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1.
Clin Genet ; 84(1): 11-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23590238

RESUMO

The potential for genomic incidental findings is increasing with the use of genome-based testing. At the same time approaches to clinical decision making are shifting to shared decision-making models involving both the healthcare community and the public. The public's voice has been nearly absent in discussions on managing incidental findings. We conducted nine focus groups and nine interviews (n = 63) with a broad cross-section of lay public groups to elucidate public viewpoints on incidental findings that could occur as a result of genome-based testing in clinical and research situations. Data were analyzed using qualitative content analysis. Participants wanted incidental findings disclosed to them whether or not these were clinical or research findings. Participants used different terms to define and describe incidental findings; they wanted to know that incidental findings are possible and be given a choice to learn about them. Personal utility was an important reason for disclosure, and participants believed that managing information is a shared responsibility between professionals and themselves. Broad public input is needed in order to understand and incorporate the public's perspective on management of incidental findings as disclosure guidelines, and policies are developed in clinical and research settings.


Assuntos
Tomada de Decisões/ética , Revelação/ética , Testes Genéticos/ética , Genômica/ética , Achados Incidentais , Adulto , Idoso , Idoso de 80 Anos ou mais , Compreensão , Feminino , Grupos Focais , Genoma Humano , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Projetos de Pesquisa , Inquéritos e Questionários
2.
Clin Infect Dis ; 33(11): 1914-21, 2001 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-11692304

RESUMO

We retrospectively investigated the clinical and histopathologic features of hospitalized patients infected with human immunodeficiency virus who had symptomatic lactic acidosis syndrome at a university teaching hospital during 1995-2000. Twelve patients were identified, 11 during 1998-2000; of these, 5 died with rapid progression to otherwise unexplained multiple-organ failure. All had extensive prior exposure to nucleoside analog reverse-transcriptase inhibitors (NRTIs). At presentation, the most commonly identified NRTI component of antiretroviral regimens was stavudine plus didanosine. Eleven patients presented with abdominal pain, nausea, and/or emesis. Eight patients had prior acute weight loss (mean [+/-SD], 12+/-5.3 kg). Median venous plasma lactate levels were > or =2-fold greater than the upper limit of normal (2.1 mmol/L). Serum transaminase levels were near normal limits at presentation. Histopathologic studies confirmed hepatic macrovesicular and microvesicular steatosis in 6 patients. Concurrent chemical pancreatitis was identified in 6 patients. The increasing number of cases identified during the study period suggests that physicians better recognize symptomatic lactic acidosis and/or that cumulative NRTI exposure may increase the risk for this syndrome.


Assuntos
Acidose Láctica/diagnóstico , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/complicações , Inibidores da Transcriptase Reversa/efeitos adversos , Acidose Láctica/etiologia , Acidose Láctica/patologia , Hospitalização , Humanos , Fígado/patologia , Radiografia Abdominal , Estudos Retrospectivos
3.
J Infect Dis ; 183(11): 1688-93, 2001 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-11343221

RESUMO

To confirm the vertical transmission of multidrug-resistant (MDR) human immunodeficiency virus type 1 (HIV-1) and to assess its impact on further evolution of drug-resistant virus in an infant, proviral DNA amplified from infected peripheral blood mononuclear cell cultures was sequenced to identify reverse transcriptase (RT) and protease (PR) mutations. The infant had proviral DNA with evidence of RT mutations (M41L, L74V, and T215Y) and 3 PR substitutions (K20R, M36I, and V82A). After delivery, the mother's proviral DNA had the same substitutions. Phylogenetic analyses of these HIV-1 RT and PR sequences indicated epidemiological linkage. Plasma drug susceptibility was determined by using a recombinant virus assay. Plasma HIV-1 obtained after the infant's birth demonstrated reduced susceptibility to zidovudine and ritonavir. Thus, vertical transmission of MDR HIV-1 was demonstrated in the setting of detectable maternal plasma viremia. Further accumulation of broad MDR in the infant's virus to 3 antiretroviral classes occurred, despite postnatal therapy.


Assuntos
Resistência a Múltiplos Medicamentos/genética , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Transmissão Vertical de Doenças Infecciosas , Complicações Infecciosas na Gravidez/virologia , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Resistência Microbiana a Medicamentos/genética , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Protease de HIV/genética , Transcriptase Reversa do HIV/genética , HIV-1/genética , Humanos , Recém-Nascido , Testes de Sensibilidade Microbiana , Mutagênese , Mutação , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Inibidores de Proteases/farmacologia , Provírus/genética , Estudos Retrospectivos , Ritonavir/farmacologia , Zidovudina/farmacologia
4.
J Infect Dis ; 183(3): 401-8, 2001 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-11133371

RESUMO

To assess the value of phenotypic drug susceptibility testing as a predictor of antiretroviral treatment response in human immunodeficiency virus (HIV)-infected people, drug susceptibility testing was performed retrospectively on plasma samples collected at baseline in a cohort of 86 antiretroviral-experienced, HIV-infected people experiencing treatment failure and initiating a new antiretroviral treatment regimen. Two separate criteria for reduced drug susceptibility were evaluated. In multivariate analyses, phenotypic susceptibility was an independent predictor of time to treatment failure (adjusted hazards ratio [HR], 0.70; 95% confidence interval [CI], 0.55-0.90; and adjusted HR, 0.76; 95% CI, 0.61-0.95, with reduced drug susceptibility cutoffs defined as 4.0-fold and 2.5-fold higher than reference virus IC(50) values, respectively). Previous protease inhibitor experience was also a significant independent predictor. Notably, drug susceptibility predicted on the basis of treatment history alone was not predictive of time to treatment failure. In this cohort, phenotypic testing results enhanced the ability to predict sustained long-term suppression of virus load.


Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Resistência Microbiana a Medicamentos , Resistência a Múltiplos Medicamentos , Quimioterapia Combinada , Feminino , HIV-1/isolamento & purificação , HIV-1/fisiologia , Humanos , Masculino , Fenótipo , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Prospectivos , RNA Viral/sangue , Inibidores da Transcriptase Reversa/uso terapêutico , Fatores de Risco , Falha de Tratamento , Carga Viral
5.
Curr Protoc Immunol ; Chapter 12: Unit 12.9, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-18432713

RESUMO

This unit presents an assay that has proven useful as an initial screening test is an HIV cytopathic effect (CPE) inhibition assay in which immortalized T cell lines (e.g., ATH8 or MT2) that are profoundly sensitive to the cytopathic effect of certain strains of HIV are utilized as target cells. Additional protocols assess the anti-HIV activity of certain candidate agents by measuring inhibition of syncytium formation or p24 gag protein production by ELISA. Calculation of the 50% inhibitory concentration (IC(50)) is also presented.


Assuntos
Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Avaliação Pré-Clínica de Medicamentos/métodos , HIV/fisiologia , Linhagem Celular , Efeito Citopatogênico Viral/efeitos dos fármacos , Humanos , Técnicas Imunológicas
6.
AIDS Res Hum Retroviruses ; 16(14): 1325-36, 2000 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-11018852

RESUMO

From data on HIV-1 genotypes collected from antiretroviral trial participants who fail virologically, we describe methods for comparing distributions of acquired HIV-1 mutations across different treatment regimens. Given a definition of a "mutational distance" that summarizes the genetic change of a subject's virus in a way that captures the resistance cost of exposure to an antiretroviral regimen, these comparative analyses inform about the relative treatability of emergent virus by next-line therapy directed to the same viral target. The utility of the methods is illustrated by application to data from AIDS Clinical Trials Group (ACTG) Study 241. We find that patients failing zidovudine/didanosine/nevirapine accumulated a 2.41-fold greater nonnucleoside reverse transcriptase inhibitor (RTI) mutational distance than patients failing zidovudine/didanosine [95% confidence interval (1.55, 5.26), p < 0.000001], quantitating expectations that adding a nonnucleoside RTI to a double nucleoside regimen may attenuate future effectiveness of nonnucleoside RTI therapy for nucleoside-experienced patients if viremia is not suppressed. We also find that persons with extensive prior experience with suboptimal nucleoside therapy who were virologically failing zidovudine/didanosine/nevirapine or zidovudine/didanosine accumulated a similar nucleoside RTI mutational distance, implying that the addition of the nonnucleoside RTI did not preserve future nucleoside options.


Assuntos
Fármacos Anti-HIV/farmacologia , Biologia Computacional/métodos , Análise Mutacional de DNA/métodos , Resistência Microbiana a Medicamentos/genética , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/uso terapêutico , Quimioterapia Combinada , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , Humanos , Mutação , Inibidores da Transcriptase Reversa/uso terapêutico
7.
AIDS ; 14(11): 1553-61, 2000 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-10983642

RESUMO

OBJECTIVE: To compare the virologic activity of continued lamivudine (3TC) versus a switch to delavirdine (DLV) when initiating protease inhibitor therapy in nucleoside-experienced patients. DESIGN: Randomized, open-label, multi-center study. SETTING: Adult AIDS clinical trials units. PATIENTS: Protease and non-nucleoside reverse transcriptase inhibitor-naive patients who had received 3TC plus zidovudine (ZDV), stavudine (d4T), or didanosine (ddl) for at least 24 weeks. INTERVENTIONS: Patients with plasma HIV-1 RNA levels > 500 copies/ml who previously received d4T + 3TC or ddI + 3TC were randomized to ZDV + 3TC + indinavir (IDV) or ZDV + DLV + IDV. MAIN OUTCOME MEASURES: Primary endpoints were the proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at 24 weeks, and occurrence of serious adverse events. The proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at week 48 was a secondary endpoint. RESULTS: At week 24, 58% of subjects in the ZDV + 3TC + IDV arm and 73% in the ZDV + DLV + IDV arm had plasma HIV-1 RNA levels < or = 200 copies/ml (P = 0.29). At week 48, plasma HIV-1 RNA levels were < or = 200 copies/ml in 48% and 83%, respectively (P = 0.007). Rash and hyperbilirubinemia occurred more frequently in the DLV arm than in the 3TC arm. Steady-state plasma IDV levels were higher among patients in the DLV arm as compared with the 3TC arm. CONCLUSIONS: Substituting DLV for 3TC when adding IDV improved virologic outcome in nucleoside-experienced patients. This result might be explained, in part, by the positive effect of DLV on IDV pharmacokinetics.


Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Delavirdina/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , Indinavir/uso terapêutico , Lamivudina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Estavudina/uso terapêutico , Zidovudina/uso terapêutico , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Adulto , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Feminino , Inibidores da Protease de HIV/sangue , Humanos , Indinavir/sangue , Masculino , Fatores de Tempo , Carga Viral
8.
J Clin Microbiol ; 38(7): 2715-21, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10878069

RESUMO

The performances of two methods of nucleotide sequencing were compared for the detection of drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase (RT) in viruses isolated from highly RT inhibitor-experienced individuals. Of 11,677 amino acids deduced from population PCR products by both cycle sequencing and sequencing by hybridization to high-density arrays of oligonucleotide probes, 97.4% were concordant by both methods, 0.8% were discordant, and 1.7% had an ambiguous determination by at least one method. A higher rate of discordance (3.9%) was observed among RT inhibitor resistance-associated codons. In 45% of the isolates, RT codon 67 was deduced as the wild-type Asp by hybridization sequencing but as the zidovudine resistance-associated Asn by cycle sequencing. In other resistance-associated codon discordances, cycle sequencing also more commonly called a known resistance-associated amino acid than hybridization sequencing did. The nucleotide sequence in the vicinity of several codons with discordant calls influenced population-based hybridization sequencing. For isolates evaluated by additional sequencing of molecular clones of PCR products by both methods, the discordance between methods was less frequent (0.4% of all 5,994 amino acids and 0 of 494 drug resistance-associated codons). At positions which were discordant or ambiguous in the population sequences, the results of sequencing of clones by both methods were usually in agreement with the population cycle sequencing result. In summary, most RT codons were highly concordant by both methods of population-based sequencing, with discordances due in large part to genetic mixtures within or adjacent to discordant codons.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Inibidores da Transcriptase Reversa/farmacologia , Análise de Sequência de DNA/métodos , Fármacos Anti-HIV/uso terapêutico , Códon/genética , Método Duplo-Cego , Resistência Microbiana a Medicamentos/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Dados de Sequência Molecular , Hibridização de Ácido Nucleico , Reação em Cadeia da Polimerase/métodos , Inibidores da Transcriptase Reversa/uso terapêutico
9.
JAMA ; 283(18): 2417-26, 2000 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-10815085

RESUMO

OBJECTIVE: Assays for drug resistance testing in human immunodeficiency virus type 1 (HIV-1) infection are now available and clinical studies suggest that viral drug resistance is correlated with poor virologic response to new therapy. The International AIDS Society-USA sought to update prior recommendations to provide guidance for clinicians regarding indications for HIV-1 resistance testing. PARTICIPANTS: An International AIDS Society-USA 13-member physician panel with expertise in basic science, clinical research, and patient care involving HIV resistance to antiretroviral drugs was reconvened to provide recommendations for the clinical use of drug resistance testing. EVIDENCE AND CONSENSUS PROCESS: The full panel met regularly between January and October 1999. Resistance and resistance testing data appearing in the last decade through April 2000 and presentations at national and international research conferences were reviewed. Recommendations and considerations were developed by 100% group consensus, acknowledging that definitive data to support final recommendations are not yet available. CONCLUSIONS: Emerging data indicate that despite limitations, resistance testing should be incorporated into patient management in some settings. Resistance testing is recommended to help guide the choice of new regimens after treatment failure and for guiding therapy for pregnant women. It should be considered in treatment-naive patients with established infection, but cannot be firmly recommended in this setting. Testing also should be considered prior to initiating therapy in patients with acute HIV infection, although therapy should not be delayed pending the results. Expert interpretation is recommended given the complexity of results and assay limitations.


Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Adulto , Fármacos Anti-HIV/uso terapêutico , Ensaios Clínicos como Assunto , DNA Viral/análise , Resistência Microbiana a Medicamentos/genética , Quimioterapia Combinada , Feminino , Genótipo , HIV-1/genética , Humanos , Fenótipo , Reação em Cadeia da Polimerase , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , RNA Viral/análise , Falha de Tratamento
11.
AIDS ; 14(1): 31-6, 2000 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-10714565

RESUMO

OBJECTIVE: To determine whether analysis of sequence variation in reverse transcriptase at baseline can explain differences in response to combination antiretroviral therapy. METHODS: Amino acid sequences of reverse transcriptase obtained from baseline isolates from 55 patients included in a trial of zidovudine and didanosine versus zidovudine/didanosine/nevirapine (ACTG241) were analysed. Simple and multiple linear regression were used to determine the relationship between numbers and identity of mutations at baseline and virological response after 8 and 48 weeks. RESULTS: Numbers of baseline zidovudine resistance mutations were predictive of short-term response (week 8). Amino acid identity at position 215 explained > 20% of the variation in response at week 8, but less at week 48. Multiple regression identified the combinations: 215 + 44 and 41 + 202, each of which explained about 30% of the variation in week 8 response. A model incorporating amino acids 214 + 215 + 60 + 202 + baseline viral load explained > 40% of the variation in response at week 48. Unexpectedly, the mutant combination 601 + 215Y/F responded threefold better than 60V + 215Y/F over 48 weeks. CONCLUSIONS: Use of clinical data to analyse virological response to combination therapy has revealed effects of baseline amino acid mutations at sites not previously identified as being important in antiretroviral resistance. Predictors of long-term responses were different from those involved in the short term and may require more complex analysis.


Assuntos
Síndrome da Imunodeficiência Adquirida/virologia , Fármacos Anti-HIV/uso terapêutico , Transcriptase Reversa do HIV/genética , HIV-1/genética , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/enzimologia , Análise Mutacional de DNA , Método Duplo-Cego , Resistência Microbiana a Medicamentos , Quimioterapia Combinada , Humanos , Nevirapina/uso terapêutico , Placebos , Mutação Puntual , Análise de Regressão , Inibidores da Transcriptase Reversa/uso terapêutico , Análise de Sequência de Proteína , Carga Viral , Zidovudina/uso terapêutico
12.
J Infect Dis ; 181(3): 904-11, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10720511

RESUMO

Resistance mutations selected in reverse transcriptase (RT) by incompletely suppressive therapy with combination zidovudine and didanosine with or without nevirapine were identified in 141 human immunodeficiency virus type 1 isolates from peripheral blood mononuclear cells of 57 individuals in the AIDS Clinical Trials Group protocol 241. After prolonged treatment (16-48 weeks), the most common nevirapine-selected mutations were RT 181C (15/30 isolates [50%]), 190A (15/30 [50%]), and 101E (9/30 [30%]). RT 103N and 188L, which individually confer cross-resistance to all nonnucleoside RT inhibitors, were seen in a minority of viruses (6/30 [20%] and 4/30 [13%], respectively). Didanosine-resistance mutations arose rarely. A newly recognized mutation, RT 44D, was selected by the nucleosides. Two distinct zidovudine-resistance mutational patterns were noted. Mutations selected during treatment with zidovudine, didanosine, and nevirapine differed among individuals and changed over time. Resistance testing is necessary to identify which mutations are selected by nevirapine-containing combinations.


Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Didanosina/administração & dosagem , Transcriptase Reversa do HIV/genética , HIV-1 , Mutação , Nevirapina/administração & dosagem , Zidovudina/administração & dosagem , Códon , Método Duplo-Cego , Resistência a Medicamentos , Quimioterapia Combinada , Humanos , Reação em Cadeia da Polimerase
14.
J Infect Dis ; 180(4): 1043-9, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10479129

RESUMO

Many amino acid (aa) sites in reverse transcriptase (RT) have been implicated in resistance to nucleoside (NRTI) and nonnucleoside antiretrovirals. Interactions between these in response to combination therapy remain poorly understood. In a trial (ACTG 241) of zidovudine/didanosine (ddI) versus zidovudine/ddI/nevirapine in nucleoside-experienced patients, baseline sequence data from the RT coding region was analyzed from 55 individuals. Sequences were clustered by use of a parsimony method and the virological responses (ratio of baseline viral load to viral load after of therapy) for each cluster were analyzed at week 8 and week 48. Both clusters and genotype at aa 215 were significantly associated with virological response at both time points, whereas viral load showed a stronger association with sequence clusters. Sequence clusters identified one group of patients who never developed high-level resistance to NRTIs despite prior nucleoside exposure and poor suppression of viral replication.


Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , Síndrome da Imunodeficiência Adquirida/sangue , Sequência de Aminoácidos , Didanosina , Quimioterapia Combinada , Evolução Molecular , Transcriptase Reversa do HIV/química , HIV-1/enzimologia , Humanos , Dados de Sequência Molecular , Nevirapina/uso terapêutico , Alinhamento de Sequência , Fatores de Tempo , Carga Viral , Zidovudina
15.
AIDS ; 13(6): 685-94, 1999 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-10397563

RESUMO

OBJECTIVE: To study the antiviral activity of lamivudine (3TC) plus zidovudine (ZDV), didanosine (ddl), or stavudine (d4T). DESIGN: Randomized, placebo-controlled, partially double-blinded multicenter study. SETTING: Adult AIDS Clinical Trials Units. PATIENTS: Treatment-naive HIV-infected adults with 200-600x10(6) CD4 T lymphocytes/l. INTERVENTIONS: Patients were openly randomized to a d4T or a ddl limb, then randomized in a blinded manner to receive: d4T (80 mg/day), d4T plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos; or ddl (400 mg/day), ddl plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos. After 24 weeks 3TC was added for patients assigned to the monotherapy arms. MAIN OUTCOME MEASURE: The reduction in plasma HIV-1 RNA level at weeks 24 and 48. RESULTS: Two hundred ninety-nine patients were enrolled. After 24 weeks the mean reduction in plasma HIV-1 RNA copies/ml from baseline was 0.49 log10 (d4T monotherapy) versus 1.03 log10 (d4T plus 3TC; P = 0.001), and 0.68 log10 (ddl monotherapy) versus 0.82 log10 (ddl plus 3TC; P>0.22). After 48 weeks the mean reduction was 1.08 log10 (d4T plus 3TC) versus 1.01 log10 (ZDV plus 3TC) in the d4T limb (P = 0.66), and 0.94 log10 (ddl plus 3TC) versus 0.88 log10 (ZDV plus 3TC; P = 0.70) in the ddl limb. CONCLUSIONS: 3TC added significantly to the virologic effects of d4T, but not ddl, in treatment-naive patients. 3TC plus d4T produced virologic changes comparable to those of 3TC plus ZDV. These results support the use of 3TC with either ZDV or d4 as a component of initial combination antiretroviral therapy.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Didanosina/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , HIV-1/fisiologia , Humanos , Masculino , RNA Viral/sangue , Estavudina/uso terapêutico , Carga Viral , Zidovudina/uso terapêutico
16.
J Infect Dis ; 180(1): 99-105, 1999 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10353867

RESUMO

Since 1993, trends in perinatal human immunodeficiency virus (HIV) transmission have been monitored by use of chart review of patients identified at a central diagnostic laboratory. In the population studied, either pre- or postnatal antiretroviral therapy to the infant increased from 21% in 1993 to 95% in 1997. Concurrently, the number of HIV-infected infants declined from 25 in 1993 to 4 in 1997. The complete Pediatric AIDS Clinical Trials Group Protocol 076 regimen was the most effective in reducing transmission (3.1%). Twenty-two of 35 infants who became infected in 1995-1997 had mothers who did not receive antiretroviral therapy, although counseling practices improved with time. In 1995, 87% of the mothers of HIV-seropositive infants were counseled, whereas in 1997, 96% were counseled (P<.005). None of 59 infants tested had high-level phenotypic zidovudine resistance, although 5 (8.8%) of 57 infants had virus isolates with at least one mutation in the reverse transcriptase gene associated with reduced phenotypic susceptibility to zidovudine.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/prevenção & controle , Doenças do Recém-Nascido/prevenção & controle , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Zidovudina/uso terapêutico , Ensaios Clínicos como Assunto , Aconselhamento/tendências , Resistência Microbiana a Medicamentos , Tratamento Farmacológico/tendências , Feminino , Soropositividade para HIV , Humanos , Recém-Nascido , North Carolina , Cooperação do Paciente , Gravidez
17.
Virology ; 259(1): 154-65, 1999 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-10364500

RESUMO

We investigated the effect of selection pressures on evolution of HIV-1 pol in 51 patients after switching to a new antiretroviral combination reverse transcriptase (RT) inhibitor therapy. Evolution of the protease (PR) and RT reading frames were analysed separately. Pairwise evolutionary distances (ED) were calculated between sequences from baseline and week 8 and between baseline and week 48 of protocol therapy. ED were calculated for all substitutions and for synonymous and nonsynonymous substitutions separately. At week 8 when HIV RNA reduction (selection pressure) was high, significantly more divergence in pol in both synonymous and nonsynonymous substitutions was found in patients with substantial RNA reduction (strong responders). Separate analyses of PR and RT revealed significantly greater ED in the RT (under selection pressure) of strong compared with nonresponders, whereas divergence between PR genes (not under selection pressure) did not differ in those two groups. Such differential evolution indicates that PR and RT were genetically unlinked and suggests recombination. The rapid increase of ED over the first 8 weeks was followed by only a minimal further rise by week 48, suggesting that selection of preexisting quasispecies accounted for the early changes. A disproportionally high number of synonymous substitutions accounted for the observed divergence and indicated that such genetic changes may not be completely silent.


Assuntos
Fármacos Anti-HIV/farmacologia , Evolução Molecular , Produtos do Gene pol/genética , Genoma Viral , HIV-1/efeitos dos fármacos , HIV-1/genética , Inibidores da Transcriptase Reversa/farmacologia , Produtos do Gene pol/efeitos dos fármacos , Genes Virais , Humanos , Análise de Sequência
18.
Antimicrob Agents Chemother ; 43(1): 121-8, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9869576

RESUMO

The population pharmacokinetics of nevirapine (NVP), zidovudine (ZDV), and didanosine (ddI) were evaluated in a total of 175 patients infected with human immunodeficiency virus randomized to receive either a double combination of ZDV plus ddI or a triple combination of NVP plus ZDV plus ddI as a substudy of the AIDS Clinical Trials Group Protocol 241. Levels (approximating 3.5 determinations/patient) of the three drugs in plasma were measured during 44 of a total 48 weeks of study treatment, and a set of potential covariates was available for nonlinear mixed-effect modeling analysis. A one-compartment model with zero-order input and first-order elimination was fitted to the NVP data. Individual oral clearance (CL) and volume of distribution (V) averaged 0.0533 liters/h/kg of body weight and 1.17 liters/kg, respectively. Gender was the only covariate which significantly correlated with the CL of NVP. ZDV and ddI data were described by a two-compartment model with zero-order input and first-order elimination. Individual mean oral CL, VSS (volume of distribution at steady state), and V of ZDV were 1.84 liters/h/kg and 6.68 and 2.67 liters/kg, respectively, with body weight and age as correlates of CL and body weight as a correlate of VSS. The average individual oral CL, VSS, and V of ddI were 1.64 liters/h/kg and 3.56 and 2.74 liters/kg, respectively, with body weight as a significant correlate of both CL and VSS. The relative bioavailability (F) of ZDV and ddI in the triple combination compared to that in the double combination was also evaluated. No significant effects of the combination regimens on the F of ddI were detected (FTRIPLE = 1.05 and FDOUBLE = 1 by definition), but the F of ZDV was markedly reduced by the triple combination, being only 67.7% of that of the double combination. Large (>50%) intraindividual variability was associated with both ZDV and ddI pharmacokinetics. Individual cumulative area under the plasma drug level-time curve of the three drugs was calculated for the entire study period as a measure of drug exposure based on the individual data and the final-model estimates of structural and statistical parameters.


Assuntos
Fármacos Anti-HIV/farmacocinética , Didanosina/farmacocinética , Infecções por HIV/metabolismo , Nevirapina/farmacocinética , Zidovudina/farmacocinética , Síndrome da Imunodeficiência Adquirida/metabolismo , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Didanosina/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Nevirapina/administração & dosagem , Zidovudina/administração & dosagem
19.
J Infect Dis ; 177(6): 1549-53, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9607832

RESUMO

Mechanisms underlying the delay in dominance of syncytium-inducing (SI) phenotype HIV-1 (human immunodeficiency virus type 1) in vivo are unknown. Both random mutational events and selective pressures operative only late in the disease process have been suggested to underlie the shift from CCR5 to alternative coreceptor usage. Among the moderately advanced patients who entered AIDS Clinical Trials Group protocol 241, SI viral phenotype was more common among CCRS/delta(ccr5) heterozygotes (7/7, 100%) than among CCR5/CCR5 homozygotes (29/88, 33%; P < .001, Fisher's exact test). Other characteristics did not differ at study entry by CCR5 genotype, including median CD4 cell counts, plasma RNA levels, and infectious HIV-1 titers in circulating cells. These data indicate that CCR5/delta(ccr5) heterozygosity, which decreases cell-surface levels of CCR5 available to serve as an HIV-1 entry coreceptor, is a selective pressure for evolution of T cell line-tropic viruses that use an alternative coreceptor.


Assuntos
Infecções por HIV/virologia , HIV-1/genética , Heterozigoto , Receptores CCR5/genética , Seleção Genética , Adulto , Feminino , Genótipo , Células Gigantes/virologia , Infecções por HIV/genética , Infecções por HIV/metabolismo , HIV-1/patogenicidade , Humanos , Masculino , Fenótipo , Receptores CCR5/metabolismo
20.
JAMA ; 279(24): 1984-91, 1998 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-9643863

RESUMO

OBJECTIVES: To review current knowledge of the biology and clinical implications of human immunodeficiency virus (HIV) resistance to antiretroviral drugs, describe assays for measuring resistance, and assess their use in clinical practice. PARTICIPANTS: The International AIDS Society-USA assembled a panel of 13 physicians with expertise in basic science, clinical research, and patient care relevant to HIV resistance to antiretroviral drugs. EVIDENCE: We reviewed available data from published reports and presented at national and international research conferences. Basic science research, clinical trial results, and expert opinions were used to form the basis of this report. Data on methods for and characteristics of specific genotypic and phenotypic assays were obtained from manufacturers and service providers. CONSENSUS PROCESS: The panel met regularly between October 1997 and April 1998. Panel subgroups developed and discussed different sections of the report before discussing them with the entire panel. Conclusions and suggested approaches to the use of resistance testing were determined by group consensus. CONCLUSIONS: Plasma HIV RNA level and CD4+ cell count are the primary values that should be used to guide the initiation of antiretroviral therapy and subsequent changes in therapy. Possible causes of treatment failure other than development of drug resistance that should be considered are adherence, drug potency, and pharmacokinetic issues. Genotypic and phenotypic testing for HIV resistance to antiretroviral drugs may prove useful for individual patient management. Assays under development need validation, standardization, and a clearer definition of their clinical roles. Possible current roles of resistance testing for choosing an initial regimen or changing antiretroviral therapy, as well as possible implications of the presence or absence of phenotypic resistance and genotypic changes, are discussed.


Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Resistência Microbiana a Medicamentos/genética , Quimioterapia Combinada , Genes Virais , Genótipo , Inibidores da Protease de HIV/farmacologia , HIV-1/genética , Humanos , Mutação , Fenótipo , Inibidores da Transcriptase Reversa/farmacologia , Carga Viral
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