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Biomedical subjects

D William Cameron

Publications and source records attributed to D William Cameron.

At least 19 recordsLinked to original sources
PubMed2006

Comparison of the risks of atherosclerotic events versus death from other causes associated with antiretroviral use.

BACKGROUND: Studies considering the risk of atherosclerotic disease (AtD) associated with the use of HAART have reported inconsistent results. METHODS: Data on antiretroviral therapy (ART) use, risk factors for cardiovascular disease (CVD), AtD and death from other causes in 18 603 HIV-infected patients from two established cohorts were evaluated. The relative hazards of AtD and death from other causes were calculated using a proportional hazards competing risks framework. The impact of protease inhibitor (PI)-containing, non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing or PI + NNRTI-containing regimens on these outcomes were compared to nucleoside reverse transcriptase inhibitor (NRTI)-only regimens or stopping therapy, adjusting for known CVD risk factors. RESULTS: In 77 480 person-years of follow-up (median duration 3.49 years) there were 318 AtD events including 92 myocardial infarctions and 2044 deaths. Older age, hypertension, diabetes mellitus, having smoked and HIV disease stage were significantly associated with increased risk of AtD. PI- and NNRTI-containing regimens significantly reduced the joint risk of either AtD or death from other causes compared to NRTI-only or stopping therapy [hazard ratio (HR) for PI-containing ART, 0.76, 95% confidence interval (CI), 0.73-0.78, P< 0.001; NNRTI-containing ART, 0.69, 95% CI, 0.65-0.74; P< 0.001). PI-containing ART was associated with a borderline significant increased risk of myocardial infarction (cause-specific HR for PI-containing ART 1.19, 95% CI, 1.01-1.40, P = 0.04) but not with increased risk of AtD compared to NRTI-only regimens or stopping therapy (cause-specific HR for PI-containing ART, 1.03, 95% CI, 0.95-1.13, P = 0.44). CONCLUSIONS: Overall benefits of PI- and NNRTI-based ART in reducing mortality significantly outweigh any risks of AtD in the "short-term" follow-up of this study. Traditional cardiac risk factors play an important role in determining AtD risk status.

Adolescent↗
PubMed2006

Adherence with isoniazid for prevention of tuberculosis among HIV-infected adults in South Africa.

BACKGROUND: Tuberculosis (TB) is the most common opportunistic infection in HIV-infected adults in developing countries. Isoniazid (INH) is recommended for treatment of latent TB infection, however non-adherence is common. The purpose of this study was to apply in-house prepared isoniazid (INH) urine test strips in a clinical setting, and identify predictors of positive test results in an adherence questionnaire in HIV-infected adults taking INH for prevention of TB. METHODS: Cross-sectional study of adherence using a questionnaire and urine test strips for detection of INH metabolites at two hospitals in Pietermaritzburg, South Africa. Participants were aged at least 18 years, HIV positive, and receiving INH for prevention of tuberculosis disease. Univariate and multivariate analyses are used to identify factors relevant to adherence. RESULTS: 301 consecutive patients were recruited. 28% of participants had negative urine tests. 32 (37.2%, 95% CI25.4, 45.0) of the 86 patients who received INH from peripheral pharmacies said the pharmacy had run out of INH at some time, compared with central hospital pharmacies (p = 0.0001). In univariate analysis, a negative test was associated with self-reported missed INH doses (p = 0.043). Each 12-hour increment since last reported dose increased the likelihood of a negative test by 34% (p = 0.0007). Belief in INH safety was associated with a positive test (p = 0.021). In multivariate analysis, patients who believed INH is important for prevention of TB disease were more likely to be negative (p = 0.0086). CONCLUSION: Adequate drug availability at peripheral pharmacies remains an important intervention for TB prevention. Key questions may identify potentially non-adherent patients. In-house prepared urine tests strips are an effective and cheap method of objectively assessing INH adherence, and could be used an important tool in TB control programs.

AIDS-Related Opportunistic Infections↗
PubMed2006

The benefits and risks of bacille Calmette-Guérin vaccination among infants at high risk for both tuberculosis and severe combined immunodeficiency: assessment by Markov model.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccine is given to Canadian Aboriginal neonates in selected communities. Severe reactions and deaths associated with BCG have been reported among infants born with immunodeficiency syndromes. The main objective of this study was to estimate threshold values for severe combined immunodeficiency (SCID) incidence, above which BCG is associated with greater risk than benefit. METHODS: A Markov model was developed to simulate the natural histories of tuberculosis (TB) and SCID in children from birth to 14 years. The annual risk of tuberculous infection (ARI) and SCID incidence were varied in analyses. The model compared a scenario of no vaccination to intervention with BCG. Appropriate variability and uncertainty analyses were conducted. Outcomes included TB incidence and quality-adjusted life years (QALYs). RESULTS: In sensitivity analyses, QALYs were lower among vaccinated infants if the ARI was 0.1% and the rate of SCID was higher than 4.2 per 100,000. Assuming an ARI of 1%, this threshold increased to 41 per 100,000. In uncertainty analyses (Monte Carlo simulations) which assumed an ARI of 0.1%, QALYs were not significantly increased by BCG unless SCID incidence is 0. With this ARI, QALYs were significantly decreased among vaccinated children if SCID incidence exceeds 23 per 100,000. BCG is associated with a significant increase in QALYs if the ARI is 1%, and SCID incidence is below 5 per 100,000. CONCLUSION: The possibility that Canadian Aboriginal children are at increased risk for SCID has serious implications for continued BCG use in this population. In this context, enhanced TB Control--including early detection and treatment of infection--may be a safer, more effective alternative.

BCG Vaccine↗
PubMed2006

Time-dependent interaction between lopinavir/ritonavir and fexofenadine.

This study investigated the effect of single-dose and steady-state lopinavir/ritonavir on the exposure to fexofenadine, as a measure of P-glycoprotein activity. Sixteen volunteers (8 women) received single-dose oral fexofenadine 120 mg alone, in combination with single-dose ritonavir 100 mg or lopinavir/ritonavir 400/100 mg (randomized 1:1, stratified by sex), and in combination with steady-state lopinavir/ritonavir 400/100 mg twice daily. Single-dose ritonavir and lopinavir/ritonavir increased the area under the fexofenadine plasma concentration-time curve from 0 to infinity (AUC(infinity)) by 2.2- and 4.0-fold, respectively (P < .02). Steady-state lopinavir/ritonavir increased the fexofenadine AUC(infinity) by 2.9-fold. No changes were observed in the fexofenadine elimination half-life (P > .12). The fexofenadine AUC(infinity) was increased by lopinavir/ritonavir, likely due to increased bioavailability secondary to P-glycoprotein inhibition. After repeated administration of lopinavir/ritonavir, the interaction was attenuated compared to the single-dose effect, although a net inhibitory effect was maintained. Time-dependent inhibition of P-glycoprotein by lopinavir/ritonavir should be considered when P-glycoprotein substrates are coadministered.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2005

CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults.

BACKGROUND: HIV patients are vaccine hyporesponsive. METHODS: We evaluated CPG 7909, a synthetic oligodeoxynucleotide containing immunostimulatory CpG motifs, as an adjuvant to Engerix-B. A randomized, double-blind controlled trial was conducted to determine safety and hepatitis B virus (HBV) immunogenicity in adult HIV subjects on effective antiretroviral therapy. HBV-susceptible subjects, half of whom had failed previous vaccination, were vaccinated at 0, 1 and 2 months with a double dose of Engerix-B with/without (+/-) 1 mg CPG 7909. HBV immune subjects (anti-HBsAg titres > or = 10 mIU/l) received either CPG 7909 alone or saline. Safety, anti-HBs titres and lymphocyte proliferation response (LPR) to HBsAg were assessed over 12 months. RESULTS: Vaccinations with Engerix B +/- CPG 7909 were well tolerated locally and systemically. HIV suppression and CD4 cell counts were maintained. Anti-HBs titers were significantly higher in vaccinees receiving CPG 7909, for all time points after the second dose. Seroprotective titres (> or = 10 mIU/ml) by 6 and 8 weeks, and 12 months were found in 89, 89, and 100% of subjects receiving CPG 7909 compared to 53, 42, and 63% of controls respectively (P = 0.029, 0.005, and 0.008). HBsAg LPR was increased at all time-points up to 12 months after vaccination with addition of CPG 7909 (P < 0.05). CONCLUSIONS: Addition of CPG 7909 achieves rapid, higher, and sustained HBV seroprotection and increases HBV-specific T helper cell response to HBV vaccine in HIV subjects. These results confirm a potential adjuvant role for CPG 7909 in vaccine hyporesponsive populations including those living with HIV.

Adjuvants, Immunologic↗
PubMed2005

In vitro and in vivo activity of combination antimicrobial agents on Haemophilus ducreyi.

OBJECTIVES: Development of single dose antibiotic treatments for chancroid has been followed by drug-resistant Haemophilus ducreyi in endemic areas. We examined the activity and interactions of antimicrobial agents and combinations against H. ducreyi. METHODS: We evaluated the in vitro susceptibility of three virulent strains of H. ducreyi to ceftriaxone, azithromycin, rifabutin and streptomycin, and each two-drug combination by the agar dilution method. We then tested each two-antibiotic combination for activity by the chequerboard method. Lastly, we chose the antibiotic combination with the lowest fractional inhibitory concentration index (FICI) and tested combined sub-therapeutic doses, the highest doses which had no effect alone on lesion healing compared with controls, for in vivo interaction in the temperature-dependent rabbit model of H. ducreyi infection. RESULTS: Each H. ducreyi strain was susceptible in vitro to each antibiotic and two-antibiotic combination, and combined ceftriaxone and streptomycin had the lowest FICI at 0.63. In five treated animals versus three untreated controls, combined sub-therapeutic doses of ceftriaxone (0.05 mg/kg) and streptomycin (10 mg/kg) reduced mean (SD) duration of culture positivity from 7.3 (1.1) to 2.6 (1.7) days (P<0.001), time to 50% reduction in lesion size from 9.7 (1.5) to 5.8 (0.8) days (P<0.005), and time to resolution of ulcer from 11.7 (2.3) to 6.6 (1.7) days (P<0.05). CONCLUSIONS: Ceftriaxone and streptomycin have in vivo synergic interaction against H. ducreyi lesions in the temperature-dependent rabbit model of infection. Antibiotic combinations may be evaluated clinically as single-dose therapy for chancroid.

Animals↗
PubMed2005

Effect of alcohol use and highly active antiretroviral therapy on plasma levels of hepatitis C virus (HCV) in patients coinfected with HIV and HCV.

BACKGROUND: The interactions between human immunodeficiency virus (HIV), hepatitis C virus (HCV), alcohol, and antiretroviral therapy are complex. METHODS: We retrospectively assessed persons coinfected with HIV and HCV who achieved HIV suppression to < 500 copies/mL and continued to take antiretrovirals for > or = 6 months. Frozen plasma specimens were retrieved for quantitation of HCV RNA levels at baseline and 3, 6, and 12 months after beginning antiretroviral treatment. RESULTS: Median HCV RNA levels increased (0.35 log10 IU/mL) at month 3 (n = 44). HCV RNA levels decreased to below baseline by 12 months in patients consuming < 50 g of alcohol/day, whereas patients consuming > or = 50 g/day had a sustained increase (> 0.6 log10 IU/mL) from baseline (P = .04). CONCLUSIONS: Because low levels of HCV RNA are predictive of a virological response to therapy for HCV infection, it may be advantageous to first achieve suppression of HIV RNA and then initiate treatment for HCV infection in patients coinfected with HIV and HCV. Excess alcohol consumption with therapy for HIV infection increases HCV RNA levels and may impede the effectiveness of this treatment strategy.

Adult↗
PubMed2005

Attenuated Salmonella typhimurium SL3261 as a vaccine vector for recombinant antigen in rabbits.

Oral live Salmonella vaccine vectors expressing recombinant guest antigens help stimulate systemic, mucosal, humoral, and cell-mediated immune responses against Salmonella and recombinant antigens. It may be possible to use them effectively against Haemophilus ducreyi, the bacterium that causes chancroid, a sexually transmitted genital ulcer disease. This study aimed to test the feasibility of using oral Salmonella vaccine vectors for the evaluation of chancroid vaccine candidates in the temperature-dependent rabbit model of H. ducreyi infection, an in vivo quantitative virulence assay of inducible immunity. We identified 10(8) to 10(9) CFU to be a safe and immunogenic oral dose range of S. typhimurium SL3261, by monitoring post-administration onset and course of illness and antibody titre by enzyme immunoassay (EIA). We successfully transduced plasmid pTETnir15 into the strain to produce recombinant S. typhimurium SL3261(pTETnir15), successfully expressed tetanus toxin fragment C (TetC) in it, and elicited serum anti-TetC titres of 1:6400 by EIA, 4 weeks after inoculation. The course of experimentally induced H. ducreyi skin lesions in rabbits treated with SL3261(pTETnir15) was similar to that in saline-treated controls. We describe a framework that successfully uses Salmonella as a vector for recombinant control antigen in the rabbit model of H. ducreyi infection, and is suitable for pre-clinical evaluation of Salmonella vector-based H. ducreyi vaccine antigen candidates.

Administration, Oral↗
PubMed2005

Use of intravenous immunoglobulin for treatment of neurologic conditions: a systematic review.

BACKGROUND: Given the increasing use of intravenous immunoglobulin (IVIG) for various neurologic conditions and uncertainty pertaining to its benefits and harms, a systematic review was conducted of randomized controlled trials (RCTs) evaluating IVIG for all neurologic indications for which there was at least one published trial. STUDY DESIGN AND METHODS: For this systematic review, a systematic search strategy was applied to MEDLINE (1966-June 2003) and the Cochrane Register of Controlled Trials (June 2003) to identify potentially eligible RCTs comparing IVIG to placebo or an active control. All dosage regimens were considered. Abstracts were excluded, and no restriction was placed on language of publication. Two investigators independently performed data extraction with a standardized form. Measures of effect were calculated for each trial independently, and studies were pooled based on clinical and methodologic judgment as to its appropriateness. Where pooling of trials was inappropriate, a qualitative discussion of findings is provided. RESULTS AND CONCLUSIONS: Thirty-seven trials representing 14 conditions were identified. IVIG is more effective than placebo for treatment of relapsing-remitting multiple sclerosis and idiopathic chronic inflammatory demyelinating polyneuropathy. There is also potential benefit for treatment of multifocal motor neuropathy, myasthenia gravis, dermatomyositis, stiff-person syndrome, and Lambert-Eaton myasthenic syndrome. There was insufficient evidence to determine whether IVIG therapy was more effective than plasma exchange for Guillain-Barré syndrome. There was also insufficient evidence regarding paraprotein-associated polyneuropathy. No evidence of benefit was observed for secondary progressive multiple sclerosis or inclusion body myositis.

Adrenal Cortex Hormones↗
PubMed2004

Co-administration of CpG oligonucleotides enhances the late affinity maturation process of human anti-hepatitis B vaccine response.

We assessed the avidity maturation process elicited by human immunization with alum-adsorbed HBsAg alone or with a novel adjuvant containing CpG motifs (CpG 7909). Mean avidity indexes and distribution of low- and high-avidity anti-HBs indicated that avidity maturation essentially takes place late after priming. CpG 7909 markedly enhanced this affinity maturation process, increasing the pool of high-avidity antibodies. The influence of CpG 7909 was antigen-specific, isotype-specific and distinct from the influence on anti-HBs production, as avidity did not correlate with anti-HBs IgG titers. This is the first demonstration that a novel human adjuvant may induce antibodies with higher antigen-binding affinity.

Adjuvants, Immunologic↗
PubMed2004

Interpretation of undetectable hepatitis C virus RNA levels in HIV-hepatitis C virus co-infection.

Individuals with positive hepatitis C virus (HCV) antibody titres, normal transaminase levels, and undetectable HCV-RNA levels are generally considered to have cleared the previous hepatitis C infection. We report the emergence of plasma HCV RNA within a cohort of HIV and HCV seropositive/plasma HCV-RNA-negative patients initiating highly active antiretroviral therapy. Our observations challenge conventional wisdom that HCV polymerase chain reaction-negative patients with normal liver enzymes are 'cured'.

AIDS-Related Opportunistic Infections↗
PubMed2004

The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum.

OBJECTIVE: The objective of this study was to explore the pharmacokinetics of nelfinavir and its active metabolite hydroxy-t-butylamidenelfinavir (M8) during pregnancy and post partum. METHODS: Eleven human immunodeficiency virus type 1-infected pregnant women receiving 1250 mg nelfinavir twice daily were enrolled. Pharmacokinetics of nelfinavir and M8 were assessed over a 12-hour period during pregnancy (median, 32 weeks' gestation; range, 31-36 weeks) and post partum (median, 8 weeks post partum; range, 6-15 weeks). Drug concentrations were analyzed by HPLC coupled to tandem mass spectroscopy, and pharmacokinetic parameters were calculated by use of noncompartmental methods. RESULTS: The median area under the plasma concentration-time curve from 0 to 12 hours (AUC 0-12), the maximal plasma concentration (C max), and the concentration at the end of the dosing interval (C 12) for nelfinavir post partum were 33.5 h . microg/mL, 5.80 microg/mL, and 1.40 microg/mL, respectively. The values for the geometric mean ratio (GMR) (third trimester/post partum) for the nelfinavir AUC 0-12 , C max , and C 12 were 0.76 (90% confidence interval [CI], 0.54-1.06), 0.81 (90% CI, 0.57-1.15), and 0.43 (90% CI, 0.25-0.76), respectively. The GMR values for the M8 AUC 0-12 , C max , and C 12 were 0.32 (90% CI, 0.18-0.55), 0.31 (90% CI, 0.19-0.51), and 0.30 (90% CI, 0.14-0.64), respectively. The median ratio values of the AUC 0-12 of M8 and nelfinavir (M8/nelfinavir) during the third trimester and post partum were 11% and 27%, respectively (GMR, 0.42 [90% CI, 0.33-0.53]). CONCLUSIONS: Nelfinavir exposure was reduced during pregnancy, and the reduction was statistically significant for C 12 . M8 concentrations were about 70% lower during pregnancy compared with post partum, suggesting either induction of hepatic cytochrome P450 (CYP) 3A4 or inhibition of CYP2C19, or both, during pregnancy. Because 8 of 11 women had subtherapeutic nelfinavir trough concentrations during pregnancy, the safety and efficacy of therapeutic drug monitoring should be investigated.

Adult↗
PubMed2002

Review of the effect of highly active antiretroviral therapy on hepatitis C virus (HCV) RNA levels in human immunodeficiency virus and HCV coinfection.

The effect of anti-human immunodeficiency virus (HIV) treatment on hepatitis C virus (HCV) RNA levels in HIV-HCV-coinfected persons is uncertain. Although it is commonly believed that, with the initiation of HIV treatment, there may be an initial increase followed by a gradual decrease of HCV RNA levels to lower than those at pretreatment, the published studies evaluating this are of small and heterogeneous populations, are limited in follow-up, and have conflicting results. A prospective clinical trial of sufficient size and duration may help clarify this issue. This may be clinically relevant, because lower HCV RNA levels are a predictive factor for favorable response to HCV antiviral therapy.

Anti-HIV Agents↗
PubMed2002

Normalization of natural killer cell function and phenotype with effective anti-HIV therapy and the role of IL-10.

OBJECTIVES: Natural killer (NK) cell function is likely to be important in controlling HIV infection and opportunistic pathogens. We therefore evaluated NK function and phenotype over the course of antiretroviral therapy (ART) and examined the potential mechanisms of altered NK activity in HIV infection. METHODS: We measured NK cell percentage, NK cytolytic activity (both by flow cytometry) and plasma IL-10 concentrations (by enzyme-linked immunosorbent assay) in 10 HIV-seropositive patients before and over one year of effective ART. To examine potential mechanisms of altered NK activity, we measured NK receptor expression in ART treated and untreated HIV-positive individuals by flow cytometry. As IL-10 enhances NK activity, we studied the effect of IL-10 on NK receptor expression and activity in peripheral blood mononuclear cells (PBMC) from HIV-seronegative individuals. RESULTS: NK cytolytic activity was elevated in HIV infection and decreased with ART to levels observed in HIV-negative individuals. A greater proportion of NK cells from untreated HIV-positive individuals expressed the NK receptors CD158a and CD161 than either HIV-negative volunteers or effectively treated HIV-positive patients. NK cells from PBMC incubated with IL-10 demonstrated increases in CD158a, CD161 and CD94 expression and increases in cytolytic activity. The treatment-associated decrease in NK activity paralleled a decrease in IL-10 production. CONCLUSION: The observation that IL-10 alters NK receptor expression similar to that observed in HIV infection, and the fact that NK receptor expression and activity normalize in parallel with ART-induced reduction of circulating IL-10 levels supports a role for IL-10 in NK cell activity and HIV immunopathogenesis.

Anti-HIV Agents↗
PubMed2002

Field evaluation of the Merlin immediate HIV-1 and -2 test for point-of-care detection of human immunodeficiency virus antibodies.

The Merlin Immediate HIV-1 and -2 Test (Merlin point-of-care [POC] test; Merlin Biomedical & Pharmaceutical) is a nitrocellulose membrane flow immunoassay performed at the POC with the use of blood obtained from a fingerprick. The results of this test were compared with those of enzyme immunoassay (EIA) performed on venous blood samples in the laboratory. Positive results of both tests were confirmed by a Western blot (WB). The study included 553 adults with known HIV (human immunodeficiency virus) seropositivity (all of whom had positive Merlin POC test results) and 2659 adults with unknown HIV serostatus (20 of whom had positive EIA/WB results; 19 of the 20 also had positive Merlin-POC test results). The sensitivity of the Merlin POC test was 95.0% for patients with an unknown HIV serostatus and 99.83% for those with a positive serostatus. For previously untested subjects, the test's specificity and positive predictive value were 100%, its negative predictive value was 99.96%, and its overall accuracy was 99.96%. The Merlin POC test is highly accurate for the detection of HIV antibodies.

AIDS Serodiagnosis↗