Cross-sectional analysis of cognitive function using multivariate normative comparisons in men with HIV disease Background: Prevalence estimates of cognitive impairment in HIV disease vary widely. Here we used multivariate normative comparison (MNC) with identify individuals with impaired cognition, and to compare the results with those using the Frascati and Gisslén criteria. Methods: The current project used data collected before October 2014 from bisexual/gay men from the Multicenter AIDS Cohort Study. A total of 2904 men (mean age 39.7 years, 52.7% seropositive) had complete data in six cognitive domains at their first neuropsychological evaluation. T-scores were computed for each domain and the MNC was applied to detect impairment among seronegative and seropositive groups. Results: The MNC classified 6.26% of seronegative men as being impaired using a predetermined 5% false discovery rate. By contrast, the Frascati and the Gisslén criteria identified 24.54 and 11.36% of seronegative men as impaired. For seropositive men, the percentage impairment was 7.45, 25.73, and 11.69%, respectively, by the MNC, Frascati and Gisslén criteria. When we used seronegative men without medical comorbidities as the control group, the MNC, the Frascati and the Gisslén criteria identified 5.05, 27.07, and 4.21% of the seronegative men, and 4.34, 30.95, and 4.48% of the seropositive men as having cognitive impairment. For each method, serostatus was not associated with cognitive impairment. Conclusion: The MNC controls the false discovery rate and therefore avoids the low specificity that characterizes the Frascati and Gisslén criteria. More research is needed to evaluate the sensitivity of the MNC method in a seropositive population that may be sicker and older than the current study sample and that includes women.

Pre-exposure prophylaxis differentially alters circulating and mucosal immune cell activation in herpes simplex virus type 2 seropositive women Objective: Oral tenofovir-based pre-exposure prophylaxis (PrEP) is an important tool for prevention of new HIV infections, which also reduces subclinical herpes simplex virus type 2 (HSV-2) shedding and symptomatic lesions in HIV-negative, HSV-2-seropositive individuals. However, the impact of PrEP on mucosal immunity has not been examined in detail. Design: Here we evaluate paired genital tissue and systemic immune profiles to characterize the immunological effects of PrEP in HIV-negative, HSV-2-seropositive African women sexually exposed to HIV. Methods: We compared local and systemic innate and T-cell characteristics in samples collected during PrEP usage and 2 months after PrEP discontinuation. Results: We found that frequencies of cervical CCR5+CD4+ cells, regulatory T cells, and tissue macrophages were significantly reduced during PrEP use compared with after PrEP discontinuation. In contrast, peripheral blood CD4+ and CD8+ T cells expressing markers of activation and trafficking were increased during PrEP usage. Conclusion: Together, our data are consistent with PrEP altering immunity differentially in the female genital tract compared with circulation in HSV-2+ women. Further study including comparison with HSV-2 negative women is needed to define the overall impact and mechanisms underlying these effects. These results point to the critical need to study the human mucosal compartment to characterize immune responses to mucosal infections.

The proportion of CD57+ cells among effector CD8+ T cells is lower in HIV controllers compared with antiretroviral therapy-treated patients Background: HIV infection has often been linked to faster immune ageing. We sought to determine whether or not treatment-naive spontaneous HIV-1 controllers (HICs) and ART-exposed patients differ with regard to the expression of cell senescence markers. Methods: Eighty-eight chronically infected HICs and ART-exposed patients (median time since infection: 15 years) with an undetectable plasma HIV RNA load (at least for the previous 2 years) were included. We used flow cytometry to measure immunosenescence markers (KLRG-1 and CD57) expression in fresh blood samples collected from patients and healthy donors. Results: For the CD8+ T-cell population as a whole, the ART-exposed but not the HIC patients exhibited a much higher proportion of KLRG-1+ and CD57+ CD8+ T cells than healthy blood donors. For the CD8+ T-cell subsets, HICs had a lower proportion of CD57+ effector CD8+ T cells than ART patients or healthy blood donors, whereas the proportions of KLRG-1+ effector were similar. A similar trend was observed for terminal effectors. No impact of age, sex or standard parameters of infection (CD4+ percentage, protective HLA allele, viral blips) was observed. The difference in the proportion of CD57+ cells between HICs and ART was observed more specifically in long-term infected patients (>20 years). However, whenever considering the CD57− effector memory and effector subsets, the cytotoxic granule content was greater in HICs than in ART. Conclusion: The proportion of CD57+ effector CD8+ T cells is lower in HICs than in ART-exposed patients. This profile may be beneficial by ensuring limited senescence associated with consistent cytotoxic potential.

Time to viral rebound and safety after antiretroviral treatment interruption in postpartum women compared with men Objective(s): The short-term safety of treatment interruptions, a necessary part of cure studies, is not well established, particularly in women. We explored viral rebound kinetics and safety in a group of postpartum women discontinuing ART and compared results to men in historical interruption trials. Design: Prospective evaluation of time to virologic rebound. Methods: One thousand and seventy-six asymptomatic, virally suppressed, postpartum women living with HIV enrolled in the PROMISE trial with baseline CD4+ cell counts at least 350 cells/μl underwent antiretroviral treatment (ART) discontinuation. Proportion with virologic suppression at weeks 4 and 12 were compared with participants in ACTG treatment interruption trials (91% male population). Results: In PROMISE, using interval censored methods, the estimated median time to HIV viral rebound was 2 weeks. An estimated 6% of women would remain virally suppressed at 30 weeks. Of those who had viral rebound by 30 weeks (N = 993), less than 4% experienced grade 3 or higher laboratory events, and 1% experienced WHO stage 2 or higher clinical events. Overall, less than 1% of participants progressed from WHO Stage 1 to Stage 2 or higher after discontinuation of ART, and 3.9% experienced a decline in CD4+ cell count to less than 350 cells/μl or local treatment guidelines. A significantly higher proportion of women in PROMISE (25.4%) were virologically suppressed (<400 copies/ml) at 12 weeks compared with ACTG NWCS 371 participants (6.4%). Conclusion: Temporary treatment interruptions in healthy, HIV-infected women with high CD4+ cell counts can be well tolerated. Potential sex differences need to be considered in cure studies examining time to virologic rebound.

Risk of developing cerebral β-amyloid plaques with posttranslational modification among HIV-infected adults Objectives: Evidence of accelerated brain aging among HIV-infected adults argues for the increased risk of developing cerebral β-amyloid (Aβ) plaques. We compared the frequency of Aβ plaque-bearing cases in our HIV cohort with that in a general cohort reported by Braak et al. We explored posttranslationally modified Aβ forms (N3pE, E22P, phospho-Ser8) in plaques and E22P-Aβ in the postmortem cerebrospinal fluid (CSF) in the HIV cohort. Design: Clinicopathological study of HIV-infected adults. Methods: To assess frontal Aβ plaque deposition, we conducted immunohistochemistry for generic Aβ (4G8) and three modified Aβ forms. We determined CSF E22P-Aβ levels by ELISA. Results: We found 4G8-Aβ plaques in 29% of 279 HIV-infected cases. Within the age range of 31–70 years, the frequency of 4G8-Aβ plaque-bearing cases was higher in our HIV cohort (n  = 273) compared with the general cohort (n = 1110) overall (29.3 vs. 25.8%) and across four age groups by decade (odds ratio 2.35, P  < 0.0001). In HIV-infected cases with (n = 37) and without (n = 12) 4G8-Aβ plaques, modified Aβ forms occurred in order: N3pE, E22P, and phospho-Ser8. In CSF assays of HIV-infected cases with (n = 27; 17 focal, 10 widespread) and without (n = 11) 4G8-Aβ plaques, the median E22P-Aβ/Aβ40 ratio was higher among cases with widespread plaques than in cases with focal or absent plaques (P = 0.047). Conclusion: Our findings suggest HIV-infected adults are at increased risk of developing cerebral Aβ plaques. The occurrence of modified Aβ forms in order suggests the progression stages of Aβ plaque deposition. The potential for E22P-Aβ as a CSF biomarker of cerebral Aβ plaques should be investigated.

Treatment outcome in dually HIV-1 and HIV-2 coinfected patients living in Spain Background: Whereas HIV-1 has spread globally, HIV-2 is mainly found in West Africa where dual HIV-1/HIV-2 coinfection is nowadays uncommon. Herein, we report the rate, main characteristics, and treatment outcomes of all dually infected patients living in Spain. Methods: We identified retrospectively all persons coinfected with HIV-1 recorded at the Spanish HIV-2 registry. Dual infection had been confirmed using PCR in plasma and/or cells, and/or using discriminatory serological tests. Results: From a total of 373 individuals with HIV-2 recorded at the Spanish registry, 34 (9.1%) were coinfected with HIV-1. Compared with HIV-2 monoinfected persons, dually infected patients were more often male (67.6%), presented with lower median CD4+ cell counts (204 cells/μl), and had developed more frequently AIDS events (26.5%). Although 61.7% came from West Africa, 6 (17.6%) were native Spaniards. HIV-1 non-B subtypes were recognized in 75% of coinfected patients, being the most prevalent CRF02_AG. At baseline, 45% of dually infected patients had undetectable plasma HIV-2 RNA. After a median follow-up of 32 (13–48) months on antiretroviral therapy, dually infected patients achieved undetectable viremia in 85% for HIV-1, in 80% for HIV-2; and in 70% for both viruses. Median CD4+ cell counts reached up to 418 cells/μl. Conclusion: Roughly 9% of individuals with HIV-2 infection living in Spain are coinfected with HIV-1. Overall, 70% of dually infected patients achieved viral suppression for both viruses under antiretroviral therapy. Given the relatively large population of West Africans living in Spain and the continuous migration flow from HIV-2 endemic areas, HIV-1/HIV-2 coinfection should always be excluded at first diagnosis in all HIV-seroreactive persons.

Serious clinical events in HIV-positive persons with chronic kidney disease Objectives: Predictors of chronic kidney disease (CKD) amongst HIV-positive persons are well established, but insights into the prognosis after CKD including the role of modifiable risk factors are limited. Design: Prospective cohort study. Methods: D:A:D participants developing CKD (confirmed, >3 months apart, eGFR ≤ 60 ml/min per 1.73 m2 or 25% eGFR decrease when eGFR ≤ 60 ml/min per 1.73 m2) were followed to incident serious clinical events (SCE); end stage renal and liver disease (ESRL and ESLD), cardiovascular disease (CVD), AIDS-defining and non-AIDS-defining malignancies (NADM), other AIDS or death, 6 months after last visit or 1 February 2016. Poisson regression models considered associations between SCE and modifiable risk factors. Results: During 2.7 (IQR 1.1–5.1) years median follow-up 595 persons with CKD (24.1%) developed a SCE [incidence rate 68.9/1000 PYFU (95% confidence interval 63.4–74.4)] with 8.3% (6.9–9.0) estimated to experience any SCE at 1 year. The most common SCE was death (12.7%), followed by NADM (5.8%), CVD (5.6%), other AIDS (5.0%) and ESRD (2.9%). Crude SCE ratios were significantly higher in those with vs. without CKD, strongest for ESRD [65.9 (43.8–100.9)] and death [4.8 (4.3–5.3)]. Smoking was consistently associated with all CKD-related SCE. Diabetes predicted CVD, NADM and death, whereas dyslipidaemia was only significantly associated with CVD. Poor HIV-status predicted other AIDS and death, eGFR less than 30 ml/min per 1.73 m2 predicted CVD and death and low BMI predicted other AIDS and death. Conclusion: In an era where many HIV-positive persons require less monitoring because of efficient antiretroviral treatment, persons with CKD carry a high burden of SCE. Several potentially modifiable risk factors play a central role for CKD-related morbidity and mortality.

Racial/ethnic and HIV risk category disparities in preexposure prophylaxis discontinuation among patients in publicly funded primary care clinics Objective: Dissemination of preexposure prophylaxis (PrEP) is a priority for reducing new HIV infections, especially among vulnerable populations. However, there are limited data available on PrEP discontinuation following initiation, an important component of the PrEP cascade. Design: Patients receiving PrEP within the San Francisco Department of Public Health Primary Care Clinics (SFPCC) are included in a PrEP registry if they received a PrEP prescription, were not receiving postexposure prophylaxis, and not known to be HIV-positive. Methods: We calculated PrEP discontinuation for patients initiating PrEP at any time from January 2012 to July 2017 and evaluated their association with demographic and risk variables using Cox regression analysis. Results: Overall, 348 patients received PrEP over the evaluation period. The majority (84%) were men, and the cohort was racially/ethnically diverse. The median duration of PrEP use was 8.3 months. In adjusted analysis, PrEP discontinuation was lower among older patients (aHR 0.89; 95% CI 0.80–0.99; P = 0.03); but higher among black patients (compared with white patients; aHR 1.87; 95% CI 1.27–2.74; P = 0.001), patients who inject drugs (aHR 4.80; 95% CI 2.66–8.67; P < 0.001), and transgender women who have sex with men (compared with MSM; aHR 1.94; 95% CI 1.36–2.77; P < 0.001). Conclusion: Age, racial/ethnic, and risk category disparities in PrEP discontinuation were identified among patients in a public health-funded primary care setting. Further efforts are needed to understand and address PrEP discontinuation among priority populations to maximize the preventive impact of PrEP, and reverse HIV-related disparities at a population level.

Pharmacokinetics and safety of a raltegravir-containing regimen in HIV-infected children aged 2–12 years on rifampicin for tuberculosis Objectives: Drug–drug interactions limit current antiretroviral treatment options for HIV-infected children with tuberculosis (TB). Rifampicin (RIF) induces UDP-glucuronosyltransferase activity, accelerating the clearance of raltegravir (RAL). We sought to establish an optimal and well tolerated dose of RAL when administered with RIF to HIV and TB co-infected children. Design: P1101 is a phase I/II open-label dose-finding study of RAL with RIF for children 2 to less than 12 years of age beginning treatment for HIV and active TB. Setting: Four sites in South Africa. Methods: Chewable RAL was given at 12 mg/kg per dose twice daily (twice the usual pediatric dose) with two nucleoside reverse transcriptase inhibitors. Intensive RAL pharmacokinetic sampling was conducted 5 to 8 days after antiretroviral therapy was initiated; a fourth antiretroviral agent was then added. Results: Children were recruited into two age-defined groups: cohort 1 (2 to <6 years old) and cohort 2 (6 to <12 years old). Pharmacological targets [geometric mean (GM) AUC12 h of 14–45 μmol/l h and GM C12 h ≥75 nmol/l) were reached in both cohort 1 (28.8 μmol/l h and 229 nmol/l) and cohort 2 (38.8 μmol/l h and 228 nmol/l). The RAL-based ART was well tolerated by most participants: one participant discontinued treatment because of grade 4 hepatitis that was possibly treatment-related. At week 8, 22 of 24 participants (92%) had HIV RNA concentrations below 400 copies/ml; 19 of 24 (79%) were below 50 copies/ml. Conclusion: Giving 12 mg/kg twice daily of the chewable RAL formulation achieved pharmacokinetic targets safely in HIV-infected children receiving RIF for TB.

Prevalence and risk factors of prolonged QT interval and electrocardiographic abnormalities in persons living with HIV Objective: Abnormal ECGs are associated with increased risk of arrhythmias and sudden cardiac death. We aimed to investigate the prevalence and associated risk factors of prolonged QTc and major ECG abnormalities, in persons living with HIV (PLWH) and uninfected controls. Design: PLWH aged at least 40 years were recruited from the Copenhagen comorbidity in HIV infection (COCOMO) study and matched on sex and age to uninfected controls from the Copenhagen General Population Study. Methods: ECGs were categorized according to Minnesota Code Manual of ECG Findings definition of major abnormalities. A QT interval corrected for heart rate (QTc) greater than 440 ms in men and greater than 460 ms in women was considered prolonged. Pathologic Q-waves were defined as presence of major Q-wave abnormalities. Results: ECGs were available for 745 PLWH and 2977 controls. Prolonged QTc was prevalent in 9% of PLWH and 6% of controls, P = 0.052. Pathologic Q-waves were more common in PLWH (6%) than in controls (4%), P = 0.028. There was no difference in prevalence of major ECG abnormalities between PLWH and controls, P = 0.987. In adjusted analyses, HIV was associated with a 3.6 ms (1.8–5.4) longer QTc interval, P < 0.001, and HIV was independently associated with prolonged QTc [adjusted odds ratio: 1.59 (1.14–2.19)], P = 0.005. HIV was borderline associated to pathologic Q-waves after adjusting, P = 0.051. Conclusion: HIV was associated with higher odds ratio of prolonged QTc after adjustment for cardiovascular risk factors, but analyses were not adjusted for QT-prolonging medication. Although evidence indicated more pathologic Q-waves in PLWH, the risk seemed to be associated mainly with an adverse risk profile.