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David B Clifford

Publications and source records attributed to David B Clifford.

At least 19 recordsLinked to original sources
PubMed2007

Frequency and phenotype of JC virus-specific CD8+ T lymphocytes in the peripheral blood of patients with progressive multifocal leukoencephalopathy.

JC virus (JCV)-specific CD8+ cytotoxic T lymphocytes (CTL) are associated with a favorable outcome in patients with progressive multifocal leukoencephalopathy (PML) and cross-recognize the polyomavirus BK virus (BKV). We sought to determine the frequency and phenotype in fresh blood of CD8+ T cells specific for two A*0201-restricted JCV epitopes, VP1(p36) and VP1(p100), and assess their impact on JC and BK viremia and viruria in 15 healthy subjects, eight human immunodeficiency virus-positive (HIV+) individuals, and nine HIV+ patients with PML (HIV+ PML patients) classified as survivors. After magnetic pre-enrichment of CD8+ T cells, epitope-specific cells ranged from 0.001% to 0.022% [corrected] by tetramer staining, with no significant difference among the three study groups. By use of seven-color flow cytometry, there was no predominant differentiation phenotype subset among JCV-specific CD8+ T cells in healthy individuals, HIV+ subjects, or HIV+ PML patients. However, in one HIV+ PML patient studied in the acute phase, there was a majority of activated effector memory cells. BKV DNA was undetectable in all blood samples by quantitative PCR, while a low JC viral load was found in the blood of only one HIV+ and two HIV+ PML patients. JCV and BKV DNA were detected in 33.3% and 13.3% of all urine samples, respectively, independent of the presence of JCV-specific CTL. The detection of JCV DNA in the urine was associated with the presence of a JCV VP1(p100) CTL response. Immunotherapies aiming at increasing the cellular immune response against JCV may be valuable in the treatment of HIV+ individuals with PML.

Adult↗
PubMed2006

Oxidant stress and peripheral neuropathy during antiretroviral therapy: an AIDS clinical trials group study.

BACKGROUND: Peripheral neuropathy that complicates HIV nucleoside reverse transcriptase inhibitor (NRTI) therapy is likely caused by mitochondrial injury. Mitochondria play a central role in regulating oxidant stress. We explored the relationships between oxidant stress and NRTI-induced peripheral neuropathy. METHODS: The AIDS Clinical Trials Group (ACTG) studied the cases of 384 antiretroviral-naive individuals randomized to receive didanosine/stavudine or zidovudine/lamivudine, plus efavirenz, nelfinavir, or both. The participants were followed for up to 3 years. Peripheral neuropathy was ascertained by signs and symptoms. We performed a case-control study of ACTG 384 participants. Peripheral neuropathy cases and nonneuropathy control subjects were selected from didanosine/stavudine recipients. Alternate control subjects were selected from zidovudine/lamivudine recipients who developed peripheral neuropathy. Oxidant stress was assessed by quantifying F2-isoprostanes (F2-IsoPs) in cryopreserved plasma. RESULTS: Seventy-five cases, 71 control subjects, and 18 alternate control subjects were identified. The median baseline F2-IsoP values were 53 (interquartile range [IQR], 40-85), 57 (IQR, 41-77), and 53 (IQR, 47-101) pg/mL, respectively, and did not differ between cases and control subjects (P = 0.78) or alternate control subjects (P = 0.60). Changes in F2-IsoPs from baseline to time of peripheral neuropathy did not differ significantly between cases (median, 10 [IQR, -17 to 26] pg/mL) and control subjects (median, 4 [IQR, -11 to 17] pg/mL; P = 0.48) or alternate control subjects (median, 1 [IQR, -48 to 10] pg/mL; P = 0.21). CONCLUSIONS: Peripheral neuropathy that complicates antiretroviral therapy with NRTIs was not associated with increased systemic oxidant stress assessed by plasma F2-IsoPs.

Adult↗
PubMed2006

Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy.

OBJECTIVE: Peripheral neuropathy (PN) often complicates nucleoside reverse transcriptase inhibitor (NRTI) therapy of HIV infection and may involve mitochondrial dysfunction. Since iron deficiency is associated with some types of PN, and iron is essential for mitochondrial function, we tested the hypothesis that hemochromatosis (HFE) gene mutations influence susceptibility to NRTI-induced PN. DESIGN: Case-control study involving multicenter, AIDS Clinical Trials Group (ACTG) protocol 384 and ACTG Human DNA Repository specimens. METHODS: Study participants were randomized to receive three- or four-drug antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine, given with efavirenz, nelfinavir, or both, with up to three years of follow-up. PN was ascertained based on signs and symptoms. HFE C282Y and H63D genotypes were determined, and associations with PN were assessed using logistic regression. RESULTS: : Of 509 participants, 147 (29%) developed PN, 73% of whom had been randomized to receive ddI plus d4T. Among ddI/d4T-ever-treated individuals, HFE C282Y heterozygotes developed PN on ddI/d4T significantly less often than C282Y non-carriers, adjusting for age, CD4 lymphocyte count and viral load at baseline, and concomitant antiretroviral drugs [6% vs. 35%, respectively, in whites; adjusted odds ratio (OR), 0.17; 95% confidence interval (CI) 0.03-0.83; P = 0.021]. Regardless of race/ethnicity, ddI/d4T-associated PN was uncommon in C282Y heterozygotes [race-adjusted OR, 0.30; 95% CI 0.09-0.96); P = 0.042]. CONCLUSIONS: Iron-loading HFE mutations such as C282Y are associated with a decreased risk of PN during antiretroviral therapy. This finding has potential implications for the prediction and prevention of NRTI-associated PN, particularly in populations at risk of iron deficiency.

Adolescent↗
PubMed2006

Histoplasmoma: isolated central nervous system infection with Histoplasma capsulatum in a patient with AIDS. Case report and brief review of the literature.

Histoplasma capsulatum is endemic to the Ohio and Mississippi River valleys. Exposure to H. capsulatum is very common in this region and usually follows a benign clinical course. However, immunocompromised hosts, like those with HIV/AIDS, are more susceptible to symptomatic infection, and have a greater chance of developing disseminated disease. We report an unusual case of a patient with AIDS presenting with a single ring-enhancing brain lesion and a focal neurological deficit. Workup was unrevealing, and brain biopsy was felt to represent too much risk as the lesion was located at the right tegmentum. The lesion enlarged over a period of months, and he underwent radiation therapy after the lesion caused obstructive hydrocephalus. He expired soon after completion of radiation therapy. At autopsy, the mass lesion was noted to contain organisms constant with H. capsulatum, pathologically consistent with a histoplasmoma.

AIDS-Related Opportunistic Infections↗
PubMed2006

Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) was reported to have developed in three patients treated with natalizumab. We conducted an evaluation to determine whether PML had developed in any other treated patients. METHODS: We invited patients who had participated in clinical trials in which they received recent or long-term treatment with natalizumab for multiple sclerosis, Crohn's disease, or rheumatoid arthritis to participate. The clinical history, physical examination, brain magnetic resonance imaging (MRI), and testing of cerebrospinal fluid for JC virus DNA were used by an expert panel to evaluate patients for PML. We estimated the risk of PML in patients who completed at least a clinical examination for PML or had an MRI. RESULTS: Of 3417 patients who had recently received natalizumab while participating in clinical trials, 3116 (91 percent) who were exposed to a mean of 17.9 monthly doses underwent evaluation for PML. Of these, 44 patients were referred to the expert panel because of clinical findings of possible PML, abnormalities on MRI, or a high plasma viral load of JC virus. No patient had detectable JC virus DNA in the cerebrospinal fluid. PML was ruled out in 43 of the 44 patients, but it could not be ruled out in one patient who had multiple sclerosis and progression of neurologic disease because data on cerebrospinal fluid testing and follow-up MRI were not available. Only the three previously reported cases of PML were confirmed (1.0 per 1000 treated patients; 95 percent confidence interval, 0.2 to 2.8 per 1000). CONCLUSIONS: A detailed review of possible cases of PML in patients exposed to natalizumab found no new cases and suggested a risk of PML of roughly 1 in 1000 patients treated with natalizumab for a mean of 17.9 months. The risk associated with longer treatment is not known.

Antibodies, Monoclonal↗
PubMed2006

Multilocus genetic interactions and response to efavirenz-containing regimens: an adult AIDS clinical trials group study.

OBJECTIVE: For the HIV-1 reverse transcriptase inhibitor efavirenz, variant drug transporter gene ABCB1 may predict virologic response but not plasma efavirenz exposure. Conversely, variant drug metabolizing enzyme gene CYP2B6 predicts greater plasma efavirenz exposure but not virologic response. We examined whether long-term responses to efavirenz, and/or plasma efavirenz exposure, are better predicted by multilocus genetic interactions than by individual polymorphisms. MATERIALS AND METHODS: We studied antiretroviral-naïve study participants randomized to receive efavirenz (with or without nelfinavir) plus two nucleoside analogues in study ACTG 384, and who had DNA available for analysis. Participants were followed up for up to 3 years. Nine single nucleotide polymorphisms in ABCB1, CYP2B6, CYP3A4, CYP3A5 and CYP2C19 were identified. Gene-gene interactions were identified using multifactor dimensionality reduction. RESULTS: Among 340 efavirenz recipients, higher efavirenz AUC24 h values were associated with a single locus model involving CYP2B6 516G>T (73% accuracy; P<0.001). This was also the best model among blacks (69% accuracy; P<0.001), whereas among whites the best model involved a gene-gene interaction between CYP2B6 516G>T and ABCB1 2677G>T (82% accuracy, P<0.001). Among 155 participants who received efavirenz without nelfinavir, virologic failure was associated with a two-locus interaction between ABCB1 2677G>T and CYP2B6 516G>T (65% accuracy, P<0.001). Toxicity failure was best predicted by an interaction between ABCB1 2677G>T and ABCB1 3435C>T (71% accuracy, P<0.001). CONCLUSIONS: Multilocus genetic interactions between variant drug metabolism and transporter genes may predict efavirenz pharmacokinetics and treatment responses. This finding may have implications for better individualizing antiretroviral therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study.

BACKGROUND: Efavirenz has a long plasma half-life and a low genetic barrier to resistance. Simultaneously stopping treatment with all agents in efavirenz-containing regimens may result in functional efavirenz monotherapy that selects for drug-resistant human immunodeficiency virus type 1. Lower plasma efavirenz clearance is associated with a cytochrome P450 2B6 gene (CYP2B6) polymorphism (516G-->T) that is more frequent among African American individuals than among European American individuals. METHODS: We characterized relationships between this polymorphism and predicted plasma efavirenz concentration-time profiles after discontinuation of therapy with use of data obtained from subjects receiving therapy. Pharmacokinetic parameters were estimated using population-based methods. Concentrations after discontinuation of therapy were predicted from subject-specific estimates. RESULTS. Median estimated efavirenz half-lives were 23, 27, and 48 h for patients with CYP2B6 position 516 GG (78 patients), GT (60), and TT (14) genotypes, respectively (P<.001). After therapy was stopped, plasma efavirenz concentrations in patients with GG, GT, and TT genotypes were predicted to exceed 46.7 ng/mL (the estimated protein-adjusted 95% inhibitory concentration for wild-type virus) for a median of 5.8 days (interquartile range [IQR], 4.4-8.3 days), 7.0 days (IQR, 5.0-8.0 days), and 14 days (IQR, 11.1-21.2 days), respectively (P<.001). Plasma efavirenz levels were predicted to exceed 46.7 ng/mL for >21 days in 5% of subjects with GG genotype, 5% of subjects with GT genotype, and 29% of subjects with TT genotype. CONCLUSIONS: The CYP2B6 position 516 TT genotype or a prolonged measured elimination half-life may predict increased risk of developing drug resistance among patients who discontinue efavirenz-containing regimens. This has implications for strategies to safely discontinue antiretroviral regimens while avoiding the emergence of drug resistance.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals.

BACKGROUND: Efavirenz is a commonly used antiretroviral drug that causes neurologic side effects in more than 50% of patients. OBJECTIVE: To characterize efavirenz-associated neurologic symptoms in a randomized, controlled study of initial antiretroviral treatment. DESIGN: Substudy of a randomized, double-blind, controlled trial of combination antiretroviral regimens (A5095) that was performed between March 2001 and January 2002. SETTING: Multicenter academic clinical trial units. PARTICIPANTS: HIV-infected patients who were initiating therapy in the context of a controlled trial. MEASUREMENTS: Neuropsychological performance measures, including the Digit Symbol Substitution Test and the Trail Making Test (Parts A and B); symptom questionnaires; standardized assessments of sleep quality, anxiety, and depression; and efavirenz plasma concentrations. RESULTS: Twenty of 303 (6.6%) enrolled participants prematurely discontinued the study. Neuropsychological performance improved in both groups over time without significant differences between patients who were receiving efavirenz and those who were not. The efavirenz group experienced more neurologic symptoms at week 1 (P < 0.001) but not at weeks 4, 12, or 24. A sleep index revealed that participants receiving efavirenz had more "bad dreams" during the first week of therapy (P = 0.038). No significant changes in anxiety or depressed mood were noted. Changes in efavirenz-associated neurologic symptoms were correlated to efavirenz plasma concentrations at week 1 but not at later time points. Twelve (6%) patients receiving efavirenz stopped taking the drug before the end of the study because of central nervous system symptoms. LIMITATIONS: Participant selection may have been biased in favor of patients with fewer psychiatric complications. The study design permitted substitution of a new drug in place of efavirenz in cases of treatment-limiting toxicity. CONCLUSIONS: In a large controlled trial, efavirenz use was associated with neurologic symptoms distinct from depression and anxiety that began early in therapy but resolved by week 4. Improvement in neuropsychological performance was comparable in patients who were receiving efavirenz and those who were not.

Adult↗
PubMed2005

Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study.

BACKGROUND: Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment. METHODS: Adult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5, and MDR1 were characterized. RESULTS: The 504 participants in the genetic study included 340 efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both efavirenz and nelfinavir). Of the participants, 49% were white, 31% were black, and 19% were Hispanic. Plasma exposure to efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G-->T and CYP2C19 681G-->A, respectively. Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G-->A. CONCLUSIONS: Genetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study.

OBJECTIVE: HIV nucleoside reverse transcriptase inhibitors (NRTI) can cause peripheral neuropathy that is a result of mitochondrial injury. Polymorphisms in the mitochondrial genome define haplogroups that may have functional implications. The objective of this study was to determine if NRTI-associated peripheral neuropathy is associated with European mitochondrial haplogroups. DESIGN: Case-control study of Adult AIDS Clinical Trials Group (ACTG) study 384 and ACTG Human DNA Repository participants. METHODS: ACTG study 384 was a treatment strategy trial of antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine given with efavirenz, nelfinavir, or both. Subjects were followed for up to 3 years. Peripheral neuropathy was ascertained based on signs and symptoms. For this analysis, polymorphisms that define European mitochondrial haplogroups were characterized in a majority of ACTG 384 participants, and associations with peripheral neuropathy were assessed using logistic regression. RESULTS: A total of 509 subjects were included in this analysis of whom 250 (49%) were self-identified as white, non-Hispanic. Mitochondrial haplogroup T was more frequent in subjects who developed peripheral neuropathy. Among 137 white subjects randomized to receive ddI plus d4T, 20.8% of those who developed peripheral neuropathy belonged to mitochondrial haplogroup T compared to 4.5% of control subjects (odds ratio, 5.4; 95% confidence interval, 1.4-25.1; P = 0.009). Independent predictors of peripheral neuropathy were randomization to receive ddI plus d4T, older age, and mitochondrial haplogroup T. CONCLUSIONS: A common European mitochondrial haplogroup may predict NRTI-associated peripheral neuropathy. Future studies should validate this relationship, and evaluate non-European mitochondrial haplogroups and other NRTI toxicities.

Adolescent↗
PubMed2005

Undetectable cerebrospinal fluid HIV RNA and beta-2 microglobulin do not indicate inactive AIDS dementia complex in highly active antiretroviral therapy-treated patients.

OBJECTIVE: To assess whether nonelevated cerebrospinal fluid (CSF) markers could delineate inactive AIDS dementia complex (ADC) in patients receiving highly active antiretroviral therapy (HAART), using neuropsychologic performance change as an indicator of ADC stability. METHODS: We used data from the abacavir (ABC) ADC trial (n = 78) and examined the patients' neuropsychologic performance change with the Reliable Change Index according to 3 cutoff groups: (1) CSF viral load (VL) <100 copies/mL, (2) CSF beta-2 microglobulin (beta2m) <2.2 mg/L, and (3) CSF VL and CSF beta2m below cutoffs. RESULTS: CSF marker cutoff groups did not define neuropsychologic change. Linear regression showed that only CSF VL was a weak predictor of neuropsychologic performance change. CONCLUSION: HAART-treated ADC patients with baseline CSF markers of viral and immunologic inactivity did not necessarily have inactive ADC when followed over 12 weeks. More sensitive CSF markers to judge the activity of ADC are urgently needed, whereas the interpretation of these markers should be considered with caution in HAART-treated ADC patients.

AIDS Dementia Complex↗
PubMed2005

Clinical validation of the NeuroScreen.

The NeuroScreen comprises two easily administered components: the Brief NeuroCognitive Screen (BNCS), designed to estimate the frequency of human immunodeficiency virus (HIV)-associated cognitive disorders; and the Brief Peripheral Neuropathy Screen (BPNS), for distal sensory polyneuropathy (DSPN) in HIV. In this study, both the NeuroScreen and a more extensive standardized validation neurodiagnostic evaluation were administered to HIV-positive subjects (N = 301) enrolled in two large cohort studies at multiple sites. BNCS performance was summarized in the form of a demographically adjusted mean z-score, the NPZ3. The area under the receiver-operating characteristic (ROC) curve for the BNCS as compared to the reference standard neuropsychological (NP) evaluation was 0.74 (95% confidence interval [CI] 0.69, 0.79). Using a cut-point of -0.33 on the NPZ3 provided a correct classification rate of 68%, with roughly balanced sensitivity (65%) and specificity (72%). Under the assumption of a 30% prevalence of cognitive impairment, the calculated positive predictive value (PPV) of the BNCS was 86%. Relative to its reference standard, a modified Total Neuropathy Score (TNS) administered by a neurologist, the BPNS gave a similar correct diagnostic classification rate of 78%; sensitivity 49% [95%, 60%]; specificity 88% [95% Cl82%, 91%]. Under the assumption of a 40% prevalence of DSPN, the PPV of the BPNS was 72%. These predictive values suggest that the NeuroScreen will be useful for tracking trends in the prevalence of HIV-associated neurologic disease in large cohorts in the era of combination antiretroviral therapy. However, because it yields substantial numbers of false positives and negatives, the NeuroScreen may be less useful in evaluating individual patients.

AIDS Dementia Complex↗
PubMed2005

Neurologic consequences of hepatitis C and human immunodeficiency virus coinfection.

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) share overlapping, large worldwide distribution. The implications of coinfection are being explored because of the importance of these viruses and demographic factors that favor coinfection. The nervous system is affected by HIV in a variety of ways resulting in significant disease of all levels of the nervous system. Emerging evidence that HCV can also impact the nervous system raises concerns that detrimental interactions might occur. Several reports addressing the manifestations of coinfection support independent contributions for both HIV and HCV on central nervous system performance, but not on distal sensory neuropathy. Neuropsychological testing reveals independent contributions resulting in poorer performance in coinfection in several drug-abusing cohorts. Motor physiologic testing substantiates performance deficits from HCV in coinfected subjects as does testing in treatment naive coinfected subjects. Although ongoing deficits attributed to HCV may be seen during HIV treatment, these deficits may be less apparent in advanced HIV disease. Current evidence supports independent contributions of HCV and HIV to neurological impairment. Preliminary evidence suggests that coinfection-related impairment does not appear to accelerate HIV-1-associated cognitive disease.

HIV Infections↗
PubMed2005

The neuropsychological and neurological impact of hepatitis C virus co-infection in HIV-infected subjects.

OBJECTIVE: To evaluate the effect of hepatitis C virus (HCV)/HIV co-infection on neuropsychological performance and neurological status in HIV/HCV treatment-naive HIV-1-infected individuals we conducted a cross-sectional study using baseline data from an HIV therapy trial. METHODS: HCV status was determined by the presence of anti-HCV antibodies. Neuropsychological function was evaluated by Trailmaking tests, and the Digit Symbol Task. Depression was assessed using the Center for Epidemiologic Studies--Depression Scale. Sleep quality was evaluated by the Pittsburgh Sleep Quality Index and anxiety by the State-Trait Anxiety Inventory for Adults. A questionnaire was designed grading the severity of a variety of symptoms. RESULTS: Of 264 patients with HCV status data, 30 were HCV positive and 234 were HCV negative. Both groups were comparable except that HCV-positive individuals had a higher prevalence of intravenous drug use and lower educational level. The HCV-positive group had a significantly lower neuropsychological performance overall. Multivariate modeling supported an association between HCV infection status with test performance in the Digit Symbol Task and mood parameters even when controlling for potentially confounding variables. Marginal differences were noted with respect to symptom questionnaire scores and global sleep. No differences were noted with respect to anxiety. CONCLUSION: The findings suggest that HCV/HIV co-infection has an adverse impact on neuropsychological function. HCV may also be associated with depressed mood, particularly somatic depressive symptoms. Although confounding contributors to neuropsychological performance are difficult to exclude, exploratory modeling supports the association between HCV infection status and some impairment of neuropsychological performance and depressed mood.

Adult↗
PubMed2004

Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study.

OBJECTIVES: Efavirenz is an effective antiretroviral agent, but central nervous system side effects occur commonly, and population (racial) differences in pharmacokinetics and response have been reported. Efavirenz is metabolized by cytochrome P4502B6 (CYP2B6). We investigated whether polymorphisms in CYP2B6, CYP3A4, CYP3A5, and MDR1 were associated with efavirenz central nervous system side effects and pharmacokinetics. DESIGN: Twenty-four week cohort from a randomized study. METHODS: Adult AIDS Clinical Trials Group study A5097s examined relationships between central nervous system side effects and efavirenz plasma concentration-time profiles in HIV-infected subjects. Efavirenz plasma pharmacokinetics were estimated by a population-based method. Central nervous system symptoms were assessed by questionnaires and neuropsychological testing. RESULTS: Study subjects included 89 (57%) European-Americans, 50 (32%) African-Americans, and 15 (10%) Hispanics. The CYP2B6 T/T genotype at position 516 (GlnHis) was more common in African-Americans (20%) than in European-Americans (3%), and was associated with greater efavirenz plasma exposure (P < 0.0001). The median efavirenz [area-under-the-curve] (0-24 h) according to G/G, G/T, and T/T genotype was 44 (n = 78), 60 (n = 60), and 130 (n = 14) mug.h/ml, respectively (P < 0.0001). The CYP2B6 G516T genotype was also associated with central nervous system symptoms at week 1 (P = 0.036). Analysis of DNA from other subjects confirmed population differences in frequency of the G516T variant. No associations were apparent with the other polymorphisms studied. CONCLUSIONS: A CYP2B6 allelic variant that is more common in African-Americans than in Europeans-Americans was associated with significantly greater efavirenz plasma exposure during HIV therapy. Inter-individual differences in metabolism may, in part, explain susceptibility to efavirenz central nervous system side effects.

Acquired Immunodeficiency Syndrome↗
PubMed2003

The evolving face of human immunodeficiency virus-related progressive multifocal leukoencephalopathy: defining a consensus terminology.

There is a need for consistent definition of human immunodeficiency virus (HIV)-associated cases of progressive multifocal leukoencephalopathy (PML), especially following the profound disease changes that have resulted from the use of highly active antiretroviral therapy (HAART). According to the criteria used for diagnosis, PML cases should be either referred to as "histology-confirmed," with evidence of JC virus (JCV) infection in brain, "laboratory-confirmed," with detection of JCV DNA in cerebrospinal fluid (CSF), or "possible," in the presence of typical clinical and radiological picture, but no demonstration of JCV infection. Disease outcome should be defined by the evidence or lack of evidence of disease activity, rather than using survival or other variables. Disease activity should be based on clinical (scored neurological examination), radiological (magnetic resonance imaging), and virological (JCV DNA levels in CSF) indicators, to be assessed regularly, e.g., every 3 months until evidence of disease arrest or death. Furthermore, parallel assessments of other HIV-associated manifestations, including CD4+ cell counts and viral load, are required. A standard patient classification would be helpful for clinical management of PML patients, for their inclusion in clinical studies, and also will increase our current knowledge of PML and its evolution in relation with HAART.

Acquired Immunodeficiency Syndrome↗