ISTC TB Training Modules 2009 Initial Treatment of Tuberculosis Instructor’s Guide and Teaching Notes Module: Initial Treatment of Tuberculosis ISTC Standards covered: 7, 8, 10, 13, 17, and 21 Module Time: Approximately 60 minutes Alternate slides: Introductory ISTC slides Interactive options: Ideas for interactive discussions are offered on many of the slides in this module. Participant discussion can enhance active learning, but will add more time to the lecture and must be planned for. Additional Material: Slides containing related material may be found in the following modules: TB and HIV Infection: Treatment, Management of Drug-resistant Tuberculosis. Test Questions: May be attached or inserted within presentation for discussion purposes, or alternatively, combined with questions from other modules to produce evaluation tool. The full text of the ISTC and all supporting references are available at www.istcweb.org Other useful Resources/References: Treatment of Tuberculosis: Guidelines for National Programmes, Third Edition. World Health Organization, 2003. www.who.int/tb ATS/CDC/IDSA Statement: Treatment of Tuberculosis. American Thoracic Society/Centers for Disease Control/Infectious Diseases Society of America, Am J Respir Crit Care Med 2003; 167(4):603-62. www.thoracic.org Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition. Freiden TR ed., World Health Organization, 2004. www.who.int/tb Saukkonen JJ, et al. An official ATS statement: Hepatotoxicity of antituberculosis drugs. Am J Resp Crit Care Med 2006; 174(8): 935-52 [Image Credit: World Lung Foundation/Gary Hampton] Your name Institution/organization Meeting Date International Standards 7, 8, 10, 13, 17, 21

Initial Treatment of Tuberculosis ISTC TB Training Modules 2009 Objectives: At the end of this presentation, participants will have an understanding of: Drug regimens used in the initial treatment of both pulmonary and extrapulmonary tuberculosis The basis for the public health benefits of treating tuberculosis The clinical and microbiological effects of treatment The rationale for patient monitoring and reporting The main adverse effects of antituberculosis drugs It is intended that after completion of this module the student will be able to describe the approach to and rationale for the initial treatment of tuberculosis. These objectives represent the key points in the presentation. [Review content of slide] ISTC TB Training Modules 2009

Initial Treatment of Tuberculosis ISTC TB Training Modules 2009 Overview: Effect of appropriate treatment on public health First-line treatment recommendations Treatment of extrapulmonary tuberculosis Monitoring of treatment Adverse reactions Recording and reporting Initial Treatment of Tuberculosis Overview: [Review content of slide] Lecture/module includes International Standards for Tuberculosis Care 7, 8, 10, 13, 17, and 21. [Image credits: World Lung Foundation/Gary Hampton (top); Erlina Burhan, MD, Persahabatan Hospital (bottom)] International Standards 7, 8, 10, 13, 17, and 21 ISTC TB Training Modules 2009

ISTC TB Training Modules 2009 Standards for Treatment ISTC TB Training Modules 2009 This slide emphasizes the fact that treatment for TB is both a matter of individual health and public health and that adherence to treatment must be assured to have confidence that the patient will be cured. Assessing adherence and addressing poor adherence may (likely will) require collaboration between the provider and a program or facility that is capable of ensuring adherence. The main interventions to prevent the spread of TB in the community are the detection of patients with infectious TB and providing them with effective treatment to ensure a rapid and lasting cure. Consequently, treatment for TB is not only a matter of individual health, it is also a matter of public health. [Image credit: World Lung Foundation/Gary Hampton] ISTC TB Training Modules 2009

ISTC TB Training Modules 2009 Initial Treatment of Tuberculosis Standards 7 & 8 Standards 7 and 8 relate to treatment of the new, previously untreated case of TB. The information relates to both pulmonary and extrapulmonary TB, although most of the public health issues relate to pulmonary TB. Differences in the treatment of extrapulmonary TB are presented at the end of the discussion. The photos include a chest radiograph showing extensive bilateral upper lobe opacities consistent with TB and a patient with lymph node TB (swelling and erythema of an anterior cervical node together with a sinus tract from spontaneous rupture of a supraclavicular node). [Image credits: Francis J. Curry National Tuberculosis Center, University of California, San Francisco (top); Austin Brewin, MD (bottom).] ISTC TB Training Modules 2009

Standard 7: Public Health Responsibility ISTC Training Modules 2008 ISTC TB Training Modules 2009 Any practitioner treating a patient for tuberculosis is assuming an important public health responsibility to prevent ongoing transmission of the infection and the development of drug resistance. To fulfill this responsibility the practitioner must not only prescribe an appropriate regimen, but also utilize local public health services and other agencies, when necessary, to assess the adherence of the patient and to address poor adherence when it occurs. [Read Standard] Standard 7 emphasizes that treatment for TB is both a matter of individual health and public health and that it is the responsibility of the provider to both prescribe the correct regimen and to ensure adherence to the regimen. Assessing adherence and addressing poor adherence may (likely will) require collaboration between the provider and a program or facility that is capable of ensuring adherence. ISTC TB Training Modules 2009 6

Effect of Treatment on Public Health ISTC TB Training Modules 2009 Why is TB Treatment a Public Health Measure? Effective treatment rapidly kills organisms, reducing the bacillary population in respiratory secretions, thus reducing the potential for transmission. Effective multiple-drug treatment greatly reduces the risk of resistant organisms emerging. Effective treatment decreases the duration and severity of illness and reduces the risk of death. The main interventions to prevent the spread of TB in the community are the detection of patients with infectious TB and providing them with effective treatment to ensure a rapid and lasting cure. Consequently, treatment for TB is not only a matter of individual health, such as is provided by, for example, treatment of hypertension or diabetes mellitus, it is also a matter of public health. All providers, public and private, who undertake to treat a patient with TB, must have the knowledge to prescribe a standard treatment regimen and the means to ensure adherence to the regimen until treatment is completed. National or local TB programs commonly possess mechanisms and tools to ensure adherence with treatment and, when properly organized, can offer these to non-program providers. Failure of a provider to ensure adherence could be equated with, for example, failure to ensure that a child receives the full set of immunizations. Communities and patients deserve to be assured that providers treating TB are doing so in accordance with this principle and are, thereby, meeting this standard. ISTC TB Training Modules 2009

Effect of Treatment on Public Health ISTC TB Training Modules 2009 Effects of Treatment on the Incidence of Tuberculosis in Peru 220 DOTS 1990 200 case finding 180 Pulmonary TB cases/100,000 160 This slide shows the effect of an effective drug regimen that was closely supervised to ensure adherence. Peru began a DOTS program in late 1990. Because of the increased coverage of the program, more cases were found and, initially, case rates increased. However with the continued effectiveness of the program case rates began falling at the rate of approximately 6% per year. Because of the decrease in case rates, Peru “graduated” from the list of 22 high-burden TB countries. [The module “Fostering and Assessing Adherence to Treatment” describes approaches to enhance patient adherence and treatment supervision.] 140 120 PTB falling at 6%/yr 100 1980 1985 1990 1995 2000 ISTC TB Training Modules 2009

Standard 8: Initiation of Treatment ISTC Training Modules 2008 ISTC TB Training Modules 2009 (1 of 2) All patients (including those with HIV infection) who have not been treated previously should receive an internationally accepted first-line treatment regimen using drugs of known bioavailability. The initial phase should consist of two months of isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB). Standard 8 contains several concepts and has been divided into 2 parts. [Read Standard] This part describes the most widely-used and effective initial phase of the initial drug regimen. There are 3 major points to be made with this slide: An accurate history is critical. Patients who have been treated previously have a greater risk of drug resistance and are assessed as described in Standard 11 [Drug-resistant Tuberculosis module]. The drugs used must be quality assured with known bioavailabiity. Poor quality drugs are common and lead to poor outcomes. For maximum efficacy, 4 drugs should be given in the initial phase. A large number of well-designed clinical trials have provided the evidence base for this standard and several sets of treatment recommendations based on these studies have been written in the past few years. All these data indicate that a rifampicin-containing regimen is the backbone of antituberculosis chemotherapy and is highly effective in treating TB caused by drug-susceptible M. tuberculosis. It is also clear from these studies that the minimum duration of treatment for smear and/or culture-positive TB is six months. For the six-month treatment duration to be maximally effective, the regimen must include pyrazinamide during the initial two-month phase and rifampicin must be included throughout the full six months. There are several variations in the frequency of drug administration that have been shown to produce acceptable results. [Image credit: World Lung Foundation/Gary Hampton] ISTC TB Training Modules 2009 9 9

Effect of Treatment on Bacillary Population ISTC TB Training Modules 2009 Mixed population (susceptible and resistant) INH resistant bacilli Emergence of INH resistant strain because of ineffective treatment (INH monotherapy) Log cfu Effective multi-drug treatment rapidly reduces the bacillary population. Within 2 weeks of beginning appropriate chemotherapy the number of organisms in sputum is decreased from ~107 (107 would be a typical number of bacilli to find in the sputum of a person with cavitary pulmonary TB) to 104 (104 is the approximate threshold for detecting acid fast organisms by sputum smear microscopy). This greatly decreases (but does not completely eliminate) the potential for transmission. Further treatment beyond the initial period is intended to kill the remaining organisms that persist through the initial period. In all populations of M.tb there is a small number of organisms that are resistant to each of the drugs used. If treatment does not contain at least two drugs to which the organisms are susceptible, a bacillary population that is resistant to one or more of the first line drugs emerges. Effective multi-drug therapy 0 2 4 6 8 10 12 14 16 18 20 22 24 Weeks ISTC TB Training Modules 2009

Unintended Monotherapy and Resistance ISTC TB Training Modules 2009 Months of Rx 5 7 9 INH RIF EMB Smear + Culture Susceptibility R* R S* S In this hypothetical example a patient is begun on treatment with an initial 2 drug regimen, a clear mistake. The organisms were initially resistant to isoniazid, although the treating provider was unaware of this. After 5 months of treatment, the smear was still positive and the organisms had become resistant to rifampicin because the resistance to isoniazid prevented the eradication of the few organisms that were rifampicin resistant and the rifampicin resistant strain proliferated. Again the provider was not aware of the resistance that had occurred. Because the smear was still positive, the provider added ethambutol. This is also a clear mistake. A single drug should never be added to a failing regimen. A sputum specimen, after 9 months of treatment, was still positive. In effect the patient had been treated with ethambutol alone for the last 4 months of the regimen and the organisms that were resistant to ethambutol proliferated. This result would have been prevented if a regimen of isoniazid, rifampicin, ethambutol and pyrazinamide had been used in the initial 2 months of treatment. [Interactive option: This is a very important concept in the management of TB treatment. Stop to ask if there are any questions or clarifications needed.] * Results not known to clinician ISTC TB Training Modules 2009

ISTC TB Training Modules 2009 Treatment Goals ISTC TB Training Modules 2009 Microbiological Goals of Antituberculosis Chemotherapy Kill tubercle bacilli rapidly (early bactericidal effect) Prevent the emergence of drug resistance Eliminate persistent bacilli to prevent relapse (sterilizing effect) The previous slides presented the individual and public health goals of treatment for TB. This slide defines the microbiological goals of treatment. [Review content of slide] Antituberculosis drugs operate in a complimentary way to accomplish these goals as shown in the next slide. ISTC TB Training Modules 2009

Activities of Antituberculosis Drugs ISTC TB Training Modules 2009 Drug Early bactericidal activity Preventing drug resistance Sterilizing activity Isoniazid ++++ +++ ++ Rifampicin Pyrazinamide + Streptomycin Ethambutol ++ - +++ This table shows the relative activities of the first line antituberculosis drugs. Isoniazid has the most potent early bactericidal effect and is also effective in preventing resistance, but has less sterilizing effect. Rifampicin has a weaker early effect but is more potent than isoniazid in its sterilizing activity. Pyrazinamide is only effective as a sterilizing agent. [Note: relatively poor agent for prevention of drug resistance] Streptomycin has an intermediate effect in all three activities as does ethambutol. Highest ++++ High +++ Intermediate ++ Low + ISTC TB Training Modules 2009

Standard 8: Continuation of Treatment ISTC TB Training Modules 2009 (2 of 2) The continuation phase should consist of isoniazid and rifampicin given for four months The doses of antituberculosis drugs used should conform to international recommendations Standard 8 continued: [Read Standard] The second part of Standard 8 describes the continuation phase regimen. First, the major point is that it is preferable to use rifampicin throughout the continuation phase. [Previous recommendations for a continuation phase of six months of isoniazid and ethambutol is no longer recommended (WHO 2009 pending publication).] A review of the outcomes of treatment of TB in patients with HIV infection clearly shows that TB relapse is minimized by the use of a regimen containing rifampicin throughout a six-month course. Thus, the 6 month regimen containing rifampicin throughout the entire course is preferable in patients with HIV infection to minimize the risk of relapse; however, the patient’s HIV stage, the need for, and availability of, antiretroviral drugs, and the quality of treatment supervision/support must be considered in choosing an appropriate continuation phase of therapy. Second, the shortest total duration of treatment is 6 months. Although regimens of less than 6 months have been evaluated in clinical trials, a Cochrane systematic review on this topic, and a more recent review found that regimens <6 months have an unacceptably high rate of relapse. The current international standard, therefore, is a regimen administered for a minimum duration of 6 months. Finally, although there is no evidence that fixed dose combinations (FDCs) are superior to individual drugs, expert opinion suggests that they may reduce inadvertent monotherapy and may decrease the frequency of acquired drug resistance and medication errors. FDCs also reduce the number of tablets to be consumed and may thereby increase adherence to recommended treatment regimens. [Gelband H., et al. Regimens of less than six months for treating tuberculosis. Cochrane Database Syst Rev 2000(2):CD001362; and Santha T, et al. What is the optimum duration of treatment? In: Friedan TR, ed. Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition. Geneva: WHO,2004] [Image credit: Stop TB Partnership, Global Drug Facility, www.stoptb.org/gdf] Fixed-dose combinations (FDCs) of two (INH and RIF), three (INH, RIF, and PZA), and four (INH, RIF, PZA, and EMB) drugs are highly recommended ISTC TB Training Modules 2009 14

Treatment Recommendations ISTC TB Training Modules 2009 New Patients (not previously treated) Initial Phase (2 months) Continuation Phase (4 months) INH, RIF, PZA, EMB daily INH, RIF daily INH, RIF, PZA, EMB1 3x/wk. INH, RIF 3x/wk Treatment recommendations for new patients (not previously treated). This slide presents the standard recommended six-month course of treatment for new patients with the option of 3x per week dosing. Note that a systematic review found little evidence of difference in failure or relapse rates with daily or 3x weekly regimens in HIV-negative patients. However, 3x per week dosing was associated with higher rates of acquired drug resistance. Further comments for 3x per week dosing are also noted on slide. Note: All patients with TB and HIV infection should be evaluated to determine if antiretroviral therapy is indicated during the course of treatment for TB. [Additional information on this topic, including dosing recommendations for TB if living with HIV, can be found in TB and HIV Infection: Introduction and Diagnosis module.] [Pediatric dosing covered in Pediatric module.] [Interactive option: Ask participants about what their standard practice is locally for the initiation and continuation phases of treatment.] [World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, Third Edition. Geneva: World Health Organization, 2003. – Note slide reflects updated version pending 2009] 1. Associated with higher rate of acquired drug resistance and must be given using directly-observed therapy. Where feasible, daily dosing is preferred. May consider daily initiation phase, then 3x week continuation phase. 3x weekly dosing not recommended if living with HIV or living in an HIV-prevalent setting. ISTC TB Training Modules 2009

ISTC TB Training Modules 2009 Dose Recommendations ISTC TB Training Modules 2009 Adults: mg/kg (range) Drug Daily 3x Week INH 5 (4-6), max 300/d 10 (8-12), max 900/d RIF 10 (8-12), max 600/d 10 (8-12) max 600/ d PZA 25 (20-30), max 2000/d 35 (30-40), max 3000/d EMB 15 (15-20), max 1600/d 30 (25-35), max 2400/d Streptomycin 15 (12-18) The evidence base for currently recommended anti-TB drug dosages derives from human clinical trials, animal models, pharmacokinetic and toxicity studies. The evidence on drug dosages and safety and the biological basis for dosage recommendations have been extensively reviewed in publications by the WHO, The Union, the ATS, the CDC, and IDSA. Intermittent administration of anti-TB drugs enables supervision to be provided more efficiently and economically with no reduction in efficacy. The evidence on effectiveness of intermittent regimens was reviewed recently. These reviews, based on several trials, suggest that anti-TB treatment may be given intermittently 3 times a week throughout or twice weekly in the continuation phase without apparent loss of effectiveness. However, the WHO and The Union do not recommend the use of twice-weekly intermittent regimens because of the potentially greater consequences of missing 1 of the 2 doses. Treatment of TB in special clinical situations such the presence of liver disease, renal disease, pregnancy, and HIV infection may require modification of the standard regimen or alterations in dosage or frequency of drug administration. [For further guidance in these situations: World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, Third Edition. Geneva: World Health Organization, 2003; ATS/CDC/IDSA Statement: Treatment of Tuberculosis. American Thoracic Society/Centers for Disease Control/Infectious Diseases Society of America, Am J Respir Crit Care Med 2003; 167(4):603-62.] ISTC TB Training Modules 2009

Standard 17: Treat Co-morbid Disease ISTC TB Training Modules 2009 (1 of 2) All providers should conduct a thorough assessment for co-morbid conditions that could affect tuberculosis treatment response or outcome At the time the treatment plan is developed, the provider should identify additional services that would support an optimal outcome for each patient and incorporate these services into an individualized plan of care Treatment plans should include an assessment for other co-morbid conditions that may affect treatment success. This concept is outlined in ISTC Standard 17 [Read Standard]. ISTC TB Training Modules 2009

Standard 17: Treat Co-morbid Disease ISTC Training Modules 2008 ISTC TB Training Modules 2009 (2 of 2) This plan should include assessment of and referrals for treatment of other illnesses with particular attention to those known to affect treatment outcome, for instance care for diabetes mellitus, drug and alcohol treatment programs, tobacco smoking cessation programs, and other psychosocial support services, or to such services as antenatal or well baby care Successful treatment of co-morbid conditions can positively affect tuberculosis outcomes and therefore is an important part of overall tuberculosis care. [Read Standard – continued]. [Image Credit: Dr. Richard Brostrom/Saipan TB Program] ISTC TB Training Modules 2009 18

ISTC TB Training Modules 2009 Treatment of Extrapulmonary TB This slide introduces the topic of extrapulmonary TB. Three extrapulmonary sites are shown: CT scan of the head showing 2 enhancing lesions consistent with intracranial tuberculomas. Cervical lymphadenopathy with a large swollen node in the anterior cervical chain and spontaneously draining supraclavicular nodes Involvement of the lumbar spine with destruction of part of the body of a lower lumbar vertebra and soft tissue swelling anterior to the vertebra. The disc spaces are also narrowed. [Image credits: Francis J. Curry National Tuberculosis Center (top); Austin Brewin, MD (center); Francis J. Curry National Tuberculosis Center (bottom).] ISTC TB Training Modules 2009

Treatment of Extrapulmonary TB ISTC TB Training Modules 2009 In general, extrapulmonary tuberculosis is treated the same as pulmonary tuberculosis Some experts recommend extending the duration of therapy in patients with: Meningeal tuberculosis Bone/joint tuberculosis Corticosteroids may be useful adjunctive treatment in some forms of extrapulmonary tuberculosis [Review content of slide] The emphasis in this slide is that there are minimal differences between the treatment of pulmonary and extrapulmonary sites of TB. Whereas with pulmonary TB there is extensive published evidence on the most effective treatment regimens, there is not much information for treatment of extrapulmonary sites, thus there is generally more controversy. [Recommended adult steroid dosing: Prednisone 60 mg/day for 4 weeks, then reduce to 30 mg/day for 4 weeks, then 15 mg/day for 2 weeks, then 5 mg/day for one week. ATS/CDC/IDSA Statement: Treatment of Tuberculosis. Am J Respir Crit Care Med 2003; 167(4):603-62.] ISTC TB Training Modules 2009

Treatment of Extrapulmonary TB ISTC TB Training Modules 2009 Treatment Duration and Use of Steroids Site Length of Rx (mos.) Corticosteroids Lymph node 6 No Bone/Joint 6-9 Pleural Pericarditis Yes CNS 9-12 Disseminated Genitourinary Abd/Peritoneal Other than for bone and joint and CNS tuberculosis, the duration of treatment is the same as for pulmonary TB. There are data that support the use of corticosteroids in treating tuberculous pericarditis and CNS tuberculosis. ISTC TB Training Modules 2009

ISTC TB Training Modules 2009 Monitoring Treatment for TB and Public Health Reporting Standards 10, 13, & 21 Patient monitoring is necessary for both initial treatment and re-treatment. Adequate monitoring involves both patent evaluations and recording of the relevant clinical and microbiological data. [Image credit: World Lung Foundation/Gary Hampton] ISTC TB Training Modules 2009

Standard 10: Monitoring Treatment ISTC Training Modules 2008 ISTC TB Training Modules 2009 (1 of 2) Response to therapy in patients with pulmonary tuberculosis should be monitored by follow-up sputum smear microscopy (2 specimens) at the time of completion of the initial phase of treatment (2 months). If the sputum smear is positive at completion of the initial phase, sputum smears should be examined again at 3 months and, if possible, culture and drug susceptibility testing should be performed. [Read Standard] Patient monitoring and treatment supervision are two separate functions. (1) Patient monitoring is necessary to evaluate the response of the disease to treatment and to identify adverse drug reactions. For the latter function, contact between the patient and a provider is necessary. (2) To judge response of pulmonary TB to treatment, the most expeditious method is sputum smear microscopy. Ideally, where quality-assured laboratories are available, sputum cultures, as well as smears, should be performed for monitoring. Having a positive sputum smear at completion of the initiation phase should trigger an assessment of the patient’s adherence and a careful reevaluation to determine if co-morbid conditions are present that might interfere with response to treatment. However, a positive smear at the end of the initiation phase is not an indication to prolong this phase of treatment. If the smear is positive at the end of month two, a repeat sputum smear should be obtained at the end of month three – and if positive, culture with drug-susceptibility testing should be performed. 1 of 2 ISTC TB Training Modules 2009 23

Standard 10: Monitoring Treatment ISTC Training Modules 2008 ISTC TB Training Modules 2009 (2 of 2) In patients with extrapulmonary TB and in children, the response to treatment is best assessed clinically. Standard 10 continued: [Read Standard] In patients with extra-pulmonary TB and in children, clinical evaluations may be the only available means of assessing the response to treatment. [Image credit: World Lung Foundation/Gary Hampton] 2 of 2 ISTC TB Training Modules 2009 24 24

Monitoring: Timing of Sputum Specimens ISTC TB Training Modules 2009 Initial Phase Continuation Phase Isoniazid Rifampicin Pyrazinamide Ethambutol Routine sputum specimens are to be obtained at the time of the diagnostic evaluation, at completion of the initial phase of treatment, at 5 months to assess for treatment failure, and at the end of the continuation phase (6 months) to confirm that treatment has been successful. [*As noted in Standard 10, an additional sputum may be obtained at the end of month 3 if the smear remains positive at the end of the intensive phase.] By WHO criteria, having a positive sputum at 5 months defines treatment failure, indicating the need to assess for drug resistance. [Standard 11 – see Drug-resistant TB module.] A person who completes 6 months of treatment and has negative sputum smears at the time of completion is defined as cured. If sputum is not examined at the end of treatment, the patient is defined as having completed treatment. For purposes of defining outcome, those who are cured and those who have completed treatment are considered to have been successfully treated. Months 0 1 2 3 4 5 6 Assessment for failure Diagnostic End of intensive phase Completion [*Obtain if smear-positive at month 2] ISTC TB Training Modules 2009

Treatment Outcomes for Pulmonary TB ISTC TB Training Modules 2009 1.2% 50% 10% 98% 64% Dead Sputum negative 32% Sputum positive 20% Appropriate chemotherapy is highly successful in the initial treatment of pulmonary TB, whereas poor chemotherapy not only has a substantially lower rate of success and higher death rates but serves to create chronic sputum positive patients, likely with drug-resistant organisms. Analysis of cohorts of patients enables programs, institutions, and individual practitioners to determine the level of success of treatment in their setting and to identify weaknesses in treatment. This can only be accomplished when there is systematic monitoring of patients and recording of treatment results. [Reference: Grzybowski S et al. Results in pulmonary tuberculosis patients under various treatment program conditions. Bull Int Union Tuberc 1978; (53)2: 70-5] 18% 0.8% No Chemotherapy Poor Chemotherapy Good Chemotherapy Grzybowski S et al, Bull Int Union Tuberc 1978; (53)2: 70-5 ISTC TB Training Modules 2009

Monitoring: Adverse Reactions ISTC TB Training Modules 2009 Adverse Reaction Drugs Rash PZA, INH, RIF, EMB Gastrointestinal intolerance PZA, RIF Liver toxicity PZA, INH, RIF Peripheral neuropathy INH, (EMB) Optic neuritis EMB Gout PZA These are the most common adverse drug reactions that occur in patients being treated for TB. [Review content of slide] All drugs can cause skin rash which, rarely, can be severe. Gastrointestinal upset can usually be managed with alterations in dosing schedules and symptomatic measures. Liver toxicity is the most common severe reaction. Each of the three agents listed can cause liver toxicity. In a large review clinical hepatitis occurred in 0.6% of patients taking INH alone, 1.6% of patients taking INH and other drugs but not RIF, 2.7% of patients taking INH and RIF and 1.1% of patients taking RIF plus other drugs but not INH. In addition studies of RIF/PZA with no other drugs for treatment of latent TB infection showed an unacceptable rate of hepatitis. This combination is no longer recommended. [For a more complete review of the adverse effects of antituberculosis drugs see: ATS/CDC/IDSA Statement: Treatment of Tuberculosis. American Thoracic Society/Centers for Disease Control/Infectious Diseases Society of America, Am J Respir Crit Care Med 2003; 167(4):603-62.] Drugs are listed in order of relative likelihood of causing adverse reaction. INH/RIF and RIF/PZA appear to have synergistic effects in causing hepatitis ISTC TB Training Modules 2009

Adverse Reactions: Rash ISTC TB Training Modules 2009 Classic drug-related rash Severe skin rash from thioacetazone The rash due to anti-TB drugs is similar to that seen with other drug-related rashes (example here actually due to amoxicillin) with a erythematous, maculopapular appearance. Although skin rashes are generally mild, they may be severe, including Stevens Johnson Syndrome which may be fatal. In the bottom example, the skin reaction was from thioacetazone, a drug which is not commonly used because of the frequency of severe skin reactions especially in persons with HIV infection. [Image credits: Catalog of Clinical Images/ Charlie Goldberg, MD, www.medicine.ucsd.edu (top); World Lung Foundation/Paul Nunn (bottom)] ISTC TB Training Modules 2009

Drug-induced Hepatotoxicity ISTC TB Training Modules 2009 Hepatotoxic reactions: Transaminase elevation age-dependent with INH Transaminase elevation dose-dependent with PZA Cholestasis (increase in bilirubin and alkaline phosphatase) with RIF Symptoms imply significant hepatotoxicity (Mild transaminase elevation may not be clinically significant) Because drug-induced hepatitis is the most common severe adverse effect, providers should be aware of the patterns of abnormalities and the general approach to management. INH, RIF, and PZA may all cause transaminase elevation. In addition, the reactions to specific first-line drugs can show the following: [Review content of slide] Overall, how adverse reactions are handled will depend on the severity of symptoms and the available facilities for evaluation and management. [Mild transaminase elevations may not be treatment limiting. One recommended strategy suggests that elevated liver enzymes of 5x upper limit of normal without symptoms or 3x upper limit of normal with symptoms serve as the thresholds for holding and re-evaluating TB treatment due to possible drug-related hepatotoxicity.] [For detailed information: Saukkonen JJ, et al. An official ATS statement: Hepatotoxicity of antituberculosis drugs. Am J Resp Crit Care Med 2006; 174(8): 935-52] ISTC TB Training Modules 2009

Managing Hepatotoxicity ISTC TB Training Modules 2009 Management Hold all medications and follow liver enzymes for significant hepatotoxicity Re-challenge depends on circumstances and severity of liver dysfunction In general, patients should be restarted with EMB (the least hepatotoxic drug) and RIF, usually followed in several days by INH if there is no worsening of liver function Once a significant hepatotoxic reaction is suspected, all medications should be held and liver enzymes monitored for signs of recovery. Alternate causes should be excluded (ex. viral hepatitis). If a re-challenge is deemed safe: The combination of EMB and RIF is least likely to be hepatotoxic and may be re-introduced first. If there is no worsening of liver function, INH can then be added with close observation. If there is no worsening of liver function after adding the INH, it can be assumed that PZA alone or in combination caused the adverse reaction and PZA should not be restarted. Without PZA the minimum duration of treatment is 9 months. [For detailed information: Saukkonen JJ, et al. An official ATS statement: Hepatotoxicity of antituberculosis drugs. Am J Resp Crit Care Med 2006; 174(8): 935-52] ISTC TB Training Modules 2009

Standard 13: Monitoring Record ISTC TB Training Modules 2009 A written record of all medications given, bacteriologic response, and adverse reactions should be maintained for all patients [Read Standard] There is a sound rationale and clear benefits of a record keeping system. The recording and reporting system enables targeted, individualized follow-up to identify patients who are failing therapy. It also helps in facilitating continuity of care, particularly in settings (e.g. large hospitals) where the same practitioner might not see the patient every visit. A good record of medications given, results of investigations such as smears, cultures, and CXR, and progress notes on clinical improvement, adverse events, and adherence will provide for more uniform monitoring and ensure a high standard of care. Records are important to provide continuity when patients move from one care provider to another and enable tracing of patients who miss appointments. In patients who default and then return for treatment, and patients who relapse after treatment completion, it is critical to review previous records in order to assess the likelihood of drug resistance. Lastly, management of complicated cases (e.g., MDR-TB) is not possible without an adequate record of previous treatment, adverse events, and drug susceptibility results. It should be noted that, wherever patient records are concerned, care must be taken to insure confidentiality of the information. [Image credit: World Lung Foundation/Gary Hampton] ISTC TB Training Modules 2009

Standard 21: Reporting Cases ISTC TB Training Modules 2009 All providers must report both new and retreatment tuberculosis cases and their treatment outcomes to local public health authorities, in conformance with applicable legal requirements and policies. [Read Standard] An additional record keeping step is the appropriate reporting of both new and retreatment cases to the local public health authorities. Reporting TB cases to the local TB control program is an essential public health function, and in many countries is legally mandated. An effective reporting system enables a determination of the overall effectiveness of TB control programs, of resource needs, and of the true distribution and dynamics of the disease within the population as a whole. A system of recording and reporting information on TB cases and their treatment outcomes is also one of the key elements of the DOTS strategy Finally, a system of recording and reporting ensures accountability. [Image credit: World Lung Foundation/Gary Hampton] ISTC TB Training Modules 2009 ISTC Training Modules 2008

Initial Treatment of Tuberculosis ISTC TB Training Modules 2009 Summary: Appropriate treatment and assessment of adherence to treatment is an important public health issue. The use of internationally accepted first-line treatment regimens is associated with a high cure rate and a low risk of acquired drug resistance. [Review content of slide] ISTC TB Training Modules 2009

Initial Treatment of Tuberculosis ISTC TB Training Modules 2009 Summary (cont.): Pulmonary and extrapulmonary TB are generally treated with the same regimens. (Exception: extended duration in meningeal and bone/joint disease.) Treatment includes assessment and services for co-morbid conditions that may effect tuberculosis treatment outcomes Monitoring for both response to treatment and for potential adverse events is essential. [Review content of slide] ISTC TB Training Modules 2009

Summary: ISTC Standards Covered* ISTC TB Training Modules 2009 Standard 7: Practitioners assume an important public health responsibility in ensuring both appropriate treatment regimens and assessment of treatment adherence for their patients. And in summary, the International Standards reviewed: [Review content of slide] * Abbreviated versions ISTC TB Training Modules 2009

Summary: ISTC Standards Covered* ISTC TB Training Modules 2009 Standard 8: All patients (including those with HIV infection) who have not been previously treated should receive an internationally accepted treatment regimen of known bioavailability: Initial phase: 2 months INH, RIF, PZA, and EMB Continuation phase: 4 months INH and RIF The doses of anti-TB drugs used should conform to international recommendations. Fixed-dose combinations are highly recommended. [Review content of slide] * Abbreviated versions ISTC TB Training Modules 2009

Summary: ISTC Standards Covered* ISTC TB Training Modules 2009 Standard 10: Response to therapy in patients with pulmonary TB should be monitored by follow-up 2 sputum smears at the end of the initial phase, and if positive, repeated at the end of 3 months (if positive at 3 months, obtain culture and DST). In extrapulmonary TB and in children, the response to treatment is best assessed clinically. [Review content of slide] * Abbreviated versions ISTC TB Training Modules 2009

Summary: ISTC Standards Covered* ISTC TB Training Modules 2009 Standard 13: A written record of all medications given, bacteriologic responses, and adverse reactions should be maintained for all patients. Standard 17: All providers should conduct a thorough assessment and provide services or referrals for co-morbid conditions with particular attention to those known to effect treatment outcome [Review content of slide] * Abbreviated versions ISTC TB Training Modules 2009

Summary: ISTC Standards Covered* ISTC TB Training Modules 2009 Standard 21: All providers must report both new and retreatment TB cases and their treatment outcomes to local public health authorities [Review content of slide] [End] * Abbreviated versions ISTC TB Training Modules 2009

ISTC TB Training Modules 2009 Alternate Slides Alternate Slides: Offer additional options that may be added or substituted into module. See Facilitator’s Guide for further information. ISTC TB Training Modules 2009

ISTC TB Training Modules 2009 Purpose of ISTC ISTC TB Training Modules 2009 ISTC Training Modules 2008 The International Standards for Tuberculosis Care (ISTC): Are intended to unite public and private sectors in providing a uniformly accepted level of care for all patients with, or suspected of having, TB. Describes the essential elements of TB care that should be available everywhere. Provides a vehicle for mobilizing professional societies globally in support of TB programs. Serves as a powerful advocacy tool to ensure that the essential elements are available. [Image Credit: World Lung Foundation/Jad Davenport ] ISTC TB Training Modules 2009 41

ISTC TB Training Modules 2009 ISTC: Key Points ISTC TB Training Modules 2009 21 Standards (revised/renumbered in 2009) Differ from existing guidelines: standards present what should be done, whereas, guidelines describe how the action is to be accomplished Evidence-based, living document Developed in tandem with Patients’ Charter for Tuberculosis Care Handbook for using the International Standards for Tuberculosis Care The ISTC consist of 21 evidence-based standards. The original 17 standards from 2006 were revised and renumbered in 2009. Standards differ from existing guidelines in that standards present what should be done, whereas, guidelines describe how the action is to be accomplished. To meet the requirements of the Standards, approaches and strategies, determined by local circumstances and practices and developed in collaboration with local and national public health authorities, will be necessary. There are many situations in which the level of care can, and should, go beyond what is specified in the Standards. The Standards should be viewed as a living document that will be revised as technology, resources, and circumstances change. Revisions to the original document released December 2005 are currently underway. Funded (Oct 1, 2004) by USAID via TBCTA, development was supervised by an international steering committee (28 members / 14 countries) chosen to represent perspectives relevant to tuberculosis care and control. The Standards are also intended to serve as a companion to and support for the Patients’ Charter for Tuberculosis Care developed in tandem with the Standards. A Handbook for using the International Standards for Tuberculosis Care is also available (2007). The Handbook presents suggestions and guidance, based mainly on country-level experiences, for using the ISTC as a tool to foster and guide the delivery of high-quality care by all practitioners providing TB care. [Resource: www.istcweb.org] ISTC TB Training Modules 2009

ISTC TB Training Modules 2009 ISTC: Key Points ISTC TB Training Modules 2009 Audience: all health care practitioners, public and private Scope: diagnosis, treatment, and public health responsibilities; intended to complement local and national guidelines Rationale: sound tuberculosis control requires the effective engagement of all providers in providing high quality care and in collaborating with TB control programs The Standards are addressed to all healthcare providers, private and public, who care for persons with proven tuberculosis or with symptoms and signs suggestive of TB. Three categories of activities are addressed by the Standards: diagnosis, treatment, and public health responsibilities of all providers. The ISTC are intended to be complementary to local and national TB control policies that are consistent with the World Health Organization (WHO) recommendations. In many parts of the world there is great variability in the quality of tuberculosis care, and poor quality care continues to plague global tuberculosis control efforts. Effective engagement of all providers in providing high quality care in collaboration with TB control programs is key to the promotion of sound tuberculosis control. ISTC TB Training Modules 2009

ISTC TB Training Modules 2009 Questions Questions: May be used for interactive discussion, course evaluation, or continuing medical education purposes. See Facilitator Guide for further information. ISTC TB Training Modules 2009

Initial Treatment of Tuberculosis ISTC TB Training Modules 2009 1. A 28 year-old woman taking standard four-drug treatment for TB for five weeks now complains of nausea, vomiting, and right upper-quadrant discomfort. When seen in clinic she is noted to have scleral icterus and right upper-quadrant tenderness. Her urine is dark colored. What is the appropriate action to take at this time? Stop all drugs Stop isoniazid Give pyridoxine (vitamin B6) Replace pyrazinamide with streptomycin Correct Answer: A ISTC TB Training Modules 2009

Initial Treatment of Tuberculosis ISTC TB Training Modules 2009 2. A 68 year-old woman with smear-positive TB needs to start treatment. She lives too far to be given directly-observed treatment (DOT) by your office. Which treatment regimen is preferred for this patient? Isoniazid and ethambutol for twelve months Isoniazid/rifampicin/ethambutol for the first two months, followed by isoniazid/rifampicin for an additional four months Fixed-dose combination of isoniazid/rifampicin/pyrazinamide for nine months Fixed-dose combinations of isoniazid/rifampicin/ethambutol/pyrazinamide for the first two months, followed by isoniazid/rifampicin for an additional four months Correct Answer: D ISTC TB Training Modules 2009

Initial Treatment of Tuberculosis ISTC TB Training Modules 2009 3. In considering treatment for extrapulmonary disease, all of the following statements are correct except: Extrapulmonary disease is a sign of disseminated disease, and therefore always requires a longer duration of treatment Most presentations of extrapulmonary TB can be treated with the same standard six month regimens used for pulmonary TB Extending the duration of therapy is recommended by many experts for central nervous system (CNS) and bone/joint extrapulmonary TB Corticosteroids are sometimes recommended for pericardial and central nervous system (CNS) extrapulmonary TB Correct Answer: A ISTC TB Training Modules 2009