Eric S Daar

Harbor-UCLA Medical Center, Torrance, California, United States

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Publications (201)1268.59 Total impact

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    ABSTRACT: HIV-infected men who have sex with men (MSM) are nearly universally co-infected with cytomegalovirus (CMV). In this study of 45 HIV-infected MSM virologically suppressed on ART, we found that presence of seminal CMV DNA shedding and higher levels of systemic cellular HIV RNA transcription were both independently associated with increased PD-1 expression on circulating CD4 T cells, but not with higher levels of senescent (CD57) T cells. Additionally, greater HIV RNA transcription was associated with lower CD57 expression on CD8 T cells. Although causality cannot be inferred from this retrospective study, these results suggest that asymptomatic CMV replication and residual cellular HIV transcription may contribute to persistent immune dysregulation during suppressive ART.
    No preview · Article · Jan 2016 · JAIDS Journal of Acquired Immune Deficiency Syndromes
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    ABSTRACT: Background Epstein Barr virus (EBV) and human papillomavirus (HPV) can co-exist in pharyngeal and cervical malignancies. However, the natural history and factors associated with persistent HPV infection among HIV-infected men who have sex with men (MSM) are unclear. Methods 131 HIV-infected MSM were followed for 48 weeks and screened for multiple co-infections, including seminal EBV DNA and high risk (HR)-HPV messenger RNA (mRNA) at several sites (semen, anal, pharynx). Primary analysis tested if seminal EBV shedding was associated with increased prevalence of HR-HPV at baseline using univariate tests and multivariable logistic regression. In participants with detectable anal HR-HPV at baseline, we tested if presence of seminal EBV shedding at baseline was also predictive of reduced HR-HPV clearance by log-rank test (over 48 weeks of follow-up). Results Baseline prevalence of HR-HPV was: anal 44 % (N = 54/121); pharynx 3.8 % (N = 5/131); semen 7.1 % (N = 7/98). Seminal EBV shedding was present in 28 % of participants and was associated with more than double the prevalence of detectable anal HR-HPV mRNA (71.4 % for EBV shedders versus 33.3 % for non-shedders, p < 0.01). In participants with detectable anal HR-HPV at baseline, we found increased persistence of HR-HPV over 48 weeks of follow-up (measured as time to first negative HR-HPV test in the EBV shedding group (p < 0.01). Conclusions Seminal EBV shedding was associated with an increased risk of having detectable anal HR-HPV in a cohort of HIV-infected MSM on suppressive ART. Future studies should examine if co-infection with EBV and HR-HPV may act synergistically in pathogenesis of anal cancer in HIV-infected individuals.
    Full-text · Article · Dec 2015 · BMC Infectious Diseases
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    ABSTRACT: Objective: The cytokine/chemokine network is the language used by the innate and adaptive immune system to orchestrate effective immune responses. Here, we describe the cross-sectional association between cytokine levels and stage of HIV infection to gain novel insights into HIV-1 immunopathogenesis and identify novel therapeutic targets. Design: Concentrations of 31 cytokine/chemokines were retrospectively measured in blood and semen collected from 252 individuals enrolled in 4 well-characterized cohorts: HIV-uninfected, HIV-infected in early phase of infection, HIV-infected in late phase of infection, and HIV-infected on ART. Methods: Cytokine/chemokine levels were measured by multiplex-bead-array. Comparisons between groups were performed by Mann-Whitney U-test and p-values were adjusted for multiple comparisons using the Benjamini-Hochberg method. Results: HIV-infection skewed the cytokine/chemokine network towards a pro-inflammatory response in both blood and semen. Such changes emerged within the first weeks of infection and were maintained thereafter: among untreated HIV-infected individuals, none of the 31 measured cytokines were significantly different between early and later stages of infection. Suppression of plasma HIV-1-RNA with ART did not result in normalization of the levels of pro-inflammatory cytokines in blood. In contrast, in semen, several pro-inflammatory cytokines were even further up regulated in ART-treated compared to HIV-uninfected and HIV-untreated individuals. Conclusions: The profound disruption in the cytokine network is evident in blood and semen from the earliest stage of HIV-infection shortly after the first detection of systemic viremia. These changes are maintained throughout the chronic phase of the infection and do not normalize despite ART and suppression of plasma HIV-1-RNA.
    No preview · Article · Nov 2015 · AIDS (London, England)
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    ABSTRACT: We conducted a prospective, randomized controlled trial of an internet-based safer-sex intervention to reduce HIV transmission risk behaviors. HIV-infected men who have sex with men (n = 179) were randomized to receive a monthly internet survey alone or a monthly survey plus tailored risk reduction messages over 12 months. The primary outcome was the cumulative sexually transmitted infection (STI) incidence over 12 months. Secondary outcomes included self-reported unprotected sex with an at risk partner and disclosure of HIV status to partners. In a modified intent to treat analysis, there was no difference in 12-month STI incidence between the intervention and control arms (30 vs. 25 %, respectively; p = 0.5). Unprotected sex decreased and disclosure increased over time in both study arms. These improvements suggest that addition of the risk-reduction messages provided little benefit beyond the self-monitoring of risky behavior via regular self-report risk behavior assessments (as was done in both study arms).
    No preview · Article · Oct 2015 · AIDS and Behavior
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    ABSTRACT: The Navigation Program is a health department-community agency collaboration to re-engage lost HIV clinic patients in Los Angeles County using best practices from disease investigator services(DIS) locator activities and ARTAS, a CDC-recommended intervention. Clinic databases were reviewed to identify HIV patients who: 1)had no HIV care visits in 6-12 months and last viral load was greater than 200 copies/ml; 2)had no HIV care visits in >12 months; 3)were newly-diagnosed and never in care; or 4)were recently released from jail/prison/other institution with no regular HIV medical provider. Patients were contacted by trained Navigators using locator information from clinic medical records, HIV/STD surveillance and people-finder databases and offered enrollment in a modified ARTAS intervention. Among the 1,139 lost clinic patients identified, 36% were in care elsewhere, 29% could not be located, 8% returned to the clinic independently, 4% declined enrollment and 7%(n=78) were located and enrolled in the intervention. Participants received an average of 4.5 Navigator sessions over 11.6 hours. Among re-engaged patients, 68% linked within 3 months, 85% linked within 6 months and 94% linked within 12 months and 82% of linked patients were retained in care 12-months post-study enrollment. The percentage of linked patients virally suppressed was compared at time of linkage by the Navigators(52%) to a second viral load measure following linkage to care(63%)(chi-square=11.8; p-value=0.01). The combined DIS/ARTAS model of re-engagement was effective for locating and re-engaging lost HIV clinic patients. Access to HIV surveillance data is critical for the efficient identification of persons truly in need of re-engagement.
    No preview · Article · Oct 2015 · JAIDS Journal of Acquired Immune Deficiency Syndromes
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    ABSTRACT: We investigated the associations between methamphetamine (meth) use, immune function, and the dynamics of HIV and cytomegalovirus [CMV] in the blood and genital tract of HIV-infected ART-suppressed subjects. Self-reported meth use was associated with increased CD4(+) and CD8(+) T-cell proliferation (Ki67(+), p < 0.005), CD4(+) T-cell activation (CD45RA(-)CD38(+), p = 0.005) and exhaustion (PD-1(+), p = 0.0004) in blood, compared to non-meth users. Meth use was also associated with a trend towards higher blood HIV DNA levels (p = 0.09) and more frequent shedding of CMV in seminal plasma (p = 0.002). To explore possible mechanisms, we compared ex vivo spontaneous and antigen-specific proliferation in PBMC collected from subjects with and without positive meth detection in urine (Utox+ vs. Utox-). Despite higher levels of spontaneous proliferation, lymphocytes from Utox+ meth users had a significantly lower proliferative capacity after stimulation with a number of pathogens (CMV, candida, mycobacterium, toxoplasma, HIV, p < 0.04 in all cases), compared to Utox- participants. Our findings suggest that meth users have greater proliferation and exhaustion of the immune system. Meth use is also associated with a loss of control of CMV replication, which could be related to loss of immune response to pathogens. Future studies should consider meth use as a potential modulator of T-cell responses.
    Full-text · Article · Aug 2015 · Scientific Reports
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    ABSTRACT: Tenofovir disoproxil fumarate (TDF) causes kidney toxicity in some patients. We carried out genomewide analyses to identify associations with plasma tenofovir clearance and change in creatinine clearance (CrCl) during the first 6 months after initiating therapy among patients randomized to TDF/emtricitabine-containing regimens in AIDS Clinical Trials Group protocol A5202. Pharmacokinetic analyses involved 501 patients randomized to the tenofovir arm. CrCl analyses involved 1096 patients, including 548 controls randomized to abacavir-containing regimens. All had been randomized to also receive atazanavir/ritonavir or efavirenz. Multivariable linear regression and generalized least squares models were used to test for associations between polymorphisms and tenofovir clearance and CrCl change, with Bonferroni correction. Planned subanalyses considered candidate genes and polymorphisms. Median CrCl at baseline was 116 ml/min (interquartile range 99.8-135.5). The median change in CrCl after 6 months was -0.5 ml/min (-10.7 to +10.8) and 2.2 (interquartile range -9.9 to +13.2) in tenofovir and abacavir arms, respectively. In genomewide analyses SLC17A1 rs12662869 was found to be associated with an increase in tenofovir clearance (P=7.1×10). In candidate gene analysis for tenofovir clearance, most polymorphisms evaluated were in ABCC4. In the ABCC4 region, the lowest P-value was for CLDN10 rs12866697 (P=1.4×10). Among African Americans, SLC22A2 rs3127573 was associated with a greater 6-month CrCl increase in the tenofovir arm after correcting for multiple comparisons (P=3.3×10). Among patients randomized to receive TDF/emtricitabine in A5202, there were no significant genomewide associations with change in CrCl. This study did not replicate polymorphisms previously implicated in tenofovir-associated renal injury.
    No preview · Article · Jul 2015 · Pharmacogenetics and Genomics
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    ABSTRACT: Sexually transmitted infections (STI) are common among HIV-infected men who have sex with men (MSM). While behavioral factors are important in STI acquisition, other biological factors such as immune modulation due to chronic viral infection may further predispose to STI acquisition. Post Hoc analysis including data collected over 12 months of follow-up from 131 HIV-infected MSM receiving antiretroviral therapy and screened for incident bacterial STI every 3 months. Genital secretions collected at baseline were used to measure herpesvirus replication and inflammatory cytokines. Baseline predictors of STI were determined using survival analysis of time to incident STI. All participants were seropositive for cytomegalovirus (CMV), and 52% had detectable genital CMV at baseline. Thirty-five individuals acquired STI during follow-up, sometimes with multiple pathogen (17 syphilis, 21 gonorrhea, 14 chlamydia). Syphilis acquisition was associated with genital CMV replication at baseline (19.1% CMV-shedders versus 4.8% non-shedders, p=0.03) and younger age (p=0.02). Lower seminal MCP-1 was associated with higher seminal CMV levels and with syphilis acquisition (p<0.01). For syphilis acquisition, in multivariable Cox-Proportional Hazard model adjusted hazard rates were 3.56 (95%CI:1.00-12.73) for baseline CMV replication and 2.50 (0.92-6.77) for younger age. This post hoc analysis suggest that CMV-associated decrease in seminal MCP-1 levels might predispose HIV-infected MSM to syphilis acquisition, but not other STI. Future studies should determine underlying mechanisms and if a causal association exists.
    Full-text · Article · Jun 2015 · PLoS ONE
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    ABSTRACT: Among patients with HIV infection, changes in the kidney filtration marker cystatin C after initiation of antiretroviral therapy (ART) may be related to changes in body composition or biomarkers of inflammation. ACTG A5224s was a substudy of A5202, which randomly assigned ART-naive HIV-infected subjects to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or ritonavir-boosted atazanavir. This analysis explored changes in cystatin C from 0 to 96 weeks. Of the 269 subjects, 85% were male and 66% white non-Hispanics; baseline mean CD4 count was 236 cells per cubic millimeter and cystatin C was 0.89 mg/L. Cystatin C decreased significantly within each arm; however, ritonavir-boosted atazanavir attenuated the beneficial effects of ART on cystatin C compared to EFV. Compared to ABC/3TC, TDF/FTC led to a marginally significant attenuation for percent change analyses only. Higher baseline body mass index and HIV RNA were associated with larger reductions in cystatin C in multivariable models. At baseline, cystatin C was positively correlated with high-sensitivity C-reactive protein (Spearman r = 0.25), interleukin 6 (r = 0.34), soluble intercellular adhesion molecule (r = 0.36), soluble vascular cell adhesion molecule (r = 0.54), tumor necrosis factor α (r = 0.57), and soluble TNF-α receptor I (r = 0.70, all P < 0.001). Reductions in cystatin C from 0 to 96 weeks correlated with reductions in all inflammatory biomarkers (r = 0.39-0.58, P < 0.001) except for high-sensitivity C-reactive protein (r = 0.01, P = 0.89) and IL-6 (r = 0.08, P = 0.24). The beneficial effect of ART on cystatin C concentrations is attenuated by boosted ATV when compared to EFV. Reductions in cystatin C after ART are associated with reductions in systemic inflammation.
    No preview · Article · Jun 2015 · JAIDS Journal of Acquired Immune Deficiency Syndromes
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    ABSTRACT: Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice.
    Full-text · Article · Mar 2015 · PLoS Medicine
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    ABSTRACT: Many hepatitis C virus regimens are unlikely to be compared head to head. In more difficult to treat populations where there is no standard of care, trials are single arm. We describe a flexible meta-analysis platform in this setting. Our meta-analysis is literature based. We illustrate our methodology and show how inference can be extended to single-arm trials. As an example, in the single arm setting, a regimen with response rates of 84, 72 and 54% in genotype 1a across treatment naive, previous partial responders and previous null responders, respectively, would have 95% probability of superiority to IFN-α + RBV + TPV. This is a rigorous approach to comparative effectiveness that accounts for varying patient populations and plans for the incorporation of emerging treatments.
    Preview · Article · Mar 2015 · Journal of Comparative Effectiveness Research
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    ABSTRACT: Substance using HIV patients are at risk for non-adherence, and most prior interventions in this population have had only modest effects on adherence. Contingency management (CM) is a promising intervention. The Centralized Off-site Adherence Enhancement (CARE) program involved 12 telephone-delivered substance and adherence-targeted cognitive behavior therapy sessions coupled with CM for adherence to antiretroviral therapy (ART) and counseling participation. CM involved 6 weeks of escalating reinforcement for taking prescribed doses followed by 6 weeks of tapering variable rate reinforcement, and separate reinforcement for counseling ($806 possible). Participants’ adherence was measured by devices which wirelessly provided real-time notification of device-opening. HIV infected patients on ART (N = 10) with recent stimulant or alcohol use completed 10.2 of 12 possible telephone sessions, spent 42.8 min/call, and rated the counseling 6.2 on a 1–7 scale. Medication adherence improved from 81 to 93 % (p = 0.04). CARE appears to be acceptable and engaging.
    Full-text · Article · Feb 2015 · AIDS and Behavior
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    ABSTRACT: In this article, we examine the effectiveness of a variety of HIV diagnosis interventions in recently HIV-diagnosed men who have sex with men (MSM). These interventions use the preventive potential of postdiagnosis behavior change (PDBC), as measured by the reduction in the number of new infections. Empirical evidence for PDBC was presented in the behavioral substudy of the Southern California Acute Infection and Early Disease Research Program. In previous modeling work, we demonstrated the existing preventive effects of PDBC. However, a large proportion of new infections among MSM are either undiagnosed or diagnosed late, and the preventive potential of PDBC is not fully utilized. We derive empirical, stochastic, network-based models to examine the effectiveness of several diagnosis interventions that account for PDBC among MSM over a 10-year period. These interventions involve tests with shorter detection windows, more frequent testing, and individualized testing regimens. We find that individualized testing interventions (i.e., testing individuals every three partners or 3 months, whichever is first, or every six partners or 6 months, whichever is first) result in significantly fewer new HIV infections than the generalized interventions we consider. This work highlights the potential of individualized interventions for new public health policies in HIV prevention. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jan 2015 · Annals of Epidemiology
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    ABSTRACT: HIV-associated brain injury persists despite antiretroviral therapy (cART), but contributing factors remain poorly understood. We postulated that inflammation-associated biomarkers will be associated with cerebral injury on proton magnetic resonance spectroscopy (MRS) in chronically HIV-infected subjects. Five biomarkers were measured in 197 HIV-infected subjects: soluble CD14, MCP-1, IP-10, MIP-1β, and fractalkine. Levels of N-acetyl aspartate (NAA), Choline (Cho), Myoinositol (MI), Glutamate+Glutamine (Glx), and Creatine (Cr) were acquired in the midfrontal cortex (MFC), frontal white matter (FWM), and basal ganglia (BG). Predictive models were built via linear regression and the best models were chosen using the Akaike Information Criterion. Increases in plasma or CSF MCP-1 were associated with lower NAA/Cr in the MFC and BG while metabolite changes in the FWM for NAA/Cr, GlxCr and Cho/Cr were explained almost exclusively by a single factor, sCD14. Plasma and CSF levels of this factor were also significantly associated with Glx/Cr in MFC and BG. Higher CSF FKN was associated with higher NAA/Cr in BG. Best predictors for higher Cho/Cr in BG and MFC were CSF sCD14 and CSF MIP-1β. Plasma and CSF IP-10 were only associated with Cho/Cr in MFC. Of the three models that simultaneously accounted for both plasma and CSF, there were more associations between CSF biomarkers and MRS metabolites. Markers of inflammation and immune activation, in particular MCP-1 and sCD14, predominantly reflecting CNS sources, contribute to the persistence of brain injury in a metabolite and region dependent manner in chronically HIV-infected patients on stable cART.
    No preview · Article · Jan 2015 · JAIDS Journal of Acquired Immune Deficiency Syndromes

  • No preview · Article · Jan 2015 · Journal of Comparative Effectiveness Research
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    ABSTRACT: Background. Phenome-Wide Association Studies (PheWAS) identify genetic associations across multiple phenotypes. Clinical trials offer opportunities for PheWAS to identify pharmacogenomic associations. We describe the first PheWAS to use genome-wide genotypic data and to utilize human immunodeficiency virus (HIV) clinical trials data. As proof-of-concept, we focused on baseline laboratory phenotypes from antiretroviral therapy-naive individuals. Methods. Data from 4 AIDS Clinical Trials Group (ACTG) studies were split into 2 datasets: Dataset I (1181 individuals from protocol A5202) and Dataset II (1366 from protocols A5095, ACTG 384, and A5142). Final analyses involved 2547 individuals and 5 954 294 imputed polymorphisms. We calculated comprehensive associations between these polymorphisms and 27 baseline laboratory phenotypes. Results. A total of 10 584 (0.17%) polymorphisms had associations with P < .01 in both datasets and with the same direction of association. Twenty polymorphisms replicated associations with identical or related phenotypes reported in the Catalog of Published Genome-Wide Association Studies, including several not previously reported in HIV-positive cohorts. We also identified several possibly novel associations. Conclusions. These analyses define PheWAS properties and principles with baseline laboratory data from HIV clinical trials. This approach may be useful for evaluating on-treatment HIV clinical trials data for associations with various clinical phenotypes.
    Full-text · Article · Dec 2014 · Open Forum Infectious Diseases
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    ABSTRACT: Efavirenz and abacavir are components of recommended first-line regimens for HIV-1 infection. We used genome-wide genotyping and clinical data to explore genetic associations with virologic failure among patients randomized to efavirenz-containing or abacavir-containing regimens in AIDS Clinical Trials Group (ACTG) protocols. Virologic response and genome-wide genotype data were available from treatment-naive patients randomized to efavirenz-containing (n=1596) or abacavir-containing (n=786) regimens in ACTG protocols 384, A5142, A5095, and A5202. Meta-analysis of association results across race/ethnic groups showed no genome-wide significant associations (P<5×10) with virologic response for either efavirenz or abacavir. Our sample size provided 80% power to detect a genotype relative risk of 1.8 for efavirenz and 2.4 for abacavir. Analyses focused on CYP2B genotypes that define the lowest plasma efavirenz exposure stratum did not show associations nor did analysis limited to gene sets predicted to be relevant to efavirenz and abacavir disposition. No single polymorphism is associated strongly with virologic failure with efavirenz-containing or abacavir-containing regimens. Analyses to better consider context, and that minimize confounding by nongenetic factors, may show associations not apparent here.
    No preview · Article · Nov 2014 · Pharmacogenetics and Genomics

  • No preview · Article · Oct 2014 · Open Forum Infectious Diseases
  • Katya R. Calvo · Eric S. Daar
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    ABSTRACT: Antiretroviral therapy (ART)-experienced individuals may choose to modify their regimens because of suboptimal virologic response, poor tolerability, convenience, or to minimize interactions with other medications or food. Constructing a new regimen for any of these reasons requires a thorough review of prior antiretroviral drug use and available drug resistance results. This article summarizes the strategies used in managing the ART-experienced individual who is considering a modification in therapy at the time of suboptimal virologic response or while virologically suppressed on a stable regimen.
    No preview · Article · Sep 2014 · Infectious Disease Clinics of North America
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    ABSTRACT: Background: Antiretroviral therapy (ART) is associated with improved kidney function; however, the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) has been associated with decreased kidney function and proteinuria. Methods: We examined changes in urine protein:creatinine (UPCR) and urine albumin:creatinine (UACR) ratios in 245 ART-naive participants in A5202 randomized in a substudy to blinded NRTI (abacavir/lamivudine, ABC/3TC, n = 124 or TDF/emtricitabine, TDF/FTC, n = 121) with open-label protease inhibitor (PI) atazanavir/ritonavir or nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. Results: At baseline, 18% of participants had clinically significant proteinuria (UPCR ≥200 mg/g), and 11% had clinically significant albuminuria (UACR ≥30 mg/g). The prevalence of clinically significant proteinuria and albuminuria decreased from baseline to week 96 in all treatment groups. In intention-to-treat analyses, there was a significant effect of NRTI component on fold change in UPCR (P = 0.011) and UACR (P = 0.018) from baseline to week 96, with greater improvements in participants randomized to ABC/3TC. There was no significant effect of NNRTI/PI component on fold change in UPCR (P = 0.23) or UACR (P = 0.88), and no significant interactions between NRTI and NNRTI/PI components. Conclusions: In this prespecified secondary analysis, ART initiation was associated with improvements in proteinuria and albuminuria, with significantly greater improvements in participants randomized to ABC/3TC versus TDF/FTC. These are the first data from a randomized trial to suggest that initiation of TDF/FTC may not be associated with the same degree of improvement in proteinuria and albuminuria that have been reported with other regimens. Future studies should consider the long-term clinical significance of these findings.
    No preview · Article · Sep 2014 · JAIDS Journal of Acquired Immune Deficiency Syndromes

Publication Stats

9k Citations
1,268.59 Total Impact Points

Institutions

  • 2003-2015
    • Harbor-UCLA Medical Center
      • Department of Pediatrics
      Torrance, California, United States
  • 2002-2015
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
  • 1990-2015
    • University of California, Los Angeles
      • Division of Infectious Diseases
      Los Ángeles, California, United States
  • 2014
    • George Washington University
      Washington, Washington, D.C., United States
  • 2011
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2002-2009
    • University of Pittsburgh
      • Division of Infectious Diseases
      Pittsburgh, Pennsylvania, United States
  • 2006-2007
    • San Diego State University
      • Department of Psychology
      San Diego, California, United States
  • 2004
    • Los Angeles Harbor College
      Los Ángeles, California, United States
  • 1991-2001
    • Cedars-Sinai Medical Center
      • • Division of Infectious Diseases
      • • Department of Medicine
      Los Ángeles, California, United States
  • 1999
    • Children's Hospital Los Angeles
      Los Ángeles, California, United States