Integrase Strand Transfer Inhibitors & Weight Gain in Children with Perinatal HIV

Background: In the past, HIV infection was associated with weight loss due to metabolic wasting. Now with early initiation of antiretroviral therapy (ART) an increasing number of patients are being classified as overweight/ obese both prior to initiation and during the course of ART. Certain integrase strand transfer inhibitors (INSTIs) have been associated with weight gain in the adult population, but data in the pediatric population is lacking. This study explores the association of ART with an INSTI backbone and changes in weight and body mass index (BMI) in children with perinatal HIV who are followed in the HIV clinic at Riley Hospital. Methods: We performed a retrospective review of 59 patients with perinatally acquired HIV from 2016 to 2021. Weight, BMI, z-score, blood pressure (BP) percentiles, and lipid panels were recorded from the patients’ most recent visit. BMI and BP percentiles were compared between patients on Bictegravir, Dolutegravir, and Elvitegravir. For patients currently on an INSTI-backbone ART regimen, BMI was compared before and up to 5 years after INSTI initiation. Results: In our cross-sectional analysis between patients on Bictegravir, Dolutegravir, and Elvitegravir there was no significant difference in BMI (p=0.859), systolic BP percentile (p=0.188), or diastolic BP percentile (p=0.541). In our longitudinal analysis, we observed a significant increase in BMI over 3 years compared to pre-INSTI initiation (p=0.049). In addition, we observed an upwards trend with patients on Bictegravir (p=0.094) and Elvitegravir (p=0.121). Conclusion/Impact: Our study suggests that ART regimens with an INSTI backbone are associated with greater increases in BMIs. Our study is limited by a small n, but provides pilot data to direct future studies. It also illustrates that emphasis on healthy body weight maintenance may be necessary when patients are placed on ART regimens with INSTI backbones.

Dental caries and its association with the oral microbiomes and HIV in young children—Nigeria (DOMHaIN): a cohort study

Background This study seeks to understand better the mechanisms underlying the increased risk of caries in HIV-infected school-aged Nigerian children by examining the relationship between the plaque microbiome and perinatal HIV infection and exposure. We also seek to investigate how perinatal HIV infection and exposure impact tooth-specific microbiomes' role on caries disease progression. Methods The participants in this study were children aged 4 to 11 years recruited from the University of Benin Teaching Hospital (UBTH), Nigeria, between May to November 2019. Overall, 568 children were enrolled in three groups: 189 HIV-infected (HI), 189 HIV-exposed but uninfected (HEU) and 190 HIV-unexposed and uninfected (HUU) as controls at visit 1 with a 2.99% and 4.90% attrition rate at visit 2 and visit 3 respectively. Data were obtained with standardized questionnaires. Blood samples were collected for HIV, HBV and HCV screening; CD4, CD8 and full blood count analysis; and plasma samples stored for future investigations; oral samples including saliva, buccal swabs, oropharyngeal swab, tongue swab, dental plaque were collected aseptically from participants at different study visits. Conclusions Results from the study will provide critical information on how HIV exposure, infection, and treatment, influence the oral microbiome and caries susceptibility in children. By determining the effect on community taxonomic structure and gene expression of dental microbiomes, we will elucidate mechanisms that potentially create a predisposition for developing dental caries. As future plans, the relationship between respiratory tract infections, immune and inflammatory markers with dental caries in perinatal HIV infection and exposure will be investigated.

An HIV Vaccine Protective Allele in FCGR2C Associates With Increased Odds of Perinatal HIV Acquisition

In the Thai RV144 HIV-1 vaccine trial, a three-variant haplotype within the Fc gamma receptor 2C gene (FCGR2C) reduced the risk of HIV-1 acquisition. A follow-on trial, HVTN702, of a similar vaccine candidate found no efficacy in South Africa, where the predominant population is polymorphic for only a single variant in the haplotype, c.134-96C>T (rs114945036). To investigate a role for this variant in HIV-1 acquisition in South Africans, we used the model of maternal-infant HIV-1 transmission. A nested case-control study was conducted of infants born to mothers living with HIV-1, comparing children with perinatally-acquired HIV-1 (cases, n = 176) to HIV-1-exposed uninfected children (controls, n = 349). All had received nevirapine for prevention of mother-to-child transmission. The FCGR2C copy number and expression variants (c.−386G>C, c.−120A>T c.169T>C, and c.798+1A>G) were determined using a multiplex ligation-dependent probe amplification assay and the c.134-96C>T genotype with Sanger sequencing. The copy number, genotype and allele carriage were compared between groups using univariate and multivariate logistic regression. The FCGR2C c.134-96C>T genotype distribution and copy number differed significantly between HIV-1 cases and exposed-uninfected controls (P = 0.002, PBonf = 0.032 and P = 0.010, PBonf = > 0.05, respectively). The FCGR2C c.134-96T allele was overrepresented in the cases compared to the controls (58% vs 42%; P = 0.001, PBonf = 0.016). Adjusting for birthweight and FCGR2C copy number, perinatal HIV-1 acquisition was associated with the c.134-96C>T (AOR = 1.89; 95% CI 1.25-2.87; P = 0.003, PBonf = 0.048) and c.169C>T (AOR = 2.39; 95% CI 1.45-3.95; P = 0.001, PBonf = 0.016) minor alleles but not the promoter variant at position c.−386G>C. The c.134-96C>T variant was in strong linkage disequilibrium with the c.169C>T variant, but remained significantly associated with perinatal acquisition when adjusted for c.169C>T in multivariate analysis. In contrast to the protective effect observed in the Thai RV144 trial, we found the FCGR2C variant c.134-96T-allele associated with increased odds of perinatal HIV-1 acquisition in South African children. These findings, taken together with a similar deleterious association found with HIV-1 disease progression in South African adults, highlight the importance of elucidating the functional relevance of this variant in different populations and vaccination/disease contexts.

Neuropsychological and Psychosocial Functioning of Children with Perinatal HIV-Infection in The Netherlands

Advances in antiretroviral treatment improved the life expectancy of perinatally HIV-infected children. However, growing up with HIV provides challenges in daily functioning. This cross-sectional cohort study investigated the neuropsychological and psychosocial functioning of a group of perinatally HIV-infected children in the Netherlands and compared their outcomes with Dutch normative data and outcomes of a control group of uninfected siblings. The children’s functioning was assessed with internationally well-known and standardized questionnaires, using a multi-informant approach, including the perspectives of caregivers, teachers, and school-aged children. In addition, we explored the associations of socio-demographic and medical characteristics of the HIV-infected children with their neuropsychological and psychosocial functioning. Caregivers reported compromised functioning when compared to Dutch normative data for HIV-infected children in the areas of attention, sensory processing, social-emotional functioning, and health-related quality of life. Teachers reported in addition compromised executive functioning for HIV-infected children. A comparison with siblings revealed differences in executive functioning, problems with peers, and general health. The concurrent resemblance between HIV-infected children and siblings regarding problems in other domains implies that social and contextual factors may be of influence. A family-focused approach with special attention to the child’s socio-environmental context and additional attention for siblings is recommended.

Ethically designing research to inform multidimensional, rapidly evolving policy decisions: Lessons learned from the PROMISE HIV Perinatal Prevention Trial

Research in rapidly evolving policy contexts can lead to the following ethical challenges for sponsors and researchers: the study’s standard of care can become different than what patients outside the study receive, there may be political or other pressure to move ahead with unproven interventions, and new findings or revised policies may decrease the relevance of ongoing studies. These ethical challenges are considerable, but not unprecedented. In this article, we review the case of a multinational, randomized, controlled perinatal HIV prevention trial, the “PROMISE” (Promoting Maternal Infant Survival Everywhere) study. PROMISE compared the relative efficacy and safety of interventions to prevent mother to child transmission of HIV. The sponsor engaged an independent international ethics panel to address controversy about the study’s standard of care and relevance as national and international guidelines changed. This ethics panel concluded that continuing the PROMISE trial as designed was ethically permissible because: (1) participants in all arms received interventions that were effective, and there was insufficient evidence about whether one intervention was more effective or safer than the other, and (2) data from PROMISE could be useful for a diverse range of stakeholders. In general, trials designed to inform rapidly evolving policy issues should develop mechanisms to revisit social value while recognizing that the value of research varies for diverse stakeholders with legitimate reasons to weigh evidence differently. We conclude by providing four reasons that trials may depart from the standard of care after a change in policy, while remaining ethically justifiable, and by suggesting how to improve existing trial oversight mechanisms to address evolving social value.

Insights from Clonal Expansion and HIV Persistence in Perinatal Infections

The latent HIV reservoir forms early in the course of infection and is maintained for life despite effective antiretroviral treatment (ART), including early treatment. Perinatal HIV infection presents a unique opportunity to limit seeding of the reservoir through early ART. However, a greater understanding of the persistence of the integrated proviruses is needed for targeting the residual proviruses that form barriers to cure. A study was performed by Bale and Katusiime et al. (M. J. Bale, M. G.