Medicines

TB treatment overview

Treating TB effectively and promptly is important to both protect patients and prevent the spread of TB. People diagnosed with TB and HIV should start TB treatment immediately and then begin antiretroviral treatment within two weeks if they have a low CD4 count (<50 cells/mm3), or within two months if the CD4 count is above 50 cells/mm3. The standard TB treatment regimen is a six-month course of antibiotics, but the duration and drugs used may vary according to a patient’s age and type of TB. TB treatment can also be used to prevent infection with the bacterium from turning into active disease. Treating TB takes longer than other types of bacterial infections because the bacteria that cause TB grow slowly. Even so, pending and future research may help reduce treatment times.

Contents

Preventive therapy

As there is no widely effective vaccine for TB, using TB drugs to treat latent TB infection (LTBI) is one of the best ways to prevent active TB disease. If active disease has been ruled out, the most common treatment for latent TB infection is isoniazid. Isoniazid preventive therapy (IPT) reduces the risk of developing active TB. The standard regimen is 300 mg daily of isoniazid for 6-9 months in adults and adolescents and 5 mg/kg for children; the World Health Organization recommends 36 months or more of treatment for people with HIV, including children.

Clinical trials have shown short courses of preventive therapy — such as using rifampicin alone for four months, or once-weekly isoniazid and rifapentine together for 12 weeks — to be as effective as isoniazid for 6-9 months. These regimens are in use in the U.S. and other low transmission settings. However, it is unclear if these regimens are appropriate for high burden settings, as research has shown that in settings with high rates of TB transmission, the benefits of isoniazid preventive therapy last only as long as the treatment itself. The below table compares various treatment regimens for latent TB infection:

Latent TB infection treatment regimens

Drugs                                          Duration                 Interval                   Minimum number of doses

isoniazid                                     36 months                  Daily                          1080
isoniazid                                      9 months                   Daily                           270
isoniazid                                      6 months                   Daily                           180
isoniazid and rifapentine              3 months                   Once weekly                 12
rifampicin                                    4 months                   Daily                           120

[Adapted from U.S. Centers for Disease Control and Prevention]

Currently, there is no validated regimen to treat latent infection with drug-resistant strains of TB. The European Center for Disease Prevention and Control (ECDC) recommends finding contacts of people with drug-resistant TB and conducting individual risk assessments that consider the risk for progression to TB disease, the drug-susceptibility pattern of the source case of infection, and the risk for adverse drug events if preventive therapy is initiated. More research is needed both to identify safe and effective treatment options for those infected with drug-resistant TB, and to guide follow up in cases where preventive therapy is not initiated.

Treatment for drug-sensitive TB (DS-TB)

The standard six-month course of treatment consists of two phases: the intensive phase (the first two months) and the continuation phase (the last four months). Treatment may differ for patients with extrapulmonary TB (TB outside of the lungs).

During the intensive phase of standard treatment, patients take a daily combination of four medications: isoniazid, rifampicin, pyrazinamide and ethambutol. These four drugs are referred to as first-line drugs, and are off-patent and cheap. In place of rifampicin, rifapentine may be used to allow for intermittent dosing, or rifabutin may be used as it has fewer interactions with HIV medicines and opioid substitution therapy, but these are more expensive than rifampicin and not available in all TB programs.

These medicines are used in combination to prevent the bacteria from developing resistance. Within a few weeks of beginning treatment, most patients will start to feel better. If treatment is working, most patients become non-infectious during the intensive phase.

Once the intensive phase is completed, the continuation phase of treatment begins. During this four-month phase, normally only isoniazid and rifampicin (the two most powerful first-line drugs) are taken on a daily basis. If the patient has taken medications regularly and achieves two negative TB tests, his/her TB is considered cured upon completion.

Side effects, particularly nausea and abdominal pain, are relatively common. Urine and tears can turn orange, which is harmless but disconcerting if patients are not warned. More severe side effects, such as joint pain, visual impairment, liver damage, and peripheral neuropathy (nerve damage) are less common, but can be serious when they do occur. More information about each first-line drug and its side effects can be found in TAG’s Activist’s Guide to TB Drugs.

First-line drugs:

isoniazid (H or INH)
rifampicin (R or RIF)
ethambutol (E or EMB)
pyrazinamide (Z or PZA)
rifabutin (RBT)
rifapentine (P or RPT)

Treatment for drug-resistant TB (DR-TB)

Drug-resistant TB (DR-TB) is TB that has developed mutations that make the four standard first-line drugs ineffective. Drug resistance can arise when medicines are sub-standard, doses are skipped, treatment is interrupted or stopped too soon, or when treatment regimens are inappropriately designed or dosed. Drug-resistant TB can also infect people directly in community or healthcare settings.

Drug-resistant TB is lengthier, more expensive and more difficult to treat than drug-sensitive TB. TB that is resistant to at least isoniazid and rifampicin is called multi-drug resistant (MDR) TB. Extensively drug-resistant TB (XDR-TB) is MDR-TB that is also resistant to a second-line injectable drug (amikacin, kanamycin, or capreomycin) and a fluoroquinolone. Pre-XDR-TB is MDR-TB that is resistant to either a second-line injectable or a fluoroquinolone. Treatment for drug-resistant TB takes longer (up to two years), is less effective (global cure rates are around 50%) and has more side effects.

Guidelines from the World Health Organization on how to construct an appropriate regimen for drug-resistant TB are available here.

More information about each second-line drug and its side effects can be found in TAG’s Activist’s Guide to TB Drugs.

Second-line drugs:

Injectables (parenteral agents)

  • kanamycin (KAN, KM or K)
  • amikacin (AMK or Am)
  • capreomycin (CAP or Cm)
  • streptomycin (STR or S)

Fluoroquinolones

  • moxifloxacin (MXF, Mox or Mfx)
  • levofloxacin (LVX, LEV or Lfx)
  • ofloxacin (Ofx)

Oral bacteriostatic

  • ethionamide (ETH or Eto)
  • prothionamide (Pto)
  • cycloserine (Cs)
  • terizidone (Trd)
  • p-aminosalicylic acid (PAS)

Agents with unclear efficacy for TB

  • clofazimine (CFZ or CLF)
  • linezolid (LZD or LNZ) – more information can be found in TAG’s Activist’s Guide to Linezolid
  • amoxicillin/clavulanate (AMC or Amx/Clv)
  • high dose isoniazid (H or INH)
  • thioacetazone (Thz)
  • imipenem/cilastatin (Imi or Imi/Cls)
  • clarithromycin (CLR)

Novel drugs

New drugs in clinical trials for tuberculosis

Drug                            Sponsor(s)                  Phase                       Class

bedaquiline                    Janssen                     IIb/III                  diarylquinoline
delamanid                      Otsuka                         III                     nitroimidazole
AZD5847                    AstraZeneca                      IIa                    oxazolidinone
PA-824                        TB Alliance                      III                     nitroimidazole
SQ109                    Sequella/Infectex              IIb/III                   ethylenediamine
sutezolid                       Sequella                        IIa                    oxazolidinone

[Adapted from TAG’s 2014 Pipeline Report]

AZD5847

AZD5847, like linezolid and sutezolid, is an oxazolidinone that shows activity against DR-TB. As linezolid has serious side effects, including optic and peripheral neuropathy and anemia, safer oxazolidinones are needed. AZD5847 has appeared well-tolerated in the very short, small trials that have been conducted. To learn more about the ongoing development of AZD5847, read TAG’s Pipeline Report. In early 2014, AZD5847’s sponsor, AstraZeneca announced the cessation of their Neglected Tropical Diseases, Tuberculosis and Malaria program; they have stated commitment to continuing the development of AZD5847 for TB.

Pretomanid (PA-824)

Pretomanid (previously called PA-824) is a nitroimidazole (like delamanid). The TB Alliance is developing pretomanid in combinations for both drug-sensitive and drug-resistant TB. Pretomanid appears safe and effective so far, though it may affect the rate at which the heart conducts electrical impulses, known as QT prolongation. To learn more about the ongoing development of pretomanid, read TAG’s Pipeline Report

SQ109

SQ109 is an ethylenediamine antibiotic, in the same drug class as ethambutol, but early test tube and mouse studies do not show cross-resistance between the two drugs. While SQ109 appears safe and well-tolerated, no evidence from human studies indicates that the drug could shorten or otherwise improve TB therapy. To read more about the development of SQ109, see TAG’s Pipeline Report.

Sutezolid

Sutezolid, like linezolid and AZD5847, is an oxazolidinone. As linezolid has serious side effects, including eye and nerve damage and anemia, safer oxazolidinones are needed. A small study of sutezolid in TB patients found it safe and active against TB, however, temporary spikes in liver enzymes were observed though they did not cause any clinical effects. In July 2013, Pfizer off-loaded Sutezolid to a small private pharmaceutical company, Sequella (also the sponsor of SQ109). To learn more about the ongoing development of sutezolid, read TAG’s Pipeline Report.