Iqbal Master Clinical Manager King Dinuzulu Hospital complex MDR TB UPDATE AWACC 2018

Transcription

1 Iqbal Master Clinical Manager King Dinuzulu Hospital complex MDR TB UPDATE AWACC 2018

2 Challenges MDR faced & what was achieved The current program Key drugs The New Regimens Stats

3 Limited facilities/ MDR beds- in Primitive conditions KDHC (only unit ) - Prefab buildings with Wood Borer Limited follow up Patients refused to be admitted far from home Policy of admitting until culture conversion Long waiting lists with increased deaths No National MDR policy / Guideline MRC had Guideline Document Poor documentation of stats & outcomes Poor Infection control measures Little separation of TB / MDR TB Limited Drugs - with high treatment failure rates Experts said treat Sensitive TB properly and we need not worry about DR TB Some visionaries were justifiably concerned!

4 KDHC MDR Clinic- Single Room attached to a Mortuary

5 Virally suppressed RVD patients were dying of TB Cultured isolates revealed XDR TB Could no longer hide from DR TB National Made Key decisions DR TB would become a priority program Clinicians sent to Latvia for DR TB training (Dec 2006) Tugela Ferry would change the face of DR TB in the world

6 Increased and unpacked the MDR beds in all provinces Opened Decentalized units in almost every District Dedicated funding for the MDR Program For infrastructure / Human resource /Medicines Adopted a model of decentralized care approved by WHO / modeled on Umzinyathi district program Outpatient initiation of stable MDR patients Initiated MDR treatment at clinic level Move to offer MDR care at CHC / PHC level ( work in progress ) National Goal Put all MDR patients on treatment within 5 days (Achieved in many areas) National TB Program assessed the situation, engaged with stakeholders and put in policies that dramatically improved the situation

7 Formed an expert committee Designed country specific guidelines /Engaged with WHO Regular training on MDR for nurses and clinician NIMDR training Support (Nurse initiated MDR Rx) Partner Support to strengthen program -NGOs Active support for Research to get answers (Stream/NIX) Design program specific tools Electronic DR TB register/mdr Register (paper based )/tools Program success can only be assessed with good data Dept successfully increased the knowledge base on MDR and facilitated data capture to assess success of program

8 Implemented GXP/LPA/Reflex test. Rapid Screening / Diagnosis Poor Outcomes High Mortality/Toxic drugs/long Regimens Roll out of new drugs BDQ/LZD/DLM (2013) world leaders Shorter regimens (2017) Substitution for Drug Toxcity (Oto-Nephrotoxicity) Roll out of a Strong ARV program Support for new program (ECGs/ audio / training) Measures allowed rapid diagnosis / shorter regimens / less toxicities / increased knowledge / improved outcomes

9 Date History of SA DR-TB Program Before Individualized treatment MDR Standard Treatment 6 Mths/ 18 Mths Kana/Moxi/Ethio/PZA/Teriz XDR / PReXDR - Individualized treatment Implementation of new drug program (BCAP ) BDQ + LZD for - XDR /Pre-XDRs MDRs Rx - Drug toxicities + Rx failures Pregnancy 2017 (June KZN) Short MDR Regimen & Short BDQ regimen Except for XDR/ Pre-Xdrs / Complex TB 2017 (Mar 2018) DCAP BDQ/LZD/DLM - for XDR / PRe-XDRs 2018 ( July) Injection Free regimen for MDRs

10 Bedaquiline is used for 24 weeks Long half life ( 5 months) 400 mg (daily) for 2 weeks / 200 mg (3 times a week) for 22 weeks BDQ can be extended in certain cases (Discussion with NCAC) Levofloxacin preferred to Moxifloxacin with BDQ (lower QTCf risk) Monitoring ECG - 2 weekly for 1 st month & monthly thereafter Drug Interactions QT prolongation - Enzyme Induction ARV switch often required Need to Switch EFV in FDC (Decreases BDQ levels) Can Switch - EFV to NVP or to Alluvia (Lopinavir/Retonovir) / Depends on Baseline CD4 / Hepatitis / Allergies / Viral suppression Raltegravir / Rilpivarine / Dolutegravir are also future options in public sector BDQ is used for 6 months 10/4/2018 Dr. Norbert Ndjeka 10

11 XDR or Pre- XDR MDR TB MDR - Both inha and KatG mutation MDR with known intolerance or developed intolerance to 2 nd line Rx Drug Toxicities Pre-XDR or XDR - with limited RX options Drugs compromised by failure/ poor adherence Age < 18 years Pre-XDR, XDRs, Treatment Failure, Drug toxicities Pregnancy & MDR/XDR MDR Rx failures (without proven XDR/Pre-XDRs) 11

12 BDQ excretion occurs in breast milk 6-12 times higher levels than in plasma ( rats) No human studies European guidelines suggest Formula Feed Some reports of lower growth in babies Thus from safety issue (for now) Assess risk to newborn ( positivity of mother) social circumstances and support available Weigh up risk vs benefit

13 Slowly have Expanded Bedaquiline access Sites still not ready Montobello /Stanger/ Vryheid / Hlabisa Requirements to expand Knowledge, understanding & training on MDR & BDQ issues ECG machine Adequate recording & reporting Competence in managing MDRs

14 Linezolid no effect on the QT interval Currently using 600mg OD Can be reduced to 300mg if A/E Long term usage is associated with serious A/E Bone marrow suppression Thrombocytopaenia / Anaemia / Neutropaenia Avoid or transfuse if Hb < 8 g/dl Severe peripheral neuropathy Optic neuritis reversable if picked up early Lactic acidosis -? due to mitochondrial toxicity Monitoring Regular FBC Assess vision Snelllen +? Ishihara tests Assess Neuropathy 14

15 Novel TB Drug related to Metronidazole (Otsuka) Bound by albumin Safety Established in children No ARV switch required ECG monitoring required (QT issues) Possible Low barrier for resistance than BDQ Not registered used as section 21 drug Available via a Compassionate usage program DCAP program

16 DCAP (400 donated courses) Registered with MCC (SAHPRA)/ National Research Program Only registered sites and clinicians can access ( 4 including KDHC) SAHPRA has restricted further expansion so far KDHC 130 patients ( 6 mths) ~ 200 in SA Primary recommendation All XDRs / Pre-XDRs esp - FQ resistance / treatment failures (BDQ/LZD & Delaminid can be used together) Indications Where BDQ contraindicated QTC years of age and < 65 years > 20 to 30 kgs Anaemia to replace LZD Diabetes Mellitus - expected poor outcomes Compassionate usage program Treatment failures falling outside DCAP criteria Difficult, complicated process (Pregnant ladies /> 65 years/ No access to DCAP/< 6 years)

17 Plan Assess & reinforce Adherence Complete adequate course of treatment (12-24 mths) Do a Extended Sensitivity test Culture sent to NICD ( National Lab ) Linezolid /Rifabutin /BDQ and Clofazimine Look at salvage regimen based on above NICD test Consider Carbepenams / DLM / BDQ /LZD Consider Surgery Optimize HAART Enhanced adherence counselling & commitment Non BDQ/LZD failures considered for the NIX study

18 WHO convened a meeting on July 2018 Meta-analyses of patients in multiple studies and trials To Compile evidence based MDR guidelines preliminary document WHO revised MDR guidelines (preliminary) Compiled a List of medications recommended for long regimens Short course regimens can be used in selected patients but with stricter criteria ( some African and Asian countries) Substitution with BDQ in a short regimen not recommended Not yet enough evidence for a Short Bedaquiline regimen Injectables recommended in short course but amikacin (not Kanamycin) The SA MDR program under tremendous pressure to implement injection free regimens SA experts confident enough to implement an injection free short regimen.

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20 Summary of MDR-TB Regimens in SA Standard Short Regimen All new patients 4-6 Km + Mfx + Cfz + Eto + Z + H + E / 5 Mfx + Cfz + Z + E Short Bedaquiline Regimen Switched If A/Es 4-6 Bdq + Lfx + Cfz + Eto + Z + H + E / 5 Lfx + Cfz + Z + E Standard Extended Regimen Severe X/Pulm TB 6-8 Km + Mfx + Cfz + Eto + Z + H + E / Mfx + Cfz + Z + E Individualised Extended Regimen mths Xdr /Pre-XDR/Both mutations/ Failures - Pyridoxine Supplementation All regimes including Cycloserine, Terizidone or high dose INH should add pyridoxine/b6

21 4-6 months (Intensive Phase): Kanamycin INH high-dose Ethio Mfx Cfz Z - E BDQ 6 mths LZD 2 mths LFX 6 months 5 months (Continuation Phase): Mfx Cfz Z E LFX 6 months Indications RR-TB, MDR-TB, Rif mono TB Uncomplicated EPTB Pregnant women NCAC Children > 12 MFX could be used after BDq to use up stock or if Levo short

22 DURATION OF DRUGS ADMINISTRATION Linezolid Isoniazid high dose Bedaquiline Levofloxacin Clofazamine Pyrazinamide Ethambutol 2 MONTHS 4 MONTHS 6 MONTHS 9 MONTHS Continue for another 2 months if smears still positive at 4/12 Continue in some 22

23 LONG REGIMEN = GROUP A & B DRUGS IN NEW WHO HIERARCHY OF DRUGS 23

24 6 8 months (Intensive Phase): Bdq Lzd Lfx Cfz Tzd 12 months (Continuation Phase): Lfx Cfz Tzd Indications Previous exposure to 2nd line anti-tb agents 1 month MDR TB with Both INH mutation Pre-XDR (INJ) Where 2 nd line resistance is suspected. Close contact of pre/xdr, both INH mutations, Complicated/severe EPTB (CNS, osteoarticular,? pericardial) Extensive disease When clinician is unsure if short course ok If toxicity to core drugs - can be substituted with 2 drugs from category C 24

25 6 8 months (Intensive Phase): Bdq Lzd Cfz Tzd + (DLM or PAS) + (Ethio or hdinh) + Z 12 months (Continuation Phase): Lzd Cfz Tzd + (Ethio or hdinh) + Z Indications XDR / PRe-XDR (FQ) 2nd line Treatment failure 25

26 Patients on injectable regimen will continue Patients on injectable with toxicities (renal toxicity or ototoxicity) will be switched to BDQ as per existing policy Provincial TB in consultation with key role players will decide on timeline for roll out Children Injection free is possible in children LZD can be used in all age categories DLM or PAS used instead of BDQ until BDQ dosaging approved DLM can be used down to age 3 (not in DCAP )

27 KZN Team

28 KZN Bedaquiline Program Data 17/8/2018 Patients applications received 4852 Patients approved by KDHC 4682 Application per site - KDHC 2722 Doris Goodwin 373 Cath Booth 279 Don Mackenzie 267 Murchison 214 Estcourt 142 Manguzi 137

29 HIV Status NO of Pat. % HIV POS 3755/ % Age Patients % < % % 18 to % 30 to % 40 to % 50 to % > % Total 4854

30 Indication for BDQ Pregnancy % INH mutations % XDR % PReXDR % Ototoxicity % 4854

31 Rx success Died LTFU Failure 0 PreXDR(FQ) - 78 PreXDR(SLI) - 33 XDR - 87 BCAP program was mainly in XDRs and Pre-XDRs Marked improvement in XDR outcomes Some provinces XDR outcomes better than MDR outcomes

32 HIV IN KDHC PATIENTS 2015 (EDR) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 98% 76% 24% Pos Neg ON ART 32 32

33 MDR AND XDR IN KDHC FROM Manual Data from Electronic Data from MDR XDR

34 70.0% 62.6% 60.0% 58.8% 58.3% 57.7% 54.1% 59.0% 55.7% 50.0% Rx success 44.0% Default 40.0% Died 30.0% failure 20.0% 10.0% 20% 16.0% 10.8% 10% 8.10% 9.2% 9.50% 20.3% 24.9% 14.50% 13.70% 23.4% 22.9% 23.5% 15.60% 16.30% 12.29% 1.60% 1.70% 1.80% 1.70% 1.0% 1.0% 1.6% 0.0%

35 70% 60% 58% 62% 58% 58% 54% 59% 55% 50% 44% 46% 44% 48% 40% 30% 31% 35% 33% 34% MDR XDR 20% 18% 10% 0%

36 Failure-2.5 LTFU KDHC Outcomes Rx Success Died LTFU Failure Died Rx Success

37 1. Yes 2. No 3. Not sure

38 1. Amikacin/Moxi/BDQ/PAS/Ethio/INH 2. Kana/Levo/Terizidone/PZA/Clofaz/INH 3. BDQ/LZD/Clofaz/Levo/ Terizidone 4. BDQ/PZA/EMB/Levo/INH/Ethio

39 1. Continue AZT/#TC/Alluvia its fine 2. Change to TDF/#TC/Alluvia 3. Change to AZT/#TC/NVP 4. Change to D4T/#TC/Dolutegravir

40 1. Yes we are doing well 2. Doing Ok under the circumstances. 3. Not sure Time will tell 4. I m scared. We are messing up big time Fools rush in where angels fear to tread

41 Paediatric MDR needs attention Paediatric Case finding is weak (Not diagnosed) No child friendly preparations - suboptimal preps Data entry is Lagging - real time needed? New drugs - are they affordable? Funding for the program New drugs / Human resource/ Maintainance Retention of experienced MDR staff? Defaulter rates remain high ( 23% ) Are we doing enough to protect the new drugs Bedaquiline is being offered to all - (including defaulters) Will we lose the new drugs because of high defaulter rates? Are the outcomes in the short course in RSA as good as expected Will injection free regimens prove to be effective?

42 34 year old male patient - HIV Positive (on ARVS) Diagnosed as MDR in Nov 2015 Gene Xpert - RR Applied for Bedaquiline for Ototoxicity Started a MDR regimen with Bedaquiline & Linezolid in Dec 2015 Defaulted MDR and ARV therapy after 1 month Returned in 2017 GXP RR Reflex test showed XDR TB Extended Testing showed Resistance to Bedaquiline BDQ was compromised after 1 mth exposure & default BDQ has a long half life (5 mths) Even if you default all your meds / BDQ is in tissues and can become resistant. Poor compliance poses a real risk to the new drugs

43 As an MDR program we have had to face many challenges but with good leadership we have achieved and overcome much. We have become the leaders and the visionaries on the world map But yet the war is not won and there are still more challenges that face us. We need to be firm, unite and continue the struggle, so that we can hopefully overcome our nemesis, our arch enemy, the scourge that is TB!

44 All health care workers who have worked diligently in HIV and TB. Often beyond the call of duty (in suboptimal situations) May you be richly rewarded! Thank you!