Tuberculosis: What's new in diagnos6cs and management? Colin Menezes, Department of Internal Medicine, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand.
Objec6ves of this talk: Discuss what is new in the diagnos6cs of tuberculosis in South Africa. Discuss what is new in the management of drug sensi6ve and resistant tuberculosis. Discuss the management of TB in the selng of HIV co-infec6on drug interac6ons and side effects.
Epidemiology of tuberculosis The WHO es6mated 10.4 million new TB cases in 2015, and 580,000 people were es6mated to have had MDR-TB or RR-TB worldwide. An es6mated 9.7% of people with MDR-TB had XDR-TB. People living with HIV accounted for 1.2 million of all new cases. TB is s6ll one of the top 10 causes of death the number of TB deaths fell by 22% between 2000 and 2015 but there s6ll were 1.4 million deaths. South Africa is one of the countries with the highest burden of TB. It has an incidence of 454,000 cases of ac6ve TB with MDR-TB accoun6ng for about 3.3% of these new TB cases. WHO 2015; h`ps://www.tbfacts.org/
Tuberculosis in the cri6cally ill pa6ent Some of the reasons for ICU admission include organ failure - acute respiratory failure, liver failure and renal failure. Mortality for pa6ents admi`ed with ac6ve TB and respiratory failure requiring mechanical ven6la6on is poor, with in-hospital mortali6es of 33 to 67%. It is a treatable disease and a proac6ve approach is required. Delays to star6ng therapy can be associated with worse survival. TB pa6ents in ICU present special challenges - confirma6on of the diagnosis, providing effec6ve an6-tuberculosis treatment in the selng of poor absorp6on and organ dysfunc6on, is a challenge. Hagan G et al. Cri6cal Care 2013; 17:240
Diagnosis of TB In clinical prac6ce, the diagnosis can be difficult. Culture is the gold standard it has the highest sensi6vity for confirming ac6ve TB but take 4-6 weeks. Although microscopy is rapid and inexpensive, it has a low sensi6vity. Nucleic acid amplifica6on tests are highly sensi6ve for the rapid detec6on of MTB in a variety of specimens. South African Na/onal Tuberculosis Management Guidelines 2014
Xpert MTB/RIF Automated molecular plakorm to detect MTB complex and rifampicin resistance - targe6ng specific muta6ons in the rpob gene in sputum. Results available within 2 hours. It can also be used on CSF, aspirates and 6ssue. More sensi6ve test than smear microscopy, therefore it is possible to detect TB in smear nega6ve pa6ents in fact, case detec6on rates in HIV posi6ve pa6ents have increased by 45%. South African Na6onal Tuberculosis Management Guidelines 2014. Lawn et al, Clin Infect Dis 2012; 54: 1071-9.
Genotype MTBDRplus assay for first line drugs This a PCR based hybridisa6on assay. Can only be performed on smear or culture posi6ve sputum. Compared to phenotypic DST, results available within 48 hours. Simultaneously detects MTB complex, muta6ons in the rpob gene (rifampicin resistance) and muta6ons on the katg gene (higher levels of isoniazid resistance) and inha gene (lower levels of isoniazid resistance which is associated with ethionamide resistance). Cannot be used for monitoring pa6ents on treatment. South African Na6onal Tuberculosis Management Guidelines 2014
MDR with inha and katg muta6ons
What s new in TB diagnos6cs? MTBDRsl The availability of rapid second line drug tes6ng in MDR TB smear posi6ve and nega6ve pa6ents to exclude XDR TB. Allows for the rapid detec6on of fluoroquinolone and second line injectable resistance. It is now available with the introduc6on of the short MDR- TB treatment regimen. Cannot be used for monitoring pa6ents on treatment. Proposed South African draq 2017 guidelines courtesy of Dr Nazir Ismail, NICD
Evalua6on of the genotype MTBDRsl version 2.0 assay for second-line drug resistance detec6on of Mycobacterium tuberculosis isolates in South Africa Gardee Y, Dreyer AW, Koornhof HJ, Omar SV, da Silva P, Bhyat Z, Ismail NA. 2017. Evalua6on of the genotype MTBDRsl version 2.0 assay for second-line drug resistance detec6on of Mycobacterium tuberculosis isolates in South Africa. J Clin Microbiol 55:791 800. FLQ SLID Published studies Sensitivity Specificity Sensitivity Specificity Tagliani et al (n=228) 83.6 100 86.4 90.1 Gardee et al (n=268) 100 98.9 89.2 98.5
XDR TB
Anything new in the treatment of drug-suscep6ble tuberculosis? Current treatment includes a four drug regimen. This allows for a more than 95% cure rate. Use of rifampin with isoniazid allowed treatment to be shortened from 18 to 9 months, and the addi6on of pyrazinamide for the ini6al 2 months, allowed further shortening to 6 months. Trials conducted between 1948 and 1986 showed comple6on of 6 months therapy lead to a cure of drug sensi6ve tuberculosis. This is s6ll excep6onally long compared to dura6on of treatment of other bacterial infec6ons. It is associated with toxicity, affec6ng adherence which results in the interrup6on or discon6nua6on of treatment. By adding a fluoroquinolone, trials were undertaken to shorten treatment further to 4 months. Fox W et al. Int J Tuberc Lung Dis 1999; 3: S231-S279. Tuberculosis Trials Consor6um, Division of TB Elimina6on, CDC. Public Health Rep 2001; 116: 41-9. Nunn AJ et al. Int J Tuberc Lung Dis 2010; 14: 241-2.
Drug-suscep6ble TB disease: fluoroquinolone-containing regimens vs. the standard TB drug regimen. Unfortunately, higher relapse rates were noted at 18 months of follow-up, even though at 2 months a slightly higher (not sta6s6cally significant) rate of culture conversion was noted. No evidence of reduc6on of adverse events and no difference in all-cause and TB-related mortality was noted. As a result, there is a concern that this may lead to a rise in resistance and loss of fluoroquinolones for the treatment of drug-resistant TB. Therefore, fluoroquinolones not recommended for now. Gillespie SH et al. N Engl J Med. 2014;371(17):1577-87. Merle CS et al. N Engl J Med. 2014;371(17):1588-98. Jindani A et al. N Engl J Med. 2014;371(17):1599-608. Jawahar MS et al. PLoS One. 2013;8(7):e67030. WHO Guidelines for treatment of drugsuscep6ble tuberculosis and pa6ent care (2017 update)
Change in ART guidelines - ART interac6ons with rifampicin? Adult an6retroviral therapy guidelines 2017. S Afr J HIV Med. 2017;18(1), a776.
What s new in the treatment of drug resistant TB disease? Two new drugs are available for the treatment of drug resistant TB this includes bedaquiline and delamanid. The leprosy drug, clofazimine, repurposed for the treatment of MDR TB. In addi6on, with the availability of rapid second line resistance tes6ng one can opt for the short Bangladesh MDR TB regimen. Criteria for the short MDR TB regimen include confirmed rifampicin resistance or MDR TB with no resistance to second line injectables or fluoroquinolones. WHO Guidelines for treatment of drug-resistant tuberculosis and pa6ent care (2016 update)
Bedaquiline as a new drug for DR-TB It offers a new mechanism by specifically inhibi6ng mycobacterial adenosine triphosphate synthase enzyme. When given with other exis6ng MDR-TB drugs - increases the propor6on of sputum culture conversion to nega6ve aqer 2 and 6 months of treatment, essen6ally reducing the 6me to culture conversion and offering a shorter treatment dura6on. Approved by SA MCC for the na6onal TB program to treat XDR- TB or pre-xdr TB pa6ents in December 2012 via the Bedaquiline Clinical Access Programme (BCAP). Now registered in South Africa since October 2014 for use in HIV-nega6ve or HIVposi6ve, ART naïve pa6ents, 18 years or older and have laboratory confirmed MDR-TB. It is offered via the TB Directorate within the NDOH. South African draq 2017 guidelines courtesy of Dr Xavier Padinilam, Sizwe Hospital, Johannesburg.
Delamanid as a new drug for DR-TB A nitroimidazole with ac6vity against replica6ng bacilli through inhibi6on of mycolic acid synthesis and ac6ve against nonreplica6ng bacilli through genera6on of reac6ve nitrogen intermediates. When given with other exis6ng MDR-TB drugs - shown to improve sputum-culture conversion at 2 months. One must have the standard background therapy for MDR TB disease when using delamanid. Delamanid will be introduced in South Africa in a phased approach similar to bedaquiline via the Delamanid Clinical Access Programme. It is currently not registered in SA. South African draq 2017 guidelines courtesy of Dr Xavier Padinilam,, Sizwe Hospital, Johannesburg. Gler MT et al. N Engl J Med 2012; 366:2151-2160.
Clofazimine It is thought that it acts by inhibi6ng the forma6on of matrixes within the MTB DNA and thus delaying the growth of the bacterium. It was discovered in 1954 for TB treatment. At the 6me, the drug proved to be ineffec6ve at trea6ng TB but showed efficacy in trea6ng leprosy. A meta-analysis of studies show that it could have a major role in the treatment of MDR TB. The most effec6ve treatment regimen required to achieve a relapse-free cure of 87.9% includes a minimum of 9 months with clofazimine, ga6floxacin, ethambutol and pyrazinamide throughout the treatment period supplemented by prothionamide, kanamycin and high-dose isoniazid during an intensive phase of a minimum of 4 months. Dey T et al. J An6microb. Chemother. 2013. 68: 284 293. South African draq 2017 guidelines courtesy of Dr Xavier Padinilam, Sizwe Hospital, Johannesburg. h`p://www.tbonline.info.
The short MDR TB treatment regimen Up to now, the total treatment dura6on recommended for MDR-TB pa6ents 18 20 months. However the op6mal dura6on of treatment has been a ma`er of debate for years. Shorter regimens have recently been evaluated in Bangladesh and in other countries in Africa. The WHO guidelines have been updated in May 2016 in accordance with these findings, and have included a recommenda6on for the use of shorter treatment op6ons if criteria are met. WHO Guidelines for treatment of drug-resistant tuberculosis and pa6ent care (2016 update)
Treatment success rates: shorter MDR-TB regimen vs longer MDR-TB regimens WHO Guidelines for treatment of drug-resistant tuberculosis and pa6ent care (2016 update)
Short MDR TB regimen Bangladesh Regimen This includes a dura6on 9 to 12 months in adult, and paediatric popula6ons. Intensive phase: 4-6 months of Kanamycin, Moxifloxacin, Ethionamide, Clofazimine, Ethambutol, Pyrazinamide, INH (high dose). Con6nua6on phase: 5-6 months of Moxifloxacin, Clofazimine, Ethambutol, Pyrazinamide. Pregnant women offered the possibility of this short regimen with linezolid or bedaquiline or delamanid. Pa6ents need to be treated at a referral centre aqer approval has been received from the Na6onal Advisory Commi`ee. South African draq 2017 guidelines courtesy of Dr Xavier Padinilam. WHO Guidelines for treatment of drug-resistant tuberculosis and pa6ent care (2016 update)
Proposed algorithm Proposed South African draq 2017 guidelines courtesy of Dr Nazir Ismail, NICD
An6-TB drugs recommended for the treatment of rifampicin resistant and MDR TB update) WHO Guidelines for treatment of drug-resistant tuberculosis and pa6ent care (2016
Shared side effects of TB drugs and ART Meintjes G et al. Adult an6retroviral therapy guidelines 2017. S Afr J HIV Med. 2017;18(1), a776.
Conclusion South Africa is currently using all WHO endorsed DR-TB technologies and treatment therapies. All pa6ents should be tested for drug resistance as per diagnos6c algorithm. Early detec6on of SLT resistance is available since Jan 2017 but one must send off pdst. Need to monitor closely for drug side effects.