The Body Covers: The 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy
908 Plus Lopinavir/Ritonavir Does Not Appear to Be a Viable Regimen for HIV-Infected Patients
September 15, 2003
One of the toughest problems HIV treaters confront on a daily basis is the care of treatment-experienced patients who are currently failing their antiretroviral regimen. For those patients, innovative treatment strategies have been developed, such as the use of double-boosted protease inhibitors combined with other agents. One combination that had been previously used was that of lopinavir/ritonavir (LPV/r, Kaletra) and amprenavir (APV, Agenerase). The interactions between these two agents were the subject of extensive discussion a couple of years ago (see coverage from The XIV International AIDS Conference 2002). In the end, it was concluded that both the lopinavir and amprenavir levels were significantly decreased when these protease inhibitors were combined.
GW433908 (better known as "908") is a phosphor ester pro-drug of amprenavir. In a recent study conducted by AACTG, 908/ritonavir was compared with lopinavir/ritonavir and 908 plus lopinavir/ritonavir for the treatment of experienced patients. All patients were also treated with tenofovir (TDF, Viread) and one or two NRTIs selected by virtual phenotype. As part of this study, a pharmacokinetic (PK) analysis was then conducted to better define the PK interactions between these protease inhibitors.
The investigators in Chapel Hill, North Carolina, measured the PK parameters of lopinavir/ritonavir and amprenavir/ritonavir alone and in combination (700 mg 908 + 400 mg/100 mg lopinavir/ritonavir) in HIV-infected subjects. They assessed whether lopinavir and/or amprenavir drug exposures (the area under the curve [AUC]) AUC12h and C12h were significantly lower when given in combination than when given alone. Of the 33 subjects able to be evaluated in this study, eight received lopinavir/ritonavir, eight received 908/ritonavir and 17 received lopinavir/ritonavir plus 908.
Investigators found that at 12 hours, the AUC for both amprenavir and lopinavir were decreased when 908 and lopinavir/ritonavir were combined. The ritonavir concentrations remained comparable between groups, suggesting that the drop in amprenavir and lopinavir levels was not mediated by ritonavir.
The investigators suggested that the altered PK parameters observed in this study may be due to a decreased absorption in the gut epithelium, but other mechanisms affecting the CYP3A4 cannot be completely ruled out. Data mentioned by the authors, but not presented in this study, suggested that the interaction between 908 and lopinavir/ritonavir cannot be overcome by increasing the ritonavir levels (i.e., adding more ritonavir to the regimen), or by separating the dosage of 908 and lopinavir/ritonavir by four to 12 hours.
Although tenofovir has been found to interact with atazanavir (ATV, Reyataz), and some investigators have suggested the possibility that it may also interact with other protease inhibitors, it does not appear to have played a roll in the findings observed in this study. In fact, the amprenavir and ritonavir concentrations observed in this study in the 908/ritonavir arm, and the lopinavir and ritonavir concentrations in the lopinavir/ritonavir arm were similar to what has already been published elsewhere.
This study (ACTG A5143) was appropriately ended after this data became available, so there is no information on virologic outcomes on those patients, and no correlation can be established about lower amprenavir and/or lopinavir levels and virologic responses.
Given what we already know about the PK interactions between amprenavir and lopinavir/ritonavir, and the similarities between amprenavir and 908, I doubt that the combination of 908 and lopinavir/ritonavir would have been used much for the treatment of experienced patients. Nevertheless, it is nice to see that a PK study confirming these expected interactions was performed. I agree strongly with the author that based on the lower drug exposure observed with this study, the combination of 908 plus lopinavir/ritonavir does not appear to be a viable regimen for HIV-infected patients because this combination may put patients at risk for virologic failure.
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