Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis
Limitations of These Guidelines
The limitations of the information available for writing these guidelines should be noted. First, drug-drug interaction studies are often done among healthy HIV-uninfected volunteers. Such studies reliably predict the nature of a drug-drug interaction (e.g., that rifampin decreases the serum concentrations of efavirenz). In cases of extreme interactions, such as that between rifampin and unboosted protease-inhibitors, data from healthy volunteers can be definitive. However, healthy volunteer studies seldom provide the needed data regarding tolerability, dosing, and pharmacokinetic variability to determine the optimal management of an interaction in patients with HIV-related tuberculosis receiving multidrug therapy. In this update of the guidelines we emphasize studies performed among patients with HIV-related tuberculosis, particularly those that evaluate HIV treatment outcomes (like virologic suppression or immunologic response to antiretrovirals) or tuberculosis treatment outcomes (such as treatment failure with emergence of resistance, or relapse after antituberculosis treatment). Second, rates of drug metabolism often differ markedly between individuals; part of that variance may be due to genetic polymorphisms in drug-metabolizing enzymes. Therefore, drug interactions and their relevance may not be the same in genetically different populations. Third, we included in the body of evidence studies that have been presented at international conferences but that have not yet completed the peer review process and been published. Fourth, it is very difficult to predict the outcome of complex drug interactions, such as those that might occur when three drugs with CYP3A activity are used together (e.g., rifabutin, atazanavir and efavirenz). Therapeutic drug monitoring, if available, may be helpful in such situations. Finally, while pharmacokinetic and efficacy data in pregnant women and children receiving tuberculosis drugs and antiretrovirals are limited, we highlighted key recent findings that shed light on management options in these populations. Our recommendations for these key special populations are based primarily on expert opinion.