Combining new drugs reduces TB

Papers four, five and six in The Lancet series on Tuberculosis look at effect of drugs, vaccines, biomarkers and diagnostics with estimates that the combined effect of all four could reduce TB incidence by 94% by 2050.

The forth paper

This paper looks at developments in diagnostics and biomarkers. There remains a desperate need for a more accurate, cheap point-of-care test applicable in TB and HIV endemic areas; and more investment is needed in biomarkers which could be predictors of whether someone is more likely be cured from TB by treatment or relapse, and their potential immunity conferred by a future vaccine.

The biomarkers aspects of the paper are covered by Professor Alimuddin Zumla, University College, London, and colleagues; while the diagnostics issues are covered by Dr Mark Perkins, Foundation for Innovative New Diagnostics, Geneva, Switzerland, and colleagues.

TB detection remains difficult

The authors say: “Tuberculosis case detection remains difficult, partly because of inaccurate diagnostic methods. Investments have yielded some progress in development of new diagnostics, although the existing pipeline is limited for tests for sputum-smear-negative cases, childhood tuberculosis, and accurate prediction of reactivation of latent tuberculosis.”

The biomarker nearest qualification is 2-month culture conversion as a predictor of relapse.

Mycobacteria helps indicates drug-resistant TB

This gives an indication how quickly the mycobacterium which causes TB is cleared from sputum by treatment. Mycobacteria not cleared from sputum after months of treatment may indicate drug-resistant TB, patient non-compliance with taking drugs, or that a longer period of treatment could be required. 

The authors say that several diagnostics and diagnostic strategies have been endorsed by the World Health Organisation (WHO) and are being introduced into clinical use and national TB programs.

In 2009, data was published on the first automated molecular test for tuberculosis, the Xpert MTB/RIF. This assay avoids many pitfalls of conventional nucleic acid amplification tests (safety, contamination, ease of use, etc), can be done by staff with little training, and can be used for case detection or MDR TB screening.

They add that clinical and field studies are needed to assess whether programmatic introduction of new diagnostics contributes to improved individual patient outcomes and a measurable beneficial public health effect.

Simple, inexpensive tests still unavailable

The authors conclude: “Despite new, sensitive, automated molecular platforms for detection of tuberculosis and drug resistance, a simple, inexpensive point-of-care test is still not available.”

“The effect of any new tests will depend on the method and extent of their introduction, the strength of the laboratories, and the degree to which access to appropriate therapy follows access to diagnosis.

“Translation of scientific progress in biomarkers and diagnostics into clinical and public health programs is possible—with political commitment, increased funding, and engagement of all stakeholders.”

The fifth page

This paper discusses new drugs in development, and says that ten compounds have progressed into the clinical development pipeline, including six new compounds specifically developed for tuberculosis. This paper is written by Dr Zhenkun Ma, Global Alliance for TB Drug Development, New York, USA, and colleagues.

The authors say: “Despite this progress, the global TB drug pipeline is insufficient to address the unmet needs for treatment. Additional and sustainable funding is needed to further improve the pipeline...

The main challenges in the development of new treatments are the needs for novel drug regimens, new trial designs, studies in paediatric populations, increased clinical trial capacity, clear regulatory guidelines, and biomarkers for prediction of the long-term outcome.”

Ensuring new drugs are used responsibly, with drug selection and patient adherence correctly managed, is also essential to prevent resistance to new regimens developing rapidly.

The funding shortfall to support TB drug research and development is 75%, according to a new report by Médecins Sans Frontières. 

Developing new drugs an unworthy investment

The authors say: “Development of new drugs for TB is lengthy, expensive, and risky, and the expected revenues are too small to justify commercial investment... New financing and market incentive mechanisms are needed to encourage pharmaceutical and biotechnology companies to invest in drug discovery and development, particularly in late-stage clinical trials."
They conclude: “To eliminate TB as a public health concern by 2050, all responsible parties need to work together to strengthen the global anti-tuberculosis drug pipeline and support the development of new anti-tuberculosis drug regimens.”

The sixth paper

This paper looks at TB vaccine development and is written by Prof Stefan H E Kaufmann, Max Planck Institute for Infection Biology, Berlin, Germany, and colleagues. 

They say: “New vaccines are urgently needed if we want to reach the goal of substantially reducing the incidence of TB by 2050. Despite a steady increase in funding over the past decade, there is still a striking financial shortfall for vaccine research and development for TB...”

“The present BCG vaccination regimen protects newborn babies (not adults) against severe TB... Protection induced by BCG vaccination against adolescent and adult TB, the most prevalent form of the disease, is insufficient.”

11 vaccine clinical trials

Despite this shortfall, 11 vaccine candidates have entered clinical trials: most are pre-exposure vaccines and will most likely prevent TB disease. They are intended to either replace BCG or to be given after BCG as boosters (either protein adjuvant formulations or recombinant viral carriers).

The authors add that post-exposure vaccines are also required and, ultimately, vaccines are needed that either prevent infection or achieve sterile eradication. They say vaccine trial sites with appropriate infrastructure are urgently needed.

The authors conclude: “The most recent prediction calculates a reduction in TB incidence of 39–52% by 2050 as a result of new pre-exposure vaccines; a reduction in incidence of 10–27% from new drugs that shorten duration of treatment and are effective against drug-resistant strains; and an additional reduction of 13–42% from new measures allowing reliable and fast diagnosis of TB.”

“Combined, these three new measures could reduce TB incidence by up to 71%. Incidence could be further reduced by up to 94% by mass vaccination campaigns, new post-exposure vaccines, and drugs for latent infection.” (The Lancet, September 2010)

Information provided by

Professor Alimuddin Zumla, University College, London. T) +44-207-6799311 E)

Dr Mark Perkins, Foundation for Innovative New Diagnostics, Geneva, Switzerland. T) +41 22-7100590 E)

For Dr Zhenkun Ma, Global Alliance for TB Drug Development, New York, USA, please contact Joanna Breitstein T) +1 646 616-8633 / +1 917-361-0683 E) /  

Prof Stefan H E Kaufmann, Max Planck Institute for Infection Biology, Berlin, Germany. T) +49-30-28460-500 extension 502 / +49-170-56 272 47 (but e-mail preferred) E) kaufmann@mpiib-berlin.mpg

For Series paper 4 see:

For Series paper 5 see:

For Series paper 6 see:

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