HIV-associated Tuberculous Meningitis Research Articles

Recently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy

After Mycobacterium tuberculosis (Mtb) infection, many effector T cells traffic to the lungs, but few become activated. Here we use an antigen receptor reporter mouse (Nur77-GFP) to identify recently activated CD4 T cells in the lungs. These Nur77-GFPHI cells contain expanded TCR clonotypes, have elevated expression of co-stimulatory genes such as Tnfrsf4/OX40, and are functionally more protective than Nur77-GFPLO cells. By contrast, Nur77-GFPLO cells express markers of terminal exhaustion and cytotoxicity, and the trafficking receptor S1pr5, associated with vascular localization. A short course of immunotherapy targeting OX40+ cells transiently expands CD4 T cell numbers and shifts their phenotype towards parenchymal protective cells. Moreover, OX40 agonist immunotherapy decreases the lung bacterial burden and extends host survival, offering an additive benefit to antibiotics. CD4 T cells from the cerebrospinal fluid of humans with HIV-associated tuberculous meningitis commonly express surface OX40 protein, while CD8 T cells do not. Our data thus propose OX40 as a marker of recently activated CD4 T cells at the infection site and a potential target for immunotherapy in tuberculosis.

1490. Predictors of Early Mortality in HIV-associated Tuberculous Meningitis

Abstract Background Tuberculous meningitis (TBM) mortality averages at 27% but may reach 70% in HIV co-infection. High MRC severity grade, lower cerebrospinal fluid (CSF) white blood cell count (WBC) count, low weight, low CD4 and low plasma sodium were linked to mortality in Vietnam. Prognostic factors in African adults with HIV-associated TBM are unknown. We sought to determine the baseline factors predictive of death in HIV-positive Ugandan adults with TBM. Methods We prospectively enrolled patients who received TBM treatment and were classified as definite, probable or possible TBM by the uniform case definition from January 2019 to March 2023 in two National Referral Hospitals in Uganda. Participants received standard quadruple TB and corticosteroid therapy. We assessed association between baseline clinical and CSF characteristics (WBC< 5, 5-100, >100 cells/µl), antiretroviral therapy (ART) status and 14-day mortality. Results In 261 participants, median age was 36 years, 46% were women, median CD4 count was 74 cells/µl. 27% had definite, 39% probable, and 34% possible TBM. 142 (54%) had baseline CSF WBC < 5, 50 (19%) had 5-100, and 69 (27%) had >100 cells/µl. Overall, 14-day mortality was 25.9%. Mortality was 73.6% in participants with CSF WBC count < 5, 7.5% in 5-100, and 18.9% in >100 cells/µl, p=0.0012. Factors associated with 14-day mortality were MRC severity grade, CSF WBC, CSF opening pressure (OP), CSF protein and glucose, CD4 count. ART status did not influence survival. The hazard of 14-day mortality was 4 times as high for those with CSF WBC < 5 cells/µl as for those with >100 cells/ µl (95%CI 1.47-11.5, P=0.004). However, on adjustment for Glasgow Coma Scale (GCS), CSF OP, glucose, and CD4 count the association was less significant (aHR, 2.93, 0.82-10.4, P=0.13). Conclusion 14-day mortality varied significantly by baseline CSF WBC group, being extremely high (73.6%) in those with a paucity of CSF inflammation (WBC < 5 cells/µl). Those with intermediate inflammation (CSF WBC 5-100 cells/µl) had lowest mortality in-line with the damage response framework parabola. The association with acellular CSF and mortality was ameliorated by adjustment for CD4 count. CSF inflammation is at predictor of mortality in HIV-associated TBM and CSF WBC-directed corticosteroid therapy needs further exploration. Disclosures All Authors: No reported disclosures

Safety and tolerability of adjunctive linezolid with high or standard dose rifampin for the treatment of adults with HIV-associated tuberculous meningitis in Uganda: preliminary findings from the ALTER trial (S25.003)

<h3>Objective:</h3> To analyze preliminary safety data from the <b>A</b>djunctive <b>L</b>inezolid for the <b>T</b>reatment of Tub<b>ER</b>culous Meningitis (ALTER) trial, a phase II trial of high or standard-dose rifampin with or without linezolid 1200 mg for the first 4 weeks of treatment on a backbone of isoniazid, pyrazinamide, and ethambutol. <h3>Background:</h3> Better treatments are needed for tuberculous meningitis (TBM), which leads to mortality in excess of 50%. Linezolid penetrates into cerebrospinal fluid and is effective against TB. Little is known about its use in often critically ill TBM patients. <h3>Design/Methods:</h3> Persons with HIV (PWH) with definite or suspected TBM were recruited from a rural hospital in southwestern Uganda. Participants were seen on day 2, weeks 1, 2, 4, 8, 12, 18, and 24 for symptom assessment, medication adherence, physical examination, visual testing, neuropathy screening, and/or safety labs. <h3>Results:</h3> Of 23 participants enrolled (52% women, mean age 37 years, 78% with moderate to severe TBM grade), 12 were allocated to linezolid. Median CD4 count was 150 cells/mm³, (IQR 81–331) and 7 were on anti-retroviral therapy (ART). Twelve serious adverse events (SAEs) occurred, 6 among those on linezolid. The six included, sepsis (n=2), aspiration pneumonia (n=1), ART-related Stevens-Johnson syndrome (n=1), dehydration (n=1), and hyponatremia (n=1). Seven participants died, 2 on linezolid. No SAE was determined to be related to linezolid. No participants required linezolid discontinuation or dose reduction. Three participants developed ≥grade 3 hyponatremia. No ≥grade 3 anemia, thrombocytopenia, or neutropenia occurred. Mild grade 1 or 2 neuropathy symptoms were reported, more commonly among linezolid recipients (55% versus 0%, p=0.025), but resolved after treatment ended. <h3>Conclusions:</h3> In this preliminary analysis, linezolid was generally safe and well tolerated in TBM patients. Data from the completed trial will increase the power to determine if linezolid is safe to use with high and standard dose rifampin in PWH and TBM. <b>Disclosure:</b> Dr. Kibengo has nothing to disclose. Dr. Kabarambi has nothing to disclose. Mr. Kafeero has nothing to disclose. Dr. Patrick has nothing to disclose. Dr. NAKIMBUGWE has nothing to disclose. Mr. Ssemaganda has nothing to disclose. Mr. Tayebwa has nothing to disclose. The institution of Dr. Nahid has received research support from NIH . The institution of Fiona Cresswell has received research support from Janssen. Dr. Chow has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Medicolegal consulting. The institution of Dr. Chow has received research support from NIH.

A Phase 2A Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid, With or Without Aspirin, for Human Immunodeficiency Virus-Associated Tuberculous Meningitis: The LASER-TBM Trial.

Drug regimens that include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in tuberculous meningitis (TBM). Safety data on their use in combination and in the context of human immunodeficiency virus (HIV) are needed to inform clinical trial design. We conducted a phase 2, open-label, parallel-design, randomized, controlled trial to assess the safety of high-dose rifampicin, linezolid, and high-dose aspirin in HIV-associated TBM. Participants were randomized (1.4:1:1) to 3 treatment arms (1, standard of care [SOC]; 2, SOC + additional rifampicin [up to 35 mg/kg/d] + linezolid 1200 mg/d reducing after 28 days to 600 mg/d; 3, as per arm 2 + aspirin 1000 mg/d) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. A total of 52 participants with HIV-associated TBM were randomized; 59% had mild disease (British Medical Research Council (MRC) grade 1) vs 39% (grade 2) vs 2% (grade 3). AESI or death occurred in 10 of 16 (63%; arm 3) vs 4 of 14 (29%; arm 2) vs 6 of 20 (30%; arm 1; P = .083). The cumulative proportion of AESI or death (Kaplan-Meier) demonstrated worse outcomes in arm 3 vs arm 1 (P = .04); however, only 1 event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) between arms. High-dose rifampicin and adjunctive linezolid can safely be added to the standard of care in HIV-associated TBM. Larger studies are required to determine whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit. NCT03927313.

Cognitive Impairment in Tuberculous Meningitis.

Cognitive impairment is reported as a common complication in adult tuberculous meningitis (TBM), yet few studies have systematically assessed the frequency and nature of impairment. Moreover, the impact of impairment on functioning and medication adherence has not been described. A cognitive test battery (10 measures assessing 7 cognitive domains) was administered to 34 participants with human immunodeficiency virus (HIV)-associated TBM 6 months after diagnosis. Cognitive performance was compared with that a comparator group of 66 people with HIV without a history of tuberculosis. A secondary comparison was made between participants with TBM and 26 participants with HIV 6 months after diagnosis of tuberculosis outside the central nervous system (CNS). Impact on functioning was evaluated, including through assessment of medication adherence. Of 34 participants with TBM, 16 (47%) had low performance on cognitive testing. Cognition was impaired across all domains. Global cognitive performance was significantly lower in participants with TBM than in people with HIV (mean T score, 41 vs 48, respectively; P < .001). These participants also had lower global cognition scores than those with non-CNS tuberculosis (mean global T score, 41 vs 46; P = .02). Functional outcomes were not significantly correlated with cognitive performance in the subgroup of participants in whom this was assessed (n = 19). Low cognitive performance following HIV-associated TBM is common. This effect is independent of, and additional to, effects of HIV and non-CNS tuberculosis disease. Further studies are needed to understand longer-term outcomes, clarify the association with treatment adherence, a key predictor of outcome in TBM, and develop context-specific tools to identify individuals with cognitive difficulties in order to improve outcomes in TBM.

Neurocognitive outcomes of HIV-associated tuberculous meningitis

Background: The toll of tuberculous meningitis (TBM) in both mortality and disability is considerable, but advancements in rehabilitation have the potential to improve the functional abilities and the quality of survivors’ lives. However, the typical phenotype of neurocognitive impairment in TBM survivors remains unstudied in HIV-predominant populations in sub-Saharan Africa. Methods: We tested 36 survivors of TBM in Uganda with a comprehensive battery of neurocognitive assessments at 8 and 24 weeks after diagnosis, and compared results to a representative cohort of HIV-uninfected Ugandans. Results: While participants had a broad range of impairments at eight weeks, there was marked improvement by 24 weeks, when a phenotype of impairment including deficits in motor functioning, verbal learning and memory, processing speed, and executive function emerged. These deficits were present despite good clinician-rated functional status. The majority (23/27, 85%) had evidence of moderate to severe depression at week 8, and at week 24 (18/24, 75%). Conclusion: These findings highlight the need for more comprehensive neurocognitive assessment in the survivors of TBM, and further investment in and study of rehabilitation, including management of depression, to improve long-term outcomes in this population.

Differences in cytokine and chemokine profiles in cerebrospinal fluid caused by the etiology of cryptococcal meningitis and tuberculous meningitis in HIV patients.

The roles of cytokines and chemokines in HIV-associated cryptococcal meningitis (HCM) and HIV-associated tuberculous meningitis (HTBM) are debatable. In sum, 34 HIV-infected patients without meningitis, 44 HCM patients and 27 HTBM patients were enrolled for study. The concentrations of 22 cytokines/chemokines in cerebrospinal fluid (CSF) were assayed at admission. Principal component analysis (PCA), Pearson's and logistic regression analyses were used to assess the role of cytokines/chemokines in HCM and HTBM. We found the levels of T helper (Th)17, Th1 [interleukin (IL)-12p40, interferon (IFN)-γ, tumor necrosis factor (TNF)-α and TNF-β and Th2 (IL-2/4/5/6/10)] cytokines were elevated in patients with meningitis compared with those in HIV-infected patients without central nervous system (CNS) infection. Furthermore, the IL-1Ra, IL-12p40, IL-17α and monocyte chemotactic protein-1 (MCP-1) levels were higher in HCM patients, while the IFN-γ, regulated upon activation, normal T cell expressed and secreted (RANTES) and interferon-inducible protein-10 (IP)-10 levels were higher in HTBM patients. Elevated CSF concentrations of IL-17a, TNF-β, IL-5, IL-12p40 and IL-1Rα were closely related to meningitis, but elevated IP-10, MCP-1, RANTES and IFN-γ levels and CSF white blood cells (WBCs) were protective factors against HCM. Our study suggested that HIV-infected patients with low CSF WBCs have a high risk of HCM. Th1, Th2 and Th17 cytokines/chemokines mediate differences in the pathogenesis of HCM and TBM. Overexpressed proinflammatory MCP-1, RANTES, IFN-γ and IP-10 in CSF are protective factors against HCM but not HTBM.

Study protocol for a phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis [LASER-TBM

Background: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM. Methods: In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM. Clinicaltrials.gov registration: NCT03927313 (25/04/2019)

Study protocol for a phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis [LASER-TBM

Background: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM. Methods: In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM. Clinicaltrials.gov registration: NCT03927313 (25/04/2019).

Cerebrospinal Fluid Bacillary Load by Xpert MTB/RIF Ultra Polymerase Chain Reaction Cycle Threshold Value Predicts 2-Week Mortality in Human Immunodeficiency Virus-Associated Tuberculous Meningitis.

BackgroundThe World Health Organization recommends GeneXpert MTB/RIF Ultra (Xpert Ultra), a fully automated polymerase chain reaction (PCR) assay, as the initial tuberculous meningitis (TBM) diagnostic test. The assay’s PCR cycle threshold (Ct) values represent the number of PCR cycles required for probe signal to be detected (low Ct value = high bacillary load) and may approximate tuberculosis (TB) bacillary load. We measured the relationship between cerebrospinal fluid (CSF) TB bacillary load with mortality. MethodsWe prospectively enrolled 102 human immunodeficiency virus (HIV)–positive Ugandans with probable or definite TBM from April 2015 to August 2019. Xpert Ultra Ct tertiles and semi-quantitative categories were separately analyzed as predictors of 2-week mortality. We investigated associations between Ct and baseline clinical and CSF parameters. ResultsSubjects with Ct values in the low tertile (ie, high bacillary load) had 57% 2-week mortality—worse than the intermediate (17%) and high (25%) Ct tertiles and Xpert Ultra–negative (30%) probable TBM cases (P = .01). In contrast, the reported semi-quantitative Xpert Ultra categorization was less precise; with the medium to low category trending toward worse 2-week survival (42%) compared with very low (28%), trace (26%), and negative (30%) categories (P = .48). Ct tertile was significantly associated with baseline CSF lactate (P = .03). ConclusionsHigh CSF TB bacillary load, as measured by Xpert Ultra Ct tertile, is associated with an almost 2-fold higher 2-week mortality in HIV-associated TBM and is a better predictor than the reported Xpert Ultra semi-quantitative category. Xpert Ultra Ct values could identify TBM patients at increased risk of death who may benefit from enhanced supportive care.

Diagnostic tests for tuberculous meningitis

Tuberculous meningitis is the most serious manifestation of tuberculosis, with mortality in approximately 50% of HIV co-infected people. 1 Marais S Pepper DJ Schutz C Wilkinson RJ Meintjes G Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting. PLoS One. 2011; 6e20077 Crossref PubMed Scopus (69) Google Scholar A major factor contributing to the poor outcome of tuberculous meningitis is delayed diagnosis due to a lack of rapid, accurate diagnostic tests. Until recently, these tests were restricted to smear microscopy of cerebrospinal fluid (CSF) and microbiological culture. The former tends operationally to be of low sensitivity and the latter often renders a result too late to be clinically meaningful. The diagnosis of drug-resistant disease presents further difficulties. Xpert MTB/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: a prospective validation studyXpert Ultra detected tuberculous meningitis with higher sensitivity than Xpert and MGIT culture in this HIV-positive population. However, with a negative predictive value of 93%, Xpert Ultra cannot be used as a rule-out test. Clinical judgment and novel highly sensitive point-of-care tests are still required. Full-Text PDF Open AccessXpert MTB/RIF Ultra versus Xpert MTB/RIF for the diagnosis of tuberculous meningitis: a prospective, randomised, diagnostic accuracy studyXpert Ultra was not statistically superior to Xpert for the diagnosis of tuberculous meningitis in HIV-uninfected and HIV-infected adults. A negative Xpert Ultra or Xpert test does not rule out tuberculous meningitis. New diagnostic strategies are urgently required. Full-Text PDF Open Access

Xpert MTB/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: a prospective validation study

SummaryIntroductionTuberculous meningitis accounts for 1–5% of tuberculosis cases. Diagnostic delay contributes to poor outcomes. We evaluated the performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis diagnosis.MethodsIn this prospective validation study, we tested the cerebrospinal fluid (CSF) of adults presenting with suspected meningitis (ie, headache or altered mental status with clinical signs of meningism) to the Mulago National Referral Hospital and Mbarara Regional Referral Hospital in Uganda. We centrifuged the CSF, resuspended the cell pellet in 2 mL CSF, and tested 0·5 mL aliquots with Xpert Ultra, Xpert MTB/RIF (Xpert), and mycobacterial growth indicator tube (MGIT) culture. We quantified diagnostic performance against the uniform case definition of probable or definite tuberculous meningitis and a composite microbiological reference standard.FindingsFrom Nov 25, 2016, to Jan 24, 2019, we screened 466 adults with suspected meningitis and tested 204 for tuberculous meningitis. Uniform clinical case definition classified 51 participants as having probable or definite tuberculous meningitis. Against this uniform case definition, Xpert Ultra had 76·5% sensitivity (95% CI 62·5–87·2; 39 of 51 patients) and a negative predictive value of 92·7% (87·6–96·2; 153 of 165), compared with 55·6% sensitivity (44·0–70·4; 25 of 45; p=0·0010) and a negative predictive value of 85·8% (78·9–91·1; 121 of 141) for Xpert and 61·4% sensitivity (45·5–75·6; 27 of 44; p=0·020) and negative predictive value of 85·2% (77·4–91·1; 98 of 115) for MGIT culture. Against the composite microbiological reference standard, Xpert Ultra had sensitivity of 92·9% (80·5–98·5; 39 of 42), higher than Xpert at 65·8% (48·6–80·4; 25 of 38; p=0·0063) and MGIT culture at 72·2% (55·9–86·2; 27 of 37; p=0·092). Xpert Ultra detected nine tuberculous meningitis cases missed by Xpert and MGIT culture.InterpretationXpert Ultra detected tuberculous meningitis with higher sensitivity than Xpert and MGIT culture in this HIV-positive population. However, with a negative predictive value of 93%, Xpert Ultra cannot be used as a rule-out test. Clinical judgment and novel highly sensitive point-of-care tests are still required.FundingWellcome Trust, National Institute of Health, National Institute of Neurologic Diseases and Stroke, Fogarty International Center, and National Institute of Allergy and Infectious Diseases.

Pattern of Anti-Tuberculosis Drug Resistance in HIV-Associated Tuberculous Meningitis Patients

Multidrug-resistant tuberculosis (MDR-TB) is a major public health problem worldwide. Human immunodeficiency virus (HIV) infection-associated tuberculous meningitis (TBM) further complicates the patient management and causes poor prognosis. A cross-sectional study was carried out to determine anti-TB drug susceptibility pattern of Mycobacterium tuberculosis (MTB) isolates from HIV-associated TBM patients at Waibagi, Thakayta and Mingaladon Specialist Hospitals in Yangon, Myanmar. From January to October 2017, cerebrospinal fluid (CSF) specimens collected from 140 HIV infected patients with clinically presumptive TBM were applied for isolation and drug susceptibility testing. First-line drug susceptibility testing were carried out by solid culture-based proportion method. Drug susceptibility patterns of pyrazinamide, fluoroquinolones and second-line injectable drugs were determined by liquid culture-based Mycobacterial Growth Indicator Tube method. There were 17 culture positives and confirmed as MTB out of 140 specimens. Among them,10 isolates (58.8%) were resistant to at least one of the first-line anti-TB drugs. Eight isolates (47.1%) showed multidrug resistance but there was no extensively drug resistance. HIV-associated TBM patients with previous anti-TB treatment history and CD4 cell count of less than 100 cells/μl were significantly more prone to develop drug resistance. These findings highlight burdens of anti-TB drug resistance among HIVassociated TBM patients and support the need of elaborative management strategies.

Xpert Ultra and TB meningitis: advancing towards policy revision?

Tuberculous meningitis (TBM) is a devastating condition with high mortality and survivors are often left with severe neurological sequelae. HIV-associated TBM can have mortality rates exceeding 60% (1). Early diagnosis and initiation of treatment is critical for survival. Unfortunately the diagnosis of TBM can be more of an art than a science, as a recent report in the Lancet by Bahr and colleagues highlights. There is currently no diagnostic test with high sensitivity and specificity.

Adding Streptomycin to an Intensified Regimen for Tuberculous Meningitis Improves Survival in HIV-Infected Patients.

In low- and middle-income countries, the mortality of HIV-associated tuberculous meningitis (TM) continues to be unacceptably high. In this observational study of 228 HIV-infected patients with TM, we compared the mortality during the first nine months of patients treated with standard antituberculosis therapy (sATT), intensified ATT (iATT), and iATT with streptomycin (iATT + STM). The iATT included levofloxacin, ethionamide, pyrazinamide, and double dosing of rifampicin and isoniazid and was given only during the hospital admission (median 7 days, interquartile range 6–9). No mortality differences were seen in patients receiving the sATT and the iATT. However, patients receiving the iATT + STM had significant lower mortality than those in the sATT group (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.24 to 0.93). After adjusting for other covariates, the mortality hazard of the iATT + STM versus the sATT remained statistically significant (adjusted HR 0.2, 95% CI 0.09 to 0.46). Other factors associated with mortality were previous ATT and low albumin concentrations. The mortality risk increased exponentially only with CD4+ lymphocyte concentrations below 100 cells/μL. In conclusion, the use of iATT resulted in a clinically important reduction in mortality compared with the standard of care only if associated with STM. The results of this study deserve further research.

The diagnosis and medical management of tuberculous meningitis in adults

Tuberculous meningitis (TBM) is a medical emergency for which tuberculosis (TB) treatment should be initiated as soon as possible after diagnosis. Owing to the low diagnostic yields of confirmatory tests, TBM is often diagnosed based on suggestive clinical and cerebrospinal fluid findings, evidence for TB outside the central nervous system (CNS), typical brain imaging features and exclusion of other causes of meningitis. TB drug regimens used in TBM may be suboptimal as they are informed by studies of TB outside the CNS, rather than being based on randomised controlled trials in TBM. TBM has a high mortality and the management of HIV-co-infected patients is further complicated by neurological TB-immune reconstitution inflammatory syndrome (IRIS), which frequently occurs after starting antiretroviral therapy (ART) during TBM treatment and contributes to the poor outcome in HIV-associated TBM. HIV-infected TBM patients due to start ART should be counselled about the risk of developing neurological TB-IRIS, typical symptoms that could be expected and need to return to hospital should any of these develop. Currently, the only evidence-based treatment for TB-IRIS is with corticosteroids, which should be considered in all cases of neurological TB-IRIS.

Advances in the diagnosis and treatment of tuberculous meningitis

Early diagnosis and treatment of tuberculous meningitis (TBM) saves lives, but current laboratory diagnostic tests lack sensitivity and the best treatment regimens are uncertain. This article reviews the advances towards better TBM diagnosis and treatments made over the last 2 years. A modified Ziehl-Neelsen stain, interferon-gamma release assays and Mycobacterium tuberculosis antigen detection assays have all shown promise as new TBM diagnostic tests. HIV-associated TBM carries an especially grave prognosis and there are new data describing the optimal timing of antiretroviral treatment initiation and the clinical predictors of TBM immune reconstitution inflammatory syndrome. The pharmacokinetic and pharmacodynamic properties of different fluoroquinolones for TBM treatment have been compared, and there are intriguing new data to suggest higher doses of rifampicin given intravenously may improve the survival. Finally, there are preliminary data to suggest that the beneficial effect of adjunctive corticosteroids on TBM survival may be augmented by aspirin and predicted by a polymorphism in a gene responsible for eicosanoid synthesis. Much remains to be done to improve the outcome from TBM. There have been important advances in the treatment, which may influence treatment guidelines in the near future, but there remains an urgent need for better diagnostic tests.

Frequency, Severity, and Prediction of Tuberculous Meningitis Immune Reconstitution Inflammatory Syndrome

Tuberculosis immune reconstitution inflammatory syndrome (IRIS) is a common cause of deterioration in human immunodeficiency virus (HIV)-infected patients receiving tuberculosis treatment after starting antiretroviral therapy (ART). Potentially life-threatening neurological involvement occurs frequently and has been suggested as a reason to defer ART. We conducted a prospective study of HIV-infected, ART-naive patients with tuberculous meningitis (TBM). At presentation, patients started tuberculosis treatment and prednisone; ART was initiated 2 weeks later. Clinical and laboratory findings were compared between patients who developed TBM-IRIS (TBM-IRIS patients) and those who did not (non-TBM-IRIS patients). A logistic regression model was developed to predict TBM-IRIS. Forty-seven percent (16/34) of TBM patients developed TBM-IRIS, which manifested with severe features of inflammation. At TBM diagnosis, TBM-IRIS patients had higher cerebrospinal fluid (CSF) neutrophil counts compared with non-TBM-IRIS patients (median, 50 vs 3 cells ×10(6)/L, P = .02). Mycobacterium tuberculosis was cultured from CSF of 15 TBM-IRIS patients (94%) compared with 6 non-TBM-IRIS patients (33%) at time of TBM diagnosis; relative risk of developing TBM-IRIS if CSF was Mycobacterium tuberculosis culture positive = 9.3 (95% confidence interval [CI], 1.4-62.2). The combination of high CSF tumor necrosis factor (TNF)-α and low interferon (IFN)-γ at TBM diagnosis predicted TBM-IRIS (area under the curve = 0.91 [95% CI, .53-.99]). TBM-IRIS is a frequent, severe complication of ART in HIV-associated TBM and is characterized by high CSF neutrophil counts and Mycobacterium tuberculosis culture positivity at TBM presentation. The combination of CSF IFN-γ and TNF-α concentrations may predict TBM-IRIS and thereby be a means to individualize patients to early or deferred ART.

Hiv-1 Drug Resistance in Antiretroviral-Naive Individuals with H I V-1-Associated Tuberculous Meningitis Initiating Antiretroviral Therapy in Vietnam

Access to antiretroviral therapy (ART) for HIV-infected individuals in Vietnam is rapidly expanding, but there are limited data on HIV drug resistance (HIVDR) to guide ART strategies. We retrospectively conducted HIVDR testing in 220 ART-naive individuals recruited to a randomized controlled trial of immediate versus deferred ART in individuals with HIV-associated tuberculous meningitis in Ho Chi Minh City (HCMC) from 2005-2008. HIVDR mutations were identified by population sequencing of the HIV pol gene and were defined based on 2009 WHO surveillance drug resistance mutations (SDRMs). We successfully sequenced 219/220 plasma samples of subjects prior to ART; 218 were subtype CRF01_AE and 1 was subtype B. SDRMs were identified in 14/219 (6.4%) subjects; 8/14 were resistant to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs; T69D, L74V, V75M, M184V/I and K219R), 5/14 to non-nucleoside reverse transcriptase inhibitors (NNRTIs; K103N, V106M, Y181C, Y188C and G190A), 1/14 to both NRTIs and NNRTIs (D67N and Y181C) and none to protease inhibitors. After 6 months of ART, eight subjects developed protocol-defined virological failure. HIVDR mutations were identified in 5/8 subjects. All five had mutations with high-level resistance to NNRTIs and three had mutations with high-level resistance to NRTIs. Due to a high early mortality rate (58%), the effect of pre-existing HIVDR mutations on treatment outcome could not be accurately assessed. The prevalence of WHO SDRMs in ART-naive individuals with HIV-associated tuberculous meningitis in HCMC from 2005-2008 is 6.4%. The SDRMs identified conferred resistance to NRTIs and/or NNRTIs, reflecting the standard first-line ART regimens in Vietnam.

Influence of Antituberculosis Drug Resistance and Mycobacterium tuberculosis Lineage on Outcome in HIV-Associated Tuberculous Meningitis

HIV-associated tuberculous meningitis (TBM) has high mortality. Aside from the devastating impact of multidrug resistance (MDR) on survival, little is understood about the influence of other bacterial factors on outcome. This study examined the influence of Mycobacterium tuberculosis drug resistance, bacterial lineage, and host vaccination status on outcome in patients with HIV-associated TBM. Mycobacterium tuberculosis isolates from the cerebrospinal fluid of 186 patients enrolled in two studies of HIV-associated TBM in Ho Chi Minh City, Vietnam, were tested for resistance to first-line antituberculosis drugs. Lineage genotyping was available for 122 patients. The influence of antituberculosis drug resistance and M. tuberculosis lineage on 9-month mortality was analyzed using Kaplan-Meier survival analysis and Cox multiple regression models. Isoniazid (INH) resistance without rifampin resistance was associated with increased mortality (adjusted hazard ratio [HR], 1.78, 95% confidence interval [CI], 1.18 to 2.66; P = 0.005), and multidrug resistance was uniformly fatal (n = 8/8; adjusted HR, 5.21, 95% CI, 2.38 to 11.42; P < 0.0001). The hazard ratio for INH-resistant cases was greatest during the continuation phase of treatment (after 3 months; HR, 5.05 [95% CI, 2.23 to 11.44]; P = 0.0001). Among drug-susceptible cases, patients infected with the "modern" Beijing lineage strains had lower mortality than patients infected with the "ancient" Indo-Oceanic lineage (HR, 0.29 [95% CI, 0.14 to 0.61]; P = 0.001). Isoniazid resistance, multidrug resistance, and M. tuberculosis lineage are important determinants of mortality in patients with HIV-associated TBM. Interventions which target these factors may help reduce the unacceptably high mortality in patients with TBM.