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OBJECTIVE The biological significance of [¹¹C]choline (CHO) uptake in human tumours is unclear and probably linked to choline kinase-α (CHKα) expression and cell proliferation. We directly compared CHO with [¹⁸F]fluorothymidine (FLT), an imaging biomarker of proliferation, by positron emission tomography (PET) in patients with breast cancer to investigate whether cell proliferation is an important determinant of CHO uptake. Furthermore, we evaluated CHKα and the Ki67-labelling index (LIKi67) in tumour biopsies. METHODS Sequential CHO-PET and FLT-PET within the same imaging session were performed in 21 patients with oestrogen receptor (ER)-positive breast cancer (28 lesions). Average and maximum CHO standardized uptake values (SUV) at 60 min: SUV60,av, and SUV60,max, and the rate constant of net irreversible uptake, Ki, were compared with FLT uptake at 60 min: SUV60,av and SUV60,max. Biopsies were stained for CHKα and LIKi67 in eight cases. RESULTS Tumours were equally visible on CHO-PET and FLT-PET imaging. Tumour CHO-PET strongly correlated with FLT imaging variables (Pearson's r=0.83; P

OBJECTIVES: The use of transient elastography to assess liver stiffness measurement (LSM) has now become widely available for the diagnosis of liver fibrosis as a rapid, noninvasive test (it is still not approved for use in the United States). It has previously been showed as an accurate method of representing the state of liver fibrosis with concomitant evaluation of liver biopsy and the histologic scoring system METAVIR. We performed a meta-analysis to further assess its use in comparison with liver biopsy. METHODS: Studies from the literature were analyzed with a median liver stiffness value in kilopascal given for fibrosis stages according to histopathologic findings on biopsy and best discriminant cutoff levels in kilopascals for significant fibrosis (>or=F2) and cirrhosis (F4). RESULTS: A total of 22 studies were selected comprising 4,430 patients; chronic hepatitis C infection was the most common etiology of fibrosis. The pooled estimates for significant fibrosis (>or=F2) measured 7.71 kPa (LSM cutoff value) with a sensitivity of 71.9% [95% confidence interval (CI): 71.4%-72.4%] and specificity of 82.4% (95% CI: 81.9-82.9%), whereas for cirrhosis (F4) the results showed a cutoff of 15.08 kPa with a sensitivity of 84.45% (95% CI: 84.2-84.7%) and specificity of 94.69% (95% CI: 94.3%-95%). CONCLUSIONS: Further evaluation of transient elastography to assess LSM is required in prospective studies to potentially increase the sensitivity and establish its clinical utility.

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.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.Of 4183 HIV-positive patients, 1175 were identified as having a recorded creatinine value120 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 value120 micromol/L in patients exposed to tenofovir DF (rate ratio vs. no antiretrovirals = 0.22, 95% confidence interval [CI]: 0.07-0.69; P0.001) 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 value120 micromol/L subsequent to exposure. An alternative etiology of renal dysfunction was found in 75 (90%) of these individuals.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.

Summary: The development of resistance to any of the currently licensed non-nucleoside reverse transcriptase inhibitors (NNRTI) invariably leads to cross-resistance to the drugs in that class. New NNRTI, that have the promise of being active even when such ‘signature’ mutations are present, are in development. Such novel therapies could be effective after current NNRTI failure as there would probably be no cross-resistance. We assessed the short-term efficacy and safety of a next generation NNRTI, TMC 125, a diarylpyrimidine derivative that has in vitro activity against NNRTI resistant HIV-1. TMC 125 was studied in HIV-1 infected patients with high-level phenotypic NNRTI resistance in an open-label phase IIa trial. Methods: Sixteen individuals receiving an NNRTI-containing antiretroviral regimen (efavirenz or nevirapine) with an HIV-1 RNA viral load of . 2000 copies/ml and phenotypic resistance to NNRTI, received TMC 125 for 7 days, as a substitute for their current NNRTI in their failing therapy. Full pharmacokinetic profiles were investigated. Findings: The primary end point – viral load decay rate per day – was 0.13 log10 RNA copies/ml per day. Over 7 days, we observed a median 0.89 log10 decrease in HIV-1 viral load; seven individuals (44%) had a decrease of . 1 log10. The most significant adverse effects were grade I diarrhoea (31%) and a mild headache (25%). Steady-state drug levels were achieved by day 6. Interpretation: TMC 125, a next generation NNRTI, is well tolerated and demonstrates significant and rapid antiviral activity in patients with high levels of phenotypic NNRTI resistance to current NNRTI.

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.

Background: Tenofovir is a novel nucleotide analogue recommended for use in HIV-1 infected treatment-experienced patients. Recent data suggest an effect on Hepatitis B virus (HBV) replication. We therefore investigated the use of tenofovir in HIV-1 and HBV co-infected individuals. Methods: Twenty HIV-1/HBV co-infected patients with a median of 108 weeks lamivudine experience (range, 0-270 weeks) received tenofovir 245 mg daily in addition to or as part of their combination antiretroviral therapy. Their immunologic parameters and HIV-1 RNA and HBV DNA viral loads were followed over a period of 52 weeks. In addition, their HBV DNA polymerase was sequenced at baseline to measure the frequency of YMDD mutations that are associated with lamivudine resistance. Findings: A significant decrease in HBV DNA viral load (4 × log 10 ) and alanine aminotransferase levels was observed. There were no significant overall differences between the lamivudine-experienced (n = 15) and -naive (n = 5) individuals and tenofovir was well tolerated. Five patients (25%) underwent HBe antigen seroconversion during the study period. Out of the 15 lamivudine-experienced individuals, 10 had YMDD mutations and one had YIDD mutations in HBV DNA. Interpretation: These results indicate that 52 weeks of tenofovir in addition to antiretroviral therapy is active against HBV, and it appears to overcome lamivudine resistance.

We report a case of the nucleoside reverse transcriptase inhibitors, stavudine and lamivudine inducing Fanconi syndrome in a patient. The presence of simultaneous lactic acidosis suggests mitochondrial toxicity within the proximal renal tubular cells as the likely pathogenesis. We recommend that both the above nucleosides be added to the list of antiretroviral drugs that can induce Fanconi syndrome and that patients on stavudine and lamivudine be monitored carefully for early signs of Fanconi syndrome.

It is well known that HIV-associated Kaposi's sarcoma (HIV-KS) has a higher incidence at lower CD4 cell counts. A recent letter by Maurer et al.[1] described a cluster of nine individuals presenting with HIV-KS with CD4 cell counts greater than 300 cells/μl and suppression of HIV viraemia. The a