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. Clinical Trials Registration. NCT02369406.

Altered Response Pattern following AZD5582 Treatment of SIV-Infected, ART-Suppressed Rhesus Macaque Infants.

The "shock and kill" strategy for HIV-1 cure incorporates latency-reversing agents (LRA) in combination with interventions that aid the host immune system in clearing virally reactivated cells. LRAs have not yet been investigated in pediatric clinical or preclinical studies. Here, we evaluated an inhibitor of apoptosis protein (IAP) inhibitor (IAPi), AZD5582, that activates the noncanonical NF-κB (ncNF-κB) signaling pathway to reverse latency. Ten weekly doses of AZD5582 were intravenously administered at 0.1 mg/kg to rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen for over 1 year. During AZD5582 treatment, on-ART viremia above the limit of detection (LOD, 60 copies/mL) was observed in 5/8 infant RMs starting at 3 days post-dose 4 and peaking at 771 copies/mL. Of the 135 measurements during AZD5582 treatment in these 5 RM infants, only 8 were above the LOD (6%), lower than the 46% we have previously reported in adult RMs. Pharmacokinetic analysis of plasma AZD5582 levels revealed a lower Cmax in treated infants compared to adults (294 ng/mL versus 802 ng/mL). RNA-Sequencing of CD4+ T cells comparing pre- and post-AZD5582 dosing showed many genes that were similarly upregulated in infants and adults, but the expression of key ncNF-κB genes, including NFKB2 and RELB, was significantly higher in adult RMs. Our results suggest that dosing modifications for this latency reversal approach may be necessary to maximize virus reactivation in the pediatric setting for successful "shock and kill" strategies. IMPORTANCE While antiretroviral therapy (ART) has improved HIV-1 disease outcome and reduced transmission, interruption of ART results in rapid viral rebound due to the persistent latent reservoir. Interventions to reduce the viral reservoir are of critical importance, especially for children who must adhere to lifelong ART to prevent disease progression. Here, we used our previously established pediatric nonhuman primate model of oral SIV infection to evaluate AZD5582, identified as a potent latency-reversing agent in adult macaques, in the controlled setting of daily ART. We demonstrated the safety of the IAPi AZD5582 and evaluate the pharmacokinetics and pharmacodynamics of repeated dosing. The response to AZD5582 in macaque infants differed from what we previously showed in adult macaques with weaker latency reversal in infants, likely due to altered pharmacokinetics and less inducibility of infant CD4+ T cells. These data supported the contention that HIV-1 cure strategies for children are best evaluated using pediatric model systems.

Frequent Development of Broadly Neutralizing Antibodies in Early Life in a Large Cohort of Children With Human Immunodeficiency Virus.

BACKGROUND: Recent studies have indicated that broadly neutralizing antibodies (bnAbs) in children may develop earlier after human immunodeficiency virus (HIV) infection compared to adults. METHODS: We evaluated plasma from 212 antiretroviral therapy-naive children with HIV (1-3 years old). Neutralization breadth and potency was assessed using a panel of 10 viruses and compared to adults with chronic HIV. The magnitude, epitope specificity, and immunoglobulin (Ig)G subclass distribution of Env-specific antibodies were assessed using a binding antibody multiplex assay. RESULTS: One-year-old children demonstrated neutralization breadth comparable to chronically infected adults, whereas 2- and 3-year-olds exhibited significantly greater neutralization breadth (P = .014). Likewise, binding antibody responses increased with age, with levels in 2- and 3-year-old children comparable to adults. Overall, there was no significant difference in antibody specificities or IgG subclass distribution between the pediatric and adult cohorts. It is interesting to note that the neutralization activity was mapped to a single epitope (CD4 binding site, V2 or V3 glycans) in only 5 of 38 pediatric broadly neutralizing samples, which suggests that most children may develop a polyclonal neutralization response. CONCLUSIONS: These results contribute to a growing body of evidence suggesting that initiating HIV immunization early in life may present advantages for the development of broadly neutralizing antibody responses.

A Randomized Trial of Point-of-Care Early Infant Human Immunodeficiency Virus (HIV) Diagnosis in Zambia.

BACKGROUND: Point-of-care (POC) early infant diagnosis (EID) provides same-day results and the potential for immediate initiation of antiretroviral therapy (ART). METHODS: We conducted a pragmatic trial at 6 public clinics in Zambia. HIV-exposed infants were individually randomized to either (1) POC EID (onsite testing with the Alere q HIV-1/2 Detect) or (2) enhanced standard of care (SOC) EID (off-site testing at a public laboratory). Infants with HIV were referred for ART and followed for 12 months. Our primary outcome was defined as alive, in care, and virally suppressed at 12 months. RESULTS: Between March 2016 and November 2018, we randomized 4000 HIV-exposed infants to POC (n=1989) or SOC (n=2011). All but 2 infants in the POC group received same-day results, while the median time to result in the SOC group was 27 (interquartile range: 22-30) days. Eighty-one (2%; 95% confidence interval [CI]: 1.6-2.5%) infants were diagnosed with HIV. Although ART initiation was high, there were 15 (19%) deaths, 15 (19%) follow-up losses, and 31 (38%) virologic failures. By 12 months, only 20 of 81 (25%; 95% CI: 15-34%) infants with HIV were alive, in care, and virally suppressed: 13 (30%; 16-43%) infants in the POC group vs 7 (19%; 6-32%) in the SOC group (RR: 1.56; .7-3.50). CONCLUSIONS: POC EID eliminated diagnostic delays and accelerated ART initiation but did not translate into definitive improvement in 12-month outcomes. In settings where centralized EID is well functioning, POC EID is unlikely to improve pediatric HIV outcomes. CLINICAL TRIALS REGISTRATION: This trial is registered at https://clinicaltrials.gov (NCT02682810).

Emergence of Resistance in HIV-1 Integrase with Dolutegravir Treatment in a Pediatric Population from the IMPAACT P1093 Study.

P1093 is a multicenter, open-label, phase I/II study of pharmacokinetics, safety, and tolerability of dolutegravir plus an optimized background regimen in pediatric participants aged 4 weeks to <18 years with HIV-1. Most participants were highly treatment experienced. We report the mechanisms of emergent integrase strand transfer inhibitor (INSTI) resistance among adolescents and children receiving dolutegravir. Plasma was collected at screening and near protocol-defined virologic failure (PDVF) for population-level and, for some samples, clonal-level integrase genotyping, phenotyping, and replication capacity. HIV-1 RNA was assessed in all available plasma samples. Phylogenetic analysis of clonal integrase sequences and homology modeling of HIV-1 intasome complexes containing resistance-associated substitutions were performed. Treatment-emergent INSTI resistance was detected in 8 participants who met PDVF criteria. The rare INSTI resistance-associated substitution G118R or R263K developed in 6 participants. The on-study secondary integrase substitution E157Q or L74I was observed in 2 participants. G118R reduced dolutegravir susceptibility and integrase replication capacity more than R263K and demonstrated greater reduction in susceptibility and integrase replication capacity when present with specific secondary integrase substitutions, including L74M, T66I, and E138E/K. Continuing evolution after R263K acquisition led to reduced dolutegravir susceptibility and integrase replication capacity. Structural examination revealed potential mechanisms for G118R- and R263K-mediated INSTI resistance. G118R and R263K INSTI resistance substitutions, which are distinct to second-generation INSTIs, were detected in adolescents and children with prior virologic failure who received dolutegravir. This study provides additional molecular and structural characterization of integrase to aid in the understanding of INSTI resistance mechanisms in antiretroviral-experienced populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01302847.).

Pediatric HIV Pre-test Informational Video is Associated with Higher Knowledge Scores Compared to Counselor-Delivered Information.

Video-based pre-test information is used in high resource settings to increase HIV testing coverage but remains untested in resource-limited settings. We conducted formative and evaluative focus group discussions with healthcare workers (HCWs) and caregivers of children in Kenya to develop and refine a pediatric HIV pre-test informational video. We then assessed HIV knowledge among caregivers sequentially enrolled in one of three pre-test information groups: (1) individual HCW-led (N = 50), (2) individual video-based (N = 50), and (3) group video-based (N = 50) sessions. A brief video incorporating information on national pediatric testing, modes of HIV transmission, and dramatized testimonials of caregivers who tested children was produced in three languages. Compared to individual HCW-led sessions (mean: 7.2/9; standard deviation [SD]: 1.3), both the group video-based (mean: 7.7; SD: 0.9) and individual video-based (mean: 7.6; SD: 0.9) sessions had higher mean knowledge scores. Video-based pre-test information could enhance existing pediatric HIV testing services.

Early Initiation of Antiretroviral Therapy Following In Utero HIV Infection Is Associated With Low Viral Reservoirs but Other Factors Determine Viral Rebound.

BACKGROUND: Early HIV diagnosis allows combination antiretroviral therapy (cART) initiation in the first days of life following in utero (IU) infection. The impact of early cART initiation on infant viral reservoir size in the setting of high-frequency cART nonadherence is unknown. METHODS: Peripheral blood total HIV DNA from 164 early treated (day 0-21 of life) IU HIV-infected South African infants was measured using droplet digital PCR at birth and following suppressive cART. We evaluated the impact of cART initiation timing on HIV reservoir size and decay, and on the risk of subsequent plasma viremia in cART-suppressed infants. RESULTS: Baseline HIV DNA (median 2.8 log10 copies/million peripheral blood mononuclear cells, range 0.7-4.8) did not correlate with age at cART initiation (0-21 days) but instead with maternal antenatal cART use. In 98 infants with plasma viral suppression on cART, HIV DNA half-life was 28 days. However, the probability of maintenance of plasma aviremia was low (0.46 at 12 months) and not influenced by HIV DNA load. Unexpectedly, longer time to viral suppression was associated with protection against subsequent viral rebound. CONCLUSIONS: With effective prophylaxis against mother-to-child transmission, cART initiation timing in the first 3 weeks of life is not critical to reservoir size.

Drug Resistance Mutations Among South African Children Living With HIV on WHO-recommended ART Regimens.

BACKGROUND: Children living with human immunodeficiency virus (HIV) (CLHIV) receiving antiretroviral therapy (ART) in resource-limited settings are susceptible to high rates of acquired HIV drug resistance (HIVDR), but few studies include children initiating age-appropriate World Health Organization (WHO)-recommended first-line regimens. We report data from a cohort of ART-naive South African children who initiated first-line ART. METHODS: ART-eligible CLHIV aged 0-12 years were enrolled from 2012 to 2014 at 5 public South African facilities and were followed for up to 24 months. Enrolled CLHIV received standard-of-care WHO-recommended first-line ART. At the final study visit, a dried blood spot sample was obtained for viral load and genotypic resistance testing. RESULTS: Among 72 successfully genotyped CLHIV, 49 (68.1%) received ABC/3TC/LPV/r, and 23 (31.9%) received ABC/3TC/EFV. All but 2 children on ABC/3TC/LPV/r were <3 years, and all CLHIV on ABC/3TC/EFV were ≥3 years. Overall, 80.6% (58/72) had at least one drug resistance mutation (DRM). DRMs to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs) were found among 65% and 51% of all CLHIV, respectively, with no statistical difference by ART regimen. More CLHIV on ABC/3TC/EFV, 47.8% (11/23), were found to have 0 or only 1 effective antiretroviral drug remaining in their current regimen compared to 8.2% (4/49) on ABC/3TC/LPV/r. CONCLUSIONS: High levels of NNRTI and NRTI DRMs among CLHIV receiving ABC/3TC/LPV/r suggests a lasting impact of failed mother-to-child transmission interventions on DRMs. However, drug susceptibility analysis reveals that CLHIV with detectable viremia on ABC/3TC/LPV/r are more likely to have maintained at least 2 effective agents on their current HIV regimen than those on ABC/3TC/EFV.

Reduced neuronal population in the dorsolateral prefrontal cortex in infant macaques infected with simian immunodeficiency virus (SIV).

Pediatric HIV infection remains a global health crisis with an estimated 150,000 new mother-to-child (MTCT) infections each year. Antiretroviral therapy (ART) has improved childhood survival, but only an estimated 53% of children worldwide have access to treatment. Adding to the health crisis is the neurological impact of HIV on the developing brain, in particular cognitive and executive function, which persists even when ART is available. Imaging studies suggest structural, connectivity, and functional alterations in perinatally HIV-infected youth. However, the paucity of histological data limits our ability to identify specific cortical regions that may underlie the clinical manifestations. Utilizing the pediatric simian immunodeficiency virus (SIV) infection model in infant macaques, we have previously shown that early-life SIV infection depletes the neuronal population in the hippocampus. Here, we expand on these previous studies to investigate the dorsolateral prefrontal cortex (dlPFC). A total of 11 ART-naïve infant rhesus macaques (Macaca mulatta) from previous studies were retrospectively analyzed. Infant macaques were either intravenously (IV) inoculated with highly virulent SIVmac251 at ~1 week of age and monitored for 6-10 weeks or orally challenged with SIVmac251 from week 9 of age onwards with a monitoring period of 10-23 weeks post-infection (19-34 weeks of age), and SIV-uninfected controls were euthanized at 16-17 weeks of age. Both SIV-infected groups show a significant loss of neurons along with evidence of ongoing neuronal death. Oral- and IV-infected animals showed a similar neuronal loss which was negatively correlated to chronic viremia levels as assessed by an area under the curve (AUC) analysis. The loss of dlPFC neurons may contribute to the rapid neurocognitive decline associated with pediatric HIV infection.

Financial Incentives for Pediatric HIV Testing (FIT): Caregiver Insights on Incentive Mechanisms, Focus Populations, and Acceptability for Programmatic Scale Up.

Children living with HIV experience gaps in HIV testing globally; scaling up evidence-based testing strategies is critical for preventing HIV-related mortality. Financial incentives (FI) were recently demonstrated to increase uptake of pediatric HIV testing. As part of this qualitative follow-up study to the FIT trial (NCT03049917) conducted in Kenya, 54 caregivers participated in individual interviews. Interview transcripts were analyzed to identify considerations for scaling up FI for pediatric testing. Caregivers reported that FI function by directly offsetting costs or nudging caregivers to take action sooner. Caregivers found FI to be feasible and acceptable for broader programmatic implementation, and supported use for a variety of populations. Some concerns were raised about unintended consequences of FI, including caregivers bringing ineligible children to collect incentives and fears about the impact on linkage to care and retention if caregivers become dependent on FI.

Point-of-care p24 antigen detection for early infant diagnosis of HIV infection: cross-sectional and longitudinal studies in Zambia.

BACKGROUND: Early infant diagnosis of HIV infection is challenging in sub-Saharan Africa, particularly in rural areas, leading to delays in diagnosis and treatment. Use of a point-of-care test would overcome many challenges. This study evaluated the validity of a novel point-of-care p24 antigen detection test (LYNX) in rural and urban settings in southern Zambia. METHODS: Two studies were conducted: a cross-sectional study from 2014 to 2015 at Macha Hospital (LYNX Hospital study) and a longitudinal study from 2016 to 2018 at 12 health facilities in Southern Province, Zambia (NSEBA study). In both studies, children attending the facilities for early infant diagnosis were enrolled and a blood sample was collected for routine testing at the central lab and immediate on-site testing with the LYNX test. The performance of the LYNX test was measured in comparison to nucleic acid-based testing at the central lab. RESULTS: In the LYNX Hospital study, 210 tests were performed at a median age of 23.5 weeks (IQR: 8.9, 29.0). The sensitivity and specificity of the test were 70.0 and 100.0%, respectively. In the NSEBA study, 2608 tests were performed, including 1305 at birth and 1222 on children ≥4 weeks of age. For samples tested at birth, sensitivity was 13.6% (95% CI: 2.9, 34.9) and specificity was 99.6% (95% CI: 99.1, 99.9). While specificity was high for all ages, sensitivity increased with age and was higher for participants tested at ≥4 weeks of age (80.6%; 95% CI: 67.4, 93.7). Children with positive nucleic acid tests were more likely to be negative by the LYNX test if their mother received antiretroviral therapy during pregnancy (60.7% vs. 24.2%; p = 004). CONCLUSIONS: Considering the high specificity and moderate sensitivity that increased with age, the LYNX test could be of value for early infant diagnosis for infants ≥4 weeks of age, particularly in rural areas where centralized testing leads to long delays. Point-of-care tests with moderate sensitivity and high specificity that are affordable, easy-to-use, and easily implemented and maintained should be developed to expand access to testing and deliver same-day results to infants in areas where it is not feasible to implement nucleic acid-based point-of-care assays.

Estimating the burden of pediatric HIV in an 'A' category district in India: an epidemiological study.

BACKGROUND: India lacks epidemiological information on the disease burden of pediatric HIV. The National AIDS Control Program (NACP) estimates the numbers of HIV-positive children as a proportion of adult persons living with HIV. A third of HIV-positive children die before their first birthday and a half before they reach their second birthday. The early detection of HIV is crucial for the prevention of morbidities, growth delays, and death among HIV-positive children. METHODS: The study aimed to estimate the disease burden of pediatric HIV among children in 'A' category district of a high HIV prevalence state. An 'A' category district is defined by the presence of > 1% HIV prevalence among the general population, as estimated by HIV Sentinel Surveillance. The study used an innovative three-pronged strategy combining cross-sectional and longitudinal methods. The overall burden of pediatric HIV was calculated as a product of cases detected multiplied by a net inflation factor, for each of three strategies. RESULTS: The existing pool of HIV infection in the district is estimated to be 3266 (95% CI: 2621-4197) HIV positive children < 15 years of age, in a mid-year (2013) projected child population of about 1.4 million, thus giving an HIV prevalence of 0.23% (CI: 0.19-0.30) among children (0-14 years of age). The proportion of children among all people living with HIV in the district works out to 10.4% (CI: 8.6-13.5%). CONCLUSIONS: The study estimate of 0.23% HIV prevalence among children (0-14 years of age) is higher than the NACP estimates (0.02) and is 2.5 higher than the Karnataka state estimate (0.09)22. Similarly, the proportion of children among all persons living with HIV in Belgaum district is 10.4% in this study, as against 6.54% for India. The study methodology is replicable for other settings and other diseases.

African Multi-Site 2-Year Neuropsychological Study of School-Age Children Perinatally Infected, Exposed, and Unexposed to Human Immunodeficiency Virus.

BACKGROUND: Children living with human immunodeficiency virus (HIV) are at neuropsychological risk for cognitive and motor dysfunction. However, few prospective, multi-site studies have evaluated neuropsychological outcomes longitudinally among perinatally infected African children who received early antiretroviral treatment (ART). METHODS: We enrolled 611 children aged 5 to 11 years at 6 sites (South Africa [3], Zimbabwe, Malawi, Uganda). Of these, there were 246 children living with HIV (HIV+) who were initiated on ART before 3 years of age in a prior clinical trial comparing nevirapine to lopinavir/ritonavir (International Maternal Pediatric Adolescent Acquired Immunodeficiency Syndrome Clinical Trials [IMPAACT] P1060); 183 age-matched, exposed but uninfected (HEU) children; and 182 unexposed and uninfected (HUU) children. They were compared across 3 assessment time points (Weeks 0, 48, and 96) on cognitive ability (Kaufman Assessment Battery for Children, second edition [KABC-II]), attention/impulsivity (Tests of Variables of Attention [TOVA]), motor proficiency (Bruininks-Oseretsky Test, second edition [BOT-2]), and on the Behavior Rating Inventory of Executive Function (BRIEF). The cohorts were compared using linear mixed models, adjusting for site, child's age and sex, and selected personal/family control variables. RESULTS: The HIV+ cohort performed significantly worse than the HEU and HUU cohorts for all KABC-II, TOVA, and BOT-2 performance outcomes across all 3 time points (P values < .001). The HUU and HEU cohorts were comparable. For the KABC-II planning/reasoning subtests, the HIV+ children showed less improvement over time than the HUU and HEU groups. The groups did not differ significantly on the BRIEF. CONCLUSIONS: Despite initiation of ART in early childhood and good viral suppression at the time of enrollment, the HIV+ group had poorer neuropsychological performance over time, with the gap progressively worsening in planning/reasoning. This can be debilitating for self-management in adolescence.

Simian-Human Immunodeficiency Virus SHIV.CH505-Infected Infant and Adult Rhesus Macaques Exhibit Similar Env-Specific Antibody Kinetics, despite Distinct T-Follicular Helper and Germinal Center B Cell Landscapes.

Global elimination of pediatric human immunodeficiency virus (HIV) infections will require the development of novel immune-based approaches, and understanding infant immunity to HIV is critical to guide the rational design of these intervention strategies. Despite their immunological immaturity, chronically HIV-infected children develop broadly neutralizing antibodies (bnAbs) more frequently and earlier than adults do. However, the ontogeny of humoral responses during acute HIV infection is poorly defined in infants and challenging to study in human cohorts due to the presence of maternal antibodies. To further our understanding of age-related differences in the development of HIV-specific immunity during acute infection, we evaluated the generation of virus-specific humoral immune responses in infant (n = 6) and adult (n = 12) rhesus macaques (RMs) infected with a transmitted/founder (T/F) simian-human immunodeficiency virus (SHIV) (SHIV.C.CH505 [CH505]). The plasma HIV envelope-specific IgG antibody kinetics were similar in SHIV-infected infant and adult RMs, with no significant differences in the magnitude or breadth of these responses. Interestingly, autologous tier 2 virus neutralization responses also developed with similar frequencies and kinetics in infant and adult RMs, despite infants exhibiting significantly higher follicular T helper cell (Tfh) and germinal center B cell frequencies than adults. Finally, we show that plasma viral load was the strongest predictor of the development of autologous virus neutralization in both age groups. Our results indicate that the humoral immune response to SHIV infection develops with similar kinetics among infant and adult RMs, suggesting that the early-life immune system is equipped to respond to HIV-1 and promote the production of neutralizing HIV antibodies.IMPORTANCE There is a lack of understanding of how the maturation of the infant immune system influences immunity to HIV infection or how these responses differ from those of adults. Improving our knowledge of infant HIV immunity will help guide antiviral intervention strategies that take advantage of the unique infant immune environment to successfully elicit protective immune responses. We utilized a rhesus macaque model of SHIV infection as a tool to distinguish the differences in HIV humoral immunity in infants versus adults. Here, we demonstrate that the kinetics and quality of the infant humoral immune response to HIV are highly comparable to those of adults during the early phase of infection, despite distinct differences in their Tfh responses, indicating that slightly different mechanisms may drive infant and adult humoral immunity.

Pediatric HIV: the Potential of Immune Therapeutics to Achieve Viral Remission and Functional Cure.

PURPOSE OF REVIEW: In the absence of antiretroviral therapy (ART), more than 50% of perinatally HIV-infected children die by 2 years of age. Early ART from infancy is therefore a global recommendation and significantly improves immune health, child survival, and disease outcome. However, even early treatment does not prevent or eradicate the latent reservoir necessitating life-long ART. Adherence to life-long ART is challenging for children and longstanding ART during chronic HIV infection led to higher risks of non-AIDS co-morbidities and virologic failure in infected children. Thus, HIV-infected children are an important population for consideration for immune-based interventions to achieve ART-free remission and functional cure. This review summarizes how the uniqueness of the early life immune system can be harnessed for the development of ART-free remission and functional cure, which means complete virus control in absence of ART. In addition, recent advances in therapeutics in the HIV cure field and their potential for the treatment of pediatric HIV infections are discussed. RECENT FINDINGS: Preclinical studies and clinical trials demonstrated that immune-based interventions target HIV replication, limit size of virus reservoir, maintain virus suppression, and delay time to virus rebound. However, these studies have been performed so far only in carefully selected HIV-infected adults, highlighting the need to evaluate the efficacy of immune-based therapeutics in HIV-infected children and to design interventions tailored to the early life maturing immune system. Immune-based therapeutics alone or in combination with ART should be actively explored as potential strategies to achieve viral remission and functional cure in HIV-infected pediatric populations.

Relationship between economic insecurity, inflammation, monocyte activation and intestinal integrity in children living with HIV in Uganda.

We aimed to evaluate differences in socio-economic variables in a Ugandan cohort of children with perinatally acquired HIV (PHIVs), HIV exposed uninfected (HEU) and HIV unexposed uninfected (HIV-) children and their associations with markers of inflammation and intestinal integrity. This is a cross-sectional study in 57 PHIV, 59 HEU and 56 HIV - children aged 2-10 years old enrolled in Uganda. Mean age of all participants was 7 years and 55% were girls. Compared to HEU and HIV - children, PHIVs were more likely to have parents that only completed a primary education, live in a household without electricity and live in poverty (p≤0.034). PHIVs living in poverty had higher IL-6 (p=0.006), those with lack of electricity had higher hsCRP, IL6, sTNFRII and d-dimer (p≤0.048) and PHIVs with an unprotected water source had higher IL6 and d-dimer (p≤0.016). After adjusting for demographic and HIV variables, IL-6 and d-dimer remained associated with lack of electricity and having an unprotected water source only in PHIVs (p<0.019). Our findings suggest that addressing economic insecurity may mitigate the persistent low-level inflammation in HIV that lead to many end organ disease. Longitudinal studies are needed to better understand the impact of socioeconomic factors on HIV inflammation and comorbidities.

Integrating childhood TB: applying the care delivery value chain to improve pediatric HIV/TB services in Togo, West Africa.

The World Health Organization has prioritized integrating tuberculosis (TB) and human immunodeficiency virus (HIV) services. Diagnosis of HIV/TB coinfection in children remains a challenge worldwide for numerous reasons. The care delivery value chain (CDVC) is an effective tool that can be applied as a systemic framework for assessing health care delivery. Our objective was to apply the CDVC framework to improve pediatric HIV/TB care at an HIV center in northern Togo that serves over 130 children and 1000 adults living with HIV. Using the CDVC framework, gaps in HIV/TB care were identified, and services related to screening and diagnosis were prioritized to implement 3 distinct quality improvement cycles. Primary outcomes included percentage of children screened for TB by medical providers and percentage of diagnostic sample results received at the HIV clinic for children and adults. Improvements in the TB diagnostic process were observed, resulting in a change of sputum sample results received for both children and adults from 25% at baseline to >88% at 3 months. Given the relative low associated costs, this QI approach may be applicable and feasible in other settings to target screening and diagnosis of TB for children living with HIV worldwide.

Sankofa pediatric HIV disclosure intervention did not worsen depression scores in children living with HIV and their caregivers in Ghana.

BACKGROUND: The 'Sankofa' pediatric HIV disclosure study (2013-2017) was an intervention that aimed to address the low prevalence of disclosure of HIV status in Ghana. METHODS: We conducted a cross-sectional study at the intervention site in Kumasi, Ghana, in 2019, (2 years after study closure) and administered the 21-item Beck Depression Inventory (BDI) and the 10-item Child Depression Inventory (CDI) to caregiver-child dyads who received the intervention. RESULTS: We enrolled 65% (N = 157) of the original dyads in the present study. Between Sankofa enrollment baseline and the present study, both children and caregivers had significant (p < 0.0001) mean reductions in CDI scores and BDI scores, respectively. CDI scores of the children were significantly correlated with BDI scores of the caregivers (r = 0.019, p = 0.019). No statistically significant associations between disclosure status and either CDI score or BDI score were found. CONCLUSIONS: Our findings did not support caregivers' fears that disclosure leads to depression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01701635 (date of registration Oct 5, 2012).

'There are no more secrets': acceptability of a family-centered model of care for HIV positive children in Eswatini.

BACKGROUND: HIV-positive children have lagged adults on retention in HIV care and viral suppression. To address this gap, Eswatini's Ministry of Health started a pilot family-centered HIV care model (FCCM) targeting HIV-positive children under 20 years old and their families. METHODS: We conducted semi-structured in-depth interviews with 25 caregivers and 17 healthcare workers (HCWs) to assess acceptability of FCCM in four pilot FCCM health facilities in Hhohho region of Eswatini. Thematic analysis with inductive and deductive codes was used to identify salient themes. RESULTS: Caregivers and HCWs reported FCCM benefits including strengthening the family bond, encouragement for family members to disclose their HIV status and supporting each other in taking antiretroviral drugs. Caregivers reported that they spent fewer days in clinic, experienced shorter waiting times, and received better counseling services in FCCM compared to the standard-of-care services. FCCM implementation challenges included difficulty for families to attend clinic visits together (e.g., due to scheduling conflicts with weekend Teen Support Club meetings and weekday FCCM appointments). Both HCWs and caregivers mentioned difficulty in sharing sensitive health information in the presence of other family members. HCWs also had challenges with supporting caregivers to disclose HIV status to children and managing the larger group during clinic visits. CONCLUSIONS: FCCM for HIV-positive children was acceptable to both caregivers and HCWs, and they supported scaling-up FCCM implementation nationally. However, special considerations should be made to address the challenges experienced by participants in attending clinic visits together as a family in order to achieve the full benefits of FCCM for HIV positive children.

HIV-exposed infant follow-up in Mozambique: formative research findings for the design of a cluster randomized controlled trial to improve testing and ART initiation.

BACKGROUND: Early infant diagnosis (EID) of HIV-exposed and initiation of HIV-positive infants on anti-retroviral therapy (ART) requires a well-coordinated cascade of care. Loss-to-follow-up (LTFU) can occur at multiple steps and effective EID is impeded by human resource constraints, difficulty with patient tracking, and long waiting periods. The objective of this research was to conduct formative research to guide the development of an intervention to improve the pediatric HIV care cascade in central Mozambique. The study was conducted in Manica and Sofala Provinces where the adult HIV burden is higher than the national average. The research focused on 3 large clinics in each province, along the highly populated Beira corridor. METHODS: The research was conducted in 2014 over 3 months at six facilities and consisted of 1) patient flow mapping and collection of health systems data from postpartum, child-at-risk, and ART service registries, 2) measurement of clinic waiting times, and 3) patient and health worker focus groups. RESULTS: HIV testing and ART initiation coverage for mothers tends to be high, but EID and pediatric ART initiation are hampered by lack of patient tracking, long waiting times, and inadequate counseling to navigate the care cascade. About 76% of HIV-positive infants were LTFU and did not initiate ART. CONCLUSIONS: Effective interventions to reduce LTFU in EID and improve pediatric ART initiation should focus on patient tracking, active follow-up of defaulting patients, reduction in EID turn-around times for PCR results, and initiation of ART by nurses in child-at-risk services. TRIAL REGISTRATION: Retrospectively registered, ISRCTN67747315, July 24, 2019.