Diastolic dysfunction is associated with myocardial viral load in simian immunodeficiency virus-infected macaques.
AIDS. 2012 Feb 1;
Authors: Kelly KM, Tarwater PM, Karper JM, Bedja D, Queen SE, Tunin RS, Adams RJ, Kass DA, Mankowski JL
Abstract
OBJECTIVE:: To establish the relationship between HIV-induced cardiac diastolic dysfunction, immune responses, and virus replication in the heart using the simian immunodeficiency virus (SIV)/macaque model. DESIGN:: Cardiac diastolic dysfunction is common in HIV-infected individuals including asymptomatic patients and those treated with combination antiretroviral therapy. SIV-infected macaques develop diastolic dysfunction, serving as a useful model to establish mechanisms underlying HIV-induced cardiac dysfunction. To understand the relationship between functional cardiac impairment, viral replication in the heart, and associated host inflammatory responses, cardiac function was evaluated in SIV-infected macaques and functional decline was correlated with features of the host immune response and the extent of viral replication in both the myocardium and plasma. METHODS:: Cardiac function was evaluated longitudinally in 22 SIV-infected and eight uninfected macaques using mitral inflow and tissue Doppler echocardiography. Myocardial macrophage populations were evaluated by CD68 and CD163 immunostaining. SIV RNA levels in both myocardium and plasma were measured by qRT-PCR. RESULTS:: Echocardiographic abnormalities developed in SIV-infected macaques that closely resembled diastolic dysfunction reported in asymptomatic HIV-infected individuals. Although CD68 and CD163 were upregulated in the myocardium of SIV-infected animals, neither macrophage marker correlated with functional decline. SIV-induced diastolic dysfunction was strongly correlated with extent of SIV replication in the myocardium, implicating virus or viral proteins in the initiation and progression of cardiac dysfunction. CONCLUSION:: This study demonstrated a strong correlation between cardiac functional impairment and extent of SIV replication in the myocardium, suggesting that persistent viral replication in myocardial macrophages induce cardiomyocyte damage manifest as diastolic dysfunction.
PMID: 22301409 [PubMed - as supplied by publisher]
Effect of Intermittent Interleukin-2 Therapy on CD4+ T cell counts following antiretroviral cessation in patients with HIV (ANRS 118/NIH 04-I-0018 ILIADE Trial).
AIDS. 2012 Feb 1;
Authors: Lévy Y, Thiébaut R, Gougeon ML, Molina JM, Weiss L, Girard PM, Venet A, Morlat P, Poirier B, Lascaux AS, Boucherie C, Sereni D, Rouzioux C, Viard JP, Lane C, Delfraissy JF, Sereti I, Chêne G,
Abstract
BACKGROUND:: IL-2 therapy impacts T cell homeostasis. Whether IL-2 expanded CD4+ T cells may persist following viral rebound has not been fully investigated. METHODS:: Patients with CD4+ T cells ≥500/μL and HIV RNA <50 copies/mL were randomized to continue ART either alone (n = 67) or combined with 3 IL-2 cycles (n = 81; 6 million units) twice daily for 5 days at W0, 8, and 16) before stopping ART (W24). Patients were followed up to 168 weeks. RESULTS:: At W24, median CD4+ T cells counts were 1198 and 703/μL in the IL-2 and control groups, respectively (P < 0.001). At W72, 27% (IL-2 group) and 45% (control group) (P = 0.03) of patients were in failure (defined as: no interruption of ART at W24, CD4 drop below 350/μL or ART resumption). After W24, a biphasic decline (before and after W32) of CD4 was noted: -106 and -7 cells/μL/month in controls and -234 and -17 in IL-2 group) (all P values ≤0.0001). At W96, IL-2 expanded CD4+CD25+ T cells remained higher than in the control group (26% vs. 16%, P = 0.006). CONCLUSIONS:: In IL-2 treated patients, CD4+CD25+ T cells persisting despite viral replication allows a longer period of ART interruption.
PMID: 22301410 [PubMed - as supplied by publisher]
BACKGROUND:: While tenofovir (TDF) exposure has been associated with decreased Bone density, it remains unclear whether it is associated with increased risk of osteoporotic fractures (OF). METHODS:: Patients with any OF (defined as wrist, vertebral or hip fracture) occurring after HIV diagnosis were identified by ICD-9 code in the Veterans Affairs[Combining Acute Accent] Clinical Case Registry from 1988 to 2009. OF risk associated with cumulative exposure to TDF and other antiretrovirals (ARV) was examined in univariate analysis (UV) and multivariate models 1 (MV1 – controlling for race, age, tobacco use, diabetes, body mass index, and hepatitis C status) and model 2 (MV2 – controlling for MV1 variables + concomitant ARV exposures). RESULTS:: Among 56 660 patients evaluated, TDF exposure (total: 46 062 PY) was associated with an OF hazard ratio (HR) of 1.080 (95% CI: 1.02-1.15; p < 0.001) in UV analysis; 1.06 (0.99-1.12) in MV1 and 1.06 (0.99-1.14) in MV2. Among patients entering the cohort in the HAART era (n = 32 439), TDF exposure was associated with a yearly HR for OF of 1.16 (95% CI: 1.08-1.24; p <0.001) in UV model, 1.13 (1.05-1.21; p = 0.001) in MV1 and 1.12 (1.03-1.21; p = 0.011) in MV2. Boosted PI exposure was associated with HR of 1.11 (1.05-1.18; p = 0.001) in UV model, 1.08 (1.01-1.15; p = 0.026) in MV1 and 1.05 (0.97-1.13; p = 0.237) in MV2. Among PIs, Lopinavir/ritonavir (LPV/RTV) had an OF HR of 1.09 (CI: 1.00-1.20; p = 0.051) in MV2. CONCLUSION:: Cumulative exposure to TDF and, among PIs, LPV/RTV were independently predictive of increased risk of OF in the HAART era.
PMID: 22301411 [PubMed - as supplied by publisher]
Novel clinical trial designs for the development of new antiretroviral agents.
AIDS. 2012 Feb 1;
Authors: Mani N, Murray J, Gulick RM, Josephson F, Miller V, Miele P, Strobos J, Struble K
Abstract
The resounding success of combination antiretroviral efficacy for both treatment-naïve and -experienced patients – with 70% – 90% viral suppression rates in recent studies- has made registration trials for new agents challenging. With the inevitable specter of drug resistance, new agents must have a pathway to approval. The Forum for Collaborative HIV Research obtained input from concerned stakeholders including industry, clinical sciences, community advocacy and regulatory sciences (Food and Drug Administration and European Medicines Agency) to discuss how safety and efficacy of new agents could be demonstrated. Recognizing the shortfalls of superiority or non-inferiority trials in this environment, a new trial design for treatment-experienced patients, minimizing the risk for drug resistance but allowing full assessment of safety was proposed. The antiviral efficacy of an active investigational drug would be assessed by comparison to placebo as an add-on to a failing regimen in a short, 10-14 day study followed by institution of an optimized background regimen in both arms with investigational drug given to all patients. The follow-on stage would assess dose response, safety, durability of initial response and development of resistance. Additionally, a second safety trial could be conducted comparing patients randomized to the investigational agent plus a new OBR to those on a new OBR plus placebo. Finally, approval decisions could consider other long-term safety endpoints. Exposing treatment-naïve patients to investigational agents remains a controversial issue; stakeholders have different interpretations of risk-benefit for trials in this population which necessitate careful consideration before initiating trials in them.
PMID: 22301412 [PubMed - as supplied by publisher]
OBJECTIVES:: Fractures are common and associated with multiple risk factors. We assessed the risks for fracture associated with time-dependent, differential antiretroviral drug exposures among a cohort of persons with human immunodeficiency virus (HIV) infection. DESIGN:: Nested case-control study from an HIV cohort of 59,594 medically-insured persons with HIV infection enrolled in a medical care between January 1997 and March 2008. METHODS:: Cases were subjects with a low-impact, non-traumatic fracture identified by ICD-9-CM codes; non-cases were 1:4 matched and without fracture. RESULTS:: Cases comprised 2,411 persons with HIV infection with fractures who were risk-set matched to 9,144 persons with HIV infection without fractures. Exposure to antiretroviral (ARV) therapy by drug class and by duration (any drug/class) was associated with reduced risk for fracture. Drug-specific ARV exposures over time identified an increased risk for fracture associated with darunavir, delavirdine and saquinavir while reduced risk was associated with efavirenz, emtricitabine, lamivudine, tenofovir, and zidovudine. An initial null risk became a reduced risk with increased duration for nevirapine. In a similar pattern, abacavir, didanosine, nelfinavir, ritonavir and stavudine were initially associated with increased risk for fracture, after which the risk became null with increased duration of exposure. Null or uncertain risk for fracture was associated with amprenavir, atazanavir, enfuvirtide, fosamprenavir, indinavir, lopinavir, tipranavir, and zalcitabine. CONCLUSIONS:: ur findings suggest an overall reduced risk for facture in persons treated versus not treated with ARV drugs for HIV infection. Differential drug-specific exposure-response relationships for fracture will need to be further evaluated in other study populations.
PMID: 22301413 [PubMed - as supplied by publisher]
Pathogen prevalence may determine maintenance of antigen-specific T-cell responses in HIV-infected individuals.
AIDS. 2012 Feb 1;
Authors: Schuetz A, Dirks J, Sester U, Haule A, Elias N, Geldmacher C, Sanga E, Maboko L, Reither K, Hoelscher M, Meyerhans A, Sester M
Abstract
OBJECTIVE:: To assess the effect of antigen-exposure on the T-cell repertoire in the chronic phase of HIV-infection. DESIGN:: This is a prospective cross-sectional study. METHODS:: HIV-seropositive patients and immunocompetent controls from tuberculosis low and high-endemic countries were recruited. Mycobacterium tuberculosis (purified protein derivative; PPD)-specific CD4 T-cell responses were quantified directly from whole blood using flow-cytometric analysis of intracellular cytokines after specific stimulation. T-cell reactivity toward cytomegalovirus (CMV) or Staphylococcus aureus Enterotoxin B (SEB) served as control. RESULTS:: In a low-endemic region, HIV-seropositive patients showed lower frequencies of PPD-specific T-cells compared to immunocompetent individuals. This was not due to a general loss of immunity toward recall antigens, as T-cell immunity toward CMV or SEB was preserved. In line with continuous antigen exposure, HIV-seropositive patients from a high-endemic region showed preserved PPD-specific T-cell frequencies that were not different from those found in HIV-seronegative controls. Likewise, both groups did not differ in recall T-cell responses toward CMV or SEB. CONCLUSION:: A lower prevalence and frequency of PPD-specific immunity is a typical feature of HIV-related immunosuppression in low-endemic regions. In contrast, PPD-specific responses are maintained in HIV-seropositive individuals in regions with high tuberculosis prevalence. This suggests constant skewing and restriction of specific T-cell immunity toward environmental antigens in HIV-seropositive individuals.
PMID: 22301414 [PubMed - as supplied by publisher]
Elevated cytokine and chemokine levels in the placenta are associated with in utero HIV-1 mother-to-child transmission.
AIDS. 2012 Feb 1;
Authors: Kumar SB, Rice CE, Milner DA, Ramirez NC, Iv WE, Mwapasa V, Turner AN, Kwiek JJ
Abstract
OBJECTIVE:: To determine if there is an association between cytokine and chemokine levels in plasma isolated from the placenta and HIV-1 mother-to-child transmission (MTCT). DESIGN:: We designed a case-control study of HIV-infected, pregnant women enrolled in the Malaria and HIV in Pregnancy cohort. Participants were recruited in Blantyre, Malawi from 2000-04. Cases were women whose children were HIV-1 DNA-positive at birth (in utero MTCT) or HIV-1 DNA-negative at birth and HIV-1 DNA-positive at 6-weeks post-partum (intrapartum MTCT); controls were women whose children were HIV-1 DNA-negative both at birth and 6-weeks post-partum. METHODS:: After delivery, blood was isolated from an incision on the basal plate of the placenta. We used a Luminex assay to simultaneously quantify 27 cytokines, chemokines, and growth factors in placental plasma. HIV-1 RNA copies were quantified with the Roche Amplicor kit. RESULTS:: Levels of IL-4, IL-5, IL-6, IL-7, IL-9, eotaxin, IL1Ra and IP-10 were significantly elevated in placental plasma isolated from cases of in utero HIV-1 MTCT. In contrast, only GCSF was elevated in placental plasma isolated from cases of intrapartum MTCT. After adjusting for maternal age, gestational age, and peripheral CD4+ T cell count, every log10 increase in placental IP-10 was associated with a three-fold increase in the prevalence of in utero HIV-1 MTCT. CONCLUSIONS:: Elevated cytokine and chemokine levels in placental plasma were associated with in utero and not intrapartum MTCT. IP-10, which is both a T-cell chemokine and potentiator of HIV-replication, was robustly and independently associated with prevalent, in utero MTCT.
PMID: 22301415 [PubMed - as supplied by publisher]
CD4 T-cell regeneration in HIV-1 elite controllers.
AIDS. 2012 Feb 1;
Authors: Yang Y, Al-Mozaini M, Buzon MJ, Beamon J, Ferrando-Martinez S, Ruiz-Mateos E, Rosenberg ES, Pereyra F, Yu XG, Lichterfeld M
Abstract
BACKGROUND:: Elite controllers spontaneously control HIV-1 replication, which in many cases is associated with preservation of normal CD4 T-cell counts. However, a subset of elite controllers has progressive CD4 T-cell losses despite undetectable viral loads, for reasons that remain undefined. Here, we assessed mechanisms of CD4 T-cell homeostasis in elite controllers with progressive vs. nonprogressive HIV-1 disease courses. METHODS:: Flow cytometry assays were used to determine the proliferation, activation and apoptosis levels of naive T cells in elite controllers with high or low CD4 T-cell counts and reference cohorts of HIV-1-negative and HAART-treated persons. Thymic output was measured by sjTREC/βTREC ratios, and the frequency of circulating recent thymic emigrants was flow cytometrically determined by surface expression of protein tyrosine kinase 7. RESULTS:: Proportions of naive T cells in elite controllers were severely reduced and closely resemble those of HIV-1 patients with progressive disease. Despite reductions in naive T cells, most elite controllers were able to maintain normal total CD4 T-cell counts by preservation of uncompromised thymic function in conjunction with extrathymic processes that led to elevated levels of circulating recent thymic emigrants. In contrast, elite controllers with low CD4 T-cell counts had reduced thymic output that mirrored thymic dysfunction during untreated progressive HIV-1 infection. CONCLUSION:: These results indicate that both thymic and extrathymic mechanisms contribute to CD4 T-cell maintenance in elite controllers and support the idea that CD4 T-cell homeostasis and control of viral replication are distinct but frequently coinciding processes.
PMID: 22301416 [PubMed - as supplied by publisher]
OBJECTIVES:: To estimate nevirapine pharmacokinetics and examine its association with rash and/or hepatotoxicity in women starting antiretroviral treatment in the ACTG A5208/OCTANE study in Africa. DESIGN:: In HIV-infected, non-pregnant women with screening CD4<200 cells/mm randomized to nevirapine (twice daily, after 14-day once-daily lead-in period) plus tenofovir/emtricitabine, single nevirapine blood samples were collected 14 and 28 days following randomization. Rash and hepatotoxicity that occurred during therapy, or within 7 days after the last dose of nevirapine, were defined as toxicity. METHODS:: Nevirapine pharmacokinetics were modeled by population pharmacokinetic analysis. Individual Bayesian pharmacokinetic estimates were used to calculate clearance, 24-hour area under the curve, and predicted plasma concentrations. RESULTS:: Median week 4 nevirapine clearance was 2.0 L/hr. Among the 359 women, 194 (54%) developed a rash of any grade; 82 (23%) had grade 2+ and 9 (3%) had grade 3+ rash. Median clearance was 1.7L/hr for subjects exhibiting 3+ rash versus 2.0 L/hr in women without 3+ rash (p = 0.046). The odds of developing 3+ rash was 50% higher for every 20% decrease in clearance (p = 0.046). Nevirapine discontinuation due to rash/liver toxicity was significantly more common among women with pretreatment CD4 count > 250 cells/mm (p = 0.003). CONCLUSIONS:: In this study, HIV-infected African women starting a nevirapine-based antiretroviral regimen had a lower nevirapine clearance compared to previous reports. Severe rash, but not hepatotoxicity, was associated with higher NVP exposure. Albeit observed in a small number of women, baseline CD4≥250 cells/mm was significantly associated with NVP toxicity.
PMID: 22301417 [PubMed - as supplied by publisher]
Efficacy and safety of once-daily ritonavir-boosted darunavir plus abacavir/lamivudine for treatment-naïve patients: A pilot study.
AIDS. 2012 Jan 10;
Authors: Nishijima T, Tsukada K, Teruya K, Gatanaga H, Kikuchi Y, Oka S
Abstract
The efficacy and safety of once-daily darunavir/ritonavir plus fixed-dose abacavir/lamivudine was examined in 22 treatment-naïve patients with HIV-1 infection. Three patients discontinued antiretroviral therapy due to mild adverse events. Among 18 patients who continued therapy, 66.7% had viral load <50 copies/ml at week 48. Only two patients experienced virologic failure with the emergence of resistant virus. This pilot study demonstrated the viral efficacy and safety of darunavir/ritonavir plus abacavir/lamivudine.
PMID: 22233654 [PubMed - as supplied by publisher]
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