Participation of women in HIV clinical trials: the IPEC-FIOCRUZ experience

Jordan E Lake1, Ruth K Friedman2, Cynthia B Cunha2, Sandra W Cardoso2, Valdilea G Veloso2, Judith S Currier1, Beatriz Grinsztejn21Division of Infectious Diseases, University of California at Los Angeles, Los Angeles, CA, USA; 2Fundação Oswaldo Cruz – Instituto de Pesquisa Clínica Evandro Chagas/IPEC, Rio de Janeiro, State of Rio de Janeiro, BrazilBackground: Fifty percent of people living with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) worldwide are female. In Brazil, for example, 240,000 women are infected with HIV, rates of infection in women have increased over the last two decades, and addressing HIV prevention and treatment for women at risk for, or living with, HIV/AIDS remains a challenge. To better address the needs of women living with HIV in Brazil, the Instituto de Pesquisa Clínica Evandro Chagas – Fundação Oswaldo Cruz (IPEC-FIOCRUZ) HIV Women’s Cohort was established in 1996 to study the natural history of women seeking HIV care. This analysis describes the characteristics of women in the cohort who participated in HIV clinical trials between 1999 and 2008.Methods: A total of 736 Women’s Cohort participants were in active follow-up and 665 participants from the Women’s Cohort were included in univariable and multivariable analyses to determine socioeconomic and sociodemographic factors associated with women’s participation in HIV clinical trials at our site.Results: Of the complete cohort, 23% participated in a clinical trial between January 1999 and July 2008. Odds of participation decreased for women who were younger than 35 years old, currently employed, had an HIV-positive sexual partner, and/or who reported a lifetime history of illicit drug use. Alternatively, the odds of participation increased for women who had more than 8 years of formal education, were living independently, and/or were married or cohabitating.Conclusion: The rate of participation in HIV clinical trials by women in the IPEC-Fiocruz Cohort was similar to other published cohorts, but identification of local risk factors and barriers to participation remains important. Our analysis offers a novel description of the factors associated with participation in HIV clinical trials among women in care at IPEC-FIOCRUZ in Rio de Janeiro, Brazil.Keywords: AIDS, Brazil, South America, clinical trial participation&nbsp

Incidência e preditores de gestação em mulheres com HIV/Aids no Rio de Janeiro

OBJETIVO: Identificar incidencia y predictores de la primera gestación entre mujeres con VIH/Sida. MÉTODOS: Estudio prospectivo de cohorte conducido en Rio de Janeiro, Sureste de Brasil, entre 1996 y 2003. El estudio incluyó 225 mujeres acompañadas hasta la primera gestación o hasta el primer evento considerado censura (histerectomía, ligadura tubárica, menopausia, 50 años de edad, pérdida de acompañamiento, óbito o final de diciembre de 2003). Se estimaron las tasas de incidencia de gestación y de aborto, y se usaron modelos de riesgos proporcionales de Cox para identificar las características de la visita de inclusión asociadas con el riesgo de gestación. RESULTADOS: Las mujeres fueron acompañadas por 565 persona/años, con promedio de acompañamiento de 3 años por mujer. La edad promedio fue de 32 años (DP:7), y 54,7% eran blancas. Sesenta gestaciones fueron observadas en 39 mujeres y 18 resultaron en abortos inducidos (tasas de incidencia de 6,9% y 2,1% mujeres/año, respectivamente). Las gestaciones repetidas ocurrieron en 33,3% de las mujeres (13/39). Fue observado el mayor riesgo de gestación entre mujeres jóvenes (HR=3,42; IC 95%:1,69;6,95) y entre aquellas que vivían con sus parejas (HR=1,89; IC 95%: 1,00;3,57). El menor riesgo de gestación estuvo asociado a la mayor escolaridad (HR=0,43; IC95%:0,19;0,99) y al uso de terapia antirretroviral (HR=0,61; IC95%:0,31;1,17). CONCLUSIONES: La incidencia de gestación en la cohorte fue menor al compararse con aquella observada en la población general. Características sociodemográficas deben ser consideradas en el manejo de los deseos reproductivos de mujeres VIH-positivas en edad reproductiva. Los programas de VIH/SIDA deben incluir consejos reproductivos y contraceptivos para prevenir la transmisión del VIH para sus parejas y prole.OBJETIVO: Identificar incidência e preditores incidência da primeira gestação entre mulheres com HIV/Aids. MÉTODOS: Estudo prospectivo de coorte conduzido entre 1996 e 2003 no Rio de Janeiro, RJ, com 225 mulheres acompanhadas até a primeira gestação ou até o primeiro evento considerado censura (histerectomia, ligadura tubárea, menopausa, 50 anos de idade, perda de acompanhamento, óbito ou final de dezembro de 2003). Taxas de incidência de gestação e de aborto foram estimadas e modelos de riscos proporcionais de Cox foram usados para identificar as características da visita de inclusão associadas com o risco de gestação. RESULTADOS: As mulheres foram acompanhadas por 565 pessoas/ano, com média de acompanhamento de 3 anos por mulher. A idade média foi de 32 anos (DP: 7) e 54,7% eram brancas. Sessenta gestações foram observadas em 39 mulheres e 18 resultaram em abortos induzidos (taxas de incidência de 6,9% e 2,1% mulheres/ano, respectivamente). Gestações repetidas ocorreram em 33,3% das mulheres (13/39). Maior risco de gestação foi observado entre mulheres jovens (HR = 3,42; IC95%:1,69;6,95) e entre aquelas vivendo com seus parceiros (HR = 1,89; IC95%:1,00;3,57). Menor risco de gestação esteve associado à maior escolaridade (HR = 0,43; IC95%:0,19;0,99) e ao uso de terapia anti-retroviral (HR = 0,61; IC95%:0,31;1,17). CONCLUSÕES: A incidência de gestação na coorte foi menor se comparada àquela observada na população geral. Características sociodemográficas devem ser consideradas no manejo dos desejos reprodutivos de mulheres HIV-positivas em idade reprodutiva. Os programas de HIV/Aids devem incluir aconselhamento reprodutivo e contraceptivo para prevenir a transmissão do HIV para seus parceiros e prole.OBJECTIVE: To assess incidence and predictors of first pregnancy among women with HIV/AIDS. METHODS: Prospective cohort study was conducted in Rio de Janeiro, southeastern Brazil, between 1996 and 2003. This study comprised 225 women with HIV/AIDS followed up until their first pregnancy or first censored event (hysterectomy, tubal ligation, menopause, 50 years of age, loss to follow-up, death or the end of December 2003). Pregnancy and abortion rates were estimated, and Cox proportional hazards models were used to identify baseline characteristics associated with pregnancy risk. RESULTS: The women were followed up for 565 person/years with a median follow-up of 3 years per women. The mean age was 32 years (SD: 7), and 54.7% were white. There were 60 pregnancies in 39 women, and 18 were terminated (induced abortions), accounting for a rate of 6.9% and 2.1% women/year, respectively. Repeated pregnancies occurred in 33.3% of the women (13/39). Higher pregnancy risk was seen among younger women (HR=3.42; 95%CI: 1.69;6.95) and those living with their partners (HR=1.89; 95%CI: 1.00;3.57). Lower pregnancy risk was associated with higher education level (HR=0.43; 95%CI: 0.19;0.99) and use of antiretroviral therapy (HR=061; 95%CI: 0.31;1.17). CONCLUSIONS: Lower pregnancy rates were found in our cohort than in the general population. Sociodemographic characteristics should be taken into consideration in the management of reproductive health in HIV-positive childbearing age women. Reproductive and family planning counseling must be incorporated into HIV/AIDS programs for women to help preventing HIV transmission to their partners and offspring

C-Reactive Protein, Erythrocyte Sedimentation Rate and Orthopedic Implant Infection

BACKGROUND: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) have been shown to be useful for diagnosis of prosthetic hip and knee infection. Little information is available on CRP and ESR in patients undergoing revision or resection of shoulder arthroplasties or spine implants. METHODS/RESULTS: We analyzed preoperative CRP and ESR in 636 subjects who underwent knee (n=297), hip (n=221) or shoulder (n=64) arthroplasty, or spine implant (n=54) removal. A standardized definition of orthopedic implant-associated infection was applied. Receiver operating curve analysis was used to determine ideal cutoff values for differentiating infected from non-infected cases. ESR was significantly different in subjects with aseptic failure infection of knee (median 11 and 53.5 mm/h, respectively, p=<0.0001) and hip (median 11 and 30 mm/h, respectively, p=<0.0001) arthroplasties and spine implants (median 10 and 48.5 mm/h, respectively, p=0.0033), but not shoulder arthroplasties (median 10 and 9 mm/h, respectively, p=0.9883). Optimized ESR cutoffs for knee, hip and shoulder arthroplasties and spine implants were 19, 13, 26, and 45 mm/h, respectively. Using these cutoffs, sensitivity and specificity to detect infection were 89 and 74% for knee, 82 and 60% for hip, and 32 and 93% for shoulder arthroplasties, and 57 and 90% for spine implants. CRP was significantly different in subjects with aseptic failure and infection of knee (median 4 and 51 mg/l, respectively, p<0.0001), hip (median 3 and 18 mg/l, respectively, p<0.0001), and shoulder (median 3 and 10 mg/l, respectively, p=0.01) arthroplasties, and spine implants (median 3 and 20 mg/l, respectively, p=0.0011). Optimized CRP cutoffs for knee, hip, and shoulder arthroplasties, and spine implants were 14.5, 10.3, 7, and 4.6 mg/l, respectively. Using these cutoffs, sensitivity and specificity to detect infection were 79 and 88% for knee, 74 and 79% for hip, and 63 and 73% for shoulder arthroplasties, and 79 and 68% for spine implants. CONCLUSION: CRP and ESR have poor sensitivity for the diagnosis of shoulder implant infection. A CRP of 4.6 mg/l had a sensitivity of 79 and a specificity of 68% to detect infection of spine implants

HIV-1 and recombinant gp120 affect the survival and differentiation of human vessel wall-derived mesenchymal stem cells

BAckground:HIV infection elicits the onset of a progressive immunodeficiency and also damages several other organs and tissues such as the CNS, kidney, heart, blood vessels, adipose tissue and bone. In particular, HIV infection has been related to an increased incidence of cardiovascular diseases and derangement in the structure of blood vessels in the absence of classical risk factors. The recent characterization of multipotent mesenchymal cells in the vascular wall, involved in regulating cellular homeostasis, suggests that these cells may be considered a target of HIV pathogenesis. This paper investigated the interaction between HIV-1 and vascular wall resident human mesenchymal stem cells (MSCs). RESULTS: MSCs were challenged with classical R5 and X4 HIV-1 laboratory strains demonstrating that these strains are able to enter and integrate their retro-transcribed proviral DNA in the host cell genome. Subsequent experiments indicated that HIV-1 strains and recombinant gp120 elicited a reliable increase in apoptosis in sub-confluent MSCs. Since vascular wall MSCs are multipotent cells that may be differentiated towards several cell lineages, we challenged HIV-1 strains and gp120 on MSCs differentiated to adipogenesis and endotheliogenesis. Our experiments showed that the adipogenesis is increased especially by upregulated PPAR\u3b3 activity whereas the endothelial differentiation induced by VEGF treatment was impaired with a downregulation of endothelial markers such as vWF, Flt-1 and KDR expression. These viral effects in MSC survival and adipogenic or endothelial differentiation were tackled by CD4 blockade suggesting an important role of CD4/gp120 interaction in this context. CONCLUSIONS: The HIV-related derangement of MSC survival and differentiation may suggest a direct role of HIV infection and gp120 in impaired vessel homeostasis and in genesis of vessel damage observed in HIV-infected patients

Secondary Prevention of Suicide

Leo Sher and colleagues discuss recent research on interventions to prevent secondary suicide and discuss the additional research that is needed

Substituting abacavir for hyperlipidemia-associated protease inhibitors in HAART regimens improves fasting lipid profiles, maintains virologic suppression, and simplifies treatment

BACKGROUND: Hyperlipidemia secondary to protease inhibitors (PI) may abate by switching to anti-HIV medications without lipid effects. METHOD: An open-label, randomized pilot study compared changes in fasting lipids and HIV-1 RNA in 104 HIV-infected adults with PI-associated hyperlipidemia (fasting serum total cholesterol >200 mg/dL) who were randomized either to a regimen in which their PI was replaced by abacavir 300 mg twice daily (n = 52) or a regimen in which their PI was continued (n = 52) for 28 weeks. All patients had undetectable viral loads (HIV-1 RNA <50 copies/mL) at baseline and were naïve to abacavir and non-nucleoside reverse transcriptase inhibitors. RESULTS: At baseline, the mean total cholesterol was 243 mg/dL, low density lipoprotein (LDL)-cholesterol 149 mg/dL, high density lipoprotein (HDL)-cholesterol 41 mg/dL, and triglycerides 310 mg/dL. Mean CD4+ cell counts were 551 and 531 cells/mm(3 )in the abacavir-switch and PI-continuation arms, respectively. At week 28, the abacavir-switch arm had significantly greater least square mean reduction from baseline in total cholesterol (-42 vs -10 mg/dL, P < 0.001), LDL-cholesterol (-14 vs +5 mg/dL, P = 0.016), and triglycerides (-134 vs -36 mg/dL, P = 0.019) than the PI-continuation arm, with no differences in HDL-cholesterol (+0.2 vs +1.3 mg/dL, P = 0.583). A higher proportion of patients in the abacavir-switch arm had decreases in protocol-defined total cholesterol and triglyceride toxicity grades, whereas a smaller proportion had increases in these toxicity grades. At week 28, an intent-to treat: missing = failure analysis showed that the abacavir-switch and PI-continuation arms did not differ significantly with respect to proportion of patients maintaining HIV-1 RNA <400 or <50 copies/mL or adjusted mean change from baseline in CD4+ cell count. Two possible abacavir-related hypersensitivity reactions were reported. No significant changes in glucose, insulin, insulin resistance, C-peptide, or waist-to-hip ratios were observed in either treatment arm, nor were differences in these parameters noted between treatments. CONCLUSION: In hyperlipidemic, antiretroviral-experienced patients with HIV-1 RNA levels <50 copies/mL and CD4+ cell counts >500 cells/mm(3), substituting abacavir for hyperlipidemia-associated PIs in combination antiretroviral regimens improves lipid profiles and maintains virologic suppression over a 28-week period, and it simplifies treatment

Myocarditis in CD8-Depleted SIV-Infected Rhesus Macaques after Short-Term Dual Therapy with Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Background: Although highly active antiretroviral therapy (HAART) has dramatically reduced the morbidity and mortality associated with HIV infection, a number of antiretroviral toxicities have been described, including myocardial toxicity resulting from the use of nucleotide and nucleoside reverse transcriptase inhibitors (NRTIs). Current treatment guidelines recommend the use of HAART regimens containing two NRTIs for initial therapy of HIV-1 positive individuals; however, potential cardiotoxicity resulting from treatment with multiple NRTIs has not been addressed. Methodology/Principal Findings: We examined myocardial tissue from twelve CD8 lymphocyte-depleted adult rhesus macaques, including eight animals infected with simian immunodeficiency virus, four of which received combined antiretroviral therapy (CART) consisting of two NRTIs [(9-R-2-Phosphonomethoxypropyl Adenine) (PMPA) and (+/−)-beta-2′,3′-dideoxy-5-fluoro-3′-thiacytidine (RCV)] for 28 days. Multifocal infiltrates of mononuclear inflammatory cells were present in the myocardium of all macaques that received CART, but not untreated SIV-positive animals or SIV-negative controls. Macrophages were the predominant inflammatory cells within lesions, as shown by immunoreactivity for the macrophage markers Iba1 and CD68. Heart specimens from monkeys that received CART had significantly lower virus burdens than untreated animals (p<0.05), but significantly greater quantities of TNF-α mRNA than either SIV-positive untreated animals or uninfected controls (p<0.05). Interferon-γ (IFN-γ), IL-1β and CXCL11 mRNA were upregulated in heart tissue from SIV-positive monkeys, independent of antiretroviral treatment, but CXCL9 mRNA was only upregulated in heart tissue from macaques that received CART. Conclusions/Significance: These results suggest that short-term treatment with multiple NRTIs may be associated with myocarditis, and demonstrate that the CD8-depleted SIV-positive rhesus monkey is a useful model for studying the cardiotoxic effects of combined antiretroviral therapy in the setting of immunodeficiency virus infection

Patient and surgery related factors associated with fatigue type polyethylene wear on 49 PCA and DURACON retrievals at autopsy and revision

<p>Abstract</p> <p>Background</p> <p>Polyethylene wear is an important factor for longevity of total knee arthroplasty. Proven and suspicious factors causing wear can be grouped as material, patient and surgery related. There are more studies correlating design and/or biomaterial factors to in vivo wear than those to patient and surgery related factors. Many retrieval studies just include revision implants and therefore may not be representative. This study is aimed to correlate patient- and surgery- related factors to visual wear score by minimizing design influence and include both autopsy and revision implants. Comparison between the groups was expected to unmask patient and surgery-related factors responsible for wear.</p> <p>Methods</p> <p>The amount of joint side wear on polyethylene retrievals was measured using a modification of an established visual wear score. Fatigue type wear was defined as summation of the most severe wear modes of delamination, pitting and cracks. Analysis of patient and surgery related variables suspicious to cause wear included prospectively sampled patient activity which was measured by self reported walking capacity. Statistical analysis was done by univariate analysis of variance. Activity level and implantation time were merged to an index of use and correlated to the wear score.</p> <p>Results</p> <p>Wear score after comparable implantation time was significantly less in the autopsy group. Even so, fatigue type wear accounted for 84 and 93 % of total wear score on autopsy and revision implants respectively. A highly significant influence on wear score was found in time of implantation (p = 0.002), level of activity (p = 0.025) and inserts belonging to revision group (p = 0.006). No influence was found for the kind of patella replacement (p = 0.483). Body mass index and accuracy of component alignment had no significant influence on visual wear score. Fatigue-type wear in the medial compartment was closely correlated to the index of use in the autopsy (R²= 0.383) and the revision group (R²= 0.813).</p> <p>Conclusion</p> <p>The present study's finding of substantial fatigue type wear in both autopsy and revision retrievals supports the theory that polyethylene fatigue strength is generally exceeded in this type of prosthesis. Furthermore, this study correlated fatigue-type polyethylene wear to an index of use as calculated by activity over time. Future retrieval studies may use activity over time as an important patient related factor correlated to the visual wear score. When evaluating total knee arthroplasty routine follow up, the surgeon must think of substantial wear present even without major clinical signs.</p

The Role of Natural Killer (NK) Cells and NK Cell Receptor Polymorphisms in the Assessment of HIV-1 Neutralization

The importance of innate immune cells in HIV-1 pathogenesis and protection has been highlighted by the role of natural killer (NK) cells in the containment of viral replication. Use of peripheral blood mononuclear cells (PBMC) in immunologic studies provides both HIV-1 target cells (ie. CD4+ T cells), as well as anti-HIV-1 effector cells, such as NK cells. In this study, NK and other immune cell populations were analyzed in HIV-negative donor PBMC for an impact on the anti-HIV activity of polyclonal and monoclonal antibodies. NK cell percentages were significantly higher in donor PBMC that supported lower levels of viral replication. While the percentage of NK cells was not directly associated with neutralization titers, NK cell-depletion significantly diminished the antiviral antibody activity by up to three logs, and polymorphisms in NK killer immunoglobulin receptor (KIR) and FcγRIIIa alleles appear to be associated with this affect. These findings demonstrate that NK cells and NK cell receptor polymorphisms may influence assessment of traditional HIV-1 neutralization in a platform where antibody is continuously present. This format appears to simultaneously assess conventional entry inhibition (neutralization) and non-neutralizing antibody-dependent HIV inhibition, which may provide the opportunity to delineate the dominant antibody function(s) in polyclonal vaccine responses