Showing papers in "AIDS in 2020"

Characteristics and outcomes of COVID-19 in patients with HIV: a multicentre research network study

Abstract: OBJECTIVE: We studied clinical outcomes of COVID-19 infection in patients living with HIV (PLH) in comparison to non-HIV population. DESIGN: Analysis of a multicentre research network TriNETX was performed including patients more than 10 years of age diagnosed with COVID-19. METHODS: Outcomes in COVID-19 positive patients with concurrent HIV (PLH) were compared with a propensity-matched cohort of patients without HIV (non-PLH). RESULTS: Fifty thousand one hundred and sixty-seven patients with COVID-19 were identified (49,763 non-PLH, 404 PLH). PLH were more likely to be men, African-American, obese and have concurrent hypertension, diabetes, chronic kidney disease and nicotine dependence compared with non-PLH cohort (all P values <0.05). We performed 1 : 1 matching for BMI, diabetes, hypertension, chronic lung diseases, chronic kidney disease, race, history of nicotine dependence and sex. In unmatched analysis, PLH had higher mortality at 30 days [risk ratio 1.55, 95% confidence interval (95% CI): 1.01-2.39] and were more likely to need inpatient services (risk ratio 1.83, 95% CI: 1.496-2.24). After propensity score matching, no difference in mortality was noted (risk ratio 1.33, 95% CI: 0.69-2.57). A higher proportion of PLH group needed inpatient services (19.31 vs. 11.39%, risk ratio 1.696, 95% CI: 1.21-2.38). Mean C-reactive protein, ferritin, erythrocyte sedimentation rate and lactate dehydrogenase levels after COVID-19 diagnosis were not statistically different and mortality was not different for PLH with a history of antiretroviral treatment. CONCLUSION: Crude COVID-19 mortality is higher in PLH; however, propensity-matched analyses revealed no difference in outcomes, showing that higher mortality is driven by higher burden of comorbidities. Early diagnosis and intensive surveillance are needed to prevent a 'Syndemic' of diseases in this vulnerable cohort.

Clinical characteristics, risk factors, and incidence of symptomatic coronavirus disease 2019 in a large cohort of adults living with HIV: a single-center, prospective observational study.

Abstract: BACKGROUND: It is unclear how characteristics, risk factors, and incidence of coronavirus disease 2019 (COVID-19) in people living with HIV (PLWH) differ from the general population. METHODS: Prospective observational single-center cohort study of adult PLWH reporting symptoms of COVID-19. We assessed clinical characteristics, risk factors for COVID-19 diagnosis and severity, and standardized incidence rate ratio for COVID-19 cases in PLWH cohort and in Barcelona. RESULTS: From 1 March 2020 to 10 May 2020, 53 out of 5683 (0.9% confidence interval 0.7-1.2%) PLWH were diagnosed with COVID-19. Median age was 44 years, CD4 T cells were 618/µl and CD4/CD8 was 0.90. All but two individuals were virologically suppressed. Cough (87%) and fever (82%) were the most common symptoms. Twenty-six (49%) were admitted, six (14%) had severe disease, four (8%) required ICU admission, and two (4%) died. Several laboratory markers (lower O2 saturation and platelets, and higher leukocytes, creatinine, lactate dehydrogenase, C reactive protein, procalcitonin, and ferritin) were associated with COVID-19 severity. No HIV or antiretroviral-related factors were associated with COVID-19 diagnosis or severity. Standardized incidence rate ratios of confirmed or confirmed/probable COVID-19 in PLWH were 38% (95% confidence interval 27-52%, P < 0.0001) and 33% (95% confidence interval 21-50%, P < 0.0001), respectively relative to the general population. CONCLUSION: PLWH with COVID-19 did not differ from the rest of the HIV cohort. Clinical presentation, severity rate, and mortality were not dependent on any HIV-related or antiretroviral-related factor. COVID-19 standardized incidence rate was lower in PLWH than in the general population. These findings should be confirmed in larger multicenter cohort studies.

Viral suppression rates in a safety-net HIV clinic in San Francisco destabilized during COVID-19

Abstract: The COVID-19 pandemic is expected to hinder US End the HIV Epidemic goals. We evaluated viral suppression and retention-in-care before and after telemedicine was instituted, in response to shelter-in-place mandates, in a large, urban HIV clinic. The odds of viral nonsuppression were 31% higher postshelter-in-place (95% confidence interval = 1.08-1.53) in spite of stable retention-in-care and visit volume, with disproportionate impact on homeless individuals. Measures to counteract the effect of COVID-19 on HIV outcomes are urgently needed.

HIV infection and COVID-19: risk factors for severe disease.

Abstract: We performed an observational prospective monocentric study in patients living with HIV (PLWH) diagnosed with COVID-19. Fifty-four PLWH developed COVID-19 with 14 severe (25.9%) and five critical cases (9.3%), respectively. By multivariate analysis, age, male sex, ethnic origin from sub-Saharan Africa and metabolic disorder were associated with severe or critical forms of COVID-19. Prior CD4 T cell counts did not differ between groups. No protective effect of a particular antiretroviral class was observed.

Disproportionate burden of coronavirus disease 2019 among racial minorities and those in congregate settings among a large cohort of people with HIV.

Abstract: BACKGROUND: Many people living with HIV (PLWH) have comorbidities which are risk factors for severe coronavirus disease 2019 (COVID-19) or have exposures that may lead to acquisition of severe acute respiratory distress syndrome coronavirus 2 There are few studies, however, on the demographics, comorbidities, clinical presentation, or outcomes of COVID-19 in people with HIV OBJECTIVE: To evaluate risk factors, clinical manifestations, and outcomes in a large cohort of PLWH with COVID-19 METHODS: We systematically identified all PLWH who were diagnosed with COVID-19 at a large hospital from 3 March to 26 April 2020 during an outbreak in Massachusetts We analyzed each of the cases to extract information including demographics, medical comorbidities, clinical presentation, and illness course after COVID-19 diagnosis RESULTS: We describe a cohort of 36 PLWH with confirmed COVID-19 and another 11 patients with probable COVID-19 Almost 85% of PLWH with confirmed COVID-19 had a comorbidity associated with severe disease, including obesity, cardiovascular disease, or hypertension Approximately 77% of PLWH with COVID-19 were non-Hispanic Black or Latinx whereas only 40% of the PLWH in our clinic were Black or Latinx Nearly half of PLWH with COVID-19 had exposure to congregate settings In addition to people with confirmed COVID-19, we identified another 11 individuals with probable COVID-19, almost all of whom had negative PCR testing CONCLUSION: In the largest cohort to date of PLWH and confirmed COVID-19, almost all had a comorbidity associated with severe disease, highlighting the importance of non-HIV risk factors in this population The racial disparities and frequent link to congregate settings in PLWH and COVID-19 need to be explored urgently

Incident HIV among pregnant and breast-feeding women in sub-Saharan Africa: a systematic review and meta-analysis.

Abstract: Objectives A previous meta-analysis reported high HIV incidence among pregnant and breast-feeding women in sub-Saharan Africa (SSA), but limited evidence of elevated risk of HIV acquisition during pregnancy or breast-feeding when compared with nonpregnant periods. The rapidly evolving HIV prevention and treatment landscape since publication of this review may have important implications for maternal HIV incidence. Design Systematic review and meta-analysis. Methods We searched four databases and abstracts from relevant conferences through 1 December 2018, for literature on maternal HIV incidence in SSA. We used random-effects meta-analysis to summarize incidence rates and ratios, and to estimate 95% prediction intervals. We evaluated potential sources of heterogeneity with random-effects meta-regression. Results Thirty-seven publications contributed 100 758 person-years of follow-up. The estimated average HIV incidence rate among pregnant and breast-feeding women was 3.6 per 100 person-years (95% prediction interval: 1.2--11.1), while the estimated average associations between pregnancy and risk of HIV acquisition, and breast-feeding and risk of HIV acquisition, were close to the null. Wide 95% prediction intervals around summary estimates highlighted the variability of HIV incidence across populations of pregnant and breast-feeding women in SSA. Average HIV incidence appeared associated with age, partner HIV status, and calendar time. Average incidence was highest among studies conducted pre-2010 (4.1/100 person-years, 95% prediction interval: 1.1--12.2) and lowest among studies conducted post-2014 (2.1/100 person-years, 95% prediction interval: 0.7--6.5). Conclusion Substantial HIV incidence among pregnant and breast-feeding women in SSA, even in the current era of combination HIV prevention and treatment, underscores the need for prevention tailored to high-risk pregnant and breast-feeding women.

Coronavirus disease 2019 and Pneumocystis jirovecii pneumonia: a diagnostic dilemma in HIV.

Abstract: COVID-19 and Pneumocystis jirovecii pneumonia: a diagnostic dilemma in HIV Coleman H1*, Snell LB2, Simons R1, Douthwaite ST3, Lee MJ1. Affiliations: 1. Harrison Wing, Department of HIV, Guys’ and St Thomas’ NHS Foundation Trust, London, UK 2. Centre for Clinical Infection & Diagnostics Research, King’s College London, London, UK 3. Department of Virology, Guys’ and St Thomas’ NHS Foundation Trust, London, UK

No overall change in the rate of weight gain after switching to an integrase-inhibitor in virologically suppressed adults with HIV.

Abstract: Objective:Excessive weight gain has been reported with integrase strand transfer inhibitors (INSTIs). We evaluated weight changes in virologically suppressed adults with HIV who switched from non-INSTI regimens to raltegravir (RAL)-containing or dolutegravir (DTG)-containing antiretroviral therapy.D

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells.

Abstract: Objective: Our objective was to investigate the mechanisms that govern natural killer (NK)-cell responses to HIV, with a focus on specific receptor--ligand interactions involved in HIV recognition by NK cells. Design and methods: We first performed a mass cytometry-based screen of NK-cell receptor expression patterns in healthy controls and HIV individuals. We then focused mechanistic studies on the expression and function of T cell immunoreceptor with Ig and ITIM domains (TIGIT). Results: The mass cytometry screen revealed that TIGIT is upregulated on NK cells of untreated HIV women, but not in antiretroviral-treated women. TIGIT is an inhibitory receptor that is thought to mark exhausted NK cells; however, blocking TIGIT did not improve anti-HIV NK-cell responses. In fact, the TIGIT ligands CD112 and CD155 were not upregulated on CD4 T cells in vitro or in vivo, providing an explanation for the lack of benefit from TIGIT blockade. TIGIT expression marked a unique subset of NK cells that express significantly higher levels of NK-cell-activating receptors (DNAM-1, NTB-A, 2B4, CD2) and exhibit a mature/adaptive phenotype (CD57, NKG2C, LILRB1, FcRγ, Syk). Furthermore, TIGIT NK cells had increased responses to mock-infected and HIV-infected autologous CD4 T cells, and to PMA/ionomycin, cytokine stimulation and the K562 cancer cell line. Conclusion: TIGIT expression is increased on NK cells from untreated HIV individuals. Although TIGIT does not participate directly to the response to HIV-infected cells, it marks a population of mature/adaptive NK cells with increased functional responses.

The switch from tenofovir disoproxil fumarate to tenofovir alafenamide determines weight gain in patients on rilpivirine-based regimen.

Abstract: OBJECTIVE To investigate whether the switch from tenofovir disoproxil fumarate/emtricitabine/rilpivirine (TDF/FTC/RPV) to tenofovir alafenamide (TAF)/FTC/RPV is associated with weight gain in people living with HIV (PLWHIV). DESIGN Retrospective single-centre study. METHODS All PLWHIV on TDF/FTC/RPV who switched to TAF/FTC/RPV from January 2017 to December 2018 were considered if they had at least two weight measures in the year before and two after the switch. The weight trend across the study was evaluated by a generalized linear model for repeated measures, with pair comparison performed by Bonferroni adjustment. RESULTS Two hundred and fifty-two patients on TDF/FTC/RPV were included, 65% men, mean age 51.2 years (±9.6), history of 18 (±18.2) years of HIV infection and CD4 T-cell count of 744 (±329) cells/μl. All had HIV-RNA 25 kg/m), lower CD4 T-cell count (≤500 cells/μl) and history of previous drug abuse. The frequency of BMI greater than 25 kg/m rose from 122/252 patients (48.4%), to 133/252 (52.8%) (P < 0.0001). CONCLUSION TAF appears to have an impact on weight gain, similarly to what observed in naive patients, also in experienced PLWHIV with good virologic control.

Clinical characteristics, comorbidities and outcomes among persons with HIV hospitalized with coronavirus disease 2019 in Atlanta, Georgia.

Abstract: BACKGROUND: There are limited data describing the presenting characteristics and outcomes among US persons with HIV (PWH) requiring hospitalization for coronavirus disease 2019 (COVID-19). METHODS: We performed a case series of all PWH sequentially admitted with COVID-19 from 8 March 2020 to 23 April 2020 at three hospitals in Atlanta, Georgia. Sociodemographic, clinical and HIV-associated characteristics were collected. RESULTS: Of 530 confirmed COVID-19 cases hospitalized during this period, 20 occurred among PWH (3.8%). The median age was 57 (Q1-Q3, 48-62) years, 65% were men, and 85% were non-Hispanic Black. Presenting median symptom duration was 5 (Q1-Q3, 3-7) days; cough (90%), fever (65%), malaise (60%) and dyspnea (60%) were most common. On admission, 40% of patients required oxygenation support and 65% had an abnormal chest radiograph. Median length of hospitalization was 5 (Q1-Q3, 4-12) days, 30% required intensive care, 15% required intubation, and 15% died. Median CD4 cell count prior to admission was 425 (Q1-Q3, 262-815) cells/µl and 90% of patients had HIV-1 RNA less than 200 copies/ml. Half of the patients had at least five comorbidities; hypertension (70%), dyslipidemia (60%) and diabetes (45%) were most prevalent. All three patients who died had CD4 cell count more than 200, HIV suppression and each had a total of five comorbidities. CONCLUSION: The multisite series in the Southern United States provides characteristics and early outcomes of hospitalized PWH with COVID-19. Nearly all patients had controlled HIV and a high comorbidity burden. Additional study of COVID-19 among PWH is needed to determine the role of age, comorbidities and HIV control in mediating COVID-19 presentation and its sequelae.

Productive HIV infection in astrocytes can be established via a nonclassical mechanism.

Abstract: Objective Astrocytes are proposed to be a critical reservoir of HIV in the brain. However, HIV infection of astrocytes is inefficient in vitro except for cell-to-cell transmission from HIV-infected cells. Here, we explore mechanisms by which cell-free HIV bypasses entry and postentry barriers leading to a productive infection. Methods HIV infection of astrocytes was investigated by a variety of techniques including transfection of CD4-expressing plasmid, treatment with lysosomotropic agents or using a transwell culture system loaded with HIV-infected lymphocytes. Infection was monitored by HIV-1 p24 in culture supernatants and integrated proviral DNA was quantified by Alu-PCR. Results Persistent HIV infection could be established in astrocytes by transfection of proviral DNA, transduction with VSV-G-pseudotyped viruses, transient expression of CD4 followed by HIV infection, or simultaneous treatment with lysosomotropic chloroquine or Tat-HA2 peptide with HIV infection. In absence of these treatments, HIV entered via endocytosis as seen by electronmicroscopy and underwent lysosomal degradation without proviral integration, indicating endocytosis is a dead end for HIV in astrocytes. Nevertheless, productive infection was observed when astrocytes were in close proximity but physically separated from HIV-infected lymphocytes in the transwell cultures. This occurred with X4 or dual tropic R5X4 viruses and was blocked by an antibody or antagonist to CXCR4. Conclusion A CD4-independent, CXCR4-dependent mechanism of viral entry is proposed, by which immature HIV particles from infected lymphocytes might directly bind to CXCR4 on astrocytes and trigger virus--cell fusion during or after the process of viral maturation. This mechanism may contribute to the formation of brain HIV reservoirs.

Development and Validation of the First Point-of-Care Assay to Objectively Monitor Adherence to HIV Treatment and Prevention in Real-Time in Routine Settings.

Abstract: Objective:HIV prevention and treatment studies demonstrate that pharmacologic adherence metrics are more accurate than self-report. Currently available metrics use liquid-chromatography/tandem-mass-spectrometry (LC-MS/MS), which is expensive and laboratory-based. We developed a specific and sensitiv

Risk factors for loss to follow-up from antiretroviral therapy programmes in low-income and middle-income countries.

Abstract: Introduction Loss to follow-up (LTFU) rates from antiretroviral treatment (ART) programmes in low- and middle-income countries (LMIC) are high, leading to poor treatment outcomes and onward transmission of HIV. Knowledge of risk factors is required to address LTFU. In this systematic review, risk factors for LTFU are identified and meta-analyses performed. Methods PubMed, Embase, Psycinfo and Cochrane were searched for studies that report on potential risk factors for LTFU in adults who initiated ART in LMICs. Meta-analysis was performed for risk factors evaluated by at least five studies. Pooled effect estimates and their 95% confidence intervals (95% CI) were calculated using random effect models with inverse variance weights. Risk of bias was assessed and sensitivity analyses performed. Results Eighty studies were included describing a total of 1 605 320 patients of which 87.4% from sub-Saharan Africa. The following determinants were significantly associated with an increased risk of LTFU in meta-analysis: male sex, older age, being single, unemployment, lower educational status, advanced WHO stage, low weight, worse functional status, poor adherence, nondisclosure, not receiving cotrimoxazole prophylactic therapy when indicated, receiving care at secondary level and more recent year of initiation. No association was seen for CD4 cell count, tuberculosis at baseline, regimen, and geographical setting. Conclusion There are several sociodemographic, clinical, patient behaviour, treatment-related and system level risk factors for LTFU from ART programs. Knowledge of risk factors should be used to better target retention interventions and develop tools to identify high-risk patients.

The People Living with HIV Stigma Index 2.0: generating critical evidence for change worldwide.

Abstract: Objective(s) To describe the process of updating the People Living with HIV (PLHIV) Stigma Index (Stigma Index) to reflect current global treatment guidelines and to better measure intersecting stigmas and resilience. Design Through an iterative process driven by PLHIV, the Stigma Index was revised, pretested, and formally evaluated in three cross-sectional studies. Methods Between March and October 2017, 1153 surveys (n = 377, Cameroon; n = 390, Senegal; n = 391, Uganda) were conducted with PLHIV at least 18 years old who had known their status for at least 1 year. PLHIV interviewers administered the survey on tablet computers or mobile phones to a diverse group of purposively sampled respondents recruited through PLHIV networks, community-based organizations, HIV clinics, and snowball sampling. Sixty respondents participated in cognitive interviews (20 per country) to assess if questions were understood as intended, and eight focus groups (Uganda only) assessed relevance of the survey, overall. Results The Stigma Index 2.0 performed well and was relevant to PLHIV in all three countries. HIV-related stigma was experienced by more than one-third of respondents, including in HIV care settings. High rates of stigma experienced by key populations (such as MSM and sex workers) impeded access to HIV services. Many PLHIV also demonstrated resilience per the new PLHIV Resilience Scale. Conclusion The Stigma Index 2.0 is now more relevant to the current context of the HIV/AIDS epidemic and response. Results will be critical for addressing gaps in program design and policies that must be overcome to support PLHIV engaging in services, adhering to antiretroviral therapy, being virally suppressed, and leading healthy, stigma-free lives.

High levels of genetically intact HIV in HLA-DR+ memory T cells indicates their value for reservoir studies.

Abstract: Objective The contribution of HLA-DR+ memory CD4 T cells to the HIV reservoir during prolonged antiretroviral therapy is unclear as these cells are commonly excluded when assessing for replication-competent HIV. To address this issue, we examined the distribution of genetically intact HIV DNA within HLA-DR- and HLA-DR+ memory CD4 T cells and the RNA transcriptional profile of these cells during antiretroviral therapy. Design/methods Full-length DNA sequencing was used to examine the HIV DNA landscape within HLA-DR+ and HLA-DR- memory CD4 T cells. RNA quantification and sequencing was used to interrogate the relationship between HLA-DR status and HIV RNA transcription. Results HLA-DR+ CD4 T cells contained a high frequency of genetically intact HIV genomes, contributing over half of the genetically intact viral sequences to the reservoir. Expansions of genetically identical sequences were identified in all T-cell subsets, indicating that cellular proliferation maintains genetically intact and defective viral DNA during therapy. Intracellular HIV RNA levels in HLA-DR+ and HLA-DR- T cells were not statistically different by either long terminal repeat quantitative PCR quantification or single-genome RNA sequencing of the p6-RT region. Conclusion The high proportion of intact viral DNA sequences in the proliferative HLA-DR+ subset suggests they are critical in maintaining HIV infection during effective therapy. As such, these cells should be included in any immune intervention targeting HIV during effective therapy.

The impact of localized implementation: determining the cost-effectiveness of HIV prevention and care interventions across six United States cities.

Abstract: Author(s): Krebs, Emanuel; Zang, Xiao; Enns, Benjamin; Min, Jeong E; Behrends, Czarina N; Del Rio, Carlos; Dombrowski, Julia C; Feaster, Daniel J; Gebo, Kelly A; Golden, Matthew; Marshall, Brandon DL; Metsch, Lisa R; Schackman, Bruce R; Shoptaw, Steven; Strathdee, Steffanie A; Nosyk, Bohdan; Localized Economic Modeling Study Group | Abstract: ObjectiveEffective interventions to reduce the public health burden of HIV/AIDS can vary in their ability to deliver value at different levels of scale and in different epidemiological contexts. Our objective was to determine the cost-effectiveness of HIV treatment and prevention interventions implemented at previously documented scales of delivery in six US cities with diverse HIV microepidemics.DesignDynamic HIV transmission model-based cost-effectiveness analysis.MethodsWe identified and estimated previously documented scale of delivery and costs for 16 evidence-based interventions from the US CDC's Compendium of Evidence-Based Interventions and Best Practices for HIV Prevention. Using a model calibrated for Atlanta, Baltimore, Los Angeles, Miami, New York City and Seattle, we estimated averted HIV infections, quality-adjusted life years (QALY) gained and incremental cost-effectiveness ratios (healthcare perspective; 3% discount rate, 2018$US), for each intervention and city (10-year implementation) compared with the status quo over a 20-year time horizon.ResultsIncreased HIV testing was cost-saving or cost-effective across cities. Targeted preexposure prophylaxis for high-risk MSM was cost-saving in Miami and cost-effective in Atlanta ($6123/QALY), Baltimore ($18 333/QALY) and Los Angeles ($86 117/QALY). Interventions designed to improve antiretroviral therapy initiation provided greater value than other treatment engagement interventions. No single intervention was projected to reduce HIV incidence by more than 10.1% in any city.ConclusionCombination implementation strategies should be tailored to local epidemiological contexts to provide the most value. Complementary strategies addressing factors hindering access to HIV care will be necessary to meet targets for HIV elimination in the United States.

Global status of Toxoplasma gondii infection and associated risk factors in people living with HIV.

Abstract: Objective Toxoplasma infection remains as the most common cause of focal brain lesions among people living with HIV (PLHIV) despite the decline in opportunistic infections with the introduction of antiretroviral treatment. This study was conducted to provide a summary of evidence about the seroprevalence of Toxoplasma gondii and prevalence of active T. gondii infection and associated risk factors among PLHIV. Design Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Scopus, PubMed, Science Direct and EMBASE were searched from 1997 to July 2018. All peer-reviewed original research articles describing T. gondii infection among PLHIV with different diagnostic methods were included. Methods Incoherence and heterogeneity between studies were quantified by I index and Cochran's Q test. Publication and population bias were assessed with funnel plots and Egger's regression asymmetry test. All statistical analyses were performed using StatsDirect. Results In total, 111 studies from 37 countries assessing 66 139 blood samples were included in this study. The pooled prevalence of T. gondii infection among PLHIV was 3.24% by IgM and 26.22% by molecular methods using the random-effects model. Pooled seroprevalence of T. gondii by IgG was 44.22%. There was a relationship between Toxoplasma prevalence and sex, raw meat consumption, contact with cat and knowledge about toxoplasmosis. Conclusion High Toxoplasma seroprevalence among PLHIV observed in this study emphasizes the need for implementing screening and prophylaxis tailored to the local context. Owing to the serious and significant clinical manifestations of the parasite in case of reactivation, early identification of seropositivity for initiating prophylaxis among those with a CD4 cell count of less than 200 cells/ml is recommended.

Presence of asymptomatic cytomegalovirus and Epstein--Barr virus DNA in blood of persons with HIV starting antiretroviral therapy is associated with non-AIDS clinical events.

Abstract: Author(s): Gianella, Sara; Moser, Carlee; Vitomirov, Andrej; McKhann, Ashley; Layman, Laura; Scott, Brianna; Caballero, Gemma; Lada, Steven; Bosch, Ronald J; Hoenigl, Martin; Lurain, Nell; Landay, Alan; Lederman, Michael M; Hunt, Peter W; Smith, Davey | Abstract: BACKGROUND:Even with antiretroviral therapy (ART), persons with HIV (PWH) experience increased morbidity/mortality. Cytomegalovirus (CMV) and Epstein-Barr-Virus (EBV) co-infections likely exacerbate inflammatory-related diseases. OBJECTIVE:To determine if presence of detectable CMV or EBV DNA in peripheral blood mononuclear cells (PBMC) is associated with non-AIDS events among PWH receiving modern ART. DESIGN:We performed a case-control study of PWH starting ART and HIV-suppressed at year 1 and thereafter, 140 cases who experienced non-AIDS events and 305 matched controls. Events included myocardial infarction, stroke, malignancy, serious bacterial infection or death. METHODS:Blood samples were studied pre-ART, 1-year post-ART and pre-event. Controls had an event-free follow-up equal or greater than cases. CMV and EBV levels were measured in PBMC. Conditional logistic regression analysis assessed associations and adjusted for relevant covariates; Spearman's correlations compared CMV and EBV levels with other biomarkers. RESULTS:CMV was detected in PBMC of 25% of participants, EBV was detected in g 90%. Higher EBV levels were associated with increased risk of events at all time points (odds ratio (OR) per one IQR = 1.5-1.7, all p l 0.009). At year 1, detectable CMV was associated with increased risk of events in most adjusted models (OR = 1.4-1.8, p-values ranging 0.03-0.17). Higher levels of CMV and EBV correlated with multiple inflammatory markers and lower CD4/CD8 ratio. CONCLUSIONS:In PWH starting ART, CMV and EBV in PBMC were associated with development of non-AIDS events. Clinical trials will be needed to understand causal mechanisms and ways to interrupt them.

Investigating the effect of antiretroviral switch to tenofovir alafenamide on lipid profiles in people living with HIV.

Abstract: BACKGROUND Whilst reporting improved renal and bone safety profiles, studies have noted changes in lipid profiles among people living with HIV (PLWH) receiving antiretroviral therapy (ART) switching away from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF). We aimed to characterize changes in lipids observed after switching to TAF-containing ART in a real-world setting. METHODS A prospective study on PLWH enrolled in the UCD-ID Cohort study who switched to TAF-containing ART. Routine laboratory data [including lipids (total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides], ART history and use of lipid-lowering therapy (LLT) were analysed preswitch and postswitch to TAF. Dyslipidaemia was classified according to the National Cholesterol Education Program-Adult Panel III (NCEP-ATP III). Change in lipid parameters and change in the proportion of individuals with dyslipidaemia postswitch was assessed using the paired t-test and the Stuart--Maxwell test, respectively. RESULTS Of 775 PLWH enrolled in the cohort, 238 switched to TAF containing ART, of whom 194 had both preswitch and postswitch lipids measured a median (IQR) 24 (14-41) weeks postswitch to TAF. TC, LDL, HDL, triglycerides and TC : HDL ratio significantly increased postswitch [mean change (SE) mmol/l; +0.37 (0.06), P < 0.001; +0.25 (0.06), P < 0.001; +0.05 (0.02), P = 0.003, +0.13 (0.07), P = 0.02, and +0.16 (0.08), P = 0.013) respectively]. There were significant increases in the proportions of PLWH with more severe dyslipidaemia postswitch across TC and LDL (both P < 0.001). CONCLUSION These data suggest clinically relevant, worsening lipid profiles postswitch to TAF, with a larger proportion of PLWH exceeding recommended lipid thresholds postswitch. How these changes will impact on cardiovascular risk or need for LLT remains to be determined.

Viral suppression and factors associated with failure to achieve viral suppression among pregnant women in South Africa.

Abstract: Objective To describe viral load levels among pregnant women and factors associated with failure to achieve viral suppression (viral load ≤50 copies/ml) during pregnancy. Design Between 1 October and 15 November 2017, a cross-sectional survey was conducted among 15-49-year-old pregnant women attending antenatal care (ANC) at 1595 nationally representative public facilities. Methods Blood specimens were taken from each pregnant woman and tested for HIV. Viral load testing was done on all HIV-positive specimens. Demographic and clinical data were extracted from medical records or self-reported. Survey logistic regression examined factors associated with failure to achieve viral suppression. Result Of 10 052 HIV-positive participants with viral load data, 56.2% were virally suppressed. Participants initiating antiretroviral therapy (ART) prior to pregnancy had higher viral suppression (71.0%) by their third trimester compared with participants initiating ART during pregnancy (59.3%). Booking for ANC during the third trimester vs. earlier: [adjusted odds ratio (AOR) 1.8, 95% confidence interval (CI):1.4-2.3], low frequency of ANC visits (AOR for 2 ANC visits vs. ≥4 ANC visits: 2.0, 95% CI:1.7-2.4), delayed initiation of ART (AOR for ART initiated at the second trimester vs. before pregnancy:2.2, 95% CI:1.8-2.7), and younger age (AOR for 15-24 vs. 35-49 years: 1.4, 95% CI:1.2-1.8) were associated with failure to achieve viral suppression during the third trimester. Conclusion Failure to achieve viral suppression was primarily associated with late ANC booking and late initiation of ART. Efforts to improve early ANC booking and early ART initiation in the general population would help improve viral suppression rates among pregnant women. In addition, the study found, despite initiating ART prior to pregnancy, more than one quarter of participants did not achieve viral suppression in their third trimester. This highlights the need to closely monitor viral load and strengthen counselling and support services for ART adherence.

COVID-19 attack rate in HIV-infected patients and in PrEP users.

Abstract: OBJECTIVE: A new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) emerged in China during late 2019 and resulted in the coronavirus disease 2019 (COVID-19) pandemic which peaked in France in March-April 2020. Immunodeficiency, precariousness and promiscuity could increase the risk of COVID-19 in HIV-infected patients and in preexposure prophylaxis (PrEP) users. No epidemiological data are available in these two populations. We report COVID-19 attack rate in HIV-infected patients and in PrEP users in the Rhone department, France, and compared it with the general population. DESIGN: Retrospective analysis of a laboratory database. METHODS: COVID-19 testing strategy in France was centered on symptomatic infections, hospitalized patients and symptomatic healthcare workers while most asymptomatic cases were not confirmed. SARS-CoV-2 positivity rate on PCR assays and COVID-19 attack rate were determined in HIV-infected patients and in PrEP users. COVID-19 attack rate in the general population was estimated from health authorities' database and demographic data. A corrected attack rate taking into account the laboratory representativeness was calculated. RESULTS: From March to April 2020, 24 860 samples from 19 113 patients (HIV-infected 77, PrEP users 27, others 19 009) were assessed for SARS-CoV-2 PCR assay. The positivity rate appeared similar in HIV-infected patients (15.6%), in PrEP users (14.8%) and in other patients (19.1%). The crude/corrected COVID-19 attack rate appeared similar in HIV-infected patients (0.31/0.38%) and in PrEP users (0.38/0.42%), and of the same order as the estimated attack rate in the general population (0.24%). CONCLUSION: The risk of symptomatic COVID-19 in France appeared similar in HIV-infected patients and in PrEP users compared with the general population.

Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients.

Abstract: BACKGROUND Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in AMBER (NCT02431247). METHODS Treatment-naive, HIV-1-positive adults [screening plasma viral load ≥1000 copies/ml; CD4 cell count >50 cells/μl) were randomized (1 : 1) to D/C/F/TAF (N = 362) or D/C plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) (N = 363) over at least 48 weeks. After week 48, patients could continue on or switch to D/C/F/TAF in an open-label extension phase until week 96. RESULTS At week 96, D/C/F/TAF exposure was 626 patient-years (D/C/F/TAF arm) and 109 patient-years (control arm post switch), week 96 virologic suppression (viral load <50 copies/ml; FDA-Snapshot, from baseline) was 85.1% (308/362) (D/C/F/TAF) and 83.7% (304/363) (control). Week 96 virologic failure (viral load ≥50 copies/ml; FDA-Snapshot) was 5.5% (20/362) and 4.4% (16/363), respectively. No darunavir, primary protease inhibitor or tenofovir resistance-associated mutations (RAMs) were observed post baseline. In one patient in each arm, an M184I and/or V RAM was detected. Few adverse event-related discontinuations (3% D/C/F/TAF; <1% control post switch) and no deaths occurred on D/C/F/TAF. Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the control arm post switch. Increases in total-cholesterol/high-density-lipoprotein--cholesterol rtio at week 96 were +0.25 versus baseline (D/C/F/TAF) and +0.24 versus switch (control). CONCLUSION At week 96, D/C/F/TAF resulted in high virologic response and low virologic failure rates, with no resistance development to darunavir or TAF/TDF. Bone, renal and lipid safety were consistent with known D/C/F/TAF component profiles. Control arm safety post switch was consistent with the D/C/F/TAF arm. AMBER week 96 results confirm the efficacy, high barrier to resistance and bone/renal safety benefits of D/C/F/TAF for treatment-naive patients.

Diverging trends in incidence of HIV versus other sexually transmitted infections in HIV-negative MSM in Amsterdam.

Abstract: OBJECTIVES We investigated changes in incidence rates of HIV and sexually transmitted infections (STIs) and trends in sexual behavior in MSM from 2009 to 2017. DESIGN Open prospective cohort study. METHODS HIV-negative MSM enrolled in the Amsterdam Cohort Studies were included. Participants semiannually completed a questionnaire on sexual behavior and were tested for HIV-1, syphilis, and urethral, anal and pharyngeal chlamydia and gonorrhea. Time trends in incidence rates were analyzed using exponential survival models. RESULTS During follow-up, 42 of 905 MSM acquired HIV. The HIV incidence rate was 1.9/100 person-years [95% confidence interval (CI) 1.0-3.7] in 2009 and decreased to 0.5/100 person-years (95% CI 0.2-1.4) in 2017 (P = 0.03). The largest decrease was observed in participants aged at least 35 years (P = 0.005), while the trend remained stable in 18-34 year olds (P = 0.4). The incidence rate for any bacterial STI was 16.8/100 person-years (95% CI 13.4-21.0) in 2010, and increased to 33.1/100 person-years (95% CI 29.0-37.9) in 2017 (P < 0.001). Between 2009 and 2017, the percentage reporting condomless anal sex with casual partners increased from 26.9 to 39.4% (P < 0.001), and the mean number of casual partners from eight (95% CI 8-8) to 11 (95% CI 10-11) (P = 0.05). Condomless anal sex with steady partner(s) remained stable over time (P = 0.5). CONCLUSION Among MSM in Amsterdam, incidence rates of HIV versus other STI show diverging trends. The increase in STI incidence coincides with a decrease in condom use with casual partners. The decrease in HIV incidence, despite increased sexual risk behavior, suggests that other HIV prevention methods have been successful in reducing HIV transmission among MSM.

Tenofovir alafenamide vs. tenofovir disoproxil fumarate: an updated meta-analysis of 14 894 patients across 14 trials.

Abstract: Background Both tenofovir disoproxil fumarate (TDF)/emtricitabine and tenofovir alafenamide (TAF)/emtricitabine demonstrate excellent efficacy and safety overall, but concerns remain over specific changes in markers of bone and renal function. Lower plasma tenofovir concentrations are seen with TAF and in unboosted regimens. We assess TAF vs. TDF safety with and without booster coformulation. Methods A previous systematic review was updated with recent clinical trials. TAF vs. TDF efficacy and safety were compared in boosted and unboosted subgroups. Efficacy was measured by viral suppression. Key safety endpoints included all adverse events, serious adverse events, Grades 3-4 adverse events and adverse event discontinuation. Further specific renal and bone markers were also assessed. Results A total of 14 clinical trials comparing TDF and TAF regimens were identified. A significant difference (P = 0.0004) in efficacy was shown in the boosted subgroup in favour of TAF, but no difference was seen in the unboosted subgroup. There were no significant differences between TAF and TDF for any of the key safety endpoints analysed. No differences were seen for the bone markers analysed. No difference was found for renal tubular events. There was a difference in risk for discontinuation due to renal adverse events when boosted (P = 0.03), but none when unboosted. Conclusion Across all main safety endpoints, no differences between TAF and TDF are seen. Boosted TDF regimens were associated with lesser comparative efficacy than boosted TAF and a higher risk of renal event discontinuation. However, modern antiretroviral regimens are more commonly unboosted. This study finds no difference in efficacy or safety in unboosted TAF vs. TDF.

Mortality and causes of death in people living with HIV in the era of combination antiretroviral therapy compared with the general population in Japan.

Abstract: Objectives To determine the mortality and causes of death in people living with HIV (PLHIV) in Japan. Design A prospective cohort study at AIDS Clinical Center, Tokyo, which treats approximately 10% of PLHIV in care in Japan. Methods Either PLHIV who visited our center for the first time between January 2005 and December 2014 or PLHIV who started their regular visit before January 2005 and visited us between January and March 2005 were included and followed by the end of 2016. Causes of death were defined according to the CoDe protocol. Results Two thousand, seven hundred and ninety-seven PLHIV were analysed with total of 18 858 person-years of follow-up, which constitutes 14% of the estimated number of PLHIV in care in Japan. One hundred and sixty-five (5.9%) PLHIV died with all-cause mortality rate of 8.75 per 1000 person-years. All-cause mortality rate for PLHIV in care in Japan was estimated to be 8.75 per 1000 person-years (95% CI 5.53-12.0). Among causes of death, AIDS-defining illnesses accounted for 39% and malignancy contributed to 47%. Standardized mortality ratio (SMR) for all-cause mortality, malignancy-related mortality, and suicide were 5.96 (95% CI 5.05-6.87), 7.76 (95% CI 6.02-9.51), and 3.24 (95% CI 1.54-4.94), respectively. Even among the patients who were diagnosed early or without history of AIDS, SMR was four times higher than the general population. Conclusion Mortality of PLHIV, even among those with early diagnosis, is substantially higher than that of the general population in Japan, highlighting the importance of further efforts towards prevention, early diagnosis and prompt treatment initiation.

Oral preexposure prophylaxis continuation, measurement and reporting

Abstract: Objective The aim of this study was to appropriately plan for rollout and monitor impact of oral preexposure prophylaxis (PrEP) It is important to understand PrEP continuation and come to a consensus on how best to measure PrEP continuation This study reviews data on PrEP continuation to document how it is reported, and to compare continuation over time and across populations Design A systematic review and meta-analysis Methods We searched MEDLINE, Embase and Global Health and reviewed abstracts from HIV conferences from 2017 to 2018 for studies reporting primary data on PrEP continuation Findings were summarized along a PrEP cascade and continuation was presented by population at months 1, 6 and 12, with random-effects meta-analysis Results Of 2578 articles and 596 abstracts identified, 41 studies were eligible covering 22 034 individuals Continuation data were measured and reported inconsistently Results showed high discontinuation at month 1 and persistent discontinuation at later time points in many studies Pooled continuation estimates were 66% at month 1 [n = 5348; 95% confidence interval (95% CI): 48-82], 63% at month 6 (n = 13 629; 95% CI: 48-77) and 71% at month 12 (n = 14 933; 95% CI: 60-81; higher estimate than previous timepoints due to inclusion of different studies) Adequate data were not available to reliably compare estimates across populations Conclusion This review found that discontinuation at one month was high, suggesting PrEP initiations may be a poor measure of effectiveness Continuation declined further over time in many studies, indicating existing cross-sectional indicators may not be adequate to understand PrEP use patterns Studies do not measure continuation consistently, and consensus is needed

Factors associated with hospital admission for COVID-19 in HIV patients.

Abstract: This study reports on hospital admission and outcomes of 69 HIV-infected individuals who were diagnosed with SARS-CoV-2 infection between February and May 2020, in a network of Italian centres. Patients' characteristics and median days between symptoms and diagnosis were similar by hospital admission, whereas admitted patients had lower nadir CD4 cells and current lymphocytes count. These values were also correlated to worse COVID-19 outcome. Antiretroviral drugs did not seem to be associated with disease severity.

Comorbidities of HIV infection: role of Nef-induced impairment of cholesterol metabolism and lipid raft functionality.

Abstract: Combination antiretroviral therapy has dramatically changed the outcome of HIV infection, turning it from a death sentence to a manageable chronic disease. However, comorbidities accompanying HIV infection, such as metabolic and cardio-vascular diseases, as well as cognitive impairment, persist despite successful virus control by combination antiretroviral therapy and pose considerable challenges to clinical management of people living with HIV. These comorbidities involve a number of pathological processes affecting a variety of different tissues and cells, making it challenging to identify a common cause(s) that would link these different diseases to HIV infection. In this article, we will present evidence that impairment of cellular cholesterol metabolism may be a common factor driving pathogenesis of HIV-associated comorbidities. Potential implications for therapeutic approaches are discussed.

Plasma and antibody glycomic biomarkers of time to HIV rebound and viral setpoint.

Abstract: Objective HIV cure research urgently needs to identify pre-analytic treatment interruption (ATI) biomarkers of time-to-viral-rebound and viral setpoint to mitigate the risk of ATI and accelerate development of a cure. We previously reported that galactosylated IgG glycans, G2, negatively correlate with cell-associated HIV DNA and RNA during antiretroviral therapy (ART). We hypothesized that this and other plasma glycomic traits can predict time-to-viral-rebound and viral setpoint upon ART cessation. Design We profiled the circulating glycomes (plasma and bulk IgG) of two geographically distinct cohorts: Philadelphia Cohort - 24 HIV-infected, ART-suppressed individuals who had participated in an open-ended ATI study without concurrent immunomodulatory agents. Johannesburg Cohort - 23 HIV-infected, ART-suppressed individuals who had participated in a 2-week ATI. Methods Capillary electrophoresis and lectin microarray were used for glycomic analyses. Cox proportional-hazards model and log-rank test were used for statistical analyses. Results Higher pre-ATI levels of the IgG glycan, G2, were significantly associated with a longer time-to-viral-rebound (hazard ratio = 0.12, P = 0.05). In addition to G2, we identified several predictive glycomic traits in plasma, for example, levels of FA2BG1, a non-sialylated, core-fucosylated glycan, associated with a longer time-to-viral-rebound (hazard ratio = 0.023, P = 0.05), whereas FA2G2S1, a sialylated glycan, associated with a shorter time-to-viral-rebound (hazard ratio = 24.1, P = 0.028). Additionally, pre-ATI plasma glycomic signatures associated with a lower viral setpoint, for example, T-antigen (Galβ1-3GalNAc) (r = 0.75, P = 0.0007), or a higher viral setpoint, for example, polylactosamine (r = -0.58, P = 0.01). These results were initially validated in the Johannesburg Cohort. Conclusion We describe first-in-class, non-invasive, plasma and IgG glycomic biomarkers that inform time-to-viral-rebound and viral setpoint in two geographically distinct cohorts.