Short term GABA antagonist treatment improves long term sleep quality, memory, and decision-making in a Down syndrome mouse model.

Down syndrome (DS) is a common genetic condition affecting people worldwide. It involves cognitive disabilities for which there are no drug therapies. The Ts65Dn mouse model of DS shows cognitive impairment due to a reduction in neuron number and connectivity as well as excessive neuronal activity, as GABA antagonist treatment restores memory in these mice.

Correction: Caregivers of children with HIV in Botswana prefer monthly IV Broadly Neutralizing Antibodies (bNAbs) to daily oral ART.

[This corrects the article DOI: 10.1371/journal.pone.

Caregivers of children with HIV in Botswana prefer monthly IV Broadly Neutralizing Antibodies (bNAbs) to daily oral ART.

Introduction: Monthly intravenous infusion of broadly neutralizing monoclonal antibodies may be an attractive alternative to daily oral antiretroviral treatment for children living with HIV. However, acceptability among caregivers remains unknown.

Methods: We evaluated monthly infusion of dual bNAbs (VRCO1LS and 10-1074) as a treatment alternative to ART among children participating in the Tatelo Study in Botswana.

Growth and micronutrient status parameters of Nigerian preterm infants consuming preterm formula or breastmilk.

Background: Moderate-to-late preterm infants (32-34 weeks GA) have increased risk of neonatal morbidities compared to term infants, however dedicated nutritional guidelines are lacking.

Methods: Moderate-to-late preterm infants received a preterm formula (n = 17) or breastmilk (n = 24) from age 2-10 weeks in a non-randomized, open-label observational study. Anthropometric measurements were assessed bi-weekly.

Correction: Youth and healthcare workers' perspectives on the feasibility and acceptability of self-testing for HIV, Hepatitis and Syphilis among young people: Qualitative findings from a pilot study in Gaborone, Botswana.

[This corrects the article DOI: 10.1371/journal.pone.

No increased in utero and peripartum HIV acquisition risk in HIV-exposed preterm infants.

Background: Limited data exist on the differential risk of HIV acquisition between infants born preterm versus those born at term to women living with HIV (WLHIV). With a reported increase in preterm delivery among pregnant WLHIV, understanding the risk of vertical transmission of HIV in preterm infants can inform strategies to optimise the timing of diagnostic testing, antiretroviral prophylaxis, and infant feeding.

Objectives: To describe the prevalence and timing of HIV acquisition, in utero versus perinatal, among infants with perinatal HIV exposure born prior to 37 weeks completed gestation age compared to those born at term in the Botswana-based Mpepu study and explore predictors of infant HIV acquisition.

Broadly neutralizing antibody treatment maintained HIV suppression in children with favorable reservoir characteristics in Botswana.

Broadly neutralizing antibodies (bNAbs) may provide an alternative to standard antiretroviral treatment (ART) for controlling HIV-1 replication and may have immunotherapeutic effects against HIV-1 reservoirs. We conducted a prospective clinical trial with two HIV-1 bNAbs (VRC01LS and 10-1074) in children ( = 25) who had previously initiated small-molecule ART treatment before 7 days of age and who continued treatment for at least 96 weeks. Both bNAbs were dosed intravenously every 4 weeks, overlapping with ART for at least 8 weeks and then continued for up to 24 weeks or until detectable viremia of HIV-1 RNA rose above 400 copies per milliliter in the absence of ART.

Antibody interventions in HIV: broadly neutralizing mAbs in children.

Purpose Of Review: Treatment strategies for children with HIV are evolving, with considerations beyond plasma viremic control that raise the possibility of reducing or eliminating latent reservoirs to achieve posttreatment control. Novel strategies that maintain HIV viral suppression and allow time off small molecule antiretroviral therapy (ART) are of high priority. Trials with broadly neutralizing mAbs (bNAbs) have begun in children and may become a viable alternative treatment option.

Immune Modulation of HIV-1 Reservoir Size in Early-Treated Neonates.

Immune mechanisms that modulate human immunodeficiency virus-1 (HIV-1) reservoir size in neonates are poorly understood. Using samples from neonates who initiated antiretroviral therapy shortly after birth, we demonstrate that interleukin-8-secreting CD4 T cells, which are selectively expanded in early infancy, are more resistant to HIV-1 infection and inversely correlated with the frequency of intact proviruses at birth. Moreover, newborns with HIV-1 infection displayed a distinct B-cell profile at birth, with reduction of memory B cells and expansion of plasmablasts and transitional B cells; however, B-cell immune perturbations were unrelated to HIV-1 reservoir size and normalized after initiation of antiretroviral therapy.

Brief Report: Long-Term Clinical, Immunologic, and Virologic Outcomes Among Early-Treated Children With HIV in Botswana: A Nonrandomized Controlled Clinical Trial.

Background: Early antiretroviral treatment (ART) improves outcomes in children, but few studies have comprehensively evaluated the impact of ART started from the first week of life.

Methods: Children diagnosed with HIV within 96 hours of life were enrolled into the Early Infant Treatment Study in Botswana and followed on ART for 96 weeks. Nevirapine, zidovudine, and lamivudine were initiated; nevirapine was switched to lopinavir/ritonavir between weeks 2-5 in accordance with gestational age.

Immune correlates of HIV-1 reservoir cell decline in early-treated infants.

Initiation of antiretroviral therapy (ART) in infected neonates within hours after birth limits viral reservoir seeding but does not prevent long-term HIV-1 persistence. Here, we report parallel assessments of HIV-1 reservoir cells and innate antiviral immune responses in a unique cohort of 37 infected neonates from Botswana who started ART extremely early, frequently within hours after birth. Decline of genome-intact HIV-1 proviruses occurs rapidly after initiation of ART and is associated with an increase in natural killer (NK) cell populations expressing the cytotoxicity marker CD57 and with a decrease in NK cell subsets expressing the inhibitory marker NKG2A.

Prolonged Cotrimoxazole Prophylaxis Has No Impact on Child Growth in the First Two Years of Life: Findings from a Randomized Controlled Trial in Botswana.

We investigated the impact of prolonged cotrimoxazole prophylaxis on growth in 2848 HIV-exposed uninfected children enrolled in the Mpepu study, a randomized, placebo-controlled trial in Botswana. No significant differences in mean weight-for-age, length-for-age, or weight-for-length z scores between placebo and cotrimoxazole arms were observed overall through 18 months.

Are morbidity and mortality estimates from randomized controlled trials externally valid? A comparison of outcomes among infants enrolled into an RCT or a cohort study in Botswana.

Background: The external validity of the randomized controlled trial (RCT) refers to the extent to which the results of the RCT apply to the relevant, non-trial population and is impacted by its eligibility criteria, its organization, and its delivery of the intervention. Here, we compared the outcomes of mortality and hospitalization between an RCT and a cohort study that concurrently enrolled HIV-exposed uninfected (HEU) newborns in Botswana.

Methods: The Mpepu Study (the RCT) was a clinical trial which determined that co-trimoxazole (CTX) provided no survival benefit for HEUs, allowing both arms of the RCT to be used.

Patterns of pretreatment drug resistance mutations of very early diagnosed and treated infants in Botswana.

Objective: To describe the occurrence of HIV drug resistance mutations (DRMs) in both intact and defective HIV-1 cell-associated DNA (HIV-1 CAD) among early-treated infants.

Design: The Botswana EIT Study (ClinicalTrials.gov NCT02369406) initiated antiretroviral therapy (ART) in the first week of life and evaluated HIV-1 in plasma and peripheral blood mononuclear cells (PBMCs).

Factors Associated with Infant Feeding Choices Among Women with HIV in Botswana.

Introduction: In resource-constrained settings, infant feeding decisions among women with HIV (WHIV) must balance the risk of infant HIV acquisition from breastfeeding with increased mortality associated with formula feeding. WHO guidelines recommend countries principally promote a single feeding method for WHIV, either breastfeeding or formula feeding. In 2016, Botswana revised its policy of formula feeding for infants born to WHIV, instead promoting exclusive breastfeeding during the first 6 months of life.

Viral Reservoir in Early-Treated Human Immunodeficiency Virus-Infected Children and Markers for Sustained Viral Suppression.

Background: The impact of very early infant treatment on human immunodeficiency virus (HIV) reservoir, and markers for treatment success, require study.

Methods: The Early Infant Treatment Study (EIT) enrolled 40 children living with HIV started on antiretroviral treatment (ART) at <7 days of age, with 23 who had started treatment between 30-365 days to serve as controls. Quantitative HIV DNA was evaluated every 1-3 months in peripheral blood mononuclear cells.

Decreased diarrheal and respiratory disease in HIV exposed uninfected children following vaccination with rotavirus and pneumococcal conjugate vaccines.

Background: Rotavirus vaccine (RV) and pneumococcal vaccine (PCV) decrease diarrheal and respiratory disease incidence and severity, but there are few data about the effects of these vaccines among HIV-exposed uninfected (HEU) children.

Methods: We recorded RV and PCV vaccination history in a placebo-controlled trial that studied the need for cotrimoxazole among HEU infants in Botswana (the Mpepu Study). We categorized infants by enrollment before or after the simultaneous April 2012 introduction of RV and PCV, and compared diagnoses of diarrhea and pneumonia (grade 3/4), hospitalizations, and deaths from both disease conditions through the 12-month study visit by vaccine era/status across two sites (a city and a village) by Kaplan-Meier estimates.

Child HIV Exposure and CMV Seroprevalence in Botswana: No Associations With 24-Month Growth and Neurodevelopment.

Background: We sought to identify predictors of child cytomegalovirus (CMV) infection overall and by maternal HIV status and to assess associations of child CMV status with growth and neurodevelopmental outcomes at 24 months of age in Botswana.

Methods: Data and samples were used from the Botswana-based observational Tshipidi study (2010-2014), enrolling pregnant women living with and without HIV and following their infants through 2 years of age. Child plasma samples were tested at 18 months of age for anti-CMV immunoglobulin G (IgG).

Hepatitis B virus prevalence and vaccine antibody titers in children HIV exposed but uninfected in Botswana.

Background: Botswana introduced the HBV vaccine at birth for all newborns in 2000. To the best of our knowledge, since the introduction of HBV vaccination, there have been limited data for vaccine response to HBV and its impact on early childhood HBV infections among children HIV exposed but uninfected in Botswana.

Aims: To determine the prevalence of hepatitis B surface antigen (HBsAg) and HBV vaccine response in 18 months old children HIV exposed but uninfected in Botswana.

HIV diagnostic algorithm requires confirmatory testing for initial indeterminate or positive screens in the first week of life.

Background: Risk for nondiagnostic and false-positive HIV testing has not been quantified for neonates.

Methods: From April 2015 to July 2018, we screened HIV-exposed infants in Botswana less than 96 h from birth by qualitative DNA PCR. Repeat blood draws for DNA and RNA PCR testing occurred for initial positive and indeterminate results to establish final diagnosis.

Mother-to-Child HIV Transmission With In Utero Dolutegravir vs. Efavirenz in Botswana.

Background: A large-scale evaluation of mother-to-child transmission (MTCT) with dolutegravir (DTG)-based antiretroviral treatment (ART) has not been conducted previously.

Setting: Botswana was the first African country to change from efavirenz (EFV)/tenofovir (TDF)/emtricitabine (FTC) to DTG/TDF/FTC first-line ART.

Methods: From April 2015 to July 2018, the Early Infant Treatment Study offered HIV DNA testing at <96 hours of life.

Drug resistance after cessation of efavirenz-based antiretroviral treatment started in pregnancy.

Background: To reduce risk of antiretroviral resistance when stopping efavirenz (EFV)-based antiretroviral treatment (ART), staggered discontinuation of antiretrovirals (an NRTI tail) is recommended. However, no data directly support this recommendation.

Objectives: We evaluated the prevalence of HIV drug resistance mutations in pregnant women living with HIV who stopped efavirenz (EFV)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) postpartum.

Safety and Efficacy of Starting Antiretroviral Therapy in the First Week of Life.

Background: Early antiretroviral therapy (ART) is recommended for infants with human immunodeficiency virus (HIV) infection. However, few antiretroviral options are available for neonates.

Methods: The Early Infant Treatment Study in Botswana tested HIV-exposed infants within 96 hours of birth, and HIV-infected infants started nevirapine (NVP) 6 mg/kg twice daily, zidovudine (ZDV), and lamivudine (3TC) at age < 7 days.