Four measures of antiretroviral medication adherence and virologic response in AIDS clinical trials group study 359

AIDS Clinical Trials Group (ACTG) 359 was a randomized, partially double-blinded factorial study of 6 antiretroviral regimens, all including saquinavir, among HIV-infected persons in whom prior therapy had failed (n = 258). Counts of remaining saquinavir capsules were determined between weeks 0 and 4; at weeks 4, 8, and 16, self-reported adherence was estimated from 2-day report of doses skipped, therapeutic coverage, and percent of doses taken were determined by electronic monitoring devices applied to saquinavir bottles, and the saquinavir 24-hour area under the curve (AUC) was estimated. Relationships were evaluated among these 4 adherence measures and the primary endpoint of week 16 HIV RNA change. Thirty percent of 254 subjects had HIV RNA < or =500 copies/mL at week 16. Only self-reported adherence and saquinavir AUC were significantly associated with week 16 HIV RNA change (P = 0.019 and 0.023, respectively), and these measures were higher in subjects with week 16 HIV RNA < or =500 copies/mL (P = 0.03 and 0.008, respectively). The ability to detect a correlation between electronically monitored adherence and virologic response was limited by the small sample size. Self-reported adherence and saquinavir AUC were significant predictors of virologic response, in this evaluation. These findings provide insight into methods of assessing and improving adherence to antiretroviral regimens.     

Kaposi's sarcoma in AIDS patients: Long-term treatment with recombinant interferon alpha-2A and chemotherapy

Summary We evaluated the response to therapy and outcome in patients with HIV-associated KS. Eighteen of 26 patients with newly diagnosed KS were treated continuously with IFN until progression of the disease occurred. In most patients with progressive disease, chemotherapy, usually with vinca alcaloid derivatives was instituted. Results were disappointing: 10 of 26 patients (38.5%) died after a median follow-up period of 4.5 months. Survival was shortest in patients who developed opportunistic infections, malignant lymphoma, or had a low OKT₄/OKT₈ ratio. Only one patient showed a complete remission and one patient had a partial remission under IFN therapy. Five additional patients had stable disease. Chemotherapy was without measurable effect on KS in patients who had progressive disease under IFN. IFN therapy was associated with various, not life-threatening adverse effects and was best tolerated by patients with a low OKT₄/OKT₈ ratio. Our results indicate that only a small portion of AIDS patients with KS seem to benefit from a continuous treatment with IFN.Abbreviations AIDS Acquired immunodeficiency syndrome - CNS Central nervous system - ELISA Enzyme linked immunosorbent assay - ESR Erythrocyte sedimentation rate - HIV Human immunodeficiency virus - IFN Recombinant interferon alpha-2a - KS Kaposi's sarcoma - WHO World Health Organization     

Kaposi's sarcoma in the bone marrow of a patient with AIDS

The authors report a case of Kaposi's sarcoma (KS) involving the bone marrow of a patient with acquired immune deficiency syndrome (AIDS). The morphologic features, differential diagnosis, immunostaining pattern, and unusually low frequency of marrow involvement by AIDS-related KS are discussed.     

Incidence and trends in Kaposi's sarcoma in the era of effective antiretroviral therapy

OBJECTIVE: To evaluate the impact of antiretroviral and antiherpesvirus therapies on the incidence of KS and assess trends in incidence of Kaposi's sarcoma (KS) in a large multicenter HIV/AIDS surveillance system between 1990 and 1998. METHODS: Incidence was calculated per 100 person-years (py); the effects of therapies on risk for KS were calculated by using multivariate Poisson regression controlling for gender, race/ethnicity, age, HIV exposure mode, CD4+ cell count, and calendar year. Antiretroviral therapy was defined as monotherapy, dual therapy, or triple therapy (95% of triple therapy regimens contained a protease inhibitor). Acyclovir, ganciclovir, and foscarnet were the antiherpesvirus therapies evaluated. RESULTS: There were 37,303 HIV-infected people in the study contributing 70,238 py. Those prescribed triple antiretroviral therapy had a 50% reduction in the incidence of KS (95% confidence interval, 20%-70%) compared with those who were not prescribed antiretroviral therapy and there was a reduction in risk for KS among persons prescribed foscarnet (p =.05). Overall, KS incidence declined an estimated 8.8% per year (observed incidence 4. 1 per 100 py in 1990 to 0.7 per 100 py in 1998; p <.001). CONCLUSION: Incidence of KS is declining in this large U.S. population and may continue to decline as new, more effective antiretroviral agents are developed and used widely.     

Histogenesis of Kaposi's sarcoma associated with AIDS: a histologic, immunohistochemical and enzyme histochemical study

Twenty-one cases (25 biopsies including 9 frozen biopsies) of Kaposi's sarcoma associated with the acquired immune deficiency syndrome (AIDS) were examined immunohistochemically, lectin-histochemically, and enzyme histochemically to ascertain the histogenesis of the lesion. The Kaposi's sarcomas were histologically subtyped according to a modified Schmid's classification (granulation tissue-like-, angiosarcoma-like- and spindle cell type). In almost all lesions, many atypical vasoforming cells and at least some spindle cells without definite evidence of vasoformation by conventional microscopy were positive for factor VIII-related antigen, BMA 120 (a new monoclonal antibody to an endothelial cell-specific antigen), Ulex europaeus I (UEA-I), alkaline phosphatase and ATPase. Linear reaction products for BMA 120 and UEA-I, suggesting the luminal surface of immature vascular channels, were sometimes recognized in the positive spindle cells. Electron micrographs confirmed endothelial characteristics, such as irregular and fragmented but distinct basal lamina and numerous pinocytotic vesicles, in both the UEA-I- and ATPase-positive spindle cells. Among spindle cells negative for the endothelial markers, there were many macrophages as a stromal reaction to tumor tissue, identified by monoclonal antibodies to macrophages (KiM 6, 7, 8 and EBM 11), acid phosphatase and alpha-naphthyl acetate esterase. The results of the immuno- and enzyme histochemical investigations did not correlate with the different histologic types of Kaposi's sarcoma. However, our results strongly suggest that tumor cells of Kaposi's sarcoma are derived from vascular endothelial cells rather than lymphatic endothelium.     

Interferon-alpha2b with protease inhibitor-based antiretroviral therapy in patients with AIDS-associated Kaposi sarcoma: an AIDS malignancy consortium phase I trial

We evaluated the safety and maximum tolerated dose of interferon (IFN)-alpha2b in combination with protease inhibitor-based highly active antiretroviral therapy (HAART) in a phase 1 study in 14 patients with AIDS-associated Kaposi sarcoma (KS). Planned IFN dose levels were 0, 1, 5, 10, and 15 million IU administered by daily subcutaneous injection. Dose-limiting toxicities were neutropenia and malaise. The maximum tolerated IFN dose was 5 million IU/d. The median CD4 count increased from 260 cells/muL at baseline to a maximum on-study value of 359 cells/muL. In 6 patients with paired baseline and on-study values, the median HIV RNA level decreased from 20,179 copies/mL to a minimum on-study value of 309 copies/mL. Of 13 patients whose KS response could be evaluated, 5 showed objective tumor regression. Responses occurred in HAART-experienced and HAART-naive subjects. Five patients, including 2 responders, 2 with stable KS, and 1 with progression, had serial measurements of Kaposi sarcoma herpesvirus (KSHV) load. None of these patients, irrespective of treatment arm or KS response, showed durable clearance of KSHV from plasma or peripheral blood mononuclear cells. This study establishes a safe dose of IFN that can be used with HAART and, potentially, with other inhibitors of KS in future clinical trials.     

NK cell activity controls human herpesvirus 8 latent infection and is restored upon highly active antiretroviral therapy in AIDS patients with regressing Kaposi's sarcoma

Kaposi's sarcoma (KS) develops upon reactivation of human herpesvirus 8 (HHV8) infection and virus dissemination to blood and tissue cells, including endothelial and KS spindle cells where the virus is mostly present in a latent form. However, this may likely require the presence of compromised host immune responses and/or the evasion of infected cells from the host immune response.In this regard, mechanisms of evasion of productively infected cells from both CTL and NK cell responses, and resistance of latently infected cells from specific CTL, have already been shown. Here we show that cells which are latently infected by HHV8 are indeed efficiently lysed by NK cells from individuals with a normal immune response. Notably, NK cell-mediated immunity was found to be significantly reduced in AIDS patients with progressing KS as compared to both HIV-negative patients with indolent classic KS or normal blood donors. However, it was restored after treatment with the highly active antiretroviral therapy (HAART) in AIDS-KS patients, that showed regression and clearance of HHV8 from PBMC. By contrast, AIDS-KS patients with a more aggressive disease and no clinical response had persistent HHV8 viremia associated with reduced NK cell cytotoxicity. These results suggest a key role for NK cells in the control of HHV8 latent infection, KS development, and in disease remission upon HAART.     

Chylothorax as fatal complication in fulminating Kaposi's sarcoma in a patient with AIDS

Kaposi's sarcoma (KS) is one of the earliest and most frequent manifestations of the acquired immunodeficiency syndrome. About 20 percent of all German AIDS patients present with KS as their first sign of AIDS. Visceral involvement occurs in up to 40% percent of patients with disseminated KS [1, 2, 3]. Fatal complications are known in pulmonary and gastrointestinal KS. They include respiratory failure and fatal bleeding [1, 2]. To our knowledge an arrosion of the thoracic duct with chylothorax has not yet been reported.     

Cognitive-behavioral group therapy in obsessive-compulsive disorder: a randomized clinical trial

BACKGROUND: The present study was designed to verify the efficacy of cognitive-behavioral group therapy (CBGT) in reducing obsessive-compulsive symptoms and the intensity of overvalued ideas, as well as in improving the patient's quality of life. METHODS: Forty-seven patients meeting DSM-IV criteria for obsessive-compulsive disorder (OCD) were randomly assigned to either 12 weekly CBGT sessions or a waiting list (control group). Treated patients were followed for three months. RESULTS: There was a significant reduction in the Yale-Brown Obsessive-Compulsive Scale (p < 0.001), in the National Institute of Mental Health Obsessive-Compulsive Scale (p < 0.001), in the Overvalued Ideas Scale (p < 0.001), and a significant improvement in the quality of life in the four domains of the World Health Organization Quality of Life Assessment Scale: physical (p < 0.001), psychological (p < 0.017), social (p < 0.018) and environmental (p < 0.04). No significant reduction was found in the Hamilton Rating Scale for Anxiety (p = 0.111) and the Hamilton Rating Scale for Depression (p = 0.271). The concomitant use of anti-obsessional medications did not influence the results. The rate of improved patients was 69.6% in the treated group and 4.2% in the control group (p < 0.001). The therapeutic gains were maintained and an additional reduction in symptoms was observed during the 3-month follow-up period. CONCLUSIONS: The results suggest that CBGT is effective in reducing the intensity of OCD symptoms and of overvalued ideas, and that it improves the OCD patient's quality of life in a short period of time.     

Myogenic cells in Kaposi's sarcoma: an ultrastructural study.

An ultrastructural study of a metastatic Kaposi's sarcoma in a cervical lymph node demonstrated the presence of endothelial cells, smooth muscle cells, fibroblasts and myofibroblasts. Some of these cells exhibited phagocytic activity in relation to extravasated red blood cells. The ultrastructural features favour the suggestion of an origin of Kaposi's sarcoma from pluripotential mesenchymal cells which may differentiate into more specialised cell types including endothelial, smooth muscle, fibroblastic and myofibroblastic cells.     

Treating anxiety disorders in children with group cognitive-behaviorial therapy: a randomized clinical trial

A randomized clinical trial evaluated the therapeutic efficacy of group cognitive-behavioral therapy (GCBT) versus a wait-list control (WLC) condition to treat anxiety disorders in children. Results indicated that GCBT, with concurrent parent sessions, was highly efficacious in producing and maintaining treatment gains. Children in GCBT showed substantial improvement on all the main outcome measures, and these gains were maintained at 3-, 6-, and 12-month follow-ups. Children in the WLC condition did not show improvements from the pre- to the postwait assessment point. These findings are discussed in terms of the need to continue to advance the development of practical, as well as conceptual, knowledge of efficacious treatment for anxiety disorders in children.     

Efficacy of antiretroviral therapy adherence interventions: a research synthesis of trials, 1996 to 2004

OBJECTIVE: To conduct a quantitative review of published trials of antiretroviral therapy (ART) adherence interventions. DESIGN: A research synthesis of published ART adherence intervention outcome studies. SAMPLE: ART adherence intervention outcome studies meeting inclusion criteria published between 1996 and December 2004 (k=24). MAIN OUTCOME MEASURE: Effect sizes (ESs [d]) were calculated for each study outcome, producing 25 immediate postintervention outcomes and an additional 13 follow-up ESs. Reported pre- to post-ART adherence between groups (k = 15) or within groups (k = 10) served as the main outcome converted to standardized ES. RESULTS: ART adherence interventions had a small effect (d = 0.35, odds ratio [OR] = 1.88) that varied considerably across studies. Interventions that specifically enrolled participants with known or anticipated problems with ART adherence demonstrated medium effects on adherence (d = 0.62, OR = 3.07). Interventions that did not target their participants on similar criteria had quite small effects(d = 0.19, OR = 1.41). Adherence improvements showed no tendency to decay across time. CONCLUSIONS: Outcomes of studies targeting those with poor ART adherence had stronger effects than those intervening with groups of individuals who were mixed in terms of pretest levels of adherence. Adherence intervention outcome studies must carefully delineate their target populations, because defining individuals as "on ART" does not provide the level of specificity needed to design and implement effective interventions.     

Hyaline globules in Kaposi's sarcoma: a light microscopic and immunohistochemical study.

Hyaline globules (HG) were detected in 51 of 54 Kaposi's sarcoma (KS) lesions (94.4%), including all four non-acquired immunodeficiency syndrome (AIDS) cases of cutaneous KS in this group of cases. Thus, there was no correlation between the presence of HG and the presence or absence of AIDS, nor could we demonstrate any relationship between the presence or prominence of HG and either the histologic pattern or anatomical distribution of KS. HG were located mainly in the cytoplasm of perivascular cells, histiocytoid cells, and spindle-shaped cells and occasionally in endothelial cells lining vessels or slit-like spaces. Extracellular HG were also seen. HG stained positively with periodic acid-Schiff with and without diastase digestion and with phosphotungstic acid-hematoxylin. HG were immunohistochemically negative for alpha 1-antitrypsin, alpha 1-antichymotrypsin, lysozyme, and Factor VIII-related antigen, but the cells containing HG were often positive for alpha 1-antichymotrypsin and occasionally for alpha 1-antitrypsin and Factor VIII-related antigen. HG were also detected in five of six angiosarcomas, two of ten pyogenic granulomas, and seven of 32 inflammatory granulation tissues. These were immunohistochemically similar to HG in KS. Thus, HG are not specific for KS. We support the interpretation that HG are most likely digested erythrocytes.