Rifabutin and rifampicin (rifampin) cause a very marked fall indelavirdine plasma levels: rifabutin levels are raised when delavirdine dose is increased to compensate for this. Rifabutin doesnot affect efavirenz levels,whereas efavirenz decreases rifabutin levels. There is usually no important interaction between rifabutin and nevirapine,although some patients may have a higher riskof rifabutin adverse effects. Neither efavirenz nor nevirapine affect rifampicin levels, but rifampicin modestly reduces levels of these NNRTIs, and thereis some debate about whether it is necessary to increase their dose.
Clinical evidence,mechanism, importance and management
In a controlled study in 7 HIV-positive patients taking delavirdine mesilate 400mg three times daily for 30 days, addition of rifabutin 300mg daily from days 16 to 30 caused a fivefold increase in delavirdine clearance, and an 84 % fall in steady-state plasma levels (See reference number 1). This was presumably due to enzyme-inducing effects of rifabutin. A similar study using rifampicin in place of rifabutin found that rifampicin caused a 27-fold increase in clearance of delavirdine, and steady-state plasma levels became almost undetectable (See reference number 2).
In another study,(See reference number 3) where dose of delavirdine was titrated to achieve a trough level of at least 5 micromol/L, AUC of rifabutin was found to increase by 242%.
It has been recommended that combination of delavirdine and rifampicin should be considered as contraindicated because effects of interaction are so large (See reference number 2). The CDC in US and manufacturer recommend that neither rifabutin nor rifampicin should be used with delavirdine (See reference number 4,5)
Rifabutin. In a study in healthy subjects concurrent use of efavirenz 600mg once daily and rifabutin 300mg once daily for 2 weeks resulted in a modest 38 % decrease in AUC of rifabutin and a 45 % decrease in minimum levels, but no change in efavirenz levels (See reference number 6). The CDC in US state that combination is probably clinically useful, and they suggest increasing dose of rifabutin to 450mg or 600mg daily, or 600mg two to three times weekly (See reference number 4). In one study doubling rifabutin dose from 300mg twice weekly to 600mg twice weekly when starting efavirenz resulted in rifabutin AUCs that were 20 % higher than baseline values (See reference number 7). However,in one analysis, 8 of 35 patients (23%) taking efavirenz and given rifabutin 450mg once daily were found to have sub-therapeutic rifabutin levels, and they were switched to isoniazid (See reference number 8). Concurrent use should therefore be closely monitored.
In patients with HIV and tuberculosis concurrent use of HAART including efavirenz 600mg once daily with antitubercular therapy including rifampicin 480 to 720mg daily decreased AUC of efavirenz by 22 % and decreased trough concentration by 25 % (although large interpatient variability was observed). Overall pharmacokinetics of efavirenz 800mg daily with rifampicin were similar to those
of efavirenz 600mg daily without rifampicin. The pharmacokinetics of rifampicin were not substantially altered by efavirenz (See reference number 9). A similar 26 % reduction in efavirenz AUC was reported in a study in healthy subjects (See reference number 10). The CDC in US suggest that it may be advisable to increase efavirenz dose to 800mg daily when used with rifampicin,(See reference number 4) and UK manufacturer also recommends this (See reference number 11). However, in one analysis 7 of 9 patients receiving rifampicin and efavirenz 800mg daily developed significant clinical toxicity and were found to have efavirenz levels markedly higher than therapeutic range (See reference number 12). In another study in Thai patients taking rifampicin,median efavirenz plasma levels were comparable between those receiving 600mg daily and 800mg daily and similar virological outcomes were seen (See reference number 13,14). Therefore,a 600mg dose of efavirenz may be sufficient in some patients. Concurrent use should be well monitored.
Rifabutin. In one study, pharmacokinetics of nevirapine were only minimally affected by rifabutin in 19 patients, when compared with historical data (See reference number 15). The manufacturer notes that concurrent use of rifabutin with nevirapine caused a minor 9 % increase in nevirapine clearance and a 17 % increase in its AUC, and a 28 % increase in maximum steady-state rifabutin levels (See reference number 16,17). They say that because of high intersubject variability, some patients may experience large increases in rifabutin exposure and may be at higher risk of adverse effects. Concurrent use should be well monitored and undertaken cautiously. The CDC in US state that combination of nevirapine and rifabutin can be used (See reference number 4).
Rifampicin (Rifampin). The manufacturer states that AUC of nevirapine was reduced by 58 % by rifampicin in 14 subjects, when compared with historical data. There was no change in steady-state rifampicin pharmacokinetics (See reference number 16,17). Based on these pharmacokinetic data, manufacturer suggests that concurrent use of rifampicin with nevirapine is not recommended, and that rifabutin may be considered instead, with close monitoring of adverse effects (See reference number 16,17). A further study in HIV-positive patients with tuberculosis found that rifampicin caused a 31 % decrease in AUC of nevirapine and a non-significant 21 % decrease in its trough concentration (See reference number 18). The authors of this study suggested that there is probably no need to increase nevirapine dose, since trough levels were still sufficiently above level needed for antiviral activity (See reference number 18). Moreover, subsequent observational data supported continued efficacy of standard dose nevirapine when it was used with rifampicin (See reference number 19). Similarly, others have reported successful use of nevirapine with twice weekly rifampicin with little effect on trough nevirapine levels (See reference number 20). In yet another study, concurrent use of rifampicin and nevirapine reduced nevirapine levels by about 18 % with no reduction in virological response, although proportion of patients with trough levels below recommended level was much higher (29.7% versus 6.8%) at 8 weeks (See reference number 21). In contrast, in another study in 13 patients taking nevirapine 200mg twice daily, addition of rifampicin 450mg or 600mg daily caused a 46 % reduction in AUC of nevirapine, and a 53 % reduction in minimum levels, with 8 of patients having a nevirapine trough level below therapeutic range (3 micrograms/mL). In 7 of patients who had a reduction in minimum levels to less than therapeutic range, increasing dose of nevirapine to 300mg twice daily for 2 weeks increased levels to above therapeutic range in all patients without increasing adverse effects (See reference number 22). The CDC in US state that combination of nevirapine and rifampicin should only be used if clearly indicated and with careful monitoring, because of insufficient data on whether dose adjustments are necessary (See reference number 4). Further study is needed.
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