Resistance to the anti-tuberculosis (TB) drug rifampicin (Rifadin / Rimactane) in HIV-positive patients is most likely to develop if the drug is taken intermittently during the first two months of treatment, according to a retrospective study published in the 1st July edition of Clinical Infectious Diseases. The study also showed that the risk of resistance was not affected by whether the patients took rifampicin or the similar drug rifabutin (Mycobutin).
Rifampicin is a key drug in the treatment of active TB. In the United Kingdom and the United States, it is usually given alongside three other drugs for around two months in the ‘intensive phase’ of TB treatment. After this, it is given with one other drug, such as isoniazid, for four months. The aim of this ‘continuation phase’ is to reduce the chance of a TB relapse occurring.
Interactions with protease inhibitors and non-nucleoside reverse transcriptase inhibitors mean that patients on highly active antiretroviral therapy (HAART) usually take rifabutin instead of rifampicin. Both drugs are members of the rifamycin class of antibiotic drugs, and taking either drug can lead to rifampicin resistance.
Clinical trials have shown the two drugs to have similar levels of effectiveness in treating TB. However, there is some concern over whether their use could lead to drug resistance, treatment failure and relapse of TB. This is a particular concern when the drugs are given to HIV-positive patients, and when they are given intermittently – two or three times per week – rather than every day.
To assess the risk of resistance and relapse, investigators from New York City conducted a review of medical records of TB patients diagnosed in the city between 1997 and 2000. This included HIV-positive and –negative patients, and patients receiving the drugs dosed with different schedules. Only patients with TB that was susceptible to rifampicin at diagnosis were included in the study.
“The risk of acquired [rifampicin] resistance does not depend on the rifamycin used but, rather, on the dosing of [rifampicin] during the intensive phase of treatment,” they conclude. “Patients who have co-infection with TB and HIV should not receive twice-weekly regimens during the intensive phase of treatment.”
The investigators found that the 807 HIV-positive patients in their analysis were more likely to develop resistance to rifampicin than the 2054 HIV-negative patients (0.9 vs. 0.1%). After correcting for the site of the TB in the body and treatment adherence, this was found to represent a 5.5-fold increase in the likelihood of resistance developing (95% confidence interval [CI]: 1.4 – 21.5).
When they looked at the HIV-positive patients, the researchers found that none of the 57 patients treated with rifabutin developed rifampicin resistance, and only one (less than 1%) of the 395 given a combination of rifabutin and rifampicin. Six (2%) of the 355 patients taking rifampicin alone developed resistance to the drug. These differences were not statistically significant.
The investigators also examined the dosing schedule of the HIV-positive patients receiving rifampicin treatment. They found that the patients starting intermittent dosing of rifampicin during the ‘intensive phase’ of treatment – the first eight weeks - had a higher risk of resistance than those who never received intermittent dosing (hazard ratio [HR] = 6.4; 95% CI: 1.1 – 38.4).
These patients also had a higher risk of TB relapse (HR = 6.7; 95% CI: 1.1 – 40.1). These associations were upheld when the researchers restricted their analysis to patients with a CD4 cell count below 100 cells/mm3.
However, the investigators found that starting intermittent treatment with rifampicin after the intensive phase of treatment did not increase the risks of resistance or relapse.
“The findings of the present study support current Centers for Disease Control and Prevention recommendations against the use of intermittent regimens during the intensive phase of treatment for patients with TB and advanced HIV infection,” write the investigators. “For HIV-infected patients with TB, the critical time for development of resistance to [rifampicin] may be in the first two months of treatment.”
There was no effect of treatment regimen or dosing schedule on the risk of treatment failure. However, the investigators were unable to assess whether use of intermittent rifabutin treatment in the intensive phase of treatment would have increased the rate of resistance, as none of the patients in their cohort took this treatment regimen.
Li J et al. Relapse and acquired rifampin resistance in HIV-infected patients with tuberculosis treated with rifampin- or rifabutin-based regimens in New York City, 1997-2000. Clin Infect Dis 41: 83-91, 2005.