Randomized Dose-Ranging Controlled Trial of AQ-13, a Candidate Antimalarial, and Chloroquine in Healthy Volunteers

OBJECTIVES: To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug–resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans. DESIGN: Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose. SETTING: Tulane–Louisiana State University–Charity Hospital General Clinical Research Center in New Orleans. PARTICIPANTS: 126 healthy adults 21–45 years of age. INTERVENTIONS: 10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13. OUTCOME MEASURES: Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation. RESULTS: No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract–related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0–14.7 l/h versus 9.5–11.3 l/h; p ≤ 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ. CONCLUSIONS: These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Retrospective cohort study comparing two versus three blood culture sets in people who inject drugs

The current standard of drawing two vs three blood culture sets lacks adequate guidance. Because people who inject drugs are at higher risk for bacteraemia and life-threatening infection, consideration of a third blood culture becomes more important. To investigate the risks and benefits of obtaining two versus three blood culture sets. Retrospective cohort study of adults who inject drugs at a multicentre catch-net hospital system from 2017–2022. 998 people who inject drugs and 2278 blood culture sets were analysed. There were 1618 episodes with two blood culture sets and 660 episodes with three. A potential benefit of adding a third blood culture was seen in 30 (4.5%) episodes. However, only 13 (2.0%) episodes showed pathogen-identifying benefit, as 17 (2.6%) involved known inadequately treated infections or the same pathogen in another culture. The number of blood culture sets needed to achieve diagnostic benefit was 51. There were more contaminants for three blood culture sets (65, 9.8%) than for two (114, 7.0%) (p  The benefits of possibly isolating a pathogen from a third blood culture set do not universally outweigh the risks for contaminant growth for people who inject drugs. A third blood culture should be considered in specific clinical scenarios (i.e. inadequately treated endocarditis and osteomyelitis).</p

Risk Factors for Low CD4+ Count Recovery Despite Viral Suppression among Participants Initiating Antiretroviral Treatment with CD4+ Counts > 500 cells/mm3: Findings from the Strategic Timing of AntiRetroviral Treatment (START) Trial.

BACKGROUND Low CD4+ recovery among HIV-positive individuals who achieve virologic suppression is common but has not been studied among individuals initiating treatment at CD4+ counts > 500 cells/mm. SETTING United States, Africa, Asia, Europe & Israel, Australia, Latin America. METHODS Among immediate-ART participants in the Strategic Timing of AntiRetroviral Therapy trial, low CD4+ recovery was defined as a CD4+ increase < 50 cells/mm from baseline after 8 months despite viral load ≤ 200 copies/mL. Risk factors for low recovery were investigated with logistic regression. RESULTS 39.7% of participants had low CD4+ recovery. Male gender (OR 1.53, p = 0.007), lower screening CD4+ (OR 1.09 per 100 fewer cells/mm, p = 0.004), higher baseline CD8+ (OR 1.05 per 100 more cells/mm, p < 0.001), and lower HIV RNA (OR 1.93 per log10 decrease, p < 0.001) were associated with low CD4+ recovery. D-dimer had a quadratic association with low CD4+ recovery, with lowest odds occurring at 0.32 μg/mL. At lower HIV RNA levels, odds of low recovery were elevated across levels of screening CD4+ count, but at higher levels, odds of low CD4+ recovery were greater among those with lower versus higher screening CD4+. CONCLUSION Low CD4+ recovery is frequent among participants starting ART at high CD4+ counts. Risk factors include male gender, lower screening CD4+ cell counts, higher CD8+ cell counts, and lower HIV RNA levels. More follow-up is required to determine the impact of low CD4+ recovery on clinical outcomes

The Duration of Zidovudine Benefit in Persons With Asymptomatic HIV Infection: Prolonged Evaluation of Protocol 019 of the AIDS Clinical Trials Group

Objective.—To determine the durability of zidovudine-induced delay in clinical progression of asymptomatic human immunodeficiency virus (HIV) disease and to assess the relationship between this effect and the entry CD4+ cell count.Design and Interventions.—Extended follow-up data from subjects participating in protocol 019 of the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group were examined. Subjects were offered a total daily dose of 500 mg of open-label zidovudine after the unblinding of the original randomized trial in 1989. Original treatment groups included placebo, 500 mg of zidovudine, or 1500 mg of zidovudine daily in divided doses. Three distinct analyses were conducted to assess the duration of zidovudine's effect on progression to AIDS or death: (1) analysis of all follow-up information from all subjects, (2) analysis of all subjects but with follow-up of original placebo-assigned subjects censored at the time open-label zidovudine was initiated, and (3) analysis of the effect of initiating zidovudine in subjects initially assigned to receive placebo.Setting.—University-based and university-affiliated AIDS research clinics participating in AIDS Clinical Trials Group protocol 019.Patients.—A total of 1565 asymptomatic HIV-infected subjects with entry CD4+ cell counts less than 0.50×109/L (500/μL).Main Outcome Measure.—Time to progression to AIDS or death.Results.—During follow-up of up to 4.5 years (mean, 2.6 years), 232 subjects progressed to AIDS or died. In each of the three analyses described herein, zidovudine was associated with a significant (P=.008,.004,.007) decrease in the risk of such progression. However, each of these analyses also indicated a decreasing placebo:zidovudine relative risk with duration of use (P=.002,.08,.04), suggesting a nonpermanent effect. The duration of benefit appeared to be related to entry CD4+ cell count, with greater benefit in those with higher counts at entry. No significant differences in survival were found between those originally randomized to zidovudine or placebo.Conclusions.—Zidovudine at 500 mg/d caused a significant delay in progression to AIDS or death, but its earlier use in asymptomatic disease was not associated with an additional prolongation of survival compared with delayed initiation. The delay in progression diminished over time especially in subjects with entry CD4+ cell counts less than 0.30×109/L (300/μL). Treatment strategies that alter drug regimens before the loss of zidovudine benefit should be explored.(JAMA. 1994;272:437-442

Patterns of Antiretroviral Therapy Use and Immunologic Profiles at Enrollment in the REPRIEVE Trial

BackgroundPatterns of antiretroviral therapy (ART) use and immunologic correlates vary globally, and contemporary trends are not well described.MethodsThe REPRIEVE trial (Randomized Trial to Prevent Vascular Events in HIV) enrolled persons with human immunodeficiency virus (HIV) who were aged 40-75 years, receiving ART, and had low-to-moderate cardiovascular disease risk. ART use was summarized within Global Burden of Disease (GBD) super-regions, with adjusted linear and logistic regression analyses examining associations with immune parameters and key demographics.ResultsA total of 7770 participants were enrolled, with a median age of 50 years (interquartile range, 45-55 years); 31% were female, 43% were black or African American, 15% were Asian, 56% had a body mass index &gt;25 (calculated as weight in kilograms divided by height in meters squared), and 49% were current or former smokers. The median CD4 T-cell count was 620/µL (interquartile range, 447-826/ µ L), and the median duration of prior ART use, 9.5 years (5.3-14.8) years. The most common ART regimens were nucleoside/nucleotide reverse-transcriptase inhibitor (NRTI) plus nonnucleoside reverse-transcriptase inhibitor (43%), NRTI plus integrase strand transfer inhibitor (25%), and NRTI plus protease inhibitor (19%). Entry ART varied by GBD region, with shifts during the trial enrollment period. In adjusted analyses, entry CD4 cell count and CD4/CD8 ratio were associated with GBD region, sex, entry regimen, duration of ART, and nadir CD4 cell count; CD4 and CD8 cell counts were also associated with body mass index and smoking status.ConclusionsThere were substantial variations in ART use by geographic region and over time, likely reflecting the local availability of specific medications, changes in treatment guidelines and provider/patient preferences. The analyses of CD4 cell counts and CD4/CD8 ratios may provide valuable insights regarding immune correlates and outcomes in people living with HIV.Clinical trials registrationNCT02344290