Publications by authors named "Deborah McMahon"

57 Publications

Targeting xenobiotic nuclear receptors PXR and CAR to prevent cobicistat hepatotoxicity.

Toxicol Sci 2021 Feb 25. Epub 2021 Feb 25.

Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Liver-related diseases including drug-induced liver injury are becoming increasingly prominent in AIDS patients. Cobicistat (COBI) is the backbone of multiple regimens for antiretroviral therapy. The current work investigated the mechanisms of adverse drug-drug interactions associated with COBI that lead to liver damage. For individuals co-infected with HIV and tuberculosis (TB), the World Health Organization recommends the initiation of TB treatment followed by antiretroviral therapy. Rifampicin (RIF), a first line anti-TB drug, is a human specific activator of pregnane X receptor (PXR). Using PXR-humanized mice, we found that RIF-mediated PXR activation potentiates COBI hepatotoxicity. In contrast, rifabutin, a PXR-neutral analog of RIF, has no impact on COBI hepatotoxicity. Because of the crosstalk between PXR and the constitutive androstane receptor (CAR), the role of CAR in COBI hepatotoxicity was also investigated. Similar to PXR, ligand-dependent activation of CAR also potentiates COBI hepatotoxicity. Our further studies illustrated that PXR and CAR modulate COBI hepatotoxicity through the CYP3A4-dependent pathways. In summary, the current work determined PXR and CAR as key modulators of COBI hepatotoxicity. Given the fact that many prescription drugs and herbal supplements can activate PXR and CAR, these two receptors should be considered as targets to prevent COBI hepatotoxicity in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/toxsci/kfab023DOI Listing
February 2021

HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite long-term therapy.

JCI Insight 2021 Feb 8;6(3). Epub 2021 Feb 8.

Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.

Antiretroviral therapies (ARTs) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which reseed replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.142640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934865PMC
February 2021

A phase I/II randomized, placebo-controlled trial of romidepsin in persons with HIV-1 on suppressive antiretroviral therapy to assess safety and activation of HIV-1 expression (A5315).

J Infect Dis 2020 Dec 22. Epub 2020 Dec 22.

University of Pittsburgh, Pittsburgh, PA.

Background: Romidepsin (RMD) is a histone deacetylase inhibitor reported to reverse HIV-1 latency. We sought to identify doses of RMD that were safe and induced HIV-1 expression.

Methods: Enrollees had HIV-1 RNA <40 copies/ml on ART. Measurements included RMD levels, plasma viremia by single copy HIV-1 RNA assay, HIV-1 DNA, cell-associated unspliced HIV-1 RNA (CA-RNA), acetylation of histone H3-lysine-9 (H3K9ac+) and phosphorylation of transcription factor P-TEFb. Wilcoxon tests were used for comparison.

Results: 43 participants enrolled in the single dose Cohorts 1-3 of 0.5, 2, and 5 mg/m 2 (36 RMD; 7 placebo) and 16 enrolled in the multi-dose Cohort 4 of 5 mg/m 2 (13 RMD; 3 placebo). One grade 3 event (neutropenia) was possibly treatment-related. No significant changes in viremia were observed in Cohorts 1-4 compared to placebo. In Cohort 4, observed pharmacodynamic effects of RMD were reduced proportions of CD4+ T cells 24 hours after infusions 2, 3, and 4 (median -3.5% to -4.5%) vs. placebo (+0.5% to 1%; p≤0.022) and increases in H3K9ac+ and phosphorylated P-TEFb in CD4 + T cells compared to placebo (p≤0.02).

Conclusions: RMD infusions were safe but did not increase plasma viremia or unspliced CA-RNA despite pharmacodynamic effects on CD4 + T cells. The trial is registered with ClinicalTrials.gov, number NCT01933594.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiaa777DOI Listing
December 2020

Selective Decay of Intact HIV-1 Proviral DNA on Antiretroviral Therapy.

J Infect Dis 2021 Feb;223(2):225-233

Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: HIV-1 proviruses persist in people on antiretroviral therapy (ART) but most are defective and do not constitute a replication-competent reservoir. The decay of infected cells carrying intact compared with defective HIV-1 proviruses has not been well defined in people on ART.

Methods: We separately quantified intact and defective proviruses, residual plasma viremia, and markers of inflammation and activation in people on long-term ART.

Results: Among 40 participants tested longitudinally from a median of 7.1 years to 12 years after ART initiation, intact provirus levels declined significantly over time (median half-life, 7.1 years; 95% confidence interval [CI], 3.9-18), whereas defective provirus levels did not decrease. The median half-life of total HIV-1 DNA was 41.6 years (95% CI, 13.6-75). The proportion of all proviruses that were intact diminished over time on ART, from about 10% at the first on-ART time point to about 5% at the last. Intact provirus levels on ART correlated with total HIV-1 DNA and residual plasma viremia, but there was no evidence for associations between intact provirus levels and inflammation or immune activation.

Conclusions: Cells containing intact, replication-competent proviruses are selectively lost during suppressive ART. Defining the mechanisms involved should inform strategies to accelerate HIV-1 reservoir depletion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiaa532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857155PMC
February 2021

Association of Male Sex and Obesity With Residual Plasma Human Immunodeficiency Virus 1 Viremia in Persons on Long-Term Antiretroviral Therapy.

J Infect Dis 2021 Feb;223(3):462-470

Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Background: Although adipose tissue has been proposed to harbor part of the human immunodeficiency virus 1 (HIV-1) reservoir, the influence of host characteristics, including sex and body mass index (BMI), on measures of HIV-1 persistence during antiretroviral therapy (ART) are incompletely understood.

Methods: We evaluated age, sex, BMI, waist circumference, years on ART, pre-ART HIV-1 RNA, pre-ART CD4+ T-cell count, and initial ART regimen with measures of HIV-1 persistence in blood (residual viremia, cellular HIV-1 DNA and RNA) in a cohort of 295 individuals with well-documented long-term virologic suppression (HIV-1 RNA <50 copies/mL) on ART (AIDS Clinical Trials Group study A5321).

Results: Men were more likely than women to have detectable plasma HIV-1 RNA by single-copy assay (52% vs 29%; P = .003), and the proportion of participants with detectable residual viremia increased in a stepwise fashion by BMI category (normal weight or underweight, 38%; overweight, 50%; and obese, 55%). ART regimen type was not associated with measures of HIV-1 persistence after controlling for ART duration.

Conclusions: Sex and obesity are independently associated with residual viremia in people on long-term ART. Additional studies to confirm these relationships and to define the mechanisms by which sex and obesity affect HIV-1 persistence are needed to inform HIV-1 cure strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiaa373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881329PMC
February 2021

ABCG2 Deficiency Does Not Alter Dolutegravir Metabolism and Pharmacokinetics.

J Pharmacol Exp Ther 2020 07 17;374(1):38-43. Epub 2020 Apr 17.

Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy (J.Z., X.T., A.I.S., X.M.) and Division of Infectious Disease, Department of Medicine (D.K.M.), University of Pittsburgh, Pittsburgh, Pennsylvania

Dolutegravir (DTG) is a potent integrase inhibitor of human immunodeficiency virus. Because DTG is a substrate of the efflux transporter ABCG2 and ABCG2 is highly polymorphic, we asked whether dose adjustment of DTG is needed for ABCG2-deficient individuals. Using Abcg2-null mice, the current work investigated the impact of ABCG2 deficiency on DTG metabolism and pharmacokinetics. Compared with wild-type mice, no statistically significant difference was found in the systemic and tissue-specific (liver, kidney, and brain) pharmacokinetics of DTG in Abcg2-null mice. In addition, ABCG2 deficiency had no statistically significant impact on the production and excretion of DTG metabolites. In summary, this study demonstrated that deficiency of ABCG2 does not alter DTG metabolism and pharmacokinetics, suggesting that dose adjustment of DTG is not needed for individuals with ABCG2 deficiency. SIGNIFICANCE STATEMENT: The current work demonstrated that deficiency of ATP-binding cassette subfamily G member 2 (ABCG2) does not alter Dolutegravir (DTG) metabolism and pharmacokinetics, suggesting that dose adjustment of DTG is not needed for individuals with ABCG2 deficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.119.264424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292963PMC
July 2020

Association Between Inflammatory Pathways and Phenotypes of Pulmonary Dysfunction Using Cluster Analysis in Persons Living With HIV and HIV-Uninfected Individuals.

J Acquir Immune Defic Syndr 2020 02;83(2):189-196

Department of Medicine, University of Pittsburgh, Pittsburgh, PA.

Background: Persons living with HIV (PLWH) are at risk of developing different phenotypes of chronic lung disease, including chronic obstructive pulmonary disease. Mechanisms underlying these phenotypes are unclear.

Objective: To identify clusters of peripheral inflammatory mediators associated with pulmonary function to determine inflammatory pathways and phenotypes of chronic obstructive pulmonary disease in PLWH and HIV-uninfected individuals.

Methods: Study participants were PLWH and HIV-uninfected individuals enrolled in the Pittsburgh HIV Lung Cohort. Pulmonary function tests were performed for all participants. Chest computed tomographic scans were performed in a subset of PLWH. Plasma levels of 19 inflammatory mediators were measured by Luminex or ELISA. Clusters were identified based on the expression pattern of inflammatory mediators in PLWH and HIV-uninfected individuals, and the relationships among clinical parameters were evaluated within clusters by using cluster and network analyses.

Results: In PLWH, we identified a distinct cluster with higher levels of Th1, Th2, and Th17 inflammatory mediators with increased complexity of these mediators and inferred presence of pathogenic Th17 cell types. Individuals in this cluster had worse airway obstruction and more radiographic emphysema. In HIV-uninfected individuals, a cluster with high-grade systemic inflammation also had worse diffusing capacity for carbon monoxide.

Conclusions: Inflammatory pathways associated with pulmonary dysfunction in PLWH suggest multifaceted immune dysregulation involved in different phenotypes of pulmonary dysfunction with a potential specific contribution of the Th17 pathway to airway obstruction in PLWH. Identification of these associations may help in development of treatments that could alter the course of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000002234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193693PMC
February 2020

T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy.

AIDS 2020 01;34(1):15-24

Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts Division of Infectious Diseases, Weill Cornell Medicine, New York, New York Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania Social & Scientific Systems, Inc., Silver Spring, Maryland Department of Medicine, University of North Carolina, Chapel Hill, North Carolina Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Objective: We evaluated frequencies of T cells with high PD-1 expression (PD-1) before and after long-term effective antiretroviral therapy (ART), and determined if frequencies on-ART correlated positively with measures of HIV persistence and negatively with HIV-specific responses.

Methods: We enrolled individuals who started ART during chronic infection and had durable suppression of viremia for at least 4 years (N = 99). We assessed PD-1 T-cell frequencies at timepoints pre-ART and on-ART using flow cytometry, and evaluated how frequencies on-ART are associated with measures of HIV persistence, HIV-specific immune responses, and immune activation levels.

Results: Pre-ART, PD-1 CD4 T cells correlated positively with viremia and negatively with CD4 T-cell count. At year 1 on-ART, %PD-1 CD4 T cells decreased but then remained stable at 4 and 6-15 years on-ART, whereas %PD-1 CD8 T cells on-ART remained similar to pre-ART. PD-1 CD4 T cells correlated positively with HIV DNA pre-ART and on-ART, and with CD4 T-cell activation on-ART. PD-1 CD4 T cells negatively correlated with HIV Gag-specific and Env-specific T-cell responses but not with CMV-specific or EBV-specific responses. PD-1 CD8 T cells trended towards a negative correlation with responses to Gag and Env, but not to CMV and EBV.

Conclusion: PD-1 T cells persist in blood despite prolonged suppression on ART, correlate with HIV DNA levels, and are associated with lower HIV-specific T-cell responses but not CMV-specific or EBV-specific responses, suggesting that these cells are HIV-specific. The findings support evaluating PD-1 blockade strategies for their effect on HIV persistence and HIV-specific immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAD.0000000000002406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313719PMC
January 2020

Brief Report: No Evidence for an Association Between Statin Use and Lower Biomarkers of HIV Persistence or Immune Activation/Inflammation During Effective ART.

J Acquir Immune Defic Syndr 2019 10;82(2):e27-e31

Massachusetts General Hospital, Boston, MA.

Background: Statins exert pleiotropic anti-inflammatory and immune-modulatory effects, which might translate into antiviral activity. We evaluated whether reported current statin exposure is associated with lower levels of markers of HIV persistence and immune activation/inflammation.

Methods: We compared levels of markers of HIV viral persistence [cell-associated HIV RNA (CA-RNA), CA-DNA, and single copy assay plasma HIV RNA] and immune activation/inflammation (IL-6, IP-10, neopterin, sCD14, sCD163, and TNF-alpha) between statin users and nonusers among participants of ACTG A5321 who initiated antiretroviral therapy (ART) during chronic infection and maintained virologic suppression (HIV-1 RNA levels ≤50 copies/mL) for ≥3 years.

Results: A total of 303 participants were analyzed. Median time on the current statin was 2.9 years (1.2-5.1). There were no differences between statin users and nonusers in levels of CA-DNA (median 650 vs. 540 copies/10 CD4 T cells; P = 0.58), CA-RNA (53 vs. 37 copies/10 CD4 T cells; P = 0.12), or single copy assay (0.4 vs. 0.4 copies/mL; P = 0.45). Similarly, there were no significant differences between statin users and nonusers in markers of inflammation/activation, except for IP-10 (137 vs. 118 pg/mL; P = 0.028). Findings were unchanged after adjustment for factors including pre-ART CD4 and HIV RNA, and years on ART.

Conclusions: In this cohort of persons on long-term suppressive ART, current statin use was not associated with lower levels of HIV persistence or immune activation/inflammation. These results do not support a major role for statins in reducing HIV persistence, although an early transient effect cannot be excluded. Prospective, randomized studies are needed to confirm these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000002124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799994PMC
October 2019

Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance.

J Clin Invest 2019 07 15;129(8):3339-3346. Epub 2019 Jul 15.

University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

BACKGROUNDPersistence of HIV in sanctuary sites despite antiretroviral therapy (ART) presents a barrier to HIV remission and may affect neurocognitive function. We assessed HIV persistence in cerebrospinal fluid (CSF) and associations with inflammation and neurocognitive performance during long-term ART.METHODSParticipants enrolled in the AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321) underwent concurrent lumbar puncture, phlebotomy, and neurocognitive assessment. Cell-associated HIV DNA and HIV RNA (CA-DNA, CA-RNA) were measured by quantitative PCR (qPCR). in peripheral blood mononuclear cells (PBMCs) and in cell pellets from CSF. In CSF supernatant and blood plasma, cell-free HIV RNA was quantified by qPCR with single copy sensitivity, and inflammatory biomarkers were measured by enzyme immunoassay.RESULTSSixty-nine participants (97% male, median age 50 years, CD4 696 cells/mm3, plasma HIV RNA <100 copies/mL) were assessed after a median 8.6 years of ART. In CSF, cell-free RNA was detected in 4%, CA-RNA in 9%, and CA-DNA in 48% of participants (median level 2.1 copies/103 cells). Detection of cell-free CSF HIV RNA was associated with higher plasma HIV RNA (P = 0.007). CSF inflammatory biomarkers did not correlate with HIV persistence measures. Detection of CSF CA-DNA HIV was associated with worse neurocognitive outcomes including global deficit score (P = 0.005), even after adjusting for age and nadir CD4 count.CONCLUSIONHIV-infected cells persist in CSF in almost half of individuals on long-term ART, and their detection is associated with poorer neurocognitive performance.FUNDINGThis observational study, AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321), was supported by the National Institutes of Health (NIAID and NIMH).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI127413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668666PMC
July 2019

Allogeneic Hematopoietic Cell Transplant for HIV Patients with Hematologic Malignancies: The BMT CTN-0903/AMC-080 Trial.

Biol Blood Marrow Transplant 2019 11 4;25(11):2160-2166. Epub 2019 Jul 4.

Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.

We set out to assess feasibility and safety of allogeneic hematopoietic cell transplant in 17 persons with HIV in a phase II prospective multicenter trial. The primary endpoint was 100-day nonrelapse mortality (NRM). Patients had an 8/8 HLA-matched related or at least a 7/8 HLA-matched unrelated donor. Indications for transplant were acute leukemia, myelodysplasia, and lymphoma. Conditioning was myeloablative or reduced intensity. There was no NRM at 100 days. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 41%. At 1 year, overall survival was 59%; deaths were from relapsed/progressive disease (n = 5), acute GVHD (n = 1), adult respiratory distress syndrome (n = 1), and liver failure (n = 1). In patients who achieved complete chimerism, cell-associated HIV DNA and inducible infectious virus in the blood were not detectable. Blood and Marrow Transplant Clinical Trials Network 0903/AIDS Malignancy Consortium 080 was registered at www.clinicaltrials.gov (no. NCT01410344).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2019.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907401PMC
November 2019

Brief Report: HIV Antibodies Decline During Antiretroviral Therapy but Remain Correlated With HIV DNA and HIV-Specific T-Cell Responses.

J Acquir Immune Defic Syndr 2019 08;81(5):594-599

Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA.

Background: In people with HIV on antiretroviral therapy (ART), the relationship between HIV-specific immune responses and measures of HIV persistence is uncertain.

Methods: We evaluated 101 individuals on suppressive ART in the AIDS Clinical Trials Group A5321 cohort. Cell-associated (CA) HIV DNA and RNA levels and HIV antibody concentrations and avidity to Env/p24 were measured longitudinally at years 1, 4, and 6-15 after ART initiation. Plasma HIV RNA by single copy assay and T-cell responses (IFN-γ ELISPOT) against multiple HIV antigens were measured at the last time point.

Results: HIV antibody levels declined significantly with increasing time on ART (19%/year between year 1 and 4). HIV antibody levels correlated with T-cell responses to HIV Pol (r = 0.28, P = 0.014) and to Nef/Tat/Rev (r = 0.34; P = 0.002). HIV antibody and T-cell responses were positively associated with HIV DNA levels; for example, at the last time point (median 7 years on ART), r = 0.35 for antibody levels and HIV DNA (P < 0.001); r = 0.23 for Nef/Tat/Rev-specific T-cell responses and HIV DNA (P = 0.03). Neither antibody nor T-cell responses correlated with cell-associated HIV RNA or plasma RNA by single copy assay.

Conclusions: In individuals on long-term ART, HIV-specific antibody and T-cell responses correlate with each other and with HIV DNA levels. The positive correlation between HIV immune responses and HIV DNA implies that the immune system is sensing, but not clearing, infected cells, perhaps because of immune dysfunction. Measuring immune responses to HIV antigens may provide insight into the impact of reservoir-reducing strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000002080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625873PMC
August 2019

Pregnane X receptor activation potentiates ritonavir hepatotoxicity.

J Clin Invest 2019 04 30;129(7):2898-2903. Epub 2019 Apr 30.

Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, and.

Ritonavir (RTV) is on the World Health Organization's List of Essential Medicines for antiretroviral therapy, but can cause hepatotoxicity by unknown mechanisms. Multiple clinical studies found that hepatotoxicity occurred in 100% of participants who were pretreated with rifampicin or efavirenz followed by RTV-containing regimens. Both rifampicin and efavirenz are activators of the pregnane X receptor (PXR), a transcription factor with significant inter-species differences in ligand-dependent activation. Using PXR-humanized mouse models, we recapitulated the RTV hepatotoxicity observed in the clinic. PXR was found to modulate RTV hepatotoxicity through CYP3A4-dependent pathways involved in RTV bioactivation, oxidative stress, and endoplasmic reticulum stress. In summary, the current work demonstrated the essential roles of human PXR and CYP3A4 in RTV hepatotoxicity, which can be applied to guide the safe use of RTV-containing regimens in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI128274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597219PMC
April 2019

HIV infection is an independent risk factor for decreased 6-minute walk test distance.

PLoS One 2019 24;14(4):e0212975. Epub 2019 Apr 24.

Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

Background: Ambulatory function predicts morbidity and mortality and may be influenced by cardiopulmonary dysfunction. Persons living with HIV (PLWH) suffer from a high prevalence of cardiac and pulmonary comorbidities that may contribute to higher risk of ambulatory dysfunction as measured by 6-minute walk test distance (6-MWD). We investigated the effect of HIV on 6-MWD.

Methods: PLWH and HIV-uninfected individuals were enrolled from 2 clinical centers and completed a 6-MWD, spirometry, diffusing capacity for carbon monoxide (DLCO) and St. George's Respiratory Questionnaire (SGRQ). Results of 6-MWD were compared between PLWH and uninfected individuals after adjusting for confounders. Multivariable linear regression analysis was used to determine predictors of 6-MWD.

Results: Mean 6-MWD in PLWH was 431 meters versus 462 in 130 HIV-uninfected individuals (p = 0.0001). Older age, lower forced expiratory volume (FEV1)% or lower forced vital capacity (FVC)%, and smoking were significant predictors of decreased 6-MWD in PLWH, but not HIV-uninfected individuals. Lower DLCO% and higher SGRQ were associated with lower 6-MWD in both groups. In a combined model, HIV status remained an independent predictor of decreased 6-MWD (Mean difference = -19.9 meters, p = 0.005).

Conclusions: HIV infection was associated with decreased ambulatory function. Airflow limitation and impaired diffusion capacity can partially explain this effect. Subjective assessments of respiratory symptoms may identify individuals at risk for impaired physical function who may benefit from early intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212975PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481785PMC
December 2019

Naive CD4+ T Cells Harbor a Large Inducible Reservoir of Latent, Replication-competent Human Immunodeficiency Virus Type 1.

Clin Infect Dis 2019 11;69(11):1919-1925

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

Background: The latent human immunodeficiency virus type 1 (HIV-1) reservoir represents a major barrier to a cure. Based on the levels of HIV-1 DNA in naive (TN) vs resting memory CD4+ T cells, it is widely hypothesized that this reservoir resides primarily within memory cells. Here, we compared virus production from TN and central memory (TCM) CD4+ T cells isolated from HIV-1-infected individuals on suppressive therapy.

Methods: CD4+ TN and TCM cells were purified from the blood of 7 HIV-1-infected individuals. We quantified total HIV-1 DNA in the CD4+ TN and TCM cells. Extracellular virion-associated HIV-1 RNA or viral outgrowth assays were used to assess latency reversal following treatment with anti-CD3/CD28 monoclonal antibodies (mAbs), phytohaemagglutinin/interleukin-2, phorbol 12-myristate 13-acetate/ionomycin, prostratin, panobinostat, or romidepsin.

Results: HIV-1 DNA was significantly higher in TCM compared to TN cells (2179 vs 684 copies/106 cells, respectively). Following exposure to anti-CD3/CD28 mAbs, virion-associated HIV-1 RNA levels were similar between TCM and TN cells (15 135 vs 18 290 copies/mL, respectively). In 4/7 donors, virus production was higher for TN cells independent of the latency reversing agent used. Replication-competent virus was recovered from both TN and TCM cells.

Conclusions: Although the frequency of HIV-1 infection is lower in TN compared to TCM cells, as much virus is produced from the TN population after latency reversal. This finding suggests that quantifying HIV-1 DNA alone may not predict the size of the inducible latent reservoir and that TN cells may be an important reservoir of latent HIV-1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciz108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853701PMC
November 2019

CYP1A1 and 1B1-mediated metabolic pathways of dolutegravir, an HIV integrase inhibitor.

Biochem Pharmacol 2018 12 17;158:174-184. Epub 2018 Oct 17.

Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address:

Dolutegravir (DTG), a potent integrase inhibitor, is part of a recommended initial regimen for the treatment of human immunodeficiency virus (HIV). Prior reports demonstrated that the clearance of DTG was higher in current smokers than non-smokers, but the mechanism remains unclear. Using a metabolomic approach, M4 (an aldehyde) was identified as a novel metabolite of DTG. In addition, the formation of M4 was found to be mediated by cytochrome P450 (CYP) 1A1 and 1B1, the enzymes that can be highly induced by cigarette smoking. CYP1A1 and 1B1 were also identified as the major enzymes contributing to the formation of M1 (an N-dealkylated metabolite of DTG) and M5 (an aldehyde). Furthermore, the production of M1 and M4 was significantly increased in the lung of mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin, an inducer of CYP1A1 and 1B1. In summary, the current study uncovered the CYP1A1 and 1B1-mediated metabolic pathways of DTG. These data suggest that persons with HIV infection receiving DTG should be cautious to cigarettes, and drugs, or exposure to environmental chemicals that induce CYP1A1 and 1B1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2018.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263788PMC
December 2018

Tropheryma whipplei colonization in HIV-infected individuals is not associated with lung function or inflammation.

PLoS One 2018 4;13(10):e0205065. Epub 2018 Oct 4.

Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

Studies demonstrate that Tropheryma whipplei (T. whipplei) is present in the lungs of healthy individuals without acute respiratory symptoms or acute respiratory infection and is more common in the lungs of HIV-infected individuals and in smokers. The impact of T. whipplei colonization in the lung on local inflammation and pulmonary dysfunction in HIV-infected individuals is currently unknown. In this study, we performed specific polymerase chain reaction (PCR) and sequencing for T. whipplei in bronchoalveolar lavage (BAL) and induced sputum (IS) samples in 76 HIV-infected participants from three clinical sites. Pulmonary function and proinflammatory cytokine and chemokine levels in BAL were measured. Frequency of T. whipplei in either BAL or IS was 43.4%. The sensitivity and specificity of IS compared to BAL for detection of T. whipplei was 92.3% and 84.2%, respectively, and isolates of T. whipplei in the BAL and IS in the same subject shared genetic identity. Pulmonary function measures were not associated with T. whipplei colonization, and proinflammatory cytokine and chemokine levels in BAL and plasma as well as percentages of inflammatory cells in BAL and IS were not higher in colonized individuals. Overall, these results indicate that T. whipplei colonization in the lung is common, but may not be associated with decreased pulmonary function or inflammation in HIV-infected individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205065PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171914PMC
April 2019

Factors Associated With Progression of Lung Function Abnormalities in HIV-Infected Individuals.

J Acquir Immune Defic Syndr 2018 12;79(4):501-509

Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Background: HIV is an independent risk factor for chronic obstructive pulmonary disease; however, baseline risk factors for lung function decline remain largely unknown in this population.

Methods: HIV-infected participants in the Pittsburgh Lung HIV Cohort with at least 3 pulmonary function measurements between 2007 and 2016 were included. Pulmonary function testing including postbronchodilator (BD) spirometry and diffusion capacity for carbon monoxide (DLco) was performed every 18 months. We used a mixed-effect linear model to evaluate factors associated with pulmonary function testing and DLco decline and logistic regression models to evaluate factors associated with rapid FEV1 decline (defined as >80 mL per year) and any DLco decline.

Results: Two hundred eighty-five HIV-infected participants were included. Median baseline CD4 cell count was 521 cells per micro liter, 61.9% had an undetectable HIV viral load at baseline, and 78.5% were receiving ART. Approximately 20% of participants met Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for a diagnosis of chronic obstructive pulmonary disease at baseline. Older age and baseline GOLD stage 1 compared with stage 0 were associated with faster decline in post-BD FEV1%, whereas female sex was associated with slower decline. Similarly, female sex was associated with slower decline in DLco%. HIV-related factors including CD4 cell count, viral load, and ART use were not significantly associated with pulmonary function decline.

Conclusions: Older age, male sex, and higher baseline GOLD stage were associated with more rapid post-BD FEV1% decline in HIV-infected individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000001840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203646PMC
December 2018

The North-South Divide: Substance Use Risk, Care Engagement, and Viral Suppression Among Hospitalized Human Immunodeficiency Virus-Infected Patients in 11 US Cities.

Clin Infect Dis 2019 01;68(1):146-149

Department of Sociomedical Sciences, Columbia University Mailman School of Public Health, New York, New York.

Regional variability in human immunodeficiency virus (HIV) care engagement remains underexplored. Multiple logistic models compared HIV outcomes for participants from 5 Southern (n = 557) and 6 non-Southern (n = 670) sites. Southern participants were less likely to experience viral suppression (adjusted odds ratio [aOR], 0.52; 95% confidence interval [CI], .37-.72) and had a higher likelihood of a CD4+ count <200 cells/µL (aOR, 1.53; 95% CI, 1.17-2.00). HIV intervention and social safety net programs should be expanded.

Clinical Trials Registration: NCT01612169.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciy506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293003PMC
January 2019

Cumulative Antiretroviral Exposure Measured in Hair Is Not Associated With Measures of HIV Persistence or Inflammation Among Individuals on Suppressive ART.

J Infect Dis 2018 06;218(2):234-238

Department of Medicine, University of Pittsburgh, PA.

Data on the relationship of antiretroviral exposure to measures of human immunodeficiency virus (HIV) persistence are limited. To address this gap, multiple viral, immunologic, and pharmacologic measures were analyzed from individuals with sustained virologic suppression on therapy (median 7 years) in the AIDS Clinical Trials Group A5321 cohort. Among 110 participants on tenofovir-(TFV)-disoproxil-fumarate (TDF)/emtricitabine (FTC)-containing regimens, we found no significant correlation between hair concentrations of individual antiretrovirals (ARVs) in the regimen and measures of HIV persistence (plasma HIV-1 RNA by single copy assay, cell-associated-DNA, cell-associated RNA) or soluble markers of inflammation. These findings suggest that higher systemic ARV exposure may not impact HIV persistence or inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiy011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009579PMC
June 2018

Decreased Lung Function and All-Cause Mortality in HIV-infected Individuals.

Ann Am Thorac Soc 2018 02;15(2):192-199

1 Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Rationale: Human immunodeficiency virus (HIV) infection is associated with pulmonary disease and worse lung function, but the relationship of lung function with survival in HIV is unknown.

Objectives: To determine whether lung function is associated with all-cause mortality in HIV-infected individuals.

Methods: HIV-infected participants from cohorts in three locations underwent pre- and post-bronchodilator spirometry and determination of single-breath diffusing capacity of the lung for carbon monoxide (Dl) in 2008-2009, computed tomographic (CT) scanning of the chest for quantitative emphysema and airway measures, and echocardiography for estimated left ventricular systolic and diastolic function and tricuspid regurgitant velocity. Bivariate analysis and multivariable Cox proportional hazards models were used to determine whether decreased lung function was independently associated with increased all-cause mortality. Models were adjusted for covariates including age, sex, body mass index, smoking status, self-reported hepatitis C status, HIV viral levels, CD4 T-cell counts, hemoglobin, antiretroviral therapy, and illicit drug use.

Results: Overall, 396 HIV-infected participants underwent pulmonary function testing. Thirty-two participants (8%) died during a median follow-up period of 69 months. A post-bronchodilator FEV-to-FVC ratio less than 0.7 (hazard ratio [HR], 2.47; 95% confidence interval [CI], 1.10-5.58) and a Dl less than 60% (HR, 2.28; 95% CI, 1.08-4.82) were independently associated with worse mortality. Also, hepatitis C (HR, 2.68; 95% CI, 1.22-5.89) and baseline plasma HIV RNA level (HR per ln RNA copies/ml, 1.50; 95% CI, 1.22-1.86) were associated with mortality in HIV-infected participants. The only CT or echocardiographic measure associated with greater mortality in univariate analysis was greater wall thickness of medium-sized airways (HR for wall area percent, 1.08; 95% CI, 1.00-1.18; P = 0.051), but none of the CT or echocardiogram measures were associated with mortality in multivariable analysis.

Conclusions: Airflow obstruction and impaired diffusing capacity appear to be associated with all-cause mortality in HIV-infected persons over an average of 6 years of follow-up. These data highlight the importance of lung dysfunction in HIV-infected persons and should be confirmed in larger cohorts and with extended follow-up periods. Clinical trial registered with www.clinicaltrials.gov (NCT00869544, NCT01326572).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1513/AnnalsATS.201606-492OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822404PMC
February 2018

T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.

PLoS Pathog 2017 Sep 20;13(9):e1006629. Epub 2017 Sep 20.

Department of Microbiology Immunology and Tropical Medicine, George Washington University, Washington, District of Columbia, United States of America.

HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1006629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624641PMC
September 2017

Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation.

PLoS Pathog 2017 Apr 20;13(4):e1006285. Epub 2017 Apr 20.

Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

Antiretroviral therapy (ART) reduces levels of HIV-1 and immune activation but both can persist despite clinically effective ART. The relationships among pre-ART and on-ART levels of HIV-1 and activation are incompletely understood, in part because prior studies have been small or cross-sectional. To address these limitations, we evaluated measures of HIV-1 persistence, inflammation, T cell activation and T cell cycling in a longitudinal cohort of 101 participants who initiated ART and had well-documented sustained suppression of plasma viremia for a median of 7 years. During the first 4 years following ART initiation, HIV-1 DNA declined by 15-fold (93%) whereas cell-associated HIV-1 RNA (CA-RNA) fell 525-fold (>99%). Thereafter, HIV-1 DNA levels continued to decline slowly (5% per year) with a half-life of 13 years. Participants who had higher HIV-1 DNA and CA-RNA before starting treatment had higher levels while on ART, despite suppression of plasma viremia for many years. Markers of inflammation and T cell activation were associated with plasma HIV-1 RNA levels before ART was initiated but there were no consistent associations between these markers and HIV-1 DNA or CA-RNA during long-term ART, suggesting that HIV-1 persistence is not driving or driven by inflammation or activation. Higher levels of inflammation, T cell activation and cycling before ART were associated with higher levels during ART, indicating that immunologic events that occurred well before ART initiation had long-lasting effects despite sustained virologic suppression. These findings should stimulate studies of viral and host factors that affect virologic, inflammatory and immunologic set points prior to ART initiation and should inform the design of strategies to reduce HIV-1 reservoirs and dampen immune activation that persists despite ART.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1006285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398724PMC
April 2017

Use of rosuvastatin in HIV-associated chronic obstructive pulmonary disease.

AIDS 2017 02;31(4):539-544

aDepartment of Medicine bEpidemiology Data Coordinating Center, University of Pittsburgh School of Medicine cGraduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania dDepartment of Medicine, University of California San Francisco, San Francisco, California eDepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania fDepartment of Medicine, University of California Los Angeles, Los Angeles, California, USA.

Objectives: Chronic obstructive pulmonary disease (COPD) is more prevalent in HIV-infected individuals and is associated with persistent inflammation. Therapies unique to HIV are lacking. We performed a pilot study of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor rosuvastatin to determine effects on lung function.

Design: Randomized, placebo-controlled, triple-blinded trial.

Methods: HIV-infected individuals with abnormal lung function were recruited from an ongoing lung function study. Participants were randomized to 24 weeks of placebo (n = 11) or rosuvastatin (n = 11) using an adaptive randomization based on change in peripheral C-reactive protein levels at 30 days of treatment. Forced expiratory volume in 1 s (FEV1) and diffusing capacity for carbon monoxide (DLco)%-predicted were compared to baseline at 24 weeks in the two groups using a Wilcoxon rank-sum test. The %-predicted change at 24 weeks in pulmonary function variables was compared between groups using simulated randomization tests.

Results: The placebo group experienced a significant decline in FEV1%-predicted (P = 0.027), and no change in DLco%-predicted over 24 weeks. In contrast, FEV1%-predicted remained stable in the rosuvastatin group, and DLco%-predicted increased significantly (P = 0.027). There was no significant difference in absolute change in either measure between placebo and rosuvastatin groups.

Conclusion: In a pilot study, the use of rosuvastatin for 24 weeks appeared to slow worsening of airflow obstruction and to improve DLco in HIV-infected individuals with abnormal lung function, although comparison of absolute changes between the groups did not reach significance. This study is the first to test a therapy for COPD in an HIV-infected population, and large-scale clinical trials are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAD.0000000000001365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5263188PMC
February 2017

Adiposity influences airway wall thickness and the asthma phenotype of HIV-associated obstructive lung disease: a cross-sectional study.

BMC Pulm Med 2016 Aug 4;16(1):111. Epub 2016 Aug 4.

Department of Medicine, University of Pittsburgh, Pittsburgh, USA.

Background: Airflow obstruction, which encompasses several phenotypes, is common among HIV-infected individuals. Obesity and adipose-related inflammation are associated with both COPD (fixed airflow obstruction) and asthma (reversible airflow obstruction) in HIV-uninfected persons, but the relationship to airway inflammation and airflow obstruction in HIV-infected persons is unknown. The objective of this study was to determine if adiposity and adipose-associated inflammation are associated with airway obstruction phenotypes in HIV-infected persons.

Methods: We performed a cross-sectional analysis of 121 HIV-infected individuals assessed with pulmonary function testing, chest CT scans for measures of airway wall thickness (wall area percent [WA%]) and adipose tissue volumes (mediastinal and subcutaneous), as well as HIV- and adipose-related inflammatory markers. Participants were defined as COPD phenotype (post-bronchodilator FEV1/FVC < lower limit of normal) or asthma phenotype (doctor-diagnosed asthma or bronchodilator response). Pearson correlation coefficients were calculated between adipose measurements, WA%, and pulmonary function. Multivariable logistic and linear regression models were used to determine associations of airflow obstruction and airway remodeling (WA%) with adipose measurements and participant characteristics.

Results: Twenty-three (19 %) participants were classified as the COPD phenotype and 33 (27 %) were classified as the asthma phenotype. Body mass index (BMI) was similar between those with and without COPD, but higher in those with asthma compared to those without (mean [SD] 30.7 kg/m(2) [8.1] vs. 26.5 kg/m(2) [5.3], p = 0.008). WA% correlated with greater BMI (r = 0.55, p < 0.001) and volume of adipose tissue (subcutaneous, r = 0.40; p < 0.001; mediastinal, r = 0.25; p = 0.005). Multivariable regression found the COPD phenotype associated with greater age and pack-years smoking; the asthma phenotype with younger age, female gender, smoking history, and lower adiponectin levels; and greater WA% with greater BMI, younger age, higher soluble CD163, and higher CD4 counts.

Conclusions: Adiposity and adipose-related inflammation are associated with an asthma phenotype, but not a COPD phenotype, of obstructive lung disease in HIV-infected persons. Airway wall thickness is associated with adiposity and inflammation. Adipose-related inflammation may play a role in HIV-associated asthma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12890-016-0274-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973076PMC
August 2016

Effect of Patient Navigation With or Without Financial Incentives on Viral Suppression Among Hospitalized Patients With HIV Infection and Substance Use: A Randomized Clinical Trial.

JAMA 2016 Jul;316(2):156-70

Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia33Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia.

Importance: Substance use is a major driver of the HIV epidemic and is associated with poor HIV care outcomes. Patient navigation (care coordination with case management) and the use of financial incentives for achieving predetermined outcomes are interventions increasingly promoted to engage patients in substance use disorders treatment and HIV care, but there is little evidence for their efficacy in improving HIV-1 viral suppression rates.

Objective: To assess the effect of a structured patient navigation intervention with or without financial incentives to improve HIV-1 viral suppression rates among patients with elevated HIV-1 viral loads and substance use recruited as hospital inpatients.

Design, Setting, And Participants: From July 2012 through January 2014, 801 patients with HIV infection and substance use from 11 hospitals across the United States were randomly assigned to receive patient navigation alone (n = 266), patient navigation plus financial incentives (n = 271), or treatment as usual (n = 264). HIV-1 plasma viral load was measured at baseline and at 6 and 12 months.

Interventions: Patient navigation included up to 11 sessions of care coordination with case management and motivational interviewing techniques over 6 months. Financial incentives (up to $1160) were provided for achieving targeted behaviors aimed at reducing substance use, increasing engagement in HIV care, and improving HIV outcomes. Treatment as usual was the standard practice at each hospital for linking hospitalized patients to outpatient HIV care and substance use disorders treatment.

Main Outcomes And Measures: The primary outcome was HIV viral suppression (≤200 copies/mL) relative to viral nonsuppression or death at the 12-month follow-up.

Results: Of 801 patients randomized, 261 (32.6%) were women (mean [SD] age, 44.6 years [10.0 years]). There were no differences in rates of HIV viral suppression versus nonsuppression or death among the 3 groups at 12 months. Eighty-five of 249 patients (34.1%) in the usual-treatment group experienced treatment success compared with 89 of 249 patients (35.7%) in the navigation-only group for a treatment difference of 1.6% (95% CI, -6.8% to 10.0%; P = .80) and compared with 98 of 254 patients (38.6%) in the navigation-plus-incentives group for a treatment difference of 4.5% (95% CI -4.0% to 12.8%; P = .68). The treatment difference between the navigation-only and the navigation-plus-incentives group was -2.8% (95% CI, -11.3% to 5.6%; P = .68).

Conclusions And Relevance: Among hospitalized patients with HIV infection and substance use, patient navigation with or without financial incentives did not have a beneficial effect on HIV viral suppression relative to nonsuppression or death at 12 months vs treatment as usual. These findings do not support these interventions in this setting.

Trial Registration: clinicaltrials.gov Identifier: NCT01612169.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2016.8914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339876PMC
July 2016

Treating Hepatitis C in a Ryan White-Funded HIV Clinic: Has the Treatment Uptake Improved in the Interferon-Free Directly Active Antiviral Era?

AIDS Patient Care STDS 2016 Feb 8;30(2):51-5. Epub 2016 Jan 8.

2 Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania.

Now that highly efficacious, interferon-free (IFN-free), direct acting antivirals (DAA) for the treatment of hepatitis C (HCV) have closed the gap between treatment and cure, identifying barriers that prevent initiation of treatment is more crucial than ever. This is a retrospective study utilizing Electronic Medical Records and Prior Authorization Records to identify HCV treatment gaps, including predictors for intention-to-treat and treatment initiation in the first 15 months of a Ryan White funded human immunodeficiency virus (HIV)/HCV co-infection clinic. This study included 128 adults ≥ 18 years old with HIV and chronic HCV infection who had visited the treatment center at least once since January 2013. Provider intent-to-treat was used to differentiate patients actively considered for treatment based on documentation kept by a multidisciplinary HCV team. Members of this group who had gone on to initiate treatment were identified. Baseline characteristics were compared. Rates of active treatment consideration and treatment initiation were 30% and 14%, respectively. HCV treatment-naïve individuals were less likely to be considered for treatment [risk ratio (RR) 1.58, 95% confidence interval (CI) 1.07-2.32] and initiate therapy (RR 2.33, 95% CI 0.97-5.60). Advanced liver disease had no significant association. Black race (RR 1.96, 95% CI 0.90-4.25) and Medicaid insurance holders (RR 1.90, 95% CI 0.95-3.82) tended to be less likely to initiate therapy. The availability of IFN-free DAA regimens has yet to increase HCV treatment uptake in our HIV/HCV co-infected population. Barriers to HCV treatment initiation have shifted from medical contraindications to socioeconomic variables.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/apc.2015.0222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753579PMC
February 2016

Frequency of Antiretroviral Resistance Mutations among Infants Exposed to Single-Dose Nevirapine and Short Course Maternal Antiretroviral Regimens: ACTG A5207.

J AIDS Clin Res 2014 Nov 9;5(11). Epub 2014 Nov 9.

University of Pittsburgh, Pittsburgh, PA, USA.

Background: Intrapartum single-dose nevirapine (sdNVP) reduces HIV-1 perinatal transmission but selects NVP resistance among mothers and infants. We evaluated the frequency of antiretroviral resistance among infants with intrauterine HIV-1 infection exposed to sdNVP and maternal antenatal or breastfeeding antiretroviral therapy.

Methods: This analysis included 429 infants from sub-Saharan Africa, India and Haiti whose 422 mothers received sdNVP plus maternal study treatment. At entry mothers had CD4>250/μL and were ART-naïve except for antenatal ZDV per local standard of care. Maternal study treatment started intrapartum and included ZDV/3TC, TDF/FTC or LPV/r for 7 or 21 days in a randomized factorial design. Infants received sdNVP study treatment and ZDV if local standard of care. Infant HIV RNA or DNA PCR and samples for genotype were obtained at birth and weeks 2, 4 and 12; infants who ever breast-fed were also tested at weeks 16, 24, 48 and 96. Samples from HIV-1-infected infants were tested for drug resistance by population genotype (ViroSeq). NVP or NRTI resistance mutations were assessed using the IAS-USA mutation list.

Results: Perinatal HIV-1 transmission occurred in 17 (4.0%) infants including 12 intrauterine infections. Resistance mutations were detected among 5 (42%) intrauterine-infected infants; of these, 3 had mutations conferring resistance to NVP alone, 1 had resistance to NRTI alone, and 1 had dual-class resistance mutations. Among the 2 infants with NRTI mutations, one (K70R) was likely maternally transmitted and one (K65R) occurred in the context of breastfeeding exposure to maternal antiretroviral therapy.

Conclusions: Infants with intrauterine HIV infection are at risk of acquiring resistance mutations from exposure to maternal antiretroviral medications intrapartum and/or during breastfeeding. New approaches are needed to lower the risk of antiretroviral resistance in these infants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4172/2155-6113.1000371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625799PMC
November 2014

Plasma and Cerebrospinal Fluid Biomarkers Predict Cerebral Injury in HIV-Infected Individuals on Stable Combination Antiretroviral Therapy.

J Acquir Immune Defic Syndr 2015 May;69(1):29-35

*Emory University, Atlanta, GA; †Indiana University, Indianapolis, IN; ‡University of California, San Diego, San Diego, CA; §University of California, Los Angeles, CA; ‖University of Rochester School of Medicine, Rochester, NY; ¶University of Colorado Medical Center, Denver, CO; #University of Pittsburgh, Pittsburgh, PA; **University of Hawaii, Honolulu, HI; ††University of Florida, Gainesville, FL; and ‡‡Tufts University School of Medicine, Boston, MA.

Objectives: HIV-associated brain injury persists despite combination antiretroviral therapy, but contributing factors remain poorly understood. We postulated that inflammation-associated biomarkers will be associated with cerebral injury on proton magnetic resonance spectroscopy in chronically HIV-infected subjects.

Methods: 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, and basal ganglia (BG). Predictive models were built through linear regression, and the best models were chosen using the Akaike Information Criterion.

Results: Increases in plasma or CSF MCP-1 were associated with lower NAA/Cr in the MFC and BG, whereas metabolite changes in the frontal white matter 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 3 models that simultaneously accounted for both plasma and CSF, there were more associations between CSF biomarkers and magnetic resonance spectroscopy metabolites.

Conclusions: 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 combination antiretroviral therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000000532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424074PMC
May 2015

Relationships of pulmonary function, inflammation, and T-cell activation and senescence in an HIV-infected cohort.

AIDS 2014 Nov;28(17):2505-15

aDepartment of Medicine bDepartment of Immunology, University of Pittsburgh cUniversity of Pittsburgh Graduate School of Public Health dDepartment of Pediatrics, University of Pittsburgh, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Objective: To determine associations between circulating markers of immune activation, immune cell senescence, and inflammation with HIV-associated abnormalities of pulmonary function.

Design: HIV infection is an independent risk factor for abnormal pulmonary function. Immune activation, immune senescence, and chronic inflammation are characteristics of chronic HIV infection that have been associated with other HIV-associated comorbidities and may be related to pulmonary disease in this population.

Methods: Participants from an HIV-infected cohort (n = 147) completed pulmonary function testing (PFT). Markers of T-cell activation and senescence were determined by flow cytometry, and plasma levels of interleukin-6, interleukin-8, and C-reactive protein (CRP) were measured, as was telomere length of peripheral blood mononuclear cells (PBMC). Regression models adjusting for clinical risk factors were constructed to examine relationships between biomarkers and PFT outcomes.

Results: Activated CD25(+) T cells and activated/senescent CD69(+)/CD57(+)/CD28(null) CD4(+) T cells, interleukin-6, and CRP were associated with PFT abnormalities. Shortening of PBMC telomere length correlated with airflow obstruction and diffusing impairment. Paradoxically, circulating senescent CD57(+)/CD28(null) CD8(+) T cells were associated with better PFT outcomes.

Conclusion: Circulating T cells expressing markers of activation and inflammatory cytokine levels are independently correlated with PFT abnormalities in HIV-infected persons. Overall telomere shortening was also associated with pulmonary dysfunction. The paradoxical association of senescent CD8(+) T cells and better PFT outcomes could suggest an unrecognized beneficial compensatory function of such cells or a redistribution of these cells from the circulation to local compartments. Further studies are needed to differentiate and characterize functional subsets of local pulmonary and circulating T-cell populations in HIV-associated pulmonary dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAD.0000000000000471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403864PMC
November 2014