Long-term survival of HIV-infected patients treated with highly active antiretroviral therapy in Serbia and Montenegro

Background Highly active antiretroviral therapy (HAART) has dramatically changed the prognosis of HIV disease, even in terminally ill patients. Although these patients may survive many years after the diagnosis of AIDS if treated with HAART, some still die during treatment. Methods A retrospective study in a cohort of 481 HIV-infected patients treated with HAART between January 1998 and December 2005 was conducted to compare subgroups of long-term survivors (LTSs) and patients who died during treatment. Results A total of 48 patients survived for more than 72 months (mean 83.8 +/- standard deviation 5.6 months). Thirty patients died during treatment (mean 35.3 +/- 25.0 months), of whom nine died from non-AIDS-related causes, 18 died from AIDS-related causes, and three died as a result of HAART toxicity. Although LTSs were significantly (P=0.015) younger at HAART initiation, age below 40 years was not a predictor of long-term survival. The subgroups did not differ in the proportion of clinical AIDS cases at HAART initiation, in the prevalence of hepatitic C virus (HCV) coinfection, or in pretreatment and end-of-follow-up CD4 cell counts. In contrast, the viral load achieved during treatment was lower in the survivors (P=0.03), as was the prevalence of hepatitis B virus (HBV) coinfection (P=0.03). Usage of either protease inhibitor (PI)-containing regimens [odds ratio (OR) 9.0, 95% confidence interval (CI) 2.2-35.98, P lt 0.001] or all three drug classes simultaneously (OR 7.4, 95% CI 2.2-25.1, P lt 0.001) was associated with long-term survival. Drug holidays incorporated in structured treatment interruption (STI) were also associated with a good prognosis (OR 14.9, 95% CI 2.9-75.6, P lt 0.001). Conclusion Long-term survival was associated with PI-based HAART regimens and lower viraemia, but not with the immunological status either at baseline or at the end of follow up. STI when CD4 counts reach 350 cells/mu L, along with undetectable viraemia, was a strong predictor of long-term survival

The Prognosis of Late Presenters in the Era of Highly Active Antiretroviral Therapy in Serbia

To examine the prognosis of patients who present with very advanced HIV-induced immunodeficiency, and their response to highly active antiretroviral therapy (HAART), a series of 101 treatment naïve patients from the Serbian cohort of HIV infected patients, who presented with a CD4 count of ≤ 50/µL before commencing HAART, was retrospectively analyzed and factors influencing response to HAART and survival investigated. After a mean of three years (range 1-9) of treatment with PI-based and/or NNRTI-based regimens, a favorable response was achieved in 54.5% of the patients, treatment failure occurred in 13.9%, while 31.7% had a dissociative immunological/virological response. The overall estimated survival was eight years. Achievement of undetectable viremia during treatment appeared life saving (OR = 42.5, 95% CI 7.1 – 251.9, P = 0.000, as was a rise in CD4 cell count to over 200/μL (OR = 6.4, 95% CI 1.2-31.8, P = 0.023). However, undetectable viremia was the single predictor of longer survival (OR = 42.5, 95% CI 7.1 – 251.9, P = 0.000), regardless of the level of immune reconstitution (log rank, P = 0.31). Late presenters had a high probability of developing the metabolic syndrome while on HAART, with a median time to hyperlipidemia and lypodystrophy of 5 and 6 years, respectively. We conclude that late presenters on HAART may have a good prognosis, a prerequisite for which is sustained undetectable viremia regardless of the immune recovery

Exploring Evolutionary and Transmission Dynamics of HIV Epidemic in Serbia: Bridging Socio-Demographic With Phylogenetic Approach

Previous molecular studies of Serbian HIV epidemic identified the dominance of subtype B and presence of clusters related HIV-1 transmission, in particular among men who have sex with men (MSM). In order to get a deeper understanding of the complexities of HIV sub-epidemics in Serbia, epidemic trends, temporal origin and phylodynamic characteristics in general population and subpopulations were analyzed by means of mathematical modeling, phylogenetic analysis and latent class analysis (LCA). Fitting of the logistic curve of trends for a cumulative annual number of new HIV cases in 1984–2016, in general population and MSM transmission group, was performed. Both datasets fitted the logistic growth model, showing the early exponential phase of the growth curve. According to the suggested model, in the year 2030, the number of newly diagnosed HIV cases in Serbia will continue to grow, in particular in the MSM transmission group. Further, a detailed phylogenetic analysis was performed on 385 sequences from the period 1997–2015. Identification of transmission clusters, estimation of population growth (Ne), of the effective reproductive number (Re) and time of the most recent common ancestor (tMRCA) were estimated employing Bayesian and maximum likelihood methods. A substantial proportion of 53% of subtype B sequences was found within transmission clusters/network. Phylodynamic analysis revealed Re over one during the whole period investigated, with the steepest slopes and a recent tMRCA for MSM transmission group subtype B clades, in line with a growing trend in the number of transmissions in years approaching the end of the study period. Contrary, heterosexual clades in both studied subtypes – B and C – showed modest growth and stagnation. LCA analysis identified five latent classes, with transmission clusters dominantly present in 2/5 classes, linked to MSM transmission living in the capital city and with the high prevalence of co-infection with HBV and/or other STIs.Presented findings imply that HIV epidemic in Serbia is still in the exponential growth phase, in particular, related to the MSM transmission, with estimated steep growth curve until 2030. The obtained results imply that an average new HIV patient in Serbia is a young man with concomitant sexually transmitted infection

The metabolic syndrome, an epidemic among HIV-infected patients on HAART

Background: HAART has dramatically changed the prognosis of AIDS, but has led to long-term toxicities of antiretroviral drugs. A major chronic complication is the metabolic syndrome (MS), including hyperlipidemia, lipodystrophy (LD), and impaired glucose metabolism. Methods: A cross-sectional study of a series of 582 patients from the Serbian HIV/AIDS cohort, treated with HAART for a mean period of 3.3 +/- 2.1 years (range 1-10), was performed to evaluate the prevalence and risk factors for MS during HAART. Results: The prevalence of LID was 29.1%, with a 100% probability of development after 10 years of treatment. Risk factors for LD included female gender(OR 1.7, 95% CI 1.0-2.7, P = 0.02), age gt 40 (OR 1.7,95% CI 1.1-2.7, P = 0.01) and AIDS at HAART initiation (OR 1.9,95% CI 1.2-2.2, P lt 0.01), as well as prolonged usage of NRTIs (OR 2.7, 95% CI 1.6-4.5, P lt 0.01). The NNRTI-based regimens were less likely to induce LD than those PI-based (OR 1.87, 95% CI 1.2-2.9 vs. OR 3.7, 95% CI 2.3-6.1, respectively). Hyperlipidemia occurred in 47% of the patients, and was associated with male gender (OR 2.2, 95% CI 1.4-3.5, P lt 0.01) and prolonged usage of PI + NNRTI HAART (OR 3.0, 95% CI 1.8-4.9, P lt 0.01). In contrast, regimens composed of 2 NRTI + NNRTI were less likely to induce hyperlipidemia (OR 0.4, 95% CI 0.3-0.7, P = 0.03). Glucose intolerance and/or diabetes mellitus was recorded in 9.6%, if with AIDS at HAART initiation (OR 3.7, 95% CI 1.2-11.4, P lt 0.01), male gender (OR 5.2, 95% CI 1.8-15.1, P lt 0.01) and age gt 40 (OR 2.6, 95% CI 1.1-6.3, P = 0.02). Conclusion: MS seems an inevitable consequence of long-term successful HAART

The Prognosis of Pediatric AIDS in Serbia

To determine the outcome of HIV infection in children in a resource-limited setting, a retrospective analysis of a series of 51 pediatric cases from the Serbian cohort of HIV infected patients was performed. Twenty seven patients died in the pre-HAART era, but mono/dual antiretroviral treatment had significantly (p=0.046) prolonged survival. Of the total of 24 HAART-treated patients, 10 had clinical AIDS before HAART initiation. The mean baseline CD4 cell count was 193.9 +/- 170.0/mm(3). After a mean follow-up of 72.6 +/- 44 months, a favorable response was recorded in 62.5%, treatment failure (defined as non-achievement of undetectable viremia) in 20.8%, and a discrepant virological and immunological response (achievement of undetectable viremia but without a rise in CD4 cell counts adequate for age) in 16.7% patients. No patients died, and there were only three hospital admissions after commencing HAART. Five immune restoration inflammatory syndrome episodes were recorded, of which four were due to BCG-osis. Lipodystrophy and hyperlipidemia occurred in 18.2% and 26.3% patients, respectively. We conclude that even in suboptimal facilities, the prognosis of HIV disease among children on HAART may be rather good. The metabolic syndrome seems to emerge as an important issue among long-term surviving children on HAART

The prognosis of CMV retinitis among patients with AIDS in Serbia

Background: Cytomegalovirus (CMV) end-organ diseases, including CMV retinitis, are major opportunistic events in terminal AIDS patients. Methods: A retrospective study of 30 AIDS patients with CMV retinitis treated between 1997 and 2007 in Serbia was conducted to examine the prognosis and factors associated with survival. Results: Eighteen (60%) patients survived the mean follow-up period of 46.4 +/- 36 months. Patients' sex, mode of HIV transmission or previous AIDS diagnosis did not affect survival. Bilateral CMV retinitis predicted dissemination of CMV disease and poor prognosis (OR 7.8, 95% Cl 1.3-47.0, P = 0.012), but was not associated with blindness (P = 0.33). Among patients treated with HAART and CMV therapy the probability of surviving 10 years was 70%, while in those on CMV therapy alone, the median survival was 10 months (log rank P = 0.00). However, HAART itself was not sufficient to prevent blindness and the major predictor of blindness was a baseline CD4 cell count of less than 50/mu L (OR 6.8, 95% Cl 1.1-41.8, P = 0.03). After CMV disease, most patients suffered other opportunistic events regardless of HAART introduction. Conclusion: Even in the HAART era patients with advanced immunodeficiency and CMV retinitis may not escape from the high risk mortality group, while survivors commonly lose sight

The dissociation between virological and immunological responses to HAART

While HAART allows for the reconstitution- of immune functions in most treated HIV patients, discrepant responses including failure to achieve a significant increase in circulating CD4+ T cells despite undetectable plasma viral loads (pVL), or a good immunological response while not reaching undetectabie viremia, may occur. Thus, to evaluate the incidence of and risk factors for discrepant responses to HAART, we conducted a retrospective study of all 446 patients treated with HAART between 1 January 1998 and 31 August 2004 in our HIV unit. CD4+ T cell counts and pVL values at baseline and end of study were parameters of the type of response. Within a mean follow-up period of 33 months, discrepant immunological and virological responses occurred in even 50% patients. Of these, 174(39%) did not have a rise in CD4+ T cells to above 400 per mu l despite a good virological response (type 1 dissociation), while 49 (11.0%) had a rise in the CD4+ T cell count to at least 200 per mu l but their pVL was not undetectable (type 2 dissociation). The risk factors for immunological failure despite an undetectable pVL were baseline CD4+ T cells below 100 per mu l (OR 1.44, 95%CI 1.02-2.03) and HAART composed of three NRTIs (OR 1.92,95% CI 1.35-2.73), while usage of two NRTIs in combination with PI(s) (OR 0.36,95% CI 0.2 6-0.49), as well as simultaneous usage of all three drug classes (OR 0.37, 95% CI 0.26-0.53) were shown to be protective. The usage of PI-containing HAART regimens was protective against type 2 dissociation (OR = 0.40, 95% CI 0.19-0.83). Importantly, there were no differences in the survival of HAART-treated patients irrespective of the type of response

Biologia Futura: does the aging process contribute to the relativity of time?

In his Theory of relativity, Einstein determined that the time is relative to the reference frame of the observer. Under specific conditions, there is a difference in the elapsed time between two clocks, known as time dilation. A similar relativistic effect could be attributed to the brain operating at different frequencies, e.g., while it is slow and during the thought process. Time flow and the aging process are causally linked. Herein, we introduce physical relativity into the mind/thought context and elaborate changed perception of the time flow (the impression of the time acceleration) with aging. The phenomenology of time is observed in the context of physical and biological clock, as well as by introducing the category of ‘mind time.’ Mental processing impairment is crucial for the “aging-caused relativity of time,” while adjusting of its’ perception seems to be a matter of body/mind rest, mental hygiene and physical activity of the aging subject. We also provide a brief overview of the percep- tion of time flow in some disease states that coincide with aging. Our main idea has a perspective for future development in the interdisciplinary synergy of philosophy, physical–mathematical elaboration, experimental biology and clinical investigations