Early Treatment Initiation and Outcomes in Perinatally HIV-infected Infants and Young Children in Johannesburg, South Africa: Age, Aging, and Antiretrovirals

The 2013 case report of the “Mississippi baby,” who was started on antiretroviral therapy (ART) within 30 hours of life and maintained off-treatment remission for 27 months before HIV was once again detectable, generated renewed interest in the benefits of early ART, as well as optimism that HIV remission is a possibility if ART is started very early. The overarching goal of this dissertation was to advance our understanding of the relationship between early ART and three outcomes – the possibility of HIV remission, improved viral outcomes, and epigenetic changes – in HIV-infected infants and young children. First, a systematic review was conducted to assess current published data in support of the possibility of very early ART leading to HIV remission in infants. Evidence from this review suggested that although early ART does appear to be associated with better sustained virological control and smaller reservoir size, there are limited data at this time to support a strong link between early ART and HIV remission. Second, the association between age at ART initiation and virologic outcomes after ART initiation was empirically assessed using data from five cohorts of HIV-infected infants and young children initiating ART before 2 years of age in Johannesburg, South Africa. In three cohorts, there was no consistent evidence of an association between early ART initiation and rates of initial viral suppression. However, there was a consistent benefit of early treatment initiation on long-term viral control in two cohorts. Finally, an epigenome-wide association study was conducted to identify differential DNA methylation patterns between ART-treated HIV-infected and HIV-uninfected South African children. A total of 1,309 differentially methylated CpG sites associated with HIV status were selected (FDR q-value 0.05), after adjustment for age, sex, and cell type proportions. In addition, 315 differentially methylated regions associated with HIV status were selected (Stouffer p-value 0.05, and containing at least two or more CpG sites). Many of the genes identified in both the site and region approaches were located in the major histocompatibility complex (MHC) region on chromosome 6, a region that plays an important role in the adaptive immune system. This novel study provided evidence of an association between perinatally-acquired HIV infection and a large number of changes in DNA methylation in school-aged children on ART, and highlighted potential new lines of investigation into the biologic pathways influenced by HIV and its treatment. Overall, this dissertation increased our understanding of the timing of early ART initiation in HIV-infected infants and addressed gaps in our knowledge relevant to outcomes associated with early ART initiation. As public health practice continues to move towards infant diagnosis of HIV at birth and early life initiation of ART, these findings help to inform future research that will guide HIV care in infants

Risk Factors for Invasive Cryptococcus neoformans Diseases: A Case-Control Study

Background: Cryptococcus neoformans is a ubiquitous environmental fungus that can cause life-threatening meningitis and fungemia, often in the presence of acquired immunodeficiency syndrome (AIDS), liver cirrhosis, diabetes mellitus, or other medical conditions. To distinguish risk factors from comorbidities, we performed a hospital-based, density-sampled, matched case-control study. Methods: All new-onset cryptococcal meningitis cases and cryptococcemia cases at a university hospital in Taiwan from 2002–2010 were retrospectively identified from the computerized inpatient registry and were included in this study. Controls were selected from those hospitalized patients not experiencing cryptococcal meningitis or cryptococcemia. Controls and cases were matched by admission date, age, and gender. Conditional logistic regression was used to analyze the risk factors. Results: A total of 101 patients with cryptococcal meningitis (266 controls) and 47 patients with cryptococcemia (188 controls), of whom 32 patients had both cryptococcal meningitis and cryptococcemia, were included in this study. Multivariate regression analysis showed that AIDS (adjusted odds ratio [aOR] = 181.4; p < 0.001), decompensated liver cirrhosis (aOR = 8.5; p = 0.008), and cell-mediated immunity (CMI)-suppressive regimens without calcineurin inhibitors (CAs) (aOR = 15.9; p < 0.001) were independent risk factors for cryptococcal meningitis. Moreover, AIDS (aOR = 216.3, p < 0.001), decompensated liver cirrhosis (aOR = 23.8; p < 0.001), CMI-suppressive regimens without CAs (aOR = 7.3; p = 0.034), and autoimmune diseases (aOR = 9.3; p = 0.038) were independent risk factors for developing cryptococcemia. On the other hand, diabetes mellitus and other medical conditions were not found to be risk factors for cryptococcal meningitis or cryptococcemia. Conclusions: The findings confirm AIDS, decompensated liver cirrhosis, CMI-suppressive regimens without CAs, and autoimmune diseases are risk factors for invasive C. neoformans diseases

Patterns of drug use and HIV infection among adults in a nationally representative sample

Background: Little is known about drug use patterns among people living with HIV in comparison to an uninfected group in the general population. The aim of this study was to investigate the association between legal and illegal drug use and HIV infection in a nationally representative sample of adults in the United States. Methods: Public use data files (2005–2014) from the National Survey on Drug Use and Health (NSDUH) were used. Respondents were asked whether a medical professional had ever told them that they had HIV/AIDS. Ever (lifetime), past-year, and past month use of cigarettes, alcohol, marijuana, cocaine, heroin, hallucinogens, inhalants, and nonmedical use of psychotherapeutics was assessed. Logistic regression was used to estimate adjusted odds ratios (aOR) of the relationship between drug use and HIV infection, adjusting for demographics. Results: Of 377,787 respondents age 18 and older, 548 (0.19%) were categorized as HIV-infected. Ever use of cigarettes, tobacco, marijuana, cocaine, heroin, hallucinogens, inhalants, and psychotherapeutics was higher in HIV-infected individuals compared to HIV-uninfected individuals after adjustment for sex, age, race/ethnicity, education, total family income, and marital status. Past year and past month use was also higher for HIV-infected individuals for all substances aside from alcohol. Conclusions: In a nationally representative sample, there are higher levels of drug use and DSM-IV dependence among the HIV-infected population compared to the HIV-uninfected population. This is of concern because drug use and dependence can impede engagement in HIV care and adherence to antiretroviral therapy

Evaluation of a flipped classroom approach to learning introductory epidemiology

Background Although the flipped classroom model has been widely adopted in medical education, reports on its use in graduate-level public health programs are limited. This study describes the design, implementation, and evaluation of a flipped classroom redesign of an introductory epidemiology course and compares it to a traditional model. Methods One hundred fifty Masters-level students enrolled in an introductory epidemiology course with a traditional format (in-person lecture and discussion section, at-home assignment; 2015, N = 72) and a flipped classroom format (at-home lecture, in-person discussion section and assignment; 2016, N = 78). Using mixed methods, we compared student characteristics, examination scores, and end-of-course evaluations of the 2016 flipped classroom format and the 2015 traditional format. Data on the flipped classroom format, including pre- and post-course surveys, open-ended questions, self-reports of section leader teaching practices, and classroom observations, were evaluated. Results There were no statistically significant differences in examination scores or students’ assessment of the course between 2015 (traditional) and 2016 (flipped). In 2016, 57.1% (36) of respondents to the end-of-course evaluation found watching video lectures at home to have a positive impact on their time management. Open-ended survey responses indicated a number of strengths of the flipped classroom approach, including the freedom to watch pre-recorded lectures at any time and the ability of section leaders to clarify targeted concepts. Suggestions for improvement focused on ways to increase regular interaction with lecturers. Conclusions There was no significant difference in students’ performance on quantitative assessments comparing the traditional format to the flipped classroom format. The flipped format did allow for greater flexibility and applied learning opportunities at home and during discussion sections

Body Composition Trajectories During the First 23 Months of Life Differ by HIV Exposure Among Infants in Western Kenya: A Prospective Study.

BackgroundInfants who are HIV-exposed and uninfected have suboptimal growth patterns compared to those who are HIV-unexposed and uninfected. However, little is known about how these patterns persist beyond 1 year of life.ObjectivesThis study aimed to examine whether infant body composition and growth trajectories differed by HIV exposure during the first 2 years of life among Kenyan infants using advanced growth modeling.MethodsRepeated infant body composition and growth measurements (mean: 6; range: 2-7) were obtained from 6 weeks to 23 months in the Pith Moromo cohort in Western Kenya (n = 295, 50% HIV-exposed and uninfected, 50% male). Body composition trajectory groups were fitted using latent class mixed modeling (LCMM) and associations between HIV exposure and growth trajectories were examined using logistic regression analysis.ResultsAll infants exhibited poor growth. However, HIV-exposed infants generally grew suboptimally than unexposed infants. Across all body composition models except for the sum of skinfolds, HIV-exposed infants had a higher likelihood of belonging to the suboptimal growth groups identified by LCMM than the HIV-unexposed infants. Notably, HIV-exposed infants were 3.3 times more likely (95% CI: 1.5-7.4) to belong to the length-for-age z-score growth class that remained at a z-score of &lt; -2, indicating stunted growth. HIV-exposed infants were also 2.6 times more likely (95% CI: 1.2-5.4) to belong to the weight-for-length-for-age z-score growth class that remained between 0 and -1, and were 4.2 times more likely (95% CI: 1.9-9.3) to belong to the weight-for-age z-score growth class that indicated poor weight gain besides stunted linear growth.ConclusionsIn a cohort of Kenyan infants, HIV-exposed infants grew suboptimally compared to HIV-unexposed infants beyond 1 year of age. These growth patterns and longer-term effects should be further investigated to support the ongoing efforts to reduce early-life HIV exposure-related health disparities

Information, motivation and behavioral skills as mediators between sexual minority stigma and condomless anal sex among Black South African men who have sex with men

DATA AVAILABILITY : The data underlying the results presented in the study are available upon request from Theo Sandfort, [email protected] AVAILABILITY : The code used to achieve the results presented in the study is available upon request from Bryan Kutner, [email protected] assessed pathways between sexual minority stigma and condomless anal intercourse (CAI) among two samples of Black South African men who have sex with other men (MSM). Two cross-sectional surveys were conducted in Tshwane, South Africa; one among 199 Black MSM and another among 480 Black MSM. Men reported on external and internalized experiences of sexual minority stigma, mental health, alcohol use, information-motivation-behavioral skills (IMB) model constructs, and CAI. Structural equation modeling was used to test whether external and internalized stigma were directly and indirectly associated with CAI. In both studies, external stigma and internalized stigma were associated with CAI through IMB model constructs. These results suggest a pathway through which stigma contributes to HIV risk. For HIV prevention efforts to be effective, strengthening safer sex motivation and thus decreasing sexual risk behavior likely requires reducing sexual minority stigma that MSM experience and internalize.amfAR, NIMH, NIAAA and NIDA.https://link.springer.com/journal/10461hj2024PsychologySociologySDG-03:Good heatlh and well-bein

Age at antiretroviral therapy initiation and cell-associated HIV-1 DNA levels in HIV-1-infected children

Background The latent viral reservoir is the major obstacle to achieving HIV remission and necessitates life-long antiretroviral therapy (ART) for HIV-infected individuals. Studies in adults and children have found that initiating ART soon after infection is associated with a reduction in the size of the HIV-1 reservoir. Here we quantified cell-associated HIV-1 DNA in early-treated but currently older HIV-infected children suppressed on ART. Methods The study participants comprised of a cohort of 146 early-treated children with HIV-1 RNA <50 copies/ml enrolled as part of a clinical trial in Johannesburg, South Africa. A stored buffy coat sample collected after a median 4.3 years on ART and where HIV-1 RNA was <50 copies/ml was tested for cell-associated HIV-1 DNA levels. An in-house, semi-nested real-time quantitative hydrolysis probe PCR assay to detect total HIV-1 subtype C proviral DNA was used. Children were followed prospectively for up to 3 years after this measurement to investigate subsequent HIV-1 RNA rebound/failure while remaining on ART. Age at ART initiation, HIV-1 RNA decline prior to HIV-1 DNA measurement and other factors were investigated. Results A gradient between age at ART initiation and later HIV-1 DNA levels was observed. When ART was started 50 copies/ml whilst on ART within 3 years after the DNA measurement was 2.07 (95% CI: 1.352–3.167) times greater if the HIV-1 DNA level was above the median of 55 copies/106 cells. Conclusions Cell-associated HIV-1 DNA levels measured after more than 4 years on ART were lower the younger the age of the child when ART was initiated. This marker of the size of the viral reservoir also predicted subsequent viral rebound/treatment failure while ART was sustained. The results provide additional evidence of the benefits of prompt diagnosis and early ART initiation in newborns and infants

Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment

Background: While studies of HIV-infected adults on antiretroviral treatment (ART) report no sex differences in immune recovery and virologic response but more ART-associated complications in women, sex differences in disease progression and response to ART among children have not been well assessed. The objective of this study was to evaluate for sex differences in response to ART in South African HIV-infected children who were randomized to continue ritonavir-boosted lopinavir (LPV/r)-based ART or switch to nevirapine-based ART. Methods: ART outcomes in HIV-infected boys and girls in Johannesburg, South Africa from 2005–2010 were compared. Children initiated ritonavir-boosted lopinavir (LPV/r)-based ART before 24 months of age and were randomized to remain on LPV/r or switch to nevirapine-based ART after achieving viral suppression. Children were followed for 76 weeks post-randomization and then long-term follow up continued for a minimum of 99 weeks and maximum of 245 weeks after randomization. Viral load, CD4 count, lipids, anthropometrics, drug concentrations, and adherence were measured at regular intervals. Outcomes were compared between sexes within treatment strata. Results: A total of 323 children (median age 8.8 months, IQR 5.1-13.5), including 168 boys and 155 girls, initiated LPV/r-based ART and 195 children were randomized. No sex differences in risk of virological failure (confirmed viral load >1000 copies/mL) by 156 weeks post-randomization were observed within either treatment group. Girls switched to nevirapine had more robust CD4 count improvement relative to boys in this group through 112 weeks post-randomization. In addition, girls remaining on LPV/r had higher plasma concentrations of ritonavir than boys during post-randomization visits. After a mean of 3.4 years post-randomization, girls remaining on LPV/r also had a higher total cholesterol:HDL ratio and lower mean HDL than boys on LPV/r. Conclusions: Sex differences are noted in treated HIV-infected children even at a young age, and appear to depend on treatment regimen. Future studies are warranted to determine biological mechanisms and clinical significance of these differences. Trial registration: ClinicalTrials.gov Identifier: NCT0011772