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Russian physicians see DOTS-Plus in action
Last month, a group of physicians from prisons in the Russian province of Tomsk arrived in the United States prepared to become the first people on earth — outside the small corps of Harvard TB experts who pioneered the concept — to learn the nuts and bolts of DOTS-Plus, the controversial variation of Directly Observed Therapy, Short-Course.
The notion that patients can be treated successfully with expensive, brutally toxic medications under Spartan field conditions is one that still provokes skeptical opposition among many respected TB experts.
"I’m not saying I’m against DOTS-Plus, just that it’s fraught with some terrible problems," says Gwen Huitt, MD, co-director of the adult day unit at the mycobacterial division in the department of medicine at National Jewish Hospital in Denver. "Part of me thinks if you’re working in a developing country, and you’ve got drug-resistant cases, the best thing is to put these people in a sanitarium. Treat them as best you can, isolate them, but don’t start these second- and third-line drugs."
DOTS-Plus proponents passionately disagree. Allowing MDR-TB patients to die for lack of treatment — the kernel of realpolitik believed to make DOTS sustainable in even the most impoverished countries — is not only unethical, they contend, but eventually will lead to the takeover of resistant strains. "The point is that DOTS is fine as far as it goes, but if you give it to someone with resistance, you’ll just get more resistance," says Lee B. Reichman, MD, MPH, director of the National TB Center of the New Jersey Medical School in Newark.
Newark was the first stop on the Russians’ itinerary. Under the tutelage of experts at the center and speaking through an English translator, the group spent last month learning the nuts and bolts of how to treat MDR-TB. "They’re all extremely bright and capable, and they’re asking very good questions," Reichman reports. Among those questions was what to do with a patient on six liver-toxic products.
After Newark, the Russians were scheduled to leave for Lima, Peru, site of the model DOTS-Plus project, for a close-up look at the program.
"The meds we use get a lot of really bad press. They’re not easy to take, not by any stretch," admits Jennifer Furin, MD, PhD, a veteran of the Lima project and the director of clinical services in the program of infectious disease and social change at Harvard University in Boston. "But what we’re finding is a relatively new concept in TB treatment — that it’s possible to treat through a lot of the side effects."
"Side effects" is putting it mildly. To begin with, there’s cycloserine. "You mention cycloserine and people say, Oh, you can’t possibly use that medication; it makes everyone crazy and they have seizures,’" says Furin.
According to Huitt, in fact, 80% to 90% of patients on cycloserine suffer side effects. "For some, it’s just mild depression and trouble with tasks like balancing a checkbook," she says. In other cases, the drug has provoked suicide.
Then there’s ethionamide, which causes severe gastrointestinal distress, including nausea, vomiting, and diarrhea. In addition, ethionamide often leads to endocrine dysfunction, which can manifest itself as drug-induced diabetes, impotence in men, or menstrual irregularities in women.
Para-Amino Salicylic Acid, or PAS, is infamous for the bloating and diarrhea it causes; taken in combination with ethionamide, it’s a sure-fire guarantee a patient will experience hypothyroidism, Huitt says.
The drugs are as tricky to administer as they are hard to tolerate, Huitt adds. PAS must be taken with an acidic beverage, never with anything alkaline, not even water. Quinolones demand an empty stomach; plus, patients must avoid taking antacids, multivitamins, or anything else that might contain a metal, which would inactivate the drug. "The whole thing is just a can of worms," says Huitt. "To be honest, there aren’t even that many people in the U.S. who can work with these drugs."
Furin and her colleagues say they’ve learned to manage. "The way we look at it is that treatment for MDR is a lot like cancer chemotherapy," she says. "We train our health care workers to think about the drugs that way, so that they learn how to manage both the psychological and physical impact."
Along with providing support and monitoring carefully for compliance, community health workers in Peru look carefully for early signs of trouble, says Furin. The trick is to figure out which symptoms are unpleasant but manageable, and which ones signal life-threatening conditions, such as hepatotoxicity or renal failure.
Serious side effects are rare, she adds. "I can count on my fingers the number of times I’ve had to stop a drug." Other reactions haven’t been as bad as experts had warned. "We found when we started doing this work that most of the literature on these drugs’ side effects comes from the 1960s," she says. "There was a lot more fear about the subject than there was real data."
Though experts predicted practically all patients on cycloserine would suffer seizures and psychosis, Furin says she’s found the incidence of those symptoms is closer to 6% for seizures and 8% for psychotic symptoms. Renal failure occurs only about 2% of the time. Instead of 100% of patients on PAS and ethionamide suffering from hypothyroidism, Furin says the true proportion, in her experience, is closer to 30%.
Even when serious side effects do occur, DOTS-Plus practitioners argue against lowering dosages or dropping a medication. "Instead, we try to recognize side effects early on and treat them as aggressively as possible," Furin says. "That’s the kind of thing the Russian doctors need to see."
After Peru, the Tomsk physicians will spend the last leg of their journey in Birmingham, AL. There they’ll get further instruction from Michael Kimerling, MD, MPH, the medical director for the Russian program of the Public Health Research Institute and consultant for the medical arm of Doctors Without Borders.