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Biomedical subjects

Justin Stebbing

Publications and source records attributed to Justin Stebbing.

At least 55 records · Page 3Linked to original sources
PubMed2005

Serum interleukin (IL)-1, IL-2, sIL-2Ra, IL-6 and thrombopoietin levels in patients with chronic myeloproliferative diseases.

A number of growth factors are involved in clonal haematopoietic expansion and their clinical significance in patients with chronic myeloproliferative diseases requires further evaluation. Using enzyme-linked immunosorbent assays, we analysed serum levels of interleukin (IL)-1a, IL-1b, IL-2, IL-6, the soluble IL-2 receptor alpha (sIL-2Ra), and thrombopoietin (TPO), in 25 individuals with myelofibrosis with myeloid metaplasia (MMM), 40 with essential thrombocythaemia (ET), eight with polycythaemia vera (PV), 10 patients with chronic myeloid leukaemia (CML) and 27 normal controls. These were correlated with clinicopathological characteristics including overall survival, and histopathological bone marrow features, including angiogenesis. The serum derived from patients with MMM, ET, PV and CML contained significantly higher IL-2 and sIL-2Ra than healthy subjects, while IL-6 levels were higher only in MMM and CML than controls. IL-2, sIL-2Ra and IL-6 levels were raised during the transformation phase of CML, during progression of MMM to AML, and ET and PV to myelofibrosis (P < 0.001). There was a positive correlation between IL-2, sIL-2Ra, IL-6 and angiogenesis in bone marrow samples. Cytokines may be useful markers for predicting clinical evolution, reflecting increased angiogenesis. This requires further evaluation to guide diagnostic and therapeutic options.

Adult↗
PubMed2005

Paclitaxel for AIDS-associated Kaposi's sarcoma.

Treatment options are limited for patients with advanced acquired immunodeficiency syndrome-related Kaposi's sarcoma (AIDS-KS). The management of early stage cutaneous AIDS-KS has been revolutionized by the introduction of highly active antiretroviral therapy and for most patients highly active antiretroviral therapy alone will control early stage AIDS-KS. However, patients with advanced stage Kaposi's sarcoma with visceral disease, tumor-associated edema or extensive oral disease require systemic chemotherapy in addition to antiretrovirals. The standard first-line therapy for these affected individuals is a liposomal anthracycline, and response rates of around 70% are usually achieved. For patients with refractory or recurrent AIDS-KS, treatment algorithms are less well defined. The use of paclitaxel in these circumstances is reviewed.

Acquired Immunodeficiency Syndrome↗
PubMed2005

The rationale and development of new drugs to treat HIV infection.

Fewer than one million HIV infected individuals are currently receiving antiretroviral therapy. Present antiretroviral therapy costs between 10,000 dollars and 20,000 dollars per year, which provides excellent value for money in developed countries with a cost of about 10,000 dollars per life year saved; this compares very favourably with other therapies in chronic use. Recent studies have demonstrated a dramatic decline in HIV and AIDS related morbidity and mortality across developed countries and these reductions have been sustained since the introduction of highly active antiretroviral therapy (HAART) since 1996. The use of HAART has been associated with specific toxicities related to the drug class, problems with adherence with the subsequent emergence of viral isolates and resistance associated mutations. The replacement of older therapies with newer drugs that avoid cross resistance even within the same class of antiretroviral, represents a new hope in retroviral targeting.

Anti-HIV Agents↗
PubMed2005

New drugs for old.

The use of highly active antiretroviral therapy (HAART) has led to the emergence of viral isolates with resistance-associated mutations. Currently, new cases of highly resistant HIV infections associated with rapid progression to AIDS are being reported. The features of a new drug for HIV treatment must include selective potent activity against wild-type virus as well as against mutant virus that has been selected by the use of current antiretroviral treatment regimens. As patients in industrialised countries may live with HIV infection for decades, new drugs must also encourage adherence with simplified dosing regimens associated with favourable toxicity profiles. The replacement of older therapies with newer drugs that avoid cross resistance, even within the same class of antiretroviral, represents a new hope in retroviral targeting.

Anti-HIV Agents↗
PubMed2004

A randomized study comparing a three- and four-drug HAART regimen in first-line therapy (QUAD study).

BACKGROUND: Evidence from randomized controlled trials supports the use of triple therapy. Research is required on the effectiveness of quadruple therapy in comparison to this and the relative effectiveness of specific highly active antiretroviral therapy (HAART) combinations. METHODS: Antiretroviral-naive individuals (n = 53) with an HIV-1 viral load >100 000 copies/mL were randomized to receive three-drug HAART with zidovudine/lamivudine (Combivir) and efavirenz or quadruple therapy with zidovudine/lamivudine/abacavir (Trizivir) and efavirenz (quad regimen). Patients continued on HAART for 48 weeks with regular clinical and immunological assessment. Standard and ultrasensitive (<5 copies/mL) viral load testing was carried out. RESULTS: A DAVG (difference in averages) analysis of the fall in viral load and increase in CD4 count showed no significant differences between regimens. Triple therapy resulted in a -4.17 log change (95% CI, -4.48 to -3.85) and quadruple therapy in a -4.36 log change (95% CI, -4.68 to -4.03) in viral load. For CD4 counts, the triple therapy arm increased by 164 cells/mm(3) (95% CI 112-217) and the quadruple arm by 185 (95% CI, 133-237). In an intent-to-treat analysis, 77% of patients in the triple therapy group reached an undetectable viral load (<50 copies/mL) compared with 84.2% of the quadruple therapy group. For ultrasensitive viral load testing, 23% and 18% of each group, respectively, reached undetectable viral loads. The hazard ratio for attaining a viral load of <5 copies/mL was 0.59 (95% CI, 0.26-1.33) for quadruple versus triple therapy. Three individuals in the triple therapy arm and nine in the quadruple therapy arm discontinued treatment. CONCLUSIONS: No differences in any analyses were observed between a standard of care regimen (zidovudine/lamivudine and efavirenz) and the quad regimen (zidovudine/lamivudine/abacavir and efavirenz).

Alkynes↗
PubMed2004

HIV-associated anal cancer: has highly active antiretroviral therapy reduced the incidence or improved the outcome?

BACKGROUND: Highly active antiretroviral therapy (HAART) has reduced the incidence and improved the survival of patients with Kaposi sarcoma and AIDS-related non-Hodgkin lymphoma. We wished to evaluate its effects on incidence and survival in HIV-associated anal cancer. METHODS: We measured the incidence and survival of patients with invasive anal cancer from our prospective cohort of 8640 HIV-seropositive individuals. RESULTS: In our cohort of 8640 HIV-seropositive individuals, the incidence of invasive anal cancer (diagnosed in 26 patients) is 60 per 100,000 patient-years. This is 120 times higher than in the age- and gender-matched general population. The incidence of invasive anal cancer in the HIV cohort was 35 (95% confidence interval CI: 15-72) per 100,000 patient-years of follow-up in the pre-HAARTera (1984-1995) and 92 (95% CI: 52-149) per 100,000 patient-years of follow-up in the post-HAARTera (1996-2003) (P > 0.05). These figures are significantly higher than those for the general population (P < 0.001 for both) and give a relative risk of 67 and 176 in the pre- and post-HAART eras, respectively, compared with the general population. The 5-year overall survival is 47% (95% CI: 24%-70%), and the 5-year disease-free survival is 66% (95% CI: 45%-87%). There is no difference in overall survival between the pre- and post-HAART eras (log rank P = 0.19). CONCLUSIONS: Unlike other HIV-associated cancers, there has been no significant change in the incidence, clinical features, or overall survival since the introduction of HAART.

AIDS-Related Opportunistic Infections↗
PubMed2004

Renal dysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently: a cohort and case-control study.

BACKGROUND: Tenofovir disoproxil fumarate (tenofovir DF), the first nucleotide analogue reverse transcriptase inhibitor approved for the treatment of HIV infection, has been associated with renal dysfunction in isolated cases. We investigated the overall incidence and risk of renal dysfunction in individuals receiving tenofovir DF and compared this with other antiretrovirals. METHODS: Data from the Chelsea and Westminster cohort were analyzed to reveal HIV-positive individuals with a creatinine value greater than 120 micromol/L at any time, the upper limit of normal used by our reference laboratory. These individuals were classified according to antiretroviral exposure and time exposed. A matched case-control study was performed comparing patients who had received tenofovir DF and subsequently developed a creatinine value greater than 120 micromol/L against controls who had been treated with tenofovir DF and had not experienced a creatinine elevation. RESULTS: Of 4183 HIV-positive patients, 1175 were identified as having a recorded creatinine value >120 micromol/L. Comparison of antiretroviral-naive patients and patients exposed to tenofovir DF- and non-tenofovir DF-containing regimens revealed a lower rate ratio and probability of developing a creatinine value >120 micromol/L in patients exposed to tenofovir DF (rate ratio vs. no antiretrovirals = 0.22, 95% confidence interval [CI]: 0.07-0.69; P < 0.001) with no significant difference between HAART regimens, corrected for duration of exposure. Of the 1058 individuals who were exposed to tenofovir DF, 84 (8%) patients experienced a creatinine value >120 micromol/L subsequent to exposure. An alternative etiology of renal dysfunction was found in 75 (90%) of these individuals. CONCLUSIONS: Tenofovir DF is not associated with renal dysfunction more frequently than other antiretroviral drugs, and the occurrence of renal dysfunction in this context is usually attributable to other causes.

Adenine↗
PubMed2004

Protease inhibitors potentiate chemotherapy-induced neutropenia.

Pharmacokinetic interactions between chemotherapy and highly active antiretroviral therapy (HAART) are described, but there are few data on their clinical relevance. Patients with systemic AIDS-related non-Hodgkin lymphoma (ARL) were treated with concomitant HAART and infusional cyclophosphamide-doxorubicin-etoposide (CDE) chemotherapy. We compared neutropenia according to whether patients received protease inhibitor (PI)-based HAART or non-PI regimens. Differences in survival, response rates, immunologic parameters, and virologic parameters were also investigated. The day-10 (Mann-Whitney U test; P = .012) and day-14 (P = .025) neutrophil counts were significantly lower in patients receiving PIs, though there were no differences in the number of days of granulocyte colony-stimulating factor (G-CSF) administered between groups (P = .16). Grade 3 or 4 infections requiring hospitalization were recorded for a total of 58 (31%) of 190 cycles of CDE: 23 (48%) of 48 when prescribed PIs and 35 (25%) of 142 with concomitant PI-sparing HAART (chi(2) test; P = .0025). There were no statistically significant differences in the response rates, relapse-free survival, or disease-free survival between patients receiving PIs and those not receiving PIs. PI-based HAART appears to significantly potentiate the myelotoxicity of CDE chemotherapy. This potentiation may be a consequence of microsomal enzyme inhibition reducing the metabolism of cytotoxics in this regimen.

Antineoplastic Agents↗
PubMed2004

Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin's lymphoma.

PURPOSE: Immunosuppression induced by HIV-1 increases the risk of developing non-Hodgkin's lymphoma (NHL). We measured the influence of immunologic factors and highly active antiretroviral therapy (HAART) on this risk. As there are no data demonstrating that specific antiretroviral regimens are effective at protecting from NHL, we compared different HAART regimens. PATIENTS AND METHODS: The protective effect of HAART regimens, containing protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the development of NHL was examined in a prospectively recorded cohort of 9,621 HIV-infected individuals. Lymphocyte and natural killer subset data were also entered in univariate and multivariate analyses to establish and stratify the risk of NHL. RESULTS: From this cohort of 9,621 patients, 102 have been diagnosed with systemic AIDS-related NHL since 1996, when HAART became freely available here. By univariate analysis, increased age, higher nadir CD4 and CD8 T-cell counts, CD19 B-cell count, CD16/56 natural killer count and exposure to NNRTI or PI containing HAART conferred significant protection against NHL (P <.05). In a multivariate analysis, age, nadir CD4 and CD8 T-cell counts, and exposure to HAART were independent predictors of risk of NHL (P <.02). NNRTI-based HAART (adjusted rate ratio, 0.4; 95% CI, 0.3 to 0.5) was as protective as PI-based HAART, and these were significantly more protective than nucleoside analogues alone (rate ratio, 0.5; 95% CI, 0.4 to 0.7) or no antiretrovirals (P <.001). CONCLUSION: Effective HAART-induced maintenance of CD4 and CD8 counts protects from systemic AIDS-related NHL.

Adult↗
PubMed2004

Where does HIV live?

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed2004

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↗
PubMed2004

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↗