Omega-3 decreases IL-6 levels in HIV and human herpesvirus-8 coinfected patients in Uganda.

OBJECTIVE: Kaposi sarcoma is a HIV-associated malignancy caused by human herpesvirus-8 (HHV-8) that occurs at highest incidence in sub-Saharan Africa. Kaposi sarcoma patients often present with inflammatory symptoms associated with higher mortality. DESIGN: We conducted a double-blind, randomized, placebo-controlled study in Uganda to test whether omega-3 supplementation could reduce inflammation in HIV and HHV-8 coinfected adults. Patients with acute illness, AIDS, or advanced Kaposi sarcoma were ineligible, as were pregnant women. Participant IDs were pre-randomized, blocked by Kaposi sarcoma status, to either the omega-3 or placebo arm. METHODS: Omega-3 participants received a 3-g pill dose daily for 12 weeks (1.8-g eicosapentaenoic acid, 1.2-mg docosapentaenoic acid); placebo participants received 44.8 mg of high oleic safflower oil that appeared indistinguishable from the active supplement. Intervention effects were evaluated as the baseline-adjusted mean difference after 12 weeks between omega-3 and placebo participants in concentrations of fatty acids, inflammatory cytokines, and immune cells. RESULTS: The final study population included 56 Kaposi sarcoma patients and 11 Kaposi sarcoma-negative, HIV and HHV-8-positive participants randomized to receive either omega-3 (N = 33) or placebo (N = 34). Inflammatory cytokine IL-6 concentrations decreased in omega-3 participants (-0.78 pg/ml) but increased in placebo participants (+3.2 pg/ml; P = 0.04). We observed a trend toward decreased IL-6 after omega-3 supplementation specific to Kaposi sarcoma patients (P = 0.08). CD8 T-cell counts tended to increase in the omega-3 arm Kaposi sarcoma patients (+60 cells/µl), in contrast to decreases (-47 cells/µl) among placebo (P = 0.11). CONCLUSION: Omega-3 supplementation decreased IL-6 concentrations among HIV and HHV-8 coinfected Ugandans, which may have clinical benefit for Kaposi sarcoma patients.

Bone marrow macrophage iron stores in patients with HIV infection and AIDS-associated Kaposi's sarcoma.

Several observations have been made suggesting that excess iron is harmful to patients with HIV/AIDS disease. Bone marrow macrophage iron stores of 30 anaemic HIV infected patients (median age 32.7 years) and 20 anaemic AIDS-associated Kaposi's sarcoma patients (median age 37 years) were studied at the haematology department of the University of Maiduguri Teaching Hospital. Macrophage iron stores were assessed as either normal, decreased or increased by using grades ranging from 0 to 6. Marrow iron stores was increased in 16 (80%) of the patients with Kaposi's sarcoma and normal in 4 (20%) patients. Three of the 4 patients with normal iron stores were females of reproductive age. Regression analysis of iron status and opportunistic infection showed a positive correlation (p-value=0.001). Of the 30 patients with HIV infection, 22 (73.3%) had normal iron stores and 8 (26.7%) had decreased iron stores. All the 8 (26.7%) patients with no stainable iron in the marrow were females of reproductive age group. Iron deficiency anaemia can complicate anaemia of HIV infected patients. In view of the documented risk associated with iron supplementation in anaemic patients with HIV/AIDS disease, little caution should be exercise as regards the use of haematinics and/or blood tonics in anaemic HIV-infected or AIDS-associated Kaposi's sarcoma patients. The fact that noninvasive evaluation for iron deficiency is compromised in many individuals due to the presence of chronic inflammatory process and/or malignancy, bone marrow evaluation for iron stores still remains an important tool often underutilized by many clinicians attending to patients living with HIV/AIDS.

Immunomodulatory treatment with low-dose interferon-alpha and oral retinoic acid in lymphangioma-like Kaposi's sarcoma.

BACKGROUND: The presence of lymphangiectasis without the characteristic spindle cell proliferation may lead to diagnostic difficulties in Kaposi's sarcoma. Although the literary data mention that the lymphangioma-like tumors may occur in Kaposi's sarcoma, there have been few specific reports and case presentations published. OBSERVATIONS: A case of lymphangioma-like Kaposi's sarcoma in association with IgG/lambda type paraproteinaemia is reported in a 60-year-old man. The HSV8 DNA sequence could be detected by PCR analysis from lesional skin. CONCLUSION: The beneficial effect of alpha-2 interferon (4.5 million units per week) combined with retinoic treatment (0.5 mg/body weight of isotretinoin) caused the regression of the skin rashes while improving the values of immunological tests (T cell function, quantity of paraproteins). The patient's improved general condition and the ameliorating immunological parameters were due to the combination of two regimens applied in a low-dose the alpha-2 interferon (tumor regression) and the oral isotretinoid (antitumor activity, reduction of IL-6 receptor display) treatment.

Anti-HIV activity of extracts and compounds from algae and cyanobacteria.

The human immunodeficiency virus (HIV) is the retrovirus that causes the acquired immune deficiency disease syndrome (AIDS). This review discusses the anti-HIV activity of extracts and compounds isolated from freshwater and marine algae, and cyanobacteria (formerly called "blue-green algae"). Compounds and extracts with anti-HIV activity are also active against other retroviruses such as herpes simplex virus (HSV), but the amount of antiviral activity varies with the compound and the virus. Most of the research has focused on sulfated homopolysaccharides and heteropolysaccharides. Sulfoglycolipids, carrageenans, fucoidan, sesquiterpene hydroquinones, and other classes of compounds with anti-HIV activity that have been isolated from algae have received less attention. Most studies have used in vitro test systems, but a few in vivo studies have been carried out using compounds isolated from algae or analogs produced synthetically or isolated from other natural sources. Sulfated homopolysaccharides are more potent than sulfated heteropolysaccharides. The presence of the sulfate group is necessary for anti-HIV activity, and potency increases with the degree of sulfation. Studies using nonsulfated and sulfated homo- and heteropolysaccharides isolated from algae or other natural sources, or synthesized, have revealed the mechanisms of binding of drugs to the virion, and the mechanisms of viral binding to host cells. However, given the few classes of compounds investigated, most of the pharmacopeia of compounds in algae and cyanobacteria with antiretroviral activity is probably not known.

Radiation therapy for malignancies in the setting of HIV disease.

With the introduction of increasingly effective antiretroviral agents for the management of AIDS, the life expectancy of appropriately treated patients will continue to lengthen as will the length of time during which infected patients amy develop malignancies, both HIV-related and non-HIV-related. The management of such patients will require careful consideration of the impact of all oncologic therapy on the immune system's ability to hold the virus at bay. Radiation therapy, with its recognized immunosuppressive effects, plays an important role in the management of the major AIDS-defining neoplasms, Kaposi's sarcoma, primary central nervous system lymphoma, and cervical carcinoma, and is used in approximately 50% of patients with non-HIV-related malignancies at some point in the disease course. The judicious use of radiation therapy and proper integration of aggressive antiretroviral therapy can result in control of malignancies without contributing to the rapid progression of HIV disease.

Effect of whole-body hyperthermia on AIDS patients with Kaposi's sarcoma: a pilot study.

The safety and possible efficacy of extracorporeal whole-body hyperthermia (WBHT) were evaluated in the first FDA-approved feasibility study of WBHT in persons with AIDS. Six gay men, aged 20-50 years, CDC class C-3, underwent 1 h of WBHT at either 40 degrees C or 42 degrees C, employing a system that minimizes the physiological and biochemical changes that occur during WBHT. All subjects had Kaposi's sarcoma (KS), were free of opportunistic infections, and had significant elevations of plasma HIV RNA. During the treatment, there were no adverse side effects and all subjects tolerated WBHT without problems. KS lesions partially regressed immediately following WBHT in all subjects but returned to pretreatment status in five of six patients at 1 week. In subjects treated at 40 degrees C, CD4 counts decreased during the 8-week follow-up period; they remained unchanged, however, following 42 degrees C WBHT. Viral load remained unchanged following WBHT in subjects treated at 40 degrees C. Treatment at 42 degrees C resulted in an immediate reduction in HIV RNA that was not sustained at 1 week post-WBHT. We conclude that WBHT is safe in subjects with advanced HIV disease and that it may have a role in treating HIV infection. A larger controlled trial involving two treatments in less immunocompromised subjects is currently in progress to test this hypothesis.

Cultured AIDS-related Kaposi's sarcoma cells retain a proliferative bioenergetic profile but demonstrate reduced cytoprotective capabilities.

Features of AIDS-related Kaposi's sarcoma (AIDS-KS), such as the multifocal presentation at mucosal and epidermal sites subjected to trauma, suggest that AIDS-KS is initially a reactive hyperplasia that subsequently progresses to a neoplasia. It is recognized that there is an association between sustained inflammatory states and the subsequent development of neoplasia (e.g., ulcerative colitis/colonic adenocarcinoma). Furthermore, patients who develop AIDS-KS experience both a constant immune stimulation due to sustained high levels of virus-induced cytokines and, because of a sparing effect on their phagocytic cells, retention of the phagocytic inflammatory response. A component of phagocytic activation is the initiation of the oxidative burst, resulting in the generation of reactive oxygen species (ROS), which can be mutagenic to host cells if released beyond the phagolysosome and not inactivated. Our results demonstrate that cultured AIDS-KS cells possess decreased cytoprotective capabilities. Relative to either dermal fibroblasts, or human microvascular endothelial cells (HMECs), AIDS-KS cells contained significantly lower levels of glutathione, a tripeptide integral in both cytoprotection and maintenance of cellular thiol status. While HMECs increased catalase activity during culture in the cytokine-rich KS milieu (control medium supplemented with conditioned medium from MOT, an HTLV II-infected cell line), AIDS-KS cells demonstrated reduced catalase function under these conditions. Furthermore, HMEC cultures showed an inherent biochemical responsiveness, by increasing catalase activity following exposure to exogenous H2O2. In contrast, the catalase activity of AIDS-KS cells decreased following H2O2 challenge. Our results show that an inherent deficiency in cellular cytoprotection is present in AIDS-KS cells and suggest that oxidant stress may function in the development and progression of AIDS-KS.

Ablation of neoplasia by direct current.

The application of low-voltage direct electrical current (DEC) has been studied in animals and humans for the ablation of anal condylomata, oesophageal cancer and Kaposi's sarcoma. Twenty milliamps of DEC passed through multiple 6 cm x 1 cm, flat-plate longitudinal electrodes into the squamous mucosa of the oesophagus of healthy dogs for periods ranging from 10 min to 2 h resulted in denudation and necrosis of the oesophageal mucosa at the site of application of the current. In humans, the application of DEC to two patients with benign anal condyloma acuminata, three patients with inoperable obstructing oesophageal cancer and one patient with disseminated Kaposi sarcoma resulted in striking necrosis of tumour tissue that was confirmed by macroscopic and microscopic studies. These initial findings imply promising therapeutic potential for the use of DEC as a simple, effective, safe, low-cost alternative for ablation of neoplasia.

Clinical and immunological changes in AIDS patients following adoptive therapy with activated autologous CD8 T cells and interleukin-2 infusion.

OBJECTIVES: (1) To determine the safety and feasibility of repetitive reinfusions of activated autologous CD8 cells followed by low-dose continuous interleukin (IL)-2 infusion in patients with AIDS. (2) To study the relationships between clinical responses, surface marker phenotypic distributions and cytokine expression patterns of both cultured CD8 cells and lymphocytes in the peripheral blood compartment. DESIGN: Six adult patients with Centers for Disease Control and Prevention group IV HIV-1 disease ranging from mild to severe, were studied. All patients were receiving zidovudine prior to and during the study period, and had initial CD4 and CD8 cell counts > 50 and 200 x 10(6)/l, respectively. METHODS: Autologous CD8 T cells (10(8)-10(10)) were reinfused five times after ex vivo culture and stimulation with phytohemagglutinin and recombinant (r) IL-2. The fifth such infusion was followed by 5 days of rIL-2 infusion. Phenotypes and cytokine expression patterns of the expanded cells were determined as well as serum levels of immune mediators throughout the study. RESULTS: Patients showed stable CD4 and CD8 cell counts, p24 antigenemia, and minimal toxicity over the 24-week protocol study. Clinical improvement was observed in lymphadenopathy (six out of six), oral hairy leukoplakia (three out of four), and Kaposi's sarcoma (KS; two out of two) in the patients studied. In vivo induction of detectable levels of bioactive acid-stable interferon (IFN)-alpha, but not of other cytokines studied, upon activated CD8 cell reinfusion was associated consistently with improvement of oral hairy leukoplakia. However, partial regression of KS was observed after the CD8 cell infusion cycles and without IFN-alpha induction. In one of the two patients studied, KS regression was associated with decreased IL-1 alpha serum levels. In the other patient, who had failed previous IFN-alpha therapy, KS regression was observed after a decline in reinfused CD8 cell-associated gene expression of tumor necrosis factor (TNF)-beta. Both IL-1 alpha and TNF-beta are growth factors for KS cells. CONCLUSIONS: These observations demonstrate the feasibility and safety of ex vivo CD8 cell activation, expansion, and reinfusion, and rIL-2 infusion in AIDS patients. The findings in this Phase I trial suggest potential clinical efficacy and encourage Phase II trials. The correlations obtained between clinical and immunological states could contribute to an understanding of the relationship between CD8 T-cell function and HIV-1-associated disease progression.

[The in vitro potentiation of LAK cell cytotoxicity in cancer and aids patients induced by F3--a fractionated extract of Astragalus membranaceus].

The in vitro induction of LAK cell activity was studied in cancer and AIDS patients. F3, an immuno-regulatory component of Astragalus membranaceus was shown capable of potentiating the LAK cell inducing activity of rIL-2. The killing activity against Hs294T melanoma cell line of LAK cells induced by 50 U/ml rIL-2 in the presence of F3 (55 micrograms/ml) reached 64% which was comparable to that (60%) induced by 500 u/ml of rIL-2 alone. With F3 plus rIL-2, the effector to target cell ratio could be reduced to one-half in order to obtain an equivalent level of cytotoxicity when rIL-2 was used alone. In some patients, whose peripheral blood lymphocytes were relatively inert to rIL-2, F3 could make them responsive to rIL-2. These results imply that F3 may be useful to potentiate LAK cell activity, reduce the amount of rIL-2 and thus minimize the later's toxic side effects when used in vivo.

Systemic hyperthermia in the treatment of HIV-related Kaposi's sarcoma. A phase I study.

Ten Caucasian males with HIV-related Kaposi's sarcoma, a disseminated disease which is refractory to usual therapies, underwent a single session of systemic hyperthermia with maintenance of core temperatures at 42 degrees C for 1 h. One complete remission and 7 partial remissions were identified when assessed 30 days post-treatment. Two mixed responses were noted in patients whose tumors showed autocrine growth. At 60 days 2 of the 7 partial responders began to show tumor progression. The complete remission persisted at 120 days. Surrogate markers of HIV activity fell in all responding patients. In no patient was there evidence of HIV activation. No adverse effects of heating were noted on CMV retinitis. Hairy leukoplakia resolved with heating in all patients. CD4 counts showed no appreciable change in any of the 8 patients with a presenting CD4 count below 60. In the 2 patients who presented with a CD4 count above 400, CD4 counts rose dramatically following treatment. No deaths were noted in this phase I study. The use of systemic hyperthermia in treatment of HIV-related illness warrants further study.

Total body hyperthermia in the treatment of Kaposi's sarcoma in an HIV positive patient.

The effect of prolonged exposure to heat on the HIV has had limited exploration. This is the report of a 33-year-old white man with positive tests for HIV and multiple lesions of Kaposi's Sarcoma. The patient was exposed to total body hyperthermia of 42 degrees C for two hours. Three months following hyperthermia the patient feels improved. The lesions of Kaposi's Sarcoma have markedly regressed, and the T4 lymphocyte count has risen from 5 per cc to 330 per cc. HIV cultures (blood) remain negative. These data would indicate this modality of therapy has altered the progression of disease in this patient.

[Lymph drainage therapy in secondary lymphedema caused by Kaposi sarcoma]. / Lymphdrainagetherapie bei sekundärem Lymphödem durch Kaposi-Sarkom.

For reasons not yet known HIV infected patients in the final state of their aids disease often tend to develop Kaposi's sarcoma. These tumours result in secondary lymphatic edemas which are found on both sides of the sarcoma. They reach up to the regional lymphatic nodes blocked by the tumour cells. Depending on the state of the edema a lymphaticdrainage treatment is indicated palliatively; the patients can thus be relieved. A fundamental deterioration of prognosis is not to be expected, as all patients are anyway in the final stage of this not yet curable disease. Differing from treatment of other lymphatic edema, it is of special importance to the therapist - apart from the particular and difficult psychic burden - to pay attention to infection protection by using gloves for each single treatment.

Gastrointestinal manifestations of the acquired immunodeficiency syndrome: a review of 22 cases.

Patients with acquired immunodeficiency syndrome (AIDS) frequently have diarrhea and weight loss. We prospectively examined the upper and lower gastrointestinal tracts in 22 AIDS patients, although severe medical problems often precluded full evaluation. Ninety-six percent (21 of 22) lost weight, and 55% (12 of 22) had diarrhea. The mean (+/- SD) weight loss was 34 +/- 19 lb. Steatorrhea was found in 4 of 14 patients, and D-xylose tests were abnormal in 8 of 14 patients. Mean serum albumin was 3.3 +/- 0.8 g/dl. A significantly diminished plasma selenium level, which can influence immune function, was noted in these AIDS patients. Gastrointestinal infections were identified in 45% of patients. Although diarrhea and malabsorption were more common in the infected group, weight loss and albumin were similar in those with and without demonstrated infections. Flexible sigmoidoscopy showed that of 15 patients, there were two with Kaposi's sarcoma, 10 normals, and three with nonspecific endoscopic changes of colitis. Infection was documented in all patients with colitis. Panendoscopy of the upper gastrointestinal tract was positive for AIDS-related pathology in five of 10 patients, including two with Kaposi's sarcoma, one with Candida esophagitis, one with herpetic esophagitis, and one with gastroduodenitis (biopsy positive for cryptosporidia); five patients had a normal-appearing tract. Small bowel or colonic biopsies frequently showed nonspecific inflammatory changes, although pathogens were identified in six patients (27% of all biopsies). We conclude that a wide variety of gastrointestinal pathology, which includes infectious agents, neoplasms, and inflammatory changes, may occur in AIDS patients. Therefore, AIDS patients, particularly those with diarrhea or weight loss, deserve an intensive evaluation for remediable lesions of their gastrointestinal tracts.

Kaposi's sarcoma of the bowel--presenting as apparent ulcerative colitis.

Persistent diarrhoea with mucus-production developed in a 37 year homosexual man, and an initial diagnosis of ulcerative colitis was made after barium enema examination and rectal biopsy. The patient later developed cutaneous lesions which proved to be Kaposi's sarcoma, and the bowel lesion was also subsequently shown to be Kaposi's sarcoma. This tumour occurred as a manifestation of the acquired immune deficiency syndrome (AIDS). The patient was treated with alpha interferon, with partial regression of the skin lesions, but progression of the bowel tumour. Because of severe bowel symptoms, including episodes of subacute intestinal obstruction, the localised bowel disease was treated with radiotherapy. In view of the increasing incidence of AIDS, a diagnosis of Kaposi's sarcoma must be considered in homosexual men presenting with persistent diarrhoea, for which no infectious cause can be demonstrated.