Total Lymphocyte Count as surrogate marker for CD4 Cell Count in HIV-Infected Individuals in Gondar University Hospital, Northwest Ethiopia

ABSTRACT: BACKGROUND: The high cost of CD4 count estimation in resource-limited countries is a major challenge in initiating patients on highly active antiretroviral therapy (HAART). Therefore, assessment of inexpensive and simple laboratory diagnostic marker is mandatory to diagnose immunosuppression. OBJECTIVE: To evaluate utility of total lymphocyte count (TLC) as surrogate marker for CD4 count in HIV-infected patients. Materials and Methods In this cross sectional study, 400 ART-naive HIV-positive patients enrolled in Gondar University Hospital, from March 2011 to May 2011, were tested for CD4 count & TLC. The cutoffs were determined as: 200 cells/muL for CD4 count and 1200 cells/muL for TLC by using BD FACS count and CELL DYN 1800 Flow Cytometrys respectively. Spearman correlation between TLC and CD4 cell count were assessed. Sensitivity, specificity, positive and negative predictive values for different age a group, TLC [less than or equal to]1200 was computed for CD4 count [less than or equal to]200 cells/cu.mm. RESULTS: Among 400 ART naive HIV infected patients, 278 (69.5%) were females. The mean age of the study participants was 33.7. TLC and CD4 count were positively correlated (r = 0.33, p = 0.001). A TLC of [less than or equal to]1200 cells/m m3 was found to have a sensitivity (32.86%), specificity (95.33%), PPV (79.7%), and NPV (71.9%) for predicting a CD4 count of <200 cells/mm3. CONCLUSION: This study showed that low sensitivity and specificity of TLC as a surrogate measure for CD4 count. Moreover, CD4 cell counts of < 200 cells/mm3 were found in 96 cases (24%) with TLCs of [less than or equal to]1200 cells/mm3. Thus, 1 in 4 individuals would have been deprived of needed treatment. Therefore, we recommend keep on expansion of access to CD4 counter.     

艾滋病患者外周血淋巴细胞计数取代CD4~+T细胞计数监测HAART疗效

评价血友病合并人类免疫缺陷病毒(HIV)和丙型肝炎病毒(HCV)感染的患者接受高效抗逆转录病毒治疗(highly ac-tive anti-retroviral therapy,HAART)时总淋巴细胞计数(total lymphocyte count,TLC)与CD4+T淋巴细胞计数间的相关性。回顾性分析了61例接受HAART的血友病合并HIV和HCV感染的患者共885对TLC与CD4+T淋巴细胞计数间的相关性。TLC用于预测CD4+T淋巴细胞计数的敏感性、特异性和阳性预侧值分别在不同的TLC范围对应于CD4+T淋巴细胞计数<200个/mm3时和CD4+T淋巴细胞计数<350个/mm3时获得。结果885对TLC与CD4+T淋巴细胞计数间存在相关性(r=0.511,P<001)。TLC<1 600个/mm3对应CD4+T淋巴细胞计数<200个/mm3有62.8%的敏感性、68.1%的特异性、43.1%的阳性预测值;TLC<1 800个/mm3对应CD4+T淋巴细胞计数<350个/mm3有79.1%的敏感性、78.0%的特异性、72.5%的阳性预测值。TLC可以作为一种低廉的监测手段在AIDS患者接受HAART时用于估测CD4+T淋巴细胞计数,其敏感性、特异性和阳性预侧值在TLC<1 800个/mm3对应CD4+T淋巴细胞计数<350个/mm3时最为明显。     

Total lymphocyte count of 1200 is not a sensitive predictor of CD4 lymphocyte count among patients with HIV disease in Kampala, Uganda

Introduction

Total Lymphocyte Count (TLC) has been found to be an inexpensive and useful marker for staging disease, predicting progression to AIDS and death and monitoring response to ART. However, the correlation between TLC and CD4 has not been consistent. Access to HAART is expanding in Kampala, Uganda, yet there are no published data evaluating the utility of TLC as inexpensive surrogate marker of CD4 cell count to help guide therapeutic decisions.

Objective

To evaluate clinical illnesses and total lymphocyte count (TLC) as surrogate markers of the CD4 cell count in HIV infected persons being considered for ART.

Methods

A total of 131 patients were enrolled and evaluated by clinical assessment, TLC and CD4 count. Clinical illnesses and TLC dichotomized at various cut-point values were used to determine the sensitivity, specificity, and positive and negative predictive values (PPV and NPV) for the diagnosis of CD4 count <200 cells/mm³ among 100 participants fulfilling criteria for WHO clinical stage 2 and 3.

Results

A strong correlation was observed between TLC and CD4 (r = 0.73, p<0.0001). For all clinical syndromes, except pulmonary tuberculosis, the positive predictive values (PPV) for a CD4 count <200 cells/mm³ were high (>80%) but the negative predictive values (NPV) were low. Using the WHO recommended TLC cut-off of 1200 cells/mm³ to diagnose a CD4 less than 200 cells/mm³, the PPV was 100%, and the NPV was 32%.

Conclusion

Our data showed a good correlation between TLC and CD4 cell count. However, the WHO recommended TLC cutoff of 1200 did not identify the majority of WHO stage 2 and 3 patients with CD4 counts less than 200 cells/mm³. A more rational use of TLC counts is to treat all patients with WHO stage 2 and 3 who have a TLC <1200 and to limit CD4 counts to patients who are symptomatic but have TLC of >1200.     

Low sensitivity of total lymphocyte count as a surrogate marker to identify antepartum and postpartum Indian women who require antiretroviral therapy

BACKGROUND: Some studies support the use of total lymphocyte count (TLC) as a surrogate marker for CD4 cell count to guide antiretroviral therapy (ART) initiation. However, most of these studies have focused on nonpregnant adults. In light of expanding ART access through prevention of mother-to-child transmission (PMTCT)-plus programs in resource-limited settings, we assessed the sensitivity, specificity, and positive predictive value (PPV) of TLC for predicting low CD4 counts in antepartum and postpartum women in Pune, India. METHODS: CD4, TLC, and hemoglobin were measured at third trimester, delivery, and 6, 9, and 12 months postpartum (PP) in a cohort of 779 HIV-infected women. Optimal TLC cutoff for predicting CD4 <200 cells/mm3 was determined via logistic regression where sensitivity, specificity, PPV, and an area under the receiver operating characteristic (ROC) curve were calculated. RESULTS: Among the 779 women enrolled, 16% had WHO clinical stage 2 or higher and 7.9% had CD4 <200 cells/mm3. Using 2689 TLC-CD4 pairs, the sensitivity, specificity, and PPV of TLC <1200 cells/mm3 for predicting CD4 <200 cells/mm3 was 59%, 94%, and 47%, respectively. The sensitivity of TLC <1200 cells/mm3 cutoff ranged between 57% and 62% for time points evaluated. Addition of hemoglobin <12 g/dL or <11 g/dL increased the sensitivity of TLC to 74% to 92% for predicting CD4 <200 cells/mm3 but decreased the specificity to 33% to 69% compared to TLC alone. A combination of TLC, hemoglobin, and WHO clinical staging had the highest sensitivity but lowest specificity compared to other possible combinations or use of TLC alone. The sensitivity and specificity of TLC <1200 cells/mm3 to predict a CD4 <350 cells/mm3 was 31% and 99%, respectively. CONCLUSIONS: Our data suggest that antepartum and PP women with TLC <1200 cells/mm3 are likely to have CD4 <200 cells/mm3. However, the sensitivity of this TLC cutoff was low. Between 45% and 64% of antepartum and PP women requiring initiation of ART may not be identified by using TLC alone as a surrogate marker for CD4 <200 cells/mm3. The WHO-recommended TLC cutoff of <1200 cells/mm3 is not optimal for identifying antepartum and PP Indian women who require ART.     

Predictors of low CD4 count in resource-limited settings: based on an antiretroviral-naive heterosexual thai population

A barrier to the appropriate provision of antiretroviral therapy to treat immunosuppressed HIV-infected persons in resource-poor countries is identifying who requires treatment. The World Health Organization (WHO) has suggested using a clinical algorithm combined with a total lymphocyte count (TLC) < 1200 cells/mm as a surrogate for a CD4 count less than 200 cells/mm when it is not possible to measure the CD4 count. We evaluated various TLC levels, anemia, and body mass index and compared our data with the WHO criteria to develop a more sensitive algorithm to predict CD4 counts of < 200 cells/mm and < 350 cells/mm in 839 men and women from Thailand infected with HIV-1 subtype E (CRF01_AE). The December 2003 WHO guidelines had a sensitivity of 34.1% in men and 31.8% in women to detect persons with a CD4 count < 200 cells/mm in this HIV-infected population from Thailand. The use of a TLC < 1500 cells/mm or TLC < 2000 cells/mm combined with anemia or WHO stage II infection doubled the sensitivity to detect persons with a CD4 count < 200 (63.0% in men, 68.2% in women) with less than a 6% decrease in specificity.     

Unreported AIDS-defining opportunistic illnesses in persons reported with HIV-related severe immunosuppression.

To better estimate the distribution of AIDS cases after the 1993 change in the case definition, we assessed the proportion of persons whose AIDS diagnosis was based on laboratory criteria for severe immunosuppression (CD4 count <200 cells/microl or <14%) and who also had an unreported opportunistic illness (OI) at the time of the CD4 report. Five U.S. reporting sites (Arizona; Los Angeles County, California; New Jersey; Oregon; and Washington State) reviewed AIDS cases reported between January 1 and June 30, 1993. From these sites, 3289 immunologic cases were reported; of these cases, 322 (9.8%; range, 1.6%-16.1%) were in persons who had an unreported OI. More of those who had an unreported OI were male, members of racial groups other than white, injection drug users, and had a CD4 count of <50 cells/microl at AIDS diagnosis. Because of recent advances in OI prophylaxis and treatment of HIV infection, studies monitoring HIV-related morbidity should assess the occurrence of OIs in a sample of persons reported with HIV and severe immunosuppression. Such assessment will ensure representative ascertainment of initial AIDS-defining OIs and thus improve the usefulness of the data for public health planning and the allocation of resources for patient care.     

Long-term CD4+ T-cell response to highly active antiretroviral therapy according to baseline CD4+ T-cell count

Current treatment guidelines for HIV infection recommend a relatively late initiation of highly active antiretroviral therapy (HAART). Nevertheless, there is still a concern that immune recovery may not be as complete once CD4+ T cells have decreased below a certain threshold. This study addressed the long-term response of CD4+ T-cell counts in patients on HAART and analyzed the influence of baseline CD4+ T-cell counts, baseline viral load, and age. An observational analysis of evolution of CD4+ T cells in 861 antiretroviral therapy-naive chronic HIV-1-infected patients who started treatment consisting of at least 3 drugs in or after 1996 was performed. Patients were classified in 4 groups according to baseline CD4+ T cells: <200 cells/mm3, 200-349 cells/mm3, 350-499 cells/mm3, and >or=500 cells/mm3. The main outcome measures were proportion of patients with CD4+ T cells <200/mm3 and >500/mm3 at last determination and rate of CD4+ T-cell recovery. Patients were followed-up for a median of 173 weeks (interquartile range [IQR], 100-234). There were no differences in follow-up between the 4 groups. CD4+ T cells increased in the whole cohort from a median of 214 cells/mm3 (IQR, 90-355) to 499 cells/mm3 (IQR, 312-733) (P<0.001). Compared with the group with a baseline CD4+ T-cell count of >or=500/mm3, the relative risk of having a last determination of CD4+ T-cell counts >200 cells/mm3 was 0.79 (95% CI, 0.75-0.83), 0.92 (95% CI, 0.89-0.96) and 1 for baseline CD4+ T cells <200 cells/mm3, 200-349 cells/mm3, and 350-499 cells/mm3, respectively. The relative risk of having a last determination of CD4+ T-cell counts >500 cells/mm3 was 0.32 (95% CI, 0.27-0.39, P<0.001), 0.69 (95% CI, 0.60-0.79, P<0.001), and 0.94 (95% CI, 0.83-1.06, P=0.38) for baseline CD4+ T-cell counts <200 cells/mm3, 200-349 cells/mm3, and 350-0499 cells/mm3, respectively, compared with a baseline CD4+ T-cell count of >or=500 cells/mm3. The increase in CD4+ T cells from baseline was statistically significant and was maintained for up to 4 years of follow-up. This increase seemed to slow down after approximately 3 years and reached a plateau after 4-5 years of follow-up even in patients who achieved and maintained viral suppression in plasma. Long-term immune recovery is possible regardless of baseline CD4+ T-cell count. However, patients who start therapy with a CD4+ T-cell count <200 cells/mm3 have poorer immunologic outcome as measured by the proportion of patients with CD4+ T cells <200/mm3 or >500/mm3 at last determination. It seems that the immune recovery slows down after approximately 3 years of HAART and reaches a plateau after 4-5 years of HAART.     

CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater

OBJECTIVE: CD4 cell count changes in therapy-naive patients were investigated during 7 years of highly active antiretroviral therapy (HAART) in an observational cohort. METHODS: Three endpoints were studied: (1) time to >or=800 CD4 cells/mm in 5299 therapy-naive patients starting HAART, (2) CD4 cell count changes during 7 years of uninterrupted HAART in a subset of 544 patients, and (3) reaching a plateau in CD4 cell restoration after 5 years of HAART in 366 virologically suppressed patients. RESULTS: Among patients with <50, 50 to 200, 200 to 350, 350 to 500, and >or=500 CD4 cells/mm at baseline, respectively, 20%, 26%, 46%, 73%, and 87% reached >or=800 CD4 cells/mm within 7 years of starting HAART. Periods with HIV RNA levels >500 copies/mL and age >or=50 years were associated with lesser increases in CD4 cell counts between 6 months and 7 years. Having reached >or=800 CD4 cells/mm at 5 years, age >or=50 years, and >or=1 HIV RNA measurement >1000 copies/mL between 5 and 7 years were associated with a plateau in CD4 cell restoration. CONCLUSIONS: Restoration to CD4 cell counts >or=800 cells/mm is feasible within 7 years of HAART in most HIV-infected patients starting with >or=350 cells/mm and achieving sufficient suppression of viral replication. Particularly in patients >or=50 years of age, it may be beneficial to start earlier than current guidelines recommend.     

Baseline CD4 cell count and outcome of pegylated interferon plus ribavirin therapy in HIV/hepatitis C virus-coinfected patients

OBJECTIVE: When to start hepatitis C treatment in HIV/hepatitis C virus (HCV)-coinfected patients remains unresolved. Our objective was to determine if a baseline CD4 count >/=350 cells/mm predicts a sustained HCV response to pegylated interferon plus ribavirin. METHODS: We conducted a multicenter cohort study of HIV/HCV-coinfected patients treated for HIV in hospitals in Nice, Tourcoing, and Marseille (France). Sustained viral response (SVR) was defined as undetectable HCV RNA 24 weeks after treatment. The relation between CD4 cell count and SVR was examined separately for patients with HCV genotype 1 or non-1. RESULTS: One hundred seventy-five patients were included. In patients with HCV genotype 1, the rate of SVR was 13% and was not related to baseline CD4 cell count (odds ratio [OR] = 1.0, 95% confidence interval [CI]: 0.1 to 9.3). In patients with HCV genotype non-1, the rate of SVR was 46% and was not significantly increased by a baseline CD4 count >/=350 cells/mm (OR = 1.8, 95% CI: 0.6 to 5.9). CONCLUSIONS: Higher CD4 cell count at treatment initiation with pegylated interferon plus ribavirin did not improve treatment success probability, regardless of HCV genotype.     

HIV diagnosis at CD4 count above 500 cells/mm3 and progression to below 350 cells/mm3 without antiretroviral therapy

A trial to evaluate the risks and benefits of initiation of antiretroviral therapy (ART) in patients with high CD4 count (eg, > or =500 cells/mm3), in comparison with deferral (eg, to <350 cells/mm3), merits consideration. Two issues for consideration in designing such a trial are the proportion of patients seen in clinics who present with high CD4 count and the time it will take for those randomized to deferring ART to reach a level where ART must be initiated. Among 13,572 patients in the UK CHIC Study presenting since 1996, 3631 (27%) had a count > or =500 cells/mm3. Among 4268 ART-naive patients with at least one CD4 count in the 500 to 650 cells/mm3 range, the median time to <350 cells/mm3 (or start of ART) was 2.5 years, with a range of 2.1 to 3.1 years depending on the analysis approach. Viral load at baseline was a strong predictor of the time taken for the CD4 count to reach <350 cells/mm3, with the median ranging from 0.7 years in those with viral load > or =500,000 copies/mL to 4.7 years in those with <1000 copies/mL. This provides timely background data on ART-naive patients seen in clinical practice to support design of a trial to compare immediate with deferred ART in people with high CD4 count.     

CD4 decline and incidence of opportunistic infections in Cape Town, South Africa: implications for prophylaxis and treatment

OBJECTIVES: To determine the rate of CD4 decline and the incidence of opportunistic infections (OIs) among antiretroviral therapy-naive South African HIV-infected patients and inform timing of OI prophylaxis. METHODS: We used mixed-effect models to estimate CD4 cell decline by CD4 cell count strata in HIV-infected patients in the Cape Town AIDS Cohort between 1984 and 2000. Stratum-specific OI incidence per 100 person-years of observation was determined using incidence density analysis. RESULTS: Nine hundred seventy-four patients with 2 or more CD4 cell counts were included. CD4 counts declined by 47.1 cells/microL per year in the stratum with more than 500 cells/microL stratum, 30.6 cells/microL per year in the stratum with 351 to 500 cells/microL, and 20.5 cells/microL per year in the stratum with 201 to 350 cells/microL. Tuberculosis and oral candidiasis were the only OIs that occurred frequently in the stratum with more than 200 CD4 cells/microL. Rates of chronic diarrhea, wasting syndrome, tuberculosis, and oral and esophageal candidiasis increased in the stratum with less than 200 cells/microL, and rates of all OIs were highest in the stratum with 50 cells/microL or less. CONCLUSIONS:: CD4 cell count declines were dependent on CD4 strata and can inform timing of clinic visits and treatment initiation in South Africa. Incidence rates of OIs suggest that targeted OI prophylaxis could prevent substantial HIV-related morbidity in South Africa.     

Maternal disease stage and child undernutrition in relation to mortality among children born to HIV-infected women in Tanzania

OBJECTIVE: To examine whether maternal HIV disease stage during pregnancy and child malnutrition are associated with child mortality. DESIGN: Prospective cohort study in Tanzania. METHODS: Indicators of disease stage were assessed for 939 HIV-infected women during pregnancy and at delivery, and children's anthropometric status was obtained at scheduled monthly clinic visits after delivery. Children were followed up for survival status until 24 months after birth. RESULTS: Advanced maternal HIV disease during pregnancy (CD4 count <350 vs. >or=350 cells/mm) was associated with increased risk of child mortality through 24 months of age (hazard ratio [HR] = 1.74, 95% confidence interval [CI]: 1.32 to 2.30). CD4 count <350 cells/mm was also associated with an increased risk of death among children who remained HIV-negative during follow-up (HR = 2.00, 95% CI: 1.36 to 2.94). Low maternal hemoglobin concentration and child undernutrition were related to an increased risk of mortality in this cohort of children. CONCLUSIONS: Low maternal CD4 cell count during pregnancy is related to increased risk of mortality in children born to HIV-infected women. Care and treatment for HIV disease, including highly active antiretroviral therapy to pregnant women, could improve child survival. Prevention and treatment of undernutrition in children remain critical interventions in settings with high HIV prevalence.     

Changes in total lymphocyte count as a surrogate for changes in CD4 count following initiation of HAART: implications for monitoring in resource-limited settings

BACKGROUND: A major obstacle to the administration of highly active antiretroviral therapy (HAART) in resource-limited settings is the high cost of CD4 count testing. The total lymphocyte count (TLC) has been proposed as a surrogate marker to monitor immune response to therapy. OBJECTIVE: To assess, in a developed country setting, the capability and clinical utility of TLC change as a surrogate marker for CD4 count change in monitoring patients on HAART. METHODS: Longitudinal co-variation between changes in TLC and concomitant changes in CD4 count following the initiation of HAART was examined using a retrospective cohort study of 126 HIV-positive patients attending The Miriam Hospital, Brown University, Providence, RI. Analyses included evaluation of the direction of TLC change as a marker for direction of CD4 change, using sensitivity and specificity; evaluation of absolute change in TLC as a marker for benchmark changes in CD4 (> or =50 over 6 months, > or =100 over 12 months), using receiver-operator characteristic (ROC) curves; and a regression model of change in TLC as a function of change in CD4, to understand within-individual variation of longitudinal TLC measures. RESULTS: In the first 24 months of HAART, the sensitivity of a TLC increase as a marker for CD4 count increase over the same time period ranged from 86-94%, and the specificity ranged from 80-85%. The median change in TLC among patients with a CD4 count rise of > or =100 cells/mm at 1 year of HAART was +766 cells/mm while that of patients with a CD4 count rise of <100 cells/m was +100 cells/mm. The area under the corresponding ROC curve was 0.89, suggesting that change in TLC discriminates well between those with 1-year CD4 change of > or =100 vs. those with change <+100. From a regression analysis, we found that mean change in TLC per 1 cell/mm change in CD4 count was 7.3 (SE 1.2, P < 0.001). The degree of this association varied from individual to individual but was positive for all individuals. CONCLUSIONS: Within the first 2 years of HAART, the direction of change in TLC appears to be a strong marker for direction of concomitant change in CD4 count (sensitivity 86-94% and specificity 80-85%, depending on length of interval). Positive and negative predictive values depend on the proportion of CD4 changes that are positive. In this cohort, that proportion is 87.9%, which yields high positive predictive value (96-98%) but lower negative predictive value (43-63%). Findings from the regression model suggest that taking multiple measurements of TLC at more frequent intervals may reduce variability and potentially improve predictive accuracy.     

Micronutrient levels and HIV disease status in HIV-infected patients on highly active antiretroviral therapy in the Nutrition for Healthy Living cohort

BACKGROUND: Low serum micronutrient levels were common before widespread use of highly active antiretroviral therapy (HAART) and were associated with adverse outcomes. Few data are available on micronutrient levels in subjects taking HAART. OBJECTIVE: To determine the prevalence of low serum retinol, alpha-tocopherol, zinc, and selenium in HIV-infected subjects taking HAART and to assess the association of micronutrient levels with HIV disease status. DESIGN: Cross-sectional. SETTING: Nutrition for Healthy Living (NFHL) study. PARTICIPANTS: HIV-infected subjects on HAART. METHODS: Retinol, alpha-tocopherol, zinc, and selenium were determined in frozen serum samples from 171 men and 117 women. Low serum levels were defined as retinol <30 microg/dL, selenium <85 microg/L, alpha-tocopherol <500 microg/dL, and zinc <670 microg/L. Association of micronutrient quartiles with CD4 cell count, CD4 count <200 cells/mm, HIV viral load (VL), and undetectable VL was assessed using adjusted multivariate regression. RESULTS: Five percent of men and 14% of women had low retinol, 8% of men and 3% of women had low selenium, and 7% of men and no women had low alpha-tocopherol. Forty percent of men and 36% of women had low zinc, however. Subjects in the upper quartiles of zinc had lower log VL levels than those in the lowest quartile (significant for women). Subjects in the upper quartiles of selenium also tended to have lower VL levels compared with those in the lowest quartile. Surprisingly, women in the upper quartiles of retinol had higher log VLs than those in the lowest quartile. There was no significant association of any micronutrient with CD4 cell count or likelihood of CD4 count <200 cells/mm. The level of CD4 cell count influenced the association of retinol with log VL in men, however. In men with CD4 counts >350 cells/mm, those with higher retinol had higher log VLs compared with the lowest quartile, whereas in men with CD4 counts <350, those with higher retinol levels had lower log VLs compared with the lowest quartile. CONCLUSIONS: Low retinol, alpha-tocopherol, and selenium are uncommon in HIV-infected subjects on HAART. Zinc deficiency remains common, however. Decreased retinol levels in women and in men with CD4 counts >350 cells/mm and increased zinc and selenium levels in both genders may be associated with improved virologic control.     

Comparison of capillary based microflurometric assay for CD4+ T cell count estimation with dual platform Flow cytometry

The CD4+ T cell count estimation is an important monitoring tool for HIV disease progression and efficacy of anti-retroviral treatment (ART). Due to availability of ART at low cost in developing countries, quest for reliable cost effective alternative methods for CD4+ T cell count estimation has gained importance. A simple capillary-based microflurometric assay (EasyCD4 System, Guava Technology) was compared with the conventional flow cytometric assay for estimation of CD4+ T cell counts in 79 HIV infected individuals. CD4+ T cell count estimation by both the assays showed strong correlation (r = 0.938, p < 0.001, 95% CI 0.90 to 0.96). The Bland Altman plot analysis showed that the limits of variation were within agreeable limits of ± 2SD (-161 to 129 cells/mm³). The Easy CD4 assay showed 100% sensitivity for estimating the CD4+ T cell counts < 200 cells/mm³ and < 350 cells/mm³ and 97% sensitivity to estimate CD4+ T cell count < 500 cells/mm³. The specificity ranged from 82 to 100%. The Kappa factor ranged from 0.735 for the CD4+ T cell counts < 350 cells/mm³ to 0.771 for < 500 cells/mm³ CD4+ T cell counts. The system works with a simple protocol, is easy to maintain and has low running cost. The system is compact and generates minimum amount of waste. Hence the EasyCD4 System could be applied for estimation of CD4+ T cell counts in resource poor settings.     

Initiation of antiretroviral therapy at CD4 cell counts >/=350 cells/mm3 does not increase incidence or risk of peripheral neuropathy, anemia, or renal insufficiency

BACKGROUND: US guidelines recommend deferring initiation of highly active antiretroviral therapy (HAART) for most patients with CD4 counts >350 cells/mm in part because of concerns about antiretroviral toxicity. METHODS: Incidence rates of peripheral neuropathy, anemia, and renal insufficiency in a cohort of 2165 patients followed more than 3 years (mean) were analyzed in multivariate Cox proportional hazards models by CD4 cell counts at initiation of HAART. A nested cohort of 895 patients restricted to study participants who did or did not start HAART within a CD4 cell count stratum were also compared. RESULTS: Incidence and risks of all 3 comorbidities decreased with initiation of HAART at CD4 counts >200 cells/mm versus <200 cells/mm. Incidence and risks of renal insufficiency were similar with HAART initiation at CD4 counts >/=350 cells/mm versus 200 to 349 cells/mm, but risk of peripheral neuropathy and anemia were further decreased in persons starting HAART at a CD4 count >/=350 cells/mm. The incidence of these conditions was highest during the first 6 months of treatment at any CD4 cell count and declined up to 19-fold with further therapy. DISCUSSION: Initiating HAART at CD4 cell counts >/=200 cells/mm reduced the incidence and risk of the 3 comorbid conditions and for anemia and peripheral neuropathy as well by starting at CD4 counts >/=350 cells/mm. The incidence of each condition decreased rapidly and remained low with increasing time on HAART.     

Correlation between gag-specific CD8 T-cell responses, viral load, and CD4 count in HIV-1 infection is dependent on disease status

BACKGROUND: It still remains controversial which kind of relationships exist between HIV-1-specific CD8 T-cell responses and HIV RNA load or CD4 count over the course of the infection. This study was designed to investigate the role of HIV-specific CD8 responses in patients with different disease status. METHODS: Three cohorts of patients were selected according to CD4 count levels: long-term nonprogressors (LTNPs, n = 19), asymptomatic progressors (CD4 counts between 500 and 350 cells/mm(3), n = 14), and progressors (CD4 counts <350 cells/mm(3), n = 23). Six of the LTNPs experiencing a quick loss of CD4 T-cells and another 6 LTNPs with stable CD4 counts were followed up. T-cell responses were studied using interferon (IFN) gamma-ELISpot assay against HIV p24 and 11 pools of HIV-Gag peptides. RESULTS: No significant differences were found in Gag-specific CD8 responses among the 3 cohorts. However, inverse correlations were identified between CD8 responses and CD4 counts in asymptomatic progressors and between CD4 responses and viral loads in progressors. In addition, the sequential dynamics of CD8 responses in 6 LTNPs showed that with a quick loss of CD4 T-cells around the range of 500 to 300 cells/mm(3), more vigorous CD8 responses were induced simultaneously, and plasma viremia was still kept relatively stable. CONCLUSIONS: These data suggest that the relationship between CD8 response and viral load or CD4 count is not universally consistent throughout the entire course of HIV-1 infection. Gag-specific CD8 responses may play differential roles in different stages of HIV-1 infection, and the maintenance of a threshold level of CD4 T-cells may contribute to mediate effective HIV-specific responses in natural control of HIV-1 infection.     

Long-term CD4+ lymphocyte response following HAART initiation in a U.S. Military prospective cohort

Background

Among HIV-infected persons initiating highly active antiretroviral therapy (HAART), early CD4+ lymphocyte count increases are well described. However, whether CD4+ levels continue to increase or plateau after 4-6 years is controversial.

Methods

To address this question and identify other determinants of CD4+ response, we analyzed data for 1,846 persons from a prospective HIV military cohort study who initiated HAART, who had post-HAART CD4+ measurements, and for whom HIV seroconversion (SC) date was estimated.

Results

CD4+ count at HAART initiation was ≤ 200 cells/mm³ for 23%, 201-349 for 31%, 350-499 for 27%, and ≥500 for 19%. The first 6 months post-HAART, the greatest CD4+ increases (93-151 cells) occurred, with lesser increases (22-36 cells/year) through the first four years. Although CD4+ changes for the entire cohort were relatively flat thereafter, HIV viral load (VL) suppressors showed continued increases of 12-16 cells/year. In multivariate analysis adjusting for baseline CD4+ and post-HAART time interval, CD4+ responses were poorer in those with: longer time from HIV SC to HAART start, lower pre-HAART CD4+ nadir, higher pre-HAART VL, and clinical AIDS before HAART (P < 0.05).

Conclusions

Small but positive long-term increases in CD4+ count in virally suppressed patients were observed. CD4+ response to HAART is influenced by multiple factors including duration of preceding HIV infection, and optimized if treatment is started with virally suppressive therapy as early as possible.     

CMV pp65 antigen testing is of limited utility in the diagnosis of concomitant CMV disease in HIV-infected patients in the HAART era.

BACKGROUND: There are limited data on the utility of the CMV pp65 antigen (Ag) test for the diagnosis of concomitant CMV end-organ disease (EOD) in HIV+ patients in the highly active antiretroviral therapy era. OBJECTIVES: We sought to assess the predictive value of a single pp65 test for the diagnosis of concomitant CMV EOD in HIV-infected patients. STUDY DESIGN: A review of all pp65 Ag tests conducted at a large county teaching hospital from January 1998 through July 1999 was conducted. A diagnosis of CMV EOD required histopathologic evidence (except for retinitis). Concomitant disease was defined as CMV EOD within 30 days of Ag test. Results were reported as number of Ag positive cells/300000 cells counted. RESULTS: Two-hundred and thirty patient charts (308 antigen tests) were reviewed. The median follow-up time was 334 days. Thirty-two patients had a prior diagnosis of CMV EOD. The most common reasons for testing were fever (45), pneumonia (10), and monitoring for recurrent retinitis (8). Ag tests were positive (range 1-1042 cells) in 51 patients. Twelve patients were diagnosed with concomitant CMV EOD. A diagnosis other than CMV was made in a significant majority of patients (154). The mean initial pp65 level was significantly higher in patients with concomitant CMV EOD versus those without concomitant CMV: 314 cells versus 13 cells, P<0.0001. The overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 67, 81, 16 and 98%, respectively. Using a 50-cell cutoff and including only patients with CMV symptoms and CD4<100, improved test accuracy: sensitivity, specificity, PPV, and NPV of 60, 91, 60, and 91%. The CD4 cell count but not the HIV viral load was predictive of CMV EOD. CONCLUSIONS: The CMV pp65 Ag test is useful in excluding concomitant CMV disease, but has limited utility in the diagnosis of acute CMV disease. The highest test utility will be in patients with a high likelihood of CMV disease based on symptoms, and CD4 cell count.