Tuberculin skin testing and treatment of latent TB

1. Tuberculin skin testing and treatment of latent TB

2. The MTCT-Plus Initiative 2 Outline Terminology of TB Importance of TB among HIV infected persons Issues in tuberculin skin-testing � placement, reading, interpretation, evaluation of a positive test Issues in treatment of latent TB infection � dose of INH, side effects and their management, duration, adherence issues

3. The MTCT-Plus Initiative 3 Tuberculosis

4. The MTCT-Plus Initiative 4 Terminology of TB Tuberculin skin test (TST), PPD skin test Latent TB infection (LTBI), inactive TB, dormant TB Treatment of latent TB infection,TB preventive therapy, TB prophylaxis Active TB - TB disease Treatment of active TB The terminology of TB can be confusing, and there are many acronyms. The current preferred (at least in the US) terms are listed first, followed by some alternative termsThe terminology of TB can be confusing, and there are many acronyms. The current preferred (at least in the US) terms are listed first, followed by some alternative terms

5. Why is Tuberculosis Important in Persons with HIV Infection?

6. The MTCT-Plus Initiative 6 Why is tuberculosis important?

7. The MTCT-Plus Initiative 7 Global distribution of tuberculosis The most important point to make is that many of the countries with the highest rates of HIV � sub-Saharan Africa, SE Asia � are the countries with the highest rates of TB.The most important point to make is that many of the countries with the highest rates of HIV � sub-Saharan Africa, SE Asia � are the countries with the highest rates of TB.

8. The MTCT-Plus Initiative 8 Case #1 26 year old woman enrolled in MTCT-Plus 8 weeks after delivery Mother: CD4 cell count = 420 cells/mm3 2 year old: HIV positive Infant: HIV tests pending Mother has no symptoms and physical exam is normal Tuberculin skin testing (TST) and provision of treatment of latent TB is not routinely being done at MTCT+ sites (at present, TST is only being done routinely at Uganda sites and Soweto). The purpose of this case discussion is to try to convince sites that it is worthwhile to start TB screening and treatment of latent infection. The presenter should elicit reasons that tuberculin skin testing (TST) is or is not being done at the site. Anticipated reasons include: The national TB control program does not recommend diagnosis and treatment of latent TB That use of routine BCG vaccination during infancy (the policy in the countries of all current MTCT+ sites) � makes skin testing inaccurate (nonspecific) Doubts about the efficacy of treatment of latent infection (�Everybody is exposed�) Concern about harmful reactions tuberculin skin testing (large, blistered reactions) Concern about increasing the rate of INH resistance If sites do not bring up some of these reasons, the presenter can mention them as concerns at other MTCT+ sites (see next slide)Tuberculin skin testing (TST) and provision of treatment of latent TB is not routinely being done at MTCT+ sites (at present, TST is only being done routinely at Uganda sites and Soweto). The purpose of this case discussion is to try to convince sites that it is worthwhile to start TB screening and treatment of latent infection. The presenter should elicit reasons that tuberculin skin testing (TST) is or is not being done at the site. Anticipated reasons include: The national TB control program does not recommend diagnosis and treatment of latent TB That use of routine BCG vaccination during infancy (the policy in the countries of all current MTCT+ sites) � makes skin testing inaccurate (nonspecific) Doubts about the efficacy of treatment of latent infection (�Everybody is exposed�) Concern about harmful reactions tuberculin skin testing (large, blistered reactions) Concern about increasing the rate of INH resistance If sites do not bring up some of these reasons, the presenter can mention them as concerns at other MTCT+ sites (see next slide)

9. The MTCT-Plus Initiative 9 Case #1: Questions Would a tuberculin skin test (TST) be done as part of the initial evaluation at your site? If yes, would your site provide INH as treatment of latent TB infection if the skin test was positive? Tuberculin skin testing (TST) and provision of treatment of latent TB is not routinely being done at MTCT+ sites (at present, TST is only being done routinely at Uganda sites and Soweto). The purpose of this case discussion is to try to convince sites that it is worthwhile to start TB screening and treatment of latent infection. The presenter should elicit reasons that tuberculin skin testing (TST) is or is not being done at the site. Anticipated reasons include: The national TB control program does not recommend diagnosis and treatment of latent TB That use of routine BCG vaccination during infancy (the policy in the countries of all current MTCT+ sites) � makes skin testing inaccurate (nonspecific) Doubts about the efficacy of treatment of latent infection (�Everybody is exposed�) Concern about harmful reactions tuberculin skin testing (large, blistered reactions) Concern about increasing the rate of INH resistance If sites do not bring up some of these reasons, the presenter can mention them as concerns at other MTCT+ sites (see next slide)Tuberculin skin testing (TST) and provision of treatment of latent TB is not routinely being done at MTCT+ sites (at present, TST is only being done routinely at Uganda sites and Soweto). The purpose of this case discussion is to try to convince sites that it is worthwhile to start TB screening and treatment of latent infection. The presenter should elicit reasons that tuberculin skin testing (TST) is or is not being done at the site. Anticipated reasons include: The national TB control program does not recommend diagnosis and treatment of latent TB That use of routine BCG vaccination during infancy (the policy in the countries of all current MTCT+ sites) � makes skin testing inaccurate (nonspecific) Doubts about the efficacy of treatment of latent infection (�Everybody is exposed�) Concern about harmful reactions tuberculin skin testing (large, blistered reactions) Concern about increasing the rate of INH resistance If sites do not bring up some of these reasons, the presenter can mention them as concerns at other MTCT+ sites (see next slide)

10. Latent Tuberculosis Infection: Common Concerns about Screening and Treatment

11. The MTCT-Plus Initiative 11 Common Concerns �National TB control program does not recommend TST, treatment of latent TB� �Use of routine BCG during infancy makes skin testing inaccurate� �Treatment of latent infection won�t make a significant difference where TB is so common� �Using INH for treatment of latent TB will increase rates of INH resistance� MTCT+ staff will provide a copy of guidelines from the national TB control program of the host country � please check whether skin testing and treatment of latent TB are covered, and if so, what the guidelines are. Some recommend skin testing and treatment of latent infection only as part of contact investigation for an active, infectious cases, others recommend �. All sites are in countries using universal BCG during infancyMTCT+ staff will provide a copy of guidelines from the national TB control program of the host country � please check whether skin testing and treatment of latent TB are covered, and if so, what the guidelines are. Some recommend skin testing and treatment of latent infection only as part of contact investigation for an active, infectious cases, others recommend �. All sites are in countries using universal BCG during infancy

12. The MTCT-Plus Initiative 12 What are your national TB Control Programme Guidelines? For tuberculin skin testing among HIV infected persons? For the use of INH treatment of latent TB? It shouldn�t be difficult for us to come up with a slide specific to each country providing the guidelines about these two key It shouldn�t be difficult for us to come up with a slide specific to each country providing the guidelines about these two key

13. The MTCT-Plus Initiative 13 Effect of TB exposure on TST results in a BCG vaccinated population Setting - village in Ghana, country with universal BCG just after birth (96% coverage rate) Study - tuberculin skin testing of two kinds of households: 1) household with recently-diagnosed case of active pulmonary TB 2) neighboring households without active TB

14. The MTCT-Plus Initiative 14 TST results and TB exposure in area using BCG vaccination - results in infants/children Orient participants to this graph. On the vertical axis is the percentage of children who have a TST reaction of > 10 mm (the analysis presented similar data for a TST cut-off of 5 mm, and it did not change the conclusions of this study in any way) The horizontal axis shows two age groups of children. The group of greatest interest for MTCT+ sites will probably be those of ages 0-5 years, because it is in this group that BCG given in infancy might have the greatest effect on the tuberculin skin test. The first point is that the rate of positive skin test reactions is very low in control households - < 5%, demonstrating that use of BCG during infancy does not result in �everyone being positive�. Furthermore, the low rate of TST-positivity in control households could certainly represent true positives � these children were being raised in a community with high rates of TB; there would surely be opportunities for TB transmission outside of the household. The second point is how much higher the rate of TST positivity is among children exposed to TB in the household � more than 5 times higher than age-matched controls. It may also be worth mentioning that among children exposed to TB in the household, TST positivity was clearly associated with greater exposure to the index case � sleeping in the same room, more hours spent near the case during the day, etc. Finally, two similar studies in sub-Saharan Africa came to the same conclusion � tuberculin skin test results among children who have received BCG still correlate well with exposure to TB. These studies clearly show that the TST remains a valuable tool even among young children who have received BCGOrient participants to this graph. On the vertical axis is the percentage of children who have a TST reaction of > 10 mm (the analysis presented similar data for a TST cut-off of 5 mm, and it did not change the conclusions of this study in any way) The horizontal axis shows two age groups of children. The group of greatest interest for MTCT+ sites will probably be those of ages 0-5 years, because it is in this group that BCG given in infancy might have the greatest effect on the tuberculin skin test. The first point is that the rate of positive skin test reactions is very low in control households - < 5%, demonstrating that use of BCG during infancy does not result in �everyone being positive�. Furthermore, the low rate of TST-positivity in control households could certainly represent true positives � these children were being raised in a community with high rates of TB; there would surely be opportunities for TB transmission outside of the household. The second point is how much higher the rate of TST positivity is among children exposed to TB in the household � more than 5 times higher than age-matched controls. It may also be worth mentioning that among children exposed to TB in the household, TST positivity was clearly associated with greater exposure to the index case � sleeping in the same room, more hours spent near the case during the day, etc. Finally, two similar studies in sub-Saharan Africa came to the same conclusion � tuberculin skin test results among children who have received BCG still correlate well with exposure to TB. These studies clearly show that the TST remains a valuable tool even among young children who have received BCG

15. The MTCT-Plus Initiative 15 Conclusions � Use of TST where BCG vaccination is common In a setting of universal BCG Positive TST is strongly associated with TB exposure TST reaction is not associated with presence of BCG scar True for children and adults Interpret TST the same whether BCG has been given or not HIV-positive or recent contact � 5 mm HIV-negative, not recent contact � 10 mm

16. The MTCT-Plus Initiative 16 TST identifies persons at high risk of active TB These data come from cohort studies in Africa in which HIV-infected patients had TST done and were then followed for 2-5 years for the development of active TB. Orient participants to the graph: Vertical axis is the rate of development of active TB per year of follow-up; the horizontal axis shows three different studies. The first point is that the annual risk of developing active TB among these HIV-infected patients is high, up to 8% per year � equal to the probable lifetime risk of developing active TB among immunocompetent persons. The second point is that the risk of progression to active TB is much higher in the tuberculin skin test positive patients. Therefore, even in an area with high rates of TB, the TST identifies a group at markedly increased risk of developing active TBThese data come from cohort studies in Africa in which HIV-infected patients had TST done and were then followed for 2-5 years for the development of active TB. Orient participants to the graph: Vertical axis is the rate of development of active TB per year of follow-up; the horizontal axis shows three different studies. The first point is that the annual risk of developing active TB among these HIV-infected patients is high, up to 8% per year � equal to the probable lifetime risk of developing active TB among immunocompetent persons. The second point is that the risk of progression to active TB is much higher in the tuberculin skin test positive patients. Therefore, even in an area with high rates of TB, the TST identifies a group at markedly increased risk of developing active TB

17. The MTCT-Plus Initiative 17 Isoniazid (INH) reduces active TB rate by 60% among patients with positive TST (> 5 mm) This slide summarizes the results of 3 separate placebo-controlled studies of the efficacy of INH (for 6 months) in the treatment of latent TB infection among HIV-infected persons. The vertical axis again shows the rate of development of active TB per year of follow-up; the horizontal line shows the results of 3 separate studies. The first point is the high rate of development of active TB among the placebo recipients, 5-10% per year, confirming the results of the cohort studies just shown). INH treatment clearly decreased the rate of progression to active TB � averaging the results of the 3 studies, the rate of active TB was 60% lower among those who received INH.This slide summarizes the results of 3 separate placebo-controlled studies of the efficacy of INH (for 6 months) in the treatment of latent TB infection among HIV-infected persons. The vertical axis again shows the rate of development of active TB per year of follow-up; the horizontal line shows the results of 3 separate studies. The first point is the high rate of development of active TB among the placebo recipients, 5-10% per year, confirming the results of the cohort studies just shown). INH treatment clearly decreased the rate of progression to active TB � averaging the results of the 3 studies, the rate of active TB was 60% lower among those who received INH.

18. The MTCT-Plus Initiative 18 Adverse events in studies of INH treatment of latent TB - Uganda

19. The MTCT-Plus Initiative 19 Types of adverse events from INH for latent TB - Zambia

20. The MTCT-Plus Initiative 20 Efficacy of INH among HIV-positive, TST-negative persons in Africa The tuberculin skin test may be falsely-negative because of immune suppression. Therefore, some have suggested that all HIV-infected persons in areas with high rates of TB should receive INH. This slide shows the results of 3 placebo-controlled studies performed to evaluate this idea. Orient participants to the slide: The y-axis is the rate of developing active TB, expressed per 100 patient-years (% per year who develop active TB) The x-axis shows 3 different studies in TB-endemic areas in Africa There is no apparent effect of INH among TST-negative patients - the rate of TB among these patients is relatively high (2.5-3.5% per year), but INH does not decrease this risk. Treatment of TST-negative patients is not recommendedThe tuberculin skin test may be falsely-negative because of immune suppression. Therefore, some have suggested that all HIV-infected persons in areas with high rates of TB should receive INH. This slide shows the results of 3 placebo-controlled studies performed to evaluate this idea. Orient participants to the slide: The y-axis is the rate of developing active TB, expressed per 100 patient-years (% per year who develop active TB) The x-axis shows 3 different studies in TB-endemic areas in Africa There is no apparent effect of INH among TST-negative patients - the rate of TB among these patients is relatively high (2.5-3.5% per year), but INH does not decrease this risk. Treatment of TST-negative patients is not recommended

21. The MTCT-Plus Initiative 21 Risk of INH resistance after INH treatment for LTBI � data among HIV-positive patients

22. The MTCT-Plus Initiative 22 INH for LTBI and INH-resistance � data from placebo-controlled trials in the era prior to HIV

23. The MTCT-Plus Initiative 23 Effect of INH resistance on outcomes of treatment for active TB This slide shows the outcome of a very large cohort of patients (n = 6402) treated in 6 countries with directly observed short-course (6 month) regimens. As in previous studies, INH resistance is associated with a very small increase in the rate of treatment failure, compared with fully-susceptible isolates. For comparison, rifampin resistance markedly decreases the response to therapy.This slide shows the outcome of a very large cohort of patients (n = 6402) treated in 6 countries with directly observed short-course (6 month) regimens. As in previous studies, INH resistance is associated with a very small increase in the rate of treatment failure, compared with fully-susceptible isolates. For comparison, rifampin resistance markedly decreases the response to therapy.

24. The MTCT-Plus Initiative 24 Common concerns about screening for and treating latent TB - responses MTCT-Plus programs may be able to help bring about change in guidelines TST results correlate with TB exposure even when BCG is used TST positive patients are at greatly increased risk of active TB Treatment of latent infection � effective in decreasing risk of active TB, but only among TST-positive patients INH-resistance may be more common in those who receive INH for latent TB, but treatment can still be effective MTCT+ staff will provide a copy of guidelines from the national TB control program of the host country � please check whether skin testing and treatment of latent TB are covered, and if so, what the guidelines are. Some recommend skin testing and treatment of latent infection only as part of contact investigation for an active, infectious cases, others recommend �. All sites are in countries using universal BCG during infancyMTCT+ staff will provide a copy of guidelines from the national TB control program of the host country � please check whether skin testing and treatment of latent TB are covered, and if so, what the guidelines are. Some recommend skin testing and treatment of latent infection only as part of contact investigation for an active, infectious cases, others recommend �. All sites are in countries using universal BCG during infancy

25. Diagnosis of Latent TB Infection The Tuberculin Skin Test

26. The MTCT-Plus Initiative 26 Case 1 - continued TSTs placed and read 3 days later Woman: 10 mm 2 year old son: 6 mm Questions: Are these tests positive? What should be done now?

27. The MTCT-Plus Initiative 27 Diagnosis of latent TB with the TST The issues: Applying the tuberculin skin test Reading the test Interpreting the test � including in children Management of positive TST

28. The MTCT-Plus Initiative 28 Applying the tuberculin skin test

29. The MTCT-Plus Initiative 29 Applying the tuberculin skin test

30. The MTCT-Plus Initiative 30 Applying the tuberculin skin test

31. The MTCT-Plus Initiative 31 Reading the tuberculin skin test Read 2-3 days after placing the test Feel for induration Color change without induration is not included in the measurement Use a ruler or calipers Have someone else check if unsure Always document the exact size (mm) � not just �positive� or �negative�

32. The MTCT-Plus Initiative 32 Reading the tuberculin skin test

33. The MTCT-Plus Initiative 33 Reading the tuberculin skin test

34. The MTCT-Plus Initiative 34 Yield of TST among patients with HIV infection - Uganda Patients diagnosed with HIV at voluntary counseling and test site 1524 offered TST, 1344 (88%) accepted Of 1344 TSTs placed, 1094 (81%) were read 579 (53%) of TSTs read were positive (> 5 mm induration) 33 (5.7%) of the 579 with positive TST had active TB This study illustrates some of the challenges of screening for TB among HIV-infected persons in Africa. There was fairly good acceptance of TST - 88% Having patients return for reading the TST is always a challenge - 81% returned in this study A high percentage of skin tests were positive, presumably due to the intense exposure to TB Finally, the frequency of active TB among those with positive TST emphasizes that the first step in the management of a positive skin test is a careful evaluation for active TBThis study illustrates some of the challenges of screening for TB among HIV-infected persons in Africa. There was fairly good acceptance of TST - 88% Having patients return for reading the TST is always a challenge - 81% returned in this study A high percentage of skin tests were positive, presumably due to the intense exposure to TB Finally, the frequency of active TB among those with positive TST emphasizes that the first step in the management of a positive skin test is a careful evaluation for active TB

35. The MTCT-Plus Initiative 35 Possible ways to increase adherence with return for TST reading Stress importance of TST reading Schedule return for reading TST results with another medical appointment or support group meeting Incentive � small amount of money or coupon Help with transportation Schedule TST reading for the day of a home visit - have an outreach worker trained to read TST results

36. Positive Tuberculin Skin Tests:Evaluation and Management

37. The MTCT-Plus Initiative 37 Evaluation of a patient with positive TST Evaluate for active TB Re-check symptoms and exam � cough, fever, weight loss, enlarged lymph nodes, dyspnea Chest X-ray, if possible 33 / 579 (5.7%) of TST-positive patients had TB in Uganda Tuberculosis is a leading cause of morbidity and mortality among HIV-infected patients and WHO/UNAIDS guidelines support treatment of latent TB infection (LTBI) for persons dually infected with HIV and M. tubrerculosis. Treatment of latent TB should only be offered after active TB has been excluded via symptom checklist, clinical exam and , if needed, sputum exam or chest x-ray. In most circumstances, local protocols will govern screening for and treatment of LTBI and site medical directors will make final decisions. Tuberculosis is a leading cause of morbidity and mortality among HIV-infected patients and WHO/UNAIDS guidelines support treatment of latent TB infection (LTBI) for persons dually infected with HIV and M. tubrerculosis. Treatment of latent TB should only be offered after active TB has been excluded via symptom checklist, clinical exam and , if needed, sputum exam or chest x-ray. In most circumstances, local protocols will govern screening for and treatment of LTBI and site medical directors will make final decisions.

38. The MTCT-Plus Initiative 38 Management of patient with positive TST If no signs of active TB: Check for contraindications to INH � prior intolerance, symptoms of hepatitis (nausea, jaundice) Assess readiness for INH treatment Discuss importance of adherence with INH and with clinic visits for monitoring Offer INH treatment of latent infection to positive (>5mm) TST Adults: INH 300 mg daily plus MTCT Plus multivitamin daily x 6 months

39. The MTCT-Plus Initiative 39 Use of Isoniazid to prevent TB in pregnant women Some evidence that INH-related hepatitis may be more severe during pregnancy Risk of progression to active TB is significant Recommendation � offer INH preventive therapy to HIV-positive pregnant women with positive TST Monitor carefully for signs of hepatitis

40. The MTCT-Plus Initiative 40 Use of Isoniazid to prevent TB in infants/ children INH dose 20 mg/kg per day, maximum of 300 mg Giving INH to children who cannot swallow pills Crush tablets, give with food Don�t give with food with high sugar content Side effects of INH are rare in children

41. The MTCT-Plus Initiative 41 Adherence to INH treatment of latent TB The rates of completion of a 6-month course of INH (55-76%) are similar to those achieved in the U.S. These results illustrate the adherence challenge of long-term therapy - even though INH treatment of latent TB is simple (1 pill per day) and has few side effects, it is difficult to complete for a significant percentage of patientsThe rates of completion of a 6-month course of INH (55-76%) are similar to those achieved in the U.S. These results illustrate the adherence challenge of long-term therapy - even though INH treatment of latent TB is simple (1 pill per day) and has few side effects, it is difficult to complete for a significant percentage of patients

42. The MTCT-Plus Initiative 42 Side effects of INH Common Mild upset stomach Mild skin rash Mild decrease in energy level Uncommon, but serious Drug-induced hepatitis Seizures (very rare with standard dose of INH) Peripheral neuropathy (very rare if MTCT-Plus multivitamin is given)

43. The MTCT-Plus Initiative 43 Suggested monitoring during INH treatment of latent TB Ask about symptoms of TB Educate on the importance of evaluation in the clinic for nausea, poor appetite, dark urine, or jaundice Dispense no more than one month�s supply of INH Ask patients about symptoms of hepatitis at each visit If symptomatic, stop INH and obtain SGOT

44. The MTCT-Plus Initiative 44

45. The MTCT-Plus Initiative 45 Case 1 (continued) TST interpretation Mother: 10 mm = positive TST 2 year old son: 6 mm = positive TST No signs or symptoms of TB Both have normal CXRs Management = INH for 6 months

46. The MTCT-Plus Initiative 46 Summary TB is the most common complication of HIV in Africa Tuberculin skin test identifies persons at high risk of TB Prior history of BCG should not change TST interpretation INH preventive therapy decreases the risk of active TB by 60% TST recommended as part of initial and ongoing evaluation in MTCT-Plus

47. Effect of ART on Prevention of TB

48. The MTCT-Plus Initiative 48 Effect of ARV on incidence of active TB, by baseline CD4 cell count

49. The MTCT-Plus Initiative 49 Summary of the effect of antiretroviral therapy on rates of active TB In multiple studies done in a variety of settings, use of antiretroviral therapy decreases the rate of active TB in the population The effect of antiretroviral therapy is greatest in areas with high rates of TB and among patients with lower CD4 cell counts Decreasing the risk of active TB is an important benefit of antiretroviral therapy

50. The MTCT-Plus Initiative 50 MTCT-Plus recommends: For patients without history of active TB disease: TST at enrollment Annual TST thereafter Treatment with isoniazid for all patients with positive TST in whom active TB disease has been excluded