Susceptibility to opportunistic infections in HIV-infected patients with increased CD4 T-cell counts on antiretroviral therapy may be predicted by markers of dysfunctional effector memory CD4 T cells and B cells

OBJECTIVES: HIV-infected patients responding to combination antiretroviral therapy (ART) after experiencing severe immunodeficiency may exhibit persistent immune defects and occasionally experience opportunistic infections (OIs) despite increased CD4 T-cell counts. The investigation of immune defects in such patients was examined in this study. METHODS: CD4 effector memory T-cell (T(em)-cell) function [assessed by blood cytomegalovirus (CMV) interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot-forming cell assay (ELISPOT) counts] and B-cell dysregulation [assessed by serum immunoglobulin A (IgA) and IgE levels] were examined in 27 patients with increased CD4 T-cell counts after receiving ART for over 2 years. Two of these patients and one other had developed OIs on ART and are described in detail. RESULTS: Serum levels of IgA and IgE were higher than reference intervals (P<0.001) and CMV IFN-gamma ELISPOT counts were lower than those in non-HIV-infected controls (P<0.001) in the HIV-infected patients. Low CMV IFN-gamma ELISPOT counts were associated with high IgA levels (r=-0.5, P=0.01, Spearman's correlation test) and segregated with high IgE levels (P=0.06, Fisher's test). CMV IFN-gamma ELISPOT counts and serum IgA and IgE levels did not change significantly over a median time of 35 (range 8-60) months after the first measurement, whereas CD4 T-cell counts increased. All three patients who experienced OIs had repeatedly low CMV IFN-gamma ELISPOT counts and increased serum levels of IgA and/or IgE. CONCLUSION: Low CD4 T(em)-cell function and B-cell dysregulation are immune defects that may persist independently of changes in the CD4 T-cell count in HIV-1-infected patients responding to ART and are associated with an increased risk of developing an OI.     

Long-term trends in CD4 cell counts and impact of viral failure in individuals starting antiretroviral therapy: UK Collaborative HIV Cohort (CHIC) study

Objective

The aim of the study was to describe trends in CD4 cell counts in HIV‐infected patients after initiation of combination antiretroviral therapy (cART), according to CD4 cell count at initiation (baseline), and to quantify the implications of virological failure for these trends.

Methods

Eligible participants from the UK Collaborative HIV Cohort (CHIC) were antiretroviral‐naïve and started cART after 1997. Random effects were used to model CD4 cell count trends, accounting for multiple measurements within participants. We assessed whether CD4 cell count trends varied according to baseline CD4 cell count and separately in participants with and without post‐cART virological failure. Effects of post‐cART virological failure (>1000 HIV‐1 RNA copies/mL) on subsequent CD4 cell counts were evaluated.

Findings

A total of 7069 participants were included in the analysis (median follow‐up in all baseline CD4 cell count groups was ≥35 months). Among participants without virological failure ≥6 months after the start of cART, CD4 cell counts continued to increase up to 8 years, with little evidence that differences between baseline CD4 cell count groups diminished over time. Virological failure ≥6 months after the start of cART was associated with lower subsequent CD4 cell counts, with greater CD4 cell count reduction for more recent virological failure and higher viral load.

Conclusions

Post‐cART CD4 cell counts are strongly related to pre‐cART CD4 cell counts. CD4 cell count recovery is greatest in individuals who can avoid viral loads >1000 copies/mL while on cART.     

The impact of malnutrition on survival and the CD4 count response in HIV-infected patients starting antiretroviral therapy

BACKGROUND: The impact that malnutrition at the time of starting antiretroviral therapy (ART) has on survival and the CD4 count response is not known. METHODS: A retrospective cohort study of patients attending the national HIV referral centre in Singapore who had a CD4 count less than 250 cells/microL and a measurement of body weight performed at the time of starting ART was carried out. Demographic and clinical variables were extracted from an existing database. Body mass index (BMI) was calculated from the weight in kilograms divided by the square of the height in metres. Moderate to severe malnutrition was defined as BMI less than 17 kg/m(2). Intent-to-treat Cox models were used to determine the predictors of survival. RESULTS: A total of 394 patients were included in the analysis, of whom 79 died during a median study follow-up of 2.4 years. Moderate to severe malnutrition was present in 16% of patients at the time of starting ART, and was found to be a significant independent predictor of death [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.29-3.73, P=0.004 for those with BMI<17 compared with those with BMI>18.5] as were stage of disease (HR 2.47, 95% CI 1.20-5.07, P=0.014 for those who were at stage C compared with those at stage A) and the type of ART [HR 0.50, 95% CI 0.27-0.93, P=0.03 for highly active antiretroviral therapy (HAART) compared with non-HAART treatment]. Malnutrition did not impair the magnitude of the increase in CD4 count at 6 or 12 months. CONCLUSIONS: Malnutrition at the time of starting ART was significantly associated with decreased survival, but the effect appeared not to be mediated by impaired immune reconstitution. Given the increasing access to ART in developing countries and the high frequency of HIV-associated wasting, studies of nutritional therapy as an adjunct to the initiation of HAART are urgently needed.     

Depression severity is associated with increased risk behaviors and decreased CD4 cell counts

Depression is a common comorbidity among HIV-infected individuals. We studied the relationship between depressive symptoms, risk behaviors (risky-sexual behavior, tobacco, alcohol, and illicit drug use) and HIV outcomes. This cross-sectional study conducted in 2009 at the Washington University HIV Clinic included screening for depression with patient health questionnaire, survey of sexual behavior, illicit drug, alcohol, and tobacco use within 30 days. Sociodemographics, plasma HIV RNA levels, CD4 cell counts, and sexually transmitted disease test results were obtained from medical records. Multivariate logistic and linear regression models were used to assess the association between depressive symptoms severity and risk behaviors, HIV outcomes and combination antiretroviral therapy (cART) adherence. A total of 624 persons completed the assessment of whom 432 (69%) were male and 426 (68%) African-American. The median CD4 cell count was 410 cells/mm³ and 479 persons (77%) were on cART of whom 112 (23%) had HIV RNA level > 400 copies/mL. Overall, 96 (15%) had symptoms of major depressive disorder. Depressive symptom severity was associated with increased likelihood of high-risk drinking (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.1–5.1), current tobacco use (OR, 1.8; 95% CI, 1.1–2.9), illicit drug use (OR, 1.7; 95% CI, 1.0–2.8), and risky-sexual behavior (OR, 1.5; 95% CI, 0.8–2.7). Suboptimal cART adherence (visual analog scale < 95%) was also associated with depressive symptoms severity (p < 0.05). After adjustment for age, sex, race, receipt of cART, and cART adherence, depressive symptoms severity was independently associated with lower CD4 cell count (p < 0.05) but not with higher HIV RNA level (p = 0.39). Depression adversely affects HIV-infected individuals, requiring greater effort at utilizing multidisciplinary interventions.     

Alcohol use and immune reconstitution among HIV-infected patients on antiretroviral therapy in Nairobi,Kenya

Studies on the effects of alcohol use on HIV disease progression have been contradictory, with at least one study finding a positive effect of low alcohol consumption on CD4 count. In addition, most such studies have taken place in the developed West. We investigated the association between alcohol use and immune reconstitution through CD4 count response among HIV-infected individuals on antiretroviral therapy (ART) at an urban sub-Saharan African clinic. This was a retrospective cohort study of treatment-naïve HIV-infected adults initiating ART in Nairobi, Kenya and followed for 12 months between January 2009 and December 2012. At enrollment, a standardized questionnaire was used to collect data on sociodemographic variables and alcohol consumption. CD4 count was measured every six months. Linear regression models assessed the association between CD4 count and alcohol consumption, categorized as abstinent, moderate, or hazardous. Overall, 854 participants were included, 522 of which were women, with 85 (25.6%) men and 50 (9.6%) women reporting any alcohol use, and 8 (2.4%) men and 7 (1.3%) women reporting hazardous drinking. At baseline, alcohol use was associated with higher education and socioeconomic status. Median CD4 count was higher among alcohol users compared to those who abstained at baseline and at 6 and 12 months post-ART initiation, although this was only significant at 6 months. There were no differences in adherence between abstainers and drinkers. While overall alcohol use was significantly associated with higher CD4 counts, moderate and hazardous use treated separately were not. We conclude that, while alcohol use was associated with higher CD4 counts at 12 months post-ART, the mechanism for this association is unclear but may reflect unmeasured socioeconomic or nutritional differences. Additional research is required on the specific drinking patterns of this population and the types of alcoholic beverages consumed to clarify this relationship.     

CD38 expression on CD8 T cells has a weak association with CD4 T-cell recovery and is a poor marker of viral replication in HIV-1-infected patients on antiretroviral therapy

OBJECTIVE: The aim of the study was to determine whether the expression of CD38 on CD8 T cells can identify patients with virological failure on antiretroviral therapy (ART). DESIGN: This was a cross-sectional study of patients attending a single HIV clinic in London. METHODS: The expression of CD38 on CD8 T cells was assessed using a biologically calibrated flow cytometry protocol. Patients were characterized by lymphocyte subset and viral load measurements. Characteristics including historical CD4 T cell counts, therapeutic history, co-infections and demographics were obtained from medical records. RESULTS: Elevated levels of CD8 CD38(high) T cells were found in HIV-1-infected patients who failed to suppress viral replication with ART; however, this parameter lacked sufficient sensitivity and specificity to replace viral load testing in assessing the efficacy of ART. Increased levels of CD8 CD38(high) cells were associated with reduced CD4 T cell counts in HIV-1-infected patients on ART after correcting for known determinants of CD4 T-cell recovery. CONCLUSIONS: The expression of CD38 on CD8 T cells lacks sufficient sensitivity and specificity to be used as a surrogate marker for viral load to monitor HIV-1 infection. T-cell activation is associated with reduced CD4 T-cell reconstitution in patients receiving ART.     

HIV/AIDS患者外周血CD4+ T细胞计数和淋巴细胞计数相关性的多中心研究

目的 对淋巴细胞计数预测CD4+ T细胞计数的准确性进行评价,为临床应用提供支持.方法 在全国23个分中心共筛查2 013例未接受抗病毒治疗的HIV/AIDS患者,经流式细胞术检测CD4+ T细胞计数,分析血常规当中的淋巴细胞计数和CD4+ T细胞计数之间的相关性,绘制ROC曲线判断淋巴细胞计数预测CD4+T细胞计数的准确性,并计算其敏感度、特异度、阳性预测值和阴性预测值.结果 2 013例HIV/AIDS患者的淋巴细胞计数和CD4+ T细胞计数分别为(1 600±670)×106/L和(244±148)×106/L,两者呈现显著正相关性(r=0.482,P＜0.000 1),以淋巴细胞计数预测CD4T细胞计数＜100×106/L、＜200×106/L和＜350×106/L的AUCROC分别为0.790(95％ CI0.761 ～0.818,P＜0.000 1),0.733(95％ CI0.710 ～0.755,P ＜0.000 1)和0.732 (95％ CI0.706 ～0.758,P ＜0.000 1).结论 在HIV/AIDS患者的临床诊治中,用淋巴细胞计数预测CD4+ T细胞计数有其实用价值,可以考虑在不具备CD4+ T细胞计数直接检测时作为替代指标用于监测疾病进展,也可以在获得CD4+ T细胞计数结果之前用来初步快速判断患者病情.     

CD4 count and viral load time-courses in patients treated with highly active antiretroviral therapy and association with the CDC staging system

Objectives

The aim of the study was to analyse CD4 cell count and viral load dynamics in patients undergoing antiretroviral therapy and their association with the Centers for Disease Control and Prevention (CDC) classification system.

Methods

CD4 cell count and viral load were determined in 2982 patients who were classified according to clinical and immunological CDC stages. Measurements were carried out at baseline and at the 3rd, 6th and 12th months.

Results

Clear differences in the immunological and virological responses to therapy were observed depending on the CDC stage, with better results associated with less advanced stages. There was a marked parallelism in the CD4 cell count curves of the different CDC stages over the year of follow up, in both naïve and experienced patients, indicating that the increase in CD4 cell count at each time‐point was similar for all clinical and immunological CDC stages. However, as the baseline values were closely associated with CDC stage, the CD4 cell counts finally reached were clearly dependent on CDC stage. The highest virological responses were observed during the initial 3 months, particularly in naïve patients, but whereas naïve patients showed additional increases up to the 6th month experienced patients reached a plateau at the 3rd month. The CD4 increases were also higher during the initial 3 months but persisted during the year of follow‐up.

Conclusion

Both clinical and immunological CDC stages at baseline are highly predictive of the immunological and virological response to therapy, a finding that could have clinical implications.

     

两种机型的流式细胞仪测定CD4T细胞计数的比较研究

目的多种流式细胞仪机型应用于艾滋病防治工作中，比较不同机型间的免疫数据乃是当前迫切需要解决的问题。方法应用BDFACS Calibur和Beckman Coulter XL两种主流机型流式细胞仪，对阜阳市现场采集的183份标本[正常人41份，艾滋病病毒（HIV）阳性感染者142份]进行平行检测，观察上述两种机型对检测同一标本CD4绝对计数的影响。结果BD和XL两种机型的绝对计数结果比较显示，正常人CDd绝对计数在两种机型间的差异范围：≤10％的占57％，而〉10％占43％；检测142份HIV阳性标本，CD4绝对计数差异≤10％的占84％；而差异〉10％的占16％。在正常人标本组两机型数据间相关系数r=0．97；HIV阳性标本组数据间相关系数r=0．98，回归方程X系数均接近1。统计学检验显示，两种机型检测数据无显著性差异（P〉0．05）。结论两种机型间数据高度相关且数值相近．所测定的HIV感染者CD4细晌绡对计数可以百用．     

Changes in the uptake of antiretroviral therapy and survival in people with known duration of HIV infection in Europe: results from CASCADE

Objectives To estimate the times from HIV seroconversion to death, and to the initiation of therapy and the mean CD4 cell count at initiation. Design and methods Using Kaplan–Meier methods, allowing for late entry, we analysed CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) data from HIV-infected individuals with known dates of seroconversion. We tested the association of time to initiation of therapy and of survival with: exposure category, age, sex, presentation during acute infection and calendar year at risk (as time-dependent) in Cox proportional hazards models, stratifying by study. We estimated the mean CD4 cell count at the initiation of therapy using interval regression. Results Of 5893 seroconverters, 1613 (27.4%) died. The risk of death was 65% lower (95% CI = 57–72%) in 1997–99 compared to previous years. Being at risk in earlier calendar years, older age and a short interval between negative and positive test dates were associated with shorter survival. At the same time from seroconversion, people at risk in 1997–99, older individuals and people with a short test interval were more likely to initiate therapy. Injecting drug users (IDUs) were less likely to initiate therapy compared to those exposed through sex between men (RR = 0.79, 95% CI = 0.69–0.89). The mean CD4 cell count at therapy initiation was 205 cells/mL, which increased significantly over time. Although the earlier initiation of therapy was consistent with longer survival in the 1997–99 period, we found no evidence of this in other calendar periods. Conclusions We found a significant and substantial reduction in the risk of death and a significant trend of earlier initiation of antiretroviral therapy (ART) in the 1997–99 period. Although IDUs were less likely to initiate therapy their overall survival did not appear to differ from others. The increasing tendency to initiate ART closer to seroconversion has unknown long-term consequences which require monitoring.     

Short‐term antiretroviral therapy to prevent mother‐to‐child transmission is safe and results in a sustained increase in CD4 T‐cell counts in HIV‐1‐infected mothers*

Background

Short‐term antiretroviral therapy (START) to prevent mother‐to‐child transmission (MTCT) is currently recommended for all HIV‐1‐infected pregnant women. The objective of this study was to assess the effect on CD4 cell counts and viral load dynamics the withdrawal of START after birth could generate.

Methods

This was a 5‐year cohort study involving HIV‐1‐infected pregnant women who presented with CD4 counts >300 cells/μL and had received START to prevent MTCT.

Results

Seventy‐five pregnancies were assessed. In 24 cases, there was a history of antiretroviral therapy prior to prophylaxis. The median baseline CD4 count was 573 cells/μL. In 75% of cases, prophylaxis was started after 26.6 weeks of gestation. The median CD4 cell count increase over baseline during prophylaxis was 24.5%. In only five cases did HIV‐1 viral load remain detectable during prophylaxis. After START, CD4 cell counts did not drop significantly, and the HIV‐1 viral load plateau was near the baseline level. The estimated mean time for CD4 count to fall below 300 cells/μL was 3.5 years and was directly associated with high baseline CD4 cell count, as well as with CD4 increase after prophylaxis, whereas it was negatively correlated with previous use of antiretroviral (ARV) drugs and persistence of detectable HIV‐1 viral load during prophylaxis.

Conclusions

A potent, well‐tolerated prophylactic ARV regimen can improve CD4 cell counts during and after START. In women receiving such prophylaxis, there is a remarkable time interval for CD4 cell counts to drop to levels that indicate treatment.