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Objective: Indices of cardiovascular disease (CVD) risk, vascular endothelial dilation, arterial stiffness and endothelial repair were examined in persons with HIV (PWH) on an antiretroviral therapy (ART) that included abacavir (ABC+) in comparison with PWH on ART without abacavir (ABC-), and with HIV seronegative (HIV-) individuals., Approach: The 115 participants (63% men), aged 30-50 years, did not have CVD, metabolic, endocrine, or chronic renal conditions. PWH were on stable ART for six-months or more. Vascular assessments included flow-mediated dilation (FMD), aortic, radial and femoral arterial stiffness (cAIx, crPWV, cfPWV), and thigh and calf arterial compliance (Vmax50). Endothelial repair was indexed by endothelial progenitor cell colony forming units (EPC-CFU). Traditional CVD risk measures included blood pressure, central adiposity, lipids, insulin resistance (HOMA-IR), CRP and ASCVD score. Analyses controlled for demographics (age, sex, education), medications (antihypertensive, statin/fibrate, antipsychotic), and substance abuse (ASSIST)., Results: No group differences were observed in central adiposity, HOMA-IR, CRP, or ASCVD risk score. However, the ABC- group displayed greater dyslipidemia. The ABC+ group displayed no difference on FMD, cAIx, cfPWV or calf Vmax50 compared with other groups. When CD4 count and viral load were controlled, no additional differences between the ABC+ and ABC- groups emerged. Analyses of crPWV and thigh Vmax50 suggested supported by a trend toward lower EPC-CFU in the HIV+ groups than the HIV- group., Conclusions: Findings indicate that ABC treatment of 30-50 year-old PWH on stable ART is not likely to contribute in a robust way to higher CVD risk., Competing Interests: The authors have declared that no competing interests exist.

Test and Rapid Response Treatment (TRRT) linkage programs have demonstrated improved HIV suppression rates. This paper describes the design and implementation of the Miami TRRT initiative and its clinical impact. Assisted by a dedicated care navigator, patients receiving a reactive HIV rapid test at the Florida Department of Health STD Clinic were offered same-day HIV care at the University of Miami/Jackson Memorial Medical Center Adult HIV Outpatient Clinic. Patient retention and labs were tracked for 12 months. Of the 2337 individuals tested, 46 had a reactive HIV test; 41 (89%) consented to participate. For the 36 patients in continued care for a year, 33 (91.7%) achieved virological suppression (< 200 copies/mL) within 70 days of their reactive HIV rapid test; at 12 months, 35 (97.2%) remained suppressed, and mean CD4 T cell counts increased from 452 ± 266 to 597 ± 322 cells/mm 3 . The Miami TRRT initiative demonstrated that immediate linkage to care is feasible and improves retention and suppression in a public/academic medical center in the U.S. South.

Background: Objective adherence metrics for tenofovir (TFV) disoproxil fumarate/emtricitabine (FTC)-based pre-exposure prophylaxis (PrEP) were critical for interpretation of efficacy in PrEP clinical trials, and there is increasing interest in using drug levels to tailor interventions for reengagement and adherence. Point-of-care immunoassays for TFV, which examine short-term adherence, are in development. However, the ability of poor short-term and long-term adherence to predict future PrEP nonretention is unknown., Setting: Secondary data analysis of a large, prospective multi-site U.S. PrEP demonstration project., Methods: An adjusted Cox-proportional hazards model examined the relationship of dried blood spot (DBS) levels of FTC-triphosphate (FTC-TP) or TFV-diphosphate (TFV-DP), measures of short-term and long-term PrEP adherence, respectively, with future study nonretention., Results: Overall, 294 individuals (median age 33 years) contributed drug levels within the U.S. PrEP demonstration project. By the end of study, 27% were lost to follow-up, 25% had at least one undetectable FTC-TP level indicating poor short-term adherence, and 29% had a drug level indicating suboptimal long-term adherence (TFV-DP <700 fmol/punch). The strongest factor associated with future study nonretention using a binary drug-level cut-off was an undetectable DBS FTC-TP level (adjusted hazard ratio 6.3; 95% confidence interval 3.8 to 10.2). The suboptimal long-term adherence based on low DBS TFV-DP levels was also associated with nonretention (adjusted hazard ratio 4.3; 95% confidence interval: 2.4 to 7.6)., Conclusions: Both short- and long-term metrics of PrEP adherence are strongly associated with future loss to follow-up in a U.S. demonstration project study. Short-term metrics of adherence, once available at the point-of-care, could be used to direct real-time tailored retention and adherence interventions.

Background: Safe and effective use of pre-exposure prophylaxis (PrEP) depends on retention in care after initial engagement., Setting: The United States PrEP Demonstration Project offered daily oral tenofovir/emtricitabine to participants in San Francisco, Miami, and Washington, D.C. for 48 weeks from 2012 to 2014., Methods: The Demo Project participants' patterns of retention were assigned to 1 of 3 categories: early loss to follow-up (ELTF) within the first 12 weeks of the study, retention throughout the study, or intermittent retention in which missed or delayed visits resulted in gaps in medication availability. For each group, baseline characteristics were tabulated. A two-step multivariable analysis was performed., Results: Overall, 366/554 (66.1%) of enrolled participants were retained for all study visits, 127/554 (22.9%) had intermittent retention, and 61/554 (11.0%) ELTF. In multivariable analysis, Miami compared with San Francisco site was associated with ELTF rather than full retention [aOR 2.84; confidence interval (CI): 1.24 to 6.47] and also with intermittent rather than full retention (aOR 2.70; CI: 1.43 to 5.11). Younger age was associated with ELTF (aOR 1.80 for each 10-year decrement in age; CI: 1.26 to 2.57) and intermittent retention (aOR 1.47; CI: 1.17 to 1.84) compared with full retention. Factors associated with ELTF (but not intermittent retention) compared with full retention were black compared with white (aOR 3.32; CI: 1.09 to 10.16), reporting sex work (aOR 4.67; CI: 1.49 to 14.58), lack of regular employment (aOR 2.53; CI: 1.27 to 5.05), and lack of previous PrEP awareness (aOR 2.01; CI: 1.01 to 3.96)., Conclusions: Tailored interventions addressing causes and risk factors for loss from PrEP care may improve retention and consistency of PrEP use.

Background: HIV preexposure prophylaxis (PrEP) using daily oral tenofovir-disoproxil-fumarate/emtricitabine (TDF/FTC) is effective for preventing HIV acquisition, but concerns remain about its potential kidney toxicity. This study examined kidney function in individuals using PrEP in real-world clinical settings., Setting: Demonstration project in 2 sexually transmitted infection clinics and a community health center., Methods: We evaluated kidney function among men who have sex with men and transgender women taking tenofovir-disoproxil-fumarate/emtricitabine PrEP for up to 48 weeks. Serum creatinine and urine dipstick for protein were obtained at 12-week intervals. Kidney function was estimated using creatinine clearance (CrCl) (Cockcroft-Gault) and estimated glomerular filtration rate (eGFR) (CKD-EPI)., Results: From October 2012 to January 2014, we enrolled 557 participants (median age 33). Mean creatinine increased from baseline to week 12 by 0.03 mg/dL (4.6%) (P < 0.0001); mean CrCl decreased by 4.8 mL/min (3.0%) (P < 0.0001). These changes remained stable through week 48 (P = 0.81, P = 0.71 respectively). There were 75/478 (15.7%) participants who developed worsening proteinuria at week 12 compared with baseline (P < 0.0001), and this percent remained stable through week 48 (P = 0.73). Twenty-five participants (5.1%) developed new-onset eGFR <70 mL/min/1.73 m; independent predictors of this outcome were age ≥40 years (OR 3.79, 95% CI: 1.43 to 10.03) and baseline eGFR <90 mL/min/1.73 m (OR 9.59, 3.69-24.94)., Conclusions: In a demonstration setting, daily tenofovir-disoproxil-fumarate/emtricitabine PrEP leads to reduced CrCl and eGFR; however, these eGFR changes are based on very small changes in serum creatinine and seem to be nonprogressive after the first 12 weeks. Future studies are needed to understand the prognostic significance of these small changes.

Objective: The US preexposure prophylaxis (PrEP) Demonstration Project (U.S. Demo) evaluated MSM on PrEP postmarketing and found low seroconversion rates. The objective of this study is to examine hair levels as an adherence measure to PrEP., Design: Using an 'opt-in' design, participants of PrEP Demo were invited to enroll into a substudy where hair was collected quarterly., Methods: Tenofovir concentrations were measured in hair by liquid chromatography/tandem mass spectrometry. Hair levels consistent with ≥4 doses/week (protective in other studies) defined adequate adherence. Mixed effects multivariate logistic regression models examined factors associated with ≥4 doses/week. Separate mixed effects models evaluated the relationship between hair PrEP levels and changes in creatinine clearance (CrCl) over time., Results: Overall, 58% of U.S. Demo participants enrolled into this opt-in study; reasons for nonparticipation included insufficient hair (61%) and concerns about hairstyle (27%). Hair and dried blood spots levels consistent with ≥4 doses/week were highly concordant (84%). Hair levels showed adequate adherence in 87% of 875 person-visits (among 280 participants). Factors associated with adequate adherence in multivariate models were amphetamine use [adjusted odds ratio (aOR) 2.59 (0.97-6.9, P 0.06)], condomless receptive anal sex [aOR 2.28 (1.19-4.40, P 0.01)], and stable housing [aOR 2.63 (1.03-6.67), P 0.04]. Hair levels of tenofovir showed a monotonic relationship with decline in CrCl (P 0.01 for trend)., Conclusion: In this substudy of the U.S. PrEP demonstration project, hair and dried blood spots levels were highly concordant and hair concentrations demonstrated adequate adherence 87% of the time, with stable housing and high-risk behavior associated with higher adherence. Daily PrEP drug taking is associated with modest declines in CrCl.

Importance: Several randomized clinical trials have demonstrated the efficacy of preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) acquisition. Little is known about adherence to the regimen, sexual practices, and overall effectiveness when PrEP is implemented in clinics that treat sexually transmitted infections (STIs) and community-based clinics serving men who have sex with men (MSM)., Objective: To assess PrEP adherence, sexual behaviors, and the incidence of STIs and HIV infection in a cohort of MSM and transgender women initiating PrEP in the United States., Design, Setting, and Participants: Demonstration project conducted from October 1, 2012, through February 10, 2015 (last date of follow-up), among 557 MSM and transgender women in 2 STI clinics in San Francisco, California, and Miami, Florida, and a community health center in Washington, DC. Data were analyzed from December 18, 2014, through August 8, 2015., Interventions: A combination of daily, oral tenofovir disoproxil fumarate and emtricitabine was provided free of charge for 48 weeks. All participants received HIV testing, brief client-centered counseling, and clinical monitoring., Main Outcomes and Measures: Concentrations of tenofovir diphosphate in dried blood spot samples, self-reported numbers of anal sex partners and episodes of condomless receptive anal sex, and incidence of STI and HIV acquisition., Results: Overall, 557 participants initiated PrEP, and 437 of these (78.5%) were retained through 48 weeks. Based on the findings from the 294 participants who underwent measurement of tenofovir diphosphate levels, 80.0% to 85.6% had protective levels (consistent with ≥4 doses/wk) at follow-up visits. African American participants (56.8% of visits; P = .003) and those from the Miami site (65.1% of visits; P < .001) were less likely to have protective levels, whereas those with stable housing (86.8%; P = .02) and those reporting at least 2 condomless anal sex partners in the past 3 months (88.6%; P = .01) were more likely to have protective levels. The mean number of anal sex partners declined during follow-up from 10.9 to 9.3, whereas the proportion engaging in condomless receptive anal sex remained stable at 65.5% to 65.6%. Overall STI incidence was high (90 per 100 person-years) but did not increase over time. Two individuals became HIV infected during follow-up (HIV incidence, 0.43 [95% CI, 0.05-1.54] infections per 100 person-years); both had tenofovir diphosphate levels consistent with fewer than 2 doses/wk at seroconversion., Conclusions and Relevance: The incidence of HIV acquisition was extremely low despite a high incidence of STIs in a large US PrEP demonstration project. Adherence was higher among those participants who reported more risk behaviors. Interventions that address racial and geographic disparities and housing instability may increase the impact of PrEP.

Introduction: Preexposure prophylaxis (PrEP) is a promising approach to reducing HIV incidence. So, garnering the support of HIV providers, who are most familiar with antiretrovirals and likely to encounter patients in HIV serodiscordant relationships, to scale-up PrEP implementation is essential. We sought to determine whether certain subgroups of HIV providers were more likely to intend to prescribe PrEP., Methods: Surveys were administered to HIV providers in Miami, Florida and Washington, District of Columbia. Composite scores were developed to measure PrEP knowledge, experience, and likelihood of prescribing. Latent class analysis was used to stratify provider attitudes toward PrEP., Results: Among 142 HIV providers, 73.2% had cared for more than 20 HIV-infected patients in the previous 3 months; 17% had ever prescribed PrEP. Latent class analysis identified 2 classes of providers (entropy, 0.904); class 1 (n = 95) found PrEP less effective and perceived barriers to prescribing it; class 2 (n = 47) perceived PrEP as moderately effective and perceived fewer barriers to prescribing it. Compared with class 2, class 1 had significantly less experience with PrEP delivery (t(22.7) = 2.88, P = 0.009) and was significantly less likely to intend to prescribe to patients with multiple sex partners (20% vs. 43%, P = 0.04) and those with a drug use history (7% vs. 24%, P = 0.001)., Conclusions: Although most HIV providers found PrEP to be effective, those considering it less effective had limited knowledge and experience with PrEP and had lesser intentions to prescribe. Provider training regarding whom should receive PrEP and addressing potential barriers to PrEP provision are needed if this HIV prevention method is to be optimized.

Data supporting the use of pre-exposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) in the prevention of HIV infection after a sexual encounter continue to grow. In this review, we describe some of the research driving the various recommendations for use of antiretrovirals in prevention. In addition, current research is described regarding the establishment of viral reservoirs that argues for rethinking the timing for nPEP treatment. We discuss the variables that impact on the choice of prevention antiretrovirals, including drug distribution, drug transporters, and potential impact of race and ethnicity on these variables., (© 2014 International Union of Biochemistry and Molecular Biology.)

The purpose of this study is to evaluate whether the choice of a PI- or an efavirenz (EFV)-based HAART initial regimen impacts on the viral diversity after failure from a second, class-switch salvage regimen. Sequential HAART failures after a class switch were identified for which the genotypes showed evidence of signature mutations at each failure. Each second failure was required to be from a viral burden <400 RNA c/ml. Thirteen cases of sequential failure from an initial EFV-containing to a PI-containing regimen (EP), and 19 sequential failures from an initial PI-containing to an EFV-containing regimen (PE) were identified. The persistence of signature mutations from the first failure were evaluated at second failure and compared between the EP and PE groups. Phylogenetic trees were constructed for a subgroup of cases from existing genetic sequence information and branch length analysis was used to determine evidence of viral diversity between groups. For EP sequential therapy, 10 of 12 cases carried forward a key non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation in the second failure compared to 5 of 13 cases for PE sequential therapy (p = 0.041). Phylogenetic analysis demonstrated that there was more viral diversity in the PE group as compared to the EP group, consistent with the interpretation that mutations at the second failure added to an ancestral virus closer to baseline rather than to the dominant virus at first failure. The development of HIV viral diversity after multiple HAART failures is determined by the sequence in which the regimens are ordered.

A significant proportion of HIV-1-infected individuals on suppressive HAART regimens do not reconstitute CD4 counts well. If viral reservoirs persist and impact on CD4 reconstitution in a percentage of cases then addition of another antiretroviral agent could further suppress these reservoirs resulting in enhanced CD4 recovery. To evaluate this possibility, we studied the effect of adding abacavir to a chronically suppressive NNRTI containing HAART regimen for 8 patients on their CD4 count and expression of activation markers. Over the first 24 weeks of intensification, CD4 counts increased significantly (p=0.028). This increase continued after a year in follow-up with a significant rate of change in CD4 T-cells of 0.959+/-1.27 per week. In addition, during intensification changes in the percentage of CD38+CD8+ T-cells over time were significantly negatively correlated with changes in CD4 cell number over time above increases predicted without intensification (r(2)=0.716, p=0.008). These data support the possibility that in certain cases where suboptimal CD4 reconstitution occurs that intensification of the regimen can impact immunologic parameters.

Highly active antiretroviral therapy directed against HIV-1 has dramatically modified morbidity and mortality in infected individuals. Enthusiasm for the success of these medications have been tempered by an inability to clear virus from the infected host leaving a virus poised to leverage any advantage into one of productive survival. One mechanism used to accomplish escape from suppression secondary to antiretroviral therapy is by developing mutations. The goal of therapy has been to diminish viral replication, thereby effectively abrogating the development of these resistance-bearing mutations. This strategy has met with significant success but numerous host-viral factors impact on the ability of the clinician to persistently suppress viral load, thereby providing a window of opportunity for the virus to mutate. In particular we review evidence for ongoing viral replication in the face of suppressive antiretroviral therapy and viral replication in tissue compartments. We discuss whether viral resistance can develop during transient elevations in viral load (viral blips) or as a function of the rate of viral load decay while on therapy. Finally, we touch on the therapeutic strategy that diminished viral replication capacity of mutational species can maintain host immunity.

Interruption of all antiretroviral therapy for HIV-1 infection when therapy is failing and antiretroviral resistance has emerged is frequently associated with the disappearance of detectable resistance-associated protease and reverse transcriptase substitutions. However, the effect that discontinuation of treatment with a particular antiretroviral class has on resistance to that class when other antiretroviral therapy is continued is unknown. We investigated differences in detectable genotypic resistance to protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) among two populations: patients undergoing testing at the moment class-specific treatment failed (Group 1) and patients undergoing testing for varying periods after class-specific treatment failed and was discontinued but therapy with other antiretroviral classes continued with incomplete viral suppression (Group 2). We found that the prevalence of detectable resistance to the PI and NNRTI classes was similar in both groups despite the absence of class-specific selective pressure for lengthy periods of time in Group 2. We hypothesize that this finding may be due to nonspecific selective pressure (i.e., to nucleoside reverse transcriptase inhibitors) selecting out PI- and, to a lesser extent, NNRTI-resistant viral variants.

Genotypic resistance to all antiretroviral classes was widespread among human immunodeficiency virus type 1 isolates failing therapy. Resistance to nonnucleoside reverse transcriptase inhibitors was found most frequently and resistance to protease inhibitors was found least frequently, most likely due to differences in the number of enzymatic amino acid substitutions leading to resistance to each particular drug class.

BACKGROUND:Objective adherence metrics for tenofovir (TFV) disoproxil fumarate/emtricitabine(FTC)-based PrEP were critical for interpretation of efficacy in PrEP clinical trials, and there is increasing interest in using drug levels to tailor interventions for reengagement and adherence. Point-of-care immunoassays (POC) for TFV, which examine short-term adherence, are in development. However the ability of poor short-term and long-term adherence to predict future PrEP non-retention is unknown. SETTING:Secondary data analysis of a large, prospective multi-site U.S. PrEP demonstration project METHODS:: An adjusted Cox-proportional hazards model examined the relationship of dried blood spot (DBS) levels of FTC-triphosphate (FTC-TP) or TFV-diphosphate (TFV-DP), measures of short-term and long-term PrEP adherence, respectively, with future study non-retention. RESULTS:Overall, 294 individuals (median age 33 years) contributed drug levels within the U.S. PrEP demonstration project. By study end, 27% were lost to follow-up, 25% had at least one undetectable FTC-TP level indicating poor short-term adherence, and 29% had a drug level indicating sub-optimal long-term adherence (TFV-DP

BackgroundHIV preexposure prophylaxis (PrEP) using daily oral tenofovir-disoproxil-fumarate/emtricitabine (TDF/FTC) is effective for preventing HIV acquisition, but concerns remain about its potential kidney toxicity. This study examined kidney function in individuals using PrEP in real-world clinical settings.SettingDemonstration project in 2 sexually transmitted infection clinics and a community health center.MethodsWe evaluated kidney function among men who have sex with men and transgender women taking tenofovir-disoproxil-fumarate/emtricitabine PrEP for up to 48 weeks. Serum creatinine and urine dipstick for protein were obtained at 12-week intervals. Kidney function was estimated using creatinine clearance (CrCl) (Cockcroft-Gault) and estimated glomerular filtration rate (eGFR) (CKD-EPI).ResultsFrom October 2012 to January 2014, we enrolled 557 participants (median age 33). Mean creatinine increased from baseline to week 12 by 0.03 mg/dL (4.6%) (P < 0.0001); mean CrCl decreased by 4.8 mL/min (3.0%) (P < 0.0001). These changes remained stable through week 48 (P = 0.81, P = 0.71 respectively). There were 75/478 (15.7%) participants who developed worsening proteinuria at week 12 compared with baseline (P < 0.0001), and this percent remained stable through week 48 (P = 0.73). Twenty-five participants (5.1%) developed new-onset eGFR