Biomedical subjects

Michael Bates

Publications and source records attributed to Michael Bates.

12 recordsLinked to original sources

PubMed2007

Increased heritability of certain types of anorectal malformations.

PURPOSE: Various lines of evidence point to genetic causes for the diverse spectrum of anorectal malformations (ARMs); we therefore studied patterns of heritability in a large case series. METHODS: We searched our ARM database for all patients having family members with congenital anomalies. This group was analyzed to determine the type of ARM and the specific anomalies in affected family members. RESULTS: Thirty-nine of 1606 patients (2.4%) had a family member with a congenital anomaly. The associated non-ARM anomalies included sacral masses and gynecologic, hematologic, esophageal, duodenal, renal, and spinal anomalies. Of these, 24 patients (1.4%) had 1 or more family members with an ARM. Among females with a positive family history, 73% of patients had either a vestibular or perineal fistula, compared with only 36% in patients without a family history (P = .0004). Among males, 35% had perineal fistulas compared with only 10% of those without affected family members (P = .0051). CONCLUSIONS: A positive family history in 1.4% is supportive of a strong genetic component to ARM. The risk of having an affected family member is significantly increased in the presence of a vestibular or perineal fistula. These new data allow for more informed counseling of families with an ARM and support the need for further genetic studies.

Anal Canal↗

PubMed2006

Prevalence of CXCR4 tropism among antiretroviral-treated HIV-1-infected patients with detectable viremia.

Although CXCR4-tropic viruses are relatively uncommon among untreated human immunodeficiency virus (HIV)-infected individuals except during advanced immunodeficiency, the prevalence of CXCR4-tropic viruses among treated patients with detectable viremia is unknown. To address this issue, viral coreceptor usage was measured with a single-cycle recombinant-virus phenotypic entry assay in treatment-naive and treated HIV-infected participants with detectable viremia sampled from 2 clinic-based cohorts. Of 182 treated participants, 75 (41%) harbored dual/mixed or X4-tropic viruses, compared with 178 (18%) of the 976 treatment-naive participants (P<.001). This difference remained significant after adjustment for CD4+ T cell count and CCR5 Delta 32 genotype. Enrichment for dual/mixed/X4-tropic viruses among treated participants was largely but incompletely explained by lower pretreatment nadir CD4 + T cell counts. CCR5 inhibitors may thus be best strategically used before salvage therapy and before significant CD4 + T cell depletion.

Adult↗

PubMed2006

The independent effect of drug resistance on T cell activation in HIV infection.

OBJECTIVE: Antiretroviral-treated individuals with drug-resistant HIV experience slower CD4 cell count declines than untreated individuals, independent of degree of viremia. As immune activation independently predicts disease progression, we hypothesized that patients with drug-resistant viremia would have less immune activation than patients with wild-type viremia, independent of plasma HIV RNA levels and that these differences would not be explained by a direct drug effect of protease inhibitors. METHODS: Percentages of activated (CD38/HLA-DR) T cells were compared between untreated participants with wild-type viremia and antiretroviral-treated participants with drug-resistant viremia, after adjusting for plasma HIV RNA levels among other factors associated with T cell activation. Changes in T cell activation were also assessed in subjects discontinuing protease inhibitors while continuing other antiretroviral medications. RESULTS: Twenty-one untreated participants with wild-type viremia and 70 antiretroviral-treated participants with drug-resistant viremia were evaluated. Relative to untreated participants, those with drug-resistant viremia had 29% fewer activated CD4 (P = 0.051) and CD8 (P = 0.012) T cells after adjustment for plasma HIV RNA levels among other factors. There was no evidence for an early change in T cell activation among 13 subjects with drug-resistant viremia interrupting protease inhibitors while continuing other antiretroviral medications, but a significant increase in T cell activation with complete or partial emergence of wild-type sequences in protease. CONCLUSIONS: Antiretroviral-treated patients with drug-resistant viremia have less T cell activation than untreated patients, independent of plasma HIV RNA level. Decreased ability of drug-resistant variants to cause T cell activation likely contributes to slower CD4 cell count declines among patients with drug-resistant viremia.

ADP-ribosyl Cyclase 1↗

PubMed2005

Response to antiretroviral therapy in HIV-infected patients attending a public, urban clinic in Kampala, Uganda.

BACKGROUND: Access to antiretroviral therapy and human immunodeficiency virus (HIV) care is increasing in resource-limited settings. We evaluated clinical, behavioral, and demographic risk factors associated with virologic suppression in a public, urban clinic in Kampala, Uganda. METHODS: We conducted a cross-sectional, observational study of 137 HIV-infected patients who were receiving antiretroviral therapy at the infectious diseases clinic at Mulago Hospital (Kampala). We measured the prevalence of viral suppression, evaluated risk factors associated with virologic failure, and documented phenotypic resistance patterns and genotypic mutations. RESULTS: A total of 91 (66%) of 137 participants had an undetectable viral load (< 400 copies/mL) after a median duration of 38 weeks (interquartile range, 24-62 weeks) of antiretroviral therapy. Median CD4 cell count was 163 cells/mm3 (interquartile range, 95-260 cells/mm3). The majority of the patients (91%) were treated with nonnucleoside reverse-transcriptase inhibitor-based 3-drug regimens. In multivariate analysis, treatment with the first antiretroviral regimen was associated with viral suppression (odds ratio, 2.6; 95% confidence interval, 1.1-6.1). In contrast, a history of unplanned treatment interruption was associated with virologic treatment failure (odds ratio, 0.2; 95% confidence interval, 0.1-0.6). Of 124 participants treated with nonnucleoside reverse-transcriptase inhibitors, 27 (22%) were documented to have experienced virologic treatment failure. The most common mutation detected was K103N (found in 14 of 27 patients with virologic treatment failure). CONCLUSIONS: Although many HIV-infected people treated in Kampala, Uganda, have advanced HIV disease, the majority of patients who received antiretroviral therapy experienced viral suppression and clinical benefit. Because of the frequent use of nonnucleoside reverse-transcriptase inhibitor-based therapy, the majority of resistance was against this drug class. In resource-limited settings, initiation of therapy with a potent, durable regimen, accompanied by stable drug supplies, will optimize the likelihood of viral suppression.

Adult↗

PubMed2005

HIV-1 pol replication capacity predicts disease progression.

OBJECTIVE: To determine the influence of pol replication capacity on the natural history of HIV-1 infection. DESIGN: Pol replication capacity was measured using a recombinant virus single cycle assay on baseline plasma specimens from subjects enrolled in the Hemophilia Growth and Development Study. SETTING: Children and adolescents with hemophilia and HIV-1 infection were enrolled at multiple sites across the USA into a natural history study. PARTICIPANTS: The Hemophilia Growth and Development Study enrolled 207 HIV-1-infected hemophiliacs between 6 and 19 years of age in 1989 and 1990. Subjects were followed every 6 months through 1997 with pol replication capacity measurements available from 128 of the subjects. MAIN OUTCOME MEASURES: A univariate model defined the relationship between pol replication capacity and HIV-1 RNA and CD4 T-cell number. A random effects model assessed the ability of this measure to predict CD4 T-cell decline over time and a Cox proportional hazards model and Kaplan-Meier analyses defined how it predicts clinical progression. RESULTS: Pol replication capacity measures correlated with baseline HIV-1 RNA, R = 0.189 (P = 0.03) and CD4 T-cell number, -0.197 (P = 0.03). It also independently predicted CD4 T-cell decline over time and progression to AIDS. CONCLUSIONS: This study demonstrates that pol replication capacity independently influences the natural history of HIV-1 infection.

Adolescent↗

PubMed2004

Phenotypic impact of HIV reverse transcriptase M184I/V mutations in combination with single thymidine analog mutations on nucleoside reverse transcriptase inhibitor resistance.

OBJECTIVES: To analyse the impact of the M184I/V mutation and individual thymidine-associated mutations (TAM) on nucleoside reverse transcriptase inhibitor (NRTI) phenotypic susceptibility and compare these results with those obtained using commercial and public algorithms. DESIGN: An HIV genotypic/phenotypic database with over 27 000 samples was used to obtain the median fold change (5-95th percentile) in NRTI phenotypic susceptibility for viruses from patients containing individual TAM with or without the M184I or V mutation and for wild-type patient viruses. RESULTS: The resulting data indicated that in vitro, individual TAM do not have an equivalent impact on NRTI resistance, with some individual TAM having little or no impact on NRTI resistance (e.g. M41L or K219Q/E/H/R). In the presence of the M184I/V mutation, re-sensitization to some drugs, including zidovudine, stavudine and tenofovir was observed despite the presence of a TAM. For didanosine and abacavir, the presence of the M184V mutation and a single TAM did not result in a fold-change increase associated with decreased drug susceptibility. Analysis of public and commercial algorithms revealed a lack of concordance regarding the impact of these mutations, and with the observed phenotypic data. CONCLUSION: These analyses should assist in the creation of rules for genotypic drug resistance algorithms for a better reflection of the impact of individual TAM and also the impact of M184I/V on resistance. These data provide additional evidence that retaining lamivudine in those treatment regimens in which TAM can be selected may provide some therapeutic benefit by maintaining the M184V mutation.

Adenine↗

PubMed2003

Progressive reversion of human immunodeficiency virus type 1 resistance mutations in vivo after transmission of a multiply drug-resistant virus.

Evolution and transmission of multiply drug-resistant human immunodeficiency virus type 1 (HIV-1) may limit therapeutic options as global treatment efforts expand. However, the stability of these mutants in the absence of drug selection pressure is not known. We performed a longitudinal analysis of plasma virus from a person who acquired HIV-1 that contained multiple reverse transcriptase (RT) and protease (PR) mutations. In the absence of therapy, 5 of 12 drug resistance mutations reverted in a stepwise fashion to wild type over the course of 52 weeks. Reversion of the M184V mutation alone did not change viral replicative capacity (RC), but it led to enhanced resistance to zidovudine and tenofovir. However, reversions of a second RT mutation and 3 PR mutations were associated with an increase in viral RC, and this was temporally correlated with a marked decrease in CD4 cell number. This study demonstrates the gradual stepwise back-mutation of certain drug resistance mutations in vivo in the absence of ongoing drug selection pressure. Moreover, it suggests that, despite initially impaired viral fitness, a transmitted HIV-1 isolate with multiple drug resistance mutations can evolve to develop increased RC and significant pathogenicity.

Adult↗

PubMed2003

Practical applications of viral fitness in clinical practice.

PURPOSE OF REVIEW: To review recent clinical data regarding viral fitness and its potential utility in clinical practice. Therapeutic failure of antiretroviral regimens is often due to the development of drug resistance. The viral loads achieved by these drug-resistant variants frequently remain suppressed below pretreatment levels. Furthermore, many patients with virologic failure continue to maintain stable CD4 counts and remain clinically well. One possible explanation for these observations is that the resistant virus that emerges during failure of highly active antiretroviral therapy is less fit than its wild-type counterpart as a result of the requirement to maintain resistance mutations that allow it to replicate in the presence of antiretroviral drugs. Since there are many patients with limited treatment options due to extensive resistance or drug toxicities, or both, there is intense interest in exploring the possibility that viral fitness can be exploited for clinical benefit. This review describes the assays that are used to measure fitness and replication capacity, and investigations of their utility in clinical practice. RECENT FINDINGS: A number of methods have been developed to measure viral fitness. Replication kinetic and competitive culture assays are accurate, but labour and time intensive. The availability of a rapid, single-cycle recombinant assay that measures viral replication capacity presents the possibility that assessments of viral fitness could be incorporated into clinical management. The replication capacity assay appears to correlate with more standard measures of viral fitness, and recently accumulated data in both wild-type and drug resistant viral populations suggest that replication capacity describes an intrinsic characteristic of HIV-1. A number of investigations of the clinical utility of fitness and replication capacity assays have established correlations between these measurements and virologic and immunologic outcomes. SUMMARY: Much progress has been made in the past year in our understanding of viral fitness and replication capacity. Assays that measure these viral characteristics have the potential to expand the range of clinical strategies employed against HIV-1. Further investigations are needed to firmly establish the clinical utility of these assays.

Carbamates↗

PubMed2002

Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates.

OBJECTIVE: The routine use of phenotypic drug resistance testing in patient management has revealed that many HIV-1 strains possess significantly increased drug sensitivity, or 'hypersusceptibility' compared with wild-type viruses. This study describes hypersusceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI) and was designed to determine the prevalence of and viral characteristics associated with NNRTI hypersusceptibility in patient-derived viruses. METHODS: Retrospective analyses were performed on a large clinical laboratory dataset containing phenotypic drug susceptibility and genotypic sequence results from HIV-1 patient isolates. Genetically engineered viruses were used to confirm the role of certain nucleoside reverse transcriptase inhibitor (NRTI)-resistance mutations in NNRTI hypersusceptibility. RESULTS: Hypersusceptibility to delavirdine, efavirenz and nevirapine was detected in 10.7, 10.8 and 8.0% of more than 17,000 consecutive plasma samples submitted for phenotypic susceptibility testing. In analyses limited to a subset of viruses derived from patients with known treatment histories, NNRTI hypersusceptibility was observed significantly more frequently among viruses from NRTI experienced/NNRTI-naive patients compared with viruses from NRTI/NNRTI-naive patients. Significant inverse correlations between NRTI and NNRTI susceptibility exist among the viruses from NRTI-experienced patients. Analyses of viruses classified according to their NNRTI susceptibility identified 18 positions in reverse transcriptase where substitutions were significantly associated with NNRTI hypersusceptibility. CONCLUSIONS: NNRTI hypersusceptibility is common among patient HIV-1 isolates, especially in NRTI-resistant viruses. Genotypic correlates of hypersusceptibility are complex and not easily defined by a simple analysis of NRTI-associated resistance mutations. NNRTI hypersusceptibility may provide an explanation for the superior virologic response to NNRTI-containing salvage regimens observed in NRTI-experienced patients in several clinical trials.

Anti-HIV Agents↗

PubMed2002

Subtle decreases in stavudine phenotypic susceptibility predict poor virologic response to stavudine monotherapy in zidovudine-experienced patients.

To identify the level of phenotypic susceptibility for stavudine (d4T) that is associated with a diminished virologic response to d4T therapy, phenotyping was performed on archived baseline HIV isolates from 26 subjects who received d4T monotherapy in AIDS Clinical Trials Group (ACTG) 302 who had received >3 years of prior zidovudine (ZDV) monotherapy. Seven of 26 subjects achieved a virologic response of >0.3-log10 copies/mL reduction in plasma HIV RNA after 8 weeks of d4T. Responders had lower fold changes in susceptibility to d4T (1.0 vs. 1.6, p=.003), lower baseline viral loads (4.26 vs. 4.74 log10 copies/mL, p=.004), and fewer thymidine analog mutations (TAMS) (1 vs. 2, p=.059). Lower baseline d4T fold change in susceptibility predicted greater reductions in HIV RNA from baseline to week 8 after adjusting for baseline HIV RNA, ZDV fold change in susceptibility, and number of TAMS. Using the same phenotypic assay, drug susceptibility among 240 antiretroviral-naive patients found all HIV isolates to have d4T susceptibility <or=1.4-fold change. Using <or=1.4 as the d4T cutoff, the positive predictive value for a virologic response in this study was 44%, and the negative predictive value was 100%. d4T susceptibility greater than 1.4-fold change was associated with failure to achieve significant viral load reduction after 8 weeks of d4T monotherapy.

Adult↗

PubMed2002

Phenotypic and genotypic HIV-1 drug resistance assays provide complementary information.

To determine the extent to which genotype (GT) or phenotype (PT) methods provide HIV-1 drug resistance information that is overlapping or complementary, both tests were performed on 1378 patient plasma samples. Discordance, defined as determination of reduced susceptibility measured by PT but sensitivity by GT (PT-R/GT-S), or vice versa (PT-S/GT-R), was common: 83, 62, 43, and 28% of samples with evidence of drug resistance had at least 1, 2, 3, or 4 drugs discordant, respectively. Three types of discordance were observed: PT-R/GT-S, and PT-S/GT-R with or without the presence of mixtures at resistance-associated positions (25%, 34%, and 41% of all discordance, respectively). After accounting for mixtures, results for didanosine (30%), zalcitabine (18%), tenofovir (17%), abacavir (14%), lamivudine (12%), and amprenavir (11%) were discordant in >or= 10% of samples. PT-S/GT-R results were most common for didanosine and zalcitabine, whereas PT-R/GT-S results were most common for lamivudine and amprenavir. PT provided quantitative assessment of the degree of reduced susceptibility and identified reduced susceptibility (PT-R/GT-S) or normal susceptibility (PT-S/GT-R) that was not recognized by the GT interpretation algorithm. GT provided valuable information when mixtures were present and minor populations of drug resistant virus were not detected by phenotyping (PT-S/GT-R results). This demonstrates the complementary nature of information provided by PT and GT tests and suggests that their combined use can provide additional clinically-relevant information.

Adenine↗

PubMed2002

Distraction osteogenesis using IGF-I after nerve microreconstruction.

The discipline of limb lengthening has undergone numerous advances over the last few years. The neurologic complications surrounding this procedure are well established and described in the clinical setting, and can be deleterious for the patients in distraction osteogenesis protocols. The specific aims of the reported project were: 1) to determine the ability of IGF-I to enhance nerve regeneration in repaired nerves that are subjected to distraction only 4 weeks after nerve repair, and 2) to determine if a low dose of IGF-I applied at the time of the repair is neuroprotective to repaired nerves at this early time window. Forty adult male Sprague-Dawley rats were randomized into eight groups (n=5). Four groups (Groups A to D) underwent distraction of the femoral bone following sciatic nerve repair, and four groups served as controls (Groups E to H). Nerve reconstruction was achieved by end-to-end nerve repair (four groups, two with distraction [A, B] and two without [E, F]) and by interposition nerve grafting (four groups, two with distraction [C, D] and two without distraction [G, H]). A low dose of IGF-I was administered at the time of nerve microreconstruction. Distracted groups, despite the administration of IGF-I, demonstrated no signs of nerve regeneration, as assessed by sciatic functional index (SFI), electrophysiologic studies, and quantitative and qualitative histologic studies. Non-distracted groups showed signs of nerve regeneration. The 4-week time interval between nerve repair and distraction did not provide enough time for nerve regeneration to be completed, even if the repair was exposed to a low dose of IGF-1.

Anastomosis, Surgical↗