Associations Between Tenofovir Diphosphate in Dried Blood Spots, Impaired Physical Function, and Fracture Risk.

BACKGROUND: In this study, we evaluate associations between cumulative antiretroviral adherence/exposure, quantified using tenofovir diphosphate (TFV-DP) in dried blood spots (DBS), and human immunodeficiency virus (HIV)-related aging factors. METHODS: This is a cross-sectional analysis of younger (ages 18-35) and older (ages ≥60) persons with HIV (PWH) taking TFV disoproxil fumarate. Tenofovir diphosphate concentrations were quantified in DBS. Linear and logistic regression models were used to evaluate associations between TFV-DP and bone mineral density (BMD), physical function, frailty, and falls. RESULTS: Forty-five PWH were enrolled (23 younger, 22 older). Every 500 fmol/punch (equivalent to an increase in ~2 doses/week) increase in TFV-DP was associated with decreased hip BMD (-0.021 g/cm2; 95% confidence interval [CI], -0.040 to -0.002; P = .03). Adjusting for total fat mass, every 500 fmol/punch increase in TFV-DP was associated with higher odds of Short Physical Performance Battery impairment (score ≤10; adjusted odds ratio [OR], 1.6; 95% CI, 1.0-2.5; P = .04). Every 500 fmol/punch increase in TFV-DP was associated with slower 400-meter walk time (14.8 seconds; 95% CI, 3.8-25.8; P = .01) and remained significant after adjusting for age, lean body mass, body mass index (BMI), and fat mass (all P ≤ .01). Every 500 fmol/punch increase in TFV-DP was associated with higher odds of reporting a fall in the prior 6 months (OR, 1.8; 95% CI, 1.1-2.8; P = .02); this remained significant after adjusting for age, lean body mass, BMI, and total fat mass (all P < .05). CONCLUSIONS: Higher TFV-DP levels were associated with lower hip BMD, poorer physical function, and greater risk for falls, a concerning combination for increased fracture risk.

Among older adults, age-related changes in the stool microbiome differ by HIV-1 serostatus.

BACKGROUND: HIV-1 infection and physiological aging are independently linked to elevated systemic inflammation and changes in enteric microbial communities (dysbiosis). However, knowledge of the direct effect of HIV infection on the aging microbiome and potential links to systemic inflammation is lacking. METHODS: In a cross-sectional study of older people living with HIV (PLWH) (median age 61.5 years, N = 14) and uninfected controls (median 58 years, n = 22) we compared stool microbiota, levels of microbial metabolites (short-chain fatty acid levels, SCFA) and systemic inflammatory biomarkers by HIV serostatus and age. FINDINGS: HIV and age were independently associated with distinct changes in the stool microbiome. For example, abundances of Enterobacter and Paraprevotella were higher and Eggerthella and Roseburia lower among PLWH compared to uninfected controls. Age-related microbiome changes also differed by HIV serostatus. Some bacteria with inflammatory potential (e.g. Escherichia) increased with age among PLWH, but not controls. Stool SCFA levels were similar between the two groups yet patterns of associations between individual microbial taxa and SCFA levels differed. Abundance of various genera including Escherichia and Bifidobacterium positively associated with inflammatory biomarkers (e.g. soluble Tumor Necrosis Factor Receptors) among PLWH, but not among controls. INTERPRETATION: The age effect on the gut microbiome and associations between microbiota and microbial metabolites or systemic inflammation differed based on HIV serostatus, raising important implications for the impact of therapeutic interventions, dependent on HIV serostatus or age.

Similar tenofovir hair concentrations in men and women after directly observed dosing of tenofovir disoproxil fumarate/emtricitabine: implications for preexposure prophylaxis adherence monitoring.

OBJECTIVES: Women likely require higher adherence than men to preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) for similar efficacy. Pharmacologic metrics of adherence predict efficacy better than self-report, but expected drug levels (adherence benchmarks) must be established using directly observed therapy. We sought to evaluate whether tenofovir hair concentrations differ between women and men receiving directly observed TDF/FTC. METHODS: We assessed tenofovir hair concentrations in HIV-uninfected volunteers randomized to receive 100%, 67%, or 33% of daily dosing of TDF/FTC for 12 weeks (DOT-DBS, NCT02022657). Hair samples were collected at dosing weeks 4, 8, and 12 and every 3 weeks during a 12-week washout. Tenofovir concentrations in the proximal 1.5 cm of hair (representing ∼6 weeks of exposure) were analyzed using liquid chromatography/tandem mass spectrometry. Linear regression was used to model tenofovir hair concentrations in terms of sex, doses over the prior 6 weeks, and number of days since last dose. RESULTS: A total of 264 hair samples were analyzed from 23 female and 24 male participants. Female participants had similar tenofovir hair concentrations to men (estimated fold-difference 0.92, 95% CI 0.75-1.13, P = 0.43). The estimated fold-difference in tenofovir levels for female versus male participants did not appreciably change when age (0.93, 95% CI 0.76-1.15), weight (0.89, 95% CI 0.71-1.11), or race/ethnicity (0.95, 95% CI 0.77-1.17) were added to the model. CONCLUSION: Women and men have similar adherence benchmarks for tenofovir in hair samples. As pharmacokinetic metrics are increasingly used for PrEP monitoring, these findings provide guidance for assessing adherence via hair concentrations.

Effects of sofosbuvir-based hepatitis C treatment on the pharmacokinetics of tenofovir in HIV/HCV-coinfected individuals receiving tenofovir disoproxil fumarate.

Background: The nucleotide analogues tenofovir and sofosbuvir are considered to have low potential for drug interactions. Objectives: To determine the effect of sofosbuvir-based HCV treatment on plasma concentrations of tenofovir and cellular concentrations of tenofovir diphosphate. Methods: HIV-infected participants with acute HCV were treated for 12 weeks with sofosbuvir + ribavirin in Cohort 1 or 8 weeks with ledipasvir/sofosbuvir in Cohort 2 of AIDS Clinical Trials Group study 5327. Only participants taking tenofovir disoproxil fumarate were included in this analysis. Tenofovir in plasma, tenofovir diphosphate in dried blood spots and tenofovir diphosphate in PBMCs were measured pre-HCV therapy and longitudinally during the study using validated LC/MS-MS. Results: Fifteen and 22 men completed Cohorts 1 and 2, respectively. In Cohort 1, tenofovir diphosphate was 4.3-fold higher (95% CI geometric mean ratio 2.46-7.67; P = 0.0001) in dried blood spots and 2.3-fold higher (95% CI 1.09-4.92; P = 0.03) in PBMCs following 12 weeks of sofosbuvir + ribavirin versus study entry. Tenofovir in the plasma was unchanged. In Cohort 2, tenofovir diphosphate was 17.8-fold higher (95% CI 12.77-24.86; P < 0.0001) in dried blood spots after 8 weeks of ledipasvir/sofosbuvir versus study entry. Tenofovir plasma concentrations were 2.1-fold higher (95% CI 1.44-2.91; P = 0.0005). Despite the increase in cellular tenofovir diphosphate concentrations, only a small decline in CLCR (6%-7%) was observed in both cohorts between study entry and end of treatment. Conclusions: These data indicate an unexpected drug interaction with tenofovir disoproxil fumarate and sofosbuvir at the cellular level. Additional studies are needed to determine the mechanism and clinical significance.

Brief Report: Adherence Biomarker Measurements in Older and Younger HIV-Infected Adults Receiving Tenofovir-Based Therapy.

BACKGROUND: Concentrations of tenofovir (TFV) in hair and tenofovir diphosphate (TFV-DP) in dried blood spots (DBSs) as measures of cumulative exposure have been primarily studied in younger, HIV-uninfected individuals taking preexposure HIV prophylaxis. Data on these measures among older HIV-infected individuals are limited. METHODS: We evaluated longitudinal TFV and TFV-DP concentrations in hair and DBS, respectively, from HIV-infected adults. Multivariable model variables included age group (18-35 and 60 years and older), creatinine clearance (CrCl), hematocrit (TFV-DP), and gray hair color (TFV). RESULTS: Baseline hair TFV and DBS TFV-DP were moderately correlated [r = 0.5 (0.2 to 0.7); P = 0.001] across both age groups [younger (N = 23) and older (N = 22)]. In adjusted models, CrCl was associated with increases of 15.9% (7.4% to 25.0%); P = 0.0006, and 5.7% (-0.2% to 11.9%); P = 0.057 for TFV in hair and TFV-DP in DBS, respectively, for every 20-mL/min CrCl decrease. Although older age (versus younger age) was univariately associated with increased TFV hair levels, older age was not significantly associated with higher concentrations in hair [-1.4% (-26.7% to 32.7%); P = 0.93] or DBS [4.0% (-14.1% to 25.9%); P = 0.68] after adjustment. Similarly, gray color was not significantly associated with higher TFV levels in hair [27.6% (-11.1% to 83.0%; P = 0.18)] in adjusted models. In both adjusted and unadjusted models of TFV-DP levels in DBS, a 1% hematocrit increase was associated with a 3.3% (0.2% to 6.5%) TFV-DP increase (P = 0.04). CONCLUSIONS: Cumulative drug exposure measures (hair and DBS) were comparable in younger and older HIV-infected individuals on TFV-based therapy after adjustment for renal function.

Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy.

Studies of daily emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for HIV preexposure prophylaxis (PrEP) in men who have sex with men (MSM) modeled intracellular tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) to assess adherence and corresponding PrEP outcomes. We conducted a prospective, randomized, crossover pharmacokinetic study of TFV-DP in DBS during 33%, 67%, or 100% of daily dosing under directly observed therapy (DOT). Participants were assigned to two 12-week dosing regimens, separated by a 12-week washout. Forty-eight adults (25 women) from Denver and San Francisco were included. TFV-DP exhibited a median half-life of 17 days, reaching steady state in 8 weeks. TFV-DP was dose proportional with mean (SD) steady-state concentrations of 530 (159), 997 (267), and 1,605 (405) fmol/punch for the 33%, 67%, and 100% arms, respectively. Prior work in MSM demonstrated clinically meaningful TFV-DP thresholds of 350, 700, and 1,250 fmol/punch, which were estimated 25th percentiles for 2, 4, and 7 doses/week. In the present study, corresponding TFV-DP was within 3% of the prior estimates, and subgroups by site, race, and sex were within 14% of prior estimates, although males had 17.6% (95% confidence intervals [CIs], 6.5, 27.4%) lower TFV-DP than females. The thresholds of 350, 700, and 1,250 fmol/punch were achieved by 75% of men taking ≥1.2, 3.2, and 6 doses/week and 75% of women taking ≥0.6, 2.0, and 5.3 doses/week, indicating that lower dosing reached these thresholds for both sexes. In conclusion, TFV-DP arising from DOT was similar to previous estimates and is useful for interpreting PrEP adherence and study outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02022657.).

Inflammation and pharmacokinetics: potential implications for HIV-infection.

INTRODUCTION: The physiological changes accompanying inflammation may alter the pharmacokinetics (PK) of certain medications. Individuals infected with HIV have chronically elevated inflammatory markers despite viral suppression following effective antiretroviral therapy (ART), as well as age-related inflammation. Understanding the potential clinical implications of inflammation on the PK of medications is important for understanding dose-response relationships and necessitates future research. Areas covered: An extensive literature search was carried out using PubMed and associated bibliographies to summarize the current state of knowledge regarding altered PK in response to inflammation and its application to the field of HIV. Expert opinion: Preclinical and clinical studies show that inflammation leads to a downregulation of certain drug metabolizing enzymes and both up and down regulation of transporters depending on the transporter and cell type. Decreased gastric acidity, fluid shifts, and plasma protein alterations also occur with inflammation, leading to potential absorption, distribution, and clearance changes. More research is needed including controlled PK studies to address the clinical relevance of these observations, especially in the aging HIV-infected population. Results from future studies will enable us to better predict drug concentrations in individuals with inflammation, in line with efforts to provide personalized pharmacotherapy in our healthcare system.

Decline in Bone Mass With Tenofovir Disoproxil Fumarate/Emtricitabine Is Associated With Hormonal Changes in the Absence of Renal Impairment When Used by HIV-Uninfected Adolescent Boys and Young Men for HIV Preexposure Prophylaxis.

BACKGROUND: We aimed to define the relative importance of renal and endocrine changes in tenofovir disoproxil fumarate (TDF)-related bone toxicity. METHODS: In a study of daily TDF/emtricitabine (FTC) preexposure prophylaxis (PrEP) in human immunodeficiency virus (HIV)-uninfected young men who have sex with men, we measured changes from baseline in blood and urine markers of the parathyroid hormone (PTH)-vitamin D-fibroblast growth factor 23 (FGF23) axis, creatinine, and renal tubular reabsorption of phosphate (TRP). We explored the relationship of those variables to changes in bone mineral density (BMD). Tenofovir-diphosphate (TFV-DP) in red blood cells was used to categorize participants into high and low drug exposure groups. RESULTS: There were 101 participants, median age 20 years (range 15 to 22). Compared with low drug exposure, high-exposure participants showed increase from baseline in PTH and decline in FGF23 by study week 4, with no differences in creatinine, phosphate, or TRP. At 48 weeks, the median (interquartile range) percent decline in total hip BMD was greater in those with high- compared to low- exposure (-1.59 [2.77] vs +1.54 [3.34] %, respectively; P = .001); in high-exposure participants, this correlated with week 4 TFV-DP (inversely; r = -0.60, P = .002) and FGF23 (directly; r = 0.42; P = .039) but not other variables. CONCLUSIONS: These findings support the short-term renal safety of TDF/FTC PrEP in HIV-seronegative young men and suggest that endocrine disruption (PTH-FGF23) is a primary contributor to TDF-associated BMD decline in this age group. CLINICAL TRIALS REGISTRATION: NCT01769469.

Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates.

The coformulation of the nucleos(t)ide analogs (NA) tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC) is approved for HIV-infection treatment and prevention. Plasma TFV and FTC undergo complicated hybrid processes to form, accumulate, and retain as their active intracellular anabolites: TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP). Such complexities manifest in nonlinear intracellular pharmacokinetics (PK). In target cells, TFV-DP/FTC-TP compete with endogenous deoxynucleoside triphosphates (dNTP) at the active site of HIV reverse transcriptase, underscoring the importance of analog:dNTP ratios for antiviral efficacy. However, NA such as TFV and FTC have the potential to disturb the dNTP pool, which could augment or reduce their efficacies. We conducted a pharmacokinetics-pharmacodynamics (PKPD) study among forty subjects receiving daily TDF/FTC (300 mg/200 mg) from the first-dose to pharmacological intracellular steady-state (30 days). TFV/FTC in plasma, TFV-DP/FTC-TP and dNTPs in peripheral blood mononuclear cells (PBMC) were quantified using validated LC/MS/MS methodologies. Concentration-time data were analyzed using nonlinear mixed effects modeling (NONMEM). Formations and the accumulation of intracellular TFV-DP/FTC-TP was driven by plasma TFV/FTC, which was described by a hybrid of first-order formation and saturation. An indirect response link model described the interplay between TFV-DP/FTC-TP and the dNTP pool change. The EC50 (interindividual variability, (%CV)) of TFV-DP and FTC-TP on the inhibition of deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP) production were 1020 fmol/106 cells (130%) and 44.4 pmol/106 cells (82.5%), resulting in (90% prediction interval) 11% (0.45%, 53%) and 14% (2.6%, 35%) reductions. Model simulations of analog:dNTP molar ratios using IPERGAY dosing suggested that FTC significantly contributes to the protective effect of preexposure prophylaxis (PrEP). Simulation-based intracellular operational multiple dosing half-lives of TFV-DP and FTC-TP were 6.7 days and 33 hours. This model described the formation of intracellular TFV-DP/FTC-TP and the interaction with dNTPs, and can be used to simulate analog:dNTP time course for various dosing strategies.

Intracellular Tenofovir and Emtricitabine Anabolites in Genital, Rectal, and Blood Compartments from First Dose to Steady State.

The pharmacokinetics (PK) of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP), the active anabolites of tenofovir disoproxil fumarate (TDF), and emtricitabine (FTC) in blood, genital, and rectal compartments was determined in HIV-positive and seronegative adults who undertook a 60-day intensive PK study of daily TDF/FTC (plus efavirenz in HIV positives). Lymphocyte cell sorting, genital, and rectal sampling occurred once per subject, at staggered visits. Among 19 HIV-positive (3 female) and 21 seronegative (10 female) adults, TFV-DP in peripheral blood mononuclear cells (PBMC) accumulated 8.6-fold [95% confidence interval (CI): 7.2-10] from first-dose to steady-state concentration (Css) versus 1.7-fold (95% CI: 1.5-1.9) for FTC-TP. Css was reached in ∼11 and 3 days, respectively. Css values were similar between HIV-negative and HIV-positive individuals. Css TFV-DP in rectal mononuclear cells (1,450 fmol/106 cells, 898-2,340) was achieved in 5 days and was >10 times higher than PBMC (95 fmol/106 cells, 85-106), seminal cells (22 fmol/106 cells, 6-79), and cervical cells (111 fmol/106 cells, 64-194). FTC-TP Css was highest in PBMC (5.7 pmol/106 cells, 5.2-6.1) and cervical cells (7 pmol/106 cells, 2-19) versus rectal (0.8 pmol/106 cells, 0.6-1.1) and seminal cells (0.3 pmol/106 cells, 0.2-0.5). Genital drug concentrations on days 1-7 overlapped with estimated Css, but accumulation characteristics were based on limited data. TFV-DP and FTC-TP in cell sorted samples were highest and achieved most rapidly in CD14+ compared with CD4+, CD8+, and CD19+ cells. Together, these findings demonstrate cell-type and tissue-dependent cellular pharmacology, preferential accumulation of TFV-DP in rectal mononuclear cells, and rapid distribution into rectal and genital compartments.

Emtricitabine-Triphosphate in Dried Blood Spots as a Marker of Recent Dosing.

New objective measures of antiretroviral adherence are needed. We determined if emtricitabine triphosphate (FTC-TP) in dried blood spots (DBS) can be used as a marker of recent dosing with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC). The half-life of FTC-TP was estimated in DBS samples obtained from an intensive pharmacokinetic (PK) study of coformulated TDF-FTC in HIV-negative and HIV-infected participants. The concordance of quantifiable FTC-TP in DBS with tenofovir (TFV)/FTC in plasma was evaluated by utilizing paired plasma-DBS samples from participants enrolled in 2 large preexposure prophylaxis (PrEP) open-label trials. The time to FTC-TP nondetectability after TDF-FTC dosing was evaluated utilizing DBS from HIV-negative participants enrolled in a directly observed therapy study of variable adherence to TDF-FTC. The mean (95% confidence interval [CI]) terminal half-life of FTC-TP in the PK study was 35 (23 to 47) h. A total of 143/163 (88%) samples obtained 0 to 48 h post-TDF-FTC dose had quantifiable FTC-TP in DBS, compared with 2/93 (2%) and 0/87 (0%) obtained >48 and >96 h postdose. In 746 paired plasma-DBS samples from 445 participants enrolled in PrEP trials, when both TFV/FTC in plasma were below the limit of quantification, FTC-TP was as well in 98.9% of the samples, and when either TFV or FTC in plasma was quantifiable, FTC-TP was as well in 90.5% of the samples. The half-life of FTC-TP in DBS is short relative to that of TFV-diphosphate (TFV-DP), making it a surrogate for TFV-FTC detection in plasma. FTC-TP can be quantified in DBS simultaneously with TFV-DP, which quantifies cumulative adherence to TDF-FTC. (The clinical trials discussed in this article have been registered at ClinicalTrials.gov under identifiers NCT01040091, NCT02022657, NCT00458393, NCT01772823, and NCT02012621.).

Analysis of the Endogenous Deoxynucleoside Triphosphate Pool in HIV-Positive and -Negative Individuals Receiving Tenofovir-Emtricitabine.

Tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC), two nucleos(t)ide analogs (NA), are coformulated as an anti-HIV combination tablet for treatment and preexposure prophylaxis (PrEP). TDF/FTC may have effects on the deoxynucleoside triphosphate (dNTP) pool due to their similar structures and similar metabolic pathways. We carried out a comprehensive clinical study to characterize the effects of TDF/FTC on the endogenous dNTP pool, from baseline to 30 days of TDF/FTC therapy, in both treatment-naive HIV-positive and HIV-negative individuals. dATP, dCTP, dGTP, and TTP were quantified in peripheral blood mononuclear cells (PBMC) with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology. Forty individuals (19 HIV-positive) were enrolled and underwent a baseline visit and then received TDF/FTC for at least 30 days. Longitudinal measurements were analyzed using mixed-model segmented linear regression analysis. The dNTPs were reduced by 14% to 37% relative to the baseline level within 3 days in both HIV-negative and HIV-positive individuals (P ≤ 0.003). These reductions persisted to various degrees at day 30. These findings indicate that dNTP pools are influenced by TDF/FTC therapy. This may alter cellular homeostasis and could increase the antiviral effect through a more favorable analog/dNTP ratio. Further work is needed to elucidate mechanisms, to evaluate the clinical significance of these findings, and to further probe differences between HIV-negative and HIV-positive individuals. (This study has been registered at ClinicalTrials.gov under identifier NCT01040091.).

Relationship Between Genital Drug Concentrations and Cervical Cellular Immune Activation and Reconstitution in HIV-1-Infected Women on a Raltegravir Versus a Boosted Atazanavir Regimen.

Determinants of HIV-infected women's genital tract mucosal immune health are not well understood. Because raltegravir (RAL) achieves relatively higher genital tract concentrations than ritonavir-boosted atazanavir (ATV), we examined whether an RAL-based regimen is associated with improved cervical immune reconstitution and less activation in HIV(+) women compared to an ATV-based regimen. Peripheral blood, cervical brushings, cervical-vaginal lavage (CVL), and cervical biopsies were collected from HIV(+) women on tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) and either RAL (n=14) or ATV (n=19) with CD4(+) T cells>300 cells/mm(3) and HIV RNA<48 copies/ml. HLA-DR(+)CD38(+) T cells were measured in blood and cervical cells using flow cytometry, CD4(+) and CD8(+) T cells were quantified in cervical biopsies by immunofluorescent analysis, and HIV RNA (VL), ATV, and RAL concentrations were measured in CVL. In a linear regression model of log(CVL concentration) versus both log(plasma concentration) and treatment group, the RAL CVL level was 519% (95% CI: 133, 1,525%) higher than for ATV (p<0.001). Genital tract VL was undetectable in 90% of subjects and did not differ by regimen. There were no significant differences between groups in terms of cervical %HLA-DR(+)CD38(+)CD4(+) or CD8(+) T cells, CD4(+) or CD8(+) T cells/mm(2), or CD4:CD8 ratio. After adjusting for treatment time and group, the CVL:plasma drug ratio was not associated with the cervical CD4:CD8 ratio or immune activation (p>0.6). Despite significantly higher genital tract penetration of RAL compared to ATV, there were no significant differences in cervical immune activation or reconstitution between women on these regimens, suggesting both drug regimens achieve adequate genital tract levels to suppress virus replication.

Reduced immune activation during tenofovir-emtricitabine therapy in HIV-negative individuals.

BACKGROUND: Elevated immune activation is associated with an increased risk of HIV acquisition. Tenofovir (TFV) has immunomodulatory properties in vitro, but how this extends in vivo remains unknown. METHODS: HIV-negative adults received daily coformulated TFV disoproxil fumarate 300 mg/emtricitabine (FTC) 200 mg for 30 days followed by a 30-day washout. Markers of T-cell activation, inflammation, and cytokines were measured before drug and on days 30 (on drug) and 60 (30-day washout). Data were analyzed using one-way analysis of variance/pairwise comparisons. Intracellular disposition of TFV-diphosphate and FTC-triphosphate in CD4 and CD8 T-cells and monocytes was characterized, and the relationship with immune activation was evaluated using Pearson's correlation coefficient. RESULTS: T-cell activation was available in 19 participants. CD38/HLA-DR coexpression on CD8 T-cells decreased from baseline to day 30 (3.97% vs. 2.71%; P = 0.03) and day 60 (3.97% vs. 2.41%; P = 0.008). Soluble CD27 decreased from baseline to day 60 (184.1 vs. 168.4 pg/mL; P = 0.001). Cytokines and inflammation markers were not significantly different. TFV-diphosphate and FTC-triphosphate were approximately 4-fold higher in monocytes vs. CD4 and CD8 T-cells but neither correlated with activation markers. CONCLUSIONS: TFV disoproxil fumarate/FTC therapy was associated with decreased T-cell activation in HIV-negative adults, which could contribute to the antiviral effect of pre-exposure prophylaxis (NCT01040091; www.clinicaltrials.gov).

Dose response for starting and stopping HIV preexposure prophylaxis for men who have sex with men.

BACKGROUND: This study estimated the number of daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) doses required to achieve and maintain (after discontinuation) intracellular drug concentrations that protect against human immunodeficiency virus (HIV) infection for men who have sex with men (MSM). METHODS: Tenofovir diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs) and rectal mononuclear cells from an intensive pharmacokinetic study ("Cell-PrEP" [preexposure prophylaxis]) of 30 days of daily TDF/FTC followed by 30 days off drug were evaluated. A regression formula for HIV risk reduction derived from PBMCs collected in the preexposure prophylaxis initiative study was used to calculate inferred risk reduction. The time required to reach steady state for TFV-DP in rectal mononuclear cells was also determined. RESULTS: Twenty-one HIV-uninfected adults participated in Cell-PrEP. The inferred HIV risk reduction, based on PBMC TFV-DP concentration, reached 99% (95% confidence interval [CI], 69%-100%) after 5 daily doses, and remained >90% for 7 days after stopping drug from steady-state conditions. The proportion of participants reaching the 90% effective concentration (EC90) was 77% after 5 doses and 89% after 7 doses. The percentage of steady state for natural log [TFV-DP] in rectal mononuclear cells was 88% (95% CI, 66%-94%) after 5 doses and 94% (95% CI, 78%-98%) after 7 doses. CONCLUSIONS: High PrEP activity for MSM was achieved by approximately 1 week of daily dosing. Although effective intracellular drug concentrations persist for several days after stopping PrEP, a reasonable recommendation is to continue PrEP dosing for 4 weeks after the last potential HIV exposure, similar to recommendations for postexposure prophylaxis.