Chronic kidney disease is a major comorbidity in patients affected by HIV infection. In addition, the introduction of new antiretroviral agents that interact with creatinine transporters is raising some concerns. In this review we analyze the currently available data about three new antiretroviral drugs and one new pharmacokinetic enhancer. Three of them (rilpivirine, cobicistat, dolutegravir) have shown some interactions with renal function, while tenofovir alafenamide fumarate reduces the plasmatic concentration of the parent drug. The future use of tenofovir alafenamide seems to be encouraging in order to reduce the renal interaction of tenofovir. Rilpivirine, cobicistat, and dolutegravir reduce the tubular secretion of creatinine, inducing a decrease of estimated glomerular filtration rate according to creatinine. Rilpivirine and dolutegravir block the uptake of creatinine from the blood, inhibiting organic cation transporter 2, and cobicistat interacts with the efflux inhibiting multidrug and toxin extrusion protein 1. This effect can then be considered a "reset" of the estimated glomerular filtration rate according to creatinine. However, clinicians should carefully monitor renal function in order to identify possible alterations suggestive of a true renal functional impairment. Owing to the interference of these drugs with creatinine secretion, an alternative way of estimation of glomerular filtration rate would be desirable. However, at the moment, other methods of direct glomerular filtration rate measurement have a high impact on the patient, are not readily available, or are not reliable in HIV patients. Consequently, use of classic formulas to estimate glomerular filtration rate is still recommended. Also, tubular function needs to be carefully monitored with simple tests such as proteinuria, phosphatemia, urinary excretion of phosphate, normoglycemic glycosuria, and excretion of uric acid.
Introduction: Translation of the evidence regarding the protective role of highly active antiretroviral therapy (HAART) on HIV sexual transmission rates into sexual behaviour patterns of HIV-infected subjects remains largely unexplored. This study aims to describe frequency of self-reported condom use among women living with HIV in Italy and to investigate the variables associated with inconsistent condom use (ICU). Methods: DIDI (Donne con Infezione Da HIV) is an Italian multicentre study based on a questionnaire survey performed during November 2010 and February 2011. Women-reported frequency of condom use was dichotomized in "always" versus "at times"/"never" (ICU). Results: Among 343 women, prevalence of ICU was 44.3%. Women declared a stable partnership with an HIV-negative (38%) and with an HIV-positive person (43%), or an occasional sexual partner (19%). Among the 194 women engaged in a stable HIV-negative or an occasional partnership, 51% reported fear of infecting the partner. Nonetheless, 43% did not disclose HIV-positive status. Less than 5% of women used contraceptive methods other than condoms. At multivariable analysis, variables associated with ICU in the subgroup of women with a stable HIV-negative or an occasional HIV-unknown partner were: having an occasional partner (AOR 3.51, 95% confidence interval [CI] 1.44-8.54, p=0.005), and reporting fear of infecting the sexual partner (AOR 3.20, 95% CI 1.43-7.16, p=0.004). Current use of HAART together with virological control in plasma level did not predict ICU after adjusting for demographic, behavioural and HIV-related factors. With regard to socio-demographic factors, lower education was the only variable significantly associated with ICU in the multivariate analysis (AOR 2.27, 95% CI 1.07-4.82, p=0.03). No association was found between high adherence to HAART and ICU after adjusting for potential confounders (AOR 0.89, 95% CI 0.39-2.01, p=0.78). Conclusions: Currently in Italy, the use of HAART with undetectable HIV RNA in plasma as well as antiretroviral adherence is not associated with a specific condom use pattern in women living with HIV and engaged with a sero-discordant or an HIV-unknown partner. This might suggest that the awareness of the protective role of antiretroviral treatment on HIV sexual transmission is still limited among HIV-infected persons, at least in this country.
The introduction of highly active antiretroviral therapy reduced HIV-associated morbidity and mortality, at the cost of adverse metabolic effects that increase cardiovascular risk. The aim of this study was to evaluate the impact of exposure to protease inhibitors (PI) compared with exposure to non-nucleoside reverse transcriptase inhibitors (NNRTI) on carotid intima-media thickness (IMT) and blood flow velocity and to measure vascular involvement over a 2-year follow-up in HIV-infected patients treated with PI.
The pathogenetic bases of HAART-associated lipodystrophy are still poorly known, even if it is clear that adipose tissue and its metabolism are sensitive to antiretroviral therapy alone and/or in combination with HIV infection. The NEDD8 system is essential for the regulation of protein degradation pathways involved in cell cycle progression, morphogenesis and tumorigenesis. We investigated the possible involvement of NEED8 in adipogenesis and, consequently, in HIV-related lipodystrophy. One hundred HIV-1-infected patients were included in the study. Using an in vitro model of adipogenesis we evaluated the effects on adipogenesis of the forced expression of NEDD8 together with efavirenz, stavudine, saquinavir, amprenavir and indinavir, belonging to the three main classes of anti-HIV medications. We showed that NEDD8 expression level is higher in the peripheral blood of HIV patients developing lipodystrophy. Coherently, forced expression of NEDD8 in an in vitro model of adipogenesis was able to perturb expression of some key proteins involved in adipogenesis, such as C/EBPalpha and PPARgamma, possibly acting throughout the NEDD8/p27/beta-catenin pathway. Moreover, three out of five evaluated drugs were able to affect adipocyte differentiation: efavirenz, stavudine and saquinavir. Finally, we have shown that NEDD8 was expressed in the fat tissue of lipodystrophic patients, being significantly higher in the lipodystrophic patients with respect to the controls, thus further confirming the altered NEDD8 expression in the fat tissue of HIV-infected patients affected by lipodystrophy. Taken together, our data support the hypothesis of an implication of NEDD8 through p27 and beta-catenin pathways in the disruption of adipogenesis and consequent lipodystrophy in patients affected by HIV infection under HAART therapy with qualitative and quantitative differences according to diverse antiretroviral treatments. These evidences indicate the NEDD8/beta-catenin/p27 pathway as a possible molecular target for prevention of lipodystrophy development in patients under HAART therapy.
The highly active antiretroviral therapy (HAART) can cause a metabolic syndrome consisting of lipodystropy/lipoatrophy, dyslipidemia, and type 2 diabetes mellitus with an increased cardiovascular risk. The pathogenetic bases of HAART-associated lipodystrophy are poorly known. A genetic screen was used to evaluate proteins that are modulated in HIV-1-infected patients with or without lipodystrophy syndrome, that are routinely treated with HAART regimens. The most significant modulation was represented by FAP48 expression. Stable over-expression of FAP48 was able to alter, in vitro, adipogenesis, acting both on calcineurin and glucocorticoid pathways. Finally, we demonstrated that FAP48 over-expression was able to influence the capacity of some HIV drugs, Saquinavir and Efavirenz, but not Stavudine, Amprenavir, and Indinavir to inhibit adipocyte formation. In conclusion, this molecule could be a potential target for novel therapeutic approaches to the HAART related lipodystrophy in HIV patients.
In the present study, we investigated the ability of anti-HIV drugs to interfere with normal cell cycle progression and to induce oxidative stress by perturbing the redox environment. Our results provide evidence that anti-HIV drugs have a differential effect on adipocyte cell cycle and differentiation, being able to modify the response to oxidative stress through an increase of reactive oxygen species (ROS) that compromises the induction of phase-2 and antioxidant enzymes. In detail, saquinavir, efavirenz, and stavudine exert antiadipogenic influences on the model 3T3-L1 cell line, perturbing the oxidative response and inducing of apoptosis. When considered together, the effects of anti-HIV drugs on 3T3-L1 pre adipocytes are distinct but commonly antiadipogenic, thus suggesting another additional possible mechanism by which antiretroviral therapies could contribute to lipoatrophy.
Highly active antiretroviral therapy (HAART therapy) for HIV-1 infection has significantly increased the survival and quality of life of patients with this disease. However, in several epidemiological studies the onset of metabolic syndrome is a phenomenon reported to be extremely frequent. In the present study, genes involved in the molecular cascade responsible for the alteration of fat tissue and of lipid and glucose metabolism in patients with HIV-1 infection treated with antiretroviral therapy were identified. Towards this goal, hybridization using Atlas cDNA Expression Arrays allowed simultaneous monitoring of the expression levels of approximately 250 genes and identification of a panel of changes in relation to different therapeutic groups and in the presence of metabolic syndrome, with some genes being up-regulated, while others are down-regulated in the different subgroups of patients. The results of this analysis have shown a panel of transcriptional changes associated with oxidative stress mechanisms that provide a basis for further studies on understanding of mechanisms that, in vivo, are the foundation the metabolic disorders in patients with HIV infection.
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