TUBERCULOSIS

What is tuberculosis?

Tuberculosis (TB) is a bacterial infection caused by Mycobacterium tuberculosis or, occasionally, by one of two other related bacteria. It most often affects the lungs (pulmonary TB) but can also affect the central nervous system, lymphatic and genitourinary systems, circulation, and bones and joints. It is highly infectious and is spread from one person to another by the inhalation of airborne droplets containing the bacteria expelled by coughing or sneezing. About 90 per cent of those infected do not show any symptoms but remain carriers of the disease (latent TB). Of these, around 10 per cent will develop an active infection at some point in their lives. Conversion from latent to active disease is more likely in those whose immune system is depressed, such as those infected with HIV, and in people treated with medicines that block TNF-, which is important in the body's immune defence against TB.

Active TB is characterised by symptoms such as a cough, chest pain and the coughing up of blood in those with pulmonary TB and by fever, chills, night sweats, appetite and weight loss and fatigue in those with systemic disease. The WHO has estimated that people with active TB will infect on average 10-15 people a year and, untreated, about half of those will eventually die of TB.

Who does tuberculosis affect?

The World Health Organisation estimates that around one-third of the world's population (about 2 billion people) carry the TB bacterium and that about 8 million develop the disease each year, of whom roughly 1.6 million die. Of the active cases of TB, over 1.5 million a year occur in sub-Saharan Africa and nearly 3 million in Southeast Asia. TB was diagnosed in more than 8,000 people in the UK in 2005, and this figure is growing year by year. Nearly 3,500 cases were recorded in London alone. Almost three-quarters of those developing active TB in the UK are born in countries where it is endemic.

Present treatments and shortcomings

Recommendations for treatment of TB are contained in a guideline published by the National Institute for Health and Clinical Excellence (NICE) in March 2006. Standard treatment for active pulmonary TB consists of a six-month period of treatment with isoniazid + rifampicin, supplemented during the first two months with pyrazinamide and ethambutol. Fixed combinations such as rifampicin + isoniazid (Rifinah, sanofi-aventis) and rifampicin + isoniazid + pyrazinamide (Rifater, sanofi-aventis) are preferred. Adverse reactions are seen in about 10 per cent of those treated and may include damage to the nervous system, nausea and vomiting, flu-like reactions, liver problems and skin rash. The main problem with standard therapy is the length of time (six months) for which medication must be taken, which may result in missed doses, and treatment failure, due to the development of resistance to one or more components of the treatment.

In a small percentage (about 1 per cent) of cases in the UK, the TB organism may have become resistant to several of the medicines used for standard therapy. Treatment in this case will be carried out by a specialist, using second-line medicines to which resistance has not developed in the patient concerned. These may include capreomycin, fluoroquinolone antibiotics and others, but these may be either less effective or more toxic than standard therapy. Recently, cases of extremely treatment-resistant TB have been reported outside Western Europe, which is a cause for great concern and makes the development of new medicines an urgent necessity.

For many years, it was standard practice in the UK to vaccinate all schoolchildren with a live attenuated vaccine based on Mycobacterium bovis (BCG vaccine) developed by Calmette and Guerin at the Pasteur Institute. However, the efficacy of this vaccination in preventing TB is disputed and has been found to vary greatly from one region to another. BCG vaccination is now recommended only for babies, children and adults considered to be at high risk for TB infection, but not universally. However, there is little doubt that the development of a truly effective new vaccine could be of great public health benefit, especially in developing countries, where infection rates and deaths are high.

What's in the development pipeline?

Development efforts for TB encompass both industry and the private sector and include a number of public-private partnerships. They have benefited from funding from sources such as the Bill & Melinda Gates Foundation, the European Commission and the Wellcome Foundation, among others.

Perhaps furthest advanced in the development of new vaccines for preventing TB is an initiative from the University of Oxford Centre for Clinical Vaccinology and Tropical Medicine, supported by the Wellcome Foundation. This vaccine strategy makes use of a 'prime-boost' approach in which an initial vaccination with standard BCG vaccine is followed by a boosting dose of a modified vaccinia virus, Ankara strain (MVA), containing an antigen that is present in all strains of BCG. This BCG/MVA85A vaccine has been found to give strong immune response in Phase 1 trials and is now in Phase 2 testing in South Africa, as well as in Phase 1 trial in the UK in people also infected with HIV.

Also in Phase 2 trial is the Mtb72F/AS02A vaccine under development by GlaxoSmithKline together with the Aeras Global TB Vaccine Foundation. In Phase 1 trials, vaccination with this vaccine has produced strong and persistent cellular and antibody responses.

The third TB vaccine in clinical trial is also the subject of a partnership between Aeras and Crucell. The Ad35 recombinant vaccine is now entering Phase 1 safety testing.

New compounds for treating TB are also in development. Bayer and the Global Alliance for TB Drug Development (TB Alliance) have launched a Phase 2 trial to investigate the potential of the existing fluoroquinolone-type antibiotic moxifloxacin (Avelox) to shorten the standard six-month treatment, which would help to improve its effectiveness. Another fluoroquinolone antibiotic, gatifloxacin, (not currently available in the UK) is also under study in a WHO/EU funded Phase 3 trial for TB treatment.

Most other new treatments are in Phase 1 trial. TB Alliance is testing PA-824 and Sequella has the antibiotic SQ109, which enhances the action of isoniazid and rifampicin, and may therefore help shorten the treatment period. SciClone's SCV-07 has reached Phase 2, while other compounds at Phase 1 include the pyrrole LL 3858 (sudoterb, Lupin), OTC 67683 (Otsuka) and Tibotec's TMC 207.

Research into new vaccines and treatments for TB is now much more active than it has been for many years, and it is to be hoped that this will help overcome the enormous global public health burden that this disease, a feared killer throughout the ages, represents.

FOR FURTHER INFORMATION CONTACT:

TB Alert
22 Tiverton Road, London NW10 3HL.
Tel: 0845 456 0995 (Helpline for healthcare professionals)
Website: www.tbalert.org