Immunization in patients with HIV infection: are practical recommendations possible?

The purpose of this article is to review immunization recommendations for HIV-infected individuals in resource-constrained countries, particularly in sub-Saharan Africa. Recent evidence suggests that HIV-infected children are at risk for low immunization coverage in sub-Saharan Africa. Routine immunization is recommended for these children. In comparison with immunocompetent children, recommendations for live-attenuated vaccines differ in HIV-infected children. However, limited laboratory capacity to diagnose HIV infection amongst young children prevents the implementation of these HIV-specific guidelines in resource-constrained countries. Re-immunization has been the focus of recent research in high- and middle-income countries. Findings show that children established on highly active antiretroviral therapy have suboptimal vaccine-specific immunity and may benefit from re-immunization. Before re-immunization guidelines can be formulated for resource-constrained countries, several questions should be addressed, including whether all HIV-infected children will benefit from routine re-immunization and what optimal number of vaccine doses should be administered. Pneumococcal and influenza infections are important causes of morbidity and mortality amongst HIV-infected individuals. There is compelling evidence showing that pneumococcal conjugate vaccines will protect HIV-infected and uninfected children against invasive infection. Pneumococcal conjugate vaccines should be prioritized for introduction in countries with high HIV prevalence. Although, annual influenza immunization is recommended for HIV-infected individuals, the effectiveness in Africa remains unclear.In conclusion, this brief overview has identified several limitations of current immunization policy and practice for HIV-infected individuals living in resource-constrained countries.     

Treatment of transplant rejection: are the traditional immunosuppressants good enough?

Due to the improvement in the understanding of the anti-allogenic immune response, the success of transplantation medicine has increased rapidly over the last two decades. The knowledge that the T-lymphocyte played an integral role in transplant rejection, brought cyclosporine A and FK-506 to the fore as therapeutic immunosuppressants. However, the current mainstays in transplant rejection are not without their problems and many drug companies are exploring the possibilities of improving the available therapies by developing drugs with reduced toxicity, improved long-term survival and efficacy against chronic rejection and improved immunosuppressive selectivity. The advances in the understanding of T-cell activation and lymphocyte trafficking has highlighted ways to improve the existing therapies and more selective immunosuppressant targets.     

Combination chemotherapy for hepatitis B virus: the path forward?

Hepatitis B virus (HBV) was identified as a cause of viral hepatitis more than 30 years ago and hepatitis B vaccines have been available for almost 20 years, but HBV infection continues to be a global health problem, responsible for about 1.2 million deaths annually. By the end of this year, almost 400 million people--about 5% of the world's population and more than ten times the number infected with human immunodeficiency virus (HIV)--will be infected with HBV. Chemotherapy remains the only treatment option for controlling chronic HBV infection once acquired, but none of the many different chemotherapeutic strategies used in the past has proven consistently successful. Prospects for successful treatment of HBV have improved dramatically during the past decade due to the development of new, well tolerated and efficacious anti-HBV drugs, and to advances in our understanding of HBV replication and pathogenesis. The newer anti-HBV drugs are capable of reducing viral loads very rapidly, but the initial response is invariably followed by very much slower elimination of residual virus. As more effective anti-HBV drugs become available, the emergence of drug resistance during the slower phase of HBV elimination will probably become the most significant obstacle in the way of eventual control of HBV infection. Experience with HIV indicates that combination chemotherapy may suppress or eliminate drug resistance and methods for pre-clinical and clinical assessment of anti-HBV drug combinations are being developed. Basic research into mechanisms of drug action and interaction should assist in the design and optimisation of combination chemotherapy for HBV infection, for which additional new anti-HBV drugs will undoubtedly be required in future.     

Hepatic and peripheral T-lymphocyte patterns in patients with chronic hepatitis C infection: what correlation with histological activity?

The immunopathological processes involved in hepatic damage during chronic hepatitis C infection are not fully understood. Several works suggest the role of T helper 1 (Th1) immune response in both injury and fibrinogenesis. in this study, we have analyzed peripheral and intrahepatic T-lymphocyte subsets in liver biopsy specimens of 13 patients with definite chronic hepatitis C (CHC) to explore the possible direct role of these patterns in the evolution of necrotic inflammation and fibrogenesis scored according to the Knodell histological activity index. in particular, we have studied CD4+/CD7+ T-lymphocytes, as phenotypic marker of Th1 immune response, CD4+/CD7- as Th2 marker, and CD8+/CD38 as activated CD8+ lymphocytes. on statistical analyses we found a significant negative correlation in liver CD8+/CD38+ T-cells grading (r= -0.607; p<0.05) and staging index (r= -0.650; p<0.05) and between CD4+/CD7+ and grading (r= -0.626; p<0.05) index. in addition, we found a positive strong correlation between CD38+/CD8+ and CD4+/CD7+ T cells (r= 0.783; p<0.05) in liver tissue and between peripheral and liver resident CD8+/CD38+ (r= 683; p<0.05). moreover, the hepatic CD4+/CD7+ T-cells showed a positive correlation with peripheral CD 8+/CD38+ T-cells (r= 0.676; p<0.05). A strong positive correlation was also observed between grading and staging index (r= 0.921; p<0.01). we found no statistical correlation between the above variables and CD4+/CD7- T cells. our data could suggest that a preferential hepatic CD4+/CD7+ OR CD8+/CD38+ T cell subset was not directly associated with hepatic damage but, on the contrary, it could have been able to block liver injury. Concerning the peripheral subsets, the only CD8+/CD 38+ T-cells result reflect the CTL activity in the liver tissue. further studies are required to better understand the possible correlation between peripheral and liver resident T-helper, subset and other hepatic resident immunocompetent cells.     

Systematic review: are antibiotics detrimental or beneficial for the treatment of patients with Escherichia coli O157:H7 infection?

BACKGROUND: Escherichia coli O157:H7 is a foodborne pathogen causing haemorrhagic colitis, which is sometimes complicated by haemolytic uraemic syndrome or thrombotic thrombocytopenic purpura. AIM: To review the available evidence regarding the question of whether antibiotics are effective or harmful for the treatment of patients infected with E. coli O157:H7 infection. METHODS: We searched in the PubMed for relevant laboratory and clinical studies published between 1982 and 2005. RESULTS: In vitro studies have shown that most E. coli O157:H7 isolates are susceptible to various antibiotics, although certain antibiotics, especially at sublethal concentrations, have been found to increase the release of Shiga-like toxins, which have been associated with the development of haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura in humans. No clinical studies have indicated that antibiotics are effective in reducing the duration of E. coli O157:H7 infection or the duration of diarrhoea or bloody diarrhoea specifically, while a few studies have supported that some antibiotics, especially quinolones and fosfomycin, may prevent the development of haemolytic uraemic syndrome or thrombotic thrombocytopenic purpura. On the other hand, there are some clinical studies that associate antibiotics with a higher risk for haemolytic uraemic syndrome and/or longer duration of diarrhoea, even with high mortality. CONCLUSIONS: More randomized controlled trials are necessary in order to elucidate whether antibiotics are effective in reducing the morbidity and mortality of E. coli O157:H7 infection, rather than having a detrimental effect.     

Antiviral treatment for human immunodeficiency virus patients co-infected with hepatitis B virus: combined effect for both infections, an obtainable goal?

A large percentage of human immunodeficiency virus (HIV) patients have serological evidence of a past or present hepatitis B virus infection (HBV). Long-term survival is increasing for HIV patients because of highly active antiretroviral therapy. Therefore, the chronic hepatitis B infection may become an important determinant of disease outcome in these co-infected patients. We describe two HIV/HBV co-infected patients who were treated with extended antiviral therapy, initially indicated for the HIV infection. Lamivudine, a suppressor of viral replication in both infections, was one of these antiviral drugs. One patient showed a severe rebound of the HBV after withdrawal of lamivudine, the other patient developed a mutant hepatitis B virus after 18 months of treatment. This mutation was exclusively induced by lamivudine. These patients show that, with improved HIV-related survival, the HBV infection should be monitored carefully, thereby enabling the physician to interfere with therapy when necessary.     

Methotrexate intolerance in elderly patients with rheumatoid arthritis: what are the alternatives?

Rheumatoid arthritis (RA) in the elderly may be mild or severe, with features that are similar to those seen in younger patients. As such, the treatment regimen in the elderly is almost the same as in younger patients. Methotrexate is the most popular disease-modifying antirheumatic drug (DMARD) for the treatment of RA in the US and Europe. It has excellent efficacy and an acceptable toxicity profile. However, a number of patients do not tolerate methotrexate and an alternative DMARD should be chosen.In the elderly, choice of an alternative DMARD should be made after careful consideration of several age-related factors including concomitant diseases, existing medication, drug compliance, and altered age-related physiology and pharmacokinetics.In elderly patients with RA who are unable to tolerate methotrexate, the alternatives are hydroxychloroquine or sulfasalazine for mild-to-moderate disease and cyclosporin or leflunomide for severe disease, given in combination with low-dose oral corticosteroids. This is primarily due to their efficacy combined with a relatively low toxicity profile compared with other DMARDs, such as gold compounds, penicillamine, azathioprine and alkylating agents. Where the above DMARDs are contraindicated, anticytokine therapy should be considered.The therapy of RA is a dynamic process and requires a delicate balance of benefits and risks. Experience and familiarity with the currently available agents, and knowledge of the nature of the disease are necessary in order to make better therapeutic decisions.     

Treatment of patients with serious infections due to carbapenem-resistant Acinetobacter baumannii: How viable are the current options?

This review critically appraises the published microbiologic and clinical data on the treatment of patients with carbapenem-resistant Acinetobacter baumannii infections. Despite being recognized as an urgent threat pathogen by the CDC and WHO, optimal treatment of patients with serious CRAB infections remains ill-defined. Few commercially available agents exhibit reliable in vitro activity against CRAB. Historically, polymyxins have been the most active agents in vitro, though interpretations of susceptibility data are difficult given issues surrounding MIC testing methodologies and lack of correlation between MICs and clinical outcomes. Most available preclinical and clinical data involve use of polymyxins, tetracyclines, and sulbactam, alone and in combination. As the number of viable treatment options is limited, combination therapy with a polymyxin is often used for patients with CRAB infections, despite the significant risk of nephrotoxicity. However, no treatment regimen has been found to reduce mortality, which exceeds 40% across most studies, or substantially improve clinical response. While some newer agents, such as eravacycline and cefiderocol, have demonstrated in vitro activity, clinical efficacy has not been fully established. New agents with clinically relevant activity against CRAB isolates and favorable toxicity profiles are sorely needed.     

COX-2 expression in atherosclerosis: the good, the bad or the ugly?

Cyclooxygenase (COX) is the rate limiting enzyme catalyzing the conversion of arachidonic acid into prostanoids, lipid mediators critically implicated in a variety of physiological and pathophysiological processes, including inflammation, vascular and renal homeostasis, and immune responses. Since the early 1990s it has been appreciated that two isoforms of COX exist, referred to as COX-1 and COX-2. Although structurally homologous, COX-1 and COX-2 are regulated by two independent and quite different systems and have different functional roles. In the setting of acute ischemic syndromes it has been recognized that COX pathway plays an important role; however, whereas the function of platelet COX-1 in acute ischemic diseases is firmly established, the role of COX-2 in atherothrombosis remains controversial. The complex role of COX-2 in this setting is also confirmed by the unexpected cardiovascular side effects of long-term treatment with COX-2 inhibitors. In this article, we review the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque vulnerability, the effects of the variable expression of upstream and downstream enzymes in the prostanoid biosynthesis on COX-2 expression and inhibition.     

A systematic review of economic evaluation literature in Thailand: are the data good enough to be used by policy-makers?

In many countries, including Thailand, there is an increasing impetus to use economic evaluation to allow more explicit and transparent healthcare priority setting. However, an important question for policy makers in low- and middle-income countries is whether it is appropriate and feasible to introduce economic evaluation data into healthcare priority-setting decisions. In addition to ethical, social and political issues, information supply challenges need to be addressed. This paper systematically reviewed the literature on economic evaluation of health technology in Thailand published between 1982 and 2005. Its aim was to analyse the quantity, quality and targeting of economic evaluation studies that can provide a framework for those conducting similar reviews in other settings. The review revealed that, although the number of publications reporting economic evaluations has increased significantly in recent years, serious attention needs to be given to the quality of reporting and analysis. Furthermore, there is an absence of economic evaluation publications for 15 of the top 20 major health problems in Thailand, indicating a poor distribution of research resources towards the determination of cost-effective interventions for diminishing the disease burden of certain major health problems. If economic evaluation is only useful for policy makers when performed correctly and reported accurately, these findings depict information barriers to using economic evaluation to assist health decision-making processes in Thailand.     

Sphingolipid signalling in the cardiovascular system: good, bad or both?

Sphingolipids are biologically active lipids that play important roles in various cellular processes and the sphingomyelin metabolites ceramide, sphingosine and sphingosine-1-phosphate can act as signalling molecules in most cell types. With the recent development of the immunosuppressant drug FTY720 (Fingolimod) which after phosphorylation in vivo acts as a sphingosine-1-phosphate receptor agonist, research on the role of sphingolipids in the immune and other organ systems was triggered enormously. Since it was reported that FTY720 induced a modest, but significant transient decrease in heart rate in animals and humans, the question was raised which pharmacological properties of drugs targeting sphingolipid signalling will affect cardiovascular function in vivo. The answer to this question will most likely also indicate what type of drug could be used to treat cardiovascular disease. The latter is becoming increasingly important because of the increasing population carrying characteristics of the metabolic syndrome. This syndrome is, amongst others, characterized by obesity, hypertension, atherosclerosis and diabetes. As such, individuals with this syndrome are at increased risk of heart disease. Now numerous studies have investigated sphingolipid effects in the cardiovascular system, can we speculate whether certain sphingolipids under specific conditions are good, bad or maybe both? In this review we will give a brief overview of the pathophysiological role of sphingolipids in cardiovascular disease. In addition, we will try to answer how drugs that target sphingolipid signalling will potentially influence cardiovascular function and whether these drugs would be useful to treat cardiovascular disease.