Evaluación comparativa de medición de linfocitos CD4+ por dos técnicas: estándar nacional versus test rápido de ejecución local / Comparative evaluation of CD4+ lymphocyte measurement by two techniques: national standard versus point-of-care rapid test

ANTECEDENTES: El recuento de linfocitos CD4+ (LTCD4) es una herramienta fundamental para la evaluación y seguimiento de los pacientes que viven con VIH. En Chile, la medición de LTCD4 estandarizada es por citometría de flujo. En el sistema público se realiza en forma centralizada en tres centros. Actualmente existen tecnologías de medición rápida de recuento de LTCD4 en el lugar de atención, permitiendo optimizar la atención de pacientes con infección por VIH. OBJETIVO: Comparar la precisión de un test rápido de ejecución local versus la técnica estándar. METODOLOGÍA: Realización de ambas técnicas en un grupo de 102 pacientes durante su control regular de salud. RESULTADOS: El rango de variación promedio de los resultados entre las dos técnicas fue de 10%, con una concordancia en los recuentos de LTCD4 de 97% para el rango de CD4 < 200 cél/uL, de 88% para los pacientes con recuento de LTCD4 entre 200 y 349 cél/uL y de 67% en los rangos superiores. CONCLUSIÓN: La técnica por test rápido es un sistema fácil de aplicar, de bajo costo, con alta concordancia con la técnica estándar, lo que debería considerarse en la atención de los pacientes que viven con VIH.

BACKGROUND: The CD4+ lymphocyte cell count is an instrumental tool for the assessment and follow-up in the therapeutic management of patients living with HIV. In Chile, the standardized CD4+ lymphocyte count technique is by flow cytometry. In the public health system, it is performed centralized in 3 sites. Currently, there are technologies that allow measuring the CD4 lymphocyte count at the point of care, allowing to optimize the care of HIV-infected patients. AIM: To compare the accuracy of a point of care rapid test versus the standard technique in patients under regular care at a single HIV center. RESULTS: The average variation of the results between the two techniques was 10%, with a 97% concordance in CD4 range values for patients with CD4 below 200 cells/uL, 88% for CD4 counts between 200 and 349 cells/uL. and 67% above that range. CONCLUSION: This point of care test is an easy-to-operate, low-cost system with high correlation with the standard technique and should be considered in the care of patients living with HIV.

Adipokines as New Biomarkers of Immune Recovery: Apelin Receptor, RBP4 and ZAG Are Related to CD4+ T-Cell Reconstitution in PLHIV on Suppressive Antiretroviral Therapy.

A significant proportion of people living with HIV (PLHIV) who successfully achieve virological suppression fail to recover CD4+ T-cell counts. Since adipose tissue has been discovered as a key immune organ, this study aimed to assess the role of adipokines in the HIV immunodiscordant response. This is a multicenter prospective study including 221 PLHIV starting the first antiretroviral therapy (ART) and classified according to baseline CD4+ T-cell counts/µL (controls > 200 cells/µL and cases ≤ 200 cells/µL). Immune failure recovery was considered when cases did not reach more than 250 CD4+ T cells/µL at 144 weeks (immunological nonresponders, INR). Circulating adipokine concentrations were longitudinally measured using enzyme-linked immunosorbent assays. At baseline, apelin receptor (APLNR) and zinc-alpha-2-glycoprotein (ZAG) concentrations were significantly lower in INRs than in immunological responders (p = 0.043 and p = 0.034), and they remained lower during all ART follow-up visits (p = 0.044 and p = 0.028 for APLNR, p = 0.038 and p = 0.010 for ZAG, at 48 and 144 weeks, respectively). ZAG levels positively correlated with retinol-binding protein 4 (RBP4) levels (p < 0.01), and low circulating RBP4 concentrations were related to a low CD4+ T-cell gain (p = 0.018 and p = 0.039 at 48 and 144 weeks, respectively). Multiple regression adjusted for clinical variables and adipokine concentrations confirmed both low APLNR and RBP4 as independent predictors for CD4+ T cells at 144 weeks (p < 0.001). In conclusion, low APLNR and RBP4 concentrations were associated with poor immune recovery in treated PLHIV and could be considered predictive biomarkers of a discordant immunological response.

Regression discontinuity analysis demonstrated varied effect of Treat-All on CD4 testing among Southern African countries.

OBJECTIVE: To determine whether Treat-All policy impacted laboratory testing practices of antiretroviral therapy (ART) programs in Southern Africa. STUDY DESIGN AND SETTING: We used HIV cohort data from Lesotho, Malawi, Mozambique, South Africa, Zambia and Zimbabwe in a regression discontinuity design to estimate changes in pre-ART CD4 testing and viral load monitoring following national Treat-all adoption that occurred during 2016 to 2017. This study included more than 230,000 ART-naïve people living with HIV (PLHIV) aged five years or older who started ART within two years of national Treat-All adoption. RESULTS: We found pre-ART CD4 testing decreased following adoption of Treat-All recommendations in Malawi (-21.4 percentage points (pp), 95% confidence interval, CI: -26.8, -16.0) and in Mozambique (-8.8pp, 95% CI: -14.9, -2.8), but increased in Zambia (+2.7pp, 95% CI: +0.4, +5.1). Treat-All policy had no effect on viral load monitoring, except among females in South Africa (+7.1pp, 95% CI: +1.1, +13.0). CONCLUSION: Treat-All policy expanded ART eligibility, but led to reductions in pre-ART CD4 testing in some countries that may weaken advanced HIV disease management. Continued and expanded support of CD4 and viral load laboratory capacity is needed to further improve treatment successes and allow for uniform evaluation of ART implementation across Southern Africa.

Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48 results of a single-arm, open-label, multicentre, phase 2/3 trial.

BACKGROUND: Bictegravir is a potent integrase strand-transfer inhibitor (INSTI) with a high genetic barrier to resistance. Bictegravir, coformulated with emtricitabine and tenofovir alafenamide, is recommended by key European and US HIV treatment guidelines as the preferred single-tablet regimen for adults and adolescents. The aim of this study was to assess the pharmacokinetics, safety, and efficacy of switching to this regimen in virologically suppressed children and adolescents with HIV. METHODS: In this single-arm, open-label trial, we enrolled virologically suppressed children and adolescents (aged 6 to <18 years) with HIV at 22 hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants had a bodyweight of at least 25 kg, were virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable ART regimen for at least 6 months before screening, had a CD4 count of at least 200 cells per µL, and an estimated glomerular filtration rate of at least 90 mL/min per 1·73 m2 by the Schwartz formula at screening. All participants received the fixed-dose regimen of coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg once daily. Pharmacokinetic analysis was used for dosing confirmation, and results compared with adult values. The primary outcomes were area under the curve at the end of the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) of bictegravir, and incidence of treatment-emergent adverse events and laboratory abnormalities at week 24. Efficacy and safety analyses included all participants who received at least one dose of study drug. We report the 48-week results. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Between Sept 29, 2016 and Feb 16, 2018, we enrolled 102 participants. 100 participants received bictegravir, emtricitabine, and tenofovir alafenamide (cohort 1 [adolescents aged 12 to <18 years], n=50; cohort 2 [children aged 6 to <12 years], n=50). The mean bictegravir AUCtau was 89 100 ng × h/mL (coefficient of variation 31·0%) in adolescents (cohort 1) and 128 000 ng × h/mL (27·8%) in children (cohort 2). Compared with adults, bictegravir Ctau was 35% lower in adolescents and 11% lower in children. The 90% CIs of both parameters were within the predefined pharmacokinetic equivalence boundary and within overall range of exposures observed in adults and deemed to be safe and efficacious (geometric least-squares mean ratio [GLSM] 86·3% [90% CI 80·0-93·0] for AUCtau and 65·4% [58·3-73·3] for Ctau in adolescents; GLSM 125% [90% CI 117-134] for AUCtau and 88·9% [80·6-98·0] for Ctau for children). Bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated; most adverse events were grade 2 or less in severity and no study drug-related serious adverse events were reported. One participant discontinued study drug due to adverse events (grade 2 insomnia and anxiety). Virological suppression (HIV-1 RNA <50 copies per mL) was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48; no participants had treatment-emergent resistance. INTERPRETATION: In adolescents and children with HIV, the bictegravir, emtricitabine, and tenofovir alafenamide single-tablet regimen was well tolerated and maintained virological suppression. Our data support the treatment of HIV in adolescents and children with this single-tablet regimen. At present, the single-tablet regimen is recommended as first-line treatment in the USA for adolescents and as an alternative regimen in children and has the potential to represent an important regimen in the paediatric population. FUNDING: Gilead Sciences.

Effect of aprepitant on kynurenine to tryptophan ratio in cART treated and cART naïve adults living with HIV.

ABSTRACT: Changes in tryptophan metabolism affect human physiology including the immune system, mood, and sleep and are associated with human immunodeficiency virus (HIV) pathogenesis. This study investigates whether the treatment of HIV-infected individuals with the neurokinin-1 receptor antagonist, aprepitant, alters tryptophan metabolism.This study utilized archival samples from 3 phase 1B clinical trials "Anti-HIV Neuroimmunomodulatory Therapy with Neurokinin-1 Antagonist Aprepitant"-2 double-blinded, placebo-controlled, and 1 open-label study. We tested samples from a total of 57 individuals: 26 combination antiretroviral therapy (cART) naïve individuals receiving aprepitant, 19 cART naïve individuals receiving placebo, and 12 individuals on a ritonavir-containing cART regimen receiving aprepitant. We evaluated the effect of aprepitant on tryptophan metabolism by measuring levels of kynurenine and tryptophan in archival plasma samples and calculating the kynurenine to tryptophan ratio.Aprepitant treatment affected tryptophan metabolism in both cART treated and cART naïve individuals with more profound effects in patients receiving cART. While aprepitant treatment affected tryptophan metabolism in all HIV-infected patients, it only significantly decreased kynurenine to tryptophan ratio in cART treated individuals. Aprepitant treatment offers an opportunity to target inflammation and mood disorders frequently co-existing in chronic HIV infection.

Identification of circulating regulatory T lymphocytes with membrane markers - a new multiparameter flow cytometry protocol.

INTRODUCTION: Regulatory T cells (Tregs) are a unique CD4+ T cell subset involved in the regulation of immune responses. The traditional immunophenotype used to define Tregs includes CD4+CD25high and the expression of the transcription factor Forkhead box protein 3 (FoxP3). A complex technique of intracellular staining, transient upregulation of FoxP3 in activated conventional T lymphocytes (Tcons), and the omission of naïve CD45RA+ Tregs with downregulated FoxP3 activity but a demethylated FOXP3 promoter region may lead to inaccurate quantification. In an attempt to meet the need for a reliable and simplified enumeration strategy, we investigated different membrane markers to capture the entire Treg compartment and to identify subpopulations of Tregs. MATERIAL AND METHODS: Analyses were performed on whole blood. Tested gating strategies were based on the expression of the following membrane antigens: CD45, CD3, CD4, CD25, CD127, CD26, CD6, CD39, CD71, HLA-DR, CD45RA and CD31. Double controls with FoxP3 were performed. RESULTS: The final enumeration panel consisted of the membrane markers CD45, CD3, CD4, CD25, CD127, CD26, CD39, CD45RA and CD31. A deep analysis of T cells with the CD4+CD25+CD127low/-CD26low/-CD45RAimmunophenotype revealed high expression of FoxP3 and/or CD39, while cells with the naïve immunophenotype, CD4+CD25+CD127low/-CD26low/-CD45RA+, presented lower expression of suppressor markers. Antigen CD31 is considered to be a valuable membrane marker of thymus-derived Tregs. CONCLUSIONS: The presented 9-color panel that can be easily applied in laboratories enables reliable enumeration of Tregs with additional information about the functionality, maturity and origin of T regulatory cells.

Poor CD4/CD8 ratio recovery in HBcAb-positive HIV patients with worse immune status is associated with significantly higher CD8 cell numbers.

Low CD4+ cell count in patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection during combination antiretroviral therapy (cART) has been described; however, notably few studies have investigated coinfected patients positive for antibodies to the HBV c antigen (HBcAb). An observational retrospective study enrolling 190 patients was conducted by grouping patients with respect to HBV status and recording CD4+ T cell counts and percentages (CD4%), CD8+ T cell counts and percentages (CD8%), and the CD4+ to CD8+ T cell ratio (CD4/CD8) at the time of HIV diagnosis, at the start of treatment and at months 1, 2, 3, 4, 5, 6, 12, and 24 after beginning cART. One hundred and twenty patients (63.2%) were negative for previous HBV infection, while 70 (36.8%) were HBcAb-positive. A significant increase in the CD4/CD8 ratio was recorded in HIV monoinfected subjects compared to HBV coinfected patients from months 4 to 12 from the beginning of cART (p value = 0.02 at month 4, p value = 0.005 at month 5, p value = 0.006 at month 6, and p value = 0.008 at month 12). A significant increase in the absolute count of CD8+ T lymphocytes was described from months 2 to 24 from the start of cART in the subgroup of HBV coinfected patients with an AIDS event at the onset of HIV infection. The presence of HBcAb was observed to be associated with reduced CD4/CD8 ratio growth and a significantly higher proportion of subjects with CD4/CD8 < 0.45 in the HIV/HBV coinfected group. A significant increase in the CD8 T cell count was shown up to 24 months after the initiation of effective cART in the subgroup of patients with the worst immune status.

Immunomodulatory effect of Acanthopanax senticosus polysaccharide on immunosuppressed chickens.

The immunomodulatory effect of Acanthopanax senticosus polysaccharide (ASPS) on immunosuppressed chickens induced by cyclophosphamide (Cy) was observed in this study. Four hundred 7-day-old chickens were randomly divided into 4 groups: vaccinated control group (VC group), Cy-challenged control group (Cy group), Cy-challenged + low-dose ASPS group (ASPSL + Cy group), and Cy-challenged + high-dose ASPS group (ASPSH + Cy group). All groups except the VC group were injected with Cy at a dose of 80 mg/kg/day of BW for 3 successive days to induce immunosuppression. At the age of 10 d, the ASPSL + Cy group and ASPSH + Cy group were intramuscularly injected with 0.2 mL of ASPS at the dose of 100 and 200 mg/mL/day, respectively, once a day for 3 successive days. The Cy group was injected with saline solution in the same way as the 2 ASPS groups. At the age of 14 d, the chickens were vaccinated with Newcastle disease (ND) vaccine in all groups. On day 7, 14, 21, and 28 after the vaccination, BW, lymphocyte proliferation, the serum antibody titers of the ND vaccine, the proportion of CD4+ and CD8+ T lymphocytes, and the concentrations of interferon gamma and IL-2 were determined. The results showed that chickens were injected with Cy at a dose of 80 mg/kg of BW for 3 d displayed lower immune responses than the control group, indicating that the immunosuppressive model was successfully established. At most time points, both high and low doses of ASPS could significantly promote lymphocyte proliferation; enhance BW, antibody titers, and the proportion of CD4+ and CD8+ T lymphocytes; and raised the concentrations of interferon gamma and IL-2 in Cy-treated chickens compared with those in the Cy control group (P < 0.05). These results indicated that ASPS could resist immunosuppression induced by Cy and may be a new-type immune adjuvant to improve vaccination in normal and immunosuppressed chickens.

Development of a Microfluidic Device for CD4+ T Cell Isolation and Automated Enumeration from Whole Blood.

The development of point-of-care, cost-effective, and easy-to-use assays for the accurate counting of CD4+ T cells remains an important focus for HIV-1 disease management. The CD4+ T cell count provides an indication regarding the overall success of HIV-1 treatments. The CD4+ T count information is equally important for both resource-constrained regions and areas with extensive resources. Hospitals and other allied facilities may be overwhelmed by epidemics or other disasters. An assay for a physician's office or other home-based setting is becoming increasingly popular. We have developed a technology for the rapid quantification of CD4+ T cells. A double antibody selection process, utilizing anti-CD4 and anti-CD3 antibodies, is tested and provides a high specificity. The assay utilizes a microfluidic chip coated with the anti-CD3 antibody, having an improved antibody avidity. As a result of enhanced binding, a higher flow rate can be applied that enables an improved channel washing to reduce non-specific bindings. A wide-field optical imaging system is also developed that provides the rapid quantification of cells. The designed optical setup is portable and low-cost. An ImageJ-based program is developed for the automatic counting of CD4+ T cells. We have successfully isolated and counted CD4+ T cells with high specificity and efficiency greater than 90%.

Low immune response rate of HIV-infected patients to a single injection of hepatitis A vaccine.

OBJECTIVES: We aimed to evaluate the immune response of HIV-1 positive patients to a single injection of HAV vaccine in a context of vaccine shortage during the 2017 European outbreak. METHODS: We retrospectively enrolled all HIV-1 positive patients vaccinated by a single injection of HAV vaccine Vaqta 50®. HAV serology was performed before and>30 days after the vaccine injection. RESULTS: Among the 73 patients, HIV-1 viral load was≤50 copies/mL in 93.2% of the cases. Medians of CD4 and median ratio of T CD4/CD8 cells were 658/mm3 and 0.9, respectively. A low immune response rate (59.7%) was observed among the patients. Responders had a significantly higher CD4/CD8 cell ratio than non-responders. CONCLUSIONS: A serologic control should be recommended in this population in the event of a single injection vaccination schedule. During routine follow-up, and prior to any untoward event, physicians should assess the vaccination coverage of HIV-infected patients.

Burkitt lymphoma associated with human immunodeficiency virus infection and pulmonary tuberculosis: A case report.

INTRODUCTION: The association of human immunodeficiency virus (HIV) infection with Burkitt lymphoma is related to the presence of Epstein Barr virus infection and the impact of the HIV antigen on the expansion of B-polyclonal cells. In Southeast Europe, the association is rare, and recognizing this is important in the therapeutic decision to increase patient survival rate. The association of HIV with Burkitt lymphoma and tuberculosis is even more rarely described in the literature. PATIENT CONCERNS: We present the case of a 40-year-old patient who presented with a 3-week history of fever (max. 38.7 °C), painful axillary swelling on the right side, lumbar pain, gait disorders, headache, and night sweats. Clinical manifestations included marked weight loss (about 30 kg in the last 2 months before his admission). DIAGNOSIS: A LyCD4 count of 38/µL and a HIV1 viral load of 384,000/mm3, classified the patient into a C3 stage. A biopsy of the right axillary lymph node was performed for suspected ganglionic tuberculosis due to immunodeficiency. Histopathological examination confirmed the diagnosis of Burkitt lymphoma. Cultures on Löwenstein-Jensen medium from sputum harvested at first admission were positive for Mycobacterium tuberculosis. INTERVENTIONS: Highly active antiretroviral therapy, chemotherapeutic agents for Burkitt lymphoma, anti-tuberculous drug therapy, neurosurgical intervention of spinal cord decompression, and antibiotic therapy of the associated bacterial infection. OUTCOME: Burkitt lymphoma disseminated rapidly, with central nervous system, spinal cord, osteomuscular, adrenal, and spleen involvement. The evolution under treatment was unfavorable, with patient death occurring 6 months after diagnosis. CONCLUSIONS: The association of HIV infection with Burkitt lymphoma and tuberculosis is rare in the highly active antiretroviral therapy (HAART) era, posing prompt and multidisciplinary therapeutic management issues. Similar cases of HIV-TB and Burkitt lymphoma association have been described, but none of the other cases showed the involvement of the central nervous system or of the bilateral adrenal glands.

Time to treatment disruption in children with HIV-1 randomized to initial antiretroviral therapy with protease inhibitors versus non-nucleoside reverse transcriptase inhibitors.

BACKGROUND: Choice of initial antiretroviral therapy regimen may help children with HIV maintain optimal, continuous therapy. We assessed treatment-naïve children for differences in time to treatment disruption across randomly-assigned protease inhibitor versus non-nucleoside reverse transcriptase inhibitor-based initial antiretroviral therapy. METHODS: We performed a secondary analysis of a multicenter phase 2/3, randomized, open-label trial in Europe, North and South America from 2002 to 2009. Children aged 31 days to <18 years, who were living with HIV-1 and treatment-naive, were randomized to antiretroviral therapy with two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Time to first documented treatment disruption to any component of antiretroviral therapy, derived from treatment records and adherence questionnaires, was analyzed using Kaplan-Meier estimators and Cox proportional hazards models. RESULTS: The modified intention-to-treat analysis included 263 participants. Seventy-two percent (n = 190) of participants experienced at least one treatment disruption during study. At 4 years, treatment disruption probabilities were 70% (protease inhibitor) vs. 63% (non-nucleoside reverse transcriptase inhibitor). The unadjusted hazard ratio (HR) for treatment disruptions comparing protease inhibitor vs. non-nucleoside reverse transcriptase inhibitor-based regimens was 1.19, 95% confidence interval [CI] 0.88-1.61 (adjusted HR 1.24, 95% CI 0.91-1.68). By study end, treatment disruption probabilities converged (protease inhibitor 81%, non-nucleoside reverse transcriptase inhibitor 84%) with unadjusted HR 1.11, 95% CI 0.84-1.48 (adjusted HR 1.13, 95% CI 0.84-1.50). Reported reasons for treatment disruptions suggested that participants on protease inhibitors experienced greater tolerability problems. CONCLUSIONS: Children had similar time to treatment disruption for initial protease inhibitor and non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy, despite greater reported tolerability problems with protease inhibitor regimens. Initial pediatric antiretroviral therapy with either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor may be acceptable for maintaining optimal, continuous therapy.

Hematologic alterations and early mortality in a cohort of HIV positive African patients.

INTRODUCTION: Infection with Human Immunodeficiency Virus (HIV) is highly prevalent worldwide, especially in Sub-Saharan Africa, where anaemia is also widespread. HIV infection is known to be associated with anaemia and various other haematologic alterations, but little data on correlation with immunological and virologic conditions in treatment-naïve patients and impact on mortality are available. Our study aims to investigate hematologic features in HIV-infected individuals in Malawi and Mozambique and assesses possible correlations with early morality. MATERIAL AND METHODS: We conducted a retrospective analysis of baseline data (general details, nutritional status, full blood count and HIV infection progress data) and 12 months follow-up status for HIV+ adult patients in 22 health facilities in Malawi (11 sites) and Mozambique (11 sites) run by DREAM program. Anagraphic details, anthropometric characteristics, full blood count, CD4+ count and Viral Load data were collected from electronical medical records (EMR) for all the HIV-positive, treatment-naïve patients starting care in the sites in the period January 2007 -December 2016. Follow-up status after one year since enrolment in care was also considered. All the data extracted from the EMR were included in a dataset and then analysed. Univariate and multivariate analysis were conducted through logistical regression to investigate associations, and survival analysis analysed in a Cox regression model. RESULTS: On the whole, 22.657 patients were included; severe and moderate anaemia were observed in 1.174 (8,2%) and 4.703 (21,9%) patients respectively. Gender, nutritional status, CD4+ count, and viral load (VL) were associated with anaemia, leukopenia, and thrombocytopenia. Among 21.166 fully evaluable patients, 8.494 (40,1%) had at least one cytopenia. Any cytopenia was present in 1/3 of patients with normal nutritional status and less advanced HIV infection, and it wouldn't be diagnosed in a basic HIV care setting. During the first year of treatment, 1.725 subjects (7,6% of the entire sample) died. Anaemia, lower Red blood cells and platelets counts correlated with mortality in the first year of care, independently by body mass index, haemoglobin, CD4+ count and VL. CONCLUSIONS: Notwithstanding anaemia is known to be associated with HIV infection at diagnosis, full blood count is not routinely performed in many African countries. Our results emphasize that including the study of a broader set of parameters in the routine HIV care services in Sub-Saharan Africa would provide significant clinical information able to predict other alterations and poor outcomes.

Negative binomial mixed models for analyzing longitudinal CD4 count data.

It is of great interest for a biomedical analyst or an investigator to correctly model the CD4 cell count or disease biomarkers of a patient in the presence of covariates or factors determining the disease progression over time. The Poisson mixed-effects models (PMM) can be an appropriate choice for repeated count data. However, this model is not realistic because of the restriction that the mean and variance are equal. Therefore, the PMM is replaced by the negative binomial mixed-effects model (NBMM). The later model effectively manages the over-dispersion of the longitudinal data. We evaluate and compare the proposed models and their application to the number of CD4 cells of HIV-Infected patients recruited in the CAPRISA 002 Acute Infection Study. The results display that the NBMM has appropriate properties and outperforms the PMM in terms of handling over-dispersion of the data. Multiple imputation techniques are also used to handle missing values in the dataset to get valid inferences for parameter estimates. In addition, the results imply that the effect of baseline BMI, HAART initiation, baseline viral load, and the number of sexual partners were significantly associated with the patient's CD4 count in both fitted models. Comparison, discussion, and conclusion of the results of the fitted models complete the study.

Point-of-care CD4+ technology implementation in Free State, South Africa, was associated with improved patient health outcomes.

BACKGROUND: Point-of-care (POC) CD4+ technologies have the potential to increase patient access to treatment and care through rapid testing and result delivery at or close to where patients seek care. South African (SA) guidelines suggest the use of CD4+ testing to prioritise patients most in need of antiretroviral therapy (ART) and to support identification of patients with advanced HIV disease and opportunistic management of patients on ART. Understanding the patient impact of implementing POC CD4+ testing in the intended setting and operated by lower cadres of healthcare worker or non-professional healthcare facility staff will provide valuable insight into the appropriate use and placement of POC CD4+ technologies throughout SA. OBJECTIVES: To determine the patient impact (turnaround time of tests, loss to follow-up, and proportions of eligible patients proceeding to the next steps in the testing and treatment cascade) of implementing POC CD4+ testing technologies compared with conventional laboratory-based CD4+ testing. METHODS: This retrospective cohort study included all HIV-positive adults from 30 healthcare facilities in Free State Province, SA. Healthcare facilities were placed into two groups (POC and laboratory referral) using a stratified randomisation technique based on the presence of a POC CD4+ technology and minimal ART volumes. Patients who received a CD4+ test prior to ART initiation between September 2012 and September 2014 were included. Data were collected from patient charts and the POC devices. RESULTS: For new patients, the average time from HIV diagnosis and CD4+ testing was reduced from 7.6 days in the laboratory referral group to 4.5 days in the POC group, a decrease of almost 60%. Additionally, 59.6% of patients in the POC group received their HIV diagnosis and CD4+ test result on the same day, compared with 37.5% in the laboratory referral group (risk ratio (RR) 1.49; 95% confidence interval (CI) 1.01 - 2.18). Fewer patients were lost between HIV diagnosis and CD4+ testing (2.7% v. 8.6%) (RR 0.02; 95% CI 0.05 - 0.78) in the POC group. The average test error rate across the study time period was 8.4%; however, the error rate remained <5% for the final 5 months of the study. CONCLUSIONS: Introduction of the Alere Pima POC CD4+ technology in the Free State, operated by nurses and lay counsellors, was associated with positive patient outcomes across all parameters analysed. While this study highlighted an effective conventional laboratory network, a full costing and affordability analysis coupled with patient impact and access data from this study will provide further insight into the potential deployment strategies of POC CD4+ technologies in SA.

The effect of antiretroviral therapy on fine-needle aspiration of salivary gland masses in HIV-infected patients.

BACKGROUND: South Africa has a very high prevalence of HIV/AIDS. Salivary gland lesions are common in HIV-infected patients. The aim of this study was to determine the pathologic entities diagnosed on fine-needle aspiration (FNA) of salivary gland masses in an HIV-infected study population that now has free access to antiretroviral (ARV) therapy and how this differs from the pathologic entities before the advent of widespread ARV availability, and if the Milan system for reporting salivary gland cytopathology (MSRSGC) can be applied to HIV-infected patients. METHODS: A retrospective review was performed on confirmed HIV-infected patients who underwent FNA of salivary gland masses over a two-year period. RESULTS: A total of 360 patients underwent FNA of salivary gland masses within the designated time frame, 58.3% (210) females and 41.7% (150) males. Patient ages ranged from 7 months to 67 years with a mean age of 36.9 years. The parotid gland was the most biopsied salivary gland at 55.3% (199). The most common diagnosis made in patients on antiviral therapy was lymphoepithelial cyst while that in patients not on antiviral therapy was infectious (including abscess and mycobacterial infection). The most frequent neoplasms were non-Hodgkin lymphoma, pleomorphic adenoma and squamous-cell carcinoma. CONCLUSION: Patients on ARV therapy had higher CD4 counts, fewer infectious lesions, and more reactive and benign salivary gland lesions. Patients not on treatment had significantly lower CD4 counts and were frequently diagnosed with infectious processes. The MSRSGC is well-suited for use in HIV-infected patients.

Magnitude of Anemia and Associated Factors Among Human Immunodeficiency Virus Infected Children on Highly Active Antiretroviral Therapy at University of Gondar Comprehensive and Specialized Referral Hospital Northwest Ethiopia.

BACKGROUND: Anemia is one of the most common hematological problems in HIV infected patients in the world. The main aim of this study was to determine the magnitude of anemia and associated factors among HIV infected children on highly active antiretroviral therapy attending University of Gondar Comprehensive and Specialized Referral Hospital. METHODS: A retrospective study was conducted from 2013 to 2018 by reviewing medical records at University of Gondar Comprehensive and Specialized Referral Hospital ART clinic. Records of 238 HIV infected children on HAART were selected using a convenient sampling technique. Socio-demographic characteristics, clinical information, and hematological and immunological profiles of the study participants were collected from the patients record books. WHO cutoff value of hemoglobin was taken and adjusted to define anemia in higher altitude. Data was analyzed by using the SPSS version 20 statistical software, and odds ratios with 95% confidence intervals were used to quantify the strength of association between anemia and its potential predictors. RESULTS: The overall prevalence of anemia among HIV infected children in this study was 38.7%. Of anemic children, 48.9% had mild, 39.1% moderate, and 11.9% severe anemia. This study showed that HIV infected children on Highly Active Antiretroviral Therapy who live in rural residence had a two-fold risk of being anemia than urban dwellers (AOR = 2.151, 95% CI, 1.123 - 4.122). There was no significant association with gender, WHO clinical stage, opportunistic infections, cotrimoxazole treatment, and CD4 count percentage. CONCLUSIONS: Anemia is a common problem among the children taking highly active antiretroviral therapy. Therefore, health care workers need to routinely investigate and treat anemia, especially in rural dwellers. Furthermore, large scale and longitudinal studies are recommended to strengthen and explore the problem in depth.

Incidental Findings on Brain MRI in People with HIV Infection.

BACKGROUND: Incidental findings are a well-known complication of imaging studies done for both diagnostic and research purposes. Little is known about the rates and types of incidental findings found on brain MRI in patients with HIV infection, who may be at risk for HIV-Associated Neurocognitive Disorders (HAND). METHODS: The parent study included 108 adults with HIV infection and 125 demographically-matched uninfected controls who completed MRI and neuropsychological testing. Incidental findings were classified by the study team as vascular, neoplastic, congenital, other neurologic, or non-neurologic. Categorical measures were compared using Pearson chi-square tests; continuous measures were compared using t-tests. RESULTS: Among participants with HIV infection, 36/108 (33%) had incidental findings compared to 33/125 (26%) controls (p = 0.248). Rates of incidental findings were significantly correlated with increasing age in both participants with HIV infection (p = 0.013) and controls (p = 0.022). We found no correlation between presence of incidental findings and sex or race/ethnicity among either cohort, and no correlation with CD4 count or HAND status for the HIV-infected cohort. CONCLUSIONS: Incidental findings were common in both participants with HIV infection and controls, at higher rates than previously reported in healthy populations. There was no significant difference in prevalence between the groups.

Association Between CD4 Count and Chemoradiation Therapy Outcomes Among Cervical Cancer Patients With HIV.

BACKGROUND: In Botswana, nearly two-thirds of cervical cancer patients are HIV-positive. This study examined the relationship between CD4 count and chemoradiation therapy outcomes among cervical cancer patients with HIV. SETTING: A prospective cohort study of 231 HIV-positive women with locally invasive cervical cancer was conducted in Gaborone, Botswana from January 2015 to February 2018. METHODS: Primary outcome was survival, defined as time from scheduled end of chemoradiation therapy to death or last contact with patient. Nadir CD4 count was defined as lowest CD4 available before cancer diagnosis. Delta CD4 count was defined as improvement from nadir CD4 to CD4 at cancer diagnosis. Hazard ratio (HR) analyses were adjusted for presenting variables (age, baseline hemoglobin, cancer stage, and performance status) and treatment variables (chemotherapy cycles and radiation dose). RESULTS: Two hundred thirty-one patients were included in nadir CD4 analysis; 139 were included in delta CD4 analysis. Higher delta CD4 was significantly associated with reduced mortality after adjusting for presenting and treatment variables (CD4 100-249: HR 0.45, 95% CI: 0.21 to 0.95; CD4 ≥250: HR 0.45, 95% CI: 0.20 to 1.02). Higher nadir CD4 showed a trend toward reduced mortality after adjusting for presenting and treatment variables (HR 0.94, 95% CI: 0.84 to 1.06). CONCLUSIONS: Higher delta CD4 (greater improvement from nadir CD4 to CD4 at cervical cancer diagnosis) is significantly associated with lower mortality. Although not statistically significant, data suggest that higher nadir CD4 may reduce mortality. These results reinforce the importance of early HIV diagnosis and antiretroviral therapy initiation, as their effects influence cervical cancer outcomes years later.