Tuberculosis profile rising

22 Sep 2008

Paul Chinnock

Source: TropIKA

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Times have changed. Not so long ago, new research on tuberculosis was in short supply, there were few advances in understanding of the infection and there seemed to be little progress towards new treatments or control strategies. But, thanks to improved funding, TB research activity has increased. The last few weeks, have seen the publication of several important new studies (a few of which we discuss below) and there have been announcements of further initiatives. Also of interest is the fact that the global media has reported many of these developments; TB was previously not regarded as being of public interest but now the media has belatedly recognized that it deserves a higher profile.

New publications

One study that has attracted wide attention brings in fact bad news. Andrew Boulle et al have reported a cohort study (1) which showed that anti-tuberculosis therapy can make some HIV treatments less effective. They found that virological failure is more likely to occur if patients receiving rifampicin-based anti-tuberculosis therapy also receive nevirapine-based antiretroviral treatment. Given the high incidence of TB-HIV coinfection, the finding is of some concern.

A potentially important advance in the understanding of how Mycobacterium tuberculosis overcomes the immune system has resulted from a study by Heinz Remold et al (2). Their work on mice has shown that TB infection provokes a form of death in host cells that enables the infection to spread. Normally, infected macrophages undergo the form of cell death known as apoptosis which keeps their membranes intact, thus preventing any entrapped bacteria from spreading. However, using a virulent strain of M. tuberculosis, Remold’s team observed that it suppressed the apoptosis response and instead induced necrosis, which releases viable intracellular bacilli. The identification of the biochemical process that leads to the disabling of apoptosis by the TB bacterium may provide a new target for drug therapies.

A drug already under investigation is showing promise. A new study (3) has shown that the Johnson & Johnson drug R207910 has effectiveness against latent bacteria. R207190 was able to kill dormant bacteria by greater than 95 percent whereas current drugs like isoniazid had no effect. Uniquely, the new drug, which targets the enzyme ATP synthase, appears to be more effective in killing dormant bacteria than those that are actively replicating.

We need to know more about the processes by which strains of M. tuberculosis become resistant to isoniazid. Some light may have been shed on this by a study (4) which concludes that ‘... isoniazid-resistant strains compensate for their reduced ability to detoxify oxidative stress effectively.’

Another interesting new study (5) focused on patients considered to have extrapulmonary TB (XPTB). Parimon et al found that some XPTB patients had positive sputum culture results, despite normal chest X-ray (CXR) findings and negative HIV status. Weight loss in XPTB patients was associated with positive sputum culture results. Sputum examinations in XPTB patients, regardless of the CXR results, may therefore identify potentially infectious cases of TB.

Looking ahead

A TB vaccine phase 1 trial (i.e. clinical safety trial on volunteers) has recently begun in Germany. Vakzine Projekt Management GmbH have used genetic engineering techniques to create their VPM1002 vaccine using the established BCG vaccine as a basis. Further details may be found on Science Daily.

Meanwhile SRI International, an independent non-profit research and development organization, has announced the initiation of a tuberculosis (TB) preclinical drug evaluation programme in partnership with the US National Institute of Allergy and Infectious Diseases.

TB in Russia

While the majority of the world’s TB cases are in developing countries, there are a growing number of cases, mainly in poorer communities, in parts of the developed world. The situation in Russia is of particular concern. A series of articles by journalist Merrill Goozner in Scientific American magazine makes fascinating reading. He also talks about his reports from Russia in Scientific American podcast.

Drug resistance is common in Russian TB cases. Nevertheless, an important study (6) in the city of Tomsk has shown that extensively drug-resistant TB can be cured with aggressive treatment. Six hundred and eight patients with multidrug-resistant TB received WHO-recommended treatment. They included 29 who had XDR-TB – i.e. TB resistant not only to standard first-line agents, but also to the most effective second-line drugs (aminoglycosides, capreomycin, fluoroquinolones). Treatment failure was significantly more common with XDR than with non-XDR-TB: 31% vs. 8.5%. Nevertheless, many patients in the XDR-TB group achieved a treatment cure or completion, though the rate was still lower than that of the non-XDR group: 48.3% vs. 66.7%. These findings are encouraging news for the treatment of resistant forms of tuberculosis elsewhere.

References

1. Boulle A, Van Cutsem G, Cohen K, Hilderbrand K, Mathee S, Abrahams M, Goemaere E, Coetzee D, Maartens G (2008). Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy. JAMA; 300(5):530-539. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18677025

2. Gan H, Lee J, Ren F, Chen M, Kornfeld H, Remold HG (2008). Mycobacterium tuberculosis blocks crosslinking of annexin-1 and apoptotic envelope formation on infected macrophages to maintain virulence. Nat Immunol; 9(10):1189-1197. http://www.ncbi.nlm.nih.gov/pubmed/18794848

3. Koul A, Vranckx L, Dendouga N, Balemans W, Van den Wyngaert I, Vergauwen K, Göhlmann HW, Willebrords R, Poncelet A, Guillemont J, Bald D, Andries K (2008). Diarylquinolines Are Bactericidal for Dormant Mycobacteria as a Result of Disturbed ATP Homeostasis. J Biol Chem; 12:283(37):25273-25280. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18625705

4. O’Sullivan DM, McHugh TD, Gillespie SH (2008). The effect of oxidative stress on the mutation rate of Mycobacterium tuberculosis with impaired catalase/peroxidase function. Antimicrob Chemother; 62(4):709-712. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18577539

5. Parimon T, Spitters CE, Muangman N, Euathrongchit J, Oren E, Narita M (2008). Unexpected pulmonary involvement in extrapulmonary tuberculosis patients. Chest; 134(3):589-594. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18641092

6. Keshavjee S, Gelmanova IY, Farmer PE, Mishustin SP, Strelis AK, Andreev YG, Pasechnikov AD, Atwood S, Mukherjee JS, Rich ML, Furin JJ, Nardell EA, Kim JY, Shin SS (2008). Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet; 2008 Aug 22. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18723218

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3 Oct 2008 by Paul Chinnock:

Also speaking on the TB situation in Russia has been a senior Russian security official, Mikhail Grishankov, during discussions at the World Bank office in Moscow. He said the disease poses a threat to Russia's security and labour force.

According to Grishankov, 'social infections' such as TB and HIV are a security threat because they often affect people during their prime working years, at a time when the country is experiencing a labour shortage.

For a full report see http://www.news-medical.net/?id=41649.