Safety and immunovirologic outcomes with maraviroc combination regimens in patients with a history of past treatment failures and virologic resistance in Brazil: an open-label, multicenter phase 3b study.

Maraviroc is a first-in-class chemokine coreceptor type-5 (CCR5) antagonist with demonstrated immunovirologic activity in treatment-experienced (TE) patients with CCR5 (R5)-tropic HIV-1; however, experience in regimens containing newer antiretroviral agents is limited. The primary objective of this 96-week open-label, noncomparative, multicenter Phase 3b study (NCT00478231) was to assess the safety of maraviroc in combination with optimized background therapy (OBT), which could include recently introduced agents such as darunavir and raltegravir in TE patients in Brazil with R5 HIV-1 and limited therapeutic options. Immunovirologic activity was a secondary endpoint. Of 638 patients screened, 206 were treated and 125 completed the study. Approximately 70% were male; the mean age was 43.2 years. Most patients (65.0%) received an OBT combination of protease inhibitor plus nucleoside reverse transcriptase inhibitor. Adverse event (AE) and treatment-related AE incidence was 91.3% and 36.9%, respectively. The most common AEs were diarrhea, nasopharyngitis, and headache. Serious AEs and treatment-related serious AEs occurred in 16.5% and 4.4% of patients. Only eight patients (3.9%) discontinued due to AEs. Few AIDS-defining events were observed (4.9%). The proportion of patients with viral load <400 copies/ml increased from 2.4% at baseline to 43.9% at week 8, remaining >40% until week 48. At the end of treatment, 26.7% of patients had a viral load <400 copies/ml. Median CD4(+) cell count increased throughout the study; the mean change from baseline to end of treatment was 174.1 cells/µl. In conclusion, maraviroc, combined with different agents from multiple classes, was well tolerated in highly TE patients. Maraviroc plus OBT was associated with an immunovirologic response in this population.

Imbalance between endothelial progenitors cells and microparticles in HIV-infected patients naive for antiretroviral therapy.

BACKGROUND: Cardiovascular events have been reported among HIV-infected patients following antiretroviral therapy. However, the role of HIV itself in determining vascular damage is less described. Chronic inflammatory state might impair some regulatory endothelium properties leading to its activation, apoptosis or erosion. OBJECTIVES: To evaluate the balance between endothelial progenitor cells and microparticles in HIV-infected antiretroviral drug-naive patients. DESIGN: A case-control study comparing HIV-infected patients (n = 35) with sex-matched and age-matched healthy controls (n = 33). METHODS: Endothelial progenitor cells populations expressing CD34, CD133 and KDR were quantified by flow cytometry. Endothelial-derived microparticles, expressing CD51, and platelet-derived microparticles, expressing CD31/CD42, were also measured. Endothelial function was estimated by flow-mediated dilation. RESULTS: Lower percentages of endothelial progenitor cells (CD34/KDR) were observed in HIV-infected individuals compared with controls (0.02 vs. 0.09%, P = 0.045). In addition, endothelial microparticles concentration was higher in HIV-infected individuals (1963 vs. 436 microparticles/µl platelet-poor plasma, P = 0.003), with similar number of platelet-derived microparticles among groups. Furthermore, flow-mediated dilation was lower among HIV-infected individuals compared with controls [mean (SEM): 10 (1) and 16% (2), respectively; P = 0.03]. CONCLUSION: Our findings suggest an imbalance between endothelial progenitor cells mobilization and endothelial apoptosis. The alteration in the turnover of endothelial cells may contribute to cardiovascular events in HIV-infected patients.

Primary antiretroviral drug resistance among HIV type 1-infected individuals in Brazil.

Infection with drug-resistant human immunodeficiency virus type 1 (HIV-1) has been documented in all countries that have surveyed for it and may result in an unfavorable response to therapy. The prevalence and characteristics of individuals with transmitted resistance to antiretroviral drugs have been scarcely described in Brazil. We performed antiretroviral resistance testing prior to initiation of therapy in 400 subjects enrolled from 20 centers in 13 Brazilian cities between March and September 2007. Genotyping was conducted using PCR-amplified HIV pol products by automated sequencing, and genotype interpretation was done according to the IAS-USA consensus. Of 400 eligible participants, 387 (95.8%) were successfully tested. Seven percent of antiretroviral-naive patients carried viruses with one or more major mutation associated with drug resistance. The prevalence of these mutations was 1.0% for protease inhibitors, 4.4% for nonnucleoside reverse transcriptase inhibitors, and 1.3% for nucleoside reverse transcriptase inhibitors. The frequency of multidrug resistance among the resistant strains was 13.6%. Among subjects infected with drug-resistant virus, the majority were infected with subtype B viruses (91%). Subjects from the city of São Paulo had higher transmitted resistance mutations compared to the rest of the country. Reporting a partner taking antiretroviral medications was associated with a higher chance of harboring HIV variants with major drug resistance mutations [odds ratio = 2.57 (95% confidence interval, 1.07-6.16); p = 0.014]. Resistance testing in drug-naive individuals identified 7% of subjects with mutations associated with reduced susceptibility to antiretroviral drugs. Continued surveillance of drug-resistant HIV-1 in Brazil is warranted when guidelines for HIV prophylaxis and treatment are updated. Resistance testing among drug-naive patients prior to treatment initiation should be considered, mainly directed at subjects whose partners are already on antiretroviral therapy.

Dinamica Viral do Subtipo B do HIV-1 Brasileiro / Viral Dinamic Of Brazilian HIV-1 Subtype B

Analises do comportamento da viremia plasmatica apos a introducao de esquemas terapeuticos contendo associacoes de drogas potentes tem sido alvo de estudos, os quais conduziram a importantes informacoes sobre o comportamento do HIV-1 quando exposto a estas drogas. Nesta pesquisa, foram avaliados dez pacientes infectados pelo subtipo B brasileiro, nunca expostos a drogas anti-retrovirais, com o objetivo de avaliar possiveis diferencas na resposta virologica dos mesmos em comparacao aos estudos publicados anteriormente, os quais avaliaram o subtipo B americano. Usou-se o esquema terapeutico mais potente disponivel no momento do estudo, baseados em dados mais recentes de avaliacao da supressao viral, tendo como resultado curvas de decaimento estremamente semelhantes aos resultados de estudos previamente publicados, com queda importante destas particulas virais nas primeiras duas semanas de tratamento, correspondendo a eliminacao de particulas virus livres e a perda de celulas produtivamente infectadas, com valor medio de decaimento de 2,51logs na maioria dos pacientes estudados, seguidos por um declinio mais lento, correspondendo a manutencao da eliminacao de virions pelos reservatorios virais. Conclui-se com este estudo, o ja comprovado anteriormente, que esquemas mais potentes causam declinios mais rapidos da viremia plasmatica devido a acao destes nos compartimentos infectados pelo HIV-1.

Insuficiência adrenocortical em pacientes com síndrome de imunodeficiência adquirida (AIDS)

Pacientes com AIDS apresentam-se com perda de peso, diarréia, hipotensäo, hiponatremia, hipoglicemia e outras alteraçöes laboratoriais devidas a infecçöes oportunistas, que säo semelhantes àquelas encontradas na insuficiência adrenocortical primária (doença de Addison). Para avaliar a reserva glicocorticóide adrenal, medimos os níveis plamáticos de cortisol antes e 60min após estímulo com ACTH (250 g IV em bolo) em 28 pacientes com AIDS (todos sintomáticos), em 5 com linfadenopatia generalizada persistente (PGL), em 10 com outras doenças debilitantes (näo-AIDS) e em 32 indivíduos normais. Estudo histopatológico adrenal foi realizado em 17 pacientes com AIDS que vieram a falecer. Os limites críticos inferiores (95% de confiança) para o cortisol estimulado (pós-ACTH) e para o seu incremento absoluto foram respectivamente de: 18,4 microng/dl e 8,9 microng/dl. Assim, 5 (18%) dos pacientes com AIDS apresentaram ambos os valores abaixo dos níveis críticos (13,4 ñ 3,0 microng/dl e 0,6 ñ 1,8 micron/dl (X ñ DPM), respectivamente. Todos os 5 apresentaram necrose adrenocortical extensa à autópsia (2 também apresentaram inclusäo por citomegalovírus e 1 por Cryptococcus neoformans). A sensibilidade e a especificidade do teste rápido de estímulo com ACTH (considerando-se resposta positiva um valor do cortisol pós-ACTH >= estímulo com ACTH (considerando-se resposta positiva um valor do cortisol pós/ACTH >= 18,4 microng/dl) quando comparadas à presença ou ausência de necrose extensa foram de 71,4% e 100%, respectivamente. Nenhum dos pacientes com PGL ou doença debilitante näo AIDS tiveram resposta diminuida do cortisol ao estímulo com ACTH...