Accelerating development of new shorter TB treatment regimens in anticipation of a resurgence of multi-drug resistant TB due to the COVID-19 pandemic

The WHO 2020 global TB Report estimates that in 2019 there were an estimated 500,000 cases of multi-drug resistant TB (MDR-TB) of which only 186,772 MDR-TB cases were diagnosed, and positive treatment outcomes were achieved in 57% of them. These data highlight the need for accelerating and improving MDR-TB screening, diagnostic, treatment and patient follow-up services. The last decade has seen three new TB drugs being licensed; bedaquiline, delamanid and pretomanid, and combinations these new, existing and repurposed drugs are leading to improved cure rates. The all oral six month WHO regimen for MDR-TB is more tolerable, has higher treatment success rates and lower mortality. However, the unprecedented ongoing COVID-19 pandemic is having major direct and indirect negative impacts on health services overall, including national TB programs and TB services. This adds further to longstanding challenges for tackling MDR-TB such as cost, rollout of diagnostics and drugs, and implementation of latest WHO guidelines for MDR-TB. In light of COVID-19 disruption of TB services, it is anticipated the numbers of MDR-TB cases will rise in 2021 and 2022 and will affect treatment outcomes further. Investing more in development of new TB drugs and shorter MDR-TB treatment regimens is required in anticipation of emerging drug resistance to new TB drug regimens. There is an urgent need for protecting current investments in TB services, sustaining gains being made in TB control and accelerating roll out of TB diagnostic and treatment services

Accelerating the development of therapeutic strategies for drug-resistant tuberculosis

Recent progress in the discovery, development and evaluation of new drugs and combination regimens for drug-resistant tuberculosis through greater collaboration between industry, donors and academia provides renewed hope for overcoming the challenges in tuberculosis treatment

Interleukin 6 Is a Stronger Predictor of Clinical Events Than High-Sensitivity C-Reactive Protein or D-Dimer During HIV Infection

BACKGROUND: Interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer levels are linked to adverse outcomes in human immunodeficiency virus (HIV) infection, but the strength of their associations with different clinical end points warrants investigation. METHODS: Participants receiving standard of care in 2 HIV trials with measured biomarker levels were followed to ascertain all-cause death, non–AIDS-related death, AIDS, cardiovascular disease (CVD), and non–AIDS-defining malignancies. Hazard ratios (HRs) and 95% confidence intervals (CIs) of each end point for quartiles and log2-transformed IL-6, hsCRP, and D-dimer levels were calculated using Cox models. Marginal models modelling multiple events tested for equal effects of biomarker levels on different end points. RESULTS: Among 4304 participants, there were 157 all-cause deaths, 117 non–AIDS-related deaths, 101 AIDS cases, 121 CVD cases, and 99 non–AIDS-defining malignancies. IL-6 was more strongly associated with most end points, compared with hsCRP. IL-6 appeared to be a stronger predictor than D-dimer for CVD and non–AIDS-defining malignancies, but 95% CIs overlapped. Independent associations of IL-6 were stronger for non–AIDS-related death (HR, 1.71; 95% CI, 1.43–2.04) and all-cause death (HR, 1.56; 95% CI, 1.33–1.84) and similar for CVD (HR, 1.35; 95% CI, 1.12–1.62) and non–AIDS-defining malignancies (HR, 1.30; 95% CI, 1.06–1.61). There was heterogeneity of IL-6 (P < .001) but not hsCRP (P = .15) or D-dimer (P = .20) as a predictor for different end points. CONCLUSIONS: IL-6 is a stronger predictor of fatal events than of CVD and non–AIDS-defining malignancies. Adjuvant antiinflammatory and antithrombotic therapies should be tested in HIV-infected individuals

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Tuberculosis remains the world's leading cause of death from an infectious disease, responsible for an estimated 1 674 000 deaths annually. WHO estimated 600 000 cases of rifampicin-resistant tuberculosis in 2016-of which 490 000 were multidrug resistant (MDR), with less than 50% survival after receiving recommended treatment regimens. Concerted efforts of stakeholders, advocates, and researchers are advancing further development of shorter course, more effective, safer, and better tolerated treatment regimens. We review the developmental pipeline and landscape of new and repurposed tuberculosis drugs, treatment regimens, and host-directed therapies (HDTs) for drug-sensitive and drug-resistant tuberculosis. 14 candidate drugs for drug-susceptible, drug-resistant, and latent tuberculosis are in clinical stages of drug development; nine are novel in phase 1 and 2 trials, and three new drugs are in advanced stages of development for MDR tuberculosis. Specific updates are provided on clinical trials of bedaquiline, delamanid, pretomanid, and other licensed or repurposed drugs that are undergoing investigation, including trials aimed at shortening duration of tuberculosis treatment, improving treatment outcomes and patient adherence, and reducing toxic effects. Ongoing clinical trials for shortening tuberculosis treatment duration, improving treatment outcomes in MDR tuberculosis, and preventing disease in people with latent tuberculosis infection are reviewed. A range of HDTs and immune-based treatments are under investigation as adjunctive therapy for shortening duration of therapy, preventing permanent lung injury, and improving treatment outcomes of MDR tuberculosis. We discuss the HDT development pipeline, ongoing clinical trials, and translational research efforts for adjunct tuberculosis treatment

Increased indoleamine-2,3-dioxygenase activity is associated with poor clinical outcome in adults hospitalized with influenza in the INSIGHT FLU003Plus study

BACKGROUND: Indoleamine-2,3-dioxygenase (IDO) mediated tryptophan (TRP) depletion has antimicrobial and immuno-regulatory effects. Increased kynurenine (KYN)-to-TRP (KT) ratios, reflecting increased IDO activity, have been associated with poorer outcomes from several infections. METHODS: We performed a case-control (1:2; age and sex matched) analysis of adults hospitalized with influenza A(H1N1)pdm09 with protocol-defined disease progression (died/transferred to ICU/mechanical ventilation) after enrollment (cases) or survived without progression (controls) over 60 days of follow-up. Conditional logistic regression was used to analyze the relationship between baseline KT ratio and other metabolites and disease progression. RESULTS: We included 32 cases and 64 controls with a median age of 52 years; 41% were female, and the median durations of influenza symptoms prior to hospitalization were 8 and 6 days for cases and controls, respectively (P = .04). Median baseline KT ratios were 2-fold higher in cases (0.24 mM/M; IQR, 0.13-0.40) than controls (0.12; IQR, 0.09-0.17; P ≤ .001). When divided into tertiles, 59% of cases vs 20% of controls had KT ratios in the highest tertile (0.21-0.84 mM/M). When adjusted for symptom duration, the odds ratio for disease progression for those in the highest vs lowest tertiles of KT ratio was 9.94 (95% CI, 2.25-43.90). CONCLUSIONS: High KT ratio was associated with poor outcome in adults hospitalized with influenza A(H1N1)pdm09. The clinical utility of this biomarker in this setting merits further exploration. CLINICALTRIALSGOV IDENTIFIER: NCT01056185

Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL:secondary outcome results from a randomised controlled trial

BACKGROUND: The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial. METHODS: The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per μL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per μL. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048. FINDINGS: Patients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, 95% CI 0·26–0·57, p<0·0001). In the immediate-initiation group, average neutrophil count over follow-up was 321 cells per μL higher, and average CD4 cell count 194 cells per μL higher than the deferred-initiation group (p<0·0001). In univariable analysis, higher time-updated CD4 cell count (0·78, 0·71–0·85, p=0·0001) was associated with reduced risk of severe bacterial infection. Time-updated neutrophil count was not associated with severe bacterial infection. After adjustment for time-updated factors in multivariable analysis, particularly the CD4 cell count, the HR for immediate-initiation group moved closer to 1 (HR 0·84, 0·50–1·41, p=0·52). These results were consistent when subgroups of the severe bacterial infection composite were analysed separately. INTERPRETATION: Immediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count. FUNDING: National Institute of Allergy and Infectious Diseases National Institutes of Health, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales, Bundesministerium für Bildung und Forschung, European AIDS Treatment Network, Australian National Health and Medical Research Council, UK National Institute for Health Research and Medical Research Council, Danish National Research Foundation

Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomised controlled trial

BACKGROUND: The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial. METHODS: The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per μL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per μL. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048. FINDINGS: Patients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, 95% CI 0·26-0·57, p&lt;0·0001). In the immediate-initiation group, average neutrophil count over follow-up was 321 cells per μL higher, and average CD4 cell count 194 cells per μL higher than the deferred-initiation group (p&lt;0·0001). In univariable analysis, higher time-updated CD4 cell count (0·78, 0·71-0·85, p=0·0001) was associated with reduced risk of severe bacterial infection. Time-updated neutrophil count was not associated with severe bacterial infection. After adjustment for time-updated factors in multivariable analysis, particularly the CD4 cell count, the HR for immediate-initiation group moved closer to 1 (HR 0·84, 0·50-1·41, p=0·52). These results were consistent when subgroups of the severe bacterial infection composite were analysed separately. INTERPRETATION: Immediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count. FUNDING: National Institute of Allergy and Infectious Diseases National Institutes of Health, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales, Bundesministerium für Bildung und Forschung, European AIDS Treatment Network, Australian National Health and Medical Research Council, UK National Institute for Health Research and Medical Research Council, Danish National Research Foundation.</p

Early antiretroviral therapy at high CD4 counts does not improve arterial elasticity: A substudy of the strategic timing of antiretroviral treatment (START) trial

Background. Both human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) risk. Vascular function assessments can be used to study CVD pathogenesis. We compared the effect of immediate versus deferred ART initiation at CD4 counts >500 cells/mm3 on small arterial elasticity (SAE) and large artery elasticity (LAE). Methods. Radial artery blood pressure waveforms were recorded noninvasively. Small arterial elasticity and LAE were derived from analysis of the diastolic pulse waveform. Randomized treatment groups were compared with linear models at each visit and longitudinal mixed models. Results. Study visits involved 332 participants in 8 countries: mean (standard deviation [SD]) age 35 (10), 70% male, 66% nonwhite, 30% smokers, and median CD4 count 625 cells/mm3 and 10-year Framingham risk score for CVD 1.7%. Mean (SD) SAE and LAE values at baseline were 7.3 (2.9) mL/mmHg × 100 and 16.6 (4.1) mL/mmHg × 10, respectively. Median time on ART was 47 and 12 months in the immediate and deferred ART groups, respectively. The treatment groups did not demonstrate significant within- person changes in SAE or LAE during the follow-up period, and there was no difference in mean change from baseline between treatment groups. The lack of significant differences persisted after adjustment, when restricted to early or late changes, after censoring participants in deferred group who started ART, and among subgroups defined by CVD and HIV risk factors. Conclusions. Among a diverse global population of HIV-positive persons with high CD4 counts, these randomized data suggest that ART treatment does not have a substantial influence on vascular function among younger HIV-positive individuals with preserved immunity

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection