RESUMO
OBJECTIVES: The Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding. METHODS: MARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < -12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints. RESULTS: Eighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms. CONCLUSIONS: MVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks.
Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Antagonistas dos Receptores CCR5/administração & dosagem , Cicloexanos/administração & dosagem , Substituição de Medicamentos , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Triazóis/administração & dosagem , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Antagonistas dos Receptores CCR5/efeitos adversos , Cicloexanos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Inibidores da Protease de HIV/efeitos adversos , HIV-1/isolamento & purificação , Humanos , Maraviroc , RNA Viral/sangue , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do Tratamento , Triazóis/efeitos adversos , Carga ViralRESUMO
OBJECTIVES: Life expectancy is an important indicator informing decision making in policies relating to HIV-infected people. Studies estimating life expectancy after starting combination antiretroviral therapy (cART) have noted differences between income regions. The objective of our study was to perform a meta-analysis to assess life expectancy of HIV-positive people after starting cART, and to quantify differences between low/middle- and high-income countries. METHODS: Eight cohort studies estimating life expectancy in HIV-positive people initiating cART aged ≥ 14 years using the abridged life table method were identified. Random effects meta-analysis was used to pool estimated outcomes, overall and by income region. Heterogeneity between studies was assessed with the I2 statistic. We estimated additional years of life expected after starting cART at ages 20 and 35 years. RESULTS: Overall life expectancy in high-income countries was an additional 43.3 years [95% confidence interval (CI) 42.5-44.2 years] and 32.2 years (95% CI 30.9-33.5 years) at ages 20 and 35 years, respectively, and 28.3 (95% CI 23.3-33.3) and 25.6 (95% CI 22.1-29.2) additional years, respectively, in low/middle-income countries. In low/middle-income countries, life expectancy after starting cART at age 20 years was an additional 22.9 years (95% CI 18.4-27.5 years) for men and 33.0 years (95% CI 30.4-35.6 years) for women, but was similar in the two sexes in high-income countries. In all income regions, life expectancy after starting cART increased over calendar time. CONCLUSIONS: Our results suggest that the life expectancy of HIV-positive people after starting cART has improved over time. Monitoring life expectancy into the future is important to assess how changes to cART guidelines will affect patient long-term outcomes.
Assuntos
Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Expectativa de Vida , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Adulto JovemRESUMO
Data on markers of hepatitis C virus (HCV) disease in HIV-HCV-coinfected patients in resource-limited settings are scarce. We assessed HCV RNA, HCV genotype (GT), IL28B GT and liver fibrosis (FibroScan® ) in 480 HIV-infected patients with positive HCV antibody in four HIV treatment centres in South-East Asia. We enrolled 165 (34.4%) patients in Jakarta, 158 (32.9%) in Bangkok, 110 (22.9%) in Hanoi and 47 (9.8%) in Kuala Lumpur. Overall, 426 (88.8%) were male, the median (IQR) age was 38.1 (34.7-42.5) years, 365 (76.0%) reported HCV exposure through injecting drug use, and 453 (94.4%) were on combination antiretroviral therapy. The median (IQR) CD4 count was 446 (325-614) cells/mm3 and 208 (94.1%) of 221 patients tested had HIV-1 RNA <400 copies/mL. A total of 412 (85.8%) had detectable HCV RNA, at a median (IQR) of 6.2 (5.4-6.6) log10 IU/mL. Among 380 patients with HCV GT, 223 (58.7%) had GT1, 97 (25.5%) had GT3, 43 (11.3%) had GT6, eight (2.1%) had GT4, two (0.5%) had GT2, and seven (1.8%) had indeterminate GT. Of 222 patients with IL28B testing, 189 (85.1%) had rs12979860 CC genotype, and 199 (89.6%) had rs8099917 TT genotype. Of 380 patients with FibroScan® , 143 (37.6%) had no/mild liver fibrosis (F0-F1), 83 (21.8%) had moderate fibrosis (F2), 74 (19.5%) had severe fibrosis (F3), and 79 (20.8%) had cirrhosis (F4). One patient (0.3%) had FibroScan® failure. In conclusion, a high proportion of HIV-HCV-coinfected patients had chronic HCV infection. HCV GT1 was predominant, and 62% of patients had liver disease warranting prompt treatment (≥F2).
Assuntos
Coinfecção/complicações , Coinfecção/patologia , Infecções por HIV/complicações , Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Cirrose Hepática/patologia , Adulto , Alelos , Sudeste Asiático/epidemiologia , Contagem de Linfócito CD4 , Coinfecção/epidemiologia , Coinfecção/virologia , Feminino , Genótipo , Infecções por HIV/epidemiologia , Hepacivirus/classificação , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Anticorpos Anti-Hepatite C/sangue , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/virologia , Humanos , Interferons , Interleucinas/genética , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Carga ViralRESUMO
BACKGROUND: The involvement of B cells in allergen tolerance induction remains largely unexplored. This study investigates the role of B cells in this process, by comparing B-cell responses in allergic patients before and during allergen immunotherapy (AIT) and naturally exposed healthy beekeepers before and during the beekeeping season. METHODS: Circulating B cells were characterized by flow cytometry. Phospholipase A2 (PLA)-specific B cells were identified using dual-color staining with fluorescently labeled PLA. Expression of regulatory B-cell-associated surface markers, interleukin-10, chemokine receptors, and immunoglobulin heavy-chain isotypes, was measured. Specific and total IgG1, IgG4, IgA, and IgE from plasma as well as culture supernatants of PLA-specific cells were measured by ELISA. RESULTS: Strikingly, similar responses were observed in allergic patients and beekeepers after venom exposure. Both groups showed increased frequencies of plasmablasts, PLA-specific memory B cells, and IL-10-secreting CD73- CD25+ CD71+ BR 1 cells. Phospholipase A2-specific IgG4-switched memory B cells expanded after bee venom exposure. Interestingly, PLA-specific B cells showed increased CCR5 expression after high-dose allergen exposure while CXCR4, CXCR5, CCR6, and CCR7 expression remained unaffected. CONCLUSIONS: This study provides the first detailed characterization of allergen-specific B cells before and after bee venom tolerance induction. The observed B-cell responses in both venom immunotherapy-treated patients and naturally exposed beekeepers suggest a similar functional immunoregulatory role for B cells in allergen tolerance in both groups. These findings can be investigated in other AIT models to determine their potential as biomarkers of early and successful AIT responses.
Assuntos
Alérgenos/imunologia , Linfócitos B/imunologia , Venenos de Abelha/imunologia , Relação Dose-Resposta Imunológica , Exposição Ambiental/efeitos adversos , Hipersensibilidade/imunologia , Tolerância Imunológica , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Biomarcadores , Citocinas/biossíntese , Dessensibilização Imunológica/métodos , Humanos , Hipersensibilidade/metabolismo , Hipersensibilidade/terapia , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunofenotipagem , Ativação Linfocitária/imunologia , Exposição Ocupacional , Fosfolipases A2/metabolismoRESUMO
OBJECTIVES: The aim of the study was to assess the prevalence and characteristics associated with current smoking in an Asian HIV-positive cohort, to calculate the predictive risks of cardiovascular disease (CVD), coronary heart disease (CHD) and myocardial infarction (MI), and to identify the impact that simulated interventions may have. METHODS: Logistic regression analysis was used to distinguish associated current smoking characteristics. Five-year predictive risks of CVD, CHD and MI and the impact of simulated interventions were calculated utilizing the Data Collection on Adverse Effects of Anti-HIV Drugs Study (D:A:D) algorithm. RESULTS: Smoking status data were collected from 4274 participants and 1496 of these had sufficient data for simulated intervention calculations. Current smoking prevalence in these two groups was similar (23.2% vs. 19.9%, respectively). Characteristics associated with current smoking included age > 50 years compared with 30-39 years [odds ratio (OR) 0.65; 95% confidence interval (CI) 0.51-0.83], HIV exposure through injecting drug use compared with heterosexual exposure (OR 3.03; 95% CI 2.25-4.07), and receiving antiretroviral therapy (ART) at study sites in Singapore, South Korea, Malaysia, Japan and Vietnam in comparison to Thailand (all OR > 2). Women were less likely to smoke than men (OR 0.11; 95% CI 0.08-0.14). In simulated interventions, smoking cessation demonstrated the greatest impact in reducing CVD and CHD risk and closely approximated the impact of switching from abacavir to an alternate antiretroviral in the reduction of 5-year MI risk. CONCLUSIONS: Multiple interventions could reduce CVD, CHD and MI risk in Asian HIV-positive patients, with smoking cessation potentially being the most influential.
Assuntos
Doenças Cardiovasculares/epidemiologia , Infecções por HIV/complicações , Fumar/efeitos adversos , Fumar/epidemiologia , Adulto , Ásia/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de RiscoRESUMO
BACKGROUND: The house dust mite (HDM) allergen Der p 13 could be a lipid-binding protein able to activate key innate signaling pathways in the initiation of the allergic response. We investigated the IgE reactivity of recombinant Der p 13 (rDer p 13), its lipid-binding activities, and its capacity to stimulate airway epithelium cells. METHODS: Purified rDer p 13 was characterized by mass spectrometry, circular dichroism, fluorescence-based lipid-binding assays, and in silico structural prediction. IgE-binding activity and allergenic potential of Der p 13 were examined by ELISA, basophil degranulation assays, and in vitro airway epithelial cell activation assays. RESULTS: Protein modeling and biophysical analysis indicated that Der p 13 adopts a ß-barrel structure with a predominately apolar pocket representing a potential binding site for hydrophobic ligands. Fluorescent lipid-binding assays confirmed that the protein is highly selective for ligands and that it binds a fatty acid with a dissociation constant typical of lipid transporter proteins. The low IgE-binding frequency (7%, n = 224) in Thai HDM-allergic patients as well as the limited propensity to activate basophil degranulation classifies Der p 13 as a minor HDM allergen. Nevertheless, the protein with its presumptively associated lipid(s) triggered the production of IL-8 and GM-CSF in respiratory epithelial cells through a TLR2-, MyD88-, NF-kB-, and MAPK-dependent signaling pathway. CONCLUSIONS: Although a minor allergen, Der p 13 may, through its lipid-binding capacity, play a role in the initiation of the HDM-allergic response through TLR2 activation.
Assuntos
Alérgenos/imunologia , Antígenos de Dermatophagoides/imunologia , Antígenos de Dermatophagoides/metabolismo , Proteínas de Ligação a Ácido Graxo/imunologia , Proteínas de Ligação a Ácido Graxo/metabolismo , Imunidade Inata , Receptor 2 Toll-Like/metabolismo , Animais , Antígenos de Dermatophagoides/química , Basófilos/imunologia , Basófilos/metabolismo , Proteínas de Transporte/metabolismo , Degranulação Celular/imunologia , Dermatophagoides pteronyssinus/imunologia , Proteínas de Ligação a Ácido Graxo/química , Humanos , Imunoglobulina E/imunologia , Metabolismo dos Lipídeos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Receptor 2 Toll-Like/agonistasRESUMO
BACKGROUND: The immunomodulatory nutritional product NR100157 was developed for human immunodeficiency virus (HIV)-infected individuals. We hypothesized that targeting the compromised gastrointestinal tract of HIV-infected individuals would result in systemic immunological benefits. METHODS: In a multicenter, randomized, controlled, double-blind trial, 340 HIV-1-positive adults not on antiretroviral therapy, with CD4(+) T-cell counts <800/µL, were given either NR100157 or an isocaloric and isonitrogenous control for 52 weeks. Primary outcome was CD4(+) T-cell count. Secondary outcomes included plasma viral load (pVL), safety, and tolerability. In a pilot study (n = 20), levels of CD4(+)CD25(+) and CD8(+)CD38(+) activation were measured (n = 20). The trial is registered at the Dutch Trial Register (NTR886) and ISRCTN81868024. RESULTS: At 52 weeks, CD4(+) T-cell decline showed a 40-cell/µL difference (P = .03) in the intention-to-treat population in favor of the immunomodulatory NR100157 (control vs active, -68 ± 15 vs -28 ± 16 cells/µL/year). The change in pVL from baseline was similar between groups (P = .81). In the pilot study, the percentage of CD4(+)CD25(+) was lower in the active group (P < .05) and correlated with changes in CD4(+) T-cell count (r = -0.55, P < .05). The percentage of CD8(+)CD38(+) levels was unaffected. CONCLUSIONS: The specific immunonutritional product NR100157 significantly reduces CD4(+) decline in HIV-1-infected individuals, and this is associated with decreased levels of CD4(+)CD25(+). (This nutritional intervention is likely to affect local gut integrity and gut-associated lymphoid tissue homeostasis, which in turn translates positively to systemic effects.) Clinical Trials Registration. ISRCTN81868024.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Dieta/métodos , Infecções por HIV/imunologia , Infecções por HIV/terapia , Fatores Imunológicos/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , Dieta/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Países Baixos , Plasma/virologia , Resultado do Tratamento , Carga ViralRESUMO
OBJECTIVES: The mechanism of raltegravir (RAL)-resistant evolutions has not already been elucidated. Because the emergence of RAL resistance is usually initiated by the N155H mutant, we assessed the role of minor N155H-mutated variants in circulating RNA and archived DNA in five heavily treated patients experiencing long-term RAL therapy failure and harbouring three different resistance profiles determined by standard genotyping. METHODS: Allele-specific polymerase chain reaction (AS-PCR) was used to detect N155H mutants in longitudinal stored plasma and whole-blood samples before, during and after RAL-based regimens in five patients infected with the HIV-1 B subtype. RESULTS: No minor N155H-mutated variant was found by AS-PCR in either plasma or whole-blood samples collected at baseline and after RAL withdrawal in any of the five patients. During RAL failure, the mutation N155H was detected at different levels in three patients displaying the N155H pathway and gradually declined when the double mutant Q148H+G140S was selected in one patient. In two patients with the Q148H resistance pathway, no N155H variant was identified by AS-PCR in either viral RNA or DNA. CONCLUSIONS: The N155H mutation present at various levels from minority to majority showed no relationship with the three RAL-associated resistance profiles, suggesting that this mutant may not play a role in determining different resistance profiles. Moreover, pre-existing N155H is very infrequent and, if selected during RAL failure, the N155H mutant disappears quickly after RAL withdrawal.
Assuntos
Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Pirrolidinonas/farmacologia , Contagem de Linfócito CD4 , Farmacorresistência Viral/genética , Feminino , Genótipo , Infecções por HIV/genética , Infecções por HIV/imunologia , Integrase de HIV/genética , Integrase de HIV/imunologia , HIV-1/enzimologia , Humanos , Estudos Longitudinais , Masculino , RNA Viral , Raltegravir Potássico , Estudos Retrospectivos , Terapia de Salvação , Análise de Sequência de RNA , Falha de Tratamento , Carga ViralRESUMO
BACKGROUND: The oral provocation test (OPT) is the current gold standard to diagnose aspirin hypersensitivity syndrome although it is time-consuming and contains some systemic risks. Other reliable methods with lower side effects and shorter test duration are being investigated. OBJECTIVE: The purpose of this study was to evaluate the efficacy of the nasal provocation test (NPT) and the basophil activation test (BAT) in the diagnosis of different subtypes of aspirin sensitivity. METHODS: Thirty aspirin sensitivity patients with cutaneous and respiratory manifestations underwent NPT and BAT with lysine-ASA. NPT result was interpreted as recommended in EAACI/GA2LEN guidelines and receiver operating characteristic analysis of BAT was performed by using 15 NSAIDs tolerant volunteers as a control group. RESULTS: NPT was positive in 60% (18/30) of patients and BAT was positive in 76.7% (23/30) of patients. The incubation of basophils with 0.31 mg/ml of lysine-aspirin and using 4.6% activated basophils gives the best predictive values to diagnose aspirin sensitivity. The combination of both tests yielded positive results in 80% and 93.3% of aspirin-induced cutaneous and respiratory patterns. The agreement between NPT and BAT results was 63.3%. CONCLUSIONS: NPT and BAT are beneficial to detect patients with aspirin sensitivity. The combination of both tests have additional diagnostic values; less time-consuming than OPT and their complications are negligible. A reliable alternative method with minimum side effects is needed to diagnose aspirin sensitivity in suspected patients who have contraindications for OPT.
Assuntos
Asma Induzida por Aspirina/diagnóstico , Teste de Degranulação de Basófilos , Testes de Provocação Nasal , Adolescente , Adulto , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/imunologia , Aspirina/efeitos adversos , Aspirina/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Método Simples-Cego , Adulto JovemRESUMO
OBJECTIVE: There is growing concern regarding cardiovascular disease in HIV-infected individuals in developing countries such as Thailand. We evaluated the 10-year risk of coronary heart disease (CHD) in a Thai HIV-infected cohort using three cardiovascular risk equations, and assessed the level of agreement among their predictions. METHODS: We carried out a cross-sectional analysis of data on 785 Thai subjects followed prospectively in the HIV Netherlands Australia Thailand Collaboration (HIV-NAT) cohort study from 1996 to 2009. Cardiovascular risk factor history, along with relevant laboratory and clinical data, was collected at follow-up clinic visits. Ten-year risks of CHD were calculated using the Framingham, Ramathibodi-Electricity Generating Authority of Thailand (Rama-EGAT) and Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) risk equations. RESULTS: The mean age of the patients was 41.0 years; 55% of the subjects were male. The mean duration of antiretroviral therapy was 7.7 years. The prevalence of cardiovascular risk factors was low, with the most common risk factor being low high-density lipoprotein (HDL) (36.3%). The prevalence of high cardiovascular risk scores (defined as 10-year risk of CHD≥10%) was also low: 9.9, 2.1 and 0.8%, by the Framingham, Rama-EGAT and D:A:D scoring systems, respectively. Only eight subjects (1.0%) had a history of CHD. Bland-Altman plots showed that the Framingham equation predicted a higher risk of CVD compared with the Rama-EGAT and D:A:D equations, which agreed relatively well. CONCLUSION: The predicted cardiovascular risk in this HIV-infected Thai cohort was relatively low. The agreement among the Rama-EGAT and D:A:D risk scores suggests that both equations may be appropriate estimators of cardiovascular risk in this population.
Assuntos
Doenças Cardiovasculares/virologia , Infecções por HIV/complicações , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Austrália , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/virologia , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Medição de Risco , TailândiaRESUMO
BACKGROUND: Genetic vaccination with plasmid DNA encoding allergens is a promising potential approach for the treatment or prevention of allergy. Nonetheless, because the allergens expressed can display immunoglobulin (Ig) E reactivity, methods to deliver hypoallergenic variants can minimize the risk of type 2 helper (T(H)2) cell priming after DNA immunization. METHODS: A humanized synthetic gene encoding mature Dermatophagoides pteronyssinus group 1 (Der p 1) allergen was cloned into the pHIS expression vector carrying unmethylated CpG 2006 (CpG 2006) motif but devoid of signal sequence. The immunogenicity of this DNA construct was compared in naïve mice with that of recombinant ProDer p 1 protein adjuvanted with alum. RESULTS: Codon optimization of the cDNA encoding mature Der p 1 markedly improved allergen expression. Mature Der p 1, expressed intracellularly in Human Embryonic Kidney 293 cells (HEK 293 cells) transfected with codon-optimized Der p 1 cDNA (pHIS-mHuDer p 1), was shown to be hypoallergenic as it displayed no IgE reactivity. Intradermal vaccinations of naïve Balb/C mice with pHIS-mHuDer p 1 elicited an allergen-specific T(H)1 response characterized by the production of specific IgG2a, a very low amount of specific IgG1, and no specific IgE. Lipoplex formulation with cationic liposome composed of lecithin, N-[1-(2,3-Dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate (DOTAP) and cholesterol not only accelerated the induction of T(H)1 response but also increased its intensity. CONCLUSION: A codon-optimized DNA vaccine encoding mature Der p 1 in a lipoplex formulation could represent a promising hypoallergenic vaccine candidate for safer immunotherapy against house dust mite allergy.
Assuntos
Antígenos de Dermatophagoides/imunologia , Hipersensibilidade/imunologia , Vacinas de DNA/imunologia , Sequência de Aminoácidos , Animais , Anticorpos/sangue , Antígenos de Dermatophagoides/genética , Proteínas de Artrópodes , Sequência de Bases , Códon/genética , Cisteína Endopeptidases , DNA/química , DNA/genética , Feminino , Células HEK293 , Humanos , Hipersensibilidade/prevenção & controle , Imunização/métodos , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Plasmídeos/genética , Plasmídeos/imunologia , Reação em Cadeia da Polimerase , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Alinhamento de Sequência , Estatísticas não Paramétricas , Transfecção , Vacinas de DNA/genéticaRESUMO
OBJECTIVES: To evaluate the prevalence and risk factors of anal squamous intraepithelial lesions (ASIL), the putative anal cancer precursor, in Asian HIV positive and HIV negative men who have sex with men (MSM). METHODS: Men who underwent anal Pap smear reported clinical, sociodemographic and behavioural information collected through questionnaire and interview between January 2007 and April 2008. Chi(2) and logistic regression were used to evaluate ASIL prevalence and risk factors among HIV positive and HIV negative MSM. RESULTS: Of the 174 MSM (mean age 32.1 years), 118 (67.8%) were HIV positive. Overall, 27% had abnormal anal cytology: 13.2% had atypical squamous cells of undetermined significance (ASC-US), 11.5% had low-grade squamous intraepithelial lesion (LSIL) and 2.3% had high-grade squamous intraepithelial lesion (HSIL). Prevalence of ASIL was higher among HIV positive than HIV negative MSM (33.9% vs 12.5%; p = 0.003). Among HIV positive MSM, 16.1% had ASC-US, 14.4% had LSIL and 3.4% had HSIL and 7.1%, 5.4% and 0% in HIV negative MSM, respectively. Anal condyloma was detected in 22% of HIV positive and 16.1% (9/56) of HIV negative MSM (p = 0.5). In HIV positive MSM, anal condyloma (OR 3.42, 95% CI 1.29 to 9.04; p = 0.01) was a significant risk factor for ASIL. Highly active antiretroviral therapy use and CD4+ T cell count were not associated with ASIL. CONCLUSIONS: One-third of HIV positive and 12.5% of HIV negative MSM had ASIL. Thus, as greater numbers of HIV positive MSM live longer due to increasing access to HAART worldwide, effective strategies to screen and manage anal precancerous lesions are needed.
Assuntos
Neoplasias do Ânus/epidemiologia , Carcinoma in Situ/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Soronegatividade para HIV/fisiologia , Soropositividade para HIV/epidemiologia , Homossexualidade Masculina/estatística & dados numéricos , Adulto , Ásia/etnologia , Estudos Transversais , Humanos , Masculino , Prevalência , Fatores de Risco , Parceiros Sexuais , TailândiaRESUMO
OBJECTIVES: TMC125-C227, an exploratory phase II, randomized, controlled, open-label trial, compared the efficacy and safety of TMC125 (etravirine) with an investigator-selected protease inhibitor (PI) in nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant, protease inhibitor-naïve, HIV-1-infected patients. METHODS: Patients were randomized to TMC125 800 mg twice a day (bid) (phase II formulation; n=59) or the control PI (n=57), plus two nucleoside reverse transcriptase inhibitors (NRTIs). RESULTS: In an unplanned interim analysis, patients receiving TMC125 demonstrated suboptimal virological responses relative to the control PI. Therefore, trial enrolment was stopped prematurely and TMC125 treatment discontinued after a median of 14.3 weeks. In this first-line NNRTI-failure population, baseline NRTI and NNRTI resistance was high and reduced virological responses were observed relative to the control PI. No statistically significant relationship was observed between TMC125 exposure and virological response at week 12. TMC125 was better tolerated than a boosted PI for gastrointestinal-, lipid- and liver-related events. CONCLUSIONS: In a PI-naïve population, with baseline NRTI and NNRTI resistance and NRTI recycling, TMC125 was not as effective as first use of a PI. Therefore the use of TMC125 plus NRTIs alone may not be optimal in PI-naïve patients with first-line virological failure on an NNRTI-based regimen. Baseline two-class resistance, rather than pharmacokinetics or other factors, was the most likely reason for suboptimal responses.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , HIV-1 , Piridazinas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Esquema de Medicação , Farmacorresistência Viral/efeitos dos fármacos , Métodos Epidemiológicos , Feminino , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Piridazinas/efeitos adversos , Piridazinas/farmacocinética , Pirimidinas , RNA Viral , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/farmacocinética , Carga Viral , Adulto JovemRESUMO
BACKGROUND: The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz. METHODS: In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log(10) decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat. FINDINGS: Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI -0.9 to 12.8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0.193) or the increases in CD4-positive cells (p=0.800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine. INTERPRETATION: Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1 , Nevirapina/administração & dosagem , Oxazinas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Alcinos , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas , Ciclopropanos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Masculino , Nevirapina/efeitos adversos , Oxazinas/efeitos adversos , RNA Viral/sangue , Inibidores da Transcriptase Reversa/efeitos adversos , Falha de TratamentoRESUMO
OBJECTIVE: To evaluate the usefulness of T-cell subsets, beta-microglobulin (B2M), p24 antigen and anti-p24 antibodies as differentiating and prognostic markers in HIV-infected Thai patients. DESIGN: Sixty-one HIV-infected patients in various stages of disease (six AIDS, three AIDS-related complex, 34 persistent generalized lymphadenopathy and 18 HIV-asymptomatic) were followed prospectively for 2 years. Patients were examined and immunological markers assessed every 6 months at least. Any HIV-related complications were treated symptomatically and clinical staging was re-evaluated at each visit. Due to financial constraints, none of the patients were given antiretroviral drugs. METHODS: T-cell subsets were enumerated by indirect immunofluorescence using OKT4 or OKT8 for T-helper and T-suppressor cells, respectively. beta 2M and p24 antigen were quantified by enzyme-linked immunosorbent assay and anti-p24 antibodies were by immunoblot assay. RESULTS: Our preliminary study revealed that the decrease in CD4+ T-cells or anti-p24 titre and the increase in p24 antigen or beta 2M correlated well with disease staging, as defined by the Centers for Disease Control. Absolute number and percentage of CD4+ T-cells, absolute number of CD8+ T-cells, beta 2M level and p24 antigen and anti-p24 antibody levels at entry could be used as reliable prognostic markers for HIV progression. The combination of p24 antigen with the number of CD4+ T-cells substantially increased the prognostic value, compared with either used alone. CONCLUSIONS: The annual rate of clinical progression from asymptomatic to symptomatic HIV infection in our study was 6.8%. The results we obtained in this preliminary study may be used as baseline data for planning future therapeutic interventions in Asian patients.
Assuntos
Antígenos de Diferenciação/análise , Proteína do Núcleo p24 do HIV/análise , Infecções por HIV/sangue , Subpopulações de Linfócitos T/química , Microglobulina beta-2/análise , Adolescente , Adulto , Feminino , Seguimentos , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Tailândia/epidemiologia , Microglobulina beta-2/imunologiaRESUMO
OBJECTIVES: To assess the immunological and virological effects, safety profile and feasibility of subcutaneous interleukin-2 (scIL-2) therapy in an HIV-infected Thai population. DESIGN: Seventy-two patients with baseline CD4 cell count of > or = 350 x 10(6)/l and no history of opportunistic infection were randomized to receive antiretroviral therapy plus scIL-2 (scIL-2 group) or antiretroviral therapy alone (control group). scIL-2 was administered at one of three doses for at least 24 weeks. The main measure of treatment efficacy was change in CD4 cell count. RESULTS: The time-weighted mean change in CD4 cell count from baseline to week 24 was + 252 x 10(6)/l for the scIL-2 group compared with + 42 x 10(6)/l for the control group (P< 0.0001). Changes in plasma HIV RNA were not significantly different between the groups over the same time period: there was a 0.83 log10 copies/ml decrease for the scIL-2 group and a 0.70 log copies/ml decrease for the control group (P= 0.362). CONCLUSIONS: This study provides the most extensive experience of scIL-2 therapy in HIV-1 infected women and Asians, and demonstrates the immunological efficacy, tolerability and feasability of scIL-2 therapy in this population. Data from this study were instrumental in guiding the selection of the scIL-2 dosing regimen for ongoing phase III trials.
Assuntos
Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Interleucina-2/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Esquema de Medicação , Feminino , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , TailândiaRESUMO
BACKGROUND: Triple combination antiretroviral therapy, recommended as standard of care, is unaffordable for much of the developing world. OBJECTIVES: To establish whether half doses of zidovudine (AZT) and zalcitabine (ddC) are as effective as standard doses in a Thai population with lower body weight than Western populations and predominantly infected with HIV-1 subtype E. METHODS: A group of 116 antiretroviral naive patients, with CD4 cell counts 100-500 x 10(6) cells/l, were randomized to: AZT 200 mg three times daily plus ddC 0.75 mg three times daily versus AZT 100 mg three times daily plus ddC 0.375 mg three times daily and followed-up regularly for 48 weeks. RESULTS: The study enrolled 111 patients: 59 men and 52 women, body weight (mean +/- standard deviation) 56.4 +/- 12.3 kg, mean CD4 cell count 324 x 10(6) cells/l, mean HIV RNA 4.7 log10 copies/ml. There were no significant differences between the two groups. Twelve patients discontinued, including two deaths that were unrelated to study medication. No significant differences in adverse events were seen. Week 48 data for the standard dose and half dose arms, respectively, were mean CD4 cell count increases of 52 and 78 x 10(6) cells/l (P = 0.34), mean plasma HIV-1 RNA reduction of 1.4 and 1.1 log10 copies/ml (P = 0.10), HIV RNA of < 400 copies/ml in 52 and 20%[ (P = 0.001). Participants with higher than mean baseline CD8 cell counts (mean 1062 x 10(6) cells/l) showed greater decline in CD8 cells on standard doses. Further analysis showed improved reduction in HIV RNA (P < 0.0001) and in the percentage with undetectable HIV RNA (P = 0.0137) in the standard dose arm, corrected for baseline HIV RNA, which if < 4.75 log10 copies/ml significantly correlated with HIV RNA < 400 copies/ml at week 48. CONCLUSION: At week 48, the proportion with HIV RNA < 400 copies/ml was significantly higher in the standard dose arm; lower baseline HIV RNA correlated with better HIV RNA outcome at 48 weeks. The arms did not differ in CD4 cell response but standard doses correlated with greater CD8 cell decline.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Zalcitabina/administração & dosagem , Zidovudina/administração & dosagem , Adulto , Fármacos Anti-HIV/efeitos adversos , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , HIV-1 , Humanos , Contagem de Linfócitos , Masculino , RNA Viral/sangue , Tailândia , Zalcitabina/efeitos adversos , Zidovudina/efeitos adversosRESUMO
OBJECTIVES: To evaluate the safety and efficacy of four different regimens of didanosine (ddI) + stavudine (d4T) in HIV-infected Thais. DESIGN: Prospective, open-label, randomized study. METHODS: Patients were randomized to four regimens of high and low doses of ddI and d4T or to ddI alone. D4T was added to the ddI-alone arm after week 24. The duration of study was 48 weeks. RESULTS: Seventy-eight patients were randomized (mean CD4 cell count, 255 x 10(6)/l; mean plasma HIV-1 RNA; 4.3 log10 copies/ml). In the intent-to-treat analysis, 78% of patients in the pooled combination arms and 20% of the patients in the ddI alone arm (to which d4T was added after 24 weeks) showed plasma HIV-1 RNA < 500 copies/ml at week 24 (P < 0.001), and 59% versus 53% at week 48, respectively. In addition, the proportion of patients with < 50 HIV-1 RNA copies/ml was 13% versus 7% at week 24 (P = 0.5) and 17% versus 20% at week 48 respectively. At week 24, median CD4 cell count increases from baseline were 101 x 10(6)/l in the pooled combination versus 76 x 10(6)/l in the ddI alone arm (P = 0.78). Logistic regression modeling suggested a correlation between receiving high dose ddI and achieving HIV-1 RNA < 500 copies/ml at week 48 (P = 0.07). CONCLUSIONS: The d4T/ddI combination was superior to ddI alone in producing HIV-1 viral suppression. At week 48, > 60% of patients treated with this combination reached HIV-1 RNA levels < 500 copies/ml. Receiving high dose ddI but not d4T may correlate with a better viral suppression.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Didanosina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Estavudina/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Contagem de Linfócito CD4 , Didanosina/efeitos adversos , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , HIV-1/isolamento & purificação , Humanos , Masculino , Estudos Prospectivos , RNA Viral/sangue , Segurança , Estavudina/efeitos adversos , TailândiaRESUMO
Genetic diversity of the HIV-1 envelope gene has shown a steady increase over time in the Thai and other regional epidemics. A serial survey of subtype CRF01_AE polymerase gene (RT) diversity in Thailand was performed, using 48 novel and 15 reported sequences covering the period 1990--2000. These sequences were gathered from individuals whose sole risk factor for infection was heterosexual contact. By contrast to envelope, diversity was low and, despite a 40% increase early in the epidemic, has remained static since 1996. These results indicate that epidemic HIV-1 may be constrained within defined limits of genetic diversity at least in some genomic regions.
Assuntos
Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/genética , Sequência de Aminoácidos , Sequência de Bases , Surtos de Doenças , Evolução Molecular , Feminino , Variação Genética , Proteína gp120 do Envelope de HIV/classificação , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/sangue , Infecções por HIV/epidemiologia , Transcriptase Reversa do HIV/classificação , HIV-1/classificação , HIV-1/isolamento & purificação , Heterossexualidade , Humanos , Funções Verossimilhança , Masculino , Dados de Sequência Molecular , Filogenia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Alinhamento de Sequência , Análise de Sequência , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/virologia , Tailândia/epidemiologia , Fatores de TempoRESUMO
BACKGROUND: To assess the association between the CD4 count and clinical diseases in a cohort of Thai patients. METHODS: In all, 1902 patients who presented with human immunodeficiency virus (HIV) infection at the Chulalongkorn University Hospital in Bangkok were investigated. RESULTS: At the time of presentation 295 (15.5%) patients had acquired immunodeficiency syndrome (AIDS) and there was a highly significant tendency for lower CD4 counts in this group (median 67/mm3) than in patients free of AIDS (median 369/mm3). A total of 757 patients had data available on follow-up and were free of AIDS at the first visit. During a median follow-up of 0.9 years, 110 developed AIDS or AIDS-related death (12.2/100 person years). Subjects with CD4 count < 200/mm3 at initial visit showed over a ninefold increase in risk of developing AIDS compared to subjects with levels > or = 500/mm3 (relative risk [RR] = 9.1; 95% CI: 5.4-16.0). The rate/100 person years was 47.1 compared with 6.0 in subjects with levels > or = 500/mm3. After adjusting for initial CD4 count, homosexual men showed over a twofold increase in risk of developing AIDS compared to heterosexuals (RR = 2.4; 95% CI: 1.6-4.4) and intravenous drug users (IVDU) showed nearly a twofold increase (RR = 1.8; 95% CI: 0.9-3.9). The increased risk in homosexual men persisted even after further adjustment for clinical stage (RR = 2.2; 95% CI: 1.3-3.7) but the increased risk in IVDU was attenuated (RR = 1.5; 95% CI: 0.7-3.2) although it remained increased albeit non-significantly. Men tended to progress faster to AIDS than women but the difference was not significant. However, the faster progression in homosexual men was seen even when compared to heterosexual men only. CONCLUSION: The rate of progression of AIDS according to CD4 count group at baseline in this Thai cohort is broadly comparable with Western cohorts. It appears that heterosexuals in Thailand show slower progression to AIDS than homosexual men.
PIP: The natural history of HIV infection was investigated in a cohort of 1902 HIV-positive patients (median age, 29 years) seen at the Chulalongkorn University Hospital in Bangkok, Thailand, in 1985-90 in whom a CD4 count was performed at the initial visit. The majority (64%) were male heterosexuals; 10% were homosexual men, 10% reported intravenous drug use, and 16% were heterosexual women. At the time of study enrollment, 295 patients (15.5%) had progressed to AIDS. AIDS patients had a significantly lower CD4 count (median, 67/cu. mm) than those without AIDS (median, 369/cu. mm). Of the 757 patients who were AIDS-free at baseline and available for follow up (median time, 0.9 years), 110 developed AIDS or died from an AIDS-related cause (12.2/100 person-years). Tuberculosis was the major AIDS-defining illness in all risk groups. 50% of those with a CD4 count under 200/cu. mm at the initial visit developed AIDS within 2 years compared with 12% of those with levels of 500/cu. mm (relative risk (RR), 9.1; 95% confidence interval (CI), 5.4-16.0). The rates per 100 person-years were 47.1 and 6.0, respectively. After adjusting for initial CD4 count, homosexual men had a relative risk of developing AIDS of 2.4 (95% CI, 1.6-4.4) compared with heterosexuals; intravenous drug users had a relative risk of 1.8 (95% CI, 0.9-3.9). The increased risk in homosexual men persisted even after further adjustment for clinical stage (relative risk, 2.2; 95% CI, 1.3-3.7), but the increased risk in intravenous drug users was attenuated (RR, 1.5; 95% CI, 0.7-3.2). Older patients progressed faster to AIDS than younger patients, but there was no significant difference between men and women in the course of disease. These findings are consistent with those of studies conducted in Western countries indicating a slower progression to AIDS in heterosexual men than homosexuals and a correlation between CD4 count and rate of progression to AIDS.