Tuberculosis: An infectious killer

Mycobacterium tuberculosis is one tenacious and crafty bacteria.

It has been hanging around inside humans and causing the disease now known as tuberculosis (TB), along with all its associated complications, for thousands of years.

Archaeologists have even found evidence of spinal TB in ancient Egyptian mummies.

With 23,000 new cases in 2011 and 1,700 deaths, this infectious disease is still a fairly common problem in Malaysia.

The large majority of Malaysians will remember receiving their compulsory BCG vaccinations at the age of 12, although probably not the one they got at birth, between the years of 1961 and 2001.

From 2001 onwards, the vaccination was only given at birth, as research had found no evidence to indicate that the booster shot provided extra coverage against the disease.

The Bacille Calmette-Guérin (BCG) vaccine - currently the only vaccine available for use against TB - consists of a weakened live strain of Mycobacterium bovis, a close sibling of M. tuberculosis more commonly found in cattle.

This weakened bacterium is sufficient to stimulate the body's immune system to produce its own antibodies to protect against further invasions of similar Mycobacterium species, including M. tuberculosis, while being too weak to cause actual disease.

While the BCG vaccine is the most widely administered vaccine in the world, reaching over 80 per cent of babies and children in countries that have a national immunisation programme, its effectiveness varies according to geographical regions.

On the other hand, TB is also a treatable and curable disease, albeit through an intensive and strict drug regimen that lasts at least six months for those without the multi-drug and extremely resistant versions of the disease. Those who have drug-resistant forms of TB have a more complicated regime, which takes at least 18 months to complete.

In fact, the World Health Organisation (WHO) reports that the death rate from TB has dropped by 41 per cent since 1990, and that the estimated number of people falling ill with this airborne disease each year is declining - although very slowly - which means that the world is on track to achieve the Millennium Development Goal of reversing the spread of TB by 2015.

As such, is it possible that we will be able to eradicate this disease from humankind within our lifetimes?

That is certainly the hope - and the challenge - of the two-year World TB Day campaign, Stop TB in My Lifetime, which marks its second year today.

Current danger

According to the WHO, TB is the number two killer of humans due to a single infectious agent.

It is second only to HIV/AIDS, and is, in fact, the leading cause of death for HIV/AIDS patients themselves, resulting in about one quarter of deaths.

There were 8.7 million new cases of TB reported in 2011, while 1.4 million died from the disease in the same year, according to the WHO Global Tuberculosis Report 2012.

More worrying is the fact that multi-drug resistant TB (MDR-TB) is present in virtually all of the countries in the WHO survey.

Médecins Sans Frontières' (MSF, also known as Doctors Without Borders) Access Campaign executive director Dr Manica Balasegaram opines that drug-resistant TB in particular, represents an uncovered, and likely, growing epidemic.

According to the Report, around 3.7 per cent of new TB cases and one-fifth of previously treated cases have MDR-TB, and almost 60 per cent of these cases occur in China, India and the Russian Federation alone.

However, the WHO estimates that currently, only one of every five MDR-TB cases is being diagnosed, leaving the other 80 per cent undiagnosed, under-treated or untreated at all, and free to spread their more dangerous version of TB around.

Says Dr Manica: "Access to diagnosis may be even worse for low-income countries and certain high-burden countries like India and China.

"We are only seeing the tip of the iceberg in terms of the true burden of MDR-TB."

Aeras (a non-profit product development organisation dedicated to the development of effective tuberculosis vaccine regimens that will prevent TB infection in all age groups and will be affordable, available and adopted worldwide) vice-president and acting chief medical officer Dr Ann Ginsberg agrees, saying: "Tuberculosis largely affects people living in poverty, but because the disease is airborne, anyone can be infected.

"Recent trends show an increase in multi-drug resistant tuberculosis, which is much more difficult and costly to treat."

The cost to treat MDR-TB cases can be 200 times more expensive than the normal drug-susceptible strains, she says, with the treatment time at least two to three times longer, and the side effects, more severe.

But it is the regular TB treatment that is itself also contributing to the growth of drug-resistant TB, says Global Alliance for TB Drug Development (TB Alliance) president and chief executive officer Dr Mel Spigelman.

"First, the current options to treat the disease are inadequate, and difficult to administer properly and adhere to, which leads to incomplete treatment, and is fuelling the growth of even more deadly and difficult-to-treat drug-resistant forms of TB," he says.

"The second aspect of the disease I'd stress is that it is a truly global disease.

"It is spread through the air, and therefore, it knows no bounds - TB does not respect national borders. TB exists all throughout the world, and is an even greater threat wherever poverty exists."

According to the WHO, over 95 per cent of TB deaths occur in low- and middle-income countries, and it is among the top three causes of death for women aged 15 to 44.

Says Dr Ginsberg: "TB mostly strikes people during their most productive years, so it has a major impact on families, communities and economies.

"When a parent has TB, they are often unable to work, trapping them and their family in a cycle of poverty."

Treatment problems

A standard TB treatment regimen, as recommended by the WHO, consists of four drugs - isoniazid, rifampicin, pyrazinamide, and ethambutol or streptomycin - taken daily and/or three times a week for six months.

This regime, according to Dr Spigelman, whose non-profit organisation focuses on discovering and developing better, faster-acting and affordable TB drugs, is far from ideal.

"The standard TB treatment is too long and complicated, creating undue burdens on patients and treatment providers alike.

"This leads to patients receiving incomplete treatment, which not only doesn't achieve cure, but leads to the development of drug-resistant forms of TB," he says.

The treatment of MDR-TB is even more complex, requiring the use of at least four drugs that the doctor determines based on the patient's condition, and usually lasts 18-24 months.

According to Dr Manica, whose international non-profit medical humanitarian aid organisation treated 26,600 TB patients in 39 countries in 2011 - 1,300 of whom had drug-resistant TB, such regimes can involve taking up to 20 pills a day and enduring eight months of daily painful injections.

The drugs used, which include injectable capreomycin, cycloserine, ethionamide, moxifloxacin, pyrazinamide and para-aminosalicylic acid, also often cause severe side effects like constant nausea, psychosis, depression and permanent deafness.

Even worse, he says: "Cure rates using these drugs in current regimens are dismal; in MSF programmes, the treatment success rate is only 53 per cent for MDR-TB - or little better than one in two, and a dire 13 per cent for cases of extensively drug-resistant TB (XDR-TB).

"Globally, the average is even worse, with only 48 per cent of MDR-TB patients being successfully cured. This is clearly unacceptable, and must be significantly improved."

There are also other factors that affect a patient's access and adherence to TB treatment regimes.

Aside from the harsh side effects that make it hard for patients to stay on their medication, drug resistance testing, which is particularly crucial in cases of MDR-TB, is often incomplete or not done quickly enough, leading to critical delays in starting appropriate therapy.

Dr Manica adds that quality and cost of drugs also play major roles in this matter.

"Because TB is a disease of the poor, there are relatively few drug manufacturers that produce quality-assured supplies of some of these medicines, because there is no market and no money to be made.

"In some countries, a lack of supply and stock-outs of some medicines are not unknown.

"Because the market is small and there is often a lack of competition, some of the medicines are therefore very expensive; a course to treat MDR-TB can cost as much as US$6,000 (RM18,651)."

Dr Ginsberg also shares a study published last month in the International Journal of Tuberculosis and Lung Disease, which reported that fake and poorly made pills, which do not contain enough of the active ingredient to kill M. tuberculosis, were widely available in 17 countries where TB is prevalent.

And while many national TB control programmes provide treatment for free, she says: "In many areas, people must travel significant distances to get to treatment centres.

"This time commitment can prevent them from working, meaning many people must choose between seeking treatment, or maintaining their normal routines and jobs to ensure an income to provide food for their family."

What's needed

It is not surprising then that all three doctors agree that the present most crucial need is better and faster ways of treatment and diagnosis.

Says Dr Manica: "The need for shorter and more effective treatment for TB, especially drug-resistant forms, is critical. Patients are forced to endure long, and often, harsh treatment regimens.

"An ideal regimen should be all-oral, shorter - potentially only six months - and be much better tolerated by patients.

"New regimens also need to be more effective than what we currently have; today's cure rates of only 50 per cent are unacceptably low.

"Such a simplified and safer regimen will also allow treatment to be decentralised, and make it easier for more patients to start and stay on their medications."

Dr Spigelman agrees, saying: "The standard TB treatment is too long and complicated, creating undue burden on patients and treatment providers alike.

"This leads to patients receiving incomplete treatment, which not only doesn't achieve cure but leads to the development of drug-resistant forms of TB.

"The MDR-TB pandemic is a man-made problem resulting from inadequate TB treatments, and can only be reversed with the development of new TB treatments that can cure drug-resistant TB, and improve the treatment of TB to prevent the development of new drug resistance."

Meanwhile, as a non-profit product development organisation dedicated to developing new TB vaccines, Aeras believes that a new TB vaccine is the key to defeating the disease.

"To defeat tuberculosis, we need to develop and deliver new tools, including new vaccines.

"A vaccine that effectively prevents tuberculosis disease in adults and adolescents would have the greatest global health impact on the TB burden," says Dr Ginsberg.

Going forward

She shares that after 90-odd years of complacently relying on the BCG vaccination, researchers finally kicked into high gear over the last 10 years, trying to develop new vaccines.

"In the past decade, researchers have advanced over a dozen novel candidates into clinical testing.

"There are also approximately 25 novel vaccine constructs in early stage research or preclinical development," she says.

The most advanced candidate, MVA85A, was recently reported to have rather disappointing results in last month's issue of The Lancet.

The results of the phase IIB clinical trial, which tested the vaccine's ability to boost the protection given by the BCG vaccine in about 2,800 South African infants, showed that while the vaccine was well-tolerated and showed no signs of harm to the participants, it was not effective in providing extra protection against TB infection.

The drug front shows more promise, however, with entirely new classes of drugs that work in different ways from existing medications being developed.

December saw the accelerated approval of bedaquiline by the US Food and Drug Administration for treatment of adult pulmonary MDR-TB in combination with other drugs - the first new anti-TB drug to receive approval in 50 years, and the first and only one specifically indicated for MDR-TB.

The third and final phase of clinical trials for bedaquiline is expected to start this year.

Another drug, delamanid, is currently awaiting approval from the European Medicines Agency.

An eight-country phase III clinical trial to study this drug is currently recruiting participants.

Says Dr Manica: "As these new drugs represent entirely new classes of TB medication, the likelihood of resistance is very low, and these drugs have been shown to be more effective than existing drugs, in particular against MDR-TB.

"In trials, use of these drugs has shown more rapid and better eradication of Mycobacterium tuberculosis, while also appearing to be better tolerated than many of the agents currently used."

Meanwhile, Dr Spigelman is excited about other new treatment regimens in development, especially the combination of another new drug, PA-824, with pyrazinamide and moxifloxacin, to treat both drug-susceptible and drug-resistant TB.

PA-824 is currently being studied in various phase I and II clinical trials for safety and efficacy when used in combination with several other drugs.

As exciting as these developments are however, they are hollow if they do not reach those who need them.

As Dr Manica says: "Innovation without access is meaningless to our patients. Manufacturers, countries and donors must work aggressively to ensure these drugs reach the patients most in need of them."

A crucial point indeed when the WHO reports that there is a US$3bil (RM9.3bil) funding gap for TB care and control in low- and middle-income countries, and that research and development funding in recent years has only achieved about 32 per cent of its target.