Brian C. Zanoni

The Adolescent and Young Adult HIV Cascade of Care in the United States: Exaggerated Health Disparities

Little is known about how adolescents and young adults contribute to the declines in the cascade of care from HIV-1 diagnosis to viral suppression. We reviewed published literature from the Unites States reporting primary data for youth (13-29 years of age) at each stage of the HIV cascade of care. Approximately 41% of HIV-infected youth in the United States are aware of their diagnosis, while only 62% of those diagnosed engage medical care within 12 months of diagnosis. Of the youth who initiate antiretroviral therapy, only 54% achieve viral suppression and a further 57% are not retained in care. We estimate less than 6% of HIV-infected youth in the United States remain virally suppressed. We explore the cascade of care from HIV diagnosis through viral suppression for HIV-infected adolescents and young adults in the United States to highlight areas for improvement in the poor engagement of the infected youth population.

Risk Factors Associated with Increased Mortality among HIV Infected Children Initiating Antiretroviral Therapy (ART) in South Africa

Objective To identify demographic and clinical risk factors associated with mortality after initiation of antiretroviral therapy (ART) in a cohort of human immunodeficiency (HIV) infected children in KwaZulu-Natal, South Africa. Methods We performed a retrospective cohort study of 537 children initiating antiretroviral therapy at McCord Hospital in KwaZulu-Natal, South Africa. Data were extracted from electronic medical records and risk factors associated with mortality were assessed using Cox regression analysis. Results Overall there were 47 deaths from the cohort of 537 children initiating ART with over 991 child-years of follow-up (median 22 months on ART), yielding a mortality rate of 4.7 deaths per 100 child years on ART. Univariate analysis indicated that mortality was significantly associated with lower weight-for-age Z-score (p<0.0001), chronic diarrhea (p = 0.0002), lower hemoglobin (p = 0.002), age <3 years (p = 0.003), and CD4% <10% (p = 0.005). The final multivariable Cox proportional hazards mortality model found age less than 3 years (p = 0.004), CD4 <10% (p = 0.01), chronic diarrhea (p = 0.03), weight-for-age Z-score (<0.0001) and female gender as a covariate varying with time (p = 0.03) all significantly associated with mortality. Conclusion In addition to recognized risk factors such as young age and advanced immunosuppression, we found female gender to be significantly associated with mortality in this pediatric ART cohort. Future studies are needed to determine whether intrinsic biologic differences or socio-cultural factors place female children with HIV at increased risk of death following initiation of ART.

Impact of tuberculosis cotreatment on viral suppression rates among HIV-positive children initiating HAART.

Objective:To evaluate the association between treatment of HIV-tuberculosis (TB) coinfection and primary virologic failure among children initiating antiretroviral therapy in South Africa. Design:We performed a retrospective cohort study of 1029 children initiating antiretroviral therapy at two medical centers in KwaZulu Natal, South Africa, a region of very high TB incidence. Methods:Data were extracted from electronic medical records and charts and the impact of TB cotreatment on viral suppression at 6 and 12 months was assessed using logistic regression. Results:The overall rate of virologic suppression (<400 HIV RNA copies/ml) was 85% at 6 months and 87% at 12 months. Children who received concurrent treatment for TB had a significantly lower rate of virologic suppression at 6 months (79 vs. 88%; P = 0.003). Those who received nonnucleoside reverse transcriptase inhibitor-based HAART had similar rates of viral suppression regardless of whether they received concurrent TB therapy. In contrast, children who received protease inhibitor-based HAART had significantly lower viral suppression rates at both 6 and 12 months if treated concurrently for TB (P = 0.02 and 0.03). Multivariate logistic regression revealed that age at initiation, protease inhibitor therapy, and TB coinfection were each independently associated with primary virologic failure. Conclusion:Concurrent treatment for TB is associated with lower rates of viral suppression among children receiving protease inhibitor-based HAART, but not among those receiving nonnucleoside reverse transcriptase inhibitor-based HAART. Guidelines for the care of young HIV-TB coinfected infants should be continually evaluated, as protease inhibitor-based antiviral therapy may not provide optimal viral suppression in this population.

Aminopyrazoles with high affinity for the human neuropeptide Y5 receptor.

1,3-Disubstituted-5-aminopyrazoles were prepared based on a lead compound found through high-throughput screening of our corporate compound library in an assay measuring affinity for the human neuropeptide Y5 receptor. The target compounds were prepared by cyclization of alpha-cyanoketones with appropriate hydrazines, followed by reduction and coupling to various sulfonamido-carboxylic acids. Several of these arylpyrazoles (e.g., 19 and 45) displayed high affinity for the human NPY Y5 receptor (<20nM IC(50)s).

Pyrazolecarboxamide human neuropeptide Y5 receptor ligands with in vivo antifeedant activity.

1-Aryl-3-carboxamido-5-alkylpyrazoles were prepared based on a hit found in high-throughput screening of our corporate compound library in an assay measuring affinity for the human neuropeptide Y5 receptor. 1-(3-Trifluoromethylphenyl)-3-[N-(5-quinolinyl)carboxamido]-5-methylpyrazole (31) bound to the human neuropeptide Y5 receptor with a 80 nM IC(50 )and was shown to inhibit cumulative food consumption 43.2% 2-6 h after ip dosing in a fasting-induced feeding model in rats.

Sex Differences in HIV RNA Level and CD4 Cell Percentage During Childhood

BACKGROUND HIV-infected women have lower HIV RNA levels and higher CD4-cell counts than do men. This observation has been attributed to the immunomodulatory effects of sex steroid hormones, such as estrogen and progesterone. Limited data exist regarding potential sex differences in HIV RNA level and CD4 parameters among prepubertal children with untreated HIV infection. METHODS We examined the relationship of sex to HIV RNA level and CD4 parameters among 670 perinatally HIV-infected, antiretroviral therapy-naive African children aged <18 years (median age, 4.8 years) using multivariate linear regression. In a subset of 188 children, we used longitudinal data to compare changes in HIV RNA levels and CD4 percentage over time. Levels of CD4 and CD8 T-cell activation (CD38+HLA-DR+) were also compared between boys and girls. RESULTS Female children had lower HIV RNA levels (P = .0004) and higher CD4 percentages (P < .0001), compared to male children. Multivariate linear regression demonstrated an independent association of sex with both HIV RNA level and CD4 percentages after controlling for other covariates. Multilevel mixed-effects linear regression analysis of longitudinal HIV RNA level and CD4 parameter data showed that sex differences persisted across all observed ages. Levels of T-cell activation did not differ between the sexes. CONCLUSIONS Significant sex differences in HIV RNA levels and CD4 parameters are present in HIV-infected children before the onset of puberty. These data suggest that intrinsic genetic differences between male and female individuals, unrelated to sex steroid hormone levels, influence HIV RNA level and CD4 parameters in HIV-infected individuals.

Pediatric Response to Second-Line Antiretroviral Therapy in South Africa

Background With improved access to pediatric antiretroviral therapy (ART) in resource-limited settings, more children could experience first-line ART treatment failure. Methods We performed a retrospective cohort analysis using electronic medical records from HIV-infected children who initiated ART at McCord Hospitals Sinikithemba Clinic in KwaZulu-Natal, South Africa, from August 2003 to December 2010. We analyzed all records from children who began second-line ART due to first-line treatment failure. We used logistic regression to compare viral outcomes in Protease Inhibitor (PI)-based versus Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)-based second-line ART, controlling for time on first-line ART, sex, and whether HIV genotyping guided the regimen change. Results Of the 880 children who initiated ART during this time period, 80 (9.1%) switched to second-line ART due to therapeutic failure of first-line ART after a median of 95 weeks (IQR 65–147 weeks). Eight (10%) of the failures received NNRTI-based second-line ART, all of whom failed a PI-based first-line regimen. Seventy (87.5%) received PI-based second-line ART, all of whom failed a NNRTI-based first-line regimen. Two children (2.5%) received non-standard dual therapy as second-line ART. Six months after switching ART regimens, the viral suppression rate was significantly higher in the PI group (82%) than in the NNRTI group (29%; p = 0.003). Forty-one children (51%) were tested for genotypic resistance prior to switching to second-line ART. There was no significant difference in six month viral suppression (p = 0.38) between children with and without genotype testing. Conclusion: NNRTI-based second-line ART carries a high risk of virologic failure compared to PI-based second-line ART.

Systematic review and meta-analysis of the adolescent HIV continuum of care in South Africa: the Cresting Wave

Context South Africa has the most HIV infections of any country in the world, yet little is known about the adolescent continuum of care from HIV diagnosis through viral suppression. Objective To determine the adolescent HIV continuum of care in South Africa. Data sources We searched PubMed, Google Scholar and online conference proceedings from International AIDS Society (IAS), International AIDS Conference (AIDS) and Conference on Retrovirology and Opportunistic Infections (CROI) from 1 January 2005 to 31 July 2015. Data extraction We selected published literature containing South African cohorts and epidemiological data reporting primary data for youth (15–24 years of age) at any stage of the HIV continuum of care (ie, diagnosis, treatment, retention, viral suppression). For the meta-analysis we used six sources for retention in care and nine for viral suppression. Results Among the estimated 867 283 HIV-infected youth from 15 to 24 years old in South Africa in 2013, 14% accessed antiretroviral therapy (ART). Of those on therapy, ∼83% were retained in care and 81% were virally suppressed. Overall, we estimate that 10% of HIV-infected youth in South Africa in 2013 were virally suppressed. Limitations This analysis relies on published data from large mostly urban South Africa cohorts limiting the generalisability to all adolescents. Conclusions Despite a large increase in ART programmes in South Africa that have relatively high retention rates and viral suppression rates among HIV-infected youth, only a small percentage are virally suppressed, largely due to low numbers of adolescents and young adults accessing ART.

Predictors of poor CD4 and weight recovery in HIV-infected children initiating ART in South Africa.

Objective To identify baseline demographic and clinical risk factors associated with poor CD4 and weight response after initiation of antiretroviral therapy (ART) in a cohort of human immunodeficiency virus (HIV)-infected children in KwaZulu-Natal, South Africa. Methods We performed a retrospective cohort study of 674 children initiating antiretroviral therapy at McCord and St. Marys hospitals in KwaZulu-Natal, South Africa, from August 2003 to December 2008. We extracted data from paper charts and electronic medical records to assess risk factors associated with CD4 and weight response using logistic regression. Results From the initial cohort of 901 children <10 years old initiating ART between August 2003 and December 2008, we analyzed 674 children with complete baseline data. Viral suppression rates (<400 copies/ml) were 84% after six months of therapy and 88% after 12 months of therapy. Seventy-three percent of children achieved CD4 recovery after six months and 89% after 12 months. Weight-for-age Z-score (WAZ) improvements were seen in 58% of children after six months of ART and 64% after 12 months. After six months of ART, lower baseline hemoglobin (p = 0.037), presence of chronic diarrhea (p = 0.007), and virologic failure (p = 0.046) were all associated with poor CD4 recovery by multivariate logistic regression. After 12 months of ART, poor CD4 recovery was associated with higher baseline CD4% (p = 0.005), chronic diarrhea (p = 0.02), and virologic failure (p<0.001). Age less than 3 years at ART initiation (p = 0.0003), higher baseline CD4% (p<0.001), and higher baseline WAZ (p<0.001) were all associated with poor WAZ improvements after 6 months by multivariate logistic regression. Conclusion The presence of chronic diarrhea at baseline, independent of nutritional status and viral response, predicts poor CD4 recovery. Age at initiation of ART is an important factor in early WAZ response to ART, while viral suppression strongly predicts CD4 recovery but not WAZ improvement.

Possible use of Biolog methodology for monitoring yeast presence in alcoholic fermentation for wine-making

Aims:  A research was undertaken to explore the possibility to use Biolog system of microbial metabolic characterization for the monitoring of yeast population evolution during alcoholic fermentation for wine production.