ART-naive HIV-infected Patients Research Articles

Cost-utility analysis of the fixed-dose combination of dolutegravir/abacavir/lamivudine as initial treatment of HIV+ patients in Spain

ObjectiveFixed-dose combinations of antiretroviral drugs have meant an important step forward in simplifying treatment and improving compliance and has led to an increased effectiveness of therapy, a viral load decrease and improving the quality of life of patients.The single-table formulation of dolutegravir with abacavir and lamivudine (DTG/ABC/3TC) is a highly efficacious and well-tolerated once-daily regimen for HIV-infected patients. The objective of the study was to assess the incremental cost-utility ratio of the fixed-dose combination of (DTG/ ABC/3TC) versus the combinations emtricitabine/tenofovir/efavirenz (FTC/TDF/EFV), and darunavir/r (DRV/r) or raltegravir (RAL) with emtrici- tabine/tenofovir (FTC/TDF) or abacavir/lamivudine (ABC/3TC) as initial antiretroviral therapy in patients infected with HIV-1 from the perspective of the Spanish National Health System. MethodThe ARAMIS model, which uses a microsimulation approach to simulate the individual changes in each patient from the start of treatment to death through a Markov chain of descriptive health states of the disease, was adapted to Spain. The alternatives used for comparison were the fixed-dose combination of emtricitabine/tenofovir/efavirenz (FTC/TDF/ EFV), and the fixed-dose combinations of emtricitabine/tenofovir (FTC/TDF) or abacavir/lamivudine (ABC/3TC) with darunavir/r (DRV/r) or ral- tegravir (RAL). The probability of achieving virological suppression by the treatments included in the model was obtained from clinical trials SINGLE, SPRING-2 and FLAMINGO and the costs were expressed in € (2015). The model use the perspective of the Spanish National Health System, with a lifetime horizon and a discount rate of 3% was applied to cost and effectiveness. ResultsTreatment initiation with DTG/ABC/3TC was dominant when it was compared with treatment initiation with all the comparators: vs. FTC/TDF/EFV (-67 210.71€/QALY), vs. DRV/r + FTC/TDF or ABC/3TC (-1 787 341.44€/QALY), and vs. RAL + FTC/TDF or ABC/3TC (-1 005 117.13€/QALY). All the sensitivity analyses performed showed the consistency of these findings. ConclusionsWith the premises considered, treatment initiation with DTG/ABC/3TC STR appears to be the most cost-effective option in ARTnaive HIV infected patients from the Spanish Health System perspective

Extrapulmonary Pneumocystis jirovecii infection in an advanced HIV-infected patient: A case report and literature review

BackgroundPneumocystis jirovecii infection is the most common opportunistic infection that causes pneumonia in human immunodeficiency virus (HIV)-infected patients; however, extrapulmonary P. jirovecii infection is extremely rare after the use of antiretroviral therapy. Here, we present the second reported case of paraspinal mass caused by P. jirovecii infection in an advanced HIV-infected patient.Case presentationA 45-year-old woman presented with dyspnea on exertion, and significant weight loss within the preceding 4 months. Initial complete blood count (CBC) findings revealed pancytopenia with a hemoglobin (Hb) level of 8.9 g/dL, a white blood cell (WBC) count of 2180 cells/mm3 with 68% neutrophils, and a platelet count of 106,000 cells/mm3. Anti-HIV was positive with an absolute cluster of differentiation 4 (CD4) count of 16 cells/ mm3. A computed tomography scan of the chest revealed an enhancing soft tissue mass-like lesion at the right paravertebral region (T5-T10 level) and a thick-walled cavity lesion at the left lower lung. A CT-guided biopsy of the paravertebral mass was performed and histopathology revealed granulomatous inflammation consisting of dense aggregates of epithelioid cells and macrophages, and scattered foci of pink foamy to granular materials amidst the granulomatous inflammation. Gomori methenamine silver (GMS) staining revealed thin cystic-like structures (ascus) that were observed to be morphologically consistent with P. jirovecii. Molecular identification and DNA sequencing from the paraspinal mass was 100% identical to P. Jirovecii. The patient was successfully treated with oral trimethoprim-sulfamethoxazole for 3 weeks and antiretroviral therapy (ART) with tenofovir (TDF), lamivudine (3TC), and dolutegravir (DTG). A follow-up CT scan of the chest at 2 months after treatment showed a decrease in sizes of both the paravertebral mass and the cavitary lung lesion.ConclusionsExtrapulmonary pneumocystosis (EPCP) has become an extremely rare condition in HIV-infected patients after the widespread use of ART. EPCP should be considered in ART-naive HIV-infected patients suspected of having or diagnosed with Pneumocystis jirovecii pneumonia who present with atypical symptoms and/or signs. Histopathologic examination with GMS staining of affected tissue is necessary for the diagnosis of EPCP.

Establishment and application of a method of tagged-amplicon deep sequencing for low-abundance drug resistance in HIV-1

In the latest HIV-1 global drug resistance report released by WHO, countries are advised to strengthen pre-treatment monitoring of drug resistance in AIDS patients. In this study, we established an NGS-based segmented amplification HIV-1 drug resistance mutation detection method. The pol region of HIV-1 was divided into three short fragments for NGS. The entire amplification and sequencing panel were more cost-effective and batched by using the barcode sequence corresponding to the sample. Each parameter was evaluated using samples with known resistance variants frequencies. The nucleotide sequence error rate, amino acid error rate, and noise value of the NGS-based segmented amplification method were both less than 1%. When the threshold was 2%, the consensus sequences of the HIV-1 NL4-3 strain were completely consistent with the Sanger sequences. This method can detect the minimum viral load of the sample at 102 copies/ml, and the input frequency and detection frequency of HIV-1 resistance mutations within the range of 1%–100% had good conformity (R2 = 0.9963; R2 = 0.9955). This method had no non-specific amplification for Hepatitis B and C. Under the 2% threshold, the incidence of surveillance drug resistance mutations in ART-naive HIV-infected patients was 20.69%, among which NRTIs class resistance mutations were mainly.

Biomarkers of Endothelial Activation in Black South African HIV-Positive Subjects are Associated with Both High Viral Load and Low CD4 Counts.

The prevalence of cardiovascular death in the HIV-infected population is higher than in uninfected individuals. Growing evidence suggests that HIV infection itself is directly linked to endothelial activation and dysfunction. Therefore, the aim of this study was to investigate whether endothelial activation is present in African subjects with HIV infection and identify its possible determinants. Eighty HIV-infected treatment-naive cases, categorized into two groups based on CD4 count (38 subjects with CD4 count ≤350 cells/mm3 and 42 subjects with CD4 count >350 cells/mm3), were compared with 60 HIV-uninfected controls. A small subgroup of the HIV-infected participants (n = 13) were followed up for 18 months following initiation of antiretroviral therapy (ART). Anthropometric data, fasting lipid and glucose levels, viral load, and CD4 counts were measured as were serum levels of intercellular adhesion molecule-1 (ICAM-1), endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1, von Willebrand factor (vWF), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8). The HIV-infected low CD4 group had higher levels of ICAM-1 (p < .05), VCAM-1 (p < .0005), TNF-α (p < .005), and vWF (p < .005), compared with the controls. In the HIV-infected cohort, VCAM-1 levels were negatively associated with CD4 counts (β = -0.474; p < .0005), whereas vWF levels were positively associated with viral load (β = 0.344; p < .01). Levels of ICAM-1 and VCAM-1 were reduced by ART (p < .05 vs. baseline for both), however, levels of IL-6, IL-8, and TNF-α increased (p < .005 vs. baseline for all). Endothelial activation and inflammation are evident in African ART-naive HIV-infected patients; the former is attenuated, and the latter is increased after 18 months of ART. In HIV-infected subjects, both immunological dysregulation and viral load are associated with biomarkers of endothelial activation.

Changes in lipidomic profile by anti-retroviral treatment regimen: An ACTG 5257 ancillary study.

High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.

Prevalence and risk factors for bone mineral density changes in antiretroviral therapy-naive human immunodeficiency virus-infected adults: a Chinese cohort study.

BackgroundStudies have reported that low bone mineral density (BMD) is prevalent in human immunodeficiency virus (HIV)-infected patients; however, the factors that contribute to HIV-related BMD changes are yet to be fully understood. Due to the application of dual X-ray absorptiometry (DXA) among a select group of hospitals only, the prevalence and risk factors of low BMD in HIV-infected populations have not been intensively investigated in China. Thus, the aim of our study was to investigate the prevalence of and risk factors associated with BMD changes among antiretroviral therapy (ART)-naive HIV-positive patients in China.MethodsThe assessment of the prevalence of and risk factors associated with BMD changes was conducted among 156 ART-naive HIV-infected patients. Demographic and clinical data, as well as results of fasting blood tests were obtained from patients. Further, all patients underwent DXA scans to determine BMD, which was then used to classify patients with osteopenia/osteoporosis. The risk factors of reduced BMD were then evaluated using binary logistic regression.ResultsAmong the 156 ART-naive HIV-infected participants, osteopenia and osteoporosis were diagnosed in 48.7% (76/156) and 4.5% (7/156) of patients, respectively. The lumbar spine was most likely to have reduced BMD (49.4% [77/156]), and the proportion of osteopenia in the left hip (32.7% [51/156]) was higher than in the right hip (24.4% [38/156]). In the lumbar spine, bone loss rate in the L1 section (60.9% [95/156]) was the most significant (L2, 53.2% [83/156]; L3, 45.5% [71/156]; L4, 52.6% [82/156]). Further analysis showed that, compared with the neck (26.9% [42/156] in the left, 18.6% [29/156] in the right) and the interior (15.4% [24/156] in the left, 13.5% [21/156] in the right), the trochanter had the greatest probability of reduced BMD (46.2% [72/156] in the left, 28.8% [45/156] in the right). In the risk factor analysis, low body mass index (BMI: <18.5 kg/m2) was positively associated with reduced BMD (Exp (B) = 39.743, 95% confidence interval: 3.234–488.399, P = 0.004), and was specifically positively correlated with BMD values at three sites (r = 0.335 at right hip, r = 0.327 at left hip, r = 0.311 at lumbar spine).ConclusionReduced BMD was found in the majority of ART-naive HIV-infected patients and BMI was identified as an additional risk factor for reduced BMD. Our results show that BMD reduction was simultaneously present in the left hip, right hip, and lumbar spine among nearly one fifth of patients. Our work highlights the importance of closely monitoring BMD in ART-naive patients and provides a foundation for the clinical intervention of bone demineralization in them.

Impact of HIV/simian immunodeficiency virus infection and viral proteins on adipose tissue fibrosis and adipogenesis

HIV-infected patients receiving antiretroviral treatment (ART) often present adipose tissue accumulation and/or redistribution. adipose tissue has been shown to be an HIV/SIV reservoir and viral proteins as Tat or Nef can be released by infected immune cells and exert a bystander effect on adipocytes or precursors. Our aim was to demonstrate that SIV/HIV infection per se could alter adipose tissue structure and/or function. Morphological and functional alterations of subcutaneous (SCAT) and visceral adipose tissue (VAT) were studied in SIV-infected macaques and HIV-infected ART-controlled patients. To analyze the effect of Tat or Nef, we used human adipose stem cells (ASCs) issued from healthy donors, and analyzed adipogenesis and extracellular matrix component production using two dimensional (2D) and three-dimensional (3D) culture models. Adipocyte size and index of fibrosis were determined on Sirius red-stained adipose tissue samples. Proliferating and adipocyte 2D-differentiating or 3D-differentiating ASCs were treated chronically with Tat or Nef. mRNA, protein expression and secretion were examined by RT-PCR, western-blot and ELISA. SCAT and VAT from SIV-infected macaques displayed small adipocytes, decreased adipogenesis and severe fibrosis with collagen deposition. SCAT and VAT from HIV-infected ART-controlled patients presented similar alterations. In vitro, Tat and/or Nef induced a profibrotic phenotype in undifferentiated ASCs and altered adipogenesis and collagen production in adipocyte-differentiating ASCs. We demonstrate here a specific role for HIV/SIV infection per se on adipose tissue fibrosis and adipogenesis, probably through the release of viral proteins, which could be involved in adipose tissue dysfunction contributing to cardiometabolic alterations of HIV-infected individuals.

Circulating metabolomic profile can predict dyslipidemia in HIV patients undergoing antiretroviral therapy

Background and aimsDyslipidemia in HIV-infected patients is unique and pathophysiologically associated with host factors, HIV itself and the use of antiretroviral therapy (ART). The use of nuclear magnetic resonance spectroscopy (NMR) provides additional data to conventional lipid measurements concerning the number of lipoprotein subclasses and particle sizes. MethodsTo investigate the ability of lipoprotein profile, we used a circulating metabolomic approach in a cohort of 103 ART-naive HIV-infected patients, who were initiating non-nucleoside analogue transcriptase inhibitor (NNRTI)-based ART, and we subsequently followed up these patients for 36 months. Univariate and multivariate analyses were performed to evaluate the predictive power of NMR spectroscopy. ResultsVLDL-metabolism (including VLDL lipid concentrations, sizes, and particle numbers), total triglycerides and lactate levels resulted in good classifiers of dyslipidemia (AUC 0.903). Total particles/HDL-P ratio was significantly higher in ART-associated dyslipidemia compared to ART-normolipidemia (p = 0.001). Large VLDL-Ps were positively associated with both LDL-triglycerides (ρ 0.682, p < 0.001) and lactate concentrations (ρ 0.416, p < 0.001), the last one a marker of mitochondrial low oxidative capacity. ConclusionsOur data suggest that circulating metabolites have better predictive values for HIV/ART-related dyslipidemia onset than do the biochemical markers associated with conventional lipid measurements. NMR identifies changes in VLDL-P, lactate and LDL-TG as potential clinical markers of baseline HIV-dyslipidemia predisposition. Differences in circulating metabolomics, especially differences in particle size, are indicators of important derangements of mitochondrial function that are linked to ART-related dyslipidemia.

Prevalence and correlates of chronic kidney disease (CKD) among ART-naive HIV patients in the Niger-Delta region of Nigeria.

Widespread use of antiretroviral therapy (ART) in human immunodeficiency virus (HIV) patients has led to improved longevity with the attendant increase in noncommunicable disease prevalence including chronic kidney disease (CKD). This study documents the prevalence of CKD in a large HIV population in Southern Nigeria.This is a single center, 15-year analysis in ART-naïve patients. CKD was defined as the occurrence of estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m on 2 consecutive occasions 3 to 12 months apart using the chronic kidney disease epidemiology collaboration (CKD-EPI) equation. The Cochran-Armitage and Cuzick tests were employed to assess for trend across the years for CKD prevalence and CD4 count, respectively. Multivariable logistic regression models were used to identify independent associations with CKD.In all, 1317 patients (62.2% females) with mean age of 34.5 years and median CD4 count of 194 cells/μL were included. CKD prevalence was 13.4% (95%CI 11.6%-15.4%) using the CKD-EPI equation (without the race factor). Multivariable analysis identified increasing age and CD4 count <200 cells/μL as being independently associated with CKD occurrence.This study reports a high prevalence of CKD in ART-naïve HIV-infected patients. Measures to improve diagnosis of kidney disease and ensure early initiation of treatment should be integrated in HIV treatment programmes in this setting.

Cytopenias among ART-naive HIV-infected patients and HIV-infected patients on ART in Bali-indonesia

Cytopenias among ART-naive HIV-infected patients and HIV-infected patients on ART in Bali-indonesia

Low incidence of the immune reconstitution inflammatory syndrome among HIV-infected patients starting antiretroviral therapy in Gabon: a prospective cohort study

There is a paucity of data on the immune reconstitution inflammatory syndrome (IRIS) in the Central African region. We followed ART-naive HIV-infected patients initiating antiretroviral therapy in an HIV clinic in Gabon, for 6 months. Among 101 patients, IRIS was diagnosed in five. All IRIS cases were mucocutaneous manifestations. There were no cases of tuberculosis (TB) IRIS, but active TB (n = 20) was associated with developing other forms of IRIS (p = 0.02). Six patients died. The incidence of IRIS is low in Gabon, with mild, mucocutaneous manifestations.

Chronic HIV-1 Infection Induces B-Cell Dysfunction That Is Incompletely Resolved by Long-Term Antiretroviral Therapy.

To determine the effect of long-term antiretroviral therapy (ART) on HIV-1-induced B-cell dysfunction. Comparative study of ART-naive and ART-treated HIV-infected patients with non-HIV controls. B-cell dysfunction was examined in patients with HIV-1 infection (n = 30) who had received ART for a median time of 9.25 years (range: 1.3-21.7) by assessing proportions of CD21 B cells (a marker of B-cell exhaustion) and proportions of tumor necrosis factor-related apoptosis-inducing ligand or B and T lymphocyte attenuator B cells, and serum levels of immunoglobulin free light chains (markers of B-cell hyperactivation). The association of these markers with serum levels of IgG1 and IgG2, and production of IgG antibodies after vaccination with pneumococcal polysaccharides were also examined. ART-naive patients with HIV (n = 20) and controls (n = 20) were also assessed for comparison. ART-treated patients had increased proportions of CD21 and tumor necrosis factor-related apoptosis-inducing ligand B cells and, furthermore, although proportions of B and T lymphocyte attenuator B cells were not significantly different from controls, they correlated negatively with CD21 B cells. Proportions of CD21 B cells also correlated negatively with current CD4 T-cell counts. In ART-naive patients with HIV, free light chains correlated with CD21 B cells and IgG1, but not IgG2. Serum IgG2:IgG1 ratios were substantially lower than normal in patients with HIV and did not resolve on ART. In ART-treated patients, IgG antibody responses to pneumococcal polysaccharides after vaccination were not associated with markers of B-cell dysfunction. B-cell dysfunction persists in patients with HIV receiving long-term ART. The causes and consequences of this require further investigation.

Prevalence of Intestinal Parasitosis in Chronic Diarrhea among Art Naive HIV Infected Patients in Kano, Northern Nigeria

Prevalence of Intestinal Parasitosis in Chronic Diarrhea among Art Naive HIV Infected Patients in Kano, Northern Nigeria

HIV infection induces structural and functional changes in high density lipoproteins

Background and aimsCoronary artery disease is a growing clinical problem in HIV-infected subjects. The increased risk of coronary events in this population has been linked to low levels of HDL, but the effects of HIV infection and anti-retroviral treatment (ART) on HDL structure and function remain unknown. Here, we aimed to determine the composition and function of HDL particles isolated from ART-naive and ART-positive HIV-infected patients. Methods and resultsProteomic profiling revealed decreased levels of paraoxonase (PON) 1 and PON 3 in HDL from HIV patients relative to HDL from uninfected controls (p < 0.0001), and PON activity of HDL from control group (0.13 ± 0.01 U/μl) was significantly higher than PON activity of HDL from HIV-infected untreated subjects (0.12 ± 0.01 U/μl, p = 0.0035), subjects treated with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy (0.11 ± 0.01 U/μl, p < 0.0001), subjects treated with protease inhibitor (PI)-based therapy with detectable viral load (0.11 ± 0.01 U/μl, p < 0.0001), and PI-treated patients with undetectable viral load (0.12 ± 0.01 U/μl, p = 0.0164). Lipidomic profiling uncovered a negative correlation between CD4 T cell counts and particle sphingomyelin, lyso-phosphatidylcholine and ether-linked phosphatidylserine content in the ART-naive (R2 = 0.2611, p < 0.05; R2 = 0.2722, p < 0.05; and R2 = 0.3977, p < 0.05, respectively) but not treated HIV-infected subjects. Functional analysis demonstrated a negative correlation between cholesterol efflux capacity of HDL and viral load in the ART-naive HIV-infected group (R2 = 0.26, p = 0.026). ConclusionsTaken together, these results indicate that HIV infection associates with a number of both protein and lipid compositional changes in HDL particles. Moreover, HIV infection affects cholesterol efflux function of HDL, thus contributing to an increased risk of atherosclerosis in this patient population.

Effect of selenium supplementation on CD4+ T-cell recovery, viral suppression and morbidity of HIV-infected patients in Rwanda: a randomized controlled trial.

Objective:To examine the effect of selenium supplementation on CD4+ T-cell counts, viral suppression, and time to antiretroviral therapy (ART) initiation in ART-naive HIV-infected patients in Rwanda.Methods:A multicenter, double-blinded, placebo-controlled, randomized clinical trial was conducted. Eligible patients were HIV-infected adults (≥21 years) who had a CD4+ cell count between 400 and 650 cells/μl (ART eligibility was ≤350 cells/μl throughout the trial), and were willing to practice barrier methods of birth control. Patients were randomized to receive once-daily 200 μg selenium tablets or identical placebo. They were followed for 24 months with assessments every 6 months. Declines in CD4+ cell counts were modeled using linear regressions with generalized estimating equations and effect modification, and the composite outcome (ART eligible or ART initiation) using Cox proportional-hazards regression, both conducted with intention to treat.Results:Of the 300 participants, 149 received selenium, 202 (67%) were women, and median age was 33.5 years. The rate of CD4+ depletion was reduced by 43.8% [95% confidence interval (CI) 7.8–79.8% decrease] in the treatment arm – from mean 3.97 cells/μl per month to mean 2.23 cells/μl per month. We observed 96 composite outcome events – 45 (47%) in the treatment arm. We found no treatment effect for the composite outcome (hazard ratio 1.00, 95% CI 0.66–1.54) or viral suppression (odds ratio 1.18, 95% CI 0.71–1.94). The trial was underpowered for the composite outcome due to a lower-than-anticipated event rate. Adverse events were comparable throughout.Conclusions:This randomized clinical trial demonstrated that 24-month selenium supplementation significantly reduces the rate of CD4+ cell count decline among ART-naive patients.

Abstract 314: HIV infection iIduces Structural and Functional Changes in High Density Lipoproteins

Coronary artery disease is a growing clinical problem in HIV-infected subjects. Increased risk of coronary events in this population has been linked to low levels of HDL, but the effects of HIV infection and anti-retroviral treatment (ART) on HDL structure and function are poorly characterized. Here, we determined the composition and function of HDL particles isolated from plasma collected from ART-naive and ART-positive HIV-infected patients and compared them to HDL from a convenience control group. Proteomic profiling revealed decreased paraoxonase (PON) 1 and PON 3 in HDL from both treated and untreated HIV-positive patients, and PON activity of HDL from HIV-infected subjects was significantly lower than in control group. Lipidomic profiling found sphingomyelin and ether-linked glycerophospholipid species in the HDL particles correlated positively with viral load and negatively with CD4+ T cell counts in ART-naive subjects. Consistent with analysis of lipids, the level of PLTP showed a significant positive correlation with viral load and negative correlation with CD4+ T cell counts in ART-naïve HIV-positive samples. Given the low PON1 and 3 levels in HDL from HIV-infected subjects, we tested for the level of oxidized phospholipids in the HDL particles from a subset of HIV+ ART-naïve and treated subjects with completely suppressed viremia. No significant differences in oxidized lipids were found between HDL from control and untreated or PI-treated subjects, but a significant increase was detected in the NNRTI-treated samples. Similarly, the ratio of oxidized LDL to total LDL was significantly increased in the NNRTI-treated samples. These results suggest that reduced PON levels in HDL of HIV-infected subjects do not translate to increased levels of oxidized lipids, however, low PON may contribute to increased oxidation in NNRTI-treated patients. Finally, a negative correlation between cholesterol efflux capacity of HDL and viral load in ART-naive HIV-infected group was detected. Thus, HIV infection associates with a number of both protein and lipid compositional changes in HDL particles. Moreover, HIV infection affects cholesterol efflux function of HDL, and this may increase risk of atherosclerosis in this patient population.

Differential subcutaneous adipose tissue gene expression patterns in a randomized clinical trial of efavirenz or lopinavir-ritonavir in antiretroviral-naive patients.

Gene expression studies of subcutaneous adipose tissue may help to better understand the mechanisms behind body fat changes in HIV-infected patients who initiate antiretroviral therapy (ART). Here, we evaluated early changes in adipose tissue gene expression and their relationship to fat changes in ART-naive HIV-infected patients randomly assigned to initiate therapy with emtricitabine/tenofovir plus efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r). Patients had abdominal subcutaneous adipose tissue biopsies at baseline and week 16 and dual-energy-X-ray absorptiometry at baseline and weeks 16 and 48. mRNA changes of 11 genes involved in adipogenesis, lipid and glucose metabolism, mitochondrial energy, and inflammation were assessed through reverse transcription-quantitative PCR (RT-qPCR). Additionally, correlations between gene expression changes and fat changes were evaluated. Fat increased preferentially in the trunk with EFV and in the limbs with LPV/r (P < 0.05). After 16 weeks of exposure to the drug regimen, transcripts of CEBP/A, ADIPOQ, GLUT4, LPL, and COXIV were significantly down-regulated in the EFV arm compared to the LPV/r arm (P < 0.05). Significant correlations were observed between LPL expression change and trunk fat change at week 16 in both arms and between CEBP/A or COXIV change and trunk fat change at the same time point only in the EFV arm and not in the LPV/r arm. When combined with emtricitabine/tenofovir as standard backbone therapy, EFV and LPV/r induced differential early expression of genes involved in adipogenesis and energy metabolism. Moreover, these mRNA expression changes correlated with trunk fat change in the EFV arm. (This was a substudy of a randomized clinical trial [LIPOTAR study] registered at ClinicalTrials.gov under identifier NCT00759070.).

Contribution of genetic background and antiretroviral therapy to body fat changes in antiretroviral-naive HIV-infected adults.

To evaluate the association of host genetics with changes in limb or trunk fat in a group of antiretroviral therapy (ART)-naive HIV-infected patients prospectively followed up according to the initiation and the type of ART. Fifty single nucleotide polymorphisms (SNPs) in 26 genes, associated with obesity, insulin resistance, lipid metabolism or lipodystrophy in previously published genetic studies, were assessed in ART-naive HIV-infected Caucasian patients divided into three groups: 24 (27%) did not start ART, 29 (32.6%) received zidovudine or stavudine and 36 (40.4%) received neither zidovudine nor stavudine in their initial regimen. Patients underwent body fat measurements (using dual-energy X-ray absorptiometry) at baseline and Month 12. A multivariate model using backward stepwise elimination was used to assess the influence of SNPs and baseline levels of non-genetic covariates on changes in limb or trunk fat. The baseline characteristics were: 73% men, 17% coinfected with hepatitis C virus and/or hepatitis B virus, median age 37 years, median CD4+ T cell count 228/mm(3), median HIV-RNA 5.2 log copies/mL, median plasma glucose 85 mg/dL, median plasma insulin 9.1 IU/mL, median limb fat 5.6 kg and median trunk fat 7.0 kg. There were no baseline differences among the three groups except for the CD4+ T cell count. The decrease in limb fat was greater in the no-ART group relative to the other two groups (P < 0.05). The multivariate model showed associations of rs1801278 in IRS1 (P = 0.029, OR = 0.13), baseline viral load (P = 0.006; OR = 4.453) and baseline glucose levels (P = 0.008, OR = 0.926) with loss of limb fat, and rs2228671 in LDLR (P = 0.012, OR = 0.108), rs405509 in APOE (P = 0.048, OR = 0.205), baseline viral load (P = 0.005, OR = 0.186) and baseline CD4+ T cell count (P = 0.01, OR = 1.008) with gain of trunk fat. Specific polymorphisms in IRS1 (limb fat loss) and LDLR and APOE (trunk fat gain) were identified as independent markers of fat changes irrespective of the initiation of ART and the type of ART and deserve further validation.

Towards a better understanding of Kaposi sarcoma-associated immune reconstitution inflammatory syndrome

Towards a better understanding of Kaposi sarcoma-associated immune reconstitution inflammatory syndrome

Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma

To assess the incidence, predictors, and outcomes of Kaposi sarcoma-associated paradoxical immune reconstitution inflammatory syndrome (KS-IRIS) in antiretroviral therapy (ART)-naive HIV-infected patients with Kaposi sarcoma initiating ART in both well resourced and limited-resourced settings. Pooled analysis of three prospective cohorts of ART-naive HIV-infected patients with Kaposi sarcoma from sub-Saharan Africa (SSA) and one from the UK. KS-IRIS case definition was standardized across sites. Cox regression and Kaplan-Meier survival analysis were used to identify the incidence and predictors of KS-IRIS and Kaposi sarcoma-associated mortality. Fifty-eight of 417 (13.9%) eligible individuals experienced KS-IRIS with an incidence 2.5 times higher in the African vs. European cohorts (P=0.001). ART alone as initial Kaposi sarcoma treatment (hazard ratio 2.97, 95% confidence interval (CI) 1.02-8.69); T1 Kaposi sarcoma stage (hazard ratio 2.96, 95% CI 1.26-6.94); and plasma HIV-1 RNA more than 5 log₁₀ copies/ml (hazard ratio 2.14, 95% CI 1.25-3.67) independently predicted KS-IRIS at baseline. Detectable plasma Kaposi sarcoma-associated herpes virus (KSHV) DNA additionally predicted KS-IRIS among the 259 patients with KSHV DNA assessed (hazard ratio 2.98, 95% CI 1.23-7.19). Nineteen KS-IRIS patients died, all in SSA. Kaposi sarcoma mortality was 3.3-fold higher in Africa, and was predicted by KS-IRIS (hazard ratio 19.24, CI 7.62-48.58), lack of chemotherapy (hazard ratio 2.35, 95% CI 1.09-5.05), pre-ART CD4 cell count less than 200 cells/μl (hazard ratio 2.04, 95% CI 0.99-4.2), and detectable baseline KSHV DNA (hazard ratio 2.12, 95% CI 0.94-4.77). KS-IRIS incidence and mortality are higher in SSA than in the UK. This is largely explained by the more advanced Kaposi sarcoma disease and lower chemotherapy availability. KS-IRIS is a major contributor to Kaposi sarcoma-associated mortality in Africa. Our results support the need to increase awareness on KS-IRIS, encourage earlier presentation, referral and diagnosis of Kaposi sarcoma, and advocate on access to systemic chemotherapy in Africa.