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Challenges of MDR-TB in HIV-infected children PowerPoint Presentation

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Description : Challenges of MDR-TB in HIV-infected children.

Tags : Pediatrics, Child Health, pediatric practice, pediatrician, health providers, HIV-infected infants, Adolescent Transition, HIV-infected adolescents, epidemiology, south Africa, nutrition, MDR-TB

Published on : Jul 18, 2020 | Views : 1305 | Downloads : 5

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Challenges of MDR-TB in HIV-infected children H Simon Schaaf Desmond Tutu TB Centre Department of Paediatrics and Child Health, Stellenbosch University, and Tygerberg Children’s Hospital
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Challenges with the numbers Lancet Infect Dis 2016 Estimates for 2014: MDR-TB numbers based on model and numbers reported to Global Project on Antituberculosis Drug Resistance Surveillance at WHO and from surveys and surveillance reported between 1988 and 2014 850 000 children with TB 58 000 children INH mono-resistant TB 25 000 children MDR-TB 1 200 children XDR-TB Infected with MDR-TB - 2 million children
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DR-TB more common in HIV-infected children? No definite data in children From our 2-year surveillance periods since 2003 we could not show a difference per 2-year period However, with 14 yrs of data available in 2112 children (<13 years) with culture-confirmed TB: and both HIV status & DST known in 1738 (82.3%): Significantly more MDR/RIF resistance in HIV- infected children compared to HIV-uninfected but no difference in INH mono-resistance
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Challenges with MDR-TB diagnosis Does the child have TB disease? exclude infection only (may even be Xpert or culture-positive) exclude other conditions – more common in HIV- infected children / may co-exist with TB Need to bacteriologically confirm TB and DR-TB whenever possible obtain specimen for TB bacteriology BEFORE starting treatment (excl. in TBM/miliary TB) do DST on ALL (HIV-infected) children with a positive culture for M. tuberculosis
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Diagnosis : MDR-TB in children DR TB is a microbiological diagnosis In children often difficult (paucibacillary TB): Confirmed if DR M. tuberculosis strain is isolated from a child Probable DR-TB if there is known contact with an infectious adult DR-TB case (>78-90% concordance in several studies) Suspect DR-TB if: # a child gets worse on Rx, failing adherent Rx # an adult source case who has no DST-result is a treatment failure, a retreatment case or died of TB during adherent Rx
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Culture vs. Xpert MTB/RIF
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Challenges with DR-TB treatment “Rapidly” changing scene!? Dose-finding and safety studies for existing 2nd-line drugs, new and repurposed drugs – correct doses & safety important for HIV co-infected children on ART New shorter 9-12 month regimen recently approved by WHO for RIF-mono and strictly MDR-TB cases (4-6hdH/Eto/Mxf/Cfz/Km/Z/E+5-6Mfx/Cfz/Z/E) – limited application in SA context (need rapid 2nd-line DST – GenoType MTBDRsl LPA now approved) Many shortened/new regimens currently studied in adults: if it has efficacy in adults, then only need dose & safety evaluation in children
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Slide: courtesy Anthony Garcia-Prats
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Challenges in DR-TB treatment/ART WHO 2016 guidelines: ART is recommended for all patients with HIV and DR-TB requiring second-line anti-TB drugs irrespective of CD4 cell count, as early as possible (within the first 8 weeks) following initiation of anti- TB treatment (strong recommendation, very low- quality evidence). However: Early initiation of ART in TBM has a risk of intracranial IRIS – may be fatal. Usually treat TB a few weeks before starting ART. If ART started early – be aware of signs of raised intracranial pressure
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Drug-drug interactions WHO guidelines 2016: The complexity of ARV regimens and second-line TB treatment, each with its own toxicity profiles and some of which may be potentiated by concomitant therapy, demands rigorous clinical monitoring. Drug-drug interactions: Few known with 2nd-line drugs – pharmacovigilance NB Delamanid – no known DDIs of importance Bedaquiline – LPV/r increases Bdq and M2 (metabolite) exposure; EFV may reduce Bdq exposure by 50%: Needs further evaluation regarding relevance New ARVs such as integrase inhibitors – seem safe with second-line anti-TB drugs
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Challenges with drug administration ARVs and MDR-TB treatment together – often also supplements, treatment of other conditions Child-friendly formulations of second-line anti-TB drugs rarely available – being addressed slowly Currently all children co-infected with MDR-TB/HIV receive a daily second-line injectable agent – clinic staff often refuse to administer – often hospitalised
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Challenges with Adverse Effects Similar toxicities, e.g mitochondrial toxicity to be considered with Lzd, Bdq and NRTI’s/NNRTI’s Adverse effects of DR-TB Rx reported to be more common in HIV-infected children Need to develop injectable-sparing regimen for MDR-TB treatment
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Alphabetical Toxicity list – which drug causes what? Arthralgia/arthritis: FQNs/PZA/RFB Blood dyscrasias: INH/RIF/PZA/LZD/FQNs/PAS and more Central nervous system toxicity: headache, drowsiness, seizures, weakness, insomnia, hallucinations: FQNs Depression/Psychosis: INH/ETO/TZD Endocrine effects – hypothyroidism: PAS/ETO, gynaecomastia: ETO/INH Flu-like syndrome: RIF/RFB/PAS GIT disturbances – nausea, vomiting, abdominal pain, diarrhoea: Many! ETO/PAS/FQNs/CFZ/LZD/BDQ Expert Opinion Drug Safety – Schaaf et al – in press
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Alphabetical Toxicity List – which drug does what? Hearing impair/ototoxicity: AM/KM/CM Hair loss (alopecia): INH/ETO Idiopathic intracranial pressure: FQNs Jaundice/hepatotoxicity: PZA/INH/RIF/ETO/PAS/MFX K+ decrease: Electrolyte disturbance : CM/PAS Lactic acidosis: LZD Myelosuppression: LZD Nephrotoxicity: AM/KM/CM/SM Optic neuritis/vision disturbance/colour blindness: EMB/LZD/INH/ETO/PAS Expert Opinion Drug Safety – Schaaf et al – in press
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Alphabetical Toxicity list – which drug causes what? Peripheral neuropathy: INH/ETO/LZD/TZD Pancreatitis: LZD QTc interval prolongation: FQN/CFZ/CLA/BDQ/DLM Rashes: PZA/FQNs/TZD/PAS and many other Skin discolouration – red skin: CFZ Tendinitis/tendonopathy: FQNs Uveitis: RFB Vestibular toxicity: AM/KM/CM/SM Expert Opinion Drug Safety – Schaaf et al – in press
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59/325 (18%) were HIV-infected children – no influence on mortality Lancet Infect Dis. 2012 Own experience is that HIV-infected children do have higher mortality
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The Challenge of Prevention Appropriate TB infection control measures in all facilities caring for people with HIV and efforts to optimize adherence and completion of TB treatment are important to help reduce the incidence of MDR- TB. (WHO 2016) To effectively “bend the curve” (accelerate decline in TB incidence)—will require not only finding and treating those with TB, but will also require treating those with TB infection who may become sick in the future. (Dye C, et al. Prospects for tuberculosis elimination. Annu Rev Public Health 2013;34:271-286.) - this should include those with DR-TB infection
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Including: Vaccine, Treatment of TB disease and infection New diagnostics and healthcare for all
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Preventing MDR/XDR-TB WHO does not support drug treatment for prevention of MDR-TB – according to “Grade” system, too little data No RCT to support MDR-TB preventive therapy, but many good observational studies (prospective and retrospective) have shown that MDR-TB is preventable and preventive treatment is safe
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Seddon JA, Fred D, Amanullah F, Schaaf HS, Starke JR, Keshavjee S, Burzynski J, Furin JJ, Swaminathan S, Becerra MC. (2015) Post-exposure management of multidrug-resistant tuberculosis contacts: evidence-based recommendations. Policy Brief No. 1. Dubai, United Arab Emirates: Harvard Medical School Center for Global Health Delivery–Dubai.
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Challenge: To prevent MDR/XDR-TB This policy brief followed from a meeting of >50 TB practitioners from 19 countries on MDR-TB prevention The current evidence base is 10 observational studies (published and unpublished), including >600 contacts treated for presumed MDR-TB infection – all studies showed success in preventing MDR-TB in contacts The group felt strongly that the time for MDR-TB preventive treatment has come Fluoroquinolone-based preventive regimen preferred However – RCTs to confirm efficacy should go ahead Prevention of XDR-TB remains a problem – new drugs?
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The challenges are ours to find solutions! Acknowledgements for Financial Support: SA National Research Foundation; NIH

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