This is the first study of the steady-state pharmacokinetics of adjusted doses of LPV/r with rifampin in HIV-infected adults. Therapeutic LPV C0 trough concentrations were achieved in all participants by doubling the dose of the tablet formulation of LPV/r, although 18/20 participants achieved therapeutic LPV C0 trough concentrations with 1.5 times the dose of LPV/r (600 mg/150 mg every 12 hours). In our cohort, we consistently found a higher proportion of participants with subtherapeutic C12 trough concentrations than with subtherapeutic C0 trough concentrations. Subtherapeutic LPV C12 trough concentrations were noted on all study days.The combination of LPV/r and rifampin was relatively well tolerated in our cohort of HIV-infected individuals compared with previous healthy-volunteer studies, but this cannot be extrapolated to treating patients with tuberculosis, as we have safety data for only 22 days.
LPV is a substrate of both CYP 3A4 and p
-glycoprotein, which are inhibited by RTV (22
). The increased dose of RTV partially offsets the induction effect of rifampin and, together with the increased dose of LPV, sufficiently overcomes induction by rifampin. However, we report pharmacokinetic measurements only; the effect of the increased dose of LPV/r with rifampin on the virological response is unknown.
Most patients achieved therapeutic LPV C0 trough concentrations with 1.5 times the dose of LPV/r (600 mg/150 mg every 12 hours), making a dose-down strategy with therapeutic drug monitoring of LPV an option in patients who do not tolerate double-dose LPV/r (800 mg/150 mg every 12 hours).
For patients on protease inhibitors who have no other antiretroviral options, two strategies can be followed when treating tuberculosis: adjusting the doses of the protease inhibitor or replacing rifampin with rifabutin. In high-burden countries, rifabutin is seldom an option, owing to its high current cost and complex dosing schedule and the widespread use of fixed-dose combinations containing rifampin for treating tuberculosis. The safety and pharmacokinetics of adjusted-dose LPV/r in combination with rifampin has been studied in two healthy-volunteer studies. La Porte et al. studied the LPV/r capsule formulation and demonstrated that the induction of rifampin can be overcome by either doubling the dose of LPV/r or increasing the RTV component to the same dose as LPV (12
). Two of 10 volunteers in the LVP/r 800-mg/200-mg arm and 5 of 9 volunteers in the LPV/r 400-mg/400-mg arm were prematurely discontinued owing to hepatotoxicity. A subsequent study by Nijland et al. evaluating the pharmacokinetics of an adjusted-dose LPV/r tablet formulation with rifampin was prematurely terminated owing to very high rates of hepatotoxicity (16
There are several possible reasons why lower rates of hepatotoxicity were seen in our study. First, HIV infection may be associated with a lower risk of hepatotoxicity. High rates of hepatotoxicity occurred in non-HIV-infected individuals compared with HIV-infected individuals in studies using rifampin and pyrazinamide to treat latent tuberculosis (5
). HIV-tuberculosis-coinfected patients tolerated the combination of rifampin and saquinavir-ritonavir relatively well (14
), but high rates of hepatotoxicity were seen in healthy volunteers treated with this combination (6
). The lower risk of hepatotoxicity in HIV-infected patients might be explained by an attenuated immune response, which is thought to play an important role in idiosyncratic drug-induced hepatocellular reactions (13
). Secondly, we slowly escalated the dose of LPV/r over 2 weeks. High rates of hepatotoxicity occurred in healthy volunteers when double doses of lopinavir-ritonavir were given without dose escalations in combination with rifampin (16
). Lastly, we initiated rifampin in HIV-infected participants established on LPV/r. High rates of hepatotoxicity occurred in the healthy-volunteer studies where rifampin was introduced prior to the protease inhibitors (6
). Rifampin preinduction may rapidly generate protease inhibitor metabolites that are hepatotoxic (7
). In high-burden countries, rifampin-based antitubercular therapy will usually be commenced in patients already on protease inhibitors, given that protease inhibitors are used in second-line ART regimens.
Diurnal variation of protease inhibitors has been reported previously (8
). Absorption differences due to the effect of food may account for the differences in our C0
trough concentrations. Our cohort received a meal before the observed C0
dose was taken, while the observed C12
dose was taken after a 10-h fast.
Our study findings have several limitations. First, we assessed the effect of rifampin on LPV/r concentrations only. Tuberculosis is treated with combination antituberculosis drugs, including isoniazid, which is an inhibitor of CYP 3A4 (3
). Both LPV/r pharmacokinetics and hepatotoxicity may be different when administered with rifampin and isoniazid. Second, there may also be a disease effect of tuberculosis on both LPV/r concentrations and hepatotoxicity. Third, we evaluated hepatotoxicity for only 3 weeks. It is possible that high rates of hepatotoxicity may occur later during treatment. There may also be a carryover effect on toxicity owing to the sequential study design, with the last treatment period most affected. Fourth, RTV exposure is known to be higher in females, and our cohort was predominantly female. A greater pharmacokinetic success rate may therefore be seen in female patients (19
). Finally, our cohort consisted of HIV-infected participants who were virologically suppressed with high CD4+
counts. The risk of hepatotoxicity in this cohort may differ from that in HIV-infected individuals with tuberculosis and various degrees of immunosuppression.
In conclusion, we have described the first evaluation of steady-state pharmacokinetics of adjusted-dose LPV/r and rifampin in HIV-infected adults. We showed that it is possible to overcome the induction effect of rifampin by doubling the dose of LPV/r to 800 mg/200 mg. Compared with previous healthy-volunteer studies, our cohort of HIV-infected adults tolerated the combination of LPV/r and rifampin relatively well. Future research should study the tolerability and effectiveness of double-dose LPV/r in HIV-infected patients with tuberculosis.