Abstract
Background
Antiretroviral drugs have been associated with changes in lipids, fat mass and dat distribution. Tenofovir disoproxil fumarate (TDF) has been shown to have a more favorable ...metabolic profile than other drugs in its class. However, the metabolic effects of TDF in preexposure prophylaxis (PrEP) are unknown.
Methods
We evaluated the effects of TDF/emtricitabine (FTC) on lipids and body composition in a blinded, placebo-controlled PrEP trial. Participants enrolled in a metabolic subcohort (N = 251, TDF/FTC; N = 247, placebo) consented to fasting lipid panels, dual-energy X-ray absorptiometry scans for body composition, and pharmacologic testing of drug metabolites at baseline and every 24 weeks thereafter.
Results
Lean body mass was stable and unaffected by TDF/FTC. Body weight increased in both groups but was lower on TDF/FTC through week 72. This difference was explained by lower fat accumulation on TDF/FTC. The net median percent difference (standard error, P value) for TDF/FTC vs placebo at week 24 was −0.8% (0.4%, P = .02), +0.3% (0.4%, P = .46), and −3.8% (1.4%, P = .009) for total, lean, and fat mass, respectively. There was no apparent differential regional fat accumulation on TDF/FTC. Decreases in cholesterol, but not triglycerides, were seen in TDF/FTC participants, with detectable drug levels compared to placebo.
Conclusions
TDF/FTC for PrEP showed cholesterol reductions and appeared to transiently suppress the accumulation of weight and body fat compared to placebo. There was no evidence of altered fat distribution or lipodystrophy during daily oral TDF/FTC PrEP.
Clinical Trials Registration
NCT00458393.
Preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate /emtricitabine (TDF/FTC) leads to small losses of body fat but does not appear to affect fat distribution or lean body mass. It does modestly lower lipid levels as observed in HIV treatment.
Abstract
We found that urine tenofovir (TFV) levels >1500 ng/mL strongly predict virologic suppression among people with human immunodeficiency virus taking tenofovir alafenamide (odds ratio, 5.66; ...95% confidence interval, 1.59–20.14; P = .007). This suggests an existing point-of-care assay developed for tenofovir disoproxil fumarate will support adherence monitoring for patients on all TFV-based antiretrovirals.
We recently showed an association between strict BP control and lower mortality risk during two decades of follow-up of prior participants in the Modification of Diet in Renal Disease (MDRD) trial. ...Here, we determined the risk of ESRD and mortality during extended follow-up of the African American Study of Kidney Disease and Hypertension (AASK) trial. We linked 1067 former AASK participants with CKD previously randomized to strict or usual BP control (mean arterial pressure ≤92 mmHg or 102-107 mmHg, respectively) to the US Renal Data System and Social Security Death Index; 397 patients had ESRD and 475 deaths occurred during a median follow-up of 14.4 years from 1995 to 2012. Compared with the usual BP arm, the strict BP arm had unadjusted and adjusted relative risks of ESRD of 0.92 (95% confidence interval 95% CI, 0.75 to 1.12) and 0.95 (95% CI, 0.78 to 1.16; P=0.64), respectively, and unadjusted and adjusted relative risks of death of 0.92 (95% CI, 0.77 to 1.10) and 0.81 (95% CI, 0.68 to 0.98; P=0.03), respectively. In meta-analyses of individual-level data from the MDRD and the AASK trials, unadjusted relative risk of ESRD was 0.88 (95% CI, 0.78 to 1.00) and unadjusted relative risk of death was 0.87 (95% CI, 0.76 to 0.99) for strict versus usual BP arms. Our findings suggest that, during long-term follow-up, strict BP control does not delay the onset of ESRD but may reduce the relative risk of death in CKD.
Daily dosing of tenofovir disoproxil fumarate, with or without emtricitabine, has high efficacy in preventing human immunodeficiency virus (HIV) infection when individuals are adherent. The target ...protective plasma concentration of tenofovir (TFV), however, is not fully understood. The aim of this study is to estimate the protective TFV plasma concentration.
Participant data from TFV-based daily oral and topical active arms of phase 3 trials (iPrEx, VOICE, and Partners PrEP) were pooled (n = 2950). Individual specific risk scores (low and high risk) of acquiring HIV, based on an earlier placebo analysis, were created. Longitudinal TFV pharmacokinetics (PK), HIV outcome, individual risk scores and the effect of sex at birth data were integrated and analyzed using non-linear mixed effects models.
Around 50% of the individuals were estimated to be adherent, which differed from self-reported adherence (∼90%) and large variation between longitudinal adherence patterns were identified. Following oral administration, the estimated protective TFV trough concentration was substantially higher in high-risk females (45.8 ng/mL) compared with high-risk males (16.1 ng/mL) and to low-risk individuals (∼7.5 ng/mL). Dosing simulations indicated that high-risk women require full adherence to maintain protective levels.
Using the largest PK-HIV outcome database to date, we developed a population adherence-PK-risk-outcome model. Our results indicate that high-risk females need higher levels of plasma TFV to achieve HIV protection compared with males. HIV protection exceeds 90% in all populations if daily adherence is achieved.
Current models of HIV service delivery, with frequent facility visits, have led to facility congestion, patient and healthcare provider dissatisfaction, and suboptimal quality of services and ...retention in care. The Zambian urban adherence club (AC) is a health service innovation designed to improve on-time drug pickup and retention in HIV care through off-hours facility access and pharmacist-led group drug distribution. Similar models of differentiated service delivery (DSD) have shown promise in South Africa, but observational analyses of these models are prone to bias and confounding. We sought to evaluate the effectiveness and implementation of ACs in Zambia using a more rigorous study design.
Using a matched-pair cluster randomized study design (ClinicalTrials.gov: NCT02776254), 10 clinics were randomized to intervention (5 clinics) or control (5 clinics). At each clinic, between May 19 and October 27, 2016, a systematic random sample was assessed for eligibility (HIV+, age ≥ 14 years, on ART >6 months, not acutely ill, CD4 count not <200 cells/mm3) and willingness to participate in an AC. Clinical and antiretroviral drug pickup data were obtained through the existing electronic medical record. AC meeting attendance data were collected at intervention facilities prospectively through October 28, 2017. The primary outcome was time to first late drug pickup (>7 days late). Intervention effect was estimated using unadjusted Kaplan-Meier survival curves and a Cox proportional hazards model to derive an adjusted hazard ratio (aHR). Medication possession ratio (MPR) and implementation outcomes (adoption, acceptability, appropriateness, feasibility, and fidelity) were additionally evaluated as secondary outcomes. Baseline characteristics were similar between 571 intervention and 489 control participants with respect to median age (42 versus 41 years), sex (62% versus 66% female), median time since ART initiation (4.8 versus 5.0 years), median CD4 count at study enrollment (506 versus 533 cells/mm3), and baseline retention (53% versus 55% with at least 1 late drug pickup in previous 12 months). The rate of late drug pickup was lower in intervention participants compared to control participants (aHR 0.26, 95% CI 0.15-0.45, p < 0.001). Median MPR was 100% in intervention participants compared to 96% in control participants (p < 0.001). Although 18% (683/3,734) of AC group meeting visits were missed, on-time drug pickup (within 7 days) still occurred in 51% (350/683) of these missed visits through alternate means (use of buddy pickup or early return to the facility). Qualitative evaluation suggests that the intervention was acceptable to both patients and providers. While patients embraced the convenience and patient-centeredness of the model, preference for traditional adherence counseling and need for greater human resources influenced intervention appropriateness and feasibility from the provider perspective. The main limitations of this study were the small number of clusters, lack of viral load data, and relatively short follow-up period.
ACs were found to be an effective model of service delivery for reducing late ART drug pickup among HIV-infected adults in Zambia. Drug pickup outside of group meetings was relatively common and underscores the need for DSD models to be flexible and patient-centered if they are to be effective.
ClinicalTrials.gov NCT02776254.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Drug concentrations associated with protection from HIV-1 acquisition have not been determined. We evaluated drug concentrations among men who have sex with men in a substudy of the iPrEx trial (1). ...In this randomized placebo-controlled trial, daily oral doses of emtricitabine/tenofovir disoproxil fumarate were used as pre-exposure prophylaxis (PrEP) in men who have sex with men. Drug was detected less frequently in blood plasma and in viable cryopreserved peripheral blood mononuclear cells (PBMCs) in HIV-infected cases at the visit when HIV was first discovered compared with controls at the matched time point of the study (8% versus 44%; P < 0.001) and in the 90 days before that visit (11% versus 51%; P < 0.001). An intracellular concentration of the active form of tenofovir, tenofovir-diphosphate (TFV-DP), of 16 fmol per million PBMCs was associated with a 90% reduction in HIV acquisition relative to the placebo arm. Directly observed dosing in a separate study, the STRAND trial, yielded TFV-DP concentrations that, when analyzed according to the iPrEx model, corresponded to an HIV-1 risk reduction of 76% for two doses per week, 96% for four doses per week, and 99% for seven doses per week. Prophylactic benefits were observed over a range of doses and drug concentrations, suggesting ways to optimize PrEP regimens for this population.
Limited data are available on the long-term clinical and immunologic consequences of SARS-CoV-2 infection in people with HIV (PWH).
We measured SARS-CoV-2-specific humoral and cellular responses in ...people with and without HIV recovering from COVID-19 ( n = 39 and n = 43, respectively) using binding antibody, surrogate virus neutralization, intracellular cytokine staining, and inflammatory marker assays. We identified individuals experiencing postacute sequelae of SARS-CoV-2 infection (PASC) and evaluated immunologic parameters. We used linear regression and generalized linear models to examine differences by HIV status in the magnitude of inflammatory and virus-specific antibody and T-cell responses, as well as differences in the prevalence of PASC.
Among PWH, we found broadly similar SARS-CoV-2-specific antibody and T-cell responses as compared with a well matched group of HIV-negative individuals. PWH had 70% lower relative levels of SARS-CoV-2-specific memory CD8 + T cells ( P = 0.007) and 53% higher relative levels of PD-1+ SARS-CoV-2-specific CD4 + T cells ( P = 0.007). Higher CD4 + /CD8 + ratio was associated with lower PD-1 expression on SARS-CoV-2-specific CD8 + T cells (0.34-fold effect, P = 0.02). HIV status was strongly associated with PASC (odds ratio 4.01, P = 0.008), and levels of certain inflammatory markers (IL-6, TNF-alpha, and IP-10) were associated with persistent symptoms.
We identified potentially important differences in SARS-CoV-2-specific CD4 + and CD8 + T cells in PWH and HIV-negative participants that might have implications for long-term immunity conferred by natural infection. HIV status strongly predicted the presence of PASC. Larger and more detailed studies of PASC in PWH are urgently needed.
To determine whether the pattern of brain injury in term neonatal encephalopathy is associated with distinct prenatal and perinatal factors and to determine whether the pattern of injury is ...associated with 30-month neurodevelopmental outcome.
A total of 173 term newborns with neonatal encephalopathy from 2 centers underwent magnetic resonance imaging (MRI) at a median of 6 days of age (range, 1-24 days). Patterns of injury on MRI were defined on the basis of the predominant site of injury: watershed predominant, basal ganglia/thalamus predominant, and normal.
The watershed pattern of injury was seen in 78 newborns (45%), the basal ganglia/thalamus pattern was seen in 44 newborns (25%), and normal MRI studies were seen in 51 newborns (30%). Antenatal conditions such as maternal substance use, gestational diabetes, premature rupture of membranes, pre-eclampsia, and intra-uterine growth restriction did not differ across patterns. The basal ganglia/thalamus pattern was associated with more severe neonatal signs, including more intensive resuscitation at birth (
P
=
.001), more severe encephalopathy (
P
=
.0001), and more severe seizures (
P
=
.0001). The basal ganglia/thalamus pattern was associated with the most impaired motor and cognitive outcome at 30 months.
The patterns of brain injury in term neonatal encephalopathy are associated with different clinical presentations and neurodevelopmental outcomes. Measured prenatal risk factors did not predict the pattern of brain injury.
Coronavirus disease-2019 (COVID-19) threatens to further worsen HIV outcomes among people experiencing homelessness. We conducted an interrupted time-series analysis of care engagement and viral ...suppression among unhoused individuals in the 'POP-UP' low-barrier, high-intensity HIV primary care program during COVID-19. Among 85 patients, care engagement and viral suppression did not decrease in the 5 months following implementation of San Francisco's 'shelter-in-place' ordinance. Low-barrier, in-person HIV care for homeless individuals may be important for maintaining HIV outcomes during COVID-19.
Men in sub-Saharan Africa have lower engagement and retention in HIV services compared to women, which may result in differential survival. However, the true magnitude of difference in HIV-related ...mortality between men and women receiving antiretroviral therapy (ART) is incompletely characterized.
We evaluated HIV-positive adults ≥18 years old newly initiating ART in 4 Zambian provinces (Eastern, Lusaka, Southern, and Western). In addition to mortality data obtained from routine electronic medical records, we intensively traced a random sample of patients lost to follow-up (LTFU) and incorporated tracing outcomes through inverse probability weights. Sex-specific mortality rates and rate differences were determined using Poisson regression. Parametric g-computation was used to estimate adjusted mortality rates by sex and age. The study included 49,129 adults newly initiated on ART between August 2013 and July 2015; overall, the median age among patients was 35 years, the median baseline CD4 count was 262 cells/μl, and 37.2% were men. Men comprised a smaller proportion of individuals starting ART (37.2% versus 62.8%), tended to be older (median age 37 versus 33 years), and tended to have lower CD4 counts (median 220 versus 289 cells/μl) at the time of ART initiation compared to women. The overall rate of mortality among men was 10.3 (95% CI 8.2-12.4) deaths/100 person-years (PYs), compared to 5.5 (95% CI 4.3-6.8) deaths/100 PYs among women (difference +4.7 95% CI 2.3-7.2 deaths/100 PYs; p < 0.001). Compared to women in the same age groups, men's mortality rates were particularly elevated among those <30 years old (+6.7 deaths/100 PYs difference), those attending rural health centers (+9.4 deaths/100 PYs difference), those who had an initial CD4 count < 100 cells/μl (+9.2 deaths/100 PYs difference), and those who were unmarried (+8.0 deaths/100 PYs difference). After adjustment for potential confounders and mediators including CD4 count, a substantially higher mortality rate was predicted among men <30 years old compared to women of the same age, while women ≥50 years old had a mortality rate similar to that of age-matched men, but considerably higher than that predicted among young women (<30 years old). No clinically significant differences were evident with respect to rates of facility transfer or care disengagement between men and women. The main study limitations were the inability to successfully ascertain outcomes in all patients selected for tracing and missing clinical and laboratory data due to the use of medical records.
In this study, we found that among HIV-positive adults newly initiating ART, mortality among men exceeded mortality among women; disparities were most pronounced among young patients. Older women, however, also experienced high mortality. Specific interventions for men and older women at highest mortality risk are needed to improve HIV treatment outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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