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1 NOTICE AND DISCLAIMER This publication is intended to be a resource for physicians and other healthcare professionals who provide care and treatment to patients in resource poor settings. Reasonable efforts have been made to ensure that the material presented here is accurate, reliable, and in accord with current standards as of the date of publication. However, as new research and experience expand our knowledge, recommendations for care and treatment change. Your use of this publication is provided on an as is basis without warranty of any kind, and none of the individuals or entities listed below represent or warrant that the information contained herein is complete or accurate or free from error. It is therefore the responsibility of the individual physician or healthcare professional to use his/her best medical judgment in determining appropriate patient care or treatment. To the maximum extent permitted under applicable laws, no responsibility is assumed by any party involved in the production or publication of this publication, including without limitation, each of the contributors and authors; Partners In Health; the Program in Infectious Disease and Social Change, Harvard Medical School; Harvard Medical School Division of AIDS; the Division of Social Medicine and Health Inequalities, Brigham and Womenʹs Hospital; and each of their affiliates, divisions, directors, officers, trustees, agents and employees (referred to collectively as the Publishers and Contributors ). The Publishers and Contributors hereby disclaim all liability for errors, omissions, or any injury and/or damage (actual or perceived) to persons or property as a result of any actual or alleged product liability, libelous statement, or infringement of intellectual property or privacy rights, whether resulting from negligence or otherwise, including without limitation, from any reliance upon, use or operation of, any ideas, instructions, procedures, products or methods contained in the material included in this publication. References to specific drugs or products within this publication do not constitute endorsement by the Publishers and Contributors. Individual patient needs may vary on a case by case basis, and physicians and other healthcare professionals should consult their standard resources before prescribing specific drugs or products to their patients. This disclaimer and your use of this publication are and shall be governed and construed in accordance with the internal laws of the Commonwealth of Massachusetts, without regard to its rules concerning conflicts of laws. In the event of any conflict between foreign laws, rules and regulations and those of the United States, the laws, rules and regulations of the United States shall govern. By choosing to use this publication, you acknowledge and agree to the terms of this disclaimer. Published in the United States by Partners In Health. Subject to the rights of Partners In Health, this publication may be freely reviewed, abstracted, reproduced or translated, provided that all copyright, trademark and other proprietary notices are included in each such use. The foregoing notwithstanding, no portion of this publication may be sold or otherwise used or distributed in conjunction with any commercial purpose. PIH and Partners In Health are trademarks of Partners In Health, and the PIH logo is a United States registered service mark of Partners In Health. All other trademarks, service marks, trade names and logos appearing in this publication, including drug brands and names, are the property of their respective owners. Copyright Partners In Health All rights reserved under International and Pan American Copyright Convention BUSDOCS/

2 Chapter Six Treatment Surveillance Relay of information Monitoring for good outcomes Validation of DOT DOTS-Plus surveillance Smear microscopy Weight surveillance Laboratory data Discontinuing the parenteral agent Other changes in regimen Irregular therapy Treatment completion Conclusion 97 Table of Figures Figure 6.1 Case example 17: Positive smear during DOTS-Plus therapy 91 Figure 6.2 Case example 18: Positive culture after five months of therapy 92 Figure 6.3 Case example 19: Discontinuing the parenteral agent 94 Figure 6.4 Irregular therapy 95 Figure 6.5 Completing therapy 95 Figure 6.6 Case example 20: Completion of treatment 96 Figure 6.7 Case example 21: Relapse after DOTS-Plus 96

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4 Treatment Surveillance Designing the therapeutic regimen is only the first step in the treatment of patients with MDR TB. Once treatment has been initiated, close monitoring is necessary to ensure a good outcome for each patient. This chapter will review the key components of treatment surveillance and monitoring of patients during their 18- to 24-month course of therapy. 6.1 Relay of information Because DOTS-Plus is a labor-intensive and long process, the importance of teamwork and team communication cannot be overemphasized.there are several key steps to establishing and maintaining open channels of communication. The first is that the community health workers, the people who administer DOT, must feel supported by other members of the DOTS-Plus team. These workers are the team s first line of interaction with patients regarding compliance, side-effect management and complications of TB or its therapy. 1,2,3,4 In our program, we have used more experienced community health workers to supervise the less-experienced community health workers (at about a 1:3 ratio). The supervising community health workers visit with all the community health workers and patients and then report back to the nurses and doctors of the medical team. We have used a system of rounds, whereby the supervising community health workers review difficult cases each morning with the nurses and any doctors who are present, and the information is then sent electronically to the rest of the medical team for review. If urgent issues arise, the supervising community health workers contact the nurses directly who then contact a physician who is sent to examine the patient. Standard medical record-keeping is also of vital importance and should include: serial smear and culture results; baseline laboratories as well as routine checks of electrolytes; and evaluations from specialist consultants, (e.g. psychiatrists, pulmonologists, etc). Copies of these forms can be found in the appendices. 6.2 Monitoring for good outcomes Validation of DOT The value of directly observed therapy (DOT) in the treatment of both TB and MDR TB cannot be underestimated. 5,6,7,8,9,10,11,12,13,14,15,16 Ensuring that patients take their medications daily, as prescribed, is the first and probably most important part of effective monitoring. For DOT to be valid, patients should be observed swallowing each dose of medication. Mouth checks should be performed after each swallowing has occurred. In some settings, serum drug levels may also be checked to ensure that medications are being taken; we have not had access to such assays in Peru or Haiti. In addition, certain clinical findings such as skin bronzing with clofazimine can also help confirm that patients are indeed taking their medications DOTS-Plus surveillance The management of the MDR TB patient in DOTS-Plus treatment remains individualized and flexible throughout the duration of therapy. Treatment surveillance is carried out, in large part, by community health workers who perform frequent patient visits, collect data, and triage significant findings to physicians. Given the responsibilities of community health workers, effective training and well-designed protocols are necessary to ensure consistent patient management. Chapter Six Treatment Surveillance 89

5 Clinical, bacteriologic, laboratory, and radiographic data are followed throughout the duration of DOTS-Plus treatment, providing quantitative, objective indicators by which to gauge treatment response (see Appendix F9). Routine clinical assessment allows the team to follow signs and symptoms of recrudescent and for complications of the disease or treatment. Monthly evaluations are recommended for the first six months, as minor adverse effects are most common in the initial phase of treatment.after the first six months, patients may be seen in clinic every three to six months depending on their clinical status. Monthly smears, culture testing, and weights provide important data to screen for major side effects and potential relapse. Chest radiographs may be obtained every six months. During the course of DOTS-Plus therapy, changes in the patient s regimen may occur due to clinical or bacteriological changes (see Protocol 2). A positive smear or culture may herald a potential treatment failure and should thus prompt regimen reinforcement while confirmatory tests are pending. On the other hand, favorable response to treatment may permit discontinuation of parenteral therapy after only six months. Finally, the decision to terminate treatment follows guidelines but is also based on parameters of therapy response. Thus, the management of each DOTS-Plus patient is individualized even though treatment guidelines are themselves standardized Smear microscopy Efficacy of treatment is best assessed by regular we recommend monthly smear microscopy and culture. Relapse may be heralded by positive laboratory studies rather than clinical symptoms.while the average time to smear and culture conversion in MDR TB treatment with DOTS-Plus varies among studies, our experience has shown that a great majority of patients smear- and culture-convert by the fourth month. While it is not infrequent to see a positive smear or culture late into treatment, such a result must always raise the possibility of treatment failure (see Protocol 2). Possible causes for a positive smear or culture after four months of treatment include: Treatment failure due to inadequate therapy (i.e. an incorrect regimen, suboptimal dosing, or irregular therapy from faulty DOT) Treatment failure in spite of appropriate therapy Slow, but favorable, response to therapy Specimen collection error, lab error, or contamination Degenerated bacilli visible on smear microscopy but which fail to grow in culture 90 Chapter Six Treatment Surveillance

6 Figure 6.1 Case example 17: Positive smear during DOTS-Plus therapy AG is a 20 year-old male with primary MDR TB who receives DOTS-Plus with a regimen of CM (1 g), PAS (12 g), CS (1000 mg), AMX-CLV (1500 mg), CFZ (300 mg), and CPX(1500 mg). He smear and culture converts within the first month of therapy, and symptoms improve without further episodes of hemoptysis. CFZ is decreased from 300 mg to 200 mg after two months when he begins to bronze. In his eighth month of therapy, he is found to have a positive smear. Chest radiograph is repeated which shows no evidence of new or worsening disease. DOT is reviewed with the patient and his health promoter. AG s regimen is reviewed and adjusted. DST on initiation of DOTSPlus had demonstrated susceptibility to KM and CLR; therefore, CM is changed to KM, CLR is added, and CFZ is increased to 300 mg. Smear and culture testing is repeated, all of which are negative. Therefore, no repeat DST can be performed. His previous regimen is restored after six consecutive months of smear and culture negativity and he was felt to have had a false positive smear. When a positive smear or culture is encountered after four months of treatment, the following steps should be taken immediately: 1. Evaluate DOT to ensure correct and supervised administration. 2. Repeat smear and cultures at least twice to confirm laboratory result. 3. Obtain a new chest x-ray to evaluate for evidence of disease progression. Consider the following regimen changes until new susceptibility data is available: 1. Avoid adding a single drug to a failing regimen. 2. Change parenteral agents, if there exists a second parenteral agent with demonstrated efficacy against the infecting strain. 3. Reinforce the regimen with at least two additional drugs, if possible. 4. Optimize the doses of all drugs. 5. If a positive culture is obtained, consider treatment failure. Perform susceptibility testing to rule out recruitment of additional resistance ( amplification ).Testing to additional drugs, if available, should be considered at this time. Once new drug susceptibility data is obtained, the regimen may be adjusted according to the most recent resistance pattern. 6. If no positive culture is obtained, the prior regimen may be restored after three to six consecutive months of smear and culture negativity. 7. Consider adjuvant surgical intervention in patients with focal disease.. Chapter Six Treatment Surveillance 91

7 Figure 6.2 Case example 18: Positive culture after five months of therapy TC is a 57 year-old male with documented resistance to INH, RIF, EMB, PZA, SM, and THA. He entered into DOTS-Plus therapy with a definitive regimen of CM, CS, CPX, PAS, and AMX-CLV. His chest radiograph showed collapse and scarring of the right upper lobe. He smear- and culture-converted in his second month of therapy, and TB symptoms resolved. After six months with negative cultures, his CM was discontinued. However, in his twelfth month of treatment, the patient began to experience new-onset of fever and cough. Sputum culture yielded seven colonies, raising concern for treatment failure. A repeat culture was also positive and was sent for DST to assess for resistance amplification. Chest radiograph showed no progression of disease. DOT was reviewed with the patient and team. His regimen was reinforced adding AMK, CLR and CFZ. Given the presence of resectable disease, a surgical evaluation was undertaken.the patient underwent right upper lobectomy, and remained culture-negative throughout the remainder of his therapy Weight surveillance Monthly weights provide one of the most sensitive indicators of clinical response. 17 Underweight patients who fail to regain weight or those who continue to lose weight should receive prompt and aggressive intervention. Both body mass index (BMI) and chronological weight curves provide useful data. It should be noted, however, that during the first one to two months of therapy, some patients may lose weight as a result of treatment adverse effects. If this weight loss continues or does not reverse itself after one to two months, this is cause for concern. The following approach should be adopted in treating patients with a low BMI and/or failure to gain weight (see Protocol 1). Nutritional evaluation. Even if the patient has been previously evaluated, serial interviews and evaluations aid in understanding the patient s nutritional status and its relation to socioeconomic hardship. A calorie count, classification by food group, and a weekly expenditure report is helpful in determining effective supplementary measures and targeting nutritional education. 18 Medical evaluation. Medical causes of failure to thrive must be explored (e.g. malabsorption, severe vomiting or diarrhea, depression). Symptomatic relief of gastrointestinal side effects often improves appetite and results in weight gain. Appetite stimulants or tube feeds may be considered in severe cases of malnutrition. 19,20 Nutritional aid and education. High-calorie, high-protein diets should be provided through nutritional supplements. Patient and family counseling should be sensitive to cultural factors and economic constraints in order to increase the likelihood of impact of such counseling on the patient s diet. 21,22 Close surveillance and follow-up. Correcting nutritional status is a long-term endeavor. Close supervision, encouragement, and medical follow-up are necessary to ensure continued progress. 92 Chapter Six Treatment Surveillance

8 6.2.5 Laboratory data Routine laboratory data in addition to smear and culture should be followed on a regular basis. These data not only assist in the assessment and management of adverse effects but also contribute to an overall picture of the patient s clinical status. Based on our experiences, patients should have potassium and creatinine checked at baseline and then should be monitored closely while receiving injectable therapy. For patients 50 years of age and older, and/or patients with any co-morbid condition (e.g. diabetes, alcoholism, HIV, current or previous history of renal insufficiency), potassium and creatinine should be monitored even more closely (see Protocols 10 and 14). TSH should be screened at six months of therapy. 23, Discontinuing the parenteral agent In treating strains of M. tuberculosis, resistant to first-line drugs, the value of parenteral agents cannot be overemphasized. In our experience, patients who receive inadequate parenteral therapy are at increased risk of failing therapy, as are patients sick with strains resistant to all parenteral agents. While most of the clinical literature recommends the use of an injectable for six months and warns against high cumulative doses (>150 g) due to irreversible toxicity, it is our experience that extended daily use of these agents is well tolerated by young patients with normal renal function. A few patients sick with strains resistant to six or more drugs have received parenteral agents for the duration of therapy, up to two years. It bears mentioning that nephrotoxicity and neurotoxicity due to parenteral agents is often reversible while ototoxicity is less so. If evidence of ototoxicity, nephrotoxicity or peripheral neurotoxicity is demonstrated, treatment options include: Discontinuing parenteral agent Continuing injectable at a lower dose (especially if dose by weight remains adequate) after symptoms subside Changing to another parenteral agent with less toxicity (e.g if ototoxicity, changing from aminoglycoside to capreomycin) In extreme cases of severe disease and limited treatment options, it is occasionally necessary to continue use of the presumed offending agent. Careful consideration of the relative toxicity of the parenteral agent, the patient s clinical status, the duration of therapy, and the efficacy of the remaining regimen should guide the decision-making in such scenarios. After a minimum of six months of consecutive negative smears and cultures, the patient should be evaluated for the possibility of discontinuing the parenteral agent. The following criteria should be considered: 1. Evidence of toxicity. 2. Initial clinical and radiographic status. A patient with advanced disease (e.g. with a history of massive hemoptysis, severe respiratory compromise, disseminated or extrapulmonary TB), should ideally receive extended parenteral therapy. Likewise, aggressive therapy is recommended in patients with extensive parenchymal destruction, including cavities where concentrated bacillary loads are protected from drug penetration. Prolonged therapy may also be indicated in patients with other Chapter Six Treatment Surveillance 93

9 medical conditions, e.g. HIV co-infection. 3. Resistance pattern. In cases of high-grade drug resistance, a regimen may be severely compromised without an injectable. In fact, if the patient s strain is highly resistant, the removal of any drug from the regimen could compromise treatment outcome. 4. Clinical evolution. Ideally, a patient should have resolution of symptoms of active disease; however, chronic disease with respiratory compromise may only improve minimally to a new but stable baseline. 5. Radiographic evolution. Significant resolution of lesions is preferably demonstrated prior to discontinuing the injectable. Again, chronic radiographic characteristics, especially cavitary and fibrotic lesions, frequently improve only minimally. 6. Bacteriologic evolution. Importantly, negative monthly smears and cultures for at least six consecutive months should be demonstrated prior to discontinuing the parenteral agent. Figure 6.3 Case example 19: Discontinuing the parenteral agent LP is a 25 year-old woman with multiple treatment failures first diagnosed with TB seven years prior to initiating DOTS-Plus therapy. Her isolate demonstrates resistance to INH, RIF, PZA, SM, CM, and KM. She reports persistent cough; chest radiograph shows biapical infiltrates with minimal parenchymal destruction and no cavitary lesions. Her DOTS-Plus regimen consists of AMK, EMB, CPX,THA, CS, PAS, and AMX-CLV. She smearand culture-converts during her second month of therapy. In her eighth month of DOTS-Plus, she complains of ringing in her ears and is evaluated for discontinuation of AMK. She has had complete resolution of her pulmonary symptoms and gained 5 kg during the course of therapy. A chest radiograph shows minimal scarring in the left upper lobe. Factors that are considered in deciding when to suspend an injectable are LP s symptoms of ototoxicity; her clinical, microscopic and radiographic response; and her efficacious regimen even without an injectable. Upon evaluation, her injectable is discontinued after a total eight-month course, six months of which she was both smearand culture-negative. 6.4 Other changes in regimen Other changes in the regimen may be necessary based on toxicity (see Chapter 7) and patient tolerance. Each patient taking clofazimine should begin at a dose of 300 mg per day. Once the skin has begun to show bronzing, the dose may be lowered to 200 mg per day Irregular therapy Given the chronicity of their disease and limited treatment options, most patients will, in our experience, adhere to therapy provided adverse effects are controlled and barriers to health services are corrected. 26 Non-adherence may occur for many reasons, 27,28,29,30,31,32,33,34,35,36,37,38,39,40,41 and we have found in our experience that most of these are due to socioeconomic constraints. All possible efforts should be made to overcome these barriers and allow patients to continue with their therapy. Occasionally, however, we are confronted with a patient whose non-adherence jeopardizes his treatment; we have found that discussion among the providers, the patient, and family to determine motives of non-adherence often reveals economic or psychosocial stressors that can subsequently be amended through a multidisciplinary team approach. In patients who have continued to demon- 94 Chapter Six Treatment Surveillance

10 strate irregular attendance, we have offered a contract of commitment, wherein the patient reaffirms his or her commitment to continue therapy in exchange for continued medications and ancillary support. If further non-adherence occurs, suspension of therapy should be considered when the threat of resistance amplification outweighs the likelihood of cure. Given the threat of ongoing transmission of drug-resistant strains, this outcome is to be avoided at all costs. Figure 6.4 Irregular therapy Often socioeconomic motives for irregular therapy Multidisciplinary approach to correct obstacles to adherence Contract of commitment if continued non-adherence Treatment suspension when threat of resistance amplification outweighs likelihood of cure 6.6 Treatment completion After 18 to 24 consecutive months of culture-negative status, patients should undergo evaluation for completion of MDR TB treatment. In addition to bacteriologic response, clinical and radiographic improvement, as well as degree of drug resistance should be considered in making the decision to discontinue therapy. In patients with severe disease and those infected with highly drug-resistant strains, treatment should ideally be continued to complete 24 consecutive culture-negative months. Criteria similar to those used to discontinue the parenteral should be used for treatment completion as well. After completion of DOTS-Plus therapy, patients should be followed for two or more years with surveillance cultures every six months. Routine chest radiographs are not necessary. Clinical symptoms should be routinely evaluated and assessed as needed. Even with the best possible regimens and support, a small percentage of patients will relapse once treatment has been completed. The management of all relapses should include repeat susceptibility testing and frank discussion with the patient and family. When appropriate, patients may be considered for another individualized regimen with adjuvant surgery if the patient is a surgical candidate. Figure 6.5 Completing therapy Ideally after consecutive culture-negative months Consider clinical, radiographic, and bacteriologic response Consider degree of resistance Extended therapy in patients with severe or highly-resistant disease Follow-up includes surveillance cultures every six months for at least two years Relapses may be candidates for repeat therapy Chapter Six Treatment Surveillance 95

11 Figure 6.6 Case example 20: Completion of treatment PP is a 28 year-old male referred for DOTS-Plus after multiple treatment failures. Initial chest radiograph shows right-sided disease. Given his resistance to all first-line drugs, he receives a DOTS-Plus regimen of CM, CPX, THA, CS, and PAS. He smear- and cultureconverts after one month of treatment. At 18 months, he is evaluated for completion of DOTS-Plus. He is asymptomatic, and physical exam is normal. His chest radiograph now shows significant improvement. He is tolerating his regimen without major side effects. On evaluation for completion of DOTS-Plus, he demonstrates a favorable response to treatment; however, given the presence of residual fibrosis which may serve as a nidus for mycobacteria due to limited drug penetration, DOTS-Plus is extended to complete 24 months of therapy, with 22 months of smear and culture negativity. Figure 6.7 Case example 21: Relapse after DOTS-Plus CM is a 26 year-old female who was referred for DOTS-Plus after multiple treatment failures. Based on documented resistance to low-dose INH, RIF, EMB, PZA, CPX, and THA, she entered into DOTS-Plus treatment consisting of SM, CM, CS, CFZ, AMX-CLV, PAS, and high-dose INH. She smear converted in her fifth month of therapy and culture converted in her fourth month. After 24 months of treatment, her DOTS-Plus treatment was terminated with negative sputum smear and cultures. Her chest radiograph showed improvement from her initial study, but persistent fibrosis throughout the left lung with extensive involvement of the left upper lobe. One month after completion of treatment, CM began to experience hemoptysis for the first time in two years. Sputum studies revealed presence of viable mycobacteria. Chest radiograph demonstrated progression of the left upper lobe infiltrate. Her culture was sent for DST, including testing to additional drugs. She was referred for surgical evaluation. After frank discussion with the patient, she reinitiated individualized treatment based on these last susceptibility data. In addition to re-starting treatment, consultation was made with a surgical team for possible left upper lobectomy. 96 Chapter Six Treatment Surveillance

12 6.7 Conclusion DOTS-Plus therapy is, by necessity, quite lengthy, and close patient monitoring during therapy is the key to good patient outcomes. Smears and cultures should be followed regularly, as should nutritional parameters and other laboratory tests as indicated by the patient s clinical status.therapy must remain supervised throughout the course of treatment. After six months with negative cultures, patients can be evaluated for the discontinuation of their parenteral medication; after 18 to 24 months with negative cultures, treatment may be terminated, depending on the patient s clinical picture. Routine follow-up should be performed once treatment has been completed to ensure relapse does not occur. Chapter Six Treatment Surveillance 97