1. TPT guideline presentation_3HP trainingV3 (1).pptx

TPT TB Guidelines

1. Guidelines for Programmatic Management of Tuberculosis Preventive Treatment in India 1 National TB Elimination Programme Central TB Division, Ministry of Health & Family Welfare Government of India, New Delhi

2. 2 Refresher training on Shorter TB Preventive Treatment (TPT) regimen 19 March 2024 Virtual (ZOOM)

3. Background and programmatic milestones in scale-up of TPT Dr. Veena Dhawan Addl. Commissioner (CVAC & CTD) 3

4. Historical background of TPT TPT is not a new strategy The duration of TPT has reduced from 18 months to 1 month now. Am J Epidemiol. 2019 Dec; 188(12): 2078–2085.

5. Rationale of TPT 75% develop TB disease within one year of contact and 97% in two years ( Reichler et. al. J Inf. Dis. 2019) With TPT, the risk of developing TB disease decreases by ~60% and up to 90% among PLHIV . ( Getaham H et. al. NEJM 2015) Epidemiological modelling studies show that effective implementation of TPT alone in South-East Asia (SEA) region would result in an annual TB incidence decline of 8.3%, independent of other background interventions . ( Arinimpathy N et. al. Lancet Inf. Dis. 2016) 5

6. Burden of TB infection 6 Crude prevalence of TB infection among population age ≥15years is 31.3%; ( NaTBPS 2019-21) The risk for TB disease after infection depends on several factors- most important being immunological status risk is increased >25 times among contacts of bacteriologically confirmed TB patients compared to general populations, 16-21 times in case of HIV co-infection and 3-4 times in other immune-compromised status like diabetes, etc. Source: National TB Prevalence Survey ( NaTBPS ) 2019-21

7. National Strategic Plan (2017-25) : Prevent The NSP proposes a Detect-Treat-Prevent-Build approach Strategy – Contact tracing and TB Preventive Treatment to eligible household contacts TPT coupled with active screening for TB among HRGs Scale-up of air-borne infection control measures at health facility Explore role of immunomodulators and vaccines both preventive and therapeutic NSP target of TPT 95% of eligible persons provided TPT 7

8. ‹#›

9. Milestones achieved so far for TB prevention 9 Till 2018 Policy of TPT in PLHIV and HHC <5years (6H) National Technical Working Group (NTWG) for TB and consultative meetings f or TPT policy revision Sep’18 – May 20 Nov’20 - Apr’21 Pilot launch of PMTPT with 6H and 3RH in Kerala Received administrative approval for TPT policy expansion in HHC and other risk group from ministry Mar-Dec’22 NTEG recommended integration of TPT in vulnerable groups of ACF Sep’21 - Feb’22 NTEP rolled out PMTPT in 770 districts of which TGF TPT project supports 194 districts WHO donated ~30,000 courses of 3HP GF partners procured 15,000 courses of 3HP Guidelines for PMTPT released by Hon’ble Health Minister National trainings and district wise scale-up Aug’- Sep’21 2023 Mobilization of additional 3HP courses and P rocur ement through domestic budget Technical specification and SOP for Cy-Tb testing Incentives @Rs. 250 for treatment supporter on completion of TPT

10. TPT coverage (2017-23) 10 Source: Contact tracing report (Ni-kshay) 2023, extracted on 29 Feb 2024

11. State-wise % of eligible HHC of Pul. Bacteriologically Confirmed TB initiated on TPT (2023) 11 Source: Contact tracing report (Ni-kshay) 2023, extracted on 29 Feb 2024

12. Feedback and way forward Cascade training of block (TB units) and PHI staff on Shorter TPT regimen Monitoring through Ni-kshay contact tracing register and TPT dashboard Strengthen TPT care cascade in contacts of patient seeking care in private sector; Address apprehension of the private doctors through CME and one-to-one connect with the private doctors (CTD has developed a flipbook for doctors) Treatment support incentives @ Rs. 250 for completion of TPT Expansion of TPT in individual with other risk groups 12

13. Thank you 13

14. Evidence on TPT and safety & efficacy of Shorter TPT regimen Dr. Malik Parmar NPO – DR & Latent TB (WHO-India) 14

15. TPT works 15

16. Protection with TPT last for 6 to 19 years 16

17. Dynamic state of TB infection and action of TPT TB infection The state of ‘latent’ TB infection is misnomer. Several recent publications have argued that tuberculosis is best represented as a more dynamic spectrum of infection states reflecting the shifting balance in the host pathogen interaction. Tuberculous lesions are highly local, dynamic structures that wax and wane over time and that a simple dichotomous classification of “active” and “latent” is no longer likely. Action of TPT Boosting of IFN-ã response to a number of TB antigens within the first month of treatment Inhibits synthesis of mycolic acids, key cell wall constituents and displays a biphasic killing with rapid early bactericidal activity against actively replicating bacilli (e.g. Isoniazid) More potent sterilizing activity (e.g. Rifamycin and Pyrazinamide) for shortening the regimen duration Inhibit the trans-translational adaptation by directly binding to ribosomal protein S1 in non-replicating M.tb (e.g. Pyrazinamide) 17 Esmail H, Barry CE 3rd, Wilkinson RJ. Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies. Drug Discov Today. 2012 May;17(9-10):514-21. doi : 10.1016/j.drudis.2011.12.013. Epub 2011 Dec 20.

18. TPT reduces mortality independent of ART 18 Badje et al, CROI 2017 Long term follow-up of TEMPRANO show 37% reduction in TB mortality in PLHIV with high CD4 counts, receiving 6 months of IPT, independent of ART

19. TPT eliminates TB risk among PLHIV along with ART 19 Studies IPT alone ART alone ART plus IPT Brazil 68 52 80 South Africa 13 64 89 Botswana 65 67 97 TB risk reduction AIDS 2007: 21: 1441-8; AIDS 2009, 23:631–636; Lancet 2011: 377:1588-98 Greater TB risk reduction with combined ART and IPT

20. TPT is relatively safe (systematic review 2018) 23 RCTs & 55 non-randomised studies Rate of any AE: 3HP (11.5%), 3-4R (20%), 6H (36.1%), 9H (17.6%) Withdrawals due to AEs: 3HP (1.7%) vs 9H (6.4%), 6H (3.8%) Flu like reactions: 3HP (2.2%) vs INH (0,05%) Hepatotoxicity: 3HP (1%), 3-4R (0.01%), 6H(6.3%), 9H (3.1%) 20 A systematic review of adverse events of rifapentine and isoniazid compared to other treatments for latent tuberculosis infection: Christopher Pease, et.al., Pharmacoepidemilology and drug safety, Volume 27, Issue 6, 2018

21. No increase in risk of resistance with rifamycin based TPT Systematic review in 2016: 6 RCTs of rifamycin based TPT vs active control or placebo included Only 6 (0.09%) rifampicin resistant cases in 6808 individuals receiving rifamycin based TPT 1 (0.01%) rifampicin resistant case among 7415 individuals receiving alternative regimens RR = 3.45, (95%CI 0.72–16.56; P = 0.12) 21

22. No increase in risk of resistance with Intermittent rifamycin – 3HP In 3 studies of intermittent rifamycin based TPT there were 3 (0.06%) cases of rifampicin resistance in 4673 individuals on rifamycin-containing regimens 1 (0.02%) cases with rifampicin resistance in 4427 in control regimens RR = 3.89, (95%CI 0.44–34.56; P = 0.22). 22

23. No increase in risk of resistance with Isoniazid 23 RR of resistance 1.45 (95% CI 0.85 – 2.47 ) Similar results when stratified by HIV ( Balcells ME, Emerging Infectious Diseases, 2006) Systematic review in 2006 of published data since 1951, 13 studies, IPT = 18095, controls = 17,985

24. Evidence on safety and efficacy of 3HP and 1HP 24

25. Evidences for 3HP… 1 No significant difference in the incidence of active TB between participants given a 3HP and 6H or 9H (RR 0.73, 95% CI 0.23; 2.30). The risk for hepatotoxicity was significantly lower with 3HP in adult PLHIV (RR 0.26, 95% CI 0.12; 0.55) and in those without HIV (RR 0.16, 95% CI 0.10; 0.27) (Martinson NA et al., Sterling TR et al.) The 3HP regimen was also associated with a higher completion rate in all subgroups (adults with HIV: RR 1.25, 95% CI 1.01; 1.55; adults without HIV: RR 1.19, 95% CI 1.16; 1.22; children and adolescents: RR 1.09, 95% CI 1.03; 1.15) ( https://apps.who.int/iris/handle/10665/260233 ) Compared to 9H, it was observed that the 3HP has a better completion rate in a multicentre randomized controlled study in Taiwan (Sterling TR et al. and Sun HY et al) Systematic review of adverse events of rifapentine and isoniazid compared to other treatments for latent tuberculosis infection (23 RCTs & 55 non- randomised studies) shows lower rate of AEs with 3HP (Peace C et al.) 25

26. Evidences for 3HP… 2 No significant difference in TB incidence was found in an intention-to-treat analysis; however, a per-protocol analysis showed a lower rate of TB infection or death in participants given continuous isoniazid. In all the studies, 3HP was given under direct observation ( WHO consolidated guidelines on tuberculosis. Module 1: prevention – tuberculosis preventive treatment ) In a study of 3HP in 112 pregnant women, the rates of spontaneous abortion and birth defects were similar to those in the general population in the US (Moro RN et al) The clear advantages of these regimens are better adherence due to the shorter duration and fewer adverse events. The use of shorter rifamycin-based regimens is associated with at least 20% greater treatment completion rate (82% vs 61%). WHO recently assessed and recommended several shorter rifamycin-based regimens as alternatives to six months of isoniazid ( Alsdurf H et al.) 26

27. Prevalence of TB infection and initiation of TPT (2019-21) 27 4647 (46%) persons provided TPT 82% provided 6H 18% provided 3HP 71% TPT completion rate 66% completion rate -6H 94% completion rate -3HP

28. 3HP Drug Reactions in PLHIV from IMPAACT4TB Sentinel Sites In a programmatic setting, the IMPAACT4TB project captured retrospective clinical data from 3HP initiations amongst PLHIV in sentinel sites across 11 countries between 2020-23.  Of the 7,391 PLHIV who initiated 3HP, only 75 (1.0%) were reported to discontinue treatment due to tolerability 28 Source: IMPAACT4TB study

29. 3HP has been found to be non-inferior to 9H in children 2-18 years old Difference in Tuberculosis Disease Rates Between the 2 Treatment Regimens Over Time (MITT Population) Noninferiority criterion was met when none of the 471 patients in the combination-therapy arm developed tuberculosis vs 3 of 434 in the isoniazid-only arm (cumulative rate, 0.74%), for a difference of −0.74% and an upper bound of the 97.5% CI of the difference of +0.32%. High completion rates: 88.1% (3HP) vs 80.9% (9H) 3HP is Safe in children: No hepatotoxicity; No treatment-attributable deaths; Mild side effects, No Grade 4 AE; 3 Grade 3 AE (all cutaneous, GI and flu-like illnesses) 3HP is Tolerable in children 29 Villarino ME et al. Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3 month, 12-dose regimen of a combination of rifapentine and isoniazid. JAMA Pediatr . 2015 https://pubmed.ncbi.nlm.nih.gov/25580725/

30. Evidence for 1HP A large randomized, open label trial compared the efficacy and safety of the shorter 1HP regimen and reported that 1HP regimen is noninferior to 9 month daily isoniazid regimen (9H) in PLHIV from high TB prevalence area or had evidence of TB infection. 3,000 patients were followed for a median of 3.3 years. Treatment completion was significantly higher in 1HP compared to 9H (97% versus 90%, p<0.001). Serious adverse event occurred 6% and 7% in the group given 1HP and 9H respectively. Although lower in 1HP, the difference was not significant (p = 0.07). TB incidence was reported to be 0.65 and 0.67 per 100 person-years in the group given 1HP and 9H respectively. The rate of difference in 1HP was -0.02 per 100 person-years; upper limit of 95% confidence interval was 0.30). WHO’s guidelines on TPT also recommends 1HP as alternative option for the use across all disease burden settings and target populations including PLHIV. 30

31. 1HP and 3HP implementation in other countries and published studies Bictegravir / Tenofovir in combination with 1HP was well tolerated with a high completion rate. ( Liou et. Al. 2021 ) Retrospective evaluation of 1HP and 3HP in once daily dose Integrase Strand Transfer Inhibitor (INSTI) in PLHIV patients in Taiwan ( Lin et. Al. 2023 )  142 PLHIV received 1HP and bictegravir (BIC)-containing regimens (1HP/BIC group), 46 received 1HP and dolutegravir (DTG)-containing regimens (1HP/DTG group), 28 received 3HP and BIC-containing regimens and (3HP/BIC group), and 203 received 3HP and DTG-containing regimens (3HP/DTG group). Similar completion rates were similar in the 1HP and 3HP groups (92.7% vs 90.0%), 100% viral suppression rates in all groups Once daily dosing of TLD (tenofovir, lamivudine, dolutegravir) in Thailand Similar efficacy and safety was observed for PLHIV receiving dolutegravir and efavirenz based ART, co-administered with 1 HP or 3HP, suggesting once daily DTG doses are appropriate with 1 HP or 3 HP. 31

32. Thank you 32

33. Tests for detection of TB infection Dr. Anand / Dr. Lakshmi WHO National Consultant – TB Lab 33

34. Background of tests for TB infection Excluding TB disease is a critical step before starting TPT Confirming TBI before starting TPT may increase the certainty that individuals targeted for TPT would benefit from it. Tests also enhance confidence of providers as well as recipients to start TPT. However, there is no gold standard test to diagnose TBI or predict progression to TB disease among those infected. Currently, available tests are indirect and measure the immune response following TB exposure and hence require the person to mount an adequate immune response to provide reliable results 34

35. Comparison between TST and IGRA test 35 TST IGRA Cy-Tb Specificity Low in BCG vaccinated High also in BCG vaccinated High also in BCG vaccinated Sensitivity High High High Ease of use Field friendly, complex test interpretation Require labs and infrastructure Field friendly, single cut off allows simple test interpretation Cost of test Low High Low Manufacturing Complex old product Complex, multiple components Robust with high yield, well defined and completely characterized Children Affected by young age Affected by young age More robust PLHIV Requires info on HIV status for correct interpretation Affected by HIV and low CD4 count More robust with low CD4

36. Cy-Tb skin test Cy-Tb is the next-generation skin test for detection of TBI. Easy-to-use point-of-care test Can deliver IGRA-like performance in the field friendly skin test format Based on ESAT-6 & CFP-10 (same as those used in IGRA) specific for M. tb. Administered via intradermal injection using the Mantoux technique and read after 48-72 hours. Dosage is 0.1 ml An induration of ≥ 5 mm is considered as a positive test result, which indicates infection with M. tb. C-Tb Using a universal 5 mm cut off Storage: 2-8 C 36

37. 37 Procedure of Cy-Tb skin test

38. Logistics and reporting of Cy-Tb Provided by NTEP Cy-Tb vial: 1ml multi-dose vial (10 tests) 0.1 ml BCG syringe SOP for Cy-Tb Provided by general health system Syringe: Single use disposable syringe 2X2 gauze pads or cotton balls, alcohol swabs, gloves Puncture- resistant sharp disposable container Recording in Ni-kshay 38

39. Thank you 39

40. Algorithm for TB screening and operational aspects of TPT Dr. Ravinder Kumar 40

41. * Prioritizing pulmonary bacteriologically confirmed TB # 3-months daily Rifampicin and Isoniazid (3RH) TPT regimen is introduced in 0-15 years individuals in 6 states Target population Strategy Treatment Options # People living with HIV ( + ART) Adults and children >12 months Infants <12 months with HIV in contact with active TB HHC below 5 years of pulmonary* TB TPT to all after ruling out active TB disease   3-months weekly (12 doses) Isoniazid and Rifapentine (3HP) in persons older than 2 years OR 1 month of daily (28 doses) Isoniazid and Rifapentine (1HP) in age >/=13 years (introduction in PLHIV under NACP to begin with)   OR 6-months daily (180 doses) isoniazid (6H) HHC 5 years and above of pulmonary* TB Testing for TBI and TPT after ruling out TB disease Other risk group Person Initiating Immuno-suppressant or Anti-TNF Rx; Silicosis; Person on dialysis; Transplant recipient Malnourished, diabetes, alcohol abuse, smoker and integration with ACF Testing for TBI and TPT after ruling out TB disease TPT target group, strategy and regimen options 41 41

42. Enumeration of HHC and contact tracing Index TB patients are the pulmonary TB patients detected through passive, intensified or ACF approaches and notified in Ni-kshay from the public and private sector. For enumerating the HHC of TB patients- the first step is to enlist the index patients at every HWC and HF level. conduct home visit by the heath staff/ STS/ TBHV/ CHO and conduct contact tracing. enroll all HHC of TB patients in Ni-kshay do TB screening in HHC of TB patients through symptom screening and chest X-ray (if available). Identify HHC of pulmonary TB patients eligible for TPT and initiate TPT Contact tracing must be done during the initial home visit or virtual interaction (e- Sanjeevani ) through tele/video calls by health workers do enumeration, enrollment in Ni-kshay, counselling, screening and encouraging eligible HHC for TPT initiation at HWC or HF. 42

43. Enumeration of other risk groups To enumerate the target population for other risk groups- mapping of the institutions providing care to the specific risk groups considered eligible for TPT within the states engaged systematically by every district and TB unit. The providers need to be trained in Guidelines for TPT and enumeration and enrollment of the target population as well as their counselling, screening, TPT initiation, follow up and information management as well as monitoring of the TPT care cascade. All this should be done through Ni-kshay. 43

44. Active case finding rounds ACF rounds are an add-on to complement the contact tracing. mapping of target populations must be an integral part of the vulnerability mapping for ACF activity Enrolment in Ni-kshay Vulnerable groups considered for TPT the HHC of TB patients detected during ACF rounds. As the index pulmonary TB patients from ACF rounds are notified in Ni-kshay, their data management would follow the same steps as above for entering the information of the target population. 44

45. If <10 years, any one of current cough or fever or history of contact with TB or reported weight loss or confirmed weight loss >5% since last visit or growth curve flattening or weight for age <-2 Z-scores. Asymptomatic infants <1 year with HIV are only treated for TBI if they are household contacts of TB. TST or IGRA may identify PLHIV who will benefit most from preventive treatment. Chest radiography (CXR) may be used in PLHIV on ART, before starting TPT. Any one of cough or fever or night sweats or haemoptysis or weight loss or chest pain or shortness of breath or fatigue. In children <5 years, they should also be free of anorexia, failure to thrive, not eating well, decreased activity or playfulness to be considered asymptomatic. Including silicosis, dialysis, anti-TNF agent treatment, preparation for transplantation or other vulnerable risk groups where testing must precede before TPT. Including acute or chronic hepatitis; peripheral neuropathy (if isoniazid is used); regular and heavy alcohol consumption. Pregnancy or a previous history of TB are not contraindications. Regimen chosen based on considerations of age, strain (drug susceptible or otherwise), risk of toxicity, availability and preferences. CXR may have been carried out earlier as part of intensified case finding. Algorithm for TB screening and TPT 45 45 NO Defer preventive treatment YES Give preventive treatment 5 NO NO <5 years TST or IGRA Symptomatic? 2 Investigate for active TB Follow-up for active TB as necessary, even for patients who have completed preventive treatment   YES Abnormal YES Positive or unavailable Negative Preventive treatment contraindicated? 4 No active TB Normal or unavailable 5 years + CXR 6 Any symptom 1 of current cough or fever or weight loss or night sweats Household contact HIV positive Other risk group 3 <5 years Preventive treatment contraindicated? 4 No active TB Give preventive treatment 5 NO Preventive treatment contraindicated? 4 No active TB

46. aBCG study and TPT – intervention districts Inclusion criteria for aBCG study Special consideration Individual on TPT would be vaccinated 4 weeks after completion of TPT as per NTEP guidelines. Individuals who received aBCG vaccine and eligible for TPT to be provided TPT 4 weeks post vaccination. 46

47. Contraindications of TPT Active TB disease (absolute) Acute or chronic hepatitis Concurrent use of other hepatotoxic medications (such as nevirapine) Regular and heavy alcohol consumption Signs and symptoms of peripheral neuropathy like persistent tingling, numbness and burning sensation in the limbs Allergy or known hypersensitivity to any drugs being considered for TPT 47

48. Counselling of eligible person and family Need to share transparent information with the eligible person and family- information on TBI, need for TPT, schedule of medication, Adherence support and follow-up visits, benefits from completing the course, adverse events, actions on development of TB symptoms 48 NTEP national call center (NIKSHAY SAMPARK – Toll free number 1800116666) should be made available to the index TB patients, family member and TPT beneficiaries

49. Pre-TPT assessment 49 Medical doctor at Health facility or by CHO in tele-consultation with doctor

50. Attribution of 3HP and 1HP   6H 3RH 3HP 1HP Medicines Isoniazid Isoniazid + Rifampicin Isoniazid + Rifapentine Isoniazid + Rifapentine Duration 6 months 3 months 3 months 1 months Interval Daily Daily Weekly Daily Doses 180 84 12 28 Pill burden 1 (180 pills) 3 (252 pills) 3 (36 FDC pills) 2 pills Pregnant women Safe for use Safe for use Not known Interaction with ART No restriction Contraindicated: All PIs, NVP/most NNRTIs @ Use with caution: Tenofovir Adjust dose: Raltegravir, Dolutegravir Contraindicated: All PIs, NVP/NNRTIs, TAF Use: Tenofovir, Efavirenzes (600 mg), DTG, RAL (without dose adjustment) 50

51. Dosage of 3HP regimen Regimen Dose by age and weight band Three months of weekly rifapentine plus isoniazid (12 doses) (3HP) Age 2-14 years c Medicine, formulation 10–15 kg 16–23 kg 24–30 kg 31–34 kg >34 kg Isoniazid, 100 mg a 3 5 6 7 7 Rifapentine, 150 mg 2 3 4 5 5 Isoniazid + rifapentine FDC (150 mg/150 mg) d 2 3 4 5 5 Age >14 years c Medicine, formulation 30–35 kg 36–45 kg 46–55 kg 56–70 kg >70 kg Isoniazid, 300 mg 3 3 3 3 3 Rifapentine, 150 mg 6 6 6 6 6 Isoniazid + rifapentine FDC (300 mg/300 mg) b 3 3 3 3 3 a 300 mg formulation can be used to reduce the pill burden b Expected to become available in the near future c Dosage may differ among adults and children in overlapping weight-bands 51

52. Dosage of 1HP regimen 52 Regimen Dose by age and weight band 1HP – one month of daily rifapentine plus isoniazid (28 doses)             Age ≥ 13 years (regardless of weight band): Isoniazid: 300 mg/day Rifapentine: 600 mg/day Formulations: No. of pills HP FDC Rifapentine 300mg Isoniazid 300mg Rifapentine 150mg 2 pills OR 3 pills OR 5 pills

53. Thank you 53

54. Monitoring of TPT, management of missed doses and TPT outcomes Dr. Arvind / Dr. Hardik National Consultant – TB Prevention 54

55. Monitoring during TPT Individuals receiving TPT should be monitored at every contact with the health-care providers. Every dose of the treatment must be preferably taken under direct observation, particularly the 3HP regimen that has weekly doses. Frontline health-care workers (including community health volunteers) need to be trained to monitor and identify adverse events due to TPT. However, the decision to modify/stop TPT drugs due to adverse events or to restart (e.g. after an interruption by the person on treatment) must be taken by the treating doctor. 55

56. Effective patient centered strategies to promote adherence Effective counselling of the TPT eligible individuals and their family members. Develop a personal adherence plan with the support of family member, caregiver or health worker as per treatment regimen. Give first preference to family care giver for being treatment supporter in consultation with person and provide training Use of digital platforms (tele/video calls, 99DOTS lite/MERM), counting empty blisters, refill monitoring etc. at the level of treatment supporter to strengthen adherence monitoring. Engage the TB survivors/champions at the community level to create a peer support group for social support and continuous motivation of TPT eligible persons and their family to adhere and complete treatment as well as report any adverse events in time for resolution 56

57. Management of missed doses- 3HP TPT regimen Duration of interruption Management steps 3HP Weekly schedule of up to 3 doses missed If the missed dose is remembered within 2 days of scheduled day , the person can take the dose immediately and continue to take remaining doses following the same schedule to complete the course. If the missed dose is remembered after 2 days, the person can take the missed dose immediately and change the schedule for weekly intake to the day the missed dose was taken until treatment completion. This will avoid two weekly doses being taken less than 4 days apart. If between 1–3 weekly doses are missed, treatment is continued until all 12 doses are taken, thus prolonging the treatment duration to a maximum of 16 weeks. More than 3 weekly doses of 3HP missed If 4 or more weekly doses are missed, consider restarting the full TPT course. If adherence to a weekly routine is not possible, consider discontinuing 3HP and offering an alternative (daily) regimen. 57

58. Management of missed doses- 1HP TPT regimen Duration of interruption Management steps 1HP Less than 1 weeks If more than 23 (80%) doses out of 28 expected doses in the regimen were taken, no action is required, just complete the remaining doses. If less than 23 (80%) doses out of 28 expected doses in the regimen were taken, resume treatment immediately upon return and add the missed doses to the total treatment duration to complete the course within a maximum of 6 weeks from the first dose. More than 1 weeks If more than 7 consecutive doses were missed , consider restarting the complete course of 1HP regimen. If more than 7 doses were missed intermittently , resume preventive treatment immediately upon return and add the missed doses to the total treatment duration to complete the course within a maximum of 8 weeks from the first dose. If adherence to 1HP is not possible, consider discontinuing it and offering 3HP or an alternative daily regimen 58

59. Treatment outcome – treatment completion 59 A number of endpoints are proposed that could be used to trigger a review of persons on TPT and in some instances, changes to treatment. TB preventive treatment completion Total duration in months Expected number of doses 80% of recommended doses (days) Extended time for treatment completion (days) (treatment duration +33% additional time) 6H (daily) 6 180 144 239 3HP (weekly) 3 12 11* 120 6Lfx (daily) 6 180 144 239 4R (daily) 4 120 96 160 1HP (daily) 1 28 23 40 * 90% of recommended number of doses Treatment completion: A person initiated on TPT who completed at least: 90% of recommended dose (11/12) consumed within 133% of planned TPT duration (120 days) for 3HP or 80% of recommended dose (23/28) consumed within 133% of planned TPT duration (40 days) for 1HP

60. Treatment outcomes- other definitions Treatment failed: A person initiated on TPT who developed active TB disease any time while on TPT course. Died: A person initiated on TPT who died for any reason while on TPT course. Lost to follow-up: TPT interrupted by person for four consecutive weeks (1 month) or more for 3HP or 4R, 10 consecutive days for 1HP, eight consecutive weeks (2 months) or more for 6H or 6Lfx,. TPT discontinuation due to toxicity: A person whose TPT is permanently discontinued by the doctor due to adverse events or drug–drug interactions. Not evaluated: Such as records lost, transfer to another health facility without record of TPT completion. 60

61. TPT care cascade - Maharashtra Of the total 4181 index patients, 14,172 HHCs were screened, 36 (0.3%) HHCs diagnosed with TB 10,777 (76.3%) underwent an IGRA test 2468 (22.9%) tested positive for IGRA Of the eligible 2353 HHCs, 2159 (91.7%) were started on TPT 1958 (90.6%) completed TPT Median time between treatment initiation of index PTB patient and (a) HHC screening was 31 days; (b) TPT initiation was 64 days. 61

62. TPT care cascade - Karnataka 82.1% contact tracing visit to 301 index patients; a major challenge was index patients’ resistance to home visits fearing stigma, especially among those receiving care from the private sector. Of the 838 HHCs, 765 (91.3%) screened for TB; challenges included a lack of clarity on HHC definition and the non-availability of HHCs during house visits. Only 400 (57.8%) of the 692 eligible HHCs underwent an IGRA challenges of shortage of IGRA kit Among the 83 HHCs advised of the TPT, 81 (98%) initiated treatment 63 (77%) completed TPT. 62

63. Thank you 63

64. Special situations and adverse drug reaction Dr. Sanjay Mattoo Addl. DDG-TB (CTD) 64

65. Women and TPT Pregnancy should not disqualify women for TPT TPT can be started during antenatal and postnatal periods taking due care. Isoniazid and Rifampicin, are considered safe for use in pregnancy . Pyridoxine (Vitamin B6) supplementation should be given routinely to all pregnant and breastfeeding women on TPT. There is limited data on the efficacy and safety of Rifapentine in pregnancy. 65

66. Contraception and TPT Rifampicin and Rifapentine interact with oral and hormonal contraceptive  risk of decreased contraceptive efficacy. use an alternative (such as depot medroxyprogesterone acetate (DMPA) every eighth week or higher dose oestrogen (50μ)) in consultation with a clinician; or use another form of contraception , a barrier contraceptive or intra-uterine device. In women having hormonal contraceptive implants, the interval for replacing the implants may need to be shortened from 12 weeks to eight weeks. 66

67. Liver disease and TPT Isoniazid and rifampicin/rifapentine are associated with liver damage. baseline liver transaminase values >3 times UNL  initiation of TPT with caution End-stage liver disease  defer TPT Acute hepatitis (including acute viral hepatitis)  d efer TPT until the acute hepatitis has resolved. 6H is well-tolerated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. 67

68. Renal Failure & TPT Isoniazid and rifampicin/rifapentine are eliminated by biliary excretion. Thus, TPT can be given in standard dosages to individuals with renal failure. 68

69. People living with HIV and TPT Challenge in TPT with rifamycin-based regimen among PLHIV  drug–drug interaction. Rifampicin or rifapentine TPT regimens should not be co-administered with protease inhibitors (atazanavir/ ritonavir, lopinavir /ritonavir) or nevirapine. Rifampicin and rifapentine can be co-administered with efavirenz without dose adjustment, No dose modification be required of Doglutavir (DTG) in PLHIV while initiated on Rifapentine based regimen PLHIV receiving rifampicin (3RH) as a part of TPT, a higher dosage of raltegravir (800 mg twice daily) and double dose of Doglutavir (DTG) is required. 69

70. Babies born to mothers with TB disease and TPT If a newborn is not well  refer him/her to a specialist/pediatrician. If the newborn is well (absence of any signs or symptoms presumptive of TB) TPT must be provided. Bacille Calmette-Guérin (BCG) vaccination should not be delayed even if TPT is administered. It is advised to administer pyridoxine at 5–10 mg/day . If the infant is HIV-exposed (mother is HIV infected) and on nevirapine  start 6H TPT with rifamycin based regimen cannot be given along with nevirapine prophylaxis If the mother is taking anti-TB drugs  continue to breastfeed with appropriate practice like using a mask and cough etiquette. 70

71. TPT among people who use drugs People taking rifamycin based regimen (3HP/1HP/3RH) with OST  monitor for signs of opiate withdrawal and other adverse events. Increasing the dose of methadone or buprenorphine when taking rifamycins can lessen the risk of withdrawal. 6H is safe to use among PWUD  careful monitoring for liver toxicity is important. Drug use should never be taken as a blanket rationale for denying someone TPT. 71

72. Possible adverse event associated with TPT drugs 72 Drug Known adverse events Rare adverse events Isoniazid Asymptomatic elevation of serum liver enzyme concentrations Hepatitis Peripheral neuropathy ( paraesthesia , numbness and limb pain) Skin rash Sleepiness and lethargy Convulsions Pellagra Arthralgia Anaemia Lupoid reactions Rifampicin Gastrointestinal reactions (abdominal pain, nausea, vomiting) Hepatitis Generalized cutaneous reactions Thrombocytopenic purpura Discoloration of body fluids Osteomalacia Pseudomembranous colitis Pseudoadrenal crisis Acute renal failure Shock Haemolytic anaemia Flu-like syndrome Rifapentine Gastrointestinal reactions (abdominal pain, nausea, vomiting) Hypersensitivity reactions (flu-like symptoms) Hepatitis Discoloration of body fluids Hypotension/syncope Decrease in white blood cell and red blood cell count Decreased appetite Hyperbilirubinemia

73. Management of adverse events Individuals receiving TPT are otherwise healthy- adverse events during TPT must be minimized and promptly managed. If a severe adverse reaction is encountered- TPT must be immediately discontinued, and supportive medical care provided. Mild to moderate adverse reaction- Conservative management and continuation under observation People experiencing adverse events may need medical attention and doctor’s discretion should be exercised for management. A complete history, including concomitant medication and supplements, must be taken. The following questions may help in the assessment and in deciding actions for management of adverse events: How severe is the adverse event (mild, moderate, severe)? How serious is the event (i.e. hospitalization or prolongation of hospitalization; persistent significant disability; congenital anomaly, a life-threatening experience or likely to lead to death)? What is the immediate management (reassurance, symptomatic relief, hold/discontinue TPT, or requires a medical intervention to avert severe outcomes)? What is the underlying cause (drug related, other factors)? How will the adverse event affect future adherence (tolerability, consideration of substitution with an alternative regimen)? What is the next step (continue or restart, substitute, follow up and reassess)? 73

74. Thank you 74

75. Recording and reporting Dr. Sivavallinathan Arunachalam WHO National Consultant – Ni-kshay 75

76. Key population / risk factors for TPT 76 TPT workflow open when any of the key population/Risk factors ticked

77. Testing for TB infection 77

78. Recording in Ni-kshay 78

79. Contact tracing 79

80. Enrolment of contact 80

81. Enrolment of other risk group 81

82. Self-monitoring in TB Arogya Saathi 82

83. Assessment for transition and scale-up Dr. Hardik Solanki WHO National Consultant – TB Prevention 83

84. Key strategies for TPT scale-up under NTEP… 1 Building capacity of health-care workers at HWCs, Sub-centers and HFs (including private clinics) in the PMTPT guidelines for India. Ensuring adequate human resources to provide TPT services at all of the above facilities as well as supervisory staff at the block, district and state level. Implementing systematically active, intensified and passive case finding to detect and notify all index TB patients in the community. Mapping out facilities managing HRGs and households/workplaces of all index TB patients where the target population can be traced. Establishing diagnostic systems to rule out active TB and to detect TBI among contacts of index TB patients and high-risk/vulnerable groups. Providing TPT using newer and shorter regimens to eligible individuals who have been identified. 84

85. Key strategies for TPT scale-up under NTEP… 1 Strengthening treatment support systems for monitoring adherence and adverse events and ensuring high TPT completion rates in every centre. Strengthening the monitoring system and establishing a robust surveillance system. Designing effective communication strategies for TPT and initiating IEC campaign with community engagement to increase awareness among general population about TPT intervention to accelerate ending TB in India. Following-up up to 2 years post TPT on a six-monthly basis to monitor individuals who completed TPT for breakdown to active-TB. Every state, district and block level officer must clearly understand the requirements to organize TPT services in their respective catchment areas and prepare the health workforce and health system to be capable of effectively implementing the TPT services as an integral part of the universal health coverage (UHC) function of the health system. 85

86. Checklist to assess preparedness for implementation of TPT services… 1 Thematic area Current Status Next steps & timeline Advocacy for TPT     Inclusion of TPT plan in PIP     Expansion plan at State/ district level with timelines to complete expansion     Human resources in place at HCW/SC, HF, Block, District and State as per existing NHM (Ayushman Bharat) and NTEP norms     Training plan in place with timeline to complete training of all health workforce of HCW/SC, HF, Block, District and State     Availability of necessary diagnostics (IGRA/TST/Cy-Tb) and Chest X-ray for HRGs and HHC whenever available     Mapping of TPT centres (HWCs, SCs, HFs including private providers) and updating directory of treatment supporters     86

87. Checklist to assess preparedness for implementation of TPT services… 2 Thematic area Current Status Next steps & timeline Identification of adherence mechanisms (trained TPT supporters/ 99DOTS/MERM/refill monitoring)     TPT drug stocking and supply chain management     Storage space at SDS/DDS/TUDS/HF/HWCs to store TPT drug quantities     ADR management plan (from HF to DR-TB centres )     Communication strategy, IEC and Community engagement plan     Logistics/ trainings for recording & reporting (printing, digital platform readiness with peripheral devices and internet for use by HCW/SC staff etc )     Any other preparedness     87

88. Thank you 88

89. Supply chain management of TPT drugs and private sector engagement Ashish Chaudhary WHO National Consultant- Procurement 89

90. Purchase Order : Tablet 3HP 90 Fixed Dose Combination of Tab Rifapentine 300MG+ Isoniazid 300MG (3HP) About 37.05 lakh TPT courses M/s Lupin Ltd. & M/s Oxalis Labs 3 Tranches - Till September /October 2024

91. Purchase Order : Loose TPT Drugs 91 Loose Rifapentine-150mg and Isoniazid-100mg DT M/s J Duncan, M/s Centurion and M/s Macleods Ltd. 3 Tranches - Till September /October 2024

92. 1 st Release Order : Issued on 28 th Feb 2024 92 Next Release Order for about 3.27 lakh Patient courses – This week

93. 3HP TPT courses (State-wise) 93 SN State Name 3HP Courses 1 A & Nicobar Islands 723 2 Andhra Pradesh 1,57,723 3 Arunachal Pradesh 4,248 4 Assam 67,736 5 Bihar 2,62,400 6 Chandigarh 4,371 7 Chhattisgarh 55,592 8 DNH-DD 1,160 9 Delhi 1,00,332 10 Goa 2,859 11 Gujarat 2,57,423 12 Haryana 1,16,764 13 Himachal Pradesh 23,147 14 Jammu & Kashmir 15,604 15 Jharkhand 1,07,684 16 Karnataka 1,17,000 17 Kerala 31,075 18 Ladakh 484 SN State Name Total Patient Courses 19 Lakshadweep 32 20 Madhya Pradesh 3,19,411 21 Maharashtra 2,92,464 22 Manipur 3,024 23 Meghalaya 6,399 24 Mizoram 2,507 25 Nagaland 6,043 26 Odisha 91,488 27 Puducherry 2,027 28 Punjab 85,755 29 Rajasthan 2,71,547 30 Sikkim 2,283 31 Tamil Nadu 1,47,879 32 Telangana 1,08,659 33 Tripura 5,000 34 Uttar Pradesh 8,39,338 35 Uttarakhand 40,152 36 West Bengal 1,54,896

94. Overview of drug distribution flow All drugs used in various TPT regimens… be supplied through a centralized procurement system at the Central TB Division, MoHFW, GoI will be stored at Central Medical Services Society (CMSS) stores / Government Medical Store Depot (GMSD)/. TPT full courses will be supplied to the states from the respective GMSD/ CMSS. An advance intimation ( Release Orders ) will be communicated to states / state drug stores (SDS) to ensure requisite space in the drug stores. Drugs will be supplied in loose drug form from CTD. On receipt of drugs, the SDS shall acknowledge the receipt through the Ni- kshay Aushadhi . The SDS shall supply full courses of TPT per person with a buffer stock of 3 months to all the districts on a quarterly basis; the districts will supply further with a buffer stock of 2 months to all TUs on monthly basis; and TUs will supply further with a buffer stock of 2 month to all HF on a monthly basis. 94

95. Drug distribution flow… cont. An entire course of TPT drugs per eligible individual will remain under the custody of the trained treatment supporter till the individual completes the TPT course for the respective regimen. No need for monthly supplies in regimens of 3- or 6-months duration For maintaining inventory of TPT drug courses and for its accountability, once a full patient course of TPT drugs is issued to the trained treatment supporter of TPT eligible person, this will be taken as issue/consumption for recording and reporting under Nikshay and Nikshay-Aushadi. 95

96. Stocking norms for full TPT courses at various stocking points Level Stock for utilization Reserve stock in months of full TPT courses Drug requirements Treatment supporter One full TPT course per beneficiary 0 month Full TPT course under utilization HF drug store 0 month 2 month Reserve stock in HF at end of the month (2 x total TPT beneficiaries on Full TPT course for HF) TU drug store 0 month 2 months (Quarterly consumption/ 3) x 5 – (existing stock in TU including HF drug stores at end of the quarter) DTC drug store 0 month 3 months (Quarterly consumption/ 3) x 8 – (existing stock in DTC drug store including TU & HF drug stores at end of the quarter) SDS 0 month 3 months (Quarterly consumption/ 3) x 11 – (existing stock in SDS including stocks at all districts at end of the quarter) 96

97. Private sector engagement Dr. Mrigen Deka WHO National Consultant – Partnerships 97

98. Private sector engagement TB services to all TB patients irrespective of patient seeks care from public or private sector. A ll diagnostics, drugs, treatment support, incentives and enablers and public health action linked provisions that are available to patients in the private sector as well. R igorous efforts have been made by the States and Districts to ‘ engage’ private health providers such as establishing Patient Provider Support Agency (PPSAs) and through various PPM Schemes This has translated to a significant rise in TB notification from the private sector and provides good opportunity to extend part of public health action to all TB patients notified from the private sector, including contact tracing and TPT for their contacts. 98

99. Implementing TPT in the contact of patient seeking care in private sector Patient seeking care in private sector may come into the purview of the local public health authority either through notification in Ni- kshay , or referrals made by private practitioners themselves. In both these cases, the local public health authorities must ensure that complete details of the patients are entered into Ni- kshay and home visit of the patients conducted by the health staff (STS, TBHV, ASHA) or through PPSA staff, as may be the case in that specific area. 99

100. Opportunities for TPT through partnership options A range of TB related services can be ‘purchased’ for private sector patients. (can also be purchased for public sector patients, if specifically needed in any particular geography). Contact tracing and chemoprophylaxis (TPT) is one of the activities and available in the “Public Health Action” option under the Guidance Document on Partnerships 2019. TPT as part of the range of public health action, can also be included as an activity for PPSAs, or can be bundled with any other service such as ‘diagnostics’. States and Districts may assess the focused need for TPT in other and expanded risk group in their respective geographies. Likewise, additional channels for specimen management, X-rays, drug supply will have to be established for TPT in the private sector. States may assess their needs and purchase whole package of services as a bundle, or individual activities in the range of services needed for TPT. 100

101. Partnership options and TPT services Partnership option & TPT services 1. Patient provider support agency (PPSA) Private provider engagement Linkages for specimen transportation and diagnostics Patient management (public health action, counselling, adherence support) logistics of anti-TB drugs for TPT The PPSA is an example of a “service bundle” that covers a whole range of activities for end-to-end management of private sector 2. Public health action Counselling and adherence management Contact tracing and chemoprophylaxis (TPT) HIV counselling, testing and treatment linkage Drug susceptibility testing (DST) and linkage for DR-TB services Blood sugar testing and linkages for diabetic care Linkages for Nikshay Poshan Yojana 101

102. Partnership options and TPT services Partnership option & TPT services 3. Specimen management Collection of sputum samples, blood specimen for TBI tests Collection of respiratory (excluding sputum) and EP specimen Transportation of specimen 4. Diagnostics X-ray centres Smear microscopy (ZN/FM)/molecular diagnostics Culture (standalone) / Line Probe Assay / Culture and Drug Susceptibility Testing Pre-treatment and follow-up investigation TBI test (TBI) 5. Treatment services TB management centre DR-TB treatment centre (outdoor) DR-TB treatment centre (indoor) Specialist consultation for DR-TB patients 102

103. Partnership options and TPT services Partnership option & TPT services 6. Drug Access and Delivery Services Drug supply chain management Improving access to anti-TB drugs for TB patients notified by the private sector 7. Active TB case finding and TB prevention Active TB case finding TB prevention package for vulnerability mapping, TBI testing and TPT 8. Advocacy, Communication and Community Empowerment Advocacy Communication Community empowerment 9. Innovations Refer the further details in Guidance Document on Partnerships 2019. States/Districts must ensure to budget TPT as a separate activity since the overall engagement needed for reaching out to contacts of all private TB patients, would be much larger. 103

104. Thank you 104

105. Community engagement Sumitha Chalil WHO National Consultant – Community engagement 105

106. Strategies for engaging community in TPT implementation and scaling-up C ommunity collectives such as TB survivor/PLHIV led networks can also mobilize the community members for TPT and bring issues to the notice of the health system directly or through various platforms such as community meetings, TB forum etc. 106

107. Inform community Potential Interventions examples: Awareness & social mobilization drives/campaigns at community levels combining mass and mid media, inter-personal communication tools, etc. Sensitization and involvement of community influencers . User-friendly IEC materials on TPT which are easy to understand and help to act on information. Content for mobilization: Information on prevention, myths and facts, nutrition, health-care facilities, co-morbidities, etc. Content for beneficiaries (those undergoing TPT): A dherence, side effects, where to seek care, etc Consult community/Develop with community. Inform about benefits of TPT to individuals, families, and community with emphasizing how TPT acts as prevention and break the transmission chain of TB in the community. 107

108. IEC for TPT https://drive.google.com/drive/folders/1kbCs1VKclyuFgBFb01nOQ3ebaDmG4VkG?usp=sharing 108 Hoarding, banner and leaflet addressing community and general population FAQ leaflet for general population Flip book on TPT (technical and operational aspects) for private and public doctors Handbook for healthcare workers

109. Consult community Gather community’s opinion & inputs For developing tools and contents for communication on TPT, developing local plans for TPT implementation & scale-up, demand generation, addressing challenges T hrough community meetings, patient provider meetings, involving community representatives in planning & monitoring meetings etc. During planning, implementation (for monitoring), evaluation Consult the community for planning, implementation and monitoring the TPT intervention and scale-up 109

110. Collaborate with community Partnerships with CSOs at different levels to be explored for various interventions, based on the need assessment and potential of individual organizations (The gap analysis tools given in NTEP Partnership Guidance 2019 shall be used for needs assessment). Collaborate with the community through formal Civil Society Organizations (CSO) including NGOs, CBO, FBOs, etc. and informal groups for implementing TPT. Areas of interventions could be, but not limited to, as follows: Awareness generation , behaviour change communication & social mobilization. Capacity building of health-care facilities and frontline health workers in TPT. Case finding through screening & referral and/or testing for TBI eligible populations. Facilitating access to diagnostic services (e.g. sputum or blood specimen collection and transport, provisions for X-ray). Supporting TPT initiation & adherence through health education, counselling, follow-up support, etc. Developing TPT adherence support in community through identification and training of community treatment supporters, facilitation of treatment support groups, training of families/caregivers, implementation of Peer-support models, etc. Facilitate treatment completion & follow-up investigations . Facilitating community surveillance of TBI, TPT, ADRs, development of Active TB etc. 110

111. Empower the affected community TB champion/TB Survivor led networks may be engaged for : Encouraging contacts of TB patients and other eligible individuals for TBI screening and TPT. Providing peer counselling with psycho- social support, addressing of self- stigmatization etc. Ensuring supportive monitoring of those on TPT and providing of treatment education, suggestions on nutrition, healthy lifestyles and positive living, psychosocial support, addressing specific issues etc . Preventing TPT treatment interruptions and promoting completion of TPT. Monitoring and early identification of ADR and/or development of TB symptoms. Addressing stigma of TB in the community. Acting as a link between the community and health-care system and facilitating care seeking and feedback on health service delivery. Empower the affected community as a partner in TPT response through capacity building and involvement of TB survivors, their contacts & others who are eligible for TPT and networks of TB survivors in various facets of the response across levels. 111

112. Thank you!! 112