Antiretroviral Concentrations Research Articles

Prevalence of ABCC3-1767G/A polymorphism among patients with antiretroviral-associated hepatotoxicity.

BackgroundPlasma concentrations of antiretrovirals (ARVs) regimens have considerably varied in individuals of human immunodeficiency virus (HIV) because of variations in the expression of drug‐metabolizing and transporter genes. Transporter genes play an important role in the disposition of drugs. Polymorphism in transporter gene (ABCC3) affects the MRP3 expression and varies the treatment outcome.MethodWe examined the polymorphism of ABCC3‐1767G/A gene in a total of 165 HIV patients (out of 165 HIV patients, 34 were with and 131 were without hepatotoxicity) and 156 healthy individuals using the polymerase chain reaction–restriction fragment length polymorphism method.ResultsIn univariate analysis, we found a decreased prevalence of ABCC3 1767GA, 1767GA+AA genotypes, and 1767A allele in patients with hepatotoxicity as compared to patients without hepatotoxicity (23.5% vs. 28.2% and 23.5% vs. 30.53%; 11.76% vs. 16.41%), while a higher prevalence of 1767AA genotype was observed in HIV patients in comparison with healthy controls (2.3% vs. 1.3%, odds ratio [OR] = 1.71, 95% confidence interval [CI]: 0.23–15.03, p = .89). The frequency of ABCC3‐1767AA genotype was dispersed higher in individuals with early and advanced HIV disease stage in comparison with healthy controls (5.3% vs. 1.3%, OR = 4.73, p = .70; 8.9% vs. 1.3%, OR = 1.89, p = .91). A higher occurrence of ABCC3‐1767AA genotype was found in tobacco using HIV patients without hepatotoxicity compared with nonusers (4.7% vs. 1.1%, OR = 4.28, p = .52). The distribution of ABCC3‐1767GA genotype was higher in nevirapine receiving HIV patients irrespective of their hepatotoxicity status as compared to nonusers (30.4% vs. 9.1%, OR = 3.34, p = .22; 29.4% vs. 16.7%, OR = 1.69, p = .77). In multivariate analysis, HIV patients receiving nevirapine and with hepatotoxicity was found to have a significant risk for severity of hepatotoxicity (OR = 4.56, 95% CI: 1.60–12.99, p = .004).Conclusion ABCC3 1767G/A polymorphism was not significantly associated with susceptibility to ARV‐associated hepatotoxicity, although ABCC3 1767AA genotype designated a risk for acquisition of hepatotoxicity and advancement of the disease. Nevirapine usage emerged as an independent risk factor for hepatotoxicity severity.

Comparing self-reported medication adherence measures with hair antiretroviral concentration among people living with HIV in Guangxi, China

BackgroundAntiretroviral adherence is essential to HIV treatment efficacy. Various self-reported measures are commonly used for assessing antiretroviral adherence. Limited data are available regarding the validity of those self-reported measures in comparison with long-term objective biomarkers of adherence measures such as hair measures.MethodsSelf-reported adherence (frequency, percentage, and visual analog scale [VAS]) and hair tenofovir concentration were evaluated at a single time point from 268 people living with HIV in China. The responses to each of three self-reported measures were converted into percentage and then dichotomized as “optimal” (100%) vs. “suboptimal” (less than 100%) adherence. Two composite adherence scores (CAS) were created from the three self-reported measures: (1) an overall adherence was the average percentage of the three self-reported measures; (2) responses were termed optimal adherence if participants reporting optimal adherence in all three self-reported measures, while were termed suboptimal adherence. Hair tenofovir concentration was also dichotomized as “optimal” (above the limit of quantitation, 36 pg/mg) vs. “suboptimal” adherence (blow 36 pg/mg). Spearman correlation, kappa statistics, and logistic regression analysis were used to calculate the correlations, agreements, and predictions of self-reported measures with hair measure, respectively.ResultsOverall adherence, but any of the three self-reported adherence, was correlated with hair tenofovir concentration (r = 0.13, p < 0.05). Self-reported optimal adherence in VAS and CAS measures were agreed with and predicted optimal adherence assessed by hair measure (Kappa = 0.107, adjusted OR = 1.88, 95% CI 1.03–3.45; Kappa = 0.109, adjusted OR = 1.80, 95% CI 1.02–3.18; all p < 0.05, respectively).ConclusionVAS may be a good individual self-reported measure for antiretroviral adherence, and CAS may be a good composite self-reported measure for antiretroviral adherence.

HIV, aging, and adherence: an update and future directions.

To highlight recent data on antiretroviral adherence in older people living with HIV (PLWH), describe the most relevant pharmacokinetic antiretroviral studies, and identify critical research gaps in this population. Overall, studies have found that older PLWH are more likely to be adherent to antiretroviral therapy (ART). Although multiple methods to measure adherence are available (self-report, pharmacy refills, electronic device monitors, drug concentrations), there is currently no 'gold standard' adherence measure or sufficient evidence to suggest a preferred method in older patients. Recently, studies evaluating antiretroviral concentrations in hair and dried blood spots in older patients identified no major differences when compared with younger individuals. Similarly, although pharmacokinetic studies in older PLWH are scarce, most data reveal no significant pharmacokinetic differences in the aging population. Furthermore, no specific guidelines or treatment recommendations regarding ART dose modification or long-term toxicity in aging PLWH are available, mostly because of the exclusion of this population in clinical trials. How aging influences adherence and pharmacokinetics remains poorly understood. As the population of older PLWH increases, research focusing on adherence, toxicity, drug--drug interactions, and the influence of comorbidities is needed.

Semen Extracellular Vesicles From HIV-1-Infected Individuals Inhibit HIV-1 Replication In Vitro, and Extracellular Vesicles Carry Antiretroviral Drugs In Vivo.

Extracellular vesicles (EVs) are cell-derived vesicles with diverse functions in intercellular communication including disease and infection, and EVs seem to influence HIV-1 pathogenesis. EVs isolated from HIV-1-uninfected semen (SE), but not blood (BE), contain factors that interfere with HIV-1 infection and replication in target cells. The reason for this dichotomy is unknown. Furthermore, the effect of HIV-1 infection and antiretroviral (ARV) drugs on the anti-HIV-1 effects of SE and BE is unknown. Here, we characterize EVs and EV-free plasma isolated from HIV-infected donor semen and blood and their effects on HIV infection. EVs and EV-free plasma were purified from autologous blood and semen of HIV-negative, HIV-infected antiretroviral therapy (ART)-naïve, and HIV-infected ART-treated participants. HIV infection was assessed in a TZM-bl cell reporter system. ARV concentrations were analyzed using liquid chromatography-mass spectrometry. SE isolated from both HIV-negative and HIV-infected, ART-naïve donors inhibited HIV-1 infection, but BE and semen and blood EV-free plasma did not. By contrast, BE, SE, and EV-free plasma from HIV-infected, ART-treated donors inhibited HIV-1. Importantly, exosomes isolated from ART-treated donors contained concentrations of ARV drugs (ART-EVs) at biologically relevant inhibitory levels. The HIV-1-inhibitory phenotype of SE is independent of donor HIV-1 or ART status, and ARV drugs and their metabolites are SE- and BE-associated in vivo.

Antiretroviral concentration measurements as an additional tool to manage virologic failure in resource limited settings: a case control study

BackgroundSeveral studies demonstrate a correlation between sub-therapeutic concentrations of antiretroviral drugs and virologic failure. We examined the sensitivity, specificity and predictive values of sub-therapeutic drug levels in predicting viralogic failure.MethodsThis was a case control study with cases being samples of participants with virologic failure, and controls samples of participants with virologic suppression. We analyzed samples obtained from participants that had been on antiretroviral treatment (ART) for at least 6 months. Virologic failure was defined as HIV-RNA viral load ≥ 1000 copies/ml. Sub-therapeutic drug levels were defined according to published reference cutoffs. The diagnostic validity of drug levels for virologic failure was assessed using plasma viral loads as a gold standard.ResultsSub-therapeutic ART concentrations explained only 38.2% of virologic failure with a probability of experiencing virologic failure of 0.66 in a patient with low drug levels versus 0.25 for participants with measurements within or above the normal range. Approximately 90% of participants with ART concentrations above the lower clinical cut off did not have virologic failure.ConclusionsThese results support prior indication for therapeutic drug monitoring in cases of suspected virologic failure.

Benefits and Limits of Antiretroviral Drug Monitoring in Routine Practice

HIV infection is a chronic disease for which therapeutic adherence and tolerance require particular attention. This study aimed to assess whether and when therapeutic drug monitoring (TDM) could be associated with a benefit in routine practice. All HIV-infected patients who underwent at least one TDM at the University Hospital of Dijon (France) between 1st January 2009 and 31st December 2012 were retrospectively included. Compliance with the recommendations, the results (antiretroviral concentrations), any subsequent therapeutic modifications, and the virological results at 4-8 months were analysed each time TDM was performed. TDM was defined as "practically relevant" when low or high antiretroviral concentrations led to a change in therapy. Of the 571 patients who followed-up, 43.4% underwent TDM. TDM complying with recommendations (120 patients) was associated with a higher proportion of antiretroviral concentrations outside the therapeutic range (p=0.03). Antiretroviral treatment was modified after TDM in 22.6% of patients. Protease inhibitors, non-nucleoside reverse transcriptase inhibitors and raltegravir were more significantly modified when the measured concentration was outside the therapeutic range (p=0.008, p=0.05 and p=0.02, respectively). Overall, 11.7% of TDM was considered "practically relevant", though there was no significant correlation between subsequent changes in antiretroviral treatment and undetectable final HIV viral load. TDM may be a useful tool in the management of HIV infection in specific situations, but the overall benefit seems moderate in routine practice. TDM cannot be systematic and/or a decision tool per se, but should be included in a comprehensive approach in certain clinical situations.

Cartography of Virologic Reservoir Related to Antiretroviral Concentrations in HIV-1 Chronic Patients Treated by a First Line Treatment Containing Dolutegravir and Associated Nucleoside / Nucleotide Reverse Transcriptase Inhibitors Backbone

Cartography of Virologic Reservoir Related to Antiretroviral Concentrations in HIV-1 Chronic Patients Treated by a First Line Treatment Containing Dolutegravir and Associated Nucleoside / Nucleotide Reverse Transcriptase Inhibitors Backbone

Food Insecurity Is Associated With Lower Levels of Antiretroviral Drug Concentrations in Hair Among a Cohort of Women Living With Human Immunodeficiency Virus in the United States.

Food insecurity is a well-established determinant of suboptimal, self-reported antiretroviral therapy (ART) adherence, but few studies have investigated this association using objective adherence measures. We examined the association of food insecurity with levels of ART concentrations in hair among women living with human immunodeficiency virus (WLHIV) in the United States. We analyzed longitudinal data collected semiannually from 2013 through 2015 from the Women's Interagency HIV Study, a multisite, prospective, cohort study of WLHIV and controls not living with HIV. Our sample comprised 1944 person-visits from 677 WLHIV. Food insecurity was measured using the US Household Food Security Survey Module. ART concentrations in hair, an objective and validated measure of drug adherence and exposure, were measured using high-performance liquid chromatography with mass spectrometry detection for regimens that included darunavir, atazanavir, raltegravir, or dolutegravir. We conducted multiple 3-level linear regressions that accounted for repeated measures and the ART medication(s) taken at each visit, adjusting for sociodemographic and clinical characteristics. At baseline, 67% of participants were virally suppressed and 35% reported food insecurity. In the base multivariable model, each 3-point increase in food insecurity was associated with 0.94-fold lower ART concentration in hair (95% confidence interval, 0.89 to 0.99). This effect remained unchanged after adjusting for self-reported adherence. Food insecurity was associated with lower ART concentrations in hair, suggesting that food insecurity may be associated with suboptimal ART adherence and/or drug absorption. Interventions seeking to improve ART adherence among WLHIV should consider and address the role of food insecurity.

Cell-type specific differences in antiretroviral penetration and the effects of HIV-1 Tat and morphine among primary human brain endothelial cells, astrocytes, pericytes, and microglia

The inability to achieve adequate intracellular antiretroviral concentrations may contribute to HIV persistence within the brain and to neurocognitive deficits in opioid abusers. To investigate, intracellular antiretroviral concentrations were measured in primary human astrocytes, microglia, pericytes, and brain microvascular endothelial cells (BMECs), and in an immortalized brain endothelial cell line (hCMEC/D3). HIV-1 Tat and morphine effects on intracellular antiretroviral concentrations also were evaluated. After pretreatment for 24 h with vehicle, HIV-1 Tat, morphine, or combined Tat and morphine, cells were incubated for 1 h with equal concentrations of a mixture of tenofovir, emtricitabine, and dolutegravir at one of two concentrations (5 μM or 10 μM). Intracellular drug accumulation was measured using LC-MS/MS. Drug penetration differed depending on the drug, the extracellular concentration used for dosing, and cell type. Significant findings included: 1) Dolutegravir (at 5 μM or 10 μM) accumulated more in HBMECs than other cell types. 2) At 5 μM, intracellular emtricitabine levels were higher in microglia than other cell types; while at 10 μM, emtricitabine accumulation was greatest in HBMECs. 3) Tenofovir (5 or 10 μM extracellular dosing) displayed greater accumulation inside HBMECs than in other cell types. 4) After Tat and/or morphine pretreatment, the relative accumulation of antiretroviral drugs was greater in morphine-exposed HBMECs compared to other treatments. The opposite effect was observed in astrocytes in which morphine exposure decreased drug accumulation. In summary, the intracellular accumulation of antiretroviral drugs differed depending on the particular drug involved, the concentration of the applied antiretroviral drug, and the cell type targeted. Moreover, morphine, and to a lesser extent Tat, exposure also had differential effects on antiretroviral accumulation. These data highlight the complexity of optimizing brain-targeted HIV therapeutics, especially in the setting of chronic opioid use or misuse.

Beneficial and Adverse Effects of cART Affect Neurocognitive Function in HIV-1 Infection: Balancing Viral Suppression against Neuronal Stress and Injury.

HIV-associated neurocognitive disorders (HAND) persist despite the successful introduction of combination antiretroviral therapy (cART). While insufficient concentration of certain antiretrovirals (ARV) may lead to incomplete viral suppression in the brain, many ARVs are found to cause neuropsychiatric adverse effects, indicating their penetration into the central nervous system (CNS). Several lines of evidence suggest shared critical roles of oxidative and endoplasmic reticulum stress, compromised neuronal energy homeostasis, and autophagy in the promotion of neuronal dysfunction associated with both HIV-1 infection and long-term cART or ARV use. As the lifespans of HIV patients are increased, unique challenges have surfaced. Longer lives convey prolonged exposure of the CNS to viral toxins, neurotoxic ARVs, polypharmacy with prescribed or illicit drug use, and age-related diseases. All of these factors can contribute to increased risks for the development of neuropsychiatric conditions and cognitive impairment, which can significantly impact patient well-being, cART adherence, and overall health outcome. Strategies to increase the penetration of cART into the brain to lower viral toxicity may detrimentally increase ARV neurotoxicity and neuropsychiatric adverse effects. As clinicians attempt to control peripheral viremia in an aging population of HIV-infected patients, they must navigate an increasingly complex myriad of comorbidities, pharmacogenetics, drug-drug interactions, and psychiatric and cognitive dysfunction. Here we review in comparison to the neuropathological effects of HIV-1 the available information on neuropsychiatric adverse effects and neurotoxicity of clinically used ARV and cART. It appears altogether that future cART aiming at controlling HIV-1 in the CNS and preventing HAND will require an intricate balancing act of suppressing viral replication while minimizing neurotoxicity, impairment of neurocognition, and neuropsychiatric adverse effects. Graphical abstract Schematic summary of the effects exerted on the brain and neurocognitive function by HIV-1 infection, comorbidities, psychostimulatory, illicit drugs, therapeutic drugs, such as antiretrovirals, the resulting polypharmacy and aging, as well as the potential interactions of all these factors.

Ritonavir and cobicistat as pharmacokinetic enhancers in pregnant women

Ritonavir and cobicistat are commonly used as pharmacokinetic enhancers to boost plasma concentrations of antiretrovirals used to treat HIV infection, including the protease inhibitors atazanavir, ...

The relationship between zidovudine, lamivudine and nevirapine plasma drug levels and antiretroviral treatment outcomes in Nigeria children living with HIV

Plasma concentrations of antiretrovirals are significant and important determinants of treatment failure and toxicity. The relationship between antiretroviral pharmacokinetic exposures and immunovirological outcomes has not been extensively studied in our setting. The aim of this study was to investigate the relationship between antiretroviral plasma concentrations and virological and immunological treatment outcomes in children living with human immunodeficiency virus (HIV) A retrospective collection of demographic, clinical , laboratory data and a prospective determination of plasma drug concentrations in 120 children aged 2-14 years after two years of receiving fixed dose zidovudine, lamivudine and nevirapine tablets using a simple, rapid, sensitive and validated method of high performance liquid chromatography with UV detection for simultaneous quantification of zidovudine, lamivudine and nevirapine in human plasma. All analyses were performed using graph pad prism version 5.0. A perfect agreement (p 100 cells/mm3). At 2 years zidovudine, lamivudine and nevirapine therapeutic levels, zidovudine supra therapeutic levels ,and nevirapine subtherapeutic levels were respectively significantly associated with immunologic success (CD4%>15 %). Low nevirapine levels can be used to identify those that require adherence counseling. Despite good virological and immunological outcomes, plasma concentrations of zidovudine, lamivudine and nevirapine were not significantly associated with virological and immunological outcomes (Absolute CD4 counts) but was significantly associated with immunological outcomes (CD4%). Plasma drug levels may be good surrogates of adherence but not of treatment outcomes. Monitoring CD4% remains important to optimize paediatric HIV treatment.Keywords: Antiretroviral treatment, children, therapeutic drug monitoring, treatment outcomes, immune-virological outcomes, plasma concentrations, zidovudine, lamivudine and nevirapine

Depot Medroxyprogesterone Acetate and the Vaginal Microbiome as Modifiers of Tenofovir Diphosphate and Lamivudine Triphosphate Concentrations in the Female Genital Tract of Ugandan Women: Implications for Tenofovir Disoproxil Fumarate/Lamivudine in Preexposure Prophylaxis.

Effective concentrations of antiretrovirals in the female genital tract (FGT) are critical for suppression of viral shedding or effective preexposure prophylaxis. The disposition of tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) in the FGT have been previously described. Despite widespread use, however, lamivudine triphosphate (3TC-TP) exposure in the FGT is unknown. Depot medroxyprogesterone acetate (DMPA) and vaginal dysbiosis have been implicated in increased risk of human immunodeficiency virus (HIV) acquisition, but whether they alter TFV-DP or 3TC-TP exposure, and therefore compromise prevention efficacy, is unknown. Fifty premenopausal women living with HIV in Kampala, Uganda, and receiving daily tenofovir disoproxil fumarate/lamivudine were recruited. Ectocervical biopsies were obtained for quantification of TFV-DP and 3TC-TP using liquid chromatography-mass spectrometry. 16S ribosomal RNA gene sequencing was performed on DNA extracted from vaginal swabs. Wilcoxon rank-sum was used to test for differences between contraceptive groups. 3TC-TP concentrations were on average 17-fold greater than TFV-DP concentrations in cervical tissues. TFV-DP concentrations in cervical biopsies were 76% greater in DMPA users compared with women using nonhormonal contraception (n = 23 per group). Abundance of Lactobacillus in vaginal swabs was correlated with 3TC-TP concentrations in cervical tissues. We found that TFV-DP concentrations were significantly greater in DMPA users compared with women using nonhormonal contraception, suggesting that prevention efficacy is unlikely to be compromised by DMPA use. Similar to reports of FTC-TP, 3TC-TP exposure was significantly greater than TFV-DP in cervical tissue and was correlated with abundance of Lactobacillus. These data support lamivudine as an option for preexposure prophylaxis. NCT03377608.

HIV-1 Tat and opioids act independently to limit antiretroviral brain concentrations and reduce blood-brain barrier integrity.

Poor antiretroviral penetration may contribute to human immunodeficiency virus (HIV) persistence within the brain and to neurocognitive deficits in opiate abusers. To investigate this problem, HIV-1 Tat protein and morphine effects on blood-brain barrier (BBB) permeability and drug brain penetration were explored using a conditional HIV-1 Tat transgenic mouse model. Tat and morphine effects on the leakage of fluorescently labeled dextrans (10-, 40-, and 70-kDa) into the brain were assessed. To evaluate effects on antiretroviral brain penetration, Tat+ and Tat- mice received three antiretroviral drugs (dolutegravir, abacavir, and lamivudine) with or without concurrent morphine exposure. Antiretroviral and morphine brain and plasma concentrations were determined by LC-MS/MS. Morphine exposure, and, to a lesser extent, Tat, significantly increased tracer leakage from the vasculature into the brain. Despite enhanced BBB breakdown evidenced by increased tracer leakiness, morphine exposure led to significantly lower abacavir concentrations within the striatum and significantly less dolutegravir within the hippocampus and striatum (normalized to plasma). P-glycoprotein, an efflux transporter for which these drugs are substrates, expression and function were significantly increased in the brains of morphine-exposed mice compared to mice not exposed to morphine. These findings were consistent with lower antiretroviral concentrations in brain tissues examined. Lamivudine concentrations were unaffected by Tat or morphine exposure. Collectively, our investigations indicate that Tat and morphine differentially alter BBB integrity. Morphine decreased brain concentrations of specific antiretroviral drugs, perhaps via increased expression of the drug efflux transporter, P-glycoprotein.

Correlation of hair and plasma efavirenz concentrations in HIV-positive South Africans.

BackgroundAntiretroviral concentrations in hair provide a longer window of drug detection and are useful for measuring longer-term drug exposure. Efavirenz is an important component of first-line treatment in resource-limited settings, but its concentrations in hair have not been well studied.MethodsThis study is a supplementary to a randomised controlled trial of an adherence intervention using an electronic adherence measuring device. Hair and plasma samples were collected from human immunodeficiency virus-positive patients in Cape Town, South Africa. Previously validated liquid chromatography tandem mass spectrometry methods were used to measure efavirenz concentrations in the collected hair and plasma samples. CYP2B6 genotyping of participants was also performed. Data analysis was performed using descriptive and comparative statistics as well as regression modelling.ResultsHair samples were collected from 59% of patients enrolled in the parent study. Results indicated that hair efavirenz concentrations were significantly influenced by participants’ CYP2B6 metaboliser status. Median efavirenz concentrations for extensive, intermediate and slow metaboliser genotypes were 3.54 ng/mg, 5.11 ng/mg and 10.66 ng/mg, respectively. A strong correlation was observed between the efavirenz concentrations measured in hair and plasma samples (Spearman’s correlation coefficients, 0.672–0.741, p < 0.0001). No relationship between hair efavirenz concentrations and virological failure or adherence measured using an electronic adherence was shown.ConclusionThe results from this study provide further insight into the potential of using hair as a matrix for measuring antiretroviral concentrations. However, challenges experienced in collecting hair samples suggest that this adherence measure may have limited utility in an African population.

Metabolic syndrome and endocrine status in HIV-infected transwomen.

HIV-infected transwomen face multiple specific issues. Economic and social marginalization, sex work, substance abuse, hormonal consumption and silicone injection may affect the course of HIV infection and lead to metabolic and endocrine complications. A matched case-control study was performed between 2013 and 2015 in a University Hospital and compared metabolic syndrome (MetS), thyroid and adrenal functions in HIV-infected transwomen (i.e. cases) and cisgender HIV-infected men (i.e. controls) matched for age and antiretroviral therapy. The interaction between hormonal consumption, the course of HIV infection and antiretroviral therapy was also studied. Clinical and biological data (CD4 cell count, HIV RNA load, antiretroviral plasma drug concentration, HDL, triglycerides, glucose, cortisol, thyroid stimulating hormone, free thyroxine, prolactine) were measured. A total of 292 HIV-infected patients (100 cases and 192 controls) were prospectively included. There was no difference between the two populations in terms of frequency of MetS, but subclinical hypothyroidism and adrenal insufficiency were more frequent in cases than in controls with, respectively, 12 vs. 3% (P < 0.002) for hypothyroidism and 20 vs. 8% (P < 0.001) for adrenal insufficiency. Prolactinemia, only performed in transwomen, was often elevated (21%) but rarely confirmed as true active hyperprolactinemia (monomeric form) (3%). Although hormonal intake was frequent among transwomen (31%), no impact on antiretroviral bioavailability and efficacy was detected. In this study, no increase in the prevalence of MetS was detected in HIV-infected transwomen patients. In contrast, adrenal and thyroid functions abnormalities were frequent and should be systematically assessed in this population. No impact of hormonal intake on antiretroviral bioavailability and efficacy was detected.

Antiretroviral Drug Concentrations in Breastmilk, Maternal HIV Viral Load, and HIV Transmission to the Infant: Results From the BAN Study.

Concentration of antiretroviral (ARV) drug found in plasma, and amounts of drug excreted into breastmilk, may affect HIV viral load and potentially perinatal HIV transmission. In this cohort study with 2-phase sampling, we included mothers randomized to postpartum maternal ARVs or daily infant nevirapine during 28 weeks of breastfeeding in the Breastfeeding, Antiretrovirals, and Nutrition study. Among these, we included all mothers who transmitted HIV to their infants between 2 and 28 weeks and 15% of mothers who did not (n = 27 and 227, respectively). Spearman correlation coefficients (r) were used to assess the correlation between maternal plasma and breastmilk ARV concentration. Associations between the median effective drug concentration (EC50) and detectable maternal viral load (plasma: >40 copies per milliliter, breastmilk: >56 copies per milliliter) were assessed using mixed-effects models. Cox models were used to estimate the association between maternal or infant plasma drug concentration and breastmilk HIV transmission from 2 to 28 weeks. All ARV compounds exhibited substantial correlations between maternal plasma and breastmilk concentrations (r: 0.85-0.98, P-value <0.0001). Having plasma drug concentration above the EC50 was associated with lower odds of having detectable HIV RNA [maternal plasma odds ratio (OR) 0.64, 95% confidence interval (CI): 0.45 to 0.91; breastmilk OR 0.22, 95% CI: 0.14 to 0.35] and a reduced rate of breastmilk HIV transmission (hazard ratio 0.40, 95% CI: 0.18 to 0.93). Having breastmilk drug concentration above the EC50 was also associated with lower odds of having detectable maternal HIV RNA (plasma OR 0.62, 95% CI: 0.45 to 0.85; breastmilk OR 0.42, 95% CI: 0.29 to 0.59). Ensuring adequate drug concentration is important for viral suppression and preventing breastmilk HIV transmission.

Factors influencing hair lamivudine concentration among people living with HIV in Guangxi, China.

Hair antiretroviral concentration has served as an innovative and objective measure of antiretroviral adherence. However, some factors (for example, pharmacokinetics and hair characteristics) may contribute to the variability of hair antiretroviral concentration that may threaten the validity and reliability of the hair measure as a biomarker of adherence. This study aimed to examine the potential factors that may influence the measure of hair antiretroviral concentration. Hair samples from a cohort of 372 people living with HIV (PLHIV) receiving lamivudine (300 mg/day) in Guangxi, China. Lamivudine concentration was analysed using liquid chromatography-tandem mass spectrometry. Multivariable linear regression was used to evaluate the associations of hair lamivudine concentration with age, sex, ethnicity, height, weight, body mass index, duration of HIV diagnosis, duration of current regimen, dosing schedule, concomitant antiretroviral medications, frequency of hair washing, hair care products use, hair cosmetic treatment and self-reported adherence. Multivariable models revealed that frequency of hair washing (β=-0.221, P=0.001), dosing schedule (β=0.141, P=0.036) and self-reported adherence (β=0.160, P=0.002) were associated with hair lamivudine concentration. We observed that, among those potential factors, hair lamivudine concentration was influenced by frequency of hair washing and dosing schedule. Therefore, frequency of hair washing and dosing schedule should be considered in future research using hair lamivudine concentration as a measure of lamivudine exposure and biomarker of adherence.

Antiretroviral Concentration in Hair as a Measure for Antiretroviral Medication Adherence: A Systematic Review of Global Literature.

This review aims to validate hair antiretroviral concentration (HAC) as a measure for antiretroviral medication adherence. This review included 31 studies that analyzed a total of 11 ARV drugs in four different drug classes. The associations between HAC and non-pharmacokinetic measures were generally lower than the association between HAC and other pharmacokinetic measures: the correlation coefficients (r) ranged from - 0.20 to 0.38 for self-report or pill counts and 0.20 to 0.85 for electronic drug monitoring; HAC and other pharmacokinetic measures were positively correlated with the correlation coefficients (r) ranging from 0.20 to 0.72, 0.34 to 0.86, 0.50 to 0.85 for antiretroviral concentration in plasma, peripheral blood mononuclear cells, and dried blood spots, respectively. HAC was one of the strongest independent predictors of virologic responses. HAC of tenofovir was significantly associated with renal toxicity in large sample studies. This review suggests that HAC is a valid biomarker of antiretroviral medication adherence.

Feasibility and acceptability of novel methods to estimate antiretroviral adherence: A longitudinal study.

Due to marked reductions in morbidity and mortality, antiretroviral (ARV) adherence monitoring is of high interest. Researchers and clinicians often resort to the most feasible and cost-effective adherence methods possible, which may result in biased or inaccurate estimates and require the physical presence of a participant at a research or clinic site. The objective of our study was to evaluate the feasibility and acceptability of three objective, innovative, and remote methods to estimate ARV adherence which may be conducted with less time and financial resources in a wide range of clinic and research settings. These three methods included: (a) text-messaged photographs of pharmacy refill dates to measure refill-based adherence, (b) text-messaged photographs of ARV medications to estimate pill-count-based adherence, and (c) home-collected hair samples for the measurement of ARV concentration to determine pharmacologic-based adherence. We conducted a pilot study from March through October 2017 to examine the feasibility and acceptability of these three adherence measures and the remotely conducted study procedures in 93 adults living with HIV nationwide. From our diverse national sample of participants, 95.7% were retained until the end of the study, 89.9% sent all text messages, and 84.3% sent all hair samples. Approximately 74.2% of participants reported excellent overall experience with the study, 60.2% were very or extremely satisfied with participating in a hair collection study, and 76.3% noted extremely high likelihood of participating in a similar study including text messaging pictures of medications or refill dates. We noted high levels of feasibility and acceptability with the remote study methodology, collection of photographed and text messaged pharmacy refill dates and pill counts, and home-collected hair samples. Here we describe the feasibility and acceptability metrics, results from the exit qualitative interviews with the participants, and lessons learned. These adherence measures represent innovative approaches to expand monitoring tools for HIV treatment and prevention adherence in future research.