Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial

Background. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1060 study demonstrated short-term superiority of lopinavir/ritonavir (LPV/r) over nevirapine (NVP) in antiretroviral therapy (ART), regardless of prior NVP exposure. However, NVP-based ART had a marginal benefit in CD4 percentage (CD4%) and growth. We compared 5-year outcomes from this clinical trial

Metabolic effects of initiating lopinavir/ritonavir-based regimens among young children

ObjectiveThe aim of this study was to estimate the long-term metabolic effects of initiating a lopinavir/ritonavir (LPV/r)-based regimen as a first-line therapy for HIV-infected children less than 3 years of age in resource-limited settings.DesignA prospective cohort study after conclusion of the P1060 randomized clinical trials (ClinicalTrials.gov Identifier: NCT00307151), with an overall follow-up of 7 years.MethodsLongitudinal total cholesterol and triglyceride measures were compared between 222 and 227 children randomized to initiate LPV/r and nevirapine (NVP)-based regimens, respectively. Adipokines (adiponectin and leptin) and biomarkers of inflammation [C-reactive protein and interleukin (IL)-6], microbial translocation (lipopolysaccharide) and immune activation (sCD14), measured in 117 participants at a median of 45 weeks of follow-up, were also compared by a randomized arm.ResultsMean total cholesterol and the percentage of participants with borderline or high total cholesterol was higher in the LPV/r arm from years 3 to 7 of follow-up than in the NVP arm (adjusted relative differences ranging from 10.9 to 23.4 mg/dl and adjusted relative risks ranging from a 60% increased risk to a more than four-fold increased risk for cholesterol ≥170 mg/dl at 7 years of follow-up). Initiation of a LPV/r-based regimen was not associated with high triglycerides over follow-up or large differences in markers of metabolic syndrome, inflammation, microbial translocation or immune activation.ConclusionGiven the virologic superiority of LPV/r-based regimens in young children and open questions regarding the roll-out of dolutegravir in resource-limited settings, children are currently being maintained on LPV/r-based regimens. Our results suggest continual assessment of total cholesterol among young children initiating a LPV/r-based regimen to monitor cardiometabolic health

Killer Cell Immunoglobulin-Like Receptor Alleles Alter HIV Disease in Children

Background: HLA class I molecules are ligands for killer cell immunoglobin like receptors (KIR) that control the antiviral response of natural killer (NK) cells. However, the effects of KIR and HLA (KIR/HLA) alleles on HIV disease of children have not been studied. Methods: 993 antiretroviral naïve children with symptomatic HIV infection from PACTG protocols P152 and P300 were genotyped for KIR and HLA alleles using the Luminex platform. Linear regression was used to test the association between genotypes and baseline pre-ART HIV RNA, CD4+ lymphocyte count, and cognitive score, adjusting for age, race/ethnicity and study. The interaction between genetic markers and age was investigated. To account for multiple testing the false discovery rate (FDR) was controlled at 0.05. Results: Children with the KIR2DS4*ALL FULL LENGTH (KIR2DS4*AFL) allele had higher CD4+ lymphocyte counts. Among children ≤2 years of age, the KIR2DS4*AFL was associated with lower plasma HIV RNA and higher cognitive index scores. KIR Cent2DS3/5_1 had lower CD4+ lymphocyte counts in children ≤2 years of age, while the presence of Tel1, Tel2DS4_2, Tel2DS4_4, Tel8, Tel2DS4_6 had higher CD4+ lymphocyte counts in all children. Presence of Cent2, Cent4 and Cent8 was associated with increased HIV RNA load in children ≤2 years. Presence of KIR3DL1+Bw4 was associated with higher CD4+ lymphocyte counts in all children. Among children >2 years old, KIR3DS1+Bw4-80I was associated with higher plasma HIV RNA, and Bw6/Bw6 was associated with lower plasma HIV RNA compared to children with KIR3DS1+Bw4-80I. Conclusions: Presented data show for the first time that specific KIR alleles independently or combined with HLA ligands are associated with HIV RNA and CD4+ lymphocyte counts in infected, antiretroviral naive children; and many of these effect estimates appear to be age dependent. These data support a role for specific KIR alleles in HIV pathogenesis in children

Changes in Inflammation but Not in T-Cell Activation Precede Non-AIDS-Defining Events in a Case-Control Study of Patients on Long-term Antiretroviral Therapy.

Background:We examined changes in soluble inflammatory cytokines and T-cell activation after antiretroviral therapy (ART) initiation in an AIDS Clinical Trials Group (ACTG) nested case-control study. Methods:Cases were 143 human immunodeficiency virus (HIV)-infected adults who developed a non-AIDS event; 315 controls remained event-free. Specimens were tested pre-ART, year 1 post-ART, and at the visit preceding the event. Conditional logistic regression evaluated the associations of biomarker changes with non-AIDS events. Results:Inflammatory and most activation biomarkers declined from pre-ART to year 1 for cases and controls. Subsequently, inflammatory biomarkers remained mostly stable in controls but not cases. Cellular activation markers generally declined for both cases and controls between year 1 and the pre-event sampling. Controls with greater pre-ART RNA levels or lower CD4+ levels had higher biomarker levels while also experiencing greater biomarker declines in the first year of ART. Changes in biomarkers to year 1 showed no significant associations with non-AIDS events. Cases, however, had significantly greater increases in all plasma biomarkers (but not cellular activation) from year 1 to the visit preceding the event. Conclusions:Inflammation increases prior to non-AIDS events in treated HIV-infected adults. These biomarker changes may reflect subclinical disease processes or other alterations in the inflammatory environment that causally contribute to disease. Clinical Trials Registration:NCT00001137

Total occlusion of the common carotid artery: A modified classification and its relation to clinical status

To investigate the hemodynamics and clinical presentation of common carotid artery occlusion (CCAO), we reviewed 6,415 patients with suspected carotid artery disease in whom a color Duplex imaging (CDI) examination was performed. According to distal vessel patency, the following CDI classification of CCAO was adopted: type I (patent both distal vessels); type II (isolated patency of external carotid artery); type III (isolated patency of internal carotid artery); and type IV (both distal vessels occluded). Thirty-five (0.5%) cases met the CDI criteria for CCAO. Twenty-nine of those (83%) had at least one patent distal vessel. Ten patients (29%) presented with stroke, 20 (57%) with transient ischemic attacks (TIAs) and five (14%) were asymptomatic. The incidence of stroke was higher in type IV (50%) vs. type II (30%) and in type II vs. type I (10%) lesions. Similarly, TIAs presented more often in type II (67%) and IV (50%) vs. in type I (40%) lesions (p = 0.002). Retrograde flow in the ophthalmic artery and concomitant severe contralateral carotid artery stenosis were more often related with type II and IV lesions (p = 0.02 and 0.04, respectively). CCAO is usually accompanied by patent distal vessel(s). The proposed CCAO classification correlates well with the patients’ clinical status and may help to better clarify the outcome of this rare entity. Among the main arteries of the developed collateral circulation, only the flow direction in the ophthalmic artery may be of clinical value. (E-mail: [email protected]) (c) 2008 World Federation for Ultrasound in Medicine & Biology

Frequency of <i>KIR</i> alleles.

<p>Frequency of <i>KIR</i> alleles.</p

Association of <i>KIR/HLA</i> alleles with baseline CD4⁺ lymphocyte count.

<p>Association of <i>KIR/HLA</i> alleles with baseline CD4⁺ lymphocyte count.</p

Frequency of the <i>KIR</i> centromeric/telomeric alleles.

<p>Frequency of the <i>KIR</i> centromeric/telomeric alleles.</p

Association of <i>KIR/HLA</i> alleles with baseline HIV Log₁₀RNA.

<p>Association of <i>KIR/HLA</i> alleles with baseline HIV Log₁₀RNA.</p