Antiretroviral Therapy Adherence During and Postbreastfeeding Cessation Measured by Tenofovir Levels in Hair.

BACKGROUND: We examined change in antiretroviral treatment (ART) adherence after breastfeeding (BF) cessation using hair tenofovir (TFV) concentrations as an objective metric of medication consumption. METHODS: A subset of postpartum women in Zimbabwe randomized in IMPAACT PROMISE to take ART while BF and post-BF cessation had hair TFV measured longitudinally. Using linear mixed-effect models, we estimated differences in hair TFV levels after BF cessation, accounting for trends in levels over time regardless of BF status and change in slope after breastfeeding cessation. We also estimated the relative risk of viremia (>50 copies/mL) per doubling of hair TFV concentration. RESULTS: Among 55 women (median age 26, interquartile range 24-29 years), hair TFV levels (n = 305) were available for a median of 9 visits per woman between 3 and 29 months postpartum. Hair TFV levels ranged from undetected to 0.25 ng/mg (median 0.04 ng/mg). Controlling for trends since delivery [decline of 2.2% per month, 95% confidence interval (CI): -5.3 to 1.0], TFV levels averaged 24.4% higher (95% CI: -5.1 to 63.1) post-BF cessation than during BF, with no change in slope (0.0% per month, 95% CI: -3.8 to 3.9). Postpartum, 42% of women were ever viremic. Higher TFV levels were strongly protective; relative risk of viremia per doubling of TFV was 0.52 (95% CI: 0.43 to 0.63; P < 0.0001). CONCLUSIONS: Leveraging an objective metric of ART use, we observed modestly declining adherence across the postpartum period, but no additional decline associated with breastfeeding cessation. High viremia frequency and varying postpartum TFV levels observed highlight the importance of enhanced adherence support with viral load monitoring among postpartum women.

Comparison of efavirenz levels in blood and hair with pharmacy refills as measures of adherence and predictors of viral suppression among people living with HIV in Nigeria.

BACKGROUND: Strategies to support adherence are constrained by the lack of tools to objectively monitor medication intake in low-resource settings. Pharmacologic measures are objective, but pharmacy refill data is more accessible and cost-efficient. This study compared short-term and long-term efavirenz (EFV) drug levels with pharmacy refill adherence data (PRA) and evaluated their ability to predict viral suppression among people living with HIV in Nigeria. METHODS: Paired hair and dried blood spot (DBS) samples were obtained from 91 adults living with HIV receiving 600 mg EFV-based antiretroviral therapy (ART) and EFV concentrations were measured via validated methods using liquid-chromatography-mass-spectrometry. PRA was estimated from pharmacy records, based on the number of days a patient collected medication before or after the scheduled pick-up date. PRA was categorized into ≤ 74%, 75-94% and ≥ 95%, defined as poor, medium and high adherence, respectively. HIV viral loads closest to the hair sampling time (within 6 months) were also abstracted. Receiver Operating Characteristics (ROC) curve analyses compared the ability of adherence metrics to predict viral suppression. RESULTS: Based on PRA, 81% of participants had high adherence while 11% and 8% had medium and poor adherence, respectively. The median (IQR) EFV concentrations were 6.85 ng/mg (4.56-10.93) for hair and 1495.6 ng/ml (1050.7-2365.8) for DBS. Of the three measures of adherence, hair EFV concentration had the highest Area Under Curve (AUC) to predict viral suppression. Correlations between EFV concentrations in DBS and hair with PRA were positive (r = 0.12, P = 0.27 and r = 0.21, P = 0.05, respectively) but not strong. CONCLUSIONS: EFV concentrations in hair were the strongest predictor of viral suppression and only weakly correlated with pharmacy refill adherence data in Nigeria. This study suggests that resource-limited settings may benefit from objective adherence metrics to monitor and support adherence.

Distinct forms of migration and mobility are differentially associated with HIV treatment adherence.

OBJECTIVE: We examined whether human mobility was associated with antiretroviral treatment adherence, measured via antiretroviral hair concentrations. DESIGN: This is a cross-sectional analysis of adults on antiretroviral treatment in East Africa at baseline in an observational cohort study. METHODS: Participants reported recent mobility (overnight travel) and histories of migration (changes of residence), including reasons, frequency/duration, and locations. Hair antiretroviral concentrations were analyzed using validated methods. We estimated associations between mobility and antiretroviral concentrations via linear regression adjusted for age, sex, region, years on treatment. RESULTS: Among 383 participants, half were women and the median age was 40. Among men, 25% reported recent work-related mobility, 30% nonwork mobility, and 11% migrated in the past year (mostly across district boundaries); among women, 6 and 57% reported work-related and nonwork mobility, respectively, and 8% recently migrated (mostly within district). Those reporting work-related trips 2 nights or less had 72% higher hair antiretroviral levels (P = 0.02) than those who did not travel for work; in contrast, nonwork mobility (any duration, vs. none) was associated with 24% lower levels (P = 0.06). Intra-district migrations were associated with 59% lower antiretroviral levels than nonmigrants (P = 0.003) while inter-district migrations were not (27% higher, P = 0.40). CONCLUSION: We found that localized/intra-district migration and nonwork travel-more common among women-were associated with lower adherence, potentially reflecting care interruptions or staying with family/friends unaware of the participants' status. In contrast, short work-related trips-more common among men-were associated with higher adherence, perhaps reflecting higher income. Adherence interventions may require tailoring by sex and forms of mobility.

Associations between efavirenz concentrations, pharmacogenetics and neurocognitive performance in people living with HIV in Nigeria.

OBJECTIVE: Efavirenz (EFV) use is associated with neuropsychiatric side effects, which may include poor neurocognitive performance. We evaluated single nucleotide polymorphisms in genes that contribute to EFV pharmacokinetics and examined them in association with EFV concentrations in plasma and hair, as well as neurocognitive performance. DESIGN: Cross-sectional study in which adults with HIV receiving 600-mg EFV for at least 2 months were recruited and paired hair and dried blood spots (DBS) samples collected. METHODS: Participants (N = 93, 70.3% female) were genotyped for seven single nucleotide polymorphisms in CYP2B6, NRII3 and ABCB1 using DBS. EFV was quantified in DBS and hair using validated liquid-chromatography-tandem-mass-spectrometry methods, with plasma EFV concentrations derived from DBS levels. Participants were also administered a neurocognitive battery of 10 tests (seven domains) that assessed total neurocognitive functioning. RESULTS: Strong correlation (r = 0.66, P < 0.001) was observed between plasma and hair EFV concentrations. The median (interquartile range) hair EFV concentration was 6.85 ng/mg (4.56-10.93). CYP2B6 516G>T, (P < 0.001) and CYP2B6 983T>C (P = 0.001) were each associated with hair EFV concentrations. Similarly, 516G>T (P < 0.001) and 983T>C (P = 0.009) were significantly associated with plasma EFV concentration. No other genetic associations were observed. Contrary to other studies, total neurocognitive performance was significantly associated with plasma EFV concentrations (r = 0.23, P = 0.043) and 983T>C genotype (r = 0.38, P < 0.0005). CONCLUSION: This study demonstrated approximately three-fold and two-fold higher EFV plasma and hair concentrations, respectively, among CYP2B6 516TT compared with 516GG. Higher EFV concentrations were associated with better neurocognitive performance, requiring further study to elucidate the relationships between adherence, adverse effects and outcomes.

Tenofovir and emtricitabine concentrations in hair are comparable between individuals on tenofovir disoproxil fumarate versus tenofovir alafenamide-based ART.

Tenofovir disoproxil fumarate (TDF) in combination with emtricitabine (FTC) is the backbone for both human immunodeficiency virus (HIV) treatment and pre-exposure prophylaxis (PrEP) worldwide. Tenofovir alafenamide (TAF) with FTC is increasingly used in HIV treatment and was recently approved for PrEP among men-who-have-sex-with-men. TDF and TAF are both metabolized into tenofovir (TFV). Antiretrovirals in plasma are taken up into hair over time, with hair levels providing a long-term measure of adherence. Here, we report a simple, robust, highly sensitive, and validated high-performance liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS)-based analytical method for analyzing TFV and FTC from individuals on either TDF/FTC or TAF/FTC in small hair samples. TFV/FTC are extracted from ~5 mg hair and separated on a column using a gradient elution. The lower quantification limits are 0.00200 (TFV) and 0.0200 (FTC) ng/mg hair; the assay is linear up to 0.400 (TFV) and 4.00 (FTC) ng/mg hair. The intra-day and inter-day coefficients of variance (CVs) are 5.39-12.6% and 6.40-13.5% for TFV and 0.571-2.45% and 2.45-5.16% for FTC. TFV concentrations from participants on TDF/FTC-based regimens with undetectable plasma HIV RNA were 0.0525 ± 0.0295 ng/mg, whereas those from individuals on TAF/FTC-based regimens were 0.0426 ± 0.0246 ng/mg. Despite the dose of TFV in TDF being 10 times that of TAF, hair concentrations of TFV were not significantly different for those on TDF versus TAF regimens. Pharmacological enhancers (ritonavir and cobicistat) did not boost TFV concentrations in hair. In summary, we developed and validated a sensitive analytical method to analyze TFV and FTC in hair and found that hair concentrations of TFV were essentially equivalent among those on TDF and TAF.