Drop In CD4 Research Articles

1489. CD4+ T Cell Count and Associated Mortality in PLWHIV and Cancer at an Oncologic Center in Mexico over a 10-year Period.

Abstract Background PLWHIV and cancer have an increased risk of mortality. Previous studies show that a 100 cells/mm3 drop in CD4+ T cells following chemotherapy increases the risk of mortality by up to 30%. In Mexico almost 40% of patients have a late diagnosis. The aim of this study is to measure the mortality association between the CD4+ T cell count nadir in PLWHIV and cancer. Methods We conducted a retrospective study involving PLWHIV and cancer ≥18 yo treated at the cancer and AIDS clinic of the Instituto Nacional de Cancerología in México City from January 01, 2005, to December 31, 2015, that received chemotherapy, immunotherapy, radiotherapy and/or oncologic surgery. The baseline CD4+ T cell count, nadir during treatment, first CD4+ T cell count after treatment, one year and five years after the end of oncologic treatment were evaluated. A logistic regression (LR) model was performed considering CD4+ T cell count at baseline, nadir during oncologic treatment and the association with all-cause mortality. Institutional Review Board (IRB) of INCan approved the study (Ref/INCAN/CI/0049/2022). Results A total of 445 patients were included, median of nadir CD4+ T cell count was 122 cells/µL (IQR 48-232), 147 (32.89%) had baseline CD4+ T cell ≤100 cells/µL. Kaposi Sarcoma (46%) and non-Hodgkin lymphoma (27%) were the most frequent diagnosis. One-year mortality occurred in 72 patients (16%), from them, the cause of death was cancer in 54 (75%). Descriptive analysis by mean difference showed significant difference in CD4+ T cell count between patients who died vs. those who survived 117.7 vs 175.4 (p=0.01). In the LR model, a significant association was found between stage IV of cancer and higher mortality at 1 year (OR 2.39; CI 1.27- 4.52) and at 5 years (OR 2.21; CI 1.21-4.02). At five years, mortality was higher in patients with a second AIDS defining event (OR 2.17; CI 1.12-4.17). At one year after completed cancer treatment having a CD4+ T cell nadir >200 cells/ µL was associated with lower mortality (OR 0.29; CI 0.08 – 0.92). Conclusion This study found that having other AIDS defining events and advanced neoplastic disease was associated with higher mortality; while having a nadir ≥200 cd4+ cells/ml showed lower mortality after one year of treatment. Disclosures All Authors: No reported disclosures

Variations in CD4 counts during pregnancy in women living with HIV.

Our objective was to determine the frequency at which CD4 counts drop below 200 cells/mm3 during pregnancy in women living with HIV and to identify factors associated with this. Data from 2005 to 2020 from two prospective Canadian cohorts of pregnant women living with HIV were extracted. As per national guidelines, women received antiretroviral therapy and CD4 counts were monitored once per trimester and at delivery. Among 775 included cases, 72 (9.3%) had CD4 counts <200 cells/mm3 at the first pregnancy visit. Of the 703 remaining pregnancies with CD4 counts ≥200 cells/mm3 at the initial visit, 20 (2.8%) were associated with a drop to <200 cells/mm3 . In univariate analysis, factors associated with this drop were coinfection with hepatitis B virus or hepatitis C virus (odds ratio [OR] 4.0, 95% confidence interval [CI] 1.52-10.50), lower first visit CD4 counts (OR 0.165, 95% CI 0.08-0.34), and baseline haemoglobin levels <11 g/dL (OR 2.89, 95% CI 1.04-8.00). In multivariable analysis, only CD4 count at first visit remained independently associated with this drop. A cut-off CD4 count ≤450 cells/mm3 at the first pregnancy visit had a sensitivity of 100% to detect cases of CD4 drop to <200 cells/mm3 . A drop of CD4 count to <200 cells/mm3 is uncommon during pregnancy in women living with HIV. Our results suggest that CD4 monitoring only once in pregnancy would be safe in women whose CD4 count is >450 cells/mm3 at the first pregnancy visit.

Association of TREX1 polymorphism with disease progression in human immunodeficiency virus type-1 (HIV-1) infected patients.

The time interval between HIV-1 infection and AIDS development is not the same in all patients and depends largely on the genetic background of the individual. Polymorphisms in the TREX1 gene, the main enzyme in the clearance of cytosolic DNA, affect type 1 interferon-mediated inflammatory response in HIV-1 infection. We aimed to study the role of a single nucleotide polymorphism (rs3135941) of the TREX1 gene and the rate of disease progression in patients infected with HIV-1. A total of 190 HIV-1 infected patients were recruited. Patients' demographic and laboratory data including CD4 counts, viral load, and antiretroviral therapy (ART) were collected. The genotype of rs3135941 was determined by a PCR-SSP method. The rate of progression to AIDS was calculated with Kaplan-Meier survival analysis using Stata software. The patients were divided into rapid and slow progressors based on time interval of CD4 drop below 350/µl. Kaplan-Meier analysis revealed an accelerated disease progression in patients with TC and CC genotypes (HR = 1.49, 95% CI = 1.01-2.17). The mean values of the first 5-year CD4 counts were significantly different in patients who had CC and TC genotypes compared to the TT group (p = 0.036). The result of this study emphasizes the importance of TREX1 polymorphism in HIV-1 progression. These data warrant further investigation into the role of other polymorphisms of TREX1.

Radiotherapy in Adult Burkitt Lymphoma: A Retrospective Analysis in a Large University Center.

Radiotherapy is not usually a part of standard Burkitt lymphoma treatment. We aim to assess patient and treatment characteristics of Burkitt lymphoma, particularly RT use, and how they relate to survival. Retrospective cohort of adult patients treated from 2008 to 2019 in an academic hospital. All patients had biopsy-proven Burkitt's lymphoma staged I to IV according to St. Jude's/Murphy staging system. Patients were followed for at least six-months or until death. Forty-eight consecutive patients were selected. Median age at diagnosis was 36.9years (18-62). Median follow-up was 7.78months (0.5-187.5). Most were male (81.3%) and had good performance by ECOG scale on their first hematologist appointment (56.2% were ECOG 0). Median OS and PFS were 8.4months (interquartile range Q1-Q3: 3.96-152.2) and 8.3months (interquartile range Q1-Q3: 6.7-not reached), respectively, with 32 deaths. A total of 43 patients (89.6%) were HIV-positive and had a median CD4 + level of 193.5 cells/mm3 at diagnosis. Patients that did not present a drop in CD4 + levels after treatment had better OS than those that did (p = 0.020). 11 patients underwent radiotherapy (22.9%) who had better OS than those who did not (p = 0.015). Our findings show that adult patients living with HIV presenting Burkitt lymphoma who maintained their immune status throughout treatment had better prognosis than those who presented CD4 + cells drops. Also, patients treated with radiotherapy-either with palliative intent or as consolidation after chemotherapy-had statistically significant better OS than those not irradiated. Prospective data is warranted for radiotherapy as a consolidative and as a palliative treatment.

Long-term consequences of interpersonal violence experiences on treatment engagement and health status in people living with HIV.

To examine the impact of previous interpersonal violence (IPersV) experiences on long-term healthcare engagement and health outcomes in a large Canadian HIV-cohort. People living with HIV (PLHIV) were screened for IPersV, and their healthcare outcomes over the nine subsequent years were analyzed. A total of 1064 PLHIV were screened for past and present IPersV experiences through semistructured interviews. Follow-up included core treatment engagement (e.g. clinic visits) and health-status variables (HIV viral load, CD4+ T-cell count, mortality, comorbidities), analyzed descriptively and with longitudinal Cox regressions. At intake, 385 (36%) PLHIV reported past or present IPersV including childhood (n = 224, 21%) or adulthood experiences (n = 161, 15%) and were offered conventional social work support. Over 9 years, individuals with any IPersV experiences were 36% more likely to discontinue care, 81% more likely to experience viremia, 47% more likely to experience a drop in CD4+ cell counts below 200/μl, and 65% more likely to die compared with patients not reporting IPersV (P < 0.05). Outcomes were similar when adjusted for sociodemographic factors. Childhood IPersV in particular was linked to several of the outcomes, with higher rates of discontinuation of care, viremia, and mortality related to mental health/addiction or HIV-related complications. IPersV is associated with an increased risk over time of healthcare discontinuation, poorer long-term HIV-related health outcomes, and increased mortality, especially for patients victimized in childhood. Apart from targeted IPersV screening to initiate conventional supports (e.g. through social work), increased efforts to engage vulnerable populations in their long-term care seems warranted.

Lamivudine monotherapy as a holding regimen for HIV-positive children.

BackgroundIn resource-limited settings holding regimens, such as lamivudine monotherapy (LM), are used to manage HIV-positive children failing combination antiretroviral therapy (cART) to mitigate the risk of drug resistance developing, whilst adherence barriers are addressed or when access to second- or third-line regimens is restricted. We aimed to investigate characteristics of children placed on LM and their outcomes.MethodsWe describe the characteristics of children (age <16 years at cART start) from 5 IeDEA-SA cohorts with a record of LM during their treatment history. Among those on LM for >90 days we describe their immunologic outcomes on LM and their immunologic and virologic outcomes after resuming cART.FindingsWe included 228 children in our study. At LM start their median age was 12.0 years (IQR 7.3–14.6), duration on cART was 3.6 years (IQR 2.0–5.9) and median CD4 count was 605.5 cells/μL (IQR 427–901). Whilst 110 (48%) had no prior protease inhibitor (PI)-exposure, of the 69 with recorded PI-exposure, 9 (13%) patients had documented resistance to all PIs. After 6 months on LM, 70% (94/135) experienced a drop in CD4, with a predicted average CD4 decline of 46.5 cells/μL (95% CI 37.7–55.4). Whilst on LM, 46% experienced a drop in CD4 to <500 cells/μL, 18 (8%) experienced WHO stage 3 or 4 events, and 3 children died. On resumption of cART the average gain in CD4 was 15.65 cells/uL per month and 66.6% (95% CI 59.3–73.7) achieved viral suppression (viral load <1000) at 6 months after resuming cART.InterpretationMost patients experienced immune decline on LM. Its use should be avoided in those with low CD4 counts, but restricted use may be necessary when treatment options are limited. Managing children with virologic failure will continue to be challenging until more treatment options and better adherence strategies are available.

Brief Report: Drop in CD4+ Counts Below 200 Cells/μL After Reaching (or Starting From) Values Higher than 350 Cells/μL in HIV-Infected Patients With Virological Suppression.

The aim of the study was to quantify the risk of a drop in CD4 counts below 200 cells/μL after reaching values >350 cells/μL on antiretroviral therapy (ART) (or after starting ART with CD4 count >350 cells/μL) in the absence of virological failure. Ambulatory care services, Italy. Prospective cohort study of patients enrolled in the ICONA Foundation Study cohort who started ART with >350 CD4/μL or with ≤350 CD4/μL and reached values >350 cells/μL after virological suppression (VS, defined by 2 consecutive viral loads ≤50 copies/mL). The date of CD4 count >350 was the baseline for the analysis and those with ≥1 viral load and CD4 count after baseline were included. The primary end point was the cumulative risk (estimated using the Kaplan-Meier method) of a CD4 drop below 200 cells/μL over follow-up, which was censored at the date of virological failure (confirmed HIV-RNA >50 copies/mL), death, or last visit. Six thousand six hundred sixty-three patients were included. A confirmed CD4 drop below 200 cells/μL was never observed over a median follow-up of 45 (Q1: 21, Q3: 89) months, as long as VS was maintained. Upper limits of the 97.5% confidence interval of rates of confirmed CD4 drop below 200 cells/μL were 0.28 and 0.38/1000 person-years of follow-up for patients with ≤350 and >350 CD4 cells/μL at starting ART. In patients who started ART in Italy with >350 CD4 cells/μL or reached >350 CD4 cells/μL after VS, the risk of a CD4 drop below 200 cells/μL in those maintaining VS was negligible.

Abnormal thymic maturation and lymphoproliferation in MRL-Fas lpr/lpr mice can be partially reversed by synthetic oligonucleotides: implications for systemic lupus erythematosus and autoimmune lymphoproliferative syndrome.

MRL-Fas lpr/lpr mice represent an excellent animal model for studying non-malignant lymphoproliferation, regeneration and systemic autoimmunity. Retro-transposon insertion into the second intron of the pro-apoptotic Fas gene appears to be responsible for both lymphoproliferation and autoimmunity, while other genes are more likely to contribute to the regenerative healing characteristic of this mouse strain. Previous studies have shown that neonatal thymectomy can halt the development of abnormal lymphoproliferation. Whereas at four weeks of age primary and secondary lymphoid organs appear to be grossly intact, vigorous lymphoproliferation and autoantibody production subsequently ensues. This is first noticeable at six weeks of age, at which time lymph nodes, spleens and thymuses, but not the bone marrow, become infiltrated with abnormal B220+CD3+CD4-CD8- T cells. Around the same time, thymuses show a significant drop in CD4+CD8+double-positive T cells generating an abnormal ratio between double-positive and single-positive thymocytes. The objective of current study was to evaluate the effect of synthetic oligonucleotides-toll-like receptor antagonists on early lymphoid development in this strain of mice. Herein, we demonstrate the ability of synthetic oligonucleotides made with the nuclease-resistant phosphorothioate backbone to partially reverse abnormal lymphoproliferation and thymic involution in pre-diseased MRL-Fas lpr/lpr mice when administered intraperitoneally starting from week four of age. This curative effect of oligonucleotides was primary sequence/secondary oligonucleotide structure-independent, suggesting an effect through the toll-like receptor 7. A similar approach may potentially benefit patients with autoimmune lymphoproliferative syndrome who, like MRL-Fas lpr/lpr mice, carry a mutation in the Fas gene.

Carfilzomib and Dexamethasone in untreated symptomatic multiple myeloma

Introduction: Treatment of refractory B cell malignancies with engineered T cells expressing chimeric antigen receptors (CARs) directed against CD19 has shown dramatic anti-tumor activity. CS1 (CD319) is a highly expressed surface glycoprotein on malignant plasma cells (mPCs) and promotes their adhesion to the bone marrow niche,making it a relevant target forCARtherapy inmultiplemyeloma (MM). The present work addresses the feasibility of CAR T cell generation fromMM patients after intense chemotherapy and an analysis of their therapeutic potential against primary mPCs. Materials and methods: We designed a CS1 specific CAR with an antigen-binding domain derived from the humanized monoclonal antibody elotuzumab (HuLuc63), comprising a signaling module of CD3 zeta and CD28. CS1 CAR gene constructs were lentivirally transferred to patient bulk CD4+ or CD8+ T cells. Results: We confirmed prevalently high CS1 antigen expression on mPCs in all patients. Absolute T cell counts in peripheral blood (PB) from pre-treated MM patients were lower compared to healthy donors, with predominant drop in CD4+ T cell counts. Max 50 ml of PB were sufficient for successful generation of CS1 CAR T cells in all (n 1⁄4 5) patients, and expansion to therapeutic doses within 2 weeks. In vitro functional testing of CAR T cells showed production of IL-2 and IFNg, proliferation in response to antigen recognition and specific lysis of MM cell lines. In a FACS based cytotoxicity assay, co-culture of mPCs with autologous or allogeneic CS1 CAR T cells resulted in rapid destruction of up to 90% of mPCs in 4 hours, whereas control T cells (untransduced and CD19 CAR T cells) had no effect. In a mouse xenograft myeloma model (NSG/MM1.S) patient-derived CS1 CAR T cells showed dramatic anti-myeloma activity, comparable to CS1 CAR T cells from healthy donors. As we observed CS1 expression also on lymphocyte subsets (B, T, NK) in MM patients, the potential ability of CS1 directed CAR T cell therapy to induce fratricide towards CS1+ lymphocytes remains a concern and is focus of ongoing research. Conclusion: Our data illustrate the preclinical feasibility to generate aCS1CARTcell productwith an excellent effector function against primarymPCs, requiring only small volumes of patients’ PB and clinically acceptable lead times. Determining the optimal setting for clinical translation however still warrants careful considerations with regards to possible induction regimens and supportive care. RS-003 Carfilzomib and Dexamethasone in untreated symptomatic multiple myeloma P. Forsberg, A. Rossi, R. Pearse, A. Perry, K. Pekle, D. Jayabalan, S. Ely, M. Coleman, R. Niesvizky, T.M. Mark Department of Medicine, Division of Hematology / Oncology, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY, USA; Department of Pathology, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY, USA

Effects of rituximab on lymphocytes in multiple sclerosis and neuromyelitis optica

ObjectiveTo investigate the effect of rituximab, a B-cell targeted therapy that is used in the treatment of multiple sclerosis (MS) and neuromyelitis optica (NMO), on other immune cells such as CD4+ and CD8+ T-cells in patients with MS and NMO. Design, setting and patientsThis is a retrospective study of all patients with MS or NMO who received at least one rituximab infusion at the UCSF MS tertiary care center between May 2005 and July 2011. Main outcome measuresLinear mixed models were used to assess (a) how post-infusion cell counts changed over time compared to pre-infusion levels and one another; (b) whether the cell counts were different over multiple courses of rituximab; and (c) what was the dosing effect on the cell counts over time. ResultsRituximab initially reduced CD4+ (by 26%, p=0.0005) and CD8+ (by 22%, p=0.0006) T-cells, although these changes were only transient. Subsequent treatments with rituximab did not result in a significant drop in CD4+ or CD8+ T-cells. Changes in other cell types were also typically more marked after the first cycle of rituximab than after additional treatments. The total dose of rituximab received did not appear to have a significant effect. ConclusionsAlthough transient, rituximab-induced decrease in CD4+ and CD8+ T-cells may increase the risk of infection in susceptible individuals.

Significant Interaction between Activated Charcoal and Antiretroviral Therapy Leading to Subtherapeutic Drug Concentrations, Virological Breakthrough and Development of Resistance

A 42-year-old, treatment-experienced woman, virologically suppressed on tenofovir/emtricitabine and boosted atazanavir, experienced virological breakthrough, drop in CD4(+) T-cell count and undetectable drug concentrations. Adherence to treatment was confirmed, but repeat testing yielded similar results. After 2 months, the patient stated that she had been taking activated charcoal to manage gastrointestinal symptoms associated with her combination antiretroviral therapy, but she had recently discontinued the charcoal. Atazanavir concentrations were therapeutic but the patient's viral load rebounded and genotype testing revealed new reverse transcriptase mutations. The patient was changed to zidovudine, lamivudine, and boosted darunavir and achieved viral suppression. At 1 year follow-up, her viral load remained <40 copies/ml. According to the drug interaction probability scale, our patient experienced a probable drug interaction between activated charcoal and atazanavir/ritonavir leading to virological breakthrough and development of resistance.

Immunological Changes at Point-of-Lay Increase Susceptibility to Salmonella enterica Serovar Enteritidis Infection in Vaccinated Chickens

Chicken eggs are the main source of human Salmonella enterica serovar Enteritidis infection. S. Enteritidis infects the oviduct and ovary of the chicken leading to infection of developing eggs. Therefore, control in poultry production is a major public health priority. Vaccination of hens has proved successful in control strategies in United Kingdom leading to a 70% drop in human cases since introduced. However, as hens reach sexual maturity they become immunosuppressed and it has been postulated this leads to increased susceptibility to Salmonella infection. In this study we define the changes to the systemic and reproductive tract-associated immune system of hens throughout sexual development by flow cytometry and histology and determine changes in susceptibility to experimental S. Enteritidis challenge in naive and vaccinated hens. Changes to both systemic and local immune systems occur in chickens at sexual development around 140 days of age. The population of several leukocyte classes drop, with the greatest fall in CD4+ lymphocyte numbers. Within the developing reproductive tract there an organised structure of lymphocytic aggregates with γδ-T lymphocytes associated with the mucosa. At point-of-lay, this organised structure disappears and only scattered lymphocytes remain. Protection against Salmonella challenge is significantly reduced in vaccinated birds at point-of-lay, coinciding with the drop in CD4+ lymphocytes. Susceptibility to reproductive tract infection by Salmonella increased in vaccinated and naïve animals at 140 and 148 days of age. We hypothesise that the drop in γδ-T lymphocytes in the tract leads to decreased innate protection of the mucosa to infection. These findings indicate that systemic and local changes to the immune system increase the susceptibility of hens to S. Enteritidis infection. The loss of protective immunity in vaccinated birds demonstrates that Salmonella control should not rely on vaccination alone, but as part of an integrated control strategy including biosecurity and improved animal welfare.

Association of Soluble CD14 and Inflammatory Biomarkers With HIV-2 Disease Progression

Human immunodeficiency virus type 2 (HIV-2) infection is characterized by a slower progression than HIV type 1. It is not known whether markers of inflammation such as high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), and soluble CD14 (sCD14) may predict disease progression among HIV-2 patients. We performed longitudinal retrospective analysis using 384 samples from 71 patients included in the HIV-2 French cohort ANRS CO5 and followed for a median of 8 years. Baseline was the time of the first available measurement. Disease progression was defined by the occurrence of death, Centers for Disease Control and Prevention B/C stage HIV-related event, drop in CD4 <350 cells/µL, and HIV-2 RNA detection. Cox regression models and mixed models were used for statistical analyses. At baseline, 75% of patients were asymptomatic, 34% were treated; 30% had detectable HIV-2 RNA load, and median CD4 cell count was 415/µL. The 3 biomarkers were positively related to each other. In adjusted analyses, sCD14 was the main factor explaining variation of hsCRP and IL-6 (P < .001). Lower CD4, older age, and advanced clinical stage were associated with higher sCD14. The biomarkers were correlated with HIV-2 RNA in unadjusted analyses only. Patients with baseline levels above either the median values (hsCRP = 1.38 mg/L; IL-6 = 1.97 pg/mL) or the highest quartile (sCD14 = 1.74 µg/mL) had a higher risk of disease progression (all P < .003). After adjustment for CD4 count, only sCD14 remained significantly associated with disease progression (hazard ratio, 3.59; P = .004). In this cohort of HIV-2-infected patients, sCD14 represents a better predictive biomarker of disease progression than hsCRP or IL-6, independent of CD4.

Missed visits and decline in CD4 cell count among HIV-infected patients: a mixed method study

To determine the impact of missed visits on CD4 cell count with HIV disease in a Midwest clinic. This was a mixed method study consisting of a quantitative retrospective cohort study of missed clinic visits among HIV-infected patients, and a qualitative study to collect information on factors impacting appointment attendance. A drop in CD4 cell count greater than 50 cells/mm(3) from baseline was the primary outcome variable for the quantitative study. The exposure variable was missed visits. Of 77 patients, 16.4% experienced the outcome of interest. Lower visit proportions increased the risk of a CD4 drop (hazard ratio 0.0188, 95% confidence interval 0.001-0.292). For each 10% increase in the missed visit proportion, the risk of a CD4 drop of >50 cells/mm(3) from baseline increased by 33%. Qualitative data suggested that stigma, external support, and physician-patient interactions impacted engagement in care. These results may help providers increase patient motivation and ability to attend clinic appointments.

Effect of intermittent interleukin-2 therapy on CD4+ T-cell counts following antiretroviral cessation in patients with HIV

Interleukin (IL)-2 therapy impacts T-cell homeostasis. Whether IL-2 expanded CD4(+) T cells may persist following viral rebound has not been fully investigated. Patients with CD4(+) T cells 500/μl or more and HIV RNA less than 50 copies/ml were randomized to continue antiretroviral therapy (ART) either alone (n = 67) or combined with three IL-2 cycles (n = 81; 6 million units) twice daily for 5 days at weeks 0, 8, and 16 before stopping ART (week 24). Patients were followed up to 168 weeks. At week 24, median CD4(+) T-cell counts were 1198 and 703 cells/μl in the IL-2 and control groups, respectively (P < 0.001). At week 72, 27% (IL-2 group) and 45% (control group; P = 0.03) of patients were in failure (defined as no interruption of ART at week 24, CD4 drop below 350 cells/μl or ART resumption). After week 24, a biphasic decline (before and after week 32) of CD4 was noted -106 and -7 cells/μl per month in controls and -234 and -17 in IL-2 group (all P ≤ 0.0001). At week 96, IL-2-expanded CD4(+)CD25(+) T cells remained higher than in the control group (26 vs. 16%, P = 0.006). In IL-2-treated patients, CD4(+)CD25(+) T cells persisting despite viral replication allow a longer period of ART interruption.

Presentation and Outcome of Tuberculous Meningitis in a High HIV Prevalence Setting

Background Mycobacterium tuberculosis is a common, devastating cause of meningitis in HIV-infected persons. Due to international rollout programs, access to antiretroviral therapy (ART) is increasing globally. Starting patients with HIV-associated tuberculous meningitis (TBM) on ART during tuberculosis (TB) treatment may increase survival in these patients. We undertook this study to describe causes of meningitis at a secondary-level hospital in a high HIV/TB co-infection setting and to determine predictors of mortality in patients with TBM.MethodsA retrospective review of cerebrospinal fluid findings and clinical records over a six-month period (March 2009–August 2009). Definite, probable and possible TBM were diagnosed according to published case definitions.ResultsTBM was diagnosed in 120/211 patients (57%) with meningitis. In 106 HIV-infected patients with TBM, six-month all-cause mortality was lower in those who received antiretroviral therapy (ART) during TB treatment; hazard ratio = 0.30 (95% CI = 0.08–0.82). Factors associated with inpatient mortality in HIV-infected patients were 1) low CD4+ count at presentation; adjusted odds ratio (AOR) = 1.4 (95% confidence interval [CI] = 1.03–1.96) per 50 cells/µL drop in CD4+ count and, 2) higher British Medical Research Council TBM disease grade (2 or 3 versus 1); AOR = 4.8 (95% CI = 1.45–15.87).InterpretationStarting ART prior to or during TB treatment may be associated with lower mortality in patients with HIV-associated TBM. Advanced HIV and worse stage of TBM disease predict in-hospital mortality in patients presenting with TBM.

Evaluation of lymphocyte levels in a random sample of 218 elderly individuals from São Paulo city

Background Age-associated changes in the immune system cause decreased protection after vaccination and increased rates of infections and tumor development.MethodsLymphocyte percentages were compared by gender and age to establish differences between subtypes. Three mL blood samples were obtained from 218 randomly selected individuals (60-101 years old) who live in São Paulo city. Blood was lysed with Tris phosphate buffer and stained for 30 minutes with monoclonal antibodies (CD3PerCP, CD4FITC, CD8Pe, CD19Pe) for analysis by flow cytometry. Statistical analysis was by ANOVA.ResultsThe percentage of CD4+ T cells (p-value = 0.005) and the CD4/CD8 ratio (p-value = 0.010) were lower in men, whereas the percentage of CD8+ T cells was lower (p-value = 0.002) in women; the percentage of B cells (CD19+ ) was similar between groups. Individuals grouped by gender and age range and compared showed a drop in CD4+ cells in 75 to 79-year-old men (female: 46.1% ± 8.1% and male: 38.8% ± 10.5%; p-value = 0.023). Also, the 80 to 84-year-old group of men had a higher percentage of CD8+ (female: 20.8% ± 8.2%, and male: 27.2% ± 8.2%; p-value = 0.032). Low percentages of B cells were detected in men in the 75 to 79-year-old (p-value = 0.003), 85 to 89-year-old (p-value = 0.020) and older than 90 year old (p-value = 0.002) age ranges.ConclusionElderly men present with more changes in lymphocyte subsets compared to elderly women. These findings could demonstrate impairment in the immune response since the lower CD4+ in men would provide less help to B cells (also lower in men) in terms of antibody production. In addition, the increase in CD8+ cells in this group could represent chronic inflammation observed during the aging process.

Evaluating Patients for Second-Line Antiretroviral Therapy in India: The Role of Targeted Viral Load Testing

The identification and management of first-line antiretroviral therapy (ART) failure is a key challenge for HIV programs in resource-limited settings. In 2008, the National AIDS Control Organisation, India piloted a national strategy to provide second-line ART. We assessed the National AIDS Control Organisation second-line ART evaluation algorithm. Adult patients who had received 6 months or more of standard first-line ART were referred for second-line ART evaluation if they demonstrated CD4 decline to pre-ART values, CD4 drop to less than 50% of peak on-treatment value, failure to achieve CD4 greater than 100 c/mm(3), or development of a new World Health Organization Stage 3 or 4 AIDS-defining illness. Patients received HIV RNA testing, and those with HIV RNA 10,000 c/mL or greater qualified to switch to second-line ART. World Health Organization-defined clinical and CD4 criteria for ART failure were compared against virologic failure criteria. Between January and June 2008, 154 patients met criteria for evaluation. Of 122 (79%) patients who had HIV RNA testing, 87 (71%) had viral load 10,000 c/mL or greater and were recommended to start second-line ART, 29 (24%) had viral load less than 400 c/mL, and six (5%) had viral load between 400 and 10,000 c/mL. The positive predictive value of World Health Organization clinical/immunologic criteria to detect virologic failure was 71% (95% confidence interval, 63% to 79%). Second-line ART was initiated in the public sector in India using an approach combining clinical and immunologic evaluation with confirmation of virologic failure. Almost 25% of patients who met clinical/immunologic failure criteria demonstrated virologic suppression. Inclusion of targeted HIV RNA testing in the evaluation of treatment failure can prevent unnecessary switches to second-line ART.

Longitudinal study of CD4+ cell counts in HIV-negative pregnant patients

Objective. To evaluate the absolute CD4+, CD8+, and lymphocyte cell counts and percentages from the first trimester through 6–12 weeks post-delivery in normal human immunodeficiency virus (HIV)-negative pregnant patients.Methods. A longitudinal laboratory analysis was performed during pregnancy that involved 51 HIV-negative subjects with blood analysis obtained in all trimesters, at delivery, and 6–12 weeks post-delivery. Twenty-five HIV-negative non-pregnant controls were also evaluated. Blood was analysed for absolute CD4+, CD8+, and lymphocyte cell counts and percentages. Means, standard deviations, trends, and differences were examined.Results. The mean white blood cell (WBC) count is elevated above the non-pregnant state and this parameter increases through the pregnancy up to and including parturition. The mean absolute lymphocyte cell count, lymphocyte percentage, and absolute CD4+ cell count are significantly lower during pregnancy and the progression through pregnancy appears U-shaped. The mean absolute CD8+ cell count is not significantly different. The CD4+ and CD8+ percentages are higher during pregnancy and this elevation persists into the 6–12 week post-delivery time period. A 3-digit drop in CD4+ percentage is common during pregnancy between blood draws; whereas, a 30% decrease or more in absolute CD4+ cell count is rare.Conclusions. By longitudinal analysis, pregnancy appears to significantly elevate the mean values of the WBC count, CD4+ percentage, and CD8+ percentage, but significantly decreases the absolute lymphocyte count, lymphocyte percentage, and absolute CD4+ cell count when compared to non-pregnant controls. The mean absolute CD8+ cell count appears to be unaffected.

Influence of a Vaccination Schedule on Viral Load Rebound and Immune Responses in Successfully Treated HIV-Infected Patients

Vaccination is recommended for HIV-infected patients. Transient increases of viral load (VL) and risk of developing resistance to HAART have been described. In addition, VL rebounds could increase HIV-specific immune responses. Twenty-six successfully treated HIV-infected adults were randomized to receive a vaccination schedule or placebo during 12 months. Afterward, HAART was discontinued. Influences of vaccination over VL, genotypic mutations, different T cell subsets, and HIV-1-specific immune responses were evaluated. Patients did not present any secondary effect. No differences in incidence of detectable VL determinations were detected between groups [relative risk 0.54 (95% CI 0.23-1.26)]. No relevant resistance mutations were detected. The vaccinated group showed a significant drop in CD4(+) T cells (p = 0.046) associated with increases in activated T cells. HIV-1-specific lymphoproliferative responses increased more in the vaccinated group during the vaccination period. Viral rebound dynamics after interrupting HAART were similar in both groups. A vaccination schedule in successfully treated HIV patients was safe, was not associated with an increase in detectable VL, and did not increase the risk of developing resistance mutations. However, it induced an increase in T cell activation and a drop in CD4(+) T cells, although these changes did not influence the VL rebound dynamics after HAART interruption.