PubMed Health⌕ Search

Biomedical subjects

J S Montaner

Publications and source records attributed to J S Montaner.

At least 19 recordsLinked to original sources
PubMed2003

Discrepant results in the interpretation of HIV-1 drug-resistance genotypic data among widely used algorithms.

OBJECTIVES: The aim of this study was to assess the concordance on the interpretation of HIV-1 drug-resistance genotypic data by three widely used algorithms: Stanford University Database (SU), TruGene (Visible Genetics, Canada) (VG) and VirtualPhenotype (Virco, Belgium) (VP). METHODS: Genotypic data from 293 HIV-1-infected individuals with treatment failure was interpreted for 14 antiretroviral drugs by the three algorithms. RESULTS: Complete concordant results among the three systems for all the drugs studied were found in 40/293 (13.7%) samples. Low concordance in the interpretation was observed for most nucleoside reverse transcriptase inhibitors (NRTIs), while results agreed highly for all nonnucleoside reverse transcriptase inhibitors (NNRTIs) and most protease inhibitors (PIs). In pair-wise comparisons, discordant interpretations between SU and VP were found in over 50% of the samples for didanosine, zalcitabine, stavudine and abacavir, and the level of disagreement between VG and VP exceeded 40% for the same drugs. Major discrepancies (high-level resistance interpretation by one algorithm with sensitive interpretation by another) were observed between VG and VP in over 10% of the cases for didanosine, zalcitabine, stavudine and abacavir. On the other hand, the three algorithms had concordant results for lamivudine in over 90% of the cases. CONCLUSIONS: This work demonstrates the great level of discordance in the interpretation of genotyping results among algorithms, clearly showing the necessity for clinical validation. Moreover, these results suggest that a joint effort from the scientific community as well as national and international HIV societies is needed to achieve a consensus for the interpretation of genotypic data.

Algorithms↗
PubMed2001

Industry-sponsored clinical research: a double-edged sword.

Drug development has accelerated exponentially since the 1950s. It is difficult to estimate the relative contributions or rates of success of industry sponsored as opposed to government supported research in any field. However, it is clear that much of the therapeutic innovation of recent decades has emerged from biotechnology and pharmaceutical industry sponsored efforts. This sponsorship is leading to new stresses in the relationship between academic institutions and industry.

Academic Medical Centers↗
PubMed2001

Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy.

CONTEXT: Current recommendations for initiation of antiretroviral therapy in patients infected with human immunodeficiency virus type 1 (HIV) are based on CD4 T-lymphocyte cell counts and plasma HIV RNA levels. The relative prognostic value of each marker following initiation of therapy has not been fully characterized. OBJECTIVE: To describe rates of disease progression to death and AIDS or death among patients starting triple-drug antiretroviral therapy, stratified by baseline CD4 cell count and HIV RNA levels. DESIGN, SETTING, AND PARTICIPANTS: Population-based analysis of 1219 antiretroviral therapy-naive HIV-positive men and women aged 18 years or older in British Columbia who initiated triple-drug therapy between August 1, 1996, and September 30, 1999. MAIN OUTCOME MEASURE: Cumulative mortality rates from the initiation of triple-drug antiretroviral therapy to September 30, 2000, determined using various CD4 cell and plasma HIV RNA thresholds. RESULTS: As of September 30, 2000, 82 patients had died of AIDS-related causes, for a crude AIDS-related mortality rate of 6.7%. The product limit estimate (SE) of the cumulative mortality rate at 12 months was 2.9% (0.5%). In univariate analyses, a prior diagnosis of acquired immunodeficiency syndrome (AIDS), CD4 cell count, use of protease inhibitors, and HIV RNA level were associated with mortality. There was no difference in mortality by age or sex. Only CD4 cell count remained statistically significant in the multivariate analysis. After controlling for AIDS, protease inhibitor use, and plasma HIV RNA level at baseline, patients with CD4 cell counts of less than 50/microL were 6.67 (95% confidence interval [CI], 3.61-12.34) times and those with counts of 50/microL to 199/microL were 3.41 (95% CI, 1.93-6.03) times more likely to die than those with counts of at least 200/microL. CONCLUSION: Our data demonstrate uniformly low rates of disease progression to death and AIDS or death among patients starting antiretroviral therapy with CD4 cell counts of at least 200/microL. In our study, disease progression to death and AIDS or death was clustered among patients starting therapy with CD4 cell counts less than 200/microL.

Adult↗
PubMed2001

CCR5Delta32 and promoter polymorphisms are not correlated with initial virological or immunological treatment response.

OBJECTIVE: Natural genetic polymorphisms within the CCR5 gene and promoter have been linked to patterns of HIV-1 clinical disease progression in untreated individuals. The objective of this retrospective study was to assess the influence of the CCR5Delta32 mutation and promoter polymorphisms on virological and immunological treatment outcome in 436 antiretroviral-naive individuals initiating their first therapy, over a mean follow-up time of 22 months. METHODS: Genotypes for the CCR5Delta32 and promoter were determined by polymerase chain reaction amplification of human DNA from plasma, followed by gel electrophoresis for CCR5Delta32 or DNA sequencing for the promoter polymorphisms. Time to virological failure [defined as the second plasma viral load > or = 400 copies HIV-1 RNA/ml) and immunological failure (defined as time to achieve two successive CD4 cell counts below baseline) were analyzed by Kaplan-Meier methods. RESULTS: The five most common CCR5 promoter polymorphisms were observed at positions 208(G/T), 303(A/G), 627(C/T), 676(A/G), and 927(C/T). Allele frequencies were 0.24(208T), 0.38(303G), 0.44(627T), 0.35(676G) and 0.18(927T). The CCR5Delta32 allele frequency was 0.08. The promoter polymorphisms existed in strong linkage disequilibrium with each other and the Delta32. No significant effect of the individual CCR5Delta32 or promoter polymorphisms could be demonstrated with respect to time to treatment failure as defined by virological or immunological parameters (P > or = 0.07). Similarly, when combined CCR5Delta32 and promoter genotypes were analyzed in order to account for linkage disequilibrium, no significant effect was observed on time to virological or immunological failure (P > 0.6). CONCLUSION: CCR5Delta32 and promoter genotypes may not be of clinical relevance in predicting initial virological or immunological response to antiretroviral therapy.

Alleles↗
PubMed2001

Symptomatic elevations of lactic acid and their response to treatment manipulation in human immunodeficiency virus-infected persons: a case series.

Symptomatic lactic acidemia was seen in 5 human immunodeficiency virus-positive patients receiving combination therapy that included stavudine and > or =1 other nucleoside. Peak venous lactic acid levels of 3.1-7.4 mmol/L (normal range, 0.5-2.1 mmol/L) were associated with fatigue and rapid weight loss, whereas withdrawal of antiretrovirals led to normalization of venous lactic acid levels, symptomatic improvement, and weight gain. Resumption of an altered therapeutic regimen, which did not include stavudine but did include other nucleosides in 4 of 5 cases, did not result in recurrence of the syndrome after up to 126 days.

Adult↗
PubMed2001

World-wide variation in HIV-1 phenotypic susceptibility in untreated individuals: biologically relevant values for resistance testing.

OBJECTIVES: To examine the natural phenotypic variability in drug susceptibility among recombinant HIV-1 isolates from a large number of untreated HIV-positive individuals from wide-ranging geographic locations, and to use this information to establish biologically relevant cut-off values for phenotypic antiretroviral susceptibility testing. METHODS: Phenotypic susceptibility to 14 antiretroviral agents was determined for HIV-1 samples from > 1000 treatment-naive individuals in seven clinical trials. Samples were from the USA (n = 351), Germany (n = 306), Canada (n = 265), and South Africa (n = 358). Geometric mean fold-resistance and confidence intervals were determined relative to a standard laboratory wild-type virus. RESULTS: Baseline fold-resistance was approximately log-normally distributed for all antiretroviral agents examined. There was no evidence of large geographical differences in average antiviral susceptibility. Geometric mean fold-resistance for each of 14 antiviral agents was similar (+/- 0.5-fold) for samples derived from the USA, Canada, Germany, or South Africa. The non-nucleoside reverse transcriptase inhibitors (NNRTI) exhibited the broadest distribution of susceptibility; approximately 97.5% of all isolates had < 2.5-4.0, < 3.0-4.5, and < 5-10 fold-decrease in susceptibility to five protease inhibitors, six nucleoside analogues, and three NNRTI, respectively. No consistent geographic pattern or clade effect (B versus C) in either the mean or the distribution of baseline antiretroviral susceptibility was observed. CONCLUSIONS: Phenotypic drug susceptibility of HIV-1 in untreated individuals varies markedly from drug to drug, with broadly similar patterns world-wide. These results have important implications in defining the 'normal range' of phenotypic susceptibility to antiretroviral agents and establish biologically relevant cut-off values for this phenotypic drug susceptibility test.

Anti-HIV Agents↗
PubMed2001

Unsafe injection practices in a cohort of injection drug users in Vancouver: could safer injecting rooms help?

BACKGROUND: In several European countries safer injecting rooms have reduced the public disorder and health-related problems of injection drug use. We explored factors associated with needle-sharing practices that could potentially be alleviated by the availability of safer injecting rooms in Canada. METHODS: The Vancouver Injection Drug User Study is a prospective cohort study of injection drug users (IDUs) that began in 1996. The analyses reported here were restricted to the 776 participants who reported actively injecting drugs in the 6 months before the most recent follow-up visit, during the period January 1999 to October 2000. Needle sharing was defined as either borrowing or lending a used needle in the 6-month period before the interview. RESULTS: Overall, 214 (27.6%) of the participants reported sharing needles during the 6 months before follow-up; 106 (13.7%) injected drugs in public, and 581 (74.9%) reported injecting alone at least once. Variables independently associated with needle sharing in a multivariate analysis included difficulty getting sterile needles (adjusted odds ratio [OR] 2.7, 95% confidence interval [CI] 1.8-4.1), requiring help to inject drugs (adjusted OR 2.0, 95% CI 1.4-2.8), needle reuse (adjusted OR 1.8, 95% CI 1.3-2.6), frequent cocaine injection (adjusted OR 1.6, 95% CI 1.1-2.3) and frequent heroin injection (adjusted OR 1.5, 95% CI 1.04-2.1). Conversely, HIV-positive participants were less likely to share needles (adjusted OR 0.5, 95% CI 0.4-0.8), although 20.2% of the HIV-positive IDUs still reported sharing needles. INTERPRETATION: Despite the availability of a large needle-exchange program and targeted law enforcement efforts in Vancouver, needle sharing remains an alarmingly common practice in our cohort. We identified a number of risk behaviours--difficulty getting sterile needles, needle sharing and reuse, injection of drugs in public and injecting alone (one of the main contributing causes of overdose)--that may be alleviated by the establishment of supervised safer injecting rooms.

British Columbia↗
PubMed2001

Development of drug resistance in patients receiving combinations of zidovudine, didanosine and nevirapine.

OBJECTIVE: To evaluate the development of phenotypic and genotypic resistance to zidovudine, didanosine and nevirapine as a function of the virologic response to therapy in a group of drug-naive individuals receiving various combinations of these agents. DESIGN: All patients were enrolled in a double-blind controlled randomized trial (the INCAS study) and were selected for detailed resistance studies based on specimen availability and virologic response. METHODS: Within the three study groups (zidovudine/nevirapine, zidovudine/didanosine or zidovudine/nevirapine/didanosine), 16, 19 and 24 patients, respectively, had evaluable baseline isolates and remained in the study > 24 weeks. Phenotypic resistance to all three drugs was evaluated using the VIRCO recombinant virus assay. Genotypic sequencing was done on selected specimens from patients receiving zidovudine/nevirapine/didanosine. RESULTS: After 24 weeks, all available isolates taken from patients receiving nevirapine were resistant to this agent, while 18/21 (86%) patients receiving triple therapy carried such isolates at 30--60 weeks. At 24 weeks, zidovudine resistance developed in 4/40 isolates but was more frequent after 30--60 weeks, especially in patients on two drugs. The degree of zidovudine resistance (rise in concentration required for 50% inhibition) appeared lower in the triple therapy group compared with zidovudine/didanosine (P = 0.0004). All nevirapine-resistant isolates that were sequenced carried at least one mutation associated with resistance, most often K103N and/or Y181C. CONCLUSION: The use of highly active drug therapies may be associated with a beneficial effect on the development of antiretroviral drug resistance. The characteristics of virologic suppression that must be maintained to avoid resistance are currently being studied in hypothesis-driven clinical trials.

Anti-HIV Agents↗
PubMed2001

High exposure to nevirapine in plasma is associated with an improved virological response in HIV-1-infected individuals.

OBJECTIVE: To explore relationships between exposure to nevirapine and the virological response in HIV-1-infected individuals participating in the INCAS trial. METHODS: The elimination rate constant of plasma HIV-1 RNA (k) was calculated during the first 2 weeks of treatment with nevirapine, zidovudine and didanosine in 51 antiretroviral-naive HIV-1-infected patients. The relationships between the value of k, the time to reach an undetectable HIV-1 RNA concentration in plasma (< 20 copies/ml) and the success of therapy after 52 weeks of treatment as dependent variables and the exposure to nevirapine, baseline HIV-1 RNA and baseline CD4 cell count as independent variables, were explored using linear regression analyses, proportional hazard models and logistic analyses, respectively. RESULTS: The value of k for HIV-1 RNA in plasma was positively and significantly associated with the mean plasma nevirapine concentration during the first 2 weeks of therapy (P = 0.011) and the baseline HIV-1 RNA (P = 0.008). Patients with a higher exposure to nevirapine reached undetectable levels of HIV-1 RNA in plasma more rapidly (P = 0.03). From 12 weeks on, the median nevirapine plasma concentration was significantly correlated with success of therapy after 52 weeks (P < 0.02). CONCLUSIONS: A high exposure to nevirapine (in a twice daily regimen) is significantly associated with improved virological response in the short as well as in the long term. These findings suggest that optimization of nevirapine concentration might be used as a tool to improve virological outcome in (antiretroviral-naive) patients treated with nevirapine.

Anti-HIV Agents↗
PubMed2001

The steady-state pharmacokinetics of efavirenz and nevirapine when used in combination in human immunodeficiency virus type 1-infected persons.

The steady-state pharmacokinetics of efavirenz and nevirapine, when used in combination to treat human immunodeficiency virus type 1 (HIV-1)-infected subjects, were investigated. HIV-1-infected persons who had used efavirenz (600 mg once daily) for > or =2 weeks were eligible for study inclusion. The plasma pharmacokinetics of efavirenz were determined over 24 h. Subsequently, nevirapine (400 mg once daily) was added to the regimen. After 4 weeks, the pharmacokinetics of efavirenz and nevirapine were assessed over 24 h. The differences between the pharmacokinetic parameters of efavirenz with and without nevirapine were analyzed, and the pharmacokinetics of nevirapine were compared with those in historical control patients. The exposure to efavirenz when combined with nevirapine was significantly decreased by 22% (area under the plasma concentration vs. time curve), 36% (minimum plasma concentration), and 17% (maximum plasma concentration). Nevirapine pharmacokinetics appear to be unaffected by coadministration of efavirenz, compared with data from historical control patients.

Adult↗
PubMed2001

HIV protease and reverse transcriptase variation and therapy outcome in antiretroviral-naive individuals from a large North American cohort.

OBJECTIVE: To assess the effect of baseline HIV reverse transcriptase (RT) and protease sequence variation on virologic outcomes in a large cohort of antiretroviral-naive patients in British Columbia, Canada. METHODS: Population sequencing of RT and protease was performed on baseline viral RNA of all antiretroviral-naive patients first seeking treatment in British Columbia between June 1997 and August 1998 (n = 479). Relative risks of virological failure associated with genotypic differences from a 'standard' HIV strain (HXB2) were assessed for up to 18 months. RESULTS: The prevalence of key baseline mutations known to confer resistance to RT and protease inhibitors (PI) was 3.4 and 3.8%, respectively. No statistically significant impact on virologic outcomes could be established for these patients. However, the data suggest that some individuals (harboring a M184V mutation in RT or a V82I in protease) may have benefited from pre-therapy resistance tests. 'Secondary' mutations in the protease associated with resistance (e.g. codons 10, 36 or 63) were common, but the presence of these secondary mutations, either alone or in combination, did not appear to result in early loss of therapeutic virological suppression. Preliminary analyses suggest that an amino acid change at codon 35 in the protease may be associated with early treatment failure. CONCLUSIONS: The results suggest that routine genotyping of naive patients about to start antiretroviral therapy would be of benefit to a relatively small proportion of the population. Secondary mutations associated with resistance to PI alone were not found to affect virologic outcomes significantly.

Anti-HIV Agents↗
PubMed2001

Multiple drug rescue therapy for HIV-infected individuals with prior virologic failure to multiple regimens.

OBJECTIVES: To characterize the antiviral response and tolerability of a multi-drug rescue therapy (MDRT) among heavily pretreated patients. METHODS: Observational study conducted in a single, university-based tertiary referral clinic. Patients (n = 106) who failed several prior regimens started MDRT including at least five antiretroviral (ARV) drugs between August 1997 and June 1998. The most common starting regimen included three nucleoside reverse transcriptase inhibitors and two protease inhibitors, which was prescribed to 45 (42.5%) patients. Virologic response was defined as plasma viral load < 400 copies/ml on at least two consecutive visits. RESULTS: Median prior ARV exposure was seven drugs over a median time of 43 months. Fifty-nine percent of the patients were phenotypically (VIRCO Antivirogram) resistant at baseline to seven or more ARV. Median plasma viral load change following initiation of MDRT was -1.04 log10 copies/ml over a median of 15 months. Using intention-to-treat analysis 40% of patients had plasma viral load values < 400 copies/ml between weeks 47 and 57 of follow-up. Twenty-six patients (25%) experienced severe laboratory abnormalities or subjective adverse drug effects and six of these participants discontinued therapy. CONCLUSION: MDRT induced a substantial antiviral response in this heavily pretreated group of patients despite extensive phenotypic resistance at baseline. Adverse effects were frequent but generally manageable. Our data suggest that relying exclusively on historical, clinical and laboratory evidence may not be sufficient to rule out a possible antiviral response when multiple drug regimens are used in this heavily pretreated patient population.

Adult↗