Plasma lopinavir trough levels in a group of pregnant women on lopinavir, ritonavir, zidovudine, and lamivudine

During pregnancy, the absorption of antiretroviral drugs may not be optimal, therefore a prospective study was conducted to investigate the plasma levels of lopinavir in 26 HIV-infected pregnant women. Plasma lopinavir levels were examined in specimens obtained 12 h post-dose. The lopinavir level was found to be subtherapeutic in four women (15.4%); one patient who discontinued treatment and three (13.6%) with therapeutic levels of lopinavir had detectable HIV viral loads at the time of therapeutic drug monitoring.     

Therapeutic drug monitoring of lopinavir/ritonavir in pregnancy

Objectives

The aim of the study was to determine total and unbound lopinavir (LPV) plasma concentrations in HIV‐infected pregnant women receiving lopinavir/ritonavir (LPV/r tablet) undergoing therapeutic drug monitoring (TDM) during pregnancy and postpartum.

Methods

Women were enrolled in the study who were receiving the LPV/r tablet as part of their routine prenatal care. Demographic and clinical data were collected and LPV plasma (total) and ultrafiltrate (unbound) concentrations were determined in the first, second and third trimesters using high‐performance liquid chromatography–tandem mass spectrometry (HPLC‐MS/MS). Postpartum sampling was performed where applicable. Antepartum and postpartum trough concentrations (C_trough) were compared independently [using analysis of variance (anova )] and on a longitudinal basis (using a paired t‐test).

Results

Forty‐six women were enrolled in the study (38 Black African). Forty women initiated LPV/r treatment in pregnancy. Median (range) gestation at initiation was 25 (15–36) weeks and median (range) baseline CD4 count and viral load were 346 (14–836) cells/μL and 8724 (<50–267408) HIV‐1 RNA copies/mL, respectively. Forty women (87%) had LPV concentrations above the accepted minimum effective concentration for wild‐type virus (MEC; 1000 ng/mL). Geometric mean (95% confidence interval [CI]) total LPV concentrations in the first/second [3525 (2823–4227) ng/mL; n=16] and third [3346 (2813–3880) ng/mL; n=43] trimesters were significantly lower relative to postpartum [5136 (3693–6579) ng/mL; n=12] (P=0.006). In a paired analysis (n=12), LPV concentrations were reduced in the third trimester [3657 (2851–4463) ng/mL] vs. postpartum (P=0.021). No significant differences were observed in the LPV fraction unbound (fu%). Conclusions The above target concentrations achieved in the majority of women and similarities in the fu% suggest standard dosing of the LPV/r tablet is appropriate during pregnancy. However, reduced LPV concentrations in the second/third trimesters and potentially compromised adherence highlight the need for TDM‐guided dose adjustment in certain cases.     

Therapeutic drug monitoring of antiretroviral therapy

The concept of managing pharmacotherapy based on plasma drug concentrations has been used for decades in a variety of clinical settings. The interest in therapeutic drug monitoring (TDM) of antiretroviral drugs has grown significantly since highly active antiretroviral therapy (HAART) became a standard of care in clinical practice. A primary characteristic of TDM of antiretroviral drugs is that multiple agents are concomitantly used in HAART regimens. Inadequate drug concentrations may lead to evolution of drug resistance mutations and endanger present and future treatment options. A number of clinical trials have demonstrated that drug serum concentrations are an important factor in response to therapy for HIV, but whether TDM will become a tool for the routine management of HIV infection remains to be determined. This review includes an illustrative case report of measuring concentrations of antiretroviral drugs in a pediatric patient.     

Placental transfer and pharmacokinetics of lopinavir and other protease inhibitors in combination with nevirapine at delivery

BACKGROUND: Antiretroviral combination therapies, including nevirapine (NVP) and protease inhibitors (PI), are increasingly used in the treatment and for the prophylaxis of vertical HIV-1 transmission in HIV-1 infected pregnant women. OBJECTIVE: To determine pharmacokinetics and placental transfer of NVP and different PI in pregnancy we measured drug levels in maternal and foetal compartments at the day of delivery. DESIGN AND METHODS: We conducted a prospective study in 40 eligible HIV-1 infected pregnant women who gave birth in our hospital. A pre-dose to 6 h post-dose steady-state pharmacokinetic analysis (n = 35) of the drugs on the day of the scheduled Caesarean section was performed. In addition cord blood and amniotic fluid drug levels were measured (n = 40). RESULTS: In all women NVP plasma concentrations (n = 20) were below the recommended level. PI plasma concentrations (nelfinavir, n = 5; saquinavir, n = 3; lopinavir, n = 10; ritonavir, n = 13) were extremely variable. Cord blood and amniotic fluid drug levels suggested that NVP passes the placenta unrestricted whereas PI were detected in smaller concentrations in the foetal compartment. CONCLUSIONS: Because of the changed pharmacokinetics of antiretroviral drugs in pregnancy therapeutic drug monitoring could be important and dose adjustment should be considered. The minimal placental transfer of PI is desirable from the perspective that the foetus is protected from potentially teratogenic agents. However, it is not known if antiretroviral compounds in the foetal compartment contribute to the risk reduction of vertical HIV-1 transmission, and whether the property of missing placental transfer is in fact beneficial for the newborn.     

170例HIV感染孕妇的妊娠结局分析

目的探讨并分析HIV感染孕妇的临床特征及妊娠结局。方法收集本院2007年1月—2018年11月期间HIV感染孕妇的流行病学资料,分析其流行病学特征以及妊娠结局。结果共纳入170例HIV感染孕妇,感染的主要方式为异性性传播。近3年诊治的HIV感染孕妇数量较前几年明显增多。孕妇的主要抗病毒方案为齐多夫定或替诺福韦+拉米夫定+洛匹那韦/利托那韦。婴儿主要抗病毒方案为齐多夫定或奈韦拉平。母婴阻断成功率100%。结论HIV感染孕妇数量呈上升趋势,及时对HIV感染孕妇进行规范系统的抗病毒治疗及对HIV暴露婴儿进行预防可有效阻断HIV母婴传播。     

Steady-state nevirapine plasma concentrations are influenced by pregnancy

OBJECTIVES: Optimal plasma concentrations of antiretroviral drugs are required during pregnancy to treat maternal HIV infection and prevent mother-to-child transmission. We investigated the effect of pregnancy on nevirapine (NVP) plasma concentrations. METHODS: We included all HIV-1-infected women for whom NVP plasma concentrations were available as part of routine patient care at two university hospitals. Plasma NVP concentrations were compared for pregnant (n=45) and non-pregnant (n=152) women. Univariate and multivariate linear regression analyses were used to identify and adjust for other confounding factors associated with NVP plasma concentrations. For pregnant women who had a plasma NVP concentration available both during and outside pregnancy, a paired analysis was performed. RESULTS: Steady-state NVP plasma concentrations were lower in pregnant women: 5.2 mg/L (interquartile range 3.9-6.8) vs. 5.8 mg/L (4.3-7.7) (P=0.08). After adjusting for confounders, both pregnancy (regression coefficient=-0.90 mg/L, P=0.046) and African descent (regression coefficient=+1.13 mg/L, P=0.005) influenced NVP concentrations significantly. The paired analysis showed mean concentrations of 4.8 mg/L during pregnancy and 5.8 mg/L outside pregnancy (paired t-test, P=0.073). CONCLUSIONS: Pregnancy has a moderate but significant lowering effect on NVP plasma concentrations. Being of African descent compensates for the lowering effect of pregnancy on NVP concentrations.     

Reduced lopinavir exposure during pregnancy

BACKGROUND: Optimal antiretroviral exposure during pregnancy is critical for prevention of mother-to-child HIV transmission and for maternal health. Pregnancy can alter antiretroviral pharmacokinetics. Our objective was to describe lopinavir/ritonavir (LPV/r) pharmacokinetics during pregnancy. METHODS: We performed intensive steady-state 12-h pharmacokinetic profiles of lopinavir and ritonavir (three capsules: LPV 400 mg/r 100 mg) at 30-36 weeks gestation and 6-12 weeks postpartum. Maternal and umbilical cord blood samples were obtained at delivery. We measured LPV and ritonavir by reverse-phase high-performance liquid chromatography. Target LPV area under concentration versus time curve (AUC) was > or = 52 microg h/ml, the estimated 10th percentile LPV AUC in non-pregnant historical controls (mean AUC = 83 microg h/ml). RESULTS: Seventeen women completed antepartum evaluations; average gestational age was 35 weeks. Geometric mean antepartum LPV AUC was 44.4 microg h/ml [90% confidence interval (CI), 38.7-50.9] and 12-h post-dose concentration (C12h) was 1.6 microg/ml (90% CI, 1.1-2.5). Twelve women completed postpartum evaluations; geometric mean LPV AUC was 65.2 microg h/ml (90% CI, 49.7-85.4) and C12h was 4.6 microg/ml (90% CI, 3.7-5.7). The geometric mean ratio of antepartum/postpartum LPV AUC was 0.72 (90% CI, 0.54-0.96). Fourteen of 17 (82%) pregnant and three of 12 (25%) postpartum women did not meet our target LPV AUC. The ratio of cord blood/maternal LPV concentration in ten paired detectable samples was 0.2 +/- 0.13. CONCLUSIONS: LPV/r exposure during late pregnancy was lower compared to postpartum and compared to non-pregnant historical controls. Small amounts of lopinavir cross the placenta. The pharmacokinetics, safety, and effectiveness of increased LPV/r dosing during the third trimester of pregnancy should be investigated.     

Transplacental passage of protease inhibitors at delivery

OBJECTIVE: Although combinations of different antiretroviral drugs are increasingly used by pregnant HIV-1-infected women, few human data are available to evaluate in utero protease inhibitors (PI) exposure. The aim of this study was to assess the extent of transplacental passage of PI at delivery. METHODS: Pregnant women treated with antiretroviral drugs including PI and/or nevirapine were eligible for the study. Placental transfer was determined by comparison of drug concentrations in blood samples simultaneously collected from a peripheral maternal vein and the umbilical cord at delivery. Drug levels were determined by high-performance liquid chromatography. RESULTS: Thirteen maternal-cord blood sample pairs were evaluable for transplacental passage determination (nine nelfinavir, two ritonavir, one saquinavir, one lopinavir, two nevirapine). Median cord and maternal drug concentrations, respectively, were nelfinavir < 250 and 1110 ng/ml; ritonavir < 250 and 1113 ng/ml; saquinavir < 100 and 350 ng/ml; lopinavir < 250 and 3105 ng/ml and nevirapine 2072 and 2546 ng/ml. The cord-to-maternal blood ratio was extremely low for all PI. CONCLUSION: PI do not cross the placenta to an appreciable extent and consequently cannot be expected to exert a direct antiviral activity in utero during the whole dosing interval. Limited transfer may result from their high degree of plasma protein binding and their backwards transport through P-glycoprotein, largely expressed in the placenta. In contrast, nevirapine readily crosses the placental barrier. Such considerations may support treatment decisions in pregnant women.     

Antiretroviral drug concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly active antiretroviral therapy.

OBJECTIVE: Our objective was to determine antiretroviral drug concentrations and human immunodeficiency virus (HIV) RNA rebound in cervicovaginal fluid (CVF) in relation to blood plasma (BP) in women receiving suppressive highly active antiretroviral therapy (HAART). METHODS: Thirty-four HIV-infected women who had plasma HIV RNA levels < or =80 copies/mL for at least 6 months were enrolled. Sixty-eight paired CVF and BP drug concentrations and HIV RNA levels were determined before and 3-4 h after drug administration. For each woman and antiretroviral drug, the CVF:BP drug concentration ratios before and after drug administration were calculated. The nonparametric Wilcoxon rank sum test was used to determine if these ratios were different from 1.0. RESULTS: Lamivudine (administered to 20 patients) and tenofovir (administered to 16) had significantly higher concentrations in CVF than in BP before drug administration, with mean CVF:BP concentration ratios of 3.19 (95% confidence interval, 1.2-8.5) and 5.2 (95% confidence interval, 1.2-22.6), respectively. Efavirenz (administered to 13 patients) and lopinavir (administered to 6) had significantly lower concentrations in CVF, with mean CVF:BP concentration ratios of 0.01 (95% confidence interval, 0.00-0.03) and 0.03 (0.01-0.11), respectively. During the study visit (median time after enrollment, 6 months), BP and CVF detectable HIV RNA levels were observed 7 patients (20.6%) and 1 patient (2.9%), respectively. CONCLUSION: Despite lower CVF concentrations of key HAART components, such as efavirenz and lopinavir, virologic rebound was rare. The high concentrations of tenofovir and lamivudine in CVF may have implications for the prevention of sexual transmission during HAART and for pre-exposure or postexposure prophylaxis.     

Mother-to-child transmission of HIV infection and its prevention

An estimated 800,000 children acquired HIV-infection in 2002, most as a result of mother-to-child transmission (MTCT), and vertically-acquired HIV infection continues to be of major public health importance. Prevention of MTCT is possible with a combination of interventions including antiretroviral therapy (ART) (usually in highly active combinations), elective caesarean section and avoidance of breastfeeding, and where infected women are identified before or in pregnancy and have access to these interventions, risk of MTCT is now below 1-2%. However, prompt identification of pregnant women with HIV infection remains pressing in many developed countries; additionally, concerns have arisen regarding adherence to complex treatment regimens in pregnancy and the potential impact of HIV drug resistance. More disturbingly, most HIV-infected women live in developing countries where many pregnant women even when tested do not return for their HIV results for a variety of reasons including stigma, and where most, if not all, strategies for prevention of MTCT have been of limited accessibility and/or feasibility. However, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and other initiatives including pharmaceutical companies' donation programmes and generic antiretroviral drug production have made prevention of MTCT in resource-poor settings an increasingly realistic goal, coupled with new evidence from clinical trials on the efficacy of abbreviated regimens of antiretroviral prophylaxis, including combination therapy, to prevent MTCT. Research is additionally focussing on reducing the risk of postnatal transmission through breastfeeding, with exclusive breastfeeding, early cessation and antiretroviral prophylaxis to breastfeeding women or breastfed infants under investigation. However, the key to prevention of paediatric HIV infections is adequate prevention of infection in women of reproductive age.     

Factors associated with altered pharmacokinetics in substance users and non-substance users receiving lopinavir and atazanavir

Substance use is highly prevalent in HIV-infected individuals in the United States, and clinical management is complicated by the need for antiretroviral treatment, addiction therapy, variable medication adherence, and co-morbidities. The interrelation between HIV and substance use prompted our investigation to examine substance use and self-reported medication adherence in patients receiving the HIV-1 protease inhibitors, atazanavir (ATV) or lopinavir (LPV). ATV and LPV pharmacokinetics were determined by measuring plasma concentrations in subjects with active substance use (SU group) or with no active substance use (NSU group). No difference in adherence was observed between groups (p > 0.05). The mean SU ATV trough was 0.550+/-0.45 microg/mL; the mean NSU ATV trough was 0.780+/-0.590 microg/mL (p > 0.05). The mean SU LPV trough was 4.02+/-2.39 microg/mL; the mean NSU LPV trough was 6.67+/-0.910 microg/mL (p = 0.01). Co-factors found to be associated with variation in ATV and LPV concentrations included concurrent methadone use, cigarette smoking, and substance use status. These data indicate that chronic HIV treatment may be assisted with plasma concentration monitoring to identify those patients who may require dosage modification and/or regimen adjustment in order to optimize antiretroviral effects.     

HIV-infected pregnant women have greater adherence with antiretroviral drugs than non-pregnant women

The objective of the study was to evaluate the influence of pregnancy on the level of adherence with antiretroviral (ARV) drugs, in a prospective cohort of 72 pregnant women and 79 non-pregnant women. Adherence was measured by pill counting and self-reporting. Women were deemed adherent if 95% or more of all ARV had been taken as prescribed, in two occasions. According to pill counting, 43.1 and 17.7% of pregnant and non-pregnant women, respectively, met the criteria of adherence (P = 0.001); in the postpartum, adherence declined to 20.6% (P = 0.002). In both groups, adherence rates by self-reporting were significantly higher as compared with pill counting (P = 0.001). In multivariate regression analysis, age >29 years (odds ratio [OR] 3.58, confidence interval [CI] 95% 0.10-0.75, P = 0.011), mean number of pills/day <6 (OR 2.53, CI 95% 1.07-6.01, P = 0.035), and being pregnant (OR 3.33, CI 95% 1.36-8.13, P = 0.008) were independently associated to greater adherence.     

Experience of nevirapine use in a London cohort of HIV-infected pregnant women

¹ King's College Hospital, ² St Thomas' Hospital, ³ St George's Hospital and ⁴ St Mary's Hospital, London, UK Objective To describe the experience of four London HIV centres prescribing nevirapine (NVP) to HIV‐1 infected pregnant women with respect to immunological and virological response, tolerability and pregnancy outcome. Methods We identified all HIV‐1‐infected women who received NVP as part of a triple antiretroviral regimen during pregnancy between January 1997 and September 1999. Laboratory results, clinical events, side‐effects and pregnancy outcome were abstracted using a standardized proforma from the medical records. Results Forty‐six women were identified, 85% of whom were black African. At initiation of NVP, the median age was 29 years and the median baseline CD4 cell count and viral load were 242 cells/μL and 4.15 log₁₀ copies/mL, respectively. Thirty‐two out of 36 women who had a plasma sample obtained at, or just prior to, delivery had an undetectable viral load (< 50 to < 400 copies/mL). Adverse events that were definitely attributed to NVP included a generalized rash (n = 2) and hepatitis (n = 2). Obstetric complications occurred in nine women (19.5%), which was not statistically different (P = 0.36) from that found in a historical (1990–96) control group 7/51 (14%). The rate of preterm delivery (13%) was similar to that previously reported in HIV‐1 infected pregnant women (18%). Conclusions NVP (as part of highly active antiretroviral therapy) reduced plasma viraemia to below the limit of detection in 89% of women. It was generally well tolerated and clinical and laboratory adverse events were infrequent. There was no evidence of an increase in obstetric complications including preterm delivery during the second and third trimesters of pregnancy.     

Pregnancy outcomes and pharmacokinetics in pregnant women living with HIV exposed to long-acting cabotegravir and rilpivirine in clinical trials

Background

Limited data exist on pregnant women living with HIV exposed to cabotegravir + rilpivirine (CAB + RPV). Outcomes in pregnant participants exposed to CAB + RPV, and pharmacokinetic washout data in those exposed to CAB + RPV long-acting (LA) with live births, are presented.

Methods

Women exposed to one or more doses of CAB + RPV (oral/LA) from ViiV Healthcare-sponsored phase 2b/3/3b clinical trials and the compassionate use programme who became pregnant were included. Upon pregnancy in the trial programme, CAB + RPV was discontinued, an alternative antiretroviral regimen was initiated, and quarterly pharmacokinetic sampling for 52 weeks post-last injection was obtained. CAB + RPV continuation or alternative antiretroviral regimen initiation was decided by pregnant compassionate use programme participants and their treating physicians.

Results

As of 31 March 2021, 25 pregnancies following CAB + RPV exposure at conception were reported (five oral, 20 LA), including four who conceived during pharmacokinetic washout following treatment discontinuation. There were eight elective abortions, six miscarriages (five in first trimester), one ectopic pregnancy, and 10 live births (one oral, nine LA), including one infant born with congenital ptosis. Among participants exposed to CAB + RPV LA at conception with live births, plasma CAB and RPV washout concentrations during pregnancy were within the range of those observed in non-pregnant women.

Conclusion

In this first analysis of pregnancy outcomes following CAB + RPV exposure at conception, 10 live births, including one with congenital anomaly, were reported. Plasma CAB and RPV washout concentrations during pregnancy were within the range of those in non-pregnant women. Pregnancy surveillance within ViiV Healthcare-sponsored clinical trials is ongoing, with dedicated pregnancy studies planned.     

Free-to-total leptin ratio in maternal plasma is constant throughout human pregnancy

To clarify the mechanism of leptin resistance during pregnancy, we measured plasma leptin concentrations, free to total leptin ratio (percent free leptin) and soluble leptin receptor concentrations in pregnant women, and compared the results with those in non-pregnant women. We collected plasma samples from 23 non-pregnant and 31 pregnant women in the third trimester. Plasma samples from 5 pregnant women were collected longitudinally in each trimester. Plasma leptin concentrations in pregnant women in the second trimester (17.4 +/- 3.2 ng/ml) were higher than those in the first trimester of pregnancy (11.0 +/- 2.8 ng/ml, n = 5), as previously reported. However, percent free leptin did not change significantly throughout pregnancy. Percent free leptin correlated with total leptin concentrations (ng/ml) in non-pregnant women (r = 0.727, P < 0.0001), but not in women in the third trimester of pregnancy (r = 0.006). Constant percent free leptin during pregnancy despite increased leptin concentrations indicates increased leptin binding capacity in pregnant women, that might partly contribute to the establishment of leptin resistance. On the other hand, soluble leptin receptor concentrations showed significant negative correlation with BMI and plasma leptin concentrations in pregnant women (r = -0.470, P < 0.01 and r = -0.493, P < 0.01, respectively) but not in non-pregnant women. These data suggest the possibility that soluble leptin receptor is a minor component of leptin binding capacity in the plasma of pregnant women.     

Cerebrospinal fluid and plasma HIV-1 RNA levels and lopinavir concentrations following lopinavir/ritonavir regimen

Our objective was to study the effect of lopinavir/ritonavir on cerebrospinal fluid (CSF) viral load as part of an antiretroviral combination treatment for HIV-1 infected individuals, and to determine the steady-state concentrations of lopinavir in CSF in relationship to plasma concentrations. Paired CSF and plasma samples from 12 antiretroviral-na?ve HIV-1 infected patients starting combination therapy containing lopinavir/ritonavir were collected at baseline, and during treatment at a first follow-up at median 3.0 months (range 2.6-6.0 months), and at a second follow-up at median 12.1 months (range 6.0-16.5 months). Levels of HIV-1 RNA, CD4+ T-cell count, beta2-microglobulin, neopterin, and lopinavir concentration were analysed. In addition, CSF and plasma lopinavir concentrations in 4 patients already on combination therapy including lopinavir/ritonavir were analysed. Nine of 11 patients had undetectable viral load in CSF and 5/11 in plasma at the first follow-up. At the second follow-up 7/7 had undetectable viral load in CSF and 9/9 in plasma. Intrathecal immunoactivation, measured by neopterin and beta2-microglobulin, decreased significantly both in CSF and serum. The total CSF concentrations of lopinavir were of the same order of magnitude as the unbound concentrations in plasma. Lopinavir mean (+/-SD) concentrations were 42.1 (+/-31.5) nM in CSF and 52.7 (+/-25.2) nM unbound in plasma. We found that antiretroviral combination therapy including lopinavir/ritonavir substantially decreases the viral load, both in CSF and plasma, as well as the intrathecal immunoactivation, measured by beta2-microglobulin and neopterin. CSF concentrations of lopinavir were low, but probably sufficient to have a virological effect.