Suppression Of Plasma Viral Load Research Articles

Integrated community-based management of HIV, diabetes, and hypertension in Tanzania and Uganda: protocol for a cluster-randomized trial

Background In response to the growing burden of chronic diseases in sub-Saharan Africa, where innovative and cost-effective health solutions are imperative, this study outlines a protocol for a cluster-randomized trial that compares integrated community-based care with integrated facility-based care to improve access and outcomes for patients with HIV, diabetes, or hypertension. Methods & analysis We will conduct a pragmatic cluster-randomized trial comparing integrated community care with integrated facility care in Tanzania and Uganda. Patients living with HIV, diabetes, or hypertension, stable on treatment in health facilities, will be organised into groups of approximately 8–14 persons and randomly assigned to integrated community or facility-based care. The study has two co-primary endpoints: a composite endpoint of glycemia and blood pressure control among individuals with diabetes and/or hypertension and suppression of plasma viral load among people living with HIV. Participants will receive their drugs, adherence support, and monitoring at a community venue in the integrated community arm. Those randomised to the control arm will receive integrated facility-based care. All study participants will be followed up for 12 months. A sample size of 116 groups will provide over 80% power to detect an absolute difference in blood pressure and blood glucose control of 10% at the 5% two-sided significance level. For HIV viral suppression, the trial will have over 80% power to show non-inferiority with a delta margin = 8.5%, 7.5%, and 5.5% assuming viral suppression is 85%, 90% and 95% respectively. To allow for loss to follow-up, our target for enrolment is 124 groups, each comprising an average of 14 participants. An economic evaluation within the trial will be conducted to estimate the cost and cost-effectiveness of integrated community care compared with integrated facility care. This will be complemented by a built-in social science process evaluation. Ethics and dissemination Ethical approval was granted by the Research Ethics Committees of the University College London (UCL), the National Institute of Medical Research (Tanzania), and the Uganda Virus Research Institute (Uganda). The findings will be disseminated through journal publications and meetings with key stakeholders. Trial registration number ISRCTN Registry: ISRCTN15319595, registration date: 07 June 2022.

Unravelling the triad of neuroinvasion, neurodissemination, and neuroinflammation of human immunodeficiency virus type 1 in the central nervous system.

Since the identification of human immunodeficiency virus type 1 (HIV-1) in 1983, many improvements have been made to control viral replication in the peripheral blood and to treat opportunistic infections. This has increased life expectancy but also the incidence of age-related central nervous system (CNS) disorders and HIV-associated neurodegeneration/neurocognitive impairment and depression collectively referred to as HIV-associated neurocognitive disorders (HAND). HAND encompasses a spectrum of different clinical presentations ranging from milder forms such as asymptomatic neurocognitive impairment or mild neurocognitive disorder to a severe HIV-associated dementia (HAD). Although control of viral replication and suppression of plasma viral load with combination antiretroviral therapy has reduced the incidence of HAD, it has not reversed milder forms of HAND. The objective of this review, is to describe the mechanisms by which HIV-1 invades and disseminates in the CNS, a crucial event leading to HAND. The review will present the evidence that underlies the relationship between HIV infection and HAND. Additionally, recent findings explaining the role of neuroinflammation in the pathogenesis of HAND will be discussed, along with prospects for treatment and control.

Determinants of viral load suppression failure among HIV adults on ARV attending health care facilities: a retrospective study in Tanga region, Tanzania

BackgroundAvailability and accessibility of Antiretroviral drugs (ARV’s) improve the lives of People living with HIV (PLHIV) by improving client’s immune system to overcome infections and prevent the development of AIDS and other HIV complications. Combination therapy, early initiation of ART, newer ART drugs, single dosage and drug affordability significantly contribute in the reduction of viral multiplication and suppression of HIV to undetectable plasma levels.MethodsA retrospective longitudinal study design study was conducted from 1st October, 2018 to 30th June 2022 in all supported HIV care and treatment health facilities in Tanga region which were supported by Amref Health Africa, Tanzania. The participants were HIV adult patients aged 15 years and above on ART and attended the clinic at least once after ART initiation. Viral load suppression levels are defined with viral load <1,000 HIV RNA copies/ml (viral load suppression). Cox proportional hazard regression models were employed to identify risk factors for virological failure. P values were two-sided, and we considered a P<0.05 to be statistically significant.ResultsFifty-nine thousand five hundred three adult clients >15 years whom were on ART were included in the analysis to determine the level of plasma Viral Load suppression after being on ART. Female 41,304 (69.4%) and male 18,199 (30.6%). Only four percent (2,290) were found to be unsuppressed i.e having plasma Viral Load >1,000cp/ml while 96% (57,213) were virally suppressed. Several factors were independently associated with virologic failure that included; age between 15 - <25 years (HR: 2.82, 95% CI 1.96 – 4.04), BMI <18.5 (HR: 1.69, 95% CI 1.23 – 2.30), advanced WHO stage IV (HR: 1.60, 95% CI 1.12 – 2.24), CD4 cell count <350 (HR: 2.61, 95% CI 2.12 – 3.23), poor adherence (HR: 1.98, 95% CI 1.80 – 2.18) and not using DTG based drug (HR: 11.8, 95% CI 9.74 – 14.3).ConclusionVirologic failure was observed in this study among clients with young age, advanced WHO stage IV, not using DTG based regimen, poor drug adherence and second line regime. To improve Viral Load Suppression among these clients; the existing HIV intervention strategies should be taken care by targeting the identified risk factors.

Stem cell-derived CAR T cells show greater persistence, trafficking, and viral control compared to ex vivo transduced CAR T cells

Adoptive cell therapy (ACT) using T cells expressing chimeric antigen receptors (CARs) is an area of intense investigation in the treatment of malignancies and chronic viral infections. One of the limitations of ACT-based CAR therapy is the lack of in vivo persistence and maintenance of optimal cell function. Therefore, alternative strategies that increase the function and maintenance of CAR-expressing T cells are needed. In our studies using the humanized bone marrow/liver/thymus (BLT) mouse model and nonhuman primate model (NHP) of HIV infection, we evaluated two CAR-based gene therapy approaches. In ACT approach, we utilized cytokine enhancement and preconditioning to generate greater persistence of anti-HIV CAR+ T cells. We observed limited persistence and expansion of anti-HIV CAR T cells which led to minimal control of the virus. In our stem-cell based approach, we modified hematopoietic stem/progenitor cells (HSPCs) with anti-HIV CAR to generate anti-HIV CAR T cells in vivo. We observed CAR-expressing T cell expansion which led to better plasma viral load suppression. HSPC-derived CAR cells in infected NHPs showed superior trafficking and persistence in multiple tissues. Our results suggest a stem cell-based CAR T cell approach may be superior to generate long-term persistence and functional antiviral responses against HIV infection.

Discordance of Aqueous/Plasma HIV Replication on ART.

The study was conducted to analyze HIV dynamics across blood-retinal barrier (BRB) and the relevant risk factors for HIV-associated ocular complications. This study included a case series of 40 HIV-positive patients with ocular lesions, which were studied retrospectively. Clinical and laboratory examinations included plasma and intraocular viral load (VL). HIV VL on paired aqueous/plasma samples was available for 40 patients. Aqueous VL was negatively associated with antiretroviral treatment (ART) duration (p = 0.02 and p < 0.05), and plasma VL was independent of ART duration (p = 0.53). An aqueous/plasma discordance was found in 19/40 (47.5%) patients, eight of whom (20%) had detectable aqueous VL despite a suppressed plasma VL (escape). There were significant differences in CD4+ T-lymphocyte levels (p = 0.011 and p < 0.05) and ART duration (p = 0.007 and p < 0.05) between the patients with HIV-associated ocular complications and the patients without. This study provides a rationale for initiating ART early in the course of infection to reduce HIV VL in the aqueous humor, and raises the possibility of the ocular sanctuary where HIV replicates. Meanwhile, early and standard ART would be an optimal option to protect against ocular opportunistic infection.

Integrated management of HIV, diabetes, and hypertension in sub-Saharan Africa (INTE-AFRICA): a pragmatic cluster-randomised, controlled trial

In sub-Saharan Africa, health-care provision for chronic conditions is fragmented. The aim of this study was to determine whether integrated management of HIV, diabetes, and hypertension led to improved rates of retention in care for people with diabetes or hypertension without adversely affecting rates of HIV viral suppression among people with HIV when compared to standard vertical care in medium and large health facilities in Uganda and Tanzania. In INTE-AFRICA, a pragmatic cluster-randomised, controlled trial, we randomly allocated primary health-care facilities in Uganda and Tanzania to provide either integrated care or standard care for HIV, diabetes, and hypertension. Random allocation (1:1) was stratified by location, infrastructure level, and by country, with a permuted block randomisation method. In the integrated care group, participants with HIV, diabetes, or hypertension were managed by the same health-care workers, used the same pharmacy, had similarly designed medical records, shared the same registration and waiting areas, and had an integrated laboratory service. In the standard care group, these services were delivered vertically for each condition. Patients were eligible to join the trial if they were living with confirmed HIV, diabetes, or hypertension, were aged 18 years or older, were living within the catchment population area of the health facility, and were likely to remain in the catchment population for 6 months. The coprimary outcomes, retention in care (attending a clinic within the last 6 months of study follow-up) for participants with either diabetes or hypertension (tested for superiority) and plasma viral load suppression for those with HIV (>1000 copies per mL; tested for non-inferiority, 10% margin), were analysed using generalised estimating equations in the intention-to-treat population. This trial is registered with ISCRTN 43896688. Between June 30, 2020, and April 1, 2021 we randomly allocated 32 health facilities (17 in Uganda and 15 in Tanzania) with 7028 eligible participants to the integrated care or the standard care groups. Among participants with diabetes, hypertension, or both, 2298 (75·8%) of 3032 were female and 734 (24·2%) of 3032 were male. Of participants with HIV alone, 2365 (70·3%) of 3365 were female and 1000 (29·7%) of 3365 were male. Follow-up lasted for 12 months. Among participants with diabetes, hypertension, or both, the proportion alive and retained in care at study end was 1254 (89·0%) of 1409 in integrated care and 1457 (89·8%) of 1623 in standard care. The risk differences were -0·65% (95% CI -5·76 to 4·46; p=0·80) unadjusted and -0·60% (-5·46 to 4·26; p=0·81) adjusted. Among participants with HIV, the proportion who had a plasma viral load of less than 1000 copies per mL was 1412 (97·0%) of 1456 in integrated care and 1451 (97·3%) of 1491 in standard care. The differences were -0·37% (one-sided 95% CI -1·99 to 1·26; pnon-inferiority<0·0001 unadjusted) and -0·36% (-1·99 to 1·28; pnon-inferiority<0·0001 adjusted). In sub-Saharan Africa, integrated chronic care services could achieve a high standard of care for people with diabetes or hypertension without adversely affecting outcomes for people with HIV. European Union Horizon 2020 and Global Alliance for Chronic Diseases.

HIV drug resistance in various body compartments.

HIV drug resistance testing using blood plasma or dried blood spots forms part of international guidelines. However, as the clinical utility of assessing drug resistance in other body compartments is less well established, we review this for blood cells and samples from other body compartments. Although clinical benefit is not clear, drug resistance testing in blood cells is often performed when patients with suppressed plasma viral loads require a treatment substitution. In patients with HIV neurocognitive disease, cerebral spinal fluid (CSF) drug resistance is rarely discordant with plasma but has nevertheless been used to guide antiretroviral drug substitutions. Cases with HIV drug resistance in genital fluids have been documented but this does not appear to indicate transmission risk when blood plasma viral loads are suppressed. Drug-resistant variants, which may be selected in tissues under conditions of variable adherence and drug penetration, appear to disseminate quickly, and become detectable in blood. This may explain why drug resistance discordance between plasma and these compartments is rarely found. Partial compartmentalization of HIV populations is well established for the CSF and the genital tract but other than blood plasma, evidence is lacking to support drug resistance testing in body compartments.

A comparative study on early treatment outcome and adverse drug reaction profile of two protease inhibitor-based antiretroviral regimens in human immunodeficiency virus patients at a tertiary care teaching hospital, Rajasthan

Introduction: Second-line antiretroviral therapy (ART) regimens are used when patients develop treatment failure from first-line drug regimens. The present study is aimed to compare treatment outcome in terms of clinical, virological, and immunological effectiveness over 1 year of follow-up in human immunodeficiency virus (HIV) patients, switched to various second-line ART regimens and to assess adverse drug reactions (ADRs). Materials and Methods: A longitudinal observational study was conducted at ART center, SMS Hospital, Jaipur, after approval from Institutional Research Review Board. One hundred HIV positive patients, resistant to first line ART, switched to either of the 2 s line ART regimens were followed for 1 year for early treatment outcomes and any ADRs. Results: Out of 97 patients enrolled 65 patients received Tenofovir and 32 patients received Zidovudine (ZDV) along with lamivudine and Atazanavir/ritonavir. There was significant increment in CD4 count from the baseline value (202.51–438.52 cells/mm3) after 12 months of therapy. On comparison, CD4 cell rise was not significantly different between the two groups. However, Plasma viral load suppression was achieved insignificantly more number of patients in ZDV group than in tenofovir group: 31 (96.9%) versus 57 (87.7%), respectively. Opportunistic infections (OI) were seen in 21.5% and 28.1% patients respectively at the time of switching of second-line ART. Out of 59 ADRs reported, nausea, vomiting, diarrhea, hyperbilirubinemia, dyslipidemia, and anemia were most common. Conclusion: Nonadherence, drug resistance, and treatment failure are the major challenges in controlling HIV disease. Our study shows that both the second-line regimens were comparable in improvement in CD4 count and viral load suppression with 1 year success rate of 90.7%.

A comparative study on early treatment outcome and adverse drug reaction profile of two protease inhibitor-based antiretroviral regimens in human immunodeficiency virus patients at a tertiary care teaching hospital, Rajasthan

Introduction: Second-line antiretroviral therapy (ART) regimens are used when patients develop treatment failure from first-line drug regimens. The present study is aimed to compare treatment outcome in terms of clinical, virological, and immunological effectiveness over 1 year of follow-up in human immunodeficiency virus (HIV) patients, switched to various second-line ART regimens and to assess adverse drug reactions (ADRs). Materials and Methods: A longitudinal observational study was conducted at ART center, SMS Hospital, Jaipur, after approval from Institutional Research Review Board. One hundred HIV positive patients, resistant to first line ART, switched to either of the 2 s line ART regimens were followed for 1 year for early treatment outcomes and any ADRs. Results: Out of 97 patients enrolled 65 patients received Tenofovir and 32 patients received Zidovudine (ZDV) along with lamivudine and Atazanavir/ritonavir. There was significant increment in CD4 count from the baseline value (202.51–438.52 cells/mm3) after 12 months of therapy. On comparison, CD4 cell rise was not significantly different between the two groups. However, Plasma viral load suppression was achieved insignificantly more number of patients in ZDV group than in tenofovir group: 31 (96.9%) versus 57 (87.7%), respectively. Opportunistic infections (OI) were seen in 21.5% and 28.1% patients respectively at the time of switching of second-line ART. Out of 59 ADRs reported, nausea, vomiting, diarrhea, hyperbilirubinemia, dyslipidemia, and anemia were most common. Conclusion: Nonadherence, drug resistance, and treatment failure are the major challenges in controlling HIV disease. Our study shows that both the second-line regimens were comparable in improvement in CD4 count and viral load suppression with 1 year success rate of 90.7%.

Luminescent PLGA Nanoparticles for Delivery of Darunavir to the Brain and Inhibition of Matrix Metalloproteinase-9, a Relevant Therapeutic Target of HIV-Associated Neurological Disorders.

Human immunodeficiency virus (HIV) can independently replicate in the central nervous system (CNS) causing neurocognitive impairment even in subjects with suppressed plasma viral load. The antiretroviral drug darunavir (DRV) has been approved for therapy of HIV-infected patients, but its efficacy in the treatment of HIV-associated neurological disorders (HAND) is limited due to the low penetration through the blood–brain barrier (BBB). Therefore, innovations in DRV formulations, based on its encapsulation in optically traceable nanoparticles (NPs), may improve its transport through the BBB, providing, at the same time, optical monitoring of drug delivery within the CNS. The aim of this study was to synthesize biodegradable polymeric NPs loaded with DRV and luminescent, nontoxic carbon dots (C-Dots) and investigate their ability to permeate through an artificial BBB and to inhibit in vitro matrix metalloproteinase-9 (MMP-9) that represents a factor responsible for the development of HIV-related neurological disorders. Biodegradable poly(lactic-co-glycolic) acid (PLGA)-based nanoformulations resulted characterized by an average hydrodynamic size less than 150 nm, relevant colloidal stability in aqueous medium, satisfactory drug encapsulation efficiency, and retained emitting optical properties in the visible region of the electromagnetic spectrum. The assay on the BBB artificial model showed that a larger amount of DRV was able to cross BBB when incorporated in the PLGA NPs and to exert an enhanced inhibition of matrix metalloproteinase-9 (MMP-9) expression levels with respect to free DRV. The overall results reveal the great potential of this class of nanovectors of DRV for an efficacious treatment of HANDs.

Redefining therapeutic success in HIV patients: an expert view.

Thanks to advances in the field over the years, HIV/AIDS has now become a manageable chronic condition. Nevertheless, a new set of HIV-associated complications has emerged, related in part to the accelerated ageing observed in people living with HIV/AIDS, the cumulative toxicities from exposure to antiretroviral drugs over decades and emerging comorbidities. As a result, HIV/AIDS can still have a negative impact on patients’ quality of life (QoL). In this scenario, it is reasonable to believe that the concept of therapeutic success, traditionally associated with CD4 cell count restoration and HIV RNA plasma viral load suppression and the absence of drug resistances, needs to be redefined to include other factors that reach beyond antiretroviral efficacy. With this in mind, a group of experts initiated and coordinated the RET Project, and this group, using the available evidence and their clinical experience in the field, has proposed new criteria to redefine treatment success in HIV, arranged into five main concepts: rapid initiation, efficacy, simplicity, safety, and QoL. An extensive review of the literature was performed for each category, and results were discussed by a total of 32 clinicians with experience in HIV/AIDS (4 coordinators + 28 additional experts). This article summarizes the conclusions of these experts and presents the most updated overview on the five topics, along with a discussion of the experts’ main concerns, conclusions and/or recommendations on the most controversial issues.

Effectiveness, safety, and economic impact of the bictegravir/emtricitabine/tenofovir alafenamide regimen in real clinical practice cohort of HIV-1 infected adult patients

RESUMENIntroducciónDentro de los nuevos esquemas de tratamiento antirretroviral (TAR) destaca bictegravir (BIC), un inhibidor de la integrasa de reciente incorporación. BIC conjugado con emtricitabina (FTC) y tenofovir alafenamida (TAF) ha demostrado ser no inferior en eficacia como terapia de inicio en régimen de dosis única diaria comparado con otros TAR de inicio. El objetivo de nuestro estudio es evaluar el impacto de la inclusión de este nuevo esquema de TAR en la práctica clínica real.Material y métodosEstudio observacional, retrospectivo y descriptivo que incluyó todos los pacientes VIH adultos (edad ≥18 años) que llevaran al menos 24 semanas seguidas en tratamiento con BIC/FTC/TAF durante 1 año y medio para evaluar efectividad, seguridad e impacto económico.ResultadosSe incluyeron 115 pacientes. Los pacientes sin tratamiento previo, naive, fueron 28 (24,3%). Los pacientes pretratados presentaban una media de 42 ±9 meses de TAR previo. El porcentaje de pacientes en la semana 24 después de cambiar a BIC/FTC/TAF con carga viral plasmática suprimida fue del 88% en el grupo naive y del 94,1% en el grupo de pretratados. Se notificaron eventos adversos en 8 (7%) pacientes. El impacto económico que supuso el cambio a BIC/FTC/TAF fue de 1.202,63 €/paciente/año, representando un aumento del 9,3%. Conclusiones. Nuestros resultados se correlacionan con los resultados de dos ensayos clínicos fase 3 de no inferioridad en pacientes naive (88% y 84%) y los de un ensayo clínico fase 3 de no inferioridad en pacientes pretratados (86%). Sin embargo, observamos gran diferencia entre los altos porcentajes de pacientes que notificaron algún evento adverso en tres ensayos clínicos de fase 3 y nuestros resultados.

Neurocytoskeleton Proteins in Cerebrospinal Fluid of People With HIV-1 Subtypes B and C.

The objective was to compare the effect of HIV-1C and HIV-1B subtypes on neurofilament light (NfL) cerebrospinal fluid (CSF) levels and ratios of NfL to tau proteins. Additional comparisons were performed between people with HIV (PWH), participants with Alzheimer disease (AD), and HIV-negative controls (HIV-). We also calculated the diagnostic characteristics of CSF NfL and its ratios in HIV-associated neurocognitive disorder (HAND) diagnosis. CSF NfL, T-tau, and P-tau181 concentrations were measured using immunoassays in a total of 108 CSF samples, including PWH (n = 68), HIV- (n = 16), and participants with AD (n = 24). These proteins were compared between HIV-1B (n = 27) and HIV-1C (n = 26) using multiple linear regression adjusted for nadir CD4 and plasma viral load suppression. Comparisons between PWH, HIV-, and participants with AD were adjusted for gender and age. CSF neurocytoskeleton proteins and their ratios were comparable in HIV-1B and HIV-1C. However, the HIV-1C group had a higher proportion of samples of CSF NfL above the reference value (n = 14, 53.85%) than the HIV-1B group (n = 8, 29.63%), P = 0.098. The values of CSF NfL were higher in the AD group [2578 (1864; 3500) pg/mL] than those in PWH [683 (500; 1197) pg/mL, P < 0.001] and control [660 (539; 802) pg/mL, P = 0.012] groups. The value of CSF NfL and its ratios for HAND diagnosis were poor. The effects of HIV-1B and HIV-1C on CSF NfL and tau ratios were comparable. The differences in CSF neurocytoskeleton proteins between PWH and individuals with AD suggested they might not share the same mechanisms of impairment. Further research is necessary to evaluate CSF NfL on the differential diagnoses of HAND with AD.

Female genital tract shedding of HIV-1 is rare in women with suppressed HIV-1 in plasma.

Determine the frequency of genital HIV-1 shedding in a large cohort of women on long-term suppressive antiretroviral therapy (ART) and its association with mucosal inflammation. We measured levels of HIV-1 RNA and inflammation biomarkers in cervicovaginal lavage (CVL) from HIV-seropositive women enrolled in the Women's Interagency HIV Study (WIHS). HIV-1 was quantified (Abbott RealTime HIV-1 assay) from CVL samples of 332 WIHS participants with and without clinical evidence of genital inflammation at the time of CVL collection; participants had suppressed plasma viral load (PVL; limit of quantitation less than 20-4000 copies/ml depending on year of collection) for a median of 7.1 years [interquartile range (IQR) 3.4-9.8, Group 1] or for a median of 1.0 years (IQR = 0.5-1.0, Group 2). Twenty-two biomarkers of inflammation were measured in CVL to compare with clinical markers. HIV-1 was detected in 47% of 38 pre-ART CVL samples (median 668 copies/ml) and detection in CVL was associated with higher pre-ART PVL. HIV-1 was detected in only 1 of 38 CVL samples from these women on suppressive antiretroviral therapy for 1 year. No HIV-1 RNA was detected in 294 CVL samples from a cross-sectional set of women with suppressed PVL for a median of 7 years. Clinical inflammation markers were correlated with inflammatory biomarkers in CVL specimens, although genital inflammation was not associated with measurable genital HIV-1 shedding in these WIHS participants on ART. ART that suppresses HIV-1 in the plasma of women also prevents genital tract HIV-1 shedding, even in the presence of genital tract inflammation.

Blood amyloid-β protein isoforms are affected by HIV-1 in a subtype-dependent pattern.

This study aimed to compare serum amyloid processing biomarkers among HIV subtype B (n = 25), HIV subtype C (n = 26), healthy HIV-negative controls (n = 18), and patients with Alzheimer's disease (AD; n = 24). Immunoassays were used to measure main soluble Aβ isoforms Aβ38, Aβ40, Aβ42, and Aβ-total in serum and cerebrospinal fluid (CSF). People living with HIV (PLWH) and HIV(-) samples, including AD samples, were compared for gender and age, while HIV subtypes were compared for nadir CD4 and plasma viral load suppression. CSF/serum ratios of Aβ40, Aβ42, and Aβ-total were lower in HIV-1C group than in HIV-1B group (p = 0.020, 0.025, and 0.050, respectively). In serum, these biomarkers were comparable. Serum Aβ isoforms were significantly lower in PLWH than in AD. Serum Aβ42 levels in PLWH were decreased compared to those in control group, thus similar to Aβ42 alterations in CSF; these results were different from those observed in AD. Impaired cellular immunity, low CD4 cell count (nadir or current) influences serum Aβ metabolism in HIV-1B but not HIV-1C. However, in PLWH overall, but not in individual HIV subtype groups, greater CD4 recovery, calculated as the difference between current and nadir CD4, correlated with Aβ42/Aβ40 ratio in serum (rs 0.246; p = 0.0479). No significant correlation was found with global deficit score (GDS), an index of neurocognitive performance, age, or duration of infection. These findings are consistent with those of subtype-dependent amyloid processing in blood in chronic HIV disease.

Impact of reproductive aging on the vaginal microbiome and soluble immune mediators in women living with and at-risk for HIV infection.

BackgroundReproductive aging may impact the vaginal microbiome and genital tract mucosal immune environment and contribute to genital tract health in women living with and at-risk for HIV infection.MethodsA cross-sectional study of 102 HIV+ (51 premenopausal, 51 postmenopausal) and 39 HIV-uninfected (HIV-) (20 premenopausal, 19 postmenopausal) women was performed in Bronx and Brooklyn, NY. Cervicovaginal lavage (CVL) was collected for quantification of innate antimicrobial activity against E. coli, HSV-2 and HIV and immune mediators by Luminex and ELISA. Microbiome studies by qPCR and 16S rRNA sequencing were performed on vaginal swabs.ResultsHIV+ postmenopausal compared to premenopausal participants had lower median E. coli bactericidal activity (41% vs. 62%, p = 0.001), lower median gene copies of Lactobacillus crispatus (p = 0.005) and Lactobacillus iners (p = 0.019), lower proportions of Lactobacillus iners, higher proportions of Gardnerella and Atopobium vaginae and lower levels of human beta defensins (HBD-2, HBD-3) and secretory leukocyte protease inhibitor (SLPI), p<0.001. HSV-2 inhibitory activity was higher in HIV+ postmenopausal compared to premenopausal participants (37% vs. 17%, p = 0.001) and correlated with the proinflammatory molecules interleukin (IL) 6, IL-8, human neutrophil peptide (HNP) 1–3, lactoferrin and fibronectin. Similar trends were observed in HIV- postmenopausal compared to premenopausal participants. HIV inhibitory activity did not differ by reproductive status in the HIV+ participants but was significantly higher in HIV- postmenopausal compared to premenopausal participants and in participants with suppressed plasma viral load, and inversely correlated with gene copies of G. vaginalis and BVAB2. A significant proportion of HIV+ participants on ART exhibited HIV enhancing activity.ConclusionsHIV+ postmenopausal compared to premenopausal participants have less CVL E. coli bactericidal activity, reflecting a reduction in Lactobacilli and a greater proportion of Gardnerella and A. vaginae, and more HSV-2 inhibitory activity, reflecting increased mucosal inflammation. The effect of menopause on mucosal immunity was greater in HIV+ participants, suggesting a synergistic impact. Promotion of a lactobacillus dominant vaginal microbiome and reduced mucosal inflammation may improve vaginal health and reduce risk for shedding of HIV and potential for HIV transmission in HIV+ menopausal women.

Placental transfer of elvitegravir and cobicistat in an ex vivo human cotyledon double perfusion model

Introduction: Sustained suppression of plasma viral load is the key to preventing vertical transmission from HIV-infected women to their infants. Current guidelines recommend antiretroviral therapy for all HIV infected pregnant women, starting before the pregnancy. However, the choice of which antiretroviral medications to be used must take into account the tolerance for the developing fetus, in view of the placental transfer of the drugs used.

Cerebrospinal fluid extracellular vesicles and neurofilament light protein as biomarkers of central nervous system injury in HIV-infected patients on antiretroviral therapy.

Objective:The relationship of cerebrospinal fluid (CSF) extracellular vesicles to neurocognitive impairment (NCI) in HIV-infected individuals is unclear. Here, we characterize CSF extracellular vesicles and their association with central nervous system (CNS) injury related biomarkers [neurofilament light (NFL), S100B, neopterin] and NCI in HIV-positive individuals on combination antiretroviral therapy (cART).Design:A cross-sectional and longitudinal study of CSF samples from HIV-positive individuals on cART.Methods:NFL, S100B and neopterin were measured by ELISA in 190 CSF samples from 112 individuals (67 HIV-positive and 45 HIV-negative). CSF extracellular vesicles were isolated and characterized by electron microscopy, nanoparticle tracking analysis, immunoblotting for exosome markers (CD9, CD63, CD81, FLOT-1) and ELISA for HLA-DR.Results:HIV-positive individuals had median age 52 years, 67% with suppressed plasma viral load (< 50 copies/ml), median CD4+ nadir 66 cells/μl and CD4+ cell count 313 cells/μl. CSF NFL, S100B and neopterin levels were higher in HIV-positive vs. HIV-negative individuals, and nonsuppressed vs. suppressed HIV-positive individuals. Although CSF NFL and S100B levels were higher in NCI vs. unimpaired HIV-positive individuals (P < 0.05), only NFL was associated with NCI in adjusted models (P < 0.05). CSF extracellular vesicles were increased in HIV-positive vs. HIV-negative individuals, and NCI vs. unimpaired HIV-positive individuals (P < 0.05), and correlated positively with NFL (P < 0.001). HLA-DR was enriched in CSF extracellular vesicles from HIV-positive individuals with NCI (P < 0.05), suggesting that myeloid cells are a potential source of CSF extracellular vesicles during HIV infection.Conclusion:Increased CSF extracellular vesicles correlate with neuronal injury biomarker NFL in cART-treated HIV-positive individuals with neurocognitive impairment, suggesting potential applications as novel biomarkers of CNS injury.

Women have enhanced bone loss associated with phosphaturia and CD4+ cell restoration during initial antiretroviral therapy.

We compared bone mineral density (BMD) changes and their correlates, between men and women participating in two randomized trials of initial [antiretroviral therapy (ART)] regimens, with or without tenofovir disoproxil fumarate (TDF). Covariates in linear regression models of 48-week hip and spine %BMD changes, by dual energy X-ray absorptiometry, included baseline and 48-week changes in plasma viral load, CD4 cells, plasma C-terminal telopeptide, procollagen 1 N-terminal propeptide and glomerular filtration rates, and the 48-week area under the curve of fractional excretion of phosphate. Despite overall hip and spine BMD declines of 2.8 and 2.9%, respectively, plasma viral load suppression to less than 50 vs. at least 50 copies/ml was associated 1.0% (P = 0.02) and 0.8% (P = 0.01) less BMD decline. Women had lower baseline spine (P = 0.04; n = 59 women, 418 men) and hip BMD (P = 0.01) in adjusted models, with 1.7% more hip decline on ART than men (P = 0.001). Serum phosphate was positively associated with baseline spine BMD in women (P = 0.03) but not men, and area under the curve of fractional excretion of phosphate was negatively associated with spine BMD changes, particularly in women randomized to TDF regimens (P = 0.03 and 0.054 for interactions by sex, and randomization to TDF vs. non-TDF regimens, respectively; n = 44 women, 326 men). Women also had 0.6% (P = 0.004) more hip BMD decline than men associated with each 100 CD4 cells/μl increase on ART (P = 0.02; n = 49 women, 379 men). Women randomized to TDF-containing ART had accentuated spine loss associated with phosphaturia, and accentuated hip loss associated with CD4 restoration, regardless of TDF exposure. Viral load suppression reduced bone loss.

Biomarkers of neuronal injury and amyloid metabolism in the cerebrospinal fluid of patients infected with HIV-1 subtypes B and C.

Based on prior reports that the HIV-1 Tat protein modulates amyloid-beta (Aβ) metabolism, this study aimed to compare CSF neural injury biomarkers between 27 patients with HIV subtype B, 26 patients with HIV subtype C, 18 healthy HIV-negative controls, and 24 patients with Alzheimer's disease (AD). Immunoassays were used to measure soluble amyloid precursor protein α and β (sAPPα, sAPPβ), Aβ oligomers 38, 40, 42, and Aβ-total; phosphorylated tau (P-tau181), and total tau (T-tau). Comparisons between HIV(+) and HIV(-) (including AD) were adjusted by linear regression for gender and age; HIV subtype comparisons were adjusted for nadir CD4 and plasma viral load suppression. The p values were corrected for multiple testing with the Benjamini-Hochberg procedure. CSF Aβ-42 and Hulstaert (P-tau181) index were lower in HIV1-C than B (p=0.03, and 0.049 respectively); subtypes did not differ on other CSF biomarkers or ratios. Compared to AD, HIV(+) had lower CSF levels of T-tau, P-tau181 (p<0.001), and sAPPα (p=0.041); HIV(+) had higher CSF Aβ-42 (p=0.002) and higher CSF indexes: [Aß-42/(240+1.18T-tau)], P-tau181/Aβ-42, T-tau/Aβ-42, P-tau181/T-tau, sAPPα/β (all p≤0.01) than AD. Compared to HIV(-), HIV(+) had lower CSF Aβ-42, and T-tau (all p≤0.004). As conclusion, amyloid metabolism was influenced by HIV infection in a subtype-dependent manner. Aß-42 levels were lower in HIV1-C than B, suggesting that there may be greater deposition of Aß-42 in HIV1-C. These findings are supported by CSF Hulstaert (P-tau181) index. Differences between HIV and AD in the patterns of Aß and Tau biomarkers suggest that CNS HIV infection and AD may not share some of same mechanisms of neuronal injury.