Pharmacokinetics of Oral Tenofovir Disoproxil Fumarate in Pregnancy and Lactation: A Systematic Review
Antiviral Therapy
Abstract and Figures
Background:
Tenofovir Disoproxil Fumarate (TDF), the oral prodrug of Tenofovir (TFV), is advocated in pregnancy to for prevention of mother to child transmission (PMCT) with failure of hepatitis B immunoglobulin and vaccination. The pharmacokinetics of TDF monotherapy for PMCT-HBV is important if deployment is to emulate the success of multiple-ARVs for PMCT-HIV in resource constrained settings.
Methods:
This systematic review followed a protocol and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) guidelines. We included studies that enrolled pregnant women who received oral TDF therapy as monotherapy or in combination with other antiretrovirals (ARVs): irrespective of the reason for receiving the drug (e.g. HIV, HBV or pre exposure prophylaxis); and reported pharmacokinetics.
Results:
The AUC, Cmax and Clast, of TFV were decreased in the second and third trimester compared to first trimester or post-partum. In none of the manuscripts was the non-pregnant HBV threshold of Cmax of 300 ng/ml reached, but the EC50 of TFV is lower for treatment of HBV compared to HIV. The TFV concentration in breastfed infants was 0.03% of the recommended infant dose.
Conclusions:
Most knowledge of pharmacokinetic of TFV in pregnancy results from studies on HIV involving multiple antiretrovirals. Increased TFV clearance occurred in the second and third trimester when optimal TFV concentrations are required to maximize suppression of HBV in the window before birth. Dose or duration adjustments will be better conceptualized with concurrent analysis of the PK of TFV monotherapy and Hepatitis B pharmacodynamics in pregnancy.
![TFVmean concentration in pregnant (n=37) and non-pregnant (n=97) women with TDF pre-exposure prophylaxis [30]](https://www.researchgate.net/profile/Marieke-Bierhoff/publication/338132390/figure/fig3/AS:11431281208581423@1701428245467/TFVmean-concentration-in-pregnant-n37-and-non-pregnant-n97-women-with-TDF_Q320.jpg)
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... The concentration of albumin in human plasma typically ranges from 35 to 50 mg/mL [8], while the maximum plasma concentration of TFV, TDF, and TAF is about 27.9, 300, and 104 ng/mL, respectively [41,42]. In other words, in in vivo conditions, the albumin concen-tration is around 100,000-fold higher than the concentration of the antiretrovirals. ...
Tenofovir (TFV) is the active form of the prodrugs tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), both clinically prescribed as HIV reverse transcriptase inhibitors. The biophysical interactions between these compounds and human serum albumin (HSA), the primary carrier of exogenous compounds in the human bloodstream, have not yet been thoroughly characterized. Thus, the present study reports the interaction profile between HSA and TFV, TDF, and TAF via UV–Vis, steady-state, and time-resolved fluorescence techniques combined with isothermal titration calorimetry (ITC) and in silico calculations. A spontaneous interaction in the ground state, which does not perturb the microenvironment close to the Trp-214 residue, is classified as weak. In the case of HSA/TFV and HSA/TDF, the binding is both enthalpically and entropically driven, while for HSA/TAF, the binding is only entropically dominated. The binding constant (Ka) and thermodynamic parameters obtained via ITC assays agree with those obtained using steady-state fluorescence quenching measurements, reinforcing the reliability of the data. The small internal cavity known as site I is probably the main binding pocket for TFV due to the low steric volume of the drug. In contrast, most external sites (II and III) can better accommodate TAF due to the high steric volume of this prodrug. The cross-docking approach corroborated experimental drug-displacement assays, indicating that the binding affinity of TFV and TAF might be impacted by the presence of different compounds bound to albumin. Overall, the weak binding capacity of albumin to TFV, TDF, and TAF is one of the main factors for the low residence time of these antiretrovirals in the human bloodstream; however, positive cooperativity for TAF and TDF was detected in the presence of some drugs, which might improve their residence time (pharmacokinetic profile).
... Although power was limited in sub-group analyses, the difference between the performance of the POC TFV LFA and self-reported adherence appeared more pronounced in the sample of pregnant females in this study. Pregnant women showed higher levels of non-adherence compared to non-pregnant women and men which is consistent with the literature [23], and ART metabolism may differ during pregnancy [24,25]. Research is needed to determine whether the threshold used in the POC TFV LFA of 1500 ng is the optimal threshold for TFV detection in urine during pregnancy. ...
Background
Point‐of‐care (POC) lateral flow assays (LFA) to detect tenofovir (TFV) in urine have been developed to measure short‐term ART adherence. Limited data exist from people living with HIV in routine care.
Methods
Adults on TFV‐containing regimens, having a routine viral load (VL) at an HIV clinic in Cape Town, South Africa were enrolled in a cross‐sectional study. Patients recalled missed ART doses in the past three and 7 days and urine was tested using a POC TFV LFA. VL on the day was abstracted from medical records.
Results
Among 314 participants, 293 (93%) had VL <1000 copies/mL, 20 (6%) had no TFV detected and 24 (8%) reported ≥1 missed dose in the past 3 days. Agreement between VL ≥1000 and undetectable TFV was higher compared to 3‐day recall of ≥1 missed dose (Kappa 0.504 vs. 0.163, p = 0.015). The AUC to detect VL ≥1000 was 0.747 (95% CI 0.637–0.856) for undetectable TFV. This was statistically significantly better than for 7‐day recall (0.571 95% CI 0.476–0.666, p = 0.040) but not for 3‐day recall (0.587 95% CI 0.492–0.681, p = 0.071) of ≥1 missed dose.
Conclusion
In this largely virally suppressed cohort, TFV in urine had better agreement with VL than self‐reported adherence and was a better predictor of viraemia on two of three self‐report measures. Used in combination with VL, the POC urine TFV LFA could flag patients with viraemia in the presence of ART. Further research is needed to understand the potential application in different populations on ART, including pregnant women.
... 4,5 Previous pharmacokinetic studies on breastfeeding women using TDF have demonstrated that the concentration of tenofovir transmitted through breastmilk is low. 6 However, no evidence is available on TAF pharmacokinetics in breast milk and mother-to-infant transmission of chronic hepatitis B. For mothers with chronic hepatitis B and undergoing antiviral treatment, breastfeeding is still a controversial topic. According to clinical practice guidelines in the United States and Europe, breastfeeding should not be considered a contraindication because antivirals are minimally excreted in breast milk and are unlikely to cause substantial toxicity. ...
LINKED CONTENT
This article is linked to Kayes et al papers. To view these articles, visit https://doi.org/10.1111/apt.17040
... Confirming this estimate, the median steady state urine TFV concentration in the babies from breastfeeding mothers on TAF was 5 ng/ml. 2 Similar data have been provided for TDF. 3 The results from both studies confirm what we would predict from our understanding of chemistry. TDF and TAF are pro-drugs designed to counter the poor bioavailability of the parent drug TFV. ...
LINKED CONTENT
This article is linked to Kayes et al papers. To view these articles, visit https://doi.org/10.1111/apt.17040
... 2 Exposure to clinically significant doses of TDF or its active moiety, tenofovir (TFV) via breast milk is thought to be low based on pharmacokinetic studies of women who took TDF while breastfeeding with median breast milk/maternal plasma ratios between 0.03 and 0.07 and median ingested TFV in infants being 0.03% of the recommended infant dose. 9 TDF is rapidly converted to tenofovir which is expressed in breast milk at low concentrations (<3% serum levels). Any TFV consumed via breast milk will have very low bioavailability in the foetus due to its charged anionic state. ...
Background
Antenatal antiviral therapy (AVT) is effective in preventing mother‐to‐child transmission in chronic hepatitis B (CHB) and tenofovir disoproxil fumarate (TDF) is the preferred agent. Tenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) similar to TDF, with improved bone and renal safety. There is no data on TAF breast milk pharmacokinetics and exposure to breastfeeding infants in CHB.
Aim
To assess the pharmacokinetics of TAF/TFV in breastfeeding women with CHB on TAF monotherapy.
Methods
Pregnant women with CHB requiring AVT commenced TAF 25 mg daily at third trimester or postpartum. Sample collection occurred while breastfeeding and taking TAF for minimum 4 weeks. Maternal blood, breast milk and infant urine samples were collected. Drug concentrations were measured by LCMS/MS analyses using validated methods. Non‐compartmental analyses were performed to quantify the pharmacokinetic parameters.
Results
Eight women provided samples. In breast milk and plasma, median TAF half‐life was 0.81 and 0.94 h, respectively, and Cmax 1.69 and 120.5 ng/ml, respectively. Median maternal breast milk to plasma (M/P) ratio of TAF was 0.029 and TFV was 2.809. The relative infant dose of TAF was 0.005% of maternal dose, well below safety threshold of 5%–10%. TFV was detectable in three out of seven infant urine samples with median steady‐state concentration of 5 ng/ml being 300–2500 times less than reported adult steady‐state urine concentrations in those taking TAF and TDF, respectively.
Conclusions
In this first pharmacokinetic study of TAF monotherapy in breastfeeding women with CHB, concentrations of TAF and TFV were low in breastmilk with negligible infant exposure, supporting the use of TAF to prevent MTCT.
... Further, women continuing PrEP during pregnancy had reductions in plasma tenofovir concentrations (58%) and TFV-DP concentrations in DBS (27%) [9]. Similarly, plasma tenofovir area-under-the-concentration-time-curves (AUC) were approximately 20% lower during pregnancy compared to nonpregnant women in the context of Downloaded from https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1872/6042339 by guest on 26 December 2020 A c c e p t e d M a n u s c r i p t 5 treatment for HIV [21] and hepatitis B [22], likely due to increased renal clearance [23]. To account for physiological changes which may influence drug concentrations, tailored TFV-DP in DBS adherence benchmarks are needed in pregnant and postpartum women. ...
Background
Intracellular tenofovir diphosphate (TFV-DP) concentration measured in dried blood spots (DBS) is used to monitor cumulative adherence to pre-exposure prophylaxis (PrEP). We evaluated TFV-DP in DBS following daily oral PrEP (emtricitabine 200mg/tenofovir diphosphate 300mg) among pregnant and postpartum adolescent girls and young women (AGYW).
Methods
Directly observed PrEP was administered for 12 weeks in a pregnancy group (14-24 weeks gestation, n=20) and a postpartum group (6-12 weeks postpartum, n=20) of AGYW aged 16-24 years in sub-Saharan Africa. Weekly DBS TFV-DP was measured by validated liquid chromatography-tandem mass spectrometry assay. Week 12 TFV-DP distributions were compared between groups with the Wilcoxon test. Population pharmacokinetic models were fit to estimate steady-state concentrations and create benchmarks for adherence categories. Baseline correlates of TFV-DP were evaluated.
Results
Participant median age was 20 years (IQR:19,22). Of 3360 doses, 3352 (>99%) were directly observed. TFV-DP median half-life was ten days (IQR:7, 12) in pregnancy and 17 days (IQR:14, 21) postpartum, with steady-state achieved by five and eight weeks, respectively. Observed median steady-state TFV-DP was 965 fmol/punch (IQR:691, 1166) in pregnancy vs 1406 fmol/punch (IQR:1053, 1859) postpartum (p=0.006). Modelled median steady-state TFV-DP was 881 fmol/punch (IQR: 667,1105) in pregnancy vs 1438 fmol/punch (IQR: 1178,1919) postpartum. In pooled analysis, baseline creatinine clearance was associated with observed TFV-DP concentrations.
Conclusion
TFV-DP in African AGYW was approximately one-third lower in pregnancy than postpartum. Population-specific benchmarks provided by this study can be used to guide PrEP adherence support in pregnant/postpartum African women.
Introduction:
The HIV/AIDS epidemic has been one of the greatest challenges in global health, significantly affecting women of reproductive potential. Considerable advances in antiretroviral therapy for women living with HIV have contributed to improvements in quality of life, better reproductive and birth outcomes, and a reduced risk of perinatal transmission.
Areas covered:
Despite the progress made, persistent challenges in access and adherence to antiretroviral drugs may limit their benefits for some women. More pharmacokinetic and safety studies in pregnant and lactating women are urgently needed, as are prospective surveillance systems to evaluate associations between fetal and infant antiretroviral exposures, drug-drug interactions, and pregnancy outcomes.
Expert opinion:
Multipurpose technologies, such as combined HIV and other STI or unintended pregnancy prevention, and innovative delivery methods, such as the development of long-acting antiretrovirals, have the potential to reduce adherence challenges and enhance quality of life for women with HIV. Parallel advances in drug safety testing and surveillance are needed to ensure the health and safety of women with or at risk for HIV and children at risk for perinatal transmission.
Determining the appropriate dosing regimens of antiretroviral (ARV) drugs for pregnant individuals living with HIV-1 infection is critical to maximize maternal health and prevent perinatal HIV transmission. Throughout pregnancy, pharmacokinetics (PK) of ARVs can be significantly altered due to physiological, anatomic, and metabolic changes. As such, conducting PK studies of ARVs during pregnancy is crucial to optimize dosing regimens. In this article, we summarize available data, key issues, challenges, and considerations in interpreting results of ARV PK studies in pregnant individuals. Discussion topics include the choice of the reference population (postpartum vs historical control), pregnancy trimester-dependent changes in ARV PK, effects of pregnancy on once- versus twice-daily dosing, factors to consider for ARVs that are administered with a PK booster such as ritonavir and cobicistat, and considerations when evaluating the effects of pregnancy on unbound ARV concentrations. Common approaches for the translation of the results into clinical recommendations and rationales and considerations when making clinical recommendations are summarized. Currently, limited PK data in pregnancy are available with long-acting ARVs. Collection of PK data to characterize the PK profile of long-acting ARVs is an important goal shared by many stakeholders.
Introduction:
Mother-to-child transmission (MTCT) is mainly responsible for the global pediatric HIV and HBV epidemic. Vertical transmission can be prevented and reduced through a series of interventions at the primary healthcare level, including extensive screening of pregnant women, administration of antivirals or immune-based treatments, counselling on type of delivery and breastfeeding.
Areas covered:
In this narrative review, approved therapeutic options for the treatment of pregnant women living with HIV or HBV are discussed with special focus on efficacy and safety profiles of each agent or drug class examined. The search was performed using Medline (via PubMed), Web of Science, and Google Scholar to identify studies assessing vertical transmission of both HIV and HBV.
Expert opinion:
Elimination of MTCT of both infections is firmly endorsed by major global commitments and the integration of tailored preventive interventions into maternal and newborn health services is of strategical importance to achieve this critical target. However, further research centered on antiviral-based and immunization trials among pregnant women is urgently needed to mitigate the risk of maternal and neonatal adverse outcomes, effectively prevent transmission to the offspring and finally eliminate the pediatric HIV and HBV epidemic, one of the key global health challenges of our time.
Objective:
We evaluated peripartum tenofovir (TFV) exposure via hair measures among women living with HIV (WLHIV) in the United States.
Design:
Observational cohort study METHODS:: Hair samples were collected at or shortly after childbirth among mothers enrolled in the Surveillance Monitoring for ART Toxicities Study of the Pediatric HIV/AIDS Cohort Study (PHACS) between 6/2014-7/2016. Among mothers receiving tenofovir-disoproxil-fumarate (TDF)-based regimens during pregnancy, TFV hair concentrations were analyzed using liquid chromatography/tandem mass spectrometry. Weight-normalized TFV concentrations were log10 transformed. Multivariable linear regression assessed correlates of TFV concentrations.
Results:
Overall, 121 mothers on TDF-based ART during pregnancy had hair specimens tested for TFV concentrations and were included in the analysis. Median age at delivery was 31 years (IQR 26-36); 71% self-identified as non-Hispanic black, and 10% had unsuppressed viral loads (VL) in late pregnancy (HIV-RNA ≥400 copies/mL). Median time from birth to hair collection was 3 days (IQR 1-14) and median TFV hair concentration was 0.02 ng/mg (IQR 0.01-0.04). In multivariable models, an unsuppressed VL in late pregnancy was associated with 80% lower adjusted mean peripartum TFV concentrations than pregnancies with viral suppression (95% CI: -90% to -59%, p < 0.001). Use of TDF only in the first trimester and attaining high school graduation were also associated with lower TFV hair concentrations.
Conclusions:
Unsuppressed VL during late pregnancy was strongly associated with lower maternal TFV hair concentrations at birth, though viremia was rare. Efforts to improve maternal virological outcomes and eliminate vertical HIV transmission could incorporate drug exposure monitoring using hair or other metrics.
Objectives:
Hepatitis B virus (HBV) was believed to have minimal impact on pregnancy outcomes apart from the risk of perinatal transmission. In more recent years, there have been reports of adverse associations, most consistently preterm birth (PTB), but this is in the context of high rates of caesarean section. The aim of this study was to explore the association of HBV on pregnancy outcomes in marginalized, low-income populations on the Myanmar-Thailand border.
Methods:
HBsAg positive (+) point of care rapid detection tests results were confirmed by immunoassays. Women with a confirmed HBsAg status, HIV- and syphilis-negative at first antenatal care screening, singleton fetus and known pregnancy outcome (Aug-2012 to Dec-2016) were included. Logistic regression analysis was used to evaluate associations between HBV group (controls HBsAg negative, HBsAg+/HBeAg-, or HBsAg+/HBeAg+) and pregnancy outcome and comorbidity.
Results:
Most women were tested, 15,046/15,114 (99.6%) for HBV. The inclusion criteria were not met for 4,089/15,046 (27.2%) women due mainly to unavailability of pregnancy outcome and nonconfirmation of HBsAg+. In evaluable women 687/11,025 (6.2%) were HBsAg+, with 476/11,025 (4.3%) HBsAg+/HBeAg- and 211/11,025 (1.9%) were HBsAg+/HBeAg+. The caesarean section rate was low at 522/8,963 (5.8%). No significant associations were observed between pregnancy comorbidities or adverse pregnancy outcomes and HBV status.
Conclusions:
The results highlight the disease burden of HBV in women on the Myanmar-Thailand border and support original reports of a lack of significant associations with HBsAg+ irrespective of HBeAg status, for comorbidity, and pregnancy outcomes in deliveries supervised by skilled birth attendants.
Mother-to-child transmission is the major cause of chronic hepatitis B virus (HBV) infection. This double-blind trial tested the effect of tenofovir disoproxil fumarate (TDF) in preventing vertical transmission. Pregnant women who were HBsAg/HBeAg-positive with a HBV DNA titer ≥ 2×10⁶ IU/mL were randomly assigned to the control (n = 60) and TDF-treated (n = 60) groups. TDF treatment (oral dose 300 mg/day) was initiated at 24 weeks of gestation and continued to 4 weeks after delivery. The subjects were followed up to 28 weeks postpartum. The effects of TDF on vertical transmission, outcomes of the mothers and infants and virological changes were monitored. TDF dynamically reduced the serum HBV DNA level of the mothers, particularly during the first 4 weeks of treatment. The lower viral loads were maintained in the pregnancies until delivery. Approximately 90% and 33.9% of the TDF-treated mothers had viral loads ≤2000 IU/mL after delivery and at 28 weeks postpartum, respectively. No cervical transmission or adverse effects were observed in the TDF-treated individuals, whereas 13.5% of the infants were infected with HBV in the control group. We conclude that TDF treatment initiated at 24 weeks of gestation in high-viremia, HBsAg/HBeAg-positive mothers efficiently prevents mother-to-child HBV transmission without adverse events in mothers and infants.
Objectives:
The aim of this study was to assess the relationship between maternal viral load and mother-to-child transmission (MTCT) risk in HBeAg-positive mothers.
Methods:
PubMed and Web of Science were systematically searched. We compared MTCT incidence between maternal hepatitis B virus (HBV) DNA positive and negative group. We also examined the dose-response effect of this relationship.
Results:
21 studies with 10,142 mother-child pairs included in the studies. The mean MTCT incidence was 13.1% in maternal HBV DNA positive group, compared with 4.2% in negative group. The summary MTCT odds ratio (OR) of maternal HBV DNA positive compared with negative was 9.895 (95% CI 5.333 to 18.359; Z=7.27, P<0.00001) by random-effects model. In maternal HBV DNA <6 log10copies/ml, 6-8 log10copies/ml, >8 log10copies/ml level stratifications, the pooled MTCT incidences were 2.754% (95% CI 1.198% to 4.310%; Z=3.47, P=0.001), 9.932% (95% CI 6.349% to 13.516%; Z=5.43, P<0.00001), and 14.445% (95% CI 8.317% to 20.572%; Z=4.62, P<0.00001), respectively. A significant linear dose-response association was found between maternal viral load and MTCT risk, with the points estimate of increased MTCT risk 2.705 (95% CI: 1.808-4.047) at 6 log10copies/ml compared with reference (3 log10copies/ml), and 7.316 (95% CI: 3.268-16.378) at 9 log10copies/ml. A significant nonlinear dose-response association was also found between maternal viral load and HBV MTCT risk (model χ2=23.43, P<0.00001).
Conclusion:
Our meta-analysis indicated that maternal viral load was an important risk factor for MTCT in HBeAg-positive mothers, and maternal viral load was dose-dependent with HBV MTCT incidence.
Purpose:
To critically review pregnancy-induced pharmacokinetic changes and their clinical application.
Methods:
Structured review of Pubmed, MBASE and published books.
Results:
For many drugs, advanced pregnancy is associated with lower maternal serum concentrations. As most drug concentrations are not measured routinely, such changes are not evident to the clinician. Moreover, even for drug concentrations measured clinically, one cannot interpret lower total drug levels as evidence of lower fraction of free drug, which is the pharmacologically- active component, due to lower protein binding of many drugs in late pregnancy. Higher fractions of free drug will lead to higher rate of hepatic metabolism, especially for high extraction medications, leading to lower total drug concentrations.. Pregnancy- induced larger volume of distribution will lead to lower peak of drugs and hence may impact the achievement therapeutic levels. To further complicate matters, the adherence of many women decreases during pregnancy, mostly due to fears of adverse fetal effects. These dynamic and complex processes make changes in recommendations for dose schedule very challenging and in many cases not practical.
Conclusions:
Indeed, there are presently no pregnancy- targeted dose schedules, similar to existing dose changes, for example, in renal failure. Similar to the recent increased attention given to pharmacokinetic changes in pregnancy, well designed studies should compare dose-effect relationships in women receiving medications in different stages of pregnancy, to women receiving the same drug before, and/or after pregnancy. Whenever possible, women with chronic conditions can serve as their own controls and decrease the uncertainty created by inter- patient variability. Measuring drug effects in parallel to drug concentrations, will allow pharmacokinetic- pharmacodynamic modelling, leading to evidence-based decisions regarding changes in dose schedules during gestation.
Background:
Breast milk transfer of first-line ART from mother to infant is not fully understood.
Objectives:
To determine the concentrations of lamivudine, emtricitabine and tenofovir in maternal blood, breast milk and infant blood from breastfeeding mother-infant pairs.
Methods:
Intensive pharmacokinetic sampling of maternal dried blood spots (DBS), dried breast milk spots (DBMS) and infant DBS from 30 Ugandan and 29 Nigerian mothers receiving first-line ART and their infants was conducted. DBS and DBMS were collected pre-dose and at 5-6 timepoints up to 12 h following observed dosing. Infant DBS were sampled twice during this period. Lamivudine, emtricitabine and tenofovir were quantified using LC-MS/MS, with non-compartmental analysis to calculate key pharmacokinetic parameters.
Results:
Peak concentrations in breast milk from women taking lamivudine and emtricitabine occurred later than in plasma (4-8 h compared with 2 h for lamivudine and 2-4 h for emtricitabine). Consequently, the milk-to-plasma (M:P) ratio of lamivudine taken once daily was 0.95 (0.82-1.15) for AUC0-12, whereas for AUC12-20 this was 3.04 (2.87-4.16). Lamivudine was detectable in 36% (14/39) of infants [median 17.7 (16.3-22.7) ng/mL]. For 200 mg of emtricitabine once daily, the median M:P ratio was 3.01 (2.06-3.38). Three infants (19%) had measurable emtricitabine [median 18.5 (17.6-20.8) ng/mL]. For 300 mg of tenofovir once daily, the median M:P ratio was 0.015 (0-0.03) and no infant had measurable tenofovir concentrations.
Conclusions:
Emtricitabine and lamivudine accumulate in breast milk and were detected in breastfeeding infants. In contrast, tenofovir penetrates the breast milk to a small degree, but is undetectable in breastfeeding infants.
We assessed tenofovir exposure during pregnancy and postpartum in hepatitis B virus (HBV)-infected, HIV-uninfected, women receiving tenofovir disoproxil fumarate (TDF) to prevent mother-to-child transmission of HBV. Data from 154 women who received TDF within a randomized-controlled trial were included. Individual plasma tenofovir exposures (AUC0-24) were estimated using a population pharmacokinetic approach. Estimated geometric mean tenofovir AUC0-24 was 20% (95% CI: 19-21%) lower during pregnancy compared to postpartum; this modest reduction in the absence of HBV transmission suggests no dose adjustment is needed.
Objectives:
Pregnancy is a time of increased HIV acquisition risk and pregnancy reduces concentrations of antiretrovirals used for treatment. We assessed whether pregnancy lowers concentrations of tenofovir (TFV) and tenofovir-diphosphate (TFV-DP) among HIV-uninfected women using oral pre-exposure prophylaxis (PrEP).
Methods:
We analyzed data from an open-label PrEP study, comparing concentrations of TFV in plasma and TFV-DP in dried blood spots (DBS) among 37 pregnant women and 97 non-pregnant women. Analyses controlled for adherence from daily electronic monitoring.
Results:
The average plasma concentration of TFV among pregnant women was 34.7 ng/mL with 22.2 average recorded doses over the prior month versus 86.5 ng/mL with 23.1 doses among non-pregnant women. After controlling for adherence, TFV concentrations were 58% lower among pregnant women, a statistically significant difference of -50.4 ng/mL (95%CI -68.3 to -32.5). The average TFV-DP concentration was 450.3 fmol/punch among pregnant women and 636.7 fmol/punch among non-pregnant women. This difference was not statistically significant after adjusting for adherence; however, among those with quantifiable TFV-DP, concentrations were 27% lower during pregnancy (-202 fmol/punch [95%CI -384 to -19]). Among participants with samples before and during pregnancy, there were significant decreases during pregnancy, controlling for adherence: -28.1 ng/mL TFV (95%CI -52.3 to -4.0) and -289.2 fmol/punch TFV-DP (95%CI -439.0 to -139.3).
Conclusions:
Consistent with studies among HIV-infected women on ART, we found TFV and TFV-DP concentrations were lower during pregnancy. There is no established TFV concentration threshold to achieve HIV prevention. Additional pharmacokinetic studies and studies of PrEP efficacy in pregnancy are needed.
Background:
The nucleotide reverse transcriptase inhibitor tenofovir (TFV) is widely administered in a disoproxil prodrug form (tenofovir disoproxil fumarate, TDF) for HIV management and prevention. Recently, novel prodrugs tenofovir alafenamide fumarate (TAF) and hexadecyloxypropyl tenofovir (CMX157) have been pursued for HIV treatment while minimizing adverse effects associated with systemic TFV exposure. Dynamic and sensitive bioanalytical tools are required to characterize the pharmacokinetics of these prodrugs in systemic circulation. Two parallel methods have been developed, one to combinatorially quantify TAF and TFV, and a second method for CMX157 quantification, in plasma.
Methods:
K2EDTA plasma was spiked with TAF and TFV, or CMX157. Following the addition of isotopically labeled internal standards and sample extraction via solid phase extraction (TAF and TFV) or protein precipitation (CMX157), samples were subjected to liquid chromatographic-tandem mass spectrometric (LC-MS/MS) analysis. For TAF and TFV, separation occurred using a Zorbax Eclipse Plus C18 Narrow Bore RR, 2.1 × 50 mm, 3.5 μm column and analytes were detected on an API5000 mass analyzer; CMX157 was separated using a Kinetex C8, 2.1 × 50 mm, 2.6 μm column and quantified using an API4500 mass spectrometer. Methods were validated according to FDA Bioanalytical Method Validation guidelines.
Results:
Analytical methods: were optimized for the multiplexed monitoring of TAF and TFV, and CMX157 in plasma. The lower limits of quantification (LLOQs) for TAF, TFV, and CMX157 were 0.03, 1.0, and 0.25 ng/mL, respectively. Calibration curves were generated via weighted linear regression of standards. Intra- and inter-assay precision and accuracy studies demonstrated %CVs ≤ 14.4% and %DEVs ≤ ± 7.95%, respectively. Stability and matrix effects studies were also performed. All results were acceptable and in accordance with the recommended guidelines for bioanalytical methods. Assays were also applied to quantify in vivo concentrations of prodrugs and TFV in a preclinical study post-rectal administration.
Conclusions:
Sensitive, specific, and dynamic LC-MS/MS assays have been developed and validated for the multiplexed quantification TAF and TFV, as well as an independent assay for CMX157 quantification, in plasma. The described methods meet sufficient throughput criteria to support large research trials.
Background:
Entecavir (ETV) and tenofovir disoproxil fumarat (TDF) are the two first-line therapies recommended in the treatment of chronic hepatitis B because of having potent antiviral effect and high genetic barriers against resistance. We aimed to compare efficacy of these drugs and to evaluate predictors of viral suppression.
Methods:
This multicenter retrospective study was conducted in nucleos(t)ide analogue-naive chronic hepatitis B (CHB) patients from different 6 centers.
Results:
Of the 252 patients, 166 received ETV and 86 TDF. The two groups were similar in terms of age, gender, baseline ALT levels and fibrosis scores. ETV had significantly higher baseline HBV DNA, histological activity index and lower hepatitis B early antigen (HBeAg) seropositivity. Treatment duration was longer in ETV group (P<0.001). In univariate analysis, undetectable HBV DNA and ALT normalization rates were detected significantly higher in ETV groups (P<0.001 and 0.049, respectively). There was no significant difference between groups in terms of HBeAg seroconversion, virological breakthrough, time to virological breakthrough and time to ALT normalization. Entecavir was more effective in reducing HBV DNA levels at the 3rd, 6th and 12th months of the treatment (P=0.06, 0.021 and 0.012, respectively). However, multivariate Cox regression analysis indicated that TDF therapy compared to ETV had an increased probability of achieving complete viral suppression (HR=1, 66; 95% CI 1.21-2.33; P=0.010). Hepatitis B surface antigen (HBsAg) seroconversion was occurred in only one patient in ETV group.
Conclusion:
ETV leads to an early response on HBV DNA decline in the first year of the treatment. However, TDF is more successful than entecavir in achieving virological suppression.