How A Drug To Treat Dermal Kala-azar Is Affecting Patients’ Eyesight

Miltefosine, a drug that is used to treat the skin manifestation of Kala-azar is being linked to eye problems, including blindness

By :  Menaka Rao
Update: 2024-03-27 02:55 GMT

New Delhi and Patna: India has hit the elimination target for Kala-azar, a parasitic disease in 2024, but a drug used to treat the skin manifestation of Kala-azar is being linked to eye problems, including blindness.

Miltefosine is given to patients with Post-Kala-azar Dermal Leishmaniasis (PKDL), which is a skin manifestation of Kala-azar. Kala-azar itself is a neglected tropical disease, which is fatal if not treated. PKDL, which affects about 5-10% of treated Kala-azar patients, is seemingly innocuous, but people with PKDL are known to have the parasite in their body and can therefore unknowingly spread the disease in the community. The manifestation starts by looking like white patches on the skin (macules), and then develops into bumps on the skin (papules) and later large boils (nodules).

In 2022, the World Health Organization (WHO) first took cognisance of the problem. After further investigation and examining the data from India, the WHO's multi-technical group considered that a causal relationship between adverse ocular events and exposure to miltefosine is “at least a reasonable possibility”. The group found a causal relationship between the problem in the eye and the intake of miltefosine in 83 cases in India.

In 2022, the Indian government issued guidelines for its field staff to help prevent these eye complications. The only alternate therapy, as per the official guidelines for PKDL, is infusion of liposomal amphotericin B over four months. This requires hospitalisation, and is not a tested therapy.

The results of a multi-centre trial led by Drugs for Neglected Diseases initiative (DNDi) from India and Bangladesh with a combination of liposomal amphotericin B and miltefosine is likely to be published soon. It is a three-week treatment course.

"This therapy can be an alternative. I cannot tell you the results as they are yet to be published. But the results were acceptable,” said Shyam Sunder, retired professor of general medicine from Banaras Hindu University, Varanasi, and founder of the Kala Azar Medical Research Centre in Muzaffarpur, one of the sites of the trial.


History of the problem

The first two recorded cases of eye problems after PKDL treatment were in 2018 in the medical journal Cornea. The cases were from 2015-16, and at the time it was hypothesised that the corneal manifestation was an immune reaction, said Aditya Pradhan, ophthalmologist from Disha Eye Hospitals, Barrackpore, Kolkata and lead author of the paper.

A second paper was published the same year in Bangladesh, and it presented five patients who developed eye complications after taking miltefosine for PKDL. One of the five patients was detected too late and had to undergo evisceration of the eye--that is, gouging out the eye.

In October 2019, WHO officer Suman Saurabh collaborated with an ophthalmologist based in Darbhanga, Manish Mahabir, and published a paper on the subject. This study was a case series of four patients with PKDL from across three districts of Bihar who developed severe eye complications during treatment. One of these had gone completely blind, and had undergone corneal transplantation. This study used the WHO Uppsala Monitoring Centre causality assessment scale, where they classified the relation of their eye complication with miltefosine as “certain”--the highest assessment criteria as per the scale.

Saurabh, who now teaches Community Medicine in All India Institute of Medical Sciences, Jodhpur, said that as a WHO officer, he was in constant touch with the authorities and had communicated these findings with them. The paper talked about the need to counsel patients regarding these possible adverse ocular events during the miltefosine treatment.

In 2020, a major study was published by the Indira Gandhi Institute of Medical Sciences (IGIMS), Patna. The lead author of this paper, Rakhi Kusumesh, assistant professor at Regional Institute of Ophthalmology, met the first patient with a similar eye problem in September 2018. He was a 31-year-old man who had pain in his eye, inflammation and photophobia (difficulty looking directly at bright light).

“I had not even heard of miltefosine at the time," said Kusumesh, who is also a corneal implant surgeon. "When the first patient came to me, I thought the eye was infected. I started with antibiotics, and sent a sample for testing for microorganisms. But nothing came out. Finally I started on a corticosteroid that suppresses the immune system and then the patient started responding.”

Despite that, the patient lost his right eye and had to undergo keratoplasty, which is a corneal implant. His left eye recovered with steroids, and he gained partial vision. Kusumesh said that they got seven patients between 2018-19 with the same finding. For five of these patients, Kusumesh and her colleagues used a causality assessment of adverse drug reaction to miltefosine as per the WHO-Uppsala Monitoring Centre. The assessment revealed a “probable” association between the adverse drug reaction and miltefosine in all patients.



Rakhi Kusumesh, assistant professor at the Regional Institute of Ophthalmology at IGIMS, Patna saw seven patients with vision loss after taking miltefosine in 2018-19. She said that the patients came on their own from far-off areas in Bihar, and no support was provided to them by the government.


Miltefosine was first described as an anticancer drug, and has a very long half-life, which is the time it takes for the amount of drugs in the body to reduce to half. In the case of miltefosine, it is nearly 31 days.

“It starts with redness around the cornea," said Kusumesh. "Its exact mechanism is still not known but it can cause reaction to the outer part of the cornea causing desiccation necrolysis, which is the melting of the cornea. You will find a lot of sterile pus cells in the outer part of the cornea.”

While two of her patients needed a corneal implant, the others recovered with corticosteroids. One of the most effective treatments was just stopping the use of miltefosine. If the patient seeks care at an early stage, the outcomes are better than if the patient comes in an advanced stage.

What does early stage mean? “A slight redness in the eye, slight foreign body sensation, before the deeper part of the cornea is involved and the cornea turns completely white,” explained Kusumesh.

The prognosis changes in a matter of one to two weeks, she said. For instance, in the first two cases, they came to Kusumesh about a couple weeks after their symptoms started. Such delay is expected of villagers, often on daily wage work, living far from major hospitals like IGIMS, in Patna.


Kala-azar

Kala-azar literally means black fever, as the disease results in some greyish-blackish discolouration of skin. The scientific name is Visceral Leishmaniasis.

It is caused by a parasite, Leishmania donovani, and is transmitted to humans by the bite of female sand flies--called balumakhi.

People with this disease have bouts of fever, suffer weight loss, become anaemic and have enlarged spleen and liver, giving them a pot belly. This disease is fatal if not treated.

Kala-azar is a neglected tropical disease--because it affects the poorest of poor, the most marginalised people and ignored by the pharma industry. It is prevalent in most parts of Bihar, some parts of Jharkhand, Uttar Pradesh and West Bengal and other parts of the Indian subcontinent such as Nepal and Bangladesh.


My cornea turned white’

Iliyas Marandi’s name crops up many times during this reporting.

Marandi was about 20 years old when he was detected with PKDL. The tribal man lives in a small village, Karudi in Godda district. Marandi is a matriculate who aspired to study further. But he was working as a farm labourer, migrating to West Bengal often to supplement the income of his family. IndiaSpend spoke to him on a phone call, and later on a video call from Delhi.

Marandi got Kala-azar as a child. He had some lesions on the skin after the treatment, but was detected with PKDL only around October 2020. He took miltefosine for around two months, when his eye started hurting.

“Both my eyes hurt, mostly at night. But it would reduce again in the morning. I asked my mother to get some drops, but my eyes were not feeling better,” said Marandi.

When he went to a health centre in his block where he was getting PKDL treatment, the doctors gave him the dose for the third month. “When I told them about the pain in the eye, they ignored it. They instead told me to continue miltefosine. Un logon ne galat kiya (What they did was wrong),” said Marandi.

At the time, health workers in remote districts such as Godda were possibly not aware about this side effect, nor was any information available to them. Marandi said that despite the pain, he took miltefosine for another six to seven days, before stopping it completely. For the eye pain, he went to an eye specialist in Godda district who gave him some medicines, and asked him to wear dark glasses.



Iliyas Marandi with his mother. Marandi is a 20-year old tribal man from Godda in Jharkhand. He lost his vision after taking miltefosine for two months. Picture: arrangement with Iliyas Marandi


“The Godda eye doctor told me to go to a big centre (tertiary care hospital or specialised eye hospital). We were arranging money to go there. But before I could go to the hospital, my cornea turned white. All this happened in a span of 2-3 days,” said Marandi.

Marandi feels wronged by the health officials who did not tell him about this side effect.

“They should have told me that there could be a side effect like this," he said. "They never told me. If they had stopped the medicine when I was in pain, I would perhaps have not turned blind.”


Scrambling for treatment

Marandi said that he somehow collected money and went to Deogarh (a temple town in Jharkhand) to see an eye specialist. It only reduced his pain, but he still couldn't see.

After he lost his eyesight, his case came to the attention of the district public health circles. In 2021, the health authorities provided an ambulance for him to go to Lok Nayak Jai Prakash Eye Hospital in Hazaribagh district and Rajendra Institute of Medical Sciences (RIMS) in Ranchi, but these hospitals could not offer treatments that helped recover his eyesight.



Letter sent by Godda’s chief medical officer to help Iliyas Marandi go to Patna for treatment in February 2022. Photo Credit: Menaka Rao


On December 24, 2021, a WHO team and others went on a tour in Jharkhand to examine the Kala-azar situation, and met Marandi. Madhukar (Major), who is a clinician working in Rajendra Memorial Research Institute of Medical Sciences, Patna, a premium research institute on Kala-azar, met Marandi. "I spoke to the health officials there and said we can get him treated at Patna’s IGIMS (where Kusumesh works). I had sent three people there for a corneal implant,” said Madhukar.

A year later, in February 2022, Godda's chief medical officer sent Marandi in an ambulance to IGIMS. He however could not get a transplant there soon, as corneas were hard to come by.



Iliyas Marandi’s medical record on being examined at IGIMS, Patna. Photo Credit: Menaka Rao


Though Marandi got some help from authorities, he also spent money out of pocket for medical expenses.

Kusumesh talks about how the seven patients who came to her with this problem were completely on their own. “The patient gets keratitis (inflammation of cornea) after taking miltefosine," Kusumesh said. "Whose responsibility is it? It is strange that nobody is helping these patients. Patients were coming to me at their own expense. Corneal transplant and other treatment costs money. They were coming from endemic areas such as Gopalganj, Chhapra, and coming frequently--even weekly sometimes.”


Issuing advisories

On December 22, 2021, personnel from the National Vector-Borne Disease Control Programme which works on Kala-azar had a meeting where they decided to form a multidisciplinary group of experts including an ophthalmologist, epidemiologist clinicians, people from WHO and CARE India (now Piramal Swasthya), a non profit that partners with the government on Kala-azar elimination.

The state programme officers shared guidelines with block-level vector-borne disease control officers in early 2022, around the time Marandi was taken to Patna. “The guideline was that there needs to be a mandatory eye check for each PKDL patient prescribed miltefosine and a follow up after one month,” said Rakesh Kumar, Bihar health ministry in-charge of Kala-azar.

Government officials have not sent IndiaSpend these guidelines even after many requests, and they are not on the National Vector Borne Disease Control Programme website. IndiaSpend reached out to Tanu Jain, director of National Vector Borne Disease Control Programme and Joint Secretary, Ministry of Health and Family Welfare, Rajiv Manjhi. Though an interview was promised, repeated follow ups over two months have yielded no results. We will update this story when we receive a response.


Corneal transplant

After hearing complaints of patients such as Marandi, Care India--the non profit that works with the government in the Kala-azar programme--decided to conduct a field trip in March 2022. Asim Sil, an ophthalmologist and public health specialist from West Bengal, was roped in for this exercise.

Sil and the Care team examined 44 patients from Jharkhand and Bihar who had eye problems after taking Miltefosine. “Of the patients we examined, we found that both eyes were affected in 16 patients, and one eye in 27 patients. Half the patients that we examined had a serious kind of disability. It was either a significant loss of vision either in one eye or both eyes,” said Sil.

Is this permanent? “Yes, it's permanent if not reversed by keratoplasty.”

Sil conducted four keratoplasties in all among PKDL patients, where Care India took care of the patient’s treatment. Marandi got his implant in August 2022.

But the success of keratoplasty cannot be guaranteed. The success rate is as low as 40%. Marandi’s vision had improved after keratoplasty, but started deteriorating after six months. He could not arrange for an immediate follow-up, which damaged his optic nerve permanently, said Sil.

Sil said that unless follow up is frequent during the one-and-a-half years following surgery, vision can lapse. “We need to look after a lot of parameters to save the sight. And sometimes it happens that we need to escalate the dose of the drug, and sometimes taper the dose,” said Sil. Besides, people who work as labourers are prone to infection because of exposure to dust.


Lack of ophthalmologists

On February 10, 2022, the WHO issued a statement on the potential ocular disorders in PKDL patients treated with miltefosine. They later formed a committee which included experts from various disciplines in medicine including ophthalmologists, clinicians, public health experts, pharmacologists among others including Sil.

In March 2023, the WHO issued an advisory to minimise the risk of ocular adverse events with miltefosine for both doctors and patients (see box below). The multi-technical group considered that a causal relationship between ocular adverse events and exposure to the miltefosine is, as we said, “at least a reasonable possibility”.

The guidelines mandate clinicians to send PKDL patients to ophthalmologists to then fill out a form before prescribing miltefosine. But not every district in the Kala-azar endemic areas has an ophthalmologist.

“Actually, if you want to rule out something which is in a very early stage (of eye complication), you need a slit lamp examination which a doctor with an MBBS is not trained for,” said Kusumesh.

The WHO advisory says, “Since miltefosine has a very long half-life, it is possible that ocular changes will not heal without treatment even after the discontinuation of miltefosine. Therefore, an eye specialist should be consulted in such cases to avoid possible permanent damage.”

In Pakur district of Jharkhand for instance, there is no ophthalmologist in the public sector. The health officials said that they make do with a general physician for pre-prescription check up. In case there is a problem in the eye, they had an “arrangement” with a private ophthalmologist to do check-ups.

In Bihar, the government said that optometrists can be used in case there are no ophthalmologists. Optometrists are primary eye healthcare providers, and can examine the eyes and help diagnosis or management of disease in the eye. While the guideline is not hard and fast about eye examination done by an ophthalmologist before miltefosine, it is clear that in case of any adverse eye event, the patient should be examined by an eye doctor.


WHO guidelines

Information for healthcare professionals

Before starting the miltefosine treatment, doctor should conduct an eye examination and take the detailed history of eye disorders

In case of current or past history of ocular disorder, the benefits and the risks of treating a patient with miltefosine should be carefully considered, and advice from an ophthalmologist should be sought where feasible.

All patients should be informed before starting the treatment that in case of eye problems during the treatment (e.g. red eyes, increased watering, eye pain, blurred vision) they should discontinue miltefosine and contact their healthcare professional immediately.

If an adverse eye event happens, patients should be immediately referred to a doctor and treatment by miltefosine should be stopped.

It is possible that ocular changes will not be reversible without treatment even after discontinuation of miltefosine. Therefore, an eye specialist should be consulted in such cases to avoid the possibility of permanent damage.

Suspected adverse events should be reported to local health authorities and the national pharmacovigilance programme without delay.

Source: World Health Organization advisory, March 2023


Building local capacity

One official connected to the NVDCP who did not want to be named said that the problem “magically disappeared” after these guidelines came into force.

“The government should arrange for the training of ophthalmologists in endemic areas about this specific side effect connected to miltefosine. That is the ethical thing to do,” said Prabir Kumar Chatterjee, public health clinician who has worked in the tribal areas of Jharkhand which has a high incidence of Kala-azar. He now practices in West Bengal.

As recently as August 2023, this correspondent is aware of a case in Dumka district where the patient started losing his vision after miltefosine. The health worker there contacted Sil and made a video call, where Sil saw that his eyes were “substantially inflamed”.

Sil spoke to the treating ophthalmologist about the ocular manifestation of miltefosine, and how it can be effectively treated using a steroid. But the ophthalmologist treated him for a fungal infection, which did not work. The patient was finally convinced to go to Sil, who treated him after which the patient’s vision improved.

“It is the training of the doctors so that they feel confident to treat this patient with topical steroids. Actually, we ophthalmologists always hesitate to give steroids,” said Sil. He said such patients can be taken to district hospitals which are linked with tertiary level centres such as IGIMS.

“We have to develop local capacity," said Sil. "What we are doing from the outside is an ad hoc measure or say firefighting. PKDL is going to be there. Unless we develop a better alternative, they will be treated with miltefosine.”


Compensation for patients?

More than 9,000 patients were detected and presumably treated for PKDL between 2014 and 2024, as per the records of National Vector Borne Disease Control Programme website accessed on March 26. Bihar government’s Rakesh Kumar said that there is no record of ocular side effects related to miltefosine before 2020.

"We have no list of patients who had any such complication before 2020,” said Kumar.

Two papers documenting this side effect were released from Bihar itself, one in 2019 and one in 2020 from IGIMS, a government medical college. Many of these patients went to ophthalmologists on their own, spending their own money and resources.

“The vision of all the patients who had eye complications was restored. Nobody lost their eye in Bihar,” said Kumar, who was confident that no patient who had an eye problem could ever be hidden from public authorities. “There is no plan from our end for the patients who took miltefosine before 2020," he said. "We have linked our programme with the National Programme for Control of Blindness and Visual Impairment formally.”

“The good thing is that we are able to tackle the fresh cases. But for the old cases, the government should show their responsibility.” said Sil.

G.V.S. Murthy is the Professor of Public Health Eye Care and Disability at the International Centre for Eye Health, London School of Hygiene and Tropical Medicine, UK. Having worked with government programmes in the past, he said that there is a need to have a rapid survey of areas where Kala-azar is endemic. “The survey can be done using ASHA workers. There is a need to find out who are the people who have lost their sight and the number of such persons affected,” said Murthy.

Chatterjee, the public health clinician from West Bengal, said that the patients who took treatment and suffered any kind of eye problem should be compensated for the adverse effect by the government.

Meanwhile, Marandi is stuck at home. His mother, who is single, goes to work and tries to run the household. The health officers linked Marandi with a disability pension scheme which gets him Rs 1,000 a month. He has plans to seek help from non-profits that help develop skills for blind people.

“What can I get for Rs 1,000? I had plans to study, but right now everything seems very difficult,” said Marandi.

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