Evaluation of a pro-active strategy for managing tuberculosis-HIV co-infection in a UK tertiary care setting.

Management of tuberculosis (TB)-HIV co-infection is complicated by interactions between the diseases and their therapies. We developed and evaluated a strategy to (i) treat co-infected patients in a single co-infection clinic, (ii) maximize use of first-line drugs, (iii) delay antiretroviral therapy (ART) until two months post-TB treatment except in severe immunosuppression, (iv) commence efavirenz at 600 mg daily with therapeutic drug monitoring (TDM) and (v) target treatment completion. We conducted a prospective cohort review over 5.5 years in a UK tertiary referral center where 56 HIV-positive patients treated for TB were followed-up for a median 30 months. Main outcome measures were treatment completion, adverse events, immune reconstitution inflammatory syndrome, immunological and virological parameters, and TDM for efavirenz. Treatment completion rates were 88% (49/56); four patients were lost to local follow-up and three (5.4%) died during treatment; no deaths were TB-related. Adverse events were common (55%), but caused no treatment interruptions. Standard doses (600 mg daily) of efavirenz with rifampicin achieved or exceeded therapeutic levels in 25/28 (89%). This study supports combined management for TB-HIV co-infected patients. Delaying ART to two months post-TB treatment did not seem to result in poor clinical outcomes in this well-resourced context. Although efavirenz 600 mg daily usually achieved satisfactory levels, TDM is recommended.

ESPEN Guidelines on Enteral Nutrition: Wasting in HIV and other chronic infectious diseases.

Undernutrition (wasting) is still frequent in patients infected with the human immunodeficiency virus (HIV), despite recent decreases in the prevalence of undernutrition in western countries (as opposed to developing countries) due to the use of highly active antiretroviral treatment. Undernutrition has been shown to have a negative prognostic effect independently of immunodeficiency and viral load. These guidelines are intended to give evidence-based recommendations for the use of enteral nutrition (EN) by means of oral nutritional supplements (ONS) and tube feeding (TF) in HIV-infected patients. They were developed by an interdisciplinary expert group in accordance with officially accepted standards and is based on all relevant publications since 1985. Nutritional therapy is indicated when significant weight loss (>5% in 3 months) or a significant loss of body cell mass (>5% in 3 months) has occurred, and should be considered when the body mass index (BMI) is <18.5 kg/m(2). If normal food intake including nutritional counselling and optimal use of ONS cannot achieve an adequate nutrient intake, TF with standard formulae is indicated. Due to conflicting results from studies investigating the impact of immune-modulating formulae, these are not generally recommended. The results obtained in HIV patients may be extrapolated to other chronic infectious diseases, in the absence of available data.

Altered CD45 expression in C77G carriers influences immune function and outcome of hepatitis C infection.

BACKGROUND: A polymorphism in exon 4 (C77G) of CD45 that alters CD45 splicing has been associated with autoimmune and infectious diseases in humans. OBJECTIVE: To investigate the effect of C77G in hepatitis C virus (HCV) infected individuals and study the phenotype and function of peripheral blood mononuclear cells (PBMC) from healthy and hepatitis C infected C77G carriers. RESULTS: C77G individuals showed an increased proportion of primed CD45RA and effector memory CD8 T cells and more rapid activation of the lymphocyte specific protein tyrosine kinase (Lck) following CD3 stimulation. Transgenic mice with CD45 expression mimicking that in human C77G variants had more activated/memory T cells, more rapid proliferative responses, and activation of Lck. CONCLUSIONS: Changes in CD45 isoform expression can alter immune function in human C77G variants and CD45 transgenic mice. The C77G allele may influence the outcome of HCV infection.

Metabolic syndromes in human immunodeficiency virus infection.

Infection with human immunodeficiency virus (HIV) is associated with marked disturbance of metabolism affecting the metabolism of carbohydrates, fats and proteins. In the first decade of clinical experience of HIV, the primary clinical manifestation of such disturbed metabolism was wasting. Such wasting was often severe and contributed significantly to the morbidity and mortality of AIDS. Mechanistic studies demonstrated that in addition to the effects of altered intermediary metabolism, reduced food intake played a major role in the causation of AIDS-related wasting. More recently, potent anti-retroviral drugs have dramatically changed the clinical consequences of HIV infection. Wasting has become far less frequent among infected patients and occurs in only a small percentage of subjects on effective anti-retroviral therapy. However, a new constellation of metabolic syndromes has become apparent characterized by altered body fat distribution ('lipodystrophy'), lactic acidosis and evidence of mitochondrial dysfunction. The mechanistic basis for such syndromes is currently unclear, but is the subject of ongoing research.

Red cell exchange, erythrocytapheresis, in the treatment of malaria with high parasitaemia in returning travellers.

In severe falciparum malaria with high parasitaemia, removal of parasitized erythrocytes is generally considered to be of value as adjunctive therapy in addition to standard chemotherapy. Such removal is commonly achieved by exchange transfusion but this procedure is time-consuming and may be associated with haemodynamic disturbance. Current-generation automated cell-separator hardware and software allows prompt red cell exchange, erythrocytapheresis, in a single continuous-flow isovolaemic procedure. We describe the application of this procedure to 5 cases of severe falciparum malaria in travellers returning to the UK from the tropics. All patients also received quinine and conventional supportive therapy. In all cases, dramatic reduction in parasitaemia was achieved within 2 h with subsequent complete clinical recovery. Erythrocytapheresis has significant advantages over exchange transfusion in terms of speed, efficiency, haemodynamic stability and retention of plasma components such as clotting factors and may thus represent an improvement in adjunctive therapy for severe malaria.

Tuberculosis, malnutrition and wasting.

Malnutrition predisposes to tuberculosis, and tuberculosis causes 'consumption'. Starting from current advances and historic findings in epidemiology and immunology, we can hope to decipher the effects of macro- and micronutrient deficiency upon tuberculosis, the contribution of immune response to the pathogenesis of wasting, and the best approach to its treatment.

Determinants of energy intake and energy expenditure in HIV and AIDS.

To determine the relative importance of various factors in the causation of wasting related to human immunodeficiency virus (HIV), quantitative analysis and linear structural modeling was performed on energy metabolism data collected longitudinally and prospectively from 33 men positive for the human immunodeficiency virus at 105 time points over a 3-y period before the era of highly active antiretroviral therapy. Measured variables included energy intake, total energy expenditure, resting energy expenditure, rate of change in weight, CD4 count, clinical status, appetite, and mood. Derived variables included energy balance, activity-related energy expenditure, and physical activity level. Relative contributions were assessed by linear structural modeling based on multiple regression expressing results as path coefficients for individual relationships. The primary determinant of energy balance was energy intake (r = 0.80). Total energy expenditure made a very minor contribution to energy balance (r = -0.04). Total energy expenditure was primarily determined by activity level (r = 0.91), which itself was negatively related to the presence of opportunistic infection and CD4 count. Energy intake was related to activity level (r = 0.28) and appetite (r = 0.30), which were closely interrelated (r = 0.59). Such linear structural models allow quantitative importance to be apportioned to factors determining weight change in those infected with HIV and represent a powerful tool for future metabolic studies.

Is acute appendicitis another inflammatory condition associated with highly active antiretroviral therapy (HAART)?

OBJECTIVE: To report the occurrence of acute appendicitis as a possible manifestation of the immune restoration inflammatory syndrome (IRIS) following the commencement of highly active antiretroviral therapy (HAART) in HIV patients. DESIGN: Case-note review of HIV patients on HAART with acute appendicitis. METHODS: Review of HIV markers, antiretroviral therapy and abdominal ultrasound results of four HIV patients with acute appendicitis and the histopathology reports on the appendix in two of the patients. RESULTS: From a population of approximately 350 HIV patients on HAART, we found four patients who developed acute appendicitis within 6 months of commencing or changing HAART. CONCLUSION: Acute appendicitis occurring in HIV patients on HAART may represent a variant of IRIS. Further immunohistopathological and epidemiological evaluation will be needed to define this relationship fully.

Nutrition and immune function in human immunodeficiency virus infection.

The triad of human immunodeficiency virus (HIV) infection, nutritional status and immune function are intimately related, each factor having effects on the others. The dominant effect in this three-way relationship is the effect of HIV infection on nutritional status, an effect which, until the advent of potent anti-retroviral drugs, has been manifest primarily as wasting. Recently, more complex metabolic abnormalities have become apparent, particularly fat redistribution syndromes, hyperlipidaemia and hypercholesterolaemia. For the converse effect, the effect of nutritional state on HIV disease progression, there is good evidence that clinical outcome is poorer in individuals with compromised nutrition. However, the beneficial effects of nutritional support have been more difficult to demonstrate. For macronutrients, effective macronutrient supply improves survival in severely-malnourished individuals and may have beneficial effects in less-severely-affected individuals. Micronutrient deficiencies appear to be involved in modifying clinical HIV disease and may also be associated with enhanced mother-to-child transmission of virus, particularly in developing countries. Intervention trials in this setting are currently under way. In conclusion, the interaction of HIV infection and nutrition is of great importance not just because of the major impact that HIV infection has on nutritional state, but also because strategies to improve nutritional status, both quantitatively and qualitatively, may have a beneficial effect on the clinical and immunological course of the disease.

Short-term growth hormone administration at the time of opportunistic infections in HIV-positive patients.

OBJECTIVES: A 12-week course of recombinant human growth hormone is an effective but expensive therapy for established HIV-related wasting. Wasting in HIV disease is often episodic, coinciding with bouts of acute opportunistic infection. We hypothesized that a short course of growth hormone, targeted at the time of opportunistic infection, might improve protein metabolism thereby reducing lean tissue loss. METHODS: HIV-infected men with acute opportunistic infections, who received standard antimicrobial treatment for their infection as well as intensive nutritional counselling and oral energy supplements, were randomized to receive growth hormone or placebo for 14 days. Principal assessments were protein metabolism (measured by 13C-leucine infusion), body composition (measured by DEXA) and safety. RESULTS: There were no significant changes in outcome parameters in the placebo group (n = 11). In the growth hormone group (n = 9), protein catabolic rate decreased by 60% in the fasted state (P = 0.02 versus placebo), lean body mass increased by 2.2 kg (P = 0.03 versus baseline) and fat mass decreased by 0.7 kg (P = 0.002 versus baseline). There was no increase in adverse or serious adverse events in the growth hormone as compared with the placebo group. CONCLUSIONS: A two-week course of growth hormone at the time of acute opportunistic infection in HIV-infected patients improves protein metabolism and body composition during therapy and appears to be safe. This may represent a rational and economical approach to the use of growth hormone therapy.

Malnutrition in tuberculosis.

Tuberculosis has a dramatic effect on nutritional state and this has been borne out in all the studies that have investigated body composition in affected patients. I have included some of the key studies in this review; those I have not cited generally reach the same conclusions. Such malnutrition undoubtedly contributes to the morbidity of the disease and may also contribute to mortality, particularly in resource-poor settings where nutritional state, even in the "healthy," may be parlous. The extent to which such malnutrition also contributes to pathology remains unclear. Certainly, in other models, nutritional depletion has a major impact on immune function (Chandra, 1997) and depression of lymphocyte function cannot be a desirable commodity in an individual fighting invasive mycobacterial infection. Considering the reverse relationship, there is good evidence, both at the population level and at the clinical level, for the effect of primary malnutrition on tuberculosis, both to increase frequency of occurrence and to exacerbate clinical manifestations. It has not been possible to explore this relationship within the context of this paper but it is clearly an important aspect of the bi-directional relationship between tuberculosis and malnutrition. There is still more to be understood about the pathophysiology of the wasting seen in chronic infections such as tuberculosis but it is clear that, in addition to good anti-tuberculous therapy, such patients need a good supply of nutrition during the treatment/recovery phase. In the developed world, this may include medical measures to achieve nutritional support whereas in resource-poor settings, nutritional intake may have more to do with equitable resource distribution and community involvement in health care.

A reconstituted dilute blood clot lysis assay for the medium throughput screening of thrombolytic compounds.

Antithrombotic and clotting factors have long been targets for drug discovery, necessitating the development of blood assays to determine the efficacy of lead compounds prior to animal testing. We have developed a reconstituted blood clot lysis assay which eliminates the need for on-site donors. The assay uses whole blood stored at 4 degrees C obtained from a local blood bank, diluted 1:10 in phosphate buffer. This blood was supplemented with 125I-labeled fibrinogen and the release of radioactive fibrinopeptides from formed clots was measured. The whole blood used in this assay, which had been stored at 4 degrees C for several days, no longer formed solid or retracting clots. Thus, platelets 5-7 days ex vivo (165 x 10(6) platelets) were added to the whole blood in the presence of thrombin (0.80 IU/ml) to form clots. Solid clots formed within 2 min of thrombin addition and began retracting shortly thereafter. In the absence of any thrombolytic agent, clots fully retracted within 2.5 h and remained stable. Thrombin-stimulated clot formation was completely inhibited by heparin. Clots could be lysed in a dose-dependent fashion in the presence of tissue-type plasminogen activator. Clot lysis could be completely inhibited in a dose-dependent fashion with plasminogen activator inhibitor type 1. To demonstrate the utility of this assay as a screen for thrombolytic agents, a 14-amino-acid PAI-1-inhibitory peptide relieved the PAI-1 effect on tPA in a dose-dependent fashion. These data describe an assay for the screening of potential pro-fibrinolytic agents that target PAI-1 inhibition in a human plasma-based system that is versatile, cost-effective, and physiologically relevant and does not rely on the availability of on-site blood donors.