1. Safe and effective bedaquiline treatment of drug-resistant tuberculosis (DR-TB) within the National Bedaquiline Clinical Access Programme in South Africa
Ndjeka N1, Conradie F2, Hughes J3, Schnippel K2, Cox H4, Bantubani N5, Ferreira H6, Maartens G7, Master I8, Meintjes G7, Padanilam X9, Pym A10, Siwendu S11, Variava E6,2 1National Department of Health, South Africa, 2University of the Witwatersrand, Faculty of Health Sciences, 3Médecins Sans Frontières (MSF), 4 Medical Microbiology, University of Cape Town (UCT), 5TB/HIV Investigative Network (THINK), 6North West Department of Health, 7Department of Medicine, University of Cape Town (UCT), 8KWAZULU-NATAL PROVINCIAL DEPARTMENT OF HEALTH, , 9 Gauteng Department of Health, 10K-RITH: KwaZulu-Natal Research Institute for Tuberculosis & HIV, 11Provincial Government of Western Cape.
National TB Prevalence Survey

2. OUTLINE Background and TB burden in South Africa Methods
Bedaquiline Clinical Access Programme: results
Conclusion

3. Background
The Medicine Control Council (MCC) in South Africa approved a National Programme to treat selected DR-TB patients with bedaquiline (BDQ) in December 2012 and the programme starded in March  
BDQ is diarylquinoline compound with a new mechanism of antituberculosis action by specifically inhibiting mycobacterial ATP synthase

4. TB Burden in RSA
TB patients initiated on treatment decreasing: 406,082 to 332,170 (2009 and 2013)
Treatment success rate: 80,9 % for 2012 cohort
MDR-TB numbers initiated on treatment doubled between 2010 and 2013 (5,313 to 10,719)
MDR-TB treatment success rate of 45 % (2011 cohort > 6,000)
XDR-TB treatment success rate varies between 15 and 20 %

5. Methods
Pre-XDR and XDR TB patients at five approved sites across South Africa were selected by pre-defined criteria

6. Inclusion & Exclusion criteria
Laboratory confirmed pre-XDR and XDR-TB 
Specific inclusion criteria:
Adult male or female patient ≥18 years of age
The BR should be constructed with at least 3 anti-tuberculosis drugs to which the Patient’s infection is known to be susceptible on DST or likely to be susceptible, based on known treatment history
Negative urine pregnancy test prior to starting treatment with bedaquiline
Contraceptive methods prescribed
EXCLUSION
Pregnant or breast-feeding female.
Unstable medical conditions, known allergy to bedaquiline
Patients with the following laboratory abnormalities
Serum creatinine grade 1 or greater (> 1.0 x ULN);
Lipase grade 2 (with no signs or symptoms of pancreatitis) or greater (> 1.5 x ULN);
AST or ALT grade 2 or greater (≥ < 3.0 x ULN);
Total bilirubin grade 1 or greater (> 1.0 x ULN).

7. BDQ Clinical Access Program (BCAP)
Cases were first presented to a national Clinical Advisory Committee
Then, Janssen pharmaceutical approved BDQ with an optimised background regimen.
MCC approval on a named-patient basis

8. Treatment regimen
BDQ 400 mg once daily for 2 weeks followed by 200 mg three times a week for 22 weeks plus an Optimized Background Regimen (OBR) of selected 2nd line drugs used to treat pre- XDR or XDR
The OBR should be constructed with at least 3 anti-tuberculosis drugs to which the Patient’s infection is known to be susceptible supplied by TB programme
The OBR continued beyond the 22 weeks of BDQ

9. Results-Baseline Characteristics
Median Age :34,1 years ( IQR 25.7, 40.9)
Sex M: 56 (61.5%)
HIV infected : 55 (60.5%)
Median CD4+ : 249 (IQR 134; 356)
On LPV/r: 19 (34.5%)
On NVP 36 (65.5%)

10. Results – Baseline characteristics
Drug-resistance patterns:
XDR in 33 (36.3%)
pre-XDR TB (fluoroquinolone) in 41 (45.1%)
pre-XDRTB (injectable) in 1(18.1%)
OBR included:
Clofazimine for 68 (74.5%)
Linezolid for 64 (70%)
Levofloxacin 76 (83.5%)

11. Culture negative at start n=15 Culture negative at start n=6
Enrolled, started on BDQ and included in the analysis n=91 33 XDR-TB 41 pre XDR (FLQ) 17 pre XDR (injectable)
>24 weeks since treatment start n=60
Completed 24 weeks BDQ n=58
Died n=2
Transferred out n=1
Defaulted n=1
On continuation treatment n=54
Culture negative at start n=15
Culture converted n=33
Still culture positive n=6
Did not complete BDQ n=2
Died n=1
<25 weeks since treatment start n=31
Still on treatment n=31
Culture negative at start n=6
Culture converted n=10
Culture pending n=15
Figure 1. Interim outcomes for XDR and pre XDR TB patients enrolled in National Bedaquiline Clinical Access Programme in South Africa
60 patients started BDQ over 6 months ago and 58 patients completed 6 months of treatment (one died and one defaulted)
52 were culture negative at 6 months giving a culture negative rate at 6 months of 86.6%
31 have had less than 6 months of treatment of those 16 have had at least two negative cultures separated by 30 days.
BDQ: bedaquiline; XDR TB: extensively drug resistant TB; FLQ: fluoroquinolone
National TB Prevalence Survey

12. Culture conversion by resistance pattern
Although the numbers are small, the rate of culture conversion is not affected by resistance patterns.
National TB Prevalence Survey

13. Culture conversion by HIV status status
All patients who were HIV infected were on ART at the time of starting BDQ. There is not difference in the culture conversion rate by HIV status.
National TB Prevalence Survey

14. Results – median QTcF

15. Results – QTc
One patient developed atrial fibrillation on BDQ and was withdrawn from BDQ treatment
At BDQ start, median QTcF was 408ms (IQR ):
Median increase of 8ms (IQR ) at 2 months
14 patients had increases of >40ms
2 had QTc >500ms (BDQ temporarily withdrawn in one and the other resolved in 24 hours)

16. Results – QTcF by ART regimen
Although there are small numbers, there increase in QTcF does not appear to be greater in patients who are given LPV/ vs NVP. Also of note that that patient with a QTcF at two and three months was no NVP and not LPV/r
National TB Prevalence Survey

17. Results – QTcF by clofazimine exposure
National TB Prevalence Survey

18. Overview of SAEs in the global Safety Database in S
Overview of SAEs in the global Safety Database in S. Africa June ⱡ
 Review of 15 patients with SAE. ⫛
The general pattern and frequency of reported events including deaths and events of QT prolongation are in line with the known safety profile of BDQ
3 reports of death; none related to BDQ per the investigator
3 reports of QT prolongation with causality of probable or possible per the investigator. All 3 resolved.
3 reports of psychosis/mood disorder/delusion; none related to BDQ per the investigator. All 3 were receiving Terizidone (prodrug of cycloserine with known ADR of mood disorder)
⫛SAEs by Dr Dannemann, Sirturo Medical Leader showed:
ⱡOnly SAEs required to be reported; no site monitoring done

19. Conclusion
The programme has allowed access to better treatment hence the good interim outcomes for (pre-)XDR patients with otherwise limited options and poor prognosis
Access has already been extended to other sites bringing the total of sites to 12
Bedaquiline is now registered in South Africa and will be used next year within the TB programme under strict control

20. Thank you!!!