ObjectivesThe aim of the study was to compare the neuropsychiatric safety and tolerability of rilpivirine (TMC278) vs. efavirenz in a preplanned pooled analysis of data from the ECHO and THRIVE studies which compared the safety and efficacy of the two drugs in HIV‐1 infected treatment naïve adults.MethodsECHO and THRIVE were randomized, double‐blind, double‐dummy, 96‐week, international, phase 3 trials comparing the efficacy, safety and tolerability of rilpivirine 25 mg vs. efavirenz 600 mg once daily in combination with two background nucleoside/tide reverse transcriptase inhibitors. Safety and tolerability analyses were conducted when all patients had received at least 48 weeks of treatment or discontinued earlier. Differences between treatments in the incidence of neurological and psychiatric adverse events (AEs) of interest were assessed in preplanned statistical analyses using Fisher's exact test.ResultsAt the time of the week 48 analysis, the cumulative incidences in the rilpivirine vs. efavirenz groups of any grade 2–4 treatment‐related AEs and of discontinuation because of AEs were 16% vs. 31% (P < 0.0001) and 3% vs. 8% (P = 0.0005), respectively. The incidence of treatment‐related neuropsychiatric AEs was 27% vs. 48%, respectively (P < 0.0001). The incidence of treatment‐related neurological AEs of interest was 17% vs. 38% (P < 0.0001), and that of treatment‐related psychiatric AEs of interest was 15% vs. 23% (P = 0.0002). Dizziness and abnormal dreams/nightmares occurred significantly less frequently with rilpivirine vs. efavirenz (P < 0.01). In both groups, patients with prior neuropsychiatric history tended to report more neuropsychiatric AEs but rates remained lower for rilpivirine than for efavirenz.ConclusionsRilpivirine was associated with fewer neurological and psychiatric AEs of interest than efavirenz over 48 weeks in treatment‐naïve, HIV‐1‐infected adults.

ObjectivesThese 96‐week, ECHO/THRIVE pooled analyses evaluated data for antiretroviral treatment‐naïve, HIV‐1‐infected adults with viral load (VL) ≤ 100 000 HIV‐1 RNA copies/mL receiving rilpivirine or efavirenz.MethodsECHO and THRIVE were phase 3, randomized, double‐blind trials. Patients received rilpivirine 25 mg once daily (qd) or efavirenz 600 mg qd, with a fixed (ECHO) or investigator‐chosen (THRIVE) nucleoside/tide reverse transcriptase inhibitor (N[t]RTI) background regimen. Response rate (the percentage of patients with VL < 50 copies/mL, using an intent‐to‐treat‐population, time‐to‐loss‐of‐virological‐response algorithm), virological failure (VF), resistance development, safety and tolerability were evaluated.ResultsBaseline characteristics were comparable between the rilpivirine (n = 368) and efavirenz (n = 329) groups. At week 96, response rates [84% for rilpivirine vs. 80% for efavirenz; difference 4.0%; 95% confidence interval (CI) –1.7% to 9.7%] and incidences of VF for the resistance analysis (VFres) (8% for rilpivirine vs. 6% for efavirenz; P = 0.46) were similar in the two groups. Among patients with VFres, a comparable proportion in each group developed nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance‐associated mutations (RAMs). Among those with VFres, more patients in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs, mostly M184I/V. The mean (95% CI) CD4 cell count increased from baseline to week 96 by 224 (208–240) cells/μL in the rilpivirine group and by 206 (188–225) cells/μL in the efavirenz group. Treatment‐related grade 2–4 overall adverse events, any rash and dizziness were less frequent for rilpivirine than for efavirenz (P < 0.0001).ConclusionsRilpivirine demonstrated antiviral efficacy similar to that of efavirenz in antiretroviral treatment‐naïve adults with baseline VL ≤ 100 000 copies/mL over 96 weeks. Frequencies of VFres and emergent NNRTI RAMs in each group were similar. More patients with VFres in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs (mostly M184I/V). Rilpivirine had a more favourable safety/tolerability profile than efavirenz.

Rilpivirine (RPV, TMC278, Edurant®) is a next‐generation non‐nucleoside reverse transcriptase inhibitor (NNRTI), which demonstrated high virologic response rates and non‐inferiority versus efavirenz in two Phase III trials in HIV‐infected patients through 96 weeks [1,2]. RPV has been shown to inhibit P‐glycoprotein (P‐gp) in vitro with an apparent IC50 of 9.2 µM (3.4 µg/mL). This study evaluated the in‐vivo effect of steady‐state RPV 25 mg once daily (qd) on the single‐dose pharmacokinetics of the probe P‐gp substrate digoxin. This was a Phase I, open‐label, randomised, crossover trial in 22 HIV‐negative volunteers. Participants received in one session a single 0.5 mg dose of digoxin, and in another session RPV 25 mg qd for 16 days with a single 0.5 mg dose of digoxin in the morning of Day 11. All study drugs were taken with a breakfast. Pharmacokinetic profiles of digoxin in plasma and urine were determined over 144 hours after dosing in each session. Steady‐state RPV 24‐hour pharmacokinetic profiles in plasma were determined on Day 11. Plasma and urine samples were analysed using validated LC‐MS/MS methods. Pharmacokinetic parameters were calculated with non‐compartmental methods. The least square (LS) means and associated 90% confidence intervals (CI) of treatment ratios were calculated based on log‐transformed pharmacokinetic parameters. Safety and tolerability were assessed throughout the trial. Digoxin pharmacokinetic parameters and statistical results are summarised in Table 1. Single dose pharmacokinetic parameters of digoxin in the absense and presence of steady‐state RPV Parameter digoxin 0.5 mg alone (reference) digoxin 0.5 mg + RPV 25 mg qd (test) N 21 22 AUC4h ng.h/mL 4.44±1.21 4.46±1.31 AUClast ng.h/mL 26.6±7.38 26.0±7.86 Cmax, ng/mL 1.93±0.637 2.05±0.678 tmax, h 1.50 (0.68–3.00) 1.74 (0.65–3.02) t½, h 38.8±6.30 38.3±8.17 Durine total, % 47.7±9.51 55.7±12.2 CLR, L/h 9.46±2.54 11.2±2.66 LS means (90% CI) of digoxin pharmacokinetic parameter ratios* AUClast 0.98 (0.93–1.04)a Cmax 1.06 (0.97–1.17)a CLR 1.16 (1.07–1.25)b Ratios presented as test/reference, calculated based on log‐transformed pharmacokinetic parameters. N=21 for test and N=22 for reference. N=18 for test and N=22 for reference. The plasma and urine digoxin pharmacokinetics were unaffected by co‐administration of steady‐state RPV. The 90% CIs of the LS means ratios of the main pharmacokinetic parameters were contained within the 0.80‐1.25 boundaries of no effect. The terminal elimination half‐life of digoxin was similar in the absence or the presence of steady‐state RPV. RPV pharmacokinetic parameters were comparable to those in previous clinical trials in healthy volunteers. Administration of digoxin and RPV was generally safe and well tolerated. There were no discontinuations due to adverse events. In conclusion, RPV does not affect the pharmacokinetics of the probe P‐gp substrate digoxin. In vivo, at the recommended RPV dose of 25mg qd, the observed in‐vitro inhibition of P‐gp by RPV is not clinically relevant.

Background In the ECHO and THRIVE Phase III, randomised, double‐blind trials, rilpivirine (RPV, TMC278, EDURANT) 25 mg qd showed non‐inferiority compared to efavirenz (EFV) 600 mg qd in antiretroviral (ARV) treatment‐naïve, HIV‐1‐infected adults at Weeks 48 and 96. In Europe, RPV combined with other ARVs is approved for the treatment of ARV‐naïve adults with a viral load (VL) ≤100,000 c/mL. We present results from a pooled analysis of Week 96 data from this patient subgroup. Methods Patients received RPV 25 mg qd or EFV 600 mg qd, both with TDF/FTC (ECHO) or TDF/FTC, AZT/3TC or ABC/3TC (THRIVE). Response rate (% VL <50 c/mL, intent‐to‐treat‐time‐to‐loss‐of‐virologic response [ITT‐TLOVR]), virologic failure in the resistance analysis (VF res ) and resistance development, as well as safety and tolerability were evaluated. Results Baseline characteristics were similar between the 368 RPV and 329 EFV patients with baseline VL ≤100,000 c/mL. At Week 96, response rates (RPV 84% vs EFV 80%; difference 4.0% [95% CI: −1.7%, 9.7%]) and VF res percentages (8% vs 6%, respectively; p=0.46) (Table) were similar in each treatment group. A comparable proportion of VF res developed NNRTI resistance‐associated mutations (RAMs) in each group. More RPV than EFV VF res developed N(t)RTI RAMs (p=0.02). The increase in mean (95% CI) CD4+ cell count from baseline to Week 96 was 224 (208; 240) cells/mm 3 for RPV and 206 (188; 225) cells/mm 3 for EFV. Treatment‐related grade 2–4 overall AEs, any rash, and neurologic AEs, including dizziness were less frequent for RPV than EFV (all p<0.0001, Fisher's Exact test) (Table). RPV N=368 EFV N=329 All Up to Week 48 Weeks 48–96 All Up to Week 48 Weeks 48–96 Resistance at time of failure VF res , n (%) 28 (7.6) 20 (5.4) 7 (1.9) 20 (6.1) 14 (4.3) 6 (1.8) VF res with genotypic data N’=27 N’=19 N’=7 N’=17 N’=11 N’=6 developing NNRTI RAMs, n 10 7 2 6 5 1 developing N(t)RTI RAMs, n 12 8 3 2 2 0 Safety AEs leading to discontinuation, n (%) 18 (4.9) 13 (3.5) 3 (0.8) 22 (6.7) 18 (5.5) 2 (0.6) Grade 2–4 AEs at least possibility related to treatment, n (%) 66 (17.9) 56 (15.2) 5 (1.4) 104 (32) 97 (29.5) 12 (3.6) AEs of interest at least possibly related to treatment, n (%) Any neurological AE 70 (19.0) 67 (18.2) 1 (0.3) 135 (41.0) 132 (40.1) 2 (0.6) Dizziness 35 (9.5) 35 (9.5) 0 97 (29.5) 97 (29.5) 1 (0.3) Any psychiatric AE 61 (16.6) 54 (14.7) 2 (0.5) 75 (22.8) 68 (20.7) 5 (1.5) Abnormal dreams/nightmares 27 (7.3) 25 (6.8) 0 38 (11.6) 36 (10.9) 1 (0.3) Rash (grouped term) 9 (2.4) 8 (2.2) 1 (0.3) 43 (13.1) 43 (13.1) 0 Conclusions At Week 96, in ARV treatment‐naïve adults with baseline VL ≤100,000 c/mL, RPV demonstrated sustained antiviral efficacy similar to EFV. There were similar frequencies of RPV and EFV VF res , and RPV had a more favourable safety/tolerability profile than EFV.

Toll‐like receptors (TLRs) are transmembrane receptors that activate cells of the innate immune systems upon recognition of pathogen‐associated molecular patterns. The TLR4 is an essential component of the innate immune response to various microorganisms. We investigated the impact of TLR4 polymorphism on development of opportunistic diseases in HIV‐infected patients.

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Purpose of the study TMC278 is a next-generation investigational NNRTI with potent and sustained efficacy through 96 weeks in ARVnaive patients [1]. The current trial evaluated the PK interaction between omeprazole and TMC278. Omeprazole increases gastric pH, which can affect the solubility and gastro-intestinal absorption of TMC278. Furthermore, TMC278 has been shown to induce CYP2C19 in vitro, which may influence the omeprazole PK.

We performed a 24-week, placebo-controlled, comparative trial of hydroxyurea (HU) monotherapy, didanosine(ddI) monotherapy, and the combination of ddI plus HU administered as 1000 mg qd or 1500 mg qd in antiretroviral-naive and experienced subjects with CD4+ lymphocyte counts of 200-700 cells/mm3. Enrollment included 134 subjects. HU enhanced the antiviral activity of ddI by 1.0 log10 copies/ml after 8 weeks of therapy, with sustained responses over 24 weeks. HU alone over 4 weeks had no effect. Lamivudine resistance had little impact on antiretroviral activity when examined across treatment arms. Increases in absolute CD4+ T cell counts, but not CD4+ T cell percentages, were less in subjects who received HU compared to ddI monotherapy, and lymphoproliferative responses to antigenic and mitogenic stimuli were not altered. Subjects who received HU 1500 mg were more likely to experience dose-limiting hematological toxicities compared to those who received 1000 mg, without any additional antiviral benefit. HU may continue to have a role as a component of HIV therapy.

Objective: Comparison of stavudine (d4T), didanosine (ddl) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients.Design: Randomized, open-label.Setting: Fourteen HIV Clinical Research Centers.Patients: Two-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts greater than or equal to 200 x 10(6)/l and plasma HIV-1 RNA levels greater than or equal to 10 000 copies/ml.Interventions: Stavudine 40 mg and ddl 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV.Main outcome measures: The proportion of patients with plasma HIV-1 RNA levels < 500 copies/ml and less than or equal to 50 copies/ml and changes in CD4 cell counts were compared.Results: In an analysis of the primary endpoint, 61% of patients on d4T + ddl + IDV and 45% of patients on ZDV + 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 < 500 copies/ml [95% confidence interval (CI) for the difference between proportions, 1.7-30.3%; P = 0.0381. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels < 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddl + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% Cl, -1.4% to 25.7%; P = 0.068). At 48 weeks 41% and 35% were less than or equal to 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P > 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 x 10(6)/l cells for the d4T arm and 106 x 10(6)/l cells for the ZDV arm (P = 0.001). The occurrence of serious adverse events was not significantly different between arms.Conclusion: The combination of stavudine, ddl and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddl and a protease inhibitor as an initial antiretroviral treatment. (C) 2000 Lippincott Williams & Wilkins.

Objective: To evaluate patients with cytomegalovirus (CMV) retinitis treated with intravenous cidofovir for long-term outcomes.Design: Patients with CMV retinitis enrolled in a randomized, controlled clinical trial of intravenous cidofovir as treatment for retinitis were followed for long-term outcomes, including 21 patients initially enrolled in the deferral group who received cidofovir therapy after progression of retinitis.Setting: Thirteen tertiary care clinics specializing in AIDS care and ophthalmology.Participants: Fifty-eight patients with AIDS and small peripheral CMV retinitis lesions.Interventions: Cidofovir 5 mg/kg once weekly for 2 weeks followed by low-dose maintenance cidofovir therapy (3 mg/kg) in 35 patients or high-dose maintenance (5 mg/kg) in 23 patients.Main outcome measures: Time to progression of retinitis, drug toxicities.Results: Median time to progression of retinitis was 2.5 months. Median time to discontinuation of cidofovir because of intolerance was 6.6 months, and did not differ significantly between the two maintenance doses. Median time to discontinuation of cidofovir for intolerance other than probenecid reaction was 16.3 months for patients treated with low-dose maintenance and 5.0 months for patients treated with high-dose maintenance (P = 0.021). Proteinuria of 2+ or more occurred at a rate of 1.22/person year. In patients with sufficient follow-up to determine resolution of proteinuria, 89.9% of episodes resolved, and the median time to resolution was 20 days. Rates of probenecid intolerance and of cidofovir-associated uveitis were 0.35/person-year, and 0.20/person-year, respectively.

BackgroundNo clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available. ObjectiveTo compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV). DesignRandomized, open-label, multi-center. SettingFifteen HIV clinical research centers. PatientsTwo-hundred and four antiretroviral-naive HIV-1-infected-patients with CD4 cell counts ⩾ 200 × 106/l and HIV-1 RNA ⩾ 10 000 copies/ml (bDNA assay), modified to 5000 copies/ml. Interventiond4T 40 mg twice a day, 3TC 150 mg twice a day plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h (modified to 300 mg every 12 h) plus 3TC and IDV. MeasurementsPrimary endpoint: plasma HIV-1 RNA < 500 copies/ml. Additional endpoints: HIV-1 RNA ⩽ 50 copies/ml; change from baseline in HIV-1 RNA and CD4 cell counts; safety and adverse events. ResultsFor HIV-1 RNA, 62% of patients on d4T + 3TC + IDV and 54% of patients on ZDV + 3TC + IDV had < 500 copies/ml HIV RNA at weeks 40 through 48 [90% confidence interval, −0.204 to 0.036;P = 0.213], with 49% and 47% respectively achieving ⩽ 50 copies/ml at 48 weeks (90% CI, −0.134 to 0.096;P = 0.834). Median change in CD4 cell counts at 48 weeks was + 227 × 106/l and + 198 × 106/l for the d4T- and ZDV-containing arms, respectively. The median time-weighted average change from baseline in CD4 cell counts was significantly greater at 48 weeks in the d4T-containing arm (142 × 106/l versus 110 × 106/l;P = 0.033). Serious adverse events were not significantly different between treatment arms, but there were significant differences for frequency of adverse events of all severity with increased nausea and vomiting in the ZDV-containing arm, and increased diarrhea and rash in the d4T-containing arm. ConclusionsThese results support the choice of d4T + 3TC as a nucleoside analog pair in combination with a protease inhibitor in an initial HIV treatment regimen.

Background: Cytomegalovirus (CMV) retinitis is a common infection and a major cause of visual loss in patients with the acquired immunodeficiency syndrome (AIDS). Objective: To evaluate intravenous cidofovir as a treatment for CMV retinitis. Design: Two-stage, multicenter, phase II/III, randomized, controlled clinical trial. Setting: Ophthalmology and AIDS services at tertiary care medical centers. Patients: 64 patients with AIDS and previously untreated, small, peripheral CMV retinitis lesions (that is, patients at low risk for loss of visual acuity). Intervention: Patients were randomly assigned to one of three groups: the deferral group, in which treatment was deferred until retinitis progressed; the low-dose cidofovir group, which received cidofovir, 5 mg/kg of body weight once weekly for 2 weeks, then maintenance therapy with cidofovir, 3 mg/kg once every 2 weeks; or the high-dose cidofovir group, which received cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with cidofovir, 5 mg/kg once every 2 weeks. To minimize nephrotoxicity, cidofovir was administered with hydration and probenecid. Measurements: Progression of retinitis, evaluated in a masked manner by a fundus photograph reading center; the amount of retinal area involved by CMV; the loss of visual acuity; and morbidity. Results: Median time to progression was 64 days in the low-dose cidofovir group and 21 days in the deferral group (P = 0.052, log-rank test). The median time to progression was not reached in the high-dose cidofovir group but was 20 days in the deferral group (P = 0.009, log-rank test). Analysis of the rates of increase in the retinal area affected by CMV confirmed the data on time to progression. The three groups had similar rates of visual loss. Proteinuria of 2+ or more occurred at rates of 2.6 per person-year in the deferral group, 2.8 per person-year in the low-dose cidofovir group (P > 0.2), and 6.8 per person-year in the high-dose cidofovir group (P = 0.135). No patient developed 4+ proteinuria, but two cidofovir recipients developed persistent elevations of serum creatinine levels at more than 177 mu mol/L (2.0 mg/dL). Reactions to probenecid occurred at a rate of 0.70 per person-year. Conclusions: Intravenous cidofovir, high- or low-dose, effectively slowed the progression of CMV retinitis. Concomitant probenecid and hydration therapy, intermittent dosing, and monitoring for proteinuria seemed to minimize but not eliminate the risk for nephrotoxicity.

The objectives of the study were to examine the clinical significance of cytomegalovirus (CMV) culture results and drug susceptibilities in CMV isolates from patients with AIDS-related CMV retinitis. Blood and urine for CMV culture were obtained from 207 patients with newly diagnosed CMV retinitis who were enrolled in a randomized trial comparing foscarnet and ganciclovir. Culture-positive rates at baseline were 45% and 71% for blood and urine, respectively. Rates decreased 3- to 10-fold after initiation of either treatment. Mortality was related to both positive baseline blood and urine cultures; adjusted relative risks were 1.97 and 2.03, respectively. Positive blood cultures at baseline were associated with more rapid retinitis progression. Drug-resistant CMV was found, over comparable follow-up periods on assigned treatment, in 4 of 8 ganciclovir-assigned patients with persistent viremia and 0 of 5 foscarnet-assigned patients with persistent viremia. Results of virologic assays of blood appear to be associated with clinical outcome of CMV retinitis.