HIV-uninfected Adults Research Articles

Phase I Dose Volume Escalation of Rectally Administered PC-1005 to Assess Safety, Pharmacokinetics, and Antiviral Pharmacodynamics as a Multipurpose Prevention Technology (MTN-037)

Background: On demand, topical PrEP is desired by those preferring episodic, nonsystemic PrEP. PC-1005 gel (MIV-150, zinc, and carrageenan) exhibits in vitro antiviral HIV-1, human papillomavirus (HPV), and herpes simplex virus type 2 (HSV-2) activity, attractive for a multipurpose prevention technology candidate. We evaluated the safety, pharmacokinetics, and antiviral effect of rectally applied PC-1005. Methods: HIV-uninfected adults received a series of 3 rectal PC-1005 doses—4, 16, and 32 mL separated by 2-week washout periods. Following each dose, plasma, rectal fluid and tissue, and vaginal fluid were collected over 48 hours. Results: Thirteen adults enrolled; 12 completed all 3 doses. All 13 adverse events reported were grade 1 or 2; 5 were judged study drug related. Plasma MIV-150 peaked 1–2 h after dosing with a median peak concentrations range of 0.07–0.23 ng/mL and median half-life range of 4.9–7.4 hours across dose volumes; median concentrations were below assay quantitation limits (BLQ) 24 hours after dosing. Rectal tissue MIV-150 peaked 0.5–1 hours after dosing at 1.4 ng/g (ng/mL) (0.8, 1.9), 46.0 (30.7, 831.0), and 79.7 (11.9, 116.0), respectively, after each dose volume; median tissue concentrations were BLQ beyond 5 hours for all doses. All vaginal fluid samples were BLQ. Ex vivo antiviral assays showed 5 hours of antiviral HPV and HSV effects but no anti-HIV activity. Conclusions: MIV-150 rectal tissue concentrations were below the 100 ng/g target concentration and transient. Ex vivo assays demonstrated antiviral HSV and HPV effects but not against HIV. PC-1005 requires a more potent antiviral and longer-lasting formulation for further consideration as a multipurpose prevention technology candidate. Clinical Trials: NCT03408899.

Human Immunodeficiency Virus and CKD in the Tenofovir Era: A Prospective Parallel-Group Cohort Study From Tanzania

Rationale & ObjectiveLongitudinal research on chronic kidney disease (CKD) in sub-Saharan Africa is sparse, especially among people living with HIV. We evaluated the incidence of CKD among people living with HIV compared to HIV-uninfected controls in Tanzania. Study DesignProspective cohort study. Setting & Participants495 newly diagnosed people living with HIV who initiated antiretroviral therapy and 505 HIV-uninfected adults enrolled from public HIV clinics and followed from 2016 through 2021. The control group was recruited from HIV treatment partners from the same HIV clinics. ExposuresUntreated HIV (at baseline), antiretroviral therapy, socio-demographic information, health behaviors, hypertension, and diabetes. OutcomesIncident CKD, defined as follow-up eGFR <60 ml/min/1.73m2 with ≥25% reduction from baseline; annual eGFR change; incident albuminuria; three-year all-cause mortality. Analytical ApproachMultivariable Poisson and linear regression determined the association between HIV and other factors with baseline prevalent reduced eGFR and albuminuria, incident CKD and albuminuria, and annual eGFR change. Cox hazard regression assessed the association between baseline CKD and mortality. ResultsMedian age was 35 years and 67.5% were female. There were 101 incident CKD cases, 71 among people living with HIV and 30 among HIV-uninfected participants, equivalent to a CKD incidence of 57.9 per 1000 person-years (95% confidence interval (CI), 44.4-71.4) and 26.2 per 1000 person-years (95% CI, 16.8-35.5), respectively. People living with HIV had a more rapid eGFR decline (-6.65 versus -2.61 ml/min/1.73m2 per year). Female sex and older age were positively associated with incident CKD. Albuminuria incidence did not differ by HIV status. People living with HIV with albuminuria at baseline had higher mortality (hazard ratio, 2.13; 95% CI, 1.08-4.21). LimitationsAs an observational cohort study, there was no comparison group of HIV-positive participants on a non-tenofovir disoproxil fumarate-based antiretroviral therapy regimen. ConclusionsPeople living with HIV receiving tenofovir disoproxil fumarate-based antiretroviral therapy had a very high incidence of CKD and rapid eGFR decline. Conversely, albuminuria stabilized with antiretroviral therapy use. Expanding access to less nephrotoxic antiretroviral therapy, such as tenofovir alafenamide, is urgently needed throughout sub-Saharan Africa.

Exposure to toxic chemical elements among people living with HIV/AIDS in Northern Tanzania

Environmental exposure to toxic chemicals including cadmium (Cd), lead (Pb), and mercury (Hg), are known risk factors for cardiovascular (CVD) and kidney disease. In people living with HIV (PLWH), CVD and kidney disease are the leading cause of death. Neither traditional risk factors nor markers of HIV infection fully explain such an increased risk. It is of paramount importance to establish the epidemiology of toxic chemicals exposure in PLWH, to inform screening and prevention interventions in this vulnerable population. This cross-sectional study compares toxic chemical levels (T-Cd, T-Pb, and T-Hg) among PLWH and HIV-uninfected adults in Northwestern Tanzania. A total of 495 PLWH and 505 HIV-uninfected subjects were analyzed. Spearman's rank correlations were used to examine the relationship between toxic chemical elements by HIV status. Linear regression models were used to determine the association between exposures and outcomes of interest among study participants. In both PLWH and HIV-uninfected adults, blood T-Cd, T-Pb, and T-Hg levels were frequently found at levels above the reference value of 5, 50, and 20 μg/L, respectively. Overall, factors associated with blood toxic chemical levels included vegetable servings per week, obesity, untreated water sources, use of alcohol, and HIV. Among PLWH, weekly vegetable intake provided a protective effect against T-Cd (Coeff = −0.03, 95%CI = −0.06, −0.01) and T-Pb (Coeff = −0.05, 95%CI = −0.09, −0.01) exposure among PLWH. Alcohol intake (Coeff = 0.10, 95%CI = 0.06, 0.13), obesity (Coeff = 0.08, 95%CI = 0.02, 0.13), longer duration to indoor smoke exposure (Coeff = 0.003, 95%CI = 0.001, 0.004), and HIV infection (Coeff = 0.11, 95%CI = 0.07, 0.15) were associated with increased individuals blood T-Hg levels. Individuals in northwestern Tanzania, including PLWH, have high blood levels for T-Cd, T-Pb, and T-Hg. Factors associated with higher blood levels include water sources, obesity, use of alcohol, exposure to indoor smoke, and HIV infection.

Safety and immunogenicity of a polyvalent DNA–protein HIV vaccine with matched Env immunogens delivered as a prime–boost regimen or coadministered in HIV-uninfected adults in the USA (HVTN 124): a phase 1, placebo-controlled, double-blind randomised controlled trial

An effective HIV vaccine will most likely need to have potent immunogenicity and broad cross-subtype coverage. The aim of the HIV Vaccine Trials Network (HVTN) 124 was to evaluate safety and immunogenicity of a unique polyvalent DNA-protein HIV vaccine with matching envelope (Env) immunogens. HVTN 124 was a randomised, phase 1, placebo-controlled, double-blind study, including participants who were HIV seronegative and aged 18-50 years at low risk for infection. The DNA vaccine comprised five plasmids: four copies expressing Env gp120 (clades A, B, C, and AE) and one gag p55 (clade C). The protein vaccine included four DNA vaccine-matched GLA-SE-adjuvanted recombinant gp120 proteins. Participants were enrolled across six clinical sites in the USA and were randomly assigned to placebo or one of two vaccine groups (ie, prime-boost or coadministration) in a 5:1 ratio in part A and a 7:1 ratio in part B. Vaccines were delivered via intramuscular needle injection. The primary outcomes were safety and tolerability, assessed via frequency, severity, and attributability of local and systemic reactogenicity and adverse events, laboratory safety measures, and early discontinuations. Part A evaluated safety. Part B evaluated safety and immunogenicity of two regimens: DNA prime (administered at months 0, 1, and 3) with protein boost (months 6 and 8), and DNA-protein coadministration (months 0, 1, 3, 6, and 8). All randomly assigned participants who received at least one dose were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT03409276) and is closed to new participants. Between April 19, 2018 and Feb 13, 2019, 60 participants (12 in part A [five men and seven women] and 48 in part B [21 men and 27 women]) were enrolled. All 60 participants received at least one dose, and 14 did not complete follow-up (six of 21 in the prime-boost group and eight of 21 in the coadminstration group). 11 clinical adverse events deemed by investigators as study-related occurred in seven of 48 participants in part B (eight of 21 in the prime-boost group and three of 21 in the coadministration group). Local reactogenicity in the vaccine groups was common, but the frequency and severity of reactogenicity signs or symptoms did not differ between the prime-boost and coadministration groups (eg, 20 [95%] of 21 in the prime-boost group vs 21 [100%] of 21 in the coadministration group had either local pain or tenderness of any severity [p=1·00], and seven [33%] vs nine [43%] had either erythema or induration [p=0·97]), nor did laboratory safety measures. There were no delayed-type hypersensitivity reactions or vasculitis or any severe clinical adverse events related to vaccination. The most frequently reported systemic reactogenicity symptoms in the active vaccine groups were malaise or fatigue (five [50%] of ten in part A and 17 [81%] of 21 in the prime-boost group vs 15 [71%] of 21 in the coadministration group in part B), headache (five [50%] and 18 [86%] vs 12 [57%]), and myalgia (four [40%] and 13 [62%] vs ten [48%]), mostly of mild or moderate severity. Both vaccine regimens were safe, warranting evaluation in larger trials. US National Institutes of Health and US National Institute of Allergy and Infectious Diseases.

Immune response to the recombinant herpes zoster vaccine in people living with HIV over 50 years of age compared to non-HIV age-/gender-matched controls (SHINGR’HIV): a multicenter, international, non-randomized clinical trial study protocol

BackgroundThe burden of herpes zoster (shingles) virus and associated complications, such as post-herpetic neuralgia, is higher in older adults and has a significant impact on quality of life. The incidence of herpes zoster and post-herpetic neuralgia is increased in people living with HIV (PLWH) compared to an age-matched general population, including PLWH on long-term antiretroviral therapy (ART) with no detectable viremia and normal CD4 counts. PLWH – even on effective ART may- exhibit sustained immune dysfunction, as well as defects in cells involved in the response to vaccines. In the context of herpes zoster, it is therefore important to assess the immune response to varicella zoster virus vaccination in older PLWH and to determine whether it significantly differs to that of HIV-uninfected healthy adults or younger PLWH. We aim at bridging these knowledge gaps by conducting a multicentric, international, non-randomised clinical study (SHINGR’HIV) with prospective data collection after vaccination with an adjuvant recombinant zoster vaccine (RZV) in two distinct populations: in PLWH on long-term ART (> 10 years) over 50 years of and age/gender matched controls.MethodsWe will recruit participants from two large established HIV cohorts in Switzerland and in France in addition to age-/gender-matched HIV-uninfected controls. Participants will receive two doses of RZV two months apart. In depth-evaluation of the humoral, cellular, and innate immune responses and safety profile of the RZV will be performed to address the combined effect of aging and potential immune deficiencies due to chronic HIV infection. The primary study outcome will compare the geometric mean titer (GMT) of gE-specific total IgG measured 1 month after the second dose of RZV between different age groups of PLWH and between PLWH and age-/gender-matched HIV-uninfected controls.DiscussionThe SHINGR’HIV trial will provide robust data on the immunogenicity and safety profile of RZV in older PLWH to support vaccination guidelines in this population.Trial registrationClinicalTrials.gov NCT05575830. Registered on 12 October 2022. Eu Clinical Trial Register (EUCT number 2023-504482-23-00).

A REVIEW OF THE LITERATURE ON HIV AND NEUROPSYCHOLOGICAL FUNCTIONING IN OLDER ADULTS: IS MORE RESEARCH NEEDED?

The increase in the number of ageing people living with HIV and the documented neurocognitive impairments have highlighted the need to illuminate the existing findings and evaluate the impact that HIV has on older individuals. A review of the evidence for neuropsychological declines in memory, executive functions, attention and language in people aged 60 years or more was conducted. The databases MEDLINE, PsychINFO and Pubmed were searched for eligible studies based on keywords. Eight studies of low to high quality that looked at HIV+ older adults (≥ 60) were identified. The majority of older HIV+ adults experienced severe declines in all the cognitive domains under study. There were mixed results regarding the association among advancing age, functioning decline and HIV. Comparisons between HIV-infected and HIV-uninfected older adults showed that HIV+ subjects demonstrate higher scores of cognitive decline in memory, attention, language and executive functions. Further, comparisons among HIV+ adults, demographically matched individuals with mild cognitive impairment of the Alzheimer's type and healthy controls demonstrated that both disease groups perform worse, but the Alzheimer’s type group reports a greater decline in memory and language. Neuropsychological functioning in HIV+ adults presents great decline but studies on this population are limited. As individuals with HIV are increasingly living longer, studies should pay attention to these individuals and examine predictors of neuropsychological decline in the face of well-controlled interventions and treatments. Keywords: HIV, memory, neuropsychological function, executive functions, older adults

1492. Gender-Specific Targets for Primary Prevention in People Living with HIV : Applying Life's Simple 7 to a Gender-Stratified Population of ART-Naive People Living with HIV in Tanzania

Abstract Background Cardiovascular disease (CVD) represents a major cause of premature mortality in people living with HIV (PLWH). However, morbidity is not equal between males and females. There is a need to better understand how gender influences cardiovascular health (CVH) in PLWH in order to identify targets for intervention. Therefore, we applied the Life's Simple Seven (LS7) scale to a gender-stratified cohort of ART-Naive PLWH and HIV-uninfected controls in adults. Methods A cross-sectional analysis was conducted on a cohort of ART-naive PLWH and HIV-uninfected adults recruited from HIV clinics between June 2016 and August 2019 in Mwanza, Tanzania (HIV&amp;HTN cohort). We applied modified Life's Simple Seven (LS7) definitions (Table 1) and compared the distribution of Ideal LS7 metrics between males and females of both study groups. Each LS7 metric was categorized as ideal (2 points), intermediate (1 point) and poor (0 point) and ordinal regressions were employed to investigate associations between gender and each individual LS7 metric. Regressions were adjusted for HIV status, age, income, education level. Results Our study included 997 participants, with 493 PLWH (68.7% female) and 504 HIV-uninfected (66.4% female). As displayed in Figure 1, the distribution of Ideal LS7 metrics differed between the males and females in both study groups. Males had a higher prevalence of ideal physical activity (aOR=4.12 [95%CI=3.11 to 5.44], p&amp;lt; 0.001) and ideal BMI (aOR=5.10 [3.47 to 7.49], p&amp;lt; 0.001) but lower prevalence of ideal smoking (aOR=0.037 [0.021 to 0.065], p&amp;lt; 0.001) and ideal blood pressure (aOR= 0.65 [0.50 to 0.85], p=0.002). The magnitude of these differences also varied by HIV status such that they were larger in PLWH than HIV-uninfected group for smoking (41.3% vs 26.4%), physical activity (41.6% vs 24.8%) and blood pressure (12.7% vs 9.2%) metrics. By contrast, these differences were less pronounced in PLWH vs HIV-uninfected group for the BMI metric (23.1% vs 29.7%). Figure 1: Distribution of Ideal Life's Simple 7 metrics, stratified by gender for both PLWH and HIV-uninfected controls Conclusion Cardiovascular health profiles vary by gender and HIV status, with stark differences between male and female PLWH for most metrics. Gender-specific interventions targeting smoking cessation, blood pressure control in male PLWH and physical activity, weight loss in female PLWH are warranted to mitigate CVD risk. Disclosures All Authors: No reported disclosures

Protein Dose-Sparing Effect of AS01B Adjuvant in a Randomized Preventive HIV Vaccine Trial of ALVAC-HIV (vCP2438) and Adjuvanted Bivalent Subtype C gp120.

HVTN 120 is a phase 1/2a randomized double-blind placebo-controlled human immunodeficiency virus (HIV) vaccine trial that evaluated the safety and immunogenicity of ALVAC-HIV (vCP2438) and MF59- or AS01B-adjuvanted bivalent subtype C gp120 Env protein at 2 dose levels in healthy HIV-uninfected adults. Participants received ALVAC-HIV (vCP2438) alone or placebo at months 0 and 1. At months 3 and 6, participants received either placebo, ALVAC-HIV (vCP2438) with 200 μg of bivalent subtype C gp120 adjuvanted with MF59 or AS01B, or ALVAC-HIV (vCP2438) with 40 μg of bivalent subtype C gp120 adjuvanted with AS01B. Primary outcomes were safety and immune responses. We enrolled 160 participants, 55% women, 18-40 years old (median age 24 years) of whom 150 received vaccine and 10 placebo. Vaccines were generally safe and well tolerated. At months 6.5 and 12, CD4+ T-cell response rates and magnitudes were higher in the AS01B-adjuvanted groups than in the MF59-adjuvanted group. At month 12, HIV-specific Env-gp120 binding antibody response magnitudes in the 40 μg gp120/AS01B group were higher than in either of the 200 μg gp120 groups. The 40 μg dose gp120/AS01B regimen elicited the highest CD4+ T-cell and binding antibody responses. Clinical Trials Registration . NCT03122223.

Safety, tolerability, pharmacokinetics, and immunological activity of dual-combinations and triple-combinations of anti-HIV monoclonal antibodies PGT121, PGDM1400, 10-1074, and VRC07-523LS administered intravenously to HIV-uninfected adults: a phase 1 randomised trial

Preclinical and clinical studies suggest that combinations of broadly neutralising antibodies (bnAbs) targeting different HIV envelope epitopes might be required for sufficient prevention of infection. We aimed to evaluate the dual and triple anti-HIV bnAb combinations of PGDM1400 (V2 Apex), PGT121 (V3 glycan), 10-1074 (V3 glycan), and VRC07-523LS (CD4 binding site). In this phase 1 trial (HVTN 130/HPTN 089), adults without HIV were randomly assigned (1:1:1) to three dual-bnAb treatment groups simultaneously, or the triple-bnAb group, receiving 20 mg/kg of each antibody administered intravenously at four centres in the USA. Participants received a single dose of PGT121 + VRC07-523LS (treatment one; n=6), PGDM1400 + VRC07-523LS (treatment two; n=6), or 10-1074 + VRC07-523LS (treatment three; n=6), and two doses of PGDM1400 + PGT121 + VRC07-523LS (treatment four; n=9). Primary outcomes were safety, pharmacokinetics, and neutralising activity. Safety was determined by monitoring for 60 min after infusions and throughout the study by collecting laboratory assessments (ie, blood count, chemistry, urinalysis, and HIV), and solicited and unsolicited adverse events (via case report forms and participant diaries). Serum concentrations of each bnAb were measured by binding antibody assays on days 0, 3, 6, 14, 28, 56, 112, 168, 224, 280, and 336, and by serum neutralisation titres against Env-pseudotyped viruses on days 0, 3, 28, 56, and 112. Pharmacokinetic parameters were estimated by use of two-compartment population pharmacokinetic models; combination bnAb neutralisation titres were directly measured and assessed with different interaction models. This trial is registered with ClinicalTrials.gov, NCT03928821, and has been completed. 27 participants were enrolled from July 31, to Dec 20, 2019. The median age was 26 years (range 19-50), 16 (58%) of 27 participants were assigned female sex at birth, and 24 (89%) participants were non-Hispanic White. Infusions were safe and well tolerated. There were no statistically significant differences in pharmacokinetic patterns between the dual and triple combinations of PGT121, PGDM1400, and VRC07-523LS. The median estimated elimination half-lives of PGT121, PGDM1400, 10-1074, and VRC07-523LS were 32·2, 25·4, 27·5, and 52·9 days, respectively. Neutralisation coverage against a panel of 12 viruses was greater in the triple-bnAb versus dual-bnAb groups: area under the magnitude-breadth curve at day 28 was 3·1, 2·9, 3·0, and 3·4 for treatments one to four, respectively. The Bliss-Hill multiplicative interaction model, which assumes complementary neutralisation with no antagonism or synergism among the bnAbs, best described combination bnAb titres in the dual-bnAb and triple-bnAb groups. No pharmacokinetic interactions among the bnAbs and no loss of complementary neutralisation were observed in the dual and triple combinations. This study lays the foundation for designing future combination bnAb HIV prevention efficacy trials. US National Institute of Allergy and Infectious Diseases, US National Institute on Drug Abuse, US National Institute of Mental Health, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Brief Report: Changes in Nocturnal Heart Rate Variability in People Living With HIV During the First Year of Antiretroviral Therapy Compared With HIV-Uninfected Community Controls.

Higher nocturnal heart rate and lower nocturnal heart rate variability (HRV) is associated with increased cardiovascular disease mortality. Longitudinal studies on nocturnal HRV in people living with HIV (PLWH) are lacking. We conducted a 1-year prospective cohort study of adult PLWH and HIV-uninfected community controls in northwestern Tanzania. At enrollment, we collected data on cardiovascular risk factors and tested blood samples for hemoglobin, insulin, CD4 cell count, and C-reactive protein. We measured nocturnal HRV and heart rate at baseline and first-year follow-up. Mixed effect linear regression was used to determine predictors of lower HRV. Of the 111 enrolled participants (74 PLWH and 37 HIV-uninfected adults), 57.7% were female and the median age was 40 years. Over 1 year of follow-up, the average nocturnal heart rate was 4.5 beats/minute higher in PLWH ( P = 0.006). In the fully adjusted model (with age, sex, nocturnal heart rate, and diabetes), average nocturnal HRV was 10.5 milliseconds lower in PLWH compared with HIV-uninfected adults ( P = 0.03). Unlike with nocturnal heart rate, nocturnal HRV did not improve after 1 year of ART in PLWH or HIV-uninfected adults (fully adjusted change = -2.5 milliseconds, P = 0.45). Lower educational attainment, lesser pancreatic β-cell function, and anemia were associated with higher HRV. Nocturnal parasympathetic nervous system function was persistently lower in PLWH compared with HIV-uninfected adults even after antiretroviral therapy initiation. Improving nocturnal autonomic nervous system function could be a target for cardiovascular disease prevention in PLWH.

Humoral immune response following the inactivated quadrivalent influenza vaccination among HIV-infected and HIV-uninfected adults

BackgroundA limited amount of information is available about the immunogenicity of the quadrivalent inactivated influenza vaccine among human immunodeficiency virus (HIV)-infected individuals, especially in low and middle-income countries (LMICs). MethodsHIV-infected adults and HIV-uninfected adults received a dose of quadrivalent inactivated influenza vaccine including strains of H1N1, H3N2, BV and BY. Enzyme-linked immunosorbent assay (ELISA) and hemagglutination-inhibition assay (HAI) were used to determine IgA, IgG antibody concentration and geometric mean titers (GMT) at day 0 and day 28, respectively. Associated factors contributing to seroconversion or GMT changes were analyzed using simple logistic regression model. ResultsA total of 131 HIV-infected and 55 HIV-uninfected subjects were included in the study. In both HIV-infected and uninfected arms, IgG and IgA against influenza A and B all increased significantly at day 28 after receiving QIV (P < 0.001). GMTs of post-vaccination at day 28 showed that HIV-infected persons with CD4 + T cell counts ≤ 350 cells/mm3 were statistically less immunogenic to all strains of QIV than HIV-uninfected ones (P < 0.05). HIV-infected participants with CD4 + T cell counts ≤ 350 cells/mm3 were less likely to achieve seroconversion to QIV (H1N1, BY and BV) than HIV-uninfected individuals at day 28 after vaccination (P < 0.05). Compared with HIV-infected patients with baseline CD4 + T cell counts ≤ 350 cells/mm3, individuals with baseline CD4 + T cell counts > 350 cell/mm3 seemed more likely to generate antibody responses to H1N1 (OR:2.65, 95 %CI: 1.07–6.56) and BY (OR: 3.43, 95 %CI: 1.37–8.63), and showed a higher probability of seroconversion to BY (OR: 3.59, 95 %CI: 1.03–12.48). Compared with nadir CD4 + T cell count ≤ 350 cell/mm3, individuals with nadir CD4 + T cell count > 350 cell/mm3 showed a higher probability of seroconversion to H1N1(OR: 3.15, 95 %CI: 1.14–8.73). ConclusionInfluenza vaccination of HIV-infected adults might be effective despite variable antibody responses. HIV-positive populations with CD4 + T cell counts ≤ 350 are less likely to achieve seroconversion. Further vaccination strategies could be developed for those with low CD4 T cell counts.

Prevalence of dental caries and associated risk factors among People Living with HIV/AIDS and HIV uninfected adults at an HIV clinic in Kigali, Rwanda.

Dental caries is among the most frequent oral conditions in People Living with HIV/AIDS (PLWHA). There is a lack of baseline information on dental caries prevalence and associated risk factors among PLWHA in comparison to HIV uninfected people in Rwanda. This study was conducted to determine the prevalence of dental caries and associated risk factors among PLWHA and HIV uninfected adults at an HIV clinic of Kigali Teaching Hospital (CHUK) in Kigali, Rwanda. A comparative cross-sectional study was conducted among 200 PLWHA and 200 HIV uninfected adults aged 18 years and above attending an HIV clinic of CHUK. An oral examination was performed by a calibrated examiner. Dental caries were assessed using the WHO Decayed (D), Missing (M), and Filled Teeth (F) index (DMFT). Descriptive statistics, Chi-square, t-tests, and multiple binary logistic regression were used to analyze data. Overall, a higher prevalence (50.5%) of PLWHA had experienced dental caries (DMFT>0) compared to HIV uninfected counterparts (40.5%) (p = 0.045). The prevalence of Decayed teeth (D) was also higher (23.5%) among PLWHA compared to HIV uninfected persons (13.6%) (p = 0.011). The Mean(SD) DMFT scores among PLWHA and HIV uninfected participants were 2.28 (3.68) and 1.29 (2.21) respectively (p = 0.001). After performing multiple binary logistic regression analysis, the predictors of dental caries in PLWHA were being female (OR = 2.33; 95%CI = 1.14-4.75), frequent dental visits (OR = 4.50; 95% CI = 1.46-13.86) and detectable RNA viral load (OR = 4.50; 95% CI = 1.46-13.86). In HIV uninfected participants, the middle age range (36-45 years), and frequent dental visits were significantly associated with dental caries (OR = 6.61; 95%CI = 2.14-20.37) and (OR = 3.42; 95%CI: 1.337-8.760) respectively. The prevalence of dental caries was higher in PLWHA than in HIV uninfected counterparts. The reported higher prevalence of caries in PLWHA was associated with being female, detectable viral load, and frequent dental visits. Therefore, there is a need for effective oral health interventions specific to PLWHA in Rwanda to raise awareness of the risk of dental caries and provide preventive oral health services among this population. To ensure timely oral health care amongPLWHA, there is a need for an effort from policymakers and other stakeholders to integrate oral health care services within the HIV treatment program in Rwanda.

1343. Body fat and metabolic complications in youth with perinatally-acquired HIV

Abstract Background The role of obesity on long-term metabolic complications remains poorly understood in youth living with perinatally-acquired HIV (YPHIV). Methods The PHACS Adolescent Master Protocol (AMP) study enrolled YPHIV from 2007-2009 across 15 U.S. sites, including Puerto Rico. We included YPHIV aged 7-19 yr with body composition data assessed by whole-body dual energy x-ray absorptiometry (DXA) at baseline and 2 years later. Metabolic outcomes included homeostatic assessment of insulin resistance (HOMA-IR) and non-high-density lipoprotein cholesterol (non-HDL-C). We fit linear regression models using generalized estimating equations to assess the association of % change in body and trunk fat over 2 yr with metabolic outcomes at years 2 and 3, adjusted for potential confounders (age, race: Black vs. non-Black, Tanner stage, sex, family history, CD4, viral load, and ART). Results 232 participants had a second DXA and either HOMA-IR or non-HDL-C measured at year 2. Participant characteristics at the first DXA were: median (Q1, Q3) age 12 yr (9, 14) 70% Black, CD4 count 714 cells/mm3; 70% with HIV RNA &amp;lt; 400 copies/mL; 72% on protease inhibitor-, 25% on non-nucleoside reserve transcriptase inhibitor-, and 3% on integrase strand transfer inhibitor-based ART. The median % increase from baseline in total body and trunk fat percentage at 2 yr was 5.41% and 4.47%, respectively. The figure shows distributions of HOMA-IR and non-HDL-C. In both unadjusted and adjusted analyses (Table), for every 1% increase in total body fat percentage from baseline to 2 years, we observed a 0.002 (95%CI -0.0, 0.005) higher log10 HOMA-IR at year 3, which equals ∼ a 0.5% higher HOMA-IR. For every 1% increase in total body and trunk fat percentage over 2 years, non-HDL-C (mg/dL) was 0.19 (95%CI 0.03, 0.35) higher and 0.65 (95%CI 0.12, 1.19) higher, respectively, in unadjusted models. Results were similar but slightly attenuated when we additionally adjusted for confounders including ART. Figure:HOMA-IR and non-HDL cholesterol at baseline, year 2, and year 3Table:Unadjusted and adjusted models assessing the association of percent change in body fat and trunk fat percentage with metabolic outcomes ¹Adjusted for age (years), sex (male vs female), race (Black vs non-Black), Tanner stage (2, 3, 4-5 vs 1), family history of diabetes or cardiovascular disease (yes, not known vs no), CD4 (≤350 vs &amp;gt;350 cells/mm³), and viral load (≥400 vs &amp;lt;400 copies/mL). ²Adjusted for age (years), sex (male vs female), race (Black vs non-Black), Tanner stage (2, 3, 4-5 vs 1), family history of diabetes or cardiovascular disease (yes, not known vs no), CD4 (≤350 vs &amp;gt;350 cells/mm³), viral load (≥400 vs &amp;lt;400 copies/mL), and ARV exposure (PI without NNRTI, NNRTI without PI vs other). Conclusion Increases in adiposity over time may lead to downstream decreased insulin sensitivity and dyslipidemia in YPHIV. This is clinically significant, as even small increases in HOMA-IR have been associated with all-cause mortality in non-diabetic HIV-uninfected adults. Long-term follow-up is warranted. Disclosures Mitchell E. Geffner, MD, Adrenas: Advisor/Consultant|Adrenas: Honoraria|Ascendis: Advisor/Consultant|Ascendis: Honoraria|Aventria: Honoraria|Eton: Advisor/Consultant|Eton: Honoraria|ICON Clinical Research, LLC/Aeterna Zentaris: Advisor/Consultant|ICON Clinical Research, LLC/Aeterna Zentaris: Honoraria|McGraw-Hill: Royalties|Neurocrine Biosciences: Grant/Research Support|Novo Nordisk: Grant/Research Support|Nutritional Growth Solutions Ltd: Advisor/Consultant|Nutritional Growth Solutions Ltd: Honoraria|Pfizer, Inc.: Advisor/Consultant|Pfizer, Inc.: Honoraria|Spruce Biosciences: Grant/Research Support|UpToDate: Royalties Grace A. McComsey, MD, Gilead, Merck, ViiV, Janssen, Theratechnologies: Advisor/Consultant.

Indirect serum biomarkers perform sub optimally in screening for significant liver fibrosis among HIV-infected and uninfected adults in Uganda.

Indirect serum bio-markers present an acceptable noninvasive and cheap alternative for screening of significant liver fibrosis (SLF). Evaluation of their use in resource limited settings is important to determine their utility. We conducted a cross sectional study among 520 HIV infected and HIV uninfected adults attending care clinics in Kampala Uganda. Presence of SLF was determined using Fibroscan® liver stiffness measurement of ≥7.2KPa. The diagostic value of indirect serum bio-markers for diagnosis of SLF was evaluated using the area under the receiver operating characteristics curve (AUROC) using Fibroscan® as gold standard. Overall AUROC values for Age Platelet Index (API), Aspartate to Alanine Ratio (AAR), AST-to-Platelet Ratio Index (APRI), Fibrosis Index based on 4 Factors (FIB-4) and Gamma glutamyl transferase to Platelet Ratio Index (GPR) were 0.52, 0.49, 0.55, 0.55 and 0.54 respectively. Among HIV-infected participants AUROC values were slightly improved at predicting presence of SLF but still under 70%. Despite APRI and FIB-4 being more likely to identify participants with SLF, the overall diagnostic value of all serum bio-markers was poor with and without stratification by HIV status. We recommend the use of Fibroscan® technology as more accurate non-invasive diagnostic method for screening of SLF.

Intracellular survival of Streptococcus pneumoniae in human alveolar macrophages is augmented with HIV infection.

People Living with HIV (PLHIV) are at an increased risk of pneumococcal pneumonia than HIV-uninfected adults, but the reasons for this are still not well understood. We investigated whether alveolar macrophages (AM) mediated control of pneumococcal infection is impaired in PLHIV compared to HIV-uninfected adults. We assessed anti-bactericidal activity against Streptococcus pneumoniae of primary human AM obtained from PLHIV and HIV-uninfected adults. We found that pneumococcus survived intracellularly in AMs at least 24 hours post ex vivo infection, and this was more frequent in PLHIV than HIV-uninfected adults. Corroborating these findings, in vivo evidence showed that PLHIV had a higher propensity for harboring S. pneumoniae within their AMs than HIV-uninfected adults. Moreover, bacterial intracellular survival in AMs was associated with extracellular propagation of pneumococcal infection. Our data suggest that failure of AMs to eliminate S. pneumoniae intracellularly could contribute to the increased risk of pneumococcal pneumonia in PLHIV.

Acute Malaria in Malawian Children and Adults is Characterized by Thrombocytopenia That Normalizes in Convalescence.

BackgroundPlasmodium falciparum malaria has been linked with significant perturbations of the peripheral cell-mediated immune system during acute phase. Some of these changes include lower than normal platelet counts. Although the exact mechanisms that drive thrombocytopenia in P. falciparum malaria are not fully known, a number of hypotheses have been proposed. We conducted two sets of studies with one aimed at determining platelet counts in Malawian children, and the other in adults during acute P. falciparum malaria and a month post treatment.Materials and MethodsWe recruited a total of 113 HIV-uninfected children with acute malaria [n=54 with uncomplicated malaria (UCM), n=30 with severe malarial anemia (SMA), n=29 presenting with cerebral malaria (CM)]. We also recruited 42 HIV-uninfected healthy controls. Out of the 113 participants with malaria, 73 (65%) [n=34 (63%) UCM, n=21 (70%) SMA and n=18 (62%) CM] were successfully followed-up one month after treatment. A 5mL peripheral blood sample was collected for platelet count using HMX Haematological Analyzer analysis both at baseline (acute malaria) and at follow-up a month later. Platelet counts were also determined in blood samples of 106 HIV-uninfected adults, 47 of whom presented with UCM and 29 with severe malaria (SM) and these counts were compared to those of 30 healthy controls. Of the malaria cases, platelet counts for 44 UCM and 21 SM were determined again during follow-up a month after treatment.ResultsIn both children and adults, platelet counts were significantly lower during acute disease compared to the levels in the healthy controls with the lowest levels observed in CM (children) or SM (adults). These lower than normal levels increased close to normal levels a month post treatment.ConclusionP. falciparum malaria in Malawian children and adults was characterized by profound thrombocytopenia which recovered during convalescence.

Blood Pressure and Body Composition During First Year of Antiretroviral Therapy in People With HIV Compared With HIV-Uninfected Community Controls.

Body composition changes may explain the rapid increase in blood pressure (BP) in people with HIV (PWH) during the first year of antiretroviral therapy. We analyzed data from a cohort of PWH and HIV-uninfected adults from the same communities in Mwanza, Tanzania. Blood pressure (BP, mm Hg) and body composition data were collected at baseline and 12-month follow-up. We used multivariable linear regression to compare BP changes in PWH and HIV-uninfected adults, and the relationship between changes in body composition and changes in BP. BP data were available for 640 PWH and 299 HIV-uninfected adults. Sixty-four percent were women and the mean age was 38 years. In PWH, systolic BP (SBP) increased (114-118) whereas SBP decreased (125-123) in HIV-uninfected participants. Fat mass increased by 1.6 kg on average in PWH and was strongly associated with the change in BP (P < 0.001). The greater increase in SBP in PWH was partly explained by the lower baseline SBP but PWH still experienced a 2.2 (95% CI: 0.3-4.2) greater increase in SBP after adjustment. Weight gain partially mediated the relationship between HIV and SBP increase in PWH; a 1-kg increase in fat mass accounted for 0.8 (95% CI: 0.6-1.1) increase in SBP. Weight and fat mass increase rapidly in PWH during the first 12 months of antiretroviral therapy and contribute to a rapid increase in SBP. Interventions to prevent excessive increase in fat mass are needed for PWH.

Differential CD4+ and CD8+ T cell recognition of mycobacteria antigens in pediatric versus adult TB

Abstract T cells from young children may be limited in capacity to mount pro-inflammatory responses to intracellular pathogens, thus contributing to vulnerability to TB disease. We compared CD4+ and CD8+ T cell cytokine production in response to mycobacterial antigens and mitogen SEB, between Ugandan children &amp;lt;5 yr (PedTB) and adults (ATB) with culture-confirmed pulmonary TB. HIV-uninfected children (n=12) and adults (n=41) had blood drawn for PBMC isolation prior to TB treatment. CD4+ and CD8+ T cell production of IFNγ, IL2, and TNFα in response to ESAT6/CFP10 (EC), ESXJ, PE12/13, PE3, PPE15, and PPE51 peptide pools, and SEB, were assessed by intracellular flow cytometry. Proportions and frequencies of CD4+ and CD8+ T cells producing cytokines were compared using Fisher’s Exact and Kruskal-Wallis tests, respectively, with adjusted p-values &amp;lt;0.05 significant. PedTB and ATB had equivalent CD4+ and CD8+ T cell production of IFNγ, IL2, and TNFα, including polyfunctional responses, to EC. T cell cytokine responses to ESXJ and PPE51 were equivalent; significant differences were noted in CD4+ T cell responses to PE3 and PPE15, and CD8+ T cell responses to PE12/13. Frequencies of CD4+ T cells producing IFNγ or IL2 in response to SEB were lower (p&amp;lt;0.0001) in PedTB versus ATB. Young children with PedTB exhibited adult-like capacity to generate Th-1 cytokines in response to EC, ESXJ, and PPE 51. Pediatric responses to PE3, PPE15, and PE12/13 were impaired, suggesting that the breath of antigen recognition differs between infants and adults with TB. Differential T cell recognition of mycobacterial antigens between adults and children should be considered in development of novel T cell based diagnostics and vaccines targeting pediatric TB. Supporting from grants by NIH: AI157807; HHSN272200900053C

Airway Aging and Methylation Disruptions in HIV-associated Chronic Obstructive Pulmonary Disease.

Rationale: Age-related diseases like chronic obstructive pulmonary disease (COPD) occur at higher rates in people living with human immunodeficiency virus (PLWH) than in uninfected populations. Objectives: To identify whether accelerated aging can be observed in the airways of PLWH with COPD, manifest by a unique DNA methylation signature. Methods: Bronchial epithelial brushings from PLWH with and without COPD and HIV-uninfected adults with and without COPD (N = 76) were profiled for DNA methylation and gene expression. We evaluated global Alu and LINE-1 methylation and calculated the epigenetic age using the Horvath clock and the methylation telomere length estimator. To identify genome-wide differential DNA methylation and gene expression associated with HIV and COPD, robust linear models were used followed by an expression quantitative trait methylation (eQTM) analysis. Measurements and Main Results: Epigenetic age acceleration and shorter methylation estimates of telomere length were found in PLWH with COPD compared with PLWH without COPD and uninfected patients with and without COPD. Global hypomethylation was identified in PLWH. We identified 7,970 cytosine bases located next to a guanine base (CpG sites), 293 genes, and 9 expression quantitative trait methylation-gene pairs associated with the interaction between HIV and COPD. Actin binding LIM protein family member 3 (ABLIM3) was one of the novel candidate genes for HIV-associated COPD highlighted by our analysis. Conclusions: Methylation age acceleration is observed in the airway epithelium of PLWH with COPD, a process that may be responsible for the heightened risk of COPD in this population. Their distinct methylation profile, differing from that observed in patients with COPD alone, suggests a unique pathogenesis to HIV-associated COPD. The associations warrant further investigation to establish causality.

RISK FACTORS AND OUTCOMES OF HIV-ASSOCIATED STROKE IN ZAMBIA

<h2>ABSTRACT</h2><h3>Objective</h3> To compare risk factors and clinical outcomes between people living with HIV (PLWH) and HIV-uninfected (HIV-) adults with stroke hospitalized in Zambia. <h3>Methods</h3> Weretrospectively reviewed charts of all adults admitted to the University Teaching Hospital in Lusaka, Zambia with a clinical diagnosis of stroke between October 2018 and March 2019. Standardized data collection instruments were used to collect demographic, clinical, laboratory and imaging results. Comparison between individuals with and without HIV infection was made using t-tests for continuous parametric variables, Wilcoxon rank-sum tests for continuous non-parametric variables, and chi-square analyses for categorical variables. <h3>Results</h3> 272adults with stroke were admitted of whom 58 (21%) were PLWH. Compared to HIV- participants, PLWH were younger (48 ± 14) years versus 62 ± 18) years, p<0.001). PLWH were less likely to have hypertension (65% vs 83%, p=0.003) and more likely to have no traditional cerebrovascular risk factors (34% vs 15%, p=0.01). Deep vein thrombosis (DVT) (4% vs 1%, p=0.04) was more common during hospitalization amongst PLWH, but there was no difference in in-hospital mortality (21% vs 23%, p=0.65). Among PLWH with stroke, factors associated with in-hospital mortality were Glasgow Coma Scale (GCS) on admission (7 vs 10, p=0.046), hypertension (92% vs 59%, p=0.04) and fever (58% vs 13%, p=0.003). <h3>Conclusion</h3> This Zambian cohort of PLWH and stroke is notable for being significantly younger with fewer traditional stroke risk factors but higher rates of DVT than their HIV-uninfected counterparts. GCS on admission, hypertension and fever were associated with in-hospital mortality.