Greater carotid intima media thickness at a younger age in HIV-infected patients compared with reference values for an uninfected cohort

Objectives: In contrast to the general population, no decline in cardiovascular disease (CVD) has been noted in HIV-infected patients over the last 10 years. We compared the carotid artery intima media thickness (CIMT) of HIV-infected patients to that of age- and gender-matched reference values and determined the relationship between CVD risk factors and CIMT. Methods: A total of 292 HIV-infected patients were enrolled in the study. Data collected included vascular screening data, data obtained using a questionnaire, data obtained from laboratory assessments and CIMT measurement. Using linear regression (adjusted for age/gender/known HIV), the association between HIV-specific and classical cardiovascular risk factors and CIMT was evaluated. Results: The cohort comprised for 91% of male patients, aged 49.4 ± 10.5 years, with a known duration of HIV infection of 8.8 ± 6.7 years. The mean with standard deviation (mean ± SD) CIMT was 0.77 ± 0.19 mm, compared with 0.58 ± 0.05 mm in the controls. A steeper increase of CIMT per age was seen in the HIV-infected patients. A significant relationship between CIMT and hypertension, diabetes mellitus, smoking, systolic blood pressure, HbA1c (glycated hemoglobin) and ankle brachial index was found. Of the HIV-specific variables, only a relationship between CIMT and length of cART use and between CIMT and (inversely) current cART use was seen. Conclusions: A greater CIMT was found in HIV-infected patients compared with controls. In contrast to HIV-specific variables, classical CVD risk factors were associated with a greater CIMT and should therefore be the focus of preventive measures

Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort

Objective: We investigated the risk of AIDS and serious non-AIDS-defining diseases (non-ADDs) according to the degree of immunological recovery after 2 years of virological successful antiretroviral therapy (HAART). Design: Retrospective observational cohort study including HIV-infected patients treated with HAART resulting in viral suppression (<500 copies/ml). Methods: Patients were grouped according to their CD4 cell count after 2 years of HAART: CD4 cell count less than 200 cells/mu l (group A), 200-350 cells/mu l (group B), 351-500 cells/mu l (group C) or more than 500 cells/mu l (group D). Analysis was done to assess predictors for poor immunological recovery and the occurrence of a composite endpoint [death, AIDS, malignancies, liver cirrhosis and cardiovascular events (CVEs)], non-ADDs, CVEs and non-AIDS-defining malignancies (non-ADMs). Results: Three thousand and sixty-eight patients were included. Older age, lower CD4 cell nadir and lower plasma HIV-RNA at the start of HAART were independent predictors for a poor immunological recovery. The composite endpoint, non-ADDs and CVE were observed most frequently in group A (overall log rank, P<0.0001, P - 0.002 and P - 0.01). In adjusted analyses, age was a strong independent predictor for all endpoints. Compared with group A, patients in group D had a lower risk for the composite Conclusion: Poor immunological recovery despite virological successful HAART is associated with a higher risk for overall morbidity and mortality and CVEs in particular. This study underlines the importance of starting HAART at higher CD4 cell counts, particularly in older patients. (C) 2012 Wolters Kluwer Health | Lippincott Williams & Wilkin

Impact of triplicate testing on HIV genotypic tropism prediction in routine clinical practice

Guidelines state that the CCR5-inhibitor Maraviroc should be prescribed to patients infected with R5-tropic HIV-1 only. Therefore, viral tropism needs to be assessed phenotypically or genotypically. Preliminary clinical trial data suggest that genotypic analysis in triplicate is associated with improved prediction of virological response by increasing the detection of X4-tropic variants. Our objective was to evaluate the impact of triplicate genotypic analysis on prediction of co-receptor usage in routine clinical practice. Samples from therapy-naive and therapy-experienced patients were collected for routine tropism testing at three European clinical centres. Viral RNA was isolated from plasma and proviral DNA from peripheral blood mononuclear cells. Gp120-V3 was amplified in a triplicate nested RT-PCR procedure and sequenced. Co-receptor usage was predicted using the Geno2Pheno[coreceptor] algorithm and analysed with a false-positive rate (FPR) of 5.75%, 10%, or an FPR of 20% and according to the current European guidelines on the clinical management of HIV-1 tropism testing. A total of 266 sequences were obtained from 101 patient samples. Discordance in tropism prediction for the triplicates was observed in ten samples using an FPR of 10%. Triplicate testing resulted in a 16.7% increase in X4-predicted samples and to reclassification from R5 to X4 tropism for four cases rendering these patients ineligible for Maraviroc treatment. In conclusion, triplicate genotypic tropism testing increases X4 tropism detection in individual cases, which may prove to be pivotal when CCR5-inhibitor therapy is applied

Quantification of naive and memory T-cell turnover during HIV-1 infection

Background: In HIV infection, the homeostasis of CD4+ and CD8+ T cells is dramatically disturbed, and several studies have pointed out that T-cell turnover rates are increased. To understand how the CD4+ and CD8+ T-cell pools are affected, it is important to have quantitative insights into the lifespans of the cells constituting the different T-lymphocyte populations. Methods: We used long-term in-vivo 2H2O labeling and mathematical modeling to estimate the average lifespans of naive and memory CD4+ and CD8+ T cells in untreated (n = 4) and combination antiretroviral therapy-treated (n = 3) HIV-1-infected individuals. Results: During untreated chronic HIV-1 infection, naive CD4+ and CD8+ T cells lived on average 618 and 271 days, whereas memory CD4+ and CD8+ T cells had average lifespans of 53 and 43 days, respectively. These lifespans were at least three-fold shorter than those in healthy controls (n = 5). In patients on effective combination antiretroviral therapy with total CD4+ T-cell counts in the normal range, we found that naive CD4+ and CD8+ T-cell lifespans had not completely normalized and were still two-fold shortened. Conclusion: The average lifespan of both naive and memory CD4+ and CD8+ T cells decreased during untreated chronic HIV-1 infection. Although the turnover of the memory T-cell populations nearly normalized during effective treatment, the turnover of naive CD4+ and CD8+ T cells did not seem to normalize completely

A highly virulent variant of HIV-1 circulating in the Netherlands.

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log &lt;sub&gt;10&lt;/sub&gt; increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV-CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences-is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence