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Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: A randomised trial (DolPHIN-1 study).
Waitt, C, Orrell, C, Walimbwa, S, Singh, Y, Kintu, K, Simmons, B, Kaboggoza, J, Sihlangu, M, Coombs, JA, Malaba, T, et al
PLoS medicine. 2019;(9):e1002895
Abstract
BACKGROUND The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3). METHODS AND FINDINGS In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3-8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum. CONCLUSION Despite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy. TRIAL REGISTRATION clinicaltrials.gov NCT02245022.
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Pharmacokinetics of HIV-Integrase Inhibitors During Pregnancy: Mechanisms, Clinical Implications and Knowledge Gaps.
van der Galiën, R, Ter Heine, R, Greupink, R, Schalkwijk, SJ, van Herwaarden, AE, Colbers, A, Burger, DM
Clinical pharmacokinetics. 2019;(3):309-323
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Abstract
Prevention of mother-to-child transmission of HIV and optimal maternal treatment are the most important goals of antiretroviral therapy in pregnant women with HIV. These goals may be at risk due to possible reduced exposure during pregnancy caused by physiological changes. Limited information is available on the impact of these physiological changes. This is especially true for HIV-integrase inhibitors, a relatively new class of drugs, recommended first-line agents and hence used by a large proportion of HIV-infected patients. Therefore, the objective of this review is to provide a detailed overview of the pharmacokinetics of HIV-integrase inhibitors in pregnancy. Second, this review defines potential causes for the change in pharmacokinetics of HIV-integrase inhibitors during pregnancy. Despite increased clearance, for raltegravir 400 mg twice daily and dolutegravir 50 mg once daily, exposure during pregnancy seems adequate; however, for elvitegravir, the proposed minimal effective concentration is not reached during pregnancy. Lower exposure to these drugs may be caused by increased hormone levels and, subsequently, enhanced drug metabolism during pregnancy. The pharmacokinetics of bictegravir and cabotegravir, which are under development, have not yet been evaluated in pregnant women. New studies need to prospectively assess whether adequate exposure is reached in pregnant women using these new HIV-integrase inhibitors. To further optimize antiretroviral treatment in pregnant women, studies need to unravel the underlying mechanisms behind the changes in the pharmacokinetics of HIV-integrase inhibitors during pregnancy. More knowledge on altered pharmacokinetics during pregnancy and the underlying mechanisms contribute to the development of effective and safe antiretroviral therapy for HIV-infected pregnant women.
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Pre-exposure prophylaxis for HIV prevention during pregnancy and lactation: forget not the women and children.
Horgan, L, Blyth, CC, Bowen, AC, Nolan, DA, McLean-Tooke, AP
The Medical journal of Australia. 2019;(6):281-284
Abstract
Pregnancy is known to be a time of increased susceptibility to acquiring to human immunodeficiency virus (HIV) infection and this increased maternal risk places the unborn child at risk of vertical transmission. Pre-exposure prophylaxis (PrEP) involves the provision of antiretroviral therapy to an HIV-negative individual with ongoing risk of HIV exposure to limit the likelihood of HIV transmission. The inclusion of PrEP as part of a comprehensive strategy is recognised as an effective and safe means of reducing HIV infection in serodiscordant couples, thereby reducing the risk of vertical transmission of HIV. Current data suggest that PrEP is safe to continue during pregnancy and breastfeeding in HIV-negative women who remain vulnerable to acquiring HIV. The recent Pharmaceutical Benefits Scheme subsidisation of PrEP has reduced the financial and practical obstacles of PrEP provision, and a subsequent increase in patient awareness and acceptance of PrEP is expected. The framework for appropriately identifying and managing at-risk pregnant and lactating women requiring PrEP is poorly defined and warrants further clarification to better support clinicians and this patient group. This review discusses the current recommendations highlighting the gaps in the guidelines and makes some recommendations for future guideline development.
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HIV Retesting of HIV-Negative Pregnant Women in the Context of Prevention of Mother-to-Child Transmission of HIV in Primary Health Centers in Rural Zambia: What Did We Learn?
Mandala, J, Kasonde, P, Badru, T, Dirks, R, Torpey, K
Journal of the International Association of Providers of AIDS Care. 2019;:2325958218823530
Abstract
BACKGROUND This observational study describes implementation of HIV retesting of HIV-negative women in prevention of mother-to-child transmission (PMTCT) services in Zambia. METHODS Uptake of retesting and PMTCT services were compared across age, parity, and weeks of gestation at the time of the first HIV test, antiretrovirals regime, and HIV early diagnosis results from infants born to HIV-positive mothers. RESULTS A total of 19 090 pregnant women were tested for HIV at their first antenatal visit, 16 838 tested HIV-negative and were offered retesting 3 months later: 11 339 (67.3%) were retested; of those, 55 (0.5%) were HIV positive. Uptake of the PMTCT package by women HIV positive at retest was not different but HIV-exposed infants born to women who retested HIV positive were infected at a higher rate (11.1%) compared to those born to women who tested HIV positive at their initial test (3.2%). CONCLUSION We suggest rigorously (1) measuring the proportion of MTCT attributable to women who seroconvert during pregnancy and possibly adjust PMTCT approaches and (2) addressing the substantial loss to follow-up of HIV-negative pregnant women before HIV retesting.
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Microbial transmission from mother to child: improving infant intestinal microbiota development by identifying the obstacles.
Van Daele, E, Knol, J, Belzer, C
Critical reviews in microbiology. 2019;(5-6):613-648
Abstract
Industrialisation has introduced several lifestyle changes and medical advancements but their impact on intestinal microbiota acquisition is often overlooked. Even though these consequential changes in the microbiota could contribute to the disease burden that accompanies industrialisation, such as obesity and atopic disease. A healthy intestinal microbiota is acquired early in life but its exact origin is not fully elucidated. The maternal microbiota is a likely source because the infant and mother intestinal microbiota share identical strains. Successfully transmitting microbes from mother to child requires microbes in the maternal donor, contact between the maternal source and the infant, and an acquiring infant recipient. Transmission can be altered by changes to any of those three transmission determinants: (1) maternal microbiota sources are shaped by the mother's genotype, diet, health status and perturbing antimicrobial exposure; (2) maternal contact is reduced through C-section and formula feeding and (3) engraftment in the infant recipient is determined by host habitat filtering, the established microbes and antibiotic disruptions. This review gives an overview of the possible maternal transmission routes, the disruptions thereof, and the missing links that should be addressed in future research to investigate the maternal transmissions that are crucial for obtaining a healthy infant microbiota.
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Short-term Pasteurization of Breast Milk to Prevent Postnatal Cytomegalovirus Transmission in Very Preterm Infants.
Bapistella, S, Hamprecht, K, Thomas, W, Speer, CP, Dietz, K, Maschmann, J, Poets, CF, Goelz, R
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019;(3):438-444
Abstract
BACKGROUND Postnatally acquired cytomegalovirus (pCMV) infection through breast milk (BM) may cause severe illness and even death, yet BM is advantageous for preterm infants. Therefore, effective methods to prevent CMV transmission are needed. METHODS To assess the effectiveness of short-term pasteurization (62°C for 5 seconds) in preventing CMV transmission via BM in preterm infants. Design: Prospective interventional bicentric cohort study with infant enrollment between 6/2010 and 1/2012. A cohort from the Tuebingen neonatal intensive care unit (NICU) from 1995-1998 served as historical controls. Differences in CMV transmission were compared with reference to the cumulative time at risk for CMV transmission. Setting: Two German level-3 NICUs. Eighty-seven preterm infants of 69 CMV immunoglobulin G-positive mothers with birth weight <1500 g or gestational age <32 weeks and 83 historical controls were included. Intervention: BM samples were short-term pasteurized from postnatal day 4 to discharge. Primary endpoint: CMV status at discharge, evaluated by polymerase chain reaction and short-term microculture from urine. RESULTS Two of 87 (2.3%) study infants had a pCMV transmission. This compared to 17 of 83 (20.5%) controls. Total time under risk for infection was 9.6 years vs 10.0 years in controls, yielding an incidence of 0.21/year (95% confidence interval [CI], 0.03 to 0.75/year) vs 1.70/year (95% CI, 0.99 to 2.72/year), respectively. The risk ratio controls vs study infants was 8.3 (95% CI, 2.4 to 52.4) according to Cox proportional hazard model (P = .0003). CONCLUSIONS Short-term pasteurization significantly reduces the incidence of pCMV infection through BM in the NICU. CLINICAL TRIALS REGISTRATION NCT01178905.
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Management Algorithm for Interrupting Mother-to-Child Transmission of Hepatitis B Virus.
Hou, J, Cui, F, Ding, Y, Dou, X, Duan, Z, Han, G, Jia, J, Mao, Q, Li, J, Li, Z, et al
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2019;(10):1929-1936.e1
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Abstract
In areas where hepatitis B virus (HBV) is endemic, mother-to-child transmission (MTCT) is the major route of infection of children. Blocking MTCT of HBV therefore would reduce its prevalence. The China Foundation of Hepatitis Prevention and Control organized a team of specialists in infectious diseases, hepatology, immunology, obstetrics, and public health to develop an algorithm for interrupting MTCT of HBV, based on the most recent hepatitis B guidelines and latest evidence. This algorithm comprises 10 steps and has been adopted in clinical practice in China. Four aspects (screening, antiviral intervention during pregnancy, immunoprophylaxis, and postvaccination serologic testing) are the core components of preventing MTCT. Although the combination of passive and active immunization in newborns of hepatitis B surface antigen-positive mothers reduces MTCT of HBV, this immunoprophylaxis cannot completely eradicate MTCT. In the past decade, administration of antiviral agents to pregnant women has been shown to be safe and effective in reducing MTCT of HBV in combination with immunoprophylaxis. Aiming to achieve zero MTCT, this algorithm recommends the use of antivirals during pregnancy by women with high viral loads. Preventing MTCT is key to achieving the goal of eliminating HBV as a public health threat by 2030. Implementation and enhancement of the standardized algorithm for pregnant women with chronic HBV infection and their infants is urgently needed to prevent MTCT.
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Efficacy and safety of tenofovir in preventing mother-to-infant transmission of hepatitis B virus: a meta-analysis based on 6 studies from China and 3 studies from other countries.
Li, W, Jia, L, Zhao, X, Wu, X, Tang, H
BMC gastroenterology. 2018;(1):121
Abstract
BACKGROUND The vertical transmission of HBV from mothers to their infants at birth or in early infancy has a significant role in the endemicity of HBV infection. Tenofovir is one of the most potent anti-HBV agents with a high genetic barrier to resistance. The study is to evaluate the efficacy of tenofovir in preventing perinatal HBV transmission, as well as monitoring safety for mothers and infants. METHODS PubMed, Embase, Web of Science, and CNKI (National Knowledge Infrastructure, China) database were systematically reviewed for studies that compared the efficacy and safety of tenofovir with other treatments. Pooled estimates were expressed with weight mean difference (WMD) with 95% confidence intervals (95% CIs) and risk ratio (RR) with 95% CIs. RESULTS Nine studies involving 1046 pregnant patients met the inclusion criteria and were included in this meta-analysis. Compared with other treatments, tenofovir significantly reduced maternal HBV DNA levels (WMD = 2.33 log10 IU/mL, 95% CI: 1.01, 3.64; P < 0.001), infant HBsAg positivity rate (RR = 0.25, 95% CI: 0.16, 0.38; P < 0.001), infant HBeAg positivity rate (RR = 0.26, 95% CI: 0.14, 0.48; P < 0.001), infant HBV DNA positivity rate (RR = 0.15, 95% CI: 0.07, 0.31; P < 0.001), and immunoprophylaxis failure rate (RR = 0.31, 95% CI: 0.13, 0.73; P = 0.008). Moreover, maternal and infant safety profiles, including ALT, CK, and Cr were comparable between tenofovir and other treatment groups. CONCLUSION Based on the current evidence, our study suggested that tenofovir significantly reduced the rate of vertical transmission of HBV, as well as the HBV DNA levels in HBV-infected mothers. Moreover, tenofovir was safe and tolerable for both mothers and their infants.
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Prevention of HIV-1 Transmission Through Breastfeeding: Efficacy and Safety of Maternal Antiretroviral Therapy Versus Infant Nevirapine Prophylaxis for Duration of Breastfeeding in HIV-1-Infected Women With High CD4 Cell Count (IMPAACT PROMISE): A Randomized, Open-Label, Clinical Trial.
Flynn, PM, Taha, TE, Cababasay, M, Fowler, MG, Mofenson, LM, Owor, M, Fiscus, S, Stranix-Chibanda, L, Coutsoudis, A, Gnanashanmugam, D, et al
Journal of acquired immune deficiency syndromes (1999). 2018;(4):383-392
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BACKGROUND No randomized trial has directly compared the efficacy of prolonged infant antiretroviral prophylaxis versus maternal antiretroviral therapy (mART) for prevention of mother-to-child transmission throughout the breastfeeding period. SETTING Fourteen sites in Sub-Saharan Africa and India. METHODS A randomized, open-label strategy trial was conducted in HIV-1-infected women with CD4 counts ≥350 cells/mm (or ≥country-specific ART threshold if higher) and their breastfeeding HIV-1-uninfected newborns. Randomization at 6-14 days postpartum was to mART or infant nevirapine (iNVP) prophylaxis continued until 18 months after delivery or breastfeeding cessation, infant HIV-1 infection, or toxicity, whichever occurred first. The primary efficacy outcome was confirmed infant HIV-1 infection. Efficacy analyses included all randomized mother-infant pairs except those with infant HIV-1 infection at entry. RESULTS Between June 2011 and October 2014, 2431 mother-infant pairs were enrolled; 97% of women were World Health Organization Clinical Stage I, median screening CD4 count 686 cells/mm. Median infant gestational age/birth weight was 39 weeks/2.9 kilograms. Seven of 1219 (0.57%) and 7 of 1211 (0.58%) analyzed infants in the mART and iNVP arms, respectively, were HIV-infected (hazard ratio 1.0, 96% repeated confidence interval 0.3-3.1); infant HIV-free survival was high (97.1%, mART and 97.7%, iNVP, at 24 months). There were no significant differences between arms in median time to breastfeeding cessation (16 months) or incidence of severe, life-threatening, or fatal adverse events for mothers or infants (14 and 42 per 100 person-years, respectively). CONCLUSIONS Both mART and iNVP prophylaxis strategies were safe and associated with very low breastfeeding HIV-1 transmission and high infant HIV-1-free survival at 24 months.
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Knowledge, attitude and practice of infant feeding in the first 6 months among HIV-positive mothers at the Queen Mamohato Memorial hospital clinics, Maseru, Lesotho.
Olorunfemi, SO, Dudley, L
African journal of primary health care & family medicine. 2018;(1):e1-e12
Abstract
BACKGROUND The balance between the risks of transmission of human immunodeficiency virus (HIV) through breastfeeding and its life-saving benefits complicates decisions about infant feeding among HIV-positive mothers in the first 6 months. OBJECTIVE The aim of this study was to assess the knowledge, attitude and practice of infant feeding among HIV-positive mothers attending the prevention of mother-to-child transmission services in Maseru, Lesotho.Method and setting: This observational cross-sectional study was done by collecting data from HIV-positive mothers attending the filter clinics of Queen Mamohato Memorial hospital in Maseru, Lesotho. HIV-positive mothers with infants below the age of 6 months attending the clinics at the time of the study were interviewed using a standardised questionnaire. We described the sociodemographic profile of the mothers, the information and education received on prevention of mother-to-child transmission (PMTCT) infant feeding options, the mothers' knowledge, attitudes and practices of infant feeding, and assessed risk factors for improved knowledge, attitudes and practices. RESULTS The majority (96%) of the 191 HIV-positive mothers who participated in the survey knew about the PMTCT programme and related breastfeeding services. Most of the participants chose to breastfeed (89%), while only 8% formula-fed their infants. Knowledge received during the PMTCT programme was significantly associated with the decision to exclusively breastfeed their infants. Earlier infant feeding counselling and education was associated with more exclusively breastfeeding as compared to late infant feeding counselling (p < 0.001). CONCLUSION The study found that HIV-positive mothers attending health clinics in Maseru, Lesotho, had high knowledge, and appropriate attitudes and practices with respect to infant feeding; and that early counselling and education improved infant feeding methods among these mothers.