Correction: Lack of Mucosal Immune Reconstitution during Prolonged Treatment of Acute and Early HIV-1 Infection

BACKGROUND: During acute and early HIV-1 infection (AEI), up to 60% of CD4(+) T cells in the lamina propria of the lower gastrointestinal (GI) tract are lost as early as 2–4 wk after infection. Reconstitution in the peripheral blood during therapy with highly active antiretroviral therapy (HAART) is well established. However, the extent of immune reconstitution in the GI tract is unknown. METHODS AND FINDINGS: Fifty-four AEI patients and 18 uninfected control participants underwent colonic biopsy. Forty of the 54 AEI patients were followed after initiation of antiretroviral therapy (18 were studied longitudinally with sequential biopsies over a 3-y period after beginning HAART, and 22 were studied cross sectionally after 1–7 y of uninterrupted therapy). Lymphocyte subsets, markers of immune activation and memory in the peripheral blood and GI tract were determined by flow cytometry and immunohistochemistry. In situ hybridization was performed in order to identify persistent HIV-1 RNA expression. Of the patients studied, 70% maintained, on average, a 50%–60% depletion of lamina propria lymphocytes despite 1–7 y of HAART. Lymphocytes expressing CCR5 and both CCR5 and CXCR4 were persistently and preferentially depleted. Levels of immune activation in the memory cell population, CD45RO(+) HLA-DR(+), returned to levels seen in the uninfected control participants in the peripheral blood, but were elevated in the GI tract of patients with persistent CD4(+) T cell depletion despite therapy. Rare HIV-1 RNA–expressing cells were detected by in situ hybridization. CONCLUSIONS: Apparently suppressive treatment with HAART during acute and early infection does not lead to complete immune reconstitution in the GI mucosa in the majority of patients studied, despite immune reconstitution in the peripheral blood. Though the mechanism remains obscure, the data suggest that there is either viral or immune-mediated accelerated T cell destruction or, possibly, alterations in T cell homing to the GI tract. Although clinically silent over the short term, the long-term consequences of the persistence of this lesion may emerge as the HIV-1–infected population survives longer owing to the benefits of HAART

Implementation and Operational Research

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Beyond too little, too late and too much, too soon: a pathway towards evidence-based, respectful maternity care worldwide.

On the continuum of maternal health care, two extreme situations exist: too little, too late (TLTL) and too much, too soon (TMTS). TLTL describes care with inadequate resources, below evidence-based standards, or care withheld or unavailable until too late to help. TLTL is an underlying problem associated with high maternal mortality and morbidity. TMTS describes the routine over-medicalisation of normal pregnancy and birth. TMTS includes unnecessary use of non-evidence-based interventions, as well as use of interventions that can be life saving when used appropriately, but harmful when applied routinely or overused. As facility births increase, so does the recognition that TMTS causes harm and increases health costs, and often concentrates disrespect and abuse. Although TMTS is typically ascribed to high-income countries and TLTL to low-income and middle-income ones, social and health inequities mean these extremes coexist in many countries. A global approach to quality and equitable maternal health, supporting the implementation of respectful, evidence-based care for all, is urgently needed. We present a systematic review of evidence-based clinical practice guidelines for routine antenatal, intrapartum, and postnatal care, categorising them as recommended, recommended only for clinical indications, and not recommended. We also present prevalence data from middle-income countries for specific clinical practices, which demonstrate TLTL and increasing TMTS. Health-care providers and health systems need to ensure that all women receive high-quality, evidence-based, equitable and respectful care. The right amount of care needs to be offered at the right time, and delivered in a manner that respects, protects, and promotes human rights

Rare HIV-1 RNA–Expressing Cells Were Detected in the GI Tract during HAART

<p>Using a ³⁵S-labeled, single-stranded anti-sense RNA probe of HIV-1, in situ hybridization was performed on paraffin-embedded sections as described in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030484#s2" target="_blank">Methods</a>. Multiple (4–27) sections per patient were examined. Cells were considered positive for viral gene expression if the grain count was more than six times that of the background. Isolated and rare viral RNA–expressing cells (arrows) were detected in the LP (left panel), T cell zone, and intra-epithelial lymphocytes (right panel), respectively. Original magnification 50×.</p

The Level of Activated and Proliferating CD4⁺ and CD8⁺ T Cells Remains Elevated in the GI Tract during HAART

<div><p>Using four-color flow cytometry, co-expression of CD45RO and HLA-DR was examined on CD3⁺CD8⁺ (A) and CD3⁺CD4⁺ (B) gated lymphocytes in HIV-uninfected control participants, AEI, and patients treated for up to 1 y, 1–3 y, and 3–7 y. PBMCs are depicted in white and MMCs in grey boxes.</p> <p>(C) Using immunohistochemistry, the percentage of GI cells expressing Ki67 was determined on CD4⁺ T cells (left panel) and CD8⁺ T cells (right panel). Levels in HIV-uninfected control participants (white boxes) were compared with AEI (light grey boxes) and patients treated for up to 1 y (hatched boxes), 1–3 y (speckled boxes), and 3–7 y (dark grey boxes).</p> <p>In these plots, the boxes extend from the first to the third quartiles, enclosing the middle 50% of the data. The middle line within each box indicates the median of the data, whereas the vertical line extends from the 10th to the 90th percentile. Means of the data are represented by filled-in squares.</p></div

Effector Sites (LP) of the GI Tract Showing Persistent CD4⁺ T Cell Depletion during HAART

<div><p>Immunohistochemical characterization of immune-inductive and effector sites in rectal biopsies. Using a PC-based image-analysis system (KS 4000, Kontron) a standard area was set by the image analyzer. For the LP, a total of between ten and 15 consecutive nonoverlapping fields were analyzed for each staining. For the OLT, between two and five representative areas were chosen.</p> <p>(A) CD4⁺ T cells per unit area were determined in OLT (left panel) and LP (right panel). Mean CD4⁺ T cell numbers were compared between HIV-uninfected (white boxes), AEI (light grey boxes), and patients treated for up to 1 y (hatched boxes), 1–3 y (speckled boxes) and 3–7 y (dark grey boxes). In these plots, the boxes extend from the first to the third quartiles, enclosing the middle 50% of the data. The middle line within each box indicates the median of the data, whereas the vertical line extends from the 10th to the 90th percentile. Means of the data are represented by filled-in squares.</p> <p>(B) A biopsy section (viewed at 40× magnification) from an HIV-uninfected control participant, showing CD4⁺ T cells (stained red) within the GI LP (panel I). In contrast, a pronounced reduction in LP CD4⁺ T cells is noted in a patient with AEI (patient no. 131) in panel II which does not correct despite antiretroviral therapy for 2 y in the same patient (panel III). Another representative study patient (no. 142) is presented, where LP CD4⁺ T cell depletion during AEI (panel IV) does not correct after antiretroviral therapy for 1 y (panel V).</p></div

CD4⁺ T Cells Expressing CCR5 and CCR5/CXCR4 Are Preferentially Depleted from the GI Tract during HAART

<p>CD3⁺/CD4⁺ gated MMCs were analyzed for the expression of chemokine receptors CCR5, CXCR4, and CCR5/CXCR4 in HIV-uninfected (white boxes), AEI (light grey boxes), and patients treated for up to 1 y (hatched boxes), 1–3 y (speckled boxes), and 3–7 y (dark grey boxes). In these plots, the boxes extend from the first to the third quartiles, enclosing the middle 50% of the data. The middle line within each box indicates the median of the data, whereas the vertical line extends from the 10th to the 90th percentile. Means of the data are represented by filled-in squares.</p

Beyond too little, too late and too much, too soon: a pathway towards evidence-based, respectful maternity care worldwide.

On the continuum of maternal health care, two extreme situations exist: too little, too late (TLTL) and too much, too soon (TMTS). TLTL describes care with inadequate resources, below evidence-based standards, or care withheld or unavailable until too late to help. TLTL is an underlying problem associated with high maternal mortality and morbidity. TMTS describes the routine over-medicalisation of normal pregnancy and birth. TMTS includes unnecessary use of non-evidence-based interventions, as well as use of interventions that can be life saving when used appropriately, but harmful when applied routinely or overused. As facility births increase, so does the recognition that TMTS causes harm and increases health costs, and often concentrates disrespect and abuse. Although TMTS is typically ascribed to high-income countries and TLTL to low-income and middle-income ones, social and health inequities mean these extremes coexist in many countries. A global approach to quality and equitable maternal health, supporting the implementation of respectful, evidence-based care for all, is urgently needed. We present a systematic review of evidence-based clinical practice guidelines for routine antenatal, intrapartum, and postnatal care, categorising them as recommended, recommended only for clinical indications, and not recommended. We also present prevalence data from middle-income countries for specific clinical practices, which demonstrate TLTL and increasing TMTS. Health-care providers and health systems need to ensure that all women receive high-quality, evidence-based, equitable and respectful care. The right amount of care needs to be offered at the right time, and delivered in a manner that respects, protects, and promotes human rights