Current CD4 T-cell Count Research Articles

Polymorphisms in uncoupling protein genes UCP2 and UCP3 are not associated with HIV‐associated sensory neuropathy in African individuals

Dear Editor,Human immunodeficiency virus-associated sen-sory neuropathy (HIV-SN), due to viral and/or drug-related toxicity, is the most common neurologicalcomplication of HIV (Sacktor, 2002) and causes sig-nificant suffering and reduced quality of life (Ellis et al.,2010). The neuropathy shares several features withdiabetic neuropathy, for example, both HIV-SN anddiabetic neuropathy are small-fibre, length-dependentneuropathies that are associated with mitochondrialdysfunction and intracellular calcium dysregulation(Verkhratsky and Fernyhough, 2008; Hoke et al., 2009;Lehmann et al., 2011).Recently, minor alleles in the genes encodingmitochondrial uncoupling proteins UCP2(rs659366*A,-866G

Prevalence and Risk Factors of Low Bone Mineral Density Among Perinatally HIV-Infected Thai Adolescents Receiving Antiretroviral Therapy

Low bone mineral density (BMD) has been reported among 10%-54% of HIV-infected adolescents in developed countries. We studied the prevalence and predictors of low BMD among HIV-infected Thai adolescents receiving antiretroviral therapy. A cross-sectional study of lumbar spine (L2-L4) BMD as measured by dual-energy X-ray absorptiometry in Thai HIV-infected adolescents aged 12-20 years was performed. The BMD Z score was analyzed using age-matched healthy Thai children as a reference. Serum 25-hydroxyvitamin D was performed. Osteopenia was defined as BMD Z score ≤ -2. From October 2010 to February 2011, 101 adolescents, 50% male, with a median age of 14.3 (range: 13.0-15.7) years were enrolled. The median [interquartile range (IQR)] current CD4 T-cell count was 646 (506-796) cells per cubic millimeter and 90% had plasma HIV-1 RNA <50 copies per milliliter. The mean BMD among HIV-infected adolescents and controls were 0.855 and 0.980 g/cm (P < 0.001). The median (IQR) L2-L4 spine BMD Z score was -1.0 (-1.9 to -0.1), of which 24% had BMD Z score ≤ -2.0. The median (IQR) of 25-hydroxyvitamin D level was 24.8 (20.0-31.4) ng/mL, of which 25% had vitamin D level < 20 ng/mL. In multivariate analysis, the height for age Z score < -1.5 (adjusted odds ratio: 6.2; 95% confidence interval: 2.2 to 17.7) and history of World Health Organization clinical stage 4 before antiretroviral therapy (adjusted odds ratio: 3.7; 95% confidence interval: 1.3 to 10.7) were significantly associated with osteopenia. One fourth of HIV-infected Thai adolescents have osteopenia. Children with history of advanced-staging or having low height for age are at risk of osteopenia. Preventive measures to prevent osteopenia should be incorporated in routine care for these adolescents.

Risk Factors for Falls in HIV-Infected Persons

The incidence of and risk factors for falls in HIV-1-infected persons are unknown. Fall history during the prior 12 months, medical diagnoses, and functional assessments were collected on HIV-infected persons 45-65 years of age receiving effective antiretroviral therapy. Fall risk was evaluated using univariate and multivariate regression analyses. Of 359 subjects, 250 persons (70%) reported no falls, 109 (30%) had ≥1 fall; and 66 (18%) were recurrent fallers. Females, whites, and smokers were more likely to be recurrent fallers (P ≤ 0.05). HIV-related characteristics including current and nadir CD4 T-cell count, estimated HIV duration, and Veterans Aging Cohort Study Index scores were not predictors of falls (all P ≥ 0.09); didanosine recipients were more likely to be recurrent fallers (P = 0.04). The odds of falling increased 1.7 for each comorbidity and 1.4 for each medication (P < 0.001) and were higher in persons with cardiovascular disease, hypertension, dementia, neuropathy, arthritis, chronic pain, psychiatric disease, frailty, or disability [all odds ratio (OR) ≥ 1.8; P ≤ 0.05]. Beta-blockers, antidepressants, antipsychotics, sedatives, and opiates were independently associated with falling (all OR ≥ 2.7; P ≤ 0.01). Female gender, diabetes, antidepressants, sedatives, opiates, didanosine, exhaustion, weight loss, and difficulty with balance were the most significant predictors of falls in logistic regression (all OR ≥ 2.5; P ≤ 0.05). Middle-aged HIV-infected adults have high fall risk. Multiple comorbidities, medications, and functional impairment were predictive of falls, but surrogate markers of HIV infection or an HIV-specific multimorbidity index were not. Fall risk should be assessed routinely as part of the care of HIV-infected persons.

Hepatitis B Surface Antigen Concentrations in Patients with HIV/HBV Co-Infection

HBsAg clearance is associated with clinical cure of chronic hepatitis B virus (HBV) infection. Quantification of HBsAg may help to predict HBsAg clearance during the natural course of HBV infection and during antiviral therapy. Most studies investigating quantitative HBsAg were performed in HBV mono-infected patients. However, the immune status is considered to be important for HBsAg decline and subsequent HBsAg loss. HIV co-infection unfavorably influences the course of chronic hepatitis B. In this cross-sectional study we investigated quantitative HBsAg in 173 HBV/HIV co-infected patients from 6 centers and evaluated the importance of immunodeficiency and antiretroviral therapy. We also compared 46 untreated HIV/HBV infected patients with 46 well-matched HBV mono-infected patients. HBsAg levels correlated with CD4 T-cell count and were higher in patients with more advanced HIV CDC stage. Patients on combination antiretroviral therapy (cART) including nucleos(t)ide analogues active against HBV demonstrated significant lower HBsAg levels compared to untreated patients. Importantly, HBsAg levels were significantly lower in patients who had a stronger increase between nadir CD4 and current CD4 T-cell count during cART. Untreated HIV/HBV patients demonstrated higher HBsAg levels than HBV mono-infected patients despite similar HBV DNA levels. In conclusion, HBsAg decline is dependent on an effective immune status. Restoration of CD4 T-cells during treatment with cART including nucleos(t)ide analogues seems to be important for HBsAg decrease and subsequent HBsAg loss.

The association of CD4+ T-cell counts and cardiovascular risk in treated HIV disease

HIV-infected individuals are at high risk of developing cardiovascular disease. Whether earlier initiation of HIV therapy at higher CD4 cell counts has any effect on cardiovascular risk as assessed by endothelial function is unknown. Cross-sectional study of 74 antiretroviral-treated men with undetectable plasma HIV RNA levels. Participants underwent noninvasive assessment of endothelial function using brachial artery flow-mediated dilation (FMD). The association of nadir and current CD4 T-cell count with FMD was assessed using multivariable linear regression. The median age was 47 years [interquartile range (IQR) 42-55], median current CD4 T-cell count was 659 cells/μl (IQR 542-845), and nadir CD4 cell count was 314 cells/μl (IQR 150-490). Twenty-eight percent had hypertension, and 32% hyperlipidemia. Nadir CD4 T-cell count less than 350 cells/μl was associated with lower FMD in age-adjusted and race-adjusted analyses and remained an independent predictor of FMD after adjustment for cardiovascular risk factors (hypertension, diabetes, smoking, hyperlipidemia) and HIV-related characteristics (HIV duration, HAART duration). After multivariable adjustment, individuals with nadir CD4 T-cell count less than 350 cells/μl had a 1.22% lower FMD compared with those with higher T-cell counts [95% confidence interval (CI) -2.20 to -0.19, P=0.02]. Proximal CD4 T-cell count showed little association with FMD. Among treated HIV-infected individuals, nadir CD4 T-cell count less than 350 cells/μl is independently associated with lower FMD, suggesting that delayed therapy results in sustained harm to endothelial function. Our data support future prospective studies evaluating cardiovascular effects of HAART initiation at higher CD4 cell counts.

Factors associated with a strictly undetectable viral load in HIV‐1‐infected patients

The aim of the study was to identify factors associated with a strictly undetectable viral load (VL) using a routine sensitive real-time polymerase chain reaction (RT-PCR) technology. From a large prospective cohort, 1392 patients with a VL<50 HIV-1 RNA copies/mL while receiving a three-drug suppressive regimen for at least 1 year were included in a cross-sectional analysis. Patients were classified into three groups and compared by univariate and multivariate analysis: 479 patients with a strictly undetectable VL (group 1; 34%), 617 patients with detectable VL below the threshold of 20 copies/mL (group 2; 44%), and 296 patients with a VL of 20-50 copies/mL (group 3; 12%). Comparing groups 1 and 2, VL zenith<5 log(10) copies/mL [odds ratio (OR) 1.51; 95% confidence interval (CI) 1.15-1.99; P=0.003], current CD4 T-cell count<500 cells/μL (OR 1.44; 95% CI 1.08-1.92; P=0.01), and duration of viral suppression<50 copies/mL longer than 2 years (OR 2.32; 95% CI 1.20-4.54; P=0.01) were associated with undetectable VL. Comparing groups 1 and 3, VL zenith<5 log(10) copies/mL (OR 2.48; 95% CI 1.75-3.50; P<0.001), duration of viral suppression<50 copies/mL longer than 1 year (OR 3.33; 95% CI 1.66-6.66; P=0.0006), and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens (OR 1.45; 95% CI 1.03-2.04; P=0.03) were associated with undetectable VL. No individual drug effect was found within NNRTI molecules. Longer duration of viral suppression<50 copies/mL, lower viral load zenith and NNRTI-based regimen were independently associated with a strictly undetectable viral load. This routinely used RT-PCR assay may prove to be a valuable tool in further large-scale studies.

Factors influencing peripheral blood mononuclear cell-associated HIV-1 DNA level after long-term suppressive antiretroviral therapy in 236 patients

The objectives of this study were to determine whether peripheral blood mononuclear cell (PBMC)-associated HIV-1 DNA level in patients on long-term suppressive antiretroviral therapy (ART) was associated with plasma HIV-1 RNA level, CD4 cell count, and therapeutic factors throughout patient history. Patients receiving triple or dual therapy with plasma HIV-1 RNA below detection limit for more than 3 years were recruited in a multicentric, cross-sectional study within the eight virology laboratories of the Agence Nationale de Recherche sur le SIDA et les Hépatites virales HIV quantification working group, each one in relation with a clinical center. PBMC-associated HIV-1 DNA was quantified using a standardized real-time PCR method in all laboratories. A total of 236 patients was included. Median HIV-1 DNA was 2.8 log10 copies/10 PBMCs (interquartile range 2.4-3.0). Univariate analysis showed PBMC HIV-1 DNA level to be related to pre-ART immuno-virologic status (plasma HIV-1 RNA zenith and CD4 cell count nadir) and to current CD4 T-cell count. HIV-1 DNA was lower in patients receiving ART with inferior virologic efficacy, as they also had a higher CD4 nadir and a lower HIV-1 RNA zenith than other patients. PBMC HIV-1 DNA level was not related to therapy duration, to time spent with undetectable HIV-1 RNA or to occurrence of a blip. Plasma HIV-1 RNA zenith and CD4 cell count nadir remained predictive of HIV-1 DNA level in the multivariate model which was associated with 22% of its variability. Whatever the duration of treatment, HIV-1 DNA level during ART gives a picture of the intensity of viral replication and immune deficiency reached before starting therapy.

Dysregulation of CD28 and CTLA‐4 expression by CD4 T cells from previously immunodeficient HIV‐infected patients with sustained virological responses to highly active antiretroviral therapy

Current guidelines recommend commencing highly active antiretroviral therapy (HAART) in HIV-infected patients when CD4 T-cell counts reach 350 cells/microL. However, late-presenting HIV-infected patients with CD4 T-cell counts<50 cells/microL are still common. The ability of long-term HAART to normalize immune dysregulation in severely immunodeficient HIV-infected patients remains unclear. Here we address indices of immune dysregulation in previously severely immunocompromised HIV-infected patients treated with long-term HAART who had achieved increased CD4 T-cell counts and complete suppression of HIV viraemia. We examined expression of CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and intracellular perforin by CD4 and CD8 lymphocytes from 25 highly selected HIV-infected patients [nadir CD4 T-cell counts <50 cells/microL, >4 years on HAART and >6 months of complete viral suppression (<50 HIV-1 RNA copies/mL)] and 18 HIV-seronegative age- and sex-matched controls. HIV-infected patients had lower percentages of CD28-expressing CD4 lymphocytes and higher percentages of CTLA-4-expressing CD4 lymphocytes than controls. The percentage of CTLA-4-expressing CD4 lymphocytes correlated inversely with that of CD28-expressing CD4 lymphocytes. The proportion of CD4 lymphocytes expressing perforin was generally low. However, more HIV-infected patients than controls had >1% of CD4 lymphocytes expressing perforin [11 of 25 (44%) vs. one of 18 (5.5%)]. The percentage of CD8 lymphocytes expressing perforin did not differ between HIV-infected patients and controls. Amongst HIV-infected patients, the percentage of perforin-expressing CD8 lymphocytes correlated inversely with nadir but not current CD4 T-cell count. Expression of CD28, CTLA-4 and perforin by CD4 lymphocytes remain dysregulated in HIV-infected patients with previous severe immunodeficiency, despite increased CD4 T-cell counts and control of HIV viraemia by HAART.

IL-23 and IFN-gamma deficiency in immunodeficient HIV patients who achieved a long-term increase in CD4 T-cell counts on highly active antiretroviral therapy.

The pathogenesis of HIV infection and the susceptibility to opportunistic infections has been associated with poor type 1 cytokine production. In severely immunodeficient HIV patients who achieved increased CD4 T-cell counts on longterm highly active antiretroviral therapy, we observed reduced expression of IL-23p19 and IFN-gamma messenger RNA. Impaired IL-23-induced IFN-gamma production by memory T cells might thus contribute to opportunistic infections in a minority of patients with substantial CD4 T-cell recovery.

Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection.

To ascertain whether delaying the initiation of highly active antiretroviral therapy (HAART) compromises functional immune reconstitution in HIV-1 infection in persons who regain 'normal' CD4 T-cell counts after suppressive antiretroviral therapies. Prospective open-label study carried out at two University-affiliated HIV-outpatient clinics in the USA. Response to immunization was used as a model for in vivo functional immune competence in 29 HIV-1 infected patients with CD4 T-cell counts > 450 x 106 cells/l and HIV-RNA < 400 copies/ml for > 12 months after HAART and nine HIV-1 seronegative controls. After immunization with tetanus toxoid, diphtheria-toxoid, and keyhole limpet hemocyanin, immune response scores (IRS) were calculated using postimmunization antibody concentrations, lymphocyte proliferation, and delayed-type hypersensitivity responses to vaccine antigens. Despite normal numbers of circulating CD4 T-cells, the CD4 T-cell nadir before HAART initiation predicted the immune response to immunization (rho = 0.5; P < 0.005) while current CD4 T-cell count did not. Likewise, CD4 T-lymphocyte expression of the co-stimulatory molecule CD28 was also an independent predictor of response to immunization (rho = 0.5; P < 0.005). Even among persons who controlled HIV replication and normalized CD4 T-cell counts with HAART, pretreatment CD4 T-cell count and numbers of circulating CD4+CD28+ T-cells at immunization, but not current CD4 T-cell count, predict the ability to respond to vaccination. Delaying the initiation of HAART in chronic HIV-1 infection results in impaired functional immune restoration despite normalization of circulating CD4 T-cell numbers.