Twice-weekly therapy not enough for co-infected, CDC says in advisory
Twice-weekly therapy not enough for co-infected, CDC says in advisory
Changes will add significant expense’
TB patients with HIV and severe immune depression need daily therapy initially, and therapy three times weekly during the second phase of treatment, federal TB experts have decided. Otherwise, they may develop rifamycin resistance, according to surprising evidence from a new study. The new directive issued by the Centers for Disease Control and Prevention’s Division of TB Elimination (DTBE) is in effect at least until more data become available on the study findings, according to the Morbidity & Mortality Weekly Report for March 15, 2002.1
The new recommendation may pose a hardship for TB control programs already strapped for time and money. Many programs use twice-weekly therapy for TB patients with HIV, especially during the continuation phase of treatment. "This will certainly be a big change for us," says William R. Bishai, PhD, associate professor in the Division of Infectious Diseases of Johns Hopkins School of Medicine in Baltimore. "The majority of our costs in the continuation phase come from health-care providers. Adding an additional provider visit for the four months of the continuation phase is going to add significant expense."
Rifamycin resistance threatens short-course therapy
What prompted the change was an unexpected finding in Study 23 of the TB Trials Consortium (TBTC). Enrollment in the trial was halted after five of 156 patients experienced relapse or treatment failure and were then found to have rifamycin resistance. What alarmed investigators wasn’t the number of relapses and failures — which were actually fewer than had been predicted — but the finding of rifamycin resistance, says Rick O’Brien, MD, chief of the research and evaluation branch at the DTBE. "If you lose rifamycins, you can no longer use short-course therapy, and you have to turn to less effective drugs."
The CDC advisory applies only to patients with advanced HIV disease, which is defined as those with CD4 counts below 100/mm3. That cut-point describes many patients with HIV and active TB, experts say. "For unknown reasons, co-infected people tend to present with advanced AIDS," says William J. Burman, MD, an infectious disease specialist with the Denver Medical Health Center and chair of the Core Science Group of the TBTC. For example, the median CD4 count among the patients enrolled in Study 23 was 97, he says.
A close look at twice-weekly rifabutin
Study 23 was intended to provide a close-up look of the efficacy of twice-weekly rifabutin, says O’Brien. "We’d made the recommendation that rifabutin could replace rifampin and could be given twice weekly," he says. "But we’d never really looked at twice-weekly therapy for the co-infected in any detail." Because rifabutin avoids adverse drug interactions with protease inhibitors, it is the rifamycin of choice for HIV patients taking a protease inhibitor as part of highly active antiretroviral therapy (HAART).
The new advisory nixing twice-weekly therapy applies to co-infected patients taking any rifamycin-containing regimen, whether or not they’re receiving HAART and taking rifabutin, O’Brien adds. It was decided to apply the injunction to all rifamycins because an earlier study had already shown that once-weekly rifapentine led to high rates of rifamycin resistance in co-infected patients. Plus, there was slight anecdotal evidence suggesting even twice-weekly rifampin can also lead to resistance, O’Brien adds.
As to whether daily therapy is better than thrice weekly during the continuation phase, there aren’t enough data yet to make that call, says Burman. In his own practice, "we’ll give daily in induction, but I don’t know yet what we’ll do in continuation," he says. "We’re still discussing it."
Burman and O’Brien say that in Study 23, drug resistance probably was caused by a combination of culprits. What set the stage was probably immune suppression, which allowed mycobacteria to continue replicating later in the course of therapy, says Burman.
There’s also the possibility that the HIV-infected patients were having trouble absorbing isoniazid, rifabutin’s companion drug during the continuation phase. "It doesn’t take much INH to suppress replication," Burman notes. "Taken every day, you can probably get away with some malabsorption." But when dosing frequency is just twice a week, there may not be enough drug available for good suppression, he adds.
Pharmaco-kinetic mismatch magnified
With more actively replicating TB bugs still on the scene, the effect of the mismatch in half-lives of the two drugs was magnified, Burman and O’Brien say. Like rifapentine and INH, rifabutin and INH are metabolized at strikingly different rates. The result is that rifabutin is still hanging around many hours after INH has departed. "The strange thing is, we already knew about the half-life mismatch," says Burman. "We just didn’t think it would matter." The reason was that British trials had already shown that giving even one drug during the last four months of treatment yields very good results, Burman says. After all, by that time, a patient’s bacterial burden has been drastically reduced, and what bugs do remain aren’t replicating.
It was generally assumed, therefore, that treatment for the continuation phase was probably a lot like treating latent TB infection, so giving what amounted to monotherapy wouldn’t matter, TBTC experts reasoned. In hindsight, that probably applies to patients with competent immune systems, Burman says — not those who are severely immune-deficient.
Even though overall TB case totals for the nation continue to fall, the new recommendation shows why this is no time for funding cutbacks, Bishai says. "With these recommendations will have to come a commitment for support, since this adds to the expense of correct care," he says. "There’s been talk of cutting back in light of falling TB rates. Perhaps we should be thinking instead about adding to funding," he says. The development also underscores the urgent need to find better intermittent drug regimens, Bishai adds.
Reference
1. Notice to Readers: acquired rifamycin resistance in persons with advanced HIV disease being treated for active tuberculosis with intermittent rifamycin-based regimens. MMWR 2002; 10:214-215.
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