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E E Morgan,
S P Woods,
S L Letendre,
D R Franklin,
C Bloss,
A Goate,
R K Heaton, A C Collier,
C M Marra,
B B Gelman, [......],
D M Simpson,
J A McCutchan,
R J Ellis,
I Abramson,
A Gamst,
C Fennema-Notestine,
D M Smith,
I Grant,
F Vaida,
D B Clifford
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ABSTRACT: This is a cross-sectional, observational study to evaluate the hypothesis that HIV-seropositive (HIV+) apolipoprotein E4 (APOE4) carriers are at increased risk for HIV-associated neurocognitive disorders (HAND) compared to APOE4 noncarriers with HIV in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Group sample. APOE genotype was determined in 466 CHARTER participants with varying disease stages and histories of antiretroviral treatment who did not have severe psychiatric or medical comorbid conditions that preclude diagnosis of HAND. HAND diagnoses were based on results of comprehensive neurobehavioral evaluation and use of current neuroAIDS diagnostic criteria. HAND status consists of two levels: neuropsychologically normal status (i.e., no HAND) and any HAND diagnosis (i.e., asymptomatic neurocognitive impairment, minor neurocognitive disorder, HIV-associated dementia). Logistic regression analyses revealed no association between APOE4 carrier status and HAND, and there were no interactions between APOE4 carrier status and ethnicity, age, substance use disorders, duration of infection, or nadir CD4. Results did not differ when analysis was restricted to symptomatic HAND, and no APOE4 gene dose-dependent relationship to HAND emerged. APOE4 status was not associated with concurrent HAND in this large, well-characterized sample. This does not preclude emergence of an association between APOE4 status and HAND as this population ages. Prospective, longitudinal studies are needed to examine APOE4 as a risk factor for neurocognitive decline, incident HAND at older ages, and potential associations with cerebrospinal fluid amyloid.
Journal of NeuroVirology 02/2013; · 2.31 Impact Factor
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K Blackstone,
D J Moore,
D R Franklin,
D B Clifford, A C Collier,
C M Marra,
B B Gelman,
J C McArthur,
S Morgello,
D M Simpson,
R J Ellis,
J H Atkinson,
I Grant,
R K Heaton
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ABSTRACT: Because HIV-related neurocognitive impairment is usually mild and variable, clinical ratings (CR) and global deficit scores (GDS) are recommended for detecting HIV-associated neurocognitive disorders (HAND). The CR approach requires impairment in at least two ability domains while the GDS considers number and severity of impairments across all measures. We examined classification agreement and clinical correlates of the two methods. Neurocognitive functioning of 1574 HIV-infected participants was assessed via a comprehensive, seven-domain neuropsychological battery. Global neurocognitive impairment was defined for each participant independently by CR and GDS. Participants were classified into four categories (Dually-normal, [impaired by] CR-only, [impaired by] GDS-only, or Dually-impaired). There was 83% concordance between CR and GDS classifications; in total, 56% of participants were deemed impaired by CR and 41% were classified as impaired by GDS. Impairment by GDS virtually guaranteed CR impairment, but 16% of participants were additionally classified as impaired only by CR. As compared to Dually-normal participants, those classified as Dually and CR-only impaired were more likely to have AIDS, have more severe co-occurring conditions, have more severe depressive symptoms, be unemployed, and have more everyday functioning complaints (ps < .05). Impairment classifications of the two methods were in high agreement; however, more people were classified as impaired using the CR approach compared to the GDS approach. Those impaired according to CR-only showed fewer neurocognitive and functional deficits than the Dually-impaired participants, but more of these deficits than Dually-normal participants. The CR approach may be most appropriate for detecting more subtle forms of neurocognitive impairment. Clinicians and researchers should recognize the strengths and weaknesses of each method when evaluating neurocognitive complications in HIV.
The Clinical Neuropsychologist 06/2012; 26(6):894-908. · 2.12 Impact Factor
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ABSTRACT: It is controversial whether starting combination antiretroviral therapy (cART) during primary HIV infection (PHI) is beneficial. Subjects in this observational cohort began cART <30 days (group 1: acute treatment, n = 40), 31-180 days (group 2: early treatment, n = 82) or >180 days (group 3: delayed treatment, n = 35) after HIV infection, and were compared with 27 historical and 60 contemporary controls. Time to HIV-related diagnoses did not differ for group 1 (adjusted hazard ratio [aHR] 1.44, P = 0.3) or group 2 (aHR 1.17, P = 0.5) compared with contemporary controls, but it was delayed for both treated groups (aHR 0.38 for group 1, P = 0.01; and aHR 0.28 for group 2, P < 0.0001) compared with historical controls. Although rates of HIV-related diagnoses were similar in acutely treated subjects and contemporary controls, results were confounded by associations between higher CD4 counts, lower HIV RNA levels and delayed disease progression as reasons for deferring treatment. Randomized trials are needed to address benefits of cART during PHI.
International Journal of STD & AIDS 03/2012; 23(3):201-6. · 1.09 Impact Factor
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K Blackstone,
D J Moore,
R K Heaton,
D R Franklin,
S P Woods,
D B Clifford, A C Collier,
C M Marra,
B B Gelman,
J C McArthur,
S Morgello,
D M Simpson,
M Rivera-Mindt,
R Deutsch,
R J Ellis,
J Hampton Atkinson,
I Grant
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ABSTRACT: Three types of HIV-associated neurocognitive disorders (HAND) exist that are distinguished by presence and severity of impairment in cognitive and everyday functioning. Although well-validated neurocognitive measures exist, determining impairment in everyday functioning remains a challenge. We aim to determine whether Self-Report measures of everyday functioning are as effective in characterizing HAND as Performance-Based measures. We assessed 674 HIV-infected participants with a comprehensive neurocognitive battery; 233 met criteria for a HAND diagnosis by having at least mild neurocognitive impairment. Functional decline was measured via Self-Report and Performance-Based measures. HAND diagnoses were determined according to published criteria using three approaches to assess functional decline: (1) Self-Report measures only, (2) Performance-Based measures only, and (3) Dual-method combining Self-Report and Performance-Based measures. The Dual-method classified the most symptomatic HAND, compared to either singular method. Singular method classifications were 76% concordant with each other. Participants classified as Performance-Based functionally impaired were more likely to be unemployed and more immunosuppressed, whereas those classified as Self-Report functionally impaired had more depressive symptoms. Multimodal methods of assessing everyday functioning facilitate detection of symptomatic HAND. Singular Performance-Based classifications were associated with objective functional and disease-related factors; reliance on Self-Report classifications may be biased by depressive symptoms.
Journal of the International Neuropsychological Society 11/2011; 18(1):79-88. · 2.76 Impact Factor
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R K Heaton,
D B Clifford,
D R Franklin,
S P Woods,
C Ake,
F Vaida,
R J Ellis,
S L Letendre,
T D Marcotte,
J H Atkinson, [......],
J C McArthur,
S Morgello,
D M Simpson,
J A McCutchan,
I Abramson,
A Gamst,
C Fennema-Notestine,
T L Jernigan,
J Wong,
I Grant
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ABSTRACT: This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART).
A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment).
Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups).
The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.
Neurology 12/2010; 75(23):2087-96. · 8.31 Impact Factor
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ABSTRACT: We used positron emission tomography (PET) to evaluate the contribution of P-glycoprotein (P-gp), present at the human blood-brain barrier (BBB), to regional drug distribution in the brain. Eleven healthy volunteers underwent PET imaging with [(11)C]-verapamil before and during cyclosporine A infusion. Regional P-gp inhibition was expressed as cyclosporine A-induced percentage change in the distributional clearance of verapamil (K(1)) in the brain, normalized to the regional blood flow (rCBF). K(1) estimates were similar across gray-matter regions of the brain and lower in the white matter regions, but all these estimates were considerably lower than rCBF. Normalization of K(1) by rCBF diminished the differences in estimates related to gray matter and white matter. In contrast, the K(1) for the pituitary, which is situated outside the BBB, approximated the rCBF. The magnitude of P-gp inhibition was comparable across BBB-protected brain structures. Our results indicate that P-gp and its inhibition equally affect the distribution of drugs (and therefore their neuro-efficacy and toxicity) in the various brain regions protected by the BBB.
Clinical Pharmacology & Therapeutics 03/2010; 87(5):579-85. · 6.04 Impact Factor
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ABSTRACT: The authors assessed CSF and plasma HIV-1 RNA and neuropsychological test performance (composite neuropsychological test Z score [NPZ-4]) in 25 HIV-1-infected subjects 4 and 8 weeks after beginning potent antiretroviral therapy that included a protease inhibitor. In the 14 subjects who entered the study on no antiretroviral treatment, NPZ-4 improvement was associated with decline in CSF HIV-1 RNA at both visits (p = 0.001 and p = 0.02), and those treated with zidovudine or indinavir had greater improvement in NPZ-4 at both visits compared to those treated with other drugs (p = 0.003 and p = 0.01).
Neurology 05/2003; 60(8):1388-90. · 8.31 Impact Factor
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ABSTRACT: We report 6 cases of bacteremia due to Tsukamurella species, all of which were in immunosuppressed patients with indwelling central venous catheters (CVCs). Fewer than 20 cases of serious illness due to these gram-positive bacilli have been reported in the medical literature; these cases have mostly been ascribed to the species Tsukamurella paurometabola. Tsukamurella species are frequently misidentified as Rhodococcus or Corynebacterium species. We used high-performance liquid chromatography to identify these organisms to the genus level and 16S ribosomal RNA gene sequencing and DNA-DNA dot blots for species identification. Three of our isolates were identified as Tsukamurella pulmonis, 1 was identified as Tsukamurella tyrosinosolvans, and 1 was identified as a unique species. One isolate was not maintained long enough for species identification. All patients were successfully treated with antimicrobial therapy and CVC removal. Infection with this organism should be considered in the immunosuppressed patient with an indwelling CVC and gram-positive bacilli in the blood.
Clinical Infectious Diseases 11/2002; 35(7):e72-7. · 9.15 Impact Factor
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ABSTRACT: Adjudication of clinical events is often used as a quality assurance method in clinical research. During the design of the Viral Activation Transfusion Study (a clinical trial in patients with advanced HIV disease), a set of study endpoints was defined (primarily AIDS-defining conditions), criteria for confirmation of each event type were developed, and an adjudication procedure was established. The adjudication process included 1) an initial review of documentation of each event by two independent reviewers, 2) the opportunity to request additional information, 3) a second review either of additional documentation or of cases in which there was disagreement on first review, and 4) the consultation of a third reviewer if there was still disagreement. Overall, of 288 reported endpoints, 30% required additional documentation or more than one review, and 16% were not confirmed at the end of the adjudication process. However, these percentages varied widely over different types of events. For example, of 30 reported nonophthalmalogic cytomegalovirus events, 37% required additional documentation and 40% were not confirmed. In contrast, every one of 17 reported Pneumocystis cariini pneumonias were confirmed with no requirement for additional documentation. The results can be used to help design endpoint documentation and adjudication procedures for other studies, thereby improving data quality and reducing costs.
JAIDS Journal of Acquired Immune Deficiency Syndromes 10/2001; 28(1):43-6. · 4.43 Impact Factor
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ABSTRACT: Our objective was to assess whether HIV-1 RNA levels provide additional prognostic information beyond CD4(+) T lymphocyte counts in the prediction of subsequent HIV-1 disease progression among patients with advanced HIV-1 disease. In a nested case-control study conducted in patients with baseline CD4(+) T lymphocyte counts < 300 cells/mm(3) and receiving nucleoside reverse transcriptase inhibitors, 102 patients who progressed to an AIDS-defining event or death were matched within 10 CD4(+) T lymphocyte cells/mm(3) to patients who did not progress. The relationship between plasma HIV-1 RNA levels and HIV-1 disease progression was studied using conditional logistic regression analysis, which adjusts for the matching by baseline CD4(+) T lymphocytes. We observed a 0.10 log(10) copies/ml difference in baseline HIV-1 RNA levels between cases and their matched controls (p = 0.027). The relative risk for HIV-1 disease progression increased with increasing baseline HIV-1 RNA levels (odds ratio [OR] for a 3-fold higher HIV-1 RNA level, 1.42; 95% confidence interval [CI], 1.08--1.86), and remained important when also controlling for clinical status at baseline and CD4(+) T lymphocytes at 2 months (p = 0.038). Higher baseline HIV-1 RNA levels were associated with HIV-1 disease progression among patients with a baseline CD4(+) T lymphocyte count of 100 cells/mm(3) or greater (OR, 1.80; 95% CI, 1.15--2.81), but not among patients with a baseline CD4(+) T lymphocyte count < 100 cells/mm(3) (OR, 1.09; 95% CI, 0.73--1.63). We concluded that HIV-1 RNA levels predict subsequent HIV-1 disease progression independent of CD4(+) T lymphocyte counts. The magnitude and importance of the prognostic information contained in the HIV-1 RNA levels appear to depend on the CD4(+) T lymphocyte counts.
AIDS Research and Human Retroviruses 09/2001; 17(12):1099-105. · 2.25 Impact Factor
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D V Havlir,
R Bassett,
D Levitan,
P Gilbert,
P Tebas, A C Collier,
M S Hirsch,
C Ignacio,
J Condra,
H F Günthard,
D D Richman,
J K Wong
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ABSTRACT: In HIV-infected patients having virologic suppression (plasma HIV RNA <50 copies/mL) with antiretroviral therapy, intermittent episodes of low-level viremia have been correlated with slower decay rates of latently infected cells and increased levels of viral evolution, but the clinical significance of these episodes is unknown.
To determine if HIV-infected patients with intermittent viremia have a higher risk of virologic failure (confirmed HIV RNA >200 copies/mL).
Retrospective analysis of subjects in well-characterized cohorts, the AIDS Clinical Trials Group (ACTG) 343 trial of induction-maintenance therapy (August 1997 to November 1998) and the Merck 035 trial (ongoing since March 1995).
Two hundred forty-one ACTG 343 patients, of whom 101 received triple-drug therapy throughout the study, and a small group of 13 patients from Merck 035 having virologic suppression after 6 months of indinavir-zidovudine-lamivudine.
Association of intermittent viremia (plasma HIV RNA >50 copies/mL with a subsequent measure <50 copies/mL) with virologic failure (2 consecutive plasma HIV RNA measures >200 copies/mL) in both study groups; evidence of drug resistance in 7 patients from the small (n = 13) study group with long-term follow-up.
Intermittent viremia occurred in 96 (40%) of the 241 ACTG 343 patients of whom 32 (13%) had 2 consecutive HIV RNA values >50 copies/mL during the median 84 weeks of observation (median duration of observation after first intermittent viremia episode was 46 weeks). Of the 101 individuals receiving triple-drug therapy throughout, 29% had intermittent viremia; the proportion of episodes occurring during the maintenance period was 64% for the entire cohort and 68% for the group not receiving triple-drug therapy throughout vs 55% for those who did (P =.25). Intermittent viremia did not predict virologic failure: 10 (10.4%) of 96 patients with and 20 (13.8%) of 145 patients without intermittent viremia had virologic failure (relative risk, 0.76; 95% confidence interval [CI], 0.29-1.72). In a Cox proportional hazards model, the risk for virologic failure was not significantly greater in the ACTG 343 patients with intermittent viremia (hazard ratio, 1.28; 95% CI, 0.59-2.79). Median viral load in 10 ACTG 343 patients assessed between 24 and 60 weeks of therapy using an ultrasensitive 2.5-copies/mL detection level assay was 23 copies/mL in those with intermittent viremia vs <2.5 copies/mL in those without (P =.15). Intermittent viremia occurred in 6 of 13 patients from the small study group assessed after 76 to 260 weeks of therapy (using the 2.5-copies/mL detection level assay) and was associated with a higher steady state of viral replication (P =.03), but not virologic failure over 4.5 years of observation. Viral DNA sequences from 7 patients did not show evolution of drug resistance.
Intermittent viremia occurred frequently and was associated with higher levels of replication (Merck 035), but was not associated with virologic failure in patients receiving initial combination therapy of indinavir-zidovudine-lamivudine (ACTG 343 and Merck 035). In this population, treatment changes may not be necessary to maintain long-term virologic suppression with low-level or intermittent viremia.
JAMA The Journal of the American Medical Association 08/2001; 286(2):171-9. · 30.03 Impact Factor
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D V Havlir,
P B Gilbert,
K Bennett, A C Collier,
M S Hirsch,
P Tebas,
E M Adams,
L J Wheat,
D Goodwin,
S Schnittman,
M K Holohan,
D D Richman
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ABSTRACT: Virologic rebound can result from suboptimal antiviral potency in combination antiretroviral therapy.
Multicenter, partially blinded, prospective, randomized study of 202 HIV-infected subjects to determine whether therapy intensification improves long-term rates of virologic suppression.
Subjects had plasma HIV RNA < 200 copies/ml, CD4 cell count of > 200 x 10(6) cells/l, and treatment with indinavir (IDV) + zidovudine (ZDV) + lamivudine (3TC) for at least 6 months before randomization to stay on this regimen or to receive IDV + didanosine (ddI) + stavudine (d4T) plus or minus hydroxyurea (HU) (600 mg twice daily). Treatment failure was defined as either confirmed rebound of HIV RNA level to > 200 copies/ml or a drug toxicity necessitating treatment discontinuation.
Treatment failure occurred more frequently in subjects randomized to the HU-containing arm (32.4%), than in those taking IDV + ddI + d4T (17.6%) or IDV + ZDV + 3TC (7.6%). The time to treatment failure was shorter for the HU-containing arm compared with the IDV + ZDV + 3TC (P < 0.0001) or IDV + ddI + d4T arms (P = 0.032). Dose-limiting toxicities rather than virologic rebound accounted for the differences between treatment failure among the study arms. Pancreatitis led to treatment discontinuation in 4% of subjects in treatment arms containing ddI + d4T. Three subjects with pancreatitis died, all randomized to the HU-containing arm.
Switching to IDV + ddI + d4T + HU in patients treated with IDV + ZDV + 3TC was associated with a worse outcome, principally because of drug toxicity.
AIDS 07/2001; 15(11):1379-88. · 6.24 Impact Factor
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ABSTRACT: Mortality and morbidity related to AIDS have decreased among HIV-infected patients taking highly active anti-retroviral therapy (HAART), but previous studies may have been confounded by other changes in treatment.
To assess the benefit of HAART in patients with advanced AIDS and anemia.
Prospective, multicenter cohort study.
The Viral Activation Transfusion Study (VATS), with enrollment from August 1995 through July 1998 and follow-up through June 1999.
528 HIV-infected patients with cytomegalovirus (CMV) seropositivity or disease who were receiving a first red blood cell transfusion for anemia.
In a person-year analysis of follow-up before and after initiation of HAART, Poisson regression was used to calculate crude rate ratios and rate ratios adjusted for CD4 count, HIV RNA level, calendar period, time on study, sex, ethnicity, and injection drug use.
At baseline, patients had a median CD4(+) lymphocyte count of 0.015 x 10(9) cell/L, median plasma HIV RNA level of 4.8 log(10) copies/mL, and median hemoglobin concentration of 73 g/L. Use of HAART increased from 1% of active patients in January 1996 to 79% of active patients in January 1999. The crude death rate was 0.24 event/person-year among patients taking HAART and 0.88 event/person-year among those not taking HAART (rate ratio, 0.26; adjusted rate ratio, 0.38; P < 0.001 for both comparisons). Rates of non-CMV disease were 0.15 event/ person-year after HAART and 0.45 event/person-year before HAART (crude rate ratio, 0.34 [ P < 0.001]; adjusted rate ratio, 0.66 [ P < 0.05]). Rates of CMV disease were 0.10 event/person-year after HAART and 0.25 before HAART (crude rate ratio, 0.42 [ P < 0.01]; adjusted rate ratio, 1.01 [ P > 0.2]). Results were similar in patients with baseline CD4(+) lymphocyte counts less than 0.010 x 10(9) cells/L.
The data support an independent reduction in mortality and opportunistic events attributable to HAART, even in patients with very advanced HIV disease. However, patients with CMV infection or disease may not have a reduction in new CMV events due to HAART.
Annals of internal medicine 07/2001; 135(1):17-26. · 16.73 Impact Factor
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ABSTRACT: The Viral Activation Transfusion Study compared leukocyte-reduced to unfiltered red blood cell transfusions in human immunodeficiency virus (HIV)- and cytomegalovirus (CMV)-coinfected patients. Relationships between serially measured plasma CMV load and clinical and laboratory outcomes over a median of 12 months were examined in 511 subjects. At baseline, subjects had a median of 15 CD4(+) cells/mm(3), 25% had CMV disease, and 21.5% were viremic. No relationship was found between changes in CMV viremia and changes in HIV RNA. Increased CMV viremia was associated with a concomitant fall in Karnofsky score. Highly active antiretroviral therapy (HAART) led to a decrease in CMV viremia after a 90-day delay. After adjustment for HIV load and CD4(+) cell count, CMV viremia remained associated with an increased risk of CMV disease (relative hazard, 5.78). In late-stage HIV-infected patients, CMV viremia was associated with lower functional status and increased risk of CMV disease. HAART suppressed CMV viremia only after a delay of several months.
The Journal of Infectious Diseases 07/2001; 183(11):1673-7. · 6.41 Impact Factor
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M M Berrey,
T Schacker, A C Collier,
T Shea,
S J Brodie,
D Mayers,
R Coombs,
J Krieger,
T W Chun,
A Fauci,
S G Self,
L Corey
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ABSTRACT: Immunologic data supporting immediate antiretroviral therapy in primary human immunodeficiency virus type 1 (HIV-1) infection are emerging; however, clinical benefit has not been demonstrated. The clinical and virologic course of 47 patients who were enrolled from September 1993 through June 1996 and who were not initially treated with potent therapy was compared with the course of 20 patients who immediately began therapy with zidovudine, lamivudine, and indinavir. Demographic and baseline laboratory data were comparable. During 78 weeks of follow-up, the early-treatment cohort showed a reduced frequency of opportunistic infections (5% vs. 21.3%; relative risk, 0.11; P=.02), less frequent progression to AIDS (13% vs. 0%), and significantly less frequent nonopportunistic mucocutaneous disorders and respiratory infections (P<.01). Plasma HIV-1 RNA levels were <50 copies/mL in all patients who continued therapy; however, after 9--12 months, HIV-1 remained detectable in latently infected CD4(+) T cells and in lymph node mononuclear cells. Combination antiretroviral therapy during primary HIV-1 infection demonstrated a decreased frequency of minor opportunistic infections, mucocutaneous disorders, and respiratory infections and reduced progression to AIDS.
The Journal of Infectious Diseases 05/2001; 183(10):1466-75. · 6.41 Impact Factor
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ABSTRACT: The Viral Activation Transfusion Study (VATS) was a randomized trial that compared leukocyte-reduced transfusions with unfiltered red blood cell transfusions in HIV and cytomegalovirus (CMV) antibody-positive patients with anemia who were undergoing their first blood transfusion. The relations of the baseline qualitative and quantitative polymerase chain reaction (PCR) measures of plasma CMV viremia, HIV RNA, CD4(+) cell counts, and quality of life in these study subjects were examined. The 511 study subjects had a median CD4(+) cell count equal to 15 cells/mm3, and 110 (21.5%) had CMV viremia by qualitative assay. In multivariate models, frequency of positive qualitative CMV increased with decreasing CD4(+) cell counts (p =.04 trend), higher HIV RNA (p <.001), and a history of CMV disease (p <.001). Quantitative CMV PCR were performed on the 110 qualitative assay-positive study subjects. Median CMV viral load was 1780 copies/ml. In multivariate regression models, lower CD4(+) cell count (p =.03), and a history of CMV disease (p <.001) correlated with the level of CMV load. HIV RNA load and CMV load were not correlated. A lower Karnofsky score was associated with both the presence and quantity of CMV DNA.
JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2001; 26(4):320-5. · 4.43 Impact Factor
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A C Collier,
L A Kalish,
M P Busch,
T Gernsheimer,
S F Assmann,
T A Lane,
D M Asmuth,
M M Lederman,
E L Murphy,
P Kumar,
M Kelley,
T P Flanigan,
D K McMahon,
H S Sacks,
M S Kennedy,
P V Holland
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ABSTRACT: Allogeneic blood transfusions have immunomodulatory effects and have been associated with activation of human immunodeficiency virus (HIV) and cytomegalovirus (CMV) in vitro and of HIV in small pilot studies. Retrospective studies suggest that transfusions adversely affect the clinical course of HIV. Data in selected non-HIV-infected patients requiring blood transfusion have suggested clinical benefit with leukocyte-reduced red blood cells (RBCs).
To compare the effects of leukoreduced and unmodified RBC transfusions on survival, complications of acquired immunodeficiency syndrome, and relevant laboratory markers in HIV-infected patients.
Double-blind randomized controlled trial conducted in 11 US academic medical centers from July 1995 through June 1999, with a median follow-up of 12 months (24 months in survivors).
A total of 531 persons infected with HIV and CMV, aged 14 years or older, who required transfusions for anemia; 259 received leukoreduced transfusions and 262 received unmodified transfusions (10 did not receive the planned transfusion).
Survival and change in plasma HIV RNA level 7 days after transfusion, compared by type of transfusion.
At entry, the groups were similar in demographic, clinical, and relevant laboratory characteristics. A total of 3864 RBC units were transfused. Two hundred eighty-nine deaths occurred (151 with leukoreduced transfusion; 138 with unmodified transfusion); median survival was 13.0 and 20.5 months, respectively (relative hazard [RH], 1.20; 95% confidence interval [CI], 0.95-1.51; log-rank P =.12). Analyses adjusted for prognostic factors suggested possible worse survival with leukoreduction (RH, 1.35; 95% CI, 1.06-1.72). There was no difference in time to new opportunistic event/death or frequency of transfusion reactions. No changes in plasma HIV RNA level were seen in either group at days 7, 14, 21, or 28, even in patients not taking antiretroviral drugs. There were no differences in trends between groups in CMV DNA, CD4 cell counts, activated (CD38% or human leukocyte antigen-DR) CD8 cell counts, or plasma cytokine levels.
We found no evidence of HIV, CMV, or cytokine activation following blood transfusion in patients with advanced HIV infection. Leukoreduction provided no clinical benefit in these patients. These data demonstrate the importance of conducting controlled studies of effects of leukoreduction in different patient populations, since smaller studies in other patient populations have suggested leukoreduction may be beneficial.
JAMA The Journal of the American Medical Association 04/2001; 285(12):1592-601. · 30.03 Impact Factor
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A Seth,
J Markee,
A Hoering,
A Sevin,
D E Sabath,
J E Schmitz,
M J Kuroda,
M A Lifton,
M S Hirsch, A C Collier,
N L Letvin,
M J McElrath
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ABSTRACT: Cytotoxic T lymphocytes (CTLs) are an important defense against human immunodeficiency virus (HIV) type 1 but ultimately fail to control infection. To determine whether more efficient sustained immunity is induced by suppressing replication, the evolution of T cell phenotypes and HIV-specific CD8+ lymphocytes was prospectively investigated in 41 patients initiating combination therapy. Suppression of viremia to <200 copies/mL was associated with increases in naive cells (CD45RA+62L+) and declines in activated T cells (CD95+ cell counts and CD38+ HLA-DR+). HIV-specific tetramer-staining CD8+ T cells were detected in 6 of 10 HLA-A*0201-positive persons, which declined in 5 with treatment. CTL precursor frequencies were markedly consistent before and after treatment. Eight (72%) of 11 recognized > or =1 immunodominant epitope, representing either a new or an increased CTL response after treatment. Thus, activated CD8+ T cells, including those recognizing immunodominant epitopes, decline with combination therapy. However, the overall level of antigen-specific cells that are capable of differentiating into effectors remains stable, and the recognition of new epitopes may occur.
The Journal of Infectious Diseases 03/2001; 183(5):722-9. · 6.41 Impact Factor
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ABSTRACT: Despite US Public Health Service (USPHS) recommendations for antimicrobial prophylaxis for patients with advanced human immunodeficiency virus (HIV) disease, the proportion of patients who receive prophylaxis is not known. We measured the prevalence of antimicrobial prophylaxis use, and treatment for HIV wasting at baseline among 531 patients with advanced HIV disease enrolled in a multicenter randomized trial of red blood cell transfusion. Use of antimicrobial prophylaxis and treatment for wasting in the 30 days before enrollment was ascertained in patients eligible for primary prophylaxis, secondary prophylaxis, or both, according to USPHS guidelines. There was high utilization of primary and secondary Pneumocystis carinii pneumonia prophylaxis, variability in primary Mycobacterium avium complex prophylaxis by center, and low use of primary cytomegalovirus prophylaxis. Treatment of wasting was more common in white than nonwhite patients and in patients with HIV disease who lived in the region west of the Mississippi River of the United States versus those whose lived in the eastern region.
Clinical Infectious Diseases 02/2001; 32(1):116-23. · 9.15 Impact Factor
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ABSTRACT: To evaluate plasma population pharmacokinetics and penetration into cerebrospinal fluid (CSF) by indinavir (IDV) in HIV-infected individuals receiving IDV, zidovudine and lamivudine.
Plasma population pharmacokinetic analysis was performed on 805 IDV plasma values from 171 patients, using a non-linear mixed-effects modeling approach. CSF data from 19 patients were analyzed using an individual approach.
Mean individual Bayesian estimates for oral clearance (CL) and volume of distribution (V) by the final model that incorporated interoccasion variability were 0.75 l/h per kg [coefficient of variation (CV) 54.8%] and 1.74 l/kg (CV 82.7%), respectively. Mean model-predicted plasma IDV level at 8 h, maximal level, area under the plasma level-time curve up to 8 h and plasma half-life were 0.42 micromol/l (CV 57.5%), 9.51 micromol/l (CV 47.3%), 29.56 micromol/l x h (CV 46.9%) and 1.50 h (CV 20.9%), respectively. The mean IDV CSF level was 0.11 micromol/l (CV 49.7%) and the mean CSF:plasma concentration ratio was 0.017.
Population estimates of pharmacokinetic parameters of IDV and its CSF penetration were in excellent agreement with previously reported data from individual analyses. Intraindividual interoccasion variability of IDV pharmacokinetics was estimated to be of similar order of magnitude to its interindividual variability, which may affect response to long-term antiretroviral therapy involving IDV. CSF levels of IDV exceeded its in vitro 95% inhibitory concentration of HIV replication. Given that CSF is virtually free of protein, viral suppression in the central nervous system should be achievable with an IDV-containing regimen.
AIDS 01/2001; 14(18):2869-76. · 6.24 Impact Factor
