Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients

Haubrich, Richard; Berger, Dan; Chiliade, Philippe; Colson, Amy E.; Conant, Marcus A.; Gallant, Joel E.; Wilkin, Timothy; Nadler, Jeffrey P.; Pierone, Gerald; Saag, Michael S.; Baelen, B. Van; Lefebvre, E.

doi:10.1097/qad.0b013e3280b07b47

Cited by 106 publications

(61 citation statements)

References 7 publications

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“…This potent activity against PI-resistant HIV indicates that this new antiretroviral molecule may be particularly useful for the treatment of patients who experience treatment failure with other PI-containing regimens. In the POWER randomized clinical studies, DRV-RTV (600/100 mg twice a day) plus an optimized background regimen was more effective than regimens containing control PIs at 24 weeks (9,14). Furthermore, these responses were sustained, lasting at least until week 48 (2), with satisfactory safety and tolerability in treatment-experienced patients.…”

Section: Discussionmentioning

confidence: 86%

“…It has been suggested that HIV-1 is unlikely to develop significant resistance in patients treated with DRV, particularly if these patients have not previously been treated with other PIs (Y. Koh, T. Towata, A. K. Ghosh, and H. Mitsuya, presented In both studies, the twice-daily administration of 600/100 mg of DRV-RTV, respectively, was the most effective, with 53% of the patients in the POWER 1 study and 39% of those in the POWER 2 study showing decreases in viral loads to less than 50 copies per ml, whereas only 18% and 7% of the patients receiving control PIs in the two studies, respectively, showed such decreases in viral loads (9,14). This dose has recently been approved for use in the United States (Tibotec, October 2006) and several other countries for the treatment of HIV infection in antiretroviral treatment-experienced adult patients, including those with HIV-1 strains resistant to more than one PI.…”

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confidence: 99%

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Factors Associated with the Selection of Mutations Conferring Resistance to Protease Inhibitors (PIs) in PI-Experienced Patients Displaying Treatment Failure on Darunavir

Lambert-Niclot¹,

Flandre

Canestri

et al. 2008

Antimicrob Agents Chemother

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The objective of this study was to characterize the mutations selected by darunavir (DRV) use in protease inhibitor (PI)-experienced patients and the associated factors. We analyzed treatment failure in 54 PIexperienced human immunodeficiency virus (HIV)-infected patients on a DRV-and ritonavir-containing regimen. Viral genotyping was carried out at the baseline, at between 1 and 3 months of treatment, and at between 3 and 6 months of treatment to search for the selection of mutations conferring resistance to PIs. The median baseline HIV RNA level was 4.9 log 10 copies/ml, and the median CD4 count was 87 cells/mm 3 . At the baseline, the median numbers of resistance mutations were as follows: 3 DRV resistance mutations, 4 major PI resistance mutations, and 10 minor PI resistance mutations. The most common mutations that emerged at rebound included V32I (44%), I54M/L (24%), L33F (25%), I84V (21%), and L89V (12%). Multivariate analysis showed that higher baseline HIV RNA levels and smaller numbers of nucleoside reverse transcriptase inhibitor simultaneously used with DRV were associated with a higher risk of DRV resistance mutation selection. By contrast, L76V, a known DRV resistance mutation, was found to decrease the risk of selection of another DRV resistance mutation. The occurrence of virological failure while a patient was on DRV was associated with the selection of mutations that increased the level of DRV resistance without affecting susceptibility to tipranavir (TPV). In these PI-treated patients who displayed treatment failure while they were on a DRV-containing regimen, we confirmed the set of emerging mutations associated with DRV failure and identified the factors associated with the selection of these mutations. TPV susceptibility does not seem to be affected by the selection of a DRV resistance mutation.Virological rebound during antiretroviral treatment is often associated with the emergence of drug resistance, compromising both current and future therapy. The resistance of human immunodeficiency virus (HIV) to protease inhibitors (PIs) generally involves the accumulation of primary and secondary mutations within and outside of the active site of the retroviral protease, sometimes accompanied by mutations in one or more gag cleavage sites (3,11,19,25). The patterns of mutation selected by most of the PIs currently available have been characterized (3,12,19,25,29). In general, individual viral mutations generate only modest changes in phenotypic susceptibility to PIs. However, more than 20% of the 99 amino acids comprising the HIV protease homodimer have been shown to mutate under the selection pressure exerted by drugs (10, 24). Patients with PI-resistant HIV therefore often have viruses with highly complex genotypic patterns. Different PIs may select different primary mutations, but the secondary mutations observed tend to be common to the entire PI class, potentially limiting the success of subsequent PI treatment following the failure of any PI-containing regimen (3,12,19,25,29).The HIV type 1 (...

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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

Factors Associated with the Selection of Mutations Conferring Resistance to Protease Inhibitors (PIs) in PI-Experienced Patients Displaying Treatment Failure on Darunavir

Lambert-Niclot¹,

Flandre

Canestri

et al. 2008

Antimicrob Agents Chemother

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Section: Introductionmentioning

confidence: 99%

“…A new PI, darunavir (TMC114), has recently been shown to have considerable antiretroviral (ARV) activity in treatment-experienced patients. Darunavir boosted with low-dose ritonavir (RTV) (darunavir/RTV) led to significantly higher 24-and 48-week virological and immunological responses compared with currently available PIs in the POWER 1 and 2 (TMC114-C213 and TMC114-C202) studies in treatment-experienced HIVinfected patients, and was well tolerated [2][3][4].Given the need for lifelong antiretroviral therapy (ART), consideration of long-term toxicities is becoming increasingly important when choosing among different treatment regimens. It is therefore important to characterize the longterm tolerability profile of any new treatment, including DOI: 10.1111/j.1468-1293.00690.x HIV Medicine (2009 r 2009 British HIV Association 318 long-term metabolic abnormalities such as fat redistribution, dyslipidaemia, glucose intolerance and insulin resistance [5][6][7].…”

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confidence: 99%

Effects of ritonavir‐boosted darunavir vs. ritonavir‐boosted atazanavir on lipid and glucose parameters in HIV‐negative, healthy volunteers

Tomaka¹,

Lefebvre

Sekar³

et al. 2009

HIV Medicine

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Background Darunavir (TMC114) is a new HIV protease inhibitor (PI). DesignThis Phase I, randomized, open-label trial compared the effects of darunavir plus low-dose ritonavir (RTV) (darunavir/RTV) with those of atazanavir/RTV on lipid and glucose parameters. MethodsForty-nine HIV-negative, healthy male volunteers received RTV 100 mg once a day (qd) for 7 days, followed by either darunavir/RTV 800/100 mg qd (n 5 25) or atazanavir/RTV 300/100 mg qd (n 5 24) for 21 days. Mean changes in fasting lipid and glucose parameters at day 28 were calculated using post-RTV alone (day 7) and baseline (day À 1) values as references. Short-term safety, tolerability and RTV pharmacokinetic parameters were evaluated. ResultsAfter 7 days of RTV treatment, the mean triglyceride concentration increased by approximately 30 mg/dL in both groups, changes in other lipid and glucose parameters were relatively small. Mean concentrations of lipids and glucose over the treatment period were mostly similar between the treatment groups. Mean changes from day 7 to day 28 for the darunavir/RTV and atazanavir/RTV groups, respectively, were À 3.6 and À 0.5 mg/dL for high-density lipoprotein cholesterol; 5.0 and 5.3 mg/dL for low-density lipoprotein cholesterol; 4.9 and 1.2 mg/dL for total cholesterol; 6.4 and 14.0 mg/dL for triglycerides; À 1.7 and À 2.4 mg/dL for glucose; and À 1.4 and 0.3 mg/dL for insulin. No grade 3 or 4 lipid or glucose laboratory abnormalities were reported. Treatmentemergent hyperbilirubinaemia was reported for all volunteers (including five grade 4 cases) during atazanavir/RTV treatment. ConclusionsCo-administration of darunavir or atazanavir with low-dose RTV resulted in minor and similar changes in lipid and glucose parameters in HIV-negative healthy volunteers. IntroductionThe introduction of HIV protease inhibitors (PIs) as part of highly active antiretroviral therapy (HAART) has drastically reduced the morbidity and mortality associated with HIV infection [1]. A new PI, darunavir (TMC114), has recently been shown to have considerable antiretroviral (ARV) activity in treatment-experienced patients. Darunavir boosted with low-dose ritonavir (RTV) (darunavir/RTV) led to significantly higher 24-and 48-week virological and immunological responses compared with currently available PIs in the POWER 1 and 2 (TMC114-C213 and TMC114-C202) studies in treatment-experienced HIVinfected patients, and was well tolerated [2][3][4].Given the need for lifelong antiretroviral therapy (ART), consideration of long-term toxicities is becoming increasingly important when choosing among different treatment regimens. It is therefore important to characterize the longterm tolerability profile of any new treatment, including DOI: 10.1111/j.1468-1293.00690.x HIV Medicine (2009 r 2009 British HIV Association 318 long-term metabolic abnormalities such as fat redistribution, dyslipidaemia, glucose intolerance and insulin resistance [5][6][7]. The association between ART and changes in lipid metabolism is well documented, particularly with PIs [...

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“…12 Two randomized, controlled, phase IIb studies, POWER-1 (USA) and -2 (Europe), brought darunavir to the forefront of attention and led to an accelerated approval of darunavir for use in combination with ritonavir in adults with HIV strains that are resistant to other PIs. [13][14][15] In Romania the need for safety and efficacy data for darunavir used in subtype F HIV-1 ART-experienced patients was the starting point of this project. The primary aim of the current national multi-center prospective study was to evaluate the efficacy (CD4 cell count, viral load, and treatment compliance) of DRV/r and other ARV medications under marketed conditions in subtype F HIV-1 infected, treatment-experienced subjects in routine clinical practice in Romania.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of darunavir (Prezista®) with low-dose ritonavir and other antiretroviral medications in subtype F HIV-1 infected, treatment-experienced subjects in Romania: a post-authorization, open-label, one-cohort, non-interventional, prospective study

Benea

Streinu-Cercel

Dorobăț

et al. 2014

GERMS

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Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients

Abstract: TMC114/r treatment resulted in greater virological and immunological responses in ART-experienced patients compared with CPI at 24 weeks.

Cited by 106 publications

References 7 publications

Factors Associated with the Selection of Mutations Conferring Resistance to Protease Inhibitors (PIs) in PI-Experienced Patients Displaying Treatment Failure on Darunavir

Factors Associated with the Selection of Mutations Conferring Resistance to Protease Inhibitors (PIs) in PI-Experienced Patients Displaying Treatment Failure on Darunavir

Effects of ritonavir‐boosted darunavir vs. ritonavir‐boosted atazanavir on lipid and glucose parameters in HIV‐negative, healthy volunteers

Efficacy and safety of darunavir (Prezista®) with low-dose ritonavir and other antiretroviral medications in subtype F HIV-1 infected, treatment-experienced subjects in Romania: a post-authorization, open-label, one-cohort, non-interventional, prospective study

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