Virulent comeback

Tuberculosis re-emerges as a major threat as new drug-resistant strains develop because of mismanagement of the disease.

At the beginning of the year, doctors at Mumbais P.D. Hinduja National Hospital and Medical Research Centre reported that they had 12 patients infected with TDR-TB, or totally drug-resistant tuberculosis, a condition in which the TB bacilli is resistant to all first- and second-line drugs used in the conventional treatment of the disease. Panic ensued, forcing the Union Health Ministry to step in. It examined the patients records and declared that the term TDR was misleading, especially since the World Health Organisation (WHO) had not endorsed it. The patients, the Ministry concluded, had XDR-TB, or extensively drug-resistant TB.

There was outrage among physicians and they called it a knee-jerk reaction, but the government had its way. The term TDR is no longer used. In the meantime, four of the 12 patients died; the number of patients now under treatment at Hinduja is 15. An argument about terminology is futile when TB, a dangerous and contagious disease, long believed to be under control, is actually rampant and seemingly out of control.

News of the cases first appeared in December 2011 in a report published in the journal Clinical Infectious Diseases. Its authors, Drs. Zarir Udwadia, Rohit Amale, Kanchan Ajbani and Camilla Rodrigues of Hinduja Hospital, reported the discovery and treatment of four cases of drug-resistant TB since October 2011. Later, eight more patients were diagnosed with the disease at Hinduja. Logically, there may be many other cases in the State and the country that go undetected since facilities to identify the strain are not easily available.

The plan to house the four Hinduja patients in a sanatorium near Sangli never took off. They were offered the option of isolation, said Udwadia, but to the best of my knowledge they did not take it. They continue to live and be treated in the community. Of the 15 patients under his care, he said, Despite popular misconceptions, TDR is not synonymous with Totally Doomed. Several of these patients are doing well on complicated regimens involving salvage' drugs. Surgery is being increasingly offered as well, especially if the disease is restricted to one lung.

In response to an invitation from Thorax, the United Kingdom's premier journal of respiratory medicine, Udwadia wrote an editorial to put things in perspective: These 12 patients, sadly, hold a mirror to the way MDR-TB [multi-drug-resistant TB] is mismanaged in India. The typical patient had failed both standard short course chemotherapy... and then category 2 treatment, a single standardised retreatment regimen in the public sector. They then turned, in desperation, to multiple private practitioners whose inappropriate prescriptions only served to further amplify resistance till the micro-organisms were finally resistant to all first-line and second-line drugs tested by us at the Hinduja Hospital and Research Centre, Mumbai.

The 12 patients (mean age 32 years, six men), had seen an average of four doctors, and received a mean of 9.33 drugs for an average duration of 26 months prior to being labelled TDR-TB by us. What treatment options can we offer the damned? As Paul Farmer said: Our mission must be to treat the sick, not just the sick who can pay. Our mission must be to treat TB regardless of resistance pattern. With the very limited treatment options available, we started each patient on a salvage regimen of four new drugs. In addition, aggressive surgery (pneumonectomy) was offered to two patients despite the bilateral nature of their disease. Three patients succumbed to their disease within a few months of being labelled TDR-TB.

Strains of TB

The WHO has suggested that the acronyms XDR and MDR be used when describing strains of TB since there are set, internationally agreed upon definitions for these based on set standards for laboratories to test the bacilli against MDR resistance to three to five first-line drugs. This means the patient has to be treated with second-line drugs, usually a combination treatment with a strong likelihood of more side-effects, less efficacy and longer treatment duration. Giving them drugs that are of no use further entrenches the resistance. XDR is when the patient develops resistance to all first-line drugs and to most of the nine or so drugs that are usually part of the second-line cocktail.

TDR, by logical definition, should be a situation when there is resistance to every known drug. The WHO says the only sure-fire way to prove drug resistance is to make a culture of the patients strain of TB. This is a long-drawn-out process since the TB bacilli reproduce slowly. After the culture is grown, various drugs are tried to see what affects it. The reason the WHO has no definition for TDR-TB is because there are no commonly verified laboratory test result standards for it.

According to the WHO, TB is one of the worlds worst killers, and Indias burden is the highest in the world 300 million infected and an estimated 3,00,000 deaths every year. As Udwadia wrote, One death every two minutes, a grim statistic that has changed little over the decades. He says the situation is worse when it comes to MDR-TB.

The latest WHO report estimates that India carries 20 per cent of the worlds MDR-TB burden. Writing in Thorax, Udwadia said, These figures are a considerable underestimate because the majority of patients with MDR-TB are seen in the private sector and never notified.

Matters are not helped by the rigour demanded by the TB treatment regime. This takes a minimum of six months, and more if the case is complicated. Poor diagnosis sometimes results in a disparity between symptoms and treatment which can lead to three alarming situations the patients prolonged suffering, chance for the disease to spread, and increased chances of resistance developing. The WHO estimates that one patient with active, untreated TB can infect 15 others. A fact that has been frighteningly illustrated by the spread of XDR-TB. The first case was reported six years ago, and since then it has spread to around 70 countries.

Disquieting statistics

The WHOs worldwide TB statistics are disquieting. Until April 2011, there were approximately 4,40,000 cases of MDR-TB every year, of which 1,50,000 were fatal. There were 25,000 cases of XDR. The WHO estimated two million MDR or XDR cases in the world by 2012. No known TDR patient has survived for long. It is no wonder that news of the TDR cases at Hinduja Hospital created panic and the Centre insisted on the hospital re-categorising the patients as XDR. But, as one doctor said, The TDR cases are a result of years of neglect of the TB programme. This has been a ticking time bomb and its now exploding.

Not a new phenomenon

TDR is a new development in an old problem. India is the third country in the world to report a totally drug-resistant strain of TB. Official data on TDR-TB are inadequate. Giovanni Migliori, Director of the WHO Collaborating Centre for Tuberculosis and Lung Diseases in Tradate, Italy, said that TDR-TB was not new at all and that cases had been reported over the past decade. The first reported cases of this were in 2003 in Italy when two women died of the disease despite being under treatment for several years (normal TB treatment takes between six and eight months). In 2009, Iran reported similar cases when 15 people who were under long-term treatment succumbed to the disease.

Mismanagement of the disease is one reason for the development of new strains of TB. There are many parameters to TB management, including correct diagnosis and the right treatment regimen for the correct duration. As in most drug courses it is imperative that the entire course be followed, failing which the body develops resistance to the drug. Drug resistance also comes about because of a high degree of patient dropout. Even though the well-established treatments using isoniazid and rifampicin are effective, the duration of the treatment is no less than six months and often patients do not complete it.

No new first-line TB drugs have been developed for the last 50 years and this is believed to have contributed to the emergence of strains that are unresponsive to treatment. In the pharmaceutical research industry, funding for anti-TB drugs is not a priority despite the fact that TB, after AIDS, is the worlds leading cause of death from infectious diseases. But after the emergence of TDR-TB there has been a glimmer of interest. In 2010, there were 11 new and repurposed TB drug trials working on shortening the duration of treatment or improving therapy for resistant TB.

Testing problems

Part of the problem also lies with TB testing. The commonly used serological tests claim to diagnose TB by detecting antibodies in the blood. But these have been controversial because an antibody response need not necessarily indicate TB it could be an indication of another organism. In 2011, the WHO issued a warning saying such tests were inconsistent, imprecise and put patients lives in danger. It took a year for the Indian government to respond to this, and finally in June this year the Ministry of Health and Family Welfare issued a notification prohibiting the sale, import and use of serodiagnostic kits, repeating the WHOs warning of a year ago and saying there were safer alternatives available.

The WHO-recommended test is the sputum smear microscopy. Though a cheap and common diagnostic tool, it is not always accurate. It tends to throw up false negatives, fails to give information on drug susceptibility and the results can take weeks often enough for the patient to become a dangerous transmitter of the disease. But this century-old test was replaced in 2010 by a WHO-approved, fully-automated test called Xpert developed by a United States-based company. Apart from diagnosis, the test assesses resistance to the first-line drug rifampicin. An added advantage is that it can be used by a minimally-trained health worker and gives a result in 90 minutes. However, because of its high price, it is not in common use in India.

Drug resistance may also be because of another disease the patient may be suffering from. Most often this is HIV. The WHO estimates that 13 per cent of persons with TB also have HIV.

A 2011 WHO report said that less than 5 per cent of newly diagnosed or previously treated patients were tested for drug resistance. Besides, only about 16 per cent of patients diagnosed with DR-TB got the correct treatment. So it is not a question of a virus mutating but of man-made resistance because of poor disease management.

According to TB India 2011, Revised National TB Control Programme, an annual status report of the Union Ministry of Health and Family Welfare, the country has more new TB cases annually than any other country. The report says: In 2009, out of the estimated global annual incidence of 9.4 million TB cases, 2 million were estimated to have occurred in India, thus contributing to a fifth of the global burden of TB. It is estimated that about 40 per cent of Indian population is infected with TB bacillus. On a national scale, the high burden of TB in India is illustrated by the estimate that TB accounts for 17.6 per cent of deaths from communicable disease and for 3.5 per cent of all causes of mortality (WHO, 2004).

One of the most commonly cited reasons for poor care and poor diagnostics is lack of funds. But not finding the funds can be an even more expensive proposition for any country.