How can we protect the small minority of patients whose lives are threatened by leprosy medication?

Harka's story

Harka was following a path trodden by many of his friends and thousands of others from Nepal. In search of a better future, he had spent his money on a ticket to Saudi Arabia. Hundreds of thousands of Nepali Rupees are spent by people like Harka on the chance to work overseas, where wages are better than they are in Nepal.

Harka had arrived in Saudi Arabia with hopes of a better future, but all that fell apart just one month after he arrived. He suddenly became very sick and was admitted to an intensive care unit in Saudi Arabia before being sent back to Nepal. All the money he had spent to chase after his dreams had been wasted.

Harka had leprosy, but that wasn't what made him so sick. Harka's problem was a hypersensitivity to dapsone, one of the antibiotics that makes up the treatment for leprosy. He had been tested by TLM's team at Anandaban Hospital, who saw that he was at risk of this hypersensitivity and had asked him to stop taking that part of the treatment.

But then Harka visited a different hospital in Kathmandu, where he was told to continue taking dapsone. It was this instruction that proved fatal for Harka's Saudi Arabian dreams.

Why is dapsone included in MDT?

MDT is Multi-Drug Therapy, the course of antibiotics that cures leprosy. The white pill in the MDT blisters is dapsone.

It is the oldest serving drug in the medical arsenal to treat leprosy. Since its early usage in the 1940s, dapsone has proved to be highly efficient in reducing the bacterial burden of leprosy. Even after a period in the 1960s and 70s, when a high degree of dapsone resistance was observed, it was continued as a part of WHO-recommended MDT and has remained there since 1982.

Dapsone reactions started in the 1940s

Even as dapsone was being implemented across the world in the 1940s and 50s, serious allergic reactions (hypersensitivity) were being reported.

The symptoms usually start around 2-8 weeks after starting daily dapsone treatment and the include skin rashes, liver abnormalities and the involvement of multiple organs, which can lead to death in some cases.

Ever since those early days, all patients are taught about the symptoms of dapsone hypersensitivity so they can access treatment quickly.

The incidence of dapsone hypersensitivity differ by ethnicities. Dapsone hypersensitivity is rarely reported in Brazil and African countries but in South-Asia and China, around 1-3% of dapsone-takers are affected. This is reported in much higher proportions in Oceanian ethnicities, like Papua in Indonesia.

Once the syndrome occurs, patients require hospitalisation and suffer serious economic and psychological trauma. As leprosy patients usually come from poorer communities, it is hard for them to afford satisfactory medical services.

Roughly 10% of the dapsone hypersensitivity cases die due to lack of sophisticated medical services. The Leprosy Mission Nepal's analysis has showed a 2.6% incidence rate and a 13.7% mortality rate in leprosy cases registered at Anandaban Hospital.

Can we tell who has dapsone hypersensitivity?

In 2013, two groups in China reported the link between occurrences of dapsone hypersensitivity and a genetic risk factor, a specific human leukocyte antigen (HLA) allele called HLA-B*13:01.

Want to know that that means? Here's how ChatGPT explains it:

In simple terms, a human leukocyte antigen (HLA) allele is:

A specific version of a gene that helps your immune system recognise what belongs in your body and what doesn’t.

Breaking it down:

Human leukocyte antigens (HLAs) are proteins found on the surface of most of your cells.
They act like ID tags, showing your immune system which cells are “self.”
This helps your body fight infections while avoiding attacking itself.

An allele just means a particular version of a gene.
So an HLA allele is one specific type of HLA gene you inherited from your parents.

Very short version:
An HLA allele is a genetic “ID label” that helps your immune system tell friend from foe.

The Leprosy Mission's team in Nepal has been working to understand the extent of the problem

Divya Rana performing the HLA B 13:01 test at TLM's Mycobacterial Research Laboratory

Dr Mahesh Shah of TLM Nepal had a chance encounter with one of the Chinese researchers, Dr Wang Hongsheng. Following this, TLM Nepal collaborated with Hana Krismawati from Papua, Indonesia in writing a research grant proposal to the Leprosy Research Initiative to study the association of dapsone hypersensitivity with the HLA allele in Indonesian (Papua) and Nepali populations.

Data from Anandaban and from other independent studies in countries including Thailand, India, Taiwan and Korea have now validated the association of the HLA allele with dapsone hypersensitivity.

At present, both study groups in Indonesia and Nepal are studying the feasibility of performing an HLA test before administration of dapsone in all new leprosy cases.

The completion of the research project in June 2024 and the results from the study allowed The Leprosy Mission Nepal to secure funds to continue the tests in all new cases of leprosy before starting MDT. These techniques and their results have been shared elsewhere in Nepal, however, while Anandaban Hospital has a proper molecular facility to conduct the HLA test as a routine check-up, most of the health care providers in Nepal are unable to afford such services. More research is required to develop a field-friendly technique that can be used by basic laboratory facilities in Nepal.

Data from The Leprosy Mission Nepal's studies is compelling. About 8% of all new cases in Nepal bear the HLA allele and are at potential risk of developing dapsone hypersensitivity if dapsone is started as part of leprosy treatment.

What will the impact of this research be?

If we could identify every person who is at risk of dapsone hypersensitivity and withold that treatment from them, we could prevent the ill-health, hospitalisations, and deaths that around 1 in 12 people are currently at risk of. To make that possible, we need a field-friendly technique that can be used by basic laboratory facilities.

However, our team in Nepal also recognises that more research is required. For example, our laboratory also found that reactivation of herpesvirus during the hypersensitivity episodes correlated with increased severity and potentially fatality of the hypersensitive cases. The herpesvirus infects almost all humans during their childhood and remains in the blood in a latent stage only to be reactivated at later points in life during the periods of decreased immune capacity.

Our team will contiue this research so that all leprosy patients can access safely, timely treatment.