A randomised comparison of safety and efficacy of nevirapine vs. atazanavir/ritonavir combined with tenofovir/emtricitabine in treatment-naïve patients

Background: We report data from NEWART, a randomised phase 4 clinical trial comparing virologic efficacy and safety of nevirapine (NVP) vs. ritonavir‐boosted atazanavir (ATV/r) on a background of tenofovir/emtricitabine (TDF/FTC) in HIV‐1‐infected treatment‐naïve patients. This study enrolled patients according to CD4‐based initiation criteria for NVP (<250 cells/mm³ for women and <400 cells/mm³ for men), to reduce the likelihood of symptomatic hepatic events. NEWART was designed to support and confirm results from ARTEN, an international trial with similar design and study endpoints. Methods: A total of 152 patients were randomised 1 : 1 to open‐label NVP 200 mg twice daily or ATV/r (300/100 mg) once daily, plus once daily TDF/FTC (300/200 mg). All participants met CD4⁺ guidelines at entry. The primary endpoint for non‐inferiority was virologic response prior to and at week 48 (confirmed HIV plasma viral load <50 copies/ml, without rebound or change in ARVs). Safety data, including plasma lipids, were recorded throughout the study. Results: The primary endpoint was achieved in 46/75 (61.3%) and 50/77 (64.9%) of patients taking NVP and ATV/r, respectively. Frequency of adverse events (AEs) was similar between arms, with 88.0% of NVP‐treated patients and 94.8% of ATV/r‐treated patients experiencing at least one AE. Nine patients (12%) in each arm experienced an AE that led to discontinuation. At week 48, a significantly greater increase was seen in mean plasma HDL cholesterol (HDL‐C) in the NVP arm (9.6 mg/dl) vs. the ATV/r arm (3.5 mg/dl); p = 0.016. Also, total cholesterol (TC):HDL‐C ratio on‐treatment was ?0.38 and ?0.02 for the NVP and ATV/r arms, respectively (p = 0.038). Conclusions: Efficacy results were consistent with the ARTEN study demonstrating that NVP was non‐inferior to ATV/r when taken in combination with TDF/FTC. Rates of AEs were similar between the two arms, whereas HDL‐C increased and TC:HDL‐C decreased significantly more in patients taking NVP than ATV/r.     

Headache among patients with HIV disease: prevalence, characteristics, and associations

Background.— Headache is one of the most common medical complaints reported by individuals suffering from human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), but limited and conflicting data exist regarding their prevalence, prototypical characteristics, and relationship to HIV disease variables in the current era of highly active antiretroviral therapy (HAART). Objectives.— The aims of the present cross‐sectional study were to characterize headache symptoms among patients with HIV/AIDS and to assess relations between headache and HIV/AIDS disease variables. Methods.— Two hundred HIV/AIDS patients (49% female; mean age = 43.22 ± 12.30 years; 74% African American) from an internal medicine clinic and an AIDS outreach clinic were administered a structured headache diagnostic interview to assess headache characteristics and features consistent with International Classification of Headache Disorders (ICHD)‐II diagnostic semiologies. They also completed 2 measures of headache‐related disability. Prescribed medications, most recent cluster of differentiation (CD4) cell count, date of HIV diagnosis, possible causes of secondary headache, and other relevant medical history were obtained via review of patient medical records. Results.— One hundred seven patients (53.5%) reported headache symptoms, the large majority of which were consistent with characteristics of primary headache disorders after excluding 4 cases attributable to secondary causes. Among those who met criteria for a primary headache disorder, 88 (85.44%) met criteria for migraine, most of which fulfilled ICHD‐II appendix diagnostic criteria for chronic migraine. Fifteen patients (14.56%) met criteria for episodic or chronic tension‐type headache. Severity of HIV (as indicated by CD4 cell counts), but not duration of HIV or number of prescribed antiretroviral medications, was strongly associated with headache severity, frequency, and disability and also distinguished migraine from TTH. Conclusions.— Problematic headache is highly prevalent among patients with HIV/AIDS, most of which conform to the semiology of chronic migraine, although with some atypical features such as bilateral location and pressing/tightening quality. A low frequency of identifiable secondary causes is likely attributable to reduced frequency of opportunistic infections in the current era of HAART. Disease severity is strongly predictive of headache, highlighting the importance of physician attention to headache symptoms and of patient adherence to treatment. (Headache 2012;52:455‐466)     

受血患者输血前血清感染性指标的检测与分析

目的对受血患者输血前血清感染性指标进行检测与分析。方法选取2012年6月至2015年4月该院收治的5 790例拟进行输血治疗的患者,患者受血前进行常见传染性指标[乙型肝炎表面抗原(HBsAg)、抗丙型肝炎病毒抗体(抗-HCV)、抗人类免疫缺陷病毒抗体(抗-HIV)以及抗梅毒螺旋体抗体(抗-TP)]的检测。计算5 790例受血患者输血前各项感染性指标的阳性率、不同科室患者各项感染性指标的阳性率以及不同性别患者感染性指标的阳性率。结果HBsAg的阳性率最高,为18.2%;抗-HIV的阳性率最低,仅为0.26%;HBsAg与抗-HIV在妇产科中的阳性率最高,抗-HCV与抗-TP的阳性率在各科室中基本一致。男性受血者输血前HBsAg、抗-HCV、抗-HIV以及抗-TP的阳性率都高于女性受血者,差异有统计学意义(Ps0.05)。结论对受血患者进行血清感染性指标的检测非常有必要,能够有效阻断肝炎、艾滋病以及梅毒等血液传染性疾病的传播,保护广大受血者和医务工作者。     

HIV‐1 Tat‐induced platelet activation and release of CD154 contribute to HIV‐1‐associated autoimmune thrombocytopenia

Summary. Background: Enhanced platelet activation in human immunodeficiency virus (HIV)‐1‐infected patients has been reported and shown to strongly correlate with plasma viral load. Activated platelets are known to express and to release a variety of proteins that can modulate the immune system. Specifically, platelet‐derived CD154 has been shown to be directly involved in the development of autoimmune thrombocytopenia (ITP). The mechanism by which HIV‐1 infection leads to platelet activation and the effect of this activation on the development of HIV‐1 ITP, however, is not fully understood. Objective: We have investigated the effect of HIV‐1 Trans activating factor (Tat) on platelet activation. Results: We report that HIV‐1 Tat directly interacts with platelets and induces platelet activation resulting in platelet micro‐particle release. This activation by Tat requires the chemokine receptor CCR3 and β3‐integrin expression on platelets, as well as calcium flux. Tat‐induced activation of platelets releases platelet CD154, an immune modulator. Enhanced B‐cell activity is found in mouse spleen B cells co‐cultured with platelets treated with Tat in vitro. An early antibody response against adenovirus is found in Tat‐injected mouse immunized with adenovirus, suggesting an enhanced immune response in vivo. Conclusions: We have described a role of Tat‐induced platelet activation in the modulation of the immune system, with implications for the development of HIV‐1‐associated thrombocytopenia.     

Myocardial injury in HIV‐associated thrombotic thrombocytopenic purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) has been associated with human immunodeficiency virus (HIV) infection. With the high prevalence of HIV in sub‐Saharan Africa, HIV‐associated TTP is the most common form of this disease seen in the South African population. Several case reports describe myocardial infarction in HIV‐negative TTP patients. The case of the first HIV‐positive patient who presented with clinical signs and symptoms of TTP and myocardial injury is reported in this study. A patient with fragmentation haemolysis and thrombocytopenia presented with angina. Risk factors for ischaemic heart disease were absent. An electrocardiogram (EKG) revealed ST‐segment elevation and a significantly raised Troponin T level. The patient's HIV test was positive and a diagnosis of myocardial injury with HIV‐associated TTP was made. The patient was treated with plasma infusion and steroid therapy. Due to poor response, the therapy was changed to plasma exchange. The patient recovered fully and subsequent coronary angiography revealed normal coronary vessels. Treatment of myocardial infarction in TTP is controversial, but the treatment cornerstone should remain plasma infusion or plasma exchange. As patients are often young and do not have the classical risk factors of ischaemic heart disease, a high level of suspicion and routine exclusion of myocardial ischaemia in these patients are advised.     

Antiviral therapy for chronic hepatitis C in patients with inherited bleeding disorders: an international, multicenter cohort study

Summary. Background: Hepatitis C is a major co‐morbidity in patients with hemophilia. However, there is little information on the efficacy of antiviral therapy and long‐term follow‐up after treatment.Objectives: To assess the effect of interferon‐based (IFN‐based) therapy on hepatitis C virus (HCV) eradication, to identify determinants associated with treatment response, and to assess the occurrence of end‐stage liver disease (ESLD) after completing antiviral therapy.Patients and methods: In a multicenter cohort study, 295 treatment‐naïve hemophilia patients chronically infected with HCV were included. The effect of therapy was expressed as sustained virological response (SVR). Determinants associated with treatment response were expressed as odds ratios (ORs). Cumulative incidence of ESLD was assessed using a Kaplan–Meier survival table.Results: Among human immunodeficiency virus (HIV) negative patients (n = 235), SVR was 29% (29/101) for IFN monotherapy, 44% (32/72) for IFN with ribavirin, and 63% (39/62) for pegylated IFN (PegIFN) with ribavirin. In patients co‐infected with HIV (n = 60), IFN monotherapy, IFN with ribavirin, and PegIFN with ribavirin eradicated HCV in 7/35 (20%), 1/2 (50%), and 11/23 (48%), respectively. SVR increased with genotype 2 and 3 [OR 11.0, 95% CI: 5.8–20.5], and combination therapy (IFN and ribavirin OR 3.7, 95% CI: 1.7–8.4), PegIFN and ribavirin (OR 4.2, 95% CI: 1.8–9.5). Up to 15 years after antiviral treatment, none of the patients with a SVR relapsed and none developed ESLD. In contrast, among unsuccessfully treated patients the cumulative incidence of ESLD after 15 years was 13.0%.Conclusions: Successful antiviral therapy appears to have a durable effect and reduces the risk of ESLD considerably.     

Concentrations of tenofovir and emtricitabine in saliva: implications for preexposure prophylaxis of oral HIV acquisition

To prevent acquisition of HIV through oral sex, drugs used for preexposure prophylaxis (Prep) need to diffuse in saliva. We measured tenofovir (TFV) and emtricitabine (FTC) concentrations simultaneously in the plasma and saliva of 41 HIV-infected patients under stable antiretroviral treatment. Mean ratios of saliva/plasma concentration were 3% (±4%) and 86.9% (±124%) for TFV and FTC, respectively. Tenofovir disoproxil fumarate (TDF) should be used in combination with FTC to prevent oral acquisition of HIV.     

Pharmacogenetic study of the effects of NK2R G231E G>A and TBX21 H33Q C>G polymorphisms on asthma control with inhaled corticosteroid treatment

Background and Objective: Inhaled corticosteroids (ICS) are widely used as maintenance regimens for asthma patients. However, response to ICS shows marked inter‐individual variability. Genetic factors have been shown to be potential predictors of responsiveness to ICS. We aimed to evaluate those pharmacogenetic effects on asthma control in further detail. Methods: Fifty‐three mild‐to‐moderate asthmatics were genotyped for four genetic polymorphisms of four genes: β2‐adrenergic receptor (ADRB2), adenylate cyclase 9 (ADCY9), neurokinin receptor 2 (NK2R) and T‐box 21 (TBX21). The principal clinical outcome was the achievement of asthma control, as assessed using the Global Initiative for Asthma (GINA) guidelines. During treatment with ICS, the forced expiratory volume in 1 second (FEV₁), maximal mid‐expiratory flow (MMEF) and peak expiratory flow rate (PEFR) were monitored every 4 weeks and twice daily. Results: Forty‐eight of the 53 patients with asthma were in a controlled or partly controlled state after 12 weeks of treatment with ICS, whereas five asthmatics were in an uncontrolled state even after active treatment. Of the four genetic polymorphisms examined, NK2R G231E G>A and TBX21 H33Q C>G were significantly associated with asthma control status (P = 0·041 and P = 0·006). The subjects with wild‐type alleles at each polymorphism showed a significant association with the well‐controlled or partly controlled state, as compared to those with mutant alleles. At 5–12 weeks after ICS treatment, the NK2R G231E G>A was associated with therapeutic response to ICS, as reflected by improvement in predicted FEV₁%. Conclusion: Our results suggest that NK2R G231E G>A and TBX21 H33Q C>G are genetic predictors of response to ICS, at least with respect to asthma control status and changes in FEV₁%, in Korean patients with asthma. Further prospective validation of those associations is necessary.     

HIV‐associated pulmonary arterial hypertension: from bedside to the future

Pulmonary arterial hypertension (PAH) is a life‐threatening complication of HIV infection. The prevalence of HIV‐associated PAH (HIV‐PAH) seems not to be changed over time, regardless of the introduction of highly active antiretroviral therapy (HAART). In comparison with the incidence of idiopathic PAH in the general population (1–2 per million), HIV‐infected patients have a 2500‐fold increased risk of developing PAH. HIV‐PAH treatment is similar to that for all PAH conditions and includes lifestyle changes, general treatments and specific treatments.     

Low back pain may be caused by disturbed pain regulation

Background: Widespread pain has negative influence on outcome in low back pain (LBP) patients. Tender point (TP) examination is a standardized examination method to estimate diffuse tenderness. Aims: To assess diffuse tenderness by means of a standardized TP examination and to analyse for associations between the number of TPs and spinal structural changes as well as psycho‐social factors. Methods: Patients sick‐listed 3–16 weeks due to LBP with or without sciatica completed a questionnaire and went through a clinical low back examination and TP examination. Of 326 patients 111 had verified nerve root affection and 215 had non‐specific LBP with or without radiating pain. Disc height reductions were estimated on lateral X‐rays. Results: Multivariate logistic regression analysis showed that more than 8 TPs were strongly negatively associated with disc degeneration (Odds Ratio (OR) 0.58 (0.40–84), 95% Confidence Interval (CI): 0.39–0.84, p = 0.004) and verified nerve root affection (OR 0.15 (0.04–0.54), p = 0.004) and were positively associated with number of years since first episode of LBP (OR 1.05, CI: 1.01–1.09, p = 0.009). Furthermore, more than 8 TPs were positively associated with widespread pain, female sex and bodily distress. With all patients included, bodily distress and the number of tender points were positively associated with the intensity of LBP, but disc degeneration was only positively associated with LBP in patients with less than 6 TPs. Conclusions: The pain in patients with diffuse tenderness was rarely related to disc degeneration or nerve root affection, rather it may be caused by disturbed pain regulation.     

One‐day treatment of small molecule 8‐bromo‐cyclic AMP analogue induces cell‐based VEGF production for in vitro angiogenesis and osteoblastic differentiation

Small molecule‐based regenerative engineering is emerging as a promising strategy for regenerating bone tissue. Small molecule cAMP analogues have been proposed as novel biofactors for bone repair and regeneration and, while promising, the effect that these small molecules have on angiogenesis, a critical requirement for successful bone regeneration, is still unclear. Our previous research demonstrated that the small molecule cAMP analogue 8‐bromoadenosine‐3′,5′‐cyclic monophosphate (8‐Br‐cAMP) was able to promote initial osteoblast adhesion on a polymeric scaffold via cAMP signalling cascades. Here, we report that 8‐Br‐cAMP is capable of inducing in vitro cell‐based VEGF production for angiogenesis promotion. We first demonstrated that treating osteoblast‐like MC3T3‐E1 cells with 8‐Br‐cAMP for 1 day significantly increased VEGF production and secretion. We then demonstrated that 8‐Br‐cAMP‐induced cell‐secreted VEGF is biologically active and may promote angiogenesis, as evidenced by increased human umbilical vein endothelial cells (HUVECs) migration and tubule formation. In addition, treatment of MC3T3‐E1 cells with 8‐Br‐cAMP for as short as a single day resulted in enhanced ALP activity as well as matrix mineralization, demonstrating in vitro osteoblastic differentiation. A short‐term 8‐Br‐cAMP treatment also addresses the concern of non‐specific cytotoxicity, as our data indicate that a 1‐day 8‐Br‐cAMP treatment scheme supports cellular proliferation of MC3T3‐E1 cells as well as HUVECs. While the major concern associated with small molecule drugs is the risk of non‐specific cytotoxicity, the short exposure treatment outlined in this paper provides a very promising strategy to mitigate the risk associated with small molecules. Copyright © 2013 John Wiley & Sons, Ltd.     

HIV/AIDS knowledge, attitudes, practices and perceptions of rural nurses in South Africa

Title. HIV/AIDS knowledge, attitudes, practices and perceptions of rural nurses in South Africa. Aim. This paper is a report of a study exploring HIV/AIDS‐related knowledge, attitudes, practices and perceptions of nurses in the largely black and rural Limpopo Province of South Africa. Background. Studies of HIV/AIDS knowledge, attitudes and practices among healthcare workers in developing countries have shown gaps in knowledge and fear of contagion, coupled with ambivalent attitudes in caring for patients with HIV/AIDS and inconsistent universal precautions adherence. Method. A cross‐sectional study of a random sample of primary health care (PHC) (n = 71) and hospital nurses (n = 69) was carried out in 2005, using a questionnaire, focus groups and in‐depth interviews. Findings. Hospital nurses reported a higher frequency of care for patients with HIV/AIDS (P < 0·05), but less HIV/AIDS training when compared to PHC nurses (P < 0·001). HIV/AIDS knowledge was moderately adequate and associated with professional rank, frequency of care and training (P < 0·001). Attitudes towards patients with HIV/AIDS were mainly positive and were statistically significantly correlated with HIV/AIDS knowledge (P < 0·01) and training (P < 0·05). Three out of four nurses reported that they practised universal precautions (76·1%), but fear of occupational HIV transmission and lack of injection safety was found. Seven in 10 nurses reported previous needlestick injuries, but postexposure prophylaxis was not available in all healthcare facilities. Participants reported a higher workload because of HIV/AIDS, lack of training impacting negatively on their work, and stigma and shared confidentiality affecting them emotionally. Conclusion. There is a need for accelerated HIV/AIDS training of rural nurses and for wider implementation of universal precautions and postexposure prophylaxis availability in public health facilities in southern Africa.     

The dual role of thymidine phosphorylase in cancer development and chemotherapy

Thymidine phosphorylase (TP), also known as “platelet‐derived endothelial cell growth factor” (PD‐ECGF), is an enzyme, which is upregulated in a wide variety of solid tumors including breast and colorectal cancers. TP promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis. Elevated levels of TP are associated with tumor aggressiveness and poor prognosis. Therefore, TP inhibitors are synthesized in an attempt to prevent tumor angiogenesis and metastasis. TP is also indispensable for the activation of the extensively used 5‐fluorouracil prodrug capecitabine, which is clinically used for the treatment of colon and breast cancer. Clinical trials that combine capecitabine with TP‐inducing therapies (such as taxanes or radiotherapy) suggest that increasing TP expression is an adequate strategy to enhance the antitumoral efficacy of capecitabine. Thus, TP plays a dual role in cancer development and therapy: on the one hand, TP inhibitors can abrogate the tumorigenic and metastatic properties of TP; on the other, TP activity is necessary for the activation of several chemotherapeutic drugs. This duality illustrates the complexity of the role of TP in tumor progression and in the clinical response to fluoropyrimidine‐based chemotherapy. © 2009 Wiley Periodicals, Inc. Med Res Rev, 29, No. 6, 903–953, 2009     

Controlled-release and local delivery of therapeutic antibodies

Introduction: As HIV continues to spread worldwide, new therapies which have the potential to treat and cure infected patients need to be developed. The results observed with the “Berlin patient” who received a bone marrow transplant with HIV-resistant hematopoietic stem cells highlight the potential of HIV gene therapy to be used as an alternative treatment. With the discovery of TRIM5α, an HIV inhibitor and species-specific restriction factor, a new molecule can be evaluated as an HIV gene therapeutic. Nonhuman primate TRIM5α orthologs restrict HIV infection, whereas human TRIM5α does not. However, upon genetic modification, variations to human TRIM5α have been made which are capable of potent HIV restriction.

Areas covered: This review seeks to cover the discovery and biology of various HIV-restrictive nonhuman primate TRIM5α orthologs, modifications made to human TRIM5α to enable HIV restriction, and the use of these molecules in an HIV gene therapy setting.

Expert opinion: Engineered human TRIM5α molecules, demonstrated to be strong inhibitors of HIV infection, have the potential of being used as new HIV therapeutics in human gene therapy clinical trials. By combining TRIM5α with other highly potent anti-HIV molecules, the generation of an HIV-resistant immune system and potential cure for infected patients may be accomplished.     

HIV nursing consultants: patients' preferences and experiences about the quality of care

Aim and objectives. We were interested to find out how human immunodeficiency virus (HIV)‐patients judge the quality of care received from their HIV nursing consultants, compared with the care delivered by HIV specialists and general practitioners. Furthermore, we were interested in how the opinions of HIV patients on the HIV nursing consultant compared with the opinions of patients with rheumatic diseases on the care they receive from their specialized nurses. Background. The role of nurses has changed over the years. For patients with chronic diseases there seems to be an increasing role for nursing consultants in the delivery of care. In evaluating quality of care, patients’ views are considered important especially for the chronically ill who can be seen as experts by experience. Methods. Between February 1999 and June 2000, 250 patients, receiving care from both general practitioner and specialist, received a questionnaire [Quality of Care Through the Patient's Eyes (QUOTE)‐HIV] to assess HIV‐related quality of care, as perceived by them. Aspects were formulated as ‘importance’ and ‘performance’ statements. Items were scored on 4‐point scales. A ratio score (R_ij = P_ij/I_ij) was calculated by dividing the perceived performance score (P) of an individual patient (i), on a health service (j) by his importance score (I). A comparison was made with patients with rheumatic diseases by using data from the QUOTE‐Rheuma. Results. Patients judged the quality of care from the HIV nursing consultant as predominantly good. Five aspects showed an unfavourable ratio score (R < 1.0) which indicates room for improvement. On the dimensions ‘professional performance’ and ‘attitude of the professional’ the HIV nursing consultant scores between the general practitioner and the HIV specialist. Patients with rheumatic diseases seemed to be more satisfied than HIV patients with the care from their nurse consultant. Conclusions. The HIV nursing consultants have an important role in the care of patients infected with HIV. The HIV nursing consultants are judged as good and are ranked in between the general practitioner and the HIV specialist. Given the orientation towards a more integrated care for chronically ill patients, there should be more attention paid to the position of the HIV nursing consultant. Relevance to clinical practice. In the Netherlands and in the United Kingdom there is a tendency to a greater degree of differentiation of tasks in health care. This study shows that there is room for a position like the nursing consultant and that this is highly valued by patients.     

Cytogenetic and molecular genetic studies of follicular and papillary thyroid cancers.

Cytogenetic studies have shown frequent clonal abnormalities in papillary carcinoma (PTC) and follicular carcinoma (FTC). Loss of heterozygosity (LOH) may suggest the presence of tumor suppressor genes and has not been reported in these neoplasms. These studies were undertaken to determine if consistent chromosomal abnormalities are associated with thyroid cancer, to determine likely regions for molecular genetic investigations, and to determine if there is allelic loss in thyroid tumors. Cytogenetic analysis of 26 PTC and 5 FTC showed clonal abnormalities in 9 and included -Y, +5, or inv(10)(q11.2q21.2) in PTC, and -Y or near haploidy in FTC. Using DNA probes specific for chromosomes 1, 3, 10, 16, and 17, we carried out restriction fragment length polymorphism analysis on 6 FTC, 3 follicular adenomas (FA), and 12 PTC. LOH of all informative loci on chromosome 3p was observed in all 6 FTC, but not in FA or PTC. No LOH was observed for loci mapped to chromosome 10 in PTC. Our results suggest: cytogenetic abnormalities of chromosome 10q are associated with PTC; cytogenetic and molecular abnormalities of chromosome 3 are associated with FTC; and a tumor suppressor gene may be present on the short arm of chromosome 3 important for the development or progression of FTC.