Mortality of cytomegalovirus infection among people living with HIV: A retrospective study from a tertiary hospital in Indonesia.

BACKGROUND: There are still many patients newly diagnosed with HIV at an advanced stage in Indonesia. We aimed to identify factors associated with 1-year mortality among cytomegalovirus (CMV)-infected people living with HIV (PLHIV). METHODS: This retrospective cohort study was carried out at a tertiary-care hospital in Jakarta, Indonesia (January 2017 to December 2022). We included PLHIV with CMV end-organ disease (EOD) and CMV syndrome. The presence of CMV infection was confirmed by fulfilling one of the following criteria: (1) positive PCR from plasma, urine, cerebrospinal fluid, or other body fluids, or associated tissue for CMV EOD; (2) positive immunoglobulin M (IgM); or (3) consistent symptoms and signs of CMV retinitis. RESULTS: Out of 1737 PLHIV, 147 (8.5%, 95% CI: 7.2 to 9.9%) were diagnosed with CMV infection. Forty (27.2%, 95% CI: 20.6 to 35.1%) patients died within 1 year of being diagnosed. Only anti-retroviral therapy (ART) defaulting (aHR 3.31, 95% CI: 1.12 to 9.73) was found to be significantly associated with 1-year mortality in multivariate analysis. CONCLUSION: Defaulted ART status is significantly associated with reduced 1-year survival after CMV infection diagnosis. Patients with low CD4 counts, especially those with <50 cells/µL, should be assessed for CMV infection, monitored, and treated accordingly.

Multidisciplinary re-evaluation of neuropsychiatric events to confirm the neuropsychiatric lupus diagnosis at an Indonesian tertiary hospital.

OBJECTIVE: Neuropsychiatric SLE (NPSLE) has a broad spectrum and to date, there is no gold-standard biomarker. The diagnosis relies on clinical assessment, supporting examinations and exclusion of other possible aetiologies. One method that can be used to establish NPSLE is to conduct a re-evaluation by involving several fields of medical science. This study aims to reassess SLE cases with neuropsychiatric (NP) manifestations through multidisciplinary re-evaluation and determine the final diagnosis of NPSLE or non-NPSLE. METHODS: This retrospective cross-sectional study used medical record data from patients with SLE with NP manifestations. Inclusion criteria included patients diagnosed with SLE, who had clinical manifestations of NP and were >18 years old. Multidisciplinary re-evaluation was conducted and agreed upon the diagnosis of NPSLE or non-NPSLE. RESULTS: We included 94 subjects with a total of 132 NP events consisting of 69 NPSLE and 63 non-NPSLE. After re-evaluating NPSLE events, 33.3% were still concluded to be NPSLE. Meanwhile, from the non-NPSLE group, 22.2% were then declared as NPSLE. There were no significant differences in demographic characteristics between the NPSLE and non-NPSLE groups. The proportion of NP events in both groups was almost the same except for cerebrovascular disease manifestations which were more common in the NPSLE group. Higher Mexican SLE Disease Activity Index scores with (p<0.001) or without NP (p=0.02) were observed in the NPSLE group compared with the non-NPSLE group, as well as higher proportion of active disease (p=0.03), higher anti-double-stranded DNA titres (p<0.001) and lower values of C3 (p=0.018) and C4 (p=0.001). CONCLUSIONS: Multidisciplinary re-evaluation can be used as a method to confirm the diagnosis of NPSLE. There is a tendency for overdiagnosis of NPSLE when clinicians are faced with NP events in patients with SLE. Complete clinical and supporting data are needed to determine the final diagnosis of NPSLE.

Clinical presentation, management, and outcome of suspected central nervous system infections in Indonesia: a prospective cohort study.

BACKGROUND: Little is known about the etiology, clinical presentation, management, and outcome of central nervous system (CNS) infections in Indonesia, a country with a high burden of infectious diseases and a rising prevalence of HIV. METHODS: We included adult patients with suspected CNS infections at two referral hospitals in a prospective cohort between April 2019 and December 2021. Clinical, laboratory, and radiological assessments were standardized. We recorded initial and final diagnoses, treatments, and outcomes during 6 months of follow-up. RESULTS: Of 1051 patients screened, 793 were diagnosed with a CNS infection. Patients (median age 33 years, 62% male, 38% HIV-infected) presented a median of 14 days (IQR 7-30) after symptom onset, often with altered consciousness (63%), motor deficits (73%), and seizures (21%). Among HIV-uninfected patients, CNS tuberculosis (TB) was most common (60%), while viral (8%) and bacterial (4%) disease were uncommon. Among HIV-infected patients, cerebral toxoplasmosis (41%) was most common, followed by CNS TB (19%), neurosyphilis (15%), and cryptococcal meningitis (10%). A microbiologically confirmed diagnosis was achieved in 25% of cases, and initial diagnoses were revised in 46% of cases. In-hospital mortality was 30%, and at six months, 45% of patients had died, and 12% suffered from severe disability. Six-month mortality was associated with older age, HIV, and severe clinical, radiological and CSF markers at presentation. CONCLUSION: CNS infections in Indonesia are characterized by late presentation, severe disease, frequent HIV coinfection, low microbiological confirmation and high mortality. These findings highlight the need for earlier disease recognition, faster and more accurate diagnosis, and optimized treatment, coupled with wider efforts to improve the uptake of HIV services.

Effectiveness of transcranial direct current stimulation (tDCS) as adjunctive treatment for chronic headache in adults with clinically stable systemic lupus erythematosus (SHADE): a randomised double-blind multiarm sham controlled clinical trial.

BACKGROUND: Chronic headache is a 'silent' neuropsychiatric systemic lupus erythematosus symptom with heterogeneous prevalence, potentially reaching 54.4%. It may reduce quality of life by increasing the likelihood of depression and sleep disturbance. While pharmacotherapy remains the first-line treatment, the current management is still challenging and needs other non-invasive modalities. An effective, tolerable and disease-specific treatment modality including transcranial direct current stimulation (tDCS) is considered to reduce the frequency of chronic headaches, including in SLE. Until recently, there was no standard protocol for tDCS in treating headaches. METHODS AND ANALYSIS: SHADE is a single-centre randomised double-blind multiarm sham-controlled trial for adults with clinically stable SLE, chronic headaches and without history of traumatic brain injury, brain infection, stroke or brain tumour. Random allocation is conducted to 88 subjects into 3 treatment groups (administration at primary motor, primary sensory and dorsolateral prefrontal cortex) and control group in 1:1:1:1 ratio. The primary endpoint is reduced number of headache days after adjunctive tDCS. The secondary endpoints are reduced headache intensity, increased quality of life, increased sleep quality, decreased depression and reduced analgesics use. The outcome is measured monthly until 3-month postintervention using headache diary, 36-Item Short Form Survey, Chronic Headache Quality of Life Questionnaire, Pittsburgh Sleep Quality Index and Mini International Neuropsychiatry Interview version 10 (MINI ICD 10). Intention-to-treat analysis will be performed to determine the best tDCS electrode placement. ETHICS AND DISSEMINATION: Ethical approval had been obtained from the local Institutional Review Board of Faculty of Medicine Universitas Indonesia. Results will be published through scientific relevant peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05613582.

Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults.

BACKGROUND: Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and efficacy. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving HIV-positive adults (≥18 years of age) with tuberculous meningitis in Vietnam and Indonesia. Participants were randomly assigned to receive a 6-to-8-week tapering course of either dexamethasone or placebo in addition to 12 months of antituberculosis chemotherapy. The primary end point was death from any cause during the 12 months after randomization. RESULTS: A total of 520 adults were randomly assigned to receive either dexamethasone (263 participants) or placebo (257 participants). The median age was 36 years; 255 of 520 participants (49.0%) had never received antiretroviral therapy, and 251 of 484 participants (51.9%) with available data had a baseline CD4 count of 50 cells per cubic millimeter or less. Six participants withdrew from the trial, and five were lost to follow-up. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a subgroup that clearly benefited from dexamethasone. The incidence of secondary end-point events, including cases of immune reconstitution inflammatory syndrome during the first 6 months, was similar in the two trial groups. The numbers of participants with at least one serious adverse event were similar in the dexamethasone group (192 of 263 participants [73.0%]) and the placebo group (194 of 257 participants [75.5%]) (P = 0.52). CONCLUSIONS: Among HIV-positive adults with tuberculous meningitis, adjunctive dexamethasone, as compared with placebo, did not confer a benefit with respect to survival or any secondary end point. (Funded by the Wellcome Trust; ACT HIV ClinicalTrials.gov number, NCT03092817.).

Prognostic identifier of cerebrovascular complications in tuberculous meningitis: Meta-analysis.

INTRODUCTION: Cerebrovascular complications could occur in 15-57 % of patients with tuberculous meningitis (TBM). It is crucial to rapidly identify TBM patients who are at risk for stroke. This study aimed to find predictors of stroke in patients with TBM. METHODS: This systematic review and meta-analysis were done using literature searches through online databases up to April 30th, 2022. Three independent authors performed literature screening, data extraction, and critical appraisal of the studies. Eight studies involving 1535 samples were included. RESULTS: We analyzed data regarding demographic, comorbidity, clinical presentation, radiologic, and laboratory parameters. Overall, clinical presentation that showed outcome difference was found in patients with findings of vomiting (OR = 2.71, 95 % CI: 1.30-5.63), cranial nerve deficit (OR = 4.10, 95 % CI: 1.83-9.21), focal deficit (OR = 5.56, 95 % CI: 2.24-13.79), and altered consciousness (OR = 1.90, 95 % CI: 1.24-2.92). Some comorbidities showed significant differences such as diabetes mellitus (OR = 2.58, 95 % CI: 1.51-4.41), hypertension (OR = 5.73, 95 % CI: 3.36-9.77), ischemic heart disease (OR = 2.18, 95 % CI: 1.02-4.63), and smoking (OR = 2.65, 95 % CI: 1.22-5.77). Two radiological changes shown to have significantly higher proportions are hydrocephalus (OR = 2.50, 95 % CI: 1.74-3.58) and meningeal enhancements (OR = 3.99, 95 % CI: 1.73-9.20). CONCLUSION: Our analysis indicated that clinical presentations of vomiting, cranial nerve deficit, focal deficit, altered consciousness; comorbidity of diabetes mellitus, hypertension, smoking history, ischemic heart disease; and radiological findings of meningeal enhancement and hydrocephalus showed significant association with stroke incidence in tuberculous meningitis.

Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.

Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism. Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography-mass spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins. Results: CSF tryptophan was associated with 60-day mortality from TBM (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and -positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95% CI = 1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis. Conclusions: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy. Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).

Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.

Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism. Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography mass-spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins. Results: CSF tryptophan was associated with 60-day mortality from tuberculous meningitis (HR=1.16, 95%CI=1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and HIV-positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95%CI=1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis. Conclusion: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of mortality. These findings may reveal new targets for host-directed therapy. Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).

Encephalomyelitis associated with coronavirus disease 2019: a case report.

BACKGROUND: Despite a considerable number of articles regarding neurological manifestations associated with severe acute respiratory syndrome coronavirus 2 infection, reports on transverse myelitis and encephalitis are scarce. CASE PRESENTATION: We report a 35-year-old Asian Arab female presenting with longitudinally extensive transverse myelitis within 3 weeks after being diagnosed with mild coronavirus disease 2019 infection. Administration of high-dose methylprednisolone led to significant clinical improvement. However, 2 days after discharge, the patient was readmitted with encephalitis manifestations, consisting of fever and loss of consciousness, along with deterioration in myelitis symptoms. Severe acute respiratory syndrome coronavirus 2 antibody was detected in cerebrospinal fluid, but DNA of severe acute respiratory syndrome coronavirus 2 was not found. Clinical recovery was achieved after the administration of intravenous immunoglobulin. CONCLUSION: Longitudinally extensive transverse myelitis can be a neurological manifestation of coronavirus disease 2019 and can be followed by encephalomyelitis episodes. High-dose steroids and intravenous immunoglobulin as an immunomodulator are possible effective treatment options.

Neurological Disease Associated with Chikungunya in Indonesia.

Chikungunya virus (CHIKV) is recognized but rarely considered as a cause of central nervous system infection in endemic areas. A total of 244 patients with acute meningoencephalitis in Indonesia were retrospectively tested to identify whether any CHIKV infection was associated with neurological manifestations, especially in provinces known for CHIKV endemicity. Cerebrospinal fluid (CSF) and blood specimens were tested using CHIKV-specific real-time reverse transcription polymerase chain reaction and IgM ELISA, alongside a panel of neurotropic viruses. We report four cases of suspected or confirmed CHIKV-associated neurological disease, including CHIKV RNA detection in CSF of one patient and in acute serum of another, and CHIKV IgM in CSF of three patients and in serum of a fourth. In conclusion, CHIKV should be considered as a cause of neurologic disease in endemic areas and especially during outbreaks, in addition to the more common arboviral diseases such as dengue and Japanese encephalitis viruses.

Intractable singultus as an initial symptom of medulla oblongata tuberculoma: A rare case report.

Tuberculoma of medulla oblongata is a rare manifestation of central nervous system tuberculosis (CNS TB), which may manifest as intractable singultus as the initial symptom. It is almost impossible to obtain definite diagnosis through biopsy consider its location. Immediate thorough diagnostic workup is needed, and empirical treatment should be started. We report a case of medulla oblongata tuberculoma in an HIV-negative 38-year-old man with intractable singultus as one of the early symptoms. He was treated empirically with anti-tuberculosis therapy and his symptoms subsided within 2 weeks.

Evaluation of Retinal Structure and Optic Nerve Function Changes in Multiple Sclerosis: Longitudinal Study with 1-Year Follow-Up.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and demyelination of the central nervous system which often involves the optic nerve even though only 20% of the patients experience optic neuritis (ON). OBJECTIVE: This study aims to compare the retinal structure and optic nerve function between patients with MS and healthy controls (HCs), evaluate optic nerve alterations in MS over 1-year follow-up, and analyze its correlations with disease duration, number of relapses, degree of disability, and different subtypes. METHODS: This is a prospective cohort study involving 58 eyes of MS patients. Optic nerve function was evaluated with best-corrected visual acuity (BCVA), contrast sensitivity, and P100 latency, while the retinal structure was evaluated from the GCIPL and RNFL thickness measured with optical coherence tomography (OCT) and fundus photography. RESULTS: The MS group had lower BCVA (p=0.001), contrast sensitivity (p < 0.001), mean GCIPL thickness (p < 0.001), and mean RNFL thickness (p < 0.001) than HC. At 6 and 12 months of observations, GCIPL and RNFL (nasal quadrant) of MS patients decreased significantly (p=0.007 and p=0.004, respectively). Disease duration and the number of relapses correlated with delayed P100 latency (r = -0.61, p < 0.001 and r = -0.46, p=0.02). GCIPL and RNFL in the SPMS subtype were thinner than in RRMS. CONCLUSIONS: The retinal structure and optic nerve function of MS patients are worse than those of normal individuals. GCIPL and RNFL thinning occurs at 6 and 12 months but do not correlate with disease duration, the number of relapses, and degree of disability.

Validation of the Indonesian version of multiple sclerosis quality of life-54 (MSQOL-54 INA) questionnaire.

BACKGROUND: Quality of life assessment of patients with multiple sclerosis (MS) is not routinely performed in Indonesia due to the unavailability of the validated Indonesian version of a specific instrument. The objective of this study was to transculturally adapt and validate the Indonesian version of the MSQOL-54 (MSQOL-54 INA) questionnaire. METHODS: The transcultural adaptation was conducted by performing a standardized forward-backward method. Psychometric analysis was performed by assessing the reliability (Cronbach α), internal validation (item internal consistency and item discriminant validity), and external validation by measuring the correlation with a clinical factor such as EDSS and other demographic factors. RESULTS: Reliability test with Cronbach α showed good internal consistency (> 0.7) at each component, except for health perception (0.665) and social function (0.433). Construct validity using computation of correlation coefficient showed internal consistency in accordance with the original MSQOL-54 standard dimension, except for energy and role limitation due to emotional problems components. External validation with EDSS showed negative correlation on almost all components, except for sexual function, but both composite scores were statistically significant. CONCLUSION: MSQOL-54 INA questionnaire has good internal reliability and is proven to be valid and well-accepted by Indonesian MS patients. Therefore, it can be used by Indonesian clinicians for more comprehensive MS management.

Validity and Reliability of Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in Indonesia and the Correlation with Quality of Life.

INTRODUCTION: Multiple Sclerosis (MS) can affect cognitive function that might interfere with quality of life. Processing speed and memory are the most common area of cognitive impairment. Cognitive evaluation in daily practice is often difficult to be performed since it needs neuropsychological expert and is time-consuming. Brief International Cognitive Assessment for MS (BICAMS) is valid and practical for cognitive evaluation. This study aims to validate BICAMS in Indonesian MS patients and healthy controls (HC) and to analyse the effect of cognitive impairment on quality of life. METHODS: BICAMS, which composes Symbol Digits Modalities Test (SDMT), California Verbal Learning Test-Second Edition (CVLT-II), and Brief Visuospatial Memory Test-Revised (BVMT-R), was translated and cross-culturally adapted to Indonesian from the original BICAMS and then administered to 40 Indonesian MS patients and 66 HC matched by sex, age, and education. Test-retest reliability was performed on 16-MS patients and 42 HC. Quality of life was measured using Multiple Sclerosis Quality of Life (MSQOL-54) instrument. RESULTS: The SDMT, CVLT-II, and BVMT-R score in MS patients were significantly lower than those in HC (effect size, r: 0.61, 0.36, and 0.47, respectively). Test-retest reliability for all tests was satisfactory with correlation coefficient for SDMT, CVLT-II, and BVMT-R in MS subjects 0.86, 0.81, and 0.83, respectively. Using 5th percentile of HC score as cut-off, 15% MS subjects had impairment in one test, 27.5% in two tests, and 40% in three tests. BICAMS was moderately correlated with EDSS but was not correlated with disease duration and relapse rate. SDMT score correlated with physical function and physical and mental role limitation. CONCLUSION: BICAMS is valid and reliable for assessing cognitive function of Indonesia MS patients.

Neuromyelitis optic with positive Anti-AQP4 and Anti-SSA/Ro antibody.

Neuromyelitis Optic (NMO) is an inflammatory disorder involving central nervous system which often co-exists with other autoimmune diseases such as Sjögren's syndrome (SS). NMO manifestation could precede or follow SS, but the role of anti-SSA in the pathogenesis of NMO remains unclear. We present a case of NMO with anti-AQP4 anti-SSA antibody positive. A-44-year-old female presented with right side weakness. The symptoms began with numbness that improved spontaneously. She also complained pain and dry sensations on her eyes. Schirmer test on her left eye, antinuclear antibody (ANA) and anti-SSA antibody were positive. Cervical MRI revealed intramedullary lesion on T2-weighted-image at C2-C5 level. She was diagnosed as NMO with positive anti-AQP4 and probable SS. She received 1g methylprednisolone for 5 days proceeded with mycophenolic acid. One-year observation showed clinical improvement. Systemic autoantibodies must substansially be evaluated in NMO. Comprehensive diagnosis and providing appropriate immuno-suppressant might prevent further disability and relapse.

Proceedings of the Inaugural Strategy Meeting for the Establishment of a Southeast Asia Regional Therapeutic Plasma Exchange Consortium for Neurological Disorders.

In conjunction with the third regional Southeast Asian (SEA) therapeutic plasma exchange (TPE) conference in Kuala Lumpur, Malaysia, 25 clinicians and researchers from SEA and South Asian countries attended the inaugural strategy meeting for the establishment of a regional TPE consortium for neurological disorders. The primary objective was to establish regional collaboration to improve delivery of TPE services in SEA. A pre-meeting survey was conducted to gather insights on disease spectrum, contextual practice challenges, and the need for a regional TPE consensus. Challenges identified include limited healthcare funding in support of diagnostic workup, TPE therapy, as well as development of clinical infrastructure and expertise capacity building. There was favorable interest in developing a working plan contextualized to this region. Strategies to overcome challenges were discussed. This included the need for a comprehensive referral system and network of regional TPE centers suited to local needs, supported by innovative TPE delivery programs.

High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study).

Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. Trial registration: ISRCTN15668391 (17/06/2019).

Presentation, etiology, and outcome of brain infections in an Indonesian hospital: A cohort study.

BACKGROUND: Little detailed knowledge is available regarding the etiology and outcome of CNS infection, particularly in HIV-infected individuals, in low-resource settings. METHODS: From January 2015 to April 2016, we prospectively included all adults with suspected CNS infection in a referral hospital in Jakarta, Indonesia. Systematic screening included HIV testing, CSF examination, and neuroimaging. RESULTS: A total of 274 patients with suspected CNS infection (median age 26 years) presented after a median of 14 days with headache (77%), fever (78%), seizures (27%), or loss of consciousness (71%). HIV coinfection was common (54%), mostly newly diagnosed (30%) and advanced (median CD4 cell count 30/µL). Diagnosis was established in 167 participants (65%), including definite tuberculous meningitis (TBM) (n = 44), probable TBM (n = 48), cerebral toxoplasmosis (n = 48), cryptococcal meningitis (n = 14), herpes simplex virus/varicella-zoster virus/cytomegalovirus encephalitis (n = 10), cerebral lymphoma (n = 1), neurosyphilis (n = 1), and mucormycosis (n = 1). In-hospital mortality was 32%; 6-month mortality was 57%. The remaining survivors had either moderate or severe disability (36%) according to Glasgow Outcome Scale. CONCLUSION: In this setting, patients with CNS infections present late with severe disease and often associated with advanced HIV infection. Tuberculosis, toxoplasmosis, and cryptococcosis are common. High mortality and long-term morbidity underline the need for service improvements and further study.

Adjunctive dexamethasone for the treatment of HIV-infected adults with tuberculous meningitis (ACT HIV): Study protocol for a randomised controlled trial.

Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Co-infection with HIV increases the risk of developing TBM, complicates treatment, and substantially worsens outcome. Whether corticosteroids confer a survival benefit in HIV-infected patients with TBM remains uncertain. Hepatitis is the most common drug-induced serious adverse event associated with anti-tuberculosis treatment, occurring in 20% of HIV-infected patients. The suggested concentration thresholds for stopping anti-tuberculosis drugs are not evidence-based. This study aims to determine whether dexamethasone is a safe and effective addition to the first 6-8 weeks of anti-tuberculosis treatment of TBM in patients with HIV, and investigate alternative management strategies in a subset of patients who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy.  Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled multi-centre Phase III trial, comparing the effect of dexamethasone versus placebo on overall survival in HIV-infected patients with TBM, in addition to standard anti-tuberculosis and antiretroviral treatment. The trial will be set in two hospitals in Ho Chi Minh City, Vietnam, and two hospitals in Jakarta, Indonesia. The trial will enrol 520 HIV-infected adults. An ancillary study will perform a randomised comparison of three DILI management strategies with the aim of demonstrating which strategy results in the least interruption in rifampicin and isoniazid treatment. An identical ancillary study will also be performed in the linked randomised controlled trial of dexamethasone in HIV-uninfected adults with TBM stratified by LTA4H genotype (LAST ACT).  Discussion: Whether corticosteroids confer a survival benefit in HIV-infected patients remains uncertain, and the current evidence base for using corticosteroids in this context is limited. Interruptions in anti-tuberculosis chemotherapy is a risk factor for death from TBM. Alternative management strategies in DILI may allow the safe continuation of rifampicin and isoniazid therapy.