The shorter regimen for MDR-TB: evidence and pitfalls

Transcription

1 The shorter regimen for MDR-TB: evidence and pitfalls Helen Cox 10 November 2017

2 What is the shortened regimen? Current conventional regimen (SA): Intensive Phase (at least 6 months): PZA / (EMB) / Kana / MFX / TRD / ETO or hdinh Continuation Phase (until 18 mths post-culture conversion): PZA / (EMB) / MFX / TRD / ETO or hdinh Recommendation, May 2016 No Terizidone/ Cycloserine Added Clofazimine 7 drugs in intensive phase 2 second-line drugs in continuation phase

3 WHO recommendations for 9-12 month shortened regimen In patients with RR-TB or MDR TB: who have not been previously treated with second-line drugs, and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely a shorter MDR-TB regimen of 9-12 months may be used instead of conventional regimen Other exclusions: pregnancy, extra-pulmonary TB Conditional recommendation very low certainty of evidence

4 What is the evidence? The Bangladesh regimen 4(+) Km-Cfz-hdGfx-E-H-Z-Pto 5 hdgfx-e-z-cfz 515 patients 435 (84.5%) treatment success 50% completed treatment in 9 months 95% by 12 months Relapse: 4 relapse cases over 2 years of follow-up Aung et al Int J TB Lung Dis 2014

5 What is the evidence? Individual and aggregate meta-analysis of data from 5 countries WHO based their conditional recommendation on this analysis Country N Treatment success HIV + Bangladesh %? But low Cameroon % 20% Uzbekistan 64 70% 0% Niger 65 89% 1.7% Swaziland 24 71% 67% Poorer outcomes were associated with fluoroquinolone or pyrazinamide resistance 18% patients had grade3/4 adverse events Pooled % Shorter Conventional Loss to follow up 5% 23% Khan et al Eur Resp J 2017

6 Treatment outcomes with the conventional month regimen South Africa also reports 54% treatment success WHO Global TB Report 2017

7 STREAM stage 1 preliminary results just out Randomised controlled trial conducted in Ethiopia, South Africa, Vietnam and Mongolia Comparison of 9-month regimen similar to Bangladesh regimen (moxifloxacin instead of gatifloxacin) Non-inferiority design (10%) Modified ITT efficacy analysis N Study 9 month regimen Control month regimen Favourable outcome 164 (78.1%) 87 (80.6%) Unfavourable outcome 46 (21.9%) 21 (19.4%) Crude difference in response (95% CI) Standardised difference in response (95% CI) 2.5% (-6.9% %) 2.1% (-6.9% %) Presented at Union TB conference, Mexico, Oct 2017

8 STREAM stage 1 results, cont Study 9 month regimen Control month regimen Total assessed Unfavourable outcomes 46 (21.9%) 21(19.4%) Started 2 additional drugs Extended Tx beyond allowed (11 mths for study reg) 24 (11.4%) 6 (5.6%) 4 (1.9%) 0 (0%) Died 12 (5.7%) 6 (5.6%) Lost to follow up 6 (2.9%) 7 (6.5%) Treatment failure 0 (0%) 2 (1.9%) Presented at Union TB conference, Mexico, Oct 2017

9 STREAM stage 1 results, cont Both regimens had a high level of success (compared to programmatic results) Non-inferiority not demonstrated statistically Selected patients included in RCTs Both regimens had very low loss to follow up levels, suggesting that the main benefit from a shorter regimen, ie. less treatment fatigue, is potentially negated in an RCT where both patient groups receive personalised support and follow up. Is an RCT the best trial to use? More realistic to test under pragmatic, programmatic conditions?

10 Current use of shorter regimens (by end 2016) 2934 patients treated with shortened regimen by Oct WHO Global TB Report 2017

11 Potential advantages Reduced loss to follow up through reduced treatment duration Less arduous for patients shorter duration of both injectable and total duration More patient-centred Greater number of drugs in the intensive phase, when bacterial burden is highest Potential for reduced resistance amplification Less costly to implement (total cost estimated at US$1000, compared ~US$5000+ for conventional regimen) Potential to increase access to treatment in many high burden settings Improved efficacy (independent of reduced loss to follow up)?? But, similar efficacy in RCT - STREAM

12 Potential disadvantages Restricted eligibility to receive the shortened regimen Dependent on good treatment history and timely access to second-line drug susceptibility testing to rule out resistance to either fluoroquinolones or second-line injectables. Potential for increased resistance amplification Shorter intensive phase leaving less time to determine if patients have really culture converted before switching to the continuation phase Continuation phase contains only 2 second-line drugs (fluoroquinolone and clofazimine). Limited DST available for clofazimine. Cross-resistance between clofazimine and bedaquiline Possibly threatens potential of future bedaquiline containing regimens

13 Access to second-line drug susceptibility testing 39% of RR/MDR- TB cases received SL DST in % SL DST in South Africa WHO Global TB Report 2017, Jacobson et al, Clin Infec Dis 2017

14 Other concerns: pre-existing resistance Resistance among MDR-TB cases Global metaanalysis South African national survey Pyrazinamide 50% 59% Ethambutol 61% 44% Ethionamide 29% 45% 73% of MDR-TB in KZN has katg mutation conferring high level INH resistance Shortened regimen: Falzon et al Eur Resp J 2012, NICD National Resistance survey, 2016, Niehaus et al. PLoS ONE 2015

15 Other concerns Still requires high patient support as includes toxic drugs and is still lengthy treatment Still associated with high adverse events, including permanent hearing loss (injectable agents) Difficulties with clofazimine availability and cost - difficulties in supply Registered for the treatment of leprosy, not TB One quality assured manufacturer internationally - prioritises leprosy treatment Monitoring with culture or smear timing of results and stopping injectable/intensive phase

16 Potential impact of a shorter regimen Modelling analysis, based on representative southeast Asian setting Scenario % reduction in MDR-TB incidence in 2024 (per 100,000 popn) with shorter regimen Shorter regimen which doubles treatment access and improves efficacy (83%) Shorter regimen which only increases efficacy 23% 14% Shorter regime only improves access 11% 30% of MDR-TB cases are ineligible 2% Kendall et al. Lanc Resp Med 2016

17 Increasing access to treatment Global access to treatment = 23% of estimated burden WHO Global TB Report 2017

18 How many patients would be eligible in South Africa? 2012/14 SA National TB drug resistance survey Among MDR-TB: FLQ resistance 8.1% XDR-TB 4.9% SL INJ resistance 8.1% 13% Ofx resistance 13% SL INJ res 4.9% XDR-TB 21.1% any SL res ~79% of MDR-TB patients in SA could be eligible, but poor access to SL DST

19 Conclusions and some thoughts Some key benefits for patients and programmes Likely to reduce loss to follow up and is less arduous for patients Concerns about pre-existing resistance valid, but also present with current standardized regimens Impact on resistance amplification not clear Potential to drive improved access to second-line DST Available now for a significant proportion of patients with RR-TB in many high burden settings Results from clinical trials using shorter regimens with new drugs still awaited likely to be some years Can be seen as a interim measure to improve access to treatment and patient outcomes until more effective, tolerable and shorter regimens containing new drugs are available

20 More effective, more tolerable and shorter treatment required!