Hepatitis B reactivation during combination chemotherapy for AIDS-related lymphoma is uncommon and does not adversely affect outcome.
Explore the source record for details and available documents.
Anti-HIV Agents↗
Biomedical subjects
Mark Bower
Publications and source records attributed to Mark Bower.
The efficacy of ritonavir in the prevention of AIDS-related Kaposi's sarcoma.
Angiogenesis is thought to play a major role in the development of Kaposi's sarcoma (KS), considered by many to be a hyperplastic disorder caused in part by local production of inflammatory cytokines. The antiangiogenic effects of protease inhibitors, in particular ritonavir, have been suggested in laboratory work to lead to regression of KS, and recent data have shown the importance of ritonavir as a model of pharmaceutical development. As our clinical cohort data has shown that non-nucleoside reverse transcriptase inhibitor-based regimens are not inferior to protease inhibitor-based therapy in the prevention of KS, we investigated the specific contribution of ritonavir to chemoprevention of this AIDS-defining illness. In a logistic regression analysis, we found that ritonavir-based therapy confers no advantages compared to other regimens in the prevention of KS. This is consistent with data suggesting that regression of KS is mediated by an overall improvement in immune function and not by the effects of specific antiretrovirals.
Antiretroviral Therapy, Highly Active↗
A randomized trial to investigate the recycling of stavudine and didanosine with and without hydroxyurea in salvage therapy (RESTART).
BACKGROUND: Treatment failure during highly active antiretroviral therapy (HAART) is ultimately common and associated with the development of resistance mutations to both the specific drug in question and cross-resistance to other available treatment options. In heavily pre-treated patients, the recycling of antiretroviral agents that have been utilized previously may, however, be associated with antiviral efficacy. We therefore conducted an investigation into the concept of recycling stavudine (d4T, Zerit) and didanosine (ddI, Videx) with and without hydroxyurea, in the management of heavily pre-treated HIV-1 infected individuals requiring salvage therapy (RESTART). METHODS: We randomized 21 individuals with treatment failure to receive stavudine and didanosine or stavudine, didanosine and hydroxyurea, for 12 weeks prior to optimizing therapy. Viral load, immunological parameters, genotypic information and the virtual phenotypes were obtained at baseline and at the end of the study. RESULTS: Significant decreases in viral loads were observed in both groups during a 12 week study period (P = 0.04), the addition of hydroxyurea conferring no additional benefit. This was not predicted by information from genotypes and virtual phenotypes, and these did not reveal sensitive or specific phenotypic cut-offs for those individuals who responded to recycling. CONCLUSIONS: Salvage therapy with didanosine and stavudine can decrease viral loads in heavily pre-treated individuals. Genotypic and virtual phenotype profiles provide little additional information in this setting.
Adult↗
Nadir B cell counts are significantly correlated with the risk of Kaposi's sarcoma.
Infection with HIV-1 is known to impair B cell function. To further elucidate the role of B cells during infection and tumorigenesis, we studied their numbers in cases of AIDS-related Kaposi's sarcoma (KS) during the HAART era. Patients with AIDS-related KS were identified from a database of 4,480 HIV-1 positive individuals and the incidence of KS and rate ratio was stratified according to nadir number of B cells, measured as the CD19 count. In an unadjusted model, we observed that lower B cell counts were associated with a statistically significant increased risk of KS development (p < 0.001). We also observed a trend toward increased counts during KS resolution. When adjusted for nadir CD4 count in a multi-variable model, higher B cell counts were protective against KS development (p = 0.015). These data highlight a potential role for B cells and therefore the humoral immune system in KS aetiopathogenesis.
Acquired Immunodeficiency Syndrome↗
The evidence-based treatment of AIDS-related non-Hodgkin's lymphoma.
As we enter the third decade of the AIDS epidemic, it is apparent that a large number of cancers are more common in people with the human immunodeficiency virus type 1 (HIV). Non-Hodgkin's lymphoma (NHL) remains the second most common tumour in such patients. At the onset of the epidemic, dose-intense combination regimens were used but these were quickly abandoned in favour of dose-modified strategies because of difficulties in tolerating aggressive chemotherapy in the presence of underlying immunosuppression. With the improvements in supportive care including more effective anti-retroviral therapies, colony-stimulating factors and prophylaxis against opportunistic infections, we are returning to the traditional chemotherapeutic approaches similar to those utilised in the non-HIV infected individual including infusional regimens. In this review, we discuss the evidence for choosing particular therapies in patients with AIDS-related NHL.
Administration, Oral↗
Kaposi's sarcoma as a model for cancer immunotherapy.
Physicians have, for over a century, attempted to harness the potential therapeutic power of the immune system to treat patients with cancer. The discovery that cancer regression can be achieved by immune rejection of tumour antigens theoretically allows the eradication of neoplastic cells without toxicity to normal tissues. An understanding of the mode of presentation of tumour antigens, including those complexed to heat shock proteins by major histocompatibility complex (MHC) class I and class II molecules, and their recognition by CD8(+) and CD4(+) T cells, respectively, has further delineated the potential cancer rejection pathways involved. This also enables the sustained induction and expansion of specific anti-tumour T cells with cytolytic activity.
Animals↗
Cardiotoxicity after liposomal anthracyclines.
Explore the source record for details and available documents.
Acquired Immunodeficiency Syndrome↗
Studies on the allostimulatory function of dendritic cells from HCV-HIV-1 co-infected patients.
There is increasing recognition of the potential morbidity and mortality associated with HIV-1 and hepatitis C (HCV) co-infection. HIV appears to adversely affect HCV disease while the reciprocal effect of HCV on HIV remains controversial. We therefore studied the effect of co-infection on dendritic cell function versus HIV infection alone, as previous work has shown that HCV impairs dendritic cell (DC) function. HIV-1 positive individuals with HCV were matched for CD4 count, HIV-1 RNA viral load and therapy, to HIV-1 positive patients without HCV. Monocyte-derived DC were generated and mixed leukocyte reactions were performed. We assessed allostimulatory capacity with and without administration of exogenous Th1 cytokines, using thymidine uptake and cell division analyses with the vital dye CFSE. We found that monocyte-derived DC from co-infected individuals showed no significant differences in allostimulatory capacity to ex vivo generated DC from HIV-1 infected individuals without HCV. Unlike the situation with HCV infection alone, this impairment was not reversed by increasing concentrations of either interleukin-2 or -12. Monocyte-derived DC from HIV-1 and HCV co-infected individuals have a similar allostimulatory capacity to DC from matched patients with HIV-1 alone. These findings are compatible with results of prior clinical studies that found no evidence that HCV co-infection altered HIV disease progression and has implications for immunotherapeutic approaches in co-infected individuals.
Adult↗
Fifty years of multicentric Castleman's disease.
Benjamin Castleman first described multicentric Castleman's disease (MCD) in a series of cases in 1954. Interest in MCD has grown in recent years following an association with human immunodeficiency virus (HIV) infection. Castleman's disease is separated into localized disease and MCD. The latter is characterized by polylymphadenopathy and multiorgan involvement. Histologically, Castleman's disease is divided into the hyalinized vascular form and a plasma cell variant, the former being more common in localized disease and the latter more common in MCD. MCD is associated with Kaposi's sarcoma herpesvirus (KSHV) infection, which is alternatively termed human herpesvirus 8 (HHV8). This virus encodes a homologue of interleukin 6 (vIL 6), which may mediate some systemic features of MCD. The diagnosis of Castleman's disease is established by biopsy and treatment is often based on published case reports only, as there are no randomized trials of therapy. Surgery has less of a role in MCD than in localized disease, but debulking by splenectomy may be useful to alleviate haematological sequelae. Systemic treatments for MCD have included chemotherapy, anti-herpesvirus treatments to reduce the KSHV viral load, highly active antiretroviral therapy (HAART) to reduce HIV viraemia and latterly monoclonal antibodies against both IL 6 and CD20. The introduction of HAART has altered the natural history of HIV infection; however, its impact on MCD is difficult to ascertain. Optimization and consensus in treatment of these patients remains a target for the future.
Aged↗
Resolution of AIDS-related Castleman's disease with anti-CD20 monoclonal antibodies is associated with declining IL-6 and TNF-alpha levels.
A 32-year-old HIV-1 positive man was diagnosed with Castleman's disease following a long history of constitutional symptoms. Primary therapy with single agent rituximab was associated with a near complete response. During this time, his KSHV (Kaposi's sarcoma-associated herpesvirus) viral load decreased and we also observed immediate, large and sustained decreases in interleukin-6 (IL-6) and tumor necrosis factor-alpha levels (TNF-alpha). This highlights the close association between circulating cytokines such as IL-6 and virally-induced malignancy.
Acquired Immunodeficiency Syndrome↗
Lessons for HIV from Tuskegee.
We are fortunate to live in an era in which research allows significant progress in the therapy of the major diseases that affect us. However, evaluating their efficacy and safety is expensive, laborious and involves the study of human subjects in an appropriate manner. The principles of such trials have a heterogeneous basis encompassing the principles of utilitarianism, distributive justice, the protection of individual rights and the investigators' commitment to patients. The Tuskegee study of untreated syphilis is the longest non-therapeutic experiment on human beings in medical history. It continues to cast its shadow on the relationship between black Americans and the broader biomedical community. Parallels and the relationship with the HIV pandemic are discussed.
Anti-Bacterial Agents↗
Multiple human papillomavirus types appear to be a feature of anal not cervical intra-epithelial neoplasia.
Explore the source record for details and available documents.
Anus Neoplasms↗
Antibody-targeted MHC complex-directed expansion of HIV-1- and KSHV-specific CD8+ lymphocytes: a new approach to therapeutic vaccination.
The ability of therapeutic vaccines to generate large numbers of CD8+ T lymphocytes that have specificity for HIV-1 or other virally infected cells has enormous potential clinical value. However, approaches to produce cytotoxic T lymphocytes (CTLs) in vivo via vaccine technology have thus far been disappointing and the ex vivo production of cells for adoptive transfer is labor intensive and expensive. We describe the results of a 2-step antibody-targeting system for the production of CD8+ T lymphocytes specific for HIV-1 and Kaposi sarcoma-associated herpesvirus (KSHV), suitable for use in vivo. In 8 consecutive human leukocyte antigen-A2 (HLA-A2)-positive HIV-1-infected individuals with Kaposi sarcoma, 2 cycles of this system resulted in more than 1 Log increases of specific anti-HIV and anti-KSHV CD8+ lymphocytes. These expanded cells have an effector phenotype that includes the ability to produce interferon-gamma and CD45Ra+/CD69+ staining. We have shown that antibody-targeted B cells can function as effective antigen-presenting molecules and lead to sustained specific T-lymphocyte expansion from peripheral blood mononuclear cells (PBMCs) of immunosuppressed individuals. This approach, which offers an easy and effective protocol for the amplification of specific antiviral and antitumor CTLs, may offer significant advances for in vivo T-cell immunotherapeutic protocols.
Antigens, CD↗
Natural killer cells are not infected by Kaposi's sarcoma-associated herpesvirus in vivo, and natural killer cell counts do not correlate with the risk of developing Kaposi's sarcoma.
Although the innate immune system is implicated in the control of Kaposi's sarcoma (KS), the risk of developing KS is not associated with the nadir natural killer (NK) cell count, and NK cell counts do not significantly increase or decrease during KS resolution. KS-associated herpesvirus replication was not demonstrated in vivo or in vitro within NK cells, suggesting that NK cells do not contribute to the resolution of KS. Their role appears limited to events occurring during early infection.
Antiretroviral Therapy, Highly Active↗
A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi's sarcoma.
OBJECTIVE: To determine the incidence of Kaposi's sarcoma (KS) in a prospective longitudinal cohort of HIV-1-infected individuals before during and after the introduction of highly active antiretroviral therapy (HAART) and to compare the incidence of KS between specific HAART regimens. DESIGN: Univariate and multivariate analysis of 8640 HIV-1-infected individuals. METHODS: The protective effect of HAART regimens based on either protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI) on the development of KS was examined in prospectively recorded data to determine whether treatments based on the two types of drug were comparable with regard to a reduction in the incidence of KS. RESULTS: A total of 1204 patients with KS were identified. The incidence of KS decreased from 30/1000 patient-years prior to 1995 to 0.03/1000 patient-years in 2001. Multivariate analysis showed that age, nadir CD4 cell count and antiretroviral class exposure were significant independent predictors of KS. NNRTI-based HAART (adjusted rate ratio, 0.42; 95% confidence interval 0.24-0.37) had a similar protective effect to PI-based HAART (adjusted rate ratio, 0.47; 95% confidence interval 0.38-0.58). Most patients who develop KS on HAART [30/35 (86%)] had evidence of virological treatment failure. CONCLUSION: PI- and NNRTI-based HAART regimens are equally effective as protection against KS. This is the first study to demonstrate a decreased incidence of an AIDS-defining disease with NNRTI-based therapy.
Acquired Immunodeficiency Syndrome↗
Disease-associated dendritic cells respond to disease-specific antigens through the common heat shock protein receptor.
The most abundant intracellular proteins, heat shock proteins (HSPs), serve as molecular chaperones for regulatory and maturation pathways. Diverse families of HSPs have been shown to bind antigenic peptides and to play major roles in innate and adaptive immune responses through the common HSP receptor, CD91. HIV-1+ patients with Kaposi sarcoma (KS) were matched for CD4 count and HIV-1 RNA viral load to HIV-1+ patients without Kaposi sarcoma (and negative for Kaposisarcoma-associated herpesvirus). We then investigated the pathways used by tumor lysates, viral lysates, and viral particles in their activation. In particular, we observed immune responses after HSP depletion using antitumor antibiotics and blockade of the common HSP receptor, CD91. Despite the impaired functional capacity of dendritic cells (DCs) derived from patients with KS, DCs retain the ability to prime the adaptive arm of the immune system through the common HSP receptor, leading to phenotypic activation and stimulation of tetramer-positive CD8+ cytotoxic T cells. We also show that interferon-producing plasmacytoid DCs are selectively depleted in KS-positive compared with matched KS-negative HIV-1-infected patients. Functionally impaired DCs can effectively cross-present immune responses through the common HSP receptor. These results have important implications for the etiopathogenesis of KS and for the development and design of any compounds, including vaccines, derived from cellular lysates.
Acquired Immunodeficiency Syndrome↗
Leptomeningeal disease in AIDS-related non-Hodgkin's lymphoma.
OBJECTIVE: To evaluate clinicopathological features associated with leptomeningeal disease in systemic AIDS-related non-Hodgkin's lymphoma (NHL) and to compare outcomes to those without leptomeningeal disease. In addition to evaluate intrathecal chemoprophylaxis for patients with good immunological parameters and high risk of meningeal relapse (bone marrow, paraspinal or paranasal involvement or Burkitt's lymphoma histology). DESIGN AND METHODS: Prospective data, which has been collected on our cohort of 8640 HIV seropositive patients treated at the Chelsea and Westminster Hospital includes 176 patients with systemic AIDS-related NHL, was analysed. RESULTS: At presentation, 18 (10%) patients had meningeal involvement. There were significant associations between meningeal disease and both Burkitt's lymphoma and paraspinal or paranasal involvement. There was no difference in the overall survival between patients with or without meningeal involvement at presentation (Kaplan-Meier log-rank, P = 0.35) and the 1-year actuarial survivals are 25% [95% confidence interval (CI), 3-47%] for patients with meningeal involvement and 33% (95% CI, 26-41%) for those without. Prophylactic intrathecal chemotherapy was administered to 21 high-risk patients and four (19%) relapsed with meningeal disease. CONCLUSIONS: This single-centre experience of a large cohort has demonstrated that meningeal involvement at presentation correlates with Burkitt's lymphoma histology and paraspinal or paranasal space disease, but not with bone marrow lymphoma. It also documents that long-term survival is achievable rarely in patients who present with meningeal disease and in patients with isolated meningeal relapse.
Adult↗
HIV-related lung cancer in the era of highly active antiretroviral therapy.
OBJECTIVES: To address the impact of highly active antiretroviral therapy (HAART) on the incidence and outcome of patients with HIV-related lung cancer. DESIGN AND SUBJECTS: Patients with HIV-related lung cancer were identified from a prospective HIV data base of 8400 patients diagnosed between 1986 and 2001. Patients diagnosed with HIV-related lung cancer before 1996 were in the pre-HAART cohort whereas the remainder were in the post-HAART cohort. METHODS: The incidence of HIV-related lung cancer in the pre- and post-HAART cohorts was compared with the age and sex-matched population of south east England. Clinicopathological features, treatments and outcomes were also recorded. RESULTS: The incidence of HIV-related lung cancer increased from 0.8 (95% CI 0.2-3.2)/10(5) patient-years follow-up in the pre-HAART era to 6.7 (95% CI 3.1-13.9)/10(5) patient-years follow-up in the post-HAART era. The age and sex-matched incidence of lung cancer in south east England was 0.75 (95% CI 0.63-0.87)/10(5) patient-years, suggesting that HIV-related lung cancer only occurred more frequently in the post-HAART era (relative risk 8.93, 95% CI 4.92-19.98). The patient characteristics and outcomes were similar in the pre- and post-HAART eras, although the time interval between testing HIV positive and developing HIV-related lung cancer was longer in post-HAART patients. CONCLUSION: In this study HIV-related lung cancer occurred more frequently in the post-HAART era, when compared with the HIV-negative population. Unfortunately, the outcome of these patients remains poor despite HAART.
Antiretroviral Therapy, Highly Active↗