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Tonse Pamodzi: Developing a combination strategy to support adherence to antiretroviral therapy and HIV pre-exposure prophylaxis during pregnancy and breastfeeding.
Hill, LM, Saidi, F, Freeborn, K, Amico, KR, Rosenberg, NE, Maman, S, Phanga, T, Tsidya, M, Chirwa, S, Zimba, C, et al
PloS one. 2021;(6):e0253280
Abstract
To eliminate mother-to-child transmission of HIV (EMTCT), scalable strategies to enhance antiretroviral adherence for both antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) are needed as part of integrated HIV and maternal-child health services. We developed Tonse Pamodzi ("all of us together"), an adaptable intervention integrating biomedical and behavioral components to support HIV treatment and prevention. We describe our intervention development process, which comprised formative qualitative research, a review of the literature, and technical input from stakeholders representing the community, health systems, and policymakers. The resulting intervention, described herein, integrates patient-centered counseling and engagement of a patient-selected adherence supporter for pregnant and breastfeeding women initiating ART or PrEP. Patients receiving the intervention engage in Integrated Next Step Counseling (iNSC) sessions delivered by trained counselors to build and maintain adherence skills. Each patient also has the option of selecting an adherence supporter (partner, family member, or friend) who may participate in iNSC sessions and provide adherence support outside of these sessions. This flexible intervention is adaptable not only to ART or PrEP use, but also to the needs and preferences of each woman and the clinical context. If shown to be acceptable and feasible, the Tonse Pamodzi intervention may be an important tool in continuing efforts for EMTCT.
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Long-term growth and bone development in children of HBV-infected mothers with and without fetal exposure to tenofovir disoproxil fumarate.
Wen, WH, Chen, HL, Shih, TT, Wu, JF, Ni, YH, Lee, CN, Zhao, LL, Lai, MW, Mu, SC, Tung, YC, et al
Journal of hepatology. 2020;(6):1082-1087
Abstract
BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) is the preferred treatment to prevent maternal transmission of HBV, owing to its efficacy and safety. However, data are lacking on the long-term safety outcomes in children following fetal exposure to TDF. METHODS Children participating in a prospective, multisite trial of maternal TDF treatment during late pregnancy were recruited for follow-up visits once a year. Growth parameters, serum biochemistry, HBV serology, and bone mineral density (BMD) by dual-energy x-ray absorptiometery scan were measured. RESULTS One hundred and twenty-eight children, 71 in the TDF and 57 in the control group, completed 255 follow-up visits at the age of 2 to 7 (median, 4.08) years. No differences in z-scores for weight-for-age (0.26 ± 0.90 vs. 0.22 ± 0.99, p = 0.481), z-scores for height-for-age (0.20 ± 1.02 vs. 0.25 ± 0.98, p = 0.812), and estimated glomerular filtration rate (169.12 ± 50.48 vs. 169.06 ± 34.46 ml/min/1.73m2, p = 0.479) were detected. After adjustment for age, sex and HBV status by multiple linear regression, children in the TDF and control group had comparable levels of serum calcium, phosphorus, bone-specific alkaline phosphatase, calcidiol and BMD of lumbar spines (0.55 ± 0.01 vs. 0.57 ± 0.01 g/cm2, p = 0.159) and left hip (0.56 ± 0.01 vs. 0.56 ± 0.01 g/cm2, p = 0.926). CONCLUSIONS Children of HBV-infected mothers who did or did not receive tenofovir disoproxil fumarate treatment during late pregnancy had comparable long-term growth, renal function, and bone development up to 6-7 years after delivery. CLINICAL TRIAL NUMBER NCT01312012 (ClinicalTrials.gov) LAY SUMMARY Currently there are insufficient long-term safety data in children born to mothers who took antiviral agents during pregnancy to prevent mother-to-infant transmission of hepatitis B virus (HBV). In this study, we found that children of HBV-infected mothers who did or did not receive tenofovir disoproxil fumarate treatment during late pregnancy had comparable long-term growth, renal function, and bone development up to 6-7 years after delivery.
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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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Raltegravir versus lopinavir/ritonavir for treatment of HIV-infected late-presenting pregnant women.
Brites, C, Nóbrega, I, Luz, E, Travassos, AG, Lorenzo, C, Netto, EM
HIV clinical trials. 2018;(3):94-100
Abstract
Background Late-presenting pregnant women pose a challenge in the prevention of HIV-1 mother-to-child-transmission. We compared the safety and efficacy of raltegravir and lopinavir/ritonavir for this population. Methods We did a single-center, pilot, open-label, randomized trial in Brazil (N = 44). We randomly allocated late-presenting HIV-infected pregnant women (older than 18 years with a plasma HIV-1 RNA >1000 copies/mL) to receive raltegravir 400 mg twice a day or lopinavir/ritonavir 400/100 mg twice a day plus zidovudine and lamivudine (1:1). The primary endpoint was virological suppression at delivery (HIV-1 RNA <50 copies per mL), in all patients who received at least one dose of study drugs (modified intention-to-treat analysis). Missing information was treated as failure. We assessed safety in all patients. Results We enrolled and randomly assigned treatment to 33 patients (17 in raltegravir group) between June 2015 and June 2017. The study was interrupted by the IRB because a significant difference between arms was detected in an interim analysis. All patients completed follow up at delivery. At delivery, virological suppression was achieved by 13/17 (76.5%) of patients in raltegravir group, versus 4/16 (25.0%) in lopinavir/ritonavir group (RR 3.1, 95% CI: 1.3-7.4). Patients in raltegravir group had significantly higher proportion of virological suppression at 2, 4, and 6 weeks than lopinavir/ritonavir group. Adverse events were most of mild intensity, but patients in lopinavir/ritonavir group had significantly more gastrointestinal adverse events. There was neither discontinuation nor deaths in this trial. Conclusion Raltegravir might be a first-line option for treatment of HIV-infected late-presenting pregnant women.
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Maternal Highly Active Antiretroviral Therapy Reduces Vertical Cytomegalovirus Transmission But Does Not Reduce Breast Milk Cytomegalovirus Levels.
Slyker, JA, Richardson, B, Chung, MH, Atkinson, C, Ásbjörnsdóttir, KH, Lehman, DA, Boeckh, M, Emery, V, Kiarie, J, John-Stewart, G
AIDS research and human retroviruses. 2017;(4):332-338
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Abstract
UNLABELLED To evaluate the impact of highly active antiretroviral therapy (HAART) on CMV transmission and breast milk level in the context of maternal HIV. Specimens from a randomized trial conducted in Nairobi, Kenya between 2003-2005 were used to compare CMV transmission and breast milk levels between mother-infant pairs randomized to HAART versus short-course antenatal zidovudine plus single-dose nevirapine (ZDV/sdNVP) for prevention of mother-to-child HIV transmission (PMTCT). Fifty-one antiretroviral-naïve women ≤32 weeks gestation, and CD4 between 200-500 cells/mm3 were randomized at 34 weeks to begin either antenatal ZDV/sdNVP, or HAART through 6 months postpartum. Mean breast milk CMV levels and transmission were compared between arms. Age, sociodemographics, CD4%, and HIV plasma RNA viral load were similar between arms at baseline. CMV viral loads were measured from 243 infant plasma and 185 breast milk specimens during the first year postpartum. The probability of infant CMV infection at 12 months was 19% lower in the HAART arm compared to ZDV/sdNVP (75% vs. 94%, p = .04). All women had CMV detected in breast milk, with 72%, 98%, and 97% testing positive during the first, second, and third weeks postpartum, respectively. There was a trend for early higher mean breast milk CMV level in the HAART arm at 1 week (p = .08), and there was significantly slower decline in breast milk CMV levels (area under the curve, p = .01). HAART started during the third trimester may decrease infant CMV infections, by mechanisms independent of breast milk CMV levels. CLINICAL TRIALS REGISTRATION NCT00167674.
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Assessment of Nevirapine Prophylactic and Therapeutic Dosing Regimens for Neonates.
Cressey, TR, Punyawudho, B, Le Coeur, S, Jourdain, G, Saenjum, C, Capparelli, EV, Jittayanun, K, Phanomcheong, S, Luvira, A, Borkird, T, et al
Journal of acquired immune deficiency syndromes (1999). 2017;(5):554-560
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BACKGROUND Nevirapine (NVP) is a key component of antiretroviral prophylaxis and treatment for neonates. We evaluated current World Health Organization (WHO) weight-band NVP prophylactic dosing recommendations and investigated optimal therapeutic NVP dosing for neonates. METHODS The PHPT-5 study in Thailand assessed the efficacy of "Perinatal Antiretroviral Intensification" to prevent mother-to-child transmission of HIV in women with <8 weeks of antiretroviral treatment before delivery (NCT01511237). Infants received a 2-week course of zidovudine/lamivudine/NVP (NVP syrup/once daily: 2 mg/kg for 7 days; then 4 mg/kg for 7 days). Infant samples were assessed during the first 2 weeks of life. NVP population pharmacokinetics (PK) parameters were estimated using nonlinear mixed-effects models. Simulations were performed to estimate the probability of achieving target NVP trough concentrations for prophylaxis (>0.10 mg/L) and for therapeutic efficacy (>3.0 mg/L) using different infant dosing strategies. RESULTS Sixty infants (55% male) were included. At birth, median (range) weight was 2.9 (2.3-3.6) kg. NVP concentrations were best described by a 1-compartment PK model. Infant weight and postnatal age influenced NVP PK parameters. Based on simulations for a 3-kg infant, ≥92% would have an NVP trough >0.1 mg/L after 48 hours through 2 weeks using the PHPT-5 and WHO-dosing regimens. For NVP-based therapy, a 6-mg/kg twice daily dose produced a trough >3.0 mg/L in 87% of infants at 48 hours and 80% at 2 weeks. CONCLUSION WHO weight-band prophylactic guidelines achieved target concentrations. Starting NVP 6 mg/kg twice daily from birth is expected to achieve therapeutic concentrations during the first 2 weeks of life.
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Resistance detected by pyrosequencing following zidovudine monotherapy for prevention of HIV-1 mother-to-child-transmission.
Olson, SC, Ngo-Giang-Huong, N, Beck, I, Deng, W, Britto, P, Shapiro, DE, Bumgarner, RE, Mullins, JI, Van Dyke, RB, Jourdain, G, et al
AIDS (London, England). 2015;(12):1467-71
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Abstract
To prevent mother-to-child-transmission of HIV-1, the 2010 WHO guidelines recommended prenatal zidovudine (ZDV) monotherapy (option A). To determine if ZDV monotherapy selects for HIV resistance in antiretroviral-naive women during pregnancy, specimens from 50 individuals were examined using pyrosequencing. ZDV-resistance mutations were detected at delivery in seven women (14%, 95% confidence interval 6.6-26.5%). These data raise the question whether women administered ZDV monotherapy for prevention of mother-to-child-transmission could have higher risk of virologic failure when later started on combination antiretroviral therapy, as has been demonstrated following single-dose nevirapine prophylaxis.
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Exclusive breastfeeding among women taking HAART for PMTCT of HIV-1 in the Kisumu Breastfeeding Study.
Okanda, JO, Borkowf, CB, Girde, S, Thomas, TK, Lecher, SL
BMC pediatrics. 2014;:280
Abstract
BACKGROUND One of the most effective ways to promote the prevention of mother-to-child transmission (PMTCT) of HIV-1 in resource-limited settings is to encourage HIV-positive mothers to practice exclusive breastfeeding (EBF) for the first 6 months post-partum while they receive antiretroviral therapy (ARV). Although EBF reduces mortality in this context, its practice has been low. We studied the rate of adherence to EBF and assessed associated maternal and infant characteristics using data from a phase II PMTCT clinical trial conducted in Western Kenya which included a counseling intervention to encourage EBF by all participants. METHODS We analyzed data from the Kisumu Breastfeeding Study (KiBS), conducted between July 2003 and February 2009. This study enrolled a total of 522 HIV-1 infected pregnant women. Data on breastfeeding were available for 480 mother-infant pairs. Infant feeding and general nutrition counseling began at 35 weeks gestation and continued throughout the 6 month post-partum intervention period, following World Health Organization (WHO) infant feeding guidelines. Data on infant feeding were collected during routine clinic visits and home visits using food frequency questionnaires and dietary recall methods. Participants were instructed to exclusively breastfeed until initiation of weaning at 5.5 months post-partum. We used Kaplan-Meier methods to estimate the rates of EBF at 5.25 months post-partum, stratified by maternal and infant characteristics measured at enrollment, delivery, and 2 weeks post-partum. RESULTS The estimated EBF rate at 5.25 months post-partum was 80.4%. Only 3% of women introduced other foods (most commonly water with or without glucose, cow's milk, formula, and fruit) by 2 months; this percentage increased to 5% of women by 4 months. Women who had ≥3 previous births (p < 0.01) and who were not living with the infant's father (p = 0.04) were more likely to exclusively breastfeed. Mixed feeding was more common for male infants than for female infants (p = 0.04). CONCLUSION Exclusive breastfeeding was common in this clinical trial, which emphasized EBF as a best practice until infants reached 5.5 months of age. Counseling initiated prior to delivery and continued during the post-partum period provided a consistent message reinforcing the benefits of EBF. The findings from this study suggest high adherence to EBF in resource limited settings can be achieved by a comprehensive counseling intervention that encourages EBF.
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Population pharmacokinetic analysis of a nevirapine-based HIV-1 prevention of mother-to-child transmission program in Uganda to assess the impact of different dosing regimens for newborns.
Frank, M, Harms, G, Kunz, A, Kloft, C
Journal of clinical pharmacology. 2013;(3):294-304
Abstract
Single-dose nevirapine for mothers and newborns at delivery is the simplest prevention strategy for vertical HIV-1 transmission and hence widely used in resource-constrained settings. HIV-1-positive mothers and newborns received single-dose nevirapine in a prevention of mother-to-child HIV-1 transmission (PMTCT) program in Uganda. In a pharmacokinetic investigation, breast milk and plasma samples of mothers and newborns were collected. The nonlinear mixed-effects modeling approach was suitable for analysis (average: 1.8 samples/matrix/individual). For describing the nevirapine pharmacokinetics in mothers and newborns, a 1-compartment model was demonstrated to be sufficient. The plasma-placenta transfer could be quantified, revealing a transfer fraction of 11% to 25% (with a significant influence of time span between maternal nevirapine intake and birth) and a high transfer rate constant from maternal drug administration. Interindividual variability was moderate between mothers and high between newborns. Simulations revealed that newborns born early (<1 hour) after maternal nevirapine intake would benefit from a 3-fold higher nevirapine dosage (6 mg/kg) after birth for analogous protective plasma concentrations over the first 2 weeks. In contrast, postnatal nevirapine dosage seemed to be dispensable for newborns born late (>24 hours) after maternal nevirapine intake. These dosing recommendations should be evaluated in prospective studies, including additional antiretroviral drugs in accordance with current PMTCT guidelines.
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Long-term follow-up of children in the HIVNET 012 perinatal HIV prevention trial: five-year growth and survival.
Owor, M, Mwatha, A, Donnell, D, Musoke, P, Mmiro, F, Allen, M, Jackson, JB, Fowler, MG, Guay, LA
Journal of acquired immune deficiency syndromes (1999). 2013;(5):464-71
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OBJECTIVES To describe 5-year growth, survival, and long-term safety among children exposed to nevirapine or zidovudine in an African perinatal prevention trial, HIVNET 012. METHODS All study children who were alive at the age 18 months were eligible for an extended follow-up study. Children whose families consented were enrolled and evaluated every 6 months from 24 to 60 months. At each visit, history, physical examination, and growth measures were taken. From these measurements, Z scores based on World Health Organization (WHO) standards were computed. Serious adverse event data were collected. Data from the initial and extended follow-up cohorts were included in the analysis. RESULTS Five hundred twenty-eight study children were alive at the age 18 months, and 491 (426 HIV uninfected and 65 infected) were enrolled into the follow-up study. Both exposed but uninfected children and HIV-infected children were substantially below WHO growth standards for weight and height. Head circumference Z scores for uninfected children were comparable with WHO norms. Five-year survival rates were 93% for uninfected children versus 43% for infected children. Long-term safety and growth outcomes in the 2 study arms were similar. CONCLUSIONS Both infected and uninfected children in the 5-year HIVNET 012 follow-up showed poor height and weight growth outcomes, underscoring the need for early nutritional interventions to improve long-term growth of all infants born to HIV-infected women in resource-limited settings. Similarly, the low 5-year survival among HIV-infected children support the importance of early initiation of antiretroviral therapy. Both peripartum nevirapine and zidovudine were safe.