PubMed Health⌕ Search

Biomedical subjects

S L Walmsley

Publications and source records attributed to S L Walmsley.

At least 19 recordsLinked to original sources
PubMed2006

Assay of HIV gp41 amino acid sequence to identify baseline variation and mutation development in patients with virologic failure on enfuvirtide.

In this study, we retrospectively assessed a gp41 genotypic assay in 404 enfuvirtide-naïve individuals (340 clade B, 64 non-B clade) to determine the prevalence of baseline polymorphisms and in 41 patients virologically failing enfuvirtide to determine correlates of resistance to this agent. Conserved and polymorphic regions of gp41 were identified in clade B isolates, with 127 of 328 codons (38.7%) being highly conserved (<1.0% variation) and 74 of 328 codons (22.6%) being partially conserved (1.0-5.0% variation). Polymorphisms were observed throughout gp41 in non-B clade virus sequences compared to the clade B reference strain, ranging from 53 natural substitutions in clade D to 76 in clade A. Insertions were common at positions 3, 105, 215 and 276. In the patients failing enfuvirtide, mutations were detected in the 10 amino acid region at positions 36-45 in all plasma virus sequences. Six additional mutations were selected outside of the common region which may be clinically significant at positions 33, 73, 75, 126, and 138. Two or three mutations at positions 36-45 were observed in the majority of plasma virus sequences from patients with virologic failure following the use of enfuvirtide. Further study is required to determine the clinical relevance of the clade related polymorphisms and the new mutations identified in the patients with virologic failure.

Adult↗
PubMed2001

Non-nucleoside reverse transcriptase inhibitor failure impairs HIV-RNA responses to efavirenz-containing salvage antiretroviral therapy.

In a retrospective cohort study of salvage antiretroviral combination therapy including efavirenz, 60% of 51 patients were able to suppress HIV RNA by at least 1 log10 or to less than 50 copies/ml. A lack of the previous use of non-nucleoside reverse transcriptase inhibitors was the only factor predictive of response on multivariate analysis. No patient with a viral isolate with an increased IC50 to efavirenz by virtual phenotype had a virological response

Adult↗
PubMed2001

Improvement of HIV-specific immunity in HIV-infected twins treated with highly active antiretroviral therapy, interleukin 2, and syngeneic adoptively transferred cells.

Five HIV-seropositive twins were treated with HAART and given cycles of treatment consisting of adoptive cellular therapy from their HIV-seronegative identical twins followed by a 5-day course of intravenous IL-2. Changes in absolute and percent CD4(+) and CD8(+) cell count were monitored and compared with changes in these parameters occurring in seven age-, sex-, and disease stage-matched HIV-infected patients treated with HAART alone. Increase in the magnitude and breadth of HIV-specific immune responses was monitored in three twin subjects who received multiple treatment cycles. Absolute and percent CD4(+) cell counts rose dramatically and to significantly higher levels in the recipient twins than in control subjects treated with HAART only. The subjects who received multiple cycles of treatment developed new and increased levels of HIV-specific activated and memory cytotoxic T lymphocyte responses, and interferon gamma-secreting effector cells. Treatment consisting of HAART, adoptive cellular therapy, and IL-2 was superior to treatment with HAART alone for improving absolute and percent CD4(+) cell counts and inducing new, or increasing the magnitude of, HIV-specific immune responses in HIV infected patients.

Adult↗
PubMed2001

Trimethoprim-sulfamethoxazole induced aseptic meningitis in a renal transplant patient.

A 45-year-old man underwent renal transplant for end-stage renal disease complicating systemic lupus erythematosis. Within 24 hours of initiating Pneumocystis carinii pneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) he developed fever and confusion. Cerebrospinal fluid examination revealed a pleocytosis but cultures were negative. The patient improved within three days after cessation of the TMP-SMX but symptoms recurred rapidly upon drug rechallenge. Drug-induced aseptic meningitis is an uncommon but well described clinical entity. This is the first case described in a patient following renal transplantation. The literature is reviewed and the clinical features, diagnostic challenges and possible mechanisms of TMP-SMX-induced aseptic meningitis are discussed. This problem may be more common in the transplant population than is recognized given the difficulty of diagnosis combined with the widespread use of TMP-SMX as PCP prophylaxis.

Anti-Infective Agents↗
PubMed2001

Predictors of virological response in HIV-infected patients to salvage antiretroviral therapy that includes nelfinavir.

Different salvage strategies have been used to regain control in patients with HIV who have virological failure on combination antiretroviral therapy. We conducted a cohort study of 63 extensively antiretroviral pretreated patients who initiated nelfinavir as part of salvage therapy, to determine predictors of virological response. The maximum HIV RNA response was >0.5 log10 copies/ml reduction in 43 patients (68%), including 21 patients (33%) who had suppression to <500 copies/ml. Corresponding response rates at 24 weeks were 41 and 19%, respectively. Responders and non-responders could not be distinguished by mean baseline HIV RNA or CD4 cell count, duration of prior protease inhibitor (PI) use, introduction of an initial non-nucleoside reverse transcriptase inhibitor or the number of antiretroviral agents changed when nelfinavir was added, likely reflecting the homogeneity of the population studied. The only parameter predictive of response was virus genotype. Response rates were lower in patients with increasing numbers of primary (P=0.045) or secondary (P=0.001) PI mutations. The addition of increasing numbers of reverse transcriptase mutations further impaired response rates (P=0.004).

Adult↗
PubMed2000

Factors contributing to the lack of human immunodeficiency virus type 1 (HIV-1) transmission in HIV-1-discordant partners.

Correlates of resistance to infection by human immunodeficiency virus type 1 (HIV-1) are important for defining potential therapeutic interventions and for prophylactic vaccination. In this study, 11 couples discordant in their HIV-1 infection status were prospectively evaluated for the presence of protective factors. Behavioral characteristics of all subjects entailed a high risk of transmission. Cytotoxic T lymphocyte (CTL) responses against viruses isolated from the infected partner, and against laboratory virus isolates, were detected in 5 (45%) of 11 HIV-negative partners, including a CCR5Delta32-homozygous and a heterozygous subject. No CTL responses were observed in 6 control unexposed subjects. Marked variation in lymphocyte susceptibility to viral infection was noted. Resistance attributable to major histocompatibility complex discordance or anti-major histocompatibility complex antibodies was not identified. These results suggest that a combination of factors, including cellular immunity, viral characteristics, and coreceptor integrity, may be involved in the persistent nontransmission of HIV.

Adult↗
PubMed1998

A randomized trial of N-acetylcysteine for prevention of trimethoprim-sulfamethoxazole hypersensitivity reactions in Pneumocystis carinii pneumonia prophylaxis (CTN 057). Canadian HIV Trials Network 057 Study Group.

Hydroxylamine derivatives of sulfamethoxazole may be the reactive metabolites that cause adverse reactions to trimethoprim-sulfamethoxazole (TMP-SMX). The increased frequency of reactions observed in HIV-positive individuals is hypothesized to be due to systemic glutathione deficiency and a decreased ability to scavenge these metabolites. Two hundred and thirty-eight patients were randomized to receive or not receive N-acetylcysteine (3 g of the 20% liquid solution) 1 hour before each dose of TMP-SMX (trimethoprim 80 mg, sulfamethoxazole 400 mg) twice daily, which was initiated as primary Pneumocystis carinii pneumonia prophylaxis. Forty-five patients had to discontinue TMP-SMX within 2 months because of fever, rash, or pruritus including 25 of 102 patients (25%) who were receiving TMP-SMX alone and 20 of 96 patients (21%) who were randomized to TMP-SMX and N-acetylcysteine. The difference between treatment groups is 4% (95% confidence interval [CI]: -16%, +9%). No independent association was found with the hypersensitivity reaction and age, gender, race, HIV risk factor, prior AIDS, concurrent use of fluconazole, or baseline CD4. N-acetylcysteine at a dose of 3 g twice daily could not be shown to prevent TMP-SMX hypersensitivity reactions in patients with HIV infection.

Acetylcysteine↗
PubMed1998

Effects of vitamin E and C supplementation on oxidative stress and viral load in HIV-infected subjects.

OBJECTIVES: The HIV-infected population is known to be oxidatively stressed and deficient in antioxidant micronutrients. Since in vitro replication of HIV is increased with oxidative stress, this study assessed the effect of antioxidant vitamin supplementation on lipid peroxidation, a measure of oxidative stress, and viral load in humans. DESIGN: A randomized placebo-controlled, double-blind study. METHODS: Forty-nine HIV-positive patients were randomized to receive supplements of both DL-alpha-tocopherol acetate (800 IU daily) and vitamin C (1000 mg daily), or matched placebo, for 3 months. Plasma antioxidant micronutrient status, breath pentane output, plasma lipid peroxides, malondialdehyde and viral load were measured at baseline and at 3 months. New or recurrent infections for the 6-month period after study entry were also recorded. RESULTS: The vitamin group (n = 26) had an increase in plasma concentrations of alpha-tocopherol (P < 0.0005) and vitamin C (P < 0.005) and a reduction in lipid peroxidation measured by breath pentane (P < 0.025), plasma lipid peroxides (P < 0.01) and malondialdehyde (P < 0.0005) when compared with controls (n = 23). There was also a trend towards a reduction in viral load (mean +/- SD changes over 3 months, -0.45 +/- 0.39 versus +0.50 +/- 0.40 log10 copies/ml; P = 0.1; 95% confidence interval, -0.21 to -2.14). The number of infections reported was nine in the vitamin group and seven in the placebo group. CONCLUSION: Supplements of vitamin E and C reduce oxidative stress in HIV and produce a trend towards a reduction in viral load. This is worthy of larger clinical trials, especially in HIV-infected persons who cannot afford new combination therapies.

Adult↗
PubMed1998

Does in vitro susceptibility to rifabutin and ethambutol predict the response to treatment of Mycobacterium avium complex bacteremia with rifabutin, ethambutol, and clarithromycin? Canadian HIV Trials Network Protocol 010 Study Group.

The in vitro susceptibilities of baseline Mycobacterium avium complex (MAC) blood isolates from 86 patients with AIDS who were treated with clarithromycin, ethambutol, and rifabutin were determined to examine whether these results predict bacteriologic response to treatment. No patient received prior prophylaxis with clarithromycin or azithromycin. Minimum inhibitory concentrations (MICs) of clarithromycin for all isolates were < or = 2 micrograms/mL. The median MIC of rifabutin was between 0.25 and 0.5 microgram/mL, and all isolates were susceptible to < or = 2 micrograms of rifabutin/mL. The median MIC of ethambutol was 4 micrograms/mL, and the MIC90 was 8 micrograms/mL. There was no correlation between ethambutol susceptibility and subsequent bacteriologic clearance. At all time points through week 12, bacteriologic clearance occurred more frequently in patients with isolates for which MICs of rifabutin were lower, but this difference was statistically significant only at week 2. Susceptibility testing for baseline MAC isolates from AIDS patients not previously treated with clarithromycin or azithromycin does not appear to be useful in guiding therapy.

AIDS-Related Opportunistic Infections↗
PubMed1997

Oxidative stress and thiol depletion in plasma and peripheral blood lymphocytes from HIV-infected patients: toxicological and pathological implications.

OBJECTIVES: To determine, first, whether the plasma and lymphocytes of HIV-positive individuals and AIDS patients have alterations in the major thiols glutathione and cysteine, and/or their oxidative disulphide and mixed disulphide products; and, secondly, whether thiol/disulphide status differs in patients with sulphonamide drug hypersensitivity reactions. DESIGN: Thiols provide critical cellular defence against toxic drug reactive intermediates and endogenous oxidative stress, and may modulate HIV replication. Glutathione is reported to be low in HIV-positive individuals and AIDS patients, but this is controversial and the mechanism responsible is unknown. Also unknown is whether altered thiol/disulphide status determines the predisposition of HIV-positive and AIDS patients to drug reactions. METHODS: Thiols and disulphides were measured by high-performance liquid chromatography. RESULTS: Both plasma thiols were decreased by approximately 58% in HIV-positive individuals and AIDS patients compared with uninfected controls (P < 0.05), with increases of up to threefold in oxidized products (P < 0.05). Similarly, in lymphocytes, thiols were decreased by 30-35% (P < 0.05), with apparent increases in oxidized products. For both glutathione and cysteine, the thiol/disulphide ratios also were decreased (P < 0.05). The plasma and lymphocyte glutathione thiol/disulphide ratios were highly correlated (r = 0.7661; P = 0.0001) among all subjects. No parameters differed in patients with drug reactions, or with antiretroviral therapy. CONCLUSIONS: The enhanced thiol oxidation in HIV-positive individuals and AIDS patients indicates oxidative stress, which also contributes to thiol depletion, and may enhance damage to macromolecular targets. These mechanisms may contribute to enhanced viral replication and other pathological outcomes. HIV-positive individuals' and AIDS patients' predisposition to drug hypersensitivity reactions appears to be unrelated to thiol/disulphide status.

Analysis of Variance↗
PubMed1996

A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group.

BACKGROUND: Bacteremia with the Mycobacterium avium complex is common in patients with the acquired immunodeficiency syndrome (AIDS), but the most effective treatment for this infection remains unclear. METHODS: We randomly assigned 229 patients with AIDS and M. avium complex bacteremia to receive either rifampin (600 mg daily), ethambutol (approximately 15 mg per kilogram of body weight daily), clofazimine (100 mg daily), and ciprofloxacin (750 mg twice daily) (the four-drug group) or rifabutin (600 mg daily), ethambutol (as above), and clarithromycin (1000 mg twice daily) (the three-drug group). In the three-drug group the dose of rifabutin was reduced by half after 125 patients were randomized, because 24 of 63 patients had uveitis. RESULTS: Among 187 patients who could be evaluated, blood cultures became negative more often in the three-drug group than in the four-drug group (69 percent vs. 29 percent, P<0.001). Among patients treated for at least four weeks, the bacteremia resolved more frequently in the three-drug group (78 percent vs. 40 percent, P<0.001). In the three-drug group, bacteremia resolved more often with the 600-mg dose of rifabutin than with the 300-mg dose (P=0.025), but the latter regimen was more effective than the four-drug regimen (P<0.05). The median survival was 8.6 months in the three-drug group and 5.2 months in the four-drug group (P = 0.001). The median Karnofsky performance score was higher in the three-drug group than in the four-drug group from week 2 to week 16 (P<0.05). Mild uveitis developed in 3 of the 53 patients receiving the 300-mg dose of rifabutin, an incidence about one quarter that observed with the 600-mg dose (P<0.001). CONCLUSIONS: In patients with AIDS and M. avium complex bacteremia, treatment with the three-drug regimen of rifabutin, ethambutol, and clarithromycin leads to resolution of the bacteremia more frequently and more rapidly than treatment with rifampin, ethambutol, clofazimine, and ciprofloxacin, and survival rates are better.

AIDS-Related Opportunistic Infections↗
PubMed1996

The effect of infection and lag screw fixation on revascularization and new bone deposition in membranous bone grafts in a rabbit model.

We have suggested that rigid fixation of membranous bone grafts in the presence of infection may improve graft-recipient bone union by facilitating graft revascularzation. To test this hypothesis, we grafted autogenous membranous bone grafts to the mandibles of 94 New Zealand White rabbits. Lag screw fixation was applied in half the animals. The wounds were inoculated with a range of Staphylococcus aureus doses. Infected and noninfected rabbits were injected weekly over a 5-week course with fluorescein bone markers and with a marker of vascular endothelium (procion red) just prior to sacrifice. Revascularization and new bone deposition in the grafts were then quantified histologically for the 75 rabbits available for data collection. Infection decreased the amount of graft revascularized and the amount of new bone deposited for both rigidly fixated and nonfixated grafts. Grafts fixated with a lag screw showed a greater amount of revascularization and new bone deposition in the presence and absence of infection when compared with nonfixated grafts, supporting the hypothesis that rigid fixation of membranous bone grafts in the presence of infection may promote graft survival and union by improving revascularization and osteogenesis within the graft.

Animals↗
PubMed1995

Use of fluconazole in the treatment of candidal endophthalmitis.

Candidal endophthalmitis is a sight-threatening ocular infection that most frequently occurs as a complication of candidemia. While amphotericin B is considered the gold standard for the treatment of most invasive fungal infections, the optimal management of candidal endophthalmitis has not been determined. Fluconazole, a triazole antifungal agent, has been shown to be effective in the management of a number of invasive fungal infections in both immunocompromised and immunocompetent hosts. We describe the clinical features and outcomes for six patients with candidal endophthalmitis who were treated with fluconazole at our institutions, and we review 21 additional cases reported in the English-language literature. In total, fluconazole has been used as the sole therapy for candidal endophthalmitis in 14 patients; 16 eyes were infected. Endophthalmitis was cured in 15 of 16 eyes (94%), including five infections that were complicated by vitreitis. Successful treatment required the administration of fluconazole (100-200 mg po) daily for approximately 2 months. In addition, fluconazole has been used in combination with pars plana vitrectomy for the successful treatment of four cases of candidal endophthalmitis that were complicated by moderate to severe vitreitis. Fluconazole appears to be a safe and effective alternative or addition to conventional treatments for the management of candidal endophthalmitis. Prospective evaluation is required to more clearly define the role of this antifungal agent in the management of ocular infections due to Candida species.

Adult↗
PubMed1995

Rifabutin-associated uveitis.

OBJECTIVE: To review rifabutin-associated uveitis and discuss the mechanism and potential role of drug interactions with clarithromycin and fluconazole in contributing to this adverse event. DATA SOURCES: A MEDLINE search (1991 through September 1994) of English-language literature using the main MeSH headings "rifabutin" and "uveitis" and the subheadings "adverse effects" and "chemically induced." Relevant articles also were selected from references of identified articles. Abstracts from recent medical conferences of infectious diseases, pharmacology, and HIV were screened for additional data. STUDY SELECTION AND DATA EXTRACTION: All articles and abstracts reporting uveitis potentially related to rifabutin were considered for inclusion. Fifty-four cases were identified. Pertinent information from the case reports, as judged by the authors, was selected and synthesized for discussion. DATA SYNTHESIS: Rifabutin is being prescribed increasingly for the treatment and prophylaxis of Mycobacterium avium complex (MAC) infection in the HIV-infected population. Uveitis was initially thought to be a rare, dose-limited complication of rifabutin therapy. In an early dose-ranging tolerance study, uveitis was associated with daily doses of 1200 mg or more. Because this toxicity appeared to be dose-related, lower dosages (300-600 mg/d) of rifabutin were selected for study in subsequent clinical trials. More recent reports noting the association of uveitis with these lower dosages of rifabutin have raised concerns about the prevalence of this adverse event. In the 54 identified cases, patients presented with symptoms of unilateral or bilateral uveitis from 2 weeks to more than 7 months following initiation of rifabutin therapy. In all reported cases, patients were receiving concurrent therapy with clarithromycin and/or fluconazole, both of which have inhibitory effects on rifabutin metabolism. In most cases, uveitis resolved within 1-2 months following discontinuation of rifabutin with or without administration of topical corticosteroids. CONCLUSIONS: Rifabutin is prescribed frequently for the prophylaxis and treatment of MAC infection, especially in patients with HIV. Uveitis is a rare, dose-related toxicity of this therapy. The risk of rifabutin-associated uveitis may be increased in patients receiving concurrent therapy with clarithromycin or fluconazole because of drug interactions. Patients receiving therapy with combinations of any of these agents should be warned about signs and symptoms of uveitis and be monitored closely for the development of rifabutin toxicity. If uveitis develops, rifabutin therapy should be discontinued promptly.

Anti-Bacterial Agents↗
PubMed1994

Determination of antimicrobial susceptibilities of Canadian isolates of Haemophilus influenzae and characterization of their beta-lactamases. Canadian Haemophilus Study Group.

Susceptibility testing of 1,688 Haemophilus influenzae isolates found 484 ampicillin-resistant strains; 474 strains (28.4%) were beta-lactamase positive, and 5 strains (0.4%) were non-beta-lactamase producers. Restriction enzyme digestion of the beta-lactamase amplicon determined that, of 157 strains, 11 (7.0%) contained ROB-1 beta-lactamase and 146 (93.0%) contained a TEM-type beta-lactamase.

Ampicillin Resistance↗