***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND A novel translational pharmacology investigation was conducted by combining an in vitro efficacy target with mucosal tissue pharmacokinetic ( PK ) data and mathematical modeling to determine the number of doses required for effective human immunodeficiency virus ( HIV ) preexposure prophylaxis ( PrEP ) . METHODS A PK/pharmacodynamic ( PD ) model was developed by measuring mucosal tissue concentrations of tenofovir , emtricitabine , their active metabolites ( tenofovir diphosphate [ TFVdp ] and emtricitabine triphosphate [ FTCtp ] , respectively ) , and competing endogenous nucleotides ( dATP and dCTP ) in 47 healthy women . TZM-bl and CD4(+ ) T cells were used to identify 90 % effective concentration ( EC90 ) ratios of TFVdp to dATP and FTCtp to dCTP ( alone and in combination ) for protection against HIV . Monte-Carlo simulations were then performed to identify minimally effective dosing strategies to protect lower female genital tract and colorectal tissues . RESULTS The colorectal TFVdp concentration was 10 times higher than that in the lower female genital tract , whereas concentrations of endogenous nucleotides were 7 - 11 times lower . Our model predicted that ≥98 % of the population achieved protective mucosal tissue exposure by the third daily dose of tenofovir disoproxil fumarate plus emtricitabine . However , a minimum adherence to 6 of 7 doses/week ( 85 % ) was required to protect lower female genital tract tissue from HIV , while adherence to 2 of 7 doses/week ( 28 % ) was required to protect colorectal tissue . CONCLUSIONS This model is predictive of recent PrEP trial results in which 2 - 3 doses/week was 75%-90 % effective in men but ineffective in women . These data provide a novel approach for future PrEP investigations that can optimize clinical trial dosing strategies Background As pre-exposure prophylaxis ( PrEP ) becomes more widely used in heterosexual population s , an important consideration is its safety in infants who are breastfed by women taking PrEP . We investigated whether tenofovir and emtricitabine are excreted into breast milk and then absorbed by the breastfeeding infant in clinical ly significant concentrations when used as PrEP by lactating women . Methods and Findings We conducted a prospect i ve short-term , open-label study of daily oral emtricitabine – tenofovir disoproxil fumarate PrEP among 50 HIV-uninfected breastfeeding African mother – infant pairs between 1–24 wk postpartum ( Clinical Trials.gov Identifier : NCT02776748 ) . The primary goal was to quantify the steady-state concentrations of tenofovir and emtricitabine in infant plasma ingested via breastfeeding . PrEP was administered to women through daily directly observed therapy ( DOT ) for ten consecutive days and then discontinued thereafter . Non-fasting peak and trough sample s of maternal plasma and breast milk were obtained at drug concentration steady states on days 7 and 10 , and a single infant plasma sample was obtained on day 7 . Peak blood and breast milk sample s were obtained 1–2 h after the maternal DOT PrEP dose , while maternal trough sample s were obtained at the end of the PrEP dosing interval ( i.e. , 23 to 24 h ) after maternal DOT PrEP dose .  Tenofovir and emtricitabine concentrations were quantified using liquid chromatography-t and em mass spectrometry ( LC-MS/MS ) assays . Of the 50 mother – infant pairs enrolled , 48 % were ≤12 wk and 52 % were 13–24 wk postpartum , and median maternal age was 25 y ( interquartile range [ IQR ] 22–28 ) . During study follow-up , the median ( IQR ) daily reported frequency of infant breastfeeding was 15 times ( 12 to 18 ) overall , 16 ( 14 to 19 ) for the ≤12 weeks , and 14 ( 12 to 17 ) for the 13–24 wk infant age groups . Overall , median ( IQR ) time-averaged peak concentrations in breast milk were 3.2 ng/mL ( 2.3 to 4.7 ) for tenofovir and 212.5 ng/mL ( 140.0 to 405.0 ) for emtricitabine . Similarly , median ( IQR ) time-averaged trough concentrations in breast milk were 3.3 ng/mL ( 2.3 to 4.4 ) for tenofovir and 183.0 ng/mL ( 113.0 to 250.0 ) for emtricitabine , reflecting trough-to-peak breast milk concentration ratios of 1.0 for tenofovir and 0.8 for emtricitabine , respectively . In infant plasma , tenofovir was unquantifiable in 46/49 sample s ( 94 % ) , but emtricitabine was detectable in 47/49 ( 96 % ) ( median [ IQR ] concentration : 13.2 ng/mL [ 9.3 to 16.7 ] ) . The estimated equivalent doses an infant would ingest daily from breastfeeding were 0.47 μg/kg ( IQR 0.35 to 0.71 ) for tenofovir and 31.9 μg/kg ( IQR 21.0 to 60.8 ) for emtricitabine , translating into a < 0.01 % and 0.5 % relative dose when compared to the 6 mg/kg dose that is proposed for therapeutic treatment of infant HIV infection and for prevention of infant postnatal HIV infection ; a dose that has not shown safety concerns . No serious adverse effects were recorded during study follow-up . The key study limitation was that only a single infant sample was collected to minimize venipunctures for the children . However , maternal daily DOT and specimen collection at drug concentration steady state provided an adequate approach to address the key research question . Importantly , there was minimal variation in breast milk concentrations of tenofovir and emtricitabine ( respective median trough-to-peak concentration ratio ~1 ) , demonstrating that infants were exposed to consistent drug dosing via breast milk . Conclusion In this short-term study of daily directly observed oral PrEP in HIV-uninfected breastfeeding women , the estimated infant doses from breast milk and result ant infant plasma concentrations  for tenofovir and emtricitabine were 12,500 and > 200-fold lower than the respective proposed infant therapeutic doses , and tenofovir was not detected in 94 % of infant plasma sample s. These data suggest that PrEP can be safely used during breastfeeding with minimal infant drug exposure . Trial Registration Clinical Trials.gov , Identifier : ABSTRACT The objective of the study was to measure  antiretroviral exposures in four physiological compartments during pregnancy , delivery , and postpartum . This prospect i ve , open-label , longitudinal study collected paired blood plasma ( BP ) and genital tract ( GT ) aspirates antepartum , at delivery , and up to 12 weeks postpartum . Antiretroviral cord BP and amniotic fluid concentrations were also measured . Drug concentrations were analyzed by vali date d high-performance liquid chromatography/UV and liquid chromatography/t and em mass spectrometry methods , with secondary compartment concentrations presented as the percentage of BP . Fourteen women taking lamivudine plus zidovudine and either lopinavir-ritonavir ( n = 7 ) , nelfinavir ( n = 6 ) , or nevirapine ( n = 1 ) were enrolled ; four also received  tenofovir .  GT penetration relative to BP was highest for the nucleoside reverse transcriptase inhibitors compared to the protease inhibitors and nevirapine . Only antepartum nelfinavir GT penetration was significantly higher than in the second trimester ( geometric mean ratio [ GMR ] , 179.3 ) or third trimester ( GMR , 41.9 ) . Compared to nonpregnant historical controls , antepartum GT penetration was significantly lower ( P < 0.05 ) for zidovudine ( GMR , 0.25 ) and lopinavir ( GMR , 0.03 ) ; postpartum lopinavir GT penetration continued to be significantly lower ( GMR , 0.27 ) . Cord BP exposures were highest for lamivudine and tenofovir ( ≥100 % ) , with cord BP levels of the remaining drugs ranging from 49 to 86 % of that of the respective BP level . Amniotic exposures for lamivudine , zidovudine , tenofovir , and nelfinavir were ≥100 % , nevirapine exposure was 53 % , and lopinavir and ritonavir exposures were ≤6 % that of BP . We conclude that GT , cord BP , and amniotic fluid exposures vary within and between antiretroviral drug classes and biologic sites . Measurement of antiretroviral exposure in maternal genital secretions , cord BP , and amniotic fluid may be needed to identify signals of subtherapeutic or supratherapeutic drug exposure BACKGROUND & AIMS Fetal safety of antiviral therapies is important given the long-term treatment of women with chronic hepatitis B ( CHB ) infection who may become pregnant . We analyzed neonatal safety data from the Antiretroviral Pregnancy Registry ( APR ) , the largest safety data base in pregnancy for antivirals used for HIV and CHB . METHODS Data were extracted from APR cases prospect ively enrolled between 1989 and 2011 . Primary outcomes were major birth defects rates with exposure to all antivirals , individual classes , and drugs compared to population -based controls . Relevant to CHB , only lamivudine ( LAM ) and tenofovir disoproxil fumarate ( TDF ) had sufficient individual data for review ( ≥200 cases ) . RESULTS Of 13,711 cases analyzed , the overall birth defect prevalence ( 2.8 % , 95 % CI 2.6 - 3.1 % ) was comparable to Centers for Disease Control population -based data ( 2.72 % , 2.68 - 2.76 % , p=0.87 ) and two prospect i ve antiretroviral exposed newborn cohorts ( 2.8 % , 2.5 - 3.2 % , p=0.90 and 1.5 % , 1.1 - 2.0 % , p<0.001 ) . The birth defects prevalence between first and second/third trimesters exposure was similar ( 3.0 % vs. 2.7 % ) . No increased risk of major birth defects with LAM or TDF exposure compared to population -based controls was observed . No specific pattern of major birth defects was observed for individual antivirals or overall . CONCLUSIONS No increased risk of major birth defects including in non-live births was observed for pregnant women exposed to antivirals relevant to CHB treatment overall or to LAM or TDF compared to population -based controls . Continued safety and efficacy reporting on antivirals in pregnancy are essential to inform patients on their risks and benefits during pregnancy ABSTRACT Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 ( HIV-1 ) . The pharmacokinetics , safety , and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a r and omized , double-blind , placebo-controlled , escalating-dose study of four doses ( 75 , 150 , 300 , and 600 mg given once daily ) . Subjects received a single dose of tenofovir DF or a placebo , followed by a 7-day washout period . Thereafter , subjects received their assigned study drug once daily for 28 days . Pharmacokinetic parameters were dose proportional and demonstrated no change with repeated dosing . Reductions in plasma HIV-1 RNA were dose related at tenofovir DF doses of 75 to 300 mg , but there was no increase in virus suppression between the 300- and 600-mg dose cohorts , despite dose-proportional increases in drug exposure . Grade III or IV adverse events were limited to laboratory abnormalities , including elevated creatine phosphokinase and liver function tests , which resolved with or without drug discontinuation and without sequelae . No patients developed detectable sequence changes in the reverse transcriptase gene BACKGROUND Few data are available regarding the use of tenofovir disoproxil fumarate ( TDF ) during pregnancy for the prevention of mother-to-child transmission of hepatitis B virus ( HBV ) . METHODS In this trial , we included 200 mothers who were positive for hepatitis B e antigen ( HBeAg ) and who had an HBV DNA level higher than 200,000 IU per milliliter . Participants were r and omly assigned , in a 1:1 ratio , to receive usual care without antiviral therapy or to receive TDF ( at an oral dose of 300 mg per day ) from 30 to 32 weeks of gestation until postpartum week 4 ; the participants were followed until postpartum week 28 . All the infants received immunoprophylaxis . The primary outcomes were the rates of mother-to-child 
    Output:
    
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 .
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 .