Using Clinical Research Networks to Assess Severity of an Emerging Influenza Pandemic.

Background: Early clinical severity assessments during the 2009 influenza A H1N1 pandemic (pH1N1) overestimated clinical severity due to selection bias and other factors. We retrospectively investigated how to use data from the International Network for Strategic Initiatives in Global HIV Trials, a global clinical influenza research network, to make more accurate case fatality ratio (CFR) estimates early in a future pandemic, an essential part of pandemic response. Methods: We estimated the CFR of medically attended influenza (CFRMA) as the product of probability of hospitalization given confirmed outpatient influenza and the probability of death given hospitalization with confirmed influenza for the pandemic (2009-2011) and post-pandemic (2012-2015) periods. We used literature survey results on health-seeking behavior to convert that estimate to CFR among all infected persons (CFRAR). Results: During the pandemic period, 5.0% (3.1%-6.9%) of 561 pH1N1-positive outpatients were hospitalized. Of 282 pH1N1-positive inpatients, 8.5% (5.7%-12.6%) died. CFRMA for pH1N1 was 0.4% (0.2%-0.6%) in the pandemic period 2009-2011 but declined 5-fold in young adults during the post-pandemic period compared to the level of seasonal influenza in the post-pandemic period 2012-2015. CFR for influenza-negative patients did not change over time. We estimated the 2009 pandemic CFRAR to be 0.025%, 16-fold lower than CFRMA. Conclusions: Data from a clinical research network yielded accurate pandemic severity estimates, including increased severity among younger people. Going forward, clinical research networks with a global presence and standardized protocols would substantially aid rapid assessment of clinical severity. Clinical Trials Registration: NCT01056354 and NCT01056185

Relationship between untimed plasma lopinavir concentrations and virological outcome on second-line antiretroviral therapy.

BACKGROUND: Resource constraints in low and middle-income countries necessitate practical approaches to optimizing antiretroviral therapy outcomes. We hypothesised that an untimed plasma lopinavir concentration (UPLC) at week 12 would predict loss of virological response in those taking lopinavir as part of a second-line antiretroviral regimen. METHODS: We measured plasma lopinavir concentration at week 12 on stored samples from the SECOND-LINE study. We characterized UPLC as: detectable and optimal (≥1000 µg/l); detectable but suboptimal (≥25 to < 1000 µg/l); and undetectable (<25 µg/l). We used Cox regression to explore the relationship between UPLC and loss of virological response over 48 weeks and backwards stepwise logistic regression to explore the relationship between UPLC and other predictors of virological failure at week 48. RESULTS: At week 48, we observed virological failure in 15/32 (47%) and 53/485 (11%) of patients with undetectable and detectable UPLC, respectively, P < 0.001. Both suboptimal [adjusted hazard ratio (HR) 2.94; 95% confidence interval (CI) 1.54-5.62; P = 0.001], and undetectable (adjusted HR 3.55; 95% CI 1.89-6.64; P < 0.001) UPLC were associated with higher rates of loss of virological response over 48 weeks. In multivariate analysis, an independent association with virological failure at week 48 and undetectable UPLC was observed after adjustment (odds ratio 5.48; 95% CI 2.23-13.42; P < 0.01). CONCLUSION: In low and middle-income countries implementing a public health approach to antiretroviral therapy treatment, an untimed plasma drug concentration may provide a practical method for early identification of patients with inadequate medication adherence and facilitate timely corrective interventions to prevent virological failure.

Comparison of Dried Blood Spots Versus Conventional Plasma Collection for the Characterization of Efavirenz Pharmacokinetics in a Large-Scale Global Clinical Trial-The ENCORE1 Study.

BACKGROUND: The aim of this study was to determine the utility of dried blood spots (DBS) compared with conventional plasma collection methods for characterization of efavirenz pharmacokinetics, in the setting of a large-scale, global clinical trial (ENCORE1). METHODS: Six hundred thirty patients were recruited from 38 sites and had single matched whole blood DBS and plasma samples (mid-dose interval) taken at weeks 4 and 12 of treatment. In addition, a subgroup of patients underwent intensive DBS and plasma sampling (0-24 hours) to provide full-profile data for pharmacokinetic parameters. Efavirenz concentrations were determined by validated high-performance liquid chromatography-mass spectrometry methods. A DBS-predicted plasma concentration was derived and linear regression and Bland-Altman plots were used to compare DBS-predicted plasma concentrations with that of measured plasma concentrations. RESULTS: Efavirenz DBS and plasma concentrations were significantly correlated (R = 0.904, P < 0.001; n = 1094), and DBS concentrations were, on average, 53% ± 9.5% lower than plasma. In the main study, the DBS-predicted plasma values significantly underestimated the true measured concentration of efavirenz in plasma; the mean difference (95% confidence interval) between efavirenz DBS-predicted concentrations and measured plasma concentrations was -0.451 mg/L (-0.504 to -0.398) at week 4 (n = 561). However, in the intensive study, the mean difference was only 0.086 mg/L (-0.006 to 0.178) at 12 hours after dose (n = 46) and was not statistically significant. CONCLUSIONS: Our data show a high correlation between measurements of efavirenz concentrations in plasma and in DBS. However, DBS concentrations significantly underestimated the true measured plasma concentrations in the sparse samples taken in this large multinational ENCORE1 trial.

Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study.

BACKGROUND: ENCORE1 demonstrated non-inferiority of daily efavirenz 400 mg (EFV400) versus 600 mg (EFV600) to 96 weeks in treatment-naïve, HIV-infected adults but concerns regarding lower EFV400 concentrations remained. Therefore, relationships between EFV pharmacokinetics (PK) and key genetic polymorphisms with 96-week efficacy and safety were investigated. METHODS: Relationships between EFV PK parameters and single nucleotide polymorphisms (SNP; CYP2B6, CYP2A6, CYP3A4, NR1I3, NR1I2, ABCB1) with plasma HIV-RNA (pVL) <200 copies/mL and EFV discontinuation and adverse events at 96 weeks were explored. Receiver operating characteristic curve analysis evaluated the predictability of mid-dose interval (C12) cutoffs and 96-week pVL. RESULTS: A total of 606 patients (32 % female; 37 % African, 33 % Asian; n = 311 EFV400, n = 295 EFV600) were included. EFV PK parameters, including C12, were not associated with pVL <200 copies/mL at 96 weeks (odds ratio [OR] 5.25, 95 % confidence interval [CI] 0.41-67.90, p = 0.204). Lower risk of CNS-related adverse events was associated with CYP2B6 983TC/CC (OR 0.35, 95 % CI 0.15-0.81, p = 0.015) and higher risk was associated with CYP2B6 15582CT/TT and ABCB1 3435TT (OR 1.46, 95 % CI 1.02-2.09, p = 0.040; OR 2.31, 95 % CI 1.33-4.02, p = 0.003, respectively). Discontinuation due to adverse events (clinician decision) was independently associated with dose (OR 2.54, 95 % CI 1.19-5.43, p = 0.016). C12 between 0.47 and 0.76 mg/L provided sensitivity/specificity >90 % (100 %/92.3 to 98.9 %/92.3 %) for achieving pVL <200 copies/mL at 96 weeks. CONCLUSIONS: A higher rate of EFV-related adverse events and discontinuations due to these events for EFV600 were not driven by polymorphisms assessed. Although a single threshold concentration associated with HIV suppression may be clinically useful, it was not viable for ENCORE1. Implementation of EFV400 would improve toxicity management whilst still maintaining good efficacy.

Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study.

BACKGROUND: The week 48 primary analysis of the ENCORE1 trial established the virological non-inferiority and safety of efavirenz 400 mg compared with the standard 600 mg dose, combined with tenofovir and emtricitabine, as first-line HIV therapy. This 96-week follow-up of the trial assesses the durability of efficacy and safety of this treatment over 96 weeks. METHODS: ENCORE1 was a double-blind, placebo-controlled, non-inferiority trial done at 38 clinical sites in 13 countries. HIV-infected adult patients (≥16 years of age) with no previous antiretroviral therapy, a CD4 cell count of 50-500 cells per µL, and plasma HIV-1 viral load of at least 1000 copies per mL were randomly assigned (1:1) by an electronic case report form to receive fixed-dose daily tenofovir 300 mg and emtricitabine 200 mg plus efavirenz either 400 mg daily or 600 mg daily. Participants, physicians, and all other trial staff were masked to treatment assignment. Randomisation was stratified by HIV-1 viral load at baseline (≤ or >100 000 copies per mL). The primary endpoint was the difference in the proportions of patients in the two treatment groups with a plasma HIV-1 viral load below 200 copies per mL at week 96. Treatment groups were deemed to be non-inferior if the lower limit of the 95% CI for the difference in viral load was above -10% by modified intention-to-treat analysis. Non-inferiority was assessed in the modified intention-to-treat, per-protocol, and non-completer=failure (NC=F) populations. Adverse events and serious adverse events were summarised by treatment group. This study is registered with ClinicalTrials.gov, number NCT01011413. FINDINGS: Between Aug 24, 2011, and March 19, 2012, 636 eligible participants were enrolled and randomly assigned to the two treatment groups (324 to efavirenz 400 mg and 312 to efavirenz 600 mg). The intention-to-treat population who received at least one dose of study drug comprised 630 patients: 321 in the efavirenz 400 mg group and 309 in the efavirenz 600 mg group. 585 patients (93%; 299 in the efavirenz 400 mg group and 286 in the 600 mg group) completed 96 weeks of follow-up. At 96 weeks, 289 (90·0%) of 321 patients in the efavirenz 400 mg group and 280 (90·6%) of 309 in the efavirenz 600 mg group had a plasma HIV-1 viral load less than 200 copies per mL (difference -0·6, 95% CI -5·2 to 4·0; p=0·72), which suggests continued non-inferiority of the lower efavirenz dose. Non-inferiority was recorded for thresholds of less than 50 and less than 400 copies per mL, irrespective of baseline plasma viral load. Adverse events were reported by 291 (91%) of 321 patients in the efavirenz 400 mg group and by 285 (92%) of 309 in the 600 mg group (p=0·48). The proportions of patients reporting an adverse event that was definitely or probably related to efavirenz were 126 (39%) for efavirenz 400 mg and 148 (48%) for efavirenz 600 mg (p=0·03). The number of patients who reported serious adverse events did not differ between the groups (p=0·20). INTERPRETATION: Our findings confirm that efavirenz 400 mg is non-inferior to the standard dose of 600 mg in combination with tenofovir and emtricitabine as initial HIV therapy over 96 weeks. Fewer efavirenz-related adverse events were reported with the 400 mg efavirenz dose than with the 600 mg dose. These findings support the routine use of efavirenz 400 mg. The coadministration of rifampicin and efavirenz 400 mg needs further investigation. FUNDING: Bill & Melinda Gates Foundation, and UNSW Australia.

Efavirenz 400 mg daily remains non-inferior to 600 mg: 96 week data from the double-blind, placebo-controlled ENCORE1 study.

INTRODUCTION: ENCORE1 compared the efficacy and safety of reduced versus standard dose efavirenz (EFV) with tenofovir/emtricitabine (TDF/FTC) as first-line HIV therapy. The primary analysis at 48 weeks showed 400 mg EFV was safe and virologically non-inferior to 600 mg. This analysis explores over 96 weeks the durability of efficacy and safety. MATERIALS AND METHODS: A multinational, double-blind, placebo-controlled, non-inferiority trial in treatment-naïve HIV-positive adults randomized to TDF/FTC plus reduced (400 mg, EFV400) or standard dose (600 mg, EFV600) EFV. The difference between proportions of participants with plasma HIV RNA (VL) <200 log10 copies/mL by intention-to-treat (ITT missing=failure) was compared using a non-inferiority margin of -10%. Non-inferiority was also examined in per protocol (PP) and non-completer = failure (NC=F) populations. Adverse events (AEs) and serious adverse events (SAEs) were summarized by treatment arm. RESULTS: The ITT population comprised 630 patients (EFV400 = 321; EFV600 = 309); 32% were female; 37%, 33% and 30% were African, Asian and Caucasian, respectively. A total of 585 (EFV400 = 299; EFV600 = 286) completed 96 weeks on randomized therapy. At 96 weeks, proportions with VL <200 copies/mL were EFV400 (90.0%) and EFV600 (90.6%) (difference -0.6; 95% CI -5.2 to 4.0; p=0.72) demonstrating continued non-inferiority. Non-inferior efficacy was also observed for VL thresholds of <50 and <400 copies/mL irrespective of baseline VL (<100,000 versus ≥100,000 copies/mL). There was no between-arm difference in time to loss of virological response (>200 copies/mL) (p=0.47) or mean change from baseline VL (p=0.74). Mean change from baseline in CD4 T-cell counts at week 96 remained significantly higher for EFV400 than EFV600 (difference 25 cells/µL; 95% CI 2-48; p=0.03). There was no difference in the frequency or severity of AEs (EFV400 = 89.4%, EFV600 = 89.3%; difference 0.09; 95% CI -4.73 to 4.90; p=0.97). The proportions ever reporting an AE definitely or probably EFV-related were EFV400 (37.7%) and EFV600 (47.9%) (difference -10.2%; 95% CI -17.9 to -2.51; p=0.01). SAEs did not differ in frequency (EFV400 = 7.5%, EFV600 = 10.4%; difference -2.9%; 95% CI -7.3 to 1.6; p=0.20). CONCLUSIONS: Non-inferiority of EFV 400 mg to EFV 600 mg when combined with TDF/FTC as initial HIV therapy was confirmed at week 96. Both doses demonstrated similar safety profiles. These results support the use of a lower EFV dose as part of routine HIV management.

A randomized study of pharmacokinetics, efficacy, and safety of 2 raltegravir plus atazanavir strategies in ART-treated adults.

BACKGROUND: New antiretroviral drug classes provide opportunities to explore novel regimens. METHODS: HIV+ adults (<50 copies/mL) receiving atazanavir (ATV) were randomized to raltegravir (RAL) 400 mg + ATV 300 mg twice daily (q12h) for 4 weeks followed by RAL 800 mg + ATV/ritonavir 300/100 mg once daily (q24h) for 4 weeks or vice versa. Validated assays quantitated RAL and ATV plasma concentrations. Primary endpoint was geometric mean ratio (GMR) of ATV minimum concentration (Cmin) for q24h/q12h. Equivalence was 90% confidence interval (CI) of GMR lying between 0.80 and 1.25. Participants could consent to a total 48-week follow-up. RESULTS: Twenty-five men, mean age 45 (range, 35-57) years, were evaluated. ATV and RAL demonstrated considerable pharmacokinetic variability. There was no period or sequence effect for pharmacokinetic parameters (P > 0.1 all measures). Ninety percent CIs of ATV GMR C(min) [1.30 (90% CI: 1.08 to 1.58)] and RAL GMR C(min) [0.48 (90% CI: 0.31 to 0.75)] demonstrated nonequivalence. Seventy-six percent consented to follow-up. There were no serious adverse events and no discontinuations due to adverse events over 48 weeks; HIV RNA remained undetectable. CONCLUSIONS: In virologically suppressed adults, regimens comprising ATV plus RAL were efficacious and safe. ATV q12h troughs were lower than ritonavir-boosted atazanavir q24h; RAL q24h troughs were lower than q12h.

Lipid profiles in HIV-infected adults receiving atazanavir and atazanavir/ritonavir: systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To compare lipid profiles in HIV-infected adults receiving atazanavir-based regimens. METHODS: We conducted a systematic review of randomized controlled trials (RCTs) comparing atazanavir or atazanavir/ritonavir with a comparator and evaluated lipids at 48 weeks. We searched MEDLINE, EMBASE, CENTRAL, LILACS, Current Controlled Trials, National Institutes of Health Clinical Trials Registry, trials at AIDSinfo and HIV conference proceedings to May 2009. Standardized mean difference (SMD) between study arms in change from baseline to week 48 in lipid parameters was determined weighted by study size and 95% confidence intervals (CI) were calculated. RESULTS: Nine eligible RCTs were identified (n = 3346). SMDs (mmol/L) in four RCTs comparing atazanavir/ritonavir with a ritonavir-boosted protease inhibitor were: total cholesterol, -0.62 (95% CI -0.72, -0.51); low-density lipoprotein (LDL) cholesterol, -0.31 (95% CI -0.44, -0.17); high-density lipoprotein (HDL) cholesterol, -0.16 (95% CI -0.27, -0.06); non-HDL cholesterol, -0.58 (95% CI -0.69, -0.48); and triglycerides, -0.46 (95% CI -0.58, -0.34). Atazanavir compared with non-atazanavir (three RCTs) found lower total, LDL and non-HDL cholesterol, and triglycerides [SMD -0.87 mmol/L (95% CI -0.99, -0.76); -0.56 mmol/L (95% CI -0.67, -0.45); -0.88 mmol/L (95% CI -0.99, -0.76); and -0.56 mmol/L (95% CI -0.75, -0.36), respectively], but HDL cholesterol did not differ [-0.16 mmol/L (95% CI -0.49, 0.16)]. In the atazanavir/ritonavir versus atazanavir comparison (two RCTs), total [SMD 0.44 mmol/L (95% CI 0.23, 0.65)] and non-HDL cholesterol [SMD 0.44 mmol/L (95% CI 0.23, 0.65)] were higher, but HDL cholesterol, LDL cholesterol and triglycerides were not different. CONCLUSIONS: At 48 weeks, plasma lipid concentrations were lower with atazanavir/ritonavir than with other ritonavir-boosted protease inhibitor regimens. Total and non-HDL cholesterol were higher with atazanavir/ritonavir than atazanavir alone.

Efavirenz plasma concentrations did not predict cessation of therapy due to neuropsychiatric symptoms in a large randomized trial.

To assess whether trial participants who ceased efavirenz (EFV) because of neuropsychiatric events had elevated plasma concentrations, we performed a retrospective case-control study. EFV levels were measured by high-performance liquid chromatography in stored plasma from 35 cases and 75 matched controls. All had taken EFV for at least 4 weeks. Median EFV concentrations did not differ (P = 0.77). Measurement of EFV levels in plasma collected at variable times after the last dose did not predict central nervous system intolerance.

Restorative interventions for HIV facial lipoatrophy.

Facial lipoatrophy is a common and distressing manifestation of HIV lipodystrophy. The changes in facial appearance can reduce quality of life, self esteem and antiretroviral adherence. Apart from the modest benefits of thymidine-based nucleoside analog cessation, there are no proven therapies for lipoatrophy. Management of established fat loss can be challenging as restoration of lost fat mass is extremely gradual. Plastic surgery and cosmetic procedures can restore lost facial volume. Both biodegradable and permanent filling agents have been investigated for HIV facial lipoatrophy. Biodegradable products offer a good safety profile, but maintenance of aesthetic benefits necessitates reinjection over time. Although permanent products offer longevity and lower treatment costs, adverse events should they occur can be serious and of long duration. Despite the substantial increase in options for soft-tissue augmentation in recent years, well-performed clinical studies in HIV-infected adults with facial lipoatrophy are scarce, and long-term clinical safety data are lacking. This review will summarize available efficacy and safety data of the biodegradable and permanent agents utilized for soft-tissue augmentation in this population. Difficulties associated with comparing treatment efficacy data, assessment of facial lipoatrophy presence and severity, and measurement of facial fat will be discussed. Available data indicate that in HIV-infected adults, most filling agents have short-term clinically safety, and can provide aesthetic improvement and improve well-being, social functioning and quality of life. However, well-designed studies with objectively assessed endpoints are needed to elucidate optimal treatments for this distressing condition.

Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection.

BACKGROUND: Metabolic syndrome (MS) identifies individuals at risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Little is known about MS and its consequences following initiation of antiretroviral therapy (ART). METHODS: HIV-infected adults (881) initiating ART were evaluated for prevalence and incidence of MS and subsequent diagnosis of CVD and T2DM over a 3-year period. MS was defined by criteria of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Third Report; ATP-III) or of the International Diabetes Federation (IDF). RESULTS: The prevalence of baseline MS was 8.5% and 7.8% (ATP-III and IDF, respectively). During follow-up, 234 (12/100 patient-years) (ATP-III) and 178 (8/100 patient-years) (IDF) progressed to MS. MS at baseline had a borderline association with increased risk of CVD [ATP-III: hazard ratio (HR), 2.56; 95% confidence interval (CI), 0.86-7.60; P = 0.095; IDF: HR, 2.89; 95% CI, 0.98-8.63; P = 0.058] and was significantly associated with an increased risk of T2DM (ATP-III: HR, 4.34; 95% CI, 1.83-10.25; P = 0.001; IDF: HR, 3.33; 95% CI, 1.35-8.17; P = 0.009). Incident MS was significantly associated with an increased risk of both CVD (ATP-III: HR, 2.73; 95% CI, 1.07-6.96; P = 0.036; IDF: HR, 3.05; 95% CI, 1.20-7.75; P = 0.019) and T2DM (ATP-III: HR, 4.89; 95% CI, 2.22-10.78; P < 0.0001; IDF: HR, 4.84; 95% CI, 2.20-10.64; P < 0.0001). CONCLUSIONS: Substantial progression to MS occurs within 3 years following initiation of ART. Since baseline and incident MS identifies individuals at risk for subsequent CVD and T2DM, it warrants evaluation in patients commencing ART.

Health-related quality of life outcomes in HIV-infected patients starting different combination regimens in a randomized multinational trial: the INITIO-QoL substudy.

The health-related quality of life (HRQoL) outcomes in HIV-infected, treatment-naive patients starting different HAART regimens in a 3-year, randomized, multinational trial were compared. HRQoL was measured in a subgroup of patients enrolled in the INITIO study (153/911), using a modified version of the MOS-HIV questionnaire. The regimens compared in the INITIO trial were composed by two NRTIs (didanosine + stavudine) plus either an NNRTI (efavirenz) or a PI (nelfinavir), or both (efavirenz + nelfinavir). Primary HRQoL outcomes were Physical and Mental Health Summary scores (PHS and MHS, respectively). During follow-up, an increase of PHS score was observed in all treatment arms. The MHS score remained substantially unchanged with the four-drug combination and showed with both NNRTI- and PI-based three-drug regimens a marked trend toward improvement, which became statistically significant when a multiple imputation method was used to adjust for missing data. Overall, starting all the combination regimens compared in the INITIO study was associated with a maintained or slightly improved HRQOL status, consistently with the positive immunological and virological changes observed in the main study. The observed differences in the MHS indicate a possible HRQoL benefit associated to the use of three-drug, two-class regimens and no additional benefit for the use of four-drug, three-class regimens, confirming that three-drug, two-class regimens that include two NRTIs plus either an NNRTI or a PI should be preferred as initial treatment of HIV infection.

A randomized, multicenter, open-label study of poly-L-lactic acid for HIV-1 facial lipoatrophy.

BACKGROUND: Facial lipoatrophy can stigmatize and can reduce quality of life, self esteem, and antiretroviral adherence. Poly-L-lactic acid (PLA) injections seem safe and effective, but no randomized study has included objective endpoints. METHODS: HIV-positive adults with moderate/severe facial lipoatrophy were randomized to 4 open-label PLA treatments administered every 2 weeks from week 0 (immediate group, n = 51) or after week 24 (deferred group, n = 50). The primary endpoint was mean change in facial soft tissue volume (FSTV), as assessed by spiral computed tomography. Analyses were by intention to treat. RESULTS: At week 24, mean changes in FSTV were 0 cm3 in the intermediate group and -10 cm3 in the deferred group (between-group difference of 10 [95% confidence interval (CI): -7 to 28] cm3; P = 0.24). The immediate group had a greater mean change in soft tissue depth at the maxilla (2.2 mm [95% CI: 1.6 to 2.9]; P < 0.0001) and base of the nasal septum (1.0 mm [95% CI: 0.3 to 1.6]; P = 0.003) levels. PLA did not have an impact on peripheral fat mass, viral load, or antiretroviral adherence. Patient and physician subjectively assessed facial lipoatrophy severity (P < 0.0001), 2 of 8 Short Form-36 Health Survey and 2 of 5 Multidimensional Body-Self Relations Questionnaire-Appearance Scales, scores improved significantly. The median duration of treatment-related adverse events was 2 (interquartile range: 1 to 3) days. CONCLUSIONS: PLA did not increase FSTV, although tissue thickness in injection planes increased modestly, an improvement observed by patients. PLA was safe and well tolerated. Facial lipoatrophy severity and some quality-of-life domains improved.

Evaluation of ultrasound for assessing facial lipoatrophy in a randomized, placebo-controlled trial.

We investigated the utility of ultrasonography for assessing facial lipoatrophy changes in HIV-infected adults receiving antiretroviral therapy who participated in a 48-week, randomized, placebo-controlled trial of rosiglitazone. Ultrasound was performed at weeks 0, 24 and 48 to determine the subcutaneous fat thickness over the malar bone. Changes in facial fat assessed by ultrasonography did not correlate significantly with more established objective measures of lipoatrophy severity. The measurement of malar fat using ultrasonography is not recommended.

Influence of rosiglitazone on flow-mediated dilation and other markers of cardiovascular risk in HIV-infected patients with lipoatrophy.

BACKGROUND: Antiretroviral therapy for HIV infection is commonly complicated by lipoatrophy, insulin resistance and dyslipidaemia. In HIV-uninfected adults with insulin resistance or type 2 diabetes, thiazolidinediones can lower blood pressure and improve both insulin sensitivity and endothelial function. This study sought to investigate the effects of rosiglitazone on endothelial function and other markers of cardiovascular risk in patients with HIV-related lipoatrophy. METHODS: HIV-infected, lipoatrophic adults receiving antiretroviral therapy were randomized to receive either rosiglitazone 4 mg or matched placebo, twice daily. Percentage flow-mediated forearm arterial dilation (FMD%) was measured at weeks 0, 12, 24 and 48, together with other markers of vascular risk (blood pressure, lipids, glycaemic parameters, adiponectin and leptin). RESULTS: Out of 64 enrolled adults, 44 (69%) attended all visits (23 rosiglitazone, 21 placebo). Relative to placebo, at week 48, rosiglitazone decreased systolic blood pressure (8 mmHg, P=0.03), insulin (3 microIU/ml, P=0.02), insulin resistance (P=0.03) and leptin (0.6 ng/ml, P=0.02), whilst adiponectin was increased (3.3 microg/lml, P<0.0001). However, rosiglitazone increased total cholesterol (49.1 mg/dl, P=0.001), low-density lipoprotein cholesterol (23.5 mg/dl, P=0.01) and triglycerides (146 mg/dl, P=0.06). Mean baseline FMD% for the entire cohort was moderately impaired (4.5%). Compared with baseline, mean on-treatment FMD% increased by 0.8% with rosiglitazone and decreased by 0.3% with placebo, (mean difference 1.1%, 95% CI -0.2 to 2.5, P=0.09). CONCLUSIONS: Rosiglitazone has minimal effect on flow-mediated dilation in HIV-infected lipoatrophic adults. However, despite worsening of the lipid profile, the overall effect of rosiglitazone on the cardiovascular risk profile in these subjects was positive.

A prospective multicentre study of pharmacist initiated changes to drug therapy and patient management in acute care government funded hospitals.

AIMS: To determine the cost savings of pharmacist initiated changes to hospitalized patients' drug therapy or management in eight major acute care government funded teaching hospitals in Australia. METHODS: This was a prospective study performed in eight hospitals examining resource implications of pharmacists' interventions assessed by an independent clinical panel. Pharmacists providing clinical services to inpatients recorded details of interventions, defined as any action that directly resulted in a change to patient management or therapy. An independent clinical review panel, convened at each participating centre, confirmed or rejected the clinical pharmacist's assessment of the impact on length of stay (LOS), readmission probability, medical procedures and laboratory monitoring and quantified the resultant changes, which were then costed. RESULTS: A total of 1399 interventions were documented. Eight hundred and thirty-five interventions impacted on drug costs alone. Five hundred and eleven interventions were evaluated by the independent panels with three quarters of these confirmed as having an impact on one or more of: length of stay, readmission probability, medical procedures or laboratory monitoring. There were 96 interventions deemed by the independent panels to have reduced LOS and 156 reduced the potential for readmission. The calculated savings was $263 221 for the eight hospitals during the period of the study. This included $150 307 for length of stay reduction, $111 848 for readmission reduction. CONCLUSIONS: The annualized cost savings relating to length of stay, readmission, drugs, medical procedures and laboratory monitoring as a result of clinical pharmacist initiated changes to hospitalized patient management or therapy was $4 444 794 for eight major acute care government funded teaching hospitals in Australia.

No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial.

BACKGROUND: Lipodystrophy commonly complicates antiretroviral therapy of HIV-1 infection. Thiazolidinediones such as rosiglitazone promote subcutaneous fat growth in type 2 diabetics and adults with congenital lipodystrophy, and can prevent HIV-1 protease inhibitor toxicity to adipocytes in vitro. We postulated that rosiglitazone would improve HIV lipoatrophy. METHODS: 108 HIV-1-infected lipoatrophic adults on antiretroviral therapy were randomised to rosiglitazone 4 mg twice daily (n=53) or matching placebo (n=55) for 48 weeks. The study had 80% power to detect a 0.5 kg difference in changes in limb fat (using dual-energy X-ray absorptiometry) between groups at week 48 by intention-to-treat analysis, and a 0.7 kg difference within each protease inhibitor stratum. FINDINGS: Limb fat increased by 0.14 kg in the rosiglitazone group and 0.18 kg in the placebo group (mean difference -0.04 kg [95%CI -0.29 to 0.21]; p=0.74 by t test), with three participants (one on rosiglitazone and two controls), lost to follow-up. Rosiglitazone had no significant benefit on any other measure of lipodystrophy, despite large relative increases in plasma adiponectin (4.2 mmol/L [102%]; p<0.0001) and in three markers of insulin sensitivity (p=0.01 to 0.02). Six participants ceased study drug in each group, four participants (three on rosiglitazone and one control) for related adverse events. The main adverse effects, which seem to be almost unique to this population, were asymptomatic hypertriglyceridaemia (mean relative increase 0.9 mmol/L at week 48; p=0.04) and hypercholesterolaemia (1.5 mmol/L; p=0.001). INTERPRETATION: Rosiglitazone for 48 weeks did not improve lipoatrophy in HIV-1-infected adults receiving antiretroviral therapy. Use of less toxic antiretroviral treatment is necessary to prevent lipoatrophy.

Once-daily therapies.

Combination antiretroviral therapy is now standard treatment for HIV infection. However, adherence to these treatment regimens remains a formidable barrier, owing to their complex and demanding nature and the severity of the associated toxicities. As suboptimal adherence increases the risk of treatment failure, the need for simpler and safer regimens is imperative. A number of strategies have been used to simplify dosing regimens and reduce pill burdens. At present, several antiretroviral drugs can be used once daily, while others have demonstrated pharmacokinetic potential for once-daily dosing and a number of compounds are in clinical development. It is possible that in the future, once-daily dosing will become the standard.

Simultaneous determination of indinavir, ritonavir and lopinavir (ABT 378) in human plasma by high-performance liquid chromatography.

An isocratic reversed-phase high-performance liquid chromatographic method with ultraviolet detection at 205 nm has been validated for the determination of indinavir, ritonavir and lopinavir (ABT 378) in human plasma. The ritonavir analogue A-86093.0 was used as internal standard. Good chromatographic separation was achieved using a stainless steel column packed with 5 microm Phenomenex phenyl hexyl material operated at 40 degrees C, and a mobile phase consisting of acetonitrile-10 mM potassium phosphate buffer (50:50, v/v). The calibration curve for indinavir was linear over the range of 50 to 1000 microg/l while the ritonavir and lopinavir calibration curves were linear over the range of 100 to 15,000 microg/l. The lower limit of quantitations for indinavir, ritonavir and lopinavir were 50, 100 and 100 microg/l, respectively, using 500 microl of human plasma. The validation data showed that the assay is sensitive, specific and reproducible for determination of indinavir, ritonavir and lopinavir. This method is being used in a therapeutic drug monitoring service to quantitate these therapeutic agents in patients infected with human immunodeficiency virus.