Predictors of severe and recurrent adult anaphylaxis, and gaps in the cascade of care: a retrospective, single-centre study 2009-2018.

BACKGROUND: Anaphylaxis is a severe, potentially fatal, systemic allergic reaction. Understanding predictors of recurrent and severe anaphylaxis in adults, and identifying gaps in ongoing anaphylaxis care, is needed to minimise its impact. AIMS: To evaluate the risk factors in adults with severe and recurrent anaphylaxis presentations and to evaluate the management of patients in regard to the recommended cascade of care. METHODS: We completed a retrospective audit of adults with confirmed anaphylaxis who presented to an inner-city emergency department from 1 January 2009 through 31 December 2018. Data recorded included demographics, background history, medication use, severity, co-factors, triggers, management, discharge disposition and referral for follow-up. Data were managed in REDCap and analysed using Stata. Associations were assessed through odds ratios (ORs) and t tests. RESULTS: Six hundred sixteen individuals had 689 episodes of anaphylaxis over the audit period. Age over 65 (OR: 5.4 (95% confidence interval, CI: 2.3-13.2), P < 0.0001) and history of asthma (OR: 1.6 (95% CI: 1.03-2.5), P = 0.03) were independent risk factors for severe anaphylaxis. History of food allergy (P < 0.001) and food as the trigger were associated with recurrent presentations (OR: 2.1, 95% CI: 1.1-3.9, P = 0.01). Only 19% of patients met the recommended cascade of care, with post-adrenaline monitoring and recommending follow-up with an allergy specialist demonstrating the largest gaps. There were increased presentations with time but no difference in triggers or severity. CONCLUSIONS: Increased age and asthma were identified as risk factors for severe presentations. History of food allergy was a risk factor for recurrent presentations. Further research is needed on the gaps in care for adults with anaphylaxis to identify the reasons why, so we can better care for these patients.

A bispecific antibody that targets IL-6 receptor and IL-17A for the potential therapy of patients with autoimmune and inflammatory diseases.

Despite the success of current biological therapeutics for rheumatoid arthritis, these therapies, targeting individual cytokines or pathways, produce beneficial responses in only about half of patients. Therefore, better therapeutics are needed. IL-6 and IL-17A are proinflammatory cytokines in many autoimmune and inflammatory diseases, and several therapeutics have been developed to specifically inhibit them. However, targeting both of these cytokines with a bispecific therapeutic agent could account for their nonoverlapping proinflammatory functions and for the fact that IL-6 and IL-17A act in a positive feedback loop. Here, we present the development of MT-6194, a bispecific antibody targeting both IL-6R and IL-17A that was developed with the FynomAb technology. We also present data from mouse inflammatory disease experiments, indicating that simultaneous inhibition of both IL-6 and IL-17A yields enhanced efficacy compared with inhibition of each cytokine alone.

Socioeconomic and psychosocial factors are associated with poor treatment outcomes in Australian adults living with HIV: a case-control study.

Background A substantial minority of patients living with HIV refuse or cease antiretroviral therapy (ART), have virological failure (VF) or develop an AIDS-defining condition (ADC) or serious non-AIDS event (SNAE). It is not understood which socioeconomic and psychosocial factors may be associated with these poor outcomes. METHODS: Thirty-nine patients with poor HIV treatment outcomes, defined as those who refused or ceased ART, had VF or were hospitalised with an ADC or SNAE (cases), were compared with 120 controls on suppressive ART. A self-report survey recorded demographics, physical health, life stressors, social supports, HIV disclosure, stigma or discrimination, health care access, treatment adherence, side effects, health and treatment perceptions and financial and employment status. Socioeconomic and psychosocial covariates significant in bivariate analyses were assessed with conditional multivariable logistic regression, adjusted for year of HIV diagnosis. RESULTS: Cases and controls did not differ significantly with regard to sex (96.2% (n = 153) male) or age (mean (± s.d.) 51 ± 11 years). Twenty cases (51%) had refused or ceased ART, 35 (90%) had an HIV viral load >50 copies mL-1, 12 (31%) were hospitalised with an ADC and five (13%) were hospitalised with a new SNAE. Three covariates were independently associated with poor outcomes: foregoing necessities for financial reasons (adjusted odds ratio (aOR) 3.1, 95% confidence interval (95% CI) 1.3-7.6, P = 0.014), cost barriers to accessing HIV care (aOR 3.1, 95% CI 1.0-9.6, P = 0.049) and lower quality of life (aOR 3.8, 95% CI 1.5-9.7, P = 0.004). CONCLUSIONS: Despite universal health care, socioeconomic and psychosocial factors are associated with poor HIV outcomes in adults in Australia. These factors should be addressed through targeted interventions to improve long-term successful treatment.

A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids.

The proteasome, a validated cellular target for cancer, is central for maintaining cellular homeostasis, while fatty acid synthase (FAS), a novel target for numerous cancers, is responsible for palmitic acid biosynthesis. Perturbation of either enzymatic machine results in decreased proliferation and ultimately cellular apoptosis. Based on structural similarities, we hypothesized that hybrid molecules of belactosin C, a known proteasome inhibitor, and orlistat, a known inhibitor of the thioesterase domain of FAS, could inhibit both enzymes. Herein, we describe proof-of-principle studies leading to the design, synthesis and enzymatic activity of several novel, ß-lactone-based, dual inhibitors of these two enzymes. Validation of dual enzyme targeting through activity-based proteome profiling with an alkyne probe modeled after the most potent inhibitor, and preliminary serum stability studies of selected derivatives are also described. These results provide proof of concept for dual targeting of the proteasome and fatty acid synthase-thioesterase (FAS-TE) enabling a new approach for the development of drug-candidates with potential to overcome resistance.

Single-Tablet Emtricitabine-Rilpivirine-Tenofovir as HIV Postexposure Prophylaxis in Men Who Have Sex With Men.

BACKGROUND: Completion rates for human immunodeficiency virus (HIV) postexposure prophylaxis (PEP) are low. We investigated the adherence and safety of coformulated emtricitabine (FTC), rilpivirine (RPV), and tenofovir disoproxil fumarate (TDF) as a 3-drug, single-tablet regimen for PEP in men who have sex with men (MSM). METHODS: In an open-label, single-arm study at 2 public sexual health clinics and 2 hospital emergency departments in urban Australia, 100 HIV-uninfected MSM requiring 3-drug PEP received single-tablet FTC-RPV-TDF once daily for 28 days. The primary endpoint was premature PEP cessation or primary HIV infection through week 12. Additional endpoints were adherence (by self-report of doses missed or not ingested with a meal, by pill count, and by plasma concentrations of tenofovir and FTC at week 4); and safety (clinical and laboratory adverse events [AEs]). RESULTS: PEP completion was 92% (95% confidence interval, 85%-96%); premature cessation resulted from loss to follow-up (6%), AEs (1%), or study burden (1%). No participant was found to acquire HIV through week 12. Adherence was 98.6% (standard deviation [SD], 2.4) by pill count and 98.5% (SD, 2.7) by self-report; 86% reported taking all doses with food, and 88% of the subset tested had plasma tenofovir levels suggesting full adherence (>40 ng/mL). Eighty-eight participants experienced at least 1 clinical AE; 4 had grade 3 AEs or higher, possibly attributable to study drug. Fifty-six participants experienced at least 1 laboratory AE; 4 had AEs of grade 3 or higher, possibly attributable to study drug. CONCLUSIONS: A single-tablet regimen of FTC-RPV-TDF was well tolerated as once-daily PEP, with high levels of adherence and completion. CLINICAL TRIALS REGISTRATION: NCT01715636.

Delabeling, safety, and impact of ß-lactam allergy testing: A systematic review.

Background: To improve ß-lactam delabeling outcomes, we need to understand current practice and the evidence base regarding its outcomes, safety, and impact. Objectives: We sought to assess the existing published evidence reporting on the effectiveness of penicillin allergy testing and delabeling. Methods: We conducted a systematic review of studies reporting ß-lactam delabeling practices and outcomes after testing, including ß-lactam use and patient understanding of the delabeling result. Searches of the PubMed, Scopus, and Embase databases; clinical trial registries; and websites of professional organizations were conducted. Data were extracted from the included studies in duplicate, with a third extraction if discrepancies remained. Results: We included 284 publications (covering 98,316 participants); 173 were prospective studies, with no randomized controlled trials. The overall study quality was low. In all, 95.6% of individuals who underwent provocation testing were delabeled. Factors associated with successful delabeling could not be determined because of significant heterogeneity between studies. Anaphylaxis due to testing occurred in 0.3% of participants (95 of 31,667). Subjects who did not undergo skin testing (6,980 patients in 31 studies) before challenge had higher rates of provocation test positivity (8.8% vs 4.1% [P < .0001]) and anaphylaxis (15.9% vs 2.7% [P < .0001]) than those subjects who underwent skin testing (51,607 patients in 177 studies). Six studies (2.1%) followed patients after testing to assess their adherence to prescribing recommendations. In all, 136 participants (20.6%) were actively avoiding ß-lactams despite delabeling. Conclusions: The available data suggest that penicillin allergy testing is safe and effective in delabeling most individuals, but the evidence base is incomplete and more work is required to assess the role of skin testing and the impact that delabeling is having on prescribing habits.

Standardized testing and written communication improve patient understanding of beta-lactam allergy testing outcomes: A multicenter, prospective study.

Background: Historical penicillin allergy is commonly reported, but the lack of standardized allergy clinic practices may diminish the ability to delabel beta-lactam allergy appropriately. Objective: We sought to improve beta-lactam allergy testing and patient understanding of their antibiotic allergy status by standardizing testing and communication practices between 7 adult and pediatric hospital centers. Methods: Phase 1 prospectively described the beta-lactam allergy testing practices at each center. Following this, practice was standardized to achieve a defined panel of skin testing reagents, pro forma result letters for patients and referring doctors, and provision of medical alert jewelry to those with confirmed allergy. Testing outcomes and patient perception regarding allergy status 8 weeks postassessment were compared before (phase 1) and after standardization (phase 2). Primary outcomes were the percentage of participants delabeled after testing, and concordance rates between participant perception of their allergy status and their status as determined by the treating physician at 8-week follow-up. Results: Of 195 adult and pediatric participants (median age, 50 years; 21.5% <18 years; 36.9% males), 75% were delabeled of their beta-lactam allergy. No patient experienced anaphylaxis related to any beta-lactam delabeling testing. In phase 1, 75% of participants received written results, 52% were informed verbally, and 48% received results in more than 1 form. All phase 2 participants received written results (P < .01), 61% received verbal results from a physician as well (P > .05). At 8-week follow-up, 54% of phase 1 participants had concordant perceptions of their allergy status as the testing team versus 91.6% in phase2 (P < .001). Of the 17 participants who were delabeled and treated with a beta-lactam antibiotic during the 8-week follow-up period, there were no reported allergic reactions, although 1 participant experienced anaphylaxis following exposure to amoxicillin-clavulanic acid 1 year after delabeling. Conclusions: Standardization of testing and written patient information improved short-term patient perception of beta-lactam allergy status.

Switch from tenofovir disoproxil fumarate to raltegravir is not associated with weight gain over 96 weeks.

: Integrase strand transfer inhibitor-based antiretroviral therapy can cause weight gain. It is unknown if this is a class effect, with limited data regarding raltegravir. In 37 virologically suppressed adults (36 men, mean age 49 years) who switched from tenofovir disoproxil fumarate to raltegravir 400 mg twice daily, mean weight changes from baseline at weeks 24, 48 and 96 were not significant (maximum 0.8 kg at week 24; all P ≥ 0.16). Weight gain may not occur with all integrase strand transfer inhibitors.

A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers.

c-Met is a well-characterized oncogene that is associated with poor prognosis in many solid tumor types. While responses to c-Met inhibitors have been observed in clinical trials, activity appears to be limited to those with MET gene amplifications or mutations. We developed a c-Met targeted antibody-drug conjugate (ADC) with preclinical activity in the absence of MET gene amplification or mutation, and activity even in the context of moderate protein expression. The ADC utilized a high-affinity c-Met antibody (P3D12), that induced c-Met degradation with minimal activation of c-Met signaling, or mitogenic effect. P3D12 was conjugated to the tubulin inhibitor toxin MMAF via a cleavable linker (vc-MMAF). P3D12-vc-MMAF demonstrated potent in vitro activity in c-Met protein-expressing cell lines regardless of MET gene amplification or mutation status, and retained activity in cell lines with medium-low c-Met protein expression. In contrast, the c-Met tyrosine kinase inhibitor (TKI) PHA-665752 slowed tumor cell growth in vitro only in the context of MET gene amplification or very high protein expression. This differential activity was even more marked in vivo. P3D12-vc-MMAF demonstrated robust inhibition of tumor growth in the MET gene amplified MKN-45 xenograft model, and similar results in H1975, which expresses moderate levels of wild type c-Met without genomic amplification. By comparison, the c-Met TKI, PHA-665752, demonstrated modest tumor growth inhibition in MKN-45, and no inhibition at all in H1975. Taken together, these data suggest that P3D12-vc-MMAF may have a superior clinical profile in treating c-Met positive malignancies in contrast to c-Met pathway inhibitors.

Success and failure of initial antiretroviral therapy in adults: an updated systematic review.

BACKGROUND: We updated a prior systematic review of initial antiretroviral therapy (ART) efficacy through week 144. MATERIALS AND METHODS: Studies (1994 to July 2017) were drawn from PubMed, ClinicalTrials.gov, Cochrane Library, and major conferences; design, eligibility, patient, and ART data were abstracted. Outcomes are expressed as group size-weighted means. Mixed-effects meta-regression was used to identify sources of efficacy heterogeneity. RESULTS: Within 354 groups (181 studies, 77 999 participants), principal backbones were tenofovir-emtricitabine (TDF/TAF-FTC) (44.2%), thymidine-based (27.7%), and abacavir-lamivudine (9.7%). Principal anchors were non-nucleoside analog (49.7%), boosted protease inhibitor (28.1%), and integrase inhibitor (INSTI; 11.5%). Mean intention-to-treat efficacy (RNA <50 copies/ml) was 71.3%, 63.5% (145 groups), and 61.8% (48 groups) at weeks 48, 96, and 144, respectively (for post-2010 studies, 83.8%, 79.9%, and 77.1%). TDF/TAF-FTC and INSTI were independent predictors of greater efficacy at weeks 48, 96, and 144. Additional independent predictors at week 48 were pre-ART resistance genotyping, higher baseline CD4 cell count, and once-daily ART. Fewer pills per day predicted greater efficacy at weeks 96 and 144. Phase 4 studies yielded progressively inferior efficacy than phase 3 studies (difference 5.1% at week 48, 15.8% at week 144). Cessation through week 144 overall (29.4%) and for adverse events (8.9%) declined over time, but cessation for virological failure (5.2%) did not. CONCLUSIONS: Initial ART efficacy continues to improve, but more than 20% of post-2010 patients failed over 3 years. Real-world efficacy is lower than in phase 3 trials. Guidelines should list non-INSTI-based initial ART as nonpreferred. Strategies are needed to improve access to pre-ART genotyping and to increase early initiation of once-daily ART.

Prolonged Effect of Zoledronic Acid on Bone Mineral Density and Turnover in HIV-Infected Adults on Tenofovir: A Randomized, Open-Label Study.

Zoledronic acid (ZOL) 5 mg annually was more effective than tenofovir disoproxil fumarate (TDF) switching at increasing bone mineral density (BMD) over 24 months in HIV-infected, osteopenic adults. To determine whether the effects of ZOL would persist without further infusions, we compared changes in left hip and spine BMD over 36 months in participants randomized to ZOL 5 mg at baseline and month 12 (and to continue TDF) or to switch TDF (without receiving ZOL). We also compared changes in the plasma bone turnover markers (BTMs) C-terminal telopeptide of type 1 collagen (CTX; bone resorption), and procollagen type 1 N propeptide (P1NP; bone formation) and determined whether CTX and P1NP changes at month 3 predicted BMD changes at month 36. Changes were compared in the per-protocol populations, which included 32 (74%) of 43 participants randomized to ZOL and 37 (88%) of 42 participants who switched TDF. Despite not receiving ZOL after month 12, mean hip and spine BMD change from baseline were stable and remained greater with ZOL at month 36 than with TDF switching (spine: 7.5% versus 2.7%, mean difference 4.7%, p < 0.001; hip: 5.5% versus 1.5%, mean difference 4.0%, p < 0.001). CTX and P1NP levels declined in both groups but significantly more with ZOL. Only percent changes in P1NP at month 3 correlated inversely with BMD changes at month 36 (spine: rho = -0.442, p < 0.001; hip: rho = -0.373, p = 0.002). Two infusions of ZOL (in the presence of ongoing TDF) yielded sustained BMD increases through month 36 that remained greater than with TDF switching. © 2019 American Society for Bone and Mineral Research.

Beta-lactam congeners of orlistat as inhibitors of fatty acid synthase.

Beta-lactam derivatives of orlistat were prepared and their inhibitory activities toward the thioesterase domain of fatty acid synthase (FAS-TE) were evaluated using a recombinant form of the enzyme. While in general these derivatives showed lower potency compared to beta-lactones, a reasonably potent, lead compound (-)-9 (IC(50)=8.6microM) was discovered that suggests that this class of compounds should be evaluated further.

Novel antagonists of the thioesterase domain of human fatty acid synthase.

Fatty acid synthase (FAS) is up-regulated in a wide range of cancers and has been recently identified as a potential therapeutic target. Indeed, previous research has shown that inhibition of FAS with active site-modifying agents can block tumor cell proliferation, elicit tumor cell death, and prevent tumor growth in animal models. Here, we use a high-throughput fluorogenic screen and identify a novel pharmacophore, 5-(furan-2-ylmethylene) pyrimidine-2,4,6-trione, which inhibits the thioesterase domain of FAS. The novel antagonists are competitive inhibitors of the thioesterase domain, inhibit de novo fatty acid synthesis, and elicit FAS-dependent tumor cell death. This set of novel FAS antagonists provides an important pharmacologic lead for further development of anticancer therapeutics.

Zoledronic acid is superior to tenofovir disoproxil fumarate-switching for low bone mineral density in adults with HIV.

OBJECTIVE: To compare the effects of switching tenofovir disoproxil fumarate (TDF) or treatment with an intravenous bisphosphonate on bone mineral density (BMD) in HIV-positive adults with low bone mass. DESIGN: Two-year, randomized, open-label study at 10 sites in Australia and Spain. PARTICIPANTS: Of 112 adults on TDF-based antiretroviral therapy (ART) screened, 87 with low BMD (T-score < -1.0 at hip or spine by dual-energy X-ray absorptiometry) and undetectable plasma HIV viral load were randomized to either switch TDF to another active antiretroviral drug or to continue TDF-based ART and receive intravenous zoledronic acid (ZOL) 5 mg annually for 2 years. PRIMARY OUTCOME MEASURE: Change in lumbar spine BMD at 24 months by intention-to-treat analysis. Secondary outcomes included changes in femoral neck and total hip BMD, fractures, safety, and virological failure. RESULTS: Forty-four participants were randomized to TDF switch and 43 to ZOL, mean age 50 years (SD 11), 96% men, mean TDF duration 5.9 years (SD 3.1), and mean spine and hip T-scores -1.6 and -1.3, respectively. At 24 months, mean spine BMD increased by 7.4% (SD 4.3%) with ZOL vs. 2.9% (SD 4.5%) with TDF-switch (mean difference 4.4%, 95% CI 2.6-6.3; P < 0.001). Mean total hip BMD increased by 4.6 (SD 2.6%) and 2.6% (SD 4%), respectively (mean difference 1.9%, 95% CI 0.5-3.4; P = 0.009). There was one fracture in the ZOL group vs. seven fractures in four TDF-switch participants. Virological failure occurred in one TDF-switch participant. Other safety endpoints were similar. CONCLUSION: ZOL is more effective than switching TDF at increasing BMD in HIV-positive adults with low bone mass.

Dolutegravir with tenofovir disoproxil fumarate-emtricitabine as HIV postexposure prophylaxis in gay and bisexual men.

OBJECTIVES: Completion rates for HIV postexposure prophylaxis (PEP) are often low. We investigated the adherence and safety of dolutegravir (DTG; 50 mg daily) with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC; 300/200 mg, respectively) as three-drug PEP in gay and bisexual men. DESIGN: Open-label, single-arm study at three sexual health clinics and two emergency departments in Australia. METHODS: In total, 100 HIV-uninfected gay and bisexual men requiring PEP received DTG and TDF-FTC for 28 days. The primary end point was PEP failure (premature PEP cessation or primary HIV infection through week 12). Additional end points were adherence by self-report (n = 98) and pill count (n = 55), safety, and plasma drug levels at day 28. RESULTS: PEP completion was 90% (95% confidence interval 84-96%). Failures (occurring at a median 9 days, interquartile range 3-16) comprised loss to follow-up (9%) and adverse event resulting in study drug discontinuation (headache, 1%). No participant was found to acquire HIV through week 12. Adherence to PEP was 98% by self-report and in the 55 participants with corresponding pill count data. The most common clinical adverse events were fatigue (26%), nausea (25%), diarrhoea (21%), and headache (10%). There were only four grade 3-4 subjective adverse events. The most common laboratory adverse event was raised alanine aminotransferase (22%), but there was no case of clinical hepatitis. At day 28, the mean estimated glomerular filtration rate decrease was 14 ml/min/1.73m (SD 17, P = 0.001); an estimated glomerular filtration rate of less than 60 ml/min/1.73m occurred in 3%. CONCLUSIONS: DTG with TDF-FTC is a well tolerated option for once-daily PEP.

Total synthesis and comparative analysis of orlistat, valilactone, and a transposed orlistat derivative: Inhibitors of fatty acid synthase.

Concise syntheses of orlistat (Xenical), a two-carbon transposed orlistat derivative, and valilactone are described that employ the tandem Mukaiyama aldol-lactonization (TMAL) process as a key step. This process allows facile modification of the alpha-side chain. Versatile strategies for modifying the delta-side chain are described, involving cuprate addition and olefin metathesis. Comparative antagonistic activity of these derivatives toward a recombinant form of the thioesterase domain of fatty acid synthase is reported along with comparative activity-based profiling.

Fluorogenic phospholipid substrate to detect lysophospholipase D/autotaxin activity.

[reaction: see text] Lysophospholipase D (lysoPLD), also known as autotaxin (ATX), is an important source of the potent mitogen lysophosphatidic acid (LPA). Two fluorogenic substrate analogues for lysoPLD were synthesized in nine steps from (S)-PMB-glycerol. The substrates (FS-2 and FS-3) show significant increases in fluorescence when treated with recombinant ATX and have potential applications in screening for this emerging drug target.

3-Dimensional culture systems for anti-cancer compound profiling and high-throughput screening reveal increases in EGFR inhibitor-mediated cytotoxicity compared to monolayer culture systems.

3-dimensional (3D) culture models have the potential to bridge the gap between monolayer cell culture and in vivo studies. To benefit anti-cancer drug discovery from 3D models, new techniques are needed that enable their use in high-throughput (HT) screening amenable formats. We have established miniaturized 3D culture methods robust enough for automated HT screens. We have applied these methods to evaluate the sensitivity of normal and tumorigenic breast epithelial cell lines against a panel of oncology drugs when cultured as monolayers (2D) and spheroids (3D). We have identified two classes of compounds that exhibit preferential cytotoxicity against cancer cells over normal cells when cultured as 3D spheroids: microtubule-targeting agents and epidermal growth factor receptor (EGFR) inhibitors. Further improving upon our 3D model, superior differentiation of EC50 values in the proof-of-concept screens was obtained by co-culturing the breast cancer cells with normal human fibroblasts and endothelial cells. Further, the selective sensitivity of the cancer cells towards chemotherapeutics was observed in 3D co-culture conditions, rather than as 2D co-culture monolayers, highlighting the importance of 3D cultures. Finally, we examined the putative mechanisms that drive the differing potency displayed by EGFR inhibitors. In summary, our studies establish robust 3D culture models of human cells for HT assessment of tumor cell-selective agents. This methodology is anticipated to provide a useful tool for the study of biological differences within 2D and 3D culture conditions in HT format, and an important platform for novel anti-cancer drug discovery.

Lower arterial stiffness and Framingham score after switching abacavir to tenofovir in men at high cardiovascular risk.

Abacavir's effect on cardiovascular function has not been studied prospectively. We measured augmentation index (a measure of arterial stiffness) in 20 men who switched from abacavir to tenofovir. After 4 weeks, mean augmentation index reduced from 22% by 4% (P = 0.03) and Framingham risk score by 2% (P = 0.01), which was driven by lower total cholesterol (0.8 mmol/l; P = 0.002). Consistent trends were observed through week 24. Changes in C-reactive protein, interleukin-6 and D-dimer were inconsistent and only occurred from week 12. Abacavir may impair cardiovascular function by increasing total cholesterol levels.

Postprandial lipid effects of low-dose ritonavir vs. raltegravir in HIV-uninfected adults.

OBJECTIVE: Protease inhibitor therapy is associated with an increased risk of myocardial infarction. Half this risk appears attributable to fasting dyslipidemia, but half remains unexplained. We compared the fasting and postprandial effects of low-dose ritonavir and raltegravir on cardiovascular and metabolic risk factors. DESIGN: Randomized (1: 1), open-label study. METHODS: Twenty HIV-uninfected volunteers (14 women, mean age 32 years) received low-dose ritonavir (100 mg daily) or raltegravir (400 mg twice daily) for 4 weeks. We administered a standardized meal (3.6 MJ, 76% fat, 10% carbohydrates) at baseline and at week 4, with hourly assessments for 6 h after each meal. The primary outcome measure was incremental area under the curve (iAUC) change in postprandial lipids. RESULTS: Ritonavir induced significantly higher postprandial iAUC excursions in low-density lipoprotein (LDL) cholesterol than raltegravir, mostly in the first 3 h after food (P < 0.05). The ritonavir-related postprandial increases in LDL cholesterol at 1, 2, and 3 h were 30-65% greater than the ritonavir-related increase in fasting LDL cholesterol (0.34-0.43 vs. 0.26 mmol/l, P < 0.05 for each comparison). The postprandial iAUC and fasting LDL cholesterol changes at week 4 were significantly correlated (r = 0.64; P = 0.003). There was no between-group difference for other postprandial parameters. CONCLUSION: In HIV-uninfected adults, postprandial LDL cholesterol excursions with low-dose ritonavir were significantly greater than those with raltegravir. This postprandial effect of ritonavir increased by about 50% the previously observed adverse effect of ritonavir on fasting LDL cholesterol, and so may explain some of the hitherto unexplained association of protease inhibitor-based therapy with cardiovascular disease.