Tuberculosis Treatment

1. Tuberculosis Treatment Treatment Action Group TB/HIV Advocacy Toolkit July 2019 With thanks to Adam Almeida, Andolyn Medina, and Dr. Jennifer Furin

2. Topics to be covered • Treatment Fundamentals • How TB is Treated • Treatment in Special Groups • Treatment Research • Advocacy Priorities • Main Points

3. treatment fundamentals

4. Principles of TB treatment • The goal of treatment is to cure TB, restore health, and prevent transmission • The aim of treatment is to provide the safest and most effectivetherapy in the shortest period of time • Three basic principles of TB treatment: • Regimens must contain multiple drugsto which the organisms are susceptible to prevent against the development of resistance • Drug exposure (how much drug is in the body) must stay at a high enough level over time to kill bacteria – this means drugs must betaken regularly • Drug therapy must continue long enoughto kill all remaining TB organisms FUNDAMENTALS

5. Treatment Monitoring • How do you know it’s working? • Bacteriologic tests: to detect live TB bacteria • Smear microscopy • Solid and liquid culture • Clinical monitoring of improvement TB symptoms (e.g., weight gain) • Radiography: the use of chest X-rays The following should not be used to monitor treatment: • Nucleic Acid Amplification (line probe assays, Xpert MTB/RIF Ultra): dead TB bacilli can cause a false positive from these diagnostics FUNDAMENTALS

6. drug discovery & development and its impact on treatment 1944 streptomycin 1920 BCG vaccine 1955 cycloserine 2000 rifapentine 1934 Gold therapy abandoned 2014 rifapentine* delamanid 1962 ethambutol 1951 isoniazid 1920s 1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s 1940 actinomycin streptothricin 1957 rifampicin 1952 pyrazinamide 2012 bedaquiline 2015 WHO recommends short course regimen for drug-resistant TB 1924 Gold therapy introduced 1948 PAS thiacetazone Duration of Treatment 24 months 6 months FUNDAMENTALS *approved for treating latent TB infection

7. How TB is treated

8. Knowing which drugs to use • Drug susceptibility testing (see Diagnostics module) is essential to inform treatment regimen selection to ensure the best outcome • Everyone should have Xpert MTB/RIF Ultra as a first test, and at a minimum know whether they have rifampicin-resistance or rifampicin-sensitive TB • But further testing is needed because: • People with MDR-TB need at least a 9 month regimen • People with pre-XDR-TB or XDR-TB need an individualized regimen with at least one of the newer drugs plus linezolid(delamanid or bedaquiline) • People with isoniazid-resistant TB (that is sensitive to rifampicin) have worse treatment outcomes if they are just given standard, drug-susceptible therapy Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3786434/ TREATMENT

9. drug-susceptible TB Treatment (aka first-line) • There are two phases of treatment of drug-susceptible TB: • Initial/intensive phase: to kill actively growing germs • Continuation phase: to eliminate any remaining germs and reduce failure / relapse The WHO recommends the following regimen for those with drug-sensitive, active TB: • Two months of daily treatment with four first-line drugs (isoniazid, rifampicin, pyrazinamide, ethambutol), followed by four months of daily isoniazid and rifampicin • This also applies to most extrapulmonary TB, with longer therapy for TB of the central nervous system, bone or joints • Adjuvant corticosteroid treatment is recommended for TB meningitis and pericarditis, in cases when there is not thought to be drug resistance Source: WHO Treatment of Tuberculosis Guidelines, 4th Edition http://apps.who.int/iris/bitstream/10665/44165/1/9789241547833_eng.pdf?ua=1&ua=1 TREATMENT

10. ISONIAZID-RESISTANT TB • Isoniazid is a first-line drug for TB treatment and is included in standard short-course regimen for drug-sensitive TB • Isoniazid is a powerful drug • If there is resistance to isoniazid, a different drug regimen is needed to make up for losing isoniazid: • Levofloxacin replaces isoniazid • For the first two months: levofloxacin, rifampicin, pyrazinamide, and ethambutol are given; for the next four months: only levofloxacin and rifampicin are given • Some persons may continue to receive isoniazid as it may still have some activity against certain types of isoniazid-resistant TB strains and it often comes in the combination tablets used in treatment. TREATMENT

11. SHORTENED REGIMEN FOR Rifampicin-RESISTANT TB • In 2016, the WHO recommended a standardized, shortened drug regimen for treating TB in individuals with rifampicin-resistant TB • The shortened drug regimen is 9-12 months long (as opposed to 18-24 months) but it contains an injectable agent and it may not be as effective as longer regimens containing bedaquiline and linezolid. • The shortened treatment is specifically for people whose TB is resistant to rifampicin and has not been treated with or shown to have resistance to a second-line injectable or a fluoroquinolone. • amikacin • prothionamide or ethionamide • high-dose isoniazid • moxifloxacin or levofloxacin • clofazimine • pyrazinamide • ethambutol TREATMENT Adapted from: http://www.treatmentactiongroup.org/tb/drug-guide-2016

12. MDR- AND XDR-TB • In 2018, the WHO recommended that a majority of persons with MDR-TB be treated with all-oral longer (18-20 month) regimens. • These regimens should include at least 4-5 effective drugs; bedaquiline, linezolid, and one fluoroquinoloneshould be used as should clofazimineand/or cycloserine(terizidone) • In cases of XDR-TB, other medications such as delamanid will be needed to achieve 5 effective drugs • Other add-on agents are included to reach 5 effective drugs (including ethambutol if susceptible, pyrazinamide if susceptible, ethioamide, p-aminosalicylic acid, imipenem-cilastatin) • Kanamycin and capreomycin should no longer be used to treat MDR-TB as their use was associated with worse treatment outcomes in an analysis of 13,000 patients with MDR-TB. Source: https://www.who.int/tb/publications/2019/consolidated-guidelines-drug-resistant-TB-treatment/en/ TREATMENT

13. Operational Research and All-Oral Shorter Regimens • In 2018, the WHO recommended that persons can be treated with all-oral shorter regimens under operational research conditions. • This means that people can receive 9-12 months regimens in which bedaquiline replaces the injectable agent provided they agree to this therapy and the TB Program closely monitors them for treatment outcomes and for safety. • This recommendation was made since the current shorter regimen contains a dangerous injectable drug, and it is likely this drug can be replaced with oral options (bedaquline, linezolid). • The WHO will be reviewing data on all-oral shorter regimens and may recommend their routine use in 2020.

14. Treatment in special groups

15. TB/HIV co-infection (1 of 2) • Rifampicin, a key TB drug, reduces the amount of some antiretrovirals in the body • This requires dosing adjustments, change in HIV drugs, and/or using rifabutin instead of rifampicin • Bedaquiline interacts with some antiretrovirals • Bedaquiline should not be used with efavirenz (efavirenz reduces the amount of bedaquiline in the body) or with lopinavir/ritonavir (because both can cause side effects on the heart) • Pill burden: taking multiple drugs for TB and HIV could become overwhelming SPECIAL GROUPS

16. TB/HIV co-infection (2 of 2) • In people diagnosed with TB and HIV at the same time, timing of antiretroviral therapy (ART) is important: • A serious reaction called immune reconstitution inflammatory syndrome (IRIS) can occur in people simultaneously starting TB treatment and ART • IRIS is avoided by starting TB therapy before ART and timing is dependent on the CD4 count • For people with CD4 lymphocyte <50 cells/mm3, start ART after 2 weeks • For people with CD4 lymphocyte 50-500 cells/mm3, start ART after 8-12 weeks to prevent death and AIDS-related conditions • For people with TB meningitis, start ART after at least 8-12 weeks to prevent IRIS in the central nervous system SPECIAL GROUPS

17. Adolescent and childhood TB • Adolescents have very similar TB and metabolism to adults • Adolescents should be treated for TB as adults are but with additional counseling and adherence support • Children are at increased risk for disease progression, but also tend to have fewer bacteria and may not need as long treatment • New pediatric-friendly, appropriately dosed formulations of standard TB treatment are available • Not all second-line drugs are available in child-friendly formulations • delamanid is WHO-recommended for children age 3 years and up • bedaquiline is WHO-recommended for children age 6 years and up • In children, it can be difficult to diagnose, monitor, and assess response to treatment • Adolescents and children should be included earlier in research Source: https://www.ncbi.nlm.nih.gov/pubmed/25957923 SPECIAL GROUPS

18. TB treatment and opioid substitution therapy (OST) • Some people who have used heroin or other opiates take OST to help them stop • Methadone and buprenorphine are the most commonly used forms of OST • Rifampicin reduces methadone and buprenorphine levels in the body • People with TB on OST may need rifabutin (similar to rifampicin, but does not interact with methadone in this way) or a higher dose of OST • Bedaquiline likely also reduces the amount of methadone and buprenorphine in the body SPECIAL GROUPS

19. treatment research

20. drug development process • Preclinical (conducted in laboratories) • In vitro(in test tubes) • Animal models (In vivo) • Clinical trials (conducted in humans) • Phase I evaluates the safety, tolerability, pharmacokinetics, pharmacodynamics of a drug; usually in healthy participants for a very short amount of time • Phase IIa evaluates early bactericidal activity and dosing in participants with TB (usually two weeks) • Phase IIb evaluates anti-TB activity and early safety in slightly larger group of participants with TB (usually for 2-6 months) • Phase IIcis small like a Phase IIb but follows patients for longer like phase III to give more info about final outcome • Phase III evaluates the efficacy of the drug in a larger group of participants at multiple locations and follows patients through to final outcome (relapse-free cure, treatment failure, or death) • Phase IV collects information on the postmarketing use of the drug RESEARCH

21. New drugs in clinical trials RESEARCH http://www.pipelinereport.org/2017/tbtx

22. TB treatment RESEARCH FUNDING, 2017 RESEARCH Source: http://www.treatmentactiongroup.org/tbrd2018

23. TB RESEARCH FUNDING, 2017 RESEARCH Source: http://www.treatmentactiongroup.org/tbrd2017

24. Advocacy PRIORITIES

25. THE PUSH FOR BETTER DRUGS • Drugs used in TB treatment are far from perfect. The following are a few of the reasons why activists are advocating for better drugs: • Adherence issues • Duration of treatment • Potentially toxic side effects • Hard to tolerate (e.g., painful injections) • Drug availability and quality • Drug interactions • Poor cure rates for MDR-TB and XDR-TB • Limited child-friendly formulations for most second-line drugs • Very little information on treating MDR-TB in pregnant/lactating women ADVOCACY

26. Advocacy Priorities • Representation of people living HIV, children and pregnant women in operational and clinical studies • Clear information about optimal use of new drugs, which must be given in combination • Increased funding of basic science, later stage clinical trials, and operational research • A standardized regulatory pathway across countries and regions to accelerate the approval of promising treatments • Drugs, once developed, need to be priced affordably and registered widely • Countries must budget for both research and buying newer drugs • Expanded access and compassionate use to promising treatments preapproval to those in desperate need while ensuring appropriate use of the drugs • Uptake of the new treatment options available: delamanid (including for children), bedaquiline, and all-oral shorter regimens under operational research ADVOCACY

27. Main points

28. TB treatment takeaways • TB is curable • Treatment must be guided by drug susceptibility testing • New treatment options (all-oral, shorter regimen and bedaquiline, delamanid, linezolid, clofazimine) must be available • Much more research is needed MAIN POINTS

29. Additional Resources • Treatment Action Group (TAG) and DR-TB STAT developed An Activist’s Guide to Bedaquiline (Sirturo): treatmentactiongroup.org/tb/publications/2013/activist-guide-bedaquiline