Sandbox TB

### Empirical Anti-Tuberculosis Therapy
It should be considered that in developing countries where TB is endemic and in cases with high clinical suspicion of tuberculous pericarditis, starting with empiric antituberculous therapy is appropriate before establishing a definitive diagnosis. In the clinical settings where the diagnosis cannot be established based on bacteriology, histology, or pericardial fluid analysis, clinical response to antituberculous therapy serves as support for a diagnosis of tuberculous pericarditis.In developed countries where TB is not endemic, antituberculous therapy should generally not be initiated empirically in the absence of definitive diagnosis.

### Standard regimens for new TB patients (with presumed, or known, to have drug-susceptible TB)
 WHO no longer recommends omission of ethambutol during the intensive phase of treatment for patients with non-cavitary, smear-negative PTB or EPEPTB who are known to be HIV-negative.

### Standard regimens for new TB patients (with known or suspected high levels of Isoniazid resistance TB)

### Dosing Frequency for New TB Adult Patients with Active Tuberculosis caused by Drug-Susceptible Organisms

### Level Of Evidence in Dosing Frequency
The level of evidence of the dosage frequency came from the systematic review showed that equivalent efficacy of daily intensive-phase dosing followed by two times weekly continuation phase, however twice weekly dosing is not recommended on operational grounds. Also showed that the daily (rather than three times weekly) intensive-phase dosing may also help to prevent acquired drug resistance in TB patients starting treatment with isoniazid resistance. The systematic review found that patients with isoniazid resistance treated with a three times weekly intensive phase had significantly higher risks of failure and acquired drug resistance than those treated with daily dosing during the intensive phase.

### Standard Regimens for Previously Treated Patients
The previously treated patients should receive the 8-month regimen with first-line drugs.

# Assessment of Treatment Response

### Definition of Treatment Response

### Monitoring the Response to MDR-TB Treatment
- The use of sputum smear microscopy and culture rather than sputum smear microscopy alone is recommended for the monitoring of patients with MDR-TB during treatment

### Rapid drug susceptibility testing for Early start of Appropriate Treatment
Rapid drug susceptibility testing (DST) of isoniazid and rifampicin or of rifampicin alone is recommended over conventional testing or no testing at the time of diagnosis of TB, subject to available resources

### The role of DST in Management
Initial Phase:
Ideally, DST is done for all patients at the start of treatment, so that the most appropriate therapy for each individual can be determined. However, the goal of universal access to DST has not yet been realized for most of the worlds TB patients. While countries are expanding laboratory capacity and implementing new rapid tests (see below), WHO recommends that sputum specimens for testing susceptibility to isoniazid and rifampicin be obtained from the following patient groups at the start of treatment:
- All previously treated patients (17, 21, 22). The highest levels of MDR are found in patients whose prior course of therapy has failed (6).
- All persons living with HIV who are diagnosed with active TB, especially if they live in areas of moderate or high MDR prevalence. It is essential to detect MDR as soon as possible in persons living with HIV, given their high risk of mortality.
Continuation Phase:
In settings where rapid molecular-based DST is available, the results of MDR can be confirmed or excluded within 1-2 days, it should guide the choice of regimen.
In cases if DST is not available, the first-line drugs 2HRZES/1HRZE/5HRE if country-specific data show low or medium levels of MDR in these patients or if such data are not available
Remark: When DST results become available, regimens should be adjusted appropriately.
The Global Plan to Stop TB 20062015 sets a target for open accessibility to DST for all previously treated patients at the beginning of treatment by 2015.

### Recommendations For New Patients
- In new patients, if the specimen obtained at the end of the intensive phase 2nd month is smear-positive, sputum smear microscopy should be obtained at the end of the third month (Strong/High grade of evidence).
- In new patients, if the specimen obtained at the end of 3rd month is smear-positive, sputum culture and drug susceptibility testing (DST) should be performed (Strong/High grade of evidence)
- For smear-positive pulmonary TB patients treated with first-line drugs, sputum smear microscopy may be performed at completion of the intensive phase of treatment (Conditional/High or moderate grade of evidence).
- Sputum should be collected after the 1st dose of the intensive phase treatment at the end of the intensive phase is at 2nd month in new patients and 3rd month in previously treated patients receiving the 8-month regimen of first-line drugs. This recommendation also applies to smear-negative patients.
- Sputum specimens should be collected for smear examination at each follow-up sputum check. They should be collected without interrupting treatment and transported to the laboratory as soon as possible.
- Smear status at the end of the intensive phase is a poor predictor of which new patients will relapse.1 However, detection of a positive sputum smear remains important as a trigger for the patient assessment.
- The proportion of sputum smear positive patients converted to negative at the end of the intensive phase is an indicator of TB program performance.

# Treatment Failure
Failure to response to anti-TB drugs means;
- Smear or culture-positivity at the fifth month or later.
- Detection of MDR-TB at any point of therapy.
Treatment failure necessitate to step-wise approach to identify the causes of failure which could be due to:
- Poor supervision of the initial phase.
- Poor patient adherence.
- Poor quality of anti-TB drugs.
- Inappropriate doses of anti-TB drugs {below than recommended range).
- Slow resolution due to extensive cavitation and a heavy initial bacillary load.
- Co-morbid conditions that interfere either with adherence or with response.
- MDR M. tuberculosis with no response to the first-line treatment.
- Non-viable bacteria remain visible by microscopy.

### Drugs Groups for Treatment of MDR-TB
- Anti-TB drugs are grouped according to efficacy, experience of use and drug class.
- All the first-line anti-TB drugs are in (Group 1), except streptomycin, which is classified with the other injectable agents in (Group 2).
- All the drugs in Groups 25 (except streptomycin) are second-line, or reserve, drugs.
- The features of the cross-resistance means that resistance mutations (in M. tuberculosis bacteria) to one anti-TB drug may confer resistance to some or all of the members of the drug family of the same group and less commonly to other members of different drug groups (1).

### Guidelines for second-line Anti-TB Regimens for MDR
- In the treatment of patients with MDR-TB, a Fluoroquinolone should be used (strong recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, a Ethionamide (or prothionamide) should be used (strong recommendation, very low quality evidence).
- In the treatment of patients with MDR-TB, a later-generation fluoroquinolone rather than an earlier-generation fluoroquinolone should be used (conditional recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, four second-line antituberculosis drugs likely to be effective (including a parenteral agent), as well as pyrazinamide, should be included in the intensive phase3 (conditional recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, regimens should include at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or  prothionamide), and either cycloserine or PAS (p-aminosalicylic acid) if cycloserine cannot be used (conditional recommendation,very low quality evidence).
Major changes in recommendation for second-line Anti-TB Regimens for MDR:
- Include at least four second-line Anti-TB drugs likely to be effective as well as pyrazinamide during the intensive phase of treatment.
- No evidence found to support the use of more than four second-line anti-tuberculosis drugs in patients with extensive disease. Increasing the number of second-line drugs in a regimen is permissible if the effectiveness of some of the drugs is uncertain.
- Ethambutol may be used but is not included among the drugs making up the standard regimen.
- Group 5 drugs may be used but are not included among the drugs making up the standard regimen.

### General principles for Designing MDR-TB Treatment Regimens

# Management of Treatment Interruption

# Prevention of Adverse Effects of Drugs
- Isoniazid-induced peripheral neuropathy: Numbness or a tingling or burning sensation of the hands or feet and occurs more commonly in pregnant women and in people with the following conditions: HIV infection, alcohol dependency, malnutrition, diabetes, chronic liver disease, renal failure. Preventive treatment with Pyridoxine, 10  mg/day with anti-TB drugs. Other guidelines recommend 25 mg/day.

# Managing Side-Effects of Anti-TB Drugs

### Hepatitis and Anti-TB medications
The management of Anti-TB induced hepatitis depends on:
- Phase of the therapy (intensive or continuation phase)
- Severity of the liver disease
- Severity of the TB
- Capacity to manage the side-effects of TB drugs
- If TB treatment has been stopped, Wait for liver function tests to normalize and resolution of the clinical symptoms (nausea, abdominal pain) before reintroducing the anti-TB drugs.
- If the liver function tests is not available, it is advisable to wait for extra 2 weeks after resolution of jaundice and upper abdominal tenderness before restarting TB treatment.
- If the signs and symptoms do not resolve and the liver disease is severe, the non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fluoroquinolone should be started (or continued) for a total of 18-24 months.
- Reintroducing one drug at a time is the optimal approach, especially if the patients hepatitis was severe.
- Once drug-induced hepatitis has resolved, the drugs are reintroduced one at a time. But if symptoms recur or liver function tests become abnormal again as the drugs are reintroduced, the last drug added should be stopped.
- Some advise starting with rifampicin because it is less likely than isoniazid or pyrazinamide to cause hepatotoxicity and is the most effective agent .  After 37 days, isoniazid may be reintroduced. In patients who have experienced jaundice but tolerate the reintroduction of rifampicin and isoniazid, it is advisable to avoid pyrazinamide.
It depends on which drug is implicated as the cause of the hepatitis.
- If rifampicin is implicated, a suggested regimen without rifampicin is 2 months of Isoniazid, Ethambutol and Streptomycin followed by 10 months of Isoniazid and Ethambutol.
- If Isoniazid cannot be used, 6-9 months of Rifampicin, Pyrazinamide and Ethambutol can be considered.
- If Pyrazinamide is discontinued before the patient has completed the intensive phase, the total duration of isoniazid and rifampicin therapy may be extended to 9 months.
- If neither isoniazid nor rifampicin can be used, the non-hepatotoxic regimen consisting of Streptomycin, ethambutol and a fluoroquinolone should be continued for a total of 18-24 months.
- Hepatitis during the intensive phase of TB treatment with isoniazid, rifampicin, pyrazinamide and ethambutol: once hepatitis has resolved, restart the same drugs EXCEPT replace pyrazinamide with streptomycin to complete the 2-month course of initial therapy, followed by Rifampicin and Isoniazid for the 6-month continuation phase.
- Hepatitis during the continuation phase: once hepatitis has resolved, restart Isoniazid and Rifampicin to complete the 4-month continuationphase of therapy.

# HIV and Tuberculosis

### Screening for TB in HIV infected patients
Intensified case finding recommendation according to WHO recommendations, lately updated in 2011.
- Adults and adolescents living with HIV should be screened for TB with a clinical algorithm and those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered IPT.(Strong recommendation, moderate quality of evidence)
- Adults and adolescents living with HIV and screened for TB with a clinical algorithm and who report any one of the symptoms of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases.(Strong recommendation, moderate quality of evidence)

### Detecting Latent TB Infection in Resources Limited Situations
Tuberculin Skin Test (TST) as screening tool for latent TB
- TST is not a requirement for initiating IPT in people living with HIV. People living with HIV who have a positive TST benefit more from IPT;(Strong recommendation, moderate quality of evidence)
- TST can be used where feasible to identify such individuals.(Strong recommendation, high quality of evidence)
Interferon-gamma release assays (IGRA) as screening tool for latent TB
- IGRA has two types; Quantiferon Gold in tube test assay and T-Spot assay.
- Studies showed the ability of  IGRA  to  predict  development  of  TB  over  time, and reported its sensitivity in children and adults already infected with TB. 
- Most of studied showed a significant higher rates of indeterminate test results (non-conclusive results) with Quantiferon Gold in tube test assay in persons with HIV in comparison with non HIV persons. The sensitivity was also markedly reduced among HIV patients with low CD4 counts in comparison with HIV patients with high CD4.
- However, most of studies found no impact of low CD4 cell count on the sensitivity of T-Spot assay.
- Based on the best available evidence considering the fact that IGRA cannot distinguish between active TB disease and latent infection and most of studies were done in low TB prevalence settings, WHO do not recommended IGRA to screen people living with HIV for eligibility to receive IPT.

### Regimen's Efficacy and Duration in Prevention of TB in HIV Patients
- Adults and adolescents living with HIV who have an unknown or positive TST status and who are unlikely to have active TB should receive at least 6 months of IPT as part of a comprehensive package of HIV care. IPT should be given to such individuals irrespective of the degree of  immunosuppression,  and  also  to those  on ART,  those  who  have previously been treated for TB and pregnant women.(Strong recommendation, high quality of evidence)
- Adults and adolescents living with HIV who have an unknown or positive TST status and are unlikely to have active TB should receive at least 36 months of IPT. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Conditional recommendation, moderate quality of evidence)

### IPT and Drug -Resistant TB
- Providing IPT to people living with HIV does not increase the risk of developing INH-resistant TB. Therefore, concerns regarding the development of INH resistance should not be a barrier to providing IPT.(Strong recommendation, moderate quality of evidence)

### Prevention of TB in HIV Patients
HIV is the strongest risk factor for  tuberculosis (TB) disease in those with latent or new Mycobacterium tuberculosis infection. The risk of developing TB is about 20-37 times more in people infected with HIV than people non infected HIV. TB is responsible for more than a 25% of deaths in HIV infected people. In response to the dual epidemics of HIV and TB, the World Health Organization (WHO) recommends 12 collaborative TB/HIV activities as part of core HIV and TB prevention, care and treatment services.
- Adults and adolescents living with HIV should be screened for TB with a clinical algorithm and those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered IPT.(Strong recommendation, moderate quality of evidence1)
- Adults and adolescents living with HIV and screened with a clinical algorithm for TB, and who report any one of the symptoms of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases.(Strong recommendation, moderate quality of evidence)
- Adults and adolescents living with HIV who have an unknown or positive TST status and are unlikely to have active TB should receive at least six months of IPT as part of a comprehensive package of HIV care. IPT should be given to such individuals irrespective of the degree of  immunosuppression,  and  also  to those  on ART,  those  who  have previously been treated for TB and pregnant women.(Strong recommendation, high quality of evidence)
- Adults and adolescents living with HIV who have an unknown or positive TST status and who are unlikely to have active TB should receive at least 36 months of IPT2. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Conditional recommendation, moderate quality of evidence3)
- TST is not a requirement for initiating IPT in people living with HIV.(Strong recommendation, moderate quality of evidence)
- People living with HIV who have a positive TST benefit more from IPT; TST can be used where feasible to identify such individuals.(Strong recommendation, high quality of evidence)
- Providing IPT to people living with HIV does not increase the risk of developing isoniazid (INH)-resistant TB. Therefore, concerns regarding the development of INH resistance should not be a barrier to providing IPT.(Strong recommendation, moderate quality of evidence)
- Children living with HIV who do not have poor weight gain, fever or current cough are unlikely to have active TB.(Strong recommendation, low quality of evidence)
- Children living with HIV who have any one of the following symptoms  poor weight gain, fever, current  cough  or  contact  history  with a TB case  may have TB and should be evaluated for TB and other conditions. If the evaluation shows no TB, such children should be offered IPT regardless of their age.(Strong recommendation, low quality of evidence)
- Children living with HIV who are more than 12 months of age and who are unlikely to have active TB on symptom-based screening, and have no contact with a TB case should receive six months of IPT (10 mg/kg/day) as part of a comprehensive package of HIV prevention and care services.(Strong recommendation, moderate quality of evidence)
- In children living with HIV who are less than 12 months of age, only those children who have contact with a TB case and who are evaluated for TB (using investigations) should receive six months of IPT if the evaluation shows no TB disease.(Strong recommendation, low quality of evidence)
- All children living with HIV who have successfully completed treatment for TB disease should receive INH for an additional six months.(Conditional recommendation, low quality of evidence)
 Five-day-a-week administration is always given by DOT.
-  Mayosi, BM.; Burgess, LJ.; Doubell, AF. (2005). "Tuberculous pericarditis". Circulation. 112 (23): 360816. doi:10.1161/CIRCULATIONAHA.105.543066. PMID 16330703. Unknown parameter |month= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
-  Soler-Soler, J.; Sagrista-Sauleda, J.; Permanyer-Miralda, G. (2001). "Management of pericardial effusion". Heart. 86 (2): 23540. PMID 11454853. Unknown parameter |month= ignored (help)
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-  Saukkonen, JJ.; Cohn, DL.; Jasmer, RM.; Schenker, S.; Jereb, JA.; Nolan, CM.; Peloquin, CA.; Gordin, FM.; Nunes, D. (2006). "An official ATS statement: hepatotoxicity of antituberculosis therapy". Am J Respir Crit Care Med. 174 (8): 93552. doi:10.1164/rccm.200510-1666ST. PMID 17021358. Unknown parameter |month= ignored (help)
-  Aichelburg, MC.; Rieger, A.; Breitenecker, F.; Pfistershammer, K.; Tittes, J.; Eltz, S.; Aichelburg, AC.; Stingl, G.; Makristathis, A. (2009). "Detection and prediction of active tuberculosis disease by a whole-blood interferon-gamma release assay in HIV-1-infected individuals". Clin Infect Dis. 48 (7): 95462. doi:10.1086/597351. PMID 19245343. Unknown parameter |month= ignored (help)
-  Clark, SA.; Martin, SL.; Pozniak, A.; Steel, A.; Ward, B.; Dunning, J.; Henderson, DC.; Nelson, M.; Gazzard, B. (2007). "Tuberculosis antigen-specific immune responses can be detected using enzyme-linked immunospot technology in human immunodeficiency virus (HIV)-1 patients with advanced disease". Clin Exp Immunol. 150 (2): 23844. doi:10.1111/j.1365-2249.2007.03477.x. PMID 17672869. Unknown parameter |month= ignored (help)
-  Dheda, K.; van Zyl Smit, R.; Badri, M.; Pai, M. (2009). "T-cell interferon-gamma release assays for the rapid immunodiagnosis of tuberculosis: clinical utility in high-burden vs. low-burden settings". Curr Opin Pulm Med. 15 (3): 188200. doi:10.1097/MCP.0b013e32832a0adc. PMID 19387262. Unknown parameter |month= ignored (help)
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