CNS: Preventing an epidemic of drug-resistant tuberculosis in India

Tuberculosis (TB) is one of India's oldest and perhaps most neglected public health challenges. It is a disease caused by bacteria that are spread from person to person through the air. Chronic cough (for more than 2 weeks) and fever are the most important symptoms of TB. When a person with TB coughs, TB bacteria get ejected into the air. They can then get inhaled by another person who can become newly infected. TB usually affects the lungs, but it can also affect other parts of the body, such as the brain, lymph nodes, abdomen, or the spine. In most cases, TB is treatable and curable. However, unlike most common infectious diseases that require a few days of antibiotic treatment, TB requires several antibiotics and long-term treatment for cure.

Persons with TB must take at least 6 months of medications without interrupting them. Otherwise, TB bacteria can become resistant to the common, first-line drugs that are used. This usually happens when patients do not complete their full course of treatment; when doctors prescribe the wrong treatment, the wrong dose, or length of time for taking the drugs; when the supply of drugs is not continuous; or when poor quality drugs are used.

Multidrug-resistant TB refers to TB that is resistant to isoniazid and rifampicin, two of the most important first-line antibiotics used to treat TB. Multidrug-resistant TB requires extensive treatment (2 years or longer) with multiple drugs, and outcomes are usually poor. Treatment of drug-resistant TB is very expensive because of the high cost of second-line TB drugs.

How big is the TB problem in India?

India leads the world in its burden of TB-related morbidity, mortality and drug resistance. India has over 2 million new TB cases every year and TB kills nearly 1000 people every day. The emergence of drug resistant TB has made things worse. A 2011 Global TB Report by the World Health Organization estimated that approximately 64,000 cases of multidrug-resistant TB emerge annually from the notified cases of pulmonary TB in India. Some months ago, a team from Mumbai reported a few cases of “totally drug-resistant tuberculosis” – suggesting that this form of TB was incurable because of resistance to all the TB drugs tested.

India’s Revised National Tuberculosis Control Programme (RNTCP) is widely appreciated for having made a big contribution by expanding basic diagnostic and treatment services to cover 100% of the Indian population. Despite these achievements, TB continues to be a huge problem in India. Why? It is the result of neglect of TB as a public health problem, and mismanagement of TB patients in both the public and private sector.

The original National Tuberculosis Programme (NTP) was grossly underfunded, and failed because of low rates of case detection and cure. The revised programme (RNTCP) has reversed these trends in the public sector, with expanded access to improved diagnosis, short-course drug regimens and high cure rates. The diagnosis and treatment of patients with drug-resistant TB is one area which the RNTCP needs to address better. In the public sector, a large fraction of patients with drug-resistant TB do not get adequate drug-susceptibility testing and second-line drug treatment.

Importance of the private sector

The private sector in India, which manages more than half of all TB patients, is a continuing source of mismanagement of TB, and is largely outside the scope of the RNTCP. TB management practices in the unregulated private sector vary widely, often deviating from established standards. For example, inaccurate, blood-based, antibody tests are widely used, along with irrational drug regimens. Indeed, since antibiotics are easy available over-the-counter, antibiotic-resistance is a major threat for control of all infectious diseases. Also, there is virtually no reporting or notification of confirmed TB cases to the RNTCP by the Indian private sector.

Recognizing these problems, this year, the Ministry of Health and Family Welfare issued two governmental orders. One banned the use, sale and import of all TB antibody blood tests in India, and the other requires all healthcare providers to notify every TB case to local health authorities (e.g. district or municipal health officers). While the government must get a lot of credit for announcing these directives, it is important that mechanisms are put in place to enforce these two governmental orders.

Regardless of where patients in India seek care, the typical TB patient in India is caught between two sub-optimal options – an under-funded public programme with limited capacity to deal with drug-resistant TB, and an unregulated private sector where mismanagement is likely. Not surprisingly, patients often move from one provider to another, and between private and public sectors. And while they do this, they continue to transmit the infection to those in their families and communities. By the time a patient is adequately diagnosed and put on correct TB treatment, they may have infected nearly 15 other individuals in their homes, communities and workplaces.

To control TB and prevent drug resistance, patients, healthcare providers and the government will need to do their part.

What can patients do to prevent drug-resistant TB?

To begin with, all individuals with cough for more than 2 weeks must seek care early and get their sputum tested for TB. Indeed, this is the key message behind an ongoing media campaign called “Bulgam Bhai” (this must see ad spot can be seen on YouTube). Sputum testing is available free via thousands of designated microscopy centers run by the RNTCP. If patients seek care in the private sector, they must demand sputum testing over blood tests for TB. If TB is diagnosed, the most important thing a person can do to prevent the spread of drug-resistant TB is to take all of their medications exactly as prescribed by their health care provider. No doses should be missed and treatment should not be stopped early. Patients who cannot afford to buy drugs in the private market must seek treatment in the public sector where drugs are given free.

What can healthcare providers do to prevent drug-resistant TB?

Healthcare providers can help prevent drug-resistant TB by quickly diagnosing cases, following recommended treatment guidelines, monitoring patients’ response to treatment, and making sure therapy is completed. Healthcare providers should screen all individuals with chronic cough for TB using sputum tests such as smears, culture, or polymerase chain reaction (molecular) tests. TB disease cannot be diagnosed by any currently available blood test. Testing the sputum for TB bacteria is the only valid approach for accurately detecting pulmonary disease. Laboratories should comply with the recent ban and stop offering antibody blood tests. Furthermore, laboratories should not replace antibody TB tests with equally bad or worse alternatives such as QuantiFERON-TB Gold (which is meant for latent TB infection), and PCR on blood samples. Providers should also avoid starting anti-TB drug treatment without doing any laboratory testing to confirm the disease. If TB is confirmed, they should start treatment promptly and follow WHO or RTNCP guidelines.

For drug-sensitive TB, a standard 4-drug treatment must be started, and the total duration of treatment must not be less than 6 months. If drug-resistance is suspected, it should be confirmed using laboratory tests such as culture or molecular tests. For drug-resistant TB, second-line drug treatment must be started, and the total duration of treatment must be at least 2 years. In all forms of TB, providers must counsel their patients about the importance of adherence, and periodically check if patients are taking the medications as prescribed. Private practitioners must refer poor patients who are unable to afford TB medications to the RNTCP, where they can get free, quality-assured medications. Pharmacies and drug stores must not dispense TB drugs without a valid doctor’s prescription, and TB drugs must not be sold indiscriminately like cough syrups or placebo pills.

New TB drugs

Currently, there is a lot of excitement about the impending release of new drugs for TB. After decades, the first new TB drugs are likely to enter the market in the next 2 years. For example, trials are ongoing to evaluate a 4-month moxifloxacin-based regimen versus the 6-month standard of care in drug-sensitive TB patients. Moxifloxacin has the potential to be first new drug to treat drug-sensitive TB in nearly 50 years, and a moxifloxacin-containing regimen could shorten treatment duration by a third. If trial results are positive, this drug regimen is expected to get initial market approvals in 2014. The TB Alliance published a trial this year that showed that a novel drug combination treatment (called PaMZ) containing PA-824, moxifloxacin and pyrazinamide was highly effective. Although further trials are needed, this drug combination has the potential to treat patients with drug sensitive as well as drug resistant TB.

However, the excitement about the impending introduction of new TB drugs must be tempered with the reality of the Indian landscape. Before new TB drugs enter India, mechanisms must be put in place to ensure that they do not get abused. TB drugs must not be dispensed without prescriptions, and prescriptions must come from only qualified, allopathic practitioners. Doctors must strictly follow national and international guidelines on TB treatment, and avoid creating their own drug regimens. Fixed dose drug combinations can help improve adherence and minimize the risk of drug resistance. Indeed, when new TB drugs become available, it will be critical to ensure that doctors do not use them as single drugs, or add a single new drug to a drug regimen that is not effective – this will most definitely make the TB bacteria resistant to the new drugs. We have waited a long time for new TB drugs. We need to protect them and make sure they last.

What can the Indian government do to prevent drug-resistant TB?

The RNTCP is beginning a new phase, the National Strategic Plan (NSP), for the period 2012 – 2017, and its vision and goals were recently announced. The vision of the Government of India is for a “TB-free India” with reduction in the burden of the disease until it is no longer a major public health problem. To achieve this vision, the RNTCP has now adopted the new objective of aiming to achieve ‘universal access’ for quality diagnosis and treatment for all TB patients in the community.

This is a laudable objective. But if the NSP has to succeed, several things need to happen. First, the Indian government must increase its spending on TB control, and support the RNTCP by providing an adequate budget for the next five-year plan. If the government truly wants to achieve universal access, then it should back up the vision with adequate funding to realize it.

Second, universal access implies a large-scale engagement with the private sector in India. Currently, there is very little dialogue or collaboration between the RNTCP and the private sector and this is a major concern. Innovative business models and market-based public-private partnership models must be tried out to incentivize and engage the private sector to improve TB diagnostic and treatment practices. Getting the private sector to notify all TB cases is a good step in this direction. The RNTCP should also engage with private labs in India, to expand quality-assured diagnostic services.

Third, new diagnostics and drugs are needed to reach the goal of universal access. Existing diagnostic tests in the public sector (e.g. sputum smears) are insensitive and cannot detect drug-resistance. Widely used tests in the private sector (e.g. antibody blood tests) are highly inaccurate and banned. Investments in new, WHO-endorsed diagnostics such as Xpert MTB/RIF (GeneXpert), line probe assays and liquid cultures should therefore be a big priority for rapid diagnosis of drug-resistant TB.

Fourth, efforts must be made to better regulate TB drugs in India, to reduce rampant over-the-counter use of TB drugs. The government should also make an effort to indigenously manufacture second-line TB drugs at lower costs, or aggressively negotiate lower prices with pharma companies. Indian pharma companies can save countless lives by working with the government to supply affordable TB drugs. Fifth, the government should develop a clear strategy and advocacy plan to follow-up on its recent directives on ban of TB blood tests, and mandatory notification of all TB cases.

Lastly, the RNTCP needs to think beyond treatment of drug-resistant TB, and focus on preventing a major epidemic of drug-resistant TB. In the case of drug-resistant TB, an ounce of prevention is definitely better than a pound of cure.