New co-infection guidelines blast short-course, twice-weekly regimen
Gold standard for isoniazid prophylaxis is nine months, not six
New guidelines for treatment and prevention of TB in HIV-positive patients hold a stern reminder: What’s convenient for programs isn’t always what’s best for the patient. Last month’s official pronouncement on preventive therapy for HIV-positive patients comes as a disappointment to some program administrators, who had hoped for the go-ahead to provide the new short-course, two-month preventive regimen of pyrazinamide and rifampin (PZA/RIF) on a twice-weekly basis.
No way, the Centers for Disease Control and Prevention guidelines plainly state. Another unpleasant surprise is the reminder that when it comes to high-risk patients (including those with HIV), the duration of isoniazid prophylaxis isn’t six months; it’s nine months.
The recommendations reflect a conscious decision to drag people from the brink of wishful thinking and to clarify what the data do and don’t support, says Larry Geiter, MPH, PhD, a consultant with Sequela Research Foundation in Rockville, MD. "We wanted to make the point that recommendations for clinical decision making shouldn’t be made on a cost-effectiveness basis," says Geiter, an expert whose testimony is said to have swayed the roomful of national experts gathered to mull over the new guidelines.
"I can understand people’s disappointment," says Rick O’Brien, MD, chief of the research and evaluation branch at the CDC’s division of tuberculosis elimination. Purely from a programmatic perspective, he says, the less onerous recommendations "would have been great." The problem is that the data don’t support such recommendations, he adds.
Reaction runs across the board. To some program administrators already hit with a new round of funding cuts (see related story, p. 136), the guidelines offer powerful evidence that more study on short-course therapy is needed urgently.
"I think [rifampin and pyrazinamide] on a daily basis severely limit the advantages of short-course preventive therapy," says David Ashkin, MD, medical director of Florida’s TB control program. "We’ve had enormous amounts of difficulty getting people through preventive therapy."
Plus, preventive therapy only works if it’s in the patient’s stomach, Ashkin argues. Thus, what an intermittent course of PZA/RIF might lose in efficacy, it more than makes up for in adherence. "Even if RIF/PZA isn’t as effective by, say, 3%, you more than offset that difference if you improve adherence by 30% to 40%," he says. Besides, "in the study that was already done, the data on twice-weekly looks as if it performed as well as daily," he adds.
Partly in the hope of gathering more evidence in support of twice-weekly PZA/RIF, Ashkin is considering a trial protocol of the twice-weekly regimen.
CDC discounts results of Haitian trial
One of the investigators associated with the intermittent trial of PZA/RIF also expresses disappointment with the CDC guidelines and with the decision to discount the results of that trial, which was conducted in Haiti. "It’s unfortunate," says Jacqueline Coberly, PhD, an assistant scientist at the department of international health at the school of hygiene and public health at Johns Hopkins University in Baltimore.
The CDC discounted the results of the Haitian trial for complicated reasons, says Geiter. Most importantly, the Haitian trial used as its standard for comparison a six-month course of self-administered isoniazid (INH). However, nine to 12 months of INH, not six months, is the gold standard for HIV-infected patients and should have been the standard for comparison in the trial, he adds.
True enough, says Coberly. "There’s no question that nine months of INH is more efficacious than six," she says. "But when it comes to the probability of someone actually taking the nine months, we found only 55% of people actually finish; whereas 74% of people taking the [intermittent] PZA/RIF finish."
The trouble comes when the daily PZA/RIF and the intermittent are stacked against one another, says Geiter.
The Haitian trial and another in Zambia, the results of which haven’t yet been published, compared two months of intermittent PZA/RIF to six months of INH, Geiter says. The Haitian trial put the level of protection for intermittent PZA/RIF at 60% and at 65% for six months of INH; that trial suggested intermittent PZA/RIF might — or might not — perform as well as six months of INH. Point estimates in the Zambian trial suggested the same, slightly ambiguous conclusions.
On the other hand, a third study comparing 12 months of daily INH to two months of daily PZA/RIF left no room for doubt, says Geiter. That trial found an 80% reduction from 12 months of INH; and an 84% reduction from two months of daily PZA/RIF, which suggests that two months of daily PZA/RIF might offer even better protection than 12 months of INH, he says.
"So we’re saying that PZA/RIF on an intermittent basis is probably just as good as six months of INH but may actually be worse," he explains. "Plus, we already know six months of INH isn’t as good as 12." That, plus the way both the Haitian and Zambian trials seemed to tilt against the intermittent regimen of PZA/RIF, left intermittent PZA/RIF saddled with too many doubts, he says.
As the dust settles, other experts are taking a more philosophical stance, declaring intentions to cut their losses by ditching nine months of INH and substituting two months of daily PZA/RIF for both HIV-negative and HIV-positive patients. That regimen "has been shown to be state of the art, and I say people have no business using nine months of anything if they can use RIF/PZA," says Lee Reichmann, MD, MPH, director of the National Tuberculosis Center at New Jersey Medical School in Newark. "It’s there; it works; I’ll use it."
To keep the debate interesting, at least one expert is blasting the CDC recommendation of daily PZA/RIF as misguidedly liberal rather than overly conservative. "PZA plus rifampin? You tell my buddies at the CDC that I love them all, but that I said this is gonna be the biggest disaster they’ve ever given us," says John Sbarbaro, MD, professor of medicine at the University of Colorado Health Sciences Center in Denver. "It goes totally contrary to everything we know about PZA in the continuation phase," which, he adds, is practically the same as latency. "So why on earth add it? It merely adds hepatotoxicity. You’re going to see a ton of hepatitis with this new regimen," he says. "This whole thing will set us back for 20 years."
One of Sbarbaro’s colleagues and neighbors is more sanguine on the subject. "I don’t think PZA is exactly dangerous," says William J. Burman, MD, infectious disease expert with the Denver TB control program. "But I do think there are some concerns about its tolerability. People may not want to put up with the side effects, which are fairly common, though seldom serious: the upset stomach, the itching after doses, the myalgia."
Back to that other line in the sand, nine months of INH vs. six months, Sbarbaro as well as experts on the more pragmatic side were more understanding. "Nine months of INH? That’s just being conservative, but it makes sense," he says. "What’s better? Eighty percent of the drugs for a few months, or 30% of the drugs for a year? It’s counterintuitive, but the right answer is the second. That’s because in preventive therapy, you’re going after bugs that are dormant; and the longer you continue the therapy, the better the chance that the drugs will be there when the bugs wake up."
The nine-month rule also is important to emphasize because it helps explain why risk- benefit equations break down in the face of the higher risks for reactivation posed by HIV-positive patients, Geiter says. "Back in 1985, people began talking about a six-month regimen of IPT being more cost-effective. What kind of got lost over time is the fact that the individual patient would still benefit from taking another six months of treatment. And with HIV-positive patients, the overall risk for progressing to TB is so high that even on a cost-benefit basis, going from six to 12 months is still worthwhile."
Easier regimens won’t sacrifice efficacy
From the standpoint of what’s doable, Geiter doesn’t dispute appeals to practical arguments; he simply says it’s important not to mix the nitty-gritty of real-life decision making with the practices dictated by the data.
Plus, programs can make regimens easier without sacrificing efficacy altogether, he adds. "If a public health program wanted to say, OK, we’re going to give people PZA/RIF, but we’ll only supervise them five times a week, or three times a week, and let them self-administer on the weekend. And then maybe [we’ll] give them nine weeks of the drugs instead of eight weeks,’ in practice that makes sense, even though it’s not supported by clinical trial data," he says. "Or you could DOT [directly observed therapy] them five times a week and give them a drug holiday on the weekend. There are all kinds of things you can do within reason to be creative."
In the same way, it’s acceptable to aim for getting six months of INH into "your garden-variety, HIV-negative patient," Geiter says. "But what we’ve tended to lose sight of is that the data don’t support that. What they actually show is that maximum benefit is achieved right about at nine months, and I think over the years we’ve lost sight of that fact."
With an HIV-negative patient, the risk of reactivation after six months is only about 10% to start with. Six months of INH cuts it by 65%, so adding another three months only buys an extra 3.5%, which isn’t cost-effective in most cases, he says.
There’s a practical reason to keep the bar high, he adds. If a program formally adopts a six-month course of INH as the ideal, it’s hard to return to state legislatures after the fact and beg for more money for preventive care. On a smaller scale, he says, a primary care physician who thinks mistakenly that six months is the ideal probably will be happy with five months of treatment, and that would surely be a mistake.
Geiter sums it up this way: "If you’re going to make these decisions on a cost-effective basis, you need to be clear that’s what you’re doing. I understand the pressure people are under. I’m just saying, don’t mix clinical guidelines with cost considerations."
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