Tuberculosis (TB) is a leading cause of death globally. Progress in the control of TB is threatened by drug-resistant TB strains. This note examines the extent of, and risks posed by, drug-resistant TB. It also gives an overview of national and international TB surveillance, research into treatments and policy options to limit infections.
TB is an infectious disease caused by the bacterium Mycobacterium tuberculosis and transmitted via aerosol droplets. The bacteria usually attack the lungs but can affect any part of the body. According to statistics, one third of the world’s population carries the bacterium but does not have the disease (latent TB). Only a small proportion of these people will develop the disease and become infectious. In 2010, some 8.8 million people contracted TB causing 1.45 million deaths, including those among HIV-infected persons. Progress has been made in tackling the epidemic. Globally, the number of new/relapsing cases has fallen each year since 2006 and TB death rates have dropped by more than a third since 1990.
Medical risk factors include co-infection with HIV. People with HIV are 21 to 34 times more likely to develop TB, and accounted for about 13% of all TB cases globally in 2010. Development of the disease is also linked to certain social risk factors, notably drug or alcohol abuse, poor housing conditions, homelessness and imprisonment.
C. Drug resistant (DR) TB
Drug resistant strains have developed through inappropriate use of anti-TB drugs and poor management of the disease including infection control. Once DR-TB strains develop, they can be transmitted to others. There are several types of DR-TB:
• Drug-resistant (DR) TB is resistant to any first line drug;
• Multidrug-resistant (MDR) TB is resistant to the two most effective first line drugs, rifampicin and isoniazid;
• Extensively drug-resistant (XDR) TB is MDR-TB which is also resistant to drugs called fluoroquinolones as well as to at least one of second-line injectable drugs.
In recent years, XDR-TB patients infected with strains resistant to many other anti-TB drugs have been reported.
Global trends in TB
Most TB cases today occur in Asia and Africa, 59% and 26% respectively. The countries with the highest TB burdens are India, China, South Africa, Indonesia and Pakistan. In 2010, India had about 2.3 million TB cases, the highest figures of the world, that is a rate of 185 per 100,000 population, compared with 13.6 per 100,000 in the UK and accounted for 26% of all cases globally.
Table 1. Incidence of TB cases in 2010
Estimated Global, 2010 Notified UK, 2010
TB incidence – the number of new and relapse cases 8.8 million 8,963
TB prevalence – the absolute number of TB cases 12 million Not reported
MDR-TB cases 650,000 (prevalent cases) 81
MDR-TB is estimated to cause about 10% of all TB deaths. 40% of all MDR-TB cases in the world in 2010 are thought to be in China and India. There were 53,108 MDR-TB cases reported worldwide in 2010, of which 32,616 were reported in Europe, most in Eastern Europe. Although more people are being treated for MDR-TB, it is thought that only 16% of MDR-TB patients worldwide that need treatment are receiving it.
Due to a lack of good quality surveillance data and non-standardised surveillance methods, figures on the global burden of TB are estimated (e.g. Table 1). The most recent TB report by WHO highlighted that by 2010 no high-burden MDR-TB country undertook good quality continuous surveillance for drug-resistance.
TB trends in the UK
Data on TB incidence in the UK for 2011 shows an increase of 6.6% from the previous year. Overall, for the past twenty five years there has been a rise in TB incidence but rates appear to have been stabilising since 2005. This increase can be attributed to an increase of TB in non-UK born individuals, and ongoing TB transmission in people born in the UK, in particular those in hard to reach groups, such s the homeless and drug users. TB rates in London increased 8% in 2011, and it has the highest TB rates of any capital city in Western Europe.
The total number of cases with DR-TB in the UK has increased by over 50% in the last 10 years. The majority of patients in the UK with DR-TB were born in regions of the world where DR-TB is common, such as the Indian subcontinent or Eastern Europe. The other main risk factors for acquiring DR-TB are a previous diagnosis of TB, and homelessness or drug use.
D. TB Care and Control
WHO works towards reducing the global TB burden, helping national governments build on their progress. The Health Protection Agency and the Department of Health take the lead in the UK on TB care and control.
Rapid diagnosis and treatment completion are key to controlling TB transmission and improving patient outcomes. For TB diagnosis, the simplest and most common method is analysing sputum samples using a microscope. It is often the only test available in countries most affected by TB. It detects the most infectious cases, but is not a sensitive test and cannot discriminate between drug-susceptible TB (DS-TB) and DR-TB. Newer diagnostics are costly and unaffordable for many developing countries, so detection rates are low in countries where most TB cases occur.
The main method of drug-resistant TB detection is by growing TB bacteria in the presence of the drug. This is costly, time consuming and requires bio-secure laboratories. Diagnosis of DR-TB is thus unavailable in many countries. Africa and Asia as well as parts of Eastern Europe are unable to provide good-quality diagnostics for DR-TB due to a lack of laboratory capacity. Since 1994, 114 countries have reported surveillance data on MDR-TB. But only 42 of these perform continuous surveillance based on testing of all TB patients. The others rely on periodic surveys of samples of patients.
Take MDR-TB as a example. In the 27 countries which account for over 85% of MDR-TB cases in the world, only 1.5% of new TB cases and 5.5% of previously treated cases are laboratory-screened for MDR-TB. Failure to detect resistance may result in inappropriate treatment, premature death and increased rates of resistance and transmission.
Undiagnosed cases or delayed treatment account for most TB-related deaths. Inadequate access to newer diagnostic technologies and inaccuracy of sputum microscopy means patients may have to make multiple visits to health providers, with diagnosis often taking months. Many people cannot afford to take time off work, meet the costs of travel to the health centre or pay for treatment. Patients may also fail to seek medical help because of a lack of awareness, limited access to health services, or geographical and economic disadvantages. They may also fear the stigma and social exclusion often associated with a diagnosis.
Front line treatments
TB bacteria are very hard to kill. The standard WHO regimen is a combination of four (front-line) drugs taken for six months. The drugs used are isoniazid and rifampicin supplemented by two further drugs (pyrazinamide and ethambutol) for the first two months. DR-TB can develop if:
• Patients do not complete the full course of treatment;
• The correct therapies are not prescribed/available;
• The drugs are of sub-substandard quality.
TB treatment is lengthy and complicated. Many patients forget to take drugs in time or fail to complete courses once their symptoms improve. Clinical management techniques, such as Directly Observed Treatment and patient support can improve treatment completion. Non-adherence results in the rise of resistant strains, poor health outcomes and increased transmission. Average public sector health care costs of treating a case of TB vary worldwide, but in the UK it costs around £5,000 per patient.
Second line treatments
AA range of second line drugs can be used to supplement the front line regimen where DR-TB is encountered. MDR-TB treatment typically lasts about 20 months. The second-line drugs used often have severe side effects making it more difficult for patients to adhere to treatment. In the UK, the overall costs for treating DR-TB are £50,000 -£70,000 per patient.
Second-line TB drugs are expensive to manufacture, are produced in low quantities and often have short shelf-lives. Funding agencies such as UNITAID are working to improve affordability, access to and control of these drugs. A further concern is that such drugs are often used where they are not required, for instance to treat DS-TB. This is a particular problem in India where many anti-TB drugs are available over the counter without prescription.
E. UK TB Issues
Detection and Treatment Targets
WHO has two global targets for TB control and care:
• Detection rates of 70% - the UK meets this target. Early diagnosis is important as late detection leads to poor health outcomes and increased onward transmission. Late detection may be caused by low levels of TB awareness among the public and primary healthcare professionals.
• Treatment completion rates of 85% - the UK is not meeting this target although rates have improved from 78.4% in 2001 to 83.8% in 2010. Treatment completion at 24 months for MDR-TB cases notified in 2009 was 80%. Failure to complete treatment stimulates resistance and if no improvement is seen DR-TB is likely to rise.
Active Case Finding
Experts agree health services should focus more effort on actively seeking out cases, such as testing people the patient has come into contact with, screening high risk groups and systematically reviewing the outcomes of all cases in an area. It requires multidisciplinary teams capable of delivering all elements of TB services from diagnosis to cure. Find and Treat is an example of one such UK NHS service which screens homeless people and drug users. It is estimated that TB incidence among the homeless in London is 50 times higher than the national average. The homeless are also very likely to present late for treatment and much less likely to complete treatment, creating the perfect conditions for development and transmission of DR-TB.
Other steps in the fight against TB in the UK include identification and treatment of latent infection, and increased awareness-raising activities.
TB and Immigration
The rise in UK TB rates is largely due to TB in non-UK born individuals. Chest x-ray screening for active TB at Gatwick and Heathrow airports is to be discontinued as it is expensive and ineffective. The UK Border Agency is now rolling out pre-entry screening. Migrants, with an intention to stay more than 6 months, from 82 countries with high incidence of TB will be required to be tested for active TB in their own country before being granted a visa. This will not detect latent TB, even though evidence suggests that most cases of TB among non-UK born people develop from latent TB. Some experts have thus argued that the new pre-entry screening system will only be fully effective if combined with screening for latent TB in high-risk new arrivals.
F. Global TB Issues
Funding to fight TB
Total funding to diagnose and treat TB globally is expected to be $4.4bn in 2012. Of this, $0.6bn is expected to come from donors and the remainder from national governments. In comparison, donor funds for malaria and HIV are much higher, $1.8bn and $6.9bn respectively. The Global Fund to Fight AIDS, Tuberculosis and Malaria is a public-private partnership that funds treatment of these diseases. It accounts for 12% of all TB funding worldwide and 82% of all international funding.
An estimated 1 million cases of MDR-TB will need treating in the world between 2011 and 2015 at a cost of $7.1bn. Current funding levels are much too low to cover this. According to the WHO, if middle income countries were to fully finance their own MDR-TB treatments, donor financing could be re-directed and would almost fund the scale up of DR-TB services needed in low-income countries. As well as financing for TB control, an estimated @2bn is needed each year to advance the development of new drugs, diagnostics and vaccines for TB and conduct other essential research to improve treatment and care. However, financing slowed in 2010, reaching only one-third of the estimated target.
Drug research and development
A lack of market incentive for companies has resulted in no new TB drugs developed in over 50 years. However, donors, governments and not-for-profit organisations are investing in research and development of new TB technologies. New drugs, to which there is little pre-existing resistance, could potentially treat both DS and DR-TB more quickly, cheaply and effectively and prove vital to global TB control efforts. There are 10 TB drugs in clinical trials worldwide. The most advanced of these are bedaquiline (Tibotec) and delamanid (Otsuka). Bedaquiline has been approved for use under compassionate-use criteria for DR-TB patients for whom there are limited treatment options. Use of new drugs requires careful control to avoid inappropriate prescribing that could result in early emergence of resistance.
Bacille Calmette-Guerin (BCG) is the current vaccine in use that protects against severe forms of TB in children. But it is inconsistent in protecting against the predominant form of TB that affects adolescents or adults. UK data from 2011 showed that 71% of all TB patients were vaccinated. Developing an effective new vaccine is vital to TB and DR-TB control. Ten vaccine candidates are in Phase I or II clinical trials. It is hoped that one or two of those currently in Phase II will enter a Phase III trial in the next 2-3 years, with the possibility of licensing at least one new vaccine by 2018.
The development of cheap, accurate and rapid Point of Care (POC) TB tests is key to early diagnosis. POC tests under development could have a big impact on global detection but this will depend on the accuracy, cost and complexity of the test. Technologies that are not affordable outside of well-funded aid programmes or require laboratory support are unlikely to reach the mass of undiagnosed TB in high-burden African and Asian countries.
• In 2010 1.45 million people died from tuberculosis (TB) globally, even though the disease is curable with drug treatment;
• Drug resistant strains are now estimated to account for about 10% of all TB deaths;
• Drug resistance is a man-made problem, resulting from misuse of anti-TB drugs and poor management of the disease;
• Treatment for drug-resistant TB is more expensive, toxic and takes much longer than treatments for drug-susceptible TB;
• Early and rapid diagnosis and treatment completion are essential for controlling TB;
• In the UK, TB is a particular problem among people born abroad and hard to reach groups such as the homeless;
• Funding is required to develop better diagnostics, vaccines and anti-TB drugs.