Hepatotoxicity observed in clinical trials of aplaviroc (GW873140).

Aplaviroc (APL) was a new CCR5 antagonist that was investigated in two dose-ranging studies with antiretroviral therapy-naïve, human immunodeficiency virus-infected adults: ASCENT, in which 147 subjects were randomized 2:2:1 to receive zidovudine-lamivudine (ZDV-3TC) plus APL 600 mg twice a day (BID), APL 800 mg BID, or efavirenz (EFV), respectively, and EPIC, in which 195 subjects were randomized 2:2:2:1 to receive lopinavir-ritonavir (LPV-RTV) plus APL 200 mg BID, APL 400 mg BID, APL 800 mg once a day, or ZDV-3TC BID, respectively. Both studies (and, ultimately, the clinical development of APL) were discontinued after a mean of 14 weeks of therapy because of higher than anticipated severe liver toxicity; grade 2 or higher treatment-emergent elevations in alanine aminotransferase (ALT) levels were observed in 17/281 (6.0%) APL recipients but only 2/55 (3.6%) control recipients, while grade 2 or higher elevations in total bilirubin levels occurred in 29/281 (10.3%) APL recipients but only 4/55 (7.3%) controls. Two APL recipients developed grade 3 or higher treatment-emergent elevations in both ALT and total bilirubin levels, and one of these individuals had a severe case of hepatic cytolysis that was attributed to APL. Despite the high intersubject variability in APL plasma exposures, a Pearson correlation analysis of the combined study data did not reveal any significant associations between plasma concentrations and the liver enzyme elevations observed during the study. The mechanism for the idiosyncratic hepatotoxicity observed in the clinical trials of APL is unknown but is likely intrinsic to the molecule rather than its novel mechanism of action.

Human cytomegalovirus and acute rejection after heart transplantation are not directly associated.

Retrospective and prospective analyses of heart transplant recipients showed no significant association between acute rejection and the detection of cytomegalovirus (CMV) infection by culture or the polymerase chain reaction (PCR) for viral DNA, neither on grounds of the incidence of both conditions nor in relation to which was diagnosed first in the patient. Semiquantitative PCR of serial blood and endomyocardial biopsy specimens from individual patients revealed different patterns in the development of the viral DNA in the blood and the heart, also clear episodes of CMV infection in CMV antibody-negative recipients of hearts from CMV antibody-negative donors, none of whom went on to develop a CMV-specific antibody response. None of these findings was associated with the development of rejection in the patient. On the other hand, in those patients who did experience rejection, peak levels of CMV DNA in the blood and the heart were usually not reached until 6 weeks or more after transplantation, whereas in those in whom rejection was not detected at all during the period of observation, peak levels of CMV DNA were detected earlier, mainly within the first 6 weeks after transplantation. In several cases, the delayed increase in CMV DNA in those with rejection, albeit not the delay itself, was linked to treatment with steroids. These findings support the view that CMV infection and rejection are independent events, but that the timing of the infection, and whether or not rejection is detected, are indicative of the general status of the immune response in individual patients.

Cytomegalovirus as a cause of morbidity in heart transplantation. The experience of one center.

The accumulated data from 78 heart transplant recipients surviving for more than one month postoperatively were reviewed; the median duration of follow up was 16 months. Cytomegalovirus (CMV) disease was seen most frequently in recipients of hearts from CMV-seropositive donors, irrespective of the recipient CMV antibody status. CMV-related illness was detected in 13 patients; of the six who developed pneumonitis, five were CMV-seropositive recipients with seropositive donors. CMV was not a common cause of hepatitis or gastrointestinal symptoms.

A polymerase chain reaction to detect a spliced late transcript of human cytomegalovirus in the blood of bone marrow transplant recipients.

A reverse transcription (RT) nested polymerase chain reaction (PCR) procedure is described for detecting RNA to a spliced late gene (SLG) of human cytomegalovirus (CMV), the product of which (175 bp) is easily differentiated in agarose gels from the product when the target is unspliced viral RNA or DNA (258 bp). The SLG-RT-PCR has been compared against a semi-quantitative PCR for CMV DNA in buffy-coat specimens collected weekly after bone marrow transplantation from 3 patients and against the results of culturing these specimens for CMV both by conventional virus isolation, based on the detection of cytopathic effect, and by the early detection of infected cells by staining with virus-specific monoclonal antibodies. The detection of CMV RNA by SLG-RT-PCR correlated well with the detection of infective virus but only when the results of both culture methods were combined, in that neither culture method alone was as sensitive as the SLG-RT-PCR. The presence of SLG RNA in the circulation is of value as a marker of active CMV infection.

Randomized double-blind, placebo-controlled trial of twice-daily zidovudine in asymptomatic haemophiliacs infected with the human immunodeficiency virus type 1. European-Australian Haemophilia Collaborative Study Group.

In this double-blind, placebo-controlled trial of HIV-infected asymptomatic haemophiliacs, the efficacy of 2-year zidovudine therapy (1000 mg daily in two divided doses) in preventing progress of HIV infection was prospectively evaluated. Drug tolerance was also studied. 143 haemophiliacs from five European countries and Australia with p24 antigenaemia and/or CD4 cell counts of 0.1-0.4 x 10(9)/l were enrolled. The main measures of outcome were progression to AIDS, CDC group IV disease, symptomatic HIV-related disease, and a decrease in CD4+ T-lymphocyte count to fewer than 0.2 x 10(9)/l. There were no significant treatment differences in the proportion of patients progressing to AIDS, CDC group IV or symptomatic disease. Analysis of time to CD4+ counts less than 0.2 x 10(9)/l showed a non-significant trend in favour of zidovudine. Haemoglobin concentrations were less than 8 g/dl in 4% of zidovudine recipients; neutropenia was less than 0.75 x 10(9) cells/l in 5% of zidovudine recipients; alanine aminotransferase levels were greater than 10 times the upper normal limit in 3% of zidovudine recipients, but also in 4% of placebo recipients. Hence there was a very low prevalence of side-effects in haemophiliacs, despite the use of a higher zidovudine dosage than is currently widely used.

Investigation of an outbreak of rotavirus infection in geriatric patients by serotyping and polyacrylamide gel electrophoresis (PAGE).

An outbreak of rotavirus diarrhoea amongst patients on two wards in a geriatric unit was investigated using polyacrylamide gel electrophoresis (PAGE) and serotyping. There had been no contact between the patients on different wards but some interchange of staff had occurred so it was important to exclude the possibility that the rotavirus had been spread by staff. Two strains of rotavirus were shown to be present, one on each ward. Differences in the electropherotypes and serotypes were demonstrated, showing conclusively that transfer of virus between the wards had not occurred. Thus, serotyping and PAGE are of value in the investigation of rotavirus outbreaks in the hospital setting where cross-infection between wards is suspected.

Perinatal listeriosis. A report of six cases.

The clinical and pathological findings in six patients with perinatal listeriosis are presented. One pregnancy resulted in a live-born infant who developed listerial septicaemia but made a complete recovery following prompt treatment. The other pregnancies ended in intrauterine death. Often antecedent maternal prodromal illness preceded expulsion of a macerated fetus by only a matter of hours making early diagnosis difficult. In all cases the diagnosis of listerial infection was apparent only after the birth of the fetus or new born.