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1.
HIV Med ; 16(2): 76-87, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25174373

RESUMO

OBJECTIVES: Sustained optimal use of combination antiretroviral therapy (cART) has been shown to decrease morbidity, mortality and HIV transmission. However, incomplete adherence and treatment interruption (TI) remain challenges to the full realization of the promise of cART. We estimated trends and predictors of treatment interruption and resumption among individuals in the Canadian Observational Cohort (CANOC) collaboration. METHODS: cART-naïve individuals ≥ 18 years of age who initiated cART between 2000 and 2011 were included in the study. We defined TIs as ≥ 90 consecutive days off cART. We used descriptive analyses to study TI trends over time and Cox regression to identify factors predicting time to first TI and time to treatment resumption after a first TI. RESULTS: A total of 7633 participants were eligible for inclusion in the study, of whom 1860 (24.5%) experienced a TI. The prevalence of TI in the first calendar year of cART decreased by half over the study period. Our analyses highlighted a higher risk of TI among women [adjusted hazard ratio (aHR) 1.59; 95% confidence interval (CI) 1.33-1.92], younger individuals (aHR 1.27; 95% CI 1.15-1.37 per decade increase), earlier treatment initiators (CD4 count ≥ 350 vs. <200 cells/µL: aHR 1.46; 95% CI 1.17-1.81), Aboriginal participants (aHR 1.67; 95% CI 1.27-2.20), injecting drug users (aHR 1.43; 95% CI 1.09-1.89) and users of zidovudine vs. tenofovir in the initial cART regimen (aHR 2.47; 95% CI 1.92-3.20). Conversely, factors predicting treatment resumption were male sex, older age, and a CD4 cell count <200 cells/µL at cART initiation. CONCLUSIONS: Despite significant improvements in cART since its advent, our results demonstrate that TIs remain relatively prevalent. Strategies to support continuous HIV treatment are needed to maximize the benefits of cART.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Linfócito CD4 , Canadá/epidemiologia , Estudos de Coortes , Aconselhamento Diretivo , Esquema de Medicação , Quimioterapia Combinada , Seguimentos , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Infecções por HIV/psicologia , Humanos , Incidência , Adesão à Medicação/psicologia , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Fatores de Risco , Carga Viral
3.
Clin Nephrol ; 65(1): 13-21, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16429837

RESUMO

Indinavir is a potent HIV-1 protease inhibitor included in current antiretroviral therapeutic regimens. It is associated with renal and urological complications ascribed to indinavir crystalluria. We have previously reported that indinavir crystalluria is frequently observed soon after initiation of therapy. In a cohort of 54 asymptomatic indinavir-naive HIV-1-infected individuals during their first year of treatment with indinavir, approximately 25% of urinalyses (U/A) contained indinavir crystals. Because the determinants of the crystalluria are unknown, we examined the relationship between urine specific gravity (SG) and pH, singly and in combination, and indinavir crystalluria in these subjects. A total of 579 U/A were obtained from the study subjects at their scheduled monthly outpatient medical assessments. The frequency of indinavir crystalluria was lower in U/A with lower pH, irrespective of the SG. Conversely, U/A with high pH (> or = 6.0) had a higher frequency of indinavir crystalluria, which was further influenced by the urine SG. As a result, nearly half of the U/A (46.7%) with high pH (> or = 6.0) and intermediate-high SG (> or = 1.015) contained indinavir crystals. In conclusion, the frequency of indinavir crystalluria in asymptomatic HIV-1 infected individuals during their first year of treatment with indinavir was markedly influenced by the urine pH and SG. Our findings suggest that low urine pH may have a protective effect against indinavir crystalluria across the entire range of urine SG.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/urina , Infecções por HIV/tratamento farmacológico , Infecções por HIV/urina , Indinavir/uso terapêutico , Indinavir/urina , Adulto , Idoso , Fármacos Anti-HIV/efeitos adversos , Cristalização , Feminino , Humanos , Concentração de Íons de Hidrogênio , Indinavir/efeitos adversos , Masculino , Pessoa de Meia-Idade , Gravidade Específica , Urinálise , Urina
4.
Med Chem ; 1(2): 173-84, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16787312

RESUMO

Quantitative Structure Activity Relationship (QSAR) techniques are used routinely by computational chemists in drug discovery and development to analyze datasets of compounds. Quantitative numerical methods like Partial Least Squares (PLS) and Artificial Neural Networks (ANN) have been used on QSAR to establish correlations between molecular properties and bioactivity. However, ANN may be advantageous over PLS because it considers the interrelations of the modeled variables. This study focused on the HIV-1 Protease (HIV-1 Pr) inhibitors belonging to the peptidomimetic class of compounds. The main objective was to select molecular descriptors with the best predictive value for antiviral potency (Ki). PLS and ANN were used to predict Ki activity of HIV-1 Pr inhibitors and the results were compared. To address the issue of dimensionality reduction, Genetic Algorithms (GA) were used for variable selection and their performance was compared against that of ANN. Finally, the structure of the optimum ANN achieving the highest Pearson's-R coefficient was determined. On the basis of Pearson's-R, PLS and ANN were compared to determine which exhibits maximum performance. Training and validation of models was performed on 15 random split sets of the master dataset consisted of 231 compounds. For each compound 192 molecular descriptors were considered. The molecular structure and constant of inhibition (Ki) were selected from the NIAID database. Study findings suggested that non-covalent interactions such as hydrophobicity, shape and hydrogen bonding describe well the antiviral activity of the HIV-1 Pr compounds. The significance of lipophilicity and relationship to HIV-1 associated hyperlipidemia and lipodystrophy syndrome warrant further investigation.


Assuntos
Inteligência Artificial , Desenho de Fármacos , Inibidores da Protease de HIV/química , Peptídeos/química , Relação Quantitativa Estrutura-Atividade , Algoritmos , Simulação por Computador , Bases de Dados como Assunto , Genética , Protease de HIV/química , Protease de HIV/efeitos dos fármacos , Inibidores da Protease de HIV/farmacologia , Análise dos Mínimos Quadrados , Mimetismo Molecular , Peptídeos/classificação , Valor Preditivo dos Testes
5.
J Immunol ; 171(1): 477-88, 2003 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-12817033

RESUMO

Both the magnitude and breadth of HIV-specific immunity were evaluated longitudinally on samples collected from six subjects starting highly active antiretroviral therapy (HAART) preseroconversion (group 1), 11 recently infected subjects starting HAART postseroconversion (group 2), five subjects starting HAART in the second half of the first year of infection (group 3), and six persons starting treatment in the chronic phase of infection (group 4). HIV-specific immunity was measured by IFN-gamma ELISPOT, detecting the frequency of cells responding to a panel of HLA-restricted HIV-1 peptides. Intracellular cytokine staining was used to detect the frequency of HIV-1 Gag p55-specific CD4(+) and CD8(+) T cells in a subset of participants. The magnitude and breadth of HIV-specific responses persisted in all group 1 subjects and in 5 of 11 (45%) group 2 subjects. Both of these parameters declined in 6 of 11 (55%) group 2 and in all group 3 and 4 individuals. All persons who maintained detectable numbers of HIV-1 Gag p55-specific CD4(+) and CD8(+) T cells after starting HAART preserved the intensity and breadth of their HIV-specific effector response. Our results show that HIV-specific immunity can be preserved even if HAART is initiated beyond the acute phase of infection.


Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/imunologia , Adulto , Fatores Etários , Sequência de Aminoácidos , Relação CD4-CD8 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Linhagem Celular Transformada , Feminino , Infecções por HIV/virologia , Humanos , Interferon gama/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Estudos Retrospectivos , Carga Viral
6.
J Comput Chem ; 24(9): 1110-9, 2003 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-12759910

RESUMO

The relative energy between two different protonation sites of the Asp25' catalytic site residue is computed and analyzed for various HIV-1 Protease/inhibitor complexes and compared to the wild-type structure. By comparing calculations of negatively charged fragments of gradually increasing size up to 105 atoms we show that correct modeling of the HIV-1 Protease active site requires much larger models than the commonly used acetic acid/acetate moieties. The energy difference between the two proposed protonation sites decreases as the size of the system increases and tends to converge only when the entire catalytic triad of both monomers is taken into account. The importance of the Gly27 backbone amine groups in the stabilization of the negative charge within the catalytic site cleft is revealed. Comparison of the wild-type structure with the structures from various Pr/drug complexes indicates that the HIV-1 protease has a particular catalytic site flexibility.


Assuntos
Aminoácidos/química , Protease de HIV/química , Modelos Moleculares , Conformação Proteica , Domínio Catalítico , Ligação de Hidrogênio , Estrutura Molecular , Termodinâmica
7.
Proc AMIA Symp ; : 320-4, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12463839

RESUMO

Despite the proven clinical benefits of HAART, mortality may still occur; particularly in those with less than 50 CD4+ cells/mL and, in some cases, with a viral burden below detectable plasma levels of HIV-1 RNA. Multiple factors may predict mortality including initial response to therapy, viral factors and host immune parameters. Due to the complexity of this problem, we developed Artificial Intelligence based tools/Neural Network (NN) to optimally evaluate outcomes of therapy and predict morbidity and mortality. To further validate the accuracy of these tools, we challenged their performance with that of Cox regression modeling (RM). Our study population involved 116 HIV+ individuals who consistently maintained CD4+ count < 50 cells/mL for over 6 months. All patients were treated with antiretrovirals. To assess clinical outcomes, we developed a feedforward back-propagation Neural Network. We then compared the performance of this network to a Cox regression model. The Neural Network outscored the Cox regression model in the ROC curve areas: 0.888 vs 0.760 (HIV+ first Seropositivity to AIDS), 0.901 vs 0.758 (HIV+ first Seropositivity to Last Assessment incl. death) and 0.832 vs 0.799 (AIDS to Last Assessment incl. death), for the NN & Cox, respectively. In patients with a history of AIDS defining events and with severe T-Cell depletion, mortality occurs despite therapy. Although Neural Networks and Cox modeling were successful in predicting mortality, the Neural Network was superior in assessing risk in this population.


Assuntos
Soropositividade para HIV/mortalidade , HIV-1/imunologia , Redes Neurais de Computação , Linfócitos T/fisiologia , Biomarcadores , Contagem de Linfócito CD4 , Soropositividade para HIV/imunologia , HIV-1/genética , Homeostase , Humanos , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , RNA Viral , Curva ROC , Análise de Sobrevida
8.
AIDS Res Hum Retroviruses ; 17(10): 887-900, 2001 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-11461675

RESUMO

Five HIV-seropositive twins were treated with HAART and given cycles of treatment consisting of adoptive cellular therapy from their HIV-seronegative identical twins followed by a 5-day course of intravenous IL-2. Changes in absolute and percent CD4(+) and CD8(+) cell count were monitored and compared with changes in these parameters occurring in seven age-, sex-, and disease stage-matched HIV-infected patients treated with HAART alone. Increase in the magnitude and breadth of HIV-specific immune responses was monitored in three twin subjects who received multiple treatment cycles. Absolute and percent CD4(+) cell counts rose dramatically and to significantly higher levels in the recipient twins than in control subjects treated with HAART only. The subjects who received multiple cycles of treatment developed new and increased levels of HIV-specific activated and memory cytotoxic T lymphocyte responses, and interferon gamma-secreting effector cells. Treatment consisting of HAART, adoptive cellular therapy, and IL-2 was superior to treatment with HAART alone for improving absolute and percent CD4(+) cell counts and inducing new, or increasing the magnitude of, HIV-specific immune responses in HIV infected patients.


Assuntos
Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Infecções por HIV/terapia , Imunoterapia Adotiva , Interleucina-2/uso terapêutico , Adulto , Linfócitos T CD8-Positivos/imunologia , Terapia Combinada , Doenças em Gêmeos , Seguimentos , Infecções por HIV/sangue , Soronegatividade para HIV/imunologia , Soropositividade para HIV/sangue , Soropositividade para HIV/tratamento farmacológico , Soropositividade para HIV/imunologia , Humanos , Imunoensaio/métodos , Interferon gama/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Gêmeos Monozigóticos , Carga Viral
9.
Am J Kidney Dis ; 36(3): 507-15, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10977782

RESUMO

Indinavir is a potent protease inhibitor widely used in combination with reverse-transcriptase inhibitors to treat human immunodeficiency virus (HIV) disease. Individuals treated with indinavir are prone to develop urinary complications, including renal colic, renal calculi, lower urinary tract symptoms, and indinavir crystalluria. Although renal stones secondary to indinavir have been described and characterized, little is known about the onset, frequency, and significance of the crystalluria. To document the longitudinal characteristics of indinavir crystalluria and associated urine abnormalities, 54 asymptomatic indinavir-naive HIV-positive individuals had urinalysis testing initially weekly and then monthly during the first year of indinavir treatment. Six hundred eight urinalyses were performed (11 +/- 2 urinalysis/subject), including 579 microscopy examinations performed by a nephrologist (10 +/- 2 examinations/subject). Baseline urinalysis results were essentially normal. After the start of treatment, indinavir crystalluria was frequently observed (67% of subjects). After the first 2 weeks, indinavir crystalluria remained constant at a frequency of approximately 25% of urine sediments examined at each test point. Other urine abnormalities, principally leukocytes (>/=10/high-power field) and casts, were observed in 39% of subjects. These abnormalities were more severe in five subjects, with concomitant increasing serum creatinine levels in three of them. Additional urine findings include the predominance of low pH (/=1.025 in 66% of urinalyses). In conclusion, abnormal urinalysis results were noted frequently during the first year of treatment with indinavir. The main findings were the high proportion of subjects with crystalluria and the relatively high frequency of crystalluria observed consistently throughout. These findings may occasionally be associated with other urine abnormalities, presumably secondary to indinavir crystalluria.


Assuntos
Inibidores da Protease de HIV/efeitos adversos , Soropositividade para HIV/tratamento farmacológico , Soropositividade para HIV/urina , Indinavir/efeitos adversos , Adulto , Idoso , Estudos de Coortes , Cristalização , Feminino , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/urina , Humanos , Concentração de Íons de Hidrogênio , Indinavir/química , Indinavir/urina , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Nefelometria e Turbidimetria , Estudos Prospectivos , Gravidade Específica , Urinálise
10.
Eur J Clin Pharmacol ; 56(3): 231-40, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10952478

RESUMO

OBJECTIVE: To examine the distribution of the cytochrome P450 (CYP) CYP2D6 phenotype and its relation to genotype, concomitant medication, and disease state in human immunodeficiency virus (HIV)-positive patients. DESIGN: A cross sectional study with a longitudinal component compared individual genotypes for CYP2D6 to the CYP2D6 phenotype. METHODS: Sixty-one predominately male Caucasian, HIV-positive patients were recruited and CYP2D6 genotypes [extensive metabolizer (EM) or poor metabolizer (PM)] determined by polymerase chain reaction (PCR)-based amplification, followed by restriction fragment-length analysis. The patients were also phenotyped using dextromethorphan (DM) to determine their respective enzyme activity and assigned either a CYP2D6 EM or PM phenotype. Complete medical and treatment histories were compiled. A total of 44 patients were tested longitudinally. RESULTS: Fifty-nine patients (97%) possessed an EM genotype, consistent with previously observed distributions in demographically similar populations. In healthy seronegative populations, genotype and phenotype have been shown to be essentially interchangeable measures of CYP2D6 activity. In this cohort, 2 of the 59 patients with an EM genotype expressed a PM phenotype. In addition, 4 EM patients were less extensive DM metabolizers than any of the patients receiving medication known to inhibit CYP2D6. This apparent shift toward the PM phenotype from the EM genotype was associated with the presence of active illness. CONCLUSION: Changes may occur in HIV-positive patients such that their CYP2D6 activity approaches that of PMs, despite having an EM genotype. Neither active disease nor drug interactions alone explain the shift.


Assuntos
Síndrome da Imunodeficiência Adquirida/enzimologia , Citocromo P-450 CYP2D6/genética , Soropositividade para HIV/enzimologia , Adulto , Idoso , Contagem de Linfócito CD4 , Estudos Transversais , Feminino , Genótipo , Humanos , Lipopolissacarídeos/farmacologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo
11.
Int J STD AIDS ; 11(4): 212-9, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10772083

RESUMO

Our objective was to compare the effect of 2 regimens for treatment of Mycobacterium avium complex (MAC) bacteraemia in an HIV-positive population on symptoms and health status outcomes using a substudy of an open-label randomized controlled trial. The study was conducted in 24 hospital-based human immunodeficiency virus (HIV) clinics in 16 Canadian cities. Patients had HIV infection and MAC bacteraemia and were given either rifampin 600 mg, ethambutol 15 mg/kg daily, clofazimine 100 mg daily and ciprofloxacin 750 mg twice daily (4-drug arm) or rifabutin 600 mg daily (amended to 300 mg daily in mid-trial), ethambutol 15 mg/kg daily and clarithromycin 1000 mg twice daily (3-drug arm). The primary health status outcome was the change on the 8-item symptom subscale of the Medical Outcome Study (MOS)-HIV Health Survey adapted for MAC. Changes on other MOS-HIV subscales and on the Karnofsky score were also evaluated. Patients on the 3-drug arm had better outcomes on the MOS-HIV symptom subscale at 16 weeks (P=0.06), with statistically significant differences restricted to night sweats and fever and chills (P < 0.001). The proportion of patients improving on the symptom subscale relative to baseline was 55% on the 3-drug arm and 40% on the 4-drug arm. Patients on the 3-drug arm also had better Karnofsky score at 16 weeks (P < 0.001) and better outcomes on the social function, mental health, energy/fatigue, health distress and cognitive function subscales of the MOS-HIV. The 3-drug arm is superior to the 4-drug arm in terms of impact on MAC-associated symptoms, functional status and other aspects of health status.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antituberculosos/uso terapêutico , Bacteriemia/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/fisiopatologia , Adolescente , Adulto , Bacteriemia/fisiopatologia , Canadá , Ciprofloxacina/uso terapêutico , Claritromicina/uso terapêutico , Clofazimina/uso terapêutico , Quimioterapia Combinada , Etambutol/uso terapêutico , Nível de Saúde , Humanos , Infecção por Mycobacterium avium-intracellulare/fisiopatologia , Avaliação de Processos e Resultados em Cuidados de Saúde , Rifabutina/uso terapêutico , Rifampina/uso terapêutico , Resultado do Tratamento
12.
Am J Nephrol ; 20(6): 448-54, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11146311

RESUMO

Urinary complications observed during indinavir treatment of HIV disease are often attributed to indinavir crystalluria. In a prospective study of urinalysis during the first year of indinavir therapy, 5 of 54 asymptomatic HIV+ individuals presented severe leukocyturia (> or =100 cells/HPF) usually accompanying indinavir crystalluria. The clinical course of these 5 individuals, successfully treated for HIV and monitored for an second follow-up year, suggests that recurrence of severe leukocyturia may be an indicator of renal damage, likely tubulointerstitial disease caused by indinavir crystalluria. This is in contrast to the remaining 49 subjects, including those presenting mild leukocyturia, who did not demonstrate any evidence of renal disease. Regular urinalysis is therefore recommended in the clinical management of indinavir-treated individuals to detect early renal damage secondary to indinavir crystalluria and to prevent further renal impairment.


Assuntos
Inibidores da Protease de HIV/efeitos adversos , Soropositividade para HIV/tratamento farmacológico , Soropositividade para HIV/urina , HIV-1/imunologia , Indinavir/efeitos adversos , Leucócitos/efeitos dos fármacos , Leucocitose/induzido quimicamente , Urina/citologia , Adulto , Cristalização , Quimioterapia Combinada , Feminino , Inibidores da Protease de HIV/administração & dosagem , Humanos , Indinavir/administração & dosagem , Leucocitose/urina , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Regressão , Fatores de Tempo
13.
Br J Clin Pharmacol ; 48(6): 811-8, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10594484

RESUMO

AIMS: To gauge the effect of disease state and disease progression on the glucuronidation and sulphation of paracetamol (APAP) among HIV-positive patients and patients with AIDS. METHODS: The extent of APAP glucuronidation and APAP sulphation was assessed using a spot urine sample collected 4 h after the oral administration of 500 mg of APAP to 108 patients with AIDS or HIV infection. The molar concentrations of APAP and its glucuronide and sulphate metabolites were determined using a validated h.p.l.c. method and glucuronidation and sulphation indices were constructed using APAP metabolite/APAP molar concentration ratios. RESULTS: No effect of disease state, AIDS vs asymptomatic HIV positive vs control, on APAP glucuronidation or sulphation was observed. The patient population was studied over time and disease progression also did not significantly alter the calculated glucuronidation and sulphation indices. The effect of the concomitant administration of other therapeutic agents was assessed and in the cross sectional portion of the study dapsone appeared to significantly decrease APAP sulphation as did lamivudine. In the longitudinal portion of the study the latter effect was not observed but zidovudine was seen to increase APAP glucuronidation. The data also indicates that APAP glucuronidation may be reduced in patients who are >10% below their ideal body weight.


Assuntos
Acetaminofen/metabolismo , Síndrome da Imunodeficiência Adquirida/metabolismo , Infecções por HIV/metabolismo , Adulto , Estudos Transversais , Progressão da Doença , Feminino , Glucuronídeos/metabolismo , Glucuronosiltransferase , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Sulfatos/metabolismo , Sulfotransferases
14.
J Infect Dis ; 179(5): 1254-8, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10191232

RESUMO

The hypothesis was investigated that hepatitis C virus (HCV) infection behaves like an opportunistic infection in which progressive liver disease (PLD) is the principal manifestation. PLD in 81 hemophiliacs coinfected with HCV and human immunodeficiency virus (HIV) was compared with 53 HIV-seronegative HCV-infected hemophiliacs. Progression to AIDS and death in 22 HCV/HIV-coinfected hemophiliacs with PLD was also compared with 59 coinfected hemophiliacs who did not develop PLD. The risk of PLD occurrence associated with an HIV-positive status was 7.4 (95% confidence interval [CI], 2.2-25.5; Cox model). In the coinfected group, the risk of PLD occurrence was higher in subjects with severe AIDS-defining immunodeficiency than in those without (odds ratio, 3. 6; 95% CI, 1.3-10). Persons with PLD also had a faster progression to AIDS (P=.03, log rank test) than those without PLD. Thus, as with other chronic resident human viruses, HCV should be considered another opportunistic pathogen in HIV disease.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/virologia , Infecções por HIV/complicações , Hemofilia A/complicações , Hepacivirus , Hepatite C/complicações , Hepatopatias/virologia , Adolescente , Adulto , Progressão da Doença , Infecções por HIV/virologia , Hepatite C/virologia , Humanos , Hepatopatias/patologia , Estudos Prospectivos
15.
J Infect Dis ; 179(3): 538-47, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9952359

RESUMO

Repeated exposure to human immunodeficiency virus (HIV) does not always result in seroconversion. Understanding the conditions that permit or protect against progressive infection with HIV is important for vaccine development. Nineteen subjects at risk for HIV infection were CCR-5 genotyped and screened for virus-specific memory cytotoxic T lymphocytes (CTL). None had the Delta32CCR-5/Delta32CCR-5 genotype associated with HIV resistance. HIV-specific CTL were detected in 7 (41.1%) of 17 exposed uninfected subjects versus 0 of 14 seronegative subjects with no HIV risk factors (P=.006, chi2 test). Recognition of virus by CTL in exposed uninfected subjects was major histocompatibility complex class I-restricted and multispecific, and specificity could change with time. Activity could persist up to 34 months after the last virus exposure. The presence of HIV-specific CTL in a greater proportion of seronegative HIV-exposed versus unexposed subjects supports the notion that in some cases, virus exposure induces HIV immunity without seroconversion or disease progression.


Assuntos
Soronegatividade para HIV/genética , Soronegatividade para HIV/imunologia , HIV/imunologia , Receptores CCR5/genética , Linfócitos T Citotóxicos/imunologia , Adulto , Citotoxicidade Imunológica , Feminino , Genótipo , HIV/genética , Teste de Histocompatibilidade , Humanos , Imunidade Inata , Complexo Principal de Histocompatibilidade , Masculino , Pessoa de Meia-Idade , Ferimentos Penetrantes Produzidos por Agulha , Comportamento Sexual
16.
AIDS ; 12(16): 2125-39, 1998 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-9833853

RESUMO

BACKGROUND: CD8+ T-cell counts usually increase soon after infection with HIV, whereas CD4+ cell counts decrease. The result of these changes in T-cell subpopulation subsets in most HIV-infected subjects is inversion of the CD4 : CD8 ratio from greater than 1.0 typical of uninfected persons to less than 1.0 after infection. SUBJECTS: Six HIV-infected individuals were identified in whom the CD4 : CD8 ratio remained normal throughout follow-up (4.0-11.25 years). They all maintained levels of CD4+ cells above 500 x 10(6)/l and had never received antiretroviral therapy. Because HIV-specific cytotoxic T lymphocytes (CTL) have been implicated in control of HIV during the asymptomatic phase of disease, we screened these individuals for the presence of HIV-specific CTL activity. METHODS: CTL activity was assessed in freshly isolated peripheral blood mononuclear cells (PBMC) and in phytohaemagglutinin-stimulated interleukin-2 expanded cell lines established from PBMC. Cytotoxicity to HIV-1 env, gag, pol and nef gene products was surveyed in a 4 h 51Cr-release assay using autologous Epstein-Barr virus (EBV) transformed B cells infected with vaccinia constructs expressing each of these HIV genes. The immunodominant CTL epitope and MHC class I antigen restriction specificity of HIV-specific CTL was mapped when present. Plasma viral load was assessed by branched DNA assay. Attempts were made to isolate virus from these individuals by the PBMC coculture assay. RESULTS: None of the six immunologically normal HIV-infected (INHI) subjects exhibited direct HIV-specific CTL activity in their freshly isolated PBMC compared with 16 (47%) out of 34 HIV disease progressors (P = 0.03, chi2 test) and one out of 10 seronegative subjects. Three of the six INHI subjects had detectable memory HIV-specific precursor CTL (pCTL) activity in in vitro-activated T-cell lines compared with 25 (73.5%) out of 34 HIV-1 disease progressors and in none out of 10 seronegative individuals. All three INHI subjects had Gag-specific pCTL, and none had reverse transcriptase-specific pCTL. Plasma HIV viraemia in all six INHI subjects was below the level of detection by branched DNA assay (< 500 copies/ml). Virus could not be isolated from four of these individuals despite multiple attempts to do so by PBMC coculture assays. CONCLUSION: Direct HIV-specific CTL activity mediated by activated circulating PBMC was undetectable in six INHI individuals under conditions where it is frequently observed in HIV disease progressors. Despite the absence of cells activated for killing HIV-infected targets in the circulation of these individuals, they appeared able to control their HIV infection by maintaining normal levels of CD4 and CD8 cells and low viral load.


Assuntos
Infecções por HIV/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Relação CD4-CD8 , Células Cultivadas , Estudos de Coortes , Feminino , HIV/imunologia , HIV/isolamento & purificação , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Proteínas dos Retroviridae/imunologia , Fatores de Risco , Carga Viral
17.
AIDS ; 12(11): F103-9, 1998 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-9708399

RESUMO

OBJECTIVE: A Phase II, open-label, randomized, parallel-arm, multicentre trial to compare the antiviral activity and safety of two formulations of saquinavir (SQV), soft gelatin (SQV-SGC) and hard gelatin (SQV-HGC) capsules, in combination with two nucleoside reverse transcriptase inhibitors (NRTI), in antiretroviral-naive, HIV-1-infected individuals. PARTICIPANTS: A total of 171 people of > or = 13 years, with plasma HIV-1 RNA levels > or = 5000 copies/ml, who had received no protease inhibitor therapy, < or = 4 weeks NRTI therapy and no antiretroviral treatment within 28 days of screening. Eighty-one people were randomized to the SQV-HGC group and 90 to the SQV-SGC group. A total of 148 patients completed 16 weeks of therapy. INTERVENTION: Therapy for 16 weeks with either SQV-SGC 1200 mg or SQV-HGC 600 mg, both three times a day, in combination with two NRTI. RESULTS: Using an on-treatment analysis, patients taking SQV-SGC had a larger reduction in plasma HIV-1 RNA than those taking SQV-HGC (-2.0 versus -1.6 log10 copies/ml). Eighty per cent of those on SQV-SGC had < 400 copies HIV RNA/ml, compared with 43% in the SQV-HGC group (P = 0.001). A statistically significant difference in the area under the curve (AUC) values between the SQV-SGC and SQV-HGC arms (-1.7 versus -1.5 log10 copies/ml, respectively; P = 0.0054) was observed when withdrawals prior to week 12, major protocol violators and patients with < 75% compliance were excluded from the analysis; however, the difference between the values for the intent-to-treat population was not significant (P = 0.1929). Adverse events (mostly mild) included diarrhoea and nausea. CONCLUSIONS: SQV-SGC was generally well tolerated and gave significantly more potent suppression of plasma HIV-1 RNA in antiretroviral-naive patients than SQVHGC.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Gelatina , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Saquinavir/uso terapêutico , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Contagem de Linfócito CD4 , Química Farmacêutica , Qualidade de Produtos para o Consumidor , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Saquinavir/administração & dosagem
18.
AIDS Res Hum Retroviruses ; 14(6): 483-90, 1998 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-9566550

RESUMO

Infection with the human immunodeficiency virus (HIV) leads to a progressive immunodeficiency characterized by decreasing levels of CD4+ T lymphocytes. VaxSyn, a vaccine based on the recombinant envelope glycoprotein subunit (rgp160) of HIV-1IIIB, was used to immunize HIV-infected patients to determine whether its administration was beneficial with respect to slowing disease progression. A 3-year multicenter, randomized, placebo-controlled, double-blinded, efficacy and safety trial of repeated immunization with VaxSyn was used to evaluate the long-term impact on the progression of immunodeficiency. VaxSyn in alum, or alum alone, was given to 278 HIV-infected asymptomatic individuals with initial CD4 counts of > or =500 cells/mm3. Clinical findings, the CD4 count, and both virological and immunological parameters were followed. No significant differences were observed between the treatment and placebo control groups in rate of CD4 T cell decline, time to initiation of antiretroviral therapy, incidence of opportunistic infections, HIV RNA plasma viremia, HIV viral infectivity as measured by quantitative HIV coculture assay, and death. This study revealed no effect on either clinical or laboratory virological parameters from the administration of VaxSyn.


Assuntos
Vacinas contra a AIDS/uso terapêutico , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Vacinas Sintéticas/uso terapêutico , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Adolescente , Adulto , Contagem de Linfócito CD4 , Criança , Progressão da Doença , Feminino , Proteína gp160 do Envelope de HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Carga Viral
20.
Arch Surg ; 133(1): 25-31, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9438754

RESUMO

BACKGROUND: Lymphoreticular tissue is the most important site for human immunodeficiency virus (HIV) replication in HIV-infected individuals. OBJECTIVE: To compare the long-term effect of splenectomy on survival and time to development of acquired immunodeficiency syndrome in subjects who had undergone splenectomy with subjects who had not undergone splenectomy. DESIGN: A cohort study with a follow-up of up to 13.4 years. SETTING: Subjects were recruited from a hospital outpatient clinic population and a multicenter study of patients with hemophilia. PARTICIPANTS: Forty-five HIV-infected individuals were observed prospectively for up to 13.4 years (17 had undergone splenectomy and 28 had not undergone splenectomy). Five subjects underwent splenectomy before acquiring HIV infection and 12 underwent splenectomy during the asymptomatic phase of HIV infection. The group who did not undergo splenectomy consisted of HIV-infected individuals who were asymptomatic at study enrollment. MAIN OUTCOME MEASURES: A Cox proportional hazards model was used to test the effects of splenectomy on survival and time to development of acquired immunodeficiency syndrome when adjusting for potential confounders (age, initial CD4+ cell count, and treatment with antiretroviral drugs). Splenectomy was treated as a time-dependent covariate to account for the variation in its timing. RESULTS: During the average follow-up of 8.6 years, 9 (53%) of the 17 subjects who underwent splenectomy and 23 (82%) of the 28 subjects who did not undergo splenectomy died; acquired immunodeficiency syndrome developed in 6 (35%) of the subjects who underwent splenectomy and 23 (82%) of the subjects who did not undergo splenectomy. Splenectomy was associated with a significant reduction of risk of developing acquired immunodeficiency syndrome (adjusted relative risk [RR] <0.4, P<.05), whereas the effect on risk of mortality approached, although it did not reach, significance (adjusted RR approximately 0.5, P approximately .10). CONCLUSION: The absence of a spleen during the asymptomatic phase of HIV infection seems to have a beneficial effect on HIV disease progression.


Assuntos
Infecções por HIV/cirurgia , Esplenectomia , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Progressão da Doença , Infecções por HIV/mortalidade , Humanos , Análise Multivariada , Modelos de Riscos Proporcionais , Análise de Sobrevida
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