Should India fight leprosy with an antibiotic that might lead to TB drug resistance?

In a clinic in central Mumbai’s Chunabhatti, Ravita Yadav tightly held three-year-old Ruhi in her arms as the toddler cried loudly when a health worker poured red syrup into her mouth. The health worker then pulled out a form and started asking Ravita’s husband, Ajit Yadav, about his health before passing him a tablet.

Both daughter and father were administered the same medicine: Rifampicin, an antibiotic. “We give a single dose to close contacts of leprosy patients to prevent transmission of the disease,” said Dr VV Pai, head of Bombay Leprosy Project, a non-profit that runs the Chunabhatti clinic.

Leprosy is an infectious bacterial disease, marked by numbness or white patches on the skin. It can eventually cause limb disability if left untreated. It spreads through respiratory droplets, similar to Covid-19.

Ravita Yadav was diagnosed with leprosy in 2021. Her husband and daughter are her close contacts. “The doctor told me I have high chances of getting leprosy since I live with her,” said Ajit Yadav, who works as a daily wage labourer. He agreed to take rifampicin after a health worker said it will reduce chances of an infection.

Rifampicin was first used as a prophylaxis, or preventive medication, against leprosy in 1988 in the French Polynesia islands in the Pacific Ocean, where leprosy rates were high. Over the years, more studies found that a single dose of rifampicin was effective for some years in reducing the chances of a mild form of leprosy among the close contacts of patients.

In India, the antibiotic was incorporated into the National Leprosy Eradication Programme in 2017-’18, after a resurgence of the disease between 2005-’15 due to poor surveillance. In 2020-’21, India detected 65,147 new cases, which account for 60% of leprosy cases reported worldwide.

In 2015, a pilot project was launched in the small Union Territory of Dadra and Nagar Haveli, which was then reported to have the highest prevalence of leprsoy in India. A single dose of Rifampicin was administered to the close contacts of leprosy patients in an attempt to control new infections.

The pilot project showed promising results, and in 2017, the Union Ministry of Health and Family Welfare decided to roll out rifampicin in leprosy clinics across the country. Rifampicin is now an integral part of India’s leprosy control programme.

But experts warn that rifampicin may not be the solution to control leprosy in India. There are concerns that the antibiotic could lead to drug resistance not just against the leprosy bacteria but also against the tuberculosis bacteria.

India has a significantly high burden of tuberculosis as well as drug-resistant tuberculosis, with a high mortality rate. In 2021, India diagnosed 48,232 drug-resistant tuberculosis patients out of 19.33 lakh reported cases, according to the health ministry’s report published in March.

Rifampicin is a first-line drug in tuberculosis treatment. If a tuberculosis patient is resistant to rifampicin, then first-line drugs are likely to fail.

The Dadra and Nagar Haveli findings

In 2005, India declared that leprosy had been eliminated after cases fell below 1 per 10,000 population. But the announcement led to a drop in disease surveillance, which resulted in several new cases going undiagnosed. The bacteria quietly mushroomed in dense and poor populations, spreading through coughs or sneezes. Since a leprosy infection can take years to incubate, the high burden of the disease in India began emerging only after 2010.

Between 2006 and 2014, leprosy prevalence in Dadra and Nagar Haveli rose by 138% – no other state had such a sharp rise. A combination of factors such as a large tribal population, many of whom were unaware of symptoms and did not seek medical advice on time resulting in the spread of the infection, and poor surveillance may have contributed to the surge in leprosy cases in the Union Territory. In 2016-’17, Dadra and Nagar Haveli had 6.2 leprosy cases per 10,000 people, against 0.6 cases per 10,000 people nationally.

In 2015, a pilot project was started to provide rifampicin to close contacts of a leprosy patient in Dadra and Nagar Haveli. Since then, over a lakh have been administered the medicine.

At the International Leprosy Congress held in Hyderabad in November this year, Dadra and Nagar Haveli’s leprosy officer Dr Manoj Singh presented data collected over seven years of 77,430 people. In his presentation, Singh said that the prevalence of leprosy decreased by 83% during the reference period of seven years.

The national programme

After India had introduced Rifampicin as a frontline defence against leprosy and strengthened surveillance, it set 2030 as the new deadline for the elimination of the disease from each district.

Rifampicin is administered after assessing the contact of a leprosy patient using a set of 20 questions. They are asked if they have been exposed to the patient for over 20 hours a week for more than three months, and whether they have active tuberculosis, liver problems, jaundice, renal issues, or febrile illness. “Based on the assessment, we give Rifampicin to close contacts,” Singh said. If a close contact has tuberculosis, they are already taking rifampicin, and so an additional dose is not required.

But rifampicin is not a miracle antibiotic. Singh said several people in Dadra and Nagar Haveli contracted leprosy despite being administered the drug. This was more so among those who acquired an aggressive form, called multibacillary leprosy, in which multiple white patches sprout all over the body.

Of the 77,430 people in Dadra and Nagar Haveli who were given Rifampicin in the first seven years after the pilot project was launched, 160 developed leprosy. Singh said most of them had multibacillary leprosy. “Rifampicin seems to be working to prevent only the mild form of leprosy,” Singh said.

Experts divided over rifampicin

Some experts argue that the risks of administering rifampicin as a preventive medicine are higher than its benefits and that it may lead to drug resistance in tuberculosis and leprosy bacteria. Yet, in the absence of scientific studies, this remains a matter of debate.

A 2016 study published in the journal BioMed Central said that if rifampicin is given to contacts of leprosy patients, in the absence of symptoms of active tuberculosis, it “poses a negligible risk of generating resistance in individuals and at the population level”.

However, Anthony Samy from Alert India, a non-profit that works on leprosy and tuberculosis, said a large population in India has latent tuberculosis infection, which means that the bacteria is already present in the body but has not progressed into the disease stage. Since there is high exposure to tuberculosis in India, rifampicin can have larger implications, said Samy.

Essentially, giving the close contacts of leprosy patients rifampicin even if they do not have tuberculosis does not account for the fact that a large population has already been exposed to the tuberculosis bacteria.

Dr Pai, from the non-profit Bombay Leprosy Project, pointed out that close contacts of leprosy patients are not monitored to assess if they develop rifampicin resistance if they contract leprosy in the future. Currently, close contacts undergo follow-up checks for leprosy every three to four months. But those who do contract leprosy are not tested to check if the bacteria strains have mutations resistant to rifampicin.

“What we need is a user-friendly test to check for rifampicin resistance in these contacts,” said Pai. Leprosy officers in Gujarat, Maharashtra, Dadra and Nagar Haveli, and Daman and Diu agree that such a monitoring system is absent.

A 2018 paper in PLOS Neglected Tropical Diseases argued that India’s use of rifampicin as a prophylaxis is more harmful than assumed. The paper said that the antibiotic does not prevent multibacillary leprosy and neither does it provide protection for a reasonable amount of time. It is also not cost effective and its widespread use may promote rifampicin resistant genes in the bacteria, says the paper.

Bhushan Kumar, one of the the authors of the study, told Scroll.in over email that the concerns that the use of rifampicin to prevent leprosy may lead to resistant bacteria is “more of a theoretical possibility”. This theory is “complex and difficult to prove”, said Kumar, also the former head of skin, sexually transmitted diseases and leprosy at the Post Graduate Institute of Medical Education and Research in Chandigarh.

Bengaluru-based leprosy expert Dr P Krishnamurthy, also the chairperson of Damien Foundation of India, says that the possibility of drug resistance among those given rifampicin cannot be discounted.

Only 20% of new leprosy cases in India emerge out of contact with a leprosy patient, said Krishnamurthy. “Based on our observation, about 58% of contacts given rifampicin still end up getting leprosy,” he said. “That means we are able to prevent infection in a very small pool.”

Krishnamurthy added that the efficacy of rifampicin lasts only two years, which means the contact could be susceptible to leprosy infection after that. According to him, the government needs to weigh the pros and cons of using rifampicin based on its risk, efficacy, and cost. “Rifampicin is useful in [a] low endemic situation, where mostly contacts of patients are at risk of infection,” he said. “India is a high endemic country where everyone is at risk.”

Since rifampicin is effective against leprosy for only two years, experts say it is likely that the dose will have to be repeated in future. “Some African countries give it annually,” said Pai. “Soon, this may be introduced in India too.” Multiple doses of the medicine are more likely to induce antibiotic resistance, he said.

Adequate screening required

For now India has approved only one dose of rifampicin against leprosy. Dr Girish Thakkar, who retired as leprosy officer in Gujarat in 2021, said a single dose may not induce resistance and that a careful analysis of social and close contacts is done before rifampicin is prescribed.

But Scroll.in found Rifampicin being administered to close contacts simply based on their answers. In this case, no tests were carried out to confirm if they had tuberculosis, or liver or renal problems.

In 2015, Shafiqunissa Shaikh, 35, had contracted leprosy. Shaikh’s family lives in Basti, Uttar Pradesh, and her sister-in-law contracted tuberculosis shortly after her leprosy diagnosis. This year, Shaikh moved to Mumbai for better treatment. Her husband and two daughters were administered rifampicin as preventive medication against leprosy.

When Scroll.in met her in November, her three-year-old son was being given rifampicin. Though Shaikh’s entire family was exposed to tuberculosis through her sister-in-law, they have not been tested for it. “The health worker just asked if I had tuberculosis and I said no,” Shaikh said.

Samy, from Alert India, is concerned about the use of Rifampicin among low-income communities that have higher exposure to tuberculosis but low access to healthcare. “If they develop rifampicin resistance, we will never know whether it was due to this drug or because the bacteria itself was resistant,” he said.