Search

Drug abuse and HIV infection are interlinked. From the onset of the HIV/AIDS epidemic, the impact of illicit drug use on HIV disease progression has been a focus of many investigations. Both laboratory-based and epidemiological studies strongly indicate that drug abuse may exacerbate HIV disease progression and increase mortality and morbidity in these patients. Increase susceptibility to opportunistic infection has been implicated as one of the major causes for this detriment. Furthermore, opioids are known to elicit prevalence of neurodegenerative disorders in HIV-infected patients. Numerous authors have delineated various molecular as well as cellular mechanisms associated with neurological complications in these patients. This review gives an overview of these findings. Understanding the mechanisms will allow for the development of targeted therapies aimed at reducing the progression of neurocognitive decline in the drug abusing HIV infected individuals.

Background: In the SMART study, HIV-viral-hepatitis-coinfected persons were, compared with HIV-monoinfected persons, at higher risk of non-AIDS death if randomized to the antiretroviral therapy (ART) interruption strategy. We hypothesized that a marker of liver fibrosis, hyaluronic acid (HA), would be predictive of development of non-AIDS-related outcomes in coinfected participants in the SMART study., Methods: All participants positive for HCV RNA or hepatitis B surface antigen (HBsAg) and with stored plasma samples were included (n=675). Plasma samples were tested for HA (normal range 0-75 ng/ml) at baseline and months 6, 12 and 24 during follow-up in the drug conservation (DC; interrupt ART until CD4(+) T-cell count <250) group and the viral suppression (VS; continued use of ART) group. Time to non-AIDS death was investigated using Kaplan-Meier analysis., Results: Overall, 52 (31 in DC and 21 in VS) coinfected participants died during follow-up. Coinfected participants who were randomized to the DC group with baseline HA>75 ng/ml had a cumulative risk of non-AIDS death of 24.6% after 36 months of follow-up compared with 9.3% for participants randomized to the VS group (P=0.005), while the cumulative risk for coinfected participants with HA ≤ 75 ng/ml was 4.1% (DC) and 4.7% (VS; P=0.76). The change in HA from baseline to month 24 was 8.3 ng/ml and 4.7 ng/ml in the DC and VS group (P=0.56), respectively., Conclusions: Interruption of ART was particularly unsafe in HIV-hepatitis-coinfected individuals if plasma HA was increased. HA changed very little during follow-up and was not influenced by differences in CD4(+) T-cell count or HIV viral load.

Myopericytoma is an uncommon, benign perivascular myoid cell tumor that occurs almost exclusively in somatic soft tissues. We report 2 cases occurring in patients with acquired immunodeficiency syndrome who show unusual clinical and biologic features. One patient presented with a bronchial mass and the other developed mass lesions of the tongue, vocal cord, and brain. Histologically, oval to plump spindly tumor cells with uniform nuclei and scanty cytoplasm formed sheets or cuffs around gaping or narrow vascular spaces. Focally, these areas merged into fascicles of more elongated cells with eosinophilic cytoplasm. The tumor cells were immunoreactive for actin but not desmin, and showed uniform labeling for Epstein-Barr virus (EBV) encoded RNAs on in-situ hybridization. Both patients were alive 5 years after incomplete excision of the lesions. In conjunction with another case reported in the literature, myopericytoma occurring in acquired immunodeficiency syndrome patients exhibits several features distinct from sporadic myopericytoma: presentation in anatomic sites other than somatic soft tissues, frequent presence of multifocal disease, and association with EBV. This tumor type therefore also broadens the spectrum of neoplasms associated with EBV.

Through the mentorship process, Dr. Arthur Pardee emphasized the critical importance of bidirectional translational research-not only advancing drug development from bench to bedside, but also bringing back precious clinical material to the laboratory to assess the biologic effects of therapeutic agents on their targets. This mini-review focuses on the signal transduction pathways of Kaposi's sarcoma (KS) and on how the knowledge of such pathways has led to the rational development of molecularly targeted pathogenesis-driven therapies. Acquired immune deficiency syndrome (AIDS) related-KS results from co-infection with human immunodeficiency virus and KS herpesvirus/human herpesvirus-8 (KSHV/HHV8), which leads to the development of an angiogenic-inflammatory state that is critical in the pathogenesis of KS. KS is driven by KSHV/HHV8-specific pathways, which include viral G protein-coupled receptor (vGPCR), viral interleukin-6 (vIL-6), and viral chemokine homologues. In addition, cellular growth/angiogenic pathways, such as vascular endothelial growth factor (VEGF), insulin-like growth factor, platelet-derived growth factor (PDGF), angiopoietin and matrix metalloproteinases (MMPs) are "pirated" by KSHV/HHV8. As a very tangible example of how translational research has led to a marked improvement in patient outcome, the signal transduction inhibitor imatinib (a tyrosine kinase inhibitor of c-kit and PDGF) was administered to patients with KS whose tumors were serially biopsied. Not only did the patients' tumors regress, but also the regression was correlated with the inhibition of PDGF receptor (PDGFR) in the biopsy samples. Recent and future clinical trials of molecularly targeted therapy for the treatment of KS are a prelude to a shift in the paradigm of how KS is managed., ((c) 2006 Wiley-Liss, Inc.)

A review of Kawasaki disease (KD)-like syndromes (KDLS) in patients with human immunodeficiency virus (HIV) raised the question whether vasculitis in children and KDLS in immunocompromised adults might be etiologically related. We describe a 42-year-old white man with AIDS and Kaposi sarcoma who presented with KDLS, which was diagnosed on the basis of clinical criteria for KD. Analysis of a conjunctival tissue sample revealed endothelial cell damage with fibrin deposition and infiltration of immunoglobulin A-secreting plasma cells.

Antifungal treatment reduces the concentration of Histoplasma antigen in blood and urine, supporting a hypothesis that antigen clearance could be used to compare the activity of new agents for treating histoplasmosis. In separate trials in patients with AIDS, clinical response was similar with itraconazole (85%) and fluconazole (74%). Fungal blood cultures at week 4, however, were negative in a significantly higher proportion of patients treated with itraconazole (92.3%) than in those treated with fluconazole (61.9%) (P = 0.017). Baseline antigen concentrations were similar in the two groups: serum, P = 0.7235; and urine, P = 0.1360. After 4 weeks of treatment, the decline in antigen from baseline in serum was similar in the two treatment groups (P = 0.5237), as it was in urine (P = 0.4679). At week 12, the decline in antigen from baseline in serum also was similar in the two groups (P = 0.4911) and in urine (P = 0.2786). More rapid clearance of fungemia suggests that itraconazole is more effective than fluconazole in treating histoplasmosis. This study demonstrates that clearance of fungemia is a better measure of antifungal effect than clearance of antigen.

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.

HIV-1-infected patients are in chronic oxidative stress and clastogenic factors (CFs) are present in their plasma. CFs from patients with HIV are formed via superoxide anion radical and stimulate further superoxide production. The pathophysiolgic significance and the exact composition of the circulating clastogenic material in patients with HIV is unknown. Cytokines, such as tumor necrosis factor-alpha (TNF-alpha), are increased in the plasma of patients with HIV and TNF-alpha shows clastogenic activity in vitro. The aim of this clinical study was to compare levels of CF in HIV-1-positive patients with asymptomatic disease, opportunistic infections, and malignancies with those in HIV-1-negative control groups and to correlate CF activity with CD4+ T cell numbers, the cytokines (TNF-alpha, interleukin-2 [IL-2], IL-6), and the inflammatory markers (C-reactive protein [CRP], neopterin, granulocyte elastase). CFs were significantly increased in all HIV-1-positive patients and in HIV-1-negative patients with malignant tumors. HIV-1-positive patients with Kaposi's sarcoma showed the highest CF activity in their plasma (p < 0.08). CFs appear very early in HIV infection, and they correlate negatively with CD4+ T cells, which are an indicator of disease activity. The presence of CF in the plasma of HIV-infected patients is not a general response to a viral infection because these factors are not increased in HIV-1-negative patients with viral infection (zoster). CFs are not specific for the HIV-1 infection; they also occur in HIV-1-negative patients with malignant tumors. There was a tendency towards a positive correlation (p < 0.14) between CF and TNF-alpha but there was no positive correlation of CF with IL-2, IL-6, CRP, elastase, and neopterin levels. This indicates that TNF-alpha may be among the components of CF in HIV-1-infected patients. In addition, other unidentified components may contribute to the clastogenic activity of the plasma or the composition of CF may vary from patient to patient. Further clinical studies with larger sample populations are necessary to analyze the composition of CF in HIV-1-positive patients.

To investigate the interaction of fluconazole and zidovudine in HIV-positive non-smoking male patients with AIDS categorized as CDC group IV we studied two groups, each consisting of 10 male, non-smoking, HIV-positive patients with CDC group IV disease, with the patients in the first group additionally suffering from candida esophagitis. In the first group, the pharmacokinetics of 500 mg oral zidovudine were determined both before and after 7 days of treatment with fluconazole 400 mg/d. In the second group, the pharmacokinetics of 200 mg oral fluconazole were determined before and after 14 days of treatment with zidovudine 4 x 250 mg/d. In order to determine the microsomal enzyme activity, the 6-beta-hydroxycortisol/17-hydroxycorticosteroid ratio and antipyrine pharmacokinetic parameters were determined. 6-beta-hydroxycortisol was quantitated by RIA. The 17-hydroxycorticosteroids were determined by a colorimetric method. Zidovudine (ZDV) and zidovudine glucuronide (GZDV), and the fluconazole and antipyrine plasma and urine concentrations were measured by HPLC. Administration of fluconazole resulted in a significant increase in the half-life of zidovudine and antipyrine (0.97 +/- 0.17 h prior to vs. 1.11 +/- 0. 14 h after fluconazole administration and 11.9 +/- 1.9 h prior to vs. 13.7 +/- 3.0 h after fluconazole, respectively) while the 6-beta-hydroxycortisol excretion decreased significantly (472.3 +/- 80.6 microg/24 h before and 340.6 +/- 82.1 microg/24 h after administration of fluconazole). No changes were found in the GZDV plasma kinetics and the ZDV and GZDV urinary excretion. Treatment with ZDV did not have any impact on the half-life of fluconazole. Administration of zidovudine did, however, result in a significant reduction in antipyrine half-life (11.7 +/- 2.0 h before vs. 9.9 +/- 2.3h after ZDV) and a significant increase in 6-beta-hydroxycortisol excretion (438,7 +/- 138.2 microg/24 h before and 684.6 +/- 157.3 microg/24 h after ZDV). Since the antipyrine clearance is altered after administration of ZDV, it is assumed that zidovudine induces cytochrome P450 enzymes. This effect, however, does not alter the pharmacokinetics of fluconazole. High doses of fluconazole can inhibit the plasma elimination of both antipyrine and zidovudine, but the extent of this inhibitory effect is so small that no clinically relevant accumulation is to be expected.

Body wasting, protein catabolism, and hypoalbuminemia are complicating features of the acquired immunodeficiency syndrome (AIDS). Given their multifactorial causes, the contributing role of intestinal protein loss has not yet been fully elucidated. To quantify enteric protein leakage, determination of fecal alpha 1-antitrypsin (AAT) excretion has been established as an accurate and reliable endogenous marker. We estimated AAT concentration by standard immune nephelometry in duplicate random stool samples of 49 patients with AIDS, and we compared it to that of 43 patients with chronic inflammatory bowel disease and to 34 healthy controls. When compared with healthy persons, patients with AIDS had increased fecal AAT excretion regardless of current opportunistic intestinal infections and fecal AAT excretion similar to that of patients with quiescent chronic inflammatory bowel disease. The ratio of fecal and serum AAT concentration was not different between AIDS patients and healthy controls, although it was consistently increased in those with chronic inflammatory bowel disease. Significant intestinal protein leakage occurs in patients with AIDS, probably due to primary impairment of gut permeability. Enteric protein loss may be an important feature of human immunodeficiency virus-associated enteropathy with altered mucosal barrier function.

Ten patients with AIDS and cytomegalovirus (CMV) gastrointestinal infection were included in an open-label study to evaluate the safety, efficacy, and pharmacokinetics of 90 mg of intravenous foscarnet/kg of body weight twice daily accompanied by (pre)hydration of 500 to 750 ml. Efficacy was documented endoscopically, while safety was evaluated clinically by patient reports and physical and laboratory observation. The pharmacokinetics of foscarnet was evaluated after the first dose and following approximately 20 days of therapy. Nine patients (90%) responded histopathologically, nine (90%) responded endoscopically, and nine (90%) responded symptomatically to foscarnet therapy. Adverse events resulted in discontinuance of medication in the case of one patient. The mean maximal concentration was 621 microM following the first dose and 687 microM at steady state (P = 0.11). The apparent elimination rate constant and elimination half-life were not different between dose 1 and steady state. There were no significant changes in foscarnet excretion or renal clearance between dose 1 and steady state. The steady-state volume of distribution was 23.4 liters following the first dose and 19.0 liters at steady state (P < 0.002). Twice-daily foscarnet appeared to be safe and efficacious in the treatment of CMV gastrointestinal disease in this study, resulting in endoscopic or histologic improvement in 9 of the 10 (90%) patients. Minor changes in clearance and volume of distribution noted at steady state compared to single-dose administration are readily explained by study design, known information about foscarnet pharmacokinetics, and changes in body weight and creatinine clearance in the patients.

Abnormalities in iron metabolism have been reported in patients with acquired immunodeficiency syndrome (AIDS). To assess the frequency of abnormal hepatic iron deposition in these patients and to examine potential causes of iron overload, we analyzed the amount of iron at different cellular sites in liver sections obtained at autopsy of 78 patients with AIDS. Quantitation of serum iron and transferrin levels and estimation of total iron binding capacity was obtained using serum from 63 patients. The number of whole blood/packed red blood cell transfusions and opportunistic infections was recorded. Of the 78 patients, 25 (32%) showed a Grade 3 or 4 (0-4 scale) iron level, distributed in three patterns, i.e., in hepatocytes only, in hepatocytes and Kupffer cells, and in Kupffer cells only. In these 25 livers, 4 had cirrhosis, with no documented cause; the mean number of transfusions was 12.5; and 16 (64%) had Mycobacterium avium-Mycobacterium intracellulare infection. In the 53 livers with little or no iron, 5 had cirrhosis, with 3 of those 5 listing alcoholic liver disease or hepatitis as the cause; the mean number of transfusions was 1.4; and 18 (34%) had Mycobacterium avium-Mycobacterium intracellulare infection. Transferrin saturation was more than 50% in 6 (29%) of 21 cases with increased hepatic iron levels and in 6 (14%) of 42 cases with little or no hepatic iron. These results indicate that hepatic iron overload in patients with AIDS is associated with blood transfusions, an elevated transferrin saturation, and Mycobacterium avium-Mycobacterium intracellulare infection. Significant hepatic iron deposition in patients with AIDS with no other apparent cause of cirrhosis suggests an etiologic role for iron in hepatic injury. The increase in hepatic iron levels in these patients has potentially adverse clinical effects related to the use of transfusions, iron supplements, and iron-containing drugs.

Aims: To evaluate the expression of the alpha 5 beta 1 integrin fibronectin receptor (FNR), which mediates several processes, including phagocytosis, cell motility and the immune response, on T lymphocytes of patients with HIV-1 infection., Methods: T lymphocytes were incubated with monoclonal antibody directed against FNR and then with monoclonal antibodies, conjugated with phycoerythrin, directed against CD3, CD4 and CD8 positive cells. Expression of FNR on CD3, CD4 and CD8 positive cells was analysed using flow cytometry., Results: Normal expression of FNR was observed on CD3 positive cells from asymptomatic HIV positive patients and those with AIDS. Increased expression of FNR was observed on CD8 positive cells from asymptomatic HIV positive patients and on CD4 positive cells from patients with AIDS. Increased FNR expression was observed on CD4 positive cells from patients with AIDS, particularly those with opportunistic infections caused by Pneumocystis carinii, Mycobacterium sp, Toxoplasma gondii, and Cryptococcus neoformans., Conclusion: Increased expression of FNR on CD8 and CD4 positive cells in asymptomatic HIV positive patients and those with AIDS, respectively, may be an epiphenomenon correlated with lymphocyte activation by HIV-1 or opportunistic infection, Further study is required to determine whether upregulation of FNR expression has a direct role in the pathogenesis of AIDS.

The purpose of this study was to determine the safety and pharmacokinetics of lamivudine (3TC), a nucleoside analog that has shown potent in vitro and recent in vivo activity against human immunodeficiency virus. Sixteen human immunodeficiency virus-infected patients, six with normal renal function (creatinine clearance [CLCR], > or = 60 ml/min), four with moderate renal impairment (CLCR, 10 to 40 ml/min), and six with severe renal impairment (CLCR, < 10 ml/min), were enrolled in the study. After an overnight fast, patients were administered 300 mg of 3TC orally. Blood was obtained before 3TC administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, and 48 h afterward. Timed urine collections were performed for patients able to produce urine. Serum and urine were assayed for 3TC by reverse-phase high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were calculated by using standard noncompartmental techniques. The peak concentration of 3TC increased with decreasing renal function; geometric means were 2,524, 3,538, and 5,684 ng/ml for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. The terminal half-life also increased with decreasing renal function; geometric means were 11.5, 14.1, and 20.7 h for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. Both oral and renal clearances were linearly correlated with CLCR. A 300-mg dose of 3TC was well tolerated by all three patient groups. The pharmacokinetics of 3TC is profoundly affected by impaired renal function. Dosage adjustment, by either dose reduction or lengthening of the dosing interval, is warranted.

Hypercalcemia has been well described in a variety of neoplastic and granulomatous diseases. One mechanism for this hypercalcemia is via the excess production of 1,25-dihydroxyvitamin D from extra-renal sources. The authors describe an AIDS patient infected with Cryptococcus neoformans who had suggestive evidence of vitamin D-mediated hypercalcemia. He had an elevated serum 1,25-dihydroxyvitamin D value, a normal 25-hydroxyvitamin D value, and low values for parathyroid hormone and parathyroid hormone-related peptide. Most previously reported cases of hypercalcemia associated with fungal infections did not include sufficient evidence to implicate a role for excess 1,25-dihydroxyvitamin D production, except for two case reports involving patients with hypercalcemia with infections due to Pneumocystis carinii and Candida albicans. The authors' patient's hypercalcemia resolved during treatment of his underlying infection. Patients with hypercalcemia or in whom hypercalcemia develops during a disseminated fungal infection should have vitamin D metabolites measured as part of their work-up.

Wasting syndrome is a common complication of HIV infection and is marked by progressive weight loss and weakness, often associated with fever and diarrhea. The pathophysiologic mechanisms responsible for this syndrome are not well defined, but it is clear that this is a multifactorial process in which the relative contribution of individual etiologic factors vary among patients. Considerations include inadequate diet, malabsorptive phenomena, metabolic derangements, and cytokine activity. The onset of opportunistic infections is often accompanied by a hypermetabolic state characterized by progressive weight loss. Potential cytokines that may promote weight loss in AIDS patients include tumor necrosis factor, interleukin-1, interleukin-6, and alpha-interferon. At present there is no effective treatment. Multiple therapeutic methods, including enteral and parenteral alimentation, appetite stimulants, recombinant growth hormone, and cytokine modulators, are currently being explored.

In order to elucidate the role played by alveolar cytokines in the pathogenesis of HIV-related lung damage, levels of interleukin (IL) 1 beta, IL-2, IL-6, tumor necrosis factor (TNF)-alpha, and interferon (Ifn) were assessed on supernatant of bronchoalveolar lavage fluid from 30 consecutive HIV-1 seropositive (HIVAb+) patients with clinical and radiologic evidence of pneumonia, from 20 HIV- seronegative (HIVAb-) patients with pulmonary sarcoidosis, and from 10 HIVAb- healthy control subjects. Cytokine levels were expressed as picogram (IL-1, TNF), nanogram (IL-6), and international unit (IL-2, Ifn) per milligram of albumin per deciliter. Total and differential cell counts, cytofluorimetric enumeration of CD3+, CD3+/DR+, CD4+, CD8+, and CD8+/CD16+ cells, as well as microbiologic investigations for opportunistic agents were performed on lavage pellets. HIV-related pneumonia was characterized by higher mean alveolar level of IL-2 (12 +/- 5 IU), and by more elevated mean counts of T cells (109 +/- 16), activated T cells (60 +/- 12), and CD8+ cells (90 +/- 13)/microliters if compared with both active sarcoidosis and control subjects, where respective values of 0.2 +/- 0.1 and 0.3 +/- 0.2 IU IL-2/mgAlb/dl, of 52 +/- 11 and 7 +/- 2 T cells, of 20 +/- 5 and 1.2 +/- 0.3 activated T cells, and of 11 +/- 2 and 3 +/- 0.6 CD8+ cells per microliter were found. HIV-infected patients with opportunistic lung infections (OIs) showed the highest mean IL-2 level (21 +/- 4 IU), and higher counts of both CD8+ (117 +/- 20) and CD8+/CD16+ (36 +/- 7) cells per microliter if compared with patients without evidence of OIs (respectively, 62 +/- 13 CD8+ and 18 +/- 3 CD8+/CD16+ cells per microliter). By contrast, extremely high IL-1 levels (1,463 +/- 760 pg), and IL-2 levels similar to control subjects (3.4 +/- 1.2 IU), were found in the absence of OIs. Different mechanisms depending respectively on IL-2-mediated cytotoxic cell recruitment and activation, or IL-1-mediated tissue injury may account for HIV-related lung damage, depending on the presence or absence of opportunistic agents.