Even as tuberculosis attacks with great ferocity than ever before, there is hope as a range of new drugs, diagnostic tools and vaccines infuses zeal into the war against this highly infectious disease
Looking every bit the radiant new bride, Delhi-based public relations manager Leena Sharma, 25, embraces life with gusto-cooking for her husband, shopping for clothes, eating out. She knows well how every moment counts. Two years ago, she was one of millions of victims of a terrible war being fought in India.
It is a tale of a ferocious battle of wits between man and nature. It is also a tale of tragic apathy. The enemy is no stranger. The tuberculosis bacteria, Mycobacterium tuberculosis, reside within every third person worldwide. The arsenal against it was hundred years old. It was like defending Kargil with 19th century Enfield rifles.
Now, finally, an exciting wave of new research-from "Trojan Horse" drugs that fool the enemy to electronic "noses" that sniff it out-is about to propel the war to a more equal footing.
"For the first time in 40 years, we have a range of TB drugs in the pipeline," says Maria Freire, CEO, Global Alliance for TB Drug Development. Eight of them are undergoing clinical trials. Results from Chennai's Tuberculosis Research Centre (TRC) promise to improve treatment methods. At least four new vaccines, using cutting-edge technology, are on the anvil. Boosted by the completed sequence of the M. tuberculosis genome two years ago, Indian scientists are developing sensitive DNA-based diagnostic tools.
It is a race against time. Someone in the world dies of TB every four seconds. A third of those afflicted are Indian. Most victims are aged 18-40. TB's burden on the Indian exchequer is more than $3.3 billion (Rs 14,850 crore) every year.
This ancient conflict should have been history by now. Robert Koch identified the culprit bacteria as early as 1882, providing a tangible target for drugs. In 1921, the first-and so far the only-vaccine against the disease, Bacille Calmette-Gurin or BCG, was developed. With a spurt in discovery of antibiotics, from Streptomycin in 1944 to Rifampicin in 1963, M. tuberculosis was deemed doomed.
The bacteria proved wilier. They lay low for several decades, mutated to become resistant to all drugs, and then struck with great ferocity in the 1990s. As new strains emerged, TB figures rose again in the developed world, by 5-8 per cent annually. Cases of non-pulmonary TB, where the bacteria traverse the body to attack the lymph nodes, gastric tracts, genital tracts and even the brain, increased alongside.
In 1993 an alarmed World Health Organisation (WHO) declared TB a global emergency. What drew its attention was TB's increasingly apparent association with another terrible disease-HIV infection leads to active tuberculosis, and conversely, tuberculosis patients are more likely to develop aids.
With no signs of ebbing by 2000 investment in TB research grew. Soon, the Global Alliance for aids, Malaria and TB pledged over $2 billion. Recently, the Bill and Melinda Gates Foundation has set aside $89 million for TB vaccine research. Drug MNC AstraZeneca set up a $10 million TB research centre in Bangalore in 2003. The challenge was literally huge.
First, the detection method-of sputum samples by microscopy-was 120 years old and only 50 per cent accurate. The symptoms, persistent cough and fever, are common. X-ray interpretations are subjective. Also, there is no real protection against the bacteria. Indian studies show that the only available TB vaccine, the 83-year-old BCG vaccine, offers some protection from childhood TB, but is ineffective against its adult form. Airborne and highly infectious, TB cannot be reined in without an effective vaccine.
The third front is treatment. TB is curable. But it is tricky as it outwits any single drug. Multi-drug resistant TB is gathering ground too. The only way out is taking a cocktail of five strong antibiotics without fail for six months. Left to themselves, few patients comply beyond the two or three weeks' time it takes them to begin feeling better.
Studies have shown that if treatment stops after two months, there is a 70 per cent chance of relapse; at four months, the relapse risk is 40 per cent. It also increases multi-drug resistance. "It is a double whammy, if you stop midway," warns Pune-based doctor Bobby John.
To vanquish the bacteria, fast working, effective drugs are essential. It is not easy because the bacteria grow slowly, can hide in a human cell and lie latent for years. In fact, only one in 10 infected people develop active tuberculosis. These latent bugs evade the drugs and cause relapse. "It is an extremely 'intelligent' bacteria," says Seyed Hasnain, director, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad. Research at the CDFD has shown that the bacteria actually send "decoy" molecules at regular intervals to check the strength of the human immune system. Only when the decoy reports a weakness do the bacteria attack. In clinical trials, scientists at TRC have found that antibiotic Ofloxacin can shorten the treatment to four months. They are also initiating newer studies employing a combination of two antibiotics, Gatifloxacin and Moxifloxacin. Another new drug developed by the TB Alliance, PA-824, is to be tested. Indian companies like Lupin and Ranbaxy have tested new chemicals against TB.
Several novel vaccines are on the horizon. In 2003 Lucknow's Central Drug Research Institute developed a TB vaccine based on a related, harmless mycobacterium. It is undergoing clinical trials. Delhi University biochemist Anil Tyagi has genetically modified the old BCG strains with new TB-specific genes as enriched new vaccines. Pre-clinical results from his experiments conducted at TRC show promise. Tyagi has identified an important drug target by showing that a deletion of a particular gene brought down tuberculosis infection by 70 fold in guinea pigs. "In the tussle between bug and host, the bug wins by stripping certain host proteins. My vaccine introduces a gene which helps the host fight back," he says. In Bangalore, S. Vijaya and her team at the Indian Institute of Sciences (IISC) are developing DNA vaccines based on two genes found in the TB bacteria. US biotech firm Aeras, which has developed two vaccines, is in talks with Indian biotechnology companies for further tuberculosis research.
Diagnostic developments are slower. "A diagnostic kit for SARS took four months," says Rowan Gillies, president of the Nobel Prize-winning organisation Medicins Sans Frontieres. "We still don't have one for TB." PCR tests, using amplification of specific TB DNA sequences, are common, but highly expensive.
The WHO-backed Foundation for Innovative New Diagnostics (find) is working on a number of cheap, innovative solutions, from colour-based assays-where TB containing cultures will light up bright green-to African rats that, like sniffer dogs, can sniff out TB patients. A patented solution by AIIMS biotechnologist Jaya Tyagi helps spot the bacteria more clearly. She has also patented a specific PCR technique to detect the infection, and is working on a drug target for latent TB. Are these efforts enough? Not as long as pharma MNCs do not consider TB profitable for any serious commitment. "Drug companies have to be committed for the war against TB to succeed. And this commitment has to be driven by shareholders," says N. Balganesh, head of research and development, AstraZeneca.
India, meanwhile, has pragmatically fought with the only tool at hand-the Directly Observed Short Course (DOTs) programme, involving a six-month drug pack and a health worker to record the patient taking every dose. With an 86 per cent cure rate, India is well ahead of China and beating WHO targets. "The lessons learnt from India are powerful for other nations," says World Bank Vice-President Praful Patel. But TB kills almost five lakh Indians every year. The ancient battle still continues.