Loss to programme between HIV diagnosis and initiation of antiretroviral therapy in sub-Saharan Africa: systematic review and meta-analysis

Objectives  To assess the proportion of patients lost to programme (died, lost to follow-up, transferred out) between HIV diagnosis and start of antiretroviral therapy (ART) in sub-Saharan Africa, and determine factors associated with loss to programme. Methods  Systematic review and meta-analysis. We searched PubMed and EMBASE databases for studies in adults. Outcomes were the percentage of patients dying before starting ART, the percentage lost to follow-up, the percentage with a CD4 cell count, the distribution of first CD4 counts and the percentage of eligible patients starting ART. Data were combined using random-effects meta-analysis. Results  Twenty-nine studies from sub-Saharan Africa including 148 912 patients were analysed. Six studies covered the whole period from HIV diagnosis to ART start. Meta-analysis of these studies showed that of the 100 patients with a positive HIV test, 72 (95% CI 60-84) had a CD4 cell count measured, 40 (95% CI 26-55) were eligible for ART and 25 (95% CI 13-37) started ART. There was substantial heterogeneity between studies (P < 0.0001). Median CD4 cell count at presentation ranged from 154 to 274 cells/μl. Patients eligible for ART were less likely to become lost to programme (25%vs. 54%, P < 0.0001), but eligible patients were more likely to die (11%vs. 5%, P < 0.0001) than ineligible patients. Loss to programme was higher in men, in patients with low CD4 cell counts and low socio-economic status and in recent time periods. Conclusions  Monitoring and care in the pre-ART time period need improvement, with greater emphasis on patients not yet eligible for ART.

Variability of growth in children starting antiretroviral treatment in southern Africa

Poor growth is an indication for antiretroviral therapy (ART) and a criterion for treatment failure. We examined variability in growth response to ART in 12 programs in Malawi, Zambia, Zimbabwe, Mozambique, and South Africa.

Mean CD4 cell count changes in patients failing a first-line antiretroviral therapy in resource-limited settings

Background Changes in CD4 cell counts are poorly documented in individuals with low or moderate-level viremia while on antiretroviral treatment (ART) in resource-limited settings. We assessed the impact of on-going HIV-RNA replication on CD4 cell count slopes in patients treated with a first-line combination ART. Method Naïve patients on a first-line ART regimen with at least two measures of HIV-RNA available after ART initiation were included in the study. The relationships between mean CD4 cell count change and HIV-RNA at 6 and 12 months after ART initiation (M6 and M12) were assessed by linear mixed models adjusted for gender, age, clinical stage and year of starting ART. Results 3,338 patients were included (14 cohorts, 64% female) and the group had the following characteristics: a median follow-up time of 1.6 years, a median age of 34 years, and a median CD4 cell count at ART initiation of 107 cells/μL. All patients with suppressed HIV-RNA at M12 had a continuous increase in CD4 cell count up to 18 months after treatment initiation. By contrast, any degree of HIV-RNA replication both at M6 and M12 was associated with a flat or a decreasing CD4 cell count slope. Multivariable analysis using HIV-RNA thresholds of 10,000 and 5,000 copies confirmed the significant effect of HIV-RNA on CD4 cell counts both at M6 and M12. Conclusion In routinely monitored patients on an NNRTI-based first-line ART, on-going low-level HIV-RNA replication was associated with a poor immune outcome in patients who had detectable levels of the virus after one year of ART.

Quantitative measurements in 3-dimensional datasets of mouse lymph nodes resolve organ-wide functional dependencies

Deep tissue imaging has become state of the art in biology, but now the problem is to quantify spatial information in a global, organ-wide context. Although access to the raw data is no longer a limitation, the computational tools to extract biologically useful information out of these large data sets is still catching up. In many cases, to understand the mechanism behind a biological process, where molecules or cells interact with each other, it is mandatory to know their mutual positions. We illustrate this principle here with the immune system. Although the general functions of lymph nodes as immune sentinels are well described, many cellular and molecular details governing the interactions of lymphocytes and dendritic cells remain unclear to date and prevent an in-depth mechanistic understanding of the immune system. We imaged ex vivo lymph nodes isolated from both wild-type and transgenic mice lacking key factors for dendritic cell positioning and used software written in MATLAB to determine the spatial distances between the dendritic cells and the internal high endothelial vascular network. This allowed us to quantify the spatial localization of the dendritic cells in the lymph node, which is a critical parameter determining the effectiveness of an adaptive immune response.

Problem of Tragedy and Tragic Consciousness in Russia at the turn of the 19th Century

This project intertwines philosophical and historico-literary themes, taking as its starting point the concept of tragic consciousness inherent in the epoch of classicism. The research work makes use of ontological categories in order to describe the underlying principles of the image of the world which was created in philosophical and scientific theories of the 17th century as well as in contemporary drama. Using these categories brought Mr. Vilk to the conclusion that the classical picture of the world implied a certain dualism; not the Manichaean division between light and darkness but the discrimination between nature and absolute being, i.e. God. Mr. Vilk begins with an examination of the philosophical essence of French classical theatre of the XVII and XVIII centuries. The history of French classical tragedy can be divided into three periods: from the mid 17th to early 19th centuries when it triumphed all over France and exerted a powerful influence over almost all European countries; followed by the period of its rejection by the Romantics, who declared classicism to be "artificial and rational"; and finally our own century which has taken a more moderate line. Nevertheless, French classical tragedy has never fully recovered its status. Instead, it is ancient tragedy and the works of Shakespeare that are regarded to be the most adequate embodiment of the tragic. Consequently they still provoke a great number of new interpretations ranging from specialised literary criticism to more philosophical rumination. An important feature of classical tragedy is a system of rules and unities which reveals a hidden ontological structure of the world. The ontological picture of the dramatic world can be described in categories worked out by medieval philosophy - being, essence and existence. The first category is to be understood as a tendency toward permanency and stability (within eternity) connected with this or that fragment of dramatic reality. The second implies a certain set of permanent elements that make up the reality. And the third - existence - should be understood as "an act of being", as a realisation of permanently renewed processes of life. All of these categories can be found in every artistic reality but the accents put on one or another and their interrelations create different ontological perspectives. Mr. Vilk plots the movement of thought, expressed in both philosophical and scientific discourses, away from Aristotle's essential forms, and towards a prioritising of existence, and shows how new forms of literature and drama structured the world according to these evolving requirements. At the same time the world created in classical tragedy fully preserves another ontological paradigm - being - as a fundamental permanence. As far as the tragic hero's motivations are concerned this paradigm is revealed in the dedication of his whole self to some cause, and his oath of fidelity, attitudes which shape his behaviour. It may be the idea of the State, or personal honour, or something borrowed from the emotional sphere, passionate love. Mr. Vilk views the conflicting ambivalence of existence and being, duty as responsibility and duty as fidelity, as underlying the main conflict of classical tragedy of the 17th century. Having plotted the movement of the being/existence duality through its manifestations in 17th century tragedy, Mr. Vilk moves to the 18th century, when tragedy took a philosophical turn. A dualistic view of the world became supplanted by the Enlightenment idea of a natural law, rooted in nature. The main point of tragedy now was to reveal that such conflicts as might take place had an anti-rational nature, that they arose as the result of a kind of superstition caused by social reasons. These themes Mr. Vilk now pursues through Russian dramatists of the 18th and early 19th centuries. He begins with Sumarakov, whose philosophical thought has a religious bias. According to Sumarakov, the dualism of the divineness and naturalness of man is on the one hand an eternal paradox, and on the other, a moral challenge for humans to try to unite the two opposites. His early tragedies are not concerned with social evils or the triumph of natural feelings and human reason, but rather the tragic disharmony in the nature of man and the world. Mr Vilk turns next to the work of Kniazhnin. He is particularly keen to rescue his reputation from the judgements of critics who accuse him of being imitative, and in order to do so, analyses in detail the tragedy "Dido", in which Kniazhnin makes an attempt to revive the image of great heroes and city-founders. Aeneas represents the idea of the "being" of Troy, his destiny is the re-establishment of the city (the future Rome). The moral aspect behind this idea is faithfulness, he devotes himself to Gods. Dido is also the creator of a city, endowed with "natural powers" and abilities, but her creation is lacking internal stability grounded in "being". The unity of the two motives is only achieved through Dido's sacrifice of herself and her city to Aeneus. Mr Vilk's next subject is Kheraskov, whose peculiarity lies in the influence of free-mason mysticism on his work. This section deals with one of the most important philosophical assumptions contained in contemporary free-mason literature of the time - the idea of the trinitarian hierarchy inherent in man and the world: body - soul - spirit, and nature - law - grace. Finally, Mr. Vilk assess the work of Ozerov, the last major Russian tragedian. The tragedies which earned him fame, "Oedipus in Athens", "Fingal" and "Dmitri Donskoi", present a compromise between the Enlightenment's emphasis on harmony and ontological tragic conflict. But it is in "Polixene" that a real meeting of the Russian tradition with the age-old history of the genre takes place. The male and female characters of "Polixene" distinctly express the elements of "being" and "existence". Each of the participants of the conflict possesses some dominant characteristic personifying a certain indispensable part of the moral world, a certain "virtue". But their independent efforts are unable to overcome the ontological gap separating them. The end of the tragedy - Polixene's sacrificial self-immolation - paradoxically combines the glorification of each party involved in the conflict, and their condemnation. The final part of Mr. Vilk's research deals with the influence of "Polixene" upon subsequent dramatic art. In this respect Katenin's "Andromacha", inspired by "Polixene", is important to mention. In "Andromacha" a decisive divergence from the principles of the philosophical tragedy of Russian classicism and the ontology of classicism occurs: a new character appears as an independent personality, directed by his private interest. It was Katenin who was to become the intermediary between Pushkin and classical tragedy.

Hepatitis C coinfection is independently associated with decreased adherence to antiretroviral therapy in a population-based HIV cohort

OBJECTIVE: To characterize the impact of hepatitis C (HCV) serostatus on adherence to antiretroviral treatment (ART) among HIV-infected adults initiating ART. METHODS: The British Columbia HIV/AIDS Drug Treatment Program distributes, at no cost, all ART in this Canadian province. Eligible individuals used triple combination ART as their first HIV therapy and had documented HCV serology. Statistical analyses used parametric and non-parametric methods, including multivariate logistic regression. The primary outcome was > or = 95% adherence, defined as receiving > or = 95% of prescription refills during the first year of antiretroviral therapy. RESULTS: There were 1186 patients eligible for analysis, including 606 (51%) positive for HCV antibody and 580 (49%) who were negative. In adjusted analyses, adherence was independently associated with HCV seropositivity [adjusted odds ratio (AOR), 0.48; 95% confidence interval (CI), 0.23-0.97; P = 0.003], higher plasma albumin levels (AOR, 1.07; 95% CI, 1.01-1.12; P = 0.002) and male gender (AOR, 2.53; 95% CI, 1.04-6.15; P = 0.017), but not with injection drug use (IDU), age or other markers of liver injury. There was no evidence of an interaction between HCV and liver injury in adjusted analyses; comparing different strata of HCV and IDU confirmed that HCV was associated with poor adherence independent of IDU. CONCLUSIONS: HCV-coinfected individuals and those with lower albumin are less likely to be adherent to their ART.

Immunologic response to antiretroviral therapy in hepatitis C virus-coinfected adults in a population-based HIV/AIDS treatment program

BACKGROUND: We sought to characterize the impact that hepatitis C virus (HCV) infection has on CD4 cells during the first 48 weeks of antiretroviral therapy (ART) in previously ART-naive human immunodeficiency virus (HIV)-infected patients. METHODS: The HIV/AIDS Drug Treatment Programme at the British Columbia Centre for Excellence in HIV/AIDS distributes all ART in this Canadian province. Eligible individuals were those whose first-ever ART included 2 nucleoside reverse transcriptase inhibitors and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor and who had a documented positive result for HCV antibody testing. Outcomes were binary events (time to an increase of > or = 75 CD4 cells/mm3 or an increase of > or = 10% in the percentage of CD4 cells in the total T cell population [CD4 cell fraction]) and continuous repeated measures. Statistical analyses used parametric and nonparametric methods, including multivariate mixed-effects linear regression analysis and Cox proportional hazards analysis. RESULTS: Of 1186 eligible patients, 606 (51%) were positive and 580 (49%) were negative for HCV antibodies. HCV antibody-positive patients were slower to have an absolute (P<.001) and a fraction (P = .02) CD4 cell event. In adjusted Cox proportional hazards analysis (controlling for age, sex, baseline absolute CD4 cell count, baseline pVL, type of ART initiated, AIDS diagnosis at baseline, adherence to ART regimen, and number of CD4 cell measurements), HCV antibody-positive patients were less likely to have an absolute CD4 cell event (adjusted hazard ratio [AHR], 0.84 [95% confidence interval [CI], 0.72-0.98]) and somewhat less likely to have a CD4 cell fraction event (AHR, 0.89 [95% CI, 0.70-1.14]) than HCV antibody-negative patients. In multivariate mixed-effects linear regression analysis, HCV antibody-negative patients had increases of an average of 75 cells in the absolute CD4 cell count and 4.4% in the CD4 cell fraction, compared with 20 cells and 1.1% in HCV antibody-positive patients, during the first 48 weeks of ART, after adjustment for time-updated pVL, number of CD4 cell measurements, and other factors. CONCLUSION: HCV antibody-positive HIV-infected patients may have an altered immunologic response to ART.

Evaluation of p24-based antiretroviral treatment monitoring in pediatric HIV-1 infection: prediction of the CD4+ T-cell changes between consecutive visits

Worldwide, 700,000 infants are infected annually by HIV-1, most of them in resource-limited settings. Care for these children requires simple, inexpensive tests. We have evaluated HIV-1 p24 antigen for antiretroviral treatment (ART) monitoring in children. p24 by boosted enzyme-linked immunosorbent assay of heated plasma and HIV-1 RNA were measured prospectively in 24 HIV-1-infected children receiving ART. p24 and HIV-1 RNA concentrations and their changes between consecutive visits were related to the respective CD4+ changes. Age at study entry was 7.6 years; follow-up was 47.2 months, yielding 18 visits at an interval of 2.8 months (medians). There were 399 complete visit data sets and 375 interval data sets. Controlling for variation between individuals, there was a positive relationship between concentrations of HIV-1 RNA and p24 (P < 0.0001). While controlling for initial CD4+ count, age, sex, days since start of ART, and days between visits, the relative change in CD4+ count between 2 successive visits was negatively related to the corresponding relative change in HIV-1 RNA (P = 0.009), but not to the initial HIV-1 RNA concentration (P = 0.94). Similarly, we found a negative relationship with the relative change in p24 over the interval (P < 0.0001), whereas the initial p24 concentration showed a trend (P = 0.08). Statistical support for the p24 model and the HIV-1 RNA model was similar. p24 may be an accurate low-cost alternative to monitor ART in pediatric HIV-1 infection.

Substitutions due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large South African cohort

INTRODUCTION: The patterns and reasons for antiretroviral therapy (ART) drug substitutions are poorly described in resource-limited settings. METHODS: Time to and reason for drug substitution were recorded in treatment-naive adults receiving ART in two primary care treatment programmes in Cape Town. The cumulative proportion of patients having therapy changed because of toxicity was described for each drug, and associations with these changes were explored in multivariate models. RESULTS: Analysis included 2,679 individuals followed for a median of 11 months. Median CD4+ T-cell count at baseline was 85 cells/microl. Mean weight was 59 kg, mean age was 32 years and 71% were women. All started non-nucleoside reverse transcriptase inhibitor-based ART (60% on efavrienz) and 75% started on stavudine (d4T). After 3 years, 75% remained in care on-site, of whom 72% remained on their initial regimen. Substitutions due to toxicity of nevirapine (8% by 3 years), efavirenz (2%) and zidovudine (8%) occurred early. Substitutions on d4T occurred in 21% of patients by 3 years, due to symptomatic hyperlactataemia (5%), lipodystrophy (9%) or peripheral neuropathy (6%), and continued to accumulate over time. Those at greatest risk of hyperlactataemia or lipodystrophy were women on ART > or =6 months, weighing > or =75 kg at baseline. DISCUSSION: A high proportion of adult patients are able to tolerate their initial ART regimen for up to 3 years. In most instances treatment-limiting toxicities occur early, but continue to accumulate over time in patients on d4T. Whilst awaiting other treatment options, the risks of known toxicities could be minimized through early identification of patients at the highest risk.

Analyzing the effects of vertical acceleration and deceleration in multi-phase, debris-flow sediment-column experiments / by Christine Marie Williams.

Water-saturated debris flows are among some of the most destructive mass movements. Their complex nature presents a challenge for quantitative description and modeling. In order to improve understanding of the dynamics of these flows, it is important to seek a simplified dynamic system underlying their behavior. Models currently in use to describe the motion of debris flows employ depth-averaged equations of motion, typically assuming negligible effects from vertical acceleration. However, in many cases debris flows experience significant vertical acceleration as they move across irregular surfaces, and it has been proposed that friction associated with vertical forces and liquefaction merit inclusion in any comprehensive mechanical model. The intent of this work is to determine the effect of vertical acceleration through a series of laboratory experiments designed to simulate debris flows, testing a recent model for debris flows experimentally. In the experiments, a mass of water-saturated sediment is released suddenly from a holding container, and parameters including rate of collapse, pore-fluid pressure, and bed load are monitored. Experiments are simplified to axial geometry so that variables act solely in the vertical dimension. Steady state equations to infer motion of the moving sediment mass are not sufficient to model accurately the independent solid and fluid constituents in these experiments. The model developed in this work more accurately predicts the bed-normal stress of a saturated sediment mass in motion and illustrates the importance of acceleration and deceleration.