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1.  Outcomes by Sex Following Treatment Initiation With Atazanavir Plus Ritonavir or Efavirenz With Abacavir/Lamivudine or Tenofovir/Emtricitabine 
Smith, Kimberly Y. | Tierney, Camlin | Mollan, Katie | Venuto, Charles S. | Budhathoki, Chakra | Ma, Qing | Morse, Gene D. | Sax, Paul | Katzenstein, David | Godfrey, Catherine | Fischl, Margaret | Daar, Eric S. | Collier, Ann C. | Bolivar, Hector H. | Navarro, Sandra | Koletar, Susan L. | Gochnour, Diane | Seefried, Edward | Hoffman, Julie | Feinberg, Judith | Saemann, Michelle | Patterson, Kristine | Pittard, Donna | Currin, David | Upton, Kerry | Saag, Michael | Ray, Graham | Johnson, Steven | Santos, Bartolo | Funk, Connie A. | Morgan, Michael | Jackson, Brenda | Tebas, Pablo | Thomas, Aleshia | Kim, Ge-Youl | Klebert, Michael K. | Santana, Jorge L. | Marrero, Santiago | Norris, Jane | Valle, Sandra | Cox, Gary Matthew | Silberman, Martha | Shaik, Sadia | Lopez, Ruben | Vasquez, Margie | Daskalakis, Demetre | Megill, Christina | Shore, Jessica | Taiwo, Babafemi | Goldman, Mitchell | Boston, Molly | Lennox, Jeffrey | del Rio, Carlos | Lane, Timothy W. | Epperson, Kim | Luetkemeyer, Annie | Payne, Mary | Gripshover, Barbara | Antosh, Dawn | Reid, Jane | Adams, Mary | Storey, Sheryl S. | Dunaway, Shelia B. | Gallant, Joel | Wiggins, Ilene | Smith, Kimberly Y. | Swiatek, Joan A. | Timpone, Joseph | Kumar, Princy | Moe, Ardis | Palmer, Maria | Gothing, Jon | Delaney, Joanne | Whitely, Kim | Anderson, Ann Marie | Hammer, Scott M. | Yin, Michael T. | Jain, Mamta | Petersen, Tianna | Corales, Roberto | Hurley, Christine | Henry, Keith | Bordenave, Bette | Youmans, Amanda | Albrecht, Mary | Pollard, Richard B. | Olusanya, Abimbola | Skolnik, Paul R. | Adams, Betsy | Tashima, Karen T. | Patterson, Helen | Ukwu, Michelle | Rogers, Lauren | Balfour, Henry H. | Fox, Kathy A. | Swindells, Susan | Van Meter, Frances | Robbins, Gregory | Burgett-Yandow, Nicole | Davis, Charles E. | Boyce, Colleen | O'Brien, William A. | Casey, Gerianne | Morse, Gene D. | Hsaio, Chiu-Bin | Meier, Jeffrey L. | Stapleton, Jack T. | Mildvan, Donna | Revuelta, Manuel | Currin, David | El Sadr, Wafaa | Loquere, Avelino | El-Daher, Nyef | Johnson, Tina | Gross, Robert | Maffei, Kathyrn | Hughes, Valery | Sturge, Glenn | McMahon, Deborah | Rutecki, Barbara | Wulfsohn, Michael | Cheng, Andrew | Dix, Lynn | Liao, Qiming
This clinical trial identifies a significantly earlier time to virologic failure in women randomized to atazanavir/ritonavir compared to women randomized to efavirenz.
Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex.
Methods. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1–infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII).
Results. Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex.
Conclusions. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential.
Clinical Trials Registration NCT00118898.
PMCID: PMC3905755  PMID: 24253247
sex; atazanavir; efavirenz; abacavir; tenofovir
2.  How Have Long-Term Survivors Coped with Living with HIV? 
With advances in HIV treatment, more individuals have grown older with the disease. Little is known about factors that have helped these survivors manage everyday life with HIV. In this exploratory, qualitative study, we asked, What has helped survivors cope with challenges of living long-term with HIV? Participants were recruited from a convenience sample of persons living with HIV (PLWH) who obtained treatment at a specialty HIV clinic; 16 long-term survivors of HIV were interviewed. Mean age was 50.13 (SD = 8.30) years; mean time from diagnosis was 16.75 (SD = 5.98) years. Results were broadly dichotomized as coping mechanisms and social supports. Three themes characterized coping mechanisms: disease coping, practical coping, and emotional coping. Social supports included themes of family, friends, professionals, peer groups, and pets. In particular, the power of patient-professional relationships and meanings derived from religion/spirituality were considered influential factors by a majority of participants.
PMCID: PMC3692565  PMID: 23253776
coping; HIV; older adults; strengths perspective
3.  CD8+ T-cell Activation in HIV-1-Infected Patients Experiencing Transient Low-level Viremia During Antiretroviral Therapy 
Transient low-level viremia of 50–400 HIV RNA copies/mL (TLLV) is common during antiretroviral therapy, but its pathogenesis, consequences and optimal management are unclear. Heightened immune activation is associated with detrimental outcomes, including impaired CD4+ T-cell reconstitution. Using CD38/HLA-DR expression on CD8+ T-cells measured in two large studies, we determined associations between TLLV and immune activation levels before, during, and after TLLV. We found that TLLV does not significantly change CD8+ T-cell activation, and that higher CD8+ T-cell activation during viral suppression <50 copies/mL is associated with a modest increase in the risk of a subsequent TLLV.
PMCID: PMC3632289  PMID: 23392463
low-level; viremia; blip; immune; activation; CD8+
4.  Immunologic Failure Despite Suppressive Antiretroviral Therapy Is Related to Activation and Turnover of Memory CD4 Cells 
The Journal of Infectious Diseases  2011;204(8):1217-1226.
Background. Failure to normalize CD4+ T-cell numbers despite effective antiretroviral therapy is an important problem in human immunodeficiency virus (HIV) infection.
Methods. To evaluate potential determinants of immune failure in this setting, we performed a comprehensive immunophenotypic characterization of patients with immune failure despite HIV suppression, persons who experienced CD4+ T-cell restoration with therapy, and healthy controls.
Results. Profound depletion of all CD4+ T-cell maturation subsets and depletion of naive CD8+ T cells was found in immune failure, implying failure of T-cell production/expansion. In immune failure, both CD4+ and CD8+ cells were activated but only memory CD4+ cells were cycling at increased frequency. This may be the consequence of inflammation induced by in vivo exposure to microbial products, as soluble levels of the endotoxin receptor CD14+ and interleukin 6 were elevated in immune failure. In multivariate analyses, naive T-cell depletion, phenotypic activation (CD38+ and HLA-DR expression), cycling of memory CD4+ T cells, and levels of soluble CD14 (sCD14) distinguished immune failure from immune success, even when adjusted for CD4+ T-cell nadir, age at treatment initiation, and other clinical indices.
Conclusions. Immune activation that appears related to exposure to microbial elements distinguishes immune failure from immune success in treated HIV infection.
PMCID: PMC3218674  PMID: 21917895
5.  Chemokine (C-C Motif) Receptor 5 −2459 Genotype in Patients Receiving Highly Active Antiretroviral Therapy: Race-Specific Influence on Virologic Success 
The Journal of Infectious Diseases  2011;204(2):291-298.
Background. In patients receiving highly active antiretroviral therapy (HAART), antiretroviral drug–metabolizing enzyme and transporter gene polymorphisms, as well as chemokine receptor gene polymorphisms, may influence response to treatment.
Methods. In a North American, treated, adherent human immunodeficiency virus (HIV)–positive cohort (self-identified whites, n = 175; blacks, n = 218), we investigated whether CYP2B6 (516G>T, 983T>C), UGT2B7 (IVS1+985A>G, 802C>T), MDR1 3435C>T, chemokine (C-C motif) receptor 2 (CCR2) 190G>A, and CCR5 (−2459G>A, Δ32) polymorphisms influenced the time to achieve virologic success (TVLS).
Results. No difference in TVLS was observed between races. In Kaplan-Meier analyses, only 516G>T (log-rank P = .045 for comparison of GG, GT, and TT and P = .02 GG + GT vs TT) and −2459G>A (log-rank P = .04 for GG, GA, and AA and P = .02 for GG + GA vs AA) genotypes were significantly associated with TVLS in black patients but not in white patients. However, in the Cox proportional hazards model that included age, sex, baseline CD4+ T cell count, and baseline viral load, no significant association was observed between 516G>T and TVLS, whereas the association between −2459G>A and TVLS remained significant even after including CCR2 190G>A as well as all the drug-metabolizing enzyme and transporter genotypes.
Conclusions. These findings suggest that CCR5 −2459G>A genotype had a strong, race-specific influence on TVLS in this cohort. Understanding the possible mechanisms underlying this influence requires further studies.
PMCID: PMC3114473  PMID: 21673041
Therapeutic drug monitoring  2011;33(3):309-314.
Achieving targeted antiretroviral (ART) plasma concentrations during long-term treatment in HIV-infected patients with substance related disorders (SRD) may be challenging due to a number of factors including medication adherence, co-infection with hepatitis B or C virus, medication intolerance and drug interactions. One approach to investigate these factors is to conduct therapeutic drug monitoring (TDM) to measure ART exposure during treatment. The objective of this study was to utilize TDM to compare efavirenz and protease inhibitor pharmacokinetics in patients with and without SRDs.
This was a multi-center, cross-sectional open-label study in patients with HIV-1 infection receiving ART, with active (n=129) or without (n=146) SRD according to National Institute on Drug Abuse criteria. 275 subjects who were receiving either protease inhibitor- or efavirenz-based ART regimens for more than 6 months were enrolled at four HIV treatment centers with an equal distribution of SRD and non-SRD at each site. Patients were instructed during enrollment visits with regard to the importance of adherence prior to and after study visits. Demographics and routine clinical laboratory tests were recorded.
Among the 275 patients, 47% had SRD with at least one substance. There were no significant differences between SRD and non-SRD groups for race, gender, age, or CD4 count at entry. A significantly higher proportion of patients with SRD had an entry HIV RNA plasma concentration > 75 copies/ml compared to patients without SRD (40% vs. 28%, p=0.044). Logistic regression modeling revealed an association between HIV RNA plasma concentration and African-American race (p=0.017). A significantly higher proportion of SRDs also had an efavirenz or protease inhibitor trough concentration below the desired range (23% vs. 9%, p=0.048). Significantly lower trough concentrations were noted in patients with SRDs receiving atazanavir (0.290 vs. 0.976 µg/mL) or lopinavir (3.75 vs. 5.30 µg/mL).
The pharmacokinetic data indicate differences between HIV-infected patients with and without SRD that may influence viral load suppression during long-term ARV treatment. These findings require additional investigation in a randomized design with more intensive pharmacokinetic assessment to identify individual factors that are contributing to suboptimal ARV exposure in patients with SRDs.
PMCID: PMC3120966  PMID: 21544014
7.  Association Between Hepatitis C Virus Coinfection and Regional Adipose Tissue Volume in HIV-Infected Men and Women 
Coinfection with hepatitis C virus (HCV) is reported to be associated with a higher prevalence of lipodystrophy than HIV infection alone. We examine the association between HCV and adipose tissue volume in HIV-infected men and women.
Cross-sectional analysis of HIV-infected subjects from the study of Fat Redistribution and Metabolic Change in HIV Infection. MRI measured regional adipose tissue volume. Detectable HCV RNA defined HCV infection.
Twenty percent of 792 men and 26% of 329 women were HIV/HCV-coinfected. HIV/HCV-coinfected and HIV-monoinfected women had similar amounts of subcutaneous adipose tissue (SAT) in the leg, lower trunk, upper trunk, and arm and similar amounts of visceral adipose tissue (VAT). Similar findings were seen in men, except in the leg and VAT. After adjustment, HCV infection remained associated with more leg fat in men (12.2%, 95% confidence interval [CI]: 0.3 to 25.3; P = 0.043). Among those on stavudine, HIV-monoinfected men had less leg fat (−7% effect per year of stavudine use, 95% CI: −9 to −5; P < 0.001); a weaker association was seen in HIV/HCV-coinfected men (−2% effect, 95% CI: −7 to 3; P = 0.45). Indinavir was associated with less leg fat (−4% in HIV-monoinfected men, 95% CI: −6 to −1; P = 0.002; −5% in HIV/HCV-coinfected men, 95% CI: −11 to 2; P = 0.14).
Our findings suggest that HIV/HCV coinfection is not associated with less SAT in men and women. HCV infection seems to mitigate the loss of leg fat seen in HIV-infected men on stavudine.
PMCID: PMC3164885  PMID: 17356466
adipose tissue volume; fat distribution; hepatitis C virus; HIV; lipodystrophy
8.  Histoplasma capsulatum Prosthetic Valve Endocarditis with Negative Fungal Blood Cultures and Negative Histoplasma Antigen Assay in an Immunocompetent Patient ▿  
Journal of Clinical Microbiology  2010;48(12):4664-4666.
We report a case of Histoplasma capsulatum endocarditis in which Histoplasma antigen assay and fungal blood cultures were negative. The diagnosis was made by microscopic examination and culture of the excised valve. Histoplasma capsulatum should be considered in the differential diagnosis of culture-negative endocarditis in regions where it is endemic and in travelers.
PMCID: PMC3008473  PMID: 20926709
9.  Regional Adipose Tissue and Elevations in Serum Aminotransferases in HIV-Infected Individuals 
The association of fat distribution with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations is not well-defined in HIV-infected individuals. Obesity is associated with hepatic steatosis, and ALT is a marker of steatosis in the general population.
Cross-sectional analysis of 1119 HIV-infected and 284 control subjects. Hepatitis C virus (HCV) RNA testing determined HCV infection. Magnetic resonance imaging measured regional adipose tissue volume.
After adjustment for demographic and lifestyle factors, visceral adipose tissue (VAT) was positively associated with ALT in HIV/HCV-coinfected subjects (+9.8%, 95% confidence interval [CI]: 2.8 to 17.6), HIV-monoinfected subjects (+8.0%, 95% CI: 4.2 to 12.1), and controls (+5.9%, 95% CI: 2.0 to 10.1). In contrast, lower trunk subcutaneous adipose tissue (SAT) was negatively associated with ALT in HIV/HCV-coinfected subjects (−14.3%, 95% CI: −24.7 to −4.2) and HIV-monoinfected subjects (−11.9%, 95% CI: −18.4 to −5.3); there was a trend toward an association in controls (−7.1%, 95% CI: −22.7 to 5.9). Estimated associations between regional adipose tissue and AST were small and did not reach statistical significance.
More VAT and less lower trunk SAT are associated with elevated ALT, which likely reflects the presence of steatosis. There was little association with AST. HCV infection and having more VAT or less lower trunk SAT are independently associated with elevated ALT in HIV infection. Study regarding the association between VAT, trunk SAT, HCV, and progression of steatosis and fibrosis is needed in HIV-infected individuals.
PMCID: PMC2776053  PMID: 18285711
adipose tissue; aminotransferase levels; hepatitis C virus; HIV; lipodystrophy

Results 1-9 (9)