RESUMEN
This case-control study explored cumulative tenofovir exposure among patients with HIV/HBV co-infection with HIV viral suppression. Among patients taking tenofovir disoproxil fumarate, median TFV-DP levels in dried blood spots were â¼3-fold lower among patients with incomplete HBV viral suppression (n=4) compared to those with complete suppression (n=5) (516 vs.1456 fmol/punch).
RESUMEN
BACKGROUND: QUANTI-TAF aimed to establish tenofovir-diphosphate/emtricitabine-triphosphate (TFV-DP/FTC-TP) adherence benchmarks in dried blood spots (DBS) for persons with HIV (PWH) receiving tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART). METHODS: During a 16-week pharmacokinetic study, PWH received TAF/FTC-based ART co-encapsulated with an ingestible sensor to directly measure cumulative (enrollment to final visit) and 10-day adherence. At monthly visits, intraerythrocytic concentrations of TAF/FTC anabolites (TFV-DP/FTC-TP) in DBS were quantified by LC-MS/MS and summarized at steady-state (week 12 or 16) as median (IQR). Linear mixed-effects models evaluated factors associated with TFV-DP/FTC-TP. RESULTS: 84 participants (86% male, 11% female, and 4% transgender), predominantly receiving bictegravir/TAF/FTC (73%) enrolled. 92% completed week 12 or 16 (94% receiving unboosted ART). TFV-DP for <85% (7/72), ≥85%-<95% (9/72), and ≥95% (56/72) cumulative adherence was 2696 (2039-4108), 3117 (2332-3339), and 3344 (2605-4293) fmol/punches. All participants with ≥85% cumulative adherence had TFV-DP ≥1800 fmol/punches. Adjusting for cumulative adherence, TFV-DP was higher with boosted ART, lower BMI, and in non-Blacks. FTC-TP for <85% (14/77), ≥85%-<95% (6/77), and ≥95% (57/77) 10-day adherence was 3.52 (2.64-4.48), 4.58 (4.39-5.06), and 4.96 (4.21-6.26) pmol/punches. All participants with ≥85% 10-day adherence had FTC-TP ≥2.5 pmol/punches. Low-level viremia (HIV-1 RNA ≥20-<200 copies/mL) occurred at 60/335 (18%) visits in 33/84 (39%) participants (range: 20-149 copies/mL), with similar TFV-DP (3177 [2494-4149] fmol/punches) compared with HIV-1 RNA <20 copies/mL visits (3279 [2580-4407] fmol/punches). CONCLUSIONS: We propose PK-based TFV-DP (≥1800 fmol/punches)/FTC-TP (≥2.5 pmol/punches) benchmarks in DBS for PWH receiving unboosted TAF/FTC-based ART with ≥85% adherence. In the setting of high adherence, low-level viremia was common.
RESUMEN
The nucleos(t)ide analogs require phosphorylation to the pharmacologically active anabolites in cells. We investigated the hypothesis that single-nucleotide polymorphisms (SNPs) in genes that encode transporters and phosphodiesterase (PDE) enzymes involved in tenofovir (TFV), disoproxil fumarate (TDF), and lamivudine (3TC) disposition will be associated with concentrations of their phosphate anabolites and virologic response. Individuals with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection receiving TDF/3TC-containing antiretroviral therapy were enrolled. Steady-state TFV diphosphate (TFV-DP) and 3TC triphosphate (3TC-TP) concentrations in peripheral blood mononuclear cells (PBMCs) and dried blood spot samples were quantified. The relationship between genetic variants and TFV-DP and 3TC-TP concentrations as well as with virologic response were examined using multivariable linear regression. Of the 136 participants (median age 43 years; 63% females), 6.6% had HBV non-suppression, and 7.4% had HIV non-suppression. The multidrug resistance protein 2 (encoded by ABCC2 rs2273697) SNP was associated with 3TC-TP concentrations in PBMCs. The human organic anion transporter-1 (encoded by SLC28A2) rs11854484 SNP was associated with HIV non-suppression, and when evaluated together with SNPs with marginal associations (ABCC2 rs717620 and PDE1C rs30561), participants with two or three variants compared to those with none of these variants had an adjusted odds ratio of 48.3 (confidence interval, 4.3-547.8) for HIV non-suppression. None of the SNPs were associated with HBV non-suppression. Our study identified ABCC2 SNP to be associated with 3TC-TP concentrations in PBMCs. Also, a combination of genetic variants of drug transporters and PDE was associated with HIV non-suppression.
Asunto(s)
Fármacos Anti-VIH , Coinfección , Infecciones por VIH , Lamivudine , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Polimorfismo de Nucleótido Simple , Tenofovir , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Femenino , Masculino , Adulto , Lamivudine/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Tenofovir/uso terapéutico , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacocinética , Persona de Mediana Edad , Coinfección/tratamiento farmacológico , Coinfección/genética , Leucocitos Mononucleares/metabolismo , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/efectos de los fármacos , Organofosfatos/uso terapéutico , Organofosfatos/farmacocinética , Hepatitis B/tratamiento farmacológico , Hepatitis B/genética , Adenina/análogos & derivados , Adenina/uso terapéutico , Adenina/farmacocinética , Polifosfatos/metabolismo , Farmacogenética/métodosRESUMEN
HPTN 083 demonstrated that injectable cabotegravir (CAB) was superior to oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for HIV prevention in cisgender men and transgender women who have sex with men. We previously analyzed 58 infections in the blinded phase of HPTN 083 (16 in the CAB arm and 42 in the TDF-FTC arm). This report describes 52 additional infections that occurred up to 1 year after study unblinding (18 in the CAB arm and 34 in the TDF-FTC arm). Retrospective testing included HIV testing, viral load testing, quantification of study drug concentrations, and drug resistance testing. The new CAB arm infections included 7 with CAB administration within 6 months of the first HIV-positive visit (2 with on-time injections, 3 with ≥1 delayed injection, and 2 who restarted CAB) and 11 with no recent CAB administration. Three cases had integrase strand transfer inhibitor (INSTI) resistance (2 with on-time injections and 1 who restarted CAB). Among 34 CAB infections analyzed to date, diagnosis delays and INSTI resistance were significantly more common in infections with CAB administration within 6 months of the first HIV-positive visit. This report further characterizes HIV infections in persons receiving CAB preexposure prophylaxis and helps define the impact of CAB on the detection of infection and the emergence of INSTI resistance.
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Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Personas Transgénero , Masculino , Humanos , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Fármacos Anti-VIH/farmacología , Estudios Retrospectivos , Tenofovir/uso terapéutico , Emtricitabina/uso terapéuticoRESUMEN
BACKGROUND: HIV Prevention Trials Network 084 demonstrated that long-acting injectable cabotegravir (CAB) was superior to daily oral tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) for preventing human immunodeficiency virus (HIV) infection in sub-Saharan African women. This report describes HIV infections that occurred in the trial before unblinding. METHODS: Testing was performed using HIV diagnostic assays, viral load testing, a single-copy RNA assay, and HIV genotyping. Plasma CAB, plasma TFV, and intraerythrocytic TFV-diphosphate concentrations were determined by liquid chromatography-tandem mass spectrometry. RESULTS: Forty HIV infections were identified (CAB arm, 1 baseline infection, 3 incident infections; TDF/FTC arm, 36 incident infections). The incident infections in the CAB arm included 2 with no recent drug exposure and no CAB injections and 1 with delayed injections; in 35 of 36 cases in the TDF/FTC arm, drug concentrations indicated low or no adherence. None of the cases had CAB resistance. Nine women in the TDF/FTC arm had nonnucleoside reverse-transcriptase inhibitor resistance; 1 had the nucleoside reverse-transcriptase inhibitor resistance mutation, M184V. CONCLUSIONS: Almost all incident HIV infections occurred in the setting of unquantifiable or low drug concentrations. CAB resistance was not detected. Transmitted nonnucleoside reverse-transcriptase inhibitor resistance was common; 1 woman may have acquired nucleoside reverse-transcriptase inhibitor resistance from study drug exposure.
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Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Fármacos Anti-VIH/uso terapéutico , ARN Polimerasas Dirigidas por ADN , Dicetopiperazinas , Emtricitabina/uso terapéutico , Femenino , VIH , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Nucleósidos/uso terapéutico , Piridonas , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Tenofovir/uso terapéuticoRESUMEN
OBJECTIVES: Potential interactions between feminizing hormone therapy (FHT) and pre-exposure prophylaxis (PrEP) may be a barrier to PrEP use among transgender women (TGW). We aimed to assess the impact of FHT on PrEP plasma pharmacokinetics (PK) among TGW. METHODS: This was a PK substudy of the effects of FHT on tenofovir disoproxil fumarate/emtricitabine nested to a trans-specific PrEP demonstration study (NCT03220152). Participants were assigned to receive PrEP only (noFHT) or standardized FHT (sFHT; oestradiol valerate 2-6â mg plus spironolactone 100-300â mg) plus PrEP for 12â weeks, after which they could start any FHT (aFHT). Short- and long-term PK assessment occurred at Weeks 12 and 30-48, respectively (plasma samples prior and 0.5, 1, 2, 4, 6, 8 and 24â h after dose). Non-compartmental PK parameters of tenofovir and emtricitabine were compared as geometric mean ratios (GMRs) between noFHT and PrEP and FHT (sFHT at short-term PK; aFHT at long-term PK) participants. RESULTS: No differences in tenofovir and emtricitabine plasma PK parameters were observed between the short-term PK of noFHT (nâ=â12) and sFHT participants (nâ=â18), except for emtricitabine Cmax [GMR: 1.15 (95% CI: 1.01-1.32)], or between noFHT short-term PK and aFHT long-term PK (nâ=â13). Most participants were on oestradiol valerate 2â mg at the short-term PK (56%) and 4â mg at the long-term PK (54%). Median (IQR) oestradiol levels were 56.8 (43.2-65.4)â pg/mL at short-term PK (sFHT) and 44.8 (24.70-57.30)â pg/mL at long-term PK (aFHT). No participants in this analysis seroconverted during the study. CONCLUSIONS: Our results indicate no interaction of FHT on tenofovir levels, further supporting PrEP use among TGW using FHT.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Personas Transgénero , Fármacos Anti-VIH/uso terapéutico , Brasil , Estudios de Cohortes , Interacciones Farmacológicas , Emtricitabina/uso terapéutico , Estradiol/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Profilaxis Pre-Exposición/métodos , Espironolactona/uso terapéutico , Tenofovir/farmacocinéticaRESUMEN
BACKGROUND: Sofosbuvir is converted to its active form, 007 triphosphate (007-TP), within cells. To date, the association between treatment adherence and 007-TP in dried blood spots (DBS) and factors that influence this relationship remain unknown. OBJECTIVES: To examine relationships between adherence and 007-TP concentrations in DBS and identify factors that influence 007-TP in DBS. METHODS: Persons with HCV or HIV/HCV coinfection and self-reported drug and/or alcohol use were randomized to one of two technology-based approaches for monitoring 12â week adherence to once-daily ledipasvir/sofosbuvir. Convenience blood samples were collected every 2â weeks during treatment. 007-TP in DBS was quantified using LC/MS and analysed using mixed-effects models. RESULTS: A total of 337 observations were available from 58 participants (78% male; 21% black; 22% Hispanic/Latino; 26% cirrhotic; 78% HIV-coinfected). The mean half-life of 007-TP in DBS was 142â h (95% CI 127-156) and concentrations increased by 7.3% (95% CI 2.2-12.6) for every 10% increase in between-visit adherence. Geometric mean (95% CI) 007-TP concentrations in DBS were 301 (247-368), 544 (462-639) and 647 (571-723)â fmol/punch by adherence categories of ≤50%, >50 to ≤80%, and >80%. Adherence, time on therapy, increasing age and decreased estimated glomerular filtration rate were associated with higher 007-TP, whereas increased time since last dose, male sex, black race and higher BMI were associated with lower 007-TP. CONCLUSIONS: 007-TP has an extended half-life in DBS and concentrations increased with adherence. Further research is needed to examine additional factors that affect 007-TP and the clinical utility of this measure.
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Infecciones por VIH , Hepatitis C , Pruebas con Sangre Seca , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Hepacivirus , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Humanos , Masculino , Polifosfatos/uso terapéutico , Sofosbuvir/uso terapéuticoRESUMEN
HIV prevention and treatment with injectable cabotegravir and/or rilpivirine administered once every 4 to 8 weeks is an attractive alternative to daily therapy. Prescribed dosage and drug concentrations in plasma are based on patient data collected in clinical trials, but actual patients are expected to exhibit more variability in drug concentrations, which is important to quantify. Here, we demonstrate the first quantitative point-of-care assay with a miniature mass spectrometer to assess these drug concentrations in whole blood. Quantitative performance is obtained using paper spray ionization in combination with tandem mass spectrometry (MS/MS) in the clinically relevant concentration range of both drugs. Limits of quantitation (LoQs) of cabotegravir and rilpivirine are measured to be 750 ng/mL and 20 ng/mL, respectively. The assay turnaround time is < 4 min, and strong linear relationships are established between MS/MS responses and concentration, with percentage of relative standard deviations (RSDs) that are <15% at concentrations above the LoQs. The speed, portability, low power consumption, and specificity offered by the miniature instrument should make it an appropriate platform for measuring drug concentrations in a walk-in clinic using small volumes of patient blood.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Dicetopiperazinas , Infecciones por VIH/tratamiento farmacológico , Humanos , Sistemas de Atención de Punto , Piridonas , Rilpivirina/efectos adversos , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: The HIV Prevention Trials Network (HPTN) 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was more effective than tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) in preventing human immunodeficiency virus (HIV) in cisgender men and transgender women who have sex with men. We characterized HIV infections that occurred in the blinded phase of HPTN 083. METHODS: Retrospective testing included HIV testing, viral load testing, quantification of study drugs, and HIV drug resistance testing. RESULTS: Fifty-eight infections were evaluated, including 51 incident infections (12 in CAB arm and 39 in TDF/FTC arm). In many cases (5 in CAB arm and 37 in TDF/FTC arm), infection was associated with low or unquantifiable study drug concentrations. In 4 cases, infection occurred with on-time CAB-LA injections and expected plasma CAB concentrations. CAB exposure was associated with prolonged viral suppression and delayed antibody expression. In some cases, delayed HIV diagnosis resulted in CAB provision to participants with undetected infection, delayed antiretroviral therapy, and emergence of drug resistance; most of these infections would have been detected earlier with viral load testing. CONCLUSIONS: Early detection of HIV infection and prompt antiretroviral therapy initiation could improve clinical outcomes in persons who become infected despite CAB-LA prophylaxis. Further studies are needed to elucidate the correlates of HIV protection in persons receiving CAB-LA.
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Fármacos Anti-VIH/administración & dosificación , Dicetopiperazinas/administración & dosificación , Infecciones por VIH/prevención & control , Inhibidores de Integrasa VIH/administración & dosificación , Homosexualidad Masculina , Profilaxis Pre-Exposición , Piridonas/administración & dosificación , Personas Transgénero , Adolescente , Adulto , Femenino , Infecciones por VIH/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: Benin has a long-standing history of HIV prevention programs aimed at female sex workers (FSWs). We used data from a national survey among FSWs (2017) to assess the prevention and care cascades in this population. METHODS: Female sex workers were recruited through cluster sampling of sex work sites. A questionnaire was administered, and HIV tested. HIV-positive participants were asked to provide dried blood spots and were tested for antiretroviral and viral load. We assessed 2 prevention cascades (HIV testing and safer sex) and the treatment cascade, using a combination of self-reported and biological variables. RESULTS: Mean age of the 1086 FSWs was 30 years. Half of them were Beninese, and two-thirds had a primary school education level or less. Almost all FSWs had ever heard of HIV/AIDS. More than half (79.1%) had ever been tested, and 84.1% of the latter had been tested in the last year. In the previous 6 months, 90.1% were exposed to prevention messages. Women exposed to any HIV prevention message reported a higher level of consistent condom use in the last month (69.0%) than those who were not (48.5%, P < 0.0001). HIV prevalence was 7.7%. Among HIV-positive women, 60.6% knew their status; among those, 90.5% were on antiretroviral and 81.8% of them had a suppressed viral load. CONCLUSIONS: Despite long-standing HIV prevention programs for FSWs, the prevention indicators were often low. Linkage to care was good, viral suppression was suboptimal, but knowledge of HIV-positive status was low. Exposing women to prevention messages is necessary, as to increase HIV testing.
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Infecciones por VIH , Trabajadores Sexuales , Adulto , Benin/epidemiología , Condones , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Humanos , Prevalencia , Sexo Seguro , Trabajo SexualRESUMEN
OBJECTIVES: To determine factors associated with interindividual variability in tenofovir diphosphate (TFV-DP) concentrations in dried blood spots (DBSs) among persons living with HIV (PLWH). METHODS: PLWH who were at least 18 years old and taking tenofovir disoproxil fumarate-containing ART were prospectively recruited and enrolled from a clinical cohort and followed longitudinally (up to three visits over 48 weeks). With log-transformed TFV-DP concentrations in DBSs as the outcome, mixed-model regression analyses were used to assess associations between self-reported 3 month ART adherence, race and other clinical covariates (gender, age, BMI, CD4+ T cell count, estimated glomerular filtration rate, haematocrit, duration on current ART and anchor drug class) on TFV-DP in DBSs. RESULTS: Five hundred and twenty-seven participants (1150 person-visits) were analysed. Adjusting for race and other clinical covariates, every 10% increase in self-reported 3 month ART adherence was associated with an average TFV-DP concentration increase in DBSs of 28% (95% CI: 24%-32%; P < 0.0001). In the same model, female participants had 20% (95% CI: 3%-40%; P = 0.02) higher TFV-DP concentrations in DBSs, compared with male participants, and every 1 kg/m2 increase in BMI was associated with a decrease in TFV-DP concentration in DBSs by 2% (95% CI: -3% to -1%; P < 0.0001). CONCLUSIONS: Individual patient characteristics were predictive of TFV-DP concentration in DBSs in PLWH receiving tenofovir disoproxil fumarate-based ART. Future research to incorporate these predictors into the interpretation of this ART adherence biomarker, and to establish whether these associations extend to PLWH taking tenofovir alafenamide-containing ART, is needed.
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Fármacos Anti-VIH , Infecciones por VIH , Adenina/análogos & derivados , Adolescente , Fármacos Anti-VIH/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Organofosfatos/uso terapéutico , Tenofovir/uso terapéuticoRESUMEN
BACKGROUND: Ledipasvir/sofosbuvir increases tenofovir plasma exposures by up to 98% with tenofovir disoproxil fumarate (TDF), and exposures are highest with boosted PIs. There are currently no data on the combined use of the newer tenofovir prodrug, tenofovir alafenamide (TAF), boosted PIs and ledipasvir/sofosbuvir. OBJECTIVES: To compare the plasma and intracellular pharmacokinetics and renal safety of TAF with ledipasvir/sofosbuvir when co-administered with boosted PIs. METHODS: Persons with HIV between 18 and 70 years and on a boosted PI with TDF were eligible. The study was comprised of four phases: (1) TDF 300 mg with boosted PI; (2) TAF 25 mg with boosted PI; (3) TAF 25 mg with boosted PI and ledipasvir/sofosbuvir; and (4) TAF 25 mg with boosted PI. Pharmacokinetic sampling, urine biomarker collection [urine protein (UPCR), retinol binding protein (RBP) and ß2 microglobulin (ß2M) normalized to creatinine] and safety assessments occurred at the end of each phase. Plasma, PBMCs and dried blood spots were collected at each visit. RESULTS: Ten participants were enrolled. Plasma tenofovir exposures were 76% lower and tenofovir-diphosphate (TFV-DP) concentrations in PBMCs increased 9.9-fold following the switch to TAF. Neither of these measures significantly increased with ledipasvir/sofosbuvir co-administration, nor did TAF plasma concentrations. No significant changes in estimated glomerular filtration rate or UPCR occurred, but RBP:creatinine and ß2M:creatinine improved following the switch to TAF. CONCLUSIONS: Ledipasvir/sofosbuvir did not significantly increase plasma tenofovir or intracellular TFV-DP in PBMCs with TAF. These findings provide reassurance that the combination of TAF, boosted PIs and ledipasvir/sofosbuvir is safe in HIV/HCV-coinfected populations.
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Fármacos Anti-VIH , Infecciones por VIH , Adenina/análogos & derivados , Alanina , Fármacos Anti-VIH/uso terapéutico , Bencimidazoles , Fluorenos , Infecciones por VIH/tratamiento farmacológico , Humanos , Inhibidores de Proteasas/uso terapéutico , Sofosbuvir/uso terapéutico , Tenofovir/análogos & derivadosRESUMEN
Unfortunately, after online publication, a formatting mistake was found in Table 1 (Chemical structures and MRM transitions used for quantitation). The original article has been corrected.
RESUMEN
Inadequate adherence to chronic medications is a far-reaching problem with financial and human health consequences. By a wide margin, non-adherence is the leading cause of therapeutic failures of HIV pre-exposure chemoprophylaxis (PrEP) and antiretroviral therapy (ART). It has been proven that HIV infection can be prevented by daily dosing of emtricitabine and tenofovir disoproxil fumarate. Measurement of intracellular tenofovir diphosphate in red blood cells has been established as an effective way to assess cumulative adherence, however, the LC-MS-based analytical method developed for the purpose is both complicated and expensive. Here, we report a simple method for adherence monitoring based on direct MS quantification of intracellular tenofovir diphosphate in human whole blood. The method requires only microliters of whole blood, employs special membranes to perform plasma separation and concomitant desalting during blood collection, and uses nanoelectrospray on a triple quadrupole instrument. Quantitative performance in this proof-of-concept study includes RSDs of < 15% and successful analysis of a small number of patient samples with medium to high adherence levels. The results correlate with those of a validated LC-MS/MS method, and an R2 value of 0.9962 is achieved. This methodology has promise for extension to point-of-care testing using miniature mass spectrometers. Graphical abstract.
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Adenina/análogos & derivados , Fármacos Anti-VIH/sangre , Organofosfatos/sangre , Espectrometría de Masas en Tándem/métodos , Adenina/sangre , Adenina/normas , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/normas , Cromatografía Liquida/métodos , Humanos , Organofosfatos/normas , Prueba de Estudio Conceptual , Estándares de ReferenciaRESUMEN
BACKGROUND: Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is associated with viral suppression in persons living with HIV (PLWH) taking tenofovir disoproxil fumarate (TDF). However, its value as a predictor of future viremia remained unknown. METHODS: Blood for plasma viral load (VL) and TFV-DP in DBS were collected (up to 3 visits within 48 weeks) in PLWH on TDF. TFV-DP cut points were selected using logistic prediction models maximizing the area under the receiver operation characteristic curve, and estimated adjusted odds ratio (aOR) of future viremia (≥20 copies/mL) were compared to the highest TFV-DP category. RESULTS: Among all 451 participants in the analysis, aOR of future viremia for participants with TFV-DP <800 and 800 to <1650 fmol/punch were 4.7 (95% CI, 2.6-8.7; P < .0001) and 2.1 (95% CI, 1.3-3.3; P = .002) versus ≥1650 fmol/punch, respectively. These remained significant for participants who were virologically suppressed at the time of the study visit (4.2; 95% CI, 1.5-12.0; P = .007 and 2.2; 95% CI, 1.2-4.0; P = .01). CONCLUSIONS: TFV-DP in DBS predicts future viremia in PLWH on TDF, even in those who are virologically suppressed. This highlights the utility of this biomarker to inform about adherence beyond VL. Clinical Trials Registration. NCT02012621.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH/efectos de los fármacos , Organofosfatos/sangre , Tenofovir/uso terapéutico , Adenina/sangre , Adulto , Biomarcadores/sangre , Femenino , Infecciones por VIH/virología , Humanos , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Carga Viral , ViremiaRESUMEN
BACKGROUND: Although tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a predictor of adherence and pre-exposure prophylaxis efficacy, its utility in human immunodeficiency virus (HIV) treatment remains unknown. METHODS: DBS for TFV-DP were collected up to 3 times over 48 weeks in persons living with HIV (PLWH) who were receiving TFV disoproxil fumarate (TDF)-based therapy. Log-transformed baseline TFV-DP was compared using t-tests or analyses of variance; generalized estimating equations were used to estimate the adjusted odds ratio (aOR) of viral suppression (<20 copies/mL) based on the TFV-DP concentration at the study visit. RESULTS: We analyzed 1199 DBS from 532 participants (76 female; 101 Black, 101 Hispanic). Among the virologically-suppressed participants at baseline (n = 347), TFV-DP was lower in Blacks (geometric mean 1453, 95% confidence interval [CI] 1291-1635) vs Whites (1793, 95% CI 1678-1916; P = .002) and Hispanics (1760, 95% CI 1563-1982; P = .025); in non-boosted (1610, 95% CI 1505-1723) vs. boosted (1888, 95% CI 1749-2037; P = .002) regimens; and in non-nucleoside reverse transcription inhibitor-based (1563, 95% CI 1432-1707) vs. boosted protease inhibitor-based (1890, 95% CI 1704-2095; P = .006) and multiclass-based (1927, 95% CI 1650-2252; P = .022) regimens. The aOR of virologic suppression, after adjusting for age, gender, race, body mass index, estimated glomerular filtration rate, CD4+ T-cell count, antiretroviral drug class and duration of therapy, was 73.5 (95% CI 25.7-210.5; P < .0001) for a TFV-DP concentration ≥1850 fmol/punch compared to <350 fmol/punch. CONCLUSIONS: TFV-DP in DBS is strongly associated with virologic suppression in PLWH on TDF-based therapy and is associated with certain participant characteristics. Further research is required to evaluate this drug adherence and exposure measure in clinical practice. CLINICAL TRIALS REGISTRATION: NCT02012621.
Asunto(s)
Adenina/análogos & derivados , Antivirales/sangre , Antivirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Organofosfatos/sangre , Organofosfatos/uso terapéutico , Adenina/sangre , Adenina/uso terapéutico , Adulto , Pruebas con Sangre Seca , Femenino , Infecciones por VIH/sangre , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: Emtricitabine triphosphate (FTC-TP), the phosphorylated anabolite of emtricitabine, can be quantified in dried blood spots (DBS). We evaluated FTC-TP in DBS as a predictor of viral suppression and evaluated self-reported adherence as a predictor of FTC-TP. METHODS: Persons living with HIV (PLWH) on an FTC-containing regimen were prospectively recruited. A DBS and HIV viral load were obtained during routine clinical visits. Self-reported adherence for 3 days, 30 days and 3 months was captured. Generalized estimating equations were used to estimate the adjusted odds ratio (aOR) of viral suppression for quantifiable FTC-TP versus below the limit of quantification (BLQ). The utility of self-reported adherence to predict quantifiable FTC-TP was assessed by calculating the area under receiver operating characteristic (ROC) curve. RESULTS: One thousand one hundred and fifty-four person-visits from 514 participants who had DBS assayed for FTC-TP were included in the analysis. After adjusting for age, gender, race, BMI, ART class, ART duration, estimated glomerular filtration rate and CD4+ T cell count, the aOR (95% CI) for viral suppression for quantifiable FTC-TP versus BLQ was 7.2 (4.3-12.0; P < 0.0001). After further adjusting for tenofovir diphosphate, the aOR was 2.1 (1.2-4.0; P < 0.015). The area under the ROC curve for 3 day self-reported adherence was 0.82 (95% CI 0.75-0.88) compared with 0.70 (95% CI 0.62-0.77, P = 0.004) and 0.79 (95% CI 0.71-0.86, P = 0.32) for 3 month and 30 day self-reported adherence, respectively. CONCLUSIONS: In PLWH, FTC-TP from DBS is a strong predictor of viral suppression, even after adjusting for tenofovir diphosphate, and was best predicted by 3 day self-reported adherence.
Asunto(s)
Fármacos Anti-VIH/sangre , Pruebas con Sangre Seca , Emtricitabina/sangre , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación/estadística & datos numéricos , Carga Viral/efectos de los fármacos , Adulto , Fármacos Anti-VIH/uso terapéutico , Emtricitabina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , AutoinformeRESUMEN
BACKGROUND: Tenofovir monoester is a relatively lipophilic intermediate formed during the hydrolysis of tenofovir disoproxil to tenofovir. Its clinical pharmacokinetic profile and influence on the cellular pharmacology of tenofovir diphosphate have not been reported. METHODS: Plasma, PBMC and dried blood spots (DBS) were obtained from HIV-uninfected adults participating in a randomized, cross-over bioequivalence study of single-dose tenofovir disoproxil fumarate (TDF)/emtricitabine unencapsulated or encapsulated with a Proteus® ingestible sensor. Plasma pharmacokinetics of tenofovir monoester and tenofovir were characterized using non-compartmental methods. Relationships with tenofovir diphosphate in DBS and PBMC were examined using mixed-effects models. RESULTS: Samples were available from 24 participants (13 female; 19 white, 3 black, 2 Hispanic). Tenofovir monoester appeared rapidly with a median (range) Tmax of 0.5 h (0.25-2) followed by a rapid monophasic decline with a geometric mean (coefficient of variation) t½ of 26 min (31.0%). Tenofovir monoester Cmax was 131.6 ng/mL (69.8%) and AUC0-4 was 93.3 ng·h/mL (47.9%). The corresponding values for plasma tenofovir were 222.2 ng/mL (37.1%) and 448.1 ng·h/mL (30.0%). Tenofovir monoester AUC0-∞ (but not tenofovir AUC0-∞) was a significant predictor of tenofovir diphosphate in both PBMC (Pâ=â0.015) and DBS (Pâ=â0.005), increasing by 3.8% (95% CI 0.8%-6.8%) and 4.3% (95% CI 1.5%-7.2%), respectively, for every 10 ng·h/mL increase in tenofovir monoester. CONCLUSIONS: Tenofovir monoester Cmax and AUC0-4 were 59.2% and 20.6% of corresponding plasma tenofovir concentrations. Tenofovir monoester was significantly associated with intracellular tenofovir diphosphate concentrations in PBMC and DBS, whereas tenofovir concentrations were not. Tenofovir monoester likely facilitates cell loading, thereby increasing tenofovir diphosphate exposures in vivo.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Organofosfatos/análisis , Ácidos Fosforosos/administración & dosificación , Ácidos Fosforosos/farmacocinética , Adenina/administración & dosificación , Adenina/análisis , Adenina/farmacocinética , Adulto , Análisis Químico de la Sangre , Estudios Cruzados , Emtricitabina/administración & dosificación , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , MasculinoRESUMEN
BACKGROUND: Intracellular tenofovir diphosphate concentrations are markedly increased in HIV/HCV coinfected individuals receiving tenofovir disoproxil fumarate (TDF) with sofosbuvir-containing treatment. Sofosbuvir may inhibit the hydrolysis of TDF to tenofovir, resulting in increased concentrations of the disoproxil or monoester forms, which may augment cell loading. We sought to quantify tenofovir disoproxil and monoester concentrations in individuals receiving TDF with and without ledipasvir/sofosbuvir. METHODS: HIV/HCV coinfected participants receiving TDF-based therapy were sampled pre-dose and 1 and 4 h post-dose prior to and 4 weeks after initiating ledipasvir/sofosbuvir. Tenofovir disoproxil was not detectable. Tenofovir monoester in plasma and tenofovir diphosphate in PBMC and dried blood spots (DBS) were quantified using LC-MS/MS. Geometric mean ratios (week 4 versus baseline) and 95% CIs were generated for the pharmacokinetic parameters. P values reflect paired t-tests. RESULTS: Ten participants had complete data. At baseline, geometric mean (95% CI) tenofovir monoester plasma concentrations at 1 and 4 h post-dose were 97.4 ng/mL (33.0-287.5) and 0.74 ng/mL (0.27-2.06), respectively. With ledipasvir/sofosbuvir, tenofovir monoester concentrations at 4 h post-dose were 5.02-fold higher (95% CI 1.40-18.05; Pâ=â0.019), but did not significantly differ at 1 h post-dose (1.72-fold higher, 95% CI 0.25-11.78; Pâ=â0.54), possibly due to absorption variability. Tenofovir diphosphate in PBMC and DBS were increased 2.80-fold (95% CI 1.71-4.57; Pâ=â0.001) and 7.31-fold (95% CI 4.47-11.95; Pâ<â0.0001), respectively, after 4 weeks of ledipasvir/sofosbuvir. CONCLUSIONS: Tenofovir monoester concentrations were increased in individuals receiving TDF with ledipasvir/sofosbuvir, consistent with inhibition of TDF hydrolysis. Additional studies are needed to determine the clinical relevance of this interaction.
Asunto(s)
Adenina/análogos & derivados , Antivirales/administración & dosificación , Antivirales/farmacocinética , Bencimidazoles/administración & dosificación , Fluorenos/administración & dosificación , Ácidos Fosforosos/administración & dosificación , Sofosbuvir/administración & dosificación , Tenofovir/farmacocinética , Adenina/administración & dosificación , Adolescente , Adulto , Análisis Químico de la Sangre , Cromatografía Liquida , Interacciones Farmacológicas , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
Mental health (MH) disorders are more prevalent among persons living with HIV compared to the general population, and may contribute to suboptimal adherence to antiretroviral therapy (ART). Tenofovir-diphosphate (TFV-DP), the phosphorylated anabolite of tenofovir (TFV), is a biomarker with a 17-day half-life in red blood cells. TFV-DP can be measured in dried blood spots (DBS) using liquid chromatography/tandem mass spectrometry (LC-MS/MS) to assess adherence and cumulative drug exposure to tenofovir disoproxil fumarate (TDF)-based ART. From a larger clinical cohort (N = 807), TFV-DP concentrations and a paired HIV viral load were available from 521 participants at their enrollment visit. We used multivariable linear regression to evaluate the association between TFV-DP in DBS and engagement in MH care. After adjusting for clinical covariates, participants with MH disorders who were engaged in MH care had 40% higher TFV-DP compared to participants with MH disorders who were not engaged in MH care (p < 0.001), and similar TFV-DP to participants without MH disorders (p = 0.219). Further research is needed to identify the mechanism(s) for these findings, with the goal of optimizing engagement and retention in MH care strategies to improve ART adherence and clinical outcomes in PLWH with MH disorders.