“The food we have, the stress we take and the environment we are in cause a lot of changes in our body. They can rapidly change your gut microbial profile for the worse, making you unresponsive to treatment.” - Dr Rohit Shetty Vice chairman and chief of cornea and refractive surgery, Narayana Nethralaya
“Beneficial gut bacteria help manufacture vitamins (B12, K, B6, B5, B3, folate and biotin), enhance absorption of minerals, fight off pathogens, digest food, influence total body metabolism and metabolise drugs.” - Dr Irfana Akther Director of ICAM Wellcare Clinic
Shyamala B., 61, was diagnosed with diabetic retinopathy, for which she took anti-VEGF injections several times. But, they did not help. Doctors say there is an increasing incidence of resistance to anti-VEGF treatment.
In a world that turned blurry, Shyamala B. felt like an alien.
The images on her television screen appeared like abstract collages. She struggled to make sense of the 'breaking news' at the bottom of the screen. Some of her friends and relatives 'unfriended' her for failing to recognise them at family functions.
The 61-year-old diabetic was worried, as her vision became hazy and she started seeing double images. She was soon diagnosed with diabetic retinopathy—she had bleeding in both eyes and swelling in the central vision area of the retina (macular oedema).
Scared of injections, Shyamala was hesitant to take anti-VEGF (vascular endothelial growth factor) shots, administered at the back of the eye. She agreed only after her doctor told her that these injections are good for people with macular oedema and abnormal blood vessels in the retina.
Shyamala got anti-VEGF injections several times. Though she got used to the pain, her vision remained cloudy. What finally worked was pan retinal laser photocoagulation for the bleeding and intravitreal steroid injection for the swelling in the retina. “They worked well. The vision in her right eye improved significantly and has been stable over the past two years,” says Dr R. Rajalakshmi, head, medical retina at Dr Mohan's Diabetes Specialities Centre in Chennai, whom Shyamala consulted.
Shyamala's left eye had more severe retinopathy damage, and anti-VEGF injections hadn't helped at all. “Initially, she was unwilling to undergo surgery in the left eye. But after the right eye vision improved and was stabilised, she was motivated and she underwent a retina surgery combined with cataract surgery in the left eye last year,” says Rajalakshmi. Now, Shyamala has good vision in both eyes.
Ten years ago, most patients who received anti-VEGF treatment would get better, recalls Dr Rohit Shetty, vice chairman and chief of cornea and refractive surgery, Narayana Nethralaya in Bengaluru. “It still gives good results in 70 per cent of patients, but 30 per cent just do not respond,” he says. “Nonetheless, they keep getting the injection again and again, hoping it will work. Some of them don't get better even if you give them 20 injections. We are seeing an increase in incidence of resistance to anti-VEGF.” These non-responders have “a completely different level of diabetic process”. “The genetics of diabetes makes them resist anti-VEGF,” he says.
Researchers at Narayana Nethralaya have done numerous studies on patients who don't respond to anti-VEGF treatment. “In about 22 per cent of the patients who receive anti-VEGF treatment, the pathway of retinal bleed is different from what is known [and being treated],” says Shetty.
Non-responders to treatment are increasing in every branch of medicine, says Shetty. “The world of non-responders, which was 2 per cent earlier, has now risen to 35 to 40 per cent. Treatments are not going according to the book,” he says. “Ten years from now, 50 per cent of the patients may not tolerate the treatment that is given today. We need to put in efforts to tackle that.”
Why medicines don't work for some has caught the attention of scientists across the world. It is attributed to a variety of factors, ranging from genetic changes to antibiotic resistance. India, one of the largest consumers of antibiotics in the world, has a high prevalence of drug resistant organisms. “Multi-drug resistant tuberculosis, an emerging health crisis, requires urgent attention,” says Dr Swati Rajagopal, consultant, infectious diseases and travel medicine at Aster CMI Hospital, Bengaluru.
But, what about patients who have never used antibiotics before? They don't respond to some of the drugs and treatments, either. Scientists are exploring the whys and wherefores of this phenomenon. They say human genes are changing. “The food we have, the stress we take and the environment we are in cause a lot of changes in our body. They can rapidly change your gut microbial profile for the worse, making you unresponsive to treatment,” says Shetty.
Antidepressants won't work as effectively as they would have if the gut microbes are not taken care of, says Dr Kersi Chavda, consultant psychiatrist at Hinduja Healthcare Surgical, Mumbai. “The gut microbiota is associated with neuropsychiatric disorders such as schizophrenia, autism, anxiety and major depressive disorders, besides metabolic syndrome that includes obesity and diabetes mellitus,” he says.
In the past few years, research in neuroscience has clearly demonstrated the link between gut bacteria and the brain, says Chavda. “Recent studies show that the microbiota could activate the immune and central nervous systems,” he says. “Gut microorganisms are capable of producing and delivering neuroactive substances such as serotonin, which act on the gut-brain axis. Due to the indiscriminate use of antibiotics and changes in lifestyle, the good bacteria are affected and the bad ones become predominant, affecting those neuroactive substances. This could lead to psychological disorders as also Irritable Bowel Syndrome, autoimmune and allergic diseases and obesity.” Depression often manifests with a chronic, low-level inflammatory condition. “The gut microbial has been suggested to be the key factor in the link between unhealthy diet and depression,” says Chavda.
Recent studies on the gut bacteria offer great hope to people with treatment-resistant depression and other psychiatric problems. “It has been suggested that microorganisms be made into a new group of drugs, named 'psychomicrobiotics', for the treatment of psychiatric disorders,” says Chavda. Studies done on mice show that behaviour that mimics human anxiety, depression and even autism, induced by disruptions of the microbiome, can be restored by treating the mice with certain strains of bacteria. “Nearly all the data so far is limited to mice, but it seems likely that the human brain and gut will behave in a similar fashion,” he says.
Even probiotic supplements can play a huge role in the treatment of depression, making conventional treatment more effective. Mumbai-based Ronda, 28, would vouch for that. She consulted Chavda, complaining of depression symptoms. The antidepressants she was prescribed helped her to a certain extent, but she was still very weepy and sad. “She also complained of severe flatulence and non-specific abdominal pain as well as occasionally loose stools,” recalls Chavda. Then he added a probiotic and there was a palpable change within two weeks. “Randa was happy again. She felt she had never been so positive before,” he says. “Today, the magic mantra is to add supplementation of probiotics to conventional antidepressants to get the best beneficial results.”
Dr Irfana Akther, director of ICAM Wellcare Clinic in Bengaluru, prescribes digestive enzymes, probiotic and prebiotic supplements to all her patients regardless of their diagnosis. She always reminds her patients that it is important to maintain gut health so the medicines yield the desired results. “Beneficial gut bacteria help manufacture vitamins [B12, K, B6, B5, B3, folate and biotin], enhance absorption of minerals, fight off pathogens, digest food, influence total body metabolism and metabolise drugs,” says Akther.
The human gut contains about 1.5-2kg of bacteria, and 70 per cent of our immune system cells live in and around the gut. Akther is a proponent of Colon Hydrotherapy, a gentle colon cleanse using ozonated water that can help flush out built-up waste. She believes it can heal the damage to the gut caused by fast food and processed artificial food.
Experts say the treatment of some of the common ophthalmological diseases and conditions like myopia is becoming challenging. “Dry eye doesn't behave the same as before,” says Shetty. “People having vitamin D deficiency are the ones who come back to us with severe dry eye. This is a new-age disease. Until and unless you treat vitamin D deficiency, your eyes will bother you.” Vitamin D deficiency is common among urban people who stay indoors most of the time.
Sylvia from Norway, the happiest country in the world, would always be the odd one out at family gatherings. The 28-year-old was always under too much stress. She joined an ashram in India to learn yoga and meditation. She became a vegan and spent most of her time indoors. Three years later, she developed severe dry eye, which was resistant to conventional treatments. “We found that Sylvia had severe nutritional deficiencies owing to her dietary habits,” says Shetty. “She was treated for vitamin D and vitamin B12 deficiencies and in three months, she started showing remarkable improvement. Her eyes are now responding to the same medicines that failed earlier.”
Poor nutrition makes medicines less potent. Nutrition is especially important for children undergoing cancer treatment. “Eating the right kind of food before, during and after treatment can help children recover faster,” says Nikita Mahakal, head nutritionist, Cuddles Foundation, an NGO that provides protein- and calorie-rich supplements to children undergoing cancer treatments.
The nutritional status of Indian children presents a worrisome picture. Malnutrition is prevalent even among urban children from affluent families. Easy access to junk food makes them fall sick more often and they take longer to recover.
Your body type could influence the efficacy of drugs, says Dr V. Mohan of Dr Mohan's Diabetes Specialities Centre. “For example, obese people may respond differently from lean people,” he says.
Drug resistance is a major problem in orthopaedics, too, where implant-related infections are very common. “We see poor drug response, particularly in reference to bone tuberculosis and other chronic infections of bone and joints, too,” says Dr Shah Alam Khan, professor, department of orthopaedics, All India Institute of Medical Sciences, New Delhi. “It is also seen in ailments of joints, that is rheumatological conditions, which are mainly due to immunological reasons.”
The genetic makeup of an individual could also impact drug performance to a great extent. A classic example of this is isoniazid, a drug being used in the treatment of tuberculosis. “The metabolism or breakdown of this drug classifies people as slow or rapid acetylators. It is well known that rapid acetylators do worse than slow acetylators in some regimens. The acetylation is a genetically determined quality,” explains Khan.
Dr B.S. Ajaikumar, chairman and CEO of Healthcare Global Enterprises Ltd, lists three reasons for patients not responding to cancer treatment: biology of the patient, inappropriate technology and human error. “Thirty per cent of colon cancer patients are unresponsive to treatment,” says Ajaikumar. Sadly, many of them undergo treatments unnecessarily. Unlike earlier, it is now possible to identify the composition of the cancer cells with the help of genomics and plan treatment accordingly.
Some names have been changed.