Non-adherence to anti-hypertensive medication in low- and middle-income countries: a systematic review and meta-analysis of 92443 subjects.

Hypertension is a rising global burden, and low- and middle-income countries account for 80% of deaths due to complications of hypertension. Hypertension can be controlled by adhering to anti-hypertensive medication. However, non-adherence is an increasing challenge. This review aims to systematically evaluate non-adherence to anti-hypertensive medication among adults in low- and middle-income countries and explore factors affecting non-adherence to anti-hypertensive medication. We performed a systematic search for studies published between 1 January 2000 and 31 August 2015. A selection process was performed for data extraction with a combination of Medical Subject Headings terms: 'hypertension' and 'adherence'. Further search criteria were: language ('english'), species ('humans'), and low- and middle-income countries. A total of 22 studies met the inclusion criteria. The pooled percentage of non-adherence when using the eight-item Morisky Medication Adherence Scale (MMAS) was 63.35% (confidence of interval (CI): 38.78-87.91) and 25.45% (CI:17.23-33.76) when using the 80 and 90% cut-off scales. The factors were classified into the five dimensions of adherence defined by the World Health Organization, and the majority of the studies reported factors from the dimension 'social and economic factors'. This systematic review demonstrated considerable variation of non-adherence to anti-hypertensive medication in low- and middle-income countries depending on the methods used to estimate non-adherence. The results showed a high non-adherence when the MMAS eight-item scale was used and low when the 80 and 90% cut-off scales were used. The majority of factors affecting non-adherence to anti-hypertensive medication fell within the World Health Organization defined dimension 'social and economic factors'.

Limited impact of the thymus on immunological recovery during and after chemotherapy in patients with diffuse large B-cell lymphoma.

To investigate the impact of thymus on immunological recovery after dose-dense chemotherapy a prospective study of 17 patients diagnosed with diffuse large B-cell lymphoma (DLBCL) was conducted. Patients were monitored before, during and until 3 months after chemotherapy. The thymus was visualized using computer tomographic scans. Patients were divided into two groups according to thymic size, one group comprising of patients without detectable thymus and one group of patients with detectable thymus. Naïve CD4 and CD8 counts were measured by flow cytometry, and to measure thymic output determination of CD4+ cells containing T-cell receptor excision circles (TREC) was done. During chemotherapy, the naïve CD4 count decreased significantly as did the CD4-TREC%. Significant difference in recovery of naïve CD4 counts between patients with detectable and undetectable thymic tissue during treatment with chemotherapy was not found. CD4-TREC% was associated with lower age. It was not possible to demonstrate an association between thymic size and recovery of the naïve CD4+ cells. The study terminated 3 months after the last cycle of chemotherapy, and at that time point the naïve CD4 counts and the CD4-TREC% had not returned to pretreatment levels. However, patients with detectable thymic tissue had higher naïve CD4 counts after the first cycles of chemotherapy, suggesting that these patients may be less susceptible to infectious complications related to chemotherapy.

Regulatory T cells in human immunodeficiency virus-infected patients are elevated and independent of immunological and virological status, as well as initiation of highly active anti-retroviral therapy.

Infection with human immunodeficiency virus (HIV) causes a dysregulation of the immune system. This is caused by HIV-specific as well as non-specific mechanisms and has not been explained fully. In particular, knowledge is lacking about the potential role of host-mediated immunosuppressive mechanisms. During recent years it has become evident that a subpopulation of T cells [T regulatory (T(regs))] play a major role in sustaining tolerance to self-antigens. To investigate the influence of initiation of highly active anti-retroviral therapy (HAART) on the T(reg) level in HIV-infected patients we have conducted a prospective study enrolling treatment-naive HIV-infected patients just prior to starting treatment with HAART, measuring levels of T(regs) by flow cytometry and mRNA expression of forkhead box P3 (FoxP3) at weeks 0, 4, 12 and 24 of treatment. In this prospective study neither the percentage of CD4(+)CD25(high+) nor the expression of FoxP3 changed significantly during 24 weeks of HAART. Furthermore, HIV patients have higher T(regs) measured as percentages of CD4(+)CD25(high+) cells paralleled by higher levels of FoxP3 compared with healthy controls. The elevated level of T(regs) was found to be independent of both immunological and virological status, indicating that initiation of HAART has minor effects on the T(reg) level in HIV-infected patients.

Predictive value of soluble haemoglobin scavenger receptor CD163 serum levels for survival in verified tuberculosis patients.

Pre-treatment serum levels of sCD163 were measured in a cohort of 236 suspected tuberculosis (TB) cases from Guinea-Bissau, with a median follow-up period of 3.3 years (range 0-6.4 years). In 113 cases, the diagnosis of TB was verified by positive sputum microscopy and/or culture. Among the verified TB cases, a decreased survival rate was found in 27 patients with sCD163 levels above the upper reference limit (3.95 microg/mL). The difference in survival was significant during TB treatment (log rank, p<0.02) and after long-term follow-up (log rank, p<0.001). The decrease in survival rate during TB treatment remained significant in a multivariate Cox model controlling for human immunodeficiency virus (HIV) status, age and gender, with a mortality increase of 1.19 (95% CI, 1.04-1.36) per microg of sCD163, and a hazard ratio (HR) for sCD163 levels above the upper reference limit of 4.18 (95% CI, 1.06-16.4). The difference was not significant after excluding patients with concomitant HIV-1 and HIV-2 infection in Kaplan-Meier analyses (log rank, p 0.11). In contrast, the difference in survival remained significant in Kaplan-Meier analyses after long-term follow-up, even after excluding patients with concomitant HIV-1 and HIV-2 infection (log rank, p 0.002). In the Cox model, the mortality increase per microg of sCD163 was 1.27 (95% CI, 1.14-1.40), with an HR for elevated sCD163 levels of 2.85 (95% CI, 1.44-5.63). The HRs for concomitant HIV-1 and HIV-2 infection were 6.92 (95% CI, 3.28-14.58) and 2.48 (95% CI, 1.09-5.67), respectively. Thus, sCD163 levels appeared to be an independent predictor of survival in verified TB patients.

Acid base and electrolyte changes after hypertonic saline (7.5%) infusion: a randomized controlled clinical trial.

Hypertonic saline solutions are effective in the treatment of haemorrhagic and septic shock, elevated intracranial pressure and perioperative fluid deficits. Infusion, however, causes electrolyte and acid-base imbalance. In a randomized double-blind study, the effects of a 10-min infusion of 4 ml/kg 7.5% NaCl or 0.9% NaCl were evaluated in 14 fasting women before hysterectomy. Venous blood from the forearm was collected at baseline, 10, 20, 30, 60 and 120 min after start of the infusion for the determination of plasma electrolytes and acid-base balance. We found that 1) a median increase in plasma sodium of 11 mmol/l (range 9-13 mmol/l) and chloride of 14 mmol/l (range 9-16 mmol/l) immediately after the infusion followed by a small decrease after 2 h, 2) a minor decrease in plasma potassium in relation to the infusion followed by a significant increase of 0.3 mmol/l (range 0.1-1.4 mmol/l) above baseline after 1 h, 3) a decrease in pH of 0.05 (range 0.02-0.07) and, finally, 4) a decrease in base excess of 1.9 mmol/l (range 0.8-2.7 mmol/l). It is concluded that infusion of 7.5% NaCl in a clinical relevant dose increases plasma potassium and causes minor changes in the acid-base balance in normovolaemic women.

Enhanced glucagon-like peptide-1 (GLP-1) response to oral glucose in glucose-intolerant HIV-infected patients on antiretroviral therapy.

OBJECTIVES: We investigated whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are major regulators of glucose tolerance through the stimulation of insulin secretion, contribute to impaired glucose tolerance (IGT) among HIV-infected patients on highly active antiretroviral therapy (HAART). METHODS: Eighteen HIV-infected male patients (six lipodystrophic and 12 nonlipodystrophic) with normal glucose tolerance (NGT) were compared with 10 HIV-infected male patients (eight lipodystrophic and two nonlipodystrophic) with IGT. Plasma concentrations of GLP-1 and GIP were determined frequently during a 3-h, 75-g glucose tolerance test. Insulin secretion rates (ISRs) were calculated by deconvolution of C-peptide concentrations. RESULTS: The incremental area under the curve (incrAUC) for GLP-1 was increased by 250% in IGT patients compared with NGT patients (1455+/-422 vs. 409+/-254 pmol/L/180 min, respectively; P<0.05), whereas the incrAUC for GIP did not differ between the study groups (7689+/-1097 vs. 8041+/-998 pmol/L/180 min, respectively; not significant). In pooled study groups, the GIP incrAUC correlated positively with the ISR incrAUC without adjustment (r=0.38, P<0.05) and following adjustment for glucose incrAUC (r=0.49, P<0.01). CONCLUSIONS: Our data suggest: (1) that glucose-intolerant, HIV-infected male patients may display enhanced GLP-1 responses to oral glucose compared with normal glucose-tolerant HIV-infected male patients, which may represent a compensatory mechanism rather than explain the IGT; (2) that the GIP response may be associated with ISR independently of plasma glucose in nondiabetic HIV-infected males on HAART.

Low-dose growth hormone and human immunodeficiency virus-associated lipodystrophy syndrome: a pilot study.

BACKGROUND: Treatment with high doses (2-6 mg day(-1)) of human growth hormone (hGH) in patients with human immunodeficiency virus (HIV)-associated lipodystrophy syndrome (HALS) has been shown to increase concentrations of total insulin-like growth-factor-I (IGF-I) more than twofold greater than the normal upper range and is accompanied by adverse effects such as joint pain and glucose intolerance. MATERIALS AND METHODS: We performed a 16-week open-labelled prospective pilot study in six male HALS patients using a s.c. low-dose hGH, 0.7 mg day(-1), aiming to examine the impact on total and free IGF-I and fat distribution. Glucose metabolism was examined by oral glucose tolerance tests and hyperinsulinaemic euglycaemic clamps. RESULTS: Total IGF-I increased twofold (P < 0.01) and free IGF-I increased 2.5-fold (P < 0.01) to the level of the normal upper range. HDL-cholesterol increased (P = 0.01). Patients reported improvements of lipodystrophy, which was supported by a decreased waist-to-thigh ratio (P = 0.01), and waist-to-hip ratio (P = 0.06). Ratio of peripheral to trunk soft tissue mass increased (P = 0.01, measured by dual-energy X-ray absorptiometry scans) and a trend towards reduction in percentage of trunk fat was suggested (P = 0.12). Total fat mass, exercise capacity, glucose tolerance, glucose disposal rate and immune status, respectively, did not change (all P > 0.5). The patients did not complain of arthralgia or other known GH-related side-effects. CONCLUSIONS: Sixteen weeks' treatment of lipodystrophic HIV-infected patients with hGH, 0.7 mg day(-1), increased total and free IGF-I twofold and appeared safe and tolerable. The potential of low-dose hGH in the treatment of HIV-lipodystrophy awaits examination by placebo-controlled, randomized trials.

Infusion of hypertonic saline (7.5% NaCl) causes minor immunological changes in normovolaemic women.

BACKGROUND: Haemorrhagic shock is treated effectively by infusion of hypertonic saline/colloid solutions. Furthermore, previous studies found hypertonicity to affect immune responses in animals and in human blood cell cultures. It is unknown, however, whether hypertonic saline infusion affects immune responses in humans. METHODS: In a randomized double-blind study, we infused 4 ml kg-1 of 7.5% NaCl or 0.9% NaCl over 10 min in 20 fasting women before hysterectomy. We collected peripheral blood at baseline, 30, and 120 min after start of the infusion and before surgery for the determination of leucocyte and differential count; lymphocyte subtypes; neutrophil chemotaxis; elastase concentration; and the cytokine's tumour necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, IL-6, IL-8, IL-1 receptor antagonist (IL-1ra), and IL-10. Phytohaemagglutinin (PHA)-induced lymphocyte proliferation and natural killer cell cytotoxicity were measured before and 120 min after infusion. RESULTS: Compared with normal saline, infusion of hypertonic saline temporarily increased the number of B cells in peripheral blood (P < 0.01); increased the concentration of plasma elastase, a marker of neutrophil degranulation (P < 0.05); and decreased the number of circulating neutrophils (P < 0.001). No other effects were detected in the measured immunological parameters. CONCLUSION: The immunological consequences of hypertonic saline infusion seem to be modest and are unlikely to cause any clinical effects, at least in normovolaemic women.

Preanalytical handling of samples for measurement of plasma lactate in HIV patients.

Lactic acidosis is a feared side effect of nucleoside analog treatment, one of the cornerstones in the management of HIV infection. Precise and reliable lactate measurements are prerequisites for the diagnosis of hyperlactatemia. The effects of venous stasis, time to measurement and storage temperature on p-lactate levels, p-glucose levels, anion gap and pH were investigated. Ten HIV patients (n=8 on highly active antiretroviral therapy) and 4 healthy control subjects were studied. Blood was drawn without stasis at time 0 and with stasis for 2 and 8 min into heparin-preserved test tubes. The tubes were placed at a room temperature (25 degrees C) and on crushed ice and consecutively monitored for up to 360 min. The mean increases in p-lactate in blood kept in test tubes at 25 degrees C, measured from 0 to 60 min and from 240 to 360 min, were increased in HIV patients compared with controls (0.78 mmol/Lh +/- 0.02 vs. 0.63 mmol/Lh +/- 0.05, (p=0.009) and 0.65 mmol/Lh +/- 0.03 vs. 0.53 mmol/Lh +/- 0.05, (p=0.042)). It was found that placing the tubes on crushed ice rather than keeping them at 25 degrees C controlled glycolysis and lactate production measured over a 6-h period (0.033 mmol/Lh +/- 0.006 vs. 0.32 mmol/Lh +/- 0.01, (p<0.0001) and 0.064 mmol/Lh +/- 0.008 vs. 0.64 mmol/Lh +/- 0.02, (p<0.0001)). The total increases in lactate levels in the test tubes placed on crushed ice for 4 h and in those kept at 25 degrees C for 15 min were comparable (0.28 +/- 0.03 mmol/L vs. 0.20 +/- 0.03). Compared with storage at 25 degrees C, keeping the test tubes on crushed ice also preserved pH and anion gap over a 6-h measurement period (pH: 0.026 +/- 0.004 vs. 0.12 +/- 0.01 and anion gap: -0.8 +/- 0.4 mmol/L vs. 4.1 +/- 0.4). Two minutes of venous stasis had no influence on p-lactate levels (0.02 +/- 0.04 mmol/L, p=0.70), whereas 8 min of stasis increased p-lactate levels by 0.11 +/- 0.04 mmol/L, p=0.009. It is concluded that major errors in measurements of p-lactate, anion gap and pH can be prevented by placing test tubes on crushed ice for up to 4 h until measurement.

Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts.

Hematologic and immunologic functions were examined in 19 HIV-negative infants of HIV-positive mothers and 19 control infants of HIV-negative mothers. Control infants were selected to match for gestational age, weight, and mode of delivery. Cord blood was obtained from all infants and used for flow cytometric determination of lymphocyte subsets, including the naive CD4 count. Furthermore, to determine thymic output, cord blood mononuclear cells were used for determination of T-cell receptor excision circles (TRECs). Evaluation of progenitor cell function was done by means of colony-forming cell assay and fetal thymic organ cultures (FTOCs). Lower naive CD4 counts (459.3 +/- 68.9 vs 1128.9 +/- 146.8 cells/microL, P <.001) and reduced thymic output in infants of HIV-positive mothers were found (frequency of CD4(+) cells with TRECs was 3.6% +/- 0.7% compared with 14.3% +/- 2.2% in controls, P <.001). In combination with lower red blood cell counts in infants of HIV-positive mothers, this finding suggested impairment of progenitor cell function. Indeed, progenitors from infants of HIV-positive mothers had decreased cloning efficiency (15.7% +/- 2.6% vs 55.8% +/- 15.9%, P =.009) and seemed to generate fewer T cells in FTOCs. In conclusion, lower numbers of naive CD4(+) cells and reduced thymic output in HIV-negative infants of HIV-positive mothers may be due to impaired progenitor cell function.