RESUMEN
HIV infection is an ongoing global health issue, despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter the immune state, though this is difficult to disentangle in the clinical population. Thus, these experiments used multiplexed chemokine/cytokine arrays to assess peripheral (plasma) and brain (nucleus accumbens; NAc) expression of immune targets in the presence and absence of ART treatment in the EcoHIV mouse model. The findings identify the effects of EcoHIV infection and of treatment with bictegravir (B), emtricitabine (F), and tenofovir alafenamide (TAF) on the expression of numerous immune targets. In the NAc, this included EcoHIV-induced increases in IL-1α and IL-13 expression and B/F/TAF-induced reductions in KC/CXCL1. In the periphery, EcoHIV suppressed IL-6 and LIF expression, while B/F/TAF reduced IL-12p40 expression. In the absence of ART, IBA-1 expression was negatively correlated with CX3CL1 expression in the NAc of EcoHIV-infected mice. These findings identify distinct effects of ART and EcoHIV infection on peripheral and central immune factors and emphasize the need to consider ART effects on neural and immune outcomes.
Asunto(s)
Infecciones por VIH , Animales , Ratones , Infecciones por VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Emtricitabina/uso terapéutico , Emtricitabina/farmacología , Antirretrovirales/uso terapéutico , Antirretrovirales/farmacología , Modelos Animales de Enfermedad , Masculino , Tenofovir/uso terapéutico , Tenofovir/farmacología , Tenofovir/análogos & derivados , Citocinas/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacología , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Ratones Endogámicos C57BL , Inmunidad/efectos de los fármacos , Alanina/análogos & derivados , Alanina/uso terapéutico , Alanina/farmacología , Piperazinas/farmacología , Piperazinas/uso terapéutico , Amidas , PiridonasRESUMEN
BACKGROUND: Combination antiretroviral therapy (cART) has been reported to reduce perinatal transmission of human immunodeficiency virus (HIV) and improve maternal survival outcomes. Recent studies have associated in-utero exposure to cART drugs with adverse outcomes such as pre-eclampsia, preterm delivery, low birth weight and small-for-gestational-age births. However, the exact molecular mechanisms underlying cART-induced adverse pregnancy outcomes remain poorly defined. OBJECTIVES: To investigate the effects of cART drugs on trophoblast proliferation in the HTR-8/SVneo cell line. STUDY DESIGN: HTR-8/SVneo cells were exposed to tenofovir (0.983-9.83 µM), emtricitabine (0.809-8.09 µM) and efavirenz (0.19-1.09 µM), the individual drugs of the first-line single tablet cART regimen termed 'Atripla', and zidovudine (1.12-1.12 µM), lamivudine (0.65-6.5 µM), lopinavir (0.32-3.2 µM) and ritonavir (0.69-6.9 µM), the individual drugs of the second-line single tablet cART regimen termed 'Aluvia'. The cells were treated for 24, 48, 72 and 96 h, and trophoblast proliferation was assessed using a colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltretrazolium bromide assay. RESULTS: Two-way analysis of variance showed a significant dose-dependent decrease (p < 0.05) in trophoblast proliferation in response to individual and combined drug components of first- and second-line antiretroviral therapy. CONCLUSIONS: First- and second-line cART drugs inhibit trophoblast proliferation, and may contribute to placenta-mediated adverse pregnancy outcomes in patients with HIV.
Asunto(s)
Alquinos , Benzoxazinas , Proliferación Celular , Ciclopropanos , Emtricitabina , Tenofovir , Trofoblastos , Humanos , Trofoblastos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Línea Celular , Tenofovir/farmacología , Benzoxazinas/farmacología , Emtricitabina/farmacología , Lamivudine/farmacología , Embarazo , Zidovudina/farmacología , Lopinavir/farmacología , Ritonavir/farmacología , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Quimioterapia Combinada , Antirretrovirales/farmacología , Infecciones por VIH/tratamiento farmacológicoRESUMEN
OBJECTIVES: We aimed to investigate the evolution of weight, lipid profiles, and glucose homeostasis among virally suppressed people with HIV (PWH) who switched to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). METHODS: PWH with viral suppression who switched to BIC/FTC/TAF in Taiwan between October 2019 and May 2021 were followed for 96 weeks to examine changes in weight, lipid profiles (total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG)), and glycated hemoglobin (HbA1c) levels. RESULTS: 889 PWH with an average weight of 72.1 kg at baseline were included. At week 96, more than 95% of PWH consistently maintained plasma HIV RNA load <50 copies/mL at each 24-week interval of follow-up, while the weight change was small (+0.7 kg, P < 0.0001), although statistically significant. Baseline levels of TC, LDL-C, HDL-C, TG, and HbA1c were 191.8 mg/dL, 114.2 mg/dL, 48.9 mg/dL, 174.3 mg/dL, and 5.31%, respectively. After 96 weeks, changes were observed in TC (-11.6 mg/dL, P < 0.0001), LDL-C (-3.4 mg/dL, P = 0.0084), HDL-C (+0.6 mg/dL, P = 0.1089), TG (-30.2, P < 0.0001), and HbA1c (+0.12%, P < 0.0001). A 5% or more weight gain was associated with age of 30-40 years, normal weight at baseline, and prior use of non-integrase inhibitors or tenofovir disoproxil fumarate. Obesity was associated with development of both dyslipidaemia and diabetes mellitus after switch. CONCLUSIONS: Stable switch to BIC/FTC/TAF maintained high rates of viral suppression and had a small effect on weight and metabolic changes in virally suppressed PWH. Follow-up of the weight and metabolic changes is warranted in PWH on long-term antiretroviral therapy.
Asunto(s)
Alanina , Amidas , Fármacos Anti-VIH , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Piperazinas , Piridonas , Tenofovir/análogos & derivados , Humanos , Adulto , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacología , Emtricitabina/uso terapéutico , Emtricitabina/farmacología , LDL-Colesterol/uso terapéutico , Hemoglobina Glucada , Adenina/uso terapéutico , Tenofovir/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Combinación de MedicamentosRESUMEN
BACKGROUND: Dual regimen dolutegravir (DTG) plus lamivudine (3TC) has demonstrated non-inferior efficacy compared to DTG-based three-drug regimens (3DRs), yet directly comparative data regarding the efficacy and safety of DTG + 3TC and bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for therapy-naïve people with human immunodeficiency virus (HIV)-1 (PWH) are still limited. We aimed to assess the antiviral potency and safety profiles of DTG + 3TC vs. B/F/TAF based on antiretroviral therapy (ART)-naïve PWH in China. METHODS: This retrospective multicenter study enrolled PWH initiating ART with DTG + 3TC or B/F/TAF from 2020 to 2022 in Guangdong and Guangxi. We analyzed response rates based on target not detected (TND) status using intention-to-treat (ITT) analysis. Subgroups were formed based on baseline viral load (VL) (<100,000 vs . ≥100,000 copies/mL) and CD4 + cell count (<200 vs . ≥200 cell/µL). Median time to TND VL was assessed by Kaplan-Meier method. We also measured changes from baseline in CD4 + cell counts, CD4/CD8 ratio, lipid parameters, weight, creatinine (Cr), estimated glomerular filtration rate (eGFR), and drug-related adverse effects (DRAEs). RESULTS: We enrolled 280 participants, including 137 (48.9%) on DTG + 3TC and 143 (51.1%) on B/F/TAF. At week 48, 96.4% (132/137) on DTG+3TC and 100% (143/143) on B/F/TAF achieved TND ( P = 0.064). At week 12, TND responses were higher with B/F/TAF (78.3% [112/143]) than DTG+3TC (30.7% [42/137]) ( P <0.001). This trend held across subgroups. B/F/TAF achieved TND faster (12 weeks) than DTG+3TC (24 weeks) ( P <0.001). No differences were seen in CD4 + cell count and CD4/CD8 ratio, except in the high-VL subgroup, where B/F/TAF showed better recovery. DRAEs were significantly lower with B/F/TAF (4.9% [7/143]) than with DTG + 3TC (13.1% [18/137]) ( P = 0.016). Lipid parameters, body weight, and Cr increased in both groups over 48 weeks, with DTG+3TC showing a more favorable effect on triglycerides, high-density lipoprotein (HDL) cholesterol, and weight gain. CONCLUSIONS: In this real-life study, B/F/TAF led to a faster viral decline and fewer DRAEs compared to DTG+3TC. No significant difference was observed in the TND rate at week 48, regardless of baseline VL and CD4 + cell count. CD4 + recovery was superior for B/F/TAF in participants with high VL. The DTG + 3TC regimen had less impact on metabolic changes than B/F/TAF.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adulto , Humanos , Fármacos Anti-VIH/uso terapéutico , China , Emtricitabina/uso terapéutico , Emtricitabina/farmacología , Infecciones por VIH/tratamiento farmacológico , Lamivudine/uso terapéutico , Lamivudine/farmacología , Lípidos , Estudios RetrospectivosRESUMEN
BACKGROUND: This study aimed to determine the reasons for conversion and elucidate the safety and efficacy of transition to tenofovir alafenamide/emtricitabine/bictegravir sodium (TAF/FTC/BIC) in highly active antiretroviral therapy (HAART)-experienced HIV-infected patients in real-world settings. METHODS: We conducted a retrospective cohort study. The treatment conversion rationales, safety, and effectiveness in 1684 HIV-infected patients with previous HAART experience who switched to TAF/FTC/BIC were evaluated at Beijing Ditan Hospital from September 2021 to Auguest 2022. RESULTS: Regimen simplification (990/1684, 58.79%) was the most common reason for switching, followed by osteoporosis or osteopenia (375/1684, 22.27%), liver dysfunction (231/1684, 13.72%), decline in tenofovir alafenamide/emtricitabine/elvitegravir/cobicistat (TAF/FTC/EVG/c) with food restriction (215/1684, 12.77%), virological failure (116/1684, 6.89%), and renal dysfunction (90/1684, 5.34%). In patients receiving non-nucleotide reverse transcriptase inhibitors (NNRTI)-containing regimens, lipid panel changes 1 year after switching indicated a difference of 3.27 ± 1.10 mmol/L vs . 3.40 ± 1.59 mmol/L in triglyceride ( P = 0.014), 4.82 ± 0.74 mmol/L vs . 4.88 ± 0.72 mmol/L in total cholesterol ( P = 0.038), 3.09 ± 0.70 mmol/L vs . 3.18 ± 0.66 mmol/L in low-density lipoprotein ( P <0.001), and 0.99 ± 0.11 mmol/L vs . 0.95 ± 0.10 mmol/L in high-density lipoprotein ( P <0.001). Conversely, among patients receiving booster-containing regimens, including TAF/FTC/EVG/c and lopinavir/ritonavir (LPV/r), lipid panel changes presented decreased trends. We also observed an improved trend in viral load suppression, and alanine transaminase (ALT), aspartate transaminase (AST), estimated glomerular filtration rate (eGFR), and serum creatinine levels after the transition ( P <0.001). CONCLUSION: The transition to TAF/FTC/BIC demonstrated good treatment potency. Furthermore, this study elucidates the motivations behind the adoption of TAF/FTC/BIC in real-world scenarios, providing clinical evidence supporting the stable conversion to TAF/FTC/BIC for HAART-experienced patients.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Humanos , Terapia Antirretroviral Altamente Activa/efectos adversos , Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Tenofovir/uso terapéutico , Estudios Retrospectivos , Emtricitabina/uso terapéutico , Emtricitabina/farmacología , Adenina/uso terapéutico , LípidosRESUMEN
BACKGROUND: Since leprosy bacilli cannot grow in vitro, testing for antimicrobial resistance against Mycobacterium leprae or assessing the anti-leprosy activity of new drugs remains hard. Furthermore, developing a new leprosy drug through the traditional drug development process is not economically captivating for pharmaceutical companies. As a result, repurposing existing drugs/approved medications or their derivatives to test their anti-leprotic potency is a promising alternative. It is an accelerated method to uncover different medicinal and therapeutic properties in approved drug molecules. AIMS: The study aims to explore the binding potential of anti-viral drugs such as Tenofovir, Emtricitabine, and Lamivudine (TEL) against Mycobacterium leprae using molecular docking. METHODS: The current study evaluated and confirmed the possibility of repurposing antiviral drugs such as TEL (Tenofovir, Emtricitabine, and Lamivudine) by transferring the graphical window of the BIOVIA DS2017 with the Crystal Structure of a phosphoglycerate mutase gpm1 from Mycobacterium leprae (PDB ID: 4EO9). Utilizing the smart minimizer algorithm, the protein's energy was reduced in order to achieve a stable local minima conformation. RESULTS: The protein and molecule energy minimization protocol generated stable configuration energy molecules. The protein 4EO9 energy was reduced from 14264.5 kcal/mol to -17588.1 kcal/mol. CONCLUSION: The CHARMm algorithm-based CDOCKER run docked all three molecules (TEL) inside the 4EO9 protein binding pocket (Mycobacterium leprae). The interaction analysis revealed that tenofovir had a better binding molecule with a score of - 37.7297 kcal/mol than the other molecules.
Asunto(s)
Fármacos Anti-VIH , Lepra , Humanos , Tenofovir/farmacología , Lamivudine/farmacología , Emtricitabina/farmacología , Reposicionamiento de Medicamentos , Simulación del Acoplamiento Molecular , Fármacos Anti-VIH/farmacología , Quimioterapia Combinada , Lepra/tratamiento farmacológico , Mycobacterium lepraeRESUMEN
BACKGROUND: In Russia, before 2022, the list of vital and essential drugs for HIV-infected patients previously untreated with antiretroviral drugs included the fixed-dose combination rilpivirine/tenofovir disoproxil fumarate/emtricitabine (RPV/TDF/FTC) but not doravirine/tenofovir disoproxil fumarate/lamivudine (DOR/TDF/3TC). METHODS: An indirect comparison of the efficacy of DOR/TDF/3TC and RPV/TDF/FTC defined by virologic suppression (HIV-1 RNA of <50 copies/mL at week 48) was made. The per-patient drug costs over 1 year were compared in a cost-minimization analysis. A budget impact analysis considered the costs to the healthcare system of including DOR/TDF/3TC as a treatment option for eligible patients in Russia over a 3-year time horizon. RESULTS: The indirect treatment comparison of DOR/TDF/3TC and RPV/TDF/FTC in treatment-naïve patients with baseline HIV-1 RNA 100,000 copies/ml or less showed no statistically significant difference (RR 0.914, 95% CI 0.833-1.003). In the cost-minimization analysis, the per-patient cost of one year of treatment with RPV/TDF/FTC and DOR/TDF/3TC was, respectively, â½320,975 and â½151,192, for a saving of â½169,783. In the budget impact analysis, the adoption of DOR/TDF/3TC into clinical practice is expected to reduce drug costs by â½333 million (23.8%) in year 3. CONCLUSIONS: Fixed-dose combination DOR/TDF/3TC is equally effective and cost-saving compared to RPV/TDF/FTC from Russian vital and essential drugs list perspective.
Asunto(s)
Fármacos Anti-VIH , Medicamentos Esenciales , Infecciones por VIH , Seropositividad para VIH , VIH-1 , Adulto , Humanos , VIH-1/genética , Lamivudine/efectos adversos , Tenofovir/farmacología , Tenofovir/uso terapéutico , Análisis Costo-Beneficio , Carga Viral , Infecciones por VIH/tratamiento farmacológico , ARN Viral/farmacología , ARN Viral/uso terapéutico , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , Seropositividad para VIH/tratamiento farmacológico , Fármacos Anti-VIH/efectos adversos , Combinación de MedicamentosRESUMEN
BACKGROUND: The risk of HIV pre-exposure prophylaxis (PrEP) failure with sufficient medication adherence is extremely low but has occurred due to transmission of a viral strain with mutations conferring resistance to PrEP components tenofovir (TDF) and emtricitabine (FTC). The extent to which such strains are circulating in the population is unknown. METHODS: We used HIV surveillance data to describe primary and overall TDF/FTC resistance and concurrent viremia among people living with HIV (PLWH). HIV genotypes conducted for clinical purposes are reported as part of HIV surveillance. We examined the prevalence of HIV strains with mutations conferring intermediate to high level resistance to TDF/FTC, defining primary resistance (predominantly K65R and M184I/V mutations) among sequences reported within 3 months of HIV diagnosis and total resistance for sequences reported at any time. We examined trends in primary resistance during 2010-2019 and total resistance among all PLWH in 2019. We also monitored resistance with viremia (≥1,000 copies/mL) at the end of 2019 among PLWH. RESULTS: Between 2010 and 2019, 2,172 King County residents were diagnosed with HIV; 1,557 (72%) had a genotypic resistance test within three months; three (0.2%) had primary TDF/FTC resistance with both K65R and M184I/V mutations. Adding isolated resistance for each drug resulted in 0.3% with primary TDF resistance and 0.8% with primary FTC resistance. Of 7,056 PLWH in 2019, 4,032 (57%) had genotype results, 241 (6%) had TDF/FTC resistance and 15 (0.4% of those with a genotype result) had viremia and TDF/FTC resistance. CONCLUSIONS: Primary resistance and viremia combined with TDF/FTC resistance are uncommon in King County. Monitoring trends in TDF/FTC resistance coupled with interventions to help ensure PLWH achieve and maintain viral suppression may help ensure that PrEP failure remains rare.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Profilaxis Pre-Exposición , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral/genética , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Humanos , Salud Pública , Viremia/tratamiento farmacológicoRESUMEN
The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using cell-based, biochemical, and modeling approaches, we studied the approved HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) and emtricitabine (FTC), as well as prodrugs tenofovir alafenamide (TAF) and tenofovir disoproxilfumarate (TDF) for their antiviral effect against SARS-CoV-2. A comprehensive set of in vitro data indicates that TFV, TAF, TDF, and FTC are inactive against SARS-CoV-2. None of the NRTIs showed antiviral activity in SARS-CoV-2 infected A549-hACE2 cells or in primary normal human lung bronchial epithelial (NHBE) cells at concentrations up to 50 µM TAF, TDF, FTC, or 500 µM TFV. These results are corroborated by the low incorporation efficiency of respective NTP analogs by the SARS-CoV-2 RNA-dependent-RNA polymerase (RdRp), and lack of the RdRp inhibition. Structural modeling further demonstrated poor fitting of these NRTI active metabolites at the SARS-CoV-2 RdRp active site. Our data indicate that the HIV-1 NRTIs are unlikely direct-antivirals against SARS-CoV-2, and clinicians and researchers should exercise caution when exploring ideas of using these and other NRTIs to treat or prevent COVID-19.
Asunto(s)
Fármacos Anti-VIH , Tratamiento Farmacológico de COVID-19 , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Nucleósidos/farmacología , Nucleósidos/uso terapéutico , Nucleótidos/farmacología , Pandemias , ARN Viral , ARN Polimerasa Dependiente del ARN , SARS-CoV-2 , Tenofovir/farmacología , Tenofovir/uso terapéuticoRESUMEN
Long-acting drug delivery is a growing area of interest as it overcomes many challenges related to patient adherence to therapy and the pill burden associated with chronic illness. Injectable formulations are becoming more common and drug-releasing implants also provide several opportunities. Highly water soluble drug compounds are poor candidates for long-acting delivery. Here, the water-soluble nucleoside reverse transcriptase inhibitor emtricitabine (FTC) has been used as a novel A-B monomer in step-growth polymerisation with chloroformate functional Cn monomers, to produce new poly(carbamate/carbonate) structures with varying architecture. The polymer prodrugs were all solid at ambient temperature and have been shown to release FTC when subjected to mixed gender human plasma. Vacuum compression moulding has been used to form solid rod implants without polymer degradation; the rods show FTC release over long periods in the presence of microsomes, establishing the basis of a polymer prodrug strategy for FTC delivery.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Profármacos , ARN Polimerasas Dirigidas por ADN/uso terapéutico , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Nucleósidos , Polímeros/uso terapéutico , Profármacos/química , Inhibidores de la Transcriptasa Inversa/uso terapéutico , AguaRESUMEN
OBJECTIVE: To estimate the prevalence of NRTI and NNRTI drug resistance mutations in patients failing NNRTI-based ART in Southern Africa. STUDY DESIGN: We conducted a systematic review to identify studies reporting drug resistance mutations among adult people living with HIV (PLWH) who experienced virological failure on first-line NNRTI-based ART in Southern Africa. We used a Bayesian hierarchical meta-regression model to synthesize the evidence on the frequency of eight NRTI- and seven NNRTI-DRMs across different ART regimens, accounting for ART duration and study characteristics. RESULTS: We included 19 study populations, including 2,690 PLWH. Patients failing first-line ART including emtricitabine or lamivudine showed high levels of the M184V/I mutation after 2 years: 75.7% (95% Credibility Interval [CrI] 61.9%-88.9%) if combined with tenofovir, and 72.1% (95% CrI 56.8%-85.9%) with zidovudine. With tenofovir disoproxil fumarate, the prevalence of the K65R mutation was 52.0% (95% CrI 32.5%-76.8%) at 2 years. On efavirenz, K103 was the most prevalent NNRTI resistance mutation (57.2%, 95% CrI 40.9%-80.1%), followed by V106 (46.8%, 95% CrI 31.3%-70.4%). CONCLUSIONS: NRTI/NNRTI drug resistance mutations are common in patients failing first-line ART in Southern Africa. These patients might switch to dolutegravir-based regimen with compromised NRTIs, which could impair the long-term efficacy of ART.
Asunto(s)
Infecciones por VIH , VIH-1 , Adulto , Humanos , Lamivudine/farmacología , Lamivudine/uso terapéutico , Zidovudina/farmacología , Zidovudina/uso terapéutico , Farmacorresistencia Viral/genética , VIH-1/genética , Carga Viral , Teorema de Bayes , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Antirretrovirales/uso terapéutico , Tenofovir/farmacología , Tenofovir/uso terapéutico , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , MutaciónRESUMEN
OBJECTIVE: To describe and compare systemic and local pharmacokinetics (PK) and cervicovaginal (CV) pharmacodynamics (PD) of oral tenofovir disoproxil fumarate (TDF) in combination with emtricitabine (FTC) with tenofovir (TFV) intravaginal ring (IVR). DESIGN: Phase I, randomized, parallel-group study. Women (n = 22) used TDF/FTC oral tablets daily or TFV IVR continuously and were assessed at baseline and 14 days. METHODS: TFV and FTC concentrations were measured in plasma, CV fluid (CVF), and CV tissue. TFV-diphosphate and FTC-triphosphate were assessed in CV tissue. In vitro PD antiviral activities of TFV and FTC (using in vivo concentration ranges) were modeled in the CVF and by infecting CV tissue explants ex vivo with HIV-1BaL. RESULTS: Adverse events (AEs) were more common with oral TDF/FTC use (P < 0.01). The median CVF TFV concentrations were 106 ng/mL after use of TFV IVR vs. 102 ng/mL for TDF/FTC. The median TFV and TFV-diphosphate concentrations in CV tissue were >100-fold higher among IVR users. The median CVF FTC concentrations were 103 ng/mL. FTC and FTC-triphosphate were detected in all CV tissues from TDF/FTC users. HIV inhibitory activity of CVF increased significantly with treatment in both cohorts (P < 0.01) but was higher in TFV IVR users (P < 0.01). In vitro inhibition of tissue infection with ex vivo administration of TFV and FTC was dose dependent, with maximal efficacy achieved with 10 µg/mL TFV, 1 µg/mL FTC, and 0.1 µg/mL of TFV and FTC combined. CONCLUSIONS: Both products were safe and increased mucosal HIV inhibitory activity. In addition to systemic protection, oral TDF/FTC displays a PK/PD profile compatible with CV mucosal antiviral activity. TFV IVR resulted in fewer AEs, lower TFV plasma concentrations, higher CVF and tissue TFV and TFV-DP concentrations, and greater anti-HIV activity in CVF.
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Fármacos Anti-VIH , Infecciones por VIH , Administración Intravaginal , Administración Oral , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , Femenino , Genitales , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , TenofovirRESUMEN
OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). The aim of the study was to evaluate changes in BMD in women who switched from TDF, emtricitabine and a nonnucleoside reverse transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir, lamivudine and dolutegravir (ABC/3TC/DTG). METHODS: We conducted a randomized controlled trial in which women aged ≥ 40 years were randomized 1:2 to continue TDF/FTC/NNRTI or switch to ABC/3TC/DTG. We analysed changes in BMD at the hip and lumbar spine from baseline to week 96 using linear regression, and markers of bone turnover and kidney function using repeated measures mixed effects models with multiple imputation for missing data. We conducted exploratory analyses of weight, mental health, sleep and symptoms attributed to HIV infection and antiretroviral therapy. RESULTS: Ninety-one women [mean (standard deviation) age 50.4 (6.6) years] were randomized. Women who switched to ABC/3TC/DTG maintained viral suppression and experienced improvements in BMD at the lumbar spine (but not the neck of the femur or the total hip), bone resorption markers and proteinuria (total protein, albumin and retinol-binding protein) and modest weight gain without changes in body mass index. Although mean anxiety, depression and sleep scores did not differ between the two study arms, anxiety, depression and sleep disturbance at baseline predicted ABC/3TC/DTG discontinuation for neuropsychiatric side effects [odds ratios (95% confidence intervals) 11.9 (2.0-71.6), 16.0 (2.6-97.9) and 10.0 (1.8-56.0), respectively]. CONCLUSIONS: Switching from TDF/FTC/NNRTI to ABC/3TC/DTG improved the BMD of the lumbar spine and kidney function. These benefits need to be balanced against modest weight gain and the need for antiretroviral therapy substitutions in a proportion of participants.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Adulto , Fármacos Anti-VIH/efectos adversos , Densidad Ósea , Didesoxinucleósidos/uso terapéutico , Combinación de Medicamentos , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , Femenino , Infecciones por VIH/complicaciones , Compuestos Heterocíclicos con 3 Anillos , Humanos , Riñón , Lamivudine/farmacología , Persona de Mediana Edad , Oxazinas , Medición de Resultados Informados por el Paciente , Piperazinas , Piridonas , Inhibidores de la Transcriptasa Inversa/farmacología , Tenofovir/efectos adversosRESUMEN
BACKGROUND: Bone mineral density (BMD) loss and fat gain is common in people living with HIV (PLWH), particularly after initiating combination antiretroviral therapy (cART). Given the close metabolic interaction between bone and fat, we tested the hypotheses that changes in bone-derived hormones are associated with fat accumulation and changes in fat-derived hormones are associated with BMD loss following cART initiation. METHODS: HIV-seropositive subjects (n = 15) initiating fixed dose cART of tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/FTC/EFV) underwent dual X-ray absorptiometry (DXA) assessment pre-cART and again 12-months post-cART initiation. DXA-derived measurements included BMD at the lumbar spine, femoral neck, total hip, and trochanter and the trunk and total fat. Serum undercarboxylated osteocalcin (ucOCN), sclerostin, lipocalin-2, leptin, and adiponectin were measured pre and post-cART. Spearman's rank-order correlations assessed the cross-sectional associations between hormones and bone and fat mass pre- and post-cART. Linear regression models adjusting for baseline bone or fat mass assessed the association between hormone change and BMD/fat changes following cART initiation. RESULTS: ucOCN (p = 0.04) and lipocalin-2 (p = 0.03) increased post-cART while sclerostin, leptin, and adiponectin remained unchanged. BMD significantly decreased post-cART at all skeletal sites. Trunk and total fat increased post-cART but not significantly, while weight and BMI remained unchanged. In models adjusting for baseline BMD and fat mass, change in ucOCN was negatively associated with change in trunk (p = 0.008) and total fat (p = 0.01) and the change in leptin was positively associated with change in total hip (p = 0.03) and trochanteric BMD (p = 0.02). CONCLUSION: The current study demonstrates bone-fat crosstalk in cART initiating PLWH.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Absorciometría de Fotón , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Densidad Ósea , Estudios Transversales , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , Cuello Femoral , Infecciones por VIH/tratamiento farmacológico , HumanosRESUMEN
HIV-1 reservoirs persist in the presence of combined antiretroviral therapy (cART). However, cART has transformed HIV-1 infection into a chronic disease marked by control of HIV-1 viral load and mortality reduction. Major challenges remain, including viral resistance upon termination of cART and persistence and identification of tissue distribution of HIV-1 reservoirs. Thus, appropriate animal models that best mimic HIV-1 pathogenesis are important, and the current study complements our previously published validation of the CD34+ hematopoietic humanized mouse model for this purpose. Here we analyze viral suppression using the recently developed combination of antiretrovirals that include Tenofovir Disoproxil (TDF), Emtricitabine (FTC), and Dolutegravir (DTG), a choice based on recent clinical outcomes showing its improved antiretroviral potency, CD4+ T cell preservation, tolerability, and prevention of viral drug resistance compared to that of previous regimens. We used quantitative Airyscan-based super resolution confocal microscopy of selected mouse tissues. Our data allowed us to identify specific solid tissue reservoirs of human T cells expressing the HIV-1 core protein p24. In particular, lymph node, brain, spleen, and liver were visualized as reservoirs for residual infected cells. Marked reduction of viral replication was evident. Considering that detection and visualization of cryptic sites of HIV-1 infection in tissues are clearly crucial steps towards HIV-1 eradication, appropriate animal models with pseudo-human immune systems are needed. In fact, current studies with humans and non-human primates have limited sample availability at multiple stages of infection and cannot easily analyze the effects of differently administered combined antiretroviral treatments on multiple tissues. That is easier to manage when working with humanized mouse models, although we realize the limitations due to low human cell recovery and thus the number of cells available for thorough and comprehensive analyses. Nonetheless, our data further confirm that the CD34+ humanized mouse model is a potentially useful pre-clinical model to study and improve current anti-HIV-1 therapies.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Animales , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Ratones , Oxazinas , Piperazinas , Piridonas , Tenofovir/farmacología , Tenofovir/uso terapéutico , Carga ViralRESUMEN
Microglia, the resident brain phagocytes, likely play a key role in human immunodeficiency virus (HIV) infection of the central nervous system (CNS) and subsequent neuropathogenesis; however, the nature of the infection-induced changes that yield damaging CNS effects and the stimuli that provoke microglial activation remains elusive, especially in the current era of using antiretroviral (ARV) drugs for ARV therapy (ART). Altered microglial metabolism can modulate cellular functionality and pathogenicity in neurological disease. While HIV infection itself alters brain energy metabolism, the effect of ARV drugs, particularly those currently used in treatment, on metabolism is understudied. Dolutegravir (DTG) and emtricitabine (FTC) combination, together with tenofovir (TAF or TDF), is one of the recommended first line treatments for HIV. Despite the relatively good tolerability and safety profile of FTC, a nucleoside reverse transcriptase inhibitor, and DTG, an integrase inhibitor, adverse side effects have been reported and highlight a need to understand off-target effects of these medications. We hypothesized that similar to previous ART regimen drugs, DTG and FTC side effects involve mitochondrial dysfunction. To increase detection of ARV-induced mitochondrial effects, highly glycolytic HeLa epithelial cells were forced to rely on oxidative phosphorylation by substituting galactose for glucose in the growth media. We assessed ATP levels, resazurin oxidation-reduction (REDOX), and mitochondrial membrane potential following 24-hour exposure (to approximate effects of one dose equivalent) to DTG, FTC, and efavirenz (EFV, a known mitotoxic ARV drug). Further, since microglia support productive HIV infection, act as latent HIV cellular reservoirs, and when dysfunctional likely contribute to HIV-associated neurocognitive disorders, the experiments were repeated using BV2 microglial cells. In HeLa cells, FTC decreased mitochondrial REDOX activity, while DTG, similar to EFV, impaired both mitochondrial ATP generation and REDOX activity. In contrast to HeLa cells, DTG increased cellular ATP generation and mitochondrial REDOX activity in BV2 cells. Bioenergetic analysis revealed that DTG, FTC, and EFV elevated BV2 cell mitochondrial respiration. DTG and FTC exposure induced distinct mitochondrial functional changes in HeLa and BV2 cells. These findings suggest cell type-specific metabolic changes may contribute to the toxic side effects of these ARV drugs.
Asunto(s)
Alquinos/farmacología , Fármacos Anti-VIH/farmacología , Benzoxazinas/farmacología , Ciclopropanos/farmacología , Emtricitabina/farmacología , Células Epiteliales/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/farmacología , Microglía/efectos de los fármacos , Oxazinas/farmacología , Piperazinas/farmacología , Piridonas/farmacología , Adenosina Trifosfato/metabolismo , Línea Celular Tumoral , Células Epiteliales/metabolismo , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Células HeLa , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Microglía/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Oxazinas/metabolismo , Inhibidores de la Transcriptasa Inversa/farmacología , Latencia del Virus/efectos de los fármacos , Xantenos/metabolismoRESUMEN
Human immunodeficiency virus 1 (HIV-1) infection is a global health issue since neither a cure nor a vaccine is available. However, the highly active antiretroviral therapy (HAART) has improved the life expectancy for patients with acquired immunodeficiency syndrome (AIDS). Nucleoside reverse transcriptase inhibitors (NRTIs) are in almost all HAART and target reverse transcriptase (RT), an essential enzyme for the virus. Even though NRTIs are highly effective, they have limitations caused by RT resistance. The main mechanisms of RT resistance to NRTIs are discrimination and excision. Understanding the molecular mechanisms for discrimination and excision are essential to develop more potent and selective NRTIs. Using protein X-ray crystallography, we determined the first crystal structure of RT in its post-catalytic state in complex with emtricitabine, (-)FTC or stavudine (d4T). Our structural studies provide the framework for understanding how RT discriminates between NRTIs and natural nucleotides, and for understanding the requirement of (-)FTC to undergo a conformation change for successful incorporation by RT. The crystal structure of RT in post-catalytic complex with d4T provides a "snapshot" for considering the possible mechanism of how RT develops resistance for d4T via excision. The findings reported herein will contribute to the development of next generation NRTIs.
Asunto(s)
Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Transcriptasa Inversa del VIH/efectos de los fármacos , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/química , Catálisis , Cristalografía por Rayos X , Emtricitabina/química , Emtricitabina/farmacología , Humanos , Modelos Moleculares , Nucleótidos/química , Nucleótidos/farmacología , Inhibidores de la Transcriptasa Inversa/química , Estavudina/química , Estavudina/farmacologíaRESUMEN
BACKGROUND: Scale-up of oral pre-exposure prophylaxis (PrEP) for HIV prevention in Uganda began with serodiscordant couples (SDC) and has expanded to other most at-risk populations (MARPs). We explored knowledge, acceptability, barriers and facilitators of PrEP use among potential PrEP users in four MARPs (SDC; men who have sex with men [MSM]; female sex workers [FSW], and fisher folk). METHODS: We administered quantitative surveys to potential PrEP users in multiple settings in Central Uganda at baseline and approximately 9 months after healthcare worker (HCW) training on PrEP. RESULTS: The survey was completed by 250 potential PrEP users at baseline and 125 after HCW training; 55 completed both surveys. For these 250 participants, mean age was 28.5 years (SD 6.9), 47% were male and 6% were transgender women, with approximately even distribution across MARPs and recruitment locations (urban, peri-urban, and rural). Most (65%) had not heard about PrEP. After HCW training, 24% of those sampled were aware of PrEP, and the proportion of those who accurately described PrEP as "antiretrovirals to be used before HIV exposure" increased from 54% in the baseline survey to 74% in the second survey (p<0.001). The proportion of participants who reported HCW as a source of PrEP information increased after training (59% vs 91%, p<0.001). In both surveys, nearly all participants indicated they were willing to take PrEP if offered. The most common anticipated barriers to PrEP were stigma, transportation, accessibility, busy schedules, and forgetfulness. Closeness to home was a common facilitator for all participant categories. CONCLUSIONS: Initial awareness of PrEP was low, but PrEP knowledge and interest increased among diverse MARPs after HCW training. Demand creation and HCW training will be critical for increasing PrEP awareness among key populations, with support to overcome barriers to PrEP use. These findings should encourage the acceleration of PrEP rollout in Uganda.
Asunto(s)
Infecciones por VIH/prevención & control , Conocimientos, Actitudes y Práctica en Salud , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Profilaxis Pre-Exposición/estadística & datos numéricos , Administración Oral , Adulto , Emtricitabina/administración & dosificación , Emtricitabina/farmacología , Femenino , Humanos , Masculino , Cooperación del Paciente/estadística & datos numéricos , Encuestas y Cuestionarios , Tenofovir/administración & dosificación , Tenofovir/farmacología , UgandaRESUMEN
Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention. Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. Here, we assess the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with gastrointestinal and one with cervicovaginal biopsies. TDF/FTC induces type I/III interferon-related (IFN I/III) genes in the gastrointestinal tract, but not blood, with strong correlations between the two independent rectal biopsy groups (Spearman r = 0.91) and between the rectum and duodenum (r = 0.81). Gene set testing also indicates stimulation of the type I/III pathways in the ectocervix and of cellular proliferation in the duodenum. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence confirm IFN I/III pathway stimulation in the gastrointestinal tract. Thus, oral TDF/FTC stimulates an IFN I/III signature throughout the gut, which could increase antiviral efficacy but also cause chronic immune activation in HIV prevention and treatment settings.
Asunto(s)
Microbioma Gastrointestinal/efectos de los fármacos , VIH/efectos de los fármacos , Profilaxis Pre-Exposición/métodos , Adulto , Fármacos Anti-VIH/administración & dosificación , Antirretrovirales/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Emtricitabina/administración & dosificación , Emtricitabina/farmacología , Femenino , Microbioma Gastrointestinal/genética , Expresión Génica/genética , VIH/metabolismo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Humanos , Interferón Tipo I/uso terapéutico , Masculino , Persona de Mediana Edad , Preparaciones Farmacéuticas , Tenofovir/administración & dosificación , Tenofovir/farmacología , Transcriptoma/efectos de los fármacos , Transcriptoma/genéticaRESUMEN
The use of antiretroviral therapy (ART) as preexposure prophylaxis (PrEP) is an effective strategy for preventing HIV acquisition. The cellular consequences of PrEP exposure, however, have not been sufficiently explored to determine potential effects on health in individuals without HIV. In this study, peripheral blood mononuclear cells (PBMCs) from people without HIV were exposed to tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC) overnight. Mitochondrial mass and function were measured by flow cytometry and an Agilent XFp analyzer. Monocyte-derived macrophages (MDMs) were differentiated in 20% autologous serum for 5 days in the presence or absence of TDF or FTC, and surface markers, lipid uptake, and efferocytosis were measured by flow cytometry. MDM gene expression was measured using transcriptome sequencing (RNA-seq). Plasma lipids were measured using mass spectrometry. PBMCs exposed to TDF or FTC had decreased maximal oxygen consumption rate (OCR) and reduced mitochondrial mass. Exposure to PrEP also increased reactive oxygen species (ROS) production from monocyte subsets. Compared to MDMs cultured in medium alone, cells differentiated in the presence of TDF (829 genes) or FTC (888 genes) had significant changes in gene expression. Further, PrEP-exposed MDMs had decreased mitochondrial mass and displayed increased lipid uptake and reduced efferocytosis. Plasma biomarkers and lipid levels were also altered in vivo in individuals receiving a PrEP regimen. In conclusion, exposure of leukocytes to TDF or FTC resulted in decreased mitochondrial function and altered functional and transcriptional profiles. These findings may have important implications for the metabolic and immunologic consequences of PrEP in populations at risk for HIV acquisition.