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Darunavir Troughs Lower With Raltegravir in Cross-Sectional Study
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12th European AIDS Conference, November 11-13, 2009, Cologne, Germany
Mark Mascolini
Darunavir trough concentrations proved significantly lower in people taking the protease inhibitor (PI) with raltegravir plus nucleosides than in people taking darunavir only with nucleosides [1]. Multivariate analysis confirmed that raltegravir was independently associated with a lower darunavir trough. But the trough difference did not imperil virologic response in these patients. In fact, people taking darunavir with raltegravir were significantly more likely to have an undetectable viral load. Still, potential interactions between these drugs are important to pin down because darunavir and raltegravir may often be prescribed in the same rescue regimen.
An interaction between darunavir and raltegravir is unexpected because the drugs are metabolized on different pathways. However, other researchers recently reported that raltegravir is a substrate of P-glycoprotein, which may explain interactions with PIs [2].
Massimiliano Fabbiani (Catholic University, Rome) and colleagues at other centers compared darunavir trough levels in 38 people taking 600/100 mg of darunavir twice daily with only nucleosides and 17 taking the same dose of darunavir/ritonavir with nucleosides plus the integrase inhibitor raltegravir [1]. In people with multiple darunavir measurements, the researchers averaged the readings.
The raltegravir and no-raltegravir groups did not differ significantly in gender or racial proportions, age, injecting drug use, AIDS rate, CD4 count, HBV or HCV coinfection, or concomitant use of tenofovir, enfuvirtide, CYP 3A4 inducers, or acid-reducing agents. However, a significantly larger proportion of people taking raltegravir (13 of 17, 76.5%) than not taking raltegravir (17 of 38, 44.7%) had a viral load under 50 copies (P = 0.041).
Darunavir troughs varied substantially from one person to the next (coefficient of variation 62%, 56% without raltegravir, 70% with raltegravir). In 24 people with multiple darunavir readings, median intra-individual variation was 42% (45% without raltegravir, 26.8% with raltegravir, P = 0.594).
For the whole group, the darunavir trough averaged 3.71 mg/dL (standard deviation [SD] 2.30). Average darunavir trough was significantly higher without raltegravir (4.20 mg/L, 2.35 SD) than with raltegravir (2.6 mg/L, SD 1.84) (P = 0.018). Average ritonavir troughs did not differ significantly in the two groups.
The investigators conducted a multivariate analysis to isolate factors that may affect darunavir troughs, including gender, race, age, weight, body mass index, injecting drug use, HBV or HCV coinfection, renal impairment, time from last darunavir dose, and use of raltegravir, tenofovir, enfuvirtide, CYP 3A4 inducers, or acid-reducing agents. Only raltegravir use independently influenced darunavir troughs, lowering levels by an average 1.49 mg/L (95% confidence interval -2.83 to -0.14 mg/L, P = 0.031).
Fabbiani and coworkers advised cautious interpretation of their findings because of the cross-sectional nature of their study. They called for prospective study of people taking these two antiretrovirals to confirm the results and to determine whether they have any clinical meaning.
References
1. Fabbiani M, Di Giambenedetto S, Ragazzoni E, et al. Unexpected drug interaction between darunavir and raltegravir. 12th European AIDS Conference. November 11-13, 2009. Cologne, Germany. Abstract PE4.3/4.
2. Cianfriglia M, Dupuis ML, Galluzzo CM, Palmisano L. Interaction of the HIV integrase inhibitor raltegravir with the multidrug transporter P-glycoprotein ( MDR1-Pgp) in human MDR cells. 5th IAS Conference on HIV Pathogenesis and Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract WEPEA103. http://www.iasociety.org/Default.aspx?pageId=11&abstractId=200722063.
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