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HIV protease inhibitors in combination with boceprevir: are drug-drug interactions the same for all patients?
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Schwarze-Zander, Carolynne; Rockstroh, Jurgen K. Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.
AIDS:
10 September 2012 Correspondence
"our findings suggest that, indeed, in advanced liver disease, normal levels of HIV protease inhibitors may be found during HCV triple therapy. Unfortunately, BOC levels could not be determined in our patients as no standardized assays are currently in place. As BOC levels have been shown to decrease with HIV protease inhibitor administration, this remains of concern but may also be changed in patients with more advanced liver disease. Therefore, clearly more pharmacokinetic studies are urgently required in HIV/HCV-coinfected patients with more advanced liver fibrosis in order to better understand the true amount of drug interactions between BOC and commonly used HIV protease inhibitors and possibly make HCV triple therapy accessible for a wider number of HIV/HCV-coinfected patients in desperate need of these drugs."
The new direct acting agents, boceprevir (BOC) and telaprevir (TVR), have been approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in the USA and in Europe in 2011. Sustained virological response (SVR) rates up to 75% have been reported in phase III trials for triple therapy examining efficacy and safety of either BOC or TVR in combination with pegylated interferon and ribavirin in HCV monoinfection [1,2]. Improved treatment outcomes have also been reported for HIV/HCV-coinfected patients reaching SVR rates of up to 70% in pilot trials [3,4]. BOC and TVR are HCV protease inhibitors sharing similar metabolic routes with HIV protease inhibitors. Both are substrates and inhibitors of the cytochrome P450-3A system as well as a substrate of p-glycoprotein. BOC is additionally a substrate of aldo-ketoreductase [5]. Unfortunately, due to these complex drug-drug interactions, triple therapy is substantially limited in HIV/HCV-coinfected individuals. Indeed, recently the European Medicines Agency and the Food and Drug Administration have warned against the coadministration of BOC with the commonly available HIV protease inhibitors, as significant drug-drug interactions, which not only decrease the level of BOC but also lead to relevant decreases in the respective HIV protease inhibitor, have been reported [6-8]. Particularly, in patients with extensive prior HIV resistance and accumulation of resistance mutations, in which HIV protease inhibitor drug levels may be of great importance, the risk of resistance development and virological failure may be increased. However, most data on pharmacokinetic interactions of BOC and HIV protease inhibitors derive from pharmacokinetic studies in healthy volunteers and so far no data are available from HIV/HCV-coinfected patients with different stages of liver disease receiving BOC and HIV protease inhibitors.
Here, we report on two patients who prior to the 'Dear Healthcare Professional' letter received BOC containing HCV triple therapy in combination with a HIV protease inhibitor because prior drug interaction studies with 100 mg of ritonavir and BOC suggested that despite small alterations in drug level this would be clinically feasible [9,10]. Patient 1 was on darunavir 800 mg/ritonavir 100 mg once-daily monotherapy due to extensive nucleoside and nucleotide reverse transcriptase inhibitor resistance when HCV triple therapy with BOC was started. Liver disease had progressed to liver cirrhosis confirmed in FibroScan (Echosens, Paris, France) with a liver stiffness of 34 kPa. Trough concentration of darunavir was measured at week 5 of HCV triple therapy in the reference range with 3777 ng/ml (reference trough concentration 2400-4600 ng/ml). HIV-RNA was below detection limit (<40 copies/ml) at all times and HCV-RNA became negative at week 10.
Patient 2 had previously undergone chemotherapy for non-Hodgkin's lymphoma and was on a simplified emtricitabine once daily and fos-amprenavir 700 mg/ritonavir 100 mg twice-daily regimen. Using FibroScan, a liver stiffness of 32 kPa suggested liver cirrhosis prior to start of HCV triple therapy. Fos-amprenavir trough level was measured at week 8 of HCV triple therapy with 1699 ng/ml lying in the normal reference range (reference trough concentration 750-2500 ng/ml). HCV-RNA was measured with less than 12 IU/ml at week 11 and HIV viral load was below the detection limit of less than 40 copies/ml at all times.
Our clinical data suggest that, potentially, drug levels of HIV protease inhibitors that are coadministered with BOC may be within the normal range in patients with advanced liver disease. Indeed, various pharmacokinetic studies of HIV protease inhibitors in HIV/HCV-coinfected patients with advanced liver disease suggested higher protease inhibitor levels with more advanced stages of liver fibrosis [11]. According to the product label, dose reduction is even recommended for fos-amprenavir in patients with liver cirrhosis [12]. Many patients suffering from more advanced liver fibrosis are in particular need for triple HCV therapy, but may have acquired prior HIV resistance depending on a HIV protease inhibitor as a corner stone of their second-line or third-line therapy to maintain HIV suppression. Coadministration of HCV protease inhibitors may not be possible because of the reported HIV protease inhibitor/HCV protease inhibitor drug-drug interactions. However, our findings suggest that, indeed, in advanced liver disease, normal levels of HIV protease inhibitors may be found during HCV triple therapy. Unfortunately, BOC levels could not be determined in our patients as no standardized assays are currently in place. As BOC levels have been shown to decrease with HIV protease inhibitor administration, this remains of concern but may also be changed in patients with more advanced liver disease. Therefore, clearly more pharmacokinetic studies are urgently required in HIV/HCV-coinfected patients with more advanced liver fibrosis in order to better understand the true amount of drug interactions between BOC and commonly used HIV protease inhibitors and possibly make HCV triple therapy accessible for a wider number of HIV/HCV-coinfected patients in desperate need of these drugs.
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