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Kamkwalala AR, Garg A, Roy U, et al., 2021, Current Considerations for Clinical Management and Care of People with HIV: Findings from the 11th Annual International HIV and Aging Workshop., AIDS Res Hum Retroviruses, Vol: 37, Pages: 807-820
The number of people with HIV (PWH) aged 50 years or older continues to steadily increase. The convergence of age- and HIV-related complications in these individuals presents a challenge for both patients and clinicians alike. New findings continue to emerge, as numerous researchers evaluate the combined impact of these two factors on quality of life, physiological systems, and mental health in PWH. Since its first occurrence in 2009, the International Workshop on HIV and Aging has served as a multidisciplinary meeting to share basic biomedical data, clinical trial results, treatment strategies, and epidemiological recommendations, toward better understanding and outcomes among like-minded scientific professionals. In this article, we share a selection of key findings presented in plenary talks at the 11th Annual International Workshop on HIV and Aging, held virtually from September 30, 2020 to October 2, 2020. We will also address the future directions of HIV and aging research, to further assess how the aging process intersects with chronic HIV.
Barber TJ, Imaz A, Boffito M, et al., 2018, CSF inflammatory markers and neurocognitive function after addition of maraviroc to monotherapy darunavir/ritonavir in stable HIV patients: the CINAMMON study (vol 24, pg 98, 2018), JOURNAL OF NEUROVIROLOGY, Vol: 24, Pages: 388-389, ISSN: 1355-0284
Schipani A, Dickinson L, Boffito M, et al., 2013, Simultaneous population pharmacokinetic modelling of atazanavir and ritonavir in HIV-infected adults and assessment of different dose reduction strategies., J Acquir Immune Defic Syndr, Vol: 62, Pages: 60-66
OBJECTIVES: The objective of this study was to develop a simultaneous population pharmacokinetic (PK) model to describe atazanavir/ritonavir (ATV/RTV) PK (300/100 mg) and to assess the effect of RTV dose reduction on ATV PK. Simulations of ATV concentration-time profiles were performed at doses of ATV/RTV 300/50 mg, 200/50 mg, and 200/100 mg once daily. METHODS: A total of 288 ATV and 312 RTV plasma concentrations from 30 patients were included to build a population PK model using the stochastic approximation expectation maximization algorithm implemented in MONOLIX 3.2 software. RESULTS: A one-compartment model with first-order absorption and lag-time best described the data for both drugs in the final simultaneous model. A maximum-effect model in which RTV inhibited the elimination of ATV was used to describe the relationship between RTV concentrations and ATV clearance (CL/F). An RTV concentration of 0.22 mg/L was associated with 50% maximum inhibition of ATV CL/F. The population prediction of ATV CL/F in the absence of RTV was 16.6 L/h (relative standard error, 7.0%), and the apparent volume of distribution and absorption rate constant were 106 L (relative standard error, 8%) and 0.87 per hour (fixed), respectively. Simulated average ATV trough concentrations at ATV/RTV 300/50 mg, 200/50 mg, and 200/100 mg once daily were 45%, 63%, and 33% lower, respectively, than that of the standard dose. CONCLUSION: Although simulated median ATV trough concentrations after dose reductions were still more than the ATV minimum effective concentration (2.9-, 1.9-, and 3.6-fold for ATV/RTV 300/50 mg, 200/50 mg, and 200/100 mg, respectively); our modeling predicted a high proportion of individuals with subtherapeutic trough concentrations on the 200/50 mg dose. This suggests that 300/50 mg and 200/100 mg dosing are preferred candidate regimens in future clinical studies.
Williams I, Churchill D, Anderson J, et al., 2012, British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012, HIV MEDICINE, Vol: 13, Pages: 1-85, ISSN: 1464-2662
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Lamorde M, Byakika-Kibwika P, Boffito M, et al., 2012, Steady-state pharmacokinetics of lopinavir plus ritonavir when administered under different meal conditions in HIV-infected Ugandan adults., J Acquir Immune Defic Syndr, Vol: 60, Pages: 295-298
We investigated the effect of food on the steady-state pharmacokinetics of lopinavir and ritonavir in 12 Ugandan patients receiving lopinavir coformulated with ritonavir (LPV/r) tablets using a crossover design. Intensive pharmacokinetic sampling was performed 7 days apart after LPV/r dosing under moderate fat, high fat, and fasted meal conditions. Lopinavir and ritonavir concentrations were determined by liquid chromatography and tandem mass spectrometry. Compared with the fasted state, a high fat meal reduced lopinavir and ritonavir area under the curve by 14% and 29%, respectively. With a moderate fat meal, area under the curve for both drugs was similar to the fasted state.
Patterson B, Hughes DJ, Holyome A, et al., 2012, Measurement of hsCRP in HIV-infected individuals over the age of 50 years, HIV MEDICINE, Vol: 13, Pages: 27-27, ISSN: 1464-2662
Hughes DJ, Barber TJ, Holyome A, et al., 2012, Assessment of neurocognitive impairment in HIV-infected individuals over 50 years of age, HIV MEDICINE, Vol: 13, Pages: 26-26, ISSN: 1464-2662
Lee C, Barber T, Devitt E, et al., 2012, Outcomes of first raised ALT in HIV infection, HIV MEDICINE, Vol: 13, Pages: 53-53, ISSN: 1464-2662
Tam H, Ratcliffe D, Margetts A, et al., 2012, Use of a novel online cortical test in HIV infected subjects undergoing screening for neurocognitive impairment, HIV MEDICINE, Vol: 13, Pages: 56-57, ISSN: 1464-2662
Barber T, Hughes D, Margetts A, et al., 2012, Screening for HIV related neurocognitive impairment (NCI) in clinical practice, HIV MEDICINE, Vol: 13, Pages: 78-78, ISSN: 1464-2662
Holyome A, Hughes DJ, Mandalia S, et al., 2012, Are predictors of osteopenia and osteoporosis in HIV-infected individuals over the age of 50 years different to the general population?, HIV MEDICINE, Vol: 13, Pages: 26-26, ISSN: 1464-2662
Myers J, Rayment M, Sonecha S, et al., 2012, Room for manoeuvre when prescribing statins to dyslipidaemic patients on antiretroviral therapy., HIV Med, Vol: 13, Pages: 190-192
Jackson A, Moyle G, Dickinson L, et al., 2012, Pharmacokinetics of abacavir and its anabolite carbovir triphosphate without and with darunavir/ritonavir or raltegravir in HIV-infected subjects., Antivir Ther, Vol: 17, Pages: 19-24
BACKGROUND: Here, we aimed to investigate the pharmacokinetics of abacavir and carbovir triphosphate (CBV-TP) with darunavir/ritonavir 900/100 mg once daily or raltegravir 400 mg twice daily. METHODS: HIV-infected subjects on abacavir (600 mg once daily) underwent steady-state pharmacokinetic assessments without and with darunavir/ritonavir or raltegravir. Within-subject changes in plasma and intracellular pharmacokinetic parameters were evaluated by geometric mean ratios (GMRs) and 90% CIs. RESULTS: A total of 19 patients completed the study. With darunavir/ritonavir (versus abacavir alone), abacavir GMRs (90% CI) were 0.73 (0.66, 0.80), 0.62 (0.50, 0.77) and 0.78 (0.69, 0.87) for area under the curve (AUC), trough concentration (C(trough)) and maximum concentration (C(max)), respectively. With raltegravir, they were 1.03 (0.97, 1.10), 0.83 (0.62, 1.11) and 1.06 (0.95, 1.18), respectively. Intracellular CBV-TP GMRs (90% CI) were 0.88 (0.72, 1.07), 0.68 (0.48, 0.95) and 0.98 (0.79, 1.23) for AUC, C(trough) and C(max), respectively, with darunavir/ritonavir, and 0.96 (0.76, 1.20), 0.57 (0.33, 1.00) and 1.07 (0.85, 1.35), respectively, with raltegravir. CONCLUSIONS: There was a 27% decrease in abacavir plasma exposure with darunavir/ritonavir and no changes with raltegravir. CBV-TP C(trough) was significantly decreased with darunavir/ritonavir (32%) and showed a high inter-individual variability with raltegravir.
Hill A, Khoo S, Boffito M, et al., 2011, Should we switch to a 50-mg boosting dose of ritonavir for selected protease inhibitors?, J Acquir Immune Defic Syndr, Vol: 58, Pages: e137-e138
Jackson A, Watson V, Back D, et al., 2011, Plasma and intracellular pharmacokinetics of darunavir/ritonavir once daily and raltegravir once and twice daily in HIV-infected individuals., J Acquir Immune Defic Syndr, Vol: 58, Pages: 450-457
OBJECTIVES: To investigate the pharmacokinetics of darunavir/ritonavir and raltegravir, in HIV-infected subjects, in both plasma and at the intracellular (IC) site of action. METHODS: HIV-infected patients on antiretroviral therapy received raltegravir 400 mg twice daily for 21 days (period 1); darunavir/ritonavir 800/100 mg once daily was added for 14 days (period 2), and patients were randomized to continue raltegravir twice daily (group 1) or to switch to 800 mg once daily (group 2), then they all stopped raltegravir intake and continued darunavir/ritonavir once daily for 14 days (period 3). Drug concentrations in plasma and cells (peripheral blood mononuclear cell) were measured, and differences in geometric mean ratios (GMR) and 90% confidence intervals (CI) between period 2 versus period 3 and period 2 versus period 1 were assessed. RESULTS: Twenty-four patients completed the study. Group 1 GMR (90% CI) of darunavir area under the curve (AUC) with and without raltegravir was 1.24 (1.13 to 1.45) for plasma and 1.24 (1.07 to 1.73) for cells and for group 2 was 1.14 (1.07 to 1.24) and 1.03 (0.94 to 1.16). GMR (90% CI) of raltegravir AUC without and with darunavir/ritonavir (plasma and cells) for group 1 was 0.90 (0.73 to 1.44) and 1.02 (0.81 to 1.67) and for group 2 was 1.21 (1.03 to 1.77) and 1.27 (1.07 to 1.94). Geometric mean IC to plasma AUC ratios were 5.3 and 4.9 for darunavir in groups 1 and 2 when darunavir/ritonavir was given alone and 4.9 and 5.6 for raltegravir when given alone. These ratios were not altered by the coadministered drug. CONCLUSIONS: No remarkable interactions between darunavir/ritonavir and raltegravir in plasma or cells were seen. Raltegravir IC concentrations are higher than previously reported; the difference being due to modified cell isolation procedures that reduced drug loss caused by washing.
Boffito M, Jackson A, Amara A, et al., 2011, Pharmacokinetics of once-daily darunavir-ritonavir and atazanavir-ritonavir over 72 hours following drug cessation., Antimicrob Agents Chemother, Vol: 55, Pages: 4218-4223
The object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavir-ritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavir-ritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0- to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0- to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC(50)] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the protein-binding-corrected IC(50) for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval o
Robey RC, Mletzko S, Bower M, et al., 2011, <i>Ex</i>-<i>Vivo</i> Recognition of Late-Lytic CD8 Epitopes Specific for Kaposi's Sarcoma-Associated Herpesvirus (KSHV) by HIV/KSHV-Coinfected Individuals, VIRAL IMMUNOLOGY, Vol: 24, Pages: 211-220, ISSN: 0882-8245
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Robey R, Mletzko S, Bower M, et al., 2011, Ex-vivo recognition of late-lytic CD8 epitopes specific for Kaposi's sarcoma-associated herpesvirus (KSHV) by HIV/KSHV-coinfected individuals, HIV MEDICINE, Vol: 12, Pages: 23-23, ISSN: 1464-2662
Jackson A, D'Avolio A, Watson V, et al., 2011, Pharmacokinetics and safety of the co-administration of the antiretroviral raltegravir and the lipid-lowering drug ezetimibe in healthy volunteers., J Antimicrob Chemother, Vol: 66, Pages: 885-889
OBJECTIVES: To assess the pharmacokinetics (PK) of raltegravir and ezetimibe when co-administered to healthy volunteers. METHODS: This was a prospective, open-label, crossover study, with subjects randomly assigned to group 1 (raltegravir 400 mg twice daily, raltegravir plus ezetimibe 10 mg once daily, wash-out period, ezetimibe) or group 2 (ezetimibe, raltegravir plus ezetimibe, wash-out period, raltegravir); all phases lasted for 10 days. Steady-state full PK sampling was performed at days 10, 20 and 40. Raltegravir and ezetimibe PK parameters were determined by non-compartmental methods and comparisons in the presence of the potentially interactive drug measured by geometric mean ratio (GMR) and 95% confidence intervals (CIs). RESULTS: Twenty subjects (10 females) completed the study. Raltegravir PK parameters did not change significantly in the presence of ezetimibe: GMRs (95% CI) were 1.16 (0.89-1.51) for AUC(0-12), 1.13 (0.81-1.58) for maximum plasma concentration (Cmax) and 1.12 (0.72-1.74) for trough concentration (Ctrough). Ezetimibe AUC0-24 and Ctrough were lower in the presence of raltegravir [GMRs (95% CI) were 0.79 (0.68-0.91) for AUC0-24 and 0.78 (0.60-0.99) for Ctrough], while ezetimibe glucuronide Cmax was 40% higher (90% CI 1.17-1.66). There was marked inter-individual variability in the PK of the two drugs, especially during co-administration. CONCLUSIONS: There were no significant changes in raltegravir PK parameters with or without ezetimibe. However, in the presence of raltegravir, ezetimibe AUC0-24 and Ctrough were significantly lower (>20%) and ezetimibe glucuronide Cmax was higher. Clinical data to assess the importance of the change in ezetimibe concentrations are warranted.
Jackson A, Hill A, Puls R, et al., 2011, Pharmacokinetics of plasma lopinavir/ritonavir following the administration of 400/100 mg, 200/150 mg and 200/50 mg twice daily in HIV-negative volunteers., J Antimicrob Chemother, Vol: 66, Pages: 635-640
OBJECTIVES: Data suggest that some licensed antiretroviral doses could be reduced. We assessed the safety, tolerability and pharmacokinetics of lopinavir/ritonavir at doses of 400/100, 200/150 and 200/50 mg twice daily in HIV-negative volunteers (http://clinicaltrials.gov/ct2/show/NCT00985543). METHODS: Male and female volunteers were administered lopinavir/ritonavir at doses of 400/100 mg (two lopinavir/ritonavir Meltrex 200/50 mg tablets, Regimen 1), 200/150 mg (one Meltrex tablet, one 100 mg ritonavir capsule, Regimen 2) and 200/50 mg (one Meltrex tablet, Regimen 3). Each dose was given twice daily for 7 days sequentially, separated by a 7 day wash-out period. Lopinavir/ritonavir steady-state pharmacokinetics was assessed over 12 h at the end of each phase (days 7, 21 and 35). Pharmacokinetic parameters were compared using the 400/100 mg twice daily dose as reference, by determining geometric mean ratios (GMRs) and 90% confidence intervals. RESULTS: Twenty-two subjects (eight females) completed the study. Lopinavir AUC(0-12) (ng h/mL), C(max) (ng/mL) and the minimum concentration (C(trough)) (ng/mL) for the 400/100, 200/150 and 200/50 mg twice daily doses, respectively, were as follows: 99,599, 73,603 and 45,146; 11,965, 8939 and 6404; and 5776, 4293 and 1749. Lopinavir pharmacokinetic parameters were significantly lower for Regimens 2 and 3: GMR (90% CI) AUC(0-12), 0.74 (0.65-0.84) and 0.45 (0.40-0.51); C(max), 0.75 (0.66-0.85) and 0.54 (0.40-0.60); and C(trough), 0.74 (0.62-0.89) and 0.30 (0.25-0.36), respectively. All subjects taking the 400/100 and 200/150 mg twice daily doses, and 19 (86%) subjects taking 200/50 mg twice daily had lopinavir concentrations above the suggested minimum effective concentration of 1000 ng/mL. CONCLUSIONS: These pharmacokinetic data show that therapeutic plasma concentrations of lopinavir can be achieved with 200/150 mg of lopinavir/ritonavir twice daily (one Meltrex tablet and one 100 mg ritonavir capsule twice daily).
Ridha E, Devitt E, Boffito M, et al., 2011, Antiretroviral therapy and cardiovascular risk., BMJ Case Rep, Vol: 2011
The increase in the risk of myocardial infarction can be explained by antiretroviral-induced changes in conventional cardiovascular risk factors. Individual drugs within a drug class vary in their propensity to cause metabolic disturbances, and therefore, further studies are needed to determine the contribution of each drug to cardiovascular risk. A careful stratification of the cardiovascular risk and cardiovascular monitoring of HIV-infected individuals should be performed at baseline and at regular intervals during follow-up for this chronic medical condition. Standard primary and secondary prevention measures should be instituted in accordance with British Guidelines (Heart association, National Institute for Health and Clinical Excellence, etc for lipids, smoking and hypertension) Consideration of cardiovascular risk and drug-drug interactions when prescribing is crucial in the safe and optimum management of these patients. Careful communication between all care providers will help to avoid adverse outcomes.
Lamorde M, Byakika-Kibwika P, Okaba-Kayom V, et al., 2010, Suboptimal nevirapine steady-state pharmacokinetics during intrapartum compared with postpartum in HIV-1-seropositive Ugandan women., J Acquir Immune Defic Syndr, Vol: 55, Pages: 345-350
BACKGROUND: Conflicting data exist regarding the effect of pregnancy on steady-state nevirapine pharmacokinetics (PK), although steady-state nevirapine concentrations during pregnancy have never been characterized in sub-Saharan Africa. METHODS: This was a longitudinal intensive PK study in Ugandan pregnant women receiving nevirapine-based antiretroviral therapy. Participants underwent intensive 12-hour PK sampling during the second trimester (T2; n = 4), third trimester (T3; n = 15) and 6 weeks postpartum (PP; n = 15). HIV-1 RNA was performed within 2 weeks of each visit. Nevirapine C12 above 3000 ng/mL was classified as optimal based on the suggested value for therapeutic drug monitoring. RESULTS: The pharmacokinetics of nevirapine were influenced by pregnancy, demonstrated by a 20% reduction in the maximum concentration, minimum concentration (C12), and area under the curve between T3 and PP visits (P = 0.001, P = 0.011 and P = 0.005, respectively). Ten subjects (66.7%) had C12 values <3000 ng/mL during T3. Of these participants, 7 partcipant's C12 concentrations increased to >3000 ng/mL during the PP visit. HIV-1 RNA were <1000 copies per milliliter at T3 and <400 copies per milliliter at PP in all patients. CONCLUSIONS: Nevirapine exposure was reduced in Ugandan women during their third trimester compared with the same women PP, however, HIV RNA remained <1000 copies per milliliter. The long-term impact of intermittent suboptimal nevirapine concentrations during pregnancy is unknown.
Moyle G, Boffito M, Stoehr A, et al., 2010, Phase 2a randomized controlled trial of short-term activity, safety, and pharmacokinetics of a novel nonnucleoside reverse transcriptase inhibitor, RDEA806, in HIV-1-positive, antiretroviral-naive subjects., Antimicrob Agents Chemother, Vol: 54, Pages: 3170-3178
RDEA806 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant HIV-1. A phase 2a randomized, double-blind, placebo-controlled, dose-escalating study evaluated the short-term antiviral activity, safety, and pharmacokinetics (PKs) of RDEA806 monotherapy in antiretroviral-naïve, HIV-1-infected subjects. The subjects were randomized to four cohorts comprising four dosage regimens and two formulations of RDEA806 or placebo in a 3:1 ratio within each cohort. The investigators were blinded to the results for each cohort. The subjects received RDEA806 or placebo for 7 days. The primary end point was the change in the HIV RNA load from the baseline to day 9 for each of the four RDEA806 dose regimens compared to that achieved with placebo. The RDEA806 PKs and the immune response to RDEA806 were evaluated along with the safety and tolerability of each dose. Of a total of 48 enrolled subjects, 36 subjects (9 in each cohort) were randomized to RDEA806 study drug, and 12 (3 in each cohort) took placebo. A statistically significant decrease in the viral load from the baseline to day 9 was observed for all RDEA806 treatment groups (P<0.001). On day 9, the mean changes in the HIV RNA load from that at the baseline were -1.95 log10 copies/ml (400 mg twice a day), -1.39 log10 copies/ml (600 mg once a day [q.d.]), -1.62 log10 copies/ml (800 mg q.d.), and -1.70 log1) copies/ml (1,000 mg q.d.). The pharmacokinetics were linear and dose proportional. Treatment with RDEA806 was well tolerated, and there were no discontinuations due to adverse events. In conclusion, all doses of RDEA806 were safe and well tolerated and exhibited robust antiretroviral activity in this short-term monotherapy study with antiretroviral-naïve HIV-infected subjects. RDEA806 is a potent and promising novel NNRTI.
Randell PA, Jackson AG, Boffito M, et al., 2010, Effect of boosted fosamprenavir or lopinavir-based combinations on whole-body insulin sensitivity and lipids in treatment-naive HIV-type-1-positive men., Antivir Ther, Vol: 15, Pages: 1125-1132
BACKGROUND: Antiretroviral therapy is associated with metabolic complications, including dyslipidaemia, body fat changes and insulin resistance. Healthy volunteer studies have demonstrated a decrease in glucose disposal associated with dosing with specific antiretrovirals. METHODS: HIV-type-1-positive male participants were randomized to receive tenofovir disoproxil fumarate and lamivudine, with either fosamprenavir (FPV)/ritonavir or lopinavir (LPV)/ritonavir twice daily. A hyperinsulinaemic euglycaemic clamp was performed at baseline and at 2 weeks after commencing treatment. The homeostasis model assessment index for insulin resistance (HOMA-IR) was also calculated at these time points. Changes in lipids and lipoprotein subfractions (by nuclear magnetic resonance spectroscopy) were assessed. A pharmacokinetic assessment was undertaken at week 2. RESULTS: A total of 27 participants were enrolled. There was no significant change in whole-body insulin sensitivity or HOMA-IR from baseline or between groups. Total cholesterol increased significantly, by 6.6% with FPV and 10.9% with LPV. The changes in lipids and lipoprotein subfractions were similar between groups with increases in triglycerides, very low-density lipoprotein (VLDL) and chylomicrons, and low-density lipoprotein (LDL) particles. Although the total high-density lipoprotein (HDL) particles were not significantly altered, a decrease in small HDL particles was seen. Changes in VLDL and chylomicron particles in both groups and triglycerides and small HDL particles in the LPV group were statistically significant. CONCLUSIONS: In HIV-type-1-positive men initiating antiretroviral therapy with FPV- or LPV-based regimens, there were no significant changes in whole-body insulin sensitivity after 2 weeks. A proatherogenic lipid profile characterized by increases in triglycerides, VLDL and chylomicron particles and LDL particles, and a decrease in small HDL particles, was observed in both groups.
Hill A, van der Lugt J, Sawyer W, et al., 2009, How much ritonavir is needed to boost protease inhibitors? Systematic review of 17 dose-ranging pharmacokinetic trials., AIDS, Vol: 23, Pages: 2237-2245
BACKGROUND: Ritonavir has been evaluated at boosting doses of 50–800 mg daily with seven protease inhibitors: amprenavir, atazanavir, darunavir, indinavir, lopinavir,saquinavir and tipranavir. Minimizing the boosting dose of ritonavir could improve tolerability and lower costs. METHODS: A MEDLINE search identified 17 phamacokinetic trials using different ritonavir doses with protease inhibitors. The dose of ritonavir used was correlated with plasma levels of each boosted protease inhibitor. For the five pharmacokinetic trials of lopinavir/ritonavir, a meta-analysis was used to estimate the effects of lopinavir dose versus ritonavir dose on lopinavir pharmacokinetics. RESULTS: Saquinavir, fosamprenavir and darunavir were boosted equally well by lower(50–100 mg) versus higher doses of ritonavir. Indinavir, tipranavir and lopinavir were boosted more by higher ritonavir doses. Data on atazanavir were inconclusive. The ritonavir dose-dependence of boosting effects did not correlate with their bioavailability or their effects on ritonavir plasma levels. Atazanavir and indinavir raised plasma ritonavir levels by 69–72%, whereas saquinavir had no effects on ritonavir. Darunavir,lopinavir, tipranavir and fosamprenavir all lowered ritonavir plasma levels. For the meta-analysis of lopinavir/ritonavir trials, the 200/150 mg twice daily (b.i.d.) dose of lopinavir/ritonavir (one Meltrex 200/50mg tablet and one ritonavir 100mg b.i.d.)showed lopinavir area under the curve and minimum concentration similar to the standard 400/100mg b.i.d. dose. CONCLUSION: It may be possible to use three protease inhibitors (saquinavir, amprenavir and darunavir) with lower doses of ritonavir. A 200/150 mg b.i.d. dose of lopinavir/ritonavir could lower costs while maintaining very similar lopinavir plasma levels to the standard dose. New pharmaco enhancer drugs may need to be used at different doses to boost different antiretrovirals.
Boffito M, Jackson A, Lamorde M, et al., 2009, Pharmacokinetics and safety of etravirine administered once or twice daily after 2 weeks treatment with efavirenz in healthy volunteers., J Acquir Immune Defic Syndr, Vol: 52, Pages: 222-227
OBJECTIVE: To assess the pharmacokinetics of etravirine once and twice daily without and with a preceding efavirenz intake period in healthy volunteers. METHODS: Volunteers were randomized to receive etravirine 400 mg once daily (arm 1) or 200 mg twice daily (arm 2) for 14 days. All subjects underwent a washout period of 14 days and then took efavirenz 600 mg once daily for 14 days. Arm 1 and 2 restarted etravirine once and twice daily for 14 days. Etravirine pharmacokinetics was assessed for each phase (before and after efavirenz 14-day intake) on days 1 and 14. Efavirenz concentrations were measured daily for 14 days after intake withholding. Pharmacokinetic parameters were compared (before and after efavirenz 14-day intake) by determining geometric mean ratios and 90% confidence intervals. RESULTS: Twenty-five subjects (9 female) completed the study. Steady-state etravirine pharmacokinetic parameters were significantly lower after efavirenz intake in the once-daily and twice-daily arms: geometric mean ratios and 90% confidence intervals were 0.71 (0.62 to 0.81) for AUC 0-24, 0.78 (0.70 to 0.86) for Cmax, 0.67 (0.49 to 0.91) for Ctrough for once daily; and 0.72 (0.63 to 0.81) for AUC 0-12, 0.79 (0.70 to 0.90) for Cmax, and 0.63 (0.54 to 0.73) for Ctrough for twice daily. All subjects had detectable efavirenz concentrations 7 days after stopping efavirenz intake, 5 above the suggested minimum effective concentration of 1000 ng/mL. CONCLUSIONS: The induction effect of efavirenz persists for at least 2 weeks after stopping drug intake. The decrease in etravirine is not considered clinically significant. Further clinical data are warranted.
Bower M, Weir J, Francis N, et al., 2009, The effect of HAART in 254 consecutive patients with AIDS-related Kaposi's sarcoma, AIDS, Vol: 23, Pages: 1701-1706, ISSN: 0269-9370
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Moyle G, Boffito M, Fletcher C, et al., 2009, Steady-state pharmacokinetics of abacavir in plasma and intracellular carbovir triphosphate following administration of abacavir at 600 milligrams once daily and 300 milligrams twice daily in human immunodeficiency virus-infected subjects., Antimicrob Agents Chemother, Vol: 53, Pages: 1532-1538
Abacavir (ABC) is administered either at 600 mg once daily (ABC 600 mg QD) or 300 mg twice daily (ABC 300 mg BID) in anti-human immunodeficiency virus (anti-HIV) combination therapy. Although ABC plasma pharmacokinetics following each regimen has been well defined, no study has directly compared the regimens with respect to pharmacokinetics of ABC's active intracellular anabolite, carbovir-triphosphate (CBV-TP). In an open-label, two-period, crossover study, 34 HIV-infected male and female subjects stabilized on antiretroviral regimens containing either ABC 600 mg QD or ABC 300 mg BID received their usual doses on days -1 and 1 and then switched regimens for days 2 to 11. Serial blood samples collected on days 1 and 11 were assayed for plasma ABC and intracellular CBV-TP concentrations using validated high-performance liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods. Analysis of variance with a mixed-effect model was performed for treatment and gender comparisons. In 27 evaluable subjects, the regimens provided bioequivalent ABC daily areas under the concentration-time curve from 0 to 24 h (AUC(0-24)) and comparable CBV-TP concentrations at the end of the dosing interval (C(tau)). As expected, ABC QD resulted in 109% higher ABC maximum concentrations of drug in plasma (C(max)) than did ABC BID. ABC QD also resulted in 32% higher CBV-TP AUC(0-24) and 99% higher CBV-TP C(max) than did ABC BID. Females had a 38% higher weight-adjusted ABC AUC(0-24) and 81% higher weight-adjusted CBV-TP AUC(0-24) than did males. Virologic suppression was maintained during regimen switch, and no tolerability differences between regimens were observed. In conclusion, this study showed that ABC 600 mg QD and ABC 300 mg BID regimens led to similar intracellular CBV-TP C(tau) values, thus providing pharmacokinetic support for the interchangeability of these two regimens. Women had higher intracellular CBV-TP exp
Soodalter J, Sousa M, Boffito M, 2009, Drug-drug interactions involving new antiretroviral drugs and drug classes., Curr Opin Infect Dis, Vol: 22, Pages: 18-27
PURPOSE OF REVIEW: The aim of this article is to review the available data on new antiretroviral agents and the drug-drug interactions studied so far. RECENT FINDINGS: Several new drugs have been recently approved or are under development for the treatment of HIV infection. The pharmacokinetics of these agents is being studied to provide information about safety and efficacy, and particularly about drug-drug interactions with antiretrovirals as well as with other drugs used in HIV patients to treat comorbidities. SUMMARY: Several agents for the treatment of HIV infection are under development. With new agents being used, new drug interaction mechanisms emerge and may lead to unpredictable outcomes. When drug-drug interactions are clinically significant, dose adjustments are required to prevent toxicity and ensure virological response.
De Lorenzo F, Boffito M, Collot-Teixeira S, et al., 2009, Prevention of atherosclerosis in patients living with HIV., Vasc Health Risk Manag, Vol: 5, Pages: 287-300
UNLABELLED: INVESTIGATIONAL PRODUCT: Rosuvastatin (Crestor; Astra Zeneca). ACTIVE INGREDIENTS: Rosuvastatin (5 mg). STUDY TITLE: Prevention of Atherosclerosis in Patients Living with HIV. PHASE OF STUDY: Phase III. AIMS: PRIMARY AIM: To assess whether rosuvastatin therapy could slow the progression of the carotid intima-media thickness (C-IMT; as measured by the change in the mean IMT of the near and far walls of the distal common carotid arteries) over 2 years in HIV-infected patients (HIV-IP). SECONDARY AIMS: To assess whether rosuvastatin therapy could reduce highly sensitive C reactive protein (hs-CRP) inflammatory marker that is increased in HIV-IP.To assess the effect of rosuvastatin therapy on serum lipid levels (total cholesterol [TC], low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol and triglycerides [TG]) and apolipoproteins (APO A1, APO B and APO B/A1).To assess the safety of rosuvastatin in HIV-IP through the evaluation of clinical laboratory analyses (liver function tests and creatine kinase) and adverse events (AEs). STUDY DESIGN: Two-year randomized, double-blind, placebo-controlled, parallel group study. PLANNED SAMPLE SIZE: 320 HIV-IP. SUMMARY OF ELIGIBILITY CRITERIA: HIV-IP who are aged between 30 and 60 years, with a CD4 count. greater than 200 cells/mm(3). Patients must be stable on combination antiretroviral therapy (cART) for at least 12 months and have a 10-year CVD risk of less than 20% (using the Framingham risk score). NUMBER OF STUDY CENTERS: One. DURATION OF TREATMENT: Two years (5 mg rosuvastatin or placebo once daily). DOSE AND ROUTE OF ADMINISTRATION: Oral rosuvastatin (5 mg) once daily. The incidence of cardiovascular disease (CVD) in HIV-IP is at least three times higher than in the general population and further increases each year with combination anti-retroviral therapy (cART). The carotid atherosclerosis progression rate is 10 times higher in HIV-IP than in uninfected individuals. The aim of t
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