India's silent killer

Tuberculosis drugs have been available for free in government hospitals across India for over two decades. The country’s main TB policy, the Revised National Tuberculosis Control Programme (RNTCP), has already achieved 100% coverage and a treatment success rate of 86% - impressive for a developing country with a population of more than 1bn people.

Despite that, India faces formidable challenges in controlling the epidemic due to the emergence of Multi-Drug Resistant (MDR) and Extensively Drug Resistant (XDR) Tuberculosis and the dual epidemic of HIV and TB. These three factors have now made the government look again the national policy.

India’s real fight against TB began in 1993, when the central government initiated the Revised National Tuberculosis Control Programme – which introduced the strategy of ‘directly observed treatment, short course’ (DOTS), to provide free medical assistance to TB patients. Now, due to surge in MDR and XDR TB cases, the department of health research has recommended a new approach called the DOTS Plus programme, with added components for MDR-TB diagnosis, management and treatment. Patients are treated not just in hospitals but also at home. The treatment, however, is currently available only in nine out of 28 states.

Under the government programme, first line drugs for TB are available for free in all government hospitals across India. The country is one of the few that uses an intermittent regimen – drugs every other day – rather than giving daily doses as in developed countries. This is mainly done to reduce drug toxicity and costs per patient. For the government, the cost of treating one patient is Rs6000/month ($120).

India shoulders approximately 2.5m HIV positive cases, more than 1.8m of which are estimated to be co-infected with TB. Roughly 60-70% of HIV positive persons eventually develop TB, while autopsy studies show that more than half of AIDS-related deaths in India are due to TB.

According to the latest World Health Organization (WHO) data in March 2009, India has more than 3.4m tuberculosis patients – about a fifth of global total – making it the most TB prevalent country. Nearly 1.9m new cases are reported every year, while 2.8% of all new cases are diagnosed as MDR-TB. An estimated 30% of cases go undetected every year.

The urban-rural divide
Besides the sociological conditions of poverty, factors like overcrowding, inadequate ventilation and malnutrition ensure that the TB infection spreads more readily in a crowded country like India, says Bir Singh, professor of community medicine at India’s premier research centre, All India Institute of Medical Sciences in Delhi. ‘Considering the standard of living in the developing world, our biggest challenge is to ensure that the patients turn up for treatment. Most patients living below the poverty line are mainly migrant labourers. This makes it difficult for these patients living below the poverty line to be regular at one DOTS centre. Such patients typically discontinue treatment once they start recovering. The surge of MDR and XDR strains of TB is a direct outcome of discontinuing treatment midway.’

The latest surveillance and epidemiological study – conducted in 2002 by the Indian Council of Medical Research (ICMR) in Uttar Pradesh, India’s most populous state – established this further. The study revealed that 71% of patients diagnosed with TB were from rural areas or were living in urban slums. Only 29% of the patients belonged to middle or highincome groups, and the success rate of treatment for these was far higher by comparison.

Further, widespread availability and sale of anti-TB drugs in the open market is also seriously damaging the success rate of the TB control programme, says J. N. Banavalikar, medical superintendent of Rajan Babu TB Hospital, Delhi’s largest TB hospital. ‘Instead of giving prescription drugs, anti-TB drugs are being sold as antibiotics, over-the-counter and for common ailments. A significant proportion of anti-TB drugs are being prescribed and used without adherence to the government’s DOTS programme. The availability of these drugs is a cause of concern in the context of emerging MDR and XDR TB.’ The failure to contain these drug-resistant strains is a serious setback, he added.

Given the challenges facing India’s battle against TB, researchers are pinning their hopes on a better drug treatment regimen that could help in controlling drug resistant forms of TB rather than developing a new drug or vaccine. ‘While many new drug candidates are in the pipeline worldwide, any new drug or vaccine is a long way away. As incidence of drug resistant TB increases, time is of the essence for endemic countries. It is more practical and important that we find ways to control TB using existing tools with new approaches,’ says Nani Nair, WHO South East Asia, India.

While internationally, there is excitement about the possibility of a new vaccine for TB by 2016, researchers in India do not share the optimism. Scientists in India are unconvinced that a vaccine – if and when it is developed – that is efficient in the laboratory will prove just as effective in the testing situations of rural India. ‘Development of a TB vaccine is a complex business, especially for highly endemic countries. The vaccine developer has to keep in mind several issues like the type of vaccine, expected outcomes of vaccination and the coverage to be achieved. Thus, the possibility of a vaccine being devolved quickly is an optimism that we may not be able to share given the time that is needed to bring any vaccine into the Indian markets,’ adds V. Kumaraswami, director of the Tuberculosis Research Centre, Chennai.

Earlier this year, the Aeras Global TB Vaccine Foundation, an international organisation involved in vaccine development, claimed that a new TB vaccine will be available by 2016 for less than $2. Though the final cost of the product is not known, the research company is already in touch with Serum Institute in Pune, Maharashtra, about manufacturing the vaccine.

With the conditions of the developing world in mind, any new vaccine would have to be developed at a low cost and have high stability – capable of retaining its activity without the need for refrigeration. Most villages in India do not have proper roads to the district hospitals, nor do the hospitals have proper storage capacity. ‘Any suitable vaccine candidate has to survive poor transportation facility, the lack of proper storage systems, and lastly it must be kept in mind that the vaccine will be handled by poorly motivated healthcare workers in understaffed healthcare centres across the country. Given these hurdles, the possibility of using a new vaccine in a national healthcare programme in near future is farfetched,’ says Nirmal Kumar Ganguly, former director of the Indian Council of Medical Research.

The way forward
Meanwhile, until a new drug or vaccine becomes a reality, scientists in the Tuberculosis Research Centre in Chennai are trying to put the available anti-TB drugs in combinations that make them more effective against MDR and XDR TB. In a Phase II trial, the scientists have has already been established that a new drug, moxifloxacin, in combination with other drugs, could shorten the time needed to cure tuberculosis by several months. ‘The trial is being conducted at Chennai and Madurai in Southern India. It is at an advanced stage and we are trying to use the medicines already approved for use. Most of the research at TRC is being done in the area of utilising existing drugs and manipulating regimens to shorten the duration of treatment as well as development of novel compounds. This trial largely focuses on finding an effective drug for MDR TB,’ says V. Kumaraswami.

Recently the TRC carried out a randomised clinical trial that demonstrated for the first time that newly diagnosed pulmonary TB patients can be effectively treated with a four-month daily regimen that used ofloxacin instead of ethambutol in the four-drug regimen.

As treatment default is directly related to the duration of treatment, a reduction in the duration of TB therapy would substantially improve outcomes. However, the delivery of this new treatment being developed by TRC under the DOTS strategy poses logistical problems. The centre is therefore conducting a randomised clinical trial in which the efficacy and safety of thrice-weekly four-month gatifloxacin or moxifloxacin regimens are compared with that of the standard six-month thrice-weekly regimen.

Clinical trials are under way to assess whether shorter courses of moxifloxacin-containing regimens can cure TB as well or better than the current sixmonth regimen.

Meanwhile, the lack of new drugs or vaccines is making the scientific community look at new approaches in treating TB. While the scientific community is looking at a better combination of drugs that are already approved for use, the government is looking at ways to integrate HIV and TB activities in the state for better coverage.

‘For an accurate TB control policy, authorities need to focus on an uninterrupted supply of essential anti-TB vaccines. The gold standard till now remains the microscopic examination and culture of sputum. Though several advanced techniques have been developed, they remain unsuitable due to expense and conditions like temperature unsuitability, cold chain etc. It is important for endemic countries like India to ensure that HIV treatment and TB control efforts are coordinated,’ says Nirmal Kumar Ganguly, Indian Council of Medical Research.