Tuberculosis Treatment Treatment Action Group TB/HIV Advocacy Toolkit August 2017 With thanks to Adam Almeida and Andolyn Medina

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

treatment fundamentals

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 effective therapy in the shortest period of time Three basic principles of TB treatment: Regimens must contain multiple drugs to 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 be taken regularly Drug therapy must continue long enough to kill all remaining TB organisms FUNDAMENTALS

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 More information on WHO guidelines for monitoring TB treatment can be found at http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf FUNDAMENTALS

*approved for treating latent TB infection drug discovery & development and its impact on treatment 1944 streptomycin 1920 BCG vaccine 1955 cycloserine 2000 rifapentine 1934 Gold therapy abandoned 1951 isoniazid 1962 ethambutol 2014 rifapentine* delamanid 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

How TB is treated

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 (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

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

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 TREATMENT

SHORTENED REGIMEN FOR DRUG RESISTANT TB In 2016, the WHO approved a 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) The shortened treatment is specifically for people whose TB is resistant to rifampicin and has not been treated with or show resistance to a second-line injectable or a fluoroquinolone Source: http://www.treatmentactiongroup.org/tb/drug-guide-2016 TREATMENT

Source: http://www.treatmentactiongroup.org/tb/drug-guide-2016 MDR- AND XDR-TB Other forms of multidrug-resistant (MDR) and extensively- drug resistant TB (XDR-TB) require an 18-24 month drug treatment regimen It should include at least 5 effective drugs; if possible, pyrazinamide, one fluoroquinolone, one second-line injectable drug, and two core second-line agents including one of the newer drugs (bedaquiline or delamanid) In cases of XDR-TB, there may not be 5 effective drugs to treat Other add-on agents are included to reach 5 effective drugs (including p-aminosalicylic acid, imipenem-cilastatin) TREATMENT Source: http://www.treatmentactiongroup.org/tb/drug-guide-2016

Treatment in special groups

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 For more information on treating TB/HIV coinfection see WHO’s 2009 Treatment of Tuberculosis: guidelines for national programme which can be found at http://www.who.int/tb/publications/cds_tb_2003_313/en/ and WHO’s 2010 ART Guidelines at http://www.who.int/hiv/pub/arv/adult2010/en/index.html SPECIAL GROUPS

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 For more information on treating TB/HIV coinfection see WHO’s 2009 Treatment of Tuberculosis: guidelines for national programme which can be found at http://www.who.int/tb/publications/cds_tb_2003_313/en/ and WHO’s 2010 ART Guidelines at http://www.who.int/hiv/pub/arv/adult2010/en/index.html SPECIAL GROUPS

Adolescent and childhood TB Adolescents have very similar TB and metabolism to adults Adolescents should be treated for TB as adults are 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 Lack of pediatric formulations of most second-line drugs delamanid is WHO-recommended for children age 6 and up Difficulty diagnosing, monitoring, and assessing treatment Lack of inclusion in research of either adolescents or children, despite consensus of how to include them For more information on treating Childhood TB see WHO’s 2010 Rapid Advice: treatment of tuberculosis in children at http://whqlibdoc.who.int/publications/2010/9789241500449_eng.pdf Source: https://www.ncbi.nlm.nih.gov/pubmed/25957923 SPECIAL GROUPS

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 *for more information on opiod substitution therapy go to http://www.who.int/substance_abuse/publications/en/PositionPaper_English.pdf *for more information on TB drug interactions go to http://www.who.int/emlib/Medicines.aspx for more information on opiod substitution therapy go to http://www.who.int/substance_abuse/publications/en/PositionPaper_English.pdf SPECIAL GROUPS

treatment research

drug development process Preclinical (conducted in laboratories) In vitro (in test tubes) Animal models 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 IIc is 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

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

Source: http://www.treatmentactiongroup.org/tbrd2016 TB RESEARCH FUNDING, 2015 For more information on TB R&D funding trends check out TAG’s TB R&D Resource Tracking Report at http://www.treatmentactiongroup.org/tbrd RESEARCH Source: http://www.treatmentactiongroup.org/tbrd2016 21

Source: http://www.treatmentactiongroup.org/tbrd2016 TB RESEARCH FUNDING, 2015 RESEARCH Source: http://www.treatmentactiongroup.org/tbrd2016

Advocacy PRIORITIES

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 No appropriate child-friendly formulations for most second-line drugs Very little information on treating MDR-TB in pregnant/lactating women Note to facilitator: This list is by no means exhaustive and facilitators are encouraged to ask group to explore more gaps and challenges of TB treatment ADVOCACY

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 shortened regimen Note to facilitator: This list of advocacy issues is based on the content of this presentation and is not meant to be an exhaustive list of TB treatment advocacy issues. This list should be considered and modified as appropriate to the audience and the facilitator. ADVOCACY

Main points

TB treatment takeaways TB is curable Treatment must be guided by drug susceptibility testing New treatment options (shortened regimen, bedaquiline, delamanid, linezolid, clofazimine) must be available Much more research is needed MAIN POINTS

ADDITIONAL RESOURCES The Treatment Action Group has created ‘An Activist’s Guide to Tuberculosis Drugs’, which expands upon what has been outlined in these slide decks To access: http://www.treatmentactiongroup.org/tb/drug- guide-2016 MAIN POINTS