The good news is that tuberculosis prevention efforts appear to have broken the back of the spread of the disease, according to the World Health Organisation’s latest annual report on the scourge, with new cases of TB falling by 2.2% between 2010 and 2011. The mortality rate has decreased 41% since 1990 and access to TB care has expanded considerably since the mid nineties, when tuberculosis was declared a global emergency by the UN body, with the WHO estimating that some 20 million lives have been saved since 1995.
The bad news is that strains of TB that are resistant to the two most effective drugs, or what is known as multi-drug resistant tubercuolosis (MDR-TB), are posing a greater challenge than previously thought, with the WHO warning: “Drug-resistant TB threatens global TB control.”
When the drugs don’t work, patients require second-line drugs that are more toxic, with more serious side effects and that take many months longer to work. In the worst cases, of extensively drug-resistant TB (XDR-TB), TB bacteria are also no longer susceptible to any of the second-line anti-TB injectable drugs.
Globally, some 3.7% of new cases of TB and 20% of previously treated cases are multi-drug resistant, up from 2% in 2000. An estimated 9% of these cases are XDR, now reported in 84 countries.
India, China, Russia and South Africa represent almost 60% of MDR cases, with the highest proportion in eastern Europe and central Asia.
But even this is likely an underestimate due to incorrect diagnosis. In high-burden countries, the acknowledged MDR figure represents only one in five of the estimated MDR-TB cases — and in China and India, one in ten.
And it is in the sites of the greatest burden that the full scale of the threat is revealed. In 2000, the highest incidence of MDR was found in Estonia, at 14.1%, followed by Henan province in China (10.8%), Latvia (9%), the Ivanovo (9%) and Tomsk (6.5%) provinces in Russia, and Iran (5%).
The 2012 numbers show a frightening increase in these regions in the last dozen years. The proportion of new TB cases that are MDR were highest in Arkhangelsk province in Russia (35.1%), Belarus (32.3%), Estonia (22.9%), Kazakhstan (30.3%), Kyrgystan (26.4%), and Moldova (19.4%). In seven former Soviet republics, a fifth of new cases or more are mulit-drug resistant.
Of these MDR cases, the proportion of extensively drug-resistant TB was highest in Tajikistan (Dushanbe City and Rudaki district – 21%), Azerbaijan (Baku City – 12.7%), Belarus (11.9%), Estonia (18.7%), Latvia (12.6%), and Lithuania (16.5%). In 2000, XDR cases had yet to be discovered.
Grania Brigden, TB advisor for Médecins Sans Frontières described the galloping advance of multi-drug resistance in the WHO report an “escalating public health emergency”.
“Yet the global response is abysmal, with levels of testing and treatment remaining shockingly low,” she continued. “With barely one in twenty TB patients being tested for drug resistance, we’re just seeing the tip of the iceberg.”
In December last year, clinicians in Mumbai, India, first reported TB patients with what they termed “Total Drug Resistance”, or TDR-TB. Whether current evidence allows for the defining of resistance beyond that of XDR remains controversial. However, claims of TDR have since been made in Italy and Iran.
One of the biggest challenges the world faces in tackling the issue is that doctors are dealing with tools that could politely be described as ‘antiques’. There have been no new drugs in over 50 years. Both the Bill and Melinda Gates Foundation and a UK Parliamentary Office of Science and Technology briefing say that the reason for this is “there is limited market incentive for companies to develop them.” It is no accident that TB is regularly described as a ‘disease of poverty’.
Similarly the Bacillus Calmette–Guérin (BCG) vaccine, named for French discoverers bacteriologist Albert Calmette and veterinarian Camille Guerin, is more than 85 years old, and is losing its effectiveness.
But there are now ten drugs in clinical trials, with bedaquiline (Tibotec) and delamanid (Otsuka) the most advanced. The key is to develop medicines that do not take as long to work and with few side effects, increasing the chances of patients completing the full course of drugs, and in doing so, limiting the development of drug resistance.
In 2012, the US National Institutes of Health launched a collaborative effort called the TB International Genome Consortium. Anthony Fauci, with the NIH and the director of the National Institute of Allergy and Infectious Diseases (NIAID), told Nature: “We’ll use next generation sequencing to sequence a thousand strains of TB from around the world — Korea, Russia, Uganda — anywhere where drug resistant TB is heavily present. We’ll get a bunch of TB genomes, tie them to patient history, and use that to understand patterns of resistance.”
But most importantly, vaccine research has also made dramatic advances, going from zero TB vaccines in clinical trails at the turn of the millennium to a dozen today. And China, for example, has become one of the largest investors in TB vaccine research.
Helen McShane, a vaccine researcher at the University of Oxford, leads a team that has developed MVA85A, which boosts the effectiveness of BCG, the most clinically advanced TB vaccine currently on the table. Its first efficacy results from a trail in South Africa are expected in the first quarter of 2013. However, even if shown to be effective, the vaccine will not be widely deployed before 2018-2020, she says.
She applauds the development of new drugs and diagnostics, “but we must invest in vaccine research if our ultimate goal is to be able tor prevent the disease rather than forever chase growing drug resistance.”
“The key issue, no matter how many new compounds and individuals treated, is that we really need something bigger at the community level – a vaccine.”