Current trends and intricacies in the management of HIV-associated pulmonary tuberculosis

Human immunodeficiency virus (HIV) epidemic has undoubtedly increased the incidence of tuberculosis (TB) globally, posing a formidable global health challenge affecting 1.2 million cases. Pulmonary TB assumes utmost significance in the programmatic perspective as it is readily transmissible as well as easily diagnosable. HIV complicates every aspect of pulmonary tuberculosis from diagnosis to treatment, demanding a different approach to effectively tackle both the diseases. In order to control these converging epidemics, it is important to diagnose early, initiate appropriate therapy for both infections, prevent transmission and administer preventive therapy. Liquid culture methods and nucleic acid amplification tests for TB confirmation have replaced conventional solid media, enabling quicker and simultaneous detection of mycobacterium and its drug sensitivity profile Unique problems posed by the syndemic include Acquired rifampicin resistance, drug–drug interactions, malabsorption of drugs and immune reconstitution inflammatory syndrome or paradoxical reaction that complicate dual and concomitant therapy. While the antiretroviral therapy armamentarium is constantly reinforced by discovery of newer and safer drugs every year, only a few drugs for anti tuberculosis treatment have successfully emerged. These include bedaquiline, delamanid and pretomanid which have entered phase III B trials and are also available through conditional access national programmes. The current guidelines by WHO to start Antiretroviral therapy irrespective of CD4+ cell count based on benefits cited by recent trials could go a long way in preventing various complications caused by the deadly duo. This review provides a consolidated gist of the advancements, concepts and updates that have emerged in the management of HIV-associated pulmonary TB for maximizing efficacy, offering latest solutions for tackling drug–drug interactions and remedial measures for immune reconstitution inflammatory syndrome

Long-term Survival of Treated Tuberculosis Patients in Comparison to a General Population In South India: A Matched Cohort Study

Objectives: This study aimed to measure the mortality rate, potential years of life lost, and excess general mortality among individuals treated for pulmonary tuberculosis (TB) in a TB endemic country. Methods: A retrospective analysis was conducted on a population-based cohort study of 4022 TB patients and 12,243 gender-matched and age-matched controls from prevalence surveys conducted between 2000 and 2004 in the Thiruvallur district of Tamil Nadu, South India. Results: The mortality rate among TB patients was 59/1000 person-years. The excess standardized mortality ratio was 2.3 (95% CI: 1.7–3.1). The rate of potential years of life lost was 6.15/1000 (95% CI: 5.97–6.33) in the TB cohort compared to the general population of 1.52/1000 (95% CI: 1.46–1.60). Individuals aged >50 years, those underweight (<40 kg), with treatment failures, or lost to follow-up had higher mortality rates when compared with the rest of the TB cohort. The risk of death was significantly higher in the TB cohort until the end of the fourth year when compared with later years. Conclusion: Mortality in the TB cohort was 2.3 times higher than in the age-matched general population. Most deaths occurred in the first year after completing treatment. Post-treatment follow-ups and interventions for reducing comorbid conditions are necessary to prevent deaths

Broad and potent cross clade neutralizing antibodies with multiple specificities in the plasma of HIV-1 subtype C infected individuals.

Broadly Cross clade Neutralizing (BCN) antibodies are recognized as potential therapeutic tools and leads for the design of a vaccine that can protect human beings against various clades of Human Immunodeficiency Virus (HIV). In the present study, we screened plasma of 88 HIV-1 infected ART naïve individuals for their neutralization potential using a standard panel of 18 pseudoviruses belonging to different subtypes and different levels of neutralization. We identified 12 samples with good breadth of neutralization (neutralized &gt;90% of the viruses). Four of these samples neutralized even the difficult-to-neutralize tier-3 pseudoviruses with great potency (GMT &gt; 600). Analysis of neutralization specificities indicated that four samples had antibodies with multiple epitope binding specificities, viz. CD4-binding site (CD4BS), glycans in the V1/V2 and V3 regions and membrane proximal external region (MPER). Our findings indicate the strong possibility of identifying highly potent bNAbs with known or novel specificities from HIV-1 subtype C infected individuals from India that can be exploited as therapeutic tools or lead molecules for the identification of potential epitopes for design of a protective HIV-1 vaccine

Randomised trial to evaluate the effectiveness and safety of varying doses of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant or treatment intolerant/non-responsive multidrug-resistant pulmonary tuberculosis: study protocol.

INTRODUCTION Drug-resistant tuberculosis (DR-TB) is a global public health problem. Patients suffer for months if undiagnosed or treated inadequately, transmitting DR-TB in the community before succumbing to the disease. Early diagnosis, prompt treatment initiation and completion play a significant role in treatment success. However, extended regimens with injectable result in poor treatment adherence and outcomes. Our objective is to evaluate the effectiveness, safety and tolerability of various doses and duration of linezolid (LZD) in combination with bedaquiline (BDQ) and pretomanid (Pa) after 26 weeks of treatment in adults with pre-extensively drug-resistant or treatment intolerant/non-responsive multidrug-resistant pulmonary TB. METHODS AND ANALYSIS A multicentric, randomised pragmatic clinical trial in India will enrol participants in one of the three arms-control arm (arm 1): BDQ, Pa and LZD 600 mg daily for 26 weeks or intervention arms (arm 2): BDQ, Pa and LZD 600 mg for 9 weeks followed by 300 mg for 17 weeks or arm 3: BDQ, Pa and LZD 600 mg for 13 weeks followed by 300 mg for 13 weeks. The primary endpoint is the proportion of patients with favourable outcomes as sustained cure and treatment completion. The secondary endpoint is unfavourable outcomes, including deaths, treatment failure, toxicity/adverse events and lost to follow-up till 48 weeks post-treatment. ETHICS AND DISSEMINATION The study has been approved by the ethics committees of participating institutes and the National Institute for Research in TB. The trial results will help establish evidence towards a safe and effective dose of LZD that can be used in a fully, all-oral short course regimen for highly DR-TB patients. The results of this study will be shared with the National TB Elimination Programme of the country and the WHO guidelines development group through publications and dissemination meetings. TRIAL REGISTRATION NUMBER NCT05040126

Effectiveness and safety of Levofloxacin containing regimen in the treatment of Isoniazid mono-resistant pulmonary Tuberculosis: a systematic review

BackgroundWe aimed to determine the effectiveness and safety of the Levofloxacin-containing regimen that the World Health Organization is currently recommending for the treatment of Isoniazid mono-resistant pulmonary Tuberculosis.MethodsOur eligible criteria for the studies to be included were; randomized controlled trials or cohort studies that focused on adults with Isoniazid mono-resistant tuberculosis (HrTB) and treated with a Levofloxacin-containing regimen along with first-line anti-tubercular drugs; they should have had a control group treated with first-line without Levofloxacin; should have reported treatment success rate, mortality, recurrence, progression to multidrug-resistant Tuberculosis. We performed the search in MEDLINE, EMBASE, Epistemonikos, Google Scholar, and Clinical trials registry. Two authors independently screened the titles/abstracts and full texts that were retained after the initial screening, and a third author resolved disagreements.ResultsOur search found 4,813 records after excluding duplicates. We excluded 4,768 records after screening the titles and abstracts, retaining 44 records. Subsequently, 36 articles were excluded after the full-text screening, and eight appeared to have partially fulfilled the inclusion criteria. We contacted the respective authors, and none responded positively. Hence, no articles were included in the meta-analysis.ConclusionWe found no “quality” evidence currently on the effectiveness and safety of Levofloxacin in treating HrTB.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022290333, identifier: CRD42022290333

Efficacy and safety of once-daily nevirapine- or efavirenz-based antiretroviral therapy in HIV-associated tuberculosis: a randomized clinical trial

Background: Nevirapine (NVP) can be safely and effectively administered once-daily but has not been assessed in human immunodeficiency virus (HIV)–infected patients with tuberculosis (TB). We studied the safety and efficacy of once-daily NVP, compared with efavirenz (EFV; standard therapy); both drugs were administered in combination with 2 nucleoside reverse-transcriptase inhibitors. Methods: An open-label, noninferiority, randomized controlled clinical trial was conducted at 3 sites in southern India. HIV-infected patients with TB were treated with a standard short-course anti-TB regimen (2EHRZ3/4RH3; [2 months of Ethambutol, Isoniazid, Rifampicin, Pyrazinamide/4 months of Isoniazid and Rifampicin] thrice weekly) and randomized to receive once-daily EFV at a dose of 600 mg or NVP at a dose of 400 mg (after 14 days of 200 mg administered once daily) with didanosine 250/400 mg and lamivudine 300 mg after 2 months. Sputum smears and mycobacterial cultures were performed every month. CD4+ cell count, viral load, and liver function test results were monitored periodically. Primary outcome was a composite of death, virological failure, default, or serious adverse event (SAE) at 24 weeks. Both intent-to-treat and per protocol analyses were done, and planned interim analyses were performed. Results: A total of 116 patients (75% [87 patients] of whom had pulmonary TB), with a mean age of 36 years, a median CD4+ cell count of 84 cells/mm3, and a median viral load of 310?000 copies/mL, were randomized. At 24 weeks, 50 of 59 patients in the EFV group and 37 of 57 patients in the NVP group had virological suppression (P = .024). There were no deaths, 1 SAE, and 5 treatment failures in the EFV arm, compared with 5 deaths, 2 SAEs, and 10 treatment failures in the NVP arm. The trial was halted by the data and safety monitoring board at the second interim analysis. Favorable TB treatment outcomes were observed in 93% of the patients in the EFV arm and 84% of the patients in the NVP arm (P = .058). Conclusions: Compared with a regimen of didanosine, lamivudine, and EFV, a regimen of once-daily didanosine, lamivudine, and NVP was inferior and was associated with more frequent virologic failure and death