Conditional Economic Incentives for HIV Treatment Adherence: Aligning Adolescent Developmental Hallmarks with Behavioral Economic Theory to Improve HIV Treatment Adherence.

Adolescent-tailored antiretroviral therapy (ART) adherence interventions take place within the context of unique developmental stage. Suboptimal ART adherence among adolescents living with HIV in South Africa underscores that interventions are urgently needed to improve adherence. We conducted semistructured in-depth interviews with 35 adolescents aged 10-19 years living with HIV. In addition, 14 clinicians and 35 caregivers were interviewed to provide a diverse perspective on barriers and facilitators of medication adherence for adolescents living with HIV (ALWH). Thematic coding was utilized for this analysis. Our main findings were organized by following a priori themes: (1) acceptability of conditional economic incentives (CEIs) as an adherence intervention strategy for adolescents, (2) predicted behavioral impacts, and the (3) durability of CEIs to ensure medication adherence for adolescents in the long term. Subthemes that emerged included CEIs as tool to overcome competing demands, increasing intrinsic motivation and orientation toward the future, and optimal timing of the intervention. Exposure to a CEI intervention during early adolescence (ages 10-13) may be a particularly helpful intervention as CEIs may have long-lasting effects given that habit-formation behavior is developed during early adolescence. There is little consensus on effect duration from the perspective of adolescents, clinicians, and caregivers. Future studies should continue to explore the impact of CEIs for long-term ART adherence.

iSAY (incentives for South African youth): Stated preferences of young people living with HIV.

High adherence to antiretroviral therapy (ART) is essential for achieving viral suppression and preventing HIV transmission. Yet adherence is suboptimal among adolescents who face unique adherence challenges. Little is known about the role of conditional economic incentives (CEIs) for increasing ART adherence in this population. During 2017-2019, we conducted a mixed-methods discrete choice experiment in Cape Town, South Africa to inform the optimal design of a CEI intervention for ART adherence among youth. In-depth interviews were conducted with n = 35 adolescents (10-19 years old) living with HIV and prescribed ART, to identify attributes of a youth-centered CEI intervention for ART adherence. A discrete choice experiment was subsequently conducted with N = 168 adolescents to elicit preferences for intervention components. A rank-ordered mixed logit model was used for main results; marginal willingness-to-accept (mWTA) was then estimated. Five attributes emerged from the qualitative research as important for a CEI-based intervention for youth ART adherence: (1) incentive amount, (2) incentive format, (3) incentive recipient, (4) delivery mode, and (5) program participants. Youth had a high probability of acceptance of any incentives program (88-100%), yet they did not have a strong preference of a quarterly over a monthly program. From a maximum incentive amount of R1920 (~US$115), youth were willing to forgo up to R126 per year (~US$9) if the incentive was given in cash (versus fashion vouchers); R274 (~US$19.6) if it was open to both previously adherent and non-adherent youth (instead of non-adherent only); and up to R91 (~US$6.5) to receive incentives at a clinic setting (instead of electronically). The use of incentives over the short term during the critical age- and developmental-transition, when adolescents begin to take sole responsibility for their medication-taking behaviors, holds great promise for habituating adherence into adulthood.

"I'm doing this test so I can benefit from PrEP": exploring HIV testing barriers/facilitators and implementation of pre-exposure prophylaxis among South African adolescents.

In South Africa, adolescents are a key population in the HIV epidemic that can benefit from increased access to oral pre-exposure prophylaxis (PrEP). HIV testing is an integral component of the PrEP care continuum but adolescents in South Africa have generally low HIV testing rates; therefore, adolescents' HIV testing attitudes and behaviours must be understood to develop strategies for effective PrEP implementation. Ten focus groups were conducted with adolescents living with HIV and HIV-uninfected adolescents (n = 55), and in-depth interviews were conducted with service providers (n = 25), adolescents living with HIV (n = 10) and HIV-uninfected adolescents (n = 25). Data were collected in the Western Cape province of South Africa from 2015-2016. Thematic framework analysis was used to understand dynamics by which South African adolescents' attitudes toward HIV testing might influence intended uptake of PrEP and, reciprocally, to explore the implications of adolescents' perceptions about PrEP availability for their willingness to engage in HIV testing. While South African adolescents' current HIV testing attitudes and behaviours present barriers to intended PrEP implementation in this population, increased access to PrEP has the potential to improve their initial HIV testing rates and decrease stigma and fear around HIV testing. However, implementation of PrEP must consider specific HIV testing barriers for adolescent boys and girls, respectively. As PrEP becomes more widely available for adolescents, possible challenges noted by participants may include the potential for adolescents to reduce continued HIV testing behaviours while on PrEP and to share/use unprescribed PrEP medications among peers.

Recreational Use of HIV Antiretroviral Medication and Implications for HIV Pre-exposure Prophylaxis and Treatment.

Diversion of antiretroviral therapy (ART) for recreational use is concerning for countries with high HIV prevalence. This paper presents reports of recreational use of ART among adolescents from two HIV prevention studies in South Africa: (1) a cross-sectional survey of N = 200 adolescents and (2) a qualitative study of pre-exposure prophylaxis with N = 57 adolescents and N = 25 clinicians. Among adolescents, 3% used and 14% knew someone who used non-prescribed ART for recreational purposes. Administration included smoking (71%), snorting (15%), injecting (15%), ingesting (15%), and inserting (3%). Participants predicted increased crime as recreational use of ART increased. Future studies should investigate prevalence, composition, and diversion of ART from HIV prevention and treatment.

"I'm doing this test so I can benefit from PrEP": exploring HIV testing barriers/facilitators and implementation of pre-exposure prophylaxis among South African adolescents

In South Africa, adolescents are a key population in the HIV epidemic that can benefit from increased access to oral pre-exposure prophylaxis (PrEP). HIV testing is an integral component of the PrEP care continuum but adolescents in South Africa have generally low HIV testing rates; therefore, adolescents' HIV testing attitudes and behaviours must be understood to develop strategies for effective PrEP implementation. Ten focus groups were conducted with adolescents living with HIV and HIV-uninfected adolescents (n = 55), and in-depth interviews were conducted with service providers (n = 25), adolescents living with HIV (n = 10) and HIV-uninfected adolescents (n = 25). Data were collected in the Western Cape province of South Africa from 2015­2016. Thematic framework analysis was used to understand dynamics by which South African adolescents' attitudes toward HIV testing might influence intended uptake of PrEP and, reciprocally, to explore the implications of adolescents' perceptions about PrEP availability for their willingness to engage in HIV testing. While South African adolescents' current HIV testing attitudes and behaviours present barriers to intended PrEP implementation in this population, increased access to PrEP has the potential to improve their initial HIV testing rates and decrease stigma and fear around HIV testing. However, implementation of PrEP must consider specific HIV testing barriers for adolescent boys and girls, respectively. As PrEP becomes more widely available for adolescents, possible challenges noted by participants may include the potential for adolescents to reduce continued HIV testing behaviours while on PrEP and to share/use unprescribed PrEP medications among peers

Resting-state functional magnetic resonance imaging in clade C HIV: within-group association with neurocognitive function.

Neuroimaging abnormalities are common in chronically infected HIV-positive individuals. The majority of studies have focused on structural or functional brain outcomes in samples infected with clade B HIV. While preliminary work reveals a similar structural imaging phenotype in patients infected with clade C HIV, no study has examined functional connectivity (FC) using resting-state functional magnetic resonance imaging (rs-fMRI) in clade C HIV. In particular, we were interested to explore HIV-only effects on neurocognitive function using associations with rs-fMRI. In the present study, 56 treatment-naïve, clade C HIV-infected participants (age 32.27 ± 5.53 years, education 10.02 ± 1.72 years, 46 female) underwent rs-fMRI and cognitive testing. Individual resting-state networks were correlated with global deficit scores (GDS) in order to explore associations between them within an HIV-positive sample. Results revealed ten regions in six resting-state networks where FC inversely correlated with GDS scores (worse performance). The networks affected included three independent attention networks: the default mode network (DMN), sensorimotor network, and basal ganglia. Connectivity in these regions did not correlate with plasma viral load or CD4 cell count. The design of this study is unique and has not been previously reported in clade B. The abnormalities related to neurocognitive performance reported in this study of clade C may reflect late disease stage and/or unique host/viral dynamics. Longitudinal studies will help to clarify the clinical significance of resting-state alterations in clade C HIV.

Quantitative proteomic analysis of HIV-1 Tat-induced dysregulation in SH-SY5Y neuroblastoma cells.

Despite affecting up to 70% of HIV-positive patients and being the leading cause of dementia in patients under 40 years, the molecular mechanisms involved in the onset of HIV-associated neurocognitive disorders (HAND) are not well understood. To address this, we performed SILAC-based quantitative proteomic analysis on HIV-Tat treated SH-SY5Y neuroblastoma cells. Isolated protein was fractionated by SDS-PAGE and analyzed by nLC-MS/MS on an Orbitrap Velos. Using MaxQuant, we identified and quantified 3077 unique protein groups, of which 407 were differentially regulated. After applying an additional standard deviation-based cutoff, 29 of these were identified as highly significantly and stably dysregulated. GO term analysis shows dysregulation in both protein translation machinery as well as cytoskeletal regulation that have both been implicated in other dementias. In addition, several key cytoskeletal regulatory proteins such as ARHGEF17, the Rho GTPase, SHROOM3, and CMRP1 are downregulated. Together, these data demonstrate that HIV-Tat can dysregulate neuronal cytoskeletal regulatory proteins that could lead to the major HAND clinical manifestation-synapse loss.

Proceedings from the NIMH symposium on "NeuroAIDS in Africa: neurological and neuropsychiatric complications of HIV".

Despite major advances in HIV-1 treatment, the prevalence of HIV-associated neurocognitive disorders (HAND) remains a problem, particularly as individuals on suppressive treatment continue to live longer. To facilitate discussion on emerging and future directions in HAND research, a meeting was held in Durban, South Africa in March 2015 as part of the Society of Neuroscientists of Africa (SONA) conference. The objective of the meeting was to assess the impact of HIV subtype diversity on HAND and immunological dysfunction. The meeting brought together international leaders in the area of neurological complications of HIV-1 infection with special focus on the African population. Research presentations indicated that HAND was highly prevalent and that inflammatory cytokines and immune-activation played important roles in progression of neurocognitive impairment. Furthermore, children on antiretroviral therapy were also at risk for developing neurocognitive impairment. With respect to the effect of HIV-1 subtype diversity, analyses of HIV-1 clade C infection among South Africans revealed that clade C infection induced cognitive impairment that was independent of the substitution in HIV-1 Trans-Activator of Transcription (Tat; C31S). At the cellular level, a Zambian study showed that clade C infection resulted in reduced brain cell death compared with clade B infection suggesting clade specific variations in mediating brain cell injury. Furthermore, ex vivo Tat protein from clade CRF02_AG, prevalent in West/ Central Africa, exhibited reduced disruption of brain endothelium compared with clade B Tat protein. Discussions shed light on future research directions aimed at understanding biomarkers and disease mechanisms critical for HAND.

Neurologic complications of pediatric human immunodeficiency virus: implications for clinical practice and management challenges in the African setting.

Approximately 3.4 million children worldwide are affected with human immunodeficiency virus (HIV)/AIDS with more than 90% of them residing in sub-Saharan Africa, according to the World Health Organization. A significant proportion of the children eligible for treatment with antiretroviral therapy are not currently receiving it. Neurologic manifestations of HIV are common in both adults and children. There is a large spectrum of neurologic conditions that may be caused by the virus; however, early invasion of the central nervous system by the virus, affecting the developing fetal and infant brain, is believed to result in the most common primary HIV-related central nervous system complication, HIV encephalopathy. This article summarizes the spectrum of neuro-HIV in children, focuses on the neurocognitive and behavioral sequelae, reviews the effects of treatment on the primary neurologic effects of the disease, and discusses the specific challenges of identifying and managing these problems in resource-limited contexts, such as those found on the African continent.

Neuroimaging markers of human immunodeficiency virus infection in South Africa.

Previous studies have reported cognitive deficits among HIV-positive individuals infected with clade C virus. However, no study has examined whether individuals predominately infected with clade C virus exhibit brain atrophy relative to healthy controls. This study examined volumetric differences between 28 HIV+ individuals and 23 HIV- controls from South Africa. Volumetric measures were obtained from six regions of interest -- caudate, thalamus, corpus callosum, total cortex, total gray matter, and total white matter. HIV+ participants had significantly lower volumes in the total white matter (p<0.01), thalamus (p<0.01) and total gray matter (inclusive of cortical and subcortical regions, p<0.01). This study is the first to provide evidence of brain atrophy among HIV+ individuals in South Africa, where HIV clade C predominates. Additional research that integrates neuroimaging, comprehensive neuropsychological testing, genetic variance in clade-specific proteins, and the impact of treatment with Antiretrovirals (ARV) are necessary to understand the development of HIV-related neurocognitive disorders in South Africa.