Shorter regimens can boost adherence in latent TB infection

Eighty percent of active TB is due to prior infection, so treatment of latent tuberculosis infection (LTBI), which affects about 3% to 5% of the U.S. population, is essential to reducing disease incidence. Adherence issues and length of therapy have historically been barriers, but shorter, safer, and easier-to-use regimens now offer some potential solutions, said Amee S. Patrawalla, MD, MPH.

“Ultimately, it's better for our patients. And this brings us closer, hopefully, to TB elimination in this country,” she said. At CHEST 2019, held last October in New Orleans, Dr. Patrawalla offered attendees an overview of current treatment options for LTBI.

The most common short-course regimen, weekly isoniazid (INH) and rifapentine for 12 weeks, was shown to be effective in the PREVENT TB trial, which was published in the Dec. 8, 2011, New England Journal of Medicine. “It was not the first trial that looked at INH and rifapentine weekly, but it certainly was the most significant in terms of getting the guidance changed in the U.S.,” said Dr. Patrawalla, who is an associate professor of medicine and director of the pulmonary disease/critical care training program at Rutgers New Jersey Medical School in Newark.

The PREVENT TB investigators randomly assigned patients with LTBI and high risk for reactivation to receive daily isoniazid for nine months or the 12-dose regimen of weekly isoniazid and rifapentine. Over three years of follow-up, TB disease developed in 0.19% of the 12-dose group and 0.43% of the nine-month isoniazid group, and the combination arm was noninferior to isoniazid. However, adherence rates were 82% and 69%, respectively. “This is really the conclusion of this study and the take-home message,” Dr. Patrawalla said. The 12-dose regimen is approved for patients ages 2 years and older but not for pregnant women or women expecting to become pregnant during treatment, she said, noting that LTBI treatment is often avoided in those who are pregnant or recently postpartum due to concerns about hepatoxicity, unless they are at very high risk.

A flu-like reaction can occur with the 12-dose regimen, Dr. Patrawalla said, usually after three to four doses and on average about four hours after the dose is taken. “This is not something very easy to monitor. You're not going to have somebody in your office for four hours. …You're not necessarily going to monitor them after each and every dose,” she said. “So this is where patient education comes in, where we talk to our patients about what they can expect, when to stop their medication, and when they should call us.”

Typically, she said, a mild reaction should resolve within 24 hours. Severe reactions are extremely rare, but in patients who do require hospitalization or develop hypotension, physicians should stop the medication and not rechallenge, she said. Patients with a more mild or moderate reaction can usually continue therapy with close observation.

Previously, it was recommended that the 12-dose regimen be given as directly observed therapy, Dr. Patrawalla said. However, the iADHERE study, which was published Nov. 7, 2017, by Annals of Internal Medicine, compared adherence to the 12-dose regimen with directly observed therapy, self-administered therapy, or self-administered therapy plus text-message reminders. Rates in the directly observed therapy group and the self-administered group without reminders in the U.S. were noninferior, she said. “So in the U.S. some time ago, the CDC updated their guidance, and we do now use self-administered therapy with close monitoring for the 12-dose regimen,” Dr. Patrawalla said.

The 12-dose regimen does have some important drug interactions, she stressed. Rifapentine, a long-acting rifamycin, will interfere to some degree with oral contraceptives, some antiretroviral drugs, methadone, buprenorphine, warfarin, and phenytoin. “[For] some of the interactions, maybe you can dose-adjust the other medicine, and some, really, you just can't use them together,” Dr. Patrawalla said. The 12-dose regimen can be used in patients with HIV who are taking efavirenz, raltegravir, or dolutegravir, for example, but not in those taking a protease inhibitor, she said. In addition, the 12-dose regimen should not be used in patients who are in contact with someone who has isoniazid- or rifampin-resistant TB.

Dr. Patrawalla offered a few tips for improving adherence. “I do warn patients that while it's one dose a week, because of the formulation and the pills, for most healthy, normal-size adults, it's 10 pills once a week,” she said. “So you do have to tell them that because if you don't, they may take one pill a day.” She recommended advising patients to set an alert on their phones and get in the habit of taking the pills at the same time every week. In addition, the CDC offers free tools that can be used to help adherence, such as customizable medication logs and a symptom checklist (see sidebar).

Four months of daily rifampin as LTBI treatment has been an acceptable regimen since 2000, based on prior data, Dr. Patrawalla said. More recently, in the Aug. 2, 2018, New England Journal of Medicine, a randomized controlled trial compared four months of rifampin with nine months of isoniazid among 6,800 patients in multiple countries. Adherence was better with rifampin, 79% versus 63%, and adverse event rates, including hepatotoxicity, were lower, with no difference seen in incidence of active TB.

“Again, we have to consider our drug interactions, and rifampin is really the worst at metabolizing other drugs,” Dr. Patrawalla cautioned. “Some can be mitigated—if somebody's on a small dose of prednisone, you can probably increase their prednisone dose and get away with the rifampin—but others really will be limiting. If you really need to use something and you don't want to use isoniazid, you can consider … daily rifabutin for four months, which will interfere a little bit less.” Side effects include rashes and, rarely, thrombocytopenia, she said, aside from hepatotoxicity.

Four months of daily isoniazid and rifampin, meanwhile, is used relatively infrequently in U.S. practice, typically only in patients with evidence of prior TB on a chest X-ray, Dr. Patrawalla said. “This is latent TB infection, but clearly in somebody who has had prior untreated disease, and so while there's no real data to support this, most of us would feel more comfortable using two drugs for four months, in case there's a very low amount or undetected bacterial burden,” she said. She noted that it's essential to rule out active TB in this situation by documenting stability on the chest X-ray or testing sputum samples.

Isoniazid monotherapy is usually administered as a longer course of treatment for six or nine months and can be daily or intermittent, Dr. Patrawalla said. “There are some groups where we would not use intermittent INH, like in HIV disease, and we are most used to using it daily for nine months. If you do intermittent, which I really have never done, you should use directly observed therapy.”

Dr. Patrawalla said that she uses isoniazid monotherapy only in patients who take medications that interact with rifampin, can't tolerate rifampin or rifapentine, or have direct contact with someone with rifampin monoresistance. “To me, isoniazid is really the exception,” she said. “Most of our patients are now getting either the 12-dose regimen or four months of rifampin.”

Patients will often have questions about completing LTBI therapy, Dr. Patrawalla said: “‘I took three months of rifampin, I forgot to come back to get my fourth month, and now it's two months later. What do I do? Do I have to start over from the beginning? Can I just take that last month?’ … You are allowed some leeway, but not too much leeway,” she said.

Patients have 16 weeks to complete the 12-dose regimen, Dr. Patrawalla said. “If they took their 11th dose, and they just can't take their 12th dose, you can consider them completed. I don't tell people this up front, because you want them to take 12 doses, but this is how we can improve adherence.”

A four-month course of rifampin, 120 doses, should be completed within six months, she said. “If they took two, they went away for one, and they come back, you're still good. They just get their last two and you finish within five months,” she said. Nine-month regimens of daily isoniazid and twice-weekly isoniazid should be completed in 12 months, while six-month regimens should be completed in nine months.

When choosing a regimen, aim for shorter regimens as much as possible, consider comorbid conditions, and think about other medications and drug interactions, as well as availability, cost, and patient preference, Dr. Patrawalla advised.

“I generally prescribe one month at a time, and I make sure that the pharmacy knows they don't have two refills or three refills or four refills,” she said. “There should be some sort of monthly follow-up, but it does not necessarily need to be in person.” For example, she said, if she prescribes the 12-dose regimen, she might see patients at the first visit and then again when they come to pick up their third month of medication, but use a phone call for the second visit.

Clinicians following patients during LTBI treatment should review medication logs, ask about signs and symptoms of active TB, and consider repeating liver function tests in certain patients, especially those whose values were abnormal before beginning treatment, she said. Any adverse drug events should be reported to the CDC, and the patient's medication lists should always be reviewed to assess for potential drug-drug interactions. Finally, use follow-up calls and appointments to drive home the importance of the therapy, Dr. Patrawalla advised. “Every encounter is an opportunity to just reinforce the patient's understanding about LTBI, and why they should continue the treatment,” she said.