Treatment

How to save a life: The cure!

In the past, TB patients were quarantined, but not nowadays.  They can work as usual, but must avoid contact with other uninfected people. The good news is, TB is curable! The standard course treatment for TB is isoniazid, rifampicin, pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months. The patient is considered cured at six months (although there is still a relapse rate of 2 to 3%).                                                                                                  

If the organism is known to be fully sensitive, then treatment is with isoniazid, rifampicin, and pyrazinamide for two months, followed by isoniazid and rifampicin for four months. Ethambutol need not be used.                                                                                                                                                           

There are three types of drugs, namely first-line, second-line and third-line drugs.                                                          

All first-line anti-tuberculosis drug names have a standard three-letter and a single-letter abbreviation:                                                                                                                                                          

•                    Ethambutol is EMB or E,

•                    isoniazid is INH or H,

•                    pyrazinamide is PZA or Z,

•                    rifampicin is RMP or R.

There are six classes of second-line drugs (SLDs) used for the treatment of TB. A drug may be classed as second-line instead of first-line for one of three possible reasons: it may be less effective than the first-line drugs, it may have toxic side-effects or it may be unavailable in many developing countries. Here are a few example

 •                    aminoglycosides:  e.g., amikacin (AMK), kanamycin (KM)
 •                    polypeptides:  e.g., capreomycin, viomycin, enviomycin
 •                    Fluoroquinolones:  e.g., ciprofloxacin (CIP), levofloxacin, moxifloxacin;
 •                    thioamides:  e.g. ethionamide, prothionamide.

These are other drugs that may be useful, but are not on the WHO list of SLDs. These are instead considered third-line drugs because they are not very effective or because their efficacy has not been proven. Some examples would include:

•                    rifabutin

•                    macrolides: e.g., clarithromycin (CLR);

•                    linezolid (LZD);

•                    thioacetazone (T);

•                    thioridazine;

•                    arginine;

•                    vitamin D;

•                    R207910.

Monitoring, DOTS, and DOTS-Plus

WHO now promotes a scheme to ensure that patients complete their course of drugs. DOTS (Direct Observation Treatment, Short Course) is a major plank in the WHO Global Plan to stop TB. WHO advises that all TB patients should have their whole therapy observed. This means having health workers or responsible family members making sure that patients take their medicine regularly for six to eight months. The drugs widely used are isoniazid and rifampicin, often in combination with others.

Treatment with properly implemented DOTS has a success rate exceeding 95% and prevents the emergence of further multi-drug resistant (MDR) strains of tuberculosis. Administering DOTS, decreases the possibilities of tuberculosis from recurring, resulting in a reduction in unsuccessful treatments.

The WHO extended the DOTS programme in 1998 to include the treatment of MDR-TB (called "DOTS-Plus"). Implementation of DOTS-Plus requires the capacity to perform drug-susceptibility testing and the availability of second-line agents, in addition to all the requirements for DOTS. DOTS-Plus is therefore much more resource-expensive than DOTS, and requires much greater commitment from countries wishing to implement it.

Drug-resistant tuberculosis (MDR- and XDR-TB)

Multi-drug resistant tuberculosis (MDR-TB) is defined as TB that is resistant at least to isoniazid (INH) and rifampicin (RMP). Isolates that are multiply resistant to any other combination of anti-TB drugs but not to INH and RMP are not classed as MDR-TB. As of October 2006, "Extensively drug-resistant tuberculosis" (XDR-TB) is defined as MDR-TB that is resistant to quinolones and also to any one of kanamycin, capreomycin, or amikacin.

The principles of treatment for MDR-TB and for XDR-TB are the same. The main difference is that XDR-TB is associated with a much higher mortality rate than MDR-TB, because of a reduced number of effective treatment options. The epidemiology of XDR-TB is currently not well studied, but it is believed that XDR-TB does not transmit easily in healthy populations, but is capable of causing epidemics in populations which are already stricken by HIV and therefore more susceptible to TB infection.

Treatment of MDR-TB

The treatment and prognosis of MDR-TB are much more akin to that for cancer than to that for infection. It has a mortality rate of up to 80%, which depends on a number of factors, including:

•                    How many drugs the organism is resistant to (the fewer the better),

•                    How many drugs the patient is given (patients treated with five or more drugs do better),

•                    Whether an injectable drug is given or not (it should be given for the first three months at least),

•                    The expertise and experience of the physician responsible,

•                    How co-operative the patient is with treatment (treatment is arduous and long, and requires persistence and determination on the part of the patient),

•                    Whether the patient is HIV positive or not (HIV co-infection is associated with an increased mortality).

Treatment courses are a minimum of 18 months and may last years; it may require surgery, though death rates remain high despite optimal treatment. That said, good outcomes are still possible. Treatment courses that are at least 18 months long and which have a directly observed component can increase cure rates to 69%.

The treatment of MDR-TB must be undertaken by a physician experienced in the treatment of MDR-TB. Mortality and morbidity in patients treated in non-specialist centres is significantly superior to those patients treated in specialist centres.

Latent tuberculosis

The treatment of latent tuberculosis infection (LTBI) is essential to controlling and eliminating TB by reducing the risk that TB infection will progress to disease.

The terms "preventive therapy" and "chemoprophylaxis" have been used for decades and are preferred in the UK because it involves giving medication to people who have no active disease and are currently well, the reason for treatment is primarily to prevent people from becoming unwell. The term "latent tuberculosis treatment" is preferred in the US because the medication does not actually prevent infection: it prevents an existing silent infection from becoming active. The feeling in the US is that the term "treatment of LTBI" promotes wider implementation by convincing people that they are receiving treatment for disease. There are no convincing reasons to prefer one term over the other.

It is essential that assessment to rule out active TB is carried out before treatment for LTBI is started. To give LTBI treatment to someone with active TB is a serious error: the TB will not be adequately treated and there is a risk of developing drug-resistant strains of TB.

There are several treatment regimens available:

•                    Isoniazid for 9 months is the gold standard and is 93% effective.

•                    Isoniazid for 6 months might be adopted by a local TB program based on cost-effectiveness and patient compliance. This is the regimen currently recommended in the UK for routine use. The US guidance exclude this regimen from use in children or persons with radiographic evidence of prior tuberculosis (old fibrotic lesions). (69% effective)

•                    A twice-weekly regimen for the above two treatment regimens is an alternative if administered under (DOTS).

•                    Rifampicin for 4 months is an alternative for those who are unable to take isoniazid or who have had known exposure to isoniazid-resistant TB.

•                    Isoniazid and rifampicin may be given for 3 months.

•                    The 2-month regimen of rifampicin and pyrazinamide is no longer recommended for treatment of LTBI because of the greatly increased risk of drug-induced hepatitis and death.

•                    3-month (12-dose) regimen of weekly rifapentine and isoniazid.

Current research

There is some evidence from animal and clinical studies that suggests that moxifloxacin-containing regimens as short as four months may be as effective as six months of conventional therapy. Bayer (a German company) is currently running a Phase II clinical trial in collaboration with the TB Alliance to evaluate shorter treatment regimens for TB; encouragingly, Bayer have also promised that if the trials are successful, Bayer will make moxifloxacin affordable and accessible in countries that need it.

The following drugs are experimental compounds that are not commercially available, but which may be available from the manufacturer as part of a clinical trial or on a compassionate basis. Their efficacy and safety are unknown:

•                    PA-824 (manufactured by PathoGenesis Corporation, Seattle, Washington)

•                    R207910 (under development by Johnson & Johnson)

A Ukrainian herbal product has been the subject of several small, open label clinical trials, with promising results in TB patients and in patients with TB/HIV coinfection. Open label trials with Dzherelo/Immunoxel have also been positive in multi-drug-resistant tuberculosis patients and extensively drug-resistant tuberculosis patients. Stirling Products Ltd of Australia has announced further work in drug-resistant TB and in TB/HIV in trials in Nigeria.

V-5 Immunitor (known as "V5") is an oral hepatitis B and hepatitis C treatment vaccine administered as simple tablets. In patients co-infected with hepatitis C and tuberculosis, TB sputum clearance was unexpectedly noted within only one month. Further blinded studies at multiple trial centres suggest that V5 is equally effective against multiple drug resistant tuberculosis (MDR-TB).