Estimating HIV transmissions in a large U.S. clinic-based sample: effects of time and syndemic conditions

Introduction: Little is known about onward HIV transmissions from people living with HIV (PLWH) in care. Antiretroviral therapy (ART) has increased in potency, and treatment as prevention (TasP) is an important component of ending the epidemic. Syndemic theory has informed modelling of HIV risk but has yet to inform modelling of HIV transmissions. Methods: Data were from 61,198 primary HIV care visits for 14,261 PLWH receiving care through the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) at seven United States (U.S.) sites from 2007 to 2017. Patient-reported outcomes and measures (PROs) of syndemic conditions – depressive symptoms, anxiety symptoms, drug use (opiates, amphetamines, crack/cocaine) and alcohol use – were collected approximately four to six months apart along with sexual behaviours (mean = 4.3 observations). Counts of syndemic conditions, HIV sexual risk group and time in care were modelled to predict estimated HIV transmissions resulting from sexual behaviour and viral suppression status (HIV RNA \u3c 400/mL) using hierarchical linear modelling. Results: Patients averaged 0.38 estimated HIV transmissions/100 patients/year for all visits with syndemic conditions measured (down from 0.83, first visit). The final multivariate model showed that per 100 patients, each care visit predicted 0.05 fewer estimated transmissions annually (95% confidence interval (CI): 0.03 to 0.06; p \u3c 0.0005). Cisgender women, cisgender heterosexual men and cisgender men of undisclosed sexual orientation had, respectively, 0.47 (95% CI: 0.35 to 0.59; p \u3c 0.0005), 0.34 (95% CI: 0.20 to 0.49; p \u3c 0.0005) and 0.22 (95% CI: 0.09 to 0.35; p \u3c 0.005) fewer estimated HIV transmissions/100 patients/year than cisgender men who have sex with men (MSM). Each within-patient syndemic condition predicted 0.18 estimated transmissions/100 patients/year (95% CI: 0.12 to 0.24; p \u3c 0.0005). Each between-syndemic condition predicted 0.23 estimated HIV transmissions/100 patients/year (95% CI: 0.17 to 0.28; p \u3c 0.0005). Conclusions: Estimated HIV transmissions among PLWH receiving care in well-resourced U.S. clinical settings varied by HIV sexual risk group and decreased with time in care, highlighting the importance of TasP efforts. Syndemic conditions remained a significant predictor of estimated HIV transmissions notwithstanding the effects of HIV sexual risk group and time in care

Comprehensive genetic results for primary immunodeficiency disorders in a highly consanguineous population

Objective: To present the genetic causes of patients with primary immune deficiencies (PIDs) in Kuwait between 2004 and 2017. Methods: The data was obtained from the Kuwait National Primary Immunodeficiency Disorders Registry. Genomic DNA from patients with clinical and immunological features of PID was sequenced using Sanger sequencing (SS), next generation sequencing (NGS) of targeted genes, whole exome sequencing (WES), and/or whole genome sequencing (WGS). Functional assays were utilized to assess the biologic effect of identified variants. Fluorescence in situ hybridization (FISH) for 22q11.2 deletion and genomic hybridizations arrays were performed when thymic defects were suspected. Results: A total of 264 patients were registered during the study period with predominance of patients with immunodeficiencies affecting cellular and humoral immunity (35.2%), followed by combined immunodeficiencies with associated syndromic features (24%). Parental consanguinity and family history suggestive of PID were reported in 213 (81%) and 145 patients (55%), respectively. Genetic testing of 206 patients resulted in a diagnostic yield of 70%. Mutations were identified in 46 different genes and more than 90% of the reported genetic defects were transmitted by in an autosomal recessive pattern. The majority of the mutations were missense mutations (57%) followed by deletions and frame shift mutations. Five novel disease-causing genes were discovered. Conclusions: Genetic testing should be an integral part in the management of primary immunodeficiency patients. This will help the delivery of precision medicine and facilitate proper genetic counseling. Studying inbred populations using sophisticated diagnostic methods can allow better understanding of the genetics of primary immunodeficiency disorders

Connecting the dots: a comparison of network analysis and exploratory factor analysis to examine psychosocial syndemic indicators among HIV-negative sexual minority men

Syndemics, or comorbid and mutually reinforcing psychosocial problems, are associated with increased HIV risk among men who have sex with men (MSM). Although the dynamic interplay among syndemic indicators is theorized to be crucial for increasing risk of HIV acquisition, novel approaches are needed to understand how these syndemic problems interrelate. This study examined the associations between nine self-reported syndemic indicators in 194 MSM at high risk of HIV acquisition. We compared exploratory factor analyses (EFA) to a network analysis. In the present study, network analysis consisted of edges representing bidirectional partial polychoric correlations between nodes, which represent psychosocial syndemic indicators. EFA yielded a 1-factor solution including suicidal ideation (SI), injection drug use (IDU), depression, social anxiety, intimate partner violence, substance use, and sexual compulsivity, and excluded heavy drinking and childhood sexual abuse. Network analysis yielded a pattern of interconnectedness with the most central nodes being SI, IDU, substance use, and depression. Statistically significant relationships (absolute edge weights) were found between SI and depression, social anxiety, and IDU, and IDU and substance use. These results suggest that depression and substance use, especially more severe presentations of these conditions such as SI and IDU, are prominent interconnected components of the HIV syndemic among MSM at high risk for HIV acquisition. SI, IDU, substance use, and depression may indeed be prudent targets of intervention. Future research on the inclusion of these syndemic indicators in analytical models involving interaction terms may be warranted

Tina's ParTy line: Polysubstance use patterns in sexual minority men living with HIV who use methamphetamine

INTRODUCTIONThis cross-sectional study examined the associations of demographic, structural and psychological factors with distinct typologies of polysubstance use in sexual minority men (SMM) living with HIV who use methamphetamine. METHODSIn total, 161 SMM living with HIV who reported methamphetamine use in the past 3 months were recruited in San Francisco from 2013 to 2017 for a randomised controlled trial. A latent class analysis was conducted by leveraging baseline measures of self-reported use of 15 substances in the past 3 months as well as validated screening measures of hazardous alcohol and cannabis use. Correlates of latent class membership were examined using a three-step categorical latent variable logistic regression. RESULTSFour typologies of substance use were identified: (i) methamphetamine use only (43%); (ii) methamphetamine and crack-cocaine use (22%); (iii) party and play use-methamphetamine, gamma-hydroxybutyrate and amyl nitrites (i.e. poppers) with erectile dysfunction drugs (31%); and (iv) high polysubstance use (4%). SMM of colour and those with a history of incarceration were more commonly classified as engaging in methamphetamine and crack-cocaine use compared to party and play use. Men with higher sexual compulsivity scores were more commonly classified as engaging in party and play use and polysubstance use. DISCUSSION AND CONCLUSIONSThere is substantial heterogeneity in polysubstance use patterns among SMM living with HIV who use methamphetamine. This will inform the development of tailored substance use interventions addressing the unique needs of SMM of colour and targeting sexual compulsivity as a prominent comorbidity for some men

Estimating HIV transmissions in a large U.S. clinic-based sample: effects of time and syndemic conditions.

IntroductionLittle is known about onward HIV transmissions from people living with HIV (PLWH) in care. Antiretroviral therapy (ART) has increased in potency, and treatment as prevention (TasP) is an important component of ending the epidemic. Syndemic theory has informed modelling of HIV risk but has yet to inform modelling of HIV transmissions.MethodsData were from 61,198 primary HIV care visits for 14,261 PLWH receiving care through the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) at seven United States (U.S.) sites from 2007 to 2017. Patient-reported outcomes and measures (PROs) of syndemic conditions - depressive symptoms, anxiety symptoms, drug use (opiates, amphetamines, crack/cocaine) and alcohol use - were collected approximately four to six months apart along with sexual behaviours (mean = 4.3 observations). Counts of syndemic conditions, HIV sexual risk group and time in care were modelled to predict estimated HIV transmissions resulting from sexual behaviour and viral suppression status (HIV RNA < 400/mL) using hierarchical linear modelling.ResultsPatients averaged 0.38 estimated HIV transmissions/100 patients/year for all visits with syndemic conditions measured (down from 0.83, first visit). The final multivariate model showed that per 100 patients, each care visit predicted 0.05 fewer estimated transmissions annually (95% confidence interval (CI): 0.03 to 0.06; p < 0.0005). Cisgender women, cisgender heterosexual men and cisgender men of undisclosed sexual orientation had, respectively, 0.47 (95% CI: 0.35 to 0.59; p < 0.0005), 0.34 (95% CI: 0.20 to 0.49; p < 0.0005) and 0.22 (95% CI: 0.09 to 0.35; p < 0.005) fewer estimated HIV transmissions/100 patients/year than cisgender men who have sex with men (MSM). Each within-patient syndemic condition predicted 0.18 estimated transmissions/100 patients/year (95% CI: 0.12 to 0.24; p < 0.0005). Each between-syndemic condition predicted 0.23 estimated HIV transmissions/100 patients/year (95% CI: 0.17 to 0.28; p < 0.0005).ConclusionsEstimated HIV transmissions among PLWH receiving care in well-resourced U.S. clinical settings varied by HIV sexual risk group and decreased with time in care, highlighting the importance of TasP efforts. Syndemic conditions remained a significant predictor of estimated HIV transmissions notwithstanding the effects of HIV sexual risk group and time in care

Estimating HIV transmissions in a large U.S. clinic-based sample: effects of time and syndemic conditions.

IntroductionLittle is known about onward HIV transmissions from people living with HIV (PLWH) in care. Antiretroviral therapy (ART) has increased in potency, and treatment as prevention (TasP) is an important component of ending the epidemic. Syndemic theory has informed modelling of HIV risk but has yet to inform modelling of HIV transmissions.MethodsData were from 61,198 primary HIV care visits for 14,261 PLWH receiving care through the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) at seven United States (U.S.) sites from 2007 to 2017. Patient-reported outcomes and measures (PROs) of syndemic conditions - depressive symptoms, anxiety symptoms, drug use (opiates, amphetamines, crack/cocaine) and alcohol use - were collected approximately four to six months apart along with sexual behaviours (mean = 4.3 observations). Counts of syndemic conditions, HIV sexual risk group and time in care were modelled to predict estimated HIV transmissions resulting from sexual behaviour and viral suppression status (HIV RNA < 400/mL) using hierarchical linear modelling.ResultsPatients averaged 0.38 estimated HIV transmissions/100 patients/year for all visits with syndemic conditions measured (down from 0.83, first visit). The final multivariate model showed that per 100 patients, each care visit predicted 0.05 fewer estimated transmissions annually (95% confidence interval (CI): 0.03 to 0.06; p < 0.0005). Cisgender women, cisgender heterosexual men and cisgender men of undisclosed sexual orientation had, respectively, 0.47 (95% CI: 0.35 to 0.59; p < 0.0005), 0.34 (95% CI: 0.20 to 0.49; p < 0.0005) and 0.22 (95% CI: 0.09 to 0.35; p < 0.005) fewer estimated HIV transmissions/100 patients/year than cisgender men who have sex with men (MSM). Each within-patient syndemic condition predicted 0.18 estimated transmissions/100 patients/year (95% CI: 0.12 to 0.24; p < 0.0005). Each between-syndemic condition predicted 0.23 estimated HIV transmissions/100 patients/year (95% CI: 0.17 to 0.28; p < 0.0005).ConclusionsEstimated HIV transmissions among PLWH receiving care in well-resourced U.S. clinical settings varied by HIV sexual risk group and decreased with time in care, highlighting the importance of TasP efforts. Syndemic conditions remained a significant predictor of estimated HIV transmissions notwithstanding the effects of HIV sexual risk group and time in care

Longitudinal Associations of Syndemic Conditions with Antiretroviral Therapy Adherence and HIV Viral Suppression Among HIV-Infected Patients in Primary Care

Psychosocial syndemic conditions have received more attention regarding their deleterious effects on HIV acquisition risk than for their potential impact on HIV treatment and viral suppression. To examine syndemic conditions' impact on the HIV care continuum, we analyzed data collected from people living with HIV (N = 14,261) receiving care through The Centers for AIDS Research Network of Integrated Clinical Systems at seven sites from 2007 to 2017 who provided patient-reported outcomes ∼4-6 months apart. Syndemic condition count (depression, anxiety, substance use, and hazardous drinking), sexual risk group, and time in care were modeled to predict antiretroviral therapy (ART) adherence and viral suppression (HIV RNA <400 copies/mL) using multilevel logistic regression. Comparing patients with each other, odds of ART adherence were 61.6% lower per between-patient syndemic condition [adjusted odds ratio (AOR) = 0.384; 95% confidence interval (CI), 0.362-0.408]; comparing patients with themselves, odds of ART adherence were 36.4% lower per within-patient syndemic condition (AOR = 0.636 95% CI, 0.606-0.667). Odds of viral suppression were 29.3% lower per between-patient syndemic condition (AOR = 0.707; 95% CI, 0.644-0.778) and 27.7% lower per within-patient syndemic condition (AOR = 0.723; 95% CI, 0.671-0.780). Controlling for the effects of adherence (AOR = 5.522; 95% CI, 4.67-6.53), each additional clinic visit was associated with 1.296 times higher odds of viral suppression (AOR = 1.296; 95% CI, 1.22-1.38), but syndemic conditions were not significant. Deploying effective interventions within clinics to identify and treat syndemic conditions and bolster ART adherence and continued engagement in care can help control the HIV epidemic, even within academic medical settings in the era of increasingly potent ART

Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex

The coat protein I (COPI) complex mediates retrograde trafficking from the Golgi to the endoplasmic reticulum (ER). Five siblings with persistent bacterial and viral infections and defective humoral and cellular immunity had a homozygous p.K652E mutation in the γ1 subunit of COPI (γ1-COP). The mutation disrupts COPI binding to the KDEL receptor and impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER. Homozygous Copg1K652E mice had increased ER stress in activated T and B cells, poor antibody responses, and normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation. Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients. The ER stress-relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice. This study establishes the role of γ1-COP in the ER retrieval of KDEL-bearing chaperones and thereby the importance of ER homeostasis in adaptive immunity.11Nsciescopu

Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor κB kinase alpha (IKKα)

Inhibitor of nuclear factor kappa B kinase alpha (IKKα) is critical for p100/NF-κB2 phosphorylation and processing into p52 and activation of the noncanonical NF-κB pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKKα. The mutation preserves IKKα kinase activity but abolishes the interaction of IKKα with its activator NF-κB–inducing kinase and impairs lymphotoxin-β–driven p100/NF-κB2 processing and VCAM1 expression. Homozygous IKKαY580C/Y580C mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired Il17a expression; and are susceptible to cutaneous Staphylococcus aureus infection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRVβ repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKKα deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity