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Twelve serologically proven cases of non-A, non-B (NANB) hepatitis have been described. The clinical course was mild in 11 patients. One patient, however, presented in portal systemic encephalopathy and required steroid treatment. Nine of the 12 patients continued to exhibit raised transaminase (AST) activities six or more months after the onset of the acute hepatitis. In these immunoglobulin concentrations were normal and autoantibodies were not present in significant titre. Four patients had evidence of previous hepatitis B infection, suggesting that the route of transmission of NANB might be similar to that of hepatitis B virus. A further four patients gave a history which suggests a possible parenteral mode of transmission. Liver biopsies were carried out both in the acute (8 cases) and chronic (6 cases) phases of the disease. Histological findings in liver biopsies covered the whole spectrum of acute and chronic hepatitis and 1 patient had cirrhosis. One notable feature in these biopsies was the presence of fatty changes. [ABSTRACT FROM PUBLISHER]

A randomised controlled trial was conducted in 29 HBV carriers who had been HBs and HBe antigen positive for more than six months. Fifteen patients were treated with ARA-AMP 10 mg/kg/day given as intramuscular injections 12 hours apart for five days followed by 5 mg/kg/day for 23 days. The 14 controls received no treatment. Serum HBV-DNA polymerase, and HBV-DNA decreased in all patients during therapy. Six treated patients lost serum HBV-DNA polymerase, HBV-DNA and HBeAg, HBsAg concentrations decreased, and five developed anti-HBe. One of these six patients lost HBsAg and developed anti-HBs. No such changes were observed in the control group over a similar 18 month period of observation. A four week course of ARA-AMP inhibits HBV replication and in a significant minority of patients this is long lasting and is associated with a reduced level of inflammatory activity in the liver. [ABSTRACT FROM PUBLISHER]

The relationship between the histological diagnosis and serological and tissue markers of HBV replication in 41 Greek and 29 British patients with chronic HBV infection were studied. All the nine Greek and 13 British patients who were HBeAg positive had HBV-DNA in serum and HBcAg expression in the hepatocytes. The majority (73%) of these patients had active liver disease. Forty seven per cent of the Greek and 19% of the British patients who were anti-HBe positive continued to display HBcAg in the liver with or without HBV-DNA detected in serum. All but three of these patients had persistently active liver disease. Continuing inflammatory activity in the liver, however, was also found in 31% of anti-HBe positive patients who had no evidence of HBV replication. In these patients, other factors such as delta agent, NANB viruses, alcohol abuse or an autoimmune reaction initiated by HBV may be contributory. [ABSTRACT FROM PUBLISHER]

The pattern of replicative intermediates seen in the liver of HBe antigen and antibody positive patients was determined. During the phase of HBe antigenaemia the 3.2 Kb species of HBV-DNA (complete HBV genome) is present in the liver but not in the serum. When HBe antigen to antibody seroconversion occurs, either spontaneously or during antiviral therapy, the 3.2 Kb and lower molecular weight intermediates disappear from the liver and the 3.2 Kb band appears transiently in the serum. Integrated HBV-DNA was found in one of 15 patients during the period of HBe antigenaemia and in three of seven patients in the HBe antibody positive phase of the chronic infection before detection of primary liver cell carcinoma. Integrated sequences were found in tumour tissue of two patients with primary liver cell carcinoma who were anti-HBc positive but were absent from the tissues of two patients developing primary liver cell carcinoma at a late stage of autoimmune liver disease. These studies suggest that integration of the HBV genome occurs rarely or in only a small proportion of hepatocytes during the early (HBe antigen positive) phase of infection in Caucasians. They also show that not all primary liver cell carcinomas necessarily contain HBV-DNA. [ABSTRACT FROM PUBLISHER]

Heroin abusers are frequently found to have abnormal liver function tests and hepatic histology. Hepatitis viruses A, B, and NANB, other drugs or drug contaminants and excessive alcohol consumption are factors thought to contribute. One hundred and sixteen heroin abusers attending a London treatment centre were studied. Sixty two (53%) had a raised aspartate transaminase. This was not explained by current infection with hepatitis A and B, cytomegalo or Epstein-Barr viruses, excessive alcohol consumption (greater than 80 g/day) or concomitant drug taking. Abnormal liver function tests were as frequent in those with markers of current or past HBV infection as those without and there was evidence that both HBV infection and the cause of the abnormal liver function tests were acquired in the first few years of intravenous drug abuse. Liver biopsies from eight patients showed chronic hepatitis with a mild lobular and portal inflammatory infiltrate, fatty change and prominent sinusoidal cells. Electron microscopy showed cytoplasmic trilaminar tubular structures and dense fused membranes in dilated endoplasmic reticulum. These clinical, biochemical, serological, and histological features would suggest a major role for NANB virus infection in the aetiology of hepatitis in heroin abusers. [ABSTRACT FROM PUBLISHER]

The sera of 23% of HBe antigen positive patients with chronic hepatitis are HBV-DNA polymerase negative. These patients are probably undergoing spontaneous seroconversion from a state of high to low viral replication and do not require antiviral therapy. In chronic HBV infection rapid changes in viral replication as a result of antiviral therapy are reflected by changes in HBV-DNA and HBV-DNA polymerase but not by changes in HBe antigen concentrations. Disappearance of HBe antigen from serum may be delayed for 180 days after permanent inhibition of HBV replication with adenine arabinoside or its monophosphate derivative. [ABSTRACT FROM PUBLISHER]

In eight HBs and HBe antigen positive patients with chronic active liver disease, adenine arabinoside 5'-monophosphate (ARA-AMP) given, intravenously or intramuscularly, six or 12 hours, produced inhibition of viral replication. In five patients given a short course of therapy with 10 or 15 mg/kg/day this effect was transient and in two thrombocytopenia occurred. In three further consecutive cases given a longer course with 5 mg/kg/day after five days of the high dose, thrombocytopenia was not seen and inhibition of viral replication for up to 13 months occurred. These patients lost HBV-DNA polymerase activity, serum viral DNA and HBeAg, developed anti-HBe, and HBsAg concentrations decreased. A course of twice daily intramuscular ARA-AMP given for three to five weeks as an outpatient may be expected to produce a long-term reduction in infectivity. [ABSTRACT FROM PUBLISHER]

Changes in markers of hepatitis B viral replication and standard liver function tests were studied in 30 patients with HBsAg positive chronic liver disease starting or stopping prednisolone/azathioprine therapy, and compared with those occurring in 15 patients who did not receive therapy. On stopping prednisolone/azathioprine, 10 out of 11 HBeAg positive patients and one out of three patients negative for HBeAg and anti-HBe, lost HBV-DNA polymerase activity (p less than 0.01), five lost HBeAg, three developed anti-HBe and HBsAg concentration decreased (p less than 0.01). Only one out of seven untreated HBeAg positive patients lost HBeAg and there were no significant changes in DNA polymerase activity. In the anti-HBe positive patients, 14 starting therapy and eight untreated, there were no significant changes in the markers of viral replication - although two patients developed DNA polymerase activity on high maintenance doses of prednisolone - but a significant decrease (p less than 0.05) in aspartate transaminase in the treated group. It is concluded that the cessation of prednisolone/azathioprine therapy in HBeAg positive patients will result in a reduction in viral replication. In anti-HBe positive patients such therapy may be beneficial. [ABSTRACT FROM PUBLISHER]

Delta antigen (delta) is a transmissible agent requiring hepatitis B virus (HBV) for its replication. Antibody to delta (anti-delta) was present in nine of 71 (13%) British HBV carriers: six were intravenous drug abusers and two were haemophiliacs. Anti-delta was negative in 30 HBsAg positive homosexuals. Cirrhosis was common in patients with anti-delta and those with anti-delta positive cirrhosis were significantly younger than those with anti-delta negative cirrhosis. In British HBV carriers delta infection is associated with intravenous drug abuse and haemophilia and perhaps a more rapid progression of chronic liver disease. [ABSTRACT FROM PUBLISHER]

Virological assays for human immunodeficiency virus type 1 load and drug resistance can broadly be divided into culture-based and molecular biology-based methods. Culture-based methods give a direct measure of infectious virus load and phenotypic drug resistance, whereas molecular biology-based methods are indirect, assaying nucleic acid levels to determine virus load and point mutations associated with drug resistance. We have compared culture-based and non-culture-based methods for patients enrolled in a placebo-controlled trial of zidovudine (the Concorde Trial). Virus loads were assayed by culture of peripheral blood mononuclear cells (PBMCs) or quantitative PCR, and drug resistance was assayed in culture or in a quantitative, PCR-based point mutation assay. The rates of detection of viremia and drug resistance were higher by PCR than by culture for this population of subjects. Comparison of the virus loads by the two measures showed a good correlation for virus loads in PBMCs but a poor correlation for virus loads in plasma. The latter result probably reflected the inaccuracies of culture in assaying plasma with the low infectious virus titers seen in the study population. The concordance of phenotypic and genotypic drug resistance methods was high, with all phenotypically resistant isolates having at least one resistance-associated mutation and with no mutations being found in a drug-sensitive isolate. Genomic resistance scores (weighted sums of levels of resistance mutations) showed good correlations with the levels of phenotypic resistance, and both resistance measures were observed to increase as the duration of exposure to drug increased. Overall, non-culture-based methods were shown to correlate well with culture-based methods and offer a low-cost, high-throughput alternative. However, culture-based methods remain the final arbiters of infectious virus load and phenotypic drug resistance and are unlikely to be superseded entirely.

Objective: To test the T-helper (TH)1/TH2 cytokine paradigm in HIV infection., Design and Methods: Cytokine profiles in two separate studies of HIV patients and controls are presented: (i) a longitudinal study of HIV patients with CD4 counts > 500 x 10(6)/l tested at three timepoints compared with controls; (ii) a blinded cross-sectional study of controls and patients with high (> 500 x 10(6)/l) and low (< 500 x 10(6)/l) CD4 counts. Peripheral blood mononuclear cells (PBMC) from patients and controls were tested for the production of two type 1 [interleukin (IL)-2, interferon (IFN)-gamma] and two type 2 (IL-4, IL-10) cytokines by enzyme-linked immunosorbent assay. Both spontaneous and mitogen-induced cytokine production was measured., Results: HIV infection was noted to have the following effects on cytokine production: (i) it led to the in vivo activation of type 2 cytokines in a small group of individuals with high CD4 numbers characterized by the spontaneous release of IL-4 and IL-10. Longitudinal data showed high spontaneous IL-4 and IL-10 to be a consistent feature of the patient group (at each timepoint some patients were high producers) but to be variable in a given individual; (ii) HIV infection impaired the ability of PBMC to respond to stimuli (selected for their ability to optimally induce each cytokine) in terms of IL-2, IL-4 and IL-10 production in patients with both high and low CD4 cell counts; and (iii) conversely, HIV infection led to an overproduction of IFN-gamma in patients with high CD4 counts; patients with low CD4 produced normal levels of IFN-gamma., Conclusions: Our observations did not suggest polarization of the type 1/type 2 cytokine profile in HIV patients. Instead, the data suggested more complex changes to type 1/type 2 cytokine patterns in HIV infection than originally proposed by the TH1/TH2 dichotomy.

Objectives: Hepatitis B virus (HBV) and HIV infections share risk-factors; therefore coinfection is common. Interactions have been reported but controlled studies have been limited. Our objective was to study the effect of HIV infection on the natural history of chronic HBV infection and the reverse effect of the HBV carrier state on HIV infection., Design: Prospective observational cohort study., Setting: Open-access outpatient HIV/genitourinary medicine clinic at a Central London hospital., Patients: Total of 152 untreated homosexual male HBV carriers and 212 HBV surface antigen-negative controls (41.4 and 70.3% HIV-seropositive, respectively)., Outcome Measures: The rate of loss of serum HBV e antigen (HBeAg) and its reappearance in HIV-infected and HIV-uninfected HBV carriers; serum HBV DNA levels measured by dot-blot hybridization assay), HBV DNA polymerase activity and liver transaminase activities, the progression of HIV infection to symptomatic disease or AIDS in HIV-infected compared with HBV-HIV coinfected patients., Results: In HIV-infected HBV carriers, serum HBV DNA polymerase activity was higher, alanine aminotransferase was lower and loss of serum HBeAg (mean follow-up, 2.8 years) occurred at a lower rate when compared with HIV-uninfected HBV carriers (estimated relative hazard, 0.39; 95% confidence interval, 0.161-0.942) Concomitant chronic HBV infection had no detectable effect on the rate of progression of HIV disease after correction for lead-time bias., Conclusion: This study strengthens the evidence for a significant effect of HIV infection on the natural history of chronic HBV infection, which by prolonging the period of infectivity could have an important impact on the epidemiology of HBV infection in regions, or patient groups, with high HIV seroprevalence. There was no evidence of an important effect of HBV carriage on HIV disease progression.

Objective: To ascertain the prevalence of Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus (HHV) type 8, and cytomegalovirus (CMV) DNA in semen was investigated., Methods: Amplification by nested polymerase chain reaction was used to detect viral DNA sequences in samples from 24 HIV-infected gay men, 15 of them with Kaposi's sarcoma (KS), and 115 healthy donors., Results: Six of the 24 HIV-infected patients had detectable HHV-8 DNA in their semen: three of the 15 patients with KS and three of the nine patients without KS. CMV DNA was detected in 20 semen samples from HIV-infected patients. None of the semen samples from healthy donors had detectable HHV-8 DNA and rates of CMV DNA detection were low (3%)., Conclusions: The study demonstrates the presence of HHV-8 in semen from HIV-infected individuals with, or at risk, of developing KS and the potential for sexual transmission of the virus. We found no evidence of HHV-8 in the semen of HIV-uninfected donors.

Background: Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, may be the infectious cause of KS. Its prevalence in the general population, on the basis of detection of the virus genome, is controversial. To investigate the seroprevalence, we measured antibodies to a recombinant capsid-related (lytic cycle) KSHV antigen and a latent antigen complex., Methods: We selected potentially immunoreactive capsid-related proteins of KSHV by expressing them as recombinant proteins and testing them in western blot assays. We used a truncated recombinant protein encoded by KSHV open reading frame 65 (orf 65) to develop a diagnostic enzyme-linked immunosorbent assay (ELISA) and tested sera from HIV-infected individuals with KS, HIV-uninfected patients with "classic" KS, other HIV risk groups, and blood donors. We also compared the antibody response to this capsid-related protein to the response to latent antigen(s) in an immunofluorescence assay., Findings: 77/92 (84%) sera from KS patients reacted with the KSHV orf 65 protein and 84/103 (81.5%) reacted with KSHV latent antigen(s). The dominant immunogenic region of orf 65 is within the carboxyterminal 80 aminoacids, a region with little sequence similarity to the related Epstein-Barr virus, suggesting that orf 65 is a KSHV specific antigen. Only three sera from patients with haemophilia (1/84) or from intravenous drug users (2/63) had KSHV specific antibodies in the orf 65 assay whereas none of these sera reacted with latent antigen. Antibodies to KSHV were also infrequently found in UK and US blood donors by either assay (UK, 3/174 with orf 65 and 4/150 with latent antigen; US, 6/117 with orf 65 and 0/117 with latent antigen). They were more common among HIV-infected gay men without KS (5/16 by orf 65 ELISA, 10/33 by IFA), HIV-uninfected STD clinic attenders (14/166 by IFA), and Ugandan HIV-uninfected controls (6/17 by orf 65 ELISA, 9/17 by IFA). Antibody reactivity to the orf 65 protein (ELISA) and to latent antigen(s) (IFA) was concordant in 89% of 462 sera tested but reactive blood donor sera were discordant in both assays. Four AIDS-KS sera were unreactive in both assays., Interpretation: The distribution of antibodies to both a capsid-related recombinant protein and latent antigen(s) of KSHV strongly supports the view that infection with this virus is largely confined to individuals with, or at increased risk for, KS. However, infection with KSHV does occur, rarely, in the general UK and US population and is more common in Uganda. Antibodies to latent antigen(s) or to orf 65 encoded capsid protein will not detect all cases of KSHV infection, and a combination of several antigens will probably be required for accurate screening and confirmatory assays.

1. The major adverse effect of zidovudine (ZDV) is haematological toxicity which results in anaemia and granulocytopenia. The aim of the present study was to investigate if HIV-positive patients developing erythroid aplasia/hypoplasia are exposed to higher plasma concentrations of ZDV owing to impaired hepatic metabolism to the major metabolite, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GZDV). 2. Twelve HIV-positive male patients were studied, six having developed bone marrow aplasia/hypoplasia within the first 6 months of ZDV therapy. Each of the patients exhibiting toxicity were matched for age, weight, risk factors for HIV infection and disease stage with patients who had no evidence of early bone marrow toxicity. 3. ZDV was administered orally in doses of 3-10 mg kg-1 and blood samples taken at intervals to 6 h. Urine was collected over the whole 6 h period. ZDV and GZDV were assayed by h.p.l.c. 4. There were no significant differences in the pharmacokinetic parameters between the two groups of patients. For patients with early bone marrow toxicity the elimination half-life of ZDV was 1.10 +/- 0.16 h with an oral clearance of 2752 +/- 1031 ml min-1 compared with values of 1.06 +/- 0.18 h and 2843 +/- 730 ml min-1 seen in the control group. Similarly there was no significant difference in the pharmacokinetics of GZDV or the urinary ratio of GZDV to ZDV. 5. Therefore, despite the fact that ZDV toxicity to haematopoietic progenitor cells has been previously shown to be dose related, there was no indication from this study that it is directly related to plasma concentrations of ZDV.

Eleven patients with AIDS or AIDS-related complex who developed muscle-related symptoms whilst taking zidovudine were investigated. The clinical details of a further ten patients who did not undergo muscle biopsy are also outlined. The clinical features, quantitative muscle strength testing, electromyographic findings, serial creatine kinase levels, muscle biopsy appearance on light microscopy and the effects of zidovudine withdrawal and rechallenge are described. The spectrum of muscle disease encountered included four cases of frank myopathy diagnosed using clinical, electrophysiological and histological criteria, four patients with mild weakness and myalgia in whom muscle biopsies were normal, three patients with myalgia only and a mild increase in the interstitial cell infiltrate shown by biopsy. The patients presenting with myopathy showed no improvement on withdrawal of zidovudine but responded to immunosuppressive therapy with steroids and, in one case, thalidomide prescribed incidentally. At present, it is not yet possible to clinically define a specific zidovudine-induced myopathy that is distinct from the other effects of HIV infection on muscle structure and function. Our experience suggests that zidovudine may be implicated as a myotoxin in some patients, particularly those with myalgia and mild weakness. In those patients with severe weakness, and with biopsy findings of necrosis and inflammation, the drug effects may be difficult to separate from the primary effects of HIV.

Abnormalities at cerebral proton spectroscopy occur in patients with the acquired immunodeficiency syndrome (AIDS). N-acetyl aspartate (NAA) is believed to be a neuronal marker, and neuronal loss is thought to underlie the human immunodeficiency virus (HIV)-associated cognitive/motor complex. The proton spectra in 103 HIV-seropositive patients and 23 control subjects were compared and correlated with clinical, immunologic, and radiologic measures of HIV infection. Significant (P < .05) reductions in the mean NAA/choline (Cho) and NAA/creatine (Cr) ratios were seen in patients with immune suppression and neurologic signs. Significant increases in the Cho/Cr ratios were seen in patients with low CD4 lymphocyte counts and abnormal magnetic resonance (MR) images. Reduced NAA ratios correlated with diffuse but not focal MR imaging abnormalities. Combined MR imaging and spectroscopy provides closer relationships to clinical and immunologic measures of disease than either modality alone. Spectroscopy is an adjunct to MR imaging and augments the value of an MR imaging study.

Objective: To determine the natural history of cryptosporidial infection in HIV-infected individuals., Design: Retrospective study., Setting: University teaching hospital HIV inpatient and outpatient unit., Patients: Thirty-eight HIV-infected patients presenting with cryptosporidial diarrhoea between April 1986 and July 1991 were identified retrospectively from laboratory records., Results: Eleven of the 38 patients had a clinical remission of their diarrhoea. Median lymphocyte count of the remission group was significantly higher than that of the non-remission group (1100 and 550 x 10(6)/l, respectively; P = 0.003). Median survival times were 66 and 11.5 weeks for the remission and non-remission groups, respectively (P = 0.001). Liver function tests performed at the initial diagnosis of cryptosporidial diarrhoea were available for 28 patients. Aspartate transaminase was raised in 16 and alkaline phosphatase in 10 of these 28 patients. Ten patients showed evidence of AIDS-associated sclerosing cholangitis, one patient had an episode of acute pancreatitis and another presented with acute cholecystitis., Conclusions: This study suggests that HIV-associated cryptosporidial diarrhoea does not have a uniformly poor prognosis. Eleven out of 38 patients had a spontaneous clinical remission, which appears to be predicted by the absolute lymphocyte count. Abnormal liver function tests and hepatobiliary disease were common.

Objective: To audit hepatitis B immunisation of homosexual or bisexual men in a genitourinary medicine clinic., Design: Retrospective case note review of all homosexual and bisexual men presenting to a genitourinary clinic as new patients during 12 months in 1988 and follow up review of notes to May 1990., Setting: One department of genitourinary medicine, Middlesex Hospital., Patients: 758 homosexual or bisexual men, of whom 207 started a course of hepatitis B vaccine in 1988. Case notes were unavailable for one patient., Main Outcome Measures: The proportion of patients screened for hepatitis B virus markers, the proportion of susceptible patients immunised, the proportion completing the vaccine course, and the proportion rendered immune., Results: 25 men had been previously tested for hepatitis markers; of the 732 not previously tested, 440 (60.1%) were screened for hepatitis B markers. 207 (69%) of the 300 patients without hepatitis B serological markers started the vaccine course, and 141 (68%) completed it, with 75 (84%) of the 89 tested after immunisation being immune. An estimated 24% of susceptible new patients were rendered immune as a result of the immunisation policy. Patients who presented with a further episode of a sexually transmitted disease were more likely to have been screened (25% v 12%, p less than 0.0001) and immunised (31% v 18% p = 0.02); those known or found to be positive for HIV antibody were more likely to have been screened (23% v 14%, p = 0.047) but less likely to have been immunised (6% v 17%, p = 0.004)., Conclusions: The major failure was that in not screening; failure to immunise patients found to be susceptible and failure of compliance with the vaccine course contributed. Non-response to the vaccine was of minor importance. Improvements in vaccine delivery are required., Implications: Other providers should be encouraged to review their performance.