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1.  Maraviroc Observational Study: The Impact of Expanded Resistance Testing and Clinical Considerations for Antiretroviral Regimen Selection in Treatment-Experienced Patients 
Abstract
Maraviroc (MVC) use has trailed that of other post-2006 antiretroviral therapy (ART) options for treatment-experienced patients. We explored the impact of free tropism testing on MVC utilization in our cohort and explored barriers to MVC utilization. The Maraviroc Outcomes Study (MOS) is an investigator-initiated industry-sponsored trial where consecutive ART-experienced patients receiving routine care with viral loads ≥1,000 copies/ml, and whose provider requested resistance testing and received standardized resistance testing (SRT; phenotype, genotype, coreceptor/tropism). Sociodemographic, clinical, and ART characteristics of those receiving SRT were compared to a historical cohort (HC). Subsequently, providers were surveyed regarding factors influencing selection of salvage ART therapy. The HC (n=165) had resistance testing 7/08–9/09, while prospective SRT (n=83) patients were enrolled 9/09–8/10. In the HC, 92% had genotypes, 2% had tropism assays, and 62% (n=102) changed ART after resistance testing (raltegravir 37%, etravirine 25%, darunavir 24%, MVC 1%). In the SRT cohort, 57% (n=48) changed regimens after standardized resistance testing (darunavir 48%, raltegravir 40%, and etravirine 19%). CCR5-tropic virus was identified in 43% of the SRT group, and MVC was used in 10% [or 20% of R5 tropic patients who underwent a subsequent regimen change (n=25)], a statistically significant (p=0.01) increase in utilization. The factors most strongly influencing utilization were unique patient circumstances (60%), clinical experience (55%), and potential side effects (40%). The addition of routine tropism testing to genotypic/phenotypic testing was associated with increased MVC utilization, raising the possibility that tropism testing may present a barrier to MVC use; however, additional barriers exist, and merit further evaluation.
doi:10.1089/aid.2012.0157
PMCID: PMC3608020  PMID: 22881368
2.  The epidemiology and clinical correlates of HIV-1 co-receptor tropism in non-subtype B infections from India, Uganda and South Africa 
Background
The introduction of C-C chemokine receptor type-5 (CCR5) antagonists as antiretroviral therapy has led to the need to study HIV co-receptor tropism in different HIV-1 subtypes and geographical locations. This study was undertaken to evaluate HIV-1 co-receptor tropism in the developing world where non-B subtypes predominate, in order to assess the therapeutic and prophylactic potential of CCR5 antagonists in these regions.
Methods
HIV-1-infected patients were recruited into this prospective, cross-sectional, epidemiologic study from HIV clinics in South Africa, Uganda and India. Patients were infected with subtypes C (South Africa, India) or A or D (Uganda). HIV-1 subtype and co-receptor tropism were determined and analyzed with disease characteristics, including viral load and CD4+ and CD8+ T cell counts.
Results
CCR5-tropic (R5) HIV-1 was detected in 96% of treatment-naïve (TN) and treatment-experienced (TE) patients in India, 71% of TE South African patients, and 86% (subtype A/A1) and 71% (subtype D) of TN and TE Ugandan patients. Dual/mixed-tropic HIV-1 was found in 4% of Indian, 25% of South African and 13% (subtype A/A1) and 29% (subtype D) of Ugandan patients. Prior antiretroviral treatment was associated with decreased R5 tropism; however, this decrease was less in subtype C from India (TE: 94%, TN: 97%) than in subtypes A (TE: 59%; TN: 91%) and D (TE: 30%; TN: 79%). R5 virus infection in all three subtypes correlated with higher CD4+ count.
Conclusions
R5 HIV-1 was predominant in TN individuals with HIV-1 subtypes C, A, and D and TE individuals with subtypes C and A. Higher CD4+ count correlated with R5 prevalence, while treatment experience was associated with increased non-R5 infection in all subtypes.
doi:10.1186/1758-2652-15-2
PMCID: PMC3298508  PMID: 22281097
co-receptor; tropism; HIV-1 subtype; HIV-1 clade; CCR5 (R5); CXCR4 (X4); cellular factors
3.  Performance of the Abbott RealTime HIV-1 Viral Load Assay Is Not Impacted by Integrase Inhibitor Resistance-Associated Mutations▿ 
Journal of Clinical Microbiology  2011;49(4):1631-1634.
The Abbott RealTime HIV-1 viral load assay uses primers and probes targeted to integrase, which is also the target of integrase inhibitors such as raltegravir. Viral loads of 42 raltegravir-susceptible and 40 raltegravir-resistant specimens were determined using RealTime HIV-1 and Roche Monitor (v1.5). The differences in viral load measurements between assays were comparable in the two groups, demonstrating that the RealTime HIV-1 assay can tolerate raltegravir-selected mutations.
doi:10.1128/JCM.02253-10
PMCID: PMC3122809  PMID: 21289145
4.  Associations of Insulin-Like Growth Factor (IGF)–I and IGF-Binding Protein–3 with HIV Disease Progression in Women 
The Journal of infectious diseases  2008;197(2):319-327.
Background
The insulin-like growth factor (IGF) axis has been hypothesized to influence the rate of human immunodeficiency virus (HIV) disease progression. This premise is based largely on laboratory models showing that IGF-I stimulates thymic growth and increases lymphocyte numbers and that IGF-binding protein (IGFBP)–3 has an opposing effect, inhibiting hematopoietic stem cell development.
Methods
We studied 1422 HIV-infected women enrolled in a large cohort that entailed semiannual follow-up (initiated in 1994). Baseline serum samples were tested for IGF-I and IGFBP-3 to determine their associations with incident clinical acquired immunodeficiency syndrome (AIDS) and CD4+ T cell count decline prior to April 1996 (before the era of highly active antiretroviral therapy [HAART]).
Results
Low IGF-I levels (Ptrend = .02) and high IGFBP-3 levels (Ptrend = .02) were associated with rapid CD4+ T cell count decline. Only IGFBP-3, however, was significantly associated with AIDS incidence (hazard ratio for highest vs. lowest quartile, 2.65 [95% confidence interval, 1.30–5.42]; Ptrend = .02) in multivariable models.
Conclusions
These findings suggest that serum levels of IGFBP-3 (and possibly IGF-I) are associated with the rate of HIV disease progression in women and, more broadly, that interindividual heterogeneity in the IGF axis may influence HIV pathogenesis. If correct, the IGF axis could be a target for interventions to slow HIV disease progression and extend the time before use of HAART becomes necessary.
doi:10.1086/524848
PMCID: PMC3127259  PMID: 18177247
5.  Increased Circulating Interleukin-7 Levels in HIV-1–Infected Women 
Summary
Sex-based differences in CD4 T-cell (CD4) counts are well recognized, but the basis for these differences has not been identified. Conceivably, homeostatic factors may play a role in this process by regulating T-cell maintenance and repletion. Interleukin (IL)-7 is essential for normal T-cell production and homeostasis. We hypothesized that differences in IL-7 might contribute to sex-based differences in CD4 counts. Circulating IL-7 levels were analyzed in 299 HIV-1–infected women and men. Regression analysis estimated that IL-7 levels were 40% higher in women than in men (P = 0.0032) after controlling for CD4 count, age, and race. Given the important role of IL-7 in T-cell development and homeostasis, these findings suggest that higher IL-7 levels may contribute to higher CD4 counts in women.
PMCID: PMC3119025  PMID: 16284535
interleukin-7; sexual dimorphism; CD4-positive T cells; cytokines; sex differences
6.  Treatment with Recombinant Growth Hormone Is Associated with Modest Improvement in CD4 Lymphocyte Reconstitution in HIV-Infected Persons on Antiretroviral Therapy: Results of ACTG A5174 
Abstract
Pilot studies have suggested that treatment with recombinant human growth hormone (rhGH) is associated with increased T-lymphocyte restoration and enhanced thymic output. We evaluated the immunologic effects of rhGH on HIV+ subjects with incomplete immune reconstitution on antiretroviral therapy (ART). Sixty subjects were randomized to receive rhGH 1.5 mg scqd and ART for 48 weeks (Arm A) or continue ART alone for 24 weeks then add rhGH 3.0 mg scqd for 24 weeks (Arm B). Median baseline CD4 for Arms A and B were 223 and 219, respectively. There was little difference between Arm A and Arm B in change in total or naive CD4 cells or percentage from baseline to week 24. Only one subject in Arm A met the primary endpoint, an increase in naive CD4 percentage of at least 10 percentage points. By week 48 both Arms had statistically significant increases in naive CD4 cell count and percentage and thymus size. Within Arm B, treatment with rhGH was associated with significant increases in naive CD4+ cell count and percentage compared with ART alone. Treatment with rhGH +ART may be associated with modest increases in CD4 lymphocytes over ART alone in subjects with CD4 <350, yet the origin of these naive cells and their impact on immune function require further investigation
doi:10.1089/aid.2009.0052
PMCID: PMC2864047  PMID: 20415638
7.  HIV Tropism and Decreased Risk of Breast Cancer 
PLoS ONE  2010;5(12):e14349.
Background
During the first two decades of the U.S. AIDS epidemic, and unlike some malignancies, breast cancer risk was significantly lower for women with human immunodeficiency virus (HIV) infection compared to the general population. This deficit in HIV-associated breast cancer could not be attributed to differences in survival, immune deficiency, childbearing or other breast cancer risk factors. HIV infects mononuclear immune cells by binding to the CD4 molecule and to CCR5 or CXCR4 chemokine coreceptors. Neoplastic breast cells commonly express CXCR4 but not CCR5. In vitro, binding HIV envelope protein to CXCR4 has been shown to induce apoptosis of neoplastic breast cells. Based on these observations, we hypothesized that breast cancer risk would be lower among women with CXCR4-tropic HIV infection.
Methods and Findings
We conducted a breast cancer nested case-control study among women who participated in the WIHS and HERS HIV cohort studies with longitudinally collected risk factor data and plasma. Cases were HIV-infected women (mean age 46 years) who had stored plasma collected within 24 months of breast cancer diagnosis and an HIV viral load ≥500 copies/mL. Three HIV-infected control women, without breast cancer, were matched to each case based on age and plasma collection date. CXCR4-tropism was determined by a phenotypic tropism assay. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were estimated by exact conditional logistic regression. Two (9%) of 23 breast cancer cases had CXCR4-tropic HIV, compared to 19 (28%) of 69 matched controls. Breast cancer risk was significantly and independently reduced with CXCR4 tropism (adjusted odds ratio, 0.10, 95% CI 0.002–0.84) and with menopause (adjusted odds ratio, 0.08, 95% CI 0.001–0.83). Adjustment for CD4+ cell count, HIV viral load, and use of antiretroviral therapy did not attenuate the association between infection with CXCR4-tropic HIV and breast cancer.
Conclusions
Low breast cancer risk with HIV is specifically linked to CXCR4-using variants of HIV. These variants are thought to exclusively bind to and signal through a receptor that is commonly expressed on hyperplastic and neoplastic breast duct cells. Additional studies are needed to confirm these observations and to understand how CXCR4 might reduce breast cancer risk.
doi:10.1371/journal.pone.0014349
PMCID: PMC3002931  PMID: 21179547
8.  Growth hormone enhances thymic function in HIV-1–infected adults 
The Journal of Clinical Investigation  2008;118(3):1085-1098.
Growth hormone (GH) is an underappreciated but important regulator of T cell development that can reverse age-related declines in thymopoiesis in rodents. Here, we report findings of a prospective randomized study examining the effects of GH on the immune system of HIV-1–infected adults. GH treatment was associated with increased thymic mass. In addition, GH treatment enhanced thymic output, as measured by both the frequency of T cell receptor rearrangement excision circles in circulating T cells and the numbers of circulating naive and total CD4+ T cells. These findings provide compelling evidence that GH induces de novo T cell production and may, accordingly, facilitate CD4+ T cell recovery in HIV-1–infected adults. Further, these randomized, prospective data have shown that thymic involution can be pharmacologically reversed in humans, suggesting that immune-based therapies could be used to enhance thymopoiesis in immunodeficient individuals.
doi:10.1172/JCI32830
PMCID: PMC2248326  PMID: 18292808

Results 1-8 (8)