Despite the World Health Organization listing methadone as an essential medication, effective dose selection is challenging, especially in racial and ethnic minority populations. Subtherapeutic doses ...can result in withdrawal symptoms while supratherapeutic doses can result in overdose and death. Although CYP3A4 was conventionally considered the principal methadone metabolizing enzyme, more recent data have identified CYP2B6 as the principal enzyme. CYP2B6 has ethnically-associated polymorphisms that affect the metabolic rate. Our objective was to investigate the effects of genetic and nongenetic factors on methadone metabolism.
We measured trough plasma methadone levels in 100 participants with opioid use disorder. We assessed methadone metabolism by calculating the metabolite ratio (major metabolite: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine EDDP divided by methadone concentration). We assessed hepatic fibrosis and steatosis by transient elastography and CYP2B6 alleles, principally responsible for methadone metabolism. Mixed effects models modeled the data in 97 participants.
Participants were largely male (58%), minority (61% African American) and non-Hispanic (68%). Forty percent were HCV mono-infected, 40% were uninfected, and 20% were HCV/HIV co-infected. Female sex had significant effects on (R)- and (S)-methadone metabolism (p = 0.016 and p = 0.044, respectively). CYP2B6 loss of function (LOF) alleles significantly affected (S)-methadone metabolism (p = 0.012). Body mass index (BMI) significantly affected (R)-methadone metabolism (p = 0.034). Methadone metabolism appeared to be lower in males, in individuals with LOF alleles, and elevated BMI.
Genetic analysis, especially in minority populations, is essential to delivering individualized treatments. Although the principal methadone metabolizing enzyme remains controversial, our results suggest that sex, CYP2B6 genotype, and BMI should be incorporated into multivariate models to create methadone dosing algorithms. Methadone dosing algorithms should facilitate medication delivery, improve patient satisfaction, and diminish overdose potential.
BACKGROUNDHIV-1 viremia that is not suppressed by combination antiretroviral therapy (ART) is generally attributed to incomplete medication adherence and/or drug resistance. We evaluated individuals ...referred by clinicians for nonsuppressible viremia (plasma HIV-1 RNA above 40 copies/mL) despite reported adherence to ART and the absence of drug resistance to the current ART regimen.METHODSSamples were collected from at least 2 time points from 8 donors who had nonsuppressible viremia for more than 6 months. Single templates of HIV-1 RNA obtained from plasma and viral outgrowth of cultured cells and from proviral DNA were amplified by PCR and sequenced for evidence of clones of cells that produced infectious viruses. Clones were confirmed by host-proviral integration site analysis.RESULTSHIV-1 genomic RNA with identical sequences were identified in plasma samples from all 8 donors. The identical viral RNA sequences did not change over time and did not evolve resistance to the ART regimen. In 4 of the donors, viral RNA sequences obtained from plasma matched those sequences from viral outgrowth cultures, indicating that the viruses were replication competent. Integration sites for infectious proviruses from those 4 donors were mapped to the introns of the MATR3, ZNF268, ZNF721/ABCA11P, and ABCA11P genes. The sizes of the clones were estimated to be from 50 million to 350 million cells.CONCLUSIONThese findings show that clones of HIV-1-infected cells producing virus can cause failure of ART to suppress viremia. The mechanisms involved in clonal expansion and persistence need to be defined to effectively target viremia and the HIV-1 reservoir.FUNDINGNational Cancer Institute, NIH; Howard Hughes Medical Research Fellows Program, Howard Hughes Medical Institute; Bill and Melinda Gates Foundation; Office of AIDS Research; American Cancer Society; National Cancer Institute through a Leidos subcontract; National Institute for Allergy and Infectious Diseases, NIH, to the I4C Martin Delaney Collaboratory; University of Rochester Center for AIDS Research and University of Rochester HIV/AIDS Clinical Trials Unit.
Rituximab in combination with chemotherapy is now widely accepted as standard of care for AIDS-related lymphomas (ARLs) of B-cell origin. However, the clinical impact of rituximab in resource limited ...settings remains unknown. Different settings and patient heterogeneity may affect the effect of any given treatment. The study objectives were to determine if rituximab use was associated with improved 18-month overall survival (OS) of patients with ARLs and to identify correlates of 18-month OS. A retrospective review of medical records of adult HIV infected patients treated for high-grade large cell non-Hodgkin's lymphoma with chemotherapy +/- rituximab between 2015-2017 was conducted. Vital status and disease progression/relapse at 18 months were determined. Survival functions were estimated using Kaplan-Meier methodology. Equality of survival functions were assessed using Log-rank tests and Cox regression analysis to identify risk factors for mortality. One hundred and twenty-four eligible medical records were identified. This was a cohort of black Africans with a median age of 42 (IQR: 33-47) and a 57% male gender distribution. Overall survival at 6, 12 and 18 months for the population was 75.9%, 44.0% and 30.6% respectively. Over the study period, 72.6% of patients were diagnosed with disease progression/ relapse. There was a higher rate of rituximab use in patients who were treated at a private institution and those with medical insurance. Rituximab use was not associated with a reduction in 18-month mortality adjusted hazard ratio (aHR)1.28, (95% CI 0.63-2.60). Risk factors for 18-month mortality were male gender aHR 1.89, (95% CI 1.04-3.43), age 40+ years aHR 2.49, (1.33-4.67), receipt of <3 chemotherapy cycles aHR 2.48, (95% CI 1.33-4.60) and low socioeconomic status aHR 2.44, (95% CI 1.28-4.67). Predictors of mortality were male gender, older age, low socioeconomic status and receipt of a less than half of the recommended number of chemotherapy cycles. Rituximab use was not associated with an improvement in 18-month OS in Zimbabwean patients with ARLs.
Ending the HIV epidemic in the United States will require addressing social determinants contributing to poor care engagement among people living with HIV (PLH), such as food insecurity. Food ...insecurity is associated with poor care engagement among PLH. Yet, few studies have examined the perspectives of healthcare and social services providers on addressing food insecurity in HIV care. Guided by the Social Ecological Model, we conducted semi-structured interviews with 18 providers in New York State to understand barriers and facilitators to addressing food insecurity in HIV care. Thematic analysis illustrated eight themes across various levels of the Social Ecological Model. At the patient-level, providers perceived patients' feelings of embarrassment, shame, and judgement, and low health literacy as barriers. At the provider-level, challenges included limited time. Facilitators included fostering strong, patient-provider relationships. Barriers at the clinic-level included limited funding, while clinic resources served as facilitators. At the community-level, challenges included intersecting stigmas arising from community norms towards PLH and people who receive food assistance and limited access to healthy food. Findings suggest the need to incorporate their insights into the development of interventions that address food insecurity in HIV care.
Success with highly active antiretroviral therapy (ART) for the human immunodeficiency virus (HIV) in developing countries has been attributed to collaborative North-South resource-sharing and ...capacity-building. Academic research and training programmes have contributed towards policy entrepreneurship in a manner that influenced capacity-building within health systems. However, the documented capacity-building frameworks rarely elucidate how such programmes can be designed and implemented efficiently and sustainably.
We implemented the University of Zimbabwe (UZ)-State University of New York at Buffalo (UB) collaborative HIV clinical pharmacology capacity-building programme in Zimbabwe in 1998. We intuitively operationalized the programme around a mnemonic acronym, "RSTUVW", which spells out a supportive framework consisting of "room (space), skills, tools (equipment)", underpinned by a set of core values, "understanding, voice (clout) and will". Subsequent to our two decades of successful collaborative experience, we tested the general validity and applicability of the framework within a prospective programme aimed at expanding the role of health professionals.
Based on this collaborative North-South research and training capacity-building programme which has been positively validated in Zimbabwe, we propose this novel mnemonic acronym-based framework as an extra tool to guide sustainable capacity-building through collaborative North-South implementation research. Its extended use could also include assessment and evaluation of health systems within resource-constrained settings.
The introduction of injectable HIV pre-exposure prophylaxis (PrEP) has the potential to significantly change the biomedical HIV prevention landscape. However, effective implementation will require ...health care providers to adopt, prescribe, and administer injectable PrEP within clinical settings. This study qualitatively examined challenges and benefit of injectable PrEP implementation from the perspective of health care providers. From April to August 2022, we conducted 19 in-depth interviews with current PrEP-prescribing health care providers in New York State, including 3 physician assistants, 5 physicians, and 11 nurse practitioners. Interviews were audio-recorded, transcribed verbatim, and thematically analyzed to report semantic-level themes regarding injectable PrEP implementation. More than half of participants (61%) were aware of injectable PrEP; only 21% had experience prescribing it. Qualitative findings highlighted five themes. Three themes represented implementation challenges, including speculative concerns about side effects, appointment compliance, and practical and logistical considerations. The remaining two themes described benefits of injectable PrEP relative to oral PrEP, which included greater convenience and enhanced privacy. Findings from this qualitative study make significant applied contributions to the sparse knowledge on health care provider perspectives of injectable PrEP post-US Food and Drug Administration approval and their concerns and considerations regarding implementation in real-world clinical settings.
Covid-19: Time for a paradigm change Buonaguro, Franco M; Ascierto, Paolo A; Morse, Gene D ...
Reviews in medical virology,
September 2020, Letnik:
30, Številka:
5
Journal Article
Abstract
Background
Tenofovir alafenamide fumarate (TAF) co-formulated with elvitegravir (EVG; E), cobicistat (C), and emtricitabine (F), a recommended antiretroviral regimen, was evaluated for ...distribution and antiviral activity in cerebrospinal fluid (CSF) as well as neurocognitive (NC) performance change in participants switching from E/C/F/tenofovir disoproxil fumarate (TDF) to E/C/F/TAF.
Methods
This was a 24-week, single-arm, open-label study in treatment-experienced adults living with human immunodeficiency virus (HIV). Nine participants switched from E/C/F/TDF (150/150/200/300 mg once daily) to E/C/F/TAF (150/150/200/10 mg once daily) at week 12. CSF and total plasma concentrations of EVG, TDF, TAF, tenofovir (TFV), and HIV RNA levels were measured at baseline and week 24. NC performance was estimated by the Montreal Cognitive Assessment.
Results
EVG concentrations in CSF and the CSF:plasma ratio remained stable (P = .203) over time. Following the switch, TFV concentrations in CSF and plasma declined (P = .004), although the TFV CSF:plasma ratio increased (P = .004). At week 24, median TAF plasma concentration was 11.05 ng/mL (range, 2.84–147.1 ng/mL) 2 hours postdose but was below assay sensitivity 6 hours after dosing. TAF was below assay sensitivity in all CSF specimens. HIV RNA was ≤40 copies/mL in all CSF and plasma specimens. Three participants (33%) had NC impairment at baseline and 2 (22%) remained impaired at week 24.
Conclusions
Switch to E/C/F/TAF was associated with reductions in TFV concentrations in CSF but stable EVG concentrations that exceeded the 50% inhibitory concentration for wild-type HIV, suggesting that EVG achieves therapeutic concentrations in the central nervous system. No virologic failure or significant NC changes were detected following the switch.
Clinical Trials Registration
NCT02251236.
Switch to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide was associated with reductions in tenofovir concentrations in cerebrospinal fluid but stable therapeutic elvitegravir concentrations, without virologic failure or significant neurocognitive changes.
Monitoring adherence presents a challenge in adolescents and it is prudent to explore several options for determining their level of adherence. This study sought to determine ART adherence levels in ...adolescents and young adults (on a tenofovir-containing regimen) failing ART as measured by self-reports, pill counts and DBS tenofovir concentrations and to compare levels of agreement among the methods and determine the ability of each method to predict virological suppression.
This was a cohort study involving 107 adolescents and young adults between 10 and 24 years failing ART with viral load > 400copies/ml at enrolment. Pill count (PC) records, self-reports (SR) and DBS tenofovir concentrations (done by liquid Chromatography with tandem mass spectrometry (LC-MS/MS)) were used to determine adherence in adolescent participants failing ART in Harare. The latter was used as the reference method with a cut-off of 64 ng/ml. Determination of DBS tenofovir concentrations was also performed to rule out inadequate viral response due to low cumulative drug exposure despite high adherence (≥90 %). Longitudinal analysis was performed to determine the correlation of viral loads (VL) with adherence. The Kappa (k) coefficient was used to evaluate the level of agreement among the 3 methods.
Poor level of agreement was found between PC records and DBS tenofovir concentrations (k = −0.115). Moderate agreement was found between DBS and SR methods (k = 0.0557). Slight agreement was found between PC and SR methods (k = 0.0078). Adherence was dependent on age at HIV diagnosis (p = 0.0184) and ART initiation (p = 0.0265). Participants who were adherent were six times more likely to be suppressed at end point than their non-adherent counterparts (OR=5.7 CI 2.1 – 16.5, p < 0.0001).
Self-reported measure of adherence and pill counts exhibited poor agreement with the reference method used i.e. DBS tenofovir concentrations and are thus not effective methods of predicting virological suppression.
Participants in the present study were a subset of those in the PESU intervention ClinicalTrials.gov Identifier: NCT02833441
PDF
