Regis Kreitchmann

Pharmacokinetics and Safety of Tenofovir in HIV-Infected Women During Labor and Their Infants During the First Week of Life

Background:Data describing the pharmacokinetics and safety of tenofovir in neonates are lacking. Methods:The HIV Prevention Trials Network 057 protocol was a phase 1, open-label study of the pharmacokinetics and safety of tenofovir disoproxil fumarate (TDF) in HIV-infected women during labor and their infants during the first week of life with 4 dosing cohorts: maternal 600 mg doses/no infant dosing; no maternal dosing/infant 4 mg/kg doses on days 0, 3, and 5; maternal 900 mg doses/infant 6 mg/kg doses on days 0, 3, and 5; maternal 600 mg doses/infant 6 mg/kg daily for 7 doses. Pharmacokinetic sampling was performed on cohort 1 and 3 mothers and all infants. Plasma, amniotic fluid, and breast milk tenofovir concentrations were determined by liquid chromatographic–tandem mass spectrometric assay. The pharmacokinetic target was for infant tenofovir concentration throughout the first week of life to exceed 50 ng/mL, the median trough tenofovir concentration in adults receiving standard chronic TDF dosing. Results:One hundred twenty-two mother–infant pairs from Malawi and Brazil were studied. Tenofovir exposure in mothers receiving 600 and 900 mg exceeded that in nonpregnant adults receiving standard 300 mg doses. Tenofovir elimination in the infants was equivalent to that in older children and adults, and trough tenofovir plasma concentrations exceeded 50 ng/mL in 74%–97% of infants receiving daily dosing. Conclusions:A TDF dosing regimen of 600 mg during labor and daily infant doses of 6 mg/kg maintains infant tenofovir plasma concentration above 50 ng/mL throughout the first week of life and should be used in the studies of TDF efficacy for HIV prevention of mother-to-child transmission and early infant treatment.

Raltegravir pharmacokinetics during pregnancy.

Objective:We evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and postpartum. Methods:International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is an ongoing prospective study of antiretroviral PK during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady-state 12-hour PK profiles performed during pregnancy and at 6- to 12-week postpartum. Targets were trough concentration above 0.035 &mgr;g/mL, the estimated 10th percentile in nonpregnant historical controls. Results:Median raltegravir area under the curve was 6.6 &mgr;g·h/mL for second trimester (n = 16), 5.4 &mgr;g·h/mL for third trimester (n = 41), and 11.6 &mgr;g·h/mL postpartum (n = 38) (P = 0.03 postpartum vs second trimester, P = 0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester, and postpartum subjects, respectively, with wide variability (<0.010–0.917 &mgr;g/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were <400 copies per milliliter in 92% of women at delivery. Adverse events included elevated liver transaminases in 1 woman and vomiting in 1. All infants with known status are HIV uninfected. Conclusions:Median raltegravir area under the curve was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary.

Antiretroviral adherence during pregnancy and postpartum in Latin America

Adherence to antiretrovirals by pregnant women (and postpartum women if breastfeeding) is crucial to effectively decrease maternal viral load and decrease the risk of mother-to-child transmission of HIV. Our objectives were to describe self-reported adherence to antiretrovirals during the antepartum (after 22 weeks of pregnancy) and postpartum periods (6-12 weeks and 6 months), and identify predictors of adherence among HIV-infected women enrolled and followed in a prospective cohort study from June 2008 to June 2010 at multiple sites in Latin America. Adherence was evaluated using the number of missed and expected doses during the 3 days before the study visit. At the pre-delivery visit, 340 of 376 women (90%) reported perfect adherence. This rate significantly decreased by 6-12 weeks (171/214 [80%]) and 6 months postpartum (163/199 [82%], p<0.01). The odds for less than perfect adherence at the pre-delivery visit was significantly higher for pregnant women with current tobacco use (odds ratio [OR]=2.9, 95% confidence interval [CI]: 1.46-6.14; p=0.0029). At 6-12 weeks postpartum, the probability of non-perfect adherence increased by 6% for each 1 year increase in age (OR=1.06, 95% CI: 1.00-1.12, p=0.0497). At 6 months postpartum, the odds of nonperfect adherence was higher for those who were currently using alcohol (OR=3.04, 95% CI: 1.34-6.90; p=0.0079). Although a self-report measure of adherence based on only 3 days may lead to overestimation of actual adherence over time, women with perfect adherence had lower viral loads and higher CD4 counts. Adherence to antiretrovirals decreased significantly postpartum. Interventions should target women at high risk for lower adherence during pregnancy and postpartum, including tobacco and alcohol users.

HIV rapid testing as a key strategy for prevention of mother-to-child transmission in Brazil

OBJECTIVEnTo assess the feasibility of HIV rapid testing for pregnant women at maternity hospital admission and of subsequent interventions to reduce perinatal HIV transmission.nnnMETHODSnStudy based on a convenience sample of women unaware of their HIV serostatus when they were admitted to delivery in public maternity hospitals in Rio de Janeiro and Porto Alegre, Brazil, between March 2000 and April 2002. Women were counseled and tested using the Determine HIV1/2 Rapid Test. HIV infection was confirmed using the Brazilian algorithm for HIV infection diagnosis. In utero transmission of HIV was determined using HIV-DNA-PCR. There were performed descriptive analyses of sociodemographic data, number of previous pregnancies and abortions, number of prenatal care visits, timing of HIV testing, HIV rapid test result, neonatal and mother-to-child transmission interventions, by city studied.nnnRESULTSnHIV prevalence in women was 6.5% (N=1,439) in Porto Alegre and 1.3% (N=3.778) in Rio de Janeiro. In Porto Alegre most of women were tested during labor (88.7%), while in Rio de Janeiro most were tested in the postpartum (67.5%). One hundred and forty-four infants were born to 143 HIV-infected women. All newborns but one in each city received at least prophylaxis with oral zidovudine. It was possible to completely avoid newborn exposure to breast milk in 96.8% and 51.1% of the cases in Porto Alegre and Rio de Janeiro, respectively. Injectable intravenous zidovudine was administered during labor to 68.8% and 27.7% newborns in Porto Alegre and Rio de Janeiro, respectively. Among those from whom blood samples were collected within 48 hours of birth, in utero transmission of HIV was confirmed in 4 cases in Rio de Janeiro (4/47) and 6 cases in Porto Alegre (6/79).nnnCONCLUSIONSnThe strategy proved feasible in maternity hospitals in Rio de Janeiro and Porto Alegre. Efforts must be taken to maximize HIV testing during labor. There is a need of strong social support to provide this population access to health care services after hospital discharge.OBJETIVO: Analisar a viabilidade da testagem rapida para o HIV entre gestantes na admissao a maternidade e de intervencoes para reduzir a transmissao perinatal do HIV. METODOS: Amostra de conveniencia de mulheres que desconheciam sua situacao sorologica para o HIV quando admitidas para o parto em maternidades publicas do Rio de Janeiro, RJ, e de Porto Alegre, RS, entre marco de 2000 e abril de 2002. As mulheres foram aconselhadas e testadas com teste rapido Determine HIV1/2 na maternidade. Infeccao pelo HIV foi confirmada pelo algoritmo brasileiro para o diagnostico da infeccao pelo HIV. A transmissao intra-utero foi determinada pelo PCR-DNA-HIV. Foram realizadas analises descritivas dos dados sociodemograficos, numero de gestacoes e de abortos previos, numero de visitas de pre-natal, momento da testagem para o HIV, resultado do teste rapido para o HIV, intervencoes recebidas pelos recem-natos e de transmissao vertical do HIV, de acordo com cada cidade. RESULTADOS: A prevalencia de HIV entre as mulheres foi 6,5% (N=1.439) em Porto Alegre e 1,3% (N=3.778) no Rio de Janeiro. A maioria foi testada durante o trabalho de parto em Porto Alegre e no pos-parto, no Rio de Janeiro. Cento e quarenta e quatro criancas nasceram de 143 mulheres infectadas pelo HIV. Todos os recem-natos receberam ao menos a profilaxia com zidovudina oral, exceto um em cada cidade. Foi possivel evitar qualquer exposicao ao leite materno em 96,8% e 51,1% dos recem-natos em Porto Alegre e no Rio de Janeiro, respectivamente. A zidovudina injetavel foi administrada durante o trabalho de parto para 68,8% dos recem-natos em Porto Alegre e 27,7% no Rio de Janeiro. Entre aqueles com amostras de sangue coletadas ate 48 horas do nascimento, a transmissao intra-utero foi confirmada em quatro casos no Rio de Janeiro (4/47) e em seis casos em Porto Alegre (6/79). CONCLUSOES: A estrategia mostrou-se factivel nas maternidades do Rio de Janeiro e de Porto Alegre. Esforcos devem ser empreendidos para maximizar a testagem durante o trabalho de parto. Forte suporte social precisa ser acoplado a essa estrategia para garantir o acesso dessa populacao ao sistema de saude apos a alta da maternidade.

Syphilis in HIV-infected mothers and infants: results from the NICHD/HPTN 040 study.

Background: Untreated syphilis during pregnancy is associated with spontaneous abortion, stillbirth, prematurity and infant mortality. Syphilis may facilitate HIV transmission, which is especially concerning in low- and middle-income countries where both diseases are common. Methods: We performed an analysis of data available from NICHD/HPTN 040 (P1043), a study focused on the prevention of intrapartum HIV transmission to 1684 infants born to 1664 untreated HIV-infected women. This analysis evaluates risk factors and outcomes associated with a syphilis diagnosis in this cohort of HIV-infected women and their infants. Results: Approximately, 10% of women (n = 171) enrolled had serological evidence of syphilis without adequate treatment documented and 1.4% infants (n = 24) were dually HIV and syphilis infected. Multivariate logistic analysis showed that compared with HIV-infected women, co-infected women were significantly more likely to self-identify as non-white (adjusted odds ratio [AOR] 2.5, 95% CI: 1.5–4.2), to consume alcohol during pregnancy (AOR 1.5, 95% CI: 1.1–2.1) and to transmit HIV to their infants (AOR 2.1, 95% CI: 1.3–3.4), with 88% of HIV infections being acquired in utero. As compared with HIV-infected or HIV-exposed infants, co-infected infants were significantly more likely to be born to mothers with venereal disease research laboratory titers ≥1:16 (AOR 3, 95% CI: 1.1–8.2) and higher viral loads (AOR 1.5, 95% CI: 1.1–1.9). Of 6 newborns with symptomatic syphilis, 2 expired shortly after birth, and 2 were HIV-infected. Conclusion: Syphilis continues to be a common co-infection in HIV-infected women and can facilitate in utero transmission of HIV to infants. Most infants are asymptomatic at birth, but those with symptoms have high mortality rates.

Pharmacokinetics of an Increased Atazanavir Dose with and without Tenofovir During the Third Trimester of Pregnancy

Background:Reduced atazanavir exposure has been demonstrated during pregnancy with standard atazanavir/ritonavir dosing. We studied an increased dose during the third trimester of pregnancy. Methods:International Maternal Pediatric Adolescent AIDS Clinical Trials Group 1026s is a prospective, nonblinded, pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including 2 cohorts (with or without tenofovir) receiving atazanavir/ritonavir 300/100 mg once daily during the second trimester, 400/100 mg during the third trimester, and 300/100 mg postpartum (PP). Intensive steady-state 24-hour pharmacokinetic profiles were performed. Atazanavir concentrations were measured by high-performance liquid chromatography. Pharmacokinetic targets were the 10th percentile atazanavir area under the concentration versus time curve (AUC) (29.4 &mgr;g·hr−1·mL−1·) in nonpregnant adults on standard dose and 0.15 &mgr;g/mL, minimum trough concentration. Results:Atazanavir pharmacokinetic data were available for 37 women without tenofovir, 35 with tenofovir; median (range) pharmacokinetic parameters are presented for second trimester, third trimester, and PP and number who met target/total. Atazanavir Without Tenofovir:AUC 30.5 (9.19–93.8), 45.7 (11–88.3), and 48.8 (9.9–112.2) &mgr;g·hr−1·mL−1, and 8/14, 29/37, and 27/34 met target. C24 h was 0.49 (0.09–4.09), 0.71 (0.14–2.09), and 0.90 (0.05–2.73) &mgr;g/mL; 13/14, 36/37, and 29/34 met target. Atazanavir With Tenofovir:AUC 26.2 (6.8–60.9) (P < 0.05 compared with PP), 37.7 (0.72–88.2) (P < 0.05 compared with PP), and 58.6 (6–149) &mgr;g·hr−1·mL−1, and 7/17, 23/32, and 27/29 met target. C24 h was 0.44 (0.12–1.06) (P < 0.05 compared with PP), 0.57 (0.02–2.06) (P < 0.05 compared with PP), and 1.26 (0.09–5.43) &mgr;g/mL; 7/17, 23/32, and 27/29 met target. Atazanavir/ritonavir was well tolerated with no unanticipated adverse events. Conclusions:Atazanavir/ritonavir increased to 400/100 mg provides adequate atazanavir exposure during the third trimester and should be considered during the second trimester.

Chlamydia trachomatis and Neisseria gonorrhoeae in HIV-infected Pregnant Women and Adverse Infant Outcomes

Background: Sexually transmitted infections (STIs) in pregnancy such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) may lead to adverse infant outcomes. Methods: Individual urine specimens from HIV-infected pregnant women diagnosed with HIV during labor were collected at the time of infant birth and tested by polymerase chain reaction for CT and NG. Infant HIV infection was determined at 3 months with morbidity/mortality assessed through 6 months. Results: Of 1373 maternal urine samples, 277 (20.2%) were positive for CT and/or NG; 249 (18.1%) for CT, 63 (4.6%) for NG and 35 (2.5%) for both CT and NG. HIV infection was diagnosed in 117 (8.5%) infants. Highest rates of adverse outcomes (sepsis, pneumonia, congenital syphilis, septic arthritis, conjunctivitis, low birth weight, preterm delivery and death) were noted in infants of women with CT and NG (23/35, 65.7%) compared with NG (16/28, 57.1%), CT (84/214, 39.3%) and no STI (405/1096, 37%, P = 0.001). Death (11.4% vs. 3%, P = 0.02), low birth weight (42.9% vs. 16.9%, P = 0.001) and preterm delivery (28.6% vs. 10.2%, P = 0.008) were higher among infants of CT and NG-coinfected women. Infants who had any adverse outcome and were born to women with CT and/or NG were 3.5 times more likely to be HIV infected after controlling for maternal syphilis (odds ratio: 3.5, 95% confidence interval: 1.4–8.3). By adjusted multivariate logistic regression, infants born to mothers with any CT and/or NG were 1.35 times more likely to have an adverse outcome (odds ratio, 1.35; 95% confidence interval, 1.03–1.76). Conclusions: STIs in HIV-infected pregnant women are associated with adverse outcomes in HIV-exposed infected and uninfected infants.

Pharmacokinetics of once versus twice daily darunavir in pregnant HIV-infected women

Objective:To describe darunavir (DRV) pharmacokinetics with once-and twice-daily dosing during pregnancy and postpartum in HIV-infected women. Design:Women were enrolled in International Maternal Pediatric Adolescent AIDS Clinical Trials Network Protocol P1026s, a prospective nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included separate cohorts receiving DRV/ritonavir dosed at either 800 mg/100 mg once daily or 600 mg/100 mg twice daily. Methods:Intensive steady-state 12- or 24-hour pharmacokinetic profiles were performed during the second trimester, third trimester, and postpartum. DRV was measured using high-performance liquid chromatography (detection limit: 0.09 &mgr;g/mL). Results:Pharmacokinetic data were available for 64 women (30 once daily and 34 twice daily dosing). Median DRV area under the concentration–time curve (AUC) and maximum concentration were significantly reduced during pregnancy with both dosing regimens compared with postpartum, whereas the last measurable concentration (Clast) was also reduced during pregnancy with once daily DRV. DRV AUC with once daily dosing was reduced by 38% during the second trimester and by 39% during the third trimester. With twice daily dosing, DRV AUC was reduced by 26% in both trimesters. The median (range) ratio of cord blood/maternal delivery DRV concentration in 32 paired samples was 0.18 (range: 0–0.82). Conclusions:DRV exposure is reduced by pregnancy. To achieve DRV plasma concentrations during pregnancy equivalent to those seen in nonpregnant adults, an increased twice daily dose may be necessary. This may be especially important for treatment-experienced women who may have developed antiretroviral resistance mutations.

Reduced indinavir exposure during pregnancy

AIMnTo describe the pharmacokinetics and safety of indinavir boosted with ritonavir (IDV/r) during the second and third trimesters of pregnancy and in the post-partum period.nnnMETHODSnIMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women with a Thai cohort receiving IDV/r 400/100 mg twice daily during pregnancy through to 6-12 weeks post-partum as part of clinical care. Steady-state PK profiles were performed during the second (optional) and third trimesters and at 6-12 weeks post-partum. PK targets were the estimated 10(th) percentile IDV AUC (12.9 μg ml(-1)h) in non-pregnant historical Thai adults and a trough concentration of 0.1 μg ml(-1), the suggested minimum target.nnnRESULTSnTwenty-six pregnant women were enrolled; thirteen entered during the second trimester. Median (range) age was 29.8 (18.9-40.8) years and weight 60.5 (50.0-85.0) kg at the third trimester PK visit. The 90% confidence limits for the geometric mean ratio of the indinavir AUC(0,12 h) and Cmax during the second trimester and post-partum (ante : post ratios) were 0.58 (0.49, 0.68) and 0.73 (0.59, 0.91), respectively; third trimester/post-partum AUC(0,12 h) and Cmax ratios were 0.60 (0.53, 0.68) and 0.63 (0.55, 0.72), respectively. IDV/r was well tolerated and 21/26 women had a HIV-1 viral load < 40 copies ml(-1) at delivery. All 26 infants were confirmed HIV negative.nnnCONCLUSIONnIndinavir exposure during the second and third trimesters was significantly reduced compared with post-partum and ∼30% of women failed to achieve a target trough concentration. Increasing the dose of IDV/r during pregnancy to 600/100 mg twice daily may be preferable to ensure adequate drug concentrations.

Safety and efficacy of contraceptive implants for HIV-infected women in Porto Alegre, Brazil.

This research article describes an assessment of the safety and efficacy of contraceptive implants (Implanon) for HIV-infected women in Porto Alegre Brazil. The study exhibited that Implanon was effective and relatively safe for HIV-positive women with significant co-morbidities and should be considered for those requiring contraception. The researcher recommends that further research be done to evaluate potential interactions between antiretroviral therapy and etonogestrel. Copyright