A disintegrin and metalloprotease (ADAM) 33 protein in patients with pulmonary sarcoidosis

Background and objective: A disintegrin and metalloproteinase (ADAM) 33 is a susceptibility gene associated with inflammatory lung and skin diseases. It is selectively expressed in mesenchymal cells, and its metalloprotease activity has been linked to angiogenesis and tissue remodelling. A soluble form of ADAM33 (sADAM33) has been identified in the bronchoalveolar lavage fluid (BALF) of asthmatic patients, and its levels inversely correlate with lung function. Because of its association with inflammatory lung diseases, it was hypothesized that sADAM33 is elevated in BALF of patients with pulmonary sarcoidosis. Methods: After removal of Ig using Protein A/G and enrichment using Concanavalin A beads, sADAM33 was identified in BALF by Western blotting. A fluorescence resonance energy transfer peptide cleavage assay was used to assess ADAM33‐like activity in BALF. Results: sADAM33 protein in BALF was detected as a 25 kDa fragment, and levels were significantly increased in samples from sarcoid patients when compared to healthy controls (P < 0.05). Levels of sADAM33 were inversely correlated with lung function (FVC%) (P < 0.05) and DL_CO % predicted (P < 0.01). No difference in sADAM33 enzymatic activity was observed between healthy and sarcoid BALF samples. Conclusions: Release of sADAM33 is increased in sarcoid and may be associated with abnormal lung function. sADAM33 may be a biomarker of lung tissue inflammation and remodelling in sarcoid.     

Poxvirus vaccines for cancer and HIV therapy

The poxviridae have a long history of causing disease in society, and their biological effects in humans and other mammals have been extensively studied. In the 1980s, genetic engineering techniques were applied to vaccinia in order to create replicating recombinant vectors that could express inserted genes encoding influenza virus proteins. In animal models, these recombinant viruses were able to deliver their foreign antigens to the immune system and elicit a specific adaptive immune response. Since then, improvements in our understanding of immunobiology, as well as technical advances in bioengineering, have led to the creation and clinical testing of a large number of recombinant poxviruses as candidate vaccines. Poxviruses can infect a broad range of cells, replicate with high efficiency and elicit strong immune responses - factors that make them especially well-suited as vaccines for the prevention and treatment of human immunodeficiency virus (HIV) and cancer. Both of these diseases are characterised by chronic antigen expression in the setting of focal or global deficits in the immune system that hamper the generation of protective immunity. This review traces the history of poxviruses as pathogens and immunogens, examines some of the approaches that have been taken to design poxviral vaccines for HIV and cancer and summarises the results of existing clinical trials of these vectors. In addition, the review aims to identify some of the factors that may shape the development of future therapies based on recombinant poxviruses.     

Determinants of HIV drug resistance and public health implications in low- and middle-income countries

Global scale-up of antiretroviral therapy (ART) in low- and middle-income countries (LMICs) is an unprecedented public health achievement. With planned efforts of expanded ART access including earlier treatment initiation and the use of antiretroviral (ARV) drugs for prophylaxis, increasing levels of HIV drug resistance (HIVDR) are expected.Several factors may lead to selection and transmission of significant HIVDR in LMICs, which will lead to decreased population-level efficacy of standard first- and second-line ART regimens. These factors include low genetic barrier of some ARVs to resistance development, drug-drug interactions, inappropriate prescribing practices, interruption of drug supply, poor retention in care and lack of routine viral load monitoring.To maximize long-term effectiveness of available ARVs, policy makers and programme managers in LMICs should routinely monitor programme factors associated with emergence and transmission of HIVDR and implement routine HIVDR surveillance following standardized methods. When surveillance results suggest the need for action, specific public health interventions must be taken to adjust ART programme functioning to minimize further emergence and transmission of HIVDR.In this paper, we review ARV drug, HIV, patient and programme-related determinants of HIVDR. Additionally, we summarize the World Health Orgnization's global HIVDR surveillance and prevention strategy and describe resulting public health and policy implications.     

Optimizing HIV retesting during pregnancy and postpartum in four countries: a cost‐effectiveness analysis

IntroductionHIV retesting during late pregnancy and breastfeeding can help detect new maternal infections and prevent mother‐to‐child HIV transmission (MTCT), but the optimal timing and cost‐effectiveness of maternal retesting remain uncertain.MethodsWe constructed deterministic models to assess the health and economic impact of maternal HIV retesting on a hypothetical population of pregnant women, following initial testing in pregnancy, on MTCT in four countries: South Africa and Kenya (high/intermediate HIV prevalence), and Colombia and Ukraine (low HIV prevalence). We evaluated six scenarios with varying retesting frequencies from late in antenatal care (ANC) through nine months postpartum. We compared strategies using incremental cost‐effectiveness ratios (ICERs) over a 20‐year time horizon using country‐specific thresholds.ResultsWe found maternal retesting once in late ANC with catch‐up testing through six weeks postpartum was cost‐effective in Kenya (ICER = $166 per DALY averted) and South Africa (ICER=$289 per DALY averted). This strategy prevented 19% (Kenya) and 12% (South Africa) of infant HIV infections. Adding one or two additional retests postpartum provided smaller benefits (1 to 2 percentage point increase in infections averted versus one retest). Adding three retests during the postpartum period averted additional infections (1 to 3 percentage point increase in infections averted versus one retest) but ICERs ($7639 and in Kenya and $11 985 in South Africa) greatly exceeded the cost‐effectiveness thresholds. In Colombia and Ukraine, all retesting strategies exceeded the cost‐effectiveness threshold and prevented few infant infections (up to 31 and 5 infections, respectively).ConclusionsIn high HIV burden settings with MTCT rates similar to those seen in Kenya and South Africa, HIV retesting once in late ANC, with subsequent intervention, is the most cost‐effective strategy for preventing infant HIV infections. In these settings, two HIV retests postpartum marginally reduced MTCT and were less costly than adding three retests. Retesting in low‐burden settings with MTCT rates similar to Colombia and Ukraine was not cost‐effective at any time point due to very low HIV prevalence and limited breastfeeding.     

Optimizing antiretroviral product selection: a sample approach to improving patient outcomes, saving money, and scaling-up health services in developing countries

Over the last decade, increased funding to support HIV treatment programs has enabled millions of new patients in developing countries to access the medications they need. Today, although demand for antiretrovirals continues to grow, the financial crisis has severely constrained funding leaving countries with difficult choices on program prioritization. Product optimization is one solution countries can pursue to continue to improve patient care while also uncovering savings that can be used for further scale up or other health system needs. Program managers can make procurement decisions that actually reduce program costs by considering additional factors beyond World Health Organization guidelines when making procurement decisions. These include in-country product availability, convenience, price, and logistics such as supply chain implications and laboratory testing requirements. Three immediate product selection opportunities in the HIV space include using boosted atazanavir in place of lopinovir for second-line therapy, lamivudine instead of emtricitabine in both first-line and second-line therapy, and tenofovir + lamivudine over abacavir + didanosine in second-line therapy. If these 3 opportunities were broadly implemented in sub-Saharan Africa and India today, approximately $300 million of savings would be realized over the next 5 years, enabling hundreds of thousands of additional patients to be treated. Although the discussion herein is specific to antriretrovirals, the principles of product selection are generalizable to diseases with multiple treatment options and fungible commodity procurement. Identifying and implementing approaches to overcome health system inefficiencies will help sustain and may expand quality care in resource-limited settings.