Ray Y. Chen

Six months of drug treatment is standard of care for drug-sensitive pulmonary tuberculosis (TB). Understanding the factors determining the length of treatment required for durable cure would allow individualization of treatment durations. We conducted a prospective, randomized, controlled noninferiority trial (PredictTB) of 4 versus 6 months of chemotherapy in patients with pulmonary TB in South Africa and China. Seven hundred and four participants with newly diagnosed, drug-sensitive TB were enrolled and stratified on the basis of radiographic disease characteristics assessed by FDG PET/CT imaging. Participants with less extensive disease ( n = 273) were randomly assigned at week 16 to complete therapy after 4 months or continue receiving treatment for 6 months. This study was stopped early after an interim analysis revealed that patients assigned to the 4-month treatment arm had a higher risk of relapse. Among participants who received 4 months of chemotherapy, 17 of 141 (12.1%) experienced TB-specific unfavorable outcomes compared with only 2 of 132 (1.5%) who completed 6 months of treatment. In the nonrandomized arm that included participants with more extensive disease, only 8 of 248 (3.2%) experienced unfavorable outcomes. Total lung cavity volume and lesion glycolysis at week 16 were associated with the risk of unfavorable outcomes. PET/CT imaging at TB recurrence showed that bacteriological relapses predominantly occurred in active cavities originally present at baseline. Subsequent post hoc automated segmentation of serial PET/CT scans combined with machine learning enabled the classification of participants according to their likelihood of relapse.

“Investigation of Immune Amnesia Following Measles Infection in Select African Regions” (ClinicalTrials.gov Identifier: NCT06153979) is a prospective, observational, longitudinal study being conducted in two West African countries; Guinea and Mali. Acute measles virus (MeV) infection has been shown to result in a loss of pre-existing immunity (immune amnesia). MeV-induced immune amnesia has not been studied in West Africa where continual MeV outbreaks occur. Additionally previous studies have relied on naturally occurring exposures to viruses to examine the immune systems ability to create antibodies. Thus, the overall goal of this protocol is to investigate the impact of MeV infection on pre-existing immunity to endemic pathogens in West Africa, observe the effect of a subsequent exposure to a novel pathogen (rabies vaccine), and measure the frequency of subsequent healthcare visits. A total of 256 children aged 1–15 years are being enrolled into one of two study arms: those with acute MeV infection (cases) as confirmed by laboratory testing and without (controls). Controls must be immune to MeV (have IgG). Blood samples are collected at multiple time points including screening (Day 0), at an optional visit to repeat IgM serology for inconclusive or negative Day 0 results (Day 7–10), and during follow-up visits on Day 14, Week 13, and Week 52. These blood samples will be tested to evaluate both humoral and cellular immune responses to a panel of viruses, bacteria, and parasites, including pathogens endemic to West Africa. To explore how recent MeV infection may affect the child’s ability to respond to a new exposure, all participants will receive a rabies vaccine (as a controlled stimulus) at one of two timepoints post Day 0 visit. Biological samples will be collected after vaccination to assess if the rabies vaccine response differs: 1) between cases and controls, and 2) based on the time since acute MeV infection. In addition, the study team will collect information on healthcare encounters during the year-long follow-up to determine if there is a difference in the number of encounters by study group. The findings of this study will further the understanding of the MeV immune amnesia phenotype by understanding its impact on endemic pathogens and subsequent immune response following infection.

: Unexplained fever poses significant diagnostic challenges in resource-limited settings like Bamako, Mali, where overlapping endemic diseases include malaria, HIV/AIDS, yellow fever, typhoid, and others. This study aimed to elucidate the infectious etiologies of acute febrile illnesses in this context. Acute febrile patients of any age were enrolled after informed consent or assent. Baseline clinical and demographic data were collected, and samples were analyzed by using rapid diagnostic tests, reverse transcriptase polymerase chain reaction, ELISA, and virus-targeted metagenomic sequencing (virome capture sequencing platform for vertebrate viruses [VirCapSeq-VERT]). Among 108 enrolled subjects, most were male (51.9%) and under 15 years old (56.5%). Measles virus was identified in 39.8% of cases, primarily among children. Other findings included Plasmodium spp. (12%), Salmonella spp. (13%), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; 8.7%). The virome capture sequencing platform for vertebrate viruses was used for 101 subjects, corroborating many routine test results and identifying additional cases of measles virus (1), SARS-CoV-2 (5), and numerous other agents. Notably, nearly all subjects showed evidence of herpesviruses (90%) and anelloviruses (98%). Hemorrhagic fever viruses were not observed. With the inclusion of VirCapSeq-VERT, identifiable pathogens were found in 79.6% of cases, leaving 20.4% without a clear etiology. The identification of more than one concurrent pathogen was common (41.5%). Integrating metagenomic sequencing with routine laboratory diagnostic testing enhances the detection of pathogens in acute febrile illnesses, highlighting its potential value in identifying infectious etiologies in resource-limited settings.

“Investigation of Immune Amnesia Following Measles Infection in Select African Regions” ( ClinicalTrials.gov Identifier: NCT06153979 ) is a prospective, observational, longitudinal study being conducted in two West African countries, Guinea, and Mali. The overall goal is to investigate the impact of measles virus (MeV) infection on pre-existing immunity, vaccine response, and susceptibility to subsequent illness. A total of 256 children aged 1 to 15 years are being enrolled into one of two study arms: those with acute MeV infection (cases) and without (controls). Acute MeV is confirmed by RT-PCR testing on upper respiratory specimens or IgM detection on blood samples at screening. Blood samples are collected at multiple time points at screening (Day 0), at an optional visit to repeat IgM serology for inconclusive or negative Day 0 results (Day 7-10), and during follow-up visits on Day 14, Week 13, and Week 52. These blood samples will be tested to evaluate both humoral and cellular immune responses to endemic pathogens to measure variations in antibody diversity and antibody secreting cells (ASCs). To explore how recent MeV infection may affect the child’s ability to respond to a controlled immune stimulus, all participants will receive rabies vaccine pre-exposure prophylaxis (PrEP) using Verorab inactivated rabies vaccine. Three doses of 0.5 ml of VERORAB vaccine are administered on Days 0, 7, and 28. Biological samples will be collected after vaccination to assess if the rabies vaccine response differs: 1) between cases and controls, and 2) based on the timing of the rabies vaccination after acute measles infection. In addition, the study team will collect information on healthcare encounters during the year-long follow-up will be collected to determine if there is a difference in the number of encounters by study group. The findings of this study will further the understanding of the MeV immune amnesia phenotype.

Early bactericidal activity studies monitor daily sputum bacterial counts in individuals with tuberculosis (TB) for 14 days during experimental drug treatment. The rate of change in sputum bacterial load over time provides an informative, but imperfect, estimate of drug activity and is considered a critical step in development of new TB drugs. In this clinical study, 160 participants with TB received isoniazid, pyrazinamide, or rifampicin, components of first-line chemotherapy, and moxifloxacin individually and in combination. In addition to standard bacterial enumeration in sputum, participants underwent 2-deoxy-2-[¹⁸F]fluoro-d-glucose positron emission tomography and computerized tomography ([¹⁸F]FDG-PET/CT) at the beginning and end of the 14-day drug treatment. Quantitating radiological responses to drug treatment provided comparative single and combination drug activity measures across lung lesion types that correlated more closely with established clinical outcomes when combined with sputum enumeration compared to sputum enumeration alone. Rifampicin and rifampicin-containing drug combinations were most effective in reducing both lung lesion volume measured by CT imaging and lesion-associated inflammation measured by PET imaging. Moxifloxacin was not superior to rifampicin in any measure by PET/CT imaging, consistent with its performance in recent phase 3 clinical trials. PET/CT imaging revealed synergy between isoniazid and pyrazinamide and demonstrated that the activity of pyrazinamide was limited to lung lesion, showing the highest FDG uptake during the first 2 weeks of drug treatment. [¹⁸F]FDG-PET/CT imaging may be useful for measuring the activity of single drugs and drug combinations during evaluation of potential new TB drug regimens before phase 3 trials.

Standard treatment of drug-sensitive pulmonary tuberculosis requires six months of treatment. Several randomized clinical trials have attempted to shorten treatment to four months using various strategies but thus far all have failed. The PredictTB trial is an ongoing international randomized clinical trial testing a treatment shortening strategy whereby only drug-sensitive pulmonary TB patients who meet the study early treatment completion criteria are randomized to four vs. six months of treatment. The PredictTB early treatment completion criteria were developed based on a cohort of 92 pulmonary tuberculosis patients treated programmatically through the local tuberculosis treatment program in Cape Town, South Africa, with FDG-PET/CT scans also performed at baseline and week 4 of treatment. Patients were followed for one year after the end of therapy for programmatic treatment outcomes. This methodology paper describes how the PET/CT scans and GeneXpert cycle threshold data of this cohort were analyzed to develop the early treatment completion algorithm currently being used in the PredictTB trial.

Background: There is a growing interest in the use of F-18 FDG PET-CT to monitor tuberculosis (TB) treatment response. Tuberculosis lung lesions are often complex and diffuse, with dynamic changes during treatment and persisting metabolic activity after apparent clinical cure. This poses a challenge in quantifying scan-based markers of burden of disease and disease activity. We used semi-automated, whole lung quantification of lung lesions to analyse serial FDG PET-CT scans from the Catalysis TB Treatment Response Cohort to identify characteristics that best correlated with clinical and microbiological outcomes. Results: Quantified scan metrics were already associated with clinical outcomes at diagnosis and 1 month after treatment, with further improved accuracy to differentiate clinical outcomes after standard treatment duration (month 6). A high cavity volume showed the strongest association with a risk of treatment failure (AUC 0.81 to predict failure at diagnosis), while a suboptimal reduction of the total glycolytic activity in lung lesions during treatment had the strongest association with recurrent disease (AUC 0.8 to predict pooled unfavourable outcomes). During the first year after TB treatment lesion burden reduced; but for many patients, there were continued dynamic changes of individual lesions. Conclusions: Quantification of FDG PET-CT images better characterised TB treatment outcomes than qualitative scan patterns and robustly measured the burden of disease. In future, validated metrics may be used to stratify patients and help evaluate the effectiveness of TB treatment modalities.

There is a growing interest in the use of 18F-FDG PET-CT to monitor tuberculosis (TB) treatment response. However, TB causes complex and widespread pathology, which is challenging to segment and quantify in a reproducible manner. To address this, we developed a technique to standardise uptake (Z-score), segment and quantify tuberculous lung lesions on PET and CT concurrently, in order to track changes over time. We used open source tools and created a MATLAB script. The technique was optimised on a training set of five pulmonary tuberculosis (PTB) cases after standard TB therapy and 15 control patients with lesion-free lungs. We compared the proposed method to a fixed threshold (SUV > 1) and manual segmentation by two readers and piloted the technique successfully on scans of five control patients and five PTB cases (four cured and one failed treatment case), at diagnosis and after 1 and 6 months of treatment. There was a better correlation between the Z-score-based segmentation and manual segmentation than SUV > 1 and manual segmentation in terms of overall spatial overlap (measured in Dice similarity coefficient) and specificity (1 minus false positive volume fraction). However, SUV > 1 segmentation appeared more sensitive. Both the Z-score and SUV > 1 showed very low variability when measuring change over time. In addition, total glycolytic activity, calculated using segmentation by Z-score and lesion-to-background ratio, correlated well with traditional total glycolytic activity calculations. The technique quantified various PET and CT parameters, including the total glycolytic activity index, metabolic lesion volume, lesion volumes at different CT densities and combined PET and CT parameters. The quantified metrics showed a marked decrease in the cured cases, with changes already apparent at month one, but remained largely unchanged in the failed treatment case. Our technique is promising to segment and quantify the lung scans of pulmonary tuberculosis patients in a semi-automatic manner, appropriate for measuring treatment response. Further validation is required in larger cohorts.

Prolonged use of meropenem/amoxicillin-clavulate to treat XDR-TB may be associated with renal Fanconi syndromehttp://ow.ly/dFSD30gCKti

Background: By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01). We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment. Methods: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C. Discussion: Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified. Trial Registration: NCT02821832