Antiretroviral Therapy Intensification for Neurocognitive Impairment in Human Immunodeficiency Virus.

BACKGROUND: Neurocognitive impairment (NCI) in people with HIV (PWH) on antiretroviral therapy (ART) is common and may result from persistent HIV replication in the central nervous system. METHODS: A5324 was a randomized, double-blind, placebo-controlled, 96-week trial of ART intensification with dolutegravir (DTG) + MVC, DTG + Placebo, or Dual - Placebo in PWH with plasma HIV RNA <50 copies/mL on ART and NCI. The primary outcome was the change on the normalized total z score (ie, the mean of individual NC test z scores) at week 48. RESULTS: Of 357 screened, 191 enrolled: 71% male, 51% Black race, 22% Hispanic ethnicity; mean age 52 years; mean CD4+ T-cells 681 cells/µL. Most (65%) had symptomatic HIV-associated NC disorder. Study drug was discontinued due to an adverse event in 15 (8%) and did not differ between arms (P = .17). Total z score, depressive symptoms, and daily functioning improved over time in all arms with no significant differences between them at week 48 or later. Adjusting for age, sex, race, study site, efavirenz use, or baseline z score did not alter the results. Body mass index modestly increased over 96 weeks (mean increase 0.32 kg/m2, P = .006) and did not differ between arms (P > .10). CONCLUSIONS: This is the largest, randomized, placebo-controlled trial of ART intensification for NCI in PWH. The findings do not support empiric ART intensification as a treatment for NCI in PWH on suppressive ART. They also do not support that DTG adversely affects cognition, mood, or weight.

Comparison of efavirenz levels in blood and hair with pharmacy refills as measures of adherence and predictors of viral suppression among people living with HIV in Nigeria.

BACKGROUND: Strategies to support adherence are constrained by the lack of tools to objectively monitor medication intake in low-resource settings. Pharmacologic measures are objective, but pharmacy refill data is more accessible and cost-efficient. This study compared short-term and long-term efavirenz (EFV) drug levels with pharmacy refill adherence data (PRA) and evaluated their ability to predict viral suppression among people living with HIV in Nigeria. METHODS: Paired hair and dried blood spot (DBS) samples were obtained from 91 adults living with HIV receiving 600 mg EFV-based antiretroviral therapy (ART) and EFV concentrations were measured via validated methods using liquid-chromatography-mass-spectrometry. PRA was estimated from pharmacy records, based on the number of days a patient collected medication before or after the scheduled pick-up date. PRA was categorized into ≤ 74%, 75-94% and ≥ 95%, defined as poor, medium and high adherence, respectively. HIV viral loads closest to the hair sampling time (within 6 months) were also abstracted. Receiver Operating Characteristics (ROC) curve analyses compared the ability of adherence metrics to predict viral suppression. RESULTS: Based on PRA, 81% of participants had high adherence while 11% and 8% had medium and poor adherence, respectively. The median (IQR) EFV concentrations were 6.85 ng/mg (4.56-10.93) for hair and 1495.6 ng/ml (1050.7-2365.8) for DBS. Of the three measures of adherence, hair EFV concentration had the highest Area Under Curve (AUC) to predict viral suppression. Correlations between EFV concentrations in DBS and hair with PRA were positive (r = 0.12, P = 0.27 and r = 0.21, P = 0.05, respectively) but not strong. CONCLUSIONS: EFV concentrations in hair were the strongest predictor of viral suppression and only weakly correlated with pharmacy refill adherence data in Nigeria. This study suggests that resource-limited settings may benefit from objective adherence metrics to monitor and support adherence.

Baseline 10-Year Cardiovascular Risk Scores Predict Cognitive Function in Older Persons, and Particularly Women, Living With Human Immunodeficiency Virus Infection.

BACKGROUND: Cardiovascular disease (CVD) and associated comorbidities increase the risk of cognitive impairment in persons living with human immunodeficiency virus (PLWH). Given the potential composite effect of multiple cardiovascular risk factors on cognition, we examined the ability of the Atherosclerotic Cardiovascular Disease (ASCVD) risk score and the Framingham Heart Study Global CVD risk score (FRS) to predict future cognitive function in older PLWH. METHODS: We constructed linear regression models evaluating the association between baseline 10-year cardiovascular risk scores and cognitive function (measured by a summary z-score, the NPZ-4) at a year 4 follow-up visit. RESULTS: Among 988 participants (mean age, 52 years; 20% women), mean 10-year ASCVD risk score at entry into the cohort was 6.8% (standard deviation [SD], 7.1%) and FRS was 13.1% (SD, 10.7%). In models adjusted only for cognitive function at entry, the ASCVD risk score significantly predicted year 4 NPZ-4 in the entire cohort and after stratification by sex (for every 1% higher ASCVD risk, year 4 NPZ-4 was lower by 0.84 [SD, 0.28] overall, P = .003; lower by 2.17 [SD, 0.67] in women, P = .001; lower by 0.78 [SD, 0.32] in men, P = .016). A similar relationship was observed between FRS and year 4 NPZ-4. In multivariable models, higher 10-year ASCVD risk and FRS predicted lower NPZ-4 in women. CONCLUSIONS: Baseline 10-year ASCVD risk and FRS predicted future cognitive function in older PLWH with well-controlled infection. Cardiovascular risk scores may help to identify PLWH, especially women, who are at risk for worse cognition over time.

Pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives.

OBJECTIVE: In AIDS Clinical Trials Group study A5316, efavirenz lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions. METHODS: In A5316, women with HIV enrolled into control (no antiretrovirals), efavirenz [600 mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)], and atazanavir/ritonavir (300/100 mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel/ethinyl estradiol 120/15 µg/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol on days 7, 14, and 21. Seventeen genetic polymorphisms were analyzed. RESULTS: The 72 participants in this analysis included 25, 24 and 23 in the control, efavirenz, and atazanavir/ritonavir groups, respectively. At day 21 in the efavirenz group, CYP2B6 genotype was associated with increased plasma efavirenz exposure (P = 3.2 × 10), decreased plasma concentrations of etonogestrel (P = 1.7 × 10), and decreased ethinyl estradiol (P = 6.7 × 10). Compared to controls, efavirenz reduced median etonogestrel concentrations by at least 93% in CYP2B6 slow metabolizers versus approximately 75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in CYP2B6 slow metabolizers versus approximately 41% in normal and intermediate metabolizers. CONCLUSION: CYP2B6 slow metabolizer genotype worsens the pharmacokinetic interaction of efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in CYP2B6 slow metabolizers may reduce, but will likely not eliminate, this interaction.

Physical Activity Is Associated With Lower Odds of Cognitive Impairment in Women but Not Men Living With Human Immunodeficiency Virus Infection.

Background: Cardiovascular comorbidities are risk factors for human immunodeficiency virus (HIV)-associated cognitive impairment. Given differences in cardiometabolic risk profiles between women and men with HIV, we investigated whether associations between cardiometabolic risk factors and prevalent cognitive impairment differ by sex. Methods: Separate logistic regression models were constructed for women and men at entry into a prospective study of older persons with HIV (PWH) to assess the association of cardiometabolic and other risk factors with cognitive impairment. Results: Of 988 participants, 20% were women. Women had higher total cholesterol (194 vs 186 mg/dL; P = .027), hemoglobin A1c (5.9% vs 5.7%; P = .003), and body mass index (30.8 vs 27.4 kg/m2; P < .001) compared with men, and were less physically active (43% vs 55%; P = .005). In a multivariable model, physical activity was associated with lower odds of cognitive impairment in women (odds ratio, 0.35 [95% confidence interval, .15-.80]; P = .013) but not men. Conclusions: Physical activity may have a greater positive impact on cognitive health in women than in men with HIV. This finding should be confirmed in studies examining the longitudinal association between physical activity and incident cognitive impairment in PWH and the effect of interventions that increase physical activity on cognitive impairment in women with HIV.

Human Immunodeficiency Virus-associated Neurocognitive Impairment in Diverse Resource-limited Settings.

BACKGROUND: Neurocognitive impairment remains a common complication of human immunodeficiency virus (HIV) despite effective antiretroviral therapy (ART). We previously reported improved neurocognitive functioning with ART initiation in 7 resource-limited countries for HIV+ participants from the AIDS Clinical Trials Group (ACTG) 5199 International Neurological Study (INS). Here, we apply normative data from the International Neurocognitive Normative Study (INNS) to INS to provide previously unknown rates of neurocognitive impairment. METHODS: The A5199 INS assessed neurocognitive and neurological performance within a randomized clinical trial with 3 arms containing World Health Organization first-line recommended ART regimens (ACTG 5175; PEARLS). The ACTG 5271 INNS collected normative comparison data on 2400 high-risk HIV-negative participants from 10 voluntary counseling and testing sites aligned with INS. Normative comparison data were used to create impairment ratings for HIV+ participants in INS; associations were estimated using generalized estimating equations. RESULTS: Among 860 HIV+ adults enrolled in ACTG 5199, 55% had no neurocognitive impairment at baseline. Mild neurocognitive impairment was found in 25%, moderate in 17%, and severe in 3% of participants. With the initiation of ART, the estimated odds of impairment were reduced 12% (95% confidence interval, 9%, 14%) for every 24 weeks (P < .0001) on ART. Mild impairment dropped slightly and then remained at about 18% out to week 168. CONCLUSIONS: Almost half of HIV+ participants had neurocognitive impairment at baseline before ART, based on local norms. With ART initiation, there were significant overall reductions in neurocognitive impairment over time, especially in those with moderate and severe impairments. CLINICAL TRIALS REGISTRATION: NCT00096824.

Comparable viral decay with initial dolutegravir plus lamivudine versus dolutegravir-based triple therapy.

OBJECTIVES: To expand understanding of the virological potency of initial dolutegravir plus lamivudine dual therapy (dolutegravir/lamivudine), we compared the viral decay seen in the pilot ACTG A5353 study with the decay observed with dolutegravir plus two NRTIs in the SPRING-1 and SINGLE studies, while also exploring the impact of baseline viral load (VL). METHODS: Change in VL from baseline was calculated for timepoints shared by A5353 (n = 120, including 37 participants with pretreatment VL >100000 copies/mL), SPRING-1 (n = 51) and SINGLE (n = 417). The 95% CIs of change from baseline were determined for each observed week, using the mean log10-transformed VL, and compared between the dolutegravir/lamivudine and triple therapy groups using the Wilcoxon Rank Sum test for non-inferiority (δ = 0.5). To assess the impact of baseline VL on viral decay, we examined a bi-exponential non-linear mixed-effect model. RESULTS: The mean VL change from baseline to week 24 was -2.9 log10 copies/mL for dolutegravir/lamivudine versus -3.0 log10 copies/mL for dolutegravir-based three-drug therapy (P < 0.001). In the decay model, baseline VL >100000 copies/mL was associated with a slower initial decay rate (d1). A faster initial decay rate was seen with dolutegravir/lamivudine, which was partially offset when baseline VL was >100000 copies/mL as indicated by a significant interaction between baseline VL and drug therapy group. The secondary decay rate (d2) was not significantly different from zero, with no significant associations. CONCLUSIONS: Viral decay with dolutegravir/lamivudine was comparable to viral decay with dolutegravir-based triple therapy, even in individuals with higher pretreatment VL (>100000 copies/mL).

Dolutegravir plus lamivudine for initial treatment of HIV-1-infected participants with HIV-1 RNA <500 000 copies/mL: week 48 outcomes from ACTG 5353.

BACKGROUND: The AIDS Clinical Trials Group study A5353 demonstrated the efficacy and safety of dolutegravir and lamivudine for initial treatment of HIV-1 infection at week 24 in individuals with HIV-1 RNA 1000-500 000 copies/mL. Optimal ART for treatment-naive individuals must be durable. OBJECTIVES: The aim of this study was to estimate the efficacy and safety of dolutegravir plus lamivudine at week 48 and compare the efficacy in participants with baseline HIV-1 RNA ≤100 000 copies/mL versus >100 000 copies/mL. METHODS: Virological success was defined as HIV-1 RNA <50 copies/mL by FDA Snapshot criteria. Definition of virological failure included confirmed HIV-1 RNA >200 copies/mL at week 24 or later. The proportion of participants with virological success was estimated using two-sided exact Clopper-Pearson 95% CI. Comparison between screening HIV-1 RNA (≤100 000 versus >100 000 copies/mL) strata was carried out by Fisher's exact test. The study was registered with ClinicalTrials.gov, number NCT02582684. RESULTS: A total of 120 enrolled eligible participants were included in the analysis. At week 48, 102 of the 120 participants (85%; 95% CI 77%-91%) had virological success. Virological success was similar between screening HIV-1 RNA groups. Six (5%) participants had virological non-success and one additional participant experienced virological failure while on study but off study treatment. No new drug resistance mutations were observed. Six (5%) participants had study-related grade 3 or higher adverse events and none discontinued study treatment. CONCLUSIONS: These results add to the evidence that dolutegravir plus lamivudine is a safe and effective option for initial ART in individuals with HIV-1 RNA <500 000 copies/mL.

Dolutegravir Plus Lamivudine Maintains Human Immunodeficiency Virus-1 Suppression Through Week 48 in a Pilot Randomized Trial.

Clinical Trials Registration: NCT02263326.

Less Bone Loss With Maraviroc- Versus Tenofovir-Containing Antiretroviral Therapy in the AIDS Clinical Trials Group A5303 Study.

BACKGROUND: There is a need to prevent or minimize bone loss associated with antiretroviral treatment (ART) initiation. We compared maraviroc (MVC)- to tenofovir disoproxil fumarate (TDF)-containing ART. METHODS: This was a double-blind, placebo-controlled trial. ART-naive subjects with human immunodeficiency virus type 1 RNA load (viral load [VL]) >1000 copies/mL and R5 tropism were randomized to MVC 150 mg or TDF 300 mg once daily (1:1), stratified by VL <100 000 or ≥100 000 copies/mL and age <30 or ≥30 years. All subjects received darunavir 800 mg, ritonavir 100 mg, and emtricitabine 200 mg daily. Dual-energy X-ray absorptiometry scanning was done at baseline and week 48. The primary endpoint was percentage change in total hip bone mineral density (BMD) from baseline to week 48 in the as-treated population. RESULTS: We enrolled 262 subjects. A total of 259 subjects (130 MVC, 129 TDF) contributed to the analyses (91% male; median age, 33 years; 45% white, 30% black, 22% Hispanic). Baseline median VL was 4.5 log10 copies/mL and CD4 count was 390 cells/µL. The decline in hip BMD (n = 115 for MVC, n = 109 for TDF) at week 48 was less with MVC (median [Q1, Q3] of -1.51% [-2.93%, -0.11%] vs -2.40% [-4.30%, -1.32%] for TDF (P < .001). Lumbar spine BMD decline was also less with MVC (median -0.88% vs -2.35%; P < .001). Similar proportions of subjects in both arms achieved VL ≤50 copies/mL in as-treated and ITT analyses. CONCLUSIONS: MVC was associated with less bone loss at the hip and lumbar spine compared with TDF. MVC may be an option to attenuate ART-associated bone loss. CLINICAL TRIALS REGISTRATION: NCT01400412.

Associations of T cell activation and inflammatory biomarkers with virological response to darunavir/ritonavir plus raltegravir therapy.

OBJECTIVES: One of the goals of antiretroviral therapy (ART) is to attenuate HIV-induced systemic immune activation and inflammation. We determined the dynamics of biomarkers of immune activation, microbial translocation and inflammation during initial ART with a nucleos(t)ide-sparing regimen of darunavir/ritonavir plus raltegravir. We also evaluated associations between these biomarkers and the virological response to the regimen. METHODS: We determined baseline and week 24 and 48 levels of CD4+ and CD8+ T cell activation (% HLA-DR+/CD38+), interleukin-6 (IL-6), interferon-γ-inducible protein-10 (IP-10), soluble CD14 (sCD14), D-dimer and lipopolysaccharide. Associations between the biomarkers at baseline were assessed using Spearman's rank correlation. The Wilcoxon signed rank test analysed changes from baseline. Comparisons between groups were made using the Wilcoxon rank sum test, and Cox proportional hazards models assessed predictors of virological failure (VF). RESULTS: Assays were completed on 107 of 112 subjects after excluding five subjects who had only baseline samples. The subjects included were 94 (88%) men with a median age of 37 years, a median baseline CD4 count of 261.5 cells/mm(3) and a median baseline viral load (VL) of 75 876 copies/mL. Subjects with a baseline VL >100 000 copies/mL had higher baseline T cell activation, IL-6, IP-10, sCD14 and D-dimer. These biomarkers declined during treatment (P < 0.05). Although subjects who experienced VF had higher baseline CD4+ T cell activation (P = 0.035), only baseline VL independently predicted VF (hazard ratio for >100 000 versus ≤100 000 copies/mL was 4.5-5.6, P ≤ 0.002). CONCLUSIONS: Darunavir/ritonavir plus raltegravir attenuated immune activation, inflammation and microbial translocation. T cell activation remained higher in subjects with VF than those without. Baseline VL >100 000 copies/mL remained the primary driver of VF.

High-risk human papillomavirus among HIV-infected women with normal cervical cytology: a pilot study in Jos, Nigeria.

BACKGROUND: Cervical cancer is strongly linked to high-risk human papillomavirus (HR-HPV) and is typically preceded by cytological abnormalities. Less is known in patients with normal cervical cytology (NCC). We investigated the epidemiology of HR-HPV among HIV-infected women with NCC. METHODOLOGY: We conducted a cross-sectional study between January and June 2011 among HIV-infected women with NCC at an adult HIV clinic in Jos, Nigeria. Cervical sampling and analysis for HR-HPV by hybrid capture (HC2) with signal amplification was done to determine presence of one or more of the following HR-HPV types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 or 68. Epidemiologic factors associated with HR-HPV were determined using bivariate statistics and multivariate logistic regression. RESULTS: We evaluated 103 HIV-infected women with Pap cytology. The median age of the women was 32 years (range 21-49). Ninety-seven (94.2%) had NCC. Cervical samples for HR-HPV DNA testing were available from 89/97 (91.8%) of the HIV-infected women with NCC. Of the 89 women with cervical samples for HR-HPV DNA testing, 40 (44.9%) had detectable HR-HPV by HC2 giving a HR-HPV prevalence of 44.9% (95% CI 33.9-55.5%). Age < 30 years was associated with HR-HPV (OR 2.69 [95% CI 1.05-6.91, p = 0.039]) while history of previous abortion showed an inverse association with HR-HPV (OR 0.33[95% CI 0.15-0.94, p = 0.039]). CONCLUSION: The prevalence of HR-HPV is seemingly high among HIV-infected women with NCC in our clinical setting. These data provide support for further investigation of the clinical implications of positive HR-HPV among HIV-infected women with NCC report in cervical cancer prevention programs in Nigeria.

Brain computed tomography perfusion analysis in HIV-seropositive adults with and without neurocognitive impairment in Nigeria: outcomes and challenges of a pilot study.

Introduction: the significance of cerebrovascular disease in HIV-associated neurocognitive disorder (HAND) in a homogeneous black population has not yet been determined. This incident case-control study used CT perfusion imaging to quantify and compare regional cerebral blood flow parameters in neuro-cognitively impaired and unimpaired HIV+ participants of the Ibadan Cohort on Neuro AIDS (ICON) in Nigeria. Methods: this was an incident case-control study consisting of twenty-seven HIV+ adults, classified based on Frascati criteria into neurocognitive impaired (n=18) and unimpaired (n=9) groups, who had brain computed tomographic perfusion (CTP) with a 64-slice Toshiba T scanner. The standard deviation (SD) of regional mean transit time (MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV) values were calculated for bilateral basal ganglia (BG), frontal, parietal, temporal, and occipital regions from CT perfusion maps. The regional mean values and variability (SD) in the CTP measures were compared in the groups using an independent student t-test. Results: differentially higher variability in the bilateral CBF measures in the parietal (right; OR = 1.14, x̄ =5.61, p=0.041, CI=0.27-11.35/left; OR = 1.16, x̄=7.01, p=0.03, CI=5.6-13.47) and time to peak (TTP) measures in the basal ganglia (right; OR = 3.78, x̄=0.88, p=0.032, CI=0.081-1.67/left; OR = 2.44, x̄=1.48, p=0.020, CI=0.26-2.71) and occipital (right; OR = 2.18, x̄=1.32, p=0.018, CI=0.25-2.38/left; OR = 1.93, x̄=1.08, p=0.034, CI=0.086-2.06) regions were observed in the cognitively impaired group compared to the unimpaired group. Conclusion: the study evidence suggests that alterations in cerebral perfusion implicated in HIV-associated neurocognitive disorder may be possibly demonstrated using CTP, a readily available resource in most African countries saddled with the highest burden of HIV.

Successful Implementation Strategies in iCARE Nigeria-A Pilot Intervention with Text Message Reminders and Peer Navigation for Youth Living with HIV.

To address poor outcomes among adolescents and young adults living with HIV (AYA-HIV), iCARE Nigeria successfully piloted two-way text message antiretroviral therapy (ART) reminders together with peer navigation. Study participants had significant improvement in ART adherence and viral suppression at 48 weeks. Understanding facto of this intervention. We used explanatory, mixed methods to assess implementation outcomes (feasibility, acceptability, and adoption) and identify implementation strategies used or adapted to promote intervention success. Quantitative data included participant surveys, program records, and back-end mHealth data, and were summarized using descriptive statistics. Qualitative data were collected from key informants and focus group discussions with program staff and summarized using directed content analysis. iCARE Nigeria was feasible as evidenced by ease of recruitment, high retention of patients and peer navigators (PN), and successful deployment of initial text message reminders (99.9%). Most participants (95%) and PN (90%) found text message reminders were not bothersome or intrusive. Implementation strategies employed to facilitate intervention success included: (1) selecting, training, supervising, and matching of PN to patients; (2) tailoring frequency (daily to weekly) and mode of communication between PN and patients according to patient need; (3) routine screening for adherence challenges; (4) changing phone airtime stipends from monthly to weekly in response to rapid depletion; and (5) conducting telecommunication needs assessments, to identify and troubleshoot implementation barriers (issues with mobile devices, power availability). iCARE Nigeria was feasible and acceptable with high adoption by stakeholders. The implementation strategies identified here can be tailored for intervention scale-up in similar environments to promote ART adherence for AYA-HIV.

A randomized stepped wedge trial of an intensive combination approach to roll back the HIV epidemic in Nigerian adolescents: iCARE Nigeria treatment support protocol.

BACKGROUND: Nigeria is one of six countries with half the global burden of youth living with HIV. Interventions to date have been inadequate as AIDS-related deaths in Nigeria's youth have remained unchanged in recent years. The iCARE Nigeria HIV treatment support intervention, a combination of peer navigation and SMS text message medication reminders to promote viral suppression, demonstrated initial efficacy and feasibility in a pilot trial among youth living with HIV in Nigeria. This paper describes the study protocol for the large-scale trial of the intervention. METHODS: The iCARE Nigeria-Treatment study is a randomized stepped wedge trial of a combination (peer navigation and text message reminder) intervention, delivered to youth over a period of 48 weeks to promote viral suppression. Youth receiving HIV treatment at six clinical sites in the North Central and South Western regions of Nigeria were recruited for participation. Eligibility criteria included registration as a patient at participating clinics, aged 15-24 years, on antiretroviral therapy for at least three months, ability to understand and read English, Hausa, Pidgin English, or Yoruba, and intent to remain a patient at the study site during the study period. The six clinic sites were divided into three clusters and randomized to a sequence of control and intervention periods for comparison. The primary outcome is plasma HIV-1 viral load suppression, defined as viral load ≤ 200 copies/mL, in the intervention period versus the control period at 48 weeks of intervention. DISCUSSION: Evidence-based interventions to promote viral load suppression among youth in Nigeria are needed. This study will determine efficacy of a combination intervention (peer navigation and text message reminder) and collect data on potential implementation barriers and facilitators to inform scale-up if efficacy is confirmed. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT04950153, retrospectively registered July 6, 2021, https://clinicaltrials.gov/.

The importance of methods for site performance evaluation in REPRIEVE, a longitudinal, global, multicenter trial.

BACKGROUND: REPRIEVE, the Randomized Trial to Prevent Vascular Events in HIV, is a multicenter, primary prevention trial evaluating whether a statin can prevent major cardiovascular events in people with HIV. REPRIEVE is conducted at >100 clinical research sites (CRSs) globally. Detailed, comprehensive, and novel methods for evaluating and communicating CRS performance are required to ensure trial integrity and data quality. In this analysis we describe a comprehensive multidimensional methodology for evaluating CRS performance. METHODS: The REPRIEVE Data Coordinating and Clinical Coordinating Centers developed a robust system for evaluation of and communication with CRSs, designed to identify potential issues and obstacles to performance, provide real-time technical support, and make recommendations for process improvements to facilitate efficient trial execution. We describe these systems and evaluate their impact on participant retention, data management, and specimen management from 2019 to 2022, corresponding to the period from end of recruitment to present. This evaluation was based on pre-defined metrics, regular reviews, and bidirectional communication. RESULTS: Participant retention, data management, and specimen management all remained steady over the three-year period, although metrics varied by country of enrollment. Targeted messaging relating to certain performance metrics was effective. CONCLUSION: Site performance is vital to ensure trial integrity and achievement of key trial goals. This analysis demonstrates that utilization of a comprehensive approach allows for a thorough evaluation of CRS performance, facilitates data and specimen management, and enhances participant retention. Our approach may serve as a guidepost for maximizing future large-scale clinical trials' operational success and scientific rigor. CLINICALTRIALS: gov Identifier: NCT02344290.

Post-migration HIV acquisition among african immigrants in the U.S.

BACKGROUND: African immigrants in the U.S. are more likely to have a late HIV diagnosis than U.S.-born people, potentially leading to onward transmission. We sought to determine the proportion of African-born people living with HIV (APLWH) who (1) had tested HIV negative prior to diagnosis, and (2) likely acquired HIV in the U.S. METHODS: We interviewed APLWH from 2014 to 2017 and estimated the proportion with post-migration HIV acquisition based on clinical data, HIV testing history, immigration date, and behavioral data. RESULTS: Of 179 participants, 113 (63%) were women. Less than half (44%) reported a negative HIV test prior to diagnosis. Among 142 (79%) participants with sufficient data to evaluate post-migration HIV acquisition, we estimate that 29% acquired HIV post-migration. Most APLWH acquire HIV prior to immigration. DISCUSSION: Approximately one-quarter of APLWH acquire HIV post-migration and HIV testing is infrequent, highlighting the need for prevention efforts for African immigrants in the U.S.

No difference in anti-spike antibody and surrogate viral neutralization following SARS-CoV-2 booster vaccination in persons with HIV compared to controls (CO-HIV Study).

Background: Understanding the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination will enable accurate counseling and inform evolving vaccination strategies. Little is known about antibody response following booster vaccination in people living with HIV (PLWH). Methods: We enrolled SARS-CoV-2 vaccinated PLWH and controls without HIV in similar proportions based on age and comorbidities. Participants completed surveys on prior SARS-CoV-2 infection, vaccination, and comorbidities, and provided self-collected dried blood spots (DBS). Quantitative anti-spike IgG and surrogate viral neutralization assays targeted wild-type (WT), Delta, and Omicron variants. We also measured quantitative anti-nucleocapsid IgG. The analysis population had received full SARS-CoV-2 vaccination plus one booster dose. Bivariate analyses for continuous outcomes utilized Wilcoxon tests and multivariate analysis used linear models. Results: The analysis population comprised 140 PLWH and 75 controls with median age 58 and 55 years, males 95% and 43%, and DBS collection on 112 and 109 days after the last booster dose, respectively. Median CD4 count among PLWH was 760 cells/mm3 and 91% had an undetectable HIV-1 viral load. Considering WT, Delta, and Omicron variants, there was no significant difference in mean quantitative anti-spike IgG between PLWH (3.3, 2.9, 1.8) and controls (3.3, 2.9, 1.8), respectively (p-values=0. 771, 0.920, 0.708). Surrogate viral neutralization responses were similar in PLWH (1.0, 0.9, and 0.4) and controls (1.0, 0.9, 0.5), respectively (p-values=0.594, 0.436, 0.706). Conclusions: PLWH whose CD4 counts are well preserved and persons without HIV have similar anti-spike IgG antibody levels and viral neutralization responses after a single SARS-CoV-2 booster vaccination.

Evaluation of the iCARE Nigeria Pilot Intervention Using Social Media and Peer Navigation to Promote HIV Testing and Linkage to Care Among High-Risk Young Men: A Nonrandomized Controlled Trial.

Importance: Nigeria has the fourth-largest HIV epidemic globally, yet high levels of social stigma inhibit HIV testing among Nigerian youths and young men who have sex with men (MSM). Objective: To report pilot data from iCARE Nigeria (Intensive Combination Approach to Roll Back the Epidemic in Nigerian Adolescents), a combination intervention using social media and peer navigation to promote HIV testing and linkage to care among high-risk youths and young men (hereinafter referred to as young men), including predominantly young MSM. Design, Setting, and Participants: This nonrandomized controlled study assessed an organizational and community-level 12-month, preintervention-postintervention pilot trial of a combination intervention designed to increase HIV testing uptake, increase the rate of identified seropositive cases, and improve linkage to care among young men, including MSM, using social media outreach and peer navigation. Data were collected from June 1, 2019, to May 30, 2020. Participants were young men aged 15 to 24 years in the city of Ibadan, Nigeria, and surrounding areas. Frequencies and percentages were examined, and a Fisher exact test was used to evaluate outcomes compared with historical surveillance data. Linkage to care was defined as 2 clinic visits, including HIV confirmation, within 2 months of a positive rapid test result. Intervention: Four peer navigators conducted social media outreach promoting sexual health and guiding individuals to HIV counseling and rapid testing in clinical, community, or home-based settings. Main Outcomes and Measures: Primary outcomes included the number of young men tested for HIV at university-based iCARE catchment clinics or by iCARE peer navigators in the community, the postintervention HIV seroprevalence of these groups, and linkage to care of participants diagnosed with HIV infection. Results: A total of 339 participants underwent testing for HIV (mean [SD] age, 21.7 [1.9] years), with 283 (83.5%) referred through social media. The main referral sources for social media were WhatsApp (124 [43.8%]), Facebook (101 [35.7%]), and Grindr (57 [20.1%]). Regarding testing location, participants chose home (134 [39.5%]), community-based (202 [59.6%]), or clinic (3 [0.9%]) settings. Eighty-six participants reported no prior HIV testing. Thirty-six participants (10.6%) were confirmed as HIV seropositive; among those, 18 (50.0%) reported negative test results within the past year, and 31 (86.1%) were linked to care. In two 6-month follow-up periods, the intervention increased HIV testing by 42% and 31%, respectively, and seroprevalence increased compared with historical trends with odds ratios of 3.37 (95% CI, 1.43-8.02; P = .002) and 2.74 (95% CI, 1.10-7.11; P = .02), respectively. Conclusions and Relevance: These findings suggest that use of iCARE Nigeria was associated with increased HIV testing and linkage to care in a high-risk, difficult-to-reach population, making it a promising combination intervention for young MSM. Trial Registration: isrctn.org Identifier: ISRCTN94590823.

A multinational study of neurological performance in antiretroviral therapy-naïve HIV-1-infected persons in diverse resource-constrained settings.

Little is known about how the prevalence and incidence of neurological disease in HIV-infected patients in resource-limited settings. We present an analysis of neurological and neurocognitive function in antiretroviral naïve individuals in multinational resource-limited settings. This prospective multinational cohort study, a substudy of a large international randomized antiretroviral treatment trial, was conducted in seven low- and middle-income countries in sub-Saharan Africa, South America, and Asia. Subjects were HIV-infected and met regional criteria to initiate antiretroviral therapy. Standardized neurological examination and a brief motor-based neuropsychological examination were administered. A total of 860 subjects were studied. Overall 249 (29%) had one or more abnormalities on neurological examinations, but there was a low prevalence of HIV-associated dementia (HAD) and minor neurocognitive disorder (MND). Twenty percent of subjects had evidence of peripheral neuropathy. There were significant differences across countries (p < 0.001) in neuropsychological test performance. In this first multinational study of neurological function in antiretroviral naïve individuals in resource-limited settings, there was a substantial prevalence of peripheral neuropathy and low prevalence of dementia and other CNS diseases. There was significant variation in neurocognitive test performance and neurological examination findings across countries. These may reflect cultural differences, differences in HIV-related and unrelated diseases, and variations in test administration across sites. Longitudinal follow-up after antiretroviral treatment initiation may help to define more broadly the role of HIV in these differences as well as the impact of treatment on performance.