Publications by authors named "Mauro Schechter"

118 Publications

Pre-Exposure Prophylaxis Failure With a Multiple Drug-Resistant HIV-1 Clade C Virus in Brazil.

J Acquir Immune Defic Syndr 2022 Feb;89(2):e16

Projeto Praça Onze, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil.

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http://dx.doi.org/10.1097/QAI.0000000000002826DOI Listing
February 2022

Broadly neutralizing antibody responses in the longitudinal primary HIV-1 infection Short Pulse Anti-Retroviral Therapy at Seroconversion cohort.

AIDS 2021 11;35(13):2073-2084

Department of Infectious Diseases, King's College London, Guy's Hospital, Great Maze Pond, London, UK.

Objective: Development of immunogens that elicit an anti-HIV-1 broadly neutralizing antibody (bnAb) response will be a key step in the development of an effective HIV-1 vaccine. Although HIV-1 bnAb epitopes have been identified and mechanisms of action studied, current HIV-1 envelope-based immunogens do not elicit HIV-1 bnAbs in humans or animal models. A better understanding of how HIV-1 bnAbs arise during infection and the clinical factors associated with bnAb development may be critical for HIV-1 immunogen design efforts.

Design And Methods: Longitudinal plasma samples from the treatment-naive control arm of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) primary HIV-1 infection cohort were used in an HIV-1 pseudotype neutralization assay to measure the neutralization breadth, potency and specificity of bnAb responses over time.

Results: In the SPARTAC cohort, development of plasma neutralization breadth and potency correlates with duration of HIV infection and high viral loads, and typically takes 3-4 years to arise. bnAb activity was mostly directed to one or two bnAb epitopes per donor and more than 60% of donors with the highest plasma neutralization having bnAbs targeted towards glycan-dependent epitopes.

Conclusion: This study highlights the SPARTAC cohort as an important resource for more in-depth analysis of bnAb developmental pathways.
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http://dx.doi.org/10.1097/QAD.0000000000002988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505148PMC
November 2021

Evaluating the impact of policies recommending PrEP to subpopulations of men and transgender women who have sex with men based on demographic and behavioral risk factors.

PLoS One 2019 19;14(9):e0222183. Epub 2019 Sep 19.

Asociación Civil Selva Amazónica, Iquitos, Peru.

Introduction: Developing guidelines to inform the use of antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention in resource-limited settings must necessarily be informed by considering the resources and infrastructure needed for PrEP delivery. We describe an approach that identifies subpopulations of cisgender men who have sex with men (MSM) and transgender women (TGW) to prioritize for the rollout of PrEP in resource-limited settings.

Methods: We use data from the iPrEx study, a multi-national phase III study of PrEP for HIV prevention in MSM/TGW, to build statistical models that identify subpopulations at high risk of HIV acquisition without PrEP, and with high expected PrEP benefit. We then evaluate empirically the population impact of policies recommending PrEP to these subpopulations, and contrast these with existing policies.

Results: A policy recommending PrEP to a high risk subpopulation of MSM/TGW reporting condomless receptive anal intercourse over the last 3 months (estimated 3.3% 1-year HIV incidence) yields an estimated 1.95% absolute reduction in 1-year HIV incidence at the population level, and 3.83% reduction over 2 years. Importantly, such a policy requires rolling PrEP out to just 59.7% of MSM/TGW in the iPrEx population. We find that this policy is identical to that which prioritizes MSM/TGW with high expected PrEP benefit. It is estimated to achieve nearly the same reduction in HIV incidence as the PrEP guideline put forth by the US Centers for Disease Control, which relies on the measurement of more behavioral risk factors and which would recommend PrEP to a larger subset of the MSM/TGW population (86% vs. 60%).

Conclusions: These findings may be used to focus future mathematical modelling studies of PrEP in resource-limited settings on prioritizing PrEP for high-risk subpopulations of MSM/TGW. The statistical approach we took could be employed to develop PrEP policies for other at-risk populations and resource-limited settings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222183PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752862PMC
March 2020

Impact of Estimated Pre-Exposure Prophylaxis (PrEP) Adherence Patterns on Bone Mineral Density in a Large PrEP Demonstration Project.

AIDS Res Hum Retroviruses 2019 09 19;35(9):788-793. Epub 2019 Jun 19.

Department of Medicine, University of California, San Francisco, San Francisco, California.

Bone mineral density (BMD) declines due to tenofovir-containing pre-exposure prophylaxis (PrEP) have varied among PrEP demonstration projects, potentially related to variable adherence. Characterization of BMD changes in highly adherent individuals, estimated via tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS), can assist clinicians when counseling patients. Cisgender men who have sex with men and transwomen in the optional dual-energy X-ray absorptiometry (DXA) substudy of a large, international, open-label PrEP demonstration project, the iPrEx-open-label extension (OLE) study underwent DXA scans and DBS collection every 24 weeks, with average weekly dosing adherence patterns (2, 4, and 7 doses/week) estimated from validated TFV-DP cut-offs. The mean percent BMD change was estimated in strata of average weekly adherence by using a linear mixed-effects model to calculate the BMD decline in highly adherent individuals on PrEP for the first time. DXA/DBS data were available for 254 individuals over a median of 24 weeks in iPrEx-OLE from June 2011 to December 2013. The percent decline in spine BMD was monotonically associated with strata of increasing average weekly adherence ( < .001 trend); the value for trends using hip BMD measurements was .07. Individuals with estimated daily adherence experienced a 1.2% decrease in spine BMD and a 0.5% drop in hip BMD. In highly adherent PrEP users, we found a lower-than-expected drop in BMD when compared with previous studies. This drop is likely not clinically significant for most PrEP users. However, for those at the highest risk of fracture who plan prolonged PrEP use, alternate PrEP strategies could be considered.
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http://dx.doi.org/10.1089/AID.2018.0297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735322PMC
September 2019

Reply to Kojima and Klausner.

Clin Infect Dis 2018 10;67(9):1469-1470

Division of Infectious Diseases, University of Pittsburgh, School of Medicine, Pennyslvania.

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http://dx.doi.org/10.1093/cid/ciy345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186858PMC
October 2018

Prioritization of antiretroviral therapy in patients with high CD4 counts, and retention in care: lessons from the START and Temprano trials.

Authors:
Mauro Schechter

J Int AIDS Soc 2018 02;21(2)

Principal Investigator, Projeto Praça Onze, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Initiation of antiretroviral therapy is not a once in a lifetime opportunity. In some resource constrained settings financial limitations make it necessary to prioritize treatment initiation for some groups of patients. In developed countries, there are patients who are reluctant to initiate treatment. Subgroup analysis of the START trial can inform recommendations for which patients with CD4 counts >500 cells mm temporary postponement of treatment initiation is safer. These include individuals aged <30 years and/or with CD4/CD8 ratio of >0.8 and/or viral load of <5000. This is because these individuals are at very low risk of disease progression in the subsequent 2 to 3 years, the risk is minimally diminished by antiretroviral therapy and is virtually identical in the first 18 months of therapy regardless of treatment initiation. In addition, asymptomatic young individuals are at higher risk of loss-to-follow and of low adherence to treatment, and those with low viral loads are less likely to transmit the virus. In addition, lessons from START and Temprano can help design trials to investigate strategies to decrease losses-to-follow-up, while minimizing risks to patients.
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http://dx.doi.org/10.1002/jia2.25077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810323PMC
February 2018

Metabolic Effects of Preexposure Prophylaxis With Coformulated Tenofovir Disoproxil Fumarate and Emtricitabine.

Clin Infect Dis 2018 07;67(3):411-419

Gladstone Institute of Virology, California.

Background: Antiretroviral drugs have been associated with changes in lipids, fat mass and dat distribution. Tenofovir disoproxil fumarate (TDF) has been shown to have a more favorable metabolic profile than other drugs in its class. However, the metabolic effects of TDF in preexposure prophylaxis (PrEP) are unknown.

Methods: We evaluated the effects of TDF/emtricitabine (FTC) on lipids and body composition in a blinded, placebo-controlled PrEP trial. Participants enrolled in a metabolic subcohort (N = 251, TDF/FTC; N = 247, placebo) consented to fasting lipid panels, dual-energy X-ray absorptiometry scans for body composition, and pharmacologic testing of drug metabolites at baseline and every 24 weeks thereafter.

Results: Lean body mass was stable and unaffected by TDF/FTC. Body weight increased in both groups but was lower on TDF/FTC through week 72. This difference was explained by lower fat accumulation on TDF/FTC. The net median percent difference (standard error, P value) for TDF/FTC vs placebo at week 24 was -0.8% (0.4%, P = .02), +0.3% (0.4%, P = .46), and -3.8% (1.4%, P = .009) for total, lean, and fat mass, respectively. There was no apparent differential regional fat accumulation on TDF/FTC. Decreases in cholesterol, but not triglycerides, were seen in TDF/FTC participants, with detectable drug levels compared to placebo.

Conclusions: TDF/FTC for PrEP showed cholesterol reductions and appeared to transiently suppress the accumulation of weight and body fat compared to placebo. There was no evidence of altered fat distribution or lipodystrophy during daily oral TDF/FTC PrEP.

Clinical Trials Registration: NCT00458393.
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http://dx.doi.org/10.1093/cid/ciy083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051460PMC
July 2018

Which HIV-infected adults with high CD4 T-cell counts benefit most from immediate initiation of antiretroviral therapy? A post-hoc subgroup analysis of the START trial.

Lancet HIV 2018 04 16;5(4):e172-e180. Epub 2018 Jan 16.

School of Public Health, University of Minnesota, Minneapolis, MN, USA.

Background: Immediate initiation of antiretroviral therapy (ART) in asymptomatic adults with CD4 counts higher than 500 cells per μL, as recommended, might not always be possible in resource-limited settings. We aimed to identify subgroups of individuals who would benefit most from immediate treatment.

Methods: The START trial was a randomised controlled trial in asymptomatic, HIV-positive adults previously untreated with ART. Participants with CD4 counts higher than 500 cells per μL were randomly assigned to receive immediate ART or to defer ART until CD4 counts were lower than 350 cells per μL. The primary endpoint of the study was serious AIDS-defining illnesses or death from AIDS and serious non-AIDS illnesses or non-AIDS-related death. In this post-hoc analysis, we estimated event rates and absolute risk reduction with immediate versus deferred ART, overall and by subgroup. Subgroups were prespecified in the study protocol or formed post hoc on the basis of baseline characteristics associated with morbidity and mortality in people with HIV. For continuous characteristics, approximate terciles were chosen as subgroup cutoff points, unless different cutoffs were clinically meaningful (eg, age ≥50 years). We estimated the number needed to treat immediately with ART for 1 year to prevent one primary event. Heterogeneity in the absolute risk reduction between subgroups was assessed with bootstrap tests. The START trial is registered with ClinicalTrials.gov, number NCT00867048.

Findings: Between April 15, 2009, and Dec 23, 2013, we enrolled 4684 participants from 35 countries across five continents, of whom 2325 were assigned to immediate ART and 2359 were assigned to deferred ART. The primary endpoint occurred in 42 participants in the immediate ART group (0·58 events per 100 person-years) and 100 participants in the deferred ART group (1·37 events per 100 person-years). The absolute risk reduction was 0·80 (95% CI 0·48-1·13) per 100 person-years with immediate treatment, and the number needed to treat immediately to prevent one event was 126 (95% CI 89-208). Significant heterogeneity in absolute risk reduction with immediate ART was found across subgroups according to age (p=0·0022), CD4 to CD8 ratio (p=0·0007), and plasma HIV RNA viral load (p=0·033) at baseline. The highest absolute risk reductions and the lowest numbers needed to treat were found in participants aged 50 years or older, those with CD4 to CD8 ratios of less than 0·5, and those with plasma HIV RNA viral loads of 50 000 copies per mL or higher.

Interpretation: Asymptomatic, ART-naive adults with CD4 counts higher than 500 cells per μL who are older, have a low CD4 to CD8 ratio, or a high plasma HIV RNA viral load benefit most from immediate initiation of ART and should be prioritised for treatment.

Funding: US National Institute of Allergy and Infectious Diseases.
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http://dx.doi.org/10.1016/S2352-3018(18)30003-1DOI Listing
April 2018

Achieving Viral Suppression in 90% of People Living With Human Immunodeficiency Virus on Antiretroviral Therapy in Low- and Middle-Income Countries: Progress, Challenges, and Opportunities.

Clin Infect Dis 2018 05;66(10):1487-1491

Division of Infectious Diseases, University of Pittsburgh, School of Medicine, Pennsylvania.

Although significant progress has been made, the latest data from low- and middle-income countries show substantial gaps in reaching the third "90%" (viral suppression) of the UNAIDS 90-90-90 goals, especially among vulnerable and key populations. This article discusses critical gaps and promising, evidence-based solutions. There is no simple and/or single approach to achieve the last 90%. This will require multifaceted, scalable strategies that engage people living with human immunodeficiency virus, motivate long-term treatment adherence, and are community-entrenched and ‑supported, cost-effective, and tailored to a wide range of global communities.
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http://dx.doi.org/10.1093/cid/ciy008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190938PMC
May 2018

Systemic Inflammation, Coagulation, and Clinical Risk in the START Trial.

Open Forum Infect Dis 2017 28;4(4):ofx262. Epub 2017 Nov 28.

National Institute of Allergy and Infectious Diseases, Division of Clinical Research, Bethesda, Maryland.

Background: The Strategic Timing of AntiRetroviral Treatment (START) trial demonstrated that immediate (at CD4+ >500 cells/µL) vs deferred (to CD4+ <350 cells/µL or AIDS) antiretroviral therapy (ART) initiation reduced risk for AIDS and serious non-AIDS (SNA). We investigated associations of inflammation, coagulation, and vascular injury biomarkers with AIDS, SNA or death, and the effect of immediate ART initiation.

Methods: Biomarkers were measured from stored plasma prior to randomization and at month 8. Associations of baseline biomarkers with event risk were estimated with Cox regression, pooled across groups, adjusted for age, gender, and treatment group, and stratified by region. Mean changes over 8 months were estimated and compared between the immediate and deferred ART arms using analysis of covariance models, adjusted for levels at entry.

Results: Baseline biomarker levels were available for 4299 START participants (92%). Mean follow-up was 3.2 years. Higher levels of IL-6 and D-dimer were the only biomarkers associated with risk for AIDS, SNA or death, as well as the individual components of SNA and AIDS events (HRs ranged 1.37-1.41 per 2-fold higher level), even after adjustment for baseline CD4+ count, HIV RNA level, and other biomarkers. At month 8, biomarker levels were lower in the immediate arm by 12%-21%.

Conclusions: These data, combined with evidence from prior biomarker studies, demonstrate that IL-6 and D-dimer consistently predict clinical risk across a broad spectrum of CD4 counts for those both ART-naïve and treated. Research is needed to identify disease-modifying treatments that target inflammation beyond the effects of ART.
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http://dx.doi.org/10.1093/ofid/ofx262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751061PMC
November 2017

Immediate Initiation of Antiretroviral Therapy for HIV Infection Accelerates Bone Loss Relative to Deferring Therapy: Findings from the START Bone Mineral Density Substudy, a Randomized Trial.

J Bone Miner Res 2017 Sep 26;32(9):1945-1955. Epub 2017 Jun 26.

St Vincent's Hospital, Sydney, Australia.

Both HIV infection and antiretroviral therapy (ART) are associated with lower bone mineral density (BMD) and increased fracture risk. Because the relative contributions of ART and untreated HIV to BMD loss are unclear, it is important to quantify the effect of ART on bone. We compared the effect of early ART initiation (CD4 >500 cells/μL) with deferred ART on change in BMD in the START Bone Mineral Density substudy, a randomized trial evaluating the effect of immediate ART initiation versus deferring ART (to CD4 <350 cells/μL). BMD was measured annually at the lumbar spine and hip by dual-energy X-ray absorptiometry (DXA). Percent change in BMD by treatment assignment (intent-to-treat analysis) was estimated using longitudinal mixed models and linear regression. Baseline and follow-up DXA scans were available for 399 (195 immediate, 204 deferred) participants (median age 32 years, 80% non-white, 26% women, median CD4 count 642 cells/μL). ART (most commonly including tenofovir and efavirenz) was used for 95% and 18% of follow-up in the immediate and deferred ART groups, respectively. Through 2.2 years mean follow-up, immediate ART resulted in greater BMD declines than deferred ART at the hip (-2.5% versus -1.0%; difference -1.5%, 95% confidence interval [CI] -2.2 to -0.8, p < 0.001) and spine (-1.9% versus -0.4%; difference -1.6%, 95% CI -2.2 to -1.0, p < 0.001). BMD declines were greatest in the first year of ART. In the immediate ART group, spine BMD stabilized after year 1, whereas hip BMD declined progressively over 2 years. After year 1, BMD changes were similar in the immediate and deferred groups. No clinical, HIV-related, or ART characteristic predicted greater BMD loss in either group. All HIV treatment guidelines now recommend ART initiation at HIV diagnosis because of the reduced risk of serious clinical outcomes. Better understanding of the longer-term consequences of the observed reductions in BMD is needed.

Clinical Trials Registration: NCT00867048. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555813PMC
September 2017

Brief Report: Recovery of Bone Mineral Density After Discontinuation of Tenofovir-Based HIV Pre-exposure Prophylaxis.

J Acquir Immune Defic Syndr 2017 10;76(2):177-182

*Departments of Epidemiology and Biostatistics; †Medicine,University of California, San Francisco, San Francisco, CA; ‡Department of Health Services, University of Washington, Seattle, WA; §Department of Pharmaceutical Sciences, University of Colorado, Denver, Aurora, CO; ∥Investigaciones Médicas en Salud, Lima, Peru; ¶Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; #Bridge HIV, San Francisco Department of Public Health, San Francisco, CA; **Department of Medicine, Desmond Tutu HIV Foundation, Cape Town, South Africa; ††Projeto Praça Onze, Hospital Escola São Francisco de Assis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; ‡‡Evandro Chagas National Institute of Infectious Diseases-Fiocruz, Rio de Janeiro, Brazil; and §§Gladstone Institute of Virology and San Francisco AIDS Foundation, San Francisco, CA.

Background: Oral tenofovir disoproxil fumarate (TDF) for HIV prevention and treatment is associated with decreases in bone mineral density (BMD). Previous reports suggest that these changes may be reversible after discontinuation of TDF.

Setting: A metabolic substudy of 498 participants in a randomized, placebo-controlled HIV prevention trial of oral coformulated TDF with emtricitabine (TDF/FTC, Truvada) for HIV pre-exposure prophylaxis (PrEP) enrolling a global sample of men who have sex with men and trans women.

Methods: Participants underwent dual X-ray absorptiometry to quantify bone mineral density (BMD) in the hip and spine during PrEP and at 2 visits after stopping (median of 23 and 79 weeks post-PrEP, respectively). Results are stratified by pharmacologic measure of TDF/FTC adherence.

Results: There was no significant difference in change in hip/spine BMD at any time point between placebo and those with low adherence. Adherent participants had a mean (standard error) BMD change at TDF/FTC discontinuation of -1.02% (0.24) in the hip and -1.84% (0.36) in the spine. After stop, annualized BMD increases of 1.13% per year (0.27) in hip and 1.81% per year (0.36) in spine BMD were observed in adherent participants compared with 0.19% (0.16) and 0.74% (0.21) in the placebo group, respectively (P = 0.003, both comparisons). On average, BMD returned to baseline levels by 1 year after PrEP stop. Recovery was consistent across age, baseline BMD z-score, and treatment duration.

Conclusions: Mean BMD returns to baseline levels within 12-18 months after TDF-based PrEP discontinuation in both hip and spine with consistency across participant subgroups.

Clinical Trials Registration: clinicaltrials.gov NCT00458393.
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http://dx.doi.org/10.1097/QAI.0000000000001475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597476PMC
October 2017

International Sexual Partnerships May Be Shaped by Sexual Histories and Socioeconomic Status.

Sex Transm Dis 2017 05;44(5):306-309

From the *University of California, San Francisco, San Francisco, CA; †Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, CA; ‡Fundación Ecuatoriana Equidad, Quito Mainland, Ecuador; §Asociación Civil Impacta Salud y Educación; ¶Investigaciones Médicas en Salud, Lima; ∥Asociación Civil Selva Amazónica, Iquitos, Peru; **Instituto de Pesquisa Clinica Evandro Chagas-Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; ††San Francisco Department of Public Health, San Francisco, CA; ‡‡Fenway Health and Beth Israel Deaconess Medical Center, Boston, MA; §§Chiang Mai University, Chiang Mai, Thailand; ¶¶Praça Onze, Rio de Janeiro, Brazil; ∥∥University of Cape Town, Cape Town, South Africa; and ***Universidade de São Paulo.

Exchange sex and higher education were associated with an increased likelihood of international sexual partnerships (ISPs). Exchange sex and older age were associated with an increased likelihood of condomless sex in ISPs. Educational and socioeconomic factors may create unbalanced power dynamics that influence exchange sex and condomless sex in ISPs.
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http://dx.doi.org/10.1097/OLQ.0000000000000601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407391PMC
May 2017

Ending AIDS as a public health threat by 2030: Scientific Developments from the 2016 INTEREST Conference in Yaoundé, Cameroon.

Antivir Ther 2017 7;22(2):179-184. Epub 2017 Apr 7.

Makarere University College of Health Sciences in Kampala, Kampala, Uganda.

The underpinning theme of the 2016 INTEREST Conference held in Yaoundé, Cameroon, 3-6 May 2016 was ending AIDS as a public health threat by 2030. Focused primarily on HIV treatment, pathogenesis and prevention research in resource-limited settings, the conference attracted 369 active delegates from 34 countries, of which 22 were in Africa. Presentations on treatment optimization, acquired drug resistance, care of children and adolescents, laboratory monitoring and diagnostics, implementation challenges, HIV prevention, key populations, vaccine and cure, hepatitis C, mHealth, financing the HIV response and emerging pathogens, were accompanied by oral, mini-oral and poster presentations. Spirited plenary debates on the UNAIDS 90-90-90 treatment cascade goal and on antiretroviral pre-exposure prophylaxis took place. Joep Lange career guidance sessions and grantspersonship sessions attracted early career researchers. At the closing ceremony, the Yaoundé Declaration called on African governments; UNAIDS; development, bilateral, and multilateral partners; and civil society to adopt urgent and sustained approaches to end HIV by 2030.
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http://dx.doi.org/10.3851/IMP3165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542813PMC
June 2017

Association of age, baseline kidney function, and medication exposure with declines in creatinine clearance on pre-exposure prophylaxis: an observational cohort study.

Lancet HIV 2016 11 31;3(11):e521-e528. Epub 2016 Aug 31.

Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, CA, USA.

Background: As pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine for the prevention of HIV infection is rolled out internationally, strategies to maintain effectiveness and to minimise adverse effects merit consideration. In this study, we aimed to assess reductions in renal function and predictors of renal toxicity in a large open-label study of PrEP.

Methods: As part of the iPrEx open-label extension (OLE) study, men who have sex with men or transgender women aged 18-70 years who were HIV negative and had participated in three previous PrEP trials from Brazil, Ecuador, Peru, South Africa, Thailand, and the USA were enrolled into an open-label PrEP study. There were no restrictions on current renal function for enrolment into iPrEx OLE, in which participants were given combination tablets of tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg) and advised to take one tablet per day. At follow-up sessions every 12 weeks, participants' creatinine clearance on PrEP was estimated and in a subset of participants, hair samples were collected to measure tenofovir and emtricitabine concentrations (a measure of adherence and exposure) via liquid-chromatography-tandem-mass-spectrometry. Reductions in creatinine clearance from baseline were calculated and predictors of decline were identified by use of multivariate models. iPrEx is registered with ClinicalTrials.com, number NCT00458393.

Findings: Baseline characteristics were similar between all participants in iPrEx-OLE (1224 participants with 7475 person-visits) and those participating in the hair substudy (220 participants with 1114 person-visits). During a median of 72 weeks, the mean decline in creatinine clearance was -2·9% (95% CI -2·4 to -3·4; p<0·0001), but declines were greater for those who started PrEP at older ages: participants aged 40-50 years at baseline had declines of -4·2% (95% CI -2·8 to -5·5) and participants older than 50 years at baseline had declines of -4·9% (-3·1 to -6·8). In multivariate models, age and baseline creatinine clearance less than 90 mL/min predicted declines in renal function. We identified a monotonic association between percentage decrease in creatinine clearance and the number of doses of tenofovir disoproxil fumarate and emtricitabine taken per week, as estimated by hair concentrations of tenofovir and emtricitabine (p=0·008).

Interpretation: Our data suggest that the frequency of safety monitoring for PrEP might need to be different between age groups and that pharmacological measures can monitor for toxic effects as well as adherence.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S2352-3018(16)30153-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085869PMC
November 2016

Community-Based Interventions to Improve and Sustain Antiretroviral Therapy Adherence, Retention in HIV Care and Clinical Outcomes in Low- and Middle-Income Countries for Achieving the UNAIDS 90-90-90 Targets.

Curr HIV/AIDS Rep 2016 10;13(5):241-55

Precision Global Health, Vancouver, Canada.

Little is known about the effect of community versus health facility-based interventions to improve and sustain antiretroviral therapy (ART) adherence, virologic suppression, and retention in care among HIV-infected individuals in low- and middle-income countries (LMICs). We systematically searched four electronic databases for all available randomized controlled trials (RCTs) and comparative cohort studies in LMICs comparing community versus health facility-based interventions. Relative risks (RRs) for pre-defined adherence, treatment engagement (linkage and retention in care), and relevant clinical outcomes were pooled using random effect models. Eleven cohort studies and eleven RCTs (N = 97,657) were included. Meta-analysis of the included RCTs comparing community- versus health facility-based interventions found comparable outcomes in terms of ART adherence (RR = 1.02, 95 % CI 0.99 to 1.04), virologic suppression (RR = 1.00, 95 % CI 0.98 to 1.03), and all-cause mortality (RR = 0.93, 95 % CI 0.73 to 1.18). The result of pooled analysis from the RCTs (RR = 1.03, 95 % CI 1.01 to 1.06) and cohort studies (RR = 1.09, 95 % CI 1.03 to 1.15) found that participants assigned to community-based interventions had statistically significantly higher rates of treatment engagement. Two studies found community-based ART delivery model either cost-saving or cost-effective. Community- versus facility-based models of ART delivery resulted in at least comparable outcomes for clinically stable HIV-infected patients on treatment in LMICs and are likely to be cost-effective.
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http://dx.doi.org/10.1007/s11904-016-0325-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357578PMC
October 2016

The Effect of Depressive Symptoms on Adherence to Daily Oral PrEP in Men who have Sex with Men and Transgender Women: A Marginal Structural Model Analysis of The iPrEx OLE Study.

AIDS Behav 2016 07;20(7):1527-34

Grant Lab, J David Gladstone Institutes, GIVI, 5th Floor 1650 Owens St, San Francisco, CA, 94158, USA.

We assessed the role of depressive symptoms on adherence to daily oral FTC/TDF for HIV PrEP in cisgender men who have sex with men (MSM) and transgender women who have sex with men (TGW) using data from the iPrEx OLE study. A marginal structural logistic regression model was used to estimate the effect of time-varying CES-D scores on having protective levels of drug concentration, adjusting for confounding by sexual practices over time, prior adherence, and baseline demographic characteristics. We found a non-monotonic relationship between CES-D score and odds of protective FTC/TDF levels in MSM. We found evidence that the effect of depression on adherence varied between MSM and TGW, and that depressive symptoms did not contribute greatly to decreased adherence on a population scale. We recommend that depressive symptoms not preclude the prescription of PrEP, and that MSM and TGW be studied separately.
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http://dx.doi.org/10.1007/s10461-016-1415-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912836PMC
July 2016

Brief Report: Enhanced Normalization of CD4/CD8 Ratio With Earlier Antiretroviral Therapy at Primary HIV Infection.

J Acquir Immune Defic Syndr 2016 09;73(1):69-73

*Department of Medicine, Imperial College, London, United Kingdom; †Medical Research Council Clinical Trials Unit, University College London, London, United Kingdom; ‡Medical Research Council/Uganda Virus Research Institute Research Unit on AIDS, Entebbe, Uganda; §Kirby Institute University of New South Wales and Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia; ‖HIV Prevention Unit, Medical Research Council, Durban, South Africa; ¶Projeto Praça Onze, Hospital Escola Sao Francisco de Assis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; #Division of Infectious Diseases, Ospedale San Raffaele, Milan, Italy; **Department of HIV, Faculty of Medicine, Guys and St Thomas' NHS Trust/Kings College London, United Kingdom; and ††Hospital Clinic - IDIBAPS, University of Barcelona, Barcelona, Spain.

Background: Total CD4 T-cell counts predict HIV disease progression but do not necessarily reflect normalization of immune function. CD4/CD8 ratio is a marker of immune dysfunction, a prognostic indicator for non-AIDS mortality, and reflects viral reservoir size. Despite antiretroviral therapy (ART), recovery of CD4/CD8 ratio in chronic HIV infection is incomplete; we hypothesize enhanced CD4/CD8 ratio recovery with earlier treatment initiation in recently infected individuals.

Methods: CD4 count and CD4/CD8 ratio were analyzed using data from 2 cohorts: SPARTAC trial and the UK HIV Seroconverters Cohort where primary HIV infection (PHI) was defined as within 6 months from estimated date of infection. Using time-to-event methods and Cox proportional hazard models, we examined the effect of CD4/CD8 ratio at seroconversion on disease progression (CD4 <350 cells per cubic millimeter/ART initiation) and factors associated with time from ART initiation to CD4/CD8 normalization (ratio >1.0).

Findings: Of 573 seroconverters, 482 (84%) had abnormal CD4/CD8 ratios at HIV seroconversion. Individuals with higher CD4/CD8 ratio at seroconversion were significantly less likely to reach the disease progression endpoint [adjusted hazard ratio (aHR) (95% CI) = 0.52 (0.32 to 0.82), P = 0.005]. The longer the interval between seroconversion and ART initiation [HR (95% CI) = 0.98 per month increase (0.97, 0.99), P < 0.001], the less likely the CD4/CD8 ratio normalization. ART initiation within 6 months from seroconversion was significantly more likely to normalize [HR (95% CI) = 2.47 (1.67 to 3.67), P < 0.001] than those initiating later.

Interpretation: Most individuals presenting in PHI have abnormal CD4/CD8 ratios. The sooner the ART is initiated in PHI, the greater the probability of achieving normal CD4/CD8 ratio.
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http://dx.doi.org/10.1097/QAI.0000000000001013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981213PMC
September 2016

Symptoms, Side Effects and Adherence in the iPrEx Open-Label Extension.

Clin Infect Dis 2016 May 20;62(9):1172-7. Epub 2016 Jan 20.

Gladstone Institute of Virology and San Francisco AIDS Foundation, California.

Background: Blinded clinical trials have reported a modest and transient "start-up syndrome" with initiation of tenofovir-based pre-exposure prophylaxis (PrEP). We evaluate this phenomenon and its effect on adherence in an open-label PrEP study.

Methods: In the iPrEx open-label extension (OLE) study, an 18-month open-label, multi-site PrEP cohort taking daily oral co-formulated tenofovir/emtricitabine, we examined the prevalence and duration of PrEP-associated symptoms and their effect on adherence, assessed by drug levels in dried blood spots tested monthly for the first 3 months.

Results: Symptom reports peaked within the first month, with 39% reporting potentially PrEP-related symptoms compared to 22% at baseline. Symptoms largely resolved to pre-PrEP levels by 3 months.Symptoms varied substantially in frequency by study site (range in 1-month symptoms: 11% to 70%). Nongastrointestinal (GI) symptoms were not associated with adherence (odds ratio [OR] = 1.2, 95% confidence interval [CI], .4-3.7); however, GI-associated symptoms in the first 4 weeks were inversely associated with adherence at 4 weeks (OR = 0.47, 95% CI, .23-.96). Reports of GI symptoms were associated with 7% (95% CI, 4%-11%) of suboptimal adherence in this cohort.

Conclusions: PrEP-associated symptoms in the open-label setting occur in a minority of users and largely resolve within 3 months. GI symptoms are associated with a modest reduction in PrEP adherence, but good adherence is possible even in the presence of frequent symptom reports.

Clinical Trials Registration: Clinicaltrials.govNCT00458393.
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http://dx.doi.org/10.1093/cid/ciw022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826449PMC
May 2016

Modeling the Slow CD4+ T Cell Decline in HIV-Infected Individuals.

PLoS Comput Biol 2015 Dec 28;11(12):e1004665. Epub 2015 Dec 28.

Department of Mathematics and Statistics, and Center for Biomedical Research, Oakland University, Rochester, Michigan, United States of America.

The progressive loss of CD4+ T cell population is the hallmark of HIV-1 infection but the mechanism underlying the slow T cell decline remains unclear. Some recent studies suggested that pyroptosis, a form of programmed cell death triggered during abortive HIV infection, is associated with the release of inflammatory cytokines, which can attract more CD4+ T cells to be infected. In this paper, we developed mathematical models to study whether this mechanism can explain the time scale of CD4+ T cell decline during HIV infection. Simulations of the models showed that cytokine induced T cell movement can explain the very slow decline of CD4+ T cells within untreated patients. The long-term CD4+ T cell dynamics predicted by the models were shown to be consistent with available data from patients in Rio de Janeiro, Brazil. Highly active antiretroviral therapy has the potential to restore the CD4+ T cell population but CD4+ response depends on the effectiveness of the therapy, when the therapy is initiated, and whether there are drug sanctuary sites. The model also showed that chronic inflammation induced by pyroptosis may facilitate persistence of the HIV latent reservoir by promoting homeostatic proliferation of memory CD4+ cells. These results improve our understanding of the long-term T cell dynamics in HIV-1 infection, and support that new treatment strategies, such as the use of caspase-1 inhibitors that inhibit pyroptosis, may maintain the CD4+ T cell population and reduce the latent reservoir size.
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http://dx.doi.org/10.1371/journal.pcbi.1004665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692447PMC
December 2015

Immunological biomarkers predict HIV-1 viral rebound after treatment interruption.

Nat Commun 2015 Oct 9;6:8495. Epub 2015 Oct 9.

Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, John Radcliffe Hospital, Oxford OX1 3SY, UK.

Treatment of HIV-1 infection with antiretroviral therapy (ART) in the weeks following transmission may induce a state of 'post-treatment control' (PTC) in some patients, in whom viraemia remains undetectable when ART is stopped. Explaining PTC could help our understanding of the processes that maintain viral persistence. Here we show that immunological biomarkers can predict time to viral rebound after stopping ART by analysing data from a randomized study of primary HIV-1 infection incorporating a treatment interruption (TI) after 48 weeks of ART (the SPARTAC trial). T-cell exhaustion markers PD-1, Tim-3 and Lag-3 measured prior to ART strongly predict time to the return of viraemia. These data indicate that T-cell exhaustion markers may identify those latently infected cells with a higher proclivity to viral transcription. Our results may open new avenues for understanding the mechanisms underlying PTC, and eventually HIV-1 eradication.
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http://dx.doi.org/10.1038/ncomms9495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633715PMC
October 2015

The Safety of Tenofovir-Emtricitabine for HIV Pre-Exposure Prophylaxis (PrEP) in Individuals With Active Hepatitis B.

J Acquir Immune Defic Syndr 2016 03;71(3):281-6

*Gladstone Institutes, San Francisco, CA; †University of California, San Francisco, San Francisco, CA; ‡Projeto Praça Onze, Hospital Escola São Francisco de Assis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; §Bridge HIV, San Francisco Department of Public Health, San Francisco, CA; ‖Investigaciones Medicas en Salud, Lima, Peru; ¶Research Institute for Health Sciences and Department of Community Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; and #Fenway Institute, Fenway Health, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA.

Background: Pre-exposure prophylaxis (PrEP) with daily oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) prevents HIV infection. The safety and feasibility of HIV PrEP in the setting of hepatitis B virus (HBV) infection were evaluated.

Methods: The Iniciativa Profilaxis Pre-Exposición study randomized 2499 HIV-negative men and transgender women who have sex with men to once-daily oral FTC/TDF versus placebo. Hepatitis serologies and transaminases were obtained at screening and at the time PrEP was discontinued. HBV DNA was assessed by polymerase chain reaction, and drug resistance was assessed by population sequencing. Vaccination was offered to individuals susceptible to HBV infection.

Results: Of the 2499 participants, 12 (0.5%; including 6 randomized to FTC/TDF) had chronic HBV infection. After stopping FTC/TDF, 5 of the 6 participants in the active arm had liver function tests performed at follow-up. Liver function tests remained within normal limits at post-stop visits except for a grade 1 elevation in 1 participant at post-stop week 12 (alanine aminotransferase = 90, aspartate aminotransferase = 61). There was no evidence of hepatic flares. Polymerase chain reaction of stored samples showed that 2 participants in the active arm had evidence of acute HBV infection at enrollment. Both had evidence of grade 4 transaminase elevations with subsequent resolution. Overall, there was no evidence of TDF or FTC resistance among tested genotypes. Of 1633 eligible for vaccination, 1587 (97.2%) received at least 1 vaccine; 1383 (84.7%) completed the series.

Conclusions: PrEP can be safely provided to individuals with HBV infection if there is no evidence of cirrhosis or substantial transaminase elevation. HBV vaccination rates at screening were low globally, despite recommendations for its use, yet uptake and efficacy were high when offered.
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http://dx.doi.org/10.1097/QAI.0000000000000857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752387PMC
March 2016

Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection.

N Engl J Med 2015 Aug 20;373(9):795-807. Epub 2015 Jul 20.

Background: Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter.

Methods: We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non-AIDS-related event, or death from any cause.

Results: A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001). Hazard ratios for serious AIDS-related and serious non-AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P=0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions.

Conclusions: The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter. (Funded by the National Institute of Allergy and Infectious Diseases and others; START ClinicalTrials.gov number, NCT00867048.).
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http://dx.doi.org/10.1056/NEJMoa1506816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569751PMC
August 2015

Effects of Emtricitabine/Tenofovir on Bone Mineral Density in HIV-Negative Persons in a Randomized, Double-Blind, Placebo-Controlled Trial.

Clin Infect Dis 2015 Aug 23;61(4):572-80. Epub 2015 Apr 23.

University of California, San Francisco Gladstone Institute of Virology and Immunology, San Francisco, California.

Background: Daily preexposure prophylaxis (PrEP) with oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) decreases the risk of human immunodeficiency virus (HIV) acquisition. Initiation of TDF decreases bone mineral density (BMD) in HIV-infected people. We report the effect of FTC/TDF on BMD in HIV-seronegative men who have sex with men and in transgender women.

Methods: Dual-energy X-ray absorptiometry was performed at baseline and 24-week intervals in a substudy of iPrEx, a randomized, double-blind, placebo-controlled trial of FTC/TDF PrEP. Plasma and intracellular tenofovir concentrations were measured in participants randomized to FTC/TDF.

Results: In 498 participants (247 FTC/TDF, 251 placebo), BMD in those randomized to FTC/TDF decreased modestly but statistically significantly by 24 weeks in the spine (net difference, -0.91% [95% confidence interval {CI}, -1.44% to -.38%]; P = .001) and hip (-0.61% [95% CI, -.96% to -.27%], P = .001). Changes within each subsequent 24-week interval were not statistically significant. Changes in BMD by week 24 correlated inversely with intracellular tenofovir diphosphate (TFV-DP), which was detected in 53% of those randomized to FTC/TDF. Net BMD loss by week 24 in participants with TFV-DP levels indicative of consistent dosing averaged -1.42% ± 29% and -0.85% ± 19% in the spine and hip, respectively (P < .001 vs placebo). Spine BMD tended to rebound following discontinuation of FTC/TDF. There were no differences in fractures (P = .62) or incidence of low BMD.

Conclusions: In HIV-uninfected persons, FTC/TDF PrEP was associated with small but statistically significant decreases in BMD by week 24 that inversely correlated with TFV-DP, with more stable BMD thereafter.

Clinical Trials Registration: NCT00458393.
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http://dx.doi.org/10.1093/cid/civ324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565984PMC
August 2015

The effect of short-course antiretroviral therapy initiated in primary HIV-1 infection on interleukin-6 and D-dimer levels.

AIDS 2015 Jul;29(11):1355-61

aImperial College London bKings College Hospital NHS Foundation Trust cMedical Research Council Clinical Trials Unit at University College London, London, UK dKirby Institute, University of New South Wales, Sydney, Australia eBrighton and Sussex University Hospitals, Brighton, UK fOspedale San Raffaele, Milan, Italy gProjeto Praça Onze, Hospital Escola São Francisco de Assis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil hHospital Clinic-Institut d'investigacions Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain iLondon School of Hygiene & Tropical Medicine, London, UK. *Kholoud Porter and Sarah Fidler contributed equally to the writing of this manuscript.

Objective: Interruption of antiretroviral therapy (ART) in chronic HIV disease is associated with increased mortality, predicted by elevations in interleukin-6 (IL-6) and D-dimer. The effect of ART interruption in primary HIV-1 infection on these biomarkers is unknown.

Methods: Plasma samples from 200 HIV seroconverters enrolled in the Short Pulse Anti-Retroviral Therapy At HIV Seroconversion trial of deferred ART (standard of care) - 12 or 48 week ART (ART12 or ART48, respectively) - were analysed for IL-6 and D-dimer at weeks 0, 12, 16, 48, 52, 60 and 108 after randomization. Changes in log10 levels from weeks 0 to 12 were analysed using linear regression, as were changes from baseline to 4 weeks after stopping ART. Areas under the biomarker-time curves (AUC) to week 108 were adjusted for baseline values, and compared across all arms.

Results: Median (inter-quartile range) baseline IL-6 and D-dimer were 1.45 (0.88, 2.41) pg/ml and 0.34 (0.20, 0.50) mg/l, respectively. At week 12, D-dimer levels were significantly lower among treated compared to untreated individuals (P < 0.001), whereas IL-6 levels were similar (P = 0.23). Within 4 weeks from stopping ART, IL-6 and D-dimer levels rose by 22 and 18%, reaching pre-ART levels. Over 108-week follow-up, there was no difference between arms in IL-6 AUC (P = 0.53), but D-dimer AUC was significantly lower for ART12 and ART48 compared to standard of care (overall P = 0.008).

Conclusion: Stopping ART in primary HIV-1 infection leads to inflammatory biomarker rebound to pre-treatment levels. However, over 108-week follow-up, we found no evidence that biomarker levels were higher for those interrupting ART, compared to those remaining ART-naïve, and D-dimer levels were significantly lower.
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http://dx.doi.org/10.1097/QAD.0000000000000675DOI Listing
July 2015

HIV provider-patient communication regarding cardiovascular risk: results from the AIDS Treatment for Life International Survey.

J Int Assoc Provid AIDS Care 2014 Jul-Aug;13(4):342-5

Design: Few global studies have assessed HIV clinician-patient communication regarding cardiovascular disease (CVD) risks.

Methods: We conducted a multicountry, comparative, cross-sectional survey of HIV-infected individuals in 12 countries on 5 continents in 2010, with 100 to 200 enrollees per country. HIV-infected adults >17 years and on antiretroviral therapy were recruited in clinics and community organizations and surveyed via direct interview, telephone encounter, or online. Chi-square analyses were performed with an 80% power to detect a difference of >20%.

Results: Of 2035 participants, 37% were women. Prevalence of self-reported CVD risk factors was 28% overall, and greater CVD risk was present in 55% of patients in North America, 12% in Africa, and 26% to 28% on other continents. Only 19% of patients ever discussed CVD with their physician, and 31% had ever discussed hypertension, hypercholesterolemia, family history of CVD, or smoking; these findings were true for HIV clinicians in all regions of the world. Forty-four percent of smokers reported never discussing smoking with their HIV clinician.

Conclusion: We found that HIV clinicians worldwide are not sufficiently addressing CVD risk factors with their patients. Expanded training and education for HIV clinicians should include effective approaches to the mitigation of CV risk factors.
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January 2018

Enhanced normalisation of CD4/CD8 ratio with early antiretroviral therapy in primary HIV infection.

J Int AIDS Soc 2014 2;17(4 Suppl 3):19480. Epub 2014 Nov 2.

Department of Medicine, Imperial College, London, UK.

Introduction: Despite normalization of total CD4 counts, ongoing immune dysfunction is noted amongst those on antiretroviral therapy (ART). Low CD4/CD8 ratio is associated with a high risk of AIDS and non-AIDS events and may act as a marker of immune senescence [1]. This ratio is improved by ART although normalization is uncommon (~7%) [2]. The probability of normalization of CD4 count is improved with immediate ART initiation in primary HIV infection (PHI) [3]. We examined whether CD4/CD8 ratio similarly normalized in immediate vs. deferred ART at PHI.

Material And Methods: Using data from the SPARTAC trial and the UK Register of HIV Seroconverters, we examined the effect of ART with time (continuous) from HIV seroconversion (SC) on CD4/CD8 ratio (≥1) adjusted for sex, risk group, ethnicity, enrolment from an African site and both CD4 count and age at ART initiation. We also examined that effect by dichotomizing HIV duration at ART initiation (ART started within six months of SC: early ART; ART initiated>six months after SC: deferred). We also considered time to CD4 count normalization (≥900 cells/mm(3)).

Results: In total, 353 initiated ART with median (IQR) 97.9 (60.5, 384.5) days from estimated seroconversion; 253/353 early ART, 100 deferred ART. At one year after starting ART, 114/253 (45%) early ART had normalized CD4/8 ratio, compared with 11/99 (11%) in the deferred group, whilst 83/253 (33%) of early ART had normalized CD4 counts, compared with 3/99 (3%) in the deferred group. Individuals initiating within six months of PHI were significantly more likely to reach normal ratio than those initiating later (HR, 95% CI 2.96, 1.75 - 5.01, p<0.001). The longer after SC ART was initiated, the reduced likelihood of achieving normalization of CD4/CD8 ratio (HR 0.98, 95% CI 0.96 - 0.99 for each 30-day increase). CD4 count at ART initiation was also associated with normalization, as expected (HR 1.002, 95% CI 1.001 - 1.002, p<0.001). There was an association between normal CD4/CD8 ratio and being virally suppressed (<400 copies HIV RNA/ml) p<0.001. CD4 count normalization was also significantly more likely for those initiating early (HR 5.00, 95% CI 1.52 - 16.41, p=0.008).

Conclusions: The likelihood of achieving normalization of CD4/CD8 ratios was increased if ART was initiated within six months of PHI. Higher CD4/CD8 ratio may reflect a more "normal" immune phenotype conferring enhanced prognosis and predict post-treatment control.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224908PMC
http://dx.doi.org/10.7448/IAS.17.4.19480DOI Listing
January 2016

Streamlining HIV testing for HIV preexposure prophylaxis.

J Clin Microbiol 2015 Jan 5;53(1):179-83. Epub 2014 Nov 5.

University of California, San Francisco, California, USA Gladstone Institutes, San Francisco, California, USA.

HIV-testing algorithms for preexposure prophylaxis (PrEP) should be optimized to minimize the risk of drug resistance, the time off PrEP required to evaluate false-positive screening results, and costs and to expedite the start of therapy for those confirmed to be infected. HIV rapid tests (RTs) for anti-HIV antibodies provide results in less than 1 h and can be conducted by nonlicensed staff at the point of care. In many regions, Western blot (WB) testing is required to confirm reactive RT results. WB testing, however, causes delays in diagnosis and adds expense. The iPrEx study evaluated the safety and efficacy of daily oral emtricitabine-tenofovir disoproxil fumarate among HIV-seronegative men and transgender women who have sex with men: HIV infection was assessed with two RTs plus WB confirmation, followed by HIV-1 plasma viral load testing. During the iPrEx study, there were 51,260 HIV status evaluations among 2,499 volunteers using RTs: 142 (0.28%) had concordant positive results (100% were eventually confirmed) and 19 (0.04%) had discordant results among 14 participants; 11 were eventually determined to be HIV infected. A streamlined approach using only one RT to screen and a second RT to confirm (without WB) would have had nearly the same accuracy. Discrepant RT results are best evaluated with nucleic acid testing, which would also increase sensitivity.
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http://dx.doi.org/10.1128/JCM.01540-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290918PMC
January 2015

Patterns and correlates of PrEP drug detection among MSM and transgender women in the Global iPrEx Study.

J Acquir Immune Defic Syndr 2014 Dec;67(5):528-37

*Bridge HIV, San Francisco Department of Public Health, San Francisco, CA; Departments of †Medicine; ‡Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA; §Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO; ‖Department of Health Behavior and Health Education, University of Michigan, Ann Arbor, Michigan; ¶Gladstone Institutes, San Francisco, CA; #Asociación Civil Impacta Salud y Educación, Lima, Peru; **Investigaciones Médicas en Salud, Lima, Peru; ††Asociación Civil Selva Amazónica, Iquitos, Peru; ‡‡Fundación Ecuatoriana Equidad, Guayaquil, Ecuador; §§Instituto de Pesquisa Clinica Evandro Chagas-IPEC/FIOCRUZ, Rio de Janeiro, Brazil; ‖‖Projeto Praça Onze, Hospital Escola São Francisco de Assis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; ¶¶Universidade de São Paulo, Sao Paulo, Brazil; ##Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; ***Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; †††The Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa; ‡‡‡The Fenway Institute, Fenway Health, and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

Background: Adherence to pre-exposure prophylaxis (PrEP) is critical for efficacy. Antiretroviral concentrations are an objective measure of PrEP use and correlate with efficacy. Understanding patterns and correlates of drug detection can identify populations at risk for nonadherence and inform design of PrEP adherence interventions.

Methods: Blood antiretroviral concentrations were assessed among active arm participants in iPrEx, a randomized placebo-controlled trial of emtricitabine/tenofovir in men who have sex with men and transgender women in 6 countries. We evaluated rates and correlates of drug detection among a random sample of 470 participants at week 8 and a longitudinal cohort of 303 participants through 72 weeks of follow-up.

Results: Overall, 55% of participants (95% confidence interval: 49 to 60) tested at week 8 had drug detected. Drug detection was associated with older age and varied by study site. In longitudinal analysis, 31% never had drug detected, 30% always had drug detected, and 39% had an inconsistent pattern. Overall detection rates declined over time. Drug detection at some or all visits was associated with older age, indices of sexual risk, including condomless receptive anal sex, and responding "don't know" to a question about belief of PrEP efficacy (0-10 scale).

Conclusions: Distinct patterns of study product use were identified, with a significant proportion demonstrating no drug detection at any visit. Research literacy may explain greater drug detection among populations having greater research experience, such as older men who have sex with men in the United States. Greater drug detection among those reporting highest risk sexual practices is expected to increase the impact and cost-effectiveness of PrEP.
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http://dx.doi.org/10.1097/QAI.0000000000000351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229454PMC
December 2014
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