Jan C. C. Borleffs

Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1-infected patients treated with highly active antiretroviral therapy

BACKGROUND Prophylactic drugs for Pneumocystis carinii pneumonia (PCP) are strongly recommended for HIV-1-infected patients with CD4 cell counts of less than 200 cells/microL. Because of the highly active antiretroviral therapy (HAART) currently available, we speculated that prophylaxis can be discontinued in patients with CD4 cell counts of more than 200 cells/microL. METHODS In this prospective observational study, PCP prophylaxis (primary or secondary) was discontinued in HIV-1-infected patients whose CD4 cell count had increased above 200 cells/microL (documented twice with an interval of at least 1 month) as a result of HAART. Patients and their CD4 cell counts were monitored every 3 months. The primary endpoint of the study was the occurrence or reoccurrence of PCP. FINDINGS 78 patients were enrolled: 62 patients were receiving prophylaxis for primary prevention of PCP and 16 patients for secondary prevention of PCP. At the time of discontinuation of prophylaxis, the mean CD4 cell count was 347 cells/microL, and HIV-1-RNA was not detectable in 61 patients. The lowest mean CD4 cell count during prophylaxis was 79 cells/microL. Patients stopped prophylaxis 9.8 (SD 6.4) months after they started HAART. The mean follow-up after discontinuation of prophylaxis was 12.7 (SD 7.6) months, and none of the patients developed PCP (97.5% one-sided CI 0-4.4%). INTERPRETATION The preliminary results of this study indicate that PCP prophylaxis can be stopped safely in HIV-1-infected patients whose CD4 cell counts have increased above 200 cells/microL after treatment with HAART.

Adherence in antiretroviral therapy: a review of qualitative studies.

Since the introduction of HAART, HIVand AIDSrelated mortality has declined tremendously [1,2]. The continuous, lifelong treatment with antiretroviral therapy has significantly improved life expectancy and turned HIV from a terminal infection into a chronic disease. In HAART, adherence is of utmost importance. Poor adherence, indeed, may lead to medication failure, viral mutations and development of drug resistance [3,4]. Future treatment options become limited because of cross-resistance [5]. The risk of transmission of resistant viruses makes adherence a public health concern [6,7]. Research and daily practice have shown that strict adherence is difficult to achieve for many of the HIVinfected patients treated with antiretroviral therapy [8,9]. Adherence to HAART requires patients to behave in a way that cannot easily be incorporated into daily life.

Activation and Cell Cycle Antigens in CD4+ and CD8+ T Cells Correlate with Plasma Human Immunodeficiency Virus (HIV-1) RNA Level in HIV-1 Infection

The relationship between T cell activation and human immunodeficiency virus type 1 (HIV-1) replication was studied in HIV-infected subjects, 20 with and 10 without anti-HIV treatment. Expression of Ki-67 proliferation-associated antigen was increased in CD4+ and CD8+ T cells and correlated with HLA-DR. In subjects without anti-HIV treatment, the plasma HIV-1 RNA level correlated with HLA-DR in CD4+ T cells, with Ki-67 in CD8+ T cells, and with expression of CD38 in both T cell subsets. A proportion of treated subjects had increased T cell activation despite 4 months of highly active antiretroviral treatment (HAART). In subjects receiving HAART, a high percentage of HLA-DR+ CD4+ T cells was associated with signs of opportunistic infections. This work supports the concept that, in the natural course of HIV-1 infection, HIV replication itself leads to general T cell activation and that opportunistic infections generate additional CD4+ T cell activation and HIV replication.

The Dominant Source of CD4+ and CD8+ T-Cell Activation in HIV Infection Is Antigenic Stimulation

&NA;To distinguish between antigenic stimulation and CD4+ T‐cell homeostasis as the cause of T‐cell hyperactivation in HIV infection, we studied T‐cell activation in 47 patients before and during highly active antiretroviral therapy (HAART). We show that expression of human leukocyte antigen (HLA)‐DR, CD38, and Ki67 on T cells decreased during HAART but remained elevated over normal values until week 48 of therapy. We confirm previous reports that T‐cell activation correlates positively with plasma HIV RNA levels (suggesting antigenic stimulation), and negatively with CD4 count (suggesting CD4+ T‐cell homeostasis). However, these correlations may be spurious, because misleading, due to the well‐established negative correlation between CD4 count and plasma HIV RNA levels. To resolve this conflict, we computed partial correlation coefficients. Correcting for CD4 counts, we show that plasma HIV RNA levels contributed to T‐cell hyperactivation. Correcting for plasma HIV RNA levels, we show that CD4+ T‐cell depletion contributed to T‐cell activation. Correcting for both, activation of CD4+ and CD8+ T cells remained positively correlated. Because this suggests that CD4+ and CD8+ T‐cell activation is caused by a common additional factor, we conclude that antigenic stimulation by HIV or other (opportunistic) infections is the most parsimonious explanation for T‐cell activation in HIV infection. Persistence of HIV antigens may explain why T‐cell activation fails to revert to levels found in healthy individuals after 48 weeks of therapy.

Vertical integration in medical school: effect on the transition to postgraduate training

Medical Education 2010: 44 : 272–279

Restoration of the CD4 T cell compartment after long-term highly active Antiretroviral therapy without phenotypical signs of accelerated immunological aging

It remains uncertain whether full T cell reconstitution can be established in HIV-infected children and adults with long-term sustained virological control by highly active antiretroviral therapy (HAART). In this study, we comprehensively analyzed various phenotypical markers of CD4 T cell recovery. In addition to measuring T cell activation and proliferation markers, CD4 T cell generation and aging of the CD4 T cell compartment were assessed by measuring TCR excision circles and the fraction of CD31-expressing naive CD4 T cells. In all children and in adults with relatively high CD4 T cell counts at start of therapy (>200 cells/μl), total CD4 T cell numbers normalized within 1 year of therapy. After long-term HAART (4.4–9.6 years), naive CD4 T cell counts had normalized in both groups. Although in adults with low baseline CD4 T cell counts (<200 cells/μl) total CD4 T cell numbers normalized eventually after at least 7 years of HAART, naive CD4 T cell counts had still not recovered. TCR excision circle data showed that thymic T cell production contributed to naive T cell recovery at all ages. The fraction of CD31-expressing naive CD4 T cells was found to be normal, suggesting that the CD4 T cell repertoire was diverse after long-term HAART. Hence, under sustained viral suppression during long-term HAART, the T cell compartment has the potential to fully recover by generating new naive T cells both in children and in adults with high baseline CD4 T cells counts. Irrespective of baseline CD4 T cell counts, reconstitution occurred without a significant effect on T cell aging as reflected by markers for replicative history.

Reconstitution of naive T cells during antiretroviral treatment of HIV-infected adults is dependent on age.

Objective: To determine the influence of age on the regeneration rate of naive and memory T cells in the blood of 45 adults on highly active antiretroviral therapy (HAART). Methods: The age of the patients ranged from 25 to 57 years. Naive cells were defined as CD45RA+CD27+. Cells negative for CD45RA and/or CD27 were considered memory type cells. Results: The recovery rates of naive CD4 and CD8 T cells were similar, were negatively correlated with age and were decreasing 5% and 3.6% per year, respectively. In a multivariate regression analysis, only age was significantly correlated with the naive T cell recovery rates. The recovery rate of memory T cells showed no relation to age. The average regeneration rate of naive CD4 T cells during HAART, i.e., 0.34 × 106 cells/l per day, is not lower than regeneration rates in HIV-negative adults following cytotoxic chemotherapy or CD4 monoclonal antibody therapy. Conclusion: These observations suggest that the thymus contributes considerably to the regeneration of naive T cells in adults on HAART, and that the impact of HIV infection on naive T cell production is small, or rapidly reversible.

Implementation of simulation in surgical practice: Minimally invasive surgery has taken the lead: The Dutch experience

Minimal invasive techniques are rapidly becoming standard surgical techniques for many surgical procedures. To develop the skills necessary to apply these techniques, box trainers and/or inanimate models may be used, but these trainers lack the possibility of inherent objective classification of results. In the past decade, virtual reality (VR) trainers were introduced for training minimal invasive techniques. Minimally invasive surgery (MIS) is, by nature, very suitable for this type of training. The specific psychomotor skills and eye–hand coordination needed for MIS can be mastered largely using VR simulation techniques. It is also possible to transfer skills learned on a simulator to real operations, resulting in error reduction and shortening of procedural operating time. The authors aim to enlighten the process of gaining acceptance in the Netherlands for novel training techniques. The Dutch Societies of Surgery, Obstetrics and Gynecology, and Urology each developed individual training curricula for MIS using simulation techniques, to be implemented in daily practice. The ultimate goal is to improve patient safety. The authors outline the opinions of actors involved, such as different simulators, surgical trainees, surgeons, surgical societies, hospital boards, government, and the public. The actual implementation of nationwide training curricula for MIS is, however, a challenging step.

Filgrastim to treat neutropenia and support myelosuppressive medication dosing in HIV infection

Background: Patients with HIV infection frequently experience disease or treatment‐related myelosuppression leading to neutropenia. Neutropenia often leads to dose‐reduction or discontinuation of important myelosuppressive therapy. Objective: To examine the efficacy and safety of filgrastim for reversing neutropenia and determine the effect of this on use of myelosuppressive medications. Design: Open‐label, non‐comparative, multicentre study in 200 HIV‐positive patients with neutropenia [absolute neutrophil count (ANC) < 1.0×109/l]. Filgrastim was started at 1 &mgr;g/kg/day subcutaneously for 28 days. This initial treatment phase was followed by a maintenance phase, using 300 &mgr;g on 1‐7 days/week. In both phases the dose of filgrastim was adjusted to achieve an ANC of 2‐5×109/l. Results: Filgrastim reversed neutropenia in 98% of patients (ANC ≥2×109/l), with a median time to reversal of 2 days (range 1‐16) and a median dose of 1 &mgr;g/kg/day (range 0.5‐10). Most patients (96%) achieved reversal of neutropenia with a filgrastim dose of ≤ 300 &mgr;g/day (≤1 vial/day). Normal ANCs were then maintained with a median of 1 &mgr;g/kg/day (range 0.22‐10.6) during the treatment phase and 3×300 &mgr;g vials/week (range 1‐7) during the maintenance phase. Ganciclovir, zidovudine, co‐trimoxazole and pyrimethamine were the drugs most frequently considered to be causing neutropenia, and 83% of patients received one or more of these in the study. Filgrastim allowed > 80% of patients to increase or maintain dose‐levels of these four medications or add them to their therapy. The number of these four medications received per patient increased by > 20% during filgrastim therapy. Filgrastim was well tolerated. CD4, CD8 and total lymphocyte counts all increased slightly, and there was no difference in HIV‐1 p24 antigen levels. Conclusion: Filgrastim rapidly reverses neutropenia and maintains normal ANC in patients with HIV infection. This allows greater use of myelosuppressive medications without the potentially life‐threatening complications of neutropenia.

Effect of Escalating Doses of Recombinant Human Granulocyte Colony-Stimulating Factor (Filgrastim) on Circulating Neutrophils in Healthy Subjects

The safety profile, tolerability, pharmacodynamics, and pharmacokinetics of four doses of recombinant human granulocyte colony-stimulating factor (filgrastim) were assessed in healthy volunteers in a double-masked, placebo-controlled, parallel-group trial. Healthy subjects received subcutaneous injections of filgrastim 75 microg (n = 8), 150 microg (n = 4), 300 microg (n = 4), 600 microg (n = 8), or placebo (n = 6) daily for 10 consecutive days. Blood samples were drawn daily immediately before the injection and on days 1 and 10 serially throughout the day. Increased absolute neutrophil counts (ANCs) were seen within 90 minutes of drug administration in subjects in all dose groups, peaking approximately 12 hours after administration. This increase was dose related in subjects in the three lower dose groups. The time to peak ANC on day 10 was approximately 9 hours, with a daily ANC profile in all four dose groups that was similar to the profile on day 1. In all dose groups, ANCs were near baseline within 48 hours of discontinuation of filgrastim. Mild, reversible thrombocytopenia was reported in 4 of 10 subjects in the highest dose group. Two subjects in the filgrastim 600-microg group were withdrawn for adverse events. Filgrastim had a good safety profile and caused dose-related increases in ANC when administered to healthy volunteers for up to 10 days.