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1.
Trials ; 25(1): 311, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38720383

RESUMEN

BACKGROUND: HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. METHODS: This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. DISCUSSION: Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986.


Asunto(s)
Infecciones por VIH , Hospitalización , Levofloxacino , Rifampin , Tuberculosis , Humanos , Rifampin/uso terapéutico , Rifampin/administración & dosificación , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Tuberculosis/tratamiento farmacológico , Tuberculosis/diagnóstico , Tuberculosis/mortalidad , Levofloxacino/uso terapéutico , Resultado del Tratamiento , Ensayos Clínicos Fase III como Asunto , Antituberculosos/uso terapéutico , Antituberculosos/efectos adversos , Estudios de Equivalencia como Asunto , Quimioterapia Combinada , Prednisona/uso terapéutico , Prednisona/administración & dosificación , Prednisona/efectos adversos , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/mortalidad , Infecciones Oportunistas Relacionadas con el SIDA/microbiología , Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Factores de Tiempo
2.
Open Forum Infect Dis ; 11(4): ofae146, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38628951

RESUMEN

Background: The performance of chest x-ray (CXR) features for Pneumocystis pneumonia (PCP) diagnosis has been evaluated in small studies. We conducted a systematic review and meta-analysis to describe CXR changes in adults with HIV-associated laboratory-confirmed PCP, comparing these with non-PCP respiratory disease. Methods: We searched databases for studies reporting CXR changes in people >15 years old with HIV and laboratory-confirmed PCP and those with non-PCP respiratory disease. CXR features were grouped using consensus terms. Proportions were pooled and odds ratios (ORs) generated using random-effects meta-analysis, with subgroup analyses by CD4 count, study period, radiology review method, and study region. Results: Fifty-one studies (with 1821 PCP and 1052 non-PCP cases) were included. Interstitial infiltrate (59%; 95% CI, 52%-66%; 36 studies, n = 1380; I2 = 85%) and ground-glass opacification (48%; 95% CI, 15%-83%; 4 studies, n = 57; I2 = 86%) were common in PCP. Cystic lesions, central lymphadenopathy, and pneumothorax were infrequent. Pleural effusion was rare in PCP (0%; 95% CI, 0%-2%). Interstitial infiltrate (OR, 2.3; 95% CI, 1.4-3.9; I2 = 60%), interstitial-alveolar infiltrate (OR, 10.2; 95% CI, 3.2-32.4; I2 = 0%), and diffuse CXR changes (OR, 7.3; 95% CI, 2.7-20.2; I2 = 87%) were associated with PCP diagnosis. There was loss of association with alveolar infiltrate in African studies. Conclusions: Diffuse CXR changes and interstitial-alveolar infiltrates indicate a higher likelihood of PCP. Pleural effusion, lymphadenopathy, and focal alveolar infiltrates suggest alternative causes. These findings could be incorporated into clinical algorithms to improve diagnosis of HIV-associated PCP.

3.
J Infect Dis ; 229(4): 1200-1208, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-37740554

RESUMEN

BACKGROUND: Linezolid is evaluated in novel treatment regimens for tuberculous meningitis (TBM). Linezolid pharmacokinetics have not been characterized in this population, particularly in cerebrospinal fluid (CSF), as well as, following its co-administration with high-dose rifampicin. We aimed to characterize linezolid plasma and CSF pharmacokinetics in adults with TBM. METHODS: In the LASER-TBM pharmacokinetic substudy, the intervention groups received high-dose rifampicin (35 mg/kg) plus 1200 mg/day of linezolid for 28 days, which was then reduced to 600 mg/day. Plasma sampling was done on day 3 (intensive) and day 28 (sparse). A lumbar CSF sample was obtained on both visits. RESULTS: Thirty participants contributed 247 plasma and 28 CSF observations. Their median age and weight were 40 years (range, 27-56) and 58 kg (range, 30-96). Plasma pharmacokinetics was described by a 1-compartment model with first-order absorption and saturable elimination. Maximal clearance was 7.25 L/h, and the Michaelis-Menten constant was 27.2 mg/L. Rifampicin cotreatment duration did not affect linezolid pharmacokinetics. CSF-plasma partitioning correlated with CSF total protein up to 1.2 g/L, where the partition coefficient reached a maximal value of 37%. The plasma-CSF equilibration half-life was ∼3.5 hours. CONCLUSIONS: Linezolid was readily detected in CSF despite high-dose rifampicin coadministration. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults. Clinical Trials Registration. ClinicalTrials.gov (NCT03927313).


Asunto(s)
Rifampin , Tuberculosis Meníngea , Adulto , Humanos , Linezolid/uso terapéutico , Tuberculosis Meníngea/tratamiento farmacológico , Líquido Cefalorraquídeo
4.
Clin Infect Dis ; 78(2): 269-276, 2024 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-37874928

RESUMEN

BACKGROUND: Emerging resistance to bedaquiline (BDQ) threatens to undermine advances in the treatment of drug-resistant tuberculosis (DRTB). Characterizing serial Mycobacterium tuberculosis (Mtb) isolates collected during BDQ-based treatment can provide insights into the etiologies of BDQ resistance in this important group of DRTB patients. METHODS: We measured mycobacteria growth indicator tube (MGIT)-based BDQ minimum inhibitory concentrations (MICs) of Mtb isolates collected from 195 individuals with no prior BDQ exposure who were receiving BDQ-based treatment for DRTB. We conducted whole-genome sequencing on serial Mtb isolates from all participants who had any isolate with a BDQ MIC >1 collected before or after starting treatment (95 total Mtb isolates from 24 participants). RESULTS: Sixteen of 24 participants had BDQ-resistant TB (MGIT MIC ≥4 µg/mL) and 8 had BDQ-intermediate infections (MGIT MIC = 2 µg/mL). Participants with pre-existing resistance outnumbered those with resistance acquired during treatment, and 8 of 24 participants had polyclonal infections. BDQ resistance was observed across multiple Mtb strain types and involved a diverse catalog of mmpR5 (Rv0678) mutations, but no mutations in atpE or pepQ. Nine pairs of participants shared genetically similar isolates separated by <5 single nucleotide polymorphisms, concerning for potential transmitted BDQ resistance. CONCLUSIONS: BDQ-resistant TB can arise via multiple, overlapping processes, including transmission of strains with pre-existing resistance. Capturing the within-host diversity of these infections could potentially improve clinical diagnosis, population-level surveillance, and molecular diagnostic test development.


Asunto(s)
Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis , Humanos , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Diarilquinolinas/farmacología , Diarilquinolinas/uso terapéutico , Tuberculosis/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Genotipo , Fenotipo , Pruebas de Sensibilidad Microbiana
5.
Curr HIV/AIDS Rep ; 20(6): 379-393, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37947980

RESUMEN

PURPOSE OF REVIEW: Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Inadequate diagnostic testing and treatment regimens adapted from pulmonary tuberculosis without consideration of the unique nature of TBM are among the potential drivers. This review focuses on the progress being made in relation to both diagnosis and treatment of TBM, emphasizing promising future directions. RECENT FINDINGS: The molecular assay GeneXpert MTB/Rif Ultra has improved sensitivity but has inadequate negative predictive value to "rule-out" TBM. Evaluations of tests focused on the host response and bacterial components are ongoing. Clinical trials are in progress to explore the roles of rifampin, fluoroquinolones, linezolid, and adjunctive aspirin. Though diagnosis has improved, novel modalities are being explored to improve the rapid diagnosis of TBM. Multiple ongoing clinical trials may change current therapies for TBM in the near future.


Asunto(s)
Infecciones por VIH , Mycobacterium tuberculosis , Tuberculosis Meníngea , Tuberculosis Pulmonar , Humanos , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/tratamiento farmacológico , Tuberculosis Meníngea/microbiología , Mycobacterium tuberculosis/genética , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Rifampin/uso terapéutico , Tuberculosis Pulmonar/tratamiento farmacológico , Sensibilidad y Especificidad
6.
Antimicrob Agents Chemother ; 67(12): e0067123, 2023 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-37966227

RESUMEN

Tuberculosis meningitis (TBM) is essentially treated with the first-line regimen used against pulmonary tuberculosis, with a prolonged continuation phase. However, clinical outcomes are poor in comparison, for reasons that are only partially understood, highlighting the need for improved preclinical tools to measure drug distribution and activity at the site of disease. A predictive animal model of TBM would also be of great value to prioritize promising drug regimens to be tested in clinical trials, given the healthy state of the development pipeline for the first time in decades. Here, we report the optimization of a rabbit model of TBM disease induced via inoculation of Mycobacterium tuberculosis into the cisterna magna, recapitulating features typical of clinical TBM: neurological deterioration within months post-infection, acid-fast bacilli in necrotic lesions in the brain and spinal cord, and elevated lactate levels in cerebrospinal fluid (CSF). None of the infected rabbits recovered or controlled the disease. We used young adult rabbits, the size of which allows for spatial drug quantitation in critical compartments of the central nervous system that cannot be collected in clinical studies. To illustrate the translational value of the model, we report the penetration of linezolid from plasma into the CSF, meninges, anatomically distinct brain areas, cervical spine, and lumbar spine. Across animals, we measured the bacterial burden concomitant with neurological deterioration, offering a useful readout for drug efficacy studies. The model thus forms the basis for building a preclinical platform to identify improved regimens and inform clinical trial design.


Asunto(s)
Mycobacterium tuberculosis , Tuberculosis Meníngea , Animales , Conejos , Antituberculosos/farmacología , Sistema Nervioso Central , Tuberculosis Meníngea/tratamiento farmacológico
7.
Heliyon ; 9(11): e21962, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38034739

RESUMEN

Tuberculous meningitis treatment outcomes are poor and alternative regimens are under investigation. Reliable methods to measure drug concentrations in cerebrospinal fluid are required to evaluate distribution into the cerebrospinal fluid. A simple and quick method was developed and validated to analyse linezolid in human cerebrospinal fluid. Samples were prepared by protein precipitation followed by isocratic liquid chromatography and tandem mass spectrometry. The run time was 3.5 min. Accuracy and precision were assessed in three independent validation batches with a calibration range of 0.100-20.0 µg/mL. The method was used to analyse cerebrospinal fluid samples from patients with tuberculous meningitis enrolled in a clinical trial. Potentially infective patient samples could be decontaminated using Nanosep® nylon and Costar® nylon filter tubes under biosafety level 3 conditions before analysis. The filtration process did not significantly affect the quantification of linezolid. Linezolid concentration in cerebrospinal fluid obtained from tuberculous meningitis patients ranged from 0.197 µg/mL to 15.0 µg/mL. The ratio between average CSF and plasma linezolid concentrations varied with time, reaching a maximum of 0.9 at 6 h after dosing.

9.
AIDS Res Ther ; 20(1): 83, 2023 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-37996881

RESUMEN

BACKGROUND: The World Health Organization (WHO) recommends an evidence-based package of care to reduce mortality and morbidity among people with advanced HIV disease (AHD). Adoption of these recommendations by national guidelines in sub-Saharan Africa is poorly documented. We aimed to review national guidelines for AHD management across six selected countries in sub-Saharan Africa for benchmarking against the 2021 WHO recommendations. METHODS: We reviewed national guidelines from six countries participating in an ongoing randomized controlled trial recruiting people with AHD. We extracted information addressing 18 items of AHD diagnosis and management across the following domains: [1] Definition of AHD, [2] Screening, [3] Prophylaxis, [4] Supportive care, and [5] HIV treatment. Data from national guideline documents were compared to the 2021 WHO consolidated guidelines on HIV and an agreement score was produced to evaluate extent of guideline adoption. RESULTS: The distribution of categories of agreement varied for the national documents. Four of the six countries addressed all 18 items (Malawi, Nigeria, Sierra Leone, Uganda). Overall agreement with the WHO 2021 guidelines ranged from 9 to 15.5 out of 18 possible points: Malawi 15.5 points, Nigeria, and Sierra Leone 14.5 points, South Africa 13.5 points, Uganda 13.0 points and Botswana with 9.0 points. Most inconsistencies were reported for the delay of antiretroviral therapy (ART) in presence of opportunistic diseases. None of the six national guidelines aligned with WHO recommendations around ART timing in patients with tuberculosis. Agreement correlated with the year of publication of the national guideline. CONCLUSION: National guidelines addressing the care of advanced HIV disease in sub-Saharan Africa are available. Besides optimal timing for start of ART in presence of tuberculosis, most national recommendations are in line with the 2021 WHO standards.


Asunto(s)
Infecciones por VIH , Tuberculosis , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Nivel de Atención , Tuberculosis/tratamiento farmacológico , Tuberculosis/epidemiología , Tuberculosis/prevención & control , Estudios Longitudinales , Sudáfrica
10.
S Afr J Infect Dis ; 38(1): 522, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37780199

RESUMEN

Background: Efavirenz (EFV) is associated with neuropsychiatric symptoms. Severe neurotoxicity has been reported but the clinical phenotype and risk factors are poorly defined. Objectives: To characterise clinical presentations, risk factors and outcomes to help clinicians recognise severe neurotoxicity earlier. Method: The authors retrospectively identified adults with supratherapeutic EFV concentrations (> 4 mg/L) obtained during routine clinical care in Cape Town, South Africa. Clinical and laboratory data at the time of EFV quantification were extracted from medical records. Logistic regression was performed to identify associations with neuropsychiatric symptoms, and with severe neurotoxicity. Results: Eighty one patients were included; 62 with neuropsychiatric manifestations (most frequently ataxia [n = 20] and psychomotor slowing [n = 24]); and 19 with hepatotoxicity. Overall, 28 (34.6%) were male, 49 (60.5%) had concomitant isoniazid exposure, and median EFV concentration was 12.1 mg/L (interquartile range [IQR]: 6.6-20.0). Neuropsychiatric symptoms were associated with longer duration of EFV therapy, adjusted odds ratio (aOR) 1.3/180-day increment (95% confidence interval [CI]: 1.0-1.7); higher EFV concentrations, aOR 1.2/1 mg/L increase (95% CI: 1.0-1.4) and isoniazid exposure, aOR 8.2 (95% CI: 2.5-26.7). Severe neuropsychiatric symptoms occurred in 47 (75%) patients at a median of 5.9 months (IQR: 2.1-40.8) after EFV initiation. Severe symptoms odds were 1.2-fold higher (95% CI: 1.1-1.4) per 1 mg/L increase in EFV concentration. Symptoms resolved completely within 1 month in 25 (76%) patients with severe neurotoxicity who discontinued EFV. Conclusion: A concentration-effect relationship for severe neurotoxicity exists, which occurred late and resolved in most patients after EFV discontinuation. Contribution: The authors highlighted clinical heterogeneity and morbidity of EFV-associated neurotoxicity.

11.
S Afr J Infect Dis ; 38(1): 524, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37795202

RESUMEN

Chronic schistosomiasis affects either the genitourinary or gastrointestinal tract. Rarely, schistosomes cause ectopic disease, such as in the case of a South African woman from a non-endemic province, who presented with suspected pericardial tamponade because of tuberculosis. However, histology and polymerase chain reaction from pericardial biopsy confirmed Schistosoma haematobium. A finding of mediastinal non-Hodgkin lymphoma came to light when our patient's clinical condition unexpectedly deteriorated. Contribution: This case highlights an unusual manifestation of schistosomiasis.

16.
medRxiv ; 2023 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-37066148

RESUMEN

Background: Linezolid is being evaluated in novel treatment regimens for tuberculous meningitis (TBM). The pharmacokinetics of linezolid have not been characterized in this population, particularly in cerebrospinal fluid (CSF) where exposures may be affected by changes in protein concentration and rifampicin co-administration. Methods: This was a sub-study of a phase 2 clinical trial of intensified antibiotic therapy for adults with HIV-associated TBM. Participants in the intervention groups received high-dose rifampicin (35 mg/kg) plus linezolid 1200 mg daily for 28 days followed by 600 mg daily until day 56. Plasma was intensively sampled, and lumbar CSF was collected at a single timepoint in a randomly allocated sampling window, within 3 days after enrolment. Sparse plasma and CSF samples were also obtained on day 28. Linezolid concentrations were analyzed using non-linear mixed effects modelling. Results: 30 participants contributed 247 plasma and 28 CSF linezolid observations. Plasma PK was best described by a one-compartment model with first-order absorption and saturable elimination. The typical value of maximal clearance was 7.25 L/h. Duration of rifampicin co-treatment (compared on day 3 versus day 28) did not affect linezolid pharmacokinetics. Partitioning between plasma and CSF correlated with CSF total protein concentration up to 1.2 g/L where the partition coefficient reached a maximal value of 37%. The equilibration half-life between plasma and CSF was estimated at ∻3.5 hours. Conclusion: Linezolid was readily detected in CSF despite co-administration of the potent inducer rifampicin at high doses. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults.

17.
Front Pharmacol ; 14: 1100488, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36817137

RESUMEN

Shorter (6-9 months), fully oral regimens containing new and repurposed drugs are now the first-choice option for the treatment of drug-resistant tuberculosis (DR-TB). Clofazimine, long used in the treatment of leprosy, is one such repurposed drug that has become a cornerstone of DR-TB treatment and ongoing trials are exploring novel, shorter clofazimine-containing regimens for drug-resistant as well as drug-susceptible tuberculosis. Clofazimine's repurposing was informed by evidence of potent activity against DR-TB strains in vitro and in mice and a treatment-shortening effect in DR-TB patients as part of a multidrug regimen. Clofazimine entered clinical use in the 1950s without the rigorous safety and pharmacokinetic evaluation which is part of modern drug development and current dosing is not evidence-based. Recent studies have begun to characterize clofazimine's exposure-response relationship for safety and efficacy in populations with TB. Despite being better tolerated than some other second-line TB drugs, the extent and impact of adverse effects including skin discolouration and cardiotoxicity are not well understood and together with emergent resistance, may undermine clofazimine use in DR-TB programmes. Furthermore, clofazimine's precise mechanism of action is not well established, as is the genetic basis of clofazimine resistance. In this narrative review, we present an overview of the evidence base underpinning the use and limitations of clofazimine as an antituberculosis drug and discuss advances in the understanding of clofazimine pharmacokinetics, toxicity, and resistance. The unusual pharmacokinetic properties of clofazimine and how these relate to its putative mechanism of action, antituberculosis activity, dosing considerations and adverse effects are highlighted. Finally, we discuss the development of novel riminophenazine analogues as antituberculosis drugs.

18.
Nat Commun ; 14(1): 188, 2023 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-36635274

RESUMEN

Few studies from Africa have described the clinical impact of co-infections on SARS-CoV-2 infection. Here, we investigate the presentation and outcome of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence by an observational case cohort of SARS-CoV-2 patients. A comparator group of non SARS-CoV-2 participants is included. The study includes 104 adults with SARS-CoV-2 infection of whom 29.8% are HIV-1 co-infected. Two or more co-morbidities are present in 57.7% of participants, including HIV-1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS-CoV-2, clinical features can be typical of either SARS-CoV-2 or tuberculosis: lymphopenia is exacerbated, and some markers of inflammation (D-dimer and ferritin) are further elevated (p < 0.05). Amongst HIV-1 co-infected participants those with low CD4 percentage strata exhibit reduced total, but not neutralising, anti-SARS-CoV-2 antibodies. SARS-CoV-2 specific CD8 T cell responses are present in 35.8% participants overall but undetectable in combined HIV-1 and tuberculosis. Death occurred in 30/104 (29%) of all COVID-19 patients and in 6/15 (40%) of patients with coincident SARS-CoV-2 and tuberculosis. This shows that in a high incidence setting, tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19. The immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis.


Asunto(s)
COVID-19 , Infecciones por VIH , Tuberculosis , Adulto , Humanos , África/epidemiología , COVID-19/complicaciones , COVID-19/epidemiología , COVID-19/inmunología , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , VIH-1 , Inmunidad , SARS-CoV-2 , Tuberculosis/complicaciones , Tuberculosis/epidemiología
19.
Int J Infect Dis ; 127: 63-68, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36436752

RESUMEN

OBJECTIVES: We aimed to compare the clinical severity of Omicron BA.4/BA.5 infection with BA.1 and earlier variant infections among laboratory-confirmed SARS-CoV-2 cases in the Western Cape, South Africa, using timing of infection to infer the lineage/variant causing infection. METHODS: We included public sector patients aged ≥20 years with laboratory-confirmed COVID-19 between May 01-May 21, 2022 (BA.4/BA.5 wave) and equivalent previous wave periods. We compared the risk between waves of (i) death and (ii) severe hospitalization/death (all within 21 days of diagnosis) using Cox regression adjusted for demographics, comorbidities, admission pressure, vaccination, and previous infection. RESULTS: Among 3793 patients from the BA.4/BA.5 wave and 190,836 patients from previous waves, the risk of severe hospitalization/death was similar in the BA.4/BA.5 and BA.1 waves (adjusted hazard ratio [aHR] 1.12; 95% confidence interval [CI] 0.93; 1.34). Both Omicron waves had a lower risk of severe outcomes than previous waves. Previous infection (aHR 0.29, 95% CI 0.24; 0.36) and vaccination (aHR 0.17; 95% CI 0.07; 0.40 for at least three doses vs no vaccine) were protective. CONCLUSION: Disease severity was similar among diagnosed COVID-19 cases in the BA.4/BA.5 and BA.1 periods in the context of growing immunity against SARS-CoV-2 due to previous infection and vaccination, both of which were strongly protective.


Asunto(s)
COVID-19 , Humanos , COVID-19/diagnóstico , COVID-19/epidemiología , SARS-CoV-2 , Sudáfrica/epidemiología , Hospitalización , Laboratorios
20.
Clin Infect Dis ; 76(8): 1412-1422, 2023 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-36482216

RESUMEN

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIALS REGISTRATION: NCT03927313.


Asunto(s)
Infecciones por VIH , Tuberculosis Meníngea , Humanos , Rifampin/efectos adversos , Antituberculosos/efectos adversos , Aspirina/efectos adversos , Tuberculosis Meníngea/complicaciones , Tuberculosis Meníngea/tratamiento farmacológico , Linezolid/efectos adversos , VIH , Resultado del Tratamiento , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico
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