Thursday, April 02, 2009

A tour around tuberculosis: The problem and its solution

Tuberculosis (TB) infects nearly 15 million people worldwide and causes the death of 1.7 million each year. Individuals, especially in Southern Africa are commonly co-infected with TB and HIV, a combination with very poor prognosis. Having been largely ignored until recently TB is currently receiving significant attention from both NGOs and also industry. The latter is evaluating new vaccines as well as second line treatments of TB. The pharmaceutical sector has been playing a significant part in the combat of HIV infection in the developing world for the past decade; it is now expected to follow suit in the related area of TB

For a detailed analysis of opportunities and development in the field of TB see our brand new feature Tuberculosis - Development pipeline shows signs of life or read on


TB is a major cause of illness and death worldwide, especially in Asia and Africa. Globally, 14.4 million prevalent cases of TB, 9.2 million new cases and 1.7 million deaths from TB occurred in 2006. India and China have the highest incidence of TB worldwide; Asia and the Western Pacific account for 55% of global cases of TB

Sub-Saharan Africa also has a high incidence of TB accounting for 31% of global infection. In this region coinfection with HIV represents a massive problem. TB infection is found in over 50% of all new cases of HIV infection in Southern Africa and this results in a dramatic worsening of prognosis.

The seven major markets accounted for relatively small fractions of global cases and incidence has
been declining sharply in these countries over the last few decades and this has been accompanied by a fall in commercial incentives for pharmaceutical companies to invest in antituberculosis drug research, which has resulted in a paucity of new drugs.

Growing intent to treat supported by NGO efforts

Large pharma has however been showing an increasing appetite to treat developing world prominent disease and in particular companies have been lowering the cost of HIV treatment. This has been accompanied by significant efforts from NGOs and consequently two landmark documents in global TB control were launched in 2006: the Stop TB Strategy and the Global Plan to Stop TB.

The primary NGO aims are to increase detection and to improve treatment and a central component of these strategies is known as DOTS (directly observed treatment, short course). To ensure thorough treatment, it is often recommended that the patient takes his or her pills in the presence of someone who can supervise the therapy. In addition to implementing uptake of DOTS, major efforts are underway to increase TB detection and treatment

Despite the enormous global burden of TB, case detection rates are low, posing serious hurdles for TB control. The definitive diagnosis of TB requires identification of the mycobacterial pathogen in a patient’s secretions or tissues. Identification of the organism is necessary for drug susceptibility testing which further guides selection of treatment regimens. Conventional TB diagnosis continues to rely on tests such as sputum smear microscopy, culture, tuberculin skin test, and chest radiography. These tests have several limitations and perform poorly in populations affected by the HIV epidemic. Furthermore conventional tests for detection of drug resistance are time consuming, tedious, and inaccessible in most settings. In industrialized countries, newer technologies such as interferon gamma release assays for the diagnosis of latent infection and nucleic acid amplification tests and liquid culture for diagnosis of active TB disease are being increasingly used. However such tests have not been implemented in high-burden developing countries to any significant degree, mainly because the level of sophistication and cost that has, to date, made their routine application unfeasible.

The current TB vaccine, bacillus Calmette-Guerin (BCG) is a live vaccine that protects against severe childhood forms of disease. It also confers protection against leprosy. However it does not prevent the
reactivation of latent TB, the main source of mycobacterial spread in the community. Given the limitations of the current BCG vaccination, several novel vaccines and strategies are being investigated for both prevention and treatment of TB.

Replacement of BCG with a more effective vaccine that provides lasting protection, a new vaccine for adolescents/adults that prevents adult pulmonary TB, and an immunotherapeutic vaccine could each provide improved approaches. Given the wide use of the BCG vaccine, particularly in the developing world, a prime-boost strategy using a new TB vaccine candidate to boost the BCG vaccine is considered the best way to test and introduce new TB vaccines into endemic countries.
Public-private partnerships have been the strongest force driving TB Vaccine development. For example the Aeras Global TB Vaccine Foundation which receives NGO funding currently works on six candidate vaccines. Aeras is developing these through collaborations with companies like Crucell, GlaxoSmithKline, Sanofi Pasteur and several others. The vaccine candidates include BCG strains that have been genetically manipulated to express immunodominant antigens (recombinant BCG) and several non-living vaccines


Although the current tuberculosis treatment regimens are highly effective they are far from ideal. Many of the drugs used have side effects and even with the optimal combination of the available drugs, the duration of treatment required for curing patients cannot be reduced below six months. As a result these regimens are associated with high rates of non-adherence leading to drug resistance and increased morality. The rise in multi drug resistant and extensively drug resistant strains has also
caused concern, particularly in the developing world. Conventional short course antibiotic therapy has remained the mainstay of treatment for tuberculosis for several decades.

In 2007 the global TB antibiotics market was worth approximately $300 million with a CAGR of 2.2% from 2004-2007. Given the low incidence of TB in the seven major markets, they accounted for approximately 40% of total sales, the balance was accounted by the rest of world which includes the majority of the high burden countries.

The classes of anti-tuberculosis drugs have traditionally been divided into first and second-line drugs, with isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin being the primary first-line drugs. The most frequently recommended and effective combination is isoniazid, rifampicin, pyrazinamide and ethambutol for 2 months followed by isoniazid and rifampicin for 4 months.

Currently second line therapy represents the area with the greatest commercial opportunity since many second line drugs have greater toxicity and in the case of XDR-TB, they are simply ineffective. Newer drugs that can substantially reduce the duration of therapy and have activity against multi drug resistant and extensively drug resistant TB strains have a strong chance of gaining commercial success. Currently the products that are being investigated include the fluoroquinolones gatifloxacin and moxifloxacin, Tibotec/Johnson & Johnson’s TMC207, Chiron Pathogenesis/TB Alliance’s PA824, Otsuka Pharmaceuticals’ OPC-67683 and Sequella’s SQ-109.

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