1. SA TB Guidelines – The interface with Advanced Clinical Care Dr Kogie Naidoo Head: CAPRISA Treatment Research Programme Annual Workshop on Advanced Clinical Care Durban, 20 November 2015

2. Presentation Outline Diagnostic algorithm for DR and DS TB Retreatment TB: Revised definitions and treatment regimen ART initiation in TB patients Special considerations:  Aluvia with TB treatment  Atazanivir in TB  Ethambutol in Renal failure  Moxifloxacin and streptomycin indications TB prevention in HIV infected patients ART initiation in TB patients

3. Currently available TB Diagnostic tests

4. Which initial TB diagnostic test does WHO recommend for HIV + people with suspected TB? 1.Smear Microscopy 2.Xpert MTB/RIF 3.Culture

5. Which initial TB diagnostic test does WHO recommend for HIV + people with suspected TB? 1.Smear Microscopy 2.Xpert MTB/RIF 3.Culture

6. Where GeneXpert (GXP) is available, culture may still be required for: 1. HIV positive TB suspects, who have a negative GXP test 2. TB cases diagnosed as Rifampicin(Rif) resistant on GXP for susceptibility testing of other drugs 3. Despite a Rif susceptible result, the patient is failing treatment and treatment adherence is good and thus resistance to drugs other than Rif is suspected 4. All of the above

7. TB SUSPECTS TB and DR-TB contacts, non-contact symptomatic individuals, re-treatment after relapse, failure and default Collect one sputum specimen at the health facility under supervision GXP positive Rifampicin susceptible GXP positive Rifampicin resistant GXP positive Rifampicin unsuccessful GXP negativeGXP unsuccessful Treat as TB Start on Regimen 1 Send one specimen for microscopy Treat as MDR-TB Refer to MDR-TB Unit Treat as TB Start on Regimen 1 Collect one specimen for microscopy Culture & DST / LPA Collect one sputum specimen for a repeat GXP HIV positiveHIV negative Collect one specimen for culture and LPA or culture and DST (for R and H) Treat with antibiotics and review after 5 days Do chest x-ray Treat with antibiotics Poor response to antibiotics Clinically TB TB on chest x-ray LPA/ DST results Resistant to R and H/ R only Good response No further follow up Advise to return when symptoms recur Poor response Consider other diagnosis Refer for further investigation Treat as MDR-TB Refer to MDR-TB Unit Treat as TB Start on Regimen 1 Review culture results Follow up with microscopy Collect one specimen for microscopy, culture and DST for Rifampicin, Isoniazid, fluoroquinolone and Aminoglycoside Follow up with microscopy and culture

8. Where GeneXpert (GXP) is available, culture may still be required for: 1. HIV positive TB suspects, who have a negative GXP test 2. TB cases diagnosed as Rifampicin(Rif) resistant on GXP for susceptibility testing of other drugs 3. Despite a Rif susceptible result, the patient is failing treatment and treatment adherence is good and thus resistance to drugs other than Rif is suspected 4. All of the above

9. Advantages and Disadvantages of GXP Test Detects MTB and Rif resistance Rapid TAT Specific for MTB complex Use in CSF, gastric aspirates, lymph nodes, tissue ↓ Risk of cross- contamination & error > sensitivity than microscopy Cannot be used for monitoring treatment (cannot distinguish between live and dead bacilli) Discordant results Unsuccessful test due to lab errors, test failure or invalid results. Needs repeat with second specimen Expensive Does not detect INH resistance

10. Retreatment TB Definitions Previously treated: past TB treatment > 4 weeks & now either relapse, defaulted, or treatment failure(+/- microscopy; PTB/EPTB) Relapse: TB again after previous cure/Rx completion – either true relapse or new infection Retreatment after failure: Received full course of treatment and remains or becomes smear or culture positive at the end of the treatment period Retreatment after default: completes one month of treatment and returns foll a 2 month treatment interruption

11. Streptomycin is indicated for: 1.All categories of DS TB 2.All categories of retreatment TB 3.For patients that cannot tolerate first line TB medication 4.All of the above 5.None of the above

12. TB SUSPECTS TB and DR-TB contacts, non-contact symptomatic individuals, re-treatment after relapse, failure and default Collect one sputum specimen at the health facility under supervision GXP positive Rifampicin susceptible GXP positive Rifampicin resistant GXP positive Rifampicin unsuccessful GXP negativeGXP unsuccessful Treat as TB Start on Regimen 1 Send one specimen for microscopy Treat as MDR-TB Refer to MDR-TB Unit Treat as TB Start on Regimen 1 Collect one specimen for microscopy Culture & DST / LPA Collect one sputum specimen for a repeat GXP HIV positiveHIV negative Collect one specimen for culture and LPA or culture and DST (for R and H) Treat with antibiotics and review after 5 days Do chest x-ray Treat with antibiotics Poor response to antibiotics Clinically TB TB on chest x-ray LPA/ DST results Resistant to R and H/ R only Good response No further follow up Advise to return when symptoms recur Poor response Consider other diagnosis Refer for further investigation Treat as MDR-TB Refer to MDR-TB Unit Treat as TB Start on Regimen 1 Review culture results Follow up with microscopy Collect one specimen for microscopy, culture and DST for Rifampicin, Isoniazid, fluoroquinolone and Aminoglycoside Follow up with microscopy and culture

13. Streptomycin is indicated for: 1.All categories of DS TB 2.All categories of retreatment TB 3.For patients that cannot tolerate first line TB medication 4.All of the above 5.None of the above

14. TB Treatment if unable to treat with standard first line Missing drugPossible regimenDuration of treatment INHMoxifloxacin/ rifampicin/ ethambutol 12 months ±PZA in intensive phase RifampicinMoxifloxacin/ INH/ ethambutol 18 months(PZA or streptomycin in intensive phase) Rifampicin/INHMoxifloxacin/ ethambutol/ streptomycin 18 months PZARifampicin/INH/ ethambutolNine months

15. TB Drugs in Renal failure INH, rifampicin, PZA : biliary excretion  normal doses Streptomycin and ethambutol : can maintain at reduced dose – monitor for uveitis Safest regimen: INH, Rifampicin, pyrazinamide X 4 months followed by INH and Rifampicin x 2 months

16. Managing TB treatment Interruption Less than 1 month: extend treatment for the number of days that patient did not take treatment 1-2 months missed: do geneXpert  Sensitive: add number of days that patient did not take treatment.  Resistant: stop treatment: refer to MDR-TB unit More than 2 months missed (loss to follow up) do geneXpert  Sensitive : restart treatment  Resistant : refer MDR-TB

17. TB Prevalence & Incidence in SA: WHO Global Report 2015 696/100 000 All: 834/100 000 HIV+:509/100 000

18. Integration of TB HIV Services Screening for TB and HIV at same visit Early initiation of ARVs Co-management of Drug toxicities common to both Consideration of Drug interactions Early detection and management of TB IRIS Initiation of INH prophylaxis

19. Why start ARVs early?

20. How early should ART be initiated?

21. Balance of risks and benefits For CD4 count <50 cells/mm 3 For CD4 ≥50 cells/mm 3 Early integrated therapy has: 68% lower AIDS /death rate overshadows - 5-fold higher risk of IRIS - Increasing trend in drug switches Early integrated therapy has: No discernable benefit in AIDS /death rate - 2-fold higher risk of IRIS - ↑ drug switches Recommend: Early ART initiation as soon as possible after TB treatment initiation Defer ART initiation to start of continuation phase of TB therapy

22. SA guidelines for HIV-TB co-infected ACTIVE TB DISEASE, IRRESPECTIVE OF CD4 COUNT OR CLINICAL STAGE

23. In TB co-infection, start with TB treatment first, followed by ART as soon as possible and within 8 weeks If CD4 <50 cells/μl initiate ART within 2 weeks of starting TB treatment, when the patient’s symptoms are improving and TB treatment is tolerated If CD4 >50 cells/μl initiate ART within 2-8 weeks of starting TB treatment In cryptococcal or TB meningitis: Defer ART initiation for 4-6 weeks

24. TB service One-stop service HIV service NO To Referral HIV testing ART CPT Condoms Partially integrated HIV and TB Services provided together ART TB diagnosis and treatment Co-located Adjacent NO To Referral TB screening IPT TB diagnosis TB treatment TB contact tracing Partially integrated Models for integrated TB and HIV services delivery Integrated service delivery Source: WHO

25. Concerns of co-treating TB and HIV Overlapping Toxicity Drug Interactions IRIS

26. What are the overlapping drug toxicities with TB treatment and ARVs? 1.Liver Injury 2.Rash 3.Psychosis 4.All of the above

27. Side-effectAntiretroviral drugTB Therapy Nausea & vomitingDidanosine, Zidovudine, Ritonavir Pyrazinamide HepatitisNevirapine Efavirenz Rifampicin Isoniazid Pyrazinamide Peripheral neuropathy Stavudine Didanosine Isoniazid Rash Psychosis Renal Toxicity Nevaripine Efavirenz EFV Tenofovir Rifampicin Isoniazid Pyrazinamide Ethambutol INH/Ethambutol Rifampicin Overlapping Toxicities with co-Rx of HIV and TB

28. What are the overlapping drug toxicities with TB treatment and ARVs? 1.Liver Injury 2.Rash 3.Psychosis 4.All of the above

29. Case 1 Mrs AA is HIV + since 2010. She was initially started on TDF / 3TC and EFV. In 2014, she was changed to ABC / 3TC and Alluvia due to treatment failure. She now presents with night sweats, loss of appetite and abdominal pain. The Gene Xpert test on ascitic fluid is positive for Rif sensitive MTB

30. How to do you manage further? 1.Start TB Rx, double the dose of Alluvia immediately 2.Start TB Rx, double the dose of Alluvia over 2 weeks 3.Double the dose of Alluvia over 2 weeks then start TB Rx

31. How to do you manage further? 1.Start TB Rx, double the dose of Alluvia immediately 2.Start TB Rx, double the dose of Alluvia over 2 weeks 3.Double the dose of Alluvia over 2 weeks then start TB Rx

32. Mrs AA improves on TB Rx and completes the course. Her symptoms and signs have resolved, and her exit sputum is negative for AFB. How do you manage further? 1.Reduce Alluvia dose to 2T bd immediately 2.Continue TB Rx for two weeks longer 3.Continue the double dose (4T bd) of Alluvia until 2 weeks after TB Rx is completed

33. Mrs AA improves on TB Rx and completes the course. Her symptoms and signs have resolved, and her exit sputum is negative for AFB. How do you manage further? 1.Reduce Alluvia dose to 2T bd immediately 2.Continue TB Rx for two weeks longer 3.Continue the double dose (4T bd) of Alluvia until 2 weeks after TB Rx is completed

34. Case 2 Mr E has been on a second line regimen for a year. His regimen includes AZT/3TC/ATZ/rit because he had severe diarrhoea whilst on Aluvia. He now presents with fever and productive cough. His sputum Gene Xpert is positive for Rif sensitive MTB.

35. How do you manage further? 1.Commence TB treatment immediately 2.Double the dose of Atazanavir as you do for Aluvia 3.Atazanavir may not be given to patients on TB treatment. Refer to specialist 4.Stop the ART, treat TB, then restart ART

36. How do you manage further? 1.Commence TB treatment immediately 2.Double the dose of Atazanavir as you do for Aluvia 3.Atazanavir may not be given to patients on TB treatment. Refer to specialist 4.Stop the ART, treat TB, then restart ART

37. Drug Interactions: 1. RIF and EFV Previously reported that Rif caused a 30% decrease in EFV trough concentrations, particularly in patients >50kg. An increase in EFV dose recommended by FDA (USA) Later reports → clearance of EFV is reduced in black African patients, due to CYP enzyme polymorphisms (therefore drug levels actually increased by 30-50%) No increase in EFV dose recommended in SA

38. 2. RIF and NVP NVP clearance may vary between ethnic groups Standard NVP dose is effective when co- administered with RIF Increased hepatotoxicity, especially during the first two months of NVP containing ART

39. 3. RIF and PI PI metabolized by CYP 3A4: induced by Rifampicin and inhibited by Ritonavir Significant reduction of plasma drug levels of most PI’s, except Ritonavir LPV/r (Aluvia): Ritonavir boosted Lopinavir (400/100mg) Increase Ritonavir to 400mg daily to overcome the enzyme induction – double Aluvia dose  Usual 2T BD, increased to 3T BD for 1 wk then 4T BD  Maintain escalated dose of PI until 2 wks after TB Rx completion Rif accelerated Atazanavir/r metabolism, cannot be overcome by boosting with Ritonavir  Referral to higher centre to change PI or change Rifampicin to Rifabutin

40. TB IRIS TB diagnosed & treatment started before ART initiation No TB diagnosis before ART initiation ART Initiation Clinical deterioration of TB as a result of ART-induced immune recovery = Paradoxical TB IRIS Atypical inflammatory presentation of TB as a result of ART-induced immune recovery = Unmasking IRIS Lawn Expert Rev Anti Infect Ther, 2011.

41. TB IRIS incidence and outcomes Unmasking TB IRIS Incidence 4.8% (most common ) Paradoxical TB-IRIS Incidence 18% Onset 14 days after ART initiation in 48% Hospitalisation 25% Mortality 7%, death attributed to TB IRIS 2% Increased mortality in CNS IRIS

42. Major TB-IRIS risk factors Low CD4 count Short interval between TB treatment and ART Disseminated TB

43. TB IRIS Management Double-blind, placebo-controlled RCT Intervention: Prednisone 1.5mg/kg/day x 2 wks then 0.75mg/kg/day x 2 wks Primary outcome = hospital days Findings: Steroid arm - fewer days in hospital and fewer procedures. IRIS associated mortality same in both arms, except CNS disease Excl other causes of patient deterioration: MDR TB etc

44. What are the current guidelines for IPT for patients on ART? 1. 36 months IPT for all patients 2. 12 months IPT for all patients 3. 6 months IPT for all patients 4. 36 months IPT for TST positive, 12 months for TST negative, 6 months for TST unknown

45. INH Prophylaxis

46. What are the current guidelines for IPT for patients on ART? 1. 36 months IPT for all patients 2. 12 months IPT for all patients 3. 6 months IPT for all patients 4. 36 months IPT for TST positive, 12 months for TST negative, 6 months for TST unknown

47. Questions Are patients eligible for more IPT post TB therapy completion? 1.Yes: can be started immediately after TB treatment in all patients 2.No: patients no longer at risk for TB, having just completed TB treatment 3.Yes: can be started immediately after TB treatment but only in patients with documented bacteriologic cure

48. Questions Are patients eligible for more IPT post TB therapy completion? 1.Yes: can be started immediately after TB treatment in all patients 2.No: patients no longer at risk for TB, having just completed TB treatment 3.Yes: can be started immediately after TB treatment but only in patients with documented bacteriologic cure

49. Summary Diagnostic algorithm for DR and DS TB Retreatment TB: Revised definitions and treatment regimen ART initiation in TB patients Special considerations:  Aluvia with TB treatment  Atazanivir in TB  Ethambutol in Renal failure  Moxifloxacin and streptomycin indications TB prevention in HIV infected patients ART initiation in TB patients

50. Acknowledgements This training was supported by the Grant or Cooperative Agreement Number U2G GH001142, funded by the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the presenters and do not necessarily represent the official views of the U.S. Centers for Disease Control and Prevention or the U.S. Department of Health and Human Services