Antigen-driven T-cell turnover.

A mathematical model is developed to characterize the distribution of cell turnover rates within a population of T lymphocytes. Previous models of T-cell dynamics have assumed a constant uniform turnover rate; here we consider turnover in a cell pool subject to clonal proliferation in response to diverse and repeated antigenic stimulation. A basic framework is defined for T-cell proliferation in response to antigen, which explicitly describes the cell cycle during antigenic stimulation and subsequent cell division. The distribution of T-cell turnover rates is then calculated based on the history of random exposures to antigens. This distribution is found to be bimodal, with peaks in cell frequencies in the slow turnover (quiescent) and rapid turnover (activated) states. This distribution can be used to calculate the overall turnover for the cell pool, as well as individual contributions to turnover from quiescent and activated cells. The impact of heterogeneous turnover on the dynamics of CD4(+) T-cell infection by HIV is explored. We show that our model can resolve the paradox of high levels of viral replication occurring while only a small fraction of cells are infected

Mortality in patients with successful initial response to highly active antiretroviral therapy is still higher than in non-HIV-infected individuals.

Mortality in HIV-infected patients has decreased dramatically since the introduction of highly active antiretroviral therapy (HAART). We analyzed progression to death in a population of 3678 antiretroviral treatment-naive patients from the ATHENA national observational cohort from 24 weeks after the start of HAART. Mortality was compared with that in the general population in the Netherlands matched by age and gender. Only log-transformed CD4 cell count (hazard ratio [HR] = 0.50, 95% confidence interval [CI]: 0.40 to 0.61 per unit increase) and plasma viral load (HR = 0.30, 95% CI: 0.15 to 0.60, HIV RNA level or = 100,000 copies/mL) measured at 24 weeks and infection via intravenous drug use (IDU) (HR = 0.16, 95% CI: 0.10 to 0.26, non-IDU vs. IDU) were significantly associated with progression to death. For non-IDU patients with 600 x 10 CD4 cells/L and an HIV RNA level <100,000 copies/mL at 24 weeks, mortality was predicted to be 5.3 (95% CI: 3.5 to 8.4) and 10.4 (95% CI: 6.4 to 17.4) times higher than in the general population for 25-year-old men and women, respectively, and 1.15 (95% CI: 1.08 to 1.25) and 1.29 (95% CI: 1.16 to 1.50) times higher for 65-year-old men and women, respectively. Hence, mortality in HIV-infected patients with a good initial response to HAART is still higher than in the general population

The pain experiences of powered wheelchair users

Copyright © 2012 Informa UK, Ltd. This is the author's accepted manuscript. The final published article is available from the link below.Purpose: To explore the experience of pain and discomfort in users of electric-powered indoor/outdoor wheelchairs (EPIOCs) provided by a National Health Service. Methods: EPIOC users receiving their chair between February and November 2002 (N=74) were invited to participate in a telephone questionnaire/interview and 64 (aged 1081 years) agreed. Both specific and open-ended questions examined the presence of pain/discomfort, its severity, minimizing and aggravating factors, particularly in relation to the EPIOC and its use. Results: Most EPIOC users described experiences of pain with 17% reporting severe pain. Over half felt their pain was influenced by the wheelchair and few (25%) considered their chair eased their symptoms. The most common strategy for pain relief was taking medication. Other self-help strategies included changing position, exercise and complementary therapies. Respondents emphasized the provision of backrests, armrests, footrests and cushions which might alleviate or exacerbate pain, highlighting the importance of appropriate assessment for this high dependency group. Conclusions: Users related pain to their underlying medical condition, their wheelchair or a combination of the two. User feedback is essential to ensure that the EPIOC meets health needs with minimal pain. This becomes more important as the health condition of users changes over time

Estimating the risk of HIV transmission from homosexual men receiving treatment to their HIV-uninfected partners

Objective To determine how the risk of HIV transmission from homosexual men receiving antiretroviral treatment is related to patterns of patient monitoring and condom use. Methods A stochastic mathematical simulation model was developed of cohorts of men in the Netherlands who have sex with men (MSM), defining the parameters of the model using observational cohort data. The model incorporates viral load trends during first-line treatment, patient monitoring and different scenarios for the way in which condom use may depend on recent viral load measurements. The model does not include the effect of sexually transmitted infections on HIV transmission. Results For MSM receiving treatment, the risk of transmitting HIV to their long-term partner is 22% (uncertainty interval: 9-37%) if condoms are never used. With incomplete use (in 30% of sex acts) the risk is reduced slightly, to 17% (7-29%). However, the risk is as low as 3% (0.2-8%) when men receiving treatment use condoms only 6 months beyond their last undetectable viral load measurement. The risk is further reduced when 3 months is the time period beyond which condoms are used. Conclusions When condom use by HIV-infected men receiving combination treatment with antiretroviral agents is based on their last viral load measurement, the transmission risk is much lower than with incomplete condom use. The key message for patients is that although always using condoms during treatment is the best way to protect partners from the risk of HIV transmission, when such use cannot be achieved, the second best strategy is to use condoms whenever the last undetectable viral load was measured more than 3 months ag

Late Entry to HIV Care Limits the Impact of Anti-Retroviral Therapy in the Netherlands

To explain differences in survival in the first three years of combination anti-retroviral therapy (cART) between HIV treatment centres in The Netherlands.We developed a mathematical simulation model, parameterised using data from the ATHENA cohort that describes patients entering care, being monitored and starting cART. Three scenarios were used to represent three treatment centres with widely varying mortality rates on cART that were differentiated by: (i) the distribution of CD4 counts of patients entering care; (ii) the age distribution of patients entering care; (iii) the average rate of monitoring the patients not on cART. At the level of the treatment centre, the fraction of Dutch MSM dying in the first three years of treatment ranged from 0% to 8%. The mathematical model captured the large variation in observed mortality between the three treatment centres. Manipulating the age-distribution of patients or the frequency of monitoring did not affect the model predictions. In contrast, when the same national average distribution of CD4 count at entry was used in all the scenarios, the variation in predicted mortality between all centres was diminished.Patients entering care with low CD4 counts appears to be the main source of variation in the mortality rates between Dutch treatment centres. Recruiting HIV-infected individuals to care earlier could lead to substantial improvements in cART outcomes. For example, if patients were to present with at least 400 CD4 cells/mm(3), as they do already in some centres, then our model predicts that the mortality in the first three years of cART could be reduced by approximately 20%

Estimating the public health impact of the effect of herpes simplex virus suppressive therapy on plasma HIV-1 viral load.

OBJECTIVE: Trials of herpes simplex virus (HSV) suppressive therapy among HSV-2/HIV-1-infected individuals have reported an impact on plasma HIV-1 viral loads (PVLs). Our aim was to estimate the population-level impact of suppressive therapy on female-to-male HIV-1 sexual transmission. DESIGN AND METHODS: By comparing prerandomization and postrandomization individual-level PVL data from the first two HSV suppressive therapy randomized controlled trials in sub-Saharan Africa, we estimated the effect of treatment on duration of asymptomatic infection and number of HIV-1 transmission events for each trial. RESULTS: Assuming that a reduction in PVL is accompanied by an increased duration of HIV-1 asymptomatic infection, 4-6 years of HSV suppressive therapy produce a 1-year increase in the duration of this stage. To avert one HIV-1 transmission requires 8.8 [95% confidence interval (CI), 5.9-14.9] and 11.4 (95% CI, 7.8-27.5) women to be treated from halfway through their HIV-1 asymptomatic period, using results from Burkina Faso and South African trials, respectively. Regardless of the timing of treatment initiation, 51.6 (95% CI, 30.4-137.0) and 66.5 (95% CI, 36.7-222.6) treatment-years are required to avert one HIV-1 infection. Distributions of set-point PVL values from sub-Saharan African populations suggest that unintended adverse consequences of therapy at the population level (i.e. increased HIV-1 transmission due to increased duration of infection) are unlikely to occur in these settings. CONCLUSION: HSV suppressive therapy may avert relatively few HIV-1 transmission events per person-year of treatment. Its use as a prevention intervention may be limited; however, further research into its effect on rate of CD4 cell count decline and the impact of higher dosing schedules is warranted

Resurgence of HIV infection among men who have sex with men in Switzerland : mathematical modelling study

New HIV infections in men who have sex with men (MSM) have increased in Switzerland since 2000 despite combination antiretroviral therapy (cART). The objectives of this mathematical modelling study were: to describe the dynamics of the HIV epidemic in MSM in Switzerland using national data; to explore the effects of hypothetical prevention scenarios; and to conduct a multivariate sensitivity analysis. METHODOLOGY/PRINCIPAL FINDINGS: The model describes HIV transmission, progression and the effects of cART using differential equations. The model was fitted to Swiss HIV and AIDS surveillance data and twelve unknown parameters were estimated. Predicted numbers of diagnosed HIV infections and AIDS cases fitted the observed data well. By the end of 2010, an estimated 13.5% (95% CI 12.5, 14.6%) of all HIV-infected MSM were undiagnosed and accounted for 81.8% (95% CI 81.1, 82.4%) of new HIV infections. The transmission rate was at its lowest from 1995-1999, with a nadir of 46 incident HIV infections in 1999, but increased from 2000. The estimated number of new infections continued to increase to more than 250 in 2010, although the reproduction number was still below the epidemic threshold. Prevention scenarios included temporary reductions in risk behaviour, annual test and treat, and reduction in risk behaviour to levels observed earlier in the epidemic. These led to predicted reductions in new infections from 2 to 26% by 2020. Parameters related to disease progression and relative infectiousness at different HIV stages had the greatest influence on estimates of the net transmission rate. CONCLUSIONS/SIGNIFICANCE: The model outputs suggest that the increase in HIV transmission amongst MSM in Switzerland is the result of continuing risky sexual behaviour, particularly by those unaware of their infection status. Long term reductions in the incidence of HIV infection in MSM in Switzerland will require increased and sustained uptake of effective interventions

Development and Change at Forty

As Development and Change completes its fortieth year, this note first describes the emergence of the journal’s critical, generalist identity. It then provides a glimpse into the journal’s ‘kitchen’, comments on the transformation in global access and readership since the journal went online, and reflects on the past, present and future of journal publishing in international development studies

Estimating HIV Incidence, Time to Diagnosis, and the Undiagnosed HIV Epidemic Using Routine Surveillance Data.

BACKGROUND: Estimates of the size of the undiagnosed HIV-infected population are important to understand the HIV epidemic and to plan interventions, including "test-and-treat" strategies. METHODS: We developed a multi-state back-calculation model to estimate HIV incidence, time between infection and diagnosis, and the undiagnosed population by CD4 count strata, using surveillance data on new HIV and AIDS diagnoses. The HIV incidence curve was modelled using cubic splines. The model was tested on simulated data and applied to surveillance data on men who have sex with men in The Netherlands. RESULTS: The number of HIV infections could be estimated accurately using simulated data, with most values within the 95% confidence intervals of model predictions. When applying the model to Dutch surveillance data, 15,400 (95% confidence interval [CI] = 15,000, 16,000) men who have sex with men were estimated to have been infected between 1980 and 2011. HIV incidence showed a bimodal distribution, with peaks around 1985 and 2005 and a decline in recent years. Mean time to diagnosis was 6.1 (95% CI = 5.8, 6.4) years between 1984 and 1995 and decreased to 2.6 (2.3, 3.0) years in 2011. By the end of 2011, 11,500 (11,000, 12,000) men who have sex with men in The Netherlands were estimated to be living with HIV, of whom 1,750 (1,450, 2,200) were still undiagnosed. Of the undiagnosed men who have sex with men, 29% (22, 37) were infected for less than 1 year, and 16% (13, 20) for more than 5 years. CONCLUSIONS: This multi-state back-calculation model will be useful to estimate HIV incidence, time to diagnosis, and the undiagnosed HIV epidemic based on routine surveillance data

Measuring the Quality of Data Collection in a Large Observational Cohort of HIV and AIDS

The aim of this study was to examine the quality of data collection by studying the validity of collected data. Data were extracted from the clinic charts of two anonymous outpatients by 38 data collectors. A standard for the data to be collected was determined (168 items). The validity was measured by comparing the collected items with the standard; in this way, the percentages of the collected items that were ‘correct’ could be calculated. The percentage ‘correct’ was higher for clinic chart 1 (mean: 83% correct, SD 7%) than for clinic chart 2 (mean: 78% correct, SD 8%). All categories contained incorrectly collected data. These data were divided into missing data, incorrect start-stop dates, and surplus collected data. Almost all start-stop dates would change into ‘correct’ if ‘monthyear’ was considered correct (instead of the standard ‘daymonthyear’). Not all data collectors used specific protocols, and sources other than the written comments were not always checked. This study shows that a high proportion of data was correctly collected. However, the collection of start-stop dates was not optimal, and the collected data included surplus and missing data. Data collectors should be more knowledgeable about HIV disease and trained in the use of difficult protocols, so that they can better recognize what data to collect and how it should be collected. Among physicians, there should be more agreement about what information to record in the charts, to facilitate data extraction for data collectors