Symptomatic osteoporosis in two young HIV-positive African women.
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Adult↗
Biomedical subjects
M A Johnson
Publications and source records attributed to M A Johnson.
Rapid decline in detectability of HIV-1 drug resistance mutations after stopping therapy.
OBJECTIVE: To investigate the rate of decline of drug resistant viruses after stopping therapy. DESIGN: Twenty-five patients receiving multiple combination therapies (mean five; range three to nine drugs) for more than 3 months were tested for HIV-1 resistance on therapy and off therapy. The sample off therapy was tested 6-175 days after stopping therapy. METHODS: Patients were tested for genotypic changes associated with drug resistance using an in-house automated DNA sequencing assay to detect resistance in the protease and reverse transcriptase genes. RESULTS: All samples tested when patients were on therapy showed evidence of drug resistance (range 1-9 mutations). The patients were divided into three groups: <2 weeks after stopping therapy, median 1.1 weeks (n = 8, group A); 2 weeks-2 months, median 6.4 weeks (n = 7, group B) and 2 months-6 months, median 12.9 weeks (n = 10, group C). Of primary mutations (protease: 30N, 461/L, 82A, 90M; reverse transcriptase: 70R, 184I/V, 215 Y/F) detected on therapy 100% remained after stopping therapy in group A; 68% remained in group B and 15% remained in group C. For secondary mutations 98% remained in group A; 99% remained in group B and 57% in group C. CONCLUSIONS: This study showed a rapid decline in detectability of the majority of primary mutations within 13 weeks of stopping combination therapy. From this data, HIV-1 resistance testing to direct patients' therapy should only be carried out when on existing therapy, or < 2 weeks off therapy, if reliable decisions are to be made relating to future combinations.
Acquired Immunodeficiency Syndrome↗
Visual dysfunction in patients receiving vigabatrin: clinical and electrophysiologic findings.
BACKGROUND: Vigabatrin is an antiepileptic drug that, although relatively well tolerated, is associated with visual field constriction and other visual disturbances of unclear origin. METHODS: We performed a complete neuroophthalmologic examination and electrophysiologic studies on 39 patients receiving vigabatrin and on 11 control patients. RESULTS: Nearly 50% of patients receiving vigabatrin had constricted visual fields compared with control patients. Some of the vigabatrin patients also had reduced visual acuity and abnormal color vision. In addition, most vigabatrin patients had abnormal electroretinographic results, the severity of which correlated strongly with the degree of visual field constriction. CONCLUSIONS: Vigabatrin can cause electrophysiologic evidence of retinal dysfunction and clinically detectable disturbances of visual sensory function.
Adult↗
The isolation and genetic analysis of V79-derived etoposide sensitive Chinese hamster cell mutants: two new complementation groups of etoposide sensitive mutants.
Using a replica plating microwell method, three Chinese hamster V79-derived cell lines, designated ETO1, ETO2 and ETO3, which exhibit hypersensitivity to the non-intercalating topoisomerase II inhibitor etoposide have been isolated. Mutant lines ETO2 and ETO3 are cross-sensitive to the topoisomerase II inhibitors adriamycin and streptonigrin; however, neither mutant is sensitive to the topoisomerase I inhibitor camptothecin, the bifunctional alkylating agent mitomycin C, nor hydrogen peroxide. In contrast, ETO1 is cross-sensitive to camptothecin but displays only slight sensitivity to adriamycin, streptonigrin and hydrogen peroxide, and is not sensitive to mitomycin C. It has been established through extensive cell fusion studies that all three mutants are genetically distinct, and that ETO2 and ETO3 genetically complement all other known etoposide-sensitive Chinese hamster cell mutants (i.e., irs1, XR-1, xrs1, V3, BLM2, ADR1, ADR3, ADR4 and ADR5) thus defining two new complementation groups of etoposide sensitive mutants. Interestingly, the hybrids created by the fusion irs2TOR (thioguanine and ouabain resistant)xETO1 and the reciprocal cross ETO1TORxirs2 both exhibited a response to camptothecin intermediate with respect to V79 and ETO1. It has been hypothesised that this partial complementation may be the result of intragenic complementation and that both ETO1 and irs2 result from mutations in the gene XRCC8. This study indicates that cellular responses to topoisomerase II inhibitors are complex and hypersensitivity may result from mutations in many different genes.
Animals↗
Synthesis and glycosidase inhibitory activity of 5-thioglucopyranosylamines. Molecular modeling of complexes with glucoamylase.
The synthesis of a series of 5-thio-D-glucopyranosylarylamines by reaction of 5-thio-D-glucopyranose pentaacetate with the corresponding arylamine and mercuric chloride catalyst is reported. The products were obtained as anomeric mixtures of the tetraacetates which can be separated and crystallized. The tetraacetates were deprotected to give alpha/beta mixtures of the parent compounds which were evaluated as inhibitors of the hydrolysis of maltose by glucoamylase G2 (GA). A transferred NOE NMR experiment with an alpha/beta mixture of 7 in the presence of GA showed that only the alpha isomer is bound by the enzyme. The Ki values, calculated on the basis of specific binding of the alpha isomers, are 0.47 mM for p-methoxy-N-phenyl-5-thio-D-glucopyranosylamine (7), 0.78 mM for N-phenyl-5-thio-D-glucopyranosylamine (8), 0.27 mM for p-nitro-N-phenyl-5-thio-D-glucopyranosylamine (9) and 0.87 mM for p-trifluoromethyl-N-phenyl-5-thio-D-glucopyranosylamine (10), and the K(m) values for the substrates maltose and p-nitrophenyl alpha-D-glucopyranoside are 1.2 and 3.7 mM, respectively. Methyl 4-amino-4-deoxy-4-N-(5'-thio-alpha-D-glucopyranosyl)-alpha-D-glucopyrano side (11) is a competitive inhibitor of GA wild-type (Ki 4 microM) and the active site mutant Trp120-->Phe GA (Ki 0.12 mM). Compounds 7, 8, and 11 are also competitive inhibitors of alpha-glucosidase from brewer's yeast, with Ki values of 1.05 mM, > 10 mM, and 0.5 mM, respectively. Molecular modeling of the inhibitors in the catalytic site of GA was used to probe the ligand-enzyme complementary interactions and to offer insight into the differences in inhibitory potencies of the ligands.
Binding Sites↗
Changes in AIDS-defining illnesses in a London Clinic, 1987-1998.
OBJECTIVES: To describe the incidence of AIDS-defining illnesses within a single large clinic setting, to describe temporal changes over a 10-year period in the overall incidence and of individual AIDS-defining illnesses and to investigate the impact of HIV treatment regimen on the incidence of AIDS-defining illnesses. SUBJECTS AND METHODS: A person-years analysis was used to determine the incidence of AIDS-defining illnesses according to calendar year and stratification by CD4 lymphocyte count and treatment regimen in 1806 patients from the Royal Free Centre for HIV Medicine with at least one CD4 lymphocyte count and follow-up visit. RESULTS: Prior to 1992, the incidence of all AIDS-defining illnesses was 27.4/100 person-years of follow-up (PYFU; 95% confidence interval [CI], 22.8-32.0) and during 1997 this incidence had dropped to 6.9/100 PYFU (95% CI, 4.7-9.1; p < .0001, test for trend). The decline in incidence over time occurred in esophageal candidiasis, cytomegalovirus disease (including retinitis), Kaposi's sarcoma, lymphoma, wasting syndrome, and Pneumocystis carinii pneumonia (p < .05, test for trend), but there was no evidence of a decline in AIDS dementia or in Mycobacterium avium complex. In 1997, among patients with CD4 lymphocyte counts of < or =200 cells/mm3, the incidence rates for any AIDS-defining illness was 51.1/100 PYFU for patients taking no therapy (95% CI, 27.9-85.7), 34.5 among patients on monotherapy (95% CI, 4.2-124.6), 13.2 among patients taking dual combination therapy (95% CI, 3.6-33.8) and 6.1 among patients taking triple therapy or more complex regimens (95% CI, 0.7-22.0; p < .0001, test for trend). CONCLUSIONS: There was a considerable decline in AIDS-defining illnesses during 1996 and 1997, coinciding with the rapid development of new antiretroviral treatments and combinations of treatment. Further follow-up of large observational cohorts is essential to monitor the incidence of diagnoses less common than we were able to consider, such as tuberculosis, cryptosporidiosis, and cryptococcosis, and also to investigate whether the incidence of disease continues to fall, or whether it starts to rise again, as toxicities, compliance, drug resistance, and long-term side effects begin to appear.
AIDS Dementia Complex↗
Loss of cytomegalovirus (CMV) viraemia following highly active antiretroviral therapy in the absence of specific anti-CMV therapy.
OBJECTIVE: To determine the effect of highly active antiretroviral therapy (HAART) on cytomegalovirus (CMV) viraemia and retinitis in patients at high risk of disease. DESIGN: Sixteen patients with CMV viraemia, but no evidence of end organ disease at the time of first receipt of HAART including a protease inhibitor, were studied. No patient had ever received specific anti-CMV therapy. METHODS: CMV load in blood was measured using quantitative competitive PCR at baseline and for a median follow-up of 21 months. Regular ophthalmological screening for retinitis was conducted throughout the study period. RESULTS: All 16 patients became CMV negative by PCR following the commencement of HAART. CMV loads prior to treatment ranged from 2.0 x 10(3) to 4.1 x 10(6) copies/ml (median, 7.6 x 10(4) copies/ml). The median time to becoming PCR negative was 13.5 weeks (range, 5-40 weeks). Fourteen patients remained CMV negative throughout follow-up. CMV viraemia recurred in two patients; these individuals were indistinguishable with respect to either baseline parameters or response to antiretroviral therapy. None of the 16 patients developed CMV retinitis. CONCLUSIONS: HAART including a protease inhibitor can result in the complete suppression of CMV viraemia, an effect not previously observed in HIV-infected patients in the absence of specific anti-CMV therapy. This response correlated with protection against CMV retinitis in a group of patients at high risk of development of disease. These results help to explain why the natural history of CMV disease has altered since the introduction of such therapeutic regimens.
AIDS-Related Opportunistic Infections↗
The changing pattern of admissions to a London hospital of patients with HIV: 1988-1997. Royal Free Centre for HIV Medicine.
OBJECTIVE: To describe the changes over time in incidence of hospital admissions among patients with HIV, reasons for hospital admission, duration of stay, relationship with CD4 T-cell count and with antiretroviral treatment. METHODS: The incidence of hospital admissions during each calendar year from 1988 to 1997 inclusive was calculated using a person-years analysis. In addition the proportion of patient follow-up spent in hospital and the impact of changing treatment regimens among all patients with HIV aged > or = 14 years and with at least one CD4 T-cell count seen at the Royal Free Hospital, London was also described. RESULTS: A total of 1806 patients were investigated with median follow-up of 21.1 months. Among all patients, the proportion of follow-up time spent as an in-patient decreased from 3.9% in 1988 to 1.3% in 1997 (P = 0.0015; test for trend). Hospital admissions for any cause peaked during 1989 at 72.0 per 100 patient years of follow-up (PYFU) and was 28.5 per 100 PYFU during 1997 (P < 0.0001; test for trend). There was a statistically significant decline in the proportion of follow-up time spent as an in-patient among patients with CD4 T-cell counts of < 50 x 10(6)/l from > 30% before 1990 to < 5% during 1997 (P = 0.026; test for trend). Hospital admissions varied greatly according to treatment regimen; in 1996 and 1997 just 0.1% of follow-up time of patients on triple antiretroviral treatment regimens was spent as a hospital admission. CONCLUSIONS: Admissions to hospital began falling before the introduction of combination therapy and declined strikingly during 1996 and 1997 following the introduction of highly active antiretroviral therapy. These results have important implications for future allocation of resources and for patient management.
Adult↗
Lipodystrophy in patients naive to HIV protease inhibitors.
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Adult↗
In vivo HIV-1 replicative capacity in early and advanced infection.
OBJECTIVE: Previous studies on patients treated with potent antiretroviral therapy have shown that viral clearance rates do not tend to change between early and advanced HIV-1 infection. Our objective was to investigate whether the other major aspect of virus dynamics, viral replicative capacity, does change. In vitro work has indicated that the viral replicative, capacity increases but in vivo evidence has been lacking. METHODS: As an in vivo measure of the viral replicative capacity, we studied the rate of rebound of plasma HIV RNA level during a 1-week therapy interruption in previously untreated patients who had received 2 weeks of antiretroviral therapy. RESULTS: Such therapy in five previously drug-naive patients with high CD4 lymphocyte counts (mean, 611 x 10(6)/l) and five patients with low counts (mean, 49 x 10(6)/l) led to a mean 2.2 log10 copies/ml decrease in plasma HIV-1 levels (from 5-6 log10 copies/ml) in 2 weeks. This was similar in the two groups. Interruption of therapy for the ensuing week resulted in a stable HIV-1 level for approximately 2 days followed by a rebound towards pretherapy level, which was much more marked in the patients with low CD4 cell counts (estimated mean rise 2.22 log10 versus 1.06 log10 copies/ml; P < 0.02). After restarting therapy, HIV RNA levels returned to pre-interruption levels. CONCLUSIONS: These findings need confirmation, but the ability of HIV-1 to replicate in vivo appears to increase during HIV-1 infection. This increased replicative capacity, for which there are several potential explanations, may be the cause of gradual CD4 lymphocyte depletion.
HIV Infections↗
Interactions between beta-herpesviruses and human immunodeficiency virus in vivo: evidence for increased human immunodeficiency viral load in the presence of human herpesvirus 6.
In vitro, beta-herpesviruses can stimulate or inhibit HIV replication under particular circumstances. In order to investigate the effects of beta-herpesvirus infection on HIV replication and vice versa at an organ level, we determined the quantitative relationships between cytomegalovirus (CMV), human herpesviruses (HHV) 6 and 7, and HIV-1 proviral DNA using quantitative competitive PCR methods in 141 organs collected at autopsy from 11 AIDS patients. The presence of HHV-6 DNA in an organ was significantly associated with elevated HIV-1 proviral DNA (difference in HIV median loads, 1.3 log10 genomes; P = 0.004). Consistent with this, there was a trend for the presence of HIV-1 proviral DNA to be associated with an elevated HHV-6 load (0.44 log10 difference; P = 0.07). In contrast, there were no significant differences between viral loads in the combinations of either CMV or HHV-7 with HIV-1 proviral DNA load. Pairwise combinations of the beta-herpesviruses revealed that the quantity of HHV-7 was increased in the presence of HHV-6 (difference in median loads, 1.3 log10; P = 0.001) and the quantity of HHV-6 was increased in the presence of HHV-7 (difference in median loads, 0.7 log10; P=0.002). These results demonstrate that the presence of HHV-6 in an organ is significantly associated with an elevated HIV-1 proviral load and have implications for understanding HIV pathogenesis in the human host and the role that beta-herpesviruses, especially HHV-6, might play as cofactors in the HIV disease process.
AIDS-Related Opportunistic Infections↗
Shorter survival in HIV-positive patients with diarrhoea who excrete adenovirus from the GI tract.
Adenoviruses have been described as a cause of diarrhoea in patients infected with the human immunodeficiency virus (HIV). The prevalence of adenoviruses was studied in all HIV-positive patients presenting with diarrhoea at the Royal Free Hospital in London between 1991 and 1995. In addition, all postmortems carried out in HIV-positive individuals registered at the same centre between 1990 and 1997 were reviewed for evidence of adenovirus infection. Adenovirus was detected in 16.1% of patients presenting with diarrhoea. These individuals had a significantly lower CD4 count and were more likely to have had a diagnosis of acquired immunodeficiency syndrome (AIDS) than patients with diarrhoea in whom adenovirus was not detected. The median survival was 1 year compared with 2.4 years for those without adenoviruses; this difference remained significant (P = .008) after controlling for differences in CD4 counts between the groups. Gastrointestinal adenovirus excretion occurs at an advanced stage of HIV disease, and is associated with a poor prognosis. We suggest that adenoviruses may contribute to mortality in this population.
Adenoviridae↗
Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death.
The mechanism of selective loss of motor neurons in amyotrophic lateral sclerosis (ALS) has not been clarified. Mitochondrial pathology is present in central nervous system tissue from ALS cases and occurs as an early event in a mouse model of ALS. We demonstrate that, in sporadic ALS, there is a selective decrease in the activity of the mitochondrial DNA-encoded enzyme cytochrome c oxidase in human spinal cord motor neurons. We propose that this may not only be important in neuronal cell death but could well be caused by oxidative damage to mitochondrial DNA leading to the accumulation of mitochondrial DNA mutations.
Adult↗
Genomic location and nucleotide sequence of a serotype 3 porcine adenovirus hexon gene.
The putative hexon gene of a porcine adenovirus serotype 3 (PAV3) has been identified, cloned and the nucleotide sequence determined. The genomic location of the PAV3 hexon gene was determined and an open reading frame (ORF) encoding a polypeptide of 939 amino acids identified. Comparison of the nucleotide sequence of the putative PAV3 hexon gene with the sequence of the HAV2 hexon gene returned an overall identity of approximately 63%. A stop codon 144 nucleotides upstream and a start codon 18 nucleotides downstream of the ORF were identified and comparison with the HAV genome demonstrated that their positions corresponded to the stop site of the pVI gene and start site of the 23K gene, respectively. To confirm the correct start codon of the putative PAV3 hexon gene, the acceptor splice site for the putative PAV3 hexon gene was determined from cDNA and found to be between the two guanines immediately upstream of the first ATG in the ORF. Comparison with the HAV2 hexon protein showed overall identity of approximately 65%, with higher identity in the carboxy-terminus of approaching 76% over 380 amino acids. Multiple alignment of the PAV3 hexon amino acid sequence with other known HAV and animal adenovirus hexon sequences indicated that conservation is generally maintained but that identity is much lower within the loop structures of the protein.
Amino Acid Sequence↗
'Naïve' and 'memory' CD4+ T-cells and T-cell receptor (TCR) V beta repertoire dynamics are independent of the levels of viremia following HIV seroconversion.
The progression of 'naive' and 'memory' T-cells and the T-cell receptor Vbeta (TCR Vbeta) repertoire dynamics within the peripheral CD4+ T-cell compartment were studied in individuals following HIV seroconversion. Profound TCR Vbeta repertoire perturbations were observed within the CD4+ T-cell pool in treatment-naive patients regardless of their levels of viremia during the first 6-8 months after seroconversion. The ratio of 'naive' to 'memory' CD4+ T-cells as well as the TCR Vbeta repertoire dynamics did not appear to correlate with absolute numbers of CD4 T-cells.
Adolescent↗
Efficacy and safety of combination therapy with delavirdine and zidovudine: a European/Australian phase II trial.
The objective of the study was to investigate the safety and antiviral effect of three delavirdine dose regimens or placebo in combination with zidovudine in patients who were already taking zidovudine. Eighty-nine symptomatic HIV-1 seropositive individuals with CD4 cell counts between 50 and 350 cells/microl were included in this trial The influence of combination therapy on viral susceptibility to both zidovudine and delavirdine was investigated. Death or the occurrence, or re-occurrence of an AIDS-defining illness was considered as a clinical endpoint. The addition of delavirdine to the antiretroviral treatment regimen resulted in a significant, but transient, reduction in virus load, as determined by quantitative RNA measurements. CD4+ cell count did not change significantly. Susceptibility to zidovudine remained unchanged after 12 weeks of combination therapy, while 70% of the patients demonstrated a substantial decrease (> 10-fold) in sensitivity to delavirdine. Two patients suffered from an AIDS-defining disease during the study. No deaths occurred. Generally, the drug appeared to be safe. Skin rash was the most frequently observed adverse event (52%). In most patients the rash either resolved spontaneously or was treated successfully with a short course of antihistamines. The definite place of the compound in the management of HIV disease, in particular when given in combination with other antiretroviral agents, remains to be further explored.
Anti-HIV Agents↗
The pharmacokinetics of lamivudine in healthy Chinese subjects.
AIMS: The purpose of this study was to investigate the pharmacokinetics of daily oral doses of lamivudine administered to healthy Chinese subjects for 1 week. METHODS: Twenty-four subjects were enrolled, 12 males and 12 females, all between the ages of 18 and 40 years. After an overnight fast, all subjects received a single oral dose of 100 mg lamivudine. Blood was obtained before lamivudine administration and at regular intervals to 24 h post dose. Subsequent doses were given once daily for a total of 7 days. On the last day another full pharmacokinetic profile was obtained to 24 h postdose. Timed urine collections were performed for all subjects on day 1 only. Pharmacokinetic parameters were calculated by using standard non compartmental techniques. RESULTS: Lamivudine was well absorbed in all subjects (tmax 1 h). On day 1 and day 7 the overall geometric mean Cmax was 1304 and 1385 ng ml-1, and AUC(0,24h) was 4357 and 4353 ng ml-1 h, respectively. On average 78% of the lamivudine dose was recovered in urine as parent compound. Pharmacokinetic parameters were very similar between male and female subjects, between day 1 and day 7 and in comparison with data obtained in many other pharmacokinetic studies. CONCLUSIONS: This study demonstrated that the pharmacokinetics of lamivudine are essentially identical between Chinese and Caucasian subjects, and between males and females. It confirms 100 mg lamivudine is an appropriate dose for use in Chinese patients, providing adequate exposure for optimal antiviral effect.
Adult↗