Objective In sub-Saharan Africa, HIV-exposed uninfected (HEU) infants have higher morbidity and mortality than HIV-unexposed infants. To evaluate whether immune dysfunction contributes to this vulnerability of HEU infants, we conducted a longitudinal, observational cohort study to assess T-cell immune responses to infant vaccines (Mycobacterium bovis BCG and acellular pertussis) and staphylococcal enterotoxin B (SEB). In total, 46 HEU and 46 HIV-unexposed infants were recruited from Khayelitsha, Cape Town. Methods Vaccine-specific T-cell proliferation (Ki67 expression) and intracellular expression of four cytokines [interferon-γ, interleukin (IL)-2, IL-13 and IL-17] were measured after whole blood stimulation with antigens at 6 and 14 weeks of age. Results HEU infants demonstrated elevated BCG-specific CD4+ and CD8+ T-cell proliferative responses at 14 weeks (P = 0.041 and 0.002, respectively). These responses were significantly increased even after adjusting for birth weight, feeding mode and gestational age. Similar to BCG, increased CD4+ and CD8+ T-cell proliferation was evident in response to SEB stimulation (P = 0.004 and 0.002, respectively), although pertussis-specific T cells proliferated comparably between the two groups. Within HEU infants, maternal CD4+ cell count and length of antenatal antiretroviral exposure had no effect on T-cell proliferation to BCG or SEB. HIV exposure significantly diminished measurable cytokine polyfunctionality in response to BCG, Bordetella pertussis and SEB stimulation. Conclusion These data show for the first time, when adjusting for confounders, that exposure to HIV in utero is associated with significant alterations to CD4+ and CD8+T-cell immune responses in infants to vaccines and nonspecific antigens.

NCT02062580.

In settings with universal antiretroviral coverage and high breastfeeding rates, breastfeeding mitigates the effects of in-utero HIV exposure among infants during the first year of life. These findings support previous recommendations for exclusive breastfeeding among HIV-infected women and highlight the role that breastfeeding plays on the health of infants in settings where exclusive breastfeeding is not always feasible or where replacement feeding is recommended.

Background and Objective Semantic memory measures may be useful in tracking and predicting progression of Alzheimer disease. We investigated relationships among semantic memory tasks and their 1-year predictive value in women with Alzheimer disease. Methods We conducted secondary analyses of a randomized clinical trial of raloxifene in 42 women with late-onset mild-to-moderate Alzheimer disease. We assessed semantic memory with tests of oral confrontation naming, category fluency, semantic recognition and semantic naming, and semantic density in written narrative discourse. We measured global cognition (Alzheimer Disease Assessment Scale, cognitive subscale), dementia severity (Clinical Dementia Rating sum of boxes), and daily function (Activities of Daily Living Inventory) at baseline and 1 year. Results At baseline and 1 year, most semantic memory scores correlated highly or moderately with each other and with global cognition, dementia severity, and daily function. Semantic memory task performance at 1 year had worsened one-third to one-half standard deviation. Factor analysis of baseline test scores distinguished processes in semantic and lexical retrieval (semantic recognition, semantic naming, confrontation naming) from processes in lexical search (semantic density, category fluency).The semantic–lexical retrieval factor predicted global cognition at 1 year. Considered separately, baseline confrontation naming and category fluency predicted dementia severity, while semantic recognition and a composite of semantic recognition and semantic naming predicted global cognition. No individual semantic memory test predicted daily function. Conclusions Semantic–lexical retrieval and lexical search may represent distinct aspects of semantic memory. Semantic memory processes are sensitive to cognitive decline and dementia severity in Alzheimer disease.

Background Bacille Calmette-Guerin (BCG) is effective in preventing disseminated tuberculosis (TB) in children but may also have non-specific benefits, and is thought to improve immunity to unrelated antigens through trained innate immunity. In HIV-infected infants, there is a risk of BCG-associated adverse events. We aimed to explore whether delaying BCG vaccination by 8 weeks, when in utero HIV is excluded, affected T-cell responses to B. pertussis (BP) and tetanus toxoid (TT), in HIV-exposed, uninfected infants. Methods Infants were randomized to receive BCG vaccination at birth or 8 weeks of age. At 8 and 14 weeks, T cell proliferation and intracellular cytokine (IL-2, IL-13, IL-17, and IFN-γ) expression was analyzed in response to BP, TT and Staphylococcal enterotoxin B (SEB) antigens. Results Delaying BCG vaccination did not alter T-cell proliferation to BP or TT antigens. Infants immunized with BCG at birth had higher CD4+ T cell proliferation to SEB at 14 weeks of age (p=0.018). Birth-vaccinated infants had increased CD8+ IL-2 expression in response to BP, but not TT or SEB, at 8 weeks. Infants vaccinated with BCG at 8 weeks had significantly lower IL-13 expression by BP-specific CD4+ and CD8+ T cells at 14 weeks (p=0.032 and p=0.0035 respectively). There were no observed differences in multifunctional cytokine response to TT, BP or SEB between infants vaccinated with BCG at birth versus 8 weeks of age. Conclusion Delaying BCG vaccination until 8 weeks of age results in robust T-cellular responses to BP and TT in HIV-exposed infants. Clinical Trial Registry NCT02062580

Background Only a few recent reports have examined longitudinal adherence patterns in US clinics and its impact on immunological and virological outcomes among large cohorts initiating contemporary antiretroviral therapy (ART) in US clinics. Methods We followed all persons with HIV (PLWH) in a California clinic population initiating ART between 2010 and 2017. We estimated longitudinal adherence for each PLWH by calculating the medication possession ratio within multiple 6-month intervals using pharmacy refill records. Results During the study, 2315 PWLH were followed for a median time of 210.8 weeks and only 179 (7.7%) were lost-to-follow-up. The mean adherence was 84.9%. Age (Hazard Ratio (HR): (95% confidence interval): 1.25 (1.20–1.31) per 10-year increase) and Black race (HR: 0.62 (0.53–0.73) vs. White) were associated with adherence in the cohort. A 10% percent increase in adherence increased the odds of being virally suppressed by 37% (OR and 95% CI: 1.37 [1.33–1.41]) and was associated with an increase in mean CD4 count by 8.54 cells/ul in the next 6-month interval (p-value <0.0001). Conclusions Our study shows that despite large improvements in retention in care, demographic disparities in adherence to ART persist. Adherence was lower among younger patients and black patients. Our study confirmed the strong association between adherence to ART and viral suppression but could only establish a weak association between adherence and CD4 count. These findings reaffirm the importance of adherence and retention in care and further highlight the need for tailored patient-centered HIV Care Models as a strategy to improve PLWH’s outcomes.

Background There are few descriptions of virologic failure (VF) and acquired drug resistance (HIVDR) in large cohorts initiating contemporary antiretroviral therapy (ART). Methods We studied all persons with HIV (PWH) in a California clinic population initiating ART between 2010 and 2017. VF was defined as not attaining virologic suppression, discontinuing ART, or virologic rebound prompting change in ART. Results During the study, 2,315 PWH began ART. Six companion drugs were used in 93.3% of regimens: efavirenz, elvitegravir/c, dolutegravir, darunavir/r, rilpivirine, and raltegravir. During a median follow-up of 36 months, 214 (9.2%) PWH experienced VF (2.8 per 100 person-years) and 62 (2.7%) experienced HIVDR (0.8 per 100 person-years). In multivariable analyses, younger age, lower CD4 count, higher virus load, and atazanavir/r were associated with increased VF risk; lower CD4 count, higher virus load, and nevirapine were associated with increased HIVDR risk. Compared with efavirenz, dolutegravir, raltegravir and darunavir were associated with reduced HIVDR risk. Risks of VF and HIVDR were not significantly associated with ART initiation year. Of the 62 PWH with HIVDR, 42 received an NNRTI, 15 an INSTI, and five a PI. Among those with HIVDR on an NNRTI or first-generation INSTI, 59% acquired dual class resistance and 29% developed tenofovir resistance; those receiving a PI or dolutegravir developed just M184V. Conclusions Despite the frequent use of contemporary ART regimens, VF and HIVDR continue to occur. Further efforts are required to improve long-term ART virological responses to prevent the consequences of ongoing HIV-1 replication including virus transmission and HIVDR.

Background HIV-infected patients may be at a greater risk of Hospital-Acquired Infections (HAIs) but risks factors for HAIs have not been well described in this population. Objective The aim of this study was to examine the incidence, temporal trends and risk factors of HAIs among adult HIV positive patients. Methods This was a retrospective cohort study carried out in an academic health system in New York City which included four hospitals over a 9-year period from 2006 to 2014. Simple and multiple logistic regression models were built to determine risk factors associated with site-specific HAIs such as Urinary Tract Infections (UTIs), Pneumonia (PNUs) and Bloodstream Infections (BSIs). Findings There were 10,575 HIV positive discharges and 1,328 had HAIs: 697 UTIs, 555 BSIs and 192 PNUs. The incidence rate of HAIs decreased from 19.8 to 15.1 new infections per 1000 person-days between 2006 and 2014 (p value<0.001). In addition to the expected risk factors of urinary catheter use for UTI and central venous line use for BSI, symptomatic HIV and renal failure were significant risk factors for both UTIs (95% CI OR: (1.24, 2.27) and (1.46, 2.11) respectively) and BSIs (95% CIs OR: (2.28, 4.18) and (1.81, 2.71) respectively). Conclusion HIV-infected patients had similar risk factors for HAIs as HIV-uninfected patients. Further research is required to address how patients’ CD4 counts and viral loads affect their susceptibility to HAIs.