Scientists discover cure for strain of tuberculosis
TSAKANE, SOUTH AFRICA » When she joined a trial of new tuberculosis drugs, the dying young woman weighed just 57 pounds.
Stricken with a deadly strain of the disease, she was mortally terrified. Local nurses told her the Johannesburg hospital to which she must be transferred was very far away and infested with vervet monkeys.
“I cried the whole way in the ambulance,” Tsholofelo Msimango recalled recently. “They said I would live with monkeys and the sisters there were not nice and the food was bad and there was no way I would come back. They told my parents to fix the insurance because I would die.”
Five years later, Msimango, 25, who became the trial’s fifth enrolled patient, is now tuberculosis free. She is healthy at 103 pounds, and has a young son.
The trial she joined was small it enrolled only 109 patients but experts are calling the preliminary results groundbreaking. The drug regimen tested on Msimango has shown a 90% success rate against a deadly plague, extensively drugresistant tuberculosis.
On Wednesday, the Food and Drug Administration effectively endorsed the approach, approving the newest of the three drugs used in the regimen. Usually, the World Health Organization adopts approvals made by the FDA or its European counterpart, meaning the treatment could soon come into use worldwide. Usually, the World Health Organization eventually adopts approvals made by the FDA or its European counterpart, meaning the treatment could soon come into use worldwide.
Tuberculosis has now surpassed AIDS as the world’s leading infectious cause of death, and the socalled XDR strain is the ultimate in lethality. It is resistant to all four families of antibiotics typically used to fight the disease.
Only a tiny fraction of the 10 million people infected by TB each year get this type, but very few of those who do survive it.
There are about 30,000 cases in more than 100 countries. Threequarters of those patients die before
they even receive a diagnosis, experts believe, and among those who get typical treatment, the cure rate is only 34%.
The treatment itself is extraordinarily difficult. A typical regimen in South Africa requires up to 40 daily pills, taken for up to two years. Other countries rely on even older regimens that include daily injections of antibiotics that can have devastating side effects, including deafness, kidney failure and psychosis.
But in the trial Msimango joined, nicknamed Nix-TB, patients took only five pills a day for six months.
The pills contain just three drugs: pretomanid, bedaquiline and linezolid. (Someday, the whole regimen might come in just one pill, as HIV drugs do, one expert said.)
Until recently, some advocacy groups opposed pretomanid’s approval, saying the drug needed further testing. But other TB experts argued that the situation is so desperate that risks had to be taken.
Dr. Gerald Friedland, one of the discoverers of XDR-TB and now an emeritus professor at Yale’s medical school, called Nix “a wonderful trial” that could revolutionize treatment: “If this works as well as it seems to, we need to do this now.”
A killer appears
News that tuberculosis had
evolved a terrifying new strain first broke in 2006, when doctors at a global AIDS conference learned of a doomed group of tuberculosis patients in Tugela Ferry, a rural South African town.
Of the 53 patients in whom the strain had been detected, 52 were dead most within a month of diagnosis. They were relatively young: The median age was 35.
In the early years, XDR-TB was a death sentence. Doctors tried every drug they could think of, from those used to treat leprosy to those for urinary tract infections.
“From 2007 to 2014, we threw the kitchen sink at it,’’ said Dr. Francesca Conradie, a researcher at the University of the Witwatersrand, Johannesburg, and director of the Nix trial.
The death rate was about 80%. Sometimes the drugs killed patients. In other cases, patients died because they could not tolerate the drugs and stopped taking them.
Tuberculosis germs burrow deep into the lungs and barricade themselves inside clumps of dead cells. Breaking those nodules apart and killing all the bacteria inside requires taking drugs for months.
Nearly all antibiotics cause nausea and diarrhea. But some, especially the injections, are far tougher. “I had a patient who tried to commit suicide because of the tinnitus ringing in his ears,” said Dr. Pauline Howell, a tuberculosis researcher who runs the Nix trial at Sizwe Tropical Diseases Hospital in Johannesburg, where Ms. Msimango was treated.
“Some get hallucinations,” Howell said. “I had one patient who tried to cut open his skin because he thought bugs were crawling under it. I’ve had patients who became wheelchair-bound because of the vertigo.”
Patients can go deaf over a weekend, she said, or the nerves in their feet and hands can wither until they can no longer walk or cook. Some develop disrupted cardiac rhythms, which can trigger heart attacks.
Msimango, too, veered close to death because the drugs were too much for her.
When she was 19, she said, she caught drug-resistant TB from another young woman the temporarily homeless daughter of a friend of her mother.
Her mother had generously taken in the young woman and had told her daughter to share her bed, a common arrangement in townships like Tsakane. “A few weeks after she left, I started coughing,” Msimango said.
“She had not told us that she had drug-resistant TB and had defaulted,” she added, using a common term for dropping out of treatment.
At first, Msimango got her injections at a hospital and took her pills under her mother’s watchful eye. But they made her feel so awful that she secretly spat them out, stuffing them between the sofa cushions when her mother wasn’t looking.
After she defaulted twice herself, she was transferred to Sizwe, terrified that she would die alone.
A rush to approval?
The regimen successfully tested at Sizwe is called BPaL, shorthand for the three drugs it comprises: bedaquiline, pretomanid and linezolid.
The BPaL regimen is “bold, because it’s three killer drugs instead of two killers plus some supportive ones,” Howell said.
Most regimens, she explained, rely on two harsh drugs that can destroy bacterial walls and include others that have fewer side effects but only stop TB bacteria from multiplying.
But even the new treatment poses hazards. Short-term use of linezolid against severe hospital infections causes few problems, but use for many weeks against TB can kill nerves in the feet, making it hard to walk, or can suppress the bone marrow where blood cells are made. (To find the ideal linezolid dose, the Nix investigators have started a new trial, ZeNix.)
The FDA approved bedaquiline in 2012 for use against multi-drug resistant TB (the XDR strain is an even deadlier subset), and in 2015 the WHO followed suit.
Until Wednesday, pretomanid was in dispute, although in June an FDA advisory committee voted 14-4 to approve it.
Some advocacy groups argued at the time that the drug had been too little tested.
“Pretomanid looks like a promising drug, but it’s being rushed forward, and we don’t want to see the FDA lower the bar for approval,” Lindsay McKenna, co-director of the tuberculosis project at the Treatment Action Group, an advocacy organization, said in July.
Her organization and others had asked the FDA to first demand two of the most rigorous tests: a head-to-head comparison of pretomanid against delamanid, a related drug, and a randomized clinical trial in thousands of patients of the Nix regimen versus another used by the WHO.
Pretomanid which is named for Pretoria is not owned by a drug company but by the TB Alliance, a nonprofit based in New York that is seeking new treatments.
Dr. Mel Spigelman, the alliance’s president, had argued that a full clinical trial would be both impractical and unethical.
“Put yourself in a patient’s position,” he said. “Offered a choice between three drugs with a 90% cure rate, and 20 or more with less chance of cure who would consent to be randomized?”
Such a trial would cost $30 million and take five more years, he added: “That’s a very poor use of scarce resources.”