1 ortholog is not expressed in the lung and mice infected with M. tuberculosis do not develop tissue destruction equivalent to humans, we infected transgenic mice expressing human MMP-1 with M. tuberculosis to investigate whether MMP-1 caused lung immunopathology. In the MMP-1 transgenic mice, M. tuberculosis infection increased MMP-1 expression, resulting in alveolar destruction in lung granulomas and significantly greater collagen breakdown. In summary, MMP-1 may drive tissue destruction in TB and represents a therapeutic target to limit immunopathology.

Immune reconstitution inflammatory syndrome in HIV.

Purpose of review The purpose of this review is to describe the epidemiology, clinical features, putative immune mechanisms and management of immune reconstitution inflammatory syndrome (IRIS) using data published in the last 2 years. Recent findings Ever more conditions are reported as IRIS events. These most frequently occur with mycobacterial (tuberculosis or Mycobacterium avium complex infection) or cryptococcal disease (each in approximately 30% of cases). Definitions have been proposed for its clinical diagnosis. These suffer from a lack of prospective studies to support their predictive value. The immunopathogenesis of IRIS appears to be related to the interaction between HAART-induced changes in host immune response and the presence of (usually microbial) antigen. Increasing evidence exists that this might be an anatomically compartmentalized phenomenon, such that immune responses may be localized to specific tissue sites such as the brain. This has implications for the use of simple blood tests, such as CD4 count or change in viral load, when assessing risk of IRIS. Treatment options include immune modulation, though supportive care is typically all that is required, unless symptoms are prolonged, significant or life-threatening. Summary IRIS is common and will become more so as HAART is rolled out worldwide. Clear clinical definitions are required to avoid its over-diagnosis due to misclassification of other conditions.

Detectable Changes in The Blood Transcriptome Are Present after Two Weeks of Antituberculosis Therapy

Rationale Globally there are approximately 9 million new active tuberculosis cases and 1.4 million deaths annually. Effective antituberculosis treatment monitoring is difficult as there are no existing biomarkers of poor adherence or inadequate treatment earlier than 2 months after treatment initiation. Inadequate treatment leads to worsening disease, disease transmission and drug resistance. Objectives To determine if blood transcriptional signatures change in response to antituberculosis treatment and could act as early biomarkers of a successful response. Methods Blood transcriptional profiles of untreated active tuberculosis patients in South Africa were analysed before, during (2 weeks and 2 months), at the end of (6 months) and after (12 months) antituberculosis treatment, and compared to individuals with latent tuberculosis. An active-tuberculosis transcriptional signature and a specific treatment-response transcriptional signature were derived. The specific treatment response transcriptional signature was tested in two independent cohorts. Two quantitative scoring algorithms were applied to measure the changes in the transcriptional response. The most significantly represented pathways were determined using Ingenuity Pathway Analysis. Results An active tuberculosis 664-transcript signature and a treatment specific 320-transcript signature significantly diminished after 2 weeks of treatment in all cohorts, and continued to diminish until 6 months. The transcriptional response to treatment could be individually measured in each patient. Conclusions Significant changes in the transcriptional signatures measured by blood tests were readily detectable just 2 weeks after treatment initiation. These findings suggest that blood transcriptional signatures could be used as early surrogate biomarkers of successful treatment response.

Deaths in the era of HAART: contribution of late presentation, treatment exposure, resistance and abnormal laboratory markers

Objectives:To describe the characteristics of deaths that occur among HIV-positive individuals in the HAART era. Design:Observational database. Methods:Deaths were reviewed that occurred among HIV-positive individuals seen at the Royal Free Hospital, London between January 1998 and December 2003. Results:Over the study period, there were 121 deaths; death rates declined from approximately 2.0/100 person-years of follow-up in 1998–2000 to approximately 1.0/100 person-years of follow-up in 2001–2003. Approximately one half of deaths (45.5%) were from AIDS-related causes and 74 deaths (61.2%) occurred in individuals who had received HAART: patients had been exposed to a median of seven (range 2–14) antiretroviral drugs and two-fifths had started treatment in the pre-HAART era. Another 15 patients had received only non-HAART treatment regimens prior to death. The median pre-death CD4 cell counts were 68 and 167 cells/μl among those who had and had not received HAART; 23 (31.1%) and 4 (8.5%) had HIV RNA < 400 copies/ml, respectively. Of the patients exposed to HAART for at least 6 months and who experienced viral rebound, information was available on resistance for 26 (21.5% of the total deaths) and 19 of those tested had at least one resistance mutation (median 5, range, 1–16). Conclusions:While mortality rates among HIV-infected individuals at our centre have fallen since 1988, the deaths that do now occur are more diverse and are the result of a number of factors, including late presentation, delayed uptake of HAART and the previous use of treatment combinations that are now viewed as suboptimal.

Does immune reconstitution syndrome promote active tuberculosis in patients receiving highly active antiretroviral therapy

Objectives:To assess whether highly active anti-retroviral therapy (HAART) contributes to the presentation of active tuberculosis (TB). Design:Retrospective single-centre cohort study. Methods:A total of 111 HIV-infected individuals with active TB were identified at an urban teaching hospital between February 1997 and April 2004. Those receiving HAART at the time of TB diagnosis were assessed. Results:Nineteen of 111 (17%) were receiving HAART when TB developed. Within this group there appeared to be two distinct populations. Thirteen of 19, 12 from ethnic or social groups with high background rates of TB, developed disease a median of 41 days (range, 7–109) after starting HAART (‘early TB’ group). In six of 19 (‘late TB’ group), TB occurred a median of 358 days after HAART initiation (range, 258–598). The ‘early TB’ group had lower CD4 cell counts when starting HAART in comparison with the ‘late TB’ group (median; 87 versus 218 × 106 cells/l; P = 0.04); however no difference was observed in the rate of change of CD4 cell count (P = 0.5) or HIV load. Paradoxical reaction rate in the ‘early TB’ group was significantly greater than in the ‘late-TB’ group (62 versus 0%, P = 0.02) and greater than in a similar control population who started HAART while taking anti-TB therapy (62 versus 30%, P = 0.05). Conclusions:These data suggest anti-HIV treatment may amplify the presentation of active TB. This has implications for antiretroviral programmes in countries with high TB rates and warrants prospective investigation of a larger cohort.

Treatment of Latent Tuberculosis Infection: A Network Meta-analysis

BACKGROUND Effective treatment of latent tuberculosis infection (LTBI) is an important component of TB elimination programs. Promising new regimens that may be more effective are being introduced. Because few regimens can be directly compared, network meta-analyses, which allow indirect comparisons to be made, strengthen conclusions. PURPOSE To determine the most efficacious regimen for preventing active TB with the lowest likelihood of adverse events to inform LTBI treatment policies. DATA SOURCES PubMed, EMBASE, and Web of Science up to 29 January 2014; clinical trial registries; and conference abstracts. STUDY SELECTION Randomized, controlled trials that evaluated LTBI treatment in humans and recorded at least 1 of 2 prespecified end points (preventing active TB or hepatotoxicity), without language or date restrictions. DATA EXTRACTION Data from eligible studies were independently extracted by 2 investigators according to a standard protocol. DATA SYNTHESIS Of the 1516 articles identified, 53 studies met the inclusion criteria. Data on 15 regimens were available; of 105 possible comparisons, 42 (40%) were compared directly. Compared with placebo, isoniazid for 6 months (odds ratio [OR], 0.64 [95% credible interval {CrI}, 0.48 to 0.83]) or 12 months or longer (OR, 0.52 [CrI, 0.41 to 0.66]), rifampicin for 3 to 4 months (OR, 0.41 [CrI, 0.18 to 0.86]), and rifampicin-isoniazid regimens for 3 to 4 months (OR, 0.52 [CrI, 0.34 to 0.79]) were efficacious within the network. LIMITATIONS The risk of bias was unclear for many studies across various domains. Evidence was sparse for some comparisons, particularly hepatotoxicity. CONCLUSION Comparison of different LTBI treatment regimens showed that various therapies containing rifamycins for 3 months or more were efficacious at preventing active TB, potentially more so than isoniazid alone. Regimens containing rifamycins may be effective alternatives to isoniazid monotherapy. PRIMARY FUNDING SOURCE None.

Purified Protein Derivative–Activated Type 1 Cytokine–Producing CD4+ T Lymphocytes in the Lung: A Characteristic Feature of Active Pulmonary and Nonpulmonary Tuberculosis

Because tuberculosis (TB) is primarily a pulmonary disease, we examined the cytokine responses of CD4(+) T lymphocytes in bronchoalveolar lavage (BAL) fluid after incubation with purified protein derivative (PPD) in human immunodeficiency virus-negative patients with TB and control subjects with nontuberculous respiratory disease. Parallel blood and BAL fluid samples from each subject were incubated with or without PPD, and the proportions of CD4(+) T lymphocytes producing interferon (IFN)-gamma or tumor necrosis factor (TNF)-alpha were measured by flow cytometry. The proportions of PPD-activated IFN-gamma- and TNF-alpha-producing CD4(+) cells were low among control subjects (median, 0.33% and 0.78%, respectively). By contrast, among patients with TB, strong IFN-gamma and TNF-alpha responses were demonstrated (median, 24.0% and 32.4%, respectively), regardless of whether the TB was pulmonary or nonpulmonary. Measurement of type 1 cytokine production by CD4(+) T lymphocytes in response to PPD in BAL fluid is a promising new diagnostic test for active TB in immunocompetent individuals.