Pharmacokinetics of double-dose raltegravir in two patients with HIV infection and tuberculosis

Combined treatment of HIV infection and tuberculosis remains a challenge because of drug–drug interactions, overlapping toxicity profiles, high pill burden, and the development or presence of resistance. According to the most recent guidelines from the Centers of Disease Control and Prevention, efavirenz-based therapy is the preferred option for initial antiretroviral therapy in developed countries [1]. This recommendation, however, does not apply to patients with HIV-2 infection because this virus is intrinsically not susceptible to nonnucleoside reverse transcriptase inhibitors (NNRTIs). Because combined use of protease inhibitors with either rifampin or (reduced dose) rifabutin is not without problems in terms of toxicity [2,3] or tuberculosis relapse [4], alternative strategies for the HIV-2-infected patient with tuberculosis are urgently needed. This is also true for HIV-1-infected patients with either NNRTI resistance or intolerance. The HIV-integrase inhibitor raltegravir has activity against both HIV-1 and HIV-2 [5,6], has a safety profile that does not overlap with tuberculosis drugs, and a pill burden of only two tablets per day. There is, however, a significant negative effect of rifampin on the plasma concentrations of raltegravir [7]: the area under curve (AUC) of raltegravir was reduced by 40% due to rifampin's inducing capacity on the enzyme responsible for degradation of raltegravir: UDP-glucuronosyltransferase (UGT). A study in healthy volunteers demonstrated that doubling of the raltegravir dose [i.e. to 800 mg twice daily (b.i.d.)] compensated for this effect of rifampin, leading to a small increase of 27% in the AUC when compared with raltegravir 400 mg b.i.d. without rifampin [7]. We here report on two patients with HIV-2 infection (one with HIV-1/2 dual infection) and concurrent tuberculosis treatment including rifampin, in which we determined the pharmacokinetics of an increased dose of raltegravir (800 mg b.i.d.). Patient 1 is a 47-year-old man born on the Cape Verdian islands but living in the Netherlands for 23 years. He was admitted to the hospital where HIV-1/2 dual infection and disseminated tuberculosis were diagnosed. He was treated with isoniazid, ethambutol, pyrazinamide, and rifampin [600 mg daily (q.d.)]. His CD4 cell count was 110 cells/μl and his HIV-1 and HIV-2 RNA were 40 000 and less than 50 copies/ml, respectively. Highly-active antiretroviral therapy treatment was initiated with tenofovir 245 mg q.d., emtricitabine 200 mg q.d., and raltegravir 800 mg b.i.d. After 5 weeks, a 12-h pharmacokinetic curve was recorded after intake of raltegravir 800 mg with food, and pharmacokinetic parameters were compared with reported data in HIV-infected patients on 400 mg b.i.d. without rifampin (Table 1) [8]. HIV-1 RNA and HIV-2 RNA were 105 and less than 50 copies/ml, respectively, after 3 months of treatment. The increased dose of raltegravir was well tolerated with no clinical signs of toxicity or drug-related laboratory abnormalities.Table 1: Pharmacokinetic data for raltegravir.Patient 2 is a 41-year-old man from Mozambique living in the Netherlands since 17 years. He was diagnosed with an HIV-2 infection with CD4 cell counts of 40 cells/μl, an HIV-2 load of 1280 copies/ml and pulmonary tuberculosis. After an induction phase of 2 months with rifampin, isoniazid, ethambutol, and pyrazinamide, the last two were stopped and the patient continued with isoniazid (300 mg q.d.) and rifampin (600 mg q.d.). Furthermore, at that moment, antiretroviral therapy was started with tenofovir 245 mg q.d., emtricitabine 200 mg q.d. and raltegravir 800 mg b.i.d. In this patient, it was only possible to take blood samples at t = 2, 4, and 12 h post ingestion after 1 week of 800 mg of raltegravir b.i.d. Pharmacokinetics parameters were in the same range as in patient 1, and slightly higher than in patients on 400 mg b.i.d. without rifampin (Table 1) [8]. Raltegravir was also tolerated well in this patient. Our data are the first on the use of a double dose of raltegravir in HIV-infected patients who are concurrently treated with rifampin; they confirm the slightly higher exposure when compared with 400 mg b.i.d. of raltegravir without rifampin from the study in healthy individuals [7]. Preliminary data on pharmacokinetic/pharmacodynamic relationships for raltegravir suggest that the AUC is the most important pharmacokinetic parameter predicting optimal antiviral response [9], and the value of the AUC in our two patients was at least as high as the geometric mean value of patients treated in phase II studies with the standard dose of 400 mg b.i.d. without rifampin [8]. The phase II dose-ranging study of raltegravir demonstrated equal antiviral potency in the dose range of 100–600 mg b.i.d. [8], suggesting that moderately lower exposure to the drug than at the licensed dose of 400 mg b.i.d. is still expected to result in adequate antiviral efficacy. As a consequence, drug interactions between raltegravir and either efavirenz [10], etravirine [11], or tipranavir [12], leading to a decrease in raltegravir plasma concentrations of 36%, 34%, or 24%, respectively, are not considered clinically relevant and do not warrant a dose adjustment for raltegravir. Because rifampin causes a somewhat larger decrease in raltegravir AUC (−40% [7]) and combined use was not allowed in clinical trials, concomitant use was initially discouraged, but updated prescriber's information now recommends a dose increase to 800 mg b.i.d. [13,14] based on the healthy volunteer data. The definitive answer to the question of whether a dose increase of raltegravir is needed for patients with rifampin should come from a clinical trial that is currently ongoing (NCT00822315; http://www.clinicaltrials.gov). Based on our initial pharmacokinetic observations and the good tolerability of the increased dose of raltegravir in our patients, we support the recommended dose increase of raltegravir until more data are available. D. Burger was responsible for pharmacokinetic analyses and literature review and he wrote the article; C. Magis-Escurra, G. van den Berk and L. Gelinck were responsible for pharmacokinetic sampling, clinical management of the patient and reviewed the draft article and approved the final version.

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