Outcome of treatment of MDR-TB or drug-resistant patients treated with bedaquiline and delamanid: Results from a large global cohort.

The World Health Organization (WHO) recommends countries introduce new anti-TB drugs in the treatment of multidrug-resistant tuberculosis. The aim of the study is to prospectively evaluate the effectiveness of bedaquiline (and/or delamanid)- containing regimens in a large cohort of consecutive TB patients treated globally. This observational, prospective study is based on data collected and provided by Global Tuberculosis Network (GTN) centres and analysed twice a year. All consecutive patients (including children/adolescents) treated with bedaquiline and/or delamanid were enrolled, and managed according to WHO and national guidelines. Overall, 52 centres from 29 countries/regions in all continents reported 883 patients as of January 31st 2021, 24/29 countries/regions providing data on 100% of their consecutive patients (10-80% in the remaining 5 countries). The drug-resistance pattern of the patients was severe (>30% with extensively drug-resistant -TB; median number of resistant drugs 5 (3-7) in the overall cohort and 6 (4-8) among patients with a final outcome). For the patients with a final outcome (477/883, 54.0%) the median (IQR) number of months of anti-TB treatment was 18 (13-23) (in days 553 (385-678)). The proportion of patients achieving sputum smear and culture conversion ranged from 93.4% and 92.8% respectively (whole cohort) to 89.3% and 88.8% respectively (patients with a final outcome), a median (IQR) time to sputum smear and culture conversion of 58 (30-90) days for the whole cohort and 60 (30-100) for patients with a final outcome and, respectively, of 55 (30-90) and 60 (30-90) days for culture conversion. Of 383 patients treated with bedaquiline but not delamanid, 284 (74.2%) achieved treatment success, while 25 (6.5%) died, 11 (2.9%) failed and 63 (16.5%) were lost to follow-up.

Meropenem-clavulanate for drug-resistant tuberculosis: a follow-up of relapse-free cases.

BACKGROUND: Extensively drug-resistant tuberculosis (XDR-TB), defined as TB caused by a Mycobacterium strain resistant to at least rifampicin, isoniazid, any fluoroquinolone and one of the injectable anti-tuberculosis drugs, remains a worldwide public health threat. Among repurposed drugs empirically used for XDR-TB cases, carbapenems have been studied in vitro and in animal models, with encouraging results. However, only short-term follow-up data from clinical studies are currently available. OBJECTIVES: To study the long-term follow-up of XDR-TB cases treated with a regimen containing meropenem-clavulanate (M/Clav). DESIGN: Retrospective observational case series study at a single hospital. METHODS: All hospitalised drug-resistant TB patients who received M/Clav as part of their treatment from 2009 to 2016 were included. Demographic and clinical data were extracted from medical records. RESULTS: Eighteen XDR-TB patients were included in the analysis. The successful outcome and mortality rates were respectively 83.3% and 11.1%. No relapses were observed in cured patients after a median follow-up of 4 years. No specific adverse events were attributed to treatment with M/Clav. CONCLUSION: The rate of sustained successful treatment outcome observed here is far higher than the 26% observed in the 2014 World Health Organization XDR-TB cohort, suggesting that carbapenems may be beneficial for the treatment of difficult-to-treat TB cases.

Team approach to manage difficult-to-treat TB cases: Experiences in Europe and beyond.

As recommended by the World Health Organization (WHO), optimal management of MDR-TB cases can be ensured by a multi-speciality consultation body known as 'TB Consilium'. This body usually includes different medical specialities, competences and perspectives (e.g., clinical expertise both for adults and children; surgical, radiological and public health expertise; psychological background and nursing experience, among others), thus lowering the risk of making mistakes - or managing the patients inappropriately, in order to improve their clinical outcomes. At present, several high MDR-TB burden countries in the different WHO regions (and beyond) have introduced TB Consilium-like bodies at the national or subnational level to reach consensus on the best treatment approach for their patients affected by TB. In addition, in countries/settings where a formal system of consultation does not exist, specialized staff from MDR-TB reference centres or international organizations usually spend a considerable amount of their working time responding to phone or e-mail clinical queries on how to manage M/XDR-TB cases. The aim of this manuscript is to describe the different experiences with the TB Consilia both at the international level (European Respiratory Society - ERS/WHO TB Consilium) and in some of the countries where this experience operates successfully in Europe and beyond. The Consilium experiences are described around the following topics: (1) history, aims and focus; (2) management and funding; (3) technical functioning and structure; (4) results achieved. In addition a comparative analysis of the TB Consilia in the different countries has been performed.

Isolation unit for multidrug-resistant tuberculosis patients in a low endemic country, a step towards the World Health Organization End TB Strategy.

Tuberculosis (TB) remains a threat to public health and is the second cause of death due to a single infectious agent after HIV/AIDS. The worldwide distribution of TB is heterogeneous. The incidence is decreasing in most high-income regions, but the situation remains worrying in many parts of the world. The emergence of Mycobacterium tuberculosis strains resistant to key agents used in treatment (rifampin and isoniazid) contributes to TB transmission around the world. To achieve TB elimination, both high and low endemic countries must upscale their efforts to decrease disease transmission and improve cure rates. Management of drug-resistant TB is of particular importance. In this paper, we discuss the different models of care of multidrug-resistant TB (MDR-TB), the ethical considerations and the specific constraints present in high income countries. The management model chosen by the Belgian TB specialists in accordance with public health authorities as well as building of a specific MDR/XDR-TB isolation unit are also discussed.

Meningitis and splenic infarction due to disseminated Mycobacterium genavense infection in an HIV patient. Case report and review of the literature.

We report a case of disseminated infection with Mycobacterium genavense in a 58 year old HIV positive woman presenting with fever, diarrhea, abdominal pain and weight loss. She had a striking hepatosplenomegaly, abdominal lymphadenopathy, anaemia and thrombopenia. Direct smears and cultures of blood, stool, sputum, urine and bone marrow were negative for common and opportunistic microorganisms. Splenectomy revealed numerous acid fast bacill. Lumbar puncture also showed acid fast bacilli at direct examination. Specific PCR and 16s rRNA gene sequencing identified M. genavense. The outcome was fatal despite antimycobacterial therapy. M. genavense must be included in the differential diagnosis of fever, weight loss, lymphadenopathy and splenomegaly in immunocompromised patients. Prompt diagnosis is based on molecular biology methods. Empirical therapy, using at least three antimycobacterial agents, including clarithromycin should be introduced in case of high clinical suspicion.

Epidemiology of MDR-TB in a Belgian infectious diseases unit: a 15 years review.

INTRODUCTION: For the last 20 years the world has seen the emergence of a growing epidemic of MDR-TB, followed by the appearance of XDR-TB. Both require longer, more expensive and more toxic treatments. MDR-TB and especially XDR-TB are associated with a lower cure rate than non MDR-TB. MATERIALS AND METHODS: We reviewed retrospectively all cases of MDR-and XDR-TB managed at St Pierre University Hospital between 1996 and 2010. Epidemiological, clinical, bacteriological, treatment, follow up and outcome were collected and analysed. RESULTS: We recorded 73 instances of MDR-TB and 11 XDR-TB for a total of 78 patients. All but 4 patients were of non Belgian origin. 10 patients were co-infected with HIV. A median of 4 active drugs (1-5) were used for a median of 448 days (329-616). 41 MDR-TB (56%) and 1 XDR-TB (1%) were considered as cured and 20 are still on treatment. Since 2007, increasing resistance to second line injectable drugs, fluoroquinolones and even linezolid (1 case) is observed. Extensive resistance was mainly found in patients who had previously been mismanaged with second line agents. CONCLUSIONS: This study illustrates the growing epidemic of MDR and XDR-TB, it emphasizes the importance of proper diagnosis and adequate management of TB in patients at risk for resistance and stresses the need for new therapies.

Clinical use of the meropenem-clavulanate combination for extensively drug-resistant tuberculosis.

Mycobacterium tuberculosis strains resistant to almost all available anti-tuberculosis drugs are an increasing threat to public health worldwide. Among existing drugs with potential antimycobacterial effects, the combination of meropenem with clavulanate has been shown to have potent in vitro bactericidal activity against extensively drug-resistant tuberculosis (XDR-TB). To explore its potential clinical efficacy, a meropenem-clavulanate-containing salvage regimen was started in six patients with severe pulmonary XDR-TB, in association with the only one or two remaining active second-line drugs. Encouraging preliminary data are detailed and discussed.

[Lipids and AIDS]. / Lipides et SIDA.

HIV infection induces an early decrease of cholesterol and a late increase of triglycerides (TG) with a reduction of HDL. These changes are proportional with the lowering of CD4, which reflects the infection's severity. Both the increase of TG synthesis and the decrease of TG catabolism, in relation with a reduction of lipoprotein lipase activity, are responsible of these changes. Moreover, LDL catabolism is enhanced by macrophage scavenger receptors, due to a high proportion of small, dense LDL which are more easily oxidized. Many cytokines (interferon alpha, interleukins, TNF) play probably a pathogenic role in the dyslipidemia. Some HIV patients who received antiproteases may develop lipodystrophy with central obesity, insulino-resistance, glucose intolerance and sometimes diabetes (like in syndrome X). Other patients present a cushingoid, buffalo hump. This complication may be observed also with antiretroviral treatment other than antiproteases. The physiopathology of these findings could be in relation with structural homologies between antiproteases and some important proteins, involved in lipid and adipocyte metabolism. Cardiovascular risk linked to these perturbations is evident. The treatment is not different from the treatment for seronegative, hyperlipidemic patients: struggle against risk factors, diet advices, fibrates or statins. The antiproteases bring huge contribution to the prognosis of AIDS patients but the risk of cardiovascular complications could impair this therapeutic progress. So, it is essential to understand the pathogeny of these complications in order to discover new antiproteases, without these adverse side effects.

Neovascularization of the optic disc after highly active antiretroviral therapy in an AIDS patient with cytomegalovirus retinitis--A new immune recovery-related ocular disorder?

A patient with AIDS and cytomegalovirus (CMV) retinitis developed a massive bilateral peripheral occlusive vasculopathy with a bilateral neovascularization of the optic disc five weeks after the introduction of highly active antiretroviral therapy (HAART). No associate cause of occlusive vasculopathy was found. Occlusive vasculopathy and optic disc neovascularization may be an immune recovery-related ocular disorder.

A controlled trial of dapsone versus pyrimethamine-sulfadoxine for primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmosis in patients with AIDS.

Pneumocystis carinii pneumonia (PCP) is the most common opportunistic human immunodeficiency virus (HIV)-related infection, occurring in 85% of HIV infected patients without prophylaxis. Preventive treatment is required when CD4 cell count falls below 200 cells per cubic millimeter. Cotrimoxazole has been shown to be highly effective but alternative drug regimens are often necessary because of the frequent drug hypersensitivity exhibited by HIV infected patients. The aim of this prospective, open, randomized, one-site study, involving HIV-infected patients with a CD4 cell count below 200/mm3, or a percentage under 20%, randomly assigned to receive either dapsone 50 mg daily or Fansidar one tablet weekly, was to compare the efficacy and safety of these drugs in the primary prophylaxis of PCP. Both dapsone and Fansidar appear to be safe and effective alternative agents for the prevention of PCP. Their role in Toxoplasma gondii prophylaxis requires further evaluation.

[Manifestations, diagnosis and treatment of non-tuberculous mycobacterial infections in patients with HIV infection]. / Manifestations, diagnostic et traitement des infections mycobactériennes non tuberculeuses chez les patients porteurs du VIH.

The most frequent bacterial infections in patients infected with HIV and suffering from AIDS are non-tuberculous mycobacterial infections. Their incidence is increasing all the more as the survival of profoundly immunocompromised patients is prolonged. There are unknown factors as regards the precise origin of these infections and as to the exact epidemiology of atypical mycobacteria. It is known that 95 per cent of atypical mycobacterial infections are due to M. avium. If the pathophysiology of the infection (involving the intervention of cytokines and also factors in relation to the virulence of the germ) is imperfectly understood, the atypical mycobacteria are an independent cause of mortality in advanced stages of the disease. The clinical picture is that of a low grade fever with weight loss and a deterioration in the general physical state. There are subtle physical signs such as a fall in the functional capacity accompanied by weight loss and an unexplained anaemia these should also suggest a diagnosis. More rarely the infection will be localised. The clinical diagnosis will be confirmed by bacteriology which has been aided by recent progress in molecular biology. With the arrival of the newer macrolides it has been shown that treatment prolongs survival in a significant manner. Current recommendations consist of a treatment with a combined regime including a minimum of Clarithyromycin and Ethambutol. The place for polychemotherapy remains to be determined in particular the role for Rifabutine and Amikacine. Immunomodulation by interferon-gamma or GCSF are also under review. The duration of treatment and the necessity of long term suppressive treatment is the object of randomised studies. Prophylaxis is currently recommended for patients with CD4 < 75/mm3. The role of Rifabutine and the new macrolides remains to be determined. Finally, in a large European study the objective is to compare prophylaxis to systematic bacteriological surveillance both as regards efficacy, tolerance, and in terms of pharmaco-economics.